Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: O=O.[C:3]([N:6]1[CH2:15][CH2:14][C:13]2[CH2:12][CH2:11][CH2:10][CH2:9][C:8]=2/[C:7]/1=[CH:16]\[C:17]1[CH:22]=[CH:21][C:20]([O:23][CH3:24])=[CH:19][CH:18]=1)(=[O:5])[CH3:4].CO.C(Cl)Cl>C(OCC)C>[C:3]([N:6]1[CH2:15][CH2:14][C:13]2[CH2:12][CH2:11][CH2:10][CH2:9][C:8]=2[C@@H:7]1[CH2:16][C:17]1[CH:18]=[CH:19][C:20]([O:23][CH3:24])=[CH:21][CH:22]=1)(=[O:5])[CH3:4]
Reactant: COc1ccc(/C=C2\C3=C(CCCC3)CCN2C(C)=O)cc1
Agent: O=O
Solvent: ClCCl
Solvent: CCOCC
Solvent: CO
Product: COc1ccc(C[C@H]2C3=C(CCCC3)CCN2C(C)=O)cc1
Reaction time: 20 h
Yield: 98.1 %

Procedure:
In a glove box (<1 ppm oxygen), a 500 ml steel autoclave was charged with 2-acetyl-1-(p-methoxybenzyl)-2,3,4,6,7,8-hexahydroisoquinoline (2.43 g, 8.17 mmol) (prepared according to example 2) 40 ml of methanol, 28 ml of methylene chloride and 100 ml of a methanol solution containing 0.082 mmol of Ru(TFA)2 (BIPHEMP) as catalyst. The hydrogenation was carried out at 100° and 60 bar for 20 h. The solution was concentrated to give an oil, which was dissolved in 300 ml of diethyl ether. To removed the catalyst the ether solution was passed through a short pad of silica gel. Concentration of the filters afforded 2.4 g of (S)-2-acetyl-1-(p-methoxybenzyl)-1,2,3,4,5,6,7,8-octahydroisoquinoline as a colorless oil; e.e. 94.3%.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:14]=[CH:13][C:12]([I:15])=[CH:11][C:10]=1[CH2:16]Br)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:18]([O:22][C:23]([NH:25][CH:26]([C:32]([O:34][CH2:35][CH3:36])=[O:33])[C:27]([O:29][CH2:30][CH3:31])=[O:28])=[O:24])([CH3:21])([CH3:20])[CH3:19].[O-]CC.[Na+]>C(O)C>[CH2:1]([O:8][C:9]1[CH:14]=[CH:13][C:12]([I:15])=[CH:11][C:10]=1[CH2:16][C:26]([NH:25][C:23]([O:22][C:18]([CH3:20])([CH3:19])[CH3:21])=[O:24])([C:27]([O:29][CH2:30][CH3:31])=[O:28])[C:32]([O:34][CH2:35][CH3:36])=[O:33])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CCOC(=O)C(NC(=O)OC(C)(C)C)C(=O)OCC
Reactant: BrCc1cc(I)ccc1OCc1ccccc1
Agent: CC[O-]
Agent: [Na+]
Solvent: CCO
Product: CCOC(=O)C(Cc1cc(I)ccc1OCc1ccccc1)(NC(=O)OC(C)(C)C)C(=O)OCC
Temperature: 25 °C
Reaction time: 3 h

Procedure:
41 g (101.7 mmol) of 1-benzyloxy-2-bromomethyl-4-iodobenzene (Example 4A) are added to a solution of 28 g (101.7 mmol) of diethyl 2-[N-(tert-butoxycarbonyl)amino]malonate and 7.9 ml (101.7 mmol) of sodium ethoxide in 300 ml of ethanol. After stirring at RT for 3 h, the precipitated product is collected by suction filtration. After drying in vacuo, 55 g (90% of theory) of product are isolated.
Reaction SMILES: Cl[C:2]1[O:3][C:4]([C:7]2[N:12]=[C:11]([NH:13][C:14]3[CH:19]=[C:18]([CH3:20])[CH:17]=[CH:16][N:15]=3)[CH:10]=[CH:9][CH:8]=2)=[CH:5][N:6]=1.[NH2:21][CH2:22][C:23]1[CH:28]=[CH:27][N:26]=[CH:25][CH:24]=1.O>CC(O)C>[CH3:20][C:18]1[CH:17]=[CH:16][N:15]=[C:14]([NH:13][C:11]2[N:12]=[C:7]([C:4]3[O:3][C:2]([NH:21][CH2:22][C:23]4[CH:28]=[CH:27][N:26]=[CH:25][CH:24]=4)=[N:6][CH:5]=3)[CH:8]=[CH:9][CH:10]=2)[CH:19]=1
Reactant: Cc1ccnc(Nc2cccc(-c3cnc(Cl)o3)n2)c1
Reactant: NCc1ccncc1
Solvent: CC(C)O
Solvent: O
Product: Cc1ccnc(Nc2cccc(-c3cnc(NCc4ccncc4)o3)n2)c1
Yield: 55 %

Procedure:
A solution of [6-(2-chloro-oxazol-5-yl)-pyridin-2-yl]-(4-methyl-pyridin-2-yl)-amine (50 mg, 0.174 mmol) in iPrOH (5 ml) was treated with 4-aminomethylpyridine (53 μl) and heated to reflux for 40 h. The cooled mixture was treated with water and extracted with DCM. The combined organics were dried over MgSO4, filtered and evaporated under reduced pressure before purification by column chromatography on Al2O3 (Brockman grade III, 7% H2O), eluting with 2% EtOH in DCM. Precipitation from DCM with n-pentane afforded the title compound as pale yellow solid (34 mg, 55%). 1H NMR (300 MHz, DMSO-d6) δ 9.61 (s, 1H), 8.52 (d, J=4.6 Hz, 2H), 8.25 (t, J=5.8 Hz, 1H), 8.08 (d, J=5.0 Hz, 1H), 7.73 (s, 1H), 7.64 (t, J=7.9 Hz, 1H), 7.47 (d, J=8.3 Hz, 1H), 7.36 (d, J=4.9 Hz, 2H), 7.29 (s, 1H), 6.92 (d, J=7.6 Hz, 1H), 6.73 (d, J=5.0 Hz, 1H), 4.49 (d, J=5.7 Hz, 2H), 2.29 (s, 3H). (ESI+) m/z 359 (M+H)+.
Reaction SMILES: [CH2:1]([C:8]1[CH:9]=[N:10][C:11]2[C:16]([C:17]=1[C:18]1[CH:19]=[C:20]([OH:24])[CH:21]=[CH:22][CH:23]=1)=[CH:15][CH:14]=[CH:13][C:12]=2[C:25]([F:28])([F:27])[F:26])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Cl:29][C:30]1[CH:31]=[CH:32][C:33]([C:38]([F:41])([F:40])[F:39])=[C:34]([CH:37]=1)[CH2:35]Br>>[CH2:1]([C:8]1[CH:9]=[N:10][C:11]2[C:16]([C:17]=1[C:18]1[CH:23]=[CH:22][CH:21]=[C:20]([O:24][CH2:35][C:34]3[CH:37]=[C:30]([Cl:29])[CH:31]=[CH:32][C:33]=3[C:38]([F:40])([F:39])[F:41])[CH:19]=1)=[CH:15][CH:14]=[CH:13][C:12]=2[C:25]([F:28])([F:26])[F:27])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: FC(F)(F)c1ccc(Cl)cc1CBr
Reactant: Oc1cccc(-c2c(Cc3ccccc3)cnc3c(C(F)(F)F)cccc23)c1
Product: FC(F)(F)c1ccc(Cl)cc1COc1cccc(-c2c(Cc3ccccc3)cnc3c(C(F)(F)F)cccc23)c1

Procedure:
The title compound was prepared from 3-[3-benzyl-8-(trifluoromethyl)quinolin-4-yl]phenol and 5-chloro-2-trifluoromethylbenzyl bromide as in the procedure of Example 43. MS (ESI) m/z 572.
Reaction SMILES: [ClH:1].Cl.Cl.S1C(C2C=CN=C(NCCCN3CCN(C)CC3)N=2)=CC2C=CC=CC1=2.[CH:30]1([NH:33][C:34]([C:36]2[C:44]3[CH:43]=[C:42]([C:45]4[C:50]([Cl:51])=[CH:49][N:48]=[C:47](Cl)[N:46]=4)[S:41][C:40]=3[CH:39]=[CH:38][CH:37]=2)=[O:35])[CH2:32][CH2:31]1.C(OC([N:60]1[CH2:65][CH2:64][N:63]([CH2:66][CH2:67][NH2:68])[CH2:62][CH2:61]1)=O)(C)(C)C>>[ClH:51].[ClH:1].[ClH:51].[CH:30]1([NH:33][C:34]([C:36]2[C:44]3[CH:43]=[C:42]([C:45]4[C:50]([Cl:51])=[CH:49][N:48]=[C:47]([NH:68][CH2:67][CH2:66][N:63]5[CH2:64][CH2:65][NH:60][CH2:61][CH2:62]5)[N:46]=4)[S:41][C:40]=3[CH:39]=[CH:38][CH:37]=2)=[O:35])[CH2:32][CH2:31]1
Reactant: CC(C)(C)OC(=O)N1CCN(CCN)CC1
Reactant: O=C(NC1CC1)c1cccc2sc(-c3nc(Cl)ncc3Cl)cc12
Agent: CN1CCN(CCCNc2nccc(-c3cc4ccccc4s3)n2)CC1
Agent: Cl
Product: O=C(NC1CC1)c1cccc2sc(-c3nc(NCCN4CCNCC4)ncc3Cl)cc12

Procedure:
Using the method of [4-(benzo[b]thiophen-2-yl)-pyrimidin-2-yl]-[3-(4-methylpiperazin-1-yl)-propyl]-amine tri-hydrochloride, the title compound is synthesized from 2-(2,5-dichloro-pyrimidin-4-yl)-benzo[b]thiophene-4-carboxylic acid cyclopropylamide and 4-(2-amino-ethyl)-piperazine-1-carboxylic acid tert-butyl ester and isolated as a yellow solid (80% yield). ES+(m/z) 457 (35Cl) and 459 (37Cl) [M(free base)+H].
Reaction SMILES: [CH2:1]([Li])[CH2:2][CH2:3][CH2:4][Li].C(OCC)C.[CH2:12]([N:19]1[CH2:24][CH2:23][N:22]([CH2:25][CH2:26][C:27]#[N:28])[CH2:21][CH2:20]1)[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.[OH-].[Na+].C(N1CCNCC1)C1C=CC=CC=1>O1CCCC1>[CH2:12]([N:19]1[CH2:20][CH2:21][N:22]([CH2:25][CH2:26][C:27]2([NH2:28])[CH2:4][CH2:3][CH2:2][CH2:1]2)[CH2:23][CH2:24]1)[C:13]1[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=1
Reactant: N#CCCN1CCN(Cc2ccccc2)CC1
Reactant: [Li]CCCC[Li]
Agent: [Na+]
Agent: [OH-]
Agent: c1ccc(CN2CCNCC2)cc1
Solvent: CCOCC
Solvent: C1CCOC1
Product: NC1(CCN2CCN(Cc3ccccc3)CC2)CCCC1
Temperature: 25 °C
Reaction time: 24 h

Procedure:
CeCl3 (50.0 g,/203 mmol) was dried in vacuo for 20 hours at 150° C. After cooling to room temperature, tetrahydrofuran (500 ml) was added under nitrogen and the resulting suspension was stirred for 1 d. After cooling to −78° C., to the suspension was added dropwise butanediyl dilithium in diethylether (90 mmol), which was prepared according to the literature (J. Org. Chem., 1990, 55, 5406) and the mixture was stirred for 1 hour. To the mixture was added dropwise a solution of 3-(4-benzyl-1-piperazinyl)propanenitrile (16.0 g/70.0 mmol) in tetrahydrofuran (100 ml) and stirred for 1 d at room temperature. The mixture was poured into 2 N—NaOH (200 ml) and the whole was extracted with dichloromethane (200 ml×2). The combined extracts were washed with brine, dried over magnesium sulfate, filtered and concentrated in vacuo. The residue was purified by column chromatography (NH2 gel, 230-400 mesh/dichloromethane) to give a mixture of the titled compound and 1-benzylpiperazine (5.9 g).
Reaction SMILES: C(O[C:9]([N:11]1[CH2:15][C@H:14]([C:16]2([NH:19]C(OC(C)(C)C)=O)[CH2:18][CH2:17]2)[C@H:13]([F:27])[CH2:12]1)=O)C1C=CC=CC=1.[NH2:28][C:29]1[C:38]([F:39])=C(F)[C:36]([O:41][CH3:42])=[C:35]2[C:30]=1[C:31](=[O:50])[C:32]([C:47]([OH:49])=[O:48])=[CH:33][N:34]2[C@@H:43]1[CH2:45][C@@H:44]1[F:46].C(N(CC)CC)C>C(O)C.[C].[Pd]>[NH2:28][C:29]1[C:38]([F:39])=[C:9]([N:11]2[CH2:15][C@H:14]([C:16]3([NH2:19])[CH2:17][CH2:18]3)[C@H:13]([F:27])[CH2:12]2)[C:36]([O:41][CH3:42])=[C:35]2[C:30]=1[C:31](=[O:50])[C:32]([C:47]([OH:49])=[O:48])=[CH:33][N:34]2[C@@H:43]1[CH2:45][C@@H:44]1[F:46]
Reactant: CC(C)(C)OC(=O)NC1([C@H]2CN(C(=O)OCc3ccccc3)C[C@H]2F)CC1
Reactant: COc1c(F)c(F)c(N)c2c(=O)c(C(=O)O)cn([C@@H]3C[C@@H]3F)c12
Agent: [Pd]
Solvent: CCN(CC)CC
Solvent: CCO
Product: COc1c(N2C[C@@H](F)[C@@H](C3(N)CC3)C2)c(F)c(N)c2c(=O)c(C(=O)O)cn([C@@H]3C[C@@H]3F)c12
Reaction time: 18 h
Yield: 42.7 %

Procedure:
1-Benzyloxycarbonyl-4-(R)-(1-tert-butoxycarbonylaminocyclopropyl)-3-(S)-fluoropyrrolidine (400 mg, 1.06 mmol) was dissolved in ethanol (20 ml), and the solution was mixed with a 5% palladium-carbon catalyst (water content, 55.6%; 500 mg) and stirred for 18 hours under a hydrogen atmosphere. The catalyst was removed by celite filtration (methanol washing), and the filtrate was concentrated under reduced pressure. The thus obtained residue was dissolved in dimethyl sulfoxide (8 ml), and the solution was mixed with 5-amino-6,7-difluoro-1-[2-(S)-fluoro-1-(R)-cyclopropyl]-1,4-dihydro-8-methoxy-4-oxoquinoline-3-carboxylic acid (289 mg, 0.88 mmol) and triethylamine (2 ml) and stirred for 26 hours at 100° C. in a nitrogen atmosphere. After cooling, dimethyl sulfoxide was evaporated under reduced pressure, the thus obtained residue was dissolved in chloroform (80 ml) and washed-with a 10% citric acid aqueous solution (80 ml) and then the organic layer was dried over anhydrous sodium sulfate. After filtration, the filtrate was concentrated under reduced pressure. The thus obtained residue was subjected to flash silica gel chromatography and eluted with a mixture of chloroform:methanol=9:1, and the eluate was concentrated under reduced pressure. To the thus obtained residue, which was cooled in an ice bath, was added dropwise concentrated hydrochloric acid (5 ml), followed by 20 minutes of stirring at room temperature. After adding 1 N hydrochloric acid (30 ml) to the reaction solution, the aqueous solution was washed with chloroform (50 ml×2) and adjusted to pH 12.0 with a sodium hydroxide aqueous solution. The aqueous solution was washed with chloroform (100 ml×2), adjusted to pH 7.4 with 1 N hydrochloric acid and then extracted with chloroform (200 ml×3). The organic layers were combined, dried over anhydrous sodium sulfate and then filtered, and the filtrate was concentrated under reduced pressure. Thereafter, the resulting residue was purified by recrystallization from ethanol and then dried under reduced pressure to obtain 170 mg (42.6%) of the title compound as a yellow powder.
Reaction SMILES: [CH:1]([C:3]1[CH:8]=[CH:7][C:6]([C:9]#[C:10][C:11]2[CH:36]=[CH:35][C:14]([C:15]([N:17]([CH3:34])[C@:18]([CH3:33])([C:23]([NH:25][O:26][CH:27]3[CH2:32][CH2:31][CH2:30][CH2:29][O:28]3)=[O:24])[C:19]([NH:21][CH3:22])=[O:20])=[O:16])=[CH:13][CH:12]=2)=[CH:5][CH:4]=1)=O.[O:37]1[CH:41]=[CH:40][CH:39]=[C:38]1[CH2:42][NH2:43]>>[O:37]1[CH:41]=[CH:40][CH:39]=[C:38]1[CH2:42][NH:43][CH2:1][C:3]1[CH:4]=[CH:5][C:6]([C:9]#[C:10][C:11]2[CH:12]=[CH:13][C:14]([C:15]([N:17]([CH3:34])[C@:18]([CH3:33])([C:23]([NH:25][O:26][CH:27]3[CH2:32][CH2:31][CH2:30][CH2:29][O:28]3)=[O:24])[C:19]([NH:21][CH3:22])=[O:20])=[O:16])=[CH:35][CH:36]=2)=[CH:7][CH:8]=1
Reactant: NCc1ccco1
Reactant: CNC(=O)[C@@](C)(C(=O)NOC1CCCCO1)N(C)C(=O)c1ccc(C#Cc2ccc(C=O)cc2)cc1
Product: CNC(=O)[C@@](C)(C(=O)NOC1CCCCO1)N(C)C(=O)c1ccc(C#Cc2ccc(CNCc3ccco3)cc2)cc1

Procedure:
The same procedure as in Example 16-(2) was performed using (2S)-2-[{4-[(4-formylphenyl)ethynyl]benzoyl}(methyl)amino]-N,2-dimethyl-N′-(tetrahydro-2H-pyran-2-yloxy)propanediamide (0.12 g) as obtained in Example 16-(1) and 1-(furan-2-yl)methanamine (34 mg), whereby (2S)-2-[{4-[(4-{[(furan-2-ylmethyl)amino]methyl}phenyl)ethynyl]benzoyl}(methyl)amino]-N,2-dimethyl-N′-(tetrahydro-2H-pyran-2-yloxy)propanediamide (yellow oil) was obtained (93 mg, 67%).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[C:8](=[O:12])[NH:7][C:6](=[O:13])/[C:5]/2=[CH:14]/OC.[CH3:17][O:18][C:19]1[CH:24]=[CH:23][C:22]([CH2:25][NH:26][CH3:27])=[CH:21][C:20]=1[OH:28]>O1CCCC1>[Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[C:8](=[O:12])[NH:7][C:6](=[O:13])/[C:5]/2=[CH:14]\[N:26]([CH2:25][C:22]1[CH:23]=[CH:24][C:19]([O:18][CH3:17])=[C:20]([OH:28])[CH:21]=1)[CH3:27]
Reactant: CNCc1ccc(OC)c(O)c1
Reactant: CO/C=C1/C(=O)NC(=O)c2ccc(Br)cc21
Solvent: C1CCOC1
Product: COc1ccc(CN(C)/C=C2\C(=O)NC(=O)c3ccc(Br)cc32)cc1O
Yield: 94.9 %

Procedure:
(4E)-6-Bromo-4-(methoxymethylene)isoquinoline-1,3(2H,4H)-dione (0.15 g, 0.53 mmol) and 2-methoxy-5-methylaminomethyl-phenol (80 mg, 0.48 mmol) were stirred in tetrahydrofuran (10 mL) at room temperature. The reaction mixture is concentrated under reduced pressure. The solid material is then collected, washed with diethyl ether, water, and methanol, and then dried under vacuum to give (4Z)-6-bromo-4-{[(3-hydroxy-4-methoxybenzyl)(methyl)amino]methylene}isoquinoline-1,3(2H,4H)-dione as a yellow solid (0.19 g, 95%).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:44]=[C:43]([O:45][CH3:46])[CH:42]=[CH:41][C:4]=1[CH2:5][NH:6][CH2:7][C:8]1[CH:13]=[CH:12][N:11]=[C:10]2[N:14]([S:31]([C:34]3[CH:39]=[CH:38][C:37]([CH3:40])=[CH:36][CH:35]=3)(=[O:33])=[O:32])[C:15]([C:17]3[C:25]4[C:20](=[CH:21][C:22]([O:28][CH3:29])=[C:23]([O:26][CH3:27])[CH:24]=4)[N:19]([CH3:30])[CH:18]=3)=[CH:16][C:9]=12.[C:47]1([S:53](Cl)(=[O:55])=[O:54])[CH:52]=[CH:51][CH:50]=[CH:49][CH:48]=1>>[CH3:1][O:2][C:3]1[CH:44]=[C:43]([O:45][CH3:46])[CH:42]=[CH:41][C:4]=1[CH2:5][N:6]([CH2:7][C:8]1[CH:13]=[CH:12][N:11]=[C:10]2[N:14]([S:31]([C:34]3[CH:35]=[CH:36][C:37]([CH3:40])=[CH:38][CH:39]=3)(=[O:33])=[O:32])[C:15]([C:17]3[C:25]4[C:20](=[CH:21][C:22]([O:28][CH3:29])=[C:23]([O:26][CH3:27])[CH:24]=4)[N:19]([CH3:30])[CH:18]=3)=[CH:16][C:9]=12)[S:53]([C:47]1[CH:52]=[CH:51][CH:50]=[CH:49][CH:48]=1)(=[O:55])=[O:54]
Reactant: O=S(=O)(Cl)c1ccccc1
Reactant: COc1ccc(CNCc2ccnc3c2cc(-c2cn(C)c4cc(OC)c(OC)cc24)n3S(=O)(=O)c2ccc(C)cc2)c(OC)c1
Product: COc1ccc(CN(Cc2ccnc3c2cc(-c2cn(C)c4cc(OC)c(OC)cc24)n3S(=O)(=O)c2ccc(C)cc2)S(=O)(=O)c2ccccc2)c(OC)c1
Yield: 12.3 %

Procedure:
N-(2,4-Dimethoxybenzyl)-N-[2-(5,6-dimethoxy-1-methyl-1H-indol-3-yl)-1-(toluene-4-sulfonyl)-1H-pyrrolo[2,3-b]pyrid-4-ylmethyl]benzenesulfonamide is prepared as described in Example 211b starting with 0.80 g of (2,4-dimethoxybenzyl)[2-(5,6-dimethoxy-1-methyl-1H-indol-3-yl)-1-(toluene-4-sulfonyl)-1H-pyrrolo[2,3-b]pyrid-4-ylmethyl]amine and 0.110 g of benzenesulfonyl chloride instead of the 4-(trifluoromethoxy)benzenesulfonyl chloride used in Example 211b. 0.060 g of N-(2,4-dimethoxybenzyl)-N-[2-(5,6-dimethoxy-1-methyl-1H-indol-3-yl)-1-(toluene-4-sulfonyl)-1H-pyrrolo[2,3-b]pyrid-4-ylmethyl]benzenesulfonamide is obtained, the characteristics of which are as follows:
Reaction SMILES: C(OC(=O)[NH:7][CH2:8][C:9]1[CH:10]=[C:11]([I:21])[C:12]2[O:16][C:15]([N:17]([CH3:19])[CH3:18])=[N:14][C:13]=2[CH:20]=1)(C)(C)C.FC(F)(F)C(O)=O>C(Cl)Cl>[CH3:18][N:17]([CH3:19])[C:15]1[O:16][C:12]2[C:11]([I:21])=[CH:10][C:9]([CH2:8][NH2:7])=[CH:20][C:13]=2[N:14]=1
Reactant: CN(C)c1nc2cc(CNC(=O)OC(C)(C)C)cc(I)c2o1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CN(C)c1nc2cc(CN)cc(I)c2o1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 69.6 %

Procedure:
To a solution of Tert-butylN-{[2-(dimethylamino)-7-iodo-1,3-benzoxazol-5-yl]methyl}carbamate (120 mg, 0.29 mmol) in 4 ml of CH2Cl2 was added slowly 0.5 mL of trifluoroacetic acid and it was stirred at room temperature for 30 min. The excess of TFA was removed under vacuum. The product was purified by column chromatography (CH2Cl2/MeOH 9:1) yielding 64 mg (70%) of the title compound as a white solid. 1H NMR (CD3OD) δ 7.46 (d, 1H, J=1.5 Hz, H-6); 7.30 (d, 1H, J=1.5 Hz, H-4); 4.12 (s, 2H, CH2); 3.23, 3.24 (s, 6H, CH3×2); 13C NMR (CD3OD) δ 164.5 (C-2), 152.7 (C-7a), 144.6 (C-3a), 132.9 (C-5), 131.6 (C-6), 117.3 (C-4), 72.0 (C-7), 44.2 (CH2), 38.3 (CH3).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:29]=[CH:28][C:6]([CH2:7][NH:8][C:9]2[N:17]=[C:16]([NH:18][CH2:19][CH2:20][CH2:21][OH:22])[N:15]=[C:14]3[C:10]=2[NH:11][C:12]([NH:23][CH2:24][CH2:25][CH2:26][OH:27])=[N:13]3)=[CH:5][CH:4]=1.[CH2:30](Br)[CH:31]=[CH2:32].C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]([CH2:7][NH:8][C:9]2[N:17]=[C:16]([NH:18][CH2:19][CH2:20][CH2:21][OH:22])[N:15]=[C:14]3[C:10]=2[N:11]=[C:12]([NH:23][CH2:24][CH2:25][CH2:26][OH:27])[N:13]3[CH:31]([CH3:32])[CH3:30])=[CH:28][CH:29]=1
Reactant: COc1ccc(CNc2nc(NCCCO)nc3nc(NCCCO)[nH]c23)cc1
Reactant: C=CCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: COc1ccc(CNc2nc(NCCCO)nc3c2nc(NCCCO)n3C(C)C)cc1
Yield: 55 %

Procedure:
6-(4-Methoxybenzylamino)-2,8-bis(3-hydroxypropylamino)purine (0.07 mmol) was stirred in 2 mL dimethylformamide with 0.14 mmol of allylbromide and with 0.36 mmol of dry potassium carbonate at ambient temperature (6 hours). The solvent was evaporated to dryness and the rest extracted between ethylacetate—water. The organic layer was dried, ethylacetate was evaporated and the rest purified by column chromatograpy (silica gel, chloroform). Yield 55%. MS-ESI(+)m/z 441.4 [M+H]+
Reaction SMILES: [F:1][C:2]([F:20])([F:19])[C:3]1[C:8]([CH:9]([C:11]2[C:12]([O:17][CH3:18])=[N:13][CH:14]=[N:15][CH:16]=2)[OH:10])=[CH:7][N:6]=[CH:5][N:4]=1.[H-].[Na+].[Na+].[I-].[CH2:25](Cl)[C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1>C1COCC1.CCCCCC.CCOC(C)=O.CN(C)C=O>[F:20][C:2]([F:1])([F:19])[C:3]1[C:8]([CH:9]([C:11]2[C:12]([O:17][CH3:18])=[N:13][CH:14]=[N:15][CH:16]=2)[O:10][CH2:25][C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)=[CH:7][N:6]=[CH:5][N:4]=1
Reactant: ClCc1ccccc1
Reactant: COc1ncncc1C(O)c1cncnc1C(F)(F)F
Agent: [H-]
Agent: [I-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CCCCCC
Solvent: CN(C)C=O
Product: COc1ncncc1C(OCc1ccccc1)c1cncnc1C(F)(F)F
Temperature: 25 °C
Reaction time: 0.75 h
Yield: 52.9 %

Procedure:
1-(4-trifluoromethylpyrimidin-5-yl)-1-(4-methoxypyrimidin-5-yl)methanol (56 mg, 0.196 mmol) in THF (2.5 ml) was added dropwise to a suspension of NaH (12 mg, 0.40 mmol, 80% in mineral oil) in THF (0.5 ml) at ice-bath temperature and stirred for 45 minutes. NaI (56 mg, 0.37 mmol) was then added as a solid and benzyl chloride (50 μl, 54 mg, 0.90 mmol, 2.25 equivalent) via syringe. Dimethyl formamide (DMF) (0.5 ml) was added and the solution was allowed to warm to room temperature. When the reaction was complete, as determined by TLC (SiO2 ; hexane/EtOAc, 1:1), it was quenched with 30% aqueous HOAc, diluted with water and extracted with EtOAc (3 times). The combined extracts were washed with brine (sat.), dried (MgSO4), filtered and concentrated in vacuo to give 66 mg of crude material. Preparative thin layer chromatography (SiO2 ; hexane/EtOAc, 1:1) afforded 39 mg of 1-(4-trifluoromethylpyrimidin-5-yl)-1-(4-methoxypyrimidin-5-yl)-1-benzyloxymethane as an oil.
Reaction SMILES: [O:1]=[C:2]([C:17]1[CH:18]=[C:19]2[C:24](=[CH:25][CH:26]=1)[NH:23][C:22](=[O:27])[CH2:21][CH2:20]2)[CH2:3][CH2:4][N:5]1[CH2:10][CH2:9][N:8]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[CH2:7][CH2:6]1.[H][H]>C(O)C.[C].[Pd]>[OH:1][CH:2]([C:17]1[CH:18]=[C:19]2[C:24](=[CH:25][CH:26]=1)[NH:23][C:22](=[O:27])[CH2:21][CH2:20]2)[CH2:3][CH2:4][N:5]1[CH2:6][CH2:7][N:8]([C:11]2[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=2)[CH2:9][CH2:10]1
Reactant: [H][H]
Reactant: O=C1CCc2cc(C(=O)CCN3CCN(c4ccccc4)CC3)ccc2N1
Agent: [Pd]
Solvent: CCO
Product: O=C1CCc2cc(C(O)CCN3CCN(c4ccccc4)CC3)ccc2N1

Procedure:
2.0 Grams of 6-[1-oxo-3-(4-phenylpiperazinyl)-propyl]-3,4-dihydrocarbostyril and 0.6 g of 5%-palladium carbon were dispersed in 80 ml of ethanol and stirred at a room temperature under 2 atmospheric pressure of hydrogen gas for 5 hours. The reaction mixture was filtered for removing the palladium carbon and the mother liquor was concentrated under a reduced pressure and the residue thus obtained was recrystallized from isopropanol to obtain 1.4 g of 6-[1-hydroxy-3-(4-phenyl-1-piperazinyl)propyl]-3,4-dihydrocarbostyril in colorless needle-like crystals.
Reaction SMILES: [CH3:1][C:2]([CH3:5])([O-])[CH3:3].[K+].C(C1[CH:11]=[C:12]2[C:17](=[CH:18][CH:19]=1)[CH:16]=[C:15]([C:20]([O:22][CH3:23])=[O:21])[CH:14]=[CH:13]2)(=O)C>[Br-].C[P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.C1COCC1>[CH2:1]=[C:2]([C:5]1[CH:11]=[C:12]2[C:17](=[CH:18][CH:19]=1)[CH:16]=[C:15]([C:20]([O:22][CH3:23])=[O:21])[CH:14]=[CH:13]2)[CH3:3]
Reactant: COC(=O)c1ccc2cc(C(C)=O)ccc2c1
Reactant: CC(C)(C)[O-]
Agent: C[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Br-]
Agent: [K+]
Solvent: C1CCOC1
Product: C=C(C)c1ccc2cc(C(=O)OC)ccc2c1
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 87.9 %

Procedure:
To a suspension of methyl triphenylphosphonium bromide (2.41 g, 6.74 mmol) in THF (20 ml) was added dropwise potassium tert-butoxide (756 mg, 6.74 mmol) in THF (20 ml) at 0° C., and the mixture was stirred at room temperature for 1.5 hours. Then, methyl 6-acetyl-2-naphthoate (J. Org. Chem., 1990, 55, 319-324, 769 mg, 3.37 mmol) in THF (5 ml) was added at room temperature, and the resulting mixture was stirred at room temperature for 2 hours. The reaction was quenched with water (100 ml) and extracted with ethyl acetate-hexane (1:2). The organic layer was dried over sodium sulfate and concentrated in vacuo. The crude material was purified by silica gel column chromatography, eluting with ethyl acetate-hexane (0:100 to 1:20) to give 0.67 g (88% yield) of the title compound as white solid. 1H NMR (270 MHz, CDCl3) ppm 2.28 (3H, s), 3.99 (3H, s),5.26 (1H, s), 5.58 (1H, s), 7.74 (1H, d, J=8.6 Hz), 7.82-7.97 (3H, m), 8.05 (1H, d, J=8.6 Hz), 8.58 (1H, s). MS (ESI) m/z: not observed M+peak.
Reaction SMILES: [C:1](OCC)(=[O:7])[C:2](OCC)=[O:3].[CH3:11][N:12]([CH3:31])[C:13](=[O:30])[CH2:14][N:15]([C:22]1[CH:27]=[CH:26][C:25]([O:28][CH3:29])=[CH:24][CH:23]=1)[CH2:16][C:17]([O:19][CH2:20][CH3:21])=[O:18].CC[O-].[Na+].C(O)(=O)C>O>[CH3:31][N:12]([CH3:11])[C:13]([C:14]1[N:15]([C:22]2[CH:27]=[CH:26][C:25]([O:28][CH3:29])=[CH:24][CH:23]=2)[C:16]([C:17]([O:19][CH2:20][CH3:21])=[O:18])=[C:2]([OH:3])[C:1]=1[OH:7])=[O:30]
Reactant: CCOC(=O)CN(CC(=O)N(C)C)c1ccc(OC)cc1
Reactant: CCOC(=O)C(=O)OCC
Agent: CC[O-]
Agent: [Na+]
Solvent: CC(=O)O
Solvent: O
Product: CCOC(=O)c1c(O)c(O)c(C(=O)N(C)C)n1-c1ccc(OC)cc1
Temperature: 85 °C
Reaction time: 1.5 h
Yield: 59 %

Procedure:
Diethyl oxalate (2.54 ml, 18.6 mmol) was added dropwise to a stirred solution of ethyl 2-((2-(dimethylamino)-2-oxoethyl)(4-methoxyphenyl)amino)acetate (20) (5.21 g, 17.7 mmol) in NaOEt (21% by wt in EtOH) (27.8 ml, 74.3 mol), the mixture was stirred at 85° C. for 1.5 h. The reaction was quenched with acetic acid (10.1 ml, 177 mmol) and the resulting suspension was poured into iced water (200 mL), and extracted with EtOAc (3×100 mL), combined organics were washed with brine (200 mL), dried (MgSO4), filtered and solvents removed in vacuo to afford a brown oil. The residue was purified by silica gel chromatography (80 g, 0-10% MeOH (+1% NH3) in DCM) to afford ethyl 5-(dimethylcarbamoyl)-3,4-dihydroxy-1-(4-methoxyphenyl)-1H-pyrrole-2-carboxylate (UL1-012) (3.64 g, 53%) as a white solid: m/z 349 (M+H)+ (ES+), 347 (M−H)− (ES−). 1H NMR (400 MHz, DMSO-d6) δ: 8.60 (s, 1H), 8.46 (s, 1H), 7.08-7.01 (m, 2H), 6.90-6.82 (m, 2H), 4.00 (q, J=7.0 Hz, 2H), 3.76 (s, 3H), 2.83 (br s, 6H), 0.99 (t, J=7.1 Hz, 6H).