Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(N(CC)CC)C.[NH2:8][C@@H:9]1[CH2:15][CH2:14][C@@H:13]([C:16]2[CH:21]=[CH:20][CH:19]=[C:18]([F:22])[C:17]=2[F:23])[CH2:12][N:11]([CH2:24][C:25]([F:28])([F:27])[F:26])[C:10]1=[O:29].Cl[C:31](OC1C=CC([N+]([O-])=O)=CC=1)=[O:32].Cl.Cl.[O:45]=[C:46]1[NH:54][C:49]2=[N:50][CH:51]=[CH:52][CH:53]=[C:48]2[N:47]1[CH:55]1[CH2:60][CH2:59][NH:58][CH2:57][CH2:56]1>O1CCCC1.ClCCl>[F:23][C:17]1[C:18]([F:22])=[CH:19][CH:20]=[CH:21][C:16]=1[C@H:13]1[CH2:12][N:11]([CH2:24][C:25]([F:28])([F:26])[F:27])[C:10](=[O:29])[C@H:9]([NH:8][C:31]([N:58]2[CH2:59][CH2:60][CH:55]([N:47]3[C:48]4[C:49](=[N:50][CH:51]=[CH:52][CH:53]=4)[NH:54][C:46]3=[O:45])[CH2:56][CH2:57]2)=[O:32])[CH2:15][CH2:14]1
Reactant: N[C@@H]1CC[C@@H](c2cccc(F)c2F)CN(CC(F)(F)F)C1=O
Reactant: O=C(Cl)Oc1ccc([N+](=O)[O-])cc1
Reactant: O=c1[nH]c2ncccc2n1C1CCNCC1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Solvent: C1CCOC1
Product: O=C(N[C@@H]1CC[C@@H](c2cccc(F)c2F)CN(CC(F)(F)F)C1=O)N1CCC(n2c(=O)[nH]c3ncccc32)CC1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 62.7 %

Procedure:
Triethylamine (0.038 mL, 0.276 mmol) was added to a solution of (3R,6S)-3-amino-6-(2,3-difluorophenyl)-1-(2,2,2-trifluoroethyl)azepan-2-one (89 mg, 0.276 mmol) and 4-nitrophenyl chloroformate (56 mg, 0.276 mmol) in tetrahydrofuran (3 mL) at 0° C. After 30 min, 2-oxo-1-(4-piperidinyl)-2,3-dihydro-1H-imidazo[4,5-b]pyridine dihydrochloride (88 mg, 0.304 mmol), triethylamine (0.152 mL, 1.104 mmol), and dichloromethane (5 mL) were added and the mixture allowed to warm to ambient temperature. After 48 h, the mixture was concentrated. Purification by silica gel chromatography [100% dichloromethane→95% dichloromethane/methanol (10% ammonium hydroxide/methanol)] gave the title compound (98 mg). The title compound was converted to the HCl salt with 2M HCl in ether. MS 567.2 (M+1). 1H NMR (500 MHz, CD3OD) δ 8.11 (dd, J=7.8 Hz, 1.0 Hz, 1H), 8.00 (dd, J=5.9 Hz, 1.0 Hz, 1H), 7.34-7.31 (m, 1H), 7.19-7.13 (m, 3H), 4.86-4.83 (m, 1H), 4.62-4.57 (m, 1H), 4.49-4.41 (m, 1H), 4.33-4.25 (m, 3H), 4.12-4.04 (m, 1H), 3.51-3.46 (m, 1H), 3.18-3.14 (m, 1H), 3.09-2.96 (m, 2H), 2.51-2.44 (m, 1H), 2.33-2.25 (m, 1H), 2.22-2.10 (m, 3H), 1.90-1.81 (m, 3H).
Reaction SMILES: [NH2:1][C@H:2]([C@H:4]1[CH2:8][N:7]([C@H](C2C=CC=CC=2)C)[C:6](=[O:17])[CH2:5]1)C.F[C:19](F)(F)C(O)=O>>[NH2:1][CH2:2][C@@H:4]1[C@@H:8]([CH3:19])[NH:7][C:6](=[O:17])[CH2:5]1
Reactant: C[C@H](N)[C@@H]1CC(=O)N([C@@H](C)c2ccccc2)C1
Reactant: O=C(O)C(F)(F)F
Product: C[C@H]1NC(=O)C[C@@H]1CN
Temperature: 150 °C
Reaction time: 1.5 h

Procedure:
20 mg (R)-4-((S)-1-aminoethyl)-1-((S)-1-phenylethyl)pyrrolidine-2-one (I.22) was dissolved in trifluoroacetic acid and stirred for 90 min in the microwave at 150° C. The mixture was concentrated and used without further purification.
Reaction SMILES: CS[C:3]1[N:7]([C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9])[C@H:6]2[CH2:15][CH2:16][CH2:17][CH2:18][C@H:5]2[N:4]=1.[F:19][C:20]1[CH:21]=[C:22]([CH:25]=[CH:26][CH:27]=1)[CH2:23][NH2:24]>ClCCl>[C:11]([O:10][C:8]([N:7]1[C@H:6]2[CH2:15][CH2:16][CH2:17][CH2:18][C@H:5]2[N:4]=[C:3]1[NH:24][CH2:23][C:22]1[CH:25]=[CH:26][CH:27]=[C:20]([F:19])[CH:21]=1)=[O:9])([CH3:14])([CH3:13])[CH3:12]
Reactant: CSC1=N[C@@H]2CCCC[C@@H]2N1C(=O)OC(C)(C)C
Reactant: NCc1cccc(F)c1
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N1C(NCc2cccc(F)c2)=N[C@@H]2CCCC[C@@H]21
Temperature: 100 °C
Yield: 73.2 %

Procedure:
A mixture of intermediate 76 (200 mg, 0.0.740 mmol), 3-fluorobenzylamine (0.5 mL, 4.4 mmol) is heated at 100° C. (reaction block) overnight. The reaction mixture is cooled to RT. The reaction mixture is diluted with dichloromethane, washed with 0.1N HCl, and brine. The solvent is evaporated, and the residue triturated with EtOAc, and the insoluble material filtered to give 188 mg of the product 191. 1H NMR (CDCl3) δ 8.56 (s, 1H), 7.45-7.20 (m, 3H), 7.20-6.95 (m, 2H), 5.20-4.95 (m, 2H), 4.35-4.10 (m, 2H), 2.75-2.55 (m, 1H), 2.20-2.05 (m, 1H), 1.80-1.05 (m, 15H); MS: m/z 348 (M++1).
Reaction SMILES: [O:1]=[C:2]1[C:6]2([CH2:11][CH2:10][N:9]([C:12]([O:14][CH2:15][C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)=[O:13])[CH2:8][CH2:7]2)[N:5]([C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)[CH2:4][NH:3]1.I[C:29]1[CH:38]=[CH:37][CH:36]=[CH:35][C:30]=1[C:31]([O:33][CH3:34])=[O:32].CNCCNC.C(O)(=O)CC(CC(O)=O)(C(O)=O)O>C(#N)C.[Cu](I)I>[CH3:34][O:33][C:31]([C:30]1[CH:35]=[CH:36][CH:37]=[CH:38][C:29]=1[N:3]1[C:2](=[O:1])[C:6]2([CH2:7][CH2:8][N:9]([C:12]([O:14][CH2:15][C:16]3[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=3)=[O:13])[CH2:10][CH2:11]2)[N:5]([C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)[CH2:4]1)=[O:32]
Reactant: O=C(OCc1ccccc1)N1CCC2(CC1)C(=O)NCN2c1ccccc1
Reactant: COC(=O)c1ccccc1I
Agent: I[Cu]I
Agent: CNCCNC
Agent: O=C(O)CC(O)(CC(=O)O)C(=O)O
Solvent: CC#N
Product: COC(=O)c1ccccc1N1CN(c2ccccc2)C2(CCN(C(=O)OCc3ccccc3)CC2)C1=O
Temperature: 75 °C
Yield: 61.7 %

Procedure:
A mixture of benzyl 4-oxo-1-phenyl-1,3,8-triazaspiro[4.5]decane-8-carboxylate (2.79 g, 7.63 mmol, 1 equiv), methyl 2-iodobenzoate (2 g, 7.63 mmol, 1 equiv) potassium carbonate (2.11 g, 15.26 mmol, 2 equiv), copper(II) iodide (145.32 mg, 0.763 mmol, 0.1 equiv) and N,N′-dimethyl ethylenediamine (164.25 μl, 1.526 mmol, 0.2 equiv) in acetonitrile was heated at 75° C. for 16 h. Upon cooling 10% citric acid was added and the mixture was extracted with ethyl acetate. The organic layer was washed with water and brine, dried over MgSO4, filtered and concentrated. The residue was purified using the Biotage flash chromatography system (SNAP 100 g cartridge, Rf=0.3, gradient—5%-30% ethyl acetate in hexanes) to afford the title compound as a white powder (2.35 g, 61.57%); 1H NMR (400 MHz, DMSO-d6): δ 1.85 (d, 2H, J=14 Hz); 2.35-2.51 (m, 2H); 3.49 (bs, 2H); 3.98-4.03 (m, 2H); 5.14 (s, 2H); 6.84-6.87 (m, 3H); 7.22-7.26 (m, 2H); 7.32-7.39 (m, 5H); 7.49-7.53 (m, 1H); 7.65 (dd, 1H, J=1.6 and 1.2 Hz); 7.70-7.75 (m, 1H); 7.86 (dd, 1H, J=1.2 and 1.6 Hz); MS for C29H29N3O5 m/z 500.21 (M+H)+.
Reaction SMILES: Cl[CH2:2][C:3]1[C:4]([C:20]2[CH:25]=[CH:24][C:23]([F:26])=[CH:22][CH:21]=2)=[C:5]([C:15]([O:17][CH2:18][CH3:19])=[O:16])[C:6]([CH:12]([CH3:14])[CH3:13])=[N:7][C:8]=1[CH:9]([CH3:11])[CH3:10].[O-:27][C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1.[Na+].O>O1CCCC1>[CH:12]([C:6]1[C:5]([C:15]([O:17][CH2:18][CH3:19])=[O:16])=[C:4]([C:20]2[CH:21]=[CH:22][C:23]([F:26])=[CH:24][CH:25]=2)[C:3]([CH2:2][O:27][C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)=[C:8]([CH:9]([CH3:10])[CH3:11])[N:7]=1)([CH3:13])[CH3:14]
Reactant: CCOC(=O)c1c(C(C)C)nc(C(C)C)c(CCl)c1-c1ccc(F)cc1
Reactant: [O-]c1ccccc1
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: CCOC(=O)c1c(C(C)C)nc(C(C)C)c(COc2ccccc2)c1-c1ccc(F)cc1
Temperature: 25 °C

Procedure:
3.22 g (9.1 mmol) of the compound from Example 86 dissolved in 50 ml of absolute tetrahydrofuran are added dropwise at 0° C. to a solution of 2.11 g (18.2 mmol) of sodium phenoxide in 50 ml of absolute tetrahydrofuran and the mixture is heated to reflux for 4 days. After cooling to room temperature, the mixture is diluted using 150 ml of water and extracted several times using ether. The combined organic phases are dried over magnesium sulphate and concentrated in vacuo, and the residue is chromatographed on a column (silica gel 70-230 mesh, using petroleum ether/ethyl acetate 95.5).
Reaction SMILES: [C:1]([C:4]1[C:9]([NH:10][C:11]([C:13]2[S:14][CH:15]=[C:16]([CH:18]([CH3:20])[CH3:19])[N:17]=2)=O)=[CH:8][C:7]([Cl:21])=[C:6]([O:22][CH3:23])[CH:5]=1)(=[O:3])[CH3:2].C(C1N=C(C2C=C(O)C3C(=CC(OC)=CC=3)N=2)SC=1)(C)C>>[Cl:21][C:7]1[CH:8]=[C:9]2[C:4]([C:1]([OH:3])=[CH:2][C:11]([C:13]3[S:14][CH:15]=[C:16]([CH:18]([CH3:20])[CH3:19])[N:17]=3)=[N:10]2)=[CH:5][C:6]=1[O:22][CH3:23]
Reactant: COc1cc(C(C)=O)c(NC(=O)c2nc(C(C)C)cs2)cc1Cl
Agent: COc1ccc2c(O)cc(-c3nc(C(C)C)cs3)nc2c1
Product: COc1cc2c(O)cc(-c3nc(C(C)C)cs3)nc2cc1Cl
Yield: 70 %

Procedure:
7-Chloro-2-(4-isopropylthiazol-2-yl)-6-methoxyquinolin-4-ol 218g was synthesized from compound 217g as a yellow solid in 70% yield, according to the procedures as described for compound 218a. MS (ESI, EI+): m/z=335 (MH+).
Reaction SMILES: [CH:1]1[N:6]=[C:5]([Cl:7])[C:4]2[N:8]=[CH:9][N:10]([C@@H:11]3[O:15][C@H:14]([CH2:16][OH:17])[C@@H:13]([OH:18])[C@H:12]3[OH:19])[C:3]=2[N:2]=1.[N:20]1([CH2:25][CH2:26][NH2:27])[CH:24]=[CH:23][N:22]=[CH:21]1.C(N(CC)CC)C>C(O)C>[ClH:7].[N:20]1([CH2:25][CH2:26][NH:27][C:5]2[C:4]3[N:8]=[CH:9][N:10]([C:3]=3[N:2]=[CH:1][N:6]=2)[C@@H:11]2[O:15][C@H:14]([CH2:16][OH:17])[C@@H:13]([OH:18])[C@H:12]2[OH:19])[CH:24]=[CH:23][N:22]=[CH:21]1
Reactant: OC[C@H]1O[C@@H](n2cnc3c(Cl)ncnc32)[C@H](O)[C@@H]1O
Reactant: NCCn1ccnc1
Solvent: CCO
Solvent: CCN(CC)CC
Product: Cl
Product: OC[C@H]1O[C@@H](n2cnc3c(NCCn4ccnc4)ncnc32)[C@H](O)[C@@H]1O
Yield: 59 %

Procedure:
To a suspension of 6-chloropurine riboside (1.63 g, 5.69 mmol) in 12 ml of absolute ethanol was added 0.63 g (5.7 mmol) of 2-(imidazol-1-yl)ethylamine (prepared in accordance with Z.Obsch. Chem. 9 1933 (1939); Chem Ab. 1940 2466) plus 0.80 g (8.0 mmol) of triethylamine. The reaction mixture was heated under reflux for 77 hours. Removal of the solvent in vacuo and chromatography of the residue on silica gel eluting with a mixture of MeOH (NH3) and dichloromethane in a ratio of 14:86 gave the free base of the title compound in an amount of 1.2 g (59% yield). The material was converted to the hydrochloride salt by suspending the material in 20 ml of water at 0° centigrade and adding 1N hydrochloric acid until a pH of 2.6 was attained. The solution was frozen and lyophilized to a white powder which was passed through a column of cellulose powder eluting with a mixture of 85 parts n-butanol and 15 parts water. The appropriate fractions were combined and concentrated to give a glass which was azeotroped twice with water and then dissolved in water, frozen and lyophilized yielding 0.97 g of the title compound (41% yield) as a white powder.
Reaction SMILES: [F:1][C:2]1[C:12]([N:13]2[C:18](=[O:19])[CH:17]=[C:16]([C:20]([F:23])([F:22])[F:21])[NH:15][C:14]2=[O:24])=[CH:11][C:5]2[NH:6][C:7](=[O:10])[CH2:8][O:9][C:4]=2[CH:3]=1.[C:25](=O)([O-])[O-].[K+].[K+].CI>CN(C)C=O>[F:1][C:2]1[C:12]([N:13]2[C:18](=[O:19])[CH:17]=[C:16]([C:20]([F:21])([F:22])[F:23])[N:15]([CH3:25])[C:14]2=[O:24])=[CH:11][C:5]2[NH:6][C:7](=[O:10])[CH2:8][O:9][C:4]=2[CH:3]=1
Reactant: O=C1COc2cc(F)c(-n3c(=O)cc(C(F)(F)F)[nH]c3=O)cc2N1
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CI
Product: Cn1c(C(F)(F)F)cc(=O)n(-c2cc3c(cc2F)OCC(=O)N3)c1=O
Yield: 119.9 %

Procedure:
0.85 g of 3-(7-fluoro-3-oxo-2H-1,4-benzoxazin-6-yl)-6-trifluoromethyl 2,4(1H,3H)-pyrimidinedione was dissolved in 8.5 ml of N,N-dimethylformamide. Then 0.17 g of anhydrous potassium carbonate and 0.15 ml of methyl iodide were added and the mixed solution was stirred for hours. After the reaction was completed, N,N -dimethylformamide was distilled off and the residue was extracted with ethyl acetate by adding water. The extract was washed with a saturated sodium chloride aqueous solution and dried over anhydrous sodium sulfate, and then ethyl acetate was distilled off to obtain a crude product. This product was purified by column chromatography using chloroform as developing solvent to yield 0.53 g of the objective compound as pale yellow crystals.
Reaction SMILES: [CH2:1]([O:3][C:4]1[CH:5]=[C:6]2[C:10](=[CH:11][CH:12]=1)[N:9](CN(C)C)[CH:8]=[CH:7]2)[CH3:2].[N+:17]([CH:20]([CH3:25])[C:21]([O:23][CH3:24])=[O:22])([O-:19])=[O:18].[C:26]1(C)C=CC=CC=1.CC(C)=O>C1(C)C=CC=CC=1.C(Cl)(Cl)Cl>[CH3:24][O:23][C:21](=[O:22])[C:20]([CH3:26])([N+:17]([O-:19])=[O:18])[CH2:25][C:7]1[C:6]2[C:10](=[CH:11][CH:12]=[C:4]([O:3][CH2:1][CH3:2])[CH:5]=2)[NH:9][CH:8]=1
Reactant: COC(=O)C(C)[N+](=O)[O-]
Reactant: Cc1ccccc1
Reactant: CCOc1ccc2c(ccn2CN(C)C)c1
Solvent: ClC(Cl)Cl
Solvent: CC(C)=O
Product: CCOc1ccc2[nH]cc(CC(C)(C(=O)OC)[N+](=O)[O-])c2c1
Yield: 68 %

Procedure:
A mixture of (5-ethoxy-1H-indol-ylmethyl)-dimethyl-amine (2.18 g, 10 mmol) and commercially available methyl 2-nitro-propionate (1.60 g, 12 mmol, 1.2 equiv) in dry toluene (17 ml) is refluxed. When TLC (toluene-acetone, 9:1) indicates the absence of starting material the mixture is cooled and is diluted with chloroform (35 ml). It is subsequently washed with 10% aqueous HCl (2×10 ml), water (10 ml), 5% aqueous NaOH (2×10 ml), water (10 ml), and 20% aqueous Na2SO4 (10 ml), is dried, and the solvents are removed under reduced pressure. The residue is purified by column chromatography (light petroleum-ethyl acetate, 4:1→7:3) to give (+/−)-3-(5-ethoxy-1H-indol-3-yl)-2-methyl-2-nitro-propionic acid methyl ester (2.07 g, 68%) as a white solid. M.p. 80-82° C. (from ethyl acetate-hexane).
Reaction SMILES: Br[C:2]1[C:3]([N:20]2[CH2:25][CH2:24][CH2:23][C@@H:22]([NH:26]C(=O)OC(C)(C)C)[CH2:21]2)=[C:4]2[C:10]([NH:11][C:12](=[O:19])[C:13]3[CH:18]=[CH:17][CH:16]=[N:15][CH:14]=3)=[CH:9][NH:8][C:5]2=[N:6][CH:7]=1.[Li]C.C([Li])CCC.[Cl-:41].[NH4+]>O1CCOCC1>[ClH:41].[NH2:26][C@@H:22]1[CH2:23][CH2:24][CH2:25][N:20]([C:3]2[CH:2]=[CH:7][N:6]=[C:5]3[NH:8][CH:9]=[C:10]([NH:11][C:12](=[O:19])[C:13]4[CH:18]=[CH:17][CH:16]=[N:15][CH:14]=4)[C:4]=23)[CH2:21]1
Reactant: CC(C)(C)OC(=O)N[C@@H]1CCCN(c2c(Br)cnc3[nH]cc(NC(=O)c4cccnc4)c23)C1
Reactant: [Cl-]
Agent: [Li]C
Agent: [Li]CCCC
Agent: [NH4+]
Solvent: C1COCCO1
Product: Cl
Product: N[C@@H]1CCCN(c2ccnc3[nH]cc(NC(=O)c4cccnc4)c23)C1
Temperature: -78 °C
Reaction time: 0.17 h
Yield: 17 %

Procedure:
(R)-tert-Butyl 1-(5-bromo-3-(nicotinamido)-1H-pyrrolo[2,3-b]pyridin-4-yl)piperidin-3-ylcarbamate (125 mg, 0.243 mmol; Example 1A, Step A) was dissolved in dioxane (20 mL) and cooled to −78° C. MeLi (455 μL, 0.728 mmol) was slowly added, and the reaction was stirred for 10 minutes. n-Butyl lithium (146 μL, 0.364 mmol) was slowly added, and the reaction was stirred for 10 minutes at −78° C. Saturated ammonium chloride was then added, and the mixture was extracted several times with DCM. The layers were separated, dried, filtered, and concentrated. The residue was purified by reverse phase chromatography (Biotage Horizon, C-18 25M+, 0-80% CH3CN/water+10 mM ammonium acetate and 1% IPA). The product was dissolved in TFA (2 mL), stirred for 30 minutes, concentrated and purified by reverse phase chromatography (Biotage Horizon, C-18 12M+, 0-30% CH3CN/water+0.1% TFA). The product was redissolved in 10% MeOH in DCM (2 mL) and added dropwise to a stirred solution of 2M HCl in ether. The reaction was concentrated to give (R)—N-(4-(3-aminopiperidin-1-yl)-1H-pyrrolo[2,3-b]pyridin-3-yl)nicotinamide hydrochloride (18.5 mg, 17% yield). 1H NMR (400 MHz, D2O) δ 9.10 (s, 1H), 8.78 (d, 1H), 8.62 (dt, 1H), 7.94 (d, 1H), 7.85 (dd, 1H), 7.39 (s, 1H), 6.78 (d, 1H), 3.89 (d, 1H), 3.72 (d, 1H), 3.33 (m, 1H), 3.21-3.09 (m, 2H), 1.93 (m, 1H), 1.58 (m, 1H), 1.47 (m, 1H), 1.36 (m, 1H). LCMS (APCI+) m/z 337.1 (M+H)+, Retention time=0.43 minutes (Method 3).
Reaction SMILES: [CH2:1]([N:8]1[CH2:13][C:12]([CH3:15])([CH3:14])[C:11](Cl)=[C:10]([CH:17]=O)[CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[SH:19][CH2:20][C:21]([O:23][CH2:24][CH3:25])=[O:22].C(N(CC)CC)C>C(Cl)Cl>[CH2:1]([N:8]1[CH2:13][C:12]([CH3:14])([CH3:15])[C:11]2[S:19][C:20]([C:21]([O:23][CH2:24][CH3:25])=[O:22])=[CH:17][C:10]=2[CH2:9]1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CC1(C)CN(Cc2ccccc2)CC(C=O)=C1Cl
Reactant: CCOC(=O)CS
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCOC(=O)c1cc2c(s1)C(C)(C)CN(Cc1ccccc1)C2
Temperature: 25 °C
Yield: 34.4 %

Procedure:
To a solution of 1-benzyl-4-chloro-5,5-dimethyl-1,2,5,6-tetrahydropyridine-3-carbaldehyde (75 g, 0.28 mol) in DCM (1.2 L) was added ethyl 2-mercaptoacetate (67 g, 0.56 mol) and triethylamine (85 g, 0.84 mol) was added slowly at room temperature. Upon complete addition, the reaction mixture was heated at reflux overnight. Upon cooling to room temperature, the reaction was quenched with the addition of water. The organic layer was washed with water, dried over anhydrous Na2SO4, concentrated and purified by silica gel chromatography (0-20% EtOAc/hexane) to afford the title compound (31.7 g, 27.5% over two steps).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([O:17][CH2:18][C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)=[C:6]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=2B(O)O)[CH:7]=1.Br[C:26]1[N:31]=[C:30]([C:32]([O:34][CH2:35][CH3:36])=[O:33])[CH:29]=[CH:28][CH:27]=1.C(=O)([O-])[O-].[K+].[K+]>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.C1(C)C=CC=CC=1.C(O)C>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([O:17][CH2:18][C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)=[C:6]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=2[C:26]2[N:31]=[C:30]([C:32]([O:34][CH2:35][CH3:36])=[O:33])[CH:29]=[CH:28][CH:27]=2)[CH:7]=1
Reactant: CCOC(=O)c1cccc(Br)n1
Reactant: OB(O)c1ccccc1-c1cc(Cl)ccc1OCc1ccccc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: Cc1ccccc1
Solvent: CCO
Product: CCOC(=O)c1cccc(-c2ccccc2-c2cc(Cl)ccc2OCc2ccccc2)n1
Temperature: 90 °C
Yield: 83.4 %

Procedure:
A mixture of {5′-chloro-2′-[(phenylmethyl)oxy]-2-biphenylyl}boronic acid (1.32 g, 3.9 mmol), ethyl 6-bromopicolinate (851 mg, 3.7 mmol), potassium carbonate (2.76 g, 20 mmol) and tetrakis(triphenylphosphine)palladium(0) (232 mg, 0.2 mmol) in 1:1 toluene/ethanol (25 ml) was stirred and heated at 90° C. under nitrogen for 1.5 hours. After cooling and dilution with diethyl ether/water the organic phase was separated, dried (magnesium sulphate) and evaporated. The residue was chromatographed on silica eluting with ethyl acetate/iso-hexane (3:17) to give 1.37 g of white solid. LC/MS t=3.76, [MH+] 444.3
Reaction SMILES: [I-].[CH2:2]([N+:6]1[C:10]([CH3:11])=[C:9]([CH3:12])[S:8][C:7]=1[CH3:13])[CH2:3][CH2:4][CH3:5].[CH3:14][C:15]1[CH:19]=[CH:18][S:17][C:16]=1[C:20](Cl)=[O:21]>CN(C1C=CN=CC=1)C>[CH2:2]([N:6]1[C:10]([CH3:11])=[C:9]([CH3:12])[S:8]/[C:7]/1=[CH:13]\[C:20]([C:16]1[S:17][CH:18]=[CH:19][C:15]=1[CH3:14])=[O:21])[CH2:3][CH2:4][CH3:5]
Reactant: CCCC[n+]1c(C)sc(C)c1C
Reactant: Cc1ccsc1C(=O)Cl
Agent: CN(C)c1ccncc1
Agent: [I-]
Product: CCCCN1C(C)=C(C)S/C1=C\C(=O)c1sccc1C
Temperature: 25 °C
Reaction time: 8 h

Procedure:
In a 20 mL vial 3-butyl-2,4,5-trimethylthiazol-3-ium iodide (48 mg in 0.5 mL DMA, 0.16 mmol, 1 equiv.) was added, followed by TEA (38 mg in 0.5 mL DMA, 0.37 mmol, 2.4 equiv.) and the solution went black. DMAP (2 mg in 0.5 mL DMA, 0.016 mmol, 0.1 equiv) was added next, followed by 3-methylthiophene-2-carbonyl chloride (0.9 mL of 0.2M in DMA, 1.2 equiv). The mixture was shaken overnight at room temperature and then concentrated in vacuo. The resulting residue was taken up in 1:1 DMSO/MeOH and purified by reverse phase HPLC using a method analogous to that described in Example 53 to provide the title compound. 1H NMR (500 MHz, DMSO-d6/D2O) δ ppm 0.95 (t, 3 H) 1.34-1.43 (m, 2 H) 1.60-1.71 (m, 2 H) 2.17 (s, 3 H) 2.20 (s, 3 H) 2.47 (s, 3 H) 3.92-3.98 (m, 2 H) 6.13 (s, 1 H) 6.91-6.96 (m, 1 H) 7.46-7.52 (m, 1 H); MS (ESI) m/z 308 (M+H)+.
Reaction SMILES: [CH:1]([S:3]([OH:6])(=[O:5])=[O:4])=[CH2:2].ClCCS(Cl)(=O)=O.[C:14]1(O)[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1.Cl>>[CH:1]([S:3]([O:6][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)(=[O:5])=[O:4])=[CH2:2]
Reactant: Oc1ccccc1
Reactant: C=CS(=O)(=O)O
Agent: Cl
Agent: O=S(=O)(Cl)CCCl
Product: C=CS(=O)(=O)Oc1ccccc1

Procedure:
The aryl ester of vinylsulfonic acid can be prepared by several available techniques. U.S. Pat. No. 3,121,730 teaches reacting a beta-chloroethanesulfonyl chloride with phenol in an aqueous medium at a pH of between 7.5 and 11.5. The reaction proceeds with a loss of 2 mols of hydrogen chloride to yield phenyl vinylsulfonate. U.S. Pat. No. 3,133,948 teaches reacting carbyl sulfate with an aromatic hydroxy compound in an aqueous alkaline medium at a pH between 7.5 and 11.5 to yield a aryl vinylsulfonate.
Reaction SMILES: [OH:1]C(CCCC[C@H]1[C@@H]2[C@@H](NC(N2)=O)CS1)=O.OO.[OH:19][C:20]([CH2:22][CH2:23][CH2:24][CH2:25][C@H:26]1[C@@H:35]2[C@@H:30]([NH:31][C:32]([NH:34]2)=[O:33])[CH2:29][S:27]1=[O:28])=[O:21]>CC(O)=O>[O:33]=[C:32]1[NH:34][C@H:35]2[C@H:30]([CH2:29][S:27](=[O:1])(=[O:28])[C@H:26]2[CH2:25][CH2:24][CH2:23][CH2:22][C:20]([OH:19])=[O:21])[NH:31]1
Reactant: O=C(O)CCCC[C@@H]1SC[C@@H]2NC(=O)N[C@@H]21
Reactant: O=C(O)CCCC[C@H]1[C@H]2NC(=O)N[C@H]2CS1=O
Agent: OO
Solvent: CC(=O)O
Product: O=C(O)CCCC[C@H]1[C@H]2NC(=O)N[C@H]2CS1(=O)=O
Temperature: 25 °C
Reaction time: 65 h
Yield: 87 %

Procedure:
Following the procedure of Sachon et al.,42 D-biotin (83, 0.304 g, 1.24 mmol) was suspended in AcOH (3.0 mL) and then H2O2 (35% in H2O, 1.0 mL) was added at room temperature. The suspension became a colorless, clear solution after 10 min at room temperature, and biotin sulfoxide began to precipitate after 5 hours. The reaction was stirred at room temperature for 65 hours, then filtered. The white filter cake was then washed with 20 mL of ether and dried under reduced pressure to provide 89 as a white solid (0.298 g, 1.08 mmol, 87%).
Reaction SMILES: [C:1]([NH:4][C:5]1[S:6][CH:7]=[C:8]([C:10]([NH2:12])=O)[N:9]=1)(=[O:3])[CH3:2].C1(C)C=CC(S(Cl)(=O)=O)=CC=1.C(OCC)(=O)C.O>N1C=CC=CC=1>[C:1]([NH:4][C:5]1[S:6][CH:7]=[C:8]([C:10]#[N:12])[N:9]=1)(=[O:3])[CH3:2]
Reactant: CC(=O)Nc1nc(C(N)=O)cs1
Agent: Cc1ccc(S(=O)(=O)Cl)cc1
Solvent: CCOC(C)=O
Solvent: O
Solvent: c1ccncc1
Product: CC(=O)Nc1nc(C#N)cs1
Yield: 75 %

Procedure:
5.1 g (27.5 mmol) 2-Acetylaminothiazol-4-carboxamide was dispersed in 27 ml pyridine, and 10.5 g (55 mmol) p-tolylsulfonyl chloride was added, to carry out reaction at room temperature for 10 hr, and then 150 ml ethyl acetate and 100 ml water were added to separate the layers. The resultant organic phase was washed with diluted HCl till aqueous phase being acidic, and then washed with saturated sodium chloride, dried over anhydrous sodium sulfate, filtered, and concentrated to obtain 3.45 g 2-acetylamino-4-cyanothiazole (yield 75%) with mp 185-188° C. (ethyl acetate). 1H NMR (DMSO-d6) 2.18 (3H, s); 8.33 (1H, s); 12.55 (1H, s).
Reaction SMILES: [CH:1](=[CH:8][NH2:9])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH:10]1[C:19]2[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=2)[CH:13]=[CH:12][C:11]=1[CH:20]=[O:21].S([CH2:32][N+:33]#[C-:34])(C1C=CC(C)=CC=1)(=O)=O.C([O-])([O-])=O.[K+].[K+]>>[CH3:34][N:33]1[C:1]([C:2]2[CH:7]=[CH:6][C:5]3[C:4](=[CH:10][CH:11]=[CH:12][CH:13]=3)[CH:3]=2)=[CH:8][N:9]=[CH:32]1.[CH:10]1[C:19]2[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=2)[CH:13]=[CH:12][C:11]=1[C:20]1[O:21][CH:34]=[N:33][CH:32]=1
Reactant: NC=Cc1ccccc1
Reactant: O=Cc1ccc2ccccc2c1
Reactant: [C-]#[N+]CS(=O)(=O)c1ccc(C)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Product: Cn1cncc1-c1ccc2ccccc2c1
Product: c1ccc2cc(-c3cnco3)ccc2c1

Procedure:
Reaction of N-benzylidenemethylamine 28i or 2-naphthaldehyde 29i and tosylmethylisocyanide (Tosmic) with K2CO3 as the base yielded 1-methyl-5-(2-naphthyl)-1H-imidazole 28 or 5-(2-naphthyl)-1,3-oxazole 29, respectively:
Reaction SMILES: [C:1]1([N:7]2[C:11](O)=[CH:10][C:9]([C:13]([F:16])([F:15])[F:14])=[N:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[Cl:17]N1C(=O)CCC1=O>C(O)(C(F)(F)F)=O.C(O)(=O)C.C(O)(=O)C>[C:1]1([N:7]2[CH:11]=[C:10]([Cl:17])[C:9]([C:13]([F:16])([F:15])[F:14])=[N:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: O=C1CCC(=O)N1Cl
Reactant: Oc1cc(C(F)(F)F)nn1-c1ccccc1
Solvent: CC(=O)O
Solvent: O=C(O)C(F)(F)F
Product: FC(F)(F)c1nn(-c2ccccc2)cc1Cl
Temperature: 25 °C
Reaction time: 16 h
Yield: 22.3 %

Procedure:
A mixture of 2.28 g (10 mmol) of 1-phenyl-3-trifluoromethyl-5-hydroxypyrazole and 1.6 g (12 mmol) of N-chlorosuccinimide in 8 ml of 20% TFA/acetic acid and 32 mL of acetic acid was stirred at room temperature for 16 hours and diluted with ice/water with cooling. The white precipitate was filtered and purified by column chromatography (silica gel; 20-33% ethyl acetate/hexane) to afford 550 mg (21%) of 1-phenyl-3-trifluoromethyl-4-chloropyrazole as a solid.