Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]1[O:6][N:5]=[C:4]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)[C:3]=1[C:13]([OH:15])=O.[NH:16]1[CH2:24][CH2:23][CH:19]([C:20]([NH2:22])=[O:21])[CH2:18][CH2:17]1.F[B-](F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2C=CC=CC=2N=N1.C(N(C(C)C)CC)(C)C>CN(C)C=O>[CH3:1][C:2]1[O:6][N:5]=[C:4]([C:7]2[CH:8]=[CH:9][CH:10]=[CH:11][CH:12]=2)[C:3]=1[C:13]([N:16]1[CH2:24][CH2:23][CH:19]([C:20]([NH2:22])=[O:21])[CH2:18][CH2:17]1)=[O:15]
Reactant: NC(=O)C1CCNCC1
Reactant: Cc1onc(-c2ccccc2)c1C(=O)O
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: Cc1onc(-c2ccccc2)c1C(=O)N1CCC(C(N)=O)CC1
Temperature: 25 °C

Procedure:
5-Methyl-3-phenylisooxazole-4-carboxylic acid (40 mg, 0.197 mmol), isonipecotamide (27.5 mg, 0.215 mmol), O-(benzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium tetrafluoroborate (86.2 mg, 0.268 mmol) and diisopropylethylamine (25.4 mg, 0.197 mmol) were mixed in dimethylformamide (1.5 mL) and stirred at room temperature. Solvent was evaporated in vacuo, and the residue was taken up in methanol (1 mL), filtered and purified by preparative chromatography. The combined fractions were partitioned between NaHCO3 (sat) and ethylacetate. The organic layer was washed with water and concentrated in vacuo to afford the title compound. HRMS (ESI, pos. ion) m/z calcd for C17H19N3O3: 313.1426, found 313.1431.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[NH:8][OH:9].C([O-])(O)=O.[Na+].Cl[C:16]([O:18][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)=[O:17].O>C(Cl)Cl>[OH:9][N:8]([C:3]1[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=1[CH3:1])[C:16](=[O:17])[O:18][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1
Reactant: Cc1ccccc1NO
Reactant: O=C(Cl)Oc1ccccc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: O
Product: Cc1ccccc1N(O)C(=O)Oc1ccccc1
Temperature: -10 °C
Yield: 72 %

Procedure:
A mixture of 350 g (purity about 80%; 2.3 mol; prepared by a similar method to Bamberger et al., Ann. Chem. 316 (1901), 278) of N-(2-methylphenyl)hydroxylamine and 286.8 g (3.4 mol) of NaHCO3 in 700 ml of CH2Cl2 is treated with 447 g (2.85 mol) of phenyl chloroformate with vigorous stirring at about -10° C. The mixture is stirred for about 1 hour at -10° C. and 600 ml of water are then added dropwise, the temperature of the reaction mixture increasing to 5-10° C. and a vigorous evolution of gas occurring. The aqueous phase is then separated off and extracted once more with CH2Cl2. The combined organic phases are extracted with water, dried over MgSO4 and concentrated. The residue crystallizes and is stirred with cyclohexane. 407 g (72%) of the title compound are obtained as a colorless solid.
Reaction SMILES: [CH3:1][C:2]1[C:6]([NH:7][C:8](=O)[C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)=[C:5]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[NH:4][N:3]=1.[N+](C1C=CC=CC=1)([O-])=O.Cl[Sn](Cl)(Cl)Cl>O=P(Cl)(Cl)Cl>[CH3:1][C:2]1[C:6]2[N:7]=[C:8]([C:9]3[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=3)[C:17]3[CH:18]=[CH:19][CH:20]=[CH:21][C:16]=3[C:5]=2[NH:4][N:3]=1
Reactant: Cc1n[nH]c(-c2ccccc2)c1NC(=O)c1ccccc1
Agent: Cl[Sn](Cl)(Cl)Cl
Solvent: O=[N+]([O-])c1ccccc1
Solvent: O=P(Cl)(Cl)Cl
Product: Cc1n[nH]c2c1nc(-c1ccccc1)c1ccccc12
Temperature: 185 °C
Reaction time: 1 h

Procedure:
To a mixture of 565 mg of N-(3-Methyl-5-phenyl-1H-pyrazol-4-yl)-benzamide was added 5 mL of nitrobenzene followed by 270 μL of POCl3 and the resulting mixture was heated at 185° C. After 1 h, 0.4 mL of a SnCl4 solution (1.0 M solution in heptane) was added and the mixture was heated for an additional 2 h, then concentrated under reduced pressure and purified by means of MPLC (12 g SiO2, 35% ethyl acetate:heptane) to give the title compound as a tan solid.
Reaction SMILES: C(N(CC)CC)C.Cl.[Cl:9][C:10]1[CH:11]=[C:12]2[C:16](=[CH:17][CH:18]=1)[NH:15][CH:14]=[C:13]2[CH2:19][CH2:20][NH2:21].[CH3:22][C:23]1[O:27][C:26]([C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)=[C:25]([C:34](Cl)=[O:35])[CH:24]=1>ClCCl>[Cl:9][C:10]1[CH:11]=[C:12]2[C:16](=[CH:17][CH:18]=1)[NH:15][CH:14]=[C:13]2[CH2:19][CH2:20][NH:21][C:34]([C:25]1[CH:24]=[C:23]([CH3:22])[O:27][C:26]=1[C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1)=[O:35]
Reactant: Cc1cc(C(=O)Cl)c(-c2ccccc2)o1
Reactant: NCCc1c[nH]c2ccc(Cl)cc12
Agent: Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: Cc1cc(C(=O)NCCc2c[nH]c3ccc(Cl)cc23)c(-c2ccccc2)o1
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 86.5 %

Procedure:
Triethylamine (0.128 mL; 0.886 mmol) was added to a mixture of 2-(5-chloro-1H-indol-3-yl)ethanamine hydrochloride (0.082 g; 0.354 mmol) and 5-methyl-2-phenylfuran-3-carbonyl chloride (0.082 g; 0.372 mmol) in dichloromethane (7 mL) at room temperature. The reaction mixture was stirred at room temperature for 20 minutes and washed with water. The organic layer was concentrated under reduced pressure and the crude material was purified by flash chromatography on silica gel (eluent 2 to 10% ethyl acetate in dichloromethane) to afford 0.116 g (86%) of N-(2-(5-chloro-1H-indol-3-yl)ethyl)-5-methyl-2-phenylfuran-3-carboxamide as a solid.
Reaction SMILES: [C:1]([O:5][C:6](=[O:18])[NH:7][C@@H:8]([CH2:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)[CH2:9][OH:10])([CH3:4])([CH3:3])[CH3:2].[H-].[Na+].[C:21]([O:25][C:26](=[O:35])[C:27]1[CH:32]=[CH:31][C:30]([CH2:33]Br)=[CH:29][CH:28]=1)([CH3:24])([CH3:23])[CH3:22]>CN(C=O)C>[C:21]([O:25][C:26](=[O:35])[C:27]1[CH:28]=[CH:29][C:30]([CH2:33][O:10][CH2:9][C@@H:8]([NH:7][C:6]([O:5][C:1]([CH3:4])([CH3:2])[CH3:3])=[O:18])[CH2:11][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)=[CH:31][CH:32]=1)([CH3:24])([CH3:23])[CH3:22]
Reactant: CC(C)(C)OC(=O)c1ccc(CBr)cc1
Reactant: CC(C)(C)OC(=O)N[C@H](CO)Cc1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N[C@H](COCc1ccc(C(=O)OC(C)(C)C)cc1)Cc1ccccc1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
168.5 mg (0.67 mmol) of tert.-butyl-[(2S)-1-hydroxy-3-phenylpropane-2-yl]carbamate were added to 4.9 ml of DMF under argon and mixed with 53.6 mg (1.3 mmol) of sodium hydride (as 60% dispersion in liquid paraffin) at a temperature of 0° C. After 30 minutes 200 mg (0.74 mmol) of tert.-butyl-4-(brommethyl)benzoate was added at a temperature of 0° C. Following completion of measuring, the batch was stirred for 2 hours at RT. Afterwards, the batch was evaporated in the rotation steam boiler, the residue absorbed in ice water and the compound extracted with 50 ml of dichlormethane each. The organic phases were washed in saturated sodium hydride solution, dried over magnesium sulphate and evaporated in a vacuum. The raw product thus obtained is being purified by means of preparative HPLC. 50.2 mg (17% o. th.) of the intermediate of tert.-butyl-4-[({(2S)-2-[(tert.-butoxycarbonyl)amino]-3-phenylpropyl}oxy)methyl]benzoate were obtained.
Reaction SMILES: C(OC([N:11]1[CH:16]=[CH:15][N:14]([CH2:17][C:18]2([OH:30])[CH2:23][CH2:22][N:21]([C:24]3[CH:29]=[CH:28][N:27]=[CH:26][CH:25]=3)[CH2:20][CH2:19]2)[C:13](=[O:31])[CH2:12]1)=O)C1C=CC=CC=1.[ClH:32]>CO.C(OCC)(=O)C.[Pd]>[ClH:32].[OH:30][C:18]1([CH2:17][N:14]2[CH2:15][CH2:16][NH:11][CH2:12][C:13]2=[O:31])[CH2:19][CH2:20][N:21]([C:24]2[CH:25]=[CH:26][N:27]=[CH:28][CH:29]=2)[CH2:22][CH2:23]1
Reactant: O=C1CN(C(=O)OCc2ccccc2)C=CN1CC1(O)CCN(c2ccncc2)CC1
Agent: [Pd]
Agent: Cl
Solvent: CO
Solvent: CCOC(C)=O
Product: O=C1CNCCN1CC1(O)CCN(c2ccncc2)CC1
Temperature: 25 °C
Reaction time: 15 h

Procedure:
To a solution of 4-benzyloxycarbonyl-1-[4-hydroxy-1-(4-pyridyl)piperidin-4-ylmethyl]-2-oxo-1,2,3,4-tetrahydropyrazine (6.93 g) in methanol (100 ml) were added 4N hydrochloric acid in ethyl acetate (4 ml) and 10% palladium on carbon (2.0 g), and the mixture was stirred, under hydrogen atmosphere, at room temperature for 15 hours. The catalyst was removed by filtration, and the filtrate was concentrated and dried under reduced pressure to give colorless syrup of the title compound (5.39 g).
Reaction SMILES: [N+:1]([C:4]1[N:5]=[C:6]([C:9]([O:11][CH2:12][CH3:13])=[O:10])[NH:7][CH:8]=1)([O-:3])=[O:2].[CH:14]1([CH2:17]Br)[CH2:16][CH2:15]1.C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C.O>[CH:14]1([CH2:17][N:7]2[CH:8]=[C:4]([N+:1]([O-:3])=[O:2])[N:5]=[C:6]2[C:9]([O:11][CH2:12][CH3:13])=[O:10])[CH2:16][CH2:15]1
Reactant: BrCC1CC1
Reactant: CCOC(=O)c1nc([N+](=O)[O-])c[nH]1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: CCOC(=O)c1nc([N+](=O)[O-])cn1CC1CC1

Procedure:
15 g (81 mmol) of ethyl 4-nitro-1H-imidazole-2-carboxylate are stirred together with 13.13 g (97.2 mmol) of cyclopropylmethyl bromide and 22.4 g (162 mmol) of potassium carbonate in 165 ml of DMF at 80° C. under argon for 1 h. After cooling, the reaction mixture is diluted with water and extracted four times with ethyl acetate. The combined organic phases are washed once with water and three times with saturated sodium chloride solution, dried with magnesium sulphate and evaporated in vacuo. The crystalline residue is further used directly for the next reaction.
Reaction SMILES: Br[CH2:2][C:3]1[CH:4]=[C:5]([F:10])[C:6]([Cl:9])=[N:7][CH:8]=1.C1N2CN3CN(C2)CN1C3.C([O-])(O)=[O:22].[Na+]>C(O)(=O)C.O>[Cl:9][C:6]1[C:5]([F:10])=[CH:4][C:3]([CH:2]=[O:22])=[CH:8][N:7]=1
Reactant: Fc1cc(CBr)cnc1Cl
Reactant: O=C([O-])O
Agent: C1N2CN3CN1CN(C2)C3
Agent: [Na+]
Solvent: CC(=O)O
Solvent: O
Product: O=Cc1cnc(Cl)c(F)c1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
A mixture of 5-(bromomethyl)-2-chloro-3-fluoropyridine (2.0 g, 8.91 mmol) and hexamethylenetetramine (2.75 g, 19.6 mmol) in 50% aqueous acetic acid (53 ml) was heated to reflux. After 1 hour, the mixture was cooled to room temperature, neutralized carefully with solid NaHCO3 (73.7 g), diluted with water (400 mL) and extracted with dichloromethane (2×100 mL). The combined organic extracts were dried over anhydrous sodium sulfate, concentrated on a rotary evaporator and purified by silica gel column chromatography (hexane/ethyl acetate) to afford 6-chloro-5-fluoronicotinaldehyde as pale-yellow solid: 1H NMR (400 MHz, CDCl3) δ 10.12 (d, J=2.4 Hz, 1H), 8.72 (d, J=1.6 Hz, 1H), 7.94 (dd, J=2.0, 8.0 Hz, 1H); 19F NMR (376 MHz, CDCl3) δ −116.3.
Reaction SMILES: C(=O)([O-])[O-].[Na+].[Na+].[NH2:7][C:8]1[N:13]=[C:12](Cl)[CH:11]=[CH:10][N:9]=1.[F:15][C:16]1[CH:25]=[C:24]([F:26])[CH:23]=[C:22]2[C:17]=1[C:18]([NH:34][C:35]1[CH:36]=[C:37](B(O)O)[CH:38]=[N:39][C:40]=1[N:41]1[CH2:46][CH2:45][O:44][CH2:43][CH2:42]1)=[C:19]([CH3:33])[C:20]([C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][N:28]=1)=[N:21]2.O1CCOCC1>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.O>[NH2:7][C:8]1[N:13]=[C:12]([C:37]2[CH:36]=[C:35]([NH:34][C:18]3[C:17]4[C:22](=[CH:23][C:24]([F:26])=[CH:25][C:16]=4[F:15])[N:21]=[C:20]([C:27]4[CH:32]=[CH:31][CH:30]=[CH:29][N:28]=4)[C:19]=3[CH3:33])[C:40]([N:41]3[CH2:42][CH2:43][O:44][CH2:45][CH2:46]3)=[N:39][CH:38]=2)[CH:11]=[CH:10][N:9]=1
Reactant: Cc1c(-c2ccccn2)nc2cc(F)cc(F)c2c1Nc1cc(B(O)O)cnc1N1CCOCC1
Reactant: Nc1nccc(Cl)n1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: C1COCCO1
Solvent: O
Product: Cc1c(-c2ccccn2)nc2cc(F)cc(F)c2c1Nc1cc(-c2ccnc(N)n2)cnc1N1CCOCC1
Temperature: 120 °C

Procedure:
A solution of dichlorobis(triphenylphosphine)palladium(ii) (19.5 mg, 0.028 mmol), sodium carbonate (88 mg, 0.83 mmol), 2-amino-4-chloropyrimidine (35.9 mg, 0.28 mmol), 5-(5,7-difluoro-3-methyl-2-(pyridin-2-yl)quinolin-4-ylamino)-6-morpholinopyridin-3-ylboronic acid (0.28 mmol; described herein), 1,4-dioxane (6 mL), and water (1.5 mL) was heated in a microwave at 120° C. for 60 min. The reaction was then partitioned between EtOAc and water, and the organic layer dried (magnesium sulfate) and concentrated. Chromatography afforded N-(5-(2-amino-4-pyrimidinyl)-2-(4-morpholinyl)-3-pyridinyl)-5,7-difluoro-3-methyl-2-(2-pyridinyl)-4-quinolinamine as a yellow solid. 1H NMR (400 MHz, chloroform-d) δ ppm 8.73-8.79 (1H, m), 8.58 (1H, d, J=2.3 Hz), 8.28 (1H, d, J=5.1 Hz), 7.85-7.96 (2H, m), 7.63-7.70 (1H, m), 7.48-7.59 (2H, m), 7.41 (1H, ddd, J=6.8, 4.7, 2.2 Hz), 6.98-7.10 (2H, m), 5.35 (2H, br. s.), 3.95 (4H, d, J=2.3 Hz), 3.10-3.70 (4H, m), 2.22 (3H, s). Mass Spectrum (ESI) m/e=527.2 (M+1).
Reaction SMILES: [CH3:1][O:2][C:3]1([C:6](Cl)=[O:7])[CH2:5][CH2:4]1.Cl.[CH3:10][NH:11][O:12][CH3:13].N1C=CC=CC=1>ClCCl>[CH3:13][O:12][N:11]([CH3:10])[C:6]([C:3]1([O:2][CH3:1])[CH2:5][CH2:4]1)=[O:7]
Reactant: CNOC
Reactant: COC1(C(=O)Cl)CC1
Agent: Cl
Solvent: c1ccncc1
Solvent: ClCCl
Product: CON(C)C(=O)C1(OC)CC1
Temperature: 20 °C
Reaction time: 1 h
Yield: 84.9 %

Procedure:
10 g (74 mmol) of 1-methoxy-cyclopropane-carbonyl chloride are added at 20° C. with stirring to a mixture of 8 g (82 mmol) of N,O-dimethyl-hydroxylamine hydrochloride and 100 ml of absolute dichloromethane. 13 g (164 mmol) of absolute pyridine are then added dropwise at 0° C. The mixture is initially subsequently stirred at 20° C. for one hour and then at 40° C. for one hour, the precipitate is then filtered off and 100 ml of dichloromethane are added. The reaction mixture is washed with water, dried over sodium sulphate and concentrated by stripping off the solvent under reduced pressure. The remaining residue is subjected to a vacuum distillation. 10 g (85% of theory) of N-methoxy-N-methyl-1-methoxy-cyclopropanecarboxamide are obtained in this manner in the form of an oil having a boiling point of b.p.=125° C. at 20 mbar. ##STR35##
Reaction SMILES: [CH3:1][C:2]([CH3:9])([O:7][CH3:8])[C:3](Cl)=[N:4][OH:5].[NH:10]1[CH:14]=[CH:13][N:12]=[CH:11]1.C(N(CC)CC)C>O1CCCC1>[CH3:1][C:2]([CH3:9])([O:7][CH3:8])[C:3]([N:10]1[CH:14]=[CH:13][N:12]=[CH:11]1)=[N:4][OH:5]
Reactant: COC(C)(C)C(Cl)=NO
Reactant: c1c[nH]cn1
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: COC(C)(C)C(=NO)n1ccnc1
Yield: 85.2 %

Procedure:
A solution of 9.9 g (0.066 mol) of 2,2-dimethyl-2-methoxy-1-chloro-1-oximino-ethane is very slowly added dropwise to a mixture of 9.0 g (0.132 mol) of imidazole and 6.7 g (0.066 mol) of triethylamine in 50 ml of absolute tetrahydrofuran at 0° C., with stirring. The mixture is allowed to come to room temperature and is subsequently stirred for 10 hours. The reaction batch is filtered, the filtrate is concentrated and the concentrate is diluted with water. The product which has precipitated is filtered off with suction, washed with petroleum ether and dried. 10.3 g of 2,2-dimethyl-2-methoxy-1-(imidazol-1-yl)-1-oximino-ethane of melting point 155°-160° C. are obtained, that is to say 85% of theory. Intermediate: ##STR65##
Reaction SMILES: [N:1]1([CH2:6][CH2:7][O:8][C:9]2[CH:14]=[CH:13][C:12]([NH:15][C:16]3[N:32]=[C:19]4[CH:20]=[CH:21][CH:22]=[C:23]([C:24]5[CH:25]=[C:26]([CH2:30]O)[CH:27]=[CH:28][CH:29]=5)[N:18]4[N:17]=3)=[CH:11][CH:10]=2)[CH2:5][CH2:4][CH2:3][CH2:2]1.C(N(CC)CC)C.CS([Cl:44])(=O)=O>ClCCl>[Cl:44][CH2:30][C:26]1[CH:25]=[C:24]([C:23]2[N:18]3[N:17]=[C:16]([NH:15][C:12]4[CH:13]=[CH:14][C:9]([O:8][CH2:7][CH2:6][N:1]5[CH2:5][CH2:4][CH2:3][CH2:2]5)=[CH:10][CH:11]=4)[N:32]=[C:19]3[CH:20]=[CH:21][CH:22]=2)[CH:29]=[CH:28][CH:27]=1
Reactant: CS(=O)(=O)Cl
Reactant: OCc1cccc(-c2cccc3nc(Nc4ccc(OCCN5CCCC5)cc4)nn23)c1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: ClCc1cccc(-c2cccc3nc(Nc4ccc(OCCN5CCCC5)cc4)nn23)c1
Temperature: 0 °C
Reaction time: 8 h

Procedure:
(3-{2-[4-(2-Pyrrolidin-1-yl-ethoxy)-phenylamino]-[1,2,4]triazolo[1,5-a]pyridin-5-yl}-phenyl)-methanol (0.35 g, 0.815 mmol) was dissolved in dichloromethane (20 mL). Triethylamine (508 uμL, 3.670 mmol) was added and the mixture cooled to 0° C., then methanesulfonyl chloride (252 μL, 3.260 mmol) was added dropwise and the reaction was allowed to warm to room temperature and stirred overnight. A small sample of the desired product was purified by preparatory HPLC. RT: 2.56 min, MI: 448 and 450.18, Method: 2.
Reaction SMILES: IC.[CH3:3][C:4]1[CH:5]=[C:6]([OH:13])[C:7](=[CH:11][CH:12]=1)[C:8]([OH:10])=[O:9].[C:14](=O)([O-])[O-].[Li+].[Li+]>CN(C)C=O>[OH:13][C:6]1[CH:5]=[C:4]([CH3:3])[CH:12]=[CH:11][C:7]=1[C:8]([O:10][CH3:14])=[O:9]
Reactant: Cc1ccc(C(=O)O)c(O)c1
Reactant: O=C([O-])[O-]
Agent: [Li+]
Solvent: CI
Solvent: CN(C)C=O
Product: COC(=O)c1ccc(C)cc1O
Temperature: 60 °C
Reaction time: 3.5 h

Procedure:
Iodomethane (22.6 mL, 362 mmol, 1.1 equiv) was added to a suspension of 4-methylsalicylic acid (50.0 g, 329 mmol, 1 equiv) and lithium carbonate (26.8 g, 362 mmol, 1.1 equiv) in dimethylformamide (450 mL) at 23° C. The reaction flask was heated in an oil bath at 60° C. After 3.5 h, the warm suspension was partitioned carefully between ice water (500 mL) and ethyl acetate (800 mL). The layers were separated. The aqueous layer was extracted with ethyl acetate (800 mL). The organic layers were combined. The combined solution was washed sequentially with water (2×500 mL) then saturated aqueous sodium chloride solution (500 mL) and the washed solution was dried over sodium sulfate. The dried solution was filtered and the filtrate was concentrated. A small sample of the product (˜50 mg) was purified by flash-column chromatography (2% ethyl acetate-hexanes) and was characterized by 1H NMR, 13C NMR, IR, and HRMS. The balance of the product, methyl 2-hydroxy-4-methylbenzoate, was used directly in the next reaction without purification. TLC: (2% ethyl acetate-hexanes) Rf=0.15 (CAM); 1H NMR (500 MHz, CDCl3) δ: 10.70 (s, 1H), 7.70 (d, 1H, J=8.4 Hz), 6.79 (s, 1H), 6.69 (d, 1H, J=7.7 Hz), 3.92 (s, 3H), 2.34 (s, 3H); 13C NMR (125 MHz, CDCl3) δ: 170.5, 161.5, 147.0, 129.6, 120.4, 117.7, 109.8, 52.0, 21.8; FTIR (neat), cm−1: 3186 (m), 2956 (m), 1672 (s), 1623 (m), 1579 (m), 1504 (m), 1441 (s), 1338 (s), 1298 (s), 1250 (s), 1215 (s), 1157 (s), 1096 (s), 906 (s), 780 (s); HRMS (ESI): Calcd for (C9H10O3+H)+ 167.0703, found 167.0698.
Reaction SMILES: [C:1]1([CH3:20])[CH:6]=[CH:5][C:4]([C:7]([C:9]2[CH:17]=[CH:16][CH:15]=[C:14]3[C:10]=2[CH2:11][CH2:12][CH:13]3[C:18]#[N:19])=[O:8])=[CH:3][CH:2]=1.[OH2:21]>>[C:1]1([CH3:20])[CH:2]=[CH:3][C:4]([C:7]([C:9]2[CH:17]=[CH:16][CH:15]=[C:14]3[C:10]=2[CH2:11][CH2:12][CH:13]3[C:18]([NH2:19])=[O:21])=[O:8])=[CH:5][CH:6]=1
Reactant: Cc1ccc(C(=O)c2cccc3c2CCC3C#N)cc1
Reactant: O
Product: Cc1ccc(C(=O)c2cccc3c2CCC3C(N)=O)cc1
Temperature: 90 °C
Reaction time: 0.5 h

Procedure:
To 2.3 g. of 4-(p-toluoyl)indan-1-carbonitrile is added 75 g. of polyphosphoric acid and the mixture is worked into a homogeneous solution by heating on a water bath at 90°C for 30 minutes and, then, on an oil bath at 120°-130°C for 30 minutes. Following the addition of water to decompose the polyphosphoric acid, the reaction mixture is extracted with ethyl acetate. The extract is washed with water, 5 % aqueous sodium hydrogen carbonate and water in the order mentioned and, then, dried. It is, then, treated with activated carbon and concentrated under reduced pressure. The resultant crystalline residue is recrystallized from a mixture of ethanol and ethyl acetate. The described procedure gives 4-(p-toluoyl)indan-1-carboxamide as crystals melting at 188°-191°C.
Reaction SMILES: [NH2:1][C:2]1[N:16]=[C:15](O)[C:5]2[CH2:6][CH2:7][O:8][C:9]3[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=3[C:4]=2[N:3]=1.P(Cl)(Cl)([Cl:20])=O>>[Cl:20][C:15]1[C:5]2[CH2:6][CH2:7][O:8][C:9]3[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=3[C:4]=2[N:3]=[C:2]([NH2:1])[N:16]=1
Reactant: Nc1nc(O)c2c(n1)-c1ccccc1OCC2
Reactant: O=P(Cl)(Cl)Cl
Product: Nc1nc(Cl)c2c(n1)-c1ccccc1OCC2

Procedure:
A mixture of Example 29C (0.63 g, 2.7 mmol) and phosphorus oxychloride (10 mL) was heated at reflux for 1 hour, cooled, concentrated under reduced pressure followed by the addition of water (20 mL). The mixture was filtered and the resulting solid was taken up in 1 M HCl (20 mL) and heated at reflux for 5 minutes. The cooled mixture was basified with 1M NaOH and extracted with CH2Cl2 (3×), filtering each extraction through diatomaceous earth. The combined CH2Cl2 layers were dried (MgSO4), filtered, concentrated under reduced pressure and chromatographed on silica gel eluting with a gradient of CH2Cl2:EtOAc (20:1 and 10:1) to provide the title compound. 1H NMR (CDCl3) δ 2.94 (t, J=6.10 Hz, 2H), 4.52 (t, J=6.27 Hz, 2H), 5.15 (s, 2H), 7.13 (dd, J=7.97, 1.19 Hz, 1H), 7.21-7.30 (m, 1H), 7.41-7.49 (m, 1H), 7.82 (dd, J=7.80, 1.70 Hz, 1H); MS (M+H)+ m/z 248.
Reaction SMILES: [C:1]([C:9]1[CH:10]=[C:11]([CH2:15][C:16]([OH:18])=O)[CH:12]=[CH:13][CH:14]=1)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.S(Cl)([Cl:21])=O>>[C:1]([C:9]1[CH:10]=[C:11]([CH2:15][C:16]([Cl:21])=[O:18])[CH:12]=[CH:13][CH:14]=1)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=S(Cl)Cl
Reactant: O=C(O)Cc1cccc(C(=O)c2ccccc2)c1
Product: O=C(Cl)Cc1cccc(C(=O)c2ccccc2)c1

Procedure:
20 g of m-benzoyl-phenyl acetic acid (prepared by process of French patent No. 1,546,478) and 100 ml of thionyl chloride were refluxed for 3 hours and then evaporated to dryness. Excess thionyl chloride was removed by entrainment with benzene to obtain 21.74 g of m-benzoyl-phenyl-acetic acid chloride.
Reaction SMILES: [C:1](OC(=O)C)(=[O:3])[CH3:2].[NH2:8][CH:9]([C:22]1[CH:26]=[C:25]([Si:27]([CH3:30])([CH3:29])[CH3:28])[O:24][CH:23]=1)[CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH3:21].C(N(CC)CC)C>ClCCl>[C:1]([NH:8][CH:9]([C:22]1[CH:26]=[C:25]([Si:27]([CH3:30])([CH3:29])[CH3:28])[O:24][CH:23]=1)[CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH3:21])(=[O:3])[CH3:2]
Reactant: CC(=O)OC(C)=O
Reactant: CCCCCCCCCCCCC(N)c1coc([Si](C)(C)C)c1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCCCCCCCCCCCC(NC(C)=O)c1coc([Si](C)(C)C)c1
Reaction time: 8 h

Procedure:
Acetic anhydride (0.1 ml) was added to a solution of 3-(1-aminotridecyl)-5-trimethylsilylfuran (89.8 mg, 0.27 mmol) and triethylamine (0.1 ml) in dichloromethane (1 ml) at room temperature. Stirring was continued overnight (14 hours) while the cooling bath attained room temperature. The residue, after solvent removal, was purified by preparative TLC (20×20 cm, 1000 u; developed with 60% ethyl ether/hexane). The title amide was obtained as a pale yellow oil.
Reaction SMILES: [Cl:1][C:2]1[N:3]=[C:4]([O:9][CH2:10][C:11]2[CH:12]=[N:13][CH:14]=[CH:15][CH:16]=2)[C:5]([NH2:8])=[N:6][CH:7]=1.[Cl:17][C:18]1[C:19]([F:28])=[C:20]([S:24](Cl)(=[O:26])=[O:25])[CH:21]=[CH:22][CH:23]=1>>[Cl:17][C:18]1[C:19]([F:28])=[C:20]([S:24]([NH:8][C:5]2[C:4]([O:9][CH2:10][C:11]3[CH:12]=[N:13][CH:14]=[CH:15][CH:16]=3)=[N:3][C:2]([Cl:1])=[CH:7][N:6]=2)(=[O:26])=[O:25])[CH:21]=[CH:22][CH:23]=1
Reactant: O=S(=O)(Cl)c1cccc(Cl)c1F
Reactant: Nc1ncc(Cl)nc1OCc1cccnc1
Product: O=S(=O)(Nc1ncc(Cl)nc1OCc1cccnc1)c1cccc(Cl)c1F

Procedure:
Prepared by the method of Example 1 (reaction performed at room temperature) using 5-chloro-3-(3-pyridinylmethoxy)-2-pyrazinamine (Example 95a) (0.1 g) and 3-chloro-2-fluorobenzenesulphonyl chloride (0.1 g). Yield 0.034 g.
Reaction SMILES: [CH3:1][CH:2]1[NH:7][CH:6]([CH3:8])[CH2:5][N:4]([C:9]2[CH:14]=[CH:13][C:12]([S:15]([NH2:18])(=[O:17])=[O:16])=[CH:11][CH:10]=2)[CH2:3]1.N1(C2C=CC(S(N)(=O)=O)=CC=2)CCNCC1.FC1C=CC(S(N)(=O)=O)=CC=1.Cl[CH2:47][CH2:48][CH:49]1[C:58]2[C:53](=[CH:54][CH:55]=[CH:56][CH:57]=2)[CH:52](C)[CH2:51][O:50]1.C[C@H]1CNC[C@@H](C)N1>>[C@H:49]1([CH2:48][CH2:47][N:7]2[C@@H:6]([CH3:8])[CH2:5][N:4]([C:9]3[CH:10]=[CH:11][C:12]([S:15]([NH2:18])(=[O:16])=[O:17])=[CH:13][CH:14]=3)[CH2:3][C@H:2]2[CH3:1])[C:58]2[C:53](=[CH:54][CH:55]=[CH:56][CH:57]=2)[CH2:52][CH2:51][O:50]1
Reactant: CC1CN(c2ccc(S(N)(=O)=O)cc2)CC(C)N1
Reactant: CC1COC(CCCl)c2ccccc21
Agent: C[C@@H]1CNC[C@H](C)N1
Agent: NS(=O)(=O)c1ccc(F)cc1
Agent: NS(=O)(=O)c1ccc(N2CCNCC2)cc1
Product: C[C@@H]1CN(c2ccc(S(N)(=O)=O)cc2)C[C@H](C)N1CC[C@@H]1OCCc2ccccc21

Procedure:
Following the general procedure of EXAMPLE 49 and making non-critical variations 2-(isochroman-1-yl)ethanol-O-methanesulfonate (LXXX, 0.412 g) and 4-(3,5-dimethylpiperazin-1-yl)benzenesulfonamide [(IV), 0.433 g; prepared from 4-fluorobenzenesulfonamide, III, and cis-2,6-dimethylpiperazine, II (Aldrich), by the method of EXAMPLE 47] gives the title compound; mp 170°-175°(decomp)°; MS (m/z) 429; IR (mineral oil) 1153, 1596, 1325, 1162 and 1096 cm-1.