Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1.[N:7]1[C:14]([Cl:15])=[N:13][C:11](Cl)=[N:10][C:8]=1[Cl:9]>C(Cl)(Cl)Cl.O>[Cl:9][C:8]1[N:7]=[C:14]([Cl:15])[N:13]=[C:11]([N:1]2[CH2:6][CH2:5][O:4][CH2:3][CH2:2]2)[N:10]=1
Reactant: C1COCCN1
Reactant: Clc1nc(Cl)nc(Cl)n1
Solvent: O
Solvent: ClC(Cl)Cl
Product: Clc1nc(Cl)nc(N2CCOCC2)n1
Temperature: -5 °C
Reaction time: 1 h
Yield: 39.4 %

Procedure:
Morpholine (9.5 mL, 108 mmol)) was added to a solution of cyanuric chloride (20 g, 108 mmol) in chloroform (10 mL) and stirred at −5° C. for 1 hour. Reaction mixture was diluted with water, extracted with dichloromethane. The organic layer was dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure. Crude product was purified by silica gel (100-200 mesh) column chromatography using 5% ethyl acetate in pet-ether as an eluent to give 4-(4,6-dichloro-1,3,5-triazin-2-yl)morpholine (10 g, 39% yield).
Reaction SMILES: [N:1]1([CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][N:10]2[C:18]([O:19][CH3:20])=[N:17][C:16]3[C:11]2=[N:12][C:13]([O:22][CH2:23][CH2:24][CH2:25][CH3:26])=[N:14][C:15]=3[NH2:21])[CH2:4][CH2:3][CH2:2]1.[CH2:27](OC1N=C2C(N=C(OC)N2CCCCCCl)=C(N)N=1)[CH2:28]CC.N1CCCCC1>>[CH2:23]([O:22][C:13]1[N:12]=[C:11]2[C:16]([N:17]=[C:18]([O:19][CH3:20])[N:10]2[CH2:9][CH2:8][CH2:7][CH2:6][CH2:5][N:1]2[CH2:4][CH2:28][CH2:27][CH2:3][CH2:2]2)=[C:15]([NH2:21])[N:14]=1)[CH2:24][CH2:25][CH3:26]
Reactant: CCCCOc1nc(N)c2nc(OC)n(CCCCCN3CCC3)c2n1
Reactant: CCCCOc1nc(N)c2nc(OC)n(CCCCCCl)c2n1
Solvent: C1CCNCC1
Product: CCCCOc1nc(N)c2nc(OC)n(CCCCCN3CCCCC3)c2n1

Procedure:
Prepared similarly to Intermediate 27 from 2-(butyloxy)-9-(5-chloropentyl)-8-(methyloxy)-9H-purin-6-amine and piperidine.
Reaction SMILES: [H-].[Na+].[CH3:3][O:4][CH2:5][O:6][C:7]1[C:8]([CH3:29])=[C:9]2[C:14](=[C:15]([CH3:18])[C:16]=1[CH3:17])[O:13][C:12]([CH2:27][OH:28])([CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH3:26])[CH2:11][CH2:10]2.CN(C)C=O.Cl[C:36]1[CH:41]=[CH:40][C:39]([N+:42]([O-:44])=[O:43])=[CH:38][CH:37]=1>C1C=CC=CC=1>[CH3:3][O:4][CH2:5][O:6][C:7]1[C:8]([CH3:29])=[C:9]2[C:14](=[C:15]([CH3:18])[C:16]=1[CH3:17])[O:13][C:12]([CH2:27][O:28][C:36]1[CH:41]=[CH:40][C:39]([N+:42]([O-:44])=[O:43])=[CH:38][CH:37]=1)([CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH3:26])[CH2:11][CH2:10]2
Reactant: O=[N+]([O-])c1ccc(Cl)cc1
Reactant: CCCCCCCCC1(CO)CCc2c(C)c(OCOC)c(C)c(C)c2O1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: c1ccccc1
Product: CCCCCCCCC1(COc2ccc([N+](=O)[O-])cc2)CCc2c(C)c(OCOC)c(C)c(C)c2O1
Temperature: 50 °C

Procedure:
0.38 g of a 55% w/w suspension of sodium hydride in mineral oil was added to a mixture of 3 g of 6-methoxymethoxy-5,7,8-trimethyl-2-octylchroman-2-ylmethanol (prepared as described in Preparation 13) and 25 ml of dimethylformamide under a nitrogen stream at room temperature, and the resulting mixture was heated for 2 hours at 50° C. A mixture of 1.4 g of p-chloronitrobenzene and 2 ml of benzene was then added dropwise, whilst ice-cooling, and the resulting mixture was heated for 2 hours at 50° C. The reaction mixture was then poured into ice-water and extracted with benzene. The extract was washed with water and dried over anhydrous sodium sulfate. The solvent was removed by distillation under reduced pressure, and the residue was purified by silica gel column chromatography eluted with benzene, to give the title compound.
Reaction SMILES: [C:1]([CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH:12]1[CH2:16][CH2:15][CH2:14][C:13]1=[O:17])([O:3][CH2:4][CH3:5])=[O:2].O.C1(C)C=CC(S(O)(=O)=O)=CC=1.[C:30](O)(=[O:32])[CH3:31]>C(OC(=O)C)(=O)C>[C:30]([O:17][C:13]1[CH2:14][CH2:15][CH2:16][C:12]=1[CH2:11][CH2:10][CH2:9][CH2:8][CH2:7][CH2:6][C:1]([O:3][CH2:4][CH3:5])=[O:2])(=[O:32])[CH3:31]
Reactant: CC(=O)O
Reactant: CCOC(=O)CCCCCCC1CCCC1=O
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: CC(=O)OC(C)=O
Solvent: O
Product: CCOC(=O)CCCCCCC1=C(OC(C)=O)CCC1
Reaction time: 16 h

Procedure:
A stirred solution of 100 g. of 2-(6-carbethoxyhexyl)cyclopentan-1-one (Example 9) in 250 ml of acetic anhydride containing 0.940 g. of p-toluenesulfonic acid monohydrate is heated to boiling under partial reflux allowing distillate at 118° C. or less (i.e., acetic acid) to escape through a Vigreaux column equipped with a condenser to collect the distillate. After 16 hours, during which period active anhydride is added in portions in order to keep the solvent level at at least 100 ml., the solution is cooled and poured cautiously into a stirred cold mixture of saturated sodium bicarbonate solution (400 ml.) and hexane (250 ml.). The resulting mixture is stirred for an additional 30 minutes during which period solid sodium bicarbonate is added periodically to insure a basic solution. The hexane layer is separated and washed with saturated sodium chloride solution, dried with anhydrous magnesium sulfate and taken to dryness. Distillation of the residual oil gives 102 g. (87%) of pale yellow oil, b.p. 118° C. (0.07 mm).
Reaction SMILES: [Na].[CH3:2][CH2:3][O:4][C:5]([CH:7](P(OCC)(OCC)=O)[CH3:8])=[O:6].[CH2:17]([C:21]1[N:22]([CH2:28][C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][C:30]=2[Cl:35])[C:23]([CH:26]=O)=[CH:24][N:25]=1)[CH2:18][CH2:19][CH3:20]>C(O)C>[CH2:17]([C:21]1[N:22]([CH2:28][C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][C:30]=2[Cl:35])[C:23](/[CH:26]=[C:7](\[CH3:8])/[C:5]([O:4][CH2:3][CH3:2])=[O:6])=[CH:24][N:25]=1)[CH2:18][CH2:19][CH3:20]
Reactant: CCCCc1ncc(C=O)n1Cc1ccccc1Cl
Reactant: CCOC(=O)C(C)P(=O)(OCC)OCC
Agent: [Na]
Solvent: CCO
Product: CCCCc1ncc(/C=C(\C)C(=O)OCC)n1Cc1ccccc1Cl
Temperature: 25 °C
Reaction time: 2 h
Yield: 58.9 %

Procedure:
Ethanol (5 mL) was treated with sodium metal (0.101 g, 0.0044 g-atom), then triethyl 2-phosphonopropionate (0.953 g, 0.004 mol) in ethanol (2 mL) was added. After 5 minutes a solution of 2-n-butyl-1-(2-chlorophenyl)methyl-1H-imidazol-5-carboxaldehyde (1.1 g, 0.004 mol) in ethanol (2 mL) was added to give an initial exotherm The reaction mixture was stirred at ambient temperature under argon for 2 hours, concentrated in vacuo and the residue partitioned between water and ethyl acetate. The extract was washed, dried, and concentrated. The crude product was flash chromatographed over silica gel with an ethyl acetate/hexane gradient to provide ethyl (E)-3-[2-n-butyl-1-{(2-chlorophenyl)methyl}-1H-imidazol-5-yl]-2-methyl-2-propenoate (0.85 g, 59%) as an oil; NMR (NOE) was consistent with the structure.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[N:4][NH:5][CH:6]=1.[O:7]1[CH:12]=[CH:11][CH2:10][CH2:9][CH2:8]1.[H-].[Na+]>FC(F)(F)C(O)=O>[CH3:1][C:2]1[CH:3]=[N:4][N:5]([CH:8]2[CH2:9][CH2:10][CH2:11][CH2:12][O:7]2)[CH:6]=1
Reactant: C1=COCCC1
Reactant: Cc1cn[nH]c1
Agent: [H-]
Agent: [Na+]
Solvent: O=C(O)C(F)(F)F
Product: Cc1cnn(C2CCCCO2)c1
Temperature: 90 °C
Reaction time: 20 h
Yield: 83.2 %

Procedure:
Trifluoroacetic acid (40.0 uL, 0.519 mmol) was added to a solution of 4-methylpyrazole (0.901 g, 11.0 mmol) in dihydropyran (2.0 mL, 22 mmol). The reaction mixture was stirred at 90° C. for 20 hours. The mixture was cooled to room temperature, and then quenched with Sodium hydride (92 mg, 2.3 mmol). After stirring at room temperature for 10 minutes more, the solvent was removed under vacuum. The residue was suspended in dichloromethane, and passed through a short plug of silica, rinsed with dichloromethane. The filtrate was evaporated in vacuo to yield 1.5213 g (83%) of 4-methyl-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazole. LCMS (ESI): M+H=167.4; 1H NMR (400 MHz, DMSO-d6) δ 7.60 (s, 1H), 7.27 (s, 1H), 5.29 (d, J=9.9 Hz, 1H), 3.89 (d, J=11.2 Hz, 1H), 3.64-3.51 (m, 1H), 2.00 (overlapping s and m, 4H), 1.88 (dd, J=27.1, 13.0 Hz, 1H), 1.64 (m, 1H), 1.51 (m, 2H).
Reaction SMILES: Br[C:2]1[C:3]([F:28])=[CH:4][C:5]2[O:11][CH2:10][CH2:9][N:8]3[C:12]([CH:18]([C:20]4[C:21]([CH3:26])=[N:22][N:23]([CH3:25])[CH:24]=4)[OH:19])=[C:13]([C:15]([NH2:17])=[O:16])[N:14]=[C:7]3[C:6]=2[CH:27]=1.[CH3:29][C:30]([OH:34])([CH3:33])[C:31]#[CH:32]>>[CH3:25][N:23]1[CH:24]=[C:20]([CH:18]([OH:19])[C:12]2[N:8]3[CH2:9][CH2:10][O:11][C:5]4[CH:4]=[C:3]([F:28])[C:2]([C:32]#[C:31][C:30]([OH:34])([CH3:33])[CH3:29])=[CH:27][C:6]=4[C:7]3=[N:14][C:13]=2[C:15]([NH2:17])=[O:16])[C:21]([CH3:26])=[N:22]1
Reactant: Cc1nn(C)cc1C(O)c1c(C(N)=O)nc2n1CCOc1cc(F)c(Br)cc1-2
Reactant: C#CC(C)(C)O
Product: Cc1nn(C)cc1C(O)c1c(C(N)=O)nc2n1CCOc1cc(F)c(C#CC(C)(C)O)cc1-2
Yield: 19 %

Procedure:
3-((1,3-dimethyl-1H-pyrazol-4-yl)(hydroxy)methyl)-9-fluoro-10-(3-hydroxy-3-methylbut-1-yn-1-yl)-5,6-dihydrobenzo[f]imidazo[1,2-d][1,4]oxazepine-2-carboxamide was prepared similarly according to General Procedure G with slight modifications. 10-bromo-3-((1,3-dimethyl-1H-pyrazol-4-yl)(hydroxy)methyl)-9-fluoro-5,6-dihydrobenzo[f]imidazo[1,2-d][1,4]oxazepine-2-carboxamide was reacted with 3-methyl-1-butyne-3-ol to afford 11.3 mg of the titled compound (19% yield). M+1=436.1. 1H NMR (400 MHz, DMSO) δ 8.58 (d, J=8.5 Hz, 1H), 7.87 (br s, 1H), 7.40 (br s, 1H), 7.25 (s, 1H), 6.99 (d, J=10.5 Hz, 1H), 6.72 (d, J=6.3 Hz, 1H), 6.52 (d, J=6.2 Hz, 1H), 5.54 (s, 1H), 4.58-4.25 (m, 4H), 3.65 (s, 3H), 2.06 (s, 3H), 1.49 (s, 6H).
Reaction SMILES: CO[C:3]([C:5]1[N:6]=[C:7]([C:25]#[N:26])[C:8]2[C:13]([C:14]=1[OH:15])=[CH:12][CH:11]=[C:10]([O:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=1[CH2:23][CH3:24])[CH:9]=2)=[O:4].[CH2:27]([O:29][C:30](=[O:36])[C:31]([CH3:35])([CH3:34])[CH2:32][NH2:33])[CH3:28]>C(O)C>[CH2:27]([O:29][C:30](=[O:36])[C:31]([CH3:35])([CH3:34])[CH2:32][NH:33][C:3]([C:5]1[N:6]=[C:7]([C:25]#[N:26])[C:8]2[C:13]([C:14]=1[OH:15])=[CH:12][CH:11]=[C:10]([O:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=1[CH2:23][CH3:24])[CH:9]=2)=[O:4])[CH3:28]
Reactant: CCOC(=O)C(C)(C)CN
Reactant: CCc1ccccc1Oc1ccc2c(O)c(C(=O)OC)nc(C#N)c2c1
Solvent: CCO
Product: CCOC(=O)C(C)(C)CNC(=O)c1nc(C#N)c2cc(Oc3ccccc3CC)ccc2c1O
Temperature: 150 °C
Reaction time: 1 h
Yield: 31.4 %

Procedure:
A mixture of 1-Cyano-7-(2-ethyl-phenoxy)-4-hydroxy-isoquinoline-3-carboxylic acid methyl ester (50 mg, 0.14 mmole) and 3-amino-2,2-dimethyl-propionic acid ethyl ester (41 mg, 0.43 mmole) in anhydrous ethanol (0.7 ml) was stirred at 130° C. for two hours and 150° C. for one hour before it was cooled to room temperature, concentrated and by flash column chromatography on silica gel with a gradient of ethyl acetate and hexanes to give the title compound as a colorless oil (20.3 mg): MS: (+) m/z 462.22 (M+1), (−) m/z 460.10 (M−1).
Reaction SMILES: [CH3:1][O:2][CH2:3][CH:4]([NH2:6])[CH3:5].Cl[C:8]1[CH:13]=[CH:12][C:11]([N+:14]([O-:16])=[O:15])=[CH:10][N:9]=1>>[CH3:1][O:2][CH2:3][CH:4]([N:6]1[CH:10]=[C:11]([N+:14]([O-:16])=[O:15])[CH:12]=[CH:13][CH:8]1[NH2:9])[CH3:5]
Reactant: O=[N+]([O-])c1ccc(Cl)nc1
Reactant: COCC(C)N
Product: COCC(C)N1C=C([N+](=O)[O-])C=CC1N

Procedure:
This compound was prepared with the same method described before by using 2-methoxy-1-methylethylamine and 2-chloro-5-nitro-pyridine to give N-(2-methoxy-1-methylethyl)-2-amino-5-nitro-pyridine. LCMS calcd for C9H13N3O3 m/e 211.22, obsd 210.2 (AP, M−H). The nitro compound was hydrogenated under the same condition described before to give N2-(2-methoxy-1-methylethyl)-2,5-diaminopyridine.
Reaction SMILES: [CH:1]1([CH2:4][N:5]2[C:9]3[CH:10]=[CH:11][C:12]([S:14]([C:17]4([CH2:42][OH:43])[CH2:22][CH2:21][N:20](C(C5C=CC=CC=5)(C5C=CC=CC=5)C5C=CC=CC=5)[CH2:19][CH2:18]4)(=[O:16])=[O:15])=[CH:13][C:8]=3[N:7]=[C:6]2[CH2:44][C:45]([CH3:48])([CH3:47])[CH3:46])[CH2:3][CH2:2]1.FC(F)(F)C(O)=O>ClCCl>[CH:1]1([CH2:4][N:5]2[C:9]3[CH:10]=[CH:11][C:12]([S:14]([C:17]4([CH2:42][OH:43])[CH2:22][CH2:21][NH:20][CH2:19][CH2:18]4)(=[O:16])=[O:15])=[CH:13][C:8]=3[N:7]=[C:6]2[CH2:44][C:45]([CH3:48])([CH3:47])[CH3:46])[CH2:3][CH2:2]1
Reactant: CC(C)(C)Cc1nc2cc(S(=O)(=O)C3(CO)CCN(C(c4ccccc4)(c4ccccc4)c4ccccc4)CC3)ccc2n1CC1CC1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CC(C)(C)Cc1nc2cc(S(=O)(=O)C3(CO)CCNCC3)ccc2n1CC1CC1
Reaction time: 0.33 h
Yield: 105.2 %

Procedure:
To a solution of (4-(1-(cyclopropylmethyl)-2-neopentyl-1H-benzo[d]imidazol-5-ylsulfonyl)-1-tritylpiperidine-4-yl)methanol (STEP F, 300 mg, 0.453 mmol) in dichloromethane (6 mL) was trifluoroacetic acid (2 mL). After 20 min, the mixture was concentrated in vacuo and the residue was diluted with methanol and the solution was filtered through strong cationic exchange column (SCX). The column was washed with 1 mol/L ammonia methanol to wash out the product. The filtrate was concentrated in vacuo to give the title compound (200 mg, quantitative yield).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][C:5]2[O:10][C@@:9]([CH:12]([O:15][CH3:16])[O:13][CH3:14])([CH3:11])[C@H:8]([OH:17])[C@@H:7]([N:18]3[C:22]4[CH:23]=[CH:24][CH:25]=[CH:26][C:21]=4[NH:20][C:19]3=[N:27][C:28]#[N:29])[C:6]=2[CH:30]=1.[CH3:31][S:32](Cl)(=[O:34])=[O:33].C(N(C(C)C)CC)(C)C.C([O-])(O)=O.[Na+]>C(Cl)Cl>[CH3:31][S:32]([NH:1][C:2]1[CH:3]=[CH:4][C:5]2[O:10][C@@:9]([CH:12]([O:15][CH3:16])[O:13][CH3:14])([CH3:11])[C@H:8]([OH:17])[C@@H:7]([N:18]3[C:22]4[CH:23]=[CH:24][CH:25]=[CH:26][C:21]=4[NH:20][C:19]3=[N:27][C:28]#[N:29])[C:6]=2[CH:30]=1)(=[O:34])=[O:33]
Reactant: CS(=O)(=O)Cl
Reactant: COC(OC)[C@@]1(C)Oc2ccc(N)cc2[C@H](n2c(=NC#N)[nH]c3ccccc32)[C@H]1O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: COC(OC)[C@@]1(C)Oc2ccc(NS(C)(=O)=O)cc2[C@H](n2c(=NC#N)[nH]c3ccccc32)[C@H]1O
Temperature: 25 °C
Reaction time: 14 h
Yield: 24.8 %

Procedure:
120 mg (0.29 mmol) of the compound obtained in example 5 was dissolved in 2 ml of methylenechloride, then 23 μl (0.29 mmol) of methanesulfonyl chloride and 76 μl (0.44 mmol) of diisopropylethylamine were added thereto. The reaction was stirred at room temperature for 14 hours, saturated NaHCO3 solution was added, and aqueous layer was extracted with 30 ml of methylenechloride. Organic layer was dried over anhydrous MgSO4, concentrated under reduced pressure. The residue was purified by silica gel column chromatography (hexane:ethyl acetate=1:1), to give 35 mg (yield: 26%) of the target compound.
Reaction SMILES: [F:1][C:2]([F:17])([F:16])[C:3]1[CH:8]=[CH:7][C:6]([C:9]2[C:13]([CH2:14]O)=[CH:12][O:11][N:10]=2)=[CH:5][CH:4]=1.S(Cl)([Cl:20])=O>>[Cl:20][CH2:14][C:13]1[C:9]([C:6]2[CH:7]=[CH:8][C:3]([C:2]([F:17])([F:16])[F:1])=[CH:4][CH:5]=2)=[N:10][O:11][CH:12]=1
Reactant: O=S(Cl)Cl
Reactant: OCc1conc1-c1ccc(C(F)(F)F)cc1
Product: FC(F)(F)c1ccc(-c2nocc2CCl)cc1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 95 %

Procedure:
A mixture of 3-(4-trifluoromethylphenyl)-4-isoxazolylmethanol (6.00 g) and thionyl chloride (10.0 ml) was stirred at 0° C. for 30 min. The reaction mixture was concentrated, saturated aqueous sodium hydrogencarbonate was added to the residue, and the mixture was extracted with ethyl acetate. The ethyl acetate layer was washed with saturated brine, dried (MgSO4) and concentrated. The obtained colorless crystals were filtrated to give 4-chloromethyl-3-(4-trifluoromethylphenyl)isoxazole (6.16 g, yield 95%). The crystals were recrystallized from ethyl acetate-hexane. melting point: 84–85° C.
Reaction SMILES: [F:1][C:2]1[CH:18]=[CH:17][CH:16]=[CH:15][C:3]=1[CH2:4][C:5]1[S:9][C:8]([CH:10]2OCC[O:11]2)=[CH:7][CH:6]=1.C(=O)(O)[O-].[Na+]>CO.O.Cl>[F:1][C:2]1[CH:18]=[CH:17][CH:16]=[CH:15][C:3]=1[CH2:4][C:5]1[S:9][C:8]([CH:10]=[O:11])=[CH:7][CH:6]=1
Reactant: Fc1ccccc1Cc1ccc(C2OCCO2)s1
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: CO
Product: O=Cc1ccc(Cc2ccccc2F)s1
Temperature: 25 °C
Reaction time: 1 h
Yield: 98 %

Procedure:
2-(5-(2-Fluoro-benzyl)-thiophen-2-yl)-[1,3]dioxolane described in Preparation Example 122 (4.33 g, 16.4 mmol) was dissolved in a mixture solvent of methanol (40 mL) and water (10 mL), 1N hydrochloric acid (20 mL) was added thereto, followed by stirring at room temperature for 1 hour. An aqueous solution of saturated sodium bicarbonate was added to the reaction solution at 0° C., which was then extracted with ethyl acetate, the organic layer was washed with brine and dried over anhydrous magnesium sulfate. The solvent was evaporated in vacuo, the residue was purified by silica gel column chromatography (hexane:ethyl acetate=10:1), and the title compound (3.54 g, 16.1 mmol, 98%) was obtained as a light yellow oil.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6](Cl)[CH:5]=[CH:4][N:3]=1.[Br-].O1CCOC1[C:15]1[S:19][C:18]([Zn+])=[CH:17][CH:16]=1>O1CCCC1.CCOCC.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>[S:19]1[CH:15]=[CH:16][CH:17]=[C:18]1[C:6]1[CH:5]=[CH:4][N:3]=[CH:2][N:7]=1
Reactant: [Zn+]c1ccc(C2OCCO2)s1
Reactant: Clc1ccnc(Cl)n1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [Br-]
Solvent: C1CCOC1
Solvent: CCOCC
Product: c1csc(-c2ccncn2)c1
Temperature: 70 °C
Reaction time: 16 h

Procedure:
To a degassed 0.50 M solution of 2,4-dichloropyrimidine (1.0 eq.) and 5-(1,3-dioxolan-2-yl)-2-thienylzinc bromide 31 (1.0 eq.) in tetrahydrofuran was added tetrakis(triphenylphosphine)palladium(0) (0.050 eq.). The mixture was stirred for 16 h at 70° C. and then returned to ambient temperature and diluted with ether. The solution was washed sequentially with a 0.5 M aqueous pH 9 solution of EDTA and brine. The organic phase was dried over sodium sulfate, filtered, and concentrated. The crude material was purified by flash chromatography over silica gel (1:1:1 hexanes:ethyl acetate:dichloromethane) to give compound 32. ES/MS m/z 269 (MH+), C11H9ClN2O2S=269 g/mol.
Reaction SMILES: [H-].[Na+].[C:3]([O:11][CH2:12][CH3:13])(=[O:10])[CH2:4][C:5]([O:7][CH2:8][CH3:9])=[O:6].[C:14]([O:18][C:19]([N:21]([C:29]1[C:34]([CH3:35])=[CH:33][C:32]([CH2:36]Br)=[CH:31][N:30]=1)[C:22]([O:24][C:25]([CH3:28])([CH3:27])[CH3:26])=[O:23])=[O:20])([CH3:17])([CH3:16])[CH3:15].C(OCC)(=O)C>CN(C=O)C>[CH2:12]([O:11][C:3](=[O:10])[CH:4]([CH2:36][C:32]1[CH:31]=[N:30][C:29]([N:21]([C:22]([O:24][C:25]([CH3:28])([CH3:27])[CH3:26])=[O:23])[C:19]([O:18][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:20])=[C:34]([CH3:35])[CH:33]=1)[C:5]([O:7][CH2:8][CH3:9])=[O:6])[CH3:13]
Reactant: CCOC(=O)CC(=O)OCC
Reactant: Cc1cc(CBr)cnc1N(C(=O)OC(C)(C)C)C(=O)OC(C)(C)C
Agent: [H-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CCOC(=O)C(Cc1cnc(N(C(=O)OC(C)(C)C)C(=O)OC(C)(C)C)c(C)c1)C(=O)OCC
Reaction time: 0.25 h
Yield: 49.9 %

Procedure:
To a suspension of NaH (0.24 g, 6.0 mmol, 60%) in DMF (5 mL) was added diethyl malonate (0.91 mL, 6.0 mmol) and the mixture was stirred for 15 min. A solution 2-[N,N-bis(tert-butoxycarbonyl)amino]-5-bromomethyl-3-methyl-pyridin (2.0 g, 5.0 mmol) in DMF (5 mL) was added and the resulting solution stirred for 120 min at 60° C. Ethyl acetate was added and the mixture was washed with water and brine and dried. After evaporation of the solvent, the crude product was purified by flash chromatography (CH3OH/CH2Cl2, 1:100→1:20) to give 2-(6-[N,N-bis(tert-butoxycarbonyl)amino]-5-methyl-pyridin-3-ylmethyl)-malonic acid diethyl ester (1.2 g, 50%).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[N:8]1[C:17](=[O:18])[C:16]2[C:11](=[N:12][C:13](S(C)=O)=[N:14][CH:15]=2)[N:10]2[CH:22]=[CH:23][N:24]=[C:9]12.[CH3:25][N:26]1[C:35]2[C:30](=[CH:31][CH:32]=[C:33]([NH2:36])[CH:34]=2)[CH2:29][CH2:28][CH2:27]1>CS(C)=O.CO>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[N:8]1[C:17](=[O:18])[C:16]2[CH:15]=[N:14][C:13]([NH:36][C:33]3[CH:34]=[C:35]4[C:30]([CH2:29][CH2:28][CH2:27][N:26]4[CH3:25])=[CH:31][CH:32]=3)=[N:12][C:11]=2[N:10]2[CH:22]=[CH:23][N:24]=[C:9]12
Reactant: CN1CCCc2ccc(N)cc21
Reactant: CS(=O)c1ncc2c(=O)n(-c3ccccc3Cl)c3nccn3c2n1
Solvent: CO
Solvent: CS(C)=O
Product: CN1CCCc2ccc(Nc3ncc4c(=O)n(-c5ccccc5Cl)c5nccn5c4n3)cc21

Procedure:
A mixture of Example 1E (60.0 mg, 0.167 mmol) and 1-methyl-1,2,3,4-tetrahydroquinolin-7-amine (48.7 mg, 0.300 mmol) was heated in a capped vial at 90° C. for 1 hour. After cooling, the residue was treated with dimethylsulfoxide/methanol (2 mL). The precipitate was filtered, washed with methanol and water, and oven-dried to provide the title compound. 1H NMR (400 MHz, DMSO-d6) δ ppm 1.77-1.99 (m, 2H), 2.69 (t, J=6.26 Hz, 2H), 2.90 (s, 3H), 3.11-3.28 (m, 2H), 6.92 (d, J=7.93 Hz, 1H), 7.02 (d, J=7.32 Hz, 1H), 7.07 (s, 1H), 7.18 (s, 1H), 7.50-7.65 (m, 3H), 7.69-7.74 (m, 2H), 9.09 (s, 1H), 10.53 (s, 1H). MS (ESI+) m/z 458.2 (M+H)+.
Reaction SMILES: Br[C:2]1[N:3]=[CH:4][N:5]([C:7]2[N:12]=[C:11]([C:13]3[CH:18]=[CH:17][C:16]([Cl:19])=[CH:15][CH:14]=3)[CH:10]=[C:9]([CH3:20])[N:8]=2)[CH:6]=1.[N:21]1[CH:26]=[CH:25][CH:24]=[C:23](B(O)O)[CH:22]=1>>[Cl:19][C:16]1[CH:17]=[CH:18][C:13]([C:11]2[CH:10]=[C:9]([CH3:20])[N:8]=[C:7]([N:5]3[CH:6]=[C:2]([C:23]4[CH:22]=[N:21][CH:26]=[CH:25][CH:24]=4)[N:3]=[CH:4]3)[N:12]=2)=[CH:14][CH:15]=1
Reactant: Cc1cc(-c2ccc(Cl)cc2)nc(-n2cnc(Br)c2)n1
Reactant: OB(O)c1cccnc1
Product: Cc1cc(-c2ccc(Cl)cc2)nc(-n2cnc(-c3cccnc3)c2)n1

Procedure:
The title compound was prepared from 2-(4-bromo-imidazol-1-yl)-4-(4-chloro-phenyl)-6-methyl-pyrimidine (example E.12) (0.14 g, 0.4 mmol) and commercially available 3-pyridyl-boronic acid (0.049 g, 0.4 mmol) according to the general procedure VI. Obtained as a light yellow solid (0.027 g, 19%). MS (ISN) 346.1 [(M−H)−]; mp 179-181° C.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][CH:6]=[C:5]2[CH2:11][CH2:12][NH:13][C:14](=[O:22])[C:15]1[CH:20]=[CH:19][C:18](I)=[CH:17][CH:16]=1.[C:23]([C:25]1[CH:26]=[C:27](B(O)O)[CH:28]=[CH:29][CH:30]=1)#[N:24].C(=O)([O-])[O-].[Na+].[Na+]>C(COC)OC.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>[Cl:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][CH:6]=[C:5]2[CH2:11][CH2:12][NH:13][C:14]([C:15]1[CH:20]=[CH:19][C:18]([C:29]2[CH:28]=[CH:27][CH:26]=[C:25]([C:23]#[N:24])[CH:30]=2)=[CH:17][CH:16]=1)=[O:22]
Reactant: N#Cc1cccc(B(O)O)c1
Reactant: O=C(NCCc1c[nH]c2ccc(Cl)cc12)c1ccc(I)cc1
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: N#Cc1cccc(-c2ccc(C(=O)NCCc3c[nH]c4ccc(Cl)cc34)cc2)c1
Yield: 31.3 %

Procedure:
N-(2-(5-chloro-1H-indol-3-yl)ethyl)-3′-cyanobiphenyl-4-carboxamide was prepared according to method B with N-(2-(5-chloro-1H-indol-3-yl)ethyl)-4-iodobenzamide (0.075 g; 0.176 mmol), 3-cyanophenylboronic acid (0.027 g; 0.180 mmol), tetrakis(triphenylphosphine)palladium (0.010 g; 0.009 mmol), sodium carbonate (0.037 g; 0.353 mmol), in dimethoxyethane (3 mL) and water (1 mL), irradiated in a microwave oven at 130° C. for 15 minutes. Flash chromatography on silica gel (eluent 2 to 20% ethyl acetate in dichloromethane) furnished 0.022 g (31%) of N-(2-(5-chloro-1H-indol-3-yl)ethyl)-3′-cyanobiphenyl-4-carboxamide as a white solid.