Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]1([S:7]([Cl:10])(=[O:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[ClH:11].ClCl>[Fe]>[C:1]1([S:7]([Cl:10])(=[O:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[Cl:11][C:3]1[CH:2]=[C:1]([S:7]([Cl:10])(=[O:9])=[O:8])[CH:6]=[CH:5][CH:4]=1
Reactant: Cl
Agent: [Fe]
Agent: ClCl
Agent: O=S(=O)(Cl)c1ccccc1
Product: O=S(=O)(Cl)c1cccc(Cl)c1

Procedure:
706 g (4 mols) of benzene sulphonyl chloride and 10 g of iron filings are initially placed in a 2-liter stirrer-type apparatus. The mixture is saturated with gaseous hydrochloric acid and chlorine is introduced at 50° to 60° C until there is an increase in weight of 150 g. Distillation takes place after removal of the catalyst. 741 g of crude product of b.p.: 113° to 120° C/3 mm.Hg are obtained. By fine rectification, 133 g of benzene sulphonyl chloride (19% recovery) of b.p.: 89° C/1.3 mm.Hg and 572 g of m-chlorobenzene sulphonyl chloride (yield relative to reacted benzene sulphonyl chloride = 83% of the theoretical) of b.p.: 102° C/1.6 to 1.7 mm.Hg are obtained.
Reaction SMILES: [O:1]=[C:2]1[O:6][CH:5]([C:7]([OH:9])=O)[CH2:4][CH2:3]1.S(Cl)([Cl:12])=O>>[O:1]=[C:2]1[O:6][CH:5]([C:7]([Cl:12])=[O:9])[CH2:4][CH2:3]1
Reactant: O=S(Cl)Cl
Reactant: O=C1CCC(C(=O)O)O1
Product: O=C1CCC(C(=O)Cl)O1

Procedure:
A mixture of 4.9 g of 5-oxotetrahydrofuran-2-carboxylic acid and 5.5 ml of thionyl chloride was subjected to reflux for 2 hours. Thionyl chloride was then distilled off under reduced pressure to leave 5-oxotetrahydrofuran-2-carbonyl chloride. This product was mixed with 5.0 g of 2-aminobenzophenone, 200 ml of ethyl acetate and 200 ml of a saturated aqueous solution of sodium hydrogencarbonate, which was stirred for one hour at room temperature. The ethyl acetate layer was washed with water and dried over anhydrous magnesium sulfate, then the solvent was distilled off under reduced pressure. The residue was purified by means of a silica gel column chromatography (eluent, hexane:ethyl acetate=2:1) to give 2-(5-oxotetrahydrofuran-2-carbonyl)aminobenzophenone (6.5 g) as needles, m.p. 100° C.-102° C.
Reaction SMILES: [C:1]([C:4]([C:7]1[CH:30]=[CH:29][C:10]([CH2:11][NH:12][C:13](=[O:28])[C:14]2[CH:19]=[CH:18][CH:17]=[N:16][C:15]=2[O:20][C:21]2[CH:26]=[CH:25][C:24]([F:27])=[CH:23][CH:22]=2)=[C:9]([F:31])[CH:8]=1)([CH3:6])[CH3:5])(=O)[NH2:2].P(Cl)(Cl)(Cl)=O>>[C:1]([C:4]([CH3:6])([CH3:5])[C:7]1[CH:30]=[CH:29][C:10]([CH2:11][NH:12][C:13](=[O:28])[C:14]2[CH:19]=[CH:18][CH:17]=[N:16][C:15]=2[O:20][C:21]2[CH:26]=[CH:25][C:24]([F:27])=[CH:23][CH:22]=2)=[C:9]([F:31])[CH:8]=1)#[N:2]
Reactant: CC(C)(C(N)=O)c1ccc(CNC(=O)c2cccnc2Oc2ccc(F)cc2)c(F)c1
Solvent: O=P(Cl)(Cl)Cl
Product: CC(C)(C#N)c1ccc(CNC(=O)c2cccnc2Oc2ccc(F)cc2)c(F)c1
Temperature: 90 °C
Yield: 82.1 %

Procedure:
To N-[4-(1-Carbamoyl-1-methyl-ethyl)-2-fluoro-benzyl]-2-(4-fluoro-phenoxy)-nicotinamide (3.00 g) in a 50 mL flask was added phosphorous oxychloride (3.29 mL). The solution was heated for 1 h at 90° C. The solution was then cooled in an ice bath, poured over satd. aq. sodium carbonate (50 mL), then extracted with ethyl acetate (4×100 mL). The combined organic layers were dried over magnesium sulfate, filtered, and concentrated in vacuo, yielding the title compound (2.36 g).
Reaction SMILES: [C:1]1([CH:7]([CH2:10][CH2:11][O:12][Si](C)(C)C)[C:8]#N)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C([OH:19])C>S(=O)(=O)(O)O.O>[C:1]1([CH:7]2[CH2:10][CH2:11][O:12][C:8]2=[O:19])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: CCO
Reactant: C[Si](C)(C)OCCC(C#N)c1ccccc1
Agent: O=S(=O)(O)O
Solvent: O
Product: O=C1OCCC1c1ccccc1
Temperature: 50 °C
Reaction time: 3 h
Yield: 62 %

Procedure:
A suspension of potassium tert-butoxide (12.3 g) in toluene (200 mL) was treated dropwise with a mixture of phenylacetonitrile (12.9 g) and (2-bromoethoxy)trimethyl-silane (23.8 g) at room temperature. Upon completion of the addition, the reaction mixture was refluxed for 5 h, then cooled to room temperature and quenched by pouring onto a mixture of ice and water. The formed organic phase was separated and the aqueous phase was extracted with benzene. The combined organic phases were washed with water, dried over magnesium sulfate, filtered and concentrated on a rotary evaporator to give 2-phenyl-4-trimethylsilanyloxy-butyronitrile. The obtained butyronitrile derivative was redissolved in a mixture of ethanol (40 mL) and 70% aqueous sulfuric acid (40 mL), stirred at 50° C. for 3 h and, after cooling to room temperature, diluted with water (150 mL). The resulted organic phase was separated and the aqueous phase was extracted with benzene. The combined organic phases were washed with water, then with saturated aqueous solution of sodium bicarbonate, dried over magnesium sulfate, filtered, concentrated on a rotary evaporator and distilled in vacuum to give 11.0 g (62%) of the title compound.
Reaction SMILES: C([C:3]1[C:8]([CH2:9][CH2:10][CH2:11][CH2:12][CH3:13])=[C:7]([C:14]2[CH:19]=[CH:18][C:17]([F:20])=[CH:16][CH:15]=2)[C:6]([CH2:21][O:22][Si:23]([C:36]([CH3:39])([CH3:38])[CH3:37])([C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=2)[C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)=[C:5]([CH:40]([CH3:42])[CH3:41])[N:4]=1)=O.C1(P(=[CH:62][C:63]([O:65][CH3:66])=[O:64])(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[C:67]1(C)C=CC=CC=1>>[C:63]([CH:62]=[CH:67][C:3]1[C:8]([CH2:9][CH2:10][CH2:11][CH2:12][CH3:13])=[C:7]([C:14]2[CH:15]=[CH:16][C:17]([F:20])=[CH:18][CH:19]=2)[C:6]([CH2:21][O:22][Si:23]([C:36]([CH3:38])([CH3:39])[CH3:37])([C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=2)[C:24]2[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=2)=[C:5]([CH:40]([CH3:41])[CH3:42])[N:4]=1)([O:65][CH3:66])=[O:64]
Reactant: Cc1ccccc1
Reactant: COC(=O)C=P(c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: CCCCCc1c(C=O)nc(C(C)C)c(CO[Si](c2ccccc2)(c2ccccc2)C(C)(C)C)c1-c1ccc(F)cc1
Product: CCCCCc1c(C=CC(=O)OC)nc(C(C)C)c(CO[Si](c2ccccc2)(c2ccccc2)C(C)(C)C)c1-c1ccc(F)cc1
Temperature: 25 °C

Procedure:
A mixture of the intermediate obtained in Example 205, Step A (50 mg, 85 mmol) and methyl (triphenylphosphoranylidene)acetate (31 mg, 1.1 equiv) in toluene (5 mL) was heated to reflux for 5 h. The mixture was cooled to rt and concentrated in vacuo. Silica gel chromatography provided a yellow oil (60 mg). 1H NMR (CDCl3, 300 MHz): δ 7.96 (d, 15.1 Hz, 1H), 7.42 (m, 6H), 7.34-7.21 (m, 5H), 7.05 (s, 2H), 7.03 (s, 2H), 4.28 (s, 2H), 3.84 (s, 3H), 3.17 (sept, 6.8 Hz, 1H), 2.38 (m, 2H), 1.31 (m, 2H), 1.19 (d, 6.6 Hz, 6H), 1.14 (m, 4H), 1.00 (s, 9H), 0.79 (t, 6.6 Hz, 3H).
Reaction SMILES: C1([C:7]2[N:11]([C:12]3[CH:17]=[CH:16][C:15]([O:18][C:19]([F:22])([F:21])[F:20])=[CH:14][CH:13]=3)[N:10]=[CH:9][C:8]=2[CH2:23][C:24]2[CH:31]=[CH:30][C:27]([C:28]#N)=[CH:26][CH:25]=2)CCCCC1.[OH2:32].[OH-:33].[K+]>C(O)C>[CH2:12]1[CH2:17][CH:16]([CH:23]([C:24]2[CH:31]=[CH:30][C:27]([C:28]([OH:33])=[O:32])=[CH:26][CH:25]=2)[C:8]2[CH:9]=[N:10][N:11]([C:12]3[CH:13]=[CH:14][C:15]([O:18][C:19]([F:22])([F:20])[F:21])=[CH:16][CH:17]=3)[CH:7]=2)[CH2:15][CH2:14][CH2:13]1
Reactant: [OH-]
Reactant: N#Cc1ccc(Cc2cnn(-c3ccc(OC(F)(F)F)cc3)c2C2CCCCC2)cc1
Reactant: O
Agent: [K+]
Solvent: CCO
Product: O=C(O)c1ccc(C(c2cnn(-c3ccc(OC(F)(F)F)cc3)c2)C2CCCCC2)cc1

Procedure:
To a hot solution of 0.73 g 4-({5-cyclohexyl-1-[4-(trifluoromethoxy)phenyl]-1H-pyrazol-4-yl}methyl)benzonitrile From Step E above in 15 mL ethanol and 6 mL water was added 1.11 g potassium hydroxide. The resulting solution was refluxed under nitrogen over night. The solvents were removed under reduced pressure. The residue was re-suspended in 10 mL water and acidified with 9.0 mL 2 N HCl. The resulting solid was filtered, washed with water, and dried to give the title compound as a white solid. 1H NMR (CD3OD, 500 MHz) δ 7.95 (d, J=8.2 Hz, 2H), 7.48˜7.50 (m, 2H), 7.45 (d, J=8.6 Hz, 2H), 7.36 (s, 1H), 7.32 (d, J=8.2 Hz, 2H), 4.06 (s, 2H), 2.66 (tt, J=3.0 & 12.7 Hz, 1H), 1.69˜1.73 (m, 4H), 1.53˜1.64 (m, 3H), 1.09˜1.19 (m, 3H). LC-MS: 2.29 min. (M+H=445.2).
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6]2[N:8]([CH3:16])[C:9](=[O:15])[N:10]([CH2:11]C(C)=C)[C:5]2=[CH:4][CH:3]=1.Cl[C:18]([F:23])([F:22])[C:19](O)=O.[Na].C(O[CH2:29][CH3:30])(=O)C>C(=O)(O)[O-].[Na+]>[Cl:1][C:2]1[N:7]=[C:6]2[N:8]([CH3:16])[C:9](=[O:15])[N:10]([CH2:11][C:29]3([CH3:30])[CH2:19][C:18]3([F:23])[F:22])[C:5]2=[CH:4][CH:3]=1
Reactant: CCOC(C)=O
Reactant: C=C(C)Cn1c(=O)n(C)c2nc(Cl)ccc21
Reactant: O=C(O)C(F)(F)Cl
Agent: O=C([O-])O
Agent: [Na+]
Agent: [Na]
Product: Cn1c(=O)n(CC2(C)CC2(F)F)c2ccc(Cl)nc21
Temperature: 200 °C

Procedure:
5-chloro-3-methyl-1-(2-methylprop-2-en-1-yl)-1,3-dihydro-2H-imidazo[4,5-b]pyridin-2-one (74-1) (6 g, 25.2 mmol) was added to a round bottom flask along with chloro(difluoro)acetic acid-sodium (1:1) (38.42 g, 252 mmol) this was mixed together with a spatula then heated to 200° C. for one hour. The reaction was then cooled to room temperature and suspended in ethyl acetate and sodium bicarbonate. The suspension was washed with sodium bicarbonate, brine (×5), dried over sodium sulfate, filtered, and concentrated. The mixture was purified using normal phase chromatography (0-60% Ethyl Acetate/Hexanes), and the desired fractions were collected to produce the solid 5-chloro-1-[(2,2-difluoro-1-methylcyclopropyl)methyl]-3-methyl-1,3-dihydro-2H-imidazo[4,5-b]pyridin-2-one (74-2). HRMS (M+H)+: observed=288.0713, calculated=288.0715.
Reaction SMILES: C([O:5][C:6](=[O:24])[CH2:7][N:8]([C:15](=[O:23])[CH:16]([CH3:22])[CH2:17][S:18][C:19](=[O:21])[CH3:20])[CH2:9][C:10]1[O:14][CH:13]=[CH:12][CH:11]=1)(C)(C)C>C1(OC)C=CC=CC=1.FC(F)(F)C(O)=O>[C:19]([S:18][CH2:17][CH:16]([CH3:22])[C:15]([N:8]([CH2:9][C:10]1[O:14][CH:13]=[CH:12][CH:11]=1)[CH2:7][C:6]([OH:24])=[O:5])=[O:23])(=[O:21])[CH3:20]
Reactant: CC(=O)SCC(C)C(=O)N(CC(=O)OC(C)(C)C)Cc1ccco1
Solvent: COc1ccccc1
Solvent: O=C(O)C(F)(F)F
Product: CC(=O)SCC(C)C(=O)N(CC(=O)O)Cc1ccco1
Temperature: 25 °C
Reaction time: 2 h
Yield: 45.1 %

Procedure:
Crude N-(3-acetylthio-2-methylpropanoyl)-N-furfurylglycine tert-butyl ester (14.6 g, 0.0407 mol) was dissolved in a mixture of anisole (20 ml) and trifluoroacetic acid (65 ml). The resulting solution was stirred at room temperature for two hours. The solvent was evaporated in vacuo and the residue was distributed between ethyl acetate and saturated aqueous sodium bicarbonate. The aqueous bicarbonate extract was washed twice with ethyl acetate and then acidifed cautiously with concentrated hydrochloric acid to pH 4-5. The product was extracted several times into chloroform and the chloroform was washed twice with water. The organic phase was dried over magnesium sulfate, filtered and evaporated to give crude product as a pale yellow oil which was purified by HPLC using the following solvent system: ethyl acetate/n-hexane/acetic acid (40:60:1) to give pure product as a colorless oil (5.5 g, 44.7%). The product was purified by its DCHA salt which was prepared in ether, m.p. 140°-141° C.
Reaction SMILES: [C:1]([C:9]1[CH:18]=[CH:17][C:12]2[N:13]=[CH:14][S:15](=O)[C:11]=2[CH:10]=1)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C([O-])([O-])=[O:20].[K+].[K+].Cl[CH2:26][CH2:27][O:28][C:29]1[CH:46]=[CH:45][C:32]([O:33][CH2:34][CH2:35][CH2:36][C:37]([CH3:44])([CH3:43])[C:38]([O:40][CH2:41][CH3:42])=[O:39])=[CH:31][CH:30]=1.O>CN(C=O)C>[C:1]([C:9]1[CH:18]=[CH:17][C:12]2[N:13]([CH2:26][CH2:27][O:28][C:29]3[CH:46]=[CH:45][C:32]([O:33][CH2:34][CH2:35][CH2:36][C:37]([CH3:44])([CH3:43])[C:38]([O:40][CH2:41][CH3:42])=[O:39])=[CH:31][CH:30]=3)[C:14](=[O:20])[S:15][C:11]=2[CH:10]=1)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C(c1ccccc1)c1ccc2c(c1)S(=O)C=N2
Reactant: O=C([O-])[O-]
Reactant: CCOC(=O)C(C)(C)CCCOc1ccc(OCCCl)cc1
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: CCOC(=O)C(C)(C)CCCOc1ccc(OCCn2c(=O)sc3cc(C(=O)c4ccccc4)ccc32)cc1
Temperature: 120 °C

Procedure:
To a solution, heated at 80° C. for 2 hours, of 6-benzoyl-benzothiazolinone (1 g) in the presence of K2CO3 (1.08 g) in 10 ml of DMF there is added ethyl 5-[4-(2-chloroethoxy)phenoxy]-2,2-dimethylpentanoate (1.41 g). The reaction mixture is heated at 120° C. for 5 days and is then hydrolysed using 100 ml of water. The solution is extracted with ethyl acetate, dried over magnesium sulphate and then evaporated to dryness under reduced pressure. The residue is purified over silica gel, eluant AcOEt/PE 2/8, to yield the title compound in the form of a white powder.
Reaction SMILES: [N:1]1([C:7]([C:9]2[C:10]([C:29]([F:32])([F:31])[F:30])=[N:11][C:12]([N:15]3[C:24]4[C:19](=[CH:20][C:21]([C:25]([O:27]C)=[O:26])=[CH:22][CH:23]=4)[CH2:18][CH2:17][CH2:16]3)=[N:13][CH:14]=2)=[O:8])[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1.CO.[OH-].[Na+].Cl>O>[N:1]1([C:7]([C:9]2[C:10]([C:29]([F:30])([F:31])[F:32])=[N:11][C:12]([N:15]3[C:24]4[C:19](=[CH:20][C:21]([C:25]([OH:27])=[O:26])=[CH:22][CH:23]=4)[CH2:18][CH2:17][CH2:16]3)=[N:13][CH:14]=2)=[O:8])[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1
Reactant: COC(=O)c1ccc2c(c1)CCCN2c1ncc(C(=O)N2CCOCC2)c(C(F)(F)F)n1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: O=C(O)c1ccc2c(c1)CCCN2c1ncc(C(=O)N2CCOCC2)c(C(F)(F)F)n1
Temperature: 60 °C
Reaction time: 3 h
Yield: 98.1 %

Procedure:
To a mixture of methyl 1-[5-(morpholin-4-ylcarbonyl)-4-(trifluoromethyl)pyrimidin-2-yl]-1,2,3,4-tetrahydroquinoline-6-carboxylate (100 mg) and methanol (2 mL) was added a 1 M aqueous sodium hydroxide solution (670 μL) at room temperature, followed by stirring at 60° C. for 3 hours. To the reaction mixture were added 1 M hydrochloric acid and water, followed by stirring at room temperature for 30 minutes, and then the resulting precipitate was filtered and washed with water to obtain 1-[5-(morpholin-4-ylcarbonyl)-4-(trifluoromethyl)pyrimidin-2-yl]-1,2,3,4-tetrahydroquinoline-6-carboxylic acid (95 mg) as a white powder.
Reaction SMILES: [CH3:1][N:2]1[C@@H:7]2[C@@H:8]3[O:10][C@@H:9]3[C@H:3]1[CH2:4][CH:5]([O:11][C:12]([C:14]([OH:25])([C:20]1[S:24][CH:23]=[CH:22][CH:21]=1)[C:15]1[S:19][CH:18]=[CH:17][CH:16]=1)=[O:13])[CH2:6]2.[CH3:26][S:27]([O:30]C)(=[O:29])=[O:28]>C(#N)C>[CH3:1][N+:2]1([CH3:26])[C@@H:3]2[C@@H:9]3[O:10][C@@H:8]3[C@H:7]1[CH2:6][C@@H:5]([O:11][C:12]([C:14]([OH:25])([C:15]1[S:19][CH:18]=[CH:17][CH:16]=1)[C:20]1[S:24][CH:23]=[CH:22][CH:21]=1)=[O:13])[CH2:4]2.[CH3:26][S:27]([O-:30])(=[O:29])=[O:28]
Reactant: CN1[C@@H]2CC(OC(=O)C(O)(c3cccs3)c3cccs3)C[C@H]1[C@@H]1O[C@@H]12
Reactant: COS(C)(=O)=O
Solvent: CC#N
Product: CS(=O)(=O)[O-]
Product: C[N+]1(C)[C@@H]2C[C@@H](OC(=O)C(O)(c3cccs3)c3cccs3)C[C@H]1[C@@H]1O[C@@H]12
Temperature: 55 °C

Procedure:
75.5 g scopine di-(2-thienyl)glycolate are dissolved in 750 ml acetonitrile while heating gently. After the addition of 22 ml of methyl methanesulphonate the mixture is stirred at 55° C. After the reaction has ended about 350 ml solvent distilled off under reduced pressure. The product crystallises out and is filtered off. It is purified by recrystallisation from methanol/acetone.
Reaction SMILES: [CH2:1]([N:3]([C@H:46]1[CH2:51][CH2:50][C@H:49]([C:52]([O:54]C)=[O:53])[CH2:48][CH2:47]1)[S:4]([C:7]1[CH:8]=[C:9]([CH:43]=[CH:44][CH:45]=1)[C:10]([NH:12][C:13]1[S:14][C:15]2[CH2:42][CH2:41][CH2:40][CH2:39][C:16]=2[C:17]=1[C:18]([NH:20][C:21]1[CH:26]=[CH:25][C:24]([CH2:27][CH2:28][C:29]2[CH:38]=[CH:37][C:32]([C:33]([O:35]C)=[O:34])=[CH:31][CH:30]=2)=[CH:23][CH:22]=1)=[O:19])=[O:11])(=[O:6])=[O:5])[CH3:2].[OH-].[Na+]>C(O)C>[C:52]([C@H:49]1[CH2:50][CH2:51][C@H:46]([N:3]([CH2:1][CH3:2])[S:4]([C:7]2[CH:8]=[C:9]([CH:43]=[CH:44][CH:45]=2)[C:10]([NH:12][C:13]2[S:14][C:15]3[CH2:42][CH2:41][CH2:40][CH2:39][C:16]=3[C:17]=2[C:18]([NH:20][C:21]2[CH:26]=[CH:25][C:24]([CH2:27][CH2:28][C:29]3[CH:30]=[CH:31][C:32]([C:33]([OH:35])=[O:34])=[CH:37][CH:38]=3)=[CH:23][CH:22]=2)=[O:19])=[O:11])(=[O:6])=[O:5])[CH2:47][CH2:48]1)([OH:54])=[O:53]
Reactant: CCN([C@H]1CC[C@H](C(=O)OC)CC1)S(=O)(=O)c1cccc(C(=O)Nc2sc3c(c2C(=O)Nc2ccc(CCc4ccc(C(=O)OC)cc4)cc2)CCCC3)c1
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: CCN([C@H]1CC[C@H](C(=O)O)CC1)S(=O)(=O)c1cccc(C(=O)Nc2sc3c(c2C(=O)Nc2ccc(CCc4ccc(C(=O)O)cc4)cc2)CCCC3)c1

Procedure:
A mixture of 300 mg of methyl 4-(2-{4-[({2-[(3-{ethyl[trans-4-(methoxycarbonyl)cyclohexyl]sulfamoyl}benzoyl)amino]-4,5,6,7-tetrahydro-1-benzothiophen-3-yl}carbonyl)amino]phenyl}ethyl)benzoate, 1.5 mL of a 1.0 M aqueous sodium hydroxide solution, and 3.0 mL of ethanol was heated and refluxed overnight. The reaction mixture was concentrated under reduced pressure, and then to the obtained residue were added water, 300 mg of citric acid, and dichloromethane in this order, and the precipitate was collected by filtration. For the filtrate, the organic layer was separated and evaporated under reduced pressure. The firstly collected solid and the concentrate of the filtrate were mixed and the mixture was purified by silica gel column chromatography (chloroform-methanol). The crude product was washed with diethyl ether to obtain 203 mg of 4-{2-[4-({[2-({3-[(trans-4-carboxycyclohexyl)(ethyl)sulfamoyl]benzoyl}amino)-4,5,6,7-tetrahydro-1-benzothiophen-3-yl]carbonyl}amino)phenyl]ethyl}benzoic acid as a pale yellow crystal.
Reaction SMILES: Cl[C:2]1[C:3](=[O:15])[N:4]([C@@H:9]([CH:12]2[CH2:14][CH2:13]2)[CH2:10][CH3:11])[CH:5]=[C:6]([Cl:8])[N:7]=1.[Cl:16][C:17]1[C:18]([F:28])=[C:19]([O:26][CH3:27])[CH:20]=[C:21]2[C:25]=1[NH:24][CH2:23][CH2:22]2>>[Cl:8][C:6]1[N:7]=[C:2]([N:24]2[C:25]3[C:21](=[CH:20][C:19]([O:26][CH3:27])=[C:18]([F:28])[C:17]=3[Cl:16])[CH2:22][CH2:23]2)[C:3](=[O:15])[N:4]([C@@H:9]([CH:12]2[CH2:14][CH2:13]2)[CH2:10][CH3:11])[CH:5]=1
Reactant: CC[C@H](C1CC1)n1cc(Cl)nc(Cl)c1=O
Reactant: COc1cc2c(c(Cl)c1F)NCC2
Product: CC[C@H](C1CC1)n1cc(Cl)nc(N2CCc3cc(OC)c(F)c(Cl)c32)c1=O

Procedure:
Prepared in a similar fashion as described for Example 413 using 3,5-dichloro-1-[(1R)-1-cyclopropylpropyl]-2(1H)-pyrazinone and 7-chloro-6-fluoro-5-methoxyindoline as the starting materials. mp 128-130° C.; 1H NMR (300 MHz, CDCl3): δ 6.96 (s, 1 H), 6.79 (d, J=7.3 Hz, 1 H), 4.33 (t, J=7.9 Hz, 2H), 4.08-4.00 (m, 1 H), 3.86 (s, 3 H), 3.08 (t, J=7.7 Hz, 2 H), 1.94-1.74 (m, 2 H), 1.07-0.97 (m, 1 H), 0.92 (t, J=7.3 Hz, 3 H), 0.80-0.73 (m, 1 H), 0.55-0.44 (m, 2 H), 0.34-0.27 (m, 1H); HRMS (ESI) calcd for C19H21N3O2Cl2F (M+H)+: 412.0995; found m/z 412.1019.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([NH2:22])[C:5]2[C:10]([C:11]3[CH:16]=[CH:15][CH:14]=[C:13]([O:17][CH3:18])[CH:12]=3)=[C:9]([CH:19]([CH3:21])[CH3:20])[S:8][C:6]=2[N:7]=1.[C:23]1([C:29]2[N:34]=[CH:33][C:32]([S:35](Cl)(=[O:37])=[O:36])=[CH:31][CH:30]=2)[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1.[C:39]([OH:45])([C:41]([F:44])([F:43])[F:42])=[O:40]>>[F:42][C:41]([F:44])([F:43])[C:39]([OH:45])=[O:40].[CH3:1][C:2]1[N:7]=[C:6]2[S:8][C:9]([CH:19]([CH3:20])[CH3:21])=[C:10]([C:11]3[CH:16]=[CH:15][CH:14]=[C:13]([O:17][CH3:18])[CH:12]=3)[C:5]2=[C:4]([NH:22][S:35]([C:32]2[CH:33]=[N:34][C:29]([C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=3)=[CH:30][CH:31]=2)(=[O:36])=[O:37])[CH:3]=1
Reactant: COc1cccc(-c2c(C(C)C)sc3nc(C)cc(N)c23)c1
Reactant: O=S(=O)(Cl)c1ccc(-c2ccccc2)nc1
Solvent: O=C(O)C(F)(F)F
Product: COc1cccc(-c2c(C(C)C)sc3nc(C)cc(NS(=O)(=O)c4ccc(-c5ccccc5)nc4)c23)c1

Procedure:
Following general method outlined in Example 52, starting from 6-methyl-2-(1-methylethyl)-3-[3-(methyloxy)phenyl]thieno[2,3-b]pyridin-4-amine (40 mg, 0.128 mmol) (Description 21) and 6-phenyl-3-pyridinesulfonyl chloride (39 mg, 0.154 mmol), the title compound (12.2 mg) was isolated as a TFA salt. LCMS (B) m/z: 530 [M+1]+, Rt 3.02 min.
Reaction SMILES: [S:1]1[C:9]2[CH2:8][CH:7]([C:10]([OH:12])=[O:11])[NH:6][CH2:5][C:4]=2[CH:3]=[CH:2]1.[Cl:13][C:14]1[CH:19]=[CH:18][C:17]([N:20]=[C:21]=[O:22])=[CH:16][CH:15]=1>CN(C=O)C>[Cl:13][C:14]1[CH:19]=[CH:18][C:17]([NH:20][C:21]([C:2]2[S:1][C:9]3[CH2:8][CH:7]([C:10]([OH:12])=[O:11])[NH:6][CH2:5][C:4]=3[CH:3]=2)=[O:22])=[CH:16][CH:15]=1
Reactant: O=C=Nc1ccc(Cl)cc1
Reactant: O=C(O)C1Cc2sccc2CN1
Solvent: CN(C)C=O
Product: O=C(Nc1ccc(Cl)cc1)c1cc2c(s1)CC(C(=O)O)NC2
Temperature: 25 °C
Reaction time: 8 h
Yield: 21.8 %

Procedure:
To a solution of the crude sample 4,5,6,7-tetrahydro-thieno[3,2-c]pyridine-6-carboxylic acid (323 mg, 1.77 mmol) in DMF (10 mL), 4-chlorophenyl isocyanate (336 mg, 2.19 mmol) was added. It was stirred at room temperature overnight. After being concentrated in vacuo, the residue was purified by HPLC to give the desired product as a powder (130 mg). MS 337.3 and 339.3 (M+H, Cl pattern)
Reaction SMILES: [Cl:1][CH2:2][CH2:3][CH2:4][C:5]1[CH:12]=[CH:11][CH:10]=[CH:9][C:6]=1[CH2:7]Cl.[C:13]1(=[O:20])[CH2:18][CH2:17][CH2:16][C:15](=[O:19])[CH2:14]1.[OH-].[K+].C(OCC)(=O)C>CO>[Cl:1][CH2:2][CH2:3][CH2:4][C:5]1[CH:12]=[CH:11][CH:10]=[CH:9][C:6]=1[CH2:7][CH:14]1[C:15](=[O:19])[CH2:16][CH2:17][CH2:18][C:13]1=[O:20]
Reactant: ClCCCc1ccccc1CCl
Reactant: O=C1CCCC(=O)C1
Agent: [K+]
Agent: [OH-]
Solvent: CO
Solvent: CCOC(C)=O
Product: O=C1CCCC(=O)C1Cc1ccccc1CCCCl

Procedure:
A solution of 155 g (0.75 mol) of 2-(3-chloropropyl)benzyl chloride 2 [Page, et al., J. Amer. Chem. Soc. 75:2053 (1953)], 91 g (0.81 mol) of 1,3-cyclohexanedione I [Aldrich Chem. Co. 10,160-5; Beilstein 7, 554], and 47 g of 85% KOH in 400 ml of methanol was refluxed 16 hours. After concentrating, the residue was partitioned between benzene and dilute aqueous NaOH solution. Acidification of the aqueous phase gave a solid that was recyrstallized from ethyl acetate to give 34 g of the dione 3, mp 143°-145° C.
Reaction SMILES: Cl.Cl.[NH2:3][C@@:4]([C@@H:15]1[CH2:19][CH2:18][NH:17][CH2:16]1)([CH2:8][CH2:9][CH2:10][CH2:11][B:12]([OH:14])[OH:13])[C:5]([OH:7])=[O:6].C(N(CC)CC)C.[CH3:27][N:28](C)[CH:29]=[O:30].[N-]=C=O.[Cl:35][C:36]1[CH:41]=[CH:40]C=[CH:38][CH:37]=1>Cl>[NH2:3][C:4]([C@H:15]1[CH2:19][CH2:18][N:17]([C:29](=[O:30])[NH:28][C:27]2[CH:40]=[CH:41][C:36]([Cl:35])=[CH:37][CH:38]=2)[CH2:16]1)([CH2:8][CH2:9][CH2:10][CH2:11][B:12]([OH:14])[OH:13])[C:5]([OH:7])=[O:6]
Reactant: Clc1ccccc1
Reactant: N[C@@](CCCCB(O)O)(C(=O)O)[C@@H]1CCNC1
Reactant: CN(C)C=O
Agent: Cl
Agent: [N-]=C=O
Solvent: CCN(CC)CC
Product: NC(CCCCB(O)O)(C(=O)O)[C@H]1CCN(C(=O)Nc2ccc(Cl)cc2)C1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 6.6 %

Procedure:
A solution of (R)-2-amino-6-borono-2-((R)-pyrrolidin-3-yl)hexanoic acid (Example 35-A, Step 5, 200 mg, 0.8 mmol) and triethylamine (900 uL, 6 mmol) in N,N-dimethylformamide (4 mL, 50 mmol) was treated with 4-chlorobenzene isocyanate-(280 mg, 1.8 mmol) in a single portion. After stirring at room temperature for 30 min, the reaction was diluted with 1 N HCl (20 mL) and washed with ethyl acetate (20 mL). The aqueous solution was concentrated and purified by HPLC to give 2-amino-6-borono-2-((S)-1-(4-chlorophenylcarbamoyl)pyrrolidin-3-yl)hexanoic acid (0.021 g, 6%). 1H NMR (400 MHz, D2O, Mixture of diastereoisomers) δ 7.26 (d, J=8.1 Hz, 2H), 7.14 (d, J=8.1 Hz, 2H), 3.70-3.48 (br, m, 2H), 3.99-3.08 (br, m, 2H), 2.79-2.65 (br, m, 1H), 2.30-1.75 (br. m, 4H), 1.54-1.44 (br. m, 2H), 1.35-1.27 (br. m, 1H), 0.87 (t, J=6.5 Hz, 2H),; MS (ESI+) found for C17H25ClBN3O5 m/z (M-water+H)+ 380.2; MS; (M-water+Na)+ 403.3
Reaction SMILES: [NH:1]([C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][N:4]=1)[NH2:2].[Br:9][C:10]1[C:18]([CH3:19])=[CH:17][CH:16]=[CH:15][C:11]=1[C:12](O)=O.F[P-](F)(F)(F)(F)F.N1(O[P+](N2CCCC2)(N2CCCC2)N2CCCC2)C2C=CC=CC=2N=N1.CCN(C(C)C)C(C)C.COC1C=CC(P2(SP(C3C=CC(OC)=CC=3)(=S)S2)=S)=CC=1>C(Cl)Cl.CC#N>[Br:9][C:10]1[C:18]([CH3:19])=[CH:17][CH:16]=[CH:15][C:11]=1[C:12]1[N:4]2[CH:5]=[CH:6][CH:7]=[CH:8][C:3]2=[N:1][N:2]=1
Reactant: Cc1cccc(C(=O)O)c1Br
Reactant: NNc1ccccn1
Agent: COc1ccc(P2(=S)SP(=S)(c3ccc(OC)cc3)S2)cc1
Agent: F[P-](F)(F)(F)(F)F
Agent: c1ccc2c(c1)nnn2O[P+](N1CCCC1)(N1CCCC1)N1CCCC1
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Solvent: CC#N
Product: Cc1cccc(-c2nnc3ccccn23)c1Br
Temperature: 80 °C

Procedure:
A solution of 2-hydrazinopyridine, 97% (0.254 g, 2.325 mmol), 2-bromo-3-methylbenzoic acid (0.50 g, 2.325 mmol), benzotriazol-1-yl-oxytripyrrolidinophosphonium hexafluorophosphate (PyBOP, 1.452 g, 2.79 mmol), and DIEA (0.812 mL, 4.65 mmol) in DCM (6 mL) was stirred at RT until starting material was completely consumed (˜3 h). The mixture was concentrated and chromatographed on silica gel using 0-5% MeOH/DCM to afford a light yellow foam which was dissolved in CH3CN followed by the addition of Lawesson's reagent (0.470 g, 1.163 mmol) and heated at 80° C. for 17 h. The mixture was concentrated and chromatographed on silica gel using 25% EtOAc/hexanes and 0-5% MeOH/DCM to afford a yellow oil as 3-(2-bromo-3-methylphenyl)-[1,2,4]triazolo[4,3-a]pyridine.