Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH2:8][CH2:9][OH:10].C(N(CC)CC)C.[Br:18][CH2:19][CH2:20][CH2:21][CH2:22][C:23](Cl)=[O:24]>ClCCl>[Br:18][CH2:19][CH2:20][CH2:21][CH2:22][C:23]([NH:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH2:8][CH2:9][OH:10])=[O:24]
Reactant: Nc1ccccc1CCO
Reactant: O=C(Cl)CCCCBr
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: O=C(CCCCBr)Nc1ccccc1CCO
Yield: 100 %

Procedure:
A solution of 2-(2-aminophenyl)ethanol a2-0 (450 g, 3.28 mol, 1 eq) and triethylamine (332 g, 3.28 mol, 1 eq) in dichloromethane (2 l) is cooled at −5° C. and bromovalerylchloride (654 g, 3.28 mol, 1 eq) in dichloromethane (2 l) is added dropwise without exceeding 0° C. The organic phase is washed with HCl 1N (4×2 l) and brine (1×2 l). The aqueous layer is extracted with dichloromethane (1×2 l). The combined organic layers are dried over MgSO4, filtered and evaporated under vacuum to afford 1008 g of 5-bromo-N-[2-(2-hydroxyethyl)phenyl]pentanamide a2-1.
Reaction SMILES: [OH:1][CH:2]([CH2:26][N:27]1[CH2:32][CH2:31][N:30]([CH3:33])[CH2:29][CH2:28]1)[CH2:3][O:4][C:5]1[CH:14]=[C:13]2[C:8]([C:9](=[O:23])[N:10](COC(=O)C(C)(C)C)[CH:11]=[N:12]2)=[CH:7][C:6]=1[O:24][CH3:25].N>CO>[OH:1][CH:2]([CH2:26][N:27]1[CH2:28][CH2:29][N:30]([CH3:33])[CH2:31][CH2:32]1)[CH2:3][O:4][C:5]1[CH:14]=[C:13]2[C:8]([C:9](=[O:23])[NH:10][CH:11]=[N:12]2)=[CH:7][C:6]=1[O:24][CH3:25]
Reactant: COc1cc2c(=O)n(COC(=O)C(C)(C)C)cnc2cc1OCC(O)CN1CCN(C)CC1
Agent: N
Solvent: CO
Product: COc1cc2c(=O)[nH]cnc2cc1OCC(O)CN1CCN(C)CC1
Yield: 104.9 %

Procedure:
A solution of 7-[2-hydroxy-3-(4-methylpiperazin-1-yl)propoxy]-6-methoxy-3-(pivaloyloxymethyl)-3,4-dihydroquinazolin-4-one (4.3 g, 9.3 mmol) in methanol saturated with ammonia (100 ml) was stirred for 2 days at ambient temperature. The volatiles were removed under vacuum and the residue was triturated with ether, filtered, washed with ether and dried under vacuum to give 7-(2-hydroxy-3-(4-methylpiperazin-1-yl)propoxy)-6-methoxyquinazolin-4-one (3.4 g, quant.).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([C:23]([CH3:26])([CH3:25])[CH3:24])[S:5][C:6]=1[C:7]([N:9]1[CH2:14][CH2:13][N:12]([CH2:15][CH2:16][N:17]([CH3:19])[CH3:18])[C:11](=[O:20])[C:10]1([CH3:22])[CH3:21])=[O:8].[Cl:27][C:28]1[C:29]([Cl:37])=[C:30]([N:34]=[C:35]=[O:36])[CH:31]=[CH:32][CH:33]=1.C1COCC1>C(OCC)(=O)C>[C:23]([C:4]1[S:5][C:6]([C:7]([N:9]2[CH2:14][CH2:13][N:12]([CH2:15][CH2:16][N:17]([CH3:18])[CH3:19])[C:11](=[O:20])[C:10]2([CH3:21])[CH3:22])=[O:8])=[C:2]([NH:1][C:35]([NH:34][C:30]2[CH:31]=[CH:32][CH:33]=[C:28]([Cl:27])[C:29]=2[Cl:37])=[O:36])[CH:3]=1)([CH3:26])([CH3:25])[CH3:24]
Reactant: CN(C)CCN1CCN(C(=O)c2sc(C(C)(C)C)cc2N)C(C)(C)C1=O
Reactant: O=C=Nc1cccc(Cl)c1Cl
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: CN(C)CCN1CCN(C(=O)c2sc(C(C)(C)C)cc2NC(=O)Nc2cccc(Cl)c2Cl)C(C)(C)C1=O
Temperature: 75 °C
Yield: 66.9 %

Procedure:
A mixture of 4-(4-amino-2-tert-butylthiophene-5-carbonyl)-1-(2-(dimethylamino)ethyl)-3,3-dimethylpiperazin-2-one (0.035 g, 0.092 mmol), dichlorophenyl isocyanate (0.019 g, 0.10 mmol), and THF (2 mL) was heated at 75° C. for 2 hours. The reaction mixture was diluted with ethyl acetate, washed with saturated sodium bicarbonate, dried, the solvent eliminated under vacuum and the crude product was purified by preparative thin layer chromatography (dichloromethane:methanol, 95:5) to afford 0.035 g of 1-(5-tert-butyl-2-(1-(2-(dimethylamino)ethyl)-3,3-dimethyl-2-oxopiperazine-4-carbonyl)thiophen-3-yl)-3-(2,3-dichlorophenyl)urea. 1H NMR (400 MHz, acetone-d6): δ (ppm) 9.57 (bs, 1H); 8.86 (bs, 1H); 8.17 (d, 1H); 7.65 (s, 1H); 7.30 (m, 2H); 3.90 (m, 2H); 3.60 (m, 2H); 3.50 (t, 2H); 2.43 (t, 2H); 2.20 (s, 6H); 1.70 (s, 6H); 1.40 (s, 9H).
Reaction SMILES: Cl[C:2]1[C:3]2[S:20][C:19]([NH2:21])=[N:18][C:4]=2[N:5]=[C:6]([S:8][CH2:9][C:10]2[CH:15]=[CH:14][CH:13]=[C:12]([F:16])[C:11]=2[F:17])[N:7]=1.Cl.[NH2:23][CH:24]([CH2:27][O:28][CH3:29])[CH2:25][OH:26]>>[NH2:21][C:19]1[S:20][C:3]2[C:2]([NH:23][CH:24]([CH2:27][O:28][CH3:29])[CH2:25][OH:26])=[N:7][C:6]([S:8][CH2:9][C:10]3[CH:15]=[CH:14][CH:13]=[C:12]([F:16])[C:11]=3[F:17])=[N:5][C:4]=2[N:18]=1
Reactant: Nc1nc2nc(SCc3cccc(F)c3F)nc(Cl)c2s1
Reactant: COCC(N)CO
Agent: Cl
Product: COCC(CO)Nc1nc(SCc2cccc(F)c2F)nc2nc(N)sc12

Procedure:
Prepared by the method of example 12 step a) using the product of example 4 step b) and the product of example 40 step a).
Reaction SMILES: [CH3:1][C:2]1([CH3:28])[O:7][C:6]2[CH:8]=[CH:9][C:10]([C@H:12]3[O:16][C:15](=[O:17])[N:14]([CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][O:24][CH2:25][CH2:26][OH:27])[CH2:13]3)=[CH:11][C:5]=2[CH2:4][O:3]1.[H-].[Na+].[Br:31][C:32]1[CH:39]=[CH:38][C:35]([CH2:36]Br)=[CH:34][CH:33]=1.P([O-])([O-])([O-])=O>CN(C=O)C.O>[Br:31][C:32]1[CH:39]=[CH:38][C:35]([CH2:36][O:27][CH2:26][CH2:25][O:24][CH2:23][CH2:22][CH2:21][CH2:20][CH2:19][CH2:18][N:14]2[CH2:13][C@@H:12]([C:10]3[CH:9]=[CH:8][C:6]4[O:7][C:2]([CH3:28])([CH3:1])[O:3][CH2:4][C:5]=4[CH:11]=3)[O:16][C:15]2=[O:17])=[CH:34][CH:33]=1
Reactant: CC1(C)OCc2cc([C@@H]3CN(CCCCCCOCCO)C(=O)O3)ccc2O1
Reactant: BrCc1ccc(Br)cc1
Agent: O=P([O-])([O-])[O-]
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CC1(C)OCc2cc([C@@H]3CN(CCCCCCOCCOCc4ccc(Br)cc4)C(=O)O3)ccc2O1
Reaction time: 0.25 h
Yield: 74.3 %

Procedure:
A solution of (5R)-5-(2,2-dimethyl-4H-1,3-benzodioxin-6-yl)-3-{6-[(2-hydroxyethyl)oxy]hexyl}-1,3-oxazolidin-2-one (2.00 g) in DMF (25 ml) under nitrogen was treated with sodium hydride (244 mg, 60% in oil) and the mixture was stirred at 200 for 15 min. 4-Bromobenzyl bromide (1.40 g) was added and the mixture was stirred at 200 for 18 h. Phosphate buffer solution (50 ml, pH6.5) and water (50 ml) were added and the mixture was extracted with EtOAc. The extract was washed with water, dried (Na2SO4) and the solvent evaporated in vacuo to give a residue. The residue was purified by chromatography on flash silica gel (40 mm diameter column). Elution with EtOAc-PE (1:1) gave the title compound (2.125 g). LCMS RT=3.77 min.
Reaction SMILES: C(C[CH2:4][CH2:5][C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=1[CH2:12][CH2:13][C:14](=[O:16])[CH3:15])#N.Cl.[C:18]([OH:21])(=[O:20])[CH3:19]>>[C:18]([CH2:19][CH2:4][CH2:5][C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=1[CH2:12][CH2:13][C:14](=[O:16])[CH3:15])([OH:21])=[O:20]
Reactant: CC(=O)CCc1ccccc1CCCC#N
Reactant: CC(=O)O
Agent: Cl
Product: CC(=O)CCc1ccccc1CCCC(=O)O

Procedure:
A solution of 50 g (0.23 mol) of 4-[2-(3-cyanopropyl)phenyl]-2-butanone, 8 in 125 ml glacial acetic acid and 125 ml concentrated HCl was refluxed overnight. The solution was evaporated and the residue diluted with H2O. The precipitate was recrystallized from benzene-petroleum either to give 42.5 g of the keto acid 9, mp 59°-61° C.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]([CH3:10])=[C:7]([CH:9]=1)[NH2:8].C(N(CC)CC)C.[Cl:18][CH2:19][C:20](Cl)=[O:21].Cl>ClCCl>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]([CH3:10])=[C:7]([NH:8][C:20](=[O:21])[CH2:19][Cl:18])[CH:9]=1
Reactant: COc1ccc(C)c(N)c1
Reactant: O=C(Cl)CCl
Agent: Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COc1ccc(C)c(NC(=O)CCl)c1
Reaction time: 0.75 h

Procedure:
To a solution of 5-methoxy-2-methylaniline (7.62 g) and triethylamine (15.5 ml) in dichloromethane (150 ml) at 0-5° C. was added chloroacetyl chloride (5.0 ml) dropwise and the ice bath removed. The resulting reaction mixture was stirred for 45 min before being poured into dil HCl and extracted with dichloromethane. Organic extracts were combined, washed with water, dried (Na2SO4) and concentrated to give a brown solid that was triturated with diethyl ether to leave the sub-title compound as a beige solid (5.7 g).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([NH2:8])=[C:4]([C:9]2[NH:13][N:12]=[N:11][N:10]=2)[CH:3]=1.[Cl:14][C:15]1[CH:20]=[CH:19][C:18]([N:21]=[C:22]=[O:23])=[CH:17][C:16]=1[C:24]([F:27])([F:26])[F:25]>C1(C)C=CC=CC=1>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:22]([NH:21][C:18]2[CH:19]=[CH:20][C:15]([Cl:14])=[C:16]([C:24]([F:26])([F:25])[F:27])[CH:17]=2)=[O:23])=[C:4]([C:9]2[NH:13][N:12]=[N:11][N:10]=2)[CH:3]=1
Reactant: O=C=Nc1ccc(Cl)c(C(F)(F)F)c1
Reactant: Nc1ccc(Cl)cc1-c1nnn[nH]1
Solvent: Cc1ccccc1
Product: O=C(Nc1ccc(Cl)c(C(F)(F)F)c1)Nc1ccc(Cl)cc1-c1nnn[nH]1
Yield: 79.7 %

Procedure:
4-Chloro-2-(1H-tetrazol-5-yl)-phenylamine (500 mg) dissolved in toluene (15 ml) was treated with 4-chloro-3-trifluoromethylphenylisocyanate (600 mg) and stirred for a week. The precipitated product was filtered and then acid/base extracted and re-precipitated in aq. acid in a manner analogous to that described for 1-[4-Chloro-2-(1H-tetrazol-5-yl)-phenyl]-3-(3,5-dichloro-phenyl)-urea (Compound 12) to give 1-[4-Chloro-2-(IH-tetrazol-5-yl)-phenyl]-3-(4-chloro-3-trifluoromethyl-phenyl)-urea as a white solid (850 mg). Mp.=245-247° C.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:4]([NH:11][C:12]([NH:14]C(=O)OCC)=S)=[N:5][C:6]([O:9][CH3:10])=[CH:7][CH:8]=1.Cl.NO.C([N:26](C(C)C)CC)(C)C>C(O)C>[NH2:26][C:12]1[N:11]=[C:4]2[C:3]([O:2][CH3:1])=[CH:8][CH:7]=[C:6]([O:9][CH3:10])[N:5]2[N:14]=1
Reactant: CCN(C(C)C)C(C)C
Reactant: CCOC(=O)NC(=S)Nc1nc(OC)ccc1OC
Agent: Cl
Agent: NO
Solvent: CCO
Product: COc1ccc(OC)n2nc(N)nc12
Reaction time: 0.25 h
Yield: 61.8 %

Procedure:
A mixture of 58.4 g (0.21 mole) of ethyl [(3,6-dimethoxypyridin-2-yl)amino]carbonothioylcarbamate, 70 g (1 mole) of hydroxylamine hydrochloride and 105 mL (0.6 mole) of diisopropylethylamine in 1 liter of ethanol was heated to reflux for 12 hr. After cooling, the resulting solution was evaporated to dryness under vacuum. Water (250 ml) and diethyl ether (100 ml) were added to the residue and the mixture was stirred for 15 min. The product was collected by filtration and dried under a vacuum at room temperature to give 25.2 g of 2-amino-5,8-dimethoxy[1,2,4]triazolo[1,5-a]pyridine. mp 223-234° C. 1H NMR (DMSO-d6): δ 6.9 (d, 1H, j=8.7) 6.2 (d, 1H, j=8.4); 5.9 (s, 2H); 4.0 (s, 3H); 3.8 (s, 3H).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([Cl:22])[CH:5]=[C:6]2[C:14]=1[NH:13][C:12]1[CH:11]=[N:10][CH:9]=[C:8]([NH:15][C:16](=[O:21])[C:17]([F:20])([F:19])[F:18])[C:7]2=1.[CH3:23][C:24]1[N:32]=[CH:31][CH:30]=[CH:29][C:25]=1[C:26](O)=[O:27].CCN=C=NCCCN(C)C>N1C=CC=CC=1>[Cl:22][C:4]1[CH:5]=[C:6]2[C:14](=[C:2]([NH:1][C:26](=[O:27])[C:25]3[CH:29]=[CH:30][CH:31]=[N:32][C:24]=3[CH3:23])[CH:3]=1)[NH:13][C:12]1[CH:11]=[N:10][CH:9]=[C:8]([NH:15][C:16](=[O:21])[C:17]([F:20])([F:19])[F:18])[C:7]2=1
Reactant: Cc1ncccc1C(=O)O
Reactant: Nc1cc(Cl)cc2c1[nH]c1cncc(NC(=O)C(F)(F)F)c12
Agent: CCN=C=NCCCN(C)C
Solvent: c1ccncc1
Product: Cc1ncccc1C(=O)Nc1cc(Cl)cc2c1[nH]c1cncc(NC(=O)C(F)(F)F)c12
Temperature: 25 °C
Reaction time: 2 h
Yield: 33.4 %

Procedure:
N-(8-amino-6-chloro-9H-β-carbolin-4-yl)-2,2,2-trifluoro-acetamide (90 mg, 0.274 mmol, 1 equiv.) and 2-methylnicotinic acid (45 mg, 0.329 mmol, 1.2 equiv.) were dissolved in 1.5 ml of anhydrous pyridine under N2. EDCI (84 mg, 0.438 mmol, 1.6 equiv.) was added in one portion and the reaction mixture was stirred at room temperature for 2 hours. The reaction was quenched with water and the resulting dark solids captured by filtration. These solids were titurated in a 3:1 methanol—DMSO solution to give N-[6-chloro-4-(2,2,2-trifluoro-acetylamino)-9H-β-carbolin-8-yl]-2-methyl-nicotinamide as light yellow solids (41 mg, 3%). 1H-NMR (300 MHz, DMSO-d6): δ 11.94 (br, 1H), 11.78 (s, 1H), 10.61 (s, 1), 9.00 (s, 1), 8.64 (d, 1), 8.38 (s, 1H), 8.13 (d, 1), 8.01 (s, 1H), 7.73 (s, 1H), 7.45 (m, 1H), 2.68 (s, 3H). Formic acid standard conditions. DAD RT=1.98 min. M+H=448.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6](Cl)[CH:5]=[C:4]([CH3:9])[N:3]=1.[F:10][C:11]([F:22])([F:21])[C:12]1[CH:13]=[C:14](B(O)O)[CH:15]=[CH:16][CH:17]=1>>[CH3:9][C:4]1[CH:5]=[C:6]([C:16]2[CH:15]=[CH:14][CH:13]=[C:12]([C:11]([F:22])([F:21])[F:10])[CH:17]=2)[N:7]=[C:2]([NH2:1])[N:3]=1
Reactant: Cc1cc(Cl)nc(N)n1
Reactant: OB(O)c1cccc(C(F)(F)F)c1
Product: Cc1cc(-c2cccc(C(F)(F)F)c2)nc(N)n1

Procedure:
The title compound is synthesized according to general procedure GP4 starting from 2.0 g (14 mmol) 2-amino-4-chloro-6-methylpyrimidine and 3.4 g (18 mmol) 3-trifluoromethyl-phenyl boronic acid. Yield after extraction: 5.0 g (99%).
Reaction SMILES: [Mg].[C:2]([O:8][C:9]([CH3:12])([CH3:11])[CH3:10])(=[O:7])[CH2:3][C:4]([CH3:6])=[O:5].[C:13](Cl)(=[O:20])[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1.S(=O)(=O)(O)O>C(O)C.ClC(Cl)(Cl)Cl>[C:13]([CH:3]([C:4]([CH3:6])=[O:5])[C:2]([O:8][C:9]([CH3:10])([CH3:12])[CH3:11])=[O:7])(=[O:20])[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1
Reactant: CC(=O)CC(=O)OC(C)(C)C
Reactant: O=C(Cl)c1ccccc1
Agent: O=S(=O)(O)O
Agent: [Mg]
Solvent: ClC(Cl)(Cl)Cl
Solvent: CCO
Product: CC(=O)C(C(=O)OC(C)(C)C)C(=O)c1ccccc1
Temperature: 0 °C
Reaction time: 4 h
Yield: 73.3 %

Procedure:
5 ml of tetrachloromethane were added to 24.3 g (1 mol) of magnesium turnings in 50 ml of dry ethanol under nitrogen and in the absence of moisture. After the beginning of gas evolution, a solution of 177.7 g (1 mol) of tert-butyl acetoacetate in 100 ml of dry ethanol was slowly added dropwise, the reaction mixture being kept at reflux temperature. Stirring was carried out for a further 4 hours at this temperature, after which the mixture was cooled. 78.5 g (1 mol) of benzoyl chloride was slowly added dropwise at 10° C. Stirring was continued for a further 4 hours at room temperature and hydrolysis was then effected with a mixture of 450 ml of ice water and 25 ml of concentrated sulfuric acid. The organic phase was separated off, dried, and evaporated down under reduced pressure. 192.3 g of >96% pure tert-butyl 2-benzoylacetoacetate were obtained.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]2[C:11](=[CH:12][CH:13]=1)[N:10]([CH2:14][CH2:15][CH2:16][N:17]1[CH2:21][CH2:20][CH2:19][CH2:18]1)[C:9](=[O:22])[CH2:8][CH2:7]2)([O-])=O.O.NN>CO.[Ni]>[NH2:1][C:4]1[CH:5]=[C:6]2[C:11](=[CH:12][CH:13]=1)[N:10]([CH2:14][CH2:15][CH2:16][N:17]1[CH2:18][CH2:19][CH2:20][CH2:21]1)[C:9](=[O:22])[CH2:8][CH2:7]2
Reactant: O=C1CCc2cc([N+](=O)[O-])ccc2N1CCCN1CCCC1
Agent: [Ni]
Agent: NN
Solvent: CO
Solvent: O
Product: Nc1ccc2c(c1)CCC(=O)N2CCCN1CCCC1
Temperature: 25 °C

Procedure:
6-nitro-1-(3-(pyrrolidin-1-yl)propyl)-3,4-dihydroquinolin-2(1H)-one (89 mg, 0.293 mmol) in dry methanol (5 mL) was treated with Ra—Ni (˜0.05 g) followed by hydrazine hydrate (92 uL, 2.95 mmol) at room temperature and the resulting mixture was refluxed for 30 minutes. The reaction was cooled to room temperature, filtered through a celite bed, washed with methanol (2×10 mL). The combined methanol layer was evaporated and crude was purified by column chromatography (2 M NH3 in MeOH:CH2Cl2, 2.5:97.5). Yield: 58 mg of yellow oil (73%). 1H NMR (CDCl3) δ: 6.86 (d, J=8.4 Hz, 1H), 6.55 (dd, J=2.7, 8.4 Hz, 1H), 6.52 (d, J=2.1 Hz, 1H), 3.94 (m, 2H), 2.81-2.76 (m, 2H), 2.61-2.56 (m, 2H), 2.53-2.49 (m, 6H), 1.87-1.82 (m, 2H), 1.79-1.75 (m, 4H). MS (ESI): 274.2 (M+1).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([C:8](=[O:10])[CH3:9])[CH:5]=[N:6][CH:7]=1.[Br:11]Br>C(Cl)(Cl)Cl.C(O)(=O)C.Br>[BrH:1].[Br:1][C:2]1[CH:3]=[C:4]([C:8](=[O:10])[CH2:9][Br:11])[CH:5]=[N:6][CH:7]=1
Reactant: CC(=O)c1cncc(Br)c1
Reactant: BrBr
Agent: Br
Solvent: ClC(Cl)Cl
Solvent: CC(=O)O
Product: O=C(CBr)c1cncc(Br)c1
Temperature: 25 °C

Procedure:
4 g (0.02 mol) of 5-bromo-3-acetyl-pyridine are dissolved in 50 ml of chloroform, 5 drops of glacial acetic acid/hydrobromic acid (35%) are added and the mixture is heated to boiling. To this boiling solution, 3.2 g (0.02 mol) of bromine in 30 ml of chloroform are added dropwise over a period of 5 hours with stirring. After cooling to ambient temperature the yellow solid product is suction filtered.
Reaction SMILES: [Br:1][C:2]1[C:3]([NH2:18])=[N:4][CH:5]=[C:6]([C:8]2[CH:13]=[CH:12][C:11]([C:14]([F:17])([F:16])[F:15])=[CH:10][CH:9]=2)[CH:7]=1.C(=O)(O)[O-].[Na+].Cl[CH2:25][CH:26]=O>CCO>[Br:1][C:2]1[C:3]2[N:4]([CH:25]=[CH:26][N:18]=2)[CH:5]=[C:6]([C:8]2[CH:9]=[CH:10][C:11]([C:14]([F:17])([F:15])[F:16])=[CH:12][CH:13]=2)[CH:7]=1
Reactant: O=CCCl
Reactant: Nc1ncc(-c2ccc(C(F)(F)F)cc2)cc1Br
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCO
Product: FC(F)(F)c1ccc(-c2cc(Br)c3nccn3c2)cc1
Temperature: 23 °C
Yield: 62.3 %

Procedure:
To a mixture of 3-bromo-5-(4-trifluoromethyl-phenyl)-pyridin-2-ylamine (example C.25 step 2) (4.96 g, 16 mmol) and sodium bicarbonate (5.256 g, 63 mmol) in EtOH (20 mL) at 50° C. was dropwise added chloroacetaldehyde (50% in water, 3.66 mL, 31 mmol) within 2 h. Cooled to 23° C. and evaporated all volatiles The residue was purified by silica gel column chromatography with dichloromethane/methanol followed by trituration with heptane and very little ether to give the title compound as a white solid (3.4 g, 63%). MS (ISP) 340.9 [(M+H)+], 343.1 [(M+2+H)+].
Reaction SMILES: O1CCO[CH:2]1[CH2:6][CH2:7][CH2:8][CH2:9][N:10]1[CH2:15][CH2:14][CH:13]([C:16]2[CH:17]=[C:18]([NH:22][C:23](=[O:27])[CH:24]([CH3:26])[CH3:25])[CH:19]=[CH:20][CH:21]=2)[CH2:12][CH2:11]1.Cl.[C:29]1([N:35]([C:37]2[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=2)N)[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1>>[CH3:25][CH:24]([CH3:26])[C:23]([NH:22][C:18]1[CH:19]=[CH:20][CH:21]=[C:16]([CH:13]2[CH2:12][CH2:11][N:10]([CH2:9][CH2:8][CH2:7][C:6]3[C:30]4[C:29](=[CH:34][CH:33]=[CH:32][CH:31]=4)[N:35]([C:37]4[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=4)[CH:2]=3)[CH2:15][CH2:14]2)[CH:17]=1)=[O:27]
Reactant: CC(C)C(=O)Nc1cccc(C2CCN(CCCCC3OCCO3)CC2)c1
Reactant: NN(c1ccccc1)c1ccccc1
Agent: Cl
Product: CC(C)C(=O)Nc1cccc(C2CCN(CCCc3cn(-c4ccccc4)c4ccccc34)CC2)c1

Procedure:
Prepared by Procedure H and Scheme S using N-(3-{1-[4-(1,3-dioxolan-2-yl)butyl]-4-piperidinyl}phenyl)-2-methylpropanamide and 1,1-diphenylhydrazine hydrochloride: ESMS m/e: 480.2 (M+H)+.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([C:8]([N:10]2[CH2:15][CH2:14][N:13]([C:16]3[C:21]([CH:22]4[CH2:24][CH2:23]4)=[CH:20][C:19]([CH:25]4[CH2:27][CH2:26]4)=[CH:18][N:17]=3)[CH2:12][CH2:11]2)=[O:9])=[C:4]([S:28]([CH3:31])(=[O:30])=[O:29])[CH:3]=1.[CH3:32][C:33]1([CH3:39])[CH2:37][O:36][C:35](=[O:38])[NH:34]1>>[CH:22]1([C:21]2[C:16]([N:13]3[CH2:14][CH2:15][N:10]([C:8]([C:5]4[CH:6]=[CH:7][C:2]([N:34]5[C:33]([CH3:39])([CH3:32])[CH2:37][O:36][C:35]5=[O:38])=[CH:3][C:4]=4[S:28]([CH3:31])(=[O:30])=[O:29])=[O:9])[CH2:11][CH2:12]3)=[N:17][CH:18]=[C:19]([CH:25]3[CH2:27][CH2:26]3)[CH:20]=2)[CH2:24][CH2:23]1
Reactant: CS(=O)(=O)c1cc(Br)ccc1C(=O)N1CCN(c2ncc(C3CC3)cc2C2CC2)CC1
Reactant: CC1(C)COC(=O)N1
Product: CC1(C)COC(=O)N1c1ccc(C(=O)N2CCN(c3ncc(C4CC4)cc3C3CC3)CC2)c(S(C)(=O)=O)c1
Yield: 17.3 %

Procedure:
By reaction and treatment in the same manner as in Example 111 and using (4-bromo-2-methanesulfonylphenyl)[4-(3,5-dicyclopropylpyridin-2-yl)piperazin-1-yl]methanone (463 mg) described in Preparation Example 89 and 4,4-dimethyloxazolidin-2-one (106 mg), the title compound (85.6 mg) was obtained.
Reaction SMILES: C[O:2][C:3](=O)[C:4]1[CH:9]=[CH:8][C:7]([NH:10][S:11]([C:14]2[CH:19]=[CH:18][C:17]([C:20]([CH3:23])([CH3:22])[CH3:21])=[CH:16][CH:15]=2)(=[O:13])=[O:12])=[C:6]([C:24]2[N:28]([CH3:29])[C:27]([CH2:30][CH3:31])=[N:26][N:25]=2)[CH:5]=1.[NH3:33]>O>[C:20]([C:17]1[CH:16]=[CH:15][C:14]([S:11]([NH:10][C:7]2[CH:8]=[CH:9][C:4]([C:3]([NH2:33])=[O:2])=[CH:5][C:6]=2[C:24]2[N:28]([CH3:29])[C:27]([CH2:30][CH3:31])=[N:26][N:25]=2)(=[O:13])=[O:12])=[CH:19][CH:18]=1)([CH3:22])([CH3:23])[CH3:21]
Reactant: CCc1nnc(-c2cc(C(=O)OC)ccc2NS(=O)(=O)c2ccc(C(C)(C)C)cc2)n1C
Reactant: N
Solvent: O
Product: CCc1nnc(-c2cc(C(N)=O)ccc2NS(=O)(=O)c2ccc(C(C)(C)C)cc2)n1C
Temperature: 60 °C
Reaction time: 8 h

Procedure:
A 10 mL scintillation vial was charged with 4-(4-tert-butyl-benzenesulfonylamino)-3-(5-ethyl-4-methyl-4H-[1,2,4]triazol-3-yl)-benzoic acid methyl ester (20 mg, 0.044 mmol) and 30% NH3 in H2O (1.5 mL). The reaction was heated to 60° C. and stirred overnight. The following day, the volatiles were removed in vacuo to about 200 μL at which point the solution was purified by preparative TLC to afford 4-(4-tert-butyl-benzenesulfonylamino)-3-(5-ethyl-4-methyl-4H-[1,2,4]triazol-3-yl)-benzamide as a colorless oil: MS (ES) M+H expected 442.2, found 442.4.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:25])[CH2:4][C:5]1[CH:6]=[C:7]([C:13]2[CH:18]=[CH:17][C:16]([C:19]([F:22])([F:21])[F:20])=[CH:15][C:14]=2[CH:23]=O)[C:8]([O:11][CH3:12])=[CH:9][CH:10]=1.[CH2:26]1[C:34]2[C:29](=[CH:30][CH:31]=[CH:32][CH:33]=2)[C@H:28]([NH2:35])[C@@H:27]1[OH:36]>>[CH3:1][O:2][C:3](=[O:25])[CH2:4][C:5]1[CH:6]=[C:7]([C:13]2[CH:18]=[CH:17][C:16]([C:19]([F:21])([F:22])[F:20])=[CH:15][C:14]=2[CH2:23][NH:35][C@H:28]2[C:29]3[C:34](=[CH:33][CH:32]=[CH:31][CH:30]=3)[CH2:26][C@H:27]2[OH:36])[C:8]([O:11][CH3:12])=[CH:9][CH:10]=1
Reactant: COC(=O)Cc1ccc(OC)c(-c2ccc(C(F)(F)F)cc2C=O)c1
Reactant: N[C@H]1c2ccccc2C[C@H]1O
Product: COC(=O)Cc1ccc(OC)c(-c2ccc(C(F)(F)F)cc2CN[C@H]2c3ccccc3C[C@H]2O)c1

Procedure:
Prepared according to the procedure described in Example 25, Step 4, using the following starting materials: (2′-formyl-6-methoxy-4′-trifluoromethyl-biphenyl-3-yl)-acetic acid methyl ester and (1S,2R)-(−)-cis-1-amino-2-indanol.
Reaction SMILES: [Cl-].[Al+3].[Cl-].[Cl-].C[O:6][C:7]1[C:8](=[CH:12][CH:13]=[CH:14][CH:15]=1)[C:9]([O-:11])=[O:10].[C:16](Cl)(=[O:22])[CH2:17][CH2:18][CH2:19][CH2:20][CH3:21]>C(=S)=S>[C:16]([C:13]1[CH:12]=[C:8]([C:9]([OH:11])=[O:10])[C:7]([OH:6])=[CH:15][CH:14]=1)(=[O:22])[CH2:17][CH2:18][CH2:19][CH2:20][CH3:21]
Reactant: CCCCCC(=O)Cl
Reactant: COc1ccccc1C(=O)[O-]
Agent: [Al+3]
Agent: [Cl-]
Solvent: S=C=S
Product: CCCCCC(=O)c1ccc(O)c(C(=O)O)c1
Temperature: 2.5 °C
Reaction time: 24 h
Yield: 77 %

Procedure:
A one-liter three-neck flask is fitted with a 250 ml dropping funnel, a mechanical overhead stirrer, and a condenser with a drying tube. A mixture of anhydrous aluminum chloride (120 g., 0.9 moles) and carbon disulfide (250 ml) is placed in the flask and cooled to 0-5 degrees C. with an ice bath. A solution of methylsalicylate (45.6 g., 0.3 mole) and n-hexanoyl chloride (81.4 g., 0.6 mole) in carbon disulfide (50 ml) is then added through the dropping funnel over the course of three hours while maintaining the temperature of the reaction mixture below 10 degrees C. The reaction mixture is then allowed to warm to room temperature and stirring is continued for 24 hours. The mixture is then poured slowly onto cracked ice (500 g.) and the resulting slurry is stirred until the ice melts. The slurry is then extracted with four 50 ml portions of diethyl ether and the combined ether extracts are washed with water and dried over anhydrous sodium sulfate. Any remaining liquid is removed by evaporation in a vacuum. The resulting product is found to be n-hexanoyl methyl salicylate in a yield of 77% with a melting point of 48°-49° C.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([C:8]([C:10]2[C:15]([NH:16][S:17]([C:20]3[CH:25]=[CH:24][C:23]([C:26]([CH3:29])([CH3:28])[CH3:27])=[CH:22][CH:21]=3)(=[O:19])=[O:18])=[CH:14][C:13]([Cl:30])=[CH:12][N:11]=2)=[O:9])[CH:5]=[CH:4][CH:3]=1.[C:31](Cl)(=[O:33])[CH3:32]>N1C=CC=CC=1.O1CCOCC1>[C:26]([C:23]1[CH:22]=[CH:21][C:20]([S:17]([NH:16][C:15]2[C:10]([C:8]([C:6]3[N:7]=[C:2]([NH:1][C:31](=[O:33])[CH3:32])[CH:3]=[CH:4][CH:5]=3)=[O:9])=[N:11][CH:12]=[C:13]([Cl:30])[CH:14]=2)(=[O:18])=[O:19])=[CH:25][CH:24]=1)([CH3:27])([CH3:29])[CH3:28]
Reactant: CC(=O)Cl
Reactant: CC(C)(C)c1ccc(S(=O)(=O)Nc2cc(Cl)cnc2C(=O)c2cccc(N)n2)cc1
Solvent: C1COCCO1
Solvent: c1ccncc1
Product: CC(=O)Nc1cccc(C(=O)c2ncc(Cl)cc2NS(=O)(=O)c2ccc(C(C)(C)C)cc2)n1
Temperature: 60 °C
Reaction time: 2 h

Procedure:
N-[2-(6-amino-pyridine-2-carbonyl)-5-chloro-pyridin-3-yl]-4-tert-butyl-benzenesulfonamide (52 mg, 0.1 mmol) in pyridine/1,4-dioxane (1:1, 4 mL) was treated with acetyl chloride (100 mg) and then stirred at 60° C. for 2 h. After evaporation of solvent under reduced pressure, to the mixture was added THF (5 mL), followed by NaOH (2 N, 2 mL) and stirred at room temperature for another 2 h. The mixture was diluted with EtOAc and the organics were washed with 1 N HCl, NaHCO3 (saturated), and brine; dried over MgSO4, concentrated under reduced pressure, and purified through automated normal-phase chromatography to afford the title compound: 1H NMR (400 MHz, CDCl3) δ 10.80 (s, 1H), 8.37 (d, 1H), 8.22 (m, 2H), 8.14 (s, 1H), 7.80 (m, 3H), 7.46 (m, 3H), 2.20 (s, 3H), 1.23 (s, 9H); MS (ES) (M+H)+ expected 487.1. found 487.1.