Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]([F:16])([F:15])[C:3]1[CH:4]=[C:5]([CH:8]=[C:9]([C:11]([F:14])([F:13])[F:12])[CH:10]=1)[CH:6]=O.[CH3:17][N:18]1[N:22]=[N:21][C:20]([NH2:23])=[N:19]1.C(O)C.[BH4-].[Na+]>C1(C)C=CC=CC=1>[F:1][C:2]([F:16])([F:15])[C:3]1[CH:4]=[C:5]([CH:8]=[C:9]([C:11]([F:14])([F:13])[F:12])[CH:10]=1)[CH2:6][NH:23][C:20]1[N:21]=[N:22][N:18]([CH3:17])[N:19]=1
Reactant: Cn1nnc(N)n1
Reactant: O=Cc1cc(C(F)(F)F)cc(C(F)(F)F)c1
Agent: [BH4-]
Agent: [Na+]
Solvent: CCO
Solvent: Cc1ccccc1
Product: Cn1nnc(NCc2cc(C(F)(F)F)cc(C(F)(F)F)c2)n1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 87.6 %

Procedure:
A mixture of 3,5-bis(trifluoromethyl)benzaldehyde (4 g, 16.5 mmol), 2-methyl-2H-tetrazol-5-amine (1.96 g, 19.8 mmol) and molecular sieves (5-10 Å beads) in toluene (50 mL) was heated at reflux for 4 hours, after which time the solvent was removed. Ethanol (50 mL) and sodium borohydride (1.25 g, 33 mmol) were added. The resulting mixture was stirred at room temperature for 30 minutes and then partitioned between saturated NH4Cl (50 mL) and ethyl acetate (2×50 mL). The combined organic layers were washed with saturated NaCl (50 mL), dried (MgSO4), filtered and concentrated to yield the title compound as a white solid (4.7 g). 1H NMR (400 MHz, CDCl3) δ 4.2 (s, 3 H) 4.7 (s, 1 H) 4.7 (s, 1 H) 5.0 (t, J=6.0 Hz, 1 H) 7.8 (s, 1 H) 7.9 (s, 2 H). MS (ES+) Calc: 325.08, Found: 325.8 (M+1).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][C@H:11]([C:14]2[C:22]3[O:21][CH:20]=[CH:19][C:18]=3[CH:17]=[C:16]([F:23])[CH:15]=2)[C@H:10]([CH3:24])[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH2:25]([Li])CCC.IC>O1CCCC1>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][C@H:11]([C:14]2[C:22]3[O:21][C:20]([CH3:25])=[CH:19][C:18]=3[CH:17]=[C:16]([F:23])[CH:15]=2)[C@H:10]([CH3:24])[CH2:9]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: [Li]CCCC
Reactant: C[C@@H]1CN(C(=O)OC(C)(C)C)CC[C@@H]1c1cc(F)cc2ccoc12
Solvent: C1CCOC1
Solvent: CI
Product: Cc1cc2cc(F)cc([C@H]3CCN(C(=O)OC(C)(C)C)C[C@H]3C)c2o1
Reaction time: 0.08 h

Procedure:
A solution of 0.100 gm (0.3 mMol) (−)-cis-1-(tert-butoxycarbonyl)-3-methyl-4-(5-fluorobenzofur-7-yl)piperidine in 2 mL tetrahydrofuran was cooled to −78° C. To this solution were added 0.38 mL (0.6 mMol) n-butyllithium (1.6 M in hexane) dropwise. After stirring for 5 minutes, 0.02 mL (0.33 mMol) iodomethane were added and the reaction mixture was stirred at −78° C. for 3 hours. The solution was treated with an additional 0.06 mL (0.1 mMol) n-butyllithium (1.6 M in hexane) followed by 0.02 mL (0.33 mMol) iodomethane. After stirring for 1 hour at −78° C., an additional 0.06 mL (0.1 mMol) n-butyllithium (1.6 M in hexane) followed by 0.02 mL (0.33 mMol) iodomethane were added to the reaction mixture. The mixture was then stirred at room temperature for 14 hours and was then partitioned between 5 mL deionized water and 40 mL ethyl acetate. The organic phase was washed sequentially with 20 mL portions of saturated aqueous sodium bicarbonate and saturated aqueous sodium chloride. The organic phase was then dried over magnesium sulfate and concentrated under reduced pressure to provide (−)-cis-1-(tert-butoxycarbonyl)-3-methyl-4-(2-methyl-5-fluorobenzofur-7-yl)piperidine.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:8]2[N:9]=[C:10]([NH:12][C:13](=[O:26])[C:14]3[CH:19]=[CH:18][N:17]=[C:16]([N:20]4[CH2:25][CH2:24][O:23][CH2:22][CH2:21]4)[CH:15]=3)[S:11][C:7]=2[C:6]([CH:27]2[CH2:32][CH2:31][NH:30][CH2:29][CH2:28]2)=[CH:5][CH:4]=1.Cl.[C:34](OC(=O)C)(=[O:36])[CH3:35].C(=O)(O)[O-].[Na+]>C1COCC1.O.C(N(CC)CC)C>[C:34]([N:30]1[CH2:31][CH2:32][CH:27]([C:6]2[C:7]3[S:11][C:10]([NH:12][C:13](=[O:26])[C:14]4[CH:19]=[CH:18][N:17]=[C:16]([N:20]5[CH2:21][CH2:22][O:23][CH2:24][CH2:25]5)[CH:15]=4)=[N:9][C:8]=3[C:3]([O:2][CH3:1])=[CH:4][CH:5]=2)[CH2:28][CH2:29]1)(=[O:36])[CH3:35]
Reactant: CC(=O)OC(C)=O
Reactant: COc1ccc(C2CCNCC2)c2sc(NC(=O)c3ccnc(N4CCOCC4)c3)nc12
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: COc1ccc(C2CCN(C(C)=O)CC2)c2sc(NC(=O)c3ccnc(N4CCOCC4)c3)nc12
Reaction time: 1 h
Yield: 65.8 %

Procedure:
To a solution of 0.05 g (0.095 mMol) N-(4-methoxy-7-piperidin-4-yl-benzothiazol-2-yl)-2-morpholin-4-yl-isonicotinamide 1:2 hydrochloride in 3 ml THF were added 0.029 ml triethyl amine. At 0° C. 0.011 ml (0.11 mMol) acetic anhydride was added dropwise and stirred for 1 h. Then a mixture of 5 ml sat. aqueous sodium bicarbonate and 10 ml water were added. This was extracted three times with 15 ml ethyl acetate, the combined organic phase were dried over sodium sulfate and evaporated to dryness in vacuo. One obtained 0.031 g (66%) N-[7-(1-acetyl-piperidin-4-yl)-4-methoxy-benzothiazol-2-yl]-2-morpholin-4-yl-isonicotinamide as a white solid. F.p.: 231-233° C.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([C:11]2[N:16]=[C:15]([CH2:17][C:18]3[CH:23]=[C:22]([F:24])[CH:21]=[CH:20][C:19]=3[F:25])[C:14]([CH2:26][CH2:27][C:28]([O:30]C)=[O:29])=[CH:13][C:12]=2[F:32])(=[O:10])=[O:9])=[CH:4][CH:3]=1.[OH-].[Na+].Cl>C(O)C>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([C:11]2[N:16]=[C:15]([CH2:17][C:18]3[CH:23]=[C:22]([F:24])[CH:21]=[CH:20][C:19]=3[F:25])[C:14]([CH2:26][CH2:27][C:28]([OH:30])=[O:29])=[CH:13][C:12]=2[F:32])(=[O:10])=[O:9])=[CH:4][CH:3]=1
Reactant: COC(=O)CCc1cc(F)c(S(=O)(=O)c2ccc(Cl)cc2)nc1Cc1cc(F)ccc1F
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: O=C(O)CCc1cc(F)c(S(=O)(=O)c2ccc(Cl)cc2)nc1Cc1cc(F)ccc1F
Temperature: 25 °C
Reaction time: 3 h
Yield: 92.5 %

Procedure:
To an ethanol (8 ml) solution of methyl 3-[6-(4-chlorophenylsulfonyl)(2,5-difluorophenyl)methyl-5-fluoropyridin-3-yl]propionate (387 mg, 0.80 mmol) was added a 1N aqueous sodium hydroxide solution (4 ml). The resulting mixture was stirred at room temperature for 3 hours. The reaction mixture was acidified with 1N hydrochloric acid, followed by extraction with dichloromethane. The organic layer was dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated under reduced pressure. The residue thus obtained was washed with a mixed solvent of diethyl ether and hexane and then collected by filtration to give the title compound (349 mg, 0.74 mmol, 93%) as a white solid.
Reaction SMILES: CO[C:3]1[CH:11]=CC([N+]([O-])=O)=C2[C:4]=1CN(C)C2=O.[OH:17][C:18]1[CH:26]=[CH:25][C:24]([N+:27]([O-:29])=[O:28])=[C:23]2[C:19]=1[CH2:20][N:21]([CH3:31])[C:22]2=[O:30].C(I)(C)C>>[CH3:31][N:21]1[CH2:20][C:19]2[C:23](=[C:24]([N+:27]([O-:29])=[O:28])[CH:25]=[CH:26][C:18]=2[O:17][CH:3]([CH3:11])[CH3:4])[C:22]1=[O:30]
Reactant: COc1ccc([N+](=O)[O-])c2c1CN(C)C2=O
Reactant: CN1Cc2c(O)ccc([N+](=O)[O-])c2C1=O
Solvent: CC(C)I
Product: CC(C)Oc1ccc([N+](=O)[O-])c2c1CN(C)C2=O

Procedure:
The title compound was prepare according to the procedure for 4-Methoxy-2-methyl-7-nitro-2,3-dihydro-1H-isoindol-1-one (Compound 205B) using 4-Hydroxy-2-methyl-7-nitro-2,3-dihydro-1H-isoindol-1-one and 4-Hydroxy-2-methyl-7-nitro-2,3-dihydro-1H-isoindol-1-one (Compound 205C, 50.0 mg, 0.240 mmol) and isopropyl iodide. 1H NMR (400 MHz, CD3OD) δ=1.40 (d, J=6.1 Hz, 6 H), 3.15 (s, 3 H), 4.37 (s, 2 H), 4.80-4.87 (m, 1 H), 7.22 (d, J=8.8 Hz, 1 H), 7.86 (d, J=8.8 Hz, 1 H). MS (ES+): m/z 237.18 (100) [MH+]; HPLC: tR=0.94 min (UPLC, Analytical).
Reaction SMILES: [CH3:1][O:2][C:3]1[C:12]([NH:13][C:14](=[O:22])OC2C=CC=CC=2)=[N:11][C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[N:4]=1.[F:23][C:24]1[CH:25]=[C:26]([N:31]2[CH2:36][CH2:35][NH:34][CH2:33][CH2:32]2)[CH:27]=[C:28]([F:30])[CH:29]=1>>[CH3:1][O:2][C:3]1[C:12]([NH:13][C:14]([N:34]2[CH2:33][CH2:32][N:31]([C:26]3[CH:25]=[C:24]([F:23])[CH:29]=[C:28]([F:30])[CH:27]=3)[CH2:36][CH2:35]2)=[O:22])=[N:11][C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[N:4]=1
Reactant: COc1nc2ccccc2nc1NC(=O)Oc1ccccc1
Reactant: Fc1cc(F)cc(N2CCNCC2)c1
Product: COc1nc2ccccc2nc1NC(=O)N1CCN(c2cc(F)cc(F)c2)CC1
Yield: 74.5 %

Procedure:
Phenyl N-(2-methoxyquinoxalin-3-yl)carbamate and 1-(3,5-difluorophenyl)piperazine were reacted by the same way with the example 36 to obtain the titled compound.
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6]([C@H:9]2[CH2:14][CH2:13][C@H:12]([OH:15])[CH2:11][CH2:10]2)=[CH:5][CH:4]=1)#[N:2].[CH2:16]([C@H:21]1[CH2:26][CH2:25][C@H:24]([C:27]2[CH:32]=[CH:31][C:30]([C:33]3[CH:38]=[CH:37][C:36]([C:39](O)=[O:40])=[CH:35][CH:34]=3)=[CH:29][CH:28]=2)[CH2:23][CH2:22]1)[CH2:17][CH2:18][CH2:19][CH3:20].C1(N=C=NC2CCCCC2)CCCCC1>CN(C)C1C=CN=CC=1.ClCCl>[C:1]([C:3]1[CH:4]=[CH:5][C:6]([C@H:9]2[CH2:14][CH2:13][C@H:12]([O:15][C:39]([C:36]3[CH:35]=[CH:34][C:33]([C:30]4[CH:31]=[CH:32][C:27]([C@H:24]5[CH2:25][CH2:26][C@H:21]([CH2:16][CH2:17][CH2:18][CH2:19][CH3:20])[CH2:22][CH2:23]5)=[CH:28][CH:29]=4)=[CH:38][CH:37]=3)=[O:40])[CH2:11][CH2:10]2)=[CH:7][CH:8]=1)#[N:2]
Reactant: CCCCC[C@H]1CC[C@H](c2ccc(-c3ccc(C(=O)O)cc3)cc2)CC1
Reactant: N#Cc1ccc([C@H]2CC[C@H](O)CC2)cc1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Product: CCCCC[C@H]1CC[C@H](c2ccc(-c3ccc(C(=O)O[C@H]4CC[C@H](c5ccc(C#N)cc5)CC4)cc3)cc2)CC1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
A mixture of 1.0 g of trans-4-(p-cyanophenyl)cyclohexanol, 1.75 g of 4'-(trans-4-pentylcyclohexyl)-4-biphenylcarboxylic acid, 1.2 g of dicyclohexylcarbodiimide and 98 mg of 4-(dimethylamino)pyridine in 60 ml of dichloromethane was stirred at room temperature for 18 hours under argon gasification. The beige suspension was subsequently filtered (rinsing with dichloromethane) and the filtrate was concentrated. Low-pressure chromatography (0.5 bar) of the residue (3.1 g) on silica gel with toluene yielded 1.2 g (45%) of pure 4'-(trans-4-pentylcyclohexyl)-4-biphenylcarboxylic acid trans-4-(p-cyanophenyl)cyclohexyl ester. Recrystallization from ethyl acetate/acetone (vol. 1:4) gave white crystals of m.p. (C-N) 148.6° C. and cl.p. (N-I) 347° C.; purity 99.6%.
Reaction SMILES: Cl[C:2]1[C:3]2[CH:11]=[CH:10][N:9]=[CH:8][C:4]=2[N:5]=[CH:6][N:7]=1.[Cl:12][C:13]1[CH:21]=[C:20]2[C:16]([CH2:17][CH2:18][NH:19]2)=[CH:15][CH:14]=1.N1C=CC=CC=1.C(Cl)Cl>CN(C=O)C>[Cl:12][C:13]1[CH:21]=[C:20]2[C:16]([CH2:17][CH2:18][N:19]2[C:2]2[C:3]3[CH:11]=[CH:10][N:9]=[CH:8][C:4]=3[N:5]=[CH:6][N:7]=2)=[CH:15][CH:14]=1
Reactant: Clc1ccc2c(c1)NCC2
Reactant: Clc1ncnc2cnccc12
Solvent: c1ccncc1
Solvent: ClCCl
Solvent: CN(C)C=O
Product: Clc1ccc2c(c1)N(c1ncnc3cnccc13)CC2
Temperature: 70 °C

Procedure:
4-Chloropyrido[3,4-d]pyrimidine (0.10 g, 0.60 mmol), 6-chloroindoline (0.10 g, 0.66 mmol) and pyridine (0.14 g, 1.81 mmol) were combined in DMF (1 mL) and heated at 70° C. for 3 hours. The reaction was cooled to room temperature and then added to methylene chloride (150 mL). The organic layer was washed with saturated sodium carbonate and water and then dried over sodium sulfate. The solvent was removed by rotary evaporation and the residue purified by column chromatography (silica gel, 9/2/1—CH2Cl2/hexanes/methanol) to give the title product as a pale yellow residue (0.048 g, 28%). MP 194-6° C.; LCMS: 283 (MH+).
Reaction SMILES: [CH3:1][CH:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][C:10]=2[O:12][C:13]2[N:18]=[CH:17][C:16]([N+:19]([O-])=O)=[CH:15][N:14]=2)[O:5][CH2:4][CH2:3]1.[Cl-].[NH4+]>C1COCC1.O.[Fe]>[CH3:1][CH:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][C:10]=2[O:12][C:13]2[N:14]=[CH:15][C:16]([NH2:19])=[CH:17][N:18]=2)[O:5][CH2:4][CH2:3]1
Reactant: CC1CCOc2cccc(Oc3ncc([N+](=O)[O-])cn3)c21
Agent: [Fe]
Agent: [Cl-]
Agent: [NH4+]
Solvent: O
Solvent: C1CCOC1
Product: CC1CCOc2cccc(Oc3ncc(N)cn3)c21
Temperature: 25 °C
Reaction time: 24 h
Yield: 83.8 %

Procedure:
2-[(4-methyl-3,4-dihydro-2Hchromen-5-yl)oxy]-5-nitropyrimidine (Intermediate 216, 192 mg, 0.668 mmol) was dissolved in 9.0 mL of a 2/1 THF/water solution. Iron (187 mg, 3.34 mmol) and ammonium chloride (179 mg, 3.34 mmol) were added and the reaction mixture was stirred for 24 h at room temperature. After dilution with AcOEt and filtration over a celite pad (washing with AcOEt), the organic phase was washed (two times) with an aqueous saturated solution of NaHCO3. The organic layer was dried over Na2SO4, filtered and evaporated and the residue was purified by flash chromatography on silica gel using cyclohexane/ethyl acetate from 1:0 to 0:1 as eluents affording the title compound (144 mg).
Reaction SMILES: [O:1]=[C:2]1[NH:8][C:7]2[CH:9]=[C:10]([CH3:13])[CH:11]=[CH:12][C:6]=2[N:5]([C:14]([O:16][CH2:17][C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)=[O:15])[CH2:4][CH:3]1[NH:24][C:25]([O:27][C:28]([CH3:31])([CH3:30])[CH3:29])=[O:26].Br[CH2:33][C:34]([C:36]1[CH:41]=[CH:40][CH:39]=[CH:38][C:37]=1[CH3:42])=[O:35].[OH-].[Na+]>C1(C)C=CC=CC=1.[Br-].C([N+](CCCC)(CCCC)CCCC)CCC>[C:37]1([CH3:42])[C:36]([C:34]([CH2:33][N:8]2[C:7]3[CH:9]=[C:10]([CH3:13])[CH:11]=[CH:12][C:6]=3[N:5]([C:14]([O:16][CH2:17][C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)=[O:15])[CH2:4][CH:3]([NH:24][C:25]([O:27][C:28]([CH3:31])([CH3:30])[CH3:29])=[O:26])[C:2]2=[O:1])=[O:35])=[CH:41][CH:40]=[CH:39][CH:38]=1
Reactant: Cc1ccc2c(c1)NC(=O)C(NC(=O)OC(C)(C)C)CN2C(=O)OCc1ccccc1
Reactant: Cc1ccccc1C(=O)CBr
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [Br-]
Agent: [Na+]
Solvent: Cc1ccccc1
Product: Cc1ccc2c(c1)N(CC(=O)c1ccccc1C)C(=O)C(NC(=O)OC(C)(C)C)CN2C(=O)OCc1ccccc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 42.6 %

Procedure:
2-Oxo-3-tert-butoxycarbonylamino-5-benzyloxycarbonyl-8-methyl-1,3,4,5-tetrahydro-2H-1,5-benzodiazepine (23.1 g) was suspended in toluene (320 ml), 2-bromo-2′-methylacetophenone (13.9 g), 1N aqueous sodium hydroxide (160 ml) and tetra-n-butylammonium bromide (400 mg) were added thereto, the mixture was stirred for 2 hours at room temperature. After reaction, the reaction mixture was separated, the organic layer was washed with saturated brine, and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure, the residue was purified by silica gel column chromatography(n-hexane:ethyl acetate=4:1), to thereby obtain 12.9 g of the titled compound.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([C:16]([O:18][CH3:19])=[O:17])[C:5]2[CH:6]=[N:7][N:8]([CH:11]3[CH2:15][CH2:14][CH2:13][CH2:12]3)[C:9]=2[CH:10]=1.[OH:20][C:21]1[CH:22]=[C:23](B(O)O)[CH:24]=[CH:25][CH:26]=1.C([O-])([O-])=O.[Na+].[Na+].CO.C(Cl)Cl>O1CCOCC1.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>[CH:11]1([N:8]2[C:9]3[CH:10]=[C:2]([C:25]4[CH:24]=[CH:23][CH:22]=[C:21]([OH:20])[CH:26]=4)[CH:3]=[C:4]([C:16]([O:18][CH3:19])=[O:17])[C:5]=3[CH:6]=[N:7]2)[CH2:15][CH2:14][CH2:13][CH2:12]1
Reactant: OB(O)c1cccc(O)c1
Reactant: COC(=O)c1cc(Br)cc2c1cnn2C1CCCC1
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: ClCCl
Solvent: C1COCCO1
Solvent: CO
Product: COC(=O)c1cc(-c2cccc(O)c2)cc2c1cnn2C1CCCC1
Temperature: 100 °C
Reaction time: 1 h
Yield: 60.5 %

Procedure:
A solution of methyl 6-bromo-1-cyclopentyl-1H-indazole-4-carboxylate (1 g, 3.93 mmol), (3-hydroxyphenyl)-boronic acid (1.43 g, 4.72 mmol) and Pd(PPh3)4 (0.227 g, 0.196 mmol) in 1,4-dioxane (10.5 mL) was purged with argon for 10 min. Then, 2 M Na2CO3 solution (1.5 g, 14.2 mmol) was added to it and again argon was purged through it for 10 min. The reaction mixture was stirred at 100° C. for 1 h. After completion of the reaction, water was added to it and extraction was carried out using 5% MeOH/DCM. The combined organic layers were washed with water, dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure to afford crude material which was purified by column chromatography over silica gel (60-120 mesh size) to afford the title compound (0.8 g, 61%).
Reaction SMILES: [C:1]1(=[O:7])[CH2:6][CH2:5][CH2:4][CH:3]=[CH:2]1.C(O)(=O)C.[CH3:12][S-:13].[Na+]>C1(C)C=CC=CC=1>[CH3:12][S:13][CH:3]1[CH2:4][CH2:5][CH2:6][C:1](=[O:7])[CH2:2]1
Reactant: C[S-]
Reactant: O=C1C=CCCC1
Agent: [Na+]
Solvent: CC(=O)O
Solvent: Cc1ccccc1
Product: CSC1CCCC(=O)C1
Temperature: 25 °C
Reaction time: 8 h
Yield: 86.2 %

Procedure:
Cyclohex-2-enone (3.80 g, 95% Aldrich, 39.5 mmol uncorrected), toluene (15.31 g, HPLC grade) and glacial acetic acid (2.85 g, 47.4 mmoles, 1.20 eq, 99.7+% Aldrich) were combined in a 50 mL 3-necked round bottom flask equipped with a magnetic stirrer, reflux condenser with nitrogen oil bubbler vented to a bleach scrubber, thermometer with Therm-o-watch controller and septum. To the stirred solution was added 15 wt % sodium thiomethoxide (19.4 g of solution, 2.91 g, 41.5 mmol, 1.05 eq of NaSCH3) in portions via syringe during 19 min. The reaction temperature increased from 28.0° C. to 36.4° C. during the addition. The two-phase mixture was stirred at ambient temperature overnight. The reaction mixture was heated to about 50° C. and stirred for 7.5 h. The mixture was then allowed to cool to room temperature with stirring overnight. The phases were allowed to settle for 30 min. The lower aqueous phase was removed. The upper organic phase was washed with water (2×10 mL), dried through a cone of anhydrous magnesium sulfate and concentrated on the rotary evaporator (29 in. Hg vacuum/48° C.) to afford 4.91 g of 3-(methylthio)cyclohexanone as a clear pale yellow oil. Area % conversion by GC 95%. Raw area % 91.1%. Mass recovery 86%.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([CH3:8])=[C:4]([N+:9]([O-:11])=[O:10])[CH:3]=1.C1C(C(OO)=O)=CC=CC=1.BrN1C(=O)CCC1=O.Cl.[CH2:31]([O:33][C:34](=[O:37])[CH2:35][NH2:36])[CH3:32].C(=O)([O-])O.[Na+]>C1C=CC=CC=1.C(O)C.C(OCC)(=O)C>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][NH:36][CH2:35][C:34]([O:33][CH2:31][CH3:32])=[O:37])=[C:4]([N+:9]([O-:11])=[O:10])[CH:3]=1
Reactant: CCOC(=O)CN
Reactant: Cc1ccc(Br)cc1[N+](=O)[O-]
Agent: Cl
Agent: O=C(OO)c1ccccc1
Agent: O=C([O-])O
Solvent: CCO
Solvent: CCOC(C)=O
Solvent: c1ccccc1
Product: CCOC(=O)CNCc1ccc(Br)cc1[N+](=O)[O-]
Temperature: 80 °C
Reaction time: 48 h

Procedure:
19.8 g (91 mmol) of 4-bromo-2-nitrotoluene was dissolved in 150 ml of benzene. 50 mg of perbenzoic acid and 19.6 g (91 mmol) of N-bromosuccinimide were added to the obtained solution, and they were stirred at 80° C. for 2 days. After the treatment with ethyl acetate as the extracting solvent by an ordinary method, the obtained crude product was dissolved in 100 ml of ethanol. 12.9 g (91 mmol) of glycine ethyl ester hydrochloride and 15.3 g (182 mmol) of sodium hydrogencarbonate were added to the obtained solution, and they were stirred at 80° C. for 4 hours. The insoluble matter was filtered out, and the solvent was evaporated. After the extraction with ethyl acetate, the obtained product was washed with 1 N hydrochloric acid. The obtained aqueous layer was made basic with 1 N sodium hydroxide. After the extraction with ethyl acetate, the obtained organic layer was washed with saturated aqueous sodium chloride solution and then dried. The solvent was evaporated to obtain the title compound.
Reaction SMILES: [CH3:1][C:2]1[NH:3][C:4]2[C:5]([N:16]=1)=[C:6]1[C:11](=[CH:12][CH:13]=2)[O:10][CH2:9][C@H:8]([CH2:14]Cl)[O:7]1.[NH:17]1[CH2:22][CH:21]=[C:20]([C:23]2[C:31]3[C:26](=[CH:27][CH:28]=[CH:29][CH:30]=3)[NH:25][CH:24]=2)[CH2:19][CH2:18]1>CS(C)=O.C(OCC)(=O)C>[NH:25]1[C:26]2[C:31](=[CH:30][CH:29]=[CH:28][CH:27]=2)[C:23]([C:20]2[CH2:21][CH2:22][N:17]([CH2:14][CH:8]3[O:7][C:6]4[C:11](=[CH:12][CH:13]=[C:4]5[NH:3][C:2]([CH3:1])=[N:16][C:5]5=4)[O:10][CH2:9]3)[CH2:18][CH:19]=2)=[CH:24]1
Reactant: Cc1nc2c3c(ccc2[nH]1)OC[C@H](CCl)O3
Reactant: C1=C(c2c[nH]c3ccccc23)CCNC1
Solvent: CS(C)=O
Solvent: CCOC(C)=O
Product: Cc1nc2c3c(ccc2[nH]1)OCC(CN1CC=C(c2c[nH]c4ccccc24)CC1)O3
Temperature: 105 °C

Procedure:
A mixture of 0.50 g (2.1 mmole) of [(8R)-2-methyl-7,8-dihydro-3H-6,9-dioxa-1,3-diaza-cyclopenta[a]naphthalen-8-yl]methyl chloride and 1.0 g (5.0 mmole) of 3-(1,2,3,6-tetrahydro-4-pyridinyl)-1H-indole in 10.0 mL of DMSO was heated at 100-110° C. under nitrogen for 6 hours. The reaction was allowed to come to room temperature, diluted to 500 mL with ethyl acetate, washed with 400 mL portions of saturated aqueous sodium bicarbonate, water and saturated brine, dried over sodium sulfate, filtered and evaporated in vacuum. The residue was column chromatographed on silica gel with 1% methanol in chloroform as eluant and the product fractions concentrated in vacuum to give the desired compound as the free base. Recrystallization from ethanol with the addition of 0.12 g of fumaric acid gave 0.11 g of the (S)-enantiomer of the title compound as a yellow solid fumarate, one-quarter hydrate, m.p. 219-222° C.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([C:8]2[C:16]3[C:11](=[CH:12][CH:13]=[C:14]([C:17]4[O:21][C:20]([NH:22][CH2:23][C:24]5[CH:29]=[CH:28][C:27]([O:30][CH3:31])=[CH:26][CH:25]=5)=[N:19][N:18]=4)[CH:15]=3)[N:10]([S:32]([C:35]3[CH:41]=[CH:40][C:38]([CH3:39])=[CH:37][CH:36]=3)(=[O:34])=[O:33])[CH:9]=2)[CH:5]=[CH:4][CH:3]=1.[NH:42]1[CH2:47][CH2:46][O:45][CH2:44][CH2:43]1>>[CH3:31][O:30][C:27]1[CH:28]=[CH:29][C:24]([CH2:23][NH:22][C:20]2[O:21][C:17]([C:14]3[CH:15]=[C:16]4[C:11](=[CH:12][CH:13]=3)[N:10]([S:32]([C:35]3[CH:41]=[CH:40][C:38]([CH3:39])=[CH:37][CH:36]=3)(=[O:33])=[O:34])[CH:9]=[C:8]4[C:6]3[CH:5]=[CH:4][CH:3]=[C:2]([N:42]4[CH2:47][CH2:46][O:45][CH2:44][CH2:43]4)[N:7]=3)=[N:18][N:19]=2)=[CH:25][CH:26]=1
Reactant: C1COCCN1
Reactant: COc1ccc(CNc2nnc(-c3ccc4c(c3)c(-c3cccc(Cl)n3)cn4S(=O)(=O)c3ccc(C)cc3)o2)cc1
Product: COc1ccc(CNc2nnc(-c3ccc4c(c3)c(-c3cccc(N5CCOCC5)n3)cn4S(=O)(=O)c3ccc(C)cc3)o2)cc1
Temperature: 130 °C
Yield: 48 %

Procedure:
The solution of 5-(3-(6-chloropyridin-2-yl)-1-tosyl-1H-indol-5-yl)-N-(4-methoxybenzyl)-1,3,4-oxadiazol-2-amine (1.0 g, 1.70 mmol) and morpholine (0.178 g, 2.05 mmol) was taken in sealed tube and heated at 130° C. for 5 h, then cooled to RT and poured in cooled ice water (5 mL) and extracted with EtOAc. The combined organic layers were washed with brine, dried, filtered and concentrated to give N-(4-methoxybenzyl)-5-(3-(6-morpholinopyridin-2-yl)-1-tosyl-1H-indol-5-yl)-1,3,4-oxadiazol-2-amine (0.52 g, 48%) as an off-white solid. MS (ESI, pos. ion) m/z: 637 (M+1); 1H NMR (DMSO-d6, 400 MHz): δ ppm 8.95 (s, 1H), 8.51 (s, 1H), 8.14 (d, J=8.8 Hz, 1H), 7.99 (d, J=8.4 Hz, 2H), 7.85-7.82 (m, 1H), 7.72-7.64 (m, 2H), 7.42-7.39 (m, 3H), 7.32 (d, J=8.4 Hz, 2H), 6.9 (d, J=8.8 Hz, 2H), 6.83 (d, J=8.8 Hz, 1H), 4.3 (s, 2H), 3.75 (m, 8H), 3.56 (s, 3H), 2.31 (s, 3H).
Reaction SMILES: [C:1]([C:9]#[N:10])(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[N:11]([CH2:14][C:15]([O:17][CH2:18][CH3:19])=[O:16])=[N+:12]=[N-:13]>>[C:1]([C:9]1[N:11]([CH2:14][C:15]([O:17][CH2:18][CH3:19])=[O:16])[N:12]=[N:13][N:10]=1)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: N#CC(=O)c1ccccc1
Reactant: CCOC(=O)CN=[N+]=[N-]
Product: CCOC(=O)Cn1nnnc1C(=O)c1ccccc1
Temperature: 105 °C

Procedure:
A mixture of benzoyl cyanide (5.1 grams, 39 mmol.) and ethyl azidoacetate (5.0 grams, 39 mmol.) was heated at 105°C. for 20 hours. The solution was cooled. The crystalline product [6.5 g. (64 percent), m.p. 63°-67°C.] was separated and washed with a mixture of ethyl ether and hexane. The yield of the title product was 6.5 grams (64 percent of theoretical). The melting point was 63°-67°C. The analysis was as follows: