Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]1([C:13]2[C:14](=[O:28])[NH:15][C:16](=S)[C:17]=2[C:18]2[C:26]3[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=3)[NH:20][CH:19]=2)[C:11]2=[C:12]3[C:7](=[CH:8][CH:9]=[CH:10]2)[CH2:6][CH2:5][CH2:4][N:3]3[CH:2]=1>CO.[Ni]>[C:1]1([C:13]2[C:14](=[O:28])[NH:15][CH2:16][C:17]=2[C:18]2[C:26]3[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=3)[NH:20][CH:19]=2)[C:11]2=[C:12]3[C:7](=[CH:8][CH:9]=[CH:10]2)[CH2:6][CH2:5][CH2:4][N:3]3[CH:2]=1
Reactant: O=C1NC(=S)C(c2c[nH]c3ccccc23)=C1c1cn2c3c(cccc13)CCC2
Agent: [Ni]
Solvent: CO
Product: O=C1NCC(c2c[nH]c3ccccc23)=C1c1cn2c3c(cccc13)CCC2
Yield: 50 %

Procedure:
To a solution of 3-(5,6-dihydro-4H-pyrrolo[3,2,1-ij]quinolin-1-yl)-4-(1H-indol-3-yl)-5-thioxo-1,5-dihydro-pyrrol-2-one (4.7 g, 12 mmol) in MeOH (75 mL) under N2, with stirring, was added Raney nickel. The mixture was filtered under N2 and the filtrate evaporated. The residue obtained was purified by column chromatography (SiO2, EtOAc/hexanes), yielding 3-(5,6-dihydro-4H-pyrrolo[3,2,1-ij]quinolin-1-yl)-4-(1H-indol-3-yl)-1,5-dihydro-pyrrol-2-one as an off-white solid (2.2 g, 6 mmol, 51%). 1H NMR (400 MHz, DMSO) δ: 11.33 (s, 1H), 8.19 (s, 1H), 7.55 (s, 1H), 7.37 (dd, J=8.0, 6.0 Hz, 2H), 7.30 (d, J=2.8 Hz, 1H), 7.07 (t, J=7.6 Hz, 1H), 6.90 (t, J=8.0 Hz, 1H), 6.76 (d, J=6.4 Hz, 1H), 6.62 (m, 2H), 4.53 (s, 2H), 4.20 (t, J=5.6 Hz, 2H), 2.94 (t, J=5.6 Hz, 2H), 2.17 (m, 1H), 1.17 (m, 1H); LCMS: 354 [M+H].
Reaction SMILES: [NH2:1][C:2]1[C:3]([NH:23][C:24]2[CH:29]=[CH:28][C:27]([N:30]([CH3:38])[C:31](=[O:37])[O:32][C:33]([CH3:36])([CH3:35])[CH3:34])=[CH:26][CH:25]=2)=[N:4][CH:5]=[N:6][C:7]=1[N:8]([CH2:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)[CH2:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1.Cl[C:40](Cl)([O:42]C(=O)OC(Cl)(Cl)Cl)Cl>C(Cl)Cl>[CH2:16]([N:8]([CH2:9][C:10]1[CH:11]=[CH:12][CH:13]=[CH:14][CH:15]=1)[C:7]1[N:6]=[CH:5][N:4]=[C:3]2[C:2]=1[NH:1][C:40](=[O:42])[N:23]2[C:24]1[CH:25]=[CH:26][C:27]([N:30]([CH3:38])[C:31](=[O:37])[O:32][C:33]([CH3:34])([CH3:35])[CH3:36])=[CH:28][CH:29]=1)[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1
Reactant: CN(C(=O)OC(C)(C)C)c1ccc(Nc2ncnc(N(Cc3ccccc3)Cc3ccccc3)c2N)cc1
Reactant: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Solvent: ClCCl
Product: CN(C(=O)OC(C)(C)C)c1ccc(-n2c(=O)[nH]c3c(N(Cc4ccccc4)Cc4ccccc4)ncnc32)cc1
Reaction time: 1 h
Yield: 217.4 %

Procedure:
To a stirred solution of tert-butyl 4-(5-amino-6-(dibenzylamino)pyrimidin-4-ylamino)phenyl(methyl)carbamate (38) (5.4 g, 10.6 mmol) and TEA (2.14 g, 21.2 mmol) in dry DCM (60 mL) at 0° C. and under N2 atmosphere, was added a solution of triphosgene (1.07 g, 3.6 mmol) in dry DCM (30 mL) dropwise during 1 h. Stirring was continued for 1 h before the reaction was quenched with water (20 mL). The organic layer was separated, washed with water and brine, dried over Na2SO4, and concentrated in vacuo. The residue was purified by column chromatography (silica gel, 0 to 20% ethyl acetate in petroleum ether) to give tert-butyl 4-(6-(dibenzylamino)-8-oxo-7H-purin-9(8H)-yl)phenyl(methyl)carbamate (39) (4.2 g, 74%) as a light brown solid. LC-MS (ESI): m/z (M+1) 537.
Reaction SMILES: [Br:1][C:2]1[N:3]=[C:4]([NH2:9])[C:5]([NH2:8])=[N:6][CH:7]=1.[CH:10]1([C:13]2[N:18]=[C:17]([C:19](=N)OCC)[CH:16]=[CH:15][N:14]=2)[CH2:12][CH2:11]1.C(N(CC)CC)C.C(O)(=O)C>C(O)C>[Br:1][C:2]1[N:3]=[C:4]2[NH:9][C:19]([C:17]3[CH:16]=[CH:15][N:14]=[C:13]([CH:10]4[CH2:12][CH2:11]4)[N:18]=3)=[N:8][C:5]2=[N:6][CH:7]=1
Reactant: CCOC(=N)c1ccnc(C2CC2)n1
Reactant: Nc1ncc(Br)nc1N
Solvent: CCN(CC)CC
Solvent: CCO
Solvent: CC(=O)O
Product: Brc1cnc2nc(-c3ccnc(C4CC4)n3)[nH]c2n1
Temperature: 100 °C
Yield: 22.1 %

Procedure:
A mixture of 5-bromopyrazine-2,3-diamine (50 mg, 0.3 mmol) and ethyl 2-cyclopropylpyrimidine-4-carbimidate (Intermediate 19, 50.7 mg, 0.3 mmol), triethylamine (73.8 μL, 0.5 mmol), acetic acid (244 μL, 4.2 mmol) and ethanol (0.8 mL) was heated to 100° C. for 30 min. The mixture was concentrated and diluted with water. Then a saturated aqueous solution of sodium bicarbonate was added and the mixture was extracted with ethyl acetate. The organics were washed with brine, dried over sodium sulfate, and concentrated under reduced pressure. The crude material was purified via flash chromatography (0-5% methanol in dichloromethane) to afford 6-bromo-2-(2-cyclopropylpyrimidin-4-yl)-1H-imidazo[4,5-b]pyrazine (21 mg, 25%).
Reaction SMILES: C(Cl)Cl.Br[C:5]1[CH:6]=[C:7]([N:11]2[CH2:16][CH2:15][N:14]([CH3:17])[CH2:13][CH2:12]2)[CH:8]=[CH:9][CH:10]=1.CCN(CC)CC.[CH3:25][C:26]1([CH3:33])[C:30]([CH3:32])([CH3:31])[O:29][BH:28][O:27]1>C1(C)C=CC=CC=1.Cl[Pd]Cl>[CH3:17][N:14]1[CH2:15][CH2:16][N:11]([C:7]2[CH:8]=[CH:9][CH:10]=[C:5]([B:28]3[O:29][C:30]([CH3:32])([CH3:31])[C:26]([CH3:33])([CH3:25])[O:27]3)[CH:6]=2)[CH2:12][CH2:13]1
Reactant: CC1(C)OBOC1(C)C
Reactant: CN1CCN(c2cccc(Br)c2)CC1
Agent: Cl[Pd]Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Solvent: Cc1ccccc1
Product: CN1CCN(c2cccc(B3OC(C)(C)C(C)(C)O3)c2)CC1

Procedure:
To a solution of PdCl2 (dppf). DCM (10 mg, 0.012 mmol) in anhydrous toluene (4 ml) in an argon filled sealed microwave tube was added the 1-(3-Bromo-phenyl)-4-methyl-piperazine (100 mg, 0.39 mmol), Et3N (0.11 ml, 2 equiv.), and 4,4,5,5-tetramethyl-1,3,2-dioxaborolane (0.09 ml, 1.5 equiv). The microwave tube was evacuated and backfilled with Argon before being irradiated in a CEM Microwave reactor at 100° C. for 1 hr using an initial power of 200 W. The reaction mixture was partitioned between more toluene (6 ml) and water (10 ml), the organic layer separated, washed with water (1×10 ml), dried over MgSO4 and then evaporated in vacuo to leave a purple/brown residue which was used for suzuki coupling without further purification.
Reaction SMILES: Cl.[NH:2]1[CH2:7][CH2:6][CH2:5][CH2:4][C@@H:3]1[CH2:8][OH:9].[H-].[Na+].Cl[C:13]1[C:21]2[C:20]3[CH:22]=[C:23]([C:26]#[N:27])[N:24]=[CH:25][C:19]=3[N:18]([CH2:28][O:29][CH2:30][CH2:31][Si:32]([CH3:35])([CH3:34])[CH3:33])[C:17]=2[N:16]=[CH:15][CH:14]=1>O1CCCC1.O.C(OCC)(=O)C>[NH:2]1[CH2:7][CH2:6][CH2:5][CH2:4][C@@H:3]1[CH2:8][O:9][C:13]1[C:21]2[C:20]3[CH:22]=[C:23]([C:26]#[N:27])[N:24]=[CH:25][C:19]=3[N:18]([CH2:28][O:29][CH2:30][CH2:31][Si:32]([CH3:35])([CH3:34])[CH3:33])[C:17]=2[N:16]=[CH:15][CH:14]=1
Reactant: C[Si](C)(C)CCOCn1c2cnc(C#N)cc2c2c(Cl)ccnc21
Reactant: OC[C@H]1CCCCN1
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: C[Si](C)(C)CCOCn1c2cnc(C#N)cc2c2c(OC[C@H]3CCCCN3)ccnc21
Temperature: 40 °C
Reaction time: 0.17 h

Procedure:
To a solution of (R)-piperidin-2-ylmethanol hydrogen chloride (510 mg, 3.4 mmol) in tetrahydrofuran (12 mL) was added sodium hydride as 60% dispersion in mineral oil (270 mg, 6.8 mmol). The reaction mixture was stirred at ambient temperature for 5 minutes before 4-chloro-9-(2-trimethylsilanyl-ethoxymethyl)-9H-dipyrido[2,3-b;4′,3′-d]pyrrole-6-carbonitrile (550 mg, 1.5 mmol) was added in one portion and the reaction mixture was stirred at this temperature for 10 minutes, and then heated at 40° C. for 5 hours. The cooled mixture was diluted with water (20 mL) and ethyl acetate (50 mL). The organic layer was separated, dried over sodium sulfate, filtered, concentrated in vacuo, and purified flash chromatography (silica, 40 g, ISCO, 1-20% methanol in methylene chloride) to afford the title compound as a white solid, which was used in the next step without any further purification (470 mg, 70%).
Reaction SMILES: [CH2:1]([N:8]([CH2:22][C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)[C@H:9]1[C@H:13](O)[CH2:12][N:11]([C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])[CH2:10]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(N(S(F)(F)[F:35])CC)C>ClCCl>[CH2:1]([N:8]([CH2:22][C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)[C@H:9]1[C@H:13]([F:35])[CH2:12][N:11]([C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])[CH2:10]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CCN(CC)S(F)(F)F
Reactant: CC(C)(C)OC(=O)N1C[C@@H](O)[C@H](N(Cc2ccccc2)Cc2ccccc2)C1
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N1C[C@@H](F)[C@H](N(Cc2ccccc2)Cc2ccccc2)C1
Yield: 67.8 %

Procedure:
To a dichloromethane solution (8.7 mL) of tert-butyl (3R,4R)-3-(dibenzylamino)-4-hydroxypyrrolidine-1-carboxylate (320 mg, 0.92 mmol) synthesized in Reference Synthesis Example 71, (diethylamino)sulfur trifluoride (295 mg, 1.84 mmol) was added at 0° C. and the resultant solution was stirred at room temperature. After completion of the reaction, the reaction solution was washed with water and saturated sodium bicarbonate aqueous solution. The organic layer was dried over anhydrous magnesium sulfate and concentrated under reduced pressure to obtain a crude product (240 mg) of the title compound. The crude product was used in the next reaction as it was.
Reaction SMILES: Br[C:2]1[C:3]([O:11][CH3:12])=[N:4][C:5]([N:8]([CH3:10])[CH3:9])=[N:6][CH:7]=1.[B:13](OC(C)C)([O:18]C(C)C)[O:14]C(C)C.C([Li])CCC.[Cl-].[NH4+]>C1COCC1>[CH3:9][N:8]([CH3:10])[C:5]1[N:4]=[C:3]([O:11][CH3:12])[C:2]([B:13]([OH:18])[OH:14])=[CH:7][N:6]=1
Reactant: COc1nc(N(C)C)ncc1Br
Reactant: CC(C)OB(OC(C)C)OC(C)C
Agent: [Cl-]
Agent: [Li]CCCC
Agent: [NH4+]
Solvent: C1CCOC1
Product: COc1nc(N(C)C)ncc1B(O)O
Temperature: -70 °C
Reaction time: 0.5 h
Yield: 61.8 %

Procedure:
To a solution of 5-bromo-4-methoxy-N,N-dimethylpyrimidin-2-amine (0.300 g, 1.29 mmol) and triisopropyl borate (0.416 mL, 1.81 mmol) in 7 mL of THF at −70° C. was added butyllithium (1.6 m in hexanes, 1.13 mL, 1.81 mmol) dropwise. The reaction stirred for 30 min at −70° C. and was allowed to warm up. At −20° C. ammonium chloride (sat.) was added. The mixture was extracted with ethyl acetate (3X). The combined organic layers were dried over anhydrous sodium sulfate, filtered and concentrated to give 250 mg of crude material, which was purified by column chromatography (5% MeOH in dichloromethane) to give 157 mg of 2-(dimethylamino)-4-methoxypyrimidin-5-ylboronic acid as a white solid. ES+=198.1 (M+H).
Reaction SMILES: C([N:8]1[CH:13]2[CH2:14][CH2:15][CH:9]1[CH2:10][C:11]([C:17]1[C:22]([Br:23])=[CH:21][N:20]=[CH:19][N:18]=1)([OH:16])[CH2:12]2)C1C=CC=CC=1.C([O-])=O.[NH4+]>O.[Pd]>[Br:23][C:22]1[C:17]([C:11]2([OH:16])[CH2:12][CH:13]3[NH:8][CH:9]([CH2:15][CH2:14]3)[CH2:10]2)=[N:18][CH:19]=[N:20][CH:21]=1
Reactant: OC1(c2ncncc2Br)CC2CCC(C1)N2Cc1ccccc1
Agent: [Pd]
Agent: O=C[O-]
Agent: [NH4+]
Solvent: O
Product: OC1(c2ncncc2Br)CC2CCC(C1)N2
Yield: 44 %

Procedure:
8-Benzyl-3-(5-bromo-pyrimidin-4-yl)-8-aza-bicyclo[3.2.1]octan-3-ol (0.90 g, 2.4 mmol) was dissolved in IMS (20 mL) and water (1 mL). Palladium on carbon (10%; 0.40 g) was added under nitrogen. Ammonium formate (1.5 g, 24 mmol) was added and the mixture heated at reflux for 0.5 hour. The mixture was allowed to cool, filtered and the solvent removed by evaporation under vacuum. The residues were passed through an SCX cartridge, eluting with 2 M ammonia in methanol to give the title compound as a colourless oil (0.30 g).
Reaction SMILES: [OH:1][CH2:2][C:3]([C@H:5]([C@@H:7]([C@@H:9]([CH2:11][OH:12])[OH:10])[OH:8])[OH:6])=O.C([NH2:20])C1C=CC=CC=1.ClCCl.CO.[OH-].[NH4+]>>[OH:1][CH2:2][C:3]1([NH2:20])[O:10][C@H:9]([CH2:11][OH:12])[C@@H:7]([OH:8])[C@@H:5]1[OH:6]
Reactant: NCc1ccccc1
Reactant: O=C(CO)[C@@H](O)[C@H](O)[C@H](O)CO
Agent: [NH4+]
Agent: [OH-]
Solvent: CO
Solvent: ClCCl
Product: NC1(CO)O[C@H](CO)[C@@H](O)[C@@H]1O
Temperature: 25 °C

Procedure:
Typical procedure from fructose: 18.0 g (100 mmol) of D-(−)-fructose was treated at 0° C. with freshly distilled benzyl amine (3-8 equiv.). The reaction mixture was allowed to warm to room temperature and was then heated at 40° C. for 20 h. The TLC (dichloromethane:methanol:ammonium hydroxide 2:1:1) showed the disappearance of the starting material. The excess of benzyl amine was removed by repeated washings with petroleum ether according to the following method: 150-500 mL of petroleum ether was added into the reaction mixture and subsequently cooled to between −25 and −20° C. (dry ice-alcohol bath) until the carbohydrate-rich phase was frozen. The organic layer was then decanted, and the procedure was repeated 4-5 times. The obtained crude fructosyl amine was diluted with methanol (200-300 mL) and treated with glacial acetic acid (15-20 mL) at room temperature for 2-4 h. TLC (dichloromethane:methanol:ammonium hydroxide 20:4:0.5) showed consumption of the ketosylamine and the formation of N-benzyl-2-amino-2-deoxy-D-mannose together with N-benzyl-2-amino-2-deoxy-D-glucose in a ratio of 2:8-4:6 as the main products. The solvent was evaporated under reduced pressure and the residue purified by column chromatography (dichloromethane:methanol:ammonium hydroxide 20:4:0.5) to give N-benzyl-2-amino-2-deoxy-D-mannose as an amorphous solid (4.1-8.6 g).
Reaction SMILES: [CH3:1][C:2]1[CH:11]=[C:10](OS(C(F)(F)F)(=O)=O)[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][N:8]=2)[N:3]=1.Cl.C([NH2:24])CC>N1C=CC=CC=1>[NH2:24][C:10]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][N:8]=2)[N:3]=[C:2]([CH3:1])[CH:11]=1
Reactant: CCCN
Reactant: Cc1cc(OS(=O)(=O)C(F)(F)F)c2ncccc2n1
Agent: Cl
Solvent: c1ccncc1
Product: Cc1cc(N)c2ncccc2n1
Yield: 110.1 %

Procedure:
D1 (2.2 g) and n-propylamine hydrochloride (2.34 g) were combined in pyridine (75 ml) and the mixture refluxed for 8 h. Solvent was removed at reduced pressure, the residue dissolved in 2N sodium hydroxide and extracted with diethyl ether (×3) and DCM (×2). The combined organic phase was dried (Na2SO4) and solvent removed at reduced pressure. The residue was triturated with pentane to give the title compound (1.32 g) as a pale orange solid. 1H NMR (CDCl3) δ: 2.60 (3H, s), 5.44 (2H, bs), 6.66 (1H, s), 7.54 (1H, dd), 8.17 (1H, dd), 8.67 (1H, m).
Reaction SMILES: C1(C)C=CC=CC=1.[CH3:8][C:9]1([CH3:16])[CH2:14][CH2:13][C:12](=O)[CH2:11][CH2:10]1.C1(P(=[CH:36][C:37]([O:39][CH3:40])=[O:38])(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>ClCCl>[CH3:40][O:39][C:37](=[O:38])[CH:36]=[C:12]1[CH2:13][CH2:14][C:9]([CH3:16])([CH3:8])[CH2:10][CH2:11]1
Reactant: COC(=O)C=P(c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: CC1(C)CCC(=O)CC1
Solvent: ClCCl
Solvent: Cc1ccccc1
Product: COC(=O)C=C1CCC(C)(C)CC1
Temperature: 65 °C
Yield: 13.7 %

Procedure:
To a toluene (5 mL) solution containing 4,4-dimethyl-cyclohexanone (500 mg, 4.0 mmol) was added methyl (triphenylphosphoranylidene)acetate (2.0 g, 6.0 mmol) and the reaction was heated to 60-70° C. for 48 h. The reaction was monitored by TLC. The reaction was cooled to room temperature, diluted with dichloromethane, washed with water, concentrated under vacuum, and the crude product was purified on a silica gel column to afford (4,4-dimethyl-cyclohexylidene)-acetic acid methyl ester (100 mg, 14% yield).
Reaction SMILES: O[C:2]1([C:30]2[CH:35]=[CH:34][CH:33]=[C:32]([CH3:36])[CH:31]=2)[C:6]2[C:7]([CH3:27])=[C:8]([N:13]3[CH2:18][CH2:17][N:16]([C:19]4[CH:24]=[CH:23][C:22]([O:25][CH3:26])=[CH:21][CH:20]=4)[CH2:15][CH2:14]3)[C:9]([CH3:12])=[C:10]([CH3:11])[C:5]=2[O:4][C:3]1([CH3:29])[CH3:28]>C(O)C>[CH3:28][C:3]1([CH3:29])[CH:2]([C:30]2[CH:35]=[CH:34][CH:33]=[C:32]([CH3:36])[CH:31]=2)[C:6]2[C:7]([CH3:27])=[C:8]([N:13]3[CH2:14][CH2:15][N:16]([C:19]4[CH:20]=[CH:21][C:22]([O:25][CH3:26])=[CH:23][CH:24]=4)[CH2:17][CH2:18]3)[C:9]([CH3:12])=[C:10]([CH3:11])[C:5]=2[O:4]1
Reactant: COc1ccc(N2CCN(c3c(C)c(C)c4c(c3C)C(O)(c3cccc(C)c3)C(C)(C)O4)CC2)cc1
Solvent: CCO
Product: COc1ccc(N2CCN(c3c(C)c(C)c4c(c3C)C(c3cccc(C)c3)C(C)(C)O4)CC2)cc1
Yield: 86 %

Procedure:
Using 1-(3-hydroxy-2,2,4,6,7-pentamethyl-3-(3-methylphenyl)-2,3-dihydro-1-benzofuran-5-yl)-4-(4-methoxyphenyl)piperazine obtained in Example 40, the title compound was synthesized in the same manner as in Example 46. Yield 86%. mp. 159–161° C. (ethanol).
Reaction SMILES: [CH2:1]([N:4]([CH2:36][CH2:37][CH3:38])[CH2:5][CH2:6][CH2:7][CH2:8][N:9]([CH2:32][C:33]([OH:35])=[O:34])[CH2:10][C:11]1[CH:16]=[CH:15][C:14]([CH2:17][N:18]([CH2:26][C:27]2[NH:28][CH:29]=[CH:30][N:31]=2)[CH2:19][C:20]2[N:21]([CH3:25])[CH:22]=[CH:23][N:24]=2)=[CH:13][CH:12]=1)[CH2:2][CH3:3].[CH3:39][O:40][CH2:41][CH2:42]O>>[CH3:39][O:40][CH2:41][CH2:42][O:34][C:33](=[O:35])[CH2:32][N:9]([CH2:8][CH2:7][CH2:6][CH2:5][N:4]([CH2:1][CH2:2][CH3:3])[CH2:36][CH2:37][CH3:38])[CH2:10][C:11]1[CH:16]=[CH:15][C:14]([CH2:17][N:18]([CH2:26][C:27]2[NH:28][CH:29]=[CH:30][N:31]=2)[CH2:19][C:20]2[N:21]([CH3:25])[CH:22]=[CH:23][N:24]=2)=[CH:13][CH:12]=1
Reactant: COCCO
Reactant: CCCN(CCC)CCCCN(CC(=O)O)Cc1ccc(CN(Cc2ncc[nH]2)Cc2nccn2C)cc1
Product: CCCN(CCC)CCCCN(CC(=O)OCCOC)Cc1ccc(CN(Cc2ncc[nH]2)Cc2nccn2C)cc1
Temperature: 80 °C
Reaction time: 21 h

Procedure:
The compound (190.7 mg) obtained in Example 65-1 was dissolved in 2-methoxyethanol (4.0 ml) and the whole was stirred at 80° C. for 21 hours. After completion of the reaction, the solvent was distilled off. The resultant was added with a saturated aqueous sodium hydrogen carbonate solution and the whole was subjected to extraction with chloroform and dried with magnesium sulfate. The solvent was distilled off. The residue was purified through silica gel column chromatography (chloroform/ethyl acetate) and treated with hydrochloric acid, thereby obtaining a hydrochloride (37.9 mg) of the subject compound as a white solid.
Reaction SMILES: CS[C:3]1[C:4]2[CH:12]=[CH:11][N:10]=[CH:9][C:5]=2[N:6]=[CH:7][N:8]=1.[CH2:13]([NH2:20])[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1>>[CH2:13]([NH:20][C:3]1[C:4]2[CH:12]=[CH:11][N:10]=[CH:9][C:5]=2[N:6]=[CH:7][N:8]=1)[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1
Reactant: NCc1ccccc1
Reactant: CSc1ncnc2cnccc12
Product: c1ccc(CNc2ncnc3cnccc23)cc1
Temperature: 100 °C
Yield: 20 %

Procedure:
A mixture of 4-methylthiopyrido[3,4-d]pyrimidine (74 mg, 0.41 mmol)(see a previous experimental), and benzylamine (1 mL) is heated to 100° C. for 2 h. On cooling the mixture is concentrated under reduced pressure and purified directly by preparative tlc on silica gel eluting with CH2Cl2, to yield 4-(benzylamino)pyrido[3,4-d]pyrimidine (21.2 mg, 20%). 1H NMR (DMSO) δ 9.21 (1H, t, J=5.8 Hz), 9.19 (1H, s), 8.63 (1H, d, J=5.8 Hz), 8.58 (1H, s), 8.20 (1H, d, J=5.1 Hz), 7.41-7.30 (4H, m), 7.26 (1H, t, J=7.1 Hz).
Reaction SMILES: [I:1][C:2]1[CH:3]=[C:4]([CH:11]=[CH:12][C:13]=1[O:14][CH2:15][CH2:16][CH3:17])[C:5]([O:7]CCC)=[O:6].C(OC1C=C(C=CC=1OCCC)C(OCCC)=O)CC>>[I:1][C:2]1[CH:3]=[C:4]([CH:11]=[CH:12][C:13]=1[O:14][CH2:15][CH2:16][CH3:17])[C:5]([OH:7])=[O:6]
Reactant: CCCOC(=O)c1ccc(OCCC)c(I)c1
Agent: CCCOC(=O)c1ccc(OCCC)c(OCCC)c1
Product: CCCOc1ccc(C(=O)O)cc1I

Procedure:
When the product of Step B was substituted for propyl 3,4-dipropoxybenzoate in Example 43, Step B, the identical process afforded the title compound in 94%, as creamy solid. 1H-NMR (CDCl3) 1.04-1.15 (m, 3H); 1.83-1.94 (m, 2H); 3.99-4.08 (m, 2H); 6.8 (d, 1H, J=6 Hz); 8.04 (dd, 1H, J=3, 6 Hz); 8.5 (d, 1H, J=3 Hz).
Reaction SMILES: [F:1][C:2]1[CH:10]=[CH:9][C:8]2[N:7]([C:11]3[CH:16]=[CH:15][C:14]([F:17])=[CH:13][CH:12]=3)[C:6]3[CH2:18][CH2:19][NH:20][CH2:21][C:5]=3[C:4]=2[CH:3]=1.Br[CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][C:28]#[N:29].C(=O)([O-])[O-].[Na+].[Na+].[I-].[K+].CC(C)C(=O)C>O>[F:1][C:2]1[CH:10]=[CH:9][C:8]2[N:7]([C:11]3[CH:12]=[CH:13][C:14]([F:17])=[CH:15][CH:16]=3)[C:6]3[CH2:18][CH2:19][N:20]([CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][C:28]#[N:29])[CH2:21][C:5]=3[C:4]=2[CH:3]=1
Reactant: N#CCCCCCBr
Reactant: Fc1ccc(-n2c3c(c4cc(F)ccc42)CNCC3)cc1
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: O
Solvent: CC(=O)C(C)C
Product: N#CCCCCCN1CCc2c(c3cc(F)ccc3n2-c2ccc(F)cc2)C1

Procedure:
8-fluoro-5-(4-fluorophenyl)-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indole (10.8 g, 0.034 mole), 6-bromohexanenitrile (6.5 g, 0.37 mole), anhydrous sodium carbonate (21.6 g, 0.204 mole), potassium iodide (100 mg) and 3-methyl-2-butanone (250 ml) were combined and the mixture refluxed for 24 hours. The reaction mixture was cooled, diluted with 250 ml of water and stirred to dissolve excess sodium carbonate. The layers were separated and the aqueous layer extracted with 200 ml of methylene chloride. The organic layers were combined, dried over anhydrous magnesium sulfate, filtered and evaporated to an oil. Addition of hexane gave the title product in crystalline form [11.3 g, m.p. 90°-98° C., Rf 0.5 (9:1 ethyl acetate:methanol)].
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([O:8][CH2:9][CH2:10][N:11]([CH2:14][CH3:15])[CH2:12][CH3:13])[CH:5]=[CH:4][C:3]=1[C:16](=[O:20])[CH2:17][CH2:18][CH3:19].Cl.ClCCN1CC[O:28]CC1>>[Cl:1][C:2]1[CH:7]=[C:6]([O:8][CH2:9][CH2:10][N:11]2[CH2:12][CH2:13][O:28][CH2:15][CH2:14]2)[CH:5]=[CH:4][C:3]=1[C:16](=[O:20])[CH2:17][CH2:18][CH3:19]
Reactant: CCCC(=O)c1ccc(OCCN(CC)CC)cc1Cl
Reactant: ClCCN1CCOCC1
Agent: Cl
Product: CCCC(=O)c1ccc(OCCN2CCOCC2)cc1Cl

Procedure:
This compound is prepared by essentially the same procedure as described in Example 1 Step A except that the 2-diethylaminoethyl chloride hydrochloride of Example 1, Step A is replaced by an equimolecular quantity of N-(2-chloroethyl)morpholine hydrochloride. The product is obtained as a colorless oil upon distillation in vacuo (0.3 mm.).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[C:7]([C:9]([F:12])([F:11])[F:10])[CH:6]=[CH:5][C:4]=1B(O)O.Cl[C:17]1[C:26]2[C:21](=[CH:22][C:23]([S:29]([N:32](CC3C=CC(OC)=CC=3)[C:33]3[S:34][CH:35]=[CH:36][N:37]=3)(=[O:31])=[O:30])=[C:24]([O:27][CH3:28])[CH:25]=2)[N:20]=[CH:19][CH:18]=1.[O-]P([O-])([O-])=O.[K+].[K+].[K+].O1CCOCC1>C(C1C(C(C)(C)C)=C([Pd]Cl)C=CC=1NC)(C)(C)C.O>[CH3:28][O:27][C:24]1[CH:25]=[C:26]2[C:21](=[CH:22][C:23]=1[S:29]([NH:32][C:33]1[S:34][CH:35]=[CH:36][N:37]=1)(=[O:31])=[O:30])[N:20]=[CH:19][CH:18]=[C:17]2[C:4]1[CH:5]=[CH:6][C:7]([C:9]([F:12])([F:11])[F:10])=[CH:8][C:3]=1[O:2][CH3:1]
Reactant: COc1ccc(CN(c2nccs2)S(=O)(=O)c2cc3nccc(Cl)c3cc2OC)cc1
Reactant: COc1cc(C(F)(F)F)ccc1B(O)O
Agent: CNc1ccc([Pd]Cl)c(C(C)(C)C)c1C(C)(C)C
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: C1COCCO1
Product: COc1cc(C(F)(F)F)ccc1-c1ccnc2cc(S(=O)(=O)Nc3nccs3)c(OC)cc12

Procedure:
To a microwave vial charged with (2-methoxy-4-(trifluoromethyl)phenyl)boronic acid (35.6 mg, 0.162 mmol), 4-chloro-6-methoxy-N-(4-methoxybenzyl)-N-(thiazol-2-yl)quinoline-7-sulfonamide (70 mg, 0.147 mmol), potassium phosphate tribasic (36.5 μl, 0.441 mmol) and 1,1-bis[(di-t-butyl-p-methylaminophenyl]palladium(ii) chloride (10.41 mg, 0.015 mmol) was added Dioxane (590 μl) and Water (197 μl). The mixture was irradiated at 100° C. for 30 mins affording conversion to desired product according to LC-MS. The mixture was dried under reduced pressure. To the crude oil was added DCM (0.9 ml) and TFA (0.3 ml) was added at room temperature. After 1 hr of stirring LC-MS indicated complete PMB cleavage. The mixture was dried under reduced pressure and purified with a 25 g (15 μm spherical silica) column ramping EtOAc in heptane (0-100%, 10% DCM throughout) providing product, obtained as a film. The material was lyophilized from MeOH/H2O providing 6-methoxy-4-(2-methoxy-4-(trifluoromethyl)phenyl)-N-(thiazol-2-yl)quinoline-7-sulfonamide (53 mg, 0.107 mmol, 72.7% yield) as an off-white solid. 1H NMR (400 MHz, DMSO-d6) δ ppm 3.62 (s, 3H) 3.80 (s, 3H) 6.83 (s, 1H) 6.88 (d, J=4.60 Hz, 1H) 7.28 (d, J=4.60 Hz, 1H) 7.47-7.54 (m, 3H) 7.57 (d, J=7.63 Hz, 1H) 8.52 (s, 1H) 8.91 (d, J=4.40 Hz, 1H) 12.80 (br. s., 1H). m/z (ESI) 496.2 (M+H)+.
Reaction SMILES: C[O:2][C:3](=O)[C@@H:4]([CH3:23])[N:5]([P@@:13]([CH2:21][CH3:22])([C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)=[O:14])CC1C=CC=CC=1.[NH2:25][O:26][K].Cl>>[OH:26][NH:25][C:3](=[O:2])[C@H:4]([NH:5][P@@:13]([CH2:21][CH3:22])([C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)=[O:14])[CH3:23]
Reactant: CC[P@@](=O)(c1ccccc1)N(Cc1ccccc1)[C@H](C)C(=O)OC
Reactant: NO[K]
Agent: Cl
Product: CC[P@](=O)(N[C@H](C)C(=O)NO)c1ccccc1
Reaction time: 16 h
Yield: 33 %

Procedure:
N-((R)-Ethylphenylphosphinyl)-N-benzyl-D-alanine methyl ester (333 mg, 0.96 mmol) is treated with a solution of NH2OK (3.3 mL, 1.76M in methanol) prepared as described in Fieser and Fieser, Vol. 1, p. 478. The reaction is stirred for 16 hours at which time TLC indicates completion. The reaction mixture is neutralized with 1M aqueous HCl and the volatiles are removed. The residue is purified by silica gel flash chromatography (95:5 ethyl acetate:methanol) to give 110 mg (33%) of N-hydroxy-2(R)-[[(R)-ethylphenyl-phosphinyl]amino]-propionamide as colorless solid: MS-IS m/z 347 [M+H]+, 369 [M+Na]+. (R1 =benzyl, R2 =methyl, R3 =ethyl, R4 =phenyl).