Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1][CH2:2][C@:3]([OH:20])([CH3:19])[C:4](=[O:18])[C@@H:5]([NH:10][C:11](=[O:17])[O:12][C:13]([CH3:16])([CH3:15])[CH3:14])[CH2:6][CH:7]([CH3:9])[CH3:8].Cl[S:22]([C:25]1[C:42]([CH3:43])=[CH:41][C:28]([O:29][CH2:30][C:31]([O:33][CH2:34][C:35]2[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=2)=[O:32])=[CH:27][C:26]=1[CH3:44])(=[O:24])=[O:23].CCN(CC)CC>C(Cl)Cl.CN(C1C=CN=CC=1)C>[C:13]([O:12][C:11]([NH:10][C@@H:5]([CH2:6][CH:7]([CH3:9])[CH3:8])[C:4](=[O:18])[C@@:3]([OH:20])([CH3:19])[CH2:2][O:1][S:22]([C:25]1[C:26]([CH3:44])=[CH:27][C:28]([O:29][CH2:30][C:31]([O:33][CH2:34][C:35]2[CH:36]=[CH:37][CH:38]=[CH:39][CH:40]=2)=[O:32])=[CH:41][C:42]=1[CH3:43])(=[O:24])=[O:23])=[O:17])([CH3:14])([CH3:16])[CH3:15]
Reactant: Cc1cc(OCC(=O)OCc2ccccc2)cc(C)c1S(=O)(=O)Cl
Reactant: CC(C)C[C@H](NC(=O)OC(C)(C)C)C(=O)[C@](C)(O)CO
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: Cc1cc(OCC(=O)OCc2ccccc2)cc(C)c1S(=O)(=O)OC[C@@](C)(O)C(=O)[C@H](CC(C)C)NC(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 7 h
Yield: 34.7 %

Procedure:
Referring to FIG. 37, to a solution of the tert-butyl ((2R,4S)-1,2-dihydroxy-2,6-dimethyl-3-oxoheptan-4-yl)carbamate (0.72 g, 2.5 mmol) in DCM (30 mL) were added benzyl 2-(4-(chlorosulfonyl)-3,5-dimethylphenoxy)acetate (1.1 g, 3 mmol), Et3N (0.52 mL, 3.7 mmol) and DMAP (63 mg, 0.5 mmol). The reaction mixture was stirred at room temperature for 7 h (TLC analysis showed some starting material was left). DCM (50 mL) was added and the resulting mixture was washed with HCl solution (1 N, 30 mL) and saturated aqueous NaHCO3 (30 mL). The organic layer was dried over anhydrous Na2SO4 and concentrated under reduced pressure. The residue was purified by flash column chromatography (petroleum ether/EtOAc=10:1) to give product as a white powder (540 mg, 34.8%). LC-MS analysis confirmed the structure.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[C:9]1([C:12]([F:21])([F:20])[C:13]2[N:18]=[CH:17][C:16]([OH:19])=[CH:15][CH:14]=2)[CH2:11][O:10]1.Cl[C:23]1[CH:28]=[CH:27][C:26]([C:29]([F:32])([F:31])[F:30])=[CH:25][N:24]=1.C(=O)([O-])[O-].[Cs+].[Cs+].N#N>CS(C)=O>[F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[C:9]1([C:12]([F:20])([F:21])[C:13]2[CH:14]=[CH:15][C:16]([O:19][C:23]3[CH:28]=[CH:27][C:26]([C:29]([F:32])([F:31])[F:30])=[CH:25][N:24]=3)=[CH:17][N:18]=2)[CH2:11][O:10]1
Reactant: Oc1ccc(C(F)(F)C2(c3ccc(F)cc3F)CO2)nc1
Reactant: FC(F)(F)c1ccc(Cl)nc1
Agent: N#N
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CS(C)=O
Product: Fc1ccc(C2(C(F)(F)c3ccc(Oc4ccc(C(F)(F)F)cn4)cn3)CO2)c(F)c1
Temperature: 60 °C
Reaction time: 2.5 h
Yield: 78.1 %

Procedure:
To a magnetically stirred mixture of 6-((2-(2,4-difluorophenyl)oxiran-2-yl)difluoromethyl)pyridin-3-ol (250 mg, 0.836 mmol) (prepared as in WO 2012/177635 A1) and 2-chloro-5-(trifluoromethyl)pyridine (910 mg, 5.01 mmol) in dry DMSO (10.4 mL) was added cesium carbonate (Cs2CO3) (544 mg, 1.671 mmol) in a 20 mL vial under N2 atmosphere. The reaction mixture was stirred at 60° C. for 2.5 h, then the reaction was stopped by allowing it to cool to rt. The reaction was quenched with H2O, then extracted Et2O (3×). The combined organic extracts were washed with H2O (2×) and brine, dried by passing through a phase separator and volatiles were removed under rotary evaporation. The resulting residue was loaded onto a pad of Celite® and purified by flash chromatography (SiO2, 10-30% EtOAc/Hexanes over 10 min) to yield the title compound as a colorless oil (290 mg, 78%): 1H NMR (400 MHz, CDCl3) δ 8.56 (d, J=2.5 Hz, 1H), 8.44-8.39 (m, 1H), 7.98 (dd, J=8.6, 2.4 Hz, 1H), 7.62 (dd, J=8.6, 2.5 Hz, 1H), 7.59-7.53 (m, 1H), 7.41 (dd, J=14.7, 8.2 Hz, 1H), 7.14 (d, J=8.6 Hz, 1H), 6.89-6.82 (m, 1H), 6.77 (ddd, J=9.8, 9.0, 2.5 Hz, 1H), 3.47 (d, J=5.0 Hz, 1H), 3.03-2.97 (m, 1H). 19F NMR (376 MHz, CDCl3) δ −61.78 (s, 3F), −106.89 (dd, J=257.7, 8.4 Hz, 1F), −107.48-−108.26 (m, 2F), −109.29 (q, J=8.3 Hz, 1F); ESIMS m/z 446 ([M+H]+).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][C:5]2[N:11]([CH3:12])[C:10](=[O:13])[C:9]([CH3:15])([CH3:14])[N:8]=[C:7]([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=3[F:22])[C:6]=2[C:23]=1[Cl:24].[C:25](Cl)(Cl)=[O:26].C(N(CC)CC)C>ClCCCl>[Cl:24][C:23]1[C:6]2[C:7]([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=3[F:22])=[N:8][C:9]([CH3:15])([CH3:14])[C:10](=[O:13])[N:11]([CH3:12])[C:5]=2[CH:4]=[CH:3][C:2]=1[N:1]=[C:25]=[O:26]
Reactant: CN1C(=O)C(C)(C)N=C(c2ccccc2F)c2c1ccc(N)c2Cl
Reactant: O=C(Cl)Cl
Solvent: CCN(CC)CC
Solvent: ClCCCl
Product: CN1C(=O)C(C)(C)N=C(c2ccccc2F)c2c1ccc(N=C=O)c2Cl
Reaction time: 0.17 h

Procedure:
A solution of 3.5 g (0.01 mol) of 7-amino-6-chloro-5-(o-fluorophenyl)-1,3-dihydro-1,3,3-trimethyl-2H-1,4-benzodiazepin-2-one in 60 ml of 1,2-dichloroethane is added dropwise while stirring to a solution of 1.5 g (0.015 mol) of phosgene in ice-cooled 1,2-dichloroethane so that the reaction temperature does not exceed 10°. Subsequently, the reaction mixture is heated at reflux while stirring for a further 10 minutes, whereupon it is cooled to ca 10° and made basic with triethylamine. There is thus obtained a solution of [6-chloro-5-(o-fluorophenyl)-2,3-dihydro-1,3,3-trimethyl-2-oxo-1H-1,4-benzodiazepin-7-yl]isocyanate which can be stored in the cold for several hours with the exclusion of moisture. It is further processed without isolation of the isocyanate contained therein.
Reaction SMILES: C([O:3][C:4]([C:6]1([CH3:21])[CH2:9][CH2:8][N:7]1[C:10](=[O:20])[CH2:11][C:12]1[CH:17]=[C:16]([CH3:18])[CH:15]=[C:14]([CH3:19])[CH:13]=1)=[O:5])C.CCO.[OH-].[Na+]>CO>[CH3:19][C:14]1[CH:13]=[C:12]([CH2:11][C:10]([N:7]2[CH2:8][CH2:9][C:6]2([CH3:21])[C:4]([OH:5])=[O:3])=[O:20])[CH:17]=[C:16]([CH3:18])[CH:15]=1
Reactant: CCOC(=O)C1(C)CCN1C(=O)Cc1cc(C)cc(C)c1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: CCO
Product: Cc1cc(C)cc(CC(=O)N2CCC2(C)C(=O)O)c1
Temperature: 20 °C
Reaction time: 6 h

Procedure:
To a solution of 1-[2-(3,5-dimethyl-phenyl)-acetyl]-2-methyl-azetidine-2-carboxylic acid ethyl ester, Intermediate 94 (1 eq.) in either EtOH or MeOH was added aqueous NaOH (2N) (2 eq.). The reaction was stirred at 20° C. for 6 h. The solvent was removed under reduced pressure and the crude was partitioned between water and EtOAc. The organic layer was discarded and the aqueous layer was neutralized by addition of aqueous HCl (2N) and thoroughly extracted with EtOAc. The organic layers were combined, dried over MgSO4, filtered and concentrated under reduced pressure to afford 1-[2-(3,5-dimethyl-phenyl)-acetyl]-2-methyl-azetidine-2-carboxylic acid.
Reaction SMILES: [CH3:1][C:2]1[C:7]([N+:8]([O-])=O)=[CH:6][C:5]2[C:11]3[CH2:16][CH2:15][N:14]([CH2:17][C:18](=[O:20])[CH3:19])[CH2:13][C:12]=3[C:21](=[O:23])[O:22][C:4]=2[CH:3]=1.[H][H]>CN(C)C=O.[Ni]>[NH2:8][C:7]1[C:2]([CH3:1])=[CH:3][C:4]2[O:22][C:21](=[O:23])[C:12]3[CH2:13][N:14]([CH2:17][C:18](=[O:20])[CH3:19])[CH2:15][CH2:16][C:11]=3[C:5]=2[CH:6]=1
Reactant: CC(=O)CN1CCc2c(c(=O)oc3cc(C)c([N+](=O)[O-])cc23)C1
Reactant: [H][H]
Agent: [Ni]
Solvent: CN(C)C=O
Product: CC(=O)CN1CCc2c(c(=O)oc3cc(C)c(N)cc23)C1
Yield: 70.5 %

Procedure:
A solution of 1,2,3,4-tetrahydro-8-methyl-9-nitro-3-(2-oxopropyl)-5H-[1]benzopyrano[3,4-c]pyridin-5-one (17.2 g, 0.054 moles) in N,N-dimethylformamide (300 ml) is hydrogenated at 50 psi at 24° C. in the presence of Raney Nickel until the required amount of hydrogen has been taken up. The catalyst is filtered off and rinsed with hot N,N-dimethylformamide until free of organic material. The filtrate is slightly concentrated and cooled to give the product (10.9 g), mp 196°-198° C.
Reaction SMILES: Cl.Cl.[NH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][O:10][C:11]1[CH:12]=[C:13]([C:17]2[N:22]=[C:21]([C:23]([O:25][CH3:26])=[O:24])[CH:20]=[CH:19][CH:18]=2)[CH:14]=[CH:15][CH:16]=1.CCN(C(C)C)C(C)C.Cl[C:37](Cl)([O:39]C(=O)OC(Cl)(Cl)Cl)Cl>C(Cl)(Cl)Cl>[N:3]([CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][O:10][C:11]1[CH:12]=[C:13]([C:17]2[N:22]=[C:21]([C:23]([O:25][CH3:26])=[O:24])[CH:20]=[CH:19][CH:18]=2)[CH:14]=[CH:15][CH:16]=1)=[C:37]=[O:39]
Reactant: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Reactant: COC(=O)c1cccc(-c2cccc(OCCCCCCN)c2)n1
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: ClC(Cl)Cl
Product: COC(=O)c1cccc(-c2cccc(OCCCCCCN=C=O)c2)n1
Reaction time: 0.5 h

Procedure:
Methyl 6-(3-(6-aminohexyloxy)phenyl)picolinate dihydrochloride (19) (40 mg, 0.10 mmol) and DIEA (34 μL, 26 mg, 0.20 mmol) were dissolved in CHCl3 (0.7 mL). Triphosgene (14 mg, 0.047 mmol) was dissolved in CHCl3 (0.3 mL). The solutions were combined and a second portion of DIEA (34 μL, 26 mg, 0.20 mmol) was immediately added. The mixture was left to stand 30 min at RT and evaporated. The residue was dissolved in ethyl acetate and the precipitated DIEA hydrochloride was filtered off. The solvent was evaporated and the crude isocyanate (20) was used directly for the next step.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[C:12]([O:14][C:15]3[S:16][CH:17]=[CH:18][N:19]=3)[CH:11]=[C:10]([C:20]([OH:22])=O)[CH:9]=2)=[CH:4][CH:3]=1.[CH3:23][C:24]1[N:29]=[CH:28][C:27]([C@H:30]([NH2:32])[CH3:31])=[CH:26][N:25]=1.F[P-](F)(F)(F)(F)F.C[N+](C)=C(N(C)C)ON1C2N=CC=CC=2N=N1.C(N(CC)C(C)C)(C)C>CN(C)C=O>[CH3:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[CH:13]=[C:12]([O:14][C:15]3[S:16][CH:17]=[CH:18][N:19]=3)[CH:11]=[C:10]([C:20]([NH:32][C@@H:30]([C:27]3[CH:26]=[N:25][C:24]([CH3:23])=[N:29][CH:28]=3)[CH3:31])=[O:22])[CH:9]=2)=[CH:6][CH:7]=1
Reactant: Cc1ncc([C@@H](C)N)cn1
Reactant: Cc1ccc(-c2cc(Oc3nccs3)cc(C(=O)O)c2)cc1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: Cc1ccc(-c2cc(Oc3nccs3)cc(C(=O)N[C@H](C)c3cnc(C)nc3)c2)cc1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
To a solution of 4′-methyl-5-(thiazol-2-yloxy)biphenyl-3-carboxylic acid (50 mg, 0.16 mmol) in N,N-dimethylformamide (1 mL) were added (R)-1-(2-methylpyrimidin-5-yl)ethanamine (45 mg, 0.33 mmol), N,N,N′,N′-tetramethyl-O-(7-azabenzotriazol-1-yl)uronium hexafluorophosphate (150 mg, 0.39 mmol) and N,N-diisopropylethylamine (200 μL, 1.15 mmol). The reaction mixture was stirred at room temperature for 16 hours. LC-MS indicated the reaction was complete. The reaction mixture was purified by preparative HPLC (100×21.2 mm C18 column, CH3CN/water[10 mM Et2NH]) to afford a light color solid.
Reaction SMILES: [NH2:1][CH2:2][C:3]([C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1)=[O:4].[C:11]1([CH3:21])[CH:16]=[CH:15][C:14]([S:17](Cl)(=[O:19])=[O:18])=[CH:13][CH:12]=1.O>N1C=CC=CC=1>[C:11]1([CH3:21])[CH:16]=[CH:15][C:14]([S:17]([NH:1][CH2:2][C:3]([C:5]2[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=2)=[O:4])(=[O:19])=[O:18])=[CH:13][CH:12]=1
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Reactant: NCC(=O)c1ccccc1
Solvent: O
Solvent: c1ccncc1
Product: Cc1ccc(S(=O)(=O)NCC(=O)c2ccccc2)cc1
Temperature: 45 °C
Reaction time: 2 h
Yield: 52.5 %

Procedure:
To a solution of 2-aminoacetophenone (7.0 g, 0.05 mol) in 30 mL of pyridine was added p-toluenesulfonyl chloride (11.8 g, 120 mol %). The reaction mixture was refluxed with stirring for 2 h, cooled to 40-50° C. and poured in the cold water (150 mL). The mixture was stirred at rt for 1 h, filtered, washed with warm (~40° C.) water and then dried. Recrystallization from EtOH afforded 7.6 g (51%) of the title compound, mp 148.2-149.3° C. [lit 147-148° C. (Kemter, G.; Noack, H.; Russ, G. Z. Chem. 1963, 3, 352)]; 1H NMR (CDCl3) δ 11.48 (s, 1H, NH), 7.79 (dd, 1H, J=1.2, J=6.8), 7.72 (d, 1H, J=8.4), 7.67 (d, 1H, J=8.4), 7.44 (t, 1H, J=8), 7.21 (d, 1H, J=8), 7.02 (t, 1H, J=6), 2.55 (s, 3H), 2.36 (s, 3H); 13C NMR (CDCl3) δ 202.37, 143.83, 139.94, 136.47, 134.82, 131.87, 129.57, 127.16, 122.55, 122.18, 118.92, 28.04, 21.42; MS (EI, m/z) 289 (M+).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][CH:9]=1)[CH2:5][OH:6].[Si:10](Cl)([C:13]([CH3:16])([CH3:15])[CH3:14])([CH3:12])[CH3:11].C(N(CC)CC)C>C(Cl)Cl>[Si:10]([O:6][CH2:5][C:4]1[CH:3]=[C:2]([CH:9]=[CH:8][CH:7]=1)[NH2:1])([C:13]([CH3:16])([CH3:15])[CH3:14])([CH3:12])[CH3:11]
Reactant: Nc1cccc(CO)c1
Reactant: CC(C)(C)[Si](C)(C)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(C)(C)[Si](C)(C)OCc1cccc(N)c1
Temperature: 25 °C
Reaction time: 18 h
Yield: 56.7 %

Procedure:
To a solution of 3-aminobenzyl alcohol (2.00 g, 16.2 mmol) and tert-butyldimethylsilyl chloride (2.90 g, 19.4 mmol) in CH2Cl2 (32.5 mL) was added triethylamine (7.45 mL, 53.5 mmol). The reaction mixture was stirred for 18 hours at ambient temperature and was then partitioned between ethyl acetate and H2O. The organic phase was washed twice with H2O, twice with brine, dried over MgSO4, filtered, and concentrated in vacuo. 3-(O-t-butyldimethylsilyloxymethyl)aniline (2.18 g, 57%) was obtained as a yellow oil by chromatography on silica gel (30% ethyl acetate/hexane). 1H NMR (300 MHz, CDCl3) δ7.10 (1H, t, J=7.5 Hz), 6.67-6.72 (2H, m), 6.56 (1H, br d, J=7.5 Hz), 4.66 (2H, s), 3.63 (2H, br s), 0.94 (9H, s), 0.09 (6H, s). MS m/e 238 (M+H)+, 255 (M+NH4)30 .
Reaction SMILES: [H-].[Na+].[CH3:3][O:4][N:5]([CH3:22])[C:6]([CH:8]1[CH2:13][CH2:12][CH2:11][CH:10]([NH:14][C:15](=[O:21])[O:16][C:17]([CH3:20])([CH3:19])[CH3:18])[CH2:9]1)=[O:7].[CH3:23]I.O>C1COCC1>[CH3:3][O:4][N:5]([CH3:22])[C:6]([CH:8]1[CH2:13][CH2:12][CH2:11][CH:10]([N:14]([CH3:23])[C:15](=[O:21])[O:16][C:17]([CH3:19])([CH3:18])[CH3:20])[CH2:9]1)=[O:7]
Reactant: CON(C)C(=O)C1CCCC(NC(=O)OC(C)(C)C)C1
Reactant: CI
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: CON(C)C(=O)C1CCCC(N(C)C(=O)OC(C)(C)C)C1
Temperature: 60 °C
Reaction time: 0.5 h
Yield: 92.5 %

Procedure:
To a suspension of NaH (60%, 340 mg, 8.38 mmol) in THF (10 mL) was added dropwise a solution of tert-butyl 3-{[methoxy(methyl)amino]carbonyl}cyclohexylcarbamate (2.00 g, 6.98 mmol) in THF (10 mL)followed by methyl iodide (1.09 g, 7.68 mmol). The mixture was stirred at 60° C. for 0.5 hr. After cooled to room temperature, the mixture was poured into water and extracted with ethyl acetate. The organic phase was washed with brine, dried over Na2SO4, filtered and evaporated. The residue was purified by column chromatography on silica gel (hexane/ethyl acetate=1/1) to give tert-butyl N-[3-(N-methoxy-N-methylcarbamoyl)cyclohexyl]-N-methylcarbamate as a colorless oil (1.94 g, yield; 93%).
Reaction SMILES: [NH2:1][C@@H:2]([CH2:33][C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1)[C@@H:3]([OH:32])[CH2:4][C@@H:5]([NH:19][C:20]([C@@H:22]([NH:27][C:28](=[O:31])[O:29][CH3:30])[C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21])[CH2:6][C:7]1[CH:12]=[CH:11][C:10]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][N:14]=2)=[CH:9][CH:8]=1.[CH3:40][C:41]([CH3:63])([CH3:62])[C@H:42]([N:46]1[CH2:50][CH2:49][N:48]([CH2:51][C:52]2[CH:57]=[CH:56][CH:55]=[C:54]([N+:58]([O-:60])=[O:59])[CH:53]=2)[C:47]1=[O:61])[C:43](O)=[O:44].CCOP(ON1N=NC2C=CC=CC=2C1=O)(OCC)=O.C(N(CC)C(C)C)(C)C>C1COCC1>[CH3:40][C:41]([CH3:63])([CH3:62])[C@H:42]([N:46]1[CH2:50][CH2:49][N:48]([CH2:51][C:52]2[CH:57]=[CH:56][CH:55]=[C:54]([N+:58]([O-:60])=[O:59])[CH:53]=2)[C:47]1=[O:61])[C:43]([NH:1][C@@H:2]([CH2:33][C:34]1[CH:35]=[CH:36][CH:37]=[CH:38][CH:39]=1)[C@@H:3]([OH:32])[CH2:4][C@@H:5]([NH:19][C:20]([C@@H:22]([NH:27][C:28](=[O:31])[O:29][CH3:30])[C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21])[CH2:6][C:7]1[CH:12]=[CH:11][C:10]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][N:14]=2)=[CH:9][CH:8]=1)=[O:44]
Reactant: CC(C)(C)[C@@H](C(=O)O)N1CCN(Cc2cccc([N+](=O)[O-])c2)C1=O
Reactant: COC(=O)N[C@H](C(=O)N[C@@H](Cc1ccc(-c2ccccn2)cc1)C[C@H](O)[C@@H](N)Cc1ccccc1)C(C)(C)C
Agent: CCOP(=O)(OCC)On1nnc2ccccc2c1=O
Solvent: CCN(C(C)C)C(C)C
Solvent: C1CCOC1
Product: COC(=O)N[C@H](C(=O)N[C@@H](Cc1ccc(-c2ccccn2)cc1)C[C@H](O)[C@H](Cc1ccccc1)NC(=O)[C@@H](N1CCN(Cc2cccc([N+](=O)[O-])c2)C1=O)C(C)(C)C)C(C)(C)C
Temperature: 25 °C
Reaction time: 16 h
Yield: 73.6 %

Procedure:
A solution containing the product from Example 2C (0.065 g, 0.123 mmol) in THF (1 mL) was treated with the product from Example 125B (0.049 g, 0.147 mmol), DEPBT (0.055 g, 0.185 mmol), and N,N-diisopropylethylamine (0.102 mL, 0.615 mmol), stirred at 25° C. for 16 hours, and partitioned between ethyl acetate and 10% Na2CO3 solution. The organic phase was washed with additional 10% Na2CO3 solution and brine, dried over MgSO4, filtered and concentrated. The residue was chromatographed on silica gel eluting with 0-100% ethyl acetate/dichloromethane, followed by 0-5% methanol in ethyl acetate to give the title compound (0.077 g, 74% yield).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:26]=[CH:25][C:6]([C:7]([NH:9][C:10]2[C:11]([NH:16][C:17]([CH:19]3[CH2:24][CH2:23][NH:22][CH2:21][CH2:20]3)=[O:18])=[CH:12][CH:13]=[CH:14][CH:15]=2)=[O:8])=[CH:5][CH:4]=1.[CH:27](=O)[CH:28]([CH3:30])[CH3:29]>>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]([C:7]([NH:9][C:10]2[C:11]([NH:16][C:17]([CH:19]3[CH2:20][CH2:21][N:22]([CH2:27][CH:28]([CH3:30])[CH3:29])[CH2:23][CH2:24]3)=[O:18])=[CH:12][CH:13]=[CH:14][CH:15]=2)=[O:8])=[CH:25][CH:26]=1
Reactant: CC(C)C=O
Reactant: COc1ccc(C(=O)Nc2ccccc2NC(=O)C2CCNCC2)cc1
Product: COc1ccc(C(=O)Nc2ccccc2NC(=O)C2CCN(CC(C)C)CC2)cc1

Procedure:
Using the general procedure described in Example 3, N1-(4-methoxybenzoyl)-N2-(piperidin-4-ylcarbonyl)-1,2-benzenediamine (0.070 mmol) was reacted with isobutyraldehyde to provide 32 mg of the title product as the free base. Treatment with hydrochloric acid and concentration in vacuo yielded the salt of the title compound.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[N:11]=[C:10]([NH:12][NH2:13])[CH2:9][N:8]=[C:7]([C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=3)[C:6]=2[CH:20]=1.[F:21][C:22]([F:28])([F:27])[C:23](=O)[CH2:24][Br:25]>O1CCCC1>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[N:11]=[C:10]([NH:12][N:13]=[C:23]([C:22]([F:28])([F:27])[F:21])[CH2:24][Br:25])[CH2:9][N:8]=[C:7]([C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=3)[C:6]=2[CH:20]=1
Reactant: NNC1=Nc2ccc(Cl)cc2C(c2ccccc2)=NC1
Reactant: O=C(CBr)C(F)(F)F
Solvent: C1CCOC1
Product: FC(F)(F)C(CBr)=NNC1=Nc2ccc(Cl)cc2C(c2ccccc2)=NC1

Procedure:
In the manner given in Example 1, 7-chloro-2-hydrazino-5-phenyl-3H-1,4-benzodiazepine in tetrahydrofuran can be treated with 1,1,1-trifluoro-3-bromopropanone under nitrogen to give 7-chloro-2-[[2-bromo-1-(trifluoromethyl)ethylidene]hydrazino]-5-phenyl-3H-1,4-benzodiazepine.
Reaction SMILES: [CH:1]1([C@H:7]([OH:9])[CH3:8])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[C:10](OC(=O)C)(=[O:12])[CH3:11]>C1(C)C=CC(S(O)(=O)=O)=CC=1>[C:10]([O:9][C@@H:7]([CH:1]1[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1)[CH3:8])(=[O:12])[CH3:11]
Reactant: CC(=O)OC(C)=O
Reactant: C[C@@H](O)C1CCCCC1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Product: CC(=O)O[C@H](C)C1CCCCC1
Temperature: 35 °C
Yield: 99.9 %

Procedure:
A 2 L reaction flask was charged with (R)-1-cyclohexylethanol (980 g, synthesized as above), acetic anhydride (1 Kg), and p-toluene sulphonic acid (0.4 g), and heated at 30-40° C. for 6 hours. The reaction mixture was then transferred into a separatory funnel and washed twice in 200 mL water followed by once in 200 mL 10% sodium hydroxide (NaOH). The resulted organic layer was distilled at 5-10 mmHg to provide (R)-1-cyclohexylethyl acetate (1.3 Kg) (optical rotation: [α]D+2.59°; optical purity: 80.5% ee).
Reaction SMILES: [CH3:1][O:2][C:3]1[N:8]=[CH:7][C:6]([N:9]2[C:18]3[C:13](=[CH:14][CH:15]=[CH:16][N:17]=3)[CH:12]=[C:11]([C:19](O)=[O:20])[C:10]2=[O:22])=[CH:5][CH:4]=1.C(Cl)(=O)C([Cl:26])=O.CN(C)C=O>ClCCl>[CH3:1][O:2][C:3]1[N:8]=[CH:7][C:6]([N:9]2[C:18]3[C:13](=[CH:14][CH:15]=[CH:16][N:17]=3)[CH:12]=[C:11]([C:19]([Cl:26])=[O:20])[C:10]2=[O:22])=[CH:5][CH:4]=1
Reactant: COc1ccc(-n2c(=O)c(C(=O)O)cc3cccnc32)cn1
Reactant: O=C(Cl)C(=O)Cl
Solvent: CN(C)C=O
Solvent: ClCCl
Product: COc1ccc(-n2c(=O)c(C(=O)Cl)cc3cccnc32)cn1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
1.35 g (4.5 mmol) of 1-(6-methoxy-3-pyridinyl)-2-oxo-1,2-dihydro-1,8-naphthyridine-3-carboxylic acid was dissolved in dichloromethane (50 mL), and 2.5 mL (30 mmol) of oxalyl chloride was added thereto. One droplet of N,N-dimethylformamide was added to the above mixture, and the resulting mixture was stirred for 2 hours at room temperature. The reaction solution was concentrated under reduced pressure, and thus 1-(6-methoxy-3-pyridyl)-2-oxo-1,2-dihydro-1,8-naphthyridine-3-carboxylic acid chloride was obtained. The acid chloride thus obtained was dissolved in dichloromethane (50 mL), and 0.56 g (5.0 mmol) of 1,3-cyclohexanedione and 1.54 mL (10.8 mmol) of triethylamine were added to the above solution under ice cooling. The resulting mixture was stirred for 2 hours at room temperature. The reaction mixture was poured into water, and the mixture was extracted with dichloromethane. The organic phase was dried and concentrated. The residue was washed with diisopropyl ether, and thus 1.78 g (yield: quantitative) of the title compound was obtained as a light yellow solid.
Reaction SMILES: [CH3:1][N:2]1[CH2:8][CH2:7][CH2:6][NH:5][CH2:4][CH2:3]1.[C:9]([C:11]1[CH:16]=[CH:15][C:14]([C:17]2[CH:18]=[N:19][N:20]([C:23]3[CH:31]=[CH:30][C:26]([C:27](O)=[O:28])=[CH:25][N:24]=3)[C:21]=2[OH:22])=[C:13]([CH3:32])[CH:12]=1)#[N:10].C(O)=O>>[OH:22][C:21]1[N:20]([C:23]2[CH:31]=[CH:30][C:26]([C:27]([N:5]3[CH2:6][CH2:7][CH2:8][N:2]([CH3:1])[CH2:3][CH2:4]3)=[O:28])=[CH:25][N:24]=2)[N:19]=[CH:18][C:17]=1[C:14]1[CH:15]=[CH:16][C:11]([C:9]#[N:10])=[CH:12][C:13]=1[CH3:32]
Reactant: Cc1cc(C#N)ccc1-c1cnn(-c2ccc(C(=O)O)cn2)c1O
Reactant: CN1CCCNCC1
Solvent: O=CO
Product: Cc1cc(C#N)ccc1-c1cnn(-c2ccc(C(=O)N3CCCN(C)CC3)cn2)c1O

Procedure:
The title compound was prepared in a manner similar to Example 284 using 1-methyl-1,4-diazepane and 6-(4-(4-cyano-2-methylphenyl)-5-hydroxy-1H-pyrazol-1-yl)nicotinic acid to give a formic acid salt (67 mg, 0.145 mmol, 77%) as an off-white solid. MS: 417 (M+H). 1H NMR (400 MHz, DMSO-d6) δ ppm 1.88 (br. s., 2H) 2.35 (s, 3H) 2.54 (br. s., 2H) 2.86 (d, J=17.7 Hz, 3H) 3.01 (br. s., 1H) 3.39-3.76 (m, 5H) 7.45 (d, J=8.1 Hz, 1H) 7.50 (s, 1H) 7.78-7.91 (m, 2H) 8.04 (d, J=7.6 Hz, 1H) 8.42 (br. s., 2H) 11.65 (br. s., 1H)
Reaction SMILES: [CH2:1]([C:5]1[NH:6][C:7]2[C:12]([C:13]=1[C:14](=[O:18])[CH:15]([CH3:17])[CH3:16])=[CH:11][CH:10]=[C:9]([C:19]([O:21][CH3:22])=[O:20])[CH:8]=2)[CH:2]([CH3:4])[CH3:3].[Cl:23][C:24]1[CH:31]=[CH:30][CH:29]=[CH:28][C:25]=1[CH2:26]Br>>[Cl:23][C:24]1[CH:31]=[CH:30][CH:29]=[CH:28][C:25]=1[CH2:26][N:6]1[C:7]2[C:12](=[CH:11][CH:10]=[C:9]([C:19]([O:21][CH3:22])=[O:20])[CH:8]=2)[C:13]([C:14](=[O:18])[CH:15]([CH3:16])[CH3:17])=[C:5]1[CH2:1][CH:2]([CH3:3])[CH3:4]
Reactant: Clc1ccccc1CBr
Reactant: COC(=O)c1ccc2c(C(=O)C(C)C)c(CC(C)C)[nH]c2c1
Product: COC(=O)c1ccc2c(C(=O)C(C)C)c(CC(C)C)n(Cc3ccccc3Cl)c2c1
Yield: 86.9 %

Procedure:
Methyl 1-(2-chlorobenzyl)-2-isobutyl-3-isobutyrylindole -6-carboxylate (258 mg) was prepared from methyl 2-isobutyl-3-isobutyrylindole-6-carboxylate (210 mg) and 2-chlorobenzyl bromide (157 mg) in a similar manner to that of Example 1.
Reaction SMILES: F[C:2]1[CH:28]=[CH:27][C:5]2[N:6]=[C:7]([C:9]3[C:10]([NH2:26])=[N:11][CH:12]=[C:13]([C:15]4[CH:16]=[N:17][N:18]([CH:20]5[CH2:25][CH2:24][NH:23][CH2:22][CH2:21]5)[CH:19]=4)[CH:14]=3)[S:8][C:4]=2[CH:3]=1.[Cl:29]C1SC2C=CC=C(Cl)C=2N=1>>[Cl:29][C:27]1[C:5]2[N:6]=[C:7]([C:9]3[C:10]([NH2:26])=[N:11][CH:12]=[C:13]([C:15]4[CH:16]=[N:17][N:18]([CH:20]5[CH2:25][CH2:24][NH:23][CH2:22][CH2:21]5)[CH:19]=4)[CH:14]=3)[S:8][C:4]=2[CH:3]=[CH:2][CH:28]=1
Reactant: Nc1ncc(-c2cnn(C3CCNCC3)c2)cc1-c1nc2ccc(F)cc2s1
Reactant: Clc1nc2c(Cl)cccc2s1
Product: Nc1ncc(-c2cnn(C3CCNCC3)c2)cc1-c1nc2c(Cl)cccc2s1

Procedure:
Same procedure as 3-(6-fluorobenzothiazol-2-yl)-5-(1-piperidin-4-yl-1H-pyrazol-4-yl)-pyridin-2-ylamine except using 2,4-dichlorobenzothiazole in place of 2-chloro-6-fluorobenzothiazole to afford the title compound as a yellow solid. 1H NMR (400 MHz, DMSO-d6): δ=2.10-2.31 (m, 4H), 3.05-3.19 (m, 2H), 3.33-3.48 (m, 2H), 4.46-4.59 (m, 1H), 7.53 (t, J=7.8 Hz, 1H), 7.71 (d, J=7.3 Hz, 1H), 8.07 (s, 1H), 8.19 (d, J=8.0 Hz, 1H), 8.41 (br. s., 2H), 8.56 (s, 1H). MS (ES+): m/z=411.09/413.08 (3:1) [MH+]. HPLC: tR=2.16 min (ZQ2, polar—5 min).
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:10]=1[NH:9][CH:8]=[CH:7]2.[F:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=1B(O)O>>[F:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=1[C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:10]=1[NH:9][CH:8]=[CH:7]2
Reactant: Brc1cccc2cc[nH]c12
Reactant: OB(O)c1ccccc1F
Product: Fc1ccccc1-c1cccc2cc[nH]c12

Procedure:
Prepared by Procedure I and Scheme T using 7-bromo-1H-indole and 2-fluorophenylboronic acid: ESMS m/e: 211.9 (M+H)+.