Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]12[C:12]([NH:13][CH:14]3[CH2:19][CH2:18][CH:17]([NH2:20])[CH2:16][CH2:15]3)=[N:11][CH:10]=[N:9][C:8]=1[S:7][C:6]1[CH2:5][CH2:4][CH2:3][C:2]2=1.Br[CH2:22][CH2:23][F:24].[CH3:25]CN(C(C)C)C(C)C>CC#N>[F:24][CH2:23][CH2:22][N:20]([CH3:25])[CH:17]1[CH2:18][CH2:19][CH:14]([NH:13][C:12]2[C:1]3[C:2]4[CH2:3][CH2:4][CH2:5][C:6]=4[S:7][C:8]=3[N:9]=[CH:10][N:11]=2)[CH2:15][CH2:16]1
Reactant: CCN(C(C)C)C(C)C
Reactant: FCCBr
Reactant: NC1CCC(Nc2ncnc3sc4c(c23)CCC4)CC1
Solvent: CC#N
Product: CN(CCF)C1CCC(Nc2ncnc3sc4c(c23)CCC4)CC1
Temperature: 70 °C
Reaction time: 7 h
Yield: 79.2 %

Procedure:
Into a 100-mL round-bottom flask, a solution of 1-N-[7-thia-9,11-diazatricyclo[6.4.0.0[2,6]]dodeca-1(8),2(6),9,11-tetraen-12-yl]cyclohexane-1,4-diamine (250 mg, 0.87 mmol, 1.00 equiv) in CH3CN (15 mL) was added 1-bromo-2-fluoroethane (220 mg, 1.73 mmol, 2.00 equiv) and DIPEA (200 mg, 1.74 mmol, 2.00 equiv) at room temperature under nitrogen. The resulting solution was stirred for 7 h at 70° C. in an oil bath. After completion, the resulting mixture was concentrated under vacuum. The residue was applied onto a silica gel column with dichloromethane/methanol (20:1) to give 240 mg (83%) of the desired 1-N-(2-fluoroethyl)-4-N-[7-thia-9,11-diazatricyclo[6.4.0.0[2,6]]dodeca-1(8),2(6),9,11-tetraen-12-yl]cyclohexane-1,4-diamine as a light yellow solid. MS (ES, m/z): 334 [M+H]+.
Reaction SMILES: [NH2:1][C@H:2]1[CH2:7][CH2:6][C@H:5]([OH:8])[CH2:4][CH2:3]1.Cl[C:10](OC1C=CC([N+]([O-])=O)=CC=1)=[O:11].C(N(C(C)C)CC)(C)C.[Cl:31][C:32]1[N:36]2[CH2:37][CH2:38][NH:39][CH2:40][C:35]2=[C:34]([C:41]([NH2:43])=[O:42])[C:33]=1[C:44]1[CH:49]=[CH:48][CH:47]=[C:46]([F:50])[CH:45]=1>ClCCl>[Cl:31][C:32]1[N:36]2[CH2:37][CH2:38][N:39]([C:10]([NH:1][C@H:2]3[CH2:7][CH2:6][C@H:5]([OH:8])[CH2:4][CH2:3]3)=[O:11])[CH2:40][C:35]2=[C:34]([C:41]([NH2:43])=[O:42])[C:33]=1[C:44]1[CH:49]=[CH:48][CH:47]=[C:46]([F:50])[CH:45]=1
Reactant: NC(=O)c1c(-c2cccc(F)c2)c(Cl)n2c1CNCC2
Reactant: N[C@H]1CC[C@H](O)CC1
Reactant: O=C(Cl)Oc1ccc([N+](=O)[O-])cc1
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: NC(=O)c1c(-c2cccc(F)c2)c(Cl)n2c1CN(C(=O)N[C@H]1CC[C@H](O)CC1)CC2
Reaction time: 1 h

Procedure:
To a solution of 0.480 g (4.17 mmol) of trans-4-amino-cyclohexanol (CAS27489-62-9) in 10 ml of dichloromethane is added 0.84 g (4.17 mmol) of 4-nitrophenyl chloroformate (CAS 7693-46-1), followed by addition of 1.36 g (2.52 mmol) of diisopropylethylamine. After 1 hour at room temperature, the solvent is stripped off by evaporation under reduced pressure and the residue is suspended in 21 ml of ethyl acetate. 1.00 g (3.42 mmol) of 6-chloro-7-(3-fluorophenyl)-1,2,3,4-tetrahydropyrrolo[1,2-a]pyrazine-8-carboxamide and 0.90 g (0.70 mmol) of diisopropylethylamine are then added and the mixture is stirred for 30 minutes at reflux, to give a homogeneous solution. After cooling, the solvent is stripped off by evaporation under reduced pressure, the residue is then taken up in ethyl acetate and the solution is washed with aqueous sodium hydrogen carbonate solution and then with saturated aqueous sodium chloride solution. The organic phase is dried over sodium sulfate and then concentrated under reduced pressure. The residue is purified by two successive chromatographies on a column of silica gel, eluting with a mixture of 2 to 10% methanol in dichloromethane, to give 0.37 g of trans-6-chloro-7-(3-fluoro-phenyl)-N2-(4-hydroxycyclohexyl)-3,4-dihydropyrrolo[1,2-a]pyrazine-2,8(1H)-dicarboxamide in the form of a solid after recrystallizing from a mixture of methanol and diisopropyl ether and drying.
Reaction SMILES: [Br:1][C:2]1[N:7]=[C:6]([O:8][CH3:9])[C:5]([CH:10]=[CH:11][C:12]([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13])=[CH:4][CH:3]=1.[H][H]>C(OCC)(=O)C.[Pt]>[Br:1][C:2]1[N:7]=[C:6]([O:8][CH3:9])[C:5]([CH2:10][CH2:11][C:12]([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13])=[CH:4][CH:3]=1
Reactant: [H][H]
Reactant: COc1nc(Br)ccc1C=CC(=O)OC(C)(C)C
Agent: [Pt]
Solvent: CCOC(C)=O
Product: COc1nc(Br)ccc1CCC(=O)OC(C)(C)C
Yield: 89.8 %

Procedure:
10% platinum-activated carbon was added to a solution of tert-butyl 3-(6-bromo-2-methoxypyridin-3-yl)acrylate (727 mg) in ethyl acetate (7.3 mL), and the mixture was stirred for four hours in a hydrogen atmosphere. The reaction solution was filtered through celite and the filtrate was concentrated. The residue was purified by silica gel column chromatography (hexane:ethyl acetate=8:1) to give the title compound as a colorless oil (657 mg, 90%).
Reaction SMILES: [OH-].[K+].[CH3:3][C:4]([CH3:26])=[CH:5][CH2:6][O:7][C:8]1[CH:9]=[CH:10][C:11]2[C:12](=[O:25])[C:13]3[C:18]([O:19][C:20]=2[C:21]=1[C:22](=[O:24])[CH3:23])=[CH:17][CH:16]=[CH:15][CH:14]=3.[CH3:27][O:28][C:29]1[CH:30]=[C:31]([CH:34]=[CH:35][CH:36]=1)[CH:32]=O>C(O)C.O>[CH3:3][C:4]([CH3:26])=[CH:5][CH2:6][O:7][C:8]1[CH:9]=[CH:10][C:11]2[C:12](=[O:25])[C:13]3[C:18]([O:19][C:20]=2[C:21]=1[C:22](=[O:24])[CH:23]=[CH:32][C:31]1[CH:34]=[CH:35][CH:36]=[C:29]([O:28][CH3:27])[CH:30]=1)=[CH:17][CH:16]=[CH:15][CH:14]=3
Reactant: CC(=O)c1c(OCC=C(C)C)ccc2c(=O)c3ccccc3oc12
Reactant: COc1cccc(C=O)c1
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: COc1cccc(C=CC(=O)c2c(OCC=C(C)C)ccc3c(=O)c4ccccc4oc23)c1
Temperature: 25 °C
Yield: 57.5 %

Procedure:
A solution of KOH 50% (3 ml) is added to an equimolar solution of 3-(3-methylbut -2-enyloxy)4acetylxanthen-9one (2.4 g, 0.0075 mol) and 3-methoxy-benzaldehyde (1.01 g, 0.0075 mol) in ethanol 95%, the addition being performed under energetic stirring at room temperature. The reaction is left under stirring for one night and then diluted with water and acidified. The precipitate is separated by filtration and dried under vacuum. The compound is crystallized with methanol to give 1.9 g of product m.p. 134-36° C., 1H-NMR (CDCl3) δ: 1.69 (s, 3H); 1.72 (s, 3H); 3.84 (s, 3H); 4.71 (d, 2H, J=6.5); 5.38-5.40 (m, 1H); 6.95-6.98 (m, 1H); 7.05-7.15 (m, 2H); 7.08 (d, 1H, J=8.8 Hz); 7.09 (d, 1H, J=16 Hz); 7.23-7.42 (m, 4H); 7.65-7.72 (m, 1H); 8.32-8 (d, 1H. J=8.8 Hz); 8.42(d, 1H. J=8.9 Hz).
Reaction SMILES: Cl[N:2]1[CH2:7][CH2:6][C:5]2([O:12][C:11]3[CH:13]=[CH:14][CH:15]=[CH:16][C:10]=3[N:9]3[CH:17]=[CH:18][CH:19]=[C:8]23)[CH2:4][CH2:3]1.[F:20][C:21]1[CH:29]=[CH:28][C:27]([O:30][CH3:31])=[CH:26][C:22]=1[C:23](O)=[O:24].CCN=C=NCCCN(C)C.CCN(CC)CC.C(Cl)[Cl:51]>>[Cl:51][C:14]1[CH:15]=[CH:16][C:10]2[N:9]3[CH:17]=[CH:18][CH:19]=[C:8]3[C:5]3([CH2:6][CH2:7][N:2]([C:23]([C:22]4[CH:26]=[C:27]([O:30][CH3:31])[CH:28]=[CH:29][C:21]=4[F:20])=[O:24])[CH2:3][CH2:4]3)[O:12][C:11]=2[CH:13]=1
Reactant: COc1ccc(F)c(C(=O)O)c1
Reactant: ClN1CCC2(CC1)Oc1ccccc1-n1cccc12
Reactant: ClCCl
Agent: CCN=C=NCCCN(C)C
Solvent: CCN(CC)CC
Product: COc1ccc(F)c(C(=O)N2CCC3(CC2)Oc2cc(Cl)ccc2-n2cccc23)c1
Reaction time: 6 h

Procedure:
Chlorospiro[benzo[b]pyrrolo[1,2-d][1,4]oxazine-4,4′-piperidine] (62 mg, 0.20 mmol), 2-fluoro-5-methoxybenzoic acid (34 mg, 0.20 mmol), EDCI (38 mg, 0.20 mmol), and Et3N (56 μL, 0.40 mmol) were combined in DCM (1 mL) and the mixture was stirred for 6 h. The mixture was diluted with DCM and was washed with 1N HCl, sat. aq. sodium bicarbonate and brine. The organics were dried over sodium sulfate and were evaporated. The crude material was purified by silica gel chromatography eluting with 0-40% ethyl acetate in hexanes to provide (7-chlorospiro[benzo[b]pyrrolo[1,2-d][1,4]oxazine-4,4′-piperidine]-1′-yl)(2-fluoro-5-methoxyphenyl)methanone. ESI-MS m/z calc. 426.1, found 427.5 (M+1)+. Retention time: 2.12 minutes (3 min run). 1H NMR (400 MHz, CDCl3) δ 7.26 (d, J=8.4 Hz, 1H), 7.13-7.07 (m, 2H), 7.05-6.96 (m, 2H), 6.94-6.85 (m, 2H), 6.33 (t, J=3.2 Hz, 1H), 6.08-5.98 (m, 1H), 4.69 (d, J=13.1 Hz, 1H), 3.80 (s, 3H), 3.63-3.44 (m, 2H), 3.33 (t, J=12.8 Hz, 1H), 2.19 (d, J=13.8 Hz, 1H), 2.09-1.96 (m, 2H), 1.60 (s, 1H).
Reaction SMILES: [CH3:1][CH:2]([NH:11][NH2:12])[C:3]1[CH:8]=[CH:7][C:6]([Cl:9])=[C:5]([Cl:10])[CH:4]=1.C([O:15][C:16](=O)[CH:17]=[C:18]([NH2:22])OCC)C.C1(C)C=CC(S(O)(=O)=O)=CC=1>C(O)C.C(Cl)Cl>[NH2:22][C:18]1[NH:12][N:11]([CH:2]([CH3:1])[C:3]2[CH:8]=[CH:7][C:6]([Cl:9])=[C:5]([Cl:10])[CH:4]=2)[C:16](=[O:15])[CH:17]=1
Reactant: CCOC(=O)C=C(N)OCC
Reactant: CC(NN)c1ccc(Cl)c(Cl)c1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: CCO
Solvent: ClCCl
Product: CC(c1ccc(Cl)c(Cl)c1)n1[nH]c(N)cc1=O
Reaction time: 2 h

Procedure:
41 g of α-methyl-3,4-dichlorobenzylhydrazine, dissolved in absolute ethanol, were added dropwise to a solution of 31.8 g of β-amino-β-ethoxyacrylic acid ethyl ester and 1.5 g of p-toluenesulphonic acid in 150 ml of ethanol at room temperature under nitrogen gas. After stirring for two hours and standing overnight, the reaction solution was concentrated as far as possible on a rotary evaporator. The residue which remained was dissolved in 2 N sodium hydroxide solution. Any unconverted starting products or by-products were extracted with ether. The aqueous phase was then brought to pH 5 with acetic acid. The oil thereby produced was taken up in methylene chloride and the organic phase was dried over Na2SO4. After evaporating off the solvent, the reaction product crystallized out. It was recrystallized from methanol. Melting point 127°-129° C; yield 21 g (38.5% of theory).
Reaction SMILES: C(OC(=O)[NH:7][C:8]1[CH:13]=[C:12]([Cl:14])[C:11]([C:15]([F:18])([F:17])[F:16])=[CH:10][C:9]=1[NH:19][C:20](=[O:35])[CH2:21][C:22](=O)[C:23]1[CH:28]=[CH:27][CH:26]=[C:25]([N:29]2[CH:33]=[CH:32][N:31]=[N:30]2)[CH:24]=1)(C)(C)C.C(O)(C(F)(F)F)=O>C(Cl)Cl>[Cl:14][C:12]1[C:11]([C:15]([F:18])([F:17])[F:16])=[CH:10][C:9]2[NH:19][C:20](=[O:35])[CH2:21][C:22]([C:23]3[CH:28]=[CH:27][CH:26]=[C:25]([N:29]4[CH:33]=[CH:32][N:31]=[N:30]4)[CH:24]=3)=[N:7][C:8]=2[CH:13]=1
Reactant: CC(C)(C)OC(=O)Nc1cc(Cl)c(C(F)(F)F)cc1NC(=O)CC(=O)c1cccc(-n2ccnn2)c1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: O=C1CC(c2cccc(-n3ccnn3)c2)=Nc2cc(Cl)c(C(F)(F)F)cc2N1

Procedure:
The title compound was prepared from {5-chloro-2-[3-oxo-3-(3-[1,2,3]triazol-1-yl-phenyl)-propionylamino]-4-trifluoromethyl-phenyl}-carbamic acid tert-butyl ester (Example M50) (0.33 g, 0.63 mmol) by treatment with TFA in CH2Cl2 according to the general procedure N. Obtained as a light yellow solid (152 mg, 60%).
Reaction SMILES: [CH:1]1([N:5]2[CH2:10][CH2:9][CH:8]([O:11][C:12]3[CH:17]=[CH:16][C:15]([N:18]4[C:22]([CH3:23])=[CH:21][C:20]([C:24]([O:26]C)=O)=[C:19]4[CH3:28])=[CH:14][CH:13]=3)[CH2:7][CH2:6]2)[CH2:4][CH2:3][CH2:2]1.[NH:29]1[CH2:33][CH2:32][CH2:31][CH2:30]1>>[CH:1]1([N:5]2[CH2:6][CH2:7][CH:8]([O:11][C:12]3[CH:17]=[CH:16][C:15]([N:18]4[C:22]([CH3:23])=[CH:21][C:20]([C:24]([N:29]5[CH2:33][CH2:32][CH2:31][CH2:30]5)=[O:26])=[C:19]4[CH3:28])=[CH:14][CH:13]=3)[CH2:9][CH2:10]2)[CH2:4][CH2:3][CH2:2]1
Reactant: C1CCNC1
Reactant: COC(=O)c1cc(C)n(-c2ccc(OC3CCN(C4CCC4)CC3)cc2)c1C
Product: Cc1cc(C(=O)N2CCCC2)c(C)n1-c1ccc(OC2CCN(C3CCC3)CC2)cc1
Temperature: 100 °C
Reaction time: 16 h

Procedure:
A mixture of the methyl 1-{4-[(1-cyclobutylpiperidin-4-yl)oxy]phenyl}-2,5-dimethyl-1H-pyrrole-3-carboxylate (0.06 g) synthesized in Example 4 and pyrrolidine (0.112 g) was stirred in a sealed tube at 100° C. for 16 hours. The reaction mixture was left to cool to room temperature and concentrated under reduced pressure; the resulting residue was purified by silica gel column chromatography (NH preparative silica gel plate 0.5 mm; eluent: n-hexane/ethyl acetate=50/50) to give the titled compound as a colorless solid.
Reaction SMILES: [CH2:1]1[NH:13][CH2:12][C:11]2[NH:10][C:9]3[CH:8]=[CH:7][CH:6]=[C:5]4[C:14](=[O:17])[NH:15][N:16]=[C:2]1[C:3]=2[C:4]=34.[CH3:18][C:19]([CH3:24])([CH3:23])[CH2:20][CH:21]=O.CN1CC2NC3C=CC=C4C(=O)NN=C(C=2C=34)C1>>[CH3:18][C:19]([CH3:24])([CH3:23])[CH2:20][CH2:21][N:13]1[CH2:12][C:11]2[NH:10][C:9]3[CH:8]=[CH:7][CH:6]=[C:5]4[C:14](=[O:17])[NH:15][N:16]=[C:2]([C:3]=2[C:4]=34)[CH2:1]1
Reactant: O=C1NN=C2CNCc3[nH]c4cccc1c4c32
Reactant: CC(C)(C)CC=O
Agent: CN1CC2=NNC(=O)c3cccc4[nH]c(c2c34)C1
Product: CC(C)(C)CCN1CC2=NNC(=O)c3cccc4[nH]c(c2c34)C1

Procedure:
Compound 54 was prepared from 2,3,4,9-tetrahydro-2,4,9,10-tetraazacyclohepta[def]fluoren-8(1H)-one and 3,3-dimethylbutanal according to the procedures similar to those for Compound 44. 1H NMR (DMSO-d6) δ 11.9 (s, 1H), 9.89 (s, 1H), 7.48 (d, 1H, J=7.8 Hz), 7.43 (d, 1H, J=7.2 Hz), 7.13 (dd, 1H, J=7.2, 7.8 Hz), 3.81 (br s, 2H), 3.29 (br s, 2H), 2.57-2.58 (m, 2H), 1.43-1.46 (m, 2H), and 0.91 (s, 9H). MS (ESI) m/e [M+1]+ 311.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]([CH3:17])=[CH:7][C:8]1[CH:16]=[CH:15][CH:14]=[CH:13][C:9]=1[C:10]([OH:12])=O)=[O:5])[CH3:2].C(N(CC)CC)C.F[B-](F)(F)F.C(C(=NOC(N(C)C)=[N+](C)C)C(OCC)=O)#N.[CH2:47]([NH2:51])[CH:48]([CH3:50])[CH3:49]>CN(C)C=O>[CH2:47]([NH:51][C:10]([C:9]1[CH:13]=[CH:14][CH:15]=[CH:16][C:8]=1[CH:7]=[C:6]([CH3:17])[C:4]([O:3][CH2:1][CH3:2])=[O:5])=[O:12])[CH:48]([CH3:50])[CH3:49]
Reactant: CCOC(=O)C(C)=Cc1ccccc1C(=O)O
Reactant: CC(C)CN
Agent: CCOC(=O)C(C#N)=NOC(N(C)C)=[N+](C)C
Agent: F[B-](F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: CCOC(=O)C(C)=Cc1ccccc1C(=O)NCC(C)C
Yield: 79.5 %

Procedure:
Ethyl 3-(2-isobutylcarbamoylphenyl)-2-methylacrylate is prepared as described in Example 30, starting with 1.17 g (5.0 mmol) of 2-(2-ethoxycarbonylpropen-1-yl)benzoic acid in 10 cm3 of dimethylformamide, a solution of 0.69 cm3 (5.0 mmol) of triethylamine, 1.64 g (5.0 mmol) of O-[(cyano(ethoxycarbonyl)methylene)amino]-1,1,3,3-tetramethyluronium tetrafluoroborate (“TOTU”) in 6 cm3 of dimethylformamide and a second solution consisting of 366 mg (5.0 mmol) of isobutylamine, 0.69 cm3 (5.0 mmol) of triethylamine in 10 cm3 of dimethylformamide. 1.15 g of ethyl 3-(2isobutylcarbamoylphenyl)-2-methylacrylate are thus obtained in the form of a yellowish oil, which can be reacted in the following step without further purification.
Reaction SMILES: [CH:1]1([N:5]2[CH2:10][CH2:9][N:8]([C:11]([C:13]3[CH:14]=[C:15]4[C:19](=[CH:20][CH:21]=3)[NH:18][C:17]([C:22]([N:24]3[CH2:29][CH2:28][S:27](=[O:31])(=[O:30])[CH2:26][CH2:25]3)=[O:23])=[CH:16]4)=[O:12])[CH2:7][CH2:6]2)[CH2:4][CH2:3][CH2:2]1.[CH3:32][C:33]1[CH:34]=[C:35](B(O)O)[CH:36]=[CH:37][CH:38]=1.N1C=CC=CC=1>ClCCl.C([O-])(=O)C.[Cu+2].C([O-])(=O)C>[CH:1]1([N:5]2[CH2:6][CH2:7][N:8]([C:11]([C:13]3[CH:14]=[C:15]4[C:19](=[CH:20][CH:21]=3)[N:18]([C:37]3[CH:38]=[C:33]([CH3:32])[CH:34]=[CH:35][CH:36]=3)[C:17]([C:22]([N:24]3[CH2:29][CH2:28][S:27](=[O:30])(=[O:31])[CH2:26][CH2:25]3)=[O:23])=[CH:16]4)=[O:12])[CH2:9][CH2:10]2)[CH2:2][CH2:3][CH2:4]1
Reactant: O=C(c1ccc2[nH]c(C(=O)N3CCS(=O)(=O)CC3)cc2c1)N1CCN(C2CCC2)CC1
Reactant: Cc1cccc(B(O)O)c1
Agent: [Cu+2]
Agent: CC(=O)[O-]
Solvent: c1ccncc1
Solvent: ClCCl
Product: Cc1cccc(-n2c(C(=O)N3CCS(=O)(=O)CC3)cc3cc(C(=O)N4CCN(C5CCC5)CC4)ccc32)c1
Yield: 56 %

Procedure:
The title compound was synthesized in analogy to example 66, from [5-(4-cyclobutyl-piperazine-1-carbonyl)-1H-indol-2-yl]-(1,1-dioxothiomorpholin-4-yl)-methanone (example 202), 3-methylphenylboronic acid, copper(II) acetate and pyridine in dichloromethane, to give the desired product as a colorless foam (56%).
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[CH2:13][CH2:12][NH:11][CH2:10][CH2:9]2)=[CH:4][CH:3]=1.[F:14][C:15]([F:26])([F:25])[O:16][C:17]1[CH:24]=[CH:23][C:20]([CH:21]=O)=[CH:19][CH:18]=1.C([BH3-])#N.[Na+].C(=O)([O-])O.[Na+]>CO.C(Cl)Cl.C(O)(=O)C>[F:14][C:15]([F:25])([F:26])[O:16][C:17]1[CH:24]=[CH:23][C:20]([CH2:21][N:11]2[CH2:12][CH2:13][N:8]([C:5]3[CH:4]=[CH:3][C:2]([OH:1])=[CH:7][CH:6]=3)[CH2:9][CH2:10]2)=[CH:19][CH:18]=1
Reactant: O=Cc1ccc(OC(F)(F)F)cc1
Reactant: Oc1ccc(N2CCNCC2)cc1
Agent: O=C([O-])O
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CO
Solvent: ClCCl
Solvent: CC(=O)O
Product: Oc1ccc(N2CCN(Cc3ccc(OC(F)(F)F)cc3)CC2)cc1
Reaction time: 2 h
Yield: 56.8 %

Procedure:
4-(4-hydroxyphenyl)piperazine (3 g, 16.8 mmol) and 4-trifluoromethoxy benzaldehyde (3.36 g, 17.7 mmol) were dissolved in methanol (60 ml) and methylene chloride (15 ml). Sodium cyanoborohydride (1.59 g, 25.3 mmol) and-acetic acid (1.6 ml) were added to this solution while cooling in an ice-bath, and the mixture was stirred for 2 hours. Saturated sodium hydrogencarbonate aqueous solution and methylene chloride were added to the reaction mixture, which was extracted with methylene chloride. The extract was washed with brine, dried over magnesium sulfate, and then filtered. The filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (methylene chloride/methanol=100/1) to afford 4-[4-(4-trifluoromethoxybenzyl)piperazin-1-yl]phenol (3.36 g, yield 57%) as a colorless crystalline powder.
Reaction SMILES: [NH2:1][CH2:2][C@H:3]1[C@H:9]([C:10]2[CH:15]=[CH:14][C:13]([Cl:16])=[C:12]([F:17])[CH:11]=2)[O:8][CH2:7][CH2:6][N:5]([C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])[CH2:4]1.C(N(CC)CC)C.[CH3:32][O:33][CH2:34][C:35](Cl)=[O:36]>C1COCC1>[Cl:16][C:13]1[CH:14]=[CH:15][C:10]([C@@H:9]2[O:8][CH2:7][CH2:6][N:5]([C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])[CH2:4][C@H:3]2[CH2:2][NH:1][C:35](=[O:36])[CH2:34][O:33][CH3:32])=[CH:11][C:12]=1[F:17]
Reactant: COCC(=O)Cl
Reactant: CC(C)(C)OC(=O)N1CCO[C@@H](c2ccc(Cl)c(F)c2)[C@H](CN)C1
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: COCC(=O)NC[C@@H]1CN(C(=O)OC(C)(C)C)CCO[C@H]1c1ccc(Cl)c(F)c1
Temperature: 25 °C
Reaction time: 4 h
Yield: 71.1 %

Procedure:
To a solution of tert-butyl (6R,7R)-6-(aminomethyl)-7-(4-chloro-3-fluorophenyl)-1,4-oxazepane-4-carboxylate (1.30 g) in THF (18 mL) were added triethylamine (0.757 ml) and methoxyacetyl chloride (472 mg), and the mixture was stirred at room temperature for 4 hr. To the reaction mixture was added distilled water, and the mixture was extracted with ethyl acetate. The diluted solution was washed with distilled water and brine, and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure. The residue was purified by silica gel chromatography (hexane/ethyl acetate) to give the title compound (1.11 g).
Reaction SMILES: S(Cl)([Cl:3])=O.[NH2:5][C:6]1[C:15]2[N:16]=[C:17]([CH2:19]O)[S:18][C:14]=2[C:13]2[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=2[N:7]=1>ClCCCl>[ClH:3].[Cl:3][CH2:19][C:17]1[S:18][C:14]2[C:13]3[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=3[N:7]=[C:6]([NH2:5])[C:15]=2[N:16]=1
Reactant: O=S(Cl)Cl
Reactant: Nc1nc2ccccc2c2sc(CO)nc12
Solvent: ClCCCl
Product: Cl
Product: Nc1nc2ccccc2c2sc(CCl)nc12
Yield: 165.4 %

Procedure:
Thionyl chloride (4.92 mL, 67.6 mmol) was added to a suspension of (4-amino[1,3]thiazolo[4,5-c]quinolin-2-yl)methanol (13 g, 56 mmol) in 1,2-dichloroethane (300 mL), and the reaction was heated at reflux for two hours and then concentrated under reduced pressure to provide 16 g of 2-(chloromethyl)[1,3]thiazolo[4,5-c]quinolin-4-amine hydrochloride as a yellow solid.
Reaction SMILES: [O:1]=[C:2]1[NH:8][C:7]2[N:9]=[CH:10][CH:11]=[CH:12][C:6]=2[CH2:5][CH2:4][N:3]1[CH:13]1[CH2:18][CH2:17][N:16](C(OC(C)(C)C)=O)[CH2:15][CH2:14]1.FC(F)(F)C(O)=O.[ClH:33].C(OCC)C>ClCCl>[ClH:33].[ClH:33].[NH:16]1[CH2:15][CH2:14][CH:13]([N:3]2[CH2:4][CH2:5][C:6]3[CH:12]=[CH:11][CH:10]=[N:9][C:7]=3[NH:8][C:2]2=[O:1])[CH2:18][CH2:17]1
Reactant: CC(C)(C)OC(=O)N1CCC(N2CCc3cccnc3NC2=O)CC1
Agent: Cl
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Solvent: CCOCC
Product: O=C1Nc2ncccc2CCN1C1CCNCC1
Temperature: 25 °C
Reaction time: 4 h
Yield: 99 %

Procedure:
tert-Butyl 4-(2-oxo-4,5-dihydro-1H-pyrido[2,3-d][1,3]diazepin-3(2H)-yl)piperidine-1-carboxylate (0.51 g, 1.472 mmol) was dissolved in dichloromethane (8 ml). Trifluoroacetic acid (2 ml, 26.0 mmol) was added to the solution. The mixture was stirred at room temperature for 4 hours. All volatiles were removed by roto-vap. Residue was dissolved in dichloromethane (10 mL). 2M Hydrogen chloride in diethyl ether (2.58 ml, 5.15 mmol) was added to the mixture. The mixture was stirred at room temperature for 15 minutes and then all volatiles were removed. The resulting off-white solid was washed with anhydrous diethyl ether four times to afford the title compound as white solid in 99% yield. 1H NMR (500 MHz, D2O) δ ppm 8.01-8.29 (m, 2 H) 7.38 (t, J=6.71 Hz, 1 H) 4.63-4.88 (m, 2 H) 4.29-4.53 (m, 1 H) 3.61-3.71 (m, 2 H) 3.45-3.62 (m, 2 H) 3.01-3.27 (m, 4 H) 1.93-2.21 (m, 4 H).
Reaction SMILES: C([O:4][CH:5]1[CH:9]([O:10]C(=O)C)[CH:8](OCC(=O)C)[O:7][CH:6]1[N:19]1[CH:27]=[N:26][C:25]2[C:20]1=[N:21][C:22]([Cl:29])=[N:23][C:24]=2Cl)(=O)C.[CH3:30][NH2:31].[CH3:32][OH:33]>>[Cl:29][C:22]1[N:21]=[C:20]2[C:25]([N:26]=[CH:27][N:19]2[C@H:6]2[C@H:5]([OH:4])[C@H:9]([OH:10])[C@@H:8]([CH2:32][OH:33])[O:7]2)=[C:24]([NH:31][CH3:30])[N:23]=1
Reactant: CO
Reactant: CN
Reactant: CC(=O)COC1OC(n2cnc3c(Cl)nc(Cl)nc32)C(OC(C)=O)C1OC(C)=O
Product: CNc1nc(Cl)nc2c1ncn2[C@@H]1O[C@H](CO)[C@@H](O)[C@H]1O
Temperature: 25 °C
Reaction time: 24 h

Procedure:
3,4-diacetyloxy-2-(2,6-dichloropurin-9-yl)-5-(2-oxopropoxy)tetrahydrofuran, the compound of formula (1) (1 mmol), was suspended in a mixture of 1:4 methylamine/MeOH, and the mixture stirred at room temperature for 24 hours. The solvent was removed under reduced pressure and the residue triturated in ether, to afford (4S,2R,3R,5R)-2-[2-chloro-6-(methylamino)purin-9-yl]-5-(hydroxymethyl)oxolane-3,4-diol, a compound of formula (2) as a white solid.
Reaction SMILES: C([Li])CCC.[CH2:6]([O:8][CH2:9][CH2:10][O:11][C:12]1[CH:13]=[CH:14][C:15]([CH3:18])=[N:16][CH:17]=1)[CH3:7].CN(C)[C:21](=[O:23])[CH3:22].Cl>CCCCCC.O1CCCC1>[CH2:6]([O:8][CH2:9][CH2:10][O:11][C:12]1[CH:13]=[CH:14][C:15]([CH2:18][C:21](=[O:23])[CH3:22])=[N:16][CH:17]=1)[CH3:7]
Reactant: CCOCCOc1ccc(C)nc1
Reactant: CC(=O)N(C)C
Agent: Cl
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CCCCCC
Product: CCOCCOc1ccc(CC(C)=O)nc1
Reaction time: 0.17 h

Procedure:
2.5 ml of a 2.5 M solution of n-butyllithium in hexane are added dropwise at 5° C. to a solution of 1 g (5.5 mmol) of 5-(2-ethoxyethoxy)-2-methylpyridine in 20 ml of tetrahydrofuran. The mixture is stirred at 0°-5° C. for 10 minutes and then 530 mg (6 mmol) of N,N-dimethylacetamide dissolved in a little tetrahydrofuran are added. After stirring at room temperature for 90 minutes, the pH is adjusted to 5 with dilute hydrochloric acid and the tetrahydrofuran is stripped off. The residue is extracted with ethyl acetate, and the organic phase is dried with sodium sulphate and evaporated. Yield: 580 mg (47% of theory), content according to GC/MS: 75%.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:11]=1[N:10]=[CH:9][CH:8]=[CH:7]2.Cl.Cl[CH2:14][CH2:15][NH:16][CH2:17][CH2:18]Cl.C(O)CCCCC.[OH-].[Na+]>ClC1C=CC=CC=1Cl>[N:10]1[C:11]2[C:6](=[CH:5][CH:4]=[CH:3][C:2]=2[N:1]2[CH2:18][CH2:17][NH:16][CH2:15][CH2:14]2)[CH:7]=[CH:8][CH:9]=1
Reactant: Nc1cccc2cccnc12
Reactant: ClCCNCCCl
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: Clc1ccccc1Cl
Solvent: CCCCCCO
Product: c1cnc2c(N3CCNCC3)cccc2c1
Temperature: 25 °C
Yield: 21.6 %

Procedure:
A mixture of 8-aminoquinoline (1.5 g), bis-(2-chloroethyl)amine hydrochloride (2.04 g), o-dichlorobenzene (4.5 mL) and n-hexanol (0.45 mL) was stirred at reflux temperature for 5 h. After cooling to room temperature, the mixture was treated with 2 N NaOH (10 mL) and extracted with CH2Cl2 (3×20 mL). The purification was carried out by flash chromatography (CH2Cl2-2 N methanolic NH3) 97:3 to give 0.48 g (22%) of the title compound.
Reaction SMILES: [C:1]1([C:7]([CH2:9][C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.CO[CH:18](OC)[N:19]([CH3:21])[CH3:20]>>[CH3:18][N:19]([CH3:21])[CH:20]=[C:9]([C:10]1[CH:11]=[CH:12][CH:13]=[CH:14][CH:15]=1)[C:7]([C:1]1[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1)=[O:8]
Reactant: COC(OC)N(C)C
Reactant: O=C(Cc1ccccc1)c1ccccc1
Product: CN(C)C=C(C(=O)c1ccccc1)c1ccccc1

Procedure:
25.00 g of benzyl phenyl ketone was mixed with 92 ml of N,N-dimethylformamide dimethyl acetal and then heated at reflux for one hour. Almost all of N,N-dimethylformamide dimethyl acetal was evaporated under reduced pressure and the deposited crystal was washed with diethyl ether. After drying, 31.40 g of the desired compound was obtained as a pale yellow crystal having a melting point of 128 to 130° C.