Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: O.C1(C)C=CC(S(O)(=O)=O)=CC=1.[CH2:13]([NH:15][C:16](=[O:54])[CH2:17][CH2:18][CH2:19]/[CH:20]=[CH:21]\[CH2:22][C@H:23]1[C@@H:27]([OH:28])[CH2:26][C@@H:25]([O:29]C2CCCCO2)[C@@H:24]1/[CH:36]=[CH:37]/[C@@H:38]([O:47]C1CCCCO1)[CH2:39][CH2:40][C:41]1[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=1)[CH3:14]>CO>[CH3:14][CH2:13][NH:15][C:16]([CH2:17][CH2:18][CH2:19]/[CH:20]=[CH:21]\[CH2:22][C@@H:23]1[C@@H:24](/[CH:36]=[CH:37]/[C@@H:38]([OH:47])[CH2:39][CH2:40][C:41]2[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=2)[C@H:25]([OH:29])[CH2:26][C@@H:27]1[OH:28])=[O:54]
Reactant: CCNC(=O)CCC/C=C\C[C@@H]1[C@@H](/C=C/[C@H](CCc2ccccc2)OC2CCCCO2)[C@H](OC2CCCCO2)C[C@@H]1O
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: CO
Solvent: O
Product: CCNC(=O)CCC/C=C\C[C@@H]1[C@@H](/C=C/[C@@H](O)CCc2ccccc2)[C@H](O)C[C@@H]1O
Temperature: 25 °C
Reaction time: 2 h
Yield: 77.5 %

Procedure:
p-Toluenesulfonic acid monohydrate (0.03 g, 0.17 mmol) was added to a stirred solution of (5Z)-N-ethyl-7-((1R,2R,3R,5S)-5-hydroxy-2-((S,E)-5-phenyl-3-(tetrahydro-2H-pyran-2-yloxy)pent-1-enyl)-3-(tetrahydro-2H-pyran-2-yloxy)cyclopentyl)hept-5-enamide (2.0 g, 3.4 mmol) in methanol (20 mL). The mixture was stirred for 2 hours at room temperature. Then, the reaction mixture was washed with saturated aqueous solution of sodium bicarbonate (50 mL). The layers were separated and the aqueous layer was extracted with ethyl acetate (20 mL). The organic layers were dried over magnesium sulfate, filtered and concentrated under reduced pressure. The residue was crystallized from hexane and ethyl acetate to give Bimatoprost in a white crystalline form (77.5% yield). UPLC (ACQUITY UPLC BEH C18) analysis of the crude product showed that no 5,6-trans isomer, 15β-isomer or any other isomers were found.
Reaction SMILES: B(Br)(Br)Br.C([O:12][C:13]1[CH:14]=[C:15]([F:28])[CH:16]=[C:17]([CH:19]=[CH:20][C:21]2[CH:26]=[CH:25][C:24]([F:27])=[CH:23][CH:22]=2)[CH:18]=1)C1C=CC=CC=1.CO>C(Cl)Cl>[F:28][C:15]1[CH:16]=[C:17]([CH:19]=[CH:20][C:21]2[CH:26]=[CH:25][C:24]([F:27])=[CH:23][CH:22]=2)[CH:18]=[C:13]([OH:12])[CH:14]=1
Reactant: Fc1ccc(C=Cc2cc(F)cc(OCc3ccccc3)c2)cc1
Agent: BrB(Br)Br
Solvent: ClCCl
Solvent: CO
Product: Oc1cc(F)cc(C=Cc2ccc(F)cc2)c1
Temperature: -20 °C
Reaction time: 0.17 h
Yield: 86.1 %

Procedure:
A 1 M solution of BBr3 (9 ml, 9 mmol) in CH2Cl2 was added to a well-stirred solution of 5-benzyloxy-3,4′-difluorostilbene (0.97 g, 3 mmol) in dry CH2Cl2 (120 ml) at −78° C. The mixture was warmed to −20° C. and stirred for 10 minutes. Then MeOH was added at −78° C. The mixture was washed with saturated NaHCO3, and water. Flash chromatography gave the 3,4′-difluoro-5-hydroxystilbene (0.60 g, 86%) as white solid. Data are: 1H NMR (CDCl3, 300 MHz) δ 7.46 (m, 2H), 7.08-6.73 (m, 6H), 6.48 (dt, 1H), 4.85 (s, 1H); 13C NMR (CDCl3, 75 MHz) δ 165.05 (d), 161.78 (d), 157.06 (d), 140.43 (d), 133.06 (d), 129.40 (s), 128.45 (d), 127.25 (t), 115.95 (d), 109.42 (d), 105.91 (d), 102.60 (d); 19F NMR (CDCl3, 282 MHz) δ-31703.17 (t), −32099.92 (t); HRMS (EI+) found 232.0714 M+, calcd 232.0700 for C14H10F2O.
Reaction SMILES: [CH3:1][O:2][CH2:3][CH2:4][O:5][C:6]1[C:15]([O:16]C(C2C=CC=CC=2)=O)=[CH:14][C:13]([N+:25]([O-:27])=[O:26])=[CH:12][C:7]=1[C:8]([O:10][CH3:11])=[O:9].C(=O)([O-])[O-].[K+].[K+]>CO>[OH:16][C:15]1[C:6]([O:5][CH2:4][CH2:3][O:2][CH3:1])=[C:7]([CH:12]=[C:13]([N+:25]([O-:27])=[O:26])[CH:14]=1)[C:8]([O:10][CH3:11])=[O:9]
Reactant: COCCOc1c(OC(=O)c2ccccc2)cc([N+](=O)[O-])cc1C(=O)OC
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CO
Product: COCCOc1c(O)cc([N+](=O)[O-])cc1C(=O)OC
Temperature: 25 °C
Reaction time: 1 h
Yield: 97.2 %

Procedure:
Methyl 2-{[2-(methyloxy)ethyl]oxy}-5-nitro-3-[(phenylcarbonyl)oxy]benzoate (8.1 g, 21.6 mmol) was dissolved in methanol (150 mL) followed by the addition of potassium carbonate (3.3 g, 24 mmol). The reaction mixture was stirred at room temperature for one hour, filtered and then acidified with 4N hydrogen chloride in dioxane. It was concentrated and then re-dissolved in ethyl acetate (100 mL), washed with water and brine (100 mL each), dried over sodium sulfate, filtered and concentrated to give an oily residue which was purified by flash chromatography (silica gel, 30% ethyl acetate-hexane) to provide methyl 3-hydroxy-2-{[2-(methyloxy)ethyl]oxy}-5-nitrobenzoate (8.1 g, 21.0 mmol, 97% yield). 1H NMR (400 MHz, CDCl3): 8.69 (s, 1H), 8.24-8.23 (d, 1H), 7.95-7.94 (d, 1H), 4.31-4.29 (m, 2H), 3.95 (s, 3H), 3.79-3.77 (m, 2H), 3.58 (s, 3H).
Reaction SMILES: [C:1]1([CH:19]=[CH:20][C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[CH:6]=[CH:5][C:4]([S:7]([N:10]2[CH2:15][CH2:14][C:13]3[O:16][CH:17]=[CH:18][C:12]=3[CH2:11]2)(=[O:9])=[O:8])=[CH:3][CH:2]=1>C1(C)C(CCO)=CC=CC=1.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.[Cl-].[Rh]>[CH2:19]([C:1]1[CH:2]=[CH:3][C:4]([S:7]([N:10]2[CH2:15][CH2:14][C:13]3[O:16][CH:17]=[CH:18][C:12]=3[CH2:11]2)(=[O:9])=[O:8])=[CH:5][CH:6]=1)[CH2:20][C:21]1[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=1
Reactant: O=S(=O)(c1ccc(C=Cc2ccccc2)cc1)N1CCc2occc2C1
Agent: [Rh]
Agent: Cc1ccccc1CCO
Agent: [Cl-]
Product: O=S(=O)(c1ccc(CCc2ccccc2)cc1)N1CCc2occc2C1

Procedure:
A solution of the above 5-(stilbene-4-sulfonyl)-4,5,6,7-tetrahydrofuro[3,2-c]pyridine in 20 ml of toluene-ethanol (5:1) was hydrogenated at room temperature at atmospheric pressure over 49 mg (0.053 mmol) of chlorotris(triphenylphosphine)rhodium (I) until the starting material disappeared on TLC. After the reaction mixture was concentrated under reduced pressure, the resulting crude product was purified by silica gel column chromatography (hexane/ethyl acetate=6/1) and crystallized from diethyl ether-hexane to yield the desired product.
Reaction SMILES: [CH3:1][C:2]1[C:6]([CH3:7])=[C:5]([NH2:8])[O:4][N:3]=1.[O:9]1[C:13]([S:14](Cl)(=[O:16])=[O:15])=[CH:12][C:11]2[CH:18]=[CH:19][CH:20]=[CH:21][C:10]1=2>>[CH3:1][C:2]1[C:6]([CH3:7])=[C:5]([NH:8][S:14]([C:13]2[O:9][C:10]3[CH:21]=[CH:20][CH:19]=[CH:18][C:11]=3[CH:12]=2)(=[O:15])=[O:16])[O:4][N:3]=1
Reactant: Cc1noc(N)c1C
Reactant: O=S(=O)(Cl)c1cc2ccccc2o1
Product: Cc1noc(NS(=O)(=O)c2cc3ccccc3o2)c1C

Procedure:
N-(3,4-Dimethyl-5-isoxazolyl)benzo[b]furan-2-sulfonamide was prepared, in the same manner as described in Example 34B, from 3,4-dimethyl-5-amino isoxazole (78 mg, 0.70 mmol) and benzo[b]furan-2-sulfonyl chloride (0.46 g, 2.1 mmol) Flash chromatography (30% ethyl acetate/hexanes) provided 0.186 g of a light yellow solid, which was treated with 31 mg of NaOH in 10 ml of methanol at 25° C. for 30 minutes. Recrystallization from CHCl3 /hexanes yielded a light tan solid (90 mg, 44% yield), m.p. 160.5-163° C.
Reaction SMILES: Br[CH2:2][CH2:3][CH2:4][CH2:5][O:6][C:7]1[CH:8]=[CH:9][C:10]2[C:14]([C:15]3[CH:20]=[CH:19][C:18]([C:21]([F:24])([F:23])[F:22])=[CH:17][CH:16]=3)=[C:13]([CH3:25])[S:12][C:11]=2[CH:26]=1.[CH2:27]([NH:30][CH3:31])[CH:28]=[CH2:29]>>[CH2:27]([N:30]([CH3:31])[CH2:2][CH2:3][CH2:4][CH2:5][O:6][C:7]1[CH:8]=[CH:9][C:10]2[C:14]([C:15]3[CH:20]=[CH:19][C:18]([C:21]([F:24])([F:23])[F:22])=[CH:17][CH:16]=3)=[C:13]([CH3:25])[S:12][C:11]=2[CH:26]=1)[CH:28]=[CH2:29]
Reactant: C=CCNC
Reactant: Cc1sc2cc(OCCCCBr)ccc2c1-c1ccc(C(F)(F)F)cc1
Product: C=CCN(C)CCCCOc1ccc2c(-c3ccc(C(F)(F)F)cc3)c(C)sc2c1

Procedure:
According to the method in example 31, 6-(4-Bromo-butoxy)-2-methyl-3-(4-trifluoromethyl-phenyl)-benzo[b]thiophene and N-allyl-methylamine were converted to yield Allyl-methyl-{4-[2-methyl-3-(4-trifluoromethyl-phenyl)-benzo[b]thiophen-6-yloxy]-butyl}-amine as yellowish oil, MS: 434 (MH+).
Reaction SMILES: [NH2:1][C:2]1[C:7]([NH2:8])=[C:6]([CH3:9])[CH:5]=[CH:4][N:3]=1.[CH2:10]([O:12][C:13](OCC)(OCC)OCC)[CH3:11].C(OC(C)C)(C)C>>[CH2:10]([O:12][C:13]1[NH:1][C:2]2=[N:3][CH:4]=[CH:5][C:6]([CH3:9])=[C:7]2[N:8]=1)[CH3:11]
Reactant: CCOC(OCC)(OCC)OCC
Reactant: Cc1ccnc(N)c1N
Solvent: CC(C)OC(C)C
Product: CCOc1nc2c(C)ccnc2[nH]1
Temperature: 150 °C
Reaction time: 2 h
Yield: 68 %

Procedure:
2,3-Diamino-4-methylpyridine (U.S. Pat. No. 5,332,744; 2.00 g, 16.2 mmol) and tetraethoxymethane (15.0 mL, 71.7 mmol) were mixed, and the mixture was stirred at 150° C. for 2 hr. The mixture was cooled to room temperature, diisopropyl ether (15 mL) was added thereto and the precipitated solid was collected by filtration to give the title compound (1.96 g, 68%).
Reaction SMILES: I[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH2:8]([S:12]CCCC)[CH2:9][CH2:10][CH3:11]>>[C:2]1([S:12][CH2:8][CH2:9][CH2:10][CH3:11])[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CCCCSCCCC
Reactant: Ic1ccccc1
Product: CCCCSc1ccccc1

Procedure:
The general procedure was used to convert iodobenzene and n-butyl sulfide to the title product. Purification by flash chromatography (hexane as the eluent) gave the analytically pure product as a clear oil (310 mg, 95% yield). 1H NMR (300 MHz, CDCl3) δ 7.26–7.09 (m, 5H; Hb, Hb′, Hc, Hc′, Hd), 2.88–2.82 (t, J=4.0, 2H; He), 1.60–1.46 (m, 2H; Hf), 1.42–1.30 (m, 2H; Hg), 0.88–0.82 (t, J=3.9, 3H; methyl protons). 13C NMR (75 MHz, CDCl3) δ 136.9 (C1), 128.7 (C3′, C3, C2, C2), 125.5 (C4), 33.1 (C5), 31.1 (C6), 21.9 (C7), 13.6 (C8). Anal. Calcd. for C10H14S: C, 72.23; H, 8.49; S, 19.28; Found C, 71.97; H, 8.67; S, 19.07.
Reaction SMILES: F[C:2]1[CH:3]=[CH:4][C:5]([N+:9]([O-:11])=[O:10])=[C:6]([CH3:8])[CH:7]=1.CN1CCCC1=O.[NH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][OH:25].C([O-])([O-])=O.[K+].[K+]>O>[N+:9]([C:5]1[CH:4]=[CH:3][C:2]([NH:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][OH:25])=[CH:7][C:6]=1[CH3:8])([O-:11])=[O:10]
Reactant: NCCCCCO
Reactant: Cc1cc(F)ccc1[N+](=O)[O-]
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN1CCCC1=O
Solvent: O
Product: Cc1cc(NCCCCCO)ccc1[N+](=O)[O-]
Temperature: 60 °C
Yield: 77.5 %

Procedure:
2 g of 5-fluoro-2-nitrotoluene were added to a solution of 20 ml of N-methylpyrrolidinone, 1.6 g of 5-amino-1-pentanol and 2.14 g of K2CO3. The reaction medium was heated at 60° C. for 8 hours and, after cooling to room temperature, was then poured into a water and ice mixture. The yellow precipitate formed was filtered off, reslurried in water and then dried over P2O5. 2.38 g of 5-(4-nitro-3-methylphenylamino)pentan-1-ol (17) were obtained.
Reaction SMILES: [CH:1]([N:4]1[CH2:9][CH2:8][N:7]([C:10]2[CH:15]=[C:14]([N:16](C)[C:17](=O)C)[CH:13]=[CH:12][N:11]=2)[CH2:6][CH2:5]1)([CH3:3])[CH3:2].[ClH:21]>O.O1CCOCC1>[ClH:21].[CH:1]([N:4]1[CH2:5][CH2:6][N:7]([C:10]2[CH:15]=[C:14]([NH:16][CH3:17])[CH:13]=[CH:12][N:11]=2)[CH2:8][CH2:9]1)([CH3:3])[CH3:2]
Reactant: CC(=O)N(C)c1ccnc(N2CCN(C(C)C)CC2)c1
Agent: Cl
Solvent: C1COCCO1
Solvent: O
Product: CNc1ccnc(N2CCN(C(C)C)CC2)c1
Temperature: 25 °C
Yield: 76 %

Procedure:
A mixture of 2.5 g (9 mmol) N-[2-(4-isopropyl-piperazin-1-yl)-pyridin-4-yl]-N-methyl-acetamide and 10 ml 4N HCl in 5 ml water and 25 ml dioxane was stirred at room temperature. After evaporation of the volatiles the residue was triturated with a mixture formed from acetone and dioxane and dried under vacuum to yield 1.8 g (76%) of the title compound (intermediate 11) as light red solid. MS: (m/e): 235.2 (MH+).
Reaction SMILES: [CH3:1][N:2]([C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1)[C:3](=[O:28])[CH2:4][N:5]([C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)[C:6](=[O:21])[CH2:7][NH:8][C:9]([NH:11][C:12]1[CH:17]=[CH:16][CH:15]=[C:14]([N+:18]([O-])=O)[CH:13]=1)=[O:10].[ClH:35]>C(O)C.C(#N)C.C(OC(C)C)(C)C.C(OC(C)C)(C)C.[Pd]>[ClH:35].[NH2:18][C:14]1[CH:13]=[C:12]([NH:11][C:9](=[O:10])[NH:8][CH2:7][C:6]([N:5]([CH2:4][C:3]([N:2]([CH3:1])[C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)=[O:28])[C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)=[O:21])[CH:17]=[CH:16][CH:15]=1
Reactant: CN(C(=O)CN(C(=O)CNC(=O)Nc1cccc([N+](=O)[O-])c1)c1ccccc1)c1ccccc1
Agent: [Pd]
Agent: Cl
Solvent: CC(C)OC(C)C
Solvent: CCO
Solvent: CC#N
Product: CN(C(=O)CN(C(=O)CNC(=O)Nc1cccc(N)c1)c1ccccc1)c1ccccc1
Reaction time: 2 h

Procedure:
0.3 g of 5% palladium-on-charcoal is added to a solution of 1.8 g of N-methyl-2-{2-[3-(3-nitrophenyl)ureido]-N-phenylacetamido}-N-phenylacetamide in 100 cm3 of ethanol. The suspension obtained is stirred for 2 hours at a temperature close to 50° C under a hydrogen atmosphere (100 kPa). After cooling, the catalyst is separated off by filtration and the solution is concentrated to dryness under reduced pressure (2.7 kPa) at 35° C. The residue obtained is dissolved in 60 cm3 of an acetonitrile/diisopropyl ether mixture (20/80 by volume) and 5 cm3 of a 3.5N solution of hydrochloric acid in diisopropyl ether are added. The insoluble product formed is separated off by filtration, air-dried and recrystallization from ethanol. 0.9 g of 2-{2-[3-(3-aminophenyl)ureido]-N-phenylacetamido}-N-methyl-N-phenylacetamide hydrochloride melting at 220° C is thus obtained.
Reaction SMILES: [N:1]1([C:7]2[CH:8]=[CH:9][C:10]3[N:11]([C:13]([C:16]([F:19])([F:18])[F:17])=[N:14][N:15]=3)[N:12]=2)[CH2:6][CH2:5][NH:4][CH2:3][CH2:2]1.[CH3:20][CH:21]([O:23][C:24]1[N:29]=[CH:28][C:27]([CH:30]=O)=[CH:26][CH:25]=1)[CH3:22]>>[CH3:22][CH:21]([O:23][C:24]1[N:29]=[CH:28][C:27]([CH2:30][N:4]2[CH2:3][CH2:2][N:1]([C:7]3[CH:8]=[CH:9][C:10]4[N:11]([C:13]([C:16]([F:17])([F:18])[F:19])=[N:14][N:15]=4)[N:12]=3)[CH2:6][CH2:5]2)=[CH:26][CH:25]=1)[CH3:20]
Reactant: CC(C)Oc1ccc(C=O)cn1
Reactant: FC(F)(F)c1nnc2ccc(N3CCNCC3)nn12
Product: CC(C)Oc1ccc(CN2CCN(c3ccc4nnc(C(F)(F)F)n4n3)CC2)cn1

Procedure:
Reductive amination of 6-(piperazin-1-yl)-3-(trifluoromethyl)-[1,2,4]triazolo[4,3-b]pyridazine with 6-propan-2-yloxypyridine-3-carbaldehyde was carried out according to General Synthetic Method 7. The crude product was purified by hplc using a Waters XBridge Prep C18 OBD column, 5μ silica, 30 mm diameter, 100 mm length eluted with decreasingly polar mixtures of water (containing 0.1% aqueous ammonia) and acetonitrile as eluents to give 6-[4-[(6-propan-2-yloxypyridin-3-yl)methyl]piperazin-1-yl]-3-(trifluoromethyl)-[1,2,4]triazolo[4,3-b]pyridazine.
Reaction SMILES: Cl[C:2]1[C:7]([C:8]([O:10]CC)=O)=[CH:6][N:5]=[C:4]2[N:13]([CH2:16][C:17]3[CH:22]=[CH:21][C:20]([O:23][CH3:24])=[CH:19][CH:18]=3)[N:14]=[CH:15][C:3]=12.[C:25]1([NH:31][NH2:32])[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1>>[CH3:24][O:23][C:20]1[CH:19]=[CH:18][C:17]([CH2:16][N:13]2[C:4]3[NH:5][CH:6]=[C:7]4[C:8](=[O:10])[N:31]([C:25]5[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=5)[N:32]=[C:2]4[C:3]=3[CH:15]=[N:14]2)=[CH:22][CH:21]=1
Reactant: NNc1ccccc1
Reactant: CCOC(=O)c1cnc2c(cnn2Cc2ccc(OC)cc2)c1Cl
Product: COc1ccc(Cn2ncc3c4nn(-c5ccccc5)c(=O)c-4c[nH]c32)cc1
Temperature: 90 °C
Reaction time: 16 h

Procedure:
A suspension of compound 3 and 10 equivalents of phenyl hydrazine was stirred at 90° C. for 16 hours. Reaction was quenched with iced water. The aqueous layer was removed, residue was suspended in ethanol and stirred with 1N NaOH solution at room temperature for 1 hour. pH was adjusted to 5 using acetic acid and solvent was removed in vacuo. Compound 4 was collected by filtration.
Reaction SMILES: [CH2:1]([CH:8]1[C:16]2[C:11](=[CH:12][C:13]([F:19])=[C:14]([C:17]#[N:18])[CH:15]=2)[CH2:10][CH:9]1[NH:20][C:21](=[O:25])[O:22][CH2:23][CH3:24])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[BH4-].[Na+].[H][H]>CO.O.O.O.O.O.O.[Co](Cl)Cl>[NH2:18][CH2:17][C:14]1[CH:15]=[C:16]2[C:11]([CH2:10][CH:9]([NH:20][C:21](=[O:25])[O:22][CH2:23][CH3:24])[CH:8]2[CH2:1][C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)=[CH:12][C:13]=1[F:19]
Reactant: CCOC(=O)NC1Cc2cc(F)c(C#N)cc2C1Cc1ccccc1
Reactant: [H][H]
Agent: Cl[Co]Cl
Agent: [BH4-]
Agent: [Na+]
Solvent: O
Solvent: CO
Product: CCOC(=O)NC1Cc2cc(F)c(CN)cc2C1Cc1ccccc1
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
To a solution of ethyl 1-benzyl-6-cyano-5-fluoro-2,3-dihydro-1H-inden-2-ylcarbamate (182 mg, 0.538 mmol) in methanol (5 ml) containing cobalt(II) chloride hexahydrate (256 mg, 1.076 mmol) was added sodium borohydride (203 mg, 5.38 mmol) in small portions with caution to control the evolution of hydrogen and the exothermic reaction (approximately 1 h). The reaction mixture was stirred at room temperature for 10 min and carefully quenched by addition of 12N hydrochloric acid until the black precipitate was dissolved. The reaction mixture was carefully made alkaline with concentrated ammonia and extracted with ethyl acetate, dried, filtered and evaporated to leave the crude product ethyl 6-(aminomethyl)-1-benzyl-5-fluoro-2,3-dihydro-1H-inden-2-ylcarbamate a pale brown oil. m=184 mg (quant.)
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:26][CH2:25][N:11]2[C:12](=[O:24])[C:13]3[C:18]([C@@H:10]2[CH2:9]1)=[CH:17][C:16](Br)=[CH:15][C:14]=3[C:20]([F:23])([F:22])[F:21])=[O:7])([CH3:4])([CH3:3])[CH3:2].B1(B2OC(C)(C)C(C)(C)O2)OC(C)(C)C(C)(C)[O:28]1.C([O-])(=O)C.[K+]>CN(C=O)C.C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[C:1]([O:5][C:6]([N:8]1[CH2:26][CH2:25][N:11]2[C:12](=[O:24])[C:13]3[C:18]([C@@H:10]2[CH2:9]1)=[CH:17][C:16]([OH:28])=[CH:15][C:14]=3[C:20]([F:23])([F:22])[F:21])=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)OC(=O)N1CCN2C(=O)c3c(cc(Br)cc3C(F)(F)F)[C@@H]2C1
Reactant: CC1(C)OB(B2OC(C)(C)C(C)(C)O2)OC1(C)C
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N1CCN2C(=O)c3c(cc(O)cc3C(F)(F)F)[C@@H]2C1
Temperature: 80 °C
Reaction time: 0.25 h
Yield: 93.2 %

Procedure:
To a stirring degassed solution of N-(t-butoxycarbonyl)-(R)-1,3,4,10b-tetrahydro-9-bromo-7-trifluoromethyl-pyrazino[2,1-a]isoindol-6(2H)-one (435 mg, 1.0 mmol), bis(pinacolato)diboron (279 mg, 1.1 mmol), and potassium acetate (294 mg, 3.0 mmol) in dry DMF (5.0 mL) was added palladium(II) acetate (6.7 mg, 0.03 mmol). The reaction was heated to 80° C. for 2 h and then cooled to room temp. The reaction was quenched with water and extracted with EtOAc (3×5 mL). The organic layers were combined, dried over Na2SO4, and conc. in vacuo to a brown oil. The oil was dissolved in THF (5 mL) and acetic acid (0.05 mL) and treated with hydrogen peroxide (0.25 mL). The reaction was stirred for 15 min and then quenched with st. aq. NaHSO3. The reaction was extracted with EtOAc (3×5 mL). The organic layers were combined, dried over Na2SO4, and conc. in vacuo to a brown oil. The oil was purified by flash chromatography (silica gel, 0-70% EtOAc in hexanes) to give 347 mg of the desired product as a pale yellow solid. MS (ESI) 373 (M+H).
Reaction SMILES: Cl[O-:2].[Na+].[F:4][C:5]([F:26])([F:25])[C:6]1[CH:24]=[CH:23][C:9]2[NH:10][C:11]([S:13][CH2:14][C:15]3[CH:20]=[C:19]([O:21][CH3:22])[CH:18]=[CH:17][N:16]=3)=[N:12][C:8]=2[CH:7]=1>C(OCC)(=O)C>[F:26][C:5]([F:4])([F:25])[C:6]1[CH:24]=[CH:23][C:9]2[NH:10][C:11]([S:13]([CH2:14][C:15]3[CH:20]=[C:19]([O:21][CH3:22])[CH:18]=[CH:17][N:16]=3)=[O:2])=[N:12][C:8]=2[CH:7]=1
Reactant: [O-]Cl
Reactant: COc1ccnc(CSc2nc3cc(C(F)(F)F)ccc3[nH]2)c1
Agent: [Na+]
Solvent: CCOC(C)=O
Product: COc1ccnc(CS(=O)c2nc3cc(C(F)(F)F)ccc3[nH]2)c1
Reaction time: 0.03 h

Procedure:
600 ml of a 1.5% strength aqueous sodium hypochlorite solution are added within 3 minutes at 10° C. with vigorous stirring to a solution of 16.2 g (0.048 mole) of 5-trifluoromethyl-2-[(4-methoxy-2-pyridylmethyl)thio]-(1H)-benzimidazole in 960 ml of ethyl acetate. The mixture is then stirred for a further 2 minutes. The organic phase is separated off and is washed with 100 ml of distilled water. The aqueous phase is adjusted to pH 7-8 by addition of glacial acetic acid and is then extracted three times with ethyl acetate. The extracts are washed with water and the combined organic phases are then concentrated to a volume of 100 ml and cooled in an ice bath. The precipitate which has separated out is filtered off with suction and washed with cold ethyl acetate. Yield: 13.2 g of m.p. 166° C. (decomposition).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([N:8]2[CH:12]([OH:13])[C:11]3[S:14][CH2:15][CH2:16][S:17][C:10]=3[C:9]2=[O:18])=[N:6][CH:7]=1.[H-].[Na+].Cl[C:22]([N:24]1[CH2:29][CH2:28][N:27]([CH3:30])[CH2:26][CH2:25]1)=[O:23].C(O)C>O1CCCC1>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([N:8]2[CH:9]([O:18][C:22]([N:24]3[CH2:29][CH2:28][N:27]([CH3:30])[CH2:26][CH2:25]3)=[O:23])[C:10]3[S:17][CH2:16][CH2:15][S:14][C:11]=3[C:12]2=[O:13])=[N:6][CH:7]=1
Reactant: CN1CCN(C(=O)Cl)CC1
Reactant: O=C1C2=C(SCCS2)C(O)N1c1ccc(Cl)cn1
Agent: [H-]
Agent: [Na+]
Solvent: CCO
Solvent: C1CCOC1
Product: CN1CCN(C(=O)OC2C3=C(SCCS3)C(=O)N2c2ccc(Cl)cn2)CC1
Temperature: 5 °C
Reaction time: 4 h
Yield: 73.3 %

Procedure:
A solution of 6-(5-chloropyrid-2-yl)-5-hydroxy-7-oxo-2,3,6,7-tetrahydro-1,4-dithiino[2,3-c]pyrrole (15.0 g.) in anhydrous tetrahydrofuran (150 cc.) is treated for 15 minutes at about 10°-15° C with sodium hydride (1.44 g.), and a solution of 1-chlorocarbonyl-4-methylpiperazine (24.4 g.) in anhydrous tetrahydrofuran (200 cc.) is then added, at 5° C. The reaction mixture is stirred for 4 hours at 5° C. After evaporating the solvent under reduced pressure (20 mm.Hg), the residue is dissolved in diethyl ether (450 cc.). The ether solution is rapidly extracted twice with an ice-cold normal aqueous solution of methanesulphonic acid (total 500 cc.). The combined aqueous extracts are rendered alkaline by adding 10N sodium hydroxide solution (100 cc.). The oil which separates out is extracted with methylene chloride (250 cc.) and then with diethyl ether (300 cc.). The combined organic extracts are washed five times with distilled water (total 250 cc.), dried over anhydrous sodium sulphate, treated with decolourising charcoal (0.1 g.) and evaporated. The crystals obtained (18.0 g.; m.p. 170° C.) are dissolved in boiling ethanol (225 cc.). After filtering the boiling solution and then cooling it for 3 hours at 2° C., the crystals which have appeared are filtered off, washed three times with ice-cold ethanol (total 45 cc.) and dried under reduced pressure (20 mm.Hg). 6-(5-chloropyrid-2-yl)-5-(4-methylpiperazin-1-yl)carbonyloxy-7-oxo-2,3,6,7-tetrahydro-1,4-dithiino[2,3-c]pyrrole (15.6 g.), melting at 180° C., is thus obtained.
Reaction SMILES: Cl.[NH2:2][C@H:3]([C:8]([N:10]1[CH2:14][CH2:13][CH2:12][C@H:11]1[C:15]#[N:16])=[O:9])[C@H:4]([CH2:6][CH3:7])[CH3:5].Cl[C:18]([O:20][CH3:21])=[O:19].C(N(CC)CC)C>ClCCl>[CH3:21][O:20][C:18]([NH:2][C@H:3]([C:8]([N:10]1[CH2:14][CH2:13][CH2:12][C@H:11]1[C:15]#[N:16])=[O:9])[C@H:4]([CH2:6][CH3:7])[CH3:5])=[O:19]
Reactant: COC(=O)Cl
Reactant: CC[C@H](C)[C@H](N)C(=O)N1CCC[C@H]1C#N
Agent: Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC[C@H](C)[C@H](NC(=O)OC)C(=O)N1CCC[C@H]1C#N
Yield: 95.1 %

Procedure:
A solution of (2S)-1-(isoleucyl)pyrrolidine-2-carbonitrile hydrochloride (300 mg, 1.22 mmol; prepared according to Jenkins et al., WO95/15309), methyl chloroformate (125 mg, 1.3 mmol) and triethylamine (150 mg, 1.50 mmol) in dichloromethane (40 ml) was stirred at room temperature for 18 hours. After this time the solvent was removed in vacuo and the residue was taken up in ethyl acetate (70 ml). This solution was washed with 0.3M KHSO4, sat. NaHCO3, water and brine, dried (Na2SO4) and evaporated. The residue was purified by flash chromatography (EtOAc:Pet. Ether 60–80° C.; 4:6) yielding a colourless oil identified as the title compound (310 mg, 1.16 mmol, 95%).
Reaction SMILES: [CH2:1]([NH2:3])[CH3:2].[N:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[CH:10]=O>>[CH2:1]([NH:3][CH2:10][C:5]1[CH:6]=[CH:7][CH:8]=[CH:9][N:4]=1)[CH3:2]
Reactant: CCN
Reactant: O=Cc1ccccn1
Product: CCNCc1ccccn1

Procedure:
prepared by reaction of ethylamine with pyridine-2-carbaldehyde
Reaction SMILES: CS(Cl)(=O)=O.[CH2:6]([N:13]([CH2:29][CH2:30]O)[C:14]([NH:16][C:17]([C:19]1[CH:20]=[N:21][CH:22]=[CH:23][C:24]=1[C:25]([F:28])([F:27])[F:26])=[O:18])=[O:15])[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1.C(N(CC)CC)C>ClCCl>[CH2:6]([N:13]1[CH2:29][CH2:30][N:16]([C:17]([C:19]2[CH:20]=[N:21][CH:22]=[CH:23][C:24]=2[C:25]([F:27])([F:28])[F:26])=[O:18])[C:14]1=[O:15])[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1
Reactant: O=C(NC(=O)N(CCO)Cc1ccccc1)c1cnccc1C(F)(F)F
Agent: CS(=O)(=O)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: O=C(c1cnccc1C(F)(F)F)N1CCN(Cc2ccccc2)C1=O
Temperature: 20 °C
Reaction time: 3 h
Yield: 94.6 %

Procedure:
Methanesulfonyl chloride (0.17 ml) was added to an ice-cooled mixture of 1-benzyl-1-(2-hydroxyethyl)-3-(4-trifluoromethyl-3-pyridylcarbonyl)urea (0.70 g), and triethylamine (0.64 ml) in dichloromethane, then stirred for 3 hours at 20° C. The mixture was washed (water), dried (magnesium sulfate), evaporated and the residue purified by silica-gel chromatography, eluting with n-hexane/ethyl acetate (3:2), to give 1-benzyl-3-(4-trifluoromethyl-3-pyridylcarbonyl)-2-imidazolidinone (0.63 g, Compound S-15).