Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(O[C:6](=[O:34])[NH:7][C@@H:8]([CH3:33])[C:9]([N:11]1[CH2:16][CH2:15][CH2:14][C@@H:13]([C:17](=[O:32])[NH:18][C@@H:19]([C:21]2[CH:30]=[CH:29][C:28]3[C:23](=[CH:24][C:25]([Br:31])=[CH:26][CH:27]=3)[N:22]=2)[CH3:20])[NH:12]1)=[O:10])(C)(C)C.Cl.O1CCOCC1.[OH:42][C@@H:43]([C@@H:47]([O:49][CH3:50])[CH3:48])C(O)=O.C(N(CC)C(C)C)(C)C.F[P-](F)(F)(F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2C=CC=CC=2N=N1>ClCCl>[Br:31][C:25]1[CH:24]=[C:23]2[C:28]([CH:29]=[CH:30][C:21]([C@H:19]([NH:18][C:17]([C@@H:13]3[CH2:14][CH2:15][CH2:16][N:11]([C:9](=[O:10])[C@@H:8]([NH:7][C:6](=[O:34])[C@@H:43]([OH:42])[C@@H:47]([O:49][CH3:50])[CH3:48])[CH3:33])[NH:12]3)=[O:32])[CH3:20])=[N:22]2)=[CH:27][CH:26]=1
Reactant: CO[C@@H](C)[C@H](O)C(=O)O
Reactant: C[C@H](NC(=O)OC(C)(C)C)C(=O)N1CCC[C@@H](C(=O)N[C@H](C)c2ccc3ccc(Br)cc3n2)N1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: C1COCCO1
Solvent: ClCCl
Product: CO[C@@H](C)[C@H](O)C(=O)N[C@@H](C)C(=O)N1CCC[C@@H](C(=O)N[C@H](C)c2ccc3ccc(Br)cc3n2)N1
Temperature: 25 °C
Reaction time: 2 h
Yield: 30.7 %

Procedure:
A solution of ((S)-2-{(S)-3-[(R)-1-(7-bromo-quinolin-2-yl)-ethylcarbamoyl]-tetrahydro-pyridazin-1-yl}-1-methyl-2-oxo-ethyl)-carbamic acid tert-butyl ester (838 mg, 1.44 mmol) in dichloromethane (20 mL) was treated with hydrogen chloride in 1,4-dioxane (4 M, 1.44 mL, 5.76 mmol) and stirred for 2 h at room temperature. The solution was evaporated to dryness. The residue was dissolved in dichloromethane (20 mL) and (2S,3S)-2-hydroxy-3-methoxy-butyric acid (193 mg, 1.44 mmol) was added followed by N,N-diisopropylethylamine (1.0 mL, 5.76 mmol) and O-(benzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium hexafluorophosphate (819 mg, 2.16 mmol). The solution was stirred at room temperature for 20 h and then evaporated to dryness. The residue was purified by silica gel chromatography eluting with a gradient of acetone/ethyl acetate 1:9 to 1:1 to yield the title compound (243 mg, 31%) as a white gum. 1H NMR (300 MHz, CDCl3) δ 1.14 (d, J=6.2 Hz, 3H), 1.33-1.50 (m, 6H), 1.58 (d, J=6.7 Hz, 3H), 2.20-2.30 (m, 1H), 2.66-2.79 (m, 1H), 3.26-3.63 (m, 3H), 3.37 (s, 3H), 3.90 (d, J=11.8 Hz, 1H), 4.20 (d, J=5.1 Hz, 1H), 4.46-4.56 (m, 1H), 5.20-5.31 (m, 1H), 5.36-5.49 (m, 1H), 7.41 (d, J=8.5 Hz, 1H), 7.61-7.70 (m, 2H), 8.15 (d, J=8.5 Hz, 1H), 8.41 (s, 1H). LCMS (m/z) 550.0, 552.0 [M+H], Tr=2.05 min.
Reaction SMILES: Cl[C:2]1[N:11]=[CH:10][CH:9]=[C:8]2[C:3]=1[C:4]1[CH:16]=[C:15]([F:17])[CH:14]=[CH:13][C:5]=1[C:6](Cl)=[N:7]2.C(OC([N:25]1[C:33]2[C:28](=[CH:29][CH:30]=[CH:31][CH:32]=2)[C:27](B(O)O)=[CH:26]1)=O)(C)(C)C.C1C[O:40]CC1>C([O-])([O-])=O.[Na+].[Na+]>[F:17][C:15]1[CH:14]=[CH:13][C:5]2[C:6]([C:27]3[C:28]4[C:33](=[CH:32][CH:31]=[CH:30][CH:29]=4)[NH:25][CH:26]=3)=[N:7][C:8]3[CH:9]=[CH:10][NH:11][C:2](=[O:40])[C:3]=3[C:4]=2[CH:16]=1
Reactant: CC(C)(C)OC(=O)n1cc(B(O)O)c2ccccc21
Reactant: C1CCOC1
Reactant: Fc1ccc2c(Cl)nc3ccnc(Cl)c3c2c1
Agent: O=C([O-])[O-]
Agent: [Na+]
Product: O=c1[nH]ccc2nc(-c3c[nH]c4ccccc34)c3ccc(F)cc3c12
Temperature: 150 °C

Procedure:
To a solution of 1,6-dichloro-9-fluorobenzo[c]-1,6-naphthyridine (20 mg, 0.075 mmol) in THF (2 mL) and 2.0 M Na2CO3 (500 μL) were added [1-(tert-butoxycarbonyl)-1H-indol-3-yl]boronic acid (23.5 mg, 0.09 mmol). The solution was degassed by bubbling N2 for 5 min heated to 150° C. for 1 hr in a microwave reactor. The reaction solution was extracted with EtOAc and water, the organic layers were dried with MgSO4, filtered, and concentrated by rotary evaporation. Silcia gel column chromatography with 100% CH2Cl2 to 25% MeOH provided the 9-fluoro-6-(1H-indol-3-yl)benzo[c]-1,6-naphthyridin-1(2H)-one. LRMS (ESI) calc'd for (C20H13FN3O) [M+H]+, 330.1; found 330.1
Reaction SMILES: [F:1][C:2]([F:12])([F:11])[C:3]1[N:8]=[CH:7][C:6]([CH:9]=O)=[CH:5][N:4]=1.[CH3:13][C:14]([S@:17]([NH2:19])=[O:18])([CH3:16])[CH3:15]>ClC(Cl)C.S([O-])([O-])(=O)=O.[Cu+2]>[CH3:13][C:14]([S:17](/[N:19]=[CH:9]\[C:6]1[CH:5]=[N:4][C:3]([C:2]([F:12])([F:11])[F:1])=[N:8][CH:7]=1)=[O:18])([CH3:16])[CH3:15]
Reactant: CC(C)(C)[S@](N)=O
Reactant: O=Cc1cnc(C(F)(F)F)nc1
Agent: [Cu+2]
Agent: O=S(=O)([O-])[O-]
Solvent: CC(Cl)Cl
Product: CC(C)(C)S(=O)/N=C\c1cnc(C(F)(F)F)nc1
Temperature: 50 °C
Reaction time: 18 h
Yield: 98.7 %

Procedure:
To a solution of 2-(trifluoromethyl)pyrimidine-5-carbaldehyde (27.2 g, 99 mmol) in dichloroethane (250 mL) was added (R)-(+)-2-methyl-2-propanesulfinamide (13.3 g, 109.0 mmol) and copper(II) sulfate (31.5 g, 197.0 mmol). The mixture was heated to 50° C. After 18 h, the mixture was cooled to ambient temperature and filtered through a pad of silica gel. The filtered cake was washed with dichloromethane and the filtrate was concentrated to give the title compound (27.3 g). MS 224 [(M+1)-56].
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[C:6]([C:8]([F:11])([F:10])[F:9])[CH:5]=[CH:4][C:3]=1[N:12]1[CH2:17][CH2:16][CH2:15][C@H:14]([N:18]([CH3:26])[C:19](=[O:25])[O:20][C:21]([CH3:24])([CH3:23])[CH3:22])[CH2:13]1.C(N(CC)CC)C.[F:34][C:35]1[CH:43]=[CH:42][C:41]([I:44])=[CH:40][C:36]=1[C:37](Cl)=[O:38].CCOC(C)=O>C(Cl)Cl>[F:34][C:35]1[CH:43]=[CH:42][C:41]([I:44])=[CH:40][C:36]=1[C:37]([NH:1][C:2]1[CH:7]=[C:6]([C:8]([F:11])([F:9])[F:10])[CH:5]=[CH:4][C:3]=1[N:12]1[CH2:17][CH2:16][CH2:15][C@H:14]([N:18]([CH3:26])[C:19](=[O:25])[O:20][C:21]([CH3:22])([CH3:23])[CH3:24])[CH2:13]1)=[O:38]
Reactant: CN(C(=O)OC(C)(C)C)[C@H]1CCCN(c2ccc(C(F)(F)F)cc2N)C1
Reactant: O=C(Cl)c1cc(I)ccc1F
Solvent: ClCCl
Solvent: CCN(CC)CC
Solvent: CCOC(C)=O
Product: CN(C(=O)OC(C)(C)C)[C@H]1CCCN(c2ccc(C(F)(F)F)cc2NC(=O)c2cc(I)ccc2F)C1
Reaction time: 2 h

Procedure:
In a vial, (S)-tert-butyl 1-(2-amino-4-(trifluoromethyl)phenyl)piperidin-3-yl(methyl)carbamate (0.500 g, 1.3 mmol) was taken up in CH2Cl2. The solution was cooled to 0 deg. C and Triethylamine (0.24 ml, 1.7 mmol) and 2-fluoro-5-iodobenzoyl chloride (0.42 g, 1.5 mmol) were added. The tube was sealed and the reaction stirred for 2 h. The reaction mixture was poured into EtOAc/1N NaOH. The organic layer was dried over anhydrous sodium sulfate and concentrated in vacuo. The resulting off-white foam (S)-tert-butyl 1-(2-(2-fluoro-5-iodobenzamido)-4-(trifluoromethyl)phenyl)piperidin-3-yl(methyl)carbamate was used without further purification. MS m/z=622 [M+H]+. Calc'd for C25H28F4IN3O3: 621.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[N:9]=[CH:8][CH:7]=[C:6]2[O:15][C:16]1[CH:22]=[CH:21][C:19]([NH2:20])=[C:18]([CH3:23])[C:17]=1[CH3:24].C1(C)C=CC=CC=1.C(N(CC)CC)C.Cl[C:40](Cl)([O:42][C:43](=[O:49])OC(Cl)(Cl)Cl)Cl.[CH3:51][C:52]1[CH:57]=[CH:56][C:55]([CH3:58])=[CH:54][C:53]=1[S:59][CH:60](C)[CH2:61]O>C(Cl)Cl>[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[N:9]=[CH:8][CH:7]=[C:6]2[O:15][C:16]1[CH:22]=[CH:21][C:19]([NH:20][C:43](=[O:49])[O:42][CH2:40][CH2:61][CH2:60][S:59][C:53]2[CH:54]=[C:55]([CH3:58])[CH:56]=[CH:57][C:52]=2[CH3:51])=[C:18]([CH3:23])[C:17]=1[CH3:24]
Reactant: Cc1ccc(C)c(SC(C)CO)c1
Reactant: COc1cc2nccc(Oc3ccc(N)c(C)c3C)c2cc1OC
Reactant: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Solvent: ClCCl
Solvent: Cc1ccccc1
Solvent: CCN(CC)CC
Product: COc1cc2nccc(Oc3ccc(NC(=O)OCCCSc4cc(C)ccc4C)c(C)c3C)c2cc1OC
Temperature: 25 °C
Yield: 27.2 %

Procedure:
4-[(6,7-Dimethoxy-4-quinolyl)oxy]-2,3-dimethylaniline (72 mg) was added to toluene/triethylamine=10/1 (7 ml), and the mixture was heated under reflux to prepare a solution. A solution of triphosgene (100 mg) in methylene chloride was then added to the solution, and the mixture was heated under reflux for 15 min. Subsequently, 2-[(2,5-dimethylphenyl)sulfanyl]-1-propanol (60 mg) was added thereto, and the mixture was further stirred with heating under reflux for 2 hr. After the completion of the reaction, the reaction solution was allowed to cool to room temperature before distilled water was added thereto. The mixture was subjected to separatory extraction with chloroform, followed by washing with a 1 N aqueous hydrochloric acid solution and saturated brine. The washed solution was dried over sodium sulfate and was concentrated. The residue was purified on a column using chloroform/methanol to give the title compound (33 mg, yield 25%).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C:8]2[CH2:9][CH2:10][CH2:11][N:12]=2)[CH:5]=[CH:6][CH:7]=1.B(F)(F)F.[CH3:17]COCC.[Li]C.Cl>C1COCC1.CCOC(C)=O.O>[F:1][C:2]1[CH:3]=[C:4]([C:8]2([CH3:17])[CH2:9][CH2:10][CH2:11][NH:12]2)[CH:5]=[CH:6][CH:7]=1
Reactant: CCOCC
Reactant: Fc1cccc(C2=NCCC2)c1
Agent: Cl
Agent: FB(F)F
Agent: [Li]C
Solvent: O
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: CC1(c2cccc(F)c2)CCCN1
Temperature: -78 °C
Reaction time: 0.67 h

Procedure:
A solution of 5-(3-fluorophenyl)-3,4-dihydro-2H-pyrrole (6.1 g, 37.4 mmol) in 100 mL THF was cooled to −78° C., and boron trifluoride diethyl etherate (9.47 mL, 74.8 mmol) was added drop-wise over 5 minutes. The resulting cloudy reaction mixture was stirred at −78° C. for 40 minutes. MeLi (1.6 M in diethyl ether, 46.7 mL, 74.8 mmol) was added drop-wise over 10 minutes. The mixture was stirred at −78° C. for another 2 hours, then warmed up to ambient temperature overnight. For workup, water and EtOAc were added to the reaction mixture, and the aqueous layer was acidified with HCl solution. After separating and discarding the organic layer, the aqueous layer was basified with NaOH (6 N, aq.) to pH=12 and extracted twice with EtOAc. The combined organic extracts was dried over Na2SO4 and concentrated to get a mixture of the desired product (2-(3-fluorophenyl)-2-methylpyrrolidine) and starting material (4.3 g, 1.3:1 of the desired product:starting material, 37% yield). The crude product was used in the next step without any further purification.
Reaction SMILES: [OH:1][N:2]1[C:6]2[CH:7]=[CH:8][CH:9]=[CH:10][C:5]=2[N:4]=[N:3]1.C(N(CC)CC)C.[Cl:18][C:19]1[CH:24]=[CH:23][C:22]([S:25](Cl)(=[O:27])=[O:26])=[CH:21][CH:20]=1.O>C1C=CC=CC=1>[Cl:18][C:19]1[CH:24]=[CH:23][C:22]([S:25]([O:1][N:2]2[C:6]3[CH:7]=[CH:8][CH:9]=[CH:10][C:5]=3[N:4]=[N:3]2)(=[O:27])=[O:26])=[CH:21][CH:20]=1
Reactant: O=S(=O)(Cl)c1ccc(Cl)cc1
Reactant: On1nnc2ccccc21
Solvent: CCN(CC)CC
Solvent: c1ccccc1
Solvent: O
Product: O=S(=O)(On1nnc2ccccc21)c1ccc(Cl)cc1
Yield: 87.3 %

Procedure:
In benzene (40 ml) are dissolved 1-hydroxy-1,2,3-benzotriazole (10.6 g) and triethylamine (11.1 ml). To the solution is added dropwise a solution of p-chlorobenzenesulfonyl chloride (16.6 g) in benzene (8 ml) with stirring under ice-cooling during about 20 minutes, and the mixture is stirred at 15° C. for 4 hours. To the reaction mixture is added water and the benzene layer is separated. The aqueous layer is extracted twice with ethyl acetate (100 ml). The extract is combined with the above benzene layer, washed with a small amount of an aqueous sodium hydrogen carbonate and water in order and dried over anhydrous sodium sulfate. After drying, the solvent is distilled off under a reduced pressure. The resulting crystals are cracked in petroleum ether and separated by filtration and dried to give faint yellow crystals of 1-(p-chlorobenzensulfonyloxy)-1,2,3-benzotriazole (21.2 g), melting point: 94°-95° C. Ultraviolet spectrum (methanol): λmax 224 mμ, E=365.
Reaction SMILES: [C:1]([O:5][C:6](=[O:30])[NH:7][C@@H:8]([CH2:28]Cl)[CH2:9][O:10][Si:11]([C:24]([CH3:27])([CH3:26])[CH3:25])([C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)([CH3:4])([CH3:3])[CH3:2].[NH2:31][C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][C:33]=1[SH:38].C(=O)([O-])[O-].[Cs+].[Cs+]>CN(C=O)C.C(Cl)Cl>[C:1]([O:5][C:6](=[O:30])[NH:7][C@H:8]([CH2:9][O:10][Si:11]([C:24]([CH3:27])([CH3:26])[CH3:25])([C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)[CH2:28][S:38][C:33]1[CH:34]=[CH:35][CH:36]=[CH:37][C:32]=1[NH2:31])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)OC(=O)N[C@@H](CCl)CO[Si](c1ccccc1)(c1ccccc1)C(C)(C)C
Reactant: Nc1ccccc1S
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: ClCCl
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N[C@H](CO[Si](c1ccccc1)(c1ccccc1)C(C)(C)C)CSc1ccccc1N
Temperature: 25 °C
Reaction time: 3 h
Yield: 103.2 %

Procedure:
A solution of tert-butyl[(2R)-1-{[tert-butyl(diphenyl)silyl]oxy}-3-chloropropan-2-yl]carbamate (58, 390 mg, 0.87 mmol) in dry DMF (2.5 ml) was treated with neat 2-aminobenzenethiol (351 mg, 2.8 mmol) followed by cesium carbonate (560 mg, 1.72 mmol). The mixture was stirred at room temperature for 3 h, diluted with DCM and washed with 1M NaOH followed by saturated NaHCO3, dried over MgSO4, filtered and concentrated to afford the title compound (482 mg) as an oil, which was submitted without further purification to the next synthetic step. MS: m/z=537.2 (MH+).
Reaction SMILES: [OH:1][C:2]1[CH:9]=[CH:8][C:5]([CH:6]=O)=[CH:4][CH:3]=1.Cl[CH2:11][CH2:12][O:13][CH2:14][CH2:15][OH:16].C(=O)([O-])[O-].[K+].[K+].[NH:23]1[CH2:29][C:27](=[O:28])[NH:26][C:24]1=[O:25].O.N>O.C(#N)C>[OH:16][CH2:15][CH2:14][O:13][CH2:12][CH2:11][O:1][C:2]1[CH:9]=[CH:8][C:5]([CH:6]=[C:29]2[NH:23][C:24](=[O:25])[NH:26][C:27]2=[O:28])=[CH:4][CH:3]=1
Reactant: OCCOCCCl
Reactant: O=Cc1ccc(O)cc1
Reactant: O=C1CNC(=O)N1
Agent: N
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CC#N
Product: O=C1NC(=O)C(=Cc2ccc(OCCOCCO)cc2)N1
Temperature: 105 °C
Yield: 84.4 %

Procedure:
In a 300 mL egg-plant shaped flask, 14.7 g (120 mmol) of 4-hydroxybenzaldehyde was mixed with 16.4 g (132 mmol) of 2-(2-chloroethoxyl)ethanol, 33.2 g (240 mmol) of potassium carbonate, and 150 mL of acetonitrile. The mixture was heated at 105° C. for 14 hours with stirring. Thereafter, 1.49 g (12.0 mmol) of 2-(2-chloroethoxy) ethanol was further added, and the mixture was heated at 105° C. for 30 hours with stirring. After the liquid reaction mixture was cooled to room temperature, the solid was removed by celite filtration. The solvent was removed by distillation under reduced pressure, so that 34.6 g of a yellow viscous material mixed with a white solid was obtained. To the product was added 80 mL of water. The mixture was transferred into a separate 200 mL egg-plant shaped flask, and 15.6 g (156 mmol) of hydantoin and 14.4 g of 28% ammonia water were added to the flask. The mixture was heated at 90° C. for 12 hours with stirring. After the liquid reaction mixture was cooled to room temperature, the precipitated crystals were collected by filtration. The crystals were then washed twice with water and twice with ethanol. The crystals were dried to give 29.6 g of 5-[4-[2-(2-hydroxyethoxy)ethoxy]benzylidene]hydantoin. Subsequently, 17.5 g (60.0 mmol) of the product was added to a 200 mL egg-plant shaped flask, and 7.47 g (60 mmol) of 2-(2-chloroethoxyl)ethanol, 20.0 g (145 mmol) of potassium carbonate, and 80 mL of N,N-dimethylformamide were added to the flask. The mixture was heated at 110° C. for 3 hours with stirring. After the liquid reaction mixture was cooled to room temperature, the solid was removed by celite filtration. The solvent was removed by distillation under reduced pressure, so that 30.5 g of a yellow viscous material mixed with a white solid was obtained. The product was purified by silica gel column chromatography (developing solvent: isopropanol/toluene=1/3) to give 9.21 g of yellow crystals. The product was subjected to an activated carbon treatment with ethanol to give 6.56 g of compound 1 (yield: 25%).
Reaction SMILES: [CH3:1][Si:2]([C:5]#[CH:6])([CH3:4])[CH3:3].[CH2:7]([O:9][C:10](=[O:14])[CH:11]=[N+:12]=[N-:13])[CH3:8]>>[CH3:1][Si:2]([CH3:4])([CH3:3])[C:5]1[CH:6]=[C:11]([C:10]([O:9][CH2:7][CH3:8])=[O:14])[NH:12][N:13]=1
Reactant: CCOC(=O)C=[N+]=[N-]
Reactant: C#C[Si](C)(C)C
Product: CCOC(=O)c1cc([Si](C)(C)C)n[nH]1
Temperature: 95 °C

Procedure:
To a flame dried sealed tube equipped with a stir bar that was cooled under argon was added trimethylsilylacetylene (1.0 mL, 9.56 mmol) and ethyldiazoacetate (1.5 mL, 9.6 mmol). The tube was then sealed and heated to 95° C. over night. The next day the reaction was cooled to room temperature and the resulting mixture diluted with hexanes. It was then filtered. The precipitate was then washed with hexanes twice. It was then used without any further purification.
Reaction SMILES: [CH:1]([C:4]1[N:8]=[C:7]([N:9]2[CH2:14][CH2:13][CH:12]([OH:15])[CH2:11][CH2:10]2)[O:6][N:5]=1)([CH3:3])[CH3:2].[H-].[Na+].Cl[C:19]1[N:24]=[CH:23][N:22]=[C:21]2[N:25]([C:28]3[CH:33]=[CH:32][C:31]([S:34]([CH3:37])(=[O:36])=[O:35])=[CH:30][C:29]=3[F:38])[N:26]=[CH:27][C:20]=12.O>C1COCC1>[F:38][C:29]1[CH:30]=[C:31]([S:34]([CH3:37])(=[O:35])=[O:36])[CH:32]=[CH:33][C:28]=1[N:25]1[C:21]2=[N:22][CH:23]=[N:24][C:19]([O:15][CH:12]3[CH2:11][CH2:10][N:9]([C:7]4[O:6][N:5]=[C:4]([CH:1]([CH3:3])[CH3:2])[N:8]=4)[CH2:14][CH2:13]3)=[C:20]2[CH:27]=[N:26]1
Reactant: CS(=O)(=O)c1ccc(-n2ncc3c(Cl)ncnc32)c(F)c1
Reactant: CC(C)c1noc(N2CCC(O)CC2)n1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: CC(C)c1noc(N2CCC(Oc3ncnc4c3cnn4-c3ccc(S(C)(=O)=O)cc3F)CC2)n1
Temperature: 25 °C
Reaction time: 0.75 h

Procedure:
1-(3-Isopropyl-[1,2,4]oxadiazol-5-yl)-piperidin-4-ol (338 mg, 1.6 mmol) and sodium hydride (87 mg, 3.66 mmol) were stirred together in dry THF (2 mL) at room temperature for 30 minutes. 4-Chloro-1-(2-fluoro-4-methanesulfonyl-phenyl)-1H-pyrazolo[3,4-d]pyrimidine was then added and the reaction continued to stir at room temperature for 45 minutes. Its progress was monitored by thin layer chromatography and LCMS. The reaction was treated with water and the desired compound was extracted with ethyl acetate. Organic layer was evaporated in vacuo. Purification by HPLC provided the desired Compound A198 as a white solid (600 mg, 98%). Exact mass calculated for C22H24FN7O4S 501.53, found 502.2 (MH+).
Reaction SMILES: [CH3:1][N:2]1[C:7]2[N:8]=[CH:9][C:10]([O:12][C:13]3[CH:14]=[N:15][CH:16]=[CH:17][CH:18]=3)=[CH:11][C:6]=2[C:5](=[O:19])[N:4]([CH2:20][CH2:21][CH2:22][O:23][CH:24]2[CH2:29][CH2:28][CH2:27][CH2:26][O:25]2)[C:3]1=[O:30].[Li+].CC([N-]C(C)C)C.[Cl:39][C:40]1[CH:47]=[CH:46][C:43]([CH:44]=[O:45])=[CH:42][CH:41]=1>C1COCC1.CC(=O)OCC.O>[Cl:39][C:40]1[CH:47]=[CH:46][C:43]([CH:44]([OH:45])[C:11]2[C:6]3[C:5](=[O:19])[N:4]([CH2:20][CH2:21][CH2:22][O:23][CH:24]4[CH2:29][CH2:28][CH2:27][CH2:26][O:25]4)[C:3](=[O:30])[N:2]([CH3:1])[C:7]=3[N:8]=[CH:9][C:10]=2[O:12][C:13]2[CH:14]=[N:15][CH:16]=[CH:17][CH:18]=2)=[CH:42][CH:41]=1
Reactant: O=Cc1ccc(Cl)cc1
Reactant: Cn1c(=O)n(CCCOC2CCCCO2)c(=O)c2cc(Oc3cccnc3)cnc21
Agent: CC(C)[N-]C(C)C
Agent: [Li+]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Solvent: O
Product: Cn1c(=O)n(CCCOC2CCCCO2)c(=O)c2c(C(O)c3ccc(Cl)cc3)c(Oc3cccnc3)cnc21
Temperature: -78 °C
Reaction time: 1 h
Yield: 13.2 %

Procedure:
To a solution of 1-methyl-6-(pyridin-3-yloxy)-3-(3-((tetrahydro-2H-pyran-2-yl)oxy)propyl)pyrido[2,3-d]pyrimidine-2,4(1H,3H)-dione (400 mg, 0.97 mmol) in THF (8 mL) at −78° C. was added LDA (2M in THF, 1.94 mL, 3.88 mmol) dropwise. The reaction was stirred at −78° C. for 1 h then a solution of 4-chlorobenzaldehyde (273.5 mg, 1.94 mmol) in THF (2 mL) was added dropwise. The reaction was stirred at −78° C. for 30 min. then diluted with EA (10 mL) and water (10 mL). The organic layer was dried over Na2SO4 and concentrated to a residue was purified by chromatography eluted with PE/EA (10:1 to 1:1) to give 5-((4-chlorophenyl) (hydroxy)methyl)-1-methyl-6-(pyridin-3-yloxy)-3-(3-((tetrahydro-2H-pyran-2-yl)oxy)propyl)pyrido[2,3-d]pyrimidine-2,4(1H,3H)-dione (71 mg, 13.2% yield) as an oil. LCMS: [MH+-THP] 469 and TR=1.499 min.
Reaction SMILES: Cl[C:2]([O:4][CH3:5])=[O:3].[NH2:6][C:7]1[CH:8]=[C:9]([S:13][C:14]2[C:22]3[C:21](=[O:23])[N:20]([CH3:24])[C:19](=[O:25])[N:18]([CH2:26][CH:27]([CH3:29])[CH3:28])[C:17]=3[S:16][C:15]=2[CH2:30][C:31]2[C:40]3[C:35](=[CH:36][CH:37]=[CH:38][CH:39]=3)[CH:34]=[CH:33][CH:32]=2)[CH:10]=[CH:11][CH:12]=1.C(N(CC)CC)C.C(=O)([O-])O.[Na+]>ClCCl>[CH3:30][CH2:15][CH2:14][CH:22]([CH3:21])[CH3:17].[CH3:5][O:4][C:2]([NH:6][C:7]1[CH:8]=[C:9]([S:13][C:14]2[C:22]3[C:21](=[O:23])[N:20]([CH3:24])[C:19](=[O:25])[N:18]([CH2:26][CH:27]([CH3:28])[CH3:29])[C:17]=3[S:16][C:15]=2[CH2:30][C:31]2[C:40]3[C:35](=[CH:36][CH:37]=[CH:38][CH:39]=3)[CH:34]=[CH:33][CH:32]=2)[CH:10]=[CH:11][CH:12]=1)=[O:3]
Reactant: CC(C)Cn1c(=O)n(C)c(=O)c2c(Sc3cccc(N)c3)c(Cc3cccc4ccccc34)sc21
Reactant: COC(=O)Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCCC(C)C
Product: COC(=O)Nc1cccc(Sc2c(Cc3cccc4ccccc34)sc3c2c(=O)n(C)c(=O)n3CC(C)C)c1

Procedure:
Methyl chloroformate (0.028 ml) was added to a solution of 5-[(3-aminophenyl)thio]-3-methyl-1-(2-methylpropyl)-6-(1-naphthalenylmethyl) thieno[2,3-d]pyrimidine-2,4-(1H, 3H)-dione (60 mg) and triethylamine (0.067 ml) in anhydrous dichloromethane (2 ml) at room temperature. Further triethylamine (0.067 ml) and methyl chloroformate (0.028 ml) were added after 4 hours and 24 hours. Saturated sodium hydrogen carbonate solution (10 ml) was added and the mixture was extracted with ether (2×10 ml). The organic extracts were dried over anhydrous magnesium sulfate, filtered and evaporated under reduced pressure. The residue was purified by preparative normal-phase HPLC with dichloromethane:ethanol gradient elution and then recrystallised from ethyl acetate:isohexane to give the title compound (15 mg).
Reaction SMILES: [CH2:1]([C:3]1[C:4]([C:12]([O:14]C)=O)=[C:5]([N:9]=[C:10]=[S:11])[S:6][C:7]=1[CH3:8])C.[CH3:16][C:17]1[N:18]=[CH:19][N:20]([CH2:22][CH2:23][CH2:24][NH2:25])[CH:21]=1>>[CH3:1][C:3]1[C:4]2[C:12](=[O:14])[N:25]([CH2:24][CH2:23][CH2:22][N:20]3[CH:21]=[C:17]([CH3:16])[N:18]=[CH:19]3)[C:10](=[S:11])[NH:9][C:5]=2[S:6][C:7]=1[CH3:8]
Reactant: CCc1c(C)sc(N=C=S)c1C(=O)OC
Reactant: Cc1cn(CCCN)cn1
Product: Cc1cn(CCCn2c(=S)[nH]c3sc(C)c(C)c3c2=O)cn1

Procedure:
The compound was synthesized starting from methyl 4-ethyl-2-isothiocyanato-5-methylthiophene-3-carboxylate (0.110 g. 0.46 mmol) and 3-(4-methyl-1H-imidazol-1-yl)propan-1-amine (9) (0.063 g, 0.46 mmol) as described above.
Reaction SMILES: [O:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[CH2:6][NH:7][S:8]([C:11]1[CH:12]=[C:13]([CH:17]=[CH:18][C:19]([OH:21])=O)[CH:14]=[CH:15][CH:16]=1)(=[O:10])=[O:9].C(OC(Cl)=O)C.C(N(CC)CC)C.[OH-:35].[K+].[NH2:37]O>O1CCCC1.CO>[O:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[CH2:6][NH:7][S:8]([C:11]1[CH:12]=[C:13]([CH:17]=[CH:18][C:19]([NH:37][OH:35])=[O:21])[CH:14]=[CH:15][CH:16]=1)(=[O:10])=[O:9]
Reactant: NO
Reactant: O=C(O)C=Cc1cccc(S(=O)(=O)NCc2ccco2)c1
Reactant: [OH-]
Agent: CCOC(=O)Cl
Agent: [K+]
Solvent: CCN(CC)CC
Solvent: CO
Solvent: C1CCOC1
Product: O=C(C=Cc1cccc(S(=O)(=O)NCc2ccco2)c1)NO
Reaction time: 0.25 h

Procedure:
To a solution of 3-{3-[(furan-2-ylmethyl)-sulfamoyl]-phenyl}-acrylic acid (5z) (0.17 g, 0.55 mmol) in tetrahydrofuran (2.0 ml) at 0° C. temperature ethylchloroformate (0.072 g, 0.66 mmol) and triethylamine (0.1 ml, 0.72 mmol) were added and the resulting mixture was stirred for 15 min. To a stirred solution of KOH (0.058 g, 1.04 mmol) in methanol (0.25 ml) a solution of hydroxylamine hydrohloride (0.072 g, 1.04 mmol) in methanol (0.7 ml) was added at 0° C. The mixture was stirred for 15 min., the precipitated KCl was removed and the filtrate was added to the first solution. The reaction mixture was stirred at room temperature for 2 hours. Then the mixture was partitioned between 1N KH2PO4 solution and ethyl acetate. The organic layer was washed with water, saturated NaCl, and dried (Na2SO4). The solvent was evaporated and the residue was washed successively with dichloromathane and ethyl acetate affording the title compound (0.057 g, 32%). M.p. 165° C. 1H NMR (DMSO-d6, HMDSO) δ: 4.03 (2H, d, J=6.4 Hz); 6.23 (2H, m); 6.54 (1H, d, J=16.0 Hz); 7.38-8.05 (6H, m); 8.20 (1H, t, J=6.4 Hz); 9.09 (1H, br s); 10.83 (1H, br s). HPLC analysis on Zorbax SB-C18 column: impurities 8% (column size 4.6×150 mm; mobile phase methanol-0.1% H3PO4, gradient from 30 to 90%; detector UV 270 nm; flow rate 1.5 ml/min; sample concentration 1.0 mg/ml). Anal. Calcd for C14H14N2O5S, %: C, 52.17; H, 4.38; N, 8.69. Found %: C, 51.87; H, 4.39; N, 8.41.