Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[CH:15]=[CH:14][C:5]([C:6]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)=[O:7])=[CH:4][CH:3]=1.[C:16](Cl)(=[O:24])[O:17][C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1.O>N1C=CC=CC=1>[C:6]([C:5]1[CH:4]=[CH:3][C:2]([NH:1][C:16](=[O:24])[O:17][C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)=[CH:15][CH:14]=1)(=[O:7])[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1
Reactant: O=C(Cl)Oc1ccccc1
Reactant: Nc1ccc(C(=O)c2ccccc2)cc1
Solvent: O
Solvent: c1ccncc1
Product: O=C(Nc1ccc(C(=O)c2ccccc2)cc1)Oc1ccccc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 110.8 %

Procedure:
To 4-aminobenzophenone (1.97 g) dissolved in pyridine (50 mL), phenyl chlorocarbonate (1.38 g) was added at 0° C. and the mixture was stirred at room temperature for 1 hour. The reaction mixture was poured into water and extracted with ethyl acetate. The organic layer was dried over anhydrous Na2SO4 and evaporated. The residue was purified by column chromatography on silica gel (hexane/ethyl acetate=4/1 to 1/2) to give the subject compound (3.1 g).
Reaction SMILES: Br.Br.C([O:5][C:6]([C@@H:8]([NH:19][C@H:20]([C:22]([N:24]([CH:29]1[CH2:37][C:36]2[C:31](=[CH:32][CH:33]=[CH:34][CH:35]=2)[CH2:30]1)[CH2:25][C:26]([OH:28])=[O:27])=[O:23])[CH3:21])[CH2:9][CH2:10][CH2:11][CH2:12][CH:13]1[CH2:18][CH2:17][NH:16][CH2:15][CH2:14]1)=[O:7])C.C(O)(=O)C>[OH-].[Na+]>[C:6]([C@@H:8]([NH:19][C@H:20]([C:22]([N:24]([CH:29]1[CH2:30][C:31]2[C:36](=[CH:35][CH:34]=[CH:33][CH:32]=2)[CH2:37]1)[CH2:25][C:26]([OH:28])=[O:27])=[O:23])[CH3:21])[CH2:9][CH2:10][CH2:11][CH2:12][CH:13]1[CH2:18][CH2:17][NH:16][CH2:15][CH2:14]1)([OH:7])=[O:5]
Reactant: CCOC(=O)[C@H](CCCCC1CCNCC1)N[C@@H](C)C(=O)N(CC(=O)O)C1Cc2ccccc2C1
Agent: Br
Agent: [Na+]
Agent: [OH-]
Solvent: CC(=O)O
Product: C[C@H](N[C@@H](CCCCC1CCNCC1)C(=O)O)C(=O)N(CC(=O)O)C1Cc2ccccc2C1
Reaction time: 0.5 h
Yield: 62.2 %

Procedure:
In 6 ml of 1N aqueous sodium hydroxide is dissolved 0.25 g of N-[N-[(S)-1-ethoxycarbonyl-5-(4-piperidyl)-pentyl]-L-alanyl]-N-(indan-2-yl)glycine.dihydrobromide, and the solution is allowed to stand at room temperature for 30 minutes. The reaction solution is made weakly acidic with acetic acid and purified by column chromatography on Amberlite XAD-2 (0.1M aqueous ammonia-5% acetonitrile). The effluent is concentrated under reduced pressure and lyophilized to give 0.11 g of N-[N-[(S)-1-carboxy-5-(4-piperidyl)pentyl]-L-alanyl]-N-(indan-2-yl)glycine as a colorless powder.
Reaction SMILES: O[CH2:2][CH2:3][CH2:4][NH:5][C:6](=[O:12])[O:7][C:8]([CH3:11])([CH3:10])[CH3:9].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C(Br)(Br)(Br)[Br:33]>ClCCl>[Br:33][CH2:2][CH2:3][CH2:4][NH:5][C:6](=[O:12])[O:7][C:8]([CH3:11])([CH3:10])[CH3:9]
Reactant: BrC(Br)(Br)Br
Reactant: CC(C)(C)OC(=O)NCCCO
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Product: CC(C)(C)OC(=O)NCCCBr
Temperature: 25 °C
Reaction time: 18 h
Yield: 66.1 %

Procedure:
To a solution of tert-butyl 3-hydroxypropylcarbamate (5 g, 28.57 mmol) in dichloromethane (200 mL) was added triphenylphosphine (11.52 g, 42.85 mmol) followed by carbon tetrabromide (14.22 g, 42.85 mmol) at 0° C. The reaction mixture was stirred at rt for 18 h while monitoring by TLC. The solvent was removed under reduced pressure and the residue was purified by column chromatography (60-120 mesh silica gel) using 5-10% ethyl acetate in pet-ether to give tert-butyl 3-bromopropylcarbamate (4.5 g, 66.46%) as a light-brown liquid. 1H NMR (400 MHz, CDCl3) δ ppm 4.63 (1H, s), 3.45-3.42 (2H, t, J=6.4 Hz), 3.29-3.24 (2H, q, J=6.4 Hz), 2.08-2.01 (2H, m), 1.44 (9H, s).
Reaction SMILES: [CH3:1][N:2]([CH3:14])[C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[C:9](=[O:13])[NH:8][CH:7]=[CH:6]2.[Br:15][C:16]1[CH:26]=[CH:25][CH:24]=[C:23](Br)[C:17]=1[CH2:18][O:19][C:20](=[O:22])[CH3:21].C(=O)([O-])[O-].[K+].[K+]>CS(C)=O>[Br:15][C:16]1[CH:26]=[CH:25][CH:24]=[C:23]([N:8]2[CH:7]=[CH:6][C:5]3[C:10](=[CH:11][CH:12]=[C:3]([N:2]([CH3:14])[CH3:1])[CH:4]=3)[C:9]2=[O:13])[C:17]=1[CH2:18][O:19][C:20](=[O:22])[CH3:21]
Reactant: CN(C)c1ccc2c(=O)[nH]ccc2c1
Reactant: CC(=O)OCc1c(Br)cccc1Br
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CS(C)=O
Product: CC(=O)OCc1c(Br)cccc1-n1ccc2cc(N(C)C)ccc2c1=O
Temperature: 150 °C
Yield: 44.4 %

Procedure:
6-Dimethylamino-2H-isoquinolin-1-one (50 mg, 0.27 mmol), Acetic acid 2,6-dibromo-benzyl ester (164 mg, 532 mmol), cuprous iodide (10 mg, 0.053 mmol), and potassium carbonate (37 mg, 0.27 mmol) were deposited in sealed vessel. 3 mL DMSO was added. Argon was bubbled through the mixture for 2 minutes and the lid was tightly closed. This was heated at 150° C. for 5 hours. The resulting mixture was partitioned between ethyl acetate and water. The organic layer was washed with brine, dried over anhydrous magnesium sulfate, concentrated in vacuo, and purified by flash chromatography (gradient elution 30 to 40% ethylacetate/hexanes) to yield Acetic acid 2-bromo-6-(6-dimethylamino-1-oxo-1H-isoquinolin-2-yl)-benzyl ester (48 mg, 0.12 mmol). MS (ESI) 417.0 (M+H)+.
Reaction SMILES: [C:1]([O:5][C:6](=[O:24])[CH2:7][N:8]([CH2:17][C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][N:19]=1)[CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][C:14]([OH:16])=O)([CH3:4])([CH3:3])[CH3:2].[S:25]([NH2:35])(=[O:34])([C:27]1[CH:32]=[CH:31][C:30]([NH2:33])=[CH:29][CH:28]=1)=[O:26].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>CN(C=O)C.CCN(CC)CC>[O:16]=[C:14]([NH:33][C:30]1[CH:31]=[CH:32][C:27]([S:25](=[O:34])(=[O:26])[NH2:35])=[CH:28][CH:29]=1)[CH2:13][CH2:12][CH2:11][CH2:10][CH2:9][N:8]([CH2:17][C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][N:19]=1)[CH2:7][C:6]([O:5][C:1]([CH3:2])([CH3:3])[CH3:4])=[O:24]
Reactant: Nc1ccc(S(N)(=O)=O)cc1
Reactant: CC(C)(C)OC(=O)CN(CCCCCC(=O)O)Cc1ccccn1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)CN(CCCCCC(=O)Nc1ccc(S(N)(=O)=O)cc1)Cc1ccccn1
Yield: 31 %

Procedure:
A solution of 6-((2-tert-butoxy-2-oxoethyl)(pyridin-2-ylmethyl)amino)hexanoic acid (0.6545 g, 1.95 mmol), sulfanilamide (0.362 g, 2.10 mmol) and HATU (0.798 g, 2.10 mmol) in DMF (10 mL) and Et3N (1.0 mL) was stirred at 40° C. overnight. The reaction mixture was purified by flash chromatography over silica gel eluting with MeOH/DCM to give tert-butyl 2-((6-oxo-6-(4-sulfamoylphenylamino)hexyl)(pyridin-2-ylmethyl)amino)acetate (297 mg, 31%). ESMS m/z: 491.3 (M+H)+.
Reaction SMILES: Cl[C:2]1[C:3](=[O:16])[NH:4][C:5]2[C:10]([N:11]=1)=[CH:9][C:8]([C:12]([O:14][CH3:15])=[O:13])=[CH:7][CH:6]=2.[Cl:17][C:18]1[CH:19]=[C:20]2[C:25](=[CH:26][CH:27]=1)[NH:24][CH2:23][CH2:22][CH2:21]2>CN1C(=O)CCC1>[Cl:17][C:18]1[CH:19]=[C:20]2[C:25](=[CH:26][CH:27]=1)[N:24]([C:2]1[C:3](=[O:16])[NH:4][C:5]3[C:10]([N:11]=1)=[CH:9][C:8]([C:12]([O:14][CH3:15])=[O:13])=[CH:7][CH:6]=3)[CH2:23][CH2:22][CH2:21]2
Reactant: Clc1ccc2c(c1)CCCN2
Reactant: COC(=O)c1ccc2[nH]c(=O)c(Cl)nc2c1
Solvent: CN1CCCC1=O
Product: COC(=O)c1ccc2[nH]c(=O)c(N3CCCc4cc(Cl)ccc43)nc2c1
Temperature: 150 °C
Reaction time: 1 h

Procedure:
To a solution of methyl 3-chloro-2-oxo-1,2-dihydroquinoxaline-6-carboxylate (1.0 g, 4.19 mmol) in NMP (10.0 ml) was added 6-chloro-1,2,3,4-tetrahydroquinoline (1.20 g, 7.16 mmol) and the reaction was stirred for 1 h at 150° C. in an oil bath. The reaction mixture was cooled down to room temperature, precipitated with water (100 ml). The solids were collected by filtration and dried in an oven under reduced pressure to afford methyl 3-(6-chloro-1,2,3,4-tetrahydroquinolin-1-yl)-2-oxo-1,2-dihydroquinoxaline-6-carboxylate as a gray solid (1.0 g, crude).
Reaction SMILES: [CH3:1][N:2]1[C:6]([C:7]2[CH:8]=[C:9]([NH2:23])[CH:10]=[CH:11][C:12]=2[O:13][CH2:14][CH2:15][CH2:16][N:17]2[CH2:22][CH2:21][O:20][CH2:19][CH2:18]2)=[CH:5][CH:4]=[N:3]1.[Cl:24][C:25]1[CH:34]=[CH:33][C:28]([CH2:29][N:30]=[C:31]=[O:32])=[CH:27][CH:26]=1>C(Cl)Cl>[Cl:24][C:25]1[CH:26]=[CH:27][C:28]([CH2:29][NH:30][C:31]([NH:23][C:9]2[CH:10]=[CH:11][C:12]([O:13][CH2:14][CH2:15][CH2:16][N:17]3[CH2:22][CH2:21][O:20][CH2:19][CH2:18]3)=[C:7]([C:6]3[N:2]([CH3:1])[N:3]=[CH:4][CH:5]=3)[CH:8]=2)=[O:32])=[CH:33][CH:34]=1
Reactant: O=C=NCc1ccc(Cl)cc1
Reactant: Cn1nccc1-c1cc(N)ccc1OCCCN1CCOCC1
Solvent: ClCCl
Product: Cn1nccc1-c1cc(NC(=O)NCc2ccc(Cl)cc2)ccc1OCCCN1CCOCC1
Reaction time: 1 h
Yield: 96.8 %

Procedure:
A solution of 3-(1-methyl-1H-pyrazol-5-yl)-4-(3-morpholinopropoxy)benzenamine (0.025 g, 0.079 mmol) in CH2Cl2 (0.6 mL) was treated with 4-chlorobenzyl isocyanate (0.012 mL, 0.083 mmol). The reaction was stirred for 1 h, and concentrated and purified by RP-HPLC. Lyophilization afforded a TFA salt as a white solid (0.037 g, 78%). LCMS m/z (%)=484 (M+H35Cl, 100), 486 (M+H37Cl, 38). 1H NMR (400 MHz, DMSO-d6) δ: 9.60 (s, 1H), 8.63 (s, 1H), 7.46 (d, J=1.8 Hz, 1H), 7.43 (dd, J=2.6, 8.9 Hz, 1H), 7.40-7.29 (m, 4H), 7.07 (d, J=9.0 Hz, 1H), 6.75-6.70 (m, 1H), 6.25 (d, J=1.8 Hz, 1H), 4.26 (d, J=5.8 Hz, 2H), 4.02-3.90 (m, 4H), 3.65 (s, 3H), 3.58 (t, J=12.0 Hz, 2H), 3.34 (d, J=12.4 Hz, 2H), 3.09-2.92 (m, 4H), 2.06-1.97 (m, 2H).
Reaction SMILES: O.[NH2:2][NH2:3].[CH3:4][O:5][C:6](=[O:27])[CH2:7][C@H:8]1[CH2:13][CH2:12][C@H:11]([C:14]2[CH:19]=[CH:18][C:17]([NH:20][C:21](=[O:26])[C:22](OC)=[O:23])=[CH:16][CH:15]=2)[CH2:10][CH2:9]1>CCO>[NH:2]([C:22](=[O:23])[C:21]([NH:20][C:17]1[CH:18]=[CH:19][C:14]([C@H:11]2[CH2:12][CH2:13][C@H:8]([CH2:7][C:6]([O:5][CH3:4])=[O:27])[CH2:9][CH2:10]2)=[CH:15][CH:16]=1)=[O:26])[NH2:3]
Reactant: NN
Reactant: COC(=O)C[C@H]1CC[C@H](c2ccc(NC(=O)C(=O)OC)cc2)CC1
Solvent: CCO
Solvent: O
Product: COC(=O)C[C@H]1CC[C@H](c2ccc(NC(=O)C(=O)NN)cc2)CC1
Reaction time: 1 h

Procedure:
Hydrazine hydrate (0.361 mL) was added to a stirred solution of methyl ({4-[trans-4-(2-methoxy-2-oxoethyl)cyclohexyl]phenyl}amino)(oxo)acetate (2260 mg) in EtOH (50 mL). The mixture was stirred for 1 hour. The precipitate was filtered off, washed with Et2O, and dried under vacuum overnight to give the title compound (Intermediate 43, 1845 mg) as a solid; 1H NMR δ 10.44 (1H, s), 10.20 (1H, s), 7.70 (2H, d), 7.21 (2H, d), 4.60 (2H, s), 3.60 (3H, s), 2.42 (1H, m), 1.79 (5H, m), 1.45 (2H, m), 1.11 (2H, m); MS m/e MH+ 334.
Reaction SMILES: C(O[C@@H:5]1[C@H:10]2[C@H:11]3[C@H:21]([CH2:22][CH2:23][C@:8]2([CH3:9])[C:7](=[O:26])[CH2:6]1)[C@:19]1([CH3:20])[C:14]([CH:15]=[C:16]([O:24][CH3:25])[CH2:17][CH2:18]1)=[CH:13][CH2:12]3)(=O)C.[I-].[CH3:28][S+](C)(C)=O.[OH-].[K+]>O>[CH2:28]1[C@@H:6]2[C:7](=[O:26])[C@:8]3([CH2:23][CH2:22][C@H:21]4[C@@H:11]([CH2:12][CH:13]=[C:14]5[C@:19]4([CH3:20])[CH2:18][CH2:17][C:16]([O:24][CH3:25])=[CH:15]5)[C@@H:10]3[C@H:5]12)[CH3:9]
Reactant: C[S+](C)(C)=O
Reactant: COC1=CC2=CC[C@H]3[C@@H]4[C@@H](OC(C)=O)CC(=O)[C@@]4(C)CC[C@@H]3[C@@]2(C)CC1
Agent: [I-]
Agent: [K+]
Agent: [OH-]
Solvent: O
Product: COC1=CC2=CC[C@H]3[C@@H]4[C@@H]5C[C@@H]5C(=O)[C@@]4(C)CC[C@@H]3[C@@]2(C)CC1
Reaction time: 6 h

Procedure:
The 15α-acetoxy-3-methoxy-androsta-3,5-diene-17-one of the general formula (V) is treated with a reagent prepared in situ from trimethylsulfoxonium iodide and potassium hydroxide in a solvent, the reaction mixture is stirred for 6 hours then added to water. The precipitate is filtered off, washed to remove the mother liquor and dried. Finally the 15β,16β-methylene-3-methoxy-androsta-3,5-diene-17-one obtained (a compound of the general formula (VII)) is crystallized from methanol.
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]2[C:6]3[N:15]([NH:16][CH:17]([CH3:19])[CH3:18])[C:14]([CH2:20][CH2:21][CH3:22])=[N:13][C:7]=3[C:8]([NH2:12])=[N:9][C:10]=2[CH:11]=1.[CH2:23](N(CC)CC)[CH3:24]>C(O)CC.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2]>[CH:17]([NH:16][N:15]1[C:6]2[C:5]3[CH:4]=[CH:3][C:2]([CH:23]=[CH2:24])=[CH:11][C:10]=3[N:9]=[C:8]([NH2:12])[C:7]=2[N:13]=[C:14]1[CH2:20][CH2:21][CH3:22])([CH3:19])[CH3:18]
Reactant: CCN(CC)CC
Reactant: CCCc1nc2c(N)nc3cc(Br)ccc3c2n1NC(C)C
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: c1ccc(P(c2ccccc2)[c-]2cccc2)cc1
Solvent: CCCO
Product: C=Cc1ccc2c(c1)nc(N)c1nc(CCC)n(NC(C)C)c12
Temperature: 100 °C
Reaction time: 16 h
Yield: 63 %

Procedure:
A suspension of 7-bromo-N1-isopropyl-2-propyl-1H-imidazo[4,5-c]quinoline-1,4-diamine (1.71 g, 4.72 mmol) in 34 mL of 1-propanol was placed under an atmosphere of nitrogen. The mixture was treated with triethylamine (1.25 mL, 9.44 mmol) and then the headspace of the flask was evacuated and back-filled with nitrogen (3×). The reaction mixture was treated with potassium vinylfluoroborate (0.695 g, 5.19 mmol) and dichloro[1,1′-bis(diphenylphosphino)ferrocene]palladium (II) dichloromethane adduct (0.069 g, 0.094 mmol) and the head-space purged and backfilled as before. The reaction was heated to 100° C. After 16 h, the reaction mixture was cooled to ambient temperature and concentrated under reduced pressure. The residue was dissolved in 50 mL of CHCl3 and washed with 5% Na2CO3 solution (15 mL). There was a thick emulsion that did not fully separate. The organic portion was washed with H2O (15 mL) resulting in another slowly separating emulsion. The combined aqueous washes were back extracted with CHCl3 (15 mL). The combined organic extracts were washed with brine (15 mL), dried over Na2SO4, filtered and concentrated under reduced pressure to yield an orange solid. The solid was purified by chromatography (SiO2, 20% (80:18:2 CHCl3:MeOH:NH4OH) in CHCl3) to yield N1-isopropyl-2-propyl-7-vinyl-1H-imidazo[4,5-c]quinoline-1,4-diamine (0.92 g) as a tan solid.
Reaction SMILES: [Br:1][C:2]1[C:3]([CH3:28])=[C:4]([C:15]([NH:18][S:19]([C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][N:23]=2)(=[O:21])=[O:20])=[CH:16][CH:17]=1)[C:5]([O:7]CC1C=CC=CC=1)=[O:6]>CO.[Pd]>[Br:1][C:2]1[C:3]([CH3:28])=[C:4]([C:15]([NH:18][S:19]([C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][N:23]=2)(=[O:21])=[O:20])=[CH:16][CH:17]=1)[C:5]([OH:7])=[O:6]
Reactant: Cc1c(Br)ccc(NS(=O)(=O)c2ccccn2)c1C(=O)OCc1ccccc1
Agent: [Pd]
Solvent: CO
Product: Cc1c(Br)ccc(NS(=O)(=O)c2ccccn2)c1C(=O)O
Reaction time: 1 h
Yield: 5.5 %

Procedure:
A solution of Example 110A (150 mg, 0.32 mmol) in methanol (8 mL) was treated with 5% Pd/C (100 mg), stirred under a hydrogen atmosphere for 1 hour, and filtered through diatomaceous earth (Celite®). The filtrate was concentrated and purified by reverse-phase HPLC to provide the desired product (6.5 mg, 6.4%). 1H NMR (DMSO-d6) δ 2.31 (s, 3H), 6.99 (d, 1H), 7.58 (d, 1H), 7.69 (d, 1H), 7.88 (dd, 1H), 8.06 (dd, 1H), 8.72 (d, 1H), 10.08 (br s, 1H), 13.58 (br s, 1H); MS (ESI(−)) m/e 371 (M−H)−.
Reaction SMILES: [N:1]1([C:7](=[NH:9])[NH2:8])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[C:10]([CH:18]([CH:24]([CH2:30][CH2:31][CH3:32])[C:25]([O:27]CC)=[O:26])[C:19](OCC)=[O:20])(=O)[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1.C[O-].[Na+]>CO>[O:20]=[C:19]1[NH:8][C:7]([N:1]2[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]2)=[N:9][C:10]([C:11]2[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=2)=[C:18]1[CH:24]([CH2:30][CH2:31][CH3:32])[C:25]([OH:27])=[O:26]
Reactant: N=C(N)N1CCCCC1
Reactant: CCCC(C(=O)OCC)C(C(=O)OCC)C(=O)c1ccccc1
Agent: C[O-]
Agent: [Na+]
Solvent: CO
Product: CCCC(C(=O)O)c1c(-c2ccccc2)nc(N2CCCCC2)[nH]c1=O

Procedure:
To a solution of piperidine-1-carboximidamide (dimer complexated with H2SO4) (0.6 g; 4.71 mmol) and diethyl 2-benzoyl-3-propylsuccinate (1.51 g; 4.71 mmol) in methanol (5 mL) was slowly added a solution of sodium methoxide in methanol (25% w:w) (2.16 mL; 9.43 mmol) and the reaction was heated to reflux for 21 h. The volatiles were removed under reduced pressure and the crude residue was used as such in the next reaction.
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6]([C:11]([N:13]3[CH2:18][CH2:17][N:16]([C:19]4[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=4[O:25][CH3:26])[CH2:15][CH2:14]3)=[O:12])=[CH:7][NH:8]2)=[CH:4][CH:3]=1.Br[CH2:28][C:29]([OH:31])=[O:30]>>[Cl:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6]([C:11]([N:13]3[CH2:18][CH2:17][N:16]([C:19]4[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=4[O:25][CH3:26])[CH2:15][CH2:14]3)=[O:12])=[CH:7][N:8]2[CH2:28][C:29]([OH:31])=[O:30])=[CH:4][CH:3]=1
Reactant: O=C(O)CBr
Reactant: COc1ccccc1N1CCN(C(=O)c2c[nH]c3cc(Cl)ccc23)CC1
Product: COc1ccccc1N1CCN(C(=O)c2cn(CC(=O)O)c3cc(Cl)ccc23)CC1

Procedure:
Following general procedure II, the alkylation of (6-chloro-1H-indol-3-yl)-[4-(2-methoxy-phenyl)-piperazin-1-yl]-methanone (preparation described herein), with (commercially available) bromo-acetic acid gave the title compound.
Reaction SMILES: C(Cl)Cl.[CH3:4][O:5][C:6]1[CH:11]=[CH:10][C:9]([N:12]2[CH2:15][C:14](=C)[C:13]2=[O:17])=[CH:8][CH:7]=1.[O:18]=[O+][O-]>C(O)(C)C>[CH3:4][O:5][C:6]1[CH:11]=[CH:10][C:9]([N:12]2[CH2:15][C:14](=[O:18])[C:13]2=[O:17])=[CH:8][CH:7]=1
Reactant: C=C1CN(c2ccc(OC)cc2)C1=O
Reactant: O=[O+][O-]
Solvent: CC(C)O
Solvent: ClCCl
Product: COc1ccc(N2CC(=O)C2=O)cc1
Temperature: 25 °C

Procedure:
A 100 ml quantity of methylene chloride and 7.5 ml of isopropyl alcohol were added to 20 g of 1-(4-methoxyphenyl)3-methylene azetidine-2-one 9 and dissolved with stirring. The reaction mixture was cooled to -15° C. after which an ozone gas was introduced over a period of 30 minutes. The excess ozone gas was removed using nitrogen gas and 3 ml of thiodiethanol and 6 g of thiodicresol were added, while being warmed to room temperature and then stirred for 1 hour. The reaction mixture was filtered to remove the precipitated thiodiethanolsulfoxide and washed once with 5% aqueous sodium bicarbonate and twice with 50 ml of water, dried over anhydrous magnesium sulfate and concentrated under reduced pressure, giving 14 g of the title compound 10. The 1H-NMR spectrum of the compound was the same as that of an authentic sample. ##STR5##
Reaction SMILES: [CH:1](=[C:8]1[CH2:16][C:15]2[C:10](=[CH:11][C:12]([O:17][CH3:18])=[CH:13][CH:14]=2)[C:9]1=[O:19])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[H][H]>C(O)C.[C].[Pd]>[CH2:1]([CH:8]1[CH2:16][C:15]2[C:10](=[CH:11][C:12]([O:17][CH3:18])=[CH:13][CH:14]=2)[C:9]1=[O:19])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: [H][H]
Reactant: COc1ccc2c(c1)C(=O)C(=Cc1ccccc1)C2
Agent: [Pd]
Solvent: CCO
Product: COc1ccc2c(c1)C(=O)C(Cc1ccccc1)C2
Yield: 91.3 %

Procedure:
To a solution of 2-benzylidene-6-methoxy-1-indanone (12.25 g, 48.9 mmol) in ethanol (500 ml) was added 10% hydrous palladium-carbon (1.5 g) and catalytic reduction was carried out in a hydrogen stream at atmospheric temperature and pressure. The palladium-carbon was then filtered off and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate-hexane=2:8) to provide the title compound (yield 11.26 g, 92%; oil).
Reaction SMILES: [CH3:1][C:2]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([C:14]2[CH:19]=[CH:18][C:17]([N:20]3[CH2:24][C@H:23]([CH2:25][OH:26])[O:22][C:21]3=[O:27])=[CH:16][C:15]=2[F:28])[CH2:10][CH2:9]1)=[O:7])([CH3:4])[CH3:3].C(N(CC)CC)C.[CH3:36][S:37](Cl)(=[O:39])=[O:38]>C(Cl)Cl>[CH3:4][C:2]([O:5][C:6]([N:8]1[CH2:9][CH2:10][CH:11]([C:14]2[CH:19]=[CH:18][C:17]([N:20]3[CH2:24][C@H:23]([CH2:25][O:26][S:37]([CH3:36])(=[O:39])=[O:38])[O:22][C:21]3=[O:27])=[CH:16][C:15]=2[F:28])[CH2:12][CH2:13]1)=[O:7])([CH3:1])[CH3:3]
Reactant: CC(C)(C)OC(=O)N1CCC(c2ccc(N3C[C@H](CO)OC3=O)cc2F)CC1
Reactant: CS(=O)(=O)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N1CCC(c2ccc(N3C[C@H](COS(C)(=O)=O)OC3=O)cc2F)CC1
Temperature: 0 °C
Reaction time: 1 h

Procedure:
A solution of (R)-(-)-4-[4-[5-hydroxymethyl)-2-oxo-3-oxazolidinyl]-2-fluorophenyl]-1-piperidinecarboxylic acid 1,1-dimethylethyl ester (EXAMPLE 20, Step 5, 970 mg) and triethylamine (0.50 mL) in dry methylene chloride (9.5 mL) at 0° C. under N2 is treated with methanesulfonyl chloride (0.20 mL) dropwise. The resulting mixture is stirred at 0° C. for one hour, diluted with methylene chloride (40 mL), washed with water (10 mL), saturated aqueous sodium bicarbonate (10 mL) and saline (10 mL), dried over anhydrous sodium sulfate and concentrated under reduced pressure to give the title compound, mp 163-165° C.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:12]([C:13]3[CH:18]=[CH:17][C:16]([O:19][CH3:20])=[CH:15][CH:14]=3)[N:11]=[C:10]([CH2:21]O)[CH:9]=2)=[CH:4][CH:3]=1.P(Br)(Br)[Br:24]>C1C=CC=CC=1>[Br:24][CH2:21][C:10]1[CH:9]=[C:8]([C:5]2[CH:6]=[CH:7][C:2]([Cl:1])=[CH:3][CH:4]=2)[N:12]([C:13]2[CH:18]=[CH:17][C:16]([O:19][CH3:20])=[CH:15][CH:14]=2)[N:11]=1
Reactant: BrP(Br)Br
Reactant: COc1ccc(-n2nc(CO)cc2-c2ccc(Cl)cc2)cc1
Solvent: c1ccccc1
Product: COc1ccc(-n2nc(CBr)cc2-c2ccc(Cl)cc2)cc1
Temperature: 0 °C

Procedure:
To a solution of compound 3 (3.14 g, 10 mM) in benzene (100 ml) was added PBr3 (1.35 g, 5 mM) in benzene (10 ml) dropwise with stirring. The reaction mixture was refluxed 1 hr, cooled, poured into ice water (100 ml)and extracted with Et2O (2×100 ml). The combined organic layer was washed with 10% NaHCO3, dried (Na2SO4), filtered and concentrated to give a tan oilwhich crystallized on standing to afford compound 5, mp=88°-90° C., MS, (DCI) m/e 377 (M+1).
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6]([C:8]([O:10][CH3:11])=[O:9])[C:5]([CH3:12])=[CH:4][CH:3]=1.C1C(=O)N([Br:20])C(=O)C1.CC(N=NC(C#N)(C)C)(C#N)C>C(Cl)(Cl)(Cl)Cl>[Br:20][CH2:12][C:5]1[C:6]([C:8]([O:10][CH3:11])=[O:9])=[N:7][C:2]([Cl:1])=[CH:3][CH:4]=1
Reactant: COC(=O)c1nc(Cl)ccc1C
Reactant: O=C1CCC(=O)N1Br
Agent: CC(C)(C#N)N=NC(C)(C)C#N
Solvent: ClC(Cl)(Cl)Cl
Product: COC(=O)c1nc(Cl)ccc1CBr
Temperature: 25 °C

Procedure:
Methyl 6-chloro-3-methylpyridine-2-carboxylate (3.46 g, 18.6 mmol), NBS (3.32 g, 18.6 mmol) and AIBN (61 mg, 0.37 mmol) were stirred in refluxing CCl4 (40 mL) for 6 hours. The mixture was then cooled to room temperature and purified directly by silica gel chromatography (2-20% EtOAc/hexanes) to give the title compound as a white solid.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([CH:8]2[CH2:15][N:14]3[C:10]([S:11][CH2:12][CH2:13]3)=[N:9]2)[CH:5]=[CH:6][CH:7]=1.[CH:16](=O)[C:17]1[O:21][CH:20]=[CH:19][CH:18]=1.C([BH3-])#N.[Na+].Cl>CO.C(O)(=O)C>[CH2:16]([NH:1][C:2]1[CH:3]=[C:4]([CH:8]2[CH2:15][N:14]3[C:10]([S:11][CH2:12][CH2:13]3)=[N:9]2)[CH:5]=[CH:6][CH:7]=1)[C:17]1[O:21][CH:20]=[CH:19][CH:18]=1
Reactant: Nc1cccc(C2CN3CCSC3=N2)c1
Reactant: O=Cc1ccco1
Agent: Cl
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CO
Product: c1cc(NCc2ccco2)cc(C2CN3CCSC3=N2)c1
Reaction time: 2 h

Procedure:
A mixture of 4.4 g. (0.020 mole) of 6-(m-aminophenyl)-2,3,5,6-tetrahydroimidazo[2,1-b]thiazole, 2.1 g. (0.022 mole) furfural, 3.5 ml. acetic acid and 50 ml. methanol are placed in a reaction flask along with some molecular sieves. To this 0.63 g. (0.01 mole) of sodium cyanoborohydride is added slowly and the mixture stirred two hours. The mixture is now acidified to pH 1 with hydrochloric acid. A solid material is removed by trituration and the solvent evaporated leaving an oily residue.
Reaction SMILES: [CH2:1]([C:3]1[CH:8]=[CH:7][CH:6]=[C:5]([CH2:9][CH3:10])[C:4]=1[C:11]1[CH:12]=[C:13]2[C:19]([CH:20]=C)=[CH:18][N:17]([C:22]3[CH:27]=[CH:26][C:25]([CH:28]([CH3:30])[CH3:29])=[CH:24][CH:23]=3)[C:14]2=[CH:15][N:16]=1)[CH3:2].C1C[O:34]CC1.O>>[CH2:1]([C:3]1[CH:8]=[CH:7][CH:6]=[C:5]([CH2:9][CH3:10])[C:4]=1[C:11]1[CH:12]=[C:13]2[C:19]([CH:20]=[O:34])=[CH:18][N:17]([C:22]3[CH:27]=[CH:26][C:25]([CH:28]([CH3:30])[CH3:29])=[CH:24][CH:23]=3)[C:14]2=[CH:15][N:16]=1)[CH3:2]
Reactant: C=Cc1cn(-c2ccc(C(C)C)cc2)c2cnc(-c3c(CC)cccc3CC)cc12
Reactant: C1CCOC1
Solvent: O
Product: CCc1cccc(CC)c1-c1cc2c(C=O)cn(-c3ccc(C(C)C)cc3)c2cn1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
To a solution of 5-(2,6-diethyl-phenyl)-1-(4-isopropyl-phenyl)-3-vinyl-1H-pyrrolo[2,3-c]pyridine (400 mg, 1.0 mmol) in a THF/water mixture (3:1, 10 mL), NaIO4 (0.65 g, 3.0 mmol) and OSO4 (4% in water, 3 drops) are added and the mixture is stirred for 18 hours at room temperature. The solvent is removed under reduced pressure, and the residue is extracted with EtOAc. The combined organic extracts are washed with brine, dried (Na2SO4), and concentrated under reduced pressure. The residue is purified by chromatography on silica gel (Hexane/EtOAc, 6:1) to afford 5-(2,6-diethyl-phenyl)-1-(4-isopropyl-phenyl)-1H-pyrrolo[2,3-c]pyridine-3-carbaldehyde as a colorless oil.