Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([NH:8][C:9](=[O:26])[C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=2[NH:16][C:17]([N:19]2[CH2:24][CH2:23][C:22](=O)[CH2:21][CH2:20]2)=[O:18])=[N:6][CH:7]=1.[NH:27]1[CH2:31][CH2:30][CH2:29][CH2:28]1>>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([NH:8][C:9](=[O:26])[C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=2[NH:16][C:17]([N:19]2[CH2:24][CH2:23][CH:22]([N:27]3[CH2:31][CH2:30][CH2:29][CH2:28]3)[CH2:21][CH2:20]2)=[O:18])=[N:6][CH:7]=1
Reactant: C1CCNC1
Reactant: O=C1CCN(C(=O)Nc2ccccc2C(=O)Nc2ccc(Cl)cn2)CC1
Product: O=C(Nc1ccc(Cl)cn1)c1ccccc1NC(=O)N1CCC(N2CCCC2)CC1

Procedure:
Using a similar procedure to that described in Example 9-C, N-(5-chloropyridin-2-yl)-2-(4-oxopiperidin-1-ylcarbonyl)aminobenzamide (100 mg, 0.268 mmol) and pyrolidine (0.045 mL, 0.54 mmol) yielded the title compound.
Reaction SMILES: C(Cl)(Cl)Cl.C([O:12][C:13]1[CH:14]=[C:15]2[C:20](=[CH:21][CH:22]=1)[C:19]([F:23])=[C:18]([C:24]([O:26][C@@H:27]([C:32]([F:35])([F:34])[F:33])[CH2:28][CH2:29][CH2:30][CH3:31])=[O:25])[CH2:17][CH2:16]2)C1C=CC=CC=1.I[Si](C)(C)C>CO>[OH:12][C:13]1[CH:14]=[C:15]2[C:20](=[CH:21][CH:22]=1)[C:19]([F:23])=[C:18]([C:24]([O:26][C@@H:27]([C:32]([F:33])([F:34])[F:35])[CH2:28][CH2:29][CH2:30][CH3:31])=[O:25])[CH2:17][CH2:16]2
Reactant: CCCC[C@@H](OC(=O)C1=C(F)c2ccc(OCc3ccccc3)cc2CC1)C(F)(F)F
Agent: C[Si](C)(C)I
Solvent: ClC(Cl)Cl
Solvent: CO
Product: CCCC[C@@H](OC(=O)C1=C(F)c2ccc(O)cc2CC1)C(F)(F)F
Yield: 36.5 %

Procedure:
To 3.1 ml of a chloroform solution of 0.82 g (1.9 mmol) of the (R)1-trifluoromethylpentyl 6-benzyloxy-1-fluoro-3,4-dihydro-2-naphthalenecarboxylate obtained in the third step was dropwise added 134 μl (0.95 mmol) of iodotrimethylsilane, and they were reacted at room temperature for 30 minutes in a nitrogen atmosphere with stirring. Then, 10 ml of methanol was added to terminate the reaction. The reaction mixture was separated by column chromatography, to obtain 0.24 g of (R)1-trifluoromethylpentyl 6-hydroxy-1-fluoro-3,4-dihydro-2-naphthalenecarboxylate (yield: 37%). The 1H-NMR data of this compound are described below.
Reaction SMILES: F[C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[CH:4][CH:3]=1.Cl.Cl.[CH3:13][N:14]1[CH2:19][CH2:18][NH:17][CH2:16][C@H:15]1[CH2:20][OH:21].C(=O)([O-])[O-].[K+].[K+].CS(C)=O>C(OCC)(=O)C.O>[CH3:13][N:14]1[CH2:19][CH2:18][N:17]([C:2]2[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[CH:4][CH:3]=2)[CH2:16][C@H:15]1[CH2:20][OH:21]
Reactant: CN1CCNC[C@H]1CO
Reactant: O=[N+]([O-])c1ccc(F)cc1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CCOC(C)=O
Solvent: CS(C)=O
Product: CN1CCN(c2ccc([N+](=O)[O-])cc2)C[C@H]1CO
Temperature: 120 °C
Reaction time: 3 h

Procedure:
A mixture of 1-fluoro-4-nitrobenzene (418 μL), [(2S)-1-methylpiperazin-2-yl]methanol dihydrochloride (0.8 g), potassium carbonate (2.45 g), and dimethylsulfoxide (8 mL) was stirred at 120° C. for 3 hours. To the reactant were added water and ethyl acetate, followed by liquid separation. The organic phase was washed with saturated brine and dried over anhydrous magnesium sulfate, and then the solvent was evaporated under reduced pressure. The obtained residue was purified by silica gel column chromatography (NH2 type: eluent; ethyl acetate) to obtain [(2S)-1-methyl-4-(4-nitrophenyl)piperazin-2-yl]methanol (590 mg) as a yellow solid.
Reaction SMILES: CO[C:3]1[CH:14]=[CH:13][C:6]2[CH:7]=[CH:8][CH2:9][C:10](=[O:12])[NH:11][C:5]=2[CH:4]=1.[C:15](O)(=[O:17])C>[Pd]>[CH3:15][O:17][C:6]1[CH:13]=[CH:14][C:3]2[CH2:4][CH2:5][NH:11][C:10](=[O:12])[CH2:9][C:8]=2[CH:7]=1
Reactant: CC(=O)O
Reactant: COc1ccc2c(c1)NC(=O)CC=C2
Agent: [Pd]
Product: COc1ccc2c(c1)CC(=O)NCC2

Procedure:
56.8 gm (0.3 mol) of 8-methoxy-1,3-dihydro-2H-benzazepin-2-one (melting point: 190-191° C.), dissolved in 600 ml of glacial acetic acid, were hydrogenated in the presence of 5 gm of 10% palladium-on-charcoal at a temperature of 80° C. under a hydrogen pressure of 5 bar for 12 hours. After filtering off the catalyst, the solvent was removed in vacuo. The residue was mixed with water and neutralized with potassium carbonate. The precipitate was suction-filtered off, washed with water and dried.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([S:9]([N:12]([CH2:22][C:23]([OH:25])=[O:24])[C:13]2[CH:14]=[C:15]3[C:19](=[CH:20][CH:21]=2)[NH:18][CH2:17][CH2:16]3)(=[O:11])=[O:10])[CH:5]=[C:6]([Cl:8])[CH:7]=1.[C:26](OC(=O)C)(=[O:28])[CH3:27]>ClCCl>[C:26]([N:18]1[C:19]2[C:15](=[CH:14][C:13]([N:12]([CH2:22][C:23]([OH:25])=[O:24])[S:9]([C:4]3[CH:5]=[C:6]([Cl:8])[CH:7]=[C:2]([Cl:1])[CH:3]=3)(=[O:10])=[O:11])=[CH:21][CH:20]=2)[CH2:16][CH2:17]1)(=[O:28])[CH3:27]
Reactant: O=C(O)CN(c1ccc2c(c1)CCN2)S(=O)(=O)c1cc(Cl)cc(Cl)c1
Reactant: CC(=O)OC(C)=O
Solvent: ClCCl
Product: CC(=O)N1CCc2cc(N(CC(=O)O)S(=O)(=O)c3cc(Cl)cc(Cl)c3)ccc21
Temperature: 25 °C
Reaction time: 8 h

Procedure:
40 mg [(3,5-dichloro-phenylsulphonyl)-(2,3-dihydro-1H-indol-5-yl)-amino]-acetic acid are dissolved in 2 ml dichloromethane. 100 μl acetic anhydride are added and the mixture is stirred overnight at ambient temperature. The volatile constituents are eliminated in vacuo and the residue is purified by chromatography on silica gel with dichloromethane/methanol (99:1 to 85:15). The product thus obtained is extracted from diethyl ether/diisopropylether. The solid is suction filtered and dried in vacuo.
Reaction SMILES: [CH:1]1([N:4]([CH:18]2[CH2:23][CH2:22][NH:21][CH2:20][CH2:19]2)[S:5]([C:8]2[CH:13]=[CH:12][CH:11]=[C:10]([C:14]([F:17])([F:16])[F:15])[CH:9]=2)(=[O:7])=[O:6])[CH2:3][CH2:2]1.[F:24][C:25]1[CH:30]=[CH:29][C:28]([CH:31]([C:37]2[CH:42]=[CH:41][C:40]([F:43])=[CH:39][CH:38]=2)[CH2:32][CH2:33][C:34](O)=[O:35])=[CH:27][CH:26]=1>>[CH:1]1([N:4]([CH:18]2[CH2:23][CH2:22][N:21]([C:34](=[O:35])[CH2:33][CH2:32][CH:31]([C:37]3[CH:42]=[CH:41][C:40]([F:43])=[CH:39][CH:38]=3)[C:28]3[CH:29]=[CH:30][C:25]([F:24])=[CH:26][CH:27]=3)[CH2:20][CH2:19]2)[S:5]([C:8]2[CH:13]=[CH:12][CH:11]=[C:10]([C:14]([F:17])([F:15])[F:16])[CH:9]=2)(=[O:6])=[O:7])[CH2:3][CH2:2]1
Reactant: O=S(=O)(c1cccc(C(F)(F)F)c1)N(C1CCNCC1)C1CC1
Reactant: O=C(O)CCC(c1ccc(F)cc1)c1ccc(F)cc1
Product: O=C(CCC(c1ccc(F)cc1)c1ccc(F)cc1)N1CCC(N(C2CC2)S(=O)(=O)c2cccc(C(F)(F)F)c2)CC1

Procedure:
N-Cyclopropyl-N-{1-[4,4-bis(4-fluorophenyl)butanoyl]piperidin-4-yl}-3-trifluoromethylbenzenesulfonamide was prepared from N-cyclopropyl-N-(piperidin-4-yl)-3-trifluoromethylbenzenesulfonamide and 4,4-bis(4-fluorophenyl)butanoic acid. LC: 100%. MS: m/z=607 (M+H+). 1H NMR (CDCl3): δ 8.12 (1H, s), 8.04 (1H, d), 7.86 (1H, d), 7.69 (1H, t), 7.16 (4H, dd), 6.98 (4H, dd), 4.71 (1H, d), 3.98 (1H, d), 3.80 (1H, t), 3.68 (1H, d), 2.91 (1H, t), 2.50 (1H, t), 2.33 (2H, m), 2.21 (2H, m), 1.93 (1H, m), 1.75 (4H, m), 0.91 (4H, m);
Reaction SMILES: Cl[C:2]1[C:3](=[O:19])[N:4]([C:12]2[CH:17]=[CH:16][C:15]([Cl:18])=[CH:14][CH:13]=2)[C:5]2[C:10]([N:11]=1)=[CH:9][CH:8]=[CH:7][CH:6]=2.[C-:20]#[N:21].[K+].O>CN(C)C=O>[Cl:18][C:15]1[CH:16]=[CH:17][C:12]([N:4]2[C:5]3[C:10](=[CH:9][CH:8]=[CH:7][CH:6]=3)[N:11]=[C:2]([C:20]#[N:21])[C:3]2=[O:19])=[CH:13][CH:14]=1
Reactant: [C-]#N
Reactant: O=c1c(Cl)nc2ccccc2n1-c1ccc(Cl)cc1
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: N#Cc1nc2ccccc2n(-c2ccc(Cl)cc2)c1=O
Temperature: 140 °C
Yield: 65.1 %

Procedure:
A mixture of 3-chloro-1-(4-chlorophenyl)-1,2-dihydroquinoxalin-2-one (10.0 g) and potassium cyanide (2.5 g) in dry dimethylformamide (100 ml) was heated at 140° C. for 24 hours. The mixture was added to water and the product was extracted into chloroform. Evaporation of the solvent and crystallisation of the residue from ethanol gave the title compound (6.3 g) mp 232°-235° C.
Reaction SMILES: C(N(CC)CC)C.[NH:8]1[CH2:18][CH2:17][CH:11]([C:12]([O:14][CH2:15][CH3:16])=[O:13])[CH2:10][CH2:9]1.Cl[C:20]1[N:21]=[CH:22][C:23]2[CH:29]=[CH:28][CH2:27][N:26]([NH:30][CH2:31][C:32]3[CH:37]=[CH:36][C:35]4[O:38][CH2:39][O:40][C:34]=4[CH:33]=3)[C:24]=2[N:25]=1.O>O1CCCC1>[CH2:15]([O:14][C:12]([CH:11]1[CH2:10][CH2:9][N:8]([C:20]2[N:21]=[CH:22][C:23]3[CH:29]=[CH:28][CH2:27][N:26]([NH:30][CH2:31][C:32]4[CH:37]=[CH:36][C:35]5[O:38][CH2:39][O:40][C:34]=5[CH:33]=4)[C:24]=3[N:25]=2)[CH2:18][CH2:17]1)=[O:13])[CH3:16]
Reactant: Clc1ncc2c(n1)N(NCc1ccc3c(c1)OCO3)CC=C2
Reactant: CCOC(=O)C1CCNCC1
Solvent: O
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CCOC(=O)C1CCN(c2ncc3c(n2)N(NCc2ccc4c(c2)OCO4)CC=C3)CC1
Yield: 99.8 %

Procedure:
41 mg of triethylamine and 190 mg of ethyl isonipecotate were added to a solution of 127 mg of 2-chloro-8-(3,4-methylenedioxybenzyl)aminopyrido[2,3-d]pyrimidine in 8 ml of tetrahydrofuran. The obtained mixture was refluxed for 2 hours, followed by the addition of water. The resulting mixture was extracted with chloroform twice. The organic layers were combined, dried over magnesium sulfate, and distilled to remove the solvent. The residue was purified by silica gel chromatography (with ethyl acetate) to give 175 mg of the title compound (in a yield of 100%).
Reaction SMILES: [C-:1]#[N:2].[Na+].S(=O)(=O)(O)[OH:5].[N+:9]([C:12]1[CH:13]=[C:14]([CH:18]=[C:19]([C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[CH3:20])[CH:15]=[CH:16][CH:17]=1)([O-:11])=[O:10]>C(O)(=O)C.C(OCCCC)CCC>[CH:1]([NH:2][C:19]([C:21]1[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=1)([CH3:20])[CH2:18][C:14]1[CH:15]=[CH:16][CH:17]=[C:12]([N+:9]([O-:11])=[O:10])[CH:13]=1)=[O:5]
Reactant: CC(=Cc1cccc([N+](=O)[O-])c1)c1ccccc1
Reactant: O=S(=O)(O)O
Reactant: [C-]#N
Agent: [Na+]
Solvent: CCCCOCCCC
Solvent: CC(=O)O
Product: CC(Cc1cccc([N+](=O)[O-])c1)(NC=O)c1ccccc1
Reaction time: 48 h

Procedure:
To a suspension of sodium cyanide (34.3g, 0.7mol) in glacial acetic acid (500ml) and n-butylether (100ml) at 0° C. was added portionwise concentrated sulphuric acid (200ml). The ice bath was removed and a solution of 1-(3-nitrophenyl)-2-phenyl-1-propene (prepared from [(3-nitrophenyl)methylene]triphenylphosphorane and acetophenone, 0.5 mol) in n-butylether (100ml) was added dropwise over a period of 2 hours, then the mixture stirred for 48 hours. The mixture was poured into 1000 ml ice,and extracted with chloroform. The extracts were washed with water, dried and evaporated to a solid residue which was stirred with hexane (500 ml), filtered and dried to give N-formyl-1-(3-nitrophenyl)-2-phenyl-2-propylamine. This was treated with fumaric acid in ethyl acetate/isopropanol to give the title compound in 97% yield. Mp 234°-235° C.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH2:9][C:10]([CH3:15])([CH3:14])[C:11](O)=[O:12])[CH:6]=[CH:7][CH:8]=1.C(N(CC)CC)C.ClC(OC)=O.[N-:28]=[N+:29]=[N-:30].[Na+]>CC(C)=O.O>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH2:9][C:10]([CH3:15])([CH3:14])[C:11]([N:28]=[N+:29]=[N-:30])=[O:12])[CH:6]=[CH:7][CH:8]=1
Reactant: COc1cccc(CC(C)(C)C(=O)O)c1
Reactant: [N-]=[N+]=[N-]
Agent: COC(=O)Cl
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: CC(C)=O
Solvent: O
Product: COc1cccc(CC(C)(C)C(=O)N=[N+]=[N-])c1
Temperature: 0 °C
Reaction time: 1 h
Yield: 26.8 %

Procedure:
A mixture of 3-(3-methoxyphenyl)-2,2-dimethylpropanoic acid (200 mg, 0.96 mmol) in acetone (40 mL) and water (4 mL) was cooled to 0° C. Triethyl amine (0.18 mL, 1.3 mmol) was added to the reaction mixture followed by methyl chloroformate (118 mg, 1.25 mmol). The mixture was stirred for 1 hour at 0° C. and then another solution of sodium azide (94 mg, 1.45 mmol) in water (1 mL) was added dropwise. The reaction mixture was stirred at room temperature for another 1 hour. The mixture was diluted with water and extracted with ethyl acetate. The combined organic fractions were washed with water, dried over sodium sulfate and concentrated to give 3-(3-methoxyphenyl)-2,2-dimethylpropanoyl azide (60 mg) as a crude yellow oil, which was used without further purification.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[CH:6][N:5]=[C:4]2[N:8]([CH:12]([C:14]3[O:15][C:16]4[C:21]([C:22](=[O:30])[C:23]=3[C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=3)=[CH:20][CH:19]=[CH:18][CH:17]=4)[CH3:13])[N:9]=[C:10](I)[C:3]=12.[CH3:31][C:32]([OH:36])([C:34]#[CH:35])[CH3:33].ClCCl>C1COCC1.[Cu]I>[NH2:1][C:2]1[N:7]=[CH:6][N:5]=[C:4]2[N:8]([CH:12]([C:14]3[O:15][C:16]4[C:21]([C:22](=[O:30])[C:23]=3[C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=3)=[CH:20][CH:19]=[CH:18][CH:17]=4)[CH3:13])[N:9]=[C:10]([C:35]#[C:34][C:32]([OH:36])([CH3:33])[CH3:31])[C:3]=12
Reactant: C#CC(C)(C)O
Reactant: CC(c1oc2ccccc2c(=O)c1-c1ccccc1)n1nc(I)c2c(N)ncnc21
Agent: [Cu]I
Solvent: ClCCl
Solvent: C1CCOC1
Product: CC(c1oc2ccccc2c(=O)c1-c1ccccc1)n1nc(C#CC(C)(C)O)c2c(N)ncnc21
Yield: 68.1 %

Procedure:
To a solution of Example 57b (0.500 g, 0.981 mmoles) in THF (14 ml), 2-Methyl-3-butyn-2-ol (0.1 ml, 1.178 mmoles) diisopropylamine (0.70 ml, 4.90 mmoles), copper(I) iodide (18.6 mg, 0.098 mmoles) and) Tetrakistriphenylphosphine Palladium (0.113 g, 0.098 mmoles) were added and the system is degassed for 30 min. and heated to reflux for 4 h. The reaction mixture filtered through celite pad and washed with ethyl acetate. The filtrate was dried over sodium sulphate and concentrated under reduced pressure. The crude product was purified by column chromatography with methanol:dichloromethane to afford the title compound as brown solid (0.311 g, 68% yield). MP: 109-113° C. 1H-NMR (δ ppm, DMSO-d6, 400 MHz): δ 8.05(m,3H), 7.83(dt, J=8.6, 1.5Hz, 1H), 7.61(d, J=8.4Hz, 1H), 7.52(t, J=7.2Hz, 1H), 7.30-7.11(m, 4H), 5.84(q, J=7.1z, 1H)5.74(s,1H), 1.82(d, J=7.0Hz, 3H),1.46(s,6H). Mass: 466.09(M++1).
Reaction SMILES: Br[C:2]1[S:3][CH:4]=[CH:5][N:6]=1.[NH2:7][C:8]1[CH:9]=[C:10](C)[CH:11]=[C:12]([OH:14])[CH:13]=1.Cl.[CH3:17]CO>>[CH3:17][C:11]1[CH:10]=[CH:9][C:8]([NH:7][C:2]2[S:3][CH:4]=[CH:5][N:6]=2)=[CH:13][C:12]=1[OH:14]
Reactant: Brc1nccs1
Reactant: Cc1cc(N)cc(O)c1
Reactant: CCO
Agent: Cl
Product: Cc1ccc(Nc2nccs2)cc1O
Temperature: 90 °C
Reaction time: 24 h
Yield: 74 %

Procedure:
Following the general procedure for the synthesis of 2-R-5-(thiazol-2-ylamino)phenol, 2-bromothiazole (0.27 mL, 3.05 mmol), 5-amino-3-methylphenol (188 mg, 1.5 mmol) and 37% HCl solution (0.26 mL, 3.05 mmol) in 10% aqueous EtOH solution (5 mL) was stirred at 90° C. for 24 h. The title compound was obtained after purification by flash chromatography on silica gel (hexane:EtOAc 1/1) in 74% yield (233 mg).
Reaction SMILES: [CH:1]1([C:7]2[C:8]3[CH:9]=[CH:10][C:11]([C:28]([O:30][CH3:31])=[O:29])=[CH:12][C:13]=3[N:14]3[CH2:21][C:20](=O)[NH:19][CH2:18][C:17]4[CH:23]=[C:24]([F:27])[CH:25]=[CH:26][C:16]=4[C:15]=23)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.B.C1COCC1.Cl>C1COCC1.CO.CCOC(C)=O>[CH:1]1([C:7]2[C:8]3[CH:9]=[CH:10][C:11]([C:28]([O:30][CH3:31])=[O:29])=[CH:12][C:13]=3[N:14]3[CH2:21][CH2:20][NH:19][CH2:18][C:17]4[CH:23]=[C:24]([F:27])[CH:25]=[CH:26][C:16]=4[C:15]=23)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]1
Reactant: COC(=O)c1ccc2c(C3CCCCC3)c3n(c2c1)CC(=O)NCc1cc(F)ccc1-3
Agent: B
Agent: Cl
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Solvent: CO
Product: COC(=O)c1ccc2c(C3CCCCC3)c3n(c2c1)CCNCc1cc(F)ccc1-3
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of methyl 14-cyclohexyl-3-fluoro-7-oxo-5,6,7,8-tetrahydroindolo[2,1-a][2,5]benzodiazocine-11-carboxylate (from Step 4) in THF (0.02 M), BH3.THF (5 eq, 1 M solution in THF) was added and the solution stirred at RT for 2 h. MeOH (0.02 M) and a 1.25 M solution HCl in MeOH (0.24 M) were added carefully and left overnight to stir at RT before reducing the volume of the volatiles in vacuo and diluting with EtOAc. The organic phase was washed with aqueous NaHCO3 solution and brine, before being dried over Na2SO4, filtered and the solvent evaporated in vacuo to afford the title compound. The crude was used in the next step without further purification (quant); MS (ES+) m/z 407 (M+H)+.
Reaction SMILES: [CH3:1][N:2]1[CH:6]=[CH:5][N:4]=[C:3]1[CH:7]([NH:9][C:10]([C:12]1[C:20]2[C:15](=[N:16][CH:17]=[C:18]([C:21]3[C:29]4[C:24](=[CH:25][C:26]([Cl:30])=[CH:27][CH:28]=4)[N:23]([CH3:31])[N:22]=3)[N:19]=2)[N:14](COCC[Si](C)(C)C)[CH:13]=1)=[O:11])[CH3:8].C(Cl)Cl.C(N)CN>C(O)(C(F)(F)F)=O>[CH3:1][N:2]1[CH:6]=[CH:5][N:4]=[C:3]1[CH:7]([NH:9][C:10]([C:12]1[C:20]2[C:15](=[N:16][CH:17]=[C:18]([C:21]3[C:29]4[C:24](=[CH:25][C:26]([Cl:30])=[CH:27][CH:28]=4)[N:23]([CH3:31])[N:22]=3)[N:19]=2)[NH:14][CH:13]=1)=[O:11])[CH3:8]
Reactant: CC(NC(=O)c1cn(COCC[Si](C)(C)C)c2ncc(-c3nn(C)c4cc(Cl)ccc34)nc12)c1nccn1C
Solvent: NCCN
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CC(NC(=O)c1c[nH]c2ncc(-c3nn(C)c4cc(Cl)ccc34)nc12)c1nccn1C
Temperature: 25 °C
Reaction time: 8 h
Yield: 0 %

Procedure:
2-(6-Chloro-1-methyl-1H-indazol-3-yl)-5-(2-trimethylsilanyl-ethoxymethyl)-5H-pyrrolo[2,3-b]pyrazine-7-carboxylic acid [1-(1-methyl-1H-imidazol-2-yl)-ethyl]-amide (300 mg, 0.531 mol) was dissolved in a 4:6 solution of TFA:DCM (142 mL). After stirring at room temperature overnight, the volatiles were removed under reduced pressure. The crude material was then dissolved in dichloromethane and treated with ethylenediamine (319 mg, 5.31 mmol). After stirring at room temperature overnight, the precipitate was collected by filtration to afford 100 mg (43%) of 2-(6-chloro-1-methyl-1H-indazol-3-yl)-5H-pyrrolo[2,3-b]pyrazine-7-carboxylic acid [1-(1-methyl-1H-imidazol-2-yl)-ethyl]-amide as a yellow solid. MS: (M+H)+=435; 1H NMR (300 MHz, DMSO-d6) δ ppm 9.12 (s, 1H) 8.50-8.63 (m, 2H) 8.49-8.50 (m, 1H) 7.96 (d, J=1.51 Hz, 1H) 7.29 (dd, J=8.69, 1.51 Hz, 1H) 7.09 (s, 1H) 6.85 (s, 1H) 5.40-5.68 (m, 1H) 4.15 (s, 3H) 3.63-3.77 (m, 3H) 1.61 (d, J=6.80 Hz, 3H).
Reaction SMILES: [C:1]([OH:11])(=[O:10])[C@H:2]([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1)[OH:3].[CH2:12]([NH2:19])[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.CO>C(O)C>[C:1]([O-:11])(=[O:10])[C@H:2]([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1)[OH:3].[CH2:12]([NH3+:19])[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1
Reactant: NCc1ccccc1
Reactant: O=C(O)[C@@H](O)c1ccccc1
Solvent: CO
Solvent: CCO
Product: O=C([O-])[C@@H](O)c1ccccc1
Product: [NH3+]Cc1ccccc1

Procedure:
(S)-Mandelic acid (3.0 g; 22 mmol) was dissolved in ethanol (10 cm3) and added to a mixture of benzylamine (2.2 g; 20 mmol) and methanol (5 cm3). The white product was collected by filtration, recrystallized from water and dried in vacuo. Found: C, 69.2%; H, 6.6%; N, 5.4%. Calculated for C14H17NO3 : C, 69.47%; H, 6.62%; N, 5.40%. M.pt. 174°-175° C.
Reaction SMILES: [C:1]1([CH:6]=[CH:7][C:8](=[O:14])[CH2:9][C:10]([O:12][CH3:13])=[O:11])[CH2:5][CH2:4][CH2:3][CH:2]=1.[OH:15][C:16]1[CH:22]=[CH:21][C:19]([NH2:20])=[C:18]([CH3:23])[CH:17]=1.[CH2:24](OCC)C>C1C=CC=CC=1>[C:1]1([CH:6]=[CH:7][C:8](=[O:14])[C:9](=[CH:24][NH:20][C:19]2[CH:21]=[CH:22][C:16]([OH:15])=[CH:17][C:18]=2[CH3:23])[C:10]([O:12][CH3:13])=[O:11])[CH2:5][CH2:4][CH2:3][CH:2]=1
Reactant: Cc1cc(O)ccc1N
Reactant: CCOCC
Reactant: COC(=O)CC(=O)C=CC1=CCCC1
Solvent: c1ccccc1
Product: COC(=O)C(=CNc1ccc(O)cc1C)C(=O)C=CC1=CCCC1
Temperature: 25 °C

Procedure:
In 5 ml of benzene was dissolved 0.7 g of methyl 5-(cyclopenten-1-yl)-3-oxo-4-pentenoate, and 0.6 g of N,N-dimethylformamidodimethylacetal was added thereto. They were reacted at 70° C. for 1.5 hours. The reaction mixture was cooled to room temperature, and 0.44 g of 4-hydroxy-2-methylaniline was added thereto. The resulting mixture was subjected to reaction for addtional 1.5 hours. After completion of the reaction, 5 ml of diethyl ether was added, and the precipitated crystals were collected by filtration, and washed with 5 ml of diethyl ether to obtain 0.7 g of methyl 5-(cyclopenten-1-yl)-2-(4-hydroxy-2-methylphenylaminomethylene)-3-oxo-4-pentenoate having a melting point of 148°-151° C.
Reaction SMILES: O[CH2:2][C:3]1[CH:8]=[CH:7][C:6]([CH2:9][NH:10][C:11](=[O:13])[CH3:12])=[C:5]([N+:14]([O-:16])=[O:15])[CH:4]=1.C(N(CC)CC)C.CN(C1C=CC=CN=1)C.C1(C)C=CC(S([Cl:42])(=O)=O)=CC=1>ClCCl.O1CCCC1>[Cl:42][CH2:2][C:3]1[CH:8]=[CH:7][C:6]([CH2:9][NH:10][C:11](=[O:13])[CH3:12])=[C:5]([N+:14]([O-:16])=[O:15])[CH:4]=1
Reactant: CC(=O)NCc1ccc(CO)cc1[N+](=O)[O-]
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Agent: CN(C)c1ccccn1
Solvent: C1CCOC1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(=O)NCc1ccc(CCl)cc1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 3 h
Yield: 157.4 %

Procedure:
To a solution of N-(4-hydroxymethyl-2-nitrophenylmethyl)acetamide (9.1 g), triethylamine (6.2 ml) and dimethylaminopyridine (0.99 g) in dichloromethane (150 ml)-tetrahydrofuran (50 ml) was added p-toluenesulfonyl chloride (8.5 g) under ice-cooling. This mixture was stirred at room temperature for 3 hr. The reaction mixture was washed with water and saturated brine, and dried over anhydrous sodium sulfate. The solvent was evaporated to give a yellow oil (15.5 g). The obtained yellow oil was purified by silica gel column chromatography (developing solvent; chloroform:methanol=20:1) to give the title compound (12 g) as a pale-brown solid (7.8 g).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:12]([C:13]3[CH:18]=[CH:17][C:16]([Cl:19])=[CH:15][C:14]=3[Cl:20])[N:11]=[C:10]([C:21]([N:23]3[CH2:28][CH2:27][C:26]([C:32]4[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=4)([C:29](O)=[O:30])[CH2:25][CH2:24]3)=[O:22])[C:9]=2[CH3:38])=[CH:4][CH:3]=1.[Cl-].[NH4+].F[P-](F)(F)(F)(F)F.[N:48]1(O[P+](N(C)C)(N(C)C)N(C)C)C2C=CC=CC=2N=N1.C(N(CC)CC)C>O1CCCC1>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[N:12]([C:13]3[CH:18]=[CH:17][C:16]([Cl:19])=[CH:15][C:14]=3[Cl:20])[N:11]=[C:10]([C:21]([N:23]3[CH2:28][CH2:27][C:26]([C:32]4[CH:33]=[CH:34][CH:35]=[CH:36][CH:37]=4)([C:29]([NH2:48])=[O:30])[CH2:25][CH2:24]3)=[O:22])[C:9]=2[CH3:38])=[CH:6][CH:7]=1
Reactant: Cc1c(C(=O)N2CCC(C(=O)O)(c3ccccc3)CC2)nn(-c2ccc(Cl)cc2Cl)c1-c1ccc(Cl)cc1
Reactant: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Agent: F[P-](F)(F)(F)(F)F
Agent: [Cl-]
Agent: [NH4+]
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: Cc1c(C(=O)N2CCC(C(N)=O)(c3ccccc3)CC2)nn(-c2ccc(Cl)cc2Cl)c1-c1ccc(Cl)cc1
Yield: 44 %

Procedure:
1-{[5-(4-Chlorophenyl)-1-(2,4-dichlorophenyl)-4-methyl-1H-pyrazol-3-yl]carbonyl}-4-phenylpiperidine-4-carboxylic acid (1 eq., 12.7 mg, 0.024 mmol), ammonium chloride (10 eq., 12.7 mg, 0.24 mmol), benzotriazole-1-yl-oxytris(dimethylamino)phosphonium hexafluorophosphate (BOP) (1 eq, 10.5 mg, 0.024 mmol), and triethylamine (10.1 eq., 0.03 mL, 0.024 mmol) was stirred in tetrahydrofuran (5 mL) for 3 d. The reaction was concentrated in vacuo. The crude reaction material was then purified by silica gel column chromatography using 0-100% ethyl acetate/hexane to yield pure 1-{[5-(4-chlorophenyl)-1-(2,4-dichlorophenyl)-4-methyl-1H-pyrazol-3-yl]carbonyl}-4-phenylpiperidine-4-carboxamide (6 mg, 44%). 1H NMR (300 MHz, CHLOROFORM-d) d ppm 1.92-2.31 (m, 5H) 2.46 (d, J=13.94 Hz, 2H) 3.65 (t, J=10.36 Hz, 1H) 3.75-3.90 (m, 1H) 4.02 (d, J=13.38 Hz, 1H) 4.23 (d, J=13.00 Hz, 1H) 5.24 (br. s., 2H) 7.07 (d, J=8.38 Hz, 2H) 7.12-7.20 (m, 1H) 7.20-7.49 (m, 9H).
Reaction SMILES: [CH3:1][O:2][CH2:3][CH2:4][O:5][CH2:6][CH2:7][O:8][CH2:9]CO.ClC([O:15][CH:16]([Cl:18])[CH3:17])=O.ClC(OCCl)=[O:21]>>[C:9](=[O:21])([O:8][CH2:7][CH2:6][O:5][CH2:4][CH2:3][O:2][CH3:1])[O:15][CH:16]([Cl:18])[CH3:17]
Reactant: COCCOCCOCCO
Reactant: O=C(Cl)OCCl
Reactant: CC(Cl)OC(=O)Cl
Product: COCCOCCOC(=O)OC(C)Cl

Procedure:
This compound was prepared by following the procedure described in Preparation 1 but substituting diethylene glycol monomethylether for triethyleneglycol monomethylether and 1-chloroethyl chloroformate for chloromethyl chloroformate. Colourless oil, b.p.: 82-88° C. at 0.03 mbar.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH3:8])=[CH:4][C:3]=1[NH:9][C:10]([NH:12][C:13]1[CH:18]=[CH:17][C:16]([C:19]2[CH:24]=[CH:23][N:22]=[C:21]3[CH:25]=[C:26]([C:28]([O:30]C)=[O:29])[S:27][C:20]=23)=[CH:15][CH:14]=1)=[O:11].[OH-].[Na+].O.Cl>C1COCC1.CO>[F:1][C:2]1[CH:7]=[CH:6][C:5]([CH3:8])=[CH:4][C:3]=1[NH:9][C:10]([NH:12][C:13]1[CH:14]=[CH:15][C:16]([C:19]2[CH:24]=[CH:23][N:22]=[C:21]3[CH:25]=[C:26]([C:28]([OH:30])=[O:29])[S:27][C:20]=23)=[CH:17][CH:18]=1)=[O:11]
Reactant: COC(=O)c1cc2nccc(-c3ccc(NC(=O)Nc4cc(C)ccc4F)cc3)c2s1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Solvent: CO
Product: Cc1ccc(F)c(NC(=O)Nc2ccc(-c3ccnc4cc(C(=O)O)sc34)cc2)c1
Temperature: 70 °C

Procedure:
To a stirred solution of methyl 7-[4-({[(2-fluoro-5-methylphenyl)amino]carbonyl}amino)phenyl]thieno[3,2-b]pyridine-2-carboxylate (20 mg, 0.046 mmol) in THF/MeOH (5 ml/5 ml) was added 1M NaOH (2.0 ml, 2.0 mmol). The mixture was heated at 70° C. for 30 minutes, cooled to room temperature and poured into 50 ml of water. 1M HCl was added until pH=4 and the resulting precipitates were filtered, washed with water and dried in vacuo to give 7-[4-({[(2-fluoro-5-methylphenyl)amino]carbonyl}amino)phenyl]thieno[3,2-b]pyridine-2-carboxylic acid.