Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:8][C:9](=[O:21])[C:10]1[CH:15]=[CH:14][C:13]([CH2:16]Br)=[C:12]([N+:18]([O-:20])=[O:19])[CH:11]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:22]1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.COC1C=CC(NC2OC(C3C=CC4N=[C:61]([C:63]5[C:68]([CH3:69])=[CH:67][C:66]([CH2:70][CH2:71][C:72]([OH:74])=[O:73])=[CH:65][C:64]=5[CH3:75])NC=4C=3)=NN=2)=CC=1.C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C.C(OCC)(=O)C>[CH3:22][O:74][C:72](/[CH:71]=[CH:70]/[C:66]1[CH:67]=[C:68]([CH3:69])[C:63](/[CH:61]=[CH:16]/[C:13]2[CH:14]=[CH:15][C:10]([C:9]([O:8][CH2:1][C:2]3[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=3)=[O:21])=[CH:11][C:12]=2[N+:18]([O-:20])=[O:19])=[C:64]([CH3:75])[CH:65]=1)=[O:73]
Reactant: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Reactant: O=C(OCc1ccccc1)c1ccc(CBr)c([N+](=O)[O-])c1
Reactant: COc1ccc(Nc2nnc(-c3ccc4nc(-c5c(C)cc(CCC(=O)O)cc5C)[nH]c4c3)o2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: COC(=O)/C=C/c1cc(C)c(/C=C/c2ccc(C(=O)OCc3ccccc3)cc2[N+](=O)[O-])c(C)c1
Temperature: 100 °C

Procedure:
A mixture of 4-bromomethyl-3-nitrobenzoic acid benzyl ester (2.06 g, 5.88 mmol) and triphenylphosphine (1.54 g, 5.87 mmol) in DMF (10 mL) was heated at 100° C. for 1 h. To this solution was then added 3-(4-formyl-3,5-dimethylphenyl)-acrylic acid methyl ester (1.28 g, 5.86 mmol) (Example 1-60, step C) and potassium carbonate (1.63 g, 11.8 mmol) and the mixture was stirred for at 100° C. 18 h. The mixture was poured into ethyl acetate and extracted with water once and brine five times. The organic layer was dried, filtered, and solvent removed under reduced pressure. The residue was purified by chromatography using a 0-40% gradient of heptane/ethyl acetate to give the title compound.
Reaction SMILES: CC(C)([O-])C.[K+].[CH3:7][C:8]1[CH:9]=[CH:10][CH:11]=[C:12]2[C:16]=1[NH:15][CH:14]=[CH:13]2.[F:17][C:18]1[CH:23]=[C:22](F)[CH:21]=[C:20]([F:25])[N:19]=1>CS(C)=O.C(Cl)Cl>[F:17][C:18]1[CH:23]=[C:22]([N:15]2[C:16]3[C:12](=[CH:11][CH:10]=[CH:9][C:8]=3[CH3:7])[CH:13]=[CH:14]2)[CH:21]=[C:20]([F:25])[N:19]=1
Reactant: Cc1cccc2cc[nH]c12
Reactant: Fc1cc(F)nc(F)c1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: CS(C)=O
Solvent: ClCCl
Product: Cc1cccc2ccn(-c3cc(F)nc(F)c3)c12
Temperature: 25 °C

Procedure:
Potassium tert-butoxide (410 mg, 3.6 mmol) is added to a mixture of 7-methyl-1H-indole (470 mg, 3.6 mmol) in DMSO (20 ml) with ice cooling. Stirring is continued for 10 minutes before 2,4,6-trifluoropyridine E (350 μl, 3.6 mmol) is added dropwise. The mixture is warmed to RT and stirred for 2 h. The mixture is diluted with DCM and extracted with water. The combined organic layers are dried over MgSO4 and concentrated in vacuo. The product is purified by RP HPLC. Yield: 350 mg (40%). HPLC-MS: M+H=245; tR=1.03 min (Method—2).
Reaction SMILES: [Na].[OH:2][CH2:3][CH:4]1[O:9][CH2:8][CH2:7][N:6]([C:10]2[N:11]=[C:12]([CH2:17][C:18]([OH:20])=O)[NH:13][C:14](=[O:16])[CH:15]=2)[CH2:5]1.[Cl:21][C:22]1[CH:30]=[CH:29][CH:28]=[C:27]2[C:23]=1[CH2:24][CH2:25][NH:26]2.Cl.CN(C)CCCN=C=NCC>CN(C)C=O.N1C=CC=CC=1>[Cl:21][C:22]1[CH:30]=[CH:29][CH:28]=[C:27]2[C:23]=1[CH2:24][CH2:25][N:26]2[C:18](=[O:20])[CH2:17][C:12]1[NH:13][C:14](=[O:16])[CH:15]=[C:10]([N:6]2[CH2:7][CH2:8][O:9][CH:4]([CH2:3][OH:2])[CH2:5]2)[N:11]=1
Reactant: Clc1cccc2c1CCN2
Reactant: O=C(O)Cc1nc(N2CCOC(CO)C2)cc(=O)[nH]1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: [Na]
Solvent: CN(C)C=O
Solvent: c1ccncc1
Product: O=C(Cc1nc(N2CCOC(CO)C2)cc(=O)[nH]1)N1CCc2c(Cl)cccc21
Temperature: 25 °C
Reaction time: 20 h
Yield: 63 %

Procedure:
In a 25 ml round-bottomed flask, 71 mg of the sodium salt of [4-(2-hydroxymethylmorpholin-4-yl)-6-oxo-1,6-dihydropyrimidin-2-yl]acetic acid (example 25b, step 9b) and 38 mg of 4-chloro-2,3-dihydro-1H-indole are placed in 1 ml of dimethylformamide and 0.24 ml of pyridine, and then 57 mg of N-[3-(dimethylamino)propyl]-N′-ethylcarbodiimide hydrochloride are added. The reaction medium is stirred at ambient temperature for 20 h, then evaporated, water is added, and the resulting mixture is triturated. The solid formed is filtered off, and rinsed successively with water then with diisopropyl ether, with methylene chloride and then with pentane. The resulting solid is dried under vacuum for 2 h. (−)-2-[2-(4-Chloro-2,3-dihydroindol-1-yl)-2-oxoethyl]-6-(2-hydroxymethylmorpholin-4-yl)-3H-pyrimidin-4-one (62 mg) is isolated in the form of a pulverulent solid (yield=63%).
Reaction SMILES: Cl.[NH2:2][C@@H:3]1[CH2:8][CH2:7][C@H:6]([C:9]([NH:11][CH:12]([CH3:14])[CH3:13])=[O:10])[CH2:5][CH2:4]1.CCN(C(C)C)C(C)C.F[C:25]1[CH:30]=[C:29]([F:31])[CH:28]=[CH:27][C:26]=1[N+:32]([O-:34])=[O:33]>C(#N)C>[F:31][C:29]1[CH:28]=[CH:27][C:26]([N+:32]([O-:34])=[O:33])=[C:25]([NH:2][C@@H:3]2[CH2:4][CH2:5][C@H:6]([C:9]([NH:11][CH:12]([CH3:14])[CH3:13])=[O:10])[CH2:7][CH2:8]2)[CH:30]=1
Reactant: O=[N+]([O-])c1ccc(F)cc1F
Reactant: CC(C)NC(=O)[C@H]1CC[C@@H](N)CC1
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: CC#N
Product: CC(C)NC(=O)[C@H]1CC[C@@H](Nc2cc(F)ccc2[N+](=O)[O-])CC1
Temperature: 80 °C
Reaction time: 8 h

Procedure:
To a solution of cis-4-amino-N-isopropylcyclohexanecarboxamide hydrochloride (0.1 g, 0.453 mmol) and DIPEA (0.237 mL, 1.359 mmol) in ACN (3 mL) was added 2,4-difluoro-1-nitrobenzene (0.072 g, 0.453 mmol). The reaction was stirred overnight at 80° C. The reaction mixture was concentrated, adsorbed onto a plug of silica gel, and purified by column chromatography, eluting with 0-100% EtOAc in DCM, to provide cis-4-(5-fluoro-2-nitrophenylamino)-N-isopropylcyclohexanecarboxamide as a yellow powder (0.123 g, 84% yield).
Reaction SMILES: [CH3:1][O:2][CH2:3][CH2:4][O:5][C:6]1[CH:7]=[CH:8][C:9]2[C:10]3[C:18]([C:19]4[CH:24]=[CH:23][CH:22]=[C:21]([N+:25]([O-:27])=[O:26])[C:20]=4[CH3:28])=[N:17][NH:16][C:15](=O)[C:11]=3[NH:12][C:13]=2[CH:14]=1.P(Cl)(Cl)([Cl:32])=O>>[Cl:32][C:15]1[C:11]2[NH:12][C:13]3[CH:14]=[C:6]([O:5][CH2:4][CH2:3][O:2][CH3:1])[CH:7]=[CH:8][C:9]=3[C:10]=2[C:18]([C:19]2[CH:24]=[CH:23][CH:22]=[C:21]([N+:25]([O-:27])=[O:26])[C:20]=2[CH3:28])=[N:17][N:16]=1
Reactant: COCCOc1ccc2c(c1)[nH]c1c(=O)[nH]nc(-c3cccc([N+](=O)[O-])c3C)c12
Reactant: O=P(Cl)(Cl)Cl
Product: COCCOc1ccc2c(c1)[nH]c1c(Cl)nnc(-c3cccc([N+](=O)[O-])c3C)c12
Temperature: 25 °C
Reaction time: 1 h
Yield: 80.5 %

Procedure:
A yellow, homogeneous solution of 7-(2-methoxyethoxy)-1-(2-methyl-3-nitrophenyl)-3H-pyridazino[4,5-b]indol-4(5H)-one (0.2510 g, 0.636 mmol) in phosphoryl trichloride (20 mL, 0.636 mmol) under nitrogen was heated at 100° C. After 1 h, the reaction was cooled to room temperature and concentrated in vacuo. The residue was dissolved in cold EtOAc (250 mL) and was with ice-cold water (40 mL), ice-cold saturated aqueous NaHCO3 (40 mL), ice-cold water (40 mL) and ice-cold brine (40 mL), successively. The organic solution was dried over MgSO4 and concentrated in vacuo to give the desired product (0.2115 g, 0.512 mmol, 80% yield) as a light orange solid.
Reaction SMILES: [CH:1]([P:3](=[O:8])([O-:7])[O:4][CH2:5][CH3:6])=[CH2:2].C(OCC)(OCC)O[CH2:11][CH3:12].C(OCC)(=O)C>C(O)C>[CH:1]([P:3](=[O:7])([O:8][CH2:11][CH3:12])[O:4][CH2:5][CH3:6])=[CH2:2]
Reactant: C=CP(=O)([O-])OCC
Reactant: CCOC(OCC)OCC
Solvent: CCO
Solvent: CCOC(C)=O
Product: C=CP(=O)(OCC)OCC
Temperature: 150 °C
Yield: 83.6 %

Procedure:
25 g of vinylphosphonic acid and 70 g of diethyl 2-acetoxyethanephosphonate were heated with stirring to 180° C. 252 g of diethyl 2-acetoxyethanephosphonate were then slowly added dropwise over 14 hours while the temperature gradually increased to 200° C. and ethyl acetate distilled off. The mixture was then stirred for 9 hours at 190° C. 190 g of crude monoethyl vinylphosphonate were obtained. Distillation produced 128 g of ethyl acetate and additionally 8 g of light ends which were trapped in a cold trap downstream from the apparatus. 95 g of the crude monoethyl vinylphosphonate and 124 g of triethyl orthoformate were refluxed for 8 hours at about 75° C. The temperature was then gradually increased in the course of 5.5 hours to 150° C. while ethyl acetate and ethanol distilled off. A further 100 g of triethyl orthoformate were then added at room temperature and the mixture was gradually heated again to 150° C. while light ends distilled off. A cold trap downstream from the apparatus collected less that 1 g. The mixture was then distilled and 96.5 g of diethyl vinylphosphonate were obtained. This corresponded to a yield of about 70%, relative to the amount of vinylphosphonic acid and diethyl 2-acetoxyethanephosphonate started with. During the reaction with the orthoester, about 160 g distilled off which contained 28 percent of ethanol and about 10 percent of diethyl ether in addition to about 60 percent of ethyl formate.
Reaction SMILES: [CH2:1]([O:8][C:9]1[C:10](=[O:21])[CH:11]=[C:12]([CH:15]([OH:20])[C:16]([F:19])([F:18])[F:17])O[CH:14]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:22][NH2:23].CO>ClCCl>[CH2:1]([O:8][C:9]1[C:10](=[O:21])[CH:11]=[C:12]([CH:15]([OH:20])[C:16]([F:19])([F:18])[F:17])[N:23]([CH3:22])[CH:14]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CN
Reactant: O=c1cc(C(O)C(F)(F)F)occ1OCc1ccccc1
Solvent: ClCCl
Solvent: CO
Product: Cn1cc(OCc2ccccc2)c(=O)cc1C(O)C(F)(F)F
Reaction time: 1 h
Yield: 77 %

Procedure:
In each of four parallel synthesis tubes equipped with a magnetic stir bar was placed 5-benzyloxy-2-(2,2,2-trifluoro-1-hydroxy-ethyl)-pyran-4-one (0.90 g, 3.0 mmol), and a 2M methylamine solution in MeOH (5.5 mL, 11 mmol). The resulting solution was heated to reflux. The reaction was completed in 60 min. The solutions from the four reaction tubes were combined, and evaporated to dryness to give a semi solid mixture. The mixture was taken up in dichloromethane (15 mL) to give a thick solution. On standing, a solid product precipitated out to give the first crop of the title compound (2.90 g, 77% yield, HPLC Method 1 (Example 24); RT=13.0 min, HPLC purity (peak percent area): 99.5% at x=280 nm). 1H NMR (DMSO-d6+D2O) δ ppm: 7.64 (s, 1H), 7.37 (m, 5H), 6.49 (s, 1H), 5.38 (q, J=6.5 Hz, 1H), 4.97 (s, 2H), 3.69 (s, 3H).
Reaction SMILES: Cl[C:2]([O:5]C(=O)OC(Cl)(Cl)Cl)(Cl)Cl.N1C=CC=CC=1.Cl.C(OCCNC)(=O)C1C=CC=CC=1.[C:33]([O:41][CH2:42][CH2:43][N:44]([C:46]([N:48]1[C:52]2[CH:53]=[C:54](OC)[CH:55]=[CH:56][C:51]=2[N:50]=[C:49]1[S:59]([CH2:61][C:62]1[C:67]([CH3:68])=[C:66]([O:69][CH3:70])[C:65]([CH3:71])=[CH:64][N:63]=1)=[O:60])=[O:47])[CH3:45])(=[O:40])[C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1>O1CCCC1.C(N(CC)CC)C>[C:33]([O:41][CH2:42][CH2:43][N:44]([C:46]([N:48]1[C:52]2[CH:53]=[CH:54][C:55]([O:5][CH3:2])=[CH:56][C:51]=2[N:50]=[C:49]1[S:59]([CH2:61][C:62]1[C:67]([CH3:68])=[C:66]([O:69][CH3:70])[C:65]([CH3:71])=[CH:64][N:63]=1)=[O:60])=[O:47])[CH3:45])(=[O:40])[C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1
Reactant: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Reactant: COc1ccc2nc(S(=O)Cc3ncc(C)c(OC)c3C)n(C(=O)N(C)CCOC(=O)c3ccccc3)c2c1
Agent: CNCCOC(=O)c1ccccc1
Agent: Cl
Solvent: c1ccncc1
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: COc1ccc2c(c1)nc(S(=O)Cc1ncc(C)c(OC)c1C)n2C(=O)N(C)CCOC(=O)c1ccccc1
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
To a solution of bis(trichloromethyl)carbonate (0.344 g) in tetrahydrofuran (10 mL) was added dropwise a solution of pyridine (0.281 mL) in tetrahydrofuran (5 mL) under ice-cooling, and stirred for 30 minutes at 0° C. To the reaction solution was added 2-(methylamino)ethyl benzoate hydrochloride (0.750 g) obtained in Reference Synthetic Example 5. A solution of triethylamine (0.485 mL) in tetrahydrofuran (5 mL) was added, and stirred at 0° C. for 1 hr, and further at room temperature for 30 minutes. The reaction solution was concentrated under reduced pressure, and to the residue was added water (30 mL), and then extracted with ethyl acetate (50 mL). The ethyl acetate layer was washed with saturated brine (30 mL), and dried over anhydrous sodium sulfate, followed by concentrating under reduced pressure. The resulting oil was dissolved in tetrahydrofuran (5 mL), and the solution was added to a solution of 5-methoxy-2-[[(4-methoxy-3,5-dimethyl-2-pyridyl)methyl]sulfinyl]-1H-benzimidazole (1.0 g), triethylamine (0.808 mL) and 4-dimethylaminopyridine (0.071 g) in tetrahydrofuran (10 mL), and stirred at 40° C. for 18 hrs. The reaction solution was concentrated under reduced pressure, and to the residue was added water (30 mL), and extracted with ethyl acetate (50 mL). The ethyl acetate layer was washed with saturated brine (30 mL), and dried over anhydrous sodium sulfate, followed by concentrating under reduced pressure. The residue was purified with silica gel column chromatography (eluted with ethyl acetate:hexane=1:1, then ethyl acetate) to give a mixture of 1:1 of title compound and 2-[[[6-methoxy-2-[[(4-methoxy-3,5-dimethyl-2-pyridyl]methyl]sulfinyl]-1H-benzimidazol-1-yl]carbonyl](methyl)amino]ethyl benzoate as pale yellow amorphous solid (1.50 g).
Reaction SMILES: [CH3:1][C:2]1[C:7]([C:8]#[N:9])=[CH:6][C:5]([N+:10]([O-])=O)=[CH:4][CH:3]=1>C(O)C.C(OCC)(=O)C.[Pd]>[NH2:10][C:5]1[CH:6]=[C:7]([C:2]([CH3:1])=[CH:3][CH:4]=1)[C:8]#[N:9]
Reactant: Cc1ccc([N+](=O)[O-])cc1C#N
Agent: [Pd]
Solvent: CCOC(C)=O
Solvent: CCO
Product: Cc1ccc(N)cc1C#N
Reaction time: 1 h

Procedure:
A suspension of 8.11 g (50 mmol) of 6-methyl-3-nitrobenzonitrile and 0.81 g of 10% of palladium-on-charcoal in 50 ml of ethanol and 50 ml of ethyl acetate is hydrogenated under 2.9 bar for 1 hour. The catalyst is filtered off, the filtrate is concentrated and the residue is crystallised from ether/petroleum ether.
Reaction SMILES: [CH:1]12[O:8][CH:7]1[CH2:6][CH:5]([C:9]1[N:13]([CH3:14])[N:12]=[CH:11][C:10]=1[N+:15]([O-:17])=[O:16])[O:4][CH2:3][CH2:2]2.CO.[Cl-].[NH4+].[N-:22]=[N+:23]=[N-:24].[Na+]>O>[N:22]([CH:1]1[CH2:2][CH2:3][O:4][CH:5]([C:9]2[N:13]([CH3:14])[N:12]=[CH:11][C:10]=2[N+:15]([O-:17])=[O:16])[CH2:6][CH:7]1[OH:8])=[N+:23]=[N-:24]
Reactant: [N-]=[N+]=[N-]
Reactant: Cn1ncc([N+](=O)[O-])c1C1CC2OC2CCO1
Agent: [Cl-]
Agent: [NH4+]
Agent: [Na+]
Solvent: CO
Solvent: O
Product: Cn1ncc([N+](=O)[O-])c1C1CC(O)C(N=[N+]=[N-])CCO1
Temperature: 70 °C
Yield: 58.5 %

Procedure:
To a solution of 5-(4,8-dioxabicyclo[5.1.0]octan-5-yl)-1-methyl-4-nitro-pyrazole (1.04 g, 4.35 mmol) in 4:1 MeOH:water (30 mL) was added ammonium chloride (0.58 g, 10.88 mmol) and sodium azide (1.41 g, 21.75 mmol). The mixture was heated at 70° C. behind a blast screen for 16 hr. The MeOH was removed under reduced pressure and EtOAc (20 mL) added. The organic layer was washed with saturated aqueous NaHCO3 (20 mL), passed through a phase separation cartridge and concentrated under reduced pressure. Purification via silica gel chromatography (0-60% EtOAc/isohexane) gave 5-azido-2-(2-methyl-4-nitro-pyrazol-3-yl)oxepan-4-ol as a pale yellow gum (718 mg, 58% yield). 1H NMR (400 MHz, CDCl3) δ 8.03 (s, 1H), 5.76 (dd, J=9.3, 3.2 Hz, 1H), 4.18-4.10 (m, 1H), 4.08-4.04 (m, 4H), 3.91 (ddd, J=9.4, 6.6, 6.2 Hz, 1H), 3.79 (ddd, J=12.6, 8.6, 3.5 Hz, 1H), 2.44 (ddd, J=15.3, 9.4, 3.8 Hz, 1H), 2.37-2.29 (m, 1H), 2.24 (d, J=3.2 Hz, 1H), 2.12 (ddd, J=15.3, 5.7, 3.2 Hz, 1H), 2.06-1.96 (m, 1H).
Reaction SMILES: [CH3:1][C:2]12[CH2:22][CH:6]([N:7]([C:9]([C:11]3[CH:16]=[CH:15][C:14]([NH:17][C:18](=[O:21])[CH:19]=[CH2:20])=[CH:13][CH:12]=3)=[O:10])[CH2:8]1)[CH2:5][C:4]([CH3:24])([CH3:23])[CH2:3]2.[NH:25]1[CH2:30][CH2:29][CH2:28][CH2:27][CH2:26]1>CCO>[N:25]1([CH2:20][CH2:19][C:18]([NH:17][C:14]2[CH:13]=[CH:12][C:11]([C:9]([N:7]3[CH2:8][C:2]4([CH3:1])[CH2:22][CH:6]3[CH2:5][C:4]([CH3:24])([CH3:23])[CH2:3]4)=[O:10])=[CH:16][CH:15]=2)=[O:21])[CH2:30][CH2:29][CH2:28][CH2:27][CH2:26]1
Reactant: C=CC(=O)Nc1ccc(C(=O)N2CC3(C)CC2CC(C)(C)C3)cc1
Reactant: C1CCNCC1
Solvent: CCO
Product: CC1(C)CC2CC(C)(CN2C(=O)c2ccc(NC(=O)CCN3CCCCC3)cc2)C1
Temperature: 100 °C
Reaction time: 0.5 h
Yield: 21.8 %

Procedure:
To a mixture of N-[4-(1,3,3-trimethyl-6-aza-bicyclo[3.2.1]octane-6-carbonyl)-phenyl]-acrylamide (0.2 g, 0.613 mmol) and piperidine (120 μl, 1.23 mmol) in EtOH (10 ml) was added two drops of TEA. The resulting mixture was heated in a microwave oven at 100° C. for 25 min. The volatiles were evaporated in vacuo and the residue purified on column chromatography (silicagel) using first EtOAc followed by 4% TEA in EtOAc-EtOH 9:1 as eluents. Semi pure fractions were collected, the solvent evaporated in vacuo and the residue dissolved in 1 N HCl (2.5 ml). Water (5 ml) was added followed by diethyl ether (10 ml) and the mixture was stirred for 30 min. The organic phase was discarded and the pH of the aqueous phase adjusted to 10 with 1 N NaOH followed by extraction with diethyl ether (2×10 ml). The combined organic phases were dried (Na2SO4), filtered and evaporated in vacuo affording 55 mg (22%) of the title compound as an oil.
Reaction SMILES: [F:1][C:2]1[C:3]([C:10]2[NH:14][N:13]=[CH:12][CH:11]=2)=[C:4]([CH:7]=[CH:8][CH:9]=1)[C:5]#N.[OH-:15].[Na+].Cl.C[OH:19]>>[F:1][C:2]1[C:3]([C:10]2[NH:14][N:13]=[CH:12][CH:11]=2)=[C:4]([CH:7]=[CH:8][CH:9]=1)[C:5]([OH:19])=[O:15]
Reactant: [OH-]
Reactant: CO
Reactant: N#Cc1cccc(F)c1-c1ccn[nH]1
Agent: Cl
Agent: [Na+]
Product: O=C(O)c1cccc(F)c1-c1ccn[nH]1
Temperature: 25 °C
Yield: 99 %

Procedure:
To 3-fluoro-2-(1H-pyrazol-5-yl)benzonitrile in MeOH (3 mL) was added 2M aq. NaOH (1 mL). The reaction was heated at reflux for 15 h, then cooled to rt, acidified with 1N aq. HCl to pH=1 and extracted with EtOAc to give (210 mg, 99%) of 3-fluoro-2-(1H-pyrazol-5-yl)benzoic acid which was used crude.
Reaction SMILES: [CH3:1][N:2]([C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)[S:3]([C:6](=O)[C:7]1C=[CH:11][C:10]([NH:13]C)=[C:9]([N+:15]([O-])=O)[CH:8]=1)(=[O:5])=[O:4].O.NN.[CH4:28]>C(O)(C)C>[NH2:13][C:10]1[CH:11]=[C:6]([S:3]([N:2]([CH3:1])[C:19]2[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=2)(=[O:4])=[O:5])[CH:7]=[CH:8][C:9]=1[NH:15][CH3:28]
Reactant: C
Reactant: CNc1ccc(C(=O)S(=O)(=O)N(C)c2ccccc2)cc1[N+](=O)[O-]
Agent: NN
Solvent: CC(C)O
Solvent: O
Product: CNc1ccc(S(=O)(=O)N(C)c2ccccc2)cc1N
Reaction time: 8 h

Procedure:
N-Methyl-4-(methylamino)-3-nitro-N-phenylbenzoyl sulfonamide (9 g, 0.028 mol) was dissolved in isopropanol (90 ml). To this solution, hydrazine hydrate (11 ml), activated charcoal (2 g), and FeCl3.6H2O (0.5 g in 10 ml ethanol) were added. The reaction mixture was boiled for 8 h. The charcoal was removed by filtration. The filtrate was evaporated to dryness. The yield of 3-amino-N-methyl-4-(methylamino)-N-phenylbenzene sulfonamide was 8.1 g (99%).
Reaction SMILES: [CH3:1][CH:2]([CH2:37][CH3:38])[CH2:3][C:4]1[N:8]([CH2:9][C:10]2[CH:15]=[CH:14][C:13]([C:16]3[C:17]([C:22]([O:24]C(C)(C)C)=[O:23])=[CH:18][CH:19]=[CH:20][CH:21]=3)=[CH:12][CH:11]=2)[C:7]2[CH:29]=[C:30]3[C:35](=[CH:36][C:6]=2[N:5]=1)[CH:34]=[CH:33][CH:32]=[CH:31]3.FC(F)(F)C(O)=O>C(Cl)Cl>[CH3:1][CH:2]([CH2:37][CH3:38])[CH2:3][C:4]1[N:8]([CH2:9][C:10]2[CH:15]=[CH:14][C:13]([C:16]3[C:17]([C:22]([OH:24])=[O:23])=[CH:18][CH:19]=[CH:20][CH:21]=3)=[CH:12][CH:11]=2)[C:7]2[CH:29]=[C:30]3[C:35](=[CH:36][C:6]=2[N:5]=1)[CH:34]=[CH:33][CH:32]=[CH:31]3
Reactant: CCC(C)Cc1nc2cc3ccccc3cc2n1Cc1ccc(-c2ccccc2C(=O)OC(C)(C)C)cc1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CCC(C)Cc1nc2cc3ccccc3cc2n1Cc1ccc(-c2ccccc2C(=O)O)cc1

Procedure:
Prepared in analogous manner to Example 9 from tert.butyl 4'-[(2-(2-methylbutyl)-naphtho[2,3-d]imidazol-1-yl)-methyl]biphenyl-2-carboxylate and trifluoroacetic acid in methylene chloride.
Reaction SMILES: S1CCSC1.N(C(OC[C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1)=O)[C@H](C(N[C@H:15]([C:18]([O:20][CH2:21][CH3:22])=[O:19])CC)=O)CC(C)C.NCC1C=CC2C(=CC=CC=2)N=1>>[CH3:22][CH2:21][O:20][C:18]([CH3:15])=[O:19].[CH3:31][CH2:32][CH2:27][CH2:28][CH2:29][CH3:30]
Reactant: CCOC(=O)[C@H](CC)NC(=O)[C@H](CC(C)C)NC(=O)OCc1ccccc1
Agent: NCc1ccc2ccccc2n1
Solvent: C1CSCS1
Product: CCCCCC
Product: CCOC(C)=O
Yield: 16 %

Procedure:
This compound was prepared from 1,3-dithiolane derivative of Z-Leu-Abu-COOEt and 2-aminomethylquinoline by the procedure described in Example 38, and purified by column chromatography using AcOEt/hexane 2:1 (16% yield). Yellow solid, single spot on TLC, Rf =0.27 (AcOEt/hexane 2:1), mp 135°-138° C. 1H NMR (CDCl3) ok, MS (FAB) m/e=519 (M+1). Anal: calcd. for C29H34N4O5, 518; C, 67.16; H, 6.60; N, 10.80. Found, C, 66.89; H, 6.68; N, 10.61.
Reaction SMILES: [NH2:1][C:2]1[C:11]([N+:12]([O-])=O)=[CH:10][C:5]([C:6]([O:8][CH3:9])=[O:7])=[C:4]([CH2:15][O:16][CH3:17])[CH:3]=1.[Cl-].[NH4+].O1CCCC1.CO>O>[NH2:1][C:2]1[C:11]([NH2:12])=[CH:10][C:5]([C:6]([O:8][CH3:9])=[O:7])=[C:4]([CH2:15][O:16][CH3:17])[CH:3]=1
Reactant: COCc1cc(N)c([N+](=O)[O-])cc1C(=O)OC
Agent: [Cl-]
Agent: [NH4+]
Solvent: CO
Solvent: O
Solvent: C1CCOC1
Product: COCc1cc(N)c(N)cc1C(=O)OC
Temperature: 80 °C
Reaction time: 8 h
Yield: 105.3 %

Procedure:
To a mixed liquid of 4.70 g of methyl 4-amino-2-(methoxymethyl)-5-nitrobenzoate, 750 mg of ammonium chloride, 47.0 mL of tetrahydrofuran, 94.0 mL of methanol, and 14.0 mL of water was added 7.65 g of reduced iron, followed by stirring at 80° C. overnight. After cooling to room temperature, the insoluble materials were filtered through celite and the filtrate was evaporated under reduced pressure to obtain 4.33 g of methyl 4,5-diamino-2-(methoxymethyl)benzoate as a brown solid.
Reaction SMILES: [F:1][C:2]1[C:3]([CH3:13])=[C:4]2[C:9](=[CH:10][CH:11]=1)[NH:8][CH:7]([CH3:12])[CH2:6][CH2:5]2.C([O:16][CH:17]=[C:18]([C:24](OCC)=O)[C:19]([O:21]CC)=[O:20])C.Cl>[OH-].[Na+]>[CH3:12][CH:7]1[N:8]2[C:9]3[C:10](=[CH:11][C:2]([F:1])=[C:3]([CH3:13])[C:4]=3[CH2:5][CH2:6]1)[C:17](=[O:16])[C:18]([C:19]([OH:21])=[O:20])=[CH:24]2
Reactant: Cc1c(F)ccc2c1CCC(C)N2
Reactant: CCOC=C(C(=O)OCC)C(=O)OCC
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Product: Cc1c(F)cc2c(=O)c(C(=O)O)cn3c2c1CCC3C
Temperature: 100 °C
Reaction time: 1 h

Procedure:
A mixture of 9.3 g of 6-fluoro-5-methyl-1,2,3,4-tetrahydroquinaldine and 17 ml of diethyl ethoxymethylenemalonate was heated at 150°-160° C. for 3.5 hours, and then cooled to 100° C. To this solution was added 56 g of polyphosphoric acid, and the mixture was stirred for one hour while heating on a steam bath. The mixture was then cooled to room temperature and allowed to stand for about 72 hours. To this mixture, containing ethyl 1,2-dihydro-5,8-dimethyl-9-fluoro-1-oxo-1H,5H-benzo[ij]quinolizine-2-carboxylate, was added 250 ml of 20% aqueous sodium hydroxide to make the solution basic. The solution was then heated at its reflux temperature for 2 hours, cooled, and acidified with concentrated hydrochloric acid. The solid was separated by filtration and recrystallized from aqueous N,N-dimethylformamide. Washing with ethanol followed by drying provided 6,7-dihydro-5,8-dimethyl-9-fluoro-1-oxo-1H,5H-benzo[ij]quinolizine-2-carboxylic acid as an off-white solid, m.p. 269°-272° C. Analysis: Calculated for C15H14FNO3 : %C, 65.4; %H, 5.1; %N, 5.1; Found: %C, 65.0; %H, 5.0; %N, 5.0.
Reaction SMILES: [CH3:1][C:2]1[CH:11]=[CH:10][C:5]([C:6]([O:8][CH3:9])=[O:7])=[CH:4][C:3]=1[N+:12]([O-])=O.[CH3:15]O.[H][H]>C(OCC)(=O)C.[C].[Pd]>[NH:12]1[C:3]2[C:2](=[CH:11][CH:10]=[C:5]([C:6]([O:8][CH3:9])=[O:7])[CH:4]=2)[CH:1]=[CH:15]1
Reactant: [H][H]
Reactant: CO
Reactant: COC(=O)c1ccc(C)c([N+](=O)[O-])c1
Agent: [Pd]
Solvent: CCOC(C)=O
Product: COC(=O)c1ccc2cc[nH]c2c1
Yield: 68.7 %

Procedure:
Into a reaction flask were introduced 87.1 g of methyl 4-methyl-3-nitrobenzoate, 400 ml of methanol and 8 g of 5% palladium-carbon (Pd/C). The content of the flask was stirred at room temperature for 12 hours in an atmosphere of hydrogen at ordinary pressure. The Pd/C was removed by filtration, and methanol was distilled out from the filtrate to obtain a slightly yellow colored solid product. The product was dissolved in ethyl acetate, washed with 5% aqueous solution of NaOH, washed with 5% aqueous solution of hydrochloric acid and water, and the ethyl acetate was distilled off. Thus, 50.4 g (yield 68.7%) of methyl indole-6-carboxylate monomer was obtained.