Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[CH:9][C:8]([OH:11])=[C:7]2[C:3]=1[CH:4]=[C:5]([C:13]([O:15][CH2:16][CH3:17])=[O:14])[N:6]2[CH3:12].F[C:19]1[CH:24]=[CH:23][C:22]([N+:25]([O-:27])=[O:26])=[CH:21][CH:20]=1.[H-].[Na+]>CN(C)C=O>[Cl:1][C:2]1[CH:10]=[CH:9][C:8]([O:11][C:19]2[CH:24]=[CH:23][C:22]([N+:25]([O-:27])=[O:26])=[CH:21][CH:20]=2)=[C:7]2[C:3]=1[CH:4]=[C:5]([C:13]([O:15][CH2:16][CH3:17])=[O:14])[N:6]2[CH3:12]
Reactant: O=[N+]([O-])c1ccc(F)cc1
Reactant: CCOC(=O)c1cc2c(Cl)ccc(O)c2n1C
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCOC(=O)c1cc2c(Cl)ccc(Oc3ccc([N+](=O)[O-])cc3)c2n1C
Temperature: 25 °C
Reaction time: 5 h
Yield: 84.7 %

Procedure:
A mixture of 1.00 g (3.94 mmol) of ethyl 4-chloro-7-hydroxy-1-methyl-2-indolecarboxylate, 0.56 g (3.94 mmol) of 1-fluoro-4-nitrobenzene, 0.16 g (3.94 mmol) of 60% sodium hydride and 30 ml of dimethylformamide was stirred at room temperature for 5 hours. The reaction mixture was poured onto ice water. The mixture was then extracted with ethyl acetate. After washing with water, the extract was dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure. The resulting residue was purified by silica gel column chromatography to give 1.25 g of ethyl 4-chloro-1-methyl-7-(4-nitrophenoxy)-2-indolecarboxylate.
Reaction SMILES: [CH3:1][N:2]1[CH2:7][CH2:6][N:5]([CH2:8][CH2:9][CH2:10][NH:11][C:12]2[CH:17]=[CH:16][C:15]([N+:18]([O-])=O)=[CH:14][CH:13]=2)[CH2:4][CH2:3]1.O.NN>C(O)C.[Ni].O>[CH3:1][N:2]1[CH2:3][CH2:4][N:5]([CH2:8][CH2:9][CH2:10][NH:11][C:12]2[CH:13]=[CH:14][C:15]([NH2:18])=[CH:16][CH:17]=2)[CH2:6][CH2:7]1
Reactant: CN1CCN(CCCNc2ccc([N+](=O)[O-])cc2)CC1
Agent: [Ni]
Agent: NN
Solvent: CCO
Solvent: O
Product: CN1CCN(CCCNc2ccc(N)cc2)CC1
Temperature: 50 °C

Procedure:
A suspension of 0.1385 gms. of [3-(4-methyl-piperazin-1-yl)-propyl]-(4-nitro-phenyl)-amine in 3 mL of ethanol is heated to 50° C. Once dissolution is achieved 0.144 mL hydrazine monohydrate is addded to the solution. A Raney nickel slurry in water is added to the 50° C. solution dropwise, waiting after each addition for the gas evolution to cease. Sufficient quantities of Raney nickel have been added when continued addition of Raney nickel causes no further gas evolution. The reaction is then maintained at 50° C. for an additional hour, and subsequently is cooled to room temperature. The reaction mixture is filtered through a pad of celite (rinsing the pad with methanol). N-[3-(4-Methyl-piperazin-1-yl)-propyl]-benzene-1,4-diamine (0.116 gms.) is isolated upon evaporation of the filtrate, and is subsequently used without purification in the reaction of Example 302.
Reaction SMILES: CN(C1C=CC(N[CH:11]2[CH:17]=[CH:16][C:14](=[O:15])[CH:13]=[CH:12]2)=CC=1)C.O=C1O[C@H:24]([C@H:26](CO)O)[C:22](O)=[C:20]1O.C1C(=NC2C=CC(N)=CC=2)C=C[C:32](=[O:33])C=1>C(O)C>[CH3:32][O:33][C:11]1[C:12]2[C:13](=[CH:20][CH:22]=[CH:24][CH:26]=2)[C:14]([OH:15])=[CH:16][CH:17]=1
Reactant: O=C1O[C@H]([C@@H](O)CO)C(O)=C1O
Reactant: CN(C)c1ccc(NC2C=CC(=O)C=C2)cc1
Reactant: Nc1ccc(N=C2C=CC(=O)C=C2)cc1
Solvent: CCO
Product: COc1ccc(O)c2ccccc12

Procedure:
The other developer was the leuco indoaniline dye ##STR23## prepared from the reduction of the dye with ascorbic acid in alcohol. 0.72 g of the indoaniline dye ##STR24## was dissolved in 36 ml of ethanol and 0.432 g of ascorbic acid was added. This solution was added to the polymer premix solution after the color change from blue to brown.
Reaction SMILES: [C:1]([CH2:3][NH:4][C:5]([C@@H:7]1[CH2:12][CH2:11][CH2:10][CH2:9][C@H:8]1[CH2:13][S:14]([C:17]1[CH:22]=[CH:21][C:20](F)=[CH:19][CH:18]=1)(=[O:16])=[O:15])=[O:6])#[N:2].C(=O)([O-])[O-].[K+].[K+].[SH:30][CH2:31][CH2:32][CH2:33][OH:34]>CN(C)C=O>[C:1]([CH2:3][NH:4][C:5]([C@@H:7]1[CH2:12][CH2:11][CH2:10][CH2:9][C@H:8]1[CH2:13][S:14]([C:17]1[CH:22]=[CH:21][C:20]([S:30][CH2:31][CH2:32][CH2:33][OH:34])=[CH:19][CH:18]=1)(=[O:16])=[O:15])=[O:6])#[N:2]
Reactant: N#CCNC(=O)[C@@H]1CCCC[C@H]1CS(=O)(=O)c1ccc(F)cc1
Reactant: OCCCS
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: N#CCNC(=O)[C@@H]1CCCC[C@H]1CS(=O)(=O)c1ccc(SCCCO)cc1
Temperature: 100 °C
Reaction time: 6 h

Procedure:
trans-N-Cyanomethyl-2-(4-fluorobenzenesulfonylmethyl)-cyclohexanecarboxamide (101 mg) and potassium carbonate (73 mg) were weighed into a 5 mL vial fitted with a stir bar and cap. Dimethylformamide (1 mL) and 3-mercapto-1-propanol (45 μL) were added. The vial was flushed with nitrogen and sealed with a cap. After stirring the reaction mixture at 100° C. for 6 h, the reaction mixture was allowed to cool to room temperature and stirred overnight. The reaction mixture was diluted with acetonitrile (4 mL) and filtered to remove solids. Concentration of the filtrate followed by chromatography of the crude residue on C-18 reverse-phase HPLC provided the desired product as a white solid. 1H NMR (DMSO-d6): δ=8.56 (1H, t), 7.68 (2H, m), 7.46 (2H, m), 4.05 (2H, d), 3.49 (2H, t), 3.14 (3H, m), 2.92 (1H, d), 2.2 (1H, m), 2.0 (2H, m), 1.8 (2H, m), 1.7 (3H, m), 1.3 (1H, m), 1.13 (3H, m). MS [ESI, (M−H)−] m/z=409.3 amu
Reaction SMILES: [OH:1][C:2]1[CH:11]=[CH:10][CH:9]=[CH:8][C:3]=1[C:4]([NH:6][CH3:7])=[O:5].[CH3:12][C:13]1([CH2:16]OC2C=CC=CC=2NC(=O)C2C=CC=CC=2)[CH2:15][O:14]1>>[CH3:7][NH:6][C:4](=[O:5])[C:3]1[CH:8]=[CH:9][CH:10]=[CH:11][C:2]=1[O:1][CH2:12][C:13]1([CH3:16])[CH2:15][O:14]1
Reactant: CNC(=O)c1ccccc1O
Reactant: CC1(COc2ccccc2NC(=O)c2ccccc2)CO1
Product: CNC(=O)c1ccccc1OCC1(C)CO1

Procedure:
N-Methyl-2-[(2-methyl-2-oxiranyl)methoxy]benzamide was prepared from 2-hydroxy-N-methylbenzamide (prepared according to Cohen et al, J. Am. Chem. Soc., 1998, 20, 6277-6286.) according to the method described for N-{2-[(2-methyl-2-oxiranyl)methoxy]phenyl}benzamide.
Reaction SMILES: Br[C:2]1[CH:3]=[N:4][C:5]([C:8]2[CH:9]=[N:10][C:11]([O:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH3:22])=[CH:12][CH:13]=2)=[N:6][CH:7]=1.[F:23][C:24]1[C:29]([F:30])=[C:28]([CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH3:38])[CH:27]=[CH:26][C:25]=1B(O)O.C(=O)([O-])[O-].[Na+].[Na+].C(O)C>C1(C)C=CC=CC=1.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.O>[F:23][C:24]1[C:29]([F:30])=[C:28]([CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH3:38])[CH:27]=[CH:26][C:25]=1[C:2]1[CH:3]=[N:4][C:5]([C:8]2[CH:9]=[N:10][C:11]([O:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH3:22])=[CH:12][CH:13]=2)=[N:6][CH:7]=1
Reactant: CCCCCCCCOc1ccc(-c2ncc(Br)cn2)cn1
Reactant: CCCCCCCCc1ccc(B(O)O)c(F)c1F
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: CCO
Solvent: O
Solvent: Cc1ccccc1
Product: CCCCCCCCOc1ccc(-c2ncc(-c3ccc(CCCCCCCC)c(F)c3F)cn2)cn1
Yield: 84.1 %

Procedure:
The reaction of 3.5 mmol of 5-bromo-2-(6-octyloxypyridin-3-yl)pyrimidine, 3.85 mmol of 2,3-difluoro-4-octylphenylboronic acid, 7 mmol of sodium carbonate and 0.04 mmol of tetrakis(triphenylphosphine)palladium(0) in 20 ml of toluene: 10 ml of ethanol and 10 ml of water it carried out analogously to the procedure indicated for Example 1a). The crude product is separated off by column chromatography on silica gel 60 using heptane/ethyl acetate 9:1 (v/v) as eluent and is recrystallized from acetonitrile, giving 1.5 g (83%) of colorless crystals, X 105 SC 104 SA 127 I.
Reaction SMILES: [C:1](N1C=CN=C1)(N1C=CN=C1)=O.[O:13]=[C:14]1[CH:16]([C:17]([OH:19])=[O:18])[CH2:15]1.[CH2:20](O)[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1>C(Cl)Cl>[O:13]=[C:14]1[CH2:15][CH:16]([C:17]([O:19][CH2:20][C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)=[O:18])[CH2:1]1
Reactant: O=C(O)C1CC1=O
Reactant: O=C(n1ccnc1)n1ccnc1
Reactant: OCc1ccccc1
Solvent: ClCCl
Product: O=C1CC(C(=O)OCc2ccccc2)C1
Temperature: 25 °C
Reaction time: 16 h
Yield: 66 %

Procedure:
Slowly add carbonyldiimidazole (42.6 g, 263 mmol) to a solution of 3-oxo-cyclopropane carboxylic acid (25.0 g, 219 mmol) in DCM (500 mL), stir at RT for 2 h, add benzyl alcohol (24.17 g, 223 mmol) and stir at RT for 16 h. Add water, extract with DCM (2×), wash the combined organics with brine, dry over Na2SO4, concentrate to dryness and purify by silica gel chromatography (EtOAc/Hex) to afford the title compound (29.5 g, 66%) as a colorless syrup. 1H NMR (400 MHz, DMSO-d6): δ 7.38-7.35 (m, 5H); 5.14 (s, 2H); 3.62 (m, 5H); MS (ESI) m/z: 227.1 (M+Na−).
Reaction SMILES: [O:1]1[CH2:6][CH2:5][C:4](=[N:7][OH:8])[CH2:3][CH2:2]1.C([O-])(=O)C.C([O-])(=O)C.C([O-])(=O)C.C([O-])(=O)C.[Pb+4].[CH3:26][C:27]([CH3:32])([CH3:31])[C:28]([OH:30])=[O:29]>>[C:28]([O:30][C:4]1([N:7]=[O:8])[CH2:5][CH2:6][O:1][CH2:2][CH2:3]1)(=[O:29])[C:27]([CH3:32])([CH3:31])[CH3:26]
Reactant: ON=C1CCOCC1
Reactant: CC(C)(C)C(=O)O
Agent: CC(=O)[O-]
Agent: [Pb+4]
Product: CC(C)(C)C(=O)OC1(N=O)CCOCC1

Procedure:
4-Nitrosotetrahydro-2H-pyran-4-yl pivalate was prepared from tetrahydro-pyran-4-one oxime, lead tetraacetate and trimethylacetic acid using conditions of General Method 3. 1H NMR (360 MHz, chloroform-d) δ 3.91-4.14 (2H, m), 3.57-3.77 (2H, m), 2.10-2.29 (2H, m), 1.75-1.93 (2H, m), 1.34 (9H, s).
Reaction SMILES: [C:1]([NH:6][C:7]1[CH:12]=[C:11]([O:13][C:14]2[CH:19]=[CH:18][C:17]([NH:20][C:21](=[O:29])OC3C=CC=CC=3)=[CH:16][CH:15]=2)[CH:10]=[CH:9][N:8]=1)(=[O:5])[CH2:2][CH2:3][CH3:4].[CH:30]1([NH2:33])[CH2:32][CH2:31]1.C(N(CC)CC)C>O1CCCC1>[C:1]([NH:6][C:7]1[CH:12]=[C:11]([O:13][C:14]2[CH:15]=[CH:16][C:17]([NH:20][C:21]([NH:33][CH:30]3[CH2:32][CH2:31]3)=[O:29])=[CH:18][CH:19]=2)[CH:10]=[CH:9][N:8]=1)(=[O:5])[CH2:2][CH2:3][CH3:4]
Reactant: CCCC(=O)Nc1cc(Oc2ccc(NC(=O)Oc3ccccc3)cc2)ccn1
Reactant: NC1CC1
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CCCC(=O)Nc1cc(Oc2ccc(NC(=O)NC3CC3)cc2)ccn1

Procedure:
Phenyl N-{4-[2-(butyroylamino)pyridin-4-yl]oxyphenyl}carbamate (0.116 g), cyclopropylamine (0.034 g), triethylamine (0.041 ml) and tetrahydrofuran (10 ml) were heated together in a sealed tube at 100° C. for 1 hour. NH type silica gel was added to the reaction solution, the solvent was distilled off under reduced pressure and the reaction product was adsorbed onto the silica gel. The silica gel was charged into a dry column packed with NH type silica gel, and column purification was performed (ethyl acetate). The solvent was distilled off under reduced pressure, ethyl acetate and hexane were added to the residue, and the precipitated solid was filtered out to obtain 20 mg of the target substance as a white solid.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][CH:6]=[C:5]2[CH2:11][C:12](O)=[O:13].[H-].[H-].[H-].[H-].[Li+].[Al+3]>C1COCC1>[F:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][CH:6]=[C:5]2[CH2:11][CH2:12][OH:13]
Reactant: O=C(O)Cc1c[nH]c2ccc(F)cc12
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Product: OCCc1c[nH]c2ccc(F)cc12
Reaction time: 0.5 h
Yield: 102.5 %

Procedure:
To a solution of 5-fluoro-indol-3-acetic acid (4.3 g, 0.022 mol) in anhydrous THF (35 ml) was added LiAlH4(1.0M, 33 ml, 0.033 mol) at 0° C. The mixture was allowed to stir for 0.5 hours and, then quenched by saturated NH4Cl solution. The mixture was then filtered through celite. The filtrate was washed with IN NaOH (3×100 ml) and extracted with ethyl acetate (3×100 ml). The organic layer was dried over anhydrous sodium sulfate, filtered, and the solvent was removed under vacuum. Chromatography (10% methanol-methylene chloride) afforded 4.04 g (100%) of product as an off-white solid: mp 59-61° C.
Reaction SMILES: [Cr](Cl)([O-])(=O)=O.[NH+]1C=CC=CC=1.[C:12]([C:14]([N:19]1[C:23](=[O:24])[CH:22]=[C:21]([NH:25][C:26]2[CH:31]=[C:30]([Cl:32])[CH:29]=[CH:28][C:27]=2[CH2:33][OH:34])[C:20]1=[O:35])([CH3:18])[CH:15]([CH3:17])[CH3:16])#[N:13]>C(Cl)Cl.CCOCC>[C:12]([C:14]([N:19]1[C:23](=[O:24])[CH:22]=[C:21]([NH:25][C:26]2[CH:31]=[C:30]([Cl:32])[CH:29]=[CH:28][C:27]=2[CH:33]=[O:34])[C:20]1=[O:35])([CH3:18])[CH:15]([CH3:16])[CH3:17])#[N:13]
Reactant: CC(C)C(C)(C#N)N1C(=O)C=C(Nc2cc(Cl)ccc2CO)C1=O
Agent: O=[Cr](=O)([O-])Cl
Agent: c1cc[nH+]cc1
Solvent: ClCCl
Solvent: CCOCC
Product: CC(C)C(C)(C#N)N1C(=O)C=C(Nc2cc(Cl)ccc2C=O)C1=O
Yield: 91.7 %

Procedure:
Pyridinium chlorochromate (4.4 g, 0.0204 mol) in methylene dichloride (20 ml) is added rapidly to a methylene chloride (20 ml) solution of N-(1-cyano-1,2-dimethylpropyl)-2-(5-chloro-2-hydroxymethylanilino)maleimide (4.75 g, 0.0136 mol). After 2 hours the dark reaction mixture is diluted with ether (20 ml) and a yellow precipitate is formed and is filtered off. This solid is redissolved in ethyl acetate:methylene chloride (1:1) and is passed through a silica gel column to give a yellow solid 4.31 g, (92%) with mp 80° C. (dec.).
Reaction SMILES: [NH2:1][C@@H:2]1[CH2:7][CH2:6][CH2:5][CH2:4][C@H:3]1[OH:8].[CH3:9][C:10]1([CH3:49])[CH2:14][CH2:13][CH2:12][N:11]1[CH2:15][CH2:16][NH:17][C:18]([C:20]1[CH:21]=[CH:22][C:23]([F:48])=[C:24]([NH:26][C:27]([C:29]2[N:33]3[CH:34]=[CH:35][C:36]([C:38]4[CH:46]=[CH:45][C:41]([C:42](O)=[O:43])=[C:40]([F:47])[CH:39]=4)=[CH:37][C:32]3=[N:31][CH:30]=2)=[O:28])[CH:25]=1)=[O:19]>>[CH3:9][C:10]1([CH3:49])[CH2:14][CH2:13][CH2:12][N:11]1[CH2:15][CH2:16][NH:17][C:18]([C:20]1[CH:21]=[CH:22][C:23]([F:48])=[C:24]([NH:26][C:27]([C:29]2[N:33]3[CH:34]=[CH:35][C:36]([C:38]4[CH:46]=[CH:45][C:41]([C:42](=[O:43])[NH:1][C@@H:2]5[CH2:7][CH2:6][CH2:5][CH2:4][C@H:3]5[OH:8])=[C:40]([F:47])[CH:39]=4)=[CH:37][C:32]3=[N:31][CH:30]=2)=[O:28])[CH:25]=1)=[O:19]
Reactant: N[C@@H]1CCCC[C@H]1O
Reactant: CC1(C)CCCN1CCNC(=O)c1ccc(F)c(NC(=O)c2cnc3cc(-c4ccc(C(=O)O)c(F)c4)ccn23)c1
Product: CC1(C)CCCN1CCNC(=O)c1ccc(F)c(NC(=O)c2cnc3cc(-c4ccc(C(=O)N[C@@H]5CCCC[C@H]5O)c(F)c4)ccn23)c1

Procedure:
The title compound was prepared from (1R,2R)-2-aminocyclohexanol and 4-(3-(5-(2-(2,2-dimethylpyrrolidin-1-yl)ethylcarbamoyl)-2-fluorophenylcarbamoyl)imidazo[1,2-a]pyridin-7-yl)-2-fluorobenzoic acid (step 3) analogously to Example 7.3 step 2;
Reaction SMILES: [C:1](=[O:4])([O-])[O-].[K+].[K+].O=[C:8]1[CH2:12][N:11]([C:13]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14])[C@H:10]([C:20]([O:22][CH3:23])=[O:21])[CH2:9]1.[N+](=[C:26](P(=O)(OC)OC)C(=O)C)=[N-]>CO>[CH3:26][O:4]/[CH:1]=[C:8]1\[CH2:9][C@@H:10]([C:20]([O:22][CH3:23])=[O:21])[N:11]([C:13]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14])[CH2:12]\1
Reactant: O=C([O-])[O-]
Reactant: COP(=O)(OC)C(=[N+]=[N-])C(C)=O
Reactant: COC(=O)[C@@H]1CC(=O)CN1C(=O)OC(C)(C)C
Agent: [K+]
Solvent: CO
Product: CO/C=C1\C[C@@H](C(=O)OC)N(C(=O)OC(C)(C)C)C1
Temperature: 25 °C
Reaction time: 8 h
Yield: 3057.4 %

Procedure:
Potassium carbonate (200 g, 2.17 mmol) was added to a solution of (S)-1-tert-butyl 2-methyl 4-oxopyrrolidine-1,2-dicarboxylate (88 g, 362 mmol) and dimethyl 1-diazo-2-oxopropylphosphonate (200 g, 1.04 mol) in methanol (1 L) at 0° C. and the reaction mixture was stirred at RT overnight, quenched, concentrated, poured into water, extracted with DCM, and purified by column chromatography to provide the title intermediate (18 g, 17% yield) as a yellow oil. 1H NMR (400 MHz, CDCl3): δ(ppm) 1.406-1.457 (d, 9H, J=20.4 Hz), 2.502-2.520 (m, 1H), 2.601-2.631 (m, 1H), 2.720-2.782 (m, 1H), 3.578 (s, 3H), 3.707 (s, 3H), 3.952-3.983 (m, 1H), 4.302-4.375 (m, 1H), 4.471-4.490 (m, 1H), 5.810-5.968 (m, 1H).
Reaction SMILES: [CH3:1][CH:2]1[CH2:7][NH:6][CH2:5][CH2:4][NH:3]1.[F:8][C:9]1[CH:16]=[CH:15][C:12]([CH2:13]Br)=[CH:11][CH:10]=1>C(Cl)Cl>[F:8][C:9]1[CH:16]=[CH:15][C:12]([CH2:13][N:6]2[CH2:5][CH2:4][NH:3][CH:2]([CH3:1])[CH2:7]2)=[CH:11][CH:10]=1
Reactant: CC1CNCCN1
Reactant: Fc1ccc(CBr)cc1
Solvent: ClCCl
Product: CC1CN(Cc2ccc(F)cc2)CCN1
Reaction time: 15 h
Yield: 12 %

Procedure:
To a solution of 2-methylpiperazine (0.10 g, 1 mmol) in CH2Cl2 (2 mL) was added 4-fluorobenzyl bromide (0.125 mL, 1 mmol). The resultant mixture was stirred at ambient temperature. After 15 hours, the mixture was concentrated in vacuo to afford a solid. This solid was dissolved in CH2Cl2 and washed sequentially with water, aqueous NaHCO3 solution, then brine. The organic layer was dried over MgSO4, filtered, and concentrated to an oil. Purification by flash column chromatography afforded 0.025 g (12% yield) of 1-(4-fluorobenzyl)-3-methylpiperazine, a compound of formula (C), as a colorless oil; NMR (CDCl3) 7.3 (m, 2), 7.0 (m, 2), 3.4 (s, 2), 3.0-2.6 (m, 5), 2.0 (br s, 2), 1.6 (t, 1), 1.0 (d, 3) ppm.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:10]=[CH:11][C:12]=1[F:13])[O:5][CH2:6][C:7]([OH:9])=[O:8].O[C:15]([CH3:29])([CH3:28])[C:16]([C:18]1[CH:23]=[CH:22][C:21]([S:24]([CH3:27])(=[O:26])=[O:25])=[CH:20][CH:19]=1)=O.C1CCN2C(=NCCC2)CC1>CN(C1C=CN=CC=1)C.ClCCl>[F:1][C:2]1[CH:3]=[C:4]([CH:10]=[CH:11][C:12]=1[F:13])[O:5][C:6]1[C:7](=[O:9])[O:8][C:15]([CH3:29])([CH3:28])[C:16]=1[C:18]1[CH:19]=[CH:20][C:21]([S:24]([CH3:27])(=[O:26])=[O:25])=[CH:22][CH:23]=1
Reactant: CC(C)(O)C(=O)c1ccc(S(C)(=O)=O)cc1
Reactant: O=C(O)COc1ccc(F)c(F)c1
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Solvent: C1CCC2=NCCCN2CC1
Product: CC1(C)OC(=O)C(Oc2ccc(F)c(F)c2)=C1c1ccc(S(C)(=O)=O)cc1
Temperature: 25 °C

Procedure:
A solution of 3,4-difluorophenoxyacetic acid (0.51 g, 2.73 mmol), 2-hydroxy-2-methyl-1-(4-(methylsulfonyl)phenyl)propan-1-one (0.5g, 2.1 mmol, Step 3), CMC (1.13 g, 2.73 mmol) and DMAP (15 mg, 0.10 mmol) in dichloromethane (12 ml) was stirred at r.t. for 18 hrs. Then, DBU (0.63 ml, 4.2 mmol) was added and the reaction mixture was refluxed for 3 h. After cooling to r.t. the mixture was extracted with ethyl acetate and washed successively with water, 1 N HCl and brine. The organic layer was dried over MgSO4, filtered and the solvent evaporated under vacuum. The residue was triturated in a mixture of ethyl acetate and hexane affording the title compound as a solid. M.P.: 93-95 ° C.
Reaction SMILES: Cl[CH2:2][C:3]1[S:7][C:6]2[CH:8]=[CH:9][C:10]([N+:12]([O-:14])=[O:13])=[CH:11][C:5]=2[CH:4]=1.[CH3:15][NH:16][CH2:17][CH2:18][C:19]1[CH:24]=[CH:23][C:22]([N+:25]([O-:27])=[O:26])=[CH:21][CH:20]=1.C(=O)([O-])[O-].[K+].[K+]>C(#N)C>[CH3:15][N:16]([CH2:17][CH2:18][C:19]1[CH:24]=[CH:23][C:22]([N+:25]([O-:27])=[O:26])=[CH:21][CH:20]=1)[CH2:2][C:3]1[S:7][C:6]2[CH:8]=[CH:9][C:10]([N+:12]([O-:14])=[O:13])=[CH:11][C:5]=2[CH:4]=1
Reactant: O=[N+]([O-])c1ccc2sc(CCl)cc2c1
Reactant: CNCCc1ccc([N+](=O)[O-])cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: CN(CCc1ccc([N+](=O)[O-])cc1)Cc1cc2cc([N+](=O)[O-])ccc2s1
Reaction time: 20 h

Procedure:
A mixture of the product of part (A) above (3.20 g), N-methyl-4-nitrophenethylamine (2.52 g), anhydrous potassium carbonate (4.0 g) and acetonitrile (40 ml) was heated under reflux with stirring for 20 hours and then cooled and filtered. The residue was washed with acetonitrile, and the combined filtrate and washings were evaporated to give an oil which was chromatographed on silica gel. Elution with dichloromethane first gave impurity followed by pure product. The product-containing fractions were evaporated to give the title compound (4.17 g), m.p. 76°-78° (from isopropanol).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH2:11][CH:10]([CH2:14][CH2:15][CH2:16]Br)[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[I-].[Na+].[F:20][C:21]1[CH:28]=[CH:27][C:26]([Br:29])=[CH:25][C:22]=1[CH2:23][OH:24].[H-].[Na+]>CN(C)C=O>[F:20][C:21]1[CH:28]=[CH:27][C:26]([Br:29])=[CH:25][C:22]=1[CH2:23][O:24][CH2:16][CH2:15][CH2:14][CH:10]1[CH2:11][CH2:12][CH2:13][N:8]([C:6]([O:5][C:1]([CH3:2])([CH3:3])[CH3:4])=[O:7])[CH2:9]1
Reactant: CC(C)(C)OC(=O)N1CCCC(CCCBr)C1
Reactant: OCc1cc(Br)ccc1F
Agent: [H-]
Agent: [I-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N1CCCC(CCCOCc2cc(Br)ccc2F)C1

Procedure:
An amount of 3-[1-(t-butoxycarbonyl)piperidin-3-yl]propyl bromide (180 mg, 0.588 mmol) was dissolved in N,N-dimethylformamide (1.5 ml) in a 10 ml flask under a nitrogen atmosphere. Sodium iodide (176 mg, 1.18 mmol) was added at ambient temperature, and the resulting mixture was stirred for ten minutes. The reaction mixture was treated with 2-fluoro-5-bromobenzyl alcohol (121 mg, 0.588 mmol), delivered as a solution in 0.5 ml of N,N-dimethylformamide. To this mixture was then added sodium hydride (60%, 35 mg, 0.882 mmol) and the resulting mixture was stirred at ambient temperature for three hours. The progress of the reaction was monitored by thin layer chromatography. The reaction mixture was partitioned between 1 M potassium carbonate and methylene chloride. The aqueous fraction was back extracted with methylene chloride. The organic fractions were combined, and dried over sodium sulfate. The solvents were removed in vacuo. The desired title product was further purified by liquid chromatography.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:10]3([CH2:14][CH2:13][NH:12][CH2:11]3)[CH2:9][N:8]([C:15]([NH:17][C:18]3[S:19][C:20]([Cl:23])=[CH:21][N:22]=3)=[O:16])[C:5]2=[CH:6][CH:7]=1.[CH:24](O)=[O:25].Cl.C(N=C=NCCCN(C)C)C>CN(C=O)C.O>[Br:1][C:2]1[CH:3]=[C:4]2[C:10]3([CH2:14][CH2:13][N:12]([CH:24]=[O:25])[CH2:11]3)[CH2:9][N:8]([C:15]([NH:17][C:18]3[S:19][C:20]([Cl:23])=[CH:21][N:22]=3)=[O:16])[C:5]2=[CH:6][CH:7]=1
Reactant: O=C(Nc1ncc(Cl)s1)N1CC2(CCNC2)c2cc(Br)ccc21
Reactant: O=CO
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: O
Solvent: CN(C)C=O
Product: O=CN1CCC2(C1)CN(C(=O)Nc1ncc(Cl)s1)c1ccc(Br)cc12
Reaction time: 18 h
Yield: 54.3 %

Procedure:
The 5-bromo-N-(5-chlorothiazol-2-yl)spiro[indoline-3,3′-pyrrolidine]-1-carboxamide (160 mg, 0.387 mmol) obtained in Example 2 was dissolved in N,N′-dimethylformamide (4.0 mL). Thereafter, formic acid (22.0 μL, 0.581 mmol) and 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (148 mg, 0.774 mmol) were added to the above obtained solution, and the thus obtained mixture was then stirred for 18 hours. Thereafter, the reaction solution was diluted with water, and was then extracted with ethyl acetate. The organic layer was washed with brine, and was then dried over anhydrous sodium sulfate, followed by concentration in vacuo. The obtained residue was purified by silica gel column chromatography (chloroform:methanol=20:1) to obtain the captioned compound (92.8 mg, 54%) in the form of a white solid.
Reaction SMILES: [Cl-].[Mg+2].[Cl-].[C:4]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])(=[O:9])[CH2:5][C:6]([CH3:8])=[O:7].[CH2:15]([C:17]1[CH:22]=[CH:21][C:20]([CH2:23][C:24](Cl)=[O:25])=[CH:19][CH:18]=1)[CH3:16].C(O)(=O)CC(CC(O)=O)(C(O)=O)O>ClCCl.N1C=CC=CC=1>[C:6]([CH:5]([C:24](=[O:25])[CH2:23][C:20]1[CH:21]=[CH:22][C:17]([CH2:15][CH3:16])=[CH:18][CH:19]=1)[C:4]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9])(=[O:7])[CH3:8]
Reactant: CC(=O)CC(=O)OC(C)(C)C
Reactant: CCc1ccc(CC(=O)Cl)cc1
Agent: O=C(O)CC(O)(CC(=O)O)C(=O)O
Agent: [Cl-]
Agent: [Mg+2]
Solvent: ClCCl
Solvent: c1ccncc1
Product: CCc1ccc(CC(=O)C(C(C)=O)C(=O)OC(C)(C)C)cc1
Temperature: 0 °C
Reaction time: 2.5 h

Procedure:
A suspension of magnesium chloride (1.74 g) in dichloromethane (30 ml) was cooled to 0° C., and thereto were added t-butyl acetoacetate (3.03 ml) and pyridine (2.96 ml), and successively was added a solution of the above 4-ethylphenylacetyl chloride in dichloromethane (30 ml). The mixture was stirred at the same temperature for 2.5 hours, and an aqueous citric acid solution was added thereto. The mixture was extracted with chloroform. The extract was washed with brine, and dried over sodium sulfate. The solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (hexane:ethyl acetate=15:1) to give t-butyl 2-acetyl-4-(4-ethylphenyl)-3-oxobutyrate (4.75 g) as pale yellow oil. APCI-Mass m/Z 322 (M+NH4).