Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([N:8]([CH2:10][CH2:11][CH2:12][S:13]([C:16]1[CH:17]=[C:18]([C:22]2[CH:27]=[CH:26][C:25]([CH:28]3[N:32]([C:33]4[CH:38]=[CH:37][CH:36]=[CH:35][C:34]=4[Cl:39])[N:31]=[C:30]([C:40]([C:46]([F:49])([F:48])[F:47])([C:42]([F:45])([F:44])[F:43])[OH:41])[CH2:29]3)=[CH:24][CH:23]=2)[CH:19]=[CH:20][CH:21]=1)(=[O:15])=[O:14])C)(OC(C)(C)C)=O.FC(F)(F)C(O)=O>ClCCl>[Cl:39][C:34]1[CH:35]=[CH:36][CH:37]=[CH:38][C:33]=1[N:32]1[CH:28]([C:25]2[CH:24]=[CH:23][C:22]([C:18]3[CH:19]=[CH:20][CH:21]=[C:16]([S:13]([CH2:12][CH2:11][CH2:10][NH:8][CH3:1])(=[O:15])=[O:14])[CH:17]=3)=[CH:27][CH:26]=2)[CH2:29][C:30]([C:40]([C:46]([F:49])([F:47])[F:48])([C:42]([F:43])([F:45])[F:44])[OH:41])=[N:31]1
Reactant: CN(CCCS(=O)(=O)c1cccc(-c2ccc(C3CC(C(O)(C(F)(F)F)C(F)(F)F)=NN3c3ccccc3Cl)cc2)c1)C(=O)OC(C)(C)C
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CNCCCS(=O)(=O)c1cccc(-c2ccc(C3CC(C(O)(C(F)(F)F)C(F)(F)F)=NN3c3ccccc3Cl)cc2)c1
Temperature: 25 °C
Reaction time: 48 h
Yield: 65.7 %

Procedure:
To 5-{3′-[3-(N-BOC-N-methyl-amino)-propane-1-sulfonyl]-biphenyl-4-yl}-1-(2-chloro-phenyl)-3-[di-(trifluoromethyl)-hydroxy-methyl]-4,5-dihydro-1H-pyrazole (9.0 mg, 0.012 mmol) prepared in Example 285, were added dichloromethane (0.5 mL) and trifluoroacetic acid (9.0 uL, 0.12 mmol). The reaction mixture was stirred at room temperature for 48 hours, washed with distilled water, 1N hydrochloride, a saturated solution of sodium hydrogen carbonate, and brine, dried on anhydrous magnesium sulfate, and then concentrated under reduced pressure to give 5.0 mg of the titled compound as a pale yellow liquid.
Reaction SMILES: C[O:2][C:3](=O)[CH2:4][C:5]1[CH:10]=[CH:9][CH:8]=[C:7]([C:11]2[CH:19]=[CH:18][CH:17]=[C:16]3[C:12]=2[CH2:13][C:14](=[O:20])[NH:15]3)[CH:6]=1.[Cl-].[Cl-].[Ca+2]>O.CO.C1COCC1>[OH:2][CH2:3][CH2:4][C:5]1[CH:6]=[C:7]([C:11]2[CH:19]=[CH:18][CH:17]=[C:16]3[C:12]=2[CH2:13][C:14](=[O:20])[NH:15]3)[CH:8]=[CH:9][CH:10]=1
Reactant: COC(=O)Cc1cccc(-c2cccc3c2CC(=O)N3)c1
Agent: [Ca+2]
Agent: [Cl-]
Solvent: CO
Solvent: C1CCOC1
Solvent: O
Product: O=C1Cc2c(cccc2-c2cccc(CCO)c2)N1
Temperature: 25 °C
Reaction time: 8 h
Yield: 94.8 %

Procedure:
To a suspension of NABH4 (600 mg, 16 mmol) in 15% H2O/MeOH (6 mL) under nitrogen at rt was added dropwise a solution of [3-(2-oxo-2,3-dihydro-1H-indol-4-yl)-phenyl]-acetic acid methyl ester (450 mg, 1.6 mmol) in THF (3 mL). After stirring at rt for overnight, to the reaction was added CaCl2 (300 mg) and stirring was continued for another 5 hours. The reaction was quenched with acetic acid (2 mL), concentrated, diluted with ethyl acetate, washed with 0.5 N HCl (3×15 mL), 10% NaHCO3 (3×15 mL), brine (1×), dried and concentrated. The oily residue was purified to give 384 mg (95%) of 4-[3-(2-hydroxy-ethyl)-phenyl]-1,3-dihydro-indol-2-one.
Reaction SMILES: [CH2:1]([O:4][C:5]1([CH3:38])[CH2:10][CH2:9][N:8]([C:11]2[N:16]3[N:17]=[C:18]([C:20]4[CH:25]=[CH:24][CH:23]=[C:22](Br)[CH:21]=4)[CH:19]=[C:15]3[N:14]=[C:13]([CH3:27])[C:12]=2[C@H:28]([O:33][C:34]([CH3:37])([CH3:36])[CH3:35])[C:29]([O:31][CH3:32])=[O:30])[CH2:7][CH2:6]1)[CH:2]=[CH2:3].[CH2:39]([C:43]1[CH:48]=[CH:47][CH:46]=[CH:45][C:44]=1B1OC(=O)CN(C)CC(=O)O1)[CH2:40][CH:41]=[CH2:42].C(=O)([O-])[O-].[Na+].[Na+]>CN(C=O)C.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>[CH2:1]([O:4][C:5]1([CH3:38])[CH2:10][CH2:9][N:8]([C:11]2[N:16]3[N:17]=[C:18]([C:20]4[CH:21]=[C:22]([C:44]5[CH:45]=[CH:46][CH:47]=[CH:48][C:43]=5[CH2:39][CH2:40][CH:41]=[CH2:42])[CH:23]=[CH:24][CH:25]=4)[CH:19]=[C:15]3[N:14]=[C:13]([CH3:27])[C:12]=2[C@H:28]([O:33][C:34]([CH3:37])([CH3:36])[CH3:35])[C:29]([O:31][CH3:32])=[O:30])[CH2:7][CH2:6]1)[CH:2]=[CH2:3]
Reactant: C=CCOC1(C)CCN(c2c([C@H](OC(C)(C)C)C(=O)OC)c(C)nc3cc(-c4cccc(Br)c4)nn23)CC1
Reactant: C=CCCc1ccccc1B1OC(=O)CN(C)CC(=O)O1
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: [Na+]
Solvent: CN(C)C=O
Product: C=CCCc1ccccc1-c1cccc(-c2cc3nc(C)c([C@H](OC(C)(C)C)C(=O)OC)c(N4CCC(C)(OCC=C)CC4)n3n2)c1
Temperature: 90 °C
Yield: 85.7 %

Procedure:
To a solution of (S)-methyl 2-(7-(4-(allyloxy)-4-methylpiperidin-1-yl)-2-(3-bromophenyl)-5-methylpyrazolo[1,5-a]pyrimidin-6-yl)-2-(tert-butoxy)acetate (250 mg, 0.427 mmol) in DMF (5 mL) was added 2-(2-(but-3-en-1-yl)phenyl)-6-methyl-1,3,6,2-dioxazaborocane-4,8-dione (147 mg, 0.512 mmol), 2M sodium carbonate (0.427 mL, 0.854 mmol), and tetrakis(triphenylphosphine)palladium(0)(35 mg, 0.030 mmol). This reaction mixture was flushed with N2 and heated at 90° C. for 24 h. Upon completion of the reaction, the reaction mixture was partitioned between EtOAc and water. The organic phase was washed with water (3×), dried (MgSO4), filtered, and concentrated in vacuo to give the crude product as a brown oil. This was purified by Biotage chromatography (0-40% EtOAc/hexanes) to give 233 mg (86% yield) of (S)-methyl 2-(7-(4-(allyloxy)-4-methylpiperidin-1-yl)-2-(2′-(but-3-en-1-yl)-[1,1′-biphenyl]-3-yl)-5-methylpyrazolo[1,5-a]pyrimidin-6-yl)-2-(tert-butoxy)acetate as a colorless oil. LCMS (M+H).=637.
Reaction SMILES: Cl.[NH4+].[Cl-].[CH2:4]([NH:11][C:12]1[CH:17]=[C:16]([N+:18]([O-])=O)[N:15]=[C:14]2[N:21]([CH:24]([CH3:26])[CH3:25])[CH:22]=[N:23][C:13]=12)[C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1>CCO.[Fe]>[NH2:18][C:16]1[N:15]=[C:14]2[N:21]([CH:24]([CH3:25])[CH3:26])[CH:22]=[N:23][C:13]2=[C:12]([NH:11][CH2:4][C:5]2[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=2)[CH:17]=1
Reactant: CC(C)n1cnc2c(NCc3ccccc3)cc([N+](=O)[O-])nc21
Agent: [Fe]
Agent: Cl
Agent: [Cl-]
Solvent: CCO
Product: CC(C)n1cnc2c(NCc3ccccc3)cc(N)nc21
Temperature: 75 °C
Reaction time: 1 h
Yield: 98 %

Procedure:
To a suspension of 5.5 g of Fe in 30 mL EtOH was added slowly 2 mL 12 N HCl. The mixture was stirred at 75° C. for 1 hour. After cooling at 65° C., 12 mL 25% NH4Cl solution was added. The mixture was stirred 5 min and 6a (0.02 mol, in 5 mL EtOH) was added. The mixture is heated at 75° C. for 2 hour. After cooling to rt, 5 g celite was added the mixture was filtrated on celite and the remaining solids were washed several times with ethanol. The combined filtrates were concentrated and extracted with a CH2Cl2 and 10% Na2CO3. Concentration of the organic layer led to crystallisation of the amine IIb. Yield 98%.
Reaction SMILES: C([O:5][C:6](=[O:38])[C@@H:7]([NH:28][S:29]([C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1)(=[O:31])=[O:30])[CH2:8][NH:9][C:10]([C:12]1[CH:13]=[C:14]2[N:19]([C:20](=[O:22])[CH:21]=1)[CH:18]=[C:17]([O:23][CH2:24][CH2:25][CH2:26][NH2:27])[CH:16]=[CH:15]2)=[O:11])(C)(C)C.C(N(CC)CC)C.[CH3:46][N:47]=[C:48]=[O:49]>C(#N)C>[C:32]1([S:29]([NH:28][C@@H:7]([CH2:8][NH:9][C:10]([C:12]2[CH:13]=[C:14]3[N:19]([C:20](=[O:22])[CH:21]=2)[CH:18]=[C:17]([O:23][CH2:24][CH2:25][CH2:26][NH:27][C:48]([NH:47][CH3:46])=[O:49])[CH:16]=[CH:15]3)=[O:11])[C:6]([OH:5])=[O:38])(=[O:30])=[O:31])[CH:33]=[CH:34][CH:35]=[CH:36][CH:37]=1
Reactant: CC(C)(C)OC(=O)[C@H](CNC(=O)c1cc(=O)n2cc(OCCCN)ccc2c1)NS(=O)(=O)c1ccccc1
Reactant: CN=C=O
Solvent: CCN(CC)CC
Solvent: CC#N
Product: CNC(=O)NCCCOc1ccc2cc(C(=O)NC[C@H](NS(=O)(=O)c3ccccc3)C(=O)O)cc(=O)n2c1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 50.1 %

Procedure:
To a mixture of (S)-3-{[7-(3-amino-propoxy)-4-oxo-4H-quinolizine-2-carbonyl]-amino}-2-benzenesulfonylamino-propionic acid tert-butyl ester (10.0 mg, 0.015 mmol) in anhydrous acetonitrile (0.5 ml) were added triethylamine (4 μl, 0.030 mmol) and methyl isocyanate (1 μl, 0.015 mmol). The mixture was stirred for 5 minutes at 0° C. and 30 minutes at room temperature, quenched with water and extracted with dichloromethane (3x). The combined organic layers were dried (MgSC4) and concentrated to give 4.1 mg (81% yield) of desired product.
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[C:7](B(O)O)[CH:8]=2)[CH:3]=[CH:2]1.Br[C:14]1[CH:15]=[C:16]2[C:21](=[CH:22][CH:23]=1)[N:20]=[C:19]([NH2:24])[CH:18]=[CH:17]2.C([O-])([O-])=O.[K+].[K+]>C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.[Pd].COCCOC.CCO>[NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[C:7]([C:14]3[CH:15]=[C:16]4[C:21](=[CH:22][CH:23]=3)[N:20]=[C:19]([NH2:24])[CH:18]=[CH:17]4)[CH:8]=2)[CH:3]=[CH:2]1
Reactant: Nc1ccc2cc(Br)ccc2n1
Reactant: OB(O)c1ccc2cc[nH]c2c1
Agent: [Pd]
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: COCCOC
Solvent: CCO
Product: Nc1ccc2cc(-c3ccc4cc[nH]c4c3)ccc2n1
Temperature: 140 °C
Yield: 54.3 %

Procedure:
A mixture of 1H-indol-6-ylboronic acid (43 mg, 0.27 mmol), 6-bromoquinolin-2-amine (40 mg, 0.22 mmol), K2CO3 (3M, 100 uL), PS—PPh3-Pd (20 mg, 0.11 mmol/g), and DME/EtOH (50%, 1 mL) was heated in a microwave at 140° C. for 10 min. The resulting slurry was filtered and purified by HPLC (10-60% CH3CN/water modified with 0.1% TFA) to give 6-(1H-indol-6-yl)quinolin-2-amine (31 mg). MS (ESI, pos. ion) m/z: 260 (M+1).
Reaction SMILES: [C:1](Cl)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[N+:10]([C:13]1[CH:23]=[CH:22][C:16]2[N:17]=[C:18]([CH2:20][OH:21])[S:19][C:15]=2[CH:14]=1)([O-:12])=[O:11].C(N(CC)CC)C.O>O1CCCC1>[N+:10]([C:13]1[CH:23]=[CH:22][C:16]2[N:17]=[C:18]([CH2:20][O:21][C:1](=[O:8])[C:2]3[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=3)[S:19][C:15]=2[CH:14]=1)([O-:12])=[O:11]
Reactant: O=[N+]([O-])c1ccc2nc(CO)sc2c1
Reactant: O=C(Cl)c1ccccc1
Solvent: CCN(CC)CC
Solvent: O
Solvent: C1CCOC1
Product: O=C(OCc1nc2ccc([N+](=O)[O-])cc2s1)c1ccccc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
9 ml of benzoyl chloride was added dropwise to a solution of 15 g of the 6-nitro-2-hydroxymethylbenzothiazole obtained in the Preparation Example 2 and 11 ml of triethylamine in tetrahydrofuran at 10° C. The reaction mixture was stirred at room temperature for 1 h and water was added thereto. After extraction with ethyl acetate, the extract was dried over sodium sulfate and concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (solvent: dichloromethanol/methanol) to give 10 g of the titled compound.
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[C:9]1[CH:14]=[CH:13][C:12]([CH2:15][C:16]2[C:17](=[O:39])[N:18]([C@H:29]3[CH2:32][C@H:31]([C:33](N(OC)C)=[O:34])[CH2:30]3)[C:19]3[N:20]([N:25]=[C:26]([CH3:28])[N:27]=3)[C:21]=2[CH2:22][CH2:23][CH3:24])=[C:11]([F:40])[CH:10]=1)#[N:2].[CH3:41][Mg]Br.O1CCCC1>O1CCCC1.[Cl-].[NH4+]>[C:33]([C@H:31]1[CH2:32][C@H:29]([N:18]2[C:17](=[O:39])[C:16]([CH2:15][C:12]3[CH:13]=[CH:14][C:9]([C:4]4[C:3]([C:1]#[N:2])=[CH:8][CH:7]=[CH:6][CH:5]=4)=[CH:10][C:11]=3[F:40])=[C:21]([CH2:22][CH2:23][CH3:24])[N:20]3[N:25]=[C:26]([CH3:28])[N:27]=[C:19]23)[CH2:30]1)(=[O:34])[CH3:41]
Reactant: CCCc1c(Cc2ccc(-c3ccccc3C#N)cc2F)c(=O)n([C@H]2C[C@H](C(=O)N(C)OC)C2)c2nc(C)nn12
Reactant: C[Mg]Br
Agent: [Cl-]
Agent: [NH4+]
Solvent: C1CCOC1
Product: CCCc1c(Cc2ccc(-c3ccccc3C#N)cc2F)c(=O)n([C@H]2C[C@H](C(C)=O)C2)c2nc(C)nn12
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To a solution of trans-3-{6-[(2′-cyano-3-fluorobiphenyl-4-yl)methyl]-2-methyl-5-oxo-7-propyl[1,2,4]triazolo[1,5-a]pyrimidin-4(5H)-yl}-N-methoxy-N-methylcyclobutanecarboxamide (1.90 g) in tetrahydrofuran (5 mL) was added 1 M methylmagnesium bromide-tetrahydrofuran solution (5.3 mL), and the mixture was stirred at room temperature for 3 hr. The reaction mixture was diluted with saturated aqueous ammonium chloride solution, and the mixture was extracted with ethyl acetate. The extract was washed with saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure, and the residue was purified by silica gel chromatography [eluent: hexane/ethyl acetate=70/30→50/50 (volume ratio)] to give the title compound as a colorless amorphous compound (1.38 g, 79%).
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[C:6]([O:8][CH2:9][CH2:10][CH2:11][S:12]([CH3:15])(=[O:14])=[O:13])[CH:5]=[C:4]([CH3:16])[C:3]=1[C:17]1[CH:22]=[CH:21][CH:20]=[C:19]([CH:23]=O)[CH:18]=1.[CH3:25][C:26]1([CH3:40])[C:30]([CH3:32])([CH3:31])[O:29][B:28]([C:33]2[CH:39]=[CH:38][C:36]([NH2:37])=[CH:35][CH:34]=2)[O:27]1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].O>C(Cl)Cl>[CH3:16][C:4]1[CH:5]=[C:6]([O:8][CH2:9][CH2:10][CH2:11][S:12]([CH3:15])(=[O:13])=[O:14])[CH:7]=[C:2]([CH3:1])[C:3]=1[C:17]1[CH:22]=[CH:21][CH:20]=[C:19]([CH2:23][NH:37][C:36]2[CH:38]=[CH:39][C:33]([B:28]3[O:27][C:26]([CH3:40])([CH3:25])[C:30]([CH3:31])([CH3:32])[O:29]3)=[CH:34][CH:35]=2)[CH:18]=1
Reactant: Cc1cc(OCCCS(C)(=O)=O)cc(C)c1-c1cccc(C=O)c1
Reactant: CC1(C)OB(c2ccc(N)cc2)OC1(C)C
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: O
Solvent: ClCCl
Product: Cc1cc(OCCCS(C)(=O)=O)cc(C)c1-c1cccc(CNc2ccc(B3OC(C)(C)C(C)(C)O3)cc2)c1
Yield: 88.6 %

Procedure:
2′,6′-dimethyl-4′-(3-(methylsulfonyl)propoxy)-[1,1′-biphenyl]-3-carbaldehyde (1.0 g) synthesized according to a method described in [WO 2008/001931 pamphlet, (Reference Example 18)] and 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)aniline (0.63 g) were dissolved in methylene chloride (10 mL), and to the resultant solution, sodium triacetoxyborohydride (1.84 g) was added, followed by stirring the resultant reaction mixture at room temperature for 14 hours. To the reaction mixture, water (20 mL) was added, followed by extracting the reaction mixture with methylene chloride (20 mL) twice, and the resultant organic phase was washed sequentially with water (50 mL) and a saturated saline (50 mL) and was dried over anhydrous sodium sulfate. From the organic phase, the solvent was distilled off under reduced pressure to obtain the subject compound (1.4 g) as a colorless amorphous solid.
Reaction SMILES: [C:1]1(=[O:12])[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[C:4](=[O:11])[CH:3]=[CH:2]1.[CH2:13]([N:18]1[CH:22]=[CH:21][CH:20]=[CH:19]1)[CH2:14][CH2:15][CH2:16][CH3:17].C1(C)C=CC(S(O)(=O)=O)=CC=1>C(Cl)(Cl)Cl>[CH2:13]([N:18]1[CH:22]=[CH:21][CH:20]=[C:19]1[C:3]1[C:4](=[O:11])[C:5]2[C:10]([C:1](=[O:12])[CH:2]=1)=[CH:9][CH:8]=[CH:7][CH:6]=2)[CH2:14][CH2:15][CH2:16][CH3:17]
Reactant: CCCCCn1cccc1
Reactant: O=C1C=CC(=O)c2ccccc21
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: ClC(Cl)Cl
Product: CCCCCn1cccc1C1=CC(=O)c2ccccc2C1=O
Yield: 26 %

Procedure:
6.32 millimol of 1,4-naphthoquinone and 3.16 millimol of N-pentylpyrrole were stirred in 50 ml of chloroform in a round-bottomed flask for 5 hours at room temperature, the reaction being catalysed by addition of a few milligrams of para-toluenesulphonic acid. The reaction medium was diluted with 50 ml of chloroform and then washed four times with 50 ml of water and finally with saturated aqueous NaCl solution. The resulting organic phase was dried over Na2SO4 and then concentrated under vacuum. The product 2-(1-pentyl-1H-pyrrol-2-yl)-[1,4]-naphthoquinone was thus isolated, in the form of an oil, in a yield of 26% after purification by chromatography on a column of silica.
Reaction SMILES: [Cl:1][C:2]1[CH:21]=[C:20]([Cl:22])[CH:19]=[CH:18][C:3]=1[O:4][CH2:5][C:6]([NH:8][C:9]1[CH:10]=[C:11]([CH:15]=[CH:16][CH:17]=1)[C:12]([OH:14])=O)=[O:7].[NH2:23][CH2:24][CH2:25][CH2:26][N:27]1[CH2:32][CH2:31][O:30][CH2:29][CH2:28]1.C(Cl)CCl.C1C=CC2N(O)N=NC=2C=1.CCN(C(C)C)C(C)C>CN(CC1C=C(CN(C)C)C(O)=C(CN(C)C)C=1)C>[Cl:1][C:2]1[CH:21]=[C:20]([Cl:22])[CH:19]=[CH:18][C:3]=1[O:4][CH2:5][C:6]([NH:8][C:9]1[CH:10]=[C:11]([CH:15]=[CH:16][CH:17]=1)[C:12]([NH:23][CH2:24][CH2:25][CH2:26][N:27]1[CH2:32][CH2:31][O:30][CH2:29][CH2:28]1)=[O:14])=[O:7]
Reactant: NCCCN1CCOCC1
Reactant: O=C(COc1ccc(Cl)cc1Cl)Nc1cccc(C(=O)O)c1
Agent: CN(C)Cc1cc(CN(C)C)c(O)c(CN(C)C)c1
Agent: On1nnc2ccccc21
Solvent: ClCCCl
Solvent: CCN(C(C)C)C(C)C
Product: O=C(COc1ccc(Cl)cc1Cl)Nc1cccc(C(=O)NCCCN2CCOCC2)c1
Temperature: 25 °C
Yield: 20.6 %

Procedure:
3-[2-(2,4-dichloro-phenoxy)-acetylamino]-benzoic acid (200 mg, 0.59 mmol) and N-(aminopropyl)morpholine (0.17 ml, 1.18 mmol) in DMF 3.0 mL was added EDC (168.7 mg, 0.88 mmol), HOBt (118.9 mg, 0.88 mmol) and DIPEA (0.15 ml, 0.88 mmol). Reaction mixture was stirred at room temperature, and separated by EtoAC and brine. The organic phase was dried (MgSO4 anh) and concentrated. The residue was purified by silica gel column chromatography (CH2Cl2:MeOH=15:1) to give 3-[2-(2,4-dichloro-phenoxy)-acetylamino]-N-(3-morpholine-4-yl-propyl)-benzamide as a yellow solid (56.7 mg, 20% yield).
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][CH:4]([C@H:7]2[CH2:9][C@H:8]2[CH2:10][CH2:11][OH:12])[CH2:3][CH2:2]1.C(=O)([O-])[O-].[Cs+].[Cs+].Cl[C:20]1[N:25]=[CH:24][C:23]([O:26][CH3:27])=[CH:22][N:21]=1>CN(C=O)C.CCOC(C)=O>[CH3:27][O:26][C:23]1[CH:22]=[N:21][C:20]([N:1]2[CH2:6][CH2:5][CH:4]([C@H:7]3[CH2:9][C@H:8]3[CH2:10][CH2:11][OH:12])[CH2:3][CH2:2]2)=[N:25][CH:24]=1
Reactant: COc1cnc(Cl)nc1
Reactant: OCC[C@@H]1C[C@@H]1C1CCNCC1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: COc1cnc(N2CCC([C@H]3C[C@H]3CCO)CC2)nc1
Temperature: 25 °C
Reaction time: 0.08 h

Procedure:
2-((1S,2R)-2-(piperidin-4-yl)cyclopropyl)ethanol (2.5 g, 14.77 mmol) was dissolved in DMF (30 ml) at RT under N2 and cesium carbonate (7.22 g, 22.15 mmol) was added. The mixture was stirred at RT for 5 min and 2-chloro-5-methoxypyrimidine (2.56 g, 17.72 mmol) was added. The mixture was stirred at 100° C. overnight. The mixture was diluted with EtOAc (100 ml), washed with sat. NH4Cl (100 ml), dried over MgSO4, and the volatiles evaporated under reduced pressure. The crude material was purified by silica gel column chromatography (100 g SNAP, 20˜60% EtOAc in hexane) to afford the titled compound. LC/MS (m/z): 278 (M+H)+. Rf was 0.4 @ 50% EtOAc in hexanes (blue spot on CAM stain).
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]2[O:13][CH2:12][CH:11]([NH:14][C:15](=[O:24])OCC3C=CC=CC=3)[CH2:10][C:7]2=[N:8][CH:9]=1)([O-:3])=[O:2].[N+]([C:28]1C=C2C(NC(=O)OCC3C=CC=CC=3)COCC2=N[CH:33]=1)([O-])=O.Br.C(Cl)(=O)CC.C(N(CC)CC)C>C(Cl)Cl.C(O)(=O)C>[N+:1]([C:4]1[CH:5]=[C:10]2[CH:11]([NH:14][C:15](=[O:24])[CH2:28][CH3:33])[CH2:12][O:13][CH2:6][C:7]2=[N:8][CH:9]=1)([O-:3])=[O:2]
Reactant: O=C(NC1COc2cc([N+](=O)[O-])cnc2C1)OCc1ccccc1
Reactant: O=C(NC1COCc2ncc([N+](=O)[O-])cc21)OCc1ccccc1
Agent: Br
Agent: CCC(=O)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Solvent: CC(=O)O
Product: CCC(=O)NC1COCc2ncc([N+](=O)[O-])cc21
Temperature: 0 °C
Reaction time: 2 h
Yield: 33 %

Procedure:
A mixture of benzyl 3,4-dihydro-7-nitro-2H-pyrano[3,2-b]pyridin-3-ylcarbamate and benzyl 6,8-dihydro-3-nitro-5H-pyrano[3,4-b]pyridine-5-ylcarbamate (6.54 g, 26.23 mmol) in CH2Cl2 (55 ml) was stirred at 0° C. and 33% HBr in acetic acid (45 ml) was added. The solution was further stirred at 0° C. for 1 h then at room temperature for 2 h. The solvents were then removed. The crude mixture was dissolved in CH2Cl2/H2O 1/1 (80 ml) and the aqueous mixture adjusted to pH˜10 with 2N NaOH solution. After separation of the layers, the organic phase was washed with H2O (×2), dried over Na2SO4 and evaporated. The residue was dissolved in CH2Cl2 (400 ml) and the solution cooled to 0° C. Propionyl chloride (4.54 ml, 52 mmol) and triethylamine (7.22 ml, 52 mmol) were added and then the mixture was allowed to reach 20° C. and stirred for 4.5 h. The solution was washed successively with 1 N aqueous HCl, saturated aqueous NaHCO3 and water. The organic layer was dried (Na2SO4) and evaporated. Immediate recrystallization in acetone gave a pure fraction of N-(6,8-dihydro-3-nitro-5H-pyrano[3,4-b]pyridin-5-yl)propionamide (2.2 g, 33% for two steps) as a white solid. The remaining mixture was subjected to chromatography on silica gel (heptane:ethyl acetate, 1.5:3.5 then CH2Cl2:CH3OH, 95:5) to afford another portion of N-(6,8-dihydro-3-nitro-5H-pyrano[3,4-b]pyridin-5-yl)propionamide (1.15 mg, 17% for two steps) and N-(3,4-dihydro-7-nitro-2H-pyrano[3,2-b]pyridin-3-yl)propionamide (445 mg, 7% for two steps) as a white solid.
Reaction SMILES: [CH2:1]([C:5]1[N:6]([CH2:21][C:22]2[CH:27]=[CH:26][C:25]([C:28]3[CH:33]=[CH:32][CH:31]=[CH:30][C:29]=3[S:34](=[O:41])(=[O:40])[NH:35]C(C)(C)C)=[CH:24][CH:23]=2)[C:7](=[O:20])[N:8]([C:10]2[CH:15]=[C:14]([N+:16]([O-:18])=[O:17])[CH:13]=[CH:12][C:11]=2[Cl:19])[N:9]=1)[CH2:2][CH2:3][CH3:4].C(Cl)Cl>CO>[CH2:1]([C:5]1[N:6]([CH2:21][C:22]2[CH:27]=[CH:26][C:25]([C:28]3[CH:33]=[CH:32][CH:31]=[CH:30][C:29]=3[S:34](=[O:41])(=[O:40])[NH2:35])=[CH:24][CH:23]=2)[C:7](=[O:20])[N:8]([C:10]2[CH:15]=[C:14]([N+:16]([O-:18])=[O:17])[CH:13]=[CH:12][C:11]=2[Cl:19])[N:9]=1)[CH2:2][CH2:3][CH3:4]
Reactant: CCCCc1nn(-c2cc([N+](=O)[O-])ccc2Cl)c(=O)n1Cc1ccc(-c2ccccc2S(=O)(=O)NC(C)(C)C)cc1
Solvent: ClCCl
Solvent: CO
Product: CCCCc1nn(-c2cc([N+](=O)[O-])ccc2Cl)c(=O)n1Cc1ccc(-c2ccccc2S(N)(=O)=O)cc1

Procedure:
The title compound was prepared from 5-n-butyl-4-[[2'-(N-t-butylsulfamoyl)biphenyl-4-yl]methyl]-2-(2-chloro-5-nitrophenyl)-2,4-dihydro-3H-1,2,4-triazol-3-one (from Step B) according to the procedure of Example 8, Step B, and was obtained as a pale yellow solid, mp >90° C. (gradual), homogeneous by TLC (19:1 CH2Cl2 --MeOH); mass spectrum (FAB) m/e 542 (M+1)+.
Reaction SMILES: [CH3:1][C:2]1[CH:11]=[CH:10][C:9]2[C:4](=[CH:5][CH:6]=[C:7]([N+:12]([O-])=O)[CH:8]=2)[N:3]=1>[OH-].[OH-].[Pd+2].C(OCC)(=O)C>[CH3:1][C:2]1[CH:11]=[CH:10][C:9]2[C:4](=[CH:5][CH:6]=[C:7]([NH2:12])[CH:8]=2)[N:3]=1
Reactant: Cc1ccc2cc([N+](=O)[O-])ccc2n1
Agent: [Pd+2]
Agent: [OH-]
Solvent: CCOC(C)=O
Product: Cc1ccc2cc(N)ccc2n1
Temperature: 60 °C
Reaction time: 1.5 h

Procedure:
A mixture of 2-methyl-6-nitroquinoline (1.00 g, 5.31 mmol) and Pearlman's catalyst [palladium dihydroxide on activated charcoal (˜20% palladium); 0.10 g] in ethyl acetate (40 mL) was stirred under hydrogen gas (1 atm) at 60° C. for 1.5 h. The reaction mixture was filtered and the filtrate was rotary evaporated. This provided 0.81 g (96%) of 2-methyl-6-aminoquinoline as a yellow solid.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:8]2[C:9](=O)[O:10][C:11](=[O:13])[CH:12]=2)[CH:5]=[CH:6][CH:7]=1.O.[NH2:16][NH2:17]>O.C(O)(=O)C>[Cl:1][C:2]1[CH:3]=[C:4]([C:8]2[CH:12]=[C:11]([OH:13])[N:17]=[N:16][C:9]=2[OH:10])[CH:5]=[CH:6][CH:7]=1
Reactant: NN
Reactant: O=C1C=C(c2cccc(Cl)c2)C(=O)O1
Solvent: O
Solvent: CC(=O)O
Product: Oc1cc(-c2cccc(Cl)c2)c(O)nn1
Reaction time: 1 h

Procedure:
To a 25 mL flask was added 3-(3-chlorophenyl)furan-2,5-dione (1.7 g, 8.15 mmol) from (1a) and hydrazine hydrate (0.476 mL, 9.78 mmol) in water (6 mL) and acetic acid (4 mL). The resulting mixture was refluxed for 18 hours. The solution was cooled and placed in the refrigerator for 1 hour. The resulting precipitate was filtered and dried, then purified by flash chromatography eluting with 5% methanol/dichloromethane to give 4-(3-chlorophenyl)pyridazine-3,6-diol.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:9]([C:17]3[CH:22]=[CH:21][C:20]([S:23]([CH3:26])(=[O:25])=[O:24])=[CH:19][CH:18]=3)=[N:10][NH:11][C:12]=2[C:13]([F:16])([F:15])[F:14])=[CH:4][CH:3]=1.Br[CH2:28][C:29]#[N:30]>C1(C)C=CC=CC=1>[C:29]([CH2:28][N:11]1[C:12]([C:13]([F:16])([F:14])[F:15])=[C:8]([C:5]2[CH:6]=[CH:7][C:2]([F:1])=[CH:3][CH:4]=2)[C:9]([C:17]2[CH:22]=[CH:21][C:20]([S:23]([CH3:26])(=[O:24])=[O:25])=[CH:19][CH:18]=2)=[N:10]1)#[N:30]
Reactant: CS(=O)(=O)c1ccc(-c2n[nH]c(C(F)(F)F)c2-c2ccc(F)cc2)cc1
Reactant: N#CCBr
Solvent: Cc1ccccc1
Product: CS(=O)(=O)c1ccc(-c2nn(CC#N)c(C(F)(F)F)c2-c2ccc(F)cc2)cc1
Temperature: 190 °C
Yield: 1.8 %

Procedure:
A mixture of 4-(4-fluorophenyl)-3-[4-(methylsulfonyl)phenyl]-5-(trifluoromethyl)-1H-pyrazole (Example 1, step 3) (0.10 g), 4.2 g of bromoacetonitrile and 3 mL of toluene was heated at reflux for 2 hours. Toluene was distilled off and the mixture was heated at 190 ° C. for 24 hours. The reaction mixture was diluted with methylene chloride and filtered through silica gel. The filtrate was concentrated in vacuo and the residue was purified by HPLC (30% ethyl acetate-hexane). The second fraction eluted with 40% ethyl acetate-hexane yielding 1-cyanomethyl-4-(4-fluorophenyl)-3-[4-(methylsulfonyl)phenyl]-5-(trifluoromethyl)-1H-pyrazole (1 2 mg, 11%): mp 192-194° C.