Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:20]=[C:19]([N+:21]([O-])=O)[CH:18]=[CH:17][C:3]=1[O:4][CH:5]1[C:10]2=[C:11]([CH:14]([CH3:16])[CH3:15])[CH:12]=[CH:13][N:9]2[N:8]=[CH:7][NH:6]1.[Cl-].[NH4+]>[Zn].CO.O1CCCC1>[F:1][C:2]1[CH:20]=[C:19]([NH2:21])[CH:18]=[CH:17][C:3]=1[O:4][CH:5]1[C:10]2=[C:11]([CH:14]([CH3:15])[CH3:16])[CH:12]=[CH:13][N:9]2[N:8]=[CH:7][NH:6]1
Reactant: CC(C)c1ccn2c1C(Oc1ccc([N+](=O)[O-])cc1F)NC=N2
Agent: [Cl-]
Agent: [NH4+]
Agent: [Zn]
Solvent: CO
Solvent: C1CCOC1
Product: CC(C)c1ccn2c1C(Oc1ccc(N)cc1F)NC=N2
Reaction time: 4 h
Yield: 10 %

Procedure:
To a heterogeneous mixture of 4-(2-fluoro-4-nitrophenoxy)-5-isopropyl-3,4-dihydropyrrolo[2,1-f][1,2,4]triazine (0.044 g, 1.39 mmol, 10 equiv) in 1/1 anhydrous methanol/tetrahydrofuran (2 mL), at ambient temperature under nitrogen atmosphere, was added zinc dust (0.090 g, 0.139 mmol, 1.0 equiv) and ammonium chloride (0.075 g, 1.39 mmol, 10 equiv). The mixture was stirred for 4 h before the catalyst was filtered off and the filtrate was concentrated in vacuo to yield the title compound (0.040 g, 100%) as a solid, that was used without further purification. HRMS(ESI), 287.1308 (M+H)+ calc, 287.1300 (M+H)+ found.
Reaction SMILES: [CH2:1]([C:3]1[N:4]([C:28]2[CH:33]=[CH:32][C:31]([OH:34])=[CH:30][CH:29]=2)[C:5](=[O:27])[C:6]([CH2:12][C:13]2[CH:18]=[CH:17][C:16]([C:19]3[C:20]([C:25]#[N:26])=[CH:21][CH:22]=[CH:23][CH:24]=3)=[CH:15][CH:14]=2)=[C:7]([CH2:9][CH2:10][CH3:11])[N:8]=1)[CH3:2].[CH3:35][C:36]1([CH3:39])[CH2:38][O:37]1.C(=O)([O-])[O-].[Cs+].[Cs+]>CN(C)C(=O)C>[CH2:1]([C:3]1[N:4]([C:28]2[CH:33]=[CH:32][C:31]([O:34][CH2:35][C:36]([OH:37])([CH3:39])[CH3:38])=[CH:30][CH:29]=2)[C:5](=[O:27])[C:6]([CH2:12][C:13]2[CH:18]=[CH:17][C:16]([C:19]3[C:20]([C:25]#[N:26])=[CH:21][CH:22]=[CH:23][CH:24]=3)=[CH:15][CH:14]=2)=[C:7]([CH2:9][CH2:10][CH3:11])[N:8]=1)[CH3:2]
Reactant: CCCc1nc(CC)n(-c2ccc(O)cc2)c(=O)c1Cc1ccc(-c2ccccc2C#N)cc1
Reactant: CC1(C)CO1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CC(=O)N(C)C
Product: CCCc1nc(CC)n(-c2ccc(OCC(C)(C)O)cc2)c(=O)c1Cc1ccc(-c2ccccc2C#N)cc1
Temperature: 120 °C
Reaction time: 24 h
Yield: 64.6 %

Procedure:
To a solution of 4′-{[2-ethyl-1-(4-hydroxyphenyl)-6-oxo-4-propyl-1,6-dihydropyrimidin-5-yl]methyl}biphenyl-2-carbonitrile (0.48 g) in N,N-dimethylacetamide (10 mL) were added 2,2-dimethyloxirane (0.77 g) and cesium carbonate (0.70 g), and the mixture was stirred at 120° C. for 24 hr. The mixture was allowed to cool to room temperature. The insoluble material was filtered off, and the filtrate was diluted with ethyl acetate, washed with 1 M hydrochloric acid, saturated sodium hydrogen carbonate and saturated brine, and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure. The residue was purified by silica gel chromatography to give the title compound as a pale-yellow solid (0.36 g, 64%).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][CH:9]=1)[CH:5]=[CH2:6].C(O)(=[O:12])C.BrN1C(=O)CCC1=O.[OH-].[Na+]>O1CCOCC1.O>[Cl:1][C:2]1[CH:3]=[C:4]([CH:5]2[CH2:6][O:12]2)[CH:7]=[CH:8][CH:9]=1
Reactant: CC(=O)O
Reactant: C=Cc1cccc(Cl)c1
Agent: O=C1CCC(=O)N1Br
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: C1COCCO1
Product: Clc1cccc(C2CO2)c1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of m-chlorostyrene (5.70 g, 41.0 mmol) and acetic acid (2.33 mL, 40.9 mmol) in dioxane (33 mL) and H2O (78 mL) at 0° C. was added N-bromosuccinimide (8.02 g, 45.0 mmol) in three portions. The reaction was allowed to warm to RT After 4 hours, 2N NaOH (60 mL) was added and the reaction was allowed to stir at RT overnight. The reaction mixture was partitioned between water and EtOAc, and the aqueous phase was extracted with EtOAc. The combined organic phases were washed with brine, dried (Na2SO4), filtered and evaporated in vacuo to give 6.20 g of a slightly tinted oil which was used without further purification.
Reaction SMILES: [CH3:1][N:2]1[CH:15]([CH3:16])[CH2:14][C:5]2[NH:6][C:7]3[CH:8]=[CH:9][C:10]([CH3:13])=[CH:11][C:12]=3[C:4]=2[CH2:3]1.[OH-].[K+].[F:19][C:20]([F:30])([F:29])[C:21]1[CH:26]=[CH:25][C:24]([CH:27]=[CH2:28])=[CH:23][N:22]=1.O>CN1CCCC1=O>[CH3:1][N:2]1[CH:15]([CH3:16])[CH2:14][C:5]2[N:6]([CH2:28][CH2:27][C:24]3[CH:23]=[N:22][C:21]([C:20]([F:30])([F:19])[F:29])=[CH:26][CH:25]=3)[C:7]3[CH:8]=[CH:9][C:10]([CH3:13])=[CH:11][C:12]=3[C:4]=2[CH2:3]1
Reactant: C=Cc1ccc(C(F)(F)F)nc1
Reactant: Cc1ccc2[nH]c3c(c2c1)CN(C)C(C)C3
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: CN1CCCC1=O
Product: Cc1ccc2c(c1)c1c(n2CCc2ccc(C(F)(F)F)nc2)CC(C)N(C)C1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 5.5 %

Procedure:
To a solution of 2,3,8-trimethyl-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indole (200 mg, 0.935 mmol) in N-methyl-2-pyrolidone (2.5 mL) was added powdered KOH (463 mg, 8.27 mmol) and stirred for 10 min at RT. 2-Trifluoromethyl-5-vinyl pyridine (300 mg, 1.73 mmol) was added and stirred further for 4 h at RT. The reaction was monitored by TLC. After completion of reaction, water (10 mL) was added to the mixture, which was then filtered. Water was added to the filtrate, which was then extracted with EtOAc (50 mL). The organic layer was dried over sodium sulfate, concentrated in vacuum and the residue purified by column chromatography (100-200 mesh silica gel) to obtain 20 mg of desired compound. The free base compound was converted into the oxalate salt. 1HNMR (CDCl3, Freebase) d (ppm): 8.40 (s, 1H), 7.45 (d, 1H), 7.25 (m, 2H), 7.10 (d, 1H), 6.98 (d, 1H), 4.22 (t, 2H), 3.82 (d, 1H), 3.62 (d, 1H), 3.50 (m, 1H), 3.10 (t, 2H), 2.80 (m, 1H), 2.45 (s, 3H), 2.38 (s, 3H), 2.10 (dd, 1H), 1.10 (d, 3H).
Reaction SMILES: [Mg].II.[CH2:4](Br)C.CCl.[C:9]([C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)(=O)[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1.[Cl-].[NH4+]>C1COCC1>[C:10]1([C:9]([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)=[CH2:4])[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1
Reactant: CCBr
Reactant: O=C(c1ccccc1)c1ccccc1
Agent: CCl
Agent: II
Agent: [Cl-]
Solvent: C1CCOC1
Product: C=C(c1ccccc1)c1ccccc1
Reaction time: 1 h
Yield: 97 %

Procedure:
Into a reactor were introduced 31.6 g (1.30 mol) of magnesium and 50 mL of THF under a nitrogen atmosphere. Iodine and ethyl bromide were added to the mixture in a slight amount to ascertain initiation of a reaction. Thereafter, 600 mL of THF was added thereto, and methyl chloride gas having a regulated temperature was bubbled into the resultant mixture at a regulated rate so as to keep the mixture at 30 to 40° C. After heat generation ended and the magnesium metal was ascertained to have disappeared, the reaction mixture was stirred at that temperature for 1 hour. Subsequently, a mixture of 182 g (1.10 mol) of benzophenone and 364 mL of THF was gradually added dropwise thereto at 35 to 40° C. and this mixture was stirred for 15 hours. This reaction mixture was cooled and then poured into 10% aqueous ammonium chloride solution. The resultant mixture was stirred for 30 minutes. After liquid separation, the organic layer was washed with an aqueous sodium chloride solution and water, subsequently dried with anhydrous magnesium sulfate, and then concentrated under reduced pressure. To the concentrate were added 400 mL of toluene and 1 g of p-toluenesulfonic acid monohydrate. The resultant solution was subjected to azeotropic dehydration for 2 hours with toluene refluxing. After being cooled, the reaction mixture was washed with 2% aqueous sodium carbonate solution and water and then dried with anhydrous magnesium sulfate. Thereafter, the solvent was removed under reduced pressure. The concentrate was purified by distillation to obtain 174 g (97%) of the target compound.
Reaction SMILES: [CH2:1]([C:13]1[N:14]=[N:15][N:16]([CH2:18][C:19]([O:21]CC)=[O:20])[N:17]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH3:12].C(C1N=NN(C(C2C=CC=CC=2)C(OCC)=O)N=1)CCCCCCCCC>>[CH2:1]([C:13]1[N:14]=[N:15][N:16]([CH2:18][C:19]([OH:21])=[O:20])[N:17]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH3:12]
Reactant: CCCCCCCCCCCCc1nnn(CC(=O)OCC)n1
Agent: CCCCCCCCCCc1nnn(C(C(=O)OCC)c2ccccc2)n1
Product: CCCCCCCCCCCCc1nnn(CC(=O)O)n1

Procedure:
When in the general procedure of Example 79 an appropriate amount of ethyl 5-dodecyl-2H-tetrazole-2-acetate was substituted for ethyl (±)-5-decyl-α-phenyl-2H-tetrazole-2-acetate, the title compound was obtained, mp 89°-91° C.
Reaction SMILES: [Br:1][C:2]1[C:3](=[O:19])[NH:4][N:5]=[CH:6][C:7]=1[NH:8][C@@H:9]1[CH2:14][C@@H:13]2[CH2:15][C@@H:11]([C:12]2([CH3:17])[CH3:16])[C@H:10]1[CH3:18].Br[CH:21]([CH3:27])[C:22]([O:24][CH2:25][CH3:26])=[O:23].C(=O)([O-])[O-].[K+].[K+].[Cl-].[NH4+]>CN(C)C=O>[Br:1][C:2]1[C:3](=[O:19])[N:4]([CH:21]([CH3:27])[C:22]([O:24][CH2:25][CH3:26])=[O:23])[N:5]=[CH:6][C:7]=1[NH:8][C@@H:9]1[CH2:14][C@@H:13]2[CH2:15][C@@H:11]([C:12]2([CH3:16])[CH3:17])[C@H:10]1[CH3:18]
Reactant: C[C@@H]1[C@H]2C[C@@H](C[C@H]1Nc1cn[nH]c(=O)c1Br)C2(C)C
Reactant: CCOC(=O)C(C)Br
Agent: O=C([O-])[O-]
Agent: [Cl-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCOC(=O)C(C)n1ncc(N[C@@H]2C[C@@H]3C[C@H]([C@H]2C)C3(C)C)c(Br)c1=O
Temperature: 80 °C
Reaction time: 2 h
Yield: 54.9 %

Procedure:
4-Bromo-5-[(1R,2R,3R,5S)-2,6,6-trimethylbicyclo[3.1.1]hept-3-ylamino]pyridazin-3(2H)-one (208 mg, 0.637 mmol) in N,N-dimethylformamide (2 mL) was mixed with ethyl 2-bromopropionate (124 μL, 0.955 mmol) and potassium carbonate (132 mg, 0.955 mmol) at room temperature and stirred at 80° C. for 2 hours. After cooling, the reaction solution was mixed with saturated aqueous ammonium chloride and extracted with ethyl acetate. The resulting organic layer was washed with saturated aqueous ammonium chloride and saturated aqueous sodium chloride, dried over anhydrous magnesium sulfate and evaporated under reduced pressure to give the desired product (149 mg, 55% yield).
Reaction SMILES: [C:1]([O:9]CC)(=[O:8])[CH2:2][C:3](OCC)=O.[H-].[Na+].[CH3:14][O:15][C:16]1[CH:17]=[C:18]2[C:22](=[CH:23][CH:24]=1)[CH:21]([CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33]CBr)[CH:20]([C:36]1[CH:41]=[CH:40][C:39]([O:42]C)=[CH:38][CH:37]=1)[CH2:19]2>CN(C)C=O.O>[CH3:14][O:15][C:16]1[CH:17]=[C:18]2[C:22](=[CH:23][CH:24]=1)[CH:21]([CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:3][CH2:2][C:1]([OH:9])=[O:8])[CH:20]([C:36]1[CH:41]=[CH:40][C:39]([OH:42])=[CH:38][CH:37]=1)[CH2:19]2
Reactant: COc1ccc(C2Cc3cc(OC)ccc3C2CCCCCCCCCCBr)cc1
Reactant: CCOC(=O)CC(=O)OCC
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: COc1ccc2c(c1)CC(c1ccc(O)cc1)C2CCCCCCCCCCCC(=O)O
Temperature: 50 °C

Procedure:
A solution of diethyl malonate (0.64 g.) in dimethylformamide (10 ml.) was added to a stirred suspension of sodium hydride (0.14 g. of a 50% suspension in mineral oil) in dimethylformamide (10 ml.) which was maintained under an atmosphere of argon, and the mixture was stirred and heated to 50° C. for 5 minutes and then cooled to laboratory temperature. 10-[(1RS, 2RS)-5-Methoxy-2-p-methoxyphenylindan-1-yl]decyl bromide (1.2 g.) was added and the mixture was stirred at laboratory temperature for 16 hours and then diluted with water and extracted with diethyl ether. The extract was dried and evaporated to dryness and a solution of the residue (1.47 g.) in ethanol (10 ml.) was added dropwise to a stirred solution of potassium hydroxide (1.4 g.) in water (10 ml.) which was heated under reflux. The mixture was stirred and heated under reflux for 10 minutes, diluted with water and extracted with diethyl ether. The aqueous solution was acidified with concentrated aqueous hydrochloric acid and extracted with diethyl ether, and the extract was dried and evaporated to dryness. There was thus obtained as residue 12-[(1RS, 2RS)-5-methoxy-2-p-hydroxyphenylindan-1-yl]dodecanoic acid.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:8](=[C:9]([N+:11]([O-:13])=[O:12])[CH:10]=1)[NH:7][C:6]([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)=[C:5]2[CH:20]=O.C(O)(=O)C.[O:26]=[C:27]1[CH2:32][NH:31][CH2:30][CH2:29][NH:28]1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>ClCCl.O>[Cl:1][C:2]1[CH:3]=[C:4]2[C:8](=[C:9]([N+:11]([O-:13])=[O:12])[CH:10]=1)[NH:7][C:6]([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)=[C:5]2[CH2:20][N:31]1[CH2:30][CH2:29][NH:28][C:27](=[O:26])[CH2:32]1
Reactant: O=Cc1c(-c2ccccc2)[nH]c2c([N+](=O)[O-])cc(Cl)cc12
Reactant: O=C1CNCCN1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCl
Solvent: O
Solvent: CC(=O)O
Product: O=C1CN(Cc2c(-c3ccccc3)[nH]c3c([N+](=O)[O-])cc(Cl)cc23)CCN1
Temperature: 25 °C
Reaction time: 4 h
Yield: 86.1 %

Procedure:
5-Chloro-3-formyl-7-nitro-2-phenyl-1H-indole (0.5 g, 1.66 mmol) obtained in Step 1 was dissolved in dichloromethane (20 mL), and thereto acetic acid (0.10 g, 1.66 mmol), 2-oxopiperazine (0.3 g, 3.32 mmol) and sodium triacetoxy borohydride (0.71 g, 3.32 mmol) were added in drops. The mixture was stirred at room temperature for 4 hours. At the end of reaction, the mixture was diluted with water, and extracted with dichloromethane. The extract was washed with saturated sodium chloride solution, dried over anhydrous magnesium sulfate and filtered. The solvent was removed under reduced pressure and the residue was separated by column chromatography to give 5-chloro-7-nitro-3-(2-oxo-piperazin-4-yl)methyl-2-phenyl-1H-indole (0.55 g, Yield 86%).
Reaction SMILES: [CH:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][C:2]=1[CH2:11][O:12][CH2:13][CH:14]1[CH2:41][CH2:40][C:17]2[N:18](C(C3C=CC=CC=3)(C3C=CC=CC=3)C3C=CC=CC=3)[CH:19]=[N:20][C:16]=2[CH2:15]1.C1C2C(=CC=CC=2)C=CC=1COCC1CCC2N=CN(C(C3C=CC=CC=3)(C3C=CC=CC=3)C3C=CC=CC=3)C=2C1.C(O)(=O)C>O>[CH:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][C:2]=1[CH2:11][O:12][CH2:13][CH:14]1[CH2:41][CH2:40][C:17]2[NH:18][CH:19]=[N:20][C:16]=2[CH2:15]1
Reactant: c1ccc(C(c2ccccc2)(c2ccccc2)n2cnc3c2CCC(COCc2ccc4ccccc4c2)C3)cc1
Agent: c1ccc(C(c2ccccc2)(c2ccccc2)n2cnc3c2CC(COCc2ccc4ccccc4c2)CC3)cc1
Solvent: O
Solvent: CC(=O)O
Product: c1ccc2cc(COCC3CCc4[nH]cnc4C3)ccc2c1
Temperature: 70 °C

Procedure:
A solution of a mixture of 5-(((2-naphthyl)methoxy)methyl)-1-triphenylmethyl-4,5,6,7-tetrahydro-1H-benzimidazole and 5-(((2-naphthyl)methoxy)methyl)-3-triphenylmethyl-4,5,6,7-tetrahydro-3H-benzimidazole (590 mg, 1.1 mmol) in a mixture of glacial acetic acid (5 ml) and water (0.6 ml) was heated to 70° C. for 2 hours. The solvent was removed in vacuo. The crude product was purified by flash chromatography on silica, using DCM/methanol/25% aqueous ammonia (100:10:1) as eluent, to give 300 mg of the title compound.
Reaction SMILES: [CH2:1]([N:3]([C:22]1[CH:27]=[CH:26][C:25]([C:28]([O:30][CH3:31])=[O:29])=[CH:24][CH:23]=1)[S:4]([C:7]1[CH:8]=[C:9]([CH:19]=[CH:20][CH:21]=1)[C:10]([O:12]CC[Si](C)(C)C)=[O:11])(=[O:6])=[O:5])[CH3:2].CCCC[N+](CCCC)(CCCC)CCCC.[F-].Cl>C1COCC1>[CH2:1]([N:3]([C:22]1[CH:23]=[CH:24][C:25]([C:28]([O:30][CH3:31])=[O:29])=[CH:26][CH:27]=1)[S:4]([C:7]1[CH:8]=[C:9]([CH:19]=[CH:20][CH:21]=1)[C:10]([OH:12])=[O:11])(=[O:6])=[O:5])[CH3:2]
Reactant: CCN(c1ccc(C(=O)OC)cc1)S(=O)(=O)c1cccc(C(=O)OCC[Si](C)(C)C)c1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: Cl
Agent: [F-]
Solvent: C1CCOC1
Product: CCN(c1ccc(C(=O)OC)cc1)S(=O)(=O)c1cccc(C(=O)O)c1
Temperature: 25 °C
Reaction time: 15 h
Yield: 92 %

Procedure:
To a mixture of 330 mg of 2-(trimethylsilyl)ethyl 3-{ethyl[4-(methoxycarbonyl)phenyl]sulfamoyl}benzoate and 5.0 mL of THF was added a solution of TBAF in THF (1.0 M, 1.42 mL), followed by stirring at room temperature for 15 hours. To the reaction mixture was added a 0.1 M aqueous hydrochloric acid solution, followed by extraction with ethyl acetate. The organic layer was washed with a 0.1 M aqueous hydrochloric acid solution and a 10% aqueous citric acid solution, and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure to obtain 238 mg of 3-{ethyl[4-(methoxycarbonyl)phenyl]sulfamoyl}benzoic acid as a white solid.
Reaction SMILES: [CH2:1]([N-:3][CH2:4][CH3:5])[CH3:2].[CH2:6]([N-:8][CH2:9][CH3:10])[CH3:7].[CH2:11]([N-:13][CH2:14][CH3:15])[CH3:12].C([N-]CC)C.[Ti+4].[Ti:22](Cl)(Cl)(Cl)[Cl:23]>C1(C)C=CC=CC=1>[CH2:1]([N-:3][CH2:4][CH3:5])[CH3:2].[CH2:6]([N-:8][CH2:9][CH3:10])[CH3:7].[CH2:11]([N-:13][CH2:14][CH3:15])[CH3:12].[Cl:23][Ti+3:22]
Reactant: Cl[Ti](Cl)(Cl)Cl
Agent: [Ti+4]
Agent: CC[N-]CC
Solvent: Cc1ccccc1
Product: Cl[Ti+3]
Reaction time: 1 h

Procedure:
A 250 mL Schlenk flask is charged with toluene, 100 mL, and titanium tetrakis(diethylamide), 6.21 g (18.5 mmole). To the magnetically stirred solution is added titanium tetrachloride, 1.17 g (6.15 mmole) resulting in a gradual darkening of the solution. The mixture is stirred 1 hour while refluxing. All volatiles are removed under vacuum at room temperature leaving a yellow-brown oil. The oil is transferred to a micro distillation apparatus and distilled under vacuum. A yellow-brown liquid is obtained which distills at 112° to 118° C. (at 0.025 mm Hg). The product is determined to be chloro titanium tris(diethylamide).
Reaction SMILES: C([O:8][C:9]1[CH:14]=[CH:13][N:12]([C:15]2[CH:23]=[CH:22][C:21]3[C:17](=[C:18]([CH3:26])[N:19]([CH2:24][CH3:25])[N:20]=3)[CH:16]=2)[C:11](=[O:27])[CH:10]=1)C1C=CC=CC=1>CO.[C].[Pd]>[CH2:24]([N:19]1[C:18]([CH3:26])=[C:17]2[C:21]([CH:22]=[CH:23][C:15]([N:12]3[CH:13]=[CH:14][C:9]([OH:8])=[CH:10][C:11]3=[O:27])=[CH:16]2)=[N:20]1)[CH3:25]
Reactant: CCn1nc2ccc(-n3ccc(OCc4ccccc4)cc3=O)cc2c1C
Agent: [Pd]
Solvent: CO
Product: CCn1nc2ccc(-n3ccc(O)cc3=O)cc2c1C
Temperature: 25 °C
Reaction time: 3 h
Yield: 95.2 %

Procedure:
A suspension of 4-(benzyloxy)-1-(2-ethyl-3-methyl-2H-indazol-5-yl)pyridin-2(1H)-one (1.5 g) and 10% palladium carbon (444 mg) in methanol (30 ml) was stirred under a hydrogen atmosphere at room temperature for 3 hr. The insoluble material was filtered off, and the obtained filtrate was concentrated under reduced pressure to give the title compound (1.07 g).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:12](=[C:13]([N+:15]([O-])=O)[CH:14]=1)[NH:11][C:10]1[CH:9]=[N:8][CH:7]=[C:6]([NH:18][C:19](=[O:24])[C:20]([F:23])([F:22])[F:21])[C:5]2=1>CO>[NH2:15][C:13]1[CH:14]=[C:2]([Cl:1])[CH:3]=[C:4]2[C:12]=1[NH:11][C:10]1[CH:9]=[N:8][CH:7]=[C:6]([NH:18][C:19](=[O:24])[C:20]([F:23])([F:22])[F:21])[C:5]2=1
Reactant: O=C(Nc1cncc2[nH]c3c([N+](=O)[O-])cc(Cl)cc3c12)C(F)(F)F
Solvent: CO
Product: Nc1cc(Cl)cc2c1[nH]c1cncc(NC(=O)C(F)(F)F)c12
Reaction time: 8 h
Yield: 94.7 %

Procedure:
The crude N-(6-chloro-8-nitro-9H-β-carbolin-4-yl)-2,2,2-trifluoro-acetamide (130 mg, 0.36 mmol) was dissolved in 7 ml of MeOH and the reaction vessel was vacuum purged 3× with N2. Platinum (20 mg, 20% wt. on activated carbon) was added quickly, and the reaction vessel was again vacuum purged 3× with N2, followed by 3 additional vacuum purge cycles with H2. The reaction was allowed to stir under H2 at 1 atm overnight. Upon completion, the reaction vessel was purged of H2 and filtered over celite. The celite was washed several times with methanol until the filtrates were clear. The combined filtrates were concentrated to give N-(8-amino-6-chloro-9H-β-carbolin-4-yl)-2,2,2-trifluoro-acetamide as a yellow solid (112 mg, 95%). 1H-NMR (300 MHz, DMSO-d6): δ 11.83 (s, 1H), 8.98 (s, 1H), 8.30 (s, 1H), 7.10 (s, 1H), 6.82 (s, 1H), 5.87 (br, 2H). Formic acid standard conditions. DAD RT=1.95 min. M+H=329.
Reaction SMILES: C(N)CCC.C1(=O)OCCC1.[CH2:12]([NH:16][C:17](=O)[CH2:18][CH2:19][CH2:20][OH:21])[CH2:13][CH2:14][CH3:15].CC(C[AlH]CC(C)C)C>C1(C)C=CC=CC=1>[CH2:12]([NH:16][CH2:17][CH2:18][CH2:19][CH2:20][OH:21])[CH2:13][CH2:14][CH3:15]
Reactant: CCCCNC(=O)CCCO
Agent: CC(C)C[AlH]CC(C)C
Solvent: CCCCN
Solvent: O=C1CCCO1
Solvent: Cc1ccccc1
Product: CCCCNCCCCO
Temperature: 70 °C
Reaction time: 18 h

Procedure:
A solution of 8.1 g (110 mmol) of n-butylamine and 8.6 g of butyrolactone in 50 ml toluene was allowed to reflux under nitrogen atmosphere for 50 hours. Volatile solvents were removed in vacuo. To a solution of 3.18 gm (20 mmol) of the resultant N-butyl-4-hydroxybutyramide in 50 ml of toluene were added 120 ml (120 mmol) DIBAL(25% W). The solution was heated with stirring at 70° C. for 18 hours. After cooling to 0° C., the reaction was quenched with methanol (113 amount of DIBAL solution was used) followed by addition of saturated solution of Rochelle's salt. The mixture was extracted twice with EtOAc; the organic extracts were washed with brine and dried over Na2SO4.
Reaction SMILES: [CH3:1][NH:2][C:3]([C:5]1[CH:6]=[C:7]([CH:12]=[C:13]([C:15]2[CH:20]=[CH:19][C:18]([CH3:21])=[CH:17][N:16]=2)[CH:14]=1)[C:8]([O:10][CH3:11])=[O:9])=O.COC1C=CC(P2(=S)SP(=S)(C3C=CC(OC)=CC=3)[S:31]2)=CC=1.ClCCl>ClC(Cl)C>[CH3:1][NH:2][C:3]([C:5]1[CH:6]=[C:7]([CH:12]=[C:13]([C:15]2[CH:20]=[CH:19][C:18]([CH3:21])=[CH:17][N:16]=2)[CH:14]=1)[C:8]([O:10][CH3:11])=[O:9])=[S:31]
Reactant: COc1ccc(P2(=S)SP(=S)(c3ccc(OC)cc3)S2)cc1
Reactant: CNC(=O)c1cc(C(=O)OC)cc(-c2ccc(C)cn2)c1
Solvent: ClCCl
Solvent: CC(Cl)Cl
Product: CNC(=S)c1cc(C(=O)OC)cc(-c2ccc(C)cn2)c1
Temperature: 60 °C
Reaction time: 2 h
Yield: 112.8 %

Procedure:
To a solution of methyl 3-[(methylamino)carbonyl]-5-(5-methylpyridin-2-yl)benzoate (2.90 g, 10.2 mmol) in dichloroethane (20 mL) was added 2,4-bis-(4-methoxyphenyl)-1,3-dithia-2,4-diphosphetane 2,4-disulfide (Lawesson's reagent) (2.27 g, 5.61 mmol) and the mixture heated to 60° C. After 2 h, the reaction was cooled to ambient temperature. Dichloromethane (200 mL) was added, and the mixture washed with 100 mL of saturated aqueous sodium bicarbonate (2×) and brine (100 mL). The combined organic extracts were dried over sodium sulfate, filtered and concentrated. The residue was purified by silica gel chromatography (100% dichloromethane→90% dichloromethane/methanol) to give the title compound (1.9 g). MS 301.0 (M+1).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([Cl:8])=[CH:4][C:3]=1[NH:9][CH2:10][CH2:11][CH2:12][OH:13].O[CH:15]([CH:20]1[CH2:25][CH2:24][CH2:23][CH2:22][CH2:21]1)S([O-])(=O)=O.[Na+].C(O)C>O>[Cl:8][C:5]1[CH:6]=[CH:7][C:2]2[N:1]=[C:15]([CH:20]3[CH2:25][CH2:24][CH2:23][CH2:22][CH2:21]3)[N:9]([CH2:10][CH2:11][CH2:12][OH:13])[C:3]=2[CH:4]=1
Reactant: O=S(=O)([O-])C(O)C1CCCCC1
Reactant: Nc1ccc(Cl)cc1NCCCO
Agent: [Na+]
Solvent: CCO
Solvent: O
Product: OCCCn1c(C2CCCCC2)nc2ccc(Cl)cc21

Procedure:
A mixture of 40 parts of 3-[(2-amino-5-chlorophenyl)amino]-1-propanol, 87 parts of sodium α-hydroxycyclohexanemethanesulfonate and 200 parts of ethanol is stirred and refluxed for 10 minutes. The reaction mixture is diluted with water and the solvent is evaporated. The residue is extracted a few times with trichloromethane. The combined extracts are dried, filtered and evaporated. The oily residue is triturated in 2,2'-oxybispropane: a sticky tar precipitates. The 2,2'-oxybispropane is decanted and upon stirring at room temperature, the product is allowed to precipitate. It is filtered off and dried, yielding 6-chloro-2-cyclohexyl-1H-benzimidazole-1-propanol; mp. 120.1° C.
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[O:7]1[CH:16]2[CH:8]1[CH2:9][C:10]1[C:15]2=[CH:14][CH:13]=[CH:12][CH:11]=1.[Cl-].[Na+].[OH-].[Na+]>O>[N:1]1([CH:9]2[C:10]3[C:15](=[CH:14][CH:13]=[CH:12][CH:11]=3)[CH2:16][CH:8]2[OH:7])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: C1CCNCC1
Reactant: c1ccc2c(c1)CC1OC21
Agent: [Cl-]
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: OC1Cc2ccccc2C1N1CCCCC1
Temperature: 20 °C
Reaction time: 0.08 h

Procedure:
At 50° C. and over 5 minutes, 50 ml of piperidine and 50 ml of water were added to 21.25 g of 2,3-epoxy-indane and the mixture was maintained for 2 hours with stirring at this temperature. The solution was then cooled to 20° C. and was saturated with sodium chloride. 5 ml of sodium hydroxide were added, followed by extraction with ether. The extracts were concentrated to dryness under reduced pressure and the residue was taken up in 200 ml of ethyl acetate at 40° C., filtered, dried, and the solvents were eliminated under reduced pressure. The residue was taken up in isopropyl ether, filtered and taken to dryness to obtain 26.82 g of crude product which was purified by chromatography over silica, (eluent: ethyl acetate with 1% of triethylamine) to obtain [trans (±)] 2,3-dihydro-1-piperidinyl-1H-inden-2-ol melting at about 82° C.