Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]1([NH:11][CH2:12][CH2:13][CH2:14][N:15]2[C:19](=[O:20])[C:18]3=[CH:21][CH:22]=[CH:23][CH:24]=[C:17]3[C:16]2=[O:25])[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH2:4][CH2:3][CH2:2]1.[CH2:26]([CH:31]=O)[CH2:27][C:28]([OH:30])=[O:29].CC(O)=O.[BH3-]C#N.[Na+]>CO.O>[C:19]1(=[O:20])[N:15]([CH2:14][CH2:13][CH2:12][N:11]([CH:1]2[C:10]3[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=3)[CH2:4][CH2:3][CH2:2]2)[CH2:31][CH2:26][CH2:27][C:28]([OH:30])=[O:29])[C:16](=[O:25])[C:17]2=[CH:24][CH:23]=[CH:22][CH:21]=[C:18]12
Reactant: O=CCCC(=O)O
Reactant: O=C1c2ccccc2C(=O)N1CCCNC1CCCc2ccccc21
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CO
Solvent: O
Product: O=C(O)CCCN(CCCN1C(=O)c2ccccc2C1=O)C1CCCc2ccccc21
Temperature: 25 °C
Reaction time: 2.5 h
Yield: 82 %

Procedure:
To a solution of N-[3-(1,2,3,4-tetrahydro-1-naphthylamino)propyl]phthalimide (200 mg, 0.60 mmol) in MeOH (10 ml) were added succinic semialdehyde (15 wt. % solution in water, 0.45 ml, 0.72 mmol), HOAc (41 μl, 0.72 mmol) and NaBH3CN (45 mg, 0.72 mmol), and the mixture was stirred at RT for 2.5 h. After adding water, the mixture was extracted with chloroform, washed with water and brine, dried over sodium sulfate, and filtered. The filtrate was concentrated under vacuum to dryness, and the residue was chromatographed on silica gel (eluting with 5% methanol/chloroform) to afford 4-[[(3-phthalimido)propyl](1,2,3,4-tetrahydro-1-naphthyl)amino]butanoic acid (207 mg, 82%): MS(ES+) m/e 421 [M+H]+; 1H NMR (400 MHz, CDCl3) δ 7.83 (dd, J=5.6, 2.9 Hz, 2H), 7.72 (m, 2H), 7.65 (d, J=7.6 Hz, 1H), 7.15 (m, 1H), 7.08 (m, 1H), 7.00 (d, J=7.3 Hz, 1H), 4.28 (m, 1H) 3.75 (m, 1H), 3.65 (m, 1H), 2.80-2.55 (m, 6H), 2.47 (m, 1H), 2.30 (m, 1H), 2.06-1.86 (m, 5H), 1.74-1.66 (m, 3H).
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([C:8]([F:11])([F:10])[F:9])[CH:5]=[CH:4][C:3]=1[CH2:12][N:13]1[C:18](=[O:19])[C:17]([C:20]([O:22][CH2:23][CH3:24])=[O:21])=[C:16]([OH:25])[C:15]([CH:26]([CH3:28])[CH3:27])=[N:14]1.OC1C(C(C)C)=NNC(=O)[C:31]=1[C:40]([O:42]CC)=[O:41].[H-].[Na+].BrCC1C=CC(C(F)(F)F)=CC=1F.C[N:61](C)C=O>>[F:1][C:2]1[CH:7]=[C:6]([C:8]([F:11])([F:9])[F:10])[CH:5]=[CH:4][C:3]=1[CH2:12][N:13]1[C:18](=[O:19])[C:17]([C:20]([NH:61][CH2:31][C:40]([OH:42])=[O:41])=[O:21])=[C:16]([OH:25])[C:15]([CH:26]([CH3:28])[CH3:27])=[N:14]1.[F:1][C:2]1[CH:7]=[C:6]([C:8]([F:11])([F:10])[F:9])[CH:5]=[CH:4][C:3]=1[CH2:12][N:13]1[C:18](=[O:19])[C:17]([C:20]([O:22][CH2:23][CH3:24])=[O:21])=[C:16]([OH:25])[C:15]([CH:26]([CH3:27])[CH3:28])=[N:14]1
Reactant: CCOC(=O)c1c(O)c(C(C)C)n[nH]c1=O
Reactant: CN(C)C=O
Agent: CCOC(=O)c1c(O)c(C(C)C)nn(Cc2ccc(C(F)(F)F)cc2F)c1=O
Agent: Fc1cc(C(F)(F)F)ccc1CBr
Agent: [H-]
Product: CC(C)c1nn(Cc2ccc(C(F)(F)F)cc2F)c(=O)c(C(=O)NCC(=O)O)c1O
Temperature: 25 °C
Reaction time: 0.75 h

Procedure:
Ethyl 2-{[2-fluoro-4-(trifluoromethyl)phenyl]methyl}-5-hydroxy-6-(1-methylethyl)-3-oxo-2,3-dihydro-4-pyridazinecarboxylate. To a solution of ethyl 5-hydroxy-6-(1-methylethyl)-3-oxo-2,3-dihydro-4-pyridazinecarboxylate (example 14(a), 0.5 g, 2.210 mmol) in N,N-Dimethylformamide (DMF) (50 ml) at 0° C. was added sodium hydride (0.133 g, 3.32 mmol) in portions. The reaction mixture was stirred at room temperature for 45 minutes and then cooled back to 0° C. and 1-(bromomethyl)-2-fluoro-4-(trifluoromethyl)benzene (0.568 g, 2.210 mmol) was added portionwise. The mixture was stirred at ambient temperature for 2.5 hours then quenched with 1N HCl (2 ml) and diluted with water (10 ml). The aqueous solution was extracted with ethyl acetate (2×30 ml), the organic layers combined and washed with water (100 ml) and brine (100 ml), dried over Magnesium sulfate, filtered and solvents removed with rotary evaporation. The crude oil was purified by flash column chromatography (5-100% ethyl acetate in hexanes) to provide the title compound (ethyl 2-{[2-fluoro-4-(trifluoromethyl)phenyl]methyl}-5-hydroxy-6-(1-methylethyl)-3-oxo-2,3-dihydro-4-pyridazinecarboxylate (335 mg, 0.749 mmol, 33.9% yield) as a clear oil. 1H NMR (400 MHz, DMSO-d6) dppm 12.36 (s, 1H), 7.67-7.73 (m, 1H), 7.58 (d, J=8.84 Hz, 1H), 7.45 (t, J=7.58 Hz, 1H), 5.27 (s, 2H), 4.27 (q, J=7.07 Hz, 2H), 3.15 (sept, J=6.78 Hz, 1H), 1.26 (t, J=7.07 Hz, 3H), 1.13 (d, J=6.82 Hz, 6H). MS (ES+) m/e 403 [M+H]+.
Reaction SMILES: Cl[C:2]1[CH:7]=[N:6][CH:5]=[C:4]([O:8][CH:9]([C:11]2[CH:16]=[CH:15][CH:14]=[C:13]([F:17])[CH:12]=2)[CH3:10])[N:3]=1.[NH:18]1[CH2:23][CH2:22][NH:21][CH2:20][CH2:19]1.C([O-])([O-])=O.[K+].[K+].C(OCC)(=O)C>C(#N)C.O>[F:17][C:13]1[CH:12]=[C:11]([CH:9]([O:8][C:4]2[CH:5]=[N:6][CH:7]=[C:2]([N:18]3[CH2:23][CH2:22][NH:21][CH2:20][CH2:19]3)[N:3]=2)[CH3:10])[CH:16]=[CH:15][CH:14]=1
Reactant: CC(Oc1cncc(Cl)n1)c1cccc(F)c1
Reactant: C1CNCCN1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Solvent: O
Solvent: CCOC(C)=O
Product: CC(Oc1cncc(N2CCNCC2)n1)c1cccc(F)c1
Yield: 55 %

Procedure:
A mixture of the product from step 1 above (crude, 1.09 g,˜4.3 mmol), piperazine (1.03 g, 12.0 mmol) and K2CO3 (1.00 g, 7.2 mmol) in acetonitrile (5 mL) was heated under reflux overnight (20 h). After cooling, ethyl acetate (15 mL) and water (5 mL) were added. The ethyl acetate layer was filtered through a short column of silica gel using MeOH/ethyl ether (1:1) as eluent to give 0.72 g (55%) of the title compound as an oil. HRMS m/z calcd for C16H19N4O4F (M)+ 302.1543, found 302.1528. Anal. (C16H19N4OF .0.5H2O) C, H, N.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]([CH2:22][CH3:23])([CH2:20][CH3:21])[C:16]([O:18]C)=[O:17])=[CH:11][C:10]=1[CH3:24])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[OH-].[Na+].Cl>CO.O>[CH2:1]([O:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]([CH2:22][CH3:23])([CH2:20][CH3:21])[C:16]([OH:18])=[O:17])=[CH:11][C:10]=1[CH3:24])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CCC(CC)(C(=O)OC)c1ccc(OCc2ccccc2)c(C)c1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: CCC(CC)(C(=O)O)c1ccc(OCc2ccccc2)c(C)c1
Yield: 91.2 %

Procedure:
To a solution of compound 18 (220 mg, 0.674 mmol) in 5 ml of MeOH was added 5 ml of 20% NaOH solution in water and refluxed for 48 h. Reaction mixture is acidified to pH 1 with 1 M HCl solution and extracted with EtOAc (3×5 ml), the combined organic layers were washed with H2O and dried with Na2SO4. The solution was concentrated in vacuo to give compound 19 192 mg in 91% yield. Rf=0.10 (20% EtOAc/Hexane);
Reaction SMILES: Cl[S:2]([C:5]1[S:9][C:8]([C:10]2[CH:15]=[CH:14][C:13]([O:16][CH3:17])=[CH:12][CH:11]=2)=[CH:7][CH:6]=1)(=[O:4])=[O:3].[NH2:18][C:19]1[O:23][N:22]=[C:21]([CH3:24])[C:20]=1[Br:25]>>[Br:25][C:20]1[C:21]([CH3:24])=[N:22][O:23][C:19]=1[NH:18][S:2]([C:5]1[S:9][C:8]([C:10]2[CH:15]=[CH:14][C:13]([O:16][CH3:17])=[CH:12][CH:11]=2)=[CH:7][CH:6]=1)(=[O:4])=[O:3]
Reactant: COc1ccc(-c2ccc(S(=O)(=O)Cl)s2)cc1
Reactant: Cc1noc(N)c1Br
Product: COc1ccc(-c2ccc(S(=O)(=O)Nc3onc(C)c3Br)s2)cc1

Procedure:
N-(4-bromo-3-methyl-5-isoxazolyl)-5-(4-methoxyphenyl)thiophene-2-sulfonamide was prepared in the same manner as described in Example 1. Reaction of 5-chlorosulfonyl-2-(4-methoxyphenyl)thiophene with 5-amino-4-bromo-3-methylisoxazole gave N-(4-bromo-3-methyl-5-isoxazolyl)-5-(4-methoxyphenyl)thiophene-2-sulfonamide in 50% yield, m.p. 128°-130° C.
Reaction SMILES: [CH3:1][S:2](Cl)(=[O:4])=[O:3].[CH3:6][O:7][C:8](=[O:34])/[CH:9]=[CH:10]/[C:11]1[CH:12]=[C:13]2[C:30](=[CH:31][CH:32]=1)[O:29][C:16]1([CH2:21][CH2:20][N:19](C(OC(C)(C)C)=O)[CH2:18][CH2:17]1)[CH2:15][C:14]2=[O:33]>C(Cl)Cl>[CH3:6][O:7][C:8](=[O:34])/[CH:9]=[CH:10]/[C:11]1[CH:12]=[C:13]2[C:30](=[CH:31][CH:32]=1)[O:29][C:16]1([CH2:17][CH2:18][N:19]([S:2]([CH3:1])(=[O:4])=[O:3])[CH2:20][CH2:21]1)[CH2:15][C:14]2=[O:33]
Reactant: CS(=O)(=O)Cl
Reactant: COC(=O)/C=C/c1ccc2c(c1)C(=O)CC1(CCN(C(=O)OC(C)(C)C)CC1)O2
Solvent: ClCCl
Product: COC(=O)/C=C/c1ccc2c(c1)C(=O)CC1(CCN(S(C)(=O)=O)CC1)O2
Temperature: 25 °C
Reaction time: 8 h
Yield: 97 %

Procedure:
TEA (0.185 ml, 1.33 mmol) and methanesulfonyl chloride (0.067 ml, 0.88 mmol) were added to a suspension of (E)-3-{4-oxo-spiro[chromane-2,4′-piperidine]-6-yl}-acrylic acid methyl ester hydrochloride (150 mg, 0.44 mmol, Intermediate 1) in DCM (3 ml), and the mixture was stirred at RT overnight. The solvent was removed under vacuum and the residue was purified by column chromatography (eluent:DCM/MeOH 97:3) to give (E)-3-{1′-methanesulfonyl-4-oxo-spiro[chromane-2,4′-piperidine]-6-yl}-acrylic acid methyl ester (162 mg).
Reaction SMILES: [N:1]([CH:4]([C:6]1[N:7]=[C:8]2[S:16][CH:15]=[C:14]([CH3:17])[N:9]2[C:10](=[O:13])[C:11]=1Br)[CH3:5])=[N+:2]=[N-:3].[F:18][C:19]1[CH:20]=[N:21][CH:22]=[C:23](B2OC(C)(C)C(C)(C)O2)[CH:24]=1.C(=O)([O-])[O-].[Na+].[Na+].O>O1CCOCC1.C(OCC)(=O)C.Cl[Pd](Cl)(P(C(C)(C)C)(C(C)(C)C)C1C=CC(N(C)C)=CC=1)P(C1C=CC(N(C)C)=CC=1)(C(C)(C)C)C(C)(C)C>[N:1]([CH:4]([C:6]1[N:7]=[C:8]2[S:16][CH:15]=[C:14]([CH3:17])[N:9]2[C:10](=[O:13])[C:11]=1[C:23]1[CH:22]=[N:21][CH:20]=[C:19]([F:18])[CH:24]=1)[CH3:5])=[N+:2]=[N-:3]
Reactant: Cc1csc2nc(C(C)N=[N+]=[N-])c(Br)c(=O)n12
Reactant: CC1(C)OB(c2cncc(F)c2)OC1(C)C
Agent: CN(C)c1ccc([PH](C(C)(C)C)(C(C)(C)C)[Pd](Cl)(Cl)[PH](c2ccc(N(C)C)cc2)(C(C)(C)C)C(C)(C)C)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: O
Solvent: C1COCCO1
Product: Cc1csc2nc(C(C)N=[N+]=[N-])c(-c3cncc(F)c3)c(=O)n12
Temperature: 100 °C
Yield: 15.9 %

Procedure:
To a mixture of 7-(1-azidoethyl)-6-bromo-3-methyl-5H-[1,3]thiazolo[3,2-a]pyrimidin-5-one (0.12 g, 0.38 mmol) and 3-fluoro-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine (0.10 g, 0.46 mmol) in 1,4-dioxane (3 mL) was added a 1N solution of sodium carbonate in water (0.57 mL, 0.57 mmol) and dichloro(bis{di-tert-butyl[4-(dimethylamino)phenyl]phosphoranyl})palladium (0.014 g, 0.020 mmol). The mixture was heated at 100° C. overnight. After cooling, the mixture was diluted with ethyl acetate, washed with water, dried over Na2SO4, concentrated and purified on silica gel (0-45% ethyl acetate/hexanes) to give the desired product (0.020 g, 16%). LCMS calculated for C14H12FN6OS (M+H)+: m/z=331.1. Found: 331.0.
Reaction SMILES: CS(C)=O.[H-].[Na+].[I-].[CH3:8][S+](C)C.[CH3:12][O:13][C:14]1[CH:19]=[CH:18][C:17]([C:20](=[O:22])[CH3:21])=[CH:16][CH:15]=1>C1COCC1>[CH3:12][O:13][C:14]1[CH:19]=[CH:18][C:17]([C:20]2([CH3:8])[CH2:21][O:22]2)=[CH:16][CH:15]=1
Reactant: C[S+](C)C
Reactant: COc1ccc(C(C)=O)cc1
Agent: [H-]
Agent: [I-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CS(C)=O
Product: COc1ccc(C2(C)CO2)cc1
Temperature: 65 °C
Reaction time: 0.17 h

Procedure:
DMSO is added to NaH (1-1.8 equiv.) and heated to 65° C. for 1 h. THF is added at the same temperature and heated for another 10 min. After 10 min., the reaction mixture is cooled to 0° C. Trimethylsulfonium iodide (1-1.2 equiv.) is added and the contents are stirred for 10 min. after which the solution of 1-(4-methoxyphenyl)ethanone (1 equiv.) in THF is added dropwise. After complete addition, the reaction mixture is stirred at RT for 2 h; the reaction is monitored by LCMS. After completion, the reaction mixture is poured in ice water, extracted in diethyl ether, dried over sodium sulfate and concentrated at 25° C. to get the crude product.
Reaction SMILES: [S:1]1[CH:5]=[CH:4][S:3][C:2]1=[C:6]([C:13](=[O:22])[NH:14][C:15]1[CH:20]=[CH:19][C:18]([OH:21])=[CH:17][CH:16]=1)[C:7]([O:9][CH:10]([CH3:12])[CH3:11])=[O:8].C(N(CC)CC)C.[C:30](Cl)(=[O:32])[CH3:31]>C(Cl)Cl>[S:1]1[CH:5]=[CH:4][S:3][C:2]1=[C:6]([C:13](=[O:22])[NH:14][C:15]1[CH:16]=[CH:17][C:18]([O:21][C:30](=[O:32])[CH3:31])=[CH:19][CH:20]=1)[C:7]([O:9][CH:10]([CH3:12])[CH3:11])=[O:8]
Reactant: CC(=O)Cl
Reactant: CC(C)OC(=O)C(C(=O)Nc1ccc(O)cc1)=C1SC=CS1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(=O)Oc1ccc(NC(=O)C(C(=O)OC(C)C)=C2SC=CS2)cc1
Temperature: 0 °C
Reaction time: 1 h

Procedure:
Isopropyl 2-(1,3-dithiol-2-ylidene)-2-[N-(4-hydroxyphenyl) carbamoyl]acetate (13.5 g) and triethylamine (6.7 ml) were dissolved in methylene chloride (100 ml) and cooled to 0° C. To the mixture was added acetyl chloride (3.16 ml) dropwise and then stirred for 1 hr. The reaction mixture was washed with water and dried over anhydrous magnesium sulfate. The solution was evaporated to dryness and the residue was triturated with n-hexane to give the titled compound. (12 g), 79.1%)
Reaction SMILES: [CH3:1][O:2][C:3](=[O:18])[C:4]1[CH:16]=[C:15]([NH2:17])[CH:14]=[C:6]([C:7]([N:9]([CH3:13])[CH2:10][CH2:11][CH3:12])=[O:8])[CH:5]=1.C(N(CC)CC)C.[C:26](Cl)(=[O:28])[CH3:27].CNN(CCC)NC>ClCCl>[CH3:1][O:2][C:3](=[O:18])[C:4]1[CH:16]=[C:15]([NH:17][C:26](=[O:28])[CH3:27])[CH:14]=[C:6]([C:7]([N:9]([CH3:13])[CH2:10][CH2:11][CH3:12])=[O:8])[CH:5]=1
Reactant: CC(=O)Cl
Reactant: CCCN(C)C(=O)c1cc(N)cc(C(=O)OC)c1
Agent: CCCN(NC)NC
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCCN(C)C(=O)c1cc(NC(C)=O)cc(C(=O)OC)c1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
Dissolve 5-amino-N-methyl-N-propyl-isophthalamic acid methyl ester (1.64 g, 6.55 mmol) in dichloromethane (20 mL) and add triethylamine (0.993 g, 9.83 mmol), then acetyl chloride (772 mg, 9.83 mmol). Stir at room temperature for 1 h, add N,N-dimethylamino propylamine (0.5 mL), stir 10 min, dilute with dichloromethane, wash with 1 N HCl and saturated aqueous sodium chloride. Dry (magnesium sulfate), filter and concentrate to give the title compound as a solid.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[CH:6][N:5]=[C:4]([CH2:8][C:9]2[CH:14]=[CH:13][C:12]([NH:15]C(NC3C=CC(CC)=CC=3)=O)=[CH:11][CH:10]=2)[CH:3]=1.[F:27][C:28]([F:39])([F:38])[C:29]1[CH:34]=[CH:33][CH:32]=[C:31]([N:35]=[C:36]=[O:37])[CH:30]=1>CN(C=O)C>[NH2:1][C:2]1[N:7]=[CH:6][N:5]=[C:4]([CH2:8][C:9]2[CH:14]=[CH:13][C:12]([NH:15][C:36]([NH:35][C:31]3[CH:32]=[CH:33][CH:34]=[C:29]([C:28]([F:38])([F:39])[F:27])[CH:30]=3)=[O:37])=[CH:11][CH:10]=2)[CH:3]=1
Reactant: CCc1ccc(NC(=O)Nc2ccc(Cc3cc(N)ncn3)cc2)cc1
Reactant: O=C=Nc1cccc(C(F)(F)F)c1
Solvent: CN(C)C=O
Product: Nc1cc(Cc2ccc(NC(=O)Nc3cccc(C(F)(F)F)c3)cc2)ncn1
Reaction time: 4 h

Procedure:
The title compound is prepared as described in Example 102 but using 6-(4-aminobenzyl)-pyrimidin-4-ylamine (see Example 157), α,α,α-trifluoro-m-tolyl-isocyanate, and DMF as the solvent. The reaction mixture is stirred for 4 h. The crude product is washed with a CH2Cl2/MeOH (99/1) solution. The title compound is obtained as a white solid: ES-MS: 387.9 [M+H]+; single peak at tR=7.12 min (System 2); Rf=0.23 (CH2Cl2/MeOH, 90/10).
Reaction SMILES: Cl[C:2]1[N:7]=[CH:6][C:5]([Br:8])=[CH:4][N:3]=1.[NH:9]1[CH:14]=[CH:13][CH:12]=[N:11][C:10]1=[S:15]>CC[O-].[Na+]>[N:9]1[CH:14]=[CH:13][CH:12]=[N:11][C:10]=1[S:15][C:2]1[N:7]=[CH:6][C:5]([Br:8])=[CH:4][N:3]=1
Reactant: Clc1ncc(Br)cn1
Reactant: S=c1nccc[nH]1
Agent: CC[O-]
Agent: [Na+]
Product: Brc1cnc(Sc2ncccn2)nc1
Yield: 35 %

Procedure:
2-Chloro-5-bromopyrimidine (10 mmol) was added to a solution of pyrimidine-2-thione (10 mmol) in ethanolic 0.24 M NaOEt (45 ml), the mixture heated under reflux for 2 hours, the solvent distilled off, the residue extracted with chloroform (70 ml), the chloroform solution shaken with 2 M NaOH and with water, the dried (MgSO4) solution evaporated and the residue repeatedly extracted with pet. ether leaving the title compound. Yield 35%, m.p. 178°-180° C. (iPrOH). 1H NMR (CDCl3): δ7.13 (H-5'), 8.60 (H-4', H-6'), 8.66 (H-4, H-6).
Reaction SMILES: [Cl:1][C:2]1[CH:30]=[CH:29][C:28]([O:31][CH3:32])=[CH:27][C:3]=1[O:4][C:5]1[C:6]([NH:15][S:16](=[O:26])(=[O:25])[NH:17][CH2:18][C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)=[N:7][CH:8]=[N:9][C:10]=1[O:11][CH2:12][CH2:13][OH:14].[Br:33][C:34]1[CH:35]=[N:36][C:37](Cl)=[N:38][CH:39]=1>>[Br:33][C:34]1[CH:35]=[N:36][C:37]([O:14][CH2:13][CH2:12][O:11][C:10]2[N:9]=[CH:8][N:7]=[C:6]([NH:15][S:16](=[O:26])(=[O:25])[NH:17][CH2:18][C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)[C:5]=2[O:4][C:3]2[CH:27]=[C:28]([O:31][CH3:32])[CH:29]=[CH:30][C:2]=2[Cl:1])=[N:38][CH:39]=1
Reactant: Clc1ncc(Br)cn1
Reactant: COc1ccc(Cl)c(Oc2c(NS(=O)(=O)NCc3ccccc3)ncnc2OCCO)c1
Product: COc1ccc(Cl)c(Oc2c(NS(=O)(=O)NCc3ccccc3)ncnc2OCCOc2ncc(Br)cn2)c1
Yield: 48.4 %

Procedure:
Benzylsulfamic acid [6-[2-(5-bromo-pyrimidin-2-yloxy)-ethoxy]-5-(2-chloro-5-methoxy-phenoxy)-pyrimidin-4-yl]-amide (77 mg) (Example 212) was prepared from benzylsulfamic acid [5-(2-chloro-5-methoxy-phenoxy)-6-(2-hydroxy-ethoxy)-pyrimidin-4-yl]-amide (120 mg) (Example 211) and 5-bromo-2-chloropyrimidine (100 mg) according to the procedure described in Example 14. LC-MS: tR=5.29; [M+H]+=639.04.
Reaction SMILES: [CH3:1][S:2]([NH:5][C:6]1[CH:12]=[CH:11][C:9]([NH2:10])=[CH:8][CH:7]=1)(=[O:4])=[O:3].C(N(CC)CC)C.Br[CH2:21][C:22]([C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1)=[O:23]>CO.C(O)C>[CH3:1][S:2]([NH:5][C:6]1[CH:12]=[CH:11][C:9]([NH:10][CH2:21][C:22]([C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)=[O:23])=[CH:8][CH:7]=1)(=[O:4])=[O:3]
Reactant: CS(=O)(=O)Nc1ccc(N)cc1
Reactant: O=C(CBr)c1ccccc1
Solvent: CO
Solvent: CCN(CC)CC
Solvent: CCO
Product: CS(=O)(=O)Nc1ccc(NCC(=O)c2ccccc2)cc1
Temperature: 5 °C
Yield: 62.4 %

Procedure:
4-Methanesulfonamidoaniline (150 g, 0.8 mol) and triethylamine (81.4 g, 0.8 mol) were combined with 2.4 liters of 1:1 methanol/ethanol in a five liter round bottom flask, and stirred mechanically until all solids dissolved. 2-Bromoacetophenone (240 g, 1.2 mol) was added as a solid in several portions over a twenty minute period. The reaction was stirred at 25° C. for 14 h, during which an off-white precipitate formed. The mixture was chilled to 5° C., then the product was collected by filtration, washed with cold ethanol and dried under vacuum to yield 152 g (62%) of 2-(4-methanesulfonamidoanilino)acetophenone as an off-white solid, m.p. 165°-167° C. NMR and mass spectral data were consistent with the assigned structure.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:13])[C:4](=[O:12])[C:5]1[CH:10]=[CH:9][C:8]([OH:11])=[CH:7][CH:6]=1.Cl.Cl[CH2:16][C:17]1[CH:26]=[CH:25][C:24]2[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=2)[N:18]=1.[H-].[Na+]>CN(C)C=O>[CH3:1][O:2][C:3](=[O:13])[C:4](=[O:12])[C:5]1[CH:10]=[CH:9][C:8]([O:11][CH2:16][C:17]2[CH:26]=[CH:25][C:24]3[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=3)[N:18]=2)=[CH:7][CH:6]=1
Reactant: ClCc1ccc2ccccc2n1
Reactant: COC(=O)C(=O)c1ccc(O)cc1
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COC(=O)C(=O)c1ccc(OCc2ccc3ccccc3n2)cc1
Temperature: 50 °C
Yield: 43.7 %

Procedure:
A solution of 4-hydroxy-alpha-oxobenzeneacetic acid methyl ester (0.50 g) and 2-chloromethylquinoline hydrochloride (0.60 g) were suspended in 6 mL of dimethylformamide and 60% sodium hydride (0.224 g) was added. When gas evolution ceased, the bath temperature was raised to 50° C. for 2 hours. The reaction mixture was quenched with 0.1 mL of acetic acid and was diluted with ethyl acetate (75 mL). The mixture was washed with water (2×25 mL) and brine (1×25 mL), dried (MgSO4) and chromatographed over 100 g of silica gel, eluting with dichoromethane-ethyl acetate (50: 1) to give 0.39 g of 4-[(2-quinolinyl)methoxy]-alpha-oxobenzeneacetic acid methyl ester, mp 109°-110° C.
Reaction SMILES: [OH2:1].[OH2:2].[OH2:3].O.B(O[O-])([O-])[O-].[Na+].[Na+].[Na+].[C:13]([CH:17]1[CH2:22][C:21]([C:23]([O:25][CH2:26][CH3:27])=[O:24])=[C:20]([SH:28])[CH2:19][CH2:18]1)([CH3:16])([CH3:15])[CH3:14]>C(O)(=O)C>[C:13]([CH:17]1[CH2:22][C:21]([C:23]([O:25][CH2:26][CH3:27])=[O:24])=[C:20]([S:28]([OH:3])(=[O:2])=[O:1])[CH2:19][CH2:18]1)([CH3:16])([CH3:14])[CH3:15]
Reactant: O
Reactant: CCOC(=O)C1=C(S)CCC(C(C)(C)C)C1
Agent: [Na+]
Agent: [O-]OB([O-])[O-]
Solvent: CC(=O)O
Product: CCOC(=O)C1=C(S(=O)(=O)O)CCC(C(C)(C)C)C1
Temperature: 52.5 °C
Reaction time: 3 h
Yield: 73.1 %

Procedure:
Sodium peroxyborate tetrahydrate (38.2 g) was admixed with acetic acid (270 ml) and heated to 50 to 55° C. and then a solution of ethyl 5-t-butyl-2-mercapto-1-cyclohexene-1-carboxylate (20.1 g) synthesized in Reference Example 15 in acetic acid (31 ml) was added dropwise over 2 hours. The mixture was stirred at 50 to 55° C. for 3 hours and then at 80 to 85° C. for 7.5 hours and concentrated under reduced pressure. The residue was combined with acetonitrile (445ml) and stirred at room temperature for 3.5 hours and the resultant insolubles were filtered off. The insolubles were washed with acetonitrile (110 ml) and the filtrate and the washing were combined and concentrated under reduced pressure, and the resultant residue was dissolved in acetonitrile (320 ml) and stirred at room temperature for 15 hours. The resultant insolubles were filtered off, and the filtrate was concentrated under reduced pressure. The residue was combined with diisopropyl ether (250 ml) and the pellet which precipitated was isolated by a filtration and concentrated under reduced pressure to obtain ethyl 5-t-butyl-2-sulfo-1-cyclohexene-1-carboxylate as yellow oil (17.6 g) containing inorganic substances. This (16.4 g) was treated dropwise with thionyl chloride (49.2 ml) at 0° C. over 0.5 hours and then stirred at 80 to 90° C. for 7 hours. The solution was evaporated under reduced pressure to dryness and the residue was partitioned between ethyl acetate (200 ml) and dilute brine (240 ml) and the aqueous layer was extracted with ethyl acetate (100 ml). The combined ethyl acetate layers were washed with saturated brine (120 ml) and then dried over anhydrous sodium sulfate. The solvent was evaporated off to obtain a residue, which was purified by column chromatography on silica gel (eluent: ethyl acetate/hexane=1/10), and a desired fraction was concentrated under reduced pressure. The residue was crystallized from hexane to yield ethyl 5-t-butyl-2-chlorosulfonyl-1-cyclohexene-1-carboxylate (7.4 g) as a white crystals.
Reaction SMILES: [F:1][C:2]1[C:11]([F:12])=[C:10]2[C:5]([CH2:6][CH2:7][CH:8]([CH2:13][CH2:14][CH2:15][CH2:16][CH3:17])[O:9]2)=[C:4](I)[C:3]=1[OH:19].[C:20]([CH:22]1[CH2:27][CH2:26][CH:25]([CH2:28][CH2:29][CH3:30])[CH2:24][CH2:23]1)#[CH:21].Cl>C(N(CC)CC)C.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.[Cu]I>[F:1][C:2]1[C:11]([F:12])=[C:10]2[C:5]([CH2:6][CH2:7][CH:8]([CH2:13][CH2:14][CH2:15][CH2:16][CH3:17])[O:9]2)=[C:4]([C:21]#[C:20][CH:22]2[CH2:27][CH2:26][CH:25]([CH2:28][CH2:29][CH3:30])[CH2:24][CH2:23]2)[C:3]=1[OH:19]
Reactant: CCCCCC1CCc2c(I)c(O)c(F)c(F)c2O1
Reactant: C#CC1CCC(CCC)CC1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Agent: Cl
Solvent: CCN(CC)CC
Product: CCCCCC1CCc2c(C#CC3CCC(CCC)CC3)c(O)c(F)c(F)c2O1
Temperature: 0 °C

Procedure:
8.0 g (20.9 mmol) of 7,8-difluoro-5-iodo-2-pentylchroman-6-ol are stirred at 50° C. for 19 h together with 4.72 g (31.4 mmol) of 1-ethynyl-4-propylcyclohexane in the presence of 441 mg (0.63 mmol) of bis(triphenylphosphine)palladium(II) chloride and 120 mg (0.63 mmol) of copper(I) iodide in 90 ml of triethylamine. After cooling, the batch is added to ice/water and acidified using hydrochloric acid. The mixture is extracted a number of times with MTBE, and the combined extracts are washed with water and sat. sodium chloride soln. The solution is dried using sodium sulfate and concentrated to dryness. The residue is purified by column chromatography (SiO2, 1-chlorobutane). The phenol obtained is used directly for the following reaction.
Reaction SMILES: [C:1]1([C:3](=[CH:5][CH:6]=[CH:7][CH:8]=1)[OH:4])[OH:2].Cl[CH2:10][C:11]#[N:12].C(=O)([O-])[O-].[K+].[K+].CC(C)=O>[OH-].[Na+]>[OH:2][C:1]1[CH:8]=[CH:7][CH:6]=[CH:5][C:3]=1[O:4][CH2:10][C:11]#[N:12]
Reactant: N#CCCl
Reactant: Oc1ccccc1O
Agent: O=C([O-])[O-]
Agent: [K+]
Agent: [Na+]
Solvent: CC(C)=O
Product: N#CCOc1ccccc1O
Reaction time: 2 h

Procedure:
A mixture of catechol (11 g., 0.1 mole), chloroacetonitrile (5.3 g., 0.07 mole), finely powdered potassium carbonate (11.1 g., 0.08 mole) and acetone (75 ml.) is refluxed with stirring for 2 hours. The mixture then is treated with chloroacetonitrile (3.8 g., 0.05 mole) and potassium carbonate (7.6 g., 0.055 mole) and refluxed for 4 hours. The mixture is filtered, the solids washed with more acetone and the combined filtrate evaporated in vacuo to give an oil. The oil is dissolved in dilute sodium hydroxide solution, extracted with ether to remove 1,2-dicyanomethoxybenzene and the alkali solution acidified and extracted with ether. The extract is evaporated to dryness and the residue distilled in vacuo to give 2-(2-hydroxyphenoxy)acetonitrile.