Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]([F:15])([F:14])[C:3]1[CH:8]=[CH:7][C:6]([CH:9]2[CH2:13][CH2:12][CH2:11][NH:10]2)=[CH:5][CH:4]=1.[Cl:16][C:17]1[CH:22]=[CH:21][C:20]([S:23](Cl)(=[O:25])=[O:24])=[CH:19][CH:18]=1>>[Cl:16][C:17]1[CH:22]=[CH:21][C:20]([S:23]([N:10]2[CH2:11][CH2:12][CH2:13][CH:9]2[C:6]2[CH:7]=[CH:8][C:3]([C:2]([F:1])([F:14])[F:15])=[CH:4][CH:5]=2)(=[O:25])=[O:24])=[CH:19][CH:18]=1
Reactant: O=S(=O)(Cl)c1ccc(Cl)cc1
Reactant: FC(F)(F)c1ccc(C2CCCN2)cc1
Product: O=S(=O)(c1ccc(Cl)cc1)N1CCCC1c1ccc(C(F)(F)F)cc1

Procedure:
The title compound, white solid, m.p. 107° C. and MS: m/e=369 (M+) was prepared in accordance with the general method of example 1e from (RS)-2-(4-trifluoromethyl-phenyl)-pyrrolidine and 4-chloro-benzenesulfonyl chloride.
Reaction SMILES: C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].[C:15]([O:19][C:20](=[O:27])[NH:21][C:22]([CH3:26])([CH3:25])[CH:23]=O)([CH3:18])([CH3:17])[CH3:16].[F:28][C:29]1[C:30]([CH3:36])=[C:31]([CH:33]=[CH:34][CH:35]=1)[NH2:32].C(O)(=O)C.C(=O)(O)[O-].[Na+]>C(Cl)Cl>[C:15]([O:19][C:20](=[O:27])[NH:21][C:22]([CH3:26])([CH3:25])[CH2:23][NH:32][C:31]1[CH:33]=[CH:34][CH:35]=[C:29]([F:28])[C:30]=1[CH3:36])([CH3:18])([CH3:17])[CH3:16]
Reactant: CC(C)(C=O)NC(=O)OC(C)(C)C
Reactant: Cc1c(N)cccc1F
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: ClCCl
Product: Cc1c(F)cccc1NCC(C)(C)NC(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 16 h
Yield: 74.4 %

Procedure:
5.8 g of sodium triacetoxyborohydride (27.0 mmol) was added to a solution of 3.5 g of (1,1-dimethyl-2-oxoethyl)carbamic acid t-butyl ester obtained in Reference Example 3 (18.7 mmol), 2.25 g of 3-fluoro-2-methylaniline (18.0 mmol) and 1.0 ml of acetic acid (18.0 mmol) in methylene chloride (190 ml) under ice-cooling, and the mixture was stirred at room temperature for 16 hours. A saturated sodium bicarbonate aqueous solution was added to the reaction mixture, followed by extraction with methylene chloride. Then, the organic layer was washed with brine and dried over anhydrous sodium sulfate. After filtration, the solvent was evaporated under reduced pressure, and the residue was purified by silica gel column chromatography (elution solvent:hexane/ethyl acetate=5/1) to obtain 3.97 g of the title compound (yield: 74%).
Reaction SMILES: Cl.[CH3:2][N:3]1[C:11]2[C:6](=[N:7][C:8]([C@@H:18]([NH2:20])[CH3:19])=[C:9]([C:12]3[N:16]([CH3:17])[N:15]=[CH:14][CH:13]=3)[CH:10]=2)[CH:5]=[CH:4]1.Cl[C:22]1[N:27]=[C:26]([NH2:28])[N:25]=[C:24]2[NH:29][N:30]=[CH:31][C:23]=12.C(N(C(C)C)C(C)C)C>C(#N)C>[CH3:2][N:3]1[C:11]2[C:6](=[N:7][C:8]([C@@H:18]([NH:20][C:22]3[N:27]=[C:26]([NH2:28])[N:25]=[C:24]4[NH:29][N:30]=[CH:31][C:23]=34)[CH3:19])=[C:9]([C:12]3[N:16]([CH3:17])[N:15]=[CH:14][CH:13]=3)[CH:10]=2)[CH:5]=[CH:4]1
Reactant: C[C@H](N)c1nc2ccn(C)c2cc1-c1ccnn1C
Reactant: Nc1nc(Cl)c2cn[nH]c2n1
Agent: Cl
Solvent: CC#N
Solvent: CCN(C(C)C)C(C)C
Product: C[C@H](Nc1nc(N)nc2[nH]ncc12)c1nc2ccn(C)c2cc1-c1ccnn1C
Temperature: 120 °C
Yield: 54.2 %

Procedure:
(S)-1-(1-Methyl-6-(1-methyl-1H-pyrazol-5-yl)-1H-pyrrolo[3,2-b]pyridin-5-yl)ethanamine hydrochloride (500 mg, 1.71 mmol), 4-chloro-1H-pyrazolo[3,4-d]pyrimidin-6-amine (436 mg, 2.57 mmol), and N-ethyl-N-isopropylpropan-2-amine (0.895 mL, 5.14 mmol) were combined in acetonitrile (10 mL). The reaction mixture was heated in a microwave reactor at 120° C. for 2 hours and then concentrated. The residue was diluted with MeOH/DMSO and purified by preparative HPLC (basic mode) eluting with 35% ACN in water. The fractions containing the desired product were combined and lyophilized to give the title compound as a pale yellow solid (360 mg, 54.2%). 1H NMR (500 MHz, DMSO-d6) δ ppm 1.41 (d, J=6.83 Hz, 3 H), 3.59-3.68 (m, 3 H), 3.83 (s, 3 H), 5.57 (dd, J=13.42, 6.59 Hz, 3 H), 6.46 (d, J=1.46 Hz, 1 H), 6.61 (d, J=2.93 Hz, 1 H), 7.55 (d, J=1.46 Hz, 1 H), 7.72 (d, J=3.42 Hz, 1 H), 7.89 (s, 1 H), 7.95-8.03 (m, 2 H), 12.33 (br s, 1 H); ESI-MS m/z [M+H]+ calc'd for C19H20N10,389; found 389.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]([CH:8]=[O:9])=[N:6][CH:7]=1.[F:10][C:11]([Si](C)(C)C)([F:13])[F:12].CCCC[N+](CCCC)(CCCC)CCCC.[F-]>C1COCC1>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([CH:8]([OH:9])[C:11]([F:13])([F:12])[F:10])=[N:6][CH:7]=1
Reactant: C[Si](C)(C)C(F)(F)F
Reactant: O=Cc1ccc(Br)cn1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: C1CCOC1
Product: OC(c1ccc(Br)cn1)C(F)(F)F
Temperature: 25 °C
Reaction time: 2 h

Procedure:
5-Bromopicolinaldehyde (500 mg, 2.70 mmol) was dissolved in THF (9.0 mL) and the flask was then sealed with a septum, flushed with argon, and cooled to 0° C. (Trifluoromethyl)trimethylsilane (0.44 mL, 3.0 mmol) was then added followed by TBAF (2.7 mL, 2.7 mmol, 1M in THF). The resulting mixture was allowed to warm to ambient temperature and was stirred for 2 hours. The reaction was then quenched with water and extracted with DCM (2×). The combined organic extracts were washed with brine, dried over anhydrous MgSO4, and concentrated in vacuo. The residue was purified by MPLC on silica gel (using a gradient elution of 10-20% EtOAc/hexanes) to afford the title compound. LRMS (ESI) calc'd for C8H6BrF3O [M+H]+: 256. Found: 256.
Reaction SMILES: [Cl-].[CH3:2][O:3][CH2:4][P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.C[Si](C)(C)[N-][Si](C)(C)C.[Li+].[CH:34]([C:37]1[CH:44]=[C:43]([Br:45])[CH:42]=[C:41]([CH:46]([CH3:48])[CH3:47])[C:38]=1[CH:39]=O)([CH3:36])[CH3:35]>C1COCC1>[CH:34]([C:37]1[CH:44]=[C:43]([Br:45])[CH:42]=[C:41]([CH:46]([CH3:48])[CH3:47])[C:38]=1[CH:39]=[CH:2][O:3][CH3:4])([CH3:36])[CH3:35]
Reactant: COC[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: CC(C)c1cc(Br)cc(C(C)C)c1C=O
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Cl-]
Agent: [Li+]
Solvent: C1CCOC1
Product: COC=Cc1c(C(C)C)cc(Br)cc1C(C)C
Temperature: 0 °C
Yield: 78.8 %

Procedure:
A 150 mL of dry toluene solution of 1-iodo-2,6-diisopropyl-4-bromobenzene (17.6 g, 0.048 mol) was treated with n-BuLi (1.6 M in hexane, 75 mL) at −78° C. in 30 minutes. After stirring for 15 minutes, dry DMF (20 mL) in 50 mL of toluene was added dropwise. The resulting mixture was slowly warmed up to room temperature. After regular work up, the crude product was distilled at 140° C. under vacuum to afford 2,6-diisopropyl-4-bromobenzaldehyde (11.5 g). Methoxymethyl triphenylphosphonium chloride (18.68 g, 54.5 mmol) was suspended in 200 mL of THF at −78° C. Lithium hexamethyldisilazide (1.0 M in THF, 50 mL) was added dropwise. The resulting mixture was warmed up to 0° C. with stirring. After cooling the solution to −78° C., 2,6-diisopropyl-4-bromobenzaldehyde (11.5 g, 42.7 mmol) in 20 mL of THF was added dropwise. The mixture was slowly warmed up to room temperature and continually stirred overnight. After regular work up, the crude product was distilled at 165° C. under vacuum to afford 2,6-diisopropyl-4-bromo-β-methoxystyrene (10 g). This product was dissolved in 20 mL of dioxane and 100 mL of 18% HCl solution and refluxed at 100° C. for 6 h. After regular work up, the crude product was distilled at 160° C. under vacuum to afford 2,6-diisopropyl-4-bromophenylacetaldehyde (7.5 g).
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:18]=[C:17]2[C:12]([C:13](Cl)=[CH:14][CH:15]=[N:16]2)=[CH:11][C:10]=1[C:20]#[N:21])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[N+:22]([C:25]1[CH:30]=[CH:29][C:28]([OH:31])=[CH:27][CH:26]=1)([O-:24])=[O:23].N1C(C)=CC=CC=1C.[Na]>O1CCCC1>[CH2:1]([O:8][C:9]1[CH:18]=[C:17]2[C:12]([C:13]([O:31][C:28]3[CH:29]=[CH:30][C:25]([N+:22]([O-:24])=[O:23])=[CH:26][CH:27]=3)=[CH:14][CH:15]=[N:16]2)=[CH:11][C:10]=1[C:20]#[N:21])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=[N+]([O-])c1ccc(O)cc1
Reactant: N#Cc1cc2c(Cl)ccnc2cc1OCc1ccccc1
Agent: [Na]
Solvent: C1CCOC1
Solvent: Cc1cccc(C)n1
Product: N#Cc1cc2c(Oc3ccc([N+](=O)[O-])cc3)ccnc2cc1OCc1ccccc1
Reaction time: 2 h
Yield: 52.4 %

Procedure:
To the 7-benzyloxy-4-chloro-6-cyanoquinoline (2.60 g, 8.83 mmol) described in WO98/13350 there were added 4-nitrophenol (2.46 g, 17.7 mmol) and lutidine (2.06 ml, 17.7 mmol), and the mixture was heated and stirred at 155–158° C. for 2 hours. After returning the reaction system to room temperature, it was dissolved in tetrahydrofuran, saturated sodium bicarnobate water was added and stirred therewith for 10 minutes, the mixture was concentrated under reduced pressure, the precipitated solid was filtered out and subjected to silica gel column chromatography (Fuji Silysia NH Type, eluent—hexane:ethyl acetate=50:50→ethyl acetate alone), the fraction containing the target substance was concentrated and the obtained solid was washed with diethylether. It was then dried under reduced pressure to obtain the title compound (1.84 g, 4.63 mmol, 52.6%).
Reaction SMILES: [CH3:1][NH:2][C:3](=[O:10])[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.C([Li])CCC.[CH:16](=[O:23])[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1.[Cl-].[NH4+]>CCCCCC.O1CCCC1>[OH:23][CH:16]([C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)[C:5]1[C:4]([C:3]([NH:2][CH3:1])=[O:10])=[CH:9][CH:8]=[CH:7][CH:6]=1
Reactant: O=Cc1ccccc1
Reactant: CNC(=O)c1ccccc1
Agent: [Cl-]
Agent: [Li]CCCC
Agent: [NH4+]
Solvent: CCCCCC
Solvent: C1CCOC1
Product: CNC(=O)c1ccccc1C(O)c1ccccc1
Temperature: 5 °C

Procedure:
To a flask equipped with a stirrer, dropping funnel, condenser and gas inlet tube maintained under a nitrogen atmosphere there is added at room temperature 67.5 g. (0.5 mole) N-methyl benzamide and 1200 ml. dry tetrahydrofuran. The reaction flask is immersed in an ice bath and cooled to an internal temperature of 5° C. Stirring is initiated and 688 ml. of 1.6 M. n-butyl lithium (1.1 mole) in hexane is added dropwise over about 1 hour maintaining temperature below 8° C. The resulting dilithio salt is stirred at 5° C. for an additional hour and then a solution of 58.5 g. (0.55 mole) of benzaldehyde in 500 ml. tetrahydrofuran is added dropwise in about 1 hour maintaining the temperature between -10° to +10° C. The resulting mixture is stirred at 5° C. for 1 hour longer and 300 ml. of saturated ammonium chloride is added maintaining the temperature at about 10° C. The layers are separated and the organic phase dried over anhydrous magnesium sulfate, filtered and evaporated in vacuo to give α-hydroxy-N-methyl-α-phenyl-o-toluamide.
Reaction SMILES: [Cl:1][CH2:2][CH2:3][C:4](Cl)=[O:5].CC(C)=O.[NH2:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1.Cl>O>[Cl:1][CH2:2][CH2:3][C:4]([NH:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)=[O:5]
Reactant: Nc1ccccc1
Reactant: O=C(Cl)CCCl
Agent: Cl
Solvent: O
Solvent: CC(C)=O
Product: O=C(CCCl)Nc1ccccc1

Procedure:
A mixture of 3-chloropropionyl chloride (300 ml) and acetone (600 ml) is added dropwise to a refluxing mixture of aniline (575 ml) and acetone (600 ml). The reaction mixture is refluxed for one hour, cooled in an ice bath, and poured into a mixture of 6N HCl (500 ml) and water (3.5 l). The resulting solid is filtered, washed with water, and dried, yielding the desired product, M.P. 114°-115.5° C.
Reaction SMILES: [CH2:1]([OH:5])[CH2:2][CH2:3][OH:4].[N+](=[C:8]1[CH2:12][CH2:11][O:10][C:9]1=[O:13])=[N-]>ClCCl.C(OCC)C.C([O-])(=O)C.[Rh+2].C([O-])(=O)C>[OH:4][CH2:3][CH2:2][CH2:1][O:5][CH:8]1[CH2:12][CH2:11][O:10][C:9]1=[O:13]
Reactant: [N-]=[N+]=C1CCOC1=O
Reactant: OCCCO
Agent: [Rh+2]
Agent: CC(=O)[O-]
Solvent: ClCCl
Solvent: CCOCC
Product: O=C1OCCC1OCCCO
Temperature: 25 °C

Procedure:
Propane-1,3-diol (0.050 g, 0.657 mmol) was dissolved in dichloromethane (6.5 mL) and treated with rhodium (II) acetate (3 mg) then solution was heated to reflux. One third of a solution (ca. 2 mL) of 3-diazodihydrofuran-2(3H)-one (0.283 g, 0.986 mmol) dissolved in a mixture of dichloromethane (3 mL) and diethyl ether (2.5 mL) was added dropwise to the hot solution then the solution was heated at reflux for 30 minutes. The solution of 3-diazodihydrofuran-2(3H)-one was added in two portions (ca. 2 mL each) to the refluxing mixture in a similar manner. The reaction was cooled to ambient temperature and concentrated in vacuo. The crude oil was chromatographed on silica gel eluting with ethyl acetate/hexanes (2:1). 3-(3-Hydroxypropoxy)dihydrofuran-2(3H)-one was recovered as a colorless oil (47 mg, 45%).
Reaction SMILES: [CH3:1][CH:2]([CH3:26])[CH2:3][N:4]1[C:16]2[C:15]3[CH:14]=[CH:13][C:12]([O:17][CH:18]4[CH2:22][CH2:21][O:20][CH2:19]4)=[CH:11][C:10]=3[N:9]=[CH:8][C:7]=2[N:6]=[C:5]1[CH2:23][CH2:24][CH3:25].C1C=C(Cl)C=C(C(OO)=[O:35])C=1>>[CH3:1][CH:2]([CH3:26])[CH2:3][N:4]1[C:16]2[C:15]3[CH:14]=[CH:13][C:12]([O:17][CH:18]4[CH2:22][CH2:21][O:20][CH2:19]4)=[CH:11][C:10]=3[N+:9]([O-:35])=[CH:8][C:7]=2[N:6]=[C:5]1[CH2:23][CH2:24][CH3:25]
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: CCCc1nc2cnc3cc(OC4CCOC4)ccc3c2n1CC(C)C
Product: CCCc1nc2c[n+]([O-])c3cc(OC4CCOC4)ccc3c2n1CC(C)C
Yield: 51.3 %

Procedure:
The method described in Part M of Example 2 was used to treat 1-(2-methylpropyl)-2-propyl-7-(tetrahydrofuran-3-yloxy)-1H-imidazo[4,5-c]quinoline (1.1 g, 3.1 mmol) with mCPBA (1.07 g, 3.72 mmol). The crude product was purified by column chromatography on silica gel to afford 0.588 g of 1-(2-methylpropyl)-5-oxido-2-propyl-7-(tetrahydrofuran-3-yloxy)-1H-imidazo[4,5-c]quinoline as a yellow solid.
Reaction SMILES: [NH:1]([C:9]([O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:10])[C@H:2]([C:6]([OH:8])=[O:7])[C@@H:3]([CH3:5])[OH:4].[H-].[Na+].[CH3:18]I>C1COCC1>[NH:1]([C:9]([O:11][C:12]([CH3:14])([CH3:13])[CH3:15])=[O:10])[C@H:2]([C:6]([OH:8])=[O:7])[C@@H:3]([CH3:5])[O:4][CH3:18]
Reactant: CI
Reactant: C[C@@H](O)[C@H](NC(=O)OC(C)(C)C)C(=O)O
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CO[C@H](C)[C@H](NC(=O)OC(C)(C)C)C(=O)O
Temperature: 25 °C
Reaction time: 8 h

Procedure:
In a THF solution containing 0.8 g of Boc-Thr-OH, 100 mg of sodium hydride (60% in oil) was added under ice cooling and the resultant mixture was stirred for 30 min at room temperature. Further, 2.8 ml of methyl iodide was added and the obtained reaction mixture was stirred overnight at room temperature. The reaction mixture was evaporated under reduced pressure and the resultant residue was redissolved in ethyl acetate, washed with 5% sodium hydrogensulfite aqueous solution, water and saturated sodium chloride aqueous solution, successively, and dried over anhydrous sodium sulfate. The dried solution was evaporated under reduced pressure, dissolved in methanol, mixed with DCHA and reevaporated. Ether-hexane was added to the residue to give 0.55 g of the title compound as its DCHA salt.
Reaction SMILES: [O:1]=[S:2]1(=[O:28])[C:7]2[CH:8]=[CH:9][CH:10]=[CH:11][C:6]=2[NH:5][C:4]([C:12]2C(=O)[N:16]([N:19]=[CH:20][CH:21]([CH3:23])C)[C:15]3[CH:24]=[CH:25][S:26][C:14]=3[C:13]=2[OH:27])=[N:3]1.[CH3:29][OH:30].[BH4-].[Li+].Cl>O1CCCC1.O>[O:28]=[S:2]1(=[O:1])[C:7]2[CH:8]=[CH:9][CH:10]=[CH:11][C:6]=2[NH:5][C:4]([C:12]2[C:29](=[O:30])[N:16]([NH:19][CH2:20][CH2:21][C:23]3[CH:10]=[CH:11][CH:6]=[CH:7][CH:8]=3)[C:15]3[CH:24]=[CH:25][S:26][C:14]=3[C:13]=2[OH:27])=[N:3]1
Reactant: CC(C)C=Nn1c(=O)c(C2=NS(=O)(=O)c3ccccc3N2)c(O)c2sccc21
Reactant: CO
Agent: Cl
Agent: [BH4-]
Agent: [Li+]
Solvent: C1CCOC1
Solvent: O
Product: O=c1c(C2=NS(=O)(=O)c3ccccc3N2)c(O)c2sccc2n1NCCc1ccccc1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
The product of Example 269A (0.046 g, 0.10 mmol) in tetrahydrofuran (5 mL) and methanol (0.005 mL, 0.12 mmol) at 0° C. was treated dropwise with a 2.0M solution of lithium borohydride in tetrahydrofuran (0.06 mL, 0.12 mmol). The reaction was stirred at 25° C. for 3 hour, acidified with 1M hydrochloric acid a pH of approximately 2-4, diluted with water (10 mL), and the resulting precipitate was collected by filtration and dried. The crude product was chromatographed on silica gel with 99:1 dichloromethane/methanol to give the title compound. The sodium salt of the title compound was prepared according to the procedure of Example 1D. 1H NMR (300 MHz, DMSO-d6) δ ppm 1.26 (m, 3 H) 4.49 (m, 1 H) 5.90 (m, 1 H) 7.20 (d, J=8.09 Hz, 1 H) 7.27 (t, J=8.46 Hz, 2 H) 7.30 (m, 5 H) 7.54 (m, 2 H) 7.66 (d, J=8.09 Hz, 1 H) 15.93 (s, 1 H). MS (ESI−) m/z 465 (M−H)−.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([O:8][CH3:9])[CH:5]=[CH:4][C:3]=1[C:10]1[CH:15]=[CH:14][N:13]=[C:12](OS(C(F)(F)F)(=O)=O)[C:11]=1[N+:24]([O-:26])=[O:25].Cl.[CH:28]1([CH:32]([NH2:35])[CH2:33][CH3:34])[CH2:31][CH2:30][CH2:29]1>>[Cl:1][C:2]1[CH:7]=[C:6]([O:8][CH3:9])[CH:5]=[CH:4][C:3]=1[C:10]1[CH:15]=[CH:14][N:13]=[C:12]([NH:35][CH:32]([CH:28]2[CH2:31][CH2:30][CH2:29]2)[CH2:33][CH3:34])[C:11]=1[N+:24]([O-:26])=[O:25]
Reactant: CCC(N)C1CCC1
Reactant: COc1ccc(-c2ccnc(OS(=O)(=O)C(F)(F)F)c2[N+](=O)[O-])c(Cl)c1
Agent: Cl
Product: CCC(Nc1nccc(-c2ccc(OC)cc2Cl)c1[N+](=O)[O-])C1CCC1
Yield: 72.6 %

Procedure:
Trifluoro-methanesulfonic acid 4-(2-chloro-4-methoxy-phenyl)-3-nitro-pyridin-2-yl ester (0.50 g, 1.21 mmol), prepared substantially as described in Example 19a, and 1-cyclobutyl-propylamine HCl (0.36 g, 2.42 mmol) were treated substantially as described in Part C of Example 19a to produce 0.33 g (72%) of [4-(2-chloro-4-methoxy-phenyl)-3-nitro-pyridin-2-yl]-(1-cyclobutyl-propyl)-amine: MS (AP) m/z 375.9 [(M+H)+, 25].
Reaction SMILES: [CH3:1][O:2][C:3](=[O:18])[C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([C:10]2[N:11]=[C:12]([CH3:17])[S:13][C:14]=2[CH2:15]Br)[CH:5]=1.CC([O-])=[O:21].[K+].CO>CN(C=O)C>[CH3:1][O:2][C:3](=[O:18])[C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([C:10]2[N:11]=[C:12]([CH3:17])[S:13][C:14]=2[CH2:15][OH:21])[CH:5]=1
Reactant: COC(=O)c1cccc(-c2nc(C)sc2CBr)c1
Reactant: CC(=O)[O-]
Agent: [K+]
Solvent: CO
Solvent: CN(C)C=O
Product: COC(=O)c1cccc(-c2nc(C)sc2CO)c1
Reaction time: 0.5 h

Procedure:
3-(5-bromomethyl-2-methyl-thiazol-4-yl)-benzoic acid methyl ester was stirred in DMF (16 mL) together with KOAc (2.35 g) at 20° C. for 20 min. MeOH (32 mL) and naOMe (0.86 g) were added and stirring was continued at 50° C. for 30 min. The mixture was partitioned between AcOEt and brine and the organic layer was dried and evaporated. The residual oil was chromatographed on silica gel using AcOEt/hexane (1:1) as eluent to give 3-(5-hydroxymethyl-2-methyl-thiazol-4-yl)-benzoic acid methyl ester (2.93 g) as a white solid.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:13]([O:15]CC)=[O:14])[C:5](=[O:12])[N:6]([CH:9]([CH3:11])[CH3:10])[C:7]=1[CH3:8].[OH-].[Na+]>O1CCCC1.CO>[Cl:1][C:2]1[CH:3]=[C:4]([C:13]([OH:15])=[O:14])[C:5](=[O:12])[N:6]([CH:9]([CH3:11])[CH3:10])[C:7]=1[CH3:8]
Reactant: CCOC(=O)c1cc(Cl)c(C)n(C(C)C)c1=O
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Product: Cc1c(Cl)cc(C(=O)O)c(=O)n1C(C)C
Temperature: 25 °C
Reaction time: 16 h
Yield: 94 %

Procedure:
To a stirred solution of ethyl 5-chloro-1-isopropyl-6-methyl-2-oxo-1,2-dihydropyridine-3-carboxylate as prepared in 1(6) (203 mg, 0.79 mmol) in tetrahydrofuran (2 mL) and methanol (2 mL) was added 2N sodium hydroxide aqueous solution (2 mL) at room temperature, and the mixture was stirred at room temperature for 16 h. Then, the solvent was removed in vacuo. The residue was diluted with water (30 mL), acidified with 2N hydrochloric acid aqueous solution (pH˜2) and extracted with dichloromethane (50 mL×3). The combined organic layers were dried over magnesium sulfate and concentrated in vacuo to give 171 mg (94%) of the title compound as a white solid.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:15]([OH:17])=O)[N:5]([C:8]2[C:13]([Cl:14])=[CH:12][CH:11]=[CH:10][N:9]=2)[C:6]=1[Cl:7].[NH2:18][C:19]1[C:20]([C:31](O)=[O:32])=[CH:21][C:22]2[C:27]([C:28]=1[Cl:29])=[CH:26][CH:25]=[C:24](Br)[CH:23]=2.BrC1C=C(C(O)=O)N(C2C(Cl)=CC=CN=2)C=1.NC1C(C)=CC(Cl)=CC=1C(O)=O>>[Cl:29][C:28]1[C:19]2[N:18]=[C:15]([C:4]3[N:5]([C:8]4[C:13]([Cl:14])=[CH:12][CH:11]=[CH:10][N:9]=4)[C:6]([Cl:7])=[C:2]([Cl:1])[CH:3]=3)[O:17][C:31](=[O:32])[C:20]=2[CH:21]=[C:22]2[C:27]=1[CH:26]=[CH:25][CH:24]=[CH:23]2
Reactant: O=C(O)c1cc(Cl)c(Cl)n1-c1ncccc1Cl
Reactant: Nc1c(C(=O)O)cc2cc(Br)ccc2c1Cl
Agent: Cc1cc(Cl)cc(C(=O)O)c1N
Agent: O=C(O)c1cc(Br)cn1-c1ncccc1Cl
Product: O=c1oc(-c2cc(Cl)c(Cl)n2-c2ncccc2Cl)nc2c(Cl)c3ccccc3cc12

Procedure:
According to the same manner as that of Reference Preparation Example 71-(5), 4,5-dichloro-1-(3-chloro-2-pyridinyl)-1H-pyrrole-2-carboxylic acid and 3-amino-7-bromo-4-chloro-2-naphthoic acid were used in place of 4-bromo-1-(3-chloro-2-pyridinyl)-1H-pyrrole-2-carboxylic acid and 2-amino-5-chloro-3-methylbenzoic acid respectively to obtain 10-chloro-2-[4,5-dichloro-1-(3-chloro-2-pyridinyl)-1H-pyrrol-2-yl]-4H-naphtho[2,3-d][1,3]oxazine-4-one of the formula:
Reaction SMILES: Cl.[NH2:2][C:3]1[CH:21]=[CH:20][C:19]([Cl:22])=[CH:18][C:4]=1[C:5]([NH:7][CH2:8][C:9]1[CH:14]=[CH:13][C:12]2[O:15][CH2:16][O:17][C:11]=2[CH:10]=1)=[O:6].[C:23](Cl)(=[O:31])[O:24][C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1.C(N(C(C)C)CC)(C)C>O1CCCC1>[Cl:22][C:19]1[CH:20]=[CH:21][C:3]([NH:2][C:23]([O:24][C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)=[O:31])=[C:4]([CH:18]=1)[C:5]([NH:7][CH2:8][C:9]1[CH:14]=[CH:13][C:12]2[O:15][CH2:16][O:17][C:11]=2[CH:10]=1)=[O:6]
Reactant: O=C(Cl)Oc1ccccc1
Reactant: Nc1ccc(Cl)cc1C(=O)NCc1ccc2c(c1)OCO2
Agent: Cl
Solvent: C1CCOC1
Solvent: CCN(C(C)C)C(C)C
Product: O=C(Nc1ccc(Cl)cc1C(=O)NCc1ccc2c(c1)OCO2)Oc1ccccc1
Yield: 88 %

Procedure:
2-Amino-5-chloro-N-(3,4-methylenedioxybenzyl)benzamide hydrochloride (100 mg) was reacted with 50 μl of phenyl chlorocarbonate in 5 ml of tetrahydrofuran in the presence of 150 μl of diisopropylethylamine. The reaction mixture was subjected to extraction with ethyl acetate and water and recrystallization from ethyl acetate/hexane to give 110 mg of 5-chloro-N-(3,4-methylenedioxybenzyl)-2-phenoxycarbonylaminobenzamide (yield: 88%).
Reaction SMILES: [CH3:1][O:2][C:3]1[N:8]=[N:7][C:6]([S:9](F)(=[O:11])=[O:10])=[CH:5][CH:4]=1.[CH3:13][NH:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1>>[CH3:13][N:14]([C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)[S:9]([C:6]1[N:7]=[N:8][C:3]([O:2][CH3:1])=[CH:4][CH:5]=1)(=[O:11])=[O:10]
Reactant: COc1ccc(S(=O)(=O)F)nn1
Reactant: CNc1ccccc1
Product: COc1ccc(S(=O)(=O)N(C)c2ccccc2)nn1
Temperature: 100 °C
Yield: 53 %

Procedure:
A mixture was prepared of 6-methoxy-pyridazine-3-sulfonyl fluoride from Example 11 (1.62 mmol, 312 mg) and N-methyl aniline (24.3 mmol, 0.26 mL) and heated at 100° C. for 12 hours. The mixture was then cooled. The resulting solid residue was purified by silica gel chromatography to isolate the title compound (53%, 240 mg); M+, 279.
Reaction SMILES: C(=O)[C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([O:8][CH3:9])[CH:3]=1.[CH:11]([O:16][CH3:17])([O:14][CH3:15])OC.C(=O)(O)[O-].[Na+]>CO>[CH3:17][O:16][CH:11]([O:14][CH3:15])[C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([O:8][CH3:9])[CH:3]=1
Reactant: COC(OC)OC
Reactant: COc1cccc(C=O)c1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CO
Product: COc1cccc(C(OC)OC)c1
Temperature: 25 °C
Reaction time: 22 h

Procedure:
m-Anisaldehyde (204.3 g, 1.5 mol) was placed in a 1 liter flask under an argon atmosphere. Trimethyl orthoformate (191 g, 1.8 mol) was added quickly, followed by 150 ml anhydrous methanol. Amberlyst XN-1010 resin (2.1 g, Aldrich Chemical Co.), which had been previously boiled with methanol was added. The mixture was stirred at room temperature for 22 hours with the exclusion of moisture. Sodium bicarbonate (1.5 g) was added with stirring. After 20 minutes the mixture was filtered under vacuum into a 2 liter flask which was placed on the rotory evaporator with the water bath temperature at 40° C. Over 30 minutes the bath was heated to 80° to produce a clear, colorless oil. With magnetic stirring, the oil was pumped at 65° under vacuum (2 mm Hg) for 30 minutes. The resulting product weighted 272.5 g (99.8%). I.R. (near, cm-1): 2935, 2824, 1598, 1584, 1350, 1258, 1100, 1050, 984, 772. 1HNMR (400 MHz, CDCl3) δ 3.33 (6H, s, OCH3); 3.81 (3H, s, ArOCH3); 5.35 (1H, s, ArCH(OCH3)2 ; 6.87 (1H, br d, 8.1 Hz); 7.00-7.03 (2H, m); 7.27 (1H, t, 8.1 Hz). These data indicated that the product was pure enough for use in the next step and were consistent with the following structure: ##STR27##