Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]1([CH2:7][CH:8]=O)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH2:10]([C@@H:17]1[CH2:22][C@@H:21]([N:23]([CH2:30][C:31]2[C:40]3[C:35](=[CH:36][CH:37]=[CH:38][CH:39]=3)[N:34]=[CH:33][CH:32]=2)[C:24](=[O:29])[C:25]([F:28])([F:27])[F:26])[CH2:20][CH2:19][NH:18]1)[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1.C([O-])(=O)C.[Na+].C([BH3-])#N.[Na+].C(O)(=O)C>C(O)C>[CH2:10]([C@@H:17]1[CH2:22][C@@H:21]([N:23]([CH2:30][C:31]2[C:40]3[C:35](=[CH:36][CH:37]=[CH:38][CH:39]=3)[N:34]=[CH:33][CH:32]=2)[C:24](=[O:29])[C:25]([F:27])([F:28])[F:26])[CH2:20][CH2:19][N:18]1[CH2:8][CH2:7][C:1]1[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1)[C:11]1[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=1
Reactant: O=C(N(Cc1ccnc2ccccc12)[C@H]1CCN[C@H](Cc2ccccc2)C1)C(F)(F)F
Reactant: O=CCc1ccccc1
Agent: CC(=O)[O-]
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CCO
Product: O=C(N(Cc1ccnc2ccccc12)[C@H]1CCN(CCc2ccccc2)[C@H](Cc2ccccc2)C1)C(F)(F)F
Temperature: 25 °C
Reaction time: 16 h

Procedure:
209 μl (0.936 mmol) of phenylacetaldehyde are added dropwise over the course of 10 minutes to a solution of 100 mg (0.233 mmol) of (2R*,4S*)-2-benzyl-N-(4-quinolylmethyl)-N-trifluoroacetyl-4-piperidinamine, 58 mg (0.702 mmol) of sodium acetate, 44 mg (0.702 mmol) of sodium cyanoborohydride and 67 μl (1.17 mmol) of acetic acid in 2 ml of ethanol at room temperature. The reaction mixture is left to stir at room temperature for 16 hours. The residue after evaporation in a rotary evaporator is taken up in ethyl acetate, and the organic phase is washed with water and with brine, dried over magnesium sulfate and evaporated to dryness. The yellow oil is chromatographed on silica gel with methylene chloride/methanol/conc. ammonia (2000:50:1). The title compound is obtained as oil. TLC: methylene chloride/methanol/conc. ammonia (2000:50:1) Rf =0.33, FD-MS: M+ =531.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]([Cl:11])=[C:6]([CH:10]=1)[C:7]([OH:9])=O.C(Cl)(=O)C(Cl)=O.[C:18]1([O:24][CH2:25][CH3:26])[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1.[Cl-].[Al+3].[Cl-].[Cl-]>ClCCl.O.CN(C)C=O>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([Cl:11])=[C:6]([C:7]([C:21]2[CH:22]=[CH:23][C:18]([O:24][CH2:25][CH3:26])=[CH:19][CH:20]=2)=[O:9])[CH:10]=1
Reactant: O=C(O)c1cc(Br)ccc1Cl
Reactant: CCOc1ccccc1
Agent: O=C(Cl)C(=O)Cl
Agent: [Al+3]
Agent: [Cl-]
Solvent: ClCCl
Solvent: O
Solvent: CN(C)C=O
Product: CCOc1ccc(C(=O)c2cc(Br)ccc2Cl)cc1
Temperature: 25 °C
Reaction time: 10 h
Yield: 66.6 %

Procedure:
N,N-Dimethylforamide (9 mL) was added to a suspension of 5-bromo-2-chlorobenzoic acid (1500 g, 6.41 mol) and oxalyl chloride (975 g, 7.69 mol) in a 5 L 4-necked flask containing dichloromethane (2.8 L) at room temperature. Once the vigorous evolution of gas ceased, the reaction was stirred for 10 h at room temperature. The reaction mixture was concentrated under vacuum to give a yellow residue. The residue was dissolved in dichloromethane (1.2 L) in a 5 L 4-necked flask equipped with an internal thermometer and a water condenser. The stirred mixture was cooled to −3° C. and phenetole (799 g, 6.54 mol) was added. Aluminum (III) chloride (973 g, 6.54 mol) was added to the above solution via a solid addition funnel over 1 h while maintaining the internal temperature below 4° C. After the addition was complete, the reaction mixture was stirred for 2 h at 5˜10° C. The reaction was poured into ice (10 kg). The mixture was further stirred at 4° C. for 1 h, diluted with water (3 L), transferred to a 50 L extraction funnel and extracted with dichloromethane (10 L×2). The combined organic layers were washed with 1 N HCl (7.5 L×2), water (10 L), 1N sodium hydroxide (7.5 L×2), brine (10 L×2), dried over sodium sulfate (1000 g), and concentrated. The residue was recrystallized in absolute ethanol (3.5 L) to give the title compound as a white solid (1.450 kg, yield 67%, HPLC purity>99%). 1H NMR (CDCl3, 400 MHz): δ 7.77 (d, J=9 Hz, 2H), 7.49-7.53 (m, 1H), 7.47 (d, J=2.1 Hz, 1H), 7.30 (d, J=9 Hz, 1H), 6.90 (d, J=9 Hz, 2H), 4.10 (q, J=7.2 Hz, 2H), 1.43 (t, J=7.2 Hz, 3H).
Reaction SMILES: [CH2:1]([C:3]1[O:7][C:6]([CH2:8][CH2:9][NH:10][C:11]([NH:13][C:14]2[S:15][C:16]([C:20]3[CH:25]=[C:24]([CH3:26])[N:23]=[C:22]([S:27][CH3:28])[N:21]=3)=[C:17]([CH3:19])[N:18]=2)=[O:12])=[N:5][CH:4]=1)[CH3:2].ClC1C=C(C=CC=1)C(OO)=[O:34].CS(C1N=C(C2SC(N)=NC=2C)C=C(C)N=1)=O>>[CH2:1]([C:3]1[O:7][C:6]([CH2:8][CH2:9][NH:10][C:11]([NH:13][C:14]2[S:15][C:16]([C:20]3[CH:25]=[C:24]([CH3:26])[N:23]=[C:22]([S:27]([CH3:28])=[O:34])[N:21]=3)=[C:17]([CH3:19])[N:18]=2)=[O:12])=[N:5][CH:4]=1)[CH3:2]
Reactant: CCc1cnc(CCNC(=O)Nc2nc(C)c(-c3cc(C)nc(SC)n3)s2)o1
Reactant: O=C(OO)c1cccc(Cl)c1
Agent: Cc1cc(-c2sc(N)nc2C)nc(S(C)=O)n1
Product: CCc1cnc(CCNC(=O)Nc2nc(C)c(-c3cc(C)nc(S(C)=O)n3)s2)o1

Procedure:
This compound is prepared by oxidation of 1-[2-(5-ethyl-oxazol-2-yl)-ethyl]-3-[4-methyl-5-(6-methyl-2-methylsulfanyl-pyrimidin-4-yl)-thiazol-2-yl]-urea with m-CPBA (meta-chloroperoxy-benzoic acid) following the protocol used to prepare 5-(2-Methanesulfinyl-6-methyl-pyrimidin-4-yl)-4-methyl-thiazol-2-ylamine (intermediate AD).
Reaction SMILES: [CH3:1][C:2]1[CH:11]=[CH:10][C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3]=1CO.[CH3:14]C(C1C2C(=CC=CC=2)C=CC=1)=O>>[CH:1]([C:2]1[CH:11]=[CH:10][C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH:3]=1)=[CH2:14]
Reactant: Cc1ccc2ccccc2c1CO
Reactant: CC(=O)c1cccc2ccccc12
Product: C=Cc1ccc2ccccc2c1

Procedure:
The crude hydrogenated product may therefore be treated to recover the desired methylnaphthyl carbinol in a relatively pure form. This may be effected by distilling the crude hydrogenation product at a pressure sufficiently below atmospheric to give a temperature below that which substantial dehydration of the methylnaphthyl carbinol takes place. Alternatively, it has been found that 2-methylnaphthyl carbinol which is produced can be dehydrated in the presence of 1-acetonaphthalene to yield 2-vinylnaphthalene. The 1-acetonaphthalene remains unreacted.
Reaction SMILES: [CH:1]1[CH:6]=C2C=CC(O)=C(C3C4C(=CC=CC=4)C=CC=3O)C2=C[CH:2]=1.CC(O)C.C([Sn](CC=C)(CC=C)CC=C)C=C.[Cl:40][CH2:41][CH2:42][C:43]([C:45]1[CH:50]=[CH:49][C:48]([F:51])=[CH:47][CH:46]=1)=[O:44]>CC(C)[O-].[Ti+4].CC(C)[O-].CC(C)[O-].CC(C)[O-].C(Cl)Cl>[Cl:40][CH2:41][CH2:42][C:43]([C:45]1[CH:46]=[CH:47][C:48]([F:51])=[CH:49][CH:50]=1)([OH:44])[CH2:6][CH:1]=[CH2:2]
Reactant: Oc1ccc2ccccc2c1-c1c(O)ccc2ccccc12
Reactant: O=C(CCCl)c1ccc(F)cc1
Agent: [Ti+4]
Agent: C=CC[Sn](CC=C)(CC=C)CC=C
Agent: CC(C)[O-]
Solvent: CC(C)O
Solvent: ClCCl
Product: C=CCC(O)(CCCl)c1ccc(F)cc1
Temperature: 25 °C
Reaction time: 22 h

Procedure:
To a solution of 1,1′-bi-2-naphthol (0.2280 g, 0.80 mmol, 0.26 equiv), CH2Cl2 (5 mL) and titanium(IV) isopropoxide (0.2243 g, 0.79 mmol, 0.26 equiv) were added 2-propanol (3.1620 g, 52.6 mmol, 17 equiv), tetraallylstannane (1.2538 g, 4.43 mmol, 1.43 equiv), and 3-chloro-1-(4-fluorophenyl)propan-1-one (0.5760 g, 3.09 mmol, 1.0 equiv) successively. The reaction mixture was stirred at rt under nitrogen for 22 h. The reaction was quenched with satd aq NH4Cl and extracted with EtOAc. The organic layer was dried over Na2SO4. After the solvents were evaporated, the residue was purified by chromatography on silica gel eluted with hexanes/ethyl acetate to afford 1-chloro-3-(4-fluorophenyl)hex-5-en-3-ol as an oil.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([C:8]([NH:11][C:12]2[CH:17]=[CH:16][C:15]([I:18])=[CH:14][C:13]=2[F:19])=[CH:9][N:10]=1)[C:5]([OH:7])=O.[N:20]1([CH2:25][CH2:26][CH2:27][NH2:28])[CH:24]=[CH:23][N:22]=[CH:21]1>>[Br:1][C:2]1[CH:3]=[C:4]([C:8]([NH:11][C:12]2[CH:17]=[CH:16][C:15]([I:18])=[CH:14][C:13]=2[F:19])=[CH:9][N:10]=1)[C:5]([NH:28][CH2:27][CH2:26][CH2:25][N:20]1[CH:24]=[CH:23][N:22]=[CH:21]1)=[O:7]
Reactant: O=C(O)c1cc(Br)ncc1Nc1ccc(I)cc1F
Reactant: NCCCn1ccnc1
Product: O=C(NCCCn1ccnc1)c1cc(Br)ncc1Nc1ccc(I)cc1F

Procedure:
2-Bromo-5-(2-fluoro-4-iodo-phenylamino)-N-(3-imidazol-1-yl-propyl)-isonicotinamide was synthesized according to the General Method 3, starting with 145 mg (0.33 mmol) of 2-bromo-5-[(2-fluoro-4-iodophenyl)amino]isonicotinic acid and 103 mg (0.83 mmol) of 3-Imidazol-1-yl-propylamine. Yield: 55 mg, 30%, LC/MS: [7.31 min, 545 (M+1)]
Reaction SMILES: Cl[CH:2]1[CH2:6][CH2:5][CH:4]=[CH:3]1.[OH:7][N:8]1[C:12](=[O:13])[C:11]2=[CH:14][CH:15]=[CH:16][CH:17]=[C:10]2[C:9]1=[O:18].C(N(CC)CC)C>C(#N)C>[CH:2]1([O:7][N:8]2[C:9](=[O:18])[C:10]3=[CH:17][CH:16]=[CH:15][CH:14]=[C:11]3[C:12]2=[O:13])[CH2:6][CH2:5][CH:4]=[CH:3]1
Reactant: ClC1C=CCC1
Reactant: O=C1c2ccccc2C(=O)N1O
Solvent: CCN(CC)CC
Solvent: CC#N
Product: O=C1c2ccccc2C(=O)N1OC1C=CCC1
Yield: 69.1 %

Procedure:
A mixture of 3-chlorocyclopentene (36.9 g), N-hydroxyphthalimide (58.2 g) and triethylamine (53.9 g) in acetonitrile (370 ml) was refluxed for 2 hours. The reaction mixture was poured into icewater. The precipitated crystals were collected by filtration, washed with water and dried over phosphorus pentoxide to give N-(2-cyclopenten-1-yl)oxyphthalimide (56.5 g).
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]2[N:8]([CH2:20][CH3:21])[C:9]([C:11]([N:13]([CH:17]3[CH2:19][CH2:18]3)[CH:14]3[CH2:16][CH2:15]3)=[O:12])=[CH:10][C:5]2=[C:4]2[N:22]([CH3:25])[CH:23]=[N:24][C:3]=12.[C:26]([N:34]=[C:35]=[S:36])(=[O:33])[C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1.O>CC(C)=O>[C:26]([NH:34][C:35](=[S:36])[NH:1][C:2]1[N:7]=[C:6]2[N:8]([CH2:20][CH3:21])[C:9]([C:11]([N:13]([CH:17]3[CH2:19][CH2:18]3)[CH:14]3[CH2:16][CH2:15]3)=[O:12])=[CH:10][C:5]2=[C:4]2[N:22]([CH3:25])[CH:23]=[N:24][C:3]=12)(=[O:33])[C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1
Reactant: O=C(N=C=S)c1ccccc1
Reactant: CCn1c(C(=O)N(C2CC2)C2CC2)cc2c3c(ncn3C)c(N)nc21
Solvent: CC(C)=O
Solvent: O
Product: CCn1c(C(=O)N(C2CC2)C2CC2)cc2c3c(ncn3C)c(NC(=S)NC(=O)c3ccccc3)nc21
Temperature: 0 °C
Yield: 88.4 %

Procedure:
A solution of 4-amino-N,N-dicyclopropyl-6-ethyl-1-methyl-1,6-dihydroimidazo[4,5-d]pyrrolo[2,3-b]pyridine-7-carboxamide (example 1J, 234 mg, 0.69 mmol) and benzoyl isothiocyanate (0.1 ml, 0.83 mmol) in acetone (3 ml) was stirred at room temperature for 3 h. The reaction mixture was cooled to 0° C. and water was added. The resulting brown solid was collected by filtration and air-dried to give 4-(3-benzoylthioureido)-N,N-dicyclopropyl-6-ethyl-1-methyl-1,6-dihydroimidazo[4,5-d]pyrrolo[2,3-b]pyridine-7-carboxamide (306 mg, 88% yield)
Reaction SMILES: [NH2:1][CH2:2][CH2:3][CH2:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][N:6]=1.[S:11]([O-:15])([O-:14])(=[O:13])=[O:12].CS[C:18]([NH2:20])=[NH2+:19].CSC(N)=[NH2+]>O>[S:11]([OH:15])([OH:14])(=[O:13])=[O:12].[N:6]1[CH:7]=[CH:8][CH:9]=[CH:10][C:5]=1[CH2:4][CH2:3][CH2:2][NH:1][C:18]([NH2:20])=[NH:19]
Reactant: NCCCc1ccccn1
Reactant: O=S(=O)([O-])[O-]
Reactant: CSC(N)=[NH2+]
Solvent: O
Product: N=C(N)NCCCc1ccccn1
Product: O=S(=O)(O)O

Procedure:
A solution of 2-(3-aminopropyl)pyridine (2.72 g) and S-methylthiouronium sulphate (2.78 g) in water (40 ml) is heated under reflux for 28 hours. The product isolated by the manner described in Example 1 was recrystallized from methanol, yielding 3-(2-pyridyl)propylguanidine sulphate, m.p. 185°-187° C.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[CH:14]=[C:13]2[C:9]([C:10]([C:19](=[O:30])[NH:20][CH2:21][C:22]3[CH:27]=[CH:26][C:25]([F:28])=[C:24]([F:29])[CH:23]=3)=[C:11]([C:15]([CH3:18])([CH3:17])[CH3:16])[NH:12]2)=[CH:8][CH:7]=1)=[O:5])[CH3:2].[CH2:31](Br)[C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1.C([O-])([O-])=O.[K+].[K+]>CN(C=O)C.CCOC(C)=O>[CH2:31]([N:12]1[C:13]2[C:9](=[CH:8][CH:7]=[C:6]([C:4]([O:3][CH2:1][CH3:2])=[O:5])[CH:14]=2)[C:10]([C:19](=[O:30])[NH:20][CH2:21][C:22]2[CH:27]=[CH:26][C:25]([F:28])=[C:24]([F:29])[CH:23]=2)=[C:11]1[C:15]([CH3:18])([CH3:17])[CH3:16])[C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1
Reactant: BrCc1ccccc1
Reactant: CCOC(=O)c1ccc2c(C(=O)NCc3ccc(F)c(F)c3)c(C(C)(C)C)[nH]c2c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CCOC(=O)c1ccc2c(C(=O)NCc3ccc(F)c(F)c3)c(C(C)(C)C)n(Cc3ccccc3)c2c1
Temperature: 25 °C
Reaction time: 24 h

Procedure:
To a solution of ethyl2-tert-butyl-3-(3,4-difluorobenzylcarbamoyl)-1H-indole-6-carboxylate (Compound 115, 33 mg, 0.080 mmol) in DMF (1 ml) was added benzyl bromide (47 μl, 0.40 mmol) and K2CO3 (33 mg, 0.24 mmol). The mixture was stirred at room temperature for 24 h, diluted with EtOAc, washed with H2O and brine, dried over Na2SO4, and concentrated in vacuo. The residue was purified by chromatography on silica gel (0→30% EtOAc-hexanes) followed by PTLC (5% MeOH—CH2Cl2) to yield the title compound.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([NH:8][CH2:9][CH2:10][CH2:11][C:12]2[CH:17]=[CH:16][CH:15]=[C:14]([O:18][CH3:19])[CH:13]=2)[C:5]([Cl:20])=[CH:4][N:3]=1.[NH2:21][C:22]1[CH:23]=[C:24]([CH:27]=[CH:28][CH:29]=1)[CH2:25][OH:26].O.C1(C)C=CC(S(O)(=O)=O)=CC=1>O1CCOCC1>[Cl:20][C:5]1[C:6]([NH:8][CH2:9][CH2:10][CH2:11][C:12]2[CH:17]=[CH:16][CH:15]=[C:14]([O:18][CH3:19])[CH:13]=2)=[N:7][C:2]([NH:21][C:22]2[CH:23]=[C:24]([CH2:25][OH:26])[CH:27]=[CH:28][CH:29]=2)=[N:3][CH:4]=1
Reactant: COc1cccc(CCCNc2nc(Cl)ncc2Cl)c1
Reactant: Nc1cccc(CO)c1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: O
Solvent: C1COCCO1
Product: COc1cccc(CCCNc2nc(Nc3cccc(CO)c3)ncc2Cl)c1
Temperature: 100 °C
Yield: 80.9 %

Procedure:
To a solution of 2,5-dichloro-N-[3-(3-methoxyphenyl)propyl]pyrimidin-4-amine (0.70 g, 2.2 mmol) and 3-aminobenzyl alcohol (0.38 g, 3.0 mmol) in 1,4-dioxane (19.1 mL) was added p-toluenesulfonic acid monohydrate (0.16 g, 0.82 mmol). The mixture was heated at 100° C. for 16 hours and the reaction was complete. After cooling, the mixture was filtered under vacuum. The cake was washed with cold EtOAc and then H2O to give the desired product as an off-white powder (0.71 g, 79%). LCMS for C21H24ClN4O2 (M+H)+: m/z=399.1.
Reaction SMILES: [F:1][C:2]1[C:11]([OH:12])=[CH:10][CH:9]=[C:8]2[C:3]=1[CH:4]=[CH:5][CH:6]=[C:7]2[C:13]([OH:15])=[O:14].C([O-])([O-])=O.[Cs+].[Cs+].Cl[C:23]1[C:32]2[C:27](=[CH:28][C:29]([O:35][CH3:36])=[C:30]([O:33][CH3:34])[CH:31]=2)[N:26]=[CH:25][CH:24]=1>CS(C)=O>[CH3:34][O:33][C:30]1[CH:31]=[C:32]2[C:27](=[CH:28][C:29]=1[O:35][CH3:36])[N:26]=[CH:25][CH:24]=[C:23]2[O:12][C:11]1[C:2]([F:1])=[C:3]2[C:8](=[CH:9][CH:10]=1)[C:7]([C:13]([OH:15])=[O:14])=[CH:6][CH:5]=[CH:4]2
Reactant: COc1cc2nccc(Cl)c2cc1OC
Reactant: O=C(O)c1cccc2c(F)c(O)ccc12
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CS(C)=O
Product: COc1cc2nccc(Oc3ccc4c(C(=O)O)cccc4c3F)c2cc1OC
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
To a solution of 5-fluoro-6-hydroxy-1-naphthoic acid (1 g, 4.87 mmol) in DMSO (5 mL), Cs2CO3 (4.75 g, 14.61 mmol) was added in one portion. The mixture was stirred at RT 10 min. To the suspension, 4-chloro-6,7-dimethoxyquinoline (1.09 g, 4.87 mmol) was added and the mixture heated to 140° C. O/N. The mixture was allowed to cool to RT, pH adjusted to 7 and the resulting solid filtered and rinsed with water. The title compound was obtained as a tan solid.
Reaction SMILES: [N+:1]([CH:4]1[CH2:9][CH2:8][CH2:7][CH2:6][CH2:5]1)([O-:3])=[O:2].[OH-:10].[Na+].[CH2:12]=O.Cl>O.C(O)C>[N+:1]([C:4]1([CH2:12][OH:10])[CH2:9][CH2:8][CH2:7][CH2:6][CH2:5]1)([O-:3])=[O:2]
Reactant: O=[N+]([O-])C1CCCCC1
Reactant: [OH-]
Reactant: C=O
Agent: Cl
Agent: [Na+]
Solvent: O
Solvent: CCO
Product: O=[N+]([O-])C1(CO)CCCCC1
Reaction time: 1.5 h

Procedure:
A ethanol (5 mL) solution of nitrocyclohexane (5.00 g, 38.7 mmol) and sodium hydroxide (12.5 g, 0.3 mmol) was heated to 55° C., 35% formalin solution (3.0 mL, 35 mmol) was added, and the mixture was heated and stirred at the same temperature for 1.5 hours. The reaction mixture was diluted with water, 2M hydrochloric acid (0.5 mL, 1 mmol) was added, and the mixture was extracted with ethyl acetate (15 mL) two times. The organic layer was washed with 5% sodium bicarbonate aqueous solution (10 mL) and water (20 mL), and then dried with anhydrous sodium sulfate. The solvents were removed by distillation under reduced pressure, the residue was refined with silica gel column chromatography (Highflash 3L, manufactured by Yamazen Corporation, the mixture of hexane and ethyl acetate of 3:1 in mixing ratio), and colorless oily (1-nitro-cyclohexyl)-methanol (6.96 g) was obtained.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[C:9]2[CH:17]=[CH:16][S:15][C:10]=2[NH:11][C:12](=[O:14])[N:13]=1.[H-].[Na+].[CH3:20]I.O>CN(C)C=O>[CH3:20][O:14][C:12]1[N:13]=[C:8]([C:3]2[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=2[Cl:1])[C:9]2[CH:17]=[CH:16][S:15][C:10]=2[N:11]=1
Reactant: CI
Reactant: O=c1nc(-c2ccccc2Cl)c2ccsc2[nH]1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: COc1nc(-c2ccccc2Cl)c2ccsc2n1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a solution of 4.0 g of 4-(o-chlorophenyl)-1,2-dihydrothieno[2,3-d]pyrimidin-2-one in 80 ml of dimethylformamide is added 0.82 g of 63% sodium hydride. The resulting mixture is stirred at room temperature for 30 minutes. Then, 6.48 g of methyl iodide in 33 ml of dimethylformamide is added dropwise thereto. The mixture is stirred for 2 hours at room temperature. The reaction mixture is poured into water and extracted with chloroform. The chloroform extracts are washed with water, dried over sodium sulfate, and the solvent is removed under reduced pressure. The residue is chromatographed on silica gel, using chloroform as an eluent. From the first fraction, 2-methoxy-4-(o-chlorophenyl)-thieno[2,3-d]pyrimidine is obtained as crystals having a melting point of 172.5° - 174.5°C (after recrystallization from ether). From the second fraction, 1-methyl-4-(o-chlorophenyl)-1,2-dihydrothieno[2,3-d]pyrimidin-2-one is obtained as crystals having a melting point of 225° - 226°C (after recrystallization from chloroform-ethanol). From the third fraction, 3-methyl-4-(o-chlorophenyl)-3H-thieno[2,3-d]pyrimidin-2-one is obtained as crystals having a melting point of 190° - 192°C (after recrystallization from ethanol-ether).
Reaction SMILES: [NH2:1][CH2:2][CH2:3][CH2:4][N:5]1[C:9]([CH2:10][O:11][CH2:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)=[CH:8][S:7][C:6]1=[N:19][C:20]1[CH:25]=[CH:24][C:23]([O:26][CH3:27])=[CH:22][N:21]=1.NCCCN1C(COCC2C=CC=CC=2)=CSC1=NC1C=CC(OC(F)(F)F)=CC=1.[ClH:58]>>[NH2:1][CH2:2][CH2:3][CH2:4][N:5]1[C:9]([CH2:10][O:11][CH2:12][C:13]2[CH:18]=[CH:17][C:16]([Cl:58])=[CH:15][CH:14]=2)=[CH:8][S:7][C:6]1=[N:19][C:20]1[CH:25]=[CH:24][C:23]([O:26][CH3:27])=[CH:22][N:21]=1
Reactant: Cl
Reactant: COc1ccc(N=c2scc(COCc3ccccc3)n2CCCN)nc1
Agent: NCCCn1c(COCc2ccccc2)csc1=Nc1ccc(OC(F)(F)F)cc1
Product: COc1ccc(N=c2scc(COCc3ccc(Cl)cc3)n2CCCN)nc1

Procedure:
The compound (276 mg) obtained in Example 210 (1) was treated in a similar manner to in Example 208 (3), (4) to give the title compound (92 mg) as hydrochloride.
Reaction SMILES: [Cl:1][C:2]1[CH:11]=[C:10]2[C:5]([C:6]([N:12]3[C:20]4[C:15](=[CH:16][C:17]([O:21][CH3:22])=[CH:18][CH:19]=4)[C:14]([CH2:23][CH2:24][OH:25])=[C:13]3[CH3:26])=[N:7][CH:8]=[N:9]2)=[CH:4][CH:3]=1.[C:27](OC(=O)C)(=[O:29])[CH3:28]>C1C=CC=CC=1>[C:27]([O:25][CH2:24][CH2:23][C:14]1[C:15]2[C:20](=[CH:19][CH:18]=[C:17]([O:21][CH3:22])[CH:16]=2)[N:12]([C:6]2[C:5]3[C:10](=[CH:11][C:2]([Cl:1])=[CH:3][CH:4]=3)[N:9]=[CH:8][N:7]=2)[C:13]=1[CH3:26])(=[O:29])[CH3:28]
Reactant: CC(=O)OC(C)=O
Reactant: COc1ccc2c(c1)c(CCO)c(C)n2-c1ncnc2cc(Cl)ccc12
Solvent: c1ccccc1
Product: COc1ccc2c(c1)c(CCOC(C)=O)c(C)n2-c1ncnc2cc(Cl)ccc12

Procedure:
A solution of 1-(7-chloroquinazolin-4-yl)-3-(2-hydroxyethyl)-5-methoxy-2-methylindole (0.6g.) and acetic anhydride (0.4g.) in benzene (20ml.; dried over sodium wire) was refluxed for 15 hours. The resulting yellow solution was cooled and washed successively with saturated sodium hydrogen carbonate solution (2 × 20ml.) and water (20ml.), and dried (MgSO4). The solution was evaporated to give 2-[1-(7-chloroquinazolin-4-yl)-5-methoxy-2-methylindol-3-yl]ethyl acetate as an oil [pure by TLC (system A) and having a satisfactory NMR spectrum (--OCH3 τ 6.18)].
Reaction SMILES: [CH:1]1([CH2:7][C@H:8]([N:22]2[CH2:26][C:25]([O:27][C:28]3[C:33]([F:34])=[CH:32][CH:31]=[CH:30][C:29]=3[F:35])=[CH:24][C:23]2=[O:36])[C:9]([NH:11]C2C=CN(CC(O)(C)C)N=2)=[O:10])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.F[P-](F)(F)(F)(F)F.Br[P+](N1CCCC1)(N1CCCC1)N1CCCC1.C(N(CC)C(C)C)(C)C.[CH3:70][O:71][C:72](=[O:80])[C:73]1[CH:78]=[CH:77][C:76](N)=[N:75][CH:74]=1>ClCCl>[CH3:70][O:71][C:72](=[O:80])[C:73]1[CH:78]=[CH:77][C:76]([NH:11][C:9](=[O:10])[C@@H:8]([N:22]2[CH2:26][C:25]([O:27][C:28]3[C:29]([F:35])=[CH:30][CH:31]=[CH:32][C:33]=3[F:34])=[CH:24][C:23]2=[O:36])[CH2:7][CH:1]2[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]2)=[N:75][CH:74]=1
Reactant: CC(C)(O)Cn1ccc(NC(=O)[C@H](CC2CCCCC2)N2CC(Oc3c(F)cccc3F)=CC2=O)n1
Reactant: COC(=O)c1ccc(N)nc1
Agent: Br[P+](N1CCCC1)(N1CCCC1)N1CCCC1
Agent: F[P-](F)(F)(F)(F)F
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: COC(=O)c1ccc(NC(=O)[C@H](CC2CCCCC2)N2CC(Oc3c(F)cccc3F)=CC2=O)nc1
Temperature: 25 °C
Reaction time: 18 h
Yield: 39.2 %

Procedure:
A solution of (S)-3-cyclohexyl-2-[4-(2,6-difluoro-phenoxy)-2-oxo-2,5-dihydro-pyrrol-1-yl]-propionic acid (prepared in Example 36, 90 mg, 0.25 mmol) in dichloromethane (10 mL) was treated with bromotripyrrolidinophosphonium hexafluorophosphate (138 mg, 0.30 mmol), N,N-diisopropylethylamine (95 mg, 0.74 mmol) and 6-aminonicotinic acid methyl ester (45 mg, 0.30 mmol). The reaction mixture was stirred at 25° C. for 18 h under nitrogen. The reaction mixture was diluted with dichloromethane, washed with 2N aqueous hydrochloric acid, saturated sodium bicarbonate solution, a saturated sodium chloride solution and dried over magnesium sulfate. The organic layer was concentrated, and the crude product was purified by ISCO flash chromatography (Teledyne Isco RediSep Flash Column 12 g; 0% to 100% ethyl acetate/hexanes) to afford 6-{(S)-3-cyclohexyl-2-[4-(2,6-difluoro-phenoxy)-2-oxo-2,5-dihydro-pyrrol-1-yl]-propionylamino}-nicotinic acid methyl ester (49 mg, 40%) as a white solid: LR-ES-MS m/z calculated for C26H27F2N3O5 [M]+ 499, observed [M+H]+ 500; 1H NMR (300 MHz, DMSO-d6) δ ppm 0.85-1.35 (m, 6H) 1.49-1.88 (m, 7H) 3.86 (s, 3H) 4.31 (d, J=18.3 Hz, 1H) 4.63 (d, J=18.3 Hz, 1H) 5.03 (m, 1H) 5.07 (s, 1H) 7.30-7.52 (m, 3H) 8.16 (d, J=9.1 Hz, 1H) 8.28 (dd, J=9.1, 2.4 Hz, 1H) 8.87 (d, J=2.4 Hz, 1H) 11.32 (s, 1H).
Reaction SMILES: COC1C=CC(C)=CC=1C(N[C@H]1CCC[C@@H]1NC1C=NC(C(F)(F)F)=CN=1)=O.Cl.[F:30][C:31]([F:46])([F:45])[C:32]1[N:33]=[CH:34][C:35]([NH:38][C@H:39]2[CH2:43][CH2:42][CH2:41][C@@H:40]2[NH2:44])=[N:36][CH:37]=1.[F:47][C:48]1[CH:56]=[CH:55][CH:54]=[C:53]([N:57]2[CH:61]=[CH:60][CH:59]=[N:58]2)[C:49]=1[C:50](O)=[O:51]>>[F:47][C:48]1[CH:56]=[CH:55][CH:54]=[C:53]([N:57]2[CH:61]=[CH:60][CH:59]=[N:58]2)[C:49]=1[C:50]([NH:44][C@H:40]1[CH2:41][CH2:42][CH2:43][C@@H:39]1[NH:38][C:35]1[CH:34]=[N:33][C:32]([C:31]([F:30])([F:45])[F:46])=[CH:37][N:36]=1)=[O:51]
Reactant: N[C@H]1CCC[C@@H]1Nc1cnc(C(F)(F)F)cn1
Reactant: O=C(O)c1c(F)cccc1-n1cccn1
Agent: COc1ccc(C)cc1C(=O)N[C@H]1CCC[C@@H]1Nc1cnc(C(F)(F)F)cn1
Agent: Cl
Product: O=C(N[C@H]1CCC[C@@H]1Nc1cnc(C(F)(F)F)cn1)c1c(F)cccc1-n1cccn1

Procedure:
Prepared according to the procedure for 2-methoxy-5-methyl-N-[(1S,2S)-2-{[5-(trifluoromethyl)pyrazin-2-yl]amino}cyclopentyl]benzamide (Example 37) from (1S,2S)-1-N-[5-(trifluoromethyl)pyrazin-2-yl]cyclopentane-1,2-diamine hydrochloride (Intermediate 14; 75 mg, 0.27 mmol) and 2-fluoro-6-(1H-pyrazol-1-yl)benzoic acid (CAS number 1521055-55-9; 75 mg, 0.37 mmol) except this was purified by column chromatography (silica, 40-100% ethyl acetate/petrol) to afford the title compound.