Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[C:3]2[CH2:19][CH2:18][CH2:17][O:16][C:4]=2[N:5]=[C:6](/[CH:8]=C/C2C=CC=CC=2)[N:7]=1.[O:20]1CCOCC1.O>O.O=[Os](=O)(=O)=O>[Cl:1][C:2]1[C:3]2[CH2:19][CH2:18][CH2:17][O:16][C:4]=2[N:5]=[C:6]([CH:8]=[O:20])[N:7]=1
Reactant: C1COCCO1
Reactant: Clc1nc(/C=C/c2ccccc2)nc2c1CCCO2
Agent: O=[Os](=O)(=O)=O
Solvent: O
Product: O=Cc1nc(Cl)c2c(n1)OCCC2
Temperature: 0 °C
Reaction time: 2 h
Yield: 36 %

Procedure:
To 4-chloro-2-[(E)-2-phenylethenyl]-6,7-dihydro-5H-pyrano[2,3-d]pyrimidine (0.21 g, 0.79 mmol) was dissolved in a 2:1 solution of 1,4-dioxane/water (6 mL) and cooled to 0° C. NaIO4 (0.50 g, 2.4 mmol) and catalytic OsO4 (0.25 mL, 4% aq. solution) were added and the solution was then stirred at ambient temperature for 2 h. The reaction solution was diluted with water (10 mL) and extracted with EtOAc (4×). The organic layers were combined, dried over Na2SO4, filtered and concentrated under vacuum. The crude residue was then purified by column chromatography (silica gel) using a DCM-MeOH (90:10) to yield the desired compound as an off-white solid (0.055 g, 36%).
Reaction SMILES: [CH3:1][S:2]([NH2:5])(=[O:4])=[O:3].[H-].[Na+].CS([C:12]1[N:13]=[C:14]([C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)[C:15]2[CH:21]=[CH:20][C:19](=[O:22])[N:18]([C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=3)[C:16]=2[N:17]=1)(=O)=O.O>CN(C=O)C>[O:22]=[C:19]1[N:18]([C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)[C:16]2[N:17]=[C:12]([NH:5][S:2]([CH3:1])(=[O:4])=[O:3])[N:13]=[C:14]([C:29]3[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=3)[C:15]=2[CH:21]=[CH:20]1
Reactant: CS(N)(=O)=O
Reactant: CS(=O)(=O)c1nc(-c2ccccc2)c2ccc(=O)n(-c3ccccc3)c2n1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CS(=O)(=O)Nc1nc(-c2ccccc2)c2ccc(=O)n(-c3ccccc3)c2n1
Reaction time: 0.5 h
Yield: 51.5 %

Procedure:
To a solution of methylsulfonamide (200 mg, 2 mmol, 4 eq) in DMF (2 mL) was added NaH (80 mg, 2 mmol, 60% dispersion in mineral oil, 4 eq) and the reaction mixture was stirred for 30 min at 23°. To this solution was added a solution of 2-methanesulfonyl-4,8-diphenyl-8H-pyrido[2,3-d]pyrimidin-7-one (190 mg, 0.5 mmol) in DMF (1 mL) and the mixture was heated to 50°. After 1 h, H2O (10 mL) was added and then Et2O (10 mL), the layers were separated, and the organic layer was washed with satd aq NaCl, dried (MgSO4), filtered and the solvent was evaporated. The yellow residue was then purified by Flash chromatography to afford N-(7-oxo-4,8-diphenyl-7,8-dihydro-pyrido[2,3-d]pyrimidin-2-yl)-methanesulfonamide (101 mg, 51% yield). 1H-NMR (CDCl3) δ 2.82 (s, 3H), 6.69 (d, 1H, J=9.8 Hz), 7.31 (m, 2H), 7.59 (m, 8H), 7.91 (d, 1H, J=9.8 Hz), LC MS (m/e)=393 (MH+).
Reaction SMILES: [CH2:1]([O:8][CH2:9][N:10]1[C:14]([CH:15]([C:17]2[CH:22]=[CH:21][C:20]([N+:23]([O-:25])=[O:24])=[C:19]([O:26][CH2:27][C:28]3[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=3)[CH:18]=2)[OH:16])=[CH:13][CH:12]=[N:11]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Si:34](OS(C(F)(F)F)(=O)=O)([C:37]([CH3:40])([CH3:39])[CH3:38])([CH3:36])[CH3:35].N1C(C)=CC=CC=1C>C(Cl)Cl>[CH2:1]([O:8][CH2:9][N:10]1[C:14]([CH:15]([C:17]2[CH:22]=[CH:21][C:20]([N+:23]([O-:25])=[O:24])=[C:19]([O:26][CH2:27][C:28]3[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=3)[CH:18]=2)[O:16][Si:34]([C:37]([CH3:40])([CH3:39])[CH3:38])([CH3:36])[CH3:35])=[CH:13][CH:12]=[N:11]1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CC(C)(C)[Si](C)(C)OS(=O)(=O)C(F)(F)F
Reactant: O=[N+]([O-])c1ccc(C(O)c2ccnn2COCc2ccccc2)cc1OCc1ccccc1
Solvent: Cc1cccc(C)n1
Solvent: ClCCl
Product: CC(C)(C)[Si](C)(C)OC(c1ccc([N+](=O)[O-])c(OCc2ccccc2)c1)c1ccnn1COCc1ccccc1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A mixture of (2-benzyloxymethyl-2H-pyrazol-3-yl)-(3-benzyloxy-4-nitrophenyl)-methanol (392 mg, 0.881 mmol), TBSOTf (0.25 mL, 1.09 mmol) and 2,6-lutidine (0.153 mL, 1.32 mmol) in CH2Cl2 is stirred at RT for 2 h. The mixture is partitioned between CH2Cl2 and aqueous NaHCO3. The organic phase is dried over MgSO4 and concentrated. The residue is purified by flash chromatography to give the title compound.
Reaction SMILES: [CH3:1][C:2]1[CH:6]=[C:5]([C:7]([OH:9])=[O:8])[O:4][N:3]=1.C(=O)([O-])[O-].[Cs+].[Cs+].CO.Cl[CH2:19][N:20]1[C:30](=[O:31])[C:29]2[C:24](=[CH:25][C:26]([O:35][CH3:36])=[CH:27][C:28]=2[CH:32]([CH3:34])[CH3:33])[S:21]1(=[O:23])=[O:22]>O>[CH3:1][C:2]1[CH:6]=[C:5]([C:7]([O:9][CH2:19][N:20]2[C:30](=[O:31])[C:29]3[C:24](=[CH:25][C:26]([O:35][CH3:36])=[CH:27][C:28]=3[CH:32]([CH3:34])[CH3:33])[S:21]2(=[O:22])=[O:23])=[O:8])[O:4][N:3]=1
Reactant: COc1cc(C(C)C)c2c(c1)S(=O)(=O)N(CCl)C2=O
Reactant: Cc1cc(C(=O)O)on1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CO
Solvent: O
Product: COc1cc(C(C)C)c2c(c1)S(=O)(=O)N(COC(=O)c1cc(C)no1)C2=O
Reaction time: 0.5 h
Yield: 84.5 %

Procedure:
A mixture of 3-methylisoxazole-5-carboxylic acid (0.63 g, 5.0 mmol), cesium carbonate (0.8 g, 2.45 mmol) and methanol was stirred for 30 minutes. The solvent was removed in vacuo and the residue was dried in high vacuum for 1 hour. The residue was suspended in DMF (30 ml) and 2-chloromethyl-4-isopropyl-6-methoxysaccharin (1.0 g, 3.3 mmol) was added. The mixture was stirred at room temperature for 19 hours and was poured into water. The mixture was extracted with ethyl acetate/ether (4/1, 300 ml) and the organic layer was separated and wash with water, then brine. The solvent was removed in vacuo and the residue was purified by flash chromatography (30% ethyl acetate/hexanes) to afford 1.1 g (85%) of 4-isopropyl-6-methoxy-2-saccharinylmethyl 3-methylisoxazole-5-carboxylate as a white powder, m.p. 157°-158° C.
Reaction SMILES: C([O:5][N:6]=[C:7]1[C:16]2[C:11](=[CH:12][CH:13]=[C:14]([OH:17])[CH:15]=2)[O:10][C:9]([C:18]2[N:23]=[CH:22][N:21]3[CH:24]=[CH:25][CH:26]=[C:20]3[CH:19]=2)=[CH:8]1)(C)(C)C.Cl[CH2:28][CH2:29][CH2:30][O:31][C:32]1[CH:33]=[N:34][CH:35]=[CH:36][CH:37]=1>>[N:34]1[CH:35]=[CH:36][CH:37]=[C:32]([O:31][CH2:30][CH2:29][CH2:28][O:17][C:14]2[CH:15]=[C:16]3[C:11](=[CH:12][CH:13]=2)[O:10][C:9]([C:18]2[N:23]=[CH:22][N:21]4[CH:24]=[CH:25][CH:26]=[C:20]4[CH:19]=2)=[CH:8][C:7]3=[N:6][OH:5])[CH:33]=1
Reactant: CC(C)(C)ON=c1cc(-c2cc3cccn3cn2)oc2ccc(O)cc12
Reactant: ClCCCOc1cccnc1
Product: ON=c1cc(-c2cc3cccn3cn2)oc2ccc(OCCCOc3cccnc3)cc12

Procedure:
6-[3-(Pyridin-3-yloxy)-propoxy]-2-pyrrolo[1,2-c]pyrimidin-3-yl-chromen-4-one oxime was prepared in 9% overall yield using the method described in example 147, starting from 6-hydroxy-2-pyrrolo[1,2-c]pyrimidin-3-yl-chromen-4-one O-tert-butyl-oxime (example 81A) and 3-(3-Chloro-propoxy)-pyridine.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:16]3[C:11](=[CH:12][C:13]([OH:17])=[CH:14][CH:15]=3)[CH:10]=[CH:9]2)=[CH:4][CH:3]=1.[Br:18][CH2:19][CH2:20][CH2:21][CH2:22]Br>>[Br:18][CH2:19][CH2:20][CH2:21][CH2:22][O:17][C:13]1[CH:12]=[C:11]2[C:16](=[CH:15][CH:14]=1)[N:8]([C:5]1[CH:6]=[CH:7][C:2]([Br:1])=[CH:3][CH:4]=1)[CH:9]=[CH:10]2
Reactant: BrCCCCBr
Reactant: Oc1ccc2c(ccn2-c2ccc(Br)cc2)c1
Product: BrCCCCOc1ccc2c(ccn2-c2ccc(Br)cc2)c1

Procedure:
In analogy to example 3.1, 1-(4-Bromo-phenyl)-1H-indol-5-ol and 1,4-dibrombutane were converted to yield 5-(4-Bromo-butoxy)-1-(4-bromo-phenyl)-1H-indole as light yellow solid, mp 80-81° C., MS: 421 (M, 2Br).
Reaction SMILES: Cl[C:2]1[CH:3]=[CH:4][C:5]2[N:6]([C:8]([C@H:11]([C:13]3[C:14]([F:24])=[C:15]4[C:20](=[CH:21][C:22]=3[F:23])[N:19]=[CH:18][CH:17]=[CH:16]4)[CH3:12])=[CH:9][N:10]=2)[N:7]=1.[F-].[K+].[NH:27]1[CH2:32][CH2:31][NH:30][CH2:29][CH2:28]1>CN1C(=O)CCC1.CCOC(C)=O>[F:24][C:14]1[C:13]([C@@H:11]([C:8]2[N:6]3[N:7]=[C:2]([N:27]4[CH2:32][CH2:31][NH:30][CH2:29][CH2:28]4)[CH:3]=[CH:4][C:5]3=[N:10][CH:9]=2)[CH3:12])=[C:22]([F:23])[CH:21]=[C:20]2[C:15]=1[CH:16]=[CH:17][CH:18]=[N:19]2
Reactant: C[C@@H](c1c(F)cc2ncccc2c1F)c1cnc2ccc(Cl)nn12
Reactant: C1CNCCN1
Agent: [F-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CN1CCCC1=O
Product: C[C@@H](c1c(F)cc2ncccc2c1F)c1cnc2ccc(N3CCNCC3)nn12
Temperature: 170 °C
Reaction time: 1 h

Procedure:
6-[(S)-1-(6-chloro-imidazo[1,2-b]pyridazin-3-yl)-ethyl]-5,7-difluoro-quinoline (Intermediate B, 200 mg, 0.569 mmol), KF (371 mg, 6.26 mmol) and piperazine (490 mg, 5.69 mmol) were suspended in NMP (2.85 mL). The RM was stirred at 170° C. for 1 h. The mixture was diluted with EtOAc and washed with 1M Na2CO3 (1×) and water (2×). The aqueous was further extracted with EtOAc (2×). The combined organic layers were dried over Na2SO4, filtered and concentrated. The residue was purified by flash chromatography and afforded the title compound as a yellow foam (tR 2.78 min (conditions 1), MH+=395, 1H-NMR in DMSO-d6: 8.95 (d, 1H); 8.45 (d, 1H); 7.77 (d, 1H); 7.61 (d, 1H); 7.59 (s, 1H); 7.58 (m, 1H); 7.02 (d, 1H); 4.95 (m, 1H); 3.23 (m, 2H); 3.07 (m, 2H); 2.62 (m, 2H); 2.56 (m, 2H); 1.87 (d, 3H)).
Reaction SMILES: [C:1]1([NH:7][NH2:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH:9]1([C:12]2N(C(C)C)N=[CH:14][C:13]=2[CH:20]=[O:21])[CH2:11][CH2:10]1>>[CH:9]([C:12]1[N:7]([C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=2)[N:8]=[CH:14][C:13]=1[CH:20]=[O:21])([CH3:11])[CH3:10]
Reactant: NNc1ccccc1
Reactant: CC(C)n1ncc(C=O)c1C1CC1
Product: CC(C)c1c(C=O)cnn1-c1ccccc1

Procedure:
5-Isopropyl-1-phenyl-1H-pyrazole-4-carbaldehyde was prepared from ethyl 3-oxo-3-methyl-pentanoate and phenyl hydrazine in the same manner as 5-cyclopropyl-1-isopropyl-1H-pyrazole-4-carbaldehyde (Example 49).
Reaction SMILES: [CH2:1]([O:5][C:6]1[CH:11]=[CH:10][C:9]([S:12]([N:15]2[CH2:19][CH2:18][CH:17](OS(C)(=O)=O)[CH2:16]2)(=[O:14])=[O:13])=[CH:8][CH:7]=1)[CH2:2][CH2:3][CH3:4].[CH2:25]([NH2:32])[C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1>O1CCCC1>[CH2:25]([NH:32][CH:17]1[CH2:18][CH2:19][N:15]([S:12]([C:9]2[CH:10]=[CH:11][C:6]([O:5][CH2:1][CH2:2][CH2:3][CH3:4])=[CH:7][CH:8]=2)(=[O:14])=[O:13])[CH2:16]1)[C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1
Reactant: CCCCOc1ccc(S(=O)(=O)N2CCC(OS(C)(=O)=O)C2)cc1
Reactant: NCc1ccccc1
Solvent: C1CCOC1
Product: CCCCOc1ccc(S(=O)(=O)N2CCC(NCc3ccccc3)C2)cc1
Temperature: 100 °C
Reaction time: 48 h
Yield: 95.9 %

Procedure:
A solution of methanesulfonic acid 1-(4-butoxy-benzenesulfonyl)-pyrrolidin-3-yl ester (1.51 g, 4 mmol) in tetrahydrofuran (8 ml) was added benzylamine (3.46 g, 32 mmol) and the mixture was stirred at 100° C. for 2 days. After cooling to room temperature the tetrahydrofuran was evaporated, and the residue washed with hexanes. The solid was stirred with 10% sodium carbonate solution (30 ml) and ethyl acetate (40 ml), and the organic solution was washed brine, dried over anhydrous sodium sulfate, and filtered through Magnolsol. The filtrate was evaporated, and the residue was washed with hexanes to give 1.49 g of a white solid; m.p. 99-100° C.; MS (ES) m/z 389.0 (MH+); HRMS (EI) Calcd. for C21H28N2O3S (M+): 388.1820, Found: 388.1826.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:4]([CH3:31])=[C:5]([C:22]([O:29][CH3:30])=[C:23]([O:27][CH3:28])[C:24]=1[O:25][CH3:26])[CH2:6][C:7]1[CH:8]=[CH:9][C:10]([C:16]2[CH:21]=[CH:20][N:19]=[CH:18][CH:17]=2)=[C:11]([CH:15]=1)[C:12](O)=[O:13].[NH:32]1[CH2:37][CH2:36][O:35][CH2:34][CH2:33]1.CCN=C=NCCCN(C)C.Cl>C(Cl)Cl>[CH3:1][O:2][C:3]1[C:4]([CH3:31])=[C:5]([C:22]([O:29][CH3:30])=[C:23]([O:27][CH3:28])[C:24]=1[O:25][CH3:26])[CH2:6][C:7]1[CH:8]=[CH:9][C:10]([C:16]2[CH:17]=[CH:18][N:19]=[CH:20][CH:21]=2)=[C:11]([CH:15]=1)[C:12]([N:32]1[CH2:37][CH2:36][O:35][CH2:34][CH2:33]1)=[O:13]
Reactant: C1COCCN1
Reactant: COc1c(C)c(Cc2ccc(-c3ccncc3)c(C(=O)O)c2)c(OC)c(OC)c1OC
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: ClCCl
Product: COc1c(C)c(Cc2ccc(-c3ccncc3)c(C(=O)N3CCOCC3)c2)c(OC)c(OC)c1OC
Temperature: 25 °C
Reaction time: 6 h
Yield: 87.7 %

Procedure:
5-(3,4,5,6-Tetramethoxy-2-methylbenzyl)-2-(4-pyridyl)benzoic acid (100 mg, 0.2364 mmol) and morpholine (44 mg, 0.5057 mmol) were dissolved in methylene chloride (20 ml), then WSC-HCl (122 mg, 0.6364 mmol) was added thereto and the mixture was stirred at room temperature for 6 hours. The reaction solution was washed with water and dried and the solvent was evaporated therefrom. The residue was purified by silica gel column chromatography (5% methanol-methylene chloride) to give the title compound (102 mg, 0.2073 mmol, 88%).
Reaction SMILES: [Br:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]Br.C(O)C.[S:11]([O-:14])([O-:13])=[O:12].[Na+:15].[Na+]>O>[Na+:15].[Br:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][S:11]([O-:14])(=[O:13])=[O:12]
Reactant: O=S([O-])[O-]
Reactant: BrCCCCCBr
Agent: [Na+]
Solvent: CCO
Solvent: O
Product: O=S(=O)([O-])CCCCCBr
Yield: 44.8 %

Procedure:
To a solution of 1,5-dibromopentane (23.2 g, 101 mmol), ethanol (40 mL) and water (40 mL) was dropwise added a solution of sodium sulfite (4.24 g, 33.6 mmol) in water (15 mL) under heating under reflux over 2 hr. After heating under reflux for 2 hr, the solvent was distilled away under reduced pressure and n-hexane/ethanol was added. The precipitated crystals were washed with n-hexane and dried in vacuo to give the title compound (3.81 g, 45%).
Reaction SMILES: [CH3:1][S:2]([C:5]1[CH:22]=[CH:21][C:8]([CH2:9][N:10]2[C:18](=[O:19])[C:17]3[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=3)[C:11]2=[O:20])=[CH:7][CH:6]=1)(=[NH:4])=[O:3].[CH2:23]=O>C(O)(=O)C>[CH3:23][N:4]=[S:2]([C:5]1[CH:6]=[CH:7][C:8]([CH2:9][N:10]2[C:18](=[O:19])[C:17]3[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=3)[C:11]2=[O:20])=[CH:21][CH:22]=1)([CH3:1])=[O:3]
Reactant: C=O
Reactant: CS(=N)(=O)c1ccc(CN2C(=O)c3ccccc3C2=O)cc1
Solvent: CC(=O)O
Product: CN=S(C)(=O)c1ccc(CN2C(=O)c3ccccc3C2=O)cc1
Temperature: 100 °C

Procedure:
A mixture of 2-(4-(S-methylsulfonimidoyl)benzyl)isoindoline-1,3-dione (preparation 17b, 200 mg, 63.6 mmol) and paraformaldehyde (115 mg, 1.27 mmol) in acetic acid (2 mL) is heated in a microwave at 100° C. for 4 h. The mixture is concentrated under reduced pressure, and the residue is purified by flash chromatography on silica (gradient dichloromethane to dichloromethane/methanol 95:5). Yield: 189 mg (90% of theory); ESI mass spectrum: [M+H]+=329; r.t. HPLC: 0.45 min (X011_S03).
Reaction SMILES: [C:1]([CH2:3][C:4]1[CH:5]=[CH:6][C:7]2[O:11][CH:10]=[C:9]([C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=3)[C:8]=2[CH:18]=1)#[N:2].[N-:19]=[N+:20]=[N-:21].[Na+].[Cl-].[NH4+]>O>[C:12]1([C:9]2[C:8]3[CH:18]=[C:4]([CH2:3][C:1]4[NH:21][N:20]=[N:19][N:2]=4)[CH:5]=[CH:6][C:7]=3[O:11][CH:10]=2)[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=1
Reactant: [N-]=[N+]=[N-]
Reactant: N#CCc1ccc2occ(-c3ccccc3)c2c1
Agent: [Cl-]
Agent: [NH4+]
Agent: [Na+]
Solvent: O
Product: c1ccc(-c2coc3ccc(Cc4nnn[nH]4)cc23)cc1
Temperature: 110 °C

Procedure:
A mixture of 4.6 g. (0.02 mole) of 5-cyanomethyl-3-phenylbenzofuran, 1.5 g. of sodium azide and 1.2 g. of ammonium chloride in 15 ml. of N,N-dimethylformaide is heated at 110° C. for 20 hours. The reaction mixture is poured into 200 ml. of water and stirred. The mixture is extracted with 50 ml. of chloroform. The extracts are washed with water, then dried over magnesium sulfate. Evaporation provides a residue which is recrystallized from ethyl acetate to provide 3-phenyl-5-(1H-tetrazol-5yl)methylbenzofuran.
Reaction SMILES: Br[C:2]1[CH:11]=[C:10]2[C:5]([C:6](=[O:24])[C:7]([C:19]([O:21][CH2:22][CH3:23])=[O:20])=[CH:8][N:9]2[C:12]2[CH:17]=[CH:16][C:15]([F:18])=[CH:14][CH:13]=2)=[CH:4][CH:3]=1.C(N(CC)CC)C.[CH3:32][Si:33]([C:36]#[CH:37])([CH3:35])[CH3:34]>C(#N)C>[F:18][C:15]1[CH:16]=[CH:17][C:12]([N:9]2[C:10]3[C:5](=[CH:4][CH:3]=[C:2]([C:37]#[C:36][Si:33]([CH3:35])([CH3:34])[CH3:32])[CH:11]=3)[C:6](=[O:24])[C:7]([C:19]([O:21][CH2:22][CH3:23])=[O:20])=[CH:8]2)=[CH:13][CH:14]=1
Reactant: C#C[Si](C)(C)C
Reactant: CCOC(=O)c1cn(-c2ccc(F)cc2)c2cc(Br)ccc2c1=O
Solvent: CCN(CC)CC
Solvent: CC#N
Product: CCOC(=O)c1cn(-c2ccc(F)cc2)c2cc(C#C[Si](C)(C)C)ccc2c1=O
Temperature: 0 °C

Procedure:
To a solution of 25.4 g ethyl 7-bromo-1,4-dihydro-1-(4-fluorophenyl)-4-oxo-3-quinolinecarboxylate in 975 ml acetonitrile at 40°-50° C. was added 1.4 g cuprous iodide and 325 ml triethylamine. The air in the reaction was replaced by argon, and 1.4 g bis-triphenylphosphine palladium dichloride and 15.5 ml trimethylsilylacetylene were added. The reaction mixture was heated at reflux for one hour, then chilled to 0° C, and the product was collected to give 23.4 g ethyl 1,4-dihydro-1-(4-fluoro- phenyl)-4-oxo-7-(trimethylsilylethynyl)-3-quinolinecarboxylate. A sample of the compound was further purified by recrystallization from DMF to give a colorless solid, m.p. 247°-249° C. The corresponding carboxylic acid, obtained by hydrolysis of the ester with ethanolic hydrogen chloride, was obtained as a light-tan powder, m.p. 289° C. (decompn.).
Reaction SMILES: Cl[C:2]1[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[CH:4][C:3]=1[N+:10]([O-:12])=[O:11].[CH2:13]([NH2:16])[CH2:14][CH3:15]>C(O)(C)C>[CH2:13]([NH:16][C:2]1[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[CH:4][C:3]=1[N+:10]([O-:12])=[O:11])[CH2:14][CH3:15]
Reactant: CCCN
Reactant: N#Cc1ccc(Cl)c([N+](=O)[O-])c1
Solvent: CC(C)O
Product: CCCNc1ccc(C#N)cc1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 5 h

Procedure:
To a stirring suspension of 4-chloro-3-nitrobenzonitrile (7.30 g, 40 mmol) in isopropanol (30 mL) is added n-propylamine (9.87 mL, 120 mmol). The mixture is stirred at room temperature for 5 h, and the solid is then collected by filtration to give 4-n-propylamino-3-nitrobenzonitrile as a yellow solid. 1H NMR (CDCl3) δ 8.51 (1H, q), 8.42 (1H, br s), 7.60 (1H, m), 6.91 (1H, d), 3.33 (2H, q), 1.84-1.74 (2H, m), 1.07 (3H, t). LRMS 206.3 (MH+).
Reaction SMILES: [Cl:1][C:2]1[S:6][C:5]([C:7]([OH:9])=O)=[CH:4][C:3]=1[C:10]1[N:14]([CH3:15])[N:13]=[CH:12][CH:11]=1.[NH2:16][C@@H:17]([CH2:30][C:31]1[CH:36]=[CH:35][CH:34]=[C:33]([F:37])[CH:32]=1)[CH2:18][N:19]1[C:27](=[O:28])[C:26]2[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=2)[C:20]1=[O:29].C(N(CC)C(C)C)(C)C.C1CN([P+](Br)(N2CCCC2)N2CCCC2)CC1.F[P-](F)(F)(F)(F)F>ClCCl>[Cl:1][C:2]1[S:6][C:5]([C:7]([NH:16][C@@H:17]([CH2:30][C:31]2[CH:36]=[CH:35][CH:34]=[C:33]([F:37])[CH:32]=2)[CH2:18][N:19]2[C:27](=[O:28])[C:26]3[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=3)[C:20]2=[O:29])=[O:9])=[CH:4][C:3]=1[C:10]1[N:14]([CH3:15])[N:13]=[CH:12][CH:11]=1
Reactant: Cn1nccc1-c1cc(C(=O)O)sc1Cl
Reactant: N[C@@H](Cc1cccc(F)c1)CN1C(=O)c2ccccc2C1=O
Agent: Br[P+](N1CCCC1)(N1CCCC1)N1CCCC1
Agent: F[P-](F)(F)(F)(F)F
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: Cn1nccc1-c1cc(C(=O)N[C@@H](Cc2cccc(F)c2)CN2C(=O)c3ccccc3C2=O)sc1Cl
Temperature: 25 °C
Reaction time: 12 h

Procedure:
To a 500 mL round-bottomed flask was added 5-chloro-4-(1-methyl-1H-pyrazol-5-yl)-2-thiophenecarboxylic acid (4.2 g, 17.31 mmol), 2-[(2S)-2-amino-3-(3-fluorophenyl)propyl]-1H-isoindole-1,3(2H)-dione (6.37 g, 19.04 mmol) [prepared according to the procedure of Preparation 6], N,N-diisopropyl ethylamine (4.53 ml, 26.0 mmol) and Pybrop (12.05 g, 26.0 mmol) in dichloromethane (DCM) (150 ml). After stirring at RT for 12 h, the reaction solution was washed with H2O (2×100 mL) and the organic layer was dried Na2SO4, filtered and concentrated. The crude product was added to a silica gel column and was eluted with [EtOAc/hexanes, 1:1] to give the product [7.8 g, 86%] as a white solid: LCMS (ES) m/z 524 (M+H)+.
Reaction SMILES: O=P(Cl)(Cl)[Cl:3].CN(C)C1C=CC=CC=1.O[C:16]1[N:21]=[C:20]([S:22][CH3:23])[N:19]=[C:18]2[NH:24][N:25]=[C:26]([CH3:27])[C:17]=12>>[Cl:3][C:16]1[N:21]=[C:20]([S:22][CH3:23])[N:19]=[C:18]2[NH:24][N:25]=[C:26]([CH3:27])[C:17]=12
Reactant: CSc1nc(O)c2c(C)n[nH]c2n1
Reactant: O=P(Cl)(Cl)Cl
Solvent: CN(C)c1ccccc1
Product: CSc1nc(Cl)c2c(C)n[nH]c2n1
Reaction time: 0.17 h

Procedure:
To a mixture of POCl3 (26 mL) and of dimethylaniline (2 mL) was added crude 4-hydroxy-3-methyl-6-methylmercaptopyrazolo[3,4-d]pyrimidine (A-2) (1.46 g, 7.45 mmol). The solution was heated to reflux for 60 min until all solid dissolved. The excess of POCl3 was removed under reduced pressure. The residue was poured into ice water with vigorous stirring, it is stirred for 10 min, and the aqueous solution was extracted with ether. The ether layer was washed with cold water, dried with anhydrous Na2SO4 and concentrated to give the title compound (A-3) (1.21 g, 5.63 mmol). MS-ESI (m/z): 215.0 (M+H)+.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:20])[CH2:4][NH:5][S:6]([C:9]1[CH:14]=[CH:13][C:12]([O:15][CH2:16][CH:17]2[CH2:19][CH2:18]2)=[CH:11][CH:10]=1)(=[O:8])=[O:7].Cl[CH2:22][C:23]1[CH:28]=[CH:27][C:26]([N:29]2[N:33]=[CH:32][CH:31]=[N:30]2)=[CH:25][CH:24]=1.C([O-])([O-])=O.[K+].[K+]>CN(C=O)C>[CH3:1][O:2][C:3](=[O:20])[CH2:4][N:5]([S:6]([C:9]1[CH:14]=[CH:13][C:12]([O:15][CH2:16][CH:17]2[CH2:18][CH2:19]2)=[CH:11][CH:10]=1)(=[O:7])=[O:8])[CH2:22][C:23]1[CH:24]=[CH:25][C:26]([N:29]2[N:30]=[CH:31][CH:32]=[N:33]2)=[CH:27][CH:28]=1
Reactant: COC(=O)CNS(=O)(=O)c1ccc(OCC2CC2)cc1
Reactant: ClCc1ccc(-n2nccn2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: COC(=O)CN(Cc1ccc(-n2nccn2)cc1)S(=O)(=O)c1ccc(OCC2CC2)cc1
Reaction time: 18 h

Procedure:
To a solution of 1 g (3.3 mmol) of the compound of Stage 3.7 in 10 ml of DMF, 0.8086 g (4.175 mmol) of 2-(4chloromethyl-phenyl)-2H-[1,2,3]triazole, 0.05559 (0.33 mmol) of KI and 0.646 g (4.68 mmol) of K2CO3 are added successively at r.t. After stirring for 18 h, the reaction is quenched with ice water and the mixture is extracted with AcOEt. The combined extracts are washed with H2O, brine, dried over MgSO4 and concentrated under reduced pressure to give a solid which is washed with diethylether and MeOH to give the title compound.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([O:10][C:11]2[C:12]([CH3:18])=[N:13][N:14]([CH3:17])[C:15]=2[CH3:16])[C:5]([C:8]#[N:9])=[N:6][CH:7]=1.[N:19]1[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=1[SH:25].CN(C=O)C.[H-].[Na+]>O>[N:19]1[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=1[S:25][C:2]1[CH:3]=[C:4]([O:10][C:11]2[C:12]([CH3:18])=[N:13][N:14]([CH3:17])[C:15]=2[CH3:16])[C:5]([C:8]#[N:9])=[N:6][CH:7]=1
Reactant: Sc1ccccn1
Reactant: Cc1nn(C)c(C)c1Oc1cc(Br)cnc1C#N
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: Cc1nn(C)c(C)c1Oc1cc(Sc2ccccn2)cnc1C#N
Temperature: 0 °C
Reaction time: 8 h
Yield: 96.7 %

Procedure:
A flask was charged with 5-bromo-3-(1,3,5-trimethyl-1H-pyrazol-4-yloxy)picolinonitrile (27.77 g, 90.41 mmol), pyridine-2-thiol (10.55 g, 94.93 mmol), and DMF (300 mL). The reaction was cooled to 0° C. and 95% sodium hydride (2.741 g, 108.5 mmol) was added portionwise. The reaction was stirred at ambient temperature overnight, then carefully diluted with water (2 L) and extracted with ethyl acetate. The organic layer was washed with brine (4×500 mL), dried over sodium sulfate and concentrated to afford 5-(pyridin-2-ylthio)-3-(1,3,5-trimethyl-1H-pyrazol-4-yloxy)picolinonitrile (29.50 g, 87.43 mmol, 96.70% yield) as yellow solid.