Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:16]([CH:17]([CH:21]3[CH2:26][CH2:25][CH2:24][CH2:23][CH2:22]3)[C:18]([OH:20])=O)=[C:15]3[C:10]([CH:11]=[CH:12][CH:13]=[CH:14]3)=[N:9]2)=[CH:4][CH:3]=1.[CH:27]1([NH2:33])[CH2:32][CH2:31][CH2:30][CH2:29][CH2:28]1.F[P-](F)(F)(F)(F)F.Br[P+](N1CCCC1)(N1CCCC1)N1CCCC1.C(N(CC)C(C)C)(C)C>C(Cl)Cl>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:16]([CH:17]([CH:21]3[CH2:26][CH2:25][CH2:24][CH2:23][CH2:22]3)[C:18]([NH:33][CH:27]3[CH2:32][CH2:31][CH2:30][CH2:29][CH2:28]3)=[O:20])=[C:15]3[C:10]([CH:11]=[CH:12][CH:13]=[CH:14]3)=[N:9]2)=[CH:4][CH:3]=1
Reactant: NC1CCCCC1
Reactant: O=C(O)C(c1c2ccccc2nn1-c1ccc(Cl)cc1)C1CCCCC1
Agent: Br[P+](N1CCCC1)(N1CCCC1)N1CCCC1
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: O=C(NC1CCCCC1)C(c1c2ccccc2nn1-c1ccc(Cl)cc1)C1CCCCC1
Temperature: 25 °C
Reaction time: 120 h
Yield: 46 %

Procedure:
To an ice cold solution of [2-(4-chloro-phenyl)-2H-indazol-3-yl]-cyclohexyl-acetic acid (9 mg, 24 μmol and cyclohexylamine (2.3 μl, 24 μmol; CAS Reg. No. 108-91-8) in CH2Cl2 (1 ml) under an argon atmosphere was added bromotripyrrolidinophosphonium hexafluorophosphate (17 mg, 36 umol) and N,N-diisopropylethylamine (10 ul, 72 umol). The reaction mixture was stirred for 5 d at ambient temperature, poured onto ice water/1 N aqueous NaOH solution 1/1 and extracted two times with iPrOAc. The combined extracts were washed with ice water/1 N aqueous HCl solution 1/1 and brine and dried over Na2SO4. After filtration the solvent was removed under reduced pressure and the residue was purified by preparative thin layer chromatography (silica gel, iPrOAc/heptane) to give the title compound (5 mg, 11 μmol; 46%) as colorless foam. MS: m/e=450.3 [M+H+].
Reaction SMILES: [CH2:1]([O:8][C:9]([NH:11][C@@H:12]1[C@@H:25]([OH:26])[C@H:24]([OH:27])[C@@H:23]([CH2:28][OH:29])[O:22][C@@H:13]1[O:14][CH2:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:30]1([CH3:40])[CH:35]=[CH:34][C:33]([S:36](Cl)(=[O:38])=[O:37])=[CH:32][CH:31]=1.ClCCl>N1C=CC=CC=1>[CH2:1]([O:8][C:9]([NH:11][C@@H:12]1[C@@H:25]([OH:26])[C@H:24]([OH:27])[C@@H:23]([CH2:28][O:29][S:36]([C:33]2[CH:34]=[CH:35][C:30]([CH3:40])=[CH:31][CH:32]=2)(=[O:38])=[O:37])[O:22][C@@H:13]1[O:14][CH2:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C(N[C@H]1[C@@H](OCc2ccccc2)O[C@H](CO)[C@@H](O)[C@@H]1O)OCc1ccccc1
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Solvent: ClCCl
Solvent: c1ccncc1
Product: Cc1ccc(S(=O)(=O)OC[C@H]2O[C@H](OCc3ccccc3)[C@H](NC(=O)OCc3ccccc3)[C@@H](O)[C@@H]2O)cc1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
A solution of 30 g of benzyl 2-benzyloxycarbonylamino-2-desoxy-α-D-glucopyranoside (Heyns and Paulsen, Chem. Ber. 88, 188 (1955)) in 116 ml of pyridine was treated at 0° C. with a solution of 19.85 g of p-tolylsulfonyl chloride in 30 ml of 30 dichloromethane and stirred at room temperature for 4 hours. Then, the mixture was poured into ice-cold 2N sulfuric acid and extracted with dichloromethane. The organic phases were washed with aqueous sodium hydrogen carbonate solution, dried over magnesium sulfate and concentrated. The residue was chromatographed over silica gel with hexane/ethyl acetate and gave benzyl 2-benzyloxycarbonylamino-2-desoxy-6-O-(p-tolyl-sulfonyl)-α-D-glucopyranoside, [α]+101.80 (c 0.5; dioxan), MS: m/z 580 ([M+Na]+).
Reaction SMILES: [C:1]([NH:5][C:6]1[C:7]([CH3:27])=[N:8][C:9]2[C:14]([N:15]=1)=[C:13]([C:16]1[NH:20][C:19]([CH:21]3[CH2:23][CH2:22]3)=[C:18]([C:24]([OH:26])=O)[CH:17]=1)[CH:12]=[CH:11][CH:10]=2)([CH3:4])([CH3:3])[CH3:2].CC[N:30](C(C)C)C(C)C.N.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>CN(C=O)C.C(Cl)Cl>[C:1]([NH:5][C:6]1[C:7]([CH3:27])=[N:8][C:9]2[C:14]([N:15]=1)=[C:13]([C:16]1[NH:20][C:19]([CH:21]3[CH2:22][CH2:23]3)=[C:18]([C:24]([NH2:30])=[O:26])[CH:17]=1)[CH:12]=[CH:11][CH:10]=2)([CH3:2])([CH3:4])[CH3:3]
Reactant: CCN(C(C)C)C(C)C
Reactant: Cc1nc2cccc(-c3cc(C(=O)O)c(C4CC4)[nH]3)c2nc1NC(C)(C)C
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Agent: N
Solvent: ClCCl
Solvent: CN(C)C=O
Product: Cc1nc2cccc(-c3cc(C(N)=O)c(C4CC4)[nH]3)c2nc1NC(C)(C)C
Temperature: 25 °C
Reaction time: 8 h
Yield: 18.9 %

Procedure:
A mixture of 5-(3-(tert-butylamino)-2-methylquinoxalin-5-yl)-2-cyclopropyl-1H-pyrrole-3-carboxylic acid (418c) (0.15 g, 0.412 mmol), 0-(-7-azabenzotriazol-1-yl)-n,′n,′n,′n′-tetramethyluronium-hexafluorophosphate (GenScript Corporation, 0.196 g, 0.514 mmol), DIPEA (Sigma Aldrich, 0.179 ml, 1.029 mmol), in DMF (2.058 mL) was stirred at RT for 5 min before addition of ammonia (2.0 M solution in MeOH, 0.412 mL, 0.823 mmol). Reaction mixture was stirred at RT overnight. Additional aliquots of HATU and DIPEA were added to the reaction mixture which was stirred at RT overnight. Reaction mixture was diluted with DCM and washed with water and brine to remove DMF. Purification by Biotage (0-10% MeOH/DCM) produced 5-(3-(tert-butylamino)-2-methylquinoxalin-5-yl)-2-cyclopropyl-1H-pyrrole-3-carboxamide (418) (0.028 g, 0.078 mmol, 19% yield). 1H NMR (300 MHz, MeOH-d4) δ ppm 0.82-0.92 (m, 2H) 0.98-1.08 (m, 2H) 1.65 (s, 9H) 2.30-2.45 (m, 1H) 2.57 (s, 3H) 6.93-6.99 (m, 1H) 7.26-7.39 (m, 1H) 7.56-7.65 (m, 1H) 7.75-7.85 (m, 1H). m/z (ESI, +ve) 364.1 (M+H).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:11])[CH2:4][CH2:5][CH2:6][CH2:7][CH:8]([OH:10])[CH3:9].Cl[C:13]1[C:14]2[C:21]([C:22]3[CH:27]=[CH:26][C:25]([O:28][CH3:29])=[CH:24][CH:23]=3)=[C:20]([C:30]3[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=3)[O:19][C:15]=2[N:16]=[CH:17][N:18]=1.C(O)(=O)CC(CC(O)=O)(C(O)=O)O>C1COCC1.O>[CH3:1][O:2][C:3](=[O:11])[CH2:4][CH2:5][CH2:6][CH2:7][CH:8]([O:10][C:13]1[C:14]2[C:21]([C:22]3[CH:23]=[CH:24][C:25]([O:28][CH3:29])=[CH:26][CH:27]=3)=[C:20]([C:30]3[CH:31]=[CH:32][CH:33]=[CH:34][CH:35]=3)[O:19][C:15]=2[N:16]=[CH:17][N:18]=1)[CH3:9]
Reactant: COC(=O)CCCCC(C)O
Reactant: COc1ccc(-c2c(-c3ccccc3)oc3ncnc(Cl)c23)cc1
Agent: O=C(O)CC(O)(CC(=O)O)C(=O)O
Solvent: O
Solvent: C1CCOC1
Product: COC(=O)CCCCC(C)Oc1ncnc2oc(-c3ccccc3)c(-c3ccc(OC)cc3)c12
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
Put 1.902 g (11.9 mmol) (+/−)-6-hydroxyheptanoic acid methyl ester under argon in 20 ml THF and cool to 0° C. Add 6 ml (11.9 mmol) of a 2 M solution of the phosphazene base P2-tert.-butyl in THF and stir for a further 10 min at RT. Then cool to 0° C. again. Add 2.00 g (5.94 mmol) 4-chloro-5-(4-methoxyphenyl)-6-phenylfuro[2,3-d]pyrimidine and then stir for a further 1 h at RT. Dilute with water, acidify with 10% aqueous citric acid solution and extract twice with ethyl acetate. Combine the ethyl acetate phases and wash once with satd. sodium chloride solution. Dry over magnesium sulphate, concentrate by evaporation and purify the residue by column chromatography on silica gel (solvent: cyclohexane/ethyl acetate 9:1). 1.38 g (78.0% of theor.) of the target compound is obtained.
Reaction SMILES: C([NH:4][C:5]1[CH:6]=[C:7]2[C:12](=[CH:13][CH:14]=1)[CH:11]=[C:10]([S:15]([NH:18][CH2:19][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)(=[O:17])=[O:16])[CH:9]=[CH:8]2)(=O)C.C(O)CC.[ClH:30]>O>[ClH:30].[NH2:4][C:5]1[CH:6]=[C:7]2[C:12](=[CH:13][CH:14]=1)[CH:11]=[C:10]([S:15]([NH:18][CH2:19][C:20]1[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=1)(=[O:17])=[O:16])[CH:9]=[CH:8]2
Reactant: CC(=O)Nc1ccc2cc(S(=O)(=O)NCc3ccccc3)ccc2c1
Agent: Cl
Solvent: O
Solvent: CCCO
Product: Nc1ccc2cc(S(=O)(=O)NCc3ccccc3)ccc2c1
Temperature: 25 °C
Yield: 74.2 %

Procedure:
6-Acetylamino-N-benzylnaphthalene-2-sulfonamide (compound No. 9-1; 185 mg, 0.522 mmol) was suspended to a mixed solvent of 1-propanol (3.0 ml) and water (1.5 ml). Concentrated hydrochloric acid (1.5 ml) was added to the suspension and the mixture was refluxed for 1 hour. After cooling to room temperature, the separated crystal was collected and washed with 1-propanol and isopropyl ether to give the title compound as a light yellow crystal (135 mg, 74.2%).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([CH:8]([C:10]2[CH:15]=[CH:14][C:13]([O:16][CH3:17])=[CH:12][CH:11]=2)[NH2:9])=[CH:4][CH:3]=1.[P:18]([O-])([O:23][CH2:24][CH3:25])([O:20][CH2:21][CH3:22])=[O:19].CCN(CC)CC>C1(C)C=CC=CC=1.[NH4+].[Cl-].C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[NH2:9][CH:8]([C:10]1[CH:15]=[CH:14][C:13]([O:16][CH3:17])=[CH:12][CH:11]=1)[C:5]1[CH:6]=[CH:7][C:2]([P:18](=[O:19])([O:23][CH2:24][CH3:25])[O:20][CH2:21][CH3:22])=[CH:3][CH:4]=1
Reactant: COc1ccc(C(N)c2ccc(Br)cc2)cc1
Reactant: CCOP(=O)([O-])OCC
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [Cl-]
Agent: [NH4+]
Solvent: Cc1ccccc1
Solvent: CCN(CC)CC
Product: CCOP(=O)(OCC)c1ccc(C(N)c2ccc(OC)cc2)cc1
Temperature: 100 °C
Reaction time: 48 h

Procedure:
To a mixture of (4-bromophenyl)(4-methoxyphenyl)methanamine, 1-1-c, (2 g, 6.8 mmol), diethyl phosphate (1.1 g, 8.2 mmol) and Et3N (1.3 g, 10.2 mmol) in toluene (25 ml) was added Pd(PPh3)4 (1.5 g, 20%). The mixture was allowed to stir for two days at 100° C. The mixture was then diluted with saturated NH4Cl and extracted with EtOAc. The organic layer was dried over Na2SO4, concentrated, and purified over silica gel (5% MeOH/DCM) to obtain as an oil, 1-1-d, (1.00 g). 1HNMR (300 MHZ, DMSO-d): 1.29 (m, 6H), 3.77 (s, 3H), 4.10 (m, 4H), 5.19 (s, 1H), 6.82 (d, 2H), 7.26 (d, 2H), 7.48 (d, 2H), 7.74 (d, 2H).
Reaction SMILES: C(OC([N:8]1[CH2:15][C:14]2[C:10](=[N:11][NH:12][C:13]=2[NH2:16])[CH2:9]1)=O)(C)(C)C.[Cl:17][CH2:18][C:19]([CH2:21]C(=O)C)=O.O.[CH3:26][C:27](O)=O>>[ClH:17].[Cl:17][C:18]1[C:19]([CH3:21])=[N:16][C:13]2[N:12]([N:11]=[C:10]3[CH2:9][NH:8][CH2:15][C:14]3=2)[C:27]=1[CH3:26]
Reactant: CC(=O)CC(=O)CCl
Reactant: CC(C)(C)OC(=O)N1Cc2n[nH]c(N)c2C1
Reactant: CC(=O)O
Solvent: O
Product: Cc1nc2c3c(nn2c(C)c1Cl)CNC3
Product: Cl
Yield: 90 %

Procedure:
A solution of 3-amino-2,6-dihydro-4H-pyrrolo[3,4-c]pyrazole-5-carboxylic acid tert-butyl ester (1 g; 4.46 mmol; 1 eq.) and 3-chloroacetylacetone (0.71 mL; 6.24 mmol; 1.4 eq.) in AcOH (10 mL) was stirred at room temperature for 18 hours. The reaction was poured into water (100 mL) under vigorous stirring and the precipitate filtered off, washed with water (3×) and dried to afford the title compound (1298 mg, 90%) as an off-white solid. 1H NMR (DMSO-d6) δ 4.60-4.52 (m, 4H), 2.81 (br s, 3H), 2.60-2.57 (m, 3H), 1.48 (s, 9H). HPLC (max plot) 98.4%; Rt 3.96 min. UPLC/MS: (MS+) 323 ([M+H]+).
Reaction SMILES: [OH:1][C:2]([C:4]([F:7])([F:6])[F:5])=[O:3].C([N:15]1[CH2:24][CH2:23][C:22]2[C:17](=[N:18][C:19]([N:29]3[CH2:34][CH2:33][CH:32]([O:35][C:36]4[CH:41]=[CH:40][C:39]([F:42])=[CH:38][C:37]=4[F:43])[CH2:31][CH2:30]3)=[C:20]([NH:25][CH:26]([CH3:28])[CH3:27])[N:21]=2)[CH2:16]1)C1C=CC=CC=1>C1COCC1.CO.[OH-].[OH-].[Pd+2]>[F:43][C:37]1[CH:38]=[C:39]([F:42])[CH:40]=[CH:41][C:36]=1[O:35][CH:32]1[CH2:31][CH2:30][N:29]([C:19]2[N:18]=[C:17]3[CH2:16][NH:15][CH2:24][CH2:23][C:22]3=[N:21][C:20]=2[NH:25][CH:26]([CH3:28])[CH3:27])[CH2:34][CH2:33]1.[C:2]([OH:3])([C:4]([F:7])([F:6])[F:5])=[O:1]
Reactant: CC(C)Nc1nc2c(nc1N1CCC(Oc3ccc(F)cc3F)CC1)CN(Cc1ccccc1)CC2
Agent: [Pd+2]
Agent: [OH-]
Solvent: O=C(O)C(F)(F)F
Solvent: CO
Solvent: C1CCOC1
Product: CC(C)Nc1nc2c(nc1N1CCC(Oc3ccc(F)cc3F)CC1)CNCC2
Temperature: 25 °C
Reaction time: 3 h

Procedure:
A mixture of 6-benzyl-3-(4-(2,4-difluorophenoxyl)piperidin-1-yl)-N-isopropyl-5,6,7,8-tetrahydropyrido[3,4-b]pyrazin-2-amine TFA salt (73.0 mg, 0.120 mmol) and Pd(OH)2 on carbon (20 wt %, 7 mg, 9.97 μmol) in THF (601 μL) was stirred at rt under an atmosphere of hydrogen (balloon). After 3 h, the mixture was diluted with MeOH, filtered through a pad of Celite™, washing with MeOH, and concentrated to afford the title compound as its TFA salt (62.3 mg, 100%) as a yellow oil, which was used without further purification. ESI-MS m/z [M+H]+ 404.3.
Reaction SMILES: Cl[C:2]1[N:3]=[N:4][CH:5]=[CH:6][CH:7]=1.ClC1N=[C:13]([O:15]C)[CH:12]=[CH:11]N=1>>[N:4]1[CH:5]=[CH:6][CH:7]=[C:2]([C:6]2[CH:7]=[CH:2][C:12]([CH:13]=[O:15])=[CH:11][CH:5]=2)[N:3]=1
Reactant: COc1ccnc(Cl)n1
Reactant: Clc1cccnn1
Product: O=Cc1ccc(-c2cccnn2)cc1

Procedure:
The title compound was prepared by a procedure analogous to Reference Example 13 by substituting 3-chloropyridazine (prepared as described in WO 9724124) for the 2-chloro4-methoxypyrimidine of Reference Example 13. MS 185 (M+H)+.
Reaction SMILES: [CH3:1][C:2]1([CH3:16])[C:7](=[O:8])[CH2:6][C:5]2[CH:9]=[C:10]([N+:13]([O-:15])=[O:14])[CH:11]=[CH:12][C:4]=2[O:3]1.[H-].[Na+].[C:19](C1NC=CN=1)(C1NC=CN=1)=[O:20].[Cl-].[NH4+:32]>C(N(CC)CC)C.CN(C)C=O>[OH:8][C:7]1[C:2]([CH3:16])([CH3:1])[O:3][C:4]2[CH:12]=[CH:11][C:10]([N+:13]([O-:15])=[O:14])=[CH:9][C:5]=2[C:6]=1[C:19]([NH2:32])=[O:20]
Reactant: [NH4+]
Reactant: CC1(C)Oc2ccc([N+](=O)[O-])cc2CC1=O
Reactant: O=C(c1ncc[nH]1)c1ncc[nH]1
Agent: [Cl-]
Agent: [H-]
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: CC1(C)Oc2ccc([N+](=O)[O-])cc2C(C(N)=O)=C1O
Temperature: 0 °C
Reaction time: 14 h
Yield: 46.8 %

Procedure:
To a mixture of 41.5 g of 3,4-dihydro-2,2-dimethyl-6-nitro-2H-1-benzopyran-3-one and 500 ml of dried N,N-dimethylformamide was slowly added 8.2 g of sodium hydride (60%) in a nitrogen stream while stirring under cooling with ice. After stirring for 50 minutes, 33.5 g of carbonyl diimidazole was added thereto and the mixture stirred for 1 hour. To the reaction mixture were added 11.2 g of ammonium chloride and 29 ml of triethylamine, followed by stirring at 5° C. for 12 hours and then at room temperature for 14 hours. Ice-water was added to the reaction mixture, and the mixture was washed with diethyl ether. The aqueous layer was made acidic with hydrochloric acid and extracted with a mixed solvent of ethyl acetate and diethyl ether. The organic layer was washed with water and dried. The solvent was removed by distillation, and the residue was purified by silica gel column chromatography (developing solution: CH2Cl2 :MeOH=99:1) to obtain 23.2 g of 3-hydroxy-2,2-dimethyl-6-nitro-2H-1-benzopyran-4-carboxamide represented by formula shown below.
Reaction SMILES: O.[NH2:2][NH2:3].[C:4]([N:11]1[CH2:16][CH2:15][C:14](=O)[CH2:13][CH2:12]1)([O:6][C:7]([CH3:10])([CH3:9])[CH3:8])=[O:5].CO.[BH4-].[Na+]>C(O)C>[C:7]([O:6][C:4]([N:11]1[CH2:16][CH2:15][CH:14]([NH:2][NH2:3])[CH2:13][CH2:12]1)=[O:5])([CH3:10])([CH3:9])[CH3:8]
Reactant: NN
Reactant: CC(C)(C)OC(=O)N1CCC(=O)CC1
Agent: [BH4-]
Agent: [Na+]
Solvent: CCO
Solvent: CO
Solvent: O
Product: CC(C)(C)OC(=O)N1CCC(NN)CC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 87.8 %

Procedure:
Hydrazine hydrate (100 mL, ˜2 mol) was added to a solution of 1-Boc-4-piperidone (available from Aldrich Chemical Company, Inc., Milwaukee, Wis., USA 20.0 g, 100 mmol) in ethanol (180 mL) under nitrogen at room temperature and the reaction mixture was stirred at room temperature overnight. Methanol (180 mL) was added and the reaction mixture was cooled to 0-5° C. Sodium borohydride (14.2 g, 375 mmol) was added in portions and the reaction mixture was allowed to warm to room temperature and stir for 2 h. The solvents were evaporated under reduced pressure, dichloromethane was added and the mixture was washed with water, dried (sodium sulfate), filtered, and evaporated to give 4-hydrazino-piperidine-1-carboxylic acid tert-butyl ester (18.9 g, 88%) as a viscous oil, which was used for the next step without further purification.
Reaction SMILES: [N:1]1([C:6]2[CH:26]=[CH:25][C:9]([CH2:10][C:11]3[C:12]([Cl:24])=[N:13][C:14]4[C:19]([C:20]=3[Cl:21])=[CH:18][C:17](Br)=[CH:16][C:15]=4[CH3:23])=[CH:8][CH:7]=2)[CH:5]=[CH:4][CH:3]=[N:2]1.N1(C2C=CC(CC3C(OC)=NC4C(C=3Cl)=CC(Br)=CC=4C)=CC=2)C=CC=N1.[CH3:54][N:55]1[C:59]([C:60]([C:62]2[CH:63]=[N:64][C:65]([C:68]([F:71])([F:70])[F:69])=[CH:66][CH:67]=2)=[O:61])=[CH:58][N:57]=[CH:56]1.[Li]CCCC.C(=O)=O>>[N:1]1([C:6]2[CH:26]=[CH:25][C:9]([CH2:10][C:11]3[C:12]([Cl:24])=[N:13][C:14]4[C:19]([C:20]=3[Cl:21])=[CH:18][C:17]([C:60]([C:59]3[N:55]([CH3:54])[CH:56]=[N:57][CH:58]=3)([C:62]3[CH:63]=[N:64][C:65]([C:68]([F:70])([F:69])[F:71])=[CH:66][CH:67]=3)[OH:61])=[CH:16][C:15]=4[CH3:23])=[CH:8][CH:7]=2)[CH:5]=[CH:4][CH:3]=[N:2]1
Reactant: Cn1cncc1C(=O)c1ccc(C(F)(F)F)nc1
Reactant: Cc1cc(Br)cc2c(Cl)c(Cc3ccc(-n4cccn4)cc3)c(Cl)nc12
Agent: COc1nc2c(C)cc(Br)cc2c(Cl)c1Cc1ccc(-n2cccn2)cc1
Agent: O=C=O
Agent: [Li]CCCC
Product: Cc1cc(C(O)(c2ccc(C(F)(F)F)nc2)c2cncn2C)cc2c(Cl)c(Cc3ccc(-n4cccn4)cc3)c(Cl)nc12
Temperature: -78 °C
Reaction time: 0.17 h

Procedure:
A mixture of 3-(4-(1H-pyrazol-1-yl)benzyl)-6-bromo-2,4-dichloro-8-methylquinoline (393 mg, 0.880 mmol, Intermediate 19: step a) and (1-methyl-1H-imidazol-5-yl)(6-(trifluoromethyl)pyridin-3-yl)methanone (224 mg, 0.880 mmol, Intermediate 36: step c) in dry degassed THF (16 mL, THF was degassed with nitrogen for 1 h) was cooled to −78° C. and n-BuLi (1.6 M in hexane, 0.5 mL, 0.8 mmol) was added over 1.5 minutes. Stirring was continued at −78° C. for 10 minutes and the dry ice bath was replaced with an ice water bath. Stirring was continued for 1 hour after which the reaction mixture was quenched with saturated aqueous NH4Cl solution. EtOAc was added and the layers were separated and the aqueous mixture again extracted with EtOAc. The combined organic extracts were dried over MgSO4, filtered, and the solvents were removed under reduced pressure. Purification using flash column chromatography (5% MeOH in dichloromethane) yielded the substantially pure title compound. MS (ESI) 623.2.
Reaction SMILES: C([S:4][CH:5]([C:16]([F:19])([F:18])[F:17])[C:6]([N:8]1[CH2:15][CH2:14][CH2:13][C@H:9]1[C:10]([OH:12])=[O:11])=[O:7])(=O)C>O.N>[SH:4][CH:5]([C:16]([F:19])([F:17])[F:18])[C:6]([N:8]1[CH2:15][CH2:14][CH2:13][C@H:9]1[C:10]([OH:12])=[O:11])=[O:7]
Reactant: CC(=O)SC(C(=O)N1CCC[C@H]1C(=O)O)C(F)(F)F
Agent: N
Solvent: O
Product: O=C(O)[C@@H]1CCCN1C(=O)C(S)C(F)(F)F

Procedure:
1-(2-Acetylthio-3,3,3-trifluoropropanoyl)-L-proline (4 g.) is dissolved in a mixture of water (8 ml.) and concentrated ammonia (8 ml.) under a blanket of nitrogen. After thirty minutes at room temperature, the reaction mixture is acidified and extracted with ethyl acetate. The organic phase is dried over magnesium sulfate and concentrated to dryness in vacuo to yield 1-(2-mercapto-3,3,3-trifluoropropanoyl)-L-proline.
Reaction SMILES: C([B:3]([CH2:6][CH3:7])CC)C.[B]=O.[OH2:10]>>[CH2:6]([B:3]1[O:10][B:3]([CH2:6][CH3:7])[O:10][B:3]([CH2:6][CH3:7])[O:10]1)[CH3:7]
Reactant: O
Reactant: CCB(CC)CC
Agent: [B]=O
Product: CCB1OB(CC)OB(CC)O1
Reaction time: 120 h

Procedure:
A 500 cc round bottom flask was equipped with water cooled reflux condenser an electrically heated mantle, and a nitrogen bubbler to maintain an inert atmosphere. To the flask under nitrogen was added 70.0 g of B2O3 (Aldrich Gold Label) which had been ground to a powder in a mortar under dry nitrogen. Neat triethylborane (100.0 g) was added to the boron oxide all at one time and the reaction flask was set up for refluxing. Reflux was continued for 5 days at which point the reflux condenser was changed for a distillation condenser and the liquid was distilled in two fractions. The second fraction yielded 60 cc of a colorless liquid which distilled at 148° C. The H-1 and B-11 NMR of the second fraction indicated that it was pure triethylboroxine.
Reaction SMILES: C([N:8]1[CH2:13][CH2:12][CH:11]([O:14][C:15]2[S:16][C:17]3[CH:23]=[C:22]([C:24]4[CH2:25][CH2:26][N:27]([S:30]([CH2:33][CH2:34][CH3:35])(=[O:32])=[O:31])[CH2:28][CH:29]=4)[CH:21]=[CH:20][C:18]=3[N:19]=2)[CH2:10][CH2:9]1)C1C=CC=CC=1.C(Cl)(=O)OC(Cl)C>ClC(Cl)C.C(Cl)Cl>[NH:8]1[CH2:9][CH2:10][CH:11]([O:14][C:15]2[S:16][C:17]3[CH:23]=[C:22]([C:24]4[CH2:25][CH2:26][N:27]([S:30]([CH2:33][CH2:34][CH3:35])(=[O:32])=[O:31])[CH2:28][CH:29]=4)[CH:21]=[CH:20][C:18]=3[N:19]=2)[CH2:12][CH2:13]1
Reactant: CCCS(=O)(=O)N1CC=C(c2ccc3nc(OC4CCN(Cc5ccccc5)CC4)sc3c2)CC1
Agent: CC(Cl)OC(=O)Cl
Solvent: ClCCl
Solvent: CC(Cl)Cl
Product: CCCS(=O)(=O)N1CC=C(c2ccc3nc(OC4CCNCC4)sc3c2)CC1
Temperature: 0 °C
Reaction time: 0.25 h
Yield: 94.1 %

Procedure:
To a solution of 2-(I-benzylpiperidin-4-yloxy)-6-(1-(propylsulfonyl)-1,2,3,6-tetrahydropyridin-4-yl)benzo[d]thiazole (1.812 g, 3.54 mmol) in dichloroethane (30 mL) at 0° C. was added 1-chloroethyl carbonochloridate (0.497 mL, 4.60 mmol). Upon completion of addition, the reaction mixture was stirred at 0° C. for 15 min and then heated to reflux, where it stirred for 1 h. At the conclusion of this period, the volatiles were removed under vacuum and the resulting sample was dissolved in MeOH (30 mL) and then heated to reflux, where it stirred for 1 h. After this time, the reaction mixture was cooled to rt and then concentrated under reduced pressure to yield a residue. The residue was diluted with CH2Cl2 and washed with aq K2CO3 (saturated, 10 mL) and brine (10 mL). The organic layer was dried (Na2SO4), filtered, and then concentrated to afford Compound 15A (1.405 g, 3.33 mmol, 94% yield). LC/MS (m/z)=422 (M+H)+.
Reaction SMILES: [CH2:1]([C:3]1[C:11]2[C:6](=[C:7]([OH:17])[CH:8]=[C:9]([C:12]([O:14][CH2:15][CH3:16])=[O:13])[CH:10]=2)[NH:5][N:4]=1)[CH3:2].[H-].[Na+].I[CH2:21][CH3:22].[CH3:23][CH2:24]OC(C)=O>CN(C=O)C>[CH2:21]([O:17][C:7]1[CH:8]=[C:9]([C:12]([O:14][CH2:15][CH3:16])=[O:13])[CH:10]=[C:11]2[C:6]=1[NH:5][N:4]=[C:3]2[CH2:1][CH3:2])[CH3:22].[CH2:23]([O:17][C:7]1[CH:8]=[C:9]([C:12]([O:14][CH2:15][CH3:16])=[O:13])[CH:10]=[C:11]2[C:6]=1[N:5]([CH2:21][CH3:22])[N:4]=[C:3]2[CH2:1][CH3:2])[CH3:24]
Reactant: CCOC(C)=O
Reactant: CCOC(=O)c1cc(O)c2[nH]nc(CC)c2c1
Reactant: CCI
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCOC(=O)c1cc(OCC)c2[nH]nc(CC)c2c1
Product: CCOC(=O)c1cc(OCC)c2c(c1)c(CC)nn2CC
Temperature: 25 °C
Reaction time: 8 h
Yield: 37 %

Procedure:
To a 0° C. solution of ethyl 3-ethyl-7-hydroxy-1H-indazole-5-carboxylate (prepared as described in Acid Preparation 2) (932 mg, 3.98 mmol) in DMF (28 mL) was added 60% NaH oil dispersion (159 mg, 3.98 mmol). This mixture was stirred at 0° C. for 1 hour before the dropwise addition of a solution of iodoethane (0.32 mL, 3.98 mmol) in DMF (3 mL). The mixture was kept at 0° C. for several hours before removal of the cooling bath and allowing the reaction to warm to room temperature while stirring overnight. The reaction was diluted with EtOAc, washed with saturated aqueous NaHCO3, saturated aqueous NaCl, the organic extract was then dried over Na2SO4, filtered and concentrated. Purify by CombiFlash (80 g column, 0-30% EtOAc/hexanes) to provide ethyl 7-ethoxy-3-ethyl-1H-indazole-5-carboxylate (389 mg, 37%) and ethyl 7-ethoxy-1,3-diethyl-1H-indazole-5-carboxylate (202 mg).
Reaction SMILES: C([O:3][C:4]([C:6]1[N:7]=[C:8]([N:11]2[CH2:16][CH2:15][CH2:14][CH:13]([CH2:17][NH:18][C:19]([O:21][CH2:22][C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=3)=[O:20])[CH2:12]2)[S:9][CH:10]=1)=[O:5])C.[Li+].[OH-]>C1COCC1>[CH2:22]([O:21][C:19]([NH:18][CH2:17][CH:13]1[CH2:14][CH2:15][CH2:16][N:11]([C:8]2[S:9][CH:10]=[C:6]([C:4]([OH:5])=[O:3])[N:7]=2)[CH2:12]1)=[O:20])[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1
Reactant: CCOC(=O)c1csc(N2CCCC(CNC(=O)OCc3ccccc3)C2)n1
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Product: O=C(NCC1CCCN(c2nc(C(=O)O)cs2)C1)OCc1ccccc1

Procedure:
To a stirred solution of 2-[3-(benzyloxycarbonylamino-methyl)-piperidin-1-yl]-thiazole-4-carboxylic acid ethyl ester (439 mg, 1.15 mmol) in THF (5 mL) at RT, a 1M solution of LiOH (aq) (1.72 mL, 1.72 mmol) was added. After 16 h the solvent was evaporated in vacuo. The residue was treated with brine (25 mL) and acidified to pH 1 with 2N HCl (aq) then extracted with EtOAc (30 mL). The organic layer was separated, dried over Na2SO4, filtered and the solvent evaporated in vacuo to yield the title compound as a colorless oil. MS m/z: 355.9 (M+H). Calc'd. for C16H25N3O4S-355.45.