Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]([F:11])([F:10])[C:3]1[CH:4]=[C:5]([CH:7]=[CH:8][CH:9]=1)[NH2:6].Cl[C:13]1[N:18]=[C:17]([NH:19][C:20]2[CH:25]=[CH:24][C:23]([N:26]3[CH:30]=[C:29]([CH3:31])[N:28]=[CH:27]3)=[C:22]([O:32][CH3:33])[CH:21]=2)[CH:16]=[CH:15][CH:14]=1>>[CH3:33][O:32][C:22]1[CH:21]=[C:20]([NH:19][C:17]2[CH:16]=[CH:15][CH:14]=[C:13]([NH:6][C:5]3[CH:7]=[CH:8][CH:9]=[C:3]([C:2]([F:10])([F:11])[F:1])[CH:4]=3)[N:18]=2)[CH:25]=[CH:24][C:23]=1[N:26]1[CH:30]=[C:29]([CH3:31])[N:28]=[CH:27]1
Reactant: Nc1cccc(C(F)(F)F)c1
Reactant: COc1cc(Nc2cccc(Cl)n2)ccc1-n1cnc(C)c1
Product: COc1cc(Nc2cccc(Nc3cccc(C(F)(F)F)c3)n2)ccc1-n1cnc(C)c1

Procedure:
Prepared in analogy to example 62 from 3-trifluoromethylaniline and (6-chloro-pyridin-2-yl)-[3-methoxy-4-(4-methyl-imidazol-1-yl)-phenyl]-amine. The title compound was obtained as a brownish solid (Yield=48%). MS ISP (m/e): 440.3 (100) [(M+H)+]. 1H NMR (DMSO-D6, 300 MHz): δ (ppm)=9.24 (s, 1H), 9.13 (s, 1H), 7.93 (s, 1H), 7.82 (d, 1H), 7.65 (s, 1H), 7.55-7.40 (m, 2H), 7.36 (d, 1H), 7.25-7.10 (m, 3H), 7.00 (s, 1H), 6.32 (t, 2H), 3.54 (s, 3H), 2.15 (s, 3H).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:10]([CH:11]([C:13]3[N:14]([CH2:27][CH3:28])[N:15]=[C:16]([NH:18][CH2:19][C:20]4[CH:25]=[CH:24][C:23]([F:26])=[CH:22][CH:21]=4)[CH:17]=3)O)=[CH:9][N:8]([Si](C(C)C)(C(C)C)C(C)C)[C:5]2=[N:6][CH:7]=1.C([SiH](CC)CC)C.FC(F)(F)C(O)=O>C(#N)C>[Cl:1][C:2]1[CH:3]=[C:4]2[C:10]([CH2:11][C:13]3[N:14]([CH2:27][CH3:28])[N:15]=[C:16]([NH:18][CH2:19][C:20]4[CH:21]=[CH:22][C:23]([F:26])=[CH:24][CH:25]=4)[CH:17]=3)=[CH:9][NH:8][C:5]2=[N:6][CH:7]=1
Reactant: CCn1nc(NCc2ccc(F)cc2)cc1C(O)c1cn([Si](C(C)C)(C(C)C)C(C)C)c2ncc(Cl)cc12
Agent: CC[SiH](CC)CC
Solvent: O=C(O)C(F)(F)F
Solvent: CC#N
Product: CCn1nc(NCc2ccc(F)cc2)cc1Cc1c[nH]c2ncc(Cl)cc12
Temperature: 25 °C
Reaction time: 0.75 h
Yield: 21.9 %

Procedure:
(5-Chloro-1-triisopropylsilanyl-1H-pyrrolo[2,3-b]pyridin-3-yl)-[2-ethyl-5-(4-fluoro-benzylamino)-2H-pyrazol-3-yl]-methanol (630, 0.045 g, 0.081 mmol) was dissolved in acetonitrile (5 mL) and triethylsilane (0.4 mL, 2.0 mmol) was added, followed by trifluoroacetic acid (0.2 mL, 2.0 mmol). The reaction was stirred at room temperature for 45 minutes, then stirred at 60° C. for 45 minutes. The solvent was removed under reduced pressure, ethyl acetate was added and the organic was washed with sodium bicarbonate saturated solution and brine. After drying over anhydrous sodium sulfate, the solvent was evaporated to dryness. Purification with silica gel column chromatography eluting with a gradient of ethyl acetate (40-100%) in hexanes gave the isolation of the desired compound (P-0185, 0.0068 g, 22%). MS (ESI) [M+H+]+=384.1.
Reaction SMILES: [C:1]([O:5][C:6](=[O:36])[C:7]([O:10][C:11]1[CH:16]=[CH:15][C:14]([CH2:17][CH2:18][CH2:19][CH:20]2[C:24](=O)[N:23]([CH2:26][C:27]3[CH:32]=[CH:31][C:30]([CH3:33])=[C:29]([CH3:34])[CH:28]=3)[C:22](=[O:35])[NH:21]2)=[CH:13][CH:12]=1)([CH3:9])[CH3:8])([CH3:4])([CH3:3])[CH3:2]>C1COCC1>[C:1]([O:5][C:6](=[O:36])[C:7]([O:10][C:11]1[CH:12]=[CH:13][C:14]([CH2:17][CH2:18][CH2:19][CH:20]2[CH2:24][N:23]([CH2:26][C:27]3[CH:32]=[CH:31][C:30]([CH3:33])=[C:29]([CH3:34])[CH:28]=3)[C:22](=[O:35])[NH:21]2)=[CH:15][CH:16]=1)([CH3:8])[CH3:9])([CH3:3])([CH3:2])[CH3:4]
Reactant: Cc1ccc(CN2C(=O)NC(CCCc3ccc(OC(C)(C)C(=O)OC(C)(C)C)cc3)C2=O)cc1C
Solvent: C1CCOC1
Product: Cc1ccc(CN2CC(CCCc3ccc(OC(C)(C)C(=O)OC(C)(C)C)cc3)NC2=O)cc1C
Temperature: 25 °C
Reaction time: 32 h
Yield: 46.5 %

Procedure:
A solution of 2-(4-{3-[1-(3,4-dimethyl-benzyl)-2,5-dioxo-imidazolidin-4-yl]-propyl}-phenoxy)-2-methyl-propionic acid tert-butyl ester (0.113 g, 0.228 mmol) in THF (6 mL) was treated dropwise with 1 M solution of borane-THF complex in THF (4.4 mL, 4.4 mmol) and then stirred at room temperature under N2 for 32 h. The reaction was quenched with methanol (6 mL) and stirred at room temperature for 2 hr. The solvent was removed in vacuo to give crude product that was purified by flash chromatography using 97:3 CH2Cl2:MeOH to afford 0.051 g (47%) 2-(4-{3-[1-(3,4-dimethyl-benzyl)-2-oxo-imidazolidin-4-yl]-propyl}-phenoxy)-2-methyl-propionic acid tert-butyl ester. MS (ES+) Calc'd for C29H41N2O4 (M+1) 481. Found m/z 481 (100%). 1H NMR.
Reaction SMILES: [C:1]([C:9]1[N:13]2[CH2:14][CH2:15][CH:16]([C:17]([O:19]C(C)C)=[O:18])[C:12]2=[C:11]([Br:23])[CH:10]=1)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.CO.C(=O)([O-])[O-].[K+].[K+]>O>[C:1]([C:9]1[N:13]2[CH2:14][CH2:15][CH:16]([C:17]([OH:19])=[O:18])[C:12]2=[C:11]([Br:23])[CH:10]=1)(=[O:8])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CC(C)OC(=O)C1CCn2c(C(=O)c3ccccc3)cc(Br)c21
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CO
Product: O=C(c1ccccc1)c1cc(Br)c2n1CCC2C(=O)O

Procedure:
A solution of 336 mg. of isopropyl 5-benzoyl-7-bromo-1,2-dihydro-3H-pyrrolo[1,2-a]-pyrrole-1-carboxylate in 10 ml. of methanol is treated with a solution of 690 mg. of potassium carbonate in 5 ml. of water. The reaction mixture is refluxed under nitrogen atmosphere for 30 minitres, cooled, and evaporated to dryness. The residue is taken up in 10 ml. of 10% aqueous hydrochloric acid and 50 ml. of water and the resultant mixture extracted with ethyl acetate (2×50 ml.). The combined extracts are dried over magnesium sulfate and evaporated to dryness under reduced pressure. Crystallization of the residue from ethyl acetate-hexane affords 5-benzoyl-7-bromo-1,2-dihydro-3H-pyrrolo[1,2-a]pyrrole-1-carboxylic acid.
Reaction SMILES: [C:1]1([C:13]2[CH:18]=[CH:17][C:16]([C:19]([OH:21])=[O:20])=[C:15]([C:22]([OH:24])=O)[CH:14]=2)[CH:6]=[CH:5][CH:4]=[C:3]([C:7](O)=[O:8])[C:2]=1[C:10]([OH:12])=[O:11]>C(OC(=O)C)(=O)C>[CH:5]1[CH:4]=[C:3]2[C:7]([O:11][C:10](=[O:12])[C:2]2=[C:1]([C:13]2[CH:18]=[CH:17][C:16]3[C:19]([O:21][C:22](=[O:24])[C:15]=3[CH:14]=2)=[O:20])[CH:6]=1)=[O:8]
Reactant: O=C(O)c1ccc(-c2cccc(C(=O)O)c2C(=O)O)cc1C(=O)O
Solvent: CC(=O)OC(C)=O
Product: O=C1OC(=O)c2cc(-c3cccc4c3C(=O)OC4=O)ccc21
Yield: 80.3 %

Procedure:
Acetic anhydride (400 ml.) was added to 116 g of 2,3,3',4'-biphenyltetracarboxylic acid having a melting point of 195° to 205°C., and the mixture was heated under reflux for 4 hours. The mixture was cooled, and allowed to stand. The crystals formed were filtered to provide 83 g (yield 80% of theoretical) of 2,3,3',4'-biphenyltetracarboxylic dianhydride having a melting point of 196° to 204°C. By further concentration of the filtrate, 17 g (16%) of 2,3,3',4'-biphenyltetracarboxylic dianhydride was obtained.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][N:5]=[CH:4][C:3]=1C1C=CC=C2C=1C=NN2.CC1(C)C(C)(C)OB([C:25]2[CH:30]=[CH:29][C:28]([NH:31][S:32]([CH3:35])(=[O:34])=[O:33])=[CH:27][C:26]=2[C:36]([F:39])([F:38])[F:37])O1.BrC1C=NC=CC=1C>>[CH3:1][C:2]1[CH:7]=[CH:6][N:5]=[CH:4][C:3]=1[C:25]1[CH:30]=[CH:29][C:28]([NH:31][S:32]([CH3:35])(=[O:33])=[O:34])=[CH:27][C:26]=1[C:36]([F:37])([F:38])[F:39]
Reactant: Cc1ccncc1-c1cccc2[nH]ncc12
Reactant: CC1(C)OB(c2ccc(NS(C)(=O)=O)cc2C(F)(F)F)OC1(C)C
Agent: Cc1ccncc1Br
Product: Cc1ccncc1-c1ccc(NS(C)(=O)=O)cc1C(F)(F)F
Yield: 58 %

Procedure:
The compound of Example 240 was prepared by the procedure described for the preparation of Intermediate 1C using Intermediate 52 and 3-bromo-4-methylpyridine. The crude material was purified by reverse phase preparative HPLC using a PHENOMENEX® Luna 30×100 mm column with a linear gradient of Solvent A (10% methanol/90% water with 0.1% TFA) and Solvent B (90% methanol/10% water with 0.1% TFA) over 12 min with peak detection at 254 nM. Collected fractions were applied to a 1 g Waters OASIS® MCX cation exchange cartridge, which was washed with methanol and 2 M ammonia in methanol, to provide the title compound (43 mg, 58%) as a solid: HPLC Ret timed: 1.21 min. MS: m/z=331 [M+H]+; 1H NMR (400 MHz, CD3OD) δ ppm 8.42 (1 H, d, J=5.0 Hz), 8.24 (1 H, s), 7.70 (1 H, s), 7.60 (1 H, d, J=8.3 Hz), 7.24-7.49 (2 H, m), 3.09 (3 H, s), 2.12 (3 H, s); 19F NMR (CD3OD) δ ppm 60.8.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([CH2:8]O)[N:3]=1.S(Cl)([Cl:12])=O>C(Cl)(Cl)Cl>[Br:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([CH2:8][Cl:12])[N:3]=1
Reactant: O=S(Cl)Cl
Reactant: OCc1cccc(Br)n1
Solvent: ClC(Cl)Cl
Product: ClCc1cccc(Br)n1
Temperature: 25 °C
Reaction time: 3 h
Yield: 98.8 %

Procedure:
2-Bromo-6-hydroxymethylpyridine (5.00 g, 25.5 mmol) was dissolved in chloroform (30 ml) and thionyl chloride (2.8 ml, 38.3 mmol) was added, and the mixture was stirred at room temperature for 3 hours. After the reaction solution was concentrated, a saturated aqueous sodium bicarbonate was added to the residue and the precipitates were collected by filtration. After washing with water, the precipitates were dried in vacuo to give the title compound (5.20 g, 99%).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH2:10][OH:11])[CH:5]=[C:6]([F:9])[C:7]=1[F:8].Cl[C:13]1[CH:14]=[C:15]2[N:22](C(OC(C)(C)C)=O)[C@@H:21]([CH3:30])[CH2:20][N:16]2[C:17](=[O:19])[N:18]=1>>[CH3:30][C@H:21]1[CH2:20][N:16]2[C:17](=[O:19])[N:18]=[C:13]([O:11][CH2:10][C:4]3[CH:3]=[C:2]([F:1])[C:7]([F:8])=[C:6]([F:9])[CH:5]=3)[CH:14]=[C:15]2[NH:22]1
Reactant: OCc1cc(F)c(F)c(F)c1
Reactant: C[C@H]1Cn2c(cc(Cl)nc2=O)N1C(=O)OC(C)(C)C
Product: C[C@H]1Cn2c(cc(OCc3cc(F)c(F)c(F)c3)nc2=O)N1

Procedure:
The title compound was prepared by a procedure similar to that described for E1 starting from (3,4,5-trifluorophenyl)methanol and (S)-tert-butyl 7-chloro-2-methyl-5-oxo-2,3-dihydroimidazo[1,2-c]pyrimidine-1(5H)-carboxylate.
Reaction SMILES: C(N(CC)CC)C.[C:8](OC(=O)C)(=[O:10])[CH3:9].[C:15]([O:19][C:20]([N:22]1[CH:27]([C@@H:28]([OH:40])[C@@H:29]([NH2:39])[CH2:30][C:31]2[CH:36]=[C:35]([F:37])[CH:34]=[C:33]([F:38])[CH:32]=2)[CH2:26][O:25][CH:24]([O:41][CH2:42][CH3:43])[CH2:23]1)=[O:21])([CH3:18])([CH3:17])[CH3:16]>O1CCCC1.C(OCC)(=O)C>[C:15]([O:19][C:20]([N:22]1[C@@H:27]([C@@H:28]([OH:40])[C@@H:29]([NH:39][C:8](=[O:10])[CH3:9])[CH2:30][C:31]2[CH:32]=[C:33]([F:38])[CH:34]=[C:35]([F:37])[CH:36]=2)[CH2:26][O:25][C@H:24]([O:41][CH2:42][CH3:43])[CH2:23]1)=[O:21])([CH3:17])([CH3:18])[CH3:16]
Reactant: CC(=O)OC(C)=O
Reactant: CCOC1CN(C(=O)OC(C)(C)C)C([C@@H](O)[C@@H](N)Cc2cc(F)cc(F)c2)CO1
Solvent: CCN(CC)CC
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: CCO[C@@H]1CN(C(=O)OC(C)(C)C)[C@@H]([C@@H](O)[C@H](Cc2cc(F)cc(F)c2)NC(C)=O)CO1
Reaction time: 4 h
Yield: 66 %

Procedure:
Add triethylamine (0.030 g, 0.30 mmol) and acetic anhydride (0.024 g, 0.23 mmol) to R)-5-[(1S,2S)-2-amino-3-(3,5-difluorophenyl)-1-hydroxypropyl]-2-ethoxymorpholine-4-carboxylic acid tert-butyl ester (0.095 g, 0.228 mmol) in tetrahydrofuran (4 mL) at room temperature. Stir 4 hours and dilute with ethyl acetate. Wash with water and saturated aqueous sodium chloride, dry (magnesium sulfate), concentrate and purify (silica gel chromatography, eluting with 20:80 to 100:0 ethyl acetate:hexanes) to give the desired compound (69 mg, 66%).
Reaction SMILES: [C:1]([Si:5]([CH3:33])([CH3:32])[O:6][C@H:7]([C:23]1[CH:28]=[CH:27][C:26]([OH:29])=[C:25]([CH2:30][OH:31])[CH:24]=1)[CH2:8][NH:9][C:10]([CH3:22])([CH3:21])[CH2:11][C:12]1[CH:13]=[C:14]([CH:18]=[CH:19][CH:20]=1)[C:15](O)=[O:16])([CH3:4])([CH3:3])[CH3:2].[CH2:34]([O:36][C:37]1[CH:38]=[C:39]([CH:43]=[CH:44][CH:45]=1)[CH2:40][CH2:41][NH2:42])[CH3:35]>>[Si:5]([O:6][C@H:7]([C:23]1[CH:28]=[CH:27][C:26]([OH:29])=[C:25]([CH2:30][OH:31])[CH:24]=1)[CH2:8][NH:9][C:10]([CH3:22])([CH3:21])[CH2:11][C:12]1[CH:13]=[C:14]([CH:18]=[CH:19][CH:20]=1)[C:15]([NH:42][CH2:41][CH2:40][C:39]1[CH:43]=[CH:44][CH:45]=[C:37]([O:36][CH2:34][CH3:35])[CH:38]=1)=[O:16])([C:1]([CH3:4])([CH3:3])[CH3:2])([CH3:32])[CH3:33]
Reactant: CC(C)(Cc1cccc(C(=O)O)c1)NC[C@H](O[Si](C)(C)C(C)(C)C)c1ccc(O)c(CO)c1
Reactant: CCOc1cccc(CCN)c1
Product: CCOc1cccc(CCNC(=O)c2cccc(CC(C)(C)NC[C@H](O[Si](C)(C)C(C)(C)C)c3ccc(O)c(CO)c3)c2)c1
Yield: 67 %

Procedure:
The title compound was prepared from 3-{2-[(2R)-2-(tert-butyldimethyl silanyloxy)-2-(4-hydroxy-3-hydroxymethyl-phenyl)ethylamino]-2-methylpropyl}benzoic acid (preparation 37) and 3-ethoxyphenethylamine, using a similar method to that of preparation 158, in 67% yield.
Reaction SMILES: [NH2:1][C:2]1[CH:6]=[CH:5][NH:4][N:3]=1.CN1CCOCC1.[C:14](Cl)(=[O:21])[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1.[OH-].[Na+]>C(Cl)Cl.CO.C1COCC1>[NH:4]1[CH:5]=[CH:6][C:2]([NH:1][C:14](=[O:21])[C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)=[N:3]1
Reactant: O=C(Cl)c1ccccc1
Reactant: Nc1cc[nH]n1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: CN1CCOCC1
Solvent: ClCCl
Product: O=C(Nc1cc[nH]n1)c1ccccc1
Temperature: 25 °C
Reaction time: 16 h
Yield: 86.8 %

Procedure:
3-Aminopyrazole (9 g, 108 mmol) was dissolved in DCM (250 ml). N-methylmorpholine (26.5 g, 262 mmol) was added in one portion. Benzoyl chloride (34.86 g, 248 mmol) was added slowly at room temperature. After stirring at room temperature for 16 hours, the mixture was concentrated under reduced pressure to give a solid. The solid was dissolved in methanol (200 ml). Aqueous solution of NaOH (2.5M, 120 ml, 300 mmol) was added slowly, and THF (50 ml) was added in order to obtain a homogeneous solution. After stirring at room temperature for 20 minutes, the mixture was concentrated under reduced pressure and poured into water (300 ml). The precipitate was filtered and dried in an oven to afford 17.55 g light yellow solid, the yield was 87.7%. 1H-NMR (400 MHz, d6-DMSO): δ 12.45 (s, 1H), 10.79 (s, 1H), 7.99-8.02 (m, 2H), 7.67 (s, 1H), 7.48-7.59 (m, 3H), 6.65 (s, 1H).
Reaction SMILES: C[Si]([N-][Si](C)(C)C)(C)C.[Na+].Cl[C:12]1[CH:17]=[N:16][CH:15]=[CH:14][N:13]=1.[C:18]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])(=[O:21])[CH2:19][CH3:20]>C1(C)C=CC=CC=1>[N:13]1[CH:14]=[CH:15][N:16]=[CH:17][C:12]=1[CH:19]([CH3:20])[C:18]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21]
Reactant: CCC(=O)OC(C)(C)C
Reactant: Clc1cnccn1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Na+]
Solvent: Cc1ccccc1
Product: CC(C(=O)OC(C)(C)C)c1cnccn1
Temperature: 0 °C
Reaction time: 2 h

Procedure:
A solution of NaHMDS (1M in toluene, 349 mL, 349 mmol) was added over 5 minutes to a toluene (200 mL) solution containing chloropyrazine (20 g, 175 mmol) and t-butyl propionate (22.73 g, 175 mmol) cooled to 0° C. The solution was stirred at 0° C. for 2 hours and then at room temperature for 4 hours. The reaction was then quenched with saturated aqueous NH4Cl. The mixture was extracted with ethyl acetate and the organic layer concentrated. The residue was purified by silica gel chromatography using a hexanes/EtOAc gradient to give the indicated product. m/z=209.3 (M+H).
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[CH:7]=[N:8][N:9]([CH2:11][C:12]([OH:14])=O)[CH:10]=1)=[O:5])[CH3:2].CN(C)CCCN=C=NCC.ON1C2C=CC=CC=2N=N1.[NH:36]([C:38]([O:40][C:41]([CH3:44])([CH3:43])[CH3:42])=[O:39])[NH2:37]>ClCCl.O>[C:41]([O:40][C:38]([NH:36][NH:37][C:12](=[O:14])[CH2:11][N:9]1[CH:10]=[C:6]([C:4]([O:3][CH2:1][CH3:2])=[O:5])[CH:7]=[N:8]1)=[O:39])([CH3:44])([CH3:43])[CH3:42]
Reactant: CC(C)(C)OC(=O)NN
Reactant: CCOC(=O)c1cnn(CC(=O)O)c1
Agent: CCN=C=NCCCN(C)C
Agent: On1nnc2ccccc21
Solvent: ClCCl
Solvent: O
Product: CCOC(=O)c1cnn(CC(=O)NNC(=O)OC(C)(C)C)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 62.1 %

Procedure:
A solution of the compound (9.4 g) obtained in Example 115b, N-[3-(dimethylamino)propyl]-N′-ethylcarbodiimide (18.1 g) and 1-hydroxybenzotriazole (6.5 g) in dichloromethane (100 mL) was cooled to −20° C., and a solution of tert-butyl hydrazinecarboxylate (9.5 g) in dichloromethane (20 mL) was added dropwise. The reaction mixture was stirred at room temperature overnight, poured into water, and the mixture was extracted with ethyl acetate. The ethyl acetate layer was washed with saturated brine, dried over sodium sulfate, and concentrated under reduced pressure. The residue was purified by column chromatography (carrier: silica gel, eluent: petroleum ether/ethyl acetate/triethylamine=10/1/0.001) to give ethyl 1-{2-[2-(tert-butoxycarbonyl)hydrazino]-2-oxoethyl}-1H-pyrazole-4-carboxylate (9.2 g) as a colorless solid. The solid was dissolved in ethyl acetate (50 mL), and hydrogen chloride-ethyl acetate (50 mL) was added. The mixture was stirred at room temperature for 1 hr, and the precipitate was collected by filtration to give the title compound (6.0 g) as a colorless solid.
Reaction SMILES: [OH:1][C@@H:2]1[CH2:6][C@@H:5]([OH:7])[CH:4]=[CH:3]1.[O:8]1[CH:13]=[CH:12][CH2:11][CH2:10][CH2:9]1>C(Cl)Cl.C1(C)C=CC(S(O)(=O)=O)=CC=1>[O:8]1[CH2:13][CH2:12][CH2:11][CH2:10][CH:9]1[O:1][C@H:2]1[CH:3]=[CH:4][C@H:5]([OH:7])[CH2:6]1
Reactant: O[C@H]1C=C[C@H](O)C1
Reactant: C1=COCCC1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: ClCCl
Product: O[C@H]1C=C[C@H](OC2CCCCO2)C1
Yield: 62.8 %

Procedure:
Ten milligrams of (R)-trans-3,5-dihydroxycyclopent-1-ene and 8 milligrams of dihydropyran were stirred at room temperature for 24 hours in 1.0 milliliter of methylene chloride in the presence of 0.1 milligram of p-toluenesulfonic acid. The organic solution was first washed with an aqueous sodium bicarbonate solution and then with an aqueous sodium chloride solution followed by drying with magnesium sulfate and thereafter distilling off the solvent under reduced pressure to obtain a crude product. This product was purified by thin-layer chromatography (n-hexane:ethyl acetate = 6:4), and 11 milligrams (60%) of (R)-trans-5-tetrahydropyranyloxycyclopent-1-en-3-ol was obtained.
Reaction SMILES: [CH2:1]([S:4]([C:7]1[CH:15]=[CH:14][C:13]([NH:16][S:17]([C:20]2[S:21][CH:22]=[CH:23][CH:24]=2)(=[O:19])=[O:18])=[C:12]2[C:8]=1[CH:9]=[C:10]([C:25]([O:27]CC)=[O:26])[NH:11]2)(=[O:6])=[O:5])[CH2:2][CH3:3].CO.[OH-].[K+].C(O)(=O)CC(CC(O)=O)(C(O)=O)O>O1CCCC1>[CH2:1]([S:4]([C:7]1[CH:15]=[CH:14][C:13]([NH:16][S:17]([C:20]2[S:21][CH:22]=[CH:23][CH:24]=2)(=[O:19])=[O:18])=[C:12]2[C:8]=1[CH:9]=[C:10]([C:25]([OH:27])=[O:26])[NH:11]2)(=[O:5])=[O:6])[CH2:2][CH3:3]
Reactant: CCCS(=O)(=O)c1ccc(NS(=O)(=O)c2cccs2)c2[nH]c(C(=O)OCC)cc12
Agent: O=C(O)CC(O)(CC(=O)O)C(=O)O
Agent: [K+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Product: CCCS(=O)(=O)c1ccc(NS(=O)(=O)c2cccs2)c2[nH]c(C(=O)O)cc12
Temperature: 25 °C
Reaction time: 15 h
Yield: 92.5 %

Procedure:
To a mixed solution of ethyl 4-(propylsulfonyl)-7-[(2-thienylsulfonyl)amino]-1H-indole-2-carboxylate (0.56 g) in tetrahydrofuran (15 mL)-methanol (15 mL) was added aqueous solution (5 mL) of 85% potassium hydroxide (0.35 g), and the mixture was stirred at room temperature for 15 hr. Aqueous citric acid solution was added to the reaction mixture, and the mixture was extracted with ethyl acetate, washed with saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The obtained oil was crystallized from ethyl acetate-hexane to give the title compound (486 mg, yield 93%) as pale-yellow prism crystals. melting point 247-248° C.
Reaction SMILES: [C:1]1([CH:7]2[NH:13][CH2:12][CH2:11][NH:10][C:9](=[O:14])[CH2:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C(=O)([O-])[O-].[K+].[K+].[CH2:21](Cl)[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1>C(#N)C>[CH2:21]([N:13]1[CH:7]([C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)[CH2:8][C:9](=[O:14])[NH:10][CH2:11][CH2:12]1)[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1
Reactant: ClCc1ccccc1
Reactant: O=C1CC(c2ccccc2)NCCN1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: O=C1CC(c2ccccc2)N(Cc2ccccc2)CCN1
Yield: 83.9 %

Procedure:
1.9 g hexahydro-7-phenyl-1,4-diazepin-5-one (for preparation see Example 1C) in 30 ml acetonitrile were heated to boiling with 2.0 g potassium carbonate and 1.2 g benzyl chloride with reflux cooling for 36 hours. Then filtration was carried out and the filtrate reduced in volume. The remaining residue was shaken with 10% aqueous citric acid solution, the organic phase was separated, dried over magnesium sulfate and reduced in volume under a vacuum. 2.23 g crude 1-benzyl-hexahydro-7-phenyl-1,4-diazepin-5-one were obtained as an oil, which was used for the next synthesis stage without further purification or characterization.
Reaction SMILES: Br[C:2]1[S:3][CH:4]=[C:5]([C:7]([NH:9][C:10]2[CH:11]=[N:12][N:13]([CH3:31])[C:14]=2[C@H:15]2[O:21][CH2:20][C@@H:19]([F:22])[C@H:18]([NH:23]C(=O)OC(C)(C)C)[CH2:17][CH2:16]2)=[O:8])[N:6]=1.[CH3:32][O:33][C:34]1[C:39](B(O)O)=[CH:38][CH:37]=[CH:36][N:35]=1>>[NH2:23][C@H:18]1[C@H:19]([F:22])[CH2:20][O:21][C@H:15]([C:14]2[N:13]([CH3:31])[N:12]=[CH:11][C:10]=2[NH:9][C:7]([C:5]2[N:6]=[C:2]([C:39]3[C:34]([O:33][CH3:32])=[N:35][CH:36]=[CH:37][CH:38]=3)[S:3][CH:4]=2)=[O:8])[CH2:16][CH2:17]1
Reactant: Cn1ncc(NC(=O)c2csc(Br)n2)c1[C@@H]1CC[C@@H](NC(=O)OC(C)(C)C)[C@H](F)CO1
Reactant: COc1ncccc1B(O)O
Product: COc1ncccc1-c1nc(C(=O)Nc2cnn(C)c2[C@@H]2CC[C@@H](N)[C@H](F)CO2)cs1

Procedure:
Following the procedure for Example 101 starting from tert-butyl ((3S,4R,7S)-7-(4-(2-bromothiazole-4-carboxamido)-1-methyl-1H-pyrazol-5-yl)-3-fluorooxepan-4-yl)carbamate (Intermediate 99), and replacing 3,6-dihydro-2H-pyran-4-boronic acid pinacol ester with (2-methoxypyridin-3-yl)boronic acid gave 232. LCMS (ES+) m/z 447 (M+1).
Reaction SMILES: [Cl:1][C:2]1[C:3]([N:10]2[CH2:15][CH2:14][N:13]([C:16]3[CH:21]=[C:20]([C:22]4[CH:27]=[CH:26][C:25]([F:28])=[CH:24][CH:23]=4)[N:19]=[C:18](Cl)[N:17]=3)[C@H:12]([CH3:30])[CH2:11]2)=[N:4][C:5]([O:8][CH3:9])=[N:6][CH:7]=1.Br.[CH3:32][C@@H:33]1[CH2:37][CH2:36][CH2:35][NH:34]1.C([O-])([O-])=O.[K+].[K+]>CC#N>[Cl:1][C:2]1[C:3]([N:10]2[CH2:15][CH2:14][N:13]([C:16]3[CH:21]=[C:20]([C:22]4[CH:27]=[CH:26][C:25]([F:28])=[CH:24][CH:23]=4)[N:19]=[C:18]([N:34]4[CH2:35][CH2:36][CH2:37][C@H:33]4[CH3:32])[N:17]=3)[C@H:12]([CH3:30])[CH2:11]2)=[N:4][C:5]([O:8][CH3:9])=[N:6][CH:7]=1
Reactant: COc1ncc(Cl)c(N2CCN(c3cc(-c4ccc(F)cc4)nc(Cl)n3)[C@H](C)C2)n1
Reactant: C[C@@H]1CCCN1
Agent: Br
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: COc1ncc(Cl)c(N2CCN(c3cc(-c4ccc(F)cc4)nc(N4CCC[C@H]4C)n3)[C@H](C)C2)n1

Procedure:
Dissolve 5-chloro-4-((R)-4-(2-chloro-6-(4-fluorophenyl)pyrimidin-4-yl)-3-methylpiperazin-1-yl)-2-methoxypyrimidine (45 mg, 0.1 mmol) and (R)-2-methylpyrrolidine hydrobromide (0.2 mmol, prepared essentially as described by Nijhuis et. al. (1989) J. Org. Chem. 54:209-216) in CH3CN (2.0 mL) under nitrogen atmosphere. Add K2CO3 (55 mg, 0.4 mmol) and heat at 80° C. for 20 hours. Concentrate under vacuum, dilute with water (5.0 mL), extract with EtOAc (3×3 mL) and dry with MgSO4. Filter, and concentrate under vacuum to afford crude product and purify by flash column chromatography using 20% EtOAc/hexane to afford the title product as viscous oil. NMR (CDCl3) δ 1.3 (6H, m), 1.69 (1H, m), 1.91 (1H, m), 2.06 (2H, m), 3.21 (1H, m), 3.35 (2H, m), 3.63 (2H, m), 3.94 (3H, s), 4.28 (2H, m), 4.45 (2H, m), 4.64 (1H, bs), 6.19 (1H, s), 7.07 (2H, t), 7.97 (2H, m), 8.08 (1H, s). Mass spec m/z=498.17.
Reaction SMILES: [CH3:1][C:2]1[N:7]=[C:6](Cl)[C:5]([C:9]2[S:10][CH:11]=[CH:12][CH:13]=2)=[CH:4][N:3]=1.[O:14]1[C:22]2[C:17](=[CH:18][C:19]([CH2:23][NH2:24])=[CH:20][CH:21]=2)[O:16][CH2:15]1>C(Cl)Cl>[CH3:1][C:2]1[N:7]=[C:6]([NH:24][CH2:23][C:19]2[CH:18]=[C:17]3[C:22](=[CH:21][CH:20]=2)[O:14][CH2:15][O:16]3)[C:5]([C:9]2[S:10][CH:11]=[CH:12][CH:13]=2)=[CH:4][N:3]=1
Reactant: NCc1ccc2c(c1)OCO2
Reactant: Cc1ncc(-c2cccs2)c(Cl)n1
Solvent: ClCCl
Product: Cc1ncc(-c2cccs2)c(NCc2ccc3c(c2)OCO3)n1
Temperature: 50 °C

Procedure:
2-Methyl-5-(2-thienyl)-4-chloropyrimidine (590 mg; prepared by the same procedure as described in reference example 1) was dissolved into methylene chloride (6 ml). To the solution, (1,3-dioxaindan-5-yl)methylamine (2 ml) was added. The mixture was refluxed at 50° C. for 2 days. After reaction, the mixture was extracted with methylene chloride. The organic layer was washed with water and an aqueous saturated solution of ammonium chloride, respectively. The solution was dried over anhydrous sodium sulfate and evaporated. The residue was washed with ether to give the title compound.