Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1][C:2]1[CH:9]=[CH:8][C:7]([N+:10]([O-:12])=[O:11])=[CH:6][C:3]=1[CH:4]=O.[C:13]([NH:16][CH2:17][C:18](O)=[O:19])(=[O:15])[CH3:14].C(OC(=O)C)(=O)C.[H-].[Na+]>>[C:13]([NH:16][C:17]1[C:18](=[O:19])[O:1][C:2]2[C:3]([CH:4]=1)=[CH:6][C:7]([N+:10]([O-:12])=[O:11])=[CH:8][CH:9]=2)(=[O:15])[CH3:14]
Reactant: O=Cc1cc([N+](=O)[O-])ccc1O
Reactant: CC(=O)NCC(=O)O
Agent: [H-]
Agent: [Na+]
Solvent: CC(=O)OC(C)=O
Product: CC(=O)Nc1cc2cc([N+](=O)[O-])ccc2oc1=O
Temperature: 4 °C
Reaction time: 20 h
Yield: 60.7 %

Procedure:
A dry 100-mL round bottomed flask was charged with 7.11 g (42.5 mmol) of 2-hydroxy-5-nitrobenzaldehyde. To this flask were then added N-acetylglycine (4.98 g, 42.5 mmol) and acetic anhydride (40.1 mL, 0.43 mol). In small aliquots, 1.71 g (42.5 mmol) of sodium hydride (60% dispersion in mineral oil) was added to the flask. Reactants were observed to dissolve and after 2-5 minutes, precipitation occurred. The reaction mixture was stirred for 20 h and 7.11 mL of water were added. Following the addition of 43 mL acetic acid, the mixture was cooled to 4° C. for 4 h. The resulting precipitate was filtered and washed liberally with cold glacial acetic acid. The acetic acid was then removed as an azeotrope upon addition of 250 mL toluene and rotary evaporation to dryness, three times. The final residue was dried under vacuum to give product 1 as a beige powder (6.40 g, 25.8 mmol) in a yield of 61%. mp 277-279° C. (lit: 278° C.) FTIR (KBr) (cm−1) 3350, 3050, 1710, 1680, 1600, 1500, 1420, and 1335. 1H-NMR (DMSO-d6): δ (ppm) 9.93 (s, 1H), 8.76 (s, 1H), 8.73 (d, J=2.5 Hz, 1H), 8.28 (dd, J=2.8 Hz, J=9.1 Hz, 1H), 7.60 (d, J=9.1 Hz, 1H), 2.19 (s, 3H). 13C-NMR (DMSO-d6): δ (ppm) 171.47, 157.69, 145.07, 127.11, 124.96, 124.52, 122.79, 121.52, 118.26, 25.00. HRMS expected: 249.05240; found: 249.05339. Elemental analysis for C11H8N2O5, expected: C, 53.23; H, 3.25; N, 11.27; found: C, 53.19; H, 3.34; N, 11.06.
Reaction SMILES: [Cl-].[Al+3].[Cl-].[Cl-].[C:5]1([CH3:11])[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1.[F:12][C:13]1[CH:21]=[CH:20][C:16]([C:17](Cl)=[O:18])=[CH:15][CH:14]=1.O>C(Cl)Cl.CCCCCC>[CH3:11][C:5]1[CH:10]=[CH:9][C:8]([C:17]([C:16]2[CH:20]=[CH:21][C:13]([F:12])=[CH:14][CH:15]=2)=[O:18])=[CH:7][CH:6]=1
Reactant: Cc1ccccc1
Reactant: O=C(Cl)c1ccc(F)cc1
Agent: [Al+3]
Agent: [Cl-]
Solvent: O
Solvent: CCCCCC
Solvent: ClCCl
Product: Cc1ccc(C(=O)c2ccc(F)cc2)cc1
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 62 %

Procedure:
Aluminum chloride (3.74 g, 28 mmol) was added into a stirred solution of toluene 18 (60 mL) and 4-fluorobenzoyl chloride (3.42 g, 21.6 mmol). The solution was stirred at room temperature for 90 minutes, and then 5 mL of water was added dropwise to quench the reaction. The reaction mixture washed with water and 10% NaHCO3. The solution was then dried with anhydrous MgSO4. The solvent was removed from the solution to obtain a yellow solid. The yellow crude product was dissolved in a small amount of methylene chloride and hexane was added dropwise until precipitation occurred. The solution was then heated and the product was allowed to recrystallize to form 2.70 g of product (62% yield). 1H-NMR: δ 7.80 (dd, aromatic, 2H), 7.67 (d, aromatic, 2H), 7.26 (d, aromatic, 2H), 7.15 (t, aromatic, 2H), 2.42 (s, methyl, 3H). 13C-NMR: δ 195.0 (carbonyl); 166.2, 164.2, 143.3, 134.7, 132.2, 130.1, 129.0, 115.3 (aromatic); 21.6 (alkyl). 19F-NMR: δ −109.1 ppm.
Reaction SMILES: [CH:1]1([N:5]2[CH2:11][CH2:10][C:9]3=[CH:12][NH:13][N:14]=[C:8]3[CH2:7][CH2:6]2)[CH2:4][CH2:3][CH2:2]1.[H-].[Na+].Br[CH2:18][C:19]1[CH:26]=[CH:25][C:22]([C:23]#[N:24])=[CH:21][CH:20]=1>CN(C)C=O.CO>[CH:1]1([N:5]2[CH2:11][CH2:10][C:9]3=[CH:12][N:13]([CH2:18][C:19]4[CH:26]=[CH:25][C:22]([C:23]#[N:24])=[CH:21][CH:20]=4)[N:14]=[C:8]3[CH2:7][CH2:6]2)[CH2:2][CH2:3][CH2:4]1
Reactant: N#Cc1ccc(CBr)cc1
Reactant: c1[nH]nc2c1CCN(C1CCC1)CC2
Agent: [H-]
Agent: [Na+]
Solvent: CO
Solvent: CN(C)C=O
Product: N#Cc1ccc(Cn2cc3c(n2)CCN(C2CCC2)CC3)cc1
Temperature: 70 °C

Procedure:
6-Cyclobutyl-2,4,5,6,7,8-hexahydropyrazolo[3,4-d]azepine (may be prepared as described in Description 31) (0.03, 0.16 mmol) in dimethylformamide (2 ml) was treated with sodium hydride (60% dispersion in oil) (0.007 g, 0.172 mmol). After 20 minutes 4-(bromomethyl)benzonitrile (0.037 g, 0.172 mmol) was added and the mixture was then heated at 70° C. for 18 hours. The reaction was then cooled to room temperature, diluted with methanol and applied to a SCX ion exchange cartridge and washed with methanol and then 2M solution of ammonia in methanol. The ammonia containing fractions were then combined and reduced and the resulting crude residue was chromatographed on silica gel eluting with a 2:98 mixture of 2M ammonia in methanol and dichloromethane to furnish the title compound (E46); (MS (ES+): [M+H]+ at m/z 307.1
Reaction SMILES: Cl.[CH3:2][C:3]1[CH:4]=[C:5]([C:9]2([OH:15])[CH2:14][CH2:13][NH:12][CH2:11][CH2:10]2)[CH:6]=[CH:7][CH:8]=1.[C:16]([C:18]1[CH:31]=[CH:30][C:21]([CH2:22][N:23]2[C:27]([CH:28]=O)=[CH:26][N:25]=[CH:24]2)=[CH:20][CH:19]=1)#[N:17].C([BH3-])#N.[Na+].Cl>CO.C1COCC1.C(#N)C.C(O)(=O)C>[C:16]([C:18]1[CH:19]=[CH:20][C:21]([CH2:22][N:23]2[C:27]([CH2:28][N:12]3[CH2:11][CH2:10][C:9]([C:5]4[CH:6]=[CH:7][CH:8]=[C:3]([CH3:2])[CH:4]=4)([OH:15])[CH2:14][CH2:13]3)=[CH:26][N:25]=[CH:24]2)=[CH:30][CH:31]=1)#[N:17]
Reactant: N#Cc1ccc(Cn2cncc2C=O)cc1
Reactant: Cc1cccc(C2(O)CCNCC2)c1
Agent: Cl
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CC#N
Solvent: CC(=O)O
Solvent: C1CCOC1
Product: Cc1cccc(C2(O)CCN(Cc3cncn3Cc3ccc(C#N)cc3)CC2)c1
Temperature: 25 °C
Reaction time: 48 h

Procedure:
To a mixture of 4-(3-methylphenyl)-4-hydroxypiperidine hydrochloride (457 mg, 2.00 mmol), the aldehyde from step E (508 mg, 2.41 mmol), and 3A molecular sieves (2.0 g) in methanol (20 ml) was added sodium cyanoborohydride (2.20 ml of a 1M solution in THF, 2.20 mmol). The pH was adjusted to 5 by addition of acetic acid and the reaction stirred under argon for 48 hrs at room temperature. The solids were removed by filtration and the filtrate partitioned between EtOAc and saturated NaHCO3 solution, the organic extracts were dried (MgSO4), and the solvent evaporated in vacuo. The residue was purified by chromatography (SiO2, gradient elution, 5 to 7% MeOH in methylene chloride. The residue was converted to the corresponding hydrochloride salt by its treatment with a solution of two equivalents of HCl in aqueous acetonitrile and subsequent evaporation of solvents in vacuo.
Reaction SMILES: [H-].[Al+3].[Li+].[H-].[H-].[H-].COC(=O)C[CH:11]([C:18]1[CH:19]=[C:20]2[C:24](=[CH:25][CH:26]=1)[N:23]([S:27]([C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1)(=[O:29])=[O:28])[CH:22]=[CH:21]2)[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1.[CH3:37][O:38]C(=O)C=CC1C=C2C(=CC=1)N(S(C1C=CC=CC=1)(=O)=O)C=C2>O1CCCC1>[C:30]1([S:27]([N:23]2[C:24]3[C:20](=[CH:19][C:18]([CH:11]([C:12]4[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=4)[CH2:37][OH:38])=[CH:26][CH:25]=3)[CH:21]=[CH:22]2)(=[O:29])=[O:28])[CH:31]=[CH:32][CH:33]=[CH:34][CH:35]=1
Reactant: COC(=O)C=Cc1ccc2c(ccn2S(=O)(=O)c2ccccc2)c1
Reactant: COC(=O)CC(c1ccccc1)c1ccc2c(ccn2S(=O)(=O)c2ccccc2)c1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Product: O=S(=O)(c1ccccc1)n1ccc2cc(C(CO)c3ccccc3)ccc21
Reaction time: 1 h
Yield: 69 %

Procedure:
A solution of lithium aluminum hydride (1.0 M in THF, 5.9 mL) was added dropwise to a solution of the above obtained mixture 10/1: 3-(1-benzenesulfonyl-1H-indol-5-yl)-3-phenyl-propionic acid methyl ester and 3-(1-benzenesulfonyl-1H-indol-5-yl)-acrylic acid methyl ester CCLXVI (1.654 g, 3.935 mmol) in tetrahydrofuran (30 mL) at 0° C. After stirring for 1 hour the reaction was quenched by slow addition, at 0° C., of Rochelle salt and water. The resulting mixture was diluted with ethyl acetate and stirred at room temperature overnight. The organic layer was separated, washed with brine, dried over anhydrous sodium sulfate, filtered and evaporated under reduced pressure. The residue was purified by flash chromatography to afford 1.06 g (69% yield) of 2-(1-benzenesulfonyl-1H-indol-5-yl)-2-phenyl-ethanol CCLXVII.
Reaction SMILES: [C:1]([C:3]([O:12][Si:13]([CH3:16])([CH3:15])[CH3:14])([CH2:7][CH2:8][CH2:9][CH2:10][CH3:11])[CH:4]=[CH:5][I:6])#[CH:2].C([Mg]Br)C.[CH3:21][Si:22]([CH3:25])([CH3:24])Cl.[Cl-].[NH4+]>C1COCC1>[I:6][CH:5]=[CH:4][C:3]([C:1]#[C:2][Si:22]([CH3:25])([CH3:24])[CH3:21])([O:12][Si:13]([CH3:16])([CH3:15])[CH3:14])[CH2:7][CH2:8][CH2:9][CH2:10][CH3:11]
Reactant: C#CC(C=CI)(CCCCC)O[Si](C)(C)C
Reactant: C[Si](C)(C)Cl
Agent: CC[Mg]Br
Agent: [Cl-]
Agent: [NH4+]
Solvent: C1CCOC1
Product: CCCCCC(C#C[Si](C)(C)C)(C=CI)O[Si](C)(C)C

Procedure:
A solution of 3.3 g. of dl-3-ethynyl-1-iodo-3-trimethylsilyloxy-1-octene in 10 ml. of THF is treated at 0° C. under N2 with 3 ml. of 3M ethyl magnesium bromide and stirred at 25° C. for 1/2 hour. The mixture is then treated at 0° C. with 3.5 ml. of trimethylchlorosilane and stirred at 25° C. for an additional 21/2 hours. The whole mixture is added to aqueous ammonium chloride solution and extracted with ether. After washing with brine and drying over magnesium sulfate, the extract is evaporated. Distillation of the residue gives the title product, as an oil, 2.5 g. b.p. 79°-81° C. (0.025 mm).
Reaction SMILES: [NH2:1][C:2]1[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[CH:4][CH:3]=1.[CH3:10][C:11]1[CH:12]=[C:13]([NH:20][C:21]([C:23]2([CH3:26])[CH2:25][O:24]2)=[O:22])[CH:14]=[CH:15][C:16]=1[N+:17]([O-:19])=[O:18]>>[C:6]([C:5]1[CH:8]=[CH:9][C:2]([NH:1][CH2:26][C:23]([OH:24])([CH3:25])[C:21]([NH:20][C:13]2[CH:14]=[CH:15][C:16]([N+:17]([O-:19])=[O:18])=[C:11]([CH3:10])[CH:12]=2)=[O:22])=[CH:3][CH:4]=1)#[N:7]
Reactant: N#Cc1ccc(N)cc1
Reactant: Cc1cc(NC(=O)C2(C)CO2)ccc1[N+](=O)[O-]
Product: Cc1cc(NC(=O)C(C)(O)CNc2ccc(C#N)cc2)ccc1[N+](=O)[O-]

Procedure:
3-(4-Cyanophenylamino)-2-hydroxy-2-methyl-N-(3-methyl-4-nitrophenyl)propionamide was prepared as described in Example 52 starting from 4-aminobenzonitrile and 2-methyloxirane-2-carboxylic acid (3-methyl-4-nitrophenyl)amide. The crude product was purified by flash chromatography (dichloromethane-5% methanol). 1H NMR (400 MHz, DMSO-d6): 1.41 (3H, s), 2.52 (3H, s), 3.25 (1H, dd, J=13.5 Hz, J=5.3 Hz), 3.52 (1H, dd, J=13.5 Hz, J=7.0 Hz), 6.08 (1H, s), 6.53 (1H, m), 6.75 (2H, d, J=8.8 Hz)), 7.39 (2H, d, J=8.8 Hz), 7.79-7.83 (2H, m), 8.01 (1H, d, J=8.9 Hz), 10.02 (1H, s).
Reaction SMILES: C(O)(=O)C.[N:5]1[CH:10]=[CH:9][C:8]([CH:11]=O)=[CH:7][CH:6]=1.[C:13]([O:22][CH3:23])(=[O:21])[C:14]1[C:15](=[CH:17][CH:18]=[CH:19][CH:20]=1)[NH2:16].C([BH3-])#N.[Na+]>CO>[N:5]1[CH:6]=[CH:7][C:8]([CH2:11][NH:16][C:15]2[C:14](=[CH:20][CH:19]=[CH:18][CH:17]=2)[C:13]([O:22][CH3:23])=[O:21])=[CH:9][CH:10]=1
Reactant: COC(=O)c1ccccc1N
Reactant: O=Cc1ccncc1
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CO
Product: COC(=O)c1ccccc1NCc1ccncc1
Temperature: 25 °C
Reaction time: 12 h

Procedure:
3 mL Acetic acid and 8.6 g 4-pyridinecarbaldehyde are added to a solution of 7.5 g methyl anthranilate in 300 mL methanol. The mixture is stirred for 12 hours under nitrogen atmosphere at room temperature. 5.7 g Sodium cyanotrihydridoborate (85%) is added and the mixture is stirred for 3 hours at room temperature. Additional 1.14 g sodium cyanotrihydridoborate (85%) is added and the mixture is stirred for 12 hours at room temperature. The solvent is evaporated and the residue dissolved in ethyl acetate and washed with saturated NaHCO3 solution and saturated sodium chloride solution. The organic extract is concentrated and purified with hexane/ethyl acetate (1:1) on silica gel to yield methyl N-(4-pyridylmethyl)-anthranilate with m.p. 86° C.
Reaction SMILES: [CH3:1][C:2]1[C:20]([CH3:21])=[CH:19][CH:18]=[CH:17][C:3]=1[O:4][C:5]1[CH:10]=[CH:9][C:8]([CH:11]2[O:16][CH2:15][CH2:14][NH:13][CH2:12]2)=[CH:7][CH:6]=1.C([O-])([O-])=O.[K+].[K+].[C:28]([O:32][C:33](=[O:38])[CH2:34][CH2:35][CH2:36]Br)([CH3:31])([CH3:30])[CH3:29]>CC#N>[C:28]([O:32][C:33](=[O:38])[CH2:34][CH2:35][CH2:36][N:13]1[CH2:14][CH2:15][O:16][CH:11]([C:8]2[CH:7]=[CH:6][C:5]([O:4][C:3]3[CH:17]=[CH:18][CH:19]=[C:20]([CH3:21])[C:2]=3[CH3:1])=[CH:10][CH:9]=2)[CH2:12]1)([CH3:31])([CH3:30])[CH3:29]
Reactant: CC(C)(C)OC(=O)CCCBr
Reactant: Cc1cccc(Oc2ccc(C3CNCCO3)cc2)c1C
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: Cc1cccc(Oc2ccc(C3CN(CCCC(=O)OC(C)(C)C)CCO3)cc2)c1C
Temperature: 25 °C
Yield: 74.4 %

Procedure:
A mixture of 2-[4-(2,3-dimethyl-phenoxy)-phenyl]-morpholine (0.40 g; 1.2 mmol), K2CO3 (0.49 g; 3.6 mmol), KI (0.22 g; 1.31 mmol), 4-bromo-butyric acid tert-butyl ester (0.32 g; 1.43 mmol), and CH3CN (30 mL), was heated under reflux, overnight. After cooling to RT the mixture was concentrated in vacuo, and the residue was purified by column chromatography (SiO2, Et2O/hexanes 1:1) to afford 4-{2-[4-(2,3-dimethyl-phenoxy)-phenyl]morpholin-4-yl}-butyric acid tert-butyl ester (0.38 g).
Reaction SMILES: [NH2:1][C:2]1[CH:11]=[CH:10][CH:9]=[CH:8][C:3]=1[C:4]([NH:6][NH2:7])=[O:5].[CH:12](OCC)(OCC)OCC>C(O)C>[NH2:7][N:6]1[C:4](=[O:5])[C:3]2[C:2](=[CH:11][CH:10]=[CH:9][CH:8]=2)[N:1]=[CH:12]1
Reactant: NNC(=O)c1ccccc1N
Reactant: CCOC(OCC)OCC
Solvent: CCO
Product: Nn1cnc2ccccc2c1=O

Procedure:
A mixture of 2-aminobenzhydrazide (7.16 g, 47.4 mmol) and triethyl orthoformate (8.3 mL, 49.9 mmol) in ethanol is heated at reflux for 3.5 hours under a nitrogen atmosphere, cooled and filtered to obtain the title product as a white solid, 6.06 g (79%), mp 209°-210.5° C.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]([C:26]([O:28][C:29]([CH3:32])([CH3:31])[CH3:30])=[O:27])[C:9]1[C:14]([C:15]([O:17][CH3:18])=[O:16])=[C:13]([CH:19]=[CH2:20])[C:12]([C:21]2[NH:22][N:23]=[CH:24][CH:25]=2)=[CH:11][CH:10]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].C[N+]1([O-])CC[O:37]CC1.ClC1C=CC=C(C(OO)=O)C=1>C(Cl)Cl.CC(C1C=C(C=N[C@@H]2[C@@H](N=CC3C([O-])=C(C(C)(C)C)C=C(C(C)(C)C)C=3)CCCC2)C([O-])=C(C(C)(C)C)C=1)(C)C.[Cl-].[Mn+3]>[C:29]([O:28][C:26]([N:8]([C:6]([O:5][C:1]([CH3:4])([CH3:2])[CH3:3])=[O:7])[C:9]1[CH:10]=[CH:11][C:12]2[C:21]3=[CH:25][CH:24]=[N:23][N:22]3[CH2:20][CH:19]([OH:37])[C:13]=2[C:14]=1[C:15]([O:17][CH3:18])=[O:16])=[O:27])([CH3:32])([CH3:31])[CH3:30]
Reactant: C[N+]1([O-])CCOCC1
Reactant: C=Cc1c(-c2ccn[nH]2)ccc(N(C(=O)OC(C)(C)C)C(=O)OC(C)(C)C)c1C(=O)OC
Agent: [Mn+3]
Agent: CC(C)(C)c1cc(C=N[C@H]2CCCC[C@@H]2N=Cc2cc(C(C)(C)C)cc(C(C)(C)C)c2[O-])c([O-])c(C(C)(C)C)c1
Agent: O=C(OO)c1cccc(Cl)c1
Solvent: ClCCl
Product: COC(=O)c1c(N(C(=O)OC(C)(C)C)C(=O)OC(C)(C)C)ccc2c1C(O)Cn1nccc1-2
Temperature: 0 °C
Reaction time: 0.33 h
Yield: 11.7 %

Procedure:
To a cooled solution of methyl 6-[bis-(tert-butoxycarbonyl)amino]-3-(2H-pyrazol-3-yl)-2-vinylbenzoate (Intermediate 9, 2.4 g) in anhydrous DCM (100 mL) at 0° C. was added (S,S)-(+)-N,N′-bis(3,5-di-tert-butylsalicylidene)-1,2-cyclohexanediamino manganese (III) chloride (0.280 g) and N-methylmorpholine N-oxide (3.2 g). m-Chloroperbenzoic acid (3.8 g) was then added portionwise and the reaction mixture was stirred at 0° C. for 20 minutes. The resultant mixture was quenched by the addition of 2M aqueous sodium carbonate solution and the organic layer was separated, dried (MgSO4) and filtered. The filtrate was concentrated in vacuo and the residue was purified by chromatography on silica, eluting with a mixture of ethyl acetate and DCM with a gradient of 0-100%. The resultant material was repurified by chromatography on silica, eluting with a mixture of ethyl acetate and DCM with a gradient of 0-100% to give methyl 8-[bis-(tert-butoxycarbonyl)amino]-6-hydroxy-5,6-dihydro-pyrazolo[5,1-a]isoquinoline-7-carboxylate (0.290 g).
Reaction SMILES: [NH2:1][C:2]([NH2:4])=[S:3].[CH2:5]([NH:7][C:8]1N=C(NCC)N=[C:10](Cl)[N:9]=1)[CH3:6].[OH-].[Na+].Cl>O1CCOCC1.O>[CH2:5]([NH:7][C:8]1[N:9]=[CH:10][N:4]=[C:2]([SH:3])[N:1]=1)[CH3:6]
Reactant: CCNc1nc(Cl)nc(NCC)n1
Reactant: NC(N)=S
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1COCCO1
Solvent: O
Product: CCNc1ncnc(S)n1
Reaction time: 2 h

Procedure:
A mixture of 1.5 g of thiourea and 4 g of 2,4-bis(ethylamino)-6-chloro-1,3,5-triazine in a mixture of 20 ml of dioxane and 20 ml of water is refluxed with stirring for 2 hours in 100 ml flask. After cooling, the mixture is mixed with 1.6 g of 50% sodium hydroxide and stirred for 10 minutes. The resulting mixture is neutralized with hydrochloric acid and extracted with ethyl acetate. The extract is concentrated under reduced pressure to give 4 g of 2,4-bis(ethylamino-6-mercapto-1,3,5-triazine. The product can be used for preparation of the objective compound without isolation.
Reaction SMILES: [Cl:1][C:2]([Cl:12])=[CH:3][CH2:4][CH:5]([CH:9]([CH3:11])[CH3:10])[C:6](O)=[O:7].S(Cl)([Cl:15])=O>C1C=CC=CC=1>[Cl:1][C:2]([Cl:12])=[CH:3][CH2:4][CH:5]([CH:9]([CH3:11])[CH3:10])[C:6]([Cl:15])=[O:7]
Reactant: CC(C)C(CC=C(Cl)Cl)C(=O)O
Reactant: O=S(Cl)Cl
Solvent: c1ccccc1
Product: CC(C)C(CC=C(Cl)Cl)C(=O)Cl
Yield: 79 %

Procedure:
To 2.1 g of α-(3,3-dichloroallyl)isovaleric acid were added 3.0 g of thionyl chloride, as well as 10 g of benzene, and the mixture was refluxed for 5 hours. Then, the reaction mixture was distilled to remove the low-boiling fraction. By this procedure there was obtained α-(3,3-dichloroallyl)isovaleroyl chloride. This chloride was dissolved in 30 g of dry benzene, followed by the addition of 2.0 g of 3-phenoxybenzyl alcohol. Then, 2.0 g of pyridine were added added dropwise and the mixture was stirred at room temperature overnight. The reaction mixture was then diluted with diethyl ether, washed with dilute hydrochloric acid and water, dried over anhydrous magnesium sulfate and distilled to remove the low-boiling fraction. The residual viscous oil was purified by column chromatography to recover 3.1 g of 3-phenoxybenzyl α-(3,3-dichloroallyl)isovalerate (Compound [5]) having the following properties [yield: 79% based on α-(3,3-dichloroallyl)isovaleric acid].
Reaction SMILES: [CH3:1][O:2][C:3]([CH:5]1[CH2:11][CH2:10][CH2:9][CH2:8][N:7]2[CH:12]=[CH:13][CH:14]=[C:6]12)=[O:4].[C:15](Cl)(=[O:22])[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1>C1(C)C(C)=CC=CC=1>[CH3:1][O:2][C:3]([CH:5]1[CH2:11][CH2:10][CH2:9][CH2:8][N:7]2[C:12]([C:15](=[O:22])[C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)=[CH:13][CH:14]=[C:6]12)=[O:4]
Reactant: O=C(Cl)c1ccccc1
Reactant: COC(=O)C1CCCCn2cccc21
Solvent: Cc1ccccc1C
Product: COC(=O)C1CCCCn2c(C(=O)c3ccccc3)ccc21
Reaction time: 44 h

Procedure:
A solution of the resulting ester (1.2 g., 0.006 moles) in dry xylene (50 ml.) containing benzoyl chloride (1.5 g., 0.01 moles) is heated at reflux temperature, in a nitrogen atmosphere, for 44 hours. The solvent is removed in vacuo and the residue is purified by t.l.c. on silica gel (hexane-ethyl acetate, 3:1) to give a product in 50% yield which, when crystallized from acetone hexane, gives methyl-3-benzoyl-5,6,7,8-tetrahydro-9H-pyrrolo[1,2,a]azepine-9-carboxylate having a m.p. 98°-99° C.
Reaction SMILES: ClC1C(F)=CC(F)=C(C=1)C(NS(C)(=O)=O)=O.[Cl:17][C:18]1[C:19](F)=[CH:20][C:21]([F:31])=[C:22]([CH:30]=1)[C:23]([NH:25][S:26](=[O:29])(=[O:28])[NH2:27])=[O:24].C12(CO)CC3CC(CC(C3)C1)C2.[CH3:45][C:46]1([CH3:55])[C@H:51]2[CH2:52][C@@H:47]1[CH2:48][CH2:49][C@@H:50]2[CH2:53][OH:54]>>[Cl:17][C:18]1[C:19]([O:54][CH2:53][C@H:50]2[CH2:49][CH2:48][C@H:47]3[CH2:52][C@@H:51]2[C:46]3([CH3:55])[CH3:45])=[CH:20][C:21]([F:31])=[C:22]([CH:30]=1)[C:23]([NH:25][S:26](=[O:29])(=[O:28])[NH2:27])=[O:24]
Reactant: NS(=O)(=O)NC(=O)c1cc(Cl)c(F)cc1F
Reactant: CC1(C)[C@H]2CC[C@H](CO)[C@@H]1C2
Agent: CS(=O)(=O)NC(=O)c1cc(Cl)c(F)cc1F
Agent: OCC12CC3CC(CC(C3)C1)C2
Product: CC1(C)[C@H]2CC[C@H](COc3cc(F)c(C(=O)NS(N)(=O)=O)cc3Cl)[C@@H]1C2

Procedure:
Following the procedure as described in Example 8 and making variations as required to replace 5-chloro-2,4-difluoro-N-(methylsulfonyl)benzamide with 5-chloro-2,4-difluoro-N-sulfamoylbenzamide and adamantan-1-ylmethanol with ((1S,2S,5S)-6,6-dimethylbicyclo[3.1.1]heptan-2-yl)methanol, the title compound was obtained as a colorless solid (0.09 g, 15%): 1H NMR (300 MHz, DMSO-d6) δ 11.73 (s, 1H), 7.66 (d, J=7.5 Hz, 1H), 7.58 (s, 2H), 7.22 (d, J=12.4 Hz, 1H), 3.95 (d, J=6.8 Hz, 2H), 2.49-2.38 (m, 1H), 2.10-2.03 (m, 1H), 2.19-1.65 (m, 5H), 1.48-1.34 (m, 2H), 1.22 (s, 3H), 0.86 (s, 3H); MS (ES−) m/z 403.2, 405.2 (M−1).
Reaction SMILES: [NH2:1][CH2:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[N:9]=[C:8]([NH:13][CH2:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=1[O:21][CH3:22])[CH:7]=[CH:6]2.[F:23][C:24]1[CH:31]=[CH:30][C:27]([CH:28]=O)=[CH:26][CH:25]=1.C(O)(=O)C>ClCCCl>[F:23][C:24]1[CH:31]=[CH:30][C:27]([CH2:28][NH:1][CH2:2][C:3]2[CH:4]=[C:5]3[C:10](=[CH:11][CH:12]=2)[N:9]=[C:8]([NH:13][CH2:14][C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=2[O:21][CH3:22])[CH:7]=[CH:6]3)=[CH:26][CH:25]=1
Reactant: COc1ccccc1CNc1ccc2cc(CN)ccc2n1
Reactant: O=Cc1ccc(F)cc1
Solvent: ClCCCl
Solvent: CC(=O)O
Product: COc1ccccc1CNc1ccc2cc(CNCc3ccc(F)cc3)ccc2n1
Temperature: 25 °C
Reaction time: 60 h
Yield: 53.2 %

Procedure:
A solution of (6-aminomethyl-quinolin-2-yl)-(2-methoxy-benzyl)-amine (example 85, step B) (390 mg, 1.33 mmol), 4-fluorobenzaldehyde (181.5 mg, 1.46 mmol) and acetic acid (319.3 mg, 5.32 mmol) in 1,2-dichloroethane (15 ml) was stirred at room temperature for 30 min. Afterwards sodium triacetoxy-boron hydride (657 mg, 2.79 mmol) was added, the reaction mixture was allowed to stir for 60 h at room temperature, poured into ice/saturated NaHCO3 solution (30 ml) and extracted with dichloromethane (2×40 ml). The combined organic layers were washed with brine (30 ml), dried (MgSO4) and evaporated. The crude product was purified by flash chromatography (ethyl acetate/heptane) on silica gel to yield the title compound as colorless oil (284 mg, 53%).
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[C:6]([CH3:8])[N:5]=[C:4]([NH:9][S:10]([C:13]2[CH:18]=[CH:17][C:16]([NH:19][CH2:20][C:21]3[CH:26]=[CH:25][C:24]([N+:27]([O-])=O)=[CH:23][CH:22]=3)=[CH:15][CH:14]=2)(=[O:12])=[O:11])[N:3]=1.O.[NH3+]N>O1CCCC1.[Pd]>[NH2:27][C:24]1[CH:25]=[CH:26][C:21]([CH2:20][NH:19][C:16]2[CH:15]=[CH:14][C:13]([S:10]([NH:9][C:4]3[N:3]=[C:2]([CH3:1])[CH:7]=[C:6]([CH3:8])[N:5]=3)(=[O:12])=[O:11])=[CH:18][CH:17]=2)=[CH:22][CH:23]=1
Reactant: Cc1cc(C)nc(NS(=O)(=O)c2ccc(NCc3ccc([N+](=O)[O-])cc3)cc2)n1
Agent: [Pd]
Agent: N[NH3+]
Solvent: O
Solvent: C1CCOC1
Product: Cc1cc(C)nc(NS(=O)(=O)c2ccc(NCc3ccc(N)cc3)cc2)n1
Reaction time: 8 h
Yield: 59 %

Procedure:
18 mg (0.04 mmol) of N-(4,6-dimethylpyrimidin-2-yl)-4-(4-nitrobenzylamino)-benzenesulfonamide was dissolved in 1 ml of tetrahydrofurane. Hydrazinium hydrate (50 μl, 1.5 mmol) and catalytic amount of palladium on charcoal were added to the reaction mixture. Solution was stirred overnight. The reaction mixture was evaporated to dryness and purified on silica using gradient elution (chloroform to 4% methanol in chloroform) to obtain with a yield of 59%. MS (ESI+): m/z 406 (M+H)+, 384 (M+H)+.
Reaction SMILES: [Si:1]([O:8][C@@H:9]([CH3:15])[C:10](OCC)=[O:11])([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].CC(C[AlH]CC(C)C)C.CO.C(C(C(C([O-])=O)O)O)([O-])=O.[Na+].[K+]>C(Cl)Cl>[Si:1]([O:8][C@@H:9]([CH3:15])[CH:10]=[O:11])([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2]
Reactant: CCOC(=O)[C@H](C)O[Si](C)(C)C(C)(C)C
Agent: CC(C)C[AlH]CC(C)C
Agent: O=C([O-])C(O)C(O)C(=O)[O-]
Agent: [K+]
Solvent: CO
Solvent: ClCCl
Product: C[C@@H](C=O)O[Si](C)(C)C(C)(C)C
Temperature: -78 °C
Reaction time: 2 h
Yield: 49 %

Procedure:
To a solution of (S)-ethyl 2-(tert-butyldimethylsilyloxy)propanoate (6.3 g, 27.1 mmol) in CH2Cl2 (22 mL) was added 54.2 mL of DIBAL (1.0 M in CH2Cl2, 54.2 mmol) over 20 min at −78° C. After stirring for 2 h at −78° C., methanol (3 mL) was added to the solution at the same temperature. The mixture was allowed to warm to RT and saturated aqueous potassium sodium tartrate (60 mL) was added to the solution. The resulting mixture was vigorously stirred for 3 h. The mixture was extracted with dichloromethane (30 mL×2), and the combined extracts were washed with brine (20 mL), dried over sodium sulfate, and concentrated in vacuo. The residue was distilled under vacuum (bp 50-52° C., 0.5 mmHg) to afford 2.5 g (49%) of (S)-2-(tert-butyldimethylsilyloxy)propanal: 1H NMR (400 MHz, CHLOROFORM-d) δ 9.59 (d, J=1.3 Hz, 1H), 4.07 (dq, J=6.9, 1.3 Hz, 1H), 1.26 (d, J=6.9 Hz, 3H), 0.93 (s, 9H), 0.08 (s, 3H), 0.07 (s, 3H).