Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3]1[C:4]([NH2:10])=[N:5][CH:6]=[C:7]([CH3:9])[N:8]=1.[C:11]1([S:17](Cl)(=[O:19])=[O:18])[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1>>[CH3:1][O:2][C:3]1[C:4]([NH:10][S:17]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)(=[O:19])=[O:18])=[N:5][CH:6]=[C:7]([CH3:9])[N:8]=1
Reactant: O=S(=O)(Cl)c1ccccc1
Reactant: COc1nc(C)cnc1N
Product: COc1nc(C)cnc1NS(=O)(=O)c1ccccc1

Procedure:
Prepared by the method of Example 1 using 3-methoxy-5-methyl-2-pyrazinamine and benzenesulphonyl chloride
Reaction SMILES: C[O:2][C:3](=O)[C@@H:4]1[CH2:8][CH2:7][CH2:6][N:5]1[C:9](=[O:19])[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=1[N+:16]([O-])=O.[H][H]>CO.[C].[Pd]>[CH2:8]1[C@H:4]2[C:3](=[O:2])[NH:16][C:11]3[CH:12]=[CH:13][CH:14]=[CH:15][C:10]=3[C:9](=[O:19])[N:5]2[CH2:6][CH2:7]1
Reactant: [H][H]
Reactant: COC(=O)[C@@H]1CCCN1C(=O)c1ccccc1[N+](=O)[O-]
Agent: [Pd]
Solvent: CO
Product: O=C1Nc2ccccc2C(=O)N2CCC[C@@H]12
Yield: 76.4 %

Procedure:
To a solution of 6.4 g of (2S)-1-(2-nitrobenzoyl) proline methyl ester in 250 ml of methanol, there was added 1.5 g of a 10% palladium-carbon catalyst and then the resulting mixture was stirred at room temperature for 6 hours in a hydrogen gas atmosphere. The catalyst present in the reaction solution was filtered off and the filtrate was concentrated under reduced pressure to give 3.8 g (yield 75.2%) of the title compound as white crystals.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:10])[CH:5]([CH2:8][CH3:9])[CH2:6][CH3:7])[CH3:2].I[CH3:12]>C1COCC1>[CH2:1]([O:3][C:4](=[O:10])[C:5]([CH2:8][CH3:9])([CH3:12])[CH2:6][CH3:7])[CH3:2]
Reactant: CI
Reactant: CCOC(=O)C(CC)CC
Solvent: C1CCOC1
Product: CCOC(=O)C(C)(CC)CC
Temperature: -78 °C
Reaction time: 1 h

Procedure:
Diisopropylamine (1.13 mL, 8.05 mmol) was dissolved in THF (1 ml) under nitrogen. The mixture was cooled to −78° C. and n-Buli (3.08 mL, 7.7 mmol) was added dropwise to form LDA. A solution of 2-ethyl-butyric acid ethyl ester (0.57 mL, 3.5 mmol) in THF (2 ml) was added dropwise to this solution. The resulting mixture was stirred at −78° C. under nitrogen for 30 minutes before iodomethane (0.5 mL, 8.05 mmol) was added dropwise and the mixture was first stirred for 1 hour at −78° C., and then 30 minutes at 0° C., and finally 30 minutes at room temperature. The reaction mixture was quenched with H2O (5 ml). The mixture was extracted twice with Et2O (5 ml), washed with 2M HCl (5 ml) then dried over MgSO4.
Reaction SMILES: [BrH:1].[Cl:2][C:3]1[CH:8]=[CH:7][C:6]([N:9]=[C:10]2[N:14]([CH3:15])[C:13]([C:17]3[CH:22]=[CH:21][C:20]([Cl:23])=[C:19]([S:24](=[O:29])(=[O:28])[N:25]([CH3:27])[CH3:26])[CH:18]=3)(O)[CH2:12][S:11]2)=[CH:5][C:4]=1C.[C:31](O)(=O)C>>[BrH:1].[Cl:2][C:3]1[CH:4]=[CH:5][C:6]([N:9]=[C:10]2[N:14]([CH3:15])[C:13]([C:17]3[CH:22]=[CH:21][C:20]([Cl:23])=[C:19]([S:24](=[O:28])(=[O:29])[N:25]([CH3:26])[CH3:27])[CH:18]=3)=[CH:12][S:11]2)=[C:7]([CH3:31])[CH:8]=1
Reactant: Cc1cc(N=C2SCC(O)(c3ccc(Cl)c(S(=O)(=O)N(C)C)c3)N2C)ccc1Cl
Reactant: CC(=O)O
Agent: Br
Product: Cc1cc(Cl)ccc1N=c1scc(-c2ccc(Cl)c(S(=O)(=O)N(C)C)c2)n1C

Procedure:
Obtained by a procedure analogous to that indicated in Example 1 (b), from 2-(4-chloro-3-methylphenyl-imino)-4-(4-chloro-3-dimethylsulfamoylphenyl)-3-methylthiazolidin-4-ol hydrobromide in boiling glacial acetic acid, with subsequent precipitation with diethyl ether. Colorless crystals from glacial acetic acid; melting point 231° C. (with decomposition).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[C:6]([C:8]([F:11])([F:10])[F:9])[CH:5]=[CH:4][C:3]=1[C:12](=[O:14])[CH3:13].C(#N)C.[Br:18]N1C(=O)CCC1=O>C(OCC)C>[NH2:1][C:2]1[CH:7]=[C:6]([C:8]([F:9])([F:10])[F:11])[C:5]([Br:18])=[CH:4][C:3]=1[C:12](=[O:14])[CH3:13]
Reactant: O=C1CCC(=O)N1Br
Reactant: CC(=O)c1ccc(C(F)(F)F)cc1N
Solvent: CC#N
Solvent: CCOCC
Product: CC(=O)c1cc(Br)c(C(F)(F)F)cc1N
Reaction time: 0.5 h
Yield: 64.7 %

Procedure:
To a mixture of 11.6 g of 1-[2-amino-4-(trifluoromethyl)phenyl]ethanone, 60 mL of acetonitrile, and 230 mL of diethyl ether was added 2.85 g of Amberlyst (registered trademark) 15, and 10.1 g of N-bromosuccinimide was added thereto in three times in an ice bath. After stirring for 30 minutes in an ice bath, the mixture was stirred at room temperature overnight. The insoluble material was filtered and washed with ethyl acetate. To the filtrate were added water and ethyl acetate, and the aqueous layer was separated. The organic layer was washed with a 10% aqueous sodium thiosulfate solution and saturated brine, and dried over anhydrous magnesium sulfate, and then solvent was evaporated. The residue was purified by silica gel column chromatography (n-hexane/ethyl acetate) to obtain 10.36 g of 1[2-amino-5-bromo-4-(trifluoromethyl)phenyl]ethanone.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]2[C:10](=[CH:11][CH:12]=1)[NH:9][C:8]([C:13]([O:15][CH2:16][CH3:17])=[O:14])=[C:7]2[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)([O-:3])=[O:2].Br[CH2:25][C:26]1[CH:31]=[CH:30][C:29]([C:32]2[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=2)=[CH:28][CH:27]=1>>[C:29]1([C:32]2[CH:33]=[CH:34][CH:35]=[CH:36][CH:37]=2)[CH:28]=[CH:27][C:26]([CH2:25][N:9]2[C:10]3[C:6](=[CH:5][C:4]([N+:1]([O-:3])=[O:2])=[CH:12][CH:11]=3)[C:7]([C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)=[C:8]2[C:13]([O:15][CH2:16][CH3:17])=[O:14])=[CH:31][CH:30]=1
Reactant: BrCc1ccc(-c2ccccc2)cc1
Reactant: CCOC(=O)c1[nH]c2ccc([N+](=O)[O-])cc2c1-c1ccccc1
Product: CCOC(=O)c1c(-c2ccccc2)c2cc([N+](=O)[O-])ccc2n1Cc1ccc(-c2ccccc2)cc1

Procedure:
Ethyl 1-(1,1′-biphenyl-4-ylmethyl)-5-nitro-3-phenyl-1H-indole-2-carboxylate was prepared from ethyl 5-nitro-3-phenyl-1H-indole-2-carboxylate and 4-bromomethylbiphenyl according to the procedure of Example 1 Step 1 as a yellowish solid: 1H NMR (DMSO-d6) δ 0.95 (t, J=7.0 Hz, 3 H), 4.13 (q, J=7.0 Hz, 2 H), 5.96 (s, 2 H), 7.30-7.32 (m, 14 H), 7.62 (d, J=2.3 Hz, 1 H), 8.25 (d, J=2.8 Hz, 1 H), 8.36 (s, 1 H); MS (ESI) m/z 477 (MH+); HRMS calcd. for C30H25N2O4: 477.1815; found (ESI+): 477.1806; Anal. calcd. for C30H24N2O4: C, 75.62; H, 5.08; N, 5.88. Found: C, 75.25; H, 5.18; N, 5.47.
Reaction SMILES: [CH3:1][C:2]1[O:6][C:5]([C:7]2[CH:12]=[CH:11][C:10](C)=[CH:9][CH:8]=2)=[N:4][C:3]=1[CH2:14][CH2:15][O:16][C:17]1[CH:22]=[CH:21][C:20]([CH2:23][C@H:24]([NH:30][CH2:31]C2C=CC(F)=CC=2)[C:25]([O:27][CH2:28]C)=[O:26])=[CH:19][CH:18]=1.[F:39][C:40]1[C:47]([F:48])=[CH:46][CH:45]=[CH:44][C:41]=1C=O>>[CH3:1][C:2]1[O:6][C:5]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)=[N:4][C:3]=1[CH2:14][CH2:15][O:16][C:17]1[CH:22]=[CH:21][C:20]([CH2:23][C@H:24]([NH:30][CH2:31][C:46]2[CH:45]=[CH:44][CH:41]=[C:40]([F:39])[C:47]=2[F:48])[C:25]([O:27][CH3:28])=[O:26])=[CH:19][CH:18]=1
Reactant: CCOC(=O)[C@H](Cc1ccc(OCCc2nc(-c3ccc(C)cc3)oc2C)cc1)NCc1ccc(F)cc1
Reactant: O=Cc1cccc(F)c1F
Product: COC(=O)[C@H](Cc1ccc(OCCc2nc(-c3ccccc3)oc2C)cc1)NCc1cccc(F)c1F

Procedure:
In the same manner as in Example 7, 253.2 mg of the title compound was obtained as colorless oil from 510.0 mg of Referential Compound 3 and 191 μL of 2,3-difluorobenzaldehyde.
Reaction SMILES: O[CH2:2][CH:3]([CH3:12])[CH2:4][CH2:5][CH:6]([O:10][CH3:11])[CH:7]([CH3:9])[CH3:8].S(Cl)([Cl:15])=O.C1C=CC=CC=1>CN(C)C=O>[Cl:15][CH2:2][CH:3]([CH3:12])[CH2:4][CH2:5][CH:6]([O:10][CH3:11])[CH:7]([CH3:9])[CH3:8]
Reactant: O=S(Cl)Cl
Reactant: COC(CCC(C)CO)C(C)C
Solvent: CN(C)C=O
Solvent: c1ccccc1
Product: COC(CCC(C)CCl)C(C)C

Procedure:
A mixture of 3.4 g. of 1-hydroxy-5-methoxy-2,6-dimethylheptane and 3 g. of thionyl chloride and 60 ml. of dry benzene is treated with 0.2 ml. of dry dimethylformamide and then refluxed for 6 hours. After cooling, the mixture is decanted and 1-chloro-5-methoxy-2,6-dimethylheptane isolated by filtration through silica gel and distillation.
Reaction SMILES: P(Cl)(Cl)(Cl)=O.CN(C)[CH:8]=[O:9].[NH:11]1[C:19]2[C:14](=[CH:15][C:16]([C:20]([O:22][CH3:23])=[O:21])=[CH:17][CH:18]=2)[CH:13]=[CH:12]1.C(=O)([O-])[O-].[K+].[K+]>O>[CH:8]([C:13]1[C:14]2[C:19](=[CH:18][CH:17]=[C:16]([C:20]([O:22][CH3:23])=[O:21])[CH:15]=2)[NH:11][CH:12]=1)=[O:9]
Reactant: CN(C)C=O
Reactant: COC(=O)c1ccc2[nH]ccc2c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: O=P(Cl)(Cl)Cl
Product: COC(=O)c1ccc2[nH]cc(C=O)c2c1
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
A 1.28 ml portion of phosphoryl chloride was added dropwise to 8 ml of N,N-dimethylformamide under ice-cooling, followed by stirring at room temperature for 15 minutes. An 8 ml portion of an N,N-dimethylformamide solution of 2.00 g of methyl 1H-indole-5-carboxylate was added dropwise to this solution under ice-cooling, followed by stirring at room temperature for 1.5 hours. Under ice-cooling, 50 ml of water was added thereto and potassium carbonate was further added until the pH became 12, and the resulting solid was collected by filtration, washed with water and then dried over heating under a reduced pressure to obtain 2.19 g of methyl 3-formyl-1H-indole-5-carboxylate as a pale light brown solid.
Reaction SMILES: [Br:1][C:2]1[CH:21]=[CH:20][C:5]2[O:6][CH2:7][CH:8]([OH:19])[C:9]3[S:13][C:12]([C:14]([O:16][CH2:17][CH3:18])=[O:15])=[N:11][C:10]=3[C:4]=2[CH:3]=1.I[CH3:23]>ClCCl>[Br:1][C:2]1[CH:21]=[CH:20][C:5]2[O:6][CH2:7][CH:8]([O:19][CH3:23])[C:9]3[S:13][C:12]([C:14]([O:16][CH2:17][CH3:18])=[O:15])=[N:11][C:10]=3[C:4]=2[CH:3]=1
Reactant: CI
Reactant: CCOC(=O)c1nc2c(s1)C(O)COc1ccc(Br)cc1-2
Solvent: ClCCl
Product: CCOC(=O)c1nc2c(s1)C(OC)COc1ccc(Br)cc1-2
Reaction time: 3 h
Yield: 28.9 %

Procedure:
A suspension of ethyl 9-bromo-4-hydroxy-4,5-dihydrobenzo[2,3]oxepino[4,5-d]thiazole-2-carboxylate (500 mg, 1.35 mmol, 1.00 equiv), Ag2O (1.247 g, 4.00 equiv), and iodomethane (763 mg, 5.38 mmol, 4.00 equiv) in dichloromethane (5 mL) was stirred for 3 h at 50. The reaction was quenched with 10 mL of brine, extracted with ethyl acetate, dried over anhydrous sodium sulfate, and concentrated under vacuum. The residue was purified by a silica gel column with ethyl acetate/petroleum ether (1:20) to give 150 mg (29%) of the titled compound as a white solid; LC-MS (ES, m/z) 384, 386[M+H]+.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[CH:7][C:6]([C:12]([CH:14]1[CH2:16][CH2:15]1)=[O:13])=[C:5]2[N:17]1[CH2:22][CH2:21][CH:20]([CH2:23][N:24]2[CH2:28][CH2:27][CH2:26][CH2:25]2)[CH2:19][CH2:18]1.[Cl:29][C:30]1[CH:35]=[C:34](B2OC(C)(C)C(C)(C)O2)[CH:33]=[C:32]([O:45][CH3:46])[C:31]=1[OH:47]>>[Cl:29][C:30]1[CH:35]=[C:34]([C:2]2[CH:3]=[C:4]3[C:9](=[CH:10][CH:11]=2)[N:8]=[CH:7][C:6]([C:12]([CH:14]2[CH2:15][CH2:16]2)=[O:13])=[C:5]3[N:17]2[CH2:18][CH2:19][CH:20]([CH2:23][N:24]3[CH2:25][CH2:26][CH2:27][CH2:28]3)[CH2:21][CH2:22]2)[CH:33]=[C:32]([O:45][CH3:46])[C:31]=1[OH:47]
Reactant: COc1cc(B2OC(C)(C)C(C)(C)O2)cc(Cl)c1O
Reactant: O=C(c1cnc2ccc(Br)cc2c1N1CCC(CN2CCCC2)CC1)C1CC1
Product: COc1cc(-c2ccc3ncc(C(=O)C4CC4)c(N4CCC(CN5CCCC5)CC4)c3c2)cc(Cl)c1O
Yield: 60.8 %

Procedure:
Following general procedure D, {6-bromo-4-[4-(pyrrolidin-1-ylmethyl)piperidin-1-yl]quinolin-3-yl}(cyclopropyl)methanone (30 mg, 0.068 mmol) was reacted with 2-chloro-6-methoxy-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenol (30 mg, 0.106 mmol) to afford the desired product (21.5 mg, 61%) as a yellow solid: 1H NMR (500 MHz, CD3OD) δ 8.76 (s, 1H), 8.29 (s, 1H), 8.07-7.99 (m, 2H), 7.31 (d, J=2.0 Hz, 1H), 7.24 (d, J=2.0 Hz, 1H), 3.99 (s, 3H), 3.54 (d, J=12.4 Hz, 2H), 3.22 (t, J=11.7 Hz, 2H), 2.82 (s, 4H), 2.71 (d, J=6.5 Hz, 2H), 2.60-2.51 (m, 1H), 2.06-1.81 (m, 7H), 1.71-1.59 (m, 2H), 1.36-1.27 (m, 2H), 1.27-1.19 (m, 2H); ESI MS m/z 520 [C30H34ClN3O3+H]+; HPLC 98.6% (AUC), tR=10.70 min.
Reaction SMILES: C(N(CC)CC)C.[CH3:8][N:9]1[C:21]([CH2:22][CH:23]([CH3:25])[CH3:24])=[C:20]2[C:11]([C:12]([NH2:26])=[N:13][C:14]3[CH:15]=[CH:16][CH:17]=[CH:18][C:19]=32)=[N:10]1.Cl[C:28]([O:30][CH2:31][CH3:32])=[O:29]>ClCCl>[CH2:22]([C:21]1[N:9]([CH3:8])[N:10]=[C:11]2[C:20]=1[C:19]1[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=1[N:13]=[C:12]2[NH:26][C:28](=[O:29])[O:30][CH2:31][CH3:32])[CH:23]([CH3:24])[CH3:25]
Reactant: CCOC(=O)Cl
Reactant: CC(C)Cc1c2c(nn1C)c(N)nc1ccccc12
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCOC(=O)Nc1nc2ccccc2c2c(CC(C)C)n(C)nc12
Temperature: 4 °C
Yield: 46.7 %

Procedure:
Triethylamine (0.49 mL, 3.53 mmol) was added to a suspension of 2-methyl-1-(2-methylpropyl)-2H-pyrazolo[3,4-c]quinolin-4-amine (prepared as described in Example 3) (0.75 g, 2.95 mmol) in dichloromethane (30 mL) and cooled to 4° C. Ethyl chloroformate (0.352 g, 3.24 mmol) was added in dichloromethane (5 mL) dropwise over 5 minutes to the reaction mixture and maintained at ambient temperature for 16 hours. The reaction mixture was diluted with dichloromethane (25 mL) and washed sequentially with water (25 mL), 4% sodium bicarbonate (2×25 mL), water (25 mL), and brine (25 mL). The combined organic layers were concentrated under reduced pressure and the residue was purified via column chromatography on silica gel (80 g, eluting with 0-10% CMA/chloroform), concentrated under reduced pressure, and recrystallized from diethyl ether to afford 0.45 g of ethyl 1-isobutyl-2-methyl-2H-pyrazolo[3,4-c]quinolin-4-ylcarbamate as white crystals, mp 120-121° C.
Reaction SMILES: Cl.[NH:2]1[CH2:7][CH2:6][CH:5]([NH:8][C:9]([C:11]2[C:15]3[N:16]=[CH:17][N:18]=[C:19]([C:20]4[CH:25]=[C:24]([F:26])[CH:23]=[CH:22][C:21]=4[O:27][CH2:28][CH:29]4[CH2:31][CH2:30]4)[C:14]=3[NH:13][C:12]=2[CH3:32])=[O:10])[CH2:4][CH2:3]1.Cl[C:34]([O:36][CH2:37][CH3:38])=[O:35]>>[CH:29]1([CH2:28][O:27][C:21]2[CH:22]=[CH:23][C:24]([F:26])=[CH:25][C:20]=2[C:19]2[C:14]3[NH:13][C:12]([CH3:32])=[C:11]([C:9]([NH:8][CH:5]4[CH2:4][CH2:3][N:2]([C:34]([O:36][CH2:37][CH3:38])=[O:35])[CH2:7][CH2:6]4)=[O:10])[C:15]=3[N:16]=[CH:17][N:18]=2)[CH2:30][CH2:31]1
Reactant: Cc1[nH]c2c(-c3cc(F)ccc3OCC3CC3)ncnc2c1C(=O)NC1CCNCC1
Reactant: CCOC(=O)Cl
Agent: Cl
Product: CCOC(=O)N1CCC(NC(=O)c2c(C)[nH]c3c(-c4cc(F)ccc4OCC4CC4)ncnc23)CC1

Procedure:
Starting from 4-(2-cyclopropylmethoxy-5-fluoro-phenyl)-6-methyl-5H-pyrrolo[3,2-d]pyrimidine-7-carboxylic acid piperidin-4-ylamide hydrochloride (example D.f12) and commercially ethyl chloroformate the title compound is obtained as colorless solid.
Reaction SMILES: [CH:1]([C:3]1[S:4][C:5]([C:8]([O:10][CH2:11][CH3:12])=[O:9])=[CH:6][N:7]=1)=[CH2:2].[H][H]>CO.[Pd]>[CH2:1]([C:3]1[S:4][C:5]([C:8]([O:10][CH2:11][CH3:12])=[O:9])=[CH:6][N:7]=1)[CH3:2]
Reactant: [H][H]
Reactant: C=Cc1ncc(C(=O)OCC)s1
Agent: [Pd]
Solvent: CO
Product: CCOC(=O)c1cnc(CC)s1
Yield: 100 %

Procedure:
To a solution of ethyl 2-vinylthiazole-5-carboxylate (400 mg, 2.18 mmol) in MeOH (7 mL) is added 10% wt. Pd/C (267 mg, 0.25 mmol) at room temperature. After stirring at room temperature under a balloon of hydrogen for 1 hour, the crude is filtered to remove Pd/C. The filtrate is concentrated to give ethyl 2-ethylthiazole-5-carboxylate (404 mg). HPLC retention time=0.60 minutes (condition B); MS (m+1)=186.3; 1H NMR (400 MHz, CD3OD) δ ppm 1.35 (t, J=7.3 Hz, 2H) 1.39 (t, J=7.20 Hz, 2H) 3.07 (q, J=7.58 Hz, 2H) 4.35 (q, J=7.16 Hz, 2H) 8.22 (s, 1H)
Reaction SMILES: Cl.Cl.[N:3]1([CH2:9][CH2:10][C:11]([O:13][CH3:14])=[O:12])[CH2:8][CH2:7][NH:6][CH2:5][CH2:4]1.F[C:16]1[N:21]=[C:20]([C:22]2[NH:31][C:30](=[O:32])[C:29]3[C:24](=[CH:25][C:26]([O:35][CH3:36])=[CH:27][C:28]=3[O:33][CH3:34])[N:23]=2)[CH:19]=[CH:18][CH:17]=1.CN(C)C(N(C)C)=N>CS(C)=O.O>[CH3:34][O:33][C:28]1[CH:27]=[C:26]([O:35][CH3:36])[CH:25]=[C:24]2[C:29]=1[C:30](=[O:32])[NH:31][C:22]([C:20]1[N:21]=[C:16]([N:6]3[CH2:7][CH2:8][N:3]([CH2:9][CH2:10][C:11]([O:13][CH3:14])=[O:12])[CH2:4][CH2:5]3)[CH:17]=[CH:18][CH:19]=1)=[N:23]2
Reactant: COc1cc(OC)c2c(=O)[nH]c(-c3cccc(F)n3)nc2c1
Reactant: COC(=O)CCN1CCNCC1
Agent: CN(C)C(=N)N(C)C
Agent: Cl
Solvent: O
Solvent: CS(C)=O
Product: COC(=O)CCN1CCN(c2cccc(-c3nc4cc(OC)cc(OC)c4c(=O)[nH]3)n2)CC1
Temperature: 85 °C
Yield: 66.5 %

Procedure:
To a stirred suspension of methyl 3-(piperazin-1-yl)propanoate dihydrochloride (0.358 g, 1.46 mmol) and 2-(6-fluoropyridin-2-yl)-5,7-dimethoxyquinazolin-4(3H)-one (0.220 g, 0.73 mmol) in dry DMSO (1.5 mL) was added 1,1,3,3-tetramethylguanidine (0.336 g, 2.92 mmol). The resulting mixture was heated at 85° C. for 5 h. After that time the reaction was cooled to rt, diluted with water (20 mL) and extracted with ethyl acetate (3×25 mL). The organic phase was washed with water and brine, dried over sodium sulfate, filtered and concentrated under reduced pressure. The product was purified by flash column chromatography (silica gel, 99:1 dichloromethane/methanol to 97:3 dichloromethane/methanol) to give methyl 3-(4-(6-(5,7-dimethoxy-4-oxo-3,4-dihydroquinazolin-2-yl)pyridin-2-yl)piperazin-1-yl)propanoate (0.220 g, 66%) as an off-white solid: 1H NMR (400 MHz, CDCl3) δ 10.31 (s, 1H), 7.85 (d, J=7.42 Hz, 1H), 7.62-7.70 (m, 1H), 6.79-6.85 (m, 2H), 6.48 (d, J=2.34 Hz, 1H), 3.99 (s, 3H), 3.94 (s, 3H), 3.72 (s, 3H), 3.59-3.67 (m, 4H), 2.75-2.83 (m, 2H), 2.54-2.66 (m, 6H); ESI MS m/z 454 [M+H]+.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([CH3:8])=[CH:4][CH:3]=1.OC=[C:11]1[CH2:16][CH2:15][CH2:14][CH2:13][C:12]1=[O:17]>>[CH3:8][C:5]1[CH:4]=[C:3]2[C:2](=[CH:7][CH:6]=1)[NH:1][C:11]1[C:12](=[O:17])[CH2:13][CH2:14][CH2:15][C:16]2=1
Reactant: Cc1ccc(N)cc1
Reactant: O=C1CCCCC1=CO
Product: Cc1ccc2[nH]c3c(c2c1)CCCC3=O

Procedure:
6-Methyl-2,3,4,9-tetrahydro-1H-carbazol-1-one was prepared from p-toluidine and 2-(hydroxymethylene)cyclohexanone in a similar manner as described in Example 1 to give a tan solid. 1H-NMR (CDCl3): δ 8.65 (s, 1H), 7.43 (s, 1H), 7.30 (d, 1H), 7.20 (d, 1H), 2.98 (t, 2H), 2.65 (t, 2H), 2.45 (s, 3H), 2.26 (quint, 2H); MS m/z 220 (M+1).
Reaction SMILES: [CH:1]1([CH2:6][CH2:7][C:8]([N:10]([CH2:24][C:25]2[CH:33]=[CH:32][C:28]([C:29](O)=[O:30])=[CH:27][CH:26]=2)[C:11]2[CH:23]=[CH:22][C:14]3[O:15][C:16]([CH3:21])([CH3:20])[O:17][C:18](=[O:19])[C:13]=3[CH:12]=2)=[O:9])[CH2:5][CH2:4][CH2:3][CH2:2]1.CN1CCOCC1.ClC(OCC(C)C)=O.[O:49]([C:56]1[CH:63]=[CH:62][C:59]([CH2:60][NH2:61])=[CH:58][CH:57]=1)[C:50]1[CH:55]=[CH:54][CH:53]=[CH:52][CH:51]=1.Cl>C1COCC1>[CH:1]1([CH2:6][CH2:7][C:8]([N:10]([CH2:24][C:25]2[CH:26]=[CH:27][C:28]([C:29]([NH:61][CH2:60][C:59]3[CH:62]=[CH:63][C:56]([O:49][C:50]4[CH:51]=[CH:52][CH:53]=[CH:54][CH:55]=4)=[CH:57][CH:58]=3)=[O:30])=[CH:32][CH:33]=2)[C:11]2[CH:23]=[CH:22][C:14]3[O:15][C:16]([CH3:21])([CH3:20])[O:17][C:18](=[O:19])[C:13]=3[CH:12]=2)=[O:9])[CH2:2][CH2:3][CH2:4][CH2:5]1
Reactant: CC1(C)OC(=O)c2cc(N(Cc3ccc(C(=O)O)cc3)C(=O)CCC3CCCC3)ccc2O1
Reactant: NCc1ccc(Oc2ccccc2)cc1
Agent: CC(C)COC(=O)Cl
Agent: Cl
Solvent: C1CCOC1
Solvent: CN1CCOCC1
Product: CC1(C)OC(=O)c2cc(N(Cc3ccc(C(=O)NCc4ccc(Oc5ccccc5)cc4)cc3)C(=O)CCC3CCCC3)ccc2O1
Temperature: 0 °C
Reaction time: 0.25 h
Yield: 81.1 %

Procedure:
To a solution of 4-{[(3-cyclopentylpropanoyl)(2,2-dimethyl-4-oxo-4H-1,3-benzodioxin-6-yl)amino]methyl}benzoic acid (212 mg) in THF (2 mL) was added NMM (57 mg). The mixture was chilled at 0° C. and isobutyl chloroformate was added at once (86 mg). The mixture was stirred for 15 min. at 0° C. then 4-phenoxybenzylamine (103 mg) was added and the resulting reaction mixture was stirred 3 h at rt. An aqueous solution oh HCl (1N, 2 mL) was added and the resulting mixture was extracted with Et2O. The combined organic layers were washed with water, brine, dried over MgSO4 filtered and evaporated to give a light yellow oil. Purification by chromatography (SiO2) gave the title compound as a colorless oil (241 mg, 81%). 1H NMR (CDCl3) δ 7.56-7.42 (m, 3H), 7.21-7.00 (m, 6H), 6.95-6.67 (m, 7H), 6.21 (t, J=4.9 Hz, 1H), 4.69 (s, 2H), 4.42 (s, 1H), 4.40 (s, 1H), 1.87 (t, J=7.2 Hz, 2H), 1.54 (s, 6H), 1.48-1.14 (m, 9H), 0.85-0.64 (m, 2M). M+(ESI): 633.0; M−(ESI): 631.0. HPLC, Rt: 5.3 min (purity: 97.7%).
Reaction SMILES: [Si:1]([O:8][CH2:9][CH2:10][N:11]1[C:15]2[N:16]=[C:17]([NH2:21])[N:18]=[C:19](Cl)[C:14]=2[CH:13]=[CH:12]1)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].[O:22]1[CH:26]=[CH:25][CH:24]=[C:23]1[C:27]([NH:29][NH2:30])=[O:28]>C(O)CCC>[NH2:21][C:17]1[N:18]=[C:19]([NH:30][NH:29][C:27]([C:23]2[O:22][CH:26]=[CH:25][CH:24]=2)=[O:28])[C:14]2[CH:13]=[CH:12][N:11]([CH2:10][CH2:9][O:8][Si:1]([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2])[C:15]=2[N:16]=1
Reactant: NNC(=O)c1ccco1
Reactant: CC(C)(C)[Si](C)(C)OCCn1ccc2c(Cl)nc(N)nc21
Solvent: CCCCO
Product: CC(C)(C)[Si](C)(C)OCCn1ccc2c(NNC(=O)c3ccco3)nc(N)nc21
Temperature: 120 °C
Reaction time: 2 h

Procedure:
The title A compound, 7-[2-(t-Butyldimethylsilanyloxy)ethyl]-4-chloro-7H-pyrrolo[2,3-d]pyrimidin-2-amine (100 mg, 0.3 mmol) and 2-furoic acid hydrazide (76 mg, 0.6 mmol) are taken into 3 mL of n-butanol. The mixture is stirred at 120° C. under N2 for 2 h. The solvent is evaporated under vacuum and the residue is purified by flash chromatography using EtOAc/MeOH (95/5) as eluent to give furan-2-carboxylic acid N′-{2-amino-7-[2-(t-butyldimethylsilanyloxy)ethyl]-7H-pyrrolo[2,3-d]pyrimidin-4-yl}-hydrazide: LC/MS (M+1=417). 1H NMR (CDCl3, 400 MHz) δ-0.08 (s, 6H), 0.84 (s, 9H), 3.85 (t, 2H, J=4.8 Hz), 4.12 (t, 2H, J =4.8 Hz), 4.81 (br s, 2H, NH2), 6.26 (d, 1H, J=2.4 Hz), 6.51 (m, 1H), 6.74 (d, 1H, J=2.4 Hz), 7.20 (d, 1H, J=2.8 Hz), 7.27 (d, 1H, J=2.8 Hz), 7.49 (s, 1H).
Reaction SMILES: Cl[C:2]1[C:3]2[NH:10][CH:9]=[P:8][C:4]=2[N:5]=[CH:6][N:7]=1.NC(N)=[S:13]>C(O)C>[NH:10]1[C:3]2[C:2](=[S:13])[NH:7][CH:6]=[N:5][C:4]=2[P:8]=[CH:9]1
Reactant: NC(N)=S
Reactant: Clc1ncnc2pc[nH]c12
Solvent: CCO
Product: S=c1[nH]cnc2pc[nH]c12
Temperature: 25 °C
Yield: 53.3 %

Procedure:
A mixture of 7-chloro-1H-1,3-azaphospholo[4,5-d]pyrimidine (compound 14, 0.23 g, 1.33 mmol), thiourea (0.15 g, 2.0 mmol) and absolute ethanol (10 mL) was heated under reflux for 90 min with stirring under anhydrous conditions. The reaction mixture was cooled to 25° C. and then the solvent was evaporated in vacuo. The residue was sonicated with ice-cold water (10 mL) and the precipitate was collected by filtration, washed with cold water (3×5 mL) and dried over P2O5 in vacuo first at 25° C. and then at 100° C. to yield 0.12 g (55%) of the title compound, mp>300° C. Ir (KBr): ν710 (=P-C), 1170 and 1200 (-P=CH), 1580 (C=S), and 3280 (NH) cm-1. Uv (MeOH): λmax230 nm (ε19,400), 276 (9400), and 338 (17,200). 1H nmr (DMSO-d6): 8.11 (s, 1 H, C5H), 8.93 (dd, 1 H, JC2H,NH =5.4 Hz, JC2H,P =39.6 Hz, C2H), δ 13.15 (s, 1 H, NH), and 13.82 (s, 1 H, NH). Anal. Calcd. for C5H4N3PS.H2O: C, 32.08; H, 3.23; N, 22.45; S, 17.13. Found: C, 32.39; H, 3.61; N, 22.54; S, 17.40. ##STR11##
Reaction SMILES: [C:1]([O:4][C@@H:5]([C@H:8]([C@@H:13]([C@@H:18]([CH2:23][O:24][C:25](=[O:27])[CH3:26])[O:19][C:20](=[O:22])[CH3:21])[O:14][C:15](=[O:17])[CH3:16])[O:9][C:10](=[O:12])C)C=O)(=[O:3])[CH3:2].O[CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][C:34]([O:36][CH2:37][CH3:38])=[O:35].B(F)(F)F.CCOCC>C(Cl)Cl>[C:25]([O:24][C@H:23]1[C@@H:18]([O:19][C:20](=[O:22])[CH3:21])[C@H:13]([O:14][C:15](=[O:17])[CH3:16])[C@@H:8]([CH2:5][O:4][C:1](=[O:3])[CH3:2])[O:9][C@@H:10]1[O:12][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][C:34]([O:36][CH2:37][CH3:38])=[O:35])(=[O:27])[CH3:26]
Reactant: CC(=O)OC[C@@H](OC(C)=O)[C@@H](OC(C)=O)[C@H](OC(C)=O)[C@@H](C=O)OC(C)=O
Reactant: CCOC(=O)CCCCCO
Agent: FB(F)F
Solvent: ClCCl
Solvent: CCOCC
Product: CCOC(=O)CCCCCO[C@H]1O[C@H](COC(C)=O)[C@@H](OC(C)=O)[C@H](OC(C)=O)[C@@H]1OC(C)=O
Temperature: 25 °C
Reaction time: 96 h
Yield: 56.8 %

Procedure:
To mannose pentaacetate (10.00 g, 25.64 mmol) dissolved in 60 mL of CH2Cl2, ethyl 6-hydroxyhexanoate (8.3 mL, 51.28 mmol) was added at room temperature and then BF3.Et2O at 0° C. After 4 days under stirring at room temperature, the reaction mixture was washed twice with NaHCO3 (2×20 mL) and then with brine (20 mL). The organic layer was dried (MgSO4) and concentrated under vacuum. Compound 1 (7.14 g, 57%) was obtained after column chromatography on silica gel (hexane/AcOEt; 6:4).
Reaction SMILES: [NH2:1][C:2]1[C:10]2[C:5](=[CH:6][C:7]([Cl:11])=[CH:8][CH:9]=2)[NH:4][C:3]=1[C:12](=[O:17])[C:13]([CH3:16])([CH3:15])[CH3:14].[C:18](Cl)(=[O:20])[CH3:19]>>[C:18]([NH:1][C:2]1[C:10]2[C:5](=[CH:6][C:7]([Cl:11])=[CH:8][CH:9]=2)[NH:4][C:3]=1[C:12](=[O:17])[C:13]([CH3:14])([CH3:16])[CH3:15])(=[O:20])[CH3:19]
Reactant: CC(C)(C)C(=O)c1[nH]c2cc(Cl)ccc2c1N
Reactant: CC(=O)Cl
Product: CC(=O)Nc1c(C(=O)C(C)(C)C)[nH]c2cc(Cl)ccc12

Procedure:
The title compound was prepared according to the procedure described in Example 19 employing 3-amino-6-chloro-2-trimethylacetylindole (Example 89) and acetyl chloride. m.p.: 190-193° C. 1H-NMR (CDCl3) δ: 10.46 (1H, br s), 8.40 (1H, br s), 8.22 (1H, d, J=9.2 Hz), 7.29 (1H, s), 7.05 (1H, d, J=9.2 Hz), 2.29 (3H, s), 1.42 (9H, s)