Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C([O:5][C:6](=[O:48])[CH:7]([NH:12][C:13](=[O:47])[C:14]1[CH:19]=[CH:18][C:17]([O:20][CH3:21])=[CH:16][C:15]=1[S:22][S:23][C:24]1[CH:29]=[C:28]([O:30][CH3:31])[CH:27]=[CH:26][C:25]=1[C:32](=[O:46])[NH:33][CH:34](OC(C)(C)C)[C:35](=C=O)[CH:36]([CH3:38])[CH3:37])[CH2:8][CH:9]([CH3:11])[CH3:10])(C)(C)C.C1(OC)C=CC=CC=1.FC(F)(F)[C:59]([OH:61])=[O:60].C1(C)C=CC=CC=1>ClCCl>[C:6]([CH:7]([NH:12][C:13]([C:14]1[CH:19]=[CH:18][C:17]([O:20][CH3:21])=[CH:16][C:15]=1[S:22][S:23][C:24]1[CH:29]=[C:28]([O:30][CH3:31])[CH:27]=[CH:26][C:25]=1[C:32]([NH:33][CH:34]([CH2:35][CH:36]([CH3:37])[CH3:38])[C:59]([OH:61])=[O:60])=[O:46])=[O:47])[CH2:8][CH:9]([CH3:11])[CH3:10])([OH:5])=[O:48]
Reactant: O=C(O)C(F)(F)F
Reactant: COc1ccc(C(=O)NC(CC(C)C)C(=O)OC(C)(C)C)c(SSc2cc(OC)ccc2C(=O)NC(OC(C)(C)C)C(=C=O)C(C)C)c1
Solvent: Cc1ccccc1
Solvent: COc1ccccc1
Solvent: ClCCl
Product: COc1ccc(C(=O)NC(CC(C)C)C(=O)O)c(SSc2cc(OC)ccc2C(=O)NC(CC(C)C)C(=O)O)c1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
A solution of [S-(R*,R*)-2[2-[2-(1-tert-butoxy-carbonyl-3-methylbutylcarbamoyl)-5-methoxy-phenyldisulfanyl]-4-methoxybenzoylamino]-4-methyl-pentanoic acid tert-butyl ester (1.2 g, 1.7 mmol) and anisole (1 mL) in 10 mL dichloromethane, cooled to about 0° C., was treated dropwise with 10 mL of trifluoroacetic acid. The mixture was allowed to warm to ambient temperature. After 4 hours, 5 mL toluene was added, and the solvents were removed in vacuo. The crude product was recrystallized from methanol/water to yield 0.7 g of the title compound.
Reaction SMILES: [Br:1][C:2]1[C:3]([OH:12])=[C:4]([CH:7]=[C:8]([O:10][CH3:11])[CH:9]=1)[CH:5]=[O:6].CI.[C:15]([O-])([O-])=O.[K+].[K+].O>CC(C)=O>[Br:1][C:2]1[C:3]([O:12][CH3:15])=[C:4]([CH:7]=[C:8]([O:10][CH3:11])[CH:9]=1)[CH:5]=[O:6]
Reactant: O=C([O-])[O-]
Reactant: COc1cc(Br)c(O)c(C=O)c1
Agent: [K+]
Solvent: CI
Solvent: O
Solvent: CC(C)=O
Product: COc1cc(Br)c(OC)c(C=O)c1
Reaction time: 4 h
Yield: 66.4 %

Procedure:
A solution of 50 (10 g, 43 mmol), Methyl Iodide (7.3 g, 52 mmol), and K2CO3 (12 g, 86 mmol) in acetone (200 ml) was heated to reflux. After 4 hr, the reaction was cooled, poured into water and extracted with ether. The ether layer was dried concentrated and the product was purified by silica gel column chromatography (10%EtOAc/Hex) to give 51 as a solid (7.0 g, 67%): Mp=62-64° C.; 1H NMR (CDCl3) δ 10.32 (s, 1 H), 7.38 (d, 1 H, J=2.8 Hz), 7.28 (d, 1 H, J=3.2 Hz), 3.93 (s, 3 H), 3.82 (s, 3 H); MS 245/247 (M+H)+
Reaction SMILES: [CH:1]1([CH2:4][S:5][C:6]2[C:7]([CH3:19])=[C:8]([CH:12]=[CH:13][C:14]=2[S:15]([CH3:18])(=[O:17])=[O:16])[C:9]([OH:11])=[O:10])[CH2:3][CH2:2]1.OO.[OH2:22].C(O)(=[O:25])C>[O-][W]([O-])(=O)=O.[Na+].[Na+]>[CH:1]1([CH2:4][S:5]([C:6]2[C:7]([CH3:19])=[C:8]([CH:12]=[CH:13][C:14]=2[S:15]([CH3:18])(=[O:17])=[O:16])[C:9]([OH:11])=[O:10])(=[O:25])=[O:22])[CH2:3][CH2:2]1
Reactant: Cc1c(C(=O)O)ccc(S(C)(=O)=O)c1SCC1CC1
Reactant: CC(=O)O
Reactant: O
Agent: O=[W](=O)([O-])[O-]
Agent: OO
Agent: [Na+]
Product: Cc1c(C(=O)O)ccc(S(C)(=O)=O)c1S(=O)(=O)CC1CC1
Temperature: 60 °C
Reaction time: 48 h

Procedure:
952 mg (3.17 mmol) of 3-cyclopropylmethylthio-2-methyl-4-methylsulfonylbenzoic acid were dissolved in 15 ml of glacial acetic acid. 31 mg (0.095 mmol) of sodium tungstate(VI) dihydrate were added, and the mixture was then heated to 60° C. At this temperature, 1.44 g (30% strength, 12.7 mmol) of an aqueous hydrogen peroxide solution were carefully added dropwise. The mixture was stirred at this temperature for two days. The mixture was then cooled and, for work-up, poured into water. The mixture was extracted twice with EA, the combined organic phases were washed with an aqueous, saturated sodium bisulfite solution, and, after analytical confirmation of the absence of peroxides, the mixture was dried, filtered and freed under reduced pressure from the solvents. 744 g of the product were isolated.
Reaction SMILES: [CH:1]1([CH2:4][OH:5])[CH2:3][CH2:2]1.[H-].[Na+].Br.Cl[C:10]1[C:11]2[CH2:22][CH2:21][CH2:20][C:12]=2[C:13]2[N:14]([C:16]([NH2:19])=[N:17][N:18]=2)[N:15]=1.O>CN(C=O)C>[CH:1]1([CH2:4][O:5][C:10]2[C:11]3[CH2:22][CH2:21][CH2:20][C:12]=3[C:13]3[N:14]([C:16]([NH2:19])=[N:17][N:18]=3)[N:15]=2)[CH2:3][CH2:2]1
Reactant: Nc1nnc2c3c(c(Cl)nn12)CCC3
Reactant: OCC1CC1
Agent: Br
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: Nc1nnc2c3c(c(OCC4CC4)nn12)CCC3
Temperature: 45 °C
Reaction time: 0.5 h

Procedure:
Cyclopropylmethanol (1.78 ml) was initially charged in DMF (25 ml). Subsequently, the mixture was admixed with sodium hydride (541 mg) under argon and stirred at 45° C. for 0.5 h. Subsequently, 6-chloro-8,9-dihydro-7H-cyclopenta[d][1,2,4]triazolo[4,3-b]pyridazin-3-ylamine hydrobromide (W2.017, 1.31 g) was dissolved in DMF (20 ml) and 11.25 ml of the alkoxide solution were added in portions at 45° C. over 90 min. Then the mixture was stirred at 45° C. for another hour. After adding a little water, the mixture was dried and purified using silica gel (80 g cartridge, dichloromethane/methanol gradient of 0-20% in 60 min). 528 mg of the title compound were obtained. LC-MS rt: 0.63 min [M+H]+: 246.1 (met. b)
Reaction SMILES: [Al+3].[Cl-:2].[Cl-].[Cl-].[OH:5][C:6]1[C:14]([CH3:15])=[CH:13][CH:12]=[CH:11][C:7]=1[C:8](Cl)=[O:9].Cl.CCO[CH2:20][CH3:21]>ClC1C=CC=CC=1>[OH:5][C:6]1[C:14]([CH3:15])=[CH:13][CH:12]=[CH:11][C:7]=1[C:8]([C:21]1[CH:20]=[CH:8][C:7]([Cl:2])=[CH:6][CH:14]=1)=[O:9]
Reactant: Cc1cccc(C(=O)Cl)c1O
Reactant: [Cl-]
Reactant: CCOCC
Agent: Cl
Agent: [Al+3]
Solvent: Clc1ccccc1
Product: Cc1cccc(C(=O)c2ccc(Cl)cc2)c1O
Temperature: 100 °C

Procedure:
Chlorobenzene (78.79g, 71.6ml; 0.7mole), AlCl3, (14g, 0.105mole) were mixed, stirred and treated with a solution of 2-hydroxy-3-methylbenzoic acid chloride (12g, 0.07mole) in chlorobenzene (20ml). The mixture was stirred and heated at 100°C overnight. The cooled mixture was added to conc. HCl (10ml) and ice, extraction with ether, and ether washed with saturated sodium bicarbonate solution, dried (Na2SO4), filtered and the filtrate distilled, to give (after removal of the ether), a main fraction 2-hydroxy-3-methyl-4'-chlorobenzophenone, b.p. 148°-152°C/0.5mm (8.18g), which solidified to yellow microplates, m.p. 55°-58°C.
Reaction SMILES: [OH:1][C:2]1[CH:9]=[CH:8][C:5]([CH:6]=[O:7])=[CH:4][CH:3]=1.Br[CH2:11][CH:12]1[CH2:17][CH2:16][CH2:15][CH2:14][CH2:13]1.C([O-])([O-])=O.[K+].[K+]>CC#N>[CH:12]1([CH2:11][O:1][C:2]2[CH:9]=[CH:8][C:5]([CH:6]=[O:7])=[CH:4][CH:3]=2)[CH2:17][CH2:16][CH2:15][CH2:14][CH2:13]1
Reactant: O=Cc1ccc(O)cc1
Reactant: BrCC1CCCCC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: O=Cc1ccc(OCC2CCCCC2)cc1
Temperature: 100 °C
Yield: 82.5 %

Procedure:
A solution of 4-hydroxybenzaldehyde (0.244 g, 2.00 mmol) in CH3CN (4.0 L) was treated with bromomethylcyclohexane (0.279 g, 2.00 mmol) and K2CO3 (0.332 g, 2.40 mmol). The reaction mixture was heated to 100° C. for 1 h in a Biotage Initiator microwave synthesizer. Additional bromomethylcyclohexane (0.279 g, 2.00 mmol) and K2CO3 (0.332 g, 2.40 mmol) were added and the reaction mixture was again heated to 100° C. for 1 h in a Biotage Initiator microwave synthesizer. Additional bromomethylcyclohexane (0.279 g, 2.00 mmol) and K2CO3 (0.332 g, 2.40 mmol) were added and the reaction mixture was again heated to 100° C. for 1 h in a Biotage Initiator microwave synthesizer. Following cooling, the reaction mixture was filtered and concentrated in vacuo. Purification via flash column chromatography (10% EtOAc/hexanes) gave the title compound as a white solid (0.360 g; 82%). 1H NMR (400 MHz, DMSO-d6) δ ppm 9.86 (s, 1H) 7.85 (d, J=8.8 Hz, 2H) 7.11 (d, J=8.8 Hz, 2H) 3.89 (d, J=6.3 Hz, 2H) 1.80 (d, J=12.6 Hz, 2H) 1.61-1.79 (m, 4H) 1.13-1.32 (m, 3H) 1.07 (dd, J=12.6, 2.6 Hz, 1H) 1.01 (dd, J=11.9, 2.5 Hz, 1H). MS (ES+) m/e 219 [M+H]+.
Reaction SMILES: C([O:8][C:9]1[CH:18]=[C:17]2[C:12]([CH:13]=[CH:14][CH:15]=[C:16]2[N:19]2[CH2:24][CH2:23][N:22]([CH2:25][C:26]3[N:30]([CH2:31][C:32]4[CH:37]=[CH:36][C:35]([C:38]#[N:39])=[C:34]([F:40])[CH:33]=4)[C:29]([CH3:41])=[N:28][CH:27]=3)[CH2:21][C:20]2=[O:42])=[CH:11][CH:10]=1)C1C=CC=CC=1.[H][H]>CO.CCOC(C)=O.[Pd]>[OH:8][C:9]1[CH:18]=[C:17]2[C:12]([CH:13]=[CH:14][CH:15]=[C:16]2[N:19]2[CH2:24][CH2:23][N:22]([CH2:25][C:26]3[N:30]([CH2:31][C:32]4[CH:37]=[CH:36][C:35]([C:38]#[N:39])=[C:34]([F:40])[CH:33]=4)[C:29]([CH3:41])=[N:28][CH:27]=3)[CH2:21][C:20]2=[O:42])=[CH:11][CH:10]=1
Reactant: [H][H]
Reactant: Cc1ncc(CN2CCN(c3cccc4ccc(OCc5ccccc5)cc34)C(=O)C2)n1Cc1ccc(C#N)c(F)c1
Agent: [Pd]
Solvent: CO
Solvent: CCOC(C)=O
Product: Cc1ncc(CN2CCN(c3cccc4ccc(O)cc34)C(=O)C2)n1Cc1ccc(C#N)c(F)c1
Reaction time: 4 h

Procedure:
To a solution of the benzyl ether from Step B (419 mg, 0.75 mmol) in 6 mL of 1:1 MeOH/EtOAc was added 10% palladium on carbon (250 mg). The solution was stirred under a balloon atmosphere of hydrogen at room temperature. After 4 hours, another portion of Pd/C was added (250 mg). After 16 hours, the solution was filtered through celite. Concentration in vacuo provided the titled product which was used in the next reaction without further purification.
Reaction SMILES: Cl.[Cl:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[N:13]([C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=3[Cl:20])[N:12]=[C:11]([C:21](O)=[O:22])[C:10]=2[O:24][CH2:25][CH2:26][NH:27][CH2:28][C:29]([F:32])([F:31])[F:30])=[CH:5][CH:4]=1.C(N(CC)CC)C.C(OCC)C>ClCCCl>[Cl:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[N:13]([C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=3[Cl:20])[N:12]=[C:11]3[C:10]=2[O:24][CH2:25][CH2:26][N:27]([CH2:28][C:29]([F:30])([F:32])[F:31])[C:21]3=[O:22])=[CH:5][CH:4]=1
Reactant: O=C(O)c1nn(-c2ccccc2Cl)c(-c2ccc(Cl)cc2)c1OCCNCC(F)(F)F
Agent: Cl
Solvent: ClCCCl
Solvent: CCN(CC)CC
Solvent: CCOCC
Product: O=C1c2nn(-c3ccccc3Cl)c(-c3ccc(Cl)cc3)c2OCCN1CC(F)(F)F

Procedure:
A solution of 5-(4-chlorophenyl)-1-(2-chlorophenyl)-4-[2-(2,2,2-trifluoroethylamino)-ethoxy]-1H-pyrazole-3-carboxylic acid, hydrochloride I-1h (45 mg, 0.1 mmol), triethylamine (0.05 ml) and 1-propanephosphoric acid cyclic anhydride (0.1 ml, 0.14 mmol) in 1,2-dichloroethane (0.6 ml) were stirred for 8 hours. The reaction was diluted into ethyl ether, washed 1 N aqueous hydrochloric acid, saturated aqueous sodium bicarbonate, brine, dried (Na2SO4) and concentrated in vacuo to afford the title compound (1A-1) as a white solid, 35 mg. 1H NMR in CDCl3 (ppm): δ7.52 (d, 1H), 7.38–7.34 (m, 2H), 7.23 (d, 2H), 7.15 (d, 2H), 4.47 (brs, 2H), 4.29 (br s, 2H), 3.91 (br s, 2H); ms (LCMS) m/z=456.3 (M+1).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[N:9]=[CH:8][CH:7]=[C:6]2[O:15][C:16]1[C:22]([CH3:23])=[CH:21][C:19]([NH2:20])=[C:18]([CH3:24])[CH:17]=1.C(N(CC)CC)C.ClC(Cl)(O[C:36](=[O:42])OC(Cl)(Cl)Cl)Cl.[CH2:44]([N:46]([C:50]1[CH:55]=[CH:54][CH:53]=[C:52]([CH3:56])[CH:51]=1)[CH2:47][CH2:48][NH2:49])[CH3:45]>C(Cl)(Cl)Cl.O>[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[N:9]=[CH:8][CH:7]=[C:6]2[O:15][C:16]1[C:22]([CH3:23])=[CH:21][C:19]([NH:20][C:36]([NH:49][CH2:48][CH2:47][N:46]([CH2:44][CH3:45])[C:50]2[CH:55]=[CH:54][CH:53]=[C:52]([CH3:56])[CH:51]=2)=[O:42])=[C:18]([CH3:24])[CH:17]=1
Reactant: CCN(CCN)c1cccc(C)c1
Reactant: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Reactant: COc1cc2nccc(Oc3cc(C)c(N)cc3C)c2cc1OC
Solvent: ClC(Cl)Cl
Solvent: CCN(CC)CC
Solvent: O
Product: CCN(CCNC(=O)Nc1cc(C)c(Oc2ccnc3cc(OC)c(OC)cc23)cc1C)c1cccc(C)c1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 84.1 %

Procedure:
4-[(6,7-Dimethoxy-4-quinolyl)oxy]-2,5-dimethylaniline (100 mg) was dissolved in chloroform (10 ml) and triethylamine (1 ml) to prepare a solution. A solution of triphosgene (139 mg) in chloroform was then added to the solution, and the mixture was stirred at room temperature for 10 min. Next, N1-ethyl-N1-(3-methylphenyl)-1,2-ethanediamine (84 mg) was added thereto, and the mixture was further stirred at room temperature for one hr. Water was added to stop the reaction, and the reaction solution was then extracted with chloroform, followed by concentration. The residue was purified on a column using chloroform/methanol to give the title compound (137 mg, yield 84%).
Reaction SMILES: [Cl:1][C:2]1[C:3]([Cl:26])=[CH:4][C:5]2[CH:6]3[CH2:24][N:23]([CH3:25])[CH2:22][CH2:21][CH:7]3[N:8]([CH2:11][C:12](O)([C:14]3[CH:19]=[CH:18][N:17]=[CH:16][CH:15]=3)[CH3:13])[C:9]=2[CH:10]=1.[OH-].[K+]>S(Cl)(Cl)=O.O>[Cl:1][C:2]1[C:3]([Cl:26])=[CH:4][C:5]2[C:6]3[CH2:24][N:23]([CH3:25])[CH2:22][CH2:21][C:7]=3[N:8](/[CH:11]=[C:12](\[C:14]3[CH:15]=[CH:16][N:17]=[CH:18][CH:19]=3)/[CH3:13])[C:9]=2[CH:10]=1
Reactant: CN1CCC2C(C1)c1cc(Cl)c(Cl)cc1N2CC(C)(O)c1ccncc1
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: O=S(Cl)Cl
Product: C/C(=C/n1c2c(c3cc(Cl)c(Cl)cc31)CN(C)CC2)c1ccncc1
Temperature: 25 °C
Reaction time: 0.08 h

Procedure:
7,8-Dichloro-5-(2-hydroxy-2-(pyridin-4-yl)propyl)-2-methyl-2,3,4,4a,5,9b-hexahydro-1H-pyrido[4,3-b]indole (500 mg, 1.2 mmol) in thionylchloride (5 mL) was stirred at RT for 5 h. The reaction mixture was concentrated under reduced pressure. The residue was dissolved in N-methyl-2-pyrrolidone (5 mL) and the solution was stirred for 5 min. at RT. Powdered KOH (482 mg, 8.5 mmol) was added and the reaction mixture was heated at 100° C. for 1 h. The progress of reaction was monitored by TLC and NMR. The reaction mixture was cooled at RT, diluted with water and extracted with EtOAc. The organic layer was washed with water, dried over anhydrous sodium sulfate, concentrated under reduced pressure and the residue purified by HPLC. 1H NMR (CD3OD, formate salt) δ (ppm): 8.30 (d, 2H), 7.50 (s, 1H), 7.20 (s, 1H), 7.05 (d, 2H), 6.95 (s, 1H), 3.70 (m, 2H), 2.85 (m, 2H), 2.70 (m, 2H), 2.58 (s, 3H), 2.38 (s, 3H).
Reaction SMILES: [OH-].[Li+].[C:3]([O:7][C:8]([N:10]1[C:13]2([CH2:16][CH2:15][CH2:14]2)[CH2:12][C:11]1=[O:17])=[O:9])([CH3:6])([CH3:5])[CH3:4].C([O:20]CC)C.O>O1CCCC1>[C:3]([O:7][C:8]([NH:10][C:13]1([CH2:12][C:11]([OH:17])=[O:20])[CH2:16][CH2:15][CH2:14]1)=[O:9])([CH3:6])([CH3:5])[CH3:4]
Reactant: CCOCC
Reactant: CC(C)(C)OC(=O)N1C(=O)CC12CCC2
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)NC1(CC(=O)O)CCC1
Reaction time: 2 h

Procedure:
An 1 N aqueous solution of lithium hydroxide (227 ml, 227 mmol) was added to a solution of 2-oxo-1-azaspiro[3.3]heptane-1-carboxylic acid tert-butylester (48 g, 0.227 mmol) in tetrahydrofuran (200 ml). The reaction mixture was stirred for 2 h. Diethyl ether (200 ml) and water (200 ml) were added. The mixture was stirred for 16 h. The organic layer was isolated. The aqueous phase was extracted with diethyl ether (200 ml). The aqueous phase was acidified with a 10% aqueous solution of sodium hydrogen sulfate until pH 3. The formed precipitation was filtered off, washed with water, and dried in vacuo, to give 38.84 g of (1-(tert-butoxycarbonylamino)cyclobutyl)acetic acid.
Reaction SMILES: [C:1]1([S:7][CH2:8][C@H:9]([NH:14][C:15]2[CH:20]=[CH:19][C:18]([S:21](=[O:24])(=[O:23])[NH2:22])=[CH:17][C:16]=2[S:25]([C:28]([F:31])([F:30])[F:29])(=[O:27])=[O:26])[CH2:10][C:11](O)=[O:12])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[NH:56]1[CH2:61][CH2:60][O:59][CH2:58][CH2:57]1.CCN(C(C)C)C(C)C>CC(N(C)C)=O.CCOC(C)=O>[O:59]1[CH2:60][CH2:61][N:56]([C:11](=[O:12])[CH2:10][C@@H:9]([NH:14][C:15]2[CH:20]=[CH:19][C:18]([S:21]([NH2:22])(=[O:24])=[O:23])=[CH:17][C:16]=2[S:25]([C:28]([F:31])([F:29])[F:30])(=[O:27])=[O:26])[CH2:8][S:7][C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=2)[CH2:57][CH2:58]1
Reactant: NS(=O)(=O)c1ccc(N[C@@H](CSc2ccccc2)CC(=O)O)c(S(=O)(=O)C(F)(F)F)c1
Reactant: C1COCCN1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CCOC(C)=O
Solvent: CC(=O)N(C)C
Product: NS(=O)(=O)c1ccc(N[C@@H](CSc2ccccc2)CC(=O)N2CCOCC2)c(S(=O)(=O)C(F)(F)F)c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 88.7 %

Procedure:
A solution of (R)-4-(phenylthio)-3-(4-sulfamoyl-2-(trifluoromethylsulfonyl)phenylamino) butanoic acid (INTERMEDIATE 8, 1.99 g, 4.01 mmol) and HATU (1.83 g, 4.82 mmol) in DMA (18.0 ml) was treated with morpholine (0.35 ml, 4.02 mmol) and DIPEA (1.40 ml, 8.02 mmol). The resulting reaction mixture was stirred at room temperature for 1 hour and then diluted with EtOAc (250 ml). The organic layer was washed with water (3×250 ml), 1M aq. NaHSO4 (200 ml), and saturated aq. NaHCO3 (200 ml). The organic layer was dried (Na2SO4), filtered, and evaporated under reduced pressure to provide a sticky foam. The foam was dissolved in EtOAc (40 ml) and washed with water (2×250 ml). During the second wash material precipitated. EtOAc (80 ml) was added and the resulting mixture was shaken, resulting in redissolution of the precipitate. The mixture was further dried (Na2SO4), filtered, and evaporated under reduced pressure. The residue was dissolved in a few ml of DCM resulting in the formation of a precipitate. Finally, evaporation of the volatiles under reduced pressure afforded the title product (2.02 g, yield: 89%).
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7](/[C:10](/[CH3:16])=[CH:11]/[C:12]([O:14][CH3:15])=[O:13])=[CH:6][CH:5]=1)([O-])=O.[Cl-].[NH4+].O.O1CCCC1>[Fe].CO>[NH2:1][C:4]1[CH:5]=[CH:6][C:7](/[C:10](/[CH3:16])=[CH:11]/[C:12]([O:14][CH3:15])=[O:13])=[CH:8][CH:9]=1
Reactant: COC(=O)/C=C(\C)c1ccc([N+](=O)[O-])cc1
Agent: [Fe]
Agent: [Cl-]
Agent: [NH4+]
Solvent: C1CCOC1
Solvent: CO
Solvent: O
Product: COC(=O)/C=C(\C)c1ccc(N)cc1
Temperature: 70 °C
Reaction time: 1 h
Yield: 93.8 %

Procedure:
Compound 6a (31.7 g), iron powder (41.1 g), ammonium chloride (18.1 g), and water (173 ml) were added to a mixed solution of tetrahydrofuran (280 ml) and methanol (280 ml) in a nitrogen atmosphere. The mixture was stirred at 70° C. for 1 hour. After the reaction mixture was allowed to cool, and filtered, the filtrate was separated with ethyl acetate and water. The organic layer was washed once with water and once with a saturated sodium chloride solution, and then dried over anhydrous sodium sulfate. The solvent was distilled off, and as a result, Compound 6b (25.7 g, 94%) was obtained as an orange solid.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:12][CH2:11][CH2:10][C@H:9]1[C:13]1[NH:14][C:15]([C:18]2[CH:19]=[N:20][C:21]([C:24]3[CH:29]=[CH:28][C:27]([C:30]4[NH:31][C:32]([C@@H:35]5[CH2:39][CH2:38][CH2:37][N:36]5C(OCC5C=CC=CC=5)=O)=[N:33][CH:34]=4)=[CH:26][CH:25]=3)=[N:22][CH:23]=2)=[CH:16][N:17]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].C([O-])([O-])=O.[K+].[K+].O>CO.[Pd]>[C:1]([O:5][C:6]([N:8]1[CH2:12][CH2:11][CH2:10][C@H:9]1[C:13]1[NH:14][C:15]([C:18]2[CH:23]=[N:22][C:21]([C:24]3[CH:29]=[CH:28][C:27]([C:30]4[NH:31][C:32]([C@@H:35]5[CH2:39][CH2:38][CH2:37][NH:36]5)=[N:33][CH:34]=4)=[CH:26][CH:25]=3)=[N:20][CH:19]=2)=[CH:16][N:17]=1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)N1CCC[C@H]1c1ncc(-c2cnc(-c3ccc(-c4cnc([C@@H]5CCCN5C(=O)OCc5ccccc5)[nH]4)cc3)nc2)[nH]1
Agent: [Pd]
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CO
Solvent: O
Product: CC(C)(C)OC(=O)N1CCC[C@H]1c1ncc(-c2cnc(-c3ccc(-c4cnc([C@@H]5CCCN5)[nH]4)cc3)nc2)[nH]1
Reaction time: 3 h
Yield: 56.4 %

Procedure:
A solution of (S)-2-[5-(2-{4-[2-((S)-1-Benzyloxycarbonyl-pyrrolidin-2-yl)-3H-imidazol-4-yl]-phenyl}-pyrimidin-5-yl)-1H-imidazol-2-yl]-pyrrolidine-1-carboxylic acid tert-butyl ester (317.1 mg, 0.48 mmol) in MeOH (1 mL) was added to a stirred suspension of 10% palladium on carbon (60 mg) and K2CO3 (70 mg) in a solution of MeOH (5 mL) and H2O (0.1 mL) at room temperature under N2. The flask was charged and evacuated three times with H2 and stirred for 3 h at atmosphere pressure. Additional catalyst (20 mg) was then added and the reaction mixture was stirred further for 3 h before it was suction-filtered through diatomaceous earth (Celite®) and concentrated. The residue was diluted with MeOH, filtered through a PVDF syringe filter (13 mm×0.45 μm), distributed into 4 pHPLC vials and chromatographed (gradient elution from 20% B to 100% B over 10 min on a Phenomenex-Gemini C18 column (30×100 mm, 10 μm) where A=95% water, 5% acetonitrile, 10 mM NH4OAc, B=10% water, 90% acetonitrile, 10 mM NH4OAc). After concentration of the selected test tubes by speed vacuum evaporation, there was isolated the title compound as a yellow solid (142.5 mg, 56% yield).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][C:9]([F:12])([F:11])[F:10])=[CH:4][CH:3]=1.C([Li])(C)(C)C.[C:18](=O)=[O:19].CN(C=O)C>C1COCC1>[F:1][C:2]1[CH:3]=[CH:4][C:5]([O:8][C:9]([F:10])([F:11])[F:12])=[CH:6][C:7]=1[CH:18]=[O:19]
Reactant: O=C=O
Reactant: Fc1ccc(OC(F)(F)F)cc1
Agent: [Li]C(C)(C)C
Solvent: C1CCOC1
Solvent: CN(C)C=O
Product: O=Cc1cc(OC(F)(F)F)ccc1F
Reaction time: 0.25 h
Yield: 53 %

Procedure:
A solution of 1-fluoro-4-trifluoromethoxy-benzene (21.0 g, 117 mmol) in THF (233 mL) was cooled to <−70° C. and tert.-butyllithium (86 mL, 1.5 M in pentane, 129 mmol) was added at such a rate that temperature was kept <−70° C. Stirring in the dry ice bath was continued for 15 min, then DMF (11.6 mL, 150 mmol) was added dropwise keeping temperature <−70° C. After 30 min the reaction mixture was allowed to reach rt, quenched with saturated NH4Cl solution and extracted with diethylether. The organic phase was washed with brine, concentrated and chromatographed (SiO2, heptanes:ethyl acetate=100:0 to 80:2) to afford the title compound (11.0 g, 53%) as a light yellow oil. 1H-NMR (300 MHz, DMSO): δ=7.60 (t, J=9.2 Hz, 1H), 7.75-7.85 (m, 2H), 10.20 (s, 1H).
Reaction SMILES: F[C:2]1[C:7]([C:8]#[N:9])=[C:6]([F:10])[C:5]([C:11]#[N:12])=[C:4]([F:13])[C:3]=1[F:14].[F-].[K+].[CH2:17]([SH:21])[CH2:18][CH2:19][CH3:20].O>C(#N)C>[F:10][C:6]1[C:5]([C:11]#[N:12])=[C:4]([F:13])[C:3]([F:14])=[C:2]([S:21][CH2:17][CH2:18][CH2:19][CH3:20])[C:7]=1[C:8]#[N:9]
Reactant: N#Cc1c(F)c(F)c(F)c(C#N)c1F
Reactant: CCCCS
Agent: [F-]
Agent: [K+]
Solvent: O
Solvent: CC#N
Product: CCCCSc1c(F)c(F)c(C#N)c(F)c1C#N
Yield: 77 %

Procedure:
A 2.0 g amount of tetrafluoroisophthalonitrile and 0.87 g of potassium fluoride were dissolved in 10 ml of acetonitrile. After cooling to a temperature of 0° C., 0.90 g (1.04 ml) of n-butylmercaptan was gradually dropwise added to the mixture and the resultant mixture was stirred at a temperature of 0° C. or less for 12 hours. After 50 ml of water was added to the reaction mixture, the reaction mixture was extracted with chloroform and the extract was then washed with a saturated aqueous sodium bicarbonate solution, followed by drying with anhydrous magnesium sulfate. After distilling off the chloroform, the resultant crude product was distilled in vacuo. Thus, 2.08 g (77% yield) of the desired compound No. 52 was obtained.
Reaction SMILES: [Sn].Cl.[Cl:3][C:4]1[CH:12]=[C:11]2[C:7]([C:8](=[O:21])[N:9]([CH2:14][C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][N:16]=3)[C:10]2=O)=[CH:6][C:5]=1[S:22]([NH2:25])(=[O:24])=[O:23].O=C1C2C(=CC=CC=2)C(=O)N1.Cl.[Sn]>CO>[Cl:3][C:4]1[CH:12]=[C:11]2[C:7]([C:8](=[O:21])[N:9]([CH2:14][C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][N:16]=3)[CH2:10]2)=[CH:6][C:5]=1[S:22]([NH2:25])(=[O:24])=[O:23]
Reactant: NS(=O)(=O)c1cc2c(cc1Cl)C(=O)N(Cc1ccccn1)C2=O
Agent: Cl
Agent: O=C1NC(=O)c2ccccc21
Agent: [Sn]
Solvent: CO
Product: NS(=O)(=O)c1cc2c(cc1Cl)CN(Cc1ccccn1)C2=O
Reaction time: 6 h

Procedure:
Tin-Hydrochloric Acid Reduction of 6-Chloro-2,3-dihydro-1,3-dioxo-2-(2-pyridinylmethyl)-1H-isoindole-5-sulfonamide. A mixture of the above part (a) 1,3-dioxoisoindole (18 g., 0.051 mole), 120 ml. of methanol and 60 ml. of concentrated hydrochloric acid was heated with 30 mesh granulated tin metal added as indicated: 15 g. at 65°-70° for 6 hr., then 8 g. at 60°-65° for 16 hr. and finally 6 g. at 70°-75° for a 7 hr. period. The reaction mixture is cooled, filtered and concentrated to about 60 ml. volume. Addition of about 60 ml. of methanol to the concentrated mixture provided on standing 10 g., of a tin salt complex. This material was further purified by stirring with 1 liter of 50% methanol and 20 ml. of 1N hydrochloric acid while slowly introducing a gaseous stream of hydrogen sulfide (H2S) during a 1 hr. period at 45°-50°. The mixture is stirred at 40°-45° for 16 hr. and then concentrated slightly to remove excess H2S. Activated charcoal was added and the mixture filtered. Concentration of the filtrate to about 50 ml. and dilution with 1 ml. of 6N hydrochloric acid and cooling yielded 2.2 g. (12%) of white solid. Crystallization from aqueous methanol afforded analytically pure 6-chloro-2,3-dihydro-3-oxo-2-(2-pyridinylmethyl)-1H-isoindole-5-sulfonamide as the hydrochloride salt, m.p. 264°-266°.