Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:12][CH2:11][CH2:10][C@@:9]1([CH3:16])[C:13]([OH:15])=[O:14])=[O:7])([CH3:4])([CH3:3])[CH3:2].[Si](C=[N+]=[N-])(C)(C)[CH3:18]>CO.CCOCC>[CH3:16][C@@:9]1([C:13]([O:15][CH3:18])=[O:14])[CH2:10][CH2:11][CH2:12][N:8]1[C:6]([O:5][C:1]([CH3:4])([CH3:2])[CH3:3])=[O:7]
Reactant: C[Si](C)(C)C=[N+]=[N-]
Reactant: CC(C)(C)OC(=O)N1CCC[C@@]1(C)C(=O)O
Solvent: CO
Solvent: CCOCC
Product: COC(=O)[C@]1(C)CCCN1C(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 2 h
Yield: 76 %

Procedure:
To a stirred solution of (S)-1-(tert-butoxycarbonyl)-2-methylpyrrolidine-2-carboxylic acid 106A in methanol (100 ml) and ether (100 ml) was added TMS-Diazomethane (80 ml) (2.0 M ether solution) dropwise at 0° C. The reaction mixture was stirred at room temperature for 2 h and the reaction mixture was concentrated. The residue was purified by flash chromatography (10% EtOAc/Hexane) to give (S)-1-tent-butyl 2-methyl 2-methylpyrrolidine-1,2-dicarboxylate 106B (28.5 g, 76% overall yield) as an oil. 1H NMR (CDCl3, 400 MHz) δ 3.69 (s, 3H), 3.42-3.56 (m, 2H), 2.13-2.17 (m, 1H), 1.83-1.93 (m, 3H), 1.49 (s, 3H), 1.39 (s, 9H).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[C:9]([N:11]1[CH2:16][CH2:15][NH:14][C:13](=[O:17])[CH2:12]1)=[O:10].F[B-](F)(F)F.[CH2:23]([O+](CC)CC)[CH3:24].O.C(=O)([O-])O.[Na+]>ClCCl>[Cl:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[C:9]([N:11]1[CH2:12][C:13]([O:17][CH2:23][CH3:24])=[N:14][CH2:15][CH2:16]1)=[O:10]
Reactant: CC[O+](CC)CC
Reactant: O=C1CN(C(=O)c2ccc(F)cc2Cl)CCN1
Agent: F[B-](F)(F)F
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: O
Product: CCOC1=NCCN(C(=O)c2ccc(F)cc2Cl)C1
Temperature: 25 °C
Reaction time: 18 h
Yield: 65.1 %

Procedure:
4-[(2-Chloro-4-fluorophenyl)carbonyl]-2-piperazinone (0.770 g, 3 mmol, e.g. as prepared in Intermediate 2) was dissolved in Dichloromethane (8 mL) and to this was added triethyloxonium tetrafluoroborate (1.425 g, 7.50 mmol). The reaction mixture was stirred for 18 hours at room temperature. Dichloromethane (30 ml) and iced water (15 ml) were added and the pH was adjusted to pH 7 with solid sodium hydrogen carbonate. The organic phase was separated, washed with brine, dried and evaporated to give crude 1-[(2-chloro-4-fluorophenyl)carbonyl]-5-(ethyloxy)-1,2,3,6-tetrahydropyrazine (0.556 g) which was used without further purification.
Reaction SMILES: [Cl:1][C:2]1[C:3]([C:9]2[N:14]=[C:13]([NH:15][CH2:16][CH:17]3[CH2:22][CH2:21][O:20][CH2:19][CH2:18]3)[C:12]([CH2:23][CH3:24])=[N:11][CH:10]=2)=[CH:4][C:5](F)=[N:6][CH:7]=1.[NH2:25][CH:26]1[CH2:31][CH2:30][CH:29]([NH2:32])[CH2:28][CH2:27]1.C(N(CC)CC)C>CS(C)=O>[Cl:1][C:2]1[C:3]([C:9]2[CH:10]=[N:11][C:12]([CH2:23][CH3:24])=[C:13]([NH:15][CH2:16][CH:17]3[CH2:22][CH2:21][O:20][CH2:19][CH2:18]3)[N:14]=2)=[CH:4][C:5]([NH:25][C@H:26]2[CH2:31][CH2:30][C@H:29]([NH2:32])[CH2:28][CH2:27]2)=[N:6][CH:7]=1
Reactant: NC1CCC(N)CC1
Reactant: CCc1ncc(-c2cc(F)ncc2Cl)nc1NCC1CCOCC1
Solvent: CCN(CC)CC
Solvent: CS(C)=O
Product: CCc1ncc(-c2cc(N[C@H]3CC[C@H](N)CC3)ncc2Cl)nc1NCC1CCOCC1
Temperature: 100 °C
Reaction time: 17 h

Procedure:
6-(5-chloro-2-fluoropyridin-4-yl)-3-ethyl-N-((tetrahydro-2H-pyran-4-yl)methyl)pyrazine-2-amine (0.0053 g, 0.015 mmol) was dissolved in DMSO (1 ml). This was treated with 1,4-diaminocyclohexane (0.017 g, 0.151 mmol). The reaction mixture was then heated at 100° C. for 4 hr. Additional 1,4-diaminocyclohexane (0.017 g, 0.151 mmol) and triethylamine (0.0084 ml, 0.012 g, 0.060 mmol) were added. Heating at 100° C. was continued for 17 hr. The reaction mixture was purified using prep HPLC. The material was purified by preparative reverse-phase HPLC to give 0.0040 g of trans-N1-(5-chloro-4-(5-ethyl-6-((tetrahydro-2H-pyran-4-yl)methyl)aminopyrazin-2-yl)pyridin-2-yl)cyclohexane-1,4-diamine as the TFA salt. LCMS (m/z): 445.2 (MH+), retention time=0.54 min.
Reaction SMILES: [Cl:1][C:2]1[N:6]2[N:7]=[C:8](Cl)[CH:9]=[CH:10][C:5]2=[N:4][N:3]=1.[OH:12][CH2:13][CH:14]1[CH2:17][CH2:16][O:15]1.C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O>[Cl:1][C:2]1[N:6]2[N:7]=[C:8]([O:12][CH2:13][CH:14]3[CH2:17][CH2:16][O:15]3)[CH:9]=[CH:10][C:5]2=[N:4][N:3]=1
Reactant: OCC1CCO1
Reactant: Clc1ccc2nnc(Cl)n2n1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: Clc1nnc2ccc(OCC3CCO3)nn12
Temperature: 100 °C
Reaction time: 8 h

Procedure:
a mixture of 756 mg of commercial 3,6-dichloro[1,2,4]triazolo[4,3-b]pyridazine, 0.352 cm3 of 2-hydroxymethyloxetane and 552 mg of potassium carbonate in 8 cm3 of N,N-dimethylformamide is heated at 100° C. for 6 h and then stirred at 20° C. overnight. The reaction medium is concentrated to dryness under vacuum. The residue obtained is purified by chromatography on a Merck cartridge of 25 g of silica 15-40 μm by solid deposit, elution being carried out with a dichloromethane/methanol gradient of 100/0 to 97/03. 701 mg of 3-chloro-6-(oxetan-2-ylmethoxy)[1,2,4]triazolo[4,3-b]pyridazine are thus obtained in the form of a beige solid, the characteristics of which are as follows:
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[CH2:12][CH2:11][CH:10]([C:13]([OH:15])=O)[C:9]2=[O:16])=[CH:4][CH:3]=1.C(OC1C=[CH:29][C:28]([NH:31][C:32]2[N:37]=CN=[C:34]([O:38][C:39]3[CH:44]=[CH:43][C:42]([NH:45]C(=O)CC(NC4C=CC(F)=CC=4)=O)=[CH:41][C:40]=3[F:59])[CH:33]=2)=CC=1)C1C=CC=CC=1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C(N(C(C)C)CC)(C)C>CN(C=O)C>[NH2:37][C:32]1[CH:33]=[C:34]([O:38][C:39]2[CH:44]=[CH:43][C:42]([NH:45][C:13]([CH:10]3[CH2:11][CH2:12][N:8]([C:5]4[CH:4]=[CH:3][C:2]([F:1])=[CH:7][CH:6]=4)[C:9]3=[O:16])=[O:15])=[CH:41][C:40]=2[F:59])[CH:29]=[CH:28][N:31]=1
Reactant: O=C(O)C1CCN(c2ccc(F)cc2)C1=O
Reactant: O=C(CC(=O)Nc1ccc(Oc2cc(Nc3ccc(OCc4ccccc4)cc3)ncn2)c(F)c1)Nc1ccc(F)cc1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: Nc1cc(Oc2ccc(NC(=O)C3CCN(c4ccc(F)cc4)C3=O)cc2F)ccn1
Temperature: 25 °C
Reaction time: 8 h
Yield: 42.4 %

Procedure:
To a mixture of 1-(4-fluorophenyl)-2-oxopyrrolidine-3-carboxylic acid (0.3 mol), 4-(4-amino-2-fluorophenoxy)pyridin-2-amine (Compound B of Example 24, 21.9 mg, 0.1 mmol) in DMF (0.5 ml), was added HATU (76 mg, 0.2 mmol) and followed by diisopropylethylamine (0.1 mL, 0.57 mmol). The reaction mixture was stirred at room temperature overnight and was then quenched with 2 mL of methanol. The reaction mixture was purified by prep HPLC. The desired fractions were combined, neutralized with sat. aq. NaHCO3 solution, and concentrated in vacuo to afford the title compound (18 mg, 43%) as a white solid. 1H NMR (DMSO-d6) δ 10.76 (br s, 1H), 7.95 (d, 1H, J=7.2 Hz), 7.91 (m, 1H), 7.68 (m, 2H), 7.50 (m, 1H), 7.44 (t, 1H, J=10.0 Hz), 7.24 (m, 2H), 6.70 (m, 1H), 6.11 (d, 1H, J=2.8 Hz), 3.91 (m, 2H), 3.78 (t, 1H, J=5.0 Hz), 2.41 (m, 2H); MS (ESI+) m/z 425.15 (M+H)+.
Reaction SMILES: C([N:8]1[CH2:13][CH2:12][CH:11]([N:14]([CH3:27])[C:15]2[C:20]([NH:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[CH:19][CH:18]=[C:17]([F:26])[N:16]=2)[CH2:10][CH2:9]1)C1C=CC=CC=1.[H][H]>C(O)C.[OH-].[OH-].[Pd+2]>[CH3:27][N:14]([CH:11]1[CH2:12][CH2:13][NH:8][CH2:9][CH2:10]1)[C:15]1[C:20]([NH:21][C:22]([CH3:25])([CH3:23])[CH3:24])=[CH:19][CH:18]=[C:17]([F:26])[N:16]=1
Reactant: CN(c1nc(F)ccc1NC(C)(C)C)C1CCN(Cc2ccccc2)CC1
Reactant: [H][H]
Agent: [Pd+2]
Agent: [OH-]
Solvent: CCO
Product: CN(c1nc(F)ccc1NC(C)(C)C)C1CCNCC1

Procedure:
1-Benzyl-4-[N-methyl-N-(3-tert-butylamino-6-fluoro-2-pyridinyl)amino]piperidine (EXAMPLE 153, 900 mg, 2.43 mmol) and palladium hydroxide on carbon (350 mg) in 50 ml ethanol is hydrogenated at 40 p.s.i. hydrogen for 24 hrs. Filtration and removal of the solvent gives the title compound, which is used without further purification, NMR (300 MHz, CD3OD) 7.38, 6.61, 3.16-3.27, 2.71-2.79, 2.56, 1.84, 1.61-1.66 and 1.33δ.
Reaction SMILES: [CH2:1]([O:3][P:4]([CH2:9][C:10]1[CH:15]=[CH:14][C:13]([NH:16][C:17]2[N:22]=[C:21](Cl)[C:20]([C:24]([F:27])([F:26])[F:25])=[CH:19][N:18]=2)=[C:12]([O:28][CH3:29])[CH:11]=1)(=[O:8])[O:5][CH2:6][CH3:7])[CH3:2].[NH2:30][C:31]1[CH:32]=[CH:33][C:34]([CH:42]2[CH2:47][CH2:46][CH:45]([N:48]([CH2:50][CH3:51])[CH3:49])[CH2:44][CH2:43]2)=[C:35]2[C:39]=1[C:38](=[O:40])[N:37]([CH3:41])[CH2:36]2>>[CH2:1]([O:3][P:4]([CH2:9][C:10]1[CH:15]=[CH:14][C:13]([NH:16][C:17]2[N:22]=[C:21]([NH:30][C:31]3[CH:32]=[CH:33][C:34]([CH:42]4[CH2:43][CH2:44][CH:45]([N:48]([CH2:50][CH3:51])[CH3:49])[CH2:46][CH2:47]4)=[C:35]4[C:39]=3[C:38](=[O:40])[N:37]([CH3:41])[CH2:36]4)[C:20]([C:24]([F:27])([F:26])[F:25])=[CH:19][N:18]=2)=[C:12]([O:28][CH3:29])[CH:11]=1)(=[O:8])[O:5][CH2:6][CH3:7])[CH3:2]
Reactant: CCN(C)C1CCC(c2ccc(N)c3c2CN(C)C3=O)CC1
Reactant: CCOP(=O)(Cc1ccc(Nc2ncc(C(F)(F)F)c(Cl)n2)c(OC)c1)OCC
Product: CCOP(=O)(Cc1ccc(Nc2ncc(C(F)(F)F)c(Nc3ccc(C4CCC(N(C)CC)CC4)c4c3C(=O)N(C)C4)n2)c(OC)c1)OCC

Procedure:
This compound was prepared according to the procedure for Example 102 using diethyl(4-{[4-chloro-5-(trifluoromethyl)pyrimidin-2-yl]amino}-3-methoxybenzyl)phosphonate and 7-amino-4-{4-[ethyl(methyl)amino]cyclohexyl}-2-methyl-2,3-dihydro-1H-isoindol-1-one (Compound 236A). 1H NMR (400 MHz, MeOD) δ ppm 1.28 (t, J=7.07 Hz, 6H) 1.39 (t, J=7.33 Hz, 3H) 1.70-1.86 (m, 4H) 2.04 (br. s., 2H) 2.19 (d, J=7.83 Hz, 2H), 2.71 (br. s., 1H) 2.86 (s, 3H) 3.17-3.19 (m, 3H) 3.33 (s, 1H) 3.34-3.37 (m, 2H) 3.39 (s, 1H) 3.43-3.52 (m, 1H) 3.89 (s, 3H) 4.05-4.14 (m, 4H) 4.55 (s, 2H) 7.01 (dt, J=8.02, 2.31 Hz, 1H), 7.15 (t, J=2.02 Hz, 1H) 7.42 (d, J=8.34 Hz, 1H) 7.57 (d, J=8.08 Hz, 1H) 8.36 (br. s., 1H). MS (ES+): m/z 719.25/720.29 (100/20) [MH+]. HPLC: tR=1.17 min (UPLC TOF: polar—3 min).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:9]([CH2:12][CH3:13])[CH2:10][NH2:11])[CH:6]=[CH:7][CH:8]=1.C=O.[OH-].[K+].[CH2:18](O)C>C(O)=O>[CH2:12]([CH:9]1[C:5]2[C:6](=[CH:7][CH:8]=[C:3]([O:2][CH3:1])[CH:4]=2)[CH2:18][NH:11][CH2:10]1)[CH3:13]
Reactant: CCO
Reactant: CCC(CN)c1cccc(OC)c1
Agent: C=O
Agent: [K+]
Agent: [OH-]
Solvent: O=CO
Product: CCC1CNCc2ccc(OC)cc21
Temperature: 25 °C
Reaction time: 16 h

Procedure:
A solution of 2-(3-methoxyphenyl)-1-butanamine (25 g, 131 mmol, prepared according to the procedure described in J. Med. Chem. 1990, 33, 153-160) in formic acid (120 mL) at room temperature was treated with paraformaldehyde (4.18 g, 131 mmol), stirred for 16 hours, treated with 25% KOH (30 mL) and ethanol (100 mL), and refluxed for 2.5 hours. The mixture was cooled to room temperature, extracted with dichloromethane, and the combined extracts were dried (MgSO4), filtered, and concentrated. The concentrate was purified by flash column chromatography on silica gel with dichloromethane to provide the desired product.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([C:12]2[O:13][C:14]3[CH:20]=[C:19]([CH3:21])[CH:18]=[CH:17][C:15]=3[N:16]=2)[C:5]([NH:8][CH2:9][CH2:10][CH3:11])=[CH:6][CH:7]=1.[CH:22]1[C:27]([C:28]([OH:30])=[O:29])=[CH:26][C:25]2[C:31]([O:33][C:34](=O)[C:24]=2[CH:23]=1)=[O:32]>>[CH3:21][C:19]1[CH:18]=[CH:17][C:15]2[N:16]=[C:12]([C:4]3[CH:3]=[C:2]([N:1]4[C:31](=[O:32])[C:25]5[C:24](=[CH:23][CH:22]=[C:27]([C:28]([OH:30])=[O:29])[CH:26]=5)[C:34]4=[O:33])[CH:7]=[CH:6][C:5]=3[NH:8][CH2:9][CH2:10][CH3:11])[O:13][C:14]=2[CH:20]=1
Reactant: O=C(O)c1ccc2c(c1)C(=O)OC2=O
Reactant: CCCNc1ccc(N)cc1-c1nc2ccc(C)cc2o1
Product: CCCNc1ccc(N2C(=O)c3ccc(C(=O)O)cc3C2=O)cc1-c1nc2ccc(C)cc2o1

Procedure:
Prepared by the method of Example 15f), from 2-(3-amino-6-propylaminophenyl)-6-methylbenzoxazole (100 mg, 0.33 mmol) and 1,2,4-benzenetricarboxylic anhydride (73 mg, 0.38 mmol) the title compound was obtained (87 mg, 58%). 1H NMR (DMSO) δ 8.47–8.40(m, 2H), 8.30(s, 1H), 8.08–8.06(m, 2H), 7.68(d, 1H), 7.56(s, 1H), 7.44(dd, 1H), 7.23(d, 1H), 7.01(d, 1H), 3.34(m, 2H), 2.46(s, 3H), 1.74(m, 2H), 1.05(t, 3H). MS 454.1 m/z (M−H)−.
Reaction SMILES: [Cl:1][SiH:2]([CH2:4][SiH:5]([Cl:7])[Cl:6])[Cl:3].[CH2:8]([Cl:11])[CH:9]=[CH2:10]>C(O)(C)C.[H+].[H+].Cl[Pt-2](Cl)(Cl)(Cl)(Cl)Cl>[Cl:11][CH2:8][CH2:9][CH2:10][Si:2]([CH2:4][Si:5]([Cl:7])([Cl:6])[CH2:10][CH2:9][CH2:8][Cl:11])([Cl:3])[Cl:1]
Reactant: Cl[SiH](Cl)C[SiH](Cl)Cl
Reactant: C=CCCl
Agent: Cl[Pt-2](Cl)(Cl)(Cl)(Cl)Cl
Agent: [H+]
Solvent: CC(C)O
Product: ClCCC[Si](Cl)(Cl)C[Si](Cl)(Cl)CCCCl
Yield: 35 %

Procedure:
To a 100 ml, three neck, round bottomed flask equipped with a dropping funnel and a reflux condenser, 6 g(0.03 mole) of bisdichlorosilylmethane, 6.5 g(0.08 mole) of allyl chloride, and 60 μl of 1% chloroplatinic acid solution in isopropanol, at reflux using a 80° C. oil bath for 3 hours under the dry nitrogen atmosphere. Gas chromatography analysis showed that no bisdichlorosilylmethane was left. Vacuum distillation of the reaction products gave 3.85 g(110°-112° C./0.05 mmHg) of bis{(3-chloropropyl)dichlorosilyl]methane in 35.6% yield. Besides this product, 4.10 g of (trichlorosilyl){(3-chloropropyl)silyl}methane was also obtained in 38.0% yield and (propyldichlorosilyl){(3-chloropropyl)dichlorosilyl}methane.
Reaction SMILES: [CH3:1][C:2]1([CH3:18])[C@@H:4]([C:5]#[C:6][C:7]([O:9][CH3:10])=[O:8])[C@H:3]1[C:11]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12].N1C2C(=CC=CC=2)C=CC=1>C(OCC)(=O)C.[OH-].[Pd+2].[OH-]>[CH3:1][C:2]1([CH3:18])[C@@H:4](/[CH:5]=[CH:6]\[C:7]([O:9][CH3:10])=[O:8])[C@H:3]1[C:11]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12]
Reactant: COC(=O)C#C[C@H]1[C@@H](C(=O)OC(C)(C)C)C1(C)C
Agent: [Pd+2]
Agent: [OH-]
Solvent: CCOC(C)=O
Solvent: c1ccc2ncccc2c1
Product: COC(=O)/C=C\[C@H]1[C@@H](C(=O)OC(C)(C)C)C1(C)C
Yield: 90.9 %

Procedure:
12 g of the product of Step A in 240 cm3 of ethyl acetate were hydrogenated in the presence of 2.4 g of 10% palladium hydroxide on barium sulfate and 2.4 cm3 of quinoline. The mixture was filtered and the filtrate was evaporated to dryness to obtain 11 g of tert.-butyl(1R,cis)2,2-dimethyl-3-[(Z)-2-(methoxy carbonyl)-ethenyl]-cyclopropane carboxylate.
Reaction SMILES: [C:1]([O:5][C:6](=[O:19])[NH:7][C:8]1[CH:13]=[C:12](Cl)[C:11]([Cl:15])=[CH:10][C:9]=1[N+:16]([O-:18])=[O:17])([CH3:4])([CH3:3])[CH3:2].[C:20](=O)([O-])[O-].[K+].[K+].CB1OB(C)OB(C)O1>O1CCOCC1.O.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[C:1]([O:5][C:6](=[O:19])[NH:7][C:8]1[CH:13]=[C:12]([CH3:20])[C:11]([Cl:15])=[CH:10][C:9]=1[N+:16]([O-:18])=[O:17])([CH3:4])([CH3:3])[CH3:2]
Reactant: O=C([O-])[O-]
Reactant: CC(C)(C)OC(=O)Nc1cc(Cl)c(Cl)cc1[N+](=O)[O-]
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: CB1OB(C)OB(C)O1
Agent: [K+]
Solvent: O
Solvent: C1COCCO1
Product: Cc1cc(NC(=O)OC(C)(C)C)c([N+](=O)[O-])cc1Cl
Reaction time: 15 h
Yield: 47.6 %

Procedure:
To a suspension of (4,5-dichloro-2-nitro-phenyl)-carbamic acid tert.-butyl ester (Example A20) (10.0 g, 32.6 mmol), tetrakis(triphenylphosphine)palladium (3.76 g, 3.26 mmol) and potassium carbonate (13.5 g, 97.7 mmol) in dioxane/water (9:1; 100 ml) was added at RT trimethylboroxine (4.53 ml, 32.6 mmol). The reaction mixture was stirred under reflux conditions for 15 h, filtered, evaporated and purified by column chromatography on silica gel (hexane/ethyl acetate 19:1) to yield a light yellow solid (4.45 g, 48%).
Reaction SMILES: CN(C)C=O.[Cl:6][C:7]1[CH:12]=[C:11]([C:13]([F:16])([F:15])[F:14])[CH:10]=[CH:9][C:8]=1[OH:17].C(=O)([O-])[O-].[K+].[K+].Br[CH2:25][C:26]1[CH:31]=[CH:30][C:29]([C:32]2[N:36]([CH3:37])[N:35]=[C:34]([C:38]3[C:43]([F:44])=[CH:42][CH:41]=[CH:40][C:39]=3[Cl:45])[N:33]=2)=[CH:28][C:27]=1[Cl:46]>O>[Cl:45][C:39]1[CH:40]=[CH:41][CH:42]=[C:43]([F:44])[C:38]=1[C:34]1[N:33]=[C:32]([C:29]2[CH:30]=[CH:31][C:26]([CH2:25][O:17][C:8]3[CH:9]=[CH:10][C:11]([C:13]([F:15])([F:16])[F:14])=[CH:12][C:7]=3[Cl:6])=[C:27]([Cl:46])[CH:28]=2)[N:36]([CH3:37])[N:35]=1
Reactant: Cn1nc(-c2c(F)cccc2Cl)nc1-c1ccc(CBr)c(Cl)c1
Reactant: Oc1ccc(C(F)(F)F)cc1Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: Cn1nc(-c2c(F)cccc2Cl)nc1-c1ccc(COc2ccc(C(F)(F)F)cc2Cl)c(Cl)c1
Temperature: 25 °C
Yield: 79.5 %

Procedure:
To 30 ml of N,N-dimethylformamide are added 2-chloro-4-trifluoromethyl phenol (0.29 g) and potassium carbonate (0.25 g) and 5-(4-bromomethyl-3-chlorophenyl) 3-(2-chloro-6-fluorophenyl)-1-methyl-1H-1,2,4-triazole (0.60 g) is added thereto at room temperature with stirring, which is stirred at 120° C. for 1 hour. On completion of the reaction, the reaction solution is cooled to room temperature, poured into water and extracted with toluene. The organic layer is washed with water, dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The concentrate is purified by silica gel column chromatography to give 0.61 g of desired compound (melting point: 113.0°-114.0° C.).
Reaction SMILES: [C:1]([O:5][C:6](=[O:17])[NH:7][C@H:8]1[CH2:13][CH2:12][C@@H:11]([N:14]=[N+:15]=[N-:16])[CH2:10][CH2:9]1)([CH3:4])([CH3:3])[CH3:2].[CH3:18][O:19][C:20](=[O:23])[C:21]#[CH:22].CCN(C(C)C)C(C)C>[Cu]I.C1COCC1>[CH3:18][O:19][C:20]([C:21]1[N:16]=[N:15][N:14]([C@H:11]2[CH2:12][CH2:13][C@@H:8]([NH:7][C:6]([O:5][C:1]([CH3:4])([CH3:2])[CH3:3])=[O:17])[CH2:9][CH2:10]2)[CH:22]=1)=[O:23]
Reactant: C#CC(=O)OC
Reactant: CC(C)(C)OC(=O)N[C@H]1CC[C@@H](N=[N+]=[N-])CC1
Agent: [Cu]I
Solvent: C1CCOC1
Solvent: CCN(C(C)C)C(C)C
Product: COC(=O)c1cn([C@H]2CC[C@@H](NC(=O)OC(C)(C)C)CC2)nn1
Temperature: 25 °C

Procedure:
To a THF (30 ml) solution under Ar of (cis-4-azido-cyclohexyl)carbamic acid tert-butyl ester (3.00 g) and propiolic acid methyl ester (1.05 g) were added CuI (2.38 g) and DIPEA (3.18 ml). The resulting slurry was stirred at RT over night. After dilution with EtOAc (200 ml) the mixture was washed with H2O (200 ml), dried over Na2SO4 and the solvent was evaporated. Chromatography (silica, CH2Cl2/MeOH 95:5) yielded 2.63 g (65%) of product. White crystals. MS 325.4 (95, [M+H]+), 269.4 (100, [M−tBu].+).
Reaction SMILES: CO[CH:3]1[O:8][CH:7]([CH3:9])[C:6](=[O:10])[CH:5]=[CH:4]1.ClCl.[OH-:13].[Na+]>C(O)(=O)C.O>[CH3:9][C:7]1[O:8][CH:3]=[CH:4][C:5](=[O:13])[C:6]=1[OH:10]
Reactant: [OH-]
Reactant: COC1C=CC(=O)C(C)O1
Agent: ClCl
Agent: [Na+]
Solvent: O
Solvent: CC(=O)O
Product: Cc1occc(=O)c1O
Temperature: 25 °C

Procedure:
A solution of 6-methoxy-2-methyl-2H-pyran-3(6H)-one (0.01 mole) in 20 ml of acetic acid was treated with gaseous chlorine (0.01 mole) at room temperature. The reaction mixture was then heated to reflux for about one hour, cooled to room temperature, diluted with 20 ml of water, the pH adjusted with 50% NaOH solution to 7.0 and the reaction mixture extracted with chloroform. The chloroform extract was concentrated to yield maltol which was recrystallized from methanol to give the pure product (56%), mp 159.5°-160.5° C.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][CH:10]=1)[C:5]([OH:7])=O.[F:11][C:12]([F:21])([F:20])[C:13]1[CH:14]=[C:15]([CH:17]=[CH:18][CH:19]=1)[NH2:16].CCN(C(C)C)C(C)C.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>CN(C=O)C>[Br:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][CH:10]=1)[C:5]([NH:16][C:15]1[CH:17]=[CH:18][CH:19]=[C:13]([C:12]([F:11])([F:20])[F:21])[CH:14]=1)=[O:7]
Reactant: Nc1cccc(C(F)(F)F)c1
Reactant: O=C(O)c1cccc(Br)c1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: O=C(Nc1cccc(C(F)(F)F)c1)c1cccc(Br)c1
Temperature: 25 °C
Reaction time: 22 h

Procedure:
A mixture of 3-bromobenzoic acid (500 mg, 2.49 mmol), 3-(trifluoromethyl)aniline (0.31 ml, 2.49 mmol) and DIEA (2.06 ml, 12.45 mmol) in DMF (6 ml) was treated with HATU (1.04 g, 2.74 mmol) and the reaction mixture was stirred at room temperature for 22 hours. The reaction mixture was partitioned between ethyl acetate and water and the organic phase was washed with sat'd NaCl(aq.), dried (MgSO4), filtered, and concentrated. Elution through a flash column (silica gel 60, 230-400 mesh, 4:1 hexanes:EtOAc) gave a yellow oil which solidified on standing (622 mg, 73%).
Reaction SMILES: Cl[C:2]1[CH:24]=[CH:23][C:5]([C:6]([NH:8][C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=2[CH2:15][N:16]2[CH2:21][CH2:20][N:19]([CH3:22])[CH2:18][CH2:17]2)=[O:7])=[CH:4][N:3]=1.[CH:25]1([NH:28][C:29](=[O:46])[C:30]2[CH:35]=[CH:34][C:33]([CH3:36])=[C:32](B3OC(C)(C)C(C)(C)O3)[CH:31]=2)[CH2:27][CH2:26]1>>[CH:25]1([NH:28][C:29]([C:30]2[CH:35]=[CH:34][C:33]([CH3:36])=[C:32]([C:2]3[CH:24]=[CH:23][C:5]([C:6]([NH:8][C:9]4[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=4[CH2:15][N:16]4[CH2:21][CH2:20][N:19]([CH3:22])[CH2:18][CH2:17]4)=[O:7])=[CH:4][N:3]=3)[CH:31]=2)=[O:46])[CH2:26][CH2:27]1
Reactant: Cc1ccc(C(=O)NC2CC2)cc1B1OC(C)(C)C(C)(C)O1
Reactant: CN1CCN(Cc2ccccc2NC(=O)c2ccc(Cl)nc2)CC1
Product: Cc1ccc(C(=O)NC2CC2)cc1-c1ccc(C(=O)Nc2ccccc2CN2CCN(C)CC2)cn1

Procedure:
6-(5-Cyclopropylcarbamoyl-2-methyl-phenyl)-N-[2-(4-methylpiperazin-1-ylmethyl)phenyl]-nicotinamide was prepared from 6-chloro-N-[2-(4-methylpiperazin-1-ylmethyl)phenyl]nicotinamide (Intermediate 5) and N-cyclopropyl-4-methyl-3-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-benzamide (Intermediate 8) using General Method B. LCMS: retention time 2.36 min, MH+ 484. NMR: δH [2H6]-DMSO 11.70,(1H, b), 9.23,(1H, s), 8.50,(1H, d), 8.38,(1H, d), 8.33,(1H, d), 7.92,(1H, s), 7.83,(2H, m), 7.43,(1H, d), 7.36,(1H, t), 7.29,(1H, d), 7.11,(1H, t), 3.77,(2H, s), 2.87,(1H, m), 2.67-2.24,(11H, m), 2.13,(3H, s), 0.70,(2H, m), 0.58,(2H, m).
Reaction SMILES: N[C@@H:2]([C:7]([OH:9])=[O:8])[CH2:3][CH2:4][S:5][CH3:6].N([O-])=O.[Na+].O.[C:15]([O:18]CC)(=[O:17])[CH3:16]>C(O)(=O)C>[C:15]([O:18][C@H:2]([CH2:3][CH2:4][S:5][CH3:6])[C:7]([OH:9])=[O:8])(=[O:17])[CH3:16]
Reactant: CSCC[C@@H](N)C(=O)O
Reactant: CCOC(C)=O
Agent: O=N[O-]
Agent: [Na+]
Solvent: O
Solvent: CC(=O)O
Product: CSCC[C@@H](OC(C)=O)C(=O)O
Temperature: 25 °C
Reaction time: 1.5 h

Procedure:
D-Methionine (14.9 g, 0.10 mol) was stirred in 300 ml of acetic acid. Sodium nitrite (13.8 g, 0.2 mol) was added portionwise over 45 minutes while maintaining the temperature in the range 20°-30° C. After stirring for an additional 90 minutes at room temperature, the resulting yellow solution was stripped in vacuo to solids which were distributed between 300 ml each of water and ethyl acetate. The organic layer was separated, washed with saturated NaCl, dried over MgSO4 and stripped to yield 7.0 g of title product as a yellow oil, used directly in the next step; tlc Rf 0.08 (3:1 hexane:ethyl acetate).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:23])[C:5]([C:21]#[N:22])=[CH:6][CH:7]1[CH:12]=[C:11]([O:13][CH3:14])[C:10](OC)=[C:9]([O:17][CH3:18])[C:8]1=C=O)[CH3:2].[H][H]>[Pd].[Hg].C(O)C>[CH2:1]([O:3][C:4](=[O:23])[C:5]([C:21]#[N:22])=[CH:6][CH:7]1[CH:12]=[C:11]([O:13][CH3:14])[C:10]([C:4]([O:3][CH3:1])=[O:23])=[C:9]([O:17][CH3:18])[CH2:8]1)[CH3:2]
Reactant: [H][H]
Reactant: CCOC(=O)C(C#N)=CC1C=C(OC)C(OC)=C(OC)C1=C=O
Agent: [Pd]
Agent: [Hg]
Solvent: CCO
Product: CCOC(=O)C(C#N)=CC1C=C(OC)C(C(=O)OC)=C(OC)C1

Procedure:
A solution of 10.6 g. of α-cyano-3,5-dimethoxy-4-methoxy-carbonyl-cinnamic acid ethyl ester in 500 ml. of ethanol was hydrogenated in the presence of 0.5 g. of palladium-on-carbon (5%) at room temperature and 760 mm. of mercury. After the uptake of an equivalent of hydrogen (810 ml.), the hydrogenation was interrupted. The catalyst and partially precipitated product were removed by filtration with suction and washed on the filter with benzene. The filtrate was evaporated to dryness. The residue was recrystallized from ethyl acetate and yielded α-cyano-3,5-dimethoxy-4-methoxycarbonyl-dihydro-cinnamic acid ethyl ester having a m.p. of 119°-121°C.
Reaction SMILES: Br[C:2]1[CH:7]=[C:6]([F:8])[C:5]([C:9]([N:11]2[CH2:16][CH2:15][N:14]([C:17]3[CH:22]=[CH:21][C:20]([CH3:23])=[CH:19][N:18]=3)[CH2:13][CH2:12]2)=[O:10])=[C:4]([F:24])[CH:3]=1.[CH3:25][C:26]1([CH3:32])[O:30][C:29](=[O:31])[N:28]=[CH:27]1>>[F:24][C:4]1[CH:3]=[C:2]([N:28]2[CH2:27][C:26]([CH3:32])([CH3:25])[O:30][C:29]2=[O:31])[CH:7]=[C:6]([F:8])[C:5]=1[C:9]([N:11]1[CH2:16][CH2:15][N:14]([C:17]2[CH:22]=[CH:21][C:20]([CH3:23])=[CH:19][N:18]=2)[CH2:13][CH2:12]1)=[O:10]
Reactant: Cc1ccc(N2CCN(C(=O)c3c(F)cc(Br)cc3F)CC2)nc1
Reactant: CC1(C)C=NC(=O)O1
Product: Cc1ccc(N2CCN(C(=O)c3c(F)cc(N4CC(C)(C)OC4=O)cc3F)CC2)nc1
Yield: 47.7 %

Procedure:
By reaction and treatment in the same manner as in Example 110 and using (4-bromo-2,6-difluorophenyl)[4-(5-methylpyridin-2-yl)piperazin-1-yl]methanone (594 mg) described in Preparation Example 185 and 5,5-dimethyloxazolin-2-one (207 mg) described in Preparation Example 43, the title compound (308 mg) was obtained.