Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3]1[N:8]=[CH:7][C:6]([NH2:9])=[CH:5][CH:4]=1.[Cl:10][C:11]1[CH:12]=[C:13]([C:18]2[N:23]=[C:22]([CH3:24])[N:21]=[C:20]([N:25]([CH2:35][C:36]3[CH:41]=[CH:40][C:39]([O:42][CH3:43])=[CH:38][CH:37]=3)[CH2:26][C:27]3[CH:32]=[CH:31][C:30]([O:33][CH3:34])=[CH:29][CH:28]=3)[N:19]=2)[C:14](F)=[N:15][CH:16]=1.[Li+].C[Si]([N-][Si](C)(C)C)(C)C>C1COCC1>[Cl:10][C:11]1[CH:12]=[C:13]([C:18]2[N:23]=[C:22]([CH3:24])[N:21]=[C:20]([N:25]([CH2:26][C:27]3[CH:28]=[CH:29][C:30]([O:33][CH3:34])=[CH:31][CH:32]=3)[CH2:35][C:36]3[CH:37]=[CH:38][C:39]([O:42][CH3:43])=[CH:40][CH:41]=3)[N:19]=2)[C:14]([NH:9][C:6]2[CH:7]=[N:8][C:3]([O:2][CH3:1])=[CH:4][CH:5]=2)=[N:15][CH:16]=1
Reactant: COc1ccc(N)cn1
Reactant: COc1ccc(CN(Cc2ccc(OC)cc2)c2nc(C)nc(-c3cc(Cl)cnc3F)n2)cc1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: C1CCOC1
Product: COc1ccc(CN(Cc2ccc(OC)cc2)c2nc(C)nc(-c3cc(Cl)cnc3Nc3ccc(OC)nc3)n2)cc1
Yield: 85.5 %

Procedure:
A solution of 6-methoxypyridin-3-amine (Sigma-Aldrich Inc., 1.405 g, 11.31 mmol) and 4-(5-chloro-2-fluoropyridin-3-yl)-N,N-bis(4-methoxybenzyl)-6-methyl-1,3,5-triazin-2-amine (3.62 g, 7.54 mmol) in THF (15.00 mL) was cooled to 0° C. in an ice bath and treated with 1.0 M LiHMDS in THF (22.63 mL, 22.63 mmol). The reaction mixture was quenched with a saturated solution of NH4Cl at 0° C. and extracted with EtOAc (50 mL), dried over MgSO4, filtered and concentrated. The crude residue was re diluted with DCM and concentrated with SiO2 and chromatographed through a Redi-Sep pre-packed silica gel column on the ISCO (40 g column, 20→100% EtOAc in hexanes) to give 4-(5-chloro-2-(6-methoxypyridin-3-ylamino)pyridin-3-yl)-N,N-bis(4-methoxybenzyl)-6-methyl-1,3,5-triazin-2-amine (3.77 g, 6.45 mmol, 86% yield) as a bright yellow crystalline solid. m/z (ESI, +ve ion) 584.1 (M+H)+.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[CH:4][C:5]([S:8]([NH2:11])(=[O:10])=[O:9])=[CH:6][CH:7]=1.CN(C)C=O.C(=O)([O-])[O-].[K+].[K+].Cl[CH2:24][C:25]1[CH:26]=[C:27]([O:35][CH3:36])[C:28]([O:33][CH3:34])=[CH:29][C:30]=1[CH2:31]Cl>O>[CH3:36][O:35][C:27]1[CH:26]=[C:25]2[C:30](=[CH:29][C:28]=1[O:33][CH3:34])[CH2:31][N:11]([S:8]([C:5]1[CH:4]=[CH:3][C:2]([CH3:1])=[CH:7][CH:6]=1)(=[O:10])=[O:9])[CH2:24]2
Reactant: COc1cc(CCl)c(CCl)cc1OC
Reactant: Cc1ccc(S(N)(=O)=O)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: COc1cc2c(cc1OC)CN(S(=O)(=O)c1ccc(C)cc1)C2
Temperature: 25 °C
Yield: 95.2 %

Procedure:
1.89 g (11 mmol) of p-toluenesulfonamide was added to 20 ml of N,N-dimethylformamide, and 3.3 g (24 mmol) of pulverised potassium carbonate and 2.0 g (8.5 mmol) of 4,5-bischloromethyl veratrol were added thereto at room temperature under stirring. The mixture was stirred at room temperature for 20 hours, and after an addition of 40 ml of water, extracted with methylene chloride. The extract was washed with water, and then dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure, and the crystalline residue was washed with diisopropyl ether to obtain 2.7 g (yield: 95.2%) of the above identified compound.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][C:6](=[O:11])[CH2:5]2.C(N(CC)CC)C.[CH3:19][S:20](Cl)(=[O:22])=[O:21]>ClCCl>[O:11]=[C:6]1[CH2:5][C:4]2[C:8](=[CH:9][CH:10]=[C:2]([NH:1][S:20]([CH3:19])(=[O:22])=[O:21])[CH:3]=2)[NH:7]1
Reactant: Nc1ccc2c(c1)CC(=O)N2
Reactant: CS(=O)(=O)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CS(=O)(=O)Nc1ccc2c(c1)CC(=O)N2
Temperature: -30 °C
Yield: 90 %

Procedure:
A stirred solution of 5-amino-1,3-dihydro-indol-2-one (2 g, 13.5 mmol, prepared according to U.S. Pat. No. 6,114,371) in 30 ml of dichloromethane was added with triethylamine (1.9 ml). The solution was cooled down to −30° C. in an acetone-dry ice bath and added with methanesulfonyl chloride (1 ml, 13.5 mmol) dropwise. Upon the completion of the addition, the resulting mixture was heated at 45° C. for 1 hour until precipitate was formed. The solid was filtered, washed with water (50 ml×3) and dried in vacuo to give N-(2-oxo-2,3-dihydro-1H-indol-5-yl)-methanesulfonamide (2.7 g, 90%) as a white solid.
Reaction SMILES: Cl[S:2]([OH:5])(=[O:4])=[O:3].[N:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1>CN(C)C=O>[N:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1.[S:2](=[O:5])(=[O:4])=[O:3]
Reactant: O=S(=O)(O)Cl
Solvent: CN(C)C=O
Solvent: c1ccncc1
Product: O=S(=O)=O
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
Chlorosulfonic acid (3.0 ml, 0.0454 mol, 150 M %) was added slowly to a solution of dry pyridine (9.84 ml, 0.121 mol) in dry dimethylformamide (60 ml) which had been cooled to -10°. The resulting clear solution was stirred for 10 minutes at room temperature.
Reaction SMILES: [CH:1]1[C:9]2[C:8]3[CH:10]=[CH:11][CH:12]=[CH:13][C:7]=3[S:6][C:5]=2[CH:4]=[CH:3][CH:2]=1.[C:14](Cl)(=[O:18])[C:15]([CH3:17])=[CH2:16]>>[CH3:16][CH:15]1[CH2:17][C:10]2[C:8]3[C:9]4[CH:1]=[CH:2][CH:3]=[CH:4][C:5]=4[S:6][C:7]=3[CH:13]=[CH:12][C:11]=2[C:14]1=[O:18]
Reactant: C=C(C)C(=O)Cl
Reactant: c1ccc2c(c1)sc1ccccc12
Product: CC1Cc2c(ccc3sc4ccccc4c23)C1=O
Yield: 66 %

Procedure:
For the synthesis of the compounds according to the invention, the operation started with 2-methyl indan-1-one and, in a three-step method, the desired 2-methyl indene was obtained in a yield of over 60%. As emerges from the diagram, m-xylene (1) is converted in a first step with methacryloyl chloride. The purified indanone (2) is obtained after cleaning by distillation and Friedel-Crafts alkylation in a yield of 66%. The reduction of the indanone (2) is implemented with NaBH4. The indene (3) is obtained as a viscous fluid. By reaction of the compound (4), which is produced by addition of 1,2-dibromoethane and fluorenyl lithium, the two isomers (5) and (6) are obtained in a subsequent reaction in a yield of 45%. The desired isomer 5 can then be isolated by crystallisation from toluene/hexane in a ratio of 1:2.
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=[O:7])=[CH:4][N:3]=1.C(B(CC)[C:14]1[CH:19]=[CH:18][N:17]=[CH:16][CH:15]=1)C.Cl.[K].Cl>O1CCCC1.[Br-].C([N+](CCCC)(CCCC)CCCC)CCC.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.C(OCC)(=O)C.O>[ClH:1].[N:17]1[CH:18]=[CH:19][C:14]([C:2]2[CH:10]=[CH:9][C:5]([C:6]([OH:8])=[O:7])=[CH:4][N:3]=2)=[CH:15][CH:16]=1
Reactant: O=C(O)c1ccc(Cl)nc1
Reactant: CCB(CC)c1ccncc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: Cl
Solvent: CCOC(C)=O
Solvent: O
Solvent: C1CCOC1
Product: O=C(O)c1ccc(-c2ccncc2)nc1

Procedure:
In tetrahydrofuran (20 ml), 6-chloronicotinic acid (535 mg) and diethyl (4-pyridyl)borane (500 mg) were dissolved. To the resulting solution, tetrabutylammonium bromide (546 mg), potassium hydrochloride (570 mg), tetrakis(triphenylphosphine)palladium (0) (392 mg) and water (0.5 ml) were added, followed by heating under reflux for 6 hours. Dilute hydrochloric acid was added to the reaction mixture to make it acidic. Water and ethyl acetate were poured into the resulting mixture for extraction. The water layer so extracted was distilled off under reduced pressure. The residue was purified by chromatography through a synthetic adsorbent (“Diaion HP-20”, water ˜50% acetonitrile-water). To the resulting fraction, dilute hydrochloric acid was added to make it acidic. The solvent was then distilled off. Tetrahydrofuran was added to the residue and the precipitate was collected by filtration, whereby the title compound (269 mg, 32%) was obtained.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]([OH:10])=[O:9])=[N:6][CH:7]=1.S(=O)(=O)(O)O.[CH3:16]O>>[OH:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]([O:10][CH3:16])=[O:9])=[N:6][CH:7]=1
Reactant: CO
Reactant: O=C(O)c1ccc(O)cn1
Agent: O=S(=O)(O)O
Product: COC(=O)c1ccc(O)cn1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of 5-hydroxypyridine-2-carboxylic acid (1.0 g, 7.2 mmol) in methanol (15 mL) was added sulfuric acid (881 μL, 16.53 mmol) dropwise and the reaction mixture was stirred at room temperature overnight. The reaction mixture was concentrated in vacuo, diluted with DCM (100 mL), washed with sat. aq NaHCO3 solution. The organic layer was separated and dried with sodium sulfate, filtered and concentrated in vacuo to give methyl 5-hydroxypyridine-2-carboxylate, which was used without further purification. ESI-MS m/z calc. 150.1. found 154.1 (M+1)+; Retention time: 0.33 minutes (3 min run).
Reaction SMILES: [S:1]1[CH:5]=[CH:4][C:3]([CH:6]=O)=[C:2]1[CH:8]=O.COP([CH:16]([NH:20]C(=O)C)[C:17](=[O:19])[CH3:18])(=O)OC.C1CCN2C(=NCCC2)CC1>ClCCl>[S:1]1[C:2]2=[CH:8][N:20]=[C:16]([C:17](=[O:19])[CH3:18])[CH:6]=[C:3]2[CH:4]=[CH:5]1
Reactant: O=Cc1ccsc1C=O
Reactant: COP(=O)(OC)C(NC(C)=O)C(C)=O
Solvent: ClCCl
Solvent: C1CCC2=NCCCN2CC1
Product: CC(=O)c1cc2ccsc2cn1
Temperature: 25 °C
Yield: 43 %

Procedure:
A solution of 2,3-thiophenedicarboxaldehyde (600 mg, 4.28 mmol) in dichloromethane (50 ml) was cooled to 0° C. under an atmosphere of nitrogen. (1-Acetylamino-2-oxo-propyl)-phosphonic acid dimethyl ester (1.05 g, 4.70 mmol) was added [literature procedure: Kitamura, et al. Tet. Lett., 36(32), 1995, pp. 5769-5772], followed by DBU (0.471 ml, 4.70 mmol), and the mixture allowed to warm to ambient temperature overnight, then concentrated in vacuo, and the residue was then purified by flash chromatography (0-50% ethyl acetate in hexanes) to provide 1-thieno[2,3-c]pyridin-5-yl-ethanone as a white solid (326 mg, 43%). 1HNMR (250 MHz, CDCl3): δ 9.20 (s, 1H), 8.50 (d, 1H, J=1.02), 7.80 (d, 1H, J=5.36), 7.51 (d, 1H, J=5.36), 2.81 (s, 3H).
Reaction SMILES: [Br-].[C:2]1([S+:8]2[C:12]3[CH:13]=[CH:14][CH:15]=[CH:16][C:11]=3[C:10]3[CH:17]=[CH:18][CH:19]=[CH:20][C:9]2=3)[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[OH:21][C:22]12[CH2:31][CH:26]3[CH2:27][CH:28]([CH2:30][CH:24]([CH2:25]3)[CH2:23]1)[CH2:29]2.[C:32]([O:35][CH:36]([CH3:47])[C:37]([F:46])([F:45])[C:38]([F:44])([F:43])[S:39]([O-:42])(=[O:41])=[O:40])(=[O:34])[CH3:33].[Na].O>ClCCl>[OH:21][C:22]12[CH2:23][CH:24]3[CH2:30][CH:28]([CH2:27][C:26]([CH2:33][C:32]([O:35][CH:36]([CH3:47])[C:37]([F:46])([F:45])[C:38]([F:44])([F:43])[S:39]([O-:42])(=[O:41])=[O:40])=[O:34])([CH2:25]3)[CH2:31]1)[CH2:29]2.[C:2]1([S+:8]2[C:9]3[CH:20]=[CH:19][CH:18]=[CH:17][C:10]=3[C:11]3[CH:16]=[CH:15][CH:14]=[CH:13][C:12]2=3)[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CC(=O)OC(C)C(F)(F)C(F)(F)S(=O)(=O)[O-]
Reactant: OC12CC3CC(CC(C3)C1)C2
Agent: [Br-]
Agent: [Na]
Agent: c1ccc(-[s+]2c3ccccc3c3ccccc32)cc1
Solvent: O
Solvent: ClCCl
Product: CC(OC(=O)CC12CC3CC(CC(O)(C3)C1)C2)C(F)(F)C(F)(F)S(=O)(=O)[O-]
Yield: 97 %

Procedure:
5-phenyl-5H-dibenzo[b,d]thiophenium bromide (28.0 g, 82.04 mmol) and 3-hydroxyadamantane-acetoxy-1,1,2,2-tetrafluorobutane-1-sulfonate-sodium salt (35.68 g, 83.7 mmol) were dissolved in dichloromethane (500 mL) and water (500 mL) and stirred at r.t. for 16 h. The dichloromethane layer was separated and the aqueous phase washed with dichloromethane (3×300 mL). The combined organic layers were washed with water (4×500 mL), concentrated in vacuo and residual water removed via azeotrope with acetonitrile (2×350 mL) to afford the title compound (54.00 g, 99%) as a white solid. 1H NMR (500 MHz, (CD3)2CO) δ: 8.55 (d, J=8 Hz, 2H), 8.41 (d, J=8 Hz, 2H), 8.02 (dt, J=7.5, 0.5 Hz, 2H), 7.77-7.84 (m, 5H), 7.67 (t, J=7.5 Hz, 2H), 4.31 (t, J=6.5 Hz, 2H), 3.63 (s, 10H), 2.71 (tt, J=14, 6.5 Hz, 2H), 1.52-1.80 (m, 12H).
Reaction SMILES: Cl.C([O:5][C:6]1[CH:7]=[C:8]2[C:13](=[CH:14][C:15]=1[O:16][CH3:17])[N:12]=[CH:11][N:10]=[C:9]2[NH:18][C:19]1[CH:24]=[CH:23][CH:22]=[C:21]([Cl:25])[C:20]=1[F:26])(=O)C.O.[OH-].[Na+].C(O)(=O)C>CO>[Cl:25][C:21]1[C:20]([F:26])=[C:19]([CH:24]=[CH:23][CH:22]=1)[NH:18][C:9]1[C:8]2[C:13](=[CH:14][C:15]([O:16][CH3:17])=[C:6]([OH:5])[CH:7]=2)[N:12]=[CH:11][N:10]=1
Reactant: COc1cc2ncnc(Nc3cccc(Cl)c3F)c2cc1OC(C)=O
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CO
Solvent: CC(=O)O
Product: COc1cc2ncnc(Nc3cccc(Cl)c3F)c2cc1O
Temperature: 60 °C
Reaction time: 4.5 h
Yield: 98.2 %

Procedure:
6-Acetoxy-4-(3-chloro-2-fluoroanilino)-7-methoxyquinazoline hydrochloride from step 1 (33.5 kg, 69.6 mol) was suspended in methanol (198 kg). To the stirred suspension at 25° C. was added water (86 kg) and sodium hydroxide (31.5 kg, 32%). The resulting solution was stirred at 60° C. for 4.5 hours and then cooled to 25° C. Acetic acid (approximately 16.0 kg) was added until a pH of 5.5-6.0 was achieved at which point the product precipitates from solution. After the addition of further methanol (5.5 kg) the suspension was stirred for 90 minutes. The product was filtered then washed with 25% aqueous methanol (39.0 kg MeOH+17.0 kg Water) and then methanol (55.5 kg). The crude solid was dried under vacuum at 40° C. The crude solid was slurried with water (145 kg) and stirred for 2 hours at 65° C. The slurry was cooled to 20° C. and filtered. The filter cake was washed with methanol (2×21.5 kg), then dried under vacuum at 40° C. to give a the title product as a light brown solid (21.85 kg, 98%); 1H NMR: 3.95 (s, 3H), 7.19 (s, 1H), 7.23 (dd, 1H), 7.42 (dd, 1H), 7.50 (dd, 1H), 7.64 (s, 1H), 8.32 (s, 1H), 9.43 (s, 1H), 9.67 (br.s, 1H); Mass Spectrum: 320.4, 322.4.
Reaction SMILES: [F:1][C:2]([F:31])([F:30])[C:3]1[CH:4]=[C:5]([CH:23]=[C:24]([C:26]([F:29])([F:28])[F:27])[CH:25]=1)[C:6]([N:8]1[CH2:13][CH2:12][NH:11][CH2:10][C@H:9]1[CH2:14][C:15]1[CH:20]=[CH:19][C:18]([CH3:21])=[C:17]([CH3:22])[CH:16]=1)=[O:7].C(=O)([O-])[O-].[K+].[K+].[CH2:38](Br)[C:39]#[CH:40].O>CN(C)C=O>[F:31][C:2]([F:1])([F:30])[C:3]1[CH:4]=[C:5]([CH:23]=[C:24]([C:26]([F:27])([F:28])[F:29])[CH:25]=1)[C:6]([N:8]1[CH2:13][CH2:12][N:11]([CH2:40][C:39]#[CH:38])[CH2:10][C@H:9]1[CH2:14][C:15]1[CH:20]=[CH:19][C:18]([CH3:21])=[C:17]([CH3:22])[CH:16]=1)=[O:7]
Reactant: Cc1ccc(C[C@@H]2CNCCN2C(=O)c2cc(C(F)(F)F)cc(C(F)(F)F)c2)cc1C
Reactant: C#CCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: C#CCN1CCN(C(=O)c2cc(C(F)(F)F)cc(C(F)(F)F)c2)[C@H](Cc2ccc(C)c(C)c2)C1
Reaction time: 1 h

Procedure:
To a stirred mixture of (2R)-[3,5-bis(trifluoromethyl)benzoyl]-2-(3,4-dimethylbenzyl)piperazine (943 mg) and potassium carbonate (880 mg) in dimethylformamide (10 ml) was added propargyl bromide (0.2 ml) at room temperature. After 1 hour, the reaction mixture was poured into water (100 ml) and extracted with ethyl acetate. The extract was washed with brine and concentrated under reduced pressure. The obtained residue was purified by column chromatography on silica gel using a mixture of hexane and ethyl acetate (5:1) as eluent to give (2R)-1-[3,5-bis(trifluoromethyl)benzoyl]-2-(3,4-dimethylbenzyl)-4-propargylpiperazine (1.09 g) as an oil.
Reaction SMILES: [CH2:1]([Li])CCC.CC1(C)CCCC(C)(C)N1.[Cl:16][C:17]1[CH:22]=[N:21][CH:20]=[C:19]([Cl:23])[N:18]=1.IC.Cl>C1COCC1.C(O)C>[Cl:16][C:17]1[C:22]([CH3:1])=[N:21][CH:20]=[C:19]([Cl:23])[N:18]=1
Reactant: [Li]CCCC
Reactant: Clc1cncc(Cl)n1
Agent: CC1(C)CCCC(C)(C)N1
Agent: Cl
Solvent: C1CCOC1
Solvent: CCO
Solvent: CI
Product: Cc1ncc(Cl)nc1Cl
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
To a solution of n-butyllithium (3.8 mL, 2.5M in hexane, 9.4 mmol) in THF (40 mL) cooled to −30° C. under nitrogen was added 2,2,6,6-tetramethylpiperidine (1.7 mL, 10.1 mmol). This solution was allowed to warm to 0° C. over 20 min. and was then cooled to −70° C. A solution of 2,6-dichloropyrazine (1 g, 6.7 mmol) in THF (40 mL) was added dropwise and the resulting brown solution stirred at −70° C. for 30 min. Iodomethane (4.1 mL, 67 mmol) was then added and the solution stirred at −70° C. for a further 45 min after which time a mixture of ethanol (5 mL), THF (5 mL) and 1N HCl (1 mL) was added. The solution was allowed to warm to room temperature and was concentrated under reduced pressure. The residue was dissolved in H2O (50 mL) and the product extracted into dichloromethane (3×30 mL). The combined organic layers were washed with H2O (50 mL) and brine (50 mL) and dried (Na2SO4). The organic layer was concentrated in vacuo and the residue purified by column chromatography eluting with dichloromethane-hexane (1:1) to separate the product as a clear motile oil (820 mg).
Reaction SMILES: [C:1]([C:4]1[CH:5]=[CH:6][C:7](=[O:15])[NH:8][C:9]=1[CH:10]=[CH:11][N:12](C)C)(=O)[CH3:2].C(N)=N.C([O-])(=O)C.[NH4+]>>[CH3:2][C:1]1[N:12]=[CH:11][CH:10]=[C:9]2[C:4]=1[CH:5]=[CH:6][C:7](=[O:15])[NH:8]2
Reactant: CC(=O)c1ccc(=O)[nH]c1C=CN(C)C
Agent: CC(=O)[O-]
Agent: N=CN
Agent: [NH4+]
Product: Cc1nccc2[nH]c(=O)ccc12

Procedure:
The process according to claim 12 which comprises reacting 5-acetyl-6-(2-dimethylaminoethenyl)-2(1H)-pyridinone with formamidine or ammonium acetate to produce 5-methyl-1,6-naphthyridin-2(1H)-one.
Reaction SMILES: Cl[C:2]1[C:10]([Cl:11])=[CH:9][CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=[O:5].[OH-].[Na+].[NH3:14]>Cl[Cu].O>[NH2:14][C:2]1[C:10]([Cl:11])=[CH:9][CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=[O:5]
Reactant: N
Reactant: O=C(O)c1cccc(Cl)c1Cl
Agent: Cl[Cu]
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: Nc1c(Cl)cccc1C(=O)O
Temperature: 25 °C
Yield: 98 %

Procedure:
A solution comprising 191 parts of 2,3-dichlorobenzoic acid and 40 parts of NaOH prills in 500 parts of water, and 3 parts of CuCl are initially introduced into a 2 l V4A autoclave. 425 parts of liquid NH3 (d20 : 0.61) are then also forced in, and the autoclave is heated at 165° to 175° C. for 3 hours, during which the pressure drops from initially 50 bar to about 46 bar. When the reaction has ended, the contents of the autoclave are cooled to 25° C. and drained off over the ascending line. The reaction solution is boiled under reflux until a bottom temperature of 100° C. is reached, and the NH3 gas driven off is collected in a waste gas washer. Working up in accordance with Example 1 gives 168 parts (98% of theory) of 2-amino-3-chlorobenzoic acid of melting point 185° to 187 ° C.
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[N:10]=[N:11][C:12]1[CH:17]=[C:16]([C:18]([CH2:21][CH3:22])([CH3:20])[CH3:19])[CH:15]=[C:14]([C:23]([CH2:26][CH3:27])([CH3:25])[CH3:24])[C:13]=1[OH:28])([O-])=O.NCCNCCN>C1(C)C(C)=CC=CC=1>[OH:28][C:13]1[C:14]([C:23]([CH2:26][CH3:27])([CH3:25])[CH3:24])=[CH:15][C:16]([C:18]([CH2:21][CH3:22])([CH3:20])[CH3:19])=[CH:17][C:12]=1[N:11]1[N:10]=[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]2=[N:1]1
Reactant: CCC(C)(C)c1cc(N=Nc2ccccc2[N+](=O)[O-])c(O)c(C(C)(C)CC)c1
Agent: NCCNCCN
Solvent: Cc1ccccc1C
Product: CCC(C)(C)c1cc(-n2nc3ccccc3n2)c(O)c(C(C)(C)CC)c1
Yield: 86.5 %

Procedure:
Example 1 is repeated, except that an equivalent amount of 2-nitro-2'-hydroxy-3', 5'-di-tert.-amylazobenzene (91.6% pure) is used instead of 2-nitro-2'-hydroxy-5'-methylazobenzene and a mixture of 60 g of xylene and 40 g of diethylenetriamine is used instead of 80 g of xylene and 20 g of diethylenetriamine. The work up is analogous (filtering off the catalyst, separating off the amine bottom phase, extracting the remaining amine from the xylene top phase with water, concentration and crystallization from xylene/methanol). The title product is isolated in a yield of 86.5% of theory. Melting point: 80°-82° C.
Reaction SMILES: [CH2:1]([N:8]1[CH:12]([C:13]2[CH:18]=[CH:17][CH:16]=[C:15]([O:19][CH3:20])[CH:14]=2)[CH:11]([CH2:21][OH:22])[CH2:10][C:9]1=[O:23])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[K].[C:25]1([CH3:35])[CH:30]=[CH:29][C:28]([S:31](Cl)(=[O:33])=[O:32])=[CH:27][CH:26]=1.Cl>>[CH2:1]([N:8]1[CH:12]([C:13]2[CH:18]=[CH:17][CH:16]=[C:15]([O:19][CH3:20])[CH:14]=2)[CH:11]([CH2:21][O:22][S:31]([C:28]2[CH:29]=[CH:30][C:25]([CH3:35])=[CH:26][CH:27]=2)(=[O:33])=[O:32])[CH2:10][C:9]1=[O:23])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: COc1cccc(C2C(CO)CC(=O)N2Cc2ccccc2)c1
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Agent: Cl
Agent: [K]
Product: COc1cccc(C2C(COS(=O)(=O)c3ccc(C)cc3)CC(=O)N2Cc2ccccc2)c1
Reaction time: 3 h

Procedure:
To 21.4 gm. of 1-benzyl-4-hydroxymethyl-5-(3methoxyphenyl)pyrrolidin-2-one in 40 ml. of potassium dried pyridine was slowly added at -4° to -7°, 14.4 gm of p-toluenesulfonyl chloride. The reaction mixture was stirred for 3 hours at 15° and then diluted with 180 ml. of 10% hydrochloric acid. The gum was extracted with chloroform, dried (Na2SO4), filtered and concentrated in vacuo to provide 24.6 gm. of the desired product as an oil. ir (CHCl3): 1165-1195 cm-1 ; 1335-1375 cm-1
Reaction SMILES: F[B-](F)(F)F.[NH4+].[Br:7][C:8]1[CH:14]=[CH:13][C:11]([NH2:12])=[C:10]([CH3:15])[CH:9]=1.Cl.[N:17]([O-])=O.[Na+].C1OCCOCCOCCOCCOCCOC1>C(O)(=O)C>[Br:7][C:8]1[CH:9]=[C:10]2[C:11](=[CH:13][CH:14]=1)[NH:12][N:17]=[CH:15]2
Reactant: Cc1cc(Br)ccc1N
Reactant: O=N[O-]
Agent: C1COCCOCCOCCOCCOCCO1
Agent: Cl
Agent: F[B-](F)(F)F
Solvent: CC(=O)O
Product: Brc1ccc2[nH]ncc2c1
Temperature: 0 °C
Reaction time: 0.33 h
Yield: 152.3 %

Procedure:
Ammonium tetrafluoroborate (20.97 g, 200 mmol) was dissolved in aqueous acetic acid (500 mL AcOH/250 mL water) and cooled to 0° C. 4-Bromo-2-methyl aniline (compound if, 18.61 g, 100 mmol) and 42 mL of aqueous concentrated HCl (36% w/w, 12N, 500 mmol) were sequentially added. The mixture was stirred for 20 minutes at 0° C., and then NaNO2 (7.59 g, 110 mmol) was added. The reaction was stirred for 1 hour at 0° C. and warmed to room temperature. After 16 hours at room temperature, the mixture was concentrated under reduced pressure and the residue was azeotroped with toluene and dried under high vacuum. The solid was suspended in 500 mL of CHCl3 and KOAC (12.76 g, 130 mmol) and 18-crown-6 (7.93 g, 30 mmol) were added. The reaction was stirred for 1.5 hours at room temperature. The mixture was washed with water, dried over anhydrous MgSO4, filtered through Celite and concentrated under reduced pressure to provide 30 g of 5-bromo-1H-indazole (2f) as a tan solid. The crude material was used without further purification.
Reaction SMILES: [CH3:1][C:2]1[C:7]([OH:8])=[CH:6][CH:5]=[CH:4][N:3]=1.[H-].[Na+].[Br:11][C:12]1[CH:13]=[C:14]([N+]([O-])=O)[C:15]([C:18]#[N:19])=[N:16][CH:17]=1.O>CN(C=O)C>[Br:11][C:12]1[CH:13]=[C:14]([O:8][C:7]2[C:2]([CH3:1])=[N:3][CH:4]=[CH:5][CH:6]=2)[C:15]([C:18]#[N:19])=[N:16][CH:17]=1
Reactant: N#Cc1ncc(Br)cc1[N+](=O)[O-]
Reactant: Cc1ncccc1O
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: Cc1ncccc1Oc1cc(Br)cnc1C#N
Temperature: 25 °C
Reaction time: 8 h
Yield: 47.9 %

Procedure:
To a solution of 2-methylpyridin-3-ol (11.8 g, 108 mmol) in DMF at 0° C. was added sodium hydride (60% dispersion in oil, 4.32 g, 108 mmol) in small portions and the reaction was warmed to ambient temperature. 5-Bromo-3-nitropicolinonitrile (24.6 g, 108 mmol) was added and the reaction was stirred overnight at ambient temperature. The reaction was poured into water (1000 mL) and the aqueous layer extracted with EtOAc. The combined organic layers were washed with water and brine, dried over MgSO4 and concentrated in vacuo to yield 5-bromo-3-(2-methylpyridin-3-yloxy)picolinonitrile (15 g, 48%).