Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [H-].[Na+].[F:3][C:4]1[CH:5]=[C:6]([OH:13])[CH:7]=[CH:8][C:9]=1[N+:10]([O-:12])=[O:11].Cl[C:15]1[CH:20]=[CH:19][N:18]=[C:17]([S:21][CH3:22])[N:16]=1>CN(C=O)C>[F:3][C:4]1[CH:5]=[C:6]([CH:7]=[CH:8][C:9]=1[N+:10]([O-:12])=[O:11])[O:13][C:15]1[CH:20]=[CH:19][N:18]=[C:17]([S:21][CH3:22])[N:16]=1
Reactant: O=[N+]([O-])c1ccc(O)cc1F
Reactant: CSc1nccc(Cl)n1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CSc1nccc(Oc2ccc([N+](=O)[O-])c(F)c2)n1
Temperature: 80 °C
Reaction time: 0.5 h
Yield: 32.5 %

Procedure:
173 mg (6.85 mmol) 95% sodium hydride was given to a solution of 979 mg (6.23 mmol) 3-fluoro-4-nitrophenol in 10 ml DMF. Stirring was continued for 30 min. at room temperature. 1.00 g (6.23 mmol) 4-chloro-2-methylsulfanyl-pyrimidine was added and the mixture heated to 80° C. for 16 h. The reaction mixture was evaporated, taken up with water and extracted with ethyl acetate. The organic phase was extracted with water, dried (sodium sulphate) and evaporated. The obtained material was dissolved in ethyl acetate and purified by chromatography over silica (ethyl acetate/n-heptane 1:2) to give 570 mg 4-(3-fluoro-4-nitro-phenoxy)-2-methylsulfanyl-pyrimidine.
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][C:5]([N+:15]([O-])=O)=[C:6]([CH:14]=1)[O:7][CH2:8][C:9](OCC)=[O:10].O>C(O)(=O)C.[Fe]>[F:1][C:2]1[CH:3]=[CH:4][C:5]2[NH:15][C:9](=[O:10])[CH2:8][O:7][C:6]=2[CH:14]=1
Reactant: CCOC(=O)COc1cc(F)ccc1[N+](=O)[O-]
Agent: [Fe]
Solvent: O
Solvent: CC(=O)O
Product: O=C1COc2cc(F)ccc2N1
Temperature: 60 °C
Yield: 74.8 %

Procedure:
A solution of the 49.0 grams (0.20 mole) of ethyl 2-(5-fluoro-2-nitrophenoxy)acetate in 100 ml of glacial acetic acid was added to a warm (60° C.), stirred mixture of iron powder (50.0 grams, 0.90 mole) in 300 ml of glacial acetic acid. The reaction temperature was allowed to reach 100° C., and the mixture was stirred for approximately three hours. This mixture was poured into water, forming a precipitate. The precipitate was collected by filtration and was recrystallized from ethanol to yield 25.0 grams of 7-fluoro-2H-1,4-benzoxazin-3(4H)-one; another sample of this compound prepared in a similar manner, and then purified further, had a melting point of 205°-206° C. and an nmr spectrum which was consistent with the proposed structure.
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][NH:4][CH2:3][CH2:2]1.Br[C:8]1[CH:13]=[CH:12][C:11]([CH3:14])=[CH:10][N:9]=1.C(=O)([O-])[O-].[K+].[K+]>O1CCOCC1>[CH3:14][C:11]1[CH:12]=[CH:13][C:8]([N:1]2[CH2:6][CH2:5][NH:4][CH2:3][CH2:2]2)=[N:9][CH:10]=1
Reactant: C1CNCCN1
Reactant: Cc1ccc(Br)nc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1COCCO1
Product: Cc1ccc(N2CCNCC2)nc1

Procedure:
A solution of piperazine (215 mg, 2.5 mmoles), 2-bromo-5-methyl-pyridine (172 mg, 1 mmoles) in dioxane (1 mL) and potassium carbonate (276 mg, 2 mmoles) was irradiated by microwaves for 60 minutes at 180° C. The dioxane was removed under reduced pressure and the residue partitioned between aqueous potassium carbonate and ethyl acetate. The aqueous layer was extracted with ethyl acetate and the combined organic extracts washed twice with water, dried (MgSO4) and filtered. The filtrate was concentrated under reduced pressure and the residue was purified (silica gel, 0-10% methanol in dichloromethane) to provide the title compound as a white solid.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([C:8]2[CH:9]=[C:10]([C:23]3[N:27]([CH2:28][O:29][CH2:30][CH2:31][Si:32]([CH3:35])([CH3:34])[CH3:33])[C:26]4[CH:36]=[CH:37][CH:38]=[CH:39][C:25]=4[N:24]=3)[C:11](=[O:22])[N:12]([CH2:14][O:15][CH2:16][CH2:17][Si:18]([CH3:21])([CH3:20])[CH3:19])[N:13]=2)[CH:5]=[CH:4][N:3]=1.[NH2:40][CH2:41][CH2:42][N:43]1[CH2:48][CH2:47][O:46][CH2:45][CH2:44]1>>[N:43]1([CH2:42][CH2:41][NH:40][C:2]2[N:7]=[C:6]([C:8]3[CH:9]=[C:10]([C:23]4[N:27]([CH2:28][O:29][CH2:30][CH2:31][Si:32]([CH3:34])([CH3:33])[CH3:35])[C:26]5[CH:36]=[CH:37][CH:38]=[CH:39][C:25]=5[N:24]=4)[C:11](=[O:22])[N:12]([CH2:14][O:15][CH2:16][CH2:17][Si:18]([CH3:20])([CH3:21])[CH3:19])[N:13]=3)[CH:5]=[CH:4][N:3]=2)[CH2:48][CH2:47][O:46][CH2:45][CH2:44]1
Reactant: NCCN1CCOCC1
Reactant: C[Si](C)(C)CCOCn1nc(-c2ccnc(Cl)n2)cc(-c2nc3ccccc3n2COCC[Si](C)(C)C)c1=O
Product: C[Si](C)(C)CCOCn1nc(-c2ccnc(NCCN3CCOCC3)n2)cc(-c2nc3ccccc3n2COCC[Si](C)(C)C)c1=O
Temperature: 100 °C

Procedure:
100 mg of 6-(2-chloropyrimidin-4-yl)-2-(2-trimethylsilanylethoxymethyl)-4-[1-(2-trimethylsilanylethoxymethyl)-1H-benzimidazol-2-yl]-2H-pyridazin-3-one are suspended in 0.5 ml of N-(2-aminoethyl)morpholine, and the reaction mixture is heated at 100° C. in a microwave for 20 minutes. The product is purified by preparative RP-HPLC (0-100% acetonitrile (+0.05% formic acid) in water (+0.05% formic acid)).
Reaction SMILES: CS([C:5]1[N:6]=[CH:7][C:8]2[C:17]3[CH:16]=[CH:15][C:14]([C:18]([O:20][CH3:21])=[O:19])=[CH:13][C:12]=3[N:11]=[C:10]([C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=3)[C:9]=2[N:28]=1)(=O)=O.[CH:29]1([NH2:32])[CH2:31][CH2:30]1.O>CN1C(=O)CCC1>[CH:29]1([NH:32][C:5]2[N:6]=[CH:7][C:8]3[C:17]4[CH:16]=[CH:15][C:14]([C:18]([O:20][CH3:21])=[O:19])=[CH:13][C:12]=4[N:11]=[C:10]([C:22]4[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=4)[C:9]=3[N:28]=2)[CH2:31][CH2:30]1
Reactant: NC1CC1
Reactant: COC(=O)c1ccc2c(c1)nc(-c1ccccc1)c1nc(S(C)(=O)=O)ncc12
Solvent: O
Solvent: CN1CCCC1=O
Product: COC(=O)c1ccc2c(c1)nc(-c1ccccc1)c1nc(NC3CC3)ncc12
Temperature: 60 °C
Reaction time: 0.83 h
Yield: 77.9 %

Procedure:
methyl 3-(methylsulfonyl)-5-phenylpyrimido[4,5-c]quinoline-8-carboxylate (1.0 eq, 117 mg, 0.298 mmol) was mixed in a vial with cylopropylamine (3.0 eq, 62 ul, 0.89 mmol) in NMP (2 ml). The mixture was stirred at 60° C. for 50 minutes. Water was added and the resulting solid filtered. The material was suspended in AcOEt/hexanes and filtered to afford methyl 3-(cyclopropylamino)-5-phenylpyrimido[4,5-c]quinoline-8-carboxylate as a yellow solid (86 mg, 78% yield). LCMS (ES): >95% pure, m/z 371 [M+1]+.
Reaction SMILES: [F:1][C:2]1[C:7]([CH:8]([OH:22])[C:9]2[C:17]3[C:16]([NH:18][CH:19]([CH3:21])[CH3:20])=[N:15][CH:14]=[N:13][C:12]=3[NH:11][CH:10]=2)=[CH:6][CH:5]=[CH:4][C:3]=1[NH:23][S:24]([CH2:27][CH2:28][CH3:29])(=[O:26])=[O:25].I(C1C=CC=CC=1C(O)=O)(=O)=O.O>CS(C)=O>[F:1][C:2]1[C:7]([C:8]([C:9]2[C:17]3[C:16]([NH:18][CH:19]([CH3:21])[CH3:20])=[N:15][CH:14]=[N:13][C:12]=3[NH:11][CH:10]=2)=[O:22])=[CH:6][CH:5]=[CH:4][C:3]=1[NH:23][S:24]([CH2:27][CH2:28][CH3:29])(=[O:25])=[O:26]
Reactant: CCCS(=O)(=O)Nc1cccc(C(O)c2c[nH]c3ncnc(NC(C)C)c23)c1F
Agent: O=C(O)c1ccccc1I(=O)=O
Solvent: CS(C)=O
Solvent: O
Product: CCCS(=O)(=O)Nc1cccc(C(=O)c2c[nH]c3ncnc(NC(C)C)c23)c1F
Temperature: 25 °C
Reaction time: 1 h
Yield: 33.5 %

Procedure:
To propane-1-sulfonic acid {2-fluoro-3-[hydroxy-(4-isopropylamino-7H-pyrrolo[2,3-d]pyrimidin-5-yl)-methyl]-phenyl}-amide (78, 102 mg, 0.242 mmol) in 1 mL of dimethylsulfoxide, stabilized 2-iodoxybenzoic acid (181 mg, 45%, 0.29 mmol) is added and the reaction is stirred at room temperature for 1 hour. The reaction is poured into water and stirred for 30 minutes, and the precipitate is collected by filtration. The resulting solid is dissolved in 2 mL of tetrahydrofuran and purified by silica gel column chromatography, eluting with ethyl acetate and dichloromethane. Appropriate fractions are combined and concentrated under vacuum to give the desired compound (P-1106, 34 mg). MS (ESI) [M+H+]+=420.0.
Reaction SMILES: [C:1]([C:5]1([OH:20])[C:9]([CH3:11])([CH3:10])[CH2:8][O:7][CH:6]1[C:12]1[CH:17]=[CH:16][CH:15]=[C:14]([O:18][CH3:19])[CH:13]=1)([CH3:4])([CH3:3])[CH3:2].C1COCC1.C1C(=O)N([Br:33])C(=O)C1.[Cl-].[Na+]>O>[Br:33][C:15]1[CH:16]=[CH:17][C:12]([CH:6]2[C:5]([C:1]([CH3:2])([CH3:3])[CH3:4])([OH:20])[C:9]([CH3:11])([CH3:10])[CH2:8][O:7]2)=[CH:13][C:14]=1[O:18][CH3:19]
Reactant: O=C1CCC(=O)N1Br
Reactant: COc1cccc(C2OCC(C)(C)C2(O)C(C)(C)C)c1
Agent: [Cl-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: COc1cc(C2OCC(C)(C)C2(O)C(C)(C)C)ccc1Br
Temperature: 0 °C
Reaction time: 8 h
Yield: 47.7 %

Procedure:
2.16 g (7.77 mmol) of 3-t-butyl-3-hydroxy-2-(3-methoxyphenyl)-4,4-dimethyl-2,3,4,5-tetrahydrofuran (compound (5)) was added to a mixed solvent of 20 ml of THF and 2 ml of H2O, followed by stirring at 0° C. To this solution, 1.54 g (8.65 mmol) of NBS was added, and while gradually raising the temperature to room temperature, stirring was continued overnight. Then, 140 mg (0.787 mmol) of NBS was further added, followed by stirring for 6 hours. The reaction mixture was put into a saturated sodium chloride aqueous solution and extracted with ethyl acetate. The extract layer was washed sequentially with an aqueous sodium thiosulfate solution and a saturated sodium chloride aqueous solution, dried over anhydrous magnesium sulfate and then concentrated. The concentrated product was crystallized from a mixed solvent of ethyl acetate and hexane to obtain 1.323 g of 2-(4-bromo-3-methoxyphenyl)-3-t-butyl-3-hydroxy-4,4-dimethyl-2,3,4,5-tetrahydrofuran (compound (6)) in a yield of 47.7%.
Reaction SMILES: Br[CH2:2][C:3](=O)[C:4]([OH:6])=[O:5].[NH2:8][C:9](=[S:15])[C:10]([O:12][CH2:13][CH3:14])=[O:11].O.C([O-])(O)=O.[Na+]>O1CCOCC1>[CH2:13]([O:12][C:10]([C:9]1[S:15][C:3]([C:4]([OH:6])=[O:5])=[CH:2][N:8]=1)=[O:11])[CH3:14]
Reactant: O=C(O)C(=O)CBr
Reactant: CCOC(=O)C(N)=S
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: C1COCCO1
Product: CCOC(=O)c1ncc(C(=O)O)s1
Yield: 47.8 %

Procedure:
Bromopyruvic acid (22.7 g, 135.33 mmol) was added to a solution of ethyl 2-amino-2-thioxoacetate (Intermediate W, 18 g, 135.3 mmol) in dioxane (200 mL) and refluxed for 5 h. After completion the reaction mixture was poured into water (200 mL), the residue was basified with sat NaHCO3 and extracted with EtOAc (2×250 mL). The aqueous layer was acidified with 2N HCl and extracted with EtOAc (2×250 mL) The combined extracts were washed with water (250 mL), brine (250 mL), dried over anhydrous Na2SO4, filtered and evaporated to afford 2-(ethoxycarbonyl)thiazole-5-carboxylic acid (13 g crude). The crude was carried to next step without further purification.
Reaction SMILES: [Br:1][C:2]1[C:9]2[S:8][CH:7]=[N:6][C:5]=2[NH:4][C:3]=1[CH3:10].CS(O[CH:16]([CH3:20])[CH2:17][O:18][CH3:19])(=O)=O.C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O>[Br:1][C:2]1[C:9]2[S:8][CH:7]=[N:6][C:5]=2[N:4]([CH:16]([CH3:20])[CH2:17][O:18][CH3:19])[C:3]=1[CH3:10]
Reactant: COCC(C)OS(C)(=O)=O
Reactant: Cc1[nH]c2ncsc2c1Br
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: COCC(C)n1c(C)c(Br)c2scnc21
Temperature: 70 °C

Procedure:
To a solution of 6-bromo-5-methyl-4H-pyrrolo[2,3-d]thiazole (2.5 g, 11.52 mmol) in anhydrous N,N-dimethylformamide (20 mL) was added 1-methoxypropan-2-yl methanesulfonate (3.87 g, 23.03 mmol), and potassium carbonate (3.18 g, 23.03 mmol) followed. The resulting reaction mixture was heated to 70° C. and allowed to stir over night at 70° C. The reaction mixture was washed with water and brine, extracted with acetic ester (30 mL×3). The combined organic phase was dried by anhydrous sodium sulphate, and then filtered. The filtrate was concentrated and purified by column chromatograph on silica gel eluted with (petrol ether/acetic ester 30:1→20:1→10:1) to the title compound (2.0 g, 60%) as orange oil. LCMS (M+H+) m/z: calc'd. 287.99. found 290.9.
Reaction SMILES: Cl[C:2]1[C:3]([CH3:18])=[C:4]([CH3:17])[C:5]2[N:6]([C:8]([NH:11][CH2:12][C:13]([F:16])([F:15])[F:14])=[N:9][N:10]=2)[N:7]=1.[O-:19][CH2:20][CH3:21].[Na+].O>C(O)C>[CH2:20]([O:19][C:2]1[C:3]([CH3:18])=[C:4]([CH3:17])[C:5]2[N:6]([C:8]([NH:11][CH2:12][C:13]([F:16])([F:15])[F:14])=[N:9][N:10]=2)[N:7]=1)[CH3:21]
Reactant: Cc1c(Cl)nn2c(NCC(F)(F)F)nnc2c1C
Reactant: CC[O-]
Agent: [Na+]
Solvent: CCO
Solvent: O
Product: CCOc1nn2c(NCC(F)(F)F)nnc2c(C)c1C
Temperature: 50 °C
Reaction time: 4 h
Yield: 99.6 %

Procedure:
(6-Chloro-7,8-dimethyl-[1,2,4]triazolo[4,3-b]pyridazin-3-yl)(2,2,2-trifluoroethyl)amine (W2.150; 330 mg) was initially charged in ethanol (25 ml) and admixed with sodium ethoxide (90 mg). The reaction mixture was stirred at 50° C. for 4 h, then further sodium ethoxide (10 mg) was added and the mixture was stirred further at 50° C. for 3 h. After standing overnight, the mixture was admixed with water and dried. The residue was taken up in EA and washed three times with water. The EA phase was dried over sodium sulfate, filtered and concentrated. 340 mg of the title compound were obtained. LC-MS rt: 0.82 min [M+H]+: 290.2 (met. b)
Reaction SMILES: [I:1][C:2]1[CH:3]=[CH:4][C:5]([CH3:11])=[C:6]([CH:10]=1)[C:7]([OH:9])=[O:8].Cl.CN(C)CCCN=C=NCC.[C:24](O)([CH3:27])([CH3:26])[CH3:25]>CN(C)C1C=CN=CC=1.ClCCl.C(OCC)(=O)C>[C:24]([O:8][C:7](=[O:9])[C:6]1[CH:10]=[C:2]([I:1])[CH:3]=[CH:4][C:5]=1[CH3:11])([CH3:27])([CH3:26])[CH3:25]
Reactant: Cc1ccc(I)cc1C(=O)O
Reactant: CC(C)(C)O
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: ClCCl
Solvent: CCOC(C)=O
Product: Cc1ccc(I)cc1C(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 8 h
Yield: 65 %

Procedure:
A mixture of 5-iodo-2-methylbenzoic acid (760 mg, 2.9 mmol), 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (670 mg, 3.5 mmol), 4-dimethylaminopyridine (425 mg, 3.5 mmol), and t-butanol (1.07 g, 14.5 mmol) in dichloromethane (10 ml) was stirred at room temperature overnight. The reaction mixture was diluted with ethyl acetate (25 ml) and washed with 5% NaHCO3, 1M HCl, water and, brine. The organic phase was dried and evaporated to give a pale yellow solid 600 mg 65%.
Reaction SMILES: [Si:1]([O:8][CH2:9][CH2:10]/[CH:11]=[CH:12]/[C:13]1[CH:14]=[CH:15][C:16](/[C:21](/[C:40]2[CH:45]=[CH:44][C:43]([C:46]([CH3:49])([CH3:48])[CH3:47])=[CH:42][CH:41]=2)=[CH:22]/[C@@H:23]2[N:27]([CH2:28][C:29]3[CH:34]=[CH:33][C:32]([O:35][CH3:36])=[CH:31][C:30]=3[O:37][CH3:38])[C:26](=[O:39])[CH2:25][CH2:24]2)=[N:17][C:18]=1[O:19][CH3:20])([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].[H][H]>CO.C(OCC)(=O)C.[Pd].[Br-].[Zn+2].[Br-]>[Si:1]([O:8][CH2:9][CH2:10][CH2:11][CH2:12][C:13]1[CH:14]=[CH:15][C:16](/[C:21](/[C:40]2[CH:41]=[CH:42][C:43]([C:46]([CH3:49])([CH3:48])[CH3:47])=[CH:44][CH:45]=2)=[CH:22]/[C@@H:23]2[N:27]([CH2:28][C:29]3[CH:34]=[CH:33][C:32]([O:35][CH3:36])=[CH:31][C:30]=3[O:37][CH3:38])[C:26](=[O:39])[CH2:25][CH2:24]2)=[N:17][C:18]=1[O:19][CH3:20])([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:2])[CH3:3]
Reactant: [H][H]
Reactant: COc1ccc(CN2C(=O)CC[C@@H]2/C=C(\c2ccc(C(C)(C)C)cc2)c2ccc(/C=C/CCO[Si](C)(C)C(C)(C)C)c(OC)n2)c(OC)c1
Agent: [Pd]
Agent: [Br-]
Agent: [Zn+2]
Solvent: CCOC(C)=O
Solvent: CO
Product: COc1ccc(CN2C(=O)CC[C@@H]2/C=C(\c2ccc(C(C)(C)C)cc2)c2ccc(CCCCO[Si](C)(C)C(C)(C)C)c(OC)n2)c(OC)c1
Yield: 61.8 %

Procedure:
10% palladium-activated carbon (50 mg) and zinc(II) bromide (25 mg) were added to a solution of (5R)-5-[(E)-2-{5-[(1E)-4-{[tert-butyl(dimethyl)silyl]oxy}but-1-en-1-yl]-6-methoxypyridin-2-yl}-2-(4-tert-butylphenyl)ethenyl]-1-(2,4-dimethoxybenzyl)pyrrolidin-2-one (226 mg) in methanol (5 mL), and the mixture was stirred at room temperature for five hours in a hydrogen atmosphere. The reaction solution was diluted with ethyl acetate and filtered through celite. The filtrate was sequentially washed with water and brine and dried over anhydrous magnesium sulfate, after which the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (hexane:ethyl acetate=7:3→1:9) to give (5R)-5-[(E)-2-[5-(4-{[tert-butyl(dimethyl)silyl]oxy}butyl)-6-methoxypyridin-2-yl]-2-(4-tert-butylphenyl)ethenyl]-1-(2,4-dimethoxybenzyl)pyrrolidin-2-one as a colorless oil (140 mg, 62%).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9]2[N:14]3[N:15]=[CH:16][C:17]([C:18](O)=[O:19])=[C:13]3[N:12]=[CH:11][C:10]=2[C:21]([N:23]2[CH2:28][CH2:27][C:26]3([C:36]4[C:31](=[CH:32][CH:33]=[CH:34][CH:35]=4)[CH2:30][CH2:29]3)[CH2:25][CH2:24]2)=[O:22])=[C:4]([CH3:37])[CH:3]=1.[CH:38]1([S:41]([NH2:44])(=[O:43])=[O:42])[CH2:40][CH2:39]1>>[F:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9]2[N:14]3[N:15]=[CH:16][C:17]([C:18]([NH:44][S:41]([CH:38]4[CH2:40][CH2:39]4)(=[O:43])=[O:42])=[O:19])=[C:13]3[N:12]=[CH:11][C:10]=2[C:21]([N:23]2[CH2:24][CH2:25][C:26]3([C:36]4[C:31](=[CH:32][CH:33]=[CH:34][CH:35]=4)[CH2:30][CH2:29]3)[CH2:27][CH2:28]2)=[O:22])=[C:4]([CH3:37])[CH:3]=1
Reactant: NS(=O)(=O)C1CC1
Reactant: Cc1cc(F)ccc1Nc1c(C(=O)N2CCC3(CCc4ccccc43)CC2)cnc2c(C(=O)O)cnn12
Product: Cc1cc(F)ccc1Nc1c(C(=O)N2CCC3(CCc4ccccc43)CC2)cnc2c(C(=O)NS(=O)(=O)C3CC3)cnn12
Yield: 89.2 %

Procedure:
In the same manner as in Example 1, step 6 and using 7-(4-fluoro-2-methylphenylamino)-6-(spiro[indane-1,4′-piperidine]-1′-ylcarbonyl)pyrazolo[1,5-a]pyrimidine-3-carboxylic acid (0.04 g, 0.08 mmol) obtained in step 2 and cyclopropanesulfonamide (0.049 g, 0.40 mmol), the title compound (0.043 g, 88%) was obtained.
Reaction SMILES: O.[NH2:2][NH2:3].O=[C:5]([CH3:20])[CH:6]([C:12]([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][N:15]=1)=O)[CH2:7][C:8]([O:10][CH3:11])=[O:9].O>C(O)C>[CH3:11][O:10][C:8](=[O:9])[CH2:7][C:6]1[C:5]([CH3:20])=[N:2][NH:3][C:12]=1[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][N:15]=1
Reactant: COC(=O)CC(C(C)=O)C(=O)c1ccccn1
Reactant: NN
Solvent: CCO
Solvent: O
Product: COC(=O)Cc1c(C)n[nH]c1-c1ccccn1

Procedure:
1.170 g (23 mmol) of hydrazine hydrate were added to a solution of 5 g (21 mmol) of methyl 4-oxo-3-(pyridin-2-ylcarbonyl)pentanoate in ethanol (50 ml). The mixture was heated at reflux for 7 hours, added to water and extracted with ethyl acetate. The combined organic phases were dried with magnesium sulfate, filtrered and concentrated. This gave 2.290 g of product (41.9% of theory).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][C:5]2[S:10][CH2:9][C:8](=[O:11])[NH:7][C:6]=2[CH:12]=1.[CH2:13]([C@H:15]1[O:17][CH2:16]1)[Cl:14]>CC#N>[Cl:14][CH2:13][C@@H:15]([OH:17])[CH2:16][NH:1][C:2]1[CH:3]=[CH:4][C:5]2[S:10][CH2:9][C:8](=[O:11])[NH:7][C:6]=2[CH:12]=1
Reactant: ClC[C@@H]1CO1
Reactant: Nc1ccc2c(c1)NC(=O)CS2
Solvent: CC#N
Product: O=C1CSc2ccc(NC[C@H](O)CCl)cc2N1
Temperature: 45 °C
Reaction time: 24 h
Yield: 63.7 %

Procedure:
A suspension of 6-amino-4H-benzo[1,4]thiazin-3-one (18.0 g, 100 mmol; commercial) and Ca(OTf)2 (0.5 eq.) in MeCN (800 mL) was heated at 50° for 1 h. (S)-epichlorohydrin (18.5 g, 200 mmol) was added and the mixture was stirred at rt for 72 h and at 45° C. for 24 h. The volatiles were removed under reduced pressure. After aqueous workup and extraction with EA, the title intermediate crystallized from EA to afford a beige solid (17.38 g, 64% yield).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:9]([CH2:17][C@H:18]([OH:23])[C:19]([F:22])([F:21])[F:20])[C:10](=[O:16])[N:11]([CH2:13][C:14]#[CH:15])[N:12]=2)=[CH:4][CH:3]=1.[N:24]([C:27]1[CH:32]=[CH:31][CH:30]=[C:29]([Cl:33])[C:28]=1[Cl:34])=[N+:25]=[N-:26]>C(#N)C.O.C([O-])(=O)C.[Cu+2].C([O-])(=O)C>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:9]([CH2:17][C@H:18]([OH:23])[C:19]([F:21])([F:22])[F:20])[C:10](=[O:16])[N:11]([CH2:13][C:14]3[N:26]=[N:25][N:24]([C:27]4[CH:32]=[CH:31][CH:30]=[C:29]([Cl:33])[C:28]=4[Cl:34])[CH:15]=3)[N:12]=2)=[CH:4][CH:3]=1
Reactant: [N-]=[N+]=Nc1cccc(Cl)c1Cl
Reactant: C#CCn1nc(-c2ccc(Cl)cc2)n(C[C@H](O)C(F)(F)F)c1=O
Agent: [Cu+2]
Agent: CC(=O)[O-]
Solvent: CC#N
Solvent: O
Product: O=c1n(Cc2cn(-c3cccc(Cl)c3Cl)nn2)nc(-c2ccc(Cl)cc2)n1C[C@H](O)C(F)(F)F
Temperature: 50 °C
Reaction time: 2 h

Procedure:
124 mg (0.36 mmol) of the compound from Example 14A were dissolved in 2 ml of acetonitrile, and 0.6 mg (0.003 mmol) of copper(II) acetate monohydrate and 56 mg (0.30 mmol) of 1-azido-2,3-dichlorobenzene were added. The mixture was stirred at 50° C. for 2 h. For work-up, the crude mixture was allowed to cool to RT and filtered through a little silica gel. The product was eluted with ethyl acetate and the solution obtained was concentrated under reduced pressure. The crude product was then purified by chromatography on silica gel (mobile phase: cyclohexane/ethyl acetate 1:1). This gave 61 mg (31% of theory) of the target compound.
Reaction SMILES: Cl.Cl.[CH2:3]([O:5][C:6](=[O:12])[CH2:7][NH:8][CH2:9][CH2:10][NH2:11])[CH3:4].[C:13]([C:21]1[S:25][C:24]([S:26](Cl)(=[O:28])=[O:27])=[N:23][C:22]=1[C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1)(=[O:20])[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1>>[CH2:3]([O:5][C:6](=[O:12])[CH2:7][NH:8][CH2:9][CH2:10][NH:11][S:26]([C:24]1[S:25][C:21]([C:13](=[O:20])[C:14]2[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=2)=[C:22]([C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=2)[N:23]=1)(=[O:27])=[O:28])[CH3:4]
Reactant: CCOC(=O)CNCCN
Reactant: O=C(c1ccccc1)c1sc(S(=O)(=O)Cl)nc1-c1ccccc1
Agent: Cl
Product: CCOC(=O)CNCCNS(=O)(=O)c1nc(-c2ccccc2)c(C(=O)c2ccccc2)s1

Procedure:
The title compound was synthesized by the reaction of N-(2-aminoethyl)-glycine ethyl ester 2HCl with 5-benzoyl-4-phenyl-thiazole-2-sulfonyl chloride as per the procedure of example 1. 1H NMR (500 MHz; DMSO-d6) δ 7.46 (d, 2H), 7.36–7.24 (m, 4H), 7.19–7.11 (m, 4H), 4.05 (q, 2H), 3.28 (s, 2H), 3.19 (t, 2H), 2.66 (t, 2H), 1.16 (t, 3H).
Reaction SMILES: C(N(C(C)C)CC)(C)C.Cl.[F:11][C:12]1[CH:17]=[C:16]([S:18]([CH3:21])(=[O:20])=[O:19])[CH:15]=[CH:14][C:13]=1[C:22]1[CH:27]=[CH:26][C:25]([O:28][CH2:29][CH:30]2[CH2:35][CH2:34][NH:33][CH2:32][CH2:31]2)=[CH:24][CH:23]=1.Cl[C:37]([O:39][CH:40]([CH3:42])[CH3:41])=[O:38]>C(Cl)Cl>[F:11][C:12]1[CH:17]=[C:16]([S:18]([CH3:21])(=[O:20])=[O:19])[CH:15]=[CH:14][C:13]=1[C:22]1[CH:23]=[CH:24][C:25]([O:28][CH2:29][CH:30]2[CH2:35][CH2:34][N:33]([C:37]([O:39][CH:40]([CH3:42])[CH3:41])=[O:38])[CH2:32][CH2:31]2)=[CH:26][CH:27]=1
Reactant: CC(C)OC(=O)Cl
Reactant: CS(=O)(=O)c1ccc(-c2ccc(OCC3CCNCC3)cc2)c(F)c1
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CC(C)OC(=O)N1CCC(COc2ccc(-c3ccc(S(C)(=O)=O)cc3F)cc2)CC1
Temperature: 0 °C
Reaction time: 8 h
Yield: 97.9 %

Procedure:
Diisopropylethylamine (0.14 mL, 0.75 mmol) was added to a suspension of 4-({[2′-fluoro-4′-(methylsulfonyl)-4-biphenylyl]oxy}methyl)piperidine hydrochloride (0.10 g, 0.25 mmol) in CH2Cl2 (7 mL). The mixture was cooled to 0° C. in an ice bath, and isopropyl chloroformate (1.0M in toluene, 0.28 mL, 0.28 mmol) was added dropwise. The reaction mixture was allowed to warm to ambient temperature, and stirred overnight. The mixture was then concentrated to give the crude product as a colorless oil. The crude product was purified by chromatography on a silica gel column eluted with 5:6 EtOAc/hexane to give 0.11 g (98%) of the title compound as a white solid. 1H NMR (400 MHz, CDCl3): δ 7.80-7.70 (m, 2H), 7.65-7.55 (m, 1H), 7.50 (d, 2H, J=8.8 Hz), 6.98 (d, 2H, J=8.6 Hz), 4.92 (septet, 1H, J=6.1 Hz), 4.25-4.15 (m, 2H), 3.86 (d, 2H, J=6.3 Hz), 3.09 (s, 3H), 2.85-2.75 (m, 2H), 2.10-1.90 (m, 1H), 1.90-1.80 (m, 2H), 1.35-1.10 (m, 8H); LRMS (ESI), m/z 450 (M+H).
Reaction SMILES: Cl[CH2:2][C:3]([C:5]1[CH:14]=[CH:13][C:12]([OH:15])=[C:11]2[C:6]=1[CH:7]=[CH:8][C:9](=[O:16])[NH:10]2)=[O:4].[CH2:17]1[C:25]2[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=2)[CH2:19][CH:18]1[NH2:26]>>[OH:15][C:12]1[CH:13]=[CH:14][C:5]([C:3](=[O:4])[CH2:2][NH:26][CH:18]2[CH2:19][C:20]3[C:25](=[CH:24][CH:23]=[CH:22][CH:21]=3)[CH2:17]2)=[C:6]2[C:11]=1[NH:10][C:9](=[O:16])[CH:8]=[CH:7]2
Reactant: NC1Cc2ccccc2C1
Reactant: O=C(CCl)c1ccc(O)c2[nH]c(=O)ccc12
Product: O=C(CNC1Cc2ccccc2C1)c1ccc(O)c2[nH]c(=O)ccc12

Procedure:
5-(Chloroacetyl)-8-hydroxy-2(1H)-quinolinone (25 mg, 0.105 mmol) prepared from literature procedure (Yoshizaki, Shiro; Tanimura, Kaoru; Tamada, Shigeharu; Yabuuchi, Youichi; Nakagawa, Kazuyuki, J. Med. Chem. (1976), 19(9), 1138-42) is reacted neat with indan-2-ylamine (205 mg, 1.21 mmol) at 2.5° C. for 2 hours. The reaction mixture is purified by flash chromatography (silica, CH2Cl2/methanol 9:1). ES+ MS m/e 335 (MH+).