Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]([O:4][C:5]1[CH:25]=[CH:24][C:8]([O:9][C:10]2[CH:15]=[CH:14][C:13]([C:16]3[CH:20]=[C:19]([CH:21]([NH2:23])[CH3:22])[O:18][N:17]=3)=[CH:12][CH:11]=2)=[CH:7][CH:6]=1)([CH3:3])[CH3:2].ClC(Cl)(Cl)[C:28]([N:30]=C=O)=[O:29]>ClCCl>[CH:1]([O:4][C:5]1[CH:25]=[CH:24][C:8]([O:9][C:10]2[CH:15]=[CH:14][C:13]([C:16]3[CH:20]=[C:19]([CH:21]([NH:23][C:28]([NH2:30])=[O:29])[CH3:22])[O:18][N:17]=3)=[CH:12][CH:11]=2)=[CH:7][CH:6]=1)([CH3:2])[CH3:3]
Reactant: CC(C)Oc1ccc(Oc2ccc(-c3cc(C(C)N)on3)cc2)cc1
Reactant: O=C=NC(=O)C(Cl)(Cl)Cl
Solvent: ClCCl
Product: CC(C)Oc1ccc(Oc2ccc(-c3cc(C(C)NC(N)=O)on3)cc2)cc1
Temperature: 0 °C
Reaction time: 0.17 h
Yield: 66.9 %

Procedure:
To a solution of Example 17F (377 mg, 1.12 mmol) in dichloromethane (10 mL) at 0° C. was added trichloroacetyl isocyanate (145 μL, 1.22 mmol). The mixture was stirred at 0° C. for 10 minutes. The reaction was concentrated and the residue was dissolved in methanol (˜60 mL) and a small amount of Na2CO3 was added. The mixture was stirred at room temperature for 3 hours before being concentrated. The residue was dissolved in dichloromethane, which was washed with water (1×) and concentrated. The residue was purified on silica gel eluting with hexane and ethyl acetate gradient to give the desired product as a white solid (286 mg, 67%), MS (DCI): m/z 382 (M+H); 1H NMR (300 MHz, DMSO-d6) δ ppm 7.78-7.86 (m, 2H), 6.99-7.08 (m, 4H), 6.94-6.99 (m, 2H), 6.75 (s, 1H), 6.61 (d, J=8.46 Hz, 1H), 5.59 (br s, 2H), 4.90-5.02 (m, 1H), 4.53-4.63 (m, 1H), 1.41 (d, J=6.99 Hz, 3H), 1.27 (d, J=5.88 Hz, 6H).
Reaction SMILES: N#N.[Cl:3][C:4]1[CH:9]=[CH:8][C:7]([C:10]2[CH2:14][N:13]([CH2:15][C:16]([CH3:20])([CH3:19])[CH2:17]O)[C:12](=O)[C:11]=2[C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)=[CH:6][CH:5]=1.P12(SP3(SP(SP(S3)(S1)=S)(=S)S2)=S)=[S:29]>[OH-].[Na+]>[Cl:3][C:4]1[CH:9]=[CH:8][C:7]([C:10]2[C:11]([C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=3)=[C:12]3[N:13]([CH:14]=2)[CH2:15][C:16]([CH3:20])([CH3:19])[CH2:17][S:29]3)=[CH:6][CH:5]=1
Reactant: S=P12SP3(=S)SP(=S)(S1)SP(=S)(S2)S3
Reactant: CC(C)(CO)CN1CC(c2ccc(Cl)cc2)=C(c2ccccc2)C1=O
Agent: N#N
Agent: [Na+]
Agent: [OH-]
Product: CC1(C)CSc2c(-c3ccccc3)c(-c3ccc(Cl)cc3)cn2C1

Procedure:
At a 170-180° C. bath temperature, in a protective atmosphere of N2, 4-(4-chlorophenyl)-1-(2,2-dimethyl-3-hydroxypropyl)-3-phenyl-1,5-dihydro-pyrrol-2-on (5, 10.7 g, 0.03 mol) is melted with phosphorus pentasulfide (3.33 g, 2.5 equiv., 0.015 mol), which is added in small portions until the gas development comes to a halt (1 h). Then the cooled reaction mixture is akalyzed with caustic soda (100 mL, 10%) and extracted with chloroform; the organic phase is washed with water and dried. The residue remaining after the evaporation of chloroform is crystallized from diisopropyl ether having a melting point of 147-148° C. (5.5 g, 52%).
Reaction SMILES: [F-].[K+].[Br:3][C:4]1[C:11]([OH:12])=[C:10]([O:13][CH3:14])[CH:9]=[CH:8][C:5]=1[CH:6]=[O:7].F[C:16]1[CH:21]=[CH:20][C:19]([N+:22]([O-:24])=[O:23])=[CH:18][CH:17]=1.O>CS(C)=O>[Br:3][C:4]1[C:11]([O:12][C:16]2[CH:21]=[CH:20][C:19]([N+:22]([O-:24])=[O:23])=[CH:18][CH:17]=2)=[C:10]([O:13][CH3:14])[CH:9]=[CH:8][C:5]=1[CH:6]=[O:7]
Reactant: O=[N+]([O-])c1ccc(F)cc1
Reactant: COc1ccc(C=O)c(Br)c1O
Agent: [F-]
Agent: [K+]
Solvent: O
Solvent: CS(C)=O
Product: COc1ccc(C=O)c(Br)c1Oc1ccc([N+](=O)[O-])cc1
Temperature: 140 °C
Reaction time: 4 h
Yield: 65.4 %

Procedure:
To a stirred suspension of potassium fluoride (1.89 gm, 0.0326 mol) in dry DMSO (10 ml) was added a solution of 2-bromoisovanillin (5.0 gm, 0.0217 mol) in DMSO (10 ml). A solution of 4-fluoronitrobenzene (5.0 gm, 0.0260 mol) in DMSO (5 ml) was added to the above suspension and the reaction mixture was stirred at 140° C. for 4 h. The reaction mixture was cooled to room temperature and the contents were poured into water (150 ml) and extracted with ethyl acetate (50 ml×3). The organic extracts were combined and washed with 1N sodium hydroxide (25 ml×2), water and brine and dried over anhydrous sodium sulfate. The dried organic layer was concentrated in vacuo and the residue was purified by silica-gel column chromatography using 20% ethyl acetate-petroleum ether as the eluent to give 2-bromo-3-(p-nitrophenoxy)-4-methoxy benzaldehyde as a pale yellow solid (5.0 gm) mp: 132-140° C.
Reaction SMILES: [CH2:1]([NH:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:15][O:16][C:17]1[CH:18]=[C:19]([P:23](Cl)(Cl)=[O:24])[CH:20]=[CH:21][CH:22]=1>>[CH3:15][O:16][C:17]1[CH:18]=[C:19]([P:23]2(=[O:24])[C:3]3[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=3[CH2:1][N:8]2[C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[CH:20]=[CH:21][CH:22]=1
Reactant: COc1cccc(P(=O)(Cl)Cl)c1
Reactant: c1ccc(CNc2ccccc2)cc1
Product: COc1cccc(P2(=O)c3ccccc3CN2c2ccccc2)c1
Yield: 27 %

Procedure:
The procedure of Example 1 was employed utilizing N-benzylaniline and 3-methoxyphenyl phosphonic dichloride. The reaction of the dilithio compound and the 3-methoxyphenyl phosphonic dichloride was conducted at 0° C. to yield 1-(3-methoxyphenyl)-2-phenyl-2,3-dihydro-1H-2,1-benzazaphosphole-1-oxide (2.75 g, 27% yield) as a solid having a melting point of 170°-172° C. and the following analysis:
Reaction SMILES: Br[C:2]1[C:19]([F:20])=[CH:18][C:5]2[O:6][CH2:7][CH2:8][C:9]3[CH:13]=[C:12]([C:14]([O:16][CH3:17])=[O:15])[S:11][C:10]=3[C:4]=2[CH:3]=1.[C:21]([C@:23]1([OH:30])[CH2:27][CH2:26][N:25]([CH3:28])[C:24]1=[O:29])#[CH:22]>>[F:20][C:19]1[C:2]([C:22]#[C:21][C@:23]2([OH:30])[CH2:27][CH2:26][N:25]([CH3:28])[C:24]2=[O:29])=[CH:3][C:4]2[C:10]3[S:11][C:12]([C:14]([O:16][CH3:17])=[O:15])=[CH:13][C:9]=3[CH2:8][CH2:7][O:6][C:5]=2[CH:18]=1
Reactant: C#C[C@]1(O)CCN(C)C1=O
Reactant: COC(=O)c1cc2c(s1)-c1cc(Br)c(F)cc1OCC2
Product: COC(=O)c1cc2c(s1)-c1cc(C#C[C@]3(O)CCN(C)C3=O)c(F)cc1OCC2

Procedure:
Methyl 9-bromo-8-fluoro-4,5-dihydrobenzo[b]thieno[2,3-d]oxepine-2-carboxylate was reacted with (3R)-3-ethynyl-3-hydroxy-1-methyl-pyrrolidin-2-one similarly to as described in General Procedure F with non-critical modifications to afford (R)-methyl 8-fluoro-9-((3-hydroxy-1-methyl-2-oxopyrrolidin-3-yl)ethynyl)-4,5-dihydrobenzo[b]thieno[2,3-d]oxepine-2-carboxylate. Crude (R)-methyl 8-fluoro-9-((3-hydroxy-1-methyl-2-oxopyrrolidin-3-yl)ethynyl)-4,5-dihydrobenzo[b]thieno[2,3-d]oxepine-2-carboxylate was to General Procedure M subjected to afford 26 mg (21%) of 8-fluoro-9-[2-[(3R)-3-hydroxy-1-methyl-2-oxo-pyrrolidin-3-yl]ethynyl]-4,5-dihydrothieno[3,2-d][1]benzoxepine-2-carboxamide.
Reaction SMILES: NC1N=CC([C:8]2[C:9]([CH:26]=[O:27])=[N:10][N:11]([CH:13]3[CH2:18][CH2:17][N:16]([C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])[CH2:15][CH2:14]3)[CH:12]=2)=CC=1C1OC2C=CC=CC=2N=1.[Br:37]C1C=NNC=1C=O.C(=O)([O-])[O-].[K+].[K+].CS(OC1CCN(C(OC(C)(C)C)=O)CC1)(=O)=O>C(#N)C>[Br:37][C:8]1[C:9]([CH:26]=[O:27])=[N:10][N:11]([CH:13]2[CH2:18][CH2:17][N:16]([C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])[CH2:15][CH2:14]2)[CH:12]=1
Reactant: CC(C)(C)OC(=O)N1CCC(n2cc(-c3cnc(N)c(-c4nc5ccccc5o4)c3)c(C=O)n2)CC1
Reactant: O=Cc1[nH]ncc1Br
Agent: CC(C)(C)OC(=O)N1CCC(OS(C)(=O)=O)CC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: CC(C)(C)OC(=O)N1CCC(n2cc(Br)c(C=O)n2)CC1

Procedure:
Sodium tetrahydroborate (42.6 mg) and tert-butyl 4-[4-[6-amino-5-(1,3-benzoxazol-2-yl)-3-pyridyl]-3-formyl-pyrazol-1-yl]piperidine-1-carboxylate (550 mg) in methanol (10 ml) were stirred at room temperature for 1 hour. The reaction was incomplete and further sodium tetrahydroborate (42.6 mg) was added at room temperature and the reaction mixture was stirred at room temperature for 1 hour. The reaction mixture was diluted with dichloromethane (100 ml) and washed with water (2×20 ml), dried over magnesium sulfate and concentrated to dryness. The residue was dissolved in dichloromethane (2 ml) and the solution was cooled to 0° C. and treated with trifluoroacetic acid (3 ml). The resulting solution was allowed to stir at room temperature for 1 hour and then concentrated to dryness. The residue was re-dissolved in methanolic ammonia (7N, 5 ml) and absorbed onto silica and purified by flash chromatography on silica gel eluting with 0 to 15% methanolic ammonia (7 N) in dichloromethane. The solvent was evaporated to dryness to afford [4-[6-amino-5-(1,3-benzoxazol-2-yl)-3-pyridyl]-1-(4-piperidyl)pyrazol-3-yl]methanol (440 mg) as a solid. The tert-butyl 4-[4-[6-amino-5-(1,3-benzoxazol-2-yl)-3-pyridyl]-3-formyl-pyrazol-1-yl]piperidine-1-carboxylate used as starting material was prepared as follows: 4-bromo-2H-pyrazole-3-carbaldehyde (3 g), potassium carbonate (3.32 g) and tert-butyl 4-methylsulfonyloxypiperidine-1-carboxylate (6.23 g) in acetonitrile (150 ml) were stirred at reflux overnight. The resulting precipitate was removed by filtration and the filtrate was concentrated and purified by flash chromatography on silica gel eluting with 0 to 20% ethyl acetate in petroleum ether. The solvent was evaporated to dryness to yield tert-butyl 4-(4-bromo-3-formyl-pyrazol-1-yl)piperidine-1-carboxylate (4.10 g) as a clear colourless oil which crystallised on standing. NMR Spectrum: (CDCl3) 1.48 (s, 9H), 1.92 (dd, 1H), 1.96 (dd, 1H), 2.10-2.18 (m, 2H), 2.81-2.97 (m, 2H), 4.27 (bs, 2H), 4.28-4.38 (m, 1H), 7.543 (s, 1H), 9.96 (s, 1H); Mass spectrum: M+H+ 360.
Reaction SMILES: [C:1]1([N:7]2[C:12](=[O:13])[N:11]([CH3:14])[C:10](=[O:15])C(C#N)=[N:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.Cl.[C:19]([OH:22])(=[O:21])[CH3:20]>>[C:1]1([N:7]2[C:12](=[O:13])[N:11]([CH3:14])[C:10](=[O:15])[C:20]([C:19]([OH:22])=[O:21])=[N:8]2)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: CC(=O)O
Reactant: Cn1c(=O)c(C#N)nn(-c2ccccc2)c1=O
Agent: Cl
Product: Cn1c(=O)c(C(=O)O)nn(-c2ccccc2)c1=O
Temperature: 120 °C
Yield: 45.7 %

Procedure:
Intermediate d (7.6 g, 0.033 mol) was added to a mixed solvent of glacial acetic acid (100 mL) and HCl (72 mL, 0.86 mol). The mixture was warmed up to 120° C. and reacted under reflux for 4 h. The solvent was evaporated off. To the obtained fraction was added water (400 mL). The mixture was filtered by suction and dried to produce a solid (3.7 g) in a yield of 45.7%.
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[C:8]([NH:10][C:11](=[O:13])[CH3:12])[CH:7]=[CH:6][C:5]=1[O:14][CH3:15])([O-])=O.CO.N.[H][H]>[Pd].O>[CH3:15][O:14][C:5]1[CH:6]=[CH:7][C:8]([NH:10][C:11](=[O:13])[CH3:12])=[CH:9][C:4]=1[NH2:1]
Reactant: COc1ccc(NC(C)=O)cc1[N+](=O)[O-]
Reactant: [H][H]
Agent: [Pd]
Agent: N
Solvent: O
Solvent: CO
Product: COc1ccc(NC(C)=O)cc1N
Reaction time: 2 h

Procedure:
104 parts of 2-nitro-4-acetamidoanisole, 200 parts of methanol, 1.2 parts of a 30% aqueous solution of ammonia and 2 parts of a 50% suspension of palladium on charcoal, moist with water, in 2 parts of water are charged to an autoclave equipped with an aerating stirrer. The autoclave is pressurised with hydrogen and, at a pressure of 5 bar and a temperature of 100° C., hydrogenation is carried out for 2 hours. 2-Methoxy-5-acetamidoaniline is obtained in quantitative yield in a purity of >97% (analysis by liquid chromatography).
Reaction SMILES: [O:1]1CCO[CH:2]1[C:6]1[C:7]([O:20][CH3:21])=[CH:8][C:9]([O:18][CH3:19])=[C:10]([C:12]2[CH:17]=[N:16][CH:15]=[CH:14][N:13]=2)[CH:11]=1.C1(C)C=CC(S(O)(=O)=O)=CC=1.O>CC(C)=O>[CH3:21][O:20][C:7]1[CH:8]=[C:9]([O:18][CH3:19])[C:10]([C:12]2[CH:17]=[N:16][CH:15]=[CH:14][N:13]=2)=[CH:11][C:6]=1[CH:2]=[O:1]
Reactant: COc1cc(OC)c(C2OCCO2)cc1-c1cnccn1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: O
Solvent: CC(C)=O
Product: COc1cc(OC)c(-c2cnccn2)cc1C=O
Temperature: 25 °C
Reaction time: 3 h
Yield: 34.7 %

Procedure:
Ex-46D: 2-(5-[1,3]Dioxolan-2-yl-2,4-dimethoxy-phenyl)-pyrazine (1.02 g, 3.54 mmol) was dissolved in acetone and p-toluenesulfonic acid (100 mg, 0.53 mmol) and water (5 mL) were added. The solution was stirred for 3 h at room temperature, then concentrated on the rotavap. The resulting mixture was diluted with water (50 mL) and extracted with EtOAc (3×100 mL). The organic phase was washed with 25% saturated aqueous NaHCO3, dried over sodium sulfate, filtered, and concentrated. Drying gave 0.30 g of 2,4-dimethoxy-5-pyrazin-2-yl-benzaldehyde as a yellow solid (18% yield). 1H-NMR (CDCl3) δ 10.35 (s, 1H), 9.06 (d, J=2 Hz, 1H), 8.63–8.65 (m, 1H), 8.45 (d, J=2 Hz, 1H), 8.39 (s, 1H), 6.56 (s, 1H), 4.03 (s, 3H), 4.01 (s, 3H). HRMS m/z: calc. 244.0848, found 244.0853.
Reaction SMILES: [NH2:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][C:10]=2[NH2:12])[CH:5]=[CH:4][CH:3]=1.[OH:13][C:14]([CH3:20])([CH2:18][CH3:19])[C:15](O)=O.C(O)C.CCOCC.[ClH:29]>>[ClH:29].[CH2:18]([C:14]([CH3:20])([C:15]1[NH:1][C:2]2[CH:3]=[CH:4][CH:5]=[C:6]3[C:11]=2[C:10]([N:12]=1)=[CH:9][CH:8]=[CH:7]3)[OH:13])[CH3:19]
Reactant: Nc1cccc2cccc(N)c12
Reactant: CCC(C)(O)C(=O)O
Agent: Cl
Solvent: CCO
Solvent: CCOCC
Product: CCC(C)(O)C1=Nc2cccc3cccc(c23)N1

Procedure:
1,8-Diaminonaphthalene (44.5 g, 0.282 mole) is suspended in 400 ml of 4N hydrochloric acid. To this suspension is added 2-hydroxy-2-methyl butyric acid (50 g, 0.423 mole) and the whole is stirred and heated under reflux for 96 hours. Then the reaction mixture is allowed to cool and is filtered, yielding a gray-green solid. The solid is heated and stirred with 1 liter of refluxing ethanol, and is filtered while hot to remove unreacted starting materials. The filtrate is concentrated to dryness and the resulting solid is treated with 500 ml of boiling ethanol. After the insoluble material is removed by filtration, the filtrate was treated with charcoal, yielding a yellow solution. Addition of ether, plus cooling, yields a yellow-brown solid. Recrystallization from ethanol (charcoal) yields the desired product, α-ethyl-α-methyl-2-perimidinemethanol, hydrochloride, m.p. 266°-268° dec.).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][CH2:6][CH2:5]2.[C:11]([O:15][C:16](=O)[O:17]C(C)(C)C)([CH3:14])([CH3:13])[CH3:12].CC#N>CN(C)C1C=CN=CC=1.CCOC(C)=O>[Br:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[N:7]([C:16]([O:15][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:17])[CH2:6][CH2:5]2
Reactant: CC(C)(C)OC(=O)OC(C)(C)C
Reactant: Brc1ccc2c(c1)CCN2
Agent: CN(C)c1ccncc1
Solvent: CC#N
Solvent: CCOC(C)=O
Product: CC(C)(C)OC(=O)N1CCc2cc(Br)ccc21
Temperature: 25 °C
Reaction time: 16 h
Yield: 37.9 %

Procedure:
5-Bromoindoline (3.96 g, 20 mmol), di-t-butylcarbonate (4.37 g, 20 mmol), 4-dimethylaminopyridine (2.69 g, 22 mmol) and CH3CN (50 mL) were mixed and stirred at room temperature for 16 h. The reaction mixture was diluted with EtOAc (300 mL) and the organic solution was washed successively with water (50 mL), a 1 N HCl solution (50 mL), a saturated NaHCO3 solution (2×50 mL) and brine (25 mL). The organic layer was dried over MgSO4, filtered and concentrated in vacuo to afford a solid. Trituration with hexane and drying in vacuo provided a white solid (2.26 g, 38% yield): 1H NMR (DMSO-d6, 300 MHz): 7.36 (s, 1H), 7.29 (d, 2H, J=7), 3.86 (t, 2H, J=7), 3.04 (t, 2H, J=7), 1.48 (s, 9H).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:15])[C:4]1[CH:13]=[CH:12][C:11]([NH2:14])=[C:6]([C:7]([O:9][CH3:10])=[O:8])[CH:5]=1.[CH2:16]([O:18][C:19]1[C:27]([O:28][CH3:29])=[CH:26][CH:25]=[CH:24][C:20]=1[C:21](Cl)=[O:22])[CH3:17]>O1CCOCC1.N1C=CC=CC=1>[CH3:1][O:2][C:3](=[O:15])[C:4]1[CH:13]=[CH:12][C:11]([NH:14][C:21](=[O:22])[C:20]2[CH:24]=[CH:25][CH:26]=[C:27]([O:28][CH3:29])[C:19]=2[O:18][CH2:16][CH3:17])=[C:6]([C:7]([O:9][CH3:10])=[O:8])[CH:5]=1
Reactant: COC(=O)c1ccc(N)c(C(=O)OC)c1
Reactant: CCOc1c(OC)cccc1C(=O)Cl
Solvent: c1ccncc1
Solvent: C1COCCO1
Product: CCOc1c(OC)cccc1C(=O)Nc1ccc(C(=O)OC)cc1C(=O)OC
Yield: 97.2 %

Procedure:
Dimethyl- 4-amino-isophthalate (5 g) in 50 ml of dioxane and 10 ml of anhydrous pyridine is treated with 7.5 g of 2-ethoxy-3-methoxybenzoyl chloride at room temperature, overnight. After dilution with water, the precipitate is collected, dissolved in ethyl acetate, and washed with 5% NaHCO3 and then with water. After evaporation to dryness under vacuum, the material is crystallized from isopropyl ether, yielding dimethyl- 4-(2'-ethoxy-3'-methoxy-benzoylamino)-isophthalate (9 g; m.p. 113°-115° C.), which is dissolved in 80 ml of dioxane and treated with 70 ml of 1N NaOH at room temperature for 4 hours. After acidification with diluted HCl, the precipitate is collected under vacuum and washed with water until neutral. The yield is 7.4 g of 4-(2'-ethoxy-3'-methoxy-benzoylamino)-isophthalic acid (m.p.=244°-246° C.), which are treated with 10 ml of acetic anhydride at the reflux temperature for 10'.
Reaction SMILES: CCN(C(C)C)C(C)C.[C:10]([O:13][CH2:14][CH2:15][C:16]1[C:21]([N+:22]([O-:24])=[O:23])=[CH:20][CH:19]=[C:18]([NH2:25])[C:17]=1[F:26])(=[O:12])[CH3:11].[F:27][C:28]([F:43])([C:32]1[C:41]2[C:36](=[CH:37][CH:38]=[CH:39][CH:40]=2)[C:35]([F:42])=[CH:34][CH:33]=1)[C:29](Cl)=[O:30].FC(F)(C1C2C(=CC=CC=2)C(F)=CC=1)C(O)=O.C(Cl)(=O)C(Cl)=O>C(Cl)Cl>[C:10]([O:13][CH2:14][CH2:15][C:16]1[C:21]([N+:22]([O-:24])=[O:23])=[CH:20][CH:19]=[C:18]([NH:25][C:29](=[O:30])[C:28]([F:43])([F:27])[C:32]2[C:41]3[C:36](=[CH:37][CH:38]=[CH:39][CH:40]=3)[C:35]([F:42])=[CH:34][CH:33]=2)[C:17]=1[F:26])(=[O:12])[CH3:11]
Reactant: CC(=O)OCCc1c([N+](=O)[O-])ccc(N)c1F
Reactant: O=C(Cl)C(F)(F)c1ccc(F)c2ccccc12
Agent: O=C(Cl)C(=O)Cl
Agent: O=C(O)C(F)(F)c1ccc(F)c2ccccc12
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CC(=O)OCCc1c([N+](=O)[O-])ccc(NC(=O)C(F)(F)c2ccc(F)c3ccccc23)c1F
Temperature: 25 °C
Reaction time: 1 h
Yield: 61 %

Procedure:
To a solution of DIEA (7.8 mL) and 2-(3-amino-2-fluoro-6-nitrophenyl)ethyl acetate (4.6 g, 19 mmol), prepared as in step 8 of Example 1, in DCM (60 mL) was added 2,2-difluoro-2-(4-fluoronaphthyl)acetyl chloride (prepared by refluxing 2,2-difluoro-2-(4-fluoronaphthyl)acetic acid, as prepared in the preceding step, with oxalyl chloride) (7.8 g, 30 mmol) in DCM (40 mL). The mixture was stirred at room temperature for 1 hour. Additional DCM (100 ML) was added, and the resulting mixture was washed with 10% citric acid (3×40 mL) and brine, and dried over Na2SO4. After evaporating the solvent, the residue was purified by flash column chromatography eluting with DCM to give the title compound (5.3 g, 61%) as a yellow oil. 1H-NMR (400 MHz, CDCl3) δ 8.45 (m, 2H), 8.21 (d, J=7.0 Hz, 2H), 7.87 (s, 1H), 7.85 (t, J=4.1 Hz, 1H), 7.66 (m, 2H),7.22 (t, J=8.3 Hz, 1H), 4.34 (t, J=6.4 Hz, 2H), 3.36 (t, J=6.4 Hz, 2H), 2.00 (s, 3H).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH2:9]O)=[C:4]([N+:11]([O-:13])=[O:12])[CH:3]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C(Br)(Br)(Br)[Br:34]>C(Cl)Cl>[Br:34][CH2:9][CH2:8][C:5]1[CH:6]=[CH:7][C:2]([Cl:1])=[CH:3][C:4]=1[N+:11]([O-:13])=[O:12]
Reactant: BrC(Br)(Br)Br
Reactant: O=[N+]([O-])c1cc(Cl)ccc1CCO
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Product: O=[N+]([O-])c1cc(Cl)ccc1CCBr
Temperature: 0 °C
Reaction time: 8 h
Yield: 95.1 %

Procedure:
To a solution of 2-(4-chloro-2-nitro-phenyl)-ethanol (63.0 g, 0.31 mole) in methylene chloride (1 L) was added triphenylphosphine (81.9 g, 0.31 mole) and the mixture was cooled to 0° C. Carbon tetrabromide (103.6 g, 0.31 mole) in methylene chloride (100 mL) was added dropwise through an addition funnel. The reaction mixture was stirred at room temperature overnight. The solvent was removed in vacuo and the residue purified by flash column chromatography (silica gel, dichloromethane) to provide 78.0 g of the title compound as a light brown oil.
Reaction SMILES: [C:1]([C:5]1[CH:10]=[CH:9][C:8]([N:11]2[C:19]3[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=3)[C:13]([CH:20]=[O:21])=[C:12]2Cl)=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2].[C:23]([N:30]1[CH2:35][CH2:34][NH:33][CH2:32][CH2:31]1)([O:25][C:26]([CH3:29])([CH3:28])[CH3:27])=[O:24]>>[C:26]([O:25][C:23]([N:30]1[CH2:35][CH2:34][N:33]([C:12]2[N:11]([C:8]3[CH:9]=[CH:10][C:5]([C:1]([CH3:4])([CH3:3])[CH3:2])=[CH:6][CH:7]=3)[C:19]3[C:14]([C:13]=2[CH:20]=[O:21])=[CH:15][CH:16]=[CH:17][CH:18]=3)[CH2:32][CH2:31]1)=[O:24])([CH3:29])([CH3:27])[CH3:28]
Reactant: CC(C)(C)c1ccc(-n2c(Cl)c(C=O)c3ccccc32)cc1
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Product: CC(C)(C)OC(=O)N1CCN(c2c(C=O)c3ccccc3n2-c2ccc(C(C)(C)C)cc2)CC1
Yield: 70 %

Procedure:
1-(4-tert-Butylphenyl)-2-chloro-1H-indole-3-carboxaldehyde is reacted with 1-Boc-piperazine as described in Step 2 of Example 29 to afford 4-[1-(4-tert-butylphenyl)-3-formyl-1H-indol-2-yl]piperazine-1-carboxylic acid tert-butyl ester (70% yield) as a light yellow solid. TLC (heptane-30% ethyl acetate) Rf 0.19; ESI/MS 462 (M+H); RT=4.42 min.; NMR10.13 (1H, s); 8.13 (1H, d, J=9 Hz); 7.68 (2H, d); 7.49 (2H, d); 7.21 (2H, m); 6.95 (1H, d, J=9 Hz); 3.20 (8H, m); 1.37 (18H, s).
Reaction SMILES: O.[NH2:2]N.C[N:5]([CH2:7][CH2:8][C:9]([C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)=O)C>C(O)C>[C:11]1([C:9]2[CH2:8][CH2:7][NH:5][N:2]=2)[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1
Reactant: CN(C)CCC(=O)c1ccccc1
Reactant: NN
Solvent: O
Solvent: CCO
Product: c1ccc(C2=NNCC2)cc1
Temperature: 0 °C
Yield: 89.8 %

Procedure:
Hydrazine monohydrate (6.2 g) was dissolved in ethanol (12 ml). Thereto was dropwise added a solution of 3-(N,N-dimethylamino)propiophenone (5.4 g) dissolved in ethanol (10 ml) in a nitrogen atmosphere at room temperature. The resulting mixture was refluxed for 3 hours with heating. The reaction mixture was poured into ice water. Extraction with chloroform was conducted, followed by drying and concentration, to obtain 4 g of a title compound.
Reaction SMILES: [CH2:1]([S:8][CH:9]([CH2:19][N:20]1[CH2:25][CH2:24][S:23][CH2:22][CH2:21]1)[CH2:10][NH:11]C(=O)OCCCC)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(OCC)(=O)C.C(OCC)(=O)C.Cl>CO>[CH2:1]([S:8][CH:9]([CH2:19][N:20]1[CH2:21][CH2:22][S:23][CH2:24][CH2:25]1)[CH2:10][NH2:11])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CCCCOC(=O)NCC(CN1CCSCC1)SCc1ccccc1
Agent: Cl
Solvent: CO
Solvent: CCOC(C)=O
Product: NCC(CN1CCSCC1)SCc1ccccc1
Temperature: 25 °C
Reaction time: 4 h
Yield: 90.9 %

Procedure:
To a solution of tent-butyl [2-(benzylthio)-3-thiomorpholinopropyl]carbamate (21.46 g) in a mixed solvent of ethyl acetate (60 mL) and methanol (60 mL) was added hydrogen chloride-ethyl acetate solution (120 mL) at 0° C., and the mixture was stirred at room temperature for 4 hr. The reaction solution was concentrated, and the residue was partitioned between ethyl acetate and saturated aqueous potassium carbonate solution. The organic layer was washed with saturated brine, and dried over sodium sulfate, and the solvent was evaporated to give the title compound (14.41 g, yield 91%) as a yellow oil.
Reaction SMILES: Cl.[Cl:2][C:3]1[CH:8]=[CH:7][C:6]([CH2:9][CH2:10][O:11][CH2:12][CH2:13][NH:14]S(CCCNCCC2C3SC(=O)NC=3C(O)=CC=2)(=O)=O)=[CH:5][CH:4]=1.CO>C1COCC1>[Cl:2][C:3]1[CH:4]=[CH:5][C:6]([CH2:9][CH2:10][O:11][CH2:12][CH2:13][NH2:14])=[CH:7][CH:8]=1
Reactant: O=c1[nH]c2c(O)ccc(CCNCCCS(=O)(=O)NCCOCCc3ccc(Cl)cc3)c2s1
Agent: Cl
Solvent: C1CCOC1
Solvent: CO
Product: NCCOCCc1ccc(Cl)cc1
Yield: 252.7 %

Procedure:
The product from step b (6 g) was added portion wise to a stirred solution of boranetetrahydrofuran (1.0 M in THF, 85 ml). The reaction was then heated at reflux under an inert atmosphere for 3 hours. The reaction was cooled and methanol (10 mls) was cautiously added. The solvents were removed in vacuo and the residue redissolved in methanol (100 ml) to which was added concentrated hydrochloric acid (sg. 1.18, 4 ml). This solution was heated at reflux for 30 minutes and then the solvent removed in vacuo. The residue was taken up into water and washed with ether. Sodium bicarbonate was added and the aqueous extracted with ethyl acetate. The ethyl acetate was washed with water, brine and dried (MgSO4). The volatiles were removed in vacuo to provide the subtitle compound as a oil (5.5 g) which was used without further purification.