Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([C:4]1[CH:21]=[CH:20][C:7]([NH:8][C:9]2[C:17]([F:18])=[C:16]([F:19])[CH:15]=[CH:14][C:10]=2[C:11]([OH:13])=O)=[C:6]([F:22])[CH:5]=1)[CH:2]=[CH2:3].[NH2:23][O:24][CH2:25][CH2:26][OH:27].[Cl-].COC1N=C(OC)N=C([N+]2(C)CCOCC2)N=1>CO>[CH2:1]([C:4]1[CH:21]=[CH:20][C:7]([NH:8][C:9]2[C:17]([F:18])=[C:16]([F:19])[CH:15]=[CH:14][C:10]=2[C:11]([NH:23][O:24][CH2:25][CH2:26][OH:27])=[O:13])=[C:6]([F:22])[CH:5]=1)[CH:2]=[CH2:3]
Reactant: NOCCO
Reactant: C=CCc1ccc(Nc2c(C(=O)O)ccc(F)c2F)c(F)c1
Agent: COc1nc(OC)nc([N+]2(C)CCOCC2)n1
Agent: [Cl-]
Solvent: CO
Product: C=CCc1ccc(Nc2c(C(=O)NOCCO)ccc(F)c2F)c(F)c1
Temperature: 25 °C
Reaction time: 15 h
Yield: 87.9 %

Procedure:
2-(4-Allyl-2-fluoroanilino)-3,4-difluorobenzoic acid (700 mg, 2.28 mmol) was dissolved in MeOH (20 mL) to which was added 2-(aminooxy)ethanol (263 mg, 3.42 mmol), followed by 4-(4,6-dimethoxy-1,3,5-triazin-2-yl)-4-methymorpholinium chloride [DMT-MM, prepared according to the procedure of Kunishima et al [Tetrahedron, 55, 13159-13170 (1999)]] (946 mg, 3.42 mmol). This mixture was stirred 15 h. at room temperature. The MeOH was removed under reduced pressure and the resulting oil dissolved in EtOAc (100 mL), which was washed with water (2×100 mL), brine (100 mL) and dried (Na2SO4). The solvent was removed under reduced pressure to afford a crude yellow oil which was purified by filtration through a plug of silica gel (50% EtOAc/PE as eluant) to give 2-(4-allyl-2-fluoroanilino)-3,4-difluoro-N-(2-hydroxyethoxy)benzamide as a white solid (734 mg, 88%); m.p. (EtOAc/hexane) 173-177° C. 1H NMR [400 MHz, (CD3)2SO] δ 11.85 (br s, 1 H), 8.75 (br s, 1 H), 7.43-7.37 (m, 1 H), 7.14-7.07 (m, 1 H), 7.05-6.99 (m, 1 H), 6.90-6.81 (m, 2 H), 5.99-5.87 (m, 1 H), 5.02-5.11 (m, 2 H), 4.70 (br s, 1 H), 3.85 (t, J=4.9 Hz, 1 H), 3.57 (t, J=4.9 Hz, 1 H), 3.51-3.40 (m, 2H, obscured by H2O). Anal. calcd. for C18H17F3N2O3: C, 59.0; H, 4.7; N, 7.7. Found C, 59.1; H, 4.5; N, 7.4.
Reaction SMILES: [NH2:1][C:2]1[N:3]=[N:4][C:5]([CH3:8])=[CH:6][CH:7]=1.Cl[CH2:10][C:11](=O)[CH3:12].C([O-])(O)=O.[Na+]>CCO>[CH3:12][C:11]1[N:1]=[C:2]2[CH:7]=[CH:6][C:5]([CH3:8])=[N:4][N:3]2[CH:10]=1
Reactant: CC(=O)CCl
Reactant: Cc1ccc(N)nn1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCO
Product: Cc1cn2nc(C)ccc2n1
Temperature: 25 °C
Yield: 50.8 %

Procedure:
A solution of 3-amino-6-methyl-pyridazine (4.53 g, 41.58 mmol) in EtOH (60 mL) is treated with chloroacetone (3.5 mL, 43.66 mmol). The reaction is refluxed overnight. While it is hot, NaHCO3 (8.7 g, 103.9 mmol) is added in portions. The resulting mixture is refluxed for 2 h. It is cooled to rt and filtered through silical gel, washed with EtOAc, and concentrated. Purification of the crude material by chromatography gives the title compound (3.1 g, 21.11 mmol, 51%). 1H NMR (CDCl3): δ 2.49 (s, 3H), 2.55 (s, 3H), 6.84 (d, J=9.3 Hz, 1H), 7.64 (s, 1H), 7.70 (d, J=9.3 Hz, 1H) ppm. ES-MS (m/z): calcd for C8H9N3 (M+H)+: 148.2. found: 148.1.
Reaction SMILES: Cl.Cl.[NH2:3][C:4]1[C:5]([CH3:15])=[N:6][C:7]([CH3:14])=[CH:8][C:9]=1[C:10]([F:13])([F:12])[F:11].N.CN(C)C1C=CC=CC=1.[Br:26][CH2:27][C:28](Br)=[O:29]>CO.ClCCl>[Br:26][CH2:27][C:28]([NH:3][C:4]1[C:5]([CH3:15])=[N:6][C:7]([CH3:14])=[CH:8][C:9]=1[C:10]([F:13])([F:11])[F:12])=[O:29]
Reactant: O=C(Br)CBr
Reactant: Cc1cc(C(F)(F)F)c(N)c(C)n1
Agent: Cl
Agent: N
Solvent: CO
Solvent: ClCCl
Solvent: CN(C)c1ccccc1
Product: Cc1cc(C(F)(F)F)c(NC(=O)CBr)c(C)n1
Yield: 95.8 %

Procedure:
3-Amino-2,6-dimethyl-4-trifluoromethylpyridine dihydrochloride (15.60 g, 59.30 mmol) was dissolved in methanol (100 mL). In an ice bath, an ammonia-saturated methanol solution (300 mL) was added, and the mixture was rendered uniform. The reaction mixture was extracted from chloroform-water. The organic layer was washed with brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was dissolved in dichloromethane (200 mL), and subsequent to the addition of N,N-dimethylaniline (10.80 g, 89.12 mmol), a solution of bromoacetyl bromide (15.52 g, 76.90 mmol) in dichloromethane (40 mL) was added dropwise while stirring the mixture in an ice bath. The mixture was stirred at room temperature for two hours, and concentrated under reduced pressure. The residue was purified by column chromatography on silica gel (silica gel: 400 g; developer: hexane:acetone=10:1→4:1→3:1). Recrystallization from ethyl acetate and hexane afforded the title compound (17.68 g, 96%) as colorless needles.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:18]=[CH:17][C:12]([CH:13]=[CH:14][CH2:15]Cl)=[CH:11][CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[NH2:19][C:20]1[S:21][C:22]2[CH2:23][CH2:24][NH:25][CH2:26][CH2:27][C:28]=2[N:29]=1.CCOCC>C(Cl)(Cl)Cl>[NH2:19][C:20]1[S:21][C:22]2[CH2:23][CH2:24][N:25]([CH2:15][CH:14]=[CH:13][C:12]3[CH:17]=[CH:18][C:9]([O:8][CH2:1][C:2]4[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=4)=[CH:10][CH:11]=3)[CH2:26][CH2:27][C:28]=2[N:29]=1
Reactant: Nc1nc2c(s1)CCNCC2
Reactant: ClCC=Cc1ccc(OCc2ccccc2)cc1
Solvent: ClC(Cl)Cl
Solvent: CCOCC
Product: Nc1nc2c(s1)CCN(CC=Cc1ccc(OCc3ccccc3)cc1)CC2
Yield: 13 %

Procedure:
Prepared from 4-benzyloxy-cinnamyl chloride and 2 equivalents of 2-amino-4,5,7,8-tetrahydro-6H- thiazolo[5,4-d]azepine in chloroform for one hour at 50° C. Yield: 13% of theory, Melting point: 135°-140° C. (ether).
Reaction SMILES: Cl.Cl.[NH2:3][C:4]1[C:8]([NH2:9])=[CH:7][S:6][CH:5]=1.C1COCC1.C(N(C(C)C)C(C)C)C.[Cl:24][C:25]1[CH:30]=[CH:29][CH:28]=[C:27]([Cl:31])[C:26]=1[N:32]=[C:33]=[S:34]>C(OCC)(=O)C>[NH2:3][C:4]1[C:8]([NH:9][C:33]([NH:32][C:26]2[C:27]([Cl:31])=[CH:28][CH:29]=[CH:30][C:25]=2[Cl:24])=[S:34])=[CH:7][S:6][CH:5]=1
Reactant: S=C=Nc1c(Cl)cccc1Cl
Reactant: Nc1cscc1N
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: Nc1cscc1NC(=S)Nc1c(Cl)cccc1Cl
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
A mixture of 1.87 g of 3,4-diaminothiophene dihydrochloride, 60 ml of anhydrous THF and 2.58 g of N-ethyl-N,N-diisopropylamine was stirred at room temperature for 30 minutes and then admixed with 2.04 g of 2,6-dichlorophenyl isothiocyanate. After the mixture had been heated to 40° C. for 10 minutes, it was stirred at room temperature for approx. 18 hours, and the solvent was distilled off, and the residue admixed with water and extracted repeatedly with ethyl acetate. After the combined organic phases had been treated with activated carbon, they were dried over sodium sulfate and the solvent was again distilled off. A crystalline solid was obtained and, after stirring with a little ethyl acetate, was filtered off. M.p. 165° C.
Reaction SMILES: [C:1](=[O:8])([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])[NH2:2].[OH-].[Na+].Cl[O:12]C(C)(C)C.[Br:17][C:18]1[CH:19]=[C:20](/[CH:25]=[CH:26]/[C:27]2[CH:32]=[CH:31][C:30]([F:33])=[CH:29][CH:28]=2)[C:21]([F:24])=[N:22][CH:23]=1>C(O)CC.O.CC[C@@H]1[C@@H]2C[C@H]([C@@H](OC3C4C(=CC=CC=4)C(O[C@@H](C4C=CN=C5C=4C=C(OC)C=C5)[C@@H]4N5C[C@H](CC)[C@@H](CC5)C4)=NN=3)C3C=CN=C4C=3C=C(OC)C=C4)N(CC2)C1>[Br:17][C:18]1[CH:19]=[C:20]([C@@H:25]([NH:2][C:1](=[O:8])[O:3][C:4]([CH3:7])([CH3:6])[CH3:5])[C@@H:26]([C:27]2[CH:32]=[CH:31][C:30]([F:33])=[CH:29][CH:28]=2)[OH:12])[C:21]([F:24])=[N:22][CH:23]=1
Reactant: CC(C)(C)OCl
Reactant: Fc1ccc(/C=C/c2cc(Br)cnc2F)cc1
Reactant: CC(C)(C)OC(N)=O
Agent: CC[C@H]1CN2CC[C@H]1C[C@@H]2[C@@H](Oc1nnc(O[C@@H](c2ccnc3ccc(OC)cc23)[C@H]2C[C@@H]3CCN2C[C@@H]3CC)c2ccccc12)c1ccnc2ccc(OC)cc12
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CCCO
Product: CC(C)(C)OC(=O)N[C@H](c1cc(Br)cnc1F)[C@H](O)c1ccc(F)cc1
Temperature: 0 °C
Reaction time: 1 h
Yield: 85.8 %

Procedure:
To a solution of tert-butyl carbamate (1431 mg, 12.22 mmol) in propanol (10 mL) was added sodium hydroxide (481 mg, 12.02 mmol) in water (4 mL) followed by tert-butyl hypochlorite (1305 mg, 12.02 mmol). After 5 min the solution was cooled to 0° C. and treated with a solution of (DHQD)2PHAL (154 mg, 0.197 mmol) in propanol (4 mL). To this solution was added a solution of (E)-5-bromo-2-fluoro-3-(4-fluorostyryl)pyridine (1167 mg, 3.94 mmol) in propanol (10 mL). To this solution was added potassium osmate dihydrate (58.1 mg, 0.158 mmol) in one portion. The reaction turned light orange and was allowed to stir at 0° C. for 1 hr. The ice bath was then removed and the reaction was allowed to warm to room temperature and stirred over night. The reaction was quenched with a 10% solution of sodium thiosulfate and stirred for 30 min. The reaction was then extracted with diethylether (3×). The combined organic extracts were combined washed with water, then brine. The organic layer was separated, dried over sodium sulfate and evaporated in vacuo. The crude residue was purified by silica gel chromatography 5% acetone/95% Hexanes to 50%/50% Acetone/Hexanes to afford tert-butyl (1R,2R)-1-(5-bromo-2-fluoropyridin-3-yl)-2-(4-fluorophenyl)-2-hydroxyethylcarbamate (1450 mg, 3.38 mmol, 86% yield) along with its regioisomer as an inseparable mixture. LC/Mass spec. (Analytical HPLC method 2): RT=2.07 min. Mass=429.30 (MH)+.
Reaction SMILES: [Cl:1][CH2:2][C:3]([C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1)=[O:4].[F:11][C:12]1([F:36])[CH2:17][CH2:16][N:15]([CH:18]([C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=2)[C:19]([O:21][C@@H:22]2[CH:27]3[CH2:28][CH2:29][N:24]([CH2:25][CH2:26]3)[CH2:23]2)=[O:20])[CH2:14][CH2:13]1>C(OCC)(=O)C>[Cl-:1].[F:36][C:12]1([F:11])[CH2:17][CH2:16][N:15]([CH:18]([C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=2)[C:19]([O:21][C@@H:22]2[CH:27]3[CH2:26][CH2:25][N+:24]([CH2:2][C:3](=[O:4])[C:5]4[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=4)([CH2:29][CH2:28]3)[CH2:23]2)=[O:20])[CH2:14][CH2:13]1
Reactant: O=C(CCl)c1ccccc1
Reactant: O=C(O[C@H]1CN2CCC1CC2)C(c1ccccc1)N1CCC(F)(F)CC1
Solvent: CCOC(C)=O
Product: O=C(C[N+]12CCC(CC1)[C@@H](OC(=O)C(c1ccccc1)N1CCC(F)(F)CC1)C2)c1ccccc1
Product: [Cl-]
Temperature: 25 °C
Reaction time: 8 h
Yield: 78 %

Procedure:
2-Chloro-1-phenylethanone (31.0 mg, 0.20 mmol) was added to a solution of (R)-quinuclidin-3-yl 2-(4,4-difluoropiperidin-1-yl)-2-phenylacetate (24b) (73 mg, 0.20 mmol) in ethyl acetate (3 ml). The reaction was stirred at room temperature overnight. The solvent was evaporated under reduced pressure and the residue was triturated with Et2O (4 ml). A white precipitate was formed and it was collected by suction filtration and dried under vacuum at 40° C. overnight, to obtain (3R)-3-(2-(4,4-difluoropiperidin-1-yl)-2-phenylacetoxy)-1-(2-oxo-2-phenylethyl)-1-azoniabicyclo[2.2.2]octane chloride (81 mg, 78% yield).
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[CH2:7][N:8]1[C:16]2[C:11](=[CH:12][C:13]([NH:17][C:18]3[C:27]4[C:22](=[CH:23][CH:24]=[CH:25][C:26]=4[O:28][C@H:29]([CH3:34])[C:30]([O:32]C)=O)[N:21]=[CH:20][N:19]=3)=[CH:14][CH:15]=2)[CH:10]=[N:9]1.[NH3:35]>CO>[N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[CH2:7][N:8]1[C:16]2[C:11](=[CH:12][C:13]([NH:17][C:18]3[C:27]4[C:22](=[CH:23][CH:24]=[CH:25][C:26]=4[O:28][C@H:29]([CH3:34])[C:30]([NH2:35])=[O:32])[N:21]=[CH:20][N:19]=3)=[CH:14][CH:15]=2)[CH:10]=[N:9]1
Reactant: COC(=O)[C@@H](C)Oc1cccc2ncnc(Nc3ccc4c(cnn4Cc4ccccn4)c3)c12
Reactant: N
Solvent: CO
Product: C[C@@H](Oc1cccc2ncnc(Nc3ccc4c(cnn4Cc4ccccn4)c3)c12)C(N)=O
Temperature: 25 °C
Reaction time: 48 h
Yield: 65 %

Procedure:
A solution of methyl (2R)-2-[(4-{[1-(pyridin-2-ylmethyl)-1H-indazol-5-yl]amino}quinazolin-5-yl)oxy]propanoate (250 mg, 0.55 mmol) in methanol (3 ml) was saturated with ammonia by bubbling gaseous ammonia into the solution for a few minutes. The tube containing the solution was sealed and the mixture was stirred for 48 hours at room temperature. The precipitate was filtered, washed with ether and dried to give the title compound as a white solid (165 mg, 65%); NMR Spectrum 1.66 (d, 3H), 5.14 (q, 1H), 5.77 (s, 2H), 6.94 (d, 1H), 7.02 (d, 1H), 7.30 (m, 1H), 7.36 (d, 1H), 7.55 (br s, 1H), 7.78-7.67 (m, 4H), 7.89 (br s, 1H), 8.15 (s, 1H), 8.52 (m, 3H), 10.80 (br s, 1H); Mass spectrum MH+ 440.
Reaction SMILES: C[O:2][C:3]([C:5]1[N:6]=[N:7][C:8]([N:11]2[CH2:16][CH2:15][N:14]([C:17](=[O:28])[C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=3[C:24]([F:27])([F:26])[F:25])[CH2:13][CH2:12]2)=[CH:9][CH:10]=1)=O.[N:29]1[CH:34]=[CH:33][CH:32]=[CH:31][C:30]=1NC.[C-:37]#[N:38].[Na+]>>[N:29]1[CH:34]=[CH:33][CH:32]=[CH:31][C:30]=1[CH2:37][NH:38][C:3]([C:5]1[N:6]=[N:7][C:8]([N:11]2[CH2:16][CH2:15][N:14]([C:17](=[O:28])[C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=3[C:24]([F:25])([F:26])[F:27])[CH2:13][CH2:12]2)=[CH:9][CH:10]=1)=[O:2]
Reactant: CNc1ccccn1
Reactant: [C-]#N
Reactant: COC(=O)c1ccc(N2CCN(C(=O)c3ccccc3C(F)(F)F)CC2)nn1
Agent: [Na+]
Product: O=C(NCc1ccccn1)c1ccc(N2CCN(C(=O)c3ccccc3C(F)(F)F)CC2)nn1
Temperature: 25 °C
Reaction time: 8 h
Yield: 48 %

Procedure:
A mixture of 6-[4-(2-Trifluoromethylbenzoyl)piperazin-1-yl]pyridazine-3-carboxylic acid methyl ester (0.099 g, 0.25 mmol), pyridin-2-yl-methylamine (0.7 mL) and sodium cyanide (0.245 g, 0.5 mmol) was stirred at ambient temperature overnight and purified by column chromatography to yield the title compound in 48% yield (0.057 g). m.p. 179-181° C. 1H NMR (300 MHz, CDCl3) δ 8.81, 8.59, 8.12, 7.78-7.50, 7.37, 7.21-7.13, 6.93, 4.83, 4.17-3.66, 3.37. 13C NMR (75 MHz, CDCl3) δ 167.6, 163.3, 160.0, 156.5, 149.0, 145.3, 137.0, 134.2, 132.4, 129.5, 127.2, 122.5, 121.9, 112.3, 46.4, 44.6, 44.4, 41.3. MS (ES+) m/z 471 (M+1).
Reaction SMILES: SC(S)C([N:5]([C:11]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12])[CH:6]([CH2:9][OH:10])[CH2:7][OH:8])=O.[OH-].[Na+].II.[O-][S:24]([O-])(=[S:26])=O.[Na+].[Na+]>CCO.C(Cl)Cl>[S:24]1[CH2:16][CH2:14][CH2:17][S:26]1.[C:11]([NH:5][CH:6]([CH2:7][OH:8])[CH2:9][OH:10])([O:13][C:14]([CH3:16])([CH3:17])[CH3:15])=[O:12]
Reactant: CC(C)(C)OC(=O)N(C(=O)C(S)S)C(CO)CO
Reactant: O=S([O-])([O-])=S
Agent: II
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: ClCCl
Product: C1CSSC1
Product: CC(C)(C)OC(=O)NC(CO)CO
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A solution of dimercaptoacetyl boc-serinol (4.1 mmol) in EtOH (20 ml) was treated with 10 ml of aqueous 1 N NaOH at room temperature for 1 h. The mixture was diluted with CH2Cl2 (100 ml) and then an aqueous solution of 0.1 M iodine (4.5 mmol) is added dropwise. The reaction mixture was stirred for 2 hours at room temperature and 1 mmol of Na2S2O3 (1 M aqueous solution) was added to the reaction mixture. The organic phase was separated, washed with water (3×200 mL), dried with magnesium sulfate, and evaporated at room temperature. The crude product was chromatographed on silica gel (200 mL) using a solvent mixture of hexane and ethyl acetate (40:20) as eluent to give 1,2-dithiolane of boc-serinol.
Reaction SMILES: [N+:1]([C:4]1[C:13]([O:14][CH:15]2[CH2:20][CH2:19][O:18][CH2:17][CH2:16]2)=[CH:12][CH:11]=[CH:10][C:5]=1[C:6]([O:8][CH3:9])=[O:7])([O-])=O.C(OCC)(=O)C>CO.[Ni]>[NH2:1][C:4]1[C:13]([O:14][CH:15]2[CH2:20][CH2:19][O:18][CH2:17][CH2:16]2)=[CH:12][CH:11]=[CH:10][C:5]=1[C:6]([O:8][CH3:9])=[O:7]
Reactant: COC(=O)c1cccc(OC2CCOCC2)c1[N+](=O)[O-]
Agent: [Ni]
Solvent: CCOC(C)=O
Solvent: CO
Product: COC(=O)c1cccc(OC2CCOCC2)c1N
Temperature: 25 °C
Reaction time: 24 h
Yield: 66.3 %

Procedure:
A mixture of methyl 2-nitro-3-(tetrahydro-2H-pyran-4-yloxy)benzoate (1.3 g, 4.8 mmol) and Raney Ni (0.5 g) in MeOH (30 mL) was stirred under 1 atm of H2 at room temperature for 24 h. TLC (petroleum ether:ethyl acetate=1:1) showed the reaction was complete. The mixture was filtered, the filtrate was concentrated in vacuo. The residue was purified by chromatography (petroleum ether:ethyl acetate=20:1) to give the title compound (0.8 g, 72%) as a colorless oil.
Reaction SMILES: [C:1](O)(=O)[C:2]1[C:3](=[CH:5][CH:6]=[CH:7][CH:8]=1)[NH2:4].[C:11]([C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)(=O)[CH2:12][CH3:13].P(Cl)(Cl)([Cl:23])=O>>[Cl:23][C:1]1[C:2]2[C:3](=[CH:5][CH:6]=[CH:7][CH:8]=2)[N:4]=[C:11]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[C:12]=1[CH3:13]
Reactant: O=P(Cl)(Cl)Cl
Reactant: CCC(=O)c1ccccc1
Reactant: Nc1ccccc1C(=O)O
Product: Cc1c(-c2ccccc2)nc2ccccc2c1Cl

Procedure:
Prepared according to Procedure J using anthranilic acid and propiophenone in phosphorous oxychloride to afford a colorless solid upon purification by chromatography on silica gel. Mass Spectrum (ESI) m/e=254.0 (M+1).
Reaction SMILES: [H-].[Na+].[Br:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[S:10]([NH:13][C:14]1[S:18][C:17]2[CH2:19][CH2:20][CH2:21][CH2:22][C:16]=2[C:15]=1[C:23]([O:25][CH2:26][CH3:27])=[O:24])(=[O:12])=[O:11].[CH3:28][Si:29]([CH3:36])([CH3:35])[CH2:30][CH2:31][O:32][CH2:33]Cl>C1COCC1>[Br:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[S:10]([N:13]([C:14]1[S:18][C:17]2[CH2:19][CH2:20][CH2:21][CH2:22][C:16]=2[C:15]=1[C:23]([O:25][CH2:26][CH3:27])=[O:24])[CH2:33][O:32][CH2:31][CH2:30][Si:29]([CH3:36])([CH3:35])[CH3:28])(=[O:11])=[O:12]
Reactant: CCOC(=O)c1c(NS(=O)(=O)c2ccccc2Br)sc2c1CCCC2
Reactant: C[Si](C)(C)CCOCCl
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CCOC(=O)c1c(N(COCC[Si](C)(C)C)S(=O)(=O)c2ccccc2Br)sc2c1CCCC2
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
Sodium hydride (60% dispersion in oil, 0.081 g) was added to a solution of ethyl 2-(2-bromobenzenesulphonylamino)-4,5,6,7-tetrahydrobenzo[b]thiophene-3-carboxylate (Intermediate 39, 0.700 g) in anhydrous THF at 0° C. under nitrogen. The mixture was allowed to warm to room temperature and then stirred for 15 minutes. The mixture was then cooled to 0° C., 2-trimethysilylethoxymethyl chloride (0.360 ml) was added and the resultant mixture was stirred at room temperature for a further 64 hours. The reaction mixture was quenched by addition of saturated aqueous ammonium chloride (30 ml) and the product was extracted with ethyl acetate. The organic layer was washed with brine, dried (MgSO4) and filtered. The filtrate was evaporated to dryness and the residue was purified by chromatography on silica, eluting with a mixture of ethyl acetate and cyclohexane (0-20%) to give ethyl 2-[N-(2-bromobenzenesulphonyl)-N-(2-trimethylsilylethoxymethyl)amino]-4,5,6,7-tetrahydrobenzo[b]thiophene-3-carboxylate (0.800 g) as a colourless oil.
Reaction SMILES: [C:1]1(=[O:8])[O:7][C:5](=[O:6])[CH2:4][CH2:3][CH2:2]1.[CH3:9][O:10][CH2:11][CH2:12][N:13]1[CH2:18][CH2:17][NH:16][CH2:15][CH2:14]1>O1CCOCC1>[CH3:9][O:10][CH2:11][CH2:12][N:13]1[CH2:18][CH2:17][N:16]([C:5](=[O:6])[CH2:4][CH2:3][CH2:2][C:1]([OH:7])=[O:8])[CH2:15][CH2:14]1
Reactant: COCCN1CCNCC1
Reactant: O=C1CCCC(=O)O1
Solvent: C1COCCO1
Product: COCCN1CCN(C(=O)CCCC(=O)O)CC1
Temperature: 25 °C
Reaction time: 5 h
Yield: 98.9 %

Procedure:
1.52 g of glutaric anhydride and then 1.92 g of 1-(2-methoxyethyl)piperazine in solution in 3 cm3 of dioxane are added to 13 cm3 of dioxane. After stirring for 5 hours at room temperature, an additional 300 mg of glutaric anhydride are added and then the stirring is continued at 20° C. for 18 hours. The solvent is evaporated under reduced pressure and the resulting oil is dried at 20° C. (90 Pa) to give 3.4 g of 5-[4-(2-methoxyethyl)piperazin-1-yl]-5-oxopentanoic acid in the form of an orange-colored lacquer which is used as it is.
Reaction SMILES: Br[CH2:2][CH:3]=[C:4]1[C:10]2[CH:11]=[CH:12][CH:13]=[CH:14][C:9]=2[CH2:8][S:7][C:6]2[CH:15]=[CH:16][C:17]([Cl:19])=[CH:18][C:5]1=2.[C:20](=[O:23])([O-:22])[O-].[K+].[K+].[CH2:26]([O:28][C:29]([CH:31]1[CH2:36][CH2:35][NH:34][CH2:33][CH2:32]1)=[O:30])[CH3:27]>CN(C)C=O.ClCCl>[C:29]([OH:30])(=[O:28])[C:20]([OH:22])=[O:23].[CH2:26]([O:28][C:29]([CH:31]1[CH2:36][CH2:35][N:34]([CH2:2][CH:3]=[C:4]2[C:10]3[CH:11]=[CH:12][CH:13]=[CH:14][C:9]=3[CH2:8][S:7][C:6]3[CH:15]=[CH:16][C:17]([Cl:19])=[CH:18][C:5]2=3)[CH2:33][CH2:32]1)=[O:30])[CH3:27]
Reactant: CCOC(=O)C1CCNCC1
Reactant: O=C([O-])[O-]
Reactant: Clc1ccc2c(c1)C(=CCBr)c1ccccc1CS2
Agent: [K+]
Solvent: CN(C)C=O
Solvent: ClCCl
Product: CCOC(=O)C1CCN(CC=C2c3ccccc3CSc3ccc(Cl)cc32)CC1
Product: O=C(O)C(=O)O
Temperature: 50 °C
Reaction time: 3 h
Yield: 78.6 %

Procedure:
To a solution of 11-(2-bromoethylidene)-2-chloro-6,11-dihydrodibenzo[b,e]thiepine (1.76 g, 0.005 mol, prepared as described in Example 3) in N,N-dimethylformamide (20 ml), potassium carbonate (2.33, 0.006 mol) and 4-piperidinecarboxylic acid ethyl ester (0.86 g, 0.0055 mol) were added and the mixture was stirred at 50° C. for 3 h. The reaction mixture was diluted with dichloromethane (80 ml), the solid was filtered off and the filtrate was washed with water (4×30 ml). The dichloromethane solution was dried (MgSO4) and the solvent removed in vacuo. The oily residue (2.34 g) was dissolved in acetone and treated with an ethanolic solution of oxalic acid. The precipitated crude hydrogen oxalate salt (5.8 g) was recrystalised from aqueous ethanol, to give 1.12 g (87%) of 1-(2-(2-chloro-6,11-dihydrodibenzo[b,e]thiepin-11-ylidene)-1-ethyl)-4-piperidinecarboxylic acid ethyl ester hydrogen oxalate.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][C:5]([CH3:31])=[C:6]([CH:30]=1)[C:7]([NH:9][C:10]1[CH:11]=[N:12][C:13]([NH:16][C:17]2[CH:22]=[CH:21][C:20]([N:23]3[CH2:28][CH2:27][N:26]([CH3:29])[CH2:25][CH2:24]3)=[CH:19][CH:18]=2)=[N:14][CH:15]=1)=[O:8].C(N(C(C)C)CC)(C)C.[C:41](Cl)(=[O:52])[O:42][C:43]1[C:48]([CH3:49])=[CH:47][C:46]([CH3:50])=[CH:45][C:44]=1[CH3:51]>CN(C)C1C=CN=CC=1.ClCCl>[CH3:31][C:5]1[CH:4]=[CH:3][C:2]([NH:1][C:41](=[O:52])[O:42][C:43]2[C:48]([CH3:49])=[CH:47][C:46]([CH3:50])=[CH:45][C:44]=2[CH3:51])=[CH:30][C:6]=1[C:7](=[O:8])[NH:9][C:10]1[CH:11]=[N:12][C:13]([NH:16][C:17]2[CH:22]=[CH:21][C:20]([N:23]3[CH2:24][CH2:25][N:26]([CH3:29])[CH2:27][CH2:28]3)=[CH:19][CH:18]=2)=[N:14][CH:15]=1
Reactant: Cc1cc(C)c(OC(=O)Cl)c(C)c1
Reactant: Cc1ccc(N)cc1C(=O)Nc1cnc(Nc2ccc(N3CCN(C)CC3)cc2)nc1
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: Cc1cc(C)c(OC(=O)Nc2ccc(C)c(C(=O)Nc3cnc(Nc4ccc(N5CCN(C)CC5)cc4)nc3)c2)c(C)c1
Temperature: 25 °C
Reaction time: 20 h

Procedure:
A 16×100 mm vial was charged with 5-amino-2-methyl-N-(2-(4-(4-methylpiperazin-1-yl)phenylamino)pyrimidin-5-yl)benzamide 30 (0.100 g, 0.24 mmol), 4-(dimethylamino)pyridine (0.0059 g, 0.048 mmol), dichloromethane (2 mL), and diisopropylethylamine (0.050 ml, 0.29 mmol). A solution of mesityl carbonochloridate (0.048 g, 0.24 mmol) in dichloromethane (1 mL) was added dropwise and the reaction mixture stirred at room temperature for 20 hours. The reaction mixture was purified via column chromatography on silica gel (gradient elution with 0 to 20% methanol in dichloromethane) to afford mesityl 4-methyl-3-((2-(4-(4-methylpiperazin-1-yl)phenylamino)pyrimidin-5-yl)carbamoyl)phenylcarbamate 47 as a bright yellow solid.
Reaction SMILES: C1(S([N:10]2[C:14]3=[N:15][CH:16]=[C:17]([Cl:19])[CH:18]=[C:13]3[C:12]([CH2:20][C:21]3[CH:22]=[CH:23][C:24]([NH:27][CH2:28][C:29]4[C:30]([O:37][CH3:38])=[N:31][C:32]([O:35][CH3:36])=[CH:33][CH:34]=4)=[N:25][CH:26]=3)=[CH:11]2)(=O)=O)C=CC=CC=1.[OH-].[K+].O>CO>[Cl:19][C:17]1[CH:18]=[C:13]2[C:12]([CH2:20][C:21]3[CH:22]=[CH:23][C:24]([NH:27][CH2:28][C:29]4[C:30]([O:37][CH3:38])=[N:31][C:32]([O:35][CH3:36])=[CH:33][CH:34]=4)=[N:25][CH:26]=3)=[CH:11][NH:10][C:14]2=[N:15][CH:16]=1
Reactant: COc1ccc(CNc2ccc(Cc3cn(S(=O)(=O)c4ccccc4)c4ncc(Cl)cc34)cn2)c(OC)n1
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: COc1ccc(CNc2ccc(Cc3c[nH]c4ncc(Cl)cc34)cn2)c(OC)n1
Temperature: 60 °C
Reaction time: 4 h
Yield: 57.9 %

Procedure:
To [5-(1-Benzenesulfonyl-5-chloro-1H-pyrrolo[2,3-b]pyridin-3-ylmethyl)-pyridin-2-yl]-(2,6-dimethoxy-pyridin-3-ylmethyl)-amine (122, 60 mg, 0.11 mmol) in 10.0 mL of methanol, potassium hydroxide (0.20 g, 3.6 mmol) was added. The reaction was stirred at 60° C. for 4 hours, then poured into water and extracted with ethyl acetate. The organic layer was dried over sodium sulfate, filtered and the filtrate concentrated under vacuum. The resulting material was purified by silica gel column chromatography, eluting with 20-100% ethyl acetate in hexane. Appropriate fractions were combined and concentrated under vacuum to provide the desired compound (P-1496, 26.1 mg). MS (ESI) [M+H+]+=410.0.