Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[N:8]1[CH:12]=[CH:11][N:10]=[C:9]1[C:13]1[N:14]=[C:15]2[C:21]3[CH:22]=[C:23]([C:26]([OH:28])=O)[CH:24]=[CH:25][C:20]=3[O:19][CH2:18][CH2:17][N:16]2[CH:29]=1.[NH2:30][C:31]([CH3:35])([CH3:34])[CH2:32][OH:33]>>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[N:8]1[CH:12]=[CH:11][N:10]=[C:9]1[C:13]1[N:14]=[C:15]2[C:21]3[CH:22]=[C:23]([C:26]([NH:30][C:31]([CH3:35])([CH3:34])[CH2:32][OH:33])=[O:28])[CH:24]=[CH:25][C:20]=3[O:19][CH2:18][CH2:17][N:16]2[CH:29]=1
Reactant: CC(C)(N)CO
Reactant: O=C(O)c1ccc2c(c1)-c1nc(-c3nccn3-c3ccccc3Cl)cn1CCO2
Product: CC(C)(CO)NC(=O)c1ccc2c(c1)-c1nc(-c3nccn3-c3ccccc3Cl)cn1CCO2

Procedure:
Following the procedure for 109, 2-(1-(2-chlorophenyl)-1H-imidazol-2-yl)-5,6-dihydrobenzo[f]imidazo[1,2-d][1,4]oxazepine-10-carboxylic acid and 2-amino-2-methylpropan-1-ol gave 161. MS: (ESI+)=478.1. 1H NMR (400 MHz, DMSO) δ 8.12 (d, J=2.1 Hz, 1H), 7.63 (dd, J=6.0, 3.4 Hz, 1H), 7.53 (dd, J=6.1, 3.2 Hz, 2H), 7.50-7.44 (m, 3H), 7.36 (s, 1H), 7.28 (d, J=1.1 Hz, 1H), 7.12 (s, 1H), 6.96 (d, J=8.4 Hz, 1H), 5.00 (s, 1H), 4.41 (s, 4H), 3.55 (d, J=5.1 Hz, 2H), 1.36 (s, 6H)
Reaction SMILES: [I-].[CH3:2][P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.CC([O-])(C)C.[K+].[CH3:28][O:29][C:30]([C@H:32]1[CH2:37][CH2:36][C@H:35]([C@H:38]2[CH2:43][CH2:42][C@H:41]([C@H:44]3[CH2:49][CH2:48][C@H:47]([CH2:50][CH2:51][CH:52]=O)[CH2:46][CH2:45]3)[CH2:40][CH2:39]2)[CH2:34][CH2:33]1)=[O:31].O>C1COCC1>[CH3:28][O:29][C:30]([C@H:32]1[CH2:37][CH2:36][C@H:35]([C@H:38]2[CH2:39][CH2:40][C@H:41]([C@H:44]3[CH2:45][CH2:46][C@H:47]([CH2:50][CH2:51][CH:52]=[CH2:2])[CH2:48][CH2:49]3)[CH2:42][CH2:43]2)[CH2:34][CH2:33]1)=[O:31]
Reactant: C[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: COC(=O)[C@H]1CC[C@H]([C@H]2CC[C@H]([C@H]3CC[C@H](CCC=O)CC3)CC2)CC1
Agent: CC(C)(C)[O-]
Agent: [I-]
Agent: [K+]
Solvent: C1CCOC1
Solvent: O
Product: C=CCC[C@H]1CC[C@H]([C@H]2CC[C@H]([C@H]3CC[C@H](C(=O)OC)CC3)CC2)CC1
Temperature: -50 °C
Reaction time: 1 h

Procedure:
A mixture of 130 g (322 mmol) of methyltriphenylphosphonium iodide and 1.3 liters of THF was cooled to -50° C. To this mixture was added 33.4 g (110 mmol) of t-BuOK and the resulting mixture was stirred for one hour. To this mixture was added dropwise, while maintaining a temperature at below -50° C., a solution of 90.0 g (248 mmol) of crude trans-4-(trans-4-(trans-4-(2-formylethyl)-cyclohexyl)cyclohexyl)cyclohexane carboxylic acid methyl ester in 900 ml of THF. After the dropwise addition, the temperature of the reaction solution was gradually allowed to rise up to room temperature and the mixture was stirred for further 5 hours. After the reaction was completed by adding 500 ml of water, the reaction mixture was filtered through Celite, the solvent was distilled off under reduced pressure and the filtrate was extracted with 1.0 liter of toluene. The organic layer was washed three times with 500 ml of water and dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure and the residue was subjected to a silica gel column chromatography (a developing solvent: toluene) to give 40.0 g of crude trans-4-(trans-4-(trans-4-(3-butenyl)cyclohexyl)cyclohexyl)-cyclohexane carboxylic acid methyl ester.
Reaction SMILES: CC(C)=O.OS(O)(=O)=O.O=[Cr](=O)=O.[CH3:14][C:15]([CH3:27])([C:17]#[C:18][CH:19]([OH:26])[C:20]#[C:21][C:22]([CH3:25])([CH3:24])[CH3:23])[CH3:16]>CC(C)=O>[CH3:24][C:22]([CH3:25])([C:21]#[C:20][C:19](=[O:26])[C:18]#[C:17][C:15]([CH3:27])([CH3:16])[CH3:14])[CH3:23]
Reactant: CC(C)(C)C#CC(O)C#CC(C)(C)C
Agent: O=[Cr](=O)=O
Agent: O=S(=O)(O)O
Solvent: CC(C)=O
Product: CC(C)(C)C#CC(=O)C#CC(C)(C)C
Temperature: 0 °C
Yield: 94 %

Procedure:
The Jones' reagent (2.2 L) was added dropwise to a solution of 2,2,8,8-tetramethylnona-3,6-diyn-5-ol (500 g, 2.6 mol, prepared in Part A above) in acetone (1.5 L), and the rapid, exothermic reaction which followed was minitored by thin layer chromatography for disappearance of starting material. When this had been observed, the two-phase mixture was poured with agitation into ice/water, and the resultant precipitate was filtered and washed with water until a colorless filtrate was obtained. Air drying afforded 2,2,8,8-tetramethylnona-3,6-diyn-5-one (471 g, 94% yield) as pale yellow crystals which melted at 65-66° C. The structure of this compound was confirmed by mass spectroscopy and by 1H and 13C NMR spectroscopy.
Reaction SMILES: C[N:2](/[CH:4]=[C:5]1/[CH:6]([C:13]2[CH:20]=[CH:19][C:16]([C:17]#[N:18])=[CH:15][CH:14]=2)[CH2:7][C:8]([CH3:12])([CH3:11])[C:9]/1=O)C.[ClH:21].[NH2:22]N>C(O)C.C(O)(=O)C>[ClH:21].[CH3:11][C:8]1([CH3:12])[C:9]2[NH:22][N:2]=[CH:4][C:5]=2[CH:6]([C:13]2[CH:20]=[CH:19][C:16]([C:17]#[N:18])=[CH:15][CH:14]=2)[CH2:7]1
Reactant: NN
Reactant: CN(C)/C=C1\C(=O)C(C)(C)CC1c1ccc(C#N)cc1
Agent: Cl
Solvent: CC(=O)O
Solvent: CCO
Product: CC1(C)CC(c2ccc(C#N)cc2)c2cn[nH]c21
Temperature: 80 °C
Yield: 42 %

Procedure:
To (+/−)-4-[(2Z)-2-(dimethylaminomethylene)-4,4-dimethyl-3-oxo-cyclopentyl]benzonitrile (3.2 g, 20 mmol) in ethanol (100 mL) and acetic acid (4 drops) is added hydrazine hydrochloride (4.17 g, 60 mmol) and the reaction is heated to 80° C. for three hours. The reaction is then cooled to room temperature and concentrated in vacuo. The residue is partitioned between ethyl acetate and saturated sodium bicarbonate solution. The layers are separated and the organic is washed with brine, dried over sodium sulfate, filtered, and concentrated in vacuo. The residue is purified by silica gel flash chromatography eluting with 1:2 ethyl acetate:pet ether. The resulting material is treated with HCl in ethyl acetate to provide the title compound (2.3 g, 70%). ES/MS (m/z) 238.2 (M+1).
Reaction SMILES: [Br:1][C:2]1[NH:10][C:9]2[C:8](=[O:11])[NH:7][C:6](=[O:12])[N:5]([CH3:13])[C:4]=2[N:3]=1.Br[CH2:15][C:16]1[CH:21]=[CH:20][C:19]([Cl:22])=[CH:18][CH:17]=1.C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C.C(OCC)(=O)C>[Br:1][C:2]1[N:10]([CH2:15][C:16]2[CH:21]=[CH:20][C:19]([Cl:22])=[CH:18][CH:17]=2)[C:9]2[C:8](=[O:11])[NH:7][C:6](=[O:12])[N:5]([CH3:13])[C:4]=2[N:3]=1
Reactant: Cn1c(=O)[nH]c(=O)c2[nH]c(Br)nc21
Reactant: Clc1ccc(CBr)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: Cn1c(=O)[nH]c(=O)c2c1nc(Br)n2Cc1ccc(Cl)cc1
Temperature: 45 °C
Reaction time: 2 h
Yield: 648.9 %

Procedure:
To a solution of 8-bromo-3-methyl-1H-purine-2,6(3H,7H)-dione (10.8 g, 4.42 mmol) in DMF (200 mL) was added 1-(bromomethyl)-4-chlorobenzene (10 g, 4.86 mmol) followed by potassium carbonate (9.16 g, 6.63 mmol). The resulting mixture was stirred at 45° C. for 2 h. The mixture was diluted with ethyl acetate (300 mL) and washed with brine (200 mL). The layers were separated and the organic slurry was filtered and the filter cake was washed with ice cold ethanol, dried under vacuum to give 8-bromo-7-(4-chlorobenzyl)-3-methyl-1H-purine-2,6(3H,7H)-dione (10.6 g, 64.9% yield) as white solid. LCMS retention time 1.637 min; LCMS MH+ 369.
Reaction SMILES: [F:1][C:2]([F:12])([C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1)[C:3]([NH2:5])=O.B.C(=O)([O-])[O-].[K+].[K+]>O1CCCC1.O>[F:1][C:2]([F:12])([C:6]1[CH:7]=[CH:8][CH:9]=[CH:10][CH:11]=1)[CH2:3][NH2:5]
Reactant: NC(=O)C(F)(F)c1ccccc1
Agent: B
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: C1CCOC1
Product: NCC(F)(F)c1ccccc1
Temperature: 0 °C
Yield: 40.9 %

Procedure:
2,2-Difluoro-2-phenylacetamide (2.4 g, 14 mmol), as prepared in the preceding step, was dissolved in tetrahydrofuran (30 mL) and cooled to 0° C. To this stirred solution was added 1.0 M borane in tetrahydrofuran (35 mL, 35 mmol) dropwise in 30 minutes, and the reaction mixture was refluxed for 16 hours. After cooling to room temperature, a solution of potassium carbonate (5 g) in water (20 mL) was added to the reaction mixture. The mixture was concentrated in vacuo to about 50 mL and extracted with dichloromethane (3×50 mL). The dichloromethane layer was washed with brine, dried over Na2SO4, and concentrated in vacuo. The residue was then purified by flash column chromatography (1:1 ethyl acetate:hexane) to give the title compound as a pale yellow oil (900 mg, 41%). 1H NMR (400 MHz, CDCl3) δ 7.45 (m, 5H), 3.18 (t, 2H, J=14.5 Hz), 1.60 (s(br), 2H).
Reaction SMILES: [CH:1]1([CH2:4][C:5]2[C:6]([OH:16])=[C:7]([CH:12]=[CH:13][C:14]=2[OH:15])[C:8](OC)=[O:9])[CH2:3][CH2:2]1.[Cl-].[NH4+:18]>>[CH:1]1([CH2:4][C:5]2[C:6]([OH:16])=[C:7]([CH:12]=[CH:13][C:14]=2[OH:15])[C:8]([NH2:18])=[O:9])[CH2:3][CH2:2]1
Reactant: [NH4+]
Reactant: COC(=O)c1ccc(O)c(CC2CC2)c1O
Agent: [Cl-]
Product: NC(=O)c1ccc(O)c(CC2CC2)c1O

Procedure:
The compound of Example 15 is heated at 50° C. in a saturated ammonium chloride solution overnight. The reaction mixture is thoroughly extracted with ethyl acetate, and the solvent dried (Na2SO4) and evaporated in vacuo to afford the crude product. Chromatographic purification or silica gel using ethyl acetate/hexane (4:6) as eluant affords the product.
Reaction SMILES: [CH:1]([C:3]1[CH:8]=[CH:7][C:6]([C:9]2[O:10][CH:11]=[CH:12][CH:13]=2)=[CH:5][CH:4]=1)=O.[S:14]([NH2:24])(=[O:23])([C:16]1[CH:21]=[CH:20][C:19]([NH2:22])=[CH:18][CH:17]=1)=[O:15]>C(O)C>[S:14]([C:16]1[CH:21]=[CH:20][C:19]([N:22]=[CH:1][C:3]2[CH:8]=[CH:7][C:6]([C:9]3[O:10][CH:11]=[CH:12][CH:13]=3)=[CH:5][CH:4]=2)=[CH:18][CH:17]=1)(=[O:15])(=[O:23])[NH2:24]
Reactant: Nc1ccc(S(N)(=O)=O)cc1
Reactant: O=Cc1ccc(-c2ccco2)cc1
Solvent: CCO
Product: NS(=O)(=O)c1ccc(N=Cc2ccc(-c3ccco3)cc2)cc1
Temperature: 25 °C

Procedure:
A mixture of 2-(4-formylphenyl)furan (0.335 g, 1.95 mmol, prepared according to the method of Heterocycles, 1990, 31, 1951), sulfanilamide (0.336 g, 1.95 mmol) in ethanol (8 mL) was heated at reflux temperature for 2.5 hour. After cooling to room temperature, the crystals which collected by filtration and washed with ethanol to give the subtitle compound (0.378 g).
Reaction SMILES: [S:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[CH:3]=[C:2]1[C:10]([NH:12][C:13]1[N:21]=[CH:20][CH:19]=[CH:18][C:14]=1[C:15]([NH2:17])=[O:16])=O.[OH-].[Na+]>C(O)C>[S:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[CH:3]=[C:2]1[C:10]1[N:17]=[C:15]([OH:16])[C:14]2[CH:18]=[CH:19][CH:20]=[N:21][C:13]=2[N:12]=1
Reactant: NC(=O)c1cccnc1NC(=O)c1cc2ccccc2s1
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: Oc1nc(-c2cc3ccccc3s2)nc2ncccc12
Temperature: 25 °C
Yield: 57.3 %

Procedure:
To a solution of 2-[(1-benzothien-2-ylcarbonyl)amino]nicotinamide (0.3 g, 1.0 mmol) in ethanol (20 mL) was added NaOH (10 N, 0.3 mL, 3.0 mmol). The resulting solution was heated to reflux overnight. On cooling to rt the solvent was removed under reduced pressure. The residue was dissolved in excess of water and acidified with HCl. The resulting precipitate was filtered and washed with water to afford the product as yellow powder (0.16 g, 57%). HPLC/MS: (M+H)+ 280.0 m/z; Retention time (LC-MS)=2.66 min; 1H NMR (DMSO-D6): 13.17 (1H, s); 8.94(1H, m); 8.61(1H, s); 8.50(1H, d); 8.08(1H, d); 7.97(1H, d); 7.52(3H, m).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9]([C:11]2[C:15]([NH:16][CH:17]3[CH2:22][CH2:21][CH2:20][CH2:19][CH2:18]3)=[CH:14][NH:13][N:12]=2)=[O:10])=[CH:4][CH:3]=1.[C:23]1(=O)CCCCC1.C=O>>[F:1][C:2]1[CH:3]=[CH:4][C:5]([NH:8][C:9]([C:11]2[C:15]([N:16]([CH:17]3[CH2:18][CH2:19][CH2:20][CH2:21][CH2:22]3)[CH3:23])=[CH:14][NH:13][N:12]=2)=[O:10])=[CH:6][CH:7]=1
Reactant: O=C1CCCCC1
Reactant: O=C(Nc1ccc(F)cc1)c1n[nH]cc1NC1CCCCC1
Agent: C=O
Product: CN(c1c[nH]nc1C(=O)Nc1ccc(F)cc1)C1CCCCC1

Procedure:
This compound was prepared in a manner analogous to the compound of Example 19 by successive reductive alkylations using firstly cyclohexanone and then formaldehyde. (LC/MS: Rt 2.77 [MH]+ 316.71).
Reaction SMILES: [NH2:1][C:2]1[N:19]=[CH:18][C:17](Br)=[CH:16][C:3]=1[C:4]([N:6]=[S@@:7]([CH3:15])(=[O:14])[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)=[O:5].[OH:21][C:22]1[CH:23]=[C:24]([C:28]#[CH:29])[CH:25]=[CH:26][CH:27]=1.C(N(CC)CC)C>CCOC(C)=O.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.[Cu]I>[NH2:1][C:2]1[N:19]=[CH:18][C:17]([C:29]#[C:28][C:24]2[CH:25]=[CH:26][CH:27]=[C:22]([OH:21])[CH:23]=2)=[CH:16][C:3]=1[C:4]([N:6]=[S@@:7]([CH3:15])(=[O:14])[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)=[O:5]
Reactant: C[S@@](=O)(=NC(=O)c1cc(Br)cnc1N)c1ccccc1
Reactant: C#Cc1cccc(O)c1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Solvent: CCN(CC)CC
Solvent: CCOC(C)=O
Product: C[S@@](=O)(=NC(=O)c1cc(C#Cc2cccc(O)c2)cnc1N)c1ccccc1
Temperature: 70 °C
Reaction time: 3.3 h
Yield: 4.3 %

Procedure:
To a degassed solution containing (S)-2-amino-5-bromo-N-[methyl(oxo)phenyl-λ6-sulfanylidene]nicotinamide (106 mg, 0.3 mmol) and 3-hydroxyphenylacetylene (50 mg, 0.42 mmol) in 2.0 mL EtOAc at room temperature was added triethylamine (0.13 mL, 0.9 mmol), dichlorobis(triphenylphosphine)palladium(II) (21 mg, 0.03 mmol), and copper(I) iodide (6 mg, 0.03 mmol). The reaction was stirred at 70° C. for 3.3 hours. Additional 3-hydroxyphenylacetylene was added (50 mg, 0.42 mmol) and then again at 5.3 hours (75 mg, 0.63 mmol). The reaction was cooled to room temperature, and after 23 hours additional dichlorobis(triphenylphosphine)palladium(II) (20 mg, 0.03 mmol) was added. The reaction was heated to 60° C. and 3-hydroxyphenylacetylene (120 mg, 1.0 mmol) in 0.7 mL EtOAc (degassed) added dropwise over 7 minutes. The heat was removed after 1 hour and the reaction stirred an additional 22 hours at room temperature. The reaction was dissolved in EtOAc and washed with H2O. The EtOAc layer was extracted with 2% aqueous HCl. The combined acidic aqueous layers were washed with 30% EtOAc/hexane and then made basic with Na2CO3. The basic aqueous layer was extracted with EtOAc. Then the combined organic layers washed with brine, dried with anhydrous Na2SO4 and concentrated. The yellow oil was purified by chromatography (silica gel, CHCl3/EtOAc) to give the title compound as a white solid (5 mg, 4%).
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]([C:10]2[C:19](=[O:20])[C:18]3[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=3)[NH:12][CH:11]=2)=[O:9])=[N:6][CH:7]=1.[Br:21][C:22]1[CH:23]=[C:24]([CH:27]=[CH:28][CH:29]=1)[CH2:25]Br>CN(C=O)C>[Br:21][C:22]1[CH:23]=[C:24]([CH:27]=[CH:28][CH:29]=1)[CH2:25][N:12]1[C:13]2[C:18](=[CH:17][CH:16]=[CH:15][CH:14]=2)[C:19](=[O:20])[C:10]([C:8]([C:5]2[CH:4]=[CH:3][C:2]([CH3:1])=[CH:7][N:6]=2)=[O:9])=[CH:11]1
Reactant: Cc1ccc(C(=O)c2c[nH]c3ccccc3c2=O)nc1
Reactant: BrCc1cccc(Br)c1
Solvent: CN(C)C=O
Product: Cc1ccc(C(=O)c2cn(Cc3cccc(Br)c3)c3ccccc3c2=O)nc1
Yield: 35.1 %

Procedure:
Experimental conditions analogous to those described for Example 1 step 3 were used with 68 mg (0.257 mmol) of 3-(5-Methyl-pyridine-2-carbonyl)-1H-quinolin-4-one, 77.2 mg (0.309 mmol) of 3-bromobenzyl bromide, 12.4 mg (0.309 mmol, 60% dispersion in oil), and 1 mL of DMF. The crude product was purified by reverse phase HPLC with a C18 column, gradient of 20-70% acetonitrile—0.1% TFA to yield 39.1 mg of 1-(3-Bromo-benzyl)-3-(5-methyl-pyridine-2-carbonyl)-1H-quinolin-4-one as a white solid. LC-MSD, m/z for C23H17BrN2O2 [M+H]: 433.05 LC retention time on HPLC, C18 column gradient 20-95% acetonitrile with 0.1% TFA in 4 minutes: 2.5 min.
Reaction SMILES: [C:1]1([C:7]2[CH:14]=[CH:13][C:10]([CH:11]=O)=[CH:9][CH:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[C:15]([O:19]C(=O)CC)(=[O:18])[CH2:16][CH3:17]>>[CH3:17]/[C:16](=[CH:11]\[C:10]1[CH:13]=[CH:14][C:7]([C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=2)=[CH:8][CH:9]=1)/[C:15]([OH:19])=[O:18]
Reactant: O=Cc1ccc(-c2ccccc2)cc1
Reactant: CCC(=O)OC(=O)CC
Product: C/C(=C\c1ccc(-c2ccccc2)cc1)C(=O)O
Yield: 49 %

Procedure:
The procedure is performed in an analogous manner to that described in Example 17 (step A), starting from 4-phenylbenzaldehyde and using 6 equivalents of propionic anhydride. Yield: 49% m.p. 178° C. IR (nujol): 1670 cm-1 1H NMR (CDCl3 /TMS): 11.50 to 11.20 (broad s, 1H); 7.70 (s, 1H); 7.60 to 7.20 (m, 9H); 2.15 (s, 3H).
Reaction SMILES: [CH2:1]([O:8][C:9]([NH:11][C@@H:12]([C:16]([SH:19])([CH3:18])[CH3:17])[C:13]([OH:15])=O)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C1C=CC2N(O)N=NC=2C=1.C(Cl)CCl.[CH2:34]([O:36][CH:37]([O:42][CH2:43][CH3:44])[CH2:38][CH2:39][CH2:40][NH2:41])[CH3:35]>C(Cl)Cl>[CH2:43]([O:42][CH:37]([O:36][CH2:34][CH3:35])[CH2:38][CH2:39][CH2:40][NH:41][C:13](=[O:15])[C@@H:12]([NH:11][C:9](=[O:10])[O:8][CH2:1][C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1)[C:16]([SH:19])([CH3:18])[CH3:17])[CH3:44]
Reactant: CCOC(CCCN)OCC
Reactant: CC(C)(S)[C@H](NC(=O)OCc1ccccc1)C(=O)O
Agent: On1nnc2ccccc21
Solvent: ClCCCl
Solvent: ClCCl
Product: CCOC(CCCNC(=O)[C@@H](NC(=O)OCc1ccccc1)C(C)(C)S)OCC
Temperature: 25 °C
Reaction time: 8 h
Yield: 98.1 %

Procedure:
To a round bottom flask was added (R)-2-(benzyloxycarbonylamino)-3-mercapto-3-methylbutanoic acid (4.68 g, 16.52 mmol), HOBT (2.53 g, 16.52 mmol), EDC (3.17 g, 16.52 mmol), DCM (50 mL), TEA (2.302 mL, 16.52 mmol) and 4,4-diethoxybutan-1-amine (2.66 g, 16.52 mmol). The reaction was stirred at rt overnight. The reaction was diluted with DCM (150 mL). The organics was washed with water (2×150 mL), saturated aqueous NaCl (100 mL). The organic layer was separated, dried over MgSO4, filtered and concentrated to give (R)-benzyl 1-(4,4-diethoxybutylamino)-3-mercapto-3-methyl-1-oxobutan-2-ylcarbamate (6.90 gm, 16.2 mmol, 98% yield) as an oil.
Reaction SMILES: [F:1][C:2]1[CH:9]=[C:8]([CH2:10][CH:11]=O)[CH:7]=[C:6]([F:13])[C:3]=1[C:4]#[N:5].[N+:14]([C:17]1[CH:22]=[CH:21][C:20]([CH2:23][CH2:24][N:25]2[CH2:30][CH2:29][NH:28][CH2:27][CH2:26]2)=[CH:19][CH:18]=1)([O-:16])=[O:15].[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+]>C(Cl)Cl>[F:1][C:2]1[CH:9]=[C:8]([CH2:10][CH2:11][N:28]2[CH2:29][CH2:30][N:25]([CH2:24][CH2:23][C:20]3[CH:19]=[CH:18][C:17]([N+:14]([O-:16])=[O:15])=[CH:22][CH:21]=3)[CH2:26][CH2:27]2)[CH:7]=[C:6]([F:13])[C:3]=1[C:4]#[N:5]
Reactant: O=[N+]([O-])c1ccc(CCN2CCNCC2)cc1
Reactant: N#Cc1c(F)cc(CC=O)cc1F
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCl
Product: N#Cc1c(F)cc(CCN2CCN(CCc3ccc([N+](=O)[O-])cc3)CC2)cc1F

Procedure:
A solution of 2,6-difluoro-4-(2-oxoethyl)benzonitrile (185 mg, 1.0 mmol), 1-[2-(4-nitrophenyl)ethyl]piperazine (200 mg, 0.85 mmol) and NaBH(OAc)3 (720 mg, 3.4 mmol) in anhydrous DCM (10 mL) was stirred at ambient temperature overnight. The reaction was completed according to TLC. The reaction mixture was added 20 mL of DCM, washed with brine, separated the organic layer, dried over anhydrous sodium sulfate and concentrated. The residue was purified by preparative TLC to give the product. 1H-NMR (400 MHz, CDCl3) δ ppm 8.15˜8.17 (d, J=8.6 Hz, 2H), 7.37˜7.39 (d, J=8.6 Hz, 2H), 6.92˜6.94 (d, J=8.6 Hz, 2H), 2.50˜3.11 (m, 16H). MS m/z: 401 (M+1)+. (0.16 μM)
Reaction SMILES: Cl[CH2:2][C:3]([C:5]1[N:6]([CH3:22])[CH:7]=[C:8]([C:10]([C:12]2[CH:21]=[CH:20][C:19]3[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=3)[CH:13]=2)=[O:11])[CH:9]=1)=[O:4].[CH2:23]([NH:25][CH2:26][CH3:27])[CH3:24]>CCO>[CH:13]1[C:14]2[C:19](=[CH:18][CH:17]=[CH:16][CH:15]=2)[CH:20]=[CH:21][C:12]=1[C:10]([C:8]1[CH:9]=[C:5]([C:3](=[O:4])[CH2:2][N:25]([CH2:26][CH3:27])[CH2:23][CH3:24])[N:6]([CH3:22])[CH:7]=1)=[O:11]
Reactant: Cn1cc(C(=O)c2ccc3ccccc3c2)cc1C(=O)CCl
Reactant: CCNCC
Solvent: CCO
Product: CCN(CC)CC(=O)c1cc(C(=O)c2ccc3ccccc3c2)cn1C
Yield: 27.3 %

Procedure:
A solution of 2.5 g (0.008 mole) of 2-chloro-1-[4(2-naphthalenoyl)-1-methyl-1H-pyrrol-2-yl]ethanone and 2.5 mL (0.024 mole) of diethylamine was refluxed for 3 hr in 50 mL of EtOH. After cooling, the solvent was evaporated in vacuo. The residue was chromatographed on silica gel (90:10:1 CH2Cl2:MeOH:NH4OH). The resulting oil was treated with ethereal HCl in EtOH. The resulting gum was converted to the free base by partitioning between Et2O/NaHCO3. This was again chromatographed on silica gel (90:10:1 CH2Cl2:MeOH:NH4OH). The resulting oil was converted to the fumarate salt in 2-PrOH/EtOH. The solid was filtered to give 0.76 g (27%) of Compound 1. mp 130-132° C. CIMS m/z=349 (MH+). 1H NMR (300 MHz, CDCl3) δ 8.4 (Ar, 1H); 8.15-8.0 (Ar, 4H); 7.85 (Ar, 1H); 7.7-7.6 (Ar, 2H); 7.2 (Ar, 1H); 6.6 (s, 2H); 4.0 (s, 3H); 3.7 (s, 2H); 2.6 (q, 4H); 1.0 (t, 6H). Anal calc'd for: C22H24N2O2.C4H4O40.33H2O: C, 66.40; H, 6.14; N, 5.96. Found: C, 66.38; H, 6.43; N, 5.73, KF water 1.22.
Reaction SMILES: I[C:2]1[CH:7]=[C:6]([CH3:8])[CH:5]=[C:4]([C:9]2[CH:14]=[CH:13][C:12]([C:15]([F:18])([F:17])[F:16])=[CH:11][CH:10]=2)[N:3]=1.[Br:19][C:20]1[CH:25]=[CH:24][CH:23]=[C:22](Br)[N:21]=1>[Li]CCCC.[Zn+2].[Br-].[Br-]>[Br:19][C:20]1[N:21]=[C:22]([C:2]2[CH:7]=[C:6]([CH3:8])[CH:5]=[C:4]([C:9]3[CH:14]=[CH:13][C:12]([C:15]([F:18])([F:17])[F:16])=[CH:11][CH:10]=3)[N:3]=2)[CH:23]=[CH:24][CH:25]=1
Reactant: Cc1cc(I)nc(-c2ccc(C(F)(F)F)cc2)c1
Reactant: Brc1cccc(Br)n1
Agent: [Br-]
Agent: [Li]CCCC
Agent: [Zn+2]
Product: Cc1cc(-c2ccc(C(F)(F)F)cc2)nc(-c2cccc(Br)n2)c1

Procedure:
The title compound was prepared from 2-iodo-4-methyl-6-(4-trifluoromethyl-phenyl)-pyridine (example A.58) (5.81 g, 16 mmol), n-BuLi/ZnBr2 and commercially available 2,6-dibromopyridine (5.31 g, 22.4 mmol) according to Tetrahedron Letters 1996, 37(15), 2537 and the general procedure IVc protocol b. Obtained as a white solid (2.34 g, 37%). MS (ISP) 393.0 [(M+H)+] and 395.0 [(M+2+H)+].
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][C:5]([F:21])=[C:6]([C@:8]2([CH2:19][F:20])[CH2:13][C@@H:12]([C:14]([F:17])([F:16])[F:15])[O:11][C:10]([NH2:18])=[N:9]2)[CH:7]=1.[Cl:22][C:23]1[C:24]([C:31](O)=[O:32])=[N:25][CH:26]=[C:27]([C:29]#[N:30])[CH:28]=1.[Cl-].COC1N=C(OC)N=C([N+]2(C)CCOCC2)N=1>C1COCC1.CO>[NH2:18][C:10]1[O:11][C@H:12]([C:14]([F:17])([F:15])[F:16])[CH2:13][C@:8]([C:6]2[CH:7]=[C:2]([NH:1][C:31]([C:24]3[C:23]([Cl:22])=[CH:28][C:27]([C:29]#[N:30])=[CH:26][N:25]=3)=[O:32])[CH:3]=[CH:4][C:5]=2[F:21])([CH2:19][F:20])[N:9]=1
Reactant: NC1=N[C@](CF)(c2cc(N)ccc2F)C[C@@H](C(F)(F)F)O1
Reactant: N#Cc1cnc(C(=O)O)c(Cl)c1
Agent: COc1nc(OC)nc([N+]2(C)CCOCC2)n1
Agent: [Cl-]
Solvent: C1CCOC1
Solvent: CO
Product: N#Cc1cnc(C(=O)Nc2ccc(F)c([C@]3(CF)C[C@@H](C(F)(F)F)OC(N)=N3)c2)c(Cl)c1
Temperature: 25 °C
Reaction time: 17 h
Yield: 48.5 %

Procedure:
To solution of (4S,6S)-4-(5-amino-2-fluorophenyl)-4-(fluoromethyl)-6-(trifluoromethyl)-5,6-dihydro-4H-1,3-oxazin-2-amine (2b, 0.093 g, 0.301 mmol) and 3-chloro-5-cyano-2-pyridinecarboxylic acid (Bionet Research, 0.056 g, 0.307 mmol) in THF (1 mL) and MeOH (0.25 mL) at 0° C. was added 4-(4,6-dimethoxy-1,3,5-triazin-2-yl)-4-methylmorpholin-4-ium chloride (Aldrich, 0.084 g, 0.304 mmol). The reaction mixture was warmed to room temperature, stirred for 17 h and concentrated. Purification by flash column chromatography on silica gel (24 g, 10% to 60% EtOAc (10% 2M NH3 in MeOH) in hexanes) afforded the title compound (0.069 g, 0.146 mmol, 48.4% yield) as a pale yellow solid. MS m/z=474.0 (M+H); Calculated mass for C19H13ClF5N5O2: 473.1
Reaction SMILES: [C:1]([C:4]1[CH:14]=[CH:13][C:7]2[CH:8]=[CH:9][NH:10][S:11](=[O:12])[C:6]=2[CH:5]=1)(=[O:3])[CH3:2].[Br:15]Br>C(Cl)Cl>[Br:15][CH2:2][C:1]([C:4]1[CH:14]=[CH:13][C:7]2[CH:8]=[CH:9][NH:10][S:11](=[O:12])[C:6]=2[CH:5]=1)=[O:3]
Reactant: CC(=O)c1ccc2c(c1)S(=O)NC=C2
Reactant: BrBr
Solvent: ClCCl
Product: O=C(CBr)c1ccc2c(c1)S(=O)NC=C2

Procedure:
0.01 mol of 7-acetylbenzothiazinone, described in Am. Chem. Rome, is dissolved in 100 cm3 of methylene chloride. 0.011 mol of bromine is added dropwise and with stirring via a dropping funnel, and stirring is maintained for 13 hours. The mixture is filtered and evaporated to dryness and the residue is recrystallized.