Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: CN.O=[C:4]1[CH2:8][CH2:7][C:6]2([CH2:13][CH2:12][CH2:11][N:10]([C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])[CH2:9]2)[CH2:5]1.[BH3-][C:22]#[N:23].[Na+]>>[CH3:22][NH:23][CH:4]1[CH2:8][CH2:7][C:6]2([CH2:13][CH2:12][CH2:11][N:10]([C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])[CH2:9]2)[CH2:5]1
Reactant: CC(C)(C)OC(=O)N1CCCC2(CCC(=O)C2)C1
Reactant: [BH3-]C#N
Agent: CN
Agent: [Na+]
Product: CNC1CCC2(CCCN(C(=O)OC(C)(C)C)C2)C1
Temperature: 25 °C
Reaction time: 8 h
Yield: 99.4 %

Procedure:
To a solution of CH3NH2 (33% [w/w] in EtOH, 2 mL) was added tert-butyl 2-oxo-7-azaspiro[4.5]decane-7-carboxylate (197 mg, 0.78 mmol) and the reaction mixture was stirred at rt overnight. Then NaBH3CN (74 mg, 1.17 mmol) was added and the resulting mixture was stirred at rt for another 2 h and then concentrated in vacuo. The residue was purified by silica gel column chromatography (MeOH/DCM (v/v)=1/20) to give the title compound as colorless oil (208 mg, 100%).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:28]([F:31])([F:30])[F:29])=[C:6]([CH:27]=1)[CH2:7][N:8]1[CH2:13][CH2:12][NH:11][C:10]2[N:14]=[CH:15][C:16]([C:18]3[CH:19]=[C:20]([CH:24]=[CH:25][CH:26]=3)[C:21](O)=[O:22])=[CH:17][C:9]1=2.[CH2:32]([N:40]1[CH2:45][CH2:44][NH:43][CH2:42][CH2:41]1)[CH2:33][C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1>>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:28]([F:30])([F:31])[F:29])=[C:6]([CH:27]=1)[CH2:7][N:8]1[CH2:13][CH2:12][NH:11][C:10]2[N:14]=[CH:15][C:16]([C:18]3[CH:19]=[C:20]([C:21]([N:43]4[CH2:44][CH2:45][N:40]([CH2:32][CH2:33][C:34]5[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=5)[CH2:41][CH2:42]4)=[O:22])[CH:24]=[CH:25][CH:26]=3)=[CH:17][C:9]1=2
Reactant: c1ccc(CCN2CCNCC2)cc1
Reactant: O=C(O)c1cccc(-c2cnc3c(c2)N(Cc2cc(Cl)ccc2C(F)(F)F)CCN3)c1
Product: O=C(c1cccc(-c2cnc3c(c2)N(Cc2cc(Cl)ccc2C(F)(F)F)CCN3)c1)N1CCN(CCc2ccccc2)CC1

Procedure:
3-{1-[5-chloro-2-(trifluoromethyl)benzyl]-1,2,3,4-tetrahydropyrido[2,3-b]pyrazin-7-yl}benzoic acid was reacted with 1-phenethylpiperazine as in General Procedure 10 to give the title compound. LCMS: m/z=618.98 (M+H+); retention time=0.64 minutes.
Reaction SMILES: [CH3:1][CH:2]([C@@H:13]1[C@:30]2([CH3:31])[C@H:16]([C:17]3[C@H:27]([CH2:28][CH2:29]2)[C@:25]2([CH3:26])[C:20]([CH2:21][C@@H:22]([O:36][C:37](=[O:39])[CH3:38])[CH2:23][C@@H:24]2[O:32][C:33](=[O:35])[CH3:34])=[CH:19][CH:18]=3)[CH2:15][CH2:14]1)[CH2:3][S:4]([C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1)(=[O:6])=[O:5].C([N-]C(C)C)(C)C.[Li+].C([Li])CCC.C(NC(C)C)(C)C.[O:60]1[CH:62]([CH:63]([CH3:65])[CH3:64])[CH2:61]1.[Cl-].[NH4+]>O1CCCC1.C(OCC)C.CCCCCC>[C:33]([O:32][C@@H:24]1[C@@:25]2([CH3:26])[C:20](=[CH:19][CH:18]=[C:17]3[C@@H:27]2[CH2:28][CH2:29][C@@:30]2([CH3:31])[C@H:16]3[CH2:15][CH2:14][C@@H:13]2[C@H:2]([CH3:1])[CH:3]([S:4]([C:7]2[CH:8]=[CH:9][CH:10]=[CH:11][CH:12]=2)(=[O:6])=[O:5])[CH2:61][CH:62]([OH:60])[CH:63]([CH3:65])[CH3:64])[CH2:21][C@@H:22]([O:36][C:37](=[O:39])[CH3:38])[CH2:23]1)(=[O:35])[CH3:34]
Reactant: CC(=O)O[C@@H]1CC2=CC=C3[C@@H]4CC[C@H](C(C)CS(=O)(=O)c5ccccc5)[C@@]4(C)CC[C@@H]3[C@@]2(C)[C@@H](OC(C)=O)C1
Reactant: CC(C)C1CO1
Agent: CC(C)[N-]C(C)C
Agent: [Cl-]
Agent: [Li+]
Solvent: C1CCOC1
Solvent: CCCCCC
Solvent: CCOCC
Product: CC(=O)O[C@@H]1CC2=CC=C3[C@@H]4CC[C@H]([C@H](C)C(CC(O)C(C)C)S(=O)(=O)c5ccccc5)[C@@]4(C)CC[C@@H]3[C@@]2(C)[C@@H](OC(C)=O)C1
Temperature: -30 °C
Reaction time: 0.5 h
Yield: 40.4 %

Procedure:
In 2 ml of tetrahydrofuran was dissolved 45 mg of 20-methyl-1α,3β-diacetoxy-21-phenylsulfonylpregna-5,7-diene and the solution was cooled in a dry ice-acetone bath under argon atmosphere. A 0.35-ml portion of a lithium diisopropylamide solution prepared from 2 ml of a 1.5N hexane solution of butyllithium and 0.5 ml of diisopropylamine in 10 ml of tetrahydrofuran was added and the resulting mixture was stirred at -30° C. for 30 minutes. The mixture was again cooled in a dry ice-acetone bath and then a solution of 150 mg of 1,2-epoxy-3-methylbutane in 1 ml of tetrahydrofuran was added, and the resulting mixture was stirred at -30° C. to -20° C. for 6 hours. A saturated aqueous solution of ammonium chloride was added to the reaction mixture and the mixture was allowed to warm to ambient temperature. Diethyl ether was then added to the reaction mixture, the organic layer was separated, and the aqueous layer was extracted with diethyl ether. The organic layer was combined, washed in sequence with an aqueous solution of sodium hydrogen carbonate and an aqueous solution of sodium chloride, then dried over sodium sulfate and concentrated. The residue was purified by silica gel thin layer chromatography to give 21 mg of 1α,3β-diacetoxy-22-phenylsulfonylcholesta-5,7-dien-24-ol.
Reaction SMILES: Br[C:2]1[S:3][C:4]([CH:7]=[O:8])=[CH:5][N:6]=1.[CH3:9][C:10]1[N:11]=[CH:12][NH:13][CH:14]=1.C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C>[CH3:9][C:10]1[N:11]=[CH:12][N:13]([C:2]2[S:3][C:4]([CH:7]=[O:8])=[CH:5][N:6]=2)[CH:14]=1
Reactant: Cc1c[nH]cn1
Reactant: O=Cc1cnc(Br)s1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: Cc1cn(-c2ncc(C=O)s2)cn1
Temperature: 110 °C
Yield: 292.6 %

Procedure:
A mixture of 2-bromo-1,3-thiazole-5-carbaldehyde (10 mg, 0.068 mmol), 4-methyl-1H-imidazole (7.23 mg, 0.088 mmol), potassium carbonate (28.1 mg, 0.203 mmol) and DMF (5 ml) were heated at 110° C. for 1 h. The mixture was purified on silica gel (EtOAc/hexane 8:2) to afford 2-(4-methyl-1H-imidazol-1-yl)-1,3-thiazole-5-carbaldehyde (38.4 mg, 0.199 mmol) as a yellow solid. This aldehyde (38.4 mg, 0.199 mmol) and anhydrous potassium carbonate (110 mg, 0.795 mmol) were placed in a 25-ml flask and placed on high vacuum for 10 min. Under N2, anhydrous MeOH (2 ml) was added. To the suspension was added dimethyl (1-diazo-2-oxopropyl) phosphonate (40 μl, 0.256 mmol). The reaction was stirred at rt for 22 h. The mixture was diluted with DCM, washed with water, dried over sodium sulfate, concentrated to afford crude product, which was used in next step directly.
Reaction SMILES: [NH3:1].[CH:2]1([CH2:8][C:9](Cl)=[O:10])[CH2:7][CH2:6][CH2:5][CH2:4][CH2:3]1>C(Cl)(Cl)Cl>[CH:2]1([CH2:8][C:9]([NH2:1])=[O:10])[CH2:7][CH2:6][CH2:5][CH2:4][CH2:3]1
Reactant: O=C(Cl)CC1CCCCC1
Reactant: N
Solvent: ClC(Cl)Cl
Product: NC(=O)CC1CCCCC1
Yield: 87.8 %

Procedure:
Aqueous ammonia was added to solution of 2-cyclohexylacetyl chloride (500 mg, 3.11 mmol) in CHCl3 (10 ml). After completion of reaction, the reaction mixture was diluted with CHCl3 (2×30 ml). The organic layer was washed with saturated sodium bicarbonate solution, brine and dried over anhydrous sodium sulfate. The organic layer was concentrated under vacuum, crude compound was washed with hexane (2×8 ml) and dried to afford 400 mg (87.8%) of 2-cyclohexylacetamide.
Reaction SMILES: Cl.Cl.[NH:3]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:5]([CH:12]2[CH2:17][CH2:16][CH:15]([NH:18][CH:19]([CH:23]3[CH2:28][CH2:27][NH:26][CH2:25][CH2:24]3)[C:20]([NH2:22])=[O:21])[CH2:14][CH2:13]2)=[CH:4]1.[F:29][C:30]1[CH:40]=[CH:39][CH:38]=[CH:37][C:31]=1/[CH:32]=[CH:33]/[C:34](O)=[O:35]>>[NH:3]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:5]([CH:12]2[CH2:17][CH2:16][CH:15]([NH:18][CH:19]([CH:23]3[CH2:24][CH2:25][N:26]([C:34](=[O:35])/[CH:33]=[CH:32]/[C:31]4[CH:37]=[CH:38][CH:39]=[CH:40][C:30]=4[F:29])[CH2:27][CH2:28]3)[C:20]([NH2:22])=[O:21])[CH2:14][CH2:13]2)=[CH:4]1
Reactant: O=C(O)/C=C/c1ccccc1F
Reactant: NC(=O)C(NC1CCC(c2c[nH]c3ccccc23)CC1)C1CCNCC1
Agent: Cl
Product: NC(=O)C(NC1CCC(c2c[nH]c3ccccc23)CC1)C1CCN(C(=O)/C=C/c2ccccc2F)CC1

Procedure:
The title compound was prepared from the product of Example 1, step J, and trans-2-fluoro-cinnamic acid, by the method of Example 1, step K, giving a solid that was a mixture of cyclohexyl diastereomers by LCMS. Mass spectrum (LCMS, ESI pos.) calcd. for C30H35FN4O2: 502 (M+H). Found: 503
Reaction SMILES: [Br:1][C:2]1[CH:21]=[CH:20][C:5]2[O:6][CH2:7][CH:8]([OH:19])[CH2:9][N:10]3[C:18]4[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=4[CH:12]=[C:11]3[C:4]=2[CH:3]=1>C(Cl)Cl.[O-]S([O-])(=S)=O.[Na+].[Na+].C([O-])(O)=O.[Na+]>[Br:1][C:2]1[CH:21]=[CH:20][C:5]2[O:6][CH2:7][C:8](=[O:19])[CH2:9][N:10]3[C:18]4[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=4[CH:12]=[C:11]3[C:4]=2[CH:3]=1
Reactant: OC1COc2ccc(Br)cc2-c2cc3ccccc3n2C1
Agent: O=C([O-])O
Agent: O=S([O-])([O-])=S
Agent: [Na+]
Solvent: ClCCl
Product: O=C1COc2ccc(Br)cc2-c2cc3ccccc3n2C1
Temperature: 25 °C
Reaction time: 8 h
Yield: 70.1 %

Procedure:
DMP (742 mg, 1.749 mmol) was added to the solution of 2-bromo-7,8-dihydro-6H-benzo[2,3][1,5]oxazocino[5,4-a]indol-7-ol (500 mg, 1.46 mmol) in CH2Cl2 (5 mL) at 0° C. The mixture was stirred at room temperature overnight. The mixture was then diluted with saturated Na2S2O3 and NaHCO3 (30 mL, 30 mL). The mixture was extracted with ethyl acetate (20 mL×3). The organic layer was washed with brine (30 mL×3), dried over Na2SO4 and concentrated in vacuo. The resulting residue was purified using prep-TLC (petroleum ether:EA=3:1) to provide 2-bromo-6H-benzo[2,3][1,5]oxazocino[5,4-a]indol-7(8H)-one (350 mg, yield: 70.4%). 1H-NMR (CDCl3, 400 MHz) δ 7.55˜7.68 (m, 2H), 7.53 (t, J=6.0 Hz, 1H), 7.35˜7.37 (m, 1H), 7.28˜7.30 (m, 1H), 7.17˜7.24 (m, 1H), 7.08 (t, J=8.4 Hz, 1H), 6.70 (d, J=0.8 Hz, 1H), 4.73 (s, 2H), 4.55 (s, 2H). MS (M+H)+: 342/344.
Reaction SMILES: [CH3:1][N:2]1[C:6]([CH:7]2[C:16](=O)[C:15]3[C:14]([C:18]([O:20]CC)=O)=[CH:13][CH:12]=[CH:11][C:10]=3[NH:9][CH:8]2[C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)=[CH:5][N:4]=[CH:3]1.O.[NH2:30][NH2:31]>CO>[CH3:1][N:2]1[C:6]([CH:7]2[C:16]3=[N:30][NH:31][C:18](=[O:20])[C:14]4[CH:13]=[CH:12][CH:11]=[C:10]([C:15]=43)[NH:9][CH:8]2[C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)=[CH:5][N:4]=[CH:3]1
Reactant: CCOC(=O)c1cccc2c1C(=O)C(c1cncn1C)C(c1ccccc1)N2
Reactant: NN
Solvent: CO
Solvent: O
Product: Cn1cncc1C1c2n[nH]c(=O)c3cccc(c23)NC1c1ccccc1
Temperature: 25 °C
Reaction time: 5 h
Yield: 46 %

Procedure:
A mixture of ethyl 3-(1-methyl-1H-imidazol-5-yl)-4-oxo-2-phenyl-1,2,3,4-tetrahydroquinoline-5-carboxylate (170 mg) in 85% hydrazine monohydrate (3 mL) and methanol (3 mL) was stirred at room temperature for 5 h. Filtered and washed the cake by methanol (2 mL) to obtain a white solid. The solid was dried in vacuum at 50° C. to obtain 9-(1-methyl-1H-imidazol-5-yl)-8-phenyl-8,9-dihydro-2H-pyrido[4,3,2-de]phthalazin-3(7H)-one (70 mg, yield 46%). 1H-NMR (400 MHz, DMSO-d6) δ (ppm): 3.50 (s, 3H), 4.52-4.54 (d, J=9.2 Hz, 1H), 4.83-4.85 (d, J=9.2 Hz, 1H), 6.66 (s, 1H), 7.17-7.19 (d, J=7.6 Hz, 1H), 7.25-7.32 (m, 3H), 7.36-7.44 (m, 5H), 7.56-7.60 (t, J=8.0 Hz, 1H); LC-MS (ESI) m/z: 348 (M+1)+.
Reaction SMILES: [Cl:1][C:2]1[C:3]([F:47])=[C:4]([CH:9]([OH:46])[CH2:10][CH2:11][NH:12][C@@H:13]2[C:29]3=[N:30][C:26](=[CH:27][N:28]3COCC[Si](C)(C)C)[C:25]3[C:20](=[CH:21][C:22]([NH:39][C:40](=[O:43])[O:41][CH3:42])=[CH:23][CH:24]=3)[NH:19][C:18](=[O:44])[C@H:17]([CH3:45])[CH2:16][CH2:15][CH2:14]2)[C:5]([F:8])=[CH:6][CH:7]=1.[C:48]([O-])([O-])=[O:49].[K+].[K+]>C(#N)C>[Cl:1][C:2]1[C:3]([F:47])=[C:4]([C@@H:9]2[O:46][C:48](=[O:49])[N:12]([C@@H:13]3[C:29]4=[N:30][C:26](=[CH:27][NH:28]4)[C:25]4[C:20](=[CH:21][C:22]([NH:39][C:40](=[O:43])[O:41][CH3:42])=[CH:23][CH:24]=4)[NH:19][C:18](=[O:44])[C@H:17]([CH3:45])[CH2:16][CH2:15][CH2:14]3)[CH2:11][CH2:10]2)[C:5]([F:8])=[CH:6][CH:7]=1
Reactant: O=C([O-])[O-]
Reactant: COC(=O)Nc1ccc2c(c1)NC(=O)[C@H](C)CCC[C@H](NCCC(O)c1c(F)ccc(Cl)c1F)c1nc-2cn1COCC[Si](C)(C)C
Agent: [K+]
Solvent: CC#N
Product: COC(=O)Nc1ccc2c(c1)NC(=O)[C@H](C)CCC[C@H](N1CC[C@H](c3c(F)ccc(Cl)c3F)OC1=O)c1nc-2c[nH]1
Temperature: 75 °C

Procedure:
Methyl N-[(10R,14S)-14-{[3-(3-chloro-2,6-difluorophenyl)-3-hydroxypropyl]amino}-10-methyl-9-oxo-16-{[2-(trimethylsilyl)ethoxy]methyl}-8,16,18-triazatricyclo[13.2.1.02,7]octadeca-1(17),2,4,6,15(18)-pentaen-5-yl]carbamate: A solution of 10F (30 mg, 0.062 mmol), Intermediate 2 (36 mg, 0.108 mmol) and K2CO3 (34.0 mg, 0.246 mmol) in ACN (1 mL) was sealed and heated at 75° C. for 24 h in a 1 dram vial. The reaction mixture was cooled and filtered off the solids. The organic layer is concentrated, dissolved in MeOH and purified by reverse phase HPLC to isolate the desired product as a white solid. The solid was dissolved in MeOH, passed through HCO3 resin cartridge and concentrated to get the desired product (26 mg, 61%, free base) as a white solid. MS (ESI) m/z: 692.2 (M+H)+.
Reaction SMILES: [C:1]([CH:4]([C:11](=O)[CH3:12])[CH2:5][C:6]([O:8][CH2:9][CH3:10])=[O:7])(=O)[CH3:2].O.[NH2:15][NH2:16]>C(O)C>[CH3:2][C:1]1[C:4]([CH2:5][C:6]([O:8][CH2:9][CH3:10])=[O:7])=[C:11]([CH3:12])[NH:16][N:15]=1
Reactant: CCOC(=O)CC(C(C)=O)C(C)=O
Reactant: NN
Solvent: O
Solvent: CCO
Product: CCOC(=O)Cc1c(C)n[nH]c1C
Temperature: 25 °C
Reaction time: 2 h
Yield: 72 %

Procedure:
To a solution of ethyl 3-acetyl-4-oxopentanoate (synthesized as described D. P. Shrout and D. A. Lightner, Synth. Commun. 20 (1990), 2075) (9.676 g, 51.96 mmol) in ethanol, at 0° C., was added slowly a solution of hydrazine hydrate (2.990 g, 59.75 g) in absolute ethanol. The reaction mixture was warmed to room temperature and stirred for 2 hours. After removing ethanol under vacuum, dichloromethane and water were added to the crude product and the organic layer was separated. The aqueous layer was extracted further with dichloromethane and the combined organic extracts were washed with water. After drying over MgSO4 and evaporation of the solvent under reduced pressure, the pyrazole was isolated as a yellow oil. Yield: 72% (6.777 g, 37.2 mmol).
Reaction SMILES: Cl[C:2]1[S:6][N:5]([CH2:7][CH2:8][C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[C:4](=[O:15])[CH:3]=1.[NH:16]1[CH2:21][CH2:20][CH2:19][CH2:18][CH2:17]1.C(N(CC)CC)C.[I-].[Na+]>C(Cl)(Cl)Cl>[N:16]1([C:2]2[S:6][N:5]([CH2:7][CH2:8][C:9]3[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=3)[C:4](=[O:15])[CH:3]=2)[CH2:21][CH2:20][CH2:19][CH2:18][CH2:17]1
Reactant: O=c1cc(Cl)sn1CCc1ccccc1
Reactant: C1CCNCC1
Agent: [I-]
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: ClC(Cl)Cl
Product: O=c1cc(N2CCCCC2)sn1CCc1ccccc1
Yield: 20.8 %

Procedure:
A mixture of 2.4 g. (0.01 mole) of 5-chloro-2-phenethyl-4-isothiazolin-3-one, 0.85 g. (0.01 mole) of piperidine, 1.0 g. (0.01 mole) triethylamine and 0.1 g. sodium iodide in 10 ml of CHCl3 was heated under reflux for 18 hours. The mixture was washed with water, dried (MgSO4) and concentrated to dryness to give 2.7 g. of a liquid residue. This was purified by a dry column chromatography (11/2×20", silica gel, diisopropyl ether) to give 1.0 g. of a solid product, which was recrystallized from 100 ml of diisopropyl ether to give 0.6 g of the named product, mp 106°-108°.
Reaction SMILES: [Si:1]([O:8][C@H:9]([CH2:14][C:15](=[O:23])[CH2:16][P:17]([O:21][CH3:22])([O:19][CH3:20])=[O:18])[CH2:10][C:11]([OH:13])=[O:12])([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].[CH2:24](Br)[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1.C(=O)([O-])[O-].[K+].[K+].O>CC(C)=O.C(OCC)(=O)C>[Si:1]([O:8][C@H:9]([CH2:14][C:15](=[O:23])[CH2:16][P:17]([O:19][CH3:20])([O:21][CH3:22])=[O:18])[CH2:10][C:11]([O:13][CH2:24][C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1)=[O:12])([C:4]([CH3:5])([CH3:6])[CH3:7])([CH3:3])[CH3:2]
Reactant: COP(=O)(CC(=O)C[C@H](CC(=O)O)O[Si](C)(C)C(C)(C)C)OC
Reactant: BrCc1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Solvent: CCOC(C)=O
Solvent: O
Product: COP(=O)(CC(=O)C[C@H](CC(=O)OCc1ccccc1)O[Si](C)(C)C(C)(C)C)OC
Temperature: 25 °C
Reaction time: 6 h
Yield: 87 %

Procedure:
1.84 g (4.99 mmol.) of (R)-3-t-butyldimethylsilyloxy-6-dimethoxyphosphinyl-5-oxohexanoic acid was dissolved in 11.5 ml of acetone. To the acetone solution were added 2.56 g (15.0 mmol.) of benzyl bromide and 0.76 g (5.5 mmol,) of potassium carbonate, and the resulting mixture was vigorously stirred for 6 hours at room temperature to give a reaction solution. The reaction solution was mixed with 12 ml of water and then extracted with 12 ml of toluene. The toluene portion was dried over anhydrous magnesium sulfate and concentrated to give an oil. The oil was treated by column chromatography (eluent: ethyl acetate) to give 1.99 g (4.34 mmol.) of benzyl (R)-3-t-butyldimethylsilyloxy-6-dimethoxyphosphinyl-5-oxohexanoate (optical purity: 99% ee) as an oil (yield: 87%).
Reaction SMILES: Cl[C:2]1[N:10]=[CH:9][N:8]=[C:7]2[C:3]=1[N:4]=[CH:5][N:6]2[C:11]1[CH:12]=[C:13]([CH:20]=[CH:21][C:22]=1[CH3:23])[C:14]([NH:16][CH:17]1[CH2:19][CH2:18]1)=[O:15].[NH2:24][C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1>O1CCOCC1>[CH:17]1([NH:16][C:14](=[O:15])[C:13]2[CH:20]=[CH:21][C:22]([CH3:23])=[C:11]([N:6]3[CH:5]=[N:4][C:3]4[C:7]3=[N:8][CH:9]=[N:10][C:2]=4[NH:24][C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=3)[CH:12]=2)[CH2:19][CH2:18]1
Reactant: Cc1ccc(C(=O)NC2CC2)cc1-n1cnc2c(Cl)ncnc21
Reactant: Nc1ccccc1
Solvent: C1COCCO1
Product: Cc1ccc(C(=O)NC2CC2)cc1-n1cnc2c(Nc3ccccc3)ncnc21
Temperature: 140 °C
Yield: 46.6 %

Procedure:
The mixture of 3-(6-chloro-purin-9-yl)-N-cyclopropyl-4-methyl-benzamide (10 mg, 0.029 mmol) and aniline (14 mg, 0.15 mmol) in 0.2 mL of dioxane was heated with microwave at 140° C. for 20 minutes. It was then cooled to RT and purified by HPLC give the title compound as an off-white solid (5.2 mg, 46%). HPLC tR=2.09 min; MS m/z 385 [M+H]+.
Reaction SMILES: C1(CC([O-])=O)C=CC(C)=CC=1.C(OC(=O)C)(=O)C.C(O)(=O)C.[Na+].[Br-].O=O.[C:27]([O:30][C:31]1[CH:39]=[CH:38][C:34]([C:35](O)=[O:36])=[CH:33][CH:32]=1)(=[O:29])[CH3:28]>>[C:27]([O:30][C:31]1[CH:39]=[CH:38][C:34]([CH:35]=[O:36])=[CH:33][CH:32]=1)(=[O:29])[CH3:28]
Reactant: CC(=O)Oc1ccc(C(=O)O)cc1
Agent: Cc1ccc(CC(=O)[O-])cc1
Agent: O=O
Agent: [Br-]
Solvent: CC(=O)O
Solvent: CC(=O)OC(C)=O
Product: CC(=O)Oc1ccc(C=O)cc1
Temperature: 100 °C

Procedure:
Twenty (20) g. (0.13 moles) of p-cresylacetate, 40 g. (0.39 moles) of acetic anhydride, 40 g. (0.67 moles) of acetic acid, 0.5 g. (0.002 moles) Co(OAc)2· 4H2O, 0.49 g. (0.002 moles) Mn(OAc)2· 4H2O, and 0.43 g. (0.004 moles) NaBr were combined in a glass reactor and heated to 100° C. at atmospheric pressure under air flow of 50 ml/min. The reaction was continued for 71 hours at which time oxygen uptake ceased. Upon cooling, the reaction mixture solidified. Analysis of this material showed p-acetoxybenzoic acid in 77 mole percent yield and p-acetoxybenzaldehyde in 5 mole percent yield. No unreacted p-cresylacetate was detected. The low yield is believed to result from work-up procedures.
Reaction SMILES: C([NH:5][S:6]([C:9]1[CH:14]=[CH:13][C:12]([B:15]([OH:17])[OH:16])=[CH:11][CH:10]=1)(=[O:8])=[O:7])(C)(C)C>C(O)(C(F)(F)F)=O.CCOCC>[NH2:5][S:6]([C:9]1[CH:10]=[CH:11][C:12]([B:15]([OH:17])[OH:16])=[CH:13][CH:14]=1)(=[O:8])=[O:7]
Reactant: CC(C)(C)NS(=O)(=O)c1ccc(B(O)O)cc1
Solvent: O=C(O)C(F)(F)F
Solvent: CCOCC
Product: NS(=O)(=O)c1ccc(B(O)O)cc1

Procedure:
A solution of 4-t-butylaminosulfonylbenzene boronic acid (500 mg) in TFA (5 mL) was stirred at r.t. for 15 h. The mixture was diluted with ether and the solid material was filtered to provide the title compound.
Reaction SMILES: [F:1][C:2]([F:39])([F:38])[CH2:3][CH2:4][CH:5]([C:22]1[CH:37]=[CH:36][C:25]([C:26]([NH:28][CH2:29][CH2:30][C:31]([O:33]CC)=[O:32])=[O:27])=[CH:24][CH:23]=1)[NH:6][C:7]1[CH:8]=[N:9][C:10]([N:13]2[CH:17]=[C:16]([C:18]([F:21])([F:20])[F:19])[CH:15]=[N:14]2)=[CH:11][CH:12]=1.O1CCCC1.[OH-].[Li+]>CO>[F:39][C:2]([F:1])([F:38])[CH2:3][CH2:4][CH:5]([C:22]1[CH:37]=[CH:36][C:25]([C:26]([NH:28][CH2:29][CH2:30][C:31]([OH:33])=[O:32])=[O:27])=[CH:24][CH:23]=1)[NH:6][C:7]1[CH:8]=[N:9][C:10]([N:13]2[CH:17]=[C:16]([C:18]([F:19])([F:20])[F:21])[CH:15]=[N:14]2)=[CH:11][CH:12]=1
Reactant: CCOC(=O)CCNC(=O)c1ccc(C(CCC(F)(F)F)Nc2ccc(-n3cc(C(F)(F)F)cn3)nc2)cc1
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Product: O=C(O)CCNC(=O)c1ccc(C(CCC(F)(F)F)Nc2ccc(-n3cc(C(F)(F)F)cn3)nc2)cc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
A mixture of crude (+/−)-ethyl N-{4-[4,4,4-trifluoro-1-({6-[4-(trifluoromethyl)-1H-pyrazol-1-yl]pyridin-3-yl}amino)butyl]benzoyl}-beta-alaninate (52 mg, 0.093 mmol) was dissolved in methanol (0.20 ml) and tetrahydrofuran (0.10 ml) and treated with aqueous lithium hydroxide (0.093 ml, 0.19 mmol, 2.0M). The mixture was stirred at ambient temperature for 1 hour. The crude reaction mixture was concentrated in vacuo and the residual solid was dissolved in water (0.50 ml) and treated with aqueous 1.0M hydrochloric acid until approximately pH 6 was reached, resulting in the precipitation of racemic N-{4-[4,4,4-trifluoro-1-({6-[4-(trifluoromethyl)-1H-pyrazol-1-yl]pyridin-3-yl}amino)butyl]benzoyl}-beta-alanine as a white gummy solid. The two enantiomeric products were separated by chiral SFC Column: Chiralpak AD-H. Dimensions: 21×250 mm. Mobile Phase: 70/30 CO2/methanol, (peak 1, 0.30 g, 22% and peak 2, 0.30 g, 22%). Flow Rate: 65 mL/min. Modifier: none. Analytical SFC: Chiralpak AD-H, 4.6 mm×25 cm; SFC Mobile Phase 70:30 CO2/Methanol, 2.5 mL/min, analytical retention time: 2.97 min (Isomer 1) and 5.15 (Isomer 2). 1H NMR (400 MHz, CDCl3): δ 8.64 (s, 1H), 7.73-7.84 (m, 4H), 7.70 (d, J=8.8 Hz, 1H), 7.37-7.43 (m, 2H), 6.98 (br. dd, J=8.6, 2.0 Hz, 1H), 6.73-6.86 (m, 1H), 4.48 (br. t, J=6.3 Hz, 1H), 3.73 (br. q, J=5.9 Hz, 2H), 2.72 (br. t, J=5.8 Hz, 2H), 2.06-2.34 (m, 4H). MS (M+1): 530.3.
Reaction SMILES: [Cl:1][C:2]1[CH:8]=[C:7]([N+:9]([O-:11])=[O:10])[CH:6]=[C:5]([Cl:12])[C:3]=1N.C(O)C.N([O-])=O.[Na+].S(=O)(=O)(O)O>O>[Cl:1][C:2]1[CH:8]=[C:7]([N+:9]([O-:11])=[O:10])[CH:6]=[C:5]([Cl:12])[CH:3]=1
Reactant: Nc1c(Cl)cc([N+](=O)[O-])cc1Cl
Agent: O=N[O-]
Agent: O=S(=O)(O)O
Agent: [Na+]
Solvent: CCO
Solvent: O
Product: O=[N+]([O-])c1cc(Cl)cc(Cl)c1
Yield: 84 %

Procedure:
Amer. Chem. Soc., 72 (1950), 798, discloses that 2,6-dichloro-4-nitroaniline, ethanol and sodium nitrite can be reacted at the boil, in the absence of water and in the presence of concentrated sulfuric acid, to give 3,5-dichloronitrobenzene in a yield of 84%. A corresponding reaction to give the 3,5-dibromo derivative gives a yield of 91%. The process is unsatisfactory in respect of yield and purity of the end product and simple, reliable and economical operation, especially on an industrial scale.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[N:4][CH:5]=[C:6]([CH:16]=1)[C:7]([NH:9][CH:10]1[CH2:15][CH2:14][NH:13][CH2:12][CH2:11]1)=[O:8].[CH2:17]([O:19][C:20]1[CH:21]=[C:22]([CH:25]=[CH:26][C:27]=1[O:28][CH:29]([CH2:32][CH3:33])[CH2:30][CH3:31])[CH:23]=O)[CH3:18]>>[CH2:17]([O:19][C:20]1[CH:21]=[C:22]([CH:25]=[CH:26][C:27]=1[O:28][CH:29]([CH2:30][CH3:31])[CH2:32][CH3:33])[CH2:23][N:13]1[CH2:12][CH2:11][CH:10]([NH:9][C:7](=[O:8])[C:6]2[CH:16]=[C:2]([CH3:1])[CH:3]=[N:4][CH:5]=2)[CH2:15][CH2:14]1)[CH3:18]
Reactant: CCOc1cc(C=O)ccc1OC(CC)CC
Reactant: Cc1cncc(C(=O)NC2CCNCC2)c1
Product: CCOc1cc(CN2CCC(NC(=O)c3cncc(C)c3)CC2)ccc1OC(CC)CC
Yield: 36 %

Procedure:
The title compound (14 mg, 36%) was prepared analogously to example 30 from 5-methyl-N-(piperidin-4-yl)-nicotinamide and 3-ethoxy-4-(1-ethyl-propoxy)-benzaldehyde. MS: 440.6 (MH+)
Reaction SMILES: Cl.[NH2:2][C@H:3]([C:14]([O:16][CH3:17])=[O:15])[CH2:4][C:5]1[C:13]2[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=2)[NH:7][CH:6]=1.C(N(CC)CC)C.[CH3:25][C:26]1[CH:27]=[C:28]([CH:34]=[CH:35][CH:36]=1)[CH:29]=[CH:30][C:31](O)=[O:32].CCN=C=NCCCN(C)C.Cl>C(Cl)Cl>[CH3:25][C:26]1[CH:27]=[C:28]([CH:29]=[CH:30][C:31]([NH:2][C@H:3]([C:14]([O:16][CH3:17])=[O:15])[CH2:4][C:5]2[C:13]3[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=3)[NH:7][CH:6]=2)=[O:32])[CH:34]=[CH:35][CH:36]=1
Reactant: COC(=O)[C@@H](N)Cc1c[nH]c2ccccc12
Reactant: Cc1cccc(C=CC(=O)O)c1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COC(=O)[C@H](Cc1c[nH]c2ccccc12)NC(=O)C=Cc1cccc(C)c1
Yield: 98.4 %

Procedure:
The same procedures as in Example 146 were carried out from methyl L-tryptophanate hydrochloride (3.0 g), triethylamine (2.0 mL), 3-methylcinnamic acid (2.3 g), WSC.HCl (2.7 g), and methylene chloride (80 mL), to give the captioned compound (4.2 g, 98%) as an oily product.