Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C[O:2][C:3]([C:5]12[CH2:14][CH:9]3[CH2:10][CH:11]([CH2:13][CH:7]([CH2:8]3)[O:6]1)[CH2:12]2)=[O:4].[OH-].[Na+].Cl>CO.O>[C:5]12([C:3]([OH:4])=[O:2])[CH2:14][CH:9]3[CH2:10][CH:11]([CH2:13][CH:7]([CH2:8]3)[O:6]1)[CH2:12]2
Reactant: COC(=O)C12CC3CC(CC(C3)O1)C2
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: O=C(O)C12CC3CC(CC(C3)O1)C2
Temperature: 25 °C
Reaction time: 3 h
Yield: 83.6 %

Procedure:
To a solution of Example 54A (2.5 g, 12.6 mmol) in methanol/water (1:1, 100 mL), 5 N aqueous NaOH (3.8 mL, 19 mmol) was added. The mixture was stirred at room temperature for 3 hours and then extracted with dichloromethane to remove un-reacted starting material. The aqueous layer was acidified (pH˜2) with 6 N aqueous HCl and then extracted with dichloromethane. The combined acidic extracts were dried (Na2SO4), filtered, and concentrated under reduced pressure to afford 1.92 g of the title compound. MS (ESI+) m/z 183 (M+H)+
Reaction SMILES: [NH:1]([C:8]1[C:13]([Br:14])=[CH:12][N:11]=[C:10]([NH:15][C:16]2[CH:21]=[CH:20][C:19](I)=[CH:18][CH:17]=2)[N:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:23][N:24]([CH2:26][C:27]#[CH:28])[CH3:25]>N1CCCC1.C(Cl)Cl>[NH:1]([C:8]1[C:13]([Br:14])=[CH:12][N:11]=[C:10]([NH:15][C:16]2[CH:21]=[CH:20][C:19]([C:28]#[C:27][CH2:26][N:24]([CH3:25])[CH3:23])=[CH:18][CH:17]=2)[N:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: C#CCN(C)C
Reactant: Brc1cnc(Nc2ccc(I)cc2)nc1Nc1ccccc1
Solvent: C1CCNC1
Solvent: ClCCl
Product: CN(C)CC#Cc1ccc(Nc2ncc(Br)c(Nc3ccccc3)n2)cc1
Temperature: 80 °C
Yield: 17.8 %

Procedure:
A solution of 4-anilino-5-bromo-2-(4-iodoanilino)pyrimidine (Method 12; 200 mg, 0.40 mmol), N,N-dimethylpropargylamine (0.09 ml, 0.85 mmol) and tetrakis (triphenylphosphine)palladium (0) (25 mg, 0.02 mmol) in pyrrolidine (3 ml) was stirred for 60 hours and then heated at 80° C. for 2 hours. The mixture was diluted with DCM (10 ml) and silica (2 g) was added. Volatile material was removed by evaporation and the residue was loaded onto a Varian Mega Bond Elut column. Elution with 0–10% 2.0 M methanolic ammonia solution in DCM gave the product (30 mg, 17%). NMR: 2.2 (s, 6H), 3.4 (s, 2H), 7.2 (m, 3H), 7.4 (m, 2H), 7.6 (m, 4H), 8.2 (s, 1H), 8.6 (s, 1H), 9.5 (s, 1H); MS (MH+): 422.3, 424.3.
Reaction SMILES: [Br:1][C:2]1[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[C:4]([CH2:10][C:11]#[N:12])[CH:3]=1.ClC(Cl)C(O)=O.[BrH:19]>>[Br:19][C:6]1[C:5]2[C:4](=[CH:3][C:2]([Br:1])=[CH:9][CH:8]=2)[CH:10]=[C:11]([NH2:12])[N:7]=1
Reactant: N#CCc1cc(Br)ccc1C#N
Reactant: Br
Agent: O=C(O)C(Cl)Cl
Product: Nc1cc2cc(Br)ccc2c(Br)n1
Temperature: 0 °C
Reaction time: 0.33 h

Procedure:
4-Bromo-2-(cyanomethyl)benzonitrile (75 g, 339 mmol) was added to 2,2-dichloroacetic acid (150 mL, 339 mmol). The resulting solution was cooled to 0° C. in an ice-water bath. HBr (27.5 g, 339 mmol) was bubbled through the cold solution until a yellow precipitate crashed out of solution resulting in a yellow slurry. HBr was bubbled through the slurry for an additional 5 minutes. The solution was allowed to warm to room temperature over 1 hour. The slurry was then re-cooled to 0° C. in an ice-water bath and diethyl ether (200 mL) was added. The mixture was stirred for 20 minutes at 5° C. The product was recovered as a yellow solid by filtration (42 g, 41%). LCMS (API-ES) m/z: 303 (M+H+).
Reaction SMILES: [C:1]([NH:4][CH:5]1[CH2:14][CH2:13][C:12]2[C:7](=[C:8]([NH2:17])[CH:9]=[C:10]([F:16])[C:11]=2[CH3:15])[C:6]1=O)(=[O:3])[CH3:2].[CH2:19]([C@:21]1([OH:37])[C:33]2[CH:32]=[C:31]3[N:27]([CH2:28][CH2:29][C:30]3=O)[C:26](=[O:35])[C:25]=2[CH2:24][O:23][C:22]1=[O:36])[CH3:20].C1(C)C=CC(S([O-])(=O)=O)=CC=1.[NH+]1C=CC=CC=1>C1(C)C=CC=CC=1>[C:1]([NH:4][CH:5]1[C:6]2=[C:29]3[CH2:28][N:27]4[C:31](=[CH:32][C:33]5[C@:21]([CH2:19][CH3:20])([OH:37])[C:22](=[O:36])[O:23][CH2:24][C:25]=5[C:26]4=[O:35])[C:30]3=[N:17][C:8]3[CH:9]=[C:10]([F:16])[C:11]([CH3:15])=[C:12]([C:7]=32)[CH2:13][CH2:14]1)(=[O:3])[CH3:2]
Reactant: CC(=O)NC1CCc2c(C)c(F)cc(N)c2C1=O
Reactant: CC[C@@]1(O)C(=O)OCc2c1cc1n(c2=O)CCC1=O
Agent: Cc1ccc(S(=O)(=O)[O-])cc1
Agent: c1cc[nH+]cc1
Solvent: Cc1ccccc1
Product: CC[C@@]1(O)C(=O)OCc2c1cc1n(c2=O)Cc2c-1nc1cc(F)c(C)c3c1c2C(NC(C)=O)CC3
Temperature: 120 °C
Yield: 59.1 %

Procedure:
To 150 mg of 2-acetylamino-8-amino-6-fluoro-5-methyl-1-tetralone and 158 mg of (4S)-4-ethyl-7,8-dihydro-4-hydroxy-1H-pyrano[3,4-f]indolizine-3,6,10(4H)-trione, 30 ml of toluene and then 150 mg of pyridinium p-toluenesulfonate were added, followed by heating at an external temperature of 120° C. under reflux for 28 hours. After completion of the reaction, the solvent was removed under reduced pressure. Acetone was added to the residue and crystals so precipitated were collected by filtration, whereby 169 mg of the title compound were obtained. Melting point: 225-235° C. (decomposed)
Reaction SMILES: [Br:1][C:2]1[C:8]([CH3:9])=[CH:7][C:5]([NH2:6])=[C:4]([F:10])[CH:3]=1.N1C=CC=CC=1.[CH3:17][S:18](Cl)(=[O:20])=[O:19]>C(Cl)Cl>[Br:1][C:2]1[C:8]([CH3:9])=[CH:7][C:5]([NH:6][S:18]([CH3:17])(=[O:20])=[O:19])=[C:4]([F:10])[CH:3]=1
Reactant: CS(=O)(=O)Cl
Reactant: Cc1cc(N)c(F)cc1Br
Solvent: ClCCl
Solvent: c1ccncc1
Product: Cc1cc(NS(C)(=O)=O)c(F)cc1Br
Temperature: 25 °C
Reaction time: 2 h
Yield: 99.2 %

Procedure:
To a solution of 4-bromo-2-fluoro-5-methylaniline (2.04 g, 10.0 mmol) in anhydrous CH2Cl2 (20 ml) and pyridine (3.23 ml, 40.0 mmol) was added methanesulfonyl chloride (0.86 ml, 11.0 mmol) and the resulting mixture was stirred at room temperature for 2 h. Solvent was removed in vacuo, and the residue was partitioned between EtOAc and 1M aq. HCl. The organic layer was washed with saturated aqueous NaHCO3, brine and then dried over Na2SO4. The drying agent was filtered off, and the filtrate was concentrated to give the title compound as a solid (2.80 g, 99%).
Reaction SMILES: [ClH:1].[N:2]1[CH:7]=[CH:6][C:5]([S:8][C:9]2[CH:16]=[CH:15][C:12]([CH:13]=O)=[CH:11][CH:10]=2)=[CH:4][CH:3]=1.[C:17]([O-:21])(=[O:20])[CH2:18][CH3:19].[Na+]>C(OC(=O)CC)(=O)CC>[ClH:1].[CH3:19][C:18](=[CH:13][C:12]1[CH:15]=[CH:16][C:9]([S:8][C:5]2[CH:6]=[CH:7][N:2]=[CH:3][CH:4]=2)=[CH:10][CH:11]=1)[C:17]([OH:21])=[O:20]
Reactant: CCC(=O)[O-]
Reactant: O=Cc1ccc(Sc2ccncc2)cc1
Agent: CCC(=O)OC(=O)CC
Agent: Cl
Agent: [Na+]
Product: CC(=Cc1ccc(Sc2ccncc2)cc1)C(=O)O
Reaction time: 5 h
Yield: 55.6 %

Procedure:
A mixture of 5 g of 4-(4-pyridylthio)benzaldehyde hydrochloride, 4 g of sodium propionate and 50 ml of propionic anhydride was stirred for 5 hours at a temperature of 150° to 155° C. and concentrated under reduced pressure. Water was added to the mixture which was then heated to precipitate crystals. The resulting crystals were separated by filtration, washed with water and converted into the corresponding hydrochloride by treatment with methanolic hydrogen chloride. The resulting hydrochloride was recrystallized from a mixture of methanol and diethyl ether to obtain 3.4 g (56% yield) of 2-methyl-3-[4-(4-pyridylthio)phenyl]propenoic acid hydrochloride as colorless needles having a melting point of 213°-218° C.
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([N:10]2[CH2:15][CH2:14][NH:13][CH2:12][CH2:11]2)=[CH:6][CH:5]=1)([O-:3])=[O:2].C(N(C(C)C)CC)(C)C.[C:25](Cl)(=[O:27])[CH3:26]>ClCCl>[N+:1]([C:4]1[CH:5]=[CH:6][C:7]([N:10]2[CH2:15][CH2:14][N:13]([C:25](=[O:27])[CH3:26])[CH2:12][CH2:11]2)=[CH:8][CH:9]=1)([O-:3])=[O:2]
Reactant: CC(=O)Cl
Reactant: O=[N+]([O-])c1ccc(N2CCNCC2)cc1
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CC(=O)N1CCN(c2ccc([N+](=O)[O-])cc2)CC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 98.4 %

Procedure:
To a solution of 5.0 g (24.1 mmol) of 1-(4-nitro-phenyl)-piperazine in 100 mL of dichloromethane was added 5.04 mL (28.9 mmol) of diisopropyl-ethylamine. The solution is cooled in an ice-bath, treated with 1.89 mL (26.5 mmol) of acetyl chloride, and stirred at room temperature overnight. The reaction is washed successively with water, 0.5 M HCl, saturated sodium hydrogen carbonate, and brine, and dried over magnesium sulfate, and concentrated to give 5.91 g (98.5%) of the product as a solid.
Reaction SMILES: [F:1][C:2]1[N:7]=[C:6]([I:8])[C:5]([OH:9])=[CH:4][CH:3]=1.Cl[C:11]1[C:20]2[C:15](=[CH:16][C:17]([O:23][CH3:24])=[C:18]([O:21][CH3:22])[CH:19]=2)[N:14]=[CH:13][CH:12]=1.O>CN(C)C1C=CN=CC=1.ClC1C=CC=CC=1Cl>[F:1][C:2]1[N:7]=[C:6]([I:8])[C:5]([O:9][C:11]2[C:20]3[C:15](=[CH:16][C:17]([O:23][CH3:24])=[C:18]([O:21][CH3:22])[CH:19]=3)[N:14]=[CH:13][CH:12]=2)=[CH:4][CH:3]=1
Reactant: Oc1ccc(F)nc1I
Reactant: COc1cc2nccc(Cl)c2cc1OC
Agent: CN(C)c1ccncc1
Solvent: O
Solvent: Clc1ccccc1Cl
Product: COc1cc2nccc(Oc3ccc(F)nc3I)c2cc1OC
Temperature: 140 °C
Reaction time: 5 h
Yield: 5.6 %

Procedure:
6-Fluoro-2-iodo-pyridin-3-ol (20 mg), 4-chloro-6,7-dimethoxyquinoline (56 mg), and 4-dimethylaminopyridine (31 mg) were suspended in o-dichlorobenzene (2 ml), and the suspension was stirred at 140° C. for 5 hr. The reaction solution was cooled to room temperature, water was then added to the reaction solution, and the mixture was extracted with ethyl acetate. The ethyl acetate layer was then washed with water and saturated brine and was dried over anhydrous magnesium sulfate. The solvent was removed by distillation under the reduced pressure, and the residue was purified by thin layer chromatography using acetone-chloroform to give the title compound (2 mg, yield 6%).
Reaction SMILES: [NH2:1][C:2]1[C:3]([C:9]([OH:11])=O)=[CH:4][C:5]([Cl:8])=[N:6][CH:7]=1.O.[CH:13]([NH2:15])=O>>[Cl:8][C:5]1[N:6]=[CH:7][C:2]2[N:1]=[CH:13][NH:15][C:9](=[O:11])[C:3]=2[CH:4]=1
Reactant: NC=O
Reactant: Nc1cnc(Cl)cc1C(=O)O
Solvent: O
Product: O=c1[nH]cnc2cnc(Cl)cc12
Yield: 86 %

Procedure:
A solution of 5-amino-2-chloropyridine-4-carboxylic acid (8.1 g, 4.7 mmol) in formamide (100 mL) is stirred at 140° C. for 12 h. Dilution of the cooled mixture with water gives a precipitate of 6-chloro-3H-pyrido[3,4-d]pyrimidin-4-one (7.3 g, 86% yield). 1H NMR (DMSO) 6 12.73 (1H, m), 8.90 (1H, d, J=0.7 Hz), 8.23 (1H, s 7.97 (1H, d, J=0.7 Hz).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9]#N)=[CH:4][CH:3]=1.[OH-].[Na+].[N+:13]([C:16]1C=[CH:20][CH:19]=[CH:18][CH:17]=1)([O-])=[O:14]>CO>[F:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[O:14][N:13]=[C:16]3[CH:17]=[CH:18][CH:19]=[CH:20][C:9]=23)=[CH:6][CH:7]=1
Reactant: N#CCc1ccc(F)cc1
Reactant: O=[N+]([O-])c1ccccc1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: Fc1ccc(-c2onc3ccccc23)cc1
Temperature: 25 °C
Reaction time: 9 h

Procedure:
A total of 50.7 g (0.375 mol) of 4-fluorophenyl-acetonitrile is slowly added to a vigorously stirred, room-temperature solution of 150 g (3.75 mol) of sodium hydroxide in 750 ml of absolute methanol. After solution is complete, 46 g (0.374 mol) of nitrobenzene is slowly added. The resulting solution is warmed to 65°-70° C. and held at this temperature for 9 hours. The dark slurry is cooled to room temperature, diluted with 250 ml of 50% methanol, and cooled in an ice bath. The resulting dark precipitate is filtered and washed with cold methanol until the methanol washings were clear. The product (16) is recrystallized from toluene.
Reaction SMILES: [OH-].[K+].[OH:3][C:4]1[CH:9]=[CH:8][C:7]([C:10]2[CH:15]=[CH:14][C:13]([N+:16]([O-:18])=[O:17])=[CH:12][CH:11]=2)=[CH:6][CH:5]=1.C(O)C.Br[CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][OH:29]>O>[OH:29][CH2:28][CH2:27][CH2:26][CH2:25][CH2:24][CH2:23][O:3][C:4]1[CH:5]=[CH:6][C:7]([C:10]2[CH:15]=[CH:14][C:13]([N+:16]([O-:18])=[O:17])=[CH:12][CH:11]=2)=[CH:8][CH:9]=1
Reactant: O=[N+]([O-])c1ccc(-c2ccc(O)cc2)cc1
Reactant: OCCCCCCBr
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: O=[N+]([O-])c1ccc(-c2ccc(OCCCCCCO)cc2)cc1
Yield: 65 %

Procedure:
A solution of 71 g potassium hydroxide in 300 ml water is dripped under reflux, into a mixture of 215 g 4-hydroxy-4'-nitrobiphenyl (see Example 3) and 4000 ml ethanol. Then, 217 g 6-bromohexanol is added, subsequently, the mixture is heated under reflux for 15 h. After cooling, the solvent is removed in a vacuum and the residue is slurried up with water dried. The raw product is filtered off, washed neutral with water and recrystallized from ethanol (melting point: 119° C.); yield: 65%.
Reaction SMILES: [CH:1]([C:4]1[CH:5]=[C:6]([CH:18]=[CH:19][CH:20]=1)[O:7][CH2:8][C:9]([NH:11][CH2:12][CH2:13][CH2:14][C:15]([OH:17])=[O:16])=[O:10])([CH3:3])[CH3:2].[N+:21]([C:24]1[CH:25]=[C:26]([S:30]([CH2:33][CH2:34]O)(=[O:32])=[O:31])[CH:27]=[CH:28][CH:29]=1)([O-:23])=[O:22].CC1C=CC(S(O)(=O)=O)=CC=1.O>C1C=CC=CC=1>[N+:21]([C:24]1[CH:25]=[C:26]([S:30]([CH2:33][CH2:34][O:16][C:15](=[O:17])[CH2:14][CH2:13][CH2:12][NH:11][C:9](=[O:10])[CH2:8][O:7][C:6]2[CH:18]=[CH:19][CH:20]=[C:4]([CH:1]([CH3:3])[CH3:2])[CH:5]=2)(=[O:32])=[O:31])[CH:27]=[CH:28][CH:29]=1)([O-:23])=[O:22]
Reactant: O=[N+]([O-])c1cccc(S(=O)(=O)CCO)c1
Reactant: CC(C)c1cccc(OCC(=O)NCCCC(=O)O)c1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: c1ccccc1
Solvent: O
Product: CC(C)c1cccc(OCC(=O)NCCCC(=O)OCCS(=O)(=O)c2cccc([N+](=O)[O-])c2)c1
Yield: 97.5 %

Procedure:
A mixture of 4-(3-isopropylphenoxyactamido)butyric acid (Intermediate 24, 3.1 g, 11.1 mmol, 1.1 eq), 2-(3-nitrobenzenesulfonyl)ethanol (2.3 g, 10.0 mmol), and TsOH.H2O (0.5 g) in 100 mL of benzene was heated overnight to reflux temperature with a Dean-Stark trap. Thereafter the mixture was concentrated by evaporation and the resulting residual oil was purified by column chromatography (CH2Cl2 to 1% MeOH in CH2Cl2) to give Intermediate 25 (4.8 g, 97%) as a light yellow oil which solidified on standing.
Reaction SMILES: [CH3:1][C:2]1[O:6][C:5]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)=[N:4][C:3]=1[CH2:13][O:14][C:15]1[CH:24]=[CH:23][CH:22]=[CH:21][C:16]=1[CH:17]=[CH:18][CH:19]=O.[S:25]1[CH2:29][C:28](=[O:30])[NH:27][C:26]1=[O:31].N1CCCCC1>C(O)(=O)C>[CH3:1][C:2]1[O:6][C:5]([C:7]2[CH:8]=[CH:9][CH:10]=[CH:11][CH:12]=2)=[N:4][C:3]=1[CH2:13][O:14][C:15]1[CH:24]=[CH:23][CH:22]=[CH:21][C:16]=1[CH2:17][CH2:18][CH2:19][CH:29]1[S:25][C:26](=[O:31])[NH:27][C:28]1=[O:30]
Reactant: Cc1oc(-c2ccccc2)nc1COc1ccccc1C=CC=O
Reactant: O=C1CSC(=O)N1
Solvent: CC(=O)O
Solvent: C1CCNCC1
Product: Cc1oc(-c2ccccc2)nc1COc1ccccc1CCCC1SC(=O)NC1=O
Yield: 28 %

Procedure:
A mixture of 2-(5-methyl-2-phenyl-4-oxazolylmethoxy)cinnamaldehyde (2.00 g), 2,4-thiazolidinedione (1.10 g), piperidine (0.267 g) and acetic acid (15 ml) was heated under reflux for 2.5 hours. The reaction mixture was concentrated under reduced pressure. Crystals (1.64 g) of 5-[2-(5-methyl-2-phenyl-4-oxazolylmethoxy)cinnamilidene]-2,4-thiazolidinedione which was precipitated by addition of saturated aqueous sodium bicarbonate solution was collected by filtration and washed with ether. The crystals were dissolved in tetrahydrofuran (150 ml), and 5% palladium-carbon (1.64 g) was added. The mixture was subjected to catalytic hydrogenation at room temperature at a hydrogen pressure of 3.4 kgf/cm2. The catalyst was filtered off, and the filtrate was concentrated under reduced pressure to give crystals. The crystals were recrystallized from dichloromethane-methanol to give 5-[3-[2-(5-methyl-2-phenyl-4-oxazolylmethoxy)phenyl]-propyl]-2,4-thiazolidinedione (0.742 g, 34%). White crystals, mp. 173-174° C.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][N:3]=1.[Cl:8]C1C=CC=C(C(OO)=[O:16])C=1.C(OCC)C.Cl>CC(C)=O>[ClH:8].[NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][N+:3]=1[O-:16]
Reactant: Nc1ccccn1
Reactant: O=C(OO)c1cccc(Cl)c1
Agent: Cl
Solvent: CC(C)=O
Solvent: CCOCC
Product: Nc1cccc[n+]1[O-]
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a solution of amino pyridine (50 g, 0.53 mol) in acetone (900 OmL) a solution of 3-chloro perbenzoic acid (112.2 g, 0.65 mol) in acetone (300 mL) was added and the reaction mixture stirred at room temperature for 30 min. Diethyl ether (500 mL) was added and the solution acidified to pH 4 with concentrated HCl. The amino pyridine-N-oxide hydrochloride salt was then isolated by filtration as an off-white powder (62 g, 80%); m/z (ES+) 111; 1H NMR (d6 DMSO) d 8.14 (dd, J=6.9, 1.8 Hz, 1H), 7.66 (s, 2H, NH2), 7.47 (dt, J=7.6, 1.5 Hz, 1H), 6.99 (dd, J=8.1, 1.5 Hz, 1H), 6.72 (dt, J=7.6, 1.8 Hz, 1H).
Reaction SMILES: [C:1]([O:5][C:6](=[O:20])[NH:7][CH2:8][CH2:9][CH2:10][NH:11][CH:12]([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][N:15]=1)[CH3:13])([CH3:4])([CH3:3])[CH3:2].[CH3:21][C:22]1[C:23]([CH:28]=O)=[N:24][CH:25]=[CH:26][CH:27]=1.[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+]>C(Cl)Cl>[C:1]([O:5][C:6](=[O:20])[NH:7][CH2:8][CH2:9][CH2:10][N:11]([CH2:28][C:23]1[C:22]([CH3:21])=[CH:27][CH:26]=[CH:25][N:24]=1)[CH:12]([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][N:15]=1)[CH3:13])([CH3:2])([CH3:3])[CH3:4]
Reactant: CC(NCCCNC(=O)OC(C)(C)C)c1ccccn1
Reactant: Cc1cccnc1C=O
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCl
Product: Cc1cccnc1CN(CCCNC(=O)OC(C)(C)C)C(C)c1ccccn1

Procedure:
Using General Procedure B: Reaction of [3-(1-pyridin-2-yl-ethylamino)-propyl]-carbamic acid tert-butyl ester and 3-methyl-pyridine-2-carboxaldehyde with NaBH(OAc)3 in CH2Cl2 gave {3-[(3-methyl-pyridin-2-ylmethyl)-(1-pyridin-2-yl-ethyl)-amino]-propyl}-carbamic acid tert-butyl ester as a colorless oil.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[S:9][CH2:10][C:11]1[CH:20]=[CH:19][CH:18]=[CH:17][C:12]=1[C:13]([O:15][CH3:16])=[O:14].[O:21]1[C:25]2[CH:26]=[CH:27][CH:28]=[CH:29][C:24]=2[CH:23]=[C:22]1[S:30](Cl)(=[O:32])=[O:31]>N1C=CC=CC=1>[O:21]1[C:25]2[CH:26]=[CH:27][CH:28]=[CH:29][C:24]=2[CH:23]=[C:22]1[S:30]([NH:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[S:9][CH2:10][C:11]1[CH:20]=[CH:19][CH:18]=[CH:17][C:12]=1[C:13]([O:15][CH3:16])=[O:14])(=[O:32])=[O:31]
Reactant: O=S(=O)(Cl)c1cc2ccccc2o1
Reactant: COC(=O)c1ccccc1CSc1ccc(F)cc1N
Solvent: c1ccncc1
Product: COC(=O)c1ccccc1CSc1ccc(F)cc1NS(=O)(=O)c1cc2ccccc2o1
Yield: 54.8 %

Procedure:
Following General Procedure B, the title compound (1.6 g, 55%) was prepared from methyl 2-(((2-amino-4-fluorophenyl)thio)methyl)benzoate (1.8 g, 6.19 mmol) and benzofuran-2-sulfonyl chloride (1.3 g, 6.19 mmol) in pyridine (10 ml).
Reaction SMILES: [CH3:1][N:2]1[CH:9]=[CH:8][C:6](=[O:7])[NH:5][C:3]1=[O:4].[CH2:10]([C:12]1[CH:13]=[CH:14][C:15]2[CH:25](O)[C:20]3[N:21]=[C:22]([CH3:24])[S:23][C:19]=3[CH:18]=[CH:17][C:16]=2[CH:27]=1)[CH3:11].FC(F)(F)C(O)=O>ClCCl>[CH2:10]([C:12]1[CH:13]=[CH:14][C:15]2[CH:25]([C:8]3[C:6](=[O:7])[NH:5][C:3](=[O:4])[N:2]([CH3:1])[CH:9]=3)[C:20]3[N:21]=[C:22]([CH3:24])[S:23][C:19]=3[CH:18]=[CH:17][C:16]=2[CH:27]=1)[CH3:11]
Reactant: Cn1ccc(=O)[nH]c1=O
Reactant: CCc1ccc2c(c1)C=Cc1sc(C)nc1C2O
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CCc1ccc2c(c1)C=Cc1sc(C)nc1C2c1cn(C)c(=O)[nH]c1=O
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
1-Methyluracil (0.064 g) was added to a solution of the product from step (xi) (0.10 g) in dichloromethane (2 ml), followed by trifluoroacetic acid (1 ml). The orange solution was stirred at room temperature for 10 minutes before the solvent was removed under reduced pressure. The residue was azeotroped twice with acetonitrile, and the crude product purified by chromatography, eluting with 0-5% methanol in ethyl acetate.
Reaction SMILES: [OH:1][C@H:2]1[CH2:7][CH2:6][C@H:5]([NH:8][S:9]([C:12]2[CH:17]=[CH:16][C:15]([C:18]([F:21])([F:20])[F:19])=[CH:14][CH:13]=2)(=[O:11])=[O:10])[CH2:4][CH2:3]1.C([O-])([O-])=O.[K+].[K+].[CH2:28](Br)[CH3:29]>CN(C=O)C>[CH2:28]([N:8]([C@H:5]1[CH2:6][CH2:7][C@H:2]([OH:1])[CH2:3][CH2:4]1)[S:9]([C:12]1[CH:17]=[CH:16][C:15]([C:18]([F:21])([F:19])[F:20])=[CH:14][CH:13]=1)(=[O:11])=[O:10])[CH3:29]
Reactant: O=S(=O)(N[C@H]1CC[C@H](O)CC1)c1ccc(C(F)(F)F)cc1
Reactant: CCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCN([C@H]1CC[C@H](O)CC1)S(=O)(=O)c1ccc(C(F)(F)F)cc1
Temperature: 35 °C

Procedure:
To 4 g (12.4 mmol) trans-N-(4-Hydroxy-cyclohexyl)-4-trifluoromethyl-benzenesulfonamide in 20 ml DMF were added 5.1 g (37.1 mmol, 3.3 eq) K2CO3 and 2.04 ml (27.2 mmol, 2.2 eq) ethyl bromide. The mixture was stirred at 35° C. over night, concentrated in vacuo and dissolved in CH2Cl2 and water. The phases were separated and the inorganic one was extracted CH2Cl2, the combined organic phases were washed with brine and dried over Na2SO4. The crude product was purified by column chromatography on silica gel with CH2Cl2/MeOH 95:5 to yield 1.6 g (38%) trans-N-Ethyl-N-(4-hydroxy-cyclohexyl)-4-trifluoromethyl-benzenesulfonamide as brown oil, MS: 351(M).
Reaction SMILES: [NH2:1][CH2:2][C@@H:3]1[C@H:8]([CH3:9])[CH2:7][CH2:6][CH2:5][N:4]1[C:10]([C:12]1[CH:17]=[C:16]([CH3:18])[CH:15]=[CH:14][C:13]=1[C:19]1[N:20]=[N:21][CH:22]=[CH:23][CH:24]=1)=[O:11].F[C:26]1[CH:31]=[CH:30][C:29]([C:32]([F:35])([F:34])[F:33])=[CH:28][N:27]=1>>[CH3:9][C@@H:8]1[CH2:7][CH2:6][CH2:5][N:4]([C:10]([C:12]2[CH:17]=[C:16]([CH3:18])[CH:15]=[CH:14][C:13]=2[C:19]2[N:20]=[N:21][CH:22]=[CH:23][CH:24]=2)=[O:11])[C@@H:3]1[CH2:2][NH:1][C:26]1[CH:31]=[CH:30][C:29]([C:32]([F:35])([F:34])[F:33])=[CH:28][N:27]=1
Reactant: Cc1ccc(-c2cccnn2)c(C(=O)N2CCC[C@@H](C)[C@H]2CN)c1
Reactant: Fc1ccc(C(F)(F)F)cn1
Product: Cc1ccc(-c2cccnn2)c(C(=O)N2CCC[C@@H](C)[C@H]2CNc2ccc(C(F)(F)F)cn2)c1

Procedure:
The title compound was prepared following the same general protocol as described for Example A1, using ((2S,3R)-2-(aminomethyl)-3-methylpiperidin-1-yl)(5-methyl-2-(pyridazin-3-yl)phenyl)methanone and 2-fluoro-5-trifluoromethylpyridine. ESI-MS (m/z): 470 [M+1]+.
Reaction SMILES: Cl[C:2]1[N:7]=[CH:6][CH:5]=[C:4]([Cl:8])[N:3]=1.[F:9][C:10]1[CH:11]=[C:12]([OH:19])[CH:13]=[CH:14][C:15]=1[N+:16]([O-:18])=[O:17].C(N(C(C)C)CC)(C)C>CN1CCCC1=O>[Cl:8][C:4]1[CH:5]=[C:6]([O:19][C:12]2[CH:13]=[CH:14][C:15]([N+:16]([O-:18])=[O:17])=[C:10]([F:9])[CH:11]=2)[N:7]=[CH:2][N:3]=1
Reactant: Clc1ccnc(Cl)n1
Reactant: O=[N+]([O-])c1ccc(O)cc1F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN1CCCC1=O
Product: O=[N+]([O-])c1ccc(Oc2cc(Cl)ncn2)cc1F
Temperature: 50 °C
Reaction time: 13 h
Yield: 28.8 %

Procedure:
After dissolving 2,6-dichloropyrimidine (5.0 g) and 3-fluoro-4-nitrophenol (6.11 g) in 1-methyl-2-pyrrolidinone (25 ml) at room temperature under a nitrogen atmosphere, diisopropylethylamine (6.81 ml) was added and the mixture was stirred for 13 hours at 50° C. The reaction mixture was cooled to room temperature and then partitioned between ethyl acetate and water. The separated organic layer was washed with water, 1N aqueous sodium hydroxide, water, 10% aqueous potassium hydrogen sulfate and brine in that order and then dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure, and then ethyl acetate (25 ml) was added to the residue to precipitate crystals. The crystals were filtered and subjected to aeration drying to provide the title compound (2.61 g, 30%) as white crystals. The filtrate was concentrated under reduced pressure, and then diethyl ether (30 ml) was added to the resultant residue and the mixture was stirred. The precipitated crystals were filtered, washed with diethyl ether (5 ml×2) and subjected to aeration drying to provide the title compound (3.98 g, 44%) as white crystals.