Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:4][C:5]1[CH:6]=[C:7]([CH:12]=[C:13]([C:15]#[N:16])[CH:14]=1)[C:8]([O:10]C)=[O:9])[CH:2]=[CH2:3].[OH-].[Li+]>CO.O1CCCC1>[CH2:1]([O:4][C:5]1[CH:6]=[C:7]([CH:12]=[C:13]([C:15]#[N:16])[CH:14]=1)[C:8]([OH:10])=[O:9])[CH:2]=[CH2:3]
Reactant: C=CCOc1cc(C#N)cc(C(=O)OC)c1
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Product: C=CCOc1cc(C#N)cc(C(=O)O)c1
Temperature: 70 °C
Reaction time: 0.5 h
Yield: 71.3 %

Procedure:
A solution of methyl 3-(allyloxy)-5-cyanbenzoate (1.5 g, 6.9 mmol) in methanol-tetrahydrofuran (1:2, 30 mL) was treated with 0.5 N lithium hydroxide (17 mL, 8.3 mmol). The reaction was stirred at 70° C. for 30 minutes and then the solvent was removed in vacuo. The residue was dissolved in a small amount of water and then acidified (pH ˜4) by the addition of 2N hydrogen chloride. The precipitate was collected and dried to afford 1.0 g (74%) of 3-allyloxy-5-cyanobenzoic acid as a white solid.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:12]([O:13][CH3:14])=[N:11][C:10]2[C:9]([C:15](Cl)=[O:16])=[C:8]([CH3:18])[C:7]([N+:19]([O-:21])=[O:20])=[CH:6][C:5]=2[N:4]=1.[NH2:22][C:23]1[CH:28]=[CH:27][C:26]([CH3:29])=[CH:25][CH:24]=1>O1CCCC1>[C:26]1([CH3:29])[CH:27]=[CH:28][C:23]([NH:22][C:15]([C:9]2[C:10]3[N:11]=[C:12]([O:13][CH3:14])[C:3]([O:2][CH3:1])=[N:4][C:5]=3[CH:6]=[C:7]([N+:19]([O-:21])=[O:20])[C:8]=2[CH3:18])=[O:16])=[CH:24][CH:25]=1
Reactant: Cc1ccc(N)cc1
Reactant: COc1nc2cc([N+](=O)[O-])c(C)c(C(=O)Cl)c2nc1OC
Solvent: C1CCOC1
Product: COc1nc2cc([N+](=O)[O-])c(C)c(C(=O)Nc3ccc(C)cc3)c2nc1OC

Procedure:
Prepared from 2,3-dimethoxy-6-methyl-7-nitro-quinoxaline-5-carbonyl chloride (13) 250 mg (0.80 mmol) and p-toluidine 180 mg (1.68 mmol). Reaction was carried out in refluxing tetrahydrofuran for 50 hours, and the crude product was eluted through a flash column (7:3 hexanes:ethyl acetate), 200 mg (65%), mp 214-215° C.; 1H NMR (CDCl3): δ 8.33 (s, 1H), 7.69 (d, 2H, J=8.3 Hz), 7.65 (s, 1H), 7.15 (d, 2H, J=8.3 Hz), 4.17 (s, 3H), 4.03 (s, 3H), 2.58 (s, 3H), 2.32 (s, 3H); MS (APCI): m/z 383 (M+H). Anal Calcd. for C19H18N4O5: C, 59.68; H, 4.74; N, 14.65. Found: C, 59.97; H, 4.68; N, 14.71.
Reaction SMILES: [C:1]([O:5][CH:6]([C:12]1[C:21]([CH3:22])=[C:20](C)[C:19]2[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=2)[C:13]=1[C:24]1[CH:29]=[CH:28][C:27]([Cl:30])=[CH:26][CH:25]=1)[C:7]([O:9]CC)=[O:8])([CH3:4])([CH3:3])[CH3:2].[CH3:31][N:32]([C:34]1[CH:39]=[CH:38][C:37](B(O)O)=[CH:36][N:35]=1)[CH3:33]>>[C:1]([O:5][CH:6]([C:12]1[C:21]([CH3:22])=[C:20]([C:37]2[CH:36]=[N:35][C:34]([N:32]([CH3:33])[CH3:31])=[CH:39][CH:38]=2)[C:19]2[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=2)[C:13]=1[C:24]1[CH:29]=[CH:28][C:27]([Cl:30])=[CH:26][CH:25]=1)[C:7]([OH:9])=[O:8])([CH3:4])([CH3:2])[CH3:3]
Reactant: CCOC(=O)C(OC(C)(C)C)c1c(C)c(C)c2ccccc2c1-c1ccc(Cl)cc1
Reactant: CN(C)c1ccc(B(O)O)cn1
Product: Cc1c(C(OC(C)(C)C)C(=O)O)c(-c2ccc(Cl)cc2)c2ccccc2c1-c1ccc(N(C)C)nc1

Procedure:
2-tert-Butoxy-2-(1-(4-chlorophenyl)-4-(6-(dimethylamino)pyridin-3-yl)-3-methylnaphthalen-2-yl)acetic acid (137) was prepared in a manner similar to 2-tert-butoxy-2-(1-(4-chlorophenyl)-3,4-dimethylnaphthalen-2-yl)acetic acid of Example 125, except using 2-(N,N-dimethylamino)-pyridin-5-yl-boronic acid in the Suzuki reaction, giving the title compound. 1H-NMR: (400 MHz, DMSO-d6): δ 8.02-8.00 (m, 1H); 7.78 (m, broad, 1H); 7.72-7.69 (m, 1H); 7.67-7.65 (m, 1H); 7.52-7.49 (m, 1H); 7.45-7.36 (m, 4H); 7.23 (d, J=8.0 Hz, 2H); 5.11 (s, 1H); 2.29 (d, J=1.2 Hz, 3H); 0.93 (d, J=1.2 Hz, 9H). LCMS-ESI+ (m/z): [M+H]+ calcd for C30H32ClN2O3: 503.2; Found: 503.3.
Reaction SMILES: N[C:2]1[C:11]2[N:12]=[C:13]([CH2:25][CH2:26][CH2:27][CH3:28])[N:14]([CH2:15][CH2:16][NH:17][C:18](=[O:24])[O:19][C:20]([CH3:23])([CH3:22])[CH3:21])[C:10]=2[C:9]2[CH:8]=[CH:7][C:6](Br)=[CH:5][C:4]=2[N:3]=1.[N:30]1[CH:35]=[CH:34][CH:33]=[C:32](B(O)O)[CH:31]=1>>[CH2:25]([C:13]1[N:14]([CH2:15][CH2:16][NH:17][C:18](=[O:24])[O:19][C:20]([CH3:22])([CH3:21])[CH3:23])[C:10]2[C:9]3[CH:8]=[CH:7][C:6]([C:32]4[CH:31]=[N:30][CH:35]=[CH:34][CH:33]=4)=[CH:5][C:4]=3[N:3]=[CH:2][C:11]=2[N:12]=1)[CH2:26][CH2:27][CH3:28]
Reactant: CCCCc1nc2c(N)nc3cc(Br)ccc3c2n1CCNC(=O)OC(C)(C)C
Reactant: OB(O)c1cccnc1
Product: CCCCc1nc2cnc3cc(-c4cccnc4)ccc3c2n1CCNC(=O)OC(C)(C)C
Yield: 83.2 %

Procedure:
tert-Butyl [2-(4-amino-7-bromo-2-butyl-1H-imidazo[4,5-c]quinolin-1-yl)ethyl]carbamate (14.09 g, 30.5 mmol) and 3-pyridylboronic acid (4.31 g, 35.0 mmol) were coupled according to the method described in Part G of Example 386. The reaction was heated for 2.5 hours. The crude product was triturated with toluene (15 mL/g) at 123° C. and isolated by filtration to provide 11.31 g of tert-butyl {2-[2-butyl-7-(pyridin-3-yl)-1H-imidazo[4,5-c]quinolin-1-yl]ethyl}carbamate as a white solid.
Reaction SMILES: [F:1][CH:2]([CH2:21][CH2:22][C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)[CH2:3][CH2:4][CH2:5][CH:6]([N:10]1[CH:13]([S:14][CH3:15])[C:12]([CH2:18][CH3:19])([CH2:16][CH3:17])[C:11]1=[O:20])[C:7]([O-])=[O:8].C(C1(CC)C(SC)[N:33](CC(OC)=O)C1=O)C.FC1C=CC(CCCCCCO)=CC=1.C[O-].[Na+]>C1C=CC=CC=1>[F:1][CH:2]([CH2:21][CH2:22][C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)[CH2:3][CH2:4][CH2:5][CH:6]([N:10]1[CH:13]([S:14][CH3:15])[C:12]([CH2:18][CH3:19])([CH2:16][CH3:17])[C:11]1=[O:20])[C:7]([NH2:33])=[O:8]
Reactant: CCC1(CC)C(=O)N(CC(=O)OC)C1SC
Reactant: CCC1(CC)C(=O)N(C(CCCC(F)CCc2ccccc2)C(=O)[O-])C1SC
Agent: C[O-]
Agent: OCCCCCCc1ccc(F)cc1
Agent: [Na+]
Solvent: c1ccccc1
Product: CCC1(CC)C(=O)N(C(CCCC(F)CCc2ccccc2)C(N)=O)C1SC
Reaction time: 2 h
Yield: 13 %

Procedure:
4-Fluorophenylhexyl(3,3-diethyl-4-methylthio-2-oxoazetidin-1-yl)acetate-Methyl (3,3-diethyl-4-methylthio-2-oxo-azetidin-1-yl)acetate (0.8 g, 3.2 mmol) was dissolved in benzene with 4-fluorophenylhexylalcohol (1.3 g, 6.5 mmol) and sodium methoxide (SOmg ,0.9 mmol) and the mixture refuxed for 2 h. The reaction mixture was evaporated and diluted with EtOAc, the solution washed with water, separated, dried (K2CO3) and flash chromatographed (hexane/ethyl acetate 9:1) to give 4-fluorophenylhexyl(3,3-diethyl-4-methylthio-2-oxoazetidin-1-yl)acetamide 0.17 g, 14% as an oil.
Reaction SMILES: C1(C)C(C)=CC=CC=1.[Cl:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=1[C:16](=O)[CH:17]([CH3:30])[C:18](=[O:29])[CH2:19][C:20]([C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=1[Cl:28])=O.[Cl:32][C:33]1[CH:39]=[CH:38][CH:37]=[CH:36][C:34]=1[NH2:35]>C(Cl)(Cl)Cl>[Cl:32][C:33]1[CH:39]=[CH:38][CH:37]=[CH:36][C:34]=1[N:35]1[C:20]([C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=2[Cl:28])=[CH:19][C:18](=[O:29])[C:17]([CH3:30])=[C:16]1[C:11]1[CH:12]=[CH:13][CH:14]=[CH:15][C:10]=1[Cl:9]
Reactant: Nc1ccccc1Cl
Reactant: CC(C(=O)CC(=O)c1ccccc1Cl)C(=O)c1ccccc1Cl
Solvent: Cc1ccccc1C
Solvent: ClC(Cl)Cl
Product: Cc1c(-c2ccccc2Cl)n(-c2ccccc2Cl)c(-c2ccccc2Cl)cc1=O
Temperature: 0 °C
Yield: 15.9 %

Procedure:
To 200 ml of xylene were added 6.9 g (0.020 mole) of 1,5-bis(2-chlorophenyl)-2-methyl-1,3,5-pentanetrione, 25.5 g (0.20 mole) of 2-chloroaniline and 20.0 g of Molecular Sieves 5A. After heating the reaction mixture under reflux for 2 hours, the reaction mixture was poured into ice water, followed by addition of 200 ml of chloroform thereto and vigorous stirring of the resultant mixture. One hour later, the reaction mixture was filtered to remove solid matter. The organic layer was washed first with 50 ml of 10% hydrochloric acid and then with 50 ml of a 10% aqueous solution of sodium hydroxide. The mixture was washed further with water and was then dried over anhydrous sodium sulfate. Subsequent to removal of the sodium sulfate, the solvent was distilled off. The residue was purified by chromatography on a silica gel column (eluent: ethyl acetate) and then recrystallization from acetone to give 1.4 g of 1,2,6-tris(2-chlorophenyl)-3-methyl-4(1H)-pyridinone having a melting point of 205°-207° C.
Reaction SMILES: [NH2:1][C:2]1[CH:10]=[CH:9][C:8]([I:11])=[CH:7][C:3]=1[C:4](O)=[O:5].[NH2:12][C:13](N)=[O:14].O>CN1C(=O)CCC1>[I:11][C:8]1[CH:7]=[C:3]2[C:2](=[CH:10][CH:9]=1)[NH:1][C:13](=[O:14])[NH:12][C:4]2=[O:5]
Reactant: Nc1ccc(I)cc1C(=O)O
Reactant: NC(N)=O
Solvent: CN1CCCC1=O
Solvent: O
Product: O=c1[nH]c(=O)c2cc(I)ccc2[nH]1
Temperature: 160 °C
Yield: 87.4 %

Procedure:
A mixture of 2-amino-5-iodobenzoic acid (3.5 g) and urea (1.56 g) in NMP (15 ml) was heated at 160° C. for 6 hours then cooled. Water (200 ml) was added and the resultant precipitate was collected, washed with water and dried to give the title compound (3.35 g) as a solid. MS (CI): 289 (M+H)+.
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][C:11]([C:22]#[N:23])([C:14]2[CH:19]=[CH:18][C:17]([Cl:20])=[CH:16][C:15]=2[Cl:21])[CH2:10][CH2:9]1)=O)(C)(C)C>ClCCl.FC(F)(F)C(O)=O>[Cl:21][C:15]1[CH:16]=[C:17]([Cl:20])[CH:18]=[CH:19][C:14]=1[C:11]1([C:22]#[N:23])[CH2:12][CH2:13][NH:8][CH2:9][CH2:10]1
Reactant: CC(C)(C)OC(=O)N1CCC(C#N)(c2ccc(Cl)cc2Cl)CC1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: N#CC1(c2ccc(Cl)cc2Cl)CCNCC1
Temperature: 25 °C
Reaction time: 1 h
Yield: 99.6 %

Procedure:
To 4-cyano-4-(2,4-dichlorophenyl)-piperidine-1-carboxylic acid tert-butyl ester (0.620 g, 1.74 mmol) in dichloromethane (5 mL), trifluoroacetic acid (2 mL) was added and the solution stirred at room temperature for 1 hour. The solution was concentrated, neutralized with 10% KOH solution and extracted into 25 ml of dichloromethane. The organic layer was dried over sodium sulfate, filtered and concentrated to give 0.442 g (99%) of 4-(2,4-dichlorophenyl)-piperidine-4-carbonitrile which was used as such for the subsequent step.
Reaction SMILES: [Br:1][C:2]1[CH:10]=[CH:9][C:5]([C:6](O)=[O:7])=[CH:4][C:3]=1[Cl:11].Cl.CN(C)CCCN=C=NCC.[CH3:24][Si:25]([CH2:28][NH2:29])([CH3:27])[CH3:26].O>ClCCl>[Br:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([NH:29][CH2:28][Si:25]([CH3:27])([CH3:26])[CH3:24])=[O:7])=[CH:4][C:3]=1[Cl:11]
Reactant: O=C(O)c1ccc(Br)c(Cl)c1
Reactant: C[Si](C)(C)CN
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: O
Solvent: ClCCl
Product: C[Si](C)(C)CNC(=O)c1ccc(Br)c(Cl)c1
Temperature: 25 °C
Reaction time: 5 h

Procedure:
To a solution of 4-bromo-3-chloro-benzoic acid (commercially available) (5.0 g) in dichloromethane (30 ml) was added N-(−3-dimethylaminopropyl)-N′-ethylcarbodiimid hydrochloride (5.29 g), N,N-dimethylaminopyridine (1.19 g) and trimethylsilylmethylamine (2.85 ml). The reaction mixture was stirred at ambient temperature for 5 hours. Water and dichloromethane was added to the reaction mixture. The phases were separated and the organic phase was washed with brine, dried over sodium sulfate and filtered through silica gel. The reaction mixture was concentrated to give 4-bromo-3-chloro-N-trimethylsilanylmethyl-benzamide (4.87 g). 1H-NMR (400 MHz, CDCl3): 7.68 (d, 1H), 7.55 (s, 1H), 7.33 (d, 1H), 5.85 (s, 1H), 2.84 (d, 2H), 0.00 (s, 9H) ppm.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:18])[C:4]1[CH:5]=[C:6]([CH:14]=[C:15]([NH2:17])[CH:16]=1)[C:7]([O:9][C:10]([CH3:13])([CH3:12])[CH3:11])=[O:8].CCN(CC)CC.[Cl:26][CH2:27][CH2:28][CH2:29][C:30](Cl)=[O:31]>C(Cl)Cl>[CH3:1][O:2][C:3](=[O:18])[C:4]1[CH:5]=[C:6]([CH:14]=[C:15]([NH:17][C:30](=[O:31])[CH2:29][CH2:28][CH2:27][Cl:26])[CH:16]=1)[C:7]([O:9][C:10]([CH3:13])([CH3:11])[CH3:12])=[O:8]
Reactant: COC(=O)c1cc(N)cc(C(=O)OC(C)(C)C)c1
Reactant: O=C(Cl)CCCCl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COC(=O)c1cc(NC(=O)CCCCl)cc(C(=O)OC(C)(C)C)c1
Temperature: 0 °C
Reaction time: 3 h
Yield: 93.7 %

Procedure:
A suspension of 5-amino-isophthalic acid 1-tert-butyl ester 3-methyl ester (D79) (3.4 g, 13.5 mmol, 1 equiv) in CH2Cl2 (25 ml) was treated with NEt3 (2.32 g, 23 mmol, 1.1 equiv) and cooled to 0° C. 4-chlorobutyryl chloride (1.6 g, 15.7 mmol, 1.1 equiv) was added dropwise and the resulting solution was stirred at 0° C. for 3 h then allowed to warm to room temperature and washed with 2N aqueous HCl solution, dried over MgSO4 and concentrated in vacuo. The residue was triturated with iso-hexane and Et2O to give 5-(4-chloro-butanoylamino)-isophthalic acid 1-tert-butyl ester 3-methyl ester (D80) (4.5 g, 94%) as a white solid.
Reaction SMILES: F[C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[CH:4][CH:3]=1.[F:11][C:12]1[CH:17]=[CH:16][C:15]([OH:18])=[CH:14][C:13]=1[C:19]([F:22])([F:21])[F:20].C(=O)([O-])[O-].[K+].[K+].O>CN(C=O)C>[F:11][C:12]1[CH:17]=[CH:16][C:15]([O:18][C:2]2[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[CH:4][CH:3]=2)=[CH:14][C:13]=1[C:19]([F:20])([F:21])[F:22]
Reactant: Oc1ccc(F)c(C(F)(F)F)c1
Reactant: O=[N+]([O-])c1ccc(F)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: O=[N+]([O-])c1ccc(Oc2ccc(F)c(C(F)(F)F)c2)cc1
Temperature: 90 °C

Procedure:
To a stirred solution of 4-fluoronitrobenzene (20 mmol), 4-fluoro-3-trifluoromethylphenol (22 mmol) in DMF (50 mL) at rt, solid potassium carbonate (60 mmol) was added, and the reaction mixture was heated to 90° C. for 5 h (monitored by TLC), according to General Procedure L1. After cooling to rt, the reaction mixture was poured into cold H2O (60 mL). The resulting mixture was extracted with EtOAc (3×100 mL). The combined EtOAc extracts were washed with H2O (2×40 mL) and brine (50 mL), and dried over anhydrous sodium sulfate. The solvent was removed in vacuuo to afford the desired 1-fluoro-4-(4-nitrophenoxy)-2-(trifluoromethyl)benzene. The crude product was used directly for further transformation without further purification.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6]([CH2:8][O:9][C:10]2[CH:11]=[C:12]([O:22][C:23]3[CH:28]=[CH:27][C:26]([S:29]([CH3:32])(=[O:31])=[O:30])=[CH:25][CH:24]=3)[CH:13]=[C:14]3[C:18]=2[NH:17][C:16]([C:19](O)=[O:20])=[CH:15]3)[CH:5]=[CH:4][CH:3]=1.Cl.C[N:35](C)CCCN=C=NCC.[NH4+].ON1C2C=CC=CC=2N=N1.CN(C)C=O>O>[Cl:1][C:2]1[N:7]=[C:6]([CH2:8][O:9][C:10]2[CH:11]=[C:12]([O:22][C:23]3[CH:24]=[CH:25][C:26]([S:29]([CH3:32])(=[O:31])=[O:30])=[CH:27][CH:28]=3)[CH:13]=[C:14]3[C:18]=2[NH:17][C:16]([C:19]([NH2:35])=[O:20])=[CH:15]3)[CH:5]=[CH:4][CH:3]=1
Reactant: CS(=O)(=O)c1ccc(Oc2cc(OCc3cccc(Cl)n3)c3[nH]c(C(=O)O)cc3c2)cc1
Reactant: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Agent: [NH4+]
Solvent: CN(C)C=O
Solvent: O
Product: CS(=O)(=O)c1ccc(Oc2cc(OCc3cccc(Cl)n3)c3[nH]c(C(N)=O)cc3c2)cc1
Temperature: 25 °C
Reaction time: 15 h
Yield: 87.4 %

Procedure:
A mixture of 7-[(6-chloropyridin-2-yl)methoxy]-5-[4-(methylsulfonyl)phenoxy]-1H-indole-2-carboxylic acid (780 mg), 1-[3-(dimethylamino)propyl-3-ethylcarbodiimide hydrochloride (632 mg), 1-hydroxybenzotriazole ammonium salt (502 mg) and N,N-dimethylformamide (30 mL) was stirred at room temperature for 15 hr. Water was added to the reaction solution, and the precipitated solid was collected by filtration, and washed successively with water and diethyl ether to give the title compound (680 mg, yield 90%) as a white solid. The obtained crystals were recrystallized from N,N-dimethylformamide-water to give colorless crystals. melting point 259-260° C.
Reaction SMILES: [CH:1]1([O:6][C:7]2[CH:8]=[C:9]([C:15]3[C@H:24]4[C@H:19]([CH2:20][CH2:21][CH2:22][CH2:23]4)[C:18](=[O:25])[NH:17][N:16]=3)[CH:10]=[CH:11][C:12]=2[O:13][CH3:14])[CH2:5][CH2:4][CH2:3][CH2:2]1.[CH:26]1(Br)[CH2:32][CH2:31][CH2:30][CH2:29][CH2:28][CH2:27]1.COC1C=C(C2[C@H]3[C@H](CCCC3)C(=O)N(C)N=2)C=CC=1OC>>[CH:1]1([O:6][C:7]2[CH:8]=[C:9]([C:15]3[C@H:24]4[C@H:19]([CH2:20][CH2:21][CH2:22][CH2:23]4)[C:18](=[O:25])[N:17]([CH:26]4[CH2:32][CH2:31][CH2:30][CH2:29][CH2:28][CH2:27]4)[N:16]=3)[CH:10]=[CH:11][C:12]=2[O:13][CH3:14])[CH2:2][CH2:3][CH2:4][CH2:5]1
Reactant: COc1ccc(C2=NNC(=O)[C@H]3CCCC[C@@H]23)cc1OC1CCCC1
Reactant: BrC1CCCCCC1
Agent: COc1ccc(C2=NN(C)C(=O)[C@H]3CCCC[C@@H]23)cc1OC
Product: COc1ccc(C2=NN(C3CCCCCC3)C(=O)[C@H]3CCCC[C@@H]23)cc1OC1CCCC1

Procedure:
Prepared from compound 4 and cycloheptylbromide as described for compound 8. Crystallized from petroleum ether (60-80° C.) M.p.111-112° C.
Reaction SMILES: [Cl:1][S:2]([OH:5])(=O)=[O:3].[Br:6][C:7]1[CH:15]=[CH:14][C:10]([C:11]([OH:13])=[O:12])=[CH:9][C:8]=1[CH3:16]>>[Br:6][C:7]1[C:8]([CH3:16])=[CH:9][C:10]([C:11]([OH:13])=[O:12])=[CH:14][C:15]=1[S:2]([Cl:1])(=[O:5])=[O:3]
Reactant: O=S(=O)(O)Cl
Reactant: Cc1cc(C(=O)O)ccc1Br
Product: Cc1cc(C(=O)O)cc(S(=O)(=O)Cl)c1Br
Temperature: 0 °C

Procedure:
Chlorosulfonic acid (150 mL, 2.18 mol) was added slowly to compound of Example 1b (74 g, 0.344 mol) at 0° C. The reaction mixture was refluxed for 4.5 h and then was poured into ice-cold water (1500 mL) with stirring. The solid was filtered, washed with water till filtrate was neutral and dried to obtain the title compound. Yield: 72.40 g (66.8%); 1H NMR (DMSO-d6, 300 MHz): δ 2.40 (s, 3H, CH3), 7.80 (s, 1H, Ar), 8.30 (s, 1H, Ar); MS: m/e (ES−) 315 (M−1).
Reaction SMILES: [CH:1]([C:4]1[CH:9]=[CH:8][C:7]([S:10]([NH:13][C:14]2[CH:19]=[CH:18][C:17]([CH:20]3[CH2:23][N:22]([C:24](=O)[CH2:25][CH3:26])[CH2:21]3)=[CH:16][CH:15]=2)(=[O:12])=[O:11])=[CH:6][CH:5]=1)([CH3:3])[CH3:2].C(OCC)(=O)C>C1COCC1>[CH:1]([C:4]1[CH:9]=[CH:8][C:7]([S:10]([NH:13][C:14]2[CH:19]=[CH:18][C:17]([CH:20]3[CH2:21][N:22]([CH2:24][CH2:25][CH3:26])[CH2:23]3)=[CH:16][CH:15]=2)(=[O:11])=[O:12])=[CH:6][CH:5]=1)([CH3:3])[CH3:2]
Reactant: CCC(=O)N1CC(c2ccc(NS(=O)(=O)c3ccc(C(C)C)cc3)cc2)C1
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: CCCN1CC(c2ccc(NS(=O)(=O)c3ccc(C(C)C)cc3)cc2)C1
Yield: 67.1 %

Procedure:
Following the same procedure as described in Example 46.6, 4-isopropyl-N-[4-(1-propionyl-azetidin-3-yl)-phenyl]-benzenesulfonamide (140 mg, 0.36 mmol) in THF (18 ml) was then treated with 1M BH3. THF (3.6 ml). The crude material was chromatographied (ethyl acetate) to afford the title compound (90 mg, 67%) as a pale yellow oil.
Reaction SMILES: Cl.[CH:2]1([NH:8][NH2:9])[CH2:7][CH2:6][CH2:5][CH2:4][CH2:3]1.[CH2:10]([O:12][C:13](=[O:21])[CH:14]([C:18](=O)[CH3:19])[C:15](=O)[CH3:16])[CH3:11].N1C=CC=CC=1>C(O)C>[CH2:10]([O:12][C:13]([C:14]1[C:15]([CH3:16])=[N:9][N:8]([CH:2]2[CH2:7][CH2:6][CH2:5][CH2:4][CH2:3]2)[C:18]=1[CH3:19])=[O:21])[CH3:11]
Reactant: CCOC(=O)C(C(C)=O)C(C)=O
Reactant: NNC1CCCCC1
Agent: Cl
Solvent: CCO
Solvent: c1ccncc1
Product: CCOC(=O)c1c(C)nn(C2CCCCC2)c1C

Procedure:
Similar to Example 1, equimolar amounts of cyclohexyl hydrazine hydrochloride and 2-acetyl-3-oxobutyric Acid Ethyl Ester were combined in a solution of 50% pyridine in ethanol. Analysis confirmed synthesis of the named product (m.p. 66° C.-67° C.).
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[CH:6][C:7]([C:10]2[CH2:11][C:12]([CH3:19])([CH3:18])S[C:14]([CH3:17])([CH3:16])[CH:15]=2)=[N:8][CH:9]=1)([O-:3])=[O:2].O[O:21][S:22]([O-:24])=O.[K+]>CO.O>[N+:1]([C:4]1[CH:5]=[CH:6][C:7]([C:10]2[CH2:11][C:12]([CH3:19])([CH3:18])[S:22](=[O:24])(=[O:21])[C:14]([CH3:17])([CH3:16])[CH:15]=2)=[N:8][CH:9]=1)([O-:3])=[O:2]
Reactant: O=S([O-])OO
Reactant: CC1(C)C=C(c2ccc([N+](=O)[O-])cn2)CC(C)(C)S1
Agent: [K+]
Solvent: CO
Solvent: O
Product: CC1(C)C=C(c2ccc([N+](=O)[O-])cn2)CC(C)(C)S1(=O)=O
Temperature: 0 °C
Reaction time: 1 h
Yield: 96 %

Procedure:
A solution of 5-nitro-2-(2,2,6,6-tetramethyl-3,6-dihydro-2H-thiopyran-4-yl)-pyridine (0.300 g, 1.08 mmol, as prepared in the previous step) in MeOH (15 mL) was cooled to 0° C. and treated with oxone (984 mg, 3.23 mmol based on KHSO5 content) as a solution in water (1.5 mL). The ice bath was removed, and the mixture was allowed to stir at RT for 1 h. The mixture was diluted with water and extracted with CH2Cl2 (2×). The combined organic layers were dried over MgSO4 and concentrated in vacuo. The residue was purified on a 25-g Sepra Si 50 SPE column (Isco system: Flow rate=20 mL/min; Eluent=5% EtOAc-hexane for 0-3 min, then 5-15% EtOAc-hexane for 5-30 min) to afford the title product (322 mg, 96%) as an off-white solid. Mass spectrum (ESI, m/z): Calcd. for C14H18N2O4S, 311.1 (M+H), found 311.0.
Reaction SMILES: [C:1]([C:5]1[CH:10]=[CH:9][C:8]([S:11]([N:14]([CH2:22][C:23]([OH:25])=O)[C:15]2[CH:20]=[CH:19][C:18]([CH3:21])=[CH:17][CH:16]=2)(=[O:13])=[O:12])=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2].[CH2:26]([NH:28][CH2:29][C:30]1[NH:31][CH:32]=[N:33][CH:34]=1)[CH3:27]>>[C:1]([C:5]1[CH:10]=[CH:9][C:8]([S:11]([N:14]([C:15]2[CH:20]=[CH:19][C:18]([CH3:21])=[CH:17][CH:16]=2)[CH2:22][C:23]([N:28]([CH2:26][CH3:27])[CH2:29][C:30]2[NH:31][CH:32]=[N:33][CH:34]=2)=[O:25])(=[O:13])=[O:12])=[CH:7][CH:6]=1)([CH3:3])([CH3:2])[CH3:4]
Reactant: CCNCc1cnc[nH]1
Reactant: Cc1ccc(N(CC(=O)O)S(=O)(=O)c2ccc(C(C)(C)C)cc2)cc1
Product: CCN(Cc1cnc[nH]1)C(=O)CN(c1ccc(C)cc1)S(=O)(=O)c1ccc(C(C)(C)C)cc1

Procedure:
prepared by reaction of [(4-tert-butyl-benzenesulfonyl)-p-tolyl-amino]-acetic acid with ethyl-(3H-imidazol-4-ylmethyl)-amine
Reaction SMILES: C([O:5][C:6](=[O:30])[CH2:7][N:8]1[C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[C:10]([CH:17]2[C:21]3[CH:22]=[CH:23][C:24]([F:26])=[CH:25][C:20]=3[S:19](=[O:28])(=[O:27])[NH:18]2)=[C:9]1[CH3:29])(C)(C)C.Cl[CH2:32][C:33]1[C:34]([CH3:39])=[N:35][O:36][C:37]=1[CH3:38]>>[CH3:39][C:34]1[C:33]([CH2:32][N:18]2[CH:17]([C:10]3[C:11]4[C:16](=[CH:15][CH:14]=[CH:13][CH:12]=4)[N:8]([CH2:7][C:6]([OH:5])=[O:30])[C:9]=3[CH3:29])[C:21]3[CH:22]=[CH:23][C:24]([F:26])=[CH:25][C:20]=3[S:19]2(=[O:28])=[O:27])=[C:37]([CH3:38])[O:36][N:35]=1
Reactant: Cc1c(C2NS(=O)(=O)c3cc(F)ccc32)c2ccccc2n1CC(=O)OC(C)(C)C
Reactant: Cc1noc(C)c1CCl
Product: Cc1noc(C)c1CN1C(c2c(C)n(CC(=O)O)c3ccccc23)c2ccc(F)cc2S1(=O)=O

Procedure:
The title compound was prepared by the method described for example 14 using the product from example 13, step e) and chloromethyl-3,5-dimethyl-isoxazole. 1H NMR (DMSO-d6) δ 13.1 (bs, 1H), 7.99 (dd, J=2.4, 7.5 Hz, 1H), 7.47 (dt, J=2.1, 8.8 Hz, 1H), 7.14-6.74 (m, 4H), 5.93 (s, 1H), 5.01 (s, 2H), 4.02 (d, J=15 Hz, 1H), 3.98 (d, 1H, J=15 Hz, 1H), 2.40 (s, 3H), 2.04 (s, 3H), 1.71 (s, 3H); MS: ESI (negative): 482 (M−H).
Reaction SMILES: [CH3:1][C:2]1[N:7]=[C:6]([O:8][CH3:9])[C:5]([CH2:10]O)=[CH:4][CH:3]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C(Cl)(Cl)(Cl)[Cl:32]>>[CH3:1][C:2]1[N:7]=[C:6]([O:8][CH3:9])[C:5]([CH2:10][Cl:32])=[CH:4][CH:3]=1
Reactant: COc1nc(C)ccc1CO
Reactant: ClC(Cl)(Cl)Cl
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Product: COc1nc(C)ccc1CCl

Procedure:
3.78 g of 6-methyl-2-methoxy-3-pyridinemethanol was dissolved in 60 ml of carbon tetrachloride, 6.48 g of triphenylphosphine was added thereto, and the mixture was heated under reflux for 6 hours 30 minutes. The solvent was evaporated, n-hexane was added to the residue, and the insoluble matters were filtered off. The filtrate was evaporated, and the crude product was purified by silica gel chromatography (n-hexane:ethyl acetate=100:1), to give 2.29 g of the title compound as a colorless oil.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[CH:4][CH:3]=1.[NH:11]1[CH2:16][CH2:15][CH2:14][CH2:13][CH2:12]1.C(=O)([O-])[O-].[K+].[K+].O>CS(C)=O>[N:11]1([C:2]2[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[CH:4][CH:3]=2)[CH2:16][CH2:15][CH2:14][CH2:13][CH2:12]1
Reactant: C1CCNCC1
Reactant: O=[N+]([O-])c1ccc(Br)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CS(C)=O
Solvent: O
Product: O=[N+]([O-])c1ccc(N2CCCCC2)cc1
Temperature: 100 °C

Procedure:
0.202 g (1.0 mmol) of 1-bromo-4-nitrobenzene and 0.20 ml of piperidine (2.0 mmol) were dissolved in 3 ml of dimethylsulfoxide. 0.207 g (1.5 mmol) of potassium carbonate was added and the reaction mixture was heated to 100° C. After 2 h 100 ml of water was added, and the mixture was extracted a few times with dichloromethane. The combined organic layers were dried over sodium sulfate and evaporated to obtain crude 4-(piperidin-1-yl)-1-nitrobenzene. Following the procedure outlined in Step 2 of Example 1, but substituting 4-piperidin-1-yl-1-nitrobenzene for 1-methyl-4-(4-nitrophenyl)piperazine, afforded 4-piperidin-1-ylaniline, which was reacted with 9-chloroacridine (according to Step 4 in the procedure of Example 1) to obtain the title compound with 6% overall yield.