Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][C:5]2[O:6][C:7]([CH3:14])([CH3:13])[C:8](=[O:12])[NH:9][C:10]=2[N:11]=1.[Cl:15][C:16]1[N:21]=[C:20](Cl)[C:19]([F:23])=[CH:18][N:17]=1>CO.O.ClCCl>[Cl:15][C:16]1[N:21]=[C:20]([NH:1][C:2]2[CH:3]=[CH:4][C:5]3[O:6][C:7]([CH3:14])([CH3:13])[C:8](=[O:12])[NH:9][C:10]=3[N:11]=2)[C:19]([F:23])=[CH:18][N:17]=1
Reactant: Fc1cnc(Cl)nc1Cl
Reactant: CC1(C)Oc2ccc(N)nc2NC1=O
Solvent: CO
Solvent: O
Solvent: ClCCl
Product: CC1(C)Oc2ccc(Nc3nc(Cl)ncc3F)nc2NC1=O
Temperature: 65 °C
Reaction time: 4 h
Yield: 77 %

Procedure:
6-amino-2,2-dimethyl-4H-pyrido[3,2-b][1,4]oxazin-3-one (450 kg, 1.00 mol eq) is stirred in a mixture of methanol (1971 kg) and water (1610 kg) under a nitrogen atmosphere with heating to about 65° C. To this is added a solution of 2,4-dichloro-5-fluoro-pyrimidine in dichloromethane (545 kg 2,4-dichloro-5-fluoro-pyrimidine, 1.40 mol eq, about 50% w/w solution) over a period of about 4 hours, during which dichloromethane is distilled off. The mixture is then stirred at about 70° C. until distillation is complete and then at reflux for about 15 hours. This is then cooled to about 45° C. and filtered. The filtered solid is washed twice with methanol (2×675 kg) and then dried under vacuum at about 55° C. Once dry, the solid is slurried in 85% w/w aqueous formic acid (3150 kg) at about 50° C. for about 6 hours and then filtered. This slurry may be repeated. The resulting damp solid is cooled to about 20° C., washed twice with methanol (2×1800 kg) and dried under vacuum at about 80° C. to give the title compound (577 kg, 77%) as a colored solid.
Reaction SMILES: [CH3:1][C:2]([CH3:11])([CH2:8][CH2:9][CH3:10])[CH2:3][CH:4]([OH:7])[C:5]#[CH:6].[O:12]1[CH:17]=[CH:16][CH2:15][CH2:14][CH2:13]1>P(Cl)(Cl)(Cl)=O>[CH3:1][C:2]([CH3:11])([CH2:8][CH2:9][CH3:10])[CH2:3][CH:4]([O:7][CH:13]1[CH2:14][CH2:15][CH2:16][CH2:17][O:12]1)[C:5]#[CH:6]
Reactant: C1=COCCC1
Reactant: C#CC(O)CC(C)(C)CCC
Solvent: O=P(Cl)(Cl)Cl
Product: C#CC(CC(C)(C)CCC)OC1CCCCO1

Procedure:
Treatment of 23.1 g. (0.150 mole) of 5,5-dimethyl-1-octyn-3-ol (Example 998) with 126 g. of dihydropyran and 1 drop of phosphorus oxychloride as described in Example 995 gives the title compound.
Reaction SMILES: [CH3:1][NH:2][CH2:3][CH2:4][CH2:5][C:6]1([C:17]2[CH:22]=[CH:21][C:20]([F:23])=[CH:19][CH:18]=2)[C:10]2[CH:11]=[CH:12][C:13]([C:15]#[N:16])=[CH:14][C:9]=2[CH2:8][O:7]1.CO[C:26]1[CH2:27][CH2:28][CH2:29][CH2:30][N:31]=1>>[F:23][C:20]1[CH:21]=[CH:22][C:17]([C:6]2([CH2:5][CH2:4][CH2:3][N:2]([CH3:1])[C:26]3[CH2:27][CH2:28][CH2:29][CH2:30][N:31]=3)[C:10]3[CH:11]=[CH:12][C:13]([C:15]#[N:16])=[CH:14][C:9]=3[CH2:8][O:7]2)=[CH:18][CH:19]=1
Reactant: CNCCCC1(c2ccc(F)cc2)OCc2cc(C#N)ccc21
Reactant: COC1=NCCCC1
Product: CN(CCCC1(c2ccc(F)cc2)OCc2cc(C#N)ccc21)C1=NCCCC1
Temperature: 80 °C

Procedure:
A mixture of 0.200 g (0.64 mmol) of 1-[3-(methylamino)propyl]-1-(4-fluorophenyl)-1,3-dihydro-2-benzofuran-5-carbonitrile (Preparation 1) and 6-methoxy-2,3,4,5-tetrahydropyridine (0.080 g, 0.71 mmol, 1.1 equiv.) was heated at 80° C. for 15 hr, cooled to rt and concentrated in vacuo to a gummy residue. The crude product was purified using column chromatography to give the title product as an off-white solid, 0.060 g (24%).
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1([C:9]2[CH:14]=[CH:13][C:12]([C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=3)=[CH:11][CH:10]=2)[CH2:8][CH2:7]1)=[O:5])[CH3:2].[Cl-].[Al+3].[Cl-].[Cl-].[C:25](Cl)(=[O:27])[CH3:26].O>C(Cl)Cl>[CH2:1]([O:3][C:4]([C:6]1([C:9]2[CH:10]=[CH:11][C:12]([C:15]3[CH:16]=[CH:17][C:18]([C:25](=[O:27])[CH3:26])=[CH:19][CH:20]=3)=[CH:13][CH:14]=2)[CH2:8][CH2:7]1)=[O:5])[CH3:2]
Reactant: CC(=O)Cl
Reactant: CCOC(=O)C1(c2ccc(-c3ccccc3)cc2)CC1
Agent: [Al+3]
Agent: [Cl-]
Solvent: ClCCl
Solvent: O
Product: CCOC(=O)C1(c2ccc(-c3ccc(C(C)=O)cc3)cc2)CC1
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 108.4 %

Procedure:
To 1-(biphenyl-4-yl)cyclopropanecarboxylic acid ethyl ester (9 g, 33.8 mmol) in CH2Cl2 (100 mL) was added aluminum chloride (9.4 g, 71 mmol) followed by acetyl chloride (5.5 g, 71 mmol). The solution was stirred at room temperature for 1.5 hours then slowly poured into water. The organic layer was separated and extracted 2 times with water. The organic layer was dried and evaporated to yield 11.3 g of the title compound.
Reaction SMILES: [O:1]=[C:2]1[CH2:8][C:7]2[CH:9]=[CH:10][CH:11]=[CH:12][C:6]=2[O:5][C:4]2[C:13]([CH:17]([CH3:21])[C:18](N)=[O:19])=[CH:14][CH:15]=[CH:16][C:3]1=2.[OH-:22].[K+].[OH-].[Na+]>C(O)C.O>[O:1]=[C:2]1[CH2:8][C:7]2[CH:9]=[CH:10][CH:11]=[CH:12][C:6]=2[O:5][C:4]2[C:13]([CH:17]([CH3:21])[C:18]([OH:22])=[O:19])=[CH:14][CH:15]=[CH:16][C:3]1=2
Reactant: CC(C(N)=O)c1cccc2c1Oc1ccccc1CC2=O
Reactant: [OH-]
Agent: [K+]
Agent: [Na+]
Solvent: CCO
Solvent: O
Product: CC(C(=O)O)c1cccc2c1Oc1ccccc1CC2=O
Reaction time: 6.5 h
Yield: 84.7 %

Procedure:
To 100 mg of 2-(10,11-dihydro-11-oxo dibenzo[b,f]oxepin-4-yl)-propionamide in 2 ml of ethanol was added 400 mg of potassium hydroxide in 2 ml of water and the mixture was refluxed with stirring for 6.5 hours. After the completion of the reaction, the solvent was distilled off to obtain the residue, to which was added 2N-sodium hydroxide solution, and the resulting mixture was extracted with ethyl acetate. The aqueous layer was acidified with hydrochloric acid and extracted with ethyl acetate. The extract was washed with saturated sodium chloride solution and dried over anhydrous sodium sulfate. The solvent was distilled off to obtain brown oil, which was chromatographed over silica gel, eluted with chloroform and crystallized from acetone-n-hexane to give 85 mg of 2-(10,11-dihydro-11-oxo dibenzo[b,f]oxepin-4-yl)-propionic acid as pale yellow crystals having a melting point of 159°-160° C.
Reaction SMILES: CC1C=CC(S(O[CH2:12][CH2:13][O:14][CH2:15][CH2:16][O:17][CH2:18][C:19]#[CH:20])(=O)=O)=CC=1.[NH2:21][C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1>>[CH2:18]([O:17][CH2:16][CH2:15][O:14][CH2:13][CH2:12][NH:21][C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)[C:19]#[CH:20]
Reactant: C#CCOCCOCCOS(=O)(=O)c1ccc(C)cc1
Reactant: Nc1ccccc1
Product: C#CCOCCOCCNc1ccccc1
Yield: 53.1 %

Procedure:
2-(2-(prop-2-ynyloxy)ethoxy)ethyl 4-methylbenzenesulfonate (s-8)2 (100 mg, 0.335 mmol, 0.31 equiv.) was dissolved in aniline (102 mg, 1.10 mmol, 1 equiv.). The reaction was allowed to proceed at 100° C. in a sealed reaction vessel for 5 hours, after which time it was chromatographed (Silica Gel, 25 g RediSep pre-packed column, 0% EtOAc:Hexanes→20% EtOAc:Hexanes) to yield N-(2-(2-(prop-2-ynyloxy)ethoxy)ethyl)aniline (s-9) as a brown oil (39.0 mg, 53.1%). IR (thin film) 3393 (m), 3278 (m), 3052 (w), 2865 (m), 2115 (w), 1603 (s), 1506 (s), 1461 (w), 1320 (w), 1277 (m), 1099 (s), 1030 (w), 750 (s), 693 (s); 1H NMR (500 MHz, CDCl3) δ 7.22-7.16 (m, 2H), 6.72 (t, J=7.3 Hz, 1H), 6.67-6.63 (m, 2H), 4.22 (d, J=2.4 Hz, 2H), 4.12 (s, 1H), 3.74-3.70 (m, 4H), 3.70-3.66 (m, 2H), 3.32 (t, J=5.2 Hz, 2H), 2.46 (t, J=2.4 Hz, 1H). 13C NMR (125 MHz, CDCl3) 148.7, 129.6, 117.9, 113.5, 80.0, 75.1, 70.5, 70.1, 69.5, 58.9, 43.9. HRMS (ES+) calc'd for C13H17NO2 (M+H) m/z 220.1293 Found 220.1327.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[NH:9][CH2:10][CH2:11][CH2:12][OH:13].Cl.[C:15](O)(=O)[CH3:16]>>[Cl:8][C:6]1[CH:5]=[CH:4][C:3]2[N:9]([CH2:10][CH2:11][CH2:12][OH:13])[C:15]([CH3:16])=[N:1][C:2]=2[CH:7]=1
Reactant: CC(=O)O
Reactant: Nc1cc(Cl)ccc1NCCCO
Agent: Cl
Product: Cc1nc2cc(Cl)ccc2n1CCCO

Procedure:
A mixture of 20 parts of 3-[(2-amino-4-chlorophenyl)amino]-1-propanol, 50 parts of acetic acid and 150 parts of a hydrochloric acid solution 4 N is stirred and refluxed overnight. The reaction mixture is cooled and evaporated. The residue is dissolved in water and the solution is alkalized with ammonium hydroxide. The product is extracted with trichloromethane. The extract is dried, filtered and evaporated. The residue is crystallized from a mixture of 4-methyl-2-pentanone and 2,2'-oxybispropane, yielding 5-chloro-2-methyl-1H-benzimidazole-1-propanol.
Reaction SMILES: [F:1][C:2]1[C:7]([NH2:8])=[CH:6][CH:5]=[C:4]([C:9]2[O:10][C:11]3[CH:17]=[CH:16][C:15]([O:18][CH3:19])=[CH:14][C:12]=3[CH:13]=2)[N:3]=1.C=O.[C:22](O)(=O)C.[BH3-]C#N.[Na+]>CO.ClC(Cl)C>[F:1][C:2]1[C:7]([NH:8][CH3:22])=[CH:6][CH:5]=[C:4]([C:9]2[O:10][C:11]3[CH:17]=[CH:16][C:15]([O:18][CH3:19])=[CH:14][C:12]=3[CH:13]=2)[N:3]=1
Reactant: COc1ccc2oc(-c3ccc(N)c(F)n3)cc2c1
Reactant: CC(=O)O
Agent: C=O
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CC(Cl)Cl
Solvent: CO
Product: CNc1ccc(-c2cc3cc(OC)ccc3o2)nc1F
Temperature: 25 °C
Reaction time: 2 h
Yield: 34.9 %

Procedure:
To a stirred solution of 2-fluoro-6-(5-methoxy-benzofuran-2-yl)-pyridin-3-ylamine (97 mg, 0.376 mmol) in a mixture of MeOH (2 mL) and dichloroethane (1 mL), formaldehyde (37% solution in water, 0.167 mL, 2.23 mmol) and acetic acid (50 μL, 0.87 mmol) were added. The reaction mixture was stirred for 2 hours at room temperature, then NaCNBH3 (94 mg, 1.50 mmol) was added in one portion and the stirring was continued for 45 minutes. The reaction was then quenched by addition of water (2 mL). The volatiles were removed under reduced pressure and the residue was extracted with dichloromethane (50 mL). The organic layer was washed with water, dried over Na2SO4, filtered and concentrated. The product was purified by flash column chromatography using 20% ethyl acetate in hexane to afford [2-fluoro-6-(5-methoxy-benzofuran-2-yl)-pyridin-3-yl]-methyl-amine (35.7 mg) as an off-white solid. 1H NMR (400 MHz, CDCl3) δ: 7.64 (d, J=8.2 Hz, 1H), 7.38 (d, J=8.98 Hz, 1H), 7.09 (s, 1H), 7.03 (d, J=2.34 Hz, 1H), 6.99 (dd, J=10.15, 8.20 Hz, 1H), 6.87 (dd, J=8.78, 2.54 Hz, 1H), 4.21 (br. s, 1H), 3.85 (s, 3H), 2.94 (d, J=5.07 Hz, 3H)
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[N:8]=[C:9]=[S:10].[C:11]([NH:14][NH2:15])(=O)[CH3:12]>>[F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[N:8]1[C:11]([CH3:12])=[N:14][N:15]=[C:9]1[SH:10]
Reactant: CC(=O)NN
Reactant: Fc1ccccc1N=C=S
Product: Cc1nnc(S)n1-c1ccccc1F

Procedure:
Using the method of Example 1, Part A of U.S. Pat. No. 4,338,453, 2-fluorophenyl isothiocyanate and acethydrazide are reacted to produce 4-(2-fluorophenyl)-5-methyl-4H-1,2,4-triazole-3-thiol (mp 236°-237° C., C:H:N:S:F ratio 51.69:3.86:20.10:15.84:9.10) which is converted to 4-(2-fluorophenyl)-3-methyl-4H-1,2,4-triazole (mp 119°-120° C., C:H:N:F ratio 61.28:4.83:23.58:10.42).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:8]=[C:9]([O:11][CH3:12])[CH:10]=1)[CH2:6][NH2:7].[CH2:13]1[CH2:19][S:16](=[O:18])(=[O:17])[O:15][CH2:14]1>CC(=O)CC>[CH3:12][O:11][C:9]1[CH:8]=[C:5]([CH:4]=[C:3]([O:2][CH3:1])[CH:10]=1)[CH2:6][NH:7][CH2:14][CH2:13][CH2:19][S:16]([OH:18])(=[O:17])=[O:15]
Reactant: COc1cc(CN)cc(OC)c1
Reactant: O=S1(=O)CCCO1
Solvent: CCC(C)=O
Product: COc1cc(CNCCCS(=O)(=O)O)cc(OC)c1
Temperature: 25 °C

Procedure:
To a solution of 3,5-dimethoxybenzylamine (2.5 g, 15.0 mmol) in 2-butanone (22 mL) was added 1,3-propane sultone (1.95 g, 15.8 mmol). The mixture was stirred at reflux for 2 hours. The reaction mixture was cooled to room temperature. The solid was collected by filtration, washed with acetone (2×25 mL), and dried in vacuo. This allowed the isolation of compound BA, 2.89 g (67%).
Reaction SMILES: [CH2:1]([Sn](CCCC)(CCCC)CCCC)[CH:2]=[CH2:3].I[C:18]1[CH:23]=[CH:22][C:21]([N+:24]([O-:26])=[O:25])=[CH:20][CH:19]=1.[F-].[K+]>O1CCOCC1.C(OCC)C.[Pd].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[Cu]I>[CH2:3]([C:18]1[CH:23]=[CH:22][C:21]([N+:24]([O-:26])=[O:25])=[CH:20][CH:19]=1)[CH:2]=[CH2:1]
Reactant: C=CC[Sn](CCCC)(CCCC)CCCC
Reactant: O=[N+]([O-])c1ccc(I)cc1
Agent: [Cu]I
Agent: [Pd]
Agent: [F-]
Solvent: CCOCC
Solvent: C1COCCO1
Product: C=CCc1ccc([N+](=O)[O-])cc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 55 %

Procedure:
Add allyl tri-n-butylstannane (30.10 mmol, 9.33 ml) dropwise to a stirred solution of 4-iodo-nitrobenzene (5 g, 20.07 mmol), tetrakis-(triphenylphosphine) palladium(0) (1.16 g, 1 mmol) and copper (I) iodide (306 mg, 1.6 mmol) in 50 ml of dry 1,4-dioxane under argon atmosphere. Reflux the mixture for 24 hours and then cool to room temperature. Dilute the solution with 40 ml of diethyl ether and add 20 ml of saturated solution of KF and stir for 2 hours. Filter the mixture and wash the organic layer with water (20 ml), brine (20 ml) and dry over sodium sulfate. Evaporate the solution under reduced pressure and purify the residue by flash chromatography on silica gel using hexane-ethyl acetate as eluent (20:1) to afford 1.80 g (55%) of 1-allyl-4-nitrobenzene. Add a solution of 3-chloro-peroxybenzoic acid (5.98 g, 24.28 mmol), in 20 ml of dichloromethane to a solution of 1-allyl-4-nitro-benzene (1.8 g, 11.04 mmol) in 50 ml of dichloromethane and stir the mixture at room temperature overnight. Quench with saturated NaHCO3 (15 ml), and wash the organic layer three times with saturated NaHCO3 and dry over magnesium sulfate. Evaporate under reduced pressure to afford 1.4 g (71%) of the title compound.
Reaction SMILES: O[C:2]1([C:17]2[C:18](=[O:25])[NH:19][C:20](=[O:24])[N:21]([CH3:23])[CH:22]=2)[C:8]2[N:9]=[C:10]([CH3:12])[O:11][C:7]=2[CH2:6][CH2:5][C:4]2[CH:13]=[CH:14][CH:15]=[CH:16][C:3]1=2>FC(F)(F)C(O)=O>[CH3:12][C:10]1[O:11][C:7]2[CH:6]=[CH:5][C:4]3[CH:13]=[CH:14][CH:15]=[CH:16][C:3]=3[CH:2]([C:17]3[C:18](=[O:25])[NH:19][C:20](=[O:24])[N:21]([CH3:23])[CH:22]=3)[C:8]=2[N:9]=1
Reactant: Cc1nc2c(o1)CCc1ccccc1C2(O)c1cn(C)c(=O)[nH]c1=O
Solvent: O=C(O)C(F)(F)F
Product: Cc1nc2c(o1)C=Cc1ccccc1C2c1cn(C)c(=O)[nH]c1=O

Procedure:
A stirred solution of the product from step (ii) (280 mg) in trifluoroacetic acid (5 ml), was heated under reflux for 96 h and evaporated. The residue was slurried in toluene and evaporated (twice). Purification was by flash chromatography eluting 50% acetone in isohexane, followed by a second column eluting with 4% ethanol in dichloromethane to give a yellow solid. Yield 75 mg. Used directly in the next step.
Reaction SMILES: [Mg].II.[Cl:4][C:5]1[CH:10]=[CH:9][C:8](I)=[CH:7][C:6]=1[Cl:12].[O:13]=[C:14]1[C:23]2[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=2)[CH:17]([N:24]([CH3:28])[C:25](=[O:27])[CH3:26])[CH2:16][CH2:15]1.S(=O)(=O)(O)O>C(OCC)C.O1CCCC1>[Cl:12][C:6]1[CH:7]=[C:8]([C:14]2([OH:13])[C:23]3[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=3)[CH:17]([N:24]([CH3:28])[C:25](=[O:27])[CH3:26])[CH2:16][CH2:15]2)[CH:9]=[CH:10][C:5]=1[Cl:4]
Reactant: CC(=O)N(C)C1CCC(=O)c2ccccc21
Reactant: Clc1ccc(I)cc1Cl
Agent: II
Agent: O=S(=O)(O)O
Agent: [Mg]
Solvent: C1CCOC1
Solvent: CCOCC
Product: CC(=O)N(C)C1CCC(O)(c2ccc(Cl)c(Cl)c2)c2ccccc21
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 49.5 %

Procedure:
Magnesium turnings (2.04 g) and a crystal of iodine were stirred in dry diethyl ether (24 ml) as a solution of 1,2-dichloro-4-iodobenzene (23.17 g) in dry diethyl ether (60 ml) was added over 15 minutes. The mixture was stirred for 15 minutes and refluxed for a further 15 minutes to complete formation of the Grignard reagent. The mixture was cooled to room temperature and a solution of N-(1,2,3,4-tetrahydro-4-keto-1-naphthyl)-N-methylacetamide (12.3 g) in dry tetrahydrofuran (134 ml ) was added over 5 mutes. The mixture was stirred for 4 hours at room temperature, heated under reflux for 30 minutes, cooled and treated with 4N aqueous sulphuric acid (30 ml). The lower aqueous phase was separated and discarded, dichloromethane was added, and the solution was washed with water (2×25 ml). The organic layer was evaporated under vacuum to give a mixture of racemic cis-(1R*, 4S*)- and trans-(1R*, 4R*)-isomers (ratio 87:13 respectively by nmr spectroscopy techniques) as a light brown gum (24.5 g) which was stirred with diethyl ether (150 ml) for 1 hour, then filtered, to give the title compound as cream crystals (10.2 g, 49.5%), m.p. 146°-148° C.; Rf 0.41 (silica; chloroform, methanol; 95:5). Found: C,62.96; H,5.24; N,4.00 C19H19Cl2NO2 requires C,62.65; H,5.26; N 3.85%. GLC assay on a 2.1 m×4 mm 3% OV-17 column, temperature programmed from 100° to 275° C. at 10° C./minute, showed the product to be 96% pure (retention time 41.5 minutes) containing 3% recovered ketone.
Reaction SMILES: C[O:2][C:3]([C:5]1[N:6]([CH3:22])[S:7](=[O:21])(=[O:20])[C:8]2[C:19]3[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=3)[CH:13]=[CH:12][C:9]=2[C:10]=1[OH:11])=O.[NH2:23][CH:24]1[N:28]=[C:27]2[CH2:29][CH2:30][S:31][CH:32]=[C:26]2[S:25]1>C1(C)C(C)=CC=CC=1>[N:28]1[CH:24]([NH:23][C:3]([C:5]2[N:6]([CH3:22])[S:7](=[O:20])(=[O:21])[C:8]3[C:19]4[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=4)[CH:13]=[CH:12][C:9]=3[C:10]=2[OH:11])=[O:2])[S:25][C:26]2[C:27]=1[CH2:29][CH2:30][S:31][CH:32]=2
Reactant: NC1N=C2CCSC=C2S1
Reactant: COC(=O)C1=C(O)c2ccc3ccccc3c2S(=O)(=O)N1C
Solvent: Cc1ccccc1C
Product: CN1C(C(=O)NC2N=C3CCSC=C3S2)=C(O)c2ccc3ccccc3c2S1(=O)=O
Yield: 67 %

Procedure:
N-(5,6-Dihydro-7H-thiopyrano[4,3-d]thiazol-2-yl)-4-hydroxy-2-methyl-2H-naphtho[2,1-e]-1,2-thiazine-3-carboxamide-1,1-dioxide was prepared analogous toExample 22 from 4-hydroxy-2-methyl-2H-naphtho[2,1-e]-1,2-thiazine-3-carboxylic acid methylester-1,1-dioxide and 2-amino-5,6-dihydro-7H-thiopyrano[4,3-d]thiazole. yield: 67% of theory: m.p. 255° C (decomp.; from xylene).
Reaction SMILES: [C:1]([CH:3]([CH:7]1[C:11]([Cl:12])=[C:10](Cl)C(=O)O1)[C:4]([NH2:6])=[O:5])#[N:2].Cl.[F:16][C:17]1[CH:18]=[CH:19][C:20]([S:25]([N:28]2[CH2:33][CH2:32][CH2:31][CH2:30][CH2:29]2)(=[O:27])=[O:26])=[C:21]([CH2:23][NH2:24])[CH:22]=1.C(=O)([O-])[O-].[K+].[K+]>C(O)C>[ClH:12].[Cl:12][C:11]1[CH:7]=[C:3]([C:4]([NH2:6])=[O:5])[C:1](=[NH:2])[N:24]([CH2:23][C:21]2[CH:22]=[C:17]([F:16])[CH:18]=[CH:19][C:20]=2[S:25]([N:28]2[CH2:33][CH2:32][CH2:31][CH2:30][CH2:29]2)(=[O:27])=[O:26])[CH:10]=1
Reactant: N#CC(C(N)=O)C1OC(=O)C(Cl)=C1Cl
Reactant: NCc1cc(F)ccc1S(=O)(=O)N1CCCCC1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCO
Product: N=c1c(C(N)=O)cc(Cl)cn1Cc1cc(F)ccc1S(=O)(=O)N1CCCCC1
Temperature: 70 °C
Reaction time: 8 h
Yield: 76.1 %

Procedure:
(Step 2) A suspension of 2-cyano-2-(3,4-dichloro-5-oxo-2,5-dihydrofuran-2-yl)acetamide (1.0 g), 1-[5-fluoro-2-(piperidin-1-ylsulfonyl)phenyl]methanamine hydrochloride obtained in Step 1 (1.58 g) and potassium carbonate (1.76 g) in ethanol (10 ml) was stirred overnight at 70° C. The reaction solution was filtered through celite, and concentrated under reduced pressure. The residue was purified by basic silica gel column chromatography (ethyl acetate:hexane=7:3→1:0). The obtained residue was dissolved in methanol, 4N hydrogen chloride-ethyl acetate solution (1 ml) was added, and the mixture was crystallized from methanol-ethyl acetate. The precipitated crystals were collected by filtration, and recrystallized from methanol-ethyl acetate to give the title compound (0.75 g).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[CH:9]=[C:8]([CH:13]([CH3:17])[C:14]([OH:16])=O)[CH:7]=[CH:6]2.C(Cl)(=O)C(Cl)=O.[O:24]=[C:25]1[NH:29][CH:28]([C:30]([OH:32])=[O:31])[CH2:27][S:26]1.C(N(CC)CC)C>C1(C)C=CC=CC=1.CN(C)C=O.CN(C)C1C=CN=CC=1.O1CCCC1>[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[CH:9]=[C:8]([CH:13]([CH3:17])[C:14]([N:29]1[C@H:28]([C:30]([OH:32])=[O:31])[CH2:27][S:26][C:25]1=[O:24])=[O:16])[CH:7]=[CH:6]2
Reactant: O=C1NC(C(=O)O)CS1
Reactant: COc1ccc2cc(C(C)C(=O)O)ccc2c1
Agent: CN(C)c1ccncc1
Agent: O=C(Cl)C(=O)Cl
Solvent: CN(C)C=O
Solvent: C1CCOC1
Solvent: Cc1ccccc1
Product: COc1ccc2cc(C(C)C(=O)N3C(=O)SC[C@H]3C(=O)O)ccc2c1
Temperature: -10 °C
Reaction time: 24 h
Yield: 68.5 %

Procedure:
To a solution of 6-methoxy-α-methyl-2-naphthalenacetic acid (7.0 g, 30.4 mmoles) in toluene (100 ml) and N,N-dimethylformamide (10 ml) cooled at 0° C., oxalylchloride (5.23 ml, 61 mmoles) is added. After 2 hours at room temperature the solution is evaporated at reduced pressure. To the solution of the obtained residue dissolved in tetrahydrofuran (50 ml) a mixture is added consisting of 2-oxothiazolidin-4-carboxylic acid (4.07 g, 27.6 mmoles), 4-dimethylaminopyridine (0.84 g, 6.9 mmoles), triethylamine (7.69 ml, 55.2 mmoles) in tetrahydrofuran (50 ml) cooled at −10° C. The mixture is left at room temperature for 24 hours. The reaction mixture is washed with HCl 5%, then with water. The organic phase is anhydrified with sodium sulphate and then evaporated at reduced pressure. The obtained residue is purified by chromatography on silica gel eluting with methylene chloride/methanol 95/5. 6.79 g of the expected product are obtained in the form of an amorphous solid.
Reaction SMILES: [CH3:1][O:2][C:3]1[N:12]=[C:11]2[C:6]([CH:7]=[CH:8][C:9](=[O:29])[N:10]2[CH2:13][CH2:14][N:15]2[CH2:20][CH2:19][CH:18]([NH:21]C(=O)OC(C)(C)C)[CH2:17][CH2:16]2)=[CH:5][CH:4]=1.[ClH:30].C(OCC)(=O)C>>[ClH:30].[NH2:21][CH:18]1[CH2:17][CH2:16][N:15]([CH2:14][CH2:13][N:10]2[C:11]3[C:6](=[CH:5][CH:4]=[C:3]([O:2][CH3:1])[N:12]=3)[CH:7]=[CH:8][C:9]2=[O:29])[CH2:20][CH2:19]1
Reactant: COc1ccc2ccc(=O)n(CCN3CCC(NC(=O)OC(C)(C)C)CC3)c2n1
Agent: Cl
Solvent: CCOC(C)=O
Product: COc1ccc2ccc(=O)n(CCN3CCC(N)CC3)c2n1
Temperature: 25 °C
Reaction time: 29 h

Procedure:
To 2.8 g of tert-butyl (1-(2-(7-methoxy-2-oxo-1,8-naphthyridin-1(2H)-yl)ethyl)piperidin-4-yl)carbamate, 50 mL of a 4 mol/L hydrogen chloride/ethyl acetate solution was added, and the mixture was stirred at room temperature for 29 hours. The solvent was distilled off under reduced pressure, ethyl acetate was added to the solid thus obtained, and a crystal was filtered off and washed with ethyl acetate to obtain 2.3 g of 1-(2-(4-aminopiperidin-1-yl)ethyl)-7-methoxy-1,8-naphthyridin-2(1H)-one hydrochloride as a light yellow solid.
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]([F:26])=[C:6]([C:8]2([C:19]3[CH:24]=[CH:23][N:22]=[C:21]([CH3:25])[CH:20]=3)[C:16]3[C:11](=[C:12]([F:17])[CH:13]=[CH:14][CH:15]=3)[C:10]([NH2:18])=[N:9]2)[CH:7]=1.[C:27]([C:29]1[CH:30]=[C:31](B(O)O)[CH:32]=[N:33][CH:34]=1)#[N:28]>>[NH2:18][C:10]1[C:11]2[C:16](=[CH:15][CH:14]=[CH:13][C:12]=2[F:17])[C:8]([C:6]2[CH:7]=[C:2]([C:31]3[CH:32]=[N:33][CH:34]=[C:29]([CH:30]=3)[C:27]#[N:28])[CH:3]=[CH:4][C:5]=2[F:26])([C:19]2[CH:24]=[CH:23][N:22]=[C:21]([CH3:25])[CH:20]=2)[N:9]=1
Reactant: N#Cc1cncc(B(O)O)c1
Reactant: Cc1cc(C2(c3cc(Br)ccc3F)N=C(N)c3c(F)cccc32)ccn1
Product: Cc1cc(C2(c3cc(-c4cncc(C#N)c4)ccc3F)N=C(N)c3c(F)cccc32)ccn1
Yield: 38 %

Procedure:
The title compound was synthesized as described for Example 1 in 38% yield, starting from 1-(5-bromo-2-fluorophenyl)-4-fluoro-1-(2-methylpyridin-4-yl)-1H-isoindol-3-amine (80 mg, 0.19 mmol) and 5-cyanopyridin-3-ylboronic acid (37.1 mg, 0.25 mmol).
Reaction SMILES: O[CH2:2][C:3]1[CH:4]=[CH:5][CH:6]=[C:7]2[C:12]=1[N:11]=[C:10]1[N:13]([CH3:20])[C:14]3[CH:15]=[CH:16][CH:17]=[CH:18][C:19]=3[C:9]1=[N:8]2.S(Cl)([Cl:23])=O>C(Cl)Cl>[Cl:23][CH2:2][C:3]1[CH:4]=[CH:5][CH:6]=[C:7]2[C:12]=1[N:11]=[C:10]1[N:13]([CH3:20])[C:14]3[CH:15]=[CH:16][CH:17]=[CH:18][C:19]=3[C:9]1=[N:8]2
Reactant: O=S(Cl)Cl
Reactant: Cn1c2ccccc2c2nc3cccc(CO)c3nc21
Solvent: ClCCl
Product: Cn1c2ccccc2c2nc3cccc(CCl)c3nc21
Temperature: 0 °C
Reaction time: 3 h
Yield: 102.5 %

Procedure:
To a solution of 304 mg (1.16 mmol) of 4-hydroxymethyl-6-methylindolo[2,3-b]quinoxaline in 30 ml of methylene chloride was added 0.126 ml (1.73 mmol, 1.5 eq.) of thionyl chloride under ice-cooling, followed by stirring for 3 hours. The reaction solution was poured into 50 ml of ice water, and extracted with methylene chloride. The organic layer was washed 3 times with a saturated aqueous sodium hydrogen carbonate solution and dried over anhydrous sodium sulfate. Evaporation of the solvent gave 335 mg of the crude product 4-chloromethyl-6-methylindolo[2,3-b]quinoxaline, which was used for the next reaction without further purification.