Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:12]=[CH:11][CH:10]=[C:9]([Cl:13])[C:3]=1[C:4]([N:6]=[C:7]=[O:8])=[O:5].[Cl:14][C:15]1[CH:24]=[CH:23][C:18]([NH:19][CH2:20][C:21]#[N:22])=[CH:17][CH:16]=1>C1C=CC=CC=1>[Cl:1][C:2]1[CH:12]=[CH:11][CH:10]=[C:9]([Cl:13])[C:3]=1[C:4]([NH:6][C:7]([N:19]([CH2:20][C:21]#[N:22])[C:18]1[CH:17]=[CH:16][C:15]([Cl:14])=[CH:24][CH:23]=1)=[O:8])=[O:5]
Reactant: O=C=NC(=O)c1c(Cl)cccc1Cl
Reactant: N#CCNc1ccc(Cl)cc1
Solvent: c1ccccc1
Product: N#CCN(C(=O)NC(=O)c1c(Cl)cccc1Cl)c1ccc(Cl)cc1
Reaction time: 12 h
Yield: 80 %

Procedure:
16.0 g of 2,6-dichlorobenzoylisocyanate are added in small portions to a solution of 11.66 g of p-chloroanilino-acetonitrile in 100 ml of dry benzene with moderate cooling. After some time a substance crystallizes out, which after about 12 hours is drawn off and washed with benzene. After drying the weight is 25.25 g, i.e. 93.7% the melting point being 185° C. with spontaneous decomposition on the Kofler heating bench. Thin-layer chromatography (solvent either ethylacetate or chloroform) shows that the substance is pure, however, if desired, it may be recrystallized from 250 ml of benzene with a yield of 80%.
Reaction SMILES: C([N:3]1[CH2:9][CH2:8][C:7](=[O:10])[C:6]2[CH:11]=[CH:12][S:13][C:5]=2[CH2:4]1)=O.O>Cl.O1CCOCC1>[S:13]1[C:5]2[CH2:4][NH:3][CH2:9][CH2:8][C:7](=[O:10])[C:6]=2[CH:11]=[CH:12]1
Reactant: O=CN1CCC(=O)c2ccsc2C1
Agent: Cl
Solvent: O
Solvent: C1COCCO1
Product: O=C1CCNCc2sccc21
Temperature: 60 °C
Yield: 94.3 %

Procedure:
7-Formyl-5,6,7,8-tetrahydrothieno[2,3-c]azepin-4-one (2.6 g) prepared in the step 4 was dissolved in 4N hydrochloric acid/dioxane solution, 13.5 mL of water was added thereto and the mixture was heated at 60° C. for 6 hours with stirring. The solvent was evaporated from the reaction solution in vacuo, water was added to the residue and the mixture was subjected to extraction with diethyl ether. The resulting aqueous solution was slowly neutralized with an aqueous solution of sodium hydrogen carbonate with stirring and subjected to extraction with diethyl ether. The organic layer was separated, washed with water and a saturated solution of sodium chloride successively and dried over anhydrous magnesium sulfate and the solvent was evaporated therefrom in vacuo to give 2.1 g of the objective compound as a brown solid.
Reaction SMILES: Br[CH2:2][C:3]([C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1)=O.[CH2:11]([NH:15][C:16]([NH2:18])=[S:17])[CH:12]([CH3:14])[CH3:13].C(=O)([O-])O.[Na+]>CN(C)C=O>[CH2:11]([NH:15][C:16]1[S:17][CH:2]=[C:3]([C:5]2[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=2)[N:18]=1)[CH:12]([CH3:14])[CH3:13]
Reactant: CC(C)CNC(N)=S
Reactant: O=C(CBr)c1ccccc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CN(C)C=O
Product: CC(C)CNc1nc(-c2ccccc2)cs1
Temperature: 25 °C
Reaction time: 1 h
Yield: 72.2 %

Procedure:
A mixture of 2-bromo-1-phenylethanone (4.0 g), N-isobutylthiourea (2.60 g) and N,N-dimethylformamide (15 mL) was stirred at room temperature for 1 hr. The reaction mixture was poured into saturated aqueous sodium hydrogencarbonate, and the mixture was extracted with ethyl acetate. The ethyl acetate layer was concentrated, and the residue was purified by silica gel column chromatography with ethyl acetate-hexane (gradient of 1:9 to 2:1 by volume ratio) to give the title compound (3.30 g, 71%) as a yellow oil.
Reaction SMILES: [K+].[C:2]([C:4]1[N:5]=[C:6]([C:17]([O-:19])=O)[N:7]([CH2:9][O:10][CH2:11][CH2:12][Si:13]([CH3:16])([CH3:15])[CH3:14])[CH:8]=1)#[N:3].CCN(C(C)C)C(C)C.C1CN([P+](Br)(N2CCCC2)N2CCCC2)CC1.F[P-](F)(F)(F)(F)F.[F:53][CH:54]1[CH2:59][CH2:58][CH2:57][N:56]([C:60]2[CH:65]=[C:64]([N:66]3[CH2:71][CH2:70][N:69]([CH3:72])[CH2:68][CH2:67]3)[CH:63]=[CH:62][C:61]=2[NH2:73])[CH2:55]1>C(Cl)Cl>[F:53][CH:54]1[CH2:59][CH2:58][CH2:57][N:56]([C:60]2[CH:65]=[C:64]([N:66]3[CH2:67][CH2:68][N:69]([CH3:72])[CH2:70][CH2:71]3)[CH:63]=[CH:62][C:61]=2[NH:73][C:17]([C:6]2[N:7]([CH2:9][O:10][CH2:11][CH2:12][Si:13]([CH3:14])([CH3:15])[CH3:16])[CH:8]=[C:4]([C:2]#[N:3])[N:5]=2)=[O:19])[CH2:55]1
Reactant: CN1CCN(c2ccc(N)c(N3CCCC(F)C3)c2)CC1
Reactant: C[Si](C)(C)CCOCn1cc(C#N)nc1C(=O)[O-]
Agent: Br[P+](N1CCCC1)(N1CCCC1)N1CCCC1
Agent: F[P-](F)(F)(F)(F)F
Agent: [K+]
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CN1CCN(c2ccc(NC(=O)c3nc(C#N)cn3COCC[Si](C)(C)C)c(N3CCCC(F)C3)c2)CC1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 70 %

Procedure:
A suspension of 4-cyano-1-(2-trimethylsilanyl-ethoxymethyl)-1H-imidazole-2-carboxylate potassium salt (as prepared in Example 3, step (d), 48 mg, 0.16 mmol) in CH2Cl2 (5 mL) was treated with DIEA (68 μL, 0.39 mmol) and PyBroP (0.11 g, 0.24 mmol). The reaction stirred at room temperature for 10 min. A solution of 2-(3-fluoro-piperidin-1-yl)-4-(4-methyl-piperazin-1-yl)-phenylamine (as prepared in the previous step, 46 mg, 0.16 mmol) in CH2Cl2 (4 mL) was added, and the reaction was stirred at room temperature for 19.5 h. The reaction was diluted with CH2Cl2 and washed with saturated aqueous NaHCO3 and water. The organic layer was dried over MgSO4 and concentrated in vacuo to afford the title compound (62 mg, 70%) as an off-white solid, which was used directly in the next reaction. LC-MS (ESI, m/z): Calcd. for C27H40FN7O2Si, 542.3 (M+H), found 542.4.
Reaction SMILES: [NH2:1][C:2]1[CH:10]=[C:9]([N+:11]([O-:13])=[O:12])[C:8]([Br:14])=[CH:7][C:3]=1[C:4]([NH2:6])=[O:5].Cl[C:16](Cl)([O:18]C(=O)OC(Cl)(Cl)Cl)Cl>O1CCCC1>[O:18]=[C:16]1[NH:6][C:4](=[O:5])[C:3]2[C:2](=[CH:10][C:9]([N+:11]([O-:13])=[O:12])=[C:8]([Br:14])[CH:7]=2)[NH:1]1
Reactant: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Reactant: NC(=O)c1cc(Br)c([N+](=O)[O-])cc1N
Solvent: C1CCOC1
Product: O=c1[nH]c(=O)c2cc(Br)c([N+](=O)[O-])cc2[nH]1
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 289.1 %

Procedure:
17.3 g (66.5 mmol) of 2-amino-5-bromo-4-nitro-benzamide were dissolved in 500 ml of tetrahydrofuran and treated at 0° C. with 13 g (10.4 mmol) of triphosgene. The mixture was left to warm to room temperature and stirred for a further 1.5 hrs. Then, the solution was concentrated and triturated with water. The precipitate was filtered off under suction and dried. 8.6 g (45%) of 2,4-dioxo-6-bromo-7-nitro-1,2,3,4-tetrahydroquinazoline were obtained as yellowish crystals;
Reaction SMILES: Cl.[NH2:2][C:3]1[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[C:6]([C:13]([OH:15])=[O:14])=[CH:5][CH:4]=1.C(N1C=CN=C1)(N1C=CN=C1)=O.[C:28](O)([CH3:31])([CH3:30])[CH3:29]>C(N(CC)CC)C.CCOC(C)=O>[C:28]([O:14][C:13]([C:6]1[C:7]2[C:12](=[CH:11][CH:10]=[CH:9][CH:8]=2)[C:3]([NH2:2])=[CH:4][CH:5]=1)=[O:15])([CH3:31])([CH3:30])[CH3:29]
Reactant: CC(C)(C)O
Reactant: Nc1ccc(C(=O)O)c2ccccc12
Agent: Cl
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: CCN(CC)CC
Solvent: CCOC(C)=O
Product: CC(C)(C)OC(=O)c1ccc(N)c2ccccc12
Temperature: 25 °C
Reaction time: 12 h
Yield: 29 %

Procedure:
3.6 g (16 mmol) of 4-Amino-naphthalene-1-carboxylic acid hydrochloride, (T. Nakayama et al, Chem. Pharm. Bull, 1984, 32, 3968-3980), was suspended in 44 mL of tert-butyl alcohol and 3.3 mL of triethylamine. To this was added 3.1 g (19 mmol) of carbonyldiimidazole. An exothermic reaction was noted, and the brown solution was stirred at room temperature for 12 h. After this time, the reaction was diluted with EtOAc, filtered through diatomaceous earth and concentrated in vacuo. Purification on silica gel, eluting with 20% EtOAc-hexanes provided 1.1 g of 4-amino-naphthalene-1-carboxylic acid tert-butyl ester as an off-white solid (29%).
Reaction SMILES: C(O[C:6]([N:8]1[CH2:13][CH2:12][NH:11][CH2:10][CH2:9]1)=O)(C)(C)C.[CH3:14][O:15][C:16](=[O:24])[C:17]1[CH:22]=C[CH:20]=[C:19](Br)[CH:18]=1.C(P(C(C)(C)C)C1C=CC=CC=1C1C=CC=CC=1)(C)(C)C.CC(C)([O-])C.[Na+].C(O)(C(F)(F)F)=O>C1(C)C=CC=CC=1>[CH3:14][O:15][C:16](=[O:24])[C:17]1[CH:18]=[CH:19][CH:20]=[C:6]([N:8]2[CH2:9][CH2:10][NH:11][CH2:12][CH2:13]2)[CH:22]=1
Reactant: COC(=O)c1cccc(Br)c1
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Agent: CC(C)(C)P(c1ccccc1-c1ccccc1)C(C)(C)C
Agent: CC(C)(C)[O-]
Agent: [Na+]
Solvent: O=C(O)C(F)(F)F
Solvent: Cc1ccccc1
Product: COC(=O)c1cccc(N2CCNCC2)c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 52.5 %

Procedure:
To a mixture containing piperazine-1-carboxylic acid tert-butyl ester (400 mg, 2.16 mmol), 3-bromo-benzoic acid methyl ester (547 mg, 2.56 mmol), Pd(AcO) (32 mg, 0.14 mmol), 2-(di-t-butylphosphino)biphenyl (80 mg, 0.28 mmol) and sodium t-butoxide (400 mg, 4 mmol) in toluene (20 mL) was degassed with Ar. The reaction mixture was heated at 50 C for overnight. At the end of reaction, ethyl acetate was added and the mixture was filter through celite. After removal of solvent, TFA was added to the residue. The reaction mixture was stirred at ambient temperature for 1 hour. The excess TFA was removed under vacuum and the residue was purified using prep-HPLC to give desired product (250 mg, 37% yield for two steps) as TFA salt.
Reaction SMILES: [CH3:1][C:2]1([CH3:30])[C:6](=[O:7])[N:5]([C:8]2[CH:15]=[CH:14][C:11]([C:12]#[N:13])=[C:10]([C:16]([F:19])([F:18])[F:17])[CH:9]=2)[C:4](=[O:20])[N:3]1[CH2:21][CH2:22][CH2:23][O:24]C1CCCO1.CC1C=CC(S(O)(=O)=O)=CC=1>CO.C(OCC)(=O)C>[OH:24][CH2:23][CH2:22][CH2:21][N:3]1[C:2]([CH3:30])([CH3:1])[C:6](=[O:7])[N:5]([C:8]2[CH:15]=[CH:14][C:11]([C:12]#[N:13])=[C:10]([C:16]([F:19])([F:17])[F:18])[CH:9]=2)[C:4]1=[O:20]
Reactant: CC1(C)C(=O)N(c2ccc(C#N)c(C(F)(F)F)c2)C(=O)N1CCCOC1CCCO1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: CCOC(C)=O
Solvent: CO
Product: CC1(C)C(=O)N(c2ccc(C#N)c(C(F)(F)F)c2)C(=O)N1CCCO
Temperature: 25 °C
Reaction time: 3 h
Yield: 94.9 %

Procedure:
To a solution of compound 12a (1.03 g, 2.33 mmol) in methanol (10 mL) at room temperature was added p-TSA (88 mg, 0.46 mmol). The solution was stirred for 3 hrs at room temperature. The reaction was then diluted with ethyl acetate (50 mL), washed successively with a 10% bicarbonate and brine solution and finally dried over magnesium sulphate to give compound 13a (786 mg, 95%) which was directly used as such in the next step. 1H NMR (300 MHz, Acetone-d6) δ: 1.57 (s, 6H), 1.92 (m, 2H), 3.54, (t, 2H, J=7.38 Hz), 3.51-3.63 (m, 2H), 8.18 (m, 2H), 8.27 (s, 1H).
Reaction SMILES: [Br:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:7]2[C:3]=1[CH:4]=[C:5]([C:11]([OH:13])=O)[NH:6]2.Cl.Cl.Cl.[N:17]1([CH2:24][CH2:25][N:26]2[CH2:31][CH2:30][CH:29]([NH2:32])[CH2:28][CH2:27]2)[CH2:23][CH2:22][CH2:21][CH2:20][CH2:19][CH2:18]1.CCN(C(C)C)C(C)C.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F>CN(C=O)C>[N:17]1([CH2:24][CH2:25][N:26]2[CH2:27][CH2:28][CH:29]([NH:32][C:11]([C:5]3[NH:6][C:7]4[C:3]([CH:4]=3)=[C:2]([Br:1])[CH:10]=[CH:9][CH:8]=4)=[O:13])[CH2:30][CH2:31]2)[CH2:23][CH2:22][CH2:21][CH2:20][CH2:19][CH2:18]1
Reactant: NC1CCN(CCN2CCCCCC2)CC1
Reactant: O=C(O)c1cc2c(Br)cccc2[nH]1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: Cl
Agent: F[B-](F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: O=C(NC1CCN(CCN2CCCCCC2)CC1)c1cc2c(Br)cccc2[nH]1
Temperature: 25 °C
Reaction time: 2 h
Yield: 93.7 %

Procedure:
4-Bromo-1H-indole-2-carboxylic acid (1.5 g, 3.1 mmol), 1-(2-azepan-1-yl-ethyl)-piperidin-4-ylamine tri-hydrochloride (5) (2.1 g, 3.1 mmol) and DIEA (4.3 ml, 12.4 mmol) are dissolved under argon atmosphere in DMF (25 ml). TBTU (2.3 g, 3.4 mmol) is added at room temperature. The reaction mixture is stirred for 2 h at r.t., evaporated under high vacuum, dissolved in ethyl acetate and washed twice with 5% aqueous NaHCO3 solution. The organic layers are dried over sodium sulfate. Evaporation under reduced pressure gave 1.3 g (93%) of a beige solid.
Reaction SMILES: Cl.[CH:2]1[C:15]2[NH:14][C:13]3[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=3)[S:7][C:6]=2[CH:5]=[CH:4][C:3]=1[C:16]1[N:17]=[C:18]([CH2:21][NH2:22])[S:19][CH:20]=1.C(N(CC)CC)C.[CH3:30][O:31][C:32](Cl)=[O:33]>O1CCOCC1>[CH:2]1[C:15]2[NH:14][C:13]3[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=3)[S:7][C:6]=2[CH:5]=[CH:4][C:3]=1[C:16]1[N:17]=[C:18]([CH2:21][NH:22][C:32](=[O:33])[O:31][CH3:30])[S:19][CH:20]=1
Reactant: COC(=O)Cl
Reactant: NCc1nc(-c2ccc3c(c2)Nc2ccccc2S3)cs1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: C1COCCO1
Product: COC(=O)NCc1nc(-c2ccc3c(c2)Nc2ccccc2S3)cs1
Temperature: 0 °C
Reaction time: 3 h
Yield: 46 %

Procedure:
The compound of Example 362 (0.622 g; 2.0 mmol) is dissolved in dioxane (100 ml) cooled down to 0° C. Triethylamine is added, then, dropwise, methylchloroformate (2.5 mmol). The reaction medium is then stirred for 3 hours at ambient temperature before being poured into ice-cold water and extracted with ethyl acetate. The organic phase is dried over magnesium sulphate, filtered and concentrated under vacuum. The expected product is purified on a silica column (eluent: 10% acetone in dichloromethane). The pure fractions are combined and the solvents are evaporated off in order to produce an off-white solid with a yield of 46.0%. Melting point: 151-153° C.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([C:8]2[CH:9]([C:20]3[CH:25]=[CH:24][C:23]([I:26])=[CH:22][CH:21]=3)[O:10][C:11]3[C:16]([C:17]=2[CH3:18])=[CH:15][C:14]([OH:19])=[CH:13][CH:12]=3)[CH:5]=[CH:6][CH:7]=1.C1(C)C=CC(S([O-])(=O)=O)=CC=1.[NH+]1C=CC=CC=1.[O:44]1[CH:49]=[CH:48][CH2:47][CH2:46][CH2:45]1>C(Cl)Cl>[Br:1][C:2]1[CH:3]=[C:4]([C:8]2[CH:9]([C:20]3[CH:21]=[CH:22][C:23]([I:26])=[CH:24][CH:25]=3)[O:10][C:11]3[C:16]([C:17]=2[CH3:18])=[CH:15][C:14]([O:19][CH:45]2[CH2:46][CH2:47][CH2:48][CH2:49][O:44]2)=[CH:13][CH:12]=3)[CH:5]=[CH:6][CH:7]=1
Reactant: C1=COCCC1
Reactant: CC1=C(c2cccc(Br)c2)C(c2ccc(I)cc2)Oc2ccc(O)cc21
Agent: Cc1ccc(S(=O)(=O)[O-])cc1
Agent: c1cc[nH+]cc1
Solvent: ClCCl
Product: CC1=C(c2cccc(Br)c2)C(c2ccc(I)cc2)Oc2ccc(OC3CCCCO3)cc21
Temperature: 25 °C
Reaction time: 4 h
Yield: 89.2 %

Procedure:
To a solution of 3-(3-bromophenyl)-2-(4-iodophenyl)-4-methyl-2H-chromen-6-ol (4.95 g, 9.53 mmol) and pyridinium p-toluene sulfonate (480 mg, 1.91 mmol) in DCM (100 mL) was added 3,4-dihydro-2H-pyran (1.3 mL, 14 mmol). The reaction was stirred at room temperature for 4 h, washed (100 mL sat'd aqueous NaHCO3, 50 mL H2O, 50 mL brine), and dried (Na2SO4). The solvent was removed under reduced pressure, and the crude material was purified on a silica gel column to give 3-(3-bromophenyl)-2-(4-iodophenyl)-4-methyl-6-((tetrahydro-2H-pyran-2-yl)oxy)-2H-chromene (5.13 g, 89%) as an off-white foam. 1H NMR (DMSO-d6): δ 7.66 (d, 2H), 7.53 (m, 1H), 7.48 (m, 1H), 7.32 (m, 2H), 7.10 (dd, 2H), 7.01 (t, 1H), 6.82 (m, 1H), 6.63 (m, 1H), 6.09 (s, 1H), 5.37 (m, 1H), 3.80 (m, 1H), 3.55 (m, 1H), 2.05 (s, 3H), 1.90-1.66 (m, 3H), 1.66-1.42 (m, 3H).
Reaction SMILES: [O:1]1[C:3]2([CH2:8][CH2:7][CH2:6][N:5]([C:9]([O:11][CH3:12])=[O:10])[CH2:4]2)[CH2:2]1.[CH3:13][NH2:14]>>[OH:1][C:3]1([CH2:2][NH:14][CH3:13])[CH2:8][CH2:7][CH2:6][N:5]([C:9]([O:11][CH3:12])=[O:10])[CH2:4]1
Reactant: COC(=O)N1CCCC2(CO2)C1
Reactant: CN
Product: CNCC1(O)CCCN(C(=O)OC)C1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
9.3 g (54.3 mmol) of methyl 5-aza-1-oxaspiro[2,5]octane-5-carboxylate are added dropwise to 50 ml of methylamine solution (25% in water) and the mixture is stirred overnight at room temperature. It is then concentrated and the residue is distilled.
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][CH:4]([NH:7][C:8](=[O:14])[O:9][C:10]([CH3:13])([CH3:12])[CH3:11])[CH2:3][CH2:2]1.CCN(CC)CC.[CH3:22][C:23](OC(C)=O)=[O:24]>C(Cl)Cl>[C:10]([O:9][C:8](=[O:14])[NH:7][CH:4]1[CH2:3][CH2:2][N:1]([C:23](=[O:24])[CH3:22])[CH2:6][CH2:5]1)([CH3:11])([CH3:13])[CH3:12]
Reactant: CC(=O)OC(C)=O
Reactant: CC(C)(C)OC(=O)NC1CCNCC1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(=O)N1CCC(NC(=O)OC(C)(C)C)CC1
Temperature: 0 °C
Reaction time: 2 h

Procedure:
To a solution of tert-butyl piperidin-4-ylcarbamate (200 g, 1 mol) and Et3N (150 g, 1.5 mol) in DCM (3000 mL) was added Ac2O (102 g, 1 mol) dropwise over 1 h, while maintained the temperature at 0° C. After addition, the mixture was stirred 0° C. for another 2 h, at which time TLC showed the reaction was completed. The solution was quenched by addition of water (1 L). The organic phase was collected and washed with saturated aqueous NaHCO3 (1 L), dried (Na2SO4) and concentrated to give crude product. Four batches were run in parallel and produced a combined crude product weight of 670 g. This crude was used directly in the step. LCMS (m/z): 243.1 (M+1).
Reaction SMILES: [F:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:7]2[C:3]=1[CH:4]=[CH:5][N:6]2[C@@H:11]1[O:28][C@H:27]([CH2:29][O:30][C:31](=[O:33])[CH3:32])[C@@H:22]([O:23][C:24](=[O:26])[CH3:25])[C@H:17]([O:18][C:19](=[O:21])[CH3:20])[C@H:12]1[O:13][C:14](=[O:16])[CH3:15].CN(C)[CH:36]=[O:37].O(Cl)Cl.[P+3].O>ClCCCl>[F:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:7]2[C:3]=1[C:4]([CH:36]=[O:37])=[CH:5][N:6]2[C@@H:11]1[O:28][C@H:27]([CH2:29][O:30][C:31](=[O:33])[CH3:32])[C@@H:22]([O:23][C:24](=[O:26])[CH3:25])[C@H:17]([O:18][C:19](=[O:21])[CH3:20])[C@H:12]1[O:13][C:14](=[O:16])[CH3:15]
Reactant: CC(=O)OC[C@H]1O[C@@H](n2ccc3c(F)cccc32)[C@H](OC(C)=O)[C@@H](OC(C)=O)[C@@H]1OC(C)=O
Reactant: CN(C)C=O
Agent: ClOCl
Agent: [P+3]
Solvent: ClCCCl
Solvent: O
Product: CC(=O)OC[C@H]1O[C@@H](n2cc(C=O)c3c(F)cccc32)[C@H](OC(C)=O)[C@@H](OC(C)=O)[C@@H]1OC(C)=O
Temperature: 70 °C
Reaction time: 1 h

Procedure:
4-Fluoro-1-(2,3,4,6-tetra-O-acetyl-β-D-glucopyranosyl)-indole (3.50 g) obtained in Example 2-(3) and N,N-dimethyl-formamide (3.49 ml) were dissolved in 1,2-dichloroethane (70 ml), and thereto was added dropwise phosphorus(III) oxychloride (2.10 ml). The mixture was stirred at 70° C. for 1 hour, and thereto was added water (100 ml) at 0° C. The resultant mixture was extracted with ethyl acetate (200 ml) twice, and the combined organic layer was washed with brine (40 ml) and dried over magnesium sulfate. The insoluble materials were filtered off, and the filtrate was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (hexane:ethyl acetate=90:10-50:50) followed by recrystallization from ethyl alcohol (20 ml) to give 4-fluoro-1-(2,3,4,6-tetra-O-acetyl-β-D-glucopyranosyl)indole-3-carboxaldehyde (2.93 g) as colorless crystals. mp 190-192° C. APCI-Mass m/Z 511 (M+NH4) 1H-NMR (DMSO-d6) δ 1.64 (s, 3H), 1.98 (s, 3H), 2.00 (s, 3H), 2.05 (s, 3H), 4.12 (A part of ABX, J=12.4, 2.5 Hz, 1H), 4.17 (B part of ABX, J=12.4, 5.5 Hz, 1H), 4.33 (ddd, J=10.0, 5.5 and 2.5 Hz, 1H), 5.32 (t, J=9.8 Hz, 1H), 5.56 (t, J=9.6 Hz, 1H), 5.66 (t, J=9.3 Hz, 1H), 6.36 (d, J=9.0 Hz, 1H), 7.11 (dd, J=10.6, 8.0 Hz, 1H), 7.38 (td, J=8.1, 5.1 Hz, 1H), 7.65 (d, J=8.3 Hz, 1H), 8.53 (s, 1H), 10.0 (d, J=2.9 Hz, 1H).
Reaction SMILES: [C:1]1(=O)O[C:4](=O)[C:3]2=[CH:7][CH:8]=[CH:9][CH:10]=[C:2]12.[N+:12](CC)([O-])=[O:13].C=CCCCC>C(N(CC)CC)C>[CH3:1][C:2]1[CH2:10][CH:9]([CH2:8][CH2:7][CH2:3][CH3:4])[O:13][N:12]=1
Reactant: O=C1OC(=O)c2ccccc21
Reactant: CC[N+](=O)[O-]
Solvent: CCN(CC)CC
Solvent: C=CCCCC
Product: CCCCC1CC(C)=NO1

Procedure:
A reactor was charged with 20.0 parts phthalic anhydride, 20.9 parts nitroethane, 34.0 parts 1-hexene and heated to reflux. Then, 13.8 parts of triethylamine was slowly added over a one hour period. The mixture was refluxed for 20 hours. The product mixture was vacuum fractionally distilled to provide 3-methyl-5-butylisoxazoline in good yields.
Reaction SMILES: [O:1]=[C:2]1[C:7]([C:8]([O:10][CH3:11])=[O:9])=[CH:6][CH:5]=[CH:4][NH:3]1.[I:12]N1C(=O)CCC1=O>C(Cl)Cl>[I:12][C:5]1[CH:6]=[C:7]([C:8]([O:10][CH3:11])=[O:9])[C:2](=[O:1])[NH:3][CH:4]=1
Reactant: O=C1CCC(=O)N1I
Reactant: COC(=O)c1ccc[nH]c1=O
Solvent: ClCCl
Product: COC(=O)c1cc(I)c[nH]c1=O
Yield: 46.7 %

Procedure:
A solution containing 19.48 g of methyl 2-oxo-1,2-dihydro-3-pyridinecarboxylate and 36.15 g of N-iodosuccinimide in 500 ml of anhydrous methylene chloride is heated at reflux under a nitrogen atmosphere in the dark for 48 hours. The reaction mixture is concentrated to 150 ml under reduced pressure and the solid which forms is collected by filtration and washed with small portions of cold methylene chloride and benzene to give 16.59 g (47%) of methyl 5-iodo-2-oxo-1,2-dihydro-3-pyridinecarboxylate as a pale yellowish solid. This material is sufficiently pure for the next reaction; its properties upon recrystallization from ethyl acetate are as follows: m.p. 190°-192° C.; NMR (DMSO-d6, 300 MHz) delta 3.71 (s, 3H), 7.93 (d, 1H, J=2.26 Hz), 8.10 (d, 1H, J=2.26 Hz), IR (KBr) 2500-3050 (broad), 1725, 1630, 1585, 1475, 1425, 1320, 1260, 1235, 1180, 1150, 1105, 1065, 965, 875 and 800 cm-1 ; M/S (279, M+), 247, 127 and 93. Anal. Calcd. for C7H6INO3 : C, 30.13; H, 2.17; I, 45.48; N, 5.02. Found: C, 30.24; H, 2.22; I, 45.55: N, 4.87. The filtrate is evaporated and the residue dissolved in 500 ml of methylene chloride. The organic solution is extracted with a 10% sodium thiosulfate solution, washed with a saturated sodium chloride solution, and dried over anhydrous sodium sulfate. The solution is concentrated under reduced pressure and the residue triturated with ethyl acetate and filtered to yield an additional 5.49 g (15%) of methyl 5-iodo-2-oxo-1,2-dihydro-3-pyridinecarboxylate.
Reaction SMILES: [NH:1]1[CH2:4][CH:3]([NH:5][C:6](=[O:37])[C:7]2[CH:12]=[C:11]([O:13][CH3:14])[C:10]([NH:15][C:16]3[N:17]=[CH:18][C:19]4[N:25]([CH3:26])[C:24](=[O:27])[C:23]([F:29])([F:28])[CH2:22][N:21]([CH:30]5[CH2:34][CH2:33][CH2:32][CH2:31]5)[C:20]=4[N:35]=3)=[CH:9][C:8]=2F)[CH2:2]1.CCN(C(C)C)C(C)C.[CH3:47][S:48](Cl)(=[O:50])=[O:49]>C(Cl)Cl>[CH:30]1([N:21]2[CH2:22][C:23]([F:28])([F:29])[C:24](=[O:27])[N:25]([CH3:26])[C:19]3[CH:18]=[N:17][C:16]([NH:15][C:10]4[CH:9]=[CH:8][C:7]([C:6]([NH:5][CH:3]5[CH2:4][N:1]([S:48]([CH3:47])(=[O:50])=[O:49])[CH2:2]5)=[O:37])=[CH:12][C:11]=4[O:13][CH3:14])=[N:35][C:20]2=3)[CH2:34][CH2:33][CH2:32][CH2:31]1
Reactant: CS(=O)(=O)Cl
Reactant: COc1cc(C(=O)NC2CNC2)c(F)cc1Nc1ncc2c(n1)N(C1CCCC1)CC(F)(F)C(=O)N2C
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: COc1cc(C(=O)NC2CN(S(C)(=O)=O)C2)ccc1Nc1ncc2c(n1)N(C1CCCC1)CC(F)(F)C(=O)N2C
Reaction time: 8 h
Yield: 8.4 %

Procedure:
To a solution of N-(azetidin-3-yl)-4-(9-cyclopentyl-7,7-difluoro-5-methyl-6-oxo-6,7,8,9-tetrahydro-5H-pyrimido[4,5-b][1,4]diazepin-2-ylamino)-2-fluoro-5-methoxybenzamide (100 mg, 0.19 mmol) in DCM (2.5 mL, 1:2:2) was added DIEA (50 μL, 0.285 mmol), followed by methanesulfonyl chloride (23 μL, 0.21 mmol). After stirring overnight the solvent was removed and the product purified by reverse phase HPLC, free based, and lyophilized to yield a white solid (9.3 mg, 9%). 1H NMR (400 MHz, DMSO-d6) δ ppm 1.54-1.79 (m, 6H) 1.96 (br. s., 2H) 3.05 (s, 3H) 3.92 (s, 3H) 3.94 (d, J=1.77 Hz, 2H) 4.03-4.15 (m, 4H) 4.61-4.72 (m, 1H) 4.76-4.87 (m, 1H) 7.24 (d, J=6.57 Hz, 1H) 8.08 (s, 1H) 8.27 (d, 1H) 8.31 (s, 1H) 8.73 (d, J=3.79 Hz, 1H). [M+H] calc'd for C25H30F3N7O5S, 598. found 598.
Reaction SMILES: [C:1]1([N:7]2[C:11](=[O:12])[CH:10]([C:13]3[CH:18]=[CH:17][C:16]([CH3:19])=[CH:15][CH:14]=3)[C:9](=[O:20])[N:8]2[C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.OO.S(S([O-])=O)([O-])(=O)=[O:30].[Na+].[Na+]>C(O)(=O)C>[C:1]1([N:7]2[C:11](=[O:12])[C:10]([OH:30])([C:13]3[CH:18]=[CH:17][C:16]([CH3:19])=[CH:15][CH:14]=3)[C:9](=[O:20])[N:8]2[C:21]2[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: Cc1ccc(C2C(=O)N(c3ccccc3)N(c3ccccc3)C2=O)cc1
Reactant: O=S([O-])S(=O)(=O)[O-]
Agent: OO
Agent: [Na+]
Solvent: CC(=O)O
Product: Cc1ccc(C2(O)C(=O)N(c3ccccc3)N(c3ccccc3)C2=O)cc1
Temperature: 25 °C
Reaction time: 384 h

Procedure:
A mixture of 1,2-diphenyl-4-(4-methylphenyl)-3,5-pyrazolidinedione (1.10 g; 3.2 =mol), 35% H2O2 (0.47 ml; 5.5 mmol), and acetic acid (40 ml) was stirred 16 days at room temperature. Sodium metabisulfite (1.0 g) was added and excess acetic acid evaporated off. The residue was dissolved in hot ethyl acetate (25 ml) and benzene (25 ml) and filtered. After cooling to room temperature, the mixture was filtered and the residue recrystallized from 50% aqueous ethanol (20 ml) to give 0.58 g (53%).