Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1][C:2]1[CH:7]=[C:6]([N+:8]([O-:10])=[O:9])[CH:5]=[CH:4][C:3]=1[NH:11][C:12]([NH:14][CH:15]([C:19](OCC)=[O:20])[CH:16]([CH3:18])[CH3:17])=[O:13].[OH-].[Na+]>C(O)C.O>[OH:1][C:2]1[CH:7]=[C:6]([N+:8]([O-:10])=[O:9])[CH:5]=[CH:4][C:3]=1[NH:11][C:12]([NH:14][C:15](=[C:19]=[O:20])[CH:16]([CH3:18])[CH3:17])=[O:13]
Reactant: CCOC(=O)C(NC(=O)Nc1ccc([N+](=O)[O-])cc1O)C(C)C
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: CC(C)C(=C=O)NC(=O)Nc1ccc([N+](=O)[O-])cc1O
Temperature: 25 °C
Yield: 49.7 %

Procedure:
To a solution of N-(2-Hydroxy-4-nitrophenyl)-N'-[1-(ethoxycarbonyl)-2-methylpropyl)urea (200 mg, 0.62 mmol) in ethanol/water (10 mL/1 mL), sodium hydroxide (123 mg, 3.1 mmol) was added. The reaction mixture was stirred at reflux temperature for 16 hours. Then the reaction mixture was cooled to room temperature and all the solvent was evaporated. 3N of HCl was added to pH=1. A yellow solid precipitated, it was filtered to give desired product (86 mg, 47%). EI-MS m/z 298.3 (M+). mp: 168.4-169.2° C.
Reaction SMILES: Cl.[F:2][C:3]1[CH:4]=[C:5]([S:9]([C:12]2[CH:13]=[C:14]3[C:19](=[CH:20][CH:21]=2)[CH:18]([CH2:22][NH2:23])[CH2:17][CH2:16][CH2:15]3)(=[O:11])=[O:10])[CH:6]=[CH:7][CH:8]=1.[S:24](N)([NH2:27])(=[O:26])=[O:25].O>O1CCOCC1>[F:2][C:3]1[CH:4]=[C:5]([S:9]([C:12]2[CH:13]=[C:14]3[C:19](=[CH:20][CH:21]=2)[C@H:18]([CH2:22][NH:23][S:24]([NH2:27])(=[O:26])=[O:25])[CH2:17][CH2:16][CH2:15]3)(=[O:11])=[O:10])[CH:6]=[CH:7][CH:8]=1
Reactant: NS(N)(=O)=O
Reactant: NCC1CCCc2cc(S(=O)(=O)c3cccc(F)c3)ccc21
Agent: Cl
Solvent: O
Solvent: C1COCCO1
Product: NS(=O)(=O)NC[C@@H]1CCCc2cc(S(=O)(=O)c3cccc(F)c3)ccc21
Yield: 100.4 %

Procedure:
C-[6-(3-Fluoro-benzenesulfonyl)-1,2,3,4-tetrahydro-naphthalen-1-yl]-methylamine hydrochloride (0.25 gms, 0.7 mmole), sulfamide (70 mg) and water (10 mL) were added to 30 mL dioxane. The reaction mixture was refluxed for 24 hours, then cooled and concentrated under reduced pressure. The residue was recrystallized from EtOAc to give 280 mg of (R)—N-[6-(3-fluoro-benzenesulfonyl)-1,2,3,4-tetrahydro-naphthalen-1-ylmethyl]-aminosulfonamide, MS M+H=399.
Reaction SMILES: [NH2:1][C:2]1[S:3][CH:4]=[C:5]([CH3:7])[N:6]=1.C[Al](C)C.C[O:13][C:14]([C:16]1[CH:21]=[C:20]([C:22]2[CH:27]=[C:26]([F:28])[CH:25]=[C:24]([F:29])[CH:23]=2)[N:19]=[C:18]([CH3:30])[N:17]=1)=O>O1CCOCC1.CCCCCC>[CH3:7][C:5]1[N:6]=[C:2]([NH:1][C:14]([C:16]2[CH:21]=[C:20]([C:22]3[CH:27]=[C:26]([F:28])[CH:25]=[C:24]([F:29])[CH:23]=3)[N:19]=[C:18]([CH3:30])[N:17]=2)=[O:13])[S:3][CH:4]=1
Reactant: Cc1csc(N)n1
Reactant: COC(=O)c1cc(-c2cc(F)cc(F)c2)nc(C)n1
Agent: C[Al](C)C
Solvent: C1COCCO1
Solvent: CCCCCC
Product: Cc1csc(NC(=O)c2cc(-c3cc(F)cc(F)c3)nc(C)n2)n1
Temperature: 25 °C
Reaction time: 1 h
Yield: 57.7 %

Procedure:
To a solution of 156 mg (1.37 mmol, 1.8 equiv.) of 2-Amino-4-methylthiazole in 4 ml of dry dioxane were added 0.68 μl (1.37 mmol, 1.8 equiv.) of a 2M solution of trimethylaluminium in hexane. The solution was stirred for 1 h at room temperature. Then 200.0 mg (0.76 mmol) of 6-(3,5-Difluoro-phenyl)-2-methyl-pyrimidine-4-carboxylic acid methyl ester were added and the reaction was heated to 90° C. for 4 h. The reaction was quenched by cautious addition of 0.2 ml of water. Then approximately 1 g of anhydrous sodium sulfate were added to bind the water and the mixture was stirred vigorously for 5 min. The mixture was diluted by addition of 10 ml of methylenene chloride and filtered over Speedex filter aid which was washed with methylene chloride. The filtrate was concentrated in vaccuo and the residue was purified by flash chromatography (heptane/ethyl acetate 4:1) and recristallised from diisopropyl ether to yield the title compound (152.0 mg, 58%) as a white solid, MS (ISP): m/e=347.1 (M+H)+.
Reaction SMILES: [NH2:1][C:2]([C:4]1[CH:29]=[CH:28][C:7]([O:8][CH2:9][CH2:10][CH2:11][O:12][C:13]2[CH:14]=[C:15]3[C:19](=[CH:20][CH:21]=2)[C@H:18]([CH2:22][C:23]([O:25][CH2:26][CH3:27])=[O:24])[CH2:17][CH2:16]3)=[C:6]([CH2:30][CH2:31][CH3:32])[CH:5]=1)=[S:3].Cl[CH:34]1[CH2:39][CH2:38][CH2:37][CH2:36][C:35]1=O>CCO>[CH2:26]([O:25][C:23](=[O:24])[CH2:22][C@H:18]1[C:19]2[C:15](=[CH:14][C:13]([O:12][CH2:11][CH2:10][CH2:9][O:8][C:7]3[CH:28]=[CH:29][C:4]([C:2]4[S:3][C:34]5[CH2:39][CH2:38][CH2:37][CH2:36][C:35]=5[N:1]=4)=[CH:5][C:6]=3[CH2:30][CH2:31][CH3:32])=[CH:21][CH:20]=2)[CH2:16][CH2:17]1)[CH3:27]
Reactant: O=C1CCCCC1Cl
Reactant: CCCc1cc(C(N)=S)ccc1OCCCOc1ccc2c(c1)CC[C@H]2CC(=O)OCC
Solvent: CCO
Product: CCCc1cc(-c2nc3c(s2)CCCC3)ccc1OCCCOc1ccc2c(c1)CC[C@H]2CC(=O)OCC
Temperature: 25 °C
Yield: 42.2 %

Procedure:
A solution of ethyl ((1S)-5-{3-[4-aminocarbonothioyl)-2-propylphenoxy]propoxy}-2,3-dihydro-1H-inden-1-yl)acetate (90 mg, 0.2 mmol) (Example 144) and 2-chlorocyclohexanone (239 mg 1.8 mmol) in EtOH (anhydrous, 8 mL) was stirred at 70° C. for 48 h. The reaction mixture was cooled to rt, and then concentrated under reduced pressure. Purification by silica gel flash chromatography (EtOAc/hexane (v/v) 1:2) gave 45 mg (43%) of the title compound as a clear oil. LC-MS: RT=4.69 min; (M+H)+ 534.3.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6]2[N:8]=[C:9]([C:19]3[CH:24]=[CH:23][C:22]([F:25])=[CH:21][CH:20]=3)[N:10]([C:11]3[CH:16]=[CH:15][N:14]=[C:13]([S:17][CH3:18])[N:12]=3)[C:5]2=[CH:4][CH:3]=1.C1C=C(Cl)C=C(C(OO)=[O:34])C=1.C([O-])([O-])=O.[Na+].[Na+]>C(Cl)Cl.CC(O)=O>[Cl:1][C:2]1[N:7]=[C:6]2[N:8]=[C:9]([C:19]3[CH:24]=[CH:23][C:22]([F:25])=[CH:21][CH:20]=3)[N:10]([C:11]3[CH:16]=[CH:15][N:14]=[C:13]([S:17]([CH3:18])=[O:34])[N:12]=3)[C:5]2=[CH:4][CH:3]=1
Reactant: CSc1nccc(-n2c(-c3ccc(F)cc3)nc3nc(Cl)ccc32)n1
Reactant: O=C(OO)c1cccc(Cl)c1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: ClCCl
Solvent: CC(=O)O
Product: CS(=O)c1nccc(-n2c(-c3ccc(F)cc3)nc3nc(Cl)ccc32)n1
Yield: 103.1 %

Procedure:
5-Chloro-2-(4-fluorophenyl)-1-(2-methylthio-4-pyrimidinyl)imidazo[4,5-b]pyridine (372 mg 1 mmol) is dissolved in CH2Cl2/HOAc (7 ml 5/2) and treated with MCPBA (270 mg 70% 1.1 mmol) at 0° C. for 30 min. The reaction mixture is poured on 2N Na2CO3 and extracted with ethyl acetate three times. The combined organic phases are dried over Na2SO4, filtered, evaporated to dryness and purified by SiO2 chromatography (ethyl acetate) to yield the title compound (400 mg 100%) as yellow foam.
Reaction SMILES: Cl[CH2:2][CH2:3][CH2:4][S:5]([CH3:8])(=[O:7])=[O:6].[NH:9]1[C:17]2[CH:16]=[CH:15][CH:14]=[C:13]([OH:18])[C:12]=2[CH:11]=[CH:10]1.C([O-])([O-])=O.[K+].[K+]>CC#N>[CH3:8][S:5]([CH2:4][CH2:3][CH2:2][O:18][C:13]1[CH:14]=[CH:15][CH:16]=[C:17]2[C:12]=1[CH:11]=[CH:10][NH:9]2)(=[O:7])=[O:6]
Reactant: CS(=O)(=O)CCCCl
Reactant: Oc1cccc2[nH]ccc12
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: CS(=O)(=O)CCCOc1cccc2[nH]ccc12
Temperature: 80 °C
Reaction time: 8 h
Yield: 82 %

Procedure:
1-Chloro-3-(methanesulfonyl)-propane (160 g) was added to 1H-indol-4-ol (108.77 g) in 1 L MeCN, and 338 g K2CO3 and 13.36 g KI were added. The reaction mixture was stirred overnight at 80° C., then cooled and filtered through celite. The filtrate was vacuum distilled and solvent replaced with DCM (700 mL). The mixture was filtered, and the solvent removed in vacuo and replaced with MeOH (600 mL). The solvent was partially removed in vacuo at 40° C. and crystallization occurred. After cooling, additional MeOH was added and the slurry was filtered. The collected solid was rinsed with cold MeOH and dried overnight at 35° C. in vacuo under N2 to provide 4-(3-methanesulfonyl-propoxy)-1H-indole (82%).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([N:9]2[C:13](=[O:14])[C:12]3=[CH:15][CH:16]=[CH:17][CH:18]=[C:11]3[C:10]2=[O:19])[CH:5]=[CH:6][C:7]=1[Cl:8].Br[CH:21]([CH3:30])[C:22]([O:24][CH2:25][CH2:26][CH:27]([CH3:29])[CH3:28])=[O:23].C(=O)([O-])O.[Na+]>C(OCC)(=O)C>[Cl:8][C:7]1[CH:6]=[CH:5][C:4]([N:9]2[C:13](=[O:14])[C:12]3=[CH:15][CH:16]=[CH:17][CH:18]=[C:11]3[C:10]2=[O:19])=[CH:3][C:2]=1[NH:1][CH:21]([CH3:30])[C:22]([O:24][CH2:25][CH2:26][CH:27]([CH3:29])[CH3:28])=[O:23]
Reactant: CC(C)CCOC(=O)C(C)Br
Reactant: Nc1cc(N2C(=O)c3ccccc3C2=O)ccc1Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCOC(C)=O
Product: CC(C)CCOC(=O)C(C)Nc1cc(N2C(=O)c3ccccc3C2=O)ccc1Cl
Temperature: 150 °C
Yield: 65.3 %

Procedure:
A mixture of 1.64 g of N-(3-amino-4-chlorophenyl)phthalimide, 2.68 g of isopentyl 2-bromopropionate, and 0.60 g of sodium hydrogencarbonate was heated at 150° C. for 5 hours while stirring. While the reaction mixture was hot, ethyl acetate was added thereto, and the reaction mixture was washed successively with water and a saturated sodium chloride aqueous solution, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure, and the residue was purified by silica gel column chromatography (ethyl acetate-hexane=1:8) to give 1.63 g of the title compound (Table 1, Compound No. 5).
Reaction SMILES: [Br:1][C:2]1[CH:6]=[C:5]([C:7]2[O:12][C:11](=[O:13])[C:10]3[CH:14]=[C:15]([Cl:19])[CH:16]=[C:17]([CH3:18])[C:9]=3[N:8]=2)[N:4]([C:20]2[C:25]([Cl:26])=[CH:24][CH:23]=[CH:22][N:21]=2)[N:3]=1.[CH:27]([NH2:30])([CH3:29])[CH3:28]>O1CCCC1>[Br:1][C:2]1[CH:6]=[C:5]([C:7]([NH:8][C:9]2[C:10]([C:11]([NH:30][CH:27]([CH3:29])[CH3:28])=[O:13])=[CH:14][C:15]([Cl:19])=[CH:16][C:17]=2[CH3:18])=[O:12])[N:4]([C:20]2[C:25]([Cl:26])=[CH:24][CH:23]=[CH:22][N:21]=2)[N:3]=1
Reactant: CC(C)N
Reactant: Cc1cc(Cl)cc2c(=O)oc(-c3cc(Br)nn3-c3ncccc3Cl)nc12
Solvent: C1CCOC1
Product: Cc1cc(Cl)cc(C(=O)NC(C)C)c1NC(=O)c1cc(Br)nn1-c1ncccc1Cl
Temperature: 60 °C

Procedure:
To a solution of the benzoxazinone product of Step E (0.20 g, 0.44 mmol) in tetrahydrofuran was added isopropylamine (0.122 mL, 1.42 mmol), and the reaction mixture was heated to 60° C. for 90 minutes and then cooled to room temperature. The tetrahydrofuran solvent was evaporated under reduced pressure, and the residual solid was triturated with ether, filtered, and dried to afford the title compound, a compound of the present invention, as a solid (150 mg), m.p. 159-161° C.
Reaction SMILES: [SH:1][C:2]1[N:10]=[CH:9][CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=[O:5].Br[CH2:12][CH:13]1[CH2:15][CH2:14]1>>[CH:13]1([CH2:12][S:1][C:2]2[N:10]=[CH:9][CH:8]=[CH:7][C:3]=2[C:4]([OH:6])=[O:5])[CH2:15][CH2:14]1
Reactant: O=C(O)c1cccnc1S
Reactant: BrCC1CC1
Product: O=C(O)c1cccnc1SCC1CC1
Yield: 88 %

Procedure:
2-Mercapto-nicotinic acid (1 g, 6.4 mmol) and bromomethyl cyclopropane were reacted in the same manner as in Step A of Preparation Example 10 to obtain the title compound (1.19 g, 88%).
Reaction SMILES: [C:1]([O:5][CH2:6][CH3:7])(=[O:4])[C:2]#[CH:3].[C:8]([O:24][CH:25]1[CH2:30][C:29]([CH3:32])([CH3:31])[NH:28][C:27]([CH3:34])([CH3:33])[CH2:26]1)(=[O:23])[CH2:9][C:10]([O:12][CH:13]1[CH2:18][C:17]([CH3:20])([CH3:19])[NH:16][C:15]([CH3:22])([CH3:21])[CH2:14]1)=[O:11]>C(O)C>[C:8]([O:24][CH:25]1[CH2:30][C:29]([CH3:32])([CH3:31])[N:28]([CH:3]=[CH:2][C:1]([O:5][CH2:6][CH3:7])=[O:4])[C:27]([CH3:34])([CH3:33])[CH2:26]1)(=[O:23])[CH2:9][C:10]([O:12][CH:13]1[CH2:18][C:17]([CH3:20])([CH3:19])[N:16]([CH:3]=[CH:2][C:1]([O:5][CH2:6][CH3:7])=[O:4])[C:15]([CH3:22])([CH3:21])[CH2:14]1)=[O:11]
Reactant: C#CC(=O)OCC
Reactant: CC1(C)CC(OC(=O)CC(=O)OC2CC(C)(C)NC(C)(C)C2)CC(C)(C)N1
Solvent: CCO
Product: CCOC(=O)C=CN1C(C)(C)CC(OC(=O)CC(=O)OC2CC(C)(C)N(C=CC(=O)OCC)C(C)(C)C2)CC1(C)C
Yield: 60 %

Procedure:
150 g of ethyl propiolate were added dropwise to a solution of 270 g of bis(2,2,6,6-tetramethyl-4-piperidinyl) malonate in 400 ml of ethanol at 60° C. The mixture was then refluxed for 4 hours. The solvent was removed by distillation under reduced pressure, and recrystallization of the resulting residue from isopropanol yielded 245 g of the compound of the formula shown below in the form of a colorless solid of melting point 100°-102° C. ##STR23##
Reaction SMILES: [CH2:1]([N:8]1[CH2:13][CH2:12][C:11]([CH2:16][CH:17]=[O:18])([CH:14]=[CH2:15])[CH2:10][CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.CO.[Cr](O[Cr]([O-])(=O)=O)([O-])(=O)=O.[NH+]1C=CC=CC=1.[NH+]1C=CC=CC=1.[CH2:42]([O:44]CC)C>CN(C)C=O>[CH2:1]([N:8]1[CH2:13][CH2:12][C:11]([CH2:16][C:17]([O:44][CH3:42])=[O:18])([CH:14]=[CH2:15])[CH2:10][CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: C=CC1(CC=O)CCN(Cc2ccccc2)CC1
Reactant: CCOCC
Agent: O=[Cr](=O)([O-])O[Cr](=O)(=O)[O-]
Agent: c1cc[nH+]cc1
Solvent: CN(C)C=O
Solvent: CO
Product: C=CC1(CC(=O)OC)CCN(Cc2ccccc2)CC1
Temperature: 25 °C
Reaction time: 20 h

Procedure:
To a solution of 0.486 g of (1-benzyl-4-vinylpiperidin-4-yl)acetaldehyde in N,N-dimethylformamide (10 ml) were added 0.48 g of methanol and 4.50 g of pyridinium dichromate and the resulting mixture was stirred at room temperature for 20 hours. After adding 100 ml of diethyl ether, the reaction mixture was filtered through celite. After concentrating under reduced pressure, the residue was purified by silica gel column chromatography (eluted with dichloromethane/methanol) to thereby give 0.321 g of the title compound as a colorless oily substance.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]([OH:11])=[C:6]([C:8](=[O:10])[CH3:9])[CH:7]=1.[Cl:12][C:13]1[CH:14]=[C:15]([CH:18]=[CH:19][CH:20]=1)[CH:16]=O.CCO.[OH-].[Na+]>COC(C)(C)C>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([OH:11])=[C:6]([C:8](=[O:10])[CH:9]=[CH:16][C:15]2[CH:18]=[CH:19][CH:20]=[C:13]([Cl:12])[CH:14]=2)[CH:7]=1
Reactant: O=Cc1cccc(Cl)c1
Reactant: CC(=O)c1cc(Br)ccc1O
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: COC(C)(C)C
Product: O=C(C=Cc1cccc(Cl)c1)c1cc(Br)ccc1O
Reaction time: 0.5 h
Yield: 347.6 %

Procedure:
In a bottle, 1-(5-bromo-2-hydroxyphenyl)ethanone (25 g, 0.02 mol), 3-chlorobenzaldehyde (16.35 g, 0.12 mol), EtOH (96%, 144 mL) and NaOH (42.1 g, 1.06 mol) were combined. The mixture was stirred vigorously for 0.5 h. 2-Methoxy-2-methylpropane (300 mL) was added and the mixture was filtered. The filtrate was poured into HCl (1 N, 800 mL) and filtered to give 1-(5-bromo-2-hydroxyphenyl)-3-(3-chlorophenyl)prop-2-en-1-one (23.47 g, 60%). 1H-NMR (CDCl3): 6.88 (d, 1H), 4.35 (m, 2H), 7.49 (m, 3H), 7.61 (s, 1H), 7.80 (m, 1H), 7.93 (m, 1H), 12.56 (s, 1H).
Reaction SMILES: [C:1]1([CH2:7][C:8](=O)[CH2:9][C:10]([O:12][CH3:13])=[S:11])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C([O-])=O.[NH4+].C([BH3-])#[N:20].[Na+]>CO.CCOC(C)=O>[CH3:13][O:12][C:10](=[S:11])[CH2:9][CH:8]([NH2:20])[CH2:7][C:1]1[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: COC(=S)CC(=O)Cc1ccccc1
Reactant: [BH3-]C#N
Agent: O=C[O-]
Agent: [NH4+]
Agent: [Na+]
Solvent: CO
Solvent: CCOC(C)=O
Product: COC(=S)CC(N)Cc1ccccc1
Temperature: 25 °C
Reaction time: 18 h
Yield: 64.8 %

Procedure:
To a solution of methyl phenylthioacetoacetate (1.00 g, 4.5 mmol) in MeOH (20 ml), ammonium formate (4.26 g, 6.75 mmol) and sodium cyanoborohydride (0.42 g, 6.7 mmol) were added. The reaction mixture was stirred at room temperature for 18 h, then diluted with EtOAc and partitioned into 1M HCl. The aqueous layer was then basified to pH=8.0 with NaOH. The desired product was extracted out with EtOAc, washed with water and brine, dried over Na2SO4 and concentrated to yield 0.61 g yellow oil; MS (NH3 -CI/DDIP) Calc. for (M+H)+ : 226. Found: 226; 1H NMR (300 MHz, CDCl3)δ 7.39 (d, J=7, 2H), 7.32-7.26 (m, 3H), 7.22 (d, J=10, 1H), 3.74 (s, 3H), 3.39-3.31 (m, 1H), 3.13-3.07 (dd, J=13, J'=9, 1H), 2.91-2.83 (dd, J=12, J'=6, 1H), 2.65-2.58 (dd, J=12, J'=6, 1H), 2.46-2.38 (dd, J=16, J'=8, 1H).
Reaction SMILES: Br[CH:2]([CH2:4][CH3:5])[CH3:3].[CH3:6][C:7]([CH:9]1[CH2:14][C:13]([CH3:16])([CH3:15])[CH2:12][CH2:11][CH2:10]1)=[O:8]>>[CH3:15][C:13]1([CH3:16])[CH2:12][CH2:11][CH2:10][CH:9]([C:7]([OH:8])([CH:2]([CH3:3])[CH2:4][CH3:5])[CH3:6])[CH2:14]1
Reactant: CC(=O)C1CCCC(C)(C)C1
Reactant: CCC(C)Br
Product: CCC(C)C(C)(O)C1CCCC(C)(C)C1

Procedure:
The protocol of example 1 is carried out again with 2-bromobutane replacing bromoethane, and herbac replacing dehydroherbac.
Reaction SMILES: Cl.Cl[C:3]1[N:12]=[C:11]([N:13]([C:15]2[CH:20]=[CH:19][C:18]([O:21][CH3:22])=[C:17]([O:23][CH3:24])[CH:16]=2)[CH3:14])[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[N:4]=1.[F-].[NH4+].[CH3:27][N:28](C=O)[CH3:29]>>[CH3:24][O:23][C:17]1[CH:16]=[C:15]([N:13]([CH3:14])[C:11]2[C:10]3[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=3)[N:4]=[C:3]([N:28]([CH3:29])[CH3:27])[N:12]=2)[CH:20]=[CH:19][C:18]=1[O:21][CH3:22]
Reactant: COc1ccc(N(C)c2nc(Cl)nc3ccccc23)cc1OC
Reactant: CN(C)C=O
Agent: Cl
Agent: [F-]
Agent: [NH4+]
Product: COc1ccc(N(C)c2nc(N(C)C)nc3ccccc23)cc1OC

Procedure:
A solution of (2-chloro-quinazolin-4-yl)-(3,4-dimethoxy-phenyl)-methyl-amine hydrochloride (105 mg; 0.287 mmol) and ammonium fluoride (73 mg; 1.97 mmol) in DMF (2 mL) was heated at 90° C. After 4 days the reaction was concentrated on a rotary evaporator then saturated NaHCO3 (5 mL) and water (3 mL) were added. Product was extracted into chloroform (4×2 mL) and the combined extracts washed with water (4×2 mL) and brine (3×3 mL). This solution was dried (MgSO4), filtered through silica and washed with 100:10:1 CHCl3:MeOH:concentrated NH4OH, concentrated then purified by MPLC (12 g SiO2/0-10% (20:1 MeOH:concentrated NH4OH) in CHCl3 gradient). Product was obtained as an oil, which solidified to a tan solid under high vacuum (68 mg; 70%). 1H NMR (CDCl3) δ 7.45 (m, 1H), 7.35 (m, 1H), 6.89 (m, 1H), 6.83 (m, 1H), 6.75-6.68 (m, 2H), 6.64 (m, 1H), 3.90 (s, 3H), 3.77 (s, 3H), 3.54 (s, 3H), 3.31 (s, 6H); LC-MS (ESI+; 339 ([M+H]+).
Reaction SMILES: [F:1][C:2]([F:6])([F:5])[CH2:3][OH:4].C(N(CC)CC)C.[CH:14]1[C:23]2[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=2)[CH:17]=[CH:16][C:15]=1[S:24](Cl)(=[O:26])=[O:25]>CN(C)C1C=CN=CC=1.C(OCC)(=O)C>[CH:14]1[C:23]2[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=2)[CH:17]=[CH:16][C:15]=1[S:24]([O:4][CH2:3][C:2]([F:6])([F:5])[F:1])(=[O:25])=[O:26]
Reactant: O=S(=O)(Cl)c1ccc2ccccc2c1
Reactant: OCC(F)(F)F
Agent: CN(C)c1ccncc1
Solvent: CCOC(C)=O
Solvent: CCN(CC)CC
Product: O=S(=O)(OCC(F)(F)F)c1ccc2ccccc2c1
Reaction time: 8 h
Yield: 89 %

Procedure:
To a stirred solution of 25.0 parts of 2,2,2-trifluoroethanol in 175 parts of N,N-diethylethanamine were added portionwise 62.2 parts of 2-naphthalenesulfonyl chloride. Upon completion, a mixture of 1.5 parts of N,N-dimethyl-4-pyridinamine and 25 parts of ethyl acetate was added during a period of 20 minutes. Upon complete addition, stirring was continued overnight at room temperature. The reaction mixture was filtered and the filtrate was evaporated in vacuo. The residue was stirred in water and solidified product was filtered off under reduced pressure. The precipitated product was dissolved in dichloromethane. The organic layer was dried, filtered and evaporated in vacuo. The residue was treated with petroleum ether. After filtration, the precipitated product was crystallized from 2-propanol. The product was filtered off and dried, yielding 65.3 parts (89%) of 2,2,2-trifluoroethyl 2-naphthalenesulfonate; mp. 72.7° C. (int. 36).
Reaction SMILES: [CH3:1][C:2]1[C:6]([C@H:7]([C:25]([O:27][C:28]([CH3:31])([CH3:30])[CH3:29])=[O:26])[C@@H:8]([CH2:19][CH2:20][C:21]([F:24])([F:23])[F:22])[C:9]([O:11]CC2C=CC=CC=2)=[O:10])=[CH:5][O:4][N:3]=1.[H][H]>CO.[OH-].[OH-].[Pd+2]>[C:28]([O:27][C:25](=[O:26])[C@H:7]([C@@H:8]([CH2:19][CH2:20][C:21]([F:24])([F:22])[F:23])[C:9]([OH:11])=[O:10])[C:6]1[C:2]([CH3:1])=[N:3][O:4][CH:5]=1)([CH3:31])([CH3:29])[CH3:30]
Reactant: [H][H]
Reactant: Cc1nocc1[C@H](C(=O)OC(C)(C)C)[C@@H](CCC(F)(F)F)C(=O)OCc1ccccc1
Agent: [Pd+2]
Agent: [OH-]
Solvent: CO
Product: Cc1nocc1[C@H](C(=O)OC(C)(C)C)[C@@H](CCC(F)(F)F)C(=O)O
Yield: 46.9 %

Procedure:
In a 200 mL round-bottomed flask a colorless solution of (2R,3R)-1-benzyl 4-tert-butyl 3-(3-methylisoxazol-4-yl)-2-(3,3,3-trifluoropropyl)succinate (2.4 g, 5.44 mmol) in MeOH (Volume: 50 mL) was treated with Pearlman's Catalyst (0.076 g, 0.544 mmol) and hydrogenated using a hydrogen-filled balloon at room temperature for 1 hour until the reaction was complete (monitored by HPLC). The mixture was filtered through a 0.45 μm membrane and rinsed with MeOH. The filtrated was concentrated to give 2.03 g of crude solid. The solid was purified on Prep HPLC [C18 Luna 30×100 eluting with a gradient from 10% B to 100% B (15 min)] to afford 99% pure Intermediate (896 mg, 46% yield) as a white solid. MS(ES):m/z=352 [M+H+], m/z=350[M−H−]. 1H NMR (500 MHz, chloroform-d) δ 8.40 (s, 1H), 3.62 (d, J=10.0 Hz, 1H), 3.08 (td, J=10.0, 3.6 Hz, 1H), 2.34 (s, 3H), 2.33-2.14 (m, 2H), 2.03-1.89 (m, 2H), 1.46 (s, 9H).
Reaction SMILES: [Br:1][C:2]1[C:3]([N:22]2[CH2:26][CH2:25][C@@H:24]([OH:27])[CH2:23]2)=[N:4][CH:5]=[C:6]([CH:21]=1)[C:7]([NH:9][C:10]1[CH:15]=[CH:14][C:13]([O:16][C:17]([F:20])([F:19])[F:18])=[CH:12][CH:11]=1)=[O:8].Cl.O[C@@H:30]1CCCNC1>>[Br:1][C:2]1[C:3]([N:22]2[CH2:26][CH2:30][CH2:25][C@@H:24]([OH:27])[CH2:23]2)=[N:4][CH:5]=[C:6]([CH:21]=1)[C:7]([NH:9][C:10]1[CH:15]=[CH:14][C:13]([O:16][C:17]([F:20])([F:18])[F:19])=[CH:12][CH:11]=1)=[O:8]
Reactant: O[C@@H]1CCCNC1
Reactant: O=C(Nc1ccc(OC(F)(F)F)cc1)c1cnc(N2CC[C@@H](O)C2)c(Br)c1
Agent: Cl
Product: O=C(Nc1ccc(OC(F)(F)F)cc1)c1cnc(N2CCC[C@@H](O)C2)c(Br)c1

Procedure:
The title compound was prepared in an analogous fashion to that described in Stage 12.1 using 5-bromo-6-chloro-N-(4-(trifluoromethoxy)phenyl)nicotinamide (Example 35) and (R)-(+)-3-hydroxypiperidine hydrochloride to afford a brown oil. UPLC-MS (condition 1) tR=3.38 min, m/z=460.0-462.0 [M+H]+, m/z=458.0-461.0 [M−H]−; 1H-NMR (400 MHz, DMSO-d6) δ ppm 1.28-1.41 (m, 1H) 1.49-1.63 (m, 1H) 1.75-1.85 (m, 1H) 1.90-1.98 (m, 1H) 2.73 (dd, J=12.23, 9.29 Hz, 1H) 2.87-2.96 (m, 1H) 3.56-3.69 (m, 1H) 3.75 (d, J=12.72 Hz, 1H) 3.91 (dd, J=12.10, 3.55 Hz, 1H) 4.88 (s, 1H) 7.36 (d, J=8.80 Hz, 2H) 7.82-7.89 (m, 2H) 8.42 (d, J=2.20 Hz, 1H) 8.76 (d, J=2.20 Hz, 1H) 10.37 (s, 1H).
Reaction SMILES: Br.[CH2:2]([O:9][C:10]1[CH:15]=[CH:14][C:13]([C:16]2[N:17]=[C:18]([NH2:21])[S:19][CH:20]=2)=[CH:12][C:11]=1[O:22][CH3:23])[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.[C:24]1(C)[CH:29]=[CH:28][C:27]([S:30](Cl)(=[O:32])=[O:31])=[CH:26][CH:25]=1.Cl>N1C=CC=CC=1>[CH2:2]([O:9][C:10]1[CH:15]=[CH:14][C:13]([C:16]2[N:17]=[C:18]([NH:21][S:30]([C:27]3[CH:28]=[CH:29][CH:24]=[CH:25][CH:26]=3)(=[O:32])=[O:31])[S:19][CH:20]=2)=[CH:12][C:11]=1[O:22][CH3:23])[C:3]1[CH:4]=[CH:5][CH:6]=[CH:7][CH:8]=1
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Reactant: COc1cc(-c2csc(N)n2)ccc1OCc1ccccc1
Agent: Br
Agent: Cl
Solvent: c1ccncc1
Product: COc1cc(-c2csc(NS(=O)(=O)c3ccccc3)n2)ccc1OCc1ccccc1
Yield: 60.8 %

Procedure:
A mixture of 0.5 g of 4-(4-benzyloxy-3-methoxy-phenyl)-thiazol-2-ylamine hydrobromide with 0.27 g of p-toluenesulfonyl chloride was stirred overnight with 2 ml of pyridine. The resulting, red colored solution was poured into 50 ml of 1N hydrochloric acid and extracted three times with 50 ml of methylene chloride each time. The organic extracts were combined, dried with magnesium sulphate and concentrated. The residue was chromatographed on 40 g of Kieselgel 60 with diethyl ether/hexane (2:1) as the eluent. Concentration of the product-containing fractions yielded 0.35 g of N-[4-(4-benzyloxy-3-methoxy-phenyl)-thiazol-2-yl]-benzenesulfonamide as colorless crystals.
Reaction SMILES: Cl.[NH2:2][OH:3].[CH:4]([C:6]1[CH:11]=[CH:10][N:9]2[C:12]([C:15]3[CH:16]=[C:17]([C:21]4[C:22]([C:27]#[N:28])=[CH:23][CH:24]=[CH:25][CH:26]=4)[CH:18]=[CH:19][CH:20]=3)=[CH:13][N:14]=[C:8]2[CH:7]=1)=O>>[OH:3][N:2]=[CH:4][C:6]1[CH:11]=[CH:10][N:9]2[C:12]([C:15]3[CH:16]=[C:17]([C:21]4[C:22]([C:27]#[N:28])=[CH:23][CH:24]=[CH:25][CH:26]=4)[CH:18]=[CH:19][CH:20]=3)=[CH:13][N:14]=[C:8]2[CH:7]=1
Reactant: NO
Reactant: N#Cc1ccccc1-c1cccc(-c2cnc3cc(C=O)ccn23)c1
Agent: Cl
Product: N#Cc1ccccc1-c1cccc(-c2cnc3cc(C=NO)ccn23)c1

Procedure:
The title compound was prepared in a similar manner to that described in Example 14 using hydroxylamine hydrochloride (77 mg, 1.11 mmol) and 3′-(7-formylimidazo[1,2-α]pyridin-3-yl)biphenyl-2-carbonitrile (120 mg, 0.37 mmol) to afford a white crystalline solid (105 mg, 83%), essentially as a single geometric isomer. 1H NMR (400 MHz, d6-DMSO) δH 7.27 (1H, dd, J 1 and 7), 7.61-7.90 (8H, m), 7.90 (2H, s), 8.00 (1H, dd, J 8 and 1), 8.25 (1H, s), 8.68 (1H, d, J 7), 11.53 (1H, s); m/z (ES+) 339 (M++H).