Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([N:14]([CH:25]2[CH2:30][CH2:29][CH:28]([CH3:31])[CH2:27][CH2:26]2)[C:15]([NH:17][C:18]2[S:19][C:20]([CH:23]=O)=[CH:21][N:22]=2)=[O:16])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].Cl.[CH3:33][N:34]([CH3:44])[S:35]([N:38]1[CH2:43][CH2:42][NH:41][CH2:40][CH2:39]1)(=[O:37])=[O:36].C(N(CC)CC)C.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([N:14]([CH:25]2[CH2:30][CH2:29][CH:28]([CH3:31])[CH2:27][CH2:26]2)[C:15]([NH:17][C:18]2[S:19][C:20]([CH2:23][N:41]3[CH2:42][CH2:43][N:38]([S:35](=[O:36])(=[O:37])[N:34]([CH3:33])[CH3:44])[CH2:39][CH2:40]3)=[CH:21][N:22]=2)=[O:16])[CH2:10][CH2:9]1)=[O:7])([CH3:2])([CH3:3])[CH3:4]
Reactant: CC1CCC(N(C(=O)Nc2ncc(C=O)s2)C2CCN(C(=O)OC(C)(C)C)CC2)CC1
Reactant: CN(C)S(=O)(=O)N1CCNCC1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: Cl
Agent: [Na+]
Solvent: CCN(CC)CC
Product: CC1CCC(N(C(=O)Nc2ncc(CN3CCN(S(=O)(=O)N(C)C)CC3)s2)C2CCN(C(=O)OC(C)(C)C)CC2)CC1
Yield: 38.9 %

Procedure:
Prepared as described in general procedure (P) using 4-[3-(5-formyl-thiazol-2-yl)-1-(4-methyl-cyclohexyl)-ureido]-piperidine-1-carboxylic acid tert-butyl ester (202 mg, 0.45 mmol), piperazine sulfonic acid dimethylamide hydrochloride (132 mg, 0.58 mmol), triethyl amine (80 μL, 0.58 mmol) and sodium triacetoxyborohydride (118 mg, 0.53 mmol) to afford 110 mg (39%) of the desired product after purification.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:11]=1[N:10]=[CH:9][C:8]([CH3:12])=[C:7]2[C:13]1[CH:14]=[C:15]([OH:19])[CH:16]=[CH:17][CH:18]=1.C[O:21][C:22](=[O:33])[CH:23]([C:25]1[CH:30]=[CH:29][C:28]([CH2:31]Br)=[CH:27][CH:26]=1)[CH3:24]>>[Cl:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:11]=1[N:10]=[CH:9][C:8]([CH3:12])=[C:7]2[C:13]1[CH:14]=[C:15]([CH:16]=[CH:17][CH:18]=1)[O:19][CH2:31][C:28]1[CH:27]=[CH:26][C:25]([C@@H:23]([CH3:24])[C:22]([OH:33])=[O:21])=[CH:30][CH:29]=1
Reactant: Cc1cnc2c(Cl)cccc2c1-c1cccc(O)c1
Reactant: COC(=O)C(C)c1ccc(CBr)cc1
Product: Cc1cnc2c(Cl)cccc2c1-c1cccc(OCc2ccc([C@@H](C)C(=O)O)cc2)c1

Procedure:
This compound was prepared according to the procedure of example 41, substituting 3-(8-chloro-3-methyl-quinolin-4-yl)-phenol and 2-(4-bromomethyl-phenyl)-propionic acid methyl ester. Purification by supercritical fluid chromatography (MeOH/CO2). Electronic circular dichroism CD λmax=+6 mdeg @ 226 nm (EtOH). MS (ESI) m/z 432.
Reaction SMILES: [C:1]([C:4]1[CH:9]=[CH:8][C:7]([C:10]2[N:11]([C:20]3[CH:25]=[CH:24][C:23]([Cl:26])=[CH:22][C:21]=3[O:27][CH3:28])[CH:12]=[CH:13][C:14]=2[C:15](OCC)=[O:16])=[C:6]([CH3:29])[CH:5]=1)(=[O:3])[NH2:2].CC(C[AlH]CC(C)C)C.CCOC(C)=O.CO>C1(C)C=CC=CC=1>[Cl:26][C:23]1[CH:24]=[CH:25][C:20]([N:11]2[CH:12]=[CH:13][C:14]([CH2:15][OH:16])=[C:10]2[C:7]2[CH:8]=[CH:9][C:4]([C:1]([NH2:2])=[O:3])=[CH:5][C:6]=2[CH3:29])=[C:21]([O:27][CH3:28])[CH:22]=1
Reactant: CCOC(=O)c1ccn(-c2ccc(Cl)cc2OC)c1-c1ccc(C(N)=O)cc1C
Agent: CC(C)C[AlH]CC(C)C
Solvent: CO
Solvent: CCOC(C)=O
Solvent: Cc1ccccc1
Product: COc1cc(Cl)ccc1-n1ccc(CO)c1-c1ccc(C(N)=O)cc1C
Reaction time: 2 h
Yield: 40 %

Procedure:
A solution of ethyl 2-(4-carbamoyl-2-methylphenyl)-1-(4-chloro-2-methoxyphenyl)-1H-pyrrole-3-carboxylate (1.2 g, 2.9 mmol) in anhydrous toluene (50 mL) was cooled to −78° C., DIBAL-H (1.0 mol/L, 14.5 mL) was added dropwise, and the reaction mixture was stirred at this temperature for two hours. TLC (EtOAc: MeOH=10:1) indicated that the starting material was consumed. Saturated aqueous NH4Cl solution was added to quench the reaction, and the mixture was filtered. The filtrate was extracted with EtOAc (20 mL×3), and the combined organic layer was washed with brine (20 mL), dried over Na2SO4, filtered, concentrated, and purified by column chromatography to give the titled compound (430 mg, yield: 40.2%). 1H NMR (CD3OD 300 MHz TMS): δ 7.63 (s, 1H), 7.55 (m, 1H), 7.21 (d, J=7.8 Hz, 1H), 7.03 (d, J=8.1 Hz, 1H), 6.95 (d, J=2.1 Hz, 1H), 6.82-6.87 (m, 2H), 6.43 (d, J=3.0 Hz, 1H), 4.38 (d, J=11.7 Hz, 1H), 4.27 (d, J=11.7 Hz, 1H), 3.60 (s, 3H), 2.10 (s, 3H).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:9]=[C:10]([NH:13][C:14]3[CH:19]=[CH:18][CH:17]=[C:16]([F:20])[CH:15]=3)[S:11][CH:12]=2)=[CH:4][CH:3]=1.CC(C)(C[C:27](=O)[C:28]1[CH:33]=[CH:32][C:31](B2OC(C)(C)C(C)(C)O2)=[CH:30][CH:29]=1)C(O)=O.[C:45](=[O:48])([O-])[O-:46].[Na+].[Na+]>C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[F:20][C:16]1[CH:15]=[C:14]([NH:13][C:10]2[S:11][CH:12]=[C:8]([C:5]3[CH:6]=[CH:7][C:2]([CH:31]4[CH2:32][CH2:33][CH:28]([CH2:27][C:45]([OH:46])=[O:48])[CH2:29][CH2:30]4)=[CH:3][CH:4]=3)[N:9]=2)[CH:19]=[CH:18][CH:17]=1
Reactant: O=C([O-])[O-]
Reactant: Fc1cccc(Nc2nc(-c3ccc(Br)cc3)cs2)c1
Reactant: CC(C)(CC(=O)c1ccc(B2OC(C)(C)C(C)(C)O2)cc1)C(=O)O
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [Na+]
Product: O=C(O)CC1CCC(c2ccc(-c3csc(Nc4cccc(F)c4)n3)cc2)CC1
Temperature: 120 °C

Procedure:
To a microwave vial is added [4-(4-bromophenyl)-thiazol-2-yl]-(3-fluorophenyl)-amine (92 mg, 0.26 mmol), 2,2-dimethyl-4-oxo-4-[4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-phenyl]-butyric acid (half of the crude from last step), sodium carbonate (2M solution, 0.526 mL) and resin bound Pd(PPh3)4 (130 mg, 0.013 mmol). The reaction mixture is sparged with nitrogen for 2 min and then heated in a microwave at 120° C. for 20 min. The resin is then filtered off and the filtrate is concentrated. The residue is titrate with ether. The resulting yellow solid is purified by reverse-phase preparative HPLC to give the title compound: 1H NMR (400 MHz, DMSO-D6) δ ppm 1.24 (s, 6 H), 2.49 (d, J=3.54 Hz, 4 H), 3.34 (s, 8 H), 6.73-6.82 (m, 1H), 7.05 (s, 2 H), 7.17 (s, 3 H), 7.33 (s, 2 H), 7.35-7.40 (m, 2 H), 7.50 (s, 1 H), 7.81-7.90 (m, 5 H), 8.04 (dd,J=8.34, 2.53 Hz, 4 H), 10.56 (s, 1 H); (M+H)+=475.0.
Reaction SMILES: P(Cl)(Cl)([Cl:3])=O.[F:6][C:7]1[CH:12]=[C:11]([F:13])[CH:10]=[C:9]([F:14])[C:8]=1[CH:15]1[C:24](=O)[NH:23][C:22]2[CH:21]=[CH:20][N:19]=[N:18][C:17]=2C1=O.CN(C=O)C.[CH2:32]([Cl:34])Cl>ClCCCl>[Cl:3][C:24]1[C:15]([C:8]2[C:7]([F:6])=[CH:12][C:11]([F:13])=[CH:10][C:9]=2[F:14])=[C:32]([Cl:34])[C:17]2[N:18]=[N:19][CH:20]=[CH:21][C:22]=2[N:23]=1
Reactant: O=C1Nc2ccnnc2C(=O)C1c1c(F)cc(F)cc1F
Reactant: O=P(Cl)(Cl)Cl
Reactant: ClCCl
Solvent: ClCCCl
Solvent: CN(C)C=O
Product: Fc1cc(F)c(-c2c(Cl)nc3ccnnc3c2Cl)c(F)c1
Reaction time: 18 h

Procedure:
Phosphorus oxychloride (0.048 ml) was added to the product from Step 3 (0.05 g) in 1,2-dichloroethane (2 ml) containing a catalytic amount of DMF. The suspension was stirred and refluxed for 1 hour and then stood for 18 hours, and then refluxed for a further hour and then allowed to cool. The excess phosphorus oxychloride was evaporated to give a brown oil, which was dissolved in DCM and washed with cold water. The organic layer was separated and dried over magnesium sulphate, filtered and evaporated to give a brown oil, which was purified by flash column chromatography on silica gel (40-60) eluting with diethyl ether to give 6,8-dichloro-7-(2,4,6-trifluorophenyl)-pyrido[3,2-c]pyridazine as a yellow oil (0.015 g).
Reaction SMILES: [CH2:1]1[O:9][C:8]2[CH:7]=[CH:6][C:5]([CH3:10])=[CH:4][C:3]=2[O:2]1.[N+:11]([O-])([OH:13])=[O:12]>C(O)(=O)C>[N+:11]([C:6]1[CH:7]=[C:8]2[O:9][CH2:1][O:2][C:3]2=[CH:4][C:5]=1[CH3:10])([O-:13])=[O:12]
Reactant: Cc1ccc2c(c1)OCO2
Reactant: O=[N+]([O-])O
Solvent: CC(=O)O
Product: Cc1cc2c(cc1[N+](=O)[O-])OCO2
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 64.4 %

Procedure:
To a solution of 10 (19.0 g, 139.6 mmol) in acetic acid (180 mL) was added a solution of fuming HNO3 (10 mL) in acetic acid (70 mL) dropwise over 30 minutes. The mixture was stirred at ambient temperature for 10 minutes, then poured into a beaker containing ice to give a crystalline precipitate, which was collected by vacuum filtration and washed with water to afford the crude product. Further purification via recrystallization from CH2Cl2/hexane gave the pure product (16.3 g, 64.4%).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH2:9][CH2:10][C:11]([O:13][CH2:14][CH3:15])=[O:12])[CH:6]=[CH:7][CH:8]=1.[CH:16](OCC)=[O:17].[Na]>CCOCC>[CH:16]([CH:10]([CH2:9][C:5]1[CH:6]=[CH:7][CH:8]=[C:3]([O:2][CH3:1])[CH:4]=1)[C:11]([O:13][CH2:14][CH3:15])=[O:12])=[O:17]
Reactant: CCOC(=O)CCc1cccc(OC)c1
Reactant: CCOC=O
Agent: [Na]
Solvent: CCOCC
Product: CCOC(=O)C(C=O)Cc1cccc(OC)c1
Temperature: 25 °C
Reaction time: 16 h
Yield: 40.6 %

Procedure:
A mixture of ethyl 3-(3-methoxyphenyl)propionate (100 g) and ethyl formate (37 g) was added dropwise to a mixture of sodium wire (11 g) in stirred ether (500 ml) at 0°. The mixture was stirred at room temperature for 16 hours and evaporated to dryness. The residue was dissolved in water and extracted with ether, the extracted aqueous phase was adjusted to pH 4 with hydrochloric acid and was extracted with ether and the ether extract was evaporated to dryness to give ethyl 2-formyl-3-(3-methoxyphenyl)propionate (46.05 g).
Reaction SMILES: [O:1]=[C:2]1[C@H:7]([NH:8][C:9](=[O:15])[O:10][C:11]([CH3:14])([CH3:13])[CH3:12])[CH2:6][CH2:5][CH2:4][NH:3]1.[H-].[Na+].I[CH3:19].O>CN(C)C=O>[CH3:19][N:3]1[CH2:4][CH2:5][CH2:6][C@@H:7]([NH:8][C:9](=[O:15])[O:10][C:11]([CH3:12])([CH3:14])[CH3:13])[C:2]1=[O:1]
Reactant: CC(C)(C)OC(=O)N[C@@H]1CCCNC1=O
Reactant: CI
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CN1CCC[C@@H](NC(=O)OC(C)(C)C)C1=O
Reaction time: 0.5 h
Yield: 45.3 %

Procedure:
To a solution of (R)-tert-butyl 2-oxopiperidin-3-ylcarbamate (642 mg, 3.00 mmol) in N,N-dimethylformamide (3 mL) at room temperature was added sodium hydride (132 mg, 3.3 mmol). The reaction mixture stirred for 30 min, then iodomethane (206 μL, 3.3 mmol) was added and stirring was continued for 1 h. The reaction mixture was poured into water (50 mL) and extracted with EtOAc (100 mL), using a continuous extractor apparatus overnight. The organic extract was evaporated to dryness under vacuum and the crude residue was purified by SiO2 chromatography (23 g, CH2Cl2/MeOH/NH4OH, 100:0:0 to 94:5.7:0.3) to give 310 mg (45%) of (R)-tert-butyl 1-methyl-2-oxopiperidin-3-ylcarbamate as a colorless viscous oil.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[C:6]([C:8]([N:10]2[C:16]3[CH:17]=[CH:18][CH:19]=[CH:20][C:15]=3[CH2:14][N:13]3[C:21]([C:24]([OH:26])=O)=[CH:22][CH:23]=[C:12]3[CH2:11]2)=[O:9])[CH:5]=[CH:4][C:3]=1[C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][C:28]=1[C:33]([F:36])([F:35])[F:34].C(N1C=CN=C1)(N1C=CN=C1)=O.C(=O)(O)O.[NH2:53][C:54]([NH2:56])=[NH:55]>CN(C)C=O.O>[CH3:1][C:2]1[CH:7]=[C:6]([C:8]([N:10]2[C:16]3[CH:17]=[CH:18][CH:19]=[CH:20][C:15]=3[CH2:14][N:13]3[C:21]([C:24]([NH:55][C:54]([NH2:56])=[NH:53])=[O:26])=[CH:22][CH:23]=[C:12]3[CH2:11]2)=[O:9])[CH:5]=[CH:4][C:3]=1[C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][C:28]=1[C:33]([F:36])([F:35])[F:34]
Reactant: N=C(N)N
Reactant: Cc1cc(C(=O)N2Cc3ccc(C(=O)O)n3Cc3ccccc32)ccc1-c1ccccc1C(F)(F)F
Agent: O=C(O)O
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: CN(C)C=O
Solvent: O
Product: Cc1cc(C(=O)N2Cc3ccc(C(=O)NC(=N)N)n3Cc3ccccc32)ccc1-c1ccccc1C(F)(F)F
Temperature: 100 °C
Reaction time: 0.5 h
Yield: 46.1 %

Procedure:
10-[(2-Methyl-2′-trifluoromethyl-[1,1′-biphenyl]4-yl)-carbonyl]-10,11-dihydro-5H-pyrrolo[2,1-c][1,4]benzodiazepine-3-carboxylic acid of Example 1, Step F (0.50 g, 1.02 mmol) and 1,1′-carbonyldiimidazole (0.17 g, 1.05 mmol) were dissolved in anhydrous N,N-dimethylformamide (5 mL). After stirring for 30 minutes, guanidine carbonate (0.19 g, 1.05 mmol) was added, and the reaction was heated to 100° C. for 4 hours. After cooling, the reaction mixture was diluted with water and extracted with ethyl acetate. The organic layers were combined and dried over anhydrous sodium sulfate, filtered and concentrated in vacuo to give an orange oil. Purification was achieved by preparative HPLC on a Primesphere 5 C18 (0.2×15 cm) column using a solvent gradient from 55:45:0.1 to 90:10:0.1 acetonitrile-water-trifluoroacetic acid. After removal of the acetonitrile in vacuo, the aqueous solution was neutralized with saturated aqueous sodium bicarbonate, and then extracted with ethyl acetate. The combined organic layers were dried over anhydrous sodium sulfate, filtered and concentrated in vacuo to give 0.25 g of the title compound as a white solid.
Reaction SMILES: CO[CH:3]1[CH:7]=[CH:6][CH:5](OC)[O:4]1.[NH2:10][CH:11]([CH2:17][SH:18])[C:12]([O:14][CH2:15][CH3:16])=[O:13]>C(#N)C.S(Cl)(C1C=CC(C)=CC=1)(=O)=O>[NH2:10][CH:11]([CH2:17][S:18][C:5]1[O:4][CH:3]=[CH:7][CH:6]=1)[C:12]([O:14][CH2:15][CH3:16])=[O:13]
Reactant: CCOC(=O)C(N)CS
Reactant: COC1C=CC(OC)O1
Agent: Cc1ccc(S(=O)(=O)Cl)cc1
Solvent: CC#N
Product: CCOC(=O)C(N)CSc1ccco1
Temperature: 25 °C
Reaction time: 1 h
Yield: 31 %

Procedure:
To 16.25 g (125 mmol) of 2,5-dimethoxy-2,5-dihydrofuran and 23.20 g (125 mmol) of ethyl 2-amino-3-mercaptopropanoate in 100 ml dry acetonitrile was added approximately 0.15 g of tosyl chloride. The mixture was stirred 1 hour at room temperature under nitrogen during which time complete solution was attained which became very dark. The mixture was concentrated in vacuo, taken up in ethyl acetate, then extracted with aqueous NaHCO3 solution followed by saturated NaCl solution. The organic portion was dried over MgSO4, filtered then concentrated to 50 ml. The concentrate was then chromatographed to give 8.35 g (31.0%) of the title compound as a dark oil.
Reaction SMILES: [S:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[C:2]1[S:10][CH2:11][C:12]([OH:14])=O.[NH:15]1[CH2:21][CH2:20][CH2:19][CH2:18][C:17]2[CH:22]=[CH:23][CH:24]=[CH:25][C:16]1=2>>[S:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[C:2]1[S:10][CH2:11][C:12]([N:15]1[CH2:21][CH2:20][CH2:19][CH2:18][C:17]2[CH:22]=[CH:23][CH:24]=[CH:25][C:16]1=2)=[O:14]
Reactant: O=C(O)CSc1nc2ccccc2s1
Reactant: c1ccc2c(c1)CCCCN2
Product: O=C(CSc1nc2ccccc2s1)N1CCCCc2ccccc21
Yield: 23 %

Procedure:
The title compound was synthesized according to General Procedure B using 2-(benzo[d]thiazol-2-ylthio)acetic acid and 2,3,4,5-tetrahydro-1H-benzo[b]azepine (6) to yield 45 as a white solid (23%): MS m/z: 355 (M+H)+. Anal. Calcd. For, C19H18N2OS2: C, 64.38; H, 5.12; N, 7.90; S, 18.09. Found: C, 64.53; H, 5.06; N, 7.83; S, 17.93.
Reaction SMILES: [C@@H:1]1([N:9]2[CH:17]=[C:15]([CH3:16])[C:13](=[O:14])[NH:12][C:10]2=[O:11])[O:8][C@H:5]([CH2:6][OH:7])[C@@H:3]([OH:4])[CH2:2]1.N1C=CC=CC=1.[CH3:24][S:25](Cl)(=[O:27])=[O:26]>O>[CH3:24][S:25]([O:4][C@@H:3]1[C@@H:5]([CH2:6][O:7][S:25]([CH3:24])(=[O:27])=[O:26])[O:8][C@@H:1]([N:9]2[CH:17]=[C:15]([CH3:16])[C:13](=[O:14])[NH:12][C:10]2=[O:11])[CH2:2]1)(=[O:27])=[O:26]
Reactant: Cc1cn([C@H]2C[C@H](O)[C@@H](CO)O2)c(=O)[nH]c1=O
Reactant: CS(=O)(=O)Cl
Solvent: c1ccncc1
Solvent: O
Product: Cc1cn([C@H]2C[C@H](OS(C)(=O)=O)[C@@H](COS(C)(=O)=O)O2)c(=O)[nH]c1=O
Temperature: 0 °C
Reaction time: 18 h
Yield: 81.2 %

Procedure:
A 3 liter, 3 necked round-bottomed flask was equipped with an overhead stirrer and paddle, a 500 mL dropping funnel and a Claisen adapter containing a drying tube and a thermometer. Thymidine (200 g, 0.82M) and pyridine (750 mL) were added to the flask. The mixture was stirred and warmed with a water bath (20 mins) to give a clear solution. The solution was then cooled in an ice bath to 0°-3° C. and the dropping funnel was charged with methanesulfonyl chloride (206.5 g, 1.08M). The methanesulfonyl chloride was then added dropwise over 40 minutes with no noticeable exotherm. The solution was stirred at 0° C. for 1 hr and then stored at 5° C. for 18 hr. The light brown mixture was then poured onto rapidly stirred water (3 L) containing ice (approx. 500 g). The desired product crystallised immediately. After stirring for 0.5 hr, the product was collected by filtration and washed several times with water (3×100 mL). The white solid was then dried under vacuum overnight (crude weight, 322 g, 98% yield). The product was recrystallised from hot acetone to give 267 g of a white solid (81% yield), mp 169°-171° C. (lit. 170°-171° C.)
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[S:10][C:9](SC)=[N:8][C:7]=1[NH2:13])=[O:5])[CH3:2].[CH3:14]O.O[O:17][S:18]([O-:20])=O.[K+]>O.C(OCC)(=O)C>[CH2:1]([O:3][C:4]([C:6]1[S:10][C:9]([S:18]([CH3:14])(=[O:20])=[O:17])=[N:8][C:7]=1[NH2:13])=[O:5])[CH3:2]
Reactant: O=S([O-])OO
Reactant: CCOC(=O)c1sc(SC)nc1N
Reactant: CO
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: O
Product: CCOC(=O)c1sc(S(C)(=O)=O)nc1N
Reaction time: 0.25 h

Procedure:
After adding 41.8 g of 4-amino-2-methylsulfanylthiazole-5-carboxylic acid ethyl ester [CAS No. 39736-29-3] to 3 liters of a water:methanol=1:1 mixed solvent at room temperature, 352 g of Oxone™ was added thereto in small portions over a period of 15 minutes with stirring. The mixture was stirred at room temperature for 16 hours and then poured into a mixture of 8 liters of ethyl acetate and 5 liters of water. The organic layer was washed with 5 liters of water and 3 liters of saturated brine and then dried over anhydrous magnesium sulfate. The desiccating agent was removed by filtration, and the filtrate was concentrated under reduced pressure to give the title compound (34.5 g) as a light yellow solid.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH:12]([CH2:16][CH:17]2[CH2:21][CH2:20][CH2:19][CH2:18]2)[C:13]([OH:15])=O)[CH:5]=[CH:6][C:7]=1[S:8]([CH3:11])(=[O:10])=[O:9].F[P-](F)(F)(F)(F)F.N1(O[P+](N(C)C)(N(C)C)N(C)C)C2C=CC=CC=2N=N1.C(N(CC)CC)C.S(O)(O)(=O)=O.[NH2:61][C:62]1[NH:63][CH:64]=[CH:65][N:66]=1>C(Cl)Cl>[Br:1][C:2]1[CH:3]=[C:4]([CH:12]([CH2:16][CH:17]2[CH2:21][CH2:20][CH2:19][CH2:18]2)[C:13]([NH:61][C:62]2[NH:63][CH:64]=[CH:65][N:66]=2)=[O:15])[CH:5]=[CH:6][C:7]=1[S:8]([CH3:11])(=[O:9])=[O:10]
Reactant: CS(=O)(=O)c1ccc(C(CC2CCCC2)C(=O)O)cc1Br
Reactant: Nc1ncc[nH]1
Agent: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Agent: F[P-](F)(F)(F)(F)F
Agent: O=S(=O)(O)O
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CS(=O)(=O)c1ccc(C(CC2CCCC2)C(=O)Nc2ncc[nH]2)cc1Br
Yield: 58.9 %

Procedure:
A solution of 2-(3-bromo-4-methanesulfonyl-phenyl)-3-cyclopentyl-propionic acid (prepared as in Example 148A, 100 mg, 0.266 mmol), benzotriazol-1-yloxy-tris(dimethylamino)phosphonium hexafluorophosphate (187 mg, 0.42 mmol), triethylamine (115 μL, 1.064 mmol), and 2-aminoimidazole sulfate (56 mg, 0.42 mmol) in methylene chloride (10 mL) was stirred at 25° C. for 15 h. The reaction mixture was partitioned between water and methylene chloride. The organic layer was washed sequentially with a 1N aqueous hydrochloric acid solution (1×10 mL) and water (1×10 mL). The organic layer was dried over magnesium sulfate, filtered, and concentrated in vacuo. Biotage chromatography (FLASH 40M, Silica, ethyl acetate) afforded 2-(3-bromo-4-methanesulfonyl-phenyl)-3-cyclopentyl-N-(1H-imidazol-2-yl)-propionamide (69 mg, 53%) as a white solid: mp >210° C. (dec); EI-HRMS m/e calcd for C18H22BrN3O3S (M+) 439.0565, found 439.0566.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([NH:9][CH:10]2[CH2:15][CH2:14][N:13]([CH2:16][C:17]3[CH:22]=[CH:21][N:20]=[C:19]([C:23]4[CH:28]=[C:27]([O:29][CH3:30])[C:26]([O:31][CH3:32])=[C:25]([O:33][CH3:34])[CH:24]=4)[CH:18]=3)[CH2:12][CH2:11]2)=[CH:5][CH:4]=1.[Cl:35][CH2:36][C:37]1[CH:38]=[N:39][CH:40]=[C:41]([C:43]2[CH:48]=[C:47]([O:49][CH3:50])[C:46]([O:51][CH3:52])=[C:45]([O:53][CH3:54])[CH:44]=2)[CH:42]=1>>[ClH:35].[ClH:35].[ClH:35].[CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([N:9]([CH:10]2[CH2:11][CH2:12][N:13]([CH2:16][C:17]3[CH:22]=[CH:21][N:20]=[C:19]([C:23]4[CH:24]=[C:25]([O:33][CH3:34])[C:26]([O:31][CH3:32])=[C:27]([O:29][CH3:30])[CH:28]=4)[CH:18]=3)[CH2:14][CH2:15]2)[CH2:36][C:37]2[CH:38]=[N:39][CH:40]=[C:41]([C:43]3[CH:48]=[C:47]([O:49][CH3:50])[C:46]([O:51][CH3:52])=[C:45]([O:53][CH3:54])[CH:44]=3)[CH:42]=2)=[CH:5][CH:4]=1
Reactant: COc1ccc(NC2CCN(Cc3ccnc(-c4cc(OC)c(OC)c(OC)c4)c3)CC2)cc1
Reactant: COc1cc(-c2cncc(CCl)c2)cc(OC)c1OC
Product: COc1ccc(N(Cc2cncc(-c3cc(OC)c(OC)c(OC)c3)c2)C2CCN(Cc3ccnc(-c4cc(OC)c(OC)c(OC)c4)c3)CC2)cc1
Product: Cl

Procedure:
4-(p-Anisidino)-1-[[2-(3,4,5-trimethoxyphenyl)pyridin-4-yl]methyl]piperidine (139 mg) and 3-chloromethyl-5-(3,4,5-trimethoxyphenyl)pyridine (114 mg) were condensed by the same manner as described in Example 9. Yellow oil of a free base was converted to a trihydrochloride which gave the title compound as yellow powder.
Reaction SMILES: [CH3:1][O:2][CH2:3][O:4][CH2:5][CH2:6][C:7]1[CH:12]=[CH:11][C:10](Br)=[CH:9][CH:8]=1.C([Li])CCC.[CH2:19]([N:26]1[CH2:31][CH2:30][C:29](=[O:32])[CH2:28][CH2:27]1)[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1.O>O1CCCC1.CCCCCC>[CH2:19]([N:26]1[CH2:31][CH2:30][C:29]([C:10]2[CH:11]=[CH:12][C:7]([CH2:6][CH2:5][O:4][CH2:3][O:2][CH3:1])=[CH:8][CH:9]=2)([OH:32])[CH2:28][CH2:27]1)[C:20]1[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=1
Reactant: O=C1CCN(Cc2ccccc2)CC1
Reactant: COCOCCc1ccc(Br)cc1
Agent: [Li]CCCC
Solvent: O
Solvent: CCCCCC
Solvent: C1CCOC1
Product: COCOCCc1ccc(C2(O)CCN(Cc3ccccc3)CC2)cc1
Temperature: -20 °C
Reaction time: 0.5 h
Yield: 57.8 %

Procedure:
Into a solution of 10 g of 4-bromophenethyl methoxymethyl ether in 200 ml of tetrahydrofuran was dropped 28 ml of a 1.6 M solution of n-butyllithium in hexane at −78° C. and the resulting mixture was stirred at the same temperature for 30 minutes. After heating to −20° C., a solution of 7.0 g of 1-benzyl-4-piperidone in tetrahydrofuran (10 ml) was added thereto. The mixture was reacted at the same temperature for 2 hours. After adding water, the resulting mixture was extracted with ethyl acetate, washed with a saturated aqueous solution of sodium chloride and dried over anhydrous magnesium sulfate. After distilling off the solvent under reduced pressure, 7.6 g of the title compound was obtained as a yellow oily substance.
Reaction SMILES: CN1CCOCC1.Cl.[NH2:9][CH2:10][C:11]([O:13][CH3:14])=[O:12].[CH2:15]([C@@H:19]([CH2:23][CH:24]=[CH2:25])[C:20](O)=[O:21])[CH:16]([CH3:18])[CH3:17].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>C(Cl)Cl.O>[CH2:15]([C@@H:19]([CH2:23][CH:24]=[CH2:25])[C:20]([NH:9][CH2:10][C:11]([O:13][CH3:14])=[O:12])=[O:21])[CH:16]([CH3:18])[CH3:17]
Reactant: C=CC[C@H](CC(C)C)C(=O)O
Reactant: COC(=O)CN
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: ClCCl
Solvent: CN1CCOCC1
Solvent: O
Product: C=CC[C@H](CC(C)C)C(=O)NCC(=O)OC
Reaction time: 16 h
Yield: 59.7 %

Procedure:
Step M (1): NMM (11.0 mL, 100 mmol) was added to a mixture of methyl 2-aminoacetate hydrochloride (4.44 g, 35.3 mmol), (S)-2-isobutylpent-4-enoic acid [prepared as described in WO 2004/013098] (4.6 g, 29.5 mmol), HATU (13.4 g, 35.3 mmol in DCM (200 mL) at room temperature. The mixture was stirred for 16 h. Poured the reaction mixture into 150 mL H2O. Extracted with DCM (3×250 mL). Washed combined organic extracts with brine, dried with Na2SO4, filtered and concentrated in vacuo. The residue was purified by silica gel chromatography to give (S)-methyl 2-(2-isobutylpent-4-enamido)acetate 4.0 g (60% yield) as a colorless oil: ESI (M+H)+=228.22. 1H NMR (300 MHz, CDCl3) δ ppm 0.79-0.93 (m, 6H) 1.15-1.30 (m, 1H) 1.48-1.71 (m, 2H) 2.08-2.38 (m, 3H) 3.72 (s, 3H) 4.01 (d, J=5.12 Hz, 2H) 4.92-5.09 (m, 2H) 5.63-5.78 (m, 1H) 5.92 (s, 1H).
Reaction SMILES: C([NH2:3])C.[C:4]([NH:6][C:7](=[N:10][CH2:11][CH2:12][S:13][CH2:14][C:15]1[NH:19][CH:18]=[N:17][C:16]=1[CH3:20])SC)#[N:5].[CH2:21](O)[CH3:22]>>[C:4]([NH:6][C:7]([N:10]([CH2:21][CH3:22])[CH2:11][CH2:12][S:13][CH2:14][C:15]1[NH:19][CH:18]=[N:17][C:16]=1[CH3:20])=[NH:3])#[N:5]
Reactant: CCN
Reactant: CSC(=NCCSCc1[nH]cnc1C)NC#N
Reactant: CCO
Product: CCN(CCSCc1[nH]cnc1C)C(=N)NC#N

Procedure:
Anhydrous ethylamine (9.0 g.) was added to a solution of N-cyano-N'-[2-((4-methyl-5-imidazolyl)methylthio)ethyl]-S-methylisothiourea (Example 3(c), 5.0 g.) in ethanol. The solution was heated under reflux for 8 hours and concentrated under reduced pressure. The residue was dissolved in isopropyl alcohol, filtered, and dilute with water. The white solid obtained was recrystallised from isopropyl alcohol-ether to yield N-cyano-N'-ethyl-N'-[2-((4-methyl-5-imidazolyl)methylthio)ethyl]guanidine, m.p. 118°-120°. (Found: C, 49.6; N, 6.8; N, 31.2; S, 11.7. C11H18N6S requires: C, 49.6; H, 6.8; N, 31.6; S, 12.0).