Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][CH2:2][CH2:3][C:4]1[N:5]([CH:27]([C:34]2[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=2)[C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)[C:6]2[C:11]([C:12]=1[CH2:13][CH2:14][O:15][C:16]1[CH:25]=[CH:24][C:19]([C:20]([O:22]C)=[O:21])=[CH:18][CH:17]=1)=[CH:10][C:9]([Cl:26])=[CH:8][CH:7]=2.C([O-])(O)=O.[Na+].[C:45]1([CH2:51][S:52](Cl)(=[O:54])=[O:53])[CH:50]=[CH:49][CH:48]=[CH:47][CH:46]=1>C(Cl)Cl>[CH:27]([N:5]1[C:6]2[C:11](=[CH:10][C:9]([Cl:26])=[CH:8][CH:7]=2)[C:12]([CH2:13][CH2:14][O:15][C:16]2[CH:17]=[CH:18][C:19]([C:20]([OH:22])=[O:21])=[CH:24][CH:25]=2)=[C:4]1[CH2:3][CH2:2][NH:1][S:52]([CH2:51][C:45]1[CH:50]=[CH:49][CH:48]=[CH:47][CH:46]=1)(=[O:54])=[O:53])([C:34]1[CH:35]=[CH:36][CH:37]=[CH:38][CH:39]=1)[C:28]1[CH:29]=[CH:30][CH:31]=[CH:32][CH:33]=1
Reactant: O=S(=O)(Cl)Cc1ccccc1
Reactant: COC(=O)c1ccc(OCCc2c(CCN)n(C(c3ccccc3)c3ccccc3)c3ccc(Cl)cc23)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Product: O=C(O)c1ccc(OCCc2c(CCNS(=O)(=O)Cc3ccccc3)n(C(c3ccccc3)c3ccccc3)c3ccc(Cl)cc23)cc1
Yield: 86 %

Procedure:
To methyl 4-{2-[2-(2-aminoethyl)-1-benzhydryl-5-chloro-1H-indol-3-yl]ethoxy}benzoate (1.0 equiv) and sat. NaHCO3 (0.14 M) in CH2Cl2 (0.07 M) was added α-toluenesulfonyl chloride (1.0 equiv). After 1 h the mixture was poured into saturated sodium bicarbonate and extracted with CH2Cl2. The combined organic phase was washed with brine, dried over sodium sulfate and purified by column chromatography (gradient elution using 20% EtOAc-hexanes→50% EtOAc-hexanes) to afford 86% of the desired product.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([P:8]2(=[O:23])[C:12]3[CH:13]=[CH:14][CH:15]=[CH:16][C:11]=3[CH2:10][N:9]2[C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)=[CH:4][CH:3]=1.C(Cl)Cl.[Br:27]Br>C(OCC)C>[F:1][C:2]1[CH:3]=[CH:4][C:5]([P:8]2(=[O:23])[C:12]3[CH:13]=[CH:14][CH:15]=[CH:16][C:11]=3[CH2:10][N:9]2[C:17]2[CH:18]=[CH:19][C:20]([Br:27])=[CH:21][CH:22]=2)=[CH:6][CH:7]=1
Reactant: BrBr
Reactant: O=P1(c2ccc(F)cc2)c2ccccc2CN1c1ccccc1
Solvent: ClCCl
Solvent: CCOCC
Product: O=P1(c2ccc(F)cc2)c2ccccc2CN1c1ccc(Br)cc1
Reaction time: 1 h
Yield: 58 %

Procedure:
To a solution of 1-(4-fluorophenyl)-2-phenyl-2,3-dihydro-1H-2,1-benzazaphosphole-1-oxide (1.0 g, 0.003 mol) in 25 ml. of methylene chloride was added dropwise a solution of bromine (0.8 g, 0.1 mol) in 25 ml. of methylene chloride with constant stirring. The reaction mixture was stirred for one hour and washed with water, then sodium bisulfite, again with water, dried over magnesium sulfate and concentrated in vacuo to yield a yellow solid. The yellow solid was slurried in anhydrous diethyl ether to yield 1-(4-fluorophenyl)-2-(4-bromophenyl)-2,3-dihydro-1H-2,1-benzazaphosphole-1-oxide (0.7 g, 56.4% yield) as a white solid having a melting point of 201°-205° C. and the following analysis:
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([NH:9][CH:10]([C:12]2[CH:13]=[C:14]([C:30]([OH:32])=O)[CH:15]=[C:16]3[C:21]=2[O:20][C:19]([N:22]2[CH2:27][CH2:26][O:25][CH2:24][C@@H:23]2[CH3:28])=[CH:18][C:17]3=[O:29])[CH3:11])[CH:5]=[C:6]([F:8])[CH:7]=1.[CH3:33][NH:34][CH3:35].CN1CCOCC1>CN(C=O)C>[F:8][C:6]1[CH:5]=[C:4]([NH:9][CH:10]([C:12]2[CH:13]=[C:14]([C:30]([N:34]([CH3:35])[CH3:33])=[O:32])[CH:15]=[C:16]3[C:21]=2[O:20][C:19]([N:22]2[CH2:27][CH2:26][O:25][CH2:24][C@@H:23]2[CH3:28])=[CH:18][C:17]3=[O:29])[CH3:11])[CH:3]=[C:2]([F:1])[CH:7]=1
Reactant: CC(Nc1cc(F)cc(F)c1)c1cc(C(=O)O)cc2c(=O)cc(N3CCOC[C@@H]3C)oc12
Reactant: CNC
Solvent: CN1CCOCC1
Solvent: CN(C)C=O
Product: CC(Nc1cc(F)cc(F)c1)c1cc(C(=O)N(C)C)cc2c(=O)cc(N3CCOC[C@@H]3C)oc12
Temperature: 25 °C
Reaction time: 1 h
Yield: 59.7 %

Procedure:
2-(1H-benzo[d][1,2,3]triazol-1-yl)-1,1,3,3-tetramethylisouronium tetrafluoroborate (55.6 mg, 0.17 mmol), was added in one portion to a stirred solution of 8-(1-(3,5-difluorophenylamino)ethyl)-2-((S)-3-methylmorpholino)-4-oxo-4H-chromene-6-carboxylic acid (70 mg, 0.16 mmol), dimethylamine (0.095 mL, 0.19 mmol) and 4-methylmorpholine (0.038 mL, 0.35 mmol) in DMF (1 mL). The resulting solution was stirred at RT for 1 hour. The reaction mixture was purified by preparative HPLC using a reverse-phase column (C-18, 5 microns silica, 19 mm diameter, 100 mm length, flow rate of 40 mL/minute) and decreasingly polar mixtures of water (containing 0.2% ammonium carbonate) and acetonitrile as eluent. The fractions containing the desired compound were evaporated to dryness to afford a residue which was triturated with Et2O, filtered and dried to give 8-(1-(3,5-difluorophenylamino)ethyl)-N,N-dimethyl-2-((S)-3-methylmorpholino)-4-oxo-4H-chromene-6-carboxamide (45 mg, 61%) as a pale orange solid. Mass Spectrum: M+H+ 471. NMR Spectrum (CDCl3): 1.37 (d, 1.5H), 1.41 (d, 1.5H), 1.59 (d, 1.5H), 1.60 (d, 1.5H), 2.89 (s, 1.5H), 2.91 (s, 1.5H), 3.08 (s, 3H), 3.35-3.43 (m, 1H), 3.52-3.69 (m, 2H), 3.75-3.83 (m, 2H), 3.98-4.09 (m, 2H), 4.52 (d, 1H), 4.85-4.96 (m, 1H), 5.53 (s, 1H), 5.97 (d, 2H), 6.11 (t, 1H), 7.71 (d, 0.5H), 7.73 (d, 0.5H), 8.13 (d, 1H).
Reaction SMILES: [CH3:1][C:2]1[C:3]([CH2:14][S:15][C:16]2[NH:20][C:19]3[CH:21]=[CH:22][CH:23]=[CH:24][C:18]=3[N:17]=2)=[N:4][CH:5]=[CH:6][C:7]=1[O:8][CH2:9][C:10]([F:13])([F:12])[F:11].[OH-].[Na+].ClN1C(=[O:33])CCC1=O.S([O-])([O-])(=O)=S.[Na+].[Na+].[Cl-].[Na+]>C(#N)C.CN(C)C=O.C(OCC)(=O)C.C(O)(=O)C.O>[CH3:1][C:2]1[C:3]([CH2:14][S:15]([C:16]2[NH:17][C:18]3[CH:24]=[CH:23][CH:22]=[CH:21][C:19]=3[N:20]=2)=[O:33])=[N:4][CH:5]=[CH:6][C:7]=1[O:8][CH2:9][C:10]([F:12])([F:11])[F:13]
Reactant: Cc1c(OCC(F)(F)F)ccnc1CSc1nc2ccccc2[nH]1
Reactant: O=C1CCC(=O)N1Cl
Agent: O=S([O-])([O-])=S
Agent: [Cl-]
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CCOC(C)=O
Solvent: CC#N
Product: Cc1c(OCC(F)(F)F)ccnc1CS(=O)c1nc2ccccc2[nH]1
Reaction time: 0.03 h
Yield: 84.2 %

Procedure:
2-{[3-Methyl-4-(2,2,2-trifluoroethoxy)pyridin-2-yl]methylthio}-1H-benzimidazole (1.0 g, 2.83 mmol) was suspended in 8 ml of acetonitrile, followed by the addition of 3.5 ml of a 2N aqueous solution of sodium hydroxide. A solution (2 ml) of N-chlorosuccinimide (453 mg, 3.40 mmol) in N,N-dimethylformamide was added dropwise to the solution at −4° C. to 3° C. The reaction mixture was subsequently reacted at −3° C. to 0° C. for 1.5 hr. To the reaction mixture was added a 10% aqueous solution of sodium thiosulfate (2 ml) was added to the reaction mixture and the resulting mixture was stirred for 2 min, followed by the addition of water (20 ml) and acetic acid (0.4 ml) to adjust the solution to about pH 8.5. Ethyl acetate (20 ml) and sodium chloride (3 g) were added thereto to extract and the aqueous layer was further extracted with ethyl acetate (10 ml). The organic layers were combined, washed with a 15% aqueous solution of sodium chloride (10 ml) for three times, and the solvent was evaporated. Ethyl acetate (3 ml), hexane (7 ml) and toluene (2.5 ml) were added to the resulting oil, and then stirred at room temperature for 1 hr. The resulting crystals were collected by filtration, washed with a solvent mixture (3 ml) of 30% ethyl acetate and hexane for two times, and then dried under reduced pressure, to give the title compound (0.88 g, yield; 84.1%) as grayish white crystals. 1H-NMR (400 MHz, DMSO-d6); δ (ppm) 2.16(s, 3H), 4.74(d,J=13.7 Hz, 1H), 4.87(d,J=13.7 Hz, 1H), 4.88(d,J=8.8 Hz, 1H), 4.91(d,J=8.8 Hz, 1H), 7.08(d,J=5.9 Hz, 1H), 7.29(m, 2H), 7.56(m, 1H), 7.70(m, 1H), 8.27(d,J=5.9 Hz, 1H), 13.55(s, 1H).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][CH2:6][CH2:5]2.C[Al](C)C.[CH:15]1([N:20]2[C:32]3[C:31]4[CH:30]=[CH:29][C:28]([C:33](OC)=[O:34])=[CH:27][C:26]=4[NH:25][C:24](=[O:37])[C:23]=3[CH:22]=[N:21]2)[CH2:19][CH2:18][CH2:17][CH2:16]1.Cl.N>C1(C)C=CC=CC=1.C(OCC)(=O)C.O>[Cl:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[N:7]([C:33]([C:28]1[CH:29]=[CH:30][C:31]3[C:32]4[N:20]([CH:15]5[CH2:16][CH2:17][CH2:18][CH2:19]5)[N:21]=[CH:22][C:23]=4[C:24](=[O:37])[NH:25][C:26]=3[CH:27]=1)=[O:34])[CH2:6][CH2:5]2
Reactant: Clc1ccc2c(c1)CCN2
Reactant: COC(=O)c1ccc2c(c1)[nH]c(=O)c1cnn(C3CCCC3)c12
Agent: C[Al](C)C
Agent: Cl
Agent: N
Solvent: CCOC(C)=O
Solvent: Cc1ccccc1
Solvent: O
Product: O=C(c1ccc2c(c1)[nH]c(=O)c1cnn(C3CCCC3)c12)N1CCc2cc(Cl)ccc21
Temperature: 70 °C
Reaction time: 8 h
Yield: 46.7 %

Procedure:
Under a nitrogen atmosphere, to a solution of 148 mg of 5-chloroindoline in 1 mL of toluene was added 0.54 mL of a 1.8 M trimethylaluminum solution in toluene at 0° C., followed by stirring at room temperature for 2 hours (solution A). Under a nitrogen atmosphere, to a mixture of 100 mg of methyl 1-cyclopentyl-4-oxo-4,5-dihydro-1H-pyrazolo[4,3-c]quinoline-7-carboxylate and 3 mL of toluene was added the solution A, followed by stirring at 70° C. for 8 hours. After cooling to room temperature, to the reaction mixture was added diluted hydrochloric acid, and the mixture was poured into a mixture of water and ethyl acetate. The pH was adjusted to 10 with 28% aqueous ammonia. The insoluble material was separated by filtration. The aqueous layer was separated, the organic layer was washed with saturated brine and then dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The obtained residue was purified by silica gel column chromatography (chloroform/methanol=100/0-92/8) to obtain 65 mg of 7-[(5-chloro-2,3-dihydro-1H-indol-1-yl)carbonyl]-1-cyclopentyl-1,5-dihydro-4H-pyrazolo[4,3-c]quinolin-4-one as white powder.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]2[CH2:20][CH2:19][N:18]([C:21]([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:22])[CH2:17][CH:16]=2)=[CH:11][C:10]=1[F:28])=[O:7])([CH3:4])([CH3:3])[CH3:2]>CCOC(C)=O.[Pd]>[C:1]([O:5][C:6]([NH:8][C:9]1[CH:14]=[CH:13][C:12]([CH:15]2[CH2:16][CH2:17][N:18]([C:21]([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:22])[CH2:19][CH2:20]2)=[CH:11][C:10]=1[F:28])=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)OC(=O)Nc1ccc(C2=CCN(C(=O)OC(C)(C)C)CC2)cc1F
Agent: [Pd]
Solvent: CCOC(C)=O
Product: CC(C)(C)OC(=O)Nc1ccc(C2CCN(C(=O)OC(C)(C)C)CC2)cc1F
Temperature: 25 °C
Reaction time: 16 h

Procedure:
A mixture of tert-butyl 4-(4-((tert-butoxycarbonyl)amino)-3-fluorophenyl)-5,6-dihydropyridine-1(2H)-carboxylate (I53) (0.409 g, 1.04 mmol) and 10% Pd/C (0.043 g) in EtOAc (20 mL) was stirred for 16 hours at room temperature under a H2 atmosphere. The mixture was filtered through celite and the filtrate concentrated under reduced pressure to give the title compound (I54) (0.376 g, 92%) as a white foam; 1H NMR (400 MHz, CDCl3) δ 7.09 (dd, J=8.1, 8.1 Hz, 1H), 6.95 (m, 2H), 4.25 (m, 2H), 2.79 (dd, J=12.0, 12.0 Hz, 2H), 2.65 (m, 1H), 1.82 (m, 2H), 1.43 (s, 18H).
Reaction SMILES: [CH3:1][C:2]1([CH3:21])[CH:11]([OH:12])[C:10]2[C:5](=[CH:6][CH:7]=[C:8]([C:14]([O:16][CH2:17][CH3:18])=[O:15])[C:9]=2[CH3:13])[S:4](=[O:20])(=[O:19])[CH2:3]1.[CH3:22][S:23](Cl)(=[O:25])=[O:24]>N1C=CC=CC=1>[CH3:21][C:2]1([CH3:1])[CH:11]([O:12][S:23]([CH3:22])(=[O:25])=[O:24])[C:10]2[C:5](=[CH:6][CH:7]=[C:8]([C:14]([O:16][CH2:17][CH3:18])=[O:15])[C:9]=2[CH3:13])[S:4](=[O:20])(=[O:19])[CH2:3]1
Reactant: CS(=O)(=O)Cl
Reactant: CCOC(=O)c1ccc2c(c1C)C(O)C(C)(C)CS2(=O)=O
Solvent: c1ccncc1
Product: CCOC(=O)c1ccc2c(c1C)C(OS(C)(=O)=O)C(C)(C)CS2(=O)=O
Reaction time: 8 h
Yield: 96.5 %

Procedure:
4.1 Grams (13 mmol)of 3,3,5-trimethyl-4-hydroxy-6-ethoxycarbonylthiochroman-1,1-dioxide was dissolved in 15 ml of pyridine, and the mixture was cooled in an ice bath. 1.8 Grams (16 mmol, 1.2 eq.) of methanesulfonyl chloride was gradually added thereto. After the addition, the ice bath was removed, and the mixture was allowed to stand overnight. The reaction mixture was diluted with 200 ml of ethyl acetate, and washed with 200 ml of water, with 150 ml of a 1 wt % hydrochloric acid aqueous solution twice, with 150 ml of a saturated sodium hydrogencarbonate aqueous solution and with 50 ml of water in this order. An organic layer was dried over sodium sulfate, the solvent was distilled off, and the residue was dried under reduced pressure to give 4.9 g (yield 97%) of a brownish oil. The brownish oil solidified after allowed to stand overnight.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][N:3]=1.CCCCCC.C([Li])CCC.FC(F)(F)S(O[C:25]1[C:30]2[CH:31]=[C:32]([N+:35]([O-:37])=[O:36])[CH:33]=[CH:34][C:29]=2[O:28][C:27]([C:42]([F:45])([F:44])[F:43])([C:38]([F:41])([F:40])[F:39])[CH:26]=1)(=O)=O.O>O1CCCC1.[Cl-].[Zn+2].[Cl-].C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[F:44][C:42]([F:43])([F:45])[C:27]1([C:38]([F:39])([F:41])[F:40])[CH:26]=[C:25]([C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][N:3]=2)[C:30]2[CH:31]=[C:32]([N+:35]([O-:37])=[O:36])[CH:33]=[CH:34][C:29]=2[O:28]1
Reactant: Brc1ccccn1
Reactant: O=[N+]([O-])c1ccc2c(c1)C(OS(=O)(=O)C(F)(F)F)=CC(C(F)(F)F)(C(F)(F)F)O2
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [Cl-]
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: O
Solvent: CCCCCC
Product: O=[N+]([O-])c1ccc2c(c1)C(c1ccccn1)=CC(C(F)(F)F)(C(F)(F)F)O2
Temperature: -78 °C
Reaction time: 0.5 h

Procedure:
To 5 ml of dry tetrahydrofuran solution 0 containing 0.16 ml of 2-bromopyridine was added dropwise 1.0 ml of 1.61M n-butyllithium hexane solution under nitrogen atmosphere at -78° C. After 30 minutes, 3.2 ml of solution of 0.5M zinc chloride in dry tetrahydrofuran was added thereto and the mixture was stirred at -78° C. for 15 minutes and under ice-cooling for 15 minutes. Then, the solution of 50 mg of tetrakis(triphenylphosphine)palladium (0) and 300 mg of 4-trifluoromethanesulfonyloxy-2,2-bistrifluoromethyl-6-nitro-2H-1-benzopyran dissolved in 5 ml of dry tetrahydrofuran was added under ice-cooling to the mixture obtained above. The resultant mixture was warmed to room temperature and stirred for additional 15 hours. Water was added to the reaction mixture which was then extracted with ethyl acetate. The organic layer was washed with water and dried. The solvent was distilled off and the resultant residue was purified using silica gel column chromatography (developing solution, CH2Cl2 :hexane=1:1) to obtain 200 mg of 2,2-bistrifluoromethyl-6-nitro-4-(2-pyridyl)-2H-1-benzopyran represented by the following formula having a melting point of 105°-107° C.
Reaction SMILES: [F:1][C:2]1[C:7]([S:8]([C:11]([F:14])([F:13])[F:12])(=[O:10])=[O:9])=[CH:6][CH:5]=[CH:4][C:3]=1[CH:15]1[CH2:20][CH2:19][NH:18][CH2:17][CH2:16]1.[C:21](=O)([O-])[O-].[K+].[K+].IC>C(#N)C>[F:1][C:2]1[C:7]([S:8]([C:11]([F:14])([F:13])[F:12])(=[O:9])=[O:10])=[CH:6][CH:5]=[CH:4][C:3]=1[CH:15]1[CH2:20][CH2:19][N:18]([CH3:21])[CH2:17][CH2:16]1
Reactant: O=S(=O)(c1cccc(C2CCNCC2)c1F)C(F)(F)F
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: CI
Solvent: CC#N
Product: CN1CCC(c2cccc(S(=O)(=O)C(F)(F)F)c2F)CC1

Procedure:
Preparation according to Example 18: 4-{2-fluoro-3-[(trifluoromethyl)sulfonyl]phenyl}-piperidine (0.01 g), acetonitrile (2 ml), potassium carbonate (0.01 g) and iodomethane (0.01 g). MS m/z (rel. intensity, 70 eV) 325 (M+, 63), 324 (bp), 305 (13), 191 (32), 133 (24).
Reaction SMILES: [NH2:1][N:2]1[CH2:7][CH2:6][CH:5]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[CH2:4][CH2:3]1.C([O:22][C@@H:23]1[C@H:27]([O:28]C(=O)C2C=CC=CC=2)[C@@H:26]([CH2:37][O:38]C(=O)C2C=CC=CC=2)[O:25][C@H:24]1[N:47]1[CH:55]=[N:54][C:53]2[C:48]1=[N:49][C:50]([Cl:57])=[N:51][C:52]=2Cl)(=O)C1C=CC=CC=1.N>>[Cl:57][C:50]1[N:51]=[C:52]([NH:1][N:2]2[CH2:7][CH2:6][CH:5]([C:8]3[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=3)[CH2:4][CH2:3]2)[C:53]2[N:54]=[CH:55][N:47]([C:48]=2[N:49]=1)[C@@H:24]1[O:25][C@H:26]([CH2:37][OH:38])[C@@H:27]([OH:28])[C@H:23]1[OH:22]
Reactant: O=C(OC[C@H]1O[C@@H](n2cnc3c(Cl)nc(Cl)nc32)[C@H](OC(=O)c2ccccc2)[C@@H]1OC(=O)c1ccccc1)c1ccccc1
Reactant: NN1CCC(c2ccccc2)CC1
Agent: N
Product: OC[C@H]1O[C@@H](n2cnc3c(NN4CCC(c5ccccc5)CC4)nc(Cl)nc32)[C@H](O)[C@@H]1O
Yield: 35.4 %

Procedure:
The title compound was prepared according to method A as described above by reacting 1-amino-4-phenylpiperidine (prepared as outlined in Example 6) (0.77 g, 3.6 mmol) with 9-(2',3',5'-tri-O-benzoyl-β-D-ribofuranosyl)-2,6-dichloro-9H-purine (1.90 g, 3.0 mmol), followed by debenzoylation of the purified product using methanolic ammonia. This provided the title 2-chloro-N-(4-phenyl-1-piperidinyl)adenosine (0.49 g, 37%) as a solid which precipitated on evaporation of column chromatography fractions, mp 142°-149° C. 1H NMR (DMSO-d6) δ 3.53-3.60 (1H, m, H-5'a), 3.63-3.70 (1H, m, H-5'b), 3.95 (1H, q, H-4'), 4.13 (1H, q, H-3'), 4.51 (1H, q, H-2'), 5.07 (1H, t, 5'-0H), 5.22, 5.50 (2H, 2d, 2'- and 3'-OH), 5.84 (1H, d, H-1'), 7.18-7.35 (5H, 2m, Ar--H), 8.43 (1H, s, H-8) 9.45 (1H, s, N--H).
Reaction SMILES: [C:1](=[O:35])([O:33][CH3:34])[O:2][C:3]1[CH:8]=[C:7]([NH:9][C:10]([CH:12]2[O:17][C:16]3[CH:18]=[CH:19][C:20]([O:22][C:23]([F:26])([F:25])[F:24])=[CH:21][C:15]=3[NH:14][CH2:13]2)=[O:11])[C:6](Br)=[CH:5][C:4]=1[CH:28]1[CH2:32][CH2:31][CH2:30][CH2:29]1.C(N(CC)CC)C.[CH2:43]([OH:46])[C:44]#[CH:45].C([O-])(O)=O.[Na+]>CN(C=O)C.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.[Cu]I>[C:1](=[O:35])([O:33][CH3:34])[O:2][C:3]1[CH:8]=[C:7]([NH:9][C:10]([CH:12]2[O:17][C:16]3[CH:18]=[CH:19][C:20]([O:22][C:23]([F:26])([F:25])[F:24])=[CH:21][C:15]=3[NH:14][CH2:13]2)=[O:11])[C:6]([C:45]#[C:44][CH2:43][OH:46])=[CH:5][C:4]=1[CH:28]1[CH2:32][CH2:31][CH2:30][CH2:29]1
Reactant: C#CCO
Reactant: COC(=O)Oc1cc(NC(=O)C2CNc3cc(OC(F)(F)F)ccc3O2)c(Br)cc1C1CCCC1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Agent: O=C([O-])O
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: COC(=O)Oc1cc(NC(=O)C2CNc3cc(OC(F)(F)F)ccc3O2)c(C#CCO)cc1C1CCCC1
Temperature: 80 °C
Yield: 52.9 %

Procedure:
4-Bromo-2-cyclopentyl-5-(6-(trifluoromethoxy)-3,4-dihydro-2H-benzo[b][1,4]oxazine-2-carboxamido)phenyl methyl carbonate (812 mg, 1.45 mmol), triethylamine (2.0 mL, 14.52 mmol), prop-2-yn-1-ol (326 mg, 338 μL, 5.81 mmol), PdCl2(PPh3)2 (204 mg, 0.29 mmol), and CuI (69 mg, 0.36 mmol) were combined in DMF (6 mL) and heated at 80° C. for 1 h. The mixture was added to 300 mL of saturated aqueous NaHCO3 and then extracted with dichloromethane (3×70 mL). The organic fractions were combined, dried over MgSO4, and concentrated in vacuo. Purification by silica gel chromatography (0-100% ethyl acetate/hexanes) yielded 2-cyclopentyl-4-(3-hydroxyprop-1-ynyl)-5-(6-(trifluoromethoxy)-3,4-dihydro-2H-benzo[b][1,4]oxazine-2-carboxamido)phenyl methyl carbonate (410 mg, 53% yield). LC/MS m/z 535.4 [M+H]+.
Reaction SMILES: [Cl:1][C:2]1[C:7]([Cl:8])=[CH:6][CH:5]=[CH:4][C:3]=1[SH:9].[OH-].[K+].I[C:13]1[CH:21]=[CH:20][CH:19]=[CH:18][C:14]=1[C:15]([OH:17])=[O:16]>CN(C=O)C>[Cl:1][C:2]1[C:7]([Cl:8])=[CH:6][CH:5]=[CH:4][C:3]=1[S:9][C:13]1[CH:21]=[CH:20][CH:19]=[CH:18][C:14]=1[C:15]([OH:17])=[O:16]
Reactant: Sc1cccc(Cl)c1Cl
Reactant: O=C(O)c1ccccc1I
Agent: [K+]
Agent: [OH-]
Solvent: CN(C)C=O
Product: O=C(O)c1ccccc1Sc1cccc(Cl)c1Cl
Temperature: 25 °C

Procedure:
FIG. 2 is a flow chart for manufacturing the compound No. 1. First, 2,3-dichlorobenzenethiol (0.90 g, 5 mmol) is dissolved in 10 ml DMF solution, and 10 ml of 1N KOH(aq) is added thereinto. After stirring the mixture under room temperature for 10˜15 minutes, 2-iodobenzoic acid (1.24 g, 5 mmol) is dissolved in 10 ml of DMF solution. And then, 0.315 g of Cupper powder is added into the mixture, and the mixture is treated by a reverse flow under 120□ for 8 hours. After filtering the mixture, the filtrate is neutralized with 10 ml of 1N HCl(aq), and a precipitate will be produced. After filtering and washing the precipitate by water, 2-(2,3-dichlorophenylthio)benzoic acid is obtained.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([NH:8][C:9]2[CH:14]=[CH:13][C:12]([F:15])=[CH:11][C:10]=2[F:16])[CH:5]=[CH:4][C:3]=1[C:17]([C:19]1[CH:24]=[C:23](I)[CH:22]=[CH:21][C:20]=1[CH3:26])=[O:18].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[C:46]([Si:48]([CH3:51])([CH3:50])[CH3:49])#[CH:47]>C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd].[Cu]I>[Cl:1][C:2]1[CH:7]=[C:6]([NH:8][C:9]2[CH:14]=[CH:13][C:12]([F:15])=[CH:11][C:10]=2[F:16])[CH:5]=[CH:4][C:3]=1[C:17]([C:19]1[CH:24]=[C:23]([C:47]#[C:46][Si:48]([CH3:51])([CH3:50])[CH3:49])[CH:22]=[CH:21][C:20]=1[CH3:26])=[O:18]
Reactant: Cc1ccc(I)cc1C(=O)c1ccc(Nc2ccc(F)cc2F)cc1Cl
Reactant: C#C[Si](C)(C)C
Agent: [Cu]I
Agent: [Pd]
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Product: Cc1ccc(C#C[Si](C)(C)C)cc1C(=O)c1ccc(Nc2ccc(F)cc2F)cc1Cl
Temperature: 90 °C
Reaction time: 20 h

Procedure:
In a screw-capped vial (8 mL) was placed dry degassed triethylamine (4.0 mL) and a magnetic stirrer under argon. Compound 495 (100 mg, 0.21 mmol), Pd2(dba)3 (3.8 mg), triphenyl phosphine (5.4 mg, 0.02 mmol), CuI (1 mg) and ethynyl-trimethyl-silane (29 μL, 0.21 mmol) were added to the vial and the reaction mixture was heated under vigorously stirring at 90° C. for 20 h. The cooled reaction mixture was filtered through Decalite and concentrated in vacuo. The crude product was purified by continuous gradient flash chromatography using EtOAc/petroleum ether (40-60) (v:v=0:100 to 10:90) as the eluent to afford the title compound as foam.
Reaction SMILES: [NH2:1][C:2]1[C:11]2[N:10]=[CH:9][C:8]([CH2:12][CH2:13][C:14]3[CH:19]=[CH:18][C:17]([OH:20])=[CH:16][C:15]=3[CH3:21])=[CH:7][C:6]=2[C:5]2[CH:22]=[CH:23][C:24]([CH3:26])=[CH:25][C:4]=2[N:3]=1.Br[CH2:28][CH2:29][CH2:30][CH3:31]>>[CH2:28]([O:20][C:17]1[CH:18]=[CH:19][C:14]([CH2:13][CH2:12][C:8]2[CH:9]=[N:10][C:11]3[C:6]([CH:7]=2)=[C:5]2[CH:22]=[CH:23][C:24]([CH3:26])=[CH:25][C:4]2=[N:3][C:2]=3[NH2:1])=[C:15]([CH3:21])[CH:16]=1)[CH2:29][CH2:30][CH3:31]
Reactant: Cc1ccc2c(c1)nc(N)c1ncc(CCc3ccc(O)cc3C)cc12
Reactant: CCCCBr
Product: CCCCOc1ccc(CCc2cnc3c(N)nc4cc(C)ccc4c3c2)c(C)c1

Procedure:
2-(4-Butoxy-2-methylphenethyl)-8-methylbenzo[f][1,7]naphthyridin-5-amine was prepared following an analogous procedure to the preparation described for Example 139, but using 4-(2-(5-amino-8-methylbenzo[f][1,7]naphthyridin-2-yl)ethyl)-3-methylphenol (from Example 50) with 1-bromobutane. 1H NMR (Acetone-d6): δ 8.75 (s, 1H), 8.71 (s, 1H), 8.28 (d, 1H), 7.43 (s, 1H), 7.15 (d, 1H), 7.07 (d, 1H), 6.75 (s, 1H), 6.69 (d, 1H), 6.54 (br, 2H) 3.95 (t, 2H), 3.16 (t, 2H), 3.04 (t, 2H), 2.47 (s, 3H), 2.30 (s, 3H), 1.69-1.77 (m, 2H), 1.43-1.54 (m, 2H), 0.97 (t, 3H). LRMS [M+H]=400.2
Reaction SMILES: [N:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[C:3]([CH:11]([OH:20])[C:12]2[N:13]=[CH:14][N:15]3[CH:19]=[CH:18][S:17][C:16]=23)[CH:2]=1.[CH2:21]([Sn:25](Cl)([CH2:30][CH2:31][CH2:32][CH3:33])[CH2:26][CH2:27][CH2:28][CH3:29])[CH2:22][CH2:23][CH3:24].C[Si]([N-][Si](C)(C)C)(C)C.[Li+].C1COCC1>[O-2].[O-2].[Mn+4]>[N:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[C:3]([C:11]([C:12]2[N:13]=[CH:14][N:15]3[CH:19]=[C:18]([Sn:25]([CH2:26][CH2:27][CH2:28][CH3:29])([CH2:30][CH2:31][CH2:32][CH3:33])[CH2:21][CH2:22][CH2:23][CH3:24])[S:17][C:16]=23)=[O:20])[CH:2]=1
Reactant: OC(c1cnc2ccccc2c1)c1ncn2ccsc12
Reactant: CCCC[Sn](Cl)(CCCC)CCCC
Agent: [Mn+4]
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: C1CCOC1
Product: CCCC[Sn](CCCC)(CCCC)c1cn2cnc(C(=O)c3cnc4ccccc4c3)c2s1

Procedure:
A ketone compound (327 mg) was prepared in substantially the same manner as in step b) of Synthesis Example 1, except that 577 mg of 7-[(quinolin-3-yl)hydroxymethyl]imidazo[5,1-b]thiazole and 421 mg of manganese dioxide were used as the starting compounds. 7-(Quinolin-3-yl)carbonyl-2-(tri-n-butylstannyl)imidazo-[5,1-b]thiazole (73 mg) was prepared in substantially the same manner as in step c) of Synthesis Example 1, except that 64 mg of the ketone compound, 0.140 ml of tri-n-butylstannyl chloride, and 1.50 ml of a 1.0 N lithium bis(trimethylsilyl)amide/THF solution were used as the starting materials.