Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]1([S:4]([C:7]2[CH:15]=[CH:14][CH:13]=[C:12]3[C:8]=2[CH:9]=[N:10][N:11]3[CH:16]([CH2:23][CH:24]2[CH2:29][CH2:28][O:27][CH2:26][CH2:25]2)[C:17](N(OC)C)=[O:18])(=[O:6])=[O:5])[CH2:3][CH2:2]1.[CH:30]([Mg]Br)=[CH2:31].Cl>O1CCCC1>[CH:1]1([S:4]([C:7]2[CH:15]=[CH:14][CH:13]=[C:12]3[C:8]=2[CH:9]=[N:10][N:11]3[CH:16]([CH2:23][CH:24]2[CH2:29][CH2:28][O:27][CH2:26][CH2:25]2)[C:17](=[O:18])[CH:30]=[CH2:31])(=[O:6])=[O:5])[CH2:3][CH2:2]1
Reactant: CON(C)C(=O)C(CC1CCOCC1)n1ncc2c(S(=O)(=O)C3CC3)cccc21
Reactant: C=C[Mg]Br
Agent: Cl
Solvent: C1CCOC1
Product: C=CC(=O)C(CC1CCOCC1)n1ncc2c(S(=O)(=O)C3CC3)cccc21
Temperature: 0 °C
Reaction time: 0.33 h
Yield: 84 %

Procedure:
To a solution of 2-[4-(cyclopropylsulfonyl)-1H-indazol-1-yl]-N-methoxy-N-methyl-3-(tetrahydro-2H-pyran-4-yl)propanamide (2.30 g) in tetrahydrofuran (20 ml) was slowly added vinylmagnesium bromide (1.0M tetrahydrofuran solution: 16.4 mL) at 0° C., and the mixture was stirred at 0° C. for 20 min. The reaction mixture was poured into an ice-cooled 1M hydrochloric acid, and the mixture was extracted with ethyl acetate. The ethyl acetate layer was washed with saturated brine, dried (MgSO4), and concentrated. The residue was subjected to silica gel column chromatography to give the title compound (1.80 g, yield 84%) as a colorless oil from the fraction eluted with ethyl acetate-hexane (3:1, volume ratio). MS: 389 (MH+).
Reaction SMILES: F[CH2:2][C:3]([C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1)=O.[NH2:11][NH2:12].C(Cl)Cl>C(O)CO>[CH3:2][C:3]1[C:5]2[C:10](=[CH:9][CH:8]=[CH:7][CH:6]=2)[NH:12][N:11]=1
Reactant: O=C(CF)c1ccccc1
Reactant: NN
Solvent: ClCCl
Solvent: OCCO
Product: Cc1n[nH]c2ccccc12
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A stirred solution of 2.0 g (14.48 mmol) of 2-fluoroacetophenone (32-1) in 10 mL of ethylene glycol under nitrogen was treated with 473 uL (15.06 mmol) of hydrazine. This solution was stirred for 2 hours at room temperature and then heated at 165° C. for 40 hours. The solution was cooled to room temperature, poured into CH2Cl2 (25 mL), and extracted with H2O (2×50 mL). The organic portions were combined, dried (MgSO4), filtered and conc. in vacuo. Purification of the crude material by recrystallization from hexanes/CHCl3 gave the desired product 32-2 as a tan solid. 1H NMR (DMSO-d6): δ 7.70 (d, 1H), 7.42 (m, 2H), 7.17 (dd, 1H), 2.60 (s, 3H).
Reaction SMILES: [NH2:1][C:2]1[N:7]=[CH:6][CH:5]=[CH:4][N:3]=1.[CH2:8](OC(OCC)CBr)[CH3:9].Br>C(O)C>[N:1]1[CH:8]=[CH:9][N:3]2[CH:4]=[CH:5][CH:6]=[N:7][C:2]=12
Reactant: CCOC(CBr)OCC
Reactant: Nc1ncccn1
Agent: Br
Solvent: CCO
Product: c1cnc2nccn2c1
Yield: 81.4 %

Procedure:
A solution of 2-aminopyrimidine (0.5 g, 5.26 mmol), bromoacetaldehyde diethyl acetal (2.07 g, 10.5 mmol) and 48% aqueous hydrobromic acid (0.5 ml) in ethanol (5 ml) was heated at reflux for 18 h. The reaction was cooled and pre-adsorbed directly onto silica gel. Purification by flash chromatography eluting with dichloromethane (containing 1% conc. ammonia) on a gradient of methanol (1-3%) gave a solid which was triturated with 5% diethyl ether in isohexane to afford imidazo[1,2-a]pyrimidine (0.51 g, 82%) as a tan solid: δH (400 MHz, CDCl3) 6.92 (1H, dd, J 7 and 4), 7.59 (1H, d, J 1), 7.84 (1H, d, J 1), 8.49 (1H, dd, J 7 and 2), 8.58 (1H, dd, J 7 and 2).
Reaction SMILES: [CH3:1][C:2]1[S:6][C:5]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)=[N:4][C:3]=1[CH2:13][NH:14][C@H:15]1[CH2:20][CH2:19][C@H:18]([C:21]2[CH:30]=[CH:29][C:24]3[NH:25][C:26](=[O:28])[O:27][C:23]=3[CH:22]=2)[CH2:17][CH2:16]1.[OH-].[Na+].[BH-](OC(C)=O)(OC(C)=O)O[C:35](C)=O.[Na+]>CO>[CH3:35][N:14]([CH2:13][C:3]1[N:4]=[C:5]([C:7]2[CH:8]=[CH:9][CH:10]=[CH:11][CH:12]=2)[S:6][C:2]=1[CH3:1])[C@H:15]1[CH2:20][CH2:19][C@H:18]([C:21]2[CH:30]=[CH:29][C:24]3[NH:25][C:26](=[O:28])[O:27][C:23]=3[CH:22]=2)[CH2:17][CH2:16]1
Reactant: Cc1sc(-c2ccccc2)nc1CN[C@H]1CC[C@H](c2ccc3[nH]c(=O)oc3c2)CC1
Reactant: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: Cc1sc(-c2ccccc2)nc1CN(C)[C@H]1CC[C@H](c2ccc3[nH]c(=O)oc3c2)CC1
Reaction time: 3 h

Procedure:
A mixture of trans-6-{4-[(5-methyl-2-phenyl-thiazol-4-ylmethyl)-amino]-cyclohexyl}-3H-benzoxazol-2-one of formula 42 (510 mg, 1.12 mmol), 2N NaOH (1 mL), and p-formaldehyde (168 mg, 5.60 mmol) in MeOH (10 mL) was stirred for 3 hours, NaBH(OAc)3 (332 mg, 1,56 mmol) was added, and the mixture was stirred overnight. The reaction was quenched by addition of MeOH. Concentration under reduced pressure followed by purification by flash chromatography (silica gel, 95:5:1 CH2Cl2:MeOH:NH4OH) gave trans-6-{4-[methyl-(5-methyl-2-phenyl-thiazol-4-ylmethyl)-amino]-cyclohexyl}-3H-benzoxazol-2-one (43) (345 mg, 71%), as a white solid: mp 246-248° C.; IR (KBr): 2927, 1773 cm−1: 1H NMR (500 MHz, DMSO-d6) δ 7.88 (dd, J=8, 2 Hz, 1H), 7.44 (m, 5H), 7.15 (s, 1H), 6.98 (m, 1H), 3.75 (s, 2H), 2.53 (m, 1H), 2.48 (m, 1H), 2.48 (s, 3H), 2.24 (s, 3H), 1.86 (m, 4H), 1.47 (m, 4H); CI-MS (methane) (m/z): 434 [M+H]+; HRMS-API (m/z): [M+H]+ calcd for C25H27N3O2S, 434.1902; found, 434.1903; HPLC: method A, 12.46 minutes (99.0%); method B, 14.05 minutes (98.7%); Anal. Calcd for C25H27N3O2S.0.25H2O: C, 68.54; H, 6.33; N, 9.59. Found: C, 68.21; H, 6.07; N, 9.59.
Reaction SMILES: [Br:1][C:2]1[N:3]=[C:4]([NH:16][CH2:17][C:18]2[C:23]([F:24])=[CH:22][CH:21]=[C:20]([F:25])[C:19]=2[Cl:26])[C:5]([NH:8][C:9](=[O:15])[C:10](OCC)=[O:11])=[N:6][CH:7]=1>COCCOCCOC>[Br:1][C:2]1[N:3]=[C:4]2[N:16]([CH2:17][C:18]3[C:23]([F:24])=[CH:22][CH:21]=[C:20]([F:25])[C:19]=3[Cl:26])[C:10](=[O:11])[C:9](=[O:15])[NH:8][C:5]2=[N:6][CH:7]=1
Reactant: CCOC(=O)C(=O)Nc1ncc(Br)nc1NCc1c(F)ccc(F)c1Cl
Solvent: COCCOCCOC
Product: O=c1[nH]c2ncc(Br)nc2n(Cc2c(F)ccc(F)c2Cl)c1=O
Yield: 43 %

Procedure:
A solution of ethyl ({5-bromo-3-[(2-chloro-3,6-difluorobenzyl)amino]pyrazin-2-yl}amino)(oxo)acetate (1.20 g) in diglyme was heated at 165° C. for 16 hrs. The volatile components were removed on rotavap and then under vacuum. The residue was subjected to a silica gel column chromatography by using CH2Cl2/MeOH (9:1) as eluents, furnishing 7-bromo-1-(2-chloro-3,6-difluorobenzyl)-1,4-dihydropyrazino[2,3-b]pyrazine-2,3-dione in 43% yield (0.46 g).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([NH:11][S:12]([C:15]2[CH:20]=[CH:19][C:18]([Cl:21])=[C:17]([C:22]([F:25])([F:24])[F:23])[CH:16]=2)(=[O:14])=[O:13])[C:5]([C:8]([OH:10])=O)=[N:6][CH:7]=1.Cl.[CH3:27][NH:28][O:29][CH3:30].CCN(C(C)C)C(C)C.F[P-](F)(F)(F)(F)F.N1(O[P+](N(C)C)(N(C)C)N(C)C)C2C=CC=CC=2N=N1>>[CH3:30][O:29][N:28]([CH3:27])[C:8]([C:5]1[C:4]([NH:11][S:12]([C:15]2[CH:20]=[CH:19][C:18]([Cl:21])=[C:17]([C:22]([F:25])([F:24])[F:23])[CH:16]=2)(=[O:14])=[O:13])=[CH:3][C:2]([Cl:1])=[CH:7][N:6]=1)=[O:10]
Reactant: O=C(O)c1ncc(Cl)cc1NS(=O)(=O)c1ccc(Cl)c(C(F)(F)F)c1
Reactant: CNOC
Agent: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Product: CON(C)C(=O)c1ncc(Cl)cc1NS(=O)(=O)c1ccc(Cl)c(C(F)(F)F)c1

Procedure:
5-Chloro-3-(4-chloro-3-trifluoromethyl-benzenesulfonylamino)-pyridine-2-carboxylic acid (15.8, 38 mmol), N,O-dimethyl hydroxylamine hydrochloride (11.1 mg, 114 mmol), DIEA (41 mL, 228 mmol) methyl-m-tolyl-amine (44 mg, 0.36 mmol), and BOP (69 mg, 49 mmol), were reacted according to the procedure D for the synthesis of 5-chloro-3-(4-chloro-3-(trifluoromethyl)phenylsulfonamido)-picolinic amides at 50° C. The reaction mixture was quenched with 1 (M) HCl, extracted with EtOAc, and the organic portions were washed with 1 (M) aqueous HCl, NaHCO3 and brine. The combined organic extracts were dried (Na2SO4), filtered and concentrated under reduced pressure. The resulting residue was purified by flash column chromatography to afford 5-chloro-3-(4-chloro-3-trifluoromethyl-benzenesulfonylamino)-pyridine-2-carboxylic acid methoxy-methyl-amide: MS m/z: (M+H) 458.0.
Reaction SMILES: [CH2:1]([N:7]1[CH2:12][CH:11]2[CH:9]([CH:10]2[C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[C:8]1=O)[CH2:2][CH2:3][CH2:4][CH2:5][CH3:6].[H-].[Al+3].[Li+].[H-].[H-].[H-].O>O1CCCC1>[CH2:1]([N:7]1[CH2:12][CH:11]2[CH:9]([CH:10]2[C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[CH2:8]1)[CH2:2][CH2:3][CH2:4][CH2:5][CH3:6]
Reactant: CCCCCCN1CC2C(C1=O)C2c1ccccc1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Solvent: O
Product: CCCCCCN1CC2C(C1)C2c1ccccc1
Temperature: 60 °C
Reaction time: 64 h
Yield: 38.3 %

Procedure:
To a solution of 3-hexyl-6-phenyl-3-azabicyclo[3.1.0]hexan-2-one (Preparation 27, 40 mg, 0.15 mmol) in anhydrous tetrahydrofuran (2 ml) at room temperature under nitrogen, was added dropwise a solution of lithium aluminium hydride 1.0 M in tetrahydrofluran (0.3 ml, 0.3 mmol), then the mixture was heated to 60° C. for 4 hours, cooled and stirred at room temperature for 64 hours. Water (30 ml) was carefully added, then the mixture was extracted with ethyl acetate (2×25 ml). The combined extracts were washed with water (30 ml), dried (Na2SO4), filtered and concentrated in vacuo. The residue was purified by silica (1.5 g) column chromatography eluting with 80:20:1 ethyl acetate:hexane:ammonia solution (0.880). Product-containing fractions were combined and concentrated in vacuo to give the title compound as a pale yellow oil (14 mg, 38%).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH2:9][N:10]2[C:14]([CH3:15])=[C:13]([C:16]([NH:18][C:19]3[CH:24]=[CH:23][CH:22]=[C:21]([OH:25])[CH:20]=3)=[O:17])[N:12]=[N:11]2)[CH:5]=[CH:6][C:7]=1[Cl:8].Br[CH2:27][CH2:28][O:29]C1CCCCO1.C(=O)([O-])[O-].[K+].[K+]>C(#N)C.CN(C=O)C>[Cl:1][C:2]1[CH:3]=[C:4]([CH2:9][N:10]2[C:14]([CH3:15])=[C:13]([C:16]([NH:18][C:19]3[CH:24]=[CH:23][CH:22]=[C:21]([O:25][CH2:27][CH2:28][OH:29])[CH:20]=3)=[O:17])[N:12]=[N:11]2)[CH:5]=[CH:6][C:7]=1[Cl:8]
Reactant: Cc1c(C(=O)Nc2cccc(O)c2)nnn1Cc1ccc(Cl)c(Cl)c1
Reactant: BrCCOC1CCCCO1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CC#N
Product: Cc1c(C(=O)Nc2cccc(OCCO)c2)nnn1Cc1ccc(Cl)c(Cl)c1
Temperature: 40 °C
Reaction time: 3 h

Procedure:
To a solution of 1-[(3,4-dichlorophenyl)methyl]-N-(3-hydroxyphenyl)-5-methyl-1H-1,2,3-triazole-4-carboxamide (Example 31) (0.1 g, 0.29 mmol) in acetonitrile (10 mL) and a couple of drops of DMF, were added 2-[(2-bromoethyl)oxy]tetrahydro-2H-pyran (0.09 μl, 2 eq) and potassium carbonate (0.08 g, 2 eq). The reaction was heated at 40° C. for 1 week. After evaporation, the residue was dissolved in DCM, washed with water and dried over sodium sulphate. After purification by flash chromatography eluting with DCM/MeOH, 98/2, the crude compound was dissolved in MeOH and some drops of a concentrated HCl solution in AcOEt were added and the solution was stirred at room temperature for 3 hours. After evaporation, the compound was recrystallised (twice) from methanol and washed with a mixture of ether and pentane. The title compound was obtained as a green solid (45 mg, 36%). HRMS calculated for C19H18Cl2N4O3 (M+H)+421.0834, found: 421.0804, Rt: 2.87 min. MP: 144.9° C.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]([C:14]2[CH:19]=[CH:18][C:17]([C:20]3[C:21]([N:25](C(OCC(Cl)(Cl)Cl)=O)[C@H:26]([C:31]([O:33][CH3:34])=[O:32])[CH2:27][CH:28]([CH3:30])[CH3:29])=[N:22][O:23][N:24]=3)=[CH:16][CH:15]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].OP([O-])(O)=O.[K+]>C1COCC1.[Zn]>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]([C:14]2[CH:15]=[CH:16][C:17]([C:20]3[C:21]([NH:25][C@H:26]([C:31]([O:33][CH3:34])=[O:32])[CH2:27][CH:28]([CH3:30])[CH3:29])=[N:22][O:23][N:24]=3)=[CH:18][CH:19]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:2])([CH3:3])[CH3:4]
Reactant: COC(=O)[C@H](CC(C)C)N(C(=O)OCC(Cl)(Cl)Cl)c1nonc1-c1ccc(N2CCN(C(=O)OC(C)(C)C)CC2)cc1
Agent: O=P([O-])(O)O
Agent: [K+]
Agent: [Zn]
Solvent: C1CCOC1
Product: COC(=O)[C@H](CC(C)C)Nc1nonc1-c1ccc(N2CCN(C(=O)OC(C)(C)C)CC2)cc1
Reaction time: 4 h

Procedure:
To methyl N-(4-{4-[4-(tert-butoxycarbonyl)piperazin-1-yl]phenyl}-1,2,5-oxadiazol-3-yl)-N-[(2,2,2-trichloroethoxy)carbonyl]leucinate (605 mg, 0.932 mmol) in THF (20 mL) was added activated zinc powder (610 mg, 9.32 mmol) and an aqueous solution of KH2PO4 (1.0 M, 1.8 mL, 1.8 mmol) dropwise. After 15 min an additional aliquot of aqueous KH2PO4 solution was added (1.0 M, 1.8 mL, 1.8 mmol) and the reaction mixture was stirred for 4 hours. The zinc powder was filtered off, rinsed with Et2O and water and the product extracted with ether (2×), dried over Na2SO4, concentrated in vacuo and purified by flash chromatography over silica gel (EtOAc/Hex, 25/5) to afford methyl N-(4-{4-[4-(tert-butoxycarbonyl)piperazin-1-yl]phenyl}-1,2,5-oxadiazol-3-yl)leucinate.
Reaction SMILES: [CH3:1][C@H:2]1[NH:7][C:6](=[O:8])[CH:5]([NH:9][C:10](=[O:16])[O:11][C:12]([CH3:15])([CH3:14])[CH3:13])[CH2:4][C@H:3]1[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=1[CH3:23].CN1C(=O)N(C)CCC1.C(O[Li])(C)(C)C.[C:39]([CH2:43]OS(C(F)(F)F)(=O)=O)([F:42])([F:41])[F:40]>C1COCC1>[CH3:1][C@H:2]1[N:7]([CH2:43][C:39]([F:42])([F:41])[F:40])[C:6](=[O:8])[CH:5]([NH:9][C:10](=[O:16])[O:11][C:12]([CH3:15])([CH3:13])[CH3:14])[CH2:4][C@H:3]1[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=1[CH3:23]
Reactant: O=S(=O)(OCC(F)(F)F)C(F)(F)F
Reactant: Cc1ccccc1[C@@H]1CC(NC(=O)OC(C)(C)C)C(=O)N[C@@H]1C
Agent: [Li]OC(C)(C)C
Solvent: CN1CCCN(C)C1=O
Solvent: C1CCOC1
Product: Cc1ccccc1[C@@H]1CC(NC(=O)OC(C)(C)C)C(=O)N(CC(F)(F)F)[C@@H]1C
Temperature: 22.5 °C
Reaction time: 24 h
Yield: 76.1 %

Procedure:
To a solution of 37 (50 g, 0.164 mol) and DMPU (25 g, 0.2 mol) in THF (500 mL) was added tert-BuOLi (16.5 g, 0.2 mol) in portions at 20° C. for 0.5 h. After the mixture was degassed for 30 min at 20° C., CF3CH2OTf (45.8 g, 0.2 mol) was added at 20-25° C. The reaction was stirred for 24 h at 20-25° C. After the reaction was complete, the mixture was quenched by water, and then partitioned with water and EtOAc. The organic solution was dried over Na2SO4 and concentrated. The crude residual was further purified by flash chromatography on silica gel (2-10% EtOAc/PE) to give product 38 (50 g, 78% yield). 1H NMR (DMSO-d6, 400 MHz): δ 7.18-7.13 (m, 4H), 4.17 (m, 1H), 4.11 (br, 1H), 3.67 (m, 3H), 2.66 (s, 1H), 2.33 (d, 3H), 1.83 (t, 1H), 1.41 (s, 9H), 0.96 (d, 3H); MS (ESI) m/e [M+H]+ 405.17.
Reaction SMILES: Cl[C:2]1[N:3]=[CH:4][C:5]2[N:11]([CH3:12])[C:10](=[O:13])[CH:9]([CH3:14])[CH2:8][N:7]([CH:15]3[CH2:20][CH2:19][CH2:18][CH2:17][CH2:16]3)[C:6]=2[N:21]=1.[N:22]1[CH:27]=[CH:26][C:25]([C:28]2[O:29][C:30]3[CH:36]=[CH:35][C:34]([NH2:37])=[CH:33][C:31]=3[N:32]=2)=[CH:24][CH:23]=1.O.C1(C)C=CC(S(O)(=O)=O)=CC=1>CC(O)C>[CH:15]1([N:7]2[CH2:8][CH:9]([CH3:14])[C:10](=[O:13])[N:11]([CH3:12])[C:5]3[CH:4]=[N:3][C:2]([NH:37][C:34]4[CH:35]=[CH:36][C:30]5[O:29][C:28]([C:25]6[CH:24]=[CH:23][N:22]=[CH:27][CH:26]=6)=[N:32][C:31]=5[CH:33]=4)=[N:21][C:6]2=3)[CH2:20][CH2:19][CH2:18][CH2:17][CH2:16]1
Reactant: CC1CN(C2CCCCC2)c2nc(Cl)ncc2N(C)C1=O
Reactant: Nc1ccc2oc(-c3ccncc3)nc2c1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: O
Solvent: CC(C)O
Product: CC1CN(C2CCCCC2)c2nc(Nc3ccc4oc(-c5ccncc5)nc4c3)ncc2N(C)C1=O

Procedure:
A solution of 0.05 g (0.00016 mole) of (rac)-2-chloro-9-cyclohexyl-5,7-dimethyl-5,7,8,9-tetrahydro-pyrimido[4,5-b][1,4]diazepin-6-one (VII-19), 0.034 g, 0.00016 mole) of 2-pyridin-4-yl-benzooxazol-5-ylamine, 0.047 g, (0.00024 mole) of p-toluenesulfonic acid monohydrate and 4 mL of 2-propanol was heated at 180 degree for 2 hours in a microwave reactor. The reaction mixture was concentrated. The residue was diluted with dichloromethane and washed twice with saturated sodium bicarbonate solution. The aqueous phase was extracted with dichloromethane. The combined organic phases were washed with brine, dried anhydrous magnesium sulfate, filtered and concentrated under reduced pressure. The residue was purified by silica gel chromatography, eluting with dichloromethane-methanol (100:0-95:5) to give 0.047 g of (rac)-9-cyclohexyl-5,7-dimethyl-2-(2-pyridin-4-yl-benzooxazol-5-ylamino)-5,7,8,9-tetrahydro-pyrimido[4,5-b][1,4]diaze-pin-6-one (I-26). HRMS (ES+) m/z Calcd for C27H29N7O2+H [(M+H)+]: 484.2456. Found: 484.2456.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([CH3:8])[C:3]=1[NH:9][S:10]([C:13]1[N:22]=[C:16]2[N:17]=[CH:18]C(C)=C[N:15]2[N:14]=1)(=[O:12])=[O:11].O.[OH-].[K+].OO.Cl.S([O-])([O-])=[O:30].[Na+].[Na+]>>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([CH3:8])[C:3]=1[NH:9][S:10]([C:13]1[N:22]=[C:16]([NH:17][CH:18]=[O:30])[NH:15][N:14]=1)(=[O:12])=[O:11]
Reactant: O=S([O-])[O-]
Reactant: Cc1cnc2nc(S(=O)(=O)Nc3c(C)cccc3Cl)nn2c1
Agent: Cl
Agent: OO
Agent: [K+]
Solvent: O
Product: Cc1cccc(Cl)c1NS(=O)(=O)c1n[nH]c(NC=O)n1
Yield: 80 %

Procedure:
A solution of 4.0 g (11.8 mmol) of N-(2-chloro-6-methylphenyl)-6-methyl-1,2,4-triazolo-[1,5-a]pyrimidine-2-sulfonamide in 120 ml of water containing 2.7 g (49 mmol) of potassium hydroxide. To this solution was added 14 ml of 35 percent aqueous hydrogen peroxide via dropwise addition. A mild exotherm resulted and the rate of addition of the oxidant was used to keep the temperature between 30°-35°. After 1 h the light yellow solution was acidified with 6N aqueous HCl and excess oxidant decomposed by addition of sodium sulfite until a negative peroxide paper test was achieved. The resulting solid was collected and again dissolved in 50 ml of ethanol and a minimum amount of aqueous saturated bicarbonate. The solution was acidified with aqueous HCl to afford 3.0 g (80 percent) of product as a white powder; mp 291°-300° C. decomposition.
Reaction SMILES: P(Cl)(Cl)(Cl)(Cl)Cl.[CH2:7]([N:9]1[S:14](=[O:16])(=[O:15])[NH:13][C:12]([O:17][CH3:18])=[N:11][C:10]1=O)[CH3:8].P(Cl)(Cl)([Cl:22])=O>>[Cl:22][C:10]1[N:9]([CH2:7][CH3:8])[S:14](=[O:16])(=[O:15])[N:13]=[C:12]([O:17][CH3:18])[N:11]=1
Reactant: CCN1C(=O)N=C(OC)NS1(=O)=O
Reactant: O=P(Cl)(Cl)Cl
Agent: ClP(Cl)(Cl)(Cl)Cl
Product: CCN1C(Cl)=NC(OC)=NS1(=O)=O
Yield: 91 %

Procedure:
154 parts of phosphorus pentachloride were added, in the course of 2 minutes, to a stirred mixture of 128 parts of 6-ethyl-3-methoxy-6H-1,2,4,6-thiatriazin-5-one-1,1-dioxide in 840 parts of phosphorus oxychloride, at 25° C. The reaction mixture was stirred under reflux for 51/2 hours and then concentrated under reduced pressure. The oil which remained was taken up in 300 parts of 1,2-dichloroethane and chromatographed over neutral alumina (activity I). The solution was then evaporated down, giving 127.5 parts (91% of theory) of 5-chloro-6-ethyl-3-methoxy-6H-1,2,4,6-thiatriazine-1,1-dioxide, of melting point 63°-70° C.
Reaction SMILES: [CH3:1][C:2]1[N:3]=[C:4]([N:17]2[C:21](=[O:22])[NH:20][N:19]=[CH:18]2)[S:5][C:6]=1[C:7]([NH:9][CH2:10][C:11]1[CH:12]=[N:13][CH:14]=[CH:15][CH:16]=1)=[O:8].C(=O)([O-])[O-].[K+].[K+].CS(O[CH2:34][CH:35]1[CH2:37][C:36]1([F:39])[F:38])(=O)=O>CN(C)C=O.C(OCC)(=O)C>[F:38][C:36]1([F:39])[CH2:37][CH:35]1[CH2:34][N:20]1[C:21](=[O:22])[N:17]([C:4]2[S:5][C:6]([C:7]([NH:9][CH2:10][C:11]3[CH:12]=[N:13][CH:14]=[CH:15][CH:16]=3)=[O:8])=[C:2]([CH3:1])[N:3]=2)[CH:18]=[N:19]1
Reactant: Cc1nc(-n2cn[nH]c2=O)sc1C(=O)NCc1cccnc1
Reactant: CS(=O)(=O)OCC1CC1(F)F
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: Cc1nc(-n2cnn(CC3CC3(F)F)c2=O)sc1C(=O)NCc1cccnc1
Temperature: 25 °C
Reaction time: 20 h
Yield: 41 %

Procedure:
To a suspension of 4-methyl-2-(5-oxo-1H-1,2,4-triazol-4(5H)-yl)-N-(pyridin-3-ylmethyl)thiazole-5-carboxamide (0.15 g, 0.47 mmol) and potassium carbonate (0.10 g, 1.47 mmol) in N,N-dimethylformamide (2 mL) was added (2,2-difluorocyclopropyl)-methyl methanesulfonate (0.13 g, 0.70 mmol). The reaction mixture was kept stirring at ambient temperature for 20 hours, diluted with ethyl acetate (100 mL) and washed with water and brine. The organic solution was dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated in vacuo and the residue was purified by column chromatography to afford the title compound in 41% yield (0.08 g): mp 160-161° C.; 1H NMR (300 MHz, CDCl3) δ 8.53-8.41 (m, 2H), 8.24 (s, 1H), 7.69-7.62 (m, 1H), 7.27-7.16 (m, 2H), 4.54 (d, J=5.8 Hz, 2H), 4.00-3.81 (m, 2H), 2.58 (s, 3H), 2.08-1.91 (m, 1H), 1.56-1.41 (m, 1H), 1.40-1.10 (m, 1H); 13C NMR (75 MHz, CDCl3) δ 161.8, 153.3, 150.9, 149.8, 149.1, 148.7, 135.8, 133.9, 131.1, 123.7, 121.8, 112.7, 43.2, 41.5, 20.8, 17.2, 15.4; MS (ES+) m/z 407.1 (M+1).
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([OH:10])=[CH:6][C:5]=1[F:11])([O-])=O>C(O)C.[Pd]>[NH2:1][C:4]1[CH:9]=[CH:8][C:7]([OH:10])=[CH:6][C:5]=1[F:11]
Reactant: O=[N+]([O-])c1ccc(O)cc1F
Agent: [Pd]
Solvent: CCO
Product: Nc1ccc(O)cc1F
Reaction time: 2 h

Procedure:
In a 1 l reactor, 10 g of 4-nitro-3-fluorophenol (0.0637 mol) with a catalytic quantity of palladium adsorbed on carbon (10% by mass) in ethanol (250 ml) is hydrogenated for 2 hours under a hydrogen pressure of 1.5 bars. The reaction medium is then filtered on a millipore filter then rinsed with ethanol, followed by evaporation to dryness and the residue is triturated with diethyl ether and the reaction medium stirred in a mixture of diisopropyl ether and isopentane (1:4). After filtration of the solid and drying, a beige-coloured powder is obtained.
Reaction SMILES: [C:1]1([N:7]2[C:16]([OH:17])=[C:10]3[N:11]=[CH:12][N:13]=[C:14]([SH:15])[C:9]3=[N:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C(O)C.C(=O)([O-])[O-].[K+].[K+].Br[C:28]([CH3:35])([CH3:34])[C:29]([O:31][CH2:32][CH3:33])=[O:30]>O>[C:1]1([N:7]2[C:16]([OH:17])=[C:10]3[N:11]=[CH:12][N:13]=[C:14]([S:15][C:28]([C:29]([O:31][CH2:32][CH3:33])=[O:30])([CH3:35])[CH3:34])[C:9]3=[N:8]2)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: Oc1c2ncnc(S)c2nn1-c1ccccc1
Reactant: CCOC(=O)C(C)(C)Br
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCO
Solvent: O
Product: CCOC(=O)C(C)(C)Sc1ncnc2c(O)n(-c3ccccc3)nc12
Temperature: 80 °C
Reaction time: 6 h

Procedure:
3.66 g of 2-phenyl-3-hydroxy-7-mercapto-pyrazolo [4,3-d]pyrimidine was suspended in a solvent mixture comprising 150 ml of ethanol and 30 ml of water, and 2.5 g of anhydrous potassium carbonate was added thereto. While heating the mixture to 80° C., 3.5 g of ethyl α-bromoisobutyrate was dropwise added thereto, and the heating was continued for further 6 hours. Then, the solvent was distilled off. Water was added to the residue and the residue was dissolved. The solution was acidified with hydrochloric acid, and then extracted with chloroform. The starting material insoluble in both the aqueous layer and the chloroform layer was collected by filtration and recovered (recovered amount: 1.5 g). The chloroform layer was dried over anhydrous magnesium sulfate, and then the solvent was distilled off. The remaining solid was recrystallized from acetone.
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][C:5]([CH3:30])=[C:6]([C:8]2[CH:17]=[C:16]3[C:11]([CH:12]=[C:13]([NH:18][C:19]([CH:21]4[CH2:23][CH2:22]4)=[O:20])[N:14]=[CH:15]3)=[C:10]([CH:24]3[CH2:28][CH:27]([OH:29])[O:26][CH2:25]3)[N:9]=2)[CH:7]=1.[BH4-].[Na+]>O1CCCC1.C(OCC)(=O)C>[OH:26][CH2:25][CH:24]([C:10]1[N:9]=[C:8]([C:6]2[CH:7]=[C:2]([F:1])[CH:3]=[CH:4][C:5]=2[CH3:30])[CH:17]=[C:16]2[C:11]=1[CH:12]=[C:13]([NH:18][C:19]([CH:21]1[CH2:23][CH2:22]1)=[O:20])[N:14]=[CH:15]2)[CH2:28][CH2:27][OH:29]
Reactant: Cc1ccc(F)cc1-c1cc2cnc(NC(=O)C3CC3)cc2c(C2COC(O)C2)n1
Agent: [BH4-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: Cc1ccc(F)cc1-c1cc2cnc(NC(=O)C3CC3)cc2c(C(CO)CCO)n1
Reaction time: 1 h

Procedure:
To a solution of N-(7-(5-fluoro-2-methylphenyl)-5-(5-hydroxytetrahydrofuran-3-yl)-2,6-naphthyridin-3-yl)cyclopropanecarboxamide (45 mg, 0.11 mmol) in tetrahydrofuran (1 mL) cooled at 0° C. was added sodium tetrahydroborate (8.4 mg, 0.22 mmol), and the reaction mixture was stirred at this temperature for 1 hour. The reaction mixture was diluted with ethyl acetate (50 mL) and washed with water (100 mL). The organic layer was separated, dried over sodium sulfate, filtered, and evaporated in vacuo to afford a residue that was used in the next step without further purification.