Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[C:7]([CH2:8][O:9][C:10]2[C:18]3[N:17]=[C:16]([O:19][CH3:20])[N:15]([CH2:21][C:22]4[CH:27]=[CH:26][CH:25]=[CH:24][N:23]=4)[C:14]=3[CH:13]=[CH:12][CH:11]=2)=[C:6]([Cl:28])[CH:5]=[CH:4][C:3]=1[N:29]([CH3:46])[C:30](=[O:45])[CH2:31][NH:32][C:33]([CH:35]1[CH2:39][CH2:38][N:37]([CH:40]2[CH2:44][CH2:43][NH:42][CH2:41]2)[CH2:36]1)=[O:34].[CH3:47][N:48]=[C:49]=[O:50]>ClCCl>[Cl:1][C:2]1[C:7]([CH2:8][O:9][C:10]2[C:18]3[N:17]=[C:16]([O:19][CH3:20])[N:15]([CH2:21][C:22]4[CH:27]=[CH:26][CH:25]=[CH:24][N:23]=4)[C:14]=3[CH:13]=[CH:12][CH:11]=2)=[C:6]([Cl:28])[CH:5]=[CH:4][C:3]=1[N:29]([CH3:46])[C:30](=[O:45])[CH2:31][NH:32][C:33]([CH:35]1[CH2:39][CH2:38][N:37]([CH:40]2[CH2:44][CH2:43][N:42]([C:49]([NH:48][CH3:47])=[O:50])[CH2:41]2)[CH2:36]1)=[O:34]
Reactant: COc1nc2c(OCc3c(Cl)ccc(N(C)C(=O)CNC(=O)C4CCN(C5CCNC5)C4)c3Cl)cccc2n1Cc1ccccn1
Reactant: CN=C=O
Solvent: ClCCl
Product: CNC(=O)N1CCC(N2CCC(C(=O)NCC(=O)N(C)c3ccc(Cl)c(COc4cccc5c4nc(OC)n5Cc4ccccn4)c3Cl)C2)C1
Temperature: 25 °C

Procedure:
A solution of N-(2-((2,4-dichloro-3-(((2-methoxy-1-(pyridin-2-ylmethyl)-1H-benzo[d]imidazol-4-yl)oxy)methyl)phenyl)(methyl)amino)-2-oxoethyl)-[1,3′-bipyrrolidine]-3-carboxamide (0.20 g, 0.3 mmol) in dichloromethane (15 ml) was treated with methyl isocyanate (0.023 mL, 0.39 mmol) with stirring at room temperature for ten minutes. The reaction was evaporated, treated with methanol and evaporated to a tan solid, 0.20 g. This residue was purified by chromatography (silica gel, dichloromethane and methanol gradient) to afford 24 as a white solid, 0.06 g (28%), that was pure by LC/MS (+ESI) m/z 723 (M+), and was pure by 1HNMR (400 MHz, CDCl3) δ 8.58 (s, 1H), 7.59 (m, 1H), 7.49 (m, 2H), 7.29 (m, 1H), 7.19 (m, 1H), 7.05 (m, 1H), 6.80 (m, 2H), 5.69 (s, 2H), 5.29 (s, 2H), 4.20 (m, 4H), 3.80 (m, 1H), 3.50 (m, 3H), 3.25 (m, 5H), 2.85 (m, 7H), 2.55 (m, 2H), 2.10 (m, 5H). 13CNMR (100 MHz, CDCl3) δ 150, 148, 131, 130, 121, 122, 123, 108, 103, 65, 63, 58, 57, 51, 50, 48, 43, 42, 41, 35, 31, 30, 29, 28. Anal. Calcd for C15H21N3O3+1.0H2O: C, 56.68; H, 5.71; N, 15.11. Found: C, 56.73; H, 5.51; N, 14.82.
Reaction SMILES: [H-].[Na+].[CH2:3]([O:10][C:11]1[CH:16]=[CH:15][C:14]([N:17]2[CH2:22][CH2:21][C:20]([C:24]3[CH:29]=[CH:28][C:27]([C:30]([F:33])([F:32])[F:31])=[CH:26][CH:25]=3)([OH:23])[CH2:19][CH2:18]2)=[CH:13][CH:12]=1)[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.I[CH3:35]>CN(C)C=O>[CH2:3]([O:10][C:11]1[CH:12]=[CH:13][C:14]([N:17]2[CH2:18][CH2:19][C:20]([O:23][CH3:35])([C:24]3[CH:25]=[CH:26][C:27]([C:30]([F:33])([F:31])[F:32])=[CH:28][CH:29]=3)[CH2:21][CH2:22]2)=[CH:15][CH:16]=1)[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1
Reactant: CI
Reactant: OC1(c2ccc(C(F)(F)F)cc2)CCN(c2ccc(OCc3ccccc3)cc2)CC1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COC1(c2ccc(C(F)(F)F)cc2)CCN(c2ccc(OCc3ccccc3)cc2)CC1
Temperature: 0 °C
Reaction time: 2 h
Yield: 79 %

Procedure:
60% sodium hydride (0.225 g, 5.2 mmol) was added to an N,N-dimethylformamide solution (20 ml) of 1-(4-benzyloxyphenyl)-4-(4-trifluoromethylphenyl)piperidin-4-ol (2 g, 4.7 mmol) and iodomethane (0.585 ml, 9.4 mmol) under an argon atmosphere while ice cooling, followed by stirring at the same temperature. After 2 hours, the mixture was poured into ice water, and the precipitate was collected by filtration. The resulting solid was dissolved in ethyl acetate/dichloromethane and dried over sodium sulfate. After removing the desiccant by filtration, the solvent was distilled off. The residue was purified by silica gel column chromatography (dichloromethane:ethyl acetate=100:0→95:5) to afford the title compound as a white powder (1.64 g, 79%).
Reaction SMILES: I[C:2]1[CH:8]=[CH:7][C:5]([NH2:6])=[CH:4][CH:3]=1.[C:9]([O:13][C:14]([N:16]1[CH2:21][CH2:20][NH:19][CH2:18][CH2:17]1)=[O:15])([CH3:12])([CH3:11])[CH3:10].P([O-])([O-])([O-])=O.[K+].[K+].[K+].C(O)CO>CC(O)C.[Cu](I)I>[C:9]([O:13][C:14]([N:16]1[CH2:21][CH2:20][N:19]([C:2]2[CH:8]=[CH:7][C:5]([NH2:6])=[CH:4][CH:3]=2)[CH2:18][CH2:17]1)=[O:15])([CH3:12])([CH3:10])[CH3:11]
Reactant: Nc1ccc(I)cc1
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Agent: I[Cu]I
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Solvent: CC(C)O
Solvent: OCCO
Product: CC(C)(C)OC(=O)N1CCN(c2ccc(N)cc2)CC1
Temperature: 80 °C
Yield: 43.3 %

Procedure:
A mixture of 4-iodoaniline (0.654 g, 3 mmol), piperazine-1-carboxylic acid tert-butyl ester (0.67 g, 3.6 mmol), potassium phosphate (1.272 g, 6 mmol), ethylene glycol (0.33 ml) and copper iodide (0.03 g, 0.15 mmol) in 2-propanol (3 ml) was placed under argon in a sealed-tube and heated to 80° C. for 30 hours. After being cooled to room temperature, the medium was washed with water (50 ml) and extracted with ethyl acetate (100 ml). The organic layer was dried over MgSO4, concentrated and chromatographed (dichloromethane:acetone, 70:30) to yield 43a (0.36 g, 1.3 mmol, 43%) as a yellow powder.
Reaction SMILES: [NH2:1][C:2]1[CH:10]=[CH:9][C:5]([CH2:6][C:7]#[N:8])=[CH:4][CH:3]=1.[CH2:11]([CH:13]1[O:15][CH2:14]1)Cl.C(O)C>O>[O:15]1[CH2:14][CH:13]1[CH2:11][NH:1][C:2]1[CH:10]=[CH:9][C:5]([CH2:6][C:7]#[N:8])=[CH:4][CH:3]=1
Reactant: N#CCc1ccc(N)cc1
Reactant: ClCC1CO1
Solvent: O
Solvent: CCO
Product: N#CCc1ccc(NCC2CO2)cc1
Temperature: 25 °C
Reaction time: 3 h
Yield: 50.8 %

Procedure:
A mixture of 4-aminobenzylcyanide (10 g, 75.7 mmol), epichlorohydrine (7.9 ml, 9.25 g, 100 mmol), ethanol (15 ml) and water (10 ml) was heated under reflux for 2 hours. After cooling the reaction mixture was poured into 100 ml of water and extracted with ether (3×50 ml). The organic extracts were combined and stirred with 50 ml of 10N NaOH at room temperature for 3 hours. The organic layer was separated, washed with water until neutral, dried over MgSO4 and concentrated. The residue was chromatographed over a silica gel column eluting with a 3:1 mixture of benzene and ethyl acetate to afford 7.24 g of the title compound as an oil, yield: 51.0%.
Reaction SMILES: [OH:1]/[N:2]=[C:3](\Cl)/[C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([F:10])[CH:5]=1.[C:12]([O:17][CH2:18][CH3:19])(=[O:16])[C:13]#[C:14][CH3:15].C(N(CC)CC)C>C(OCC)C>[CH2:18]([O:17][C:12]([C:13]1[C:3]([C:4]2[CH:9]=[CH:8][CH:7]=[C:6]([F:10])[CH:5]=2)=[N:2][O:1][C:14]=1[CH3:15])=[O:16])[CH3:19]
Reactant: CC#CC(=O)OCC
Reactant: O/N=C(\Cl)c1cccc(F)c1
Solvent: CCN(CC)CC
Solvent: CCOCC
Product: CCOC(=O)c1c(-c2cccc(F)c2)noc1C
Temperature: 25 °C
Yield: 39.5 %

Procedure:
To a solution of (E)- and/or (Z)—N-hydroxy-3-fluoro-benzenecarboximidoyl chloride (11.1 g, 64 mmol) in diethylether (151 mL) was added ethyl 2-butynoate (7.2 g, 7.5 mL, 64 mmol) at 0° C. followed by the dropwise addition of triethylamine (7.8 g, 10.7 mL, 77 mmol) and the resulting mixture allowed to warm up to room temperature overnight. The mixture was then poured onto ice-water, and extracted with diethylether. The combined organic layers were then washed with water and brine, dried over sodium sulfate and evaporated. Purification by chromatography (SiO2, heptane:ethyl acetate=100:0 to 1:1) afforded the title compound (6.3 g, 39%) which was obtained as a white solid. MS: m/e=250.1 [M+H]+.
Reaction SMILES: [CH:1]1[C:10]2[C:9]3[CH:11]=[CH:12][C:13]4[CH:20]=[CH:19][CH:18]=[CH:17][C:14]=4[C:15](=[O:16])[C:8]=3[CH:7]=[CH:6][C:5]=2[CH:4]=[CH:3][CH:2]=1.[CH3:21][Li]>O1CCCC1.C(OCC)C>[OH:16][C:15]1([CH3:21])[C:8]2[CH:7]=[CH:6][C:5]3[CH:4]=[CH:3][CH:2]=[CH:1][C:10]=3[C:9]=2[CH:11]=[CH:12][C:13]2[CH:20]=[CH:19][CH:18]=[CH:17][C:14]1=2
Reactant: [Li]C
Reactant: O=c1c2ccccc2ccc2c1ccc1ccccc12
Solvent: C1CCOC1
Solvent: CCOCC
Product: CC1(O)c2ccccc2C=Cc2c1ccc1ccccc21

Procedure:
To a solution of 7H-benzo[4,5]cyclohepta[1,2-a]naphthalen-7-one (1.75 g, prepared by the method of Bergmann et al, J. Org. Chem., 1963, 28, 3341) in dry tetrahydrofuran (40 ml) at 0° C. under nitrogen was added a solution of methyl lithium in diethyl ether (8 ml of 1.4M). After 90 minutes at 0° C. the reaction was quenched by the dropwise addition of water (20 ml) and the reaction mixture extracted into diethyl ether (2×75ml). dried (Na2SO4), filtered and the solvents removed under reduced pressure to give a light brown oil (1.9 g).
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([CH:22]=[CH:23][CH:24]=1)[NH:5][C:6]1[C:15]2[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=2)[C:9]([CH:16]2OCOC[O:17]2)=[N:8][N:7]=1.[OH-].[Na+]>OS(O)(=O)=O>[CH3:1][C:2]1[CH:3]=[C:4]([CH:22]=[CH:23][CH:24]=1)[NH:5][C:6]1[C:15]2[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=2)[C:9]([CH:16]=[O:17])=[N:8][N:7]=1
Reactant: Cc1cccc(Nc2nnc(C3OCOCO3)c3ccccc23)c1
Agent: O=S(=O)(O)O
Agent: [Na+]
Agent: [OH-]
Product: Cc1cccc(Nc2nnc(C=O)c3ccccc23)c1
Temperature: 100 °C
Reaction time: 7 h

Procedure:
A suspension of 3.15 g (9.74 mmol) 1-(3-methylanilino)-4-([1,3,5]trioxan-2-yl)phthalazine in 150 ml H2SO4 (10% in H2O) is stirred for 7 h at 100° C. The suspension is cooled to RT and adjusted to alkaline pH with NaOH (20% in H2O), the title compound that precipitates out is filtered off and washed with water; 1H-NMR (DMSO-d6) 10.17 (s, HCO), 9.84 (s, HN), 9.02 (d, 1H), 8.67 (d, 1H), 8.03 (m, 2H), 7.8-7.6 (2 sb, 2H), 7.30 (t, 1H), 6.98 (d, 1H), 2.36 (s, 3H); FAB-MS (M−H)+=262.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:14]=[C:13]([O:15][CH2:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[CH:12]=[CH:11][C:10]=1[CH2:23][C:24](O)=[O:25])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1>C(OCC)C.O1CCCC1>[CH2:1]([O:8][C:9]1[CH:14]=[C:13]([O:15][CH2:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[CH:12]=[CH:11][C:10]=1[CH2:23][CH2:24][OH:25])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=C(O)Cc1ccc(OCc2ccccc2)cc1OCc1ccccc1
Solvent: C1CCOC1
Solvent: CCOCC
Product: OCCc1ccc(OCc2ccccc2)cc1OCc1ccccc1
Temperature: 25 °C
Reaction time: 168 h
Yield: 43.5 %

Procedure:
10 ml (20 mmole) 2 M borane dimethyl sulfide complex in diethyl ether was slowly added to 6.3 g (18.1 mmole) 2,4-dibenzyloxyphenyl acetic acid dissolved in 50 ml dry tetrahydrofuran cooled on an ice bath under nitrogen and then stirred for 7 days at room temperature. The reaction was quenched with water and extracted with ethyl acetate, dried with magnesium sulfate and evaporated. The crude product was purified by chromatography on silica gel using dichloromethane/methanol as eluent to give 2.63 g of the desired product and a mixture of 2,4-dibenzyloxyphenyl acetic acid and the desired product. The mixture was dissolved in 100 ml ethyl acetate, 0.152 g (4 mmole) lithium aluminum hydride was added in portions and the mixture was stirred at room temperature for 6 hours. After 4 hours some more lithium aluminum hydride was added. The reaction was quenched with 1% hydrochloric acid and the solution was filtered. The filtrate was dried with magnesium sulfate and evaporated in vacuo to give 1.3 g more of 2-[2,4-di(benzyloxy)phenyl]-1-ethanol (total yield 3.9 g, 64.4%).
Reaction SMILES: [CH2:1]([O:5][C:6]1[CH:11]=[CH:10][C:9]([CH2:12][C@H:13]([NH:18][C:19]([C@@H:21](/[CH:31]=[CH:32]/[CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][C:39]([F:48])([F:47])[CH2:40][CH2:41][CH2:42][CH2:43][CH2:44][CH2:45][CH3:46])[C@@:22]([OH:30])([CH2:26][CH2:27][O:28][CH3:29])[C:23]([OH:25])=[O:24])=[O:20])[C:14]([O:16][CH3:17])=[O:15])=[CH:8][CH:7]=1)[CH2:2][CH2:3][CH3:4].[I-].[Na+].C(=O)(O)[O-].[Na+].Cl[CH2:57][C:58]1[O:59][C:60](=[O:64])[O:61][C:62]=1[CH3:63]>CN(C=O)C>[CH2:1]([O:5][C:6]1[CH:7]=[CH:8][C:9]([CH2:12][C@H:13]([NH:18][C:19]([C@@H:21](/[CH:31]=[CH:32]/[CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][C:39]([F:47])([F:48])[CH2:40][CH2:41][CH2:42][CH2:43][CH2:44][CH2:45][CH3:46])[C@@:22]([OH:30])([CH2:26][CH2:27][O:28][CH3:29])[C:23]([O:25][CH2:57][C:58]2[O:59][C:60](=[O:64])[O:61][C:62]=2[CH3:63])=[O:24])=[O:20])[C:14]([O:16][CH3:17])=[O:15])=[CH:10][CH:11]=1)[CH2:2][CH2:3][CH3:4]
Reactant: Cc1oc(=O)oc1CCl
Reactant: CCCCCCCC(F)(F)CCCCCC/C=C/[C@H](C(=O)N[C@@H](Cc1ccc(OCCCC)cc1)C(=O)OC)[C@@](O)(CCOC)C(=O)O
Agent: O=C([O-])O
Agent: [I-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCCCCCCC(F)(F)CCCCCC/C=C/[C@H](C(=O)N[C@@H](Cc1ccc(OCCCC)cc1)C(=O)OC)[C@@](O)(CCOC)C(=O)OCc1oc(=O)oc1C
Reaction time: 22 h
Yield: 83 %

Procedure:
To the mixture of (E)-(2S,3S)-3-[(S)-2-(4-butoxy-phenyl)-1-methoxycarbonyl-ethylcarbamoyl]-12,12-difluoro-2-hydroxy-2-(2-methoxy-ethyl)-nonadec-4-enoic acid (No. 5514403, 50 mg, 0.0731 mmol), sodium iodide (16.4 mg, 0.110 mmol), sodium bicarbonate (7.4 mg, 0.877 mmol) and the DMF (1 mL) was added commercially available 4-chloromethyl-5-methyl-1,3-dioxol-2-one (15.9 μL, 0.145 mmol) at room temperature, and the mixture was stirred as it was for 22 hours. After confirming the consumption of the starting materials by LCMS, the reaction solution was filtered through a syringe filter, and purified as it was by preparative HPLC. The purified fraction was freeze-dried to obtain the title compound (48 mg, 83% yield) as yellow oil.
Reaction SMILES: C([N:4]1[C:12]2[C:7](=[CH:8][C:9]([O:15][CH3:16])=[C:10]([O:13][CH3:14])[CH:11]=2)[C:6](=[C:17](OCC)[C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[C:5]1=[O:27])(=O)C.[C:28]([N:32]([CH2:40][CH2:41][N:42]([CH3:44])[CH3:43])[C:33]1[CH:38]=[CH:37][C:36]([NH2:39])=[CH:35][CH:34]=1)(=[O:31])[CH2:29][CH3:30]>>[C:28]([N:32]([C:33]1[CH:38]=[CH:37][C:36]([NH:39]/[C:17](=[C:6]2\[C:5](=[O:27])[NH:4][C:12]3[C:7]\2=[CH:8][C:9]([O:15][CH3:16])=[C:10]([O:13][CH3:14])[CH:11]=3)/[C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)=[CH:35][CH:34]=1)[CH2:40][CH2:41][N:42]([CH3:44])[CH3:43])(=[O:31])[CH2:29][CH3:30]
Reactant: CCOC(=C1C(=O)N(C(C)=O)c2cc(OC)c(OC)cc21)c1ccccc1
Reactant: CCC(=O)N(CCN(C)C)c1ccc(N)cc1
Product: CCC(=O)N(CCN(C)C)c1ccc(N/C(=C2\C(=O)Nc3cc(OC)c(OC)cc32)c2ccccc2)cc1

Procedure:
Prepared from 1-acetyl-3-(1-ethoxy-1-phenyl-methylidene)-5,6-dimethoxy-2-indolinone and N-propionyl-N-(2-dimethylamino-ethyl)-p-phenylenediamine
Reaction SMILES: [OH:1][CH:2]([C:6]1[CH:11]=[CH:10][C:9]([C:12]2[N:16]=[C:15]([C:17]3[O:21][N:20]=[C:19]([C:22]4[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=4)[C:18]=3[C:28]([F:31])([F:30])[F:29])[O:14][N:13]=2)=[CH:8][CH:7]=1)[C:3](O)=[O:4].[NH2:32][C@@H:33]([CH3:36])[C:34]#[N:35].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CN1CCOCC1>CN(C=O)C>[C:34]([C@@H:33]([NH:32][C:3](=[O:4])[CH:2]([OH:1])[C:6]1[CH:7]=[CH:8][C:9]([C:12]2[N:16]=[C:15]([C:17]3[O:21][N:20]=[C:19]([C:22]4[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=4)[C:18]=3[C:28]([F:30])([F:31])[F:29])[O:14][N:13]=2)=[CH:10][CH:11]=1)[CH3:36])#[N:35]
Reactant: O=C(O)C(O)c1ccc(-c2noc(-c3onc(-c4ccccc4)c3C(F)(F)F)n2)cc1
Reactant: C[C@H](N)C#N
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN1CCOCC1
Solvent: CN(C)C=O
Product: C[C@@H](C#N)NC(=O)C(O)c1ccc(-c2noc(-c3onc(-c4ccccc4)c3C(F)(F)F)n2)cc1
Reaction time: 1 h
Yield: 32.8 %

Procedure:
2-Hydroxy-2-(4-(5-(3-phenyl-4-(trifluoromethyl)isoxazol-5-yl)-1,2,4-oxadiazol-3-yl)phenyl)acetic acid (Int-Vb, 25 mg, 0.058 mmol), (S)-2-aminopropanenitrile (Int-X, 6.09 mg, 0.087 mmol), HATU (28.7 mg, 0.075 mmol), and 4-methylmorpholine (23.45 mg, 0.232 mmol) were dissolved in DMF (1 mL). The reaction mixture was stirred for 1 h, and then purified by prep HPLC (PHENOMENEX® Luna 5u 21.2×250 mm gradient elution with Method 2—CH3CN/water containing 0.1% trifluoroacetic acid as defined above, 0% B to 100% B over 30 min, 20 mL/min, 220 nM, product retention=25.5 min) to provide single enantiomer N—((S)-1-cyanoethyl)-2-hydroxy-2-(4-(5-(3-phenyl-4-(trifluoromethyl)isoxazol-5-yl)-1,2,4-oxadiazol-3-yl)phenyl)acetamide (10 mg, 0.019 mmol, 32.1% yield): LCMS=484.0 [M+H]+; 1H NMR (400 MHz, methanol-d4) δ ppm 8.12-8.26 (2 H, m), 7.50-7.78 (7 H, m), 5.17 (1 H, s), 4.85-4.94 (1 H, m), 1.56 (3 H, d, J=7.26 Hz); HPLC peak RT=9.9 min (Method A).
Reaction SMILES: F[C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([O:8][CH3:9])[C:3]=1[N+:10]([O-:12])=[O:11].[CH3:13][O:14][CH2:15][CH2:16][CH2:17][NH2:18]>CN(C)C=O>[CH3:9][O:8][C:4]1[C:3]([N+:10]([O-:12])=[O:11])=[C:2]([CH:7]=[CH:6][CH:5]=1)[NH:18][CH2:17][CH2:16][CH2:15][O:14][CH3:13]
Reactant: COc1cccc(F)c1[N+](=O)[O-]
Reactant: COCCCN
Solvent: CN(C)C=O
Product: COCCCNc1cccc(OC)c1[N+](=O)[O-]
Temperature: -15 °C
Yield: 79.8 %

Procedure:
Into a 25 mL round bottomed was added 1-fluoro-3-methoxy-2-nitrobenzene (500 mg, 2.92 mmol) and N,N-dimethylforamide (5.8 mL). The flask was cooled to −15° C. and 3-methoxypropylamine (313 mg, 3.5 mmol) in N,N-dimethylforamide (2.2 mL) was slowly added. The reaction was allowed to warm to room temperature overnight. Solvent was removed under vacuum and the residue was purified by column chromatography (20% ethylacetate:hexanes) to give 3-methoxy-N-(3-methoxypropyl)-2-nitroaniline (37A) as a yellow oil (560 mg, 80% yield). ESI-MS:m/z 241.3 (M+H)+.
Reaction SMILES: [CH:1]1([C:6]2[C:15]([C:16]#[N:17])=[C:14](O)[C:13]3[C:8](=[CH:9][CH:10]=[C:11]([C:19]([F:22])([F:21])[F:20])[CH:12]=3)[N:7]=2)[CH2:5][CH2:4][CH2:3][CH2:2]1.P(Br)(Br)[Br:24]>CN(C=O)C>[Br:24][C:14]1[C:13]2[C:8](=[CH:9][CH:10]=[C:11]([C:19]([F:22])([F:21])[F:20])[CH:12]=2)[N:7]=[C:6]([CH:1]2[CH2:5][CH2:4][CH2:3][CH2:2]2)[C:15]=1[C:16]#[N:17]
Reactant: BrP(Br)Br
Reactant: N#Cc1c(C2CCCC2)nc2ccc(C(F)(F)F)cc2c1O
Solvent: CN(C)C=O
Product: N#Cc1c(C2CCCC2)nc2ccc(C(F)(F)F)cc2c1Br
Reaction time: 20 h
Yield: 76.8 %

Procedure:
To a solution of 2-cyclopentyl-4-hydroxy-6-trifluoromethyl-quinoline-3-carbonitrile (200 mg, 490 μmol) in DMF (2.00 ml) was added phosphorus tribromide (1.47 ml, 1.47 mmol) dropwise at 0° C. The reaction mixture was allowed to reach room temperature and stirring was continued for 20 h. The mixture was concentrated in vacuo and the remaining residue was poured on water. The mixture was extracted with EtOAc and the combined extracts were dried with Na2SO4 and evaporated. The resulting yellow solid was purified by column chromatography (silica gel, dichloromethane) to afford the title compound (139 mg, 77%) as white solid. MS (ESI): 369.5 (M+H)+.
Reaction SMILES: [CH:1]1[C:10]2[C:5](=[CH:6][C:7]([NH:11][C:12](=[O:28])[CH:13]([C:23]3[CH:27]=[CH:26][S:25][CH:24]=3)[CH2:14][NH:15]C(=O)OC(C)(C)C)=[CH:8][CH:9]=2)[CH:4]=[CH:3][N:2]=1.[ClH:29]>C(Cl)Cl>[ClH:29].[ClH:29].[NH2:15][CH2:14][CH:13]([C:23]1[CH:27]=[CH:26][S:25][CH:24]=1)[C:12]([NH:11][C:7]1[CH:6]=[C:5]2[C:10](=[CH:9][CH:8]=1)[CH:1]=[N:2][CH:3]=[CH:4]2)=[O:28]
Reactant: CC(C)(C)OC(=O)NCC(C(=O)Nc1ccc2cnccc2c1)c1ccsc1
Agent: Cl
Solvent: ClCCl
Product: NCC(C(=O)Nc1ccc2cnccc2c1)c1ccsc1
Reaction time: 9 h

Procedure:
To tert-butyl 3-(isoquinolin-6-ylamino)-3-oxo-2-(thiophen-3-yl)propylcarbamate (E48) in CH2Cl2 was added HCl (4N in dioxane), and the solution was stirred for 8-10 hours. The solvents were evaporated to give pure 3-amino-N-(isoquinolin-6-yl)-2-(thiophen-3-yl)propanamide dihydrochloride (E49).
Reaction SMILES: [Cl:1][C:2]1[C:10]2[NH:9][N:8]=[CH:7][C:6]=2[C:5]2[CH2:11][N:12]([CH2:21][C:22]([F:25])([F:24])[F:23])[C:13](=[O:20])[C@H:14]([CH2:16][C:17](O)=[O:18])[CH2:15][C:4]=2[CH:3]=1.[Cl:26][C:27]1[CH:28]=[CH:29][C:30]([C:35]2[CH2:36][CH2:37][NH:38][CH2:39][CH:40]=2)=[C:31]([CH:34]=1)[C:32]#[N:33].CCN(C(C)C)C(C)C.C1CN([P+](ON2N=NC3C=CC=CC2=3)(N2CCCC2)N2CCCC2)CC1.F[P-](F)(F)(F)(F)F>CN(C=O)C>[Cl:26][C:27]1[CH:28]=[CH:29][C:30]([C:35]2[CH2:40][CH2:39][N:38]([C:17](=[O:18])[CH2:16][C@H:14]3[C:13](=[O:20])[N:12]([CH2:21][C:22]([F:23])([F:25])[F:24])[CH2:11][C:5]4[C:6]5[CH:7]=[N:8][NH:9][C:10]=5[C:2]([Cl:1])=[CH:3][C:4]=4[CH2:15]3)[CH2:37][CH:36]=2)=[C:31]([CH:34]=1)[C:32]#[N:33]
Reactant: O=C(O)C[C@@H]1Cc2cc(Cl)c3[nH]ncc3c2CN(CC(F)(F)F)C1=O
Reactant: N#Cc1cc(Cl)ccc1C1=CCNCC1
Agent: F[P-](F)(F)(F)(F)F
Agent: c1ccc2c(c1)nnn2O[P+](N1CCCC1)(N1CCCC1)N1CCCC1
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: N#Cc1cc(Cl)ccc1C1=CCN(C(=O)C[C@@H]2Cc3cc(Cl)c4[nH]ncc4c3CN(CC(F)(F)F)C2=O)CC1
Temperature: 25 °C
Reaction time: 3 h
Yield: 51.9 %

Procedure:
In an oven-dried round bottom flask, (S)-2-(4-chloro-8-oxo-9-(2,2,2-trifluoroethyl)-3,6,7,8,9,10-hexahydroazepino[3,4-e]indazol-7-yl)acetic acid (50 mg, 0.133 mmol) and 5-chloro-2-(1,2,3,6-tetrahydropyridin-4-yl)benzonitrile (44.1 mg, 0.173 mmol) were dissolved in DMF (2 ml). To this solution was added DIEA (0.093 ml, 0.532 mmol) followed by PyBOP (69.3 mg, 0.133 mmol). The reaction mixture was allowed to stir at room temperature under a nitrogen atmosphere for 3 hours during which time it became dark red in color. The DMF was evaporated under high vacuum. The residue was subjected to column chromatography (silica, 20:1 CH2Cl2/2M NH3 in MeOH). The most pure fractions were collected, evaporated and again subjected to column chromatography (silica, 40:1 CH2Cl2/2M NH3 in MeOH). The fractions were collected, evaporated and dried overnight under vacuum to give (S)-5-chloro-2-(1-(2-(4-chloro-8-oxo-9-(2,2,2-trifluoroethyl)-3,6,7,8,9,10-hexahydroazepino[3,4-e]indazol-7-yl)acetyl)-1,2,3,6-tetrahydropyridin-4-yl)benzonitrile (40 mg, 0.069 mmol, 52.1% yield) as a light tan solid. 1H NMR (500 MHz, MeOD) δ ppm 1.24-1.34 (m, 1H) 2.50-2.60 (m, 3H) 2.60-2.76 (m, 2H) 2.95-3.05 (m, 1H) 3.14-3.23 (m, 2H) 3.82-3.91 (m, 1H) 3.90-4.02 (m, 1H) 4.05-4.14 (m, 1H) 4.53-4.62 (m, 2H) 5.54 (d, J=17.4 Hz, 1H) 6.07 (d, J=13.7 Hz, 1H) 7.21 (s, 1H) 7.46 (d, J=8.3 Hz, 1H) 7.64 (d, J =8.5 Hz, 1H) 7.78 (s, 1H) 8.24 (s, 1H); MS (ESI): 575 (M-1H); Rf=1.90 (4 min run).
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([C:7]2[CH:15]=[C:14]3[C:10]([CH2:11][C:12](=[O:16])[NH:13]3)=[CH:9][CH:8]=2)[CH:2]=1.[CH3:17][N:18]([CH3:31])[CH2:19][CH2:20][CH2:21][C:22]1[C:23]([CH3:30])=[C:24]([CH:28]=O)[NH:25][C:26]=1[CH3:27]>N1CCCCC1.C(O)C>[CH3:31][N:18]([CH3:17])[CH2:19][CH2:20][CH2:21][C:22]1[C:23]([CH3:30])=[C:24]([CH:28]=[C:11]2[C:10]3[C:14](=[CH:15][C:7]([C:3]4[CH:2]=[N:1][CH:6]=[CH:5][CH:4]=4)=[CH:8][CH:9]=3)[NH:13][C:12]2=[O:16])[NH:25][C:26]=1[CH3:27]
Reactant: O=C1Cc2ccc(-c3cccnc3)cc2N1
Reactant: Cc1[nH]c(C=O)c(C)c1CCCN(C)C
Solvent: CCO
Solvent: C1CCNCC1
Product: Cc1[nH]c(C=C2C(=O)Nc3cc(-c4cccnc4)ccc32)c(C)c1CCCN(C)C

Procedure:
A mixture of 6-pyridin-3-yl-1,3-dihydroindol-2-one (100 mg, 0.48 mmol), 4-(3-dimethylaminopropyl)-3,5-dimethyl-1H-pyrrole-2-carboxaldehyde (100 mg, 0.48 mmol), and piperidine (1 drop) in ethanol (2 mL) was stirred at reflux overnight. The precipitate was collected by vacuum filtration, washed with ethanol and dried to give 3-[4-(3-dimethylaminopropyl)-3,5-dimethyl-1H-pyrrol-2-ylmethylene]-6-pyridin-3-yl-1,3-dihydroindol-2-one.
Reaction SMILES: [CH3:1][C:2]1[CH:10]=[CH:9][C:5]2[N:6]=[CH:7][S:8][C:4]=2[CH:3]=1.C([Li])CCC.CN(C)[C:18](=[O:20])[CH3:19].O>C1COCC1>[C:18]([C:7]1[S:8][C:4]2[CH:3]=[C:2]([CH3:1])[CH:10]=[CH:9][C:5]=2[N:6]=1)(=[O:20])[CH3:19]
Reactant: Cc1ccc2ncsc2c1
Reactant: CC(=O)N(C)C
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: O
Product: CC(=O)c1nc2ccc(C)cc2s1
Temperature: 25 °C
Yield: 47.2 %

Procedure:
A solution of 6-methylbenzothiazole (6.1 g, 41 mmol) in anhydrous THF (150 ml) was cooled to -78° C. To the cooled solution was added, with stirring, n-butyl lithium (28.1 ml of 1.6 M n-BuLi-containing hexane solution, 45 mmol) dropwise under nitrogen atmosphere. Further, a solution of N,N-dimethyl acetamide (3.9 g, 45 mmol) in anhydrous THF (70 ml) was added dropwise to the mixture at the same temperature. After completion of the addition, the mixture was stirred for an hour, and then warmed to room temperature. The reaction mixture was poured into water, and then extracted with benzene. The extract was washed with water, dried over magnesium sulfate, and then evaporated. The resulting residual powders were subjected to purification using column chromatography on silica gel (eluant, n-hexane/ethyl acetate=95/5) to afford 2-acetyl-6-methylbenzothiazole (3.7 g, 47%) as a pale yellow powder, together with the starting material (2.5 g).