Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl.[CH3:2][C:3]1[CH:4]=[CH:5][C:6]([O:9][C:10]2[CH:15]=[CH:14][CH:13]=[C:12]([CH:16]=[C:17]3[CH2:22][CH2:21][NH:20][CH2:19][CH2:18]3)[CH:11]=2)=[N:7][CH:8]=1.[CH3:23][C:24]1[C:28]([CH3:29])=[C:27]([NH:30][C:31](=O)[O:32]C2C=CC=CC=2)[O:26][N:25]=1.NC1ON=C(C)C=1C.C(N(C(C)C)CC)(C)C>C(#N)C>[CH3:2][C:3]1[CH:4]=[CH:5][C:6]([O:9][C:10]2[CH:11]=[C:12]([CH:13]=[CH:14][CH:15]=2)[CH:16]=[C:17]2[CH2:22][CH2:21][N:20]([C:31]([NH:30][C:27]3[O:26][N:25]=[C:24]([CH3:23])[C:28]=3[CH3:29])=[O:32])[CH2:19][CH2:18]2)=[N:7][CH:8]=1
Reactant: Cc1ccc(Oc2cccc(C=C3CCNCC3)c2)nc1
Reactant: Cc1noc(NC(=O)Oc2ccccc2)c1C
Agent: Cc1noc(N)c1C
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: CC#N
Product: Cc1ccc(Oc2cccc(C=C3CCN(C(=O)Nc4onc(C)c4C)CC3)c2)nc1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
5-Methyl-2-(3-(piperidin-4-ylidenemethyl)phenoxy)pyridine hydrochloride (150 mg, 0.473 mmol, from Example 44, Step 5), phenyl 3,4-dimethylisoxazol-5-ylcarbamate (110 mg, 0.473 mmol, prepared according to the procedure described in Synthesis, 1997, 1189-1194 from 5-amino-3,4-dimethylisoxazole) and diisopropylethylamine (0.20 mL, 1.15 mmol) were combined in acetonitrile (5 mL) and stirred at room temperature. After 16 h, the reaction was concentrated and the residue was purified by silica gel chromatography (0-30% EtOAc:CH2Cl2) to afford the title compound (86 mg) as a foamy white solid. MS APCI M+ 419.3, 378.2, 281.3; 1H NMR (400 MHz, CD3OD) δ ppm 1.83 (s, 3H) 2.18 (s, 3H) 2.29 (s, 3H) 2.43 (td, J=5.86, 1.16 Hz, 2H) 2.55 (td, J=5.73, 1.20 Hz, 2H) 3.48-3.54 (m, 2H) 3.57-3.65 (m, 2H) 6.44 (s, 1H) 6.82-6.87 (m, 1H) 6.89-6.96 (m, 2H) 7.02-7.11 (m, J=7.60, 1.50, 1.06, 0.74 Hz, 1H) 7.35 (dd, J=8.77, 7.65 Hz, 1H) 7.61-7.69 (m, J=8.38, 2.46, 1.15, 0.45 Hz, 1H) 7.96 (td, J=1.60, 0.72 Hz, 1H).
Reaction SMILES: C(O[C:4](=[O:6])C)=O.ClCCl.[CH3:10][C:11]1[N:15]2[N:16]=[C:17]([C:20]3[CH:25]=[CH:24][CH:23]=[C:22]([NH2:26])[CH:21]=3)[CH:18]=[CH:19][C:14]2=[N:13][N:12]=1>ClCCl.CO>[CH3:10][C:11]1[N:15]2[N:16]=[C:17]([C:20]3[CH:21]=[C:22]([NH:26][CH:4]=[O:6])[CH:23]=[CH:24][CH:25]=3)[CH:18]=[CH:19][C:14]2=[N:13][N:12]=1
Reactant: Cc1nnc2ccc(-c3cccc(N)c3)nn12
Reactant: CC(=O)OC=O
Solvent: CO
Solvent: ClCCl
Product: Cc1nnc2ccc(-c3cccc(NC=O)c3)nn12
Reaction time: 12 h

Procedure:
To 5.53 ml of acetic-formic anhydride was added 250 ml dichloromethane followed by 10 g of 3-methyl-6-[3-(amino)-phenyl]-1,2,4-triazolo[4,3-b]pyridazine. The solution was stirred for 12 hours, then diluted with 1 liter of dichloromethane-methanol (9:1). This solution was washed with saturated aqueous sodium bicarbonate, dried, and concentrated in vacuo. The residue was recrystalized from dichloromethane-methanol to give 6.7 g of an off-white powder, mp 265°-268° C.
Reaction SMILES: OCN1[C:7](=O)[C:6]2=[CH:9][CH:10]=[CH:11][CH:12]=[C:5]2[C:4]1=O.[C:14](OC(=O)C)(=O)C.[CH2:21]=[CH:22][C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1.[CH:29]([C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][C:32]=1[CH:37]=[CH2:38])=[CH2:30]>ClC(Cl)C>[CH2:21]=[CH:22][C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1.[CH:29]([C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][C:32]=1[CH:37]=[CH2:38])=[CH2:30].[CH3:21][CH2:22][CH2:23][CH2:7][CH2:6][CH2:9][CH2:10][CH2:11][CH2:12][CH:5]([CH3:4])[CH3:14]
Reactant: CC(=O)OC(C)=O
Reactant: O=C1c2ccccc2C(=O)N1CO
Agent: C=Cc1ccccc1C=C
Solvent: CC(Cl)Cl
Solvent: C=Cc1ccccc1
Product: CCCCCCCCCC(C)C
Temperature: 60 °C

Procedure:
354 g of N-hydroxymethyl phthalimide, dissolved in 1200 g of dichlorethane, are heated for 5 hours to reflux temperature with 227 g of acetic acid anhydride. After cooling to 60° C, 150 g of a macroporous styrene polymer crosslinked with 8 % of divinyl benzene (obtained by the bead polymerisation of styrene and divinyl benzene in the presence of 60 % by weight of isododecane, based on the sum total of monomers) are swollen in this solution over a period of 30 minutes. The mixture is then heated to reflux temperature, followed by the dropwise addition with stirring over a period of 4 hours of 240 g of concentrated sulphuric acid. After stirring for another 20 hours at the same temperature, the reaction product is separated off and freed from the dichlorethane adhering to it by suspension in aqueous ammonia solution, followed by azeotropic distillation, in the same way as described in Example 1. The polymer is then heated for 10 hours to 180° C with 40 % sodium hydroxide solution in an autoclave. After the sodium hydroxide has been washed out, 540 ml of a weakly basic anion exchanger are obtained with an acid-binding capacaty for N/10 hydrochloric acid of 2.4 Val/1 and a nitrogen content of 10.6 % in the dry material.
Reaction SMILES: [CH2:1]([C:5]1[N:6]=[C:7]([CH3:27])[NH:8][C:9](=[O:26])[C:10]=1[CH2:11][C:12]1[CH:17]=[CH:16][C:15]([C:18]2[C:19]([C:24]#[N:25])=[CH:20][CH:21]=[CH:22][CH:23]=2)=[CH:14][CH:13]=1)[CH2:2][CH2:3][CH3:4].[H-].[Na+].CN(C)C=O.Cl[CH2:36][C:37]1[CH:42]=[CH:41][C:40]([O:43][CH3:44])=[CH:39][CH:38]=1>C(OCC)(=O)C>[CH2:1]([C:5]1[N:6]=[C:7]([CH3:27])[N:8]([CH2:36][C:37]2[CH:42]=[CH:41][C:40]([O:43][CH3:44])=[CH:39][CH:38]=2)[C:9](=[O:26])[C:10]=1[CH2:11][C:12]1[CH:17]=[CH:16][C:15]([C:18]2[C:19]([C:24]#[N:25])=[CH:20][CH:21]=[CH:22][CH:23]=2)=[CH:14][CH:13]=1)[CH2:2][CH2:3][CH3:4]
Reactant: CCCCc1nc(C)[nH]c(=O)c1Cc1ccc(-c2ccccc2C#N)cc1
Reactant: COc1ccc(CCl)cc1
Agent: [H-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CCCCc1nc(C)n(Cc2ccc(OC)cc2)c(=O)c1Cc1ccc(-c2ccccc2C#N)cc1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 62 %

Procedure:
A mixture of 4′-[(4-butyl-2-methyl-6-oxo-1,6-dihydropyrimidin-5-yl)methyl]biphenyl-2-carbonitrile (1 g), sodium hydride (0.17 g) and N,N-dimethylformamide (15 mL) was stirred at room temperature for 10 min, 1-(chloromethyl)-4-methoxybenzene (0.46 mL) was added, and the mixture was stirred at room temperature for 16 hr. The reaction mixture was diluted with ethyl acetate, washed with 5% aqueous potassium hydrogen sulfate solution and then with saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure and the residue was purified by silica gel column chromatography to give the title compound as a colorless solid (0.83 g, 62%).
Reaction SMILES: [O:1]=[C:2]([N:9]1[CH2:15][CH2:14][CH2:13][CH2:12][CH2:11][CH2:10]1)[CH2:3][N:4]([CH3:8])[CH2:5][CH2:6]O.S(Cl)([Cl:18])=O>C(Cl)(Cl)Cl>[Cl:18][CH2:6][CH2:5][N:4]([CH3:8])[CH2:3][C:2](=[O:1])[N:9]1[CH2:15][CH2:14][CH2:13][CH2:12][CH2:11][CH2:10]1
Reactant: O=S(Cl)Cl
Reactant: CN(CCO)CC(=O)N1CCCCCC1
Solvent: ClC(Cl)Cl
Product: CN(CCCl)CC(=O)N1CCCCCC1

Procedure:
A mixture of 5.7 g (27 mmol) of 2-{N-[2-oxo-2- (perhydro-1-azepinyl) ethyl]methylamino}ethanol, dissolved in 50 ml of chloroform, and 6 ml (excess) of thionyl chloride is heated under reflux for 2 h.
Reaction SMILES: [Cl:1][C:2]1[C:3]([F:20])=[C:4]([CH:6]=[C:7]([Cl:19])[C:8]=1[O:9][C:10]([F:18])([F:17])[CH:11]([F:16])[C:12]([F:15])([F:14])[F:13])[NH2:5].[F:21][C:22]1[CH:32]=[CH:31][CH:30]=[C:29]([F:33])[C:23]=1[C:24]([N:26]=[C:27]=[O:28])=[O:25]>ClCCCl.ClC(Cl)C>[Cl:1][C:2]1[C:3]([F:20])=[C:4]([NH:5][C:27]([NH:26][C:24](=[O:25])[C:23]2[C:29]([F:33])=[CH:30][CH:31]=[CH:32][C:22]=2[F:21])=[O:28])[CH:6]=[C:7]([Cl:19])[C:8]=1[O:9][C:10]([F:17])([F:18])[CH:11]([F:16])[C:12]([F:14])([F:15])[F:13]
Reactant: O=C=NC(=O)c1c(F)cccc1F
Reactant: Nc1cc(Cl)c(OC(F)(F)C(F)C(F)(F)F)c(Cl)c1F
Solvent: CC(Cl)Cl
Solvent: ClCCCl
Product: O=C(NC(=O)c1c(F)cccc1F)Nc1cc(Cl)c(OC(F)(F)C(F)C(F)(F)F)c(Cl)c1F
Temperature: 40 °C
Yield: 83.4 %

Procedure:
To a solution of 1.31 g 3,5-dichloro-2-fluoro-4-(1,1,2,3,3,3-hexafluoropropoxy) aniline in 5 mL 1,2-dichloroethane under an atmosphere of nitrogen at room temperature was added 0.87 g 2,6-difluorobenzoyl isocyanate dissolved in 10 mL dichloroethane dropwise over a 10 minute period. The mixture was stirred, warmed to 40° C. for a one hour period, then concentrated under vacuum to a brown solid 2.0 g. The mixture was chromatographed using a Michel-Miller low pressure silica gel column eluted with 4:1 dichloromethane/heptane. Like fractions were pooled and concentrated under vacuum to give 1.67 g of a light tan solid, mp 156°-7° C. Proton and 19F nmr spectra were consistent with the proposed structure. Anal. calcd C17H7Cl2F9N2O3 : C, 38.58; H, 1.33; N, 5.29. Found: C, 38.64; H, 1.40; N, 5.44.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH:12]=[C:11]([C:14]2[CH:19]=[CH:18][C:17]([N+:20]([O-])=O)=[CH:16][N:15]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]>CO.O1CCCC1.[Pd]>[C:1]([O:5][C:6]([N:8]1[CH2:9][CH2:10][CH:11]([C:14]2[CH:19]=[CH:18][C:17]([NH2:20])=[CH:16][N:15]=2)[CH2:12][CH2:13]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)N1CC=C(c2ccc([N+](=O)[O-])cn2)CC1
Agent: [Pd]
Solvent: CO
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1CCC(c2ccc(N)cn2)CC1
Reaction time: 2 h
Yield: 99.9 %

Procedure:
5-nitro-3′,6′-dihydro-2′H-[2,4′]bipyridinyl-1′-carboxylic acid tert-butyl ester (400 mg) from above was dissolved in methanol (50 mL) and tetrahydrofuran (10 mL). To this mixture was added 10% palladium on carbon (100 mg). The mixture was hydrogenated at 50 psi for 2 hrs. The mixture was filtered and the solvents were evaporated to give 5-amino-3′,4′,5′,6′-tetrahydro-2′H-[2,4′]bipyridinyl-1′-carboxylic acid tert-butyl ester as a white solid (363 mg). The NMR spectrum obtained on the sample is compatible with its structure.
Reaction SMILES: C(N(CC)CC)C.Cl.[Cl:9][C:10]([Cl:27])([Cl:26])[CH2:11][O:12][C:13]([C:15]1[N:20]2[C:21](=[O:24])[CH:22]([NH2:23])[C@H:19]2[S:18][CH2:17][C:16]=1[CH3:25])=[O:14].Cl[C:29]1[C:34]([O:35][C:36](=[O:53])[CH:37]([C:47]2[CH:52]=[CH:51][CH:50]=[CH:49][CH:48]=2)[C:38](OC2C=CC=CC=2)=[O:39])=[C:33](Cl)[C:32](Cl)=[C:31](Cl)[C:30]=1Cl>C(Cl)Cl>[Cl:27][C:10]([Cl:9])([Cl:26])[CH2:11][O:12][C:13]([C:15]1[N:20]2[C:21](=[O:24])[CH:22]([NH:23][C:38](=[O:39])[CH:37]([C:47]3[CH:48]=[CH:49][CH:50]=[CH:51][CH:52]=3)[C:36]([O:35][C:34]3[CH:29]=[CH:30][CH:31]=[CH:32][CH:33]=3)=[O:53])[C@H:19]2[S:18][CH2:17][C:16]=1[CH3:25])=[O:14]
Reactant: CC1=C(C(=O)OCC(Cl)(Cl)Cl)N2C(=O)C(N)[C@H]2SC1
Reactant: O=C(Oc1ccccc1)C(C(=O)Oc1c(Cl)c(Cl)c(Cl)c(Cl)c1Cl)c1ccccc1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC1=C(C(=O)OCC(Cl)(Cl)Cl)N2C(=O)C(NC(=O)C(C(=O)Oc3ccccc3)c3ccccc3)[C@H]2SC1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 80 %

Procedure:
2.8 ml. (0.02 moles) of triethylamine are added to a suspension of 3.8 g. (0.01 mole) of 7-amino-3-methyl-ceph-3-em-4-carboxylic acid trichloroethyl ester hydrochloride in 30 ml. of methylene chloride. The separated triethylamine hydrochloride is filtered off, the filtrate is cooled to 0° C., and 5.02 g (0.01 mole) of phenylmalonic acid phenylester pentachlorophenyl ester are added. The obtained clear solution is stirred at the same temperature for 30 minutes, thereafter it is washed with 2 n aqueous hydrochloride acid and the solvent is evaporated. The residue is treated with absolute ethanol. 4.7 g. (80%) of 7-(α-phenoxycarbonyl-phenylacetamido)-3-methyl-ceph-3-em-4-carboxylic acid trichloroethyl ester are obtained. The white, crystalline substance melts at 120°-125° C.
Reaction SMILES: [NH2:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][C:10]=2[O:12][CH2:13][C@@H:14]([NH2:18])[CH:15]([CH3:17])[CH3:16])[N:5]=[C:4]([CH3:19])[C:3]=1[C:20]([O:22][CH2:23][CH3:24])=[O:21].[OH:25][C:26]1[CH:27]=[C:28]([CH:32]=[CH:33][CH:34]=1)[C:29](O)=[O:30]>>[NH2:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][C:10]=2[O:12][CH2:13][C@@H:14]([NH:18][C:29](=[O:30])[C:28]2[CH:32]=[CH:33][CH:34]=[C:26]([OH:25])[CH:27]=2)[CH:15]([CH3:17])[CH3:16])[N:5]=[C:4]([CH3:19])[C:3]=1[C:20]([O:22][CH2:23][CH3:24])=[O:21]
Reactant: CCOC(=O)c1c(C)nc2cccc(OC[C@@H](N)C(C)C)c2c1N
Reactant: O=C(O)c1cccc(O)c1
Product: CCOC(=O)c1c(C)nc2cccc(OC[C@@H](NC(=O)c3cccc(O)c3)C(C)C)c2c1N

Procedure:
Prepared as in Example 24a from (S)-ethyl 4-amino-5-(2-amino-3-methylbutoxy)-2-methylquinoline-3-carboxylate (Example 95b) and 3-hydroxybenzoic acid as brown solid (35%). MS 452 (MH+).
Reaction SMILES: [F:1][C@H:2]1[C@@H:7]([C:8]2[CH:13]=[CH:12][C:11]([OH:14])=[CH:10][CH:9]=2)[CH2:6][CH2:5][NH:4][CH2:3]1.CCN(C(C)C)C(C)C.CS(O[C@H:29]1[CH2:33][CH2:32][N:31]([CH2:34][C:35]2[CH:40]=[CH:39][C:38]([CH3:41])=[CH:37][CH:36]=2)[C:30]1=[O:42])(=O)=O>CC#N>[F:1][C@H:2]1[C@@H:7]([C:8]2[CH:13]=[CH:12][C:11]([OH:14])=[CH:10][CH:9]=2)[CH2:6][CH2:5][N:4]([C@@H:29]2[CH2:33][CH2:32][N:31]([CH2:34][C:35]3[CH:40]=[CH:39][C:38]([CH3:41])=[CH:37][CH:36]=3)[C:30]2=[O:42])[CH2:3]1
Reactant: Cc1ccc(CN2CC[C@H](OS(C)(=O)=O)C2=O)cc1
Reactant: Oc1ccc([C@H]2CCNC[C@H]2F)cc1
Solvent: CC#N
Solvent: CCN(C(C)C)C(C)C
Product: Cc1ccc(CN2CC[C@@H](N3CC[C@H](c4ccc(O)cc4)[C@H](F)C3)C2=O)cc1
Temperature: 80 °C
Reaction time: 16 h
Yield: 28.7 %

Procedure:
To a solution of cis-4-(3-fluoropiperidin-4-yl)phenol (60 mg, 0.31 mmol) in 1.0 mL of CH3CN and DIPEA (0.2 mL, 1.2 mmol) at 80° C. was added a solution of (S)-1-(4-methylbenzyl)-2-oxopyrrolidin-3-yl methanesulfonate (87 mg, 0.3 mmol) in 0.5 mL of CH3CN over 1.5 h. The mixture was then stirred at 80° C. for 16 h. The mixture was allowed to cool to rt and then concentrated. The residue was purified via silica gel chromatography (4 g of silica) eluting with a gradient of 0-100% EtOAc in hexanes to give a mixture of two diastereomers, which were further separated via chiral HPLC under the following conditions: Chiralcel OD column (21×250 mm, 10μ) eluting with an isocratic mixture of 30% B where solvent A=0.1% diethylamine in n-heptane and solvent B=100% ethanol. The absolute stereochemistry of the 2 products has not been assigned and is shown and named for convenience. The first eluting isomer (Example 112, P-1) was (R)-3-((3S,4R)-3-fluoro-4-(4-hydroxyphenyl)piperidin-1-yl)-1-(4-methylbenzyl)pyrrolidin-2-one (33.8 mg, 0.086 mmol, 28% yield). 1H NMR (500 MHz, methanol-d4) δ 7.21-7.07 (m, 6H), 6.78-6.68 (m, 2H), 4.70 (d, J=48.8 Hz, 1H), 4.41 (dd, J=58.0, 14.5 Hz, 2H), 3.61 (t, J=8.8 Hz, 1H), 3.30-3.03 (m, 5H), 2.77-2.60 (m, 1H), 2.51 (t, J=11.1 Hz, 1H), 2.32 (s, 3H), 2.31-2.15 (m, 2H), 2.01 (dq, J=13.2, 8.4 Hz, 1H), 1.69 (dd, J=13.1, 2.6 Hz, 1H), (M+H)+=383.25. HPLC RT under separation conditions=8.87 min. The second eluting isomer (Example 112, P-2) was (R)-3-((3R,4S)-3-fluoro-4-(4-hydroxyphenyl)piperidin-1-yl)-1-(4-methylbenzyl)pyrrolidin-2-one (35.2 mg, 0.084 mmol, 27.3% yield), 1H NMR (500 MHz, methanol-d4) δ 7.19-7.08 (m, 6H), 6.74 (d, J=8.4 Hz, 2H), 4.66 (d, J=47.9 Hz, 1H), 4.41 (dd, J=53.7, 14.8 Hz, 2H), 3.58 (t, J=8.8 Hz, 1H), 3.42 (t, J=10.8 Hz, 1H), 3.30-3.14 (m, 2H), 3.05-2.88 (m, 2H), 2.79-2.51 (m, 2H), 2.33 (s, 3H), 2.31-2.13 (m, 2H), 2.06-1.90 (m, 1H), 1.67 (d, J=10.8 Hz, 1H), (M+H)+=383.25. HPLC RT under separation conditions=11.97 min.
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[NH:10]N)([O-:3])=[O:2].Cl.O.[NH:14]1[CH2:19][CH2:18][C:17](=O)[CH2:16][CH2:15]1>FC(F)(F)CO>[N+:1]([C:4]1[C:5]2[NH:10][C:17]3[CH2:18][CH2:19][NH:14][CH2:15][C:16]=3[C:6]=2[CH:7]=[CH:8][CH:9]=1)([O-:3])=[O:2]
Reactant: NNc1ccccc1[N+](=O)[O-]
Reactant: O=C1CCNCC1
Agent: Cl
Solvent: OCC(F)(F)F
Solvent: O
Product: O=[N+]([O-])c1cccc2c3c([nH]c12)CCNC3
Temperature: 105 °C
Yield: 55.4 %

Procedure:
2-Nitrophenylhydrazine (3.7 g, 24.2 mmol) and 4-piperidone monohydrate hydrochloride (3.7 g, 24.2 mmol) were suspended in 2,2,2-trifluoroethanol (25 mL). The resultant mixture was heated at reflux for 2 h and then concentrated. Conc. HCl (35 mL) was added in one portion. The resultant mixture was then heated at 105° C. for 15 h, and allowed to cool to rt, after which it was poured onto ice. While vigorously stirring, a 50% NaOH solution was added portionwise over 10 min until pH 12, maintaining the internal temperature at <20° C. The solid was collected via filtration and dried at room temperature under vacuum for 18 h to afford 6-nitro-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indole (2.91 g, 55%). 1H NMR (300 MHz, DMSO) δ 11.65-11.60 (br s, 1H), 7.96 (d, J=8.1 Hz, 1H), 7.80 (d, J=7.0 Hz, 1H), 7.12 (t, J=8.0 Hz, 1H), 3.86 (s, 2H), 2.99 (br s, 2H), 2.72 (br s, 2H) ppm.
Reaction SMILES: [CH3:1][CH:2]([CH3:39])[C@H:3]([NH:34][C:35](=[O:38])[O:36][CH3:37])[C:4](=[O:33])[N:5]1[C@H:10]([C:11]2[NH:15][C:14]3[C:16]4[C:21]([CH:22]=[CH:23][C:13]=3[N:12]=2)=[CH:20][C:19](B2OC(C)(C)C(C)(C)O2)=[CH:18][CH:17]=4)[CH2:9][C@@H:8]2[C@H:6]1[CH2:7]2.Br[C:41]1[CH:42]=[C:43]2[C:66](=[CH:67][CH:68]=1)[C:47]1[NH:48][C:49]([C@@H:51]3[CH2:55][C@H:54]([CH2:56][O:57][CH3:58])[CH2:53][N:52]3[C:59]([O:61][C:62]([CH3:65])([CH3:64])[CH3:63])=[O:60])=[N:50][C:46]=1[CH:45]=[CH:44]2.[O-]P([O-])([O-])=O.[K+].[K+].[K+]>COCCOC.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[CH3:37][O:36][C:35]([NH:34][C@@H:3]([CH:2]([CH3:1])[CH3:39])[C:4]([N:5]1[C@H:10]([C:11]2[NH:15][C:14]3[C:16]4[C:21]([CH:22]=[CH:23][C:13]=3[N:12]=2)=[CH:20][C:19]([C:41]2[CH:42]=[C:43]3[C:66](=[CH:67][CH:68]=2)[C:47]2[NH:48][C:49]([C@@H:51]5[CH2:55][C@H:54]([CH2:56][O:57][CH3:58])[CH2:53][N:52]5[C:59]([O:61][C:62]([CH3:65])([CH3:63])[CH3:64])=[O:60])=[N:50][C:46]=2[CH:45]=[CH:44]3)=[CH:18][CH:17]=4)[CH2:9][C@@H:8]2[C@H:6]1[CH2:7]2)=[O:33])=[O:38]
Reactant: COC[C@H]1C[C@@H](c2nc3ccc4cc(Br)ccc4c3[nH]2)N(C(=O)OC(C)(C)C)C1
Reactant: COC(=O)N[C@H](C(=O)N1[C@@H]2C[C@@H]2C[C@H]1c1nc2ccc3cc(B4OC(C)(C)C(C)(C)O4)ccc3c2[nH]1)C(C)C
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Solvent: COCCOC
Product: COC[C@H]1C[C@@H](c2nc3ccc4cc(-c5ccc6c(ccc7nc([C@@H]8C[C@H]9C[C@H]9N8C(=O)[C@@H](NC(=O)OC)C(C)C)[nH]c76)c5)ccc4c3[nH]2)N(C(=O)OC(C)(C)C)C1
Temperature: 80 °C
Yield: 100.5 %

Procedure:
To a solution of methyl (S)-3-methyl-1-oxo-1-((1R,3S,5R)-3-(7-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-naphtho[1,2-d]imidazol-2-yl)-2-azabicyclo[3.1.0]hexan-2-yl)butan-2-ylcarbamate (0.60 g, 1.1 mmol) and (2S,4S)-tert-butyl 2-(7-bromo-1H-naphtho[1,2-d]imidazol-2-yl)-4-(methoxymethyl)pyrrolidine-1-carboxylate (0.46 g, 1.0 mmol) in DME (5 mL) was added Pd(PPh3)4 (0.08 g, 0.07 mmol) and K3PO4 (2M aqueous, 1.5 mL, 3.0 mmol). The resulting solution was degassed with argon for 5 min and heated to 80° C. (external temperature, oil bath) for 18 h. The reaction mixture was then cooled to room temperature and diluted with MeOH and CH2Cl2. The solution was washed with H2O and brine, and the aqueous layers were back extracted with CH2Cl2 and MeOH (˜10:1). The organic layers were combined and dried over Na2SO4 and concentrated. The crude oil was purified by silica gel chromatography (30 to 100% EtOAc (10% MeOH)/Hexanes to 80% MeOH/EtOAc) to provide (2S,4S)-tert-butyl 2-(2′-((1R,3S,5R)-2-((S)-2-(methoxycarbonylamino)-3-methylbutanoyl)-2-azabicyclo[3.1.0]hexan-3-yl)-1H,1′H-7,7′-binaphtho[1,2-d]imidazol-2-yl)-4-(methoxymethyl)pyrrolidine-1-carboxylate (0.79 g, 71%). LCMS-ESI+: calc'd for C45H51N7O6: 785.39 (M+); Found: 786.61 (M+H+).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[C:4]([F:9])[CH:3]=1.[H-].[Na+].[CH2:12]([O:19][C:20]([N:22]1[CH2:26][CH:25]2[CH2:27][CH:28]([CH2:30][O:31][C:32]3[CH:41]=[C:40]4[C:35]([C:36](Cl)=[N:37][CH:38]=[N:39]4)=[CH:34][C:33]=3[O:43][CH3:44])[CH2:29][CH:24]2[CH2:23]1)=[O:21])[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1>CN(C=O)C.CCOC(C)=O>[CH2:12]([O:19][C:20]([N:22]1[CH2:23][CH:24]2[CH2:29][CH:28]([CH2:30][O:31][C:32]3[CH:41]=[C:40]4[C:35]([C:36]([O:8][C:5]5[CH:6]=[CH:7][C:2]([NH2:1])=[CH:3][C:4]=5[F:9])=[N:37][CH:38]=[N:39]4)=[CH:34][C:33]=3[O:43][CH3:44])[CH2:27][CH:25]2[CH2:26]1)=[O:21])[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1
Reactant: COc1cc2c(Cl)ncnc2cc1OCC1CC2CN(C(=O)OCc3ccccc3)CC2C1
Reactant: Nc1ccc(O)c(F)c1
Agent: [H-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: COc1cc2c(Oc3ccc(N)cc3F)ncnc2cc1OCC1CC2CN(C(=O)OCc3ccccc3)CC2C1
Temperature: 25 °C
Yield: 149.6 %

Procedure:
4-Amino-2-fluoro-phenol (1.53 g, 12.0 mmol) was dissolved in dry DMF (30 ml) to which was added 60% NaH (774 mg, 19.3 mmol). After the mixture was stirred at room temperature for several minutes, a suspension of 5-(4-chloro-6-methoxy-quinazolin-7-yloxymethyl)-hexahydro-cyclopenta[c]pyrrole-2-carboxylic acid benzyl ester (4.70 g, 6.7 mmol) in dry DMF (40 ml) was added. The reaction mixture was stirred at room temperature for 1-2 hrs, then diluted with EtOAc and washed with sat'd NaHCO3 (3×), H2O (1×), sat'd NaCl (1×), dried (Na2SO4), and concentrated in vacuo to give crude 5-[4-(4-amino-2-fluoro-phenoxy)-6-methoxy-quinazolin-7-yloxymethyl]-hexahydro-cyclopenta[c]pyrrole-2-carboxylic acid benzyl ester (5.6 g, 100%) which was used in the next reaction without further purification. 1H-NMR (400 MHz, DMSO): 8.50 (s, 1H), 7.48 (s, 1H), 7.34 (m, 5H), 7.28 (m, 1H), 7.02 (t, 1H), 6.48 (dd, 1H), 6.40 (dd, 1H), 5.40 (br s, 2H), 5.05 (s, 2H), 4.16 (d, 2H), 3.92 (s, 3H), 3.48 (m, 2H), 3.30 (m, 2H), 2.65 (m, 2H), 2.52 (m, 1H), 2.10 (m, 2H), 1.30 (m, 2H). LC/MS Calcd for [M+H]+ 559.2, found 559.4.
Reaction SMILES: [Cl:1][C:2]1[CH:8]=[CH:7][CH:6]=[CH:5][C:3]=1[NH2:4].[CH3:9][C:10]1([CH3:18])[CH2:17][C:15](=O)[CH2:14][C:12](=[O:13])[CH2:11]1>C(O)C.C(O)(=O)C>[Cl:1][C:2]1[CH:8]=[CH:7][CH:6]=[CH:5][C:3]=1[NH:4][C:14]1[C:12](=[O:13])[CH2:11][C:10]([CH3:18])([CH3:9])[CH2:17][CH:15]=1
Reactant: Nc1ccccc1Cl
Reactant: CC1(C)CC(=O)CC(=O)C1
Solvent: CC(=O)O
Solvent: CCO
Product: CC1(C)CC=C(Nc2ccccc2Cl)C(=O)C1

Procedure:
A mixture of 12.75 parts of 2-chloroaniline and 14 parts of dimedone is dissolved in 40 volume parts of ethanol under warming, followed by the addition of 3 drops of glacial acetic acid. The solution is refluxed in a water bath for 2 hours, after which time the ethanol is distilled off and the resulting residue is allowed to cool, whereupon yellow crystals separate. These crystals are collected by filtration, washed with ispropyl ether and recrystallized from acetone. The procedure yields 3-(2-chloroanilino-5,5-dimethyl-2-cyclohexen-1-one as colorless prisms melting at 150°-152°C. Elementary analysis: C14H16NOCL Calcd. C, 67.32; H, 6.45; N, 5.60 Found C, 67.13; H, 6.31; N, 5.82 (b) A mixture of 40 parts of dimedone and 36.4 parts of 2-chloroaniline is heated at 170°-175°C for 45 minutes followed by cooling. The resulting reaction product is recrystallized to obtain yellow cubes. The crystals are collected by filtration, washed well with isopropyl ether and recrystallized from acetone. The procedure yields colorless prisms of 3-(2-chloroanilino)-5,5-dimethyl-2-cyclohexen-1-one. Melting point: 150°-152°C. By procedures similar to those described in Example 1-(a) and (b), the following compounds are produced.
Reaction SMILES: [OH-].[Na+].[C:3]([C:5]1[C:6](=[O:22])[NH:7][C:8](=[O:21])[N:9]([C:11]2[CH:16]=[CH:15][C:14]([C:17]([F:20])([F:19])[F:18])=[CH:13][CH:12]=2)[CH:10]=1)#[N:4].[Cl:23][C:24]([Cl:28])([Cl:27])[S:25]Cl>O.ClCCl>[C:3]([C:5]1[C:6](=[O:22])[N:7]([S:25][C:24]([Cl:28])([Cl:27])[Cl:23])[C:8](=[O:21])[N:9]([C:11]2[CH:12]=[CH:13][C:14]([C:17]([F:20])([F:18])[F:19])=[CH:15][CH:16]=2)[CH:10]=1)#[N:4]
Reactant: N#Cc1cn(-c2ccc(C(F)(F)F)cc2)c(=O)[nH]c1=O
Reactant: ClSC(Cl)(Cl)Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: ClCCl
Product: N#Cc1cn(-c2ccc(C(F)(F)F)cc2)c(=O)n(SC(Cl)(Cl)Cl)c1=O
Reaction time: 2 h

Procedure:
To 290 mg of NaOH in 15 ml of water, cooled in an ice bath, is added 1.0 g (3.56 mol) of 5-cyano-1-(4-trifluoromethylphenyl)uracil. Then 15 ml of dichloromethane is added, followed by 0.725 ml of trichloromethanesulfenyl chloride in 1.5 ml of dichloromethane. The mixture is stirred for approximately 2 hr at 5°. Then dichloromethane and ice cold water are added and the layers separated. The organic phase is washed with ice cold water, dried over MgSO4 and evaporated. The product is taken up with ether, filtered and washed again with ether to yield 5-cyano-3-trichloromethanesulfenyl-1-(4-trifluoromethylphenyl)uracil, m.p. 167°-168.5°.