Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1]I.[CH3:3][C:4]([N+:18]([O-:20])=[O:19])([CH3:17])[CH2:5][C:6]1[N:7]=[C:8]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[NH:9][CH:10]=1.[OH-].[K+]>CN(C=O)C>[CH3:1][N:9]1[CH:10]=[C:6]([CH2:5][C:4]([CH3:3])([N+:18]([O-:20])=[O:19])[CH3:17])[N:7]=[C:8]1[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1
Reactant: CC(C)(Cc1c[nH]c(-c2ccccc2)n1)[N+](=O)[O-]
Reactant: CI
Agent: [K+]
Agent: [OH-]
Solvent: CN(C)C=O
Product: Cn1cc(CC(C)(C)[N+](=O)[O-])nc1-c1ccccc1
Temperature: 25 °C
Reaction time: 4 h
Yield: 82.8 %

Procedure:
Methyliodide (1.4 g) was added dropwise to a mixture of 4-(2-methyl-2-nitro-propyl)-2-phenyl-1H-imidazole (1.6 g) and fine powdered potassium hydroxide (2.19 g) in DMF (20 ml) at 20-25° C. The reaction mixture was stirred at RT for 4 h, quenched with ice/water and extracted with ethyl acetate. The organic phase washed with water and brine, dried over magnesium sulphate and concentrated. The residue was purified on silica gel using methylene chloride/methanol 2 and 5% as eluent to obtain the desired product (1.40 g) as a light yellow solid.
Reaction SMILES: Cl[C:2]1[C:7]([C:8]([F:11])([F:10])[F:9])=[CH:6][N:5]=[C:4]([NH:12][C:13]2[CH:27]=[CH:26][C:16]([CH2:17][P:18](=[O:25])([O:22][CH2:23][CH3:24])[O:19][CH2:20][CH3:21])=[CH:15][CH:14]=2)[N:3]=1.[NH2:28][C:29]1[CH:30]=[CH:31][C:32]([Br:41])=[C:33]2[C:38]=1[C:37](=[O:39])[N:36]([CH3:40])[CH:35]=[CH:34]2>>[CH2:20]([O:19][P:18]([CH2:17][C:16]1[CH:26]=[CH:27][C:13]([NH:12][C:4]2[N:3]=[C:2]([NH:28][C:29]3[CH:30]=[CH:31][C:32]([Br:41])=[C:33]4[C:38]=3[C:37](=[O:39])[N:36]([CH3:40])[CH:35]=[CH:34]4)[C:7]([C:8]([F:11])([F:10])[F:9])=[CH:6][N:5]=2)=[CH:14][CH:15]=1)(=[O:25])[O:22][CH2:23][CH3:24])[CH3:21]
Reactant: CCOP(=O)(Cc1ccc(Nc2ncc(C(F)(F)F)c(Cl)n2)cc1)OCC
Reactant: Cn1ccc2c(Br)ccc(N)c2c1=O
Product: CCOP(=O)(Cc1ccc(Nc2ncc(C(F)(F)F)c(Nc3ccc(Br)c4ccn(C)c(=O)c34)n2)cc1)OCC
Yield: 62.8 %

Procedure:
The title compound was prepared according to the procedure for Example 102 using diethyl (4-{[4-chloro-5-(trifluoromethyl)pyrimidin-2-yl]amino}benzyl)phosphonate (166.9 mg, 0.3939 mmol) and 8-amino-5-bromo-2-methylisoquinolin-1(2H)-one (Compound 123A, 120 mg, 0.47 mmol). The crude material was adsorbed onto a pre-filled silica gel loading cartridge and purified using an ISCO Combiflash system eluting first with 0-100% EtOAc:CH2Cl2 and then 15% MeOH:EtOAc. The desired fractions were pooled together and concentrated in vacuo. The material was further purified by trituration in CH2Cl2 and heptane to afford the title product (158.3 mg 62%). 1H NMR (400 MHz, DMSO-d6) δ ppm 13.28 (br s, 1H), 9.90 (s, 1H), 8.82 (br s, 1H), 8.50 (s, 1H), 7.86 (d, J=8.8 Hz, 1H), 7.70 (d, J=7.6 Hz, 1H), 7.58 (br d, J=5.6 Hz, 2H), 7.25 (dd, J=8.6, 2.3 Hz, 2H), 6.82 (d, J=7.6 Hz, 1H), 3.90-4.03 (m, 4H), 3.55 (s, 3H), 3.21 (d, J=21.2 Hz, 2H), 1.19 (t, J=6.9 Hz, 6H). MS (ES+): m/z 640.03/642.05 (96/100) [MH+]. HPLC: tR=3.90 min (ZQ3, polar—5 min).
Reaction SMILES: [CH:1]1[C:13]2[CH:12]([CH2:14][O:15][C:16]([NH:18][C@@H:19]([C:29]([OH:31])=[O:30])[CH2:20][O:21][CH2:22][C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=3)=[O:17])[C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[C:5]=2[CH:4]=[CH:3][CH:2]=1.C(OC[CH2:37][CH2:38][CH3:39])(=O)C.S(=O)(=O)(O)O.Cl[CH2:46]Cl>>[C:38]([O:30][C:29](=[O:31])[C@@H:19]([CH2:20][O:21][CH2:22][C:23]1[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=1)[NH:18][C:16]([O:15][CH2:14][CH:12]1[C:13]2[CH:1]=[CH:2][CH:3]=[CH:4][C:5]=2[C:6]2[C:11]1=[CH:10][CH:9]=[CH:8][CH:7]=2)=[O:17])([CH3:37])([CH3:39])[CH3:46]
Reactant: ClCCl
Reactant: O=C(N[C@H](COCc1ccccc1)C(=O)O)OCC1c2ccccc2-c2ccccc21
Reactant: CCCCOC(C)=O
Agent: O=S(=O)(O)O
Product: CC(C)(C)OC(=O)[C@@H](COCc1ccccc1)NC(=O)OCC1c2ccccc2-c2ccccc21
Yield: 77 %

Procedure:
N-[(9H-Fluoren-9-yl)methoxycarbonyl]-O-(benzyl)-D-serine (0.710 g, 1.70 mmole) in dichloromethane (8 mL) was treated with 1-butyl acetate (3 mL) and concentrated sulfuric acid (40 μL) in a sealed flask at 0° C. Upon completion (TLC), the reaction was quenched with of dichloromethane (10 mL) and saturated aqueous potassium bicarbonate (15 mL). The organic layer was washed with distilled water, and evaporated. The resulting residue was purified by flash column chromatography (98:2 dichloromethane/methanol) to yield the title compound as a colorless oil (0.292 g, 77%);
Reaction SMILES: C(CCNC(=O)[CH2:7][N:8]1[CH:12]=[C:11]([C:13]2[CH:22]=[CH:21][CH:20]=[C:19]3[C:14]=2[CH2:15][CH2:16][CH2:17][N:18]3[C:23](=[O:36])[CH2:24][CH2:25][CH2:26][O:27][C:28]2[CH:33]=[CH:32][CH:31]=[C:30]([CH3:34])[C:29]=2[CH3:35])[CH:10]=[N:9]1)#N.N[CH2:39][CH2:40][C:41]#N.[NH2:43][CH2:44][CH2:45][NH:46][C:47](=[O:53])[O:48][C:49]([CH3:52])([CH3:51])[CH3:50]>>[CH3:35][C:29]1[C:30]([CH3:34])=[CH:31][CH:32]=[CH:33][C:28]=1[O:27][CH2:26][CH2:25][CH2:24][C:23]([N:18]1[C:19]2[C:14](=[C:13]([C:11]3[CH:10]=[N:9][N:8]([CH2:7][C:39]4[CH:30]=[C:29]([CH:35]=[CH:41][CH:40]=4)[C:28]([NH:43][CH2:44][CH2:45][NH:46][C:47](=[O:53])[O:48][C:49]([CH3:50])([CH3:52])[CH3:51])=[O:27])[CH:12]=3)[CH:22]=[CH:21][CH:20]=2)[CH2:15][CH2:16][CH2:17]1)=[O:36]
Reactant: N#CCCN
Reactant: Cc1cccc(OCCCC(=O)N2CCCc3c(-c4cnn(CC(=O)NCCC#N)c4)cccc32)c1C
Reactant: CC(C)(C)OC(=O)NCCN
Product: Cc1cccc(OCCCC(=O)N2CCCc3c(-c4cnn(Cc5cccc(C(=O)NCCNC(=O)OC(C)(C)C)c5)c4)cccc32)c1C

Procedure:
The title compound was prepared using a procedure analogous to N-(2-cyanoethyl)-2-(4-(1-(4-(2,3-dimethylphenoxy)butanoyl)-1,2,3,4-tetrahydroquinolin-5-yl)-1H-pyrazol-1-yl)acetamide except that Example 1 was replaced with Example 95 and 3-aminopropanenitrile was replaced with tert-butyl 2-aminoethylcarbamate. LCMS, [M+H]+=666.4.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]1[CH:12]=[CH:13][CH:14]=[C:7]1[CH:6]([CH3:15])[NH:5]2.[C:16](Cl)(=[O:25])[C:17]1[CH:22]=[CH:21][CH:20]=[C:19]([O:23][CH3:24])[CH:18]=1>>[F:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]1[CH:12]=[CH:13][CH:14]=[C:7]1[CH:6]([CH3:15])[N:5]2[C:16](=[O:25])[C:17]1[CH:22]=[CH:21][CH:20]=[C:19]([O:23][CH3:24])[CH:18]=1
Reactant: COc1cccc(C(=O)Cl)c1
Reactant: CC1Nc2cc(F)ccc2-n2cccc21
Product: COc1cccc(C(=O)N2c3cc(F)ccc3-n3cccc3C2C)c1

Procedure:
7-Fluoro-5-(3-methoxybenzoyl)-4-methyl-4,5-dihydropyrrolo[1,2-a]quinoxaline was prepared from the product of Example 47 and m-anisoyl chloride according to the procedure of Example 106, Step 2. MS (ESI) m/z 337.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:12]2[C:11]([CH3:14])([CH3:13])[CH2:10][CH2:9][C:8]([CH3:16])([CH3:15])[C:7]=2[CH:6]=[C:5]([O:17][CH3:18])[C:4]=1/[CH:19]=[CH:20]/[C:21]1[CH:28]=[CH:27][C:24]([CH2:25][OH:26])=[CH:23][CH:22]=1.[H-].[Na+].[H][H].I[CH3:34]>CN(C)C=O.CO.O>[CH3:34][O:26][CH2:25][C:24]1[CH:23]=[CH:22][C:21](/[CH:20]=[CH:19]/[C:4]2[C:5]([O:17][CH3:18])=[CH:6][C:7]3[C:8]([CH3:16])([CH3:15])[CH2:9][CH2:10][C:11]([CH3:13])([CH3:14])[C:12]=3[C:3]=2[O:2][CH3:1])=[CH:28][CH:27]=1
Reactant: [H][H]
Reactant: CI
Reactant: COc1cc2c(c(OC)c1/C=C/c1ccc(CO)cc1)C(C)(C)CCC2(C)C
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CO
Solvent: O
Product: COCc1ccc(/C=C/c2c(OC)cc3c(c2OC)C(C)(C)CCC3(C)C)cc1
Temperature: 60 °C
Yield: 53.2 %

Procedure:
3.8 g (10 millimoles) of the benzyl alcohol derivative from Example 27, dissolved in 10 ml of dry dimethylformamide, were added dropwise to a suspension of 0.3 g (11 millimoles) of sodium hydride in 15 ml of dry dimethylformamide. The mixture was stirred until evolution of hydrogen had ended (after about 1 hour), and 1.56 g (11 millimoles) of iodomethane were then added dropwise while cooling with ice. The mixture was then heated at 60° C. for 5 hours. On the next day, water was added dropwise, and the precipitated solid was filtered off under suction, and dissolved in methanol at elevated temperature. When the solution was cooled to room temperature, 2 phases formed. The upper (methanol) phase was heated once again and then placed in a refrigerator. The precipitated crystals were filtered off under suction and dried. 2.1 g of the title compound of melting point 66°-68° C. were obtained in this manner.
Reaction SMILES: [C:1]([O:5][C:6](=[O:23])[C@H:7]([NH2:22])[CH2:8][CH2:9][CH2:10][N:11]1[C:19](=[O:20])[C:18]2[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=2)[C:12]1=[O:21])([CH3:4])([CH3:3])[CH3:2].C(N(CC)CC)C.[Cl:31][C:32]1[CH:37]=[CH:36][C:35]([C:38]2[CH:43]=[CH:42][C:41]([S:44](Cl)(=[O:46])=[O:45])=[CH:40][CH:39]=2)=[CH:34][CH:33]=1>ClCCl>[C:1]([O:5][C:6](=[O:23])[C@H:7]([NH:22][S:44]([C:41]1[CH:40]=[CH:39][C:38]([C:35]2[CH:36]=[CH:37][C:32]([Cl:31])=[CH:33][CH:34]=2)=[CH:43][CH:42]=1)(=[O:45])=[O:46])[CH2:8][CH2:9][CH2:10][N:11]1[C:12](=[O:21])[C:13]2[C:18](=[CH:17][CH:16]=[CH:15][CH:14]=2)[C:19]1=[O:20])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)[C@H](N)CCCN1C(=O)c2ccccc2C1=O
Reactant: O=S(=O)(Cl)c1ccc(-c2ccc(Cl)cc2)cc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(C)(C)OC(=O)[C@@H](CCCN1C(=O)c2ccccc2C1=O)NS(=O)(=O)c1ccc(-c2ccc(Cl)cc2)cc1
Reaction time: 0.5 h
Yield: 52.9 %

Procedure:
A solution of the title H compound, (2R)-amino-5-(1,3-dioxo-1,3-dihydroisoindol-2-yl)pentanoic acid t-butyl ester (1.02 g, 3.19 mmol) and triethylamine (1.34 mL, 9.61 mmol) in 20 mL of dichloromethane is treated with the title 1 compound, 4′-chlorobiphenyl-4-sulfonyl chloride (0.92 g, 3.19 mmol) at 0° C. After stirring at this temperature for 30 min, then at RT for 16 h, the solution is washed with 35 mL of 2M aqueous HCl and the organic solution is washed with brine, dried over anhydrous Na2SO4 and concentrated under reduced pressure. Chomatography on silica gel (eluant; ethyl acetate) affords 0.96 g (53%) of (2R)-(4′-chlorobiphenyl-4-sulfonylamino)-5-(1,3-dioxo-1,3-dihydroisoindol-2-yl)pentanoic acid t-butyl ester as a waxy, white solid: NMR(CDCl3) 1.21 (s, 9H), 1.60-1.68 (br m, 1H), 1.75-1.84 (br m, 3H), 3.68-3.74 (m, 2H), 3.82-3.92 (m, 1H), 5.24 (d, 1H, J=9.2), 7.44 (d, 2H, J=8.6), 7.49 (d, 2H, J=8.6), 7.65 (d, 2H, J=8.5), 7.70-7.74 (m, 2H), 7.83-7.86 (m, 2H), 7.92(d, 2H), J=8.5); IR 1774, 1712, 1348, 1162; ESI-MS 569 (M++1).
Reaction SMILES: [N:1]1([C:7]2[CH:12]=[CH:11][C:10]([N:13]3[CH:22]=[C:21]4[C:15]([CH2:16][CH2:17][NH:18][CH2:19][CH2:20]4)=[N:14]3)=[CH:9][CH:8]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[C:23]1(=O)[CH2:26][CH2:25][CH2:24]1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>ClCCl.C(O)(=O)C.CO>[CH:23]1([N:18]2[CH2:19][CH2:20][C:21]3=[CH:22][N:13]([C:10]4[CH:11]=[CH:12][C:7]([N:1]5[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]5)=[CH:8][CH:9]=4)[N:14]=[C:15]3[CH2:16][CH2:17]2)[CH2:26][CH2:25][CH2:24]1
Reactant: O=C1CCC1
Reactant: c1cc(-n2cc3c(n2)CCNCC3)ccc1N1CCCCC1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CO
Solvent: CC(=O)O
Solvent: ClCCl
Product: c1cc(-n2cc3c(n2)CCN(C2CCC2)CC3)ccc1N1CCCCC1
Temperature: 25 °C
Reaction time: 0.83 h

Procedure:
To a solution of 2-[4-(1-piperidinyl)phenyl]-2,4,5,6,7,8-hexahydropyrazolo[3,4-d]azepine (may be prepared as described in Description 43) (42 mg, 0.14 mmol) in dichloromethane (4 ml) was added cyclobutanone (30 μl, 0.42 mmol) followed by acetic acid (3 drops). The mixture was stirred at room temperature for 50 min, then treated with sodium triacetoxyborohydride (89 mg, 0.42 mmol). The mixture was stirred at room temperature for 2.5 hours, then it was diluted with methanol and purified by SCX cartridge to afford the title compound (E40). MS (ES+) m/e 351 [M+H]+.
Reaction SMILES: C(O[C:9]1[CH:14]=[N:13][N:12]([CH2:15][C:16]([C:18]2C=CC(CO)=[CH:20][C:19]=2C)=O)[C:11](=[O:27])[CH:10]=1)C1C=CC=CC=1.[CH3:28][O:29][C:30]1[CH:31]=[CH:32][C:33]([CH2:36][OH:37])=[N:34][CH:35]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OC(C)C)=O)=NC(OC(C)C)=[O:60]>C1COCC1>[CH3:28][O:29][C:30]1[CH:31]=[CH:32][C:33]([CH2:36][O:37][C:9]2[CH:14]=[N:13][N:12]([CH:15]3[CH2:16][CH2:18][CH2:19][CH2:20][O:60]3)[C:11](=[O:27])[CH:10]=2)=[N:34][CH:35]=1
Reactant: CC(C)OC(=O)N=NC(=O)OC(C)C
Reactant: Cc1cc(CO)ccc1C(=O)Cn1ncc(OCc2ccccc2)cc1=O
Reactant: COc1ccc(CO)nc1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: COc1ccc(COc2cnn(C3CCCCO3)c(=O)c2)nc1
Temperature: 0 °C
Reaction time: 3 h

Procedure:
To a solution of 5-hydroxy-2-(tetrahydro-pyran-2-yl)-2H-pyridazin-3-one (described in preparation 5a of WO 08/022,979, 705 mg, 3.59 mmol) and (5-methoxy-pyridin-2-yl)-methanol (Milestone Pharmtech, 500 mg, 3.59 mmol) in THF (10 mL) is added polymer-bound triphenylphosphine (2.40 g, 3 mmol/g, 7.2 mmol). After cooling to 0° C., diisopropyl azodicarboxylate (1.42 mL, 7.2 mmol) is added slowly. Afterwards, the reaction mixture is stirred for 3 h at room temperature. The reaction mixture is filtered and the solvent is evaporated. The residue is purified via reverse phase HPLC chromatography (Waters XBridge 5 μm, gradient 5%→90% acetonitrile in water+0.3% NH4OH).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([C:14]2[O:32][C:17]3=[CH:18][N:19]=[C:20]([C:22]4[CH:27]=[CH:26][C:25]([S:28]([CH3:31])(=[O:30])=[O:29])=[CH:24][CH:23]=4)[CH:21]=[C:16]3[CH:15]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].C(O)(=O)C>[Pd].CO>[C:1]([O:5][C:6]([N:8]1[CH2:9][CH2:10][CH:11]([CH:14]2[O:32][C:17]3=[CH:18][N:19]=[C:20]([C:22]4[CH:23]=[CH:24][C:25]([S:28]([CH3:31])(=[O:29])=[O:30])=[CH:26][CH:27]=4)[CH:21]=[C:16]3[CH2:15]2)[CH2:12][CH2:13]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)OC(=O)N1CCC(c2cc3cc(-c4ccc(S(C)(=O)=O)cc4)ncc3o2)CC1
Agent: [Pd]
Solvent: CC(=O)O
Solvent: CO
Product: CC(C)(C)OC(=O)N1CCC(C2Cc3cc(-c4ccc(S(C)(=O)=O)cc4)ncc3O2)CC1
Temperature: 50 °C

Procedure:
A mixture of 4-[5-(4-methanesulfonyl-phenyl)-furo[2,3-c]pyridin-2-yl]-piperidine-1-carboxylic acid tert-butyl ester (155 mg), acetic acid (4.0 mL) and 10% palladium on carbon (40 mg) in methanol (10 mL) is shaken under an hydrogen atmosphere (5 bar) at 50° C. The catalyst is filtered off and the filtrate is concentrated in vacuo to give the title compound. LC (method 5): tR=1.32 min; Mass spectrum (ESI+): m/z=459 [M+H]+.
Reaction SMILES: O=[C:2]1[CH2:7][CH2:6][CH2:5][CH2:4][N:3]1[C:8]1[CH:21]=[CH:20][C:11]([CH:12]=[C:13]2[S:17][C:16](=[O:18])[NH:15][C:14]2=[O:19])=[CH:10][CH:9]=1.[NH2:22][CH2:23][CH:24]([C:26]1[CH:27]=[CH:28][C:29]([OH:37])=[C:30]([NH:32][S:33]([CH3:36])(=[O:35])=[O:34])[CH:31]=1)[OH:25]>>[O:18]=[C:16]1[NH:15][C:14](=[O:19])[C:13](=[CH:12][C:11]2[CH:20]=[CH:21][C:8]([N:3]3[CH2:4][CH2:5][CH:6]([NH:22][CH2:23][CH:24]([C:26]4[CH:27]=[CH:28][C:29]([OH:37])=[C:30]([NH:32][S:33]([CH3:36])(=[O:35])=[O:34])[CH:31]=4)[OH:25])[CH2:7][CH2:2]3)=[CH:9][CH:10]=2)[S:17]1
Reactant: O=C1NC(=O)C(=Cc2ccc(N3CCCCC3=O)cc2)S1
Reactant: CS(=O)(=O)Nc1cc(C(O)CN)ccc1O
Product: CS(=O)(=O)Nc1cc(C(O)CNC2CCN(c3ccc(C=C4SC(=O)NC4=O)cc3)CC2)ccc1O

Procedure:
The title compound was prepared from 5-[4-(4-oxo-piperidin-1-yl)-benzylidene]-thiazolidine-2,4-dione (which was obtained in Example 36) and N-[5-(2-amino-1-hydroxy-ethyl)-2-hydroxy-phenyl]-methanesulfonamide (which was obtained in Example 9) according to the procedure of Example 73 as a pale yellowish solid; mp>200° C. (decomposed); 1H NMR (300 MHz, DMSO-d6), δ 1.45–1.60 (m, 2 H), 1.90–2.05 (m, 2 H), 2.70–3.50 (m, 5 H), 2.94 (s, 3 H), 3.88 (brd, J=9.9 Hz, 2 H), 4.67 (dd, J=7.2, 2.1 Hz, 1 H), 6.87 (d, J=6.3 Hz, 1 H), 7.00 (d, J=6.8 Hz, 2 H), 7.06 (dd, J=6.3, 1.5 Hz, 1 H), 7.23 (d, J=1.5 Hz, 1 H), 7.33 (s, 1 H), 7.38 (d, J=6.8 Hz, 2 H); MS (ES) m/z: 533.0 (MH+); HRMS Calcd. for C24H29N4O6S2 (MH+): 533.1529. Found: 533.1544.
Reaction SMILES: [Cl:1][C:2]1[C:3]([C:17]([OH:19])=[O:18])=[CH:4][CH:5]=[C:6]2[C:10]=1[NH:9][CH:8]=[C:7]2[C:11]1[CH2:16][CH2:15][CH2:14][CH2:13][CH:12]=1.C1COCC1.[H][H]>[OH-].[OH-].[Pd+2].CO>[Cl:1][C:2]1[C:3]([C:17]([OH:19])=[O:18])=[CH:4][CH:5]=[C:6]2[C:10]=1[NH:9][CH:8]=[C:7]2[CH:11]1[CH2:16][CH2:15][CH2:14][CH2:13][CH2:12]1
Reactant: O=C(O)c1ccc2c(C3=CCCCC3)c[nH]c2c1Cl
Reactant: [H][H]
Agent: [Pd+2]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Product: O=C(O)c1ccc2c(C3CCCCC3)c[nH]c2c1Cl
Temperature: 25 °C
Reaction time: 8 h
Yield: 97.9 %

Procedure:
32.6 grams (0.118 mol) of 7-chloro-3-cyclohexenyl-1H-indole-6-carboxylic acid was added to a one liter round bottom flask along with 250 mL of a 1:1 (v/v) mixture of THF and methanol. 3.3 grams of 20% palladium hydroxide on carbon was then added and the flask was fitted with a septa and balloon of hydrogen. The mixture was stirred overnight at room temperature. In the morning, the crude product was filtered through a pad of celite and the pad was washed with THF. The product was evaporated to dryness and triturated with cold diethyl ether to give 32.1 grams of a tan solid (98% yield, 85% purity, UV detection λ=220 nm) that was used without further purification. MS m/z 278.00 (M+H).
Reaction SMILES: [F:1][CH2:2][C:3]([CH2:17][F:18])([CH3:16])[C:4](=[O:15])[CH:5](Br)[O:6][C:7]1[CH:12]=[CH:11][C:10]([Cl:13])=[CH:9][CH:8]=1.N1C=[CH:22][N:21]=[N:20]1.[C:24](#[N:26])C>C(Cl)Cl>[F:1][CH2:2][C:3]([CH2:17][F:18])([CH3:16])[C:4](=[O:15])[CH:5]([O:6][C:7]1[CH:12]=[CH:11][C:10]([Cl:13])=[CH:9][CH:8]=1)[N:26]1[CH:22]=[N:21][N:20]=[CH:24]1
Reactant: CC(CF)(CF)C(=O)C(Br)Oc1ccc(Cl)cc1
Reactant: c1c[nH]nn1
Reactant: CC#N
Solvent: ClCCl
Product: CC(CF)(CF)C(=O)C(Oc1ccc(Cl)cc1)n1cnnc1
Temperature: 50 °C

Procedure:
82 g (0.286 mol) of 3,3-bis-fluoromethyl-1-bromo-1-(4-chlorophenoxy)-butan-2-one and 41.5 g (0.588 mol) of triazole were introduced into 600 ml of acetonitrile, the mixture was heated at 50° C. for 5 hours, the solvent was driven off under a waterpump vacuum, the residue was taken up in one liter of methylene chloride, the methylene chloride mixture was washed twice with 1,000 ml of water each time, the organic phase was dried over sodium sulphate and the solvent was distilled off. The residue was taken up in 500 ml of diisopropyl ether and the precipitate was filtered off. 6 g of 3,3-bis-fluoromethyl-1-(4-chlorophenoxy)-1-(1,2,4-triazol-4-yl)-butan-2-one (compound 3) of melting point 119°-122° C. were obtained. The mother liquor was distilled. 32.1 g (40% of theory) of 3,3-bis-fluoromethyl-1-(4-chlorophenoxy)-1-(1,2,4-triazol-1-yl)-butan-2-one (compound 4) of boiling point 160° -166° C./0.2 mm Hg were obtained.
Reaction SMILES: [Cl:1][C:2]1[N:10]=[C:9]([CH3:11])[CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=[O:5].[OH-:12].[K+].[Mn]([O-])(=O)(=O)=O.[K+].[OH2:20]>>[Cl:1][C:2]1[C:3]([C:4]([OH:6])=[O:5])=[CH:7][CH:8]=[C:9]([C:11]([OH:20])=[O:12])[N:10]=1
Reactant: [OH-]
Reactant: O
Reactant: Cc1ccc(C(=O)O)c(Cl)n1
Agent: O=[Mn](=O)(=O)[O-]
Agent: [K+]
Product: O=C(O)c1ccc(C(=O)O)c(Cl)n1

Procedure:
To a mixture of compound 2-chloro-6-methyl-nicotinic acid (25 gram, 0.146 mol) and water (1.5 L) in a 3 liter flask equipped with a mechanic stirrer and a heating mantle, potassium hydroxide (28 g, 0.5 mol) was added, the mixture turned to be a clear solution. Potassium permanganate (70 g, 0.44 mol) was added in ten batches during 36 hrs, the temperature of the reaction mixture was kept in the range of 85-95° C. during the reaction process.
Reaction SMILES: [H-].[Na+].[CH3:3][S:4]([NH2:7])(=[O:6])=[O:5].Br[CH2:9][C:10]1[C:11]([CH2:16]Br)=[CH:12][CH:13]=[CH:14][CH:15]=1>CN(C)C=O>[CH3:3][S:4]([N:7]1[CH:16]=[C:11]2[C:10]([CH:15]=[CH:14][CH:13]=[CH:12]2)=[CH:9]1)(=[O:6])=[O:5]
Reactant: CS(N)(=O)=O
Reactant: BrCc1ccccc1CBr
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CS(=O)(=O)n1cc2ccccc2c1
Temperature: 60 °C
Reaction time: 0.5 h

Procedure:
Sodium hydride (0.88 g) was suspended in 3 ml dimethyl formamide. To this stirred solution was added methanesulfonamide (0.95 g, 10 mmol) in 5 ml dimethyl formamide dropwise under nitrogen. After stirring at 60° C. for 0.5 hours, a solution of 2.64 g (10 mmol) α,α'-dibromo-o-xylene in 7 ml DMF was added at a rate appropriate to maintain the temperature at 60-70° C. The mixture was stirred at room temperature for another hour, then quenched by pouring into water. The resulting precipitate was collected and washed with water, petroleum ether and ether successively. Weight 1.57 g (80%). 1H-NMR 62.37 (s, 3H, --CH3), 4.709 (s, 4H, 2CH2). 7.25~7.35 (m. 4H, ArH).
Reaction SMILES: [CH3:1][C:2]1[O:6][N:5]=[C:4]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)[C:3]=1[C:13]([OH:15])=O.[N:16]1([CH2:22][C:23]([N:25]2[CH2:29][CH2:28][CH2:27][CH2:26]2)=[O:24])[CH2:21][CH2:20][NH:19][CH2:18][CH2:17]1.F[B-](F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2C=CC=CC=2N=N1.C(N(C(C)C)CC)(C)C>CN(C)C=O>[CH3:1][C:2]1[O:6][N:5]=[C:4]([C:7]2[CH:8]=[CH:9][CH:10]=[CH:11][CH:12]=2)[C:3]=1[C:13]([N:19]1[CH2:18][CH2:17][N:16]([CH2:22][C:23](=[O:24])[N:25]2[CH2:26][CH2:27][CH2:28][CH2:29]2)[CH2:21][CH2:20]1)=[O:15]
Reactant: Cc1onc(-c2ccccc2)c1C(=O)O
Reactant: O=C(CN1CCNCC1)N1CCCC1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: Cc1onc(-c2ccccc2)c1C(=O)N1CCN(CC(=O)N2CCCC2)CC1
Temperature: 25 °C

Procedure:
5-Methyl-3-phenylisooxazole-4-carboxylic acid (40 mg, 0.197 mmol), piperazine acetic acid pyrrolidid (42.4 mg, 0.215 mmol), O-(benzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium tetrafluoroborate (86.2 mg, 0.268 mmol) and diisopropylethylamine (25.4 mg, 0.197 mmol) were mixed in dimethylformamide (1.5 mL) and stirred at room temperature. Solvent was evaporated in vacuo, and the residue was taken up in methanol (1 mL), filtered and purified by preparative chromatography. The combined fractions were partitioned between NaHCO3 (sat) and ethylacetate. The organic layer was washed with water and concentrated in vacuo to afford the title compound. HRMS (ESI, pos. ion) m/z calcd for C21H26N4O3: 382.2005, found 382.2016.
Reaction SMILES: [N:1]([C:4]1[CH:9]=[CH:8][C:7]([N+:10]([O-])=O)=[CH:6][CH:5]=1)=[N+:2]=[N-:3].[CH2:13]([Br:16])[C:14]#[CH:15]>C1(C)C=CC=CC=1>[Br:16][CH2:13][C:14]1[N:3]=[N:2][N:1]([C:4]2[CH:9]=[CH:8][C:7]([NH2:10])=[CH:6][CH:5]=2)[CH:15]=1.[NH2:1][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1
Reactant: C#CCBr
Reactant: [N-]=[N+]=Nc1ccc([N+](=O)[O-])cc1
Solvent: Cc1ccccc1
Product: Nc1ccc(-n2cc(CBr)nn2)cc1
Product: Nc1ccccc1
Temperature: 60 °C

Procedure:
A mixture of 1-azido-4-nitrobenzene (0.5 g, 3.0 mmol), propargyl bromide (80% in toluene) (0.7 mL, 0.6 mmol) and toluene (3 mL) in a sealed tube was heated to 60° C. for 24 h. The reaction mixture was cooled to room temperature and concentrated to give two inseparable isomers 4-(4-(bromomethyl)-1H-1,2,3-triazol-1-yl)aniline and 445-(bromomethyl)-1H-1,2,3-triazol-1-yl)aniline in a 2/1 ratio (as judged by analytical HPLC analysis) which were hydrogenated to afford a mixture of 4-(4-methyl-1H-1,2,3-triazol-1-yl)aniline and 4-(5-methyl-1H-1,2,3-triazol-1-yl)aniline.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[C:6]([CH3:8])[CH:5]=[CH:4][C:3]=1[OH:9].[NH:10]1[CH2:15][CH2:14][CH:13]([C:16](O)=O)[CH2:12][CH2:11]1.[OH-].[K+]>O>[NH:10]1[CH2:15][CH2:14][CH:13]([C:16]2[O:9][C:3]3[CH:4]=[CH:5][C:6]([CH3:8])=[CH:7][C:2]=3[N:1]=2)[CH2:12][CH2:11]1
Reactant: O=C(O)C1CCNCC1
Reactant: Cc1ccc(O)c(N)c1
Agent: [K+]
Agent: [OH-]
Solvent: O
Product: Cc1ccc2oc(C3CCNCC3)nc2c1
Temperature: 180 °C
Yield: 83.4 %

Procedure:
2-Amino-4-methylphenol (400 mg) and 4-piperidinecarboxylic acid (420 mg) were mixed with polyphosphoric acid (2 g) and stirred with heating at 180° C. for 2 hours. After cooling to room temperature, the reaction was stopped by adding water. The filtrate was adjusted to pH 12 with 50% potassium hydroxide aqueous solution and then extracted with methylene chloride. The organic layer was washed with saturated brine and dried with magnesium sulfate, and then the solvent was evaporated under a reduced pressure to obtain the title compound 2-(4-piperidyl)-5-methylbenzoxazole (586 mg).