Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[C:3]([CH3:16])=[C:4]([CH:9]=[C:10]([C:12]([F:15])([F:14])[F:13])[CH:11]=1)[C:5]([O:7][CH3:8])=[O:6].[CH2:17]([N:24]1[C@@H:29]([CH3:30])[CH2:28][C:27](=O)[CH2:26][C@H:25]1[CH3:32])[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].C([O-])(O)=O.[Na+]>C1COCC1.C(O)(C(F)(F)F)=O>[CH2:17]([N:24]1[C@H:29]([CH3:30])[CH2:28][CH:27]([NH:1][C:2]2[C:3]([CH3:16])=[C:4]([CH:9]=[C:10]([C:12]([F:13])([F:14])[F:15])[CH:11]=2)[C:5]([O:7][CH3:8])=[O:6])[CH2:26][C@H:25]1[CH3:32])[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1
Reactant: COC(=O)c1cc(C(F)(F)F)cc(N)c1C
Reactant: C[C@@H]1CC(=O)C[C@H](C)N1Cc1ccccc1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O=C(O)C(F)(F)F
Solvent: C1CCOC1
Product: COC(=O)c1cc(C(F)(F)F)cc(NC2C[C@@H](C)N(Cc3ccccc3)[C@H](C)C2)c1C
Temperature: 60 °C
Reaction time: 1 h
Yield: 37 %

Procedure:
To a stirred solution of methyl 3-amino-2-methyl-5-(trifluoromethyl)benzoate (400 mg, 1.72 mmol) in THF (15 mL) and TFA (491 uL) was added (2R,6S)-1-benzyl-2,6-dimethylpiperidin-4-one (410 mg, 1.89 mmol) at 0° C. The mixture was stirred at 60° C. for 1 hour under nitrogen atmosphere. Then the mixture was cooled to 0° C. in an ice bath, sodium triacetoxyborohydride (765 mg, 3.43 mmol) was added. The reaction mixture was stirred at 23° C. for 2 hours. Then aq. NaHCO3 was added at 0° C. until pH8-9, and the content was extracted with ethylacetate. The organic layer was dried over MgSO4 and filtered. The filtrate was concentrated in vacuo. The residue was purified by silica gel column chromatography (NH—SiO2; heptane/ethylacetate=3/1) to give the titled compound as a colorless oil. (278 mg, 37% yield). 1H-NMR (400M Hz, CDCl3) δppm; 7.21-7.40 (m, 6H), 6.90 (s, 1H), 3.95 (d, J=14.0 Hz, 1H), 3.90 (s, 3H), 3.60-3.73 (m, 2H), 3.46 (d, J=14.0 Hz, 1H), 3.08-3.12 (m, 1H), 2.98-3.03 (m, 1H), 2.30 (s, 3H), 2.02-2.08 (m, 1H), 1.83-1.88 (m, 1H), 1.52-1.60 (m, 1H), 1.17-1.26 (m, 1H), 1.11 (d, J=6.8 Hz, 3H), 1.13 (d, J=6.4 Hz, 3H).
Reaction SMILES: [CH:1]1([O:6][C:7]2[CH:8]=[C:9]([CH:11]=[CH:12][C:13]=2[O:14][CH3:15])[NH2:10])[CH2:5][CH2:4][CH2:3][CH2:2]1.C(N(CC)CC)C.[Cl:23][C:24]1[CH:29]=[CH:28][CH:27]=[C:26]([Cl:30])[C:25]=1[N:31]=[C:32]=[O:33]>ClCCl>[Cl:23][C:24]1[CH:29]=[CH:28][CH:27]=[C:26]([Cl:30])[C:25]=1[NH:31][C:32]([NH:10][C:9]1[CH:11]=[CH:12][C:13]([O:14][CH3:15])=[C:7]([O:6][CH:1]2[CH2:2][CH2:3][CH2:4][CH2:5]2)[CH:8]=1)=[O:33]
Reactant: O=C=Nc1c(Cl)cccc1Cl
Reactant: COc1ccc(N)cc1OC1CCCC1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COc1ccc(NC(=O)Nc2c(Cl)cccc2Cl)cc1OC1CCCC1
Reaction time: 0.5 h
Yield: 56 %

Procedure:
A stirred solution of 3-cyclopentyloxy-4-methoxyaniline (1 g) and triethylamine (0.69 mL) in dry dichloromethane (20 mL) is treated dropwise at 0°-5° C. with a solution of 2,6-dichlorophenyl isocyanate (0.9 g) in dry dichloromethane (10 mL). The resulting mixture is stirred for 30 minutes at this temperature and then for 6 hours at room temperature. The precipitate which forms is collected and stirred with isopropanol (50 mL), with ice cooling. The resulting solid is collected and dried, to give N-(2,6-dichlorophenyl)-N'-(3-cyclopentyloxy-4-methoxyphenyl)urea (1.06 g), m.p. 203°-204° C. [Elemental analysis: C,57.2; H,5.0; N,7.0; Cl,18.2%; calculated: C,57.7; H,5.1; N,7.1; Cl,18.0%].
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([CH:9]=[CH:10][C:11]=1[OH:12])[C:5]([O:7][CH3:8])=[O:6].S(Cl)([Cl:16])(=O)=O>C(OCC)C>[Cl:16][C:10]1[CH:9]=[C:4]([CH:3]=[C:2]([OH:1])[C:11]=1[OH:12])[C:5]([O:7][CH3:8])=[O:6]
Reactant: COC(=O)c1ccc(O)c(O)c1
Reactant: O=S(=O)(Cl)Cl
Solvent: CCOCC
Product: COC(=O)c1cc(O)c(O)c(Cl)c1
Temperature: 0 °C

Procedure:
To a suspension of methyl 3,4-dihydroxybenzoate (5.0 g) in diethyl ether (300 mL) stirred at 0° C. was added sulfuryl chloride (3.7 mL) dropwise. The reaction mixture was stirred at 0° C. for 16 h. The solvent was removed in vacuo. The residue was washed with hot chloroform (2×150 mL) to afford methyl 3-chloro-4,5-dihydroxybenzoate (D68) (1.9 g) as a white solid. δH (DMSO-d6, 400 MHz): 3.78 (3H, s), 7.33 (1H, d), 7.37 (1H, d), 10.11 (2H, br s). MS (ES): C8H7ClO4 requires 202. found 203.0 (M+H+).
Reaction SMILES: [F:1][C:2]([F:36])([F:35])[C:3]1[CH:4]=[C:5]([C:13]([CH3:34])([CH3:33])[C:14]([N:16]([C:18]2[CH:19]=[N:20][C:21](Cl)=[CH:22][C:23]=2[C:24]2[CH:29]=[CH:28][C:27]([F:30])=[CH:26][C:25]=2[CH3:31])[CH3:17])=[O:15])[CH:6]=[C:7]([C:9]([F:12])([F:11])[F:10])[CH:8]=1.[S:37]1[CH2:41][CH2:40][NH:39][CH2:38]1>[OH-].[Na+]>[F:1][C:2]([F:36])([F:35])[C:3]1[CH:4]=[C:5]([C:13]([CH3:34])([CH3:33])[C:14]([N:16]([C:18]2[CH:19]=[N:20][C:21]([N:39]3[CH2:40][CH2:41][S:37][CH2:38]3)=[CH:22][C:23]=2[C:24]2[CH:29]=[CH:28][C:27]([F:30])=[CH:26][C:25]=2[CH3:31])[CH3:17])=[O:15])[CH:6]=[C:7]([C:9]([F:12])([F:11])[F:10])[CH:8]=1
Reactant: Cc1cc(F)ccc1-c1cc(Cl)ncc1N(C)C(=O)C(C)(C)c1cc(C(F)(F)F)cc(C(F)(F)F)c1
Reactant: C1CSCN1
Agent: [Na+]
Agent: [OH-]
Product: Cc1cc(F)ccc1-c1cc(N2CCSC2)ncc1N(C)C(=O)C(C)(C)c1cc(C(F)(F)F)cc(C(F)(F)F)c1
Temperature: 180 °C
Yield: 12 %

Procedure:
A mixture of 0.25 g (0.47 mmol) 2-(3,5-bis-trifluoromethyl-phenyl)-N-[6-chloro-4-(4-fluoro-2-methyl-phenyl)-pyridin-3-yl]-N-methyl-isobutyramide and 0.59 g (6.6 mmol) thiazolidine was heated three times at 180° C. for 30 minutes and once at 250° C. for 15 minutes under microwave irradiation in a sealed tube. The reaction mixture was diluted with a 0.2 M aqueous solution of sodium hydroxide and extracted with three portions of tert-butyl methyl ether. The combined organic extracts were dried over sodium sulfate and concentrated in vacuo. Flash column chromatography and drying in high vacuo (70-90° C./1-2 mbar) for three hours gave 33 mg (12%) of the title compound as a yellow oil.
Reaction SMILES: [C:1]([NH:5][Si:6](Cl)([CH3:8])[CH3:7])([CH3:4])([CH3:3])[CH3:2].[CH3:10][C:11]([CH:13]=[C:14]([CH3:16])[CH3:15])=[CH-:12].[K+]>C1COCC1>[C:1]([NH:5][Si:6]([CH3:8])([CH3:7])[CH2:12][C:11]([CH3:10])=[CH:13][C:14]([CH3:16])=[CH2:15])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)N[Si](C)(C)Cl
Reactant: [CH-]=C(C)C=C(C)C
Agent: [K+]
Solvent: C1CCOC1
Product: C=C(C)C=C(C)C[Si](C)(C)NC(C)(C)C
Reaction time: 8 h

Procedure:
To a solution of 0.612 g (3.69 mmol) of (N-t-butylamino)(chloro)dimethylsilane in 50 mL of THF was added 0.500 g (3.72 mmol) of potassium 2,4-dimethylpentadienide (prepared in a manner similar to that reported in J. Am. Chem. Soc. 1978, 100, 3258). The reaction mixture was stirred overnight. The solvent was removed, the residue was extracted with pentane and filtered. The pentane was removed in vacuo to give the product as a pale yellow oil. The yield was 0.733 g, 88.2 percent. 1H NMR (C6D6) δ 5.64 (s, 1H), 5.01 (s, 1H), 4.97 (s, 1H), 1.88(s, 2H), 1.85(s, 3H), 1.76(s, 3H), 1.09(s, 9H), 0.17 (s, 6H). 13C NMR (C6D6) δ 142.7, 136.5, 125.3, 113.2, 49.5, 34.0, 27.9, 26.5, 24.6, 2.8.
Reaction SMILES: [CH2:1](Br)[CH2:2][CH3:3].[I-].CC[O-].[Na+].[C:10]1([N:16]2[C:22]3[CH:23]=[C:24]([Cl:27])[CH:25]=[CH:26][C:21]=3[NH:20][C:19](=O)[CH2:18][C:17]2=O)[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1>>[C:10]1([N:16]2[C:22]3[CH:23]=[C:24]([Cl:27])[CH:25]=[CH:26][C:21]=3[N:20]([CH2:1][CH2:2][CH3:3])[CH2:19][CH2:18][CH2:17]2)[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1
Reactant: O=C1CC(=O)N(c2ccccc2)c2cc(Cl)ccc2N1
Reactant: CCCBr
Agent: CC[O-]
Agent: [I-]
Agent: [Na+]
Product: CCCN1CCCN(c2ccccc2)c2cc(Cl)ccc21

Procedure:
In the same manner, by acting propyl bromide or iodide in the presence of sodium ethylate, starting from 1-phenyl 8-chloro 1,2,4,5-tetrahydro 2,4-dioxo 3H-1,5-benzodiazepine, there is obtained 1-phenyl 5-propyl 8-chloro 1,2,4,5-tetrahydro 3H-1,5-benzodiazepine (R1 = H, R2 = Cl, R3 = C3H7, R4 = C6H5) melting at 192°-194° C. upon recrystallisation in ethanol.
Reaction SMILES: C[O-].[Na+].CO.[N+](C1C=CC(S([NH:18][CH:19]([C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)[C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)(=O)=O)=CC=1)([O-])=O.Cl>C(COC)OC>[CH:19]([NH2:18])([C:26]1[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=1)[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1
Reactant: O=[N+]([O-])c1ccc(S(=O)(=O)NC(c2ccccc2)c2ccccc2)cc1
Agent: C[O-]
Agent: Cl
Agent: [Na+]
Solvent: COCCOC
Solvent: CO
Product: NC(c1ccccc1)c1ccccc1
Temperature: 25 °C
Reaction time: 40 h
Yield: 95.6 %

Procedure:
A 28% sodium methoxide/methanol solution (0.34 ml; 1.51 molar equivalents) was added to a solution of N-(4-nitrobenzenesulfonyl)benzhydrylamine (402.0 mg) in dry dimethoxyethane (3 ml) at room temperature in a nitrogen atmosphere, followed by stirring for 7 hours at room temperature and for 40 hours under heating at 46 to 49° C. On the way, dry dimethoxyethane (3 ml) was further added after 7 hours, and a 28% sodium methoxide/methanol solution (0.34 ml; 1.51 molar equivalents) was further added about 18 hours after heating. The reaction mixture was cooled with ice, and 1 N hydrochloric acid (5 ml) was added. The reaction solvents were removed by evaporation under reduced pressure, and water (5 ml), 1 N hydrochloric acid (5 ml) and ether (25 ml) were added to the resulting concentrate, followed by extraction and solution separation. The organic layer was extracted again with water (5 ml). Sodium hydroxide (0.61 g) was added to the resulting aqueous layer, and extraction was conducted three times with ether (20 ml), followed by drying over sodium sulfate, filtration, concentration and drying under vacuum to obtain benzhydrylamine (191.2 mg; yield: 95.6%).
Reaction SMILES: Br[CH2:2][C:3]([O:5][CH3:6])=[O:4].C(N(CC)CC)C.[F:14][C:15]1[CH:22]=[CH:21][C:18]([CH2:19][NH2:20])=[CH:17][CH:16]=1>C1COCC1>[F:14][C:15]1[CH:22]=[CH:21][C:18]([CH2:19][NH:20][CH2:2][C:3]([O:5][CH3:6])=[O:4])=[CH:17][CH:16]=1
Reactant: COC(=O)CBr
Reactant: NCc1ccc(F)cc1
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: COC(=O)CNCc1ccc(F)cc1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
To a solution of methyl bromoacetate (24.0 mL, 254 mmol) in anhydrous THF (264 mL) was added dropwise triethylamine (35.3 mL, 254 mmol). The cloudy mixture was treated rapidly with 4-fluorobenzylamine, and the resulting viscous mixture was stirred at ambient temperature under inert atmosphere for 18 h. THF was removed in vacuo, and the resulting residue was suspended in diethyl ether. The mixture was filtered and the solids washed with excess diethyl ether. Concentration of the filtrate in vacuo afforded the title compound as a light yellow oil. 1H NMR (400 MHz, CDCl3) δ 7.31-7.27 (m, 2H), 7.04-6.99 (m, 2H), 3.77 (s, 2H), 3.74 (s, 3H), 3.41 (s, 2H), 1.82 (br s, 1H).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([NH:17][C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=2[NH:24][C:25](=[O:31])[CH2:26][CH2:27][C:28]([OH:30])=O)[CH:5]=[CH:6][C:7]=1[C:8](=[O:16])[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1[CH3:15].[NH2:32][CH2:33][CH:34]([OH:37])[CH2:35][OH:36]>>[Cl:1][C:2]1[CH:3]=[C:4]([NH:17][C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=2[NH:24][C:25](=[O:31])[CH2:26][CH2:27][C:28]([NH:32][CH2:33][CH:34]([OH:37])[CH2:35][OH:36])=[O:30])[CH:5]=[CH:6][C:7]=1[C:8](=[O:16])[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1[CH3:15]
Reactant: NCC(O)CO
Reactant: Cc1ccccc1C(=O)c1ccc(Nc2ccccc2NC(=O)CCC(=O)O)cc1Cl
Product: Cc1ccccc1C(=O)c1ccc(Nc2ccccc2NC(=O)CCC(=O)NCC(O)CO)cc1Cl

Procedure:
The reaction and work up was conducted as described in the preparation of compound 204. Starting compounds were N-(2-{[3-chloro-4-(2-methylbenzoyl)phenyl]amino}phenyl)-succinamic acid (100 mg, 0.46 mmol) (disclosed in WO 01/05746) and 3-aminopropane-1,2-diol (23 mg, 0.25 mmol). The crude product was purified by flash chromatography using DCM/MeOH/NH3(aq.) 90:10:0.5 as the eluent to afford the title compound as a yellow solid.
Reaction SMILES: C([O:4][C@@H:5]1[C@@H:10]([O:11]C(=O)C)[C@H:9]([O:15]C(=O)C)[C@@H:8]([S:19][CH3:20])[O:7][C@H:6]1[C:21]1[CH:26]=[CH:25][C:24]([CH3:27])=[C:23]([CH2:28][C:29]2[CH:34]=[CH:33][C:32]([CH2:35][CH2:36][CH2:37][CH2:38][NH2:39])=[CH:31][CH:30]=2)[CH:22]=1)(=O)C.[OH:40][CH2:41][C:42]([CH3:47])([CH3:46])[C:43]([OH:45])=O.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C>CN(C=O)C>[OH:40][CH2:41][C:42]([CH3:47])([CH3:46])[C:43]([NH:39][CH2:38][CH2:37][CH2:36][CH2:35][C:32]1[CH:31]=[CH:30][C:29]([CH2:28][C:23]2[CH:22]=[C:21]([C@H:6]3[C@H:5]([OH:4])[C@@H:10]([OH:11])[C@H:9]([OH:15])[C@@H:8]([S:19][CH3:20])[O:7]3)[CH:26]=[CH:25][C:24]=2[CH3:27])=[CH:34][CH:33]=1)=[O:45]
Reactant: CC(C)(CO)C(=O)O
Reactant: CS[C@H]1O[C@@H](c2ccc(C)c(Cc3ccc(CCCCN)cc3)c2)[C@H](OC(C)=O)[C@@H](OC(C)=O)[C@@H]1OC(C)=O
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CS[C@H]1O[C@@H](c2ccc(C)c(Cc3ccc(CCCCNC(=O)C(C)(C)CO)cc3)c2)[C@H](O)[C@@H](O)[C@@H]1O
Temperature: 25 °C
Reaction time: 4 h
Yield: 41.4 %

Procedure:
To a solution of (2S,3S,4R,5S,6R)-2-(3-(4-(4-aminobutyl)benzyl)-4-methylphenyl)-6-(methylthio)tetrahydro-2H-pyran-3,4,5-triyl triacetate (19, 55 mg, 0.10 mmol), 3-hydroxy-2,2-dimethylpropanoic acid (18 mg, 0.15 mmol), HATU (57 mg, 0.15 mmol), and DIPEA (52 μL, 0.30 mmol) were combined in DMF (1 mL) and stirred for 4 hours at room temperature. The reaction quenched with saturated aqueous NaHCO3 and extracted twice with EtOAc. The combined organic layers were washed with brine, dried with MgSO4, filtered, and concentrated under vacuum. The residue was dissolved in MeOH and treated with a few drops of NaOMe (25 wt % in MeOH) for 1 hour. The reaction was concentrated under vacuum, and the residue was purified by prep HPLC (C18 30×100 mm column, 5-40% CH3CN/10 mM aqueous ammonium formate, 45 mL/min) to give the title compound 21 as a white solid (22 mg, 41% yield). 1H NMR (400 MHz, MeOH-d4) δ ppm 6.98-7.22 (m, 7 H), 4.39 (d, J=9.6 Hz, 1 H), 4.13 (d, J=9.1 Hz, 1 H), 3.90-3.99 (m, 2 H), 3.49 (s, 2 H), 3.35-3.46 (m, 3 H), 3.19 (t, J=6.9 Hz, 2 H), 2.58 (t, J=7.5 Hz, 2 H), 2.18-2.23 (m, 3 H), 2.14 (s, 3 H), 1.60 (s, 2 H), 1.46-1.57 (m, 2 H), 1.11 (s, 6 H). MS (ES+) [M+H]+=532.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]2[N:8]([CH3:11])[N:9]=[CH:10][C:5]2=[C:4]([N:12]2[CH2:17][CH2:16][N:15]([S:18]([CH3:21])(=[O:20])=[O:19])[CH2:14][CH2:13]2)[N:3]=1.[NH:22]1[C:30]2[C:25](=[CH:26][CH:27]=[CH:28][CH:29]=2)[C:24](B2OC(C)(C)C(C)(C)O2)=[N:23]1>>[NH:22]1[C:30]2[C:25](=[C:26]([C:2]3[N:7]=[C:6]4[N:8]([CH3:11])[N:9]=[CH:10][C:5]4=[C:4]([N:12]4[CH2:17][CH2:16][N:15]([S:18]([CH3:21])(=[O:20])=[O:19])[CH2:14][CH2:13]4)[N:3]=3)[CH:27]=[CH:28][CH:29]=2)[CH:24]=[N:23]1
Reactant: CC1(C)OB(c2n[nH]c3ccccc23)OC1(C)C
Reactant: Cn1ncc2c(N3CCN(S(C)(=O)=O)CC3)nc(Cl)nc21
Product: Cn1ncc2c(N3CCN(S(C)(=O)=O)CC3)nc(-c3cccc4[nH]ncc34)nc21

Procedure:
6-Chloro-4-(4-methane sulfonyl-piperazin-1-yl)-1-methyl-1H-pyrazolo[3,4-d]pyrimidine was reacted with indazole boronic acid pinacol ester using General Procedure A. Purification on silica yielded 149. NMR: (DMSO) 2.98 (3H, s), 3.35-3.40 (4H, m), 4.11 (3H, s), 4.18-4.22 (4H, m), 7.48-7.51 (1H, m), 7.70 (1H, d), 8.30 (1H, d), 8.42 (1H, s), 8.95 (1H, s). 13.20 (1H, s). MS: (ESI+) MH+=413
Reaction SMILES: C[O:2][C:3]([C:5]1[S:6][C:7]([N:20]2[CH:24]=[N:23][C:22]([NH:25][C:26]3[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=3)=[N:21]2)=[CH:8][C:9]=1[O:10][CH:11]([C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=1[Cl:19])[CH3:12])=O.C(OCC)C.[NH3:37]>CO>[Cl:19][C:14]1[CH:15]=[CH:16][CH:17]=[CH:18][C:13]=1[CH:11]([O:10][C:9]1[CH:8]=[C:7]([N:20]2[CH:24]=[N:23][C:22]([NH:25][C:26]3[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=3)=[N:21]2)[S:6][C:5]=1[C:3]([NH2:37])=[O:2])[CH3:12]
Reactant: N
Reactant: COC(=O)c1sc(-n2cnc(Nc3ccccc3)n2)cc1OC(C)c1ccccc1Cl
Solvent: CCOCC
Solvent: CO
Product: CC(Oc1cc(-n2cnc(Nc3ccccc3)n2)sc1C(N)=O)c1ccccc1Cl
Temperature: 100 °C
Yield: 27 %

Procedure:
3-[1-(2-Chloro-phenyl)-ethoxy]-5-(3-phenylamino-[1,2,4]triazol-1-yl)-thiophene-2-carboxylic acid methyl ester (66 mg, 0.15 mmol, 1.0 Eq.) was suspended in 7M NH3 in MeOH (10 mL) and heated to 100° C. in a pressure tube for 3 days. The solvent was removed in vacuo and the product isolated by column chromatography (10% MeOH/DCM) followed by tritruation from diethyl ether to give the title compound as an off-white solid (17 mg, 0.04 mmol, 27%); 1H NMR (400 MHz, d-6 DMSO) δ. 1.72 (3H, d), 5.88 (1H, q), 6.88 (1H, t), 7.03 (1H, br s), 7.26 (1H, s), 7.30 (2H, t), 7.36-7.43 (2H, m), 7.52 (1H, dd), 7.57 (2H, d), 7.66 (1H, dd), 7.75 (1H, br s), 9.02 (1H, br s), 9.65 (1H, s).
Reaction SMILES: [F:1][C:2]1[C:7]([N:8]2[CH2:13][CH2:12][CH:11]([OH:14])[CH2:10][CH2:9]2)=[CH:6][C:5]([NH2:15])=[C:4]([NH2:16])[CH:3]=1.[C:17](=S)=[S:18].C(O)C.[K+].[Br-]>O>[F:1][C:2]1[C:7]([N:8]2[CH2:13][CH2:12][CH:11]([OH:14])[CH2:10][CH2:9]2)=[CH:6][C:5]2[N:15]=[C:17]([SH:18])[NH:16][C:4]=2[CH:3]=1
Reactant: Nc1cc(F)c(N2CCC(O)CC2)cc1N
Reactant: S=C=S
Agent: [Br-]
Agent: [K+]
Solvent: CCO
Solvent: O
Product: OC1CCN(c2cc3nc(S)[nH]c3cc2F)CC1
Yield: 62.3 %

Procedure:
6-Fluoro-5-(4-hydroxypiperidin-1-yl)-2-mercapto-1H-benzimidazole (4.5 g, 62%) was prepared by a similar procedure to that described in preparation 1 (step 5) using the diamine (6.0 g, 0.027 mol) (obtained in step 2 above), carbon disulfide (3.9 g, 0.052 mol), ethanol (30 mL) and water (5 mL). mp 268-269° C.; IR (KBr) 3397, 3124, 1487 cm-1 ; 1H NMR (DMSO-d6) δd 1.45-1.56 (m, 2H, CH2), 1.60-1.87 (m, 2H, CH2), 2.24 (s, 1H, SH), 2.64-3.92 (m, 2H, NCH2), 3.11-3.17 (m, 2H, NCH2), 3.30-3.60 (m, 1H, CH), 4.30 (brs, 1H, OH), 6.70 (d, J=7.4 Hz, 1H), 7.00 (d, J=12.6 Hz, 1H), 12.00 (brs, 1H, NH); Mass (m/z) 267 (M+.).
Reaction SMILES: [Cl:1][C:2]1[C:3]([C:15]#[CH:16])=[N:4][CH:5]=[C:6]([C:8]2[CH:13]=[CH:12][C:11]([Cl:14])=[CH:10][CH:9]=2)[CH:7]=1.I[C:18]1[CH:27]=[CH:26][C:21]([O:22][CH2:23][CH2:24][OH:25])=[CH:20][CH:19]=1>>[Cl:1][C:2]1[C:3]([C:15]#[C:16][C:18]2[CH:27]=[CH:26][C:21]([O:22][CH2:23][CH2:24][OH:25])=[CH:20][CH:19]=2)=[N:4][CH:5]=[C:6]([C:8]2[CH:13]=[CH:12][C:11]([Cl:14])=[CH:10][CH:9]=2)[CH:7]=1
Reactant: OCCOc1ccc(I)cc1
Reactant: C#Cc1ncc(-c2ccc(Cl)cc2)cc1Cl
Product: OCCOc1ccc(C#Cc2ncc(-c3ccc(Cl)cc3)cc2Cl)cc1

Procedure:
The product was prepared analogously to Example 7.1e starting from 3-chloro-5-(4-chlorophenyl)-2-ethynylpyridine and 2-(4-iodophenoxy)ethanol. Yield: 0.48 g (66% of theoretical); C21H15Cl2NO2 (M=384.255); calc.: molpeak (M+H)+384/386/388 (2Cl); found: molpeak (M+H)+: 384/386/388 (2Cl); HPLC-MS: 6.24 minutes (method B).
Reaction SMILES: C(OC(=O)[C:5]([C:15](=[O:17])[CH3:16])([CH2:12][CH2:13][CH3:14])[CH2:6][C:7]([O:9]CC)=[O:8])C.Cl>[Cl-].[Na+].O>[C:15]([CH:5]([CH2:12][CH2:13][CH3:14])[CH2:6][C:7]([OH:9])=[O:8])(=[O:17])[CH3:16]
Reactant: CCCC(CC(=O)OCC)(C(C)=O)C(=O)OCC
Agent: Cl
Agent: [Cl-]
Agent: [Na+]
Solvent: O
Product: CCCC(CC(=O)O)C(C)=O
Temperature: 105 °C

Procedure:
To 35 g of the oil, 2-acetyl-2-propyl-succinic acid diethyl ester, is added concentrated HCl (200 ml). The mixture is refluxed (oil bath 105° C.) overnight and to it is added brine (100 ml). The mixture is extracted with EtOAc (4×150 ml) and the combined extracts are extracted with 2N aqueous NaOH solution (4×100 ml). The NaOH solution is then cooled to 0° C. and acidified with concentrated HCl. The mixture is extracted with EtOAc (4×200 ml) and the combined extracts are washed with brine (200 ml), dried (Na2SO4) and evaporated in vacuo, which provides 3-acetyl-hexanoic acid as a yellow oil.
Reaction SMILES: [N+:1]([C:4]1[CH:22]=[CH:21][C:7]([O:8][C:9]2([C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=3)[CH2:14][CH2:13][NH:12][CH2:11][CH2:10]2)=[CH:6][CH:5]=1)([O-:3])=[O:2].[CH3:23][N:24]=[C:25]=[O:26]>C1C=CC=CC=1>[CH3:23][NH:24][C:25]([N:12]1[CH2:11][CH2:10][C:9]([O:8][C:7]2[CH:6]=[CH:5][C:4]([N+:1]([O-:3])=[O:2])=[CH:22][CH:21]=2)([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[CH2:14][CH2:13]1)=[O:26]
Reactant: CN=C=O
Reactant: O=[N+]([O-])c1ccc(OC2(c3ccccc3)CCNCC2)cc1
Solvent: c1ccccc1
Product: CNC(=O)N1CCC(Oc2ccc([N+](=O)[O-])cc2)(c2ccccc2)CC1
Temperature: 25 °C
Reaction time: 2 h
Yield: 106.7 %

Procedure:
To a stirred solution of 4.9 g of 4-(4-nitrophenoxy)-4-phenylpiperidine in 50 ml of benzene was added, dropwise, a solution of 0.91 g of methyl isocyanate in 15 ml of benzene. The reaction mixture was stirred at room temperature for two hours. Evaporation of the volatiles afforded a solid which was purified by means of high pressure liquid chromatography (silica gel; elution with 50% ethyl acetate/dichloromethane) to yield 6.05 g of 1-(N-methylamino)carbonyl-4-(4-nitrophenoxy)-4-phenylpiperidine, m.p. 110°-115° C.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([Cl:8])=[CH:4][C:3]=1[C:9]([C:11]1[CH:16]=[CH:15][N:14]=[CH:13][CH:12]=1)=[O:10].[CH3:17][S:18]([C:21]1[CH:26]=[CH:25][C:24]([S:27](Cl)(=[O:29])=[O:28])=[CH:23][CH:22]=1)(=[O:20])=[O:19]>>[Cl:8][C:5]1[CH:6]=[CH:7][C:2]([NH:1][S:27]([C:24]2[CH:23]=[CH:22][C:21]([S:18]([CH3:17])(=[O:20])=[O:19])=[CH:26][CH:25]=2)(=[O:29])=[O:28])=[C:3]([C:9]([C:11]2[CH:16]=[CH:15][N:14]=[CH:13][CH:12]=2)=[O:10])[CH:4]=1
Reactant: Nc1ccc(Cl)cc1C(=O)c1ccncc1
Reactant: CS(=O)(=O)c1ccc(S(=O)(=O)Cl)cc1
Product: CS(=O)(=O)c1ccc(S(=O)(=O)Nc2ccc(Cl)cc2C(=O)c2ccncc2)cc1

Procedure:
The title compound was prepared according to the general procedure for the synthesis of N-Aryl-benzenesulfonamides previously described using 116 mg of (2-amino-5-chloro-phenyl)-pyridin-4-yl-methanone and 127 mg of 4-methanesulfonyl-benzenesulfonyl chloride. 1H-NMR (400 MHz, CDCl3): δ 3.06 (s, 3H), 7.31 (d, 1H, J=2.0 Hz), 7.45 (m, 2H), 7.58 (dd, 1H, J=8.8 Hz, 2.8 Hz), 7.99 (b, 4H), 8.88 (dd, 2H, J=4.8 Hz, 1.6 Hz), 10.29 (b, 1H). MS: m/z 451.9 (M++1).
Reaction SMILES: [O:1]1[C:9]2[C:4](=[N:5][CH:6]=[CH:7][CH:8]=2)[N:3]=[CH:2]1.C([Mg]Cl)(C)C.[C:15]([O:19][C:20]([NH:22][C@@H:23]([CH2:26][CH3:27])[CH:24]=[O:25])=[O:21])([CH3:18])([CH3:17])[CH3:16]>C1COCC1>[C:15]([O:19][C:20]([NH:22][C@@H:23]([CH2:26][CH3:27])[CH:24]([C:2]1[O:1][C:9]2[C:4]([N:3]=1)=[N:5][CH:6]=[CH:7][CH:8]=2)[OH:25])=[O:21])([CH3:18])([CH3:17])[CH3:16]
Reactant: CC[C@@H](C=O)NC(=O)OC(C)(C)C
Reactant: c1cnc2ncoc2c1
Agent: CC(C)[Mg]Cl
Solvent: C1CCOC1
Product: CC[C@H](NC(=O)OC(C)(C)C)C(O)c1nc2ncccc2o1
Temperature: 0 °C
Reaction time: 2 h
Yield: 41.5 %

Procedure:
In a round bottom flask equipped with stir bar was placed oxazolo[4,5-b]pyridine (600 mg, 5 mmol) in THF (30 mL) and the reaction mixture was cooled to 0° C. under N2 atomosphere. Isopropylmagnesium chloride (2 M in THF, 2.5 mL, 5 mmol) was added. After stirring for 1 h at 0° C., (S)-2-(tert-butoxycarbonyl)aminobutyraldehyde (573 mg, 3 mmol) in THF (20 mL) was added. The ice bath was removed and the reaction mixture was allowed to warm to room temperature. After 2 h, the reaction mixture was quenched with saturated ammonium chloride solution and concentrated to dryness. The residue was extracted with EtOAc, then washed with brine, dried with anhyd. MgSO4, filtered and concentrated. The crude product was purified by chromatograph to yield 383 mg of the desired compound.