Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([N:3]=[C:4]([C:9]1[CH:14]=[CH:13][N:12]=[CH:11][CH:10]=1)OC(C)C)#[N:2].[C:15]1([S:21][CH2:22][CH2:23][NH2:24])[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1>CO>[C:1]([NH:3][C:4]([C:9]1[CH:10]=[CH:11][N:12]=[CH:13][CH:14]=1)=[N:24][CH2:23][CH2:22][S:21][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)#[N:2]
Reactant: NCCSc1ccccc1
Reactant: CC(C)OC(=NC#N)c1ccncc1
Solvent: CO
Product: N#CNC(=NCCSc1ccccc1)c1ccncc1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
Isopropyl N-cyano-4-pyridinecarboximidate (0.50 g, 2.6 mmol) was dissolved in methanol (5 ml), and 2-phenylthioethylamine (0.49 g, 3.2 mmol) was added. The mixture was stirred at room temperature for 2 hours. After the reaction was completed, the reaction solution was concentrated under reduced pressure, and the residual concentrate was subjected to chromatography on a silica gel column (WAKO GEL C-200, 10 g) eluting with chloroform-methanol (50:1). The eluted fractions were concentrated under reduced pressure and crystallized from diethyl ether to give the title compound (0.49 g, 1.7
Reaction SMILES: Br[C:2]1[CH:8]=[C:7]([C:9]([F:12])([F:11])[F:10])[C:6]([N+:13]([O-:15])=[O:14])=[CH:5][C:3]=1[NH2:4].CCN(CC)CC.[C:23]([Si:25]([CH3:28])([CH3:27])[CH3:26])#[CH:24]>C1(C)C=CC=CC=1.O.[Cu]I.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[N+:13]([C:6]1[C:7]([C:9]([F:12])([F:11])[F:10])=[CH:8][C:2]([C:24]#[C:23][Si:25]([CH3:28])([CH3:27])[CH3:26])=[C:3]([CH:5]=1)[NH2:4])([O-:15])=[O:14]
Reactant: C#C[Si](C)(C)C
Reactant: Nc1cc([N+](=O)[O-])c(C(F)(F)F)cc1Br
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Solvent: CCN(CC)CC
Solvent: Cc1ccccc1
Solvent: O
Product: C[Si](C)(C)C#Cc1cc(C(F)(F)F)c([N+](=O)[O-])cc1N
Temperature: 70 °C
Yield: 56.5 %

Procedure:
To a solution of 2-bromo-5-nitro-4-(trifluoromethyl)aniline (10.0 g, 35.1 mmol) in toluene/H2O (100 mL, 1:1, v/v) was added CuI (0.4 g, 2.10 mmol), Et3N (9.5 mL, 68.16 mmol), Pd(PPh3)2Cl2 (5.0 g, 7.12 mmol) and ethynyltrimethylsilane (5.2 g, 53 mmol) successively under an atmosphere of nitrogen at room temperature. The reaction mixture was transferred to a sealed pressure flask and heated at 70° C. for 10 h. The reaction mixture was cooled down to room temperature, filtered, evaporated in vacuo and purified by silica gel column chromatography (1 to 20% EtOAc in petroleum ether as eluant) to afford 5-nitro-4-(trifluoromethyl)-2-((trimethylsilyl)ethynyl)aniline (6.0 g, 57%) as yellow solid. 1H NMR (300 MHz, CDCl3): δ 7.67 (s, 1H), 7.13 (s, 1H), 4.86 (br s, 2H), 0.29 (s, 9H).
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[O:6][C:7]([C:10]([OH:12])=[O:11])=[CH:8][CH:9]=1)=[O:4].[H][H]>C(OCC)(=O)C.[Rh]>[CH3:1][O:2][C:3]([CH:5]1[O:6][CH:7]([C:10]([OH:12])=[O:11])[CH2:8][CH2:9]1)=[O:4]
Reactant: [H][H]
Reactant: COC(=O)c1ccc(C(=O)O)o1
Agent: [Rh]
Solvent: CCOC(C)=O
Product: COC(=O)C1CCC(C(=O)O)O1
Yield: 100.2 %

Procedure:
A mixture of furan-2,5-dicarboxylic acid monomethyl ester (1.95 g) and 5% rhodium on carbon (400 mg) in ethyl acetate (50 ml) was hydrogenated until hydrogen uptake ceased. The catalyst was filtered off and washed with ethyl acetate. The combined filtrates were evaporated to give (2.00 g) of the title compound: νmax (film) 3170, 1765 and 1720 cm-1 ; δH (CDCl3) 1.95-2.65 (4 H, m), 3.85 (3 H, s) and 4.55-4.8 (2 H, m).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([CH2:9][CH2:10]C(OC)=O)=[CH:5][CH:4]=1.[CH3:15][O:16][C:17]1[CH:25]=[CH:24][C:20]([C:21](Cl)=[O:22])=[CH:19][CH:18]=1.[C:26]([O:29][CH2:30]C)(=[O:28])C>[N+](C1C=CC=CC=1)([O-])=O>[CH3:15][O:16][C:17]1[CH:25]=[CH:24][C:20]([C:21]([C:8]2[CH:7]=[C:6]([CH:9]([CH3:10])[C:26]([O:29][CH3:30])=[O:28])[CH:5]=[CH:4][C:3]=2[O:2][CH3:1])=[O:22])=[CH:19][CH:18]=1
Reactant: COC(=O)CCc1ccc(OC)cc1
Reactant: COc1ccc(C(=O)Cl)cc1
Reactant: CCOC(C)=O
Solvent: O=[N+]([O-])c1ccccc1
Product: COC(=O)C(C)c1ccc(OC)c(C(=O)c2ccc(OC)cc2)c1
Temperature: 0 °C
Reaction time: 3 h

Procedure:
The methyl 3-(4-methoxyphenyl)propionate (10.8 g, 55.6 mmol) prepared in Example 1 and 4-methoxybenzoyl chloride (11.4 g, 66.8 mmol) were dissolved in nitrobenzene (200 ml). To the ice-chilled solution, A1C13 (26.7 g, 200.3 mmol) was added in 6 portions with vigorous stirring over a period of 3 hours. After all portions of A1C13 were added, stirring was continued for an additional 1 hour. The reaction mixture was poured into a beaker containing a mixture of ice and 120 ml of 1N CHl and stirred vigorously. The mixture was transferred into a separating funnel, which was shaken well after the addition of ethyl acetate. The organic layer in the solution was washed twice with a saturated aqueous solution of sodium bicarbonate, then twice with a saturated aqueous solution of sodium chloride. After drying over unhydrous sodium sulfate, the solvent was removed in vacuo. The residue was purified by flash column chromatography using 30% ethyl acetate/hexane to produce a pale yellow oil.
Reaction SMILES: [Cl:1][C:2]1[N:3]([CH3:14])[C:4]2[C:9]([C:10]=1[C:11]([OH:13])=O)=[CH:8][CH:7]=[CH:6][CH:5]=2.O=S(Cl)Cl.[CH3:19][NH:20][C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1>>[CH3:19][N:20]([C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)[C:11]([C:10]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[N:3]([CH3:14])[C:2]=1[Cl:1])=[O:13]
Reactant: CNc1ccccc1
Reactant: Cn1c(Cl)c(C(=O)O)c2ccccc21
Solvent: O=S(Cl)Cl
Product: CN(C(=O)c1c(Cl)n(C)c2ccccc12)c1ccccc1
Yield: 67 %

Procedure:
Similar reaction of 2-chloro-1-methylindole-3-carboxylic acid [XXI] with SOCl2 and N-methylaniline gave N-methyl-N-phenyl 2-chloro-1-methylindole-3-carboxamide [XXII: R6 =Me; R7 =Ph] (67% yield); mp (Me2CO/water) 163° C.
Reaction SMILES: [Cl:1][C:2]1[CH:23]=[CH:22][C:5]([CH2:6][NH:7][C:8]([C:10]2[N:11]=[N:12][C:13]3[C:18]([C:19]=2[OH:20])=[CH:17][C:16](I)=[CH:15][CH:14]=3)=[O:9])=[CH:4][CH:3]=1.CCN(CC)CC.[CH3:31][OH:32].Cl.CN([CH:37]=[O:38])C>Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[Cl:1][C:2]1[CH:23]=[CH:22][C:5]([CH2:6][NH:7][C:8]([C:10]2[N:11]=[N:12][C:13]3[C:18]([C:19]=2[OH:20])=[CH:17][C:16]([C:31]([O:38][CH3:37])=[O:32])=[CH:15][CH:14]=3)=[O:9])=[CH:4][CH:3]=1
Reactant: CN(C)C=O
Reactant: O=C(NCc1ccc(Cl)cc1)c1nnc2ccc(I)cc2c1O
Reactant: CO
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: Cl
Solvent: CCN(CC)CC
Product: COC(=O)c1ccc2nnc(C(=O)NCc3ccc(Cl)cc3)c(O)c2c1
Temperature: 70 °C
Yield: 64 %

Procedure:
A flame-dried flask is charged with N-(4-chlorobenzyl)-4-hydroxy-6-iodo-3-cinnolinecarboxamide (0.23 g, 0.52 mmol), NEt3 (0.15 mL, 1.08 mmol), Pd(PPh3)2Cl2 (0.071 g, 0.10 mmol), methanol (0.85 mL, 20.98 mmol), and anhydrous DMF (5 mL). The reaction is placed under a CO balloon atmosphere and heated at 70° C. for 5 h at which point TLC shows disappearance of starting material. The reaction is cooled to room temperature and poured into 40 mL 1N HCl. The resulting solid is filtered and dried. The crude solid is dissolved in CH2Cl2/MeOH and adsorbed onto silica. Purification by chromatography (eluent 1% MeOH/CH2Cl2 (1 L), 1.5% MeOH/CH2Cl2 (1 L), 2% MeOH/CH2Cl2 (3L), 3% MeOH/CH2Cl2 (1 L)) affords the desired product as an off-white solid (0.12 g, 0.33 mmol, 64%). Physical characteristics are as follows: m.p. 308-310° C.; 1H NMR (300 MHz, DMSO-d6) δ 14.37, 9.80, 8.72, 8.34, 7.83, 7.41, 4.55, 3.92; IR (drift) 1725, 1661, 1625, 1600, 1581, 1535, 1486, 1296, 1276, 1245, 1237, 1129, 823, 806, 761 cm−1; MS (EI) m/z 371 (M+), 142, 141, 140, 139, 125, 89, 88, 74, 73, 51; HRMS (FAB) calcd for C18H14ClN3O4+H1 372.0751, found 372.0757.
Reaction SMILES: CN(C)C=O.Cl[C:7]1[CH:14]=[CH:13][C:12]([N+:15]([O-:17])=[O:16])=[CH:11][C:8]=1[C:9]#[N:10].[F:18][C:19]([F:23])([F:22])[CH2:20][OH:21].[H-].[Na+]>O>[N+:15]([C:12]1[CH:13]=[CH:14][C:7]([O:21][CH2:20][C:19]([F:23])([F:22])[F:18])=[C:8]([CH:11]=1)[C:9]#[N:10])([O-:17])=[O:16]
Reactant: OCC(F)(F)F
Reactant: N#Cc1cc([N+](=O)[O-])ccc1Cl
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: N#Cc1cc([N+](=O)[O-])ccc1OCC(F)(F)F
Reaction time: 1 h
Yield: 69.7 %

Procedure:
To a dimethylformamide solution (30 ml) containing 2-chloro-5-nitrobenzonitrile (10 g) and 2,2,2-trifluoroethanol (6 g) was added sodium hydride (60% content, 2.65 g) under ice-cooling, and the mixture was stirred for 1 h. The reaction mixture was added to water and extracted with toluene. The organic layer was washed with saturated brine and dried over anhydrous magnesium sulfate, after which the solvent was evaporated under reduced pressure. Diisopropyl ether was added to the residue to allow crystallization. The crystals were recrystallized from a mixed solvent of toluene-diisopropyl ether to give 5-nitro-2-(2,2,2-trifluoroethoxy)benzonitrile (9.4 g), melting point: 94° C.
Reaction SMILES: C(O[C:6]([NH:8][C:9]1[CH:14]=[CH:13][CH:12]=[C:11]([O:15][CH:16]([CH3:18])[CH3:17])[CH:10]=1)=[O:7])(C)(C)C.C([Li])(C)(C)C.C(OCC)(=O)[C:25](OCC)=[O:26].Cl>C1COCC1>[CH:16]([O:15][C:11]1[CH:12]=[CH:13][CH:14]=[C:9]2[C:10]=1[C:25](=[O:26])[C:6](=[O:7])[NH:8]2)([CH3:17])[CH3:18]
Reactant: CC(C)Oc1cccc(NC(=O)OC(C)(C)C)c1
Reactant: CCOC(=O)C(=O)OCC
Agent: Cl
Agent: [Li]C(C)(C)C
Solvent: C1CCOC1
Product: CC(C)Oc1cccc2c1C(=O)C(=O)N2
Temperature: -20 °C
Reaction time: 2 h

Procedure:
A solution of 3.78 g (25.0 mmol) of 3-isopropoxy aniline and di-tert-butyl dicarbonate in 25 mL of THF was heated to reflux for 2 h. The solution was cooled to ambient temperature, and solvent was removed in vacuo. The residue was dissolved in 100 mL of EtOAc, and the solution was washed with three 50-mL portions of 0.5 M citric acid and 50 mL of brine. The solution was dried over MgSO4 and removal of solvent in vacuo afforded N-(t-butyloxy-carbonyl)-3-isopropoxyaniline as a white solid (5.75 g, 92%): mp 79-81° C.; 1H NMR (DMSO-d6): δ 1.21 (d, J=6.0 Hz, 6H), 1.43 (s, 9H), 4.46 (septet, J=6 Hz, 1H), 6.47 (dd, J=2.1, 8.1 Hz, 1H), 6.94 (d, J=8.1 Hz, 1H), 7.0-7.1 (m, 2H), 9.23 (s, 1H); APCI−MS: m/z 274 (M+Na)+. To a solution of 2.5 g (10 mmol) of N-(t-butyloxycarbonyl)-3-isopropoxyaniline in 15 mL of dry THF at −78° C. was added 15 mL (25 mmol) of 1.7 M t-butyllithium in hexanes. The mixture was stirred at −20° C. for 2 h. A solution of 1.84 g (12.5 mmol) of diethyl oxalate in 10 mL of dry THF was added slowly over 5 min, and the mixture was stirred at −20° C. for 2 h. The reaction mixture was then poured into 100 mL of 1.0 N HCl and extracted with two 100-mL portions of EtOAc. Solvent was removed in vacuo, and the residue was dissolved in 100 mL of a 1:1 mixture of EtOH and 6 N HCl and heated to reflux for 1 h. The mixture was cooled to ambient temperature and was extracted with four 100-mL portions of EtOAc. The combined extracts were evaporated to dryness to provide crude 4-isopropoxy-1H-indol-2,3-dione, which was dissolved in 10 mL of EtOH containing 0.50 g (2.2 mmol) of 4-sulfonamidophenylhydrazine hydrochloride. The solution was heated to 80° C. for 1 h and cooled to ambient temperature. The resulting solid was collected by vacuum filtration and purified by flash chromatography on silica gel (EtOAc/hexane 3:2) to afford the title compound as a yellow solid (0.052 g, 1.4%): mp>250° C.; 1H NMR (DMSO-d6): δ 3.35 (d, J=6 Hz, 6H), 4.74 (septet, J=6 Hz, 1H), 6.48 (d, J=7.7 Hz, 1tH), 6.69 (d, J=8 Hz, 1H), 7.14-7.2 (m, 3H), 7.47 (d, J=8.7 Hz, 2H), 7.75 (d, J=8.7 Hz, 2H), 11.01 (s, 1H), 12.79 (s, 1H); APCI−MS: m/z 373 (M−H)−. Anal. Calcd for C17H18N4O4S: C, 54.53; H, 4.85; N, 14.96; S, 8.56. Found: C, 54.46; H, 4.84; N, 14.90; S, 8.50.
Reaction SMILES: [Br:1][C:2]1[C:3](Br)=[N:4][C:5]([F:16])=[C:6]([C:14]=1[F:15])[C:7]([O:9][C:10]([CH3:13])([CH3:12])[CH3:11])=[O:8].[CH3:18][N:19]1[C:27]2[C:22](=[CH:23][C:24](B(O)O)=[CH:25][CH:26]=2)[CH:21]=[CH:20]1.C([O-])([O-])=O.[K+].[K+]>C(#N)C>[Br:1][C:2]1[C:3]([C:24]2[CH:23]=[C:22]3[C:27](=[CH:26][CH:25]=2)[N:19]([CH3:18])[CH:20]=[CH:21]3)=[N:4][C:5]([F:16])=[C:6]([C:14]=1[F:15])[C:7]([O:9][C:10]([CH3:13])([CH3:12])[CH3:11])=[O:8]
Reactant: Cn1ccc2cc(B(O)O)ccc21
Reactant: CC(C)(C)OC(=O)c1c(F)nc(Br)c(Br)c1F
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: Cn1ccc2cc(-c3nc(F)c(C(=O)OC(C)(C)C)c(F)c3Br)ccc21
Temperature: 50 °C
Reaction time: 8 h
Yield: 72 %

Procedure:
A mixture of tert-butyl 5,6-dibromo-2,4-difluoronicotinate (156 mg, 0.42 mmol), 1-methyl-1H-indol-5-ylboronic acid (80 mg, 0.46 mmol), PdCl2dppf (34 mg, 0.042 mmol), aqueous K2CO3 (2.0 M×0.6 mL, 1.2 mmol) in acetonitrile (1.8 mL) was stirred at 50° C. overnight. The mixture was cooled and extracted with ethyl acetate. The organic layers were combined and dried over sodium sulfate, then evaporated and purified by silica chromatography (0-5% ethyl acetate in hexanes) to give tert-butyl 5-bromo-2,4-difluoro-6-(1-methyl-1H-indol-5-yl)nicotinate (128 mg, 73%).
Reaction SMILES: [O:1]=[C:2]1[C:7]2[CH:8]=[CH:9][S:10][C:6]=2[CH2:5][CH2:4][N:3]1[CH2:11][CH2:12][CH:13]1[CH2:18][CH2:17][N:16]([C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])[CH2:15][CH2:14]1.CC(O)=O.[Br:30]Br>O>[Br:30][C:9]1[S:10][C:6]2[CH2:5][CH2:4][N:3]([CH2:11][CH2:12][CH:13]3[CH2:18][CH2:17][N:16]([C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])[CH2:15][CH2:14]3)[C:2](=[O:1])[C:7]=2[CH:8]=1
Reactant: BrBr
Reactant: CC(C)(C)OC(=O)N1CCC(CCN2CCc3sccc3C2=O)CC1
Solvent: CC(=O)O
Solvent: O
Product: CC(C)(C)OC(=O)N1CCC(CCN2CCc3sc(Br)cc3C2=O)CC1
Reaction time: 0.17 h

Procedure:
2-4 (0.73 g, 2.0 mmoles) was added to a 50% aqueous HOAc solution (40 ml) and after stirring at 0°-10° for 10 minutes, Br2 (0.32 g, 2.0 mmoles) was added dropwise. After stirring at 0°-10° for 3 hours, the reaction mixture was diluted with 150 ml H2O and extracted with EtOAc. The organic extract was washed with brine, dried (Na2SO4) and concentrated. The residue was purified by flash chromatography on silica gel eluting with hexane (85)/acetone (15) to give pure 3-1, Rf 0.3.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([CH:9]([NH:19][CH2:20][CH:21]([C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)[OH:22])[C:10]2[CH:15]=[CH:14][CH:13]=[C:12]([N+:16]([O-])=O)[CH:11]=2)=[CH:5][CH:4]=1.[BH4-].[Na+]>CO.O.O.O.O.O.O.[Ni](Cl)Cl>[NH2:16][C:12]1[CH:11]=[C:10]([CH:9]([NH:19][CH2:20][CH:21]([C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)[OH:22])[C:6]2[CH:7]=[CH:8][C:3]([O:2][CH3:1])=[CH:4][CH:5]=2)[CH:15]=[CH:14][CH:13]=1
Reactant: COc1ccc(C(NCC(O)c2ccccc2)c2cccc([N+](=O)[O-])c2)cc1
Agent: Cl[Ni]Cl
Agent: [BH4-]
Agent: [Na+]
Solvent: O
Solvent: CO
Product: COc1ccc(C(NCC(O)c2ccccc2)c2cccc(N)c2)cc1
Yield: 73.3 %

Procedure:
In a similar manner to that described in Example (1b), a solution of 2-{[(4-methoxyphenyl)-(3-nitrophenyl)methyl]amino}-1-phenylethanol (3.26 g) [prepared as described in step (b) above] in methanol (60 m), nickel chloride hexahydrate (4.09 g) and sodium borohydride (1.3 g) were reacted, to afford the title compound (2.2 g) as a yellow oil.
Reaction SMILES: O=[C:2]1[CH2:6][S:5][CH2:4][CH:3]1[C:7]([O:9][CH3:10])=[O:8].[F:11][C:12]1[CH:18]=[C:17]([I:19])[CH:16]=[CH:15][C:13]=1[NH2:14]>C(O)C.C(O)(=O)C>[F:11][C:12]1[CH:18]=[C:17]([I:19])[CH:16]=[CH:15][C:13]=1[NH:14][C:2]1[CH2:6][S:5][CH2:4][C:3]=1[C:7]([O:9][CH3:10])=[O:8]
Reactant: COC(=O)C1CSCC1=O
Reactant: Nc1ccc(I)cc1F
Solvent: CC(=O)O
Solvent: CCO
Product: COC(=O)C1=C(Nc2ccc(I)cc2F)CSC1
Temperature: 25 °C
Yield: 40.8 %

Procedure:
To a mixture of methyl 4-oxotetrahydrothiophene-3-carboxylate (1.75 g, 11 mmol) (commercially available or prepared using procedures similar to those described in Rossy et. al. J. Org. Chem. 1980, 45(4), 617-2) in 15 mL of ethanol was added 2-fluoro-4-iodoaniline (2.6 g, 11 mmol) followed by addition of several drops of acetic acid. The mixture was refluxed for 3 hrs. The mixture was cooled to room temperature and the product precipitated. This product was filtered off, washed with ethyl acetate, ether, dried in vacuo to afford the methyl 4-[(2-fluoro-4-iodophenyl)amino]-2,5-dihydrothiophene-3-carboxylate (1.7 g, 42%). 1H NMR (d6-DMSO): 9.80 (s, 1H), 7.71 (d, 1H), 7.49 (dd, 1H), 7.24 (t, 1H), 4.10 (t, 2H), 3.79 (t, 2H), 3.69 (s, 3H); MS (EI) for C12H11FINO2S: 380 (MH+).
Reaction SMILES: [NH2:1][S:2]([C:5]1[CH:6]=[CH:7][C:8]([OH:14])=[C:9]([CH:13]=1)[C:10]([OH:12])=[O:11])(=[O:4])=[O:3].N1C=CC=CC=1.[C:21](Cl)(=[O:23])[CH3:22].[Cl-].[Na+]>C(#N)C.C(OCC)(=O)C>[OH2:3].[C:21]([O:14][C:8]1[CH:7]=[CH:6][C:5]([S:2]([NH2:1])(=[O:3])=[O:4])=[CH:13][C:9]=1[C:10]([OH:12])=[O:11])(=[O:23])[CH3:22].[C:21]([O:14][C:8]1[CH:7]=[CH:6][C:5]([S:2]([NH2:1])(=[O:3])=[O:4])=[CH:13][C:9]=1[C:10]([OH:12])=[O:11])(=[O:23])[CH3:22]
Reactant: NS(=O)(=O)c1ccc(O)c(C(=O)O)c1
Reactant: CC(=O)Cl
Agent: [Cl-]
Agent: [Na+]
Solvent: c1ccncc1
Solvent: CC#N
Solvent: CCOC(C)=O
Product: CC(=O)Oc1ccc(S(N)(=O)=O)cc1C(=O)O
Product: O
Yield: 65.4 %

Procedure:
5-(Aminosulfonyl)-2-hydroxybenzoic acid (9.35 g, 0.043 mole) was suspended in 50 ml acetonitrile. Pyridine (4.04 ml, 0.05 mole) was added with stirring. The resulting solution was chilled in an ice bath. Acetylchloride (3.63 ml, 0.05 mole) was added dropwise in two minutes and the reaction mixture was stirred at room temperature for four hours. To the reaction mixture was added about 50 ml each of ethyl acetate and sodium chloride solution. The organic layer was separated and extracted once more with sodium chloride solution. The aqueous layers were back extracted with acetonitrile-ethyl acetate. The organic layers were combined, dried over sodium sulfate, filtered, and concentrated to a white solid. The solid was triturated in ethyl acetate and isopropyl ether with small amount of acetonitrile overnight. The solid was collected, rinsed and dried under vacuum pump pressure to give 5.03 g of title compound, mp 179°-181° C.
Reaction SMILES: N([O-])=[O:2].[Na+].N[C:6]1[C:15]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)=[CH:14][C:13]2[C:8](=[CH:9][C:10]([CH2:24][CH3:25])=[N:11][C:12]=2[CH2:22][CH3:23])[N:7]=1>O.Cl>[CH2:22]([C:12]1[N:11]=[C:10]([CH2:24][CH3:25])[CH:9]=[C:8]2[C:13]=1[CH:14]=[C:15]([C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)[C:6](=[O:2])[NH:7]2)[CH3:23]
Reactant: CCc1cc2nc(N)c(-c3ccccc3)cc2c(CC)n1
Reactant: O=N[O-]
Agent: Cl
Agent: [Na+]
Solvent: O
Product: CCc1cc2[nH]c(=O)c(-c3ccccc3)cc2c(CC)n1
Reaction time: 1 h
Yield: 49.8 %

Procedure:
A solution of sodium nitrite (3.2 g) in water (64 ml) was added dropwise over 45 minutes to a solution of compound B (2.0 g) in 2M hydrochloric acid (150 ml). The mixture wa stirred for a further 1 hour and then the suspended white solid was collected by filtration and dried under vacuum to give 5,7-diethyl-3-phenyl-1,6-naphthyridin-2(1H)-one (1.0 g); m.p. >260° C.; NMR (d6 -DMSO): 1.32(t, 3H), 1.33(t, 3H), 3.07(q, 2H), 3.47(q, 2H), 7.41(s, 1H), 7.43-7.55(m, 3H), 7.74-7.85(m, 2H), 8.31(s, 1H); mass spectrum (+ve FAB, methanol/NBA): 279 (M+H)+ ; microanalysis, found: C, 76.9; H, 6.6; N, 9.7%; C18H18N2O.0.25H2O requires: C, 76.4; H, 6.5; N, 9.9%.
Reaction SMILES: [F:1][C:2]([F:11])([F:10])[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1I.[C:12](#[N:17])[CH2:13][CH2:14][C:15]#[CH:16].C(N(CC)CC)C.O>C(#N)C.[Cu](I)I>[F:1][C:2]([F:11])([F:10])[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[C:16]#[C:15][CH2:14][CH2:13][C:12]#[N:17]
Reactant: FC(F)(F)c1ccccc1I
Reactant: C#CCCC#N
Agent: I[Cu]I
Solvent: O
Solvent: CCN(CC)CC
Solvent: CC#N
Product: N#CCCC#Cc1ccccc1C(F)(F)F
Reaction time: 16 h
Yield: 92.9 %

Procedure:
Under a nitrogen atmosphere, a solution of 15.0 grams (0.055 mole) of 2-trifluoromethylphenyl iodide, 4.8 grams (0.061 mole) of 4-pentynenitrile, 30.6 mL (0.22 mole) of triethylamine, 0.4 gram (0.0006 mole) of bis(triphenylphosphine)palladium(11) chloride, and 0.1 gram (0.0006 mole) of copper(11) iodide in 50 mL of acetonitrile was stirred at ambient temperature for 5 hours. After this time, gas chromatographic analysis (GC) of the reaction mixture indicated that the reaction was about 60% complete. The reaction mixture was warmed to 40°-45° C., where it was stirred for 16 hours. After this time the reaction mixture was poured into 300 mL of water, and the mixture was extracted with two 100 mL portions of diethyl ether. The combined extracts were washed with aqueous dilute hydrochloric acid and then were dried with magnesium sulfate. The mixture was filtered and concentrated under reduced pressure to a residual oil. The oil was subjected to column chromatography on silica gel. Elution was accomplished using 1:1 - methylene chloride and petroleum ether. The product-containing fractions were combined and concentrated under reduced pressure, yielding 11.4 grams of 5-(2-trifluoromethylphenyl)-4-pentynenitrile. The NMR spectrum was consistent with the proposed structure.
Reaction SMILES: [F:1][C:2]1[C:7]([O:8][CH3:9])=[CH:6][CH:5]=[CH:4][C:3]=1B(O)O.C(O)(=[O:15])C.OO>O1CCCC1>[F:1][C:2]1[C:7]([O:8][CH3:9])=[CH:6][CH:5]=[CH:4][C:3]=1[OH:15]
Reactant: COc1cccc(B(O)O)c1F
Reactant: CC(=O)O
Agent: OO
Solvent: C1CCOC1
Product: COc1cccc(O)c1F
Reaction time: 65 h
Yield: 81 %

Procedure:
To a solution of 2-fluoro-3-methoxy-phenylboronic acid (10.0 g, 0.059 mol) in tetrahydrofuran (160 mL) was added glacial acetic acid (60 mL). The resulting mixture was cooled to 0° C. before hydrogen peroxide (50% aqueous solution, 8 mL) was added. The resulting mixture was allowed to come to room temperature and stirred for 65 h. The mixture was evaporated and the residue was dissolved in ethyl acetate, washed with hydrochloric acid (0.5N), water and brine. The organic phase was dried, filtered and evaporated which afforded 2-fluoro-3-methoxy-phenol (6.77 g, 81%) as a pale yellow oil.
Reaction SMILES: [Cl:1][C:2]1[CH:25]=[CH:24][C:5]2[N:6]([CH:13]3[CH2:18][CH2:17][N:16](C(OCC)=O)[CH2:15][CH2:14]3)[C:7](=[O:12])[N:8]([CH2:9][C:10]#[CH:11])[C:4]=2[CH:3]=1.[OH-].[K+].CC([OH:31])C>O>[ClH:1].[Cl:1][C:2]1[CH:25]=[CH:24][C:5]2[N:6]([CH:13]3[CH2:18][CH2:17][NH:16][CH2:15][CH2:14]3)[C:7](=[O:12])[N:8]([CH2:9][C:10](=[O:31])[CH3:11])[C:4]=2[CH:3]=1
Reactant: CC(C)O
Reactant: C#CCn1c(=O)n(C2CCN(C(=O)OCC)CC2)c2ccc(Cl)cc21
Agent: [K+]
Agent: [OH-]
Solvent: O
Product: CC(=O)Cn1c(=O)n(C2CCNCC2)c2ccc(Cl)cc21
Product: Cl

Procedure:
A mixture of 14 parts of ethyl 4-[5-chloro-1,3-dihydro-2-oxo-3-(2-propynyl)-2H-benzimidazol-1-yl]-1-piperidinecarboxylate, 20 parts of potassium hydroxide, 128 parts of 2-propanol and 2.5 parts of water is stirred and refluxed overnight. After cooling, the solvent is evaporated and water is added to the residue. The product is extracted with methylbenzene. The extract is dried, filtered and evaporated. The oily residue is converted into the hydrochloride salt in 2,2'-oxybispropane and 2-propanol. The salt is filtered off and crystallized from ethanol, yielding 5-chloro-1,3-dihydro-3-(2-oxopropyl)-1-(4-piperidinyl)-2H-benzimidazol-2-one hydrochloride.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[C:9]1[N:14]2[N:15]=[C:16]([CH2:18][CH3:19])[CH:17]=[C:13]2[N:12]=[C:11]([CH3:20])[N:10]=1.[N+:21]([O-])([OH:23])=[O:22].CCOC(C)=O>C(OC(=O)C)(=O)C>[Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[C:9]1[N:14]2[N:15]=[C:16]([CH2:18][CH3:19])[C:17]([N+:21]([O-:23])=[O:22])=[C:13]2[N:12]=[C:11]([CH3:20])[N:10]=1
Reactant: CCc1cc2nc(C)nc(-c3ccc(Cl)cc3Cl)n2n1
Reactant: O=[N+]([O-])O
Solvent: CC(=O)OC(C)=O
Solvent: CCOC(C)=O
Product: CCc1nn2c(-c3ccc(Cl)cc3Cl)nc(C)nc2c1[N+](=O)[O-]
Temperature: -7.5 °C
Yield: 21.4 %

Procedure:
A solution of 4-(2,4-dichlorophenyl)-7-ethyl-2-methyl-pyrazolo[1,5-a]-1,3,5-triazine (653 mg, 2.2 mmol) in acetic anhydride (4 mL) was cooled with stirring to −5 to −10° C. A solution of fuming nitric acid (160 mg, 2.55 mmol) in acetic anhydride (2 mL) was added dropwise over 15 min. The reaction mixture was stirred at the same temperature for 3 h, then it was partitioned between water and ether three times. The combined organic layers were washed with a saturated NaHCO3 solution, dried over MgSO4 and filtered. Solvent was removed in vacuo to provide a solid. Column chromatography (EtOAc:hexanes::1:9 to 1:4) provided a solid (166 mg, 21% yield) after removal of solvent in vacuo: NMR (CDCl3, 300 MHz): δ 7.64 (d, 1H, J=8), 7.63 (d, 1H, J=2), 7.50 (dd, 1H J=8, 2), 3.19 (q, 2H, J=7), 2.94 (s, 3H), 1.32 (t, 3H, J=7).