Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[N:9]=[C:8]([CH3:15])[C:7]([CH2:16]O)=[CH:6]2.S(Cl)([Cl:20])=O>>[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[N:9]=[C:8]([CH3:15])[C:7]([CH2:16][Cl:20])=[CH:6]2
Reactant: COc1cc2cc(CO)c(C)nc2cc1OC
Reactant: O=S(Cl)Cl
Product: COc1cc2cc(CCl)c(C)nc2cc1OC

Procedure:
6,7-Dimethoxy-2-methylquinoline-3-methanol (2.31 g, 9.9 mmol) was dissolved in thionylchloride (50 ml) and refluxed for 2 h. The solution was concentrated and the residue partitioned between ethyl acetate and aqeous NaHCO3. The layers were separated and the aqeous phase extracted with ethyl acetate. The combined organic phases were washed with water and brine and dried over MgSO4. Evaporation of the solvent gave 2.48 g 6,7-dimethoxy-3-chloromethyl-2-methylquinoline.
Reaction SMILES: F[C:2]1[CH:3]=[CH:4][C:5]([N+:9]([O-:11])=[O:10])=[C:6]([OH:8])[CH:7]=1.[NH:12]1[CH2:17][CH2:16][O:15][CH2:14][CH2:13]1>C(#N)C.O>[N:12]1([C:2]2[CH:3]=[CH:4][C:5]([N+:9]([O-:11])=[O:10])=[C:6]([OH:8])[CH:7]=2)[CH2:17][CH2:16][O:15][CH2:14][CH2:13]1
Reactant: O=[N+]([O-])c1ccc(F)cc1O
Reactant: C1COCCN1
Solvent: O
Solvent: CC#N
Product: O=[N+]([O-])c1ccc(N2CCOCC2)cc1O
Temperature: 50 °C
Reaction time: 40 h
Yield: 86.7 %

Procedure:
5-Fluoro-2-nitro-phenol (3.05 g, 19.4 mmol; Alfa Aesar) in Acetonitrile (20 mL) was treated with Morpholine (3.6 mL, 41 mmol) under an atmosphere of Nitrogen. After 40 h at rt, the mixture was heated at 50° C. for 6 h to drive to completion. The mixture was concentrated to ca. ½ volume, precipitate formed and the mixture was diluted with 100 mL water. The solids were collected and washed 2×50 mL water then dried to afford 5-Morpholin-4-yl-2-nitro-phenol as a yellow solid (3.77 g, 87%). 1H-NMR (DMSO): 7.88 (d, 1H, J=9.6 Hz), 6.64 (dd, 1H, J=2.4, 9.6 Hz), 6.43 (d, 1H, J=2.4 Hz), 3.70 (t, 4H, J=4.8 Hz), 3.41 (t, 4H, J=4.8 Hz).
Reaction SMILES: [C:1]1([S:11]([N:14]2[CH2:19][CH:18]3[CH:16]([CH:17]3[NH:20][C:21]3[N:26]=CC(C(OCC)=O)=[CH:23][N:22]=3)[CH2:15]2)(=[O:13])=[O:12])[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][CH:2]=1.[OH-:32].[Na+].Cl.[CH2:35]1[CH2:39][O:38]C[CH2:36]1>CO>[CH:10]1[C:5]2[C:4](=[CH:9][CH:8]=[CH:7][CH:6]=2)[CH:3]=[CH:2][C:1]=1[S:11]([N:14]1[CH2:19][CH:18]2[CH:16]([CH:17]2[NH:20][C:21]2[N:26]=[CH:36][C:35]([C:39]([OH:38])=[O:32])=[CH:23][N:22]=2)[CH2:15]1)(=[O:13])=[O:12]
Reactant: [OH-]
Reactant: C1CCOC1
Reactant: CCOC(=O)c1cnc(NC2C3CN(S(=O)(=O)c4cccc5ccccc45)CC32)nc1
Agent: Cl
Agent: [Na+]
Solvent: CO
Product: O=C(O)c1cnc(NC2C3CN(S(=O)(=O)c4ccc5ccccc5c4)CC32)nc1
Temperature: 25 °C
Reaction time: 2.5 h
Yield: 88 %

Procedure:
To a solution of ethyl 2-{[3-(napthylsulfonyl)-3-azabicyclo[3.1.0]hex-6-yl]amino}pyrimidine-5-carboxylate (127 mg, 0.29 mmol) in THF (5 ml) and MeOH (1 ml) was added 1M NaOH (4 ml). The solution was stirred at r.t. for 2.5 h. The reaction mixture was acidified to pH˜⅚ with 2M HCl to give a white precipitate which was collected by filtration, washed with water and dried in vacuo to give the title compound as a white solid (105 mg, 88%). LC-MS purity 100%, m/z 411 [M+H]+.
Reaction SMILES: [C:1]1([NH2:9])[CH:6]=[CH:5][CH:4]=[C:3]([NH2:7])[C:2]=1[NH2:8].[OH2:10].[C:11](#N)C>>[NH2:7][C:3]1[C:2]2[NH:8][C:11](=[O:10])[NH:9][C:1]=2[CH:6]=[CH:5][CH:4]=1
Reactant: CC#N
Reactant: Nc1cccc(N)c1N
Reactant: O
Product: Nc1cccc2[nH]c(=O)[nH]c12
Temperature: 25 °C
Reaction time: 6 h
Yield: 42 %

Procedure:
0.53 g (6.5 mmol, 2 eq) of N—N′-carbonyliimidazole were added portionwise to 450.7 mg (3.24 mmol, 1 eq) of benzene-1,2,3-triamine in solution in 30 ml of acetonitrile. The reaction medium was stirred at ambient temperature for 6 hours and then heated at 70° C. overnight. The reaction was stopped by adding 50 ml of water and then extracted with ethyl acetate. The organic phases were combined, and dried over sodium sulfate. The solvents were evaporated off and then the residue was purified by chromatography on silica gel (dichloromethane/methanol/aqueous ammonia: 95/5/2). 229.9 mg of 4-amino-1,3-dihydrobenzoimidazol-2-one were obtained. Yield=42%.
Reaction SMILES: CS(O[CH2:6][C:7]1[N:12]=[CH:11][C:10]2[N:13]([C:16]3[S:17][C:18]([C:34](=[O:36])[NH2:35])=[C:19]([O:21][C@@H:22]([C:24]4[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=4[C:30]([F:33])([F:32])[F:31])[CH3:23])[CH:20]=3)[CH:14]=[N:15][C:9]=2[CH:8]=1)(=O)=O.[CH3:37][NH2:38]>CO>[CH3:37][NH:38][CH2:6][C:7]1[N:12]=[CH:11][C:10]2[N:13]([C:16]3[S:17][C:18]([C:34]([NH2:35])=[O:36])=[C:19]([O:21][C@@H:22]([C:24]4[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=4[C:30]([F:32])([F:33])[F:31])[CH3:23])[CH:20]=3)[CH:14]=[N:15][C:9]=2[CH:8]=1
Reactant: C[C@@H](Oc1cc(-n2cnc3cc(COS(C)(=O)=O)ncc32)sc1C(N)=O)c1ccccc1C(F)(F)F
Reactant: CN
Solvent: CO
Product: CNCc1cc2ncn(-c3cc(O[C@H](C)c4ccccc4C(F)(F)F)c(C(N)=O)s3)c2cn1

Procedure:
A solution of 75 mg of crude [3-(5-carbamoyl-4-{(1R)-1-[2-(trifluoromethyl)phenyl]ethoxy}-2-thienyl)-3H-imidazo[4,5-c]pyridin-6-yl]methyl methanesulfonate (example 49, step 1) and 0.32 ml methylamine (2 M solution in methanol) in 1.5 ml methanol is stirred in a microwave vial at 120° C. for 6 h in the microwave cavity. The reaction mixture is concentrated to dryness and the resulting residue is purified by preparative HPLC (ammonium formate buffer/acetonitrile, elution gradient 97/3 to 0/100 (v/v)) to obtain the title product.
Reaction SMILES: B(F)(F)F.CCOCC.[CH:10]([O:17][CH2:18][CH3:19])([O:14][CH2:15][CH3:16])OCC.[CH3:20][O:21][C:22]([O:27][CH3:28])([CH3:26])[C:23](=[O:25])[CH3:24].C(N(CC)C(C)C)(C)C.C(=O)([O-])O.[Na+]>ClCCl>[CH2:18]([O:17][CH:10]([O:14][CH2:15][CH3:16])[CH2:24][C:23](=[O:25])[C:22]([O:27][CH3:28])([O:21][CH3:20])[CH3:26])[CH3:19]
Reactant: CCOC(OCC)OCC
Reactant: COC(C)(OC)C(C)=O
Agent: FB(F)F
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Solvent: CCOCC
Product: CCOC(CC(=O)C(C)(OC)OC)OCC
Temperature: -78 °C
Reaction time: 0.17 h
Yield: 100 %

Procedure:
Boron trifluoride etherate (17.03 g, 120.0 mmol) was added drop-wise over 15 min to a cooled (−40° C.) solution of triethyl orthoformate (14.82 g, 100.0 mmol) in dichloromethane (50 ml). Stirring was continued for 10 min then the solution was transferred to an ice-water bath and stirred at 0° C. for 20 min. The mixture was cooled to −78° C., and 3,3-dimethoxy-2-butanone (6.61 g, 50.0 mmol) added followed by dropwise addition of N,N-diisopropylethylamine (19.39 g, 150.0 mmol) over 15 min. Stirring was continued for 1 h then the solution was poured onto a vigorously stirred mixture of saturated sodium hydrogencarbonate solution (500 ml) and dichloromethane (200 ml). The organic phase was separated, washed with ice-cold 1M sulfuric acid solution (2×500 ml) and ice-cold water (2×500 ml), dried over anhydrous sodium sulfate solution and evaporated to give 1,1-diethoxy-4,4-dimethoxypentan-3-one (11.72 g, 100%) as an orange oil.
Reaction SMILES: [O:1]=[CH:2][C@H:3]([C@@H:5]([C@@H:7]([CH2:9][OH:10])[OH:8])[OH:6])[OH:4].N1C=CN=C1.[C:16]([Si:20](Cl)([C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1)[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)([CH3:19])([CH3:18])[CH3:17]>CN(C=O)C.CCOC(C)=O>[Si:20]([O:1][CH2:2][C@H:3]1[O:4][C@@H:9]([OH:10])[C@@H:7]([OH:8])[CH:5]1[OH:6])([C:16]([CH3:19])([CH3:18])[CH3:17])([C:27]1[CH:28]=[CH:29][CH:30]=[CH:31][CH:32]=1)[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1
Reactant: O=C[C@@H](O)[C@H](O)[C@H](O)CO
Reactant: CC(C)(C)[Si](Cl)(c1ccccc1)c1ccccc1
Agent: c1c[nH]cn1
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CC(C)(C)[Si](OC[C@H]1O[C@@H](O)[C@@H](O)C1O)(c1ccccc1)c1ccccc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 25.7 %

Procedure:
To a stirred solution of D-arabinose (50 g, 0.33 mol) in DMF (500 mL) was added imidazole (45 g, 0.66 mol) and tert-butylchlorodiphenylsilane (109 g, 0.4 mol). After being stirred at room temperature for 2 hours, the resulting solution was diluted with EtOAc (2000 mL), washed with water, brine and dried over Na2SO4. The organic layer was concentrated in vacuo and the residue was purified by column chromatography on silica gel (eluting with 1:11 EtOAc in petroleum ether) to afford 33 g of (2R,3S,5R)-5-[[tert-butyl(diphenyl)silyl]oxymethyl]tetrahydrofuran-2,3,4-triol (compound 25a).
Reaction SMILES: [CH3:1][NH:2][C:3](=[O:20])[C@H:4]([CH2:16][CH:17]([CH3:19])[CH3:18])[NH:5]C(OCC1C=CC=CC=1)=O.[H][H]>[Pd].CO>[CH3:1][NH:2][C:3](=[O:20])[C@H:4]([CH2:16][CH:17]([CH3:19])[CH3:18])[NH2:5]
Reactant: CNC(=O)[C@H](CC(C)C)NC(=O)OCc1ccccc1
Reactant: [H][H]
Agent: [Pd]
Solvent: CO
Product: CNC(=O)[C@@H](N)CC(C)C

Procedure:
A mixture of intermediate 20A (1.20 g, 4.31 mmol) and 10% palladium on carbon (300 mg) in MeOH (30 mL) was hydrogenated with a Parr shaker under 55 psi of hydrogen gas for 3 h. After filtration through celite, the filtrate was evaporated and azeotroped with EtOAc to give the desired intermediate 20B as white solid (quant. yield). LCMS (+ESI) m/z 145.1 [M+H]+.
Reaction SMILES: [S:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[NH:3][CH2:2]1.NC1C=CC=CC=1S.C=O.[CH3:20][O:21][C:22]1[C:30]([C:31]([F:34])([F:33])[F:32])=[CH:29][C:25]([C:26](Cl)=[O:27])=[CH:24][C:23]=1[C:35]([N:37]1[CH2:41][CH2:40][CH2:39][CH2:38]1)=[O:36]>C(Cl)(Cl)Cl.C(N(CC)CC)C>[CH3:20][O:21][C:22]1[C:30]([C:31]([F:34])([F:33])[F:32])=[CH:29][C:25]([C:26]([N:3]2[C:4]3[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=3[S:1][CH2:2]2)=[O:27])=[CH:24][C:23]=1[C:35]([N:37]1[CH2:41][CH2:40][CH2:39][CH2:38]1)=[O:36]
Reactant: c1ccc2c(c1)NCS2
Reactant: COc1c(C(=O)N2CCCC2)cc(C(=O)Cl)cc1C(F)(F)F
Agent: C=O
Agent: Nc1ccccc1S
Solvent: ClC(Cl)Cl
Solvent: CCN(CC)CC
Product: COc1c(C(=O)N2CCCC2)cc(C(=O)N2CSc3ccccc32)cc1C(F)(F)F
Temperature: 25 °C
Reaction time: 2 h

Procedure:
2,3-dihydro-1,3-benzothiazole synthesized from 2-aminobenzenethiol (464 mg) and 37% formalin (0.31 mL) in the same manner as in Example 1 was dissolved in chloroform (10 mL), and triethylamine (1.03 mL) and 4-methoxy-3-(pyrrolidine-1-carbonyl)-5-trifluoromethylbenzoyl chloride were added to the solution, and then the mixture was stirred at room temperature for 2 hours. The solvent was distilled off under reduced pressure and water was added, and then the mixture was extracted with ethyl acetate. The organic layer was washed with 1N hydrochloric acid, 1N sodium hydroxide and saturated brine, and then dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure and the obtained residue was purified by silica gel column chromatography (n-hexane:ethyl acetate=1:2) to obtain the title compound (778 mg) as a pale yellow amorphous product.
Reaction SMILES: [F:1][C:2]1[C:9]([O:10][CH3:11])=[C:8]([O:12][CH3:13])[CH:7]=[CH:6][C:3]=1[CH:4]=O.FC1C=CC=C(OC)C=1OC.[Cl:25]COCCl>C(O)(=O)C>[F:1][C:2]1[C:9]([O:10][CH3:11])=[C:8]([O:12][CH3:13])[CH:7]=[CH:6][C:3]=1[CH2:4][Cl:25]
Reactant: COc1ccc(C=O)c(F)c1OC
Reactant: ClCOCCl
Agent: COc1cccc(F)c1OC
Solvent: CC(=O)O
Product: COc1ccc(CCl)c(F)c1OC

Procedure:
The 2-fluoroveratraldehyde used as indicated above is prepared as follows: 3-fluoroveratrole is reacted with monochloromethyl ether in glacial acetic acid to give 2-fluoro-3,4-dimethoxybenzyl chloride which is treated with hexamethylenetetramine in chloroform followed by refluxing in 50% acetic acid to yield the 2-fluoroveratraldehyde.
Reaction SMILES: [O:1]1CCCC1.ClCl.[O:8]1[CH:12]=[CH:11][CH:10]=[C:9]1[CH:13]([OH:15])[CH3:14].BrBr>O>[CH3:14][C:13]1[O:15][CH:12]=[CH:11][C:10](=[O:1])[C:9]=1[OH:8]
Reactant: CC(O)c1ccco1
Reactant: C1CCOC1
Agent: BrBr
Agent: ClCl
Solvent: O
Product: Cc1occc(=O)c1O
Temperature: 0 °C

Procedure:
In a 3-neck round bottom flask equipped with a magnetic stirring bar, a gas inlet tube, a thermometer and an addition funnel was added 50 ml of tetrahydrofuran and 50 ml of water. This solution was then cooled to 0° C. and chlorine (0.10 mole) was added slowly to the reaction flask while 1(2-furyl)-1-ethanol (0.09 mole) was added dropwise. The temperature of the reaction mixture was not allowed to exceed 10° C. Bromine (0.10 mole) was then added and the reaction mixture heated to reflux. Following the isolation procedure of Example 1, a yield of 5.7 g of maltol was obtained.
Reaction SMILES: [OH-].[K+].C([O:5][C:6]([CH:8]1[CH2:13][CH2:12][CH:11]([C:14]2[CH:15]=[C:16]3[C:21](=[C:22]([C:24]4[CH:29]=[CH:28][CH:27]=[C:26]([O:30][CH3:31])[CH:25]=4)[N:23]=2)[N:20]=[CH:19][CH:18]=[CH:17]3)[CH2:10][CH2:9]1)=[O:7])C>C1COCC1.C(O)C.C(OCC)(=O)C>[CH3:31][O:30][C:26]1[CH:25]=[C:24]([C:22]2[N:23]=[C:14]([CH:11]3[CH2:10][CH2:9][CH:8]([C:6]([OH:7])=[O:5])[CH2:13][CH2:12]3)[CH:15]=[C:16]3[C:21]=2[N:20]=[CH:19][CH:18]=[CH:17]3)[CH:29]=[CH:28][CH:27]=1
Reactant: CCOC(=O)C1CCC(c2cc3cccnc3c(-c3cccc(OC)c3)n2)CC1
Agent: [K+]
Agent: [OH-]
Solvent: CCOC(C)=O
Solvent: CCO
Solvent: C1CCOC1
Product: COc1cccc(-c2nc(C3CCC(C(=O)O)CC3)cc3cccnc23)c1
Temperature: 80 °C

Procedure:
Potassium hydroxide (2 M, 0.9 ml) is added to a solution of 4-[8-(3-Methoxy-phenyl)-[1,7]naphthyridin-6-yl]-cyclohexanecarboxylic acid ethyl ester (230 mg, 0.6 mmol) in THF/ethanol (6 ml:2 ml) and heated at 80° C. for 3 hours. The solution is then diluted with ethyl acetate (120 ml) and extracted with water. The aqueous layer is taken to pH 4 with 1M HCl to give a white precipitate, which is extracted into dichloromethane (DCM). The DCM layer is washed with water, then dried over magnesium sulfate, filtered and concentrated to yield the desired product. M.p 209-212° C. MS (AP+) 362.9
Reaction SMILES: [CH3:1][C:2]1[N:3]([C:7]2[CH:12]=[CH:11][C:10]([NH:13][C:14]3[N:15]=[C:16](OS(C(F)(F)F)(=O)=O)[C:17]4[CH2:23][N:22]([C:24]([O:26][C:27]([CH3:30])([CH3:29])[CH3:28])=[O:25])[CH2:21][CH2:20][C:18]=4[N:19]=3)=[CH:9][CH:8]=2)[CH:4]=[CH:5][N:6]=1.[CH2:39]([NH:46][CH2:47][CH2:48][OH:49])[C:40]1[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=1>CN(C=O)C>[CH2:39]([N:46]([CH2:47][CH2:48][OH:49])[C:16]1[C:17]2[CH2:23][N:22]([C:24]([O:26][C:27]([CH3:29])([CH3:28])[CH3:30])=[O:25])[CH2:21][CH2:20][C:18]=2[N:19]=[C:14]([NH:13][C:10]2[CH:9]=[CH:8][C:7]([N:3]3[CH:4]=[CH:5][N:6]=[C:2]3[CH3:1])=[CH:12][CH:11]=2)[N:15]=1)[C:40]1[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=1
Reactant: Cc1nccn1-c1ccc(Nc2nc3c(c(OS(=O)(=O)C(F)(F)F)n2)CN(C(=O)OC(C)(C)C)CC3)cc1
Reactant: OCCNCc1ccccc1
Solvent: CN(C)C=O
Product: Cc1nccn1-c1ccc(Nc2nc3c(c(N(CCO)Cc4ccccc4)n2)CN(C(=O)OC(C)(C)C)CC3)cc1
Temperature: 85 °C
Reaction time: 8 h
Yield: 48.4 %

Procedure:
tert-Butyl 2-(4-(2-methyl-1H-imidazol-1-yl)phenylamino)-4-(trifluoromethylsulfonyloxy)-7,8-dihydropyrido[4,3-d]pyrimidine-6(5H)-carboxylate (250 mg, 0.45 mmol, example 69c) was dissolved in DMF (2 mL). 2-(benzylamino)ethanol (68.2 mg, 0.45 mmol) was added and the reaction was stirred at 85° C. overnight. The solvent was evaporated under reduced pressure and the crude was purified by flash column chromatography using dichloromethane and methanol as eluent yielding tert-butyl 4-(benzyl(2-hydroxyethyl)amino)-2-(4-(2-methyl-1H-imidazol-1-yl)phenylamino)-7,8-dihydropyrido[4,3-d]pyrimidine-6(5H)-carboxylate (121 mg, 48.3%). MS (ES−) m/z 554 (M−H)−
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([C:11]#[C:12][C:13]2[C:21]3[C:20]([NH2:22])=[N:19][CH:18]=[N:17][C:16]=3[N:15]([C@H:23]3[CH2:27][CH2:26][NH:25][CH2:24]3)[CH:14]=2)[CH:6]=[C:7]([O:9][CH3:10])[CH:8]=1.CCN(C(C)C)C(C)C.[Br:37][CH2:38][CH:39]=[CH:40][C:41](Cl)=[O:42].C(=O)(O)[O-].[Na+]>C(Cl)(Cl)Cl>[NH2:22][C:20]1[C:21]2[C:13]([C:12]#[C:11][C:5]3[CH:4]=[C:3]([O:2][CH3:1])[CH:8]=[C:7]([O:9][CH3:10])[CH:6]=3)=[CH:14][N:15]([C@H:23]3[CH2:27][CH2:26][N:25]([C:41](=[O:42])[CH:40]=[CH:39][CH2:38][Br:37])[CH2:24]3)[C:16]=2[N:17]=[CH:18][N:19]=1
Reactant: O=C(Cl)C=CCBr
Reactant: COc1cc(C#Cc2cn([C@H]3CCNC3)c3ncnc(N)c23)cc(OC)c1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClC(Cl)Cl
Solvent: CCN(C(C)C)C(C)C
Product: COc1cc(C#Cc2cn([C@H]3CCN(C(=O)C=CCBr)C3)c3ncnc(N)c23)cc(OC)c1
Temperature: 0 °C
Reaction time: 0.25 h

Procedure:
The crude product (100 mg) of (S)-5-((3,5-dimethoxyphenyl)ethynyl)-7-(pyrrolidin-3-yl)-7H-pyrrolo[2,3-d]pyrimidin-4-amine (i.e., the intermediate obtained in Example 38 (Step 4)) was suspended in chloroform (3.0 ml). DIPEA (117 μl) was added to the suspension, and the mixture was cooled to 0° C. A solution of 4-bromobut-2-enoyl chloride (46 mg) obtained in Example 16 (Step 1) in chloroform (0.3 ml) was added thereto dropwise, and the resulting mixture was stirred at room temperature for 15 minutes. After halting the reaction using a saturated aqueous sodium bicarbonate solution, the resulting product was extracted with ethyl acetate. The organic layer was dried over anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure to obtain the title compound as a crude product (140 mg). Physical properties: m/z[M+H]+509.9, 511.9
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].Br[CH2:15][C:16]1[CH:21]=[CH:20][C:19]([C:22]2[C:23]([C:28]#[N:29])=[CH:24][CH:25]=[CH:26][CH:27]=2)=[CH:18][CH:17]=1>O1CCCC1>[C:28]([C:23]1[CH:24]=[CH:25][CH:26]=[CH:27][C:22]=1[C:19]1[CH:18]=[CH:17][C:16]([CH2:15][CH:4]([C:5]([O:7][CH2:8][CH3:9])=[O:6])[C:3]([O:11][CH2:12][CH3:13])=[O:10])=[CH:21][CH:20]=1)#[N:29]
Reactant: CCOC(=O)CC(=O)OCC
Reactant: N#Cc1ccccc1-c1ccc(CBr)cc1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CCOC(=O)C(Cc1ccc(-c2ccccc2C#N)cc1)C(=O)OCC
Yield: 95 %

Procedure:
To a mixture of sodium hydride (2.86 g) and tetrahydrofuran (250 mL) were added a solution of diethyl malonate (16.7 mL) in tetrahydrofuran (100 mL) and then 4′-(bromomethyl)biphenyl-2-carbonitrile (15 g), and the mixture was stirred at room temperature for 16 hr. The reaction mixture was concentrated under reduced pressure, and the obtained residue was extracted with 5% aqueous potassium hydrogen sulfate solution and ethyl acetate. The ethyl acetate layer was washed with saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure and the residue was purified by silica gel column chromatography to give the title compound as a colorless oil (18.3 g, 95%).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([NH:18][CH2:19][CH:20]2[CH2:25][CH2:24][NH:23][CH2:22][CH2:21]2)=[C:6]([CH:17]=1)[C:7]([NH:9][C:10]1[CH:15]=[CH:14][C:13]([Cl:16])=[CH:12][N:11]=1)=[O:8].Cl.Cl[C:28]1[CH:33]=[CH:32][N:31]=[CH:30][CH:29]=1.C(N(CC)CC)C>C(O)C>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([NH:18][CH2:19][CH:20]2[CH2:21][CH2:22][N:23]([C:28]3[CH:33]=[CH:32][N:31]=[CH:30][CH:29]=3)[CH2:24][CH2:25]2)=[C:6]([CH:17]=1)[C:7]([NH:9][C:10]1[CH:15]=[CH:14][C:13]([Cl:16])=[CH:12][N:11]=1)=[O:8]
Reactant: Clc1ccncc1
Reactant: O=C(Nc1ccc(Cl)cn1)c1cc(Cl)ccc1NCC1CCNCC1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: CCO
Product: O=C(Nc1ccc(Cl)cn1)c1cc(Cl)ccc1NCC1CCN(c2ccncc2)CC1
Yield: 14.6 %

Procedure:
Using a similar procedure to that described in Example 52, 5-chloro-N-(5-chloropyridin-2-yl)-2-(piperidin-4-ylmethyl)aminobenzamide (400 mg, 1.05 mmol), 4-chloropyridine hydrochloride (791 mg, 5.27 mmol), triethylamine (533 mg, 5.27 mmol), and ethanol (3 mL) yielded 70 mg (15%) of the title compound.
Reaction SMILES: Br.[N:2]1([C:8]([NH2:10])=[NH:9])[CH2:7][CH2:6][O:5][CH2:4][CH2:3]1.[C:11]([O:15][C:16]([N:18]1[CH2:23][CH2:22][CH:21]([C:24](=O)[CH2:25][C:26](OCC)=[O:27])[CH2:20][CH2:19]1)=[O:17])([CH3:14])([CH3:13])[CH3:12].[N+](=C1CCCCCCCCCC1C1CCCCCCCCCC1)=[N-]>C(O)C>[C:11]([O:15][C:16]([N:18]1[CH2:19][CH2:20][CH:21]([C:24]2[CH:25]=[C:26]([OH:27])[N:10]=[C:8]([N:2]3[CH2:7][CH2:6][O:5][CH2:4][CH2:3]3)[N:9]=2)[CH2:22][CH2:23]1)=[O:17])([CH3:14])([CH3:13])[CH3:12]
Reactant: CCOC(=O)CC(=O)C1CCN(C(=O)OC(C)(C)C)CC1
Reactant: N=C(N)N1CCOCC1
Agent: Br
Agent: [N-]=[N+]=C1CCCCCCCCCC1C1CCCCCCCCCC1
Solvent: CCO
Product: CC(C)(C)OC(=O)N1CCC(c2cc(O)nc(N3CCOCC3)n2)CC1
Temperature: 25 °C
Reaction time: 18 h
Yield: 32.4 %

Procedure:
Morpholine-4-carboxamidine hydrobromide (0.267 g) and 4-(2-ethoxycarbonylacetyl)-piperidine-1-carboxylic acid tert-butyl ester (0.38 g, 1.27 mmol) were stirred in ethanol (10 mL) and diazobicycloundecane (285 μl) was added. The reaction stirred for 18 hours at room temperature. The ethanol was removed under reduced pressure and water (25 mL) was added. The solution was acidified (to pH=4) with acetic acid. The product was extracted with dichloromethane (4×30 mL). The dichloromethane was removed and crude product was purified twice on silica gel (Combiflash), eluting with 10% methanol in dichloromethane to provide 4-(6-hydroxy-2-morpholin-4-ylpyrimidin-4-yl)-piperidine-1-carboxylic acid tert-butyl ester (0.15 g, 40.5% yield) as a white solid. 1H NMR (300 MHz, CDCl3/TMS): δ=5.63 (s, 1H), 4.25-4.05 (m, 2H), 3.75 (m, 8H), 2.75-2.65 (m, 2H), 2.47-2.35 (m, 1H), 1.00-1.75 (m, 2H), 1.70-1.50 (m, 2H), 1.46 (s, 9H). 13C NMR (75 MHz, CDCl3/TMS): δ=173.35, 166.87, 154.96, 154.06, 98.88, 79.70, 66.72, 45.13, 44.24, 30.64, 28.82, 27.58.
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][CH2:11][C@H:10]([O:14][C:15]2[CH:20]=[C:19]([C:21]([F:24])([F:23])[F:22])[CH:18]=[CH:17][C:16]=2[NH:25][C:26]2[C:27]3[C:34]([CH3:35])=[C:33]([C:36]([NH2:38])=[O:37])[S:32][C:28]=3[N:29]=[CH:30][N:31]=2)[CH2:9]1)=O)(C)(C)C.Cl>ClCCl.O1CCOCC1>[CH3:35][C:34]1[C:27]2[C:26]([NH:25][C:16]3[CH:17]=[CH:18][C:19]([C:21]([F:22])([F:24])[F:23])=[CH:20][C:15]=3[O:14][C@H:10]3[CH2:11][CH2:12][CH2:13][NH:8][CH2:9]3)=[N:31][CH:30]=[N:29][C:28]=2[S:32][C:33]=1[C:36]([NH2:38])=[O:37]
Reactant: Cc1c(C(N)=O)sc2ncnc(Nc3ccc(C(F)(F)F)cc3O[C@H]3CCCN(C(=O)OC(C)(C)C)C3)c12
Agent: Cl
Solvent: C1COCCO1
Solvent: ClCCl
Product: Cc1c(C(N)=O)sc2ncnc(Nc3ccc(C(F)(F)F)cc3O[C@H]3CCCNC3)c12
Temperature: 25 °C
Reaction time: 1 h

Procedure:
4-[2-((S)-1-tert-butoxycarbonyl-piperidin-3-yloxy)-4-trifluoromethyl-phenylamino]-5-methyl-thieno[2,3-d]pyrimidine-6-carboxylic acid amide (77 mg) was dissolved in dichloromethane (1 ml) and HCl in dioxan (4M; 1.5 ml) was added. The reaction was stirred at room temperature for 1 h. The solvent was removed in vacuo and the residue was purfied by chromatography to give the inteded product.
Reaction SMILES: Cl[C:2]1[N:7]=[CH:6][C:5]([S:8]([N:11]([CH:20]2[CH2:24][CH2:23][CH2:22][CH2:21]2)[CH2:12][CH:13]2[CH2:17][O:16][C:15]([CH3:19])([CH3:18])[O:14]2)(=[O:10])=[O:9])=[CH:4][CH:3]=1.O.[NH2:26][NH2:27]>>[CH:20]1([N:11]([CH2:12][CH:13]2[CH2:17][O:16][C:15]([CH3:19])([CH3:18])[O:14]2)[S:8]([C:5]2[CH:6]=[N:7][C:2]([NH:26][NH2:27])=[CH:3][CH:4]=2)(=[O:10])=[O:9])[CH2:24][CH2:23][CH2:22][CH2:21]1
Reactant: CC1(C)OCC(CN(C2CCCC2)S(=O)(=O)c2ccc(Cl)nc2)O1
Reactant: NN
Solvent: O
Product: CC1(C)OCC(CN(C2CCCC2)S(=O)(=O)c2ccc(NN)nc2)O1
Yield: 99 %

Procedure:
According to Process 4.2, starting with 0.92 g of 6-chloro-N-cyclopentyl-N-[(2,2-dimethyl-1,3-dioxolan-4-yl)methyl]pyridine-3-sulfonamide and 0.24 mL of hydrazine hydrate, 0.85 g of N-cyclopentyl-N-[(2,2-dimethyl-1,3-dioxolan-4-yl)methyl]-6-hydrazinylpyridine-3-sulfonamide is obtained in the form of a yellow oil.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[C:13]2[C:8](=[CH:9][C:10]([Br:14])=[CH:11][CH:12]=2)[NH:7][CH:6]=1)=[O:4].[C:15](=O)([O-])[O-].[K+].[K+].IC>CN(C=O)C.ClCCl>[CH3:1][O:2][C:3]([C:5]1[C:13]2[C:8](=[CH:9][C:10]([Br:14])=[CH:11][CH:12]=2)[N:7]([CH3:15])[CH:6]=1)=[O:4]
Reactant: COC(=O)c1c[nH]c2cc(Br)ccc12
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: ClCCl
Solvent: CN(C)C=O
Solvent: CI
Product: COC(=O)c1cn(C)c2cc(Br)ccc12
Reaction time: 1.5 h
Yield: 99.4 %

Procedure:
To a mixture of 6-bromo-1H-indole-3-carboxylic acid methyl ester (100 mg, 0.394 mmol), potassium carbonate (163 mg, 1.18 mmol) in DMF is added iodomethane (30 μL, 0.47 mmol). The reaction mixture is stirred for 1.5 h. Additional iodomethane (10 μL) is added and the reaction is stirred for 30 minutes. The reaction mixture is diluted with dichloromethane and filtered. The filtrate is concentrated under high vacuum, diluted with ethyl acetate, and concentrated to give the title compound (105 mg, 99%). ES/MS m/e 270.0 (M+2).