Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [H-].[Na+].[NH:3]1[CH:7]=[C:6]([C:8]#[N:9])[N:5]=[CH:4]1.[CH3:10][Si:11]([CH2:14][CH2:15][O:16][CH2:17]Cl)([CH3:13])[CH3:12]>C1COCC1>[CH3:10][Si:11]([CH3:13])([CH3:12])[CH2:14][CH2:15][O:16][CH2:17][N:3]1[CH:7]=[C:6]([C:8]#[N:9])[N:5]=[CH:4]1
Reactant: N#Cc1c[nH]cn1
Reactant: C[Si](C)(C)CCOCCl
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: C[Si](C)(C)CCOCn1cnc(C#N)c1
Temperature: 25 °C
Reaction time: 18 h
Yield: 37 %

Procedure:
To a round bottom flask was added NaH (60% in mineral oil) (200 mg, 5.22 mmol) in dry THF (12 ml), followed by the addition of 1H-imidazole-4-carbonitrile (400 mg, 4.3 mmol), SEMCl (1433 mg, 8.6 mmol). The reaction mixture was stirred at room temperature for 18 h. The reaction mixture was concentrated in vacuo. The residue was dissolved in EtOAc/sat. NaHCO3. The organic phase was separated, washed with water, brine, dried over anhy. Na2SO4, filtered and concentrated. The resulting residue was purified by flash chromatography on silica gel (0-3% MeOH/CH2Cl2). The product fractions were collected and concentrated to afford 355 mg of 1-(2-trimethylsilanyl-ethoxymethyl)-1H-imidazole-4-carbonitrile, m/z 224.6 [M+1]+.
Reaction SMILES: [CH2:1]([N:4]1[C:12]2[N:11]=[C:10]([C:13]34[CH2:20][CH:19]5[CH2:21][CH:15]([CH2:16][CH:17]3[CH2:18]5)[CH2:14]4)[NH:9][C:8]=2[C:7](=[O:22])[NH:6][C:5]1=[O:23])[CH:2]=[CH2:3].[H-].[Na+].I[CH2:27][CH2:28][CH3:29].O>CN(C)C=O>[CH2:1]([N:4]1[C:12]2[N:11]=[C:10]([C:13]34[CH2:14][CH:15]5[CH2:21][CH:19]([CH2:18][CH:17]3[CH2:16]5)[CH2:20]4)[NH:9][C:8]=2[C:7](=[O:22])[N:6]([CH2:27][CH2:28][CH3:29])[C:5]1=[O:23])[CH:2]=[CH2:3]
Reactant: CCCI
Reactant: C=CCn1c(=O)[nH]c(=O)c2[nH]c(C34CC5CC(CC3C5)C4)nc21
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: C=CCn1c(=O)n(CCC)c(=O)c2[nH]c(C34CC5CC(CC3C5)C4)nc21
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 19.8 %

Procedure:
1.00 g (3.21 mmol) of Compound G was dissolved in 30 ml of dimethylformamide, and 256 mg of sodium hydride (60%, 6.41 mmol) was added slowly to the solution at 0° C. After 30 minutes, 0.33 ml (3.4 mmol) of 1-iodopropane was added dropwise slowly at the same temperature and stirred at room temperature overnight. The resulting reaction mixture was poured into 300 ml of water, neutralized and extracted three times with 100 ml of chloroform. The organic layer was washed with a saturated aqueous sodium chloride, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (eluate: 30% ethyl acetate/hexane) to give 225 mg (yield 20%) of Compound H as a colorless needle crystal.
Reaction SMILES: CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[Cl:25][C:26]1[CH:34]=[CH:33][C:29]([C:30](O)=[O:31])=[C:28]([NH:35][S:36]([C:39]2[C:40]3[N:41]=[CH:42][CH:43]=[N:44][C:45]=3[CH:46]=[CH:47][CH:48]=2)(=[O:38])=[O:37])[CH:27]=1.Cl.[F:50][C:51]1[CH:56]=[C:55]([F:57])[CH:54]=[CH:53][C:52]=1[C@H:58]([NH2:63])[C:59]([F:62])([F:61])[F:60]>>[Cl:25][C:26]1[CH:34]=[CH:33][C:29]([C:30]([NH:63][C@@H:58]([C:52]2[CH:53]=[CH:54][C:55]([F:57])=[CH:56][C:51]=2[F:50])[C:59]([F:60])([F:62])[F:61])=[O:31])=[C:28]([NH:35][S:36]([C:39]2[C:40]3[N:41]=[CH:42][CH:43]=[N:44][C:45]=3[CH:46]=[CH:47][CH:48]=2)(=[O:37])=[O:38])[CH:27]=1
Reactant: O=C(O)c1ccc(Cl)cc1NS(=O)(=O)c1cccc2nccnc12
Reactant: N[C@@H](c1ccc(F)cc1F)C(F)(F)F
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Product: O=C(N[C@@H](c1ccc(F)cc1F)C(F)(F)F)c1ccc(Cl)cc1NS(=O)(=O)c1cccc2nccnc12

Procedure:
(S)-4-Chloro-N-[1-(2,4-difluorophenyl)-2,2,2-trifluoroethyl-1]-2-(quinoxaline-5-sulfonylamino)-benzamide. The title compound was prepared from the HATU-mediated coupling of 4-chloro-2-(quinoxaline-5-sulfonylamino)benzoic acid (EXAMPLE 3, Step B) and (S)-1-(2,4-difluorophenyl)-2,2,2-trifluoroethylamine hydrochloride and purified as described in EXAMPLE 1, Step K. MS (ESI): mass calculated for C23H14ClF5N4O3S, 556.0; m/z found, 555/557 [M−H]−. HPLC (reverse phase): RT=9.98 min. 1H NMR (400 MHz, CDCl3): 11.07 (s, 1H), 8.84-8.83 (m, 2H), 8.56 (dd, J=7.4, 1.4 Hz, 1H), 8.31 (dd, J=7.4, 1.4 Hz, 1H), 7.87 (dd, J=8.4, 7.4 Hz, 1H), 7.81 (d, J=2.0 Hz, 1H), 7.43-7.37 (m, 1H), 7.30 (d, J=8.5 Hz, 1H), 7.03-6.93 (m, 3H), 6.81-6.79 (m, 1H), 6.08-6.00 (m, 1H).
Reaction SMILES: Cl.[NH2:2][CH2:3][CH2:4][CH2:5][N:6]1[C:14](=[O:15])[C:13]2[N:12]([CH2:16][C:17]3[CH:22]=[CH:21][C:20]([Cl:23])=[CH:19][CH:18]=3)[C:11]([O:24][C:25]3[CH:30]=[CH:29][CH:28]=[C:27]([O:31][C:32]([F:35])([F:34])[F:33])[CH:26]=3)=[N:10][C:9]=2[N:8]([CH3:36])[C:7]1=[O:37].[CH3:38][S:39](Cl)(=[O:41])=[O:40]>C1COCC1.O>[Cl:23][C:20]1[CH:21]=[CH:22][C:17]([CH2:16][N:12]2[C:13]3[C:14](=[O:15])[N:6]([CH2:5][CH2:4][CH2:3][NH:2][S:39]([CH3:38])(=[O:41])=[O:40])[C:7](=[O:37])[N:8]([CH3:36])[C:9]=3[N:10]=[C:11]2[O:24][C:25]2[CH:30]=[CH:29][CH:28]=[C:27]([O:31][C:32]([F:34])([F:33])[F:35])[CH:26]=2)=[CH:18][CH:19]=1
Reactant: CS(=O)(=O)Cl
Reactant: Cn1c(=O)n(CCCN)c(=O)c2c1nc(Oc1cccc(OC(F)(F)F)c1)n2Cc1ccc(Cl)cc1
Agent: Cl
Solvent: O
Solvent: C1CCOC1
Product: Cn1c(=O)n(CCCNS(C)(=O)=O)c(=O)c2c1nc(Oc1cccc(OC(F)(F)F)c1)n2Cc1ccc(Cl)cc1
Temperature: 25 °C
Reaction time: 3 h
Yield: 39.3 %

Procedure:
1-(3-Aminopropyl)-7-(4-chlorobenzyl)-3-methyl-8-(3-(trifluoromethoxy)phenoxy)-1H-purine-2,6(3H,7H)-dione (0.10 g, 0.19 mmol, example 357) and TEA (0.80 mL, 0.57 mmol) were combined in THF (1 mL). Methanesulfonyl chloride (0.30 mL, 0.38 mmol) was added and the reaction was stirred at room temperature for 3 h. The reaction was diluted with water (100 mL) and extracted with ethyl acetate (3×75 mL). The combined extracts were dried with magnesium sulfate, filtered and evaporated under reduced pressure to an oil. The oil was purified using a 2000 micron preparative TLC plate eluted with 5% methanol/DCM. Target band was scraped off plate and eluted off silica gel with eluent to give N-(3-(7-(4-chlorobenzyl)-3-methyl-2,6-dioxo-8-(3-(trifluoromethoxy)phenoxy)-2,3,6,7-tetrahydro-1H-purin-1-yl)propyl)methanesulfonamide (0.045 g, 39% yield) as a tan solid. LCMS retention time=4.048 minutes and 99% purity, LCMS MH+ 602. 1H NMR (DMSO-d6) δ 7.59 (t, 1H, J=8 Hz), 7.45-7.48 (m, 1H), 7.39-7.43 (m, 5H), 7.31 (d, 1H, J=8 Hz), 6.96 (t, 1H), 5.43 (s, 2H), 3.91 (t, 2H, J=8 Hz), 3.29 (s, 3H), 2.96 (dd, 2H, J=4 Hz and 12 Hz), 2.87 (s, 3H), 1.69-1.79 (m, 2H).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:13])[C:4]1[C:9]([CH2:10]Br)=[CH:8][CH:7]=[CH:6][C:5]=1[Br:12].C[N+]1([O-])CC[O:18]CC1>C(#N)C>[CH3:1][O:2][C:3](=[O:13])[C:4]1[C:9]([CH:10]=[O:18])=[CH:8][CH:7]=[CH:6][C:5]=1[Br:12]
Reactant: COC(=O)c1c(Br)cccc1CBr
Reactant: C[N+]1([O-])CCOCC1
Solvent: CC#N
Product: COC(=O)c1c(Br)cccc1C=O
Temperature: 25 °C
Reaction time: 1.5 h

Procedure:
A suspension of 2-bromo-6-bromomethyl-benzoic acid methyl ester (21.8 mmol), N-methylmorpholine N-oxide (43.6 mmol) and 35 g powdered 4 Å molecular sieves in 350 mL acetonitrile was stirred for 1.5 h at room temperature. The reaction was filtered through a bed of silica, and the filtrate was purified on silica.
Reaction SMILES: [F:1][C:2]1[C:3]([CH2:35]OS(C)(=O)=O)=[C:4]([F:34])[C:5]2[O:10][C:9]([C:11]3[CH:16]=[CH:15][C:14]([NH:17][C:18](=[O:23])[C:19]([CH3:22])([CH3:21])[CH3:20])=[C:13]([F:24])[CH:12]=3)=[CH:8][C:7](=[O:25])[C:6]=2[C:26]=1[NH:27][C:28](=[O:33])[C:29]([CH3:32])([CH3:31])[CH3:30].O.[NH3:42]>CO>[NH2:42][CH2:35][C:3]1[C:2]([F:1])=[C:26]([NH:27][C:28](=[O:33])[C:29]([CH3:30])([CH3:31])[CH3:32])[C:6]2[C:7](=[O:25])[CH:8]=[C:9]([C:11]3[CH:16]=[CH:15][C:14]([NH:17][C:18](=[O:23])[C:19]([CH3:20])([CH3:22])[CH3:21])=[C:13]([F:24])[CH:12]=3)[O:10][C:5]=2[C:4]=1[F:34]
Reactant: N
Reactant: CC(C)(C)C(=O)Nc1ccc(-c2cc(=O)c3c(NC(=O)C(C)(C)C)c(F)c(COS(C)(=O)=O)c(F)c3o2)cc1F
Solvent: O
Solvent: CO
Product: CC(C)(C)C(=O)Nc1ccc(-c2cc(=O)c3c(NC(=O)C(C)(C)C)c(F)c(CN)c(F)c3o2)cc1F
Temperature: 25 °C
Reaction time: 9 h
Yield: 41 %

Procedure:
400 mg (0.687 mmol) of the above 6,8-difluoro-2-(3-fluoro-4-pivaloylaminophenyl)-7-methanesulfonyloxymethyl-5-pivaloylamino-4H-1-benzopyran-4-one was dissolved in 50 mL of an about 6N solution of ammonia in methanol and the solution was stirred at room temperature for 9 hours. Water was added to the reaction solution and the mixture was extracted twice with chloroform. The organic layer was washed once with water and once with an aqueous saturated solution of sodium chloride and dried over sodium sulfate. The solvent was distilled off under reduced pressure and the residue was purified by silica gel column chromatography (chloroform:methanol=30:1) to give 142 mg of 7-aminomethyl-6,8-difluoro-2-(3-fluoro-4-pivaloylaminophenyl)-5-pivaloylamino-4H-1-benzopyran-4-one (yield: 41%).
Reaction SMILES: [C:1]1(=O)[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[C:4]([CH:11]=[C:12]([C:22]2[CH:27]=[CH:26][C:25]([N:28]([CH3:30])[CH3:29])=[CH:24][CH:23]=2)[C:13]2[CH:18]=[CH:17][C:16]([N:19]([CH3:21])[CH3:20])=[CH:15][CH:14]=2)=[CH:3][C:2]1=[O:31].Cl.[NH2:34][OH:35]>C(O)C>[N:34]([C:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[C:4]([CH:11]=[C:12]([C:13]2[CH:14]=[CH:15][C:16]([N:19]([CH3:20])[CH3:21])=[CH:17][CH:18]=2)[C:22]2[CH:27]=[CH:26][C:25]([N:28]([CH3:29])[CH3:30])=[CH:24][CH:23]=2)=[CH:3][C:2]=1[OH:31])=[O:35]
Reactant: NO
Reactant: CN(C)c1ccc(C(=CC2=CC(=O)C(=O)c3ccccc32)c2ccc(N(C)C)cc2)cc1
Agent: Cl
Solvent: CCO
Product: CN(C)c1ccc(C(=Cc2cc(O)c(N=O)c3ccccc23)c2ccc(N(C)C)cc2)cc1
Reaction time: 5 h
Yield: 47.4 %

Procedure:
2-(1,2-naphthoquinon-4-yl)-1,1-bis(p-dimethylaminophenyl)ethylene (1.63 g; 0.004 mol) was dissolved in absolute ethanol (100 ml) by warming. To the solution, at room temperature, was added hydroxylamine hydrochloride (3.7 g;0.053 mol) and the resulting solution was stirred for 5 hours. The mixture was then evaporated to dryness treated with water and extracted with CH2Cl2. The organic extract was dried, evaporated to dryness and then chromatographed over silica (eluent:diethyl ether) to afford 2-(1-nitroso-2-hydroxynaphthalen-4-yl)-1,1-bis(p-dimethylamin ophenyl)ethylene (0.83 g;49%) as a dark brown solid.
Reaction SMILES: [CH:1]1([C@H:5]([NH:13][C:14]([C:16]2[C:21]([CH3:22])=[C:20](Br)[C:19](=[O:24])[N:18]([C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=3)[C:17]=2[CH3:31])=[O:15])[C:6]2[CH:11]=[CH:10][CH:9]=[C:8]([F:12])[CH:7]=2)[CH2:4][CH2:3][CH2:2]1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C(NCC)C.[CH3:56][Si:57]([C:60]#[CH:61])([CH3:59])[CH3:58]>[Cu]I.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.CN(C)C=O>[CH:1]1([C@H:5]([NH:13][C:14]([C:16]2[C:21]([CH3:22])=[C:20]([C:61]#[C:60][Si:57]([CH3:59])([CH3:58])[CH3:56])[C:19](=[O:24])[N:18]([C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=3)[C:17]=2[CH3:31])=[O:15])[C:6]2[CH:11]=[CH:10][CH:9]=[C:8]([F:12])[CH:7]=2)[CH2:4][CH2:3][CH2:2]1
Reactant: C#C[Si](C)(C)C
Reactant: Cc1c(C(=O)N[C@H](c2cccc(F)c2)C2CCC2)c(C)n(-c2ccccc2)c(=O)c1Br
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CN(C)C=O
Solvent: CCNCC
Product: Cc1c(C(=O)N[C@H](c2cccc(F)c2)C2CCC2)c(C)n(-c2ccccc2)c(=O)c1C#C[Si](C)(C)C
Temperature: 120 °C
Yield: 53.2 %

Procedure:
A mixture of 5-bromo-2,4-dimethyl-6-oxo-1-phenyl-1,6-dihydro-pyridine-3-carboxylic acid [(S)-cyclobutyl-(3-fluoro-phenyl)-methyl]-amide (2a, 60.0 mg, 0.124 mmol), N,N-dimethylformamide (0.6 mL), copper(I) iodide (4.5 mg, 0.024 mmol), bis(triphenylphosphine)palladium(II) chloride (9.1 mg, 0.013 mmol), triphenylphosphine (20.0 mg, 0.0762 mmol), N-ethylethanamine (0.6 mL, 6 mmol) and (trimethylsilyl)acetylene (0.052.6 mL, 0.372 mmol) was flushed with Argon and heated under microwave irradiation for 30 min at 120° C. It was evaporated in vacuo, transferred to 20 g silica gel column with 1,2-dichloroethane and separated by flash chromatography with gradient heptane-ethyl acetate to give 2,4-dimethyl-6-oxo-1-phenyl-5-trimethylsilanylethynyl-1,6-dihydro-pyridine-3-carboxylic acid [(S) -cyclobutyl-(3-fluoro-phenyl)-methyl]-amide (33 mg; yield=53%) as a pale yellow-brown solid. LC-MS (m/z) 501.7 (MH+); tR=1.94 (method C).
Reaction SMILES: [CH3:1][Mg]Br.[Cl:4][C:5]1[CH:12]=[C:11]([C:13]2[CH:14]=[N:15][CH:16]=[CH:17][C:18]=2[CH:19]=[O:20])[CH:10]=[CH:9][C:6]=1[C:7]#[N:8]>C1COCC1>[Cl:4][C:5]1[CH:12]=[C:11]([C:13]2[CH:14]=[N:15][CH:16]=[CH:17][C:18]=2[CH:19]([OH:20])[CH3:1])[CH:10]=[CH:9][C:6]=1[C:7]#[N:8]
Reactant: C[Mg]Br
Reactant: N#Cc1ccc(-c2cnccc2C=O)cc1Cl
Solvent: C1CCOC1
Product: CC(O)c1ccncc1-c1ccc(C#N)c(Cl)c1
Temperature: 0 °C
Yield: 89.4 %

Procedure:
A solution of methylmagnesium bromide (519 μl, 1.558 mmol) was added dropwise to a solution of 2-chloro-4-(4-formylpyridin-3-yl)benzonitrile (126 mg, 0.519 mmol) in dry THF (15 mL) at −50° C. The resulting mixture was slowly warmed up to 0° C. during 2 hr. The reaction was quenched by NH4Cl (solution). After extraction with CH2Cl2, dry over Na2SO4, filtration, concentration again, the residue was purified by column (CH2Cl2-MeOH, v/v, 1-3.5%) and yielded 120 mg of 2-chloro-4-(4-(1-hydroxyethyl)pyridin-3-yl)benzonitrile. ESI-MS m/z: 259 [M+1]+, Retention time 1.11 min; 1H-NMR (MeOD, 400 MHz) δ 1.29 (d, J=6.4 Hz, 3H), 4.83 (q, J=6.4 Hz, 1H), 7.50 (dd, J=8.0, 1.6 Hz, 1H), 7.71 (d, J=1.6 Hz, 1H), 7.73 (d, J=5.6 Hz, 1H), 7.92 (d, J=8.0 Hz, 1H), 8.35 (s, 1H), 8.61 (d, J=5.6 Hz, 1H).
Reaction SMILES: Cl[CH2:2][C:3]1[S:4][C:5]2[CH:11]=[CH:10][C:9]([C:12]([F:15])([F:14])[F:13])=[CH:8][C:6]=2[N:7]=1.[I-:16].[Na+]>CC(C)=O>[I:16][CH2:2][C:3]1[S:4][C:5]2[CH:11]=[CH:10][C:9]([C:12]([F:15])([F:14])[F:13])=[CH:8][C:6]=2[N:7]=1
Reactant: [I-]
Reactant: FC(F)(F)c1ccc2sc(CCl)nc2c1
Agent: [Na+]
Solvent: CC(C)=O
Product: FC(F)(F)c1ccc2sc(CI)nc2c1
Temperature: 55 °C
Reaction time: 0.25 h
Yield: 96.9 %

Procedure:
To a stirred solution of 10.79 g (42.97 mmol) of 2-(chloromethyl)-5-(trifluoromethyl)benzo[d]thiazole (Compound 3) in 86 mL of acetone was added 7.40 g (49.42 mmol) of sodium iodide. The resulting reaction mixture was heated to 55° C. for 1 hour. The reaction mixture was cooled to ambient temperature and concentrated in vacuo. The residue was partitioned between EtOAc and water, the layers separated, and the organic layer washed with water (1×). The recovered organic layer was then treated with 1.0 M Na2S2O3 and stirred vigorously for 15 minutes. The layers were then separated and the organic layer washed sequentially with water (1×) and brine (1×). The organic layer was dried over Na2SO4, filtered and concentrated in vacuo to yield 14.28 g (97% crude yield) of 2-(iodomethyl)-5-(trifluoromethyl)benzo[d]thiazole (Compound 5) that was used without further purification: 1H NMR (CDCl3, 300 MHz): δppm 8.26 (s, 1H), 7.95 (d, J=8.4 Hz, 1H), 7.66 (d, J=8.4 Hz, 1H), 4.80 (s, 2H).
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][CH:4]([N:7]2[C:13]3[CH:14]=[CH:15][CH:16]=[CH:17][C:12]=3[CH2:11][CH2:10][C:9]3[CH:18]=[CH:19][CH:20]=[CH:21][C:8]2=3)[CH2:3][CH2:2]1.[C:22]([NH:26][C:27](=[O:33])[CH2:28][CH2:29][C:30](O)=[O:31])([CH3:25])([CH3:24])[CH3:23].Cl.C(N=C=NCCCN(C)C)C.C(N(CC)CC)C>ClCCl.CN(C)C1C=CN=CC=1>[C:22]([NH:26][C:27](=[O:33])[CH2:28][CH2:29][C:30]([N:1]1[CH2:6][CH2:5][CH:4]([N:7]2[C:8]3[CH:21]=[CH:20][CH:19]=[CH:18][C:9]=3[CH2:10][CH2:11][C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][C:13]2=3)[CH2:3][CH2:2]1)=[O:31])([CH3:25])([CH3:23])[CH3:24]
Reactant: CC(C)(C)NC(=O)CCC(=O)O
Reactant: c1ccc2c(c1)CCc1ccccc1N2C1CCNCC1
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(C)(C)NC(=O)CCC(=O)N1CCC(N2c3ccccc3CCc3ccccc32)CC1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
83.2 mg (0.299 mmol) of 5-(4-piperidinyl)-10,11-dihydro-5H-dibenzo[b,f]azepine, 62.2 mg (0.359 mmol) of 4-(t-butylamino)-4-oxobutanoic acid and 82.6 mg (0.431 mmol) of 1-ethyl-3-(3′-dimethylaminopropyl)carbodiimide hydrochloride were dissolved in 5 ml of dichloromethane. 0.06 ml (0.431 mmol) of triethylamine and 3.67 mg (0.03 mmol) of 4-dimethylaminopyridine were added to the obtained solution, and they were stirred at room temperature overnight. The reaction mixture was concentrated under reduced pressure. Ethyl acetate was added thereto. After washing with 1 N aqueous hydrochloric acid solution, the organic layer was dried over anhydrous magnesium sulfate and then concentrated under reduced pressure. The residue was purified by the silica gel chromatography (dichloromethane:methanol=9:1) to obtain the title compound.
Reaction SMILES: C([N:4]1[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[C:6](=[C:13]([O:20][CH2:21][CH3:22])[C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[C:5]1=[O:23])(=O)C.C(O)C.[OH-].[Na+]>O>[CH2:21]([O:20][C:13](=[C:6]1[C:7]2[C:12](=[CH:11][CH:10]=[CH:9][CH:8]=2)[NH:4][C:5]1=[O:23])[C:14]1[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=1)[CH3:22]
Reactant: CCOC(=C1C(=O)N(C(C)=O)c2ccccc21)c1ccccc1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: CCOC(=C1C(=O)Nc2ccccc21)c1ccccc1
Temperature: 25 °C
Reaction time: 1.5 h

Procedure:
6.15 g (20 mmol) of 1-acetyl-3-(1-ethoxy-1-phenyl-methylidene)-2-indolinone are suspended in a little ethanol. 10 ml of 4N sodium hydroxide solution are added and the mixture is stirred for 1.5 hours at ambient temperature. After the addition of 100 ml of water the precipitate is suction filtered, washed with water and a little ether and dried at 80° C.
Reaction SMILES: [C:1]1([N:7]=[C:8]=[O:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH2:10]1[O:34][C:33]2[C:12](=[CH:13][C:14]3[N:18]=[C:17]([S:19]([CH2:21][C:22]4[C:27]([CH3:28])=[C:26]([O:29][CH3:30])[C:25]([CH3:31])=[CH:24][N:23]=4)=[O:20])[NH:16][C:15]=3[CH:32]=2)[O:11]1.C(N(CC)CC)C>C(Cl)Cl>[C:1]1([NH:7][C:8]([N:16]2[C:15]3[CH:32]=[C:33]4[O:34][CH2:10][O:11][C:12]4=[CH:13][C:14]=3[N:18]=[C:17]2[S:19]([CH2:21][C:22]2[C:27]([CH3:28])=[C:26]([O:29][CH3:30])[C:25]([CH3:31])=[CH:24][N:23]=2)=[O:20])=[O:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: COc1c(C)cnc(CS(=O)c2nc3cc4c(cc3[nH]2)OCO4)c1C
Reactant: O=C=Nc1ccccc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COc1c(C)cnc(CS(=O)c2nc3cc4c(cc3n2C(=O)Nc2ccccc2)OCO4)c1C
Temperature: 25 °C
Reaction time: 50 h
Yield: 4.5 %

Procedure:
Phenylisocyanate (0.20 g, 0.00167 mol) dissolved in CH2Cl2 (5 ml) was added dropwise under stirring to a solution of 5,6-methylenedioxy-2-[[(4-methoxy-3,5-dimethyl-2-pyridinyl)methyl]sulfinyl]-1H-benzimidazole (0.50 g, 0.00139 mol) and triethylamine (0.28 g, 0.00278 mol) in CH2CL2 (15 ml). The mixture was then stirred at room temperature for 50 hours. The CH2Cl2 -solution was washed with water, dried (MgSO4) and the solvent was evaporated giving the desired product as an oil (0.03 g, 5%). NMR data for the final product is given below.
Reaction SMILES: [C:1]([Cl:5])(=O)[CH2:2][CH3:3].[ClH:6].Cl.[CH:8]1[CH:17]=[CH:16][C:15]2[CH2:18][CH2:19][CH2:20][N:13]3[C:14]=2[C:9]=1[C@H:10]1[CH2:23][NH:22][CH2:21][C@H:11]1[CH2:12]3>>[ClH:5].[ClH:6].[CH2:1]([N:22]1[CH2:23][C@H:10]2[C@H:11]([CH2:12][N:13]3[CH2:20][CH2:19][CH2:18][C:15]4[CH:16]=[CH:17][CH:8]=[C:9]2[C:14]3=4)[CH2:21]1)[CH2:2][CH3:3]
Reactant: CCC(=O)Cl
Reactant: c1cc2c3c(c1)[C@H]1CNC[C@H]1CN3CCC2
Agent: Cl
Product: CCCN1C[C@H]2CN3CCCc4cccc(c43)[C@H]2C1

Procedure:
Using propionyl chloride and following the procedures described in EXAMPLE 102, (±)-cis-5,6,8,8a,9,10,11,11a-octahydro-4H-pyrido[3,2,1-ij]pyrrolo[3,4-c]quinoline free base from EXAMPLE 11 was converted into the title compound of EXAMPLE 103 as an off-white powder. 1H NMR (dmso-D6) δ: 11.10 (broad s, 1H), 6.90-6.77 (m, 2H), 6.63-6.55 (m, 1H), 3.99-3.90 (m, 1H), 3.85-3.75 (m, 1H), 3.67-3.58 (m, 1H), 3.50-3.35 (m, 2H), 3.15-2.93 (m, 4H), 2.90-2.75 (m, 3H), 2.70-2.63 (m, 2H), 1.95-1.85 (m, 2H), 1.70-1.59 (m, 2H), 0.91-0.82 (m, 3H). LRMS (ES)+: 257.1 (M+H)+.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5](Br)=[CH:4][N:3]=1.C([Mg]Cl)(C)C.CN(C)[CH:16]=[O:17].O>O1CCCC1>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([CH:16]=[O:17])=[CH:4][N:3]=1
Reactant: CN(C)C=O
Reactant: Brc1ccc(Br)nc1
Agent: CC(C)[Mg]Cl
Solvent: O
Solvent: C1CCOC1
Product: O=Cc1ccc(Br)nc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 66.1 %

Procedure:
To a solution of 2,5-dibromopyridine (2.37 g, 10.0 mmol) in tetrahydrofuran (15 mL) was added isopropylmagnesium chloride (2 mol/L in tetrahydrofuran; 5.0 mL, 10 mmol) under nitrogen atmosphere, and the mixture was stirred at room temperature for 1 h. Dimethylformamide (1.6 mL, 20 mmol) was added, and the mixture was stirred for additional 15 min. Water was added, and the mixture was extracted with ethyl acetate twice. The organic layer was washed with brine and dried on anhydrous sodium sulfate. The solvent was evaporated under reduced pressure, and the residue was purified by silica gel column chromatography (2:1 hexane/ethyl acetate) to afford 2-bromo-5-pyridinecarboxaldehyde (1.23 g, 66%).
Reaction SMILES: [CH3:1]C(C)([O-])C.[K+].[Cl:7][C:8]1[C:9]([O:19][CH:20]2[CH2:25][CH2:24][C:23](=O)[CH2:22][CH2:21]2)=[CH:10][C:11]([F:18])=[C:12]([CH:17]=1)[C:13]([O:15][CH3:16])=[O:14]>[Br-].C[P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.O1CCCC1.O>[Cl:7][C:8]1[C:9]([O:19][CH:20]2[CH2:25][CH2:24][C:23](=[CH2:1])[CH2:22][CH2:21]2)=[CH:10][C:11]([F:18])=[C:12]([CH:17]=1)[C:13]([O:15][CH3:16])=[O:14]
Reactant: COC(=O)c1cc(Cl)c(OC2CCC(=O)CC2)cc1F
Reactant: CC(C)(C)[O-]
Agent: C[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Br-]
Agent: [K+]
Solvent: C1CCOC1
Solvent: O
Product: C=C1CCC(Oc2cc(F)c(C(=O)OC)cc2Cl)CC1
Temperature: 0 °C
Reaction time: 1 h
Yield: 83.3 %

Procedure:
To a suspension of methyltriphenylphosphonium bromide (1.61 g, 4.51 mmol) in anhydrous tetrahydrofuran (20 mL) was added a solution of potassium tert-butoxide (0.541 g, 4.82 mmol) in anhydrous tetrahydrofuran (15 mL) dropwise over 3 minutes at 0° C. The mixture was stirred under a nitrogen atmosphere at 0° C. for 1 h. To this solution was added a solution of methyl 5-chloro-2-fluoro-4-((4-oxocyclohexyl)oxy)benzoate (1.05 g, 3.48 mmol) in anhydrous tetrahydrofuran (15 mL) dropwise over 3 minutes. The mixture was stirred at ambient temperature for 21 h, then diluted with water (200 mL). The mixture was extracted with ethyl acetate (200 mL) and the organic phase was washed with water (50 mL) and brine (150 mL), dried over anhydrous magnesium sulfate, filtered, and concentrated in vacuo. The residue was purified by column chromatography with a gradient of 0-10% ethyl acetate in hexanes to afford the title compound as a colorless syrup (0.866 g, 83% yield): 1H NMR (300 MHz, CDCl3) δ 7.94 (d, J=7.7 Hz, 1H), 6.67 (d, J=12.2 Hz, 1H), 4.68 (s, 2H), 4.56-4.50 (m, 1H), 3.87 (s, 3H), 2.48-2.40 (m, 2H), 2.17-2.09 (m, 2H), 1.92-1.86 (m, 4H); MS (ES+) m/z 299.00 (M+1).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:28]=[CH:27][C:26]([N:29]2[CH:33]=[N:32][N:31]=[N:30]2)=[CH:25][C:4]=1[C:5]([N:7]1[CH2:11][CH2:10][C:9]([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)([CH2:12][CH2:13]OS(C)(=O)=O)[CH2:8]1)=[O:6].I.[F:35][C:36]1[CH:58]=[CH:57][C:39]([CH2:40][N:41]2[C:45]3[CH:46]=[CH:47][CH:48]=[CH:49][C:44]=3[N:43]=[C:42]2[N:50]2[CH2:56][CH2:55][CH2:54][NH:53][CH2:52][CH2:51]2)=[CH:38][CH:37]=1>>[CH3:1][O:2][C:3]1[CH:28]=[CH:27][C:26]([N:29]2[CH:33]=[N:32][N:31]=[N:30]2)=[CH:25][C:4]=1[C:5]([N:7]1[CH2:11][CH2:10][C:9]([CH2:12][CH2:13][N:53]2[CH2:54][CH2:55][CH2:56][N:50]([C:42]3[N:41]([CH2:40][C:39]4[CH:57]=[CH:58][C:36]([F:35])=[CH:37][CH:38]=4)[C:45]4[CH:46]=[CH:47][CH:48]=[CH:49][C:44]=4[N:43]=3)[CH2:51][CH2:52]2)([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[CH2:8]1)=[O:6]
Reactant: Fc1ccc(Cn2c(N3CCCNCC3)nc3ccccc32)cc1
Reactant: COc1ccc(-n2cnnn2)cc1C(=O)N1CCC(CCOS(C)(=O)=O)(c2ccccc2)C1
Agent: I
Product: COc1ccc(-n2cnnn2)cc1C(=O)N1CCC(CCN2CCCN(c3nc4ccccc4n3Cc3ccc(F)cc3)CC2)(c2ccccc2)C1

Procedure:
Prepare by the method of Example 47.3 using 1-(2-methoxy-5-(1H-tetrazol-1-yl)benzoyl)-3-phenyl-3-(2-methanesulfonyloxyethyl)pyrrolidine (prepared from (−)-3-phenyl-3-(2-hydroxyethyl)pyrrolidine (R,R)-di-p-anisoyltartaric acid salt)(2.2 g, 4.67 mmol) and 4-(1-(4-fluorobenzyl)-1H-benzimidazol-2-yl)[1,4]diazepane hydriodic acid salt (2.82 g, 4.86 mmol) to give the title compound: Rf=0.37 (silica gel, dichloromethane/methanol/concentrated aqueous ammonia 90/10/0.1).