Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([C:23]([CH3:26])([CH3:25])[CH3:24])[S:5][C:6]=1[C:7]([N:9]1[CH2:14][CH2:13][N:12]([CH2:15][CH2:16][N:17]([CH3:19])[CH3:18])[C:11](=[O:20])[C:10]1([CH3:22])[CH3:21])=[O:8].[Cl:27][C:28]1[C:29]([Cl:37])=[C:30]([N:34]=[C:35]=[O:36])[CH:31]=[CH:32][CH:33]=1.C1COCC1>C(OCC)(=O)C>[C:23]([C:4]1[S:5][C:6]([C:7]([N:9]2[CH2:14][CH2:13][N:12]([CH2:15][CH2:16][N:17]([CH3:18])[CH3:19])[C:11](=[O:20])[C:10]2([CH3:21])[CH3:22])=[O:8])=[C:2]([NH:1][C:35]([NH:34][C:30]2[CH:31]=[CH:32][CH:33]=[C:28]([Cl:27])[C:29]=2[Cl:37])=[O:36])[CH:3]=1)([CH3:26])([CH3:25])[CH3:24]
Reactant: O=C=Nc1cccc(Cl)c1Cl
Reactant: CN(C)CCN1CCN(C(=O)c2sc(C(C)(C)C)cc2N)C(C)(C)C1=O
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: CN(C)CCN1CCN(C(=O)c2sc(C(C)(C)C)cc2NC(=O)Nc2cccc(Cl)c2Cl)C(C)(C)C1=O
Temperature: 75 °C
Yield: 66.9 %

Procedure:
A mixture of 4-(4-amino-2-tert-butylthiophene-5-carbonyl)-1-(2-(dimethylamino)ethyl)-3,3-dimethylpiperazin-2-one (0.035 g, 0.092 mmol), dichlorophenyl isocyanate (0.019 g, 0.10 mmol), and THF (2 mL) was heated at 75° C. for 2 hours. The reaction mixture was diluted with ethyl acetate, washed with saturated sodium bicarbonate, dried, the solvent eliminated under vacuum and the crude product was purified by preparative thin layer chromatography (dichloromethane:methanol, 95:5) to afford 0.035 g of 1-(5-tert-butyl-2-(1-(2-(dimethylamino)ethyl)-3,3-dimethyl-2-oxopiperazine-4-carbonyl)thiophen-3-yl)-3-(2,3-dichlorophenyl)urea. 1H NMR (400 MHz, acetone-d6): δ (ppm) 9.57 (bs, 1H); 8.86 (bs, 1H); 8.17 (d, 1H); 7.65 (s, 1H); 7.30 (m, 2H); 3.90 (m, 2H); 3.60 (m, 2H); 3.50 (t, 2H); 2.43 (t, 2H); 2.20 (s, 6H); 1.70 (s, 6H); 1.40 (s, 9H).
Reaction SMILES: [C:1]([N:4]1[CH2:9][CH2:8][C:7](=O)[CH2:6][CH2:5]1)(=[O:3])[CH3:2].C(O)(=O)C.[NH2:15][C:16]1[CH:21]=[C:20]([CH3:22])[CH:19]=[CH:18][C:17]=1[N:23]1[CH:27]=[CH:26][CH:25]=[CH:24]1>C(O)C>[C:1]([N:4]1[CH2:9][CH2:8][C:7]2([NH:15][C:16]3[C:17](=[CH:18][CH:19]=[C:20]([CH3:22])[CH:21]=3)[N:23]3[CH:24]=[CH:25][CH:26]=[C:27]23)[CH2:6][CH2:5]1)(=[O:3])[CH3:2]
Reactant: Cc1ccc(-n2cccc2)c(N)c1
Reactant: CC(=O)N1CCC(=O)CC1
Solvent: CC(=O)O
Solvent: CCO
Product: CC(=O)N1CCC2(CC1)Nc1cc(C)ccc1-n1cccc12
Reaction time: 24 h

Procedure:
8.46 g (0.06 mole) of 1-acetyl-4-piperidone and 3 ml. of glacial acetic acid are added to a solution of 12.0 g (0.06 mole) of 1-(2-amino-4-methyl-phenyl)pyrrole [Example 16(b)] in 160 ml. of absolute ethanol. The solution is refluxed under nitrogen with stirring for 24 hours and cooled. A solid precipitates and is filtered. The solid is recrystallized from absolute ethanol to give white crystals, m.p. 212°-213° C. of 1'-acetyl-4,5-dihydro-7-methylspiro[pyrrolo(1,2-a)quinoxaline-4,4'-piperidine].
Reaction SMILES: [C:1]([OH:12])(=[O:11])[C:2]1[CH:10]=[CH:9][CH:8]=[C:4]([C:5]([OH:7])=[O:6])[CH:3]=1.C([O-])(=O)C1C=CC=C(C([O-])=O)C=1.[K+].[K+].[Ag:27]>>[C:1]([O-:12])(=[O:11])[C:2]1[CH:10]=[CH:9][CH:8]=[C:4]([C:5]([O-:7])=[O:6])[CH:3]=1.[Ag+2:27]
Reactant: O=C(O)c1cccc(C(=O)O)c1
Reactant: [Ag]
Agent: O=C([O-])c1cccc(C(=O)[O-])c1
Agent: [K+]
Product: [Ag+2]

Procedure:
A reaction was carried out in the same manner as illustrated in Example 10 except that 100 g of isophthalic acid was used in place of the phthalic acid used in Example 10, whereby an aqueous solution of potassium isophthalate having a pH value of 10.2 and containing 10.0% by weight of a solid matter was obtained, which was then subjected to a double decomposition reaction conducted in the same manner as illustrated in Example 10 to obtain 230 g of silver isophthalate having a silver content of 51.5% by weight.
Reaction SMILES: [SH:1][C:2]1[CH:7]=[CH:6][N:5]=[CH:4][CH:3]=1.C(N(CC)CC)C.Br[CH2:16][CH2:17][CH2:18][OH:19]>C(Cl)Cl>[OH:19][CH2:18][CH2:17][CH2:16][S:1][C:2]1[CH:7]=[CH:6][N:5]=[CH:4][CH:3]=1
Reactant: Sc1ccncc1
Reactant: OCCCBr
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: OCCCSc1ccncc1
Temperature: 25 °C
Yield: 83.9 %

Procedure:
In 100 ml of methylene chloride were dissolved 11.1 g (100 mmol) of 4-mercaptopyridine and 13.9 ml (100 mmol) of triethylamine, and 9.04 ml (100 mmol) of 3-bromo-1-propanol was added. The mixture was stirred at room temperature for hours. The reaction mixture was washed with a 1N aqueous solution of sodium hydroxide and water and dried. Then the solvent was distilled off. The residue was purified by column chromatography (eluent: ethyl acetate) to obtain 14.2 g of the desired compound (yield: 83.9%, yellow oil).
Reaction SMILES: [O:1]=[C:2]1[C:8]2=[CH:9][C:10]3[CH:11]=[CH:12][C:13]([C:16]([OH:18])=O)=[CH:14][C:15]=3[N:7]2[CH2:6][CH2:5][CH2:4][NH:3]1.F[B-](F)(F)F.N1(OC(=[N+](C)C)N(C)C)C2C=CC=CC=2N=N1.[Cl:41][C:42]1[CH:43]=[C:44]([NH2:48])[CH:45]=[CH:46][CH:47]=1.C(N(CC)CC)C>CN(C=O)C.O>[Cl:41][C:42]1[CH:43]=[C:44]([NH:48][C:16]([C:13]2[CH:12]=[CH:11][C:10]3[CH:9]=[C:8]4[C:2](=[O:1])[NH:3][CH2:4][CH2:5][CH2:6][N:7]4[C:15]=3[CH:14]=2)=[O:18])[CH:45]=[CH:46][CH:47]=1
Reactant: Nc1cccc(Cl)c1
Reactant: O=C(O)c1ccc2cc3n(c2c1)CCCNC3=O
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Solvent: O
Product: O=C(Nc1cccc(Cl)c1)c1ccc2cc3n(c2c1)CCCNC3=O
Reaction time: 0.17 h
Yield: 56.5 %

Procedure:
To a solution of 1-oxo-2,3,4,5-tetrahydro-1H-[1,4]diazepino[1,2-a]indole-8-carboxylic acid (Intermediate J, 49 mg, 0.2 mmol) in DMF (1 mL) is added [(benzotriazol-1-yloxy)-dimethylamino-methylene]dimethyl-ammonium tetrafluoroborate (TBTU) (77 mg, 0.24 mmol) and the reaction is stirred for 10 minutes. The reaction is then treated with 3-chloro-phenylamine (28 mg, 0.22 mmol) followed by triethylamine (0.10 mL, 0.7 mmol) and is stirred for 16 h. The reaction is poured into water (20 mL) and the resulting solid is filtered. The solid is dried, suspended in MTBE (20 mL) and filtered again to afford the title compound (40 mg, 56%) as an off-white solid.
Reaction SMILES: [C:1]([OH:10])(=[O:9])[C:2]1[C:3](=[CH:5][CH:6]=[CH:7][CH:8]=1)[NH2:4].[F:11][C:12]1[CH:19]=[CH:18][C:15]([CH:16]=O)=[CH:14][CH:13]=1.C1(C)C=CC(S(O)(=O)=O)=CC=1.[BH4-].[Na+]>C1(C)C=CC=CC=1>[F:11][C:12]1[CH:19]=[CH:18][C:15]([CH2:16][NH:4][C:3]2[CH:5]=[CH:6][CH:7]=[CH:8][C:2]=2[C:1]([OH:10])=[O:9])=[CH:14][CH:13]=1
Reactant: O=Cc1ccc(F)cc1
Reactant: Nc1ccccc1C(=O)O
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: [BH4-]
Agent: [Na+]
Solvent: Cc1ccccc1
Product: O=C(O)c1ccccc1NCc1ccc(F)cc1
Temperature: 25 °C

Procedure:
A mixture of anthranilic acid (1.37 g, 1.0 mmol), 4-fluorobenzaldehyde (1.24 g, 1.0 mmol), and p-toluenesulfonic acid mohohydrate (0.025 g, 0.13 mmol) in 30 mL of anhydrous toluene was stirred at reflux for 1 h, then cooled to RT and NaBH4 (1.1 g) was added. The mixture was stirred at RT for 30 min, then quenched with MeOH. The volatiles were removed under reduced pressure and the residue was taken up in water. AcOH was added to bring pH to 4, and the mixture was extracted with EtOAc. The combined organic portions were washed with brine, dried over MgSO4, filtered, condensed, and the residue was purified by flash column chromatography to give the titled compound. MS (ES+): 246.0 (M+H)+. Calc'd for C14H12FNO2-245.09.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:8]2[O:9][CH2:10][CH2:11][O:12][C:7]=2[C:6]([C:13]([O:15][CH3:16])=[O:14])=[CH:5][CH:4]=1.[Cl:17]N1C(=O)CCC1=O>C(#N)C>[Cl:17][C:4]1[CH:5]=[C:6]([C:13]([O:15][CH3:16])=[O:14])[C:7]2[O:12][CH2:11][CH2:10][O:9][C:8]=2[C:3]=1[O:2][CH3:1]
Reactant: O=C1CCC(=O)N1Cl
Reactant: COC(=O)c1ccc(OC)c2c1OCCO2
Solvent: CC#N
Product: COC(=O)c1cc(Cl)c(OC)c2c1OCCO2
Temperature: 25 °C
Reaction time: 48 h

Procedure:
A mixture of intermediate (1) (0.118 mol) and N-chlorosuccinimide (0.125 mol) in ACN (350 ml) was stirred at room temperature for two days. The solvent was evaporated and the residue was partitioned between DCM (500 ml) and water (500 ml). The organic layer was separated, dried, filtered and the solvent was evaporated. A part of the residue was crystallized from a mixture of DIPE and ACN, yielding methyl 7-chloro-2,3-dihydro-8-methoxy-1,4-benzodioxin-5-carboxylate (intermediate 2, mp. 99° C.)
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH2:8][C:9]([OH:11])=[O:10].[CH3:12][C:13]1[CH:19]=[CH:18][CH:17]=[C:16]([CH3:20])[C:14]=1[NH2:15]>>[CH3:12][C:13]1[CH:19]=[CH:18][CH:17]=[C:16]([CH3:20])[C:14]=1[NH:15][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH2:8][C:9]([OH:11])=[O:10]
Reactant: Cc1cccc(C)c1N
Reactant: O=C(O)Cc1ccccc1Br
Product: Cc1cccc(C)c1Nc1ccccc1CC(=O)O

Procedure:
In the manner described in example 3, 2-bromophenylacetic acid was condensed with 2,6-dimethylaniline to yield 2-[(2,6-dimethylphenyl] amino] phenylacetic acid.
Reaction SMILES: [C:1]([C:5]1[CH:10]=[CH:9][C:8]([C:11](=O)[CH2:12][CH2:13][C:14]([C:16]2[CH:21]=[CH:20][C:19]([C:22]([CH3:25])([CH3:24])[CH3:23])=[CH:18][CH:17]=2)=O)=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2].[CH3:27][Si:28]([CH3:37])([CH3:36])[CH2:29][CH2:30][O:31][C:32]([NH:34][NH2:35])=[O:33].C1(C)C=CC(S(O)(=O)=O)=CC=1>C1(C)C=CC=CC=1>[CH3:27][Si:28]([CH3:37])([CH3:36])[CH2:29][CH2:30][O:31][C:32](=[O:33])[NH:34][N:35]1[C:11]([C:8]2[CH:9]=[CH:10][C:5]([C:1]([CH3:4])([CH3:3])[CH3:2])=[CH:6][CH:7]=2)=[CH:12][CH:13]=[C:14]1[C:16]1[CH:21]=[CH:20][C:19]([C:22]([CH3:25])([CH3:24])[CH3:23])=[CH:18][CH:17]=1
Reactant: CC(C)(C)c1ccc(C(=O)CCC(=O)c2ccc(C(C)(C)C)cc2)cc1
Reactant: C[Si](C)(C)CCOC(=O)NN
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: Cc1ccccc1
Product: CC(C)(C)c1ccc(-c2ccc(-c3ccc(C(C)(C)C)cc3)n2NC(=O)OCC[Si](C)(C)C)cc1
Temperature: 25 °C

Procedure:
A solution of 1,4-bis-(4-tert-butyl-phenyl)-butane-1,4-dione (377 mg, 1.08 mmol) in toluene (3 mL) was treated with hydrazinecarboxylic acid 2-trimethylsilanyl-ethyl ester (212 mg, 1.18 mmol) and p-toluene sulfonic acid (11.3 mg). The resulting solution was heated to reflux under Ar for 1.5 h, then cooled to rt and concentrated in vacuo to provide crude [2,5-Bis-(4-tert-butyl-phenyl)-pyrrol-1-yl]-carbamic acid 2-trimethylsilanyl-ethyl ester. The residue was not purified, but was deprotected immediately as follows.
Reaction SMILES: [Br:1][C:2]1[CH:8]=[C:7]([Br:9])[CH:6]=[CH:5][C:3]=1[NH2:4].[H-].[Na+].Cl[C:13]1[C:14](=[O:25])[N:15]([CH:20]([CH2:23][CH3:24])[CH2:21][CH3:22])[CH:16]=[C:17]([Cl:19])[N:18]=1>C1(C)C=CC=CC=1>[Br:1][C:2]1[CH:8]=[C:7]([Br:9])[CH:6]=[CH:5][C:3]=1[NH:4][C:13]1[C:14](=[O:25])[N:15]([CH:20]([CH2:23][CH3:24])[CH2:21][CH3:22])[CH:16]=[C:17]([Cl:19])[N:18]=1
Reactant: CCC(CC)n1cc(Cl)nc(Cl)c1=O
Reactant: Nc1ccc(Br)cc1Br
Agent: [H-]
Agent: [Na+]
Solvent: Cc1ccccc1
Product: CCC(CC)n1cc(Cl)nc(Nc2ccc(Br)cc2Br)c1=O
Yield: 44.7 %

Procedure:
2,4-Dibromoaniline (500 mg), toluene (8 mL), and sodium hydride (60% in oil, 398 mg) were stirred for 10 minutes at room temperature and then 3,5-dichloro-1-(1-ethylpropyl)-2(1H)-pyrazinone (468 mg, Example 1, part B) was added. The reaction was heated at reflux 3 hours, cooled, and quenched with water (50 mL). The mixture was extracted with ethyl acetate (100 mL), which was washed with brine, then dried and concentrated. The crude product was chromatographed on silica gel using ethyl acetate/hexane (1:19) affording 400 mg of material, which was crystallized from ether/hexane to give the title compound (240 mg). Elemental analysis: calcd. for C15H16N3OClBr2: C, 40.07; H, 3.597; N, 9.356; Cl, 7.895; Br, 35.55. Found: C, 40.41; H, 3.49; N, 9.34; Cl, 8.27; Br, 35.71.
Reaction SMILES: [N:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][C:2]=1[CH2:11][O:12][C:13]1[CH:14]=[C:15]([CH:27]=[CH:28][CH:29]=1)[C:16]([NH:18][C:19]1[CH:20]=[C:21]([CH:24]=[CH:25][CH:26]=1)[C:22]#[N:23])=[O:17].[N-:30]=[N+:31]=[N-:32].[Na+].Cl.N1C=CC=CC=1.O>CN(C=O)C>[N:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][C:2]=1[CH2:11][O:12][C:13]1[CH:14]=[C:15]([CH:27]=[CH:28][CH:29]=1)[C:16]([NH:18][C:19]1[CH:20]=[C:21]([C:22]2[NH:32][N:31]=[N:30][N:23]=2)[CH:24]=[CH:25][CH:26]=1)=[O:17]
Reactant: N#Cc1cccc(NC(=O)c2cccc(OCc3ccc4ccccc4n3)c2)c1
Reactant: [N-]=[N+]=[N-]
Agent: Cl
Agent: [Na+]
Solvent: c1ccncc1
Solvent: CN(C)C=O
Solvent: O
Product: O=C(Nc1cccc(-c2nnn[nH]2)c1)c1cccc(OCc2ccc3ccccc3n2)c1
Temperature: 100 °C

Procedure:
A mixture of 10 mmol of 3-(3-(2-quinolinylmethyloxy)benzoylamino)benzonitrile, 50 mmol of sodium azide, and 50 mmol of pyridine HCl in 30 ml of DMF is heated at 100° C. for 2 days. The reaction mixture is poured into water, and the product is collected on a filter. Recrystallization from ethyl acetate and DMF gives 5-(3-(3-(2-quinolinylmethyloxy)benzoylamino)phenyl)tetrazole.
Reaction SMILES: CC1C=CC(S(O[CH2:12][CH:13]2[O:17][C:16]3[C:18]4[CH2:19][CH2:20][CH2:21][C:22]=4[C:23]([Cl:25])=[CH:24][C:15]=3[CH2:14]2)(=O)=O)=CC=1.[N-:26]=[N+:27]=[N-:28].[Na+]>>[Cl:25][C:23]1[C:22]2[CH2:21][CH2:20][CH2:19][C:18]=2[C:16]2[O:17][CH:13]([CH2:12][N:26]=[N+:27]=[N-:28])[CH2:14][C:15]=2[CH:24]=1
Reactant: Cc1ccc(S(=O)(=O)OCC2Cc3cc(Cl)c4c(c3O2)CCC4)cc1
Reactant: [N-]=[N+]=[N-]
Agent: [Na+]
Product: [N-]=[N+]=NCC1Cc2cc(Cl)c3c(c2O1)CCC3

Procedure:
Treatment of (±)-(5-chloro-3,6,7,8-tetrahydro-2H-indeno[4,5-b]furan-2-yl)methyl 4-methylbenzenesulfonate (1.4 g, 3.70 mmol) with sodium azide (0.96 g, 14.78 mmol) generally according to the procedure described for Intermediate 24 gave (±)-(5-chloro-3,6,7,8-tetrahydro-2H-indeno[4,5-b]furan-2-yl)methyl azide as a crude oil. Treatment of the azide with sulfided platinum on carbon (5 wt. %, 0.15 g) generally according to the procedure described for Example 2 provided 0.74 g (77%) of (±)-1-(5-chloro-3,6,7,8-tetrahydro-2H-indeno[4,5-b]furan-2-yl)methanamine as a white solid, hydrochloride salt. mp 270° C. (dec); Anal. calcd. for C12H14ClNOHCl: C, 55.4; H, 5.81; N, 5.38. Found: C, 55.4; H, 5.8; N, 4.91.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([S:9]([C:12]([CH2:20][C:21]#[C:22][CH3:23])([CH2:16][C:17]#[C:18][CH3:19])[C:13](O)=[O:14])(=[O:11])=[O:10])=[CH:5][CH:4]=1.Cl.[NH2:25][OH:26]>>[OH:26][NH:25][C:13](=[O:14])[C:12]([S:9]([C:6]1[CH:7]=[CH:8][C:3]([O:2][CH3:1])=[CH:4][CH:5]=1)(=[O:11])=[O:10])([CH2:20][C:21]#[C:22][CH3:23])[CH2:16][C:17]#[C:18][CH3:19]
Reactant: CC#CCC(CC#CC)(C(=O)O)S(=O)(=O)c1ccc(OC)cc1
Reactant: NO
Agent: Cl
Product: CC#CCC(CC#CC)(C(=O)NO)S(=O)(=O)c1ccc(OC)cc1
Yield: 89 %

Procedure:
2-(4-Methoxy-benzenesulfonyl)-2-but-2-ynyl-hex-4-ynoic acid hydroxyamide was prepared according to the method as outlined in example 1. Starting from 2-(4-methoxy-benzenesulfonyl)-2-but-2-ynyl-hex-4-ynoic acid (0.27 g, 0.81 mmol) and hydroxylamine hydrochloride (0.70 g, 10 mmol), 0.23 g of the product was isolated. Yield 89%; white solid; mp 135-137° C.; MS: 349.9 (M+H)+1; 1H NMR (300 MHz, DMSO-d6) δ 1.67 (s, 6H), 2.70 -3.10 (m, 4H), 3.88 (s, 3H), 7.15 (d, J=10.0 Hz, 2H), 7.71 (d, J=10.0 Hz, 2H), 9.20 (brs, 1H), 10.90 (brs, 1H); IR (KBr, cm-1): 3301 s, 3161 m, 2922 m, 1640 m, 1595 s, 1500 m.
Reaction SMILES: [S:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[NH:3][CH2:2]1.NC1C=CC=CC=1S.C=O.[C:20]([C:22]1[CH:23]=[C:24]([CH:28]=[C:29]([CH2:33][CH3:34])[C:30]=1[O:31][CH3:32])[C:25](Cl)=[O:26])#[N:21]>ClCCl.C(N(CC)CC)C>[C:20]([C:22]1[CH:23]=[C:24]([CH:28]=[C:29]([CH2:33][CH3:34])[C:30]=1[O:31][CH3:32])[C:25]([N:3]1[C:4]2[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=2[S:1][CH2:2]1)=[O:26])#[N:21]
Reactant: CCc1cc(C(=O)Cl)cc(C#N)c1OC
Reactant: c1ccc2c(c1)NCS2
Agent: C=O
Agent: Nc1ccccc1S
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCc1cc(C(=O)N2CSc3ccccc32)cc(C#N)c1OC
Temperature: 25 °C
Reaction time: 1.5 h

Procedure:
2,3-dihydro-1,3-benzothiazole synthesized from 2-aminobenzenethiol (318 mg) and 37% formalin (0.21 mL) in the same manner as in Example 1 was dissolved in dichloromethane (6 mL), and triethylamine (0.71 mL) and 3-cyano-5-ethyl-4-methoxybenzoyl chloride (387 mg) were added to the solution, and then the mixture was stirred at room temperature for 1.5 hours. The solvent was distilled off under reduced pressure and water was added, and then the mixture was extracted with ethyl acetate. The organic layer was washed with 1N hydrochloric acid, 1N sodium hydroxide and saturated brine, and then dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure and the obtained residue was purified by silica gel column chromatography (n-hexane:ethyl acetate=6:1) to obtain the title compound (498 mg) as a yellow oily substance.
Reaction SMILES: Cl[C:2]1[N:3]=[C:4]([NH:21][C:22]2[CH:30]=[CH:29][CH:28]=[C:27]([F:31])[C:23]=2[C:24](N)=[O:25])[C:5]2[CH:10]=[CH:9][N:8]([S:11]([C:14]3[CH:19]=[CH:18][C:17]([CH3:20])=[CH:16][CH:15]=3)(=[O:13])=[O:12])[C:6]=2[N:7]=1.[CH3:32][N:33]([CH2:35][C:36]([N:38]1[C:47]2[C:42](=[CH:43][C:44]([O:49][CH3:50])=[C:45]([NH2:48])[CH:46]=2)[CH2:41][CH2:40][CH2:39]1)=[O:37])[CH3:34].Cl.O1CCOCC1>C(O)C(F)(F)F.C1COCC1.[I-].[K+]>[CH3:32][N:33]([CH3:34])[CH2:35][C:36]([N:38]1[C:47]2[C:42](=[CH:43][C:44]([O:49][CH3:50])=[C:45]([NH:48][C:2]3[N:3]4[C:4](=[N:21][C:22]5[C:23]([C:24]4=[O:25])=[C:27]([F:31])[CH:28]=[CH:29][CH:30]=5)[C:5]4[CH:10]=[CH:9][N:8]([S:11]([C:14]5[CH:19]=[CH:18][C:17]([CH3:20])=[CH:16][CH:15]=5)(=[O:13])=[O:12])[C:6]=4[N:7]=3)[CH:46]=2)[CH2:41][CH2:40][CH2:39]1)=[O:37]
Reactant: COc1cc2c(cc1N)N(C(=O)CN(C)C)CCC2
Reactant: Cc1ccc(S(=O)(=O)n2ccc3c(Nc4cccc(F)c4C(N)=O)nc(Cl)nc32)cc1
Agent: Cl
Agent: [I-]
Agent: [K+]
Solvent: C1COCCO1
Solvent: C1CCOC1
Solvent: OCC(F)(F)F
Product: COc1cc2c(cc1Nc1nc3c(ccn3S(=O)(=O)c3ccc(C)cc3)c3nc4cccc(F)c4c(=O)n13)N(C(=O)CN(C)C)CCC2
Yield: 68.7 %

Procedure:
To a suspension of 2-({2-chloro-7-[(4-methylphenyl)sulfonyl]-7H-pyrrolo[2,3-d]pyrimidin-4-yl}amino)-6-fluorobenzamide (5.0 g, 10.87 mmol), 1-[(dimethylamino)acetyl]-6-(methyloxy)-1,2,3,4-tetrahydro-7-quinolinamine (3.44 g, 13.05 mmol), and potassium iodide (0.090 g, 0.544 mmol) in trifluroethanol (250 ml) was added 4M HCl/dioxane (10.87 ml, 43.5 mmol). The reaction was heated overnight in a pressure vessel equipped with a threaded teflon cap. The reaction was diluted with THF (300 ml) and washed with saturated NaHCO3 (300 ml). The organic layer was removed, concentrated on rotovap, solids triturated from ethyl acetate/hexanes, and dried under house vacuum prior to next step to afford 5-{[1-(N,N-dimethylglycyl)-6-(methyloxy)-1,2,3,4-tetrahydro-7-quinolinyl]amino}-8-fluoro-3-[(4-methylphenyl)sulfonyl]pyrrolo[2′,3′:4,5]pyrimido[6,1-b]quinazolin-7(3H)-one (5.0 g, 68%). ESIMS (M+H)+=670.
Reaction SMILES: [F:1][CH:2]([F:25])[C:3]1[N:8]2[N:9]=[CH:10][C:11]([C:12]([OH:14])=O)=[C:7]2[N:6]=[C:5]([C:15]2[CH:20]=[CH:19][C:18]([C:21]([F:24])([F:23])[F:22])=[CH:17][CH:16]=2)[CH:4]=1.[NH2:26][C:27]1[CH:28]=[C:29]([S:33]([NH:36][CH2:37][CH:38]([CH3:40])[CH3:39])(=[O:35])=[O:34])[CH:30]=[CH:31][CH:32]=1>>[CH2:37]([NH:36][S:33]([C:29]1[CH:28]=[C:27]([NH:26][C:12]([C:11]2[CH:10]=[N:9][N:8]3[C:3]([CH:2]([F:25])[F:1])=[CH:4][C:5]([C:15]4[CH:20]=[CH:19][C:18]([C:21]([F:23])([F:24])[F:22])=[CH:17][CH:16]=4)=[N:6][C:7]=23)=[O:14])[CH:32]=[CH:31][CH:30]=1)(=[O:35])=[O:34])[CH:38]([CH3:40])[CH3:39]
Reactant: CC(C)CNS(=O)(=O)c1cccc(N)c1
Reactant: O=C(O)c1cnn2c(C(F)F)cc(-c3ccc(C(F)(F)F)cc3)nc12
Product: CC(C)CNS(=O)(=O)c1cccc(NC(=O)c2cnn3c(C(F)F)cc(-c4ccc(C(F)(F)F)cc4)nc23)c1

Procedure:
The title compound was prepared from 7-difluoromethyl-5-(4-trifluoromethyl-phenyl)-pyrazolo[1,5-a]pyrimidine-3-carboxylic acid (example C.1) and 3-amino-N-isobutyl-benzenesulfonamide [CAS 608523-95-1] according to general procedure II. Yellow solid. MS (ISP) 566.2 [(M−H)−]; mp 186° C.
Reaction SMILES: Cl.[NH2:2][CH:3]([C:9]1[CH:14]=[CH:13][C:12]([O:15][CH3:16])=[C:11]([O:17][CH3:18])[CH:10]=1)[CH2:4][C:5]([O:7][CH3:8])=[O:6].C(N(CC)CC)C.[N+:26]([C:29]1[CH:37]=[CH:36][C:32]([C:33](Cl)=[O:34])=[CH:31][CH:30]=1)([O-:28])=[O:27]>O1CCCC1>[N+:26]([C:29]1[CH:30]=[CH:31][C:32]([C:33]([NH:2][CH:3]([C:9]2[CH:14]=[CH:13][C:12]([O:15][CH3:16])=[C:11]([O:17][CH3:18])[CH:10]=2)[CH2:4][C:5]([O:7][CH3:8])=[O:6])=[O:34])=[CH:36][CH:37]=1)([O-:28])=[O:27]
Reactant: O=C(Cl)c1ccc([N+](=O)[O-])cc1
Reactant: COC(=O)CC(N)c1ccc(OC)c(OC)c1
Agent: Cl
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: COC(=O)CC(NC(=O)c1ccc([N+](=O)[O-])cc1)c1ccc(OC)c(OC)c1
Reaction time: 0.25 h
Yield: 95.8 %

Procedure:
To an ice bath cooled stirred suspension of methyl 3-amino-3-(3,4-dimethoxyphenyl)propionate hydrochloride(1.38 grams, 5.00 mmol) and triethylamine (1.5 milliliters, 10.8 mmol) in 25 milliliters of tetrahydrofuran was added 4-nitrobenzoyl chloride (0.928 grams, 5.00 mmol) in a single portion. After 15 minutes, the cooling bath was removed and the reaction mixture stirred for 45 minutes. The reaction mixture was then diluted with 50 milliliters of water. The reaction slurry was filtered and the solid washed with water, air-dried, and then dried in vacuo (60 C, <1 mm) to afford 1.86 grams (94%) of the product as a yellow powder: 1H NMR (CDCl3 /TMS, 250 MHz) δ 8.27 (d, J=8.8 Hz, 2 H), 7.98 (d, J=8.8 Hz, 2 H), 7.77 (d, J=8.1 Hz, 1 H, NH), 6.95-6.75 (m, 3 H, Ar), 5.55 (m, 1 H, CH), 3.86 & 3.85 (2 s, 6 H, 2 OCH3), 3.68 (s, 3 H, CO2 CH3), 3.00 (m, 2 H, CH2); 13C NMR (CDCl3 /TMS) δ 172.2, 164.4, 149.6, 1491, 148.7, 139.7, 132.6, 128.2, 123.8, 118.1, 111.2, 109.9, 55.9, 55.8, 52.0, 50.0, 39.3.
Reaction SMILES: [CH:1](/[C:9]1[C:18]2[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=2)[C:12]([C:19]([O:21][CH3:22])=[O:20])=[CH:11][CH:10]=1)=C\C1C=CC=CC=1.BrC1C2C(=CC=CC=2)C(C(O)=[O:35])=CC=1.S(=O)(=O)(O)O.C1(/C=C/B(O)O)C=CC=CC=1.C([O-])(O)=O.[Na+]>CCO.C1(C)C=CC=CC=1.[Pd].ClCCl.CO.CO>[CH:1]([C:9]1[C:18]2[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=2)[C:12]([C:19]([O:21][CH3:22])=[O:20])=[CH:11][CH:10]=1)=[O:35]
Reactant: COC(=O)c1ccc(/C=C/c2ccccc2)c2ccccc12
Reactant: O=C(O)c1ccc(Br)c2ccccc12
Agent: [Pd]
Agent: O=C([O-])O
Agent: O=S(=O)(O)O
Solvent: Cc1ccccc1
Solvent: CO
Solvent: ClCCl
Product: COC(=O)c1ccc(C=O)c2ccccc12

Procedure:
In Scheme 1, intermediate (2), (E)-methyl 4-styryl-1-naphthoate can be prepared by reacting commercially available 4-bromo naphthoic acid (1, Combi Blocks, San Diego, Calif.) with methanol in the presence of catalytic sulfuric acid followed by coupling with trans-2-phenylvinyl-boronic acid in EtOH/toluene with a palladium source (e.g., Pd(dppf2)Cl2) and an inorganic base such as NaHCO3. Ozonolysis can be performed on intermediate 2 in a solvent system such as dichloromethane/MeOH to provide the aldehyde 3, methyl 4-formyl-1-naphthoate. The oxime, (E/Z)-methyl 4-((hydroxyimino)methyl)-1-naphthoate (4) can be synthesized by reacting hydroxylamine hydrochloric acid with the precursor aldehyde (3) in a protic solvent such as ethanol (EtOH). The oxime is converted to the isoxazoline in a two step, one reaction pot procedure. Conversion of the oxime to the chloro-oxime with N-chlorosuccinamide in DMF and subsequent cyclization with the aryl olefin 5 (as shown below in Scheme 3A/3B) affords the desired isoxazoline intermediate 6 compounds. Saponification of the intermediate 6 compounds using a base such as LiOH or NaOH in a solvent system such as dioxane/water can be used to afford the naphthoic acid compounds (7) after acidic work-up.