Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1](=O)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8]/[CH:9]=[CH:10]\[CH2:11]/[CH:12]=[CH:13]\[CH2:14][CH2:15][CH2:16][CH2:17][CH3:18].[CH3:20][N:21]([CH3:26])[CH2:22][CH2:23][CH2:24][NH2:25].C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>O1CCCC1.C(OCC)(=O)C>[CH3:20][N:21]([CH3:26])[CH2:22][CH2:23][CH2:24][NH:25][CH2:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8]/[CH:9]=[CH:10]\[CH2:11]/[CH:12]=[CH:13]\[CH2:14][CH2:15][CH2:16][CH2:17][CH3:18]
Reactant: CCCCC/C=C\C/C=C\CCCCCCCC=O
Reactant: CN(C)CCCN
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: CCCCC/C=C\C/C=C\CCCCCCCCNCCCN(C)C
Temperature: 25 °C
Reaction time: 2 h
Yield: 29.9 %

Procedure:
A solution of (9Z,12Z)-octadeca-9,12-dienal (1.06 g, 4.0 mmol) and N,N-dimethylpropane-1,3-diamine (408 mg, 4.0 mmol) in anhydrous tetrahydrofuran (15 mL) was stirred under nitrogen for 15 minutes then sodium triacetoxyborohydride (1.7 g, 8.0 mmol). The solution was stirred for 2 hours at room temperature. Upon completion, the solution was diluted with ethyl acetate (20 mL) and washed with sodium bicarbonate (2×15 mL) and brine (15 mL). The ethyl acetate layer was dried on magnesium sulfate, filtered and concentrated in vacuo to dryness. The oil was purified by column chromatography on silica gel (eluted with 100% CH2Cl2 to 1/5/94 NH4OH/MeOH/CH2Cl2) to afford N,N-dimethyl-N′-((9Z,12Z)-octadeca-9,12-dienyl)propane-1,3-diamine as a colorless oil (420 mg, 30%).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH2:8][NH:9][CH2:10][CH2:11][SH:12].[C:13](=O)(OC1C=CC=CC=1)[O:14]C1C=CC=CC=1>>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH2:8][N:9]1[CH2:10][CH2:11][S:12][C:13]1=[O:14]
Reactant: SCCNCc1ccccc1Cl
Reactant: O=C(Oc1ccccc1)Oc1ccccc1
Product: O=C1SCCN1Cc1ccccc1Cl
Yield: 43.9 %

Procedure:
The procedure of Example 2 is followed 5.05 g (0.025 mol) of N-(2-chlorophenylmethyl)cysteamine are reacted with 5.35 g (0.025 mol) of diphenyl carbonate and then worked up. The product is purified by column chromatography (by using Kieselgel 60 of 230-400 mesh as sorbent and chloroform as eluent) to obtain 2.5 g (43.9%) of the title compound, nD30 =1.600.
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]([NH:9][C:10](=[O:19])[C:11]2[CH:16]=[CH:15][C:14]([O:17][CH3:18])=[CH:13][CH:12]=2)[CH:6]=[CH:7][CH:8]=1)#[N:2].[H-].[Na+].[CH3:22]I.O>C1COCC1>[C:1]([C:3]1[CH:4]=[C:5]([N:9]([CH3:22])[C:10](=[O:19])[C:11]2[CH:12]=[CH:13][C:14]([O:17][CH3:18])=[CH:15][CH:16]=2)[CH:6]=[CH:7][CH:8]=1)#[N:2]
Reactant: COc1ccc(C(=O)Nc2cccc(C#N)c2)cc1
Reactant: CI
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: COc1ccc(C(=O)N(C)c2cccc(C#N)c2)cc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
500 mg (1.9 mmol) N-(3-Cyano-phenyl)-4-methoxy-benzamide were dissolved in 25 ml THF and 150 mg sodium hydride (60% in oil, 3.7 mmol) were added. The reaction was stirred for 1 h at room temperature, 172 μl (2.8 mmol) methyl iodide were added and the mixture was stirred for 2 h at 60° C. To the reaction mixture water was added and subsequently extracted with ethyl acetate, dried over Na2SO4 and evaporated to dryness.
Reaction SMILES: [Br:1][C:2]1[CH:10]=[C:9]2[C:5]([CH2:6][CH2:7][C:8]2=[O:11])=[CH:4][CH:3]=1.[CH3:12][O:13][C:14](=[O:17])[CH:15]=[CH2:16]>O1CCOCC1.C1(C=CC(O)=CC=1)O>[CH3:12][O:13][C:14](=[O:17])[CH2:15][CH2:16][C:7]1([CH2:16][CH2:15][C:14]([O:13][CH3:12])=[O:17])[CH2:6][C:5]2[C:9](=[CH:10][C:2]([Br:1])=[CH:3][CH:4]=2)[C:8]1=[O:11]
Reactant: C=CC(=O)OC
Reactant: O=C1CCc2ccc(Br)cc21
Agent: Oc1ccc(O)cc1
Solvent: C1COCCO1
Product: COC(=O)CCC1(CCC(=O)OC)Cc2ccc(Br)cc2C1=O
Temperature: 50 °C
Reaction time: 14 h
Yield: 82.6 %

Procedure:
To 6-bromo-1-indanone (25 g, 0.12 mol) in dioxane (150 mL) was added Triton B (2.48 mL, 6.3 mmol) and hydroquinone (5 mg, 0.05 mmol). After stirring the mixture for 10 min at 50° C. methylacrylate (21.5 mL, 0.24 mol) in 50 mL dioxane was added. The mixture was stirred for 4 h at 50° C. and 14 h at RT. Then 2 mL methylacrylate was added and the reaction was stirred for 1 h at 50° C. The reaction mixture was poured onto water, extracted with EA and the solvents were evaporated. The residue was purified by MPLC (340 g silicagel, gradient: CH/EA 100:0 to 50:50) to give 3-[6-Bromo-2-(2-methoxycarbonyl-ethyl)-1-oxo-indan-2-yl]-propionic acid methyl ester (38 g, 84%).
Reaction SMILES: C(S[CH:5]1[N:8]([C:9](=[C:23]([O:30][C:31]2[CH:36]=[CH:35][C:34]([S:37]([CH3:39])=[O:38])=[CH:33][CH:32]=2)[C:24](=[O:29])[C:25]([CH3:28])([CH3:27])[CH3:26])[C:10]([O:12][CH2:13][C:14]2[CH:19]=[CH:18][C:17]([N+:20]([O-:22])=[O:21])=[CH:16][CH:15]=2)=[S:11])[C:7](=[O:40])[CH2:6]1)C=C.[Cl:41]Cl>ClCCl.C(Cl)(Cl)(Cl)Cl>[Cl:41][CH:5]1[N:8]([C:9](=[C:23]([O:30][C:31]2[CH:36]=[CH:35][C:34]([S:37]([CH3:39])=[O:38])=[CH:33][CH:32]=2)[C:24](=[O:29])[C:25]([CH3:28])([CH3:27])[CH3:26])[C:10]([O:12][CH2:13][C:14]2[CH:19]=[CH:18][C:17]([N+:20]([O-:22])=[O:21])=[CH:16][CH:15]=2)=[S:11])[C:7](=[O:40])[CH2:6]1
Reactant: C=CCSC1CC(=O)N1C(C(=S)OCc1ccc([N+](=O)[O-])cc1)=C(Oc1ccc(S(C)=O)cc1)C(=O)C(C)(C)C
Reactant: ClCl
Solvent: ClC(Cl)(Cl)Cl
Solvent: ClCCl
Product: CS(=O)c1ccc(OC(C(=O)C(C)(C)C)=C(C(=S)OCc2ccc([N+](=O)[O-])cc2)N2C(=O)CC2Cl)cc1
Temperature: 25 °C
Yield: 52.5 %

Procedure:
To a solution of 0.488 g of 4-nitrobenzyl 2-(4-allylthioazetidin-2-on-1-yl)-3-(4-methylsulphinylphenoxy)-3-trimethylacetylthiopropenate in dichloromethane at -20°, was added dropwise a solution of 1.58 mmol of chlorine in carbon tetrachloride. After 30 minutes the mixture was warmed to room temperature, evaporated in vacuo, and the residual oil was chromatographed over silica gel. Elution with hexane-ethyl acetate mixtures afforded 0.24 g of the title compound as a pale yellow foam (53% of the theoretical yield).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:19])[CH2:5][CH2:6][C:7]1[C:8](=[O:18])[O:9][C:10]2[C:15]([C:16]=1[OH:17])=[CH:14][CH:13]=[CH:12][CH:11]=2)[CH3:2].[Li+].CC([N-]C(C)C)C.[CH:28]1[CH:33]=[CH:32][C:31]([CH2:34]Br)=[CH:30][CH:29]=1>C1COCC1>[CH2:1]([O:3][C:4](=[O:19])[CH:5]([CH2:34][C:31]1[CH:32]=[CH:33][CH:28]=[CH:29][CH:30]=1)[CH2:6][C:7]1[C:8](=[O:18])[O:9][C:10]2[C:15]([C:16]=1[OH:17])=[CH:14][CH:13]=[CH:12][CH:11]=2)[CH3:2]
Reactant: BrCc1ccccc1
Reactant: CCOC(=O)CCc1c(O)c2ccccc2oc1=O
Agent: CC(C)[N-]C(C)C
Agent: [Li+]
Solvent: C1CCOC1
Product: CCOC(=O)C(Cc1ccccc1)Cc1c(O)c2ccccc2oc1=O
Temperature: -78 °C
Reaction time: 0.25 h

Procedure:
To a solution of 3-(4-Hydroxy-2-oxo-2H-chromen-3-yl)-propionic acid ethyl ester in THF at −78° C. was added LDA (1.5M, 3.05 mL) dropwise. A yellow precipitate was formed during the addition. The reaction was stirred at −78° C. for 15 min and allowed to warmed to 0° C. and stirred for 30 min, after which BnBr (0.24 mL in THF) was added dropwise. The reaction was warmed to room temperature, stirred for 12 hours, cooled to 0° C. and quenched with saturated ammonium chloride and extracted with EtOAc. The organic layer was washed with brine, dried over MgSO4 and conc. in vacuo to a crude colorless oil, which was purified by column chromatography to provide 2-Benzyl-3-(4-hydroxy-2-oxo-2H-chromen-3-yl)-propionic acid ethyl ester as a colorless oil (250 mg). MS: 351 [M-H].
Reaction SMILES: Cl[C:2]1C=CC=C(C(OO)=O)[CH:3]=1.C(S[C:15]1[C:16]([C:21]([NH:23][C:24]2[CH:29]=[CH:28][C:27]([C:30]([F:33])([F:32])[F:31])=[CH:26][N:25]=2)=[O:22])=[N:17][CH:18]=[CH:19][CH:20]=1)C.C(=O)(O)[O-].[Na+].[S:39]([O-:43])([O-])(=[O:41])=S.[Na+].[Na+]>C(Cl)(Cl)Cl>[CH2:2]([S:39]([C:15]1[C:16]([C:21]([NH:23][C:24]2[CH:29]=[CH:28][C:27]([C:30]([F:32])([F:33])[F:31])=[CH:26][N:25]=2)=[O:22])=[N:17][CH:18]=[CH:19][CH:20]=1)(=[O:43])=[O:41])[CH3:3]
Reactant: CCSc1cccnc1C(=O)Nc1ccc(C(F)(F)F)cn1
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: O=S([O-])([O-])=S
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClC(Cl)Cl
Product: CCS(=O)(=O)c1cccnc1C(=O)Nc1ccc(C(F)(F)F)cn1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
0.30 g of m-chloroperbenzoic acid (purity of 68%) was added to a mixture of 0.20 g of 3-ethylsulfanyl-N-(5-trifluoromethylpyridin-2-yl)picolinamide (Compound of Present Invention 2) and 3 mL of chloroform under ice cooling, and the mixture was stirred at room temperature for 2 hours. A saturated aqueous sodium bicarbonate solution and a saturated aqueous sodium thiosulfate solution were poured to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was dried over anhydrous sodium sulfate and concentrated under reduced pressure to obtain 0.11 g of 3-ethylsulfonyl-N-(5-trifluoromethylpyridin-2-yl)picolinamide (hereinafter, referred to as Compound of Present Invention 3).
Reaction SMILES: [Cl:1][C:2]1[CH:15]=[CH:14][C:5]([CH2:6][N:7]2[CH2:12][CH2:11][CH:10]([OH:13])[CH2:9][CH2:8]2)=[CH:4][CH:3]=1.C(N(CC)CC)C.[C:23]1([CH3:32])[CH:28]=[CH:27][C:26]([C:29](Cl)=[O:30])=[CH:25][CH:24]=1>C1(C)C=CC=CC=1>[CH3:32][C:23]1[CH:28]=[CH:27][C:26]([C:29]([O:13][CH:10]2[CH2:9][CH2:8][N:7]([CH2:6][C:5]3[CH:4]=[CH:3][C:2]([Cl:1])=[CH:15][CH:14]=3)[CH2:12][CH2:11]2)=[O:30])=[CH:25][CH:24]=1
Reactant: OC1CCN(Cc2ccc(Cl)cc2)CC1
Reactant: Cc1ccc(C(=O)Cl)cc1
Solvent: Cc1ccccc1
Solvent: CCN(CC)CC
Product: Cc1ccc(C(=O)OC2CCN(Cc3ccc(Cl)cc3)CC2)cc1

Procedure:
0.25 g (0.0011 mol) of 1-(4-chloro-benzyl)-piperidin-4-ol and 0.39 ml (0.0028 mol) of triethylamine were dissolved in 11 ml of toluene, treated with 0.184ml (0.0014mol) of p-toluoyl chloride and boiled at reflux for 18 hrs. The reaction mixture was concentrated and the residue was chromatographed over silica gel with ethyl acetate/hexane (1:3). 0.135 9 (39%) of 1-(4-chloro-benzyl)-piperidin-4-yl 4-methyl-benzoate was obtained as white crystals.
Reaction SMILES: [N+:1]([C:4]1[CH:51]=[CH:50][C:7]([CH2:8][CH:9]([CH2:40][C:41]2[CH:46]=[CH:45][C:44]([N+:47]([O-])=O)=[CH:43][CH:42]=2)[C:10]([O:12][CH:13]2[CH2:37][CH2:36][C@@:35]3([CH3:38])[C:15](=[CH:16][CH2:17][C@@H:18]4[C@@H:34]3[CH2:33][CH2:32][C@@:31]3([CH3:39])[C@H:19]4[CH2:20][CH2:21][C@@H:22]3[C@H:23]([CH3:30])[CH2:24][CH2:25][CH2:26][CH:27]([CH3:29])[CH3:28])[CH2:14]2)=[O:11])=[CH:6][CH:5]=1)([O-])=O.[Cl-].[NH4+]>[Zn].CO.O>[NH2:1][C:4]1[CH:5]=[CH:6][C:7]([CH2:8][CH:9]([CH2:40][C:41]2[CH:46]=[CH:45][C:44]([NH2:47])=[CH:43][CH:42]=2)[C:10]([O:12][CH:13]2[CH2:37][CH2:36][C@@:35]3([CH3:38])[C:15](=[CH:16][CH2:17][C@@H:18]4[C@@H:34]3[CH2:33][CH2:32][C@@:31]3([CH3:39])[C@H:19]4[CH2:20][CH2:21][C@@H:22]3[C@H:23]([CH3:30])[CH2:24][CH2:25][CH2:26][CH:27]([CH3:29])[CH3:28])[CH2:14]2)=[O:11])=[CH:50][CH:51]=1
Reactant: CC(C)CCC[C@@H](C)[C@H]1CC[C@H]2[C@@H]3CC=C4CC(OC(=O)C(Cc5ccc([N+](=O)[O-])cc5)Cc5ccc([N+](=O)[O-])cc5)CC[C@]4(C)[C@H]3CC[C@]12C
Agent: [Cl-]
Agent: [NH4+]
Agent: [Zn]
Solvent: CO
Solvent: O
Product: CC(C)CCC[C@@H](C)[C@H]1CC[C@H]2[C@@H]3CC=C4CC(OC(=O)C(Cc5ccc(N)cc5)Cc5ccc(N)cc5)CC[C@]4(C)[C@H]3CC[C@]12C
Yield: 69.3 %

Procedure:
2.62 g (3.75 mmol) Cholest-5-en-3-yl 2-(4-nitrobenzyl)-3-(4-nitrophenyl)-propanoate and 0.79 g (14.77 mmol) ammonium chloride were suspended in 90 ml of a mixture consisting of methanol:water 9:1. 4.90 g (74.96 mmol) zinc powder was then added in 10 minutes. The reaction mixture was then allowed to react at 45° C. for 6 hours and partitioned between dichloromethane and water; the organic phase was washed repeatedly with water, dried over sodium sulfate, filtered and concentrated by rotary evaporation. First chromatography of the residue on 50 g silica gel using toluene:ethyl acetate 1:1 as eluant and second chromatography on 50 g silica gel using tert.butyl methylether as eluant yielded 1.66 g Cholest-5-en-3-yl 2-(4-aminobenzyl)-3-(4-aminophenyl)propanoate as white powder.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:8][CH:9]1[CH2:14][CH2:13][CH2:12][CH2:11][C:10]1=O.N1C2C=CC=CC=2N=N1.[BH4-].[Na+]>O.CO>[CH3:8][CH:9]1[CH2:14][CH2:13][CH2:12][CH2:11][CH:10]1[NH:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: Nc1ccccc1
Reactant: CC1CCCCC1=O
Agent: [BH4-]
Agent: [Na+]
Agent: c1ccc2[nH]nnc2c1
Solvent: CO
Solvent: O
Product: CC1CCCCC1Nc1ccccc1
Yield: 37 %

Procedure:
In a 100-mL flask, the following mixture is heated at reflux for 30 h: 9.3 g aniline, 11.2 g 2-methylcyclohexanone and 12 g benzotriazole. Then, 200 mL of methanol and 5 g of NaBH4 in portions are added to the mixture, which is then heated at reflux for 30 min. The solution is allowed to cool, and 100 mL of water are added to the mixture, which is extracted with 2×100 mL diisopropyl ether. The organic phase is recovered, dried over magnesium sulfate and reduced to dryness. In this manner, 7 g of the desired amine are produced.
Reaction SMILES: [Br-:1].[Br-].[Br-].C([N+](CCCC)(CCCC)CCCC)CCC.C([N+](CCCC)(CCCC)CCCC)CCC.C([N+](CCCC)(CCCC)CCCC)CCC.[Cl:55][C:56]1[CH:57]=[C:58]([C:63]([CH3:68])([CH3:67])[C:64](=[O:66])[CH3:65])[CH:59]=[CH:60][C:61]=1[Cl:62]>CO.C(Cl)Cl>[Br:1][CH2:65][C:64](=[O:66])[C:63]([C:58]1[CH:59]=[CH:60][C:61]([Cl:62])=[C:56]([Cl:55])[CH:57]=1)([CH3:68])[CH3:67]
Reactant: CC(=O)C(C)(C)c1ccc(Cl)c(Cl)c1
Reactant: [Br-]
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Solvent: ClCCl
Solvent: CO
Product: CC(C)(C(=O)CBr)c1ccc(Cl)c(Cl)c1
Reaction time: 24 h
Yield: 91.7 %

Procedure:
Tetrabutylammonium tribromide (20.4 g, 41.5 mmol) was added to a solution of 3-(3,4-dichlorophenyl)-3-methylbutan-2-one (9.60 g, 41.5 mmol) in MeOH-DCM (160 mL, 1:2, v/v). After stirring 24 h, the reaction mixture was concentrated under reduced pressure and then combined with EtOAc (80 mL). The organic layer was washed with H2O (50 mL), 1N HCl (50 mL), and H2O (20 mL) successively. The organic layer was washed with brine, dried over Na2SO4, and concentrated. Purification by column chromatography afforded 1-bromo-3-(3,4-dichlorophenyl)-3-methylbutan-2-one (11.8 g, 91%). 1H NMR (400 MHz, CDCl3) δ 7.45 (d, 1H), 7.38 (d, 1H), 7.08 (d, 1H), 3.86 (s, 2H), 1.56 (s, 6H).
Reaction SMILES: [Co:1].[C:2]([OH:17])(=[O:16])[CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH3:15]>>[C:2]([O-:17])(=[O:16])[CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH3:15].[Co+2:1].[C:2]([O-:17])(=[O:16])[CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH3:15]
Reactant: CCCCCCCCCCCCCC(=O)O
Reactant: [Co]
Product: CCCCCCCCCCCCCC(=O)[O-]
Product: [Co+2]
Reaction time: 1 h

Procedure:
To an aqueous solution of cobalt chloride prepared by dissolving 239 g cobalt chloride hydrate (containing 24.4% cobalt) in 2700 ml water, 1313 g of a 80% aqueous sodium carbonate solution was added under stirring to produce an aqueous cobalt carbonate dispersion containing 58.3 g cobalt. This liquid was heated under stirring, and at a constant temperature of 55° l C., 452 g myristic acid (melt initiating temperature 50° C.) in scale form was added over a period of 15 minutes. Stirring was continuted for an additional period of 60 minutes while the temperature was held constant at 55° C. Thereafter, heating was stopped. Cobalt myristate formed in the upper layer of the reaction liquid was filtered off. It was washed with water in the same way as in Example 2, and was dried at 60° C. to obtain 508 g granular cobalt myristate (melting point 90° C.) having an average grain diameter of about 0.8 mm. The cobalt content of this product was 11.35%, and the yield of the product based on the cobalt used was 98.9%.
Reaction SMILES: [CH:1]1([NH:7][C:8]([NH:10][CH:11]2[CH2:16][CH2:15][CH2:14][CH2:13][CH2:12]2)=S)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C(Cl)(Cl)(Cl)[Cl:37].C(N(CC)CC)C.[NH:48]1[CH2:53][CH2:52][O:51][CH2:50][CH2:49]1>C(O)(C)(C)C.C(Cl)Cl>[ClH:37].[CH:1]1([NH:7][C:8]([N:48]2[CH2:53][CH2:52][O:51][CH2:50][CH2:49]2)=[N:10][CH:11]2[CH2:16][CH2:15][CH2:14][CH2:13][CH2:12]2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: S=C(NC1CCCCC1)NC1CCCCC1
Reactant: C1COCCN1
Reactant: ClC(Cl)(Cl)Cl
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Solvent: CC(C)(C)O
Product: C1CCC(N=C(NC2CCCCC2)N2CCOCC2)CC1
Product: Cl
Temperature: 25 °C

Procedure:
A mixture of 2.4 gm. (0.01 mole) of N,N'-dicyclohexylthiourea, 3.15 gm. (0.012 mole) of triphenylphosphine, 1.55 gm. (0.01 mole) of carbon tetrachloride, and 1.0 gm. (0.01 mole) of triethylamine in 25 ml. of methylene chloride is stirred for 2.5 hr. at 40°-45°. The reaction mixture is concentrated and the residue extracted several times with hot Skellysolve B. The combined Skellysolve B extracts are cooled to room temperature, filtered and evaporated. The crude N,N'-dicyclohexylcarbodiimide is reacted with 5 ml. of morpholine in 10 ml of tert-butyl alcohol at reflux for 16 hours. The reaction mixture is evaporated, toluene added and concentrated to remove residual morpholine. The residue is partitioned between ether and 10% hydrochloric acid. The acid layer is basified with 20% sodium hydroxide solution, nitrogen bubbled through the solution to remove ether and cooled at 5°. The product is collected, 2.07 gm. (70%), m.p. 105°-107°. The HCl salt is prepared and recrystallized from acetonitrile-ether, m.p. 226°-227°.
Reaction SMILES: Br[C:2]1[O:3][C:4]2[CH:16]=[CH:15][C:14]([CH2:17][S:18]([CH3:20])=[O:19])=[CH:13][C:5]=2[C:6]=1[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1.C(O)(=O)C.C(O)(=O)C(CC(O)=O)=C.[N+:34]([O-:39])([N+]([O-])=O)=[O:35]>C(Cl)(Cl)Cl.O>[CH3:20][S:18]([CH2:17][C:14]1[CH:15]=[CH:16][C:4]2[O:3][C:2]([N+:34]([O-:39])=[O:35])=[C:6]([C:7]3[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=3)[C:5]=2[CH:13]=1)=[O:19]
Reactant: CS(=O)Cc1ccc2oc(Br)c(-c3ccccc3)c2c1
Reactant: O=[N+]([O-])[N+](=O)[O-]
Agent: C=C(CC(=O)O)C(=O)O
Solvent: CC(=O)O
Solvent: ClC(Cl)Cl
Solvent: O
Product: CS(=O)Cc1ccc2oc([N+](=O)[O-])c(-c3ccccc3)c2c1
Reaction time: 2 h

Procedure:
The product of step A is dissolved in 100 ml. of acetic acid, 3.3 g. of itaconic acid is added followed by 2.3 g. of dinitrogen tetraoxide in 10 ml. of acetic acid (the latter being added dropwise). After two hours, the mixture is poured into water and extracted with diethyl ether. The ether extracts are washed with dilute sodium bicarbonate solution, with saturated sodium chloride solution, then dried. Evaporation provides a solid which is dissolved in chloroform and chromatographically fractionated on silica gel, eluting with chloroform-carbon tetrachloride, then chloroform. The desired product elutes slowly with chloroform. It is washed with hot hexane, then recrystallized from a hexane-chloroform mixture to provide 5-methylsulfinylmethyl-2-nitro-3-phenylbenzofuran, m.p. 161°-163° C. This is the product of Example 19.
Reaction SMILES: [C:1]([O:4][C:5]1[CH:6]=[C:7]2[C:12](=[CH:13][C:14]=1[C:15]([CH3:18])([CH3:17])[CH3:16])[O:11][C:10]([CH2:20][O:21][C:22]1[CH:27]=[CH:26][C:25](N)=[CH:24][CH:23]=1)([CH3:19])[CH2:9][CH2:8]2)(=[O:3])[CH3:2].N([O-])=O.[Na+].[ClH:33].[C:34]([O:38][CH2:39][CH3:40])(=[O:37])[CH:35]=[CH2:36]>CC(C)=O>[C:1]([O:4][C:5]1[CH:6]=[C:7]2[C:12](=[CH:13][C:14]=1[C:15]([CH3:18])([CH3:17])[CH3:16])[O:11][C:10]([CH2:20][O:21][C:22]1[CH:27]=[CH:26][C:25]([CH2:36][CH:35]([Cl:33])[C:34]([O:38][CH2:39][CH3:40])=[O:37])=[CH:24][CH:23]=1)([CH3:19])[CH2:9][CH2:8]2)(=[O:3])[CH3:2]
Reactant: Cl
Reactant: C=CC(=O)OCC
Reactant: CC(=O)Oc1cc2c(cc1C(C)(C)C)OC(C)(COc1ccc(N)cc1)CC2
Agent: O=N[O-]
Agent: [Na+]
Solvent: CC(C)=O
Product: CCOC(=O)C(Cl)Cc1ccc(OCC2(C)CCc3cc(OC(C)=O)c(C(C)(C)C)cc3O2)cc1

Procedure:
Following the procedure described in Preparation 51, 1.74 g of 6-acetoxy-2-(4-aminophenoxymethyl)-7-t-butyl-2-methylchroman (prepared as described in Preparation 58), 380 mg of sodium nitrite, 0.8 ml of concentrated hydrochloric acid, 4.5 g of ethyl acrylate, 65 mg of cuprous oxide and 17 ml of acetone were reacted, to give the title compound as a slightly yellow oil.
Reaction SMILES: C(NC(C)C)(C)C.C([Li])CCC.[S:13]1[CH:17]=[CH:16][CH:15]=[C:14]1[C:18]#[N:19].C(O)(=O)C[C:22](CC(O)=O)(C(O)=O)[OH:23]>O1CCCC1.O>[C:18]([C:14]1[S:13][C:17]([CH:22]=[O:23])=[CH:16][CH:15]=1)#[N:19]
Reactant: N#Cc1cccs1
Reactant: O=C(O)CC(O)(CC(=O)O)C(=O)O
Agent: [Li]CCCC
Solvent: CC(C)NC(C)C
Solvent: O
Solvent: C1CCOC1
Product: N#Cc1ccc(C=O)s1
Reaction time: 0.08 h
Yield: 55.3 %

Procedure:
A solution of diisopropylamine (35.3 ml, 0.251 moles) in tetrahydrofuran (500 ml) was cooled to −78° C. under a nitrogen blanket. To this was added 1.6M n-butyllithium in hexanes (157 ml, 0.251 moles) and allowed to stir for 5 min. Then slowly added thiopene-2-carbonitrile (21.33 ml, 0.229 moles) in tetrahydrofuran (115 ml) and allowed to stir. After 45 min. was added NN-dimethylformamide (88.66 ml, 1.145 moles) at −78° C. Citric acid (40 g) was added after 2 h. followed by water (240 ml) and stirred for 18 h. The reaction was concentrated in vacuo, transferred to a separatory funnel, diluted with brine, and extracted twice with ether. The combined ether layers were washed with brine, dried over magnesium sulfate, filtered, and the solvent removed in vacuo. Chromatography yielded 15.8 g (50%) of 2-cyano-5-formylthiophene (EX-55A) as a brown solid: 1H NMR (300 MHZ, CDCl3) d 10.02 (s, 1H), 7.79 (m, 1H), 7.30 (m, 1H).
Reaction SMILES: [NH2:1][C:2]1[N:28]([CH2:29][C:30]([OH:33])([CH3:32])[CH3:31])[C:6]2[N:7]=[C:8]([NH:11][C:12]3[CH:17]=[CH:16][C:15]([N:18]4[CH2:23][CH2:22][CH:21]([CH2:24][CH3:25])[CH2:20][CH2:19]4)=[CH:14][C:13]=3[O:26][CH3:27])[N:9]=[CH:10][C:5]=2[C:4](=[O:34])[C:3]=1[C:35]([NH2:37])=[O:36].CC[Cl:40]>ClCCl.CO.CCOCC>[ClH:40].[NH2:1][C:2]1[N:28]([CH2:29][C:30]([OH:33])([CH3:32])[CH3:31])[C:6]2[N:7]=[C:8]([NH:11][C:12]3[CH:17]=[CH:16][C:15]([N:18]4[CH2:23][CH2:22][CH:21]([CH2:24][CH3:25])[CH2:20][CH2:19]4)=[CH:14][C:13]=3[O:26][CH3:27])[N:9]=[CH:10][C:5]=2[C:4](=[O:34])[C:3]=1[C:35]([NH2:37])=[O:36]
Reactant: CCCl
Agent: CCC1CCN(c2ccc(Nc3ncc4c(=O)c(C(N)=O)c(N)n(CC(C)(C)O)c4n3)c(OC)c2)CC1
Solvent: CO
Solvent: ClCCl
Solvent: CCOCC
Product: Cl
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
To a solution of 0.25 g (0.50 mmol) of the product prepared in step 19.3 in 10 mL of a dichloromethane/methanol mixture (4/1) are added 2 mL (2 mmol) of 1.0 M hydrochloric ether. The mixture is stirred for 10 minutes at room temperature and is then diluted with ether. The precipitate is drained by suction, rinsed with ether and with pentane, and dried under vacuum. 0.28 g of the expected product is obtained in the form of a yellow solid. Yield (dihydrochloride)=96%. m.p.=200°C. (decomposition). M+H+=510.
Reaction SMILES: [CH3:1][N:2]1[CH2:33][CH2:32][C:5]2[N:6]([CH2:14][CH2:15][C:16]([N:18]3[CH2:23][CH2:22][CH:21]([NH:24]C(=O)OC(C)(C)C)[CH2:20][CH2:19]3)=[O:17])[C:7]3[CH:8]=[CH:9][C:10]([CH3:13])=[CH:11][C:12]=3[C:4]=2[CH2:3]1.FC(F)(F)C(O)=O>ClCCl>[NH2:24][CH:21]1[CH2:22][CH2:23][N:18]([C:16](=[O:17])[CH2:15][CH2:14][N:6]2[C:7]3[CH:8]=[CH:9][C:10]([CH3:13])=[CH:11][C:12]=3[C:4]3[CH2:3][N:2]([CH3:1])[CH2:33][CH2:32][C:5]2=3)[CH2:19][CH2:20]1
Reactant: Cc1ccc2c(c1)c1c(n2CCC(=O)N2CCC(NC(=O)OC(C)(C)C)CC2)CCN(C)C1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: Cc1ccc2c(c1)c1c(n2CCC(=O)N2CCC(N)CC2)CCN(C)C1
Yield: 25.6 %

Procedure:
tert-butyl 1-(3-(1,2,3,4-tetrahydro-2,8-dimethylpyrido[4,3-b]indol-5-yl)propanoyl)piperidin-4-ylcarbamate (50 mg) was stirred with trifluoroacetic acid (2 ml) in dichloromethane (2 ml) for 16 h at 25° C. to obtain 10 mg of 1-(4-aminopiperidin-1-yl)-3-(1,2,3,4-tetrahydro-2,8-dimethylpyrido[4,3-b]indol-5-yl)propan-1-one as di-TFA salt after purification by reverse-phase chromatography (C-18, 500 mm×50 mm, Mobile Phase. A=0.05% TFA in water, B=0.05% TFA in acetonitrile, Gradient: 10% B to 80% B in 30 min, injection vol. 5 mL).