Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[CH:2]([C:13]1[CH:18]=[CH:17][CH:16]=[C:15]([C:19]#[N:20])[CH:14]=1)[C:3]1[CH:12]=[CH:11][C:6]([C:7]([O:9][CH3:10])=[O:8])=[CH:5][CH:4]=1.[F:21][C:22]1[CH:23]=[C:24]([C@H:29]([CH:34]2[CH2:37][NH:36][CH2:35]2)[C:30]([F:33])([CH3:32])[CH3:31])[CH:25]=[C:26]([F:28])[CH:27]=1>>[C:19]([C:15]1[CH:14]=[C:13]([C@@H:2]([N:36]2[CH2:37][CH:34]([C@@H:29]([C:24]3[CH:23]=[C:22]([F:21])[CH:27]=[C:26]([F:28])[CH:25]=3)[C:30]([F:33])([CH3:31])[CH3:32])[CH2:35]2)[C:3]2[CH:12]=[CH:11][C:6]([C:7]([O:9][CH3:10])=[O:8])=[CH:5][CH:4]=2)[CH:18]=[CH:17][CH:16]=1)#[N:20]
Reactant: CC(C)(F)[C@H](c1cc(F)cc(F)c1)C1CNC1
Reactant: COC(=O)c1ccc(C(Br)c2cccc(C#N)c2)cc1
Product: COC(=O)c1ccc([C@@H](c2cccc(C#N)c2)N2CC([C@@H](c3cc(F)cc(F)c3)C(C)(C)F)C2)cc1

Procedure:
The title compound was prepared methyl 4-[bromo(3-cyanophenyl)methyl]benzoate and 3-[(1S)-1-(3,5-difluorophenyl)-2-fluoro-2-methylpropyl]azetidine (Step 1, Preparation 15) by the procedure described in Step 2 of Preparation 15. The product was purified by chromatography on an AD column using 30% isopropanol-heptane to afford the title compound; 1H-NMR(CDCl3) δ 1.25 (t, J=22 Hz, 6H), 2.33 (t, J=6.5 Hz, 1H), 2.83-2.89 (m, 2H), 3.05-3.22 (m, 2H), 3.65 (m, 1H), 3.92 (s, 3H), 4.34 (s, 1H), 6.68-6.71 (m, 3H), 7.21-7.8 (m, 8H); Mass Spectrum: m/e=493 (M+1).
Reaction SMILES: Cl.[CH3:2][O:3][NH2:4].[F:5][C:6]1[CH:7]=[C:8]([CH:31]=[CH:32][CH:33]=1)[CH2:9][N:10]1[C:22]2[CH2:21][CH2:20][C@@H:19]([NH:23][C:24](=[O:28])[CH:25]([CH3:27])[CH3:26])[CH2:18][C:17]=2[C:16]2[C:11]1=[CH:12][CH:13]=[C:14]([CH:29]=O)[CH:15]=2>N1C=CC=CC=1.CCOC(C)=O>[F:5][C:6]1[CH:7]=[C:8]([CH:31]=[CH:32][CH:33]=1)[CH2:9][N:10]1[C:22]2[CH2:21][CH2:20][C@@H:19]([NH:23][C:24](=[O:28])[CH:25]([CH3:26])[CH3:27])[CH2:18][C:17]=2[C:16]2[C:11]1=[CH:12][CH:13]=[C:14]([CH:29]=[N:4][O:3][CH3:2])[CH:15]=2
Reactant: CC(C)C(=O)N[C@@H]1CCc2c(c3cc(C=O)ccc3n2Cc2cccc(F)c2)C1
Reactant: CON
Agent: Cl
Solvent: c1ccncc1
Solvent: CCOC(C)=O
Product: CON=Cc1ccc2c(c1)c1c(n2Cc2cccc(F)c2)CC[C@@H](NC(=O)C(C)C)C1
Temperature: 25 °C
Reaction time: 18 h
Yield: 10.1 %

Procedure:
Add methoxyamine hydrochloride (613 mg, 7.34 mmol) to a solution of (R)-N-[9-(3-fluorobenzyl)-6-formyl-2,3,4,9-tetrahydro-1H-carbazol-3-yl]-isobutyramide (Example 200) (2.40 g, 6.11 mmol) in pyridine (40 mL). Stir the reaction mixture at room temperature for 18 h. Concentrate the reaction in-vacuo and dilute with EtOAc (175 mL). Wash the organics with water (3×75 mL), dry (MgSO4), filter, and concentrate to give the crude product (2.22 g) as a brown foam. Purify the crude product on 40 g silica gel (15-80% EtOAc/hexanes) to give 261 mg (10%) of the title compound as a yellow flaky solid. Re-purify the impure fractions on 40 g silica gel (50-80% (1% (2M NH3/MeOH)/CH2Cl2)/hexanes) and combine the purified materials to give 673 mg (26%) of the title compound as a yellow flaky solid. MS (ES): m/z 422 (M+1), 420 (M−1); HPLC (Method B): Rt=7.98 min (99%).
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([CH:9]=[CH:10][CH:11]=1)[C:5]([NH:7][NH2:8])=O.I.CS[C:15](=[NH:28])[NH:16][C:17]1[CH:22]=[CH:21][C:20]([Cl:23])=[C:19]([C:24]([F:27])([F:26])[F:25])[CH:18]=1>N1C=CC=CC=1>[Cl:23][C:20]1[CH:21]=[CH:22][C:17]([NH:16][C:15]2[NH:28][C:5]([C:4]3[CH:3]=[C:2]([OH:1])[CH:11]=[CH:10][CH:9]=3)=[N:7][N:8]=2)=[CH:18][C:19]=1[C:24]([F:25])([F:26])[F:27]
Reactant: CSC(=N)Nc1ccc(Cl)c(C(F)(F)F)c1
Reactant: NNC(=O)c1cccc(O)c1
Agent: I
Solvent: c1ccncc1
Product: Oc1cccc(-c2nnc(Nc3ccc(Cl)c(C(F)(F)F)c3)[nH]2)c1
Temperature: 25 °C
Yield: 31.3 %

Procedure:
3-hydroxybenzoic acid hydrazide (2.98 g, 19.58 mmol) and S-methyl N-[4-chloro-3-(trifluoromethyl)phenyl]isothiourea hydroiodide (7.78 g, 19.63 mmol) were suspended in 40 mL of anhydrous pyridine. The reaction mixture was refluxed for 18 hours, during which time it changed color from yellow into dark-red. Then it was cooled down to ambient temperature and poured with stirring into 250 mL of ice-water. The aqueous solution was decanted and the oily residue was purified by silica gel chromatography on Isco column using 0=>50% gradient of ethyl acetate in hexane. Solvent was removed in vacuo to give the title product as a white solid (2.176 g). 31.3% yield.
Reaction SMILES: [CH3:1][N:2]([CH3:27])[C:3]([C:5]1[CH:25]=[CH:24][C:8]([O:9][C:10]2[C:15]3[CH2:16][C:17]([CH3:20])([CH3:19])[O:18][C:14]=3[CH:13]=[C:12]([C:21]([OH:23])=O)[CH:11]=2)=[CH:7][C:6]=1[F:26])=[O:4].[NH2:28][C:29]1[CH:34]=[CH:33][C:32]([CH3:35])=[CH:31][N:30]=1>>[CH3:35][C:32]1[CH:33]=[CH:34][C:29]([NH:28][C:21]([C:12]2[CH:11]=[C:10]([O:9][C:8]3[CH:24]=[CH:25][C:5]([C:3](=[O:4])[N:2]([CH3:1])[CH3:27])=[C:6]([F:26])[CH:7]=3)[C:15]3[CH2:16][C:17]([CH3:19])([CH3:20])[O:18][C:14]=3[CH:13]=2)=[O:23])=[N:30][CH:31]=1
Reactant: Cc1ccc(N)nc1
Reactant: CN(C)C(=O)c1ccc(Oc2cc(C(=O)O)cc3c2CC(C)(C)O3)cc1F
Product: Cc1ccc(NC(=O)c2cc(Oc3ccc(C(=O)N(C)C)c(F)c3)c3c(c2)OC(C)(C)C3)nc1

Procedure:
The title compound was prepared in a similar manner as described for Example 144, from 4-(4-dimethylcarbamoyl-3-fluoro-phenoxy)-2,2-dimethyl-2,3-dihydro-benzofuran-6-carboxylic acid (143a) (60 mg, 0.16 mmol) and 2-amino-5-methylpyridine (34.8 mg, 0.321 mmol) to give a brown solid (25 mg, 34% yield). 1H NMR (400 MHz, CDCl3) δ 8.98 (br. s., 1 H) 8.19 (d, J=8.34 Hz, 1 H) 8.11 (s, 1 H) 7.66 (dd, J=8.46, 1.89 Hz, 1 H) 7.31-7.43 (m, 1 H) 7.12 (s, 1 H) 7.07 (d, J=1.26 Hz, 1 H) 6.80 (dd, J=8.59, 2.27 Hz, 1 H) 6.69 (dd, J=10.61, 2.27 Hz, 1 H) 3.14 (s, 3 H) 2.98 (s, 3 H) 2.91 (s, 2 H) 2.35 (s, 3 H) 1.50 (s, 6 H); LCMS for C26H26FN3O4 m/z 464.20 (M+H+); Anal. Calcd. for C26H26FN3O4.0.27 TFA.1.0 H2O: C, 62.22; H, 5.56; N, 8.20. Found: C, 61.87; H, 5.36; N, 8.56.
Reaction SMILES: [NH2:1][C:2]1[CH:23]=[CH:22][C:5]([O:6][CH2:7][CH2:8][N:9]2[CH2:14][CH2:13][N:12]([C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])[CH2:11][CH2:10]2)=[CH:4][C:3]=1[N+:24]([O-])=O>[Pd].C(O)C>[NH2:24][C:3]1[CH:4]=[C:5]([CH:22]=[CH:23][C:2]=1[NH2:1])[O:6][CH2:7][CH2:8][N:9]1[CH2:14][CH2:13][N:12]([C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])[CH2:11][CH2:10]1
Reactant: CC(C)(C)OC(=O)N1CCN(CCOc2ccc(N)c([N+](=O)[O-])c2)CC1
Agent: [Pd]
Solvent: CCO
Product: CC(C)(C)OC(=O)N1CCN(CCOc2ccc(N)c(N)c2)CC1
Reaction time: 2 h
Yield: 95.5 %

Procedure:
A hydrogenation vessel was charged with tert-butyl 4-(2-(4-amino-3-nitrophenoxy)ethyl)piperazine-1-carboxylate (1.74 g, 4.76 mmol), ethanol (100 mL) and 10% palladium on charcoal (w/w 50% water) (1 g). The reaction vessel was shaken on a Parr Hydrogenation under an atmosphere of hydrogen gas (40 psi). The reaction was completed in 2 hours as determined by LCMS. The reaction mixture was filtered through a plug of Celite and washed with methanol. The filtered was evaporated under pressure to give 1.53 g of tert-butyl 4-(2-(3,4-diaminophenoxy)ethyl)piperazine-1-carboxylate (95% yield) and was used in the next step without any further purification. MS (EI): 337 (MH+).
Reaction SMILES: [Br:1][C:2]1[C:3]([F:21])=[CH:4][C:5]2[CH:11]3[CH2:12][CH:9]([CH2:10]3)[N:8]3[CH:13]=[C:14]([C:16]([O:18][CH3:19])=[O:17])[N:15]=[C:7]3[C:6]=2[CH:20]=1.[C:22]([N:29]1[CH2:32][CH:31]([CH:33]=[O:34])[CH2:30]1)([O:24][C:25]([CH3:28])([CH3:27])[CH3:26])=[O:23]>>[Br:1][C:2]1[C:3]([F:21])=[CH:4][C:5]2[CH:11]3[CH2:10][CH:9]([CH2:12]3)[N:8]3[C:13]([CH:33]([CH:31]4[CH2:32][N:29]([C:22]([O:24][C:25]([CH3:28])([CH3:27])[CH3:26])=[O:23])[CH2:30]4)[OH:34])=[C:14]([C:16]([O:18][CH3:19])=[O:17])[N:15]=[C:7]3[C:6]=2[CH:20]=1
Reactant: CC(C)(C)OC(=O)N1CC(C=O)C1
Reactant: COC(=O)c1cn2c(n1)-c1cc(Br)c(F)cc1C1CC2C1
Product: COC(=O)c1nc2n(c1C(O)C1CN(C(=O)OC(C)(C)C)C1)C1CC(C1)c1cc(F)c(Br)cc1-2
Yield: 63 %

Procedure:
Methyl 10-bromo-3-((1-(tert-butoxycarbonyl)azetidin-3-yl)(hydroxy)methyl)-9-fluoro-6,7-dihydro-5H-5,7-methanobenzo[c]imidazo[1,2-a]azepine-2-carboxylate was prepared similarly according to the procedure in Example 9. Methyl 10-bromo-9-fluoro-6,7-dihydro-5H-5,7-methanobenzo[c]imidazo[1,2-a]azepine-2-carboxylate was reacted with 1-boc-3-azetidinecarboxaldehyde to afford 479 mg (63% yield) of the title compound.
Reaction SMILES: [CH2:1]([C:5]1[N:6]=[C:7]([CH3:27])[NH:8][C:9](=[O:26])[C:10]=1[CH2:11][C:12]1[CH:17]=[CH:16][C:15]([C:18]2[C:19]([C:24]#[N:25])=[CH:20][CH:21]=[CH:22][CH:23]=2)=[CH:14][CH:13]=1)[CH2:2][CH2:3][CH3:4].C(=O)([O-])[O-].[K+].[K+].Cl.Cl[CH2:36][C:37]1[N:38]=[CH:39][S:40][CH:41]=1.CN(C)C=O>C(OCC)(=O)C>[CH2:1]([C:5]1[N:6]=[C:7]([CH3:27])[N:8]([CH2:36][C:37]2[N:38]=[CH:39][S:40][CH:41]=2)[C:9](=[O:26])[C:10]=1[CH2:11][C:12]1[CH:17]=[CH:16][C:15]([C:18]2[C:19]([C:24]#[N:25])=[CH:20][CH:21]=[CH:22][CH:23]=2)=[CH:14][CH:13]=1)[CH2:2][CH2:3][CH3:4]
Reactant: CCCCc1nc(C)[nH]c(=O)c1Cc1ccc(-c2ccccc2C#N)cc1
Reactant: ClCc1cscn1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CCCCc1nc(C)n(Cc2cscn2)c(=O)c1Cc1ccc(-c2ccccc2C#N)cc1
Temperature: 90 °C
Reaction time: 2 h
Yield: 65.1 %

Procedure:
A mixture of 4′-[(4-butyl-2-methyl-6-oxo-1,6-dihydropyrimidin-5-yl)methyl]biphenyl-2-carbonitrile (1.22 g), potassium carbonate (0.94 g), 4-(chloromethyl)-1,3-thiazole hydrochloride (0.58 g) and N,N-dimethylformamide (20 mL) was stirred at 90° C. for 2 hr. The reaction mixture was diluted with ethyl acetate, washed with water and then with saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure and the residue was purified by silica gel column chromatography to give the title compound as a colorless solid (1.01 g, 66%).
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([O:7][C:8]2[CH:17]=[CH:16][C:11]([C:12]([NH:14][NH2:15])=O)=[CH:10][CH:9]=2)[CH:2]=1.I.CS[C:21](=[NH:34])[NH:22][C:23]1[CH:28]=[CH:27][C:26]([Cl:29])=[C:25]([C:30]([F:33])([F:32])[F:31])[CH:24]=1>N1C=CC=CC=1>[Cl:29][C:26]1[CH:27]=[CH:28][C:23]([NH:22][C:21]2[NH:34][C:12]([C:11]3[CH:16]=[CH:17][C:8]([O:7][C:3]4[CH:2]=[N:1][CH:6]=[CH:5][CH:4]=4)=[CH:9][CH:10]=3)=[N:14][N:15]=2)=[CH:24][C:25]=1[C:30]([F:31])([F:32])[F:33]
Reactant: NNC(=O)c1ccc(Oc2cccnc2)cc1
Reactant: CSC(=N)Nc1ccc(Cl)c(C(F)(F)F)c1
Agent: I
Solvent: c1ccncc1
Product: FC(F)(F)c1cc(Nc2nnc(-c3ccc(Oc4cccnc4)cc3)[nH]2)ccc1Cl
Yield: 12.7 %

Procedure:
4-(pyridine-3-yloxy)benzohydrazide (2.33 g, 10.2 mmol) was dissolved in ca. 70 mL of anhydrous pyridine and S-methyl N-[4-chloro-3-(trifluoromethyl)phenyl] isothiourea hydroiodide (4.04 g, 10.2 mmol) was added. The reaction mixture was refluxed for 18 hrs under Ar. The pyridine was removed in vacuo and the resulting residue was purified by silica gel chromatography using EtOAc as eluent to give the title product (0.56 g) as a white solid.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([C:8]2[N:13]=[C:12]([C:14]3[CH:19]=[CH:18][C:17]([Cl:20])=[CH:16][CH:15]=3)[CH:11]=[C:10]([C:21]([F:24])([F:23])[F:22])[N:9]=2)[CH:5]=[CH:6][CH:7]=1.[N:25]1[CH:30]=[CH:29][CH:28]=[C:27](B(O)O)[CH:26]=1>>[Cl:20][C:17]1[CH:18]=[CH:19][C:14]([C:12]2[CH:11]=[C:10]([C:21]([F:24])([F:23])[F:22])[N:9]=[C:8]([C:4]3[CH:5]=[CH:6][CH:7]=[C:2]([C:27]4[CH:26]=[N:25][CH:30]=[CH:29][CH:28]=4)[CH:3]=3)[N:13]=2)=[CH:15][CH:16]=1
Reactant: OB(O)c1cccnc1
Reactant: FC(F)(F)c1cc(-c2ccc(Cl)cc2)nc(-c2cccc(Br)c2)n1
Product: FC(F)(F)c1cc(-c2ccc(Cl)cc2)nc(-c2cccc(-c3cccnc3)c2)n1

Procedure:
The title compound was prepared from 2-(3-bromo-phenyl)-4-(4-chloro-phenyl)-6-trifluoromethyl-pyrimidine (example E.4) (0.21 g, 0.5 mmol) and commercially available 3-pyridineboronic acid (0.08 g, 0.65 mmol) according to the general procedure VI. Obtained as a white solid (0.12 g, 57%). MS (ISP) 412.3 [(M+H)+]; mp 162° C.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([C:12](=O)[C:13]([O:15]CCCCCC)=O)[CH:5]=[C:6]([N+:9]([O-:11])=[O:10])[C:7]=1[OH:8].[NH2:23][NH:24][C:25]([NH2:27])=[S:26].[OH-].[Na+].Cl>O>[OH:1][C:2]1[CH:3]=[C:4]([C:12]2[C:13](=[O:15])[NH:27][C:25]([SH:26])=[N:24][N:23]=2)[CH:5]=[C:6]([N+:9]([O-:11])=[O:10])[C:7]=1[OH:8]
Reactant: NNC(N)=S
Reactant: CCCCCCOC(=O)C(=O)c1cc(O)c(O)c([N+](=O)[O-])c1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: O=c1[nH]c(S)nnc1-c1cc(O)c(O)c([N+](=O)[O-])c1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
A suspension of 2.05 g of n-hexyl 3,4-dihydroxy-5-nitrophenylglyoxylate and 600.8 mg of thiosemicarbazide is stirred intensively at 90° for 30 minutes. The mixture is then cooled to 40° and treated with a solution of 870.1 mg of sodium hydroxide in 15 ml of water. The solution is subsequently heated to 90° for 30 minutes, cooled to room temperature and treated dropwise with 2 ml of conc. hydrochloric acid. The crystallized-out product is filtered under suction and then dissolved in ethyl acetate. The solution is washed with saturated sodium chloride solution, dried over sodium sulfate, filtered and evaporated. There is obtained 6-(3,4-dihydroxy-5-nitrophenyl)-3-mercapto-1,2,4-triazin-5(4H)-one of m.p. 282°-284° (from ethanol).
Reaction SMILES: [CH:1](=[C:3]1[C:7]([C:14]2[CH:15]=[C:16]([OH:20])[CH:17]=[CH:18][CH:19]=2)([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[CH2:6][CH:5]([CH3:21])[N:4]1[CH3:22])[CH3:2].[OH-].[K+].Br[CH2:26][C:27]([O:29][C:30]([CH3:33])([CH3:32])[CH3:31])=[O:28]>CS(C)=O.C(OCC)(=O)C>[CH:1](=[C:3]1[C:7]([C:14]2[CH:15]=[C:16]([CH:17]=[CH:18][CH:19]=2)[O:20][CH2:26][C:27]([O:29][C:30]([CH3:33])([CH3:32])[CH3:31])=[O:28])([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[CH2:6][CH:5]([CH3:21])[N:4]1[CH3:22])[CH3:2]
Reactant: CC=C1N(C)C(C)CC1(c1ccccc1)c1cccc(O)c1
Reactant: CC(C)(C)OC(=O)CBr
Agent: [K+]
Agent: [OH-]
Solvent: CCOC(C)=O
Solvent: CS(C)=O
Product: CC=C1N(C)C(C)CC1(c1ccccc1)c1cccc(OCC(=O)OC(C)(C)C)c1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
Product of Step 9 (1 g) was dissolved in dimethylsulfoxide (60 mL). To this, powdered potassium hydroxide (1 g) and tertiarybutyl bromoacetate (2.5 mL) was added. The reaction mixture was stirred under argon for 3 hr at 25° C. The reaction mixture was diluted with ethyl acetate (800 mL) and was extracted with water (twice at 200 mL each) and saturated sodium chloride in water (200 mL). The organic layer was dried on magnesium sulfate, was filtered, and was concentrated under vacuum. Crude product was loaded on a SNAP cartridge containing 100 g silica gel and eluted with a gradient of chloroform and methanol using the BIOTAGE® AB ISOLERA™ flash chromatography system. Fractions containing product were pooled and evaporated to obtain product of Step 10 as a red oil (0.26 g). 1H NMR (CDCl3): 1.3 δ (—CH—CH3 of isopropyl), 1.5 δ (—(CH3)3 of tertiarybutyl) 2.1 δ (3H, ═CH—CH3 of ethylidene) 2.9 δ (3H, —N—(CH3)), 2.8, 3.1, 3.5 δ (1H, 1H, 1H —CH2-CH—CH3 of isopropyl), 4.4 δ (1H, ═CH—CH3 of ethylidene), 4.5 (2H, —O—CH2-C(O)—) 6.8-7.5 δ (9H, phenyl rings). Mass spectrometry: m/z=408 (M+H).
Reaction SMILES: [CH3:1][C:2]1([CH3:18])[CH2:6][C:5]([C:7]2[O:11][N:10]=[C:9]([C:12]([O:14]CC)=[O:13])[C:8]=2[CH3:17])=[CH:4][CH2:3]1.[OH-].[Na+].Cl>C(O)C.O>[CH3:1][C:2]1([CH3:18])[CH2:6][C:5]([C:7]2[O:11][N:10]=[C:9]([C:12]([OH:14])=[O:13])[C:8]=2[CH3:17])=[CH:4][CH2:3]1
Reactant: CCOC(=O)c1noc(C2=CCC(C)(C)C2)c1C
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: Cc1c(C(=O)O)noc1C1=CCC(C)(C)C1
Temperature: 25 °C

Procedure:
To a stirred solution of ethyl 5-(4,4-dimethylcyclopent-1-en-1-yl)-4-methylisoxazole-3-carboxylate (243 mg, 0.975 mmol) in ethanol (5 mL), 2M NaOH (aq) (0.975 mL, 1.949 mmol) was added and the solution was stirred at room temperature. Upon completion the reaction mixture was diluted with water (30 mL) and acidified to pH 5-6 by the addition of 2M HCl (aq). The aqueous phase was extracted with EtOAc (2×20 mL) and the combined organic extracts were washed with brine (20 mL), dried over MgSO4 and filtered. The solvent was removed under reduced pressure to afford the title compound;
Reaction SMILES: [O:1]1[C:5]2[CH:6]=[C:7]([CH:10]3[CH2:15][CH2:14][NH:13][CH2:12][CH2:11]3)[CH:8]=[CH:9][C:4]=2[CH:3]=[CH:2]1.[CH:16]1([C:20]2[C:28]([C:29](=[O:32])[NH:30][CH3:31])=[CH:27][C:23]([C:24](O)=[O:25])=[C:22]([CH3:33])[CH:21]=2)[CH2:19][CH2:18][CH2:17]1.CCN=C=NCCCN(C)C.Cl.CCOC(C)=O>CN(C)C1C=CN=CC=1.CN(C)C=O>[O:1]1[C:5]2[CH:6]=[C:7]([CH:10]3[CH2:15][CH2:14][N:13]([C:24]([C:23]4[C:22]([CH3:33])=[CH:21][C:20]([CH:16]5[CH2:19][CH2:18][CH2:17]5)=[C:28]([CH:27]=4)[C:29]([NH:30][CH3:31])=[O:32])=[O:25])[CH2:12][CH2:11]3)[CH:8]=[CH:9][C:4]=2[CH:3]=[CH:2]1
Reactant: CNC(=O)c1cc(C(=O)O)c(C)cc1C1CCC1
Reactant: c1cc2ccc(C3CCNCC3)cc2o1
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CNC(=O)c1cc(C(=O)N2CCC(c3ccc4ccoc4c3)CC2)c(C)cc1C1CCC1
Temperature: 15 °C
Reaction time: 2 h
Yield: 19.4 %

Procedure:
Into a 25-mL round-bottom flask, was placed a solution of 4-(benzofuran-6-yl)piperidine (compound 63.6) (110 mg, 0.55 mmol), 4-cyclobutyl-2-methyl-5-(methylcarbamoyl)benzoic acid (compound 62.3, 135 mg, 0.55 mmol), EDC.HCl (210 mg, 1.10 mmol) and 4-dimethylaminopyridine (133.5 mg, 1.09 mmol) in N,N-dimethylformamide (3 mL). The resulting solution was stirred for 2 h at 15° C. then diluted EtOAc (60 mL). The resulting mixture was washed with aqueous saturated NH4Cl (2×20 mL) and brine (20 mL), dried (Na2SO4), filtered, and concentrated under reduced pressure. The crude product (110 mg) was purified by Prep-HPLC with the following conditions (1#-Pre-HPLC-001(SHIMADZU)): Column, SunFire Prep C18 OBD Column, 5 um, 19*150 mm; mobile phase, water with 0.05% TFA and CH3CN (51.0% CH3CN up to 60.0% in 9 min, up to 100.0% in 5 min, down to 51.0% in 1 min); Detector, Waters 2489, 254 & 220 nm. The fractions containing pure compound were combined and lyophilized to yield the title compound as a white solid (46.0 mg, 20%). m/z (ES+) 431 (M+H)+.
Reaction SMILES: [CH3:1][N:2]([CH2:15][C:16]1[CH:21]=[CH:20][N:19]=[CH:18][CH:17]=1)[C:3]([C:5]1[S:13][C:12]2[C:7](=[N:8][CH:9]=[CH:10][C:11]=2Cl)[CH:6]=1)=[O:4].[CH3:22][C:23]1[NH:24][C:25]2[C:30]([CH:31]=1)=[CH:29][C:28]([NH2:32])=[CH:27][CH:26]=2>>[CH3:1][N:2]([CH2:15][C:16]1[CH:21]=[CH:20][N:19]=[CH:18][CH:17]=1)[C:3]([C:5]1[S:13][C:12]2[C:7](=[N:8][CH:9]=[CH:10][C:11]=2[NH:32][C:28]2[CH:29]=[C:30]3[C:25](=[CH:26][CH:27]=2)[NH:24][C:23]([CH3:22])=[CH:31]3)[CH:6]=1)=[O:4]
Reactant: Cc1cc2cc(N)ccc2[nH]1
Reactant: CN(Cc1ccncc1)C(=O)c1cc2nccc(Cl)c2s1
Product: Cc1cc2cc(Nc3ccnc4cc(C(=O)N(C)Cc5ccncc5)sc34)ccc2[nH]1

Procedure:
The title compound was prepared from 7-chloro-thieno[3,2-b]pyridine-2-carboxylic acid methyl-pyridin-4-ylmethyl-amide and 2-methyl-1H-indol-5-ylamine by a method analogous to Example 1C. MS: 428 (MH+); HPLC Rf: 4.26 min; HPLC purity: 93%.
Reaction SMILES: CS(O[CH2:6][CH2:7][C@H:8]([NH:15][C:16]([C@H:18]1[N:22]([S:23]([C:26]2[CH:31]=[CH:30][C:29]([C:32]3[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=3)=[CH:28][CH:27]=2)(=[O:25])=[O:24])[CH2:21][CH2:20][S:19]1)=[O:17])[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)(=O)=O.[CH3:38][O:39][C:40](=[O:44])[CH2:41][NH:42][CH3:43]>>[CH3:38][O:39][C:40](=[O:44])[CH2:41][N:42]([CH2:6][CH2:7][C@H:8]([NH:15][C:16]([C@H:18]1[N:22]([S:23]([C:26]2[CH:27]=[CH:28][C:29]([C:32]3[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=3)=[CH:30][CH:31]=2)(=[O:25])=[O:24])[CH2:21][CH2:20][S:19]1)=[O:17])[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)[CH3:43]
Reactant: CS(=O)(=O)OCC[C@H](NC(=O)[C@@H]1SCCN1S(=O)(=O)c1ccc(-c2ccccc2)cc1)c1ccccc1
Reactant: CNCC(=O)OC
Product: COC(=O)CN(C)CC[C@H](NC(=O)[C@@H]1SCCN1S(=O)(=O)c1ccc(-c2ccccc2)cc1)c1ccccc1

Procedure:
Following the general method A as outlined in Example 16, starting from (3S)-3-({[(2S)-3-([1,1′-biphenyl]-4-ylsulfonyl)-1,3-thiazolidin-2-yl]carbonyl}amino)-3-phenylpropyl methanesulfonate (Intermediate 9) and methyl(methylamino)acetate, the title compound was obtained in 98.9% purity by HPLC.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([N:8]2[CH2:13][CH2:12][NH:11][CH2:10][CH2:9]2)[CH:5]=[CH:6][CH:7]=1.Br[CH2:15][CH2:16][CH2:17][NH:18][C:19]([C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1)([C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1)[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1.C(=O)([O-])[O-].[K+].[K+].CN(C)C=O>O>[Cl:1][C:2]1[CH:3]=[C:4]([N:8]2[CH2:13][CH2:12][N:11]([CH2:15][CH2:16][CH2:17][NH:18][C:19]([C:32]3[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=3)([C:20]3[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=3)[C:26]3[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=3)[CH2:10][CH2:9]2)[CH:5]=[CH:6][CH:7]=1
Reactant: Clc1cccc(N2CCNCC2)c1
Reactant: BrCCCNC(c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: Clc1cccc(N2CCN(CCCNC(c3ccccc3)(c3ccccc3)c3ccccc3)CC2)c1
Temperature: 90 °C
Reaction time: 6.5 h
Yield: 105.5 %

Procedure:
A mixture of 5.9 g (30 mmol) of 1-(3-chlorophenyl)piperazine, 12.55 g (33 mmol) of 3-bromo-N-(triphenylmethyl)propanamine, 6.2 g (45 mmol) of potassium carbonate and 60 ml of dimethylformamide is stirred at 90° C. for 6.5 h under argon. The mixture is then poured into iced water and is extracted with ethyl acetate. The organic phase is separated off, is washed with water, is dried and the solvent is evaporated off. 15.7 g of oily residue are obtained and are purified by chromatography on a column of silica gel by eluting with a 99/1 dichloromethane/methanol mixture, which yields 11.8 g of light yellow oil.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([CH3:8])[C:3]=1[NH:9][C:10]([NH:12][C:13]([NH:15]C(C)(C)C)=[O:14])=[NH:11].[ClH:20]>>[ClH:20].[CH3:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([CH3:8])[C:3]=1[NH:9][C:10]([NH:12][C:13]([NH2:15])=[O:14])=[NH:11]
Reactant: Cc1cccc(C)c1NC(=N)NC(=O)NC(C)(C)C
Agent: Cl
Product: Cc1cccc(C)c1NC(=N)NC(N)=O

Procedure:
A mixture of 25.7 g. (0.106 moles) of 1-(2,6-dimethylphenylamidino)-3-(t-butyl)urea and 200 ml. of conc. hydrochloric acid is refluxed for 1/2 hour. The reaction mixture is cooled, the solid filtered and washed with 10 ml. of 1:1 HCl/H2O and dried. The product is then recrystallized from ethanol-ether to obtain (2,6-dimethylphenylamidino)urea hydrochloride.
Reaction SMILES: [S:1]([C:5]1[CH:12]=[CH:11][C:8]([CH:9]=O)=[CH:7][CH:6]=1)(=[O:4])(=[O:3])[NH2:2].[F:13][C:14]1[CH:20]=[C:19]([F:21])[CH:18]=[CH:17][C:15]=1[NH2:16]>>[F:13][C:14]1[CH:20]=[C:19]([F:21])[CH:18]=[CH:17][C:15]=1[N:16]=[CH:9][C:8]1[CH:11]=[CH:12][C:5]([S:1](=[O:4])(=[O:3])[NH2:2])=[CH:6][CH:7]=1
Reactant: Nc1ccc(F)cc1F
Reactant: NS(=O)(=O)c1ccc(C=O)cc1
Product: NS(=O)(=O)c1ccc(C=Nc2ccc(F)cc2F)cc1

Procedure:
Following a procedure similar to that described in Example 1(i), but using 4-sulfamoylbenzaldehyde and 2,4-difluoroaniline as starting materials, the title compound was obtained as a white powder (yield 47%).
Reaction SMILES: C([N:8]1[CH2:13][CH2:12][Si:11]([CH3:15])([CH3:14])[CH2:10][CH2:9]1)C1C=CC=CC=1.[ClH:16].C(OCC)C>C(O)C>[ClH:16].[CH3:14][Si:11]1([CH3:15])[CH2:12][CH2:13][NH:8][CH2:9][CH2:10]1
Reactant: C[Si]1(C)CCN(Cc2ccccc2)CC1
Agent: Cl
Solvent: CCOCC
Solvent: CCO
Product: C[Si]1(C)CCNCC1
Temperature: 25 °C
Reaction time: 20 h
Yield: 54.6 %

Procedure:
To a solution of 3 (2.3 g, 10.5 mmol) in ethanol (EtOH), 6 N HCl (10.5 mmol) is added and the solvent is removed under reduced pressure. The reaction mixture is co-evaporated with EtOH (2×10 mL) and recrystallized from EtOH-diethyl ether. To a slurry of Pd/C in EtOH, an ethanolic solution of the HCl salt is added dropwise and stirred at 25° C. under hydrogen atmosphere for 20 h. The reaction mixture is filtered through celite, washed with 2×20 mL of Methanol. The filtrate is concentrated under reduced pressure to give a viscous oil which is titrated with diethyl ether to obtain the product 4 as a white solid (950 mg) in 70% yield. This compound was previously documented in WO 2006/066872.