Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:14]=[CH:13][N:12]([C:15]2[CH:20]=[C:19]3[N:21](S(C4C=CC(C)=CC=4)(=O)=O)[C:22]4[CH2:23][CH:24]5[N:29]([CH2:30][C:31]=4[C:18]3=[CH:17][CH:16]=2)[CH2:28][CH2:27][CH2:26][CH2:25]5)[C:11](=[O:42])[CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[OH-].[Na+].C(Cl)[Cl:46]>CO>[ClH:46].[CH2:1]([O:8][C:9]1[CH:14]=[CH:13][N:12]([C:15]2[CH:20]=[C:19]3[NH:21][C:22]4[CH2:23][CH:24]5[N:29]([CH2:30][C:31]=4[C:18]3=[CH:17][CH:16]=2)[CH2:28][CH2:27][CH2:26][CH2:25]5)[C:11](=[O:42])[CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: ClCCl
Reactant: Cc1ccc(S(=O)(=O)n2c3c(c4ccc(-n5ccc(OCc6ccccc6)cc5=O)cc42)CN2CCCCC2C3)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: Cl
Product: O=c1cc(OCc2ccccc2)ccn1-c1ccc2c3c([nH]c2c1)CC1CCCCN1C3
Temperature: 25 °C
Yield: 79 %

Procedure:
To a solution of 4-(benzyloxy)-1-(5-tosyl-5,6,6a,7,8,9,10,12-octahydroindolo[2,3-b]quinolizin-3-yl)-pyridin-2(1H)-one (50 mg, 0.086 mmol) in CH3OH (2 mL) and CH2Cl2 (2 mL) was added NaOH (17 mg, 0.43 mmol). The mixture was stirred at room temperature until complete. The mixture was filtered through a layer of Celite; the filtrate was concentrated; and the resulting oil was purified by flash column chromatography (silica gel, 10% CH3OH in CH2Cl2) to give the free base of the title compound (29 mg, 79%) as a yellow solid. The yellow solid was dissolved in CH3OH (2 mL) and treated with 2 N HCl in Et2O (1 mL). The resulting solid was isolated by filtration and dried under vacuum to give the title compound (18 mg, 57%) as a yellow powder: mp 270-273° C.; 1H NMR (500 MHz, CD3OD) δ 7.59 (d, J=8.0 Hz, 1H), 7.56 (d, J=8.0 Hz, 1H), 7.48-7.35 (m, 6H), 7.03 (dd, J=8.5, 1.5 Hz, 1H), 6.32 (dd, J=7.5, 3.0 Hz, 1H), 6.15 (d, J=2.5 Hz, 1H), 5.19 (s, 2H), 4.74 (d, J=14.5 Hz, 1H), 4.36 (d, J=14.5 Hz, 1H), 3.79 (d, J=13.0 Hz, 1H), 3.69-3.67 (m, 1H), 3.30-3.28 (m, 2H), 3.03 (dd, J=16.5, 10.5 Hz, 1H), 2.36-2.30 (m, 1H), 2.08-1.97 (m, 2H), 1.88-1.70 (m, 3H); ESI MS m/z 426 [M+H]+; HPLC (Method A) 98.5% (AUC), tR=12.99 min.
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6]([OH:9])=[CH:5][CH:4]=1)#[N:2].C1CCN2C(=NCCC2)CC1.Cl[C:22]([CH3:26])([CH3:25])[C:23]#[CH:24]>C(#N)C.C/C(/O)=C/C(C)=O.C/C(/O)=C/C(C)=O.[Cu]>[CH3:25][C:22]([O:9][C:6]1[CH:7]=[CH:8][C:3]([C:1]#[N:2])=[CH:4][CH:5]=1)([CH3:26])[C:23]#[CH:24]
Reactant: N#Cc1ccc(O)cc1
Reactant: C#CC(C)(C)Cl
Agent: [Cu]
Agent: CC(=O)/C=C(/C)O
Solvent: CC#N
Solvent: C1CCC2=NCCCN2CC1
Product: C#CC(C)(C)Oc1ccc(C#N)cc1
Reaction time: 7 h

Procedure:
To a solution of 4-cyanophenol (6.55 g, 55.0 mmol) in anhydrous acetonitrile (50 mL) at ~0° C. under argon was added DBU (9.90 mL, 66.2 mmol). After the solution had cooled to ~0° C., 3-chloro-3-methyl-1-butyne (7.10 g, 69.2 mmol) was added followed by copper(II) acetylacetonate (87.4 mg, 033 mmol). After stirring at ~0° C. for 7 hours, the mixture was concentrated at reduced pressure. The residue was partitioned between 1N HCl (70 mL) and toluene (300 mL). The organic fraction was washed with 1N HCl (2×60 mL), 1N NaOH (2×50 mL), 1N NaHCO3, and brine. After drying (magnesium sulfate), the solvent was removed at reduced pressure to give crude title compound as a pale yellow oil. Distillation of the crude material (bulb to bulb) afforded the title compound as a colorless, low melting solid (9.56 g).
Reaction SMILES: [Cl:1][C:2]1[CH:18]=[CH:17][C:5]2[CH2:6][CH2:7][N:8]([C:11](=[O:16])[C:12]([F:15])([F:14])[F:13])[CH2:9][CH2:10][C:4]=2[C:3]=1OS(C(F)(F)F)(=O)=O.[F:27][C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][C:29]=1[C:34]#[CH:35]>>[Cl:1][C:2]1[CH:18]=[CH:17][C:5]2[CH2:6][CH2:7][N:8]([C:11](=[O:16])[C:12]([F:14])([F:15])[F:13])[CH2:9][CH2:10][C:4]=2[C:3]=1[C:35]#[C:34][C:29]1[CH:30]=[CH:31][CH:32]=[CH:33][C:28]=1[F:27]
Reactant: C#Cc1ccccc1F
Reactant: O=C(N1CCc2ccc(Cl)c(OS(=O)(=O)C(F)(F)F)c2CC1)C(F)(F)F
Product: O=C(N1CCc2ccc(Cl)c(C#Cc3ccccc3F)c2CC1)C(F)(F)F
Yield: 66.2 %

Procedure:
Use a method similar to the General Procedure 3 to couple 7-chloro-3-(2,2,2-trifluoroacetyl)-6-trifluoromethanesulfonyloxy-2,3,4,5-tetrahydro-1H-benzo[d]azepine (425 mg, 1 mmol) with (2-fluorophenyl)-ethyne (241 mg, 2 mmol). Purify by chromatography on silica gel eluting with isohexane/EtOAc (1:0 to 1:1 gradient over 40 min) to give 7-chloro-6-(2-fluoro-phenylethynyl)-3-(2,2,2-trifluoroacetyl)-2,3,4,5-tetrahydro-1H-benzo[d]azepine (262 mg, 68%). MS (ES+) m/z: 396 (M+H)+.
Reaction SMILES: Br[C:2]1[C:3]2[C:4]3[CH:18]=[CH:17][S:16][C:5]=3[C:6](=[O:15])[NH:7][C:8]=2[C:9]([CH3:14])=[CH:10][C:11]=1[O:12][CH3:13].CC1(C)C(C)(C)OB([C:27]2[CH:32]=[CH:31][C:30]([C:33]3([CH2:37][NH:38][C:39](=[O:45])[O:40][C:41]([CH3:44])([CH3:43])[CH3:42])[CH2:36][CH2:35][CH2:34]3)=[CH:29][CH:28]=2)O1>>[C:41]([O:40][C:39](=[O:45])[NH:38][CH2:37][C:33]1([C:30]2[CH:29]=[CH:28][C:27]([C:2]3[C:3]4[C:4]5[CH:18]=[CH:17][S:16][C:5]=5[C:6](=[O:15])[NH:7][C:8]=4[C:9]([CH3:14])=[CH:10][C:11]=3[O:12][CH3:13])=[CH:32][CH:31]=2)[CH2:36][CH2:35][CH2:34]1)([CH3:44])([CH3:42])[CH3:43]
Reactant: CC(C)(C)OC(=O)NCC1(c2ccc(B3OC(C)(C)C(C)(C)O3)cc2)CCC1
Reactant: COc1cc(C)c2[nH]c(=O)c3sccc3c2c1Br
Product: COc1cc(C)c2[nH]c(=O)c3sccc3c2c1-c1ccc(C2(CNC(=O)OC(C)(C)C)CCC2)cc1
Yield: 45 %

Procedure:
Following General Procedure B, 9-bromo-8-methoxy-6-methylthieno[2,3-c]quinolin-4(5H)-one (150 mg, 0.46 mmol) was reacted with tert-butyl (1-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)cyclobutyl)methylcarbamate (270 mg, 0.70 mmol to afford the desired product (105 mg, 45%) as a light brown solid: ESI MS m/z 505 [C29H32N2O4S+H]+.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH:8]1[C:13]([C:14]([O:16][CH3:17])=[O:15])=[C:12]([CH3:18])[NH:11][C:10]([CH2:19][O:20][CH2:21][CH2:22][NH:23][CH2:24][C:25]([O:27]C)=[O:26])=[C:9]1[C:29]([O:31][CH2:32][CH3:33])=[O:30].[OH-].[Na+]>O1CCOCC1>[OH2:15].[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH:8]1[C:13]([C:14]([O:16][CH3:17])=[O:15])=[C:12]([CH3:18])[NH:11][C:10]([CH2:19][O:20][CH2:21][CH2:22][NH:23][CH2:24][C:25]([OH:27])=[O:26])=[C:9]1[C:29]([O:31][CH2:32][CH3:33])=[O:30].[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH:8]1[C:13]([C:14]([O:16][CH3:17])=[O:15])=[C:12]([CH3:18])[NH:11][C:10]([CH2:19][O:20][CH2:21][CH2:22][NH:23][CH2:24][C:25]([OH:27])=[O:26])=[C:9]1[C:29]([O:31][CH2:32][CH3:33])=[O:30]
Reactant: CCOC(=O)C1=C(COCCNCC(=O)OC)NC(C)=C(C(=O)OC)C1c1ccccc1Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1COCCO1
Product: CCOC(=O)C1=C(COCCNCC(=O)O)NC(C)=C(C(=O)OC)C1c1ccccc1Cl
Product: O
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A solution of methyl N-(2-{[4-(2-chlorophenyl)-3-ethoxycarbonyl-5-methoxycarbonyl-6-methyl-1,4-dihydropyrid-2-yl]methoxy}ethyl)aminoacetate (2.40 g) in dioxane (80 ml) was treated with 1M aqueous sodium hydroxide solution (10 ml) and the mixture stirred at room temperature for 2 hours and then evaporated. The residue was purified by ion exchange chromatography (Bio-Rad AG 50W-X8, [Trade Mark], 200-400 mesh, cation form, 40 g) eluting with dioxane initially followed by 2% pyridine in water. Appropriate fractions were combined and evaporated to give the title compound as a hemihydrate (0.56 g), m.p. 140°-150° (decomp.).
Reaction SMILES: Cl.[CH3:2][S:3]([CH:6]1[CH2:11][CH2:10][NH:9][CH2:8][CH2:7]1)(=[O:5])=[O:4].C(N(C(C)C)CC)(C)C.Cl[C:22]1[N:23]([CH2:44][C:45]([F:48])([F:47])[F:46])[C:24]2[C:29]([N:30]=1)=[C:28]([N:31]1[CH2:36][CH2:35][O:34][CH2:33][CH2:32]1)[N:27]=[C:26]([C:37]1[CH:38]=[N:39][C:40]([NH2:43])=[N:41][CH:42]=1)[N:25]=2>CN1CCCC1=O>[CH3:2][S:3]([CH:6]1[CH2:11][CH2:10][N:9]([C:22]2[N:23]([CH2:44][C:45]([F:46])([F:48])[F:47])[C:24]3[C:29]([N:30]=2)=[C:28]([N:31]2[CH2:32][CH2:33][O:34][CH2:35][CH2:36]2)[N:27]=[C:26]([C:37]2[CH:42]=[N:41][C:40]([NH2:43])=[N:39][CH:38]=2)[N:25]=3)[CH2:8][CH2:7]1)(=[O:5])=[O:4]
Reactant: CS(=O)(=O)C1CCNCC1
Reactant: Nc1ncc(-c2nc(N3CCOCC3)c3nc(Cl)n(CC(F)(F)F)c3n2)cn1
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: CN1CCCC1=O
Product: CS(=O)(=O)C1CCN(c2nc3c(N4CCOCC4)nc(-c4cnc(N)nc4)nc3n2CC(F)(F)F)CC1
Temperature: 100 °C
Reaction time: 12 h
Yield: 31.2 %

Procedure:
4-Methanesulfonylpiperidine hydrochloride (385 mg, 1.93 mmol), diisopropylethylamine (672 μl, 3.9 mmol), and N-methyl-2-pyrrolidone (2 ml) were added to 5-[8-chloro-6-morpholin-4-yl-9-(2,2,2-trifluoroethyl)-9H-purin-2-yl]pyrimidin-2-amine (200 mg, 0.48 mmol) and the resulting mixture was stirred at 100° C. for 12 hours. The reaction mixture was partitioned with ethyl acetate and water, the organic layer was dried over magnesium sulfate, and then the solvent was evaporated under reduced pressure. The residue was purified by silica gel chromatography (chloroform:methanol=20:1) to give the title compound (81 mg, 33%) as a pale yellow solid.
Reaction SMILES: [Cl:1][C:2]1[C:3]([C:27]2[S:31][C:30]([C:32]3([OH:36])[CH2:35][O:34][CH2:33]3)=[N:29][CH:28]=2)=[C:4]2[CH:10]=[C:9]([C:11]3[CH2:12][CH2:13][NH:14][CH2:15][CH:16]=3)[N:8]([S:17]([C:20]3[CH:26]=[CH:25][C:23]([CH3:24])=[CH:22][CH:21]=3)(=[O:19])=[O:18])[C:5]2=[N:6][CH:7]=1.Cl[CH2:38][C:39]([N:41]([CH3:43])[CH3:42])=[O:40].C(N(CC)CC)C>CN1CCCC1=O>[Cl:1][C:2]1[C:3]([C:27]2[S:31][C:30]([C:32]3([OH:36])[CH2:35][O:34][CH2:33]3)=[N:29][CH:28]=2)=[C:4]2[CH:10]=[C:9]([C:11]3[CH2:12][CH2:13][N:14]([CH2:38][C:39]([N:41]([CH3:43])[CH3:42])=[O:40])[CH2:15][CH:16]=3)[N:8]([S:17]([C:20]3[CH:21]=[CH:22][C:23]([CH3:24])=[CH:25][CH:26]=3)(=[O:18])=[O:19])[C:5]2=[N:6][CH:7]=1
Reactant: Cc1ccc(S(=O)(=O)n2c(C3=CCNCC3)cc3c(-c4cnc(C5(O)COC5)s4)c(Cl)cnc32)cc1
Reactant: CN(C)C(=O)CCl
Solvent: CCN(CC)CC
Solvent: CN1CCCC1=O
Product: Cc1ccc(S(=O)(=O)n2c(C3=CCN(CC(=O)N(C)C)CC3)cc3c(-c4cnc(C5(O)COC5)s4)c(Cl)cnc32)cc1
Temperature: 25 °C

Procedure:
A solution of Example 146C (0.047 g, 0.087 mmol), 2-chloro-N,N-dimethylacetamide (0.011 g, 0.091 mmol) and triethylamine (0.029 mL, 0.208 mmol) in 1-methyl-2-pyrrolidinone (0.8 mL) was heated to 75° C. for 1 hour. The reaction was cooled to ambient temperature and partitioned between water and ethyl acetate. The aqueous layer was extracted with additional ethyl acetate. The combined organic layers were washed with water (2×) and brine, dried over anhydrous sodium sulfate, filtered, and concentrated. The residue was taken directly to the next step without further purification. MS ESI(+) m/z 628.2 [M+H]+.
Reaction SMILES: [Br-].[Br-].[Br-].[NH+]1C=CC=CC=1.[NH+]1C=CC=CC=1.[NH+]1C=CC=CC=1.[NH:22]1[C:30]2[C:25](=[C:26]([C:31]3[CH:32]=[CH:33][C:34]([NH2:37])=[N:35][CH:36]=3)[CH:27]=[CH:28][CH:29]=2)[CH:24]=[CH:23]1.[OH2:38]>CC(O)(C)C.C(O)C.C(O)(=O)C.[Zn]>[NH2:37][C:34]1[N:35]=[CH:36][C:31]([C:26]2[CH:27]=[CH:28][CH:29]=[C:30]3[C:25]=2[CH2:24][C:23](=[O:38])[NH:22]3)=[CH:32][CH:33]=1
Reactant: Nc1ccc(-c2cccc3[nH]ccc23)cn1
Reactant: O
Agent: [Br-]
Agent: [Zn]
Agent: c1cc[nH+]cc1
Solvent: CCO
Solvent: CC(C)(C)O
Solvent: CC(=O)O
Product: Nc1ccc(-c2cccc3c2CC(=O)N3)cn1
Temperature: 25 °C
Reaction time: 2 h
Yield: 97 %

Procedure:
Pyridinium tribromide (90% (Aldrich), 3.7 g, 10.32 mmol) was added portion-wise over 10 minutes to a suspension of 5-(1H-indol-4-yl)-pyridin-2-ylamine (720 mg, 3.44 mmol) in 2-methyl-2-propanol (25 mL), ethanol (15 mL) and acetic acid (9 mL). The mixture was stirred at room temperature for 2 hours and then acetic acid (36 mL), water (1 mL) and zinc dust (3.2 g, 56.1 mmol) were added. Stirring was continued for 1.5 hours. Residual zinc dust was filtered and washed with methanol. The filtrate was concentrated and the syrupy residue was stirred in water (100 mL) overnight. The solid that formed was filtered, washed with water to remove zinc and pyridine salts and dried under high vacuum to give 750 mg (97%) of 4-(6-amino-pyridin-3-yl)-1,3-dihydroindol-2-one as a light brown solid.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2(O)[C:16]3[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=3)[C:10](=[O:17])[N:9]2[CH2:18][C:19]2[CH:24]=[CH:23][C:22]([N+:25]([O-:27])=[O:26])=[CH:21][CH:20]=2)=[CH:4][CH:3]=1.S(Cl)([Cl:31])=O>CN(C=O)C>[Cl:31][C:8]1([C:5]2[CH:6]=[CH:7][C:2]([Cl:1])=[CH:3][CH:4]=2)[C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[C:10](=[O:17])[N:9]1[CH2:18][C:19]1[CH:24]=[CH:23][C:22]([N+:25]([O-:27])=[O:26])=[CH:21][CH:20]=1
Reactant: O=C1c2ccccc2C(O)(c2ccc(Cl)cc2)N1Cc1ccc([N+](=O)[O-])cc1
Reactant: O=S(Cl)Cl
Solvent: CN(C)C=O
Product: O=C1c2ccccc2C(Cl)(c2ccc(Cl)cc2)N1Cc1ccc([N+](=O)[O-])cc1

Procedure:
Distilled THF (10 mL) was added to 3-(4-chlorophenyl)-3-hydroxy-2-(4-nitrobenzyl)isoindolin-1-one (200 mg, 0.52 mmol), thionyl chloride (136.8 mg, 1.15 mmol, 0.08 mL) and catalytic DMF (3 drops) as for general procedure B1. 3-Chloro-3-(4-chlorophenyl)-2-(4-nitrobenzyl)isoindolin-1-one was produced as a viscous yellow oil (208.5 mg, 0.52 mmol) which was used immediately without further purification. Distilled THF (3 mL) was added to 3-chloro-3-(4-chlorophenyl)-2-(4-nitrobenzyl)isoindolin-1-one (208.5 mg, 0.52 mmol) and the resultant solution added dropwise to cis-cyclopentene diol (260 mg, 2.6 mmol) and dried potassium carbonate (359 mg, 2.6 mmol) in distilled THF (3 mL) as for general procedure B1. Removal of the solvent yielded the crude product as a yellow oil (262 mg). The sample was purified by flash column chromatography (EtOAc:Petrol, 40:60) to yield the title product as a yellow viscous oil. (211 mg, 44.4 mmol, 85%). 1H NMR: (300 MHz, DMSO) δ ppm 1.34, (m, 1H, H15/H16) 1.74, 2.2 (m, 1H, H15/H16) 4.22 (dt, 1H, H16) 4.40 (d, 1H, J=15.99 Hz, H9/H9′), 4.63 (d, 1H, J=16.02 Hz, H9/H9′), 4.93, 4.98, (dd, 1H, H17/H18), 5.15, 5.29 (dd, 1H, H17/H18), 5.76 (m, 1H, H14) 7.26 (m, 7H, H1-H5, H10, H13), 7.66 (m, 2H, H6-H7), 7.88 (d, 1H, H8), 8.00 (m, 2H, H11, H12).
Reaction SMILES: [I:1][C:2]1[C:3]2[C:4](=[CH:8][NH:9][N:10]=2)[N:5]=[CH:6][CH:7]=1.Br[CH2:12][CH2:13][CH2:14][O:15][CH:16]1[CH2:21][CH2:20][CH2:19][CH2:18][O:17]1.C([O-])([O-])=O.[Cs+].[Cs+]>CN(C=O)C>[I:1][C:2]1[C:3]2[C:4](=[CH:8][N:9]([CH2:12][CH2:13][CH2:14][O:15][CH:16]3[CH2:21][CH2:20][CH2:19][CH2:18][O:17]3)[N:10]=2)[N:5]=[CH:6][CH:7]=1.[I:1][C:2]1[CH:7]=[CH:6][N:5]=[C:4]2[CH:8]=[N:9][N:10]([CH2:12][CH2:13][CH2:14][O:15][CH:16]3[CH2:21][CH2:20][CH2:19][CH2:18][O:17]3)[C:3]=12
Reactant: Ic1ccnc2c[nH]nc12
Reactant: BrCCCOC1CCCCO1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: Ic1ccnc2cn(CCCOC3CCCCO3)nc12
Product: Ic1ccnc2cnn(CCCOC3CCCCO3)c12
Temperature: 120 °C

Procedure:
7-Iodo-2H-pyrazolo[4,3-b]pyridine (200 mg, 0.816 mmol), 2-(3-bromopropoxy)tetrahydro-2H-pyran (182 mg, 0.816 mmol) and Cs2CO3 (532 mg, 1.633 mmol) were combined in DMF (5 mL) and the mixture was heated at 120° C. for 30 minutes in a microwave. The reaction mixture was then purified by preparative HPLC using a Sunfire Prep 5 μm C18, 75×30 mm column eluting with a gradient of 05-40% acetonitrile (containing 0.035% TFA) in water (containing 0.05% TFA) to give 7-iodo-2-(3-(tetrahydro-2H-pyran-2-yloxy)propyl)-2H-pyrazolo[4,3-b]pyridine and 7-iodo-1-(3-(tetrahydro-2H-pyran-2-yloxy)propyl)-1H-pyrazolo[4,3-b]pyridine. MS [M+H] found 388.0.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@H:9]([CH2:16][OH:17])[CH2:10][CH2:11][C:12]([O:14][CH3:15])=[O:13])=[O:7])([CH3:4])([CH3:3])[CH3:2].CO[C:20]([CH3:22])=[CH2:21].CCN(CC)CC>CC(C)=O.B(F)(F)F.CCOCC>[CH3:15][O:14][C:12](=[O:13])[CH2:11][CH2:10][C@H:9]1[CH2:16][O:17][C:20]([CH3:22])([CH3:21])[N:8]1[C:6]([O:5][C:1]([CH3:2])([CH3:4])[CH3:3])=[O:7]
Reactant: COC(=O)CC[C@@H](CO)NC(=O)OC(C)(C)C
Reactant: C=C(C)OC
Agent: FB(F)F
Solvent: CCOCC
Solvent: CC(C)=O
Solvent: CCN(CC)CC
Product: COC(=O)CC[C@H]1COC(C)(C)N1C(=O)OC(C)(C)C
Reaction time: 1 h
Yield: 71.6 %

Procedure:
(S)-methyl 4-(tert-butoxycarbonylamino)-5-hydroxypentanoate (12 g, 48.6 mmol) and isopropenyl methyl ether (44.4 g, 427.3 mmol) was dissolved in acetone (200 mL) and BF3.Et2O (0.41 mL, 2.92 mmol) was added at rt and stirred for 1 hour. The reaction was stopped by addition of Et3N (5.8 mL). The reaction solution was washed with 100 mL of saturated NaHCO3 and evaporated, and (S)-tert-butyl 4-(3-methoxy-3-oxopropyl)-2,2-dimethyloxazolidine-3-carboxylate (10 g, yield 72%) was obtained as an oil that was used in the next step without further purification.
Reaction SMILES: [C:1]1([CH2:7][C:8](Cl)=[O:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[C:11]1(OC)[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1.[CH3:19]CS.[Al+3].[Cl-].[Cl-].[Cl-]>C(=S)=S.[Cl-].[Al+3].[Cl-].[Cl-]>[C:11]1([C:8]([CH2:7][C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=2)=[O:9])[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1.[CH2:19]1[C:6]2[C:1](=[CH:2][CH:3]=[CH:4][CH:5]=2)[CH:7]=[CH:8]1
Reactant: COc1ccccc1
Reactant: CCS
Reactant: O=C(Cl)Cc1ccccc1
Agent: [Al+3]
Agent: [Cl-]
Solvent: S=C=S
Product: C1=Cc2ccccc2C1
Product: O=C(Cc1ccccc1)c1ccccc1

Procedure:
Treatment of p-methoxydeoxybenzoin (32) (FIG. 4) with PCl5 in refluxing benzene provided p-methoxy-α'-chlorostilbene 33 (Nagano, 1955), which underwent Friedel-Crafts conditions with anisole to furnish the triarylethylene 34. The carbonyl group in deoxybenzoin 32 was converted to a gem-dichloride intermediate, using phosphorous pentachloride, and with the subsequent elimination of HCl, the vinyl chloride 33 was obtained. Compound 32 was prepared using Friedel-Crafts conditions involving phenylacetyl chloride and anisole in carbon disulfide and aluminum chloride (BUCK, J. S. AND IDE, W. S. (1932), "The isomeric desoxybenzanisoins", Journal of the American Chemical Society, 54, 3012). Demethylation of 35 was accomplished with EtSH/AlCl3, and 36 was isolated by column chromatography. Drying of phenol 36 at a high temperature resulted in the formation of an indene, which was observed previously (MAGARIAN, R. A., MELTON, S. AND NATARELLI, G. (1972), "2-Chloro-1-phenylindene from 1,1-dichloro-trans-2,3-diphenylcyclopropane", Journal of Pharmaceutical Sciences, 61, 1216). Compound 36 was isolated as the diacetate (37) using column chromatography.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[N:6][C:5]([CH2:8][NH:9][CH2:10][CH:11]([CH3:13])[CH3:12])=[C:4]([CH2:14][CH2:15][CH3:16])[CH:3]=1.[F:17][C:18]1[N:23]=[C:22]([C:24](O)=[O:25])[CH:21]=[CH:20][CH:19]=1.CCN=C=NCCCN(C)C.O>C(Cl)Cl.CN(C1C=CN=CC=1)C>[Cl:1][C:2]1[N:7]=[N:6][C:5]([CH2:8][N:9]([CH2:10][CH:11]([CH3:12])[CH3:13])[C:24]([C:22]2[CH:21]=[CH:20][CH:19]=[C:18]([F:17])[N:23]=2)=[O:25])=[C:4]([CH2:14][CH2:15][CH3:16])[CH:3]=1
Reactant: CCCc1cc(Cl)nnc1CNCC(C)C
Reactant: O=C(O)c1cccc(F)n1
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Solvent: O
Solvent: ClCCl
Product: CCCc1cc(Cl)nnc1CN(CC(C)C)C(=O)c1cccc(F)n1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a stirred solution of (6-chloro-4-propyl-pyridazin-3-ylmethyl)-isobutyl-amine (940 mg, 3.89 mmol) and 6-fluoro-pyridine-2-carboxylic acid (663 mg, 4.7 mmol) in CH2Cl2 (10 ml) is added EDCI (783 mg, 4.7 mmol) and DMAP (244 mg, 2 mmol). The mixture is stirred at room temperature overnight. Water (10 ml) is added and the layers are separated. The organic layer is washed with brine (10 ml), then dried (Na2SO4) and evaporated. Flash column purification of the residue (2:1 of hexane: ethyl acetate) provides the title product. 1H NMR (CDCl3) (mixture of rotamers) 7.89 (q, 0.7H), 7.81 (q, 0.3H), 7.69 (dd, 0.3H), 7.53 (dd, 0.7H), 7.34 (s, 0.7H), 7.20 (s, 0.3H), 6.99 (dd, 0.7H1), 6.91 (dd, 0.3H), 5.19 (s, 0.6H), 5.07 (s, 1.4H), 3.41 (d, 0.6H), 3.31 (d, 1.4H1), 2.75 (t, 1.4H1), 2.48 (t, 0.6H), 2.08-2.17 (m, 1H), 1.69-1.75 (m, 1.4H1), 1.54-1.60 (m, 0.6H), 1.02 (t, 2.11H), 0.99 (d, 1.8H), 0.97 (t, 0.9H), 0.80 (d, 4.2H).
Reaction SMILES: [H-].[Na+].NC1NC2C(C=1C#N)=CC=C([N+]([O-])=[O:16])C=2.I[CH2:19][CH3:20].[NH2:21][C:22]1[N:23]([CH2:36][CH3:37])[C:24]2[C:29]([C:30]=1[C:31]#[N:32])=[CH:28][CH:27]=[C:26]([N+:33]([O-:35])=[O:34])[CH:25]=2>CCCCCC.CS(C)=O.CCOC(C)=O>[C:31]([C:30]1[C:29]2[C:24](=[CH:25][C:26]([N+:33]([O-:35])=[O:34])=[CH:27][CH:28]=2)[N:23]([CH2:36][CH3:37])[C:22]=1[NH:21][C:19](=[O:16])[CH3:20])#[N:32]
Reactant: CCn1c(N)c(C#N)c2ccc([N+](=O)[O-])cc21
Reactant: N#Cc1c(N)[nH]c2cc([N+](=O)[O-])ccc12
Reactant: CCI
Agent: [H-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CS(C)=O
Solvent: CCCCCC
Product: CCn1c(NC(C)=O)c(C#N)c2ccc([N+](=O)[O-])cc21
Reaction time: 0.33 h

Procedure:
Sodium hydride (42 mg, 1.05 mmol, 60% w/w suspension in mineral oil) is washed with hexane and taken up in dimethylsulfoxide (1 mL). A solution of 2-amino-6-nitro-1H-indole-3-carbonitrile (prepared in procedure 1T) in dimethylsulfoxide (1 mL) is added by syringe, and the resulting mixture is stirred for 20 min. Then, iodoethane (77 μL, 0.96 mmol) is added by syringe, and the mixture is stirred for 14 h. The reaction is then poured into EtOAc (50 mL), and this solution is washed with water (3×50 mL) and saturated brine (40 mL). The aqueous phases are back-extracted with EtOAc, and the organic extracts are combined, dried over Na2SO4, filtered and evaporated. The residual material is separated by column chromatography over silica gel (EtOAc/hexanes, 1/1) to afford first a small amount of a dialkylated analog, then the desired compound, 2-amino-1-ethyl-6-nitro-1H-indole-3-carbonitrile (114 mg, 52%), and finally unreacted starting material. The desired product is isolated as an orange powder.
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][C:5]2[N:11]3[CH:12]=[N:13][C:14]([C:15]([N:17]4C=C[N:19]=[CH:18]4)=[O:16])=[C:10]3[CH2:9][N:8]([CH3:22])[C:7](=[O:23])[C:6]=2[CH:24]=1.[CH3:25][O:26][CH2:27]C(=NO)N>CN(C)C=O>[F:1][C:2]1[CH:3]=[CH:4][C:5]2[N:11]3[CH:12]=[N:13][C:14]([C:15]4[O:16][N:19]=[C:18]([CH2:25][O:26][CH3:27])[N:17]=4)=[C:10]3[CH2:9][N:8]([CH3:22])[C:7](=[O:23])[C:6]=2[CH:24]=1
Reactant: CN1Cc2c(C(=O)n3ccnc3)ncn2-c2ccc(F)cc2C1=O
Reactant: COCC(N)=NO
Solvent: CN(C)C=O
Product: COCc1noc(-c2ncn3c2CN(C)C(=O)c2cc(F)ccc2-3)n1
Reaction time: 8 h

Procedure:
A mixture of 6.50 g (20 mmol) of 1-[[8-fluoro-5,6-dihydro-5-methyl-6-oxo-4H-imidazo[1,5-a][1,4]benzodiazepin-3-yl]carbonyl]imidazole, 50 ml of N,N-dimethylformamide and 2.10 g (20 mmol) of methoxyacetamidoxime is stirred at 100° overnight. After evaporation of the solvent the residue is dissolved in methylene chloride and washed with water. The organic solution is dried over magnesium sulphate and evaporated. By chromatography of the residue on silica gel while eluting with ethyl acetate and recrystallization from methylene chloride and ethyl acetate there is obtained 8-fluoro-4,5-dihydro-3-(3-methoxymethyl-1,2,4-oxadiazol-5-yl)-5-methyl-6H-imidazo[1,5-a][1,4]benzodiazepin-6-one of melting point 192°-194°.