Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH:1]1[CH2:7][CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.Cl[C:9]1[N:14]=[C:13]([CH3:15])[C:12]([CH:16]([CH2:21][CH2:22][CH3:23])[C:17]([O:19][CH3:20])=[O:18])=[C:11]([C:24]2[CH:29]=[CH:28][C:27]([CH3:30])=[CH:26][CH:25]=2)[N:10]=1>O1CCCC1>[N:1]1([C:9]2[N:14]=[C:13]([CH3:15])[C:12]([CH:16]([CH2:21][CH2:22][CH3:23])[C:17]([O:19][CH3:20])=[O:18])=[C:11]([C:24]3[CH:29]=[CH:28][C:27]([CH3:30])=[CH:26][CH:25]=3)[N:10]=2)[CH2:7][CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: CCCC(C(=O)OC)c1c(C)nc(Cl)nc1-c1ccc(C)cc1
Reactant: C1CCCNCC1
Solvent: C1CCOC1
Product: CCCC(C(=O)OC)c1c(C)nc(N2CCCCCC2)nc1-c1ccc(C)cc1
Yield: 87.1 %

Procedure:
Methyl 2-(2-(azepan-1-yl)-4-methyl-6-p-tolylpyrimidin-5-yl)pentanoate was prepared according to the general method A starting from azepane (0.152 mL; 1.32 mmol) and methyl 2-(2-chloro-4-methyl-6-p-tolylpyrimidin-5-yl)pentanoate (0.110 g; 0.264 mmol) in tetrahydrofuran (2 mL). Purification by flash-chromatography on silica gel using a gradient of ethyl acetate (5-15%) in heptane furnished 91 mg (87%) of the title compound as an oil. ESI/APCI(+): 396(M+H), 418 (M+Na). ESI/APCI(−): 394 (M−H).
Reaction SMILES: [OH:1]O.[Cl:3][C:4]1[C:5]([S:14][CH2:15][CH2:16][CH3:17])=[N:6][CH:7]=[C:8]([C:10]([F:13])([F:12])[F:11])[CH:9]=1>C(O)(=O)C>[Cl:3][C:4]1[C:5]([S:14]([CH2:15][CH2:16][CH3:17])=[O:1])=[N:6][CH:7]=[C:8]([C:10]([F:11])([F:12])[F:13])[CH:9]=1
Reactant: CCCSc1ncc(C(F)(F)F)cc1Cl
Reactant: OO
Solvent: CC(=O)O
Product: CCCS(=O)c1ncc(C(F)(F)F)cc1Cl
Temperature: 25 °C
Reaction time: 14 h

Procedure:
8.4 g (0.124 mol) of 50% strength hydrogen peroxide were added with stirring at 15-20° C. in the course of 15 minutes to a mixture of 31 g (0.1213 mol) of 3-chloro-2-n-propylthio-5-trifluoromethylpyridine in 150 ml of acetic acid, during which process the temperature rose to 27° C. in the course of 6 hours. After the reaction mixture had been stirred for 14 hours at 25° C., it was poured into ice-water and extracted 3 times with methylene chloride. The organic phase was washed with water and saturated sodium hydrogen carbonate solution, dried and concentrated in vacuo, yielding 32 g (97.2% of theory) of the title compound of m.p. 51-53° C.
Reaction SMILES: [Br:1][C:2]1[C:3]([F:18])=[CH:4][C:5]([F:17])=[C:6](/[C:8](=[N:10]/[S:11]([C:13]([CH3:16])([CH3:15])[CH3:14])=[O:12])/[CH3:9])[CH:7]=1.Br[C:20]([F:27])([F:26])[C:21]([O:23][CH2:24][CH3:25])=[O:22]>>[CH2:24]([O:23][C:21](=[O:22])[C:20]([F:27])([F:26])[C@@:8]([C:6]1[CH:7]=[C:2]([Br:1])[C:3]([F:18])=[CH:4][C:5]=1[F:17])([NH:10][S@@:11]([C:13]([CH3:16])([CH3:15])[CH3:14])=[O:12])[CH3:9])[CH3:25]
Reactant: C/C(=N\S(=O)C(C)(C)C)c1cc(Br)c(F)cc1F
Reactant: CCOC(=O)C(F)(F)Br
Product: CCOC(=O)C(F)(F)[C@](C)(N[S@](=O)C(C)(C)C)c1cc(Br)c(F)cc1F

Procedure:
Starting from 2-methyl-propane-2-sulfinic acid [1-(5-bromo-2,4-difluoro-phenyl)-eth-(E)-ylidene]-amide (intermediate A2E) and ethyl 2-bromo-2,2-difluoroacetate, the product (R)-3-(5-bromo-2,4-difluoro-phenyl)-2,2-difluoro-3-((R)-2-methyl-propane-2-sulfinylamino)-butyric acid ethyl ester was obtained as an orange oil. MS (ISP): m/z=462.1 [M+H]+ and 464.1 [M+2+H]−.
Reaction SMILES: [CH3:1][NH:2][C:3]1[N:8]=[C:7](Cl)[N:6]=[C:5]([Cl:10])[N:4]=1.[Cl:11][C:12]1[CH:13]=[C:14]([CH:16]=[C:17]([Cl:19])[CH:18]=1)[NH2:15].C(Cl)Cl.[K+].[Br-]>>[Cl:11][C:12]1[CH:13]=[C:14]([NH:15][C:7]2[N:8]=[C:3]([NH:2][CH3:1])[N:4]=[C:5]([Cl:10])[N:6]=2)[CH:16]=[C:17]([Cl:19])[CH:18]=1
Reactant: Nc1cc(Cl)cc(Cl)c1
Reactant: CNc1nc(Cl)nc(Cl)n1
Agent: [Br-]
Agent: [K+]
Solvent: ClCCl
Product: CNc1nc(Cl)nc(Nc2cc(Cl)cc(Cl)c2)n1
Yield: 10 %

Procedure:
The title compound was synthesized from 2-methylamino-4,6-dichloro-1,3,5-triazine and 3,5-dichloroaniline using a similar procedure to the one used in 2, except with a longer reaction time (18 h instead of 2 h). Yield: 10%; Tm 242° C.; FTIR (CH2Cl2/KBr) 3275, 3184, 3126, 3081, 2960, 2920, 2849, 1641, 1606, 1573, 1546, 1534, 1507, 1448, 1425, 1388, 1306, 1279, 1253, 1237, 1229, 1205, 1165, 1126, 1115, 1107, 1092, 1035, 984, 954, 937, 869, 854, 837, 809, 793, 753, 725 cm−1; 1H NMR (300 MHz, DMSO-d6, 298 K) δ 10.39, 10.23 (s, s, 1H), 8.24 (s, 1H), 7.86, 7.83 (d, d, 3J=1.8 Hz, 2H), 7.23, 7.20 (t, t, 3J=1.8 Hz, 1H), 2.86, 2.82 (s, d, 3J=4.7 Hz, 3H) ppm; 13C NMR (75 MHz, DMSO-d6): δ 167.7, 165.7, 165.5, 163.6, 162.9, 141.5, 133.83, 133.77, 121.5, 117.8, 117.6, 27.29, 27.23 ppm; HRMS (EI) calcd. for C10H8Cl3N5 (m/e): 302.9845. found: 302.9839.
Reaction SMILES: [CH2:1]([O:8][C:9]([NH:11][C@H:12]([CH2:19][CH2:20]OS(C)(=O)=O)[CH2:13]OS(C)(=O)=O)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl.[NH2:27][OH:28].C([O-])(O)=O.[Na+]>CCN(CC)CC.CS(C)=O.Cl>[CH2:1]([O:8][C:9]([NH:11][C@@H:12]1[CH2:19][CH2:20][N:27]([OH:28])[CH2:13]1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CS(=O)(=O)OCC[C@H](COS(C)(=O)=O)NC(=O)OCc1ccccc1
Reactant: NO
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: CS(C)=O
Product: O=C(N[C@@H]1CCN(O)C1)OCc1ccccc1
Temperature: 60 °C
Yield: 85 %

Procedure:
(R)-2-(Benzyloxycarbonylamino)-1,4-dimethanesulfonyloxybutane (2.0 g; 5.06 mmol) was dissolved in a Et3N/DMSO mixture (1:1, 20 ml). Hydroxylamine hydrochloride (1.4 g; 20.2 mmol) was added and the mixture was heated at 60° C. over night. The mixture was poured in aqueous HCl (the pH was adjusted to pH=6 with NaHCO3) and extracted twice with AcOEt. The organic phase was washed with water and dried over Na2SO4. The solids were filtered off and the solvent was removed. A light yellow oil (1.4 g, purity 73%) was obtained (yield: 85%). The crude title compound was used as is.
Reaction SMILES: [CH3:1][N:2]1[C:6]2=[N:7][CH:8]=[C:9]([CH2:11][CH2:12]OS(C3C=CC(C)=CC=3)(=O)=O)[CH:10]=[C:5]2[O:4][C:3]1=[O:24].[C:25]1([N:31]2[CH2:36][CH2:35][NH:34][CH2:33][CH2:32]2)[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1.C(N(CC)CC)C>O1CCOCC1>[CH3:1][N:2]1[C:6]2=[N:7][CH:8]=[C:9]([CH2:11][CH2:12][N:34]3[CH2:35][CH2:36][N:31]([C:25]4[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=4)[CH2:32][CH2:33]3)[CH:10]=[C:5]2[O:4][C:3]1=[O:24]
Reactant: Cc1ccc(S(=O)(=O)OCCc2cnc3c(c2)oc(=O)n3C)cc1
Reactant: c1ccc(N2CCNCC2)cc1
Solvent: C1COCCO1
Solvent: CCN(CC)CC
Product: Cn1c(=O)oc2cc(CCN3CCN(c4ccccc4)CC3)cnc21
Temperature: 25 °C

Procedure:
3-methyl-6-[2-(p-toluenesulfonyloxy)ethyl]oxazolo[4,5-b]pyridin-2(3H)-one of Preparation 15 (210 mg, 1.2 mmol) is dissolved in 1,4-dioxane (8 ml). N-phenylpiperazine (0.10 ml, 1.38 mmol) and triethylamine (0.18 ml, 1.3 mmol) are added in succession to the reaction mixture. Stirring is maintained at room temperature for 24 hours. After the solvent has been evaporated off under reduced pressure, the residue is taken up in water. Extraction is carried out with dichloromethane and the organic phase is dried over magnesium sulfate and filtered, and then the solvent is evaporated off. The title product is purified by chromatography on silica gel (eluant: dichloromethane/methanol: 95/5). The yield obtained is 91%. ##STR66##
Reaction SMILES: [CH3:1][C:2]1[O:3][C:4]2[C:10]([CH3:11])=[CH:9][CH:8]=[CH:7][C:5]=2[CH:6]=1.CC1C2[O:20]C=CC=2C=CC=1>>[CH3:11][C:10]1[C:4]2[O:3][C:2]([CH:1]=[O:20])=[CH:6][C:5]=2[CH:7]=[CH:8][CH:9]=1
Reactant: Cc1cc2cccc(C)c2o1
Reactant: Cc1cccc2ccoc12
Product: Cc1cccc2cc(C=O)oc12

Procedure:
2,7-Dimethyl-benzofuran. 7-Methyl-benzofuran (of. compound (2) g.) is subjected to a WILSMEYER reaction to form 7-methyl-benzofuran-2-aldehyde which is converted into 2,7-dimethyl-benzofuran by a WOLFF-KISHNER reaction by the method described in Bull.Soc.Chim.France 29, 1875 (1952). The product thus obtained has the following peaks in its MS: 146 (100%), 145 (92%) and 131 (32%).
Reaction SMILES: [CH2:1]([C:4]1[C:9]([C:10]([CH3:13])([CH3:12])[CH3:11])=[C:8]([OH:14])[C:7]([CH:15]([CH3:17])[CH3:16])=[CH:6][C:5]=1[OH:18])[CH2:2][CH3:3].[CH:19](OC)(OC)OC.[CH:26]([C:28]([CH3:30])=[O:29])=[CH2:27]>CO>[CH3:19][O:29][C:28]1([CH3:30])[CH2:26][CH2:27][C:6]2[C:5](=[C:4]([CH2:1][CH2:2][CH3:3])[C:9]([C:10]([CH3:11])([CH3:13])[CH3:12])=[C:8]([OH:14])[C:7]=2[CH:15]([CH3:17])[CH3:16])[O:18]1
Reactant: C=CC(C)=O
Reactant: COC(OC)OC
Reactant: CCCc1c(O)cc(C(C)C)c(O)c1C(C)(C)C
Solvent: CO
Product: CCCc1c2c(c(C(C)C)c(O)c1C(C)(C)C)CCC(C)(OC)O2
Temperature: 3 °C

Procedure:
Dissolve 2-propyl-3-t-butyl-4-hydroxy-5-isopropylphenol (2.0mol) and trimethyl orthoformate (0.3L) in methanol (1.2L) and degas. Place under a nitrogen atmosphere and cool to 3° C. and add concentrated sulfuric acid (5mL). Add, by dropwise addition, methyl vinyl ketone (340mL, 4.0mol) and stir without cooling for 44 hours. Pour into aqueous sodium hydrogen caronate and extract into ethyl ether. Dry (MgSO4) and evaporate the solvent in vacuo to give 2-methoxy-2-methyl-7-t-butyl-5-isopropyl-8-propyl-chroman-6-ol.
Reaction SMILES: [CH:1]([O:14][CH:15]1[CH2:20][CH2:19][NH:18][CH2:17][CH2:16]1)([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH:21]([C:23]1[C:24]([C:28]([O:30][CH2:31][CH3:32])=[O:29])=[N:25][NH:26][CH:27]=1)=O.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>ClCCl>[CH:1]([O:14][CH:15]1[CH2:20][CH2:19][N:18]([CH2:21][C:23]2[C:24]([C:28]([O:30][CH2:31][CH3:32])=[O:29])=[N:25][NH:26][CH:27]=2)[CH2:17][CH2:16]1)([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CCOC(=O)c1n[nH]cc1C=O
Reactant: c1ccc(C(OC2CCNCC2)c2ccccc2)cc1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCl
Product: CCOC(=O)c1n[nH]cc1CN1CCC(OC(c2ccccc2)c2ccccc2)CC1
Temperature: 25 °C
Yield: 83.8 %

Procedure:
4-Benzhydryloxypiperidine (1.0 g, 3.7 mmol) synthesized in Production Example 1, ethyl 4-formylpyrazole-3-carboxylate (630 mg, 3.7 mmol), and dichloromethane (30 mL) were fed to the system, and the atmosphere of the system was replaced with argon gas, and the system was cooled by ice. At 0° C., sodium triacetoxyborohydride (1.2 g, 5.6 mmol) was added thereto, and the mixture was heated to a room temperature. After the disappearance of the raw material was confirmed by TLC, the reaction mixture was quenched with a saturated sodium hydrogen carbonate solution. The reaction mixture was separated into a water layer and an organic layer, and the water layer was extracted with dichloromethane again. The extract was combined to the organic layer. The combined organic layer was dried over sodium sulfate, and the solvent was distilled off. The resulting residue was purified by silica gel column chromatography (hexane:ethyl acetate=1:1) to give the title compound (1.3 g, 83%).
Reaction SMILES: [CH2:1]([N:7]1[C:12](=[O:13])[C:11]([CH3:14])=[CH:10][N:9]([CH3:15])[C:8]1=[O:16])[CH2:2][CH2:3][CH2:4][CH:5]=[CH2:6].C[N+]1([O-])CC[O:21]CC1.[OH2:25].S(S([O-])=O)([O-])=O.[Na+].[Na+]>C(O)(C)(C)C.CC(C)=O.[Os](=O)(=O)(=O)=O>[OH:25][CH:5]([CH2:6][OH:21])[CH2:4][CH2:3][CH2:2][CH2:1][N:7]1[C:12](=[O:13])[C:11]([CH3:14])=[CH:10][N:9]([CH3:15])[C:8]1=[O:16]
Reactant: O
Reactant: C=CCCCCn1c(=O)c(C)cn(C)c1=O
Reactant: C[N+]1([O-])CCOCC1
Agent: O=[Os](=O)(=O)=O
Agent: O=S([O-])S(=O)[O-]
Agent: [Na+]
Solvent: CC(C)(C)O
Solvent: CC(C)=O
Product: Cc1cn(C)c(=O)n(CCCCC(O)CO)c1=O
Yield: 89 %

Procedure:
A solution of 3-(5-hexenyl)-1-methylthymine (2.00 g, 9 mmol), 4-methylmorpholine-N-oxide (1.17 mg, 10 mmol), and osmium tetroxide (0.15 ml of a 2.5% solution in t-butanol) in acetone (15 ml) and water (10 ml) was stirred for 20 hours. Saturated aqueous sodium hydrosulfite solution (10 ml) was added and after 15 minutes of stirring, the mixture was extracted with 20% ethanol-dichloromethane (4×40 ml). The combined organic layers were dried over sodium sulfate and the solvents were evaporated under vacuum to give a solid residue. The solid was recrystallized (ethanol) to give 3-(5,6-dihydroxyhexyl)-1-methylthymine (2.00 g, 89% yield).
Reaction SMILES: C(=C1C[N:5]([C:7]([O:9][C:10]([CH3:13])([CH3:12])[CH3:11])=[O:8])C1)C.C[N+]1([O-])CC[O:18][CH2:17][CH2:16]1.C(OCC)(=O)C.[CH3:28][C:29]([CH3:31])=[O:30].O>[Os](=O)(=O)(=O)=O>[OH:30][C:29]1([CH:17]([OH:18])[CH3:16])[CH2:31][N:5]([C:7]([O:9][C:10]([CH3:11])([CH3:12])[CH3:13])=[O:8])[CH2:28]1
Reactant: C[N+]1([O-])CCOCC1
Reactant: CC(C)=O
Reactant: CC=C1CN(C(=O)OC(C)(C)C)C1
Agent: O=[Os](=O)(=O)=O
Solvent: CCOC(C)=O
Solvent: O
Product: CC(O)C1(O)CN(C(=O)OC(C)(C)C)C1
Reaction time: 120 h
Yield: 63 %

Procedure:
1,1-Dimethylethyl 3-ethylideneazetidine-1-carboxylate (506 mg, 2.76 mmol), and 4-methylmorpholine N-oxide (1.04 g, 8.89 mmol) were dissolved in acetone/water (4:1; 30 mL) and osmium tetroxide (2.5 wt. % in t-butanol; 0.2 mL) was added. The solution was stirred at ambient for 5 days, then was quenched with saturated sodium bisulfite (2 mL) and concentrated in vacuo. The residue was partitioned between ethyl acetate and brine. The aqueous portion was extracted with ethyl acetate. The combined organic portion was washed with brine, dried over anhydrous sodium sulfate, filtered and concentrated in vacuo. Column chromatography (silica gel, ethyl acetate) gave 1,1-dimethylethyl 3-hydroxy-3-(1-hydroxyethyl)azetidine-1-carboxylate (375 mg, 1.73 mmol, 63% yield): 1H NMR (400 MHz, CDCl3): 4.00-3.77 (m, 5H), 2.65 (br s, 1H), 1.86, (br s, 1H), 1.44 (s, 9H), 1.25 (d, 3H).
Reaction SMILES: S(Cl)([Cl:3])=O.[CH3:5]O.[NH2:7][C@@H:8]([CH2:12][CH2:13][CH2:14][NH:15][C:16]([O:18][CH2:19][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)=[O:17])[C:9]([OH:11])=[O:10]>C(OC)(C)(C)C>[ClH:3].[NH2:7][C@@H:8]([CH2:12][CH2:13][CH2:14][NH:15][C:16]([O:18][CH2:19][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)=[O:17])[C:9]([O:11][CH3:5])=[O:10]
Reactant: O=S(Cl)Cl
Reactant: CO
Reactant: N[C@@H](CCCNC(=O)OCc1ccccc1)C(=O)O
Solvent: COC(C)(C)C
Product: COC(=O)[C@@H](N)CCCNC(=O)OCc1ccccc1
Product: Cl

Procedure:
While cooling with ice, and under an argon atmosphere, 240 ml of thionyl chloride are added dropwise to 300 ml of abs. methanol, after which 40 g (150 mmol) of (2S)-2-amino-5-benzyloxycarbonylaminopentanoic acid (1.1) are added and the mixture is allowed to react at room temperature for 3 h and at 4° C. overnight. The solution is poured into methyl tert-butyl ether, the solvent is decanted off and the residue is triturated with diethyl ether. After filtering off with suction, 29.14 g (61%) of (1.2) are obtained as a colorless solid.
Reaction SMILES: [CH2:1]([N:3]=[C:4]=[O:5])[CH3:2].[CH3:6][C:7]([C:10]1[CH:15]=[C:14]([CH:16]([NH:23][OH:24])[C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[CH:13]=[C:12]([C:25]([CH3:28])([CH3:27])[CH3:26])[C:11]=1[OH:29])([CH3:9])[CH3:8]>C1(C)C=CC=CC=1>[CH3:26][C:25]([C:12]1[CH:13]=[C:14]([CH:16]([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[N:23]([OH:24])[C:4]([NH:3][CH2:1][CH3:2])=[O:5])[CH:15]=[C:10]([C:7]([CH3:6])([CH3:8])[CH3:9])[C:11]=1[OH:29])([CH3:28])[CH3:27]
Reactant: CC(C)(C)c1cc(C(NO)c2ccccc2)cc(C(C)(C)C)c1O
Reactant: CCN=C=O
Solvent: Cc1ccccc1
Product: CCNC(=O)N(O)C(c1ccccc1)c1cc(C(C)(C)C)c(O)c(C(C)(C)C)c1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
Ethyl isocyanate (0.404 g, 0.0057 mole) is added to a solution of 1.64 g (0.005 mole) of 2,6 bis(1,1-dimethylethyl)-4-[(hydroxyamino)phenylmethyl]phenol in 50 mL toluene. After stirring at room temperature for 30 minutes the reaction mixture is concentrated to half its volume (rotary evaporator) and diluted with n-hexane. The solid is filtered off, washed with n-hexane, and recrystallized from Et2O-cyclohexane to give white crystals, 1.35 g (68%), m.p. 158°-159.5° C.
Reaction SMILES: [CH3:1][N:2]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[C:4]([S:11]([C:14]2[CH:19]=[CH:18][C:17]([OH:20])=[CH:16][CH:15]=2)(=[O:13])=[O:12])=[C:3]1[CH:21]([CH3:23])[CH3:22].C(=O)([O-])[O-].[K+].[K+].[Br:30][CH2:31][CH2:32][CH2:33]Br.O>CN(C)C=O>[CH3:1][N:2]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[C:4]([S:11]([C:14]2[CH:19]=[CH:18][C:17]([O:20][CH2:33][CH2:32][CH2:31][Br:30])=[CH:16][CH:15]=2)(=[O:13])=[O:12])=[C:3]1[CH:21]([CH3:23])[CH3:22]
Reactant: CC(C)c1c(S(=O)(=O)c2ccc(O)cc2)c2ccccc2n1C
Reactant: BrCCCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: CC(C)c1c(S(=O)(=O)c2ccc(OCCCBr)cc2)c2ccccc2n1C
Temperature: 100 °C
Yield: 70.5 %

Procedure:
To a solution of 2.8 g (0.0085 mol) of 1-methyl-2-isopropyl-3-(4-hydroxy-benzenesulphonyl)indole in 100 ml of N,N-dimethyl formamide were added 14 g of anhydrous and crushed potassium carbonate. After that 6.8 g (0.037 mol) of 1,3-dibromopropane were added and the medium was heated at 100° C. for 0.5 hour. The mixture was poured into water, extracted with ethyl ether and the ethereal fraction was washed with water, dried on anhydrous sodium sulphate, filtered and evaporated to obtain 2.7 g of 1-methyl-3-[4-(3-bromo-propoxy)benzenesulphonyl]-2-isopropyl-indole (yield: 69%). This crude bromopropoxy derivative was dissolved in 60 ml of dimethylsulphoxide and 2.2 g (0.03 mol) of tert-butylamine were added. The medium was then stirred at room-temperature for 48 hours, poured into water and extracted with ethyl ether. The ethereal solution was then washed with water, dried on anhydrous sodium sulphate, filtered and evaporated. The crude product so obtained (2.3 g) was then purified by chromatography on a silica column (solvent:methanol).
Reaction SMILES: C(N(CC)CC)C.[F:8][C:9]1[CH:17]=[CH:16][CH:15]=[CH:14][C:10]=1[C:11](Cl)=[O:12].[NH2:18][C:19]1[CH:31]=[C:30]([C:32]2[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=2)[CH:29]=[CH:28][C:20]=1[C:21]([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:22].C(=O)([O-])O.[Na+]>C(Cl)Cl>[F:8][C:9]1[CH:17]=[CH:16][CH:15]=[CH:14][C:10]=1[C:11]([NH:18][C:19]1[CH:31]=[C:30]([C:32]2[CH:33]=[CH:34][CH:35]=[CH:36][CH:37]=2)[CH:29]=[CH:28][C:20]=1[C:21]([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:22])=[O:12]
Reactant: CC(C)(C)OC(=O)c1ccc(-c2ccccc2)cc1N
Reactant: O=C(Cl)c1ccccc1F
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(C)(C)OC(=O)c1ccc(-c2ccccc2)cc1NC(=O)c1ccccc1F
Reaction time: 1 h

Procedure:
0.063 mL of triethylamine and 0.040 mL of 2-fluorobenzoyl chloride were added to 3.0 mL of Methylene chloride solution containing 60 mg of tert-butyl 2-amino-4-phenylbenzoate at room temperature sequentially and stirred at the same temperature for 1 hour. 0.51 g of aminomethylated polystyrene was added to the reaction mixture and stirred at room temperature overnight. A saturated sodium hydrogen carbonate aqueous solution was added to the reaction mixture, and the organic layer was separated, and the solvent was evaporated under reduced pressure. The obtained residue was purified with silica gel column chromatography [Flash Tube 2008 manufactured by Trikonex Company, eluent; hexane:ethyl acetate=4:1] to obtain tert-butyl 2-(2-fluorobenzamido)-4-phenylbenzoate.
Reaction SMILES: [CH3:1][C:2]1[C:3]([C:8]([OH:10])=[O:9])=[N:4][CH:5]=[CH:6][CH:7]=1.[C:11](=O)([O-])[O-].[K+].[K+].IC>CC(C)=O>[CH3:11][O:9][C:8]([C:3]1[C:2]([CH3:1])=[CH:7][CH:6]=[CH:5][N:4]=1)=[O:10]
Reactant: O=C([O-])[O-]
Reactant: Cc1cccnc1C(=O)O
Agent: [K+]
Solvent: CI
Solvent: CC(C)=O
Product: COC(=O)c1ncccc1C
Yield: 57.1 %

Procedure:
Heat a mixture of 3-methylpicolinic acid (1.0 g, 7.3 mmol), potassium carbonate (4.1 g, 29.7 mmol), and iodomethane (4.4 g, 31.0 mmol) in acetone (35 mL) overnight under reflux. Filter, wash the residue with EtOAc, and concentrate in vacuo. Pass through a short plug of silica gel eluting with hexane/EtOAc (1:1) to provide 2-methoxycarbonyl-3-methylpyridine as a pale yellow liquid (630 mg, 57%). To a solution of 2-methoxycarbonyl-3-methylpyridine in anhydrous THF (10 mL) at 0° C., add with stirring a solution of 1M lithium aluminum hydride in THF (5 mL, 5 mmol), and continue stirring for 30 min at 0° C. Allow the mixture to warm to ambient temperature and quench cautiously with 0.5M aqueous NaOH. Heat the mixture at 60° C. for 40 min, cool to ambient temperature, extract with EtOAc, dry over anhydrous Na2SO4 and concentrate in vacuo. Purify by chromatography on silica gel eluting with hexane/EtOAc (4:3) to give the desired intermediate (90 mg, 18%).
Reaction SMILES: [CH3:1][CH:2]([N:4]1[CH2:9][CH2:8][CH:7]([C:10]([O:12]CC)=O)[CH2:6][CH2:5]1)[CH3:3].O.[NH2:16][NH2:17]>C(O)C>[CH3:1][CH:2]([N:4]1[CH2:9][CH2:8][CH:7]([C:10]([NH:16][NH2:17])=[O:12])[CH2:6][CH2:5]1)[CH3:3]
Reactant: CCOC(=O)C1CCN(C(C)C)CC1
Reactant: NN
Solvent: O
Solvent: CCO
Product: CC(C)N1CCC(C(=O)NN)CC1
Temperature: 25 °C

Procedure:
3.60 g (18.1 mmol) of ethyl 1-(1-methylethyl)piperidin-4-carboxylate and 1.00 g (19.9 mmol) of hydrazine hydrate were initially charged in 15 ml of ethanol and stirred at reflux for 16 h. The reaction mixture was cooled to RT and concentrated, and the residue was lyophilized. The crude product was triturated with diethyl ether (25 ml), filtered off and dried. This gave 1.91 g (57% of theory) of the product.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[N:4][CH:5]=[C:6]([C:9]=1[NH:10][CH3:11])[C:7]#[N:8].[H-].[Na+].Br[CH2:15][C:16]([O:18][CH2:19][CH3:20])=[O:17].C(OCC)C>CN(C=O)C>[CH2:19]([O:18][C:16]([C:15]1[N:10]([CH3:11])[C:9]2[C:2]([Cl:1])=[CH:3][N:4]=[CH:5][C:6]=2[C:7]=1[NH2:8])=[O:17])[CH3:20]
Reactant: CCOC(=O)CBr
Reactant: CNc1c(Cl)cncc1C#N
Agent: [H-]
Agent: [Na+]
Solvent: CCOCC
Solvent: CN(C)C=O
Product: CCOC(=O)c1c(N)c2cncc(Cl)c2n1C
Reaction time: 0.25 h
Yield: 60.1 %

Procedure:
5-Chloro-4-methylamino-nicotinonitrile (340 mg, 2.02 mmol) was dissolved in DMF (5 mL) and the solution cooled in an ice-bath. This solution was treated portionwise with sodium hydride (120 mg, 60% in oil, 3.03 mmol). The ice-bath was removed and stirring continued for 15 minutes at room temperature before treating the mixture with ethyl bromoacetate (508 mg, 3.03 mmol). The reaction mixture was then partitioned between ethyl acetate and water. The organic layer was isolated, washed with water followed by brine then dried (MgSO4) and evaporated to give a solid. Trituration of the resultant solid with diethyl ether gave the title compound (308 mg, 60%) as a cream solid. 1H NMR (CDCl3) 8.90 (1H, s), 8.26 (1H, s), 8.26 (1H, s, br), 4.43 (2H, q, J=7.0 Hz), 4.28 (3H, s), 1.44 (3H, t, J=7.0 Hz)
Reaction SMILES: [CH2:1]([CH:8]1[O:12][C:11](=[O:13])[CH:10]=[C:9]1[OH:14])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH:15](=O)[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1.[Cl:23][C:24]1[CH:25]=[C:26]2[C:30](=[CH:31][CH:32]=1)[NH:29][CH:28]=[C:27]2[CH2:33][CH2:34][NH:35][C:36](=[O:38])[CH3:37]>>[CH2:1]([CH:8]1[O:12][C:11](=[O:13])[C:10]([CH:15]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[C:28]2[NH:29][C:30]3[C:26]([C:27]=2[CH2:33][CH2:34][NH:35][C:36](=[O:38])[CH3:37])=[CH:25][C:24]([Cl:23])=[CH:32][CH:31]=3)=[C:9]1[OH:14])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=C1C=C(O)C(Cc2ccccc2)O1
Reactant: CC(=O)NCCc1c[nH]c2ccc(Cl)cc12
Reactant: O=Cc1ccccc1
Product: CC(=O)NCCc1c(C(C2=C(O)C(Cc3ccccc3)OC2=O)c2ccccc2)[nH]c2ccc(Cl)cc12

Procedure:
Using general procedure C, 5-benzyl-4-hydroxy-5H-furan-2-one (Lit. 13) was reacted with benzaldehyde and N-[2-(5-chloro-1H-indol-3-yl)-ethyl]-acetamide (Lit. 2) to give the title compound as a white solid. MS: 513.1 ([M−H]−).