Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]1=[S:7].Br[C:9]1[CH:10]=[C:11]([O:17][C:18]2[C:19]([CH3:25])=[N:20][CH:21]=[CH:22][C:23]=2[CH3:24])[C:12]([C:15]#[N:16])=[N:13][CH:14]=1.CN(C=O)C.[H-].[Na+]>O>[CH3:25][C:19]1[C:18]([O:17][C:11]2[C:12]([C:15]#[N:16])=[N:13][CH:14]=[C:9]([S:7][C:2]3[CH:3]=[CH:4][CH:5]=[CH:6][N:1]=3)[CH:10]=2)=[C:23]([CH3:24])[CH:22]=[CH:21][N:20]=1
Reactant: S=c1cccc[nH]1
Reactant: Cc1ccnc(C)c1Oc1cc(Br)cnc1C#N
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: Cc1ccnc(C)c1Oc1cc(Sc2ccccn2)cnc1C#N
Temperature: 0 °C
Reaction time: 8 h
Yield: 92.2 %

Procedure:
Pyridine-2(1H)-thione (0.768 g, 6.90 mmol) and 5-bromo-3-(2,4-dimethylpyridin-3-yloxy)picolinonitrile (2.00 g, 6.58 mmol) were added to DMF (12 mL) and cooled to 0° C. 95% Sodium hydride (0.174 g, 6.90 mmol) was slowly added and the reaction was warmed to ambient temperature and stirred overnight. The reaction mixture was poured into water (100 mL) and stirred for 30 minutes. A cloudy milky solution that was not filterable resulted. The reaction was extracted twice with ethyl acetate. The combined organic layers were washed twice with water and brine, dried, and concentrated. The residue was purified over silica gel (2:3 to 0:1 hexane:ethyl acetate) to afford 3-(2,4-dimethylpyridin-3-yloxy)-5-(pyridin-2-ylthio)picolinonitrile (2.03 g, 6.07 mmol, 92.3% yield) as a white powder.
Reaction SMILES: [OH:1][C:2]1([C:9]([F:12])([F:11])[F:10])[CH2:7][CH2:6][C:5](=O)[CH2:4][CH2:3]1.[CH:13]1([NH2:16])[CH2:15][CH2:14]1.[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+].C(O)(=O)C.[OH-].[Na+]>ClCCCl>[CH:13]1([NH:16][CH:5]2[CH2:6][CH2:7][C:2]([C:9]([F:12])([F:11])[F:10])([OH:1])[CH2:3][CH2:4]2)[CH2:15][CH2:14]1
Reactant: O=C1CCC(O)(C(F)(F)F)CC1
Reactant: NC1CC1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Agent: [OH-]
Solvent: CC(=O)O
Solvent: ClCCCl
Product: OC1(C(F)(F)F)CCC(NC2CC2)CC1
Temperature: 25 °C
Reaction time: 13 h
Yield: 93 %

Procedure:
4-hydroxy-4-(trifluoromethyl)cyclohexanone (570 mg, 3.13 mmol) was dissolved in 1,2-dichloroethane (20 ml), followed by sequential addition of cyclopropylamine (0.24 ml, 3.44 mmol), NaBH(OAc)3 (1.06 g, 5.01 mmol), and acetic acid (0.18 ml, 3.13 mmol), and then the resulting mixture was stirred at room temperature under nitrogen stream for 13 hours. The resulting reaction liquid was neutralized by addition of 10% aqueous NaOH solution, and extracted with 5% MeOH/MC (20 ml×3). The organic layer was dried over anhydrous sodium sulfate, followed by filtration, concentration, and vacuum drying, to obtain 650 mg of yellow solid (93%).
Reaction SMILES: [NH:1]1[C:7]2[CH:8]=[CH:9][CH:10]=[CH:11][C:6]=2[CH2:5][CH2:4][CH2:3][CH2:2]1.C(N(CC)CC)C.[N+:19]([C:22]1[CH:30]=[CH:29][C:25]([C:26](Cl)=[O:27])=[CH:24][CH:23]=1)([O-:21])=[O:20]>ClCCl>[N+:19]([C:22]1[CH:23]=[CH:24][C:25]([C:26]([N:1]2[C:7]3[CH:8]=[CH:9][CH:10]=[CH:11][C:6]=3[CH2:5][CH2:4][CH2:3][CH2:2]2)=[O:27])=[CH:29][CH:30]=1)([O-:21])=[O:20]
Reactant: c1ccc2c(c1)CCCCN2
Reactant: O=C(Cl)c1ccc([N+](=O)[O-])cc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: O=C(c1ccc([N+](=O)[O-])cc1)N1CCCCc2ccccc21
Temperature: 0 °C
Reaction time: 1.5 h
Yield: 77 %

Procedure:
To a solution of 5.0 g of 1,2,3,4-tetrahydro-5H-1-benzazepine and 5.91 ml of triethylamine in 50 ml of dichloromethane, chilled in an ice bath, is added, dropwise, 6.32 g of 4-nitrobenzoyl chloride in 75 ml of dichloromethane. The mixture is stirred at 0° C. for 1.5 hr and then at room temperature for 18 hours. The mixture is washed with H2O, 2M HCl, 1M NaOH and dried (Na2SO4). The solvent is removed and the residue re-crystallized from ethanol with the aid of activated carbon to give 7.75 g of light yellow crystals, m.p. 148.5°-150.5° C.
Reaction SMILES: [CH3:1][C:2]([C:4]1[CH:12]=[CH:11][C:9]([OH:10])=[C:6]([O:7][CH3:8])[CH:5]=1)=[O:3].N1C=CC=CC=1.[C:19](O)(=[O:21])[CH3:20]>C1COCC1>[C:19]([O:10][C:9]1[CH:11]=[CH:12][C:4]([C:2](=[O:3])[CH3:1])=[CH:5][C:6]=1[O:7][CH3:8])(=[O:21])[CH3:20]
Reactant: CC(=O)O
Reactant: COc1cc(C(C)=O)ccc1O
Solvent: c1ccncc1
Solvent: C1CCOC1
Product: COc1cc(C(C)=O)ccc1OC(C)=O
Temperature: 25 °C
Reaction time: 3 h

Procedure:
As shown in the above-described reaction formula, acetovanillone (500 mg, 3 mM) dissolved in 20 ml of THF was mixed with 0.5 ml of pyridine and 0.6 ml of anhydrous acetic acid. The mixture was stirred for 3 hours at room temperature. The resulting product was recovered with the extraction with diethylether and dried with anhydrous magnesium sulfate to remove remaining solvent. The remaining residue was performed to Silica gel column chromatography with a mobile phase (n-hexane:ethylacetate=4:1) to obtain white solid type of 4-acetyl-2-methoxyphenyl acetate (1; 625 mg).
Reaction SMILES: [CH2:1]([C@H:8]([CH2:19][C:20]([CH2:22]Cl)=[O:21])[C:9]([O:11][CH2:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Na+].[I-].[NH:26]1[CH2:31][CH2:30][O:29][CH2:28][CH2:27]1>CN(C)C=O.C(OCC)(=O)C>[CH2:1]([C@H:8]([CH2:19][C:20](=[O:21])[CH2:22][N:26]1[CH2:31][CH2:30][O:29][CH2:28][CH2:27]1)[C:9]([O:11][CH2:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C(CCl)C[C@@H](Cc1ccccc1)C(=O)OCc1ccccc1
Reactant: C1COCCN1
Agent: [I-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: O=C(C[C@@H](Cc1ccccc1)C(=O)OCc1ccccc1)CN1CCOCC1
Yield: 65.5 %

Procedure:
The resultant compound from Example 34 (610 mg, 1.84 mmol) in dimethylformamide (10 ml) was treated with NaI (33 mg, 0.22 mmol) and morpholine (0.60 ml, 6.88 mmol). After 2 h the mixture was diluted with ethyl acetate, washed with water and brine, and then dried over Na2SO4, and evaporated. Chromatography of the residue on silica gel with 60% ethyl acetate/40% hexane afforded 460 mg (65%) of an oil. 1H NMR (CDCl3) δ7.05-7.40 (m,10H), 5.11 (d,1H), 5.06 (d,1H), 3.68 (m,4H), 3.22-3.32 m,1H), 3.15 (d,1H), 3.08 (d,1H), 3.05 (m,1H), 2.87 (dd,1H), 2.77 (dd,1H), 2.35-2.50 (m,5H).
Reaction SMILES: [CH3:1][S:2][C:3]1[N:8]=[CH:7][N:6]=[C:5]([O:9][C:10]2[CH:15]=[CH:14][C:13]([NH2:16])=[CH:12][CH:11]=2)[CH:4]=1.[Cl:17][C:18]1[CH:23]=[CH:22][C:21]([N:24]=[C:25]=[O:26])=[CH:20][C:19]=1[C:27]([F:30])([F:29])[F:28]>C1COCC1>[Cl:17][C:18]1[CH:23]=[CH:22][C:21]([NH:24][C:25]([NH:16][C:13]2[CH:14]=[CH:15][C:10]([O:9][C:5]3[CH:4]=[C:3]([S:2][CH3:1])[N:8]=[CH:7][N:6]=3)=[CH:11][CH:12]=2)=[O:26])=[CH:20][C:19]=1[C:27]([F:28])([F:29])[F:30]
Reactant: O=C=Nc1ccc(Cl)c(C(F)(F)F)c1
Reactant: CSc1cc(Oc2ccc(N)cc2)ncn1
Solvent: C1CCOC1
Product: CSc1cc(Oc2ccc(NC(=O)Nc3ccc(Cl)c(C(F)(F)F)c3)cc2)ncn1
Reaction time: 8 h
Yield: 71.2 %

Procedure:
A solution of 4-(6-methylsulfanyl-pyrimidin-4-yloxy)-phenylamine (1.3 g, 5.5 mmol) in THF (24 ml) is cooled to 0° C. A solution of 4-chloro-3-(trifluoromethyl)phenyl isocyanate (1.22 g, 5.5 mmol) in THF (24 ml) is added dropwise and stirring is continued overnight at r.t. The solvent is evaporated and the crude product is purified by silica gel chromatography using an ethyl acetate/heptane eluent (1:1) to give 1.78 g (70%) of a white solid.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([F:11])([F:10])[F:9])=[CH:4][CH:3]=1.C(N(CC)CC)C.[CH3:19][C:20]([CH3:25])([CH3:24])[C:21](Cl)=[O:22]>ClCCl>[F:11][C:8]([F:9])([F:10])[C:5]1[CH:6]=[CH:7][C:2]([NH:1][C:21](=[O:22])[C:20]([CH3:25])([CH3:24])[CH3:19])=[CH:3][CH:4]=1
Reactant: CC(C)(C)C(=O)Cl
Reactant: Nc1ccc(C(F)(F)F)cc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(C)(C)C(=O)Nc1ccc(C(F)(F)F)cc1
Temperature: 25 °C
Yield: 98.4 %

Procedure:
A solution of dichloromethane (200 mL), 4-aminobenzotrifluoride (32.0 g, 199 mmol) and triethylamine (40 g, 396 mmol) was cooled to 0° C. under a dry nitrogen atmosphere. Trimethylacetyl chloride (32.9 g, 273 mmol) was added drop-wise over 2 hours, maintaining the temperature below 10° C. After the addition, the contents were allowed to warm to room temperature for 2 hours. The reaction was washed with water (2×200 mL), saturated ammonium chloride solution (2×200 mL), dried over sodium sulfate and filtered. The solvent was removed in vacuo to afford a white solid, N-(4-trifluoromethylphenyl)-2,2-dimethylpropanamide (48.0 g, 98%): mp 157-159° C. 1H NMR (CDCl3/300 MHz) 7.61 (ab, 4H, J=8.7, Δν=28.6 Hz), 7.47 (br s, 1H), 1.33 (s, 9H). ESHRMS m/z 246.1123 (M+H+, Calc'd 246.1106). Anal. Calc'd for C12H14F3NO: C, 58.77; H, 5.75; N, 5.71. Found: C, 58.28; H, 5.79; N, 5.65.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[S:10][CH:11]=[C:12]([CH2:14]O)[N:13]=2)=[CH:5][CH:4]=1.P(Br)(Br)[Br:17].O>C1(C)C=CC=CC=1>[Br:17][CH2:14][C:12]1[N:13]=[C:9]([C:6]2[CH:7]=[CH:8][C:3]([O:2][CH3:1])=[CH:4][CH:5]=2)[S:10][CH:11]=1
Reactant: COc1ccc(-c2nc(CO)cs2)cc1
Reactant: BrP(Br)Br
Solvent: Cc1ccccc1
Solvent: O
Product: COc1ccc(-c2nc(CBr)cs2)cc1
Temperature: 120 °C
Yield: 91.5 %

Procedure:
To a solution of [2-(4-Methoxy-phenyl)-thiazol-4-yl]-methanol (0.12 g, 0.50 mmol) in 3 ml of toluene was added PBr3 (0.078 ml, 0.813 mmol) and the reaction mixture was heated at 120° C. for 20 min under nitrogen atmosphere. After the completion of the reaction mixture (TLC monitoring), water (25 mL) was added and extracted with ethyl acetate (3×50 mL). The combined organics was washed with water, brine, dried (Na2SO4), filtered and concentrated to get the desired product (0.13 g, 84%).
Reaction SMILES: C(O[C:6]([NH:8][C@@H:9]([CH2:24][CH:25]1[CH2:30][CH2:29][CH2:28][CH2:27][CH2:26]1)[C@@H:10]([OH:23])[CH2:11][C@@H:12]([CH3:22])[C:13]([NH:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH3:21])=[O:14])=[O:7])(C)(C)C.Cl.[C:32]([O:36][C:37]([NH:39][C@H:40](C(O)=O)[CH2:41][C:42]1[N:43]=[CH:44][S:45][CH:46]=1)=[O:38])([CH3:35])([CH3:34])[CH3:33].C(P(=O)(OCC)OCC)#N.C(N(CC)CC)C>O1CCOCC1>[C:32]([O:36][C:37]([NH:39][C@H:40]([C:6]([NH:8][C@@H:9]([CH2:24][CH:25]1[CH2:26][CH2:27][CH2:28][CH2:29][CH2:30]1)[C@@H:10]([OH:23])[CH2:11][C@@H:12]([CH3:22])[C:13]([NH:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH3:21])=[O:14])=[O:7])[CH2:41][C:42]1[N:43]=[CH:44][S:45][CH:46]=1)=[O:38])([CH3:35])([CH3:33])[CH3:34]
Reactant: CC(C)(C)OC(=O)N[C@@H](Cc1cscn1)C(=O)O
Reactant: CCCCCCNC(=O)[C@H](C)C[C@H](O)[C@H](CC1CCCCC1)NC(=O)OC(C)(C)C
Agent: CCOP(=O)(C#N)OCC
Agent: Cl
Solvent: CCN(CC)CC
Solvent: C1COCCO1
Product: CCCCCCNC(=O)[C@H](C)C[C@H](O)[C@H](CC1CCCCC1)NC(=O)[C@H](Cc1cscn1)NC(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 83.4 %

Procedure:
A mixture of 412 mg (0.96 mmole) of (2R, 4S, 5S)-5-(t-butoxycarbonyl)amino-6-cyclohexyl-N-hexyl-4-hydroxy-2-methylhexanamide (prepared as described in Preparation 7) and 8.0 ml of a 4N solution of hydrogen chloride in dioxane was stirred at room temperature for 30 minutes. At the end of this time, the reaction mixture was freed from the solvent by distillation under reduced pressure, and the residue was mixed with benzene. The solvent was then removed by distillaticn under reduced pressure. This operation was repeated three times in total, and the final residue was dried in vacuo for 8 hours. The dried material was then suspended in 50 ml of anhydrous tetrahydrofuran, and 289 mg (1.06 mmole) of N-(t-butoxycarbonyl)-3-(4-thiazolyl)-L-alanine were added to the resulting suspension. 0.17 ml (1.06 mmole) of 95% diethyl cyanophosphonate and 0.6 ml (4.3 mmole) of triethylamine were then added, in that order, whilst ice-cooling and under an atmosphere of nitrogen, to the resulting mixture, and the mixture was stirred for 15 hours. At the end of this time, the reaction mixture was concentrated by distillation under reduced pressure, after which the residue was mixed with water and the crystals which deposited were collected by filtration. The crystals were then dissolved in methylene chloride and dried over anhydrous magnesium sulfate, after which the solvent was removed by distillation under reduced pressure. The resulting residue was triturated with diisopropyl ether to afford 465 mg of the title compound as a white powder, melting at 156°-158° C.
Reaction SMILES: [CH3:1][O:2][C:3]1([C:8]([OH:10])=O)[CH2:7][CH2:6][CH2:5][CH2:4]1.C1N=C[N:13](C(N2C=NC=C2)=O)C=1.[NH4+].[OH-].O>CCOC(C)=O>[CH3:1][O:2][C:3]1([C:8]([NH2:13])=[O:10])[CH2:7][CH2:6][CH2:5][CH2:4]1
Reactant: O=C(n1ccnc1)n1ccnc1
Reactant: COC1(C(=O)O)CCCC1
Agent: [NH4+]
Agent: [OH-]
Solvent: CCOC(C)=O
Solvent: O
Product: COC1(C(N)=O)CCCC1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 100.7 %

Procedure:
A solution of 1-methoxycyclopentanecarboxylic acid (0.9 g, 6.24 mmol) in EtOAc (30 mL) was treated with CDI (1.316 g, 8.12 mmol), stirred at RT for 0.5 h, treated with NH4OH (˜15M, 0.729 mL, ˜10.9 mmol) and stirred at RT overnight. The mixture was treated with water, extracted with EtOAc (3×) and the combined organics were washed with brine, dried over Na2SO4 and concentrated to dryness to afford 1-methoxycyclopentanecarboxamide (900 mg, 101%). 1H NMR (400 MHz, CDCl3): δ 6.45 (br s, 1H), 5.42 (br s, 1H), 3.24 (s, 3H), 2.07-2.04 (m, 2H), 1.90-1.87 (m, 2H), 1.75-1.73 (m, 4H).
Reaction SMILES: Cl[C:2]1[S:6][C:5]([C:7](=[O:9])[CH3:8])=[CH:4][C:3]=1[N+:10]([O-:12])=[O:11].[F:13][C:14]1[C:19]([F:20])=[C:18]([Cl:21])[C:17]([F:22])=[C:16]([F:23])[C:15]=1[SH:24]>>[Cl:21][C:18]1[C:17]([F:22])=[C:16]([F:23])[C:15]([S:24][C:2]2[S:6][C:5]([C:7](=[O:9])[CH3:8])=[CH:4][C:3]=2[N+:10]([O-:12])=[O:11])=[C:14]([F:13])[C:19]=1[F:20]
Reactant: Fc1c(F)c(Cl)c(F)c(F)c1S
Reactant: CC(=O)c1cc([N+](=O)[O-])c(Cl)s1
Product: CC(=O)c1cc([N+](=O)[O-])c(Sc2c(F)c(F)c(Cl)c(F)c2F)s1
Yield: 58.2 %

Procedure:
Prepared by a similar procedure to that described for example 1 from the 1-(5-chloro-4-nitro-2-thienyl)ethanone (205 mg, 1.0 mmol) and 2,3,5,6-tetrafluoro-4-chloro-benzenethiol (216 mg, 0.98 mmol) to afford the title product as a solid (220 mg, 57% yield). 1H NMR (400 MHz, d6-DMSO) δ: 8.55 (1H, s), 3.37 (3H, s). MS m/z: 384.12, 386.12 [M+H]+.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9]2[C:14]([C:15]([F:18])([F:17])[F:16])=[CH:13][N:12]=[C:11]([NH:19][C:20]3[CH:34]=[CH:33][C:23]([CH2:24][P:25](=[O:32])([O:29][CH2:30][CH3:31])[O:26][CH2:27][CH3:28])=[CH:22][CH:21]=3)[N:10]=2)=[C:4]([C:35](=[O:38])[NH:36][CH3:37])[CH:3]=1.CC1(C)[O:44][C@@H:43]([CH2:45][N:46]2[CH:50]=[C:49](B3OC(C)(C)C(C)(C)O3)[CH:48]=[N:47]2)[CH2:42][O:41]1>>[OH:44][C@H:43]([CH2:42][OH:41])[CH2:45][N:46]1[CH:50]=[C:49]([C:2]2[CH:7]=[CH:6][C:5]([NH:8][C:9]3[C:14]([C:15]([F:16])([F:18])[F:17])=[CH:13][N:12]=[C:11]([NH:19][C:20]4[CH:34]=[CH:33][C:23]([CH2:24][P:25](=[O:32])([O:26][CH2:27][CH3:28])[O:29][CH2:30][CH3:31])=[CH:22][CH:21]=4)[N:10]=3)=[C:4]([C:35](=[O:38])[NH:36][CH3:37])[CH:3]=2)[CH:48]=[N:47]1
Reactant: CCOP(=O)(Cc1ccc(Nc2ncc(C(F)(F)F)c(Nc3ccc(Br)cc3C(=O)NC)n2)cc1)OCC
Reactant: CC1(C)OC[C@H](Cn2cc(B3OC(C)(C)C(C)(C)O3)cn2)O1
Product: CCOP(=O)(Cc1ccc(Nc2ncc(C(F)(F)F)c(Nc3ccc(-c4cnn(C[C@H](O)CO)c4)cc3C(=O)NC)n2)cc1)OCC
Temperature: 25 °C

Procedure:
The title compound was prepared using the procedure from Example 97 with Diethyl (4-{[4-{[4-bromo-2-(methylcarbamoyl)phenyl]amino}-5-(trifluoromethyl)pyrimidin-2-yl]amino}benzyl)phosphonate (Example 106) and 1-{[(4S)-2,2-dimethyl-1,3-dioxolan-4-yl]methyl}-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (Compound 101A). After Suzuki reaction and SPE pre-purification, the dried material was dissolved in DCM and 1.0 M HCl in ether was added. The mixture was stirred at room temperature for half an hour. The crude was ourified by MDP. MS (ES+): m/z 678.38 (100) [MH+]; HPLC: tR=0.87 min (UPLC, purity).
Reaction SMILES: [O:1]1CCOCC1.[O:7]1[C:12]2[CH:13]=[CH:14][C:15]([CH2:17][NH:18][CH:19]3[CH2:24][CH2:23][C:22]([CH2:27][CH2:28][N:29]4[C:38]5[C:33](=[CH:34][CH:35]=[C:36]([O:39][CH3:40])[CH:37]=5)[C:32]([CH3:41])=[CH:31][C:30]4=[O:42])([C:25]#[N:26])[CH2:21][CH2:20]3)=[CH:16][C:11]=2[O:10][CH2:9][CH2:8]1.[OH-].[K+].C(O)C>C(OCC)C>[O:7]1[C:12]2[CH:13]=[CH:14][C:15]([CH2:17][NH:18][CH:19]3[CH2:24][CH2:23][C:22]([CH2:27][CH2:28][N:29]4[C:38]5[C:33](=[CH:34][CH:35]=[C:36]([O:39][CH3:40])[CH:37]=5)[C:32]([CH3:41])=[CH:31][C:30]4=[O:42])([C:25]([NH2:26])=[O:1])[CH2:21][CH2:20]3)=[CH:16][C:11]=2[O:10][CH2:9][CH2:8]1
Reactant: COc1ccc2c(C)cc(=O)n(CCC3(C#N)CCC(NCc4ccc5c(c4)OCCO5)CC3)c2c1
Reactant: C1COCCO1
Agent: [K+]
Agent: [OH-]
Solvent: CCOCC
Solvent: CCO
Product: COc1ccc2c(C)cc(=O)n(CCC3(C(N)=O)CCC(NCc4ccc5c(c4)OCCO5)CC3)c2c1
Temperature: 25 °C

Procedure:
To 1 mL of a 1,4-dioxane solution containing 30 mg of 4-((2,3-dihydro-1,4-benzodioxin-6-ylmethyl)amino)-1-(2-(7-methoxy-4-methyl-2-oxoquinolin-1(2H)-yl)ethyl)cyclohexanecarbonitrile, 1 mL of 20% aqueous potassium hydroxide solution and 1 mL of ethanol were added at room temperature and refluxed with heating for 4 hours. Further, 1 mL of 20% aqueous potassium hydroxide solution was added and refluxed with heating for 4 hours, thereafter 1.5 mL of 20% aqueous potassium hydroxide solution was further added and refluxed with heating for 9.5 hours. After 1 mL of 20% aqueous potassium hydroxide solution and 0.5 mL of ethanol were added and refluxed with heating for 1 hour, further 1 mL of 20% aqueous potassium hydroxide solution was added and refluxed with heating for 8 hours. After 1 mL of 20% aqueous potassium hydroxide solution was added and refluxed with heating for 6 hours, the reaction mixture was cooled to the room temperature, the solvent was removed under reduced pressure. The residue was adjusted to pH 11 with 2.0 mol/L hydrochloric acid and chloroform was added. The organic layer was separated, and the aqueous layer was extracted with chloroform. The organic layer and extracts were combined, washed with aqueous saturated sodium chloride solution, dried over anhydrous magnesium sulfate, and the solvent was removed under reduced pressure. To the residue thus obtained, diethyl ether was added, and the resulting solid was filtered to give 21 mg of 4-((2,3-dihydro-1,4-benzodioxin-6-ylmethyl)amino)-1-(2-(7-methoxy-4-methyl-2-oxoquinolin-1(2H)-yl)ethyl)cyclohexanecarboxamide as a white solid.
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[C:9]1[CH:14]=[CH:13][C:12]([CH2:15][N:16]2[C:24]3[C:19](=[CH:20][C:21]([C:25]([OH:27])=O)=[CH:22][CH:23]=3)[C:18]([CH3:28])=[C:17]2[CH3:29])=[CH:11][CH:10]=1)#[N:2].[C:30]1([CH:36]([NH2:39])[CH2:37][CH3:38])[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1>>[C:1]([C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[C:9]1[CH:14]=[CH:13][C:12]([CH2:15][N:16]2[C:24]3[C:19](=[CH:20][C:21]([C:25]([NH:39][CH:36]([C:30]4[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=4)[CH2:37][CH3:38])=[O:27])=[CH:22][CH:23]=3)[C:18]([CH3:28])=[C:17]2[CH3:29])=[CH:11][CH:10]=1)#[N:2]
Reactant: CCC(N)c1ccccc1
Reactant: Cc1c(C)n(Cc2ccc(-c3ccccc3C#N)cc2)c2ccc(C(=O)O)cc12
Product: CCC(NC(=O)c1ccc2c(c1)c(C)c(C)n2Cc1ccc(-c2ccccc2C#N)cc1)c1ccccc1

Procedure:
The title compound was prepared following the same protocol as described in Step 8, Example 1, using 1-((2′-cyano-[1,1′-biphenyl]-4-yl)methyl)-2,3-dimethyl-1H-indole-5-carboxylic acid instead of the 1-((2′-(tert-butoxycarbonyl)biphenyl-4-yl)methyl)-2,3-dimethyl-1H-indole-5-carboxylic acid, and 1-phenylpropan-1-amine instead of the (S)-1-(4-bromophenyl)ethanamine. ESI-MS (m/z): 498 [M+H]+.
Reaction SMILES: [CH3:1][C:2]1[N:3]=[CH:4][NH:5][C:6]=1[CH2:7][S:8][CH2:9][CH2:10][NH2:11].[Cl:12][C:13]1[CH:18]=[CH:17][C:16]([S:19]([NH:22][C:23](=[N:26][CH3:27])SC)(=[O:21])=[O:20])=[CH:15][CH:14]=1>C(#N)C>[Cl:12][C:13]1[CH:14]=[CH:15][C:16]([S:19]([NH:22][C:23]([NH:26][CH3:27])=[N:11][CH2:10][CH2:9][S:8][CH2:7][C:6]2[NH:5][CH:4]=[N:3][C:2]=2[CH3:1])(=[O:20])=[O:21])=[CH:17][CH:18]=1
Reactant: CN=C(NS(=O)(=O)c1ccc(Cl)cc1)SC
Reactant: Cc1nc[nH]c1CSCCN
Solvent: CC#N
Product: CNC(=NCCSCc1[nH]cnc1C)NS(=O)(=O)c1ccc(Cl)cc1
Yield: 59.1 %

Procedure:
A solution of 4-methyl-5-((2-aminoethyl)thiomethyl)imidazole (3.33 g.) and N-(4-chlorobenzenesulphonyl)-N' ,S-dimethylisothiourea (5.40 g.) in acetonitrile was heated under reflux for 24 hours. Concentration, followed by recrystallisation from aqueous ethanol afforded N-(4-chlorobenzenesulphonyl)-N'-methyl-N"-[2-((4-methyl-5-imidazolyl)methylthio)ethyl]guanidine (4.6 g.), m.p. 153°-154°.
Reaction SMILES: ClS(C1C=CC(C(O)=O)=CC=1)(=O)=O.C(N1CCNCC1)C.[Cl:22][C:23]1[CH:29]=[CH:28][C:26]([NH2:27])=[CH:25][C:24]=1[C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][N:31]=1.[CH2:36]([N:38]1[CH2:43][CH2:42][N:41]([S:44]([C:47]2[CH:55]=[CH:54][C:50]([C:51](O)=[O:52])=[CH:49][CH:48]=2)(=[O:46])=[O:45])[CH2:40][CH2:39]1)[CH3:37]>>[Cl:22][C:23]1[CH:29]=[CH:28][C:26]([NH:27][C:51](=[O:52])[C:50]2[CH:54]=[CH:55][C:47]([S:44]([N:41]3[CH2:40][CH2:39][N:38]([CH2:36][CH3:37])[CH2:43][CH2:42]3)(=[O:46])=[O:45])=[CH:48][CH:49]=2)=[CH:25][C:24]=1[C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][N:31]=1
Reactant: Nc1ccc(Cl)c(-c2ccccn2)c1
Reactant: CCN1CCN(S(=O)(=O)c2ccc(C(=O)O)cc2)CC1
Agent: CCN1CCNCC1
Agent: O=C(O)c1ccc(S(=O)(=O)Cl)cc1
Product: CCN1CCN(S(=O)(=O)c2ccc(C(=O)Nc3ccc(Cl)c(-c4ccccn4)c3)cc2)CC1

Procedure:
1 g of 4-(chlorosulfonyl)benzoic acid was reacted with 570 mg of 1-ethylpiperazine via Procedure H. 75 mg of 4-chloro-3-(pyridin-2-yl)aniline was coupled to 4-(4-ethylpiperazin-1-ylsulfonyl)benzoic acid via Procedure G and purified by reverse phase HPLC to yield N-(4-chloro-3-(pyridin-2-yl)phenyl)-4-(4-ethylpiperazin-1-ylsulfonyl). MS (Q1) 485 (M)+.
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][C:5]([Cl:8])=[CH:4][C:3]=1[N+:9]([O-:11])=[O:10].[NH2:12][C:13]1[S:14][CH:15]=[CH:16][C:17]=1[C:18]#[N:19].O.[OH-].[Li+]>CS(C)=O>[Cl:8][C:5]1[CH:6]=[CH:7][C:2]([NH:12][C:13]2[S:14][CH:15]=[CH:16][C:17]=2[C:18]#[N:19])=[C:3]([N+:9]([O-:11])=[O:10])[CH:4]=1
Reactant: O=[N+]([O-])c1cc(Cl)ccc1Cl
Reactant: N#Cc1ccsc1N
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: CS(C)=O
Product: N#Cc1ccsc1Nc1ccc(Cl)cc1[N+](=O)[O-]
Reaction time: 1.5 h
Yield: 86.1 %

Procedure:
Combine 1,4-dichloro-2-nitro-benzene (3.87 g, 20.13 mmol), 2-aminothiophene-3-carbonitrile (2.50 g, 20.13 mmol), and DMSO (25.0 ml). Add lithium hydroxide monohydrate (1.69 g, 40.27 mmol) all at once and then stir the mixture at ambient temperature for 24 hours. Pour the mixture onto ice chips and stir it for 1.5 hours. Remove the resulting orange precipitate by vacuum filtration and then dry it under vacuum to give 4.85 g (86%) of the title compound: mass spectrum (ion spray): m/z=279.1 (M+1).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([C:26]([CH3:29])([CH3:28])[CH3:27])[C:5]([O:24][CH3:25])=[C:6]([CH2:8][C:9]([C:13]2[CH:18]=[CH:17][C:16]([NH:19][S:20]([CH3:23])(=[O:22])=[O:21])=[CH:15][CH:14]=2)([C:11]#N)[CH3:10])[CH:7]=1.CC(C[AlH]CC(C)C)C.CC[O:41]CC>C(Cl)Cl>[Br:1][C:2]1[CH:3]=[C:4]([C:26]([CH3:29])([CH3:28])[CH3:27])[C:5]([O:24][CH3:25])=[C:6]([CH2:8][C:9]([C:13]2[CH:18]=[CH:17][C:16]([NH:19][S:20]([CH3:23])(=[O:22])=[O:21])=[CH:15][CH:14]=2)([CH:11]=[O:41])[CH3:10])[CH:7]=1
Reactant: CCOCC
Reactant: COc1c(CC(C)(C#N)c2ccc(NS(C)(=O)=O)cc2)cc(Br)cc1C(C)(C)C
Agent: CC(C)C[AlH]CC(C)C
Solvent: ClCCl
Product: COc1c(CC(C)(C=O)c2ccc(NS(C)(=O)=O)cc2)cc(Br)cc1C(C)(C)C
Temperature: 25 °C
Reaction time: 5 h
Yield: 34 %

Procedure:
To a solution of 288 (766 mg, 1.599 mmol) in DCM (10 mL) at 0° C. was added DIBAL (3.2 mL, 3.2 mmol, 1.0M in DCM). The reaction mixture was gradually warmed to RT overnight. LCMS indicated incomplete conversion. Additional DIBAL (3.2 mL, 3.2 mmol) was added and the reaction mixture was stirred for an additional 5 h. The reaction mixture was cooled to 0° C. and diluted with ether (20 mL). The reaction was quenched by careful addition of 6N HCl (1.5 mL). The resulting suspension was extracted with EtOAc and the organic extracts were dried (Na2SO4), filtered and concentrated in vacuo. The crude residue was purified by SiO2 chromatograph eluting with an EtOAc/hexane gradient (20% to 30% EtOAc) to afford 263 mg (34%) of N-{4-[2-(5-bromo-3-tert-butyl-2-methoxy-phenyl)-1-formyl-1-methyl-ethyl]-phenyl}-methanesulfonamide (292) as a tan oil.