Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: COC[O:4][C:5]1[CH:6]=[C:7]([C:16]2[N:17]=[C:18]3[C:24]([C:25](=[O:30])[C:26]([CH3:29])([CH3:28])[CH3:27])=[CH:23][N:22]([CH2:31][O:32][CH2:33][CH2:34][Si:35]([CH3:38])([CH3:37])[CH3:36])[C:19]3=[N:20][CH:21]=2)[CH:8]=[C:9]([N:11]2[CH2:15][CH2:14][CH2:13][CH2:12]2)[CH:10]=1.Cl.C(OCC)(=O)C.C([O-])([O-])=O.[Na+].[Na+]>C(Cl)Cl>[OH:4][C:5]1[CH:6]=[C:7]([C:16]2[N:17]=[C:18]3[C:24]([C:25](=[O:30])[C:26]([CH3:29])([CH3:27])[CH3:28])=[CH:23][N:22]([CH2:31][O:32][CH2:33][CH2:34][Si:35]([CH3:38])([CH3:37])[CH3:36])[C:19]3=[N:20][CH:21]=2)[CH:8]=[C:9]([N:11]2[CH2:15][CH2:14][CH2:13][CH2:12]2)[CH:10]=1
Reactant: COCOc1cc(-c2cnc3c(n2)c(C(=O)C(C)(C)C)cn3COCC[Si](C)(C)C)cc(N2CCCC2)c1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: ClCCl
Product: CC(C)(C)C(=O)c1cn(COCC[Si](C)(C)C)c2ncc(-c3cc(O)cc(N4CCCC4)c3)nc12
Reaction time: 2.5 h
Yield: 72.4 %

Procedure:
To a solution of 1-[2-(3-methoxymethoxy-5-pyrrolidin-1-yl-phenyl)-5-(2-trimethylsilanyl-ethoxymethyl)-5H-pyrrolo[2,3-b]pyrazin-7-yl]-2,2-dimethyl-propan-1-one (492 mg, 0.91 mmol) in CH2Cl2 (1.5 ml) was added a solution of 10% ethanolic hydrogen chloride (4 ml, dry). The flask was capped and stirred for 2.5 hours. The volatile material was stripped (rotovap). Ethyl acetate (25 ml) and aqueous 5% Na2CO3 (25 ml) was added and the 2 phase system vigorously stirred for 3 minutes. The material was partitioned and the organic phase collected and washed with brine (25 ml). The aqueous phases were back extracted with EtOAc (2×20 ml). The organics were combined, dried (MgSO4), filtered and stripped to provide a crude semi-solid. The material was purified by preparative TLC, eluting with 38% ethyl acetate in hexanes to afford 326 mg of 1-[2-(3-hydroxy-5-pyrrolidin-1-yl-phenyl)-5-(2-trimethylsilanyl-ethoxymethyl)-5H-pyrrolo[2,3-b]pyrazin-7-yl]-2,2-dimethyl-propan-1-one as a yellow-brown solid.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([S:8][CH3:9])[N:5]=[C:4]([N:10]2[C:14]3[CH:15]=[CH:16][CH:17]=[CH:18][C:13]=3[N:12]=[C:11]2[CH:19]([F:21])[F:20])[CH:3]=1.C(=O)([O-])[O-].[K+].[K+].[NH:28]1[CH2:33][CH2:32][O:31][CH2:30][CH2:29]1.O>CN(C)C=O>[F:20][CH:19]([F:21])[C:11]1[N:10]([C:4]2[CH:3]=[C:2]([N:28]3[CH2:33][CH2:32][O:31][CH2:30][CH2:29]3)[N:7]=[C:6]([S:8][CH3:9])[N:5]=2)[C:14]2[CH:15]=[CH:16][CH:17]=[CH:18][C:13]=2[N:12]=1
Reactant: CSc1nc(Cl)cc(-n2c(C(F)F)nc3ccccc32)n1
Reactant: C1COCCN1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: CSc1nc(N2CCOCC2)cc(-n2c(C(F)F)nc3ccccc32)n1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of 1-[6-chloro-2-(methylsulfanyl)pyrimidin-4-yl]-2-(difluoromethyl)-1H-benzimidazole (2.2 g) in N,N-dimethylformamide (11 mL) were added potassium carbonate (1.4 g) and morpholine (0.88 mL), and the mixture was stirred at room temperature for 1 hour. To the reaction solution was added water, followed by extraction with ethyl acetate. The organic layer was washed with saturated brine and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure and then the residue was purified by silica gel column chromatography (hexane:ethyl acetate) to obtain 2-(difluoromethyl)-1-[2-(methylsulfanyl)-6-morpholin-4-ylpyrimidin-4-yl]-1H-benzimidazole (2.1 g) as a white powder.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:34])/[C:5](/[F:33])=[C:6](\[CH3:32])/[CH:7]=[CH:8]/[C:9](/[F:31])=[C:10](\[C:13]1[C:22]([O:23]COC)=[CH:21][C:20]2[C:19]([CH3:28])([CH3:27])[CH2:18][CH2:17][C:16]([CH3:30])([CH3:29])[C:15]=2[CH:14]=1)/[CH2:11][CH3:12])[CH3:2].Cl>CC(O)C.C1COCC1>[CH2:1]([O:3][C:4](=[O:34])/[C:5](/[F:33])=[C:6](\[CH3:32])/[CH:7]=[CH:8]/[C:9](/[F:31])=[C:10](\[C:13]1[C:22]([OH:23])=[CH:21][C:20]2[C:19]([CH3:27])([CH3:28])[CH2:18][CH2:17][C:16]([CH3:30])([CH3:29])[C:15]=2[CH:14]=1)/[CH2:11][CH3:12])[CH3:2]
Reactant: CCOC(=O)/C(F)=C(C)/C=C/C(F)=C(/CC)c1cc2c(cc1OCOC)C(C)(C)CCC2(C)C
Agent: Cl
Solvent: C1CCOC1
Solvent: CC(C)O
Product: CCOC(=O)/C(F)=C(C)/C=C/C(F)=C(/CC)c1cc2c(cc1O)C(C)(C)CCC2(C)C
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of (2Z,4E,6E)-2,6-difluoro-7-(3-methoxymethoxy-5,5,8,8-tetramethyl-5,6,7,8-tetrahydro-naphthalen-2-yl)-3-methyl-nona-2,4,6-trienoic acid ethyl ester (Compound 19, 2-E/Z mixture, 387 mg, 0.81 mmol) in i-PrOH (2 mL) and THF (2 mL) was added conc. HCl (1.0 mL). The mixture was stirred at ambient temperature for overnight, extracted with EtOAc (×3). The combined organic layer was washed with brine, dried over Na2SO4, and concentrated in vacuo. The residue was purified by flash column chromatography on silica gel (5% EtOAc-hexane) to give the title compound as a 2-E/Z mixture (370 mg, 100%). This mixture was used directly for the next alkylation reaction.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:20])[C@@H:4](OS(C)(=O)=O)[CH2:5][CH2:6][O:7][Si:8]([C:11]([CH3:14])([CH3:13])[CH3:12])([CH3:10])[CH3:9].[I-:21].[Na+]>CC(=O)CC>[CH3:1][O:2][C:3](=[O:20])[CH:4]([I:21])[CH2:5][CH2:6][O:7][Si:8]([C:11]([CH3:14])([CH3:13])[CH3:12])([CH3:10])[CH3:9]
Reactant: [I-]
Reactant: COC(=O)[C@H](CCO[Si](C)(C)C(C)(C)C)OS(C)(=O)=O
Agent: [Na+]
Solvent: CCC(C)=O
Product: COC(=O)C(I)CCO[Si](C)(C)C(C)(C)C
Temperature: 90 °C

Procedure:
A solution of 2.89 g (8.85 mmol) of (S)-4-(tert-butyl-dimethyl-silanyloxy)-2-methanesulfonyloxy-butyric acid methyl ester in 90 ml of 2-butanone was treated with 2.65 g (17.70 mmol) of sodium iodide and stirred at 90° C. for 1¼ h. The reaction was cooled, filtered and evaporated. The residue was suspended in dichloromethane treated with Na2SO4 and filtered to give after evaporation 2.94 g (93%) of the titled compound as dark brown oil. MS: 343.0 (M-CH3)+.
Reaction SMILES: N1CCCC1.C(OC([O:13][C:14]1[C:26]([C:27]([F:30])([F:29])[F:28])=[CH:25][CH:24]=[C:23]([CH2:31][O:32][C:33]2[CH:38]=[CH:37][C:36]([C:39]3[CH:44]=[CH:43][CH:42]=[C:41]([CH2:45][C:46]([O:48][CH3:49])=[O:47])[C:40]=3[CH3:50])=[CH:35][CH:34]=2)[C:15]=1[C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])=O)(C)(C)C>O1CCCC1>[OH:13][C:14]1[C:26]([C:27]([F:29])([F:30])[F:28])=[CH:25][CH:24]=[C:23]([CH2:31][O:32][C:33]2[CH:38]=[CH:37][C:36]([C:39]3[CH:44]=[CH:43][CH:42]=[C:41]([CH2:45][C:46]([O:48][CH3:49])=[O:47])[C:40]=3[CH3:50])=[CH:35][CH:34]=2)[C:15]=1[C:16]([O:18][C:19]([CH3:20])([CH3:21])[CH3:22])=[O:17]
Reactant: COC(=O)Cc1cccc(-c2ccc(OCc3ccc(C(F)(F)F)c(OC(=O)OC(C)(C)C)c3C(=O)OC(C)(C)C)cc2)c1C
Solvent: C1CCNC1
Solvent: C1CCOC1
Product: COC(=O)Cc1cccc(-c2ccc(OCc3ccc(C(F)(F)F)c(O)c3C(=O)OC(C)(C)C)cc2)c1C
Temperature: 40 °C
Reaction time: 1 h
Yield: 100.5 %

Procedure:
Pyrrolidine (3 μl, 0.036 mmol) was added to a solution of tert-butyl 2-[(tert-butoxycarbonyl)oxy]-6-[({3′-[(methoxycarbonyl)methyl]-2′-methyl-1,1′-biphenyl-4-yl}oxy)methyl]-3-(trifluoromethyl)benzoate (19 mg, 0.030 mmol) obtained in Example (33-4) in tetrahydrofuran (1 ml), and the mixture was stirred at 40° C. for 1 hour. The residue obtained by removing the solvent under reduced pressure was purified by silica gel preparative thin layer chromatography (developing solvent: n-hexane/ethyl acetate=3/1) to give tert-butyl 2-hydroxy-6-[({3′-[(methoxycarbonyl)methyl]-2′-methyl-1,1′-biphenyl-4-yl}oxy)methyl]-3-(trifluoromethyl)benzoate as a colorless oil (16 mg, yield: 100%).
Reaction SMILES: F[C:2]1[CH:3]=[C:4]([CH:7]=[C:8]([C:10]([F:13])([F:12])[F:11])[CH:9]=1)[C:5]#[N:6].[NH:14]1[CH2:19][CH2:18][O:17][CH2:16][CH2:15]1>>[N:14]1([C:2]2[CH:3]=[C:4]([CH:7]=[C:8]([C:10]([F:13])([F:12])[F:11])[CH:9]=2)[C:5]#[N:6])[CH2:19][CH2:18][O:17][CH2:16][CH2:15]1
Reactant: C1COCCN1
Reactant: N#Cc1cc(F)cc(C(F)(F)F)c1
Product: N#Cc1cc(N2CCOCC2)cc(C(F)(F)F)c1

Procedure:
The title compound is prepared using an analogous method as described in Example 1.1, utilising 3-fluoro-5-(trifluoromethyl)-benzonitrile (Lancaster Synthesis GmbH) and morpholine (Fluka, Buchs, Switzerland), with a reaction temperature of 105° C. for 14 hours.
Reaction SMILES: [CH2:1]([O:8][CH:9]1[CH2:14][CH2:13][C:12](=[O:15])[CH2:11][CH2:10]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:16](=[O:19])([O-])[O-].[NH4+:20].[NH4+:21].[C-]#N.[K+]>C(O)C>[NH:20]1[CH2:13][C:12](=[O:15])[NH:21][C:16]1=[O:19].[CH2:1]([O:8][CH:9]1[CH2:14][CH2:13][C:12](=[O:15])[CH2:11][CH2:10]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C([O-])[O-]
Reactant: [NH4+]
Agent: O=C1CCC(OCc2ccccc2)CC1
Agent: [C-]#N
Agent: [K+]
Solvent: CCO
Product: O=C1CNC(=O)N1
Temperature: 60 °C

Procedure:
4-Benzyloxycyclohexanone 41 is dissolved in 30 mL of 50% ethanol containing ammonium carbonate and potassium cyanide is added (Step 38). The mixture will be warmed to 60° C. for 2 h and evaporated to dryness in vacuo. The residue is extracted with 40 mL of hot methanol, filtered, and the filter cake washed with 20 mL of hot methanol. The methanol solutions are combined, solvent evaporated, and the residue chromatographed on silica gel using CH2Cl2 /methanol 90:10 to yield 42.
Reaction SMILES: [C:1]([C:4]1[CH:23]=[CH:22][CH:21]=[CH:20][C:5]=1[C:6](C1C2C(=CC=CC=2)N(CC)C=1C)=[O:7])(O)=[O:2].C(C1C=CC=CC=1C(C1C2C(=CC=CC=2)N(CCCCC)C=1C)=O)(O)=O>>[C:1]1([C:4]2[C:5](=[CH:20][CH:21]=[CH:22][CH:23]=2)[CH2:6][O:7]1)=[O:2]
Reactant: CCn1c(C)c(C(=O)c2ccccc2C(=O)O)c2ccccc21
Agent: CCCCCn1c(C)c(C(=O)c2ccccc2C(=O)O)c2ccccc21
Product: O=C1OCc2ccccc21

Procedure:
If the 3-(2'-carboxybenzoyl)-1-ethyl-2-methyl-indole in Example 1 is replaced by an equimolar amount of 3-(2'-carboxybenzoyl)-1-n-pentyl-2-methyl-indole, with the procedure otherwise being as described in Example 1, there is obtained 3.6 g of a phthalide compound of the formula ##STR15## which melts at 162°-163° C. The colour former develops on silton clay a blue colour of λ max. 600 nm.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:20])[C:4]1[CH:9]=[C:8]([N:10]([CH3:14])[CH2:11][CH2:12][CH3:13])[N:7]=[C:6]([NH:15][S:16]([CH3:19])(=[O:18])=[O:17])[CH:5]=1.IC.[C:23](=O)([O-])[O-].[K+].[K+]>CN(C=O)C.[Br-].C([N+](CCCC)(CCCC)CCCC)CCC.C(OCC)(=O)C>[CH3:1][O:2][C:3](=[O:20])[C:4]1[CH:9]=[C:8]([N:10]([CH3:14])[CH2:11][CH2:12][CH3:13])[N:7]=[C:6]([N:15]([S:16]([CH3:19])(=[O:18])=[O:17])[CH3:23])[CH:5]=1
Reactant: CCCN(C)c1cc(C(=O)OC)cc(NS(C)(=O)=O)n1
Reactant: O=C([O-])[O-]
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [Br-]
Agent: [K+]
Solvent: CI
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CCCN(C)c1cc(C(=O)OC)cc(N(C)S(C)(=O)=O)n1
Yield: 87.3 %

Procedure:
Dissolve 2-methanesulfonylamino-6-(methylpropylamino)-isonicotinic acid methyl ester (87 mg, 2.89 mmol) and iodomethane (0.27 mL, 4.33 mmoles) in DMF (10 mL). Add potassium carbonate (639 mg, 4.62 mmol) and tetrabutylammonium bromide (93 mg, 0.98 mmol) and stir at room temperature 1 h. Dilute with ethyl acetate (80 mL), wash with 10% aqueous potassium carbonate (2×15 mL), 0.1 N citric acid (2×15 mL), 1 N lithium chloride (2×15 mL) and saturated aqueous sodium chloride (15 mL). Concentrate organic layer and purify (silica gel chromatography, eluting with 10:90 to 40:60 ethyl acetate:hexanes to give the title compound (796 mg, 87%).
Reaction SMILES: Cl[CH2:2][O:3][C:4](=[O:29])[C:5]1[CH:10]=[CH:9][C:8]([NH:11][C:12](=[O:28])[CH2:13][NH:14][C:15]([O:17][CH2:18][C:19]2[CH:24]=[CH:23][C:22]([N+:25]([O-:27])=[O:26])=[CH:21][CH:20]=2)=[O:16])=[CH:7][CH:6]=1.[I-:30].[Na+]>CC(C)=O>[I:30][CH2:2][O:3][C:4](=[O:29])[C:5]1[CH:10]=[CH:9][C:8]([NH:11][C:12](=[O:28])[CH2:13][NH:14][C:15]([O:17][CH2:18][C:19]2[CH:24]=[CH:23][C:22]([N+:25]([O-:27])=[O:26])=[CH:21][CH:20]=2)=[O:16])=[CH:7][CH:6]=1
Reactant: O=C(CNC(=O)OCc1ccc([N+](=O)[O-])cc1)Nc1ccc(C(=O)OCCl)cc1
Reactant: [I-]
Agent: [Na+]
Solvent: CC(C)=O
Product: O=C(CNC(=O)OCc1ccc([N+](=O)[O-])cc1)Nc1ccc(C(=O)OCI)cc1
Temperature: 25 °C
Reaction time: 16 h
Yield: 49.3 %

Procedure:
A solution of chloromethyl-4[N-(4-nitrobenzyloxycarbonyl)glycylamino]benzoate (1.0 g) in dry acetone (30 ml) was treated with finely-ground sodium iodide (3.6 g) and the mixture stirred at room temperature for 16 h. The mixture was filtered, the filtrate evaporated under reduced pressure and the residue dissolved in dichloromethane (50 ml) and washed with sodium thiosulphate (10%. aq. solution) until colourless. The organic phase was washed with water (20 ml), saturated aqueous NaCl (20 ml) and dried (MgSO4). The solvent was evaporated and the residue crystallised from ethyl acetate to afford the title compound as a white solid (0.600 g), m.p. 162°-4° C.; νmax (Nujol) 3300, 1735, 1690, 1610, and 1525 cm-1 ; δH (CDCl3 /D6 -DMSO) 3.90 (2H, d, J 6 Hz), 5.23 (2H, s), 6.18 (2H, s), 6.18 (2H, s), and 7.35-8.20 (10H, m).
Reaction SMILES: C[O:2][C:3](=[O:24])[C:4]1[CH:9]=[C:8]([C:10]2[S:11][CH:12]=[C:13]([C:15]3[CH:20]=[CH:19][C:18]([Cl:21])=[C:17]([Cl:22])[CH:16]=3)[N:14]=2)[CH:7]=[CH:6][C:5]=1Br.[F:25][C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][C:27]=1B(O)O>>[Cl:22][C:17]1[CH:16]=[C:15]([C:13]2[N:14]=[C:10]([C:8]3[CH:9]=[C:4]([C:3]([OH:2])=[O:24])[C:5]([C:27]4[CH:28]=[CH:29][CH:30]=[CH:31][C:26]=4[F:25])=[CH:6][CH:7]=3)[S:11][CH:12]=2)[CH:20]=[CH:19][C:18]=1[Cl:21]
Reactant: COC(=O)c1cc(-c2nc(-c3ccc(Cl)c(Cl)c3)cs2)ccc1Br
Reactant: OB(O)c1ccccc1F
Product: O=C(O)c1cc(-c2nc(-c3ccc(Cl)c(Cl)c3)cs2)ccc1-c1ccccc1F
Yield: 33.8 %

Procedure:
Using the conditions of General Procedure B for Suzuki Coupling and Hydrolysis in Parallel Mode, 2-bromo-5-[4-(3,4-dichloro-phenyl)-thiazol-2-yl]-benzoic acid methyl ester (which may be prepared as described for Intermediate 6; 89 mg, 0.2 mmol) was reacted with 2-fluorophenylboronic acid (available from Combi-Blocks Inc.; 56 mg, 0.4 mmol). The resulting ester was hydrolyzed and the acid was purified to give 4-[4-(3,4-dichloro-phenyl)-thiazol-2-yl]-2′-fluoro-biphenyl-2-carboxylic acid (30 mg, 34%). 1H NMR (400 MHz, DMSO-d6) δ 13.11 (br s, 1H), 8.48 (s, 2H), 8.34 (s, 1H), 8.28 (d, J=7.8 Hz, 1H), 8.09 (d, J=8.3 Hz, 1H), 7.77 (d, J=6.5 Hz, 1H), 7.56 (d, J=6.5 Hz, 1H), 7.39-7.48 (m, 2H), 7.20-7.35 (m, 2H).
Reaction SMILES: [Cl:1][C:2]1[C:3]([F:59])=[C:4]([C@@H:8]2[C@:12]([C:15]3[CH:20]=[CH:19][C:18]([Cl:21])=[CH:17][C:16]=3[F:22])([C:13]#[N:14])[C@H:11]([CH2:23][C:24]([CH3:27])([CH3:26])[CH3:25])[NH:10][C@H:9]2[C:28]([NH:30][C:31]2[CH:56]=[CH:55][C:34]([C:35]([O:37][CH:38]([O:40][C:41](=[O:54])[NH:42][CH2:43][C:44]([O:46]CC3C=CC=CC=3)=[O:45])[CH3:39])=[O:36])=[CH:33][C:32]=2[O:57][CH3:58])=[O:29])[CH:5]=[CH:6][CH:7]=1.[H][H]>C(OCC)(=O)C.[Pd]>[Cl:1][C:2]1[C:3]([F:59])=[C:4]([C@@H:8]2[C@:12]([C:15]3[CH:20]=[CH:19][C:18]([Cl:21])=[CH:17][C:16]=3[F:22])([C:13]#[N:14])[C@H:11]([CH2:23][C:24]([CH3:25])([CH3:26])[CH3:27])[NH:10][C@H:9]2[C:28]([NH:30][C:31]2[CH:56]=[CH:55][C:34]([C:35]([O:37][CH:38]([O:40][C:41]([NH:42][CH2:43][C:44]([OH:46])=[O:45])=[O:54])[CH3:39])=[O:36])=[CH:33][C:32]=2[O:57][CH3:58])=[O:29])[CH:5]=[CH:6][CH:7]=1
Reactant: [H][H]
Reactant: COc1cc(C(=O)OC(C)OC(=O)NCC(=O)OCc2ccccc2)ccc1NC(=O)[C@@H]1N[C@@H](CC(C)(C)C)[C@](C#N)(c2ccc(Cl)cc2F)[C@H]1c1cccc(Cl)c1F
Agent: [Pd]
Solvent: CCOC(C)=O
Product: COc1cc(C(=O)OC(C)OC(=O)NCC(=O)O)ccc1NC(=O)[C@@H]1N[C@@H](CC(C)(C)C)[C@](C#N)(c2ccc(Cl)cc2F)[C@H]1c1cccc(Cl)c1F
Yield: 64.4 %

Procedure:
To a solution of 1-(2-(benzyloxy)-2-oxoethylcarbamoyloxy)ethyl 4-((2R,3S,4R,5S)-3-(3-chloro-2-fluorophenyl)-4-(4-chloro-2-fluorophenyl)-4-cyano-5-neopentylpyrrolidine-2-carboxamido)-3-methoxybenzoate (Example 23, 35.8 mg, 0.042 mmol) in ethyl acetate (8 mL) was added 10% palladium on carbon (12 mg). The content was stirred at room temperature under 1 atm of hydrogen for 2 h. Palladium on carbon solids were filtered off and washed with ethyl acetate. The solution was concentrated to give 2-((1-(4-((2R,3S,4R,5S)-3-(3-chloro-2-fluorophenyl)-4-(4-chloro-2-fluorophenyl)-4-cyano-5-neopentylpyrrolidine-2-carboxamido)-3-methoxybenzoyloxy)ethoxy)carbonylamino)acetic acid as a white solid (20.6 mg, 61%)). MS (ES+) m/z calcd. for C36H37Cl2F2N4O8 [(M+H)+]: 761, found: 761.
Reaction SMILES: [OH-].[K+].[NH:3]1[CH:7]=[CH:6][CH:5]=[C:4]1[C:8]([NH:10][NH2:11])=[O:9].[C:12](=S)=[S:13].Cl>CO>[NH:3]1[CH:7]=[CH:6][CH:5]=[C:4]1[C:8]1[O:9][C:12]([SH:13])=[N:11][N:10]=1
Reactant: S=C=S
Reactant: NNC(=O)c1ccc[nH]1
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: CO
Product: Sc1nnc(-c2ccc[nH]2)o1
Reaction time: 0.5 h

Procedure:
Potassium hydroxide (4.78 g, 85.3 mmol) was solved in methanol (125 ml). 1H-pyrrole-2-carbohydrazide (9.7 g, 77.5 mmol) was added and the mixture was stirred for 30 minutes. Carbon disulfide (14.7 g, 193.8 mmol) was added to the mixture followed by stirring at 65° C. for 15 h. Another equivalent of carbon disulfide (5.90 g, 77.5 mmol) was added followed by stirring at 65° C. for 4 days. Aqueous hydrochloric acid (1 M) was added in excess quantity, the mixture was stirred and filtered and washed with aqueous hydrochloric acid. Yield 10 g (77%).
Reaction SMILES: [OH:1][C:2]1[CH:18]=[CH:17][C:5]([CH:6]=[C:7]2[C:12](=[O:13])[O:11][C:10]([CH3:15])([CH3:14])[O:9][C:8]2=[O:16])=[CH:4][CH:3]=1.[CH:19]1([Mg]Cl)[CH2:21][CH2:20]1>C1COCC1>[CH:19]1([CH:6]([C:5]2[CH:4]=[CH:3][C:2]([OH:1])=[CH:18][CH:17]=2)[CH:7]2[C:8](=[O:16])[O:9][C:10]([CH3:15])([CH3:14])[O:11][C:12]2=[O:13])[CH2:21][CH2:20]1
Reactant: CC1(C)OC(=O)C(=Cc2ccc(O)cc2)C(=O)O1
Reactant: Cl[Mg]C1CC1
Solvent: C1CCOC1
Product: CC1(C)OC(=O)C(C(c2ccc(O)cc2)C2CC2)C(=O)O1

Procedure:
To a solution of 21.1 (8.00 g, 32 mmol) in THF (100 mL) was added a 2.0 M solution of cyclopropylmagnesium chloride in THF (97 mL, 193 mmol (commercially available from Aldrich)) dropwise at 0° C. over 1 hour. Upon completion of the addition, the mixture was quenched with 1 N HCl and extracted with EtOAc. The combined organic layers were washed with brine, dried over MgSO4, filtered, and concentrated. The crude product was chromatographed on silica gel (20-30% EtOAc/hexane) to afford 21.2.
Reaction SMILES: [O:1]=[C:2]1[CH2:6][CH2:5][CH2:4][N:3]1[CH2:7][C:8]([O:10]CC)=O.[CH3:13][C:14]([N:18]1[CH2:23][CH2:22][CH2:21][CH2:20][CH2:19]1)([CH3:17])[CH2:15][NH2:16]>>[CH3:17][C:14]([N:18]1[CH2:23][CH2:22][CH2:21][CH2:20][CH2:19]1)([CH3:13])[CH2:15][NH:16][C:8](=[O:10])[CH2:7][N:3]1[CH2:4][CH2:5][CH2:6][C:2]1=[O:1]
Reactant: CC(C)(CN)N1CCCCC1
Reactant: CCOC(=O)CN1CCCC1=O
Product: CC(C)(CNC(=O)CN1CCCC1=O)N1CCCCC1

Procedure:
From 8.56 g. of ethyl 2-oxo-1-pyrrolidineacetate and 12.5 g. of 2-methyl-2-(1-piperidinyl)propylamine [J.A.C.S. 68, 13 (1946)], following the procedure of Example 9, there is obtained N-[2-methyl-2-(1-piperidinyl)propyl]-2-oxo-1-pyrrolidineacetamide; m.p. 69° C. after crystallization from heptane.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:12]2[S:13][CH:14]=[CH:15][N:16]=2)[CH:5]=[CH:6][C:7]=1[O:8][CH:9]([CH3:11])[CH3:10].C([O-])(=O)C.[Na+].[Br:22]Br>C(O)(=O)C>[Br:22][C:14]1[S:13][C:12]([C:4]2[CH:5]=[CH:6][C:7]([O:8][CH:9]([CH3:11])[CH3:10])=[C:2]([Cl:1])[CH:3]=2)=[N:16][CH:15]=1
Reactant: CC(C)Oc1ccc(-c2nccs2)cc1Cl
Reactant: BrBr
Agent: CC(=O)[O-]
Agent: [Na+]
Solvent: CC(=O)O
Product: CC(C)Oc1ccc(-c2ncc(Br)s2)cc1Cl
Temperature: 20 °C

Procedure:
To a solution of 2-{3-chloro-4-[(1-methylethyl)oxy]phenyl}-1,3-thiazole (D70) (1.5 g) and sodium acetate (0.970 g) in acetic acid (10 mL) stirred at room temperature was added a solution of Br2 (0.31 ml) in acetic acid (1 mL) dropwise during 30 min. The reaction mixture was stirred at 20° C. until start material was consumed completely. The reaction mixture was basified with 2M NaOH. The resulting solution was diluted with ethyl acetate. The mixture was washed with brine. The organic phase was dried over anhydrous sodium sulphate and evaporated in vacuo. The crude product was purified by column chromatography to give 5-bromo-2-{3-chloro-4-[(1-methylethyl)oxy]phenyl}-1,3-thiazole (D71) (1.2 g). MS (ES): C12H11BrClNOS requires 332. found 333.0 (M+H+).
Reaction SMILES: I[C:2]1[N:3]=[CH:4][N:5](C(C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[CH:6]=1.C([Mg]Br)C.[N+:30]([C:33]1[CH:42]=[CH:41][CH:40]=[C:39]2[C:34]=1[CH2:35][CH2:36][CH2:37][C:38]2=O)([O-:32])=[O:31].[Cl-].[NH4+]>ClCCl>[N+:30]([C:33]1[CH:42]=[CH:41][CH:40]=[C:39]2[C:34]=1[CH2:35][CH2:36][CH:37]=[C:38]2[C:2]1[N:3]=[CH:4][NH:5][CH:6]=1)([O-:32])=[O:31]
Reactant: Ic1cn(C(c2ccccc2)(c2ccccc2)c2ccccc2)cn1
Reactant: O=C1CCCc2c1cccc2[N+](=O)[O-]
Agent: CC[Mg]Br
Agent: [Cl-]
Agent: [NH4+]
Solvent: ClCCl
Product: O=[N+]([O-])c1cccc2c1CCC=C2c1c[nH]cn1
Reaction time: 0.5 h

Procedure:
A solution of 4-iodo-1-trityl-1H-imidazole (5.5 g, 13 mmol) (prepared as described by Kirk, K. J. Heterocyclic Chem. (1985), 22, 57-59) in dichloromethane (50 mL) was treated with ethylmagnesium bromide (3.0 M in diethyl ether, 4.2 mL) over 4 minutes, stirred for 30 minutes, treated with 5-nitrotetralone (prepared as described by Zhang, M J. Amer. Chem. SoC, (1994), 116, 4852-4857), stirred for 6 hours, treated with ammonium chloride solution (50 mL) and extracted with a mixture of diethyl ether (300 mL) and ethyl acetate (50 mL). The organic layer was isolated, treated with dichloromethane (500 mL) to dissolve the product which started to crystallize, dried (MgSO4), filtered, concentrated, treated with trifluoroacetic acid (80 mL), stirred for 48 hours, concentrated to an oil, neutralized with sodium bicarbonate solution and extracted twice with dichloromethane. The combined dichloromethane layers were dried (MgSO4), filtered and concentrated. The residue was purified on silica gel with a gradient of 5%-10% methanol/dichloromethane to provide the desired compound.
Reaction SMILES: C([O:8][C:9]1[C:29]([Cl:30])=[CH:28][C:12]([CH2:13][N:14]([N:23]2[CH:27]=[N:26][N:25]=[CH:24]2)[C:15]2[CH:22]=[CH:21][C:18]([C:19]#[N:20])=[CH:17][CH:16]=2)=[CH:11][C:10]=1[Cl:31])C1C=CC=CC=1>[Pd].CO.C1COCC1.CCOC(C)=O>[Cl:31][C:10]1[CH:11]=[C:12]([CH:28]=[C:29]([Cl:30])[C:9]=1[OH:8])[CH2:13][N:14]([N:23]1[CH:27]=[N:26][N:25]=[CH:24]1)[C:15]1[CH:16]=[CH:17][C:18]([C:19]#[N:20])=[CH:21][CH:22]=1
Reactant: N#Cc1ccc(N(Cc2cc(Cl)c(OCc3ccccc3)c(Cl)c2)n2cnnc2)cc1
Agent: [Pd]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Solvent: CO
Product: N#Cc1ccc(N(Cc2cc(Cl)c(O)c(Cl)c2)n2cnnc2)cc1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
Palladium on charcoal (100 mg, 10% Pd) was added to a solution of 4-[(4-benzyloxy-3,5-dichloro-benzyl)-[1,2,4]triazol-4-yl-amino]-benzonitrile (CAB02119, 1.13 g, 2.50 mmol) in MeOH/THF/EtOAc (30 mL/30 mL/40 mL). The mixture was stirred under hydrogen atmosphere (balloon) for 18 h at room temperature. The reaction mixture was filtered through celite and the clear colourless filtrate was concentrated under reduced pressure. The residue was suspended in 2-propanol (20 mL) and heated to reflux for 5 minutes. The white solid was filtered off after cooling to room temperature and dried under high vacuum. Yield: 306 mg (34%). 1H-NMR (400 MHz, d6-DMSO) δ 4.97 (s, 2H, —CH2Ar), 6.76 (d, J=9.0 Hz, 2H), 7.31 (s, 2H), 7.77 (d, J=9.0 Hz, 2H), 8.85 (s, 2H), 10.29 (s, 1H, —OH). 13C-NMR (100 MHz, CDCl3) δ=56.57, 103.76, 114.55, 119.69, 122.89, 128.14, 129.46, 134.58, 144.03, 149.46, 151.85. LRMS (FAB+): 360.0 (100,
Reaction SMILES: CC([C@H]1[N:9]2[CH2:10][CH2:11][CH2:12][C@:8]2([CH2:13][CH:14]=[CH2:15])[C:7](=[O:16])[O:6]1)(C)C.[ClH:17]>CO.O>[ClH:17].[CH:13]([C@:8]1([C:7]([OH:16])=[O:6])[CH2:12][CH2:11][CH2:10][NH:9]1)=[CH:14][CH3:15]
Reactant: C=CC[C@]12CCCN1[C@H](C(C)(C)C)OC2=O
Agent: Cl
Solvent: CO
Solvent: O
Product: CC=C[C@]1(C(=O)O)CCCN1
Temperature: 25 °C
Reaction time: 24 h

Procedure:
3-(1,1-Dimethylethyl)-5,6,7,7a-tetrahydro-7a-(2-propenyl)-(3S-cis)-1H,3H-pyrrolo[1,2-c]oxazol-1-one (7.98 g) was dissolved in a mixture of methanol (170 ml) and water (40 ml). Silica gel (20 g) was added and the reaction was stirred for 24 h at ambient temperature. The silica was removed by filtration, washed with methanol (100 ml) and water (50 ml) and the filtrate and washes were combined, then evaporated to leave an oil which was taken up in 1M HCl (100 ml). The solution was washed with CH2Cl2 (4×50 ml) then evaporated to dryness. Residual water was removed by azeotropic evaporation with methanol to leave a brown solid (5 g) which was dried in vacuo over P2O5, leached with boiling chloroform and crystallised from methanol to give the title compound (3.68 g) m.p. 180°-183° , [α]D +50° (MeOH, C=1%).