Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:15][CH2:14][CH2:13][C@H:9]1[C:10](O)=[O:11])=[O:7])([CH3:4])([CH3:3])[CH3:2].Cl.[CH3:17][N:18](C)[CH2:19]CCN=C=NCC.Cl.CNC.C(Cl)Cl>CN(C)C1C=CN=CC=1.O>[C:1]([O:5][C:6]([N:8]1[CH2:15][CH2:14][CH2:13][C@H:9]1[C:10]([N:18]([CH3:19])[CH3:17])=[O:11])=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)OC(=O)N1CCC[C@H]1C(=O)O
Reactant: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Agent: CNC
Agent: Cl
Solvent: O
Solvent: ClCCl
Product: CN(C)C(=O)[C@@H]1CCCN1C(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 4 h
Yield: 92.5 %

Procedure:
A mixture of 1-(tert-butoxycarbonyl)-L-proline (10.75 g), 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (10.6 g), dimethylamine hydrochloride (5.33 g), 4-dimethylaminopyridine (6.1 g) and methylene chloride (200 ml) was stirred at ambient temperature for 4 hours. The mixture was poured into water. The organic layer was separated, washed in turn with a 1N aqueous potassium hydrogen sulphate solution, with a 5% aqueous sodium bicarbonate solution and brine, dried over magnesium sulphate and evaporated to give 1-(tert-butoxycarbonyl)-N,N-dimethyl-L-prolinamide (11.2 g); NMR Spectrum: (CDCl3) 1.4 and 1.5 (2 s, 9H), 1.8–1.9 (m, 2H), 1.95–2.2 (m, 2H), 3.0 and 3.1 (2 d, 6H), 3.35–3.6 (m, 2H), 4.55 and 4.7 (2 m, 1H).
Reaction SMILES: [C:1]1([CH:7]2[C:15]3[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=3)[NH:9][CH2:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH3:16][C:17]([CH3:22])=[CH:18][C:19](Cl)=[O:20]>>[CH3:16][C:17]([CH3:22])=[CH:18][C:19]([N:9]1[C:10]2[C:15](=[CH:14][CH:13]=[CH:12][CH:11]=2)[CH:7]([C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)[CH2:8]1)=[O:20]
Reactant: CC(C)=CC(=O)Cl
Reactant: c1ccc(C2CNc3ccccc32)cc1
Product: CC(C)=CC(=O)N1CC(c2ccccc2)c2ccccc21
Yield: 57.8 %

Procedure:
The procedure of Example 16 was repeated using 1.95 g of 3-phenylindoline and 1.5 g of 3,3-dimethylacryloyl chloride. In this way 1.6 g of the desired N-(3,3-dimethylacryloyl)-3-phenylindoline having a melting point of 97°-8° C. was obtained.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:8]2[C:9]([O:17][CH3:18])=[N:10][C:11]([CH3:16])=[C:12]([CH:15]=2)[CH:13]=O)[CH:5]=[CH:6][CH:7]=1.[Cl:19]C1C=C(C2C(OC)=NC(C)=C(C=2)C#N)C=CC=1.[H-].C([Al+]CC(C)C)C(C)C>C(Cl)Cl>[Cl:19][CH2:13][C:12]1[C:11]([CH3:16])=[N:10][C:9]([O:17][CH3:18])=[C:8]([C:4]2[CH:5]=[CH:6][CH:7]=[C:2]([Cl:1])[CH:3]=2)[CH:15]=1
Reactant: COc1nc(C)c(C=O)cc1-c1cccc(Cl)c1
Reactant: COc1nc(C)c(C#N)cc1-c1cccc(Cl)c1
Agent: CC(C)C[Al+]CC(C)C
Agent: [H-]
Solvent: ClCCl
Product: COc1nc(C)c(CCl)cc1-c1cccc(Cl)c1
Temperature: -78 °C
Reaction time: 0.05 h
Yield: 72 %

Procedure:
5-(3-Chlorophenyl)-6-methoxy-2-methylnicotinaldehyde. To a cooled solution, −78° C., of 5-(3-chlorophenyl)-6-methoxy-2-methylnicotinonitrile (500 mg, 1.9 mmol) in DCM (15 mL), under nitrogen, was added diisobutylaluminium hydride (1 M in hexanes, 4.8 mL, 4.8 mmol) drop-wise, over 3 minutes. The reaction mixture was stirred at −78° C. for 1 h. The reaction was carefully quenched by addition of saturated sodium fluoride (1 mL). After stirring for 30 minutes the suspension was filtered and the filtrate concentrated under reduced pressure. Purification (FCC, SiO2, 0-50%, EtOAc/hexanes) afforded the title compound (358 mg, 72%). [M+H]=262.05.
Reaction SMILES: Cl[C:2]1[C:7]([C:8]2[NH:9][CH:10]=[CH:11][N:12]=2)=[CH:6][CH:5]=[C:4]([Cl:13])[N:3]=1.C1(=O)O[CH2:17][CH2:16][O:15]1.C(=O)([O-])[O-].[Cs+].[Cs+]>CN(C)C=O>[Cl:13][C:4]1[CH:5]=[CH:6][C:7]2[C:8]3[N:9]([CH:10]=[CH:11][N:12]=3)[CH2:17][CH2:16][O:15][C:2]=2[N:3]=1
Reactant: O=C1OCCO1
Reactant: Clc1ccc(-c2ncc[nH]2)c(Cl)n1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: Clc1ccc2c(n1)OCCn1ccnc1-2

Procedure:
A mixture of 0.856 g (4.00 mmol) of 2,6-dichloro-3-(1H-imidazol-2-yl)pyridine, 704 mg (8.00 mmol) of ethylene carbonate and 2930 mg (9.00 mmol) of cesium carbonate was heated in 25.0 ml of N,N-dimethylformamide for 13 hours at 90° C. The mixture was filtered, the filtrate concentrated in high vacuum, the residue purified on 10 g of silica column eluting with 80% of ethyl acetate in heptane to give 9-chloro-5,6-dihydroimidazo[1,2-d]pyrido[3,2-f][1,4]oxazepine. Yield 0.359 g (41%). M/z 222.0, calc. 221.04. 1H NMR (500 MHz, CDCl3) δ 8.84 (d, J=8.2, 1H), 7.18 (s, 1H), 7.15 (d, J=8.2, 1H), 7.02 (s, 1H), 4.63-4.57 (m, 2H), 4.47-4.41 (m, 2H)
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[NH:9][NH2:10].[C:11]([O:16][CH2:17][CH3:18])(=[O:15])[C:12]([CH3:14])=O.C(O)(=O)C>C(O)C>[Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[NH:9][N:10]=[C:12]([CH3:14])[C:11]([O:16][CH2:17][CH3:18])=[O:15]
Reactant: NNc1ccc(Cl)cc1Cl
Reactant: CCOC(=O)C(C)=O
Solvent: CCO
Solvent: CC(=O)O
Product: CCOC(=O)C(C)=NNc1ccc(Cl)cc1Cl
Temperature: 25 °C
Yield: 82.4 %

Procedure:
A mixture of 2,4-dichlorophenylhydrazine (16.00 g, 0.075 mol), ethyl pyruvate (14.47 g, 10.3 mL, 0.12 mol), glacial acetic acid (0.9 mL), absolute ethanol (105 mL) was refluxed for 2 hours. After cooling at room temperature, the solid which formed was filtered and recrystallized from ethanol to give 17.0 g (83%) of the title compound, mp 118-120° C. (from ethanol).
Reaction SMILES: [CH3:1][C:2]1[C:3]2[CH:16]=[CH:15][CH:14]=[CH:13][C:4]=2[S:5][C:6]=1[CH:7]1[CH2:12][NH:11][CH2:10][CH2:9][NH:8]1.Cl[C:18]1[CH:27]=[C:26]2[C:21]([C:22](=[O:33])[C:23]([C:30]([OH:32])=[O:31])=[CH:24][N:25]2[CH2:28][CH3:29])=[CH:20][C:19]=1[F:34]>N1C=CC=CC=1>[CH2:28]([N:25]1[C:26]2[C:21](=[CH:20][C:19]([F:34])=[C:18]([N:11]3[CH2:10][CH2:9][NH:8][CH:7]([C:6]4[S:5][C:4]5[CH:13]=[CH:14][CH:15]=[CH:16][C:3]=5[C:2]=4[CH3:1])[CH2:12]3)[CH:27]=2)[C:22](=[O:33])[C:23]([C:30]([OH:32])=[O:31])=[CH:24]1)[CH3:29]
Reactant: CCn1cc(C(=O)O)c(=O)c2cc(F)c(Cl)cc21
Reactant: Cc1c(C2CNCCN2)sc2ccccc12
Solvent: c1ccncc1
Product: CCn1cc(C(=O)O)c(=O)c2cc(F)c(N3CCNC(c4sc5ccccc5c4C)C3)cc21

Procedure:
A 2 g portion of 2-(3-methylbenzo[b]thien-2-yl)piperazine was added to 7 ml of pyridine. A 780 mg portion of 7-chloro-1-ethyl-6-fluoro-1,4-dihydro-4-oxo-3-quinolinecarboxylic acid was added and the mixture was heated in a pressure bottle, under argon at 120°-130° C. for 18 hours. The solid was collected, washed with pyridine, then ether and recrystallized from dimethylformamide, giving 540 mg of the desired product, mp 302°-304° C. (dec.).
Reaction SMILES: [OH:1][CH2:2][CH2:3][CH:4]1[O:6][C:5]1([CH:8]1[CH:15]([O:16][CH3:17])[CH:14]([O:18][C:19]([N:21]2[CH2:26][CH2:25][O:24][CH2:23][CH2:22]2)=[O:20])[CH2:13][CH2:12][C:9]21[O:11][CH2:10]2)[CH3:7].O1CCCC1.[H-].[Na+].[CH2:34](Br)[C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1>CN(C)C=O>[CH2:34]([O:1][CH2:2][CH2:3][CH:4]1[O:6][C:5]1([CH:8]1[CH:15]([O:16][CH3:17])[CH:14]([O:18][C:19]([N:21]2[CH2:22][CH2:23][O:24][CH2:25][CH2:26]2)=[O:20])[CH2:13][CH2:12][C:9]21[O:11][CH2:10]2)[CH3:7])[C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1
Reactant: COC1C(OC(=O)N2CCOCC2)CCC2(CO2)C1C1(C)OC1CCO
Reactant: BrCc1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CN(C)C=O
Product: COC1C(OC(=O)N2CCOCC2)CCC2(CO2)C1C1(C)OC1CCOCc1ccccc1
Reaction time: 2 h
Yield: 26.8 %

Procedure:
To a solution of 4-[3-(2-hydroxyethyl)-2-methyloxiranyl]-5-methoxy-6-(morpholinocarbonyloxy)-1-oxaspiro[2,5]octane (14.4 mg) in a mixture of anhydrous tetrahydrofuran (1 ml) and N,N-dimethylformamide (1 ml) was added sodium hydride (60% oil dispersion, 4.7 mg) in one portion under ice cooling. The mixture was stirred for half an hour at the same temperature and benzylbromide (13.3 mg) was added. After sitrred for 2 hours at ambient temperature, the reaction was quenched with water (2 ml) and extracted with diethyl ether (1 ml) three times. The combined organic layers were washed with water, dried, and evaporated in vacuo. The residue was purified by column chromatography on silica gel (diethyl ether/n-hexane =1/1) to give 4-[3-(2-benzyloxyethyl)-2-methyloxiranyl]-5-methoxy-6-(morpholinocarbonyloxy)-1-oxaspiro[2,5]octane (4.8 mg).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:18])[CH:5]([CH2:8][C:9]1[CH:14]=[CH:13][C:12]([N+:15]([O-])=O)=[CH:11][CH:10]=1)[CH2:6][CH3:7])[CH3:2].[H][H]>C(OCC)(=O)C.[Pd]>[CH2:1]([O:3][C:4](=[O:18])[CH:5]([CH2:8][C:9]1[CH:10]=[CH:11][C:12]([NH2:15])=[CH:13][CH:14]=1)[CH2:6][CH3:7])[CH3:2]
Reactant: CCOC(=O)C(CC)Cc1ccc([N+](=O)[O-])cc1
Reactant: [H][H]
Agent: [Pd]
Solvent: CCOC(C)=O
Product: CCOC(=O)C(CC)Cc1ccc(N)cc1

Procedure:
28 g of 2-(p-nitrobenzyl)-butyric acid ethyl ester are dissolved in 200 ml ethyl acetate. The solution is added with 1 g of 10% Pd/C and hydrogenated in a Parr apparatus until complete absorption of hydrogen. After filtering and evaporation from solvent about 25 g of product are obtained as a sufficiently pure oil for the successive reactions.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([O:8][CH3:9])[N:5]=[C:4]([NH:10][CH2:11][CH2:12][C:13]2[CH:18]=[CH:17][C:16]([O:19][CH3:20])=[C:15]([F:21])[CH:14]=2)[CH:3]=1.[C:22]([C:24]1[CH:25]=[C:26](B(O)O)[CH:27]=[CH:28][CH:29]=1)#[N:23].C([O-])([O-])=O.[Cs+].[Cs+]>C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.O.COCCOC>[F:21][C:15]1[CH:14]=[C:13]([CH2:12][CH2:11][NH:10][C:4]2[N:5]=[C:6]([O:8][CH3:9])[N:7]=[C:2]([C:28]3[CH:29]=[C:24]([CH:25]=[CH:26][CH:27]=3)[C:22]#[N:23])[CH:3]=2)[CH:18]=[CH:17][C:16]=1[O:19][CH3:20]
Reactant: COc1nc(Cl)cc(NCCc2ccc(OC)c(F)c2)n1
Reactant: N#Cc1cccc(B(O)O)c1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: O
Solvent: COCCOC
Product: COc1nc(NCCc2ccc(OC)c(F)c2)cc(-c2cccc(C#N)c2)n1
Yield: 56.6 %

Procedure:
(6-chloro-2-methoxy-pyrimidin-4-yl)-[2-(3-fluoro-4-methoxyphenyl)-ethyl]amine [1.6 g, Intermediate (5)], 3-cyano-phenylboronic acid [1.5 g, Intermediate (6)], Cs2CO3 (8.3 g) and tetrakis(triphenylphosphine)palladium (45 mg) in a solution of water (8 mL) and ethylene glycol dimethyl ether (32 mL) is heated at 90° C. for 16 hours. The solution is poured into water and extracted twice with EtOAc (200 mL). The combined extracts are dried over sodium sulfate, filtered, and evaporated. The residue is subjected to chromatography on silica gel eluting with EtOAc to give 3-{6-[2-(3-fluoro-4-methoxy-phenyl)-ethylamino]-2-methoxy-pyrimidin-4-yl}-benzonitrile [1.1 g, Example 1]. MS: 379 (M+H); 1H NMR (CDCl3): δ 8.3 (1H, s); 8.2 (1H, d (J=5.1 Hz)); 7.9 (1H, d (J=5.1 Hz)); 7.6 (1H, t); 7-7.2 (4H, m); 6.4 (1H, s); 5 (1H, m); 3.95 (3H, s); 3.8 (3H, s); 3.7 (2H, t); 3 (2H, t).
Reaction SMILES: [OH:1][C@@H:2]1[CH2:21][CH2:20][C@@:19]2([CH3:22])[C@@H:4]([CH2:5][CH2:6][C@@H:7]3[C@@H:18]2[C@@H:17]([O:23][C:24](=[O:27])[CH2:25]I)[CH2:16][C@@:15]2([CH3:28])[C@H:8]3[CH2:9][CH2:10][C@@H:11]2[C:12](=[O:14])[CH3:13])[CH2:3]1.[CH2:29]([NH:33][CH2:34][CH3:35])[CH2:30][CH2:31][CH3:32]>ClCCl>[CH2:29]([N:33]([CH2:25][C:24]([O:23][C@H:17]1[CH2:16][C@@:15]2([CH3:28])[C@@H:8]([CH2:9][CH2:10][C@@H:11]2[C:12](=[O:14])[CH3:13])[C@H:7]2[C@H:18]1[C@:19]1([CH3:22])[C@@H:4]([CH2:5][CH2:6]2)[CH2:3][C@H:2]([OH:1])[CH2:21][CH2:20]1)=[O:27])[CH2:34][CH3:35])[CH2:30][CH2:31][CH3:32]
Reactant: CCCCNCC
Reactant: CC(=O)[C@H]1CC[C@H]2[C@@H]3CC[C@H]4C[C@H](O)CC[C@]4(C)[C@H]3[C@@H](OC(=O)CI)C[C@]12C
Solvent: ClCCl
Product: CCCCN(CC)CC(=O)O[C@H]1C[C@]2(C)[C@@H](C(C)=O)CC[C@H]2[C@@H]2CC[C@H]3C[C@H](O)CC[C@]3(C)[C@H]21

Procedure:
3α-Hydroxy-11β-iodoacetoxy-5α-pregnan-20-one (1.5 g) was stirred with N-butyl-N-ethylamine (3 ml) in dichloromethane (60 ml) at 20° for 21 hours. The solution was washed with water and the solvent was evaporated at reduced pressure. The residue was triturated with water giving a solid which was recrystallised from aqueous methanol to give title compound (1.2 g), m.p. 111°-112.5°, [α]D +93.5°.
Reaction SMILES: Br[C:2]1[S:3][C:4]([NH:8][C:9](=[O:11])[CH3:10])=[C:5]([Br:7])[N:6]=1.C(NCC)C>C(O)C.[Ni]>[Br:7][C:5]1[N:6]=[CH:2][S:3][C:4]=1[NH:8][C:9](=[O:11])[CH3:10]
Reactant: CC(=O)Nc1sc(Br)nc1Br
Agent: [Ni]
Solvent: CCO
Solvent: CCNCC
Product: CC(=O)Nc1scnc1Br
Temperature: 25 °C
Reaction time: 12 h
Yield: 77.8 %

Procedure:
A mixture of N-(2,4-dibromothiazol-5-yl)acetamide from example 1.4 (0.35 g, 1.17 mmol), diethylamine (0.085 g, 1.17 mmol) and Raney Ni (0.14 g, 2.33 mmol) in ethanol (50 mL) was stirred at room temperature for 12 h in a 100 mL round-bottomed flask to give a black solution. The reaction mixture was filtered and concentrated to give the title compound (0.20 g, 0.91 mmol, 78%) as a yellow solid which was directly used for the next step without purification.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([C:8](=[O:10])[CH3:9])=[CH:4][CH:3]=1.[F:11][CH:12]([CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH3:30])[CH2:13]OS(C1C=CC(C)=CC=1)(=O)=O.[OH-].[K+]>C(O)CCC>[F:11][CH:12]([CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH3:30])[CH2:13][O:1][C:2]1[CH:7]=[CH:6][C:5]([C:8](=[O:10])[CH3:9])=[CH:4][CH:3]=1
Reactant: CCCCCCC(F)COS(=O)(=O)c1ccc(C)cc1
Reactant: CC(=O)c1ccc(O)cc1
Agent: [K+]
Agent: [OH-]
Solvent: CCCCO
Product: CCCCCCC(F)COc1ccc(C(C)=O)cc1
Temperature: 0 °C
Yield: 42 %

Procedure:
Then, 6.3 g of p-hydroxyacetophenone and 12.7 g of 2-fluorooctyl-p-toluenesulfonate were dissolved in 35 ml of butanol. To the solution, a solution of 3.1 g of potassium hydroxide in 40 ml of butanol was added dropwise, followed by heat-refluxing for 6 hours. After the reaction, the reaction mixture was poured into 200 ml of ice water and extracted with isopropyl ether. The organic layer was washed with water and dried with anhydrous magnesium sulfate, followed by distilling-off of the solvent to precipitate a crystal. The crystal was purified by silica gel column chromatography to obtain 4.7 g of p-(2-fluorooctyloxy)acetophenone.
Reaction SMILES: [CH2:1]=[CH:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.[CH3:9][SiH:10]([Cl:12])[Cl:11].C[Si](C)(C)NC(N[Si](C)(C)C)=O.C(O)C>[Pt].C1(C)C=CC=CC=1>[CH2:1]([CH2:9][SiH:10]([Cl:12])[Cl:11])[CH2:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1
Reactant: C[SiH](Cl)Cl
Reactant: C=Cc1ccccc1
Agent: [Pt]
Agent: C[Si](C)(C)NC(=O)N[Si](C)(C)C
Solvent: CCO
Solvent: Cc1ccccc1
Product: Cl[SiH](Cl)CCCc1ccccc1
Yield: 84 %

Procedure:
Reaction between styrene and methyldichlorosilane with platinum catalyst in the presence of N,N′-bis(trimethylsilyl)urea. 0.481 g Styrene and 0.549 g methyldichlorosilane were introduced into a glass tube, and an ethanol solution containing 0.124 mg N,N′-bis(trimethylsilyl)urea (6.2 wt %) was added with a microsyringe. 1 mg Of a toluene solution of a 0-valent platinum complex of divinylsiloxane (0.04 wt % platinum content) was added. The tube was sealed with Teflon tape and a septum and then placed in a 100° C. oil bath where it was heated for 20 minutes. After cooling, the tube contents were analyzed by gas chromatography revealing a styrene conversion of 89% and a phenethylmethyldichlorosilane yield of 84%. The ratio between the phenethylmethyldichlorosilane and the (α-methylbenzyl)methyldichlorosilane was 21:1.
Reaction SMILES: [NH2:1][C:2]1[C:3]2[C:8]([N:9]=[C:10]3[C:15]=1[C:14](=[O:16])[CH2:13][CH2:12][CH2:11]3)=[CH:7][CH:6]=[CH:5][CH:4]=2.[H-].[Na+].[CH3:19][N:20]([CH3:24])[CH2:21][CH2:22]Cl.[Cl-]>CN(C)C=O>[CH3:19][N:20]([CH3:24])[CH2:21][CH2:22][NH:1][C:2]1[C:3]2[C:8]([N:9]=[C:10]3[C:15]=1[C:14](=[O:16])[CH2:13][CH2:12][CH2:11]3)=[CH:7][CH:6]=[CH:5][CH:4]=2
Reactant: CN(C)CCCl
Reactant: Nc1c2c(nc3ccccc13)CCCC2=O
Agent: [Cl-]
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CN(C)CCNc1c2c(nc3ccccc13)CCCC2=O
Temperature: 60 °C

Procedure:
To a suspension of 9-amino-3,4-dihydroacridin-1(2H)-one (10.0 g) in 100 ml of dimethylformamide was added a 50% suspension of sodium hydride in oil (2.9 g). To this was added 2-dimethylaminoethyl chloride (6.5 g). The mixture was heated to 60° C. pot temperature for 2.5 hours, an additional 2.7 g of the chloride was added and this was heated for an additional 1 hour.
Reaction SMILES: [NH2:1][C:2]1[C:10]2[C:5](=[N:6][C:7]([CH3:14])=[C:8]([CH2:12][CH3:13])[C:9]=2[CH3:11])[S:4][C:3]=1[C:15]([OH:17])=O.N=C=N.[C:21]1([C:27]2NN=[N:29][N:28]=2)[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1>ClC(Cl)C.CN(C=O)C>[CH2:12]([C:8]1[C:9]([CH3:11])=[C:10]2[C:2]([NH2:1])=[C:3]([C:15]3[O:17][C:27]([C:21]4[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=4)=[N:28][N:29]=3)[S:4][C:5]2=[N:6][C:7]=1[CH3:14])[CH3:13]
Reactant: c1ccc(-c2nnn[nH]2)cc1
Reactant: CCc1c(C)nc2sc(C(=O)O)c(N)c2c1C
Agent: N=C=N
Solvent: CN(C)C=O
Solvent: CC(Cl)Cl
Product: CCc1c(C)nc2sc(-c3nnc(-c4ccccc4)o3)c(N)c2c1C
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 56.2 %

Procedure:
To a solution of 3-amino-5-ethyl-4,6-dimethyl-thieno[2,3-b]pyridine-2-carboxylic acid (0.16 g, 0.63 mmol) in a mixture of dichloroethane (8 mL) and DMF (2 mL) was added PS-carbodiimide (1.0 g, 1.26 mmol). The mixture was shaken for 15 min at room temperature, followed by the addition of 5-phenyltetrazole (0.042 g, 0.32 mmol). Then, the mixture was shaken at 80° C. overnight. The resin was then removed by filtration and washed with hot chloroform (2×5 mL). The filtrate was evaporated in vacuum to dryness and purified by chromatography (silica gel, dichloromethane/ethyl acetate, 9/1) to furnish the product 5-ethyl-4,6-dimethyl-2-(5-phenyl-[1,3,4]oxadiazol-2-yl)-thieno[2,3-b]pyridin-3-yl amine (0.063 g, 56%).
Reaction SMILES: [Br:1][CH2:2][CH2:3][CH2:4][S:5][C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1.[C:12](Cl)(=[O:15])[CH2:13][CH3:14].[Cl-].[Al+3].[Cl-].[Cl-]>ClCCl>[Br:1][CH2:2][CH2:3][CH2:4][S:5][C:6]1[CH:11]=[CH:10][C:9]([C:12](=[O:15])[CH2:13][CH3:14])=[CH:8][CH:7]=1
Reactant: BrCCCSc1ccccc1
Reactant: CCC(=O)Cl
Agent: [Al+3]
Agent: [Cl-]
Solvent: ClCCl
Product: CCC(=O)c1ccc(SCCCBr)cc1

Procedure:
To a solution of thioether from Example 1, (460 g, 2 moles) and propionyl chloride (202 g, 2.2 moles) in dichloromethane (8 L) at -15° C. was added in portions of approximately 30 g over 1 hour, aluminum chloride (320 g, 2.4 moles). After two hours at -15° C. the reaction mixture was quenched with ice until it became colorless. 1N HCl (2 L) was added and the reaction mixture was stirred until two clear phases were obtained (approximately 30 minutes). The organic layer was siphoned off and dried (Na2SO4). Evaporation afforded an oil which crystallized upon addition of hexane (2 L) and cooling in ice water bath; yield 470 g, m.p. 40°-41° C.
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:18]=[CH:17][C:16]([CH:19]([CH:23]2[CH2:29][CH2:28][CH2:27][CH2:26][CH2:25][CH2:24]2)[C:20]([NH2:22])=[S:21])=[CH:15][CH:14]=1.Cl[CH2:31][C:32](=O)[CH3:33].C(=O)(O)[O-].[Na+]>O>[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]=[CH:15][C:16]([CH:19]([CH:23]2[CH2:29][CH2:28][CH2:27][CH2:26][CH2:25][CH2:24]2)[C:20]2[S:21][CH:31]=[C:32]([CH3:33])[N:22]=2)=[CH:17][CH:18]=1
Reactant: NC(=S)C(c1ccc(OCc2ccc3ccccc3n2)cc1)C1CCCCCC1
Reactant: CC(=O)CCl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Product: Cc1csc(C(c2ccc(OCc3ccc4ccccc4n3)cc2)C2CCCCCC2)n1

Procedure:
1.5 g (0.0037 mol) of the compound from Example III and 5 ml of chloroacetone are heated with 10 ml of water at 100° C. in an oil bath for 30 minutes. The mixture is then neutralised with sodium bicarbonate solution and extracted with methylene chloride. After the extract has been dried with sodium sulphate, it is concentrated to dryness in vacuo, and the residue is recrystallised in diisopropyl ether.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([N:9]2[C:13]([CH3:14])=[C:12]([C:15]([OH:17])=O)[CH:11]=[N:10]2)[CH:5]=[CH:6][C:7]=1[F:8].[NH2:18][C:19]1[CH:20]=[CH:21][C:22]([N:27]2[CH2:32][CH2:31][N:30]([CH:33]3[CH2:38][CH2:37][O:36][CH2:35][CH2:34]3)[CH2:29][CH2:28]2)=[C:23]([CH:26]=1)[C:24]#[N:25]>>[C:24]([C:23]1[CH:26]=[C:19]([NH:18][C:15]([C:12]2[CH:11]=[N:10][N:9]([C:4]3[CH:5]=[CH:6][C:7]([F:8])=[C:2]([F:1])[CH:3]=3)[C:13]=2[CH3:14])=[O:17])[CH:20]=[CH:21][C:22]=1[N:27]1[CH2:32][CH2:31][N:30]([CH:33]2[CH2:38][CH2:37][O:36][CH2:35][CH2:34]2)[CH2:29][CH2:28]1)#[N:25]
Reactant: Cc1c(C(=O)O)cnn1-c1ccc(F)c(F)c1
Reactant: N#Cc1cc(N)ccc1N1CCN(C2CCOCC2)CC1
Product: Cc1c(C(=O)Nc2ccc(N3CCN(C4CCOCC4)CC3)c(C#N)c2)cnn1-c1ccc(F)c(F)c1
Yield: 53.7 %

Procedure:
By the reaction and treatment in the same manner as in Example 64 using 1-(3,4-difluorophenyl)-5-methylpyrazole-4-carboxylic acid (0.7 g) and 5-amino-2-[4-(3,4,5,6-tetrahydro-2H-pyran-4-yl)piperazin-1-yl]benzonitrile (1.0 g), the title compound (0.8 g) was obtained, melting point: 235° C.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C:8]2[C:17]3[C:12](=[CH:13][CH:14]=[C:15]([O:18][CH3:19])[CH:16]=3)[C:11](=[O:20])[N:10]([CH3:21])[C:9]=2[C:22]([OH:24])=O)[CH:5]=[CH:6][CH:7]=1.[CH3:25][NH:26][CH3:27]>ClC(Cl)C.CN(C1C=CN=CC=1)C>[F:1][C:2]1[CH:3]=[C:4]([C:8]2[C:17]3[C:12](=[CH:13][CH:14]=[C:15]([O:18][CH3:19])[CH:16]=3)[C:11](=[O:20])[N:10]([CH3:21])[C:9]=2[C:22]([N:26]([CH3:27])[CH3:25])=[O:24])[CH:5]=[CH:6][CH:7]=1
Reactant: COc1ccc2c(=O)n(C)c(C(=O)O)c(-c3cccc(F)c3)c2c1
Reactant: CNC
Agent: CN(C)c1ccncc1
Solvent: CC(Cl)Cl
Product: COc1ccc2c(=O)n(C)c(C(=O)N(C)C)c(-c3cccc(F)c3)c2c1
Reaction time: 0.5 h

Procedure:
The acid chloride of 11 (80 mg, 0.mmol mmol) was added to a solution of excess dimethylamine in dichloroethane containing a catalytic amount of DMAP at room temperature. After stirring for 30 min the reaction mixture was washed with 1M HCl then brine. Drying (Na2SO4) and concentration gave the amide 12.
Reaction SMILES: [C:1]1([OH:7])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH2:8]=[O:9]>>[CH:8](=[O:9])[C:2]1[C:1](=[CH:6][CH:5]=[CH:4][CH:3]=1)[OH:7]
Reactant: Oc1ccccc1
Reactant: C=O
Product: O=Cc1ccccc1O

Procedure:
A method in which a salicylaldehyde is prepared in good yield by one step reaction using as starting materials a phenol and a formaldehyde and a specific catalyst (a base represented by a tertiary amine and/or an organometallic salt):
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[O:11][CH2:10][CH2:9][C:8]([C:12]([O:14][CH3:15])=[O:13])=[CH:7][C:6]=2[CH:16]=1.[N+:17]([O-])([OH:19])=[O:18]>O>[Cl:1][C:2]1[CH:3]=[C:4]([N+:17]([O-:19])=[O:18])[C:5]2[O:11][CH2:10][CH2:9][C:8]([C:12]([O:14][CH3:15])=[O:13])=[CH:7][C:6]=2[CH:16]=1
Reactant: O=[N+]([O-])O
Reactant: COC(=O)C1=Cc2cc(Cl)ccc2OCC1
Solvent: O
Product: COC(=O)C1=Cc2cc(Cl)cc([N+](=O)[O-])c2OCC1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
Methyl 2,3-dihydro-7-chloro-1-benzoxepin-4-carboxylate (1.0 g) was added to nitric acid (4.5 ml, d=1.42) under ice-cooling and the mixture was stirred at ambient temperature for 2 hours. The mixture was poured into water and the isolated precipitate was collected by filtration to give methyl 2,3-dihydro-7-chloro-9-nitro-1-benzoxepin-4-carboxylate (1.04 g).
Reaction SMILES: [C:1]([O:8]CC)(=[O:7])[C:2](OCC)=O.[O-]CC.[K+].[N+:15]([C:18]1[CH:23]=[CH:22][CH:21]=[C:20](C)[C:19]=1[CH3:25])([O-:17])=[O:16]>CCOCC>[CH3:25][C:19]1([CH2:2][C:1]([OH:8])=[O:7])[C:18]([N+:15]([O-:17])=[O:16])=[CH:23][CH:22]=[CH:21][CH2:20]1
Reactant: CCOC(=O)C(=O)OCC
Reactant: Cc1cccc([N+](=O)[O-])c1C
Agent: CC[O-]
Agent: [K+]
Solvent: CCOCC
Product: CC1(CC(=O)O)CC=CC=C1[N+](=O)[O-]
Yield: 45 %

Procedure:
Diethyl oxalate (30 mL) in 20 mL of dry ether was added with stirring to 19 g of potassium ethoxide suspended in 50 mL of dry ether. The mixture was cooled in an ice bath and 20 mL of 3-nitro-o-xylene in 20 mL of dry ether was slowly added. The thick dark red mixture was refluxed for 0.5 hr, concentrated, and treated with 10% sodium hydroxide until almost all of the solid dissolved. Hydrogen peroxide (30%) was then added to the dark red mixture until the red color changed to yellow. The mixture was treated alternately with 10% sodium hydroxide and 30% hydrogen peroxide until the dark red color was no longer present. The solid was filtered off and the filtrate acidified with 6 N hydrochloric acid. The resulting precipitate was collected by vacuum filtration, washed with water, and dried under vacuum to give 9.8 g (45% yield) of 1-methyl-6-nitrophenylacetic acid as an off-white solid. The solid was hydrogenated in methanol over 10% palladium on carbon to give 9.04 g of 4-methyl-2-oxindole as a white solid.