Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: O[C:2]1[CH:7]=[C:6]([CH3:8])[N:5]([CH3:9])[C:4](=[O:10])[C:3]=1[C:11](=[O:26])[CH:12]=[CH:13][C:14]1[CH:19]=[CH:18][CH:17]=[C:16]([O:20][CH2:21][C:22]([O:24][CH3:25])=[O:23])[CH:15]=1.[H-].[Na+].[Cl-].[CH2:30]([NH2:33])[C:31]#[CH:32]>CN(C)C=O.O>[CH2:30]([NH:33][C:2]1[CH:7]=[C:6]([CH3:8])[N:5]([CH3:9])[C:4](=[O:10])[C:3]=1[C:11](=[O:26])[CH:12]=[CH:13][C:14]1[CH:19]=[CH:18][CH:17]=[C:16]([O:20][CH2:21][C:22]([O:24][CH3:25])=[O:23])[CH:15]=1)[C:31]#[CH:32]
Reactant: COC(=O)COc1cccc(C=CC(=O)c2c(O)cc(C)n(C)c2=O)c1
Reactant: C#CCN
Agent: [Cl-]
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: C#CCNc1cc(C)n(C)c(=O)c1C(=O)C=Cc1cccc(OCC(=O)OC)c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 10.2 %

Procedure:
To a solution of 0.71 g of 4-hydroxy-3-[3-[3-(methoxycarbonylmethoxy)phenyl]-1-oxo-2-propenyl]-1,6-dimethyl-2(1H)-pyridinone in 5 ml of dimethylformamide was added 0.090 g of sodium hydride (60% oily), and this was stirred at room temperature for 1 hour. 0.46 g of paratoluenesulfonyl chloride was added thereto, this was stirred at room temperature for 4 hours, then, 0.60 g of propargylamine was added, and this was stirred at room temperature overnight. To the reaction solution was added water, the solvent was distilled off under reduced pressure, and the residue was subjected to silica gel column chromatography to obtain 0.080 g of 4-propargylamino-3-[3-[3-(methoxycarbonylmethoxy)phenyl]-1-oxo-2-propenyl]-1,6-dimethyl-2(1H)-pyridinone [Compound No. (13b)] as a yellow crystal.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[C:7](Cl)=[N:8][C:9]([C:12]2[CH:17]=[CH:16][C:15]([O:18][CH2:19][CH2:20][CH2:21][CH3:22])=[CH:14][CH:13]=2)=[N:10][CH:11]=1)=[O:5])[CH3:2].C(N(CC)CC)C>C(OCC)(=O)C.[H][H].[Pd]>[CH2:1]([O:3][C:4]([C:6]1[CH:11]=[N:10][C:9]([C:12]2[CH:17]=[CH:16][C:15]([O:18][CH2:19][CH2:20][CH2:21][CH3:22])=[CH:14][CH:13]=2)=[N:8][CH:7]=1)=[O:5])[CH3:2]
Reactant: [H][H]
Reactant: CCCCOc1ccc(-c2ncc(C(=O)OCC)c(Cl)n2)cc1
Agent: [Pd]
Solvent: CCN(CC)CC
Solvent: CCOC(C)=O
Product: CCCCOc1ccc(-c2ncc(C(=O)OCC)cn2)cc1
Yield: 79.9 %

Procedure:
This compound (V) (3.3 g, 10 mmols) was dissolved in ethyl acetate (30 ml), followed by agitating the solution together with Pd/C (5%) (0.6 g) and triethylamine (1.0 g) in hydrogen atmosphere at room temperature for 3 hours, filtering off Pd/C, adding toluene (100 ml), washing the resulting fluid with 2N-hydrochloric acid (50 ml), washing it with water till the washing water became pH 7, drying the toluene phase over anhydrous magnesium sulfate, filtering off magnesium sulfate, concentrating under reduced pressure to obtain white crystals and recrystallizing the crystals from methanol to obtain ethyl-2-(4-butyloxyphenyl)-5-pyrimidinecarboxylate (VI) (2.4 g) (yield: 80%) having a melting point 99.1° C.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6](Cl)[CH:5]=[C:4]([C:9]([O:11][CH3:12])=[O:10])[N:3]=1.[CH:13]1([CH2:19][NH2:20])[CH2:18][CH2:17][CH2:16][CH2:15][CH2:14]1.C(N(CC)CC)C.O>C1COCC1>[Cl:1][C:2]1[N:3]=[C:4]([C:9]([O:11][CH3:12])=[O:10])[CH:5]=[C:6]([NH:20][CH2:19][CH:13]2[CH2:18][CH2:17][CH2:16][CH2:15][CH2:14]2)[N:7]=1
Reactant: NCC1CCCCC1
Reactant: COC(=O)c1cc(Cl)nc(Cl)n1
Solvent: C1CCOC1
Solvent: O
Solvent: CCN(CC)CC
Product: COC(=O)c1cc(NCC2CCCCC2)nc(Cl)n1
Reaction time: 0.5 h

Procedure:
A cooled (0° C.) solution of methyl 2,4-dichloropyrimidine-6-carboxylate (Apollo, OR2558, 2.62 g; 12.7 mmol) in anhydrous THF (95 mL) was treated with a solution of cyclohexanemethylamine (Aldrich, 1.68 mL; 12.66 mmol) and triethylamine (1.93 mL; 13.92 mmol) in THF (35 mL). The reaction mixture was stirred during 30 min. Water (50 mL) was poured into the reaction mixture, which was extracted with EtOAc. The combined organic extracts were dried over magnesium sulfate, filtered and concentrated, which was purified by column chromatography (silica) eluting with cyclohexane containing increasing amounts of EtOAc. The title product was obtained as a white solid.
Reaction SMILES: FC(F)(F)C(O)=O.[NH:8]1[CH2:12][CH2:11][C@H:10]([CH2:13][NH:14][C:15]([C:17]2[S:18][C:19]([Cl:22])=[CH:20][CH:21]=2)=[O:16])[CH2:9]1.[N+](C1C=CC([O:32][C:33](=O)[NH:34][C:35]2[CH:40]=[CH:39][C:38]([N:41]3[CH:46]=[CH:45][CH:44]=[CH:43][C:42]3=[O:47])=[CH:37][C:36]=2[F:48])=CC=1)([O-])=O>>[F:48][C:36]1[CH:37]=[C:38]([N:41]2[CH:46]=[CH:45][CH:44]=[CH:43][C:42]2=[O:47])[CH:39]=[CH:40][C:35]=1[NH:34][C:33]([N:8]1[CH2:12][CH2:11][C@H:10]([CH2:13][NH:14][C:15]([C:17]2[S:18][C:19]([Cl:22])=[CH:20][CH:21]=2)=[O:16])[CH2:9]1)=[O:32]
Reactant: O=C(NC[C@H]1CCNC1)c1ccc(Cl)s1
Reactant: O=C(Nc1ccc(-n2ccccc2=O)cc1F)Oc1ccc([N+](=O)[O-])cc1
Solvent: O=C(O)C(F)(F)F
Product: O=C(NC[C@H]1CCN(C(=O)Nc2ccc(-n3ccccc3=O)cc2F)C1)c1ccc(Cl)s1

Procedure:
50.4 Using general method H, 5-chloro-thiophene-2-carboxylic acid ((S)-1-pyrrolidin-3-ylmethyl)-amide trifluoro acetate was reacted with [2-fluoro-4-(2-oxo-2H-pyridin-1-yl)-phenyl]-carbamic acid 4-nitro-phenyl ester to give (R)-3-{[(5-chloro-thiophene-2-carbonyl)-amino]-methyl}-pyrrolidine-1-carboxylic acid[2-fluoro-4-(2-oxo-2H-pyridin-1-yl)-phenyl]-amide. White solid. MS 475.0 ([M+H]+)
Reaction SMILES: [CH:1]([C:4]1[CH:5]=[CH:6][C:7]([S:10]([NH:13][C:14]2[C:19]([O:20][C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=3[O:27][CH3:28])=[C:18]([O:29][CH2:30][CH2:31][NH2:32])[N:17]=[C:16]([C:33]3[N:38]=[CH:37][CH:36]=[CH:35][N:34]=3)[N:15]=2)(=[O:12])=[O:11])=[N:8][CH:9]=1)([CH3:3])[CH3:2].[S:39]1[CH:43]=[CH:42][CH:41]=[C:40]1[S:44](Cl)(=[O:46])=[O:45]>>[CH:1]([C:4]1[CH:5]=[CH:6][C:7]([S:10]([NH:13][C:14]2[C:19]([O:20][C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=3[O:27][CH3:28])=[C:18]([O:29][CH2:30][CH2:31][NH:32][S:44]([C:40]3[S:39][CH:43]=[CH:42][CH:41]=3)(=[O:46])=[O:45])[N:17]=[C:16]([C:33]3[N:34]=[CH:35][CH:36]=[CH:37][N:38]=3)[N:15]=2)(=[O:11])=[O:12])=[N:8][CH:9]=1)([CH3:3])[CH3:2]
Reactant: O=S(=O)(Cl)c1cccs1
Reactant: COc1ccccc1Oc1c(NS(=O)(=O)c2ccc(C(C)C)cn2)nc(-c2ncccn2)nc1OCCN
Product: COc1ccccc1Oc1c(NS(=O)(=O)c2ccc(C(C)C)cn2)nc(-c2ncccn2)nc1OCCNS(=O)(=O)c1cccs1

Procedure:
According to the procedure described in Example 4a) 129 mg 5-isopropyl-N-[6-(2-aminoethoxy)-5-(o-methoxyphenoxy)-2-(2-pyrimidinyl)-4-pyrimidinyl]-2-pyridine sulfonamide was reacted with thiophene-2-sulfonylchloride to give 105 mg 5-isopropyl-N-[6-(2-(2-thiophenesulfonylamino)-ethoxy)-5-(o-methoxyphenoxy)-2-(2-pyrimidinyl)-4-pyrimidinyl]-2-pyridine sulfonamide. LC-MS: tR=5.00 min, [M+1]+=684.60, [M−1]−=682.70.
Reaction SMILES: [N:1]1([C:5](=[O:36])[CH2:6][C:7]2[CH:34]=[CH:33][C:10]([O:11][CH2:12][CH2:13][C@@H:14]3[CH2:16][C@@H:15]3[CH:17]3[CH2:22][CH2:21][N:20](C(OCC4C=CC=CC=4)=O)[CH2:19][CH2:18]3)=[CH:9][C:8]=2[F:35])[CH2:4][CH2:3][CH2:2]1>CO.[Pd]>[N:1]1([C:5](=[O:36])[CH2:6][C:7]2[CH:34]=[CH:33][C:10]([O:11][CH2:12][CH2:13][C@@H:14]3[CH2:16][C@@H:15]3[CH:17]3[CH2:18][CH2:19][NH:20][CH2:21][CH2:22]3)=[CH:9][C:8]=2[F:35])[CH2:4][CH2:3][CH2:2]1
Reactant: O=C(Cc1ccc(OCC[C@@H]2C[C@@H]2C2CCN(C(=O)OCc3ccccc3)CC2)cc1F)N1CCC1
Agent: [Pd]
Solvent: CO
Product: O=C(Cc1ccc(OCC[C@@H]2C[C@@H]2C2CCNCC2)cc1F)N1CCC1
Reaction time: 4 h

Procedure:
To a solution of benzyl 4-((1R,2S)-2-{2-[4-(2-azetidin-1-yl-2-oxoethyl)-3-fluorophenoxy]ethyl}cyclopropyl)piperidine-1-carboxylate (590 mg, 1.32 mmol) in 8 mL anhydrous methanol at ambient temperature was added palladium on carbon (80.0 mg, 0.676 mmol), 10% by weight. The solution was stirred under hydrogen for 4 hours and filtered. The crude product was concentrated to the title compound as white solid and used for the next step. LC/MS 361.3 (M+H)+.
Reaction SMILES: [H-].[Na+].[C:3]([O:10][CH2:11][CH3:12])(=[O:9])[C:4]([O:6]CC)=O.C(O)C.[CH3:16][C:17]([C:19]1[CH:24]=[CH:23][CH:22]=[C:21]([Cl:25])[C:20]=1[Cl:26])=[O:18]>C(O)(=O)C.O.CCOCC>[Cl:26][C:20]1[C:21]([Cl:25])=[CH:22][CH:23]=[CH:24][C:19]=1[C:17](=[O:18])[CH2:16][C:4](=[O:6])[C:3]([O:10][CH2:11][CH3:12])=[O:9]
Reactant: CC(=O)c1cccc(Cl)c1Cl
Reactant: CCOC(=O)C(=O)OCC
Agent: [H-]
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CCOCC
Solvent: CCO
Product: CCOC(=O)C(=O)CC(=O)c1cccc(Cl)c1Cl
Temperature: 0 °C
Reaction time: 0.67 h
Yield: 34.4 %

Procedure:
To 14 g of sodium hydride (50%) were added dropwise 21.3 g of diethyl oxalate, 0.54 ml of ethanol and then 160 ml of ether solution containing 30 g of 2,3-dichloroacetophenone with stirring under cooling with ice. The reaction was carried out under the state free from water. The reaction was continued at room temperature for 40 minutes with stirring after the dropping and further carried out for 45 minutes under reflux. The reaction mixture was poured into ice-cold water containing 17.5 g of acetic acid and after stirring the mixture was filtered. The organic layer was separated, dehydrated and concentrated. The residue was recrystallized from n-hexane to obtain 14.5 g of ethyl 4-(2,3-dichlorophenyl)-2,4-dioxobutyrate (white needles, m.p. 57°-58° C.).
Reaction SMILES: [CH2:1]([C:3]1[C:8](=[O:9])[NH:7][C:6]([CH3:10])=[C:5]([C:11]2[S:15][C:14]([S:16](Cl)(=[O:18])=[O:17])=[CH:13][CH:12]=2)[CH:4]=1)[CH3:2].[NH2:20][CH2:21][CH2:22][NH:23][C:24](=[O:26])[CH3:25]>>[CH2:1]([C:3]1[C:8](=[O:9])[NH:7][C:6]([CH3:10])=[C:5]([C:11]2[S:15][C:14]([S:16]([NH:20][CH2:21][CH2:22][NH:23][C:24](=[O:26])[CH3:25])(=[O:18])=[O:17])=[CH:13][CH:12]=2)[CH:4]=1)[CH3:2]
Reactant: CC(=O)NCCN
Reactant: CCc1cc(-c2ccc(S(=O)(=O)Cl)s2)c(C)[nH]c1=O
Product: CCc1cc(-c2ccc(S(=O)(=O)NCCNC(C)=O)s2)c(C)[nH]c1=O
Yield: 71 %

Procedure:
5-(5-Ethyl-2-methyl-6-oxo-1,6-dihydropyridin-3-yl)thiophene-2-sulfonyl chloride is reacted with N-(2-aminoethyl)acetamide as described in Step 5, Example 24 to give the title compound as a yellow solid (71% yield). LC/MS: RT 3.60 min; m/e 384 (M+H); 1H NMR (CDCl3, δ, ppm): 11.53 (1H, br), 7.50 (1H, d), 7.25 (1H, s), 6.90 (1H, d), 6.13 (1H, br), 5.90 (1H, br), 3.42 (31H, m), 3.20 (2H, m), 2.40-2.60 (5H, m), 2.00 (3H, m), 1.20 (3H, t).
Reaction SMILES: [CH2:1]([O:3][C:4]1[C:5]([N:18]2[C:27]3[C:22](=[CH:23][C:24]([S:28](OC4C(F)=C(F)C(F)=C(F)C=4F)(=[O:30])=[O:29])=[CH:25][CH:26]=3)[CH:21]=[CH:20][C:19]2=[O:43])=[CH:6][C:7]([F:17])=[C:8]([C:10]2[CH:15]=[CH:14][CH:13]=[C:12]([F:16])[CH:11]=2)[CH:9]=1)[CH3:2].[O:44]1[CH:48]=[CH:47][C:46]([NH2:49])=[N:45]1.C1COCC1.C[Si]([N-][Si](C)(C)C)(C)C.[Li+]>Cl.CCOC(C)=O>[CH2:1]([O:3][C:4]1[C:5]([N:18]2[C:27]3[C:22](=[CH:23][C:24]([S:28]([NH:49][C:46]4[CH:47]=[CH:48][O:44][N:45]=4)(=[O:29])=[O:30])=[CH:25][CH:26]=3)[CH:21]=[CH:20][C:19]2=[O:43])=[CH:6][C:7]([F:17])=[C:8]([C:10]2[CH:15]=[CH:14][CH:13]=[C:12]([F:16])[CH:11]=2)[CH:9]=1)[CH3:2]
Reactant: Nc1ccon1
Reactant: CCOc1cc(-c2cccc(F)c2)c(F)cc1-n1c(=O)ccc2cc(S(=O)(=O)Oc3c(F)c(F)c(F)c(F)c3F)ccc21
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: Cl
Agent: [Li+]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: CCOc1cc(-c2cccc(F)c2)c(F)cc1-n1c(=O)ccc2cc(S(=O)(=O)Nc3ccon3)ccc21
Reaction time: 1.5 h
Yield: 80.8 %

Procedure:
A solution of perfluorophenyl 1-(5-ethoxy-2,3′-difluoro-[1,1′-biphenyl]-4-yl)-2-oxo-1,2-dihydroquinoline-6-sulfonate (398 mg, 0.638 mmol), isoxazol-3-amine (66.0 pdr, 0.894 mmol) and THF (6383 μl) was cooled in an ice-bath for 15 min, then lithium bis (trimethylsilyl)amide (1M in THF) (1596 μl, 1.596 mmol) was added dropwise. After 1.5 h, the mixture was diluted with 1N aq. HCl and EtOAc. The layers were separated, and the organic layer was washed with 1N aq. HCl. The aq. layers were combined and extracted with EtOAc (2×). The combined organic extracts were dried over sodium sulfate, filtered, and concentrated. The crude material was absorbed onto a plug of silica gel and purified by chromatography through a Redi-Sep pre-packed silica gel column (40 g), eluting with a gradient of 0% to 70% EtOAc in heptane, to provide 1-(5-ethoxy-2,3′-difluoro-[1,1′-biphenyl]-4-yl)-N-(isoxazol-3-yl)-2-oxo-1,2-dihydroquinoline-6-sulfonamide (270 mg, 81% yield) as light-yellow solid. m/z [M+H]+=524.0. NMR (400 MHz, DMSO-d6) δ ppm 0.97 (t, J=6.99 Hz, 2 H) 4.01-4.13 (m, 2 H) 6.42 (s, 1 H) 6.82 (d, J=9.68 Hz, 1 H) 6.88 (d, J=9.10 Hz, 1 H) 7.27-7.37 (m, 1 H) 7.43 (d, J=6.94 Hz, 1 H) 7.50-7.67 (m, 4 H) 7.86 (dd, J=8.95, 2.20 Hz, 1 H) 8.24 (d, J=9.59 Hz, 1 H) 8.37 (d, J=2.05 Hz, 1 H) 8.69 (s, 1 H) 11.66 (br. s., 1H).
Reaction SMILES: [Cl-].[Cl-].[Ca+2].[C:4]([NH:7][C:8]([CH2:19][C:20]1[CH:25]=[CH:24][C:23]([C:26]2[S:27][C:28]3[C:33]([N:34]=2)=[CH:32][CH:31]=[C:30]([C:35]2([C:38]4[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=4)[CH2:37][CH2:36]2)[N:29]=3)=[C:22]([F:44])[CH:21]=1)([C:14](OCC)=[O:15])[C:9](OCC)=[O:10])(=[O:6])[CH3:5].[BH4-].[Na+].C(Cl)Cl>O.C1COCC1.C(O)C>[F:44][C:22]1[CH:21]=[C:20]([CH:25]=[CH:24][C:23]=1[C:26]1[S:27][C:28]2[C:33]([N:34]=1)=[CH:32][CH:31]=[C:30]([C:35]1([C:38]3[CH:39]=[CH:40][CH:41]=[CH:42][CH:43]=3)[CH2:37][CH2:36]1)[N:29]=2)[CH2:19][C:8]([NH:7][C:4](=[O:6])[CH3:5])([CH2:14][OH:15])[CH2:9][OH:10]
Reactant: CCOC(=O)C(Cc1ccc(-c2nc3ccc(C4(c5ccccc5)CC4)nc3s2)c(F)c1)(NC(C)=O)C(=O)OCC
Agent: [BH4-]
Agent: [Ca+2]
Agent: [Cl-]
Solvent: ClCCl
Solvent: CCO
Solvent: C1CCOC1
Product: CC(=O)NC(CO)(CO)Cc1ccc(-c2nc3ccc(C4(c5ccccc5)CC4)nc3s2)c(F)c1
Temperature: 0 °C
Reaction time: 2 h

Procedure:
A solution of CaCl2 (0.159 g, 1.43 mmol) in 1.00 ml of water was added to a solution of diethyl 2-acetamido-2-((3-fluoro-4-(5-(1-phenylcyclopropyl)thiazolo[5,4-b]pyridin-2-yl)phenyl)methyl)malonate (0.330 g, 0.573 mmol) in THF (10.00 ml) and ethanol (10.00 ml). The reaction was cooled to 0° C. in ice bath before the addition of sodium borohydride (0.108 g, 2.87 mmol) was added and the solution became a yellow mixture. The reaction mixture was allowed to stir at ambient temperature for 2 h. DCM (5 ml) and additional sodium borohydride (0.108 g, 2.87 mmol) was added. After 18 h, the reaction was poured over DCM/1 N HCl, and the organic layer was washed with 1 N HCl, dried over MgSO4, filtered, and concentrated in vacuo. The residue was purified by silica gel chromatography, 40 g column, 0-15% MeOH/DCM to give N-(2-(3-fluoro-4-(5-(1-phenylcyclopropyl)thiazolo[5,4-b]pyridin-2-yl)benzyl)-1,3-dihydroxypropan-2-yl)acetamide. MS (ESI) m/z: calculated: 491.2; Observed: 492.1 (M++1).
Reaction SMILES: [C:1]([C:3]1[S:7][C:6]([C@:8]23[CH2:16][NH:15][CH2:14][C@H:13]2[CH2:12][S:11][C:10]([NH:17][C:18](=[O:25])[C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)=[N:9]3)=[CH:5][CH:4]=1)#[N:2].C(N(C(C)C)CC)(C)C.Cl[C:36]1[N:41]=[C:40]([C:42]([OH:45])([CH3:44])[CH3:43])[C:39]([F:46])=[CH:38][N:37]=1>O1CCOCC1.C(OCC)(=O)C>[C:1]([C:3]1[S:7][C:6]([C@:8]23[CH2:16][N:15]([C:36]4[N:41]=[C:40]([C:42]([OH:45])([CH3:44])[CH3:43])[C:39]([F:46])=[CH:38][N:37]=4)[CH2:14][C@H:13]2[CH2:12][S:11][C:10]([NH:17][C:18](=[O:25])[C:19]2[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=2)=[N:9]3)=[CH:5][CH:4]=1)#[N:2]
Reactant: N#Cc1ccc([C@]23CNC[C@H]2CSC(NC(=O)c2ccccc2)=N3)s1
Reactant: CC(C)(O)c1nc(Cl)ncc1F
Solvent: CCOC(C)=O
Solvent: C1COCCO1
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)(O)c1nc(N2C[C@H]3CSC(NC(=O)c4ccccc4)=N[C@@]3(c3ccc(C#N)s3)C2)ncc1F
Yield: 88.8 %

Procedure:
To a stirred clear and colorless solution of N-[(4aR,7aR)-7a-(5-cyanothiophen-2-yl)-4,4a,5,6,7,7a-hexahydropyrrolo[3,4-d][1,3]thiazin-2-yl]benzamide (0.806 mmol) in 1,4-dioxane (16 mL) is added diisopropylethylamine (422 μL, 2.42 mmol) and 2-(2-chloro-5-fluoropyrimidin-4-yl)propan-2-ol (1.54 g, 8.06 mmol). The solution is heated to reflux for 14 hours. The pale yellow solution is allowed to cool, diluted with ethyl acetate (80 mL) and hexanes (20 mL), and washed with dilute aqueous sodium bicarbonate (30 mL, prepared from saturated aqueous sodium bicarbonate (15 mL) and water (15 mL), water (2×20 mL), and brine (20 mL). The organic phase is dried over sodium sulfate, filtered, and concentrated under reduced pressure. The residue is purified by silica gel chromatography, eluting with a hexanes/diethyl ether, gradient from 80:20 to 0:100, to give the title compound (374 mg, 89% over two steps) as a pale yellow glass. MS/ES (m/z) 523.2 (M+H).
Reaction SMILES: [C:1]([C:5]1[N:6]=[C:7]([N:16]2[CH2:20][CH2:19][C:18]([F:22])([F:21])[CH2:17]2)[C:8]2[N:13]=[N:12][N:11]([CH2:14][CH3:15])[C:9]=2[N:10]=1)([CH3:4])([CH3:3])[CH3:2].C(C1N=C(N2CCC(F)(F)C2)C2N=NNC=2N=1)(C)(C)C.BrCC1[CH:50]=[CH:49][C:48]([Cl:51])=[CH:47][CH:46]=1>>[C:1]([C:5]1[N:6]=[C:7]([N:16]2[CH2:20][CH2:19][C:18]([F:21])([F:22])[CH2:17]2)[C:8]2[N:13]=[N:12][N:11]([CH2:14][C:15]3[CH:50]=[CH:49][C:48]([Cl:51])=[CH:47][CH:46]=3)[C:9]=2[N:10]=1)([CH3:2])([CH3:3])[CH3:4]
Reactant: CCn1nnc2c(N3CCC(F)(F)C3)nc(C(C)(C)C)nc21
Reactant: Clc1ccc(CBr)cc1
Agent: CC(C)(C)c1nc(N2CCC(F)(F)C2)c2nn[nH]c2n1
Product: CC(C)(C)c1nc(N2CCC(F)(F)C2)c2nnn(Cc3ccc(Cl)cc3)c2n1

Procedure:
In analogy to the procedure described for the synthesis of 5-tert-butyl-7-(3,3-difluoro-pyrrolidin-1-yl)-3-ethyl-3H-[1,2,3]triazolo[4,5-d]pyrimidine (example 61), the title compound was prepared from 5-tert-butyl-7-(3,3-difluoropyrrolidin-1-yl)-3H-[1,2,3]triazolo[4,5-d]pyrimidine and 1-(bromomethyl)-4-chlorobenzene and isolated as white solid (5.8 mg, 35%). MS(m/e): 407.4 (MH+).
Reaction SMILES: [CH3:1][C:2]1([CH3:27])[CH2:6][O:5][C:4]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=2[C:13]2[CH:18]=[CH:17][C:16]([CH2:19][O:20]C3CCCCO3)=[CH:15][CH:14]=2)=[N:3]1.Cl.C(=O)([O-])O.[Na+]>CO>[CH3:1][C:2]1([CH3:27])[CH2:6][O:5][C:4]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=2[C:13]2[CH:14]=[CH:15][C:16]([CH2:19][OH:20])=[CH:17][CH:18]=2)=[N:3]1
Reactant: CC1(C)COC(c2ccccc2-c2ccc(COC3CCCCO3)cc2)=N1
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CO
Product: CC1(C)COC(c2ccccc2-c2ccc(CO)cc2)=N1
Temperature: 25 °C
Reaction time: 2 h
Yield: 97.8 %

Procedure:
4.0 g (10.9 mmol) of 4,4-dimethyl-2-(4'-tetrahydropyranyloxymethylbiphenyl-2-yl)oxazoline was dissolved in methanol (50 ml), and 6N hydrochloric acid (15 ml) was added thereto, followed by stirring at room temperature for 2 hours. The reaction liquid was poured into a saturated aqueous solution of sodium hydrogencarbonate, followed by the extraction with chloroform. After washing with water and drying, vacuum concentration was conducted. The residue was purified by silica gel column chromatography (a n-hexane/ethyl acetate system) to give 3.0 g of the title compound (yield 98%).
Reaction SMILES: F[C:2]1[CH:11]=[CH:10][C:5]([C:6]([O:8][CH3:9])=[O:7])=[C:4]([O:12][CH2:13][O:14][CH3:15])[CH:3]=1.CS(C)=O.[CH2:20]([S-:22])[CH3:21].[Na+]>O>[CH2:20]([S:22][C:2]1[CH:11]=[CH:10][C:5]([C:6]([O:8][CH3:9])=[O:7])=[C:4]([O:12][CH2:13][O:14][CH3:15])[CH:3]=1)[CH3:21]
Reactant: COCOc1cc(F)ccc1C(=O)OC
Reactant: CC[S-]
Agent: [Na+]
Solvent: O
Solvent: CS(C)=O
Product: CCSc1ccc(C(=O)OC)c(OCOC)c1
Reaction time: 19 h

Procedure:
To a solution of methyl 4-fluoro-2-(methoxymethoxy)-benzoate (10.6 g, 50 mmol) and DMSO (20 mL), under nitrogen, was added sodium ethanethiolate (5.8 g, 55 mmol) in portions. The exothermic reaction was stirred for 19 h, diluted with water, and extracted with ethyl acetate. The organic layer was concentrated; and the residue was dissolved in ether, filtered through diatomaceus earth, and concentrated to give intermediate methyl 4-(ethylthio)-2-(methoxymethoxy)benzoate.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][N:5]2[C:8](=[O:11])[NH:9][N:10]=[C:4]2[C:3]=1[I:12].C(N(CC)C(C)C)(C)C.[CH3:22][O:23][CH2:24]Cl>CN(C=O)C>[Br:1][C:2]1[CH:7]=[CH:6][N:5]2[C:8](=[O:11])[N:9]([CH2:22][O:23][CH3:24])[N:10]=[C:4]2[C:3]=1[I:12]
Reactant: COCCl
Reactant: O=c1[nH]nc2c(I)c(Br)ccn12
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: COCn1nc2c(I)c(Br)ccn2c1=O
Temperature: 20 °C
Reaction time: 3 h
Yield: 97.3 %

Procedure:
To a solution of 7-bromo-8-iodo-[1,2,4]triazolo[4,3-a]pyridin-3(2H)-one (1.0 g, 2.94 mmol) in DMF (10 mL) and N,N-diisopropylethylamine (2.6 mL, 14.7 mmol) at 20° C. was added chloromethyl methyl ether (473 mg, 5.9 mmol). The resulting reaction mixture was stirred for an additional 3 h at 20° C. and then quenched by addition of H2O (25 mL). The quenched reaction mixture was extracted with Et2O/EtOAc (2:1, 3×50 mL). The combined organic extract was washed with saturated aqueous NaHCO3 solution (30 mL), then brine (30 mL), dried over MgSO4, filtered and concentrated in vacuo to obtain the title compound as a light yellow solid (1.1 g, 2.86 mmol). MS: [M+H]+=384.0. 1H NMR (400 MHz, CDCl3) δ 3.46 (s, 3H), 5.34 (s, 2H), 6.68 (d, J=7.15 Hz, 1H), 7.65 (d, J=7.15 Hz, 1H).
Reaction SMILES: [N:1]1([C:7]2[CH:8]=[CH:9][C:10]3[S:15](=[O:17])(=[O:16])[CH2:14][CH2:13][NH:12][C:11]=3[CH:18]=2)[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1.Cl[C:20]1[C:29]2[C:24](=[CH:25][C:26]([O:31][CH3:32])=[C:27]([Cl:30])[CH:28]=2)[N:23]=[C:22]([CH3:33])[C:21]=1[CH3:34].C(=O)([O-])[O-].[Cs+].[Cs+].C1C=CC(P(C2C(C3C(P(C4C=CC=CC=4)C4C=CC=CC=4)=CC=C4C=3C=CC=C4)=C3C(C=CC=C3)=CC=2)C2C=CC=CC=2)=CC=1>O1CCOCC1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[Cl:30][C:27]1[CH:28]=[C:29]2[C:24](=[CH:25][C:26]=1[O:31][CH3:32])[N:23]=[C:22]([CH3:33])[C:21]([CH3:34])=[C:20]2[N:12]1[C:11]2[CH:18]=[C:7]([N:1]3[CH2:2][CH2:3][O:4][CH2:5][CH2:6]3)[CH:8]=[CH:9][C:10]=2[S:15](=[O:17])(=[O:16])[CH2:14][CH2:13]1
Reactant: O=S1(=O)CCNc2cc(N3CCOCC3)ccc21
Reactant: COc1cc2nc(C)c(C)c(Cl)c2cc1Cl
Agent: [Pd]
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Agent: O=C([O-])[O-]
Solvent: C1COCCO1
Product: COc1cc2nc(C)c(C)c(N3CCS(=O)(=O)c4ccc(N5CCOCC5)cc43)c2cc1Cl

Procedure:
Prepared according to procedure T using 6-morpholin-4-yl-3,4-dihydro-2H-1,4-benzothiazine 1,1-dioxide (0.134 g, 0.5 mmol), 4,6-dichloro-7-methoxy-2,3-dimethylquinoline (0.256 g, 1 mmol), cesium carbonate (0.326 g, 1 mmol), Pd2(dba)3 (0.046 g, 0.05 mmol) and (±) BINAP (0.047 g, 0.075 mmol) in 1,4-dioxane (2 mL). After purification by HPLC 4-(6-chloro-7-methoxy-2,3-dimethyl-4-quinolinyl)-6-(4-morpholinyl)-3,4-dihydro-2H-1,4-benzothiazine 1,1-dioxide was obtained. 1H NMR (500 MHz, DMSO-d6) δ ppm 8.10 (1H, s), 7.60 (1H, s), 7.48-7.54 (1H, m), 6.56 (1H, m), 5.51 (1H, dd, J=1.8, 0.9 Hz), 4.12 (2H, br. s.), 3.93 (3H, s), 3.56 (4H, dd, J=5.1, 4.6 Hz), 2.87 (4H, dd, J=5.3, 4.8 Hz), 2.72 (3H, s), 2.55 (2H, m). Mass Spectrum (ESI) m/e=489 (M+1).
Reaction SMILES: [NH2:1][C:2]1[C:7]([Cl:8])=[CH:6][CH:5]=[CH:4][C:3]=1[SH:9].[OH-].[K+].[Cl:12][C:13]1[CH:18]=[CH:17][CH:16]=[C:15]([N+:19]([O-:21])=[O:20])[C:14]=1Cl>CCO>[Cl:8][C:7]1[CH:6]=[CH:5][CH:4]=[C:3]([S:9][C:14]2[C:15]([N+:19]([O-:21])=[O:20])=[CH:16][CH:17]=[CH:18][C:13]=2[Cl:12])[C:2]=1[NH2:1]
Reactant: Nc1c(S)cccc1Cl
Reactant: O=[N+]([O-])c1cccc(Cl)c1Cl
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Product: Nc1c(Cl)cccc1Sc1c(Cl)cccc1[N+](=O)[O-]
Temperature: 25 °C

Procedure:
The 2-amino-3-chlorobenzenthiol (550 mg, 3.95 mmol) was dissolved in EtOH (10 mL) followed by KOH (220 mg, 3.95 mmol). To this mixture was added a solution of 1,2-dichloro-3-nitrobenzene (760 mg, 3.95 mmol) in EtOH (10 mL). The resulting reaction mixture was refluxed for 8 h to 12 h. The reaction was allowed to cool to room temperature and the residue was extracted with EtOAc and 1 mol dm−3 H3PO4. The organic layer was dried over MgSO4, filtered and evaporated to give a crude material. This crude material was purified by flash silica gel chromatography.