Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[S:6][C:5]([NH2:7])=[N:4][C:3]=1[C:8]1[CH:9]=[N:10][CH:11]=[CH:12][CH:13]=1.[CH:14](N)=[O:15].N>C(O)=O.O>[Cl:1][C:2]1[S:6][C:5]([NH:7][CH:14]=[O:15])=[N:4][C:3]=1[C:8]1[CH:9]=[N:10][CH:11]=[CH:12][CH:13]=1
Reactant: NC=O
Reactant: Nc1nc(-c2cccnc2)c(Cl)s1
Agent: N
Solvent: O
Solvent: O=CO
Product: O=CNc1nc(-c2cccnc2)c(Cl)s1

Procedure:
5-Chloro-4-(pyridin-3-yl)-thiazol-2-amine (20 g) was dissolved in formic acid (40 ml) and formamide (20 ml) and the mixture was heated at 90° C. for six hours. After cooling, the mixture was diluted with water (240 ml) and basified with aqueous ammonia solution. The resulting solid was isolated by filtration, and dried in vacuo at 60° C. to give N-[5-chloro-4-(pyridin-3-yl)-thiazol-2-yl]-formamide, (22,8 g) Mp 229° C.
Reaction SMILES: [N:1]1([C@H:6]2[CH2:10][CH2:9][CH2:8][C@H:7]2[NH2:11])[CH2:5][CH2:4][CH2:3][CH2:2]1.[Cl:12][C:13]1[CH:21]=[CH:20][C:16]([C:17](O)=[O:18])=[C:15]([CH3:22])[CH:14]=1>>[Cl:12][C:13]1[CH:21]=[CH:20][C:16]([C:17]([NH:11][C@@H:7]2[CH2:8][CH2:9][CH2:10][C@@H:6]2[N:1]2[CH2:2][CH2:3][CH2:4][CH2:5]2)=[O:18])=[C:15]([CH3:22])[CH:14]=1
Reactant: N[C@@H]1CCC[C@@H]1N1CCCC1
Reactant: Cc1cc(Cl)ccc1C(=O)O
Product: Cc1cc(Cl)ccc1C(=O)N[C@@H]1CCC[C@@H]1N1CCCC1

Procedure:
The title compound, light brown viscous oil, MS: m/e=307.2 [(M+H)+], was prepared in accordance with the general method of example 5 from cis-2-pyrrolidin-1-yl-cyclopentylamine (intermediate Q) and 4-chloro-2-methylbenzoic acid.
Reaction SMILES: [CH3:1][N:2]([CH3:17])[C:3]([C:5]1[C:13]([N+:14]([O-:16])=[O:15])=[CH:12][CH:11]=[CH:10][C:6]=1[C:7]([OH:9])=[O:8])=[O:4].[CH2:18](OC1C=C(C=C(N)C=1)C(OCC=C)=O)[CH:19]=[CH2:20]>>[CH3:1][N:2]([CH3:17])[C:3]([C:5]1[C:13]([N+:14]([O-:16])=[O:15])=[CH:12][CH:11]=[CH:10][C:6]=1[C:7]([O:9][CH2:20][CH:19]=[CH2:18])=[O:8])=[O:4]
Reactant: CN(C)C(=O)c1c(C(=O)O)cccc1[N+](=O)[O-]
Reactant: C=CCOC(=O)c1cc(N)cc(OCC=C)c1
Product: C=CCOC(=O)c1cccc([N+](=O)[O-])c1C(=O)N(C)C

Procedure:
2-Dimethylaminocarbonyl-3-nitrobenzoic acid (1 g) was to the allyl ester by a similar method to that described in example 1 for the formation of allyl 3-allyloxy-5-aminobenzoate giving allyl 2-dimethylaminocarbonyl-3-nitrobenzoate (0.88 g). Nmr (DMSO-d6): δ 2.45 (s, 3H); 2.97 (s, 3H); 4.79 (dd, 2H); 5.28-5.47 (m, 2H); 5.9-6.1 (m, 1H); 7.81 (t, 1H); 8.28-8.4 (dq, 2H).
Reaction SMILES: [CH:1]([OH:4])([CH3:3])[CH3:2].S(=O)(=O)(O)O.[N+:10]([C:13]1[CH:34]=[CH:33][C:16]([CH2:17][C@@H:18]([C:30](O)=[O:31])[NH:19][C:20](=[O:29])[C:21]2[C:26]([Cl:27])=[CH:25][CH:24]=[CH:23][C:22]=2[Cl:28])=[CH:15][CH:14]=1)([O-:12])=[O:11]>O1CCCC1>[CH:1]([O:4][C:30](=[O:31])[C@H:18]([CH2:17][C:16]1[CH:15]=[CH:14][C:13]([N+:10]([O-:12])=[O:11])=[CH:34][CH:33]=1)[NH:19][C:20](=[O:29])[C:21]1[C:26]([Cl:27])=[CH:25][CH:24]=[CH:23][C:22]=1[Cl:28])([CH3:3])[CH3:2]
Reactant: O=C(N[C@@H](Cc1ccc([N+](=O)[O-])cc1)C(=O)O)c1c(Cl)cccc1Cl
Reactant: CC(C)O
Agent: O=S(=O)(O)O
Solvent: C1CCOC1
Product: CC(C)OC(=O)[C@H](Cc1ccc([N+](=O)[O-])cc1)NC(=O)c1c(Cl)cccc1Cl
Temperature: 50 °C
Reaction time: 120 h

Procedure:
Isopropanol (130 mL), tetrahydrofuran (50 mL) and sulfuric acid (0.44 mL) were added to 4-nitro-N-(2,6-dichlorobenzoyl)-L-phenylalanine (2.95 g, 7.70 mmol) and stirred at 50° C. for 5 days. After removing the solvent under reduced pressure, the obtained solid material was washed with water and dried to obtain 3.28 g of a white solid material.
Reaction SMILES: [CH2:1]([O:8][C:9]1[C:17]2[C:12](=[CH:13][C:14]([N+:18]([O-])=O)=[CH:15][CH:16]=2)[N:11]([CH2:21][C:22]2[CH:31]=[CH:30][C:25]([C:26]([O:28][CH3:29])=[O:27])=[CH:24][C:23]=2[O:32][CH3:33])[N:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(O)(=O)C>CCOCC.[Zn]>[NH2:18][C:14]1[CH:13]=[C:12]2[C:17]([C:9]([O:8][CH2:1][C:2]3[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=3)=[N:10][N:11]2[CH2:21][C:22]2[CH:31]=[CH:30][C:25]([C:26]([O:28][CH3:29])=[O:27])=[CH:24][C:23]=2[O:32][CH3:33])=[CH:16][CH:15]=1
Reactant: COC(=O)c1ccc(Cn2nc(OCc3ccccc3)c3ccc([N+](=O)[O-])cc32)c(OC)c1
Agent: [Zn]
Solvent: CCOCC
Solvent: CC(=O)O
Product: COC(=O)c1ccc(Cn2nc(OCc3ccccc3)c3ccc(N)cc32)c(OC)c1
Reaction time: 2 h
Yield: 84.7 %

Procedure:
Zinc dust (0.065 g.) was added to a stirred mixture of methyl 4-(3-benzyloxy-6-nitroindazol-1-ylmethyl)-3-methoxybenzoate (CC) (0.043 g.) and acetic acid (0.9 ml.). The mixture was stirred for 2 hours, diluted with ether, and filtered. The filtrate was washed with water, brine, dried (MgSO4), and evaporated to give methyl 4-(6-amino-3-benzyloxyindazol-1-ylmethyl)-3-methoxybenzoate (DD) (0.034 g., 85%) as a brown oil, and was used without further purification as described below.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([C:8](Cl)=[O:9])[N:3]=1.ClC1C=CC=C(C(O)=O)N=1.S(Cl)(Cl)=O.[Br:25][C:26]1[CH:32]=[C:31]([C:33]([F:42])([C:38]([F:41])([F:40])[F:39])[C:34]([F:37])([F:36])[F:35])[CH:30]=[C:29]([C:43]([F:46])([F:45])[F:44])[C:27]=1[NH2:28]>>[Br:25][C:26]1[CH:32]=[C:31]([C:33]([F:42])([C:34]([F:36])([F:37])[F:35])[C:38]([F:39])([F:41])[F:40])[CH:30]=[C:29]([C:43]([F:44])([F:45])[F:46])[C:27]=1[NH:28][C:8](=[O:9])[C:4]1[CH:5]=[CH:6][CH:7]=[C:2]([Cl:1])[N:3]=1
Reactant: O=C(Cl)c1cccc(Cl)n1
Reactant: Nc1c(Br)cc(C(F)(C(F)(F)F)C(F)(F)F)cc1C(F)(F)F
Agent: O=C(O)c1cccc(Cl)n1
Solvent: O=S(Cl)Cl
Product: O=C(Nc1c(Br)cc(C(F)(C(F)(F)F)C(F)(F)F)cc1C(F)(F)F)c1cccc(Cl)n1

Procedure:
According to the method of 1-3 of Example 1, a target compound was prepared from 2-chloropyridine-6-carboxylic acid chloride prepared from 2-chloropyridine-6-carboxylic acid and thionyl chloride, and 2-bromo-4-(perfluoropropan-2-yl)-6-(trifluoromethyl)aniline obtained in 1-2 of Example 1.
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([CH3:10])=[CH:6][CH:5]=1)([O-])=O.CS(C)=[O:13]>CN(C)C=O>[NH2:1][C:4]1[CH:9]=[CH:8][C:7]([CH:10]=[O:13])=[CH:6][CH:5]=1
Reactant: Cc1ccc([N+](=O)[O-])cc1
Reactant: CS(C)=O
Solvent: CN(C)C=O
Product: Nc1ccc(C=O)cc1

Procedure:
The procedure of Example 1 was followed except that 3.2 g (4.8% by weight of the p-nitrotoluene) of dimethylsulfoxide were substituted for the N,N-dimethylformamide, to obtain 38.3 g (0.317 mol) of p-aminobenzaldehyde and then 39.1 g (0.320 mol) of p-hydroxybenzaldehyde. Thus, the yield of the p-hydroxybenzaldehyde was 65.8%, based on the weight of p-nitrotoluene used.
Reaction SMILES: [C:1]([O:5][C:6](=[O:20])[NH:7][C:8]1[CH:13]=[C:12]([C:14]([F:17])([F:16])[F:15])[C:11]([Cl:18])=[CH:10][C:9]=1[NH2:19])([CH3:4])([CH3:3])[CH3:2].C([O:25][C:26](=O)[CH2:27][C:28](=[O:41])[C:29]1[CH:34]=[CH:33][CH:32]=[C:31]([C:35]2[CH:36]=[N:37][CH:38]=[CH:39][CH:40]=2)[CH:30]=1)(C)(C)C>>[C:1]([O:5][C:6](=[O:20])[NH:7][C:8]1[CH:13]=[C:12]([C:14]([F:17])([F:16])[F:15])[C:11]([Cl:18])=[CH:10][C:9]=1[NH:19][C:26](=[O:25])[CH2:27][C:28](=[O:41])[C:29]1[CH:34]=[CH:33][CH:32]=[C:31]([C:35]2[CH:36]=[N:37][CH:38]=[CH:39][CH:40]=2)[CH:30]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)CC(=O)c1cccc(-c2cccnc2)c1
Reactant: CC(C)(C)OC(=O)Nc1cc(C(F)(F)F)c(Cl)cc1N
Product: CC(C)(C)OC(=O)Nc1cc(C(F)(F)F)c(Cl)cc1NC(=O)CC(=O)c1cccc(-c2cccnc2)c1

Procedure:
The title compound was prepared from (2-amino-4-chloro-5-trifluoromethyl-phenyl)-carbamic acid tert-butyl ester (Example J24) (230 mg, 0.74 mmol) and 3-oxo-3-(3-pyridin-3-yl-phenyl)-propionic acid tert-butyl ester (Example K1) (220 mg, 0.74 mmol) according to the general procedure M. Obtained as a light yellow solid (260 mg, 66%).
Reaction SMILES: [C:1]([NH:4][C:5]1[C:13]([Cl:14])=[CH:12][C:8]([C:9]([OH:11])=O)=[C:7]([O:15][CH3:16])[CH:6]=1)(=[O:3])[CH3:2].C(N(CC)CC)C.C(Cl)(=O)OCC.[C:30]([N:33]1[CH2:37][C@@H:36]([NH2:38])[CH2:35][C@H:34]1[CH2:39][OH:40])(=[O:32])[CH3:31]>ClCCl.O>[C:1]([NH:4][C:5]1[C:13]([Cl:14])=[CH:12][C:8]([C:9]([NH:38][C@@H:36]2[CH2:37][N:33]([C:30](=[O:32])[CH3:31])[C@H:34]([CH2:39][OH:40])[CH2:35]2)=[O:11])=[C:7]([O:15][CH3:16])[CH:6]=1)(=[O:3])[CH3:2]
Reactant: COc1cc(NC(C)=O)c(Cl)cc1C(=O)O
Reactant: CC(=O)N1C[C@@H](N)C[C@H]1CO
Agent: CCOC(=O)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Solvent: O
Product: COc1cc(NC(C)=O)c(Cl)cc1C(=O)N[C@H]1C[C@@H](CO)N(C(C)=O)C1
Reaction time: 0.5 h
Yield: 75.7 %

Procedure:
9.84 g of 4-acetylamino-5-chloro-2-methoxybenzoic acid, and 4.5 g of triethylamine were dissolved in 40 ml of dichloromethane, and 4.60 g of ethyl chlorocarbonate was added dropwise to the solution at not higher than 10° C. After stirring at the same temperature for 30 minutes, a solution of 7.03 g of (2S,4S)-(−)-1-acetyl-4-amino-2-hydroxymethylpyrrolidine in dichloromethane (20 ml) was added dropwise. After stirring at the same temperature overnight, water (20 ml) was added, precipitated crystals were filtered, and the resulting crystals were dried in a warm air at 50 to 55° C. to obtain 11.74 g of 4-acetylamino-5-chloro-2-methoxy-N-[(2S,4S)-1-acetyl-2-hydroxymethyl-4-pyrrolidinyl]benzamide.
Reaction SMILES: [C:1]([NH:4][C:5]1[S:9][C:8]2[CH2:10][CH2:11][CH2:12][CH2:13][C:7]=2[C:6]=1[C:14](=[O:21])[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)(=[O:3])[CH3:2].[H-].[Na+].[CH3:24]I.O>CN(C)C=O>[CH3:24][CH2:2][C:1]([NH:4][C:5]1[S:9][C:8]2[CH2:10][CH2:11][CH2:12][CH2:13][C:7]=2[C:6]=1[C:14](=[O:21])[C:15]1[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=1)=[O:3]
Reactant: CC(=O)Nc1sc2c(c1C(=O)c1ccccc1)CCCC2
Reactant: CI
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CCC(=O)Nc1sc2c(c1C(=O)c1ccccc1)CCCC2
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a solution of 5.0 g of 2-acetylamino-3-benzoyl-4,5,6,7-tetrahydrobenzo[b ]thiophene in 60 ml of dimethylformamide is added 0.9 g of 63% sodium hydride. The mixture is stirred at room temperature for 30 minutes. Then 71.3 g of methyl iodide in 20 ml of dimethylformamide is added thereto. The mixture is stirred at room temperature for 3 hours, then poured into water, and extracted with benzene. The benzene extracts are washed with water, dried over sodium sulfate, and the solvent is removed under reduced pressure to give 2-(N-methylacetylamino)-3-benzoyl-4,5,6,7-tetrahydrobenzo[b] thiophene as an oil. This layer chromatography (Kiesel gel) shows the Rf value of 0.44 using a mixture of ethyl acetate and chloroform (1 : 1 V/V).
Reaction SMILES: Br[C:2]1[CH:3]=[N:4][CH:5]=[C:6]([Br:9])[C:7]=1[CH3:8].[C:10]([Cu])#[N:11].CCOC(C)=O>CN(C=O)C>[Br:9][C:6]1[C:7]([CH3:8])=[C:2]([C:10]#[N:11])[CH:3]=[N:4][CH:5]=1
Reactant: N#C[Cu]
Reactant: Cc1c(Br)cncc1Br
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: Cc1c(Br)cncc1C#N

Procedure:
A mixture of 3,5-dibromo-4-methylpyridine (16 g, 64 mmol) and CuCN (6.2 g, 69 mmol) in 150 mL of DMF was refluxed for 4 hours before cooled down. The reaction mixture was poured to 1 L of EtOAc with stirring and the precipitate was removed by filtration. The filtrate was washed with water, brine, dried over anhydrous Na2SO4 and concentrated. The residue was purified by column chromatography to afford 5-bromo-4-methylpyridine-3-carbonitrile.
Reaction SMILES: [CH3:1][C:2]1([CH3:10])[C:4]([CH3:6])([CH3:5])[CH:3]1[C:7](Cl)=[O:8].[C:11]1([C:17]2[CH:25]=[CH:24][CH:23]=[C:22]3[C:18]=2[CH2:19][CH:20]([OH:26])[CH2:21]3)[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1.N1C=CC=CC=1>C1(C)C=CC=CC=1>[CH3:1][C:2]1([CH3:10])[C:4]([CH3:6])([CH3:5])[CH:3]1[C:7]([O:26][CH:20]1[CH2:19][C:18]2[C:22](=[CH:23][CH:24]=[CH:25][C:17]=2[C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[CH2:21]1)=[O:8]
Reactant: CC1(C)C(C(=O)Cl)C1(C)C
Reactant: OC1Cc2cccc(-c3ccccc3)c2C1
Solvent: c1ccncc1
Solvent: Cc1ccccc1
Product: CC1(C)C(C(=O)OC2Cc3cccc(-c4ccccc4)c3C2)C1(C)C
Yield: 63.2 %

Procedure:
In a manner similar to Example 12A, the reaction of 1.09 g (0.007 mole) of 2,2,3,3-tetramethylcyclopropanecarbonyl chloride and 1.5 g (0.007 mole) of (+)-4-phenyl-2-indanol (EE ≥95%) in the presence of 0.7 g (0.009 mole) of pyridine and 20 ml of toluene gave 1.48 g of (+)-4-phenyl-2-indanyl 2,2,3,3-tetramethylcyclopropanecarboxylate, EE≥95%. The nmr spectrum was consistent with the proposed structure.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:8]2[C:9]([CH3:15])=[C:10]([C:12]([OH:14])=O)[O:11][C:7]=2[CH:6]=[CH:5][C:4]=1[CH3:16].[C:17]([O:21][C:22](=[O:44])[C@@H:23]([NH:27][S:28]([C:31]1[CH:36]=[CH:35][C:34]([C:37]2[CH:42]=[CH:41][C:40]([NH2:43])=[CH:39][CH:38]=2)=[CH:33][CH:32]=1)(=[O:30])=[O:29])[CH:24]([CH3:26])[CH3:25])([CH3:20])([CH3:19])[CH3:18].F[P-](F)(F)(F)(F)F.N1(O[P+](N(C)C)(N(C)C)N(C)C)C2C=CC=CC=2N=N1.C(N(CC)C(C)C)(C)C>[Cl-].[Na+].O.CN(C=O)C>[C:17]([O:21][C:22](=[O:44])[C@@H:23]([NH:27][S:28]([C:31]1[CH:32]=[CH:33][C:34]([C:37]2[CH:38]=[CH:39][C:40]([NH:43][C:12]([C:10]3[O:11][C:7]4[CH:6]=[CH:5][C:4]([CH3:16])=[C:3]([O:2][CH3:1])[C:8]=4[C:9]=3[CH3:15])=[O:14])=[CH:41][CH:42]=2)=[CH:35][CH:36]=1)(=[O:30])=[O:29])[CH:24]([CH3:26])[CH3:25])([CH3:19])([CH3:20])[CH3:18]
Reactant: CC(C)[C@H](NS(=O)(=O)c1ccc(-c2ccc(N)cc2)cc1)C(=O)OC(C)(C)C
Reactant: COc1c(C)ccc2oc(C(=O)O)c(C)c12
Agent: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Agent: F[P-](F)(F)(F)(F)F
Agent: [Cl-]
Solvent: CCN(C(C)C)C(C)C
Solvent: O
Solvent: CN(C)C=O
Product: COc1c(C)ccc2oc(C(=O)Nc3ccc(-c4ccc(S(=O)(=O)N[C@H](C(=O)OC(C)(C)C)C(C)C)cc4)cc3)c(C)c12
Temperature: 25 °C
Reaction time: 24 h
Yield: 73.3 %

Procedure:
To 45 mg (0.2 mmol) of 4-methoxy-3,5-dimethyl-benzofuran-2-carboxylic acid was added 124 mg (1.5 eq) of (S)-2-(4′-amino-biphenyl-4-sulfonylamino)-3-methyl-butyric acid tert-butyl ester, BOP (106 mg, 1.2 eq), N,N-diisopropylethylamine (31 mg, 1.2 eq) and 2 mL of DMF. The mixture was stirred at room temperature for 24 h. Brine was added and the mixture was extracted with ethyl acetate. The combined organic solution was washed with 2N HCl and water. Removal of the solvent from the organic solution gave the crude product, which was purified by column chromatography on silica gel to give 89 mg of (S)-2-{4′-[(4-methoxy-3,5-dimethyl-benzofuran-2-carbonyl)-amino]-biphenyl-4-sulfonylamino}-3-methyl-butyric acid tert-butyl ester as an off-white solid.
Reaction SMILES: C(ON=O)(C)(C)C.N[C:9]1[C:16]([Br:17])=[CH:15][C:12]([C:13]#[N:14])=[CH:11][C:10]=1[Br:18]>CN(C)C=O>[Br:17][C:16]1[CH:15]=[C:12]([CH:11]=[C:10]([Br:18])[CH:9]=1)[C:13]#[N:14]
Reactant: N#Cc1cc(Br)c(N)c(Br)c1
Agent: CC(C)(C)ON=O
Solvent: CN(C)C=O
Product: N#Cc1cc(Br)cc(Br)c1
Temperature: 50 °C
Reaction time: 0.5 h

Procedure:
To a stirred solution of t-butylnitrite (53.5 μL, 0.449 mmoles) in 1 ml sieve dried dimethylformamide at 50° C. under an atmosphere of nitrogen was added a solution of 4-amino-3,5-dibromobenzonitrile (50 mg, 0.179 mmoles) in 1 mL of DMF. The mixture was stirred at 50° C. for 0.5 hour and partitioned between diethyl ether, ice-water, and ammonium chloride. The organic phase was separated, washed with water and brine, dried over anhydrous sodium, filtered, and evaporated.
Reaction SMILES: CI.[Cl:3][C:4]1[CH:5]=[C:6]([CH:31]=[CH:32][C:33]=1[O:34][CH3:35])[CH2:7][NH:8][C:9]1[C:18]2[C:13](=[CH:14][CH:15]=[C:16]([C:19]3[NH:23][N:22]=[N:21][N:20]=3)[CH:17]=2)[C:12]([N:24]2[CH2:29][CH2:28][CH:27]([OH:30])[CH2:26][CH2:25]2)=[N:11][N:10]=1.[C:36](=O)([O-])[O-].[K+].[K+].CN(C)C=O>O>[Cl:3][C:4]1[CH:5]=[C:6]([CH:31]=[CH:32][C:33]=1[O:34][CH3:35])[CH2:7][NH:8][C:9]1[C:18]2[C:13](=[CH:14][CH:15]=[C:16]([C:19]3[N:23]([CH3:36])[N:22]=[N:21][N:20]=3)[CH:17]=2)[C:12]([N:24]2[CH2:25][CH2:26][CH:27]([OH:30])[CH2:28][CH2:29]2)=[N:11][N:10]=1
Reactant: O=C([O-])[O-]
Reactant: COc1ccc(CNc2nnc(N3CCC(O)CC3)c3ccc(-c4nnn[nH]4)cc23)cc1Cl
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Solvent: CI
Product: COc1ccc(CNc2nnc(N3CCC(O)CC3)c3ccc(-c4nnnn4C)cc23)cc1Cl
Temperature: 25 °C
Reaction time: 3 h
Yield: 19.4 %

Procedure:
0.037 ml methyl iodide was added to a mixture of 0.25 g 1-[4-[(3-chloro-4-methoxybenzyl)amino]-6-(1H-1,2,3,4-tetrazole-5-yl)-1-phthalazinyl]-4-piperidinol, 1.2 g potassium carbonate and 5 ml dimethylformamide, and stirred at room temperature for 3 hr. Water was added to the reaction solution, and the precipitated insoluble matters were collected by filtration. Then, purified by silica gel column chromatography to give 50 mg of the title compound.
Reaction SMILES: C(OC([N:8](C(OC(C)(C)C)=O)[C:9]1[C:10]2[C:11]3[C:12](=[N:24][N:25]([CH2:27][C:28]4[C:33]([CH3:34])=[C:32]([O:35][CH3:36])[C:31]([CH3:37])=[CH:30][N:29]=4)[N:26]=2)[CH2:13][CH:14](CS([O-])(=O)=O)[C:15]=3[CH2:16][S:17][N:18]=1)=O)(C)(C)C.C(=O)([O-])[O-].[K+].[K+].C(=O)(O)[O-].[Na+]>CN(C)C=O>[CH3:36][O:35][C:32]1[C:31]([CH3:37])=[CH:30][N:29]=[C:28]([CH2:27][N:25]2[N:24]=[C:12]3[CH:13]=[CH:14][C:15]4[CH2:16][S:17][N:18]=[C:9]([NH2:8])[C:10]([C:11]=43)=[N:26]2)[C:33]=1[CH3:34]
Reactant: COc1c(C)cnc(CN2N=C3CC(CS(=O)(=O)[O-])C4=C3C(=N2)C(N(C(=O)OC(C)(C)C)C(=O)OC(C)(C)C)=NSC4)c1C
Agent: O=C([O-])O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: COc1c(C)cnc(Cn2nc3ccc4c-3c(n2)C(N)=NSC4)c1C
Temperature: 70 °C
Reaction time: 6 h
Yield: 36.4 %

Procedure:
A mixture composed of 4-[bis(tert-butoxycarbonyl)amino]-2-[(4-methoxy-3,5-dimethylpyridin-2-yl)methyl]-2,7,8,9-tetrahydro-6-thia-1,2,3,5-tetraazabenzo[cd]azulen-8-ylmethanesulfonate of Example 35 (65 mg), dehydrated N,N-dimethylformamide (1 mL) and potassium carbonate (14 mg) was heated with stirring at 70° C. for six hours. The reaction mixture was cooled and a saturated sodium bicarbonate solution was added, followed by extraction with ethyl acetate. The organic layer was washed with brine, and then dried over anhydrous sodium sulfate. After filtration, the filtrate was concentrated under reduced pressure. Dichloromethane (2 mL) and trifluoroacetic acid (1 mL) were added to the resulting residue, and the mixture was stirred at room temperature for one hour. After confirming that the raw material disappeared, the reaction mixture was concentrated under reduced pressure. A saturated sodium bicarbonate solution was added to the residue, followed by extraction with ethyl acetate. The organic layer was washed with brine, and then dried over sodium sulfate and filtered. Then, the filtrate was concentrated under reduced pressure. The resulting residue was purified by silica gel thin-layer chromatography (chloroform-methanol) to obtain the title compound (12.9 mg, 36%) as a solid.
Reaction SMILES: ClC1N=CC2C=C(C(NC)=O)N(C3CCCC3)C=2N=1.NC1N=CC([N:27]2[C:34](=[O:35])[CH2:33][C@H:32]3[N:36]([C:37]([O:39][C:40]([CH3:43])([CH3:42])[CH3:41])=[O:38])[C@H:29]([CH2:30][CH2:31]3)[CH2:28]2)=CC=1>>[C:40]([O:39][C:37]([N:36]1[CH:32]2[CH2:31][CH2:30][CH:29]1[CH2:28][NH:27][C:34](=[O:35])[CH2:33]2)=[O:38])([CH3:43])([CH3:41])[CH3:42]
Reactant: CC(C)(C)OC(=O)N1[C@@H]2CC[C@H]1CC(=O)N(c1ccc(N)nc1)C2
Agent: CNC(=O)c1cc2cnc(Cl)nc2n1C1CCCC1
Product: CC(C)(C)OC(=O)N1C2CCC1CC(=O)NC2
Yield: 78 %

Procedure:
Following general N—C coupling procedure 1, 2-chloro-7-cyclopentyl-N-methyl-7H-pyrrolo[2,3-d]pyrimidine-6-carboxamide was combined with (1R,6S)-tert-butyl 3-(6-aminopyridin-3-yl)-4-oxo-3,9-diazabicyclo[4.2.1]nonane-9-carboxylate which gave (1R,6S)-3-[6-(7-cyclopentyl-6-methylcarbamoyl-7H-pyrrolo[2,3-d]pyrimidin-2-ylamino)-pyridin-3-yl])-4-oxo-3,9-diaza-bicyclo[4.2.1]nonane-9-carboxylic acid tert-butyl ester (200 mg) in 78% yield. MS 575.8 m/z (M+H)
Reaction SMILES: [CH2:1]([CH:3]([S:12][C:13]#[N:14])[C:4]([C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1)=C)[CH3:2].[BrH:15].C(O)(=O)C.O>C(O)(=O)C>[Br:15][C:13]1[S:12][C:3]([CH2:1][CH3:2])=[C:4]([C:6]2[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=2)[N:14]=1
Reactant: C=C(c1ccccc1)C(CC)SC#N
Reactant: Br
Solvent: CC(=O)O
Solvent: O
Product: CCc1sc(Br)nc1-c1ccccc1
Temperature: 130 °C
Reaction time: 2 h
Yield: 74.2 %

Procedure:
To a solution of 1-ethyl-2-phenylprop-2-en-1-yl thiocyanate (4.15 g, 20.2 mmol) in acetic acid (40 ml) was added a 25% hydrogen bromide/acetic acid (40 ml) solution, and the mixture was stirred at 130° C. for 2 hours. Water was poured into the reaction solution, and the mixture was extracted with chloroform. The extract was washed with water and dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography (hexane:ethyl acetate=9:1) to give the desired product (4.02 g, 74.2%) as an oil.
Reaction SMILES: [CH3:1]C1CCCCO1.[OH:8][C:9]1([C:15]#[C:16][CH2:17][O:18][CH:19]2[CH2:24][CH2:23][CH2:22][CH2:21][O:20]2)[CH2:14][CH2:13][O:12][CH2:11][CH2:10]1>>[OH:8][C:9]1(/[CH:15]=[CH:16]/[CH2:17][O:18][CH:19]2[CH2:24][CH2:23][CH2:22][CH2:21][O:20]2)[CH2:10][CH2:11][O:12][CH:13]([CH3:1])[CH2:14]1
Reactant: OC1(C#CCOC2CCCCO2)CCOCC1
Reactant: CC1CCCCO1
Product: CC1CC(O)(/C=C/COC2CCCCO2)CCO1

Procedure:
The desired compound was prepared according to the method of Example 3, step 1, except substituting 4-hydroxy-4-[3-tetrahydropyran-2-yloxy)-prop-1-ynyl]-2-methyltetrahydropyran, prepared as in step 1, for 4-hydroxy-4-[3-(tetrahydropyran-2-yloxy)-prop-1-ynyl]tetrahydropyran.
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].Br[CH2:8][CH2:9][CH2:10][CH2:11][CH2:12]Br.CN(C)C=O.[NH2:19][C:20]1[CH:21]=[CH:22][C:23]([O:30][CH2:31][C:32]2[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=2)=[C:24]([CH:29]=1)[C:25]([O:27][CH3:28])=[O:26]>C(OCC)(=O)C.O>[CH2:31]([O:30][C:23]1[CH:22]=[CH:21][C:20]([N:19]2[CH2:12][CH2:11][CH2:10][CH2:9][CH2:8]2)=[CH:29][C:24]=1[C:25]([O:27][CH3:28])=[O:26])[C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1
Reactant: BrCCCCCBr
Reactant: COC(=O)c1cc(N)ccc1OCc1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: COC(=O)c1cc(N2CCCCC2)ccc1OCc1ccccc1
Temperature: 70 °C
Reaction time: 0.5 h

Procedure:
Potassium carbonate (5.1 g) and 1,5-dibromopentane (2.5 mL) were sequentially added to an N,N-dimethylformamide (23 mL) solution of methyl 5-amino-2-(benzyloxy)benzoate (4.6 g), followed by stirring at 50 to 55° C. for 1 hour, at 55 to 60° C. for 1 hour, at 70° C. for 1 hour and 30 minutes, and then at 75 to 80° C. for 1 hour and 30 minutes. The reaction mixture was cooled to room temperature, and then water and ethyl acetate were added thereto. The organic layer was separated, washed with a saturated aqueous solution of sodium chloride, and dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The obtained residue was purified by silica gel column chromatography [Kanto Chemical Co., Inc., silica gel 60 (spherical), eluent: 95-65% hexane/ethyl acetate] to obtain 4.3 g of methyl 2-(benzyloxy)-5-(piperidin-1-yl)benzoate as a light yellow oily substance.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([CH3:8])[CH:5]=[CH:4][C:3]=1[C:9](=[O:22])[CH:10]([C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)C(OCC)=O.Cl.[OH-].[Na+]>C1COCC1.O>[F:1][C:2]1[CH:7]=[C:6]([CH3:8])[CH:5]=[CH:4][C:3]=1[C:9](=[O:22])[CH2:10][C:16]1[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=1
Reactant: CCOC(=O)C(C(=O)c1ccc(C)cc1F)c1ccccc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: Cc1ccc(C(=O)Cc2ccccc2)c(F)c1
Temperature: 25 °C
Yield: 79.2 %

Procedure:
Ethyl 3-(2-fluoro-4-methylphenyl)-3-oxo-2-phenylpropanoate (8.0 g, 26.6 mmol) was dissolved in THF (20 mL) and hydrogen chloride (37% wt., 32.0 mL, 400 mmol) was added. The reaction was brought to reflux overnight. After cooled to room temperature, the reaction was diluted with H2O (100 mL) and neutralized to pH 8 with NaOH (4.0 M aq.). The mixture was extracted with EtOAc (3×75 mL), dried over MgSO4, and purified by column chromatography to give the title compound as a clear oil (4.81 g). LCMS m/z=229.1 [M+H]+; 1H NMR (400 MHz, DMSO-d6) δ ppm 2.36 (s, 3H), 4.28 (s, 2H), 7.11-7.18 (m, 2H), 7.19-7.26 (m, 3H), 7.27-7.34 (m, 2H), 7.77 (t, J=8.21 Hz, 1H).