Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [H-].[Na+].[O:3]=[C:4]1[CH2:9][CH2:8][N:7]([C:10]2[CH:23]=[CH:22][C:13]([CH2:14][CH:15]3[S:19][C:18](=[O:20])[NH:17][C:16]3=[O:21])=[CH:12][CH:11]=2)[CH2:6][CH2:5]1.CN(C=O)C.Br[CH2:30][C:31]([O:33][C:34]([CH3:37])([CH3:36])[CH3:35])=[O:32]>O>[O:20]=[C:18]1[N:17]([CH2:30][C:31]([O:33][C:34]([CH3:37])([CH3:36])[CH3:35])=[O:32])[C:16](=[O:21])[CH:15]([CH2:14][C:13]2[CH:12]=[CH:11][C:10]([N:7]3[CH2:8][CH2:9][C:4](=[O:3])[CH2:5][CH2:6]3)=[CH:23][CH:22]=2)[S:19]1
Reactant: O=C1CCN(c2ccc(CC3SC(=O)NC3=O)cc2)CC1
Reactant: CC(C)(C)OC(=O)CBr
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CC(C)(C)OC(=O)CN1C(=O)SC(Cc2ccc(N3CCC(=O)CC3)cc2)C1=O
Temperature: 25 °C
Reaction time: 1 h
Yield: 76 %

Procedure:
Sodium hydride (60% in mineral oil, 66 mg, 1.65 mmol) was added into a mixture of 5-[4-(4-oxo-1-piperidinyl)benzyl]-1,3-thiazolidine-2,4-dione (500 mg, 1.65 mmol) (which was obtained in Example 38), and DMF. The mixture was stirred for 1 hour at room temperature, and then tert-butyl bromoacetate (0.36 mL, 2.47 mmol) was added. The new mixture was stirred for 30 minutes, poured into water, and extracted with ethyl acetate. The organic extracts were dried over MgSO4. Evaporation and purification by flash chromatography (hexanes/ethyl acetate 3/1) gave a viscous oil (525 mg, 76% yield); 1H NMR (300 MHz, DMSO-d6) δ 1.40 (s, 9 H), 2.40 (m, 4H), 2.9 (m, 1H), 3.45 (m, 1H), 3.56 (m, 4H), 4.20 (s, 2H), 5.05 (m, 1H), 6.97 (m, 2H), 7.18 (m, 2H); MS (ES) m/z: 419 (MH+); Anal. Calcd. for C15H16N2O3S: C, 60.27; H, 6.26; N, 6.69. Found: C, 60.21; H, 6.44; N, 6.52.
Reaction SMILES: [ClH:1].Cl.[NH2:3][C@H:4]1[CH2:9][CH2:8][C@H:7]([CH2:10][CH2:11][N:12]2[CH2:16][C@H:15]3[C:17]4[CH:18]=[C:19]([C:25]#[N:26])[CH:20]=[CH:21][C:22]=4[O:23][CH2:24][C@@H:14]3[CH2:13]2)[CH2:6][CH2:5]1.[Cl:27][C:28]1[N:33]=[CH:32][CH:31]=[CH:30][N:29]=1.C(=O)([O-])[O-].[Na+].[Na+].Cl>C(O)C>[ClH:27].[ClH:1].[N:29]1[CH:30]=[CH:31][CH:32]=[N:33][C:28]=1[NH:3][C@H:4]1[CH2:9][CH2:8][C@H:7]([CH2:10][CH2:11][N:12]2[CH2:16][C@H:15]3[C:17]4[CH:18]=[C:19]([C:25]#[N:26])[CH:20]=[CH:21][C:22]=4[O:23][CH2:24][C@@H:14]3[CH2:13]2)[CH2:6][CH2:5]1
Reactant: Clc1ncccn1
Reactant: N#Cc1ccc2c(c1)[C@@H]1CN(CC[C@H]3CC[C@H](N)CC3)C[C@H]1CO2
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCO
Product: N#Cc1ccc2c(c1)[C@@H]1CN(CC[C@H]3CC[C@H](Nc4ncccn4)CC3)C[C@H]1CO2

Procedure:
A suspension of 0.715 g of the compound of Example 1 (2.2 mmol), 0.303 mg of 2-chloropyrimidine and 0.47 g of sodium carbonate in 45 ml of ethanol is heated at reflux for 72 hours. After filtering, the solvents are then evaporated off After extraction with ethyl acetate and drying (MgSO4), evaporation yields an oil which is purified by chromatography on a silica column using a mixture of dichloromethane/methanol/ammonium hydroxide (98/2/0.2) as eluant to yield, after converting to a salt in ethanol in the warm state using 1N ethereal HCl, the title product.
Reaction SMILES: CC(OC(/N=N/C(OC(C)C)=O)=O)C.[OH:15][CH2:16][C@@H:17]1[O:21][C:20](=[O:22])[N:19]([C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)[CH2:18]1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.O[C:49]1[CH:53]=[N:52][S:51][N:50]=1>C1COCC1>[S:51]1[N:52]=[CH:53][C:49]([O:15][CH2:16][C@@H:17]2[O:21][C:20](=[O:22])[N:19]([C:23]3[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=3)[CH2:18]2)=[N:50]1
Reactant: Oc1cnsn1
Reactant: O=C1O[C@@H](CO)CN1c1ccccc1
Agent: CC(C)OC(=O)/N=N/C(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: O=C1O[C@@H](COc2cnsn2)CN1c1ccccc1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
Diisopropylazodicarboxylate (4.45 g, 22 mmol) was added dropwise to a stirred solution of 5(R)-hydroxymethyl-3-phenyloxazolidin-2-one (Gregory et al. J. Med, Chem, 32, 1673 (1989); 4.25 g,22 mmol), triphenyl phosphine (5.76 g, 22 mmol) and 3-hydroxy-1,2,5-thiadiazole (Weinstock et al, J.Org. Chem, 32, 2823 (1967)) (2.04 g, 20 mmol) in 30 ml THF, in an ice-bath. After stirring at ambient temperature for two hours and evaporating in vacuo, the resulting oil was purified by chromatography (Merck 9385 silica. Gradient elution from isohexane to ca. 50% EtOAc/isohexane to give a white solid. Further purification by flash chromatography on silica using 1% MeOH/dichloromethane was necessary to remove remaining diisopropylcarboxyhydrazine yielding the title product as a white crystalline solid (4.7 g, 83%). MS: ESP+ (M+H)+=278.
Reaction SMILES: Br[C:2]1[S:6][C:5]([CH2:7][OH:8])=[CH:4][CH:3]=1.[CH2:9]([C:13]1[CH:18]=[CH:17][C:16](B(O)O)=[CH:15][CH:14]=1)[CH2:10][CH2:11][CH3:12].C([O-])([O-])=O.[K+].[K+]>C1(C)C=CC=CC=1.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>[CH2:9]([C:13]1[CH:18]=[CH:17][C:16]([C:2]2[S:6][C:5]([CH2:7][OH:8])=[CH:4][CH:3]=2)=[CH:15][CH:14]=1)[CH2:10][CH2:11][CH3:12]
Reactant: OCc1ccc(Br)s1
Reactant: CCCCc1ccc(B(O)O)cc1
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: [K+]
Solvent: Cc1ccccc1
Product: CCCCc1ccc(-c2ccc(CO)s2)cc1
Temperature: 95 °C
Reaction time: 8 h
Yield: 18.9 %

Procedure:
A mixture of 60.2 (0.300 g, 1.55 mmol), 4-n-butylbenzeneboronic acid 60.3 (0.553 g, 3.11 mmol), K2CO3 (0.644 g, 4.66 mmol), and Pd(PPh3)4 (0.180 g, 0.16 mmol) in toluene (5 mL) was stirred overnight at 95° C. The mixture was cooled to room temperature, filtered through a pad of silica gel (EtOAc), and concentrated. The crude product was chromatographed on silica gel (0-40% EtOAc/hexane) to afford 60.4 (0.072 g, 19%). 1H NMR (400 MHz, CDCl3) δ 7.49 (d, 2H), 7.18 (d, 2H), 7.13 (d, 1H), 6.97 (d, H), 4.82 (s, 2H), 2.62 (t, 2H), 1.60 (m, 2H), 1.37 (m, 2H), 0.93 (t, 3H).
Reaction SMILES: [C:1]1([CH2:7][CH2:8][OH:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH2:10]=O.Cl>>[CH2:10]1[C:6]2[C:1](=[CH:2][CH:3]=[CH:4][CH:5]=2)[CH2:7][CH2:8][O:9]1
Reactant: OCCc1ccccc1
Reactant: C=O
Agent: Cl
Product: c1ccc2c(c1)CCOC2
Temperature: 25 °C
Reaction time: 2 h
Yield: 85.3 %

Procedure:
2-phenylethanol (48.8 g,) and paraformaldehyde (15 g,) were mixed and stirred on an ice bath while a stream of hydrogen chloride gas was passed vigorously through the suspension for 2 hr. The ice-bath was removed and the flow of hydrogen chloride was decreased. The mixture was stirred at room temperature for a further 4 hr. during which time the mixture cleared, after which the reaction mixture stood overnight at room temperature. Aqueous sodium hydroxide solution (100 g/100 ml) was added cautiously, with stirring to the reaction mixture over a period of 30 min. The mixture was heated at reflux for 2 hr., cooled and the oil extracted with ether (3×100 ml). The ether layer was dried (magnesium sulphate) and the solvent removed in vacuo. The residue was distilled under vacuum to give isochroman (45.7 g, b.pt 84.5°-85°/8 mmHg)
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[C:7]([OH:24])=[C:8]2[C:16](Cl)=[C:15](Cl)[N:14]([CH2:19][CH2:20][CH:21]([CH3:23])[CH3:22])[C:9]2=[C:10]([C:12]#[N:13])[N:11]=1)=[O:5])[CH3:2].C([O-])=O.[NH4+]>C(OCC)(=O)C.[Pd]>[CH2:1]([O:3][C:4]([C:6]1[C:7]([OH:24])=[C:8]2[CH:16]=[CH:15][N:14]([CH2:19][CH2:20][CH:21]([CH3:23])[CH3:22])[C:9]2=[C:10]([C:12]#[N:13])[N:11]=1)=[O:5])[CH3:2]
Reactant: CCOC(=O)c1nc(C#N)c2c(c1O)c(Cl)c(Cl)n2CCC(C)C
Agent: [Pd]
Agent: O=C[O-]
Agent: [NH4+]
Solvent: CCOC(C)=O
Product: CCOC(=O)c1nc(C#N)c2c(ccn2CCC(C)C)c1O
Yield: 89.5 %

Procedure:
To a suspension of 7-cyano-2,3-dichloro-4-hydroxy-1-(3-methyl-butyl)-1H-pyrrolo[2,3-c]pyridine-5-carboxylic acid ethyl ester (0.66 g, 1.78 mmol), example 96(f), and ammonium formate (2.25 g, 35.7 mmol) in 62 mL of ethyl acetate was added 10 wt. % palladium on carbon (312 mg). The reaction mixture was refluxed for 1 h. The catalyst was filtered off, and the filtrate was concentrated to afford 0.48 g of a white solid. MS: (+) m/z 302.3 (M+1).
Reaction SMILES: [H-].[Na+].[C:3]([O:7][C:8]([N:10]1[CH2:15][CH2:14][CH:13]([OH:16])[CH2:12][CH2:11]1)=[O:9])([CH3:6])([CH3:5])[CH3:4].[CH3:17]I>CN(C)C=O>[C:3]([O:7][C:8]([N:10]1[CH2:15][CH2:14][CH:13]([O:16][CH3:17])[CH2:12][CH2:11]1)=[O:9])([CH3:6])([CH3:4])[CH3:5]
Reactant: CC(C)(C)OC(=O)N1CCC(O)CC1
Reactant: CI
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COC1CCN(C(=O)OC(C)(C)C)CC1
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
To a suspension of 60% sodium hydride (939 mg) in dimethylformamide (30 ml) was added 1-t-butoxycarbonyl-4-hydroxypiperidine (3.15 g) under ice-water cooling and the mixture was stirred at 0° C. for 0.5 hour. To the solution was added methyl iodide (1.17 ml) under ice-water cooling and the mixture was stirred at 0° C. for 1 hour. The mixture was partitioned between ethyl acetate and water. The organic layer was separated, washed with water and brine, dried over magnesium sulfate, and evaporated in vacuo. The residue was purified by silica gel column chromatography eluting with a mixture of hexane and ethyl acetate (3:1) to give 1-t-butoxycarbonyl-4-methoxypiperidine as colorless oil (2.84 g).
Reaction SMILES: [I-:1].[K+].N([O-])=O.[Na+].N[C:8]1[CH:15]=[C:14]([C:16]([F:19])([F:18])[F:17])[CH:13]=[CH:12][C:9]=1[C:10]#[N:11].O>C(#N)C>[I:1][C:8]1[CH:15]=[C:14]([C:16]([F:19])([F:18])[F:17])[CH:13]=[CH:12][C:9]=1[C:10]#[N:11]
Reactant: [I-]
Reactant: N#Cc1ccc(C(F)(F)F)cc1N
Agent: O=N[O-]
Agent: [K+]
Agent: [Na+]
Solvent: CC#N
Solvent: O
Product: N#Cc1ccc(C(F)(F)F)cc1I
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
Potassium iodide (5.6 g, 34 mmol) and sodium nitrite (2.4 g, 35 mmol) were added to a solution of 2-amino-4-trifluoromethyl-benzonitrile (2.58 g, 14 mmol) in acetonitrile (60 mL). The resultant mixture was cooled to 0° C. in an ice-water bath with magnetic stirring. Ice-cold concentrated HCl (14 mL) was added slowly drop-wise to the reaction mixture, causing the reaction mixture to become cloudy and deep red in color. The reaction mixture was stirred at 0° C. for 30 minutes, then warmed to room temperature. Stirring at room temperature proceeded for 3 hours. The reaction mixture was poured into water, and the resulting suspension was extracted with ethyl acetate. The organic layer was dried (Na2SO4), filtered, and concentrated to give a purple liquid. A solution of this crude product and dichloromethane (200 mL) was evaporated onto silica gel, and the dry silica gel-supported product was loaded onto a silica gel column. Manual flash chromatography using 5% ethyl acetate in hexanes afforded 2-iodo-4-trifluoromethyl-benzonitrile as 3.58 g (87%) of a purple, crystalline solid.
Reaction SMILES: [CH2:1]([NH:5][CH2:6][C:7]1[NH:8][C:9]2[CH:15]=[CH:14][CH:13]=[CH:12][C:10]=2[N:11]=1)[CH2:2][CH2:3][CH3:4].C([O-])(O)=O.[Na+].[F:21][C:22]1[C:30]([F:31])=[CH:29][CH:28]=[CH:27][C:23]=1[C:24](Cl)=[O:25]>C1(C)C=CC=CC=1.C(OCC)(=O)C>[CH2:1]([N:5]([CH2:6][C:7]1[NH:8][C:9]2[CH:15]=[CH:14][CH:13]=[CH:12][C:10]=2[N:11]=1)[C:24](=[O:25])[C:23]1[CH:27]=[CH:28][CH:29]=[C:30]([F:31])[C:22]=1[F:21])[CH2:2][CH2:3][CH3:4]
Reactant: CCCCNCc1nc2ccccc2[nH]1
Reactant: O=C(Cl)c1cccc(F)c1F
Agent: O=C([O-])O
Agent: [Na+]
Solvent: Cc1ccccc1
Solvent: CCOC(C)=O
Product: CCCCN(Cc1nc2ccccc2[nH]1)C(=O)c1cccc(F)c1F
Temperature: 25 °C
Reaction time: 3 h
Yield: 58.2 %

Procedure:
2-butylaminomethylbenzimidazole (2.6 g, 13 mmol) was dissolved in 30 mL toluene. Saturated NaHCO3 solution (30 mL) was added followed by 2,3-difluorobenzoyl chloride (1.3 mL, 10 mmol). The reaction mixture was stirred at room temperature for 3 hours. The reaction mixture was diluted with 100 mL ethyl acetate then washed 1×100 mL 1N NaOH followed by 1×100 mL H2O. The organic phase was dried over MgSO4, filtered, and then concentrated. The residue was purified by flash chromatography eluting with 1/1 ethyl acetate/hexane followed by ethyl acetate to afford 2.0 g N-butyl-N-(1H-benzoimidazol-2-ylmethyl)-2,3-difluorobenzamide.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6](Cl)[C:5]([F:9])=[CH:4][N:3]=1.[F:10][C:11]1[CH:17]=[CH:16][C:14]([NH2:15])=[CH:13][CH:12]=1>>[F:10][C:11]1[CH:17]=[CH:16][C:14]([NH:15][C:2]2[N:7]=[C:6]([NH:15][C:14]3[CH:16]=[CH:17][C:11]([F:10])=[CH:12][CH:13]=3)[C:5]([F:9])=[CH:4][N:3]=2)=[CH:13][CH:12]=1
Reactant: Nc1ccc(F)cc1
Reactant: Fc1cnc(Cl)nc1Cl
Product: Fc1ccc(Nc2ncc(F)c(Nc3ccc(F)cc3)n2)cc1

Procedure:
In like manner to the preparation of N2,N4-bis(3-hydroxyphenyl)-5-fluoro-2,4-pyrimidinediamine, 2,4-dichloro-5-fluoropyrimidine and 4-fluoroaniline were reacted to yield N2,N4-bis(4-fluorophenyl)-5-fluoro-2,4-pyrimidinediamine. 1H NMR (CDCl3): δ 8.79 (d, 2H, J=5.4 Hz), 7.40 (m, 2H), 7.30 (m, 2H), 6.90 (m, 4H); 19NMR (CDCl3): −32425 (s, 1F), −32940 (s, 1F), −45525 (s, 1F); LCMS: ret. time: 23.53 min.; purity: 100%; MS (m/e): 317 (MH+).
Reaction SMILES: C(S[C:4]1[NH:5][C:6](=[O:14])[C:7]2[CH2:12][S:11][CH:10]([CH3:13])[C:8]=2[N:9]=1)C.Cl.CC(O)=[O:18]>O>[CH3:13][CH:10]1[C:8]2[NH:9][C:4](=[O:18])[NH:5][C:6](=[O:14])[C:7]=2[CH2:12][S:11]1
Reactant: CC(=O)O
Reactant: CCSc1nc2c(c(=O)[nH]1)CSC2C
Agent: Cl
Solvent: O
Product: CC1SCc2c1[nH]c(=O)[nH]c2=O
Yield: 80 %

Procedure:
To a suspension of 2-(ethylthio)-7-methylthieno[3,4-d]pyrimidin-4(3H,5H,7H)-one (3.96 g, 17.3 mmol) in water (20 mL) was added 2.0 mL of conc. HCl and 4.0 mL of AcOH. The mixture was heated to reflux overnight then cooled and the precipitated solid collected by filtration, washed with water and methanol, evaporated and dried to obtain 7-methylthieno[3,4-d]pyrimidine-2,4(1H,3H,5H,7H)-dione as a white solid (2.52 g, 80%). Without further purification, the crude product was used directly in the next step.
Reaction SMILES: [CH2:1]([N:8]1[C:18](=[O:19])[CH:17]2[CH:12]([CH2:13][C:14](=[O:23])[CH2:15][CH:16]2[CH:20]([CH3:22])[CH3:21])[S:9]1(=[O:11])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[BH4-].[Na+].[CH3:26]I.[H-].[Na+]>>[CH2:1]([N:8]1[C:18](=[O:19])[CH:17]2[C:12](=[CH:13][CH:14]([O:23][CH3:26])[CH2:15][CH:16]2[CH:20]([CH3:21])[CH3:22])[S:9]1(=[O:11])=[O:10])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CI
Reactant: CC(C)C1CC(=O)CC2C1C(=O)N(Cc1ccccc1)S2(=O)=O
Agent: [BH4-]
Agent: [H-]
Agent: [Na+]
Product: COC1C=C2C(C(=O)N(Cc3ccccc3)S2(=O)=O)C(C(C)C)C1

Procedure:
2-Benzyl-4-isopropyl-6-oxo-tetrahydrosaccharin of preparation 21 is reduced with sodium borohydride and methylated with methyl iodide in the presence of sodium hydride to provide 2-benzyl-4-isopropyl-6-methoxy-tetrahydrosaccharin. This is debenzylated and chloromethylated as in preparation 21 to provide 2-chloromethyl-4-isopropyl-6-methoxy-4,5,6,7-tetrahydrosaccharin.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:7]=[CH:6][S:5][CH:4]=1.[CH2:8](O)[CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14]C.O.C1(C)C=CC(S(O)(=O)=O)=CC=1>C1(C)C=CC=CC=1>[CH2:1]([O:2][C:3]1[CH:7]=[CH:6][S:5][CH:4]=1)[CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH3:14]
Reactant: CCCCCCCCO
Reactant: COc1ccsc1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: Cc1ccccc1
Solvent: O
Product: CCCCCCCCOc1ccsc1
Temperature: 130 °C
Yield: 96 %

Procedure:
A mixture of 3-methoxythiophene (7.28 g, 63.76 mmol), 1-octanol (20.09 mL, 127.53 mmol), p-toluenesulfonic acid monohydrate (1.21 g, 6.38 mmol) and 60 mL toluene was heated in a 130° C. bath for 15 hours under argon. After dichloromethane/water extraction, the organic layer was dried over anhydrous Na2SO4. After solvent evaporation, the residue was purified by column chromatography (silica gel 3:1 hexane:dichloromethane) to give 2′ as a colorless solid (13.00 g, 96%). 1H NMR (CDCl3, 300 MHz, ppm): δ 7.18-7.21 (m, 1H), 6.78-6.80 (m, 1H), 6.25-6.26 (m, 1H), 3.97 (t, 2H, 6.6 Hz), 1.76-1.85 (m, 2H), 1.33-1.48 (m, 10H), 0.91-0.95 (m, 3H).
Reaction SMILES: [S:1](Cl)([C:4]1[C:16]2[CH:15]=[CH:14][CH:13]=[C:9]([N:10]([CH3:12])[CH3:11])[C:8]=2[CH:7]=[CH:6][CH:5]=1)(=[O:3])=[O:2].[Br:18][C:19]1[C:20]([CH3:36])=[N:21][O:22][C:23]=1[NH:24][S:25]([C:28]1[CH:32]=[CH:31][S:30][C:29]=1[C:33]([NH2:35])=[O:34])(=[O:27])=[O:26].[H-].[Na+]>O>[Br:18][C:19]1[C:20]([CH3:36])=[N:21][O:22][C:23]=1[NH:24][S:25]([C:28]1[CH:32]=[CH:31][S:30][C:29]=1[C:33]([NH:35][S:1]([C:4]1[C:16]2[C:8](=[C:9]([N:10]([CH3:12])[CH3:11])[CH:13]=[CH:14][CH:15]=2)[CH:7]=[CH:6][CH:5]=1)(=[O:3])=[O:2])=[O:34])(=[O:27])=[O:26]
Reactant: Cc1noc(NS(=O)(=O)c2ccsc2C(N)=O)c1Br
Reactant: CN(C)c1cccc2c(S(=O)(=O)Cl)cccc12
Agent: [H-]
Agent: [Na+]
Solvent: O
Product: Cc1noc(NS(=O)(=O)c2ccsc2C(=O)NS(=O)(=O)c2cccc3c(N(C)C)cccc23)c1Br
Temperature: 25 °C
Reaction time: 1 h
Yield: 33.6 %

Procedure:
Dansylchloride (90.2 mg, 0.328 mmol) was added to a solution of N-(4-bromo-3-methyl-5-isoxazolyl)-2-(aminocarbonyl)thiophene-3-sulfonamide (Example 89) (100 mg, 0.273 mmol) and NaH (43.7 mg, 60% dispersion in mineral oil, 1.10 mmol). The reaction was stirred at room temperature for 1 hour. Water was added to quench the reaction and THF was stripped off on a rotavap. The aqueous residue was partitioned between 1N HCl and EtOAc. The organic layer was dried (MgSO4). The solid was filtered and the filtrate concentrated. The residue was recrystalized from EtOAc to give N-(4-bromo-3-methyl-5-isoxazolyl)-2-[(5-dimethylamino-1-naphthyl)sulfonylaminocarbonyl]thiophene-3-sulfonamide (55 mg., 34% yield) as a white powder (m.p. 184-186° C.).
Reaction SMILES: C([O:3][C:4](=[O:29])[CH:5]=[CH:6][C:7]1[CH:12]=[CH:11][C:10]([C:13](=[C:21]2[CH2:27][CH2:26][CH2:25][CH2:24][CH2:23][CH2:22]2)[C:14]2[CH:19]=[CH:18][C:17]([OH:20])=[CH:16][CH:15]=2)=[C:9]([F:28])[CH:8]=1)C.[OH-].[Na+]>C1COCC1.C(O)C>[C:21]1(=[C:13]([C:14]2[CH:19]=[CH:18][C:17]([OH:20])=[CH:16][CH:15]=2)[C:10]2[CH:11]=[CH:12][C:7]([CH:6]=[CH:5][C:4]([OH:29])=[O:3])=[CH:8][C:9]=2[F:28])[CH2:27][CH2:26][CH2:25][CH2:24][CH2:23][CH2:22]1
Reactant: CCOC(=O)C=Cc1ccc(C(=C2CCCCCC2)c2ccc(O)cc2)c(F)c1
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CCO
Product: O=C(O)C=Cc1ccc(C(=C2CCCCCC2)c2ccc(O)cc2)c(F)c1
Temperature: 65 °C
Yield: 8.3 %

Procedure:
To a solution of 3-{4-[cycloheptylidene-(4-hydroxy-phenyl)-methyl]-3-fluoro-phenyl}acrylic acid ethyl ester (176) (0.8 g, 2.15 mmol) in THF (10 mL) and ethanol (10 mL) was added 1 N sodium hydroxide (21 mL). The reaction mixture was heated at 65° C. for 2.5 h. The reaction mixture was partially concentrated to remove the EtOH and THF. To the basic aqueous mixture was added 1 N HCl to pH˜1 (according to litmus paper). The acidic aqueous solution was extracted with dichloromethane and the organic extract was washed with brine, dried over Na2SO4, filtered and concentrated. The crude material was triturated with dichloromethane, filtered and dried to give 0.065 g (10%) of compound 177 as a white powder. 1H NMR (400 MHz, DMSO-d6): δ 1.51 (b, 8H), 2.09 (m, 2H), 2.25 (m, 2H), 6.52 (d, J=16.1 Hz, 1H), 6.65 (d, J=8.4 Hz, 2H), 6.92 (d, J=8.4 Hz, 2H), 7.19 (t, J=7.8 Hz, 1H), 7.43-7.49 (m, 1H), 7.51-7.53 (m, 2H), 9.32 (s, 1H), 12.43 (s, 1H). HRMS (ESI) Calcd for C23H22FO3: 365.1553 (M−H)−. Found: 365.1543.
Reaction SMILES: [NH2:1][C:2]1[N:6]([C@H:7]2[CH2:12][CH2:11][C@H:10]([OH:13])[CH2:9][CH2:8]2)[C:5]2[CH:14]=[CH:15][C:16]([C:18]([O:20][CH2:21][CH3:22])=[O:19])=[CH:17][C:4]=2[N:3]=1.CN(C)C=O.N1C=CN=C1.[Si:33](Cl)([C:36]([CH3:39])([CH3:38])[CH3:37])([CH3:35])[CH3:34]>C(OCC)(=O)C>[NH2:1][C:2]1[N:6]([C@H:7]2[CH2:12][CH2:11][C@H:10]([O:13][Si:33]([C:36]([CH3:39])([CH3:38])[CH3:37])([CH3:35])[CH3:34])[CH2:9][CH2:8]2)[C:5]2[CH:14]=[CH:15][C:16]([C:18]([O:20][CH2:21][CH3:22])=[O:19])=[CH:17][C:4]=2[N:3]=1
Reactant: CCOC(=O)c1ccc2c(c1)nc(N)n2[C@H]1CC[C@H](O)CC1
Reactant: CC(C)(C)[Si](C)(C)Cl
Agent: c1c[nH]cn1
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CCOC(=O)c1ccc2c(c1)nc(N)n2[C@H]1CC[C@H](O[Si](C)(C)C(C)(C)C)CC1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
Ethyl 2-amino-1-(trans-4-hydroxycyclohexyl)-1H-benzimidazole-5-carboxylate (0.97 g, 0.0032 mol) was dissolved in N,N-dimethylformamide (10 mL, 0.2 mol) at room temperature. 1H-Imidazole (0.50 g, 0.0074 mol) and tert-butyldimethylsilyl chloride (0.53 g, 0.0035 mol) were added and the mixture stirred at room temperature for 1 hour. The reaction mixture was diluted with ethyl acetate and washed with saturated bicarbonate then brine. The organics were collected and dried over sodium sulfate and concentrated. The crude solid was purified by combiflash chromatography using methylene chloride and methanol as eluent. Product fractions were concentrated to give an off white solid (1.099 g). MS (ESI (+)m/z) 418.04 (M+H+)
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[N:7]([CH2:11][C@H:12]([OH:14])[CH3:13])[N:6]=[C:5]2[C:15]#[N:16].N1C=CN=C1.[Si:22](Cl)([C:25]([CH3:28])([CH3:27])[CH3:26])([CH3:24])[CH3:23]>C(Cl)Cl.CN(C1C=CN=CC=1)C>[NH2:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[N:7]([CH2:11][C@H:12]([O:14][Si:22]([C:25]([CH3:28])([CH3:27])[CH3:26])([CH3:24])[CH3:23])[CH3:13])[N:6]=[C:5]2[C:15]#[N:16]
Reactant: CC(C)(C)[Si](C)(C)Cl
Reactant: C[C@@H](O)Cn1nc(C#N)c2cc(N)ccc21
Agent: CN(C)c1ccncc1
Agent: c1c[nH]cn1
Solvent: ClCCl
Product: C[C@H](Cn1nc(C#N)c2cc(N)ccc21)O[Si](C)(C)C(C)(C)C
Temperature: 25 °C
Reaction time: 8 h
Yield: 83.8 %

Procedure:
(R)-5-amino-1-(2-hydroxypropyl)-1H-indazole-3-carbonitrile (180 mg, 0.832 mmol) was taken up in DCM (6 mL) and imidazole (227 mg, 3.33 mmol) and DMAP (10.17 mg, 0.083 mmol) were added, followed by TBS-Cl (439 mg, 2.91 mmol). The reaction was stirred at room temperature overnight. The reaction mixture was quenched with saturated NH4Cl solution and diluted with DCM. The organic layer was collected and washed with brine, dried over Na2SO4, filtered, and concentrated. The crude material was purified by flash column chromatography eluting with 0-40% EtOAc/Hex. (R)-5-amino-1-(2-((tert-butyldimethylsilyl)oxy)propyl)-1H-indazole-3-carbonitrile (230.5 mg) was obtained as an orange solid.
Reaction SMILES: [F:1][C:2]1[CH:11]=[C:10]([F:12])[CH:9]=[C:8]2[C:3]=1[C:4]([NH:20][C:21]1[CH:22]=[N:23][CH:24]=[C:25]([N:27]3[CH2:32][CH2:31][O:30][CH2:29][CH2:28]3)[CH:26]=1)=[C:5]([CH3:19])[C:6]([N:13]1[CH2:18][CH2:17][NH:16][CH2:15][CH2:14]1)=[N:7]2.[CH:33]1([S:38](Cl)(=[O:40])=[O:39])[CH2:37][CH2:36][CH2:35][CH2:34]1>>[CH:33]1([S:38]([N:16]2[CH2:15][CH2:14][N:13]([C:6]3[C:5]([CH3:19])=[C:4]([NH:20][C:21]4[CH:22]=[N:23][CH:24]=[C:25]([N:27]5[CH2:32][CH2:31][O:30][CH2:29][CH2:28]5)[CH:26]=4)[C:3]4[C:8](=[CH:9][C:10]([F:12])=[CH:11][C:2]=4[F:1])[N:7]=3)[CH2:18][CH2:17]2)(=[O:40])=[O:39])[CH2:37][CH2:36][CH2:35][CH2:34]1
Reactant: Cc1c(N2CCNCC2)nc2cc(F)cc(F)c2c1Nc1cncc(N2CCOCC2)c1
Reactant: O=S(=O)(Cl)C1CCCC1
Product: Cc1c(N2CCN(S(=O)(=O)C3CCCC3)CC2)nc2cc(F)cc(F)c2c1Nc1cncc(N2CCOCC2)c1

Procedure:
Prepared according to Procedure M using 5,7-difluoro-3-methyl-N-(5-morpholinopyridin-3-yl)-2-(piperazin-1-yl)quinolin-4-amine (50.0 mg, 0.11 mmol) and cyclopentylsulfonyl chloride to give 2-(4-(cyclopentylsulfonyl)piperazin-1-yl)-5,7-difluoro-3-methyl-N-(5-morpholinopyridin-3-yl)quinolin-4-amine. 1H NMR (CDCl3) δ ppm 1.54-1.58 (m, 2H), 1.67 (s, 2H), 1.80-1.85 (m, 2H), 1.96-1.99 (m, 2H), 2.08 (s, 3H), 3.05 (t, J=4.4 Hz, 4H), 3.33 (s, 4H), 3.39 (t, J=4.8 Hz, 4H), 3.69 (t, J=3.6 Hz, 5H), 6.51 (s, 1H), 7.15-7.20 (m, 1H), 7.30 (d, J=11.2 Hz, 1H), 7.52 (s, 1H), 7.78 (s, 1H), 8.37 (s, 1H). Mass Spectrum (ESI) m/e=573.1 (M+1).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][CH:6]=[C:5]([O:9][CH3:10])[C:4]=1[C:11]1[CH:16]=[CH:15][C:14](/[C:17](/[CH3:21])=[CH:18]/[CH2:19][OH:20])=[CH:13][CH:12]=1.[CH2:22]([O:24][C@@H:25]([CH2:31][C:32]1[CH:37]=[CH:36][C:35](O)=[CH:34][CH:33]=1)[C:26]([O:28][CH2:29][CH3:30])=[O:27])[CH3:23]>>[CH3:10][O:9][C:5]1[CH:6]=[CH:7][CH:8]=[C:3]([O:2][CH3:1])[C:4]=1[C:11]1[CH:12]=[CH:13][C:14](/[C:17](/[CH3:21])=[CH:18]/[CH2:19][O:20][C:35]2[CH:34]=[CH:33][C:32]([CH2:31][C@H:25]([O:24][CH2:22][CH3:23])[C:26]([O:28][CH2:29][CH3:30])=[O:27])=[CH:37][CH:36]=2)=[CH:15][CH:16]=1
Reactant: COc1cccc(OC)c1-c1ccc(/C(C)=C/CO)cc1
Reactant: CCOC(=O)[C@H](Cc1ccc(O)cc1)OCC
Product: CCOC(=O)[C@H](Cc1ccc(OC/C=C(\C)c2ccc(-c3c(OC)cccc3OC)cc2)cc1)OCC
Yield: 46.2 %

Procedure:
The title compound (0.41 g, 80% yield) was prepared from (E)-3-(2′,6′-dimethoxy-biphenyl-4-yl)-but-2-en-1-ol (0.50 g, 1.76 mmol) and (S)-ethyl 2-ethoxy-3-(4-hydroxyphenyl)-propionate (0.44 g, 1.85 mmol) by a procedure analogous to that described in example 52c.