Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[N:7]=[CH:6][C:5]([NH:8][CH3:9])=[CH:4][CH:3]=1.C([Mg]Cl)(C)C.[CH:15]([C:18]1[NH:22][N:21]=[C:20]([NH:23][C:24]2[C:25]3[CH2:41][CH2:40][CH2:39][C:26]=3[N:27]=[C:28]([N:30]3[CH2:34][CH2:33][CH2:32][C@@H:31]3[C:35](OC)=[O:36])[N:29]=2)[CH:19]=1)([CH3:17])[CH3:16]>C1COCC1>[F:1][C:2]1[N:7]=[CH:6][C:5]([N:8]([CH3:9])[C:35]([C@H:31]2[CH2:32][CH2:33][CH2:34][N:30]2[C:28]2[N:29]=[C:24]([NH:23][C:20]3[CH:19]=[C:18]([CH:15]([CH3:17])[CH3:16])[NH:22][N:21]=3)[C:25]3[CH2:41][CH2:40][CH2:39][C:26]=3[N:27]=2)=[O:36])=[CH:4][CH:3]=1
Reactant: CNc1ccc(F)nc1
Reactant: COC(=O)[C@H]1CCCN1c1nc2c(c(Nc3cc(C(C)C)[nH]n3)n1)CCC2
Agent: CC(C)[Mg]Cl
Solvent: C1CCOC1
Product: CC(C)c1cc(Nc2nc(N3CCC[C@@H]3C(=O)N(C)c3ccc(F)nc3)nc3c2CCC3)n[nH]1
Temperature: 0 °C
Reaction time: 0.33 h
Yield: 6.8 %

Procedure:
To a solution of 6-fluoro-N-methylpyridin-3-amine (272 mg, 2.16 mmol) in THF (70 mL) was added isopropyl magnesium chloride solution 2M in THF (1.08 mL, 2.16 mmol) dropwise at 0° C. The mixture was allowed to stir at 0° C. for 20 min. Then, a solution of (R)-methyl 1-(4-(5-isopropyl-1H-pyrazol-3-ylamino)-6,7-dihydro-5H-cyclopenta[d]pyrimidin-2-yl)pyrrolidine-2-carboxylate (200 mg, 0.54 mmol) in THF (3 mL) was added and the reaction mixture was allowed to stir at RT for 2 h. The reaction was quenched with saturated ammonium chloride solution (50 mL) and the mixture was extracted with EtOAc (3×50 mL). The combined organic layer was washed with brine and dried over anhydrous sodium sulfate. Removal of EtOAc under reduced pressure gave an oily residue that was purified by reverse phase HPLC to afford 17 mg of (R)—N-(6-fluoropyridin-3-yl)-1-(4-(5-isopropyl-1H-pyrazol-3-ylamino)-6,7-dihydro-5H-cyclopenta[d]pyrimidin-2-yl)-N-methylpyrrolidine-2-carboxamide. 1HNMR (400 MHz, CDCl3) δ (ppm): 1.20-1.35 (m, 6H), 1.79-2.25 (m, 6H), 2.57-2.68 (m, 2H), 2.79-2.82 (m, 2H), 2.91-3.01 (m, 1H), 3.30 (s, 3H), 3.59-3.80 (m, 2H), 4.35-4.45 (m, 1H), 6.16 (s, 1H), 6.90-7.05 (m, 2H), 8.01 (brs, 1H), 8.40 (brs, 1H). The other enantiomer is prepared using the (S) chiral starting material.
Reaction SMILES: [NH2:1][C:2]1[S:3][CH:4]=[C:5]([CH2:7][C:8](=[O:20])[NH:9][C:10]2[CH:15]=[CH:14][CH:13]=[C:12]([C:16]([F:19])([F:18])[F:17])[CH:11]=2)[N:6]=1.[CH3:21][N:22]=[C:23]=[O:24].O>N1C=CC=CC=1>[CH3:21][NH:22][C:23](=[O:24])[NH:1][C:2]1[S:3][CH:4]=[C:5]([CH2:7][C:8](=[O:20])[NH:9][C:10]2[CH:15]=[CH:14][CH:13]=[C:12]([C:16]([F:19])([F:17])[F:18])[CH:11]=2)[N:6]=1
Reactant: Nc1nc(CC(=O)Nc2cccc(C(F)(F)F)c2)cs1
Reactant: CN=C=O
Solvent: O
Solvent: c1ccncc1
Product: CNC(=O)Nc1nc(CC(=O)Nc2cccc(C(F)(F)F)c2)cs1
Reaction time: 8 h
Yield: 84.6 %

Procedure:
A solution of 10 g (0.033 mole) of 2-amino-4-(3-trifluoromethylphenylcarbamoylmethyl)thiazole, and 2.3 g (0.04 mole) of methyl isocyanate in 50 ml of pyridine was heated at 50° for 3 hours. The reaction solution was mixed with 400 ml of water and allowed to stand overnight in the refrigerator. On the following morning, the crystalline solid was collected and dried in the oven. There was obtained 10 g of the desired product, m.p. 200°14 203°. N.M.R. (dimethyl-d6 sulfoxide) ∂ 2.7-2.8 (CH3, doublet), 6.8 (hetero-aromatic), 7.3-8.1 (aromatic), 10.4 (HNC=O).
Reaction SMILES: [O:1]1[C:5]2=[CH:6][N:7]=[C:8]([CH2:10][OH:11])[CH:9]=[C:4]2[CH:3]=[CH:2]1>C(O)C.[H][H].[Pd]>[O:1]1[C:5]2=[CH:6][N:7]=[C:8]([CH2:10][OH:11])[CH:9]=[C:4]2[CH2:3][CH2:2]1
Reactant: OCc1cc2ccoc2cn1
Reactant: [H][H]
Agent: [Pd]
Solvent: CCO
Product: OCc1cc2c(cn1)OCC2
Yield: 99.6 %

Procedure:
Furo[2,3-c]pyridin-5-ylmethanol (1.29 g, 8.7 mmol) was dissolved in ethanol (50 ml) and hydrogenated under 1 atmosphere of hydrogen at room temperature over 10% palladium on carbon for 18 h. The mixture was filtered and the filtrate evaporated to dryness to provide the desired compound (1.31 g, 100%).
Reaction SMILES: [C:1]1(=[O:11])[O:6][C:4](=[O:5])[C:3]2=[CH:7][CH:8]=[CH:9][CH:10]=[C:2]12.[CH3:12][C:13]1[NH:14][C:15]2[C:20]([CH:21]=1)=[CH:19][C:18](C)=[CH:17][CH:16]=2>C(Cl)CCl>[C:12]1([C:13]2[NH:14][C:15]3[C:20]([C:21]=2[C:4]([C:3]2[CH:7]=[CH:8][CH:9]=[CH:10][C:2]=2[C:1]([OH:6])=[O:11])=[O:5])=[CH:19][CH:18]=[CH:17][CH:16]=3)[CH:4]=[CH:3][CH:2]=[CH:10][CH:9]=1
Reactant: Cc1ccc2[nH]c(C)cc2c1
Reactant: O=C1OC(=O)c2ccccc21
Solvent: ClCCCl
Product: O=C(O)c1ccccc1C(=O)c1c(-c2ccccc2)[nH]c2ccccc12
Yield: 65.5 %

Procedure:
A mixture of 5.0 g (0.034 mole) of phthalic anhydride and 5.0 g (0.034 mole) of 2,5-dimethylindole in 30 ml of ethylene dichloride was refluxed for 20 hours, cooled and the separated solid filtered off and dried to obtain 3.8 g of 2-[(2,5-dimethyl-3-indolyl)carbonyl]benzoic acid (Formula VIII: R0 =R1 =R2 =R3 =R6 =H; R5 =CH3 ; Y1 =CH3) as a pink-colored solid melting at 198°-200° C.
Reaction SMILES: [C:1]([O:5][C:6](=[O:39])[NH:7][C:8]1([C:12]2[CH:17]=[CH:16][C:15]([C:18]3[C:23]([C:24]4[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=4)=[CH:22][N:21]4[N:30]=[C:31]([C:33]5[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=5)[CH:32]=[C:20]4[N:19]=3)=[CH:14][CH:13]=2)[CH2:11][CH2:10][CH2:9]1)([CH3:4])([CH3:3])[CH3:2].C1C(=O)N([Br:47])C(=O)C1>C(Cl)(Cl)Cl.C(Cl)Cl>[C:1]([O:5][C:6](=[O:39])[NH:7][C:8]1([C:12]2[CH:13]=[CH:14][C:15]([C:18]3[C:23]([C:24]4[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=4)=[CH:22][N:21]4[N:30]=[C:31]([C:33]5[CH:34]=[CH:35][CH:36]=[CH:37][CH:38]=5)[C:32]([Br:47])=[C:20]4[N:19]=3)=[CH:16][CH:17]=2)[CH2:11][CH2:10][CH2:9]1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)NC1(c2ccc(-c3nc4cc(-c5ccccc5)nn4cc3-c3ccccc3)cc2)CCC1
Reactant: O=C1CCC(=O)N1Br
Solvent: ClCCl
Solvent: ClC(Cl)Cl
Product: CC(C)(C)OC(=O)NC1(c2ccc(-c3nc4c(Br)c(-c5ccccc5)nn4cc3-c3ccccc3)cc2)CCC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 69.7 %

Procedure:
To a solution of compound 9-1 (104 mg, 0.2 mmol) in CHCl3 (5 mL) was added NBS (40 mg 0.22 mmol.) and the mixture was stirred at room temperature overnight. The mixture was diluted with 15 mL of DCM, the combined organic phase was washed with 0.1N HClaq and brine, dried over anhydrous Na2SO4 and concentrated. The residue was purified by prep.TLC to give 83 mg of 9-3.
Reaction SMILES: Cl[C:2]([N:4]1[C:10]2[CH:11]=[CH:12][CH:13]=[CH:14][C:9]=2[NH:8][C:7](=[O:15])[C:6]2=[CH:16][S:17][C:18]([CH3:19])=[C:5]12)=[O:3].[CH2:20]([N:22]([CH2:25][CH:26]1[CH2:31][CH2:30][CH2:29][CH2:28][N:27]1[CH2:32][CH2:33][NH2:34])[CH2:23][CH3:24])[CH3:21].Cl>C(#N)C>[CH2:20]([N:22]([CH2:25][CH:26]1[CH2:31][CH2:30][CH2:29][CH2:28][N:27]1[CH2:32][CH2:33][NH:34][C:2]([N:4]1[C:10]2[CH:11]=[CH:12][CH:13]=[CH:14][C:9]=2[NH:8][C:7](=[O:15])[C:6]2=[CH:16][S:17][C:18]([CH3:19])=[C:5]12)=[O:3])[CH2:23][CH3:24])[CH3:21]
Reactant: CCN(CC)CC1CCCCN1CCN
Reactant: Cc1scc2c1N(C(=O)Cl)c1ccccc1NC2=O
Agent: Cl
Solvent: CC#N
Product: CCN(CC)CC1CCCCN1CCNC(=O)N1c2ccccc2NC(=O)c2csc(C)c21
Yield: 55 %

Procedure:
Prepared analogously to Example 1 from 4-(chlorocarbonyl)-4,9-dihydro-3-methyl-10H-thieno[3,4-b][1,5]benzodiazepin-10-one and (+)-2-[2-[(diethylamino)methyl]-piperidin-l-yl]ethanamine in a yield of 55% of theory. Colourless crystals, m.p. 131°-132° C. (acetonitrile); [α]D20 =-13.66° (dilute aqueous hydrochloric acid).
Reaction SMILES: [CH3:1][O:2][C:3]1[C:4](=[O:36])[C:5]([CH3:35])=[C:6]([CH2:12][C:13]2[CH:14]=[CH:15][C:16]([O:31]C(=O)C)=[C:17]([CH:30]=2)[C:18]([NH:20][C:21]2[CH:26]=[CH:25][C:24]([C:27](=[O:29])[CH3:28])=[CH:23][CH:22]=2)=[O:19])[C:7](=[O:11])[C:8]=1[O:9][CH3:10].C(=O)([O-])O.[Na+]>CO.O>[CH3:1][O:2][C:3]1[C:4](=[O:36])[C:5]([CH3:35])=[C:6]([CH2:12][C:13]2[CH:14]=[CH:15][C:16]([OH:31])=[C:17]([CH:30]=2)[C:18]([NH:20][C:21]2[CH:22]=[CH:23][C:24]([C:27](=[O:29])[CH3:28])=[CH:25][CH:26]=2)=[O:19])[C:7](=[O:11])[C:8]=1[O:9][CH3:10]
Reactant: COC1=C(OC)C(=O)C(Cc2ccc(OC(C)=O)c(C(=O)Nc3ccc(C(C)=O)cc3)c2)=C(C)C1=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CO
Solvent: O
Product: COC1=C(OC)C(=O)C(Cc2ccc(O)c(C(=O)Nc3ccc(C(C)=O)cc3)c2)=C(C)C1=O
Yield: 65.2 %

Procedure:
N-[5-(5,6-Dimethoxy-3-methyl-1,4-benzoquinon-2-yl)methyl-2-acetoxybenzoyl]-4-acetylaniline (0.100 g, 0.204 mmol) was dissolved in methanol (6 ml) and after adding thereto an aqueous saturated sodium hydrogencarbonate solution (3 ml), the solution was stirred at room temperature for 3 hours. After the completion of reaction, the reaction solution was diluted with water and then extracted with ethyl acetate. The extract was washed with water and then dried, and the solvent was removed by distillation. The obtained residue was purified by preparative thin-layer chromatography (hexand:ethyl acetate=1:2) and then recrystallized from ether to obtain the titled compound (0.060 g, 0.133 mmol, 65%).
Reaction SMILES: [C:1]([NH:4][NH:5][C:6]([NH2:8])=[O:7])(N)=[O:2].[CH:9]1(N)[CH2:14][CH2:13][CH2:12][CH2:11][CH2:10]1.Cl>CN1CCCC1=O>[CH:9]1([N:8]2[C:6](=[O:7])[NH:5][NH:4][C:1]2=[O:2])[CH2:14][CH2:13][CH2:12][CH2:11][CH2:10]1
Reactant: NC(=O)NNC(N)=O
Reactant: NC1CCCCC1
Agent: Cl
Solvent: CN1CCCC1=O
Product: O=c1[nH][nH]c(=O)n1C1CCCCC1

Procedure:
118 g of hydrazodicarbonamide and 100 g of cyclohexyl amine are stirred in 100 ml of N-methyl pyrrolidone for 2 hours at 160° C., for 7 hours at 175° C. and for 10 hours at 200° C. The solvent is then distilled off in vacuo and the residue is triturated with 100 ml of a 10% sodium hydroxide solution. The deposit is isolated by filtration under suction and the filtrate is neutralised with 10% hydrochloric acid. A deposit is precipitated and is isolated by filtration under suction, washed with water and dried in vacuo, giving 132 g (76% of the theoretical yield) of 4-cyclohexyl-1,2,4-triazolidine-3,5-dione (identical with the compounds produced in accordance with Example 2).
Reaction SMILES: [C:1]([C@H:5]1[CH2:10][CH2:9][C@H:8]([O:11][C:12]2[CH:13]=[C:14]3[C:19](=[CH:20][CH:21]=2)[CH:18]=[C:17]([C@:22]2([CH3:28])[CH2:26][O:25]C(=O)[NH:23]2)[CH:16]=[CH:15]3)[CH2:7][CH2:6]1)([CH3:4])([CH3:3])[CH3:2].C(O)C.O.[OH-].[Li+]>O>[NH2:23][C@@:22]([C:17]1[CH:16]=[CH:15][C:14]2[C:19](=[CH:20][CH:21]=[C:12]([O:11][C@H:8]3[CH2:7][CH2:6][C@H:5]([C:1]([CH3:4])([CH3:3])[CH3:2])[CH2:10][CH2:9]3)[CH:13]=2)[CH:18]=1)([CH3:28])[CH2:26][OH:25]
Reactant: CC(C)(C)[C@H]1CC[C@H](Oc2ccc3cc([C@]4(C)COC(=O)N4)ccc3c2)CC1
Agent: [Li+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: CC(C)(C)[C@H]1CC[C@H](Oc2ccc3cc([C@@](C)(N)CO)ccc3c2)CC1

Procedure:
(R)-4-[6-trans-(4-tert-Butyl-cyclohexyloxy)-naphthalen-2-yl]-4-methyl-oxazolidin-2-one (Example 24, 0.03878 g, 0.0001016 mol) was dissolved in Ethanol (1.00 mL, 0.0171 mol) in a capped 40 mL vial equipped with a magnetic stir bar. 4.2 M of lithium hydroxide monohydrate in water (1.00 mL) was added and the reaction was refluxed overnight. TLC analysis showed that the reaction was complete. The solvent was removed under vacuum. The product was diluted in methylene chloride (5 mL) and water was added (5 mL). The layers were separated and the organic phase was then concentrated to dryness under vacuum, and purified by HPLC to give 48 mg of the title compound (13% yield). MS: m/z=339.47 [M−NH2]+. 1H NMR (400 MHz, MeOD) δ 0.92-0.97 (m, 9H), 1.10-1.20 (m, 1H), 1.23-1.35 (m, 2H), 1.39-1.51 (m, 2H), 1.79 (s, 3H), 1.90-1.98 (m, 2H), 2.29 (dd, J=12.55, 2.01 Hz, 2H), 3.81-3.86 (m, 1H), 3.91-3.96 (m, 1H), 4.32-4.43 (m, 1H), 7.19 (dd, J=8.78, 2.51 Hz, 1H), 7.28 (d, J=2.26 Hz, 1H), 7.53 (dd, J=8.66, 2.13 Hz, 1 H), 7.80-7.89 (m, 3H)
Reaction SMILES: [NH2:1][C:2]1[N:7]=[CH:6][C:5]([C:8]2[CH:9]=[CH:10][C:11]([F:22])=[C:12]([C:14]([N:16]3[CH2:21][CH2:20][O:19][CH2:18][CH2:17]3)=O)[CH:13]=2)=[CH:4][C:3]=1[C:23]1[N:24]=[N:25][N:26]([CH:28]([CH3:30])[CH3:29])[CH:27]=1.B(F)(F)F.CCOCC.[BH4-].[Na+]>C1COCC1>[F:22][C:11]1[CH:10]=[CH:9][C:8]([C:5]2[CH:4]=[C:3]([C:23]3[N:24]=[N:25][N:26]([CH:28]([CH3:29])[CH3:30])[CH:27]=3)[C:2]([NH2:1])=[N:7][CH:6]=2)=[CH:13][C:12]=1[CH2:14][N:16]1[CH2:17][CH2:18][O:19][CH2:20][CH2:21]1
Reactant: CC(C)n1cc(-c2cc(-c3ccc(F)c(C(=O)N4CCOCC4)c3)cnc2N)nn1
Agent: FB(F)F
Agent: [BH4-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CCOCC
Product: CC(C)n1cc(-c2cc(-c3ccc(F)c(CN4CCOCC4)c3)cnc2N)nn1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 41.5 %

Procedure:
To a solution of [5-[6-amino-5-(1-isopropyltriazol-4-yl)-3-pyridyl]-2-fluoro-phenyl]-morpholino-methanone (150 mg, 0.365 mmol) in THF (10.0 mL) was added BF3.Et2O (0.25 mL, 1.827 mmol) at 0° C. and stirred for 30 min. After 30 min, NaBH4 (69 mg, 1.827 mmol) was added at 0° C. and stirred at room temperature for 18 h. After cooling to 0° C., quenched with MeOH (2 mL) and heated to reflux for 6 h. The reaction mixture was diluted with EtOAc (20 mL), washed with water (20 mL), dried over anhydrous Na2SO4 and solvent was evaporated under reduced pressure. Crude compound was purified by column using 100-200 mesh silica gel. The column was eluted with 5% MeOH in DCM to afford 60 mg (yield: 41.66%) of the title compound as white solid.
Reaction SMILES: [CH3:1]/[C:2](=[CH:8]\[C:9]1[CH:14]=[CH:13][C:12]([C:15]2[CH:20]=[CH:19][CH:18]=[C:17]([NH:21][CH3:22])[CH:16]=2)=[CH:11][CH:10]=1)/[C:3]([O:5][CH2:6][CH3:7])=[O:4].[CH2:23]([N:30]=[C:31]=[O:32])[CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH3:29]>>[CH2:23]([NH:30][C:31](=[O:32])[N:21]([C:17]1[CH:16]=[C:15]([C:12]2[CH:13]=[CH:14][C:9](/[CH:8]=[C:2](\[CH3:1])/[C:3]([O:5][CH2:6][CH3:7])=[O:4])=[CH:10][CH:11]=2)[CH:20]=[CH:19][CH:18]=1)[CH3:22])[CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH3:29]
Reactant: CCCCCCCN=C=O
Reactant: CCOC(=O)/C(C)=C/c1ccc(-c2cccc(NC)c2)cc1
Product: CCCCCCCNC(=O)N(C)c1cccc(-c2ccc(/C=C(\C)C(=O)OCC)cc2)c1
Yield: 88 %

Procedure:
1.0 g (3.4 mmol) of ethyl (E)-2-methyl-3-(3′-methylaminobiphenyl-4-yl)acrylate is mixed with 2 mL of heptyl isocyanate and the medium is irradiated by microwave for 30 minutes at a temperature of 100° C. in an Emrys Optimizer machine. The residue obtained is purified by chromatography on a column of silica eluted with a 9/1 heptane/ethyl acetate mixture. 1.2 g (88%) of ethyl (E)-3-[3′-(3-heptyl-1-methylureido)biphenyl-4-yl]-2-methylacrylate are obtained.
Reaction SMILES: [CH3:1][C:2]([CH3:13])([CH3:12])[C@@H:3]([C:5]([O:7][C:8]([CH3:11])([CH3:10])[CH3:9])=[O:6])[NH2:4].C(N(CC)CC)C.[CH3:21][S:22](Cl)(=[O:24])=[O:23]>ClCCl.CN(C)C1C=CN=CC=1>[CH3:1][C:2]([CH3:13])([CH3:12])[C@@H:3]([C:5]([O:7][C:8]([CH3:11])([CH3:10])[CH3:9])=[O:6])[NH:4][S:22]([CH3:21])(=[O:24])=[O:23]
Reactant: CC(C)(C)OC(=O)[C@@H](N)C(C)(C)C
Reactant: CS(=O)(=O)Cl
Agent: CN(C)c1ccncc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(C)(C)OC(=O)[C@@H](NS(C)(=O)=O)C(C)(C)C
Temperature: 25 °C
Yield: 99.7 %

Procedure:
A solution of tert-butyl 3-methyl-L-valinate (50 mg, 0.223 mmol) in dichloromethane (1 mL) at 0° C. was treated with 4-(dimethylamino)pyridine (5.4 mg, 0.045 mmol), triethylamine (93.4 μL, 0.67 mmol), and methanesulfonyl chloride (34.5 L, 0.45 mmol), and the mixture was warmed to 25° C. for 1 h. The mixture was washed with 5% potassium bisulfate, saturated sodium bicarbonate, brine, and dried over MgSO4, filtered, and the solvents were evaporated to give the crude title compound (59 mg, 100%).
Reaction SMILES: Cl[CH2:2][C:3]1[N:12]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=2[Cl:19])[C:11](=[O:20])[C:10]2[C:5](=[CH:6][C:7]([N+:21]([O-:23])=[O:22])=[CH:8][CH:9]=2)[N:4]=1.O.[SH:25][C:26]1[N:34]=[CH:33][N:32]=[C:31]2[C:27]=1[NH:28][CH:29]=[N:30]2.C([O-])([O-])=O.[K+].[K+]>CN(C=O)C>[Cl:19][C:14]1[CH:15]=[CH:16][CH:17]=[CH:18][C:13]=1[N:12]1[C:11](=[O:20])[C:10]2[C:5](=[CH:6][C:7]([N+:21]([O-:23])=[O:22])=[CH:8][CH:9]=2)[N:4]=[C:3]1[CH2:2][S:25][C:26]1[N:34]=[CH:33][N:32]=[C:31]2[C:27]=1[N:28]=[CH:29][NH:30]2
Reactant: O=c1c2ccc([N+](=O)[O-])cc2nc(CCl)n1-c1ccccc1Cl
Reactant: Sc1ncnc2nc[nH]c12
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: O=c1c2ccc([N+](=O)[O-])cc2nc(CSc2ncnc3[nH]cnc23)n1-c1ccccc1Cl
Yield: 73.8 %

Procedure:
Prepared according to Procedure C using Intermediate 2o (216 mg, 0.617 mmol), 6-mercaptopurine monohydrate (116 mg, 0.681 mmol), K2CO3 (94 mg, 0.680 mmol), and DMF (4 mL). The crude product was recrystallized from EtOH to provide 212 mg of a yellow crystalline solid (74%), mp 218.0-218.3° C. (decomposes). 1H NMR (DMSO-d6) δ: 13.56 (br s, 1H); 8.49 (s, 1H); 8.42 (s, 1H); 8.38-8.45 (m, 2H); 8.31 (d, J=8.4 Hz, 1H); 7.81 (d, J=6.5 Hz, 1H); 7.68 (d, J=6.7 Hz, 1H); 7.43-7.58 (m, 2H); 4.53 (s, 2H). 13C NMR (DMSO-d6) ppm: 157.7, 154.4, 153.3, 149.8, 149.3, 147.6, 145.2, 141.4, 131.5, 129.8, 129.7, 129.2, 128.4, 127.1, 126.7, 122.7, 120.3, 119.4, 29.9. MS (ES): m/z 466.0 (M+). Anal. calcd. for C20H12ClN7O3S.0.4C2H6O.0.05KCl: C, 51.19; H, 2.97; Cl, 7.63; N, 20.09; S, 6.57. Found: C, 51.27; H, 2.88; Cl, 7.40; N, 20.04; S, 6.52.
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:11]=1[N:10]=[CH:9][CH:8]=[C:7]2[NH:12][C:13]([NH:15][C:16]1[N:21]=[C:20]([CH:22]2[CH2:27][CH2:26][NH:25][CH2:24][CH2:23]2)[CH:19]=[CH:18][CH:17]=1)=[O:14].[BH4-].[Na+].Cl.C(Cl)Cl.CO.[CH3:36][C:37]([CH3:39])=O>>[F:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:11]=1[N:10]=[CH:9][CH:8]=[C:7]2[NH:12][C:13]([NH:15][C:16]1[N:21]=[C:20]([CH:22]2[CH2:23][CH2:24][N:25]([CH:37]([CH3:39])[CH3:36])[CH2:26][CH2:27]2)[CH:19]=[CH:18][CH:17]=1)=[O:14]
Reactant: CC(C)=O
Reactant: O=C(Nc1cccc(C2CCNCC2)n1)Nc1ccnc2c(F)cccc12
Agent: Cl
Agent: [BH4-]
Agent: [Na+]
Solvent: ClCCl
Solvent: CO
Product: CC(C)N1CCC(c2cccc(NC(=O)Nc3ccnc4c(F)cccc34)n2)CC1

Procedure:
To a solution of 50 mg of 1-(8-fluoro-quinolin-4-yl)-3-(1′,2′,3′,4′,5′,6′-hexahydro-[2,4′]bipyridinyl-6-yl)-urea (example 62) (0.137 mmol) in 50 ml of acetone were added 26 mg of sodium borohydride (0.684 mmol) in small portions. The reaction was slightly exotherm. After stirring the reaction mixture over night a small amount of 2M HCl was added to the reaction mixture up to a pH of 3 to destroy the excess of sodium borohydride. After neutralization with sodium bicarbonate, acetone was evaporated under reduced pressure, water added to the residue, the reaction mixture extracted three times with DCM, the organic phases combined and dried over sodium sulfate and the solvent evaporated under reduced pressure. 45 mg of the desired product were obtained as off white powder (yield: 81%) after column chromatography (silica gel, DCM/MeOH 98/2).
Reaction SMILES: C([O:8][C:9](=[O:33])[CH2:10][C@@H:11]([C:20]([NH:22][CH:23]([C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1)[CH2:24][CH2:25][CH3:26])=[O:21])[NH:12][C:13]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14])C1C=CC=CC=1.[H][H]>C(OCC)(=O)C.[C].[Pd]>[C:27]1([CH:23]([NH:22][C:20](=[O:21])[C@H:11]([CH2:10][C:9]([OH:33])=[O:8])[NH:12][C:13]([O:15][C:16]([CH3:19])([CH3:17])[CH3:18])=[O:14])[CH2:24][CH2:25][CH3:26])[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1
Reactant: [H][H]
Reactant: CCCC(NC(=O)[C@H](CC(=O)OCc1ccccc1)NC(=O)OC(C)(C)C)c1ccccc1
Agent: [Pd]
Solvent: CCOC(C)=O
Product: CCCC(NC(=O)[C@H](CC(=O)O)NC(=O)OC(C)(C)C)c1ccccc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 91.9 %

Procedure:
3.50 g of Compound 1 obtained in Synthesis Example 1 was dissolved in 15 mL of ethyl acetate, and 0.656 g of 5% palladium carbon (50% moisture content) was added thereto. Then, the inside of the reaction system was substituted with hydrogen, and the reaction system was stirred at room temperature overnight and subjected to hydrogenolysis. The 5% palladium carbon was filtered off, and washed with 80 mL of ethyl acetate. Then, the organic layers were combined, distilled under reduced pressure to remove ethyl acetate, and then dried under vacuum, thereby to give 2.58 g of Compound 2.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6](Cl)[N:5]=[C:4]([NH:9][C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[N:3]=1.[CH2:16]1[O:25][C:24]2[CH:23]=[CH:22][C:20]([NH2:21])=[CH:19][C:18]=2[O:17]1>>[O:25]1[C:24]2[CH:23]=[CH:22][C:20]([NH:21][C:6]3[N:5]=[C:4]([NH:9][C:10]4[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=4)[N:3]=[C:2]([Cl:1])[N:7]=3)=[CH:19][C:18]=2[O:17][CH2:16]1
Reactant: Clc1nc(Cl)nc(Nc2ccccc2)n1
Reactant: Nc1ccc2c(c1)OCO2
Product: Clc1nc(Nc2ccccc2)nc(Nc2ccc3c(c2)OCO3)n1
Yield: 42 %

Procedure:
The reaction of 4,6-dichloro-N-phenyl-[1,3,5]triazine-2-amine with 3,4-methylenedioxyaniline using the method described for the synthesis of CT-32028 provided CT-32042 (51 mg, 42% yield). 1H NMR (d6-DMSO) δ 10.05-10.29 (m, 2H), 7.57-7.80 (m, 2H), 7.21-7.42 (m, 3H), 6.80-7.13 (m, 3H), 6.03 (s, 2H).
Reaction SMILES: [NH2:1][C:2]1[C:7]([NH2:8])=[CH:6][CH:5]=[CH:4][N:3]=1.[Cl:9][CH:10]([CH3:13])[C:11]#N.C>O>[Cl:9][CH:10]([C:13]1[NH:1][C:2]2=[N:3][CH:4]=[CH:5][CH:6]=[C:7]2[N:8]=1)[CH3:11]
Reactant: Nc1cccnc1N
Reactant: CC(Cl)C#N
Solvent: O
Product: CC(Cl)c1nc2cccnc2[nH]1
Temperature: 80 °C

Procedure:
5.2 g of 2,3-diaminopyridine in 209 g of polyphosphoric acid are heated at 120° C. for 0.5 h. The solution is cooled to 80° C. and 4.6 ml of 2-chloropropionitrile are added. Thereafter, the reaction mixture is heated to 180° C. for 2.5 h. After cooling, the polyphosphoric acid is hydrolysed with 150 ml of water. After reheating to 90° C., charcoal is added under vigorous stirring. Subsequently, the suspension is filtered through a celite pad while still hot (70° C.). The filter cake is rinsed with 100 ml of water and the pH value of the filtrate is adjusted to pH 4 using 9 M aqueous sodium hydroxide solution. The mixture is extracted twice each with 250 ml of ethyl acetate, the combined organic phases are dried using sodium sulfate, concentrated and lyophilized from ethanol/water to give 3.56 g of the title compound as a light brown, amorphous solid. MS: 182.2/184.2 (MH+, 100%/32%). M.p. 132° C. TLC: Rf=0.60 (dichloromethane/methanol 8:1).
Reaction SMILES: FC(F)(F)C(O)=O.[Cl:8][C:9]1[C:10]2[C:17]([C:18]3[CH:23]=[CH:22][C:21]([NH:24]C(=O)OC(C)(C)C)=[C:20]([O:32][CH3:33])[CH:19]=3)=[CH:16][N:15]([CH:34]3[CH2:38][CH2:37][CH2:36][CH2:35]3)[C:11]=2[N:12]=[CH:13][N:14]=1>ClCCl>[Cl:8][C:9]1[C:10]2[C:17]([C:18]3[CH:23]=[CH:22][C:21]([NH2:24])=[C:20]([O:32][CH3:33])[CH:19]=3)=[CH:16][N:15]([CH:34]3[CH2:35][CH2:36][CH2:37][CH2:38]3)[C:11]=2[N:12]=[CH:13][N:14]=1
Reactant: COc1cc(-c2cn(C3CCCC3)c3ncnc(Cl)c23)ccc1NC(=O)OC(C)(C)C
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: COc1cc(-c2cn(C3CCCC3)c3ncnc(Cl)c23)ccc1N
Temperature: 25 °C
Reaction time: 3 h
Yield: 100 %

Procedure:
Trifluoroacetic acid (2 ml) was added dropwise to a solution of tert-butyl N-[4-(4-chloro-7-cyclopentyl-7H-pyrrolo[2,3-d]pyrimidin-5-yl)-2-methoxyphenyl]carbamate (0.58 g, 1.31 mmol) in dichloromethane (20 ml) at 0° C. The ice bath was removed and the reaction mixture was stirred at room temperature for 3 h. Most of trifluoroacetic acid and dichloromethane were removed under reduced pressure. The residue was redissolved in dichloromethane and washed with saturated aqueous sodium bicarbonate solution, dried over magnesium sulfate, filtered and evaporated to give 4-(4-chloro-7-cyclopentyl-7H-pyrrolo[2,3-d]pyrimidin-5-yl)-2-methoxyaniline as white solids (0.45 g, 1.31 mmol): 1H NMR (DMSO-d6, 400 MHz) δ 8.61 (s, 1H), 7.78 (s, 1H), 6.97 (d, 1H), 6.85 (dd, 1H), 6.67 (d, 1H), 5.20 (m, 1H), 4.78 (broad, 2H), 3.81 (s, 3H), 2.18 (m, 2H), 1.88-2.00 (m, 4H), 1.72 (m, 2H); MH+343.