Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3]1[C:8]2[N:9]=[C:10]([C:12]([F:15])([F:14])[F:13])[NH:11][C:7]=2[CH:6]=[CH:5][CH:4]=1.[Br:16]N1C(=O)CCC1=O>C(Cl)(Cl)Cl>[Br:16][C:6]1[C:7]2[NH:11][C:10]([C:12]([F:15])([F:13])[F:14])=[N:9][C:8]=2[C:3]([O:2][CH3:1])=[CH:4][CH:5]=1
Reactant: COc1cccc2[nH]c(C(F)(F)F)nc12
Reactant: O=C1CCC(=O)N1Br
Solvent: ClC(Cl)Cl
Product: COc1ccc(Br)c2[nH]c(C(F)(F)F)nc12
Reaction time: 2 h
Yield: 13.4 %

Procedure:
A solution of 7-methoxy-2-trifluoromethylbenzimidazole (50 g) in chloroform (100 ml) was cooled to 0° C., and N-bromosuccinimide (4.5 g) added. The mixture was stirred for 2 h. It was then washed with 5% aqueous sodium metabisulphite (50 ml), dried over magnesium sulphate, evaporated in vacuo and purified by flash chromatography eluting with 25% ethyl acetate in hexane to yield the title compound as a white solid (1.0 g).
Reaction SMILES: [CH:1]1([Mg]Br)[CH2:3][CH2:2]1.[F:6][C:7]([F:17])([F:16])[C:8]([C:10]1[S:14][C:13]([SH:15])=[N:12][CH:11]=1)=[O:9].[NH4+].[Cl-]>C1COCC1>[CH:1]1([C:8]([C:10]2[S:14][C:13]([SH:15])=[N:12][CH:11]=2)([OH:9])[C:7]([F:16])([F:6])[F:17])[CH2:3][CH2:2]1
Reactant: Br[Mg]C1CC1
Reactant: O=C(c1cnc(S)s1)C(F)(F)F
Agent: [Cl-]
Agent: [NH4+]
Solvent: C1CCOC1
Product: OC(c1cnc(S)s1)(C1CC1)C(F)(F)F
Reaction time: 1 h

Procedure:
Cyclopropylmagnesium bromide (0.5 M in THF, 7.00 mL, 3.52 mmol) was added dropwise to solution of 2,2,2-trifluoro-1-(2-mercapto-1,3-thiazol-5-yl)ethanone (0.300 g, 1.41 mmol) in THF(3 mL) at 0° C. After 1 h, saturated aqueous NH4Cl was added and the aqueous layer was extracted with EtOAc (3×). The combined organics were washed with brine, dried (Na2SO4) and concentrated. The residue was purified by chromatography on silica gel (toluene/acetone; 85:15) to yield the title compound.
Reaction SMILES: C([O:3][C:4](=O)[C:5]([N:7]1[CH2:13][CH2:12][C:11]2[CH:14]=[C:15]([O:18][CH2:19][C:20]3[CH:25]=[CH:24][CH:23]=[C:22]([F:26])[CH:21]=3)[CH:16]=[CH:17][C:10]=2[CH2:9][CH2:8]1)=[O:6])C.Cl.FC1C=C(C=CC=1)COC1C=CC2CC[NH:41]CCC=2C=1.C([ClH]C(=O)C(Cl)=O)C>C(N(CC)CC)C>[F:26][C:22]1[CH:21]=[C:20]([CH:25]=[CH:24][CH:23]=1)[CH2:19][O:18][C:15]1[CH:16]=[CH:17][C:10]2[CH2:9][CH2:8][N:7]([C:5](=[O:6])[C:4]([NH2:41])=[O:3])[CH2:13][CH2:12][C:11]=2[CH:14]=1
Reactant: CCOC(=O)C(=O)N1CCc2ccc(OCc3cccc(F)c3)cc2CC1
Reactant: Fc1cccc(COc2ccc3c(c2)CCNCC3)c1
Agent: Cl
Solvent: CCN(CC)CC
Product: NC(=O)C(=O)N1CCc2ccc(OCc3cccc(F)c3)cc2CC1
Yield: 88 %

Procedure:
[7-(3-Fluoro-benzyloxy)-1,2,4,5-tetrahydro-benzo[d]azepin-3-yl]-oxo-acetic acid ethyl ester: The title compound was prepared in analogy to Example 1d) from 7-(3-fluoro-benzyloxy)-2,3,4,5-tetrahydro-1H-benzo[d]azepine hydrochloride [Example 1c)] and ethyl oxalic acid chloride with triethylamine as the base. Yield: 88% of theory as a colourless oil; MS: m/e=372 (M+H)+.
Reaction SMILES: [Cl:1][C:2]1[C:3]([Cl:11])=[N:4][CH:5]=[C:6]([CH:10]=1)[C:7]([OH:9])=O.[CH2:12]([NH2:14])[CH3:13]>O1CCCC1.CN(C)C=O>[Cl:1][C:2]1[C:3]([Cl:11])=[N:4][CH:5]=[C:6]([CH:10]=1)[C:7]([NH:14][CH2:12][CH3:13])=[O:9]
Reactant: O=C(O)c1cnc(Cl)c(Cl)c1
Reactant: CCN
Solvent: CN(C)C=O
Solvent: C1CCOC1
Product: CCNC(=O)c1cnc(Cl)c(Cl)c1
Temperature: 25 °C
Reaction time: 18 h
Yield: 70 %

Procedure:
2.0 g of O-(7-azabenzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium hexafluorophosphine (5.2 mmol) were added to 1.0 g of 5,6-dichloronicotinic acid (5.2 mmol) dissolved in 2.4 mL of tetrahydrofuran and 2.5 mL of dimethylformamide, and stirred at room temperature for 10 minutes. 2.6 mL of ethylamine in 2.0 M tetrahydrofuran solution (5.2 mmol) was added thereto, and refluxed under heating and stirring for 18 hours. The mixture was cooled to room temperature, concentrated under reduced pressure to be dissolved in ethyl acetate, and washed with water. The organic layer was dried over magnesium sulfate, and concentrated under reduced pressure. The residue was separated by column chromatography (eluting solvent: chloroform/methanol=20/1) to obtain 0.8 g of 5,6-dichloro-N-ethyl-nicotinamide (yield 70%).
Reaction SMILES: [F:1][C:2]1[CH:25]=[C:24]([F:26])[CH:23]=[CH:22][C:3]=1[O:4][C:5]1[CH:6]=[C:7](F)[C:8]([C:11]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=2[O:19][CH3:20])=O)=[N:9][CH:10]=1.CCO.C(N(CC)C(C)C)(C)C.[NH2:39][NH2:40]>CCOC(C)=O>[F:1][C:2]1[CH:25]=[C:24]([F:26])[CH:23]=[CH:22][C:3]=1[O:4][C:5]1[CH:6]=[C:7]2[NH:40][N:39]=[C:11]([C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=3[O:19][CH3:20])[C:8]2=[N:9][CH:10]=1
Reactant: NN
Reactant: COc1ccccc1C(=O)c1ncc(Oc2ccc(F)cc2F)cc1F
Solvent: CCO
Solvent: CCOC(C)=O
Solvent: CCN(C(C)C)C(C)C
Product: COc1ccccc1-c1n[nH]c2cc(Oc3ccc(F)cc3F)cnc12
Temperature: 25 °C
Reaction time: 4 h
Yield: 5.7 %

Procedure:
[5-(2,4-Difluoro-phenoxy)-3-fluoro-pyridin-2-yl]-(2-methoxy-phenyl)-methanone (560 mg, 1.5 mmol) was added to 17 mL of EtOH and the reaction mixture was heated until all solid had dissolved. The reaction mixture was cooled, and (N,N-diisopropyl)ethylamine (0.21 mL, 2.3 mmol) and hydrazine (0.1 mL, 3.1 mmol) were added. The reaction mixture was stirred for four hours at room temperature, and then was taken up in 60 mL of EtOAc, washed four times with 20 mL of water, dried (MgSO4). The organic solvent was filtered and concentrated under reduced pressure. The residue was purified by flash chromatography 40 mm×7.5 cm) with 4: to 1:1 hexanes/EtOAc to yield 0.03 g of 6-(2,4-difluoro-phenoxy)-3-(2-methoxy-phenyl)-1H-pyrazolo[4,3-b]pyridine. Mass Spec. M+H=354. Mp: 143.2-144.9° C.
Reaction SMILES: [CH:1]([N:4]1[C:13]2[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=2)[CH:7]=[C:6]([C:14](Cl)=[O:15])[C:5]1=[O:17])([CH3:3])[CH3:2].[CH:18]1[C:23]([N+:24]([O-:26])=[O:25])=[CH:22][CH:21]=[C:20]([OH:27])[CH:19]=1>C1(C)C=CC=CC=1>[CH:1]([N:4]1[C:13]2[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=2)[CH:7]=[C:6]([C:14]([O:27][C:20]2[CH:19]=[CH:18][C:23]([N+:24]([O-:26])=[O:25])=[CH:22][CH:21]=2)=[O:15])[C:5]1=[O:17])([CH3:3])[CH3:2]
Reactant: O=[N+]([O-])c1ccc(O)cc1
Reactant: CC(C)n1c(=O)c(C(=O)Cl)cc2ccccc21
Solvent: Cc1ccccc1
Product: CC(C)n1c(=O)c(C(=O)Oc2ccc([N+](=O)[O-])cc2)cc2ccccc21
Temperature: 25 °C
Reaction time: 8 h
Yield: 40.2 %

Procedure:
To a solution of 1.0 g of l-isopropyl-2-oxo-1,2-dihydro-3-quinolinecarbonyl chloride in 30 ml of toluene was added 0.55 g of p-nitrophenol. The mixture was stirred overnight at room temperature. After solvent was distilled off, the residue was extracted with ether. The solvent was again distilled off. The resulting solid was washed with a small quantity of cold ether to give 0.56 g of 4-nitrophenyl 1-isopropyl-2-oxo-1,2-dihydro-3-quinolinecarboxylate.
Reaction SMILES: [N:1]([C@H:4]1[CH2:9][CH2:8][NH:7][CH2:6][C@H:5]1[OH:10])=[N+:2]=[N-:3].C(N(CC)C(C)C)(C)C.Br[CH2:21][CH2:22][OH:23].C(OC(N[C@@H]1CCN(CCO)C[C@@H]1C(OC)=O)=O)C1C=CC=CC=1>>[N:1]([C@H:4]1[CH2:9][CH2:8][N:7]([CH2:21][CH2:22][OH:23])[CH2:6][C@H:5]1[OH:10])=[N+:2]=[N-:3]
Reactant: [N-]=[N+]=N[C@H]1CCNC[C@H]1O
Reactant: OCCBr
Agent: COC(=O)[C@H]1CN(CCO)CC[C@H]1NC(=O)OCc1ccccc1
Solvent: CCN(C(C)C)C(C)C
Product: [N-]=[N+]=N[C@H]1CCN(CCO)C[C@H]1O
Yield: 93 %

Procedure:
Cis(±)4-azidopiperidin-3-ol (prepared following the procedure described in WO 2005/066176 for the chiral material) (0.945 g, 6.65 mmol), N,N-diisopropylethylamine (1.7 mL, 10 mmol) and 2-bromoethanol (0.61 mL, 8.64 mmol) were reacted as described for Intermediate 37, except heating for one hour. The solvent was removed under reduced pressure. The residue was taken up in dichloromethane (100 mL), washed with 1M sodium hydroxide solution (30 mL) and the aqueous phase was back extracted five times with dichloromethane (5×100 mL). The combined organic phases were dried over sodium sulfate. Chromatography on silica gel with dichloromethane/methanol 3:1 gave 1.15 g (93%) of the product as a colorless oil.
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][C:5]([N+:9]([O-:11])=[O:10])=[C:6]([CH3:8])[CH:7]=1.[Br:12]N1C(=O)CCC1=O>C(Cl)(Cl)Cl>[Br:12][CH2:8][C:6]1[CH:7]=[C:2]([F:1])[CH:3]=[CH:4][C:5]=1[N+:9]([O-:11])=[O:10]
Reactant: O=C1CCC(=O)N1Br
Reactant: Cc1cc(F)ccc1[N+](=O)[O-]
Solvent: ClC(Cl)Cl
Product: O=[N+]([O-])c1ccc(F)cc1CBr

Procedure:
574 g (3.70 mol) of 5-fluoro-2-nitrotoluene and 659 g (3.70 mol) of N-bromosuccinimide were introduced into 3.7 l of chloroform, 30.0 g (183 mmol) of 2,2′-azobis-2-methylpropanenitrile were added, and the mixture was heated under reflux with irradiation by a UV lamp for 18 h. Cooling was followed by filtration with suction, and the filtrate was concentrated, the residue was taken up in diethyl ether and filtered with suction, and the filtrate was concentrated. The residue was dissolved in dichloromethane and petroleum ether and purified by flash chromatography (mobile phase: petroleum ether/ethyl acetate gradient) to result in 92.0 g (10% of theory) of the title compound.
Reaction SMILES: CCCCCCCCCC(O)=O.CCCCCCCC(O)=O.[CH3:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][CH2:40][CH2:41][CH2:42][CH2:43][C:44]([O:46][CH2:47][CH:48]([OH:51])[CH2:49][OH:50])=[O:45]>>[C:44]([OH:46])(=[O:45])[CH2:43][CH2:42][CH2:41][CH2:40][CH2:39][CH2:38][CH2:37][CH2:36][CH2:35][CH2:34][CH2:33][CH2:32][CH2:31][CH2:30][CH2:29][CH2:28][CH2:27][CH2:26][CH2:25][CH2:24][CH3:23].[OH:46][CH2:47][CH:48]([CH2:49][OH:50])[OH:51]
Reactant: CCCCCCCCCCCCCCCCCCCCCC(=O)OCC(O)CO
Agent: CCCCCCCCCC(=O)O
Solvent: CCCCCCCC(=O)O
Product: CCCCCCCCCCCCCCCCCCCCCC(=O)O
Product: OCC(O)CO

Procedure:
Typically, about 118 kg of a mixture of C10:0 and C8:0 fatty acids (55:45 weight ratio) is preheated to the esterification temperature and adjusted to the requisite pressure. This fatty acid mixture is used to esterify about 16.8 kg of monobehenin at an 18:1 acid to monobehenin mole ratio at esterification temperature 245° C. (The monobehenin is commercially produced by molecular distillation of behenic acid/glycerol reaction products and comprises 98.1% monoglyceride, 0.5% diglyceride, 0.1% free glycerol, and 0.3% diglycerol.) The monobehenin is added incrementally as a liquid over a 60 minute period to the melted fatty acids. The esterification pressure ranges from 700 mmHg to 1520 mmHg. A pressure of 700 mmHg is initially used, but is increased as necessary to prevent the mixture containing the fatty acids from boiling over.
Reaction SMILES: [CH2:1]([N:3]([CH:19]1[CH2:24][CH2:23][N:22]([CH3:25])[CH2:21][CH2:20]1)[C:4]1[C:5]([CH3:18])=[C:6]([CH:11]=[C:12]([C:14]([F:17])([F:16])[F:15])[CH:13]=1)[C:7]([O:9]C)=[O:8])[CH3:2].[OH-].[Na+].Cl>CO>[CH2:1]([N:3]([CH:19]1[CH2:24][CH2:23][N:22]([CH3:25])[CH2:21][CH2:20]1)[C:4]1[C:5]([CH3:18])=[C:6]([CH:11]=[C:12]([C:14]([F:16])([F:15])[F:17])[CH:13]=1)[C:7]([OH:9])=[O:8])[CH3:2]
Reactant: CCN(c1cc(C(F)(F)F)cc(C(=O)OC)c1C)C1CCN(C)CC1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: CCN(c1cc(C(F)(F)F)cc(C(=O)O)c1C)C1CCN(C)CC1
Temperature: 50 °C
Reaction time: 3 h

Procedure:
To a stirred solution of methyl 3-[ethyl(1-methylpiperidin-4-yl)amino]-2-methyl-5-(trifluoromethyl)benzoate (700 mg, 1.95 mmol) in methanol (15 mL) was added aq. NaOH (5M, 590 ul, 2.93 mmol). The reaction mixture was stirred at 50° C. for 3 hours. After cooling to 23° C., HCl (2 M) was added to the mixture. The mixture was acidified to pH=5 and was concentrated in vacuo to give the titled compound as crude products (1.26 g).
Reaction SMILES: Br[C:2]1[C:3](=[O:15])[N:4]([CH3:14])[C:5](=[O:13])[C:6]=1[N:7]1[CH2:12][CH2:11][O:10][CH2:9][CH2:8]1.C([O-])([O-])=O.[Cs+].[Cs+].O.CC1(C)C(C)(C)OB([C:31]2[CH:48]=[CH:47][C:34]([O:35][CH2:36][C:37]3[CH:46]=[CH:45][C:44]4[C:39](=[CH:40][CH:41]=[CH:42][CH:43]=4)[N:38]=3)=[CH:33][CH:32]=2)O1>CN(C=O)C.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[CH3:14][N:4]1[C:3](=[O:15])[C:2]([C:31]2[CH:32]=[CH:33][C:34]([O:35][CH2:36][C:37]3[CH:46]=[CH:45][C:44]4[C:39](=[CH:40][CH:41]=[CH:42][CH:43]=4)[N:38]=3)=[CH:47][CH:48]=2)=[C:6]([N:7]2[CH2:12][CH2:11][O:10][CH2:9][CH2:8]2)[C:5]1=[O:13]
Reactant: CC1(C)OB(c2ccc(OCc3ccc4ccccc4n3)cc2)OC1(C)C
Reactant: CN1C(=O)C(Br)=C(N2CCOCC2)C1=O
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Solvent: O
Product: CN1C(=O)C(c2ccc(OCc3ccc4ccccc4n3)cc2)=C(N2CCOCC2)C1=O
Temperature: 80 °C
Yield: 42.9 %

Procedure:
To a stirred solution of 3-bromo-1-methyl-4-morpholino-1H-pyrrole-2,5-dione (100 mg, 0.36 mol) in DMF (40 mL) were added Cs2CO3 (415 mg, 1.27 mmol), water (5 mL), and Pd(Ph3P)4 (84 mg, 0.072 mmol). 2-((4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenoxy)methyl)quinoline (138 mg, 0.38 mmol) was then added and the reaction mixture was heated at 80° C. for 3 h, filtered through a pad of Celite® and the filtrate was then concentrated in vacuo to obtain the crude product. The crude material was purified via silica gel column chromatography eluting with 60% EtOAc hexanes to afford 1-methyl-3-morpholino-4-(4-(quinolin-2-ylmethoxy)phenyl)-1H-pyrrole-2,5-dione (70 mg, 45%). 1H NMR (500 MHz, d6-DMSO): δ 8.42 (d, J=7.2 Hz, 1 H), 8.1 (t, J=7.2 Hz, 2 H) 7.78 (t, J=7.8 Hz, 1 H), 7.70 (d, J=7.2 Hz, 1 H), 7.64 (t, J=7.2 Hz, 1 H), 7.28 (d, J=7.4 Hz, 2 H), 7.12 (d, J=7.4 Hz, 2 H), 5.38 (s, 2 H), 3.62-3.58 (m, 4 H), 3.45-3.39 (m, 4 H), 2.96 (s, 3 H); MS: M+H: m/z=430.2 HPLC: 96%, (Condition-C).
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[N:11]=[C:10](Br)[C:9]2[N:13]=[C:14]([C:16]([CH3:19])([CH3:18])[CH3:17])[S:15][C:8]=2[C:7]=1[OH:20])=[O:5])[CH3:2].C([Sn](CCCC)(CCCC)[C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1)CCC>>[CH2:1]([O:3][C:4]([C:6]1[N:11]=[C:10]([C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)[C:9]2[N:13]=[C:14]([C:16]([CH3:19])([CH3:18])[CH3:17])[S:15][C:8]=2[C:7]=1[OH:20])=[O:5])[CH3:2]
Reactant: CCCC[Sn](CCCC)(CCCC)c1ccccc1
Reactant: CCOC(=O)c1nc(Br)c2nc(C(C)(C)C)sc2c1O
Product: CCOC(=O)c1nc(-c2ccccc2)c2nc(C(C)(C)C)sc2c1O

Procedure:
The title compound was prepared from 4-bromo-2-tert-butyl-7-hydroxy-thiazolo[4,5-c]pyridine-6-carboxylic acid ethyl ester and tributylphenyl tin under conditions analogous to the experimental procedure found in example 169(a). MS (ESI+): m/z 412.0 (M+1).
Reaction SMILES: OS(O)(=O)=O.[CH3:6][C:7](=[CH2:9])[CH3:8].[CH2:10]([O:17][C:18]([NH:20][C:21](=[O:27])[C@@H:22]([C@H:24]([CH3:26])[OH:25])[NH2:23])=[O:19])[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1.C(=O)=O.CC(C)=O>C(Cl)Cl>[CH2:10]([O:17][C:18]([NH:20][C:21](=[O:27])[C@@H:22]([C@H:24]([CH3:26])[O:25][C:7]([CH3:9])([CH3:8])[CH3:6])[NH2:23])=[O:19])[C:11]1[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=1
Reactant: C[C@H](O)[C@@H](N)C(=O)NC(=O)OCc1ccccc1
Reactant: C=C(C)C
Agent: O=C=O
Agent: O=S(=O)(O)O
Solvent: CC(C)=O
Solvent: ClCCl
Product: C[C@H](OC(C)(C)C)[C@@H](N)C(=O)NC(=O)OCc1ccccc1
Reaction time: 96 h
Yield: 90.3 %

Procedure:
Concentrated H2SO4 (0.1 ml) and isobutylene (35 ml, 390 mmol) are added to a suspension of N-benzyloxycarbonyl-D-threonineamide (4.2 g, 16.6 mmol) in methylene chloride (35 ml) kept in a pressure resistant vessel cooled with dry ice/acetone. The reaction vessel is sealed and the temperature is allowed to raise up to the room value. After 4 days, excess isobutylene is evaporated off and the organic solution is washed with aqueous 5% Na2CO3 (3×30 ml), 5% citric acid (20 ml) and then with water up to pH 6. The organic phase is dried over MgSO4 and concentrated to dryness yielding the compound of the title as a clear oil (4.62 g, 90%).
Reaction SMILES: [NH2:1][C:2]1[C:3]([Cl:18])=[N:4][C:5]2[C:10]([C:11]=1[NH:12][CH2:13][C:14]([CH3:17])([OH:16])[CH3:15])=[CH:9][CH:8]=[CH:7][CH:6]=2.[C:19]1(C)C(C)=CC=CC=1>C(OC(OCC)OCC)C>[Cl:18][C:3]1[C:2]2[N:1]=[CH:19][N:12]([CH2:13][C:14]([CH3:15])([CH3:17])[OH:16])[C:11]=2[C:10]2[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=2[N:4]=1
Reactant: Cc1ccccc1C
Reactant: CC(C)(O)CNc1c(N)c(Cl)nc2ccccc12
Solvent: CCOC(OCC)OCC
Product: CC(C)(O)Cn1cnc2c(Cl)nc3ccccc3c21
Temperature: 80 °C

Procedure:
A suspension of 1-[(3-amino-2-chloro-4-quinolinyl)amino]-2-methyl-2-propanol (5 g from EXAMPLE 13) in xylene (50 mL) and triethylorthoformate (5 mL) was heated at 80° C. until no starting material remained as determined by thin layer chromatography. The resulting solution was cooled, and the precipitated product was isolated by filtration and washed with xylene (3×10 mL).
Reaction SMILES: [C:1]([C:3]1[N:8]=[CH:7][C:6]([NH:9][S:10]([CH2:13][CH2:14][NH:15]C(=O)OC(C)(C)C)(=[O:12])=[O:11])=[CH:5][C:4]=1[NH:23][C:24]1[CH:29]=[C:28]([CH3:30])[CH:27]=[C:26]([CH3:31])[N:25]=1)#[N:2].FC(F)(F)C(O)=O>ClCCl>[NH2:15][CH2:14][CH2:13][S:10]([NH:9][C:6]1[CH:7]=[N:8][C:3]([C:1]#[N:2])=[C:4]([NH:23][C:24]2[CH:29]=[C:28]([CH3:30])[CH:27]=[C:26]([CH3:31])[N:25]=2)[CH:5]=1)(=[O:12])=[O:11]
Reactant: Cc1cc(C)nc(Nc2cc(NS(=O)(=O)CCNC(=O)OC(C)(C)C)cnc2C#N)c1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: Cc1cc(C)nc(Nc2cc(NS(=O)(=O)CCN)cnc2C#N)c1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of tert-butyl [2-({6-cyano-5-[(4,6-dimethylpyridin-2-yl)amino]pyridin-3-yl}sulfamoyl)ethyl]carbamate (100 mg, 0.22 mmol) in dichloromethane (1.8 mL) was added trifluoroacetic acid (0.26 mL, 3.4 mmol). The reaction mixture was stirred for 1 hour at room temperature. The reaction mixture was concentrated under reduced pressure to afford 2-amino-N-{6-cyano-5-[(4,6-dimethylpyridin-2-yl)amino]pyridin-3-yl}ethanesulfonamide, which was used without further purification. MS ESI calc'd. for C15H19N6O2S [M+H]+ 347. found 347.
Reaction SMILES: C([O:3][C:4](=[O:34])[CH2:5][CH2:6][C:7]1[CH:12]=[CH:11][C:10]([O:13][C:14]2[CH:19]=[C:18]([CH3:20])[CH:17]=[C:16]([O:21][C:22]3[CH:27]=[CH:26][C:25]([C:28]([F:31])([F:30])[F:29])=[CH:24][C:23]=3Br)[CH:15]=2)=[CH:9][C:8]=1[CH3:33])C.[F:35][C:36]([F:48])([F:47])[O:37][C:38]1[CH:43]=[CH:42][CH:41]=[CH:40][C:39]=1B(O)O>>[CH3:33][C:8]1[CH:9]=[C:10]([O:13][C:14]2[CH:15]=[C:16]([O:21][C:22]3[CH:23]=[CH:24][C:25]([C:28]([F:30])([F:31])[F:29])=[CH:26][C:27]=3[C:39]3[CH:40]=[CH:41][CH:42]=[CH:43][C:38]=3[O:37][C:36]([F:48])([F:47])[F:35])[CH:17]=[C:18]([CH3:20])[CH:19]=2)[CH:11]=[CH:12][C:7]=1[CH2:6][CH2:5][C:4]([OH:34])=[O:3]
Reactant: CCOC(=O)CCc1ccc(Oc2cc(C)cc(Oc3ccc(C(F)(F)F)cc3Br)c2)cc1C
Reactant: OB(O)c1ccccc1OC(F)(F)F
Product: Cc1cc(Oc2ccc(CCC(=O)O)c(C)c2)cc(Oc2ccc(C(F)(F)F)cc2-c2ccccc2OC(F)(F)F)c1

Procedure:
The title compound is prepared by reacting the compound of 3-{4-[3-(2-bromo-4-trifluoromethyl-phenoxy)-5-methyl-phenoxy]-2-methyl-phenyl}-propionic acid ethyl ester with 2-trifluoromethoxyphenyl boronic acid as in Example 38 to afford 0.058 g (39%). 1H NMR (400 MHz, CDCl3); HRMS (ES+) m/z exact mass calculated for C31H25O5F6 591.1606, found 591.1619.
Reaction SMILES: [CH:1]1([N:7]=[C:8]2[S:12][C:11]([C:13]3[CH:20]=[CH:19][C:16]([C:17]#[N:18])=[CH:15][CH:14]=3)=[N:10][N:9]2[CH3:21])[CH2:6][CH2:5][CH:4]=[CH:3][CH2:2]1.C([O-])([O-])=[O:23].[Na+].[Na+].OO>C(O)C.O>[CH:1]1([N:7]=[C:8]2[S:12][C:11]([C:13]3[CH:14]=[CH:15][C:16]([C:17]([NH2:18])=[O:23])=[CH:19][CH:20]=3)=[N:10][N:9]2[CH3:21])[CH2:6][CH2:5][CH:4]=[CH:3][CH2:2]1
Reactant: O=C([O-])[O-]
Reactant: Cn1nc(-c2ccc(C#N)cc2)sc1=NC1CC=CCC1
Agent: OO
Agent: [Na+]
Solvent: CCO
Solvent: O
Product: Cn1nc(-c2ccc(C(N)=O)cc2)sc1=NC1CC=CCC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 64 %

Procedure:
To a solution of 4-[5-(cyclohex-3-enylimino)-4-methyl-4,5-dihydro-[1,3,4]thiadiazol-2-yl]-benzonitrile from protocol I76 (0.94 mmol, 280 mg) in ethanol (41 mL), a solution of Na2CO3 [3N] (12.3 mmol, 4.1 mL), and a solution of H2O2 at 30% in water (3.33 mL) were added. The mixture was stirred overnight at RT and concentrated under reduced pressure. The residue was stirred in water several hours, filtered, and dried under vacuum to afford the pure product. Yield: 64%.
Reaction SMILES: [CH2:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH2:4][CH2:3][C:2]1=[O:11].[Li+].[CH3:13][CH:14]([N-]C(C)C)[CH3:15].C(Br)C=C>C1COCC1>[O:11]=[C:2]1[CH2:3][CH2:4][C:5]2[C:10](=[CH:9][CH:8]=[CH:7][CH:6]=2)[CH:1]1[CH2:15][CH:14]=[CH2:13]
Reactant: O=C1CCc2ccccc2C1
Reactant: CC(C)[N-]C(C)C
Agent: [Li+]
Solvent: C=CCBr
Solvent: C1CCOC1
Product: C=CCC1C(=O)CCc2ccccc21
Temperature: 0 °C
Reaction time: 24 h
Yield: 33.3 %

Procedure:
To a solution of 7.3 g (50 mmol) 2-tetralone in 75 ML THF in a 3-neck round-bottomed flask, equipped with a gas inlet and septum, was added 36.7 mL LDA (55 mmol, 1.5 M in cyclohexane) at −30° C. under a nitrogen atmosphere. The solution was allowed to warm to 0° C. over a 30-minute period and 5.6 mL (65 mmol) allyl bromide was added. TLC analysis was used to monitor the reaction. After stirring for 24 hours at room temperature, the reaction mixture was quenched with 10% sodium bisulfate to pH 2-3. After removal of THF under reduced pressure, the mixture was extracted with ethyl acetate (2×1 L) and the combined organic layers were washed with brine, dried (MgSO4), filtered and concentrated in vacuo. The crude product was purified by liquid chromatography on 800 g of silica gel 60 (230-400 m), eluting with 1 L of hexane, followed by 5 L of 5% ethyl acetate/hexane, and collecting 40 mL fractions. Fractions 65-82 gave 3.1 g (33%) of pure 1,2,3,4Tetrahydro-2-oxo-1-(2-propenyl)-naphthalene as a light yellow oil.
Reaction SMILES: Cl[C:2]1[CH:3]=[C:4]([C:19]([OH:21])=[O:20])[C:5]([CH3:18])=[C:6]2[C:11]=1[S:10](=[O:13])(=[O:12])[CH2:9][CH2:8][CH:7]2[O:14][CH2:15][CH2:16][CH3:17].[OH-].[K+].O>[Zn].C(O)C>[CH2:15]([O:14][CH:7]1[C:6]2[C:11](=[CH:2][CH:3]=[C:4]([C:19]([OH:21])=[O:20])[C:5]=2[CH3:18])[S:10](=[O:13])(=[O:12])[CH2:9][CH2:8]1)[CH2:16][CH3:17]
Reactant: CCCOC1CCS(=O)(=O)c2c(Cl)cc(C(=O)O)c(C)c21
Agent: [K+]
Agent: [OH-]
Agent: [Zn]
Solvent: CCO
Solvent: O
Product: CCCOC1CCS(=O)(=O)c2ccc(C(=O)O)c(C)c21
Yield: 81.7 %

Procedure:
A 50-ml egg-plant type flask was charged with 1.36 g (0.0041 mol) of 8-chloro-4-n-propoxy-5-methylthiochroman-6-carboxylic acid-1,1-dioxide, 1.35 g (0.02 mol) of potassium hydroxide, 0.81 g (0.012 mol) of a zinc powder, 10 ml of water and 6 ml of ethanol, and the mixture was refluxed under heat for 10 hours. After allowed to cool, insolubles were removed by filtration, and the ethanol was distilled off under reduced pressure. Then, while the remainder was cooled with ice, 50 ml of 5% hydrochloric acid was added to adjust the pH to 1. The reaction mixture was extracted with ethyl acetate. The ethyl acetate layer was washed with 2% hydrochloric acid, washed with a saturated sodium chloride aqueous solution, and dried over anhydrous sodium sulfate. The solvent was removed under reduced pressure to give 1.0 g of 4-n-propoxy-5-methylthiochroman-6-carboxylic acid-1,1-dioxide (Compound 32) shown in Table 2.
Reaction SMILES: [CH3:1][CH:2]1[CH:7]([N:8]2[CH:12]=[CH:11][N:10]=[CH:9]2)[C:6](=[O:13])[C:5]2[CH:14]=[CH:15][CH:16]=[CH:17][C:4]=2[O:3]1.O.O1CCC[CH2:20]1>>[CH3:1][CH:2]1[CH:7]([N:8]2[CH:12]=[CH:11][N:10]=[CH:9]2)[C:6]([CH3:20])([OH:13])[C:5]2[CH:14]=[CH:15][CH:16]=[CH:17][C:4]=2[O:3]1
Reactant: C1CCOC1
Reactant: CC1Oc2ccccc2C(=O)C1n1ccnc1
Solvent: O
Product: CC1Oc2ccccc2C(C)(O)C1n1ccnc1
Reaction time: 1 h

Procedure:
A solution of 2-methyl-3-(1-imidazolyl)-2,3-dihydro-4H-1-benzopyran-4-one (0.53 g) in anhydrous tetrahydrofurane (20 ml) was added to the reaction mixture, which was refluxed moderately for 30 minutes and then for 1 hour on a water bath. The mixture was cooled, poured into a mixture of crushed ice and water (100 ml) and extracted with CHCl3 (100 ml). The organic layer, dried on anhydrous Na2SO4 and evaporated to dryness under vacuum, afforded 2-methyl-3-(1-imidazolyl)-2,3-dihydro-4-methyl-benzopyran-4-ol (0.3 g);