Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C1(O[C:8](=[O:30])[NH:9][C:10]2[S:14][N:13]=[C:12]([O:15][CH2:16][C:17]3[C:22]([F:23])=[CH:21][C:20]([CH3:24])=[C:19]([F:25])[C:18]=3[F:26])[C:11]=2[C:27](=[O:29])[NH2:28])C=CC=CC=1.[NH2:31][CH2:32][CH2:33][CH:34]([OH:42])[CH2:35][CH2:36][N:37]1[CH2:41][CH2:40][CH2:39][CH2:38]1>>[OH:42][CH:34]([CH2:35][CH2:36][N:37]1[CH2:38][CH2:39][CH2:40][CH2:41]1)[CH2:33][CH2:32][NH:31][C:8](=[O:30])[NH:9][C:10]1[S:14][N:13]=[C:12]([O:15][CH2:16][C:17]2[C:22]([F:23])=[CH:21][C:20]([CH3:24])=[C:19]([F:25])[C:18]=2[F:26])[C:11]=1[C:27]([NH2:28])=[O:29]
Reactant: Cc1cc(F)c(COc2nsc(NC(=O)Oc3ccccc3)c2C(N)=O)c(F)c1F
Reactant: NCCC(O)CCN1CCCC1
Product: Cc1cc(F)c(COc2nsc(NC(=O)NCCC(O)CCN3CCCC3)c2C(N)=O)c(F)c1F

Procedure:
The title compound was prepared from [4-carbamoyl-3-(2,3,6-trifluoro-4-methyl-benzyloxy)-isothiazol-5-yl]-carbamic acid phenyl ester and 1-amino-5-pyrrolidin-1-yl-pentan-3-ol by the procedure analogous to Example 1. MS (APCI, m/z): 516 [M+H]+.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9]#[N:10])=[CH:4][CH:3]=1.Cl[C:12]1[CH:20]=[CH:19][C:15]([C:16]([NH2:18])=[O:17])=[CH:14][N:13]=1>CO.C(OCC)(=O)C>[C:9]([CH2:8][C:5]1[CH:6]=[CH:7][C:2]([NH:1][C:12]2[CH:20]=[CH:19][C:15]([C:16]([NH2:18])=[O:17])=[CH:14][N:13]=2)=[CH:3][CH:4]=1)#[N:10]
Reactant: N#CCc1ccc(N)cc1
Reactant: NC(=O)c1ccc(Cl)nc1
Solvent: CO
Solvent: CCOC(C)=O
Product: N#CCc1ccc(Nc2ccc(C(N)=O)cn2)cc1

Procedure:
Combine 4-aminophenylacetonitrile (5.0 g, 37.9 mmol) and 6-chloro-nicotinamide (6.3 g, 40.3 mmol) in a flask and heat at 150° C. for 5 hours. Cool, dissolve the residue in methanol, dilute with ethyl acetate, then wash with saturated aqueous sodium bicarbonate solution. Dry the organic layer over sodium chloride/magnesium sulfate, filtered, and concentrated on a rotary evaporator to yield the crude product (10 g). The crude product was purified by flash column chromatography on silica gel eluting with 10% aqueous ammonium hydroxide in ethanol and chloroform to yield 6-(4-cyanomethyl-phenylamino)-nicotinamide. Triturate the resulting solid with hot isopropanol, collect the precipitate to yield 6-(4-cyanomethyl-phenylamino)-nicotinamide (1.8 g): 1H NMR (DMSO-D6, 300.00 MHz): 9.48 (s, 1H), 8.69 (d, 1H, J=2.1 Hz), 8.03-7.71 (m, 4H), 7.31-7.21 (m, 3H), 6.85 (d, 1H, J=8.8 Hz), 3.97 (s, 2H).
Reaction SMILES: [Si:1]([O:18][CH2:19][CH2:20][O:21][C:22]1[CH:27]=[CH:26][C:25]([N+:28]([O-])=O)=[CH:24][N:23]=1)([C:14]([CH3:17])([CH3:16])[CH3:15])([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[H][H]>CO.[Pd]>[NH2:28][C:25]1[CH:26]=[CH:27][C:22]([O:21][CH2:20][CH2:19][O:18][Si:1]([C:14]([CH3:17])([CH3:16])[CH3:15])([C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)[C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)=[N:23][CH:24]=1
Reactant: CC(C)(C)[Si](OCCOc1ccc([N+](=O)[O-])cn1)(c1ccccc1)c1ccccc1
Reactant: [H][H]
Agent: [Pd]
Solvent: CO
Product: CC(C)(C)[Si](OCCOc1ccc(N)cn1)(c1ccccc1)c1ccccc1
Yield: 100.9 %

Procedure:
Compound B (106 g) was dissolved in methanol (1.35 l) and hydrogenated at atmospheric pressure over 10% palladium on charcoal catalyst (10.6 g). When hydrogen uptake was complete, the catalyst was removed by filtration through diatomaceous earth. Volatile material was then removed from the filtrate by evaporation to give 5-amino-2-[2-(t-butyldiphenylsilyl)oxyethoxy]pyridine (C) (99.4 g), as an oil which was used without further purification; NMR (d6 -DMSO): 0.95(s,9H), 3.9(t,2H), 4.25(t,2H), 4.7(brs,2H), 6.5(d,1H), 7.0(dd,1H), 7.35-7.75 (complex m,7H), 7.6-7.75(m,4H).
Reaction SMILES: C[O:2][C:3](=[O:19])/[CH:4]=[CH:5]/[C:6]1[CH:15]=[C:14]2[C:9]([CH:10]=[CH:11][CH:12]=[N:13]2)=[CH:8][C:7]=1[N+:16]([O-:18])=[O:17].[OH-].[Na+].CO.Cl>O>[N+:16]([C:7]1[CH:8]=[C:9]2[C:14](=[CH:15][C:6]=1/[CH:5]=[CH:4]/[C:3]([OH:19])=[O:2])[N:13]=[CH:12][CH:11]=[CH:10]2)([O-:18])=[O:17]
Reactant: COC(=O)/C=C/c1cc2ncccc2cc1[N+](=O)[O-]
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: O=C(O)/C=C/c1cc2ncccc2cc1[N+](=O)[O-]

Procedure:
(E)-3-(6-Nitroquinolin-7-yl)-acrylic acid methyl ester (1 g; 3.9 mmol) was suspended in 2N NaOH (2.9 ml; 5.8 mmol) and MeOH (39 ml) and stirred at 55° C. for 1 h. The clear solution was cooled, treated with 2N HCl (3.2 ml; 6.4 mmol), diluted with water (70 ml) and the precipitated title compound filtered and dried (900 mg; 94%).
Reaction SMILES: Cl.Cl.[CH2:3]([C:7]1[N:12]=[N:11][C:10]([O:13][CH:14]2[CH2:19][CH2:18][NH:17][CH2:16][CH:15]2[CH2:20][OH:21])=[CH:9][C:8]=1[C:22]1[CH:27]=[CH:26][C:25]([O:28][CH:29]2[CH2:34][CH2:33][CH2:32][CH2:31][CH2:30]2)=[CH:24][CH:23]=1)[CH2:4][CH2:5][CH3:6].C=O.[C:37](O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>C(O)(=O)C.C(Cl)Cl>[CH2:3]([C:7]1[N:12]=[N:11][C:10]([O:13][CH:14]2[CH2:19][CH2:18][N:17]([CH3:37])[CH2:16][CH:15]2[CH2:20][OH:21])=[CH:9][C:8]=1[C:22]1[CH:23]=[CH:24][C:25]([O:28][CH:29]2[CH2:34][CH2:33][CH2:32][CH2:31][CH2:30]2)=[CH:26][CH:27]=1)[CH2:4][CH2:5][CH3:6]
Reactant: CCCCc1nnc(OC2CCNCC2CO)cc1-c1ccc(OC2CCCCC2)cc1
Reactant: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: C=O
Agent: Cl
Agent: [Na+]
Solvent: ClCCl
Solvent: CC(=O)O
Product: CCCCc1nnc(OC2CCN(C)CC2CO)cc1-c1ccc(OC2CCCCC2)cc1
Reaction time: 0.08 h

Procedure:
A suspension of {4-[6-butyl-5-(4-cyclohexyloxy-phenyl)-pyridazin-3-yloxy]-piperidin-3-yl}-methanol dihydrochloride (0.059 mmol, 30 mg), 37% paraformaldehyde (0.205 mmol, 16 mg), and 1 drop of acetic acid in 3 mL of DCM was stirred for 5 min then added sodium triacetoxyborohydride (0.205 mmol, 43 mg) and continued stirring for 0.5 h at room temperature. Quenched with water, solvent was evaporated, the residue was diluted with ethyl acetate, and then washed with saturated NaHCO3 solution, brine. The organic layer was dried (Na2SO4), filtered and concentrated under reduced pressure. The resultant residue was purified by column chromatography using 5% methanolic solution of ammonia (2.0 M ammonia in methanol) in DCM to provide {4-[6-butyl-5-(4-cyclohexyloxy-phenyl)-pyridazin-3-yloxy]-1-methyl-piperidin-3-yl}-methanol.
Reaction SMILES: [NH2:1][C:2]1[S:3][CH:4]=[C:5]([CH2:7][C:8]([OH:10])=O)[N:6]=1.[NH2:11][C@H:12]1[CH2:15][N:14]([S:16]([OH:19])(=[O:18])=[O:17])[C:13]1=[O:20]>>[NH2:1][C:2]1[S:3][CH:4]=[C:5]([CH2:7][C:8]([NH:11][C@H:12]2[CH2:15][N:14]([S:16]([OH:19])(=[O:18])=[O:17])[C:13]2=[O:20])=[O:10])[N:6]=1
Reactant: N[C@H]1CN(S(=O)(=O)O)C1=O
Reactant: Nc1nc(CC(=O)O)cs1
Product: Nc1nc(CC(=O)N[C@H]2CN(S(=O)(=O)O)C2=O)cs1

Procedure:
Following the procedure of Example 1 but substituting an equivalent amount of 2-amino-4-thiazoleacetic acid for the formyl protected reactant and (3S)-3-amino-2-oxo-1-azetidinesulfonic acid, inner salt for the 4-methyl reactant, one obtains as a result of the enzymatic coupling (3S)-3-[[[2-amino-4-thiazolyl]acetyl]amino]-2-oxo-1-azetidinesulfonic acid, zwitterion. Again, the structure is confirmed by analytical and bioassay techniques.
Reaction SMILES: [OH:1][CH2:2][C:3]1[C:8]2[N:9]=[C:10]([C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=3)[S:11][C:7]=2[CH:6]=[CH:5][CH:4]=1>C(Cl)Cl.[O-2].[O-2].[Mn+4]>[C:12]1([C:10]2[S:11][C:7]3[C:8](=[C:3]([CH:2]=[O:1])[CH:4]=[CH:5][CH:6]=3)[N:9]=2)[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=1
Reactant: OCc1cccc2sc(-c3ccccc3)nc12
Agent: [Mn+4]
Agent: [O-2]
Solvent: ClCCl
Product: O=Cc1cccc2sc(-c3ccccc3)nc12

Procedure:
26.5 g (0.11 mol) of the compound from Example III were dissolved in 400 ml of methylene chloride and the mixture was boiled under reflux with 50 g of manganese dioxide (active) overnight. After cooling, the solid was filtered off with suction and the filtrate was concentrated.
Reaction SMILES: [OH:1][C:2]1[CH:10]=[C:9]2[C:5]([CH2:6][CH2:7][C:8]2=[O:11])=[CH:4][CH:3]=1.CC1C=CC(S(OC[CH2:24][CH2:25][CH2:26][O:27][CH3:28])(=O)=O)=CC=1.[I-].[K+].C(=O)([O-])[O-].[K+].[K+]>C(#N)C.O>[CH3:28][O:27][CH2:26][CH2:25][CH2:24][O:1][C:2]1[CH:10]=[C:9]2[C:5]([CH2:6][CH2:7][C:8]2=[O:11])=[CH:4][CH:3]=1
Reactant: O=C1CCc2ccc(O)cc21
Reactant: COCCCCOS(=O)(=O)c1ccc(C)cc1
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: O
Solvent: CC#N
Product: COCCCOc1ccc2c(c1)C(=O)CC2
Temperature: 80 °C
Reaction time: 5 h
Yield: 50 %

Procedure:
To a solution of 6-hydroxyindan-1-one (1.48 g) in acetonitrile (30 mL) were added 4-methoxybutyl 4-methylbenzenesulfonate (2.93 g), potassium iodide (166 mg) and potassium carbonate (2.07 g), and the mixture was heated to stir at 80° C. for 5 hours. To the reaction mixture was added water under ice-cooling, and then the mixture was extracted with ethyl acetate. The organic layer was washed with saturated saline, dried over sodium sulfate, and then concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (eluent: n-hexane/ethyl acetate=7/3), and then triturated with n-hexane/isopropyl ether (2:1) to give 6-(3-methoxypropoxy)indan-1-one [REx(11-1)] (1.1 g) as a colorless powder.
Reaction SMILES: [CH3:1][NH:2][CH2:3][C:4]1[CH:13]=[CH:12][C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[N:5]=1.[N+:14]([C:17]1[CH:27]=[CH:26][C:20]([O:21][CH2:22][C@@H:23]2[CH2:25][O:24]2)=[CH:19][CH:18]=1)([O-:16])=[O:15]>C(#N)C>[CH3:1][N:2]([CH2:3][C:4]1[CH:13]=[CH:12][C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[N:5]=1)[CH2:25][C@H:23]([OH:24])[CH2:22][O:21][C:20]1[CH:19]=[CH:18][C:17]([N+:14]([O-:16])=[O:15])=[CH:27][CH:26]=1
Reactant: O=[N+]([O-])c1ccc(OC[C@@H]2CO2)cc1
Reactant: CNCc1ccc2ccccc2n1
Solvent: CC#N
Product: CN(Cc1ccc2ccccc2n1)C[C@H](O)COc1ccc([N+](=O)[O-])cc1
Yield: 62.9 %

Procedure:
2-(Methylaminomethyl)quinoline (4.47 g, 25.96 mmol) in acetonitrile (30 mL) was added to a stirring solution of (S)-(+)-2-[(4-nitrophenoxy)methyl]oxirane (4.23 g, 21.67 mmol) in acetonitrile (10 mL). The reaction was lightly refluxed under N2 for 24 hours, cooled and concentrated in vacuo. The residue was purified by HPLC dried and heated under vacuum to afford 5.01 g (63%) of product which was used directly in the next step.
Reaction SMILES: [Br:1][C:2]1[CH:6]=[N:5][N:4]([CH3:7])[C:3]=1[C:8]1[CH:9]=[C:10]([NH2:16])[CH:11]=[CH:12][C:13]=1[O:14][CH3:15].[Cl:17][C:18]1[CH:23]=[C:22]([Cl:24])[CH:21]=[CH:20][C:19]=1[N:25]=[C:26]=[O:27]>C(Cl)Cl>[Br:1][C:2]1[CH:6]=[N:5][N:4]([CH3:7])[C:3]=1[C:8]1[CH:9]=[C:10]([NH:16][C:26]([NH:25][C:19]2[CH:20]=[CH:21][C:22]([Cl:24])=[CH:23][C:18]=2[Cl:17])=[O:27])[CH:11]=[CH:12][C:13]=1[O:14][CH3:15]
Reactant: O=C=Nc1ccc(Cl)cc1Cl
Reactant: COc1ccc(N)cc1-c1c(Br)cnn1C
Solvent: ClCCl
Product: COc1ccc(NC(=O)Nc2ccc(Cl)cc2Cl)cc1-c1c(Br)cnn1C
Yield: 69.1 %

Procedure:
3-(4-Bromo-2-methyl-2H-pyrazol-3-yl)-4-methoxy-phenylamine (0.031 g, 0.11 mmol) was treated with 2,4-dichlorophenyl isocyanate (0.021 g, 0.11 mmol, 1.0 equiv.) in CH2Cl2 (2 mL), in a similar manner as described in Example 1.2 to afford Compound 3 (0.036 g, 0.076 mmol, 69%) as a white solid. LCMS m/z (%)=469 (M+H79Br35Cl35Cl, 60), 471 (M+H79Br35Cl37Cl&81Br35Cl35Cl, 100), 473 (M+H81Br35Cl37Cl79Br37Cl37Cl, 54), 475 (M+H81Br37Cl37Cl, 4), 1H NMR (400 MHz, acetone-d6) δ: 8.81 (s, 1H), 8.36 (d, J=9.0 Hz, 1H), 7.91 (s, 1H), 7.69 (dd, J=2.7, 9.0 Hz, 1H), 7.50 (s, 1H), 7.48 (d, J=2.4 Hz, 1H), 7.45 (d, J=2.7 Hz, 1H), 7.34 (dd, J=2.4, 9.0 Hz, 1H), 7.15 (d, J=9.0 Hz, 1H), 3.83 (s, 3H), 3.69 (s, 3H).
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([CH3:8])[N:5]=[C:4]([N:9]([CH2:19][C:20]2[CH:25]=[CH:24][C:23]([O:26][CH3:27])=[CH:22][CH:21]=2)[CH2:10][C:11]2[CH:16]=[CH:15][C:14]([O:17][CH3:18])=[CH:13][CH:12]=2)[N:3]=1.[F:28][C:29]1[C:34](B(O)O)=[CH:33][C:32]([CH:38]([C:40]2[CH:45]=[CH:44][C:43]([S:46][CH3:47])=[CH:42][CH:41]=2)[CH3:39])=[CH:31][N:30]=1.C([O-])(=O)C.[K+]>O1CCOCC1>[F:28][C:29]1[C:34]([C:2]2[N:7]=[C:6]([CH3:8])[N:5]=[C:4]([N:9]([CH2:19][C:20]3[CH:25]=[CH:24][C:23]([O:26][CH3:27])=[CH:22][CH:21]=3)[CH2:10][C:11]3[CH:16]=[CH:15][C:14]([O:17][CH3:18])=[CH:13][CH:12]=3)[N:3]=2)=[CH:33][C:32]([CH:38]([C:40]2[CH:41]=[CH:42][C:43]([S:46][CH3:47])=[CH:44][CH:45]=2)[CH3:39])=[CH:31][N:30]=1
Reactant: CSc1ccc(C(C)c2cnc(F)c(B(O)O)c2)cc1
Reactant: COc1ccc(CN(Cc2ccc(OC)cc2)c2nc(C)nc(Cl)n2)cc1
Agent: CC(=O)[O-]
Agent: [K+]
Solvent: C1COCCO1
Product: COc1ccc(CN(Cc2ccc(OC)cc2)c2nc(C)nc(-c3cc(C(C)c4ccc(SC)cc4)cnc3F)n2)cc1
Temperature: 100 °C
Reaction time: 8 h
Yield: 82.2 %

Procedure:
4-Chloro-N,N-bis(4-methoxybenzyl)-6-methyl-1,3,5-triazin-2-amine (1.4126 g, 3.6704 mmol), 2-fluoro-5-(1-(4-(methylthio)phenyl)ethyl)pyridin-3-ylboronic acid (1.2342 g, 4.2390 mmol), Am-Phos (140.4 mg, 0.1983 mmol), and potassium acetate (1.531 g, 15.60 mmol) were suspended in 1,4-dioxane (20 mL) and water (4 mL), and nitrogen was bubbled through the suspension for 15 s. Then, the flask was fitted with a reflux condenser and placed in a preheated oil bath (100° C.), and stirred under nitrogen overnight. Then, the reaction was cooled to room temperature, diluted with water (40 mL), and extracted with EtOAc. The organic extracts were combined, dried over sodium sulfate, filtered through a Celite® (diatomaceous earth) pad, concentrated, and purified on a silica gel filter (600 mL fritted filter with about 3 inches of silica gel; DCM to 100:1 DCM/MeOH to 75:1 DCM/MeOH). The fractions with product were collected, concentrated, and dried under high vacuum, first at room temperature, and then in a water bath (about 50° C.) to give 4-(2-fluoro-5-(1-(4-(methylthio)phenyl)ethyl)pyridin-3-yl)-N,N-bis(4-methoxybenzyl)-6-methyl-1,3,5-triazin-2-amine (1.797 g). 1H NMR (CDCl3, 400 MHz) δ 8.34 (dd, J=8.90 Hz, 2.45 Hz, 1H), 8.15 (d, J=1.96 Hz, 1H), 7.24-7.17 (m, 6H), 7.16-7.11 (m, 2H), 6.86 (dd, J=10.17 Hz, 8.61 Hz, 4H), 4.82 (s, 2H), 4.78 (s, 2H), 4.20 (q, J=7.30 Hz, 1H), 3.82 (s, 3H), 3.81 (s, 3H), 2.53 (s, 3H), 2.45 (s, 3H), 1.67 (d, J=7.24 Hz, 3H). m/z (ESI, pos. ion) 596 (M+H)+.
Reaction SMILES: [I-].[Na+].Cl[Si](C)(C)C.C[O:9][C:10]1[C:11](=[O:28])[C:12]([C:17]2[N:21]([C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=3)[N:20]=[CH:19][CH:18]=2)=[N:13][N:14]([CH3:16])[CH:15]=1.O>C(#N)C>[OH:9][C:10]1[C:11](=[O:28])[C:12]([C:17]2[N:21]([C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=3)[N:20]=[CH:19][CH:18]=2)=[N:13][N:14]([CH3:16])[CH:15]=1
Reactant: COc1cn(C)nc(-c2ccnn2-c2ccccc2)c1=O
Agent: C[Si](C)(C)Cl
Agent: [I-]
Agent: [Na+]
Solvent: O
Solvent: CC#N
Product: Cn1cc(O)c(=O)c(-c2ccnn2-c2ccccc2)n1
Temperature: 25 °C
Yield: 77 %

Procedure:
To a solution of sodium iodide (3.75 g) in acetonitrile (150 mL) was added chlorotrimethylsilane (3.17 mL) with stirring at room temperature, and the mixture was stirred for min. Then, 5-methoxy-1-methyl-3-(1-phenyl-1H-pyrazol-5-yl)pyridazin-4(1H)-one (1.41 g) was added, and the mixture was stirred for 30 min at the same temperature, and further refluxed for 3 hr. The reaction mixture was allowed to cool to room temperature, poured into water and the mixture was stirred for 30 min. The mixture was extracted with ethyl acetate, and the organic layer was washed successively with aqueous sodium thiosulfate solution and saturated brine, dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The obtained residue was triturated with ethyl acetate-diisopropyl ether, collected by filtration, and dried to give the title compound (1.032 g) as white needles.
Reaction SMILES: [Si:1]([O:8][CH2:9][CH2:10][CH2:11][O:12][C:13]1[CH:14]=[CH:15][C:16]([N+:21]([O-:23])=[O:22])=[C:17]([CH:20]=1)[CH:18]=[O:19])([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].[CH:24]([Mg]Br)=[CH2:25].Cl>C1COCC1>[Si:1]([O:8][CH2:9][CH2:10][CH2:11][O:12][C:13]1[CH:14]=[CH:15][C:16]([N+:21]([O-:23])=[O:22])=[C:17]([CH:18]([OH:19])[CH:24]=[CH2:25])[CH:20]=1)([C:4]([CH3:6])([CH3:7])[CH3:5])([CH3:3])[CH3:2]
Reactant: CC(C)(C)[Si](C)(C)OCCCOc1ccc([N+](=O)[O-])c(C=O)c1
Reactant: C=C[Mg]Br
Agent: Cl
Solvent: C1CCOC1
Product: C=CC(O)c1cc(OCCCO[Si](C)(C)C(C)(C)C)ccc1[N+](=O)[O-]
Reaction time: 2 h
Yield: 80 %

Procedure:
5-[3'-(t-Butyidimethylsilyloxy)propyloxy]-2-nitrobenzaldehyde (5.80 g) is dissolved in dry THF (35 ml), and thereto is added with stirring vinyl-magnesium bromide (1.7 equivalent) in THF solution in a dry ice-acetone bath. The mixture is stirred for two hours, and thereto is added 5% hydrochloric acid (30 ml). The mixture is stirred at room temperature, extracted with ethyl acetate, and purified by silica gel column chromatography to give 1-{5'-[3"-(t-butyldimethylsilyloxy)propyloxy]-2'-nitrophenyl}-2-propen-1-ol (5.02 g).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:9]2[CH2:15][C:14](=[O:16])[O:13][C:11](=[O:12])[CH2:10]2)[CH:5]=[CH:6][C:7]=1[Cl:8].C([N:19]([CH2:22]C)[CH2:20][CH3:21])C>C(Cl)Cl>[Cl:1][C:2]1[CH:3]=[C:4]([CH:9]([CH2:10][C:11]([N:19]([CH2:20][C:21]2[CH:3]=[CH:4][CH:9]=[CH:10][C:11]=2[O:13][CH3:14])[CH3:22])=[O:12])[CH2:15][C:14]([OH:13])=[O:16])[CH:5]=[CH:6][C:7]=1[Cl:8]
Reactant: O=C1CC(c2ccc(Cl)c(Cl)c2)CC(=O)O1
Reactant: CCN(CC)CC
Solvent: ClCCl
Product: COc1ccccc1CN(C)C(=O)CC(CC(=O)O)c1ccc(Cl)c(Cl)c1
Temperature: 0 °C
Reaction time: 2 h

Procedure:
3-(3,4-Dichlorophenyl)glutaric anhydride (5.9 g) in CH2Cl2 (80 mL) at 0° C. was treated sequentially with N-methyl-N-[2-methoxyphenyl)methyl]amine (3.8 g), triethylamine (3.5 mL) and N,N-dimethylaminopyridine (278 mg). The mixture was stirred at 0° C. for two hours then allowed to warm to room temperature and stirred for 20 hours. The reaction mixture was washed with 1N HCl (1×100 mL) and brine (1×100 mL). The organic layers were dried over MgSO4, filtered and concentrated to afford the title compound (9.3 g).
Reaction SMILES: [CH3:1][S:2]([N:5]1[CH2:10][CH:9]=[C:8]([C:11]2[CH:12]=[C:13]3[CH2:19][C@@:18]([CH3:26])([CH:20]4[CH2:25][CH2:24][NH:23][CH2:22][CH2:21]4)[O:17][C:14]3=[CH:15][N:16]=2)[CH2:7][CH2:6]1)(=[O:4])=[O:3].Cl[C:28]1[N:33]=[CH:32][C:31]([C:34]([F:37])([F:36])[F:35])=[CH:30][N:29]=1.C(=O)([O-])[O-].[K+].[K+]>CS(C)=O>[CH3:1][S:2]([N:5]1[CH2:6][CH:7]=[C:8]([C:11]2[CH:12]=[C:13]3[CH2:19][C@@:18]([CH3:26])([CH:20]4[CH2:25][CH2:24][N:23]([C:28]5[N:33]=[CH:32][C:31]([C:34]([F:37])([F:36])[F:35])=[CH:30][N:29]=5)[CH2:22][CH2:21]4)[O:17][C:14]3=[CH:15][N:16]=2)[CH2:9][CH2:10]1)(=[O:3])=[O:4]
Reactant: C[C@@]1(C2CCNCC2)Cc2cc(C3=CCN(S(C)(=O)=O)CC3)ncc2O1
Reactant: FC(F)(F)c1cnc(Cl)nc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CS(C)=O
Product: C[C@@]1(C2CCN(c3ncc(C(F)(F)F)cn3)CC2)Cc2cc(C3=CCN(S(C)(=O)=O)CC3)ncc2O1

Procedure:
The title compound is prepared from (S)-5-(1-methanesulfonyl-1,2,3,6-tetrahydro-pyridin-4-yl)-2-methyl-2-piperidin-4-yl-2,3-dihydro-furo[2,3-c]pyridine (Intermediate 41; the configuration of the stereocenter is arbitrarily assigned) and 2-chloro-5-(trifluoromethyl)pyrimidine in dimethylsulfoxide at 105° C. in the presence of potassium carbonate. LC (method 4): tR=1.14 min; Mass spectrum (ESI+): m/z=524 [M+H]+.
Reaction SMILES: [C:1]([CH2:6][N:7]1[C:11]([SH:12])=[N:10][N:9]=[N:8]1)([C:3]([OH:5])=[O:4])=[O:2].[OH-].[Na+]>C(O)C.[Zn]>[C:3]([CH:1]([OH:2])[CH2:6][N:7]1[C:11]([SH:12])=[N:10][N:9]=[N:8]1)([OH:5])=[O:4]
Reactant: O=C(O)C(=O)Cn1nnnc1S
Agent: [Na+]
Agent: [OH-]
Agent: [Zn]
Solvent: CCO
Product: O=C(O)C(O)Cn1nnnc1S
Temperature: 25 °C
Reaction time: 3.5 h
Yield: 42.1 %

Procedure:
1-Oxalomethyl-1H-tetrazole-5-thiol (0.94 g) was dissolved in aqueous 60% ethanol (15 ml) containing sodium hydroxide (1.4 g) and to this solution was added portionwise zinc powder (0.98 g). The mixture was stirred at room temperature for 3.5 hours. After removal of zinc powder by filtration, ethanol was removed under reduced pressure and the remained aqueous solution was adjusted to pH 2.0 with 10% hydrochloric acid. Extraction with ethyl acetate, drying over magnesium sulfate and evaporation gave an oil which was triturated with a mixture of diisopropyl ether and n-hexane (1:1). The crystals were filtered and washed with a mixture of diisopropyl ether and n-hexane (1:1) to give 1-(2-carboxy-2-hydroxyethyl)-1H-tetrazole-5-thiol (0.40 g), mp 143° to 146° C.,
Reaction SMILES: [C:1]([C:3]1[N:4]=[C:5]([NH:23][CH2:24][C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)[C:6](=[O:22])[N:7]([C:9]2[CH:10]=[C:11]([CH:18]=[CH:19][C:20]=2[CH3:21])[C:12]([NH:14][CH:15]2[CH2:17][CH2:16]2)=[O:13])[CH:8]=1)#[N:2].N.[OH:32]O.O>CO>[CH:15]1([NH:14][C:12]([C:11]2[CH:18]=[CH:19][C:20]([CH3:21])=[C:9]([N:7]3[C:6](=[O:22])[C:5]([NH:23][CH2:24][C:25]4[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=4)=[N:4][C:3]([C:1]([NH2:2])=[O:32])=[CH:8]3)[CH:10]=2)=[O:13])[CH2:16][CH2:17]1
Reactant: OO
Reactant: Cc1ccc(C(=O)NC2CC2)cc1-n1cc(C#N)nc(NCc2ccccc2)c1=O
Agent: N
Solvent: CO
Solvent: O
Product: Cc1ccc(C(=O)NC2CC2)cc1-n1cc(C(N)=O)nc(NCc2ccccc2)c1=O
Reaction time: 12 h

Procedure:
To a stirred solution of 3-[5-cyano-2-oxo-3-[(phenylmethyl)amino]-1(2H)-pyrazinyl]-N-cyclopropyl-4-methyl-benzamide (Example 104, 100 mg) in methanol (1 mL) was added conc. ammonia solution (1 mL) followed by 30% hydrogen peroxide solution (1 mL). After 12 h, water was added and the mixture was extracted with dichloromethane. The pooled organics were washed with brine, dried (MgSO4), filtered and the solvent removed. Purification by preparative HPLC (Gemini column, 0.1% ammonia:acetonitrile eluent) afforded the title compound (31 mg).
Reaction SMILES: [O:1]1[CH2:6][CH2:5][CH2:4][CH2:3][CH:2]1[O:7][CH2:8][CH2:9][O:10][CH:11]1[CH2:16][CH2:15][NH:14][CH2:13][CH2:12]1.[CH3:17][S:18](Cl)(=[O:20])=[O:19]>>[CH3:17][S:18]([N:14]1[CH2:13][CH2:12][CH:11]([O:10][CH2:9][CH2:8][O:7][CH:2]2[CH2:3][CH2:4][CH2:5][CH2:6][O:1]2)[CH2:16][CH2:15]1)(=[O:20])=[O:19]
Reactant: C1CCC(OCCOC2CCNCC2)OC1
Reactant: CS(=O)(=O)Cl
Product: CS(=O)(=O)N1CCC(OCCOC2CCCCO2)CC1
Yield: 79.1 %

Procedure:
Using 4-[2-(tetrahydro-2H-pyran-2-yloxy)ethoxy]piperidine (561 mg, 2.54 mmol) synthesized in (17b) and methanesulfonyl chloride (375 μL, 3.06 mmol), the desired title compound (618 mg, yield 83%) was obtained by the same method as in Reference Example 2 (2c).
Reaction SMILES: [B-](F)(F)(F)F.[B-](F)(F)(F)F.C1[N+]2(CCl)CC[N+]([F:21])(CC2)C1.[C:22]([O:26][C:27](=[O:36])[NH:28][C:29]1[N:30]([CH3:35])[N:31]=[C:32]([CH3:34])[CH:33]=1)([CH3:25])([CH3:24])[CH3:23]>C(Cl)Cl.CN(C=O)C>[C:22]([O:26][C:27](=[O:36])[NH:28][C:29]1[N:30]([CH3:35])[N:31]=[C:32]([CH3:34])[C:33]=1[F:21])([CH3:25])([CH3:24])[CH3:23]
Reactant: Cc1cc(NC(=O)OC(C)(C)C)n(C)n1
Reactant: F[N+]12CC[N+](CCl)(CC1)CC2
Agent: F[B-](F)(F)F
Solvent: ClCCl
Solvent: CN(C)C=O
Product: Cc1nn(C)c(NC(=O)OC(C)(C)C)c1F
Temperature: 25 °C
Reaction time: 1 h

Procedure:
Selectfluor® [140681-55-6] (66 mmol) was added portionwise to a solution of (2,5-dimethyl-2H-pyrazol-3-yl)-carbamic acid tert-butyl ester [1246552-45-3] (32.7 mmol) in CH2Cl2 (800 mL) and DMF (800 mL) at 0° C. and then the reaction was warmed to rt. After 1 h, the mixture was quenched with H2O and extracted with CH2Cl2. The organic phase was dried (Na2SO4), filtered and concentrated. The residue was purified using a RediSep® silica gel column to afford the title compound. ESI-MS: tR=0.83 min, [M+H]+ 230 (LC-MS 1).
Reaction SMILES: Cl[C:2]([CH3:26])([CH3:25])[C:3]([C:5]1[CH:24]=[CH:23][C:8]([C:9]([C:11]2[CH:16]=[CH:15][C:14]([C:17](=[O:22])[C:18]([CH3:21])(Cl)[CH3:19])=[CH:13][CH:12]=2)=[O:10])=[CH:7][CH:6]=1)=[O:4].[NH:27]1[CH2:32][CH2:31][O:30][CH2:29][CH2:28]1>>[O:30]1[CH2:31][CH2:32][N:27]([C:2]([CH3:26])([CH3:25])[C:3]([C:5]2[CH:24]=[CH:23][C:8]([C:9]([C:11]3[CH:16]=[CH:15][C:14]([C:17](=[O:22])[C:18]([CH3:21])([N:27]4[CH2:32][CH2:31][O:30][CH2:29][CH2:28]4)[CH3:19])=[CH:13][CH:12]=3)=[O:10])=[CH:7][CH:6]=2)=[O:4])[CH2:28][CH2:29]1
Reactant: CC(C)(Cl)C(=O)c1ccc(C(=O)c2ccc(C(=O)C(C)(C)Cl)cc2)cc1
Reactant: C1COCCN1
Product: CC(C)(C(=O)c1ccc(C(=O)c2ccc(C(=O)C(C)(C)N3CCOCC3)cc2)cc1)N1CCOCC1

Procedure:
78 g of 4,4'-bis-(2-chloro-2-methyl-propanoyl)benzophenone is boiled with 250 ml of morpholine for 15 hours. The excess morpholine is then distilled off under reduced pressure and the residue is crystallized from ethanol. 4,4'-bis-(2-Morpholino-2-methyl-propanoyl)-benzophenone is obtained; m.p. 145°-147°.