Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([NH:6][C:7]([NH2:9])=[S:8])[CH2:2][CH2:3][CH2:4][CH3:5].[C:10]([CH2:12][C:13](OCC)=[O:14])#[N:11].[O-]CC.[Na+].C(O)(=O)C>C(O)C.O>[NH2:11][C:10]1[N:6]([CH2:1][CH2:2][CH2:3][CH2:4][CH3:5])[C:7](=[S:8])[NH:9][C:13](=[O:14])[CH:12]=1
Reactant: CCOC(=O)CC#N
Reactant: CCCCCNC(N)=S
Agent: CC[O-]
Agent: [Na+]
Solvent: O
Solvent: CC(=O)O
Solvent: CCO
Product: CCCCCn1c(N)cc(=O)[nH]c1=S
Temperature: 75 °C
Reaction time: 8 h
Yield: 65.5 %

Procedure:
N-Pentylthiourea (10.0 g, 0.068 mol) was mixed with ethyl cyanoacetate (9.3 g, 0.082 mol) and sodium ethoxide (6.4 g, 0.094 mol) in ethanol (60 mL). The mixture was stirred at 75° C. overnight. After cooling, a solution of 10% acetic acid in water (150 mL) was added. The solid formed was collected by filtration and washed with water to afford the desired product (9.5 g, 65% yield). LCMS calculated for C9H16N3OS: (M+H) 214.1; found 214.1.
Reaction SMILES: [SH:1][C:2]1[N:7]=[CH:6][CH:5]=[CH:4][N:3]=1.[CH2:8](O[K])C.[Cl-].[CH:13]([C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)=[CH2:14]>C(O)C>[CH:13]([C:15]1[CH:20]=[CH:19][C:18]([CH2:8][S:1][C:2]2[N:7]=[CH:6][CH:5]=[CH:4][N:3]=2)=[CH:17][CH:16]=1)=[CH2:14]
Reactant: CCO[K]
Reactant: C=Cc1ccccc1
Reactant: Sc1ncccn1
Agent: [Cl-]
Solvent: CCO
Product: C=Cc1ccc(CSc2ncccn2)cc1
Yield: 92 %

Procedure:
10 mmole of 2-mercaptopyrimidine was dissolved in 20 ml of ethanol in stirring. 10 mole of EtOK was added to the solution, stirred for 5 minutes. Then, 10 mmole of 4-vinylbenzene chloride was added, and stirred overnight. The white precipitate was removed by filtration, the solvent in the filtrate was removed in vacuum. The obtained liquid was separated with a Si gel column (solvents: 1 ethylacetate/3 hexane). 2.1 g product was obtained. Yield: 92%. 1H NMR (CD3Cl): 8.51 (2H, d, JH-H=4.60), 7.38 (4H, m), 6.94 (1H, t, JH-H=4.60), 6.68 (1H, m), 5.70 (1H, d, JH-H=17.58), 5.21 (1H, d, JH-H=10.95), 4.40 (2H, s).
Reaction SMILES: Cl.[CH3:2][S:3][C:4]1[CH:9]=[CH:8][C:7]([NH:10][NH2:11])=[CH:6][CH:5]=1.[CH3:12][C:13]([CH3:20])([CH3:19])[C:14](=O)[CH2:15][C:16]#[N:17]>C(O)C.C(OCC)(=O)C>[C:13]([C:14]1[CH:15]=[C:16]([NH2:17])[N:10]([C:7]2[CH:8]=[CH:9][C:4]([S:3][CH3:2])=[CH:5][CH:6]=2)[N:11]=1)([CH3:20])([CH3:19])[CH3:12]
Reactant: CSc1ccc(NN)cc1
Reactant: CC(C)(C)C(=O)CC#N
Agent: Cl
Solvent: CCO
Solvent: CCOC(C)=O
Product: CSc1ccc(-n2nc(C(C)(C)C)cc2N)cc1
Yield: 95 %

Procedure:
Concentrated hydrochloric acid (1 mL) was added dropwise to a mixture of 4-methylthiophenyl hydrazine (2 g, 10.5 mmol) and 4,4-dimethyl-3-oxopentane nitrile (1.44 g, 11.5 mmol) in ethanol (30 mL) and the mixture was heated under reflux for 18 hours. The cooled mixture was then diluted with ethyl acetate, washed with saturated sodium hydrogen carbonate solution, dried over magnesium sulfate and concentrated in vacuo. The residue was purified by column chromatography on silica gel, eluting with dichloromethane:methanol, 100:0 to 97:3 to afford the title compound as a yellow oil that crystallised on standing (2.59 g, 95% yield).
Reaction SMILES: [CH3:1][C:2]1[CH:11]=[C:10]([CH3:12])[C:9]2[C:8](=O)[CH2:7][CH:6]([C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=3)[CH2:5][C:4]=2[N:3]=1.[C:20]([NH:23][NH2:24])([NH2:22])=[NH:21].[ClH:25].Cl.O>C(O)C>[ClH:25].[NH:23]([N:24]=[C:8]1[CH2:7][CH:6]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[CH2:5][C:4]2[N:3]=[C:2]([CH3:1])[CH:11]=[C:10]([CH3:12])[C:9]1=2)[C:20]([NH2:22])=[NH:21]
Reactant: N=C(N)NN
Reactant: Cc1cc(C)c2c(n1)CC(c1ccccc1)CC2=O
Agent: Cl
Solvent: CCO
Solvent: O
Product: Cc1cc(C)c2c(n1)CC(c1ccccc1)CC2=NNC(=N)N
Yield: 60.9 %

Procedure:
A mixture of 2,4-dimethyl-7-phenyl-5,6,7,8-tetrahydroquinolin-5-one (0.30 g), aminoguanidine hydrochloride (0.14 g), concentrated hydrochloric acid (0.06 ml), water (0.06 ml) and ethanol (30 ml) was refluxed for 4 hours. Under reduced pressure, the solvent was evaporated, and the residue was dissolved in water. The solution was washed with diethylether, and to the solution was added sodium hydrogen carbonate solution. The mixture was extracted with ethyl acetate, and the organic layer was washed with water and saturated brine, and dried with magnesium sulfate. Under reduced pressure, the solvent was evaporated, and the residue was dissolved in ethanol. To the solution was added 1N hydrochloric acid, and the solvent was evaporated. The residue was recrystallized from ethanol to give 5-guanidinoimino-2,4-dimethyl-7-phenyl-5,6,7,8-tetrahydroquinoline hydrochloride (Compound 83) (0.25 g) as colorless crystals.
Reaction SMILES: [C:1]([C:3]1[CH:10]=[CH:9][C:6]([CH:7]=[O:8])=[CH:5][CH:4]=1)#[N:2].[C-:11]#[N:12].[K+]>C(O)C.O>[O:8]=[C:7]([C:6]1[CH:9]=[CH:10][C:3]([C:1]#[N:2])=[CH:4][CH:5]=1)[CH2:1][C:3]1[CH:10]=[CH:9][C:6]([C:11]#[N:12])=[CH:5][CH:4]=1
Reactant: N#Cc1ccc(C=O)cc1
Reactant: [C-]#N
Agent: [K+]
Solvent: CCO
Solvent: O
Product: N#Cc1ccc(CC(=O)c2ccc(C#N)cc2)cc1

Procedure:
To a solution of 25 g of p-cyanobenzaldehyde in 50 ml of ethanol was added 5 g of potassium cyanide in 10 ml of water. The mixture was heated at reflux for 1 hr, cooled, and the crystalline product was filtered and washed with cold ethanol. Recrystallization from acetic acid afforded 4.7 g of the part (a) title compound, mp. 209°-215° C.
Reaction SMILES: [OH:1][C:2]1[CH:10]=[CH:9][C:5]([CH2:6][CH2:7][OH:8])=[CH:4][CH:3]=1.[H-].[Na+].[N+:13]([C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=1[S:22](Cl)(=[O:24])=[O:23])([O-:15])=[O:14].CCO[CH2:29][CH3:30]>O1CCCC1.O>[N+:13]([C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=1[S:22]([O:1][C:2]1[CH:10]=[CH:9][C:5]([CH2:6][CH2:7][O:8][S:22]([C:30]2[CH:29]=[CH:19][CH:18]=[CH:17][C:16]=2[N+:13]([O-:15])=[O:14])(=[O:24])=[O:23])=[CH:4][CH:3]=1)(=[O:24])=[O:23])([O-:15])=[O:14]
Reactant: CCOCC
Reactant: O=[N+]([O-])c1ccccc1S(=O)(=O)Cl
Reactant: OCCc1ccc(O)cc1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: O=[N+]([O-])c1ccccc1S(=O)(=O)OCCc1ccc(OS(=O)(=O)c2ccccc2[N+](=O)[O-])cc1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 90 %

Procedure:
To a mixture of 2.76 g (20 mmol) of 4-hydroxyphenethyl alcohol in 70 mL of anhydrous tetrahydrofuran at rt was added 4.8 g (200 mmol) of sodium hydride (95%, dry powder). After stirring at rt for 10 min, 18.5 g (80 mmol) of 2-nitrobenzenesulfonyl chloride was added. After the resulting mixture was stirred at rt for 16 h, 250 mL of ether was added. The mixture was cooled to 0° C. and water was slowly added to the the mixture to quench excess sodium hydride. After quenching process was completed, additional 300 mL of water was added. The resulting precipitate was collected via filtration, washed with water and dried in vacuo to yield 2-nitrobenzenesulfonic acid 2-[4-(2-nitrobenzenesulfonyloxy)-phenyl]-ethyl ester as a white powder (9.13 g, 90%): MS (ESI) 509 [M+H]+.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C@@:15]3([CH2:20][CH2:19][O:18][C:17]([NH2:21])=[N:16]3)[C:14]3[CH:13]=[C:12](Cl)[N:11]=[C:10]([F:23])[C:9]=3[O:8][C:5]2=[CH:6][CH:7]=1.[F:24][C:25]1[CH:26]=[C:27](B(O)O)[CH:28]=[N:29][CH:30]=1.[F:34][C:35]1[CH:40]=[C:39](B(O)O)[CH:38]=[CH:37][N:36]=1>>[F:23][C:10]1[C:9]2[O:8][C:5]3[C:4]([C@@:15]4([CH2:20][CH2:19][O:18][C:17]([NH2:21])=[N:16]4)[C:14]=2[CH:13]=[C:12]([C:39]2[CH:38]=[CH:37][N:36]=[C:35]([F:34])[CH:40]=2)[N:11]=1)=[CH:3][C:2]([C:27]1[CH:28]=[N:29][CH:30]=[C:25]([F:24])[CH:26]=1)=[CH:7][CH:6]=3
Reactant: NC1=N[C@@]2(CCO1)c1cc(Br)ccc1Oc1c2cc(Cl)nc1F
Reactant: OB(O)c1ccnc(F)c1
Reactant: OB(O)c1cncc(F)c1
Product: NC1=N[C@@]2(CCO1)c1cc(-c3cncc(F)c3)ccc1Oc1c2cc(-c2ccnc(F)c2)nc1F

Procedure:
The title compound was synthesized by steps analogous to those described in method A1 above, but using intermediate 15B, 5-fluoropyridin-3-ylboronic acid and 2-fluoropyridine-4-boronic acid.
Reaction SMILES: [CH2:1]([C:3]1[NH:4][CH:5]=[CH:6][CH:7]=1)[CH3:2].O.[C:9]([OH:13])(=[O:12])[CH:10]=O.[NH3:14].Cl>>[CH2:1]([C:3]1[NH:4][C:5]([CH:10]([C:9]([OH:13])=[O:12])[NH2:14])=[CH:6][CH:7]=1)[CH3:2]
Reactant: N
Reactant: O=CC(=O)O
Reactant: CCc1ccc[nH]1
Agent: Cl
Solvent: O
Product: CCc1ccc(C(N)C(=O)O)[nH]1
Reaction time: 4 h
Yield: 43 %

Procedure:
2-Ethylpyrrole (4.75 g., 0.05 mole) was added dropwise to a stirred solution of glyoxylic acid hydrate (2.3 g., 0.025 mole) in 0.880 sp. gr. ammonia solution (25 ml.) at 50°. The mixture was stirred at 50° for 4 hours, then cooled, acidified to pH 5.5 with concentrated hydrochloric acid and filtered. The resulting solid was washed with water, triturated with cold, then hot; methanol and dried in vacuo to afford DL-2-(5-ethyl-2-pyrrolyl)glycine (1.8 g., 43%), M.P. 188° (decomp.).
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[S:6][C:7]([C:33]2(O)[CH2:38][CH2:37][CH2:36][CH:35]=[CH:34]2)=[CH:8][C:9]=1[N:10]([C:24]([C@H:26]1[CH2:31][CH2:30][C@H:29]([CH3:32])[CH2:28][CH2:27]1)=[O:25])[C@H:11]1[CH2:16][CH2:15][C@H:14]([O:17][CH:18]2[CH2:23][CH2:22][CH2:21][CH2:20][O:19]2)[CH2:13][CH2:12]1)=[O:4].C([SiH](CC)CC)C.FC(F)(F)C(O)=[O:50].C([O-])(O)=O.[Na+]>C(Cl)Cl>[CH3:1][O:2][C:3]([C:5]1[S:6][C:7]([C:33]2[CH2:38][CH2:37][CH2:36][CH:35]([OH:50])[CH:34]=2)=[CH:8][C:9]=1[N:10]([C:24]([C@H:26]1[CH2:27][CH2:28][C@H:29]([CH3:32])[CH2:30][CH2:31]1)=[O:25])[C@H:11]1[CH2:12][CH2:13][C@H:14]([O:17][CH:18]2[CH2:23][CH2:22][CH2:21][CH2:20][O:19]2)[CH2:15][CH2:16]1)=[O:4]
Reactant: COC(=O)c1sc(C2(O)C=CCCC2)cc1N(C(=O)[C@H]1CC[C@H](C)CC1)[C@H]1CC[C@H](OC2CCCCO2)CC1
Reactant: O=C(O)C(F)(F)F
Agent: CC[SiH](CC)CC
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Product: COC(=O)c1sc(C2=CC(O)CCC2)cc1N(C(=O)[C@H]1CC[C@H](C)CC1)[C@H]1CC[C@H](OC2CCCCO2)CC1
Reaction time: 3.5 h

Procedure:
A solution of 5-(1-hydroxy-cyclohex-2-enyl)-3-{(trans-4-methyl-cyclohexanecarbonyl)-[trans-4-(tetrahydro-pyran-2-yloxy)-cyclohexyl]-amino}-thiophene-2-carboxylic acid methyl ester (48 mg, 0.086 mmol) in DCM (1 mL) was cooled to −50° C. Triethylsilane (43 μl, 0.27 mmol) was added followed by gradual addition of trifluoroacetic acid (total 22 μl, 0.28 mmol) (4 μl to 6 μl every 30 min). The mixture was stirred at −40° C. to −50° C. for 3.5 h. Aqueous NaHCO3 was added and the mixture was allowed to come to room temperature. It was extracted with DCM, washed with brine, dried (MgSO4) and evaporated. The crude was left at room temperature for 2 days and purified by chromatography over silica gel (hexane-EtOAc mixtures) yielding 5-(3-Hydroxy-cyclohex-1-enyl)-3-{(trans-4-methyl-cyclohexanecarbonyl)-[trans-4-(tetrahydro-pyran-2-yloxy)-cyclohexyl]-amino}-thiophene-2-carboxylic acid methyl ester (22 mg, 45%).
Reaction SMILES: [CH:1]1([CH2:4][O:5][C:6]2[N:11]=[N:10][C:9]([NH2:12])=[CH:8][CH:7]=2)[CH2:3]C1.Br[CH2:14][C:15]([C:17]1[CH:22]=[CH:21][C:20]([O:23][CH2:24][CH3:25])=[CH:19][CH:18]=1)=O.[C:26](=O)([O-])O.[Na+]>C(O)C>[CH2:24]([O:23][C:20]1[CH:21]=[CH:22][C:17]([C:15]2[CH2:14][N:10]3[N:11]([CH3:26])[C:6]([O:5][CH2:4][CH2:1][CH3:3])=[CH:7][CH:8]=[C:9]3[N:12]=2)=[CH:18][CH:19]=1)[CH3:25]
Reactant: CCOc1ccc(C(=O)CBr)cc1
Reactant: O=C([O-])O
Reactant: Nc1ccc(OCC2CC2)nn1
Agent: [Na+]
Solvent: CCO
Product: CCCOC1=CC=C2N=C(c3ccc(OCC)cc3)CN2N1C
Reaction time: 3 h

Procedure:
A stirred mixture of 6-cyclopropylmethoxypyridazin-3-amine (165 mg, 1 mmol), 2-bromo-1-(4-ethoxyphenyl)ethanone (243 mg, 1 mmol) and ethanol (10 mL) was heated under reflux for 3 hours. Sodium hydrogen carbonate (84 mg, 1 mmol) was added and the refluxing was continued for another 3 hours. The mixture was evaporated. The residue was extracted with chloroform (50 mL) and the extract washed with saturated, aqueous, sodium chloride solution (50 mL), dried (MgSO4) and evaporated. The residue was purified by flash chromatography on silica gel. Elution with 1% methanol in dichloromethane afforded Compound 33 (140 mg). 1H n.m.r. (CDCl3) δ 0.30-0.42, m, 2H; 0.60-0.74, m, 2H; 1.20-1.38, m, 1H; 1.40, t, 3H; 4.04, q, 2H; 4.14, d, 2H; 6.70, d, 1H; 6.96, d, 2H; 7.74, d, 1H; 7.80, d, 2H; 7.88, s, 1H.
Reaction SMILES: C([C@H]1COC(=O)N1[C:14](=[O:25])[C@H:15]([C:17]1[CH:22]=[CH:21][C:20]([O:23][CH3:24])=[CH:19][CH:18]=1)[CH3:16])C1C=CC=CC=1.[O-:26]O.[Li+].O[Li].O.OO>C1COCC1.O.C(OCC)(=O)C>[CH3:24][O:23][C:20]1[CH:19]=[CH:18][C:17]([C@H:15]([CH3:16])[C:14]([OH:25])=[O:26])=[CH:22][CH:21]=1
Reactant: COc1ccc([C@H](C)C(=O)N2C(=O)OC[C@@H]2Cc2ccccc2)cc1
Reactant: [O-]O
Agent: OO
Agent: [Li+]
Agent: [Li]O
Solvent: O
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: COc1ccc([C@H](C)C(=O)O)cc1
Yield: 100 %

Procedure:
To a mechanically stirred solution of the above amide (27) (56.2 g) in THF (750 mL) and H2O (250 mL) at 0° C. was added a solution of lithium hydroperoxide prepared by adding a solution of LiOH.H2O (10.4 g) in H2O (250 mL) to 30% H2O2 (84 mL). After stirring for 1 h at 0° C. the excess peroxide was destroyed by the slow addition of a solution of Na2SO3 (103 g) in H2O (500 mL) (exothermic!). After removing most of the THF by evaporation the remaining solution was washed with CH2Cl2 twice to remove recoverable (S)-4-benzyl-2-oxazolidinone, acidified to pH ~2 with 3N HCl and extracted twice with ethyl acetate to isolate the product. The ethyl acetate phases were combined, washed with saturated NaCl, dried over MgSO4 and evaporated to give TLC pure product, (28) (29.87 g, 100%). TLC Rf 0.49 (95:4:1 CHCl3 :MeOH:HOAc) Rf 0.33 streaks (98:2 CHCl3 :MeOH); 1H NMR (CDCl3)δ1.5(3H, d, J=7 HZ), 2.25 (2H, br s), 2.78 (3H, s), 4.08 (1H, q), 7.15 (4H, q).
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].[NH2:7][CH: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][CH2:9]1.Cl[C:22]1[CH:30]=[CH:29][CH:28]=[C:27]([F:31])[C:23]=1[C:24]([OH:26])=[O:25]>CN(C)C=O>[CH2:14]([N:11]1[CH2:12][CH2:13][CH:8]([NH:7][C:22]2[CH:30]=[CH:29][CH:28]=[C:27]([F:31])[C:23]=2[C:24]([OH:26])=[O:25])[CH2:9][CH2:10]1)[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1
Reactant: NC1CCN(Cc2ccccc2)CC1
Reactant: O=C(O)c1c(F)cccc1Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: O=C(O)c1c(F)cccc1NC1CCN(Cc2ccccc2)CC1
Temperature: 140 °C
Yield: 35.8 %

Procedure:
Potassium carbonate (8.9 g), 4-amino-1-benzylpiperidine (18.5 g), cupric oxide (0.6 g) and dimethylformamide (25 ml) are added to 2-chloro-6-fluorobenzoic acid (11.3 g) and the mixture is reacted with heating at 140° C. for 6 hours. After the reaction, the solvent is concentrated and to the resulting residue are added water (200 ml) and active carbon (1 g). The mixture is refluxed for 30 minutes. After filtration, the filtrate is cooled and then adjusted to pH 8.0 with diluted hydrochloric acid. The precipitated crystal is collected by filtration and washed successively with water and methanol to give 2(1-benzyl-4-piperidinylamino)-6-fluorobenzoic acid (7.6 g) as white powders, m.p.: 233°-236° C.
Reaction SMILES: [CH2:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH2:3][CH:2]1[N:10]([C:20]1[S:21][CH:22]=[CH:23][N:24]=1)[CH2:11][CH2:12][CH:13]1[CH2:18][CH2:17][CH2:16][CH2:15][N:14]1[CH3:19].[CH3:25][I:26]>ClCCCl>[I-:26].[CH3:19][N+:14]1([CH3:25])[CH2:15][CH2:16][CH2:17][CH2:18][CH:13]1[CH2:12][CH2:11][N:10]([CH:2]1[CH2:3][C:4]2[C:9](=[CH:8][CH:7]=[CH:6][CH:5]=2)[CH2:1]1)[C:20]1[S:21][CH:22]=[CH:23][N:24]=1
Reactant: CN1CCCCC1CCN(c1nccs1)C1Cc2ccccc2C1
Reactant: CI
Solvent: ClCCCl
Product: C[N+]1(C)CCCCC1CCN(c1nccs1)C1Cc2ccccc2C1
Product: [I-]
Temperature: 25 °C
Reaction time: 16 h

Procedure:
To a stirred solution of compound 54 (0.25 g, 0.733 mmol) in DCE (5 mL) was added methyl iodide (0.2 mL, 2.93 mmol) and the reaction mixture was stirred at rt for 16 hours in a sealed tube. The reaction mixture was concentrated and the crude material purified by column chromatography on neutral alumina eluting with 1% methanol-DCM to provide a solid compound. The solid material crystallized from methanol-ether to provide the desired compound as an off white solid.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:12](=[CH:13][CH:14]=1)[NH:11][C:10]1[C:9](=O)[CH2:8][CH2:7][CH2:6][C:5]2=1.[F:16][C:17]1[CH:23]=[CH:22][CH:21]=[CH:20][C:18]=1[NH2:19]>>[Br:1][C:2]1[CH:3]=[C:4]2[C:12](=[CH:13][CH:14]=1)[NH:11][C:10]1[CH:9]([NH:19][C:18]3[CH:20]=[CH:21][CH:22]=[CH:23][C:17]=3[F:16])[CH2:8][CH2:7][CH2:6][C:5]2=1
Reactant: Nc1ccccc1F
Reactant: O=C1CCCc2c1[nH]c1ccc(Br)cc21
Product: Fc1ccccc1NC1CCCc2c1[nH]c1ccc(Br)cc21

Procedure:
6-Bromo-N-(2-fluorophenyl)-2,3,4,9-tetrahydro-1H-carbazol-1-amine was prepared from 6-bromo-2,3,4,9-tetrahydro-1H-carbazol-1-one (200 mg, 0.76 mmol) and 2-fluoroaniline (168 mg, 1.51 mmol) in a similar manner as described above to give 37 mg (14%) of a white solid; 1H-NMR (DMSO-d6): δ 11.04 (s, 1H), 7.55 (d, 1H), 7.23 (d, 1H), 7.12 (dd, 1H), 7.05-6.85 (m, 3H), 6.59-6.54 (m, 1H), 5.53 (m, 1H), 4.87-4.82 (m, 1H), 2.68-2.57 (m, 2H), 2.04-1.92 (m, 2H), 1.87-1.72 (m, 2H).
Reaction SMILES: [NH:1]1[CH2:4][CH:3]([CH2:5][C:6]2[N:7]([C:12]3[CH:17]=[CH:16][C:15]([C:18]4[CH:27]=[C:26]5[C:21]([CH:22]=[CH:23][CH:24]=[N:25]5)=[CH:20][CH:19]=4)=[CH:14][C:13]=3[F:28])[C:8](=[O:11])[NH:9][N:10]=2)[CH2:2]1.C(N(CC)C(C)C)(C)C.[CH3:38][N:39]1[CH2:43]CC[C:40]1=[O:44].CN(C)C(Cl)=O>ClCCl>[F:28][C:13]1[CH:14]=[C:15]([C:18]2[CH:27]=[C:26]3[C:21]([CH:22]=[CH:23][CH:24]=[N:25]3)=[CH:20][CH:19]=2)[CH:16]=[CH:17][C:12]=1[N:7]1[C:8](=[O:11])[NH:9][N:10]=[C:6]1[CH2:5][CH:3]1[CH2:4][N:1]([C:40]([N:39]([CH3:43])[CH3:38])=[O:44])[CH2:2]1
Reactant: CN1CCCC1=O
Reactant: O=c1[nH]nc(CC2CNC2)n1-c1ccc(-c2ccc3cccnc3c2)cc1F
Agent: CN(C)C(=O)Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CN(C)C(=O)N1CC(Cc2n[nH]c(=O)n2-c2ccc(-c3ccc4cccnc4c3)cc2F)C1
Temperature: 25 °C
Reaction time: 0.03 h
Yield: 18 %

Procedure:
In a round bottom flask under nitrogen at room temperature, a mixture of 5-(3-azetidinylmethyl)-4-[2-fluoro-4-(7-quinolinyl)phenyl]-2,4-dihydro-3H-1,2,4-triazol-3-one (0.38 mmol) in dichloromethane (2 mL) was treated with N,N-diisopropylethylamine (0.77 mmol) by syringe and stirred for 2 min. The starting material did not dissolve. N-methyl-2-pyrrolidone (2 mL) was added to the mixture and some material dissolved. The mixture was heated with a heat gun to accelerate dissolution and was then left to cool to room temperature. Dimethylcarbamoyl chloride (0.38 mmol) was then added dropwise by syringe to the reaction, which was stirred for 1 h. The reaction mixture was concentrated to remove the dichloromethane. The resultant solution was directly purified by reverse phase HPLC (10-70% acetonitrile/water with 0.1% NH4OH) and subsequently purified by silica gel chromatography (0-3% methanol/ethyl acetate) to provide the title compound as a white solid (31 mg, 18%). MS(ES)+ m/e 447.2 [M+H]+.
Reaction SMILES: [NH2:1][C@H:2]([C@@H:6]([OH:10])[CH:7]([CH3:9])[CH3:8])[C:3]([OH:5])=[O:4].C([O-])(O)=O.[Na+].[C:16](=O)([O-:37])[O:17][C:18]1C(C)=C(C2C=CC(C3C=CC=CC=3)=CC=2)C=CN=1.[C:39]1([C:45]2[CH:50]=[CH:49][C:48](C3C=CN(C([O-])=O)C(=O)C=3C)=[CH:47][CH:46]=2)[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=1>O.C1COCC1>[OH:10][C@@H:6]([CH:7]([CH3:9])[CH3:8])[C@@H:2]([N:1]([C:48]1[CH:47]=[CH:46][C:45]([C:39]2[CH:40]=[CH:41][CH:42]=[CH:43][CH:44]=2)=[CH:50][CH:49]=1)[C:16]([O:17][CH3:18])=[O:37])[C:3]([OH:5])=[O:4]
Reactant: CC(C)[C@H](O)[C@@H](N)C(=O)O
Reactant: Cc1c(-c2ccc(-c3ccccc3)cc2)ccn(C(=O)[O-])c1=O
Reactant: Cc1c(-c2ccc(-c3ccccc3)cc2)ccnc1OC(=O)[O-]
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: COC(=O)N(c1ccc(-c2ccccc2)cc1)[C@@H](C(=O)O)[C@@H](O)C(C)C
Reaction time: 15 h
Yield: 50 %

Procedure:
To a stirred diastereomeric mixture containing (2R*,3R*)- and (2R*,3S*)-2-amino-3-hydroxy-4-methyl-pentanoic acid (0.05 g, 0.34 mmol) and NaHCO3 (0.03 g, 0.34 mmol) in H2O (2.0 mL), at rt, the isomeric mixture containing (4-phenylphenyl)-methyl-2-pyridyl carbonate and (4-phenylphenyl)-methyl-2-oxopyridine-1-carboxylate (0.45 g, 1.48 mmol) [prepared as for example 17, step 1] in THF (2.0 mL) was added. After 15 h at rt, the crude mixture was rotary evaporated to remove the organics and subsequently extracted with Et2O (3×10 mL). The aqueous phase was acidified with 2.0 M HCl solution to pH 2-3 and subsequently extracted with AcOEt (3×20 mL). The organic fraction was dried over Na2SO4, filtered and concentrated to dryness to afford the title compound (0.06 g, 50% over 2 steps), as a diastereoisomeric mixture (anti:syn=8:2), as an off-white solid, which was used in the next step without further purification. MS (ESI) m/z: 358 [M−H]+; (ESI) m/z: 356 [M−H]−. 1H NMR (DMSO-d6) δ 0.82 (d, J=6.55 Hz, 3H), 0.88 (d, J=6.92 Hz, 3H), 1.62-1.79 (m, 1H), 3.17 (dd, J=2.87, 9.15 Hz, 1H), 3.51 (d, J=9.16 Hz, 1H), 5.05 (s, 2H), 7.32-7.41 (m, 1H), 7.41-7.52 (m, 4H), 7.66 (td, J=1.74, 6.70, 7.42 Hz, 4H) (reported data refer to the major anti diastereoisomer).
Reaction SMILES: [NH2:1][CH2:2][CH2:3][CH2:4][CH2:5][C@H:6]([N:17]([S:22]([C:25]1[CH:30]=[CH:29][C:28]([NH2:31])=[CH:27][CH:26]=1)(=[O:24])=[O:23])[CH2:18][CH:19]([CH3:21])[CH3:20])[CH2:7][O:8][C:9](=[O:16])[C:10]1[CH:15]=[CH:14][CH:13]=[N:12][CH:11]=1.C(N(CC)CC)C.C(Cl)CCl.C1C=CC2N(O)N=NC=2C=1.[CH3:53][O:54][C:55]([NH:57][C@@H:58]([CH:62]([C:69]1[CH:74]=[CH:73][CH:72]=[CH:71][CH:70]=1)[C:63]1[CH:68]=[CH:67][CH:66]=[CH:65][CH:64]=1)[C:59](O)=[O:60])=[O:56]>CN(C=O)C>[NH2:31][C:28]1[CH:27]=[CH:26][C:25]([S:22]([N:17]([CH2:18][CH:19]([CH3:21])[CH3:20])[C@@H:6]([CH2:5][CH2:4][CH2:3][CH2:2][NH:1][C:59](=[O:60])[C@@H:58]([NH:57][C:55]([O:54][CH3:53])=[O:56])[CH:62]([C:69]2[CH:70]=[CH:71][CH:72]=[CH:73][CH:74]=2)[C:63]2[CH:68]=[CH:67][CH:66]=[CH:65][CH:64]=2)[CH2:7][O:8][C:9](=[O:16])[C:10]2[CH:15]=[CH:14][CH:13]=[N:12][CH:11]=2)(=[O:24])=[O:23])=[CH:30][CH:29]=1
Reactant: CC(C)CN([C@@H](CCCCN)COC(=O)c1cccnc1)S(=O)(=O)c1ccc(N)cc1
Reactant: COC(=O)N[C@H](C(=O)O)C(c1ccccc1)c1ccccc1
Agent: On1nnc2ccccc21
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Solvent: ClCCCl
Product: COC(=O)N[C@H](C(=O)NCCCC[C@@H](COC(=O)c1cccnc1)N(CC(C)C)S(=O)(=O)c1ccc(N)cc1)C(c1ccccc1)c1ccccc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 20 %

Procedure:
The product of step B, (2S)-nicotinic acid 6-amino-2-[(4-amino-benzenesulfonyl)-isobutyl-amino]-hexyl ester (100 mg, 0.22 mmol) was dissolved in anhydrous. DMF (2 mL) and treated with 0.062 mL (0.45 mmol) of triethylamine followed by EDC (100 mg, 0.56 mmol), HOBt (75 mg, 0.56 mmol) and (2S)-2-methoxycarbonylamino-3,3-diphenyl-propionic acid (56 mg, 0.19 mmol). The mixture was stirred overnight at room temperature. The product was extracted with ethyl acetate (40 mL) and water (40 mL). The organic layer was separated and dried with Na2SO4, then evaporated to give 160 mg of crude oil. The residue was purified by flash chromatography with a mixture of eluents hexane/ethyl acetate (2/8). The title compound was obtained as a clear oil in 20% yield (25 mg).
Reaction SMILES: [NH2:1][CH2:2][C@H:3]([NH:7][S:8]([C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)(=[O:10])=[O:9])[C:4]([OH:6])=[O:5].[CH3:17][C:18]1[CH:19]=[CH:20][C:21]([S:24]([OH:27])(=[O:26])=[O:25])=[CH:22][CH:23]=1.O>CCO>[C:18]1([CH3:17])[CH:19]=[CH:20][C:21]([S:24]([OH:27])(=[O:25])=[O:26])=[CH:22][CH:23]=1.[CH2:17]([NH:1][CH2:2][C@H:3]([NH:7][S:8]([C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)(=[O:10])=[O:9])[C:4]([OH:6])=[O:5])[CH3:18]
Reactant: NC[C@H](NS(=O)(=O)c1ccccc1)C(=O)O
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: CCO
Solvent: O
Product: CCNC[C@H](NS(=O)(=O)c1ccccc1)C(=O)O

Procedure:
Acid 2-1b (13.20 g, 54.1 mmol) was suspended in 500 mL EtOH, p-TsOH--H2O (11.3 g, 59 mmol) was added and the mixture was heated at reflux overnight. After distilling off the solvent, fresh EtOH was added and distilled off, then more EtOH was added and the mixture was distilled to 100 mL at which point 800 mL ether was added. After cooling to 4°, solvent was decanted from the gum which was rinsed with additional ether, and dried, providing 35-2 as a hygroscopic glass. Additional 35-2 was recovered from the solvent phase by concentration and triturating with ether (2×).