Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: O[C:2]1[C:7]2=[C:8]([C:11]3[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=3)[CH:9]=[CH:10][N:6]2[N:5]=[C:4]([C:17]2[CH:18]=[C:19]([S:23]([NH2:26])(=[O:25])=[O:24])[CH:20]=[N:21][CH:22]=2)[N:3]=1.CN([P+](ON1N=NC2C=CC=CC1=2)(N(C)C)N(C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C.[CH2:63]([NH2:70])[C:64]1[CH:69]=[CH:68][CH:67]=[CH:66][CH:65]=1>C1COCC1>[CH2:63]([NH:70][C:2]1[C:7]2=[C:8]([C:11]3[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=3)[CH:9]=[CH:10][N:6]2[N:5]=[C:4]([C:17]2[CH:18]=[C:19]([S:23]([NH2:26])(=[O:24])=[O:25])[CH:20]=[N:21][CH:22]=2)[N:3]=1)[C:64]1[CH:69]=[CH:68][CH:67]=[CH:66][CH:65]=1
Reactant: NS(=O)(=O)c1cncc(-c2nc(O)c3c(-c4ccccc4)ccn3n2)c1
Reactant: NCc1ccccc1
Agent: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: C1CCOC1
Solvent: CCN(C(C)C)C(C)C
Product: NS(=O)(=O)c1cncc(-c2nc(NCc3ccccc3)c3c(-c4ccccc4)ccn3n2)c1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 20.1 %

Procedure:
5-(4-Hydroxy-5-phenylpyrrolo[2,1-f][1,2,4]triazin-2-yl)pyridine-3-sulfonamide (0.100 g, 0.272 mmol) was dissolved in THF (10 mL) and BOP reagent (0.181 g, 0.408 mmol) and DIPEA (0.143 mL, 0.817 mmol) were added. The reaction mixture was stirred at room temperature for 30 min. Benzylamine (0.0440 g, 0.408 mmol) in THF (3 mL) was added and the reaction mixture was stirred at room temperature for 14 h. The reaction mixture was concentrated under reduced pressure and water was added (30 mL). The resulting aqueous solution was extracted with ethyl acetate. The organic layer was separated, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified by prep HPLC (Condition B-61 as described in general methods) to obtain 5-(4-(benzylamino)-5-phenylpyrrolo[2,1-f][1,2,4]triazin-2-yl)pyridine-3-sulfonamide (0.0250 g, 20.1%). LCMS Condition B-38: retention time 2.08 min, [M+1]=457.2. HPLC Condition B-5: retention time 20.11 min, Purity 97.00%. 1H NMR (400 MHz, DMSO-d6) δ ppm 4.84 (d, J=5.6 Hz, 2H), 6.76 (t, J=5.6 Hz, 1H), 6.84 (d, J=2.8 Hz, 1H), 7.30 (t, J=7.2 Hz, 1H), 7.34 (t, J=7.6 Hz, 2H), 7.40-7.45 (m, 3H), 7.48 (t, J=7.6 Hz, 2H), 7.55 (dd, J=1.6, J=3.4 Hz, 2H), 7.68 (br s, 2H), 7.95 (d, J=2.4 Hz, 1H), 8.94 (t, J=2.2 Hz, 1H), 9.05 (d, J=2.4 Hz, 1H), 9.53 (d, J=1.6 Hz, 1H).
Reaction SMILES: C([N:5]1[C:25](=[O:26])[N:8]2[C:9]([C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=3[CH3:24])=[C:10]([C:14]([CH3:17])([CH3:16])[CH3:15])[N:11]=[C:12]([Cl:13])[C:7]2=[N:6]1)(C)(C)C.[Cl-].[Cl-].[Cl-].[Al+3]>ClC(Cl)C>[C:14]([C:10]1[N:11]=[C:12]([Cl:13])[C:7]2[N:8]([C:25](=[O:26])[NH:5][N:6]=2)[C:9]=1[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=1[CH3:24])([CH3:17])([CH3:15])[CH3:16]
Reactant: Cc1ccccc1-c1c(C(C)(C)C)nc(Cl)c2nn(C(C)(C)C)c(=O)n12
Agent: [Al+3]
Agent: [Cl-]
Solvent: CC(Cl)Cl
Product: Cc1ccccc1-c1c(C(C)(C)C)nc(Cl)c2n[nH]c(=O)n12
Temperature: 100 °C

Procedure:
A suspension of 440 mg of 2,6-di-tert-butyl-8-chloro-5-o-tolyl-2H-[1,2,4]triazolo[4,3-a]pyrazin-3-one and 504 mg of aluminum trichloride in dichloroethane (12.0 mL) was heated to 100° C. After one h, the reaction was cooled to ambient temperature and the excess aluminum reagent was quenched by the careful addition of water. This mixture was diluted with chloroform and the layers were separated. The organic layer was washed with water and then sat. sodium chloride solution, dried over sodium sulfate, filtered, and concentrated. The residue was purified by silica gel chromatography to afford 6-tert-butyl-8-chloro-5-o-tolyl-2H-[1,2,4]triazolo[4,3-a]pyrazin-3-one as a yellow solid. MS (M+H−)=315.1.
Reaction SMILES: O[Li].O.[C:4]12([C:14]3[CH:15]=[C:16]([C:22]4[CH:33]=[CH:32][C:25](/[CH:26]=[CH:27]/[C:28]([O:30]C)=[O:29])=[CH:24][CH:23]=4)[CH:17]=[CH:18][C:19]=3[O:20][CH3:21])[CH2:13][CH:8]3[CH2:9][CH:10]([CH2:12][CH:6]([CH2:7]3)[CH2:5]1)[CH2:11]2>C1COCC1.O>[C:4]12([C:14]3[CH:15]=[C:16]([C:22]4[CH:23]=[CH:24][C:25](/[CH:26]=[CH:27]/[C:28]([OH:30])=[O:29])=[CH:32][CH:33]=4)[CH:17]=[CH:18][C:19]=3[O:20][CH3:21])[CH2:13][CH:8]3[CH2:9][CH:10]([CH2:12][CH:6]([CH2:7]3)[CH2:5]1)[CH2:11]2
Reactant: COC(=O)/C=C/c1ccc(-c2ccc(OC)c(C34CC5CC(CC(C5)C3)C4)c2)cc1
Agent: [Li]O
Solvent: O
Solvent: C1CCOC1
Product: COc1ccc(-c2ccc(/C=C/C(=O)O)cc2)cc1C12CC3CC(CC(C3)C1)C2
Temperature: 25 °C
Reaction time: 48 h
Yield: 93.9 %

Procedure:
455 mg (10.8 mmol) of LiOH.H2O were dissolved in 90 ml of THF:H2O 1:1; 873 mg (2.17 mmol) of methyl E-4(3-(1-adamantyl)-4-methoxyphenyl)cinnamate were added and the solution thus obtained was kept under stirring at room temperature for 2 days. The THF was evaporated, acidified with 2N HCl and the white precipitate was filtered. The solid was washed with AcOEt and Et2O, to obtain 792 mg (94%) of the title compound.
Reaction SMILES: [CH:1]1[C:18]2[CH:17]=[CH:16][C:15]3[C:6](=[CH:7][CH:8]=[C:9]4[C:14]=3[CH:13]=[CH:12][CH:11]=[CH:10]4)[C:5]=2[CH:4]=[C:3]([C:19](OCC)=[O:20])[CH:2]=1.[Li+].[BH4-].Cl>C1COCC1>[CH:1]1[C:18]2[CH:17]=[CH:16][C:15]3[C:6](=[CH:7][CH:8]=[C:9]4[C:14]=3[CH:13]=[CH:12][CH:11]=[CH:10]4)[C:5]=2[CH:4]=[C:3]([CH2:19][OH:20])[CH:2]=1
Reactant: CCOC(=O)c1ccc2ccc3c4ccccc4ccc3c2c1
Agent: Cl
Agent: [BH4-]
Agent: [Li+]
Solvent: C1CCOC1
Product: OCc1ccc2ccc3c4ccccc4ccc3c2c1
Yield: 98.3 %

Procedure:
A solution of ethyl chrysene-3-carboxylate (19E 17.7 g, 0.059 mol) in 40 mL THF was treated with LiBH4 (Morton Thiokol, Inc.-Alfa Products, PO Box 299, 152 Andover St., Danvers, MA 01923, 2.7 g, 0.12 mol) in three portions then refluxed for 3 days. The reaction mixture was poured into ice and acidified carefully to pH 1 with 1N HCl. The precipitate was filtered and recrystallized from THF/hexane to afford 14.98 g (98%) of 3-chrysenemethanol mp 187°-189°, (C, H).
Reaction SMILES: [NH2:1][C:2]1[CH:11]=[C:10]2[C:5]([CH:6]=[CH:7][CH:8]=[N:9]2)=[CH:4][CH:3]=1.[CH3:12][C:13]1[CH:14]=[C:15]([CH:19]=[CH:20][C:21]=1[C:22]1[CH:27]=[CH:26][N:25]=[CH:24][CH:23]=1)[C:16](O)=[O:17]>>[CH3:12][C:13]1[CH:14]=[C:15]([CH:19]=[CH:20][C:21]=1[C:22]1[CH:27]=[CH:26][N:25]=[CH:24][CH:23]=1)[C:16]([NH:1][C:2]1[CH:11]=[C:10]2[C:5]([CH:6]=[CH:7][CH:8]=[N:9]2)=[CH:4][CH:3]=1)=[O:17]
Reactant: Cc1cc(C(=O)O)ccc1-c1ccncc1
Reactant: Nc1ccc2cccnc2c1
Product: Cc1cc(C(=O)Nc2ccc3cccnc3c2)ccc1-c1ccncc1

Procedure:
Using the procedure outlined in Example 56, the title compound was prepared from 7-aminoquinoline (D55) (25 mg, 0.17 mmol) and 3-methyl-4-(4-pyridyl)benzoic acid (D57) (44 mg, 0.21 mmol) as an orange solid. 1H NMR (400 MHz, CDCl3) δ (ppm): 8.91(dd, 1H), 8.70 (d, 2H), 8.22 (m, 2H), 8.14 (dd, 1H), 8.11 (dd, 1H), 7.84 (m, 3H), 7.36 (m, 2H), 7.28 (m, 2H), 2.37 (s, 3H).
Reaction SMILES: [CH3:1][O:2][C:3]([CH:5]([CH2:9][C:10]1[CH:15]=[CH:14][C:13]([O:16][CH2:17][CH2:18][C:19]2[N:20]=[C:21]([C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=3)[O:22][C:23]=2[CH3:24])=[CH:12][CH:11]=1)[C:6]([OH:8])=[O:7])=[O:4].[CH:31]([N-]C(C)C)(C)C.[Li+].CI.[Cl-].[NH4+]>O1CCCC1>[CH3:1][O:2][C:3]([C:5]([CH3:31])([CH2:9][C:10]1[CH:11]=[CH:12][C:13]([O:16][CH2:17][CH2:18][C:19]2[N:20]=[C:21]([C:25]3[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=3)[O:22][C:23]=2[CH3:24])=[CH:14][CH:15]=1)[C:6]([OH:8])=[O:7])=[O:4]
Reactant: COC(=O)C(Cc1ccc(OCCc2nc(-c3ccccc3)oc2C)cc1)C(=O)O
Reactant: CC(C)[N-]C(C)C
Agent: [Cl-]
Agent: [Li+]
Agent: [NH4+]
Solvent: C1CCOC1
Solvent: CI
Product: COC(=O)C(C)(Cc1ccc(OCCc2nc(-c3ccccc3)oc2C)cc1)C(=O)O
Yield: 112.9 %

Procedure:
To a solution of 2-methoxycarbonyl-3-[4-[2-(5-methyl-2-phenyl-4-oxazolyl)ethoxy]phenyl]propionic acid (4.10 g, 10.0 mmol) obtained in Example 1 in tetrahydrofuran (50 ml) was dropwise added lithium diisopropylamide (1.5 M cyclohexane solution, 15.0 ml, 22.5 mmol) at −78° C. under argon atmosphere. The mixture was stirred at said temperature and methyl iodide (2.5 ml, 40 mmol) was dropwise added. The mixture was stirred at said temperature for 2 hr and 10% aqeuous ammonium chloride (20 ml) was added. The organic layer was separated and the aqueous layer was extracted with ethyl acetate (50 ml). The obtained organic layers were combined, washed with saturated brine (10 ml), dried over magnesium sulfate and concentrated under reduced pressure to give the crude title compound (4.78 g).
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:19]=[CH:18][C:12]2[CH2:13][CH2:14][NH:15][CH2:16][CH2:17][C:11]=2[CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:20]1(=O)[CH2:24][CH2:23][CH2:22][CH2:21]1>>[CH2:1]([O:8][C:9]1[CH:19]=[CH:18][C:12]2[CH2:13][CH2:14][N:15]([CH:20]3[CH2:24][CH2:23][CH2:22][CH2:21]3)[CH2:16][CH2:17][C:11]=2[CH:10]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: c1ccc(COc2ccc3c(c2)CCNCC3)cc1
Reactant: O=C1CCCC1
Product: c1ccc(COc2ccc3c(c2)CCN(C2CCCC2)CC3)cc1

Procedure:
Title compound (E2) was prepared from 7-benzyloxy-1,2,4,5-tetrahydro-benzo[d]azepine (D2) and cyclopentanone using the method described for Example 1; MS (ES+) m/e 322 [M+H]+.
Reaction SMILES: C(OC(=O)[NH:10][C@@:11]1([CH3:57])[C:15]2=[C:16]([Cl:33])[N:17]=[C:18]([NH:21][CH2:22][C:23]3[CH:28]=[CH:27][CH:26]=[C:25]([C:29]([F:32])([F:31])[F:30])[CH:24]=3)[C:19](=[O:20])[N:14]2[C@H:13]([C:34](=[O:56])[NH:35][CH2:36][C:37]2[CH:42]=[CH:41][C:40]([C:43]([NH:45]C(OCC3C=CC=CC=3)=O)=[NH:44])=[CH:39][CH:38]=2)[CH2:12]1)C1C=CC=CC=1.[H][H]>CO.[Pd]>[C:43]([C:40]1[CH:39]=[CH:38][C:37]([CH2:36][NH:35][C:34]([C@H:13]2[N:14]3[C:19](=[O:20])[C:18]([NH:21][CH2:22][C:23]4[CH:28]=[CH:27][CH:26]=[C:25]([C:29]([F:30])([F:31])[F:32])[CH:24]=4)=[N:17][C:16]([Cl:33])=[C:15]3[C@@:11]([NH2:10])([CH3:57])[CH2:12]2)=[O:56])=[CH:42][CH:41]=1)(=[NH:44])[NH2:45]
Reactant: C[C@@]1(NC(=O)OCc2ccccc2)C[C@@H](C(=O)NCc2ccc(C(=N)NC(=O)OCc3ccccc3)cc2)n2c1c(Cl)nc(NCc1cccc(C(F)(F)F)c1)c2=O
Reactant: [H][H]
Agent: [Pd]
Solvent: CO
Product: C[C@@]1(N)C[C@@H](C(=O)NCc2ccc(C(=N)N)cc2)n2c1c(Cl)nc(NCc1cccc(C(F)(F)F)c1)c2=O
Reaction time: 4 h
Yield: 112.3 %

Procedure:
The compound (34 mg, 0.0325 mmol) obtained from Step B was dissolved in MeOH (0.5 mL) and 10% Pd/C (7 mg) was added. A hydrogen balloon was attached and the reaction allowed to stir for approximately 4 h at which time MS indicated a complete reaction. The reaction was filtered and concentrated under vacuum to give the product as a white solid (20 mg, 79% yield). 1HNMR (300 MHz, CD3OD) δ 1.56 (s, 3H) 2.25 (m, 1H) 2.45 (m, 1H) 4.5 (m, 2H) 4.6 (m, 2H) 5.1 (m, 1H) 7.5–7.8 (m, 8H).
Reaction SMILES: Cl[C:2]1[C:3]([F:23])=[CH:4][C:5]2[C:6]([CH:22]=1)=[N:7][C:8]1[N:9]([CH:19]3[CH2:21][CH2:20]3)[CH:10]=[C:11]([C:16]([OH:18])=[O:17])[C:12](=[O:15])[C:13]=1[CH:14]=2.[CH3:24][N:25]1[CH2:30][CH2:29][NH:28][CH2:27][CH2:26]1>N1C=CC=CC=1>[CH:19]1([N:9]2[C:8]3[N:7]=[C:6]4[CH:22]=[C:2]([N:28]5[CH2:29][CH2:30][N:25]([CH3:24])[CH2:26][CH2:27]5)[C:3]([F:23])=[CH:4][C:5]4=[CH:14][C:13]=3[C:12](=[O:15])[C:11]([C:16]([OH:18])=[O:17])=[CH:10]2)[CH2:21][CH2:20]1
Reactant: CN1CCNCC1
Reactant: O=C(O)c1cn(C2CC2)c2nc3cc(Cl)c(F)cc3cc2c1=O
Solvent: c1ccncc1
Product: CN1CCN(c2cc3nc4c(cc3cc2F)c(=O)c(C(=O)O)cn4C2CC2)CC1
Yield: 52.9 %

Procedure:
1-Cyclopropyl-7-fluoro-8-(4-methyl-1-piperazinyl)-4-oxo-1,4-dihydro-benzo[b][1,8]naphthyridine-3-carboxylic acid is prepared under the conditions of Reference Example 5 but starting from 1 g of 8-chloro-1-cyclopropyl-7-fluoro-4-oxo-1,4-dihydro-benzo[b][1,8]naphthyridine-3-carboxylic acid and 3 g of 1-methylpiperazine in 10 cm3 of pyridine. After recrystallizing from 10 cm3 of dimethylformamide, 0.63 g of 1-cyclopropyl-7-fluoro-8-(4-methyl-1-piperazinyl)-4-oxo-1,4-dihydro-benzo[b][1,8]naphthyridine-3-carboxylic acid is obtained in the form of a yellow solid melting at 250° C.
Reaction SMILES: [CH:1](=[O:10])[C:2]1[CH:7]=[CH:6][C:5]([O:8][CH3:9])=[CH:4][CH:3]=1.[CH:11]([Mg]Br)=[CH2:12]>O1CCCC1>[CH3:9][O:8][C:5]1[CH:6]=[CH:7][C:2]([CH:1]([OH:10])[CH:11]=[CH2:12])=[CH:3][CH:4]=1
Reactant: C=C[Mg]Br
Reactant: COc1ccc(C=O)cc1
Solvent: C1CCOC1
Product: C=CC(O)c1ccc(OC)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 51 %

Procedure:
To a solution of p-anisaldehyde (1.54 ml) in tetrahydrofuran (20 ml) at −10° C. under argon was added dropwise vinyl magnesium bromide (1 M in THF, 12.5 ml). The solution was stirred overnight at room temperature and quenched by addition of saturated aqueous ammonium chloride (20 ml). The organic phase was separated, dried over sodium sulfate and concentrated in vacuo. The residue was purified by column chromatography (SiO2, ethyl acetate:cyclohexan 7:3) to give 1.05 g of the desired product as a colorless oil (51%) which was characterized by its mass and NMR spectra.
Reaction SMILES: [CH3:1][S:2]([O:5][C:6]1[CH:11]=[CH:10][C:9]([OH:12])=[C:8]([C:13]([CH3:17])([CH3:16])[CH2:14][OH:15])[CH:7]=1)(=[O:4])=[O:3].CO[C:20](OC)([CH3:22])[CH3:21].C1(C)C=CC(S(O)(=O)=O)=CC=1>C1(C)C=CC=CC=1>[CH3:1][S:2]([O:5][C:6]1[CH:11]=[CH:10][C:9]2[O:12][C:20]([CH3:22])([CH3:21])[O:15][CH2:14][C:13]([CH3:17])([CH3:16])[C:8]=2[CH:7]=1)(=[O:4])=[O:3]
Reactant: CC(C)(CO)c1cc(OS(C)(=O)=O)ccc1O
Reactant: COC(C)(C)OC
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: Cc1ccccc1
Product: CC1(C)OCC(C)(C)c2cc(OS(C)(=O)=O)ccc2O1

Procedure:
A mixture of 4-hydroxy-3-(2-hydroxy-1,1-dimethylethyl)phenyl methylsulphonate (10 parts) (from Example 1), 2,2-dimethoxypropane (17 parts) and p-toluenesulphonic acid (0.1 parts) was heated in toluene (90 parts) with distillation of low boiling fraction and slow addition of further 2,2-dimethoxypropane (17 parts) for 1 hour. The resulting solution was cooled, washed with aqueous sodium hydroxide solution and with water, dried over magnesium sulphate and the solvent evaporated off under reduced pressure. The crude product was distilled yielding 9 parts of 4,5-dihydro-2,2,5,5-tetramethyl-1,3-benzodioxepin-7-yl methanesulphonate, boiling point 130°-142° C./0.2 mm Hg. Recrystallisation from aqueous ethanol gave the pure product (4.8 parts), melting point 65°-67° C.
Reaction SMILES: Cl.C([N:9]1[CH2:14][CH2:13][O:12][CH:11]([CH2:15][O:16]S(C2C=CC(C)=CC=2)(=O)=O)[CH2:10]1)C1C=CC=CC=1.[O-][CH2:28][CH3:29].[Na+]>C(O)C>[CH2:28]([O:16][CH2:15][CH:11]1[O:12][CH2:13][CH2:14][NH:9][CH2:10]1)[CH3:29]
Reactant: CC[O-]
Reactant: Cc1ccc(S(=O)(=O)OCC2CN(Cc3ccccc3)CCO2)cc1
Agent: Cl
Agent: [Na+]
Solvent: CCO
Product: CCOCC1CNCCO1
Temperature: 70 °C
Reaction time: 24 h
Yield: 82.2 %

Procedure:
4-Benzyl-2-(p-toluenesulfonyloxymethyl)morpholine hydrochloride [cf. Reference Example 11-(1)] (3 g) and sodium ethoxide (2 g) are added to ethanol (150 ml), and the mixture is stirred at 70° C. for 24 hours. The reaction mixture is concentrated under reduced pressure, and to the residue is added saturated aqueous sodium hydrogen carbonate, and the mixture is extracted with ethyl acetate. The extract is washed with saturated aqueous sodium hydrogen carbonate solution, dried over anhydrous magnesium sulfate and distilled under reduced pressure to remove the solvent. The residue is purified by silica gel column chromatography (eluted by chloroform-methanol=40:1) and further subjected to bulb-to-bulb distillation (at 162° C., 0.4 mmHg) to give the title compound (0.9 g) as colorless liquid.
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]2[O:9][CH2:8][S:7][C:6]=2[CH:10]=1.[Li]CCCC.[CH3:16][C:17]1([CH3:24])[C:21]([CH3:23])([CH3:22])[O:20][BH:19][O:18]1.[NH4+].[Cl-]>O1CCCC1>[O:9]1[C:5]2[CH:4]=[CH:3][C:2]([B:19]3[O:20][C:21]([CH3:23])([CH3:22])[C:17]([CH3:24])([CH3:16])[O:18]3)=[CH:10][C:6]=2[S:7][CH2:8]1
Reactant: CC1(C)OBOC1(C)C
Reactant: Brc1ccc2c(c1)SCO2
Agent: [Cl-]
Agent: [Li]CCCC
Agent: [NH4+]
Solvent: C1CCOC1
Product: CC1(C)OB(c2ccc3c(c2)SCO3)OC1(C)C
Temperature: -70 °C
Reaction time: 0.5 h

Procedure:
5-Bromobenzo[d][1,3]oxathiole (1.0 g, 4.6 mmol, prepared as described in Cabiddu, Salvatore; Cerioni, Giovanni; Cocco, Maria Teresa; Maccioni, Antonio; Plumitallo, Antonio, Journal of Heterocyclic Chemistry 1982, 19, 135-139) was dissolved in dry tetrahydrofuran (12 mL), cooled to −70° C., treated in portions with n-BuLi (2.5 M; 1.9 mL, 4.8 mmol) and stirred at −70° C. for 30 min. 4,4,5,5-Tetramethyl-1,3,2-dioxaborolane (900 mg, 4.8 mmol) was added and stirring was continued for 1.5 h during which the temperature rose to −30° C. The mixture was treated with saturated NH4Cl (5 mL) and extracted with ethyl acetate (2×25 mL). The combined extracts were washed with saturated NaCl (10 mL), dried (Na2SO4) and evaporated to give the title compound which was used without further purification (1.2 g, 99%): 1H NMR (400 MHz, CDCl3) δ 7.62 (d, J=1.1 Hz, 1H), 7.48 (dd, J=8.0, 1.3 Hz, 1H), 6.82 (d, J=8.1 Hz, 1H), 5.69 (s, 2H), 1.32 (s, 12H); EIMS m/z 264.
Reaction SMILES: [F:1][C:2]1[C:3]([NH:12][C:13]2[CH:18]=[CH:17][C:16]([C:19]#[CH:20])=[CH:15][C:14]=2[F:21])=[C:4]([CH:8]=[CH:9][C:10]=1[F:11])[C:5]([OH:7])=[O:6]>C(O)C.[Pd]>[CH2:19]([C:16]1[CH:17]=[CH:18][C:13]([NH:12][C:3]2[C:2]([F:1])=[C:10]([F:11])[CH:9]=[CH:8][C:4]=2[C:5]([OH:7])=[O:6])=[C:14]([F:21])[CH:15]=1)[CH3:20]
Reactant: C#Cc1ccc(Nc2c(C(=O)O)ccc(F)c2F)c(F)c1
Agent: [Pd]
Solvent: CCO
Product: CCc1ccc(Nc2c(C(=O)O)ccc(F)c2F)c(F)c1
Temperature: 25 °C
Reaction time: 2 h
Yield: 92.1 %

Procedure:
The product of Step C, 3,4-difluoro-2-[(4-ethynyl-2-fluorophenyl)amino]benzoic acid (300 mg, 1.03 mmol), was dissolved in absolute ethanol (30 mL) and 5% Pd/C (30 mg) added. This mixture was stirred under an atmosphere of hydrogen (60 psi) for 2 hours at room temperature. The Pd/C was removed over Celite®, which was washed well with additional ethanol, then the solvent removed from the resultant filtrate under reduced pressure to afford 2-[(4-ethyl-2-fluorophenyl)amino]-3,4-difluorobenzoic acid as an off-white solid (280 mg, 92%); m.p. (EtOAc/hexanes) 199–201° C. 1H NMR [400 MHz, (CD3)2SO] δ 14.10 (br s, 1 H), 9.31 (br s, 1 H), 7.80 (ddd, J=8.5, 6.1, 1.9 Hz, 1 H), 7.09 (dd, J=12.4, 1.5 Hz, 1 H), 7.04–6.92 (m, 3 H), 2.52 (q, J=7.6 Hz, 2 H), 1.17 (t, J=7.5 Hz, 3 H).
Reaction SMILES: C(N(CC)CC)C.[CH3:8][N:9]=[C:10]=[O:11].[Cl:12][C:13]1[CH:18]=[C:17]([C:19]([F:22])([F:21])[F:20])[CH:16]=[C:15]([F:23])[C:14]=1[O:24][C:25]1[CH:29]=[C:28]([CH3:30])[NH:27][N:26]=1.Cl>C(OCC)(=O)C>[CH3:8][NH:9][C:10]([N:27]1[C:28]([CH3:30])=[CH:29][C:25]([O:24][C:14]2[C:15]([F:23])=[CH:16][C:17]([C:19]([F:22])([F:20])[F:21])=[CH:18][C:13]=2[Cl:12])=[N:26]1)=[O:11]
Reactant: Cc1cc(Oc2c(F)cc(C(F)(F)F)cc2Cl)n[nH]1
Reactant: CN=C=O
Agent: Cl
Solvent: CCOC(C)=O
Solvent: CCN(CC)CC
Product: CNC(=O)n1nc(Oc2c(F)cc(C(F)(F)F)cc2Cl)cc1C
Temperature: 25 °C
Reaction time: 4 h
Yield: 56.9 %

Procedure:
Triethylamine (0.13 g, 1.3 mmol) and methyl isocyanate (0.07 g, 1.2 mmol) were added to a solution of 3-(2-chloro-6-fluoro-4-trifluoromethylphenyloxy)-5-methylpyrazole (0.32 g, 1.1 mmol) in ethyl acetate (10 ml), and the mixture was stirred at room temperature for 4 hours. After completion of the reaction, the reaction mixture was poured into 2N hydrochloric acid and extracted with ethyl acetate (10 ml×3). An organic layer was washed with water, dried over anhydrous magnesium sulfate and filtered to remove a desiccant, and the solvent was distilled off from the filtrate under reduced pressure. The resultant crude product was purified with a silica gel column (ethyl acetate/hexane=1/10), to give a white solid of N-methyl-3-(2-chloro-6-fluoro-4-trifluoromethylphenyloxy)-5-methylpyrazole-1-carboxamide (0.22 g, yield: 56.9%). mp: 87-88° C.; 1H-NMR (CDCl3, TMS, ppm): δ 2.59 (s, 3H), 2.88 (d, J=5.0 Hz, 3H), 5.80 (s, 1H), 6.55-6.75 (m, 1H), 7.40 (dd, JHF=2.0 and 9.3 Hz, 1H), 7.56 (s, 1H).
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH:3]=[CH:2]1.[H-].[Na+].[S:12](Cl)([C:15]1[CH:21]=[CH:20][C:18]([CH3:19])=[CH:17][CH:16]=1)(=[O:14])=[O:13].Cl>CN(C=O)C>[S:12]([N:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH:3]=[CH:2]1)([C:15]1[CH:21]=[CH:20][C:18]([CH3:19])=[CH:17][CH:16]=1)(=[O:14])=[O:13]
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Reactant: c1ccc2[nH]ccc2c1
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: Cc1ccc(S(=O)(=O)n2ccc3ccccc32)cc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 82.4 %

Procedure:
To a solution of indole 81 (10 g, 85 mmol) in DMF (50 mL) at 0° C. was added NaH (60% dispersion in mineral oil 4 g) and tosylchloride (24 g, 128 mmol) portionwisely. And the reaction mixture was stirred at room temperature for 2 h. The resulting solution was acidified with 2.0 M HCl, and organic layer was extracted with Et2O. After evaporating the volatile material with reduced pressure, the residue was purified by silica column chromatography to obtain titled compound 82 (19 g, 84%).
Reaction SMILES: [CH2:1]([N:5]1[C:17]2[C:16]3[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=3[N+:10]([O-])=[CH:9][C:8]=2[N:7]=[CH:6]1)[CH:2]([CH3:4])[CH3:3].P(Cl)(Cl)([Cl:21])=O>>[Cl:21][C:9]1[C:8]2[N:7]=[CH:6][N:5]([CH2:1][CH:2]([CH3:4])[CH3:3])[C:17]=2[C:16]2[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=2[N:10]=1
Reactant: CC(C)Cn1cnc2c[n+]([O-])c3ccccc3c21
Reactant: O=P(Cl)(Cl)Cl
Product: CC(C)Cn1cnc2c(Cl)nc3ccccc3c21

Procedure:
A mixture of 9.95 g (0.0412 mole) of 1-isobutyl-1H-imidazo [4,5-c]quinolin-5-oxide (from Example 54) and 100 ml of phosphorus oxychloride was heated at its reflux temperature for 2.5 hours, and was then cooled and poured into ice with stirring. Basification (to pH 9-10) with 50% aqueous sodium hydroxide solution was followed by extraction with dichloromethane. The extracts were dried over sodium chloride and sodium bicarbonate, and were then evaporated to provide a solid residue. A sample of the residue was recrystallized from diethyl ether to provide 4-chloro-1-isobutyl-1H-imidazo [4,5-c]quinoline, m.p. 134°-136° C. Analysis: Calculated for C14H17ClN3 : %C, 64.7; H, 5.4; %N, 16.2; Found: %C, 64.3; %H, 5.3; %N, 16.3.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:10]=[CH:11][C:12]=1[CH2:13][C:14]1[C:15]2[CH:22]=[C:21]([N+:23]([O-])=O)[CH:20]=[CH:19][C:16]=2[S:17][CH:18]=1)[C:6]([O:8][CH3:9])=[O:7].C(=O)(O)[O-].[Na+]>C(O)C>[NH2:23][C:21]1[CH:20]=[CH:19][C:16]2[S:17][CH:18]=[C:14]([CH2:13][C:12]3[CH:11]=[CH:10][C:5]([C:6]([O:8][CH3:9])=[O:7])=[CH:4][C:3]=3[O:2][CH3:1])[C:15]=2[CH:22]=1
Reactant: COC(=O)c1ccc(Cc2csc3ccc([N+](=O)[O-])cc23)c(OC)c1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCO
Product: COC(=O)c1ccc(Cc2csc3ccc(N)cc23)c(OC)c1
Yield: 54.6 %

Procedure:
Stannous chloride dihydrate (0.38 g.) was added to a stirred solution of (I) (0.12 g.) in ethanol (5 ml.), under an atmosphere of nitrogen. The mixture was heated under reflux for 2 hours. The cooled mixture was basified with saturated aqueous sodium bicarbonate (15 ml.) and extracted with ethyl acetate (2×25 ml.). The extracts were dried (MgSO4) and evaporated. The residual oil was purified by flash chromatography on silica gel (50 ml.), eluting with 3:7 v/v ethyl acetate:hexane to give methyl 4-(5-aminobenzo[b]thien-3-ylmethyl)-3-methoxybenzoate (H) (0.06 g., 54 % ) as an oil; NMR (80 MHz, DMSO-d6): 3.84 (s,3H, OCH3), 3.91(s,3H, OCH3), 4.03(s,2H, CH2 --Ar), 5.0(br s,2H, NH2), 6.80(m,2H), 7.14(m,2H), 7.52(m,3H).
Reaction SMILES: [OH:1][C:2]1[CH:30]=[CH:29][C:5]([C:6]([C:8]2[CH:28]=[CH:27][C:11]([CH2:12][S:13][C:14]3[N:23]([CH3:24])[C:22](=[O:25])[C:21]4[C:16](=[CH:17][CH:18]=[CH:19][C:20]=4[CH3:26])[N:15]=3)=[CH:10][CH:9]=2)=[O:7])=[CH:4][CH:3]=1.Cl.[N:32]1[CH:37]=[CH:36][C:35]([CH2:38]Cl)=[CH:34][CH:33]=1.C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C>[CH3:24][N:23]1[C:22](=[O:25])[C:21]2[C:16](=[CH:17][CH:18]=[CH:19][C:20]=2[CH3:26])[N:15]=[C:14]1[S:13][CH2:12][C:11]1[CH:27]=[CH:28][C:8]([C:6](=[O:7])[C:5]2[CH:4]=[CH:3][C:2]([O:1][CH2:38][C:35]3[CH:36]=[CH:37][N:32]=[CH:33][CH:34]=3)=[CH:30][CH:29]=2)=[CH:9][CH:10]=1
Reactant: Cc1cccc2nc(SCc3ccc(C(=O)c4ccc(O)cc4)cc3)n(C)c(=O)c12
Reactant: ClCc1ccncc1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: Cc1cccc2nc(SCc3ccc(C(=O)c4ccc(OCc5ccncc5)cc4)cc3)n(C)c(=O)c12
Yield: 22.2 %

Procedure:
A solution of 2-[4-(4-hydroxybenzoyl)benzylthio]-3,5-dimethyl-4(3H)-quinazolinone (369 mg), 4-picolyl chloride hydrochloride (144 mg) and potassium carbonate (350 mg) in DMF (5 ml) was stirred at room temperature for 3 days. This reaction mixture was concentrated and the residue was dissolved in ethyl acetate, washed with water, dried, and concentrated. The residue was recrystallized from ethyl acetate-chloroform to provide the title compound as colorless solid (99 mg).