Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][CH2:2][C:3]([NH:12][C:13](=[O:19])[O:14][C:15]([CH3:18])([CH3:17])[CH3:16])([CH2:8][CH2:9][O:10][CH3:11])[CH2:4][CH2:5][O:6][CH3:7].C(=O)([O-])O.[Na+].[C:25](=O)([O:41]N1C(=O)CCC1=O)[O:26][CH2:27][CH:28]1[C:40]2[CH:39]=[CH:38][CH:37]=[CH:36][C:35]=2[C:34]2[C:29]1=[CH:30][CH:31]=[CH:32][CH:33]=2.[Cl-].[Na+]>O1CCOCC1.O.C(OCC)(=O)C>[CH3:11][O:10][CH2:9][CH2:8][C:3]([NH:12][C:13](=[O:19])[O:14][C:15]([CH3:16])([CH3:18])[CH3:17])([CH2:4][CH2:5][O:6][CH3:7])[CH2:2][NH:1][C:25](=[O:41])[O:26][CH2:27][CH:28]1[C:40]2[CH:39]=[CH:38][CH:37]=[CH:36][C:35]=2[C:34]2[C:29]1=[CH:30][CH:31]=[CH:32][CH:33]=2
Reactant: COCCC(CN)(CCOC)NC(=O)OC(C)(C)C
Reactant: O=C(OCC1c2ccccc2-c2ccccc21)ON1C(=O)CCC1=O
Agent: O=C([O-])O
Agent: [Cl-]
Agent: [Na+]
Solvent: C1COCCO1
Solvent: O
Solvent: CCOC(C)=O
Product: COCCC(CCOC)(CNC(=O)OCC1c2ccccc2-c2ccccc21)NC(=O)OC(C)(C)C
Reaction time: 2 h
Yield: 69.7 %

Procedure:
To a suspension of tert-butyl (3-(aminomethyl)-1,5-dimethoxypentan-3-yl)carbamate (G21, 275 mg) and sodium hydrogencarbonate (400 mg) in 1,4-dioxane (4 mL) and water (4 mL), 9-fluorenylmethyl succinimidyl carbonate (261 mg) was added under ice cooling, and the mixture was stirred at the same temperature for 2 hours, and then stirred at room temperature for 1 hour. To the reaction mixture, ethyl acetate and saturated aqueous sodium chloride were added. The organic layer was separated, and dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure. The obtained residue was purified by silica gel column chromatography (eluent, 100 to 30% hexane in ethyl acetate) to obtain (9H-fluoren-9-yl)methyl tert-butyl (4-methoxy-2-(2-methoxyethyl)butane-1,2-diyl)dicarbamate (G22, 269 mg).
Reaction SMILES: [CH3:1][C:2]([CH3:9])([CH2:6][CH2:7][CH3:8])[C:3]([NH2:5])=[O:4].[Cl:10]O>C(OCC)(=O)C>[Cl:10][NH:5][C:3](=[O:4])[C:2]([CH3:9])([CH3:1])[CH2:6][CH2:7][CH3:8]
Reactant: CCCC(C)(C)C(N)=O
Reactant: OCl
Solvent: CCOC(C)=O
Product: CCCC(C)(C)C(=O)NCl
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 88.7 %

Procedure:
A stirred suspension of 2,2-dimethyl valeramide (35 g, 271 mmol) in ethyl acetate (200 ml) was cooled to 0° C. and hypochlorous acid (40.0 g of 36.2% solution, 276 mmol) was added dropwise over 12 minutes. The resulting clear yellow solution was then stirred for 30 minutes at room temperature, the organic phase separated and dried (MgSO4) and the ethyl acetate removed in vacuo to give 39.35 g of low-melting solid product.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]([CH3:15])[CH:9]1[CH2:14][CH2:13][NH:12][CH2:11][CH2:10]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].Br[C:17]1[S:18][C:19]([C:23]([O:25][CH2:26][CH3:27])=[O:24])=[C:20]([CH3:22])[N:21]=1.C(N(C(C)C)CC)(C)C>>[C:1]([O:5][C:6]([N:8]([CH3:15])[CH:9]1[CH2:10][CH2:11][N:12]([C:17]2[S:18][C:19]([C:23]([O:25][CH2:26][CH3:27])=[O:24])=[C:20]([CH3:22])[N:21]=2)[CH2:13][CH2:14]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CCOC(=O)c1sc(Br)nc1C
Reactant: CN(C(=O)OC(C)(C)C)C1CCNCC1
Solvent: CCN(C(C)C)C(C)C
Product: CCOC(=O)c1sc(N2CCC(N(C)C(=O)OC(C)(C)C)CC2)nc1C
Yield: 87.6 %

Procedure:
The same operation as in Example (217a) was performed using 4-[(tert-butoxycarbonyl)(methyl)amino]piperidine (386 mg, 1.80 mmol), ethyl 2-bromo-4-methylthiazole-5-carboxylate (300 mg, 1.20 mmol) and diisopropylethylamine (0.42 mL, 2.40 mmol), to obtain 403 mg of the title compound as a colorless oily substance (88%).
Reaction SMILES: Br[C:2]1[N:3]=[CH:4][N:5]([CH3:7])[CH:6]=1.CN(C)CC(O)=O.C(=O)([O-])[O-].[K+].[K+].[NH:21]1[CH:25]=[C:24]([CH:26]=[O:27])[CH:23]=[N:22]1>[Cu]I.CS(C)=O>[CH3:7][N:5]1[CH:6]=[C:2]([N:21]2[CH:25]=[C:24]([CH:26]=[O:27])[CH:23]=[N:22]2)[N:3]=[CH:4]1
Reactant: O=Cc1cn[nH]c1
Reactant: Cn1cnc(Br)c1
Agent: [Cu]I
Agent: CN(C)CC(=O)O
Agent: O=C([O-])[O-]
Solvent: CS(C)=O
Product: Cn1cnc(-n2cc(C=O)cn2)c1
Temperature: 110 °C

Procedure:
In an oven-dried flask, combine 4-bromo-1-methyl-1H-imidazole (0.200 g, 1.24 mmol), copper (I) iodide (0.022 g, 0.113 mmol), N,N-dimethylglycine (0.023 g, 0.226 mmol), and potassium carbonate (0.312 g, 2.26 mmol). Purge with nitrogen 3 times. Add 1-H-pyrazole-4-carboxaldehyde (0.109 g, 1.13 mmol), and DMSO (1.7 mL). Heat to 110° C. for 48 hr. Cool to ambient temperature and partition between ethyl acetate and water. Separate organic layer and extract aqueous layer twice with ethyl acetate. Dry combined organic layers (magnesium sulfate), filter and concentrate. Add copper (I) iodide (0.022 g, 0.113 mmol), N,N-dimethylglycine (0.023 g, 0.226 mmol), potassium carbonate (0.312 g, 2.26 mmol), and DMSO (1.7 mL). Purge with nitrogen 3 times. Heat to 110° C. for 18 hr. Cool to ambient temperature and partition between ethyl acetate and water. Separate organic layer and extract aqueous layer twice with ethyl acetate. Dry combined organic layers (magnesium sulfate), filter, concentrate, and purify (silica gel chromatography, eluting with 50:50 to 100:0 ethyl acetate:hexanes) to give the title preparation (39 mg, 20%). GC-MS: m/z=176 [M+].
Reaction SMILES: C([CH:3]([C:23]([OH:25])=[O:24])[N:4]([C:15]1[CH:20]=[CH:19][CH:18]=[C:17]([Cl:21])[C:16]=1[CH3:22])[S:5]([C:8]1[CH:13]=[CH:12][C:11]([CH3:14])=[CH:10][CH:9]=1)(=[O:7])=[O:6])C.[OH-].[Na+]>C(O)C.O1CCOCC1>[Cl:21][C:17]1[C:16]([CH3:22])=[C:15]([N:4]([S:5]([C:8]2[CH:9]=[CH:10][C:11]([CH3:14])=[CH:12][CH:13]=2)(=[O:6])=[O:7])[CH2:3][C:23]([OH:25])=[O:24])[CH:20]=[CH:19][CH:18]=1
Reactant: CCC(C(=O)O)N(c1cccc(Cl)c1C)S(=O)(=O)c1ccc(C)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: C1COCCO1
Solvent: CCO
Product: Cc1ccc(S(=O)(=O)N(CC(=O)O)c2cccc(Cl)c2C)cc1
Temperature: 60 °C
Reaction time: 8 h
Yield: 88.3 %

Procedure:
35.8 g of ethyl N-(3-chloro-2-methylphenyl)-N-[(4-methylphenyl)sulfonyl]glycine was dissolved in 157 mL of ethanol and 157 mL of 1,4-dioxane, and 157 mL of a 1 M aqueous sodium hydroxide solution was added thereto, followed by stirring at 60° C. overnight. The reaction liquid was cooled to room temperature, and then concentrated under reduced pressure. The residue was dissolved in water, acidified by addition of 1 M hydrochloric acid, and then extracted with ethyl acetate. The organic layer was washed with saturated brine, and then dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure to obtain 29.3 g of N-(3-chloro-2-methylphenyl)-N-[(4-methylphenyl)sulfonyl]glycine.
Reaction SMILES: C[O:2][C:3](=[O:22])[CH:4]=[CH:5][C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=1[S:12](=[O:21])(=[O:20])[NH:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1.[OH-].[Na+]>CO>[C:14]1([NH:13][S:12]([C:7]2[CH:8]=[CH:9][CH:10]=[CH:11][C:6]=2[CH:5]=[CH:4][C:3]([OH:22])=[O:2])(=[O:21])=[O:20])[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=1
Reactant: COC(=O)C=Cc1ccccc1S(=O)(=O)Nc1ccccc1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: O=C(O)C=Cc1ccccc1S(=O)(=O)Nc1ccccc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 70.1 %

Procedure:
3-(2-phenylsulfamoyl-phenyl)-acrylic acid methyl ester (34a) (0.30 g, 0.94 mmol) was dissolved in methanol (4 ml), 1N NaOH solution (2.82 ml, 2.82 mmol) was added and the resultant solution was stirred at ambient temperature overnight. The reaction mixture was partitioned between ethyl acetate and water. The aqueous layer was acidified with 10% HCl solution and stirred at ambient temperature for 1 hour. The precipitated solid was filtered, washed with water and dried in desiccator over P2O5. The title compound (0.2 g, 70%) was obtained as a white solid. 1H NMR (DMSO-d6, HMDSO), δ: 6.40 (1H, d, J=16.0 Hz); 6.93-7.32 (5H, m); 7.45-8.00 (5H, m); 8.47 (1H, d, J=16.0 Hz); 10.59 (1H, br s).
Reaction SMILES: [CH3:1][C:2]1[NH:6][N:5]=[C:4]([C:7]([OH:9])=O)[CH:3]=1.CCN=C=NCCCN(C)C.Cl.C1C=CC2N(O)N=NC=2C=1.O[N:33]=[C:34]([C:36]1[CH:41]=[CH:40][C:39]([O:42][C:43]([F:46])([F:45])[F:44])=[CH:38][CH:37]=1)[NH2:35]>CN(C=O)C.O>[CH3:1][C:2]1[NH:6][N:5]=[C:4]([C:7]2[O:9][N:35]=[C:34]([C:36]3[CH:37]=[CH:38][C:39]([O:42][C:43]([F:44])([F:45])[F:46])=[CH:40][CH:41]=3)[N:33]=2)[CH:3]=1
Reactant: NC(=NO)c1ccc(OC(F)(F)F)cc1
Reactant: Cc1cc(C(=O)O)n[nH]1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: O
Product: Cc1cc(-c2nc(-c3ccc(OC(F)(F)F)cc3)no2)n[nH]1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a mechanically stirred solution of 5-methyl-1H-pyrazole-3-carboxylic acid (15.3 g, 0.121 mol) in dry DMF (600 mL) was added EDCl (23.3 g, 0.121 mol), HOBT (16.4 g, 0.121 mol) and N′-hydroxy-4-(trifluoromethoxy)benzenecarboximidamide (26.7 g, 0.121 mol). The mixture was stirred at rt for 2 h, and then warmed to 140° C. and stirred for further 5 h. After being cooled to rt, the mixture was diluted with water (2 L) and extracted with ethyl acetate.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:10]=[C:11]2[N:21]([C:22](OC(C)(C)C)=[O:23])[CH2:20][CH:19]([CH2:29][Cl:30])[C:12]2=[C:13]2[C:18]=1[N:17]=[CH:16][CH:15]=[CH:14]2)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl.Cl.[CH3:33][N:34]([CH3:49])[CH2:35][CH2:36][O:37][C:38]1[CH:48]=[CH:47][C:41](/[CH:42]=[CH:43]/C(O)=O)=[CH:40][CH:39]=1.CCN=C=NCCCN(C)C>CC(N(C)C)=O.O1CCOCC1>[CH2:1]([O:8][C:9]1[CH:10]=[C:11]2[N:21]([C:22](=[O:23])/[CH:43]=[CH:42]/[C:41]3[CH:47]=[CH:48][C:38]([O:37][CH2:36][CH2:35][N:34]([CH3:49])[CH3:33])=[CH:39][CH:40]=3)[CH2:20][CH:19]([CH2:29][Cl:30])[C:12]2=[C:13]2[C:18]=1[N:17]=[CH:16][CH:15]=[CH:14]2)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CC(C)(C)OC(=O)N1CC(CCl)c2c1cc(OCc1ccccc1)c1ncccc21
Reactant: CN(C)CCOc1ccc(/C=C/C(=O)O)cc1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: CC(=O)N(C)C
Solvent: C1COCCO1
Product: CN(C)CCOc1ccc(/C=C/C(=O)N2CC(CCl)c3c2cc(OCc2ccccc2)c2ncccc32)cc1
Temperature: 25 °C
Reaction time: 30 h
Yield: 70.7 %

Procedure:
A suspension of 14 (0.20 g, 0.47 mmol) in cooled (0° C.) dioxane (5 mL) was saturated with HCl, allowed to warm to r.t. over 1 h and evaporated. (E)-4-[2-(Dimethylamino)ethoxy]cinnamic acid hydrochloride (0.13 g, 0.47 mmol) [Atwell et al., J. Med. Chem., 1999, 42, 3400], EDCI (0.27 g, 1.42 mmol) and DMA (3 mL) were added to the remaining yellow solid, and the red mixture was stirred at r.t. for 30 h. The mixture was partitioned between CH2Cl2 and 5% NaHCO3 solution. The aqueous layer was extracted with CH2Cl2 (×3). The CH2Cl2 extracts were dried (brine, Na2SO4). Flash chromatography (Alumina, EtOAc/MeOH; 49:1, then 24:1) gave 2-(4-{(1E)-3-[5-(benzyloxy)-1-(chloromethyl)-1,2-dihydro-3H-pyrrolo[3,2-f]quinolin-3-yl]-3-oxo-1-propenyl}phenoxy)-N,N-dimethylethanamine (17c) (0.18 g, 70%) as a yellow solid: mp 172–175° C.; 1H NMR [(CD3)2SO]δ 8.76 (dd, J=4.1, 1.4, 1 H), 8.47 (bs, 1 H), 8.35 (dd, J=8.5, 1.4, 1 H), 7.76 (d, J=8.7, 2 H), 7.67 (d, J=15.3, 1 H), 7.58 (d, J=7.3, 2 H), 7.54 (dd, J=8.5, 4.1, 1 H), 7.44 (t, J=7.2, 2 H), 7.37 (t, J=7.2, 1 H), 7.08 (d, J=15.3, 1 H), 7.02 (d, J=8.7, 2 H), 5.31 (s, 2 H), 4.55 (dd, J=10.7, 9.5, 1 H), 4.44 (dd, J=10.9, 2.5, 1 H), 4.30 (m, 1 H), 4.11 (t, J=5.8, 2 H), 3.99 (dd, J=11.0, 3.0, 1 H), 3.91 (dd, J=11.2, 7.2, 1 H), 2.64 (t, J=5.7, 2 H), 2.23 (s, 6 H); 13C NMR [(CD3)2SO]δ 164.1, 160.1, 154.6, 147.1, 142.6, 142.2, 137.2, 136.7, 131.1, 130.1, 128.3, 127.83, 127 78, 127.3, 125.1, 122.3, 116.9, 115.7, 114.7, 101.6, 70.0, 65.9, 57.5, 52.9, 47.8, 45.4, 40.1.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([C:19]2[S:23][C:22]([C:24]3(O)[CH2:29][CH2:28][S:27][CH2:26][CH2:25]3)=[N:21][CH:20]=2)[CH:5]=[C:6]([NH:8][C:9]2[N:14]=[C:13]([C:15]([F:18])([F:17])[F:16])[CH:12]=[CH:11][N:10]=2)[CH:7]=1.CCO.COCCN(S(F)(F)[F:44])CCOC>C(Cl)Cl.O>[F:44][C:24]1([C:22]2[S:23][C:19]([C:4]3[CH:5]=[C:6]([NH:8][C:9]4[N:14]=[C:13]([C:15]([F:18])([F:16])[F:17])[CH:12]=[CH:11][N:10]=4)[CH:7]=[C:2]([CH3:1])[CH:3]=3)=[CH:20][N:21]=2)[CH2:25][CH2:26][S:27][CH2:28][CH2:29]1
Reactant: Cc1cc(Nc2nccc(C(F)(F)F)n2)cc(-c2cnc(C3(O)CCSCC3)s2)c1
Reactant: COCCN(CCOC)S(F)(F)F
Solvent: O
Solvent: CCO
Solvent: ClCCl
Product: Cc1cc(Nc2nccc(C(F)(F)F)n2)cc(-c2cnc(C3(F)CCSCC3)s2)c1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 74.1 %

Procedure:
To a solution of the product of Step 1 (250 mg, 0.552 mmol) in CH2Cl2 (5 ml) were added EtOH (0.05 mL) and Deoxo-fluor (0.509 ml, 2.76 mmol). The reaction was stirred at room temperature for 30 minutes, diluted with water (5 mL) and extracted with EtOAc (2×10 mL). The combined organic layers were washed with brine, dried (MgSO4), filtered and evaporated. Column chromatography on silica (gradient elution, 0 to 25% EtOAc in hexanes) afforded the title compound (0.186 g, 0.409 mmol, 74% yield) as a pale yellow foam. MS ESI: [M+H]+ m/z 455.0. 1H NMR (500 MHz, DMSO-d6) δ 10.29 (s, 1H), 8.83 (d, J=4.9, 1H), 8.10 (d, J=2.7, 1H), 8.03 (bs, 1H), 7.47 (bs, 1H), 7.28 (d, J=4.9, 1H), 7.20 (bs, 1H), 2.94-2.89 (m, 2H), 2.69-2.66 (m, 2H), 2.39-2.75 (m, 7H). rhSYK activity=++.
Reaction SMILES: C([NH:4][C:5]1[CH:6]=[CH:7][C:8]2[C:17]3[CH:12]([CH2:13][C:14](=[O:18])[NH:15][N:16]=3)[CH2:11][CH2:10][C:9]=2[CH:19]=1)(=O)C.C(O)C>O.NN>[NH2:4][C:5]1[CH:6]=[CH:7][C:8]2[C:17]3[CH:12]([CH2:13][C:14](=[O:18])[NH:15][N:16]=3)[CH2:11][CH2:10][C:9]=2[CH:19]=1
Reactant: CC(=O)Nc1ccc2c(c1)CCC1CC(=O)NN=C21
Agent: NN
Solvent: CCO
Solvent: O
Product: Nc1ccc2c(c1)CCC1CC(=O)NN=C21
Yield: 42.7 %

Procedure:
8-Acetamido-4,4a,5,6-tetrahydrobenzo[h]cinnolin-3[2H]-one (0.7 g) was suspended in hydrazine hydrate (13 ml) and ethanol (2 ml) and heated under reflux for 2 hours. The hot solution was filtered through diatomaceous earth and the filtrate extracted with chloroform. Evaporation of the dried (MgSO4) extract gave a gum which was crystallised by trituration with 1-propanol. The crude solid was fractionated by flash chromatography (CHCl3 eluant) and from the appropriate fraction was obtained 8-amino-4,4a,5,6-tetrahydrobenzo[h]cinnolin-3[2H]-one (0.25 g; m.p. 290-1° from n-propanol/water)ν(Nujol mull) 3465, 3350, 3230, 1658, 1617, 1585 cm-1 ; δ(DMSO-d6) 1.2-1.7 (1H,m,5-H), 1.8-2.9 (6H,m,4,4a,5,6-H) 5.35 (2H,s,NH2), 6.34 (1H,m,7-H), 6.46 (1H,m,9-H), 7.66 (1H,d,10-H), 10.5 (1H,s,NHCO) M+ 215.
Reaction SMILES: C[O:2][C:3]([C:5]1[C:9]([NH:10][C:11](=[O:27])[CH2:12][O:13][C:14]2[CH:19]=[CH:18][C:17]([C:20]3[CH:25]=[CH:24][C:23]([F:26])=[CH:22][CH:21]=3)=[CH:16][CH:15]=2)=[CH:8][S:7][CH:6]=1)=[O:4].[OH-].[Na+]>C(O)C>[F:26][C:23]1[CH:22]=[CH:21][C:20]([C:17]2[CH:18]=[CH:19][C:14]([O:13][CH2:12][C:11]([NH:10][C:9]3[C:5]([C:3]([OH:4])=[O:2])=[CH:6][S:7][CH:8]=3)=[O:27])=[CH:15][CH:16]=2)=[CH:25][CH:24]=1
Reactant: COC(=O)c1cscc1NC(=O)COc1ccc(-c2ccc(F)cc2)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: O=C(COc1ccc(-c2ccc(F)cc2)cc1)Nc1cscc1C(=O)O
Temperature: 25 °C
Reaction time: 48 h
Yield: 96.7 %

Procedure:
To 4-[2-(4′-fluoro-biphenyl-4-yloxy)-acetylamino]-thiophene-3-carboxylic acid methyl ester (100 mg, 0.259 mmol) in ethanol (6 mL) was added a solution of sodium hydroxide (1N, 0.39 mL, 0.39 mmol) and the reaction was stirred at room temperature for 2 days. After such time the reaction mixture was filtered through glass wool and the filtrate was then neutralized by addition of a solution of hydrochloric acid (1N, 0.39 mL). Additional water was added to the solution (in excess of 10 mL) before the precipitate was filtered, washed with water and dried in vacuo to yield the title compound as a white solid (93 mg, 80%).
Reaction SMILES: [CH:1]1([C:4]2[C:5]([O:18][CH2:19][C:20]34[CH2:30][CH:29]3[CH2:28][C:23]3(OCC[O:24]3)[CH2:22][CH2:21]4)=[CH:6][C:7]([F:17])=[C:8]([CH:16]=2)[C:9]([O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:10])[CH2:3][CH2:2]1.O.FC(F)(F)C(O)=O>O1CCCC1.C(OCC)(=O)C>[CH:1]1([C:4]2[C:5]([O:18][CH2:19][C:20]34[CH2:30][CH:29]3[CH2:28][C:23](=[O:24])[CH2:22][CH2:21]4)=[CH:6][C:7]([F:17])=[C:8]([CH:16]=2)[C:9]([O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:10])[CH2:3][CH2:2]1
Reactant: CC(C)(C)OC(=O)c1cc(C2CC2)c(OCC23CCC4(CC2C3)OCCO4)cc1F
Solvent: O
Solvent: O=C(O)C(F)(F)F
Solvent: CCOC(C)=O
Product: CC(C)(C)OC(=O)c1cc(C2CC2)c(OCC23CCC(=O)CC2C3)cc1F
Temperature: 25 °C
Reaction time: 16 h
Yield: 90.5 %

Procedure:
To a solution of tert-butyl 5-cyclopropyl-2-fluoro-4-(spiro[bicyclo[4.1.0]heptane-3,2′-[1,3]dioxolan]-6-ylmethoxy)benzoate (0.61 g, 1.86 mmol) in tetrahydrofuran (2.0 mL) was added water (2.0 mL) followed by trifluoroacetic acid (0.75 g, 6.56 mmol). The reaction solution was stirred at ambient temperature for 16 hours. The reaction mixture was diluted with ethyl acetate (20 mL), washed with a solution of aqueous sodium hydroxide (2.0 mL, 3 M). The organic layer was separated and concentrated in vacuo to afford the title compound as a colorless gum (0.63 g, quant.): 1H NMR (300 MHz, CDCl3) δ 7.36 (d, J=8.4 Hz, 1H), 6.43 (d, J=12.6 Hz, 1H), 3.91 (d, J=9.3 Hz, 1H), 3.71 (d, J=9.3 Hz, 1H), 2.72 (dd, J=18.4, 5.4 Hz, 1H), 2.56-2.32 (m, 4H), 2.20-2.07 (m, 2H), 1.99-1.92 (m, 1H), 1.53 (s, 9H), 1.21-0.79 (m, 5H), 0.70 (t, J=5.3 Hz, 1H), 0.63-0.58 (m, 2H); MS (ES+) m/z 397.2 (M+23).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:6]=[CH:7][C:8]=1[S:9](=[O:12])(=[O:11])[NH2:10])[NH2:5].[Cl:13][CH2:14][C:15](Cl)=[O:16]>>[Cl:13][CH2:14][C:15]([NH:5][C:4]1[CH:6]=[CH:7][C:8]([S:9](=[O:12])(=[O:11])[NH2:10])=[C:2]([Cl:1])[CH:3]=1)=[O:16]
Reactant: O=C(Cl)CCl
Reactant: Nc1ccc(S(N)(=O)=O)c(Cl)c1
Product: NS(=O)(=O)c1ccc(NC(=O)CCl)cc1Cl

Procedure:
3-Chloro-4-sulphamoylaniline (20.6 g) and chloroacetyl chloride (20 ml) were refluxed 45 min and the mixture worked up as in Example 2(a) to yield 23.5 g m.p.: 214°-216°.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([CH2:7][C@H:8]2[C@H:17]([OH:18])[C:16]3[C:11](=[CH:12][CH:13]=[C:14]([OH:19])[CH:15]=3)[O:10][CH2:9]2)[CH:2]=1.[Cl:20][C:21]1[CH:26]=[CH:25][CH:24]=[C:23]([CH2:27]Br)[N:22]=1>>[Cl:20][C:21]1[N:22]=[C:23]([CH2:27][O:19][C:14]2[CH:15]=[C:16]3[C:11](=[CH:12][CH:13]=2)[O:10][CH2:9][C@@H:8]([CH2:7][C:3]2[CH:2]=[N:1][CH:6]=[CH:5][CH:4]=2)[C@@H:17]3[OH:18])[CH:24]=[CH:25][CH:26]=1
Reactant: Clc1cccc(CBr)n1
Reactant: Oc1ccc2c(c1)[C@@H](O)[C@H](Cc1cccnc1)CO2
Product: O[C@@H]1c2cc(OCc3cccc(Cl)n3)ccc2OC[C@H]1Cc1cccnc1

Procedure:
By the method of Example 5, 500 mg (1.95 mmol) of trans-3-(3-pyridyl)methyl-4,6-chromandiol and 442 mg (2.14 mmol) of 2-chloro-6-(bromomethyl)pyridine were converted to present title product, purified by flash chromatography on a silica gel column using isopropyl alcohol:ethyl acetate:CH2Cl2, 1:2:17 as eluant, to yield 0.11 g (14%) of present title compound as a glass.
Reaction SMILES: [N+:1]([C:4]1[CH:12]=[C:11]([Cl:13])[CH:10]=[CH:9][C:5]=1[C:6](Cl)=[O:7])([O-:3])=[O:2].[CH3:14][C:15]1([CH3:26])[C:20](=[O:21])[C:19]([CH3:23])([CH3:22])[C:18](=[O:24])[CH2:17][C:16]1=[O:25].C(N(CC)CC)C.CC(C)(O)C#N>C(Cl)Cl>[N+:1]([C:4]1[CH:12]=[C:11]([Cl:13])[CH:10]=[CH:9][C:5]=1[C:6]([CH:17]1[C:16](=[O:25])[C:15]([CH3:26])([CH3:14])[C:20](=[O:21])[C:19]([CH3:23])([CH3:22])[C:18]1=[O:24])=[O:7])([O-:3])=[O:2]
Reactant: O=C(Cl)c1ccc(Cl)cc1[N+](=O)[O-]
Reactant: CC1(C)C(=O)CC(=O)C(C)(C)C1=O
Agent: CC(C)(O)C#N
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC1(C)C(=O)C(C(=O)c2ccc(Cl)cc2[N+](=O)[O-])C(=O)C(C)(C)C1=O
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 46.5 %

Procedure:
2-Nitro-4-chlorobenzoyl chloride (2.2 g, 10 mmol) and 4,4,6,6-tetramethyl-1,3,5-cyclohexanetrione (1.8 g, 10 mmol) were dissolved in methylene chloride. Triethylamine was added and the resulting solution stirred at room temperature for 30 minutes. The solution was washed with 1 normal hydrochloric acid (1N HCl), and saturated sodium chloride (brine), dried over anhydrous magnesium sulfate (MgSO4) and concentrated under vacuum. The residue was dissolved in 20 ml acetonitrile. Triethylamine (5 ml, 3.5 equivalents) and acetone cyanohydrin (0.5 g, 0.6 equivalent) were added and the mixture stirred at room temperature for 4 hours. After dilution with ether, the solution was washed with 1N HCl and extracted with 5% K2CO3. The basic extract was acidified with HCl and extracted with ether. The ether extract was washed with brine, dried over MgSO4 and concentrated under vacuum, yielding 2.2 g of crude product. This was recrystallized from benzene to remove syncarpic acid still present. Concentration of the mother liquor under vacuum gave 1.7 g of the desired product as an oil, which solidified on standing (m.p. 76°-82° C.). It was identified as such as nuclear magnetic resonance spectroscopy, infrared spectroscopy and mass spectroscopy.
Reaction SMILES: [C:1]1(=[O:7])[O:6][C:4](=[O:5])[CH:3]=[CH:2]1.[OH-:8].[NH4+:9].[OH-].[Na+]>O>[C:1]([O-:6])(=[O:7])/[CH:2]=[CH:3]\[C:4]([OH:8])=[O:5].[NH4+:9]
Reactant: [OH-]
Reactant: O=C1C=CC(=O)O1
Agent: [NH4+]
Agent: [Na+]
Solvent: O
Product: O=C([O-])/C=C\C(=O)O
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
Following the examples of U.S. Pat. No. 4,839,461, a slurry of 9.8 g (0.1 mole) maleic anhydride was dissolved in 20 ml water at 80°-95° C. and stirred for 30 minutes while allowing the mixture to cool to 25° C. To this colorless solution at 25° C. was added 13 g of 30% aqueous solution of ammonium hydroxide (0.11 mol NH3) to give a colorless solution. This solution was boiled to dryness over a period of 30 minutes at approximately 100°-115° C. to give a white crystalline solid. The solid was tumbled under nitrogen at 100 Torr, at 145°-150° C. for 4 hours to give a water insoluble, pinkish-tan brittle grasslike solid weighing 11.4 g. This solid was dissolved in 26.2 g of an aqueous solution containing 1.36 g of sodium hydroxide to form a clear red-brown solution, pH 7.0, containing 25% solids.
Reaction SMILES: C(S(N1CCC(C2C3C(=C(C(N)=O)C=C(C4SC(CNCC(C)CC)=CC=4)C=3)NC=2)CC1)(=O)=O)C.[CH:36]([C:38]1[S:42][C:41]([B:43]([OH:45])[OH:44])=[CH:40][CH:39]=1)=O.[CH3:46][O:47][CH2:48][CH2:49][NH2:50].[BH3-]C#N.[Na+]>>[CH3:46][O:47][CH2:48][CH2:49][NH:50][CH2:36][C:38]1[S:42][C:41]([B:43]([OH:45])[OH:44])=[CH:40][CH:39]=1
Reactant: O=Cc1ccc(B(O)O)s1
Reactant: COCCN
Agent: CCC(C)CNCc1ccc(-c2cc(C(N)=O)c3[nH]cc(C4CCN(S(=O)(=O)CC)CC4)c3c2)s1
Agent: [BH3-]C#N
Agent: [Na+]
Product: COCCNCc1ccc(B(O)O)s1
Yield: 61 %

Procedure:
Following the general procedure of 3-[1-(ethylsulfonyl)-4-piperidinyl]-5-(5-{[(2-methylbutyl)amino]methyl}-2-thienyl)-1H-indole-7-carboxamide, (5-formyl-2-thienyl)boronic acid (50 mg, 0.32 mmol), [2-(methyloxy)ethyl]amine (24 mg, 0.32 mmol), and NaCNBH3 (40 mg, 0.64 mmol) were reacted to give 42 mg of crude [5-({[2-(methyloxy)ethyl]amino}methyl)-2-thienyl]boronic acid. The crude [5-({[2-(methyloxy)ethyl]amino}methyl)-2-thienyl]boronic acid was then reacted with 5-bromo-3-[1-(ethylsulfonyl)-4-piperidinyl]-1H-indole-7-carboxamide (65 mg, 0.157 mmol), K2CO3 (130 mg, 0.942 mmol), and tetrakis(triphenylphosphine)palladium(0) (4 mg, 0.003 mmol) to give impure title compound. The impure title compound was repurified using the HPLC and ammonium hydroxide SPE workup shown in preparation of 3-[1-(ethylsulfonyl)-4-piperidinyl]-5-(5-{[(2-methylbutyl)amino]methyl}-2-thienyl)-1H-indole-7-carboxamide to give 15 mg of the title compound (15%).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[N:4][C:5]2[N:6]([N:8]=[C:9]([C:11]([OH:13])=O)[CH:10]=2)[CH:7]=1.[CH:14]([CH:17]1[C:26]2[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=2)[CH2:20][CH2:19][NH:18]1)([CH3:16])[CH3:15]>>[Br:1][C:2]1[CH:3]=[N:4][C:5]2[N:6]([N:8]=[C:9]([C:11]([N:18]3[CH2:19][CH2:20][C:21]4[C:26](=[CH:25][CH:24]=[CH:23][CH:22]=4)[CH:17]3[CH:14]([CH3:16])[CH3:15])=[O:13])[CH:10]=2)[CH:7]=1
Reactant: O=C(O)c1cc2ncc(Br)cn2n1
Reactant: CC(C)C1NCCc2ccccc21
Product: CC(C)C1c2ccccc2CCN1C(=O)c1cc2ncc(Br)cn2n1

Procedure:
In close analogy to the procedure described in Example 1, 6-bromo-pyrazolo[1,5-a]pyrimidine-2-carboxylic acid is reacted with 1-Isopropyl-1,2,3,4-tetrahydro-isoquinoline to provide the title compound in moderate yield.