Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[C:2]1C=C(SC2C3C(=CC(C)=CC=3)NC=2CCC(N)=O)C=C(Cl)[CH:7]=1.[Cl:25][C:26]1[CH:31]=[CH:30][C:29]([S:32][C:33]2[C:41]3[C:36](=[CH:37][CH:38]=[C:39]([CH3:42])[CH:40]=3)[NH:35][C:34]=2[C:43]([OH:45])=[O:44])=[CH:28][CH:27]=1.C(Cl)(=O)C(Cl)=O.CCO>C1COCC1>[Cl:25][C:26]1[CH:27]=[CH:28][C:29]([S:32][C:33]2[C:41]3[C:36](=[CH:37][CH:38]=[C:39]([CH3:42])[CH:40]=3)[NH:35][C:34]=2[C:43]([O:45][CH2:2][CH3:7])=[O:44])=[CH:30][CH:31]=1
Reactant: Cc1ccc2[nH]c(C(=O)O)c(Sc3ccc(Cl)cc3)c2c1
Reactant: Cc1ccc2c(Sc3cc(Cl)cc(Cl)c3)c(CCC(N)=O)[nH]c2c1
Agent: O=C(Cl)C(=O)Cl
Solvent: CCO
Solvent: C1CCOC1
Product: CCOC(=O)c1[nH]c2ccc(C)cc2c1Sc1ccc(Cl)cc1
Yield: 76 %

Procedure:
Following the method used to prepare 24a, the use of 1b (0.23 mmol) and oxalyl chloride in THF followed by allowing the intermediate acid chloride to react with EtOH (5 mL) provided 61 mg (76%) of product 10 as a white solid, mp 158-160° C. 1H NMR (300 MHz, DMSO-d6) δ 1.24 (t, J=7 Hz, 3H), 2.34 (s, 3H), 4.30 (q, J=7 Hz, 2H), 7.05 (d, J=8 Hz, 2H), 7.16 (d, J=8 Hz, 1H), 7.26-7.29 (m, 3H), 7.46 (d, J=9 Hz, 1H), 12.38 (s, 1H). LC-MS (CI): m/z 346.1 [(M+H)+ C18H16ClNO2S requires 345.06]. Purity (100%). Calcd for C18H16ClNO2S: C, 62.51; H, 4.66; N, 4.05; S, 9.27; Cl, 10.25. Found: C, 62.37; H, 4.60; N, 3.95; S, 9.21; Cl, 10.30.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]2[C:10](=[CH:11][CH:12]=1)[NH:9][N:8]=[CH:7]2)([O-:3])=[O:2].[Br:13]N1C(=O)CCC1=O>C(Cl)(Cl)(Cl)Cl.N(C(C)(C)C#N)=NC(C)(C)C#N>[Br:13][C:7]1[C:6]2[C:10](=[CH:11][CH:12]=[C:4]([N+:1]([O-:3])=[O:2])[CH:5]=2)[NH:9][N:8]=1
Reactant: O=C1CCC(=O)N1Br
Reactant: O=[N+]([O-])c1ccc2[nH]ncc2c1
Agent: CC(C)(C#N)N=NC(C)(C)C#N
Solvent: ClC(Cl)(Cl)Cl
Product: O=[N+]([O-])c1ccc2[nH]nc(Br)c2c1
Yield: 130.5 %

Procedure:
To a solution of 12.4 g of 5-nitro-1H-indazole in 100 ml carbon tetrachloride were added 16.2 g of N-bromosuccinimide and 0.62 g of 2,2′-azobisisobutyronitrile, and the mixture was heated under reflux for 1 hour. The reaction mixture was cooled, and the resulting crystals were filtrated and washed with diethyl ether, to give 24.0 g of the title compound as a pale yellow powder.
Reaction SMILES: [CH3:1][Li].[CH2:3]([O:7][C:8]1[CH:19]=[N:18][CH:17]=[CH:16][C:9]=1[C:10](N(OC)C)=[O:11])[CH:4]([CH3:6])[CH3:5].O>C1COCC1.Cl>[CH2:3]([O:7][C:8]1[CH:19]=[N:18][CH:17]=[CH:16][C:9]=1[C:10](=[O:11])[CH3:1])[CH:4]([CH3:5])[CH3:6]
Reactant: [Li]C
Reactant: CON(C)C(=O)c1ccncc1OCC(C)C
Agent: Cl
Solvent: O
Solvent: C1CCOC1
Product: CC(=O)c1ccncc1OCC(C)C
Temperature: 0 °C
Reaction time: 1 h

Procedure:
Methyl lithium (4.6 mL, 7.4 mmol, 1.6M in Et2O, Aldrich) was added dropwise to a solution of 3-isobutoxy-N-methoxy-N-methylisonicotinamide (0.88 g, 3.7 mmol) in 15 mL of THF at 0° C. The reaction mixture was allowed to stir at 0° C. for an additional 1 h. To the resulting mixture were added 1 mL of water and 2 drops of conc HCl. The layers were separated and the aqueous layer was washed twice with 20 mL portions of Et2O. The combined organic layers were washed with brine, dried over sodium sulfate, and concentrated under reduced pressure. The product was purified by SiO2 flash chromatography (50:50 hexanes/ethyl acetate) to 450 mg (63%) of the title compound. 1H-NMR (400 MHz, d6-DMSO): δ 8.54 (s, 1H), 8.27 (d, 1H), 7.41 (d, 1H), 4.01 (d, 2H), 2.55 (s, 3H), 2.06 (m, 1H), 0.99 (d, 6H). MS (EI) for C12H18N2O2: 194 (MH+).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[C:7]([O:9][CH3:10])[CH:6]=[CH:5][C:4]=1[C:11]1[N:16]([CH2:17][C:18]([O:20]CC)=[O:19])[C:15](=[S:23])[NH:14][C:13](=[O:24])[CH:12]=1.[OH-].[Na+]>CO>[CH3:1][O:2][C:3]1[CH:8]=[C:7]([O:9][CH3:10])[CH:6]=[CH:5][C:4]=1[C:11]1[N:16]([CH2:17][C:18]([OH:20])=[O:19])[C:15](=[S:23])[NH:14][C:13](=[O:24])[CH:12]=1
Reactant: CCOC(=O)Cn1c(-c2ccc(OC)cc2OC)cc(=O)[nH]c1=S
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: COc1ccc(-c2cc(=O)[nH]c(=S)n2CC(=O)O)c(OC)c1
Temperature: 35 °C
Reaction time: 3 h
Yield: 99.8 %

Procedure:
To a solution of ethyl 2-(6-(2,4-dimethoxyphenyl)-4-oxo-2-thioxo-3,4-dihydropyrimidin-1(2H)-yl)acetate (6.8 g, 20.3 mmol) in methanol (34 mL) was added 6N aqueous NaOH (16.9 mL), and the solution was stirred at 35° C. for 3 hours. The mixture was concentrated under reduced pressure, and water (100 mL) was added. The aqueous layer was washed with ethyl acetate (2×200 mL), and acidified with concentrated HCl to pH˜2. The resultant acidic aqueous solution was extracted with EtOAc (3×200 mL), and the combined organic layers were dried with sodium sulfate, and concentrated under reduced pressure to give the title compound 6.53 g (99%) as a white solid.
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]([CH:9]=[CH:10][C:11]=1[O:12][CH:13]([CH3:15])[CH3:14])[C:6](Cl)=[O:7])#[N:2].O[NH:17][C:18](=[NH:37])[C:19]1[CH:27]=[CH:26][CH:25]=[C:24]2[C:20]=1[CH:21]=[N:22][N:23]2[CH2:28][C:29]([CH3:36])([CH3:35])[C:30]([O:32][CH2:33][CH3:34])=[O:31].C(N(CC)CC)C>C(#N)C>[C:1]([C:3]1[CH:4]=[C:5]([C:6]2[O:7][N:17]=[C:18]([C:19]3[CH:27]=[CH:26][CH:25]=[C:24]4[C:20]=3[CH:21]=[N:22][N:23]4[CH2:28][C:29]([CH3:35])([CH3:36])[C:30]([O:32][CH2:33][CH3:34])=[O:31])[N:37]=2)[CH:9]=[CH:10][C:11]=1[O:12][CH:13]([CH3:15])[CH3:14])#[N:2]
Reactant: CCOC(=O)C(C)(C)Cn1ncc2c(C(=N)NO)cccc21
Reactant: CC(C)Oc1ccc(C(=O)Cl)cc1C#N
Solvent: CCN(CC)CC
Solvent: CC#N
Product: CCOC(=O)C(C)(C)Cn1ncc2c(-c3noc(-c4ccc(OC(C)C)c(C#N)c4)n3)cccc21
Temperature: 25 °C
Reaction time: 1 h
Yield: 68.1 %

Procedure:
3-Cyano-4-[(1-methylethyl)oxy]benzoyl chloride (D106) (0.398 mmol) in acetonitrile (3.00 ml) at room temperature was treated with ethyl 3-{4-[(hydroxyamino)(imino)methyl]-1H-indazol-1-yl}-2,2-dimethylpropanoate (D103) (101 mg, 0.332 mmol) followed by triethylamine (0.069 ml, 0.498 mmol). The resulting yellow solution was stirred at room temperature for 1 hr, refluxed overnight, for a further 24 hours and again overnight then cooled to room temperature and concentrated in vacuo. Purification of the residue by flash chromatography on silica gel [gradient ethyl acetate/cyclohexane] gave the title compound (107 mg, 68%) as a colourless solid. MS (ES) C26H27N5O4 requires 473, found 474 [M+H]+
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([Cl:8])[C:3]=1[C:9]1[C:20](=[O:21])[N:19]([CH3:22])[C:12]2[N:13]=[C:14](SC)[N:15]=[CH:16][C:11]=2[CH:10]=1.[CH:23]([NH2:26])([CH3:25])[CH3:24]>>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([Cl:8])[C:3]=1[C:9]1[C:20](=[O:21])[N:19]([CH3:22])[C:12]2[N:13]=[C:14]([NH:26][CH:23]([CH3:25])[CH3:24])[N:15]=[CH:16][C:11]=2[CH:10]=1
Reactant: CC(C)N
Reactant: CSc1ncc2cc(-c3c(Cl)cccc3Cl)c(=O)n(C)c2n1
Product: CC(C)Nc1ncc2cc(-c3c(Cl)cccc3Cl)c(=O)n(C)c2n1

Procedure:
This compound was prepared by a procedure similar to that described in Example 40 starting with 6-(2,6-dichlorophenyl)-8-methyl-2-methylsulfanyl-8H-pyrido[2,3-d]pyrimidin-7-one of Example 37 and isopropylamine; mp 194°-196° C.
Reaction SMILES: [N:1]1([CH2:6][CH:7]2[CH2:12][CH2:11][NH:10][CH2:9][CH2:8]2)[CH2:5][CH2:4][CH2:3][CH2:2]1.F[C:14]1[CH:21]=[CH:20][C:17]([CH:18]=[O:19])=[CH:16][C:15]=1[CH3:22]>>[CH3:22][C:15]1[CH:16]=[C:17]([CH:20]=[CH:21][C:14]=1[N:10]1[CH2:11][CH2:12][CH:7]([CH2:6][N:1]2[CH2:5][CH2:4][CH2:3][CH2:2]2)[CH2:8][CH2:9]1)[CH:18]=[O:19]
Reactant: Cc1cc(C=O)ccc1F
Reactant: C1CCN(CC2CCNCC2)C1
Product: Cc1cc(C=O)ccc1N1CCC(CN2CCCC2)CC1

Procedure:
Prepared from the product of Example 4 and 4-fluoro-3-methyl-benzaldehyde.
Reaction SMILES: CC1C=CC(N[N:9]=[C:10]2[C:15]3=[N:16][C:17]4[C:22]([C:23](=[O:24])[N:14]3[CH2:13][CH2:12][CH2:11]2)=[CH:21][CH:20]=[CH:19][CH:18]=4)=CC=1.[OH-].[NH4+]>O>[CH3:23][C:22]1[CH:21]=[C:20]2[C:11]3[CH2:12][CH2:13][N:14]4[C:23](=[O:24])[C:22]5[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=5[N:16]=[C:15]4[C:10]=3[NH:9][C:19]2=[CH:18][CH:17]=1
Reactant: Cc1ccc(NN=C2CCCn3c2nc2ccccc2c3=O)cc1
Agent: [NH4+]
Agent: [OH-]
Solvent: O
Product: Cc1ccc2[nH]c3c(c2c1)CCn1c-3nc2ccccc2c1=O
Temperature: 180 °C
Reaction time: 0.5 h
Yield: 63 %

Procedure:
1 g. of 6-[(4-Methyl-phenyl)-hydrazono]-6,7,8,9-tetrahydro-11H-pyrido [2,1-b] quinazoline-11-one is added in small portions to 10 g. of polyphosphoric acid heated to 180° C. within 5 minutes. After adding the above substance the reaction mixture is stirred for 30 minutes at 180° C. After cooling the mixture is diluted to 40 ml. of water and the pH of the solution is adjusted to 5 by adding 25 V/W% ammoniumhydroxide solution. The precipitated crystals are filtered and washed with water. After drying the product is dissolved in dimethylformamide and treated with active charcoal at 100° C. The dimethylformamide solution is diluted with water whereafter yellowish-white crystals are obtained which are filtered and washed with water. After drying 0.6 g. (63%) of 10-methyl-7,8-dihydro-5H,13H-indolo [2', 3';3,4]-pyrido [2,1-b] quinazoline-5-one are obtained.
Reaction SMILES: [O:1]=[C:2]([C:19]1[N:23]([CH3:24])[N:22]=[C:21]([CH3:25])[C:20]=1[CH3:26])[CH:3]([C:6]1[C:10]([CH2:11][CH3:12])=[N:9][N:8]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[N:7]=1)[C:4]#[N:5].[C:27](Cl)(=[O:32])[C:28]([CH3:31])([CH3:30])[CH3:29]>C1(C)C(C)=CC=CC=1>[CH3:29][C:28]([CH3:31])([CH3:30])[C:27]([O:1]/[C:2](/[C:19]1[N:23]([CH3:24])[N:22]=[C:21]([CH3:25])[C:20]=1[CH3:26])=[C:3](\[C:6]1[C:10]([CH2:11][CH3:12])=[N:9][N:8]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[N:7]=1)/[C:4]#[N:5])=[O:32]
Reactant: CC(C)(C)C(=O)Cl
Reactant: CCc1nn(-c2ccccc2)nc1C(C#N)C(=O)c1c(C)c(C)nn1C
Solvent: Cc1ccccc1C
Product: CCc1nn(-c2ccccc2)nc1/C(C#N)=C(\OC(=O)C(C)(C)C)c1c(C)c(C)nn1C
Temperature: 70 °C
Yield: 93 %

Procedure:
In a 3 L-reaction flask, 156.8 g (0.45 mol) of 3-oxo-2-(2-phenyl-5-ethyl-1,2,3-triazol-4-yl)-3-(1,3,4-trimethylpyrazol-5-yl)propionitrile and 900 g of xylene were added, the temperature was raised to 70° C., and 162.7 g (1.35 mol) of pivaloyl chloride was added dropwise under reflux over 10 hours while removing hydrogen chloride under a reduced pressure at 68 to 71° C./10 to 13 kPa. After reacting as such for 5 hours, 740 g of a mixture of pivaloyl chloride and xylene was distilled off at 70° C. under a reduced pressure in order to remove excess pivaloyl chloride. After adding 156 g of warm water of 70° C., 70 g of 2.7% sodium hydrogen carbonate aqueous solution was added dropwise. After separating the resulting aqueous phase, the resulting organic phase was washed with 156 g of warm water of 70° C., the resulting aqueous phase was separated to obtain a xylene solution containing 181 g (yield 93.0%) of (2E)-3-(2,2-dimethylpropanoyloxy)-2-(2-phenyl-5-ethyl-1,2,3-triazol-4-yl)-3-(1,3,4-trimethylpyrazol-5-yl)acrylonitrile. After distilling off most of xylene at 90° C. under a reduced pressure, 540 g of acetonitrile was added, and crystallization was carried out by gradually cooling from 70° C. After stirring at 0° C. for 1 hour, the resulting crystal was filtered, and dried to obtain 163.5 g (yield 84%) of (2E)-3-(2,2-dimethylpropanoyloxy)-2-(2-phenyl-5-ethyl-1,2,3-triazol-4-yl)-3-(1,3,4-trimethylpyrazol-5-yl)acrylonitrile (melting point: 119° C.).
Reaction SMILES: [C:1]([OH:6])(=O)[CH:2]([CH3:4])[CH3:3].[NH:7]1[CH2:12][CH2:11][CH:10]([OH:13])[CH2:9][CH2:8]1>>[OH:13][CH:10]1[CH2:11][CH2:12][N:7]([C:1](=[O:6])[CH:2]([CH3:4])[CH3:3])[CH2:8][CH2:9]1
Reactant: OC1CCNCC1
Reactant: CC(C)C(=O)O
Product: CC(C)C(=O)N1CCC(O)CC1

Procedure:
Prepared as in Example Da from isobutyric acid and piperidin-4-ol as a colorless oil (43%). MS 172 (MH+).
Reaction SMILES: C([O:4][C@@H:5]1[C@@H:19]([O:20]C(=O)C)[C@H:18]([O:24]C(=O)C)[CH2:17][S:16][C@H:6]1[O:7][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=1[C:14]#[N:15])(=O)C.C[O-].[Na+]>CO>[O:7]([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=1[C:14]#[N:15])[C@@H:6]1[S:16][CH2:17][C@@H:18]([OH:24])[C@H:19]([OH:20])[C@H:5]1[OH:4]
Reactant: CC(=O)O[C@@H]1[C@@H](OC(C)=O)[C@H](OC(C)=O)CS[C@H]1Oc1ccccc1C#N
Agent: C[O-]
Agent: [Na+]
Solvent: CO
Product: N#Cc1ccccc1O[C@@H]1SC[C@@H](O)[C@H](O)[C@H]1O
Yield: 87.6 %

Procedure:
If the procedure described in Preparation LXXXIV is followed starting from 1.26 g (3.2.10-3 mol) of 2-cyanophenyl 2,3,4-tri-O-acetyl-5-thio-β-D-xylopyranoside and 0.2 ml of a solution of sodium methylate in methanol (8% w/v of Na), reacted in 70 ml of methanol for 30 min, 0.75 g (yield: 88%) of the expected product is obtained after precipitation in ether and lyophilization.
Reaction SMILES: [F:1][C:2]([F:23])([F:22])[C:3]1[CH:4]=[C:5]([C:13]2([C:18]([F:21])([F:20])[F:19])[CH2:17][CH2:16][NH:15][CH2:14]2)[CH:6]=[C:7]([C:9]([F:12])([F:11])[F:10])[CH:8]=1.Br[C:25]1[CH:26]=[C:27]2[C:31](=[CH:32][CH:33]=1)[CH:30]([NH:34][C:35](=[O:38])[CH2:36][CH3:37])[CH2:29][CH2:28]2.CC(C)([O-])C.[Na+]>C1(C)C=CC=CC=1.C(OCC)(=O)C.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd].CC1(C)C2C(=C(P(C3C=CC=CC=3)C3C=CC=CC=3)C=CC=2)OC2C(P(C3C=CC=CC=3)C3C=CC=CC=3)=CC=CC1=2>[F:12][C:9]([F:10])([F:11])[C:7]1[CH:6]=[C:5]([C:13]2([C:18]([F:21])([F:19])[F:20])[CH2:17][CH2:16][N:15]([C:25]3[CH:26]=[C:27]4[C:31](=[CH:32][CH:33]=3)[CH:30]([NH:34][C:35](=[O:38])[CH2:36][CH3:37])[CH2:29][CH2:28]4)[CH2:14]2)[CH:4]=[C:3]([C:2]([F:22])([F:1])[F:23])[CH:8]=1
Reactant: CCC(=O)NC1CCc2cc(Br)ccc21
Reactant: FC(F)(F)c1cc(C(F)(F)F)cc(C2(C(F)(F)F)CCNC2)c1
Agent: [Pd]
Agent: CC(C)(C)[O-]
Agent: CC1(C)c2cccc(P(c3ccccc3)c3ccccc3)c2Oc2c(P(c3ccccc3)c3ccccc3)cccc21
Solvent: Cc1ccccc1
Solvent: CCOC(C)=O
Product: CCC(=O)NC1CCc2cc(N3CCC(c4cc(C(F)(F)F)cc(C(F)(F)F)c4)(C(F)(F)F)C3)ccc21
Temperature: 100 °C
Reaction time: 2 h
Yield: 72.6 %

Procedure:
3-[3,5-bis(trifluoromethyl)phenyl]-3-(trifluoromethyl)pyrrolidine (0.46 g) and N-(5-bromo-2,3-dihydro-1H-inden-1-yl)propanamide (0.35 g) were dissolved in toluene and deaeration procedure was performed three times under argon atmosphere. Sodium tert-butoxide (0.25 g), Xantphos (0.05 g) and tris(dibenzylideneacetone)dipalladium (0) (chloroform adduct) (0.03 g) were added to the mixture and heated and stirred at 100° C. under argon atmosphere for 2 hours. The solution was cooled to room temperature and the reaction liquid was diluted with ethyl acetate followed by washing with water and brine. The organic layer was dried over anhydrous magnesium sulfate. The desiccant was filtered and separated, the solvent was evaporated off under reduced pressure, and the residue was purified by a silica gel chromatography to obtain N-(5-{3-[3,5-bis(trifluoromethyl)phenyl]-3-(trifluoromethyl)pyrrolidin-1-yl}-2,3-dihydro-1H-inden-1-yl)propanamide (0.51 g).
Reaction SMILES: [C:1]([C:5]1[CH:9]=[C:8]([NH2:10])[O:7][N:6]=1)([CH3:4])([CH3:3])[CH3:2].C[Al](C)C.[CH3:15][C:16]1([S:22]([CH:25]2[CH2:30][CH2:29][O:28][CH2:27][CH2:26]2)(=[O:24])=[O:23])[CH2:20][CH2:19][O:18][C:17]1=[O:21]>C(Cl)Cl.C1(C)C=CC=CC=1>[C:1]([C:5]1[CH:9]=[C:8]([NH:10][C:17](=[O:21])[C:16]([CH3:15])([S:22]([CH:25]2[CH2:26][CH2:27][O:28][CH2:29][CH2:30]2)(=[O:24])=[O:23])[CH2:20][CH2:19][OH:18])[O:7][N:6]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: CC1(S(=O)(=O)C2CCOCC2)CCOC1=O
Reactant: CC(C)(C)c1cc(N)on1
Agent: C[Al](C)C
Solvent: Cc1ccccc1
Solvent: ClCCl
Product: CC(C)(C)c1cc(NC(=O)C(C)(CCO)S(=O)(=O)C2CCOCC2)on1
Temperature: 45 °C
Reaction time: 0.25 h
Yield: 69.3 %

Procedure:
To a solution of 3-tert-butyl-isoxazol-5-ylamine (0.421 g; 3.00 mmol) in methylene chloride (10 mL) was added dropwise the trimethylaluminum (1.50 mL of a 2.0 M solution in toluene; 3.0 mmol). The mixture was stirred 15 minutes and 3-methyl-3-(tetrahydro-pyran-4-sulfonyl)-dihydro-furan-2-one (0.596 g; 2.40 mmol) was added. The mixture was heated to 45° C. overnight, cooled to room temperature, carefully quenched with 0.5 mL methanol, applied to a plug of silica gel and eluted with ethyl acetate. Removal of the volatiles in vacuo provided a residue which was purified by silica gel chromatography using ethyl acetate and hexanes as the eluent. The product-rich fractions were concentrated in vacuo to provide 0.646 g of the desired product. 1H NMR (CDCl3) δ 9.92 (bs, 1H), 6.29 (s, 1H), 4.11-3.92 (m, 4H), 3.86 (m, 1H), 3.60 (m, 1H), 3.40 (m, 2H), 2.57 (m, 1H), 2.36 (m, 1H), 2.12-1.90 (m, 4H), 1.80 (s, 3H), 1.32 (s, 9H). MS (ESI): m/e 389 (M+H).
Reaction SMILES: [NH2:1][C:2]1[CH:10]=[C:9]([C:11]2[C:16]([C:17]([F:20])([F:19])[F:18])=[CH:15][CH:14]=[CH:13][N:12]=2)[CH:8]=[CH:7][C:3]=1[C:4]([NH2:6])=[O:5].N1C=CC=CC=1.[Cl-].[CH2:28]([O:30][C:31](=[O:37])[CH2:32][CH2:33][C:34](Cl)=O)[CH3:29].CC[O-].[Na+]>C1COCC1.CCO>[CH2:28]([O:30][C:31](=[O:37])[CH2:32][CH2:33][C:34]1[N:6]=[C:4]([OH:5])[C:3]2[C:2](=[CH:10][C:9]([C:11]3[C:16]([C:17]([F:20])([F:18])[F:19])=[CH:15][CH:14]=[CH:13][N:12]=3)=[CH:8][CH:7]=2)[N:1]=1)[CH3:29]
Reactant: NC(=O)c1ccc(-c2ncccc2C(F)(F)F)cc1N
Reactant: CCOC(=O)CCC(=O)Cl
Agent: CC[O-]
Agent: [Cl-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: c1ccncc1
Solvent: CCO
Product: CCOC(=O)CCc1nc(O)c2ccc(-c3ncccc3C(F)(F)F)cc2n1
Temperature: 25 °C
Reaction time: 0.33 h

Procedure:
To a solution of 2-amino-4-(3-trifluoromethyl-pyridin-2-yl)-benzamide (0.5 mmol) and pyridine (0.55 mmol) in THF (5 ml), add 3-chlorocarbonyl-propionic acid ethyl ester chloride (0.55 mmol). Stir the mixture for 20 minutes at room temperature, add 20 ml of 21% NaOEt in EtOH, and stir for 30 minutes at 50° C. Concentrate, add water, filter, acidify to pH 6, and collect the precipitate to give 3-[4-hydroxy-7-(3-trifluoromethyl-pyridin-2-yl)-quinazolin-2-yl]-propionic acid ethyl ester.
Reaction SMILES: [CH3:1][C:2]1[C:7]([C:8]2[N:9]([C:17]3[CH:22]=[CH:21][C:20]([S:23](CC[Si](C)(C)C)(=[O:25])=[O:24])=[CH:19][CH:18]=3)[CH:10]=[C:11]([C:13]([F:16])([F:15])[F:14])[N:12]=2)=[CH:6][CH:5]=[CH:4][N:3]=1.[N+:32](CCCC)(CCCC)(CCCC)CCCC.[F-].C([O-])(=O)C.[Na+].NOS(O)(=O)=O>C1COCC1.O.C(OCC)(=O)C>[CH3:1][C:2]1[C:7]([C:8]2[N:9]([C:17]3[CH:22]=[CH:21][C:20]([S:23]([NH2:32])(=[O:25])=[O:24])=[CH:19][CH:18]=3)[CH:10]=[C:11]([C:13]([F:16])([F:15])[F:14])[N:12]=2)=[CH:6][CH:5]=[CH:4][N:3]=1
Reactant: Cc1ncccc1-c1nc(C(F)(F)F)cn1-c1ccc(S(=O)(=O)CC[Si](C)(C)C)cc1
Reactant: CCCC[N+](CCCC)(CCCC)CCCC
Agent: CC(=O)[O-]
Agent: NOS(=O)(=O)O
Agent: [F-]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Solvent: O
Product: Cc1ncccc1-c1nc(C(F)(F)F)cn1-c1ccc(S(N)(=O)=O)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 83.7 %

Procedure:
To a solution of 2-methyl-3-[1-[4-[[2-(trimethylsilyl)ethyl]sulfonyl]phenyl]-4-(trifluoromethyl)-1H-imidazol-2-yl]pyridine from Step 1 (0.234 g, 0.5 mmol) in 1.5 mL of dry THF was added n-Bu4NF (1.5 mL of 1.0M THF solution, 1.5 mmol). The mixture was heated to reflux for 1 hour and cooled to room temperature. A solution of sodium acetate (0.19 g, 2.3 mmol) in 3 mL of water and hydroxylamine-O-sulfonic acid (0.28 g, 2.5 mmol) were added sequentially and the mixture was stirred for 1 hour. Water (7 mL) and ethyl acetate (7 mL) were added. The organic phase was separated and washed with sat. NaHCO3 solution, water, and brine, dried over MgSO4 and filtered. The filtrate was concentrated and the residue was purified by chromatography on silica gel (ethyl acetate/acetone, 95:5) to give 0.16 g of 4-[2-(2-methylpyridin-3-yl)-4-(trifluoromethyl)-1H-imidazol-1-yl]benzenesulfonamide as a colorless solid (84%): mp 235-237° C. Anal. Calc'd. for C16H13F3N4O2S: C, 50.26; H, 3.43; N, 14.65; S, 8.39. Found: C, 50.06; H, 3.29; N, 14.44; S, 8.52.
Reaction SMILES: [OH:1][CH2:2][C@@H:3]1[O:7][C:6]([C:8]2[NH:12][C:11]([C:13]3[CH:14]=[C:15]([CH:37]=[C:38]([O:40][C@@H:41]([CH3:45])[CH2:42][O:43][CH3:44])[CH:39]=3)[O:16][C:17]3[CH:18]=[CH:19][C:20]([S:23]([N:26](CC4C=CC(OC)=CC=4)[CH3:27])(=[O:25])=[O:24])=[N:21][CH:22]=3)=[CH:10][CH:9]=2)=[N:5][CH2:4]1>FC(F)(F)C(O)=O>[OH:1][CH2:2][C@@H:3]1[O:7][C:6]([C:8]2[NH:12][C:11]([C:13]3[CH:14]=[C:15]([CH:37]=[C:38]([O:40][C@@H:41]([CH3:45])[CH2:42][O:43][CH3:44])[CH:39]=3)[O:16][C:17]3[CH:18]=[CH:19][C:20]([S:23]([NH:26][CH3:27])(=[O:24])=[O:25])=[N:21][CH:22]=3)=[CH:10][CH:9]=2)=[N:5][CH2:4]1
Reactant: COC[C@H](C)Oc1cc(Oc2ccc(S(=O)(=O)N(C)Cc3ccc(OC)cc3)nc2)cc(-c2ccc(C3=NC[C@H](CO)O3)[nH]2)c1
Solvent: O=C(O)C(F)(F)F
Product: CNS(=O)(=O)c1ccc(Oc2cc(O[C@@H](C)COC)cc(-c3ccc(C4=NC[C@H](CO)O4)[nH]3)c2)cn1
Reaction time: 6 h
Yield: 75.8 %

Procedure:
5-(3-{5-[(5R)-5-Hydroxymethyl-4,5-dihydro-1,3-oxazol-2-yl]-1H-pyrrol-2-yl}-5-[(1S)-2-methoxy-1-methylethoxy]phenoxy)-N-(4-methoxybenzyl)-N-methylpyridine-2-sulfonamide (292 mg, 0.47 mmol) synthesized in Example (127a) was dissolved in trifluoroacetic acid (2 mL), and stirring was carried out at 45° C. for 6 hours. The solvent was distilled off under reduced pressure, methylene chloride and triethylamine were added in small portions to the residue, and the solvent was distilled off again under reduced pressure. The resulting residue was purified using silica gel column chromatography (elution solvent: methanol/methylene chloride=0%-4%) to afford the desired compound (184 mg, yield 100%) as a white solid.
Reaction SMILES: [C:1](=[O:15])([O:12][CH:13]=[CH2:14])[O:2][C:3]1[CH:8]=CC([N+]([O-])=O)=CC=1.OCC[O:19][C:20](=[O:24])[C:21]([CH3:23])=[CH2:22].CS(C)=O.[OH-].[Na+]>O>[C:1](=[O:15])([O:12][CH:13]=[CH2:14])[O:2][CH2:3][CH2:8][O:24][C:20](=[O:19])[C:21]([CH3:23])=[CH2:22]
Reactant: C=COC(=O)Oc1ccc([N+](=O)[O-])cc1
Reactant: C=C(C)C(=O)OCCO
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CS(C)=O
Product: C=COC(=O)OCCOC(=O)C(=C)C

Procedure:
A solution of p-nitrophenyl vinyl carbonate, hydroxyethylmethacrylate, DMSO and sodium hydroxide is stirred at room temperature for a minimum of 12 hours. Reaction completion is monitored by G.C. The solution is drowned into water and the mixture extracted with ethyl acetate. The product solution is washed with water, dried with magnesium sulfate, then stripped to an oil under vacuum. The crude product is then purified.
Reaction SMILES: [CH2:1]([OH:9])[CH2:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.[C:10]1([CH3:20])[CH:15]=[CH:14][C:13]([S:16](Cl)(=[O:18])=[O:17])=[CH:12][CH:11]=1>N1C=CC=CC=1.C(OCC)(=O)C>[CH3:20][C:10]1[CH:15]=[CH:14][C:13]([S:16]([O:9][CH2:1][CH2:2][C:3]2[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=2)(=[O:18])=[O:17])=[CH:12][CH:11]=1
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Reactant: OCCc1ccccc1
Solvent: c1ccncc1
Solvent: CCOC(C)=O
Product: Cc1ccc(S(=O)(=O)OCCc2ccccc2)cc1
Reaction time: 16 h
Yield: 51.2 %

Procedure:
To a stirred solution of phenethyl alcohol (0.50 mL, 4.17 mmol) in pyridine (4 mL) at 0° C. was added p-toluenesulfonyl chloride (0.80 g, 4.18 mmol). The reaction mixture was stirred for 16 h, and then diluted with ethyl acetate (75 mL). The organic solution was washed with 10% aqueous hydrochloric acid (2×25 mL), saturated aqueous sodium bicarbonate (50 mL) and brine (25 mL), then dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated in vacuo and the residue was purified by column chromatography eluting with 0-20% ethyl acetate in hexane to afford the title compound as a light yellow liquid (0.59 g, 51%): 1H NMR (300 MHz, CDCl3) δ 7.69 (d, J=8.3 Hz, 2H), 7.31-7.20 (m, 5H), 7.11 (dd, J=7.4, 1.7 Hz, 2H), 4.21 (t, J=7.1 Hz, 2H), 2.96 (t, J=7.1 Hz, 2H), 2.43 (s, 3H); MS (ES+) m/z 299.2 (M+23).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9]([OH:11])=O)=[CH:4][CH:3]=1.[CH2:12]([NH2:19])[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1>>[CH2:12]([NH:19][C:9](=[O:11])[CH2:8][C:5]1[CH:4]=[CH:3][C:2]([Br:1])=[CH:7][CH:6]=1)[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1
Reactant: O=C(O)Cc1ccc(Br)cc1
Reactant: NCc1ccccc1
Product: O=C(Cc1ccc(Br)cc1)NCc1ccccc1
Yield: 82 %

Procedure:
Amide coupling of 4-Bromophenylacetic acid with benzylamine was done according to procedures in Step 10A for Example 5B to give N-Benzyl-2-(4-bromo-phenyl)-acetamide in 82% yield. 1H NMR (400 MHz, DMSO-D6) δ ppm 3.5 (s, 2 H) 4.3 (d, J=5.8 Hz, 2 H) 7.2 (dd, J=7.8, 5.6 Hz, 5 H) 7.3 (m, 2 H) 7.5 (d, J=8.3 Hz, 2 H) 8.6 (t, J=5.9 Hz, 1 H).