Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C([N:8]([CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][O:35][CH2:36][CH2:37][CH2:38][CH2:39][C:40]1[CH:45]=[CH:44][CH:43]=[C:42]([S:46]([CH:49]2[CH2:53][CH2:52][CH2:51][CH2:50]2)(=[O:48])=[O:47])[CH:41]=1)[CH2:9][C@@H:10]([C:12]1[CH:13]=[CH:14][C:15]([O:21]CC2C=CC=CC=2)=[C:16]([NH:18][CH:19]=[O:20])[CH:17]=1)[OH:11])C1C=CC=CC=1.[C:54]([OH:57])(=[O:56])[CH3:55]>CCO.[Pd].[OH-].[OH-].[Pd+2]>[C:54]([OH:57])(=[O:56])[CH3:55].[CH:49]1([S:46]([C:42]2[CH:41]=[C:40]([CH2:39][CH2:38][CH2:37][CH2:36][O:35][CH2:34][CH2:33][CH2:32][CH2:31][CH2:30][CH2:29][NH:8][CH2:9][C@@H:10]([C:12]3[CH:13]=[CH:14][C:15]([OH:21])=[C:16]([NH:18][CH:19]=[O:20])[CH:17]=3)[OH:11])[CH:45]=[CH:44][CH:43]=2)(=[O:48])=[O:47])[CH2:53][CH2:52][CH2:51][CH2:50]1
Reactant: O=CNc1cc([C@@H](O)CN(CCCCCCOCCCCc2cccc(S(=O)(=O)C3CCCC3)c2)Cc2ccccc2)ccc1OCc1ccccc1
Agent: [Pd+2]
Agent: [Pd]
Agent: [OH-]
Solvent: CCO
Solvent: CC(=O)O
Product: O=CNc1cc([C@@H](O)CNCCCCCCOCCCCc2cccc(S(=O)(=O)C3CCCC3)c2)ccc1O

Procedure:
5-{(1R)-2-[Benzyl(6-{4-[3-(cyclopentylsulfonyl)phenyl]butoxy}hexyl)amino]-1-hydroxyethyl}-2-(benzyloxy)phenylformamide (17 mg) was dissolved in EtOH (10 ml) and glacial acetic acid (1 ml) added. The solution was hydrogenated using 10% palladium on carbon (50% water by weight, 7 mg) and 20% palladium hydroxide on carbon (7 mg) for 20 h. The catalyst was removed by filtration and the filtrate was evaporated in vacuo. The residue was purified on an isolute aminopropyl cartridge (2 g), eluting with MeOH-DCM mixtures. Evaporation of the appropriate fractions with AcOH gave the title compound, (5 mg) LCMS RT=2.53 min, ES+ve 561 (MH)+
Reaction SMILES: [Mg].Br[C:3]12[CH2:12][CH:7]3[CH2:8][CH:9]([CH2:11][CH:5]([CH2:6]3)[CH2:4]1)[CH2:10]2.[P:13]([Cl:16])(Cl)Cl>CCOCC>[C:3]12([P:13]([C:3]34[CH2:12][CH:7]5[CH2:8][CH:9]([CH2:11][CH:5]([CH2:6]5)[CH2:4]3)[CH2:10]4)[Cl:16])[CH2:12][CH:7]3[CH2:8][CH:9]([CH2:11][CH:5]([CH2:6]3)[CH2:4]1)[CH2:10]2
Reactant: ClP(Cl)Cl
Reactant: BrC12CC3CC(CC(C3)C1)C2
Agent: [Mg]
Solvent: CCOCC
Product: ClP(C12CC3CC(CC(C3)C1)C2)C12CC3CC(CC(C3)C1)C2
Temperature: -45 °C
Reaction time: 0.5 h

Procedure:
An oven-dried, round-bottom flask was charged with magnesium turnings (15.3 g, 0.63 mol) and 1-bromoadamantane (9.0 g, 0.041 mol). The flask was evacuated and backfilled with argon two times. To the reaction vessel 45 mL ether was added and the mixture was gently refluxed for 15 hours, without mechanical stirring. The resulting solution of Grignard reagent was taken up in a syringe, and added very slowly dropwise to a separate flame-dried, two-necked, round-bottom flask equipped with a reflux condenser which had been charged with PCl3 (0.9 mL, 10 mmol) and 15 mL ether which had been coooled to −40° C. During the addition the temperature was monitored and kept below -25° C. The resulting mixture was stirred for 30 minutes at −45° C., then the cooling bath was removed and the reaction mixture was allowed to warm slowly to room temperature. After stirring for an additional 30 minutes at room temperature, the reaction vessel was placed into a heated oilbath (37° C.) and was gently refluxed for 22 hours. The mixture was cooled to room temperature, and the solution was filtered through a cannula filter. The solvent as well as some of the adamantane byproduct was removed in vacuo, without exposing the product to air to afford crude di-1-adamantylchlorophosphine.
Reaction SMILES: C[O:2][C:3]([C:5]1[N:6]=[CH:7][N:8]([C:10]([C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[CH:9]=1)=[O:4].[OH-].[Na+].Cl>CO.O.C(OCC)(=O)C>[C:10]([N:8]1[CH:9]=[C:5]([C:3]([OH:4])=[O:2])[N:6]=[CH:7]1)([C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)([C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1
Reactant: COC(=O)c1cn(C(c2ccccc2)(c2ccccc2)c2ccccc2)cn1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CO
Solvent: CCOC(C)=O
Product: O=C(O)c1cn(C(c2ccccc2)(c2ccccc2)c2ccccc2)cn1
Temperature: 25 °C
Reaction time: 18 h
Yield: 95.1 %

Procedure:
A solution of 1-trityl-1H-imidazole-4-carboxylic acid methyl ester (1.75 g, 4.60 mmol) in methanol (50 mL) at 25° C. was treated with a 1N aqueous sodium hydroxide solution (13.8 mL, 13.8 mmol). The reaction was stirred at 25° C. for 18 h and then heated to 50° C. for 1.5 h. At this time, the reaction was cooled to 25° C. and diluted with water (150 mL). The aqueous layer was brought to pH=1 by treatment with a 1N aqueous hydrochloric acid solution and then diluted with ethyl acetate (250 mL). The resulting precipitated product was collected by filtration. The filtrate was extracted with ethyl acetate (1×150 mL). The combined organics were then washed with a saturated aqueous sodium chloride solution (1×100 mL), dried over magnesium sulfate, filtered, and concentrated in vacuo. The two batches of product were combined to afford 1-trityl-1H-imidazole-4-carboxylic acid (1.55 g, 95.1%.) as a white solid: LR-MS for C23H18N2O2 (M+H)+ at m/z=355.
Reaction SMILES: Cl[C:2]1[C:10](C)=[C:9](Cl)[C:8]([N+:13]([O-])=O)=[CH:7][C:3]=1C(O)=O.[O-]S(S([O-])=O)=O.[Na+].[Na+].Cl.[C:25](=[O:28])([O-])[O-:26].[Na+].[Na+]>COCCO.O>[CH:3]1[C:2]([C:25]([OH:26])=[O:28])=[CH:10][CH:9]=[C:8]([NH2:13])[CH:7]=1
Reactant: O=C([O-])[O-]
Reactant: Cc1c(Cl)c(C(=O)O)cc([N+](=O)[O-])c1Cl
Agent: Cl
Agent: O=S([O-])S(=O)[O-]
Agent: [Na+]
Solvent: O
Solvent: COCCO
Product: Nc1ccc(C(=O)O)cc1
Temperature: 25 °C

Procedure:
55 g of 2,4-dichloro-3-methyl-5-nitrobenzoic acid and 141.6 g of Na2S2O4 are boiled in a mixture of 440 ml of glycol monomethyl ether and 440 ml of water for 3 hours. 620 ml of 1/2-concentrated HCl are added to the still warm solution and the mixture is then boiled up once more. After cooling to room temperature, the mixture is poured into 1.5 l of water and brought to pH 5 with sodium carbonate. 24.6 g of aminobenzoic acid are obtained. Melting point: 202°-3°.
Reaction SMILES: F[C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[N+:9]([O-:11])=[O:10].[O-:12][S:13]([O-:15])=[O:14].[Na+].[Na+].O>CCO>[F:8][C:6]1[CH:5]=[CH:4][C:3]([N+:9]([O-:11])=[O:10])=[C:2]([S:13]([OH:15])(=[O:14])=[O:12])[CH:7]=1
Reactant: O=[N+]([O-])c1ccc(F)cc1F
Reactant: O=S([O-])[O-]
Agent: [Na+]
Solvent: CCO
Solvent: O
Product: O=[N+]([O-])c1ccc(F)cc1S(=O)(=O)O
Yield: 22.6 %

Procedure:
In a similar fashion using route 39 general procedure 95, 2,4-difluoronitrobenzene (2.0 g, 12.0 mmol) in EtOH (24 ml) and Na2SO3 (3.6 g, 28 mmol) in EtOH:water (32 ml: 40 ml) at 70° C. for 14 h gave the title compound (0.6 g) which was used in the next step without further purification. The structure was confirmed by 1H NMR.
Reaction SMILES: [F:1][C:2]1[C:25]([N:26]2[CH2:32][CH2:31][CH2:30][N:29]([CH3:33])[CH2:28][CH2:27]2)=[CH:24][C:5]2[NH:6][C:7]([C:9]3[C:21]4[C:20]5[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=5)[C:14](=[N:22]O)[C:13]=4[CH:12]=[CH:11][CH:10]=3)=[N:8][C:4]=2[CH:3]=1>[Ni].C(O)C.O1CCCC1>[F:1][C:2]1[C:25]([N:26]2[CH2:32][CH2:31][CH2:30][N:29]([CH3:33])[CH2:28][CH2:27]2)=[CH:24][C:5]2[NH:6][C:7]([C:9]3[C:21]4[C:20]5[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=5)[CH:14]([NH2:22])[C:13]=4[CH:12]=[CH:11][CH:10]=3)=[N:8][C:4]=2[CH:3]=1
Reactant: CN1CCCN(c2cc3[nH]c(-c4cccc5c4-c4ccccc4C5=NO)nc3cc2F)CC1
Agent: [Ni]
Solvent: CCO
Solvent: C1CCOC1
Product: CN1CCCN(c2cc3[nH]c(-c4cccc5c4-c4ccccc4C5N)nc3cc2F)CC1
Yield: 76.1 %

Procedure:
The procedure used in Example 6 is followed, starting from 950 mg of 4-[5-fluoro-6-(4-methylperhydro-1,4-diazepin-1-yl)-1H-benzimidazol-2-yl]-9H-fluoren-9-one oxime (Z,E), obtained in the previous stage, and 135 mg of Raney nickel in 20 ml of ethanol and 20 ml of tetrahydrofuran for 16 hours at 60° C. under an initial hydrogen pressure of one bar. After filtration of the catalyst, concentration to dryness under reduced pressure, and then purification by formation of a paste with diisopropyl ether, in this way we obtain 700 mg of 4-[5-fluoro-6-(4-methylperhydro-1,4-diazepin-1-yl)-1H-benzimidazol-2-yl]-9H-fluoren-9(R,S)-ylamine, in the form of an orange powder which is used as it is in the following stage.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[NH:8][C:9]([NH:11][C:12]1[CH:17]=[CH:16][C:15]([Cl:18])=[C:14]([S:19]([NH:22][CH2:23][CH2:24][NH:25]C(OC(C)(C)C)=O)(=[O:21])=[O:20])[C:13]=1[OH:33])=[O:10].[F:34][C:35]([F:40])([F:39])[C:36]([OH:38])=[O:37]>>[F:34][C:35]([F:40])([F:39])[C:36]([OH:38])=[O:37].[NH2:25][CH2:24][CH2:23][NH:22][S:19]([C:14]1[C:13]([OH:33])=[C:12]([NH:11][C:9]([NH:8][C:3]2[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=2[Br:1])=[O:10])[CH:17]=[CH:16][C:15]=1[Cl:18])(=[O:20])=[O:21]
Reactant: CC(C)(C)OC(=O)NCCNS(=O)(=O)c1c(Cl)ccc(NC(=O)Nc2ccccc2Br)c1O
Solvent: O=C(O)C(F)(F)F
Product: NCCNS(=O)(=O)c1c(Cl)ccc(NC(=O)Nc2ccccc2Br)c1O
Yield: 34 %

Procedure:
Following the general procedure for Boc deprotection outlined in example 36, N-(2-bromophenyl)-N′[3-[N″-[2-(tert-butoxycarbonylamino)ethyl]aminosulfonyl]4-chloro-2-hydroxyphenyl] urea (80 mg, 0.14 mmol) was stirred in trifluoroacetic acid to form the desired product (22 mg, 34%). LC-MS 465.0 (M+).
Reaction SMILES: [NH2:1][CH2:2][CH:3]1[CH2:8][CH2:7][N:6]([C:9]([O:11][CH2:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)=[O:10])[CH2:5][CH2:4]1.Cl[C:20]1[C:25]([C:26]([F:29])([F:28])[F:27])=[CH:24][CH:23]=[CH:22][N:21]=1>>[CH2:12]([O:11][C:9]([N:6]1[CH2:7][CH2:8][CH:3]([CH2:2][NH:1][C:20]2[C:25]([C:26]([F:29])([F:28])[F:27])=[CH:24][CH:23]=[CH:22][N:21]=2)[CH2:4][CH2:5]1)=[O:10])[C:13]1[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=1
Reactant: NCC1CCN(C(=O)OCc2ccccc2)CC1
Reactant: FC(F)(F)c1cccnc1Cl
Product: O=C(OCc1ccccc1)N1CCC(CNc2ncccc2C(F)(F)F)CC1
Temperature: 100 °C

Procedure:
A mixture of benzyl 4-(aminomethyl)piperidine-1-carboxylate (EXAMPLE 13, Step 1) (1 g, 4.03 mmol) and 2-chloro-3-trifluoromethylpyridine (0.25 g) was heated to 100° C. for 12 h. The reaction mixture was cooled and partitioned between EtOAc and pH5.2 citrate buffer. The organic layer was washed with brine, dried over anhydrous sodium sulfate, and the solvent evaporated to give a crude product. Purification by flash column chromatography (5–50% EtOAc hexane) afforded the title compound. M.S (M+1): 394.
Reaction SMILES: [CH3:1][O:2][CH2:3][C:4]1[CH:20]=[CH:19][C:7]([C:8]([NH:10][C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=2[O:17][CH3:18])=[O:9])=[CH:6][CH:5]=1.Cl.Cl[CH2:23][CH2:24][N:25]1[CH2:30][CH2:29][CH:28]([C:31](=[O:39])[C:32]2[CH:37]=[CH:36][C:35]([F:38])=[CH:34][CH:33]=2)[CH2:27][CH2:26]1.[I-].[Na+].[H-].[Na+]>CN(C=O)C>[F:38][C:35]1[CH:34]=[CH:33][C:32]([C:31]([CH:28]2[CH2:29][CH2:30][N:25]([CH2:24][CH2:23][N:10]([C:11]3[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=3[O:17][CH3:18])[C:8](=[O:9])[C:7]3[CH:6]=[CH:5][C:4]([CH2:3][O:2][CH3:1])=[CH:20][CH:19]=3)[CH2:26][CH2:27]2)=[O:39])=[CH:37][CH:36]=1
Reactant: O=C(c1ccc(F)cc1)C1CCN(CCCl)CC1
Reactant: COCc1ccc(C(=O)Nc2ccccc2OC)cc1
Agent: Cl
Agent: [H-]
Agent: [I-]
Solvent: CN(C)C=O
Product: COCc1ccc(C(=O)N(CCN2CCC(C(=O)c3ccc(F)cc3)CC2)c2ccccc2OC)cc1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 54.7 %

Procedure:
In an atmosphere of argon, 4-methoxymethyl-N-(2-methoxyphenyl)benzamide (126 mg, 0.464 mmol), 1-(2-chloroethyl)-4-(4-fluorobenzoyl)piperidine hydrochloride (157 mg, 0.511 mmol) and sodium iodide (154 mg, 1.02 mmol) were dissolved in DMF (3 ml) to which was subsequently added sodium hydride (40 mg, 60%, 1.0 mmol) at room temperature. After stirring at room temperature for 10 minutes and then at 60° C. for 3.5 hours, DMF was removed by evaporation. The resulting residue was diluted with water (10 ml) and extracted with ethyl acetate, and the organic layer was washed with water and saturated brine and then dried on anhydrous sodium carbonate. Thereafter, the solvent was removed by evaporation, and the resulting residue was purified by subjecting it to a silica gel column chromatography (methylene chloride:methanol=80:1-ethyl acetate) to obtain 128 mg (54.7%) of the title compound in the form of colorless oil.
Reaction SMILES: N1C[CH2:3][CH2:4][C:5]=1[NH:6][S:7]([C:10]1[CH:11]=[C:12]([NH:16][C:17](=[O:31])[C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=2[O:24][C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)[CH:13]=[CH:14][CH:15]=1)(=[O:9])=[O:8].CN(C)S(C1C=C(NC(=O)C2C=CC=CC=2OC2C=CC=CC=2)C=CC=1)(=O)=O.CN(C)S(C1C=CC(OC)=C(NC(=O)C2C=CC=CC=2OC2C=CC=CC=2)C=1)(=O)=O.NS(C1C=C(NC(=O)C2C=C([N+]([O-])=O)C=CC=2OC2C=CC(OC)=CC=2)C=CC=1)(=O)=O.C1(NS(C2C=C(NC(=O)C3C=CC=CC=3CC3C=CC=CC=3)C=CC=2)(=O)=O)CC1.C(C1C=CC=CC=1SC1C=CC=CC=1C(NC1C=C(S(N(C)C)(=O)=O)C=C(C)C=1C)=O)#N.C(C1C=CC=CC=1SC1C=CC=CC=1C(NC1C=C(S(N(CC)CC)(=O)=O)C=C(C)C=1C)=O)#N.CN(C)S(C1C=CC(C)=C(NC(=O)C2C=CC=CC=2CC2C=CC=CC=2)C=1)(=O)=O.C(C1C=CC=CC=1SC1C=CC=CC=1C(NC1C=C(S(N(CC)CC)(=O)=O)C=CC=1C)=O)#N.CN(C)S(C1C=CC(C)=C(NC(=O)C2C=CC=CC=2SC2C=CC(C(F)(F)F)=CC=2[N+]([O-])=O)C=1)(=O)=O.C(C1C=CC=CC=1SC1C=CC=CC=1C(NC1C=C(S(N(CC)CC)(=O)=O)C=CC=1OC)=O)#N.NS(C1C=C(NC(=O)C2C=CC=CC=2C(=O)C2C=CC(SC)=C([N+]([O-])=O)C=2)C=CC=1OC)(=O)=O.ClC1C=CC(C(C2C=CC=CC=2C(NC2C=C(S(NCC)(=O)=O)C=CC=2OC)=O)=O)=CC=1[N+]([O-])=O.FC(F)SC1C=CC(NC2C=CC=CC=2C(NC2C=CC=C(S(NCC3OC=CC=3)(=O)=O)C=2)=O)=CC=1>>[CH:5]1([NH:6][S:7]([C:10]2[CH:11]=[C:12]([NH:16][C:17](=[O:31])[C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=3[O:24][C:25]3[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=3)[CH:13]=[CH:14][CH:15]=2)(=[O:9])=[O:8])[CH2:3][CH2:4]1
Reactant: O=C(Nc1cccc(S(=O)(=O)NC2=NCCC2)c1)c1ccccc1Oc1ccccc1
Agent: CCN(CC)S(=O)(=O)c1cc(C)c(C)c(NC(=O)c2ccccc2Sc2ccccc2C#N)c1
Agent: CCN(CC)S(=O)(=O)c1ccc(C)c(NC(=O)c2ccccc2Sc2ccccc2C#N)c1
Agent: CCN(CC)S(=O)(=O)c1ccc(OC)c(NC(=O)c2ccccc2Sc2ccccc2C#N)c1
Product: O=C(Nc1cccc(S(=O)(=O)NC2CC2)c1)c1ccccc1Oc1ccccc1

Procedure:
N-[3-[[(3,4-dihydro-2H-pyrrol-5-yl)amino]sulfonyl]phenyl]-2-phenoxy-benzamide; N-[3-[(dimethylamino)sulfonyl]phenyl]-2-phenoxy-benzamide; N-[5-[(dimethylamino)sulfonyl]-2-methoxyphenyl]-2-phenoxy-benzamide; N-[3-(aminosulfonyl)phenyl]-2-(4-methoxyphenoxy)-5-nitro-benzamide; N-[3-[(cyclopropylamino)sulfonyl]phenyl]-2-(phenylmethyl)-benzamide; 2-[(2-cyanophenyl)thio]-N-[5-[(dimethylamino)sulfonyl]-2,3-dimethylphenyl]-benzamide; 2-[(2-cyanophenyl)thio]-N-[5-[(diethylamino)sulfonyl]-2,3-dimethylphenyl]-benzamide; N-[5-[(dimethylamino)sulfonyl]-2-methylphenyl]-2-(phenylmethyl)-benzamide; 2-[(2-cyanophenyl)thio]-N-[5-[(diethylamino)sulfonyl]-2-methylphenyl]-benzamide; N-[5-[(dimethylamino)sulfonyl]-2-methylphenyl]-2-[[2-nitro-4-(trifluoromethyl)phenyl]thio]-benzamide; 2-[(2-cyanophenyl)thio]-N-[5-[(diethylamino)sulfonyl]-2-methoxyphenyl]-benzamide; N-[3-(aminosulfonyl)-4-methoxyphenyl]-2-[4-(methylthio)-3-nitrobenzoyl]-benzamide; 2-(4-chloro-3-nitrobenzoyl)-N-[5-[(ethylamino)sulfonyl]-2-methoxyphenyl]-benzamide; and 2-[[4-[(difluoromethyl)thio]phenyl]amino]-N-[3-[[(2-furanylmethyl)amino]sulfonyl]phenyl]-benzamide.
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[CH:9][C:5]([CH:6]=[N:7][OH:8])=[CH:4][CH:3]=1.ClN1C(=O)CCC1=O.[NH2:19][C:20]1[CH:21]=[C:22]([CH:40]=[CH:41][C:42]=1[C:43]#[N:44])[C:23]([NH:25][C:26]1[C:31]([CH3:32])=[CH:30][C:29]([C:33]([C:35]([F:38])([F:37])[F:36])=[CH2:34])=[CH:28][C:27]=1[CH3:39])=[O:24]>CN(C)C=O.O.C(OCC)(=O)C.C(N(CC)CC)C>[NH2:19][C:20]1[CH:21]=[C:22]([CH:40]=[CH:41][C:42]=1[C:43]#[N:44])[C:23]([NH:25][C:26]1[C:27]([CH3:39])=[CH:28][C:29]([C:33]2([C:35]([F:36])([F:37])[F:38])[O:8][N:7]=[C:6]([C:5]3[CH:9]=[CH:10][C:2]([Cl:1])=[CH:3][CH:4]=3)[CH2:34]2)=[CH:30][C:31]=1[CH3:32])=[O:24]
Reactant: C=C(c1cc(C)c(NC(=O)c2ccc(C#N)c(N)c2)c(C)c1)C(F)(F)F
Reactant: ON=Cc1ccc(Cl)cc1
Agent: O=C1CCC(=O)N1Cl
Solvent: CCOC(C)=O
Solvent: O
Solvent: CCN(CC)CC
Product: Cc1cc(C2(C(F)(F)F)CC(c3ccc(Cl)cc3)=NO2)cc(C)c1NC(=O)c1ccc(C#N)c(N)c1
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 58.6 %

Procedure:
4-Chloro-benzaldehyde oxime (6.64 g, 42.70 mmol) and N-chlorosuccinimide (“NCS”) (5.70 g, 42.70 mmol) were dissolved in N,N-dimethylformamide (40 ml). The reaction mixture was stirred at ambient temperature for 90 minutes. A solution of 3-amino-4-cyano-N-[2,6-dimethyl-4-(1-trifluoromethyl-vinyl)-phenyl]-benzamide (4.4 g, 12.20 mmol) (Example I5) and triethylamine (5.95 mL, 0.66 mmol) in N,N-dimethylformamide (40 ml) was added and the reaction mixture was stirred at ambient temperature for 18 hours. The reaction mixture was diluted with water (500 ml) and ethyl acetate (500 ml) and the phases were separated. The organic phase was washed twice with water and the aqueous phases were extracted once with ethyl acetate. The combined organic phases were dried over sodium sulfate and concentrated. The residue was purified by column chromatography on silica gel (eluent: cyclohexane/ethyl acetate 3:1) to give 3-amino-N-{4-[3-(4-chloro-phenyl)-5-trifluoromethyl-4,5-dihydro-isoxazol-5-yl]-2,6-dimethyl-phenyl}-4-cyano-benzamide (3.67 g, 59% yield). LC/MS (Method A): 513 (MH+); RT: 2.04. 1H-NMR (CDCl3, 400 MHz): 7.62 (m, 3H), 7.45 (d, 1H), 7.40 (m, 2H), 7.36 (s, 2H), 7.31 (s, 1H), 7.18 (d, 1H), 4.63 (s, 2H), 4.08 (d, 1H), 3.76 (d, 1H), 2.30 (s, 6H) ppm.
Reaction SMILES: [CH2:1]([OH:17])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH3:16].C(O[CH2:22][C:23](=[CH2:29])[C:24]([O:26][CH2:27][CH3:28])=[O:25])(=O)C.CN(C1C=CC=CN=1)C>ClCCl>[CH2:1]([O:17][CH2:29][C:23](=[CH2:22])[C:24]([O:26][CH2:27][CH3:28])=[O:25])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH3:16]
Reactant: CCCCCCCCCCCCCCCCO
Reactant: C=C(COC(C)=O)C(=O)OCC
Agent: CN(C)c1ccccn1
Solvent: ClCCl
Product: C=C(COCCCCCCCCCCCCCCCC)C(=O)OCC
Reaction time: 8 h
Yield: 39.3 %

Procedure:
To a mixture of 1.1 g of 1-hexadecanol and 400 mg of 2-[(acetyloxy)methyl]-2-propenoic acid, ethyl ester in 15 ml of dichloromethane is added 550 mg of dimethylaminopyridine. This mixture is stirred overnight, then the solvent is evaporated and the residue subjected to preparative tlc (25% ethyl acetate/petroleum ether), to give 324 mg of the desired compound.
Reaction SMILES: O[CH2:2][CH2:3][N:4]([CH:30]([CH3:32])[CH3:31])[C:5]([C:7]1[C:12]([O:13][CH2:14][C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)=[C:11]([OH:21])[N:10]=[C:9]([CH2:22][C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=2[Br:29])[N:8]=1)=[O:6].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.CCOC(/N=N/C(OCC)=O)=O>ClCCl>[CH2:14]([O:13][C:12]1[C:11](=[O:21])[N:10]=[C:9]([CH2:22][C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=2[Br:29])[N:8]2[CH2:2][CH2:3][N:4]([CH:30]([CH3:32])[CH3:31])[C:5](=[O:6])[C:7]=12)[C:15]1[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=1
Reactant: CC(C)N(CCO)C(=O)c1nc(Cc2ccccc2Br)nc(O)c1OCc1ccccc1
Agent: CCOC(=O)/N=N/C(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Product: CC(C)N1CCn2c(Cc3ccccc3Br)nc(=O)c(OCc3ccccc3)c2C1=O
Reaction time: 0.17 h
Yield: 29 %

Procedure:
To a stirred solution of 5-benzyloxy-2-(2-bromobenzyl)-6-hydroxypyrimidine-4-carboxylic acid (2-hydroxyethyl)-isopropylamide (151) (400 mg, 0.8 mmol) in dichloromethane (10 mL) was added triphenyl phosphine (310.55 mg, 1.18 mmol) at room temperature. The mixture was stirred for 10 min. Then DEAD (0.186 mL, 1.18 mmol) was added at room temperature and the mixture was stirred for another 2 h. After completion of the reaction, the mixture was concentrated under reduced pressure to get a crude product, which was purified using a normal silica column using 2% methanol in dichloromethane to afford 9-benzyloxy-6-(2-bromobenzyl)-2-isopropyl-3,4-dihydro-2H-pyrazino[1,2-c]pyrimidine-1,8-dione (169) (112 mg, 29%) as a white solid.
Reaction SMILES: C1(C)C=CC=CC=1.[NH:8]1[CH2:12][CH2:11][CH2:10][CH2:9]1.[O:13]1[C:17]2([CH2:22][CH2:21][CH:20]([CH:23]3[CH2:28][CH2:27][C:26](=O)[CH2:25][CH2:24]3)[CH2:19][CH2:18]2)[O:16][CH2:15][CH2:14]1>O>[O:13]1[C:17]2([CH2:18][CH2:19][CH:20]([CH:23]3[CH2:28][CH2:27][C:26]([N:8]4[CH2:12][CH2:11][CH2:10][CH2:9]4)=[CH:25][CH2:24]3)[CH2:21][CH2:22]2)[O:16][CH2:15][CH2:14]1
Reactant: C1CCNC1
Reactant: O=C1CCC(C2CCC3(CC2)OCCO3)CC1
Solvent: O
Solvent: Cc1ccccc1
Product: C1=C(N2CCCC2)CCC(C2CCC3(CC2)OCCO3)C1
Temperature: 25 °C

Procedure:
Toluene (200 ml) and pyrrolidine (90 ml) were added to 4-(1,4-dioxaspiro[4.5]decan-8-yl)cyclohexanone (100 g) in a reaction vessel equipped with a Dean-Stark apparatus under an atmosphere of nitrogen. The mixture was refluxed for 3 hours while the water formed was removed by a Dean-Stark apparatus. After the reaction mixture had been cooled to a room temperature, it was washed with brine, and dried over anhydrous magnesium sulfate. The toluene was distilled off to give 1-(4-(1,4-dioxaspiro[4.5]decan-8-yl)cyclohex-1-enyl)pyrrolidine (105.8 g).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([NH:13][C:14]2[CH:23]=[CH:22][C:17]([C:18]([O:20][CH3:21])=[O:19])=[CH:16][C:15]=2[N+:24]([O-])=O)[C:9](OC)=[O:10])=[CH:4][CH:3]=1.[H][H]>[Pd].CO>[F:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]2[C:9](=[O:10])[NH:24][C:15]3[C:14](=[CH:23][CH:22]=[C:17]([C:18]([O:20][CH3:21])=[O:19])[CH:16]=3)[NH:13]2)=[CH:4][CH:3]=1
Reactant: [H][H]
Reactant: COC(=O)c1ccc(NC(C(=O)OC)c2ccc(F)cc2)c([N+](=O)[O-])c1
Agent: [Pd]
Solvent: CO
Product: COC(=O)c1ccc2c(c1)NC(=O)C(c1ccc(F)cc1)N2
Temperature: 30 °C
Reaction time: 8 h

Procedure:
Into a 100-mL round-bottom flask, was placed methyl 4-(1-(4-fluorophenyl)-2-methoxy-2-oxoethylamino)-3-nitrobenzoate (3.5 g, 9.67 mmol, 1.00 equiv), methanol (50 mL), and palladium on carbon (10%) (500 mg). Hydrogen gas was introduced to the reaction and it was stirred overnight at 30° C. in an oil bath. Then the solids were filtered off and the filtrate was concentrated in vacuo. This resulted in 2.6 g (90%) of methyl 2-(4-fluorophenyl)-3-oxo-1,2,3,4-tetrahydroquinoxaline-6-carboxylate as a light yellow solid.
Reaction SMILES: C1(N=C=NC2CCCCC2)CCCCC1.[O:16]1[CH:20]=[CH:19][CH:18]=[C:17]1[CH:21]=[CH:22][C:23]([OH:25])=O.[C:26]([CH:28]1[CH2:30][NH:29]1)#[N:27]>C(OCC)C>[O:16]1[CH:20]=[CH:19][CH:18]=[C:17]1[CH:21]=[CH:22][C:23]([N:29]1[CH2:30][CH:28]1[C:26]#[N:27])=[O:25]
Reactant: O=C(O)C=Cc1ccco1
Reactant: N#CC1CN1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Solvent: CCOCC
Product: N#CC1CN1C(=O)C=Cc1ccco1
Reaction time: 8 h

Procedure:
The same compound is obtained by introducing 2.1 g. dicyclohexylcarbodiimide, dissolved in 10 ml. diethyl ether, at 0° C. into a solution of 1.38 g. β-(2-furyl)acrylic acid and 0.68 g. 2-cyanoaziridine in 30 ml. diethyl ether, stirring for 2 hours at 0° C. and leaving to stand overnight at ambient temperature; after analogous purification on a silica gel column, there is obtained 0.9 g. of an oil which solidifies after standing for several days. After trituration with petroleum ether, the compound melts at 59°-61° C.
Reaction SMILES: N[C@@H](C(O)=O)CC1C2C(=CC=CC=2)NC=1.O1C2C=CC=CC=2C=C1C=O.[CH3:27][O:28][C:29]([C@@H:31]1[CH2:43][C:42]2[C:41]3[C:36](=[CH:37][CH:38]=[CH:39][CH:40]=3)[NH:35][C:34]=2[C@H:33]([C:44]2[O:45][C:46]3[CH:52]=[CH:51][CH:50]=[CH:49][C:47]=3[CH:48]=2)[NH:32]1)=[O:30]>>[CH3:27][O:28][C:29]([C@H:31]1[CH2:43][C:42]2[C:41]3[C:36](=[CH:37][CH:38]=[CH:39][CH:40]=3)[NH:35][C:34]=2[C@H:33]([C:44]2[O:45][C:46]3[CH:52]=[CH:51][CH:50]=[CH:49][C:47]=3[CH:48]=2)[NH:32]1)=[O:30]
Reactant: COC(=O)[C@@H]1Cc2c([nH]c3ccccc23)[C@H](c2cc3ccccc3o2)N1
Agent: N[C@H](Cc1c[nH]c2ccccc12)C(=O)O
Agent: O=Cc1cc2ccccc2o1
Product: COC(=O)[C@H]1Cc2c([nH]c3ccccc23)[C@H](c2cc3ccccc3o2)N1
Yield: 44 %

Procedure:
Condensation of (R)-(+)-tryptophan with benzo-furan-2-carbaldehyde produced Intermediates 3 and 4 by the same method described above for Intermediates 1 and 2. The crude mixture of diastereomers was separated by chromatography (Biotage 75M, 20% ethyl acetate/80% hexanes) to give 2.85 g (44%) of (1R,3R)-1-benzofuran-2-yl-2,3,4,9-tetrahydro-1H-β-carboline-3-carboxylic acid methyl ester (Intermediate 4) and 950 mg (15%) of (1S,3R)-1-benzofuran-2-yl-2,3,4,9-tetrahydro-1H-p-carboline-3-carboxylic acid methyl ester (Intermediate 3) as foams.