Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([C:5]1[CH:40]=[CH:39][C:8]([C:9]([NH:11][C:12]2[CH:17]=[CH:16][CH:15]=[C:14]([C:18]3[N:19]=[C:20]([NH:26][C:27]4[CH:32]=[CH:31][C:30]([NH:33][CH3:34])=[C:29]([N+:35]([O-])=O)[CH:28]=4)[C:21](=[O:25])[N:22]([CH3:24])[CH:23]=3)[C:13]=2[CH3:38])=[O:10])=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2].C(O)C.[H][H]>[Pd].C(OCC)(=O)C>[NH2:35][C:29]1[CH:28]=[C:27]([NH:26][C:20]2[C:21](=[O:25])[N:22]([CH3:24])[CH:23]=[C:18]([C:14]3[C:13]([CH3:38])=[C:12]([NH:11][C:9](=[O:10])[C:8]4[CH:39]=[CH:40][C:5]([C:1]([CH3:3])([CH3:4])[CH3:2])=[CH:6][CH:7]=4)[CH:17]=[CH:16][CH:15]=3)[N:19]=2)[CH:32]=[CH:31][C:30]=1[NH:33][CH3:34]
Reactant: CNc1ccc(Nc2nc(-c3cccc(NC(=O)c4ccc(C(C)(C)C)cc4)c3C)cn(C)c2=O)cc1[N+](=O)[O-]
Reactant: [H][H]
Agent: [Pd]
Solvent: CCO
Solvent: CCOC(C)=O
Product: CNc1ccc(Nc2nc(-c3cccc(NC(=O)c4ccc(C(C)(C)C)cc4)c3C)cn(C)c2=O)cc1N
Yield: 85.1 %

Procedure:
A mixture of 4-tert-butyl-N-{2-methyl-3-[4-methyl-6-(4-methylamino-3-nitro-phenylamino)-5-oxo-4,5-dihydro-pyrazin-2-yl]-phenyl}-benzamide (3) (500 mg), 10% palladium-on-carbon (100 mg), ethanol (50 mL), and ethyl acetate (100 mL) was hydrogenated at room temperature and 40 psi hydrogen for 16 hr. The mixture was filtered through a celite pad, washing with ethyl acetate (2×100 mL). The combined filtrates were evaporated to give N-{3-[6-(3-amino-4-methylamino-phenylamino)-4-methyl-5-oxo-4,5-dihydro-pyrazin-2-yl]-2-methyl-phenyl}-4-tert-butyl-benzamide (4) as a yellow solid (402 mg), m/z 512.08 (MH+).
Reaction SMILES: [CH3:1][C:2]1[C:3]([C:16]([C:18]2[CH:23]=[CH:22][C:21]([CH2:24][C:25]#[N:26])=[CH:20][CH:19]=2)=[CH2:17])=[CH:4][C:5]2[C:6]([CH3:15])([CH3:14])[CH2:7][CH2:8][C:9]([CH3:13])([CH3:12])[C:10]=2[CH:11]=1.[OH-:27].[Na+]>CC(O)(C)C>[CH3:1][C:2]1[C:3]([C:16]([C:18]2[CH:23]=[CH:22][C:21]([CH2:24][C:25]([NH2:26])=[O:27])=[CH:20][CH:19]=2)=[CH2:17])=[CH:4][C:5]2[C:6]([CH3:15])([CH3:14])[CH2:7][CH2:8][C:9]([CH3:12])([CH3:13])[C:10]=2[CH:11]=1
Reactant: C=C(c1ccc(CC#N)cc1)c1cc2c(cc1C)C(C)(C)CCC2(C)C
Reactant: [OH-]
Agent: [Na+]
Solvent: CC(C)(C)O
Product: C=C(c1ccc(CC(N)=O)cc1)c1cc2c(cc1C)C(C)(C)CCC2(C)C
Temperature: 100 °C
Yield: 32.7 %

Procedure:
To a solution of 4-[1-(3,5,5,8,8-pentamethyl-5,6,7,8-tetrahydro-naphthalen-2-yl)-vinyl]-phenyl-acetonitrile (15 mg, 0.044 mmol) in 1 mL of t-BuOH was added NaOH (1 mL of 2N solution, 2 mmol). The mixture was heated at 100° C. for 24 hours. After acidification and extraction with EtOAc, the organic fraction was dried over Na2SO4, filtered and concentrated in vacuo. Purification by PTLC gave 5.2 mg of the amide product.
Reaction SMILES: FC(F)(F)S([O:6][Si:7]([C:10]([CH3:13])([CH3:12])[CH3:11])([CH3:9])[CH3:8])(=O)=O.[F:16][C:17]1[N:22]=[CH:21][C:20]([CH:23]([CH3:26])[CH2:24]O)=[CH:19][CH:18]=1.C(N(CC)C(C)C)(C)C>C(Cl)Cl>[Si:7]([O:6][CH2:24][CH:23]([C:20]1[CH:19]=[CH:18][C:17]([F:16])=[N:22][CH:21]=1)[CH3:26])([C:10]([CH3:11])([CH3:12])[CH3:13])([CH3:8])[CH3:9]
Reactant: CC(CO)c1ccc(F)nc1
Reactant: CC(C)(C)[Si](C)(C)OS(=O)(=O)C(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CC(CO[Si](C)(C)C(C)(C)C)c1ccc(F)nc1
Temperature: 0 °C
Reaction time: 2.5 h
Yield: 78.2 %

Procedure:
Tert-butyldimethylsilyl trifluoromethanesulfonate (2.160 mL, 9.41 mmol) was added to a solution of 2-(6-fluoropyridin-3-yl)propan-1-ol (1.39 g, 8.96 mmol) and N,N-diisopropylethylamine (3.35 mL, 19.26 mmol) in CH2Cl2 (45 mL) at 0° C., and the resulting mixture stirred at 0° C. for 2.5 h. The reaction mixture was subsequently concentrated onto silica gel and chromatographically purified (silica gel, 0 to 20% EtOAc/hexanes) to provide 5-(1-(tert-butyldimethylsilyloxy)propan-2-yl)-2-fluoropyridine (1.89 g, 7.01 mmol, 78% yield) as a colorless oil. 1H NMR (400 MHz, CDCl3) δ 8.06 (d, J=2.2 Hz, 1H), 7.65 (td, J=8.1, 2.5 Hz, 1H), 6.86 (dd, J=8.4, 2.9 Hz, 1H), 3.58-3.69 (m, 2H), 2.93 (sxt, J=6.7 Hz, 1H), 1.28 (d, J=7.0 Hz, 3H), 0.84 (s, 9H), −0.04 (s, 3H), −0.05 (s, 3H). 19F NMR (377 MHz, CDCl3) δ −72.06 (d, J=6.0 Hz, 1 F). m/z (ESI, +ve) 270.3 (M+H)+.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([CH:8]([CH:10]2[S:15][CH2:14][CH2:13][CH2:12][S:11]2)[CH3:9])=[CH:4][CH:3]=1.C([Li])(CC)C.[Br:21][CH2:22][CH2:23][CH2:24][CH2:25]Br.C(OCC)(=O)C>O1CCCC1>[Br:21][CH2:22][CH2:23][CH2:24][CH2:25][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([CH:10]2[S:15][CH2:14][CH2:13][CH2:12][S:11]2)[CH3:9])=[CH:4][CH:3]=1
Reactant: BrCCCCBr
Reactant: CC(c1ccc(Br)cc1)C1SCCCS1
Agent: [Li]C(C)CC
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: CC(c1ccc(CCCCBr)cc1)C1SCCCS1
Temperature: 25 °C
Reaction time: 1.5 h

Procedure:
A solution of 4-bromo-1-(1,3-dithian-2-yl)ethylbenzene (27.2 g, 94 mmol) in tetrahydrofuran (200 ml) was charged with sec-butyllithium (99 ml, 1.3M in cyclohexane, 0.13 mole) dropwise at -78° C. under nitrogen. The mixture was stirred at ambient temperature for 1.5 hours, and then quenched with 1,4-dibromobutane (42 g, 0.2 mole). After being stirred for 3 hours, the mixture was poured into ethyl acetate, and then washed with water and brine. The organic solution was then dried (Na2SO4) and concentrated to an oil. The crude product was purified by flash chromatography over a silica gel column. The 4-(4-bromobutyl)-1-(1,3-dithian-2-yl)-ethylbenzene thus purified was a light oil, 22.3 g.
Reaction SMILES: [Cl:1][C:2]1[CH:29]=[CH:28][C:5]([CH2:6][N:7]2[C:15]3[C:10](=[CH:11][C:12]([CH:16]=[C:17]4[S:21][C:20](=[O:22])[N:19]([CH2:23][CH2:24][NH:25][CH3:26])[C:18]4=[O:27])=[CH:13][CH:14]=3)[CH:9]=[N:8]2)=[C:4]([C:30]([F:33])([F:32])[F:31])[CH:3]=1.[CH3:34][S:35](Cl)(=[O:37])=[O:36]>>[Cl:1][C:2]1[CH:29]=[CH:28][C:5]([CH2:6][N:7]2[C:15]3[C:10](=[CH:11][C:12](/[CH:16]=[C:17]4/[C:18](=[O:27])[N:19]([CH2:23][CH2:24][N:25]([CH3:26])[S:35]([CH3:34])(=[O:37])=[O:36])[C:20](=[O:22])[S:21]/4)=[CH:13][CH:14]=3)[CH:9]=[N:8]2)=[C:4]([C:30]([F:31])([F:33])[F:32])[CH:3]=1
Reactant: CNCCN1C(=O)SC(=Cc2ccc3c(cnn3Cc3ccc(Cl)cc3C(F)(F)F)c2)C1=O
Reactant: CS(=O)(=O)Cl
Product: CN(CCN1C(=O)S/C(=C\c2ccc3c(cnn3Cc3ccc(Cl)cc3C(F)(F)F)c2)C1=O)S(C)(=O)=O

Procedure:
N-{2-[(5Z)-5-({1-[4-Chloro-2-(trifluoromethyl)benzyl]-1H-indazol-5-yl}methylidene)-2,4-dioxo-1,3-thiazolidin-3-yl]ethyl}-N-methylmethane sulfonamide was prepared from 5-[1-(4-chloro-2-trifluoromethylbenzyl)-1H-indazol-5-ylmethylene]-3-(2-methylaminoethyl)thiazolidine-2,4-dione (from Example 394) and methanesulfonyl chloride following General Procedure U.
Reaction SMILES: [CH:1]1([NH:4][C:5](=[O:24])[C:6]2[CH:11]=[CH:10][C:9]([CH3:12])=[C:8]([C:13]3[CH:14]=[C:15]4[C:20](=[CH:21][CH:22]=3)[C:19](=[O:23])[NH:18][CH:17]=[CH:16]4)[CH:7]=2)[CH2:3][CH2:2]1.Cl.Cl[CH2:27][C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][N:29]=1>>[CH:1]1([NH:4][C:5](=[O:24])[C:6]2[CH:11]=[CH:10][C:9]([CH3:12])=[C:8]([C:13]3[CH:14]=[C:15]4[C:20](=[CH:21][CH:22]=3)[C:19](=[O:23])[N:18]([CH2:27][C:28]3[CH:33]=[CH:32][CH:31]=[CH:30][N:29]=3)[CH:17]=[CH:16]4)[CH:7]=2)[CH2:2][CH2:3]1
Reactant: ClCc1ccccn1
Reactant: Cc1ccc(C(=O)NC2CC2)cc1-c1ccc2c(=O)[nH]ccc2c1
Agent: Cl
Product: Cc1ccc(C(=O)NC2CC2)cc1-c1ccc2c(=O)n(Cc3ccccn3)ccc2c1

Procedure:
The title compound was prepared according to the method of Example 123 using the product of Example 11 and 2-(chloromethyl)pyridine hydrochloride.
Reaction SMILES: [OH:1][C:2]1[CH:9]=[CH:8][C:7]([CH3:10])=[CH:6][C:3]=1[CH:4]=[O:5].C([O-])([O-])=O.[K+].[K+].Br[CH2:18][C:19]([O:21][CH2:22][CH3:23])=[O:20]>CN(C=O)C>[CH:4]([C:3]1[CH:6]=[C:7]([CH3:10])[CH:8]=[CH:9][C:2]=1[O:1][CH2:18][C:19]([O:21][CH2:22][CH3:23])=[O:20])=[O:5]
Reactant: Cc1ccc(O)c(C=O)c1
Reactant: CCOC(=O)CBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCOC(=O)COc1ccc(C)cc1C=O
Reaction time: 0.17 h
Yield: 76.6 %

Procedure:
To a solution of 2-hydroxy-5-methylbenzaldehyde (2 g, 14.69 mmol) in 22 mL of DMF was added K2CO3 (4.06 g, 29.4 mmol) under N2 at room temperature. After the mixture was stirred for 10 min, ethyl 2-bromoacetate (1.625 mL, 14.69 mmol) was added. The reaction mixture was stirred at room temperature overnight, and filtered through Celite to remove solids. The filtrate was concentrated under reduced pressure, and the resulting residue was purified by silica gel flash chromatography, 100% Heptane-20% Ethyl Acetate/80% Heptane, to give a white solid, ethyl 2-(2-formyl-4-methylphenoxy)acetate (2.5 g). LCMS retention time=1.19 minutes (LC method 3); MS (m+1)=222.9. 1H NMR (400 MHz, DMSO-d6) δ 1.20 (t, J=7.1 Hz, 3H), 2.28 (s, 3H), 4.17 (q, J=7.2 Hz, 2H), 4.95 (s, 2H), 7.08 (d, J=8.6 Hz, 1H), 7.45 (ddd, J=8.6, 2.5, 0.6 Hz, 1H), 7.51 (d, J=2.2 Hz, 1H), 10.41 (s, 1H).
Reaction SMILES: [S:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[C:6]([NH:8][C:9]1[CH:10]=[CH:11][CH:12]=[C:13]2[C:17]=1[NH:16][C:15]([C:18]([OH:20])=O)=[CH:14]2)=[O:7].[NH:21]1[CH2:26][CH2:25][CH2:24][CH2:23][CH2:22]1.N1(O)C2C=CC=CC=2N=N1.Cl.CN(C)CCCN=C=NCC>C(OCC)(=O)C.CN(C)C=O>[N:21]1([C:18]([C:15]2[NH:16][C:17]3[C:13]([CH:14]=2)=[CH:12][CH:11]=[CH:10][C:9]=3[NH:8][C:6]([C:2]2[S:1][CH:5]=[CH:4][CH:3]=2)=[O:7])=[O:20])[CH2:26][CH2:25][CH2:24][CH2:23][CH2:22]1
Reactant: C1CCNCC1
Reactant: O=C(O)c1cc2cccc(NC(=O)c3cccs3)c2[nH]1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: O=C(Nc1cccc2cc(C(=O)N3CCCCC3)[nH]c12)c1cccs1
Temperature: 25 °C
Reaction time: 48 h
Yield: 93 %

Procedure:
To a mixture of 7-[(2-thienylcarbonyl)amino]-1H-indole-2-carboxylic acid (100 mg), piperidine (42 μL), 1H-1,2,3-benzotriazol-1-ol (75 mg) and N,N-dimethylformamide (4 mL) was added N-[3-(dimethylamino)propyl]-N′-ethylcarbodiimide hydrochloride (94 mg) at 4° C., and the mixture was stirred at room temperature for 2 days. The reaction mixture was diluted with ethyl acetate, washed with aqueous sodium hydrogencarbonate solution, water and saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The obtained residue was subjected to silica gel column chromatography (ethyl acetate:hexane=1:9-6:4) and the obtained oil was recrystallized from diethyl ether to give the title compound (115 mg, yield 93%) as colorless prism crystals. melting point 131-132° C.
Reaction SMILES: [CH2:1]([C:5]1[N:9]2[CH:10]=[CH:11][CH:12]=[CH:13][C:8]2=[C:7]([C:14](=[O:19])C(F)(F)F)[N:6]=1)[CH2:2][CH2:3][CH3:4].[OH-:20].[K+]>CCO>[CH2:1]([C:5]1[N:9]2[CH:10]=[CH:11][CH:12]=[CH:13][C:8]2=[C:7]([C:14]([OH:19])=[O:20])[N:6]=1)[CH2:2][CH2:3][CH3:4]
Reactant: CCCCc1nc(C(=O)C(F)(F)F)c2ccccn12
Reactant: [OH-]
Agent: [K+]
Solvent: CCO
Product: CCCCc1nc(C(=O)O)c2ccccn12
Temperature: 25 °C
Reaction time: 15 h
Yield: 61.9 %

Procedure:
To a solution of 1-(3-butyl-imidazo[1,5-a]pyridin-1-yl)-2,2,2-trifluoro-ethanone (400 mg, 1.48 mmol) in EtOH (10 mL) was added KOH (830 mg, 14.8 mmol). The mixture was stirred at ambient temperature for 15 h. After this time the mixture was concentrated, diluted with water (10 mL) and acidified to pH 3 with 2N HCl. The aqueous mixture was extracted with ethyl acetate (3×50 mL) and the combined organic layers were dried over anhydrous sodium sulfate and concentrated in vacuo to yield the title compound (200 mg, 62%). 1H NMR (DMSO-d6) δ 12.1 (1H), 8.38 (1H), 7.99 (1H), 7.18 (1H), 6.90 (1H), 2.99 (2H), 1.75 (2H), 1.38 (2H), 0.92 (3H); m/z (M+H)=219.0.
Reaction SMILES: [F:1][C:2]([F:9])([F:8])[C:3]1[N:4]=[CH:5][NH:6][CH:7]=1.[CH2:10]=[O:11]>CC(C)=O>[F:1][C:2]([F:9])([F:8])[C:3]1[N:4]=[CH:5][N:6]([CH2:10][OH:11])[CH:7]=1
Reactant: FC(F)(F)c1c[nH]cn1
Reactant: C=O
Solvent: CC(C)=O
Product: OCn1cnc(C(F)(F)F)c1
Temperature: 140 °C
Reaction time: 4 h
Yield: 98.3 %

Procedure:
The mixture of 1.80 g of 4-(trifluoromethyl)-1H-imidazole, 0.78 g of paraformaldehyde was stirred at 140° C. for 4 hours. After the reaction mixture was cooled to room temperature, acetone was added. The mixture was filtered, and then the filtrate was concentrated under reduced pressure to obtain 2.16 g of 4-(trifluoromethyl)-1H-imidazole-1-ylmethanol.
Reaction SMILES: [Cl:1][C:2]([Cl:11])([Cl:10])[C:3]([C:5]1[NH:6][CH:7]=[CH:8][CH:9]=1)=[O:4].[Al+3].[Cl-].[Cl-].[Cl-].Cl[CH:17](Cl)[O:18]C>C(Cl)Cl.[N+](C)([O-])=O>[Cl:11][C:2]([Cl:1])([Cl:10])[C:3]([C:5]1[NH:6][CH:7]=[C:8]([CH:17]=[O:18])[CH:9]=1)=[O:4]
Reactant: O=C(c1ccc[nH]1)C(Cl)(Cl)Cl
Reactant: COC(Cl)Cl
Agent: [Al+3]
Agent: [Cl-]
Solvent: C[N+](=O)[O-]
Solvent: ClCCl
Product: O=Cc1c[nH]c(C(=O)C(Cl)(Cl)Cl)c1
Temperature: 0 °C
Reaction time: 2 h

Procedure:
To a solution of the compound obtained in Step A (87 mmoles) and AlCl3 in a DCM/nitromethane mixture (80 ml/80 ml) there is added, dropwise, at −30° C., dichloro-methoxy-methane (130.5 mmoles). After stirring for two hours, the reaction mixture is poured into 800 ml of ice-cold water. The aqueous phase is extracted with AcOEt, and then the organic phases are combined. The organic phase is washed with saturated aqueous NaCl solution, dried over sodium sulphate, filtered and evaporated to dryness to yield the title product (brown crystals), which is used directly in the next Step.
Reaction SMILES: [NH2:1][C:2]1[C:11]2[C:6](=[C:7](Br)[CH:8]=[CH:9][CH:10]=2)[N:5]=[N:4][C:3]=1[C:13]([NH:15][CH2:16][CH2:17][CH3:18])=[O:14].[CH3:19][O:20][C:21]1[CH:26]=[CH:25][C:24]([Cl:27])=[CH:23][C:22]=1B(O)O>>[NH2:1][C:2]1[C:11]2[C:6](=[C:7]([C:26]3[CH:25]=[C:24]([Cl:27])[CH:23]=[CH:22][C:21]=3[O:20][CH3:19])[CH:8]=[CH:9][CH:10]=2)[N:5]=[N:4][C:3]=1[C:13]([NH:15][CH2:16][CH2:17][CH3:18])=[O:14]
Reactant: CCCNC(=O)c1nnc2c(Br)cccc2c1N
Reactant: COc1ccc(Cl)cc1B(O)O
Product: CCCNC(=O)c1nnc2c(-c3cc(Cl)ccc3OC)cccc2c1N
Yield: 76.2 %

Procedure:
Using method A, 4-amino-8-bromo-N-propyl-cinnoline-3-carboxamide (150 mg, 0.485 mmol) and 2-methoxy-5-chloro-phenylboronic acid (186 mg, 1.000 mmol) were reacted to afford the title compound (137 mg, 77% yield) as a white solid. 1H NMR (300 MHz, CDCl3) δ 8.54 (br, 1H), 7.89 (m, 1H), 7.71 (m, 2H), 7.40-7.29 (m, 2H), 6.95 (m, 1H), 3.45 (apparent quartet, J=7.0 Hz, 2H), 1.65 (apparent sextet, J=7.0 Hz, 3H). MS APCI, m/z=371 (M+H). HPLC 2.00 min.
Reaction SMILES: C1(=O)[N:5]([CH:6]2[CH2:9][N:8]([CH:10]([C:17]([OH:19])=[O:18])[C:11]3[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=3)[C:7]2=[O:20])C(=O)C2=CC=CC=C12.CN(C)CCCN.CO>O>[NH2:5][CH:6]1[CH2:9][N:8]([CH:10]([C:17]([OH:19])=[O:18])[C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[C:7]1=[O:20]
Reactant: O=C(O)C(c1ccccc1)N1CC(N2C(=O)c3ccccc3C2=O)C1=O
Agent: CN(C)CCCN
Solvent: CO
Solvent: O
Product: NC1CN(C(C(=O)O)c2ccccc2)C1=O
Temperature: 25 °C
Reaction time: 18 h
Yield: 54.5 %

Procedure:
3-Phthalimido-1-(α-carboxybenzyl)-2-azetidinone (350 mg.) and N,N-dimethyl-1,3-propanediamine (310 mg.) were added to methanol (6 ml.), and the mixture was stirred at ambient temperature for 18 hours. Water (6 ml.) was poured into the reaction mixture under ice-cooling and then the mixture was adjusted to pH 5.8 to 6.0 with cation-exchange resin IRC-50 (Trade Mark, maker: Rohm & Haas Co.,) (20 ml.). The resin was removed by filtration and the filtrate was evaporated to dryness under reduced pressure. Acetonitrile was added to the residue (190 mg.) obtained and then the mixture was stirred under ice-cooling for 2.5 hours. The powder was collected by filtration to give 3-amino-1-(α-carboxybenzyl)-2-azetidinone (120 mg.).
Reaction SMILES: C([O:3][C:4]([C:6]1[NH:7][C:8]([CH:19]=O)=[C:9]([CH2:12][CH2:13][C:14]([O:16]CC)=[O:15])[C:10]=1[CH3:11])=[O:5])C.[CH3:21][C:22]1[CH:30]=[CH:29][CH:28]=[C:27]2[C:23]=1[CH2:24][C:25](=[O:31])[NH:26]2.[OH-].[K+]>N1CCCCC1.C(O)C>[C:14]([CH2:13][CH2:12][C:9]1[C:10]([CH3:11])=[C:6]([C:4]([OH:3])=[O:5])[NH:7][C:8]=1[CH:19]=[C:24]1[C:23]2[C:27](=[CH:28][CH:29]=[CH:30][C:22]=2[CH3:21])[NH:26][C:25]1=[O:31])([OH:16])=[O:15]
Reactant: CCOC(=O)CCc1c(C=O)[nH]c(C(=O)OCC)c1C
Reactant: Cc1cccc2c1CC(=O)N2
Agent: [K+]
Agent: [OH-]
Solvent: C1CCNCC1
Solvent: CCO
Product: Cc1cccc2c1C(=Cc1[nH]c(C(=O)O)c(C)c1CCC(=O)O)C(=O)N2
Temperature: 90 °C
Reaction time: 2 h
Yield: 95.2 %

Procedure:
A mixture of 5-formyl-4-(2-ethoxycarbonylethyl)-3-methyl-1H-pyrrole-2-carboxylic acid ethyl ester (281 mg), 4-methyl-2-oxindole (147 mg) and piperidine (2 drops) in ethanol (2 mL) was stirred at 90° C. for 2 hours. Potassium hydroxide (213 mg) was added, the temperature was increased to 95° C. and held there for 1 hour. The reaction mixture was cooled and concentrated. The residue was dissolved into water and acidified with 2 N hydrochloric acid to pH 2. The precipitate was filtered, washed with water and dried in a vacuum oven overnight to give 337 mg (95%) of 4-(2-carboxyethyl)-3-methyl-5-(4-methyl-2-oxo-1,2-dihydroindol-3-ylidenemethyl)-1H-pyrrole-2-carboxylic acid.
Reaction SMILES: F[B-](F)(F)F.F[B-](F)(F)F.ClC[N+]12CC[N+]([F:21])(CC1)CC2.[C:22]1([CH:29]=[CH:28][CH:27]=[C:25]([OH:26])[CH:24]=1)[OH:23]>C(#N)C.C(OCC)C>[F:21][C:27]1[CH:28]=[CH:29][C:22]([OH:23])=[CH:24][C:25]=1[OH:26]
Reactant: F[N+]12CC[N+](CCl)(CC1)CC2
Reactant: Oc1cccc(O)c1
Agent: F[B-](F)(F)F
Solvent: CC#N
Solvent: CCOCC
Product: Oc1ccc(F)c(O)c1
Temperature: 100 °C

Procedure:
[1-(Chloromethyl)-4-fluoro-1,4-diazoniabicyclo[2.2.2]octane bis(tetrafluoroborate)] (SELECTFLUOR) (1.61 g., 4.54 mmoles) in anhydrous acetonitrile (50 mL) was treated with resorcinol (0.500 g., 4.54 mmoles) and heated at 100° C. overnight. The reaction was diluted with diethyl ether, washed with H2O (2×), saturated NaHCO3 (2×), brine, dried (Na2SO4), filtered, and the filtrate concentrated under reduced pressure. MS (DCI) m/z 129 (M+H)+.
Reaction SMILES: O.[NH2:2][NH2:3].[C:4]([O:8][C:9](=[O:24])[NH:10][C:11]([C:17]1[CH:22]=[CH:21][CH:20]=[C:19]([Br:23])[CH:18]=1)([CH3:16])[C:12](=O)[C:13]#[CH:14])([CH3:7])([CH3:6])[CH3:5]>CCO>[C:4]([O:8][C:9](=[O:24])[NH:10][C:11]([C:17]1[CH:22]=[CH:21][CH:20]=[C:19]([Br:23])[CH:18]=1)([C:12]1[CH:13]=[CH:14][NH:3][N:2]=1)[CH3:16])([CH3:7])([CH3:6])[CH3:5]
Reactant: NN
Reactant: C#CC(=O)C(C)(NC(=O)OC(C)(C)C)c1cccc(Br)c1
Solvent: O
Solvent: CCO
Product: CC(C)(C)OC(=O)NC(C)(c1cccc(Br)c1)c1cc[nH]n1
Temperature: 25 °C
Reaction time: 1 h
Yield: 86.6 %

Procedure:
Hydrazine hydrate (2.48 mL, 51.10 mmol) was added to a solution of rac-[1-(3-bromo-phenyl)-1-methyl-2-oxo-but-3-ynyl]-carbamic acid tert-butyl ester (1.8 g, 5.11 mmol) in EtOH (30 mL) and the mixture was stirred at room temperature for 1 hour. The solvent was removed in vacuo and the residue was dissolved in DCM and washed with water. The organic layer was separated, dried (MgSO4), filtered and the solvents evaporated in vacuo. The crude product was purified by flash column chromatography (silica gel; AcOEt in DCM 0/100 to 50/50). The desired fractions were collected and concentrated in vacuo to yield rac-[1-(3-bromo-phenyl)-1-(1H-pyrazol-3-yl)-ethyl]-carbamic acid tert-butyl ester (1.62 g, 87% yield) as a white solid.
Reaction SMILES: Cl.[CH3:2][O:3][C:4]1[CH:5]=[C:6]2[C:27](=[CH:28][C:29]=1[O:30][CH3:31])[C:10]1([CH2:15][CH2:14][N:13]([CH2:16][CH2:17][C:18]3[CH:23]=[CH:22][C:21]([N+:24]([O-:26])=[O:25])=[CH:20][CH:19]=3)[CH2:12][CH2:11]1)[NH:9][CH2:8][C:7]2=[O:32].[N+:33]([C:36]1[CH:43]=[CH:42][C:39]([CH2:40]Br)=[CH:38][CH:37]=1)([O-:35])=[O:34]>C(O)C>[CH3:2][O:3][C:4]1[CH:5]=[C:6]2[C:27](=[CH:28][C:29]=1[O:30][CH3:31])[C:10]1([CH2:15][CH2:14][N:13]([CH2:16][CH2:17][C:18]3[CH:19]=[CH:20][C:21]([N+:24]([O-:26])=[O:25])=[CH:22][CH:23]=3)[CH2:12][CH2:11]1)[N:9]([CH2:40][C:39]1[CH:42]=[CH:43][C:36]([N+:33]([O-:35])=[O:34])=[CH:37][CH:38]=1)[CH2:8][C:7]2=[O:32]
Reactant: O=[N+]([O-])c1ccc(CBr)cc1
Reactant: COc1cc2c(cc1OC)C1(CCN(CCc3ccc([N+](=O)[O-])cc3)CC1)NCC2=O
Agent: Cl
Solvent: CCO
Product: COc1cc2c(cc1OC)C1(CCN(CCc3ccc([N+](=O)[O-])cc3)CC1)N(Cc1ccc([N+](=O)[O-])cc1)CC2=O

Procedure:
A mixture of 6,7-dimethoxy-1'-[2-(4-nitrophenyl)ethyl]-spiro[1,2,3,4-tetrahydro-isoquinoline- 1,4'-piperidin]-4-one hydrochloride (0.33 g) sodium bicarbonate (0.1 g) and p-nitrobenzylbromide (0.25 g) in ethanol were refluxed for 18 hours. The reaction was concentrated and chromotographed on silica (methylene chloride/methanol, 90:10) to give 60 mg upon concentration and crystallization of the dihydrochloride salt from isopropanol. mp 174°-177° C.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4](/[C:12](=[N:16]\[O:17][CH:18]2[CH2:22][CH2:21][CH2:20][CH2:19]2)/[C:13]([OH:15])=O)[CH:5]=[CH:6][C:7]=1[S:8]([CH3:11])(=[O:10])=[O:9].[NH2:23][C:24]1[CH:28]=[CH:27][N:26]([CH2:29][C:30]2[CH:31]=[C:32]([NH:36][C:37](=[O:39])[CH3:38])[CH:33]=[CH:34][CH:35]=2)[N:25]=1.C(N(CC)C(C)C)(C)C>C(Cl)Cl>[C:37]([NH:36][C:32]1[CH:31]=[C:30]([CH:35]=[CH:34][CH:33]=1)[CH2:29][N:26]1[CH:27]=[CH:28][C:24]([NH:23][C:13](=[O:15])/[C:12](/[C:4]2[CH:5]=[CH:6][C:7]([S:8]([CH3:11])(=[O:9])=[O:10])=[C:2]([Cl:1])[CH:3]=2)=[N:16]/[O:17][CH:18]2[CH2:22][CH2:21][CH2:20][CH2:19]2)=[N:25]1)(=[O:39])[CH3:38]
Reactant: CC(=O)Nc1cccc(Cn2ccc(N)n2)c1
Reactant: CS(=O)(=O)c1ccc(/C(=N\OC2CCCC2)C(=O)O)cc1Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CC(=O)Nc1cccc(Cn2ccc(NC(=O)/C(=N/OC3CCCC3)c3ccc(S(C)(=O)=O)c(Cl)c3)n2)c1
Yield: 41.4 %

Procedure:
(E)-(3-Chloro-4-methanesulfonyl-phenyl)-cyclopentyloxyimino-acetic acid (prepared as in Example 1, 100 mg, 0.29 mmol), N-[3-(3-amino-pyrazol-1-ylmethyl)-phenyl]-acetamide (67 mg, 0.29 mmol) and N,N-diisopropylethylamine (151 μL, 0.87 mmol) were combined in methylene chloride (1.5 mL) and cooled in an ice bath. O-(7-Azabenzotriazole-1-yl)-N,N,N′N′-tetramethyluronium hexafluorophosphate (110 mg, 0.29 mmol) was added and the ice bath was removed. The residue was treated with saturated aqueous sodium bicarbonate solution (1 mL) and extracted with chloroform (2×3 mL). The combined organic phases were dried over sodium sulfate and evaporated in vacuo. The residue was purified by flash column chromatography (Merck silica gel 60, 40-63 μm; 50% ethyl acetate/chloroform to 80% ethyl acetate/hexanes) to afford (E)-N-[1-(3-acetylamino-benzyl)-1H-pyrazol-3-yl]-2-(3-chloro-4-methanesulfonyl-phenyl)-2-cyclopentyloxyimino-acetamide (67 mg, 42%) as a white solid after lyophilization from aqueous acetonitrile: LC-MS (ESI) m/e calcd for C26H28ClN5O5S [M+] 557.15, found 558 [M+H+]; H1-NMR (400 MHz, CDCl3) δ ppm 1.63 (m, 4 H, 2×CH2), 1.84 (m, 4 H, 2×CH2), 2.16 (s, 3 H, CO2CH3), 3.29 (s, 3 H, SO2CH3), 4.86 (m, 1 H, OCH), 5.20 (s, 2H, NCH2), 6.75 (d, J=2.3 Hz, 1 H, Ar), 6.92 (brd, J=7.7 Hz, 1 H, Ar), 7.29 (brt, J=8.0 Hz, 1 H, Ar), 7.37 (m, 3 H, 2 Ar and NH), 7.43 (brd, J=7.9 Hz, 1 H, Ar), 7.54 (dd, Jo=8.2, Jm=1.5 Hz, 1 H, Ar), 7.64 (d, Jm=1.5 Hz, 1 H, Ar), 8.17 (d, Jo=8.2 Hz, 1 H, Ar), 9.20 (s, 1 H, NH).
Reaction SMILES: [CH3:1][NH:2][CH3:3].[OH:4][CH:5]([C:12]1[CH:17]=[C:16]([Cl:18])[CH:15]=[CH:14][C:13]=1[N:19]1[C:23]([CH2:24]Cl)=[N:22][C:21]([C:26]([NH2:28])=[O:27])=[N:20]1)[C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1.[I-].[Na+]>CO.CCOCC>[OH:4][CH:5]([C:12]1[CH:17]=[C:16]([Cl:18])[CH:15]=[CH:14][C:13]=1[N:19]1[C:23]([CH2:24][N:2]([CH3:3])[CH3:1])=[N:22][C:21]([C:26]([NH2:28])=[O:27])=[N:20]1)[C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1
Reactant: CNC
Reactant: NC(=O)c1nc(CCl)n(-c2ccc(Cl)cc2C(O)c2ccccc2)n1
Agent: [I-]
Agent: [Na+]
Solvent: CCOCC
Solvent: CO
Product: CN(C)Cc1nc(C(N)=O)nn1-c1ccc(Cl)cc1C(O)c1ccccc1

Procedure:
6.8 ml of 33% ethanolic dimethylamine solution is added to a solution of 5.6 g (about 0.015 mole) of 1-[2-(α-hydroxybenzyl)-4-chlorophenyl]-5-(chloromethyl)-1H-1,2,4-triazole-3-carboxamide and 0.225 g of sodium iodide in 80 ml of methanol, and the whole is refluxed for 5 hours with stirring. The reaction mixture is thereupon concentrated in vacuo. Water and saturated sodium carbonate solution are added to the residue until the pH-value has reached 10, and extraction is performed twice with ethyl acetate. The organic phase is washed with water, and is then extracted three times with 1 N hydrochloric acid solution. Sodium carbonate is added to the aqueous acidified extracts until the pH-value of 10 is obtained. The base that the precipitated is taken up in ether; the ether solution is washed twice with water and once with saturated sodium chloride solution; it is dried over sodium sulphate and concentrated in vacuo to yield amorphous 1-[2-(α-hydroxybenzyl)-4-chlorophenyl]-5-[(dimethylamino)-methyl] -1H-1,2,4-triazole-3-carboxamide. This is converted as follows into the crystalline hydrochloride: the crude base is dissolved in ethyl acetate, and ethereal hydrogen chloride solution is added until the pH-value is 4. The precipitated hydrochloride is filtered off with suction and washed with ethyl acetate and ether. After drying in vacuum, there is obtained 1-[2-(α-hydroxybenzyl)-4-chlorophenyl]-5-[(dimethylamino)-methyl]-1H-1,2,4-triazole-3-carboxamide-hydrochloride, m.p. 155°-157° (with decomposition).