Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([NH2:8])=[C:4]([C:9]2[NH:10][N:11]=[C:12]([CH:14]3[CH2:16][CH2:15]3)[N:13]=2)[CH:3]=1.Cl[CH2:18][C:19](Cl)=[O:20].[OH-].[Na+].Cl>O1CCOCC1.N1C=CC=CC=1.C(OCC)C>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]2[NH:8][C:19](=[O:20])[CH2:18][N:10]3[C:9](=[N:13][C:12]([CH:14]4[CH2:16][CH2:15]4)=[N:11]3)[C:4]=2[CH:3]=1
Reactant: Nc1ccc(Cl)cc1-c1nc(C2CC2)n[nH]1
Reactant: O=C(Cl)CCl
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCOCC
Solvent: C1COCCO1
Solvent: c1ccncc1
Product: O=C1Cn2nc(C3CC3)nc2-c2cc(Cl)ccc2N1
Temperature: 10 °C
Reaction time: 0.5 h
Yield: 65.4 %

Procedure:
A suspension of 4-chloro-2-(5-cyclopropyl-2H-[1,2,4]triazol-3-yl)-phenylamine (3.95 g, 16.8 mmol) in dioxane (120 mL) and pyridine (1.5 mL) was cooled to 10° C. A solution of chloroacetyl chloride (1.54 mL, 19.3 mmol) in diethylether (5 mL) was then added dropwise over 15 min. The reaction mixture was stirred at this temperature for 30 min and was then treated within 10 min with aqueous sodium hydroxide (2 N, 20.2 mL, 40.4 mmol). The mixture was stirred for 22 h at ambient temperature. After the addition of aqueous HCl (1 N, 2.5 mL) the resulting mixture was evaporated. The residue was stirred for 45 min in water (100 mL) and ethyl acetate (5 mL). The resulting crystals were filtered off and washed with water. Drying in vacuo and trituration with ethyl acetate afforded the title compound (3.02 g, 65%) which was obtained as an off-white solid. MS: m/e=275.0 [M+H]+.
Reaction SMILES: [SH:1][C:2]1[N:3]=[C:4]2[CH:13]=[CH:12][CH:11]=[CH:10][N:5]2[C:6](=[O:9])[C:7]=1[CH3:8].Br[CH2:15][C:16]1[CH:31]=[CH:30][C:19]([C:20]([C:22]2[CH:27]=[CH:26][C:25]([CH2:28]Br)=[CH:24][CH:23]=2)=[O:21])=[CH:18][CH:17]=1.Cl.[C:33]1([N:39]2[CH2:44][CH2:43][NH:42][CH2:41][CH2:40]2)[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1.C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C>[CH3:8][C:7]1[C:6](=[O:9])[N:5]2[CH:10]=[CH:11][CH:12]=[CH:13][C:4]2=[N:3][C:2]=1[S:1][CH2:15][C:16]1[CH:31]=[CH:30][C:19]([C:20](=[O:21])[C:22]2[CH:27]=[CH:26][C:25]([CH2:28][N:42]3[CH2:43][CH2:44][N:39]([C:33]4[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=4)[CH2:40][CH2:41]3)=[CH:24][CH:23]=2)=[CH:18][CH:17]=1
Reactant: c1ccc(N2CCNCC2)cc1
Reactant: O=C(c1ccc(CBr)cc1)c1ccc(CBr)cc1
Reactant: Cc1c(S)nc2ccccn2c1=O
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: Cc1c(SCc2ccc(C(=O)c3ccc(CN4CCN(c5ccccc5)CC4)cc3)cc2)nc2ccccn2c1=O
Yield: 16.8 %

Procedure:
A solution of 2-mercapto-3-methyl-4H-pyrido[1,2-a]pyrimidin-4-one (298 mg), 4,4'-bis(bromomethyl)benzophenone (934 mg), phenylpiperazine hydrochloride (402 mg) and potassium carbonate (850 mg) in DMF (30 ml) was stirred at room temperature for 10 hours. This reaction mixture was concentrated and the residue was dissolved in chloroform, washed with water, dried, and concentrated. The residue was purified by silica gel column chromatography (hexane: ethyl acetate =1:1) to provide the title compound as colorless solid (146 mg).
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7](/[C:10](=[CH:19]\[CH:20]2[CH2:25][CH2:24][O:23][CH2:22][CH2:21]2)/[C:11]([NH:13][C:14]2[S:15][CH:16]=[CH:17][N:18]=2)=[O:12])=[CH:6][CH:5]=1)([O-])=O.O.[NH4+].[Cl-]>CCO.C1COCC1.[Fe]>[NH2:1][C:4]1[CH:9]=[CH:8][C:7](/[C:10](=[CH:19]\[CH:20]2[CH2:25][CH2:24][O:23][CH2:22][CH2:21]2)/[C:11]([NH:13][C:14]2[S:15][CH:16]=[CH:17][N:18]=2)=[O:12])=[CH:6][CH:5]=1
Reactant: O=C(Nc1nccs1)/C(=C/C1CCOCC1)c1ccc([N+](=O)[O-])cc1
Agent: [Fe]
Agent: [Cl-]
Agent: [NH4+]
Solvent: O
Solvent: C1CCOC1
Solvent: CCO
Product: Nc1ccc(/C(=C\C2CCOCC2)C(=O)Nc2nccs2)cc1
Reaction time: 4.5 h

Procedure:
A stirred suspension of (E)-2-(4-nitrophenyl)-3-(tetrahydropyran-4-yl)-N-thiazol-2-ylacrylamide (EXAMPLE 81, 1.54 g, 4.0 mmol) in EtOH (54 mL) and THF (31 mL) was treated with H2O (13 mL), saturated aqueous NH4Cl (13 mL), and Fe powder (1.49 g, 26.7 mmol). After 4.5 h at 20° C., the reaction mixture was filtered through Celite, washing with CH2Cl2. The combined filtrates were concentrated and the residue was dissolved in CH2Cl2. The CH2Cl2 solution was washed with H2O and dried (MgSO4). Filtration, solvent evaporation, and column chromatography (EtOAc-MeOH, 19:1) gave (E)-2-(4-aminophenyl)-3-(tetrahydropyran-4-yl)-N-thiazol-2-ylacrylamide; m/z (ES+)=330.1 [M+H]+. A stirred solution of this compound (104 mg, 291 μmol) in anhydrous CH2Cl2 (4 mL) was treated with MeSO2Cl (90 μL, 1165 μmol) and pyridine (94 μL, 1165 μmol). After 16 h, the mixture was diluted with CH2Cl2 (25 mL), before being extracted twice with 2M NaOH. The combined aqueous extracts were washed with Et2O, before being acidified with 12M HCl to pH 1 and extracted twice with CH2Cl2. The combined organic extracts were washed with brine and dried (MgSO4). Filtration and solvent evaporation afforded the title compound: RTB=1.26 min; m/z (ES+)=408.0 [M+H]+.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([C:8]([C:10]2[C:14]3[CH:15]=[N:16][CH:17]=[CH:18][C:13]=3[N:12]([C:19]([CH3:30])([CH3:29])[CH2:20][O:21][Si:22]([C:25]([CH3:28])([CH3:27])[CH3:26])([CH3:24])[CH3:23])[CH:11]=2)=[O:9])[CH:5]=[N:6][CH:7]=1.[C:31]([C:33]1[CH:38]=[CH:37][C:36]([CH2:39][C:40](O)=[O:41])=[CH:35][CH:34]=1)#[N:32]>>[Si:22]([O:21][CH2:20][C:19]([N:12]1[C:13]2[CH:18]=[CH:17][N:16]=[CH:15][C:14]=2[C:10]([C:8]([C:4]2[CH:3]=[C:2]([NH:1][C:40](=[O:41])[CH2:39][C:36]3[CH:37]=[CH:38][C:33]([C:31]#[N:32])=[CH:34][CH:35]=3)[CH:7]=[N:6][CH:5]=2)=[O:9])=[CH:11]1)([CH3:30])[CH3:29])([C:25]([CH3:28])([CH3:27])[CH3:26])([CH3:23])[CH3:24]
Reactant: CC(C)(CO[Si](C)(C)C(C)(C)C)n1cc(C(=O)c2cncc(N)c2)c2cnccc21
Reactant: N#Cc1ccc(CC(=O)O)cc1
Product: CC(C)(CO[Si](C)(C)C(C)(C)C)n1cc(C(=O)c2cncc(NC(=O)Cc3ccc(C#N)cc3)c2)c2cnccc21

Procedure:
Prepared according to Method Z (Preparation 8) using (5-Amino-pyridin-3-yl)-{1-[2-(tert-butyl-dimethyl-silanyloxy)-1,1-dimethyl-ethyl]-1H-pyrrolo[3,2-c]pyridin-3-yl}-methanone (Preparation TT) and 4-cyanophenylacetic acid.
Reaction SMILES: [CH:1]1([CH2:6][CH2:7][NH:8][CH2:9][C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[CH2:5][CH2:4][CH2:3][CH2:2]1.Br[CH2:17][CH2:18][CH2:19][N:20]1C(=O)C2=CC=CC=C2C1=O.O.NN.Cl>C(#N)C.C(O)C>[CH:1]1([CH2:6][CH2:7][N:8]([CH2:9][C:10]2[CH:11]=[CH:12][CH:13]=[CH:14][CH:15]=2)[CH2:17][CH2:18][CH2:19][NH2:20])[CH2:2][CH2:3][CH2:4][CH2:5]1
Reactant: O=C1c2ccccc2C(=O)N1CCCBr
Reactant: c1ccc(CNCCC2CCCC2)cc1
Agent: Cl
Agent: NN
Solvent: O
Solvent: CC#N
Solvent: CCO
Product: NCCCN(CCC1CCCC1)Cc1ccccc1
Temperature: 25 °C

Procedure:
Combine 20.3 g (0.1 mol) N-[2-(cyclopentyl)ethyl] benzenemethanamine and 26.8 g (0.1 mol) of N-(3-bromopropyl)phthalimide in 100 mL of acetonitrile. Heat the reaction mixture at reflux and monitor the progress of the reaction by thin-layer chromatography on silica gel. At the completion of the reaction remove the solvent in vacuo. To the residue add 100 mL of ethanol and 15 g (0.3 mol) of hydrazine hydrate. Reflux the reaction mixture and follow the progress of the reaction by thin-layer chromatography on silica gel. At the completion of the reaction, cool the mixture and add 50 mL of 4N hydrochloric acid. Reflux the mixture for ca. 15 min. then cool to room temperature. Filter the resulting solid. Evaporate the filtrate in vacuo, then add 100 mL of 4N sodium hydroxide solution (pH 11). Extract the aqueous mixture with four 100 mL portions of methylene chloride. Combine the organic extracts and dry over anhydrous sodium sulfate. Remove the drying agent by filtration and evaporate the solvent in vacuo to obtain the title compound.
Reaction SMILES: [Cl:1][C:2]1[N+:11]([O-:12])=[C:10]([Cl:13])[CH:9]=[CH:8][C:3]=1C(OC)=O.[NH2:14][NH2:15].[CH3:16][OH:17]>C(O)(C)C>[Cl:13][C:10]1[CH:9]=[C:8]([C:16]([NH:14][NH2:15])=[O:17])[CH:3]=[C:2]([Cl:1])[N+:11]=1[O-:12]
Reactant: COC(=O)c1ccc(Cl)[n+]([O-])c1Cl
Reactant: NN
Reactant: CO
Solvent: CC(C)O
Product: NNC(=O)c1cc(Cl)[n+]([O-])c(Cl)c1
Reaction time: 18 h

Procedure:
To a cold stirred mixture of 8.75 g (0.039 mole) of methyl 2,6-dichloronicotinate N-oxide in 50 ml of methanol was added dropwise 2.0 g (0.063 mole) of hydrazine in 14 ml of methanol. After complete addition the mixture was stirred for one hour then placed in a freezer for approximately 18 hours. The solvent was then removed by distillation under reduced pressure to leave a solid. The solid was stirred in isopropanol then filtered. The filter cake was added to 75 ml of refluxing ethanol and the resulting mixture filtered hot to yield 4.3 g of 2,6-dichloro-4-pyridinecarboxylic acid hydrazide 1-oxide as a solid.
Reaction SMILES: [C:1]([C:3]1[O:4][C:5]2[CH:11]=[CH:10][C:9]([N:12]3[CH2:17][CH2:16][N:15](C(OC(C)(C)C)=O)[CH2:14][CH2:13]3)=[CH:8][C:6]=2[CH:7]=1)#[N:2].C(Cl)[Cl:26]>CCOC(C)=O>[Cl-:26].[C:1]([C:3]1[O:4][C:5]2[CH:11]=[CH:10][C:9]([N:12]3[CH2:17][CH2:16][NH2+:15][CH2:14][CH2:13]3)=[CH:8][C:6]=2[CH:7]=1)#[N:2]
Reactant: ClCCl
Reactant: CC(C)(C)OC(=O)N1CCN(c2ccc3oc(C#N)cc3c2)CC1
Solvent: CCOC(C)=O
Product: N#Cc1cc2cc(N3CC[NH2+]CC3)ccc2o1
Product: [Cl-]
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
The above piperazine (85.3 mg, 0.261 mmol) was dissolved in 5 mL of DCM and 5 mL of EtOAc, and cooled to 0° C. Hydrogen chloride gas was bubbled through the mixture for 30 seconds. The reaction stirred for 30 minutes, warming to ambient temperature. The slurry was concentrated to afford 4-(2-cyano-1-benzofuran-5-yl)piperazin-1-ium chloride.
Reaction SMILES: [CH:1]1([N:4]2[C:13]3[C:8](=[CH:9][C:10]([I:14])=[CH:11][CH:12]=3)[C:7](=[O:15])[C:6]([C:16]([O:18]CC)=O)=[CH:5]2)[CH2:3][CH2:2]1.[Cl:21][C:22]1[CH:29]=[CH:28][C:25]([CH2:26][NH2:27])=[CH:24][CH:23]=1.ClCCl.Cl>CO>[Cl:21][C:22]1[CH:29]=[CH:28][C:25]([CH2:26][NH:27][C:16]([C:6]2[C:7](=[O:15])[C:8]3[C:13](=[CH:12][CH:11]=[C:10]([I:14])[CH:9]=3)[N:4]([CH:1]3[CH2:2][CH2:3]3)[CH:5]=2)=[O:18])=[CH:24][CH:23]=1
Reactant: NCc1ccc(Cl)cc1
Reactant: CCOC(=O)c1cn(C2CC2)c2ccc(I)cc2c1=O
Agent: Cl
Solvent: CO
Solvent: ClCCl
Product: O=C(NCc1ccc(Cl)cc1)c1cn(C2CC2)c2ccc(I)cc2c1=O
Temperature: 180 °C

Procedure:
To a flask containing ethyl 1-cyclopropyl-6-iodo-4-oxo-1,4-dihydro-3-quinolinecarboxylate from Preparation No. 19 (0.19 g) is added p-chlorobenzylamine (1.0 mL). The reaction is tightly capped and heated to 180° C. for 1 hour. The reaction is cooled to room temperature and partioned between dichloromethane containing methanol and dilute hydrochloric acid. The aqueous layer is extracted with dichloromethane and the combined organic layers are washed with brine, dried and concentarted under reduced pressure. The residue is adsorbed onto silica and chromatographed on silica eluting with 2% to 6% methanol in dichloromethane. The product containing fractions are evaporated to give 0.10 g of the title compound as a tan solid.
Reaction SMILES: [CH:1]1([CH2:5][O:6][C:7]2[CH:15]=[CH:14][CH:13]=[C:12]3[C:8]=2[CH:9]=[C:10]([C:16]([OH:18])=[O:17])[NH:11]3)[CH2:4][CH2:3][CH2:2]1.[CH3:19][O:20][C:21]1[N:26]=[CH:25]C(CCO)=CC=1.C(OC(C1NC2C(C=1)=C(O)C=CC=2)=O)C>>[CH3:19][O:20][C:21]1[N:26]=[CH:25][C:4]([CH2:1][CH2:5][O:6][C:7]2[CH:15]=[CH:14][CH:13]=[C:12]3[C:8]=2[CH:9]=[C:10]([C:16]([OH:18])=[O:17])[NH:11]3)=[CH:3][CH:2]=1
Reactant: COc1ccc(CCO)cn1
Reactant: O=C(O)c1cc2c(OCC3CCC3)cccc2[nH]1
Agent: CCOC(=O)c1cc2c(O)cccc2[nH]1
Product: COc1ccc(CCOc2cccc3[nH]c(C(=O)O)cc23)cn1

Procedure:
4-[2-(6-Methoxy-pyridin-3-yl)-ethoxy]-1H-indole-2-carboxylic acid (16n) is synthesized analogous to 16a from 4-[2-(6-methoxy-pyridin-3-yl)-ethanol and 4-hydroxy-1H-indole-2-carboxylic acid ethyl ester.
Reaction SMILES: [C:1]1(=[O:7])[NH:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[H-].[Na+].[Cl:10][C:11]1[CH:12]=[C:13]([CH:16]=[CH:17][C:18]=1[F:19])[CH2:14]Br>CN1CCCC1=O>[Cl:10][C:11]1[CH:12]=[C:13]([CH:16]=[CH:17][C:18]=1[F:19])[CH2:14][N:6]1[CH2:5][CH2:4][CH2:3][CH2:2][C:1]1=[O:7]
Reactant: Fc1ccc(CBr)cc1Cl
Reactant: O=C1CCCCN1
Agent: [H-]
Agent: [Na+]
Solvent: CN1CCCC1=O
Product: O=C1CCCCN1Cc1ccc(F)c(Cl)c1
Reaction time: 0.5 h

Procedure:
To a cold (0° C.) solution of valerolactam (153.30 g, 1.54 mol) in anhydrous 1-methyl-2-pyrrolidinone (3.5 L), sodium hydride (67.7 g, 1.69 mol, 60% dispersion in oil) was added over a period of 5 minutes. The reaction mixture was stirred for 30 minutes, and a solution of 3-chloro-4-fluorobenzylbromide (345.5 g, 1.54 mol) in 1-methyl-2-pyrrolidinone (200 mL) was added over 30 minutes at 0° C. The reaction mixture was stirred at 0° C. for 1 hour, and was allowed to warm up and stirred at room temperature overnight. The reaction mixture was quenched with distilled water (5 L), and extracted with dichloromethane (three times; 2 L, 1 L, 1 L). The organic extracts were combined, washed with water (3×; 4 L each time). The residual oil was dissolved in ethyl acetate (4 L), and extracted with water (3×; 2 L each time). The organic layer was separated, concentrated under vacuum to give the title product that solidified upon standing.
Reaction SMILES: Cl[C:2]1[CH:3]=[C:4]([CH:9]=[CH:10][N:11]=1)[C:5]([O:7][CH3:8])=[O:6].[CH3:12][C:13]1([C:16]([NH2:18])=[O:17])[CH2:15][CH2:14]1>>[CH3:12][C:13]1([C:16]([NH:18][C:2]2[CH:3]=[C:4]([CH:9]=[CH:10][N:11]=2)[C:5]([O:7][CH3:8])=[O:6])=[O:17])[CH2:15][CH2:14]1
Reactant: CC1(C(N)=O)CC1
Reactant: COC(=O)c1ccnc(Cl)c1
Product: COC(=O)c1ccnc(NC(=O)C2(C)CC2)c1
Yield: 86 %

Procedure:
The title compound is prepared in 86% yield (0.30 g, a white solid) from methyl 2-chloroisonicotinate (0.25 g, 1.46 mmol) and 1-methylcyclopropanecarboxamide by the similar manner in Step-1 of Carboxylic acid-4.
Reaction SMILES: [N:1]([CH2:4][C@H:5]1[CH2:14][CH2:13][C:12]2[C:7](=[C:8]([C:16]3[CH:21]=[CH:20][C:19]([Cl:22])=[CH:18][C:17]=3[Cl:23])[C:9]([F:15])=[CH:10][CH:11]=2)[O:6]1)=[N+]=[N-].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>C1COCC1.O>[ClH:22].[Cl:23][C:17]1[CH:18]=[C:19]([Cl:22])[CH:20]=[CH:21][C:16]=1[C:8]1[C:9]([F:15])=[CH:10][CH:11]=[C:12]2[C:7]=1[O:6][C@@H:5]([CH2:4][NH2:1])[CH2:14][CH2:13]2
Reactant: [N-]=[N+]=NC[C@H]1CCc2ccc(F)c(-c3ccc(Cl)cc3Cl)c2O1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Solvent: O
Product: Cl
Product: NC[C@H]1CCc2ccc(F)c(-c3ccc(Cl)cc3Cl)c2O1
Yield: 86.3 %

Procedure:
Treatment of (2R)-2-(azidomethyl)-8-(2,4-dichlorophenyl)-7-fluorochroman (0.22 g, 0.62 mmol) with polymer-bound triphenylphosphine (3 mmol/g, 0.35 g, 1.05 mmol) in THF (10 mL) and water (0.5 mL) according to the procedure described for Example 69, Step 10 provided 97 mg (43%) of ((2R)-8-(2,4-dichlorophenyl)-7-fluorochroman-2-yl)methanamine hydrochloride as a white solid salt, mp 164–166° C.; MS (ESI) m/z 326.0 ([M+H]+); [α]D25=−26.00° (c=1% SOLN, MeOH).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[C@@H:12]([C:13](OC)=[O:14])[CH2:11][CH2:10][C@H:9]1[C:17]([OH:19])=[O:18])=[O:7])([CH3:4])([CH3:3])[CH3:2].[BH4-].[Li+]>C(OCC)C.CO>[C:1]([O:5][C:6]([N:8]1[C@@H:12]([CH2:13][OH:14])[CH2:11][CH2:10][C@H:9]1[C:17]([OH:19])=[O:18])=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: COC(=O)[C@H]1CC[C@@H](C(=O)O)N1C(=O)OC(C)(C)C
Agent: [BH4-]
Agent: [Li+]
Solvent: CCOCC
Solvent: CO
Product: CC(C)(C)OC(=O)N1[C@@H](CO)CC[C@H]1C(=O)O
Temperature: 70 °C
Reaction time: 0.17 h
Yield: 88.8 %

Procedure:
To an ice cold solution of (2S,5R)-1-(tert-butoxycarbonyl)-5-(methoxycarbonyl)pyrrolidine-2-carboxylic acid (1.17 g, 4.07 mmol) in 70 mL diethyl ether and 0.330 mL methanol was added lithium borohydride (2M in THF, 4.0 mL, 8.14 mmol). After 10 minutes, the ice bath was removed and the reaction was heated at reflux overnight. As the reaction had not proceeded, a solvent swap to THF was performed, and the resulting mixture was heated at 70° C. overnight. The reaction mixture was cooled to 0° C. and quenched with 1N HCl and then extracted into ethyl acetate, dried over sodium sulphate, filtered and concentrated under reduced pressure to give the crude product as a white semi-solid (886 mg)
Reaction SMILES: Br[C:2]1[CH:8]=[CH:7][C:5]([NH2:6])=[C:4]([N+:9]([O-:11])=[O:10])[CH:3]=1.[C:12](C1C=CC(B(O)O)=CC=1)#[N:13].C([O-])([O-])=O.[Na+].[Na+].[C:29]1(C)[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1.CCO.O>C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[NH2:6][C:5]1([C:12]#[N:13])[CH:7]=[CH:8][C:2]([C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)=[CH:3][CH:4]1[N+:9]([O-:11])=[O:10]
Reactant: Cc1ccccc1
Reactant: Nc1ccc(Br)cc1[N+](=O)[O-]
Reactant: N#Cc1ccc(B(O)O)cc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: CCO
Product: N#CC1(N)C=CC(c2ccccc2)=CC1[N+](=O)[O-]
Temperature: 100 °C
Yield: 85 %

Procedure:
A solution of 4-bromo-2-nitroaniline (1.92 g, 8.85 mmol) and 4-cyanophenylboronic acid (1.3 g, 8.85 mmol) in toluene/EtOH/water (3/1/1.5, 40 mL) was degassed thoroughly before the addition of Na2CO3 (2.8 g, 26.55 mmol) and Pd(PPh3)4 (511 mg, 0.44 mmol). The reaction was heated to 100° C. for 5 hours. After cooling the reaction was filtered through celite, washing through with EtOAc (3×20 mL). The filtrate was washed with water (2×30 mL), dried over Na2SO4 and concentrated in vacuo. The residue was purified using silica gel column chromatography eluting with 2-3% MeOH in DCM to afford the title compound as a yellow solid (1.8 g, 85%).
Reaction SMILES: [Cl:1][C:2]1[C:3](=[O:30])[C@H:4]2[CH2:29][C@@:7]3([C:18]=1[C:17]1[CH:16]=[CH:15][C:14]4[N:13]([S:19]([C:22]5[CH:27]=[CH:26][C:25]([CH3:28])=[CH:24][CH:23]=5)(=[O:21])=[O:20])[N:12]=[CH:11][C:10]=4[C:9]=1[CH2:8]3)[CH2:6][CH2:5]2.[Cl:31][C:32]1[C:33](=[O:60])[C@H:34]2[CH2:59][C@@:37]3([C:48]=1[C:47]1[CH:46]=[CH:45][C:44]4[C:40](=[CH:41][N:42]([S:49]([C:52]5[CH:57]=[CH:56][C:55]([CH3:58])=[CH:54][CH:53]=5)(=[O:51])=[O:50])[N:43]=4)[C:39]=1[CH2:38]3)[CH2:36][CH2:35]2.[BH4-].[Na+]>C(O)C>[Cl:1][C:2]1[C@H:3]([OH:30])[C@H:4]2[CH2:29][C@@:7]3([C:18]=1[C:17]1[CH:16]=[CH:15][C:14]4[N:13]([S:19]([C:22]5[CH:23]=[CH:24][C:25]([CH3:28])=[CH:26][CH:27]=5)(=[O:20])=[O:21])[N:12]=[CH:11][C:10]=4[C:9]=1[CH2:8]3)[CH2:6][CH2:5]2.[Cl:31][C:32]1[C@H:33]([OH:60])[C@H:34]2[CH2:59][C@@:37]3([C:48]=1[C:47]1[CH:46]=[CH:45][C:44]4[C:40](=[CH:41][N:42]([S:49]([C:52]5[CH:53]=[CH:54][C:55]([CH3:58])=[CH:56][CH:57]=5)(=[O:50])=[O:51])[N:43]=4)[C:39]=1[CH2:38]3)[CH2:36][CH2:35]2
Reactant: Cc1ccc(S(=O)(=O)n2ncc3c4c(ccc32)C2=C(Cl)C(=O)[C@@H]3CC[C@@]2(C4)C3)cc1
Reactant: Cc1ccc(S(=O)(=O)n2cc3c4c(ccc3n2)C2=C(Cl)C(=O)[C@@H]3CC[C@@]2(C4)C3)cc1
Agent: [BH4-]
Agent: [Na+]
Solvent: CCO
Product: Cc1ccc(S(=O)(=O)n2cc3c4c(ccc3n2)C2=C(Cl)[C@H](O)[C@@H]3CC[C@@]2(C4)C3)cc1
Product: Cc1ccc(S(=O)(=O)n2ncc3c4c(ccc32)C2=C(Cl)[C@H](O)[C@@H]3CC[C@@]2(C4)C3)cc1
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
A mixture of (8R,10aS)-6-chloro-3-[(4-methylphenyl)sulfonyl]-3,9,10,11-tetrahydro-8,10a-methanoazuleno[2,1-e]indazol-7(8H)-one and (8R,10aS) -6-chloro-2-[(4-methylphenyl)sulfonyl]-2,9,10,11-tetrahydro-8,10a-methanoazuleno[2,1-e]indazol-7(8H) -one prepared as described in Step 1 (0.026 g, 0.059 mmol) was dissolved in 0.5 mL of ethanol, cooled to 0° C., and sodium borohydride (0.013 g, 0.34 mmol) was added. After 30 minutes, the reaction was quenched by addition of three drops of saturated NH4Cl, diluted with dichloromethane, and dried over MgSO4. The solution was filtered through a pad of silica gel, rinsing with EtOAc, and concentrated under reduced pressure to give (7R,8R,10aS)-6-chloro-3-[(4-methylphenyl)sulfonyl]-3,7,8,9,10,11-hexahydro-8,10a-methanoazuleno[2,1-e]indazol-7-ol and (7R,8R,10aS)-6-chloro-2-[(4-methylphenyl)sulfonyl]-2,7,8,9,10,11-hexahydro-8,10a-methanoazuleno[2,1-e]indazol-7-ol.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([C:8]([O:10][CH2:11][CH3:12])=[O:9])[N:5]([CH3:7])[CH:6]=1.C(=O)([O-])[O-].[Na+].[Na+].[Cl:19][C:20]1[CH:25]=[CH:24][C:23](B(O)O)=[C:22]([O:29][CH3:30])[CH:21]=1.C(Cl)(Cl)Cl>CN(C)C=O.O.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[Cl:19][C:20]1[CH:25]=[CH:24][C:23]([C:2]2[CH:3]=[C:4]([C:8]([O:10][CH2:11][CH3:12])=[O:9])[N:5]([CH3:7])[CH:6]=2)=[C:22]([O:29][CH3:30])[CH:21]=1
Reactant: CCOC(=O)c1cc(Br)cn1C
Reactant: COc1cc(Cl)ccc1B(O)O
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: ClC(Cl)Cl
Solvent: O
Solvent: CN(C)C=O
Product: CCOC(=O)c1cc(-c2ccc(Cl)cc2OC)cn1C
Yield: 254.5 %

Procedure:
Ethyl 4-bromo-1-methyl-1H-pyrrole-2-carboxylate (5.00 g, 21.6 mmol) prepared in the Step 10-1-2 was dissolved in N,N-dimethylformamide (20 ml)/water (5 ml), and sodium carbonate (6.87 g, 64.8 mmol), tetrakis(triphenylphosphine)palladium (120 mg, 0.1 mmol) and 4-chloro-2-methoxyphenylboronic acid (8.04 g, 4.32 mmol) was added to the solution. The mixture was heated under reflux for 5 hours. After the mixture was allowed to cool, water and chloroform was added to the mixture. The organic phase was collected by separation and dried over anhydrous magnesium sulfate. The solvent was distilled off, and the resulting residue was purified by silica gel column chromatography (ethyl acetate:n-hexane=1:3) to give the title compound (3.23 g, 51%).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([CH:15]=[CH:16][C:17]=1[O:18][CH3:19])[C:5]([NH:7][C:8]1[CH:13]=[CH:12][C:11]([Cl:14])=[CH:10][CH:9]=1)=[O:6].[Cl:20][C:21]1[CH:22]=[C:23]([N:28]=[C:29]=[S:30])[CH:24]=[C:25]([Cl:27])[CH:26]=1>CN(C=O)C.O>[Cl:14][C:11]1[CH:10]=[CH:9][C:8]([NH:7][C:5](=[O:6])[C:4]2[CH:15]=[CH:16][C:17]([O:18][CH3:19])=[C:2]([NH:1][C:29]([NH:28][C:23]3[CH:24]=[C:25]([Cl:27])[CH:26]=[C:21]([Cl:20])[CH:22]=3)=[S:30])[CH:3]=2)=[CH:13][CH:12]=1
Reactant: COc1ccc(C(=O)Nc2ccc(Cl)cc2)cc1N
Reactant: S=C=Nc1cc(Cl)cc(Cl)c1
Solvent: CN(C)C=O
Solvent: O
Product: COc1ccc(C(=O)Nc2ccc(Cl)cc2)cc1NC(=S)Nc1cc(Cl)cc(Cl)c1
Reaction time: 8 h
Yield: 61.6 %

Procedure:
A mixture of 3-amino-N-(4-chlorophenyl)-4-methoxy-benzamide from Example 2 (1.113 g, 4.02 mmol) and 3,5-dichlorophenyl isothiocyanate (0.820 g, 4.02 mmol) in DMF (10 mL) was allowed to stand at room temperature overnight. The mixture was then diluted with 50 mL H2O and the precipitate collected by filtration and dried. Trituration in first ether then ethyl acetate followed by filtration afforded the product (1.19 g); m.p. 180-185° C.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]([F:12])([F:11])[F:10])=[CH:5][C:4]=1[N:13]1[CH2:18][CH2:17][NH:16][CH2:15][CH2:14]1.[CH:19]12[N:26]([C:27](=[O:38])[CH:28]([C:32]3[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=3)[CH2:29][CH2:30]Cl)[CH:23]([CH2:24][CH2:25]1)[CH2:22][CH2:21][CH2:20]2.C(N(C(C)C)CC)(C)C.[I-].[K+].O.Cl.Cl>CN(C)C=O>[CH:23]12[N:26]([C:27](=[O:38])[CH:28]([C:32]3[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=3)[CH2:29][CH2:30][N:16]3[CH2:15][CH2:14][N:13]([C:4]4[CH:5]=[C:6]([C:9]([F:10])([F:12])[F:11])[CH:7]=[CH:8][C:3]=4[O:2][CH3:1])[CH2:18][CH2:17]3)[CH:19]([CH2:25][CH2:24]1)[CH2:20][CH2:21][CH2:22]2
Reactant: O=C(C(CCCl)c1ccccc1)N1C2CCCC1CC2
Reactant: COc1ccc(C(F)(F)F)cc1N1CCNCC1
Agent: Cl
Agent: [I-]
Agent: [K+]
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Solvent: O
Product: COc1ccc(C(F)(F)F)cc1N1CCN(CCC(C(=O)N2C3CCCC2CC3)c2ccccc2)CC1
Yield: 67.5 %

Procedure:
The title compound was prepared from 4-(2-methoxy-5-trifluoromethyl-phenyl)-piperazine 0.7 g, 2.3 mmole, prepared according to the method reported in example 2), 1-(8-aza-bicyclo[3.2.1]oct-8-yl)-4-chloro-2-phenyl-butan-1-one (0.7 g, 2.3 mmole), diisopropylethylamine (0.4 g, 3.0 mmole) and potassium iodide (0.5 g, 3.0 mmole) in dimethylformamide (25 mL) in the manner described in example 2 to yield 0.8 g of title product as the hydrochloride hemihydrate, m.p. 198°-199° C.