Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[CH:9]=[CH:8][S:7][C:6]=1[NH:10][CH:11]=[C:12]([C:18]([O:20][CH2:21][CH3:22])=[O:19])[C:13]([O:15][CH2:16][CH3:17])=[O:14])=[O:4].C(Cl)(Cl)Cl.[Br:27]Br>N1C=CC=CC=1>[Br:27][C:8]1[S:7][C:6]([NH:10][CH:11]=[C:12]([C:18]([O:20][CH2:21][CH3:22])=[O:19])[C:13]([O:15][CH2:16][CH3:17])=[O:14])=[C:5]([C:3]([O:2][CH3:1])=[O:4])[CH:9]=1
Reactant: BrBr
Reactant: CCOC(=O)C(=CNc1sccc1C(=O)OC)C(=O)OCC
Solvent: c1ccncc1
Solvent: ClC(Cl)Cl
Product: CCOC(=O)C(=CNc1sc(Br)cc1C(=O)OC)C(=O)OCC
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
To a solution of 3.3 parts of diethyl (3-methoxycarbonylthienyl)aminomethylenemalonate in a mixture of 20 parts by volume of chloroform and 4 parts by volume of pyridine, 0.6 part by volume of bromine is added dropwise. The solution is further stirred at room temperature for 15 minutes, after which the reaction mixture is washed with dilute hydrochloric acid, an aqueous sodium hydrogen carbonate solution and water, followed by drying over Na2SO4. The solvent is distilled off to give diethyl (5-bromo-3-methoxycarbonylthienyl)aminomethylenemalonate. Recrystallization from ethanol gives light-yellowish needles melting at 129°-130° C.
Reaction SMILES: [Cl:1][C:2]1[CH:12]=[CH:11][C:10]([NH:13][C:14]([NH2:16])=[O:15])=[CH:9][C:3]=1[C:4]([O:6][CH2:7][CH3:8])=[O:5].[CH3:17][CH2:18][O:19][C:20]([CH:22]1[C:26](=O)[CH2:25][CH2:24][CH2:23]1)=[O:21].O>C1C=CC=CC=1.O.C1(C)C=CC(S(O)(=O)=O)=CC=1>[Cl:1][C:2]1[CH:12]=[CH:11][C:10]([NH:13][C:14]([NH:16][C:23]2[CH2:24][CH2:25][CH2:26][C:22]=2[C:20]([O:19][CH2:18][CH3:17])=[O:21])=[O:15])=[CH:9][C:3]=1[C:4]([O:6][CH2:7][CH3:8])=[O:5]
Reactant: CCOC(=O)C1CCCC1=O
Reactant: CCOC(=O)c1cc(NC(N)=O)ccc1Cl
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: O
Solvent: c1ccccc1
Product: CCOC(=O)C1=C(NC(=O)Nc2ccc(Cl)c(C(=O)OCC)c2)CCC1

Procedure:
48.4 g of ethyl 2-chloro-5-ureido-benzoate and 31.2 g of ethyl cyclopentanone-2-carboxylate are heated under reflux for 6 hours in 500 ml of benzene and 2 g of toluene-4-sulphonic acid monohydrate. The water formed is removed by means of a water separator. The reaction mixture is subsequently evaporated to dryness, the residue is dissolved in 700 ml of diethyl ether and the solution is filtered. The filtrate is evaporated to dryness and the residue is purified by chromatography on 1.5 g of silica gel using diethyl ether/n-hexane (1:2) as the eluent. There is obtained ethyl 2-chloro-5-{3-[2-(ethoxycarbonyl)-1-cyclopenten-1-yl]ureido}-benzoate as colourless crystals. The product is recrystallized from diethyl ether/n-hexane, m.p. 110°-112° C.
Reaction SMILES: [F:1][C:2]1[CH:10]=[CH:9][C:8]([F:11])=[CH:7][C:3]=1[C:4](=S)[NH2:5].[NH2:12][NH2:13]>CCO>[F:1][C:2]1[CH:10]=[CH:9][C:8]([F:11])=[CH:7][C:3]=1[C:4](=[NH:5])[NH:12][NH2:13]
Reactant: NC(=S)c1cc(F)ccc1F
Reactant: NN
Solvent: CCO
Product: N=C(NN)c1cc(F)ccc1F
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 24.9 %

Procedure:
To a stirred solution of 2,5-difluorobenzothioamide (22.5 g, 129.7 mmol) in EtOH (150 mL) was added hydrazine (6.1 mL, 194.5 mmol). After stirring at room temperature for 30 min, reaction was complete by LC/MS and white solid precipitated. The precipitate was filtered and washed with Hexanes to afford 2,5-difluorobenzimidohydrazide (5.52 g, 94%).
Reaction SMILES: Br[C:2]1[N:7]=[C:6]([CH:8]=[O:9])[CH:5]=[CH:4][CH:3]=1.[C:10]([C:12]1[CH:13]=[C:14](B(O)O)[CH:15]=[CH:16][C:17]=1[F:18])#[N:11].C(=O)([O-])[O-].[Cs+].[Cs+]>O1CCOCC1>[F:18][C:17]1[CH:16]=[CH:15][C:14]([C:2]2[CH:3]=[CH:4][CH:5]=[C:6]([CH:8]=[O:9])[N:7]=2)=[CH:13][C:12]=1[C:10]#[N:11]
Reactant: O=Cc1cccc(Br)n1
Reactant: N#Cc1cc(B(O)O)ccc1F
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: C1COCCO1
Product: N#Cc1cc(-c2cccc(C=O)n2)ccc1F
Temperature: 80 °C

Procedure:
To a solution of 6-bromopicolinaldehyde (1.00 g, 5.38 mmol) in dioxane (30 mL) at ambient temperature was added 3-cyano-4-fluorophenylboronic acid (0.887 g, 5.38 mmol), 2M cesium carbonate (8.1 mL, 16.2 mmol) and 1,1′-bis(diphenylphosphino)ferrocene-palladium(II)dichloride dichloromethane complex (0.220 g, 0.269 mmol). The mixture was degassed (3× vacuum/purge N2), then heated at 80° C. overnight. The mixture was cooled, concentrated and partitioned between water and CH2Cl2. The organic layer was concentrated and purified by chromatography (30% ethyl acetate:hexanes) to provide 2-fluoro-5-(6-formylpyridin-2-yl)benzonitrile. To a solution of 2-fluoro-5-(6-formylpyridin-2-yl)benzonitrile (0.500 g, 2.21 mmol) in methanol (20 mL) at ambient temperature was added D-valinol (0.25 mL, 2.2 mmol), acetic acid (0.50 mL, 8.8 mmol) followed by MP-cyanoborohydride (2.49 mmol/g; 1.0 g). After 2 hours, the mixture was filtered, concentrated, and the residue partitioned between ether and 1M NaOH. The organic layer was concentrated and purified by chromatography to provide 362 mg (52%) of the title compound. MS (DCI+) m/z 314 (M+H); 1H NMR (400 MHz, DMSO-d6) δ 8.62 (dd, J=6.3, 2.3 Hz, 1H), 8.52 (ddd, J=8.9, 5.3, 2.4 Hz, 1H), 7.97-7.84 (m, 2H), 7.66 (t, J=9.0 Hz, 1H), 7.49 (dd, J=7.4, 1.1 Hz, 1H), 3.92 (d, J=3.6 Hz, 2H), 3.52-3.43 (m, 1H), 2.40-2.22 (m, 2H), 1.93-1.76 (m, 1H), 0.89 (dd, J=9.5, 6.9 Hz, 6H).
Reaction SMILES: [C:1]([O:20][CH:21]([CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH:37]=[CH:38][CH2:39][CH2:40][CH2:41][CH2:42][CH2:43][CH2:44][CH2:45][CH3:46])[CH2:22][C:23]([NH:25][CH2:26][C:27]([OH:29])=O)=[O:24])(=[O:19])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH:9]=[CH:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH3:18].[NH2:47][C@H:48]([C:56]([OH:58])=[O:57])[CH2:49][C:50]1[CH:55]=[CH:54][CH:53]=[CH:52][CH:51]=1>>[C:1]([O:20][CH:21]([CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH:37]=[CH:38][CH2:39][CH2:40][CH2:41][CH2:42][CH2:43][CH2:44][CH2:45][CH3:46])[CH2:22][C:23]([NH:25][CH2:26][C:27]([NH:47][C@H:48]([C:56]([OH:58])=[O:57])[CH2:49][C:50]1[CH:55]=[CH:54][CH:53]=[CH:52][CH:51]=1)=[O:29])=[O:24])(=[O:19])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH:9]=[CH:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH3:18]
Reactant: N[C@@H](Cc1ccccc1)C(=O)O
Reactant: CCCCCCCCC=CCCCCCCCC(=O)OC(CCCCCCCC=CCCCCCCCC)CC(=O)NCC(=O)O
Product: CCCCCCCCC=CCCCCCCCC(=O)OC(CCCCCCCC=CCCCCCCCC)CC(=O)NCC(=O)N[C@@H](Cc1ccccc1)C(=O)O
Yield: 73.3 %

Procedure:
Starting from N-[3-(9-octadecenoyloxy)-11-eicosenoyl]glycine (2.0 g) prepared by the method described in Example 40 and L-phenylalanine (2.64 g), N-[N-[3-(9-octadecenoyloxy)-11-eicosenoyl]glycyl]-L-phenylalanine (1.8 g) was obtained as powders according to a similar manner to that of Example 29.
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]([C:8]2[NH:9][C:10]([CH:13]([C:21]3[CH:26]=[CH:25][C:24]([S:27]([CH:30]4[CH2:32][CH2:31]4)(=[O:29])=[O:28])=[CH:23][CH:22]=3)[CH2:14][CH:15]3[CH2:20][CH2:19][O:18][CH2:17][CH2:16]3)=[CH:11][CH:12]=2)=[N:6][CH:7]=1.[SH:33][CH2:34][C:35]([O:37][CH2:38][CH3:39])=[O:36]>CN(C)C=O.C(OCC)(=O)C.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[CH:30]1([S:27]([C:24]2[CH:25]=[CH:26][C:21]([CH:13]([C:10]3[NH:9][C:8]([C:5]4[N:6]=[CH:7][C:2]([S:33][CH2:34][C:35]([O:37][CH2:38][CH3:39])=[O:36])=[CH:3][CH:4]=4)=[CH:12][CH:11]=3)[CH2:14][CH:15]3[CH2:20][CH2:19][O:18][CH2:17][CH2:16]3)=[CH:22][CH:23]=2)(=[O:29])=[O:28])[CH2:32][CH2:31]1
Reactant: CCOC(=O)CS
Reactant: O=S(=O)(c1ccc(C(CC2CCOCC2)c2ccc(-c3ccc(Br)cn3)[nH]2)cc1)C1CC1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CCOC(=O)CSc1ccc(-c2ccc(C(CC3CCOCC3)c3ccc(S(=O)(=O)C4CC4)cc3)[nH]2)nc1
Temperature: 25 °C
Yield: 54 %

Procedure:
To a solution of 5-bromo-2-(5-{1-[4-(cyclopropylsulfonyl)phenyl]-2-(tetrahydro-2H-pyran-4-yl)ethyl}-1H-pyrrol-2-yl)pyridine (200 mg) in N,N-dimethylformamide (1 mL) were added ethyl sulfanylacetate (98 μL) and tetrakistriphenylphosphinepalladium(0) (230 mg), and the mixture was stirred using a microwave synthesis apparatus at 120° C. for 3 hr. After cooling to room temperature, the reaction mixture was diluted with ethyl acetate and washed with water. The ethyl acetate layer was washed with saturated brine, dried (MgSO4) and concentrated. The residue was subjected to silica gel column chromatography, and the title compound (117 mg, yield 54%) was obtained as a yellow amorphous solid from a fraction eluted with ethyl acetate-hexane (3:2, volume ratio). MS: 555 (MH+).
Reaction SMILES: [Cl:1][C:2]1[CH:13]=[C:12]([N+:14]([O-])=O)[CH:11]=[CH:10][C:3]=1[CH2:4][N:5]1[CH2:9][CH2:8][CH2:7][CH2:6]1>[Ni].CO>[Cl:1][C:2]1[CH:13]=[C:12]([NH2:14])[CH:11]=[CH:10][C:3]=1[CH2:4][N:5]1[CH2:6][CH2:7][CH2:8][CH2:9]1
Reactant: O=[N+]([O-])c1ccc(CN2CCCC2)c(Cl)c1
Agent: [Ni]
Solvent: CO
Product: Nc1ccc(CN2CCCC2)c(Cl)c1

Procedure:
A suspension of 1.00 g (4.155 mmol) 1-(2-chloro-4-nitro-benzyl)-pyrrolidine (140a) and 100 mg Raney nickel in 30 mL MeOH were hydrogenated at RT and 10 psi. The catalyst was filtered off and the filtrate evaporated down i. vac.
Reaction SMILES: [F:1][C:2]([F:14])([F:13])[C:3]1[C:8]([OH:9])=[C:7]([N+:10]([O-])=O)[CH:6]=[CH:5][CH:4]=1.[Sn](Cl)Cl.[OH-].[Na+]>C(O)C>[NH2:10][C:7]1[CH:6]=[CH:5][CH:4]=[C:3]([C:2]([F:1])([F:13])[F:14])[C:8]=1[OH:9]
Reactant: O=[N+]([O-])c1cccc(C(F)(F)F)c1O
Agent: Cl[Sn]Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: Nc1cccc(C(F)(F)F)c1O
Temperature: 80 °C
Reaction time: 2 h
Yield: 87.9 %

Procedure:
A mixture of 6-trifluoromethyl-2-nitrophenol(1.84 g, 8.67 mmol) and tin (II) chloride (6.0 g, 26.2 mmol) in ethanol(150 mL) was heated at 80° C. under argon. After 2 hours, the starting material has disappeared and the solution was allowed to cool down and then poured into ice. The pH was made slightly basic (pH7-8), by addition of solid NaOH, before being extracted with ethyl acetate. The organic phase was washed with brine, dried over MgSO4 and filtered. The solvent was evaporated and chromatography of the resulting solid on silica gel (4% MeOH/CH2Cl2) gave the desired product(1.35 g, 88%). 1H NMR (CD3OD): δ 6.93 (d, 1H), 6.82 (t, 1H), 6.78 (d, 1H).
Reaction SMILES: [NH2:1][CH2:2][C@@H:3]([NH:21][C:22](=[O:34])[C:23]1[CH:28]=[CH:27][C:26]([O:29][CH:30]([CH3:32])[CH3:31])=[C:25]([Cl:33])[CH:24]=1)[CH2:4][C:5]1[CH:10]=[CH:9][C:8]([C:11]2[N:12]=[C:13]3[C:18]([Br:19])=[CH:17][CH:16]=[CH:15][N:14]3[CH:20]=2)=[CH:7][CH:6]=1.CC(OC([NH:42][C@@H:43]([C:45](O)=[O:46])[CH3:44])=O)(C)C.CCN=C=NCCCN(C)C.Cl>C(Cl)Cl.O1CCOCC1>[NH2:42][C@@H:43]([C:45]([NH:1][CH2:2][C@@H:3]([NH:21][C:22](=[O:34])[C:23]1[CH:28]=[CH:27][C:26]([O:29][CH:30]([CH3:32])[CH3:31])=[C:25]([Cl:33])[CH:24]=1)[CH2:4][C:5]1[CH:10]=[CH:9][C:8]([C:11]2[N:12]=[C:13]3[C:18]([Br:19])=[CH:17][CH:16]=[CH:15][N:14]3[CH:20]=2)=[CH:7][CH:6]=1)=[O:46])[CH3:44]
Reactant: C[C@@H](NC(=O)OC(C)(C)C)C(=O)O
Reactant: CC(C)Oc1ccc(C(=O)N[C@H](CN)Cc2ccc(-c3cn4cccc(Br)c4n3)cc2)cc1Cl
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: ClCCl
Solvent: C1COCCO1
Product: CC(C)Oc1ccc(C(=O)N[C@H](CNC(=O)[C@@H](C)N)Cc2ccc(-c3cn4cccc(Br)c4n3)cc2)cc1Cl
Temperature: 25 °C
Reaction time: 1 h
Yield: 25 %

Procedure:
A solution of N-((1S)-2-amino-1-{[4-(8-bromoimidazo[1,2-a]pyridin-2-yl)phenyl]methyl}ethyl)-3-chloro-4-[(1-methylethyl)oxy]benzamide (0.28 mmol), N-{[(1,1-dimethylethyl)oxy]carbonyl}-D-alanine (0.56 mmol), EDCI (0.56 mmol), and TEA (1.12 mmol) stirred in methylene chloride (2 mL) at RT for 18 h. The reaction was then treated with 4 M HCl in 1,4-dioxane (2 mL) and stirred at RT for 1 h. The mixture was then concentrated in vacuo, redissolved in ethyl acetate (25 mL) and washed with saturated aqueous sodium bicarbonate solution (1×10 mL). The organic layer was concentrated in vacuo, and purification of the residue by Gilson reverse phase HPLC afforded the title product as a white solid (25%). ESMS [M+H]+: 613.2.
Reaction SMILES: [CH2:1]([N:8]1[CH2:13][CH2:12][N:11]([CH2:14][C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[CH2:10][C@@H:9]1[CH2:21][OH:22])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.CCN(C(C)C)C(C)C.[CH3:32][S:33](Cl)(=[O:35])=[O:34]>C(Cl)Cl>[CH3:32][S:33]([O:22][CH2:21][C@H:9]1[CH2:10][N:11]([CH2:14][C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[CH2:12][CH2:13][N:8]1[CH2:1][C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1)(=[O:35])=[O:34]
Reactant: OC[C@H]1CN(Cc2ccccc2)CCN1Cc1ccccc1
Reactant: CS(=O)(=O)Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CS(=O)(=O)OC[C@H]1CN(Cc2ccccc2)CCN1Cc1ccccc1
Temperature: 0 °C
Reaction time: 0.02 h
Yield: 87.5 %

Procedure:
A mixture of (R)-(1,4-dibenzylpiperazin-2-yl)methanol (4.00 g, 13.49 mmol, US2007/0088039) and Hünig's base (2.35 mL, 13.49 mmol) in CH2Cl2 (27 mL) was stirred at 0° C. and methanesulfonyl chloride (1.04 mL, 13.49 mmol) was added drop-wise. The reaction mixture was filtered through a short pad of silica gel, using 19:1 CH2Cl2/Et2O (1000 mL) to rinse. The filtrate was concentrated in vacuo while maintaining the temperature below 25° C. Diethyl ether was added to the residue, the resulting slurry was placed in a sonicator for 1 min, filtered through a fitted funnel and the filtrate was concentrated to give a white solid ((2R)-1,4-dibenzyl-2-piperazinyl)methyl methanesulfonate (4.42 g).
Reaction SMILES: [OH:1][C:2]([C:4]([F:7])([F:6])[F:5])=[O:3].[F:8][C:9]1[CH:36]=[CH:35][C:12]([CH2:13][N:14]2[CH2:19][CH2:18][N:17]3[C:20](=[O:33])[C:21]([CH2:26][CH:27]4[CH2:32][CH2:31][CH2:30][NH:29][CH2:28]4)=[C:22]([OH:25])[C:23]([OH:24])=[C:16]3[C:15]2=[O:34])=[CH:11][CH:10]=1.[CH:37]1([CH:40]=O)[CH2:39][CH2:38]1.C([BH3-])#N.[Na+]>CO>[OH:3][C:2]([C:4]([F:7])([F:6])[F:5])=[O:1].[CH:37]1([CH2:40][N:29]2[CH2:30][CH2:31][CH2:32][CH:27]([CH2:26][C:21]3[C:20](=[O:33])[N:17]4[CH2:18][CH2:19][N:14]([CH2:13][C:12]5[CH:11]=[CH:10][C:9]([F:8])=[CH:36][CH:35]=5)[C:15](=[O:34])[C:16]4=[C:23]([OH:24])[C:22]=3[OH:25])[CH2:28]2)[CH2:39][CH2:38]1
Reactant: O=CC1CC1
Reactant: O=C1c2c(O)c(O)c(CC3CCCNC3)c(=O)n2CCN1Cc1ccc(F)cc1
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: O=C(O)C(F)(F)F
Solvent: CO
Product: O=C1c2c(O)c(O)c(CC3CCCN(CC4CC4)C3)c(=O)n2CCN1Cc1ccc(F)cc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of 2-(4-fluorobenzyl)-8,9-dihydroxy-7-(piperidin-3-ylmethyl)-3,4-dihydro-2H-pyrido[1,2-a]pyrazine-1,6-dione mono TFA salt (50 mg, 0.097 mmol) in anhydrous methanol (2 mL) under nitrogen, cyclopropanecarboxaldehyde (9 μL, 0.116mmol) was added and the solution was stirred at room temperature for one hour. Sodium cyanoborohydride (8 mg, 0.129 mmol) was added and the solution was stirred for another hour. The reaction mixture was concentrated under vacuum and the residue was purified by prep “HPLC [Gilson semi preparative HPLC system using a Waters Nova Pak column (10×40 mm I.D. cartridge, C18, 6 μM pore size) eluting with 95-5% water (0.10% TFA)/acetonitrile (0.10% TFA) gradient at 35 mL/min]. The product fractions were collected and lyophilized to provide the title compound as white solid.
Reaction SMILES: C1(C)C=CC(S([O-])(=O)=O)=CC=1.[NH+]1C=CC=CC=1.[F:18][C:19]1[C:20]([C:44]2[CH:49]=[CH:48][CH:47]=[C:46]([O:50][CH3:51])[C:45]=2[F:52])=[CH:21][C:22](=[O:43])[N:23]([CH2:25][CH2:26][C@@:27]([CH3:42])([S:38]([CH3:41])(=[O:40])=[O:39])[C:28]([NH:30][O:31]C2CCCCO2)=[O:29])[CH:24]=1>C(O)C>[F:18][C:19]1[C:20]([C:44]2[CH:49]=[CH:48][CH:47]=[C:46]([O:50][CH3:51])[C:45]=2[F:52])=[CH:21][C:22](=[O:43])[N:23]([CH2:25][CH2:26][C@@:27]([CH3:42])([S:38]([CH3:41])(=[O:40])=[O:39])[C:28]([NH:30][OH:31])=[O:29])[CH:24]=1
Reactant: COc1cccc(-c2cc(=O)n(CC[C@](C)(C(=O)NOC3CCCCO3)S(C)(=O)=O)cc2F)c1F
Agent: Cc1ccc(S(=O)(=O)[O-])cc1
Agent: c1cc[nH+]cc1
Solvent: CCO
Product: COc1cccc(-c2cc(=O)n(CC[C@](C)(C(=O)NO)S(C)(=O)=O)cc2F)c1F
Temperature: 50 °C
Reaction time: 8 h
Yield: 63.5 %

Procedure:
Pyridinium p-toluenesulfonate (190 mg, 0.76 mmol) was added to a solution of (2R)-4-[5-fluoro-4-(2-fluoro-3-methoxyphenyl)-2-oxopyridin-1(2H)-yl]-2-methyl-2-(methylsulfonyl)-N-(tetrahydro-2H-pyran-2-yloxy)butanamide (777 mg, 1.51 mmol) in ethanol (15 mL). The reaction was heated to 50° C. and stirred at this temperature overnight. Additional pyridinium p-toluenesulfonate (118 mg, 0.47 mmol) was added to the solution and the reaction was heated at 60° C. for 3 h. The reaction was allowed to cool to rt and the precipitate was collected via filtration. The solid was washed with ethanol (15 mL) and hexanes (15 mL) and dried in vacuo to afford the title compound as a white solid (413 mg, 63.5%). MS (LCMS) m/z 431.0 (M+1). 1H NMR (400 MHz, DMSO-d6) δ ppm 1.57 (s, 1H) 2.08-2.25 (m, 0H) 2.41-2.56 (m, 1H) 3.02-3.19 (m, 3H) 3.71-3.85 (m, 1H) 3.88 (s, 3H) 3.98-4.13 (m, 1H) 6.47 (d, J=7.02 Hz, 1H) 6.93-7.08 (m, 1H) 7.19-7.36 (m, 2H) 8.04 (d, J=5.66 Hz, 1H) 9.24 (d, J=1.56 Hz, 1H) 11.07 (d; J=1.56 Hz, 1H).
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[C:6]([CH3:8])[CH:5]=[C:4]([CH3:9])[C:3]=1[OH:10].[Cl:11][C:12](Cl)([O:14]C(=O)OC(Cl)(Cl)Cl)Cl.N1C=CC=CC=1>C(Cl)Cl>[Cl:11][C:12]([O:10][C:3]1[C:4]([CH3:9])=[CH:5][C:6]([CH3:8])=[CH:7][C:2]=1[CH3:1])=[O:14]
Reactant: Cc1cc(C)c(O)c(C)c1
Reactant: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Solvent: ClCCl
Solvent: c1ccncc1
Product: Cc1cc(C)c(OC(=O)Cl)c(C)c1
Temperature: 0 °C

Procedure:
2,4,6-trimethylphenol (272 mg, 2.00 mmol, 1.0 equiv) was dissolved in CH2Cl2 (3.33 mL, 0.3 M) under nitrogen (N2) and cooled to 0° C. Triphosgene (208 mg, 0.700 mmol, 0.35 equiv) was dissolved in CH2Cl2 (3.33 mL) and added dropwise, followed by pyridine (0.162 mL, 2.00 mmol, 1.0 equiv). The mixture was allowed to warm to 25° C. over 18 h, at which point the reaction was quenched with 10 mL 1 normal (N) hydrochloric acid (HCl; aq) and extracted with EtOAc. The organic layer was washed with 1 N HCl (aq), dried over Na2SO4, and concentrated to give mesityl chloroformate as an oil (88% purity by 1H NMR spectroscopy). The chloroformate so prepared was used directly in the next step without further purification.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]2[C:12](=[CH:13][CH:14]=1)[NH:11][C:10]1[CH2:9][CH2:8][CH:7]([N:15]([CH3:17])[CH3:16])[CH2:6][C:5]2=1.[F:18][C:19]([F:30])([F:29])[C:20]1[CH:28]=[CH:27][C:23]([C:24](O)=[O:25])=[CH:22][CH:21]=1>>[F:18][C:19]([F:29])([F:30])[C:20]1[CH:28]=[CH:27][C:23]([C:24]([NH:1][C:2]2[CH:3]=[C:4]3[C:12](=[CH:13][CH:14]=2)[NH:11][C:10]2[CH2:9][CH2:8][CH:7]([N:15]([CH3:17])[CH3:16])[CH2:6][C:5]3=2)=[O:25])=[CH:22][CH:21]=1
Reactant: CN(C)C1CCc2[nH]c3ccc(N)cc3c2C1
Reactant: O=C(O)c1ccc(C(F)(F)F)cc1
Product: CN(C)C1CCc2[nH]c3ccc(NC(=O)c4ccc(C(F)(F)F)cc4)cc3c2C1
Yield: 35.5 %

Procedure:
Beginning with 9.2 mg (0.040 mMol) 6-amino-3-(dimethyl)amino-1,2,3,4-tetrahydro-9H-carbazole and 19.2 mg (0.101 mMol) 4-trifluoromethylbenzoic acid, 5.7 mg (35%) of the title compound were recovered as a beige solid.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[CH:6][C:7]([N:10]2[CH2:15][CH2:14][CH2:13][CH2:12][C:11]2=[O:16])=[N:8][CH:9]=1)([O-])=O>CO.C1COCC1.[Ni]>[NH2:1][C:4]1[CH:5]=[CH:6][C:7]([N:10]2[CH2:15][CH2:14][CH2:13][CH2:12][C:11]2=[O:16])=[N:8][CH:9]=1
Reactant: O=C1CCCCN1c1ccc([N+](=O)[O-])cn1
Agent: [Ni]
Solvent: CO
Solvent: C1CCOC1
Product: Nc1ccc(N2CCCCC2=O)nc1
Yield: 48.3 %

Procedure:
5′-Nitro-3,4,5,6-tetrahydro-[1,2′]bipyridinyl-2-one (0.66 g, 2.98 mmol) was dissolved in 1:1 MeOH/THF (50 mL) and hydrogenated over RaNi (1 g) at 4285 psi/mole for 0.8 h. The catalyst was filtered, and the filtrate concentrated. The crude solid was purified by recrystalization from THF and hexanes to give the product as a yellow solid (0.275 g, 48%). MS: APCI (AP+): 192.1 (M)+.
Reaction SMILES: [C:1]([C:4]1[CH:9]=[CH:8][C:7]([CH:10]2[CH2:15][CH2:14][CH:13]([CH2:16][C:17]([OH:19])=O)[CH2:12][CH2:11]2)=[CH:6][CH:5]=1)(=[O:3])[CH3:2].Cl.Cl.[NH2:22][CH:23]1[CH2:28][CH2:27][N:26]([CH2:29][C:30]2[CH:35]=[CH:34][C:33]([Cl:36])=[C:32]([Cl:37])[CH:31]=2)[CH2:25][CH2:24]1.CCN=C=NCCCN(C)C.Cl.C1C=CC2N(O)N=NC=2C=1>CN(C=O)C.C(N(CC)CC)C>[C:1]([C:4]1[CH:5]=[CH:6][C:7]([CH:10]2[CH2:15][CH2:14][CH:13]([CH2:16][C:17]([NH:22][CH:23]3[CH2:28][CH2:27][N:26]([CH2:29][C:30]4[CH:35]=[CH:34][C:33]([Cl:36])=[C:32]([Cl:37])[CH:31]=4)[CH2:25][CH2:24]3)=[O:19])[CH2:12][CH2:11]2)=[CH:8][CH:9]=1)(=[O:3])[CH3:2]
Reactant: CC(=O)c1ccc(C2CCC(CC(=O)O)CC2)cc1
Reactant: NC1CCN(Cc2ccc(Cl)c(Cl)c2)CC1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: CC(=O)c1ccc(C2CCC(CC(=O)NC3CCN(Cc4ccc(Cl)c(Cl)c4)CC3)CC2)cc1
Reaction time: 12 h
Yield: 58.3 %

Procedure:
[4-(4-Acetylphenyl)cyclohexyl]acetic acid (2.0 g) and 4-amino-1-(3,4-dichlorobenzyl)piperidine dihydrochloride (2.5 g) were suspended in DMF (50 mL), and triethylamine (2.1 mL), EDC hydrochloride (1.6 g) and HOBt (1.3 g) were added to the suspension. The suspension was stirred for 12 hrs. The reaction mixture was washed with water and then saturated brine and dried, and the solvent was evaporated under reduced pressure. Diisopropyl ether was added to the residue to crystallize to give the title compound (2.2 g) as a white solid. melting point: 168° C.
Reaction SMILES: [C:1]([NH:9][CH:10]1[CH2:15][CH2:14][NH:13][CH2:12][CH2:11]1)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl[C:17]1([F:28])[CH:22]=[CH:21][C:20]([C:23](=[O:27])[CH2:24][CH2:25][CH3:26])=[CH:19][CH2:18]1.[I-].[Na+]>CN(C)C=O>[F:28][C:17]1[CH:18]=[CH:19][C:20]([C:23](=[O:27])[CH2:24][CH2:25][CH2:26][N:13]2[CH2:14][CH2:15][CH:10]([NH:9][C:1](=[O:8])[C:2]3[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=3)[CH2:11][CH2:12]2)=[CH:21][CH:22]=1
Reactant: O=C(NC1CCNCC1)c1ccccc1
Reactant: CCCC(=O)C1=CCC(F)(Cl)C=C1
Agent: [I-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: O=C(CCCN1CCC(NC(=O)c2ccccc2)CC1)c1ccc(F)cc1
Yield: 28.6 %

Procedure:
4-Benzamidopiperidine (2.0 g.), 4'-chloro-p-fluorobutyrophenone (1.0 g.) and a trace of sodium iodide in dimethylformamide (5 ml.) were maintained at 70° C. for 18 hours. On cooling, the solid which separated was collected, suspended in water, and refiltered. Recrystallisation from ethanol-water gave the title compound (0.52 g.), m.p. 161°-2° C. (Found: C, 71.9; H, 6.85; N, 7.5. C22H25FN2O2 requires C, 71.7; H, 6.8; N, 7.6%).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([F:8])=[CH:4][C:3]=1[C:9]([N:11]([CH2:15][C:16]1[N:20]([CH2:21][CH2:22][CH3:23])[C:19]2[CH:24]=[CH:25][C:26]([CH2:28]O)=[CH:27][C:18]=2[N:17]=1)[CH2:12][CH2:13][CH3:14])=[O:10].S(Cl)([Cl:32])=O>>[F:1][C:2]1[CH:7]=[CH:6][C:5]([F:8])=[CH:4][C:3]=1[C:9]([N:11]([CH2:15][C:16]1[N:20]([CH2:21][CH2:22][CH3:23])[C:19]2[CH:24]=[CH:25][C:26]([CH2:28][Cl:32])=[CH:27][C:18]=2[N:17]=1)[CH2:12][CH2:13][CH3:14])=[O:10]
Reactant: CCCN(Cc1nc2cc(CO)ccc2n1CCC)C(=O)c1cc(F)ccc1F
Reactant: O=S(Cl)Cl
Product: CCCN(Cc1nc2cc(CCl)ccc2n1CCC)C(=O)c1cc(F)ccc1F
Yield: 93 %

Procedure:
(2,5-difluorophenyl)-N-{[5-(hydroxymethyl)-1-propylbenzimidazol-2-yl]methyl}-N-propylcarboxamide 0.96 g (2.3 mmole) is treated with 30 mL of thionyl chloride for 15 min a room temperature. The resulting mixture is concentrated in vacuo and partitioned between 100 mL sat NaHCO3 and 100 mL of ethyl acetate. The ethyl acetate layer is dried over anhydrous Na2SO4 and concentrated in vacuo. The resulting oil is chroamtoagraphed 50% ethyl acetate/hexanes to afford 0.9 g (93%) of (2,5-difluorophenyl)-N-{[5-(chloromethyl)-1-propylbenzimidazol-2-yl]methyl)-N-propylcarboxamide.
Reaction SMILES: [CH3:1][N:2]1[C:8](=O)[C:7]2[CH:10]=[CH:11][CH:12]=[CH:13][C:6]=2[N:5]2[CH:14]=[N:15][C:16]([C:17]([O:19][CH2:20][CH3:21])=[O:18])=[C:4]2[CH2:3]1.COC1C=CC(P2(=S)SP(=S)(C3C=CC(OC)=CC=3)[S:31]2)=CC=1>C1(C)C=CC=CC=1>[CH3:1][N:2]1[C:8](=[S:31])[C:7]2[CH:10]=[CH:11][CH:12]=[CH:13][C:6]=2[N:5]2[CH:14]=[N:15][C:16]([C:17]([O:19][CH2:20][CH3:21])=[O:18])=[C:4]2[CH2:3]1
Reactant: COc1ccc(P2(=S)SP(=S)(c3ccc(OC)cc3)S2)cc1
Reactant: CCOC(=O)c1ncn2c1CN(C)C(=O)c1ccccc1-2
Solvent: Cc1ccccc1
Product: CCOC(=O)c1ncn2c1CN(C)C(=S)c1ccccc1-2

Procedure:
670 mg (2.3 mmol) of ethyl 5,6-dihydro-5-methyl-6-oxo-4H-imidazo[1,5-a][1,4]benzodiazepine-3-carboxylate and 497 mg (1.23 mmol) of 2,4-bis(p-methoxyphenyl)-1,3,2,4-dithiadiphosphetane-2,4-disulphide are heated to boiling under reflux for 2.5 hours in 5 ml of absolute toluene. The mixture is chromatographed on silica gel with ethyl acetate and there is obtained ethyl 5,6-dihydro-5-methyl-6-thioxo-4H-imidazo[1,5-a][1,4]benzodiazepine-3-carboxylate of melting point 164°-165° C.