Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: CN(C)[C:3](=O)[S:4][C:5]1[C:14]2[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=2)[C:8]([N+:15]([O-:17])=[O:16])=[CH:7][CH:6]=1.[OH-].[K+].BrC[C:24]([O:26]C(C)(C)C)=[O:25]>CO>[N+:15]([C:8]1[C:9]2[C:14](=[CH:13][CH:12]=[CH:11][CH:10]=2)[C:5]([S:4][CH2:3][C:24]([OH:26])=[O:25])=[CH:6][CH:7]=1)([O-:17])=[O:16]
Reactant: CN(C)C(=O)Sc1ccc([N+](=O)[O-])c2ccccc12
Reactant: CC(C)(C)OC(=O)CBr
Agent: [K+]
Agent: [OH-]
Solvent: CO
Product: O=C(O)CSc1ccc([N+](=O)[O-])c2ccccc12
Temperature: 25 °C
Reaction time: 12 h

Procedure:
97 mg 19 was suspended in 1 ml methanol, to which, in Argon atmosphere, was added 1.4 ml KOH solution (1M in CH3OH). The resulting mixture was stirred at room temperature for 12 hours affording a homogenous solution. 103 μl tert butyl bromoacetate was added through syringe. The reaction solution was continued for 12 hours and concentrated. The residue was dissolved in water and acidified with solid NaHSO4. The yellow precipitate was filtered and washed with water. Dried in air, 78.8 mg (85.6%, 2 steps) yellow solid was obtained. 1H NMR (400 MHz, CDCl3) δ 8.63 (d, J=8.4 Hz, 1H), 8.40 (d, J=8.4 Hz, 1H), 8.18 (d, J=8.1 Hz, 1H), 7.77 (t, J=7.6 Hz, 1H), 7.69 (t, J=7.6 Hz, 1H), 7.53 (d, J=8.4 Hz, 1H), 3.91 (s, 2H). LRMS (ES−) 218 (M—H—CO2)−; HRMS (ES−) m/z calculated for C12H8NO4S (M−H)− 262.0180, found 262.0180.
Reaction SMILES: [Br:1][C:2]([F:12])([F:11])[S:3]([C:6]1[N:10]=[CH:9][NH:8][N:7]=1)(=[O:5])=[O:4].[N:13]1([C:18](Cl)=[O:19])[CH2:17][CH2:16][CH2:15][CH2:14]1>N1C=CC=CC=1.O>[Br:1][C:2]([F:11])([F:12])[S:3]([C:6]1[N:10]=[CH:9][N:8]([C:18]([N:13]2[CH2:17][CH2:16][CH2:15][CH2:14]2)=[O:19])[N:7]=1)(=[O:4])=[O:5]
Reactant: O=S(=O)(c1nc[nH]n1)C(F)(F)Br
Reactant: O=C(Cl)N1CCCC1
Solvent: c1ccncc1
Solvent: O
Product: O=C(N1CCCC1)n1cnc(S(=O)(=O)C(F)(F)Br)n1
Temperature: 25 °C
Reaction time: 16 h
Yield: 61.9 %

Procedure:
To a solution of 0.12 g (0.45 mmol) 3-(bromodifluoromethylsulfonyl)-1,2,4-triazole, prepared as above, in 0.5 ml dry pyridine was added 0.07 g (0.54 mmol) pyrrolidine-1-carbonyl chloride and the mixture was agitated for 16 h at room temperature. The reaction mixture was then diluted with water and extracted with ether. The resulting organic layer was washed successively with dilute hydrochloric acid, water and saturated sodium bicarbonate solution, dried over MgSO4 and evaporated to give 0.1 g (65% yield) of the desired 3-(bromodifluoromethylsulfonyl)-1-(pyrrolidinocarbonyl)-1,2,4-triazole as a pale yellow oil: 1H NMR (CDCl3) δ(ppm) 9.1 (1H), 4.0 (2H), 3.7 (2H), 2.1 (4H).
Reaction SMILES: Cl[CH2:2][CH2:3][C:4]1[C:9](=[O:10])[N:8]2[CH:11]=[CH:12][CH:13]=[CH:14][C:7]2=[N:6][C:5]=1[CH3:15].[NH:16]1[CH2:21][CH2:20][CH:19]([NH:22][C:23]2[N:24]([CH2:32][C:33]3[CH:38]=[N:37][CH:36]=[CH:35][N:34]=3)[C:25]3[C:30]([N:31]=2)=[CH:29][N:28]=[CH:27][N:26]=3)[CH2:18][CH2:17]1.C(=O)([O-])[O-].[Na+].[Na+].CN(C)C(=O)C>O>[CH3:15][C:5]1[N:6]=[C:7]2[CH:14]=[CH:13][CH:12]=[CH:11][N:8]2[C:9](=[O:10])[C:4]=1[CH2:3][CH2:2][N:16]1[CH2:17][CH2:18][CH:19]([NH:22][C:23]2[N:24]([CH2:32][C:33]3[CH:38]=[N:37][CH:36]=[CH:35][N:34]=3)[C:25]3[C:30]([N:31]=2)=[CH:29][N:28]=[CH:27][N:26]=3)[CH2:20][CH2:21]1
Reactant: c1cnc(Cn2c(NC3CCNCC3)nc3cncnc32)cn1
Reactant: Cc1nc2ccccn2c(=O)c1CCCl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CC(=O)N(C)C
Solvent: O
Product: Cc1nc2ccccn2c(=O)c1CCN1CCC(Nc2nc3cncnc3n2Cc2cnccn2)CC1
Temperature: 90 °C
Yield: 31.6 %

Procedure:
A mixture of 1.45 parts of 3-(2-chloroethyl)-2-methyl-4H-pyrido-[1,2-a]pyrimidin-4-one, 2 parts of N-(4-piperidinyl)-9-(2-pyrazinylmethyl)-9H-purin-8-amine, 1 part of sodium carbonate and 45 parts of N,N-dimethylacetamide was stirred and heated overnight at 90° C. The reaction mixture was poured into water. The product was extracted with trichloromethane. The extract was dried, filtered and evaporated. The residue was purified by column chromatography over silica gel using a mixture of trichloromethane and methanol. saturated with ammonia, (95:5 by volume) as eluent. The pure fractions were collected and the eluent was evaporated. The residue was crystallized from acetonitrile. The product was filtered off and dried, yielding 0.9 parts (31.6%) of 2-methyl-3-[2-[4-[[9-(2-pyrazinylmethyl)-9H-purin-8-yl]amino]-1-piperidinyl]-ethyl]-4H-pyrido[1,2-a]pyrimidin-4-one; mp. 180.1° C. (compound 87).
Reaction SMILES: [Cl:1][C:2]1[C:3]([N+:9]([O-])=O)=[C:4]([OH:8])[CH:5]=[CH:6][CH:7]=1.[Sn](Cl)Cl.[OH-].[Na+]>C(O)C>[NH2:9][C:3]1[C:2]([Cl:1])=[CH:7][CH:6]=[CH:5][C:4]=1[OH:8]
Reactant: O=[N+]([O-])c1c(O)cccc1Cl
Agent: Cl[Sn]Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: Nc1c(O)cccc1Cl
Temperature: 80 °C
Reaction time: 2 h
Yield: 71.1 %

Procedure:
A mixture of 3-chloro-2-nitrophenol (250 mg, 1.4 mmol) and tin (II) chloride (1.2 g, 5.3 mmol) in ethanol (50 mL) was heated at 80° C. under argon. After 2 hours, the starting material has disappeared and the solution was allowed to cool down and then poured into ice. The pH was made slightly basic (pH7-8), by addition of solid NaOH, before being extracted with ethyl acetate. The organic phase was washed with brine, dried over MgSO4 and filtered. The solvent was evaporated and chromatography of the resulting solid on silica gel (4%MeOH/CH2CH2) gave the desired product (143 mg, 69 %). 1H NMR (CD3OD): d 6.75 (t, 1H), 6.70 (d, 1H), 6.65 (d, 1H).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C@@H:9]([NH:13][C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])[C:10]([OH:12])=[O:11])=[CH:4][CH:3]=1.[C:21]([O-])([O-])=O.[Cs+].[Cs+].IC.Cl>CN(C=O)C>[CH3:21][O:11][C:10](=[O:12])[C@H:9]([NH:13][C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])[CH2:8][C:5]1[CH:4]=[CH:3][C:2]([Br:1])=[CH:7][CH:6]=1
Reactant: CC(C)(C)OC(=O)N[C@H](Cc1ccc(Br)cc1)C(=O)O
Reactant: O=C([O-])[O-]
Agent: Cl
Agent: [Cs+]
Solvent: CN(C)C=O
Solvent: CI
Product: COC(=O)[C@@H](Cc1ccc(Br)cc1)NC(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a solution of (R)-3-(4-Bromo-phenyl)-2-tert-butoxycarbonylamino-propionic acid (1.0 g, 2.91 mmol) in DMF (5 mL) is added Cs2CO3 (1.041 g, 3.2 mmol) and the mixture is stirred at room temperature for 30 minutes. Then iodomethane (1.031 g, 7.26 mmol) is added and the mixture is stirred at room temperature about 72 hours. The pH is adjusted to 5˜6 by adding 1N HCl then the mixture is extracted with EtOAc. The combined organic layers were washed with water and brine, dried over MgSO4, filtered and concentrated to give (R)-3-(4-bromo-phenyl)-2-tert-butoxycarbonylamino-propionic acid methyl ester. HPLC Retention time 1.49 minutes (condition C): MS 358.3 (M−1).
Reaction SMILES: C(NC(C)C)(C)C.C([Li])CCC.[Br:13][C:14]1[CH:15]=[CH:16][C:17]2[S:21][CH:20]=[CH:19][C:18]=2[CH:22]=1.Cl[Si:24]([CH3:27])([CH3:26])[CH3:25]>C1COCC1>[Br:13][C:14]1[CH:15]=[CH:16][C:17]2[S:21][C:20]([Si:24]([CH3:27])([CH3:26])[CH3:25])=[CH:19][C:18]=2[CH:22]=1
Reactant: C[Si](C)(C)Cl
Reactant: Brc1ccc2sccc2c1
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CC(C)NC(C)C
Product: C[Si](C)(C)c1cc2cc(Br)ccc2s1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 98.9 %

Procedure:
To a solution of diisopropylamine (15.5 mL, 110 mmol) in THF (100 mL) at 0° C. was added n-butyllithium (40 mL of 2.5M in hexanes, 100 mmol). The resultant reaction solution was stirred at 0° C. for 30 minutes and then cooled to −40° C., before it was cannulated to a solution of 5-bromobenzothiophene (10.5 g, 50.0 mmol) and chlorotrimethylsilane (12.7 mL, 100 mmol) in THF (150 mL) at −78° C. The reaction solution was stirred at −78° C. for 1 hour, and then it was quenched with aqueous ammonium chloride at −78° C. and warmed to room temperature. The resultant mixture was extracted with ethyl acetate and the organic extract obtained was washed with brine, dried over sodium sulfate and concentrated in vacuo. The residue obtained was purified by flash column chromatography (hexanes to 98:2 hexanes/ethyl acetate) to give the desired 5-bromo-2-trimethylsilylbenzothiophene (14.1 g, 98%) as a clear colorless oil: 1H NMR (500 MHz, CDCl3) δ 7.93 (d, J=2.0 Hz, 1H), 7.72 (d, J=8.5 Hz, 1H), 7.39 (dd, J=8.5, 2.0 Hz, 1H), 7.37 (s, 1H), 0.38 (s, 9H).
Reaction SMILES: [CH2:1]([O:3][C:4]1[CH:11]=[C:10]([CH2:12][C:13]([NH:15][CH:16]([C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=2[N:27]2[CH2:32][CH2:31][CH2:30][CH2:29][CH2:28]2)[CH2:17][CH:18]([CH3:20])[CH3:19])=[O:14])[CH:9]=[CH:8][C:5]=1[CH2:6]Cl)[CH3:2].[C-:33]#[N:34].[Na+]>>[CH2:1]([O:3][C:4]1[CH:11]=[C:10]([CH2:12][C:13]([NH:15][CH:16]([C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=2[N:27]2[CH2:28][CH2:29][CH2:30][CH2:31][CH2:32]2)[CH2:17][CH:18]([CH3:19])[CH3:20])=[O:14])[CH:9]=[CH:8][C:5]=1[CH2:6][C:33]#[N:34])[CH3:2]
Reactant: [C-]#N
Reactant: CCOc1cc(CC(=O)NC(CC(C)C)c2ccccc2N2CCCCC2)ccc1CCl
Agent: [Na+]
Product: CCOc1cc(CC(=O)NC(CC(C)C)c2ccccc2N2CCCCC2)ccc1CC#N

Procedure:
Prepared analogously to Example 29 from 2-ethoxy-4-[N-(1-(2-piperidino-phenyl)-3-methyl-1-butyl)-aminocarbonylmethyl]benzyl chloride with sodium cyanide.
Reaction SMILES: [C:1]([NH:4][C:5]1[CH:6]=[CH:7][C:8]([S:15]([CH2:18][C:19]2[CH:24]=[CH:23][CH:22]=[C:21]([O:25][C:26](=[O:28])[CH3:27])[CH:20]=2)(=[O:17])=[O:16])=[C:9]2[C:14]=1[N:13]=[CH:12][CH:11]=[CH:10]2)(=[O:3])[CH3:2].ClC1C=CC=C(C(OO)=[O:37])C=1>>[C:1]([NH:4][C:5]1[CH:6]=[CH:7][C:8]([S:15]([CH2:18][C:19]2[CH:24]=[CH:23][CH:22]=[C:21]([O:25][C:26](=[O:28])[CH3:27])[CH:20]=2)(=[O:17])=[O:16])=[C:9]2[C:14]=1[N+:13]([O-:37])=[CH:12][CH:11]=[CH:10]2)(=[O:3])[CH3:2]
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: CC(=O)Nc1ccc(S(=O)(=O)Cc2cccc(OC(C)=O)c2)c2cccnc12
Product: CC(=O)Nc1ccc(S(=O)(=O)Cc2cccc(OC(C)=O)c2)c2ccc[n+]([O-])c12
Temperature: 25 °C
Reaction time: 72 h

Procedure:
8-Acetamido-5-(m-acetoxybenzylsulfonyl)quinoline (3.98 g, 10 mmole) was dissolved in 30 ml of dichlomethane and treated with m-chloroperbenzoic acid (2.03 g). The solution was stirred for 3 days at room temperature. Some m-chlorobenzoic acid which separated was filtered off and the filtrate concentrated to a syrup. On boiling with 40 ml 2-propanol a pale yellow solid was induced to crystallize. After chilling in an ice bath, the solid was filtered off, washed with 2-propanol and ether, and dried to yield 3.8 g (92 percent). The structure was confirmed by NMR.
Reaction SMILES: C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[C:20]([OH:23])(=[S:22])[CH3:21].[Cl:24][C:25]1[CH:30]=[C:29]([CH3:31])[C:28]([NH:32][C:33]([C:35]2[N:36]([C:44]3[C:49]([Cl:50])=[CH:48][CH:47]=[CH:46][N:45]=3)[N:37]=[C:38]([C:40]([F:43])([F:42])[F:41])[CH:39]=2)=[O:34])=[C:27]([C:51](=[O:57])[NH:52][CH2:53][CH:54](O)[CH3:55])[CH:26]=1>C1COCC1>[Cl:24][C:25]1[CH:30]=[C:29]([CH3:31])[C:28]([NH:32][C:33]([C:35]2[N:36]([C:44]3[C:49]([Cl:50])=[CH:48][CH:47]=[CH:46][N:45]=3)[N:37]=[C:38]([C:40]([F:41])([F:43])[F:42])[CH:39]=2)=[O:34])=[C:27]([CH:26]=1)[C:51]([NH:52][CH2:53][CH:54]([S:22][C:20](=[O:23])[CH3:21])[CH3:55])=[O:57]
Reactant: Cc1cc(Cl)cc(C(=O)NCC(C)O)c1NC(=O)c1cc(C(F)(F)F)nn1-c1ncccc1Cl
Reactant: CC(O)=S
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: CC(=O)SC(C)CNC(=O)c1cc(Cl)cc(C)c1NC(=O)c1cc(C(F)(F)F)nn1-c1ncccc1Cl
Temperature: 0 °C
Reaction time: 1 h
Yield: 87.9 %

Procedure:
To a solution of 2.55 g (9.7 mmol) triphenylphosphine in 250 ml THF is added at a temperature of 0° C. 2.25 g (9.7 mmol) diterbutylazodicarboxylate in 25 ml THF. The solution is stirred for 1 hour at a temperature of 0° C. Then 0.35 ml (4.85 mmol) thioacetic acid is added and a white suspension is formed immediately. After that, a solution of 2.5 g (4.85 mmol) 2-(3-chloro-pyridin-2-yl)-5-trifluoromethyl-2H-pyrazole-3-carboxylic acid [4-chloro-2-(2-hydroxy-propylcarbamoyl)-6-methyl-phenyl]-amide in 30 ml THF is slowly added at a temperature of 0° C. The solution is stirred for 1 hour at a temperature of 0° C., and then 15 hours at 25° C., and then evaporated. The residue is submitted to flash-chromatography (ethyl acetate 1, hexane 2) to give 2.45 g (88%) white crystals (m.p. 137-139° C.).
Reaction SMILES: [Cl:1][C:2]1[CH:8]=[C:7]([Cl:9])[C:6]([O:10][CH3:11])=[CH:5][C:3]=1[NH2:4].[H-].[Na+].Cl[C:15]1[C:20]([C:21]#[N:22])=[CH:19][N:18]=[C:17]2[S:23][C:24]([CH3:26])=[CH:25][C:16]=12>O1CCCC1>[Cl:1][C:2]1[CH:8]=[C:7]([Cl:9])[C:6]([O:10][CH3:11])=[CH:5][C:3]=1[NH:4][C:15]1[C:20]([C:21]#[N:22])=[CH:19][N:18]=[C:17]2[S:23][C:24]([CH3:26])=[CH:25][C:16]=12
Reactant: COc1cc(N)c(Cl)cc1Cl
Reactant: Cc1cc2c(Cl)c(C#N)cnc2s1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: COc1cc(Nc2c(C#N)cnc3sc(C)cc23)c(Cl)cc1Cl
Temperature: 25 °C
Reaction time: 8 h
Yield: 74.8 %

Procedure:
A mixture of 2,4-dichloro-5-methoxyaniline (0.15 g, 0.73 mmol) and 60% sodium hydride (50 mg, 1.25 mmol) in 15 mL of tetrahydrofuran is heated at reflux for 1 hour. The solution is cooled and 4-chloro-2-methylthieno[2,3-b]pyridine-5-carbonitrile (0.06 g, 0.29 mmol) is added. The reaction mixture is heated at reflux for 3 hours then allowed to stir at room temperature overnight. The resultant black solution is partitioned between ethyl acetate and water. The organic layer is washed with water, dried over magnesium sulfate, filtered and concentrated in vacuo. The residue is purified by flash column chromatography eluting with 3:7 ethyl acetate:hexane. The fractions containing product are combined and concentrated. Diethyl ether is added and the insoluble material collected by filtration to provide 79 mg of 4-[(2,4-dichloro-5-methoxyphenyl)amino]-2-methylthieno[2,3-b]pyridine-5-carbonitrile as a tan solid, mp 179–181° C.; 1H NMR (DMSO-d6) δ 2.57 (s, 3H), 3.85 (s, 3H), 7.32 (s, 1H), 7.39 (s, 1H), 7.74 (s, 1H), 8.35 (s, 1H), 9.61 (s, 1H); MS 362.1 (M−H)−
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]([S:10]([NH:13][C:14]2[S:15][CH:16]=[CH:17][N:18]=2)(=[O:12])=[O:11])[CH:6]=[CH:7][C:8]=1F)#[N:2].[Cl:19][C:20]1[CH:25]=[CH:24][C:23]([OH:26])=[C:22]([C:27]2[N:31]([CH3:32])[N:30]=[CH:29][CH:28]=2)[CH:21]=1.C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O>[Cl:19][C:20]1[CH:25]=[CH:24][C:23]([O:26][C:8]2[CH:7]=[CH:6][C:5]([S:10]([NH:13][C:14]3[S:15][CH:16]=[CH:17][N:18]=3)(=[O:12])=[O:11])=[CH:4][C:3]=2[C:1]#[N:2])=[C:22]([C:27]2[N:31]([CH3:32])[N:30]=[CH:29][CH:28]=2)[CH:21]=1
Reactant: N#Cc1cc(S(=O)(=O)Nc2nccs2)ccc1F
Reactant: Cn1nccc1-c1cc(Cl)ccc1O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: Cn1nccc1-c1cc(Cl)ccc1Oc1ccc(S(=O)(=O)Nc2nccs2)cc1C#N

Procedure:
3-Cyano-4-fluoro-N-1,3-thiazol-2-ylbenzenesulfonamide, (Preparation 46, 500 mg, 0.00176 mol), 4-chloro-2-(1-methyl-1H-pyrazol-5-yl)phenol, (Preparation 89, 370 mg, 0.00177 mol) and potassium carbonate (700 mg, 0.00287 mol) were stirred in dimethylformamide (5 mL) at 80° C. for 24 hours. The reaction mixture was cooled and partitioned between ethyl acetate (150 mL) and aqueous hydrochloric acid (80 mL of 2 molar), the organic layer was dried over anhydrous sodium sulphate, filtered and the solvents removed in vacuo to give an orange solid. The solid was triturated with diethyl ether (20 mL) to give the title compound as an orange powder, (680 mg).
Reaction SMILES: [NH2:1][C:2]1[S:12][C:5]2[CH2:6][O:7][C:8]([CH3:11])([CH3:10])[CH2:9][C:4]=2[C:3]=1[C:13]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14].[C:20]1([N:26]=[C:27]=[S:28])[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1>O1CCCC1>[CH3:10][C:8]1([CH3:11])[O:7][CH2:6][C:5]2[S:12][C:2]([NH:1][C:27]([NH:26][C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)=[S:28])=[C:3]([C:13]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14])[C:4]=2[CH2:9]1
Reactant: CC(C)(C)OC(=O)c1c(N)sc2c1CC(C)(C)OC2
Reactant: S=C=Nc1ccccc1
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)c1c(NC(=S)Nc2ccccc2)sc2c1CC(C)(C)OC2
Yield: 30.6 %

Procedure:
To a solution of tert-butyl 2-amino-5,5-dimethyl-5,7-dihydro-4H-thieno[2,3-c]pyran-3-carboxylate (0.100 g, 0.353 mmol, 1 eq) in dry tetrahyrofuran (5 mL) under argon was added phenyl isothiocyanate (0.05 mL, 0.388 mmol, 1.1 eq). The mixture was heated at reflux for 16 hours. The solvent was evaporated in vacuo. Purification by reverse-phase chromatography (0-100% CH3CN: Water ramp over 20 min) afforded the desired product tert-butyl 5,5-dimethyl-2-(3-phenylthioureido)-5,7-dihydro-4H-thieno[2,3-c]pyran-3-carboxylate as a yellow solid (0.045 g, 0.108 mmol, 30% yield). 1H NMR (400 MHz, DMSO) δ 11.92 (s, 1H), 11.05 (s, 1H), 7.50 (d, J=7.6, 2H), 7.42 (t, J=7.9, 2H), 7.26 (t, J=7.3, 1H), 4.61 (s, 2H), 2.65 (s, 2H), 1.53 (s, 9H), 1.23 (s, 6H).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C:8]2([CH2:14][CH2:15][N:16]3[C@H:21]4[CH2:22][CH2:23][C@@H:17]3[CH2:18][CH:19]([N:24]3[C:28]5[CH:29]=[CH:30][CH:31]=[CH:32][C:27]=5[N:26]=[C:25]3[CH3:33])[CH2:20]4)[CH2:13][CH2:12][NH:11][CH2:10][CH2:9]2)[CH:5]=[CH:6][CH:7]=1.[Cl:34][C:35]1[CH:43]=[C:42]([F:44])[C:41]([S:45]([NH:48][CH:49]2[CH2:53][CH2:52][CH2:51][CH2:50]2)(=[O:47])=[O:46])=[CH:40][C:36]=1[C:37](O)=[O:38].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>>[Cl:34][C:35]1[C:36]([C:37]([N:11]2[CH2:10][CH2:9][C:8]([C:4]3[CH:5]=[CH:6][CH:7]=[C:2]([F:1])[CH:3]=3)([CH2:14][CH2:15][N:16]3[C@H:21]4[CH2:22][CH2:23][C@@H:17]3[CH2:18][CH:19]([N:24]3[C:28]5[CH:29]=[CH:30][CH:31]=[CH:32][C:27]=5[N:26]=[C:25]3[CH3:33])[CH2:20]4)[CH2:13][CH2:12]2)=[O:38])=[CH:40][C:41]([S:45]([NH:48][CH:49]2[CH2:53][CH2:52][CH2:51][CH2:50]2)(=[O:46])=[O:47])=[C:42]([F:44])[CH:43]=1
Reactant: O=C(O)c1cc(S(=O)(=O)NC2CCCC2)c(F)cc1Cl
Reactant: Cc1nc2ccccc2n1C1C[C@H]2CC[C@@H](C1)N2CCC1(c2cccc(F)c2)CCNCC1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Product: Cc1nc2ccccc2n1C1C[C@H]2CC[C@@H](C1)N2CCC1(c2cccc(F)c2)CCN(C(=O)c2cc(S(=O)(=O)NC3CCCC3)c(F)cc2Cl)CC1
Yield: 40 %

Procedure:
0.103 g (0.23 mmol) 1-((1R,5S)-8-{2-[4-(3-fluorophenyl)piperidin-4-yl]ethyl}-8-azabicyclo[3.2.1]oct-3-yl)-2-methyl-1H-benzimidazole and 0.148 g (0.46 mmol) 2-chloro-4-fluoro-5-[(cyclopentylamino)sulfonyl]benzoic acid were combined following the HATU general procedure in Example 5. This compound was purified by reverse phase chromatography on a 0-100% gradient of 0.1% TFA in water in acetonitrile. 0.068 g obtained (40% yield). 1H NMR (300 MHz, DMSO-d6) δ 9.32-9.49 (br, 1H), 8.13-8.25 (m, 2H), 7.73-7.91 (m, 3H), 7.39-7.56 (m, 2H), 7.08-7.30 (m, 3H), 5.00-5.15 (m, 1H), 4.03-4.16 (m, 2H), 3.83-4.02 (m, 1H), 3.35-3.58 (m, 2H), 3.19-3.33 (m, 2H), 3.16 (s, 1H), 2.94-3.08 (m, 2H), 2.67-2.80 (m, 6H), 2.54-2.65 (m, 1H), 2.02-2.26 (m, 8H), 1.72-2.01 (m, 2H), 1.47-1.67 (m, 4H), 1.26-1.44 (m, 4H)
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[C:6]([N+:8]([O-:10])=[O:9])[CH:5]=[CH:4][C:3]=1[N:11]=[C:12]1[S:16][CH2:15][C:14]2([CH2:20][CH2:19][CH2:18][CH2:17]2)[NH:13]1.Br[CH2:22][CH:23]([CH2:26][CH3:27])[CH2:24][CH3:25]>>[CH3:1][C:2]1[CH:7]=[C:6]([N+:8]([O-:10])=[O:9])[CH:5]=[CH:4][C:3]=1[N:11]=[C:12]1[S:16][CH2:15][C:14]2([CH2:17][CH2:18][CH2:19][CH2:20]2)[N:13]1[CH2:22][CH:23]([CH2:26][CH3:27])[CH2:24][CH3:25]
Reactant: Cc1cc([N+](=O)[O-])ccc1N=C1NC2(CCCC2)CS1
Reactant: CCC(CC)CBr
Product: CCC(CC)CN1C(=Nc2ccc([N+](=O)[O-])cc2C)SCC12CCCC2

Procedure:
1-(Hydroxymethyl)cyclopentanamine was prepared according to Method B1c. The 2-hydroxyethylamine was sequentially reacted with SOCl2 and 2-methyl-4-nitrophenyl isothiocyanate according to Method C2a to give 2-(2-methyl-4-nitrophenylimino)-3-thia-1-azaspiro[4.4]nonane. The thiazolidine was reacted with 1-bromo-2-ethylbutane according to Method D2a to afford 2-(2-methyl-4-nitrophenylimino)-1-(2-ethyl-1-butyl)-3-thia-1-azaspiro[4.4]nonane.
Reaction SMILES: Cl[C:2]1[C:11]([CH3:12])=[C:10]([Cl:13])[C:9]2[C:4](=[CH:5][C:6]([F:15])=[CH:7][C:8]=2[F:14])[N:3]=1.[CH3:16][S:17]([C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=1B(O)O)=[O:18]>>[Cl:13][C:10]1[C:9]2[C:4](=[CH:5][C:6]([F:15])=[CH:7][C:8]=2[F:14])[N:3]=[C:2]([C:20]2[CH:21]=[CH:22][CH:23]=[CH:24][C:19]=2[S:17]([CH3:16])=[O:18])[C:11]=1[CH3:12]
Reactant: Cc1c(Cl)nc2cc(F)cc(F)c2c1Cl
Reactant: CS(=O)c1ccccc1B(O)O
Product: Cc1c(-c2ccccc2S(C)=O)nc2cc(F)cc(F)c2c1Cl

Procedure:
Essentially prepared according to Procedure F using 2,4-dichloro-5,7-difluoro-3-methylquinoline (250 mg, 1.00 mmol) and 2-(methylsulfinyl)phenylboronic acid to give 4-chloro-5,7-difluoro-3-methyl-2-(2-(methylsulfinyl)phenyl)quinoline. Mass Spectrum (ESI) m/e=352.1 (M+1).
Reaction SMILES: [CH:1]1([C:7]2[N:11]([CH2:12][C:13]3[CH:21]=[CH:20][C:16]([C:17]([OH:19])=O)=[CH:15][CH:14]=3)[N:10]=[C:9]([C:22]3[CH:27]=[CH:26][C:25]([O:28][C:29]([F:32])([F:31])[F:30])=[CH:24][CH:23]=3)[CH:8]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.Cl.CN(C)CCCN=C=NCC.O.ON1C2C=CC=CC=2N=N1.O.[NH2:57][C:58]1[NH:62][N:61]=[N:60][N:59]=1>CN(C=O)C.O>[CH:1]1([C:7]2[N:11]([CH2:12][C:13]3[CH:21]=[CH:20][C:16]([C:17]([NH:57][C:58]4[NH:62][N:61]=[N:60][N:59]=4)=[O:19])=[CH:15][CH:14]=3)[N:10]=[C:9]([C:22]3[CH:23]=[CH:24][C:25]([O:28][C:29]([F:31])([F:32])[F:30])=[CH:26][CH:27]=3)[CH:8]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: Nc1nnn[nH]1
Reactant: O=C(O)c1ccc(Cn2nc(-c3ccc(OC(F)(F)F)cc3)cc2C2CCCCC2)cc1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: O
Product: O=C(Nc1nnn[nH]1)c1ccc(Cn2nc(-c3ccc(OC(F)(F)F)cc3)cc2C2CCCCC2)cc1
Reaction time: 16 h

Procedure:
A solution of 128 mg product from Step D above, 66.3 mg 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (EDC), 46.8 mg 1-hydroxybenzotriazole hydrate (HOBt) in 1 mL DMF was stirred at room temperature for 30 minutes. 5-Aminotetrazole monohydrate (35.7 mg) was added and the mixture stirred for additional 16 hours. Precipitate the product by adding 1 mL water to the reaction mixture. Collect the product by filtration, wash it with 1:1 DMF and water, water, and MeCN, and dry to give the title compound as a white solid. 1H NMR (CD3OD, 500 MHz) δ 7.995 (d, J=8.2 Hz, 2H), 7.86 (d, J=8.6 Hz, 2H), 7.27˜7.29 (m, 4H), 6.58 (s, 1H), 5.52 (s, 2H), 2.59˜2.65 (m, 1H), 1.75˜1.81 (m, 4H), 1.69˜1.73 (m, 1H), 1.39˜1.46 (m, 2H), 1.24˜1.37 (m, 3H). LC-MS: 2.32 min. (M+H=512.3).
Reaction SMILES: [OH-].[Na+:2].[OH:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[C:10]1[N:11]=[C:12]([CH2:15][CH2:16][CH2:17][CH2:18][C:19]([OH:21])=[O:20])[O:13][CH:14]=1>O>[Na+:2].[Na+:2].[OH:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[C:10]1[N:11]=[C:12]([CH2:15][CH2:16][CH2:17][CH2:18][C:19]([O-:21])=[O:20])[O:13][CH:14]=1.[OH:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[C:10]1[N:11]=[C:12]([CH2:15][CH2:16][CH2:17][CH2:18][C:19]([O-:21])=[O:20])[O:13][CH:14]=1
Reactant: O=C(O)CCCCc1nc(-c2ccccc2O)co1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: O=C([O-])CCCCc1nc(-c2ccccc2O)co1
Temperature: 25 °C
Yield: 107.8 %

Procedure:
Add a solution of NaOH (1.15 g, 28.75 mmol) in water (5 mL) to a suspension of 5-[4-(2-hydroxy-phenyl)-oxazol-2-yl]-pentanoic acid (compound of Example 6, 3.76 g, 14.38 mmol) in water (30 mL) and stir at room temperature. Heat to 50° C. for 1 h, filter hot solution, concentrate, place in 50-60° C. vacuum oven overnight Scrape and crush solids, place in 50-60° C. vacuum oven for 60 hours to afford the title compound (4.39 g, 100%). MS (IS) 260 (M−1)−.