Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]1([C:7]2[CH:8]=[N:9][CH:10]=[CH:11][CH:12]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH3:13][Li]>O1CCCC1.CCOCC>[CH3:13][C:10]1[CH:11]=[CH:12][C:7]([C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)=[CH:8][N:9]=1
Reactant: [Li]C
Reactant: c1ccc(-c2cccnc2)cc1
Solvent: C1CCOC1
Solvent: CCOCC
Product: Cc1ccc(-c2ccccc2)cn1
Temperature: 0 °C
Reaction time: 1 h
Yield: 21.3 %

Procedure:
A solution of 3-(phenyl)pyridine (1.55 g, 10 mmol) in tetrahydrofuran (10 ml) was stirred at −78° C. and treated with methyllithium (1.4 M, 7.5 mL, 10 mmol) in ether. The resulting yellow solution was stirred for 1 h, allowed to warm to 0° C., stirred 1 h, quenched with saturated ammonium chloride, and extracted with ether. The combined organic phase was washed with water and with brine, dried (MgSO4), and concentrated in vacuo. The residue was chromatographed (silica gel, 25% ethyl acetate/hexane) to give the title compound (0.36 g).
Reaction SMILES: [OH:1][C:2]1[CH:3]=[CH:4][C:5]([CH3:8])=[N:6][CH:7]=1.[H-].[Na+].[I-].[CH3:12][CH2:13][CH3:14].O>CN(C=O)C>[CH3:12][CH:13]([O:1][C:2]1[CH:3]=[CH:4][C:5]([CH3:8])=[N:6][CH:7]=1)[CH3:14]
Reactant: Cc1ccc(O)cn1
Reactant: CCC
Agent: [H-]
Agent: [I-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: Cc1ccc(OC(C)C)cn1
Temperature: 25 °C
Reaction time: 8 h
Yield: 84 %

Procedure:
5-hydroxy-2-methylpyridine (11.0 g, 100 mmol) was dissolved in N,N′-dimethylformamide (100 mL), added sodium hydride (7.2 g, 150 mmol) and 1-methylethane iodide (12 mL, 121 mmol) under ice-cold conditions, and the mixture was stirred at room temperature overnight. Then, 1-methylethane iodide (4 mL) was added, and the mixture was stirred at 60° C. for 4 hours. The reaction solution was added water, and extracted with diethylether. The organic layer was washed with brine, dried over sodium sulfate, and concentrated in vacuo. The obtained residue was purified by silica-gel column chromatography (hexane/ethyl acetate), and 5-(1-methylethoxy)-2-methylpyridine (12.7 g (yield 84%)) was obtained as a yellow oil.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([OH:11])[C:5](=[CH:9][CH:10]=1)[C:6]([OH:8])=[O:7].C([O-])(=O)C.[Na+].[Br:17]Br>CO>[Br:17][C:10]1[CH:9]=[C:5]([C:6]([OH:8])=[O:7])[C:4]([OH:11])=[CH:3][C:2]=1[Cl:1]
Reactant: O=C(O)c1ccc(Cl)cc1O
Reactant: BrBr
Agent: CC(=O)[O-]
Agent: [Na+]
Solvent: CO
Product: O=C(O)c1cc(Br)c(Cl)cc1O
Temperature: -70 °C
Yield: 50.1 %

Procedure:
Methanol (2.1 liters) was added to 4-chlorosalicylic acid (60 g) and sodium acetate (120 g), and the mixture was cooled to -70° C. and stirred. To this mixture was added dropwise a solution of bromine (55.7 g) in methanol (557 ml) over 1.5 hours. After the reaction mixture was allowed to warm to room temperature, the solvent was distilled off under reduced pressure. The residue was acidified by addition of dilute hydrochloric acid (2 liters). The precipitate was filtered off, dissolved in ethyl acetate, dried over anhydrous magnesium sulfate, and the solvent was concentrated. The deposited crystals were recrystallized from hydrous ethanol to obtain 5-bromo-4-chlorosalicylic acid (43.8 g, mp. 208°-213° C.). According to the same manner as that described in Reference Example 1, by using this compound as the starting compound, 6-bromo-7-chloro-2,2-dimethyl-2H-1,3-benzoxazin-4-one (29.2 g) (Compound A-26) was obtained. The physical properties are shown in Table 1.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:10]=[C:11]2[C:15](=[CH:16][CH:17]=1)[NH:14][CH:13]=[CH:12]2)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[H-].[Na+].Br[CH2:21][C:22]([O:24][CH3:25])=[O:23]>CN(C=O)C>[CH3:25][O:24][C:22](=[O:23])[CH2:21][N:14]1[C:15]2[C:11](=[CH:10][C:9]([O:8][CH2:1][C:2]3[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=3)=[CH:17][CH:16]=2)[CH:12]=[CH:13]1
Reactant: c1ccc(COc2ccc3[nH]ccc3c2)cc1
Reactant: COC(=O)CBr
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COC(=O)Cn1ccc2cc(OCc3ccccc3)ccc21
Temperature: 25 °C
Reaction time: 4.5 h
Yield: 74.1 %

Procedure:
To a solution of 5-benzyloxyindole (1.67 g, 7.489 mmol) in DMF (50 mL) was added sodium hydride (60% dispersion in mineral oil, 389 mg, 9.735 mmol). The resulting suspension was stirred at rt for 1 h at which time methyl bromoacetate (1.26 g, 8.238 mmol) was added. The resulting solution was stirred at rt for 4.5 h. The reaction was quenched with sat. aqueous ammonium chloride solution (25 mL), and diluted with EtOAc (50 mL). The organic layer was washed three times with water. The aqueous layer was extracted with EtOAc again and the combined organic layers were dried over magnesium sulfate, filtered, and concentrated via rotary evaporation. The resulting brown oil was purified on silica gel (hexanes/EtOAc 1:1) to give the title compound as a brownish oil (1.64 g, 74%). LC/MS m/z 296 (M+H)+, RT 3.21 min; 1H NMR (400 MHz, CDCl3) δ 7.35-7.37 (m, 2H), 7.23-7.30 (m, 3H), 7.02-7.08 (m, 2H), 6.95 (d, 1H), 6.87 (dd, 1H), 6.37 (dd, 1H), 5.01 (s, 2H), 4.72 (s, 2H), 3.64 (s, 3H).
Reaction SMILES: [N:1]1[C:9]([NH2:10])=[C:8]2[C:4]([N:5]([CH2:11][C@@H:12]3[O:18][C@H:17]([CH2:19][OH:20])[C@@H:15]([OH:16])[C@H:13]3[OH:14])[CH:6]=[N:7]2)=[N:3][CH:2]=1.[C:21](Cl)(=[O:28])[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1.C(=O)([O-])O.[Na+].C(Cl)(Cl)Cl>N1C=CC=CC=1>[C:21]([NH:10][C:9]1[N:1]=[CH:2][N:3]=[C:4]2[C:8]=1[N:7]=[CH:6][N:5]2[CH2:11][C@@H:12]1[O:18][C@H:17]([CH2:19][OH:20])[C@@H:15]([OH:16])[C@H:13]1[OH:14])(=[O:28])[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1
Reactant: Nc1ncnc2c1ncn2C[C@@H]1O[C@H](CO)[C@@H](O)[C@H]1O
Reactant: O=C(Cl)c1ccccc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: c1ccncc1
Solvent: ClC(Cl)Cl
Product: O=C(Nc1ncnc2c1ncn2C[C@@H]1O[C@H](CO)[C@@H](O)[C@H]1O)c1ccccc1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 102 %

Procedure:
2,5-Anhydro-1-deoxy-1- (adenin-9-yl) -D-allitol (916 mg) was subjected to azeotropic dehydration with anhydrous pyridine and then suspended in 15 ml of anhydrous pyridine. To the suspension was added 2.75 g of benzoyl chloride dropwise under ice-cooling. After the mixture was reacted at room temperature for 2 hours, it was poured into a mixture of 114 g of ice, 9 g of sodium hydrogen carbonate and 100 ml of chloroform and extracted with chloroform. The chloroform layer was concentrated and ethanol/pyridine was added to the residue. Then, 13 ml of 2N-sodium hydroxide solution and 13 ml of ethanol were added under water-cooling and the reaction was carried out at room temperature for 30 minutes. This reaction mixture was neutralized by adding about 13 ml of 2N-hydrochloric acid under cooling and concentrated under reduced pressure. The residue was washed with ether and the aqueous layer was concentrated under reduced pressure. The residue was purified by reversed phase column chromatography (methanol/water) to provide 1.28 g of the desirable compound. m.p. 85°-90° C.
Reaction SMILES: [F:1][C:2]([F:12])([F:11])[C:3]1[NH:8][C:7](=[O:9])[NH:6][C:5](=[O:10])[CH:4]=1.[Br:13]Br>O>[Br:13][C:4]1[C:5](=[O:10])[NH:6][C:7](=[O:9])[NH:8][C:3]=1[C:2]([F:1])([F:11])[F:12]
Reactant: BrBr
Reactant: O=c1cc(C(F)(F)F)[nH]c(=O)[nH]1
Solvent: O
Product: O=c1[nH]c(C(F)(F)F)c(Br)c(=O)[nH]1
Temperature: 25 °C

Procedure:
6-(Trifluoromethyl)uracil (4.0 g., 0.22 mole) was dissolved in 75 ml. water at 70°C. Bromine (3.55 g., 0.022 mole) was added in portions with vigorous stirring. A white precipitate formed almost immediately. The suspension was allowed to cool to room temperature and then chilled before being filtered. The product after air drying weighed 4.75 g. (82.5%) and had a melting point of 231°-234°C. The analytical sample melting point was 236°-240°C. After recrystallization from water.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:37]=[CH:36][C:6]([C:7]([NH:9][C:10]2[C:11]([NH:24][C:25](=[O:35])[C:26]3[CH:31]=[CH:30][C:29]([CH2:32][CH2:33][CH3:34])=[CH:28][CH:27]=3)=[CH:12][C:13]([O:16][Si](C(C)(C)C)(C)C)=[CH:14][CH:15]=2)=[O:8])=[CH:5][CH:4]=1.[F-].C([N+](CCCC)(CCCC)CCCC)CCC>O1CCCC1.O>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]([C:7]([NH:9][C:10]2[C:11]([NH:24][C:25](=[O:35])[C:26]3[CH:31]=[CH:30][C:29]([CH2:32][CH2:33][CH3:34])=[CH:28][CH:27]=3)=[CH:12][C:13]([OH:16])=[CH:14][CH:15]=2)=[O:8])=[CH:36][CH:37]=1
Reactant: CCCc1ccc(C(=O)Nc2cc(O[Si](C)(C)C(C)(C)C)ccc2NC(=O)c2ccc(OC)cc2)cc1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: O
Solvent: C1CCOC1
Product: CCCc1ccc(C(=O)Nc2cc(O)ccc2NC(=O)c2ccc(OC)cc2)cc1
Reaction time: 0.25 h
Yield: 85.6 %

Procedure:
To a solution of N1-(4-methoxybenzoyl)-N2-(4-propylbenzoyl)-4-(tert-butyldimethylsilyloxy)-1,2-benzenediamine (360 mg, 0.69 mmol) in tetrahydrofuran (20 mL) cooled to 0° C. was added a 1 M solution of tetra-n-butylammonium fluoride in tetrahydrofuran (1.4 mL, 1.4 mmol). After 15 min, the reaction mixture was diluted with water and partitioned with ethyl acetate. The organic layer was dried (magnesium sulfate), filtered, and concentrated in vacuo. The residue was chromatographed (silica gel, 10% ethyl acetate/90% methylene chloride to 40% ethyl acetate/60% methylene chloride) to give 239 mg (86%) of the title compound as a white solid.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6](Cl)[CH:5]=[CH:4][N:3]=1.[F:9][C:10]1[CH:11]=[C:12]([NH:17][C:18](=[O:20])[CH3:19])[CH:13]=[CH:14][C:15]=1[OH:16].C([O-])([O-])=O.[K+].[K+]>CC#N>[Cl:1][C:2]1[N:7]=[C:6]([O:16][C:15]2[CH:14]=[CH:13][C:12]([NH:17][C:18](=[O:20])[CH3:19])=[CH:11][C:10]=2[F:9])[CH:5]=[CH:4][N:3]=1
Reactant: CC(=O)Nc1ccc(O)c(F)c1
Reactant: Clc1ccnc(Cl)n1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: CC(=O)Nc1ccc(Oc2ccnc(Cl)n2)c(F)c1
Yield: 78.1 %

Procedure:
A mixture of 2,4-dichloropyrimidine (Aldrich, 1.5 g, 10.0 mmol), N-(3-fluoro-4-hydroxyphenyl)acetamide (0.85 g, 5.0 mmol), K2CO3 (0.76 g, 5.5 mmol), and CH3CN (100 mL) was heated at reflux for 2 h. The mixture was concentrated and the residue partitioned between EtOAc and saturated NaHCO3 solution. The EtOAc phase was washed with sat NaHCO3 solution, brine, dried (MgSO4) and concentrated in vacuo. The crude product was purified by flash chromatography using a gradient form 30% EtOAc in hexanes to 100% EtOAc to give the title compound (1.1 g, 78%) as a white solid. 1H NMR (DMSO-d6) δ 10.22 (s, 1H), 8.63 (d, 1H, J=5.6 Hz), 7.74 (dd, 1H, J=12.6, 2.4 Hz), 7.34-7.26 (m, 3H), 2.01 (s, 3H).
Reaction SMILES: C(OC(N1[CH2:13][CH2:12][N:11]([CH2:14][C:15]2[CH:20]=[CH:19][C:18]([C@@H:21]3[O:30][C:25]4=[N:26][CH:27]=[CH:28][CH:29]=[C:24]4[O:23][CH2:22]3)=[CH:17][CH:16]=2)[CH2:10][CH2:9]1)=O)(C)(C)C.N1CC[CH:34]([CH:37]2[CH2:42][CH2:41][CH:40]([C:43]([OH:45])=[O:44])[CH2:39][CH2:38]2)CC1>>[O:23]1[C:24]2[C:25](=[N:26][CH:27]=[CH:28][CH:29]=2)[O:30][C@@H:21]([C:18]2[CH:19]=[CH:20][C:15]([CH2:14][N:11]3[CH2:10][CH2:9][CH:34]([CH:37]4[CH2:42][CH2:41][CH:40]([C:43]([OH:45])=[O:44])[CH2:39][CH2:38]4)[CH2:13][CH2:12]3)=[CH:16][CH:17]=2)[CH2:22]1
Reactant: CC(C)(C)OC(=O)N1CCN(Cc2ccc([C@H]3COc4cccnc4O3)cc2)CC1
Reactant: O=C(O)C1CCC(C2CCNCC2)CC1
Product: O=C(O)C1CCC(C2CCN(Cc3ccc([C@H]4COc5cccnc5O4)cc3)CC2)CC1

Procedure:
Compound 265 is prepared from Intermediate C and 4-piperidin-4-yl-cyclohexanecarboxylic acid according to General Method H. (LC/MS method 16: ES+ m/z 437.4 [M+H]+, Rt=2.58 min).
Reaction SMILES: [OH:1][NH:2][C:3]([N:5]1[CH2:10][CH2:9][CH:8]([CH:11]2[O:29][C:14]3=[CH:15][N:16]=[C:17]([C:19]4[CH:24]=[CH:23][C:22]([S:25]([CH3:28])(=[O:27])=[O:26])=[CH:21][CH:20]=4)[CH:18]=[C:13]3[CH2:12]2)[CH2:7][CH2:6]1)=[NH:4].[C:30](Cl)(=O)[CH2:31][CH2:32][CH3:33]>>[CH3:28][S:25]([C:22]1[CH:23]=[CH:24][C:19]([C:17]2[CH:18]=[C:13]3[CH2:12][CH:11]([CH:8]4[CH2:7][CH2:6][N:5]([C:3]5[N:4]=[C:30]([CH2:31][CH2:32][CH3:33])[O:1][N:2]=5)[CH2:10][CH2:9]4)[O:29][C:14]3=[CH:15][N:16]=2)=[CH:20][CH:21]=1)(=[O:27])=[O:26]
Reactant: CS(=O)(=O)c1ccc(-c2cc3c(cn2)OC(C2CCN(C(=N)NO)CC2)C3)cc1
Reactant: CCCC(=O)Cl
Product: CCCc1nc(N2CCC(C3Cc4cc(-c5ccc(S(C)(=O)=O)cc5)ncc4O3)CC2)no1

Procedure:
The title compound is prepared from N-hydroxy-4-[5-(4-methanesulfonyl-phenyl)-2,3-dihydro-furo[2,3-c]pyridin-2-yl]-piperidine-1-carboxamidine and butyryl chloride following a procedure analogous to that described in Example 8. LC (method 5): tR=1.30 min; Mass spectrum (ESI+): m/z=469 [M+H]+.
Reaction SMILES: [CH2:1]([C@@H:8]1[CH2:12][O:11][C:10](=[O:13])[N:9]1[C:14](=[O:23])[CH2:15][C:16]1[CH:21]=[CH:20][C:19]([Br:22])=[CH:18][CH:17]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:24][Si]([N-][Si](C)(C)C)(C)C.[Na+].CI>C1COCC1>[CH2:1]([C@@H:8]1[CH2:12][O:11][C:10](=[O:13])[N:9]1[C:14](=[O:23])[C@@H:15]([C:16]1[CH:17]=[CH:18][C:19]([Br:22])=[CH:20][CH:21]=1)[CH3:24])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: C[Si](C)(C)[N-][Si](C)(C)C
Reactant: O=C(Cc1ccc(Br)cc1)N1C(=O)OC[C@H]1Cc1ccccc1
Agent: [Na+]
Solvent: CI
Solvent: C1CCOC1
Product: C[C@@H](C(=O)N1C(=O)OC[C@H]1Cc1ccccc1)c1ccc(Br)cc1
Temperature: -78 °C
Reaction time: 3 h
Yield: 17.9 %

Procedure:
To a solution of 76A (380 mg, 1.01 mmol) in THF (5 mL) at −78° C., was added NaHMDS (1.3 mL, 1.0M, 1.3 mmol), dropwise. The solution was stirred at −78° C. for 3 h. A solution of MeI (0.62 mL, 10 mmol) in 2 mL THF was added. The solution was stirred −78° C. for 3 h, and −40° C. for 1 h. The reaction was quenched with sat. NH4Cl and extracted with EtOAc (3×20 mL). The organic layer washed with brine, dried (Na2SO4), and concentrated. Purification via flash chromatography (0-30% EtOAc in hexanes) gives 76B (70 mg, 18%). MS (ESI) m/z 388.3 (M+H)+.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[C:6]([CH3:8])[CH:5]=[C:4]([CH3:9])[C:3]=1[S:10]([NH:13][CH:14]([CH2:19]O)[C:15]([F:18])([F:17])[F:16])(=[O:12])=[O:11].[H-].[Na+].C1(C)C=CC(S(Cl)(=O)=O)=CC=1>C1COCC1.O>[F:16][C:15]([F:18])([F:17])[CH:14]1[CH2:19][N:13]1[S:10]([C:3]1[C:2]([CH3:1])=[CH:7][C:6]([CH3:8])=[CH:5][C:4]=1[CH3:9])(=[O:12])=[O:11]
Reactant: Cc1cc(C)c(S(=O)(=O)NC(CO)C(F)(F)F)c(C)c1
Agent: Cc1ccc(S(=O)(=O)Cl)cc1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: Cc1cc(C)c(S(=O)(=O)N2CC2C(F)(F)F)c(C)c1
Temperature: 25 °C
Yield: 99.8 %

Procedure:
To a solution of 690 mg (2.22 mmol) of 2,4,6-trimethyl-N-(2,2,2-trifluoro-1-hydroxymethylethyl)benzenesulfonamide in 10 mL of THF was added 180 mg (4.5 mmol) of 60% sodium hydride in mineral oil in several portions followed by 475 mg (2.5 mmol) of p-toluenesulfonyl chloride. The mixture stirred at room temperature over night and was then diluted with water and extracted with three 20 mL portions of ethyl acetate. The combined organic layers were washed with three 20 mL portions of saturated aqueous sodium bicarbonate solution, 20 mL of brine, and two 20 mL portions of saturated aqueous ammonium chloride solution, dried over magnesium sulfate, filtered, and concentrated in vacuo to afford 650 mg (99%) of 2-trifluoromethyl-1-(2,4,6-trimethylbenzenesulfonyl)aziridine as an oil which solidified to a waxy solid upon standing.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:25])[C:4]1[CH:9]=[CH:8][C:7]([O:10][CH:11]2[CH2:16][CH2:15][N:14]([C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])[CH2:13][CH2:12]2)=[CH:6][C:5]=1[OH:24].I[CH3:27].[H-].[Na+]>CN(C=O)C>[CH3:1][O:2][C:3](=[O:25])[C:4]1[CH:9]=[CH:8][C:7]([O:10][CH:11]2[CH2:12][CH2:13][N:14]([C:17]([O:19][C:20]([CH3:22])([CH3:21])[CH3:23])=[O:18])[CH2:15][CH2:16]2)=[CH:6][C:5]=1[O:24][CH3:27]
Reactant: COC(=O)c1ccc(OC2CCN(C(=O)OC(C)(C)C)CC2)cc1O
Reactant: CI
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COC(=O)c1ccc(OC2CCN(C(=O)OC(C)(C)C)CC2)cc1OC

Procedure:
4-(N-t-Butoxycarbonyl-4-piperidinyloxy)-2-hydroxybenzoic acid methyl ester from Step 1 was methylated with iodomethane and sodium hydride in DMF using the procedure in Step 2 of Example 11. The crude product was purified by pressurized silica gel column chromatography using a gradient elution of 20-40% EtOAc-hexane. 4-(N-t-Butoxycarbonyl-4-piperidinyloxy)-2-methoxybenzoic acid methyl ester was obtained as an oil (88% yield).
Reaction SMILES: [F-:1].[Cs+].Cl[C:4]1[CH:5]=[C:6]([CH:9]=[CH:10][N:11]=1)[C:7]#[N:8].O>S1(CCCC1)(=O)=O>[F:1][C:4]1[CH:5]=[C:6]([CH:9]=[CH:10][N:11]=1)[C:7]#[N:8]
Reactant: N#Cc1ccnc(Cl)c1
Reactant: [F-]
Agent: [Cs+]
Solvent: O
Solvent: O=S1(=O)CCCC1
Product: N#Cc1ccnc(F)c1
Temperature: 100 °C
Yield: 89345.7 %

Procedure:
Cesium fluoride (30 g, 0.22 mmol) was slurried in dry sulfolane (150 mL) and concentrated via vacuum distillation at 0.5 mm Hg. After removal of 20% of the solvent, the suspension was cooled and 2-chloroisonicotinonitrile (15 g, 0.11 mmol) was added, then stirred and heated at 100° C. for 20 h. It was cooled to 25° C., poured into H2O (200 mL) and extracted with Et2O. The Et2O phase was washed with H2O, then brine, dried over Na2SO4, filtered and concentrated in vacuo. The residue was purified by column chromatography over SiO2 with CH2Cl2 to give 2-fluoroisonicotinonitrile (12.0 g) as a low-melting colorless solid: EIMS m/z: 122 ([M]+); 1H NMR (CDCl3): δ 8.45 (dd, 1H), 7.47 (dd, 1H), 7.24 (m, 1H).
Reaction SMILES: [Cl:1][C:2]1[C:3]([OH:15])=[CH:4][C:5]2[CH:9]=[C:8]([CH2:10][CH2:11][CH3:12])[S:7][C:6]=2[C:13]=1[Cl:14].Br[CH2:17][C:18]([O:20][CH2:21][CH3:22])=[O:19].C(=O)([O-])[O-].[K+].[K+].CC(=O)CC>CN(C)C=O>[CH2:21]([O:20][C:18](=[O:19])[CH2:17][O:15][C:3]1[C:2]([Cl:1])=[C:13]([Cl:14])[C:6]2[S:7][C:8]([CH2:10][CH2:11][CH3:12])=[CH:9][C:5]=2[CH:4]=1)[CH3:22]
Reactant: CCOC(=O)CBr
Reactant: CCCc1cc2cc(O)c(Cl)c(Cl)c2s1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CCC(C)=O
Product: CCCc1cc2cc(OCC(=O)OCC)c(Cl)c(Cl)c2s1
Reaction time: 72 h
Yield: 58.9 %

Procedure:
A mixture of 11.5 g of 6,7-dichloro-5-hydroxy-2-n-propylbenzo[b]thiophene, 8.82 g of ethyl bromoacetate, 7.52 g of potassium carbonate, 135 ml of 2-butanone and 9 ml of dimethylformamide is stirred for 3 days. The reaction mixture is filtered and 100 ml of water and 100 ml of ether are added. The layers are separated and the aqueous layer is extracted 2 times with 100-ml portions of ether. The combined organic layers are dried, filtered and the filtrate is evaporated to give an oil which crystallizes from hexane. Recrystallization from ether-hexane gives 9 g of ethyl[ (6,7-dichloro-2-n-propylbenzo[b]thien-5-yl)oxy]acetate, mp 62°-63°.
Reaction SMILES: [Br:1][CH2:2][C:3](Br)=[O:4].[NH2:6][C:7]1[N:8]=[N:9][C:10]([CH3:13])=[CH:11][CH:12]=1.C(N(CC)CC)C>C(Cl)(Cl)Cl>[Br:1][CH2:2][C:3]([NH:6][C:7]1[N:8]=[N:9][C:10]([CH3:13])=[CH:11][CH:12]=1)=[O:4]
Reactant: Cc1ccc(N)nn1
Reactant: O=C(Br)CBr
Solvent: CCN(CC)CC
Solvent: ClC(Cl)Cl
Product: Cc1ccc(NC(=O)CBr)nn1
Reaction time: 3.5 h

Procedure:
A solution of bromoacetyl bromide (0.22 mL) in dry CHCl3 (4 mL) was added slowly to a suspension of 3-amino-6-methylpyridazine (0.24 g) and triethylamine (0.47 mL) in dry CHCl3 (45 mL) at room temperature. The brown mixture was allowed to stir for 3.5 hr, then quenched with H2O (1.5 mL) and stirred for 20 mins before concentrating under reduced pressure to a brown solid. The crude product was purified by silica gel chromatography eluting with 1-2% MeOH/dichloromethane. The relevant fractions were combined and evaporated to give the title compound (0.20 g) as a pinkish/beige solid.
Reaction SMILES: C[O:2][C:3](=[O:40])[C:4]1[CH:9]=[CH:8][C:7]([O:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH3:24])=[C:6]([O:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH3:39])[CH:5]=1.[OH-].[K+].O.Cl>C(O)C>[CH2:26]([O:25][C:6]1[CH:5]=[C:4]([CH:9]=[CH:8][C:7]=1[O:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH3:24])[C:3]([OH:40])=[O:2])[CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH3:39]
Reactant: CCCCCCCCCCCCCCOc1ccc(C(=O)OC)cc1OCCCCCCCCCCCCCC
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: CCCCCCCCCCCCCCOc1ccc(C(=O)O)cc1OCCCCCCCCCCCCCC
Temperature: 25 °C
Reaction time: 48 h
Yield: 100.2 %

Procedure:
A mixture of 35 g of product from Example 103, 7.5 g of potassium hydroxide, 30 ml of water and 500 ml of ethyl alcohol is heated at reflux for 24 hours. The reaction is then stirred at room temperature for 48 hours and acidified to pH 2 with concentrated hydrochloric acid. The mixture is concentrated in vacuo, diluted with water and extracted with chloroform. The combined organic layers are washed with saturated sodium chloride, dried and concentrated in vacuo to give 34.2 g of the desired product.
Reaction SMILES: [O:1]([C:3]1[CH:8]=[CH:7][C:6]([C:9]2[N:18]=[C:17]([C:19]([OH:21])=O)[C:16]3[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=3)[N:10]=2)=[CH:5][CH:4]=1)[CH3:2].Cl.[OH:23][C:24]1[C:33]([N:34]([CH3:36])[CH3:35])=[CH:32][CH:31]=[C:30]2[C:25]=1[CH2:26][CH2:27][NH:28][CH2:29]2>>[O:1]([C:3]1[CH:4]=[CH:5][C:6]([C:9]2[N:18]=[C:17]([C:19]([N:28]3[CH2:27][CH2:26][C:25]4[C:30](=[CH:31][CH:32]=[C:33]([N:34]([CH3:36])[CH3:35])[C:24]=4[OH:23])[CH2:29]3)=[O:21])[C:16]3[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=3)[N:10]=2)=[CH:7][CH:8]=1)[CH3:2]
Reactant: COc1ccc(-c2nc(C(=O)O)c3ccccc3n2)cc1
Reactant: CN(C)c1ccc2c(c1O)CCNC2
Agent: Cl
Product: COc1ccc(-c2nc(C(=O)N3CCc4c(ccc(N(C)C)c4O)C3)c3ccccc3n2)cc1
Yield: 14 %

Procedure:
Reaction of 2-(4-methoxylphenyl)quinazoline-4-carboxylic acid with 5-hydroxy-6-dimethylamino-1,2,3,4-tetrahydroisoquinoline hydrochloride gave compound 25 (14% yield) as a brown solid. 1H NMR (300 MHz, CDCl3) δ 2.64 and 2.69 (d, 6H), 2.85 and 3.09 (2t, 2H), 3.59 and 4.20 (2t, 2H), 3.92 (s, 3H), 4.49 and 5.09 (2s, 2H), 6.33 and 6.82 (2d, 1H), 6.96 and 7.15 (2d, 1H), 7.03-7.07 (m, 2H), 7.50-7.60 (m, 1H), 7.86-8.01 (m, 2H), 8.08-8.12 (m, 1H), 8.57-8.63 (m, 2H); MS (ESI) m/z 455 ([M+H]+).
Reaction SMILES: [CH3:1][NH2:2].[Br:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[S:10](Cl)=[O:11].O>ClCCl>[Br:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[S:10]([NH:2][CH3:1])=[O:11]
Reactant: CN
Reactant: O=S(Cl)c1ccccc1Br
Solvent: ClCCl
Solvent: O
Product: CNS(=O)c1ccccc1Br
Temperature: -10 °C
Yield: 82.7 %

Procedure:
Liquified methylamine (36.3 mL, 0.817 mol) was added slowly to a stirred solution of 2-bromobenzenesulfinyl chloride (48.9 g, 0.204 mol) in dichloromethane (489 mL) cooled below -70° C. The reaction mixture was allowed to warm to -10° C. and was then shaken with water (489 mL). The layers were separated, and the dichloromethane layer was washed with water (2×245 mL), dried (Na2SO4), and filtered. Evaporation of the solvent left a pale yellow oil (44.4 g) that mostly crystallized on standing. This was dissolved in dichloromethane and chromatographed on a column of silica gel using 2:1 dichloromethaneether as eluant. Fractions containing product (Rf =0.52, UV) were evaporated to leave 2-bromo-N-methylbenzenesulfinamide as a white crystalline solid (39.5 g) melting at 66°-70° C.
Reaction SMILES: [NH:1]1[CH:5]=[C:4]([C:6]([NH:8][NH2:9])=[O:7])[N:3]=[CH:2]1.[C:10](OC)(OC)(OC)[CH2:11][CH2:12][CH3:13]>C(O)C>[CH2:11]([C:10]1[N:3]2[CH:2]=[N:1][CH:5]=[C:4]2[C:6](=[O:7])[NH:8][N:9]=1)[CH2:12][CH3:13]
Reactant: NNC(=O)c1c[nH]cn1
Reactant: CCCC(OC)(OC)OC
Solvent: CCO
Product: CCCc1n[nH]c(=O)c2cncn12

Procedure:
A mixture of 3.8 gm. of imidazole-4-carboxylic acid hydrazide, 30 ml. of trimethyl orthobutyrate and 150 ml. of ethanol is refluxed overnight. The mixture is evaporated giving a solid which is washed with petroleum ether and filtered. This solid is combined with 100 ml. of diphenyl ether and heated at 240°-250° C. for 15 minutes. The mixture is cooled, petroleum ether is added and the mixture is filtered. The solid is triturated with hot petroleum ether and filtered giving the desired product, m.p. 116°-117° C.