Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([C:8]1[CH:16]=[CH:15][C:11]([C:12]([OH:14])=O)=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(Cl)(=O)C(Cl)=O.C(N(CC)CC)C.[NH2:30][C:31]1[CH:41]=[CH:40][C:34]([C:35]([O:37][CH2:38][CH3:39])=[O:36])=[CH:33][C:32]=1[F:42]>ClCCl.CN(C=O)C>[CH2:1]([C:8]1[CH:9]=[CH:10][C:11]([C:12]([NH:30][C:31]2[CH:41]=[CH:40][C:34]([C:35]([O:37][CH2:38][CH3:39])=[O:36])=[CH:33][C:32]=2[F:42])=[O:14])=[CH:15][CH:16]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CCOC(=O)c1ccc(N)c(F)c1
Reactant: O=C(O)c1ccc(Cc2ccccc2)cc1
Agent: O=C(Cl)C(=O)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: CCOC(=O)c1ccc(NC(=O)c2ccc(Cc3ccccc3)cc2)c(F)c1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
A solution of 4-benzylbenzoic acid (1.06 g, 5 mmole) in dichloromethane (10 mL) was added oxalyl dichloride (1 mL) followed by a few drops of DMF at 0° C. The resulting mixture was stirred room temperature for 3 hours. Removal of the solvents gave the residue which was dissolved in dichloromethane (2 mL) and added to the solution of triethylamine (1.4 mL, 10 mmol) and ethyl 4-amino-3-fluorobenzoate (916 mg, 5 mmole) in dichloromethane (50 mL) at 0° C. After stirring at room temperature for 48 hours, the mixture was washed with saturated sodium bicarbonate and 1 N HCl. The combined organic extracts were washed with brine, dried and concentrated under reduced pressure to give the residue which was purification by silica gel chromatography on ISCO system. The desired product was obtained as an off white solid: 1H NMR (400 MHz, CDCl3) δ 8.63 (t, J=8.8 Hz, 1H), 8.20 (s, 1H), 7.83 (m, 4H), 7.18-7.35 (m, 6H), 4.39 (q, J=7.2 Hz, 1H), 4.07 (s, 2H), 1.40 (t, J=7.2 Hz, 3H).
Reaction SMILES: [C:1]1([N:7]([C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)[C:8](=[O:23])[O:9][CH2:10][CH:11]2[CH2:20][CH2:19][C:18]3[C:13](=[CH:14][CH:15]=[CH:16][C:17]=3[O:21]C)[CH2:12]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.NC(C(O)=O)CCSC>CS(O)(=O)=O>[C:24]1([N:7]([C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)[C:8](=[O:23])[O:9][CH2:10][CH:11]2[CH2:20][CH2:19][C:18]3[C:13](=[CH:14][CH:15]=[CH:16][C:17]=3[OH:21])[CH2:12]2)[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=1
Reactant: COc1cccc2c1CCC(COC(=O)N(c1ccccc1)c1ccccc1)C2
Agent: CS(=O)(=O)O
Agent: CSCCC(N)C(=O)O
Product: O=C(OCC1CCc2c(O)cccc2C1)N(c1ccccc1)c1ccccc1
Temperature: 25 °C
Reaction time: 22 h
Yield: 4.4 %

Procedure:
A suspension of (1,2,3,4-tetrahydro-5-methoxy-2-naphthyl)methyl N,N-diphenylcarbamate (1.93 g) and DL-methionine (7.43 g) in methanesulfonic acid (47.9 ml) was stirred at room temperature for 22 hours, then poured into ice water. The resulting mixture was extracted with ethyl acetate. The extract was washed successively with brine (twice), aqueous sodium bicarbonate and brine, dried over magnesium sulfate, and evaporated in vacuo. The residue was chromatographed (toluene-ethyl acetate) over silica gel to afford (1,2,3,4-tetrahydro-5-hydroxy-2-naphthyl)methyl N,N-diphenylcarbamate (82 mg) as yellow solids. mp: 96°-98° C.
Reaction SMILES: C([O:8][C@H:9]1[C@@H:17]([C@H:18]([OH:20])[CH3:19])[O:16][C@H:15]2[C@H:11]([N:12]=[C:13]([N:21](C)[C:22](=O)OC(C)(C)C)[S:14]2)[C@H:10]1[F:30])C1C=CC=CC=1.B(Cl)(Cl)Cl>C(Cl)Cl>[F:30][C@@H:10]1[C@H:11]2[N:12]=[C:13]([NH:21][CH3:22])[S:14][C@H:15]2[O:16][C@H:17]([C@H:18]([OH:20])[CH3:19])[C@@H:9]1[OH:8]
Reactant: C[C@@H](O)[C@H]1O[C@@H]2SC(N(C)C(=O)OC(C)(C)C)=N[C@@H]2[C@@H](F)[C@H]1OCc1ccccc1
Agent: ClB(Cl)Cl
Solvent: ClCCl
Product: CNC1=N[C@@H]2[C@@H](F)[C@@H](O)[C@@H]([C@@H](C)O)O[C@@H]2S1
Temperature: 25 °C
Reaction time: 3 h
Yield: 96.9 %

Procedure:
To a solution of tert-butyl ((3aR,5R,6S,7R,7aR)-6-(benzyloxy)-7-fluoro-5-((R)-1-hydroxyethyl)-5,6,7,7a-tetrahydro-3aH-pyrano[3,2-d]thiazol-2-yl)(methyl)carbamate (0.116 g, 0.264 mmol) and PMB (0.20 g, 1.3 mmol) in anhydrous DCM (6 mL) at −78° C. under N2, was added BCl3 (1.0 M in DCM, 1.2 mL, 1.2 mmol). The mixture was stirred for ˜3 h while the temperature of the cooling bath slowly warmed to room temperature. The reaction mixture was cooled at −78° C., quenched with mixed MeOH/DCM and then concentrated to dryness. The residue was purified on silica gel by flash column chromatography (1.0 M NH3 in MeOH/DCM, 1:10), affording (3aR,5R,6S,7R,7aR)-7-fluoro-5-((R)-1-hydroxyethyl)-2-(methylamino)-5,6,7,7a-tetrahydro-3aH-pyrano[3,2-d]thiazol-6-ol as a white solid (0.064 g, 97%). 1H NMR (400 MHz, CDCl3) δ 6.43 (dd, J=1.4, 6.5 Hz, 1H), 4.51 (ddd, J=3.2, 8.2, 48.2 Hz, 1H), 4.35-4.32 (m, 1H), 4.30-4.22 (m, 1H), 4.03-3.96 (m, 1H), 3.57 (d, J=8.2 Hz, 1H), 2.86 (s, 3H), 1.20 (d, J=6.3 Hz, 3H); 13C NMR (100 MHz, CD3OD) δ 164.40, 95.50 (d, J=183.3 Hz), 92.85 (d, J=8.6 Hz), 78.33 (d, J=6.2 Hz), 69.39 (d, J=20.8 Hz), 66.14 (d, J=16.5 Hz), 65.95 (d, J=8.4 Hz), 30.23, 20.71; MS, (ES, m/z) [M+H]+ 251.1.
Reaction SMILES: [Br:1][C:2]1[CH:14]=[CH:13][C:5]2[O:6][C:7]3[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=3[C:4]=2[CH:3]=1.[Br:15]Br>>[Br:15][C:10]1[CH:11]=[CH:12][C:7]2[O:6][C:5]3[CH:13]=[CH:14][C:2]([Br:1])=[CH:3][C:4]=3[C:8]=2[CH:9]=1
Reactant: Brc1ccc2oc3ccccc3c2c1
Reactant: BrBr
Product: Brc1ccc2oc3ccc(Br)cc3c2c1
Yield: 50 %

Procedure:
The procedure for the synthesis of 19 was followed (1 eq. bromine was used) to prepare 20 from 19 as white crystals in a 50% yield. 1H NMR (400 MHz, CDCl3, 298 K): δ(ppm) 8.04-8.03 (d, J=2.00 Hz, 2H), 7.60-7.59 (d, J=2.00 Hz, 1H), 7.58-7.57 (d, J=2.00 Hz, 1H), 7.47 (s, 1H), 7.44 (s, 1H).
Reaction SMILES: [Cl:1][C:2]1[C:7]2[C:8](=[O:21])[N:9]3[CH2:20][CH2:19][C@H:10]3[C:11]3[N:12]([CH:13]=[N:14][C:15]=3[C:16](O)=[O:17])[C:6]=2[CH:5]=[CH:4][C:3]=1[F:22].C(N1C=CN=C1)([N:25]1C=CN=C1)=O.C(=O)=O.N>CN(C)C=O>[Cl:1][C:2]1[C:7]2[C:8](=[O:21])[N:9]3[CH2:20][CH2:19][C@H:10]3[C:11]3[N:12]([CH:13]=[N:14][C:15]=3[C:16]([NH2:25])=[O:17])[C:6]=2[CH:5]=[CH:4][C:3]=1[F:22]
Reactant: O=C(O)c1ncn2c1[C@@H]1CCN1C(=O)c1c-2ccc(F)c1Cl
Reactant: O=C(n1ccnc1)n1ccnc1
Agent: N
Agent: O=C=O
Solvent: CN(C)C=O
Product: NC(=O)c1ncn2c1[C@@H]1CCN1C(=O)c1c-2ccc(F)c1Cl
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 78.9 %

Procedure:
40 g (124 mmol) of (S)-8-chloro-7-fluoro-12,12a-dihydro-9-oxo-9H,11H-azeto[2,1-c]imidazo[1,5-a][1,4]benzodiazepine-1-carboxylic acid were suspended in 190 ml of N,N-dimethylformamide and treated portionwise at room temperature with 21 g (129.5 mmol) of 1,1'-carbonyldiimidazole. After completion of the CO2 evolution the clear brown solution was stirred at 50° for 30 min., cooled and treated dropwise with 30 ml of conc. ammonia at a temperature below 25° within about 10 min. After stirring for 30 minutes the suspension obtained was poured into 700 ml of ice-water, stirred at room temperature for 30 min. and filtered, whereupon the crystals were rinsed with a small amount of water. After drying there were obtained 31.36 g (78%) of (S)-8-chloro-7-fluoro-12,12a-dihydro-9-oxo-9H,11H-azeto[2,1-c]imidazo[1,5-a][1,4]benzodiazepine-1-carboxamide of m.p. 296°-298°.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:9](O)([C:26]([F:29])([F:28])[F:27])[CH2:10][C:11]([C:13]2[S:17][C:16]([C:18]([O:20][CH3:21])=[O:19])=[C:15]3[CH2:22][CH2:23][CH2:24][CH2:25][C:14]=23)=[O:12])[CH:5]=[C:6]([Cl:8])[CH:7]=1.O=S(Cl)Cl.N1C=CC=CC=1>C(Cl)Cl.[NH4+].[Cl-]>[CH3:21][O:20][C:18]([C:16]1[S:17][C:13]([C:11](=[O:12])[CH:10]=[C:9]([C:4]2[CH:5]=[C:6]([Cl:8])[CH:7]=[C:2]([Cl:1])[CH:3]=2)[C:26]([F:29])([F:28])[F:27])=[C:14]2[CH2:25][CH2:24][CH2:23][CH2:22][C:15]=12)=[O:19]
Reactant: COC(=O)c1sc(C(=O)CC(O)(c2cc(Cl)cc(Cl)c2)C(F)(F)F)c2c1CCCC2
Agent: [Cl-]
Agent: [NH4+]
Solvent: c1ccncc1
Solvent: O=S(Cl)Cl
Solvent: ClCCl
Product: COC(=O)c1sc(C(=O)C=C(c2cc(Cl)cc(Cl)c2)C(F)(F)F)c2c1CCCC2
Yield: 99.9 %

Procedure:
Stir a mixture of methyl 3-(3-(3,5-dichlorophenyl)-4,4,4-trifluoro-3-hydroxyl butanoyl)-4,5,6,7-tetrahydrobenzo[c]thiophene-1-carboxylate (9.1 g, 18.9 mmol), SOCl2 (9.0 g, 5.5 mL, 75.6 mmol) and pyridine (2.99 g, 3.1 mL, 37.8 mmol) in anhydrous DCM (100 mL) at ambient temperature overnight. Dilute the resultant mixture with saturated NH4Cl aqueous solution. Extract the aqueous mixture with DCM (100 mL×3). The combined organic layers are washed with brine, dried over anhydrous Na2SO4 and concentrated under vacuum. Purify the residue by silica gel chromatograph (PE:EtOAc 50:1) to afford 3-[3-(3,5-Dichloro-phenyl)-4,4,4-trifluoro-but-2-enoyl]-4,5,6,7-tetrahydro-benzo[c]thiophene-1-carboxylic acid methyl ester as an orange solid (8.75 g, 100%). (m/z): 463 (M+1).
Reaction SMILES: [Br:1][CH2:2][C:3](Cl)=[O:4].[CH3:6][NH:7][CH2:8][CH2:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1>C(Cl)Cl>[CH3:6][N:7]([CH2:8][CH2:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)[C:3](=[O:4])[CH2:2][Br:1]
Reactant: O=C(Cl)CBr
Reactant: CNCCc1ccccc1
Solvent: ClCCl
Product: CN(CCc1ccccc1)C(=O)CBr
Temperature: -25 °C
Reaction time: 0.25 h

Procedure:
To a solution of 27.07 g (171.95 mmol) of bromoacetyl chloride in 100 ml of methylene chloride, cooled to -25° C. by means of an external cooling bath, is added dropwise a solution of 46.5 g (343.9 mmol) of N-methyl-N-phenethyl amine in 50 ml of methylene chloride over a period of 11/2 hours. The reaction mixture is stirred at -25° C. for additional 15 minutes and then allowed to equilibrate to room temperature. The reaction mixture is then partitioned between methylene chloride and water. The organic layer is washed with 1N aqueous HCl solution and water, dried over magnesium sulfate and concentrated in vacuo to give N-methyl-N-phenethyl-2-bromoacetamide which is used directly in the next step.
Reaction SMILES: C[O:2][C:3]1[CH:16]=[C:15]2[C:6]([N:7]3[C:12]([CH2:13][O:14]2)=[N:11][NH:10][C:9](=[O:17])[CH:8]3[CH3:18])=[CH:5][C:4]=1[N+:19]([O-:21])=[O:20].NC1C=CC(OC)=CC=1O.[Cl-].[Li+]>CN(C=O)C>[OH:2][C:3]1[CH:16]=[C:15]2[C:6]([N:7]3[C:12]([CH2:13][O:14]2)=[N:11][NH:10][C:9](=[O:17])[CH:8]3[CH3:18])=[CH:5][C:4]=1[N+:19]([O-:21])=[O:20]
Reactant: COc1cc2c(cc1[N+](=O)[O-])N1C(=NNC(=O)C1C)CO2
Agent: COc1ccc(N)c(O)c1
Agent: [Cl-]
Agent: [Li+]
Solvent: CN(C)C=O
Product: CC1C(=O)NN=C2COc3cc(O)c([N+](=O)[O-])cc3N21
Temperature: 150 °C
Yield: 68 %

Procedure:
A solution of 7-methoxy-4-methyl-6-nitro-2,10-dihydro-9-oxa-1,2,4a-triaza-phenanthren-3-one (prepared from 2-amino-5-methoxyphenol using the similar procedure detailed in Example #56, Step A-D and Example #106, Step A, 1 g, 3.42 mmol) and lithium chloride (0.44 g, 10.27 mmol) in DMF (10 mL) was heated at 150° C. for 3 h. The reaction mixture was cooled to ambient temperature and the solvent was removed in vacuo. The residue was purified by column chromatography on silica gel (eluting with 50% EtOAc in petroleum ether) to give 7-hydroxy-4-methyl-6-nitro-2,10-dihydro-9-oxa-1,2,4a-triaza-phenanthren-3-one (0.65 g, 68%) as a red solid. TLC (eluting with 50% EtOAc in petroleum ether) Rf=0.5.
Reaction SMILES: CS(C)=O.C(Cl)(=O)C(Cl)=O.[OH:11][CH:12]([C@H:22]1[CH2:27][CH2:26][C@H:25]([C@H:28]2[CH2:33][CH2:32][C@H:31]([CH2:34][CH2:35][CH2:36][CH2:37][CH3:38])[CH2:30][CH2:29]2)[CH2:24][CH2:23]1)[CH2:13][C:14]1[CH:19]=[CH:18][C:17]([F:20])=[C:16]([F:21])[CH:15]=1.C(N(CC)CC)C>C(Cl)Cl.O>[O:11]=[C:12]([C@H:22]1[CH2:27][CH2:26][C@H:25]([C@H:28]2[CH2:33][CH2:32][C@H:31]([CH2:34][CH2:35][CH2:36][CH2:37][CH3:38])[CH2:30][CH2:29]2)[CH2:24][CH2:23]1)[CH2:13][C:14]1[CH:19]=[CH:18][C:17]([F:20])=[C:16]([F:21])[CH:15]=1
Reactant: CCCCC[C@H]1CC[C@H]([C@H]2CC[C@H](C(O)Cc3ccc(F)c(F)c3)CC2)CC1
Agent: O=C(Cl)C(=O)Cl
Solvent: O
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCCCC[C@H]1CC[C@H]([C@H]2CC[C@H](C(=O)Cc3ccc(F)c(F)c3)CC2)CC1
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
2.34 ml (33 mmol) of dimethyl sulfoxide were added at −60° under stirring in an argon atomosphere to a solution of 1.44 ml (16.5 mmol) of oxalyl chloride in 38 ml of methylene chloride and then a solution of 5.89 g (15 mmol) of 1-hydroxy-1-[trans-4-(trans-4-pentylcyclohexyl)cyclohexyl]-2-(3,4-difluorophenyl)ethane in 160 ml of methylene chloride was added over a period of 1 hr. After 15 minutes, 10.45 ml (75 mmol) of triethylamine were added and stirred for 2 hours and 50 minutes, and gradually raised to room temperature. 75 ml of water were added to stop the reaction. An organic layer and an aqueous layer were separated, the aqueous layer was extracted with methylene chloride, an extract combined with the organic layer was dried over anhydrous magnesium sulfate. The solvent was distilled off and the concentrate was purified by column chromatography (elution solvent: toluene:heptane=2:1). Further, the eluate was recrystallized from heptane-solmix and toluene-solmix to obtain 4.83 g of the title compound (82%, Cr 111.9-112.8 Iso).
Reaction SMILES: [CH:1]1([CH2:4][CH2:5][O:6][C:7]2[N:15]=[C:14]3[C:10]([N:11]=[C:12]([O:22]C)[N:13]3[CH2:16][CH:17]3[CH2:21][CH2:20][O:19][CH2:18]3)=[C:9]([NH2:24])[N:8]=2)[CH2:3][CH2:2]1.Cl.O.[OH-].[Na+]>CO.O1CCOCC1>[NH2:24][C:9]1[N:8]=[C:7]([O:6][CH2:5][CH2:4][CH:1]2[CH2:3][CH2:2]2)[N:15]=[C:14]2[C:10]=1[NH:11][C:12](=[O:22])[N:13]2[CH2:16][CH:17]1[CH2:21][CH2:20][O:19][CH2:18]1
Reactant: COc1nc2c(N)nc(OCCC3CC3)nc2n1CC1CCOC1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: C1COCCO1
Solvent: CO
Product: Nc1nc(OCCC2CC2)nc2c1[nH]c(=O)n2CC1CCOC1
Temperature: 25 °C
Reaction time: 4 h
Yield: 77.4 %

Procedure:
To a solution of 2-[(2-cyclopropylethyl)oxy]-8-methoxy-9-(tetrahydro-3-furanylmethyl)-9H-purin-6-amine (103.8 mg) in methanol (5 mL) was added 4N HCl in 1,4-dioxane (2 mL) and the reaction mixture was stirred at room temperature for 4 h. The reaction was evaporated under reduced pressure to give a gum. Water (3 mL) was added to give a white solid. The mixture was adjusted to pH 7 by adding 2N sodium hydroxide solution and the white solid was filtered off under suction, then washed with a few drops of MeOH. The material was air dried under suction, then in a vacuum oven (50° C.) to give the title compound as white solid (77 mg).
Reaction SMILES: [F:1][C:2]([F:19])([F:18])[C:3]1[CH:4]=[CH:5][C:6]2[CH2:7][C@@H:8]3[CH2:17][NH:16][CH2:15][CH2:14][N:9]3[C:10](=[O:13])[C:11]=2[CH:12]=1.C1C(=O)N([Br:27])C(=O)C1>OS(O)(=O)=O>[Br:27][C:5]1[C:6]2[CH2:7][C@@H:8]3[CH2:17][NH:16][CH2:15][CH2:14][N:9]3[C:10](=[O:13])[C:11]=2[CH:12]=[C:3]([C:2]([F:1])([F:18])[F:19])[CH:4]=1
Reactant: O=C1CCC(=O)N1Br
Reactant: O=C1c2cc(C(F)(F)F)ccc2C[C@@H]2CNCCN12
Agent: O=S(=O)(O)O
Product: O=C1c2cc(C(F)(F)F)cc(Br)c2C[C@@H]2CNCCN12
Reaction time: 48 h
Yield: 25.5 %

Procedure:
A solution of (R)-8 trifluoromethyl-1,2,3,4,11,11a-hexahydro-pyrazino[1,2-b]isoquinolin-6-one (245 mg, 0.9 mmol) in H2SO4 (2 mL) was treated with NBS (210 mg, 1.17 mmol) at room temperature. After 48 h, the reaction mixture was quenched with saturated aqueous NaHCO3 and diluted with EtOAc (15 mL). The solution was extracted with EtOAc (50 mL) and the organic layer was dried over Na2SO4, filtered, and concentrated in vacuo to afford a yellow oil. Purification of the oil by flash column chromatography (SiO2, 96:4:1 methylene chloride/methanol/triethylamine) provided (R)-10-bromo-8-trifluoromethyl-1,2,3,4,11,11a-hexahydropyrazino[1,2-b]isoquinolin-6-one (80 mg, 25%) as an off-white solid. MS (ESI) 349 (M+H).
Reaction SMILES: [CH2:1]([O:3][P:4]([CH:9]([P:21](=[O:24])([OH:23])[OH:22])[CH:10]([C:15]1[CH:16]=[N:17][CH:18]=[CH:19][CH:20]=1)[CH2:11][CH2:12][CH2:13]Br)(=[O:8])[O:5][CH2:6][CH3:7])[CH3:2].[C:25]([O-:28])(=[S:27])[CH3:26].[Na+]>CC(C)=O>[CH2:1]([O:3][P:4]([CH:9]([P:21](=[O:24])([OH:23])[OH:22])[CH:10]([C:15]1[CH:16]=[N:17][CH:18]=[CH:19][CH:20]=1)[CH2:11][CH2:12][CH2:13][S:27][C:25](=[O:28])[CH3:26])(=[O:8])[O:5][CH2:6][CH3:7])[CH3:2]
Reactant: CCOP(=O)(OCC)C(C(CCCBr)c1cccnc1)P(=O)(O)O
Reactant: CC([O-])=S
Agent: [Na+]
Solvent: CC(C)=O
Product: CCOP(=O)(OCC)C(C(CCCSC(C)=O)c1cccnc1)P(=O)(O)O
Temperature: 50 °C
Reaction time: 12 h

Procedure:
A solution of [5-bromo-2-(3-pyridinyl)pentylidene]bis [phosphonic acid] diethyl ester (5.0 mmol) is stirred in dry acetone (35 ml) and sodium thioacetate (5.2 mmol) is added. The mixture is stirred at 50° C. for 12 hours. After cooling to room temperature the solvent is removed under reduced pressure. The crude residue is dissolved in methylene chloride and washed with water. The organic layer is then dried and concentrated under reduced pressure. The desired product is purified by flash chromatography using a 5-10% isopropanol in methylene chloride gradient on silica gel.
Reaction SMILES: [C:1]([C:4]1[C:16]2[NH:15][C:14]3[C:9](=[CH:10][CH:11]=[C:12]([C:17]([OH:20])([CH3:19])[CH3:18])[CH:13]=3)[C:8]=2[C:7]([C:21]2[C:22]([CH3:36])=[C:23]([N:27]3[C:31](=[O:32])[CH2:30][CH:29]([C:33]([OH:35])=O)[CH2:28]3)[CH:24]=[CH:25][CH:26]=2)=[CH:6][CH:5]=1)(=[O:3])[NH2:2].[CH3:37][NH:38][CH3:39].C(Cl)CCl.C1C=CC2N(O)N=NC=2C=1>C1COCC1.C(Cl)Cl.CN(C=O)C>[CH3:37][N:38]([CH3:39])[C:33]([CH:29]1[CH2:28][N:27]([C:23]2[C:22]([CH3:36])=[C:21]([C:7]3[C:8]4[C:9]5[C:14](=[CH:13][C:12]([C:17]([OH:20])([CH3:18])[CH3:19])=[CH:11][CH:10]=5)[NH:15][C:16]=4[C:4]([C:1]([NH2:2])=[O:3])=[CH:5][CH:6]=3)[CH:26]=[CH:25][CH:24]=2)[C:31](=[O:32])[CH2:30]1)=[O:35]
Reactant: Cc1c(-c2ccc(C(N)=O)c3[nH]c4cc(C(C)(C)O)ccc4c23)cccc1N1CC(C(=O)O)CC1=O
Reactant: CNC
Agent: On1nnc2ccccc21
Solvent: C1CCOC1
Solvent: CN(C)C=O
Solvent: ClCCl
Product: Cc1c(-c2ccc(C(N)=O)c3[nH]c4cc(C(C)(C)O)ccc4c23)cccc1N1CC(C(=O)N(C)C)CC1=O
Reaction time: 8 h
Yield: 15.5 %

Procedure:
A solution of 1-(3-(1-carbamoyl-7-(2-hydroxypropan-2-yl)-9H-carbazol-4-yl)-2-methylphenyl)-5-oxopyrrolidine-3-carboxylic acid (Intermediate 81-27, 49 mg, 0.101 mmol), dimethylamine (2 M in THF, 0.252 mL, 0.505 mmol), EDC (38.7 mg, 0.202 mmol) and HOBT (30.9 mg, 0.202 mmol) in THF (2 mL) was stirred at rt overnight. Additional dimethylamine (2 M in THF, 0.252 mL, 0.505 mmol), EDC (38.7 mg, 0.202 mmol) and HOBT (30.9 mg, 0.202 mmol) were added along with DMF (0.5 mL) and the mixture was again stirred overnight. The mixture was diluted with DCM, washed with NaHCO3 (aq), dried and concentrated. The residue was purified by preparative HPLC, and the appropriate effluent fractions were made basic with 1 M aqueous sodium hydroxide and extracted twice with DCM. The organic phase was washed with water, dried and concentrated. The residue was purified by column chromatography (eluting with DCM-methanol-ammonia) to provide 4-(3-(4-(dimethylcarbamoyl)-2-oxopyrrolidin-1-yl)-2-methylphenyl)-7-(2-hydroxypropan-2-yl)-9H-carbazole-1-carboxamide as a white solid (8 mg, 15%). 1H NMR (400 MHz, methanol-d4) δ 7.91 (1H, d, J=7.7 Hz), 7.73 (1H, d, J=1.1 Hz), 7.40-7.49 (2H, m), 7.33 (1H, dd, J=6.5, 2.3 Hz), 7.07 (1H, ddd, J=8.5, 1.4, 1.3 Hz), 7.01 (1H, d, J=7.9 Hz), 6.94 (1H, br. s.), 3.84-4.13 (3H, m), 3.13 (3H, 2 s), 2.97 (3H, 2 s), 2.85-2.94 (1H, m), 2.74-2.83 (1H, m), 1.93 (3H, s), 1.57 (6H, 2 s). Mass spectrum m/z 495.1 (M+H—H20)+.
Reaction SMILES: [C:1]([S:5]([NH2:7])=[O:6])([CH3:4])([CH3:3])[CH3:2].[Cl:8][C:9]1[CH2:10][CH:11]2[C:32](=O)[CH:14]([CH2:15][C:16]=1/[CH:17]=[CH:18]/[C:19]1[CH:23]=[C:22]([C:24]3[CH:29]=[CH:28][C:27]([F:30])=[CH:26][CH:25]=3)[N:21]([CH3:31])[N:20]=1)[CH2:13][CH2:12]2.C(OCC)(=O)C>C1COCC1.[Cl-].[Na+].O.[O-]CC.[Ti+4].[O-]CC.[O-]CC.[O-]CC>[Cl:8][C:9]1[CH2:10][CH:11]2[CH2:12][CH2:13][CH:14](/[C:32]/2=[N:7]/[S:5]([C:1]([CH3:4])([CH3:3])[CH3:2])=[O:6])[CH2:15][C:16]=1/[CH:17]=[CH:18]/[C:19]1[CH:23]=[C:22]([C:24]2[CH:29]=[CH:28][C:27]([F:30])=[CH:26][CH:25]=2)[N:21]([CH3:31])[N:20]=1
Reactant: Cn1nc(/C=C/C2=C(Cl)CC3CCC(C2)C3=O)cc1-c1ccc(F)cc1
Reactant: CC(C)(C)S(N)=O
Agent: [Ti+4]
Agent: CC[O-]
Agent: [Cl-]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Solvent: O
Product: Cn1nc(/C=C/C2=C(Cl)CC3CCC(C2)/C3=N/S(=O)C(C)(C)C)cc1-c1ccc(F)cc1
Yield: 99.5 %

Procedure:
tert-Butylsulphinamide (3.0, 24 mmol) followed by titanium (IV) ethoxide (4.6 ml, 36 mmol) was added to a stirring solution of the product of Step 3 (4.56 g, 11 mmol) in dry THF (10 ml) and the resulting solution was heated to reflux for 18 hrs. The reaction was poured into a stirring solution of brine (200 ml) and then ethyl acetate (100 ml) was added and the mixture filtered through celite. The filtrate was partitioned and the aqueous layer was further extracted with ethyl acetate (2×50 ml). The combined organic extract was washed with brine, dried over MgSO4 and concentrated in vacuo, to afford N((9Z)-3-chloro-4-{(E)-2-[5-(4-fluorophenyl)-1-methyl-1H-pyrazol-3-yl]vinyl}bicyclo[4.2.1]non-3-en-9-ylidene)-2-methylpropane-2-sulfinamide (5.19 g, 99%). m/z (ES+) 474 (MH)+. Compound taken directly onto next Step.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:12]([CH:13]([CH:16]3[CH2:21][CH2:20][CH2:19][CH2:18][CH2:17]3)[CH2:14][OH:15])[C:11]3[CH:22]=[CH:23][CH:24]=[CH:25][C:10]=3[N:9]=2)=[CH:4][CH:3]=1.[CH3:26][O:27][C:28](=[O:37])[C:29]1[CH:34]=[CH:33][CH:32]=[C:31]([F:35])[C:30]=1O.N(C(OC(C)(C)C)=O)=NC(OC(C)(C)C)=O>>[CH3:26][O:27][C:28](=[O:37])[C:29]1[CH:34]=[CH:33][C:32]([O:15][CH2:14][CH:13]([N:12]2[C:11]3[CH:22]=[CH:23][CH:24]=[CH:25][C:10]=3[N:9]=[C:8]2[C:5]2[CH:6]=[CH:7][C:2]([Cl:1])=[CH:3][CH:4]=2)[CH:16]2[CH2:21][CH2:20][CH2:19][CH2:18][CH2:17]2)=[C:31]([F:35])[CH:30]=1
Reactant: COC(=O)c1cccc(F)c1O
Reactant: OCC(C1CCCCC1)n1c(-c2ccc(Cl)cc2)nc2ccccc21
Agent: CC(C)(C)OC(=O)N=NC(=O)OC(C)(C)C
Product: COC(=O)c1ccc(OCC(C2CCCCC2)n2c(-c3ccc(Cl)cc3)nc3ccccc32)c(F)c1

Procedure:
The title compound was prepared in analogy to Example 4, intermediate, from 2-[2-(4-chloro-phenyl)-benzoimidazol-1-yl]-2-cyclohexyl-ethanol and 3-fluoro-hydroxy-benzoic acid methyl ester (commercially available) and replacing di-ethyl azodicarboxylate by di-tert-butyl azodicarboxylate. White solid (91%). MS (Turbo Spray): m/z=507.3 [M+H].
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][CH:10]=1)[C:5]([NH2:7])=[O:6].C(=O)([O-])[O-].[K+].[K+].[CH2:17](Br)[CH:18]=[CH2:19].CO>C(#N)C.C(Cl)Cl>[CH2:19]([O:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][CH:10]=1)[C:5]([NH2:7])=[O:6])[CH:18]=[CH2:17]
Reactant: C=CCBr
Reactant: NC(=O)c1cccc(O)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CO
Solvent: CC#N
Solvent: ClCCl
Product: C=CCOc1cccc(C(N)=O)c1

Procedure:
To 3-hydroxybenzamide (274 mg; 2.0 mM) under a nitrogen atmosphere was added potassium carbonate (276 mg; 21.0 mM). This was dissolved in acetonitrile (20 ml) containing allyl bromide (169 ul; 2.0 mM). The mixture was refluxed for 5 hours, and the reaction followed by T.L.C.: 10% MeOH: 90% CH2Cl2. The excess solvent was then removed under vacuum, the organics extracted into dichloromethane, dried, and the solvent removed, to yield a white solid. This was recrystallised from hot water to produce a white "needle" solid (63%) as the final product.
Reaction SMILES: [O:1]1[C:5]2([CH2:10][CH2:9][C:8]([C:11]3[CH:20]=[CH:19][C:14]([C:15]([O:17][CH3:18])=[O:16])=[C:13]([CH3:21])[CH:12]=3)=[CH:7][CH2:6]2)[O:4][CH2:3][CH2:2]1.[H][H]>CCOC(C)=O.[Pt](=O)=O>[O:1]1[C:5]2([CH2:10][CH2:9][CH:8]([C:11]3[CH:20]=[CH:19][C:14]([C:15]([O:17][CH3:18])=[O:16])=[C:13]([CH3:21])[CH:12]=3)[CH2:7][CH2:6]2)[O:4][CH2:3][CH2:2]1
Reactant: COC(=O)c1ccc(C2=CCC3(CC2)OCCO3)cc1C
Reactant: [H][H]
Agent: O=[Pt]=O
Solvent: CCOC(C)=O
Product: COC(=O)c1ccc(C2CCC3(CC2)OCCO3)cc1C
Reaction time: 0.75 h

Procedure:
To a degassed solution of the title compound from Example 13 Step B (606 mg, 2.10 mmol) in EtOAc (15 mL) was added platinum(IV) oxide (150 mg). The reaction mixture was fitted with a 3-way adapter with a hydrogen balloon attached. The reaction flask was then evacuated and back-filled with hydrogen. After this process was repeated three times, the reaction mixture was placed under a hydrogen atmosphere, then was stirred vigorously. After 45 min, the reaction mixture was filtered through Celite, rinsing with EtOAc. The mixture was then concentrated in vacuo to provide the title compound, which was used without further purification: LCMS m/z 259.4 [M−CH3O]+.