Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [O:1]1[C@H:3]2[CH:4]=[C:5]3[C@@H:21]([C@@:22]4([CH3:28])[CH2:23][CH2:24][C@H:25]([OH:27])[CH2:26][C:2]124)[CH2:20][CH2:19][C@@:18]1([CH3:29])[C@H:6]3[CH2:7][CH2:8][C@@H:9]1[C@H:10]([CH3:17])[CH2:11][CH2:12][CH2:13][CH:14]([CH3:16])[CH3:15].[NH2:30][CH2:31][CH2:32][CH2:33][CH2:34][NH:35][CH2:36][CH2:37][CH2:38][NH2:39].C(O)CCC>COC(C)(C)C>[CH3:17][C@@H:10]([C@@H:9]1[C@@:18]2([CH3:29])[CH2:19][CH2:20][C@@H:21]3[C@@:22]4([CH3:28])[CH2:23][CH2:24][C@H:25]([OH:27])[CH2:26][C@:2]4([OH:1])[C@H:3]([NH:39][CH2:38][CH2:37][CH2:36][NH:35][CH2:34][CH2:33][CH2:32][CH2:31][NH2:30])[CH:4]=[C:5]3[C@@H:6]2[CH2:7][CH2:8]1)[CH2:11][CH2:12][CH2:13][CH:14]([CH3:15])[CH3:16]
Reactant: CC(C)CCC[C@@H](C)[C@H]1CC[C@H]2C3=C[C@@H]4OC45C[C@@H](O)CC[C@]5(C)[C@H]3CC[C@]12C
Reactant: NCCCCNCCCN
Solvent: CCCCO
Solvent: COC(C)(C)C
Product: CC(C)CCC[C@@H](C)[C@H]1CC[C@H]2C3=C[C@@H](NCCCNCCCCN)[C@@]4(O)C[C@@H](O)CC[C@]4(C)[C@H]3CC[C@]12C
Temperature: 25 °C
Yield: 58 %

Procedure:
5,6α-epoxicholest-7-en-3β-ol (8.9 g, 22.1 mmol, 1 eq) and spermidine (6.4 g, 44.1 mmol, 2 eq) were charged in a round-bottomed flask equipped with a magnetic stirrer bar. 1-Butanol (70 ml, 5 vol) was added and the mixture heated to reflux for 40 h. The reaction mixture was cooled at r.t., diluted with methyl-tertbutyl-ether (5 vol) and washed with water (5 vol) and with brine (5 vol). The organic layer was passed through a silica pad (40 g) eluted with methyl-tertbutyl-ether (3 vol) then 10% Methanol/ethyl acetate (60 vol). Fractions of interest were pooled and the solvent was removed under reduced pressure to give Dendrogenin B (5α-Hydroxy-6β-[4-(3-aminopropylamino)-butylamino]-cholest-7-en-3β-ol) as a white solid (7.0 g, 58%). In same conditions, use of ethanol as solvent (40 vol) and Ca(OTf)2 as catalyst gave a 14% yield.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:11]=[C:10]([O:12][CH3:13])[CH:9]=[CH:8][C:4]=1[C:5](Cl)=[O:6].[CH:14]([NH:17][CH:18]([CH3:20])[CH3:19])([CH3:16])[CH3:15]>ClCCl>[CH3:1][O:2][C:3]1[CH:11]=[C:10]([O:12][CH3:13])[CH:9]=[CH:8][C:4]=1[C:5]([N:17]([CH:18]([CH3:20])[CH3:19])[CH:14]([CH3:16])[CH3:15])=[O:6]
Reactant: COc1ccc(C(=O)Cl)c(OC)c1
Reactant: CC(C)NC(C)C
Solvent: ClCCl
Product: COc1ccc(C(=O)N(C(C)C)C(C)C)c(OC)c1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
A stirred solution of 2,4-dimethoxybenzoyl chloride (10.0 g, 50 mmol) in 10 mL of dichloromethane at 0° C. is treated with 30 mL of diisopropylamine. This solution is stirred at room temperature for 1 hour and the resulting solution is partitioned between ethyl acetate and water. The organic layer is washed with 1N hydrochloride solution, 1N sodium hydroxide solution, water and brine, dried over sodium sulfate and concentrated in vacuo to give 2,4-dimethoxy-N,N-bis(1-methylethyl)benzamide.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:20]=[CH:21][C:22]=1[O:23][CH3:24])[C:6]([N:8]1[C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[C@H:11](O)[CH2:10][C@@H:9]1[CH3:19])=[O:7].[NH:25]1[C:33]2[C:28](=[CH:29][CH:30]=[CH:31][CH:32]=2)[CH2:27][CH2:26]1>>[N:25]1([CH:11]2[C:12]3[C:17](=[CH:16][CH:15]=[CH:14][CH:13]=3)[N:8]([C:6](=[O:7])[C:5]3[CH:20]=[CH:21][C:22]([O:23][CH3:24])=[C:3]([O:2][CH3:1])[CH:4]=3)[CH:9]([CH3:19])[CH2:10]2)[C:33]2[C:28](=[CH:29][CH:30]=[CH:31][CH:32]=2)[CH2:27][CH2:26]1
Reactant: c1ccc2c(c1)CCN2
Reactant: COc1ccc(C(=O)N2c3ccccc3[C@H](O)C[C@@H]2C)cc1OC
Product: COc1ccc(C(=O)N2c3ccccc3C(N3CCc4ccccc43)CC2C)cc1OC
Yield: 51.1 %

Procedure:
Starting with cis-1-(3,4-dimethoxybenzoyl)-2-methyl-1,2,3,4-tetrahydro-4-quinolinol (400 mg, 1.22 mmol) prepared in Reference Example 1 and indoline (436 mg, 3.66 mmol), the same procedure as shown in Example 1 was repeated to give the titled compound (267 mg, yield: 51%) as a white crystal. (cis:trans=1:1.8)
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([O:28][CH3:29])=[C:6]([CH:27]=1)[CH2:7][C@@H:8]([CH2:12][NH:13][CH2:14][C:15]1[C:20]([O:21][CH3:22])=[CH:19][C:18]([O:23][CH3:24])=[CH:17][C:16]=1[O:25][CH3:26])[C:9]([OH:11])=O.Cl.C([O:33][C:34](=[O:37])[CH2:35][NH2:36])C.ON1C2C=CC=CC=2N=N1.Cl.CN(C)CCCN=C=NCC>C(#N)C.C(N(CC)CC)C>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([O:28][CH3:29])=[C:6]([CH:27]=1)[CH2:7][C@@H:8]([CH2:12][NH:13][CH2:14][C:15]1[C:16]([O:25][CH3:26])=[CH:17][C:18]([O:23][CH3:24])=[CH:19][C:20]=1[O:21][CH3:22])[C:9]([NH:36][CH2:35][C:34]([OH:37])=[O:33])=[O:11]
Reactant: COc1cc(OC)c(CNC[C@H](Cc2cc(Cl)ccc2OC)C(=O)O)c(OC)c1
Reactant: CCOC(=O)CN
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CCN(CC)CC
Solvent: CC#N
Product: COc1cc(OC)c(CNC[C@H](Cc2cc(Cl)ccc2OC)C(=O)NCC(=O)O)c(OC)c1
Temperature: 25 °C
Reaction time: 0.67 h

Procedure:
To a solution of (2S)-2-(5-chloro-2-methoxybenzyl)-3-[(2,4,6-trimethoxybenzyl)amino]propionic acid (1g) in acetonitrile (10 ml), glycine ethyl ester hydrochloride (345 mg), 1-hydroxy benzotriazole (478 mg), and triethylamine (0.35 ml) were added at room temperature, and the mixture was stirred at room temperature for 40 minutes. At room temperature, N-(3-dimethylaminopropyl)-N′-ethylcarbodiimide hydrochloride (678 mg) was added to the reaction solution, and the mixture was stirred for 3 hours. The reaction solution was concentrated in vacuo, and ethyl acetate was added to the obtained residue. Then the mixture was washed with saturated aqueous sodium bicarbonate and saturated brine, an the organic layer was concentrated. To the obtained residue, isopropyl alcohol (5 ml) and 5N aqueous sodium hydroxide solution were added, and the mixture was stirred at room temperature for 3 hours. The reaction solution was adjusted with 5N hydrochloric acid to pH 5, then the precipitated crystals were obtained by filtration and dried to obtain the title compound (978 mg) as a colorless crystal. The various types of spectral data match with those of Example 326.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][N:6]=[C:5]2[C:11]1[CH:16]=[CH:15][C:14]([F:17])=[CH:13][CH:12]=1.[N+:18]([C:21]1[CH:22]=[C:23]([CH:26]=[CH:27][CH:28]=1)[CH:24]=[CH2:25])([O-:20])=[O:19]>>[N+:18]([C:21]1[CH:22]=[C:23](/[CH:24]=[CH:25]/[C:2]2[CH:3]=[C:4]3[C:8](=[CH:9][CH:10]=2)[NH:7][N:6]=[C:5]3[C:11]2[CH:16]=[CH:15][C:14]([F:17])=[CH:13][CH:12]=2)[CH:26]=[CH:27][CH:28]=1)([O-:20])=[O:19]
Reactant: Fc1ccc(-c2n[nH]c3ccc(Br)cc23)cc1
Reactant: C=Cc1cccc([N+](=O)[O-])c1
Product: O=[N+]([O-])c1cccc(/C=C/c2ccc3[nH]nc(-c4ccc(F)cc4)c3c2)c1
Yield: 37.3 %

Procedure:
The title compound (0.134 g, 52% yield) was prepared as described in Example 132 D, using 5-bromo-3-(4-fluorophenyl)-1H-indazole (0.291 g, 1.0 mmol) and 3-nitrostyrene (0.298 g, 2.0 mmol). 1H NMR (CDCl3) δ 10.12 (br s, 1H), 8.41 (t, 1H), 8.11 (ddd, 1H), 8.07 (s, 1H), 7.97 (m, 2H), 7.82 (d, 1H), 7.73 (dd, 1H), 7.54 (m, 2H), 7.40 (d, 1H), 7.26 (m, 2H), 7.16 (d, 1H); ES-MS (m/z) 360 [M+1]+.
Reaction SMILES: [Cl:1][C:2]1[NH:6][C:5]([CH2:7][CH2:8][CH3:9])=[N:4][CH:3]=1.CO[CH:12]([N:15]([CH3:17])[CH3:16])OC.C(N(CC)CC)C>ClC1C=CC=CC=1>[Cl:1][C:2]1[C:3](=[CH:12][N:15]([CH3:17])[CH3:16])[N:4]=[C:5]([CH2:7][CH2:8][CH3:9])[N:6]=1
Reactant: COC(OC)N(C)C
Reactant: CCCc1ncc(Cl)[nH]1
Solvent: Clc1ccccc1
Solvent: CCN(CC)CC
Product: CCCC1=NC(=CN(C)C)C(Cl)=N1

Procedure:
A solution of 5-chloro-2-propyl-1H-imidazole (0.72 g, 5 mmol), dimethoxymethyldimethylamine (0.77 g, approximately 92 percent pure, 6 mmol) and triethylamine (0.10 g, 1 mmol) in chlorobenzene (25 ml) was heated for 1 hour at 60° C. and for 2 hours under reflux. Removing the solvent in a rotavapor gave the title compound in virtually quantitative yield. Data concerning the product was:
Reaction SMILES: [C:1](=[O:55])([O:24][C:25]1[C:26]([CH3:54])=[C:27]2[C:32](=[C:33]([CH3:36])[C:34]=1[CH3:35])[O:31][C:30]([CH3:53])([CH2:37][CH2:38][CH2:39][CH:40]([CH3:52])[CH2:41][CH2:42][CH2:43][CH:44]([CH3:51])[CH2:45][CH2:46][CH2:47][CH:48]([CH3:50])[CH3:49])[CH2:29][CH2:28]2)[O:2][CH:3]([CH2:15][O:16]CC1C=CC=CC=1)[CH:4]([OH:14])[CH2:5][O:6]CC1C=CC=CC=1.C(O)C.[H][H]>[C].[Pd].C(O)(=O)C>[C:1](=[O:55])([O:24][C:25]1[C:26]([CH3:54])=[C:27]2[C:32](=[C:33]([CH3:36])[C:34]=1[CH3:35])[O:31][C:30]([CH3:53])([CH2:37][CH2:38][CH2:39][CH:40]([CH3:52])[CH2:41][CH2:42][CH2:43][CH:44]([CH3:51])[CH2:45][CH2:46][CH2:47][CH:48]([CH3:49])[CH3:50])[CH2:29][CH2:28]2)[O:2][CH:3]([CH2:15][OH:16])[CH:4]([OH:14])[CH2:5][OH:6]
Reactant: [H][H]
Reactant: Cc1c(C)c2c(c(C)c1OC(=O)OC(COCc1ccccc1)C(O)COCc1ccccc1)CCC(C)(CCCC(C)CCCC(C)CCCC(C)C)O2
Agent: [Pd]
Solvent: CCO
Solvent: CC(=O)O
Product: Cc1c(C)c2c(c(C)c1OC(=O)OC(CO)C(O)CO)CCC(C)(CCCC(C)CCCC(C)CCCC(C)C)O2
Yield: 128.2 %

Procedure:
A mixture comprising 4.4 g of 3-benzyloxy-1-benzyloxymethyl-2-hydroxypropyl 2,5,7,8-tetramethyl-2-(4',8', 12'-trimethyltridecyl)-6-chromanyl carbonate, 0.5 g of 5% palladium carbon, 150 ml of ethanol and 5 ml of acetic acid was catalytically reduced in a hydrogen gas stream of 4 kg/cm2 until no hydrogen was absorbed any more (approximately 6 hours). After filtering off the catalyst, the filtrate was concentrated to thereby reduce the amount to approximately 1/3. Then it was poured into water and extracted with ether. The extract was successively washed with an aqueous solution of sodium hydrogencarbonate and water, and dried over magnesium sulfate. After distilling off the solvent, the obtained oily residue was purified by column chromatography (silica gel, hexane : ethyl acetate=2:1) to thereby give 4.3 g of the title compound as a colorless viscous liquid.
Reaction SMILES: Cl.[Cl:2][CH:3]([C:6]1[CH:11]=[CH:10][N:9]=[CH:8][CH:7]=1)[CH2:4]Cl.[CH2:12]([OH:14])[CH3:13]>>[ClH:2].[Cl:2][CH:3]([C:6]1[CH:11]=[CH:10][N:9]=[CH:8][CH:7]=1)[CH2:4][O:14][CH2:12][CH3:13]
Reactant: ClCC(Cl)c1ccncc1
Reactant: CCO
Agent: Cl
Product: CCOCC(Cl)c1ccncc1

Procedure:
About 2 g of 4-(1,2-dichloroethyl)pyridine hydrochloride were refluxed in absolute ethanol overnight. Excess ethanol was then evaporated, and the remaining traces were removed on a vacuum pump. The process resulted in the production of 2.5 g of 4-(1-chloro-2-ethoxyethyl)pyridine hydrochloride.
Reaction SMILES: [CH:1]1([CH2:7][N:8]2[C:12]([C:13]3[CH:18]=[C:17]([C:19]([CH3:22])([CH3:21])[CH3:20])[CH:16]=[C:15]([C:23]([CH3:26])([CH3:25])[CH3:24])[CH:14]=3)=[CH:11][C:10]([S:27](O)(=[O:29])=[O:28])=[C:9]2[CH3:31])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.C(Cl)(C([Cl:36])=O)=O>C(Cl)Cl>[CH:1]1([CH2:7][N:8]2[C:12]([C:13]3[CH:18]=[C:17]([C:19]([CH3:22])([CH3:21])[CH3:20])[CH:16]=[C:15]([C:23]([CH3:26])([CH3:25])[CH3:24])[CH:14]=3)=[CH:11][C:10]([S:27]([Cl:36])(=[O:29])=[O:28])=[C:9]2[CH3:31])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: O=C(Cl)C(=O)Cl
Reactant: Cc1c(S(=O)(=O)O)cc(-c2cc(C(C)(C)C)cc(C(C)(C)C)c2)n1CC1CCCCC1
Solvent: ClCCl
Product: Cc1c(S(=O)(=O)Cl)cc(-c2cc(C(C)(C)C)cc(C(C)(C)C)c2)n1CC1CCCCC1
Temperature: 0 °C
Reaction time: 2 h
Yield: 97.9 %

Procedure:
To a solution of compound 5c (1.0 g, 2.2 mmol) in CH2Cl2 (10 mL) was added (COCl)2 (0.8 g, 6.6 mmol) dropwise at 0° C. Then this mixture was stirred at 0° C. for 2 h and concentrated to obtain compound 5d (1.0 g, 100%).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[C:6]([O:8][C:9]([F:12])([F:11])[F:10])[CH:5]=[CH:4][C:3]=1[OH:13].C([O-])([O-])=O.[K+].[K+].Br[CH:21]([CH3:23])[CH3:22].C(OCC)(=O)C>CN(C)C=O>[Br:1][C:2]1[CH:7]=[C:6]([O:8][C:9]([F:11])([F:12])[F:10])[CH:5]=[CH:4][C:3]=1[O:13][CH:21]([CH3:23])[CH3:22]
Reactant: CC(C)Br
Reactant: Oc1ccc(OC(F)(F)F)cc1Br
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CC(C)Oc1ccc(OC(F)(F)F)cc1Br
Temperature: 25 °C
Reaction time: 14 h

Procedure:
To a solution of 2-bromo-4-trifluoromethoxyphenol (Description 11; 1 g, 3.9 mmol) and K2CO3 (1.1 g, 7.8 mmol) in dimethylformamide (15 ml) was added 2-bromopropane (0.55 ml, 5.9 mmol). The solution was stirred for 14 h. at room temperature under an atmosphere of nitrogen. Waster (200 ml) and ethyl acetate (3×70 ml) was added to the solution and the organic phase washed with water (100 ml), brine (100 ml) and dried (MgSO4). The solvent was removed in vacuo and the residue purified by chromatography on silica gel (eluting with 5% ethyl acetate in hexane) to give the title compound. 1H NMR (250 MHz, CDCl3) δ1.38 (6H, d, J 6.1 Hz), 4.53 (1H, m), 6.88 (1H, d, J, 9 Hz), 7.12 (1H, dd, J 8.8, 2.6 Hz), and 7.43 (1H, d, J 2.8 Hz).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]([N+:9]([O-:11])=[O:10])=[C:6]([CH:8]=1)[NH2:7].[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+].[CH3:26][S:27][C:28]1[S:29][C:30]2[CH:36]=[C:35]([CH:37]=O)[CH:34]=[CH:33][C:31]=2[N:32]=1>C(O)(C(F)(F)F)=O.C(Cl)Cl>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([N+:9]([O-:11])=[O:10])=[C:6]([CH:8]=1)[NH:7][CH2:37][C:35]1[CH:34]=[CH:33][C:31]2[N:32]=[C:28]([S:27][CH3:26])[S:29][C:30]=2[CH:36]=1
Reactant: CSc1nc2ccc(C=O)cc2s1
Reactant: Nc1cc(Br)ccc1[N+](=O)[O-]
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CSc1nc2ccc(CNc3cc(Br)ccc3[N+](=O)[O-])cc2s1
Reaction time: 0.25 h
Yield: 73 %

Procedure:
To a stirred mixture of 5-bromo-2-nitroaniline (714 mg, 4.0 mmol) in TFA (7 mL) at −15° C. under argon, was added NaBH(OAc)3 (1.2 g, 5.4 mmol) in small portions. The mixture was stirred for 15 min, then a solution of 2-(methylthio)benzo[d]thiazole-6-carbaldehyde in CH2Cl2 (2 mL) was added dropwise. The mixture was stirred for 30 min then concentrated under reduced pressure to give a red oil. The oil was partitioned between EtOAc (200 mL) and saturated aq NaHCO3 (100 mL). The organic layer was separated and washed with brine (100 mL). The organic layer was separated, dried over Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by silica gel flash chromatography eluting with a gradient of 100% hexanes to 50% hexanes in EtOAc to afford 5-bromo-N-((2-(methylthio)benzo[d]thiazol-6-yl)methyl)-2-nitroaniline (1.1 g, 73%) as a yellow solid. LCMS (ESI) m/z 409, 411 (M+H)+.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([CH:14]=O)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[N:16]1[CH:21]=[CH:20][C:19]([CH:22]2[CH2:27][CH2:26][NH:25][CH2:24][CH2:23]2)=[CH:18][CH:17]=1.C([BH3-])#N.[Na+]>CO.C(O)(=O)C>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([CH2:14][N:25]2[CH2:26][CH2:27][CH:22]([C:19]3[CH:18]=[CH:17][N:16]=[CH:21][CH:20]=3)[CH2:23][CH2:24]2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)OC(=O)N1CCC(C=O)CC1
Reactant: c1cc(C2CCNCC2)ccn1
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CO
Solvent: CC(=O)O
Product: CC(C)(C)OC(=O)N1CCC(CN2CCC(c3ccncc3)CC2)CC1
Yield: 37.8 %

Procedure:
To a solution of 1-(tert-butoxycarbonyl)-4-(formyl)piperidine (2.59 g) and 4-(4-pyridyl)piperidine (1.97 g) in methanol/acetic acid (99:1) was added sodium cyanoborohydride (2.29 g) portionwise over 30 minutes and the resultant suspension stirred at ambient temperature for 3 hours. The suspension was quenched by addition of saturated aqueous sodium bicarbonate solution and the resulting mixture extracted with ethyl acetate. The organic phase was dried (Na2SO4) and evaporated. The residue was purified by chromatography eluting with 5% methanol in dichloromethane to give 1-tert-butoxycarbonyl-4-[4-(4-pyridyl)-1-piperidylmethyl]piperidine (1.65 g) as a solid.
Reaction SMILES: [CH:1](=[N:8][NH:9][C:10]1[CH:19]=[CH:18][CH:17]=[CH:16][C:11]=1[C:12]([O:14][CH3:15])=[O:13])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl[CH:21]([C:27]([O-])=[O:28])[C:22]([O:24][CH2:25][CH3:26])=[O:23]>C1(C)C=CC=CC=1>[CH:1](=[N:8][N:9]([C:10]1[CH:19]=[CH:18][CH:17]=[CH:16][C:11]=1[C:12]([O:14][CH3:15])=[O:13])[C:27](=[O:28])[CH2:21][C:22]([O:24][CH2:25][CH3:26])=[O:23])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CCOC(=O)C(Cl)C(=O)[O-]
Reactant: COC(=O)c1ccccc1NN=Cc1ccccc1
Solvent: Cc1ccccc1
Product: CCOC(=O)CC(=O)N(N=Cc1ccccc1)c1ccccc1C(=O)OC
Temperature: 25 °C
Yield: 67.4 %

Procedure:
Methyl 2-[2-benzylidenehydrazino]benzoate (5.29 g, 20.81 mmol) in toluene (80 mL) was reacted with ethyl chloromalonate (2.68 mL, 25.0 mmol) at reflux for 4 hours. The reaction mixture was cooled to 25° C. and concentrated under vacuum. The residue was triturated with diethyl ether and hexanes (3:1) to give methyl 2-[2-benzylidene-1-(3-ethoxy-3-oxopropanoyl)hydrazino]benzoate (5.17 g, 70%). MS (DCI) m/z 355 (M+H)+. 1H NMR (300 MHz, DMSO-d6) ppm 3.32 (s, 2 H) 3.69 (s, 3 H) 3.73 (s, 3 H) 7.16 (s, 1 H) 7.32 (dd, J=7.72, 1.10 Hz, 1 H) 7.40 (m, 3 H) 7.63 (m, 2 H) 7.70 (td, J=7.63, 1.29 Hz, 1 H) 7.85 (td, J=7.72, 1.47 Hz, 1 H) 8.10 (dd, J=7.72, 1.47 Hz, 1 H).
Reaction SMILES: ClC1C=C(C=CC=1)C(OO)=[O:6].[CH:12]1([S:17]([C:19]2[CH:20]=[C:21]([CH2:25][CH2:26][CH2:27][CH2:28][O:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][N:36]3[CH2:40][C@@H:39]([C:41]4[CH:52]=[CH:51][C:44]5[O:45][C:46]([CH3:50])([CH3:49])[O:47][CH2:48][C:43]=5[CH:42]=4)[O:38][C:37]3=[O:53])[CH:22]=[CH:23][CH:24]=2)=[O:18])[CH2:16][CH2:15][CH2:14][CH2:13]1>C(Cl)Cl>[CH:12]1([S:17]([C:19]2[CH:20]=[C:21]([CH2:25][CH2:26][CH2:27][CH2:28][O:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][N:36]3[CH2:40][C@@H:39]([C:41]4[CH:52]=[CH:51][C:44]5[O:45][C:46]([CH3:49])([CH3:50])[O:47][CH2:48][C:43]=5[CH:42]=4)[O:38][C:37]3=[O:53])[CH:22]=[CH:23][CH:24]=2)(=[O:6])=[O:18])[CH2:16][CH2:15][CH2:14][CH2:13]1
Reactant: CC1(C)OCc2cc([C@@H]3CN(CCCCCCOCCCCc4cccc(S(=O)C5CCCC5)c4)C(=O)O3)ccc2O1
Reactant: O=C(OO)c1cccc(Cl)c1
Solvent: ClCCl
Product: CC1(C)OCc2cc([C@@H]3CN(CCCCCCOCCCCc4cccc(S(=O)(=O)C5CCCC5)c4)C(=O)O3)ccc2O1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 85.3 %

Procedure:
3-Chloroperoxybenzoic acid (0.088 g) was added to a stirred, cooled (ice-bath) solution of (5R)-3-(6-{4-[3-(cyclopentylsulfinyl)phenyl]butoxy}hexyl)-5-(2,2-dimethyl-4H-1,3-benzodioxin-6-yl)-1,3-oxazolidin-2-one (0.097 g) in DCM (10 ml). The solution was stirred for 0.5 h at room temperature. The solution was diluted with DCM and washed with 2N NaOH solution, water, dried (Na2SO4) and evaporated to give the title compound (0.085 g)
Reaction SMILES: [CH3:1][N:2]1[CH2:7][CH2:6][C:5]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)([OH:8])[CH2:4][CH2:3]1.[H-].[Na+].Cl[C:18]1[CH:27]=[CH:26][C:25]2[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=2)[N:19]=1.O>CS(C)=O>[CH3:1][N:2]1[CH2:7][CH2:6][C:5]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)([O:8][C:18]2[CH:27]=[CH:26][C:25]3[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=3)[N:19]=2)[CH2:4][CH2:3]1
Reactant: Clc1ccc2ccccc2n1
Reactant: CN1CCC(O)(c2ccccc2)CC1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CS(C)=O
Product: CN1CCC(Oc2ccc3ccccc3n2)(c2ccccc2)CC1
Temperature: 25 °C
Yield: 23.6 %

Procedure:
A solution of 1-methyl-4-phenyl-4-piperidinol (7.65 g, 40 mM) in DMSO (50 ml) was treated with 50% sodium hydride dispersion (2 g, 40 mM) and warmed to 80° until a homogenous solution was obtained. After cooling to room temperature, the mixture was treated with a solution of 2-chloroquinoline (6.55 g, 40 mM) in DMSO (10 ml). After 24 hours the mixture was poured on to water (250 ml) and extracted with toluene (3×250 ml). After drying and evaporation of the solvents, the residue crystallised from cyclohexane to give recovered 1-methyl-4-phenyl-4-piperidinol (2.7 g). Chromatography of the mother liquors on Grade III silica, using 3% methanol in chloroform as eluant gave the title compound (3 g) contaminated with a small quantity of 2-quinolone which was removed by crystallisation from cyclohexane. Recrystallisation of the mother liquors from pentane gave the title compound (1.2 g) m.p. 80°-1° C.
Reaction SMILES: [H][H].[CH3:3][N:4]([CH3:20])[CH2:5][CH2:6][CH2:7][O:8][C:9]1[C:10]([F:19])=[CH:11][C:12]([N+:16]([O-])=O)=[C:13]([NH2:15])[CH:14]=1>C(O)C.[Pd]>[CH3:20][N:4]([CH3:3])[CH2:5][CH2:6][CH2:7][O:8][C:9]1[CH:14]=[C:13]([NH2:15])[C:12]([NH2:16])=[CH:11][C:10]=1[F:19]
Reactant: [H][H]
Reactant: CN(C)CCCOc1cc(N)c([N+](=O)[O-])cc1F
Agent: [Pd]
Solvent: CCO
Product: CN(C)CCCOc1cc(N)c(N)cc1F
Yield: 90.6 %

Procedure:
In a 25 ml autoclave, dissolve 350 mg of 5-(3-dimethylaminopropoxy)-4-fluoro-2-nitrophenylamine, obtained in the previous stage, in 20 ml of ethanol, add 40 mg of 10% palladium-on-charcoal and then subject to an initial hydrogen pressure of 1 bar at 20° C. for 16 hours. After cooling, the volume of hydrogen absorbed is 123 ml. After filtration of the catalyst and then concentration to dryness under reduced pressure, we obtain 280 mg of 4-(3-dimethylaminopropoxy)-5-fluorobenzene-1,2-diamine, in the form of a viscous black oil, which is used as it is in the following stage, with the following characteristic:
Reaction SMILES: [C:1]([O:5][C:6](=[O:24])[NH:7][C@@H:8]([CH2:17][C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)[C@H:9]([OH:16])[CH2:10][NH:11]OC(C)C)([CH3:4])([CH3:3])[CH3:2].[CH3:25][S:26]([NH:29][C:30]1[NH:31][C:32]2[CH:38]=[C:37]([S:39](Cl)(=[O:41])=[O:40])[CH:36]=[CH:35][C:33]=2[N:34]=1)(=[O:28])=[O:27]>N1C=CC=CC=1>[C:1]([O:5][C:6](=[O:24])[NH:7][C@@H:8]([CH2:17][C:18]1[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=1)[C@@H:9]([OH:16])[CH:10]([NH:11][S:39]([C:37]1[CH:36]=[CH:35][C:33]2[N:34]=[C:30]([NH:29][S:26]([CH3:25])(=[O:28])=[O:27])[NH:31][C:32]=2[CH:38]=1)(=[O:41])=[O:40])[O:5][CH:1]([CH3:3])[CH3:2])([CH3:2])([CH3:3])[CH3:4]
Reactant: CS(=O)(=O)Nc1nc2ccc(S(=O)(=O)Cl)cc2[nH]1
Reactant: CC(C)ONC[C@@H](O)[C@H](Cc1ccccc1)NC(=O)OC(C)(C)C
Solvent: c1ccncc1
Product: CC(C)OC(NS(=O)(=O)c1ccc2nc(NS(C)(=O)=O)[nH]c2c1)[C@H](O)[C@H](Cc1ccccc1)NC(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 8 h

Procedure:
tert-Butyl-N-((1S,2R)-1-benzyl-3-(isopropyloxy)amino-2-hydroxypropyl)carbamate (86 mg, 0.25 mmol) was combined with 2-[(methylsulfonyl)amino]benzimidazol-5-ylsulfonyl chloride (77 mg, 0.25 mmol) in anhydrous pyridine (1 ml) with a catalytic amount of N,N-dimethylaminopyridine. The reaction was stirred at room temperature overnight. The solvent was evaporated under vacuum. The crude mixture was diluted in EtOAc and washed with water and brine. Organic phase was dried with MgSO4 and solvent was removed in vacuo. Purification by TLC prep (2% MeOH/CH2Cl2). Recovered 56 mg (37%) of product as a white solid. HPLC showed the material to be 98% pure; Ret. time=9.87 min. 1H NMR (CDCl3): 7.12-8.04 (m, 8H), 6.5 (m, 1H), 4.47-4.51 (m, 2H), 3.68 (m, 2H), 3.22 (s, 3H), 2.81-2.88 (m, 3H), 1.75 (m, 2H), 1.22 (s, 9H), 1.16 (d, 6H). MS (ES+): obs. M+H@ 612.1 amu.
Reaction SMILES: Cl[CH2:2][CH2:3][CH2:4][N:5]1[C:13](=[O:14])[N:8]2[CH:9]=[CH:10][CH:11]=[CH:12][C:7]2=[N:6]1.[NH:15]1[CH2:20][CH:19]=[C:18]([C:21]2[C:29]3[C:24](=[CH:25][CH:26]=[CH:27][CH:28]=3)[NH:23][CH:22]=2)[CH2:17][CH2:16]1.[I-].[K+].C(=O)([O-])[O-].[K+].[K+]>O.CC(C)=O>[NH:23]1[C:24]2[C:29](=[CH:28][CH:27]=[CH:26][CH:25]=2)[C:21]([C:18]2[CH2:19][CH2:20][N:15]([CH2:2][CH2:3][CH2:4][N:5]3[C:13](=[O:14])[N:8]4[CH:9]=[CH:10][CH:11]=[CH:12][C:7]4=[N:6]3)[CH2:16][CH:17]=2)=[CH:22]1
Reactant: O=c1n(CCCCl)nc2ccccn12
Reactant: C1=C(c2c[nH]c3ccccc23)CCNC1
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: CC(C)=O
Solvent: O
Product: O=c1n(CCCN2CC=C(c3c[nH]c4ccccc34)CC2)nc2ccccn12
Reaction time: 18 h
Yield: 59.1 %

Procedure:
2-(3-Chloro-propyl)-2H-[1,2,4]triazolo[4,3-a]pyridin-3-one 211 mg (1 mmol was loaded into a round bottomed flask, followed by 396 mg (2eq) of 3-(1,2,3,6-Tetrahydro-pyridin-4-yl)-1H-indole, 1.0 gram of potassium iodide, 1.0 gram of potassium carbonate, 100 ml acetone. The mixture was stirred under nitrogen for 18 hours. It was then poured into about 300 ml water and extracted with ethyl acetate (2×200 ml). The combined organic layers were dried over magnesium sulfate and filtered and concentrated. Flash column chromatography using 10%˜100% ethyl acetate/hexane and yielded 220 mg of product (59%). mp: 173.3° C. M+:374.0; (300 MHz, CDCl3): 8.60 (s, 1H, NH), 7.90 (d, 1H), 7.75(d, 1H), 7.34(d, 1H), 7.11(m, 5H), 6.44(m, 1H), 6.16(s, 1H), 4.12 (t, CH2), 3.22 (d, CH2), 2.70 (t, CH2) 2.60(m, 4H), 2.17 (t, CH2).