Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl.[C:2]([C:4]1([NH:7][C:8]([C@@H:10]2[CH2:14][C@@H:13]([S:15]([C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=3[C:24]([F:27])([F:26])[F:25])(=[O:17])=[O:16])[CH2:12][NH:11]2)=[O:9])[CH2:6][CH2:5]1)#[N:3].[F:28][C:29]1[CH:37]=[CH:36][C:32]([C:33](O)=[O:34])=[CH:31][CH:30]=1>>[C:2]([C:4]1([NH:7][C:8]([C@@H:10]2[CH2:14][C@@H:13]([S:15]([C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=3[C:24]([F:27])([F:25])[F:26])(=[O:17])=[O:16])[CH2:12][N:11]2[C:33](=[O:34])[C:32]2[CH:36]=[CH:37][C:29]([F:28])=[CH:30][CH:31]=2)=[O:9])[CH2:5][CH2:6]1)#[N:3]
Reactant: O=C(O)c1ccc(F)cc1
Reactant: N#CC1(NC(=O)[C@@H]2C[C@@H](S(=O)(=O)c3ccccc3C(F)(F)F)CN2)CC1
Agent: Cl
Product: N#CC1(NC(=O)[C@@H]2C[C@@H](S(=O)(=O)c3ccccc3C(F)(F)F)CN2C(=O)c2ccc(F)cc2)CC1

Procedure:
L54. (2S,4R)-4-(2-trifluoromethyl-benzenesulfonyl)-pyrrolidine-2-carboxylic acid (1-cyano-cyclopropyl)-amide hydrochloride from experiment K5 was coupled with 4-fluorobenzoic acid in analogy to experiment A1 to give (2S,4R)-1-(4-fluoro-benzoyl)-4-(2-trifluoromethyl-benzenesulfonyl)-pyrrolidine-2-carboxylic acid (1-cyano-cyclopropyl)-amide as a pale yellow solid. MS: 510.2 [M+H]+.
Reaction SMILES: [Li+].[BH4-].CON(C)[C:6](=[O:41])[CH:7]([NH:33][C:34]([O:36][C:37]([CH3:40])([CH3:39])[CH3:38])=[O:35])[CH2:8][CH2:9][CH2:10][C:11]1[CH:16]=[CH:15][C:14]([O:17][C:18]2[CH:23]=[CH:22][CH:21]=[C:20]([O:24][CH2:25][C:26]3[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=3)[CH:19]=2)=[CH:13][C:12]=1[Cl:32].O.[CH2:44]1COCC1>C(O)C>[CH2:25]([O:24][C:20]1[CH:19]=[C:18]([CH:23]=[CH:22][CH:21]=1)[O:17][C:14]1[CH:15]=[CH:16][C:11]([CH2:10][CH2:9][CH2:8][CH:7]([NH:33][C:34]([O:36][C:37]([CH3:38])([CH3:39])[CH3:40])=[O:35])[CH:6]([OH:41])[CH3:44])=[C:12]([Cl:32])[CH:13]=1)[C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1
Reactant: CON(C)C(=O)C(CCCc1ccc(Oc2cccc(OCc3ccccc3)c2)cc1Cl)NC(=O)OC(C)(C)C
Reactant: C1CCOC1
Agent: [BH4-]
Agent: [Li+]
Solvent: CCO
Solvent: O
Product: CC(O)C(CCCc1ccc(Oc2cccc(OCc3ccccc3)c2)cc1Cl)NC(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 1 h

Procedure:
LiBH4 (50 mg) was added to the compound of Example 130 in a mixture of THF (15 mL) and ethanol (3 mL). The mixture was stirred at room temperature for 1 hour. Following addition of water, the mixture was extracted with ethyl acetate and the extract was washed sequentially with water and a saturated aqueous solution of sodium chloride. The organic phase was then dried over anhydrous sodium sulfate. The solvent was concentrated and the residue was purified on a silica gel column chromatography (hexane:ethyl acetate=1:1) to give the desired product as a colorless oil (320 mg).
Reaction SMILES: [CH2:1]([O:3][C:4]1[C:5]([OH:15])=[C:6]([CH:10]=[C:11]([CH:13]=O)[CH:12]=1)[C:7]([OH:9])=[O:8])[CH3:2].[C:16]1([C:22](=O)[CH2:23][C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1.[NH2:31][C:32]([NH2:34])=[O:33].Cl>CCO.CO.CCOC(C)=O>[CH2:1]([O:3][C:4]1[C:5]([OH:15])=[C:6]([CH:10]=[C:11]([CH:13]2[C:23]([C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=3)=[C:22]([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)[NH:34][C:32](=[O:33])[NH:31]2)[CH:12]=1)[C:7]([OH:9])=[O:8])[CH3:2]
Reactant: CCOc1cc(C=O)cc(C(=O)O)c1O
Reactant: NC(N)=O
Reactant: O=C(Cc1ccccc1)c1ccccc1
Agent: Cl
Solvent: CCOC(C)=O
Solvent: CCO
Solvent: CO
Product: CCOc1cc(C2NC(=O)NC(c3ccccc3)=C2c2ccccc2)cc(C(=O)O)c1O
Yield: 5.8 %

Procedure:
To a mixture of 3-ethoxy-5-formyl-2-hydroxybenzoic acid (Intermediate 37) (130 mg, 0.60 mmol), 1,2-diphenylethanone (150 mg, 0.76), and urea (80 mg, 1.3 mmol) in anhydrous EtOH (5 mL) was added concentrated HCl solution (0.2 mL), the reaction mixture was refluxed overnight. TLC (EtOAc:MeOH=10:1) showed about 50% of the starting materials were consumed. The reaction mixture was concentrated, and purified by column chromatograph (EtOAc:MeOH=40:1) and preparative HPLC to afford Compound 77 as a yellow solid (15 mg, yield: 5.6%). 1H NMR (DMSO-d6 400 MHz): δ 11.37 (s, 1H), 8.66 (s, 1H), 7.47 (s, 1H), 7.43 (d, J=2.0 Hz, 1H), 7.25-7.27 (m, 3H), 7.21-7.25 (m, 2H), 7.14 (d, J=2.0 Hz, 1H), 6.97-7.05 (m, 3H), 6.81 (d, J=2.4 Hz, 2H), 5.10 (d, J=2.8 Hz, 1H), 3.97-4.02 (m, 2H), 1.31 (t, J=6.8 Hz, 3H); MS (ESI): m/z 431.1 [M+1]+.
Reaction SMILES: [NH:1]1[CH2:4][CH:3]([O:5][C:6]2[CH:11]=[C:10]([O:12][CH2:13][C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=3)[CH:9]=[CH:8][N:7]=2)[CH2:2]1.Br[C:21]1[CH:26]=[CH:25][C:24]([C@@H:27]([NH:29][C:30](=[O:32])[CH3:31])[CH3:28])=[CH:23][CH:22]=1>>[CH2:13]([O:12][C:10]1[CH:9]=[CH:8][N:7]=[C:6]([O:5][CH:3]2[CH2:4][N:1]([C:21]3[CH:26]=[CH:25][C:24]([C@@H:27]([NH:29][C:30](=[O:32])[CH3:31])[CH3:28])=[CH:23][CH:22]=3)[CH2:2]2)[CH:11]=1)[C:14]1[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=1
Reactant: c1ccc(COc2ccnc(OC3CNC3)c2)cc1
Reactant: CC(=O)N[C@@H](C)c1ccc(Br)cc1
Product: CC(=O)N[C@@H](C)c1ccc(N2CC(Oc3cc(OCc4ccccc4)ccn3)C2)cc1

Procedure:
Example 8.7 is prepared analogously to 8.1. 2-(Azetidin-3-yloxy)-4-benzyloxy-pyridine (IX.3) and (S)—N-[1-(4-bromo-phenyl)-ethyl]-acetamide (I.1) are used as starting materials.
Reaction SMILES: N([O-])=O.[Na+].N[C:6]1[CH:18]=[CH:17][C:9]([CH2:10][C:11]2[CH:12]=[N:13][CH:14]=[CH:15][CH:16]=2)=[CH:8][CH:7]=1.[OH-:19].[Na+]>O.S(=O)(=O)(O)O>[OH:19][C:6]1[CH:18]=[CH:17][C:9]([CH2:10][C:11]2[CH:12]=[N:13][CH:14]=[CH:15][CH:16]=2)=[CH:8][CH:7]=1
Reactant: Nc1ccc(Cc2cccnc2)cc1
Reactant: [OH-]
Agent: O=N[O-]
Agent: O=S(=O)(O)O
Agent: [Na+]
Solvent: O
Product: Oc1ccc(Cc2cccnc2)cc1
Temperature: 160 °C
Reaction time: 0.17 h

Procedure:
A solution of sodium nitrite (0.350 g) in water (1.5 ml) is cooled in ice, and added, with stirring, to a cold (ice-bath) solution of 3-(4'-aminobenzyl)pyridine (Preparation 10, 0.920 g, 0.0050 mole) in water (3.75 ml), concentrated sulfuric acid (2.5 ml), and ice (7 g). This solution in turn is added dropwise to a third solution of water (5 ml) and sulfuric acid (6.25 ml) that is maintained at 160° C. in an oil bath. The resulting solution is kept at 160° C. for 10 min and then cooled to room temperature. The pH of the solution is adjusted to 7.0 by addition of aqueous 50% sodium hydroxide. The resulting mixture is extracted 4 times with 25 ml of ether. The aqueous portion is further extracted continuously with ether for 40 hr. The ether extracts are washed with brine, dried over MgSO4, filtered, and concentrated under reduced pressure. The crystalline residue is decolorized with activated charcoal and is recrystallized from acetone-hexane, giving a first crop (0.426 g) of the titled crystals, with a melting point of 182°-185° C. A second crop (0.034 g) and third crop (0.050 g, total 0.510 g, 0.00276 mole, 55%) of titled crystals are also obtained. Recrystallization of the first crop from acetone-hexane gives the titled product as colorless crystals with a melting point of 184°-186° C. IR (nujol) peaks are observed at 2900, 2800, 2720, 2680, 2600, 1615, 1590, 1580, 1515, 1485, 1280, 1250, 845, 800, 710, and 640 cm-1.
Reaction SMILES: [CH3:1]N(C)C=O.O=P(Cl)(Cl)Cl.[NH:11](/[C:18](/[CH3:25])=[CH:19]\[C:20]([O:22][CH2:23][CH3:24])=[O:21])[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1>C(Cl)Cl.C(OCC)(=O)C>[CH3:25][C:18]1[C:19]([C:20]([O:22][CH2:23][CH3:24])=[O:21])=[CH:1][C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[N:11]=1
Reactant: CN(C)C=O
Reactant: CCOC(=O)/C=C(/C)Nc1ccccc1
Solvent: O=P(Cl)(Cl)Cl
Solvent: ClCCl
Solvent: CCOC(C)=O
Product: CCOC(=O)c1cc2ccccc2nc1C
Temperature: 25 °C
Reaction time: 3 h
Yield: 58.1 %

Procedure:
A solution of 140 g of dimethylformamide (1.92 mole ) in 500 mL of methylene chloride is mechanically stirred under a condenser/scrubber in an ice bath while 295 g of POCl3 (1.92 mol) is added dropwise over a 40 minute period. The reaction is stirred for a further 3 hour period, during which time the bath temperature is allowed to warm to room temperature. The reaction is then diluted with 2 L of methylene chloride, cooled in an ice bath, and treated dropwise with 394 g of ethyl β-anilinocrotonate (1.92 mol) over a 1 hour period. After stirring at room temperature for 26 hours, the reaction is heated at reflux temperature for 48 hours, cooled in an ice bath, quenched with 500 mL ice water, and treated portionwise with concentrated NH4OH to pH 6. The phases are separated and the organic phase is concentrated in vacuo to give a solid residue which is redissolved in 1.5 L ethyl acetate, filtered, and the filtrate saturated with gaseous hydrogen chloride. The resultant solid precipitate is filtered off, washed thoroughly with ethyl acetate, dissolved in water and basified with concentrated NH4OH. The basic aqueous mixture is extracted with 1:1 hexanes-ethyl acetate; the organic phase is concentrated in vacuo to afford 240 g of the title product, mp 70°-72° C.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[CH:9]=[N:8][CH:7]=[CH:6]2.[F:13][C:14]([F:20])([F:19])[CH2:15][CH2:16][CH2:17]I.[OH-].[Na+].[O-][O-].[Na+].[Na+]>O1CCCC1.ClCCl>[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[CH:9]=[N:8][CH:7]=[C:6]2[CH2:17][CH2:16][CH2:15][C:14]([F:20])([F:19])[F:13]
Reactant: COc1ccc2cnccc2c1
Reactant: FC(F)(F)CCCI
Agent: [Na+]
Agent: [O-][O-]
Agent: [OH-]
Solvent: ClCCl
Solvent: C1CCOC1
Product: COc1ccc2cncc(CCCC(F)(F)F)c2c1
Temperature: 25 °C
Reaction time: 2 h
Yield: 30.4 %

Procedure:
2 g 6-Methoxy-isoquinoline were dissolved in 25 mL of dry tetrahydrofuran. 12.56 mL of a 1 M solution of potassium triethyl borohydrate were added dropwise. The solution was allowed to stir at room temperature for 2 h, then 3.29 g of 4,4,4-Trifluoro-1-iodobutane were added dropwise. The solution was allowed to stir overnight, then 32 mL of 1M sodium hydroxide and 12 mL of sodium peroxide solution (35%) were added. Stirring was continued for another 3 hrs, then the solution was diluted with dichloromethane, extracted with water and brine and the organic layer was dried over sodium sulfate and evaporated to dryness. Silica gel chromatography yields 1.03 g of the desired product.
Reaction SMILES: [CH3:1][CH:2]([N:4]1[C:12](/[CH:13]=[CH:14]/[C@H:15]([OH:24])[CH2:16][C@H:17]([OH:23])[CH2:18][C:19]([O:21]C)=[O:20])=[C:11]([C:25]2[CH:30]=[CH:29][C:28]([F:31])=[CH:27][CH:26]=2)[C:10]2[C:5]1=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH3:3].[OH-].[Na+:33]>C(OCC)(=O)C.O>[CH3:3][CH:2]([N:4]1[C:12](/[CH:13]=[CH:14]/[CH:15]([OH:24])[CH2:16][CH:17]([OH:23])[CH2:18][C:19]([O-:21])=[O:20])=[C:11]([C:25]2[CH:26]=[CH:27][C:28]([F:31])=[CH:29][CH:30]=2)[C:10]2[CH:9]=[CH:8][CH:7]=[CH:6][C:5]1=2)[CH3:1].[Na+:33]
Reactant: COC(=O)C[C@@H](O)C[C@@H](O)/C=C/c1c(-c2ccc(F)cc2)c2ccccc2n1C(C)C
Agent: [Na+]
Agent: [OH-]
Solvent: CCOC(C)=O
Solvent: O
Product: CC(C)n1c(/C=C/C(O)CC(O)CC(=O)[O-])c(-c2ccc(F)cc2)c2ccccc21
Temperature: 25 °C
Yield: 70.1 %

Procedure:
Fluvastatin methyl ester (3.0 g) was dissolved in ethyl acetate (90 ml), a solution of NaOH (0.2 g) in water (1 ml) was added and the mixture was stirred at room temperature over night. The product was isolated by filtration under nitrogen, washed with ethyl acetate (50 ml) and dried at 50° C. in a vacuum oven for 24 h to obtain 1.52 g (49.7%) of fluvastatin sodium crystal Form LXXVII.
Reaction SMILES: Br[C:2]1[CH:15]=[N:14][C:5]2[NH:6][CH2:7][CH2:8][C:9](=[O:13])[N:10]([CH3:12])[CH2:11][C:4]=2[CH:3]=1.[C:16]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])(=[O:19])[CH:17]=[CH2:18].C(N(C(C)C)C(C)C)C.CC1C=CC=CC=1P(C1C=CC=CC=1C)C1C=CC=CC=1C>CN(C=O)C.CC([O-])=O.CC([O-])=O.[Pd+2]>[CH3:12][N:10]1[C:9](=[O:13])[CH2:8][CH2:7][NH:6][C:5]2[N:14]=[CH:15][C:2](/[CH:18]=[CH:17]/[C:16]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])=[CH:3][C:4]=2[CH2:11]1
Reactant: CN1Cc2cc(Br)cnc2NCCC1=O
Reactant: C=CC(=O)OC(C)(C)C
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: Cc1ccccc1P(c1ccccc1C)c1ccccc1C
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CN1Cc2cc(/C=C/C(=O)OC(C)(C)C)cnc2NCCC1=O
Temperature: 110 °C
Reaction time: 0.5 h

Procedure:
A suspension of 8-bromo-5-methyl-2,3,5,6-tetrahydropyrido[2,3-b][1,5]diazocin-4(1H)-one (670 mg, 2.48 mmol), tert-butyl acrylate (1.8 mL, 12.4 mmol) and (i-Pr)2EtN (1.3 mL, 7.44 mmol) in 30 mL of DMF:Propionitriole (4:1) was de-oxygenated with Ar for 30 min. The mixture was treated with Pd(OAc)2 (19.4 mg, 0.09 mmol) and P(o-tol)3 (51.7 mg, 0.18 mmol) then heated to 110° C. for 16 h. The hot mixture was filtered through a pad of celite. The filtrate was diluted with 100 mL H2O then extracted with 2×100 mL ethyl acetate. The resulting brown solid was triturated with a solution of hexanes:ethyl acetate (4:1) followed by filtration to yield the brown solid product. Yield 391 mg (50%); 1H NMR (400 MHz, CDCl3) δ 8.17 (s, 1H), 7.51 (s, 1H), 7.49 (d, J=16.4 Hz, 1H), 6.26 (d, J=16.0 Hz, 1H), 5.22 (bm, 1H), 4.55 (s, 2H), 3.66 (q, J=7.2 Hz, 2H), 3.07 (t, J=7.2 Hz, 2H), 2.81 (s, 3H), 1.55 (s, 9H); ESI MS m/z 318 [C17H23N3O3+H]+
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[C:7](Cl)(=[O:11])[C:8](Cl)=[O:9].CC1NC=CC=1.[CH2:19]([OH:21])[CH3:20]>C(Cl)Cl>[CH2:19]([O:21][C:7](=[O:11])[C:8]([C:6]1[NH:1][C:3]([CH3:2])=[CH:4][CH:5]=1)=[O:9])[CH3:20]
Reactant: O=C(Cl)C(=O)Cl
Reactant: c1ccncc1
Reactant: CCO
Agent: Cc1ccc[nH]1
Solvent: ClCCl
Product: CCOC(=O)C(=O)c1ccc(C)[nH]1
Reaction time: 0.25 h

Procedure:
Pyridine (8.80 g.) in dry methylene chloride (100 ml.) was added dropwise to a stirred solution of oxalyl chloride (13.96 g.) in dry methylene chloride (300 ml.) at -70° to give a white precipitate. The mixture was stirred at -70° for 15 minutes and then a solution of 2-methylpyrrole (8.10 g.) in dry methylene chloride (75 ml.) was added over 30 minutes. The mixture was stirred at -70° for a further 3 hours and then allowed to warm up to -20° giving a clear solution. Ethanol (25 ml.) was added and the solution was allowed to reach room temperature. The solution was washed with N hydrochloric acid (3×100 ml.) followed by water (3×100 ml.) and then dried over sodium sulphate. Evaporation of the solvent gave a dark oil which solidified on standing. The solid was dissolved in hot petroleum ether (B.P. 60°-80°) and some insoluble material was filtered off. The solid which crystallized from the cooled filtrate was chromatographed on silica gel. Elution with a mixture of chloroform and petroleum ether (B.P. 60°-80°) (3:1) gave a solid which was crystallized from petroleum ether (B.P. 60°-80°) to give 5-methyl-2-pyrrolylglyoxylic acid ethyl ester (11.4 g.), M.P. 72°-74°. Found: C, 59.72; H, 6.54; N, 7.47. C9H11NO3 requires: C, 59.66; H, 6.16; N, 7.77%.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][CH:9]=1)[CH2:5][OH:6].[CH3:10][O:11][C:12](=[O:16])[C:13](Cl)=[O:14].O>O1CCCC1>[CH3:10][O:11][C:12]([C:13]([NH:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][CH:9]=1)[CH2:5][OH:6])=[O:14])=[O:16]
Reactant: Nc1cccc(CO)c1
Reactant: COC(=O)C(=O)Cl
Solvent: O
Solvent: C1CCOC1
Product: COC(=O)C(=O)Nc1cccc(CO)c1
Temperature: 25 °C
Reaction time: 1.5 h

Procedure:
To a solution of 4.93 g of m-aminobenzyl alcohol in 50 ml of tetrahydrofuran was added dropwise a solution of 3.7 ml of chloroglyoxylic acid methyl ester in 20 ml of tetrahydrofuran, and this was stirred at room temperature for 1.5 hours. To the reaction solution was added water, and this was extracted with ethyl acetate, and washed with an aqueous saturated sodium chloride solution. After dried over anhydrous magnesium sulfate, the solvent was distilled off under reduced pressure, and the resulting residue was subjected to silica gel column chromatography to obtain 5.10 g of 3-[(methoxycarbonyl)carbonylamino]benzyl alcohol as a white solid.
Reaction SMILES: [CH2:1]([O:3][C:4]([CH:6]1[CH2:14][C:10]2[S:11][CH:12]=[CH:13][C:9]=2[CH2:8][CH2:7]1)=[O:5])[CH3:2].ClCCl.[Cl-].[Al+3].[Cl-].[Cl-].[CH3:22][O:23]C(Cl)Cl>O.C(Cl)(Cl)Cl>[CH2:1]([O:3][C:4]([CH:6]1[CH2:14][C:10]2[S:11][C:12]([CH:22]=[O:23])=[CH:13][C:9]=2[CH2:8][CH2:7]1)=[O:5])[CH3:2]
Reactant: CCOC(=O)C1CCc2ccsc2C1
Reactant: COC(Cl)Cl
Agent: [Al+3]
Agent: [Cl-]
Solvent: ClCCl
Solvent: O
Solvent: ClC(Cl)Cl
Product: CCOC(=O)C1CCc2cc(C=O)sc2C1
Reaction time: 0.25 h

Procedure:
A mixture of 6-ethoxycarbonyl-4,5,6,7-tetrahydrobenzo[b]thiophene (0.80 g) and dichloromethane (CH2Cl2) was dropwise added to a mixture of aluminum chloride (AlCl3) (1.01 g) and CH2Cl2 (5 ml) under ice-water cooling, and was stirred under the same conditions for 15 minutes. A mixture of 1,1-dichloromethyl methyl ether (0.52 ml) and CH2Cl2 (3 ml) was thereto added, and was stirred under the same conditions for 10 minutes. The reaction mixture was added into a mixture of CHCl3, ice, and water. The separated organic layer was washed with water, and brine, and dried over MgSO4. After evaporation of the filtrate, the resulting oil was purified by chromatography on silica gel (n-hexane-AcOEt as eluent) to give 6-ethoxycarbonyl-2-formyl-4,5,6,7-tetrahydrobenzo[b]thiophene (0.33 g).
Reaction SMILES: [NH2:1][CH2:2][C@H:3]([N:5]1[CH:9]=[CH:8][C:7]([C:10]2[CH:17]=[CH:16][C:13]([C:14]#[N:15])=[C:12]([C:18]([F:21])([F:20])[F:19])[CH:11]=2)=[N:6]1)[CH3:4].[C:22]([C:25]1[CH:29]=[C:28]([C:30](O)=[O:31])[NH:27][N:26]=1)(=[O:24])[CH3:23].C1C=CC2N(O)N=NC=2C=1.CCN(C(C)C)C(C)C.CCN=C=NCCCN(C)C>C(Cl)Cl>[C:22]([C:25]1[CH:29]=[C:28]([C:30]([NH:1][CH2:2][C@H:3]([N:5]2[CH:9]=[CH:8][C:7]([C:10]3[CH:17]=[CH:16][C:13]([C:14]#[N:15])=[C:12]([C:18]([F:20])([F:21])[F:19])[CH:11]=3)=[N:6]2)[CH3:4])=[O:31])[NH:27][N:26]=1)(=[O:24])[CH3:23]
Reactant: CC(=O)c1cc(C(=O)O)[nH]n1
Reactant: C[C@H](CN)n1ccc(-c2ccc(C#N)c(C(F)(F)F)c2)n1
Agent: CCN=C=NCCCN(C)C
Agent: On1nnc2ccccc21
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CC(=O)c1cc(C(=O)NC[C@@H](C)n2ccc(-c3ccc(C#N)c(C(F)(F)F)c3)n2)[nH]n1
Yield: 73.3 %

Procedure:
The title compound was synthesized from (R)-4-(1-(1-aminopropan-2-yl)-1H-pyrazol-3-yl)-2-(trifluoromethyl)benzonitrile (381 mg, 1.3 mmol), 3-acetyl-1H-pyrazole-5-carboxylic acid (200 mg, 1.3 mmol), HOBt (210 mg, 1.55 mmol), DIPEA (0.271 mL, 1.55 mmol) and EDCI (298 mg, 1.55 mmol) using DCM as solvent using the method of Example 34(d) affording 410 mg of the title compound. 1H NMR (400 MHz; d6-DMSO): δ 1.50 (d, 3H), 2.47 (s, 3H), 3.63 (m, 2H), 4.69 (m, 1H), 7.03 (d, 1H), 7.25 (bs, 1H), 7.90 (d, 1H), 8.18 (m, 2H), 8.27 (m, 1H), 14.15 (bs, 1H).
Reaction SMILES: [Br:1][C:2]1[S:10][C:9]2[C:4](=[N:5][CH:6]=[CH:7][C:8]=2[O:11][C:12]2[CH:17]=[CH:16][C:15]([N+:18]([O-])=O)=[CH:14][C:13]=2[F:21])[CH:3]=1.[NH4+].[Cl-].O>CCO.[Fe]>[Br:1][C:2]1[S:10][C:9]2[C:4](=[N:5][CH:6]=[CH:7][C:8]=2[O:11][C:12]2[CH:17]=[CH:16][C:15]([NH2:18])=[CH:14][C:13]=2[F:21])[CH:3]=1
Reactant: O=[N+]([O-])c1ccc(Oc2ccnc3cc(Br)sc23)c(F)c1
Agent: [Fe]
Agent: [Cl-]
Agent: [NH4+]
Solvent: O
Solvent: CCO
Product: Nc1ccc(Oc2ccnc3cc(Br)sc23)c(F)c1
Reaction time: 0.67 h
Yield: 91.3 %

Procedure:
To a mixture of compound 50 (1.0 g, 2.96 mmol) and NH4Cl (46 mg, 0.86 mmol) in EtOH (29 mL)/water (15 mL) at 100° C., Fe (1.4 g, 25.15 mmol) was added in one portion and the mixture was refluxed with vigorous stirring for 40 min. The mixture was filtered through Celite®, the Celite® washed with EtOH and the combined filtrate concentrated under reduced pressure. The residue was suspended in EtOAc, washed with water; the organic phase was dried over anhydrous Na2SO4 and evaporated affording title compound 225 (916.15 mg, 91% yield). MS (m/z): 338.9 (96%), 340.9 (100%).
Reaction SMILES: [CH3:1][N:2]1[C:6]([NH:7][C:8](=[O:12])[CH:9]([CH3:11])[CH3:10])=[CH:5][C:4]([C:13]2[CH:14]=[N:15][CH:16]=[CH:17][CH:18]=2)=[N:3]1.[H-].[Na+].I[CH2:22][CH3:23].O>CN(C=O)C.C(OCC)(=O)C>[CH2:22]([N:7]([C:6]1[N:2]([CH3:1])[N:3]=[C:4]([C:13]2[CH:14]=[N:15][CH:16]=[CH:17][CH:18]=2)[CH:5]=1)[C:8](=[O:12])[CH:9]([CH3:11])[CH3:10])[CH3:23]
Reactant: CCI
Reactant: CC(C)C(=O)Nc1cc(-c2cccnc2)nn1C
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Solvent: O
Product: CCN(C(=O)C(C)C)c1cc(-c2cccnc2)nn1C
Reaction time: 0.5 h
Yield: 30.6 %

Procedure:
To a solution of N-(1-methyl-3-(pyridine-3-yl)-1H-pyrazol-5-yl)isobutyramide (0.08 g, 0.33 mmol) in DMF (0.66 ml) at 0° C. was added sodium hydride (0.016 g, 0.39 mmol, 60% dispersion in mineral oil) in one portion and the suspension was stirred for 30 minutes. The ice bath was removed and stirred for an additional 30 minutes. Iodoethane (0.06 g, 0.39 mmol) was added in one portion and stirred overnight at room temperature. Water and ethyl acetate were added and the resulting biphasic mixture was separated. The aqueous layer was extracted one time with ethyl acetate. The combined organic extracts were washed with brine, dried (MgSO4), filtered and concentrated to dryness. The crude product was purified by silica gel chromatography to give the title compound as a clear oil (27.5 mg, 30%): 1H NMR (300 MHz, CDCl3) δ 9.00 (bs, 1H), 8.57 (s, 1H), 8.09 (dd, J=7.9 Hz, 1H), 7.34 (dd, 1H), 6.48 (s, 1H), 4.00 (m, 1H), 3.76 (s, 3H), 3.36 (m, 1H), 2.33 (m, 1H), 1.17 (t, J=7.1 Hz, 3H), 1.08 (t, J=6.7 Hz, 6H); ESIMS m/z 273 (M+H).
Reaction SMILES: F[C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[C:4]([O:11][CH3:12])[C:3]=1[F:13].CS(C)=O.[CH:18]([N:21]1[CH2:26][CH2:25][NH:24][CH2:23][CH2:22]1)([CH3:20])[CH3:19].C(=O)([O-])[O-].[K+].[K+]>O>[F:13][C:3]1[C:4]([O:11][CH3:12])=[C:5]([N+:8]([O-:10])=[O:9])[CH:6]=[CH:7][C:2]=1[N:24]1[CH2:25][CH2:26][N:21]([CH:18]([CH3:20])[CH3:19])[CH2:22][CH2:23]1
Reactant: CC(C)N1CCNCC1
Reactant: COc1c([N+](=O)[O-])ccc(F)c1F
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CS(C)=O
Solvent: O
Product: COc1c([N+](=O)[O-])ccc(N2CCN(C(C)C)CC2)c1F
Temperature: 70 °C
Reaction time: 8 h
Yield: 103.6 %

Procedure:
A pressure flask was charged with 1,2-difluoro-3-(methyloxy)-4-nitrobenzene (3.5 g, 18.5 mmol), dimethylsulfoxide (100 mL), isopropyl piperazine (5.41 mL, 22.2 mmol) and potassium carbonate (5.1 g, 37.04 mmol). The resulting slurry was warmed to 70° C. and stirred overnight. The next morning, the orange solution was poured into water and extracted with diethyl ether. The organic layer was dried over sodium sulfate, taken to a residue under reduced pressure, and purified via chromatography on SiO2 (0 to 10% MeOH/CH2CL2 with 0.2% NH3) to afford 1-[2-fluoro-3-(methyloxy)-4-nitrophenyl]-4-(1-methylethyl)piperazine as a yellow solid (5.7 g, quant. yield). 1H NMR (400 MHz, CDCl3) δ ppm 1.10 (d, J=6.60 Hz, 6 H), 2.71 (s, 4 H), 2.76 (s, 1 H), 3.29 (s, 4 H), 4.03 (s, 3 H), 6.64 (dd, J=9.53, 8.07 Hz, 1 H), 7.70 (dd, J=9.35, 2.02 Hz, 1 H).
Reaction SMILES: [NH:1]([C:3]([C:5]1[NH:6][C:7]2[C:12]([CH:13]=1)=[CH:11][CH:10]=[CH:9][C:8]=2[NH:14][S:15]([C:18]1[S:19][CH:20]=[CH:21][CH:22]=1)(=[O:17])=[O:16])=[O:4])[NH2:2].[CH:23](OC)(OC)OC>>[O:4]1[CH:23]=[N:2][N:1]=[C:3]1[C:5]1[NH:6][C:7]2[C:12]([CH:13]=1)=[CH:11][CH:10]=[CH:9][C:8]=2[NH:14][S:15]([C:18]1[S:19][CH:20]=[CH:21][CH:22]=1)(=[O:17])=[O:16]
Reactant: COC(OC)OC
Reactant: NNC(=O)c1cc2cccc(NS(=O)(=O)c3cccs3)c2[nH]1
Product: O=S(=O)(Nc1cccc2cc(-c3nnco3)[nH]c12)c1cccs1
Temperature: 100 °C
Reaction time: 8 h
Yield: 38.2 %

Procedure:
A mixture of N-[2-(hydrazinocarbonyl)-1H-indol-7-yl]thiophene-2-sulfonamide (0.28 g) and trimethyl orthoformate (0.13 g) was stirred at 100° C. overnight. The reaction mixture was concentrated, and the residue was subjected to silica gel column chromatography and the title compound (0.11 g, yield 39%) was obtained as colorless crystals from a fraction eluted with tetrahydrofuran-hexane (1:1, volume ratio). The crystals were recrystallized from ethyl acetate-hexane. melting point 271-272° C. (decomposition).