Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH3:1].[CH3:2][C:3]1[S:4][C:5]([S:9](Cl)(=[O:11])=[O:10])=[C:6]([CH3:8])[N:7]=1>C1COCC1>[CH3:2][C:3]1[S:4][C:5]([S:9]([NH2:1])(=[O:11])=[O:10])=[C:6]([CH3:8])[N:7]=1
Reactant: Cc1nc(C)c(S(=O)(=O)Cl)s1
Reactant: N
Solvent: C1CCOC1
Product: Cc1nc(C)c(S(N)(=O)=O)s1
Temperature: -78 °C
Reaction time: 1 h
Yield: 97 %

Procedure:
Liquid ammonia was added dropwise via a CO2/acetone condenser to a solution of 2,4-dimethylthiazole-5-sulfonyl chloride (260 mg, 1.228 mmol) in THF (3 mL) at −78° C. until the volume had approximately doubled (˜10 min). The reaction was stirred at −78° C. for 1 h and then allowed to slowly warm to rt. The reaction was concentrated to dryness and the residue was diluted with CH2Cl2. The slurry was filtered to remove the solids and the solution was concentrated to yield 2,4-dimethylthiazole-5-sulfonamide (230 mg, 1.2 mmol, 97% yield) as a light yellow solid. LC-MS retention time 0.43 min; m/z 191 (MH−). LC data was recorded on a Shimadzu LC-10AS liquid chromatograph equipped with a Phenomenex-Luna 10 u C18 3.0×50 mm column using a SPD-10AV UV-Vis detector at a detector wave length of 220 nM. The elution conditions employed a flow rate of 5 ml/min, a gradient of 100% solvent A/0% solvent B to 0% solvent A/100% solvent B, a gradient time of 3 min, a hold time of 1 min, and an analysis time of 4 min where solvent A was 5% acetonitrile/95% H2O/10 mM ammonium acetate and solvent B was 5% H2O/95% acetonitrile/10 mM ammonium acetate. MS data was determined using a Micromass Platform for LC in electrospray mode.
Reaction SMILES: [H-].[Na+].[C:3]1([CH2:13][NH:14][C:15]2[O:19][N:18]=[C:17]([C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)[CH:16]=2)[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[CH:6]=[CH:5][CH:4]=1.Br[CH2:27][C:28]([O:30][CH2:31][CH3:32])=[O:29].C(=O)(O)[O-].[Na+]>CN(C=O)C>[CH2:31]([O:30][C:28](=[O:29])[CH2:27][N:14]([CH2:13][C:3]1[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[CH:6]=[CH:5][CH:4]=1)[C:15]1[O:19][N:18]=[C:17]([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[CH:16]=1)[CH3:32]
Reactant: c1ccc(-c2cc(NCc3cccc4ccccc34)on2)cc1
Reactant: CCOC(=O)CBr
Agent: O=C([O-])O
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCOC(=O)CN(Cc1cccc2ccccc12)c1cc(-c2ccccc2)no1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 79.2 %

Procedure:
Charged flask with a 60% sodium hydride in oil dispersion (64.0 mg, 1.6 mmol) and suspended in DMF (1 ml). A DMF (1 ml) solution of naphthalen-1-ylmethyl-(3-phenylisoxazol-5-yl)-amine (300 mg, 1.0 mmol ) was added and the mixture stirred under argon at rt for 30 min resulting in a light yellow solution. After adding ethyl bromoacetate (333 μl, 3.0 mmol), the reaction was stirred at rt for 1 hr, poured into 10% sodium bicarbonate (aq) and extracted with ethyl acetate (3×). The extracts were combined, washed with brine, dried over magnesium sulfate, filtered and concentrated in vacuo to give a crude oil (370 mg). Flash chromatography on silica gel (15% ethyl acetate in hexane) gave the title compound as a colorless oil (306 mg, 73.9%).
Reaction SMILES: [CH3:1][S:2][C:3]1[CH:10]=[CH:9][C:6]([CH2:7]Cl)=[CH:5][CH:4]=1.[CH2:11]([O:13][P:14]([O:18]CC)[O:15][CH2:16][CH3:17])[CH3:12]>>[CH3:1][S:2][C:3]1[CH:10]=[CH:9][C:6]([CH2:7][P:14](=[O:18])([O:15][CH2:16][CH3:17])[O:13][CH2:11][CH3:12])=[CH:5][CH:4]=1
Reactant: CCOP(OCC)OCC
Reactant: CSc1ccc(CCl)cc1
Product: CCOP(=O)(Cc1ccc(SC)cc1)OCC

Procedure:
4-Methylmercaptobenzyl chloride (160 g, 0.94 mol) was added dropwise, under nitrogen, with stirring to 183 g (1.1 mole) of triethylphosphite which was heated at reflux. When the addition of the 4-methylmercaptobenzyl chloride was completed, the mixture was refluxed for additional 4 hours. The product was distilled in vacuo to yield 229 g (89%) of water clear, viscous liquid bp 142°-145° C. (0.025 mm).
Reaction SMILES: C[O:2][C:3](=[O:27])[C@@H:4]([N:12]1[CH2:16][C:15]([O:17][C:18]2[CH:23]=[CH:22][C:21]([Cl:24])=[CH:20][C:19]=2[Cl:25])=[CH:14][C:13]1=[O:26])[CH2:5][CH:6]1[CH2:11][CH2:10][CH2:9][CH2:8][CH2:7]1.[OH-].[Li+]>O1CCCC1.O>[CH:6]1([CH2:5][C@H:4]([N:12]2[CH2:16][C:15]([O:17][C:18]3[CH:23]=[CH:22][C:21]([Cl:24])=[CH:20][C:19]=3[Cl:25])=[CH:14][C:13]2=[O:26])[C:3]([OH:27])=[O:2])[CH2:11][CH2:10][CH2:9][CH2:8][CH2:7]1
Reactant: COC(=O)[C@H](CC1CCCCC1)N1CC(Oc2ccc(Cl)cc2Cl)=CC1=O
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: O=C(O)[C@H](CC1CCCCC1)N1CC(Oc2ccc(Cl)cc2Cl)=CC1=O
Temperature: 23 °C
Reaction time: 2 h
Yield: 75.3 %

Procedure:
To a stirred solution of (S)-3-cyclohexyl-2-[4-(2,4-dichloro-phenoxy)-2-oxo-2,5-dihydro-pyrrol-1-yl]-propionic acid methyl ester (340 mg, 0.001 mol) in tetrahydrofuran-water (3:1, 10 mL) was added lithium hydroxide (106 mg, 0.003 mol). The reaction mixture was stirred at 23° C. for 2 h. After this time, the mixture was concentrated and the reaction mixture was diluted with water. The reaction mixture was acidified with 2N hydrochloric acid, during which time precipitation occurred. The precipitate was removed by filtration, washed with cold water and dried in vacuo to obtain (S)-3-cyclohexyl-2-[4-(2,4-dichloro-phenoxy)-2-oxo-2,5-dihydro-pyrrol-1-yl]-propionic acid (300 mg, 78%) as a light yellow solid.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][O:4][CH2:5][C:6]1[NH:7][C:8]([CH3:28])=[C:9]([C:24]([O:26][CH3:27])=[O:25])[CH:10]([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=2[Cl:23])[C:11]=1[C:12]([O:14][CH2:15][CH3:16])=[O:13].[C:29](N1C=CN=C1)([N:31]1[CH:35]=[CH:34][N:33]=[CH:32]1)=[O:30].CN1CCOCC1>O1CCCC1>[Cl:23][C:18]1[CH:19]=[CH:20][CH:21]=[CH:22][C:17]=1[CH:10]1[C:9]([C:24]([O:26][CH3:27])=[O:25])=[C:8]([CH3:28])[NH:7][C:6]([CH2:5][O:4][CH2:3][CH2:2][NH:1][C:29]([N:31]2[CH:35]=[CH:34][N:33]=[CH:32]2)=[O:30])=[C:11]1[C:12]([O:14][CH2:15][CH3:16])=[O:13]
Reactant: CCOC(=O)C1=C(COCCN)NC(C)=C(C(=O)OC)C1c1ccccc1Cl
Reactant: O=C(n1ccnc1)n1ccnc1
Solvent: CN1CCOCC1
Solvent: C1CCOC1
Product: CCOC(=O)C1=C(COCCNC(=O)n2ccnc2)NC(C)=C(C(=O)OC)C1c1ccccc1Cl
Yield: 66.2 %

Procedure:
A solution of 2-(2-aminoethoxy)methyl-4-(2-chlorophenyl)-3-ethoxycarbonyl-5-methoxycarbonyl-6-methyl-1,4-dihydropyridine (20.4 g), carbonyldiimidazole (8.9 g) and N-methylmorpholine (20 ml) in tetrahydrofuran (500 ml) was stirred at room temperature for 2 hours and then evaporated. The residue was partitioned between ethyl acetate and water and the organic layer washed with water, dried (Na2SO4), and evaporated. The residual solid was washed with diethyl ether and dried to give the title compound (16.6 g), m.p. 149°-151° C. Found: C,57.35; H,5.54; N,11.22. C24H27ClN4O6 requires: C,57.54; H,5.43; N,11.18%.
Reaction SMILES: [F:1][C:2]1[CH:12]=[CH:11][C:5]2[N:6]([CH3:10])[C:7](=O)[NH:8][C:4]=2[CH:3]=1.CCN(C1C=CC=CC=1)CC.P(Cl)(Cl)([Cl:26])=O>>[Cl:26][C:7]1[N:6]([CH3:10])[C:5]2[CH:11]=[CH:12][C:2]([F:1])=[CH:3][C:4]=2[N:8]=1
Reactant: Cn1c(=O)[nH]c2cc(F)ccc21
Reactant: O=P(Cl)(Cl)Cl
Solvent: CCN(CC)c1ccccc1
Product: Cn1c(Cl)nc2cc(F)ccc21
Temperature: 0 °C
Reaction time: 2 h

Procedure:
3.9 g 5-fluoro-1-methyl-1,3-dihydro-benzimidazole-2-one are suspended in 80 ml phosphorus oxychloride and the reaction mixture is stirred for 2 hours at reflux temperature. 50 ml diethylaniline are added. The reaction mixture is stirred for a further 10 minutes at reflux temperature and slowly mixed with ice water. The product is extracted with dichloromethane and purified by chromatography (silica gel, cyclohexane, methylene chloride/acetone 20/1). 1.4 g product are obtained as a solid. M.p=138-141° C.
Reaction SMILES: [CH3:1][N:2]1[C:6]2[CH:7]=[CH:8][C:9]([N:11]3[CH2:15][C@H:14]([C:16]([O:18]CCCC)=O)[O:13][C:12]3=[O:23])=[CH:10][C:5]=2[S:4][C:3]1=[O:24].[CH2:25]([CH2:27][NH2:28])[OH:26]>C(#N)C>[OH:26][CH2:25][CH2:27][NH:28][C:16]([C@@H:14]1[O:13][C:12](=[O:23])[N:11]([C:9]2[CH:8]=[CH:7][C:6]3[N:2]([CH3:1])[C:3](=[O:24])[S:4][C:5]=3[CH:10]=2)[CH2:15]1)=[O:18]
Reactant: NCCO
Reactant: CCCCOC(=O)[C@H]1CN(c2ccc3c(c2)sc(=O)n3C)C(=O)O1
Solvent: CC#N
Product: Cn1c(=O)sc2cc(N3C[C@H](C(=O)NCCO)OC3=O)ccc21
Temperature: 25 °C
Reaction time: 18 h

Procedure:
A solution of butyl(5R)-3-(2,3-dihydro-3-methyl-2-oxo-6-benzothiazolyl)-2-oxo-5-oxazolidinecarboxylate (EXAMPLE 29, Step 2, 300 mg, 0.856 mmol) in acetonitrile (3.4 mL) is treated with ethanolamine (103 μL, 1.71 mmol) and stirred at ambient temperature for 18 h. Solvent is removed under reduced pressure, and the crude product is triturated and filtered from hot ethyl acetate to give the title compound, mp 217-219° C.; MS (ESI+) for C14H15N3O5S m/z 338 (M+H)+; [α]25D−43 (c 0.99, DMSO).
Reaction SMILES: [CH2:1]([O:5][C:6]1[CH:28]=[CH:27][C:9]([C:10]([N:12]2[C:20]3[C:15](=[C:16]([CH:21]=[CH:22][C:23]([OH:25])=[O:24])[CH:17]=[CH:18][CH:19]=3)[CH:14]=[C:13]2[CH3:26])=[O:11])=[CH:8][CH:7]=1)[CH2:2][CH2:3][CH3:4].[H][H]>CO.C(OCC)(=O)C.[Pd]>[CH2:1]([O:5][C:6]1[CH:28]=[CH:27][C:9]([C:10]([N:12]2[C:20]3[C:15](=[C:16]([CH2:21][CH2:22][C:23]([OH:25])=[O:24])[CH:17]=[CH:18][CH:19]=3)[CH:14]=[C:13]2[CH3:26])=[O:11])=[CH:8][CH:7]=1)[CH2:2][CH2:3][CH3:4]
Reactant: CCCCOc1ccc(C(=O)n2c(C)cc3c(C=CC(=O)O)cccc32)cc1
Reactant: [H][H]
Agent: [Pd]
Solvent: CO
Solvent: CCOC(C)=O
Product: CCCCOc1ccc(C(=O)n2c(C)cc3c(CCC(=O)O)cccc32)cc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 8.3 %

Procedure:
To a solution of 3-(1-(4-butoxybenzoyl)-2-methylindol-4-yl)acrylic acid (300 mg; prepared in Example 4) in methanol-ethyl acetate (5 ml+5 ml) was added palladium on activated carbon (100 mg) at room temperature. The inside of the vessel was replaced with hydrogen and the mixture was stirred at room temperature for 2 hours. The mixture was filtered through Celite (trademark). The filtrate and washing with chloroform were combined, and then concentrated under reduced pressure. The residue was purified by column chromatography on silica gel (chloroform-methanol) to give the title compound (25 mg) having the following physical data.
Reaction SMILES: C([O:3][C:4](=[O:33])[CH2:5][CH:6]1[S:10][C:9]([C:11]2[NH:12][C:13]3[C:18]([CH:19]=2)=[CH:17][C:16]([O:20][C:21]2[CH:22]=[N:23][C:24]([S:27]([CH3:30])(=[O:29])=[O:28])=[CH:25][CH:26]=2)=[CH:15][C:14]=3[CH2:31][CH3:32])=[N:8][CH2:7]1)C.CO.[OH-].[K+]>O1CCCC1>[CH2:31]([C:14]1[CH:15]=[C:16]([O:20][C:21]2[CH:22]=[N:23][C:24]([S:27]([CH3:30])(=[O:28])=[O:29])=[CH:25][CH:26]=2)[CH:17]=[C:18]2[C:13]=1[NH:12][C:11]([C:9]1[S:10][CH:6]([CH2:5][C:4]([OH:33])=[O:3])[CH2:7][N:8]=1)=[CH:19]2)[CH3:32]
Reactant: CCOC(=O)CC1CN=C(c2cc3cc(Oc4ccc(S(C)(=O)=O)nc4)cc(CC)c3[nH]2)S1
Agent: [K+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Product: CCc1cc(Oc2ccc(S(C)(=O)=O)nc2)cc2cc(C3=NCC(CC(=O)O)S3)[nH]c12
Temperature: 25 °C
Reaction time: 15 h
Yield: 88.4 %

Procedure:
To a solution of ethyl[2-(7-ethyl-5-{[6-(methylsulfonyl)pyridin-3-yl]oxy}-1H-indol-2-yl)-4,5-dihydro-1,3-thiazol-5-yl]acetate (3.0 g), methanol (15 mL), and tetrahydrofuran (30 mL) was added an aqueous solution (10 mL) of potassium hydroxide (1.1 g), and the mixture was stirred at room temperature for 15 hr. The reaction solution was concentrated, acidified with aqueous citric acid solution, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over magnesium sulfate, filtered and concentrated under reduced pressure. The obtained pale-yellow crystals were washed with ethyl acetate-hexane to give the title compound (2.5 g, yield 88%) as pale-yellow crystals.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:12][CH2:11][CH:10]([CH3:13])[CH:9]1[CH:14]=[CH:15][CH2:16][OH:17])=[O:7])([CH3:4])([CH3:3])[CH3:2].CCN(CC)CC.[CH3:25][S:26](Cl)(=[O:28])=[O:27]>C(Cl)Cl>[C:1]([O:5][C:6]([N:8]1[CH2:12][CH2:11][CH:10]([CH3:13])[CH:9]1[CH:14]=[CH:15][CH2:16][O:17][S:26]([CH3:25])(=[O:28])=[O:27])=[O:7])([CH3:3])([CH3:2])[CH3:4]
Reactant: CC1CCN(C(=O)OC(C)(C)C)C1C=CCO
Reactant: CS(=O)(=O)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC1CCN(C(=O)OC(C)(C)C)C1C=CCOS(C)(=O)=O
Reaction time: 0.08 h

Procedure:
To a solution containing 62 (6.0 g, 0.025 mol) in DCM (25 mL) at 0° C. was added Et3N (4.5 mL, 0.032 mol). After 5 min, a solution containing methanesulfonylchloride (2.33 mL, 0.03 mol) in DCM (5 mL) was added drop wise. After 2 h, TLC analysis revealed complete consumption of 62 [1:1 hexanes/EtOAc, Rf(63)=0.5, Rf(62)=0.4]. The reaction mixture was poured onto ice-water and extracted with DCM. The organic extracts were washed with water, brine, and dried over anhydrous Na2SO4, filtered, and concentrated to afford 7.05 g (89%) of crude 63 as a pale brown oil which was used without further purification. 1H NMR (CDCl3, 300 MHz) δ5.8-5.5 (m, 2H), 4.69 (d. J=6.15 Hz, 2H), 3.85-3.3 (m, 3H), 3.0 (s, 3H), 2.0-1.9 (m, 1H), 1.55-1.30 (m, 1H), 1.40 (s, 9H), 1.0 (d, J=6.74 Hz, 3H) ppm.
Reaction SMILES: [N:1]1[C:9]([NH2:10])=[C:8]2[C:4]([NH:5][CH:6]=[N:7]2)=[N:3][CH:2]=1.[H-].[Na+].Br[CH2:14][C:15]1[N:19]([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[C:18]2[CH:26]=[CH:27][CH:28]=[CH:29][C:17]=2[N:16]=1>CN(C=O)C>[C:20]1([N:19]2[C:18]3[CH:26]=[CH:27][CH:28]=[CH:29][C:17]=3[N:16]=[C:15]2[CH2:14][N:5]2[CH:6]=[N:7][C:8]3[C:4]2=[N:3][CH:2]=[N:1][C:9]=3[NH2:10])[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=1
Reactant: BrCc1nc2ccccc2n1-c1ccccc1
Reactant: Nc1ncnc2[nH]cnc12
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: Nc1ncnc2c1ncn2Cc1nc2ccccc2n1-c1ccccc1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 6.5 %

Procedure:
To a mixture of 9H-purin-6-ylamine (61 mg, 0.454 mmol) in DMF (1 mL) was added NaH (60% in mineral oil, 18 mg, 0.454 mmol) and the suspension was stirred at RT for 10 min under a nitrogen atmosphere. 2-Bromomethyl-1-phenyl-1H-benzoimidazole from Example 5 (0.454 mmol) in DMF (3 mL) was subsequently added and the reaction mixture was stirred at RT for 1 h. The crude reaction mixture was loaded onto an Isolute® SCX-2 cartridge which was washed with MeOH and the product eluted with 2M NH3/MeOH. The product containing fractions were combined and concentrated under reduced pressure. The resulting residue was purified by column chromatography (Si—PCC, gradient 0-10% MeOH in DCM), then triturated with diethyl ether and purified by preparative HPLC (Phenomenex Gemini 5 μm C18 on a gradient 20-98% 0.1% HCO2H in acetonitrile/water). Crystallization from EtOAc/MeOH afforded 106 as a white solid (10 mg, 6%). LCMS: RT 3.47 min [M+H]+ 342.1. 1H NMR (CDCl3, 400 MHz): δ 8.21 (1H, s), 7.87 (1H, s), 7.84 (1H, d, J=8.01 Hz), 7.48-7.43 (3H, m), 7.36-7.20 (4H, m), 7.12 (1H, d, J=8.03 Hz), 5.57 (2H, s), 5.50 (2H, br)
Reaction SMILES: [CH3:1][S:2](Cl)(=[O:4])=[O:3].[F:6][C:7]1[C:12]2[CH2:13][NH:14][CH2:15][CH2:16][S:17][C:11]=2[CH:10]=[CH:9][CH:8]=1.Cl.C(N(CC)CC)C>ClCCl>[F:6][C:7]1[C:12]2[CH2:13][N:14]([S:2]([CH3:1])(=[O:4])=[O:3])[CH2:15][CH2:16][S:17][C:11]=2[CH:10]=[CH:9][CH:8]=1
Reactant: Fc1cccc2c1CNCCS2
Reactant: CS(=O)(=O)Cl
Agent: Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CS(=O)(=O)N1CCSc2cccc(F)c2C1
Temperature: 25 °C
Reaction time: 0.33 h

Procedure:
A solution of methanesulphonyl chloride (1.83 g) in dichloromethane (30 ml) was added dropwise at room temperature to a stirred solution of 6-fluoro-2,3,4,5-tetrahydro-1,4-benzothiazepine (2.65 g, prepared in a similar manner to its hydrochloride, Example 3 above) and triethylamine (1.6 g) in dichloromethane (60 ml). The reaction mixture was stirred at room temperature for 20 minutes, washed with water, dried and the solvent was removed by evaporation. Purification of the residue by flash chromatography using dichloromethane as eluent gave 6-fluoro-4-methylsulphonyl-2,3,4,5-tetrahydro-1,4-benzothiazepine, which was recrystallised from hexane. Yield 3.3 g (m.p. 115°-117° C.).
Reaction SMILES: [CH:1]([C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([CH:10]([CH3:12])[CH3:11])[C:5]=1[N:13]=[C:14]=[N:15][C:16]1[C:21]([CH:22]([CH3:24])[CH3:23])=[CH:20][CH:19]=[CH:18][C:17]=1[CH:25]([CH3:27])[CH3:26])([CH3:3])[CH3:2].[CH2:28]([N:30]([CH2:32][CH3:33])[OH:31])[CH3:29].[OH-].[Na+]>C1COCC1>[CH:22]([C:21]1[CH:20]=[CH:19][CH:18]=[C:17]([CH:25]([CH3:27])[CH3:26])[C:16]=1[NH:15][C:14](=[N:13][C:5]1[C:6]([CH:10]([CH3:12])[CH3:11])=[CH:7][CH:8]=[CH:9][C:4]=1[CH:1]([CH3:3])[CH3:2])[O:31][N:30]([CH2:32][CH3:33])[CH2:28][CH3:29])([CH3:24])[CH3:23]
Reactant: CC(C)c1cccc(C(C)C)c1N=C=Nc1c(C(C)C)cccc1C(C)C
Reactant: CCN(O)CC
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Product: CCN(CC)OC(=Nc1c(C(C)C)cccc1C(C)C)Nc1c(C(C)C)cccc1C(C)C
Temperature: 25 °C
Reaction time: 22 h
Yield: 32.3 %

Procedure:
To a solution of bis(2,6-diisopropylphenyl)carbodiimide (4.35 g, 12 mmol) and N,N-diethylhydroxylamine (1.6 g, 18 mmol) in THF (20 ml) is added finely powdered NaOH (48 mg) and the mixture is stirred at room temperature for 22 hours. The reaction mixture is then filtered and the filtrate is evaporated on the rotary evaporator below 45° C. The residue is recrystallized twice from acetonitrile to afford 1.75 g of the title compound as a white solid, mp. 113-116° C.
Reaction SMILES: [CH:1]1[C:6]([CH2:7][C@H:8]([NH2:12])[C:9]([OH:11])=[O:10])=[CH:5][CH:4]=[C:3]([N+:13]([O-:15])=[O:14])[CH:2]=1.[OH-].[Na+].[CH3:18][O:19][C:20](Cl)=[O:21]>O>[CH3:18][O:19][C:20]([NH:12][C@H:8]([C:9]([OH:11])=[O:10])[CH2:7][C:6]1[CH:5]=[CH:4][C:3]([N+:13]([O-:15])=[O:14])=[CH:2][CH:1]=1)=[O:21]
Reactant: N[C@@H](Cc1ccc([N+](=O)[O-])cc1)C(=O)O
Reactant: COC(=O)Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: COC(=O)N[C@@H](Cc1ccc([N+](=O)[O-])cc1)C(=O)O
Temperature: 25 °C
Reaction time: 8 h
Yield: 91.7 %

Procedure:
To a stirred mixture of H-phe(4-NO2)-OH (11.4 g, 50.0 mmol) and NaOH (2.0 g, 50.0 mmol) in water (450 mL) at 0° C. was added methylchloroformate (4.25 mL, 55.0 mmol) and NaOH (2.2 g in 45 mL water) simultaneously. 1N NaOH was then added to adjust PH ˜9. The reaction mixture was stirred at ambient temperature overnight, the pH was adjust to 10 by adding more aqueous NaOH and the mixture was extracted with ether (2×75 mL). The aqueous layer was acidified to a pH=3 with 5N HCl, and extracted with ethyl acetate (2×400 mL). The combined ethyl acetate layers were dried (MgSO4), filtered and concentrated under reduced pressure to provide the titled compound (12.3 g). MS (ESI (−)) m/e 267 (M−H)+; 1H NMR (300 MHz, DMSO-d6) 8.16 (d, 2H), 7.60-7.52 (m, 3H), 4.28-4.18 (m, 1H), 3.47 (s, 3H), 3.26-3.17 (m, 1H), 3.05-2.92 (m, 1H).
Reaction SMILES: [NH:1]1[CH:5]=[CH:4][C:3]([C:6]([O:8][CH3:9])=[O:7])=[N:2]1.C(=O)([O-])[O-].[Cs+].[Cs+].CS(O[CH2:21][C:22]([F:25])([F:24])[F:23])(=O)=O.O>CN(C=O)C>[F:23][C:22]([F:25])([F:24])[CH2:21][N:1]1[CH:5]=[CH:4][C:3]([C:6]([O:8][CH3:9])=[O:7])=[N:2]1
Reactant: CS(=O)(=O)OCC(F)(F)F
Reactant: COC(=O)c1cc[nH]n1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Solvent: O
Product: COC(=O)c1ccn(CC(F)(F)F)n1
Temperature: 25 °C
Reaction time: 16 h
Yield: 18.9 %

Procedure:
Methyl 1H-pyrazole-3-carboxylate (1.0 g, 7.94 mmol) was dissolved in DMF (25 mL) and cesium carbonate (12.9 g, 39.7 mmol) was added. The mixture was cooled to 0 C and 2,2,2-trifluoroethyl methanesulfonate (2.4 mL, 19.8 mmol) was gradually added. The mixture was warmed to room temperature and stirred for 16 h. Water was added and the mixture was extracted with EtOAc (3×25 mL). The combined organic extracts were washed with brine (3×10 mL) and concentrated under vacuum. The residue was purified by FCC, eluting with hexane followed by 0.5% MeOH in DCM to afford the title compound as a yellow oil (0.312 g, 19%). Method D HPLC-MS: MH+ requires m/z=209 Found: m/z=209, Rt=2.08 min (98%).
Reaction SMILES: [CH3:1][C@H:2]1[CH2:7][CH2:6][C@H:5]([N:8]([CH2:22]C2C=CN=CC=2)[C:9](=[O:21])[NH:10][C:11]2[S:12][C:13]([S:16][CH2:17][C:18]([OH:20])=[O:19])=[CH:14][N:15]=2)[CH2:4][CH2:3]1.C([C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][N:32]=1)=O>>[CH3:1][C@H:2]1[CH2:3][CH2:4][C@H:5]([N:8]([CH2:22][C:31]2[CH:36]=[CH:35][CH:34]=[CH:33][N:32]=2)[C:9](=[O:21])[NH:10][C:11]2[S:12][C:13]([S:16][CH2:17][C:18]([OH:20])=[O:19])=[CH:14][N:15]=2)[CH2:6][CH2:7]1
Reactant: O=Cc1ccccn1
Reactant: C[C@H]1CC[C@H](N(Cc2ccncc2)C(=O)Nc2ncc(SCC(=O)O)s2)CC1
Product: C[C@H]1CC[C@H](N(Cc2ccccn2)C(=O)Nc2ncc(SCC(=O)O)s2)CC1

Procedure:
The compound was prepared following an analogous procedure to the one described for the synthesis of {2-[3-(trans-4-methyl-cyclohexyl)-3-pyridin-4-ylmethyl-ureido]-thiazol-5-ylsulfanyl}-acetic acid using 2-formyl-pyridine.
Reaction SMILES: S(C1C=CC(C)=CC=1)(O[CH:5]1[CH2:10][CH2:9][C:8]([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[CH2:7][CH2:6]1)(=O)=O.[NH:30]1[CH2:35][CH2:34][CH:33]([N:36]2[C:40]3[CH:41]=[CH:42][CH:43]=[CH:44][C:39]=3[NH:38][C:37]2=[O:45])[CH2:32][CH2:31]1.C(=O)([O-])[O-].[K+].[K+].[I-].[K+]>CN(C)C=O>[C:11]1([C:8]2([C:17]3[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=3)[CH2:7][CH2:6][CH:5]([N:30]3[CH2:31][CH2:32][CH:33]([N:36]4[C:40]5[CH:41]=[CH:42][CH:43]=[CH:44][C:39]=5[NH:38][C:37]4=[O:45])[CH2:34][CH2:35]3)[CH2:10][CH2:9]2)[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=1
Reactant: O=c1[nH]c2ccccc2n1C1CCNCC1
Reactant: Cc1ccc(S(=O)(=O)OC2CCC(c3ccccc3)(c3ccccc3)CC2)cc1
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: CN(C)C=O
Product: O=c1[nH]c2ccccc2n1C1CCN(C2CCC(c3ccccc3)(c3ccccc3)CC2)CC1
Temperature: 55 °C
Reaction time: 47 h

Procedure:
A mixture of 4.1 g of 4,4-diphenylcyclohexyl tosylate, 2.2 g of 4-piperidyl-2-benzimidazolinone, 1.5 g of potassium carbonate, 1.5 g of potassium iodide and 50 ml of dimethylformamide is stirred at 55° C for 47 hours. The reaction mixture is cooled to room temperature and poured into ice water. The precipitate is collected by filtration and dissolved in chloroform under warming. The solution is washed with water and dried over sodium sulfate, and the chloroform is removed under reduced pressure. To the residue is added ether, and the mixture is cooled. The precipitated crystals are collected by filtration and recrystallized twice from a mixture of methanol and chloroform. The crystals are dried at 100° C under reduced pressure for many hours, because the solvent is not easily removable. Thus is obtained 1-[1-(4,4-diphenylcyclohexyl)-4-piperidyl]-2-benzimidazolinone as light gray crystals, melting at 289°-293° C.
Reaction SMILES: [NH2:1][CH:2]1[CH2:7][CH2:6][N:5]([CH2:8][C:9]2[CH:18]=[CH:17][C:16]3[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=3)[CH:10]=2)[CH2:4][CH2:3]1.N[C:20]([NH:22][C:23]([C:25]1[CH:26]=[C:27]2[C:32](=[CH:33][CH:34]=1)[N:31]=[CH:30][CH:29]=[CH:28]2)=[O:24])=[O:21]>N1C=CC=CC=1>[CH:10]1[C:11]2[C:16](=[CH:15][CH:14]=[CH:13][CH:12]=2)[CH:17]=[CH:18][C:9]=1[CH2:8][N:5]1[CH2:4][CH2:3][CH:2]([NH:1][C:20]([NH:22][C:23]([C:25]2[CH:26]=[C:27]3[C:32](=[CH:33][CH:34]=2)[N:31]=[CH:30][CH:29]=[CH:28]3)=[O:24])=[O:21])[CH2:7][CH2:6]1
Reactant: NC1CCN(Cc2ccc3ccccc3c2)CC1
Reactant: NC(=O)NC(=O)c1ccc2ncccc2c1
Solvent: c1ccncc1
Product: O=C(NC(=O)c1ccc2ncccc2c1)NC1CCN(Cc2ccc3ccccc3c2)CC1
Reaction time: 8 h
Yield: 13.6 %

Procedure:
A suspension of 4-amino-1-(2-naphthalenylmethyl)piperidine (1.4 g, 5.83 mmol) and N-aminocarbonyl-6-quinolinecarboxamide (1.08 g, 5.02 mmol) in pyridine (7 cm3) was refluxed for 7 hours. The mixture was left at room temperature overnight then more 4-amino-1-(2-naphthalenylmethyl)piperidine (0.3 g, 1.4 mmol) was added and refluxing was continued for 5 hours. Undissolved solid was filtered off from the hot mixture and the filtrate was diluted with water (8 cm3) and filtered again. The filtrate was further diluted with water and cooled in ice. The deposited solid was collected and dried (0.46 g,) then recrystallised from ethanol (50 cm3) to give 0.30 g of the title compound, m.p. 211°-13° C.