Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(NC(C)C)(C)C.C([Li])CCC.[Cl:13][C:14]1[CH:19]=[CH:18][CH:17]=[C:16]([F:20])[N:15]=1.CN(C)[CH:23]=[O:24]>O1CCCC1>[Cl:13][C:14]1[CH:19]=[CH:18][C:17]([CH:23]=[O:24])=[C:16]([F:20])[N:15]=1
Reactant: CN(C)C=O
Reactant: Fc1cccc(Cl)n1
Agent: [Li]CCCC
Solvent: CC(C)NC(C)C
Solvent: C1CCOC1
Product: O=Cc1ccc(Cl)nc1F
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
Diisopropylamine (1.14 ml, 8.0 mmol) was taken up in 8 mL tetrahydrofuran and cooled to −78° C. n-Buyllithium (4.8 ml, 7.6 mmol) was added dropwise. The flask was then warmed to 0° C. in an ice bath and stirred for 30 minutes. The reaction mixture was then added dropwise to a cooled (−78° C.) solution of 2-chloro-6-fluoropyridine (1.0 g, 7.60 mmol) in tetrahydrofuran (25.3 ml). The reaction mixture was stirred at −78° C. for one hour. Dimethylformamide (0.88 ml, 11.4 mmol) was added dropwise and the mixture was stirred an additional 2 hours at −78° C. The reaction was quenched via the addition of 1N aqueous hydrochloric acid and allowed to warm to room temperature. The resulting biphasic mixture was extracted twice with ethyl acetate. The combined organics were dried over magnesium sulfate, filtered, and concentrated in vacuo. The crude residue was purified by flash chromatography (silica, 0-17% ethyl acetate/hexanes) to afford the title compound.
Reaction SMILES: [C:1]([O:5][C:6](=[O:18])[N:7]([CH3:17])[CH2:8][CH2:9][NH:10]C(=O)C(F)(F)F)([CH3:4])([CH3:3])[CH3:2].[OH-].[Li+]>CO>[C:1]([O:5][C:6](=[O:18])[N:7]([CH2:8][CH2:9][NH2:10])[CH3:17])([CH3:4])([CH3:2])[CH3:3]
Reactant: CN(CCNC(=O)C(F)(F)F)C(=O)OC(C)(C)C
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Product: CN(CCN)C(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 8 h
Yield: 17.9 %

Procedure:
To a solution of methyl-[2-(2,2,2-trifluoro-acetylamino)-ethyl]-carbamic acid tert-butyl ester (1.04 g, 3.85 mmol) in methanol (60 mL) was added 1 M aqueous lithium hydroxide (34 mL, 34.00 mmol). The mixture was stirred at room temperature overnight. It was then concentrated and ethyl acetate (50 mL) was added. The precipitate was filtered off and the filtrate concentrated to give 120 mg (18%) of (2-amino-ethyl)-methyl-carbamic acid tert-butyl ester. 1H-NMR (250 MHz, CDCl3) δ 3.22 (t, J=6.5 Hz, 2H), 2.72-2.86 (m, 5H), 1.36 (s, 9H).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([C:8](=[O:12])[CH2:9][CH2:10][CH3:11])=[CH:4][C:3]=1[OH:13].[CH3:14][C:15](OC(C)=O)=[O:16]>C(Cl)(Cl)Cl>[C:8]([C:5]1[CH:6]=[CH:7][C:2]([NH:1][C:15](=[O:16])[CH3:14])=[C:3]([OH:13])[CH:4]=1)(=[O:12])[CH2:9][CH2:10][CH3:11]
Reactant: CCCC(=O)c1ccc(N)c(O)c1
Reactant: CC(=O)OC(C)=O
Solvent: ClC(Cl)Cl
Product: CCCC(=O)c1ccc(NC(C)=O)c(O)c1
Reaction time: 0.08 h
Yield: 92.5 %

Procedure:
To a solution of 1-(4-amino-3-hydroxyphenyl)butan-1-one (0.71 g, 4.0 mmol) in CHCl3 (8 mL) was added Ac2O (0.4 mL, 4.2 mmol, 1.06 eq) at 0° C. After 5 min, reaction was quenched with H2O then extracted with CH2Cl2 (3×30 mL). Solvent was removed under reduced pressure to afford N-(4-butyryl-2-hydroxyphenyl)acetamide (0.81 g, 3.7 mmol, 93%) with ca. 80% purity which was used in the next step without further purification.
Reaction SMILES: [NH2:1][CH2:2][CH:3]1[S:7][C:6]([C:8]2[NH:9][C:10]3[C:15]([CH:16]=2)=[CH:14][CH:13]=[CH:12][C:11]=3[N:17]([CH3:26])[S:18]([C:21]2[S:22][CH:23]=[CH:24][CH:25]=2)(=[O:20])=[O:19])=[N:5][CH2:4]1.[C:27](OC(=O)C)(=[O:29])[CH3:28].O>CN(C)C(=O)C>[CH3:26][N:17]([S:18]([C:21]1[S:22][CH:23]=[CH:24][CH:25]=1)(=[O:20])=[O:19])[C:11]1[CH:12]=[CH:13][CH:14]=[C:15]2[C:10]=1[NH:9][C:8]([C:6]1[S:7][CH:3]([CH2:2][NH:1][C:27](=[O:29])[CH3:28])[CH2:4][N:5]=1)=[CH:16]2
Reactant: CN(c1cccc2cc(C3=NCC(CN)S3)[nH]c12)S(=O)(=O)c1cccs1
Reactant: CC(=O)OC(C)=O
Solvent: CC(=O)N(C)C
Solvent: O
Product: CC(=O)NCC1CN=C(c2cc3cccc(N(C)S(=O)(=O)c4cccs4)c3[nH]2)S1
Reaction time: 0.5 h
Yield: 68 %

Procedure:
To a solution of N-{2-[5-(aminomethyl)-4,5-dihydro-1,3-thiazol-2-yl]-1H-indol-7-yl}-N-methylthiophene-2-sulfonamide (0.27 g) in N,N-dimethylacetamide (6 mL) was added acetic anhydride (0.10 mL) at 0° C., and the mixture was stirred for 30 min. Water was added to the reaction mixture, and the precipitated solid was collected by filtration, washed with water, and dried. The obtained solid was subjected to silica gel column chromatography to give the title compound (0.20 g, yield 68%) as pale-yellow crystals from a fraction eluted with ethyl acetate-hexane (95:5, volume ratio). melting point 212-213° C.
Reaction SMILES: [N:1]([CH2:4][CH2:5][O:6][CH2:7][CH2:8][O:9][CH2:10][CH2:11][O:12][CH2:13][C:14]#[CH:15])=[N+]=[N-].O.[Na+].[Cl-].C(Cl)Cl>C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C1COCC1>[NH2:1][CH2:4][CH2:5][O:6][CH2:7][CH2:8][O:9][CH2:10][CH2:11][O:12][CH2:13][C:14]#[CH:15]
Reactant: C#CCOCCOCCOCCN=[N+]=[N-]
Agent: [Cl-]
Agent: [Na+]
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Solvent: O
Solvent: ClCCl
Product: C#CCOCCOCCOCCN
Temperature: 25 °C
Reaction time: 3 h

Procedure:
in a 50 mL flask, 3 (150 mg, 0.7 mmol), Ph3P were dissolved in 10 mL THF. The reaction mixture was stirred at rt for 3 hr. To the reaction mixture was added H2O (1 mL) the resultant mixture was stirred for 36 hr at rt. The solvent was evaporated and the residue was purified by FCC to afford 4 as slightly yellow oil (131 mg, quant.). 1H NMR (400 MHz, CDCl3): δ 1.46 (br, 2H), 2.35 (t, J=1.6 Hz, 1H), 2.73 (t, J=5.2 Hz, 2H), 3.38 (t, J=5.2 Hz, 2H) 3.50-3.59 (m, 10H), 4.08 (m, 2H). 13C NMR (100 MHz, CDCl3): δ 41.72, 58.34, 69.04, 70.21, 70.36, 70.54, 73.36, 74.63, 79.60. ESIMS calcd for C9H18NO3 [M+H]+ 188.13, found: 188.16. FTIR (NaCl plate, CH2Cl2): 1118 (C—O str), 2111 (C≡C str), 2869 (C—H str), 3249 (N—H str).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[CH:13]=[CH:12][C:11]([CH3:14])=[CH:10][CH:9]=1.[Br:15]N1C(=O)CCC1=O>C(Cl)(Cl)(Cl)Cl>[F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[CH:9]=[CH:10][C:11]([CH2:14][Br:15])=[CH:12][CH:13]=1
Reactant: O=C1CCC(=O)N1Br
Reactant: Cc1ccc(-c2ccccc2F)cc1
Solvent: ClC(Cl)(Cl)Cl
Product: Fc1ccccc1-c1ccc(CBr)cc1
Yield: 39.8 %

Procedure:
A mixture of 8.70 g of 2-fluoro-4′-methylbiphenyl, 8.32 g of N-bromosuccinimide, 0.10 g of 2,2′-azobisisobutylonitrile and 150 ml of carbon tetrachloride was heat-refluxed for 5 hours. The reaction solution was washed with water, and the organic layer was concentrated. The resulting residue was purified through silica-gel column chromatography (eluent: a mixture of hexane and ethyl acetate at a ratio of 9:1) to obtain crude 2-fluoro-4′-bromomethylbiphenyl. Further, this compound was crystallized from hexane to give 4.93 g of 2-fluoro-4′-bromomethylbiphenyl.
Reaction SMILES: N[CH2:2][C:3]1([OH:15])[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][C:11]=2[O:13][CH3:14])[CH2:6][CH2:5][CH2:4]1.N([O-])=O.[Na+]>C(O)(=O)C.O>[CH3:14][O:13][C:11]1[C:12]2[CH2:2][C:3](=[O:15])[CH2:4][CH2:5][CH2:6][C:7]=2[CH:8]=[CH:9][CH:10]=1
Reactant: COc1cccc2c1C(O)(CN)CCC2
Agent: O=N[O-]
Agent: [Na+]
Solvent: O
Solvent: CC(=O)O
Product: COc1cccc2c1CC(=O)CCC2
Reaction time: 2 h
Yield: 46.3 %

Procedure:
To a suspension of 1-aminomethyl-1-hydroxy-8-methoxy-1,2,3,4-tetrahydronaphthalene (2.54 g) in 10% acetic acid was added dropwise a solution of sodium nitrite (1.27 g) in water (6.4 ml) under ice-cooling. The mixture was stirred at the same temperature for 2 hours and then partitioned between ethyl acetate and water. The organic layer was separated, washed with an aqueous sodium bicarbonate solution and brine, dried over magnesium sulfate and evaporated in vacuo. The residue was purified by column chromatography on silica gel eluting with a mixture of hexane and ethyl acetate (10:1) to afford 4-methoxy-6,7,8,9-tetrahydro-5H-benzocyclohepten-6-one (1.08 g).
Reaction SMILES: [CH2:1]([NH2:8])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][NH2:7].[CH3:9][C@:10]12[CH2:27][CH2:26][C@H:25]3[C@@H:15]([CH2:16][CH2:17][C@@H:18]4[C@:23]3([CH3:24])[CH2:22][CH2:21][CH2:20][CH2:19]4)[C@@H:14]1[CH2:13][CH2:12][C:11]2=O.C([BH3-])#N.[Na+].[OH-].[Na+]>O1CCCC1.C(O)(=O)C.CO>[CH3:9][C@:10]12[CH2:27][CH2:26][C@H:25]3[C@@H:15]([CH2:16][CH2:17][C@@H:18]4[C@:23]3([CH3:24])[CH2:22][CH2:21][CH2:20][CH2:19]4)[C@@H:14]1[CH2:13][CH2:12][C@@H:11]2[NH:7][CH2:6][CH2:5][CH2:4][CH2:3][CH2:2][CH2:1][NH2:8]
Reactant: NCCCCCCN
Reactant: C[C@]12CCCC[C@@H]1CC[C@@H]1[C@@H]2CC[C@]2(C)C(=O)CC[C@@H]12
Agent: [BH3-]C#N
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CC(=O)O
Solvent: CO
Product: C[C@]12CCCC[C@@H]1CC[C@@H]1[C@@H]2CC[C@]2(C)[C@@H](NCCCCCCN)CC[C@@H]12
Yield: 124.9 %

Procedure:
A 100 ml round-bottomed flask, equipped with a magnetic stir bar, condenser, and nitrogen inlet tube, was charged with 1,6-hexanediamine (0.904 g) and 15 ml of methanol. The solution was treated with glacial acetic acid until the pH was 6.7. To this mixture was added 15 ml of tetrahydrofuran, 5α-androstan-17-one (0.704 g) and sodium cyanoborohydride (0.228 g). The mixture was heated to reflux for 18 h. After cooling, the solution was made basic with aqueous 2M sodium hydroxide to a pH of 13-14. The solution was extracted with chloroform (3×) and the combined organic layers were washed with water and brine, dried (Na2SO4), filtered, and concentrated to give 1.2 g of an oil.
Reaction SMILES: [N:1]1(C2C=CC(CC3C(Cl)=NC4C(C=3Cl)=CC(Br)=CC=4)=CC=2)[CH:5]=[CH:4][CH:3]=[N:2]1.[Cl:26][C:27]1[C:36]([CH2:37][C:38]2[CH:43]=[CH:42][C:41](S(C)(=O)=O)=[CH:40][CH:39]=2)=[C:35]([Cl:48])[C:34]2[C:29](=[C:30]([CH3:57])[CH:31]=[C:32]([C:49]([C:51]3[N:55]([CH3:56])[CH:54]=[N:53][CH:52]=3)=[O:50])[CH:33]=2)[N:28]=1>O=P(Cl)(Cl)Cl>[N:1]1([C:41]2[CH:42]=[CH:43][C:38]([CH2:37][C:36]3[C:27]([Cl:26])=[N:28][C:29]4[C:34]([C:35]=3[Cl:48])=[CH:33][C:32]([C:49]([C:51]3[N:55]([CH3:56])[CH:54]=[N:53][CH:52]=3)=[O:50])=[CH:31][C:30]=4[CH3:57])=[CH:39][CH:40]=2)[CH:5]=[CH:4][CH:3]=[N:2]1
Reactant: Clc1nc2ccc(Br)cc2c(Cl)c1Cc1ccc(-n2cccn2)cc1
Reactant: Cc1cc(C(=O)c2cncn2C)cc2c(Cl)c(Cc3ccc(S(C)(=O)=O)cc3)c(Cl)nc12
Solvent: O=P(Cl)(Cl)Cl
Product: Cc1cc(C(=O)c2cncn2C)cc2c(Cl)c(Cc3ccc(-n4cccn4)cc3)c(Cl)nc12
Temperature: 105 °C

Procedure:
A heterogeneous mixture of 2-(4-(1H-pyrazol-1-yl)benzyl)malonic acid (2.42 g 9.29 mmol, Intermediate 4: step b), (4-amino-3-methylphenyl)(1-methyl-1H-imidazol-5-yl)methanone (2 g, 9.29 mmol, Intermediate 13: step c) and POCl3 (10 mL) was heated at 105° C. for 4 hours. The mixture was cooled to room temperature, concentrated to remove excess POCl3 and ice water was added. The mixture was treated with NH4OH (kept adding ice during addition) to a basic pH 8-9 and the aqueous was then extracted with DCM. The DCM extracts were dried (Na2SO4), evaporated in vacuo and chromatographed (DCM/EtOAc, gradient) to provide the crude product. Pure product was precipitated with MeOH, filtered and dried to provide the title compound as a yellow solid.
Reaction SMILES: [CH3:1][C:2]([C@@H:4]1[C@@:8]2([CH3:24])[CH2:9][CH2:10][C@@H:11]3[C@:21]4([CH3:22])[C:15](=[CH:16][C:17]([CH2:19][CH2:20]4)=[O:18])[C@@H:14]([OH:23])[CH2:13][C@H:12]3[C@@H:7]2[CH2:6][CH2:5]1)=[O:3].[C:25]1(=[O:31])[O:30][C:28](=[O:29])[CH2:27][CH2:26]1.Cl>N1C=CC=CC=1>[C:25]([O:23][C@@H:14]1[C:15]2[C@:21]([CH3:22])([CH2:20][CH2:19][C:17](=[O:18])[CH:16]=2)[C@@H:11]2[C@H:12]([C@H:7]3[C@:8]([CH3:24])([CH2:9][CH2:10]2)[C@@H:4]([C:2](=[O:3])[CH3:1])[CH2:5][CH2:6]3)[CH2:13]1)(=[O:31])[CH2:26][CH2:27][C:28]([OH:30])=[O:29]
Reactant: O=C1CCC(=O)O1
Reactant: CC(=O)[C@H]1CC[C@H]2[C@@H]3C[C@H](O)C4=CC(=O)CC[C@]4(C)[C@H]3CC[C@]12C
Agent: Cl
Solvent: c1ccncc1
Product: CC(=O)[C@H]1CC[C@H]2[C@@H]3C[C@H](OC(=O)CCC(=O)O)C4=CC(=O)CC[C@]4(C)[C@H]3CC[C@]12C
Temperature: 0 °C

Procedure:
Two grams of 6α-hydroxyprogesterone is refluxed for 1 hour in 20 ml. of pyridine with 4 g. of succinic acid anhydride. After cooling, the solution is stirred into ice water and acidified with 1N hydrochloric acid. The smeary precipitation product is separated and dissolved in methylene chloride; the solution is washed with hydrochloric acid and water and evaporated under vacuum. The residue (2.57 g. of foam) is dissolved in methanol, combined with carbon, filtered, and the filtrate concentrated under vacuum. By trituration of the residue with pentane, 2.1 g. of amorphous (3,20-dioxo-4-pregnen-6α-yl) hydrogen succinate is produced. UV: ε238 = 14,100.
Reaction SMILES: [OH:1][CH:2]1[C:7]2[NH:8][C:9]3[CH:10]=[CH:11][C:12]([CH3:15])=[CH:13][C:14]=3[C:6]=2[C:5](=[O:16])[N:4]([CH3:17])[CH2:3]1.[CH3:18][C:19]1[CH:24]=[CH:23][C:22]([CH:25]=[CH2:26])=[CH:21][N:20]=1.[OH-].[K+]>CN1C(=O)CCC1>[OH:1][CH:2]1[C:7]2[N:8]([CH2:26][CH2:25][C:22]3[CH:21]=[N:20][C:19]([CH3:18])=[CH:24][CH:23]=3)[C:9]3[CH:10]=[CH:11][C:12]([CH3:15])=[CH:13][C:14]=3[C:6]=2[C:5](=[O:16])[N:4]([CH3:17])[CH2:3]1
Reactant: Cc1ccc2[nH]c3c(c2c1)C(=O)N(C)CC3O
Reactant: C=Cc1ccc(C)nc1
Agent: [K+]
Agent: [OH-]
Solvent: CN1CCCC1=O
Product: Cc1ccc2c(c1)c1c(n2CCc2ccc(C)nc2)C(O)CN(C)C1=O

Procedure:
The title compound is prepared from a mixture of 3,4-dihydro-4-hydroxy-2,8-dimethyl-2H-pyrido[4,3-b]indol-1(5H)-one, 2-methyl-5-vinylpyridine and KOH (5-7 equiv) in NMP at a temperature ranging between 25 deg C. to 100 deg C. The product obtained is isolated by preparative HPLC.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH2:8][C:9]([OH:11])=[O:10])[CH:5]=[CH:6][CH:7]=1.S(=O)(=O)(O)O.[CH2:17](O)[CH3:18]>>[CH2:17]([O:10][C:9](=[O:11])[CH2:8][C:4]1[CH:5]=[CH:6][CH:7]=[C:2]([Cl:1])[CH:3]=1)[CH3:18]
Reactant: O=C(O)Cc1cccc(Cl)c1
Reactant: CCO
Agent: O=S(=O)(O)O
Product: CCOC(=O)Cc1cccc(Cl)c1
Yield: 86.8 %

Procedure:
(3-Chloro-phenyl)-acetic acid (6.03 g, 0.03 mol) was dissolved in ethanol (37.7 mL) and treated with a catalytic amount of sulfuric acid. The reaction mixture was heated under reflux for 12 h. The reaction was concentrated in vacuo. Flash chromatography (Merck Silica gel 60, 230-400 mesh, 50/50 hexanes/ethyl acetate) afforded (3-chloro-phenyl)-acetic acid ethyl ester (6.10 g, 86.8%) as a clear oil: EI-HRMS m/e calcd for C10H11ClO2(M+) 198.0448, found 198.0442.
Reaction SMILES: [C:1]1([CH2:7][C:8](Cl)=[O:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[C:11]1([S:17][CH3:18])[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1.O>C(Cl)(Cl)Cl>[CH3:18][S:17][C:11]1[CH:16]=[CH:15][C:14]([C:8](=[O:9])[CH2:7][C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=2)=[CH:13][CH:12]=1
Reactant: O=C(Cl)Cc1ccccc1
Reactant: CSc1ccccc1
Solvent: ClC(Cl)Cl
Solvent: O
Product: CSc1ccc(C(=O)Cc2ccccc2)cc1
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 64.4 %

Procedure:
To a cold (0° C.) solution of phenylacetyl chloride (92.8 g, 0.6 mol) in CHCl3 (1.2 L) was added AICl3 (80 g, 0.6 mol) in portions. Thioanisole (62.1 g, 0.5 mol) was then added dropwise. The resulting mixture was stirred at r.t. for 1.5 h. The mixture was poured into 4 L of ice and water and extracted with CHCl3. The combined organic extracts were dried over MgSO4, filtered and concentrated. The residue was slurried in 300 mL of 20% EtOAc/hexane, filtered and washed with hexane to give 78 g of the title compound.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]([C:21]([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:22])[CH2:9][C:10]1[CH:15]=[C:14]([N+:16]([O-:18])=[O:17])[CH:13]=[CH:12][C:11]=1[NH:19][CH3:20])=[O:7])([CH3:4])([CH3:3])[CH3:2].C(=O)([O-])[O-].[K+].[K+].C(#N)C.[C:37](Cl)(=[O:39])[CH3:38]>C(OCC)(=O)C>[C:24]([O:23][C:21]([N:8]([C:6]([O:5][C:1]([CH3:4])([CH3:3])[CH3:2])=[O:7])[CH2:9][C:10]1[CH:15]=[C:14]([N+:16]([O-:18])=[O:17])[CH:13]=[CH:12][C:11]=1[N:19]([C:37](=[O:39])[CH3:38])[CH3:20])=[O:22])([CH3:27])([CH3:26])[CH3:25]
Reactant: CNc1ccc([N+](=O)[O-])cc1CN(C(=O)OC(C)(C)C)C(=O)OC(C)(C)C
Reactant: CC(=O)Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CC#N
Product: CC(=O)N(C)c1ccc([N+](=O)[O-])cc1CN(C(=O)OC(C)(C)C)C(=O)OC(C)(C)C
Yield: 55 %

Procedure:
To a mixture of the compound (540 mg) obtained in Example 446, potassium carbonate (1.96 g) and acetonitrile (30 ml), acetyl chloride(890 mg) was added and heated under reflux for 24 h. Ethyl acetate was added to the reaction mixture, which was washed with water, dried with magnesium sulfate and concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (eluent, methylene chloride:ethyl acetate=5:1) to give 330 mg of the titled compound (yield, 55%).
Reaction SMILES: CC(OI1(OC(C)=O)(OC(C)=O)OC(=O)C2C=CC=CC1=2)=O.C(O)(C)(C)C.[CH2:28]([O:30][C:31](=[O:49])[CH:32](O)[CH:33]([CH3:47])[C:34](=O)[C:35]1[S:39][C:38]([C:40]2[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=2)=[N:37][CH:36]=1)[CH3:29].C(O)(=O)C.O.[NH2:55][NH2:56]>ClCCl>[CH2:28]([O:30][C:31]([C:32]1[NH:55][N:56]=[C:34]([C:35]2[S:39][C:38]([C:40]3[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=3)=[N:37][CH:36]=2)[C:33]=1[CH3:47])=[O:49])[CH3:29]
Reactant: CCOC(=O)C(O)C(C)C(=O)c1cnc(-c2ccccc2)s1
Reactant: NN
Agent: CC(=O)OI1(OC(C)=O)(OC(C)=O)OC(=O)c2ccccc21
Solvent: ClCCl
Solvent: CC(=O)O
Solvent: O
Product: CCOC(=O)c1[nH]nc(-c2cnc(-c3ccccc3)s2)c1C
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 24.8 %

Procedure:
A mixture of 0.39 g (0.91 mmol) of Dess-Martin periodinane and 0.07 g (0.91 mmol) of tert-butyl alcohol in dichloromethane (2 ml) was allowed to stir at room temperature for 20 minutes. The solution was cooled to 0° C. and to this was added 0.15 g (0.45 mmol) of the above-prepared 2-hydroxy-3-methyl-4-oxo-4-(2-phenyl-thiazol-5-yl)-butyric acid ethyl ester in dichloromethane (2 ml). The reaction was stirred at 0° C. for 3 hours and quenched with sodium bisulfite in 50% aqueous sodium bicarbonate. The mixture was diluted with dichloromethane and allowed to stir for 20 minutes at room temperature. The organic phase was washed twice with aqueous sodium bicarbonate, once with water, once with brine, and dried over sodium sulfate. The solvent was evaporated under reduced pressure and dissolved in ethyl alcohol (5 ml). 41 mg (0.68 mmol) of glacial acetic acid was added followed by the addition of 34 mg (0.68 mmol) of hydrazine monohydrate. The solution was allowed to stir at room temperature for 4 hours. The solvent was evaporated under reduced pressure and the residue was purified by chromatography on silica gel using 1:99 ethyl alcohol:dichloromethane as eluant to give 0.035 g of the title compound (25%). 1H NMR (500 MHz, CDCl3) δ 8.08 (s, 1H) 8.00 (d, 2H) 7.47 (m, 3H) 4.45 (q, 2H) 2.54 (s, 3H) 1.44 (t, 3H).
Reaction SMILES: [CH2:1]([O:8][C@@H:9]1[CH2:13][CH2:12][CH2:11][C@H:10]1[NH:14][C:15]1[C:16]2[S:24][CH2:23][CH2:22][C:17]=2[N:18]=[C:19](Cl)[N:20]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.O[C:26]1[CH:31]=[CH:30][C:29]([N:32]2[CH2:37][CH2:36][NH:35][CH2:34][CH2:33]2)=[CH:28][CH:27]=1>O1CCOCC1>[CH2:1]([O:8][C@@H:9]1[CH2:13][CH2:12][CH2:11][C@H:10]1[NH:14][C:15]1[C:16]2[S:24][CH2:23][CH2:22][C:17]=2[N:18]=[C:19]([N:35]2[CH2:36][CH2:37][N:32]([C:29]3[CH:30]=[CH:31][CH:26]=[CH:27][CH:28]=3)[CH2:33][CH2:34]2)[N:20]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: Oc1ccc(N2CCNCC2)cc1
Reactant: Clc1nc2c(c(N[C@@H]3CCC[C@H]3OCc3ccccc3)n1)SCC2
Solvent: C1COCCO1
Product: c1ccc(CO[C@@H]2CCC[C@H]2Nc2nc(N3CCN(c4ccccc4)CC3)nc3c2SCC3)cc1
Yield: 92.3 %

Procedure:
0.450 g (1.2 mmol) of ((1R,2R)-2-benzyloxycyclopentyl)(2-chloro-6,7-dihydrothieno[3,2-d]pyrimidin-4-yl)amine (chiral) (VIII) and 0.760 mL (5.0 mmol) of 1-phenylpiperazine (III) are placed in 5 mL of dioxane, then reacted for 1 hour at 160° C. in the microwave. The reaction mixture is concentrated by evaporation, and the residue is combined with water and extracted with dichloromethane. The organic phase is separated off using a phase separator and evaporated to dryness. The crude product I is purified by chromatography through a 100 g silica gel cartridge with a solvent mixture of petroleum ether/ethyl acetate 8/2. 0.540 g of the product (89%) is obtained (m.p. 100° C.-105° C.). 1H NMR (400 MHz, DMSO): 7.36-7.18 (7H, m); 6.91 (2H, d); 6.79 (1H, t); 6.39 (1H, d); 4.59-4.40 (3H, m); 3.95-3.89 (1H, m); 3.79-3.69 (4H, m); 3.23 (2H, t); 3.11-3.03 (4H, m); 2.99 (2H, t); 2.11-2.00 (1H, m); 1.93-1.79 (1H, m); 1.77-1.50 (4H, m).
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[C:13]2[C:8](=[CH:9][CH:10]=[C:11]([N+:14]([O-:16])=[O:15])[CH:12]=2)[NH:7][N:6]=1)=[O:4].C(Cl)Cl.[H-].[Na+].Cl[C:23]([C:36]1[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=1)([C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1)[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1>C1COCC1>[CH3:1][O:2][C:3]([C:5]1[C:13]2[C:8](=[CH:9][CH:10]=[C:11]([N+:14]([O-:16])=[O:15])[CH:12]=2)[N:7]([C:23]([C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)([C:36]2[CH:37]=[CH:38][CH:39]=[CH:40][CH:41]=2)[C:30]2[CH:31]=[CH:32][CH:33]=[CH:34][CH:35]=2)[N:6]=1)=[O:4]
Reactant: COC(=O)c1n[nH]c2ccc([N+](=O)[O-])cc12
Reactant: ClC(c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: ClCCl
Solvent: C1CCOC1
Product: COC(=O)c1nn(C(c2ccccc2)(c2ccccc2)c2ccccc2)c2ccc([N+](=O)[O-])cc12
Temperature: 0 °C
Reaction time: 0.33 h

Procedure:
Suspension of 5-nitro-1H-indazole-3-carboxylic acid methyl ester 18AP (7 g, 31.67 mmol) in THF (130 ml) and DCM (15 ml) was added to a NaH (60% in Mineral Oil, 1.61 g, 41.17 mmol) at 0° C. H2 gas was evolved. Chlorotriphenyl methane (8.83 g, 31.67 mmol) was added after stirring for 20 min at 0° C. Reaction mixture was subjected to heat at 60° C. for overnight. It was then cooled to room temperature and concentrated under reduced pressure. Solid was redissolved in DCM and filtered. Filtrate was concentrated under reduced pressure to give desired 5-nitro-1-trityl-1H-indazole-3-carboxylic acid methyl ester 19AP (12.95 g, 88%).
Reaction SMILES: Br[C:2]1[CH:38]=[CH:37][C:5]([CH2:6][N:7]2[C:11]3[CH:12]=[CH:13][C:14]([O:16][CH2:17][C:18]4[CH:27]=[CH:26][C:25]5[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=5)[N:19]=4)=[CH:15][C:10]=3[N:9]=[C:8]2[C@@H:28]2[C@H:30]([C:31]([O:33]C)=[O:32])[C:29]2([CH3:36])[CH3:35])=[C:4]([F:39])[CH:3]=1.[CH3:40][O:41][C:42]1[N:47]=[CH:46][C:45](B(O)O)=[CH:44][CH:43]=1>>[F:39][C:4]1[CH:3]=[C:2]([C:45]2[CH:46]=[N:47][C:42]([O:41][CH3:40])=[CH:43][CH:44]=2)[CH:38]=[CH:37][C:5]=1[CH2:6][N:7]1[C:11]2[CH:12]=[CH:13][C:14]([O:16][CH2:17][C:18]3[CH:27]=[CH:26][C:25]4[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=4)[N:19]=3)=[CH:15][C:10]=2[N:9]=[C:8]1[C@@H:28]1[C@H:30]([C:31]([OH:33])=[O:32])[C:29]1([CH3:36])[CH3:35]
Reactant: COC(=O)[C@H]1[C@@H](c2nc3cc(OCc4ccc5ccccc5n4)ccc3n2Cc2ccc(Br)cc2F)C1(C)C
Reactant: COc1ccc(B(O)O)cn1
Product: COc1ccc(-c2ccc(Cn3c([C@@H]4[C@H](C(=O)O)C4(C)C)nc4cc(OCc5ccc6ccccc6n5)ccc43)c(F)c2)cn1

Procedure:
The title compound was prepared using similar methods to those in Example 97 using racemic methyl cis-3-[1-(4-bromo-2-fluorobenzyl)-5-(quinolin-2-ylmethoxy)-1H-benzimidazol-2-yl]-2,2-dimethylcyclopropanecarboxylate and (6-methoxypyridin-3-yl)boronic acid in Step A. MS (ESI): mass calcd. for C36H31FN4O4, 602.23; m/z found, 603.1 [M+H]+. 1H NMR (500 MHz, CDCl3) δ 8.34 (d, J=2.5, 1H), 8.20 (d, J=8.5, 1H), 8.11 (d, J=8.5, 1H), 7.83 (d, J=8.2, 1H), 7.76-7.70 (m, 2H), 7.68 (d, J=8.5, 1H), 7.57-7.53 (m, 1H), 7.33-7.23 (m, 4H), 7.14-7.11 (m, 1H), 6.93-6.89 (m, 1H), 6.82 (d, J=8.5, 1H), 5.46 (d, J=17, 1H), 5.43 (s, 2H), 5.41 (d, J=17, 1H), 3.97 (s, 3H), 2.34 (d, J=8.2, 1H), 2.14 (d, J=8.2, 1H), 1.32 (s, 3H), 1.05 (s, 3H).