Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[CH2:2][CH2:3][CH2:4][C:5]([C:7]1[CH:12]=[CH:11][C:10](F)=[CH:9][CH:8]=1)=O.[NH:14]1[CH:18]=[CH:17][N:16]=[CH:15]1>>[N:14]1([C:10]2[CH:11]=[CH:12][C:7]([C:5]3[C:15]4[N:14]([CH:18]=[CH:17][N:16]=4)[CH2:2][CH2:3][CH:4]=3)=[CH:8][CH:9]=2)[CH:18]=[CH:17][N:16]=[CH:15]1
Reactant: c1c[nH]cn1
Reactant: O=C(CCCCl)c1ccc(F)cc1
Product: C1=C(c2ccc(-n3ccnc3)cc2)c2nccn2CC1

Procedure:
Combine 50 g (0.25 mol) of 4-chloro-4'-fluorobutyrophenone with 120 g (1.76 mol) of imidazole, and heat to 175° C. for 18 hr. Isolation of the product from 500 g of silica gel, followed by crystallization from ethyl acetate, provides the title compound.
Reaction SMILES: [OH:1]O.[CH:3]1([C:6]2[N:10](C(=O)C)[N:9]=[C:8]([NH:14][C:15]3[C:20](B4OC(C)(C)C(C)(C)O4)=[CH:19][N:18]=[C:17]([C:30]4[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=4)[N:16]=3)[CH:7]=2)[CH2:5][CH2:4]1.O>C1COCC1>[CH:3]1([C:6]2[NH:10][N:9]=[C:8]([NH:14][C:15]3[C:20]([OH:1])=[CH:19][N:18]=[C:17]([C:30]4[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=4)[N:16]=3)[CH:7]=2)[CH2:5][CH2:4]1
Reactant: CC(=O)n1nc(Nc2nc(-c3ccccc3)ncc2B2OC(C)(C)C(C)(C)O2)cc1C1CC1
Reactant: OO
Solvent: O
Solvent: C1CCOC1
Product: Oc1cnc(-c2ccccc2)nc1Nc1cc(C2CC2)[nH]n1
Reaction time: 1 h
Yield: 8 %

Procedure:
30% H2O2 (10 mL) was added to the solution of 1-(5-cyclopropyl-3-(2-phenyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyrimidin-4-ylamino)-1H-pyrazol-1-yl)ethanone (200 mg, 0.45 mmol, 1.0 eq) in THF (5 mL) at 0° C. The mixture was stirred for 1 h and water was added. The solid was collected and dissolved in methanol (8 mL). To the solution was added 5 N NaOH (4 mL). The mixture was stirred for 2 h at room temperature and concentrated. To the residue was added ethanol and EtOAc. The emerged solid was filtered off. The filtrate was concentrated and the residue was recrystallized with CH2Cl2 and ethyl ether to give 4-(5-cyclopropyl-1H-pyrazol-3-ylamino)-2-phenylpyrimidin-5-ol (Compound 55) (10 mg, 8% over 2 steps). LC-MS (m/z)=294.0 [M+H]+. 1H NMR (400 MHz, DMSO-d6): δ 0.69-0.74 (m, 2H), 0.93-0.98 (m, 2H), 1.85-1.89 (m, 1H), 6.52 (bs, 1H), 7.40-7.47 (m, 3H), 7.93 (s, 1H), 8.22 (d, J=7.6 Hz, 2H), 8.41 (bs, 1H), 10.43 (bs, 1H), 12.09 (bs, 1H).
Reaction SMILES: [ClH:1].[CH:2]1([O:7][C:8]2[CH:15]=[C:14]([O:16][CH3:17])[CH:13]=[CH:12][C:9]=2[C:10]#[N:11])[CH2:6][CH2:5][CH2:4][CH2:3]1.[CH2:18]([OH:20])[CH3:19]>>[ClH:1].[CH:2]1([O:7][C:8]2[CH:15]=[C:14]([O:16][CH3:17])[CH:13]=[CH:12][C:9]=2[C:10](=[NH:11])[O:20][CH2:18][CH3:19])[CH2:3][CH2:4][CH2:5][CH2:6]1
Reactant: COc1ccc(C#N)c(OC2CCCC2)c1
Reactant: CCO
Agent: Cl
Product: CCOC(=N)c1ccc(OC)cc1OC1CCCC1
Temperature: 25 °C
Reaction time: 0.75 h

Procedure:
Hydrogen chloride gas was passed through a solution of 2-cyclopentyloxy-4-methoxy-benzonitrile (120 mg, 0.552 mmol) in anhydrous ethanol (15 mL) at 0° C. After 45 min, hydrogen chloride gas was stopped and the reaction vessel was sealed with a septum. After stirring at room temperature for 3 d, the reaction vessel was cooled to 0° C. and the septum was removed. The solvent was removed in vacuo to afford ethyl 2-cyclopentyloxy-4-methoxy-benzimidate hydrochloride as a yellow oil (169 mg). It was dissolved methanol (2 mL) and meso-1,2-bis-(4-chloro-phenyl)-ethane-1,2-diamine (160 mg, 0.569 mmol) was added. The solution was heated at 85° C. for 2 h. The solvent was removed and the residue was taken into diethyl ether. It was washed with sodium bicarbonate solution, water and dried over anhydrous sodium sulfate and concentrated in vacuo. The residue was purified by flash chromatography (Biotage system, KP-Sil™ 32-63 μm, 60 Å silica gel) eluting with 0-25% diethyl ether in methylene chloride to afford 4,5-bis-(4-chloro-phenyl)-2-(2-cyclopentyloxy-4-methoxy-phenyl)-4,5-dihydro-1H-imidazole as a white foam (102 mg, 37%). HR-MS (ES, m/z) calculated for C27H27N2O2Cl2 [(M+H)+] 481.1448, observed 481.1444.
Reaction SMILES: [N:1]([C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1)=[O:2].[CH3:9][N:10]([NH2:12])[CH3:11]>C(O)C>[CH3:9][N:10]([CH3:11])[N:12]=[N+:1]([O-:2])[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1
Reactant: CN(C)N
Reactant: O=Nc1ccccc1
Solvent: CCO
Product: CN(C)N=[N+]([O-])c1ccccc1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of 7.5 g. of nitrosobenzene in 80 ml. of ethanol at 0° was added in a dropwise manner 4.2 g. of unsymmetrical-dimethylhydrazine as a saturated solution in ethanol. After stirring at 0° for 2 hours, the reaction mixture was allowed to warm to 25° C. and stirred for 16 hours longer. The solution was concentrated in vacuo, and the red-brown oil was chromatographed on silica gel in benzene. The product was eluted with 5-10 percent ethyl acetate in benzene. Three grams of 3,3-dimethyl-1-phenyltriazene-1-oxide was obtained as a light brown oil which gave a suitable n.m.r. spectrum.
Reaction SMILES: [C:1](Cl)(=[O:13])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH3:12].[CH3:15][N:16]([CH3:20])[CH2:17][CH2:18][OH:19]>>[C:1]([O:19][CH2:18][CH2:17][N:16]([CH3:20])[CH3:15])(=[O:13])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH3:12]
Reactant: CCCCCCCCCCCC(=O)Cl
Reactant: CN(C)CCO
Product: CCCCCCCCCCCC(=O)OCCN(C)C

Procedure:
The procedure of Example II is repeated employing lauroyl chloride and 2-dimethylaminoethanol to form 2-dimethylaminoethyl laurate. When the intermediate is quarternized with 1-bromodecane, the softening compound produced is N-(2-dodecanoyloxyethyl)-N,N-dimethyldodecanaminium bromide.
Reaction SMILES: [N:1]1[C:10]2[C:5](=[CH:6][C:7]([C:11]([OH:13])=O)=[CH:8][CH:9]=2)[N:4]=[CH:3][CH:2]=1.[NH2:14][C:15]1[CH:16]=[C:17]([NH:22][C:23](=[O:32])[CH2:24][CH2:25][CH:26]2[CH2:31][CH2:30][CH2:29][CH2:28][CH2:27]2)[CH:18]=[CH:19][C:20]=1[CH3:21]>>[CH:26]1([CH2:25][CH2:24][C:23]([NH:22][C:17]2[CH:18]=[CH:19][C:20]([CH3:21])=[C:15]([NH:14][C:11]([C:7]3[CH:6]=[C:5]4[C:10](=[CH:9][CH:8]=3)[N:1]=[CH:2][CH:3]=[N:4]4)=[O:13])[CH:16]=2)=[O:32])[CH2:31][CH2:30][CH2:29][CH2:28][CH2:27]1
Reactant: Cc1ccc(NC(=O)CCC2CCCCC2)cc1N
Reactant: O=C(O)c1ccc2nccnc2c1
Product: Cc1ccc(NC(=O)CCC2CCCCC2)cc1NC(=O)c1ccc2nccnc2c1

Procedure:
Using an analogous procedure to that described in Example 5, quinoxaline-6-carboxylic acid was reacted with N-(3-amino4-methylphenyl)-3-cyclohexylpropionamide to give the title compound; NMR Spectrum: (DMSOd6) 0.76-0.97 (m, 2H), 1.04-1.24 (m, 3H), 1.40-1.78 (m, 8H), 2.2 (s, 3H), 2.28 (t, 2H), 7.17 (d, 1H), 7.39 (d, 1H), 7.69 (s, 1H), 8.22 (d, 1H), 8.44 (d, 1H), 8.74 (s, 1H), 9.05 (m, 2H), 9.84 (s, 1H), 10.25 (s, 1H); Mass Spectrum: M+H+ 417.
Reaction SMILES: FC(F)(F)C(O)=O.[Cl:8][C:9]1[CH:14]=[C:13]2[NH:15][C:16](=[O:38])[C:17]3([CH:21]([C:22]4[CH:27]=[CH:26][CH:25]=[C:24]([Cl:28])[C:23]=4[F:29])[CH:20]([C:30]([OH:32])=O)[NH:19][CH:18]3[CH2:33][C:34]([CH3:37])([CH3:36])[CH3:35])[C:12]2=[CH:11][CH:10]=1.C(N(C(C)C)CC)(C)C.C1(P(Cl)(C2C=CC=CC=2)=O)C=CC=CC=1.[CH3:63][O:64][C:65]1[CH:71]=[C:70]([N:72]2[CH:76]=[N:75][N:74]=[N:73]2)[CH:69]=[CH:68][C:66]=1[NH2:67]>>[CH3:63][O:64][C:65]1[CH:71]=[C:70]([N:72]2[CH:76]=[N:75][N:74]=[N:73]2)[CH:69]=[CH:68][C:66]=1[NH:67][C:30]([CH:20]1[NH:19][CH:18]([CH2:33][C:34]([CH3:36])([CH3:35])[CH3:37])[C:17]2([C:12]3[C:13](=[CH:14][C:9]([Cl:8])=[CH:10][CH:11]=3)[NH:15][C:16]2=[O:38])[CH:21]1[C:22]1[CH:27]=[CH:26][CH:25]=[C:24]([Cl:28])[C:23]=1[F:29])=[O:32]
Reactant: CC(C)(C)CC1NC(C(=O)O)C(c2cccc(Cl)c2F)C12C(=O)Nc1cc(Cl)ccc12
Reactant: COc1cc(-n2cnnn2)ccc1N
Agent: O=P(Cl)(c1ccccc1)c1ccccc1
Solvent: CCN(C(C)C)C(C)C
Solvent: O=C(O)C(F)(F)F
Product: COc1cc(-n2cnnn2)ccc1NC(=O)C1NC(CC(C)(C)C)C2(C(=O)Nc3cc(Cl)ccc32)C1c1cccc(Cl)c1F
Yield: 29.9 %

Procedure:
In a manner similar to the method described in Example 5, rac-(2′S,3′R,4′S,5′R)-6-chloro-4′-(3-chloro-2-fluoro-phenyl)-2′-(2,2-dimethyl-propyl)-2-oxo-1,2-dihydro-spiro[indole-3,3′-pyrrolidine]-5′-carboxylic acid trifluoroacetic acid prepared in Example 4 (0.25 g, 0.43 mmol), was reacted with diisopropylethylamine (0.29 g, 2.2 mmol), diphenylphosphinic chloride (0.21 g, 0.89 mmol), then reacted with 2-methoxy-4-(1H-tetrazol-1-yl)aniline (Bionet) (0.13 g, 0.66 mmol) to give rac-(2′S,3′R,4′S,5′R)-6-chloro-4′-(3-chloro-2-fluoro-phenyl)-2′-(2,2-dimethyl-propyl)-2-oxo-1,2-dihydro-spiro[indole-3,3′-pyrrolidine]-5′-carboxylic acid (2-methoxy-4-tetrazol-1-yl-phenyl)-amide as a white solid (Yield 82 mg, 30%).
Reaction SMILES: [Li]C(CC)C.CN(CCN(C)C)C.[Cl:14][C:15]1[CH:16]=[C:17]([CH:21]=[CH:22][C:23]=1[F:24])[C:18]([OH:20])=[O:19].[Cl:25]C(Cl)(Cl)C(Cl)(Cl)Cl>O1CCCC1.O>[Cl:25][C:16]1[C:15]([Cl:14])=[C:23]([F:24])[CH:22]=[CH:21][C:17]=1[C:18]([OH:20])=[O:19]
Reactant: ClC(Cl)(Cl)C(Cl)(Cl)Cl
Reactant: O=C(O)c1ccc(F)c(Cl)c1
Agent: CN(C)CCN(C)C
Agent: [Li]C(C)CC
Solvent: O
Solvent: C1CCOC1
Product: O=C(O)c1ccc(F)c(Cl)c1Cl
Reaction time: 0.5 h

Procedure:
sBuLi (97 mL, 126 mmol) was dissolved in tetrahydrofuran (THF) (200 mL) at −78° C. and TMEDA (19.02 mL, 126 mmol) was added. 3-chloro-4-fluorobenzoic acid (10 g, 57.3 mmol, commercially available from e.g. Sigma-Aldrich, Fluorochem or Apollo) dissolved in tetrahydrofuran (THF) (50 mL) was added dropwise at −78° C. and the solution stirred at this temperature for 30 minutes. Hexachloroethane (54.2 g, 229 mmol) dissolved in tetrahydrofuran (THF) (200 mL) was added dropwise and the solution stirred to room temperature over 4 hours. Water (25 mL) was added and the solution concentrated in vacuo. The residue was partitioned between diethyl ether (300 mL) and saturated sodium bicarbonate solution (50 mL) and extracted with saturated sodium bicarbonate solution (3×50 mL). The aqueous phase was acidified to pH1 with 5N hydrochloric acid, extracted with diethyl ether (3×200 mL), combined extracts dried over anhydrous magnesium sulfate and concentrated in vacuo to afford a crude solid (9.21 g). The crude solid was recrystalised from heptane/diethyl ether to afford the desired product in 4.91 g.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:18]=[CH:17][CH:16]=[CH:15][C:10]=1[CH:11]=[CH:12][CH2:13]Cl)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[NH2:19][C:20]1[S:21][C:22]2[CH2:23][CH2:24][NH:25][CH2:26][CH2:27][C:28]=2[N:29]=1.CCOCC>C(Cl)(Cl)Cl>[NH2:19][C:20]1[S:21][C:22]2[CH2:23][CH2:24][N:25]([CH2:13][CH:12]=[CH:11][C:10]3[CH:15]=[CH:16][CH:17]=[CH:18][C:9]=3[O:8][CH2:1][C:2]3[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=3)[CH2:26][CH2:27][C:28]=2[N:29]=1
Reactant: ClCC=Cc1ccccc1OCc1ccccc1
Reactant: Nc1nc2c(s1)CCNCC2
Solvent: ClC(Cl)Cl
Solvent: CCOCC
Product: Nc1nc2c(s1)CCN(CC=Cc1ccccc1OCc1ccccc1)CC2
Yield: 36 %

Procedure:
Prepared from 2-benzyloxy-cinnamyl chloride and 2 equivalents of 2-amino-4,5,7,8-tetrahydro-6 H-thiazolo[5,4-d]azepine in chloroform for 5 hours at 50° C. Yield: 36% of theory, Melting point: 103°-107° C. (ether).
Reaction SMILES: [Mg].[CH:2]1(Br)[CH2:7][CH2:6][CH2:5][CH2:4][CH2:3]1.[CH2:9]([O:11][C:12](=[O:18])[C:13](OCC)=[O:14])[CH3:10].Cl>C1COCC1>[CH:2]1([C:13](=[O:14])[C:12]([O:11][CH2:9][CH3:10])=[O:18])[CH2:7][CH2:6][CH2:5][CH2:4][CH2:3]1
Reactant: CCOC(=O)C(=O)OCC
Reactant: BrC1CCCCC1
Agent: Cl
Agent: [Mg]
Solvent: C1CCOC1
Product: CCOC(=O)C(=O)C1CCCCC1
Reaction time: 0.5 h

Procedure:
To a suspension of magnesium turnings (2.20 g, 90.32 mmol) in THF (100 mL) was added cyclohexyl bromide (9.27 mL, 75.27 mmol). The mixture was sonicated (note 1) for 30 min, the supernatant liquid was decanted into an addition funnel and added to a solution of diethyloxalate (22.0 g, 146.14 mmol) in THF (240 mL) at −10° C. over one hour. After 30 minutes, 10% HCl (75 mL) was added the mixture was and stirred 15 minutes. Layers were separated and the aqueous layer was extracted with Et2O (100 mL). Combined organics were washed (brine), dried over Na2SO4, and concentrated in vacuo. The residue was purified by flash chromatography (EtOAc/hexanes), affording the title compound as a clear oil. 1H NMR (400 MHz, CDCl3) δ ppm 1.15-1.40 (m, 5H) 1.56-1.94 (m, 8H) 2.97-3.05 (m, 1H) 4.30 (q, J=7.32 Hz, 2H).
Reaction SMILES: Cl[C:2]1[N:3]=[N:4][C:5]([C:8]2[CH:13]=[CH:12][C:11]([O:14][CH3:15])=[C:10]([O:16][CH:17]([CH3:19])[CH3:18])[CH:9]=2)=[CH:6][CH:7]=1.O.[NH2:21][NH2:22]>C(O)CCC>[NH:21]([C:2]1[N:3]=[N:4][C:5]([C:8]2[CH:13]=[CH:12][C:11]([O:14][CH3:15])=[C:10]([O:16][CH:17]([CH3:19])[CH3:18])[CH:9]=2)=[CH:6][CH:7]=1)[NH2:22]
Reactant: COc1ccc(-c2ccc(Cl)nn2)cc1OC(C)C
Reactant: NN
Solvent: O
Solvent: CCCCO
Product: COc1ccc(-c2ccc(NN)nn2)cc1OC(C)C
Temperature: 0 °C
Yield: 76.6 %

Procedure:
25 g (90 mmol) of 3-chloro-6-[4-methoxy-3-(1-methylethoxy)phenyl]pyridazine are boiled under reflux with 22.5 g (0.45 mol) of hydrazine hydrate in 200 ml of butanol for 12 hours. The reaction mixture is subsequently diluted to three to four times the volume with ice-water, and the precipitate is filtered off and recrystallized from isopropanol/cyclohexane. 18.9 g (76.8%) of 3-hydrazino-6-[4-methoxy-3-(1-methylethoxy)phenyl]pyridazine of m.p. 116° C. are obtained.
Reaction SMILES: [OH:1][CH:2]([C:8]1[CH:13]=[CH:12][CH:11]=[C:10]([C:14]([F:17])([F:16])[F:15])[CH:9]=1)[C:3](=[NH:7])[O:4]CC.C(N(CC)CC)C.[C:25](Cl)(Cl)=[O:26]>O1CCCC1>[F:17][C:14]([F:15])([F:16])[C:10]1[CH:9]=[C:8]([CH:2]2[O:1][C:25](=[O:26])[NH:4][C:3]2=[O:7])[CH:13]=[CH:12][CH:11]=1
Reactant: CCOC(=N)C(O)c1cccc(C(F)(F)F)c1
Reactant: O=C(Cl)Cl
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: O=C1NC(=O)C(c2cccc(C(F)(F)F)c2)O1
Reaction time: 1.5 h
Yield: 69 %

Procedure:
Ethyl 1-hydroxy-1-(3-trifluoromethylphenyl)methane carboximidate (9.5 g., 0.038 mole) was dissolved in 500 ml. of tetrahydrofuran and cooled to 0°-5° C. Triethylamine (7.68 g., 0.076 mole) was added and the solution perfused with phosgene for 35 minutes at 0°-5° C. After stirring for 1.5 hours, isolation and recrystallization according to Example 3 gave 5-(3-trifluoromethylphenyl)-oxazolidine-2,4-dione (6.4 g., 69%, m.p. 93°-96° C.). A second recrystallization from toluene gave purified product (4.9 g., 53% over-all; m.p. 97°-99° C., m/e 245).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:11]([F:14])([F:13])[F:12])=[C:6]([CH:10]=1)[C:7](Cl)=[O:8].[CH:15]1([CH2:18][CH2:19][CH2:20][NH:21][C:22]([C:24]2[N:25]=[N:26][C:27]([N:30]3[CH2:35][CH2:34][NH:33][CH2:32][CH2:31]3)=[CH:28][CH:29]=2)=[O:23])[CH2:17][CH2:16]1>>[CH:15]1([CH2:18][CH2:19][CH2:20][NH:21][C:22]([C:24]2[N:25]=[N:26][C:27]([N:30]3[CH2:31][CH2:32][N:33]([C:7](=[O:8])[C:6]4[CH:10]=[C:2]([Cl:1])[CH:3]=[CH:4][C:5]=4[C:11]([F:14])([F:13])[F:12])[CH2:34][CH2:35]3)=[CH:28][CH:29]=2)=[O:23])[CH2:17][CH2:16]1
Reactant: O=C(NCCCC1CC1)c1ccc(N2CCNCC2)nn1
Reactant: O=C(Cl)c1cc(Cl)ccc1C(F)(F)F
Product: O=C(NCCCC1CC1)c1ccc(N2CCN(C(=O)c3cc(Cl)ccc3C(F)(F)F)CC2)nn1

Procedure:
Following the procedure of Example 3, making variations only as required to use 5-chloro-2-trifluoromethylbenzoyl chloride in place of isoxazole-5-carbonyl chloride to react with 6-piperazin-1-yl-pyridazine-3-carboxylic acid (3-cyclopropylpropyl)amide, the title compound was obtained as a white solid (73% yield). 1H NMR (300 MHz, CDCl3) δ 8.05, 7.86, 7.68-7.65, 7.53-7.5, 7.35, 6.99, 4.05-3.99, 3.89-3.67, 3.52-3.46, 3.37-3.34, 1.75-1.6, 1.31-1.24, 0.71-0.62, 0.43-0.37, 0.02-0.03. 13C NMR (75 MHz, CDCl3) δ 165.9, 162.9, 159.9, 145.4, 138.8, 135.93, 135.9, 129.7, 128.6, 128.4, 121.4, 112.6, 46.3, 44.5, 44.3, 41.3, 39.2, 31.9, 29.5, 10.5, 4.4. MS (ES+) m/z 496.3 (M+1).
Reaction SMILES: [CH3:1][C:2]1([CH3:11])[CH2:7][CH2:6][CH:5]([CH2:8][CH2:9]O)[CH2:4][CH2:3]1.[BrH:12]>S(=O)(=O)(O)O>[Br:12][CH2:9][CH2:8][CH:5]1[CH2:6][CH2:7][C:2]([CH3:11])([CH3:1])[CH2:3][CH2:4]1
Reactant: CC1(C)CCC(CCO)CC1
Reactant: Br
Agent: O=S(=O)(O)O
Product: CC1(C)CCC(CCBr)CC1
Temperature: 90 °C
Reaction time: 7 h

Procedure:
A mixture of 2-(4,4-dimethylcyclohexyl)ethanol (WO99/59971) (2 g, 12.8 mmol), concentrated sulphuric acid (750 μl) and 48% hydrobromic acid (3 ml) was stirred at 90° C. for 7 hours. The cooled mixture was then carefully quenched by the addition of water (25 ml), and the mixture was extracted with dichloromethane (3×30 ml). The combined organic extracts were washed with 2M sodium carbonate solution and brine (30ml), then dried (MgSO4) and concentrated under reduced pressure. The residual black gum was purified by distillation to afford the title compound, 330 mg. 1H-NMR (CDCl3, 400 MHz) δ: 0.82 (2×s, 6H), 1.02-1.20 (m, 4H), 1.35 (m, 3H), 1.50 (m, 2H), 1.78 (m, 2H), 3.40 (t, 2H).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:6]=[CH:7][C:8]=1[CH3:9])N.S(=O)(=O)(O)[OH:11].N([O-])=O.[Na+].CCCCCC>O>[Cl:1][C:2]1[CH:3]=[C:4]([OH:11])[CH:6]=[CH:7][C:8]=1[CH3:9]
Reactant: O=S(=O)(O)O
Reactant: Cc1ccc(N)cc1Cl
Agent: O=N[O-]
Agent: [Na+]
Solvent: O
Solvent: CCCCCC
Product: Cc1ccc(O)cc1Cl
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 91 %

Procedure:
283.0 g of 3-chloro-4-methylaniline, 1000 ml of water and 500 ml of concentrated sulfuric acid were mixed, initially at room temperature. The temperature of the mixture rose to 95° C. The mixture was stirred at room temperature for 30 minutes, cooled to 5° C. and a solution of 145 g of sodium nitrite in 500 ml of water was slowly added (1.5 hours) to the stirred mixture at 5°-10° C., then the mixture was stirred at about 5° C. for one hour. The resulting solution was added over two hours to a stirred solution of 1.2 liters of concentrated sulfuric acid in 2 liters of water, at 105°-110° C., and the resulting mixture was stirred at 110° C. for one hour, then held at room temperature for 18 hours. Then 3.5 liters of hexane was added, the mixture was stirred for 30 minutes, allowed to stand, and the two liquid phases were separated. The hexane phase was filtered, washed with water, dried (MgSO4) and concentrated to dryness to give crude (91%) 3-chloro-4-methylphenol (3A).
Reaction SMILES: [NH2:1][CH2:2][CH2:3][CH2:4][N:5]([CH2:10][C:11]1[CH:16]=[CH:15][CH:14]=[C:13]([C:17]2[CH:22]=[CH:21][N:20]=[C:19]([NH:23][CH2:24][CH2:25][C:26]3[CH:31]=[CH:30][C:29]([OH:32])=[CH:28][CH:27]=3)[N:18]=2)[CH:12]=1)[S:6]([CH3:9])(=[O:8])=[O:7].[C:33]1([S:39](Cl)(=[O:41])=[O:40])[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1>>[OH:32][C:29]1[CH:28]=[CH:27][C:26]([CH2:25][CH2:24][NH:23][C:19]2[N:18]=[C:17]([C:13]3[CH:12]=[C:11]([CH:16]=[CH:15][CH:14]=3)[CH2:10][N:5]([S:6]([CH3:9])(=[O:8])=[O:7])[CH2:4][CH2:3][CH2:2][NH:1][S:39]([C:33]3[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=3)(=[O:41])=[O:40])[CH:22]=[CH:21][N:20]=2)=[CH:31][CH:30]=1
Reactant: O=S(=O)(Cl)c1ccccc1
Reactant: CS(=O)(=O)N(CCCN)Cc1cccc(-c2ccnc(NCCc3ccc(O)cc3)n2)c1
Product: CS(=O)(=O)N(CCCNS(=O)(=O)c1ccccc1)Cc1cccc(-c2ccnc(NCCc3ccc(O)cc3)n2)c1

Procedure:
Compound 2 was coupled with benzenesulfonyl chloride following procedure D. LC-MS showed the product had the expected M+H+ of 596. 1H NMR (Varian 300 MHz, CD3OD, shifts relative to the solvent peak at 3.3 ppm) δ 8.3 (d, 1H), 8.0 (d, 1H) 7.5 (m, 3H) 7.3 (d, 2H), 7.2 (m, 4H), 6.7 (d, 4H), 4.4 (s, 2H), 4.2 (s, 2H), 3.6 (t, 2H), 3.2 (t, 2H), δ 2.9 (s, 3H), 2.7 (t, 2H), 2.7 (t, 2H), δ 1.6 (m, 2H).
Reaction SMILES: [H-].[Na+].[CH:3]1([S:6]([NH2:9])(=[O:8])=[O:7])[CH2:5][CH2:4]1.[CH3:10][S:11]([C:14]1[CH:19]=[CH:18][C:17]([C:20]2[CH:25]=[CH:24][CH:23]=[C:22]([CH:26]3[C:35]([CH3:37])([CH3:36])[CH2:34][C:33]4[C:28](=[CH:29][CH:30]=[C:31]([C:38](O)=[O:39])[CH:32]=4)[NH:27]3)[CH:21]=2)=[CH:16][CH:15]=1)(=[O:13])=[O:12].C(N1C=CN=C1)(N1C=CN=C1)=O>CN(C)C=O>[CH3:10][S:11]([C:14]1[CH:15]=[CH:16][C:17]([C:20]2[CH:25]=[CH:24][CH:23]=[C:22]([CH:26]3[C:35]([CH3:37])([CH3:36])[CH2:34][C:33]4[C:28](=[CH:29][CH:30]=[C:31]([C:38]([NH:9][S:6]([CH:3]5[CH2:5][CH2:4]5)(=[O:8])=[O:7])=[O:39])[CH:32]=4)[NH:27]3)[CH:21]=2)=[CH:18][CH:19]=1)(=[O:13])=[O:12]
Reactant: CC1(C)Cc2cc(C(=O)O)ccc2NC1c1cccc(-c2ccc(S(C)(=O)=O)cc2)c1
Reactant: NS(=O)(=O)C1CC1
Agent: O=C(n1ccnc1)n1ccnc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CC1(C)Cc2cc(C(=O)NS(=O)(=O)C3CC3)ccc2NC1c1cccc(-c2ccc(S(C)(=O)=O)cc2)c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 20.2 %

Procedure:
To a suspension of 60% sodium hydride (91 mg, 2.2 mmol) in N,N-dimethylformamide (1.5 mL) was added cyclopropanesulfonamide (278 mg, 2.3 mmol) at room temperature. The resulting mixture was stirred at 25° C. for 1 h. A solution of 2-(4′-methanesulfonyl-biphenyl-3-yl)-3,3-dimethyl-1,2,3,4-tetrahydro-quinoline-6-carboxylic acid (100 mg, 0.23 mmol) and 1,1′-carbonyldiimidazole (75 mg, 0.46 mmol) in N,N-dimethylformamide (2.0 mL) was stirred at 70° C. After stirring at 70° C. for 1 h, the above suspension of cyclopropanesulfonamide and sodium hydride in N,N-dimethylformamide was added and the mixture was allowed to stir at 25° C. for 1 h. Purification by Waters automated flash system (column: Xterra 30 mm×100 mm, sample manager 2767, pump 2525, detector: ZQ mass and UV 2487, solvent system: acetonitrile and 0.1% ammonium hydroxide in water) afforded cyclopropanesulfonic acid [2-(4′-methanesulfonyl-biphenyl-3-yl)-3,3-dimethyl-1,2,3,4-tetrahydro-quinoline-6-carbonyl]-amide (25 mg, 20%) as a white solid: LC/MS m/e calcd for C28H30N2O5S2 (M+H)+: 539.69, observed: 539.1.
Reaction SMILES: C([O:3][C:4]([C:6]1[C:7](Cl)=[N:8][C:9]2[C:14]([CH:15]=1)=[CH:13][C:12]([Br:16])=[CH:11][CH:10]=2)=[O:5])C.[NH2:18][C@@H:19]([C:27]([OH:29])=[O:28])[CH2:20][C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1>>[Br:16][C:12]1[CH:13]=[C:14]2[C:9](=[CH:10][CH:11]=1)[N:8]=[C:7]([NH:18][C@@H:19]([C:27]([OH:29])=[O:28])[CH2:20][C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)[C:6]([C:4]([OH:3])=[O:5])=[CH:15]2
Reactant: CCOC(=O)c1cc2cc(Br)ccc2nc1Cl
Reactant: N[C@H](Cc1ccccc1)C(=O)O
Product: O=C(O)c1cc2cc(Br)ccc2nc1N[C@H](Cc1ccccc1)C(=O)O

Procedure:
In close analogy to the procedure described in Example 32, 6-bromo-2-chloroquinoline-3-carboxylic acid ethyl ester is reacted with D-phenylalanine to provide the title compound in good yield.
Reaction SMILES: [CH3:1][C:2]([C:4]1[CH:9]=[CH:8][C:7]([C:10]([F:13])([F:12])[F:11])=[CH:6][CH:5]=1)=[O:3].Br.[OH2:15]>CS(C)=O>[F:13][C:10]([F:11])([F:12])[C:7]1[CH:8]=[CH:9][C:4]([C:2](=[O:3])[CH:1]=[O:15])=[CH:5][CH:6]=1
Reactant: CC(=O)c1ccc(C(F)(F)F)cc1
Reactant: O
Agent: Br
Solvent: CS(C)=O
Product: O=CC(=O)c1ccc(C(F)(F)F)cc1
Temperature: 70 °C
Reaction time: 9.5 h
Yield: 59 %

Procedure:
4-Trifluoromethylacetophenone (11.14 mmol, 2.096 g) was dissolved in dimethyl sulfoxide (13 mL), and 48% hydrobromic acid (5.4 mL) was gradually added at room temperature. After 9.5 hours of stirring at 70° C., the reactor was cooled to room temperature. The reaction solution was poured into water and stirred for about 16 hours. The precipitated solid was recovered by filtration, washed with water and dried by means of a vacuum pump to give the desired product as a yellow solid (1.3116 g, yield 59%).
Reaction SMILES: [Cl:1][S:2]([OH:5])(=O)=[O:3].[F:6][C:7]1[CH:19]=[CH:18][C:10]([O:11][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)=[CH:9][CH:8]=1>>[F:6][C:7]1[CH:19]=[CH:18][C:10]([O:11][C:12]2[CH:17]=[CH:16][C:15]([S:2]([Cl:1])(=[O:5])=[O:3])=[CH:14][CH:13]=2)=[CH:9][CH:8]=1
Reactant: Fc1ccc(Oc2ccccc2)cc1
Reactant: O=S(=O)(O)Cl
Product: O=S(=O)(Cl)c1ccc(Oc2ccc(F)cc2)cc1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
Chlorosulfonic acid (26 mL, 0.392 mole) was added dropwise to ice-cooled 4-fluorophenoxybenzene (36.9 grams, 0.196 mole) with mechanical stirring. When addition was complete, the mixture was stirred at room temperature for 4 hours. The mixture was then poured into ice water. The product, 4-(4fluorophenoxy)benzene-sulfonylchloride (18.6 grams, 33%) was collected by filtration and dried in the air.