Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[O:9][C:10]([CH3:13])=[N:11][N:12]=2)=[CH:4][C:3]=1[C:14]1[CH:19]=[CH:18][C:17]([C:20](Cl)=[O:21])=[CH:16][CH:15]=1.[CH3:23][N:24]([CH2:26][C:27]1[CH:28]=[C:29]([CH:31]=[CH:32][C:33]=1[O:34][CH3:35])[NH2:30])[CH3:25]>>[CH3:25][N:24]([CH2:26][C:27]1[CH:28]=[C:29]([NH:30][C:20]([C:17]2[CH:18]=[CH:19][C:14]([C:3]3[CH:4]=[C:5]([C:8]4[O:9][C:10]([CH3:13])=[N:11][N:12]=4)[CH:6]=[CH:7][C:2]=3[CH3:1])=[CH:15][CH:16]=2)=[O:21])[CH:31]=[CH:32][C:33]=1[O:34][CH3:35])[CH3:23]
Reactant: Cc1nnc(-c2ccc(C)c(-c3ccc(C(=O)Cl)cc3)c2)o1
Reactant: COc1ccc(N)cc1CN(C)C
Product: COc1ccc(NC(=O)c2ccc(-c3cc(-c4nnc(C)o4)ccc3C)cc2)cc1CN(C)C

Procedure:
N-[3-(Dimethylaminomethyl)-4-methoxyphenyl]-2′-methyl-5′-(5-methyl-1,3,4-oxadiazol-2-yl)-1,1′-biphenyl-4-carboxamide was prepared from 2′-methyl-5′-(5-methyl-1,3,4-oxadiazol-2-yl)-1,1′-biphenyl-4-carbonyl chloride and 3-(dimethylaminomethyl)-4-methoxyaniline using method K. LCMS; retention time 2.65 min, MH+ 457.
Reaction SMILES: [CH3:1][O:2][CH:3]([O:23][CH3:24])[C:4]1[C:13]([CH2:14][N:15]2[CH2:20][CH2:19][N:18]([CH3:21])[CH2:17][C:16]2=[O:22])=[CH:12][C:11]2[CH2:10][CH2:9][CH2:8][NH:7][C:6]=2[N:5]=1.[Si](OCC1C=C2C(=NC=1C(OC)OC)N([C:49]([O:51][C:52]1[CH:57]=[CH:56][CH:55]=[CH:54][CH:53]=1)=[O:50])CCC2)(C(C)(C)C)(C)C>>[CH3:1][O:2][CH:3]([O:23][CH3:24])[C:4]1[N:5]=[C:6]2[C:11]([CH2:10][CH2:9][CH2:8][N:7]2[C:49]([O:51][C:52]2[CH:57]=[CH:56][CH:55]=[CH:54][CH:53]=2)=[O:50])=[CH:12][C:13]=1[CH2:14][N:15]1[CH2:20][CH2:19][N:18]([CH3:21])[CH2:17][C:16]1=[O:22]
Reactant: COC(OC)c1nc2c(cc1CN1CCN(C)CC1=O)CCCN2
Reactant: COC(OC)c1nc2c(cc1CO[Si](C)(C)C(C)(C)C)CCCN2C(=O)Oc1ccccc1
Product: COC(OC)c1nc2c(cc1CN1CCN(C)CC1=O)CCCN2C(=O)Oc1ccccc1

Procedure:
From intermediate 81, synthesized in an analogous manner to intermediate 38, the title compound was obtained as a light yellow oil. (UPLC-MS 6) tR 0.73; ESI-MS 455.3 [M+H]+.
Reaction SMILES: [C:1]1([P:7]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[I-:20].[Na+].Cl[CH2:23][C:24]1[S:28][C:27]([C:29]2[CH:34]=[CH:33][C:32]([Cl:35])=[CH:31][CH:30]=2)=[N:26][C:25]=1[CH3:36]>O1CCCC1>[I-:20].[Cl:35][C:32]1[CH:31]=[CH:30][C:29]([C:27]2[S:28][C:24]([CH2:23][P+:7]([C:1]3[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=3)([C:8]3[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=3)[C:14]3[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=3)=[C:25]([CH3:36])[N:26]=2)=[CH:34][CH:33]=1
Reactant: Cc1nc(-c2ccc(Cl)cc2)sc1CCl
Reactant: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Agent: [I-]
Agent: [Na+]
Solvent: C1CCOC1
Product: Cc1nc(-c2ccc(Cl)cc2)sc1C[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Reaction time: 5 h

Procedure:
Triphenylphosphine (1.15 g, 4.26 mmol) and sodium iodide (580 mg, 3.87 mmol) were added to 5-chloromethyl-2-(4-chlorophenyl)-4-methylthiazole (1.00 g, 3.87 mmol) in tetrahydrofuran (20 mL). The reaction mixture was stirred for 5 hours while being stirred. Subsequently, the crystallized powdery product was collected by filtration and washed with hexane to give 2.43 g (quant.) of the desired compound as a colorless powder.
Reaction SMILES: Br[CH2:2][C:3]([N:5]1[C:13]2[C:8](=[CH:9][C:10]([O:17][CH3:18])=[C:11]([N+:14]([O-])=O)[CH:12]=2)[CH2:7][CH2:6]1)=[O:4].C([O-])([O-])=O.[K+].[K+].[CH2:25]([NH:27][CH2:28][CH2:29][OH:30])[CH3:26]>ClCCl>[NH2:14][C:11]1[CH:12]=[C:13]2[C:8]([CH2:7][CH2:6][N:5]2[C:3](=[O:4])[CH2:2][N:27]([CH2:25][CH3:26])[CH2:28][CH2:29][OH:30])=[CH:9][C:10]=1[O:17][CH3:18]
Reactant: CCNCCO
Reactant: COc1cc2c(cc1[N+](=O)[O-])N(C(=O)CBr)CC2
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: ClCCl
Product: CCN(CCO)CC(=O)N1CCc2cc(OC)c(N)cc21
Temperature: 25 °C
Reaction time: 3 h
Yield: 101.2 %

Procedure:
The 1-(bromoacetyl)-5-(methyloxy)-6-nitro-2,3-dihydro-1H-indole (4.0 g, 12.7 mmol) was dissolved in 50 mL of dicholomethane, then K2CO3 (4.4 g, 31.7 mmol) and 2-(ethylamino)ethanol (2.3 g, 25.4 mmol) in 10 mL dichloromethane were added, the reaction was stirred at RT for 3 hours. After filtration, the organic layers were washed with water (2×100 mL)and dried over Na2SO4. The solvent was removed to yield the 2-[{2-[6-amino-5-(methyloxy)-2,3-dihydro-1H-indol-1-yl]-2-oxoethyl}(ethyl)amino]ethanol as a yellow solid (3.77 g, 92%).1HNMR (400 MHz, DMSO-d6) δ ppm: 0.94 (t, J=7.14 Hz,3 H), 2.45 (s, 2 H), 2.60 (m, 4 H), 3.18 (t, J=8.42 Hz, 2 H), 3.40 (t, J=6.13 Hz,2H), 3.84 (s, 3 H), 4.19 (t, J=8.51 Hz, 2 H), 7.29 (s, 1 H), 8.43 (s, 1 H).
Reaction SMILES: C[O:2][C:3]1[CH:4]=[C:5]([CH:15]=[CH:16][C:17]=1[O:18]C)[C:6]([CH2:8][CH2:9][C:10]([O:12][CH2:13][CH3:14])=[O:11])=[O:7].B(Br)(Br)Br>ClCCl>[OH:2][C:3]1[CH:4]=[C:5]([CH:15]=[CH:16][C:17]=1[OH:18])[C:6]([CH2:8][CH2:9][C:10]([O:12][CH2:13][CH3:14])=[O:11])=[O:7]
Reactant: CCOC(=O)CCC(=O)c1ccc(OC)c(OC)c1
Agent: BrB(Br)Br
Solvent: ClCCl
Product: CCOC(=O)CCC(=O)c1ccc(O)c(O)c1

Procedure:
Ethyl 3-(3,4-dimethoxybenzoyl)propionate was demethylated with boron tribromide in dichloromethane at -80°C to give ethyl 3-(3,4-dihydroxybenzoyl)propionate, m.p. 116°-117°C.
Reaction SMILES: Cl[C:2]1[CH:10]=[CH:9][CH:8]=[C:7]2[C:3]=1[CH:4]([OH:23])[N:5](C1C=CC3C(=NC(Cl)=CC=3)N=1)[C:6]2=O.Cl.ClC(N1CCN(C)CC1)=O.C(N(CC)CC)C.N1C=CC=CC=1>O.C(Cl)Cl>[C:4]1(=[O:23])[C:3]2[C:7](=[CH:8][CH:9]=[CH:10][CH:2]=2)[CH2:6][NH:5]1
Reactant: O=C1c2cccc(Cl)c2C(O)N1c1ccc2ccc(Cl)nc2n1
Agent: CN1CCN(C(=O)Cl)CC1
Agent: Cl
Solvent: ClCCl
Solvent: O
Solvent: CCN(CC)CC
Product: O=C1NCc2ccccc21
Yield: 117 %

Procedure:
The procedure followed is as in Example 28, but using 4-chloro-2-(7-chloro-1,8-naphthyridin-2-yl)-3-hydroxy-1-isoindolinone (2 g.), 4-chlorocarbonyl-1-methyl-piperazine hydrochloride (6.9 g.), triethylamine (6.5 cc., equivalent to 4.7 g.), pyridine (30 cc.) and methylene chloride (200 cc.). When the reaction has ended, the reaction mixture is taken up in water (200 cc.). A precipitate which forms is filtered off. After decanting from the methylene chloride layer, the aqueous layer is extracted with methylene chloride (400 cc.). The combined organic layers are dried over anhydrous sodium sulphate (10 g.). After filtration followed by concentration, the residue is washed with water. The mother liquor is extracted with methylene chloride (100 cc.). After evaporation of the methylene chloride, the residue is chromatographed on silica gel (125 g.), elution being carried out with a mixture of methylene chloride and ethyl acetate (9/1 by volume), and fractions of 50 cc. being collected. Fractions 1 to 21 (1,050 cc.) yield isoindolinone starting material (0.9 g.) and fractions 22 to 25 (200 cc.) yield a product (0.3 g.) which is recrystallised from acetonitrile (6 cc.). This gives 4-chloro-2-(7-chloro-1,8-naphthyridin-2-yl)-3-(4-methyl-piperazinyl)-carbonyloxy-1-isoindolinone (0.2 g.), melting at 191°-193° C.
Reaction SMILES: [CH2:1]([SH:3])[CH3:2].C(N(CC)CC)C.[Cl:11][C:12]1[CH:29]=[C:28]([C:30]([F:33])([F:32])[F:31])[CH:27]=[CH:26][C:13]=1[O:14][C:15]1[CH:16]=[C:17]([S:24]Cl)[C:18]([N+:21]([O-:23])=[O:22])=[CH:19][CH:20]=1>CCOCC>[CH2:1]([S:3][S:24][C:17]1[C:18]([N+:21]([O-:23])=[O:22])=[CH:19][CH:20]=[C:15]([O:14][C:13]2[CH:26]=[CH:27][C:28]([C:30]([F:31])([F:32])[F:33])=[CH:29][C:12]=2[Cl:11])[CH:16]=1)[CH3:2]
Reactant: CCS
Reactant: O=[N+]([O-])c1ccc(Oc2ccc(C(F)(F)F)cc2Cl)cc1SCl
Solvent: CCN(CC)CC
Solvent: CCOCC
Product: CCSSc1cc(Oc2ccc(C(F)(F)F)cc2Cl)ccc1[N+](=O)[O-]
Reaction time: 2 h
Yield: 98 %

Procedure:
1.62 parts by weight of ethanethiol and 2.6 parts by weight of triethylamine were added simultaneously to a solution of 10 parts by weight of 3-(2'-chloro-4'-trifluoromethylphenoxy)-6-nitrobenzenesulfenyl chloride in 100 parts by volume of absolute ether, and stirring was continued for a further 2 hours at room temperature. The reaction mixture was filtered, and the filtrate was extracted with dilute aqueous hydrochloric acid and water, dried over magnesium sulfate, filtered, and evaporated down under reduced pressure. 8 parts by weight (98% yield) of 3-(2'-chloro-4'-trifluoromethylphenoxy)-6-nitrophenyl ethyl disulfide of refractive index nD25 : 1.6067 were obtained (compound No. 4).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]([C:14]2[CH:23]=[C:22]3[C:17]([CH2:18][CH2:19][N:20]([CH2:25][C:26](O)=[O:27])[C:21]3=[O:24])=[CH:16][CH:15]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].Cl.Cl.[NH2:31][C@H:32]([C:39]1[CH:40]=[N:41][CH:42]=[CH:43][CH:44]=1)[CH2:33][C:34]([O:36][CH2:37][CH3:38])=[O:35].C(Cl)CCl.C1C=CC2N(O)N=NC=2C=1.CN1CCOCC1.[Li+].[OH-]>CN(C=O)C.CCOC(C)=O.O.CO>[CH2:37]([O:36][C:34](=[O:35])[CH2:33][C@@H:32]([C:39]1[CH:40]=[N:41][CH:42]=[CH:43][CH:44]=1)[NH:31][C:26](=[O:27])[CH2:25][N:20]1[CH2:19][CH2:18][C:17]2[C:22](=[CH:23][C:14]([N:11]3[CH2:10][CH2:9][N:8]([C:6]([O:5][C:1]([CH3:2])([CH3:4])[CH3:3])=[O:7])[CH2:13][CH2:12]3)=[CH:15][CH:16]=2)[C:21]1=[O:24])[CH3:38]
Reactant: CC(C)(C)OC(=O)N1CCN(c2ccc3c(c2)C(=O)N(CC(=O)O)CC3)CC1
Reactant: CCOC(=O)C[C@H](N)c1cccnc1
Agent: Cl
Agent: On1nnc2ccccc21
Agent: [Li+]
Solvent: CN1CCOCC1
Solvent: CO
Solvent: ClCCCl
Product: CCOC(=O)C[C@H](NC(=O)CN1CCc2ccc(N3CCN(C(=O)OC(C)(C)C)CC3)cc2C1=O)c1cccnc1

Procedure:
A solution of [7-(4-t-butoxycarbonylpiperazin-1-yl)-3,4-dihydro-1(1H)-isoquinolinone-2-yl]acetic acid (1-5) (195 mg, 0.5 mmol), ethyl 3-amino-3(S)-(3-pyridyl)propionate dihydrochloride (1-6) (Rico et al, J. Org. Chem. 1993, vol. 58, p. 7948; 127 mg, 0.55 mmol), EDC (105 mg, 0.55 mmol), HOBT (74 mg, 0.55 mmol) and 4-methylmorpholine (0.12 mL, 1.1 mmol) in DMF (5 mL) was stirred at room temperature for 16 hours. The mixture was diluted with EtOAc and water and the pH adjusted to ~pH 7 with 1N LiOH. The solution was extracted with EtOAc (3×), dried (MgSO4) and the solvent removed in vacuo. Purification of the residue by column chromatography (10% MeOH in EtOAc) gave 1-7. Rf (silica, 10% MeOH in EtOAc)=0.43.
Reaction SMILES: Cl[C:2]1[CH:3]=[CH:4][C:5]([OH:21])=[C:6]([NH:8][C:9]2[CH:14]=[CH:13][C:12]([N+]([O-])=O)=[CH:11][C:10]=2[N+:18]([O-:20])=[O:19])[CH:7]=1.[N+](C1C=C([N+]([O-])=O)C=CC=1N1C2C=C(Cl)C=CC=2OC1=O)([O-])=O>>[OH:21][C:5]1[CH:4]=[CH:3][CH:2]=[CH:7][C:6]=1[NH:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1[N+:18]([O-:20])=[O:19]
Reactant: O=[N+]([O-])c1ccc(Nc2cc(Cl)ccc2O)c([N+](=O)[O-])c1
Agent: O=c1oc2ccc(Cl)cc2n1-c1ccc([N+](=O)[O-])cc1[N+](=O)[O-]
Product: O=[N+]([O-])c1ccccc1Nc1ccccc1O

Procedure:
N-(5-chloro-2-hydroxyphenyl)-2,4-dinitroaniline from N-(2,4-dinitrophenyl)-5-chloro-2-benzoxazolinone. The product was used without further purification.
Reaction SMILES: [Si]([O:8][C:9]1[CH:14]=[CH:13][C:12]([CH2:15][N:16]2[C:20]3=[N:21][C:22]([CH3:26])=[CH:23][C:24]([CH3:25])=[C:19]3[N:18]=[C:17]2[CH2:27][CH3:28])=[CH:11][C:10]=1[Cl:29])(C(C)(C)C)(C)C.[F-].C([N+](CCCC)(CCCC)CCCC)CCC>C1COCC1>[Cl:29][C:10]1[CH:11]=[C:12]([CH2:15][N:16]2[C:20]3=[N:21][C:22]([CH3:26])=[CH:23][C:24]([CH3:25])=[C:19]3[N:18]=[C:17]2[CH2:27][CH3:28])[CH:13]=[CH:14][C:9]=1[OH:8]
Reactant: CCc1nc2c(C)cc(C)nc2n1Cc1ccc(O[Si](C)(C)C(C)(C)C)c(Cl)c1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: C1CCOC1
Product: CCc1nc2c(C)cc(C)nc2n1Cc1ccc(O)c(Cl)c1
Temperature: 25 °C
Reaction time: 2 h
Yield: 90.1 %

Procedure:
To a solution of 0.294 g (0.661 mmol) of the product of Step D dissolved in 4 mL of THF was added 0.69 mL (0.69 mmol) of a 1.0M solution of tetra-n-butylammonium fluoride in THF, and the reaction mixture was stirred 2 hours at room temperature. The reaction was then concentrated in vacuo and purified by filtration through a silica gel pad eluted with chloroform. Evaporation of the filtrate and drying in vacuo afforded 0.188 g (87%) of the title compound.
Reaction SMILES: Cl[C:2]1[CH:10]=[C:9]([Cl:11])[CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=[O:5].[C:12]([OH:21])(=[O:20])[C:13]1[C:14](=[CH:16][CH:17]=[CH:18][CH:19]=1)[SH:15].C(=O)([O-])[O-].[K+].[K+].[OH-].[K+]>C(O)C1C=CC=CC=1.[Cu]>[Cl:11][C:9]1[CH:8]=[CH:7][C:3]([C:4]([OH:6])=[O:5])=[C:2]([S:15][C:14]2[CH:16]=[CH:17][CH:18]=[CH:19][C:13]=2[C:12]([OH:21])=[O:20])[CH:10]=1
Reactant: O=C(O)c1ccc(Cl)cc1Cl
Reactant: O=C(O)c1ccccc1S
Agent: [Cu]
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: OCc1ccccc1
Product: O=C(O)c1ccccc1Sc1cc(Cl)ccc1C(=O)O
Temperature: 115 °C
Yield: 70 %

Procedure:
A mixture of 2,4-dichlorobenzoic acid (7.64 g), thiosalicylic acid (7.16 g), anhydrous potassium carbonate (22 g), and copper powder (300 mg) was suspended in benzyl alcohol and this suspension was heated under N2 atmosphere at 110-120° C. for 3 hours. After cooling, 10% aqueous potassium hydroxide solution (120 ml) was added and extracted with ether. The aqueous layer was filtered and acidified with 6N HCl. The resulting precipitated product was isolated by filtration. Recrystallization from aqueous methanol gave 4-chloro-2,2'-thiodibenzoic acid (compound No. 1) in an amount of 8.56 g (yield: 70%). m.p. 241-242° C.
Reaction SMILES: [Si:1](Cl)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].[CH3:9][N:10]([CH3:23])[C:11]([C:13]1[CH:21]=[CH:20][C:16]2[O:17][CH2:18][O:19][C:15]=2[C:14]=1[OH:22])=[O:12].N1C=CN=C1>C(Cl)Cl>[CH3:9][N:10]([CH3:23])[C:11]([C:13]1[CH:21]=[CH:20][C:16]2[O:17][CH2:18][O:19][C:15]=2[C:14]=1[O:22][Si:1]([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2])=[O:12]
Reactant: CC(C)(C)[Si](C)(C)Cl
Reactant: CN(C)C(=O)c1ccc2c(c1O)OCO2
Agent: c1c[nH]cn1
Solvent: ClCCl
Product: CN(C)C(=O)c1ccc2c(c1O[Si](C)(C)C(C)(C)C)OCO2
Temperature: 25 °C
Reaction time: 3 h
Yield: 82 %

Procedure:
t-Butyldimethylsilyl chloride (4.02 g, 26.67 mmol) in CH2Cl2 (25 ml) was added to a solution of N,N-dimethyl-4-hydroxy-1,3-benzodioxole-5-carboxamide (5) (4.49 g, 20.5 mmol) and imidazole (3.63 g, 53.3 mmol) in CH2Cl2 (25 ml). The solution was stirred for 3 h at rt, during which time a white solid precipitated. The mixture was washed with brine, dried over MgSO4 and concentrated. Chromatography on silica (hexane/ethyl acetate, 1:1) afforded 9 (5.44 g, 82%) as a crystalline solid. 1H NMR (270 MHz, CDCl3) ε 6.75 (d, J=8.0 Hz, 1H), 6.50 (d, J=8.0 Hz, 1H), 5.92 (s, 2H), 3.03 (s, 3H), 2.87 (s, 3H), 0.94 (s, 9H), 0.16 (bs, 6H). 13C NMR (100 MHz, CDCl3) ε 168.9 (C), 149.3 (C), 137.0 (C), 135.5 (C), 124.9 (C), 121.4 (CH), 102.8 (CH), 101.0 (CH2), 38.2 (CH3), 34.9 (CH3), 25.4 (3CH3), 18.1 (C), -4.6 (2CH3).
Reaction SMILES: Cl.CCO.[CH3:5][C:6]1[N:10]=[C:9]([C:11]23[CH2:16][CH:15]2[CH2:14][N:13](C(OC(C)(C)C)=O)[CH2:12]3)[O:8][N:7]=1>C(O)C>[C:11]12([C:9]3[O:8][N:7]=[C:6]([CH3:5])[N:10]=3)[CH2:16][CH:15]1[CH2:14][NH:13][CH2:12]2
Reactant: Cc1noc(C23CC2CN(C(=O)OC(C)(C)C)C3)n1
Agent: Cl
Solvent: CCO
Product: Cc1noc(C23CNCC2C3)n1
Yield: 99.8 %

Procedure:
HCl/EtOH (8.49 mL of 2.53 M solution) was added to tert-butyl 1-(3-methyl-1,2,4-oxadiazol-5-yl)-3-azabicyclo[3.1.0]hexane-3-carboxylate (104) (1.9 g, 7.16 mmol) in 5 mL of ethanol. The solution was refluxed for 5 minutes, cooled and condensed to a white solid. The crude solid was crystallized from ethanol and diethyl ether, obtained 1.18 g of white solid hydrochloride salt MS (ESI) m/z 165.8[M+H]+. 1H NMR (CDCl3) δ: 1.18 (m, 2H), 1.50 (s, 3H), 3.42 (m, 3H), 3.74 (m, 2H), 9.64 (s, 2H).
Reaction SMILES: Cl[C:2]1[CH:11]=[C:10]([CH3:12])[C:9]2[C:4](=[CH:5][CH:6]=[C:7]([OH:13])[CH:8]=2)[N:3]=1.[NH2:14][C@H:15]1[C@H:19]([O:20][CH3:21])[CH2:18][N:17]([C:22](=[O:35])[CH2:23][C:24]2[CH:29]=[CH:28][C:27]([O:30][C:31]([F:34])([F:33])[F:32])=[CH:26][CH:25]=2)[CH2:16]1.O1CCOCC1.CC(C)([O-])C.[Na+]>C(OCC)(=O)C.O.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[OH:13][C:7]1[CH:8]=[C:9]2[C:4](=[CH:5][CH:6]=1)[N:3]=[C:2]([NH:14][C@H:15]1[C@H:19]([O:20][CH3:21])[CH2:18][N:17]([C:22](=[O:35])[CH2:23][C:24]3[CH:25]=[CH:26][C:27]([O:30][C:31]([F:32])([F:33])[F:34])=[CH:28][CH:29]=3)[CH2:16]1)[CH:11]=[C:10]2[CH3:12]
Reactant: Cc1cc(Cl)nc2ccc(O)cc12
Reactant: CO[C@@H]1CN(C(=O)Cc2ccc(OC(F)(F)F)cc2)C[C@H]1N
Agent: [Pd]
Agent: CC(C)(C)[O-]
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: CCOC(C)=O
Solvent: O
Solvent: C1COCCO1
Product: CO[C@@H]1CN(C(=O)Cc2ccc(OC(F)(F)F)cc2)C[C@H]1Nc1cc(C)c2cc(O)ccc2n1
Temperature: 65 °C
Reaction time: 3 h
Yield: 17.1 %

Procedure:
To a mixture of 2-chloro-6-hydroxy-4-methylquinoline (0.153 g), Pd2(dba)3 (0.036 g), (±)-BINAP (0.073 g), 1-((3R,4R)-3-amino-4-methoxypyrrolidin-1-yl)-2-(4-trifluoromethoxyphenyl)ethanone (0.25 g), and 1,4-dioxane (7 mL) was added sodium t-butoxide (0.241 g) under nitrogen atmosphere, and the mixture was stirred at 65° C. for 3 h. Pd2(dba)3 (0.036 g), (±)-BINAP (0.073 g), and sodium t-butoxide (0.241 g) were further added, and the mixture was stirred at 65° C. for 5 h. The reaction mixture was diluted with ethyl acetate and water, then the interlayer was removed by Celite filtration, and the organic layer washed with saturated brine. The organic layer was dried with anhydrous magnesium sulfate, the desiccant was removed by filtration, the filtrate was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (silica gel, chloroform/methanol and NH silica gel, ethyl acetate) to obtain colorless amorphous 1-((3R,4R)-3-(6-hydroxy-4-methylquinolin-2-ylamino)-4-methoxypyrrolidin-1-yl)-2-(4-trifluoromethoxyphenyl)ethanone (0.064 g).
Reaction SMILES: [NH2:1][CH2:2][C:3]1[CH:4]=[C:5]([CH:24]=[CH:25][C:26]=1[OH:27])[C:6]([C:8]1[C:9]([Cl:23])=[C:10]([Cl:22])[C:11]2[O:15][CH:14]([C:16]([O:18]CC)=[O:17])[CH2:13][C:12]=2[CH:21]=1)=[O:7].Cl>C(O)C>[ClH:22].[NH2:1][CH2:2][C:3]1[CH:4]=[C:5]([CH:24]=[CH:25][C:26]=1[OH:27])[C:6]([C:8]1[C:9]([Cl:23])=[C:10]([Cl:22])[C:11]2[O:15][CH:14]([C:16]([OH:18])=[O:17])[CH2:13][C:12]=2[CH:21]=1)=[O:7]
Reactant: CCOC(=O)C1Cc2cc(C(=O)c3ccc(O)c(CN)c3)c(Cl)c(Cl)c2O1
Agent: Cl
Solvent: CCO
Product: NCc1cc(C(=O)c2cc3c(c(Cl)c2Cl)OC(C(=O)O)C3)ccc1O

Procedure:
A sample of crude ethyl 5-(3-aminomethyl-4-hydroxybenzoyl)-6,7-dichloro-2,3-dihydrobenzofuran-2-carboxylate (600 mg.) was dissolved in 10 ml. of ethanol and treated with 4% aqueous HCl (125 ml.) for five hours at reflux.
Reaction SMILES: CO[C:3](=[O:27])[C:4]1[CH:9]=[CH:8][C:7]([O:10][CH2:11][C:12]2[C:13]([C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=3)=[N:14][O:15][C:16]=2[C:17]([F:20])([F:19])[F:18])=[N:6][CH:5]=1.[CH2:28]([CH2:30][NH2:31])[OH:29]>>[OH:29][CH2:28][CH2:30][NH:31][C:3](=[O:27])[C:4]1[CH:9]=[CH:8][C:7]([O:10][CH2:11][C:12]2[C:13]([C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=3)=[N:14][O:15][C:16]=2[C:17]([F:18])([F:19])[F:20])=[N:6][CH:5]=1
Reactant: COC(=O)c1ccc(OCc2c(-c3ccccc3)noc2C(F)(F)F)nc1
Reactant: NCCO
Product: O=C(NCCO)c1ccc(OCc2c(-c3ccccc3)noc2C(F)(F)F)nc1
Yield: 24 %

Procedure:
As described for example 129, 6-(3-phenyl-5-trifluoromethyl-isoxazol-4-ylmethoxy)-nicotinic acid methyl ester (100 mg, 0.26 mmol) was converted, using ethanolamine instead of methylamine (2 M in THF), to the title compound (26 mg, 24%) which was obtained as an off white solid. MS: m/e=408.3 [M+H]+.
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([C:8]2[CH:13]=[C:12]([F:14])[CH:11]=[C:10]([F:15])[CH:9]=2)[N:5]2[N:16]=[C:17]([CH3:20])[C:18]([I:19])=[C:4]2[N:3]=1.CCN(C(C)C)C(C)C.[NH:30]1[CH2:34][CH2:33][CH2:32][C@H:31]1[CH2:35][OH:36]>C(#N)C>[F:15][C:10]1[CH:9]=[C:8]([C:6]2[N:5]3[N:16]=[C:17]([CH3:20])[C:18]([I:19])=[C:4]3[N:3]=[C:2]([N:30]3[CH2:34][CH2:33][CH2:32][C@H:31]3[CH2:35][OH:36])[CH:7]=2)[CH:13]=[C:12]([F:14])[CH:11]=1
Reactant: Cc1nn2c(-c3cc(F)cc(F)c3)cc(Cl)nc2c1I
Reactant: OC[C@@H]1CCCN1
Solvent: CC#N
Solvent: CCN(C(C)C)C(C)C
Product: Cc1nn2c(-c3cc(F)cc(F)c3)cc(N3CCC[C@H]3CO)nc2c1I

Procedure:
5-Chloro-7-(3,5-difluorophenyl)-3-iodo-2-methylpyrazolo[1,5-a]pyrimidine obtained in Step 3, DIPEA (0.35 mL) and (S)-2-pyrrolidinemethanol (401 mg) are stirred in an acetonitrile (60 mL) solvent for 2.5 hours at 90° C. The reaction solvent is removed by distillation under reduced pressure. The remainder is purified by column chromatography to yield the target compound. 1H NMR (CDCl3, 300 MHz); δ 7.46 (m, 2H), 6.98 (m, 1H), 6.13 (s, 1H), 4.45 (br, 1H), 3.85-3.57 (m, 5H), 2.38 (s, 3H), 2.08-2.04 (m, 3H), 1.77 (m, 1H).
Reaction SMILES: [NH2:1][C@H:2]1[CH2:7][CH2:6][C@H:5]([NH:8][C:9]2[CH:10]=[C:11]([N:28]([CH:38]3[CH2:40][CH2:39]3)CC3C=CC(OC)=CC=3)[C:12]3[N:13]([C:15]([C:18]([NH:20][C:21]4[CH:26]=[CH:25][N:24]=[C:23]([F:27])[CH:22]=4)=[O:19])=[CH:16][N:17]=3)[N:14]=2)[CH2:4][CH2:3]1>C(O)(C(F)(F)F)=O>[NH2:1][C@H:2]1[CH2:3][CH2:4][C@H:5]([NH:8][C:9]2[CH:10]=[C:11]([NH:28][CH:38]3[CH2:39][CH2:40]3)[C:12]3[N:13]([C:15]([C:18]([NH:20][C:21]4[CH:26]=[CH:25][N:24]=[C:23]([F:27])[CH:22]=4)=[O:19])=[CH:16][N:17]=3)[N:14]=2)[CH2:6][CH2:7]1
Reactant: COc1ccc(CN(c2cc(N[C@H]3CC[C@H](N)CC3)nn3c(C(=O)Nc4ccnc(F)c4)cnc23)C2CC2)cc1
Solvent: O=C(O)C(F)(F)F
Product: N[C@H]1CC[C@H](Nc2cc(NC3CC3)c3ncc(C(=O)Nc4ccnc(F)c4)n3n2)CC1
Temperature: 70 °C

Procedure:
6-((trans)-4-aminocyclohexylamino)-8-(cyclopropyl(4-methoxybenzyl)amino)-N-(2-fluoropyridin-4-yl)imidazo[1,2-b]pyridazine-3-carboxamide (25B) was dissolved in TFA (2 mL) and heated at 70° C. for 2 hrs. The reaction mixture was concentrated and purified by HPLC (Phenomenex Axia Luna 5 micron 30×100 mm) 20% B (Solvent B=90% MeOH-10% H2O-0.1% TFA) to 100% B in A (Solvent A=10% MeOH-90% H2O-0.1% TFA) to afford 6-((trans)-4-aminocyclohexylamino)-8-(cyclopropylamino)-N-(2-fluoropyridin-4-yl)imidazo[1,2-b]pyridazine-3-carboxamide (23 mg, 43.2% yield) as a white solid. LC/MS (Phenomenex Luna 5 micron C18 4.6×30 mm, 0 to 100 B in 2 min with 1 min hold time, Flow rate=5 mL/min, detection at 254 nm, Solvent A: 10% methanol/90% water/0.1% TFA; Solvent B: 10% water/90% methanol/0.1% TFA). Rt=1.448 minutes. [M+H]=425.29. 1H NMR (400 MHz, MeOD) δ ppm 8.08-8.26 (1H, m), 8.04 (1H, s), 7.60-7.74 (1H, m), 7.29-7.45 (1H, m), 5.99-6.16 (1H, m), 3.61-3.92 (1H, m), 3.08-3.28 (1H, m), 2.48-2.69 (1H, m), 2.26-2.48 (2H, m), 2.07-2.28 (2H, m), 1.37-1.69 (4H, m), 0.79-1.00 (2H, m), 0.53-0.76 (2H, m).
Reaction SMILES: [CH:1]([C:3]1[CH:10]=[CH:9][CH:8]=[CH:7][C:4]=1[C:5]#[N:6])=[CH2:2].C(=O)(O)[O-:12].[Na+].ClCCl.C1C=C(Cl)C=C(C(OO)=O)C=1>O>[O:12]1[CH2:2][CH:1]1[C:3]1[CH:10]=[CH:9][CH:8]=[CH:7][C:4]=1[C:5]#[N:6]
Reactant: O=C([O-])O
Reactant: C=Cc1ccccc1C#N
Agent: O=C(OO)c1cccc(Cl)c1
Agent: [Na+]
Solvent: ClCCl
Solvent: O
Product: N#Cc1ccccc1C1CO1
Temperature: 25 °C
Reaction time: 8 h
Yield: 13.1 %

Procedure:
Into a 100-mL round-bottom flask was placed 2-ethenylbenzonitrile (2.73 g, 21.14 mmol, 1.00 equiv), sodium bicarbonate (1.77 g, 21.07 mmol, 4.61 equiv), dichloromethane (20 mL) and water (20 mL). Then m-CPBA (10.9 g, 63.16 mmol, 2.25 equiv) was added at 0° C. in several batches. The resulting solution was stirred overnight at room temperature and then concentrated under vacuum. The residue was applied onto a silica gel column with PE/EA (50:1). Purification afforded 400 mg (13%) of 2-(oxiran-2-yl)benzonitrile as a yellow oil.
Reaction SMILES: [CH2:1]([N:8]1[C:13]2[N:14]=[C:15]([S:20][CH3:21])[N:16]=[C:17]([NH:18][NH2:19])[C:12]=2[C:11](=O)[CH:10]([C:23]([O:25][CH2:26][CH3:27])=[O:24])[CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1>Cl.O1CCOCC1>[CH2:1]([N:8]1[C:13]2[C:12]3[C:11](=[N:19][NH:18][C:17]=3[N:16]=[C:15]([S:20][CH3:21])[N:14]=2)[CH:10]([C:23]([O:25][CH2:26][CH3:27])=[O:24])[CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CCOC(=O)C1CN(Cc2ccccc2)c2nc(SC)nc(NN)c2C1=O
Agent: Cl
Solvent: C1COCCO1
Product: CCOC(=O)C1CN(Cc2ccccc2)c2nc(SC)nc3[nH]nc1c23
Yield: 12.3 %

Procedure:
Ethyl 8-benzyl-4-hydrazinyl-2-(methylthio)-5-oxo-5,6,7,8-tetrahydropyrido[2,3-d]pyrimidine-6-carboxylate (45 g) was taken in 4M dioxane-HCl (500 mL) and refluxed for 16 h. The reaction was concentrated under reduced pressure. Aq. NaHCO3 (250 mL) was added to the residue and the mixture was extracted with dichloromethane (200 mL×3). The combined organic layer was washed with water (500 mL), brine (500 mL), dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure to give a residue which was purified by column chromatography (silica gel) using 0-10% tetrahydrofuran in dichloromethane as the eluent. The obtained product was further purified by crystallization from EtOAc to afford pure ethyl 5-benzyl-7-(methylthio)-1,3,4,5-tetrahydro-1,2,5,6,8-pentaazaacenaphthylene-3-carboxylate as a solid (5.2 g, 12.3% yield over 3 steps). LCMS: 370 (M+1)+; HPLC: 95.60% (254 nm); 1H NMR (DMSO-d6, 400 MHz) δ 13.15 (s, 1H); 7.38-7.30 (m, 5H); 4.92 (d, J=15.2 Hz, 1H); 4.67 (d, J=15.6 Hz, 1H); 4.34 (t, J=4.8 Hz, 1H); 4.06-3.96 (m, 2H); 3.88-3.79 (m, 2H); 2.5 (s, 3H); 1.08 (t, J=7.2 Hz, 3H).