Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl.[CH3:2][C:3]1[N:7]([CH:8]2[CH2:12][CH2:11][NH:10][CH2:9]2)[N:6]=[N:5][CH:4]=1.C1CCN2C(=NCCC2)CC1.[CH:24]1([N:27]2[C:36]3[C:31](=[CH:32][C:33]([F:40])=[C:34](F)[C:35]=3[O:37][CH3:38])[C:30](=[O:41])[C:29]([C:42]([OH:44])=[O:43])=[CH:28]2)[CH2:26][CH2:25]1>C(#N)C>[CH:24]1([N:27]2[C:36]3[C:31](=[CH:32][C:33]([F:40])=[C:34]([N:10]4[CH2:11][CH2:12][CH:8]([N:7]5[C:3]([CH3:2])=[CH:4][N:5]=[N:6]5)[CH2:9]4)[C:35]=3[O:37][CH3:38])[C:30](=[O:41])[C:29]([C:42]([OH:44])=[O:43])=[CH:28]2)[CH2:25][CH2:26]1
Reactant: Cc1cnnn1C1CCNC1
Reactant: COc1c(F)c(F)cc2c(=O)c(C(=O)O)cn(C3CC3)c12
Agent: Cl
Solvent: C1CCC2=NCCCN2CC1
Solvent: CC#N
Product: COc1c(N2CCC(n3nncc3C)C2)c(F)cc2c(=O)c(C(=O)O)cn(C3CC3)c12
Yield: 6.9 %

Procedure:
3-(5-methyl-1,2,3-triazol-1-yl)pyrrolidine hydrochloride (64 mg, 0.34 mmol) and DBU (77 mg, 0.51 mmol) was added to a suspension of 1-cyclopropyl-6,7-difluoro-8-methoxy-1,4-dihydro-4-oxoquinoline-3-carboxylic acid (50 mg, 0.17 mmol) in acetonitrile (5 ml). The reaction mixture was refluxed for 18 hrs and then concentrated to dryness. The residue was triturated with water and thus separated solid was filtered, washed with water, acetonitrile and dried to give 5 mg of title product. m.p. 226°-228° C.; 1H NMR (TFA) δ: 9.35 (s, 1H), 8.32 (s, 1H), 8.08 (d, 1H), 5.72 (m, 1H), 4.30-4.80 (m, 4H), 4.10 (m, 1H), 3.80 (s, 3H), 2.90 (m, 2H), 2.72 (s, 3H), 1.12-1.64 (m, 4H).
Reaction SMILES: CON(C)[C:4](=[O:15])[C:5]1[CH:10]=[CH:9][C:8]([C:11]([F:14])([F:13])[F:12])=[CH:7][CH:6]=1.[CH3:17][CH:18]([CH3:23])[CH2:19][CH2:20][Mg]Br>C1COCC1>[CH3:17][CH:18]([CH3:23])[CH2:19][CH2:20][C:4]([C:5]1[CH:10]=[CH:9][C:8]([C:11]([F:14])([F:13])[F:12])=[CH:7][CH:6]=1)=[O:15]
Reactant: CC(C)CC[Mg]Br
Reactant: CON(C)C(=O)c1ccc(C(F)(F)F)cc1
Solvent: C1CCOC1
Product: CC(C)CCC(=O)c1ccc(C(F)(F)F)cc1
Yield: 77 %

Procedure:
With the similar conditions of Example 29, steps (a) and (c), reaction of N-Methoxy-N-methyl-4-trifluoromethyl-benzamide, compound 31 a, with 3-methyl-1-butyl magnesium bromide, compound 29a, in THF gave the title compound in 77% yield; Calcd MW 244.26. Found MH+ 245.2.
Reaction SMILES: [O:1]=[C:2]1[NH:7][N:6]=[C:5]([C:8](O)=O)[CH:4]=[CH:3]1.[Cl:11][C:12]1[CH:13]=[C:14]([NH2:19])[C:15]([NH2:18])=[CH:16][CH:17]=1.C([O-])(O)=O.[Na+]>O>[Cl:11][C:12]1[CH:17]=[CH:16][C:15]2[N:18]=[C:8]([C:5]3[CH:4]=[CH:3][C:2](=[O:1])[NH:7][N:6]=3)[NH:19][C:14]=2[CH:13]=1
Reactant: O=C(O)c1ccc(=O)[nH]n1
Reactant: Nc1ccc(Cl)cc1N
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Product: O=c1ccc(-c2nc3ccc(Cl)cc3[nH]2)n[nH]1
Yield: 17 %

Procedure:
A mixture of 6-oxo-1,6-dihydropyridazine-3-carboxylic acid (0.790 g, 5.000 mmol) and 4-chlorobenzene-1,2-diamine (0.720 g, 5.000 mmol) was added to pre-heated (150° C.) polyphosphoric acid (5 g) with stirring, and the reaction was stirred at 150 C for 2 hours. Water was added to the reaction mixture, and the resulting solution was neutralized with NaHCO3, and extracted with ethyl acetate. The organic phase was dried and evaporated to afford 6-(6-chloro-1H-benzoimidazol-2-yl)-2H-pyridazin-3-one as a dark solid (0.210 g, 0.85 mmol, 17% yield).
Reaction SMILES: [C:1]([C:4]1[NH:5][NH:6][C:7](=[O:9])[CH:8]=1)([OH:3])=[O:2].[C:10](OCC)(=O)[CH2:11]C(C(OCC)=O)=O.NN>>[C:1]([C:4]1[N:5]=[N:6][C:7](=[O:9])[CH:8]=1)([O:3][CH2:10][CH3:11])=[O:2]
Reactant: O=C(O)c1cc(=O)[nH][nH]1
Reactant: CCOC(=O)CC(=O)C(=O)OCC
Agent: NN
Product: CCOC(=O)C1=CC(=O)N=N1

Procedure:
3-carboxy-1H-pyrazol-5-one, for example, can thus be prepared by reacting diethyl oxalacetate with hydrazine to yield 3-(carboethoxy)-pyrazol-5-one, followed by refluxing in aqueous HCl solution to hydrolyze the ethyl ester.
Reaction SMILES: [C:1]1([CH2:7][CH:8]([OH:11])[CH2:9][NH2:10])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.O=[C:13]([CH3:30])[CH2:14][O:15][C:16]1[CH:29]=[CH:28][C:19]([CH2:20][CH:21]2[S:25][C:24](=[O:26])[NH:23][C:22]2=[O:27])=[CH:18][CH:17]=1>C1C=CC=CC=1>[C:1]1([CH2:7][CH:8]([OH:11])[CH2:9][NH:10][CH:13]([CH3:30])[CH2:14][O:15][C:16]2[CH:17]=[CH:18][C:19]([CH2:20][CH:21]3[S:25][C:24](=[O:26])[NH:23][C:22]3=[O:27])=[CH:28][CH:29]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: CC(=O)COc1ccc(CC2SC(=O)NC2=O)cc1
Reactant: NCC(O)Cc1ccccc1
Solvent: c1ccccc1
Product: CC(COc1ccc(CC2SC(=O)NC2=O)cc1)NCC(O)Cc1ccccc1
Reaction time: 2 h
Yield: 39.8 %

Procedure:
550 mg of 3-phenyl-2-hydroxypropylamine (prepared as described in Preparation 17) and 1.0 g of 5-[4-(2-oxopropoxy)benzyl]thiazolidine-2,4-dione were suspended in 30 ml of anhydrous benzene, and the resulting suspension was heated under reflux for 30 minutes while removing water. Subsequently, the solvent was removed by evaporation under reduced pressure. The resulting oily product was dissolved in 20 ml of anhydrous methanol, 670 mg of sodium cyanoborohydride was added to the solution, whilst ice-cooling, and the mixture was stirred for 2 hours in a stream of nitrogen gas. After this, the reaction mixture was left to stand overnight, and then the solvent was removed by evaporation under reduced pressure. Water was added to the resulting residue, which was then extracted with ethyl acetate. The extract was washed with a saturated aqueous solution of sodium chloride and dried over anhydrous sodium sulfate. The solvent was removed from the extract by evaporation under reduced pressure, and the resulting residue was applied to a silica gel chromatography column, which was eluted with a 5:1 by volume mixture of ethyl acetate and ethanol, and crystallized from ethyl acetate, to give 590 mg of the title compound, melting at 145° C. to 152° C.
Reaction SMILES: [F:1][C:2]([F:13])([F:12])[C:3]1[CH:4]=[C:5]([CH2:9][C:10]#[N:11])[CH:6]=[CH:7][CH:8]=1.CO[CH:16](OC)[N:17]([CH3:19])[CH3:18].CN(C)CCN(C)C>>[CH3:18][N:17]([CH3:19])[CH:16]=[C:9]([C:5]1[CH:6]=[CH:7][CH:8]=[C:3]([C:2]([F:1])([F:12])[F:13])[CH:4]=1)[C:10]#[N:11]
Reactant: N#CCc1cccc(C(F)(F)F)c1
Reactant: COC(OC)N(C)C
Agent: CN(C)CCN(C)C
Product: CN(C)C=C(C#N)c1cccc(C(F)(F)F)c1
Temperature: 25 °C
Yield: 49.6 %

Procedure:
A mixture of 2-(3-(trifluoromethyl)phenyl)acetonitrile (4.55 g, 24.58 mmol), 1,1-dimethoxy-N,N-dimethylmethanamine (13.10 ml, 98 mmol), and N1,N1,N2,N2-tetramethylethane-1,2-diamine (0.737 ml, 4.92 mmol) were heated to reflux for 5 h. After cooling to RT, the mixture was partitioned between saturated aqueous NH4Cl and EtOAc and extracted three times with EtOAc. The combined organics were washed with brine, dried over Na2SO4, and concentrated in vacuo. After absorbing on celite, the compound was purified by Isco (40 g silica, 10% to 70% EtOAc/hexanes) to give pure 3-(dimethylamino)-2-(3-(trifluoromethyl)phenyl)acrylonitrile (2.93 g, 50% yield).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][CH:10]=1)[C:5]([OH:7])=[O:6].[N+:11]([O-])([OH:13])=[O:12].O>S(=O)(=O)(O)O>[F:1][C:2]1[CH:10]=[CH:9][C:8]([N+:11]([O-:13])=[O:12])=[C:4]([CH:3]=1)[C:5]([OH:7])=[O:6]
Reactant: O=C(O)c1cccc(F)c1
Reactant: O=[N+]([O-])O
Agent: O=S(=O)(O)O
Solvent: O
Product: O=C(O)c1cc(F)ccc1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 1 h
Yield: 92.9 %

Procedure:
To a solution of 3-fluorobenzoic acid (7.9 g, 56 mmol) in conc. sulphuric acid (50 mL) cooled to 0° C. was added fuming nitric acid (4.7 g, 67 mmol) dropwise. After the addition the solution was warmed to room temperature and stirring continued for 1 h. The solution was poured into water (750 mL) and extracted with ethyl acetate (3×100 mL). The combined extracts were dried (MgSO4) and concentrated in vacuo to yield 5-fluoro-2-nitrobenzoic acid as a pale yellow solid (9.6 g, 52 mmol, 93%).
Reaction SMILES: [OH:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH:7]1[CH2:12][C:11](=[O:13])[C:10]2[CH:14]=[CH:15][CH:16]=[CH:17][C:9]=2[O:8]1.Cl.C([O:24]N=O)CC(C)C>C(O)C>[OH:24][C:12]1[C:11](=[O:13])[C:10]2[CH:14]=[CH:15][CH:16]=[CH:17][C:9]=2[O:8][C:7]=1[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2][OH:1]
Reactant: CC(C)CCON=O
Reactant: O=C1CC(CCCCCO)Oc2ccccc21
Agent: Cl
Solvent: CCO
Product: O=c1c(O)c(CCCCCO)oc2ccccc12
Reaction time: 1 h

Procedure:
2,3-dihydro-2-(5-hydroxypentyl)-4H-1-benzopyran-4-one (0.23 g) is dissolved in ethanol 95% (5 ml), and the solution is refluxed under stirring. HCl (6.2 ml) and isoamylnitrite (1.2 ml) are then added drop by drop. Stirring and heating are then stopped and the reaction mixture is allowed to stand for ca. 1 hour. The solvent is evaporated, water is then added and the product extracted with diethyl ether. The ethereal phase is dried by addition of anhydrous Na2SO4. After filtration and evaporation of the solvent an oil is obtained which is purified by chromatography with silica gel column and the mixture diethyl ether:methanol 98:2 as the eluent. 3-hydroxy-2-(5-hydroxypentyl)-4H-1-benzopyran-4-one (99.2 mg) is obtained. By crystallisation in cycloesane or diethyl ether the product in crystalline form is obtained (m.p.=111-112° C.).
Reaction SMILES: [OH:1][C:2]1[C:7]([O:8][CH3:9])=[CH:6][C:5]([I:10])=[CH:4][C:3]=1[O:11][CH3:12].[CH:13](I)([CH3:15])[CH3:14].[H-].[Na+].O>CN(C)C=O>[I:10][C:5]1[CH:6]=[C:7]([O:8][CH3:9])[C:2]([O:1][CH:13]([CH3:15])[CH3:14])=[C:3]([O:11][CH3:12])[CH:4]=1
Reactant: CC(C)I
Reactant: COc1cc(I)cc(OC)c1O
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: COc1cc(I)cc(OC)c1OC(C)C
Temperature: 50 °C
Reaction time: 2.5 h
Yield: 83.4 %

Procedure:
To a solution of 25.0 g (89.3 mmol) of 4-hydroxy-1-iodo-3,5-dimethoxybenzene in dimethylformamide (125 mL) were added 26.7 mL (267 mmol) of isopropyl iodide and 4.7 g (108 mmol) of a 55 wt. % sodium hydride dispersion in mineral oil. The reaction mixture was stirred at 50° C. for 2.5 hours. With ice cooling, water (125 mL) was added and the mixture was extracted with toluene-hexane (2:1). The organic layers were combined, dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue was purified by column chromatography on silica gel to yield crude crystals. The crude crystals were recrystallized from methanol, whereby 24.0 g of 1-iodo-4-isopropoxy-3,5-dimethoxybenzene was obtained as a colorless crystalline powder (mp: 56.0 to 57.0° C., yield: 83%).
Reaction SMILES: [Br-].[F:2][C:3]1[CH:4]=[C:5]([CH:26]=[CH:27][CH:28]=1)[CH2:6][P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.CC(C)([O-])C.[K+].[CH:35]1[C:44]2[C:39](=[CH:40][CH:41]=[CH:42][CH:43]=2)[CH:38]=[CH:37][C:36]=1[CH:45]=O.O>C1COCC1>[F:2][C:3]1[CH:4]=[C:5]([CH:6]=[CH:45][C:36]2[CH:37]=[CH:38][C:39]3[C:44](=[CH:43][CH:42]=[CH:41][CH:40]=3)[CH:35]=2)[CH:26]=[CH:27][CH:28]=1
Reactant: Fc1cccc(C[P+](c2ccccc2)(c2ccccc2)c2ccccc2)c1
Reactant: O=Cc1ccc2ccccc2c1
Agent: CC(C)(C)[O-]
Agent: [Br-]
Agent: [K+]
Solvent: C1CCOC1
Solvent: O
Product: Fc1cccc(C=Cc2ccc3ccccc3c2)c1
Temperature: -30 °C
Yield: 83.9 %

Procedure:
In the step, 35.00 g (77.55 mmol) of (3-fluorobenzyl)triphenylphosphonium bromide was suspended in 150 ml of THF, and the suspension was cooled to −30° C. and added with 10.25 g (=88.61 mmols) of potassium t-butoxide under stirring. After the addition was finished, the reaction solution was stirred at the same temperature for 1 hour, a 50 ml THF solution of 8.65 g (=55.38 mmol) of 2-naphthoaldehyde was dropped into the same, and then the mixture was slowly heated to room temperature. After being stirred for 18 hours, the reaction mixture was added into iced water, and the mixture was extracted thrice with toluene. The extract was washed thrice with water and then dried with anhydrous MgSO4. After the solvent was evaporated under a reduced pressure, the obtained yellow solid of 43.34 g was purified with silica gel chromatography using heptane as the eluent to obtain 11.54 g of 2-[2-(3-fluorophenyl)vinyl]naphthalene as a white solid.
Reaction SMILES: C([O:4][C:5]1[CH:6]=[C:7]([C:11]2[N:20]=[C:19]([NH:21][C:22]3[CH:23]=[C:24]4[C:28](=[CH:29][CH:30]=3)[N:27]([C:31]([O:33][C:34]([CH3:37])([CH3:36])[CH3:35])=[O:32])[N:26]=[CH:25]4)[C:18]3[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=3)[N:12]=2)[CH:8]=[CH:9][CH:10]=1)(=O)C.[NH4+].[OH-]>CO>[OH:4][C:5]1[CH:6]=[C:7]([C:11]2[N:20]=[C:19]([NH:21][C:22]3[CH:23]=[C:24]4[C:28](=[CH:29][CH:30]=3)[N:27]([C:31]([O:33][C:34]([CH3:37])([CH3:36])[CH3:35])=[O:32])[N:26]=[CH:25]4)[C:18]3[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=3)[N:12]=2)[CH:8]=[CH:9][CH:10]=1
Reactant: CC(=O)Oc1cccc(-c2nc(Nc3ccc4c(cnn4C(=O)OC(C)(C)C)c3)c3ccccc3n2)c1
Agent: [NH4+]
Agent: [OH-]
Solvent: CO
Product: CC(C)(C)OC(=O)n1ncc2cc(Nc3nc(-c4cccc(O)c4)nc4ccccc34)ccc21
Temperature: 25 °C
Reaction time: 48 h

Procedure:
To a solution of give tert-butyl 5-(2-(3-acetoxyphenyl)quinazolin-4-ylamino)-1H-indazole-1-carboxylate (5.85 g, 11.8 mmole) in anhydrous MeOH (400 mL) was added 28% (wt/v) NH4OH solution (6.50 mL). The reaction mixture was stirred at ambient temperature for 48 h. The crude product was filtered and washed with ether followed by hexane and dried under high vacuum overnight to give tert-butyl 5-(2-(3-hydroxyphenyl)-quinazolin-4-ylamino)-1H-indazole-1-carboxylate. (4.85 g, mmol, 91%).
Reaction SMILES: [NH2:1][C:2]1[C:3]2[N:4]([C:8]([C@H:12]3[CH2:17][CH2:16][C@H:15]([C:18]([NH2:20])=[O:19])[CH2:14][CH2:13]3)=[N:9][C:10]=2I)[CH:5]=[CH:6][N:7]=1.C(OC([N:28]1[C:36]2[C:31](=[CH:32][CH:33]=[CH:34][CH:35]=2)[CH:30]=[C:29]1B(O)O)=O)(C)(C)C.C(=O)([O-])[O-].[Na+].[Na+]>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.COCCOC.O>[NH2:1][C:2]1[C:3]2[N:4]([C:8]([C@H:12]3[CH2:17][CH2:16][C@H:15]([C:18]([NH2:20])=[O:19])[CH2:14][CH2:13]3)=[N:9][C:10]=2[C:29]2[NH:28][C:36]3[C:31]([CH:30]=2)=[CH:32][CH:33]=[CH:34][CH:35]=3)[CH:5]=[CH:6][N:7]=1
Reactant: Nc1nccn2c1c(I)nc2[C@H]1CC[C@H](C(N)=O)CC1
Reactant: CC(C)(C)OC(=O)n1c(B(O)O)cc2ccccc21
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: COCCOC
Product: Nc1nccn2c1c(-c1cc3ccccc3[nH]1)nc2[C@H]1CC[C@H](C(N)=O)CC1

Procedure:
trans-4-(8-Amino-1-iodoimidazo[1,5-a]pyrazin-3-yl)cyclohexanecarboxamide (40 mg, 0.10 mmol), 1-(tert-butoxycarbonyl)-1H-indole-2-boronic acid (33 mg, 0.12 mmol), and sodium carbonate (33 mg, 0.3 mmol) were added to DME:Water (5:1) (2 mL) and the mixture degassed with Argon for 10 min. Tetrakis(triphenylphosphine)palladium(0) (8.0 mg, 0.007 mmol) was then added and the reaction mixture microwaved at 110° C. for 1 h, The mixture was concentrated in vacuo, taken up in DMSO, and purified by mass-directed preparative HPLC to afford desired product. 1H NMR (d6-DMSO, 400 MHz): □ 11.50 (br s, 1H), 7.72 (m, 1H), 7.58 (m, 1H), 7.46 (dd, J=7.6, 0.4 Hz, 1H), 7.25 (br s, 1H), 7.13 (m, 1H), 7.08-7.00 (m, 2H), 6.70 (br s, 1H), 6.69 (br s, 1H), 3.16 (m, 1H), 2.20 (m, 1H), 2.10-1.80 (m, 4H) and 1.65 (m, 4H). MS (ES+): m/z 375.17 [MH+].
Reaction SMILES: [OH:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:5]([CH3:15])([CH2:12][CH2:13][CH3:14])[C:4](=[O:16])[C:3]=1[C:17]1[NH:22][C:21]2[CH:23]=[CH:24][C:25]([O:27][CH2:28][C:29]([NH2:31])=[O:30])=[CH:26][C:20]=2[S:19](=[O:33])(=[O:32])[N:18]=1.[OH-].[Na+:35]>O>[NH2:31][C:29](=[O:30])[CH2:28][O:27][C:25]1[CH:24]=[CH:23][C:21]2[NH:22][C:17]([C:3]3[C:4](=[O:16])[C:5]([CH3:15])([CH2:12][CH2:13][CH3:14])[C:6]4[C:11](=[CH:10][CH:9]=[CH:8][CH:7]=4)[C:2]=3[O-:1])=[N:18][S:19](=[O:32])(=[O:33])[C:20]=2[CH:26]=1.[Na+:35]
Reactant: CCCC1(C)C(=O)C(C2=NS(=O)(=O)c3cc(OCC(N)=O)ccc3N2)=C(O)c2ccccc21
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: CCCC1(C)C(=O)C(C2=NS(=O)(=O)c3cc(OCC(N)=O)ccc3N2)=C([O-])c2ccccc21
Temperature: 25 °C
Reaction time: 1 h
Yield: 95.6 %

Procedure:
A suspension of the product of Example 26I (0.096 g) in water (2 mL) was treated with 0.997N sodium hydroxide solution (0.166 mL, 0.166 mmol) and stirred at 25° C. for 1 hour. The solution was lyophilized to give the title compound (0.078 g, 79% two steps). 1H NMR (300 MHz, DMSO-d6): δ ppm 0.66 (m, 3 H) 1.32 (m, 4 H) 1.63 (m, 2 H) 2.08 (m, 1 H) 4.47 (m, 2 H) 7.30 (m, 8 H) 8.00 (m, 1 H) 15.38 (m, 1 H). MS (ESI−) m/z 468 (M−H)−.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([Cl:34])[C:5]([N:8]2[CH2:13][CH2:12][N:11]([C:14]3[CH:19]=[C:18]([C:20]4[CH:25]=[CH:24][C:23]([F:26])=[CH:22][CH:21]=4)[N:17]=[C:16]([N:27]4[CH2:31][CH2:30][CH2:29][C@@H:28]4[CH3:32])[N:15]=3)[C@H:10]([CH3:33])[CH2:9]2)=[N:6][CH:7]=1.[CH3:35][N:36](C=O)C>[C-]#N.[C-]#N.[Zn+2].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>[F:26][C:23]1[CH:24]=[CH:25][C:20]([C:18]2[N:17]=[C:16]([N:27]3[CH2:31][CH2:30][CH2:29][C@@H:28]3[CH3:32])[N:15]=[C:14]([N:11]3[CH2:12][CH2:13][N:8]([C:5]4[C:4]([Cl:34])=[CH:3][C:2]([C:35]#[N:36])=[CH:7][N:6]=4)[CH2:9][C@H:10]3[CH3:33])[CH:19]=2)=[CH:21][CH:22]=1
Reactant: CN(C)C=O
Reactant: C[C@@H]1CN(c2ncc(Br)cc2Cl)CCN1c1cc(-c2ccc(F)cc2)nc(N2CCC[C@@H]2C)n1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [C-]#N
Agent: [Zn+2]
Product: C[C@@H]1CN(c2ncc(C#N)cc2Cl)CCN1c1cc(-c2ccc(F)cc2)nc(N2CCC[C@@H]2C)n1
Temperature: 25 °C

Procedure:
To a mixture of 4-[4-(5-bromo-3-chloro-pyridin-2-yl)-2-(R)-methyl-piperazin-1-yl]-6-(4-fluoro-phenyl)-2-(2-(S)-methyl-pyrrolidin-1-yl)-pyrimidine (700 mg) and Zn(CN)2 (94 mg) in DMF, add Pd(PPh3)4 (77 mg, 0.067 mmol). Purge the reaction mixture for 10 min with dry N2. Heat the stirring reaction mixture overnight at 80° C., cool to room temperature and partition between water and EtOAc. Dry the solution (Na2SO4), concentrate under reduced pressure. Purify the residue by flash column eluting with EtOAc-Hexanes (1:1) to afford the title compound as a white solid.
Reaction SMILES: B(O)O.Br[C:5]1[CH:6]=[C:7]([CH:10]=[CH:11][N:12]=1)[CH:8]=[O:9].[O:13]1[CH:17]=[CH:16][CH:15]=[C:14]1B(O)O>>[O:13]1[CH:17]=[CH:16][CH:15]=[C:14]1[C:5]1[CH:6]=[C:7]([CH:10]=[CH:11][N:12]=1)[CH:8]=[O:9]
Reactant: O=Cc1ccnc(Br)c1
Reactant: OB(O)c1ccco1
Agent: OBO
Product: O=Cc1ccnc(-c2ccco2)c1

Procedure:
2-(furan-2-yl)isonicotinaldehyde was prepared using the general boronic acid coupling procedure for 2-bromoisonicotinaldehyde and furan-2-ylboronic acid (39.6 mg, 93.2 mg theoretical, 42.5%). LC-MS m/z 174.2 (M+1).
Reaction SMILES: [N+:1]([C:4]1[CH:10]=[C:9]([C:11]2[CH:20]=[CH:19][C:18]3[C:13](=CC=CC=3)[CH:12]=2)[CH:8]=[CH:7][C:5]=1[NH2:6])([O-])=O.[BH4-].[Na+]>CO.[Pd]>[C:11]1([C:9]2[CH:8]=[CH:7][C:5]([NH2:6])=[C:4]([NH2:1])[CH:10]=2)[CH:12]=[CH:13][CH:18]=[CH:19][CH:20]=1
Reactant: Nc1ccc(-c2ccc3ccccc3c2)cc1[N+](=O)[O-]
Agent: [Pd]
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Product: Nc1ccc(-c2ccccc2)cc1N

Procedure:
To a suspension of 2 g (9.3 mmol) of product obtained in Example 28 in 20 ml of methanol are slowly added 0.2 g of palladium on carbon and 0.7 g of NaBH4. After the addition of NaBH4 has ended, the reaction is already complete. The reaction mixture is filtered through shell lime and washed with ethyl acetate, and the solvents are removed under reduced pressure. This gives 1.52 g (70%).
Reaction SMILES: [N:1]12[CH2:9][C:5]([C:10]3[CH:11]=[CH:12][C:13](O)=[N:14][CH:15]=3)([CH2:6][CH2:7][CH2:8]1)[CH2:4][CH2:3][CH2:2]2.P(Cl)(Cl)([Cl:19])=O.[OH-].[Na+]>>[Cl:19][C:13]1[N:14]=[CH:15][C:10]([C:5]23[CH2:9][N:1]([CH2:8][CH2:7][CH2:6]2)[CH2:2][CH2:3][CH2:4]3)=[CH:11][CH:12]=1
Reactant: O=P(Cl)(Cl)Cl
Reactant: Oc1ccc(C23CCCN(CCC2)C3)cn1
Agent: [Na+]
Agent: [OH-]
Product: Clc1ccc(C23CCCN(CCC2)C3)cn1
Temperature: 140 °C
Reaction time: 0.75 h
Yield: 42.4 %

Procedure:
1 g (4.59 mmol) of 5-(1-azabicyclo[3.3.1]non-5-yl)pyridin-2-ol obtained in Example 1, in solution in 12.8 mol (137.7 mmol) of phosphorus oxychloride, is introduced into a sealed tube and the combined mixture is subsequently stirred at 140° C. for 45 minutes. The reaction mixture is subsequently brought back to ambient temperature, poured onto 200 g of crushed ice and stirred for 15 minutes. The medium is then very slowly adjusted to pH 10 with a concentrated sodium hydroxide solution. The combined mixture is subsequently extracted twice with chloroform and the organic phases are subsequently combined, dried over sodium sulfate, filtered and concentrated under reduced pressure to provide 461 mg of the desired compound in the form of a brown powder.
Reaction SMILES: [C:1]([C:5]1[CH:36]=[CH:35][C:8]([C:9]([N:11]2[C@@H:15]([C:16]3[S:20][CH:19]=[N:18][CH:17]=3)[C@@H:14]([C:21]3[CH:26]=[N:25][CH:24]=[CH:23][N:22]=3)[CH2:13][C@@:12]2([CH3:34])[C:27]([O:29]C(C)(C)C)=[O:28])=[O:10])=[CH:7][C:6]=1[O:37][CH3:38])([CH3:4])([CH3:3])[CH3:2].C(O)(C(F)(F)F)=O>>[C:1]([C:5]1[CH:36]=[CH:35][C:8]([C:9]([N:11]2[C@@H:15]([C:16]3[S:20][CH:19]=[N:18][CH:17]=3)[C@@H:14]([C:21]3[CH:26]=[N:25][CH:24]=[CH:23][N:22]=3)[CH2:13][C@@:12]2([CH3:34])[C:27]([OH:29])=[O:28])=[O:10])=[CH:7][C:6]=1[O:37][CH3:38])([CH3:2])([CH3:3])[CH3:4]
Reactant: COc1cc(C(=O)N2[C@@H](c3cncs3)[C@@H](c3cnccn3)C[C@@]2(C)C(=O)OC(C)(C)C)ccc1C(C)(C)C
Solvent: O=C(O)C(F)(F)F
Product: COc1cc(C(=O)N2[C@@H](c3cncs3)[C@@H](c3cnccn3)C[C@@]2(C)C(=O)O)ccc1C(C)(C)C

Procedure:
The tert-butyl ester from stage A was deprotected with TFA in a similar manner to that described in Example 1 to afford the title compound as a solid.
Reaction SMILES: [CH2:1]([C:8]1[CH:9]=[N:10][C:11]2[C:16]([C:17]=1[C:18]1[CH:19]=[C:20]([NH2:24])[CH:21]=[CH:22][CH:23]=1)=[CH:15][CH:14]=[CH:13][C:12]=2[C:25]([F:28])([F:27])[F:26])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH2:29]([O:31][C:32]1[CH:39]=[C:38]([O:40][CH2:41][CH3:42])[CH:37]=[CH:36][C:33]=1[CH:34]=O)[CH3:30]>>[CH2:1]([C:8]1[CH:9]=[N:10][C:11]2[C:16]([C:17]=1[C:18]1[CH:19]=[C:20]([NH:24][CH2:34][C:33]3[CH:36]=[CH:37][C:38]([O:40][CH2:41][CH3:42])=[CH:39][C:32]=3[O:31][CH2:29][CH3:30])[CH:21]=[CH:22][CH:23]=1)=[CH:15][CH:14]=[CH:13][C:12]=2[C:25]([F:28])([F:26])[F:27])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: Nc1cccc(-c2c(Cc3ccccc3)cnc3c(C(F)(F)F)cccc23)c1
Reactant: CCOc1ccc(C=O)c(OCC)c1
Product: CCOc1ccc(CNc2cccc(-c3c(Cc4ccccc4)cnc4c(C(F)(F)F)cccc34)c2)c(OCC)c1

Procedure:
This compound was prepared according to the procedure of example 66, substituting 3-(3-benzyl-8-trifluoromethyl-quinolin-4-yl)-phenylamine and 2,4-diethoxybenzaldehyde. MS (ESI) m/z 557.
Reaction SMILES: [SH:1][CH2:2][CH2:3][OH:4].[Na+].[Cl-].P([O-])([O-])([O-])=O.[Na+].[Na+].[Na+].Br[C:16]1[C:21](=[O:22])[NH:20][C:18](=[O:19])[C:17]=1Br>CN(C=O)C>[OH:4][CH2:3][CH2:2][S:1][C:17]1[C:18](=[O:19])[NH:20][C:21](=[O:22])[C:16]=1[S:1][CH2:2][CH2:3][OH:4]
Reactant: OCCS
Reactant: O=C1NC(=O)C(Br)=C1Br
Agent: O=P([O-])([O-])[O-]
Agent: [Cl-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: O=C1NC(=O)C(SCCO)=C1SCCO
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 53.3 %

Procedure:
To 2-mercaptoethanol (683.8 μl, 9.8 mmol) in buffer (100 ml, 150 mM NaCl, 100 mM sodium phosphate, pH 8.0, 5.0% DMF) was added di-bromomaleimide (1 g, 3.9 mmol) in DMF (2.5 ml, final concentration DMF 7.5%). The reaction was stirred for 30 min at RT and lithium chloride (20 g) was added. The aqueous reaction mixture was extracted with ethyl acetate (7×150 ml). The organic layers were combined, the solvent removed in vacuo and the residual material was purified by flash chromatography on silica gel (petroleum ether:ethyl acetate, gradient elution from 1:1 to 1:9). Fractions containing the product were collected and the solvent were removed in vacuo. The still impure product was purified by flash chromatography on silica gel (methanol:dichloromethane, gradient elution from 0.5-10.0% methanol) to afford the desired compound as a yellow solid (518 mg, 53%). λmax (50 mM sodium phosphate, pH 6.2, 40% MeCN, 2.5% DMF)/318 nm (ε/dm3 mol−1 cm−1 1855); 1H NMR (500 MHz, MeOD): δ=3.74 (t, 4H, J=6.4, 2×HO—CH2), 3.41 (t, 4H, J=6.3, 2×S—CH2) 13C NMR (125 MHz, MeOD): δ=168.5 (C), 137.2 (C), 62.3 (CH2), 34.4 (CH2); IR (solid, cm−1): 3344 (s), 2500 (m), 2078 (w); MS (EI) m/z, (%): 250 (M, 43), 232 (100), 161 (37); Mass calc. for C8H11O4NS2: 250.02077. Found: 250.02126; m.p. 46-50° C.