Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:8]=[C:9]([Cl:12])[C:10]=1[OH:11])[C:5](O)=[O:6].B.C1COCC1>C1COCC1>[Cl:1][C:2]1[CH:3]=[C:4]([CH2:5][OH:6])[CH:8]=[C:9]([Cl:12])[C:10]=1[OH:11]
Reactant: O=C(O)c1cc(Cl)c(O)c(Cl)c1
Agent: B
Solvent: C1CCOC1
Product: OCc1cc(Cl)c(O)c(Cl)c1
Temperature: 60 °C
Yield: 99.3 %

Procedure:
To a solution of 3,5-dichloro-4-hydroxybenzoic acid (4.0 g, 19.3 mmol) in THF (60 ml) under argon was added borane-THF complex (39.0 mmol, 39.0 ml of 1 M solution in THF) dropwise. After addition, the reaction mixture was heated at 60° C. for 6 h, then quenched with water and extracted with ethyl acetate three times. The organic extract was washed with water, then brine, dried (sodium sulfate) and concentrated in vacuo to afford the title compound (3.7 g, 99%) as white solid. 1H NMR (400 MHz, CDCl3) δ 7.28 (s, 2H), 5.83 (s, 1H), 4.59 (s, 2H), MS: (M+1-H2O)=175
Reaction SMILES: CNC.[CH3:4][N:5]([CH:7]=[O:8])[CH3:6].[F:9][C:10]1[CH:29]=[CH:28][C:13]([O:14][CH2:15][CH2:16][CH2:17][NH:18]C(=O)OC2C=CC=CC=2)=[C:12]([N+:30]([O-:32])=[O:31])[CH:11]=1>O>[F:9][C:10]1[CH:29]=[CH:28][C:13]([O:14][CH2:15][CH2:16][CH2:17][NH:18][C:7](=[O:8])[N:5]([CH3:6])[CH3:4])=[C:12]([N+:30]([O-:32])=[O:31])[CH:11]=1
Reactant: O=C(NCCCOc1ccc(F)cc1[N+](=O)[O-])Oc1ccccc1
Reactant: CN(C)C=O
Agent: CNC
Solvent: O
Product: CN(C)C(=O)NCCCOc1ccc(F)cc1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 24 h
Yield: 82 %

Procedure:
A 50% dimethylamine aqueous solution (2.5 ml) was added to a DMF solution (25 ml) of phenyl [3-(4-fluoro-2-nitrophenoxy)propyl]carbamate (5.89 g, 17.6 mmol), and the mixture was stirred at room temperature for 24 hours. Water was added to the reaction mixture, and the resulting mixture was extracted with ethyl acetate. The organic layer was washed with a saturated sodium chloride aqueous solution twice, and concentrated under reduced pressure. The residue was then purified by silica gel column chromatography (dichloromethane:ethyl acetate=19:1→4:1→2:1). The purified product was concentrated to dryness under reduced pressure to thereby obtain 4.10 g of oily pale yellow 3-[3-(4-fluoro-2-nitrophenoxy)propyl]-1,1-dimethyl urea (yield: 82%).
Reaction SMILES: [CH3:1][N:2]([CH3:7])[CH2:3][CH2:4][NH:5][CH3:6].[CH2:8]([O:15][CH2:16][C:17](Cl)=[O:18])[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1>ClCCl>[CH2:8]([O:15][CH2:16][C:17]([N:5]([CH2:4][CH2:3][N:2]([CH3:7])[CH3:1])[CH3:6])=[O:18])[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1
Reactant: CNCCN(C)C
Reactant: O=C(Cl)COCc1ccccc1
Solvent: ClCCl
Product: CN(C)CCN(C)C(=O)COCc1ccccc1
Temperature: 0 °C
Reaction time: 8 h

Procedure:
N,N,N′-Trimethylethylenediamine (99, 0.17 mL, 1.308 mmol) was dissolved in 5 mL of dichloromethane and cooled to 0° C. in an ice-water bath. 2-Benzyloxyacetyl chloride (100, 0.2 mL, 1.267 mmol) was added to the above solution dropwise and the mixture was allowed to warm to room temperature. After overnight, the reaction was complete and the mixture was concentrated and used in the next step without purification as HCl salt: 1H NMR (400 MHz, CDCl3): δ 2.86 (s, 3H), 2.87 (s, 3H), 3.09 (s, 3H), 3.16 (q, J=5.5, 2H), 3.85 (t, J=6.6, 2H), 4.24 (s, 2H), 4.63 (s, 2H), 7.30-7.39 (m, 5H).
Reaction SMILES: [Cl:1][C:2]1[C:7]([Cl:8])=[CH:6][C:5]([Cl:9])=[CH:4][C:3]=1B(O)O.[NH2:13][C:14]1[C:19](Cl)=[N:18][CH:17]=[CH:16][N:15]=1.C(=O)([O-])[O-].[Na+].[Na+]>C(O)C.C1C=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>[NH2:13][C:14]1[C:19]([C:3]2[CH:4]=[C:5]([Cl:9])[CH:6]=[C:7]([Cl:8])[C:2]=2[Cl:1])=[N:18][CH:17]=[CH:16][N:15]=1
Reactant: Nc1nccnc1Cl
Reactant: OB(O)c1cc(Cl)cc(Cl)c1Cl
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: [Na+]
Solvent: c1ccccc1
Solvent: CCO
Product: Nc1nccnc1-c1cc(Cl)cc(Cl)c1Cl

Procedure:
A solution of 2,3,5-trichlorobenzeneboronic acid (1.54 g, 6.82 mmol) in absolute ethanol (1.5 ml) was added slowly to a mixture of 2-amino-3-chloropyrazine (0.589 g, 4.54 mmol) and tetrakis(triphenylphosphine)palladium(0) (0.299 g, 0.259 mmol) in benzene (10.5 ml)/2M aqueous sodium carbonate (4.54 ml). The mixture was refluxed for 17 hours. The cooled reaction mixture was partitioned between water and ethylacetate (50 ml). The organic layer was washed with water (2×30 ml), dried (MgSO4) and evaporated. The crude product was purified by flash chromatography using chloroform to 0.5% methanol/chloroform as the eluent. The product was then crystallised from 40-60 petrol. Yield 0.15 g, 12% M.p. 142-143° C.
Reaction SMILES: Cl[C:2]1[C:3]([N+:14]([O-:16])=[O:15])=[CH:4][C:5]2[O:10][CH:9]([CH3:11])[C:8](=[O:12])[NH:7][C:6]=2[CH:13]=1.[NH:17]1[CH:21]=[CH:20][N:19]=[CH:18]1.C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C.C(OCC)(=O)C.[Cu]>[N:17]1([C:2]2[C:3]([N+:14]([O-:16])=[O:15])=[CH:4][C:5]3[O:10][CH:9]([CH3:11])[C:8](=[O:12])[NH:7][C:6]=3[CH:13]=2)[CH:21]=[CH:20][N:19]=[CH:18]1
Reactant: c1c[nH]cn1
Reactant: CC1Oc2cc([N+](=O)[O-])c(Cl)cc2NC1=O
Agent: [Cu]
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CC1Oc2cc([N+](=O)[O-])c(-n3ccnc3)cc2NC1=O

Procedure:
485 mg of 6-chloro-7-nitro-2-methyl-1,4-benzoxazin-3-one is stirred with 136 mg of imidazole and 332 mg of potassium carbonate in 15 ml of DMF with the addition of copper powder for 6 hours at 180° C. It is diluted with ethyl acetate, extracted with brine, and the organic phase is dried. The crude product is purified by column chromatography with ethyl acetate with the addition of ethanol. 88 mg results.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([CH:10]=[CH:11][C:12]=1[F:13])[C:5]([O:7][CH2:8][CH3:9])=[O:6].N1C=CC=CC=1.[F:20][C:21]1[CH:26]=[CH:25][CH:24]=[C:23]([F:27])[C:22]=1[S:28](Cl)(=[O:30])=[O:29]>C(Cl)Cl>[F:20][C:21]1[CH:26]=[CH:25][CH:24]=[C:23]([F:27])[C:22]=1[S:28]([NH:1][C:2]1[CH:3]=[C:4]([CH:10]=[CH:11][C:12]=1[F:13])[C:5]([O:7][CH2:8][CH3:9])=[O:6])(=[O:30])=[O:29]
Reactant: CCOC(=O)c1ccc(F)c(N)c1
Reactant: O=S(=O)(Cl)c1c(F)cccc1F
Solvent: c1ccncc1
Solvent: ClCCl
Product: CCOC(=O)c1ccc(F)c(NS(=O)(=O)c2c(F)cccc2F)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 73 %

Procedure:
To a solution of ethyl 3-amino-4-fluorobenzoate (5.47 g, 30 mmol) and pyridine (2.55 mL, 33 mmol) in DCM (150 mL) was added 2,6-difluorobenzenesulfonyl chloride (4.45 mL, 33 mmol). The reaction was stirred overnight at rt. After 16 h, the reaction mixture was concentrated, triturated with ether, and dried in vacuo to generate 7.87 g (66% yield) of the product of Step A as a white powder. MS (ESI): 360 (M+H).
Reaction SMILES: C(OC([NH:8][CH:9]([CH2:15][CH3:16])[C@H:10]([OH:14])[C:11]([OH:13])=O)=O)(C)(C)C.O[NH:18][C:19]([CH:21]1[CH2:23][CH2:22]1)=[NH:20]>ClCCl>[NH2:8][CH:9]([CH2:15][CH3:16])[C@@H:10]([C:11]1[O:13][N:20]=[C:19]([CH:21]2[CH2:23][CH2:22]2)[N:18]=1)[OH:14]
Reactant: CCC(NC(=O)OC(C)(C)C)[C@H](O)C(=O)O
Reactant: N=C(NO)C1CC1
Solvent: ClCCl
Product: CCC(N)[C@H](O)c1nc(C2CC2)no1
Temperature: 15 °C
Reaction time: 3 h

Procedure:
A solution of (S)-3-tert-Butoxycarbonylamino-2-hydroxy-pentanoic acid (2.00 g, 8.57 mmol) and N-Hydroxy-cyclopropanecarboxamidine (1.03 g, 10.29 mmol) in dichloromethane (20 mL) was stirred at 0° C. and 1.25 equivalents of N-cyclohexylcarbodiimide-N′-methyl polystyrene (1.70 mmol/g, 6.30 g, 10.72 mmol) was added in portions. The reaction mixture stirred under nitrogen for three hours while warming to 15° C. The reaction mixture was filtered, the resin washed with dichloromethane and the filtrate evaporated under vacuum to dryness. [LC/MS m/z=338 (M+H+Na)] The residue was dissolved in tetrahydrofuran (20 mL) and heated in a microwave reactor (Smith Creator) at 160° C. for three minutes, cooled to room temperature and evaporated under vacuum to dryness. [LC/MS m/z=320 (M+H+Na)]. The residue was dissolved in dichloromethane (50 mL) and stirred at room temperature as a 50 mL solution of 50% trifluoroacetic acid in dichloromethane was added dropwise. After three hours the reaction was evaporated under vacuum to dryness and dissolved in 50 mL of dichloromethane again. Three equivalents of Silicycle triamine-3 was added and the mixture stirred at room temperature overnight. The mixture was filtered and washed with dichloromethane. Evaporate under vacuum to give 1.04 g (61% overall). [LC/MS m/z=198 (M+H)]
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:22])[CH2:5][C:6]1[CH:11]=[CH:10][CH:9]=[C:8]([O:12][C:13]2[CH:18]=[CH:17][C:16]([Br:19])=[CH:15][C:14]=2[CH2:20]Br)[CH:7]=1)[CH3:2].[NH:23]1[CH2:27][CH2:26][CH2:25][C:24]1=[O:28].[H-].[Na+]>O1CCOCC1>[CH2:1]([O:3][C:4](=[O:22])[CH2:5][C:6]1[CH:11]=[CH:10][CH:9]=[C:8]([O:12][C:13]2[CH:18]=[CH:17][C:16]([Br:19])=[CH:15][C:14]=2[CH2:20][N:23]2[CH2:27][CH2:26][CH2:25][C:24]2=[O:28])[CH:7]=1)[CH3:2]
Reactant: O=C1CCCN1
Reactant: CCOC(=O)Cc1cccc(Oc2ccc(Br)cc2CBr)c1
Agent: [H-]
Agent: [Na+]
Solvent: C1COCCO1
Product: CCOC(=O)Cc1cccc(Oc2ccc(Br)cc2CN2CCCC2=O)c1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
[3-(4-Bromo-2-bromomethyl-phenoxy)-phenyl]-acetic acid ethyl ester (0.15 g, 0.35 mmol) and 2-pyrrolidinone (0.05 g, 0.53 mmol) were combined in 1,4-dioxane (10 mL). Sodium hydride (60% in mineral oil; 0.03 g, 0.7 mmol) was added, and the reaction was stirred at room temperature for 2 hours to give the title compound, which was used as a crude solution in the hydrolysis step.
Reaction SMILES: Cl[CH:2]([CH2:6][CH3:7])[C:3](=[O:5])[CH3:4].[Cl:8][C:9]1[CH:14]=[CH:13][C:12]([OH:15])=[CH:11][CH:10]=1.C(=O)(O)[O-].[K+].[I-].[K+]>CC(C)=O>[Cl:8][C:9]1[CH:14]=[CH:13][C:12]([O:15][CH:2]([CH2:6][CH3:7])[C:3](=[O:5])[CH3:4])=[CH:11][CH:10]=1
Reactant: Oc1ccc(Cl)cc1
Reactant: CCC(Cl)C(C)=O
Agent: O=C([O-])O
Agent: [I-]
Agent: [K+]
Solvent: CC(C)=O
Product: CCC(Oc1ccc(Cl)cc1)C(C)=O
Yield: 62.1 %

Procedure:
A solution of 3-chloro-2-pentanone (10 g) in acetone (50 ml) was added dropwise to a stirred mixture of 4-chlorophenol (11 g), potassium bicarbonate (20 g) and potassium iodide (1 g) in acetone (100 ml). After the addition was completed the mixture was heated under reflux for 6 hours. The mixture was then filtered, washed with acetone and the acetone was evaporated under reduced pressure. The residue was dissolved in ether (150 ml), and the ethereal mixture was washed with 300 ml of a 10% aqueous solution of sodium hydroxide followed by 300 ml of water. The mixture was then dried over magnesium sulphate. The solvent was evaporated and the residue was distilled under reduced pressure to give 3-(4-chlorophenoxy)-2-pentanone (10.96 g).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9]([N:11]([CH2:18][CH3:19])[CH:12]2[CH2:17][CH2:16][NH:15][CH2:14][CH2:13]2)=[O:10])=[CH:4][CH:3]=1.C([O-])(O)=O.[Na+].[Na+].[I-].Cl[CH2:28][CH2:29][NH:30][C:31]([NH:33][C:34]1[CH:39]=[C:38]([CH3:40])[N:37]=[C:36]([CH3:41])[CH:35]=1)=[O:32]>C1COCC1>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9]([N:11]([CH:12]2[CH2:17][CH2:16][N:15]([CH2:28][CH2:29][NH:30][C:31]([NH:33][C:34]3[CH:39]=[C:38]([CH3:40])[N:37]=[C:36]([CH3:41])[CH:35]=3)=[O:32])[CH2:14][CH2:13]2)[CH2:18][CH3:19])=[O:10])=[CH:4][CH:3]=1
Reactant: Cc1cc(NC(=O)NCCCl)cc(C)n1
Reactant: CCN(C(=O)Cc1ccc(Cl)cc1)C1CCNCC1
Agent: O=C([O-])O
Agent: [I-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CCN(C(=O)Cc1ccc(Cl)cc1)C1CCN(CCNC(=O)Nc2cc(C)nc(C)c2)CC1
Temperature: 50 °C
Reaction time: 648 h

Procedure:
A suspension of 2-(4-chloro-phenyl)-N-ethyl-N-piperidin-4-yl-acetamide (Example A10., 3.37 g, 12.0 mmol), NaHCO3 (5.4 g, 64 mmol), NaI (1.2 g, 8 mmol) and 1-(2-chloro-ethyl)-3-(2,6-dimethyl-pyridin-4-yl)-urea (Example D1, 1.82 g 8 mmol) in THF (40 mL) is stirred at 50° C. for 27 days. The mixture is quenched with Na2CO3 (150 mL) and extracted with CH2Cl2 (3×100 mL). The organic extracts are washed with sat. aq. Na2CO3 (70 mL), dried (Na2SO4), filtered and evaporated. The residue is purified by MPLC to provide the title compound.
Reaction SMILES: [NH2:1][C:2]1[N:6]([C:7]2[CH:8]=[CH:9][C:10](=[O:13])[NH:11][CH:12]=2)[N:5]=[C:4]([C:14]([CH3:17])([CH3:16])[CH3:15])[CH:3]=1.Cl[C:19]([O:21][C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)=[O:20]>>[C:14]([C:4]1[CH:3]=[C:2]([NH:1][C:19](=[O:20])[O:21][C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)[N:6]([C:7]2[CH:8]=[CH:9][C:10](=[O:13])[NH:11][CH:12]=2)[N:5]=1)([CH3:17])([CH3:16])[CH3:15]
Reactant: CC(C)(C)c1cc(N)n(-c2ccc(=O)[nH]c2)n1
Reactant: O=C(Cl)Oc1ccccc1
Product: CC(C)(C)c1cc(NC(=O)Oc2ccccc2)n(-c2ccc(=O)[nH]c2)n1
Yield: 12.1 %

Procedure:
Following the procedure in Example 118A, 5-(5-amino-3-tert-butyl-1H-pyrazol-1-yl)pyridin-2(1H)-one (46 mg, 0.19 mmol) was treated with phenyl chloroformate (0.10 mL, 0.79 mmol) to afford phenyl 3-tert-butyl-1-(6-oxo-1,6-dihydropyridin-3-yl)-1H-pyrazol-5-ylcarbamate (8 mg, 0.023 mmol, 12%). 1H NMR (300 MHz, MeOD) δ 7.68 (d, 2H), 7.38 (t, 2H), 7.23 (t, 1H), 7.09 (br s, 2H), 6.63 (d, 1H), 6.34 (s, 1H), 1.30 (s, 9H); LC-MS (ESI) m/z 353 (M+H)+.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:11]([O:12][CH3:13])=[CH:10][CH:9]=[CH:8][C:4]=1[CH2:5][CH2:6][NH2:7].[CH3:14][O:15][C:16]1[CH:17]=[C:18]([CH2:24][C:25](Cl)=[O:26])[CH:19]=[CH:20][C:21]=1[O:22][CH3:23]>>[CH3:1][O:2][C:3]1[C:11]([O:12][CH3:13])=[CH:10][CH:9]=[CH:8][C:4]=1[CH2:5][CH2:6][NH:7][C:25](=[O:26])[CH2:24][C:18]1[CH:19]=[CH:20][C:21]([O:22][CH3:23])=[C:16]([O:15][CH3:14])[CH:17]=1
Reactant: COc1ccc(CC(=O)Cl)cc1OC
Reactant: COc1cccc(CCN)c1OC
Product: COc1ccc(CC(=O)NCCc2cccc(OC)c2OC)cc1OC

Procedure:
prepared from 2,3-dimethoxyphenethylamine (Lindemann, Helv. Chim. Acta. 1949, 32, 69-75) and 3,4-dimethoxyphenylacetyl chloride; mp 80° C. (lit.29 79-80° C.); IR 3315, 2962, 2838, 1636, 1593, 1548; 1H NMR δ 2.61 (t, 2H), 3.22-3.30 (m, 4H), 3.58 (s, 3H), 3.64 (s, 6H), 3.67 (s, 3H), 6.22 (brs, 1H), 6.44-6.79 (m, 6H); 13C NMR δ 30.0, 41.0, 43.7, 55.9, 56.2, 56.3, 60.9, 111.2, 111.9, 112.9, 122.0, 122.6, 124.4, 127.9, 133.1, 147.5, 148.5, 149.5, 153.1, 171.9.
Reaction SMILES: C([O:5][C:6]([N:8]1[CH2:12][CH2:11][C@H:10]([O:13][C:14]2[CH:21]=[CH:20][C:17]([CH:18]=[O:19])=[CH:16][C:15]=2[O:22][CH3:23])[CH2:9]1)=O)(C)(C)C.[CH:24](O)=O>ClCCl.C(Cl)(Cl)Cl>[C:6]([N:8]1[CH2:12][CH2:11][C@H:10]([O:13][C:14]2[CH:21]=[CH:20][C:17]([CH:18]=[O:19])=[CH:16][C:15]=2[O:22][CH3:23])[CH2:9]1)(=[O:5])[CH3:24]
Reactant: COc1cc(C=O)ccc1O[C@H]1CCN(C(=O)OC(C)(C)C)C1
Reactant: O=CO
Solvent: ClC(Cl)Cl
Solvent: ClCCl
Product: COc1cc(C=O)ccc1O[C@H]1CCN(C(C)=O)C1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
5.5 g of 4-[((3S)-1-tert-butoxycarbonyl-3-pyrrolidinyl)oxy]-3-methoxybenzaldehyde was dissolved in 20 ml of dichloromethane, followed by the addition of 30 ml of formic acid. The thus prepared mixture was stirred at room temperature for 1 hour and then at 50° C. for 1 hour. The solvent and formic acid were distilled off under a reduced pressure, and the resulting residue was dissolved in 100 ml of tetrahydrofuran. The thus prepared solution was mixed with 2.68 g of acetyl chloride, and 8.63 g of triethylamine was added dropwise thereto while stirring under ice cooling. Thereafter, the solvent was distilled off, and the residue thus obtained was dissolved in chloroform, and washed with water, followed by drying of the resulting organic layer. After distilling off the solvent, the resulting residue was purified by subjecting it to silica gel column chromatography using toluene as an elution solvent, thereby obtaining 4.3 g of 4-[((3S)-1-acetyl-3-pyrrolidinyl)oxy]-3-methoxybenzaldehyde as a viscous oil.
Reaction SMILES: [CH:1]([NH:4][C:5]1[CH:10]=[CH:9][C:8]([O:11][CH3:12])=[CH:7][CH:6]=1)([CH3:3])[CH3:2].C(N(CC)CC)C.[Br:20][CH2:21][C:22](Br)=[O:23]>ClCCl>[Br:20][CH2:21][C:22]([N:4]([CH:1]([CH3:3])[CH3:2])[C:5]1[CH:10]=[CH:9][C:8]([O:11][CH3:12])=[CH:7][CH:6]=1)=[O:23]
Reactant: COc1ccc(NC(C)C)cc1
Reactant: O=C(Br)CBr
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COc1ccc(N(C(=O)CBr)C(C)C)cc1
Temperature: 25 °C
Yield: 94.4 %

Procedure:
To a solution of isopropyl-(4-methoxy-phenyl)-amine (25.11 g) in dichloromethane (250 mL) was added triethylamine (15.38 g) with stirring at ambient temperature. The solution was cooled in an ice bath (<3° C.) and bromoacetyl bromide (30.68 g) dissolved in dichloromethane (100 mL) was added dropwise over a 45 minute period with stirring and cooling in an ice bath. The reaction mix was stirred overnight at ambient temperature, washed with 0.3N HCl (300 mL) and brine (300 mL), dried over sodium sulfate, filtered, and evaporated under reduced pressure to give a dark brown oil. The oil was filtered through a pad of silica gel (150 g) which was eluted with ethyl acetate/hexane (1:1, 900 mL) and the filtrate evaporated under reduced pressure to afford the title compound (41.05 g) as a brown oil which crystallized on standing. 1H NMR (300 MHz, CDCl3): d 1.04(d, J=6.8 Hz, 6H), 3.53(s, 2H), 3.84(s, 3H), 4.93(m, 1H), 6.93(d, J=9.1 Hz, 2H), 7.10(d, J=9.1 Hz, 3H) TLC (EtOAc/Hexane(3:17)): Rf =0.18.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([NH:11][C:12]([CH3:15])([CH3:14])[CH3:13])(=[O:10])=[O:9])=[CH:4][CH:3]=1.C1C(=O)N([Br:23])C(=O)C1>C(Cl)Cl>[NH2:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([NH:11][C:12]([CH3:15])([CH3:14])[CH3:13])(=[O:10])=[O:9])=[CH:4][C:3]=1[Br:23]
Reactant: CC(C)(C)NS(=O)(=O)c1ccc(N)cc1
Reactant: O=C1CCC(=O)N1Br
Solvent: ClCCl
Product: CC(C)(C)NS(=O)(=O)c1ccc(N)c(Br)c1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 53.1 %

Procedure:
To a solution of 4-amino-N-tert-butyl-benzenesulfonamide (J. Med. Chem. (2003), 46(16), 3463-3475, 228 mg, 1.00 mmol) in DCM (10 mL), NBS (178 mg, 1.00 mmol) was added. The resulting mixture was stirred at RT for 30 min and washed with satd NaHCO3 (10 mL) and 10% aq Na2S2O3 (10 mL). The organic layer was separated, dried and concentrated to obtain 4-amino-3-bromo-N-tert-butyl-benzenesulfonamide (163 mg, 53%).
Reaction SMILES: Cl.[CH3:2][O:3][C:4]1[CH:9]=[CH:8][C:7]([C:10]2[N:14]([C:15]3[CH:24]=[CH:23][C:18]([O:19][CH2:20][CH2:21][NH2:22])=[CH:17][CH:16]=3)[N:13]=[C:12]([C:25]([F:28])([F:27])[F:26])[CH:11]=2)=[CH:6][CH:5]=1.[O-:29][C:30]#[N:31].[Na+]>O.C(O)C>[CH3:2][O:3][C:4]1[CH:5]=[CH:6][C:7]([C:10]2[N:14]([C:15]3[CH:24]=[CH:23][C:18]([O:19][CH2:20][CH2:21][NH:22][C:30]([NH2:31])=[O:29])=[CH:17][CH:16]=3)[N:13]=[C:12]([C:25]([F:28])([F:26])[F:27])[CH:11]=2)=[CH:8][CH:9]=1
Reactant: N#C[O-]
Reactant: COc1ccc(-c2cc(C(F)(F)F)nn2-c2ccc(OCCN)cc2)cc1
Agent: Cl
Agent: [Na+]
Solvent: CCO
Solvent: O
Product: COc1ccc(-c2cc(C(F)(F)F)nn2-c2ccc(OCCNC(N)=O)cc2)cc1

Procedure:
To a solution of 2-{4-[5-(4-methoxyphenyl)-3-(tri-fluoromethyl)-1H-pyrazol-1-yl]phenoxy}ethanamine hydrochloride obtained by Example 96 (200 mg) in water (10 ml) and ethanol (5 ml) was added sodium cyanate (314 mg) at room temperature.
Reaction SMILES: O.[NH:2]1[CH2:7][CH2:6][C:5](=[O:8])[CH2:4][CH2:3]1.[Cl:9][C:10]1[CH:11]=[C:12]2[C:16](=[CH:17][CH:18]=1)[NH:15][C:14]([C:19]([NH:21][CH:22]([CH2:26][C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1)[C:23](O)=[O:24])=[O:20])=[CH:13]2>C(OCC)(=O)C>[CH2:26]([CH:22]([NH:21][C:19]([C:14]1[NH:15][C:16]2[C:12]([CH:13]=1)=[CH:11][C:10]([Cl:9])=[CH:18][CH:17]=2)=[O:20])[C:23](=[O:24])[N:2]1[CH2:7][CH2:6][C:5](=[O:8])[CH2:4][CH2:3]1)[C:27]1[CH:28]=[CH:29][CH:30]=[CH:31][CH:32]=1
Reactant: O=C1CCNCC1
Reactant: O=C(NC(Cc1ccccc1)C(=O)O)c1cc2cc(Cl)ccc2[nH]1
Solvent: CCOC(C)=O
Solvent: O
Product: O=C1CCN(C(=O)C(Cc2ccccc2)NC(=O)c2cc3cc(Cl)ccc3[nH]2)CC1

Procedure:
4-Piperidone monohydrate (2.0 mmol) and 2-[(5-chloro-1H-indole-2-carbonyl)-amino]-3-phenyl-propionic acid (1.0 mmol) were coupled according to procedure A (0-25° C. reaction temperature) substituting the following workup: the reaction mixture was diluted with ethyl acetate, the resulting solution washed with 2 N NaOH and 2 N HCl, the suspension filtered and the solids dried: Yield 111 mg, 26%; HPLC (60/40) 8.88 minutes (92%); PBMS 424/426 (MH+, 100%); mp 258-261° C.; PBMS 424/426 (MH+, 100%);
Reaction SMILES: Cl.Cl.[Br:3][C:4]1[CH:5]=[CH:6][C:7]([C:10]2([NH2:13])[CH2:12][CH2:11]2)=[N:8][CH:9]=1.C(N(CC)CC)C.[CH3:21][S:22](Cl)(=[O:24])=[O:23]>C(Cl)Cl>[Br:3][C:4]1[CH:5]=[CH:6][C:7]([C:10]2([NH:13][S:22]([CH3:21])(=[O:24])=[O:23])[CH2:11][CH2:12]2)=[N:8][CH:9]=1
Reactant: NC1(c2ccc(Br)cn2)CC1
Reactant: CS(=O)(=O)Cl
Agent: Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CS(=O)(=O)NC1(c2ccc(Br)cn2)CC1
Reaction time: 16 h
Yield: 61.5 %

Procedure:
Commercially available 1-(5-bromopyridin-2-yl)cyclopropanamine dihydrochloric acid salt (494 mg, 1.73 mmol) is dissolved in CH2Cl2 (11.5 mL, 0.15M) and had 3.1 eq. of triethylamine (543 mg, 5.36 mmol) added to it. 1.1 eq. of methanesulfonyl chloride (218 mg, 1.9 mmol) is then added and the mixture stirred for 16 hours. Dichloromethane (20 mL) is added and washed with NaHCO3 (sat, aq). The solvent is evaporated to give the title compound (310 mg): m/z (Cl) 293 [M+H].
Reaction SMILES: [NH2:1][C:2]1[CH:16]=[CH:15][C:5]2[C:6](=[O:14])[NH:7][C:8]3[C:13]([C:4]=2[CH:3]=1)=[CH:12][CH:11]=[CH:10][N:9]=3.Br[CH2:18][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=1[Cl:25]>>[Cl:25][C:20]1[CH:21]=[CH:22][CH:23]=[CH:24][C:19]=1[CH2:18][NH:1][C:2]1[CH:16]=[CH:15][C:5]2[C:6](=[O:14])[NH:7][C:8]3[C:13]([C:4]=2[CH:3]=1)=[CH:12][CH:11]=[CH:10][N:9]=3
Reactant: Nc1ccc2c(=O)[nH]c3ncccc3c2c1
Reactant: Clc1ccccc1CBr
Product: O=c1[nH]c2ncccc2c2cc(NCc3ccccc3Cl)ccc12
Yield: 6.3 %

Procedure:
The title compound was synthesized according to the procedure described for the preparation of Example 458 using 70 (139 mg, 0.66 mmol) and 1-(bromo-methyl)-2-chlorobenzene (162 mg, 0.79 mmol) to provide 470 (14 mg, 6% yield) as a white powder. LC-MS (M+H=337, obsd.=337). 1H NMR (400 MHz, DMSO-D6) δ 11.51 (s, 1H), 8.56 (d, J=6.8, 1H), 8.42 (dd, J=1.6, 4.7, 1H), 8.01 (d, J=8.8, 1H), 7.44 (m, 2H), 7.39 (d, J=2.1, 1H), 7.29 (m, 2H), 7.18 (m, 2H), 6.95 (dd, J=2.1, 8.8, 1H), 4.58 (d, J=5.9, 2H).
Reaction SMILES: [C:1]([C:4]1[C:5](=[O:15])[O:6][C:7]([OH:14])=[C:8]([C:11](=[O:13])[CH3:12])[C:9]=1[OH:10])(=O)[CH3:2].[Cl:16][C:17]1[CH:23]=[CH:22][C:20]([NH2:21])=[CH:19][CH:18]=1>C1(C)C=CC=CC=1>[C:11]([C:8]1[C:7](=[O:14])[O:6][C:5](=[O:15])[C:4](=[C:1]([NH:21][C:20]2[CH:22]=[CH:23][C:17]([Cl:16])=[CH:18][CH:19]=2)[CH3:2])[C:9]=1[OH:10])(=[O:13])[CH3:12]
Reactant: CC(=O)c1c(O)oc(=O)c(C(C)=O)c1O
Reactant: Nc1ccc(Cl)cc1
Solvent: Cc1ccccc1
Product: CC(=O)C1=C(O)C(=C(C)Nc2ccc(Cl)cc2)C(=O)OC1=O

Procedure:
3,5-Diacetyl-4,6-dihydroxy-2H-pyran-2-one (5.3 g.) is dissolved in 200 ml. of boiling toluene and an equimolar amount of p-chloroaniline is added. The mixture is refluxed for 12 hours, cooled and filtered to yield 5-acetyl-3-[1-(p-chlorophenylamino)ethylidene]-4-hydroxy-2H-pyran-2,6(3H)-dione, m.p. 205°-206° C.
Reaction SMILES: [CH2:1]([C:3]1[CH:8]=[C:7]([C:9]2[N:13]=[C:12]([C:14]3[CH:19]=[C:18]([CH3:20])[N:17]=[C:16]([CH2:21][CH3:22])[CH:15]=3)[O:11][N:10]=2)[CH:6]=[C:5]([CH3:23])[C:4]=1[OH:24])[CH3:2].[CH2:25]([C@@H:27]1[O:29][CH2:28]1)Cl>[OH-].[Na+].C(O)(C)C.CC(=O)OCC>[CH2:21]([C:16]1[CH:15]=[C:14]([C:12]2[O:11][N:10]=[C:9]([C:7]3[CH:6]=[C:5]([CH3:23])[C:4]([O:24][CH2:25][C@@H:27]4[CH2:28][O:29]4)=[C:3]([CH2:1][CH3:2])[CH:8]=3)[N:13]=2)[CH:19]=[C:18]([CH3:20])[N:17]=1)[CH3:22]
Reactant: ClC[C@H]1CO1
Reactant: CCc1cc(-c2nc(-c3cc(C)c(O)c(CC)c3)no2)cc(C)n1
Agent: [Na+]
Agent: [OH-]
Solvent: CC(C)O
Solvent: CCOC(C)=O
Product: CCc1cc(-c2nc(-c3cc(C)c(OC[C@@H]4CO4)c(CC)c3)no2)cc(C)n1
Reaction time: 24 h

Procedure:
To a solution of 2-ethyl-4-[5-(2-ethyl-6-methyl-pyridin-4-yl)-[1,2,4]oxadiazol-3-yl]-6-methyl-phenol (89 mg, 0.276 mmol) in 3 N aq. NaOH (1 mL) and isopropanol (4 mL), (R)-epichlorohydrine (142 mg, 1.53 mmol) is added. The mixture is stirred at rt for 24 h before another portion of (R)-epichlorohydrine (142 mg; 1.53 mmol) is added. Stirring is continued for another 24 h at rt. The mixture is diluted with EA (50 mL) and washed with 1M aq. NaOH (10 mL) and brine (10 mL). The org. phase is dried over MgSO4, filtered and evaporated to give crude (S)-2-ethyl-4-[3-(3-ethyl-5-methyl-4-oxiranylmethoxy-phenyl)-[1,2,4]oxadiazol-5-yl]-6-methyl-pyridine; LC-MS*: tR=1.11* min; [M+1]+=380.24.