Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C:9]2[C:10]3[CH2:29]O[CH2:27][CH2:26][C:11]=3[N:12]([C:14]([NH:16][C@@H:17]([C:22]([CH3:25])([CH3:24])[CH3:23])[C:18]([NH:20][CH3:21])=[O:19])=[O:15])[N:13]=2)[CH:5]=[CH:6][C:7]=1[F:8].[O:30]1[C:34]2(CCC(=O)CC2)[O:33][CH2:32][CH2:31]1>>[F:1][C:2]1[CH:3]=[C:4]([C:9]2[C:10]3[CH2:29][C:34]4([O:33][CH2:32][CH2:31][O:30]4)[CH2:27][CH2:26][C:11]=3[N:12]([C:14]([NH:16][C@@H:17]([C:22]([CH3:23])([CH3:25])[CH3:24])[C:18]([NH:20][CH3:21])=[O:19])=[O:15])[N:13]=2)[CH:5]=[CH:6][C:7]=1[F:8]
Reactant: CNC(=O)[C@@H](NC(=O)n1nc(-c2ccc(F)c(F)c2)c2c1CCOC2)C(C)(C)C
Reactant: O=C1CCC2(CC1)OCCO2
Product: CNC(=O)[C@@H](NC(=O)n1nc(-c2ccc(F)c(F)c2)c2c1CCC1(C2)OCCO1)C(C)(C)C

Procedure:
Compound 63 was prepared according to the procedure described for the synthesis of compound 28 by replacing tetrahydro-4H-pyran-4-one with 1,4-dioxaspiro[4.5]decan-8-one in the synthesis of intermediate 16. LCMS (+ESI) m/z=463.2 [M+H]+.
Reaction SMILES: C[O:2][C:3]1[CH:4]=[C:5]([C@H:9]([CH2:16][CH3:17])[C@@H:10]([CH3:15])[CH2:11][N:12]([CH3:14])[CH3:13])[CH:6]=[CH:7][CH:8]=1.CS(O)(=O)=O.CSC>>[CH3:14][N:12]([CH3:13])[CH2:11][C@H:10]([CH3:15])[C@H:9]([C:5]1[CH:4]=[C:3]([OH:2])[CH:8]=[CH:7][CH:6]=1)[CH2:16][CH3:17]
Reactant: CC[C@@H](c1cccc(OC)c1)[C@@H](C)CN(C)C
Agent: CS(=O)(=O)O
Solvent: CSC
Product: CC[C@@H](c1cccc(O)c1)[C@@H](C)CN(C)C
Temperature: 5 °C

Procedure:
Accordingly the compound (2R,3R)-3-(3-methoxyphenyl)-N,N,2-trimethylpentan-1-amine of Formula-VII was taken in pre cooled methanesulfonic acid and stirred at 0-10° C. Charged dimethyl sulfide to the reaction solution and raised the temperature of the reaction to 55-60° C. Maintained the reaction at 55-60° C. for 2-3 hours and cooled the reaction to 20-30° C. Quenched the reaction mass in ice cold water and extracted the reaction solution with toluene. Separated the aqueous layer and adjusted the pH to 9-10 with dilute aqueous sodium hydroxide solution. Extracted the aqueous layer with toluene and separated the toluene layer. Concentrated the solvent under reduced pressure to isolate the compound 3-[(2R,3R)-1-(dimethylamino)-2-methylpentan-3-yl]phenol of Formula-I.
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][CH:11]([C:14]([NH:16][C:17]2[CH:18]=[C:19]([C:23]3[N:28]=[C:27]([C:29]4[C:30]([O:37][CH3:38])=[N:31][C:32]([O:35][CH3:36])=[N:33][CH:34]=4)[CH:26]=[C:25](Cl)[N:24]=3)[CH:20]=[CH:21][CH:22]=2)=[O:15])[CH2:10][CH2:9]1)=O)(C)(C)C.[NH:40]1[CH2:45][CH2:44][O:43][CH2:42][CH2:41]1>C(#N)C>[CH3:36][O:35][C:32]1[N:31]=[C:30]([O:37][CH3:38])[C:29]([C:27]2[CH:26]=[C:25]([N:40]3[CH2:45][CH2:44][O:43][CH2:42][CH2:41]3)[N:24]=[C:23]([C:19]3[CH:20]=[CH:21][CH:22]=[C:17]([NH:16][C:14]([CH:11]4[CH2:12][CH2:13][NH:8][CH2:9][CH2:10]4)=[O:15])[CH:18]=3)[N:28]=2)=[CH:34][N:33]=1
Reactant: C1COCCN1
Reactant: COc1ncc(-c2cc(Cl)nc(-c3cccc(NC(=O)C4CCN(C(=O)OC(C)(C)C)CC4)c3)n2)c(OC)n1
Solvent: CC#N
Product: COc1ncc(-c2cc(N3CCOCC3)nc(-c3cccc(NC(=O)C4CCNCC4)c3)n2)c(OC)n1
Temperature: 100 °C
Yield: 29 %

Procedure:
A mixture of 2-[3-(1-tert-butoxycarbonylpiperidin-4-ylcarbonylamino)phenyl]-6-chloro-4-(2,4-dimethoxypyrimidin-5-yl)pyrimidine (0.072 g), morpholine (0.056 g) and acetonitrile (2.5 ml) was stirred under an atmosphere of nitrogen and heated to 100° C. for 5 minutes using microwave radiation. The reaction mixture was evaporated. Toluene was added and the mixture was re-evaporated. Trifluoroacetic acid (3 ml) was added to the material so obtained and the mixture was stirred at ambient temperature for 3 hours. The mixture was evaporated. Toluene was added and the mixture was re-evaporated and the residue was purified by column chromatography on an ‘Isolute SCX’ column (1 g) by initially washing the column with methylene chloride and then with methanol (5 ml) followed by elution with a 7M methanolic ammonia solution. The material so obtained was dried under vacuum. There was thus obtained the title compound as a solid (0.019 g); NMR Spectrum: (CDCl3) 1.68-1.84 (m, 2H), 1.91-2.0 (m, 2H), 2.37-2.5 (m, 1H), 2.63-2.76 (m, 2H), 3.14-3.27 (m, 2H), 3.74-3.91 (m, 8H), 7.07 (s, 1H), 7.12 (s, 1H), 7.42 (t, 1H), 8.03 (d, 1H), 8.21 (d, 1H), 8.31 (s, 1H), 9.37 (s, 1H); Mass Spectrum: M+H+ 506.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([S:9](Cl)(=[O:11])=[O:10])[CH:5]=[CH:6][C:7]=1[F:8].Cl.[CH3:14][NH:15][CH3:16].C(N(CC)CC)C.O>ClCCl>[F:1][C:2]1[CH:3]=[C:4]([S:9]([N:15]([CH3:16])[CH3:14])(=[O:11])=[O:10])[CH:5]=[CH:6][C:7]=1[F:8]
Reactant: CNC
Reactant: O=S(=O)(Cl)c1ccc(F)c(F)c1
Agent: Cl
Solvent: ClCCl
Solvent: O
Solvent: CCN(CC)CC
Product: CN(C)S(=O)(=O)c1ccc(F)c(F)c1
Temperature: 25 °C
Reaction time: 2 h
Yield: 25.4 %

Procedure:
Commercially available 3,4-difluorophenylsulfonylchloride (117 μL, 0.87 mmol) was dissolved in dichloromethane (5 mL), and dimethylamine hydrochloride (59 mg, 0.73 mmol) and triethylamine (203 μL, 1.45 mmol) were added, followed by stirring at room temperature for 2 hours. To the reaction solution, water (15 mL) was added, followed by extraction twice with dichloromethane (15 mL), and washing was carried out with saturated brine (15 mL), followed by drying over sodium sulfate. The solvent was distilled off under reduced pressure, followed by vacuum drying, to afford the desired compound (41.0 mg, yield 26%) as a colorless oil.
Reaction SMILES: [OH-].[Na+].[CH3:3][C:4]1([CH3:11])[CH2:8][CH:7]([Cl:9])[CH2:6][C:5]1=[O:10].[F:12][C:13]1[CH:20]=[CH:19][C:16]([CH:17]=O)=[CH:15][CH:14]=1>C(O)C>[CH3:3][C:4]1([CH3:11])[CH2:8][CH:7]([Cl:9])[C:6](=[CH:17][C:16]2[CH:19]=[CH:20][C:13]([F:12])=[CH:14][CH:15]=2)[C:5]1=[O:10]
Reactant: O=Cc1ccc(F)cc1
Reactant: CC1(C)CC(Cl)CC1=O
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: CC1(C)CC(Cl)C(=Cc2ccc(F)cc2)C1=O
Reaction time: 0.5 h
Yield: 69 %

Procedure:
10% strength aqueous sodium hydroxide solution (50 cc) is added to a mixture of 2,2-dimethyl-4-chloro-1-cyclopentanone (10 g) and 4-fluorobenzaldehyde (8.4 g) in ethanol (100 cc) at 0° C. After 30 minutes, a thick slurry is filtered and the solid washed and then dried. 2,2-Dimethyl-4-chloro-5-(4-fluorobenzylidene)-1-cyclopentanone (11.8 g), m.p. 69° C., is obtained. Sodium hydride (3.1 g; 80% strength dispersion in mineral oil) in anhydrous DMSO (50 cc) is heated to 80° C. until the solid is dissolved completely. The solution is then diluted with THF (100 cc) and thereafter cooled to -10° C. A solution of trimethylsulphonium iodide (11.5 g) in dimethyl sulphoxide (80 cc) is added to the mixture in the course of 10 minutes and the mixture is stirred for 15 minutes at -10° C. A solution of 2,2-dimethyl-4-chloro- 5-(4-fluorobenzylidene)-1-cyclopentanone (11.8 g) is then added in THF (100 cc). The mixture thereby produced is left at room temperature, then poured into water and extracted with ether, washed with water, dried and distilled. 7-(4-Fluorobenzylidene)-4,4-dimethyl-1-oxaspiro[2.4]hept-5-ene, used directly for the next step, is obtained.
Reaction SMILES: C(OC([N:8]([CH2:21][CH:22]1[CH2:27][CH2:26][N:25]([C:28]2[CH:29]=[C:30]([CH:34]=[CH:35][CH:36]=2)[C:31]([OH:33])=[O:32])[CH2:24][CH:23]1[C:37]1[CH:42]=[CH:41][CH:40]=[CH:39][C:38]=1[F:43])[C@@H:9]([C:11]1[C:20]2[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=2)[CH:14]=[CH:13][CH:12]=1)[CH3:10])=O)(C)(C)C.[ClH:44].C(OCC)(=O)C>C(OCC)(=O)C>[ClH:44].[F:43][C:38]1[CH:39]=[CH:40][CH:41]=[CH:42][C:37]=1[CH:23]1[CH:22]([CH2:21][NH:8][C@@H:9]([C:11]2[C:20]3[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=3)[CH:14]=[CH:13][CH:12]=2)[CH3:10])[CH2:27][CH2:26][N:25]([C:28]2[CH:29]=[C:30]([CH:34]=[CH:35][CH:36]=2)[C:31]([OH:33])=[O:32])[CH2:24]1
Reactant: C[C@H](c1cccc2ccccc12)N(CC1CCN(c2cccc(C(=O)O)c2)CC1c1ccccc1F)C(=O)OC(C)(C)C
Agent: Cl
Solvent: CCOC(C)=O
Product: C[C@@H](NCC1CCN(c2cccc(C(=O)O)c2)CC1c1ccccc1F)c1cccc2ccccc12
Reaction time: 1 h

Procedure:
To a solution of 161 mg of the crude 3-[4-({(tert-butoxycarbonyl)[(1R)-1-(1-naphthyl)ethyl]amino}methyl)-3-(2-fluorophenyl)piperidin-1-yl]benzoic acid in 2.0 mL of ethyl acetate was added 1.00 mL of a 4 M hydrogen chloride/ethyl acetate solution at room temperature, followed by stirring for 1 hour. The solvent was removed by distillation under reduced pressure. The residue was purified by reverse phase silica gel column chromatography (acetonitrile-0.001 M hydrochloric acid) to obtain 58 mg of 3-[3-(2-fluorophenyl)-4-({[(1R)-1-(1-naphthyl)ethyl]amino}methyl)piperidin-1-yl]benzoic acid hydrochloride as a white solid.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([NH:9][C:10]2[CH:19]=[C:13]3CN(C)[CH2:16][CH2:17][N:12]3[N:11]=2)[C:5](=[O:8])[NH:6][N:7]=1.[CH2:20](N1C=CC(N)=N1)C.BrC1C(=O)NN=C(Cl)C=1>>[Cl:1][C:2]1[CH:3]=[C:4]([NH:9][C:10]2[CH:19]=[CH:13][N:12]([CH2:17][CH3:16])[N:11]=2)[C:5](=[O:8])[N:6]([CH3:20])[N:7]=1
Reactant: CCn1ccc(N)n1
Reactant: CN1CCn2nc(Nc3cc(Cl)n[nH]c3=O)cc2C1
Agent: O=c1[nH]nc(Cl)cc1Br
Product: CCn1ccc(Nc2cc(Cl)nn(C)c2=O)n1
Yield: 94 %

Procedure:
Using the same general procedure as described for the preparation of 101m, reaction of 1-ethyl-3-amino-1H-pyrazole (500 mg, 4.50 mmol) with 4-bromo-6-chloropyridazin-3(2H)-one (1.00 g, 4.50 mmol) afforded 102g in 94% yield (1.07 g) as an amorphous yellow solid: mp 173-175° C.; 1H NMR (300 MHz, DMSO-d6) δ 9.61 (s, 1H), 7.71 (s, 1H), 7.64 (d, J=2.4 Hz, 1H), 6.19 (d, J=2.4 Hz, 1H), 4.10 (q, J=7.2 Hz, 2H), 3.65 (s, 3H), 1.37 (t, J=7.2 Hz, 3H); MS (ESI+) m/z 254.0 (M+H).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([F:8])[C:3]=1[O:9][C:10]1[CH:15]=[CH:14][C:13]([N+:16]([O-])=O)=[CH:12][CH:11]=1.O.NN>CO.[Ni]>[F:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([F:8])[C:3]=1[O:9][C:10]1[CH:11]=[CH:12][C:13]([NH2:16])=[CH:14][CH:15]=1
Reactant: O=[N+]([O-])c1ccc(Oc2c(F)cccc2F)cc1
Agent: [Ni]
Agent: NN
Solvent: O
Solvent: CO
Product: Nc1ccc(Oc2c(F)cccc2F)cc1
Reaction time: 0.25 h
Yield: 90.8 %

Procedure:
Into a 500 mL, 3-necked round-bottom flask purged and maintained under an inert atmosphere of nitrogen, was placed a solution of 1,3-difluoro-2-(4-nitrophenoxy)benzene (20 g, 79.62 mmol, 1.00 equiv) in methanol (200 mL), Raney Nickel (2 g). A solution of hydrazine hydrate (12.67 g) in methanol (50 mL) was added dropwise with stirring in 15 min. The resulting solution was stirred for 12 h at 25° C., then filtrated and the filtrate was concentrated under vacuum. The residue was diluted with f ethyl acetate, washed with water and brine, and dried over anhydrous sodium sulfate and concentrated under vacuum to give 16 g (91%) of 4-(2,6-difluorophenoxy)aniline as black oil.
Reaction SMILES: C(=O)([O-])O[CH2:3][CH:4]=[CH:5][C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1.[Br:14][C:15]1[CH:21]=[CH:20][CH:19]=[CH:18][C:16]=1[NH2:17]>>[C:4]([CH:5]([C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1)[NH:17][C:16]1[CH:18]=[CH:19][CH:20]=[CH:21][C:15]=1[Br:14])#[CH:3]
Reactant: Nc1ccccc1Br
Reactant: O=C([O-])OCC=Cc1ccccc1
Product: C#CC(Nc1ccccc1Br)c1ccccc1
Reaction time: 16 h
Yield: 66 %

Procedure:
The general procedure was followed with cinnamyl carbonate (0.188 g, 0.979 mmol) and o-bromoaniline (0.215 g, 1.25 mmol). The reaction was conducted at room temperature for 16 h. 1H NMR analysis of the crude reaction mixture indicated the ratio of regioisomers to be 93/7. The mixture was purified by flash column chromatography on silica gel (1.5% ethyl acetate in hexanes) to give the title compound (0.185 g, 66%). HPLC analysis indicated the enantiomeric excess of the product was 94% [Diacel CHIRALCEL OD-H (0.46 cm×25 cm); hexane/2-propanol=99.75/0.25; flow rate=0.6 mL/1 min; detection wavelength=254 nm; TR=14.8 (minor), 23.9 (major) min]: [α]DRT=(c, CHCl3). 1H NMR (400.13 MHz, CDCl3) δ 7.46-7.25 (m, 6H), 7.07 (td, J=7.6, 0.8 Hz, 1H), 6.55 (t, J=7.6 Hz, 2 H), 6.07 (ddd, J=16.8, 10.4, 6.0 Hz, 1H), 5.27 (d, J=10.0 Hz, 1H), 5.24 (t, J=1.2 Hz, 1H), 4.98 (t, J=5.6 Hz, 1H), 4.75 (d, J=5.2 Hz, 1H). 13C NMR (100.59 MHz, CDCl3) δ 143.82, 141.13, 138.58, 132.26, 128.79, 128.26, 127.54, 126.94, 118.05, 116.25, 112.71, 109.91, 60.53. Anal. Calcd for C15H14NBr: C, 62.52; H, 4.90; N, 4.86; Br, 27.73. Found: C, 62.77; H, 4.92; N, 4.87; Br, 27.46.
Reaction SMILES: [CH:1]1([CH:6]([NH:17][C:18]2[CH:26]=[CH:25][C:21]([C:22](O)=[O:23])=[CH:20][CH:19]=2)[C:7]2[S:8][C:9]3[CH:16]=[CH:15][CH:14]=[CH:13][C:10]=3[C:11]=2[CH3:12])[CH2:5][CH2:4][CH2:3][CH2:2]1.[CH3:27][NH:28][CH2:29][CH2:30][C:31]([O:33][CH2:34][CH3:35])=[O:32].O.ON1C2C=CC=CC=2N=N1.Cl.C(N=C=NCCCN(C)C)C.[Cl-].[NH4+]>CN(C)C=O.C(N(CC)CC)C>[CH:1]1([CH:6]([NH:17][C:18]2[CH:26]=[CH:25][C:21]([C:22]([N:28]([CH3:27])[CH2:29][CH2:30][C:31]([O:33][CH2:34][CH3:35])=[O:32])=[O:23])=[CH:20][CH:19]=2)[C:7]2[S:8][C:9]3[CH:16]=[CH:15][CH:14]=[CH:13][C:10]=3[C:11]=2[CH3:12])[CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: CCOC(=O)CCNC
Reactant: Cc1c(C(Nc2ccc(C(=O)O)cc2)C2CCCC2)sc2ccccc12
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CCN(CC)CC
Solvent: O
Solvent: CN(C)C=O
Product: CCOC(=O)CCN(C)C(=O)c1ccc(NC(c2sc3ccccc3c2C)C2CCCC2)cc1
Temperature: 25 °C
Reaction time: 5 h
Yield: 58 %

Procedure:
To a mixture of 4-{[cyclopentyl(3-methyl-1-benzothiophen-2-yl)methyl]amino}benzoic acid (300 mg) synthesized in Example A63(3), ethyl 3-(methylamino)propanoate (161 mg), 1-hydroxybenzotriazole monohydrate (188 mg), triethylamine (343 μL) and N,N-dimethylformamide (10 mL) was added 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (236 mg), and the mixture was stirred at room temperature for 5 hr. Saturated aqueous ammonium chloride solution was added to quench the reaction, and the reaction mixture was extracted with ethyl acetate. The extract was washed with saturated aqueous sodium hydrogen carbonate solution and saturated brine, dried over magnesium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (30-70% ethyl acetate/hexane) to give the title object compound (228 mg, 58%) as a pale-brown oil.
Reaction SMILES: C(OC([N:11]1[CH2:20][CH2:19][C:18]2[C:13](=[CH:14][C:15]([O:21][C:22]3[CH:27]=[CH:26][C:25]([C:28](=[O:32])[N:29]([CH3:31])[CH3:30])=[CH:24][CH:23]=3)=[CH:16][CH:17]=2)[CH2:12]1)=O)C1C=CC=CC=1.C(O)C>[Pd].[H][H]>[CH3:30][N:29]([CH3:31])[C:28](=[O:32])[C:25]1[CH:24]=[CH:23][C:22]([O:21][C:15]2[CH:14]=[C:13]3[C:18]([CH2:19][CH2:20][NH:11][CH2:12]3)=[CH:17][CH:16]=2)=[CH:27][CH:26]=1
Reactant: [H][H]
Reactant: CN(C)C(=O)c1ccc(Oc2ccc3c(c2)CN(C(=O)OCc2ccccc2)CC3)cc1
Agent: [Pd]
Solvent: CCO
Product: CN(C)C(=O)c1ccc(Oc2ccc3c(c2)CNCC3)cc1

Procedure:
A mixture of 10% palladium on carbon (1.50 g), 7-(4-dimethylcarbamoyl-phenoxy)-3,4-dihydro-1H-isoquinoline-2-carboxylic acid benzyl ester (2 mL), and ethanol (200 mL) is shaken in hydrogen atmosphere (3 bar) at room temperature for 2 h. Then the catalyst is separated by filtration and the filtrate is concentrated. The residue is purified by chromatography on silica gel (methanol/methanol containing 1% ammionia 1:0→0:1) to furnish the title compound that is precipitated from dioxane with 6 M HCl in dioxane.
Reaction SMILES: [CH:1]1([C:4]2[C:5]([N:13]3[CH2:18][CH2:17][N:16]([C:19]([C:21]4[CH:26]=[CH:25][C:24](I)=[CH:23][CH:22]=4)=[O:20])[CH2:15][CH2:14]3)=[N:6][CH:7]=[C:8]([CH:10]3[CH2:12][CH2:11]3)[CH:9]=2)[CH2:3][CH2:2]1.[CH3:28][C@@H:29]1[O:33][C:32](=[O:34])[NH:31][CH2:30]1>>[CH:1]1([C:4]2[C:5]([N:13]3[CH2:18][CH2:17][N:16]([C:19]([C:21]4[CH:26]=[CH:25][C:24]([N:31]5[CH2:30][C@H:29]([CH3:28])[O:33][C:32]5=[O:34])=[CH:23][CH:22]=4)=[O:20])[CH2:15][CH2:14]3)=[N:6][CH:7]=[C:8]([CH:10]3[CH2:12][CH2:11]3)[CH:9]=2)[CH2:3][CH2:2]1
Reactant: C[C@H]1CNC(=O)O1
Reactant: O=C(c1ccc(I)cc1)N1CCN(c2ncc(C3CC3)cc2C2CC2)CC1
Product: C[C@H]1CN(c2ccc(C(=O)N3CCN(c4ncc(C5CC5)cc4C4CC4)CC3)cc2)C(=O)O1
Yield: 76.9 %

Procedure:
By reaction and treatment in the same manner as in Example 149 and using [4-(3,5-dicyclopropylpyridin-2-yl)piperazin-1-yl](4-iodophenyl)methanone (473 mg) described in Preparation Example 95 and (S)-5-methyloxazolidin-2-one (121 mg) described in Preparation Example 42, the title compound (343 mg) was obtained.
Reaction SMILES: [CH3:1][S:2][C:3](SC)=[N:4][C:5]#[N:6].[CH2:9]([NH2:13])[C:10]#[C:11][CH3:12]>C(#N)C>[C:5]([NH:4][C:3](=[N:13][CH2:9][C:10]#[C:11][CH3:12])[S:2][CH3:1])#[N:6]
Reactant: CC#CCN
Reactant: CSC(=NC#N)SC
Solvent: CC#N
Product: CC#CCN=C(NC#N)SC

Procedure:
A solution of dimethyl cyanodithioiminocarbonate (10.00 g, 0.0684 mole) and 2-butyn-1-amine (4.73 g, 0.0684 mole) in acetonitrile (200 ml) was stirred at 25° for 0.5 hour, and then at reflux for 2.5 hours. The mixture was cooled, then filtered to yield the title compound, mp 180°-183°.
Reaction SMILES: CS(Cl)(=O)=O.[F:6][C:7]1[CH:8]=[C:9]([NH:14][CH2:15][C:16]([NH:18][C:19]2[CH:24]=[CH:23][CH:22]=[C:21]([CH2:25]O)[C:20]=2[CH3:27])=[O:17])[CH:10]=[CH:11][C:12]=1[F:13].C(N(CC)C(C)C)(C)C.[C:37]([N:40]1[CH2:45][CH2:44][NH:43][CH2:42][CH2:41]1)(=[O:39])[CH3:38]>O1CCCC1>[C:37]([N:40]1[CH2:45][CH2:44][N:43]([CH2:25][C:21]2[C:20]([CH3:27])=[C:19]([NH:18][C:16](=[O:17])[CH2:15][NH:14][C:9]3[CH:10]=[CH:11][C:12]([F:13])=[C:7]([F:6])[CH:8]=3)[CH:24]=[CH:23][CH:22]=2)[CH2:42][CH2:41]1)(=[O:39])[CH3:38]
Reactant: Cc1c(CO)cccc1NC(=O)CNc1ccc(F)c(F)c1
Reactant: CC(=O)N1CCNCC1
Agent: CS(=O)(=O)Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: C1CCOC1
Product: CC(=O)N1CCN(Cc2cccc(NC(=O)CNc3ccc(F)c(F)c3)c2C)CC1
Temperature: 25 °C
Reaction time: 1.5 h

Procedure:
Methane sulphonyl chloride (0.06ml) was added to a solution of the product of step (d) (0.12 g) and N,N-diisopropylethylamine (0.28 ml) in tetrahydrofuran (3ml). The reaction mixture was stirred at room temperature for 1.5 hours. A solution of 1-acetylpiperazine (0. 15 g) in tetrahydrofuran (1 ml) was added and the mixture was heated at reflux for 2 hours. The reaction mixture was partitioned between ethyl acetate and water and the organic phase was washed with water and brine, dried (MgSO4) and evaporated. The crude product was triturated with ethyl acetate/isohexane to give the product as a pale yellow solid.
Reaction SMILES: [C:1]([C:5]1[CH:41]=[CH:40][C:8]([C:9]([NH:11][C:12]2[CH:39]=[CH:38][CH:37]=[CH:36][C:13]=2[C:14]([NH:16][C:17]2[CH:18]=[CH:19][C:20]3[N:24]=[CH:23][N:22](S(C4C=CC(C)=CC=4)(=O)=O)[C:21]=3[CH:35]=2)=[O:15])=[O:10])=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2].[N+](C1C=CC=CC=1C(NC1C=CC2N=CN(S(C3C=CC(C)=CC=3)(=O)=O)C=2C=1)=O)([O-])=O.C(C1C=CC(C(Cl)=O)=CC=1)(C)(C)C.O[Li].O>O1CCOCC1.O>[N:22]1[C:21]2[CH:35]=[C:17]([NH:16][C:14](=[O:15])[C:13]3[CH:36]=[CH:37][CH:38]=[CH:39][C:12]=3[NH:11][C:9](=[O:10])[C:8]3[CH:7]=[CH:6][C:5]([C:1]([CH3:2])([CH3:4])[CH3:3])=[CH:41][CH:40]=3)[CH:18]=[CH:19][C:20]=2[NH:24][CH:23]=1
Reactant: Cc1ccc(S(=O)(=O)n2cnc3ccc(NC(=O)c4ccccc4NC(=O)c4ccc(C(C)(C)C)cc4)cc32)cc1
Agent: CC(C)(C)c1ccc(C(=O)Cl)cc1
Agent: Cc1ccc(S(=O)(=O)n2cnc3ccc(NC(=O)c4ccccc4[N+](=O)[O-])cc32)cc1
Agent: [Li]O
Solvent: C1COCCO1
Solvent: O
Product: CC(C)(C)c1ccc(C(=O)Nc2ccccc2C(=O)Nc2ccc3[nH]cnc3c2)cc1
Reaction time: 16 h

Procedure:
By methods substantially equivalent to those described in Examples 1-B and 1-C, 3.7 g (6.5 mmol) of crude 2-[(4-t-butylbenzoyl)amino]-N-(1-tosylbenzimidazol-6-yl)benzamide was prepared from 2-nitro-N-(1-tosylbenzimidazol-6-yl)benzamide and 4-t-butylbenzoyl chloride. This material was dissolved in p-dioxane (50 mL) and a solution of LiOH.H2O (0.48 g, 11 mmol) in water (25 mL) was added with vigorous stirring. After 16 h, the solvents were removed in vacuo and the residue was partitioned between chloroform and satd aq NaHCO3. The phases were separated and the organic phase was washed with water, followed by brine, then dried over MgSO4, filtered and concentrated in vacuo. The residue was triturated with ether, filtered and the solid was dissolved in a minimal amount of chloroform and chromatographed over a silica gel column with 10% methanol/chloroform. The product containing fractions were combined and concentrated in vacuo to give 0.97 g (36% overall) of off-white solid.
Reaction SMILES: [CH3:1][C@H:2]1[N:7]([CH3:8])[CH2:6][CH:5]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[N:4]([CH2:15][C:16]([O:18]C)=[O:17])[C:3]1=[O:20].[Li+:21].[OH-].Cl>C1COCC1>[CH3:1][C@H:2]1[N:7]([CH3:8])[CH2:6][CH:5]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[N:4]([CH2:15][C:16]([O-:18])=[O:17])[C:3]1=[O:20].[Li+:21]
Reactant: COC(=O)CN1C(=O)[C@@H](C)N(C)CC1c1ccccc1
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Product: C[C@@H]1C(=O)N(CC(=O)[O-])C(c2ccccc2)CN1C
Temperature: 25 °C
Reaction time: 4 h

Procedure:
A solution of methyl [(3R)-3,4-dimethyl-2-oxo-6-phenylpiperazin-1-yl]acetate from Step B (50 mg, 0.18 mmol) in THF (1 mL) was added 1 N aqueous LiOH (0.20 mL, 0.20 mmol) and the resulting mixture was stirred at ambient temperature for 4 h. The mixture was adjusted to pH 6 by addition of 1 N HCl and concentrated to dryness in vacuo to give the title compound. MS: m/z=263 (M+1).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:20])[C:4]1[CH:9]=[CH:8][C:7](Cl)=[N:6][C:5]=1[NH:11][C:12]1[CH:17]=[CH:16][C:15]([Br:18])=[CH:14][C:13]=1[F:19].[CH3:21][O-:22].[Na+].CO>C(O)(=O)C>[CH3:1][O:2][C:3](=[O:20])[C:4]1[CH:9]=[CH:8][C:7]([O:22][CH3:21])=[N:6][C:5]=1[NH:11][C:12]1[CH:17]=[CH:16][C:15]([Br:18])=[CH:14][C:13]=1[F:19]
Reactant: COC(=O)c1ccc(Cl)nc1Nc1ccc(Br)cc1F
Reactant: C[O-]
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CO
Product: COC(=O)c1ccc(OC)nc1Nc1ccc(Br)cc1F
Temperature: 62.5 °C
Reaction time: 16 h
Yield: 88.1 %

Procedure:
To a mixture of 2-(4-bromo-2-fluorophenylamino)-6-chloro-nicotinic acid methyl ester (2.00 g, 5.56 mmol) and sodium methoxide (0.791 g, 13.9 mmol) was added MeOH (50 mL) to give a slurry that was stirred at 60-65° C. for 16 hours under N2. Additional sodium methoxide (0.791 g, 13.9 mmol) was added and the reaction mixture was allowed to stir another 3 days at 60-65° C. The reaction mixture was cooled to room temperature and glacial acetic acid was added dropwise until the pH was 7. The resulting suspension was filtered and washed with H2O to yield a pink solid that was collected and dried under vacuum to yield 1.74 g (88%) pure desired product.
Reaction SMILES: [CH2:1]([CH2:3][NH2:4])[OH:2].COC1C=CC(O)=CC=1.[C:14](Cl)(=[O:18])[C:15]([CH3:17])=[CH2:16]>C(#N)C>[OH:2][CH2:1][CH2:3][NH:4][C:14](=[O:18])[C:15]([CH3:17])=[CH2:16]
Reactant: NCCO
Reactant: C=C(C)C(=O)Cl
Agent: COc1ccc(O)cc1
Solvent: CC#N
Product: C=C(C)C(=O)NCCO
Reaction time: 1 h

Procedure:
To a 500 mL, four-neck round bottom flask equipped with a mechanical stirrer, a thermometer, a 200 mL dropping funnel, and a nitrogen inlet/outlet, 48.8 g of ethanolamine (0.8 moles), 80 mg of 4-methoxyphenol and 100 mL of acetonitrile were added. The mixture was cooled below 0° C. with an ice/water bath. To this solution, 41.8 g of freshly distilled methacryloyl chloride (0.4 mole) in 100 mL of acetonitrile was added through the dropping funnel. The addition rate was controlled so that the reaction temperature was kept below 0° C. At the end of addition, the pH of the reaction mixture was adjusted to 7 with either methacryloyl chloride or ethanolamine solution. While keeping the reaction solution cold (below 5° C.), the ethanol-amine HCl salts were filtered out. To the filtrate, 200 mL of deionized water and 40 g of Dowex MR-3C resin, which was pre-washed with two bed volumes of 1/1 ratio acetonitrile/water mixture for three times, were added. The resin was removed by filtration after agitating for one hour. The filtrate was concentrated to about 160 g by vacuum distillation. The final solution has the following properties: HPLC and FT-1R analysis indicates there is no ester formation; HEMAA concentration: 23.5% (wt/wt); pH=6.9 at 25° C; Conductivity=3.9 μS/cm at 25° C.; Viscosity=1.9 cPs at 25° C. The yield of HEMAA was about 73%.