Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:12]=[C:11]2[C:6]([C:7]([CH3:24])=[CH:8][C:9](=[O:23])[N:10]2[CH2:13][CH2:14][C:15]2([C:21]#[N:22])[CH2:20][CH2:19][NH:18][CH2:17][CH2:16]2)=[CH:5][CH:4]=1.[O:25]1[CH2:30][CH2:29][O:28][C:27]2[CH:31]=[C:32]([CH2:35][CH:36]=O)[CH:33]=[CH:34][C:26]1=2.C([BH3-])#N.[Na+].C(=O)([O-])O.[Na+]>C(Cl)(Cl)Cl.O.ClCCl.C(O)(=O)C.CO>[O:25]1[C:26]2[CH:34]=[CH:33][C:32]([CH2:35][CH2:36][N:18]3[CH2:19][CH2:20][C:15]([CH2:14][CH2:13][N:10]4[C:11]5[C:6](=[CH:5][CH:4]=[C:3]([O:2][CH3:1])[CH:12]=5)[C:7]([CH3:24])=[CH:8][C:9]4=[O:23])([C:21]#[N:22])[CH2:16][CH2:17]3)=[CH:31][C:27]=2[O:28][CH2:29][CH2:30]1
Reactant: COc1ccc2c(C)cc(=O)n(CCC3(C#N)CCNCC3)c2c1
Reactant: O=CCc1ccc2c(c1)OCCO2
Agent: O=C([O-])O
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CO
Solvent: ClCCl
Solvent: CC(=O)O
Product: COc1ccc2c(C)cc(=O)n(CCC3(C#N)CCN(CCc4ccc5c(c4)OCCO5)CC3)c2c1
Reaction time: 0.92 h
Yield: 80.1 %

Procedure:
To 5 mL of methanol solution containing 0.20 g of 4-(2-(7-methoxy-4-methyl-2-oxo-1,2-dihydroquinolin-1-yl)ethyl)piperidine-4-carbonitrile, 1.5 mL of dichloromethane solution containing 0.33 g of (2,3-dihydrobenzo[b](1,4)dioxin-6-yl)acetaldehyde and 70 μL of acetic acid were added at room temperature, and stirred at the same temperature for 55 min. 77 mg of sodium cyanoborohydride was added at room temperature, and stirred 1 hour and 50 min, thereafter 0.5 mL of dichloromethane solution containing 0.10 g of (2,3-dihydrobenzo[b](1,4)dioxin-6-yl)acetaldehyde was further added and stirred for 1 hour. To the reaction mixture, water, chloroform and aqueous saturated sodium hydrogen carbonate solution were added, the organic layer was separated, and the aqueous layer was extracted with chloroform. The organic layer and extracts were combined, washed with aqueous saturated sodium chloride solution, thereafter dried over anhydrous magnesium sulfate, and the solvent was removed under reduced pressure. The residue thus obtained was purified by flash silica gel column chromatography[gradient elution of chloroform:methanol=99:1-97:3], to give 0.24 g of 1-(2-(2,3-dihydro-1,4-benzodioxin-6-yl)ethyl)-4-(2-(7-methoxy-4-methyl-2-oxo-1,2-dihydroquinolin-1-yl)ethyl)piperidine-4-carbonitrile as a white foam.
Reaction SMILES: [O:1]1[C:6]2[CH:7]=[CH:8][C:9]([CH2:11][NH:12][C:13]3[N:18]=[CH:17][N:16]=[C:15]4[N:19]([C:22]5[CH:27]=[CH:26][CH:25]=[C:24](I)[CH:23]=5)[N:20]=[CH:21][C:14]=34)=[CH:10][C:5]=2[O:4][CH2:3][CH2:2]1.[C:29]([Si](C)(C)C)#[CH:30].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C(=O)([O-])[O-].[K+].[K+]>CO.C(Cl)(Cl)Cl.C(N(CC)CC)C.CN(C)C=O>[O:1]1[C:6]2[CH:7]=[CH:8][C:9]([CH2:11][NH:12][C:13]3[N:18]=[CH:17][N:16]=[C:15]4[N:19]([C:22]5[CH:27]=[CH:26][CH:25]=[C:24]([C:29]#[CH:30])[CH:23]=5)[N:20]=[CH:21][C:14]=34)=[CH:10][C:5]=2[O:4][CH2:3][CH2:2]1
Reactant: C#C[Si](C)(C)C
Reactant: Ic1cccc(-n2ncc3c(NCc4ccc5c(c4)OCCO5)ncnc32)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClC(Cl)Cl
Solvent: CCN(CC)CC
Solvent: CO
Product: C#Cc1cccc(-n2ncc3c(NCc4ccc5c(c4)OCCO5)ncnc32)c1
Temperature: 30 °C
Yield: 95 %

Procedure:
50 ml of dimethylformamide was charged into a 250 ml 4 necked round bottom flask, connected to a mechanical stirrer, thermometer socket, condenser, addition funnel and nitrogen gas bubbler. 10.0 g (20.60 mmol) of (2,3-Dihydro-benzo[1,4]dioxin-6-yl methyl)-[1-(3-iodo-phenyl)-1H-pyrazolo[3,4-d]pyrimidin-4-yl)amine (Compound No. 25), 14.50 g (0.146 mol) of ethynyl trimethyl silane, 46.0 mg of palladium acetate hexakis(acetato)tri palladium (II) 108.0 mg of triphenyl phosphine and 20.6 ml of triethyl amine were charged. Maintained the mass temperature at 25-35° C. for 30-45 min. Reaction mass temperature was raised to 80-85° C. Maintained the mass temperature at 80-85° C. for 4 hours. Reaction mass temperature was cooled to 50-55° C. and maintained for 2 hours. Reaction mass temperature was cooled to 25-30° C. and maintained for overnight under stirring. Solvent was completely distilled off under vacuum. The crude oil present was dissolved in 160 ml of water and compound was extracted with 300 ml of chloroform. Organic layer was dried with sodium sulphate. Sodium sulphate was filtered and washed the sodium sulphate with 50 ml of chloroform. Distilled off chloroform completely under vacuum. 9.50 g Of crude oil (Compound No. 13) was obtained. Compound was characterized by Mass spectrum [455 (M+1)]. 9.0 g of crude oil was dissolved in 85 ml of methanol and 85 ml of chloroform mixture. 11.30 g of potassium carbonate was added. Maintained the mass temperature at 25-35° C. for 14 hours. Distilled of the solvent completely under vacuum. 7.50 g Of crude oil was obtained. Crude oil was purified by the column chromatography with hexane and ethyl acetate mixture as mobile phase. Obtained 3.60 g (yield; 45.70% by theory) of product.
Reaction SMILES: S([O-])([O-])(=O)=O.[Mg+2].S(=O)(=O)(O)O.[CH3:12][O:13][C:14]1[CH:19]=[CH:18][C:17]([CH2:20][CH2:21][C:22]([OH:24])=[O:23])=[CH:16][CH:15]=1.[C:25](O)([CH3:28])([CH3:27])[CH3:26]>ClCCl>[CH3:12][O:13][C:14]1[CH:15]=[CH:16][C:17]([CH2:20][CH2:21][C:22]([O:24][C:25]([CH3:28])([CH3:27])[CH3:26])=[O:23])=[CH:18][CH:19]=1
Reactant: CC(C)(C)O
Reactant: COc1ccc(CCC(=O)O)cc1
Agent: O=S(=O)(O)O
Agent: O=S(=O)([O-])[O-]
Agent: [Mg+2]
Solvent: ClCCl
Product: COc1ccc(CCC(=O)OC(C)(C)C)cc1

Procedure:
To a fast stirring suspension of anhydrous magnesium sulfate (4.81 g, 40.0 mmol) in dichloromethane (40 ml) was added sulfuric acid (0.55 ml, 10.32 mmol). The reaction was vigorously stirred for 15 minutes at room temperature and then 3-(4-methoxyphenyl)propionic acid (1.8 g, 9.99 mmol) and tert-butanol (4.78 ml, 50.0 mmol) were added. The reaction was sealed and stirred at room temperature overnight. The reaction was quenched with 75 mL of saturated sodium bicarbonate solution and washed with water (2×50 mL) and brine (1×50 mL). The organic layer was dried over sodium sulfate, filtered, concentrated, and purified by flash chromatography on silica gel (0 to 80% ethyl acetate/hexanes) to afford tert-butyl 3-(4-methoxyphenyl)propanoate. 1H NMR (CDCl3, 500 MHz) δ 7.11 (d, J=8.7 Hz, 2H), 6.82 (d, J=8.7 Hz, 2H), 3.78 (s, 3H), 2.85 (t, J=7.7 Hz, 2H), 2.50 (t, J=7.7 Hz, 2H), 1.42 (s, 9H).
Reaction SMILES: [Br:1][C:2]1[C:7]2[O:8][CH2:9][O:10][C:6]=2[CH:5]=[C:4]([CH:11](O)[CH:12]([CH3:14])[CH3:13])[CH:3]=1.C([SiH](CC)CC)C.FC(F)(F)C(O)=O.O>ClCCl>[Br:1][C:2]1[C:7]2[O:8][CH2:9][O:10][C:6]=2[CH:5]=[C:4]([CH2:11][CH:12]([CH3:14])[CH3:13])[CH:3]=1
Reactant: CC(C)C(O)c1cc(Br)c2c(c1)OCO2
Agent: CC[SiH](CC)CC
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Solvent: O
Product: CC(C)Cc1cc(Br)c2c(c1)OCO2
Temperature: 0 °C
Reaction time: 0.25 h
Yield: 51.7 %

Procedure:
To a cold solution (0° C.) of 1-(7-bromo-benzo[1,3]dioxol-5-yl)-2-methyl-propan-1-ol (498 mg, 1.82 mmol) in dry dichloromethane (10 mL) was added triethylsilane (0.6 mL, 3.65 mmol). After 15 minutes, trifluoroacetic acid was added to the reaction and the mixture stirred at 0° C. for 45 minutes. Water was poured into the reaction mixture and the layers separated. The organic layer was further washed with water, aqueous NaHCO3 and brine, dried (MgSO4), filtered and evaporated. The residue was purified on silica gel (5% ethyl acetate in hexane) to give 242 mg of 4-bromo-6-isobutyl-benzo[1,3]dioxole (52%). 1H NMR (300 MHz; CDCl3): δ 0.90 (d, J=6.3 Hz, 6H), 1.81 (m, 1H), 2.39 (d, J=7.5 Hz, 2H), 6.01 (s, 2H), 6.58 (s, 1H), 6.76 (s, 1H).
Reaction SMILES: [O:1]=[C:2]1[N:6]([C@@H:7]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[CH3:8])[CH2:5][CH:4]([C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])[CH2:3]1.C=O.[H-].[Na+].C(O)(=O)C[C:28](CC(O)=O)(C(O)=O)[OH:29]>CN(C)C=O>[OH:29][CH2:28][C@:4]1([C:15]([O:17][C:18]([CH3:20])([CH3:19])[CH3:21])=[O:16])[CH2:3][C:2](=[O:1])[N:6]([C@@H:7]([C:9]2[CH:10]=[CH:11][CH:12]=[CH:13][CH:14]=2)[CH3:8])[CH2:5]1
Reactant: C[C@H](c1ccccc1)N1CC(C(=O)OC(C)(C)C)CC1=O
Reactant: O=C(O)CC(O)(CC(=O)O)C(=O)O
Agent: C=O
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: C[C@H](c1ccccc1)N1C[C@@](CO)(C(=O)OC(C)(C)C)CC1=O
Reaction time: 0.5 h
Yield: 23 %

Procedure:
To a solution of tert-butyl 5-oxo-1-[(1R)-1-phenylethyl]pyrrolidine-3-carboxylate (4.00 g, 13.8 mmol) in N,N-dimethylformamide (40 mL), paraformaldehyde (0.830 g, 27.7 mmol) and sodium hydride (0.600 g, 55% in oil, 13.8 mmol) were added at room temperature, and the mixture was stirred at the same temperature for 30 minutes. To the reaction mixture, 10% aqueous solution of citric acid (150 mL) was added in an ice bath, and the solution was extracted with ethyl acetate (300 mL×2). The organic layer was washed with water (100 mL×2) and saturated aqueous solution of sodium chloride (100 mL), and dried with anhydrous sodium sulfate. After the filtration, the filtrate was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (elusion by hexane:ethyl acetate, 7:3→1:4) to obtain 1.03 g (23%) of the title compound as a white solid.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][C:6]([C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)=[CH:5]2.[H-].[Na+].Cl[CH2:20][C:21]1[N:26]=[C:25]([C:27]([O:29][CH3:30])=[O:28])[CH:24]=[CH:23][CH:22]=1.[Cl-].[NH4+]>CN(C)C=O.C(OCC)(=O)C.O>[Cl:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[N:7]([CH2:20][C:21]1[N:26]=[C:25]([C:27]([O:29][CH3:30])=[O:28])[CH:24]=[CH:23][CH:22]=1)[C:6]([C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)=[CH:5]2
Reactant: Clc1ccc2[nH]c(-c3ccccc3)cc2c1
Reactant: COC(=O)c1cccc(CCl)n1
Agent: [Cl-]
Agent: [H-]
Agent: [NH4+]
Solvent: O
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: COC(=O)c1cccc(Cn2c(-c3ccccc3)cc3cc(Cl)ccc32)n1
Reaction time: 0.25 h
Yield: 43.9 %

Procedure:
To a solution of 5-chloro-2-phenylindole (154 mg) in N,N-dimethylformamide (1.5 mL) was added sodium hydride (dispersed in liquid paraffin, minimum 55%, 31 mg) at room temperature, and the mixture was stirred for 15 minutes. Methyl 6-(chloromethyl)pyridine-2-carboxylate (126 mg) was added and this resulting mixture was stirred at 50 to 60° C. for additional 18 hours. Water, ethyl acetate and a saturated aqueous ammonium chloride solution were added to the reaction mixture. The organic layer was separated. The aqueous layer was extracted with ethyl acetate. The combined organic layers were washed successively with water and saturated saline, dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue was purified by aminopropylated silica gel column chromatography (eluting solvent: ethyl acetate-hexane) to obtain the title compound (112 mg).
Reaction SMILES: [S:1]1[C:5]([NH:6][C:7](=[O:13])[O:8][C:9]([CH3:12])([CH3:11])[CH3:10])=[CH:4][N:3]=[CH:2]1.[Br:14]N1C(=O)CCC1=O>C(Cl)(Cl)Cl>[Br:14][C:4]1[N:3]=[CH:2][S:1][C:5]=1[NH:6][C:7](=[O:13])[O:8][C:9]([CH3:10])([CH3:12])[CH3:11]
Reactant: O=C1CCC(=O)N1Br
Reactant: CC(C)(C)OC(=O)Nc1cncs1
Solvent: ClC(Cl)Cl
Product: CC(C)(C)OC(=O)Nc1scnc1Br
Reaction time: 1 h

Procedure:
To a solution of tert-butyl thiazol-5-ylcarbamate (WO 2007/071955) (607 mg, 3.0 mmol) in chloroform (50 mL) was added N-bromosuccinimide (542 mg, 3.04 mmol) at 0° C. After 1 h, reaction was quenched by addition of saturated NaHCO3 solution (50 mL). The layers were separated, and the mixture extracted with CHCl3 (3×50 mL). The combined organic extracts were dried (MgSO4), filtered and concentrated. 1H NMR (CDCl3) δ8.37 (d, J=0.6 Hz, 1H), 7.05 (br s, 1H), 1.55 (s, 9H); MH+ 278.9.
Reaction SMILES: [O:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[C:3]([CH2:10][CH2:11]O)=[CH:2]1.C1(C)C=CC(S(Cl)(=O)=O)=CC=1.S(C1C=CC(C)=CC=1)([O-])(=O)=O.[F:35][C:36]1[CH:37]=[C:38]2[C:43](=[C:44]([N:46]3[CH2:51][CH2:50][NH:49][CH2:48][CH2:47]3)[CH:45]=1)[N:42]=[CH:41][CH:40]=[CH:39]2.C(N(CC)C(C)C)(C)C>N1C=CC=CC=1.CS(C)=O>[O:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[C:3]([CH2:10][CH2:11][N:49]2[CH2:50][CH2:51][N:46]([C:44]3[CH:45]=[C:36]([F:35])[CH:37]=[C:38]4[C:43]=3[N:42]=[CH:41][CH:40]=[CH:39]4)[CH2:47][CH2:48]2)=[CH:2]1
Reactant: Fc1cc(N2CCNCC2)c2ncccc2c1
Reactant: OCCc1coc2ccccc12
Agent: Cc1ccc(S(=O)(=O)Cl)cc1
Agent: Cc1ccc(S(=O)(=O)[O-])cc1
Solvent: c1ccncc1
Solvent: CCN(C(C)C)C(C)C
Solvent: CS(C)=O
Product: Fc1cc(N2CCN(CCc3coc4ccccc34)CC2)c2ncccc2c1
Reaction time: 48 h

Procedure:
To a stirred solution of 2-(1-benzofuran-3-yl)ethanol (815 mg, 5 mmol) in anhydrous pyridine (20 ml), p-toluenesulfonyl chloride (1.14 g, 6.0 mmol) was added. The reaction mixture was kept at 0° C. for 48 hrs and quenched with ice cold water. The reaction mixture was extracted with chloroform, washed well with water, and dried over anhydrous MgSO4. It was then filtered and concentrated. The crude product obtained was taken to next step without any purification. A mixture of tosylate (316 mg. 1 mmol) (obtained by the above mentioned process) and 6-fluoro-8-piperazino quinoline (231 mg, 1 mmol) was heated at 120° C. in DMSO in the presence of N,N-diisopropylethylamine (5 ml, excess) for 24 hrs. At the end, reaction mixture was quenched with water and extracted with chloroform. The organic layer was washed with water and dried over anhydrous MgSO4 and concentrated to dryness. The dark colored solid was purified by silica-gel column chromatography by initially eluting it with 70% ethyl acetate:hexane and then with 55% methanol:ethyl acetate. The product, 8-{4-[2-(1-benzofuran-3-yl)ethyl]-1-piperazinyl}-6-fluoroquinoline, was isolated as yellow oil. Yield: 220 mg (58%); (M+H): 376. 1HNMR (400 MHz, CDCl3):δ 8.82˜8.80 (dd, J1=1.7 Hz, J2=1.7 Hz, 1H), 8.08˜8.03 (dd, J1=1.8 Hz, J2=1.8 Hz, 1H), 7.69˜6.32 (m, 8H), 3.50˜2.63 (m, 12H).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]=[C:9]=[O:10])=[CH:4][CH:3]=1.[CH3:11][O:12][C:13]1[CH:14]=[C:15]2[C:20](=[CH:21][C:22]=1[O:23][CH3:24])[N:19]=[CH:18][N:17]=[C:16]2[NH:25][C:26]1[S:27][C:28]2[CH:34]=[C:33]([NH2:35])[CH:32]=[CH:31][C:29]=2[N:30]=1.ClCCl>CO>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9]([NH:35][C:33]2[CH:32]=[CH:31][C:29]3[N:30]=[C:26]([NH:25][C:16]4[C:15]5[C:20](=[CH:21][C:22]([O:23][CH3:24])=[C:13]([O:12][CH3:11])[CH:14]=5)[N:19]=[CH:18][N:17]=4)[S:27][C:28]=3[CH:34]=2)=[O:10])=[CH:4][CH:3]=1
Reactant: COc1cc2ncnc(Nc3nc4ccc(N)cc4s3)c2cc1OC
Reactant: O=C=Nc1ccc(Cl)cc1
Solvent: CO
Solvent: ClCCl
Product: COc1cc2ncnc(Nc3nc4ccc(NC(=O)Nc5ccc(Cl)cc5)cc4s3)c2cc1OC

Procedure:
1-(4-Chlorophenyl)-3-[2-(6,7-dimethoxyquinazolin-4-ylamino)benzothiazol-6-yl]urea was prepared from 4-chlorophenyl isocyanate (17.4 mg, 0.113 mmol) and N2-(6,7-dimethoxyquinazolin-4-yl)benzothiazole-2,6-diamine (40 mg, 0.113 mmol) according to GP 3. Preparative TLC of the reaction mixture (dichloromethane:methanol=9:1) furnished a yellowish solid (33.9 mg, 67 μmol, 59%). LC/ESI-MS: m/z=507 [M(35Cl)+H]+; m/z=505 [M(35Cl)−H]−; R′, =3.50 min.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[C:11]([CH:13]=[CH2:14])[CH:12]=1)[C:9](=[O:15])[CH2:8][CH2:7][C:6]2([CH3:17])[CH3:16].[N+](=[CH2:20])=[N-].C(OCC)(=O)C>C(OCC)C.CCCCCC.C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[CH:13]1([C:11]2[CH:12]=[C:3]([O:2][CH3:1])[CH:4]=[C:5]3[C:10]=2[C:9](=[O:15])[CH2:8][CH2:7][C:6]3([CH3:17])[CH3:16])[CH2:20][CH2:14]1
Reactant: C=[N+]=[N-]
Reactant: C=Cc1cc(OC)cc2c1C(=O)CCC2(C)C
Agent: [Pd+2]
Agent: CC(=O)[O-]
Solvent: CCCCCC
Solvent: CCOC(C)=O
Solvent: CCOCC
Product: COc1cc(C2CC2)c2c(c1)C(C)(C)CCC2=O
Temperature: -25 °C
Yield: 83 %

Procedure:
A stirred, cooled (−40° C.) solution of 6-methoxy-4,4-dimethyl-8-vinyl-3,4-dihydro-2H-naphthalen-1-one (Intermediate 155, 51.7 g, 7.4 mmol) in diethyl ether (10 mL) was treated with a solution of diazomethane in ether (40 mmol in 50 mL of ether) followed by palladium(II)acetate (0.08 g) and the resulting reaction mixture was warmed to −25° C. when effervescence was observed. The reaction mixture was then filtered through a plug of silica and the filtrate was evaporated to afford a dark brown residue that was subjected to flash column chromatography over silica gel (23-400 mesh) using 20% ethyl acetate in hexane as the eluent to afford the title product as a pale yellow solid (1.5 g, 83%).
Reaction SMILES: [C:1]([C:4]1[C:8]2[CH:9]=[CH:10][C:11]3[CH:12]=[N:13][C:14](S(C)(=O)=O)=[N:15][C:16]=3[C:7]=2[N:6]([CH:21]2[CH2:26][CH2:25][N:24]([C:27]([O:29][C:30]([CH3:33])([CH3:32])[CH3:31])=[O:28])[CH2:23][CH2:22]2)[N:5]=1)(=[O:3])[NH2:2].[NH:34]1[CH2:38][CH2:37][CH2:36][CH2:35]1>C1COCC1>[C:1]([C:4]1[C:8]2[CH:9]=[CH:10][C:11]3[CH:12]=[N:13][C:14]([N:34]4[CH2:38][CH2:37][CH2:36][CH2:35]4)=[N:15][C:16]=3[C:7]=2[N:6]([CH:21]2[CH2:26][CH2:25][N:24]([C:27]([O:29][C:30]([CH3:33])([CH3:32])[CH3:31])=[O:28])[CH2:23][CH2:22]2)[N:5]=1)(=[O:3])[NH2:2]
Reactant: CC(C)(C)OC(=O)N1CCC(n2nc(C(N)=O)c3ccc4cnc(S(C)(=O)=O)nc4c32)CC1
Reactant: C1CCNC1
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1CCC(n2nc(C(N)=O)c3ccc4cnc(N5CCCC5)nc4c32)CC1
Temperature: 25 °C
Reaction time: 1 h
Yield: 51.1 %

Procedure:
To a solution of tert-butyl 4-[3-carbamoyl-8-(methylsulfonyl)-1H-pyrazolo[4,3-h]quinazolin-1-yl]piperidine-1-carboxylate 30 mg (0.063 mmol) in THF (3 ml), pyrrolidine 70 μl (1 mmol) was added. The solution was stirred at room temperature for 1 hour and monitored by LC/MS. The reaction mixture was cooled to room temperature; the separated solid was filtered and washed with diethyl ether to afford tert-butyl 4-[3-carbamoyl-8-(pyrrolidin-1-yl)-1H-pyrazolo[4,3-h]quinazolin-1-yl]piperidine-1-carboxylate 15 mg (50%). LC/MS (m/z): 475.0 [M+H]+, HPLC (254 nm) method 4 Rt 2.01 min.
Reaction SMILES: C1(C)C=CC(S(O)(=O)=O)=CC=1.[NH2:12][C:13]1([CH2:19][C:20]([O:22][CH3:23])=[O:21])[CH2:18][CH2:17][O:16][CH2:15][CH2:14]1.N[C@H](C(O)=O)CC(C)C.C(N(C(C)C)CC)(C)C.[O:42](C(OC(C)(C)C)=O)[C:43]([O:45][C:46]([CH3:49])([CH3:48])[CH3:47])=O>O1CCOCC1>[C:46]([O:45][C:43]([NH:12][C:13]1([CH2:19][C:20]([O:22][CH3:23])=[O:21])[CH2:14][CH2:15][O:16][CH2:17][CH2:18]1)=[O:42])([CH3:49])([CH3:48])[CH3:47]
Reactant: COC(=O)CC1(N)CCOCC1
Reactant: CC(C)(C)OC(=O)OC(=O)OC(C)(C)C
Agent: CC(C)C[C@H](N)C(=O)O
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: CCN(C(C)C)C(C)C
Solvent: C1COCCO1
Product: COC(=O)CC1(NC(=O)OC(C)(C)C)CCOCC1
Temperature: 25 °C
Reaction time: 60 h

Procedure:
To a solution of methyl 2-(4-aminotetrahydro-2H-pyran-4-yl)acetate p-toluenesulfonic acid salt (prepared in the similar manner as described in Bioorg. Med. Chem. Leu. 2006, 16, 2699-2704, 1.0 g, 2.9 mmol) in anhydrous dioxane (5 mL) was sequentially added diisopropylethylamine (1 mL, 5.8 mmol) and (BOC)2O (1.26 g, 5.8 mmol) at room temperature. Upon completion of addition, the reaction mixture was stirred at room temperature for 60 h, concentrated under reduced pressure and partitioned between ethyl acetate (30 mL) and 1N HCl (10 mL). The ethyl acetate layer was washed with 1N NaOH (10 mL), brine (10 mL), dried over sodium sulfate and concentrated under reduced pressure to yield the title compound (1.0 g) as an oil, which was used in the next step without further purification.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[O:12][CH:11]=[N:10][CH:9]=2)=[C:4]([O:13][CH3:14])[CH:3]=1.[CH:15]1[CH:20]=[CH:19][C:18]([O:21][C:22](OC2C=CC=CC=2)=[N:23][C:24]#[N:25])=[CH:17][CH:16]=1>C(#N)C>[C:18]1([O:21][C:22](=[N:1][C:2]2[CH:7]=[CH:6][C:5]([C:8]3[O:12][CH:11]=[N:10][CH:9]=3)=[C:4]([O:13][CH3:14])[CH:3]=2)[NH:23][C:24]#[N:25])[CH:19]=[CH:20][CH:15]=[CH:16][CH:17]=1
Reactant: N#CN=C(Oc1ccccc1)Oc1ccccc1
Reactant: COc1cc(N)ccc1-c1cnco1
Solvent: CC#N
Product: COc1cc(N=C(NC#N)Oc2ccccc2)ccc1-c1cnco1
Temperature: 25 °C
Yield: 94 %

Procedure:
A mixture of 1D (0.200 g, 1.05 mmol) and diphenyl cyanocarbonimidate (0.258 g, 1.05 mmol) in 10 mL of acetonitrile was stirred at reflux for 40 h. As the reaction mixture cooled to room temperature, a yellow solid precipitated out of solution. The volume of solvent was reduced by half, and ether was added. Vacuum filtration afforded 0.330 g (94%) of 15A as a pale yellow solid which was 97% pure by LC/MS (retention time=3.48 min.; M+=335.15. Column: YMC S5 ODS 4.6×5.0 mm Ballistic. Solvent A=10% MeOH, 90% H2O, 0.1% TFA; Solvent B=90% MeOH, 10% H2O, 0.1% TFA).
Reaction SMILES: F[P-](F)(F)(F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2N=CC=CC=2N=N1.Cl.Cl.[C:27]([O:30][C@@H:31]1[C@@H:68]([O:69][C:70](=[O:72])[CH3:71])[C@H:67]([O:73][C:74](=[O:76])[CH3:75])[C@@H:66]([CH2:77][O:78][C:79](=[O:81])[CH3:80])[O:65][C@H:32]1[O:33][C:34]1[C:38]([CH2:39][C:40]2[CH:45]=[CH:44][C:43](/[CH:46]=[CH:47]/[CH2:48][CH2:49][N:50]3[CH2:55][CH2:54][CH2:53][C:52]4([CH2:60][CH2:59][NH:58][CH2:57][CH2:56]4)[CH2:51]3)=[CH:42][C:41]=2[CH3:61])=[C:37]([CH:62]([CH3:64])[CH3:63])[NH:36][N:35]=1)(=[O:29])[CH3:28].[CH3:82][C:83]([O:86][C:87]([NH:89][CH2:90][C:91](O)=[O:92])=[O:88])([CH3:85])[CH3:84].C(N(C(C)C)CC)(C)C>ClCCl>[C:83]([O:86][C:87](=[O:88])[NH:89][CH2:90][C:91]([N:58]1[CH2:57][CH2:56][C:52]2([CH2:51][N:50]([CH2:49][CH2:48]/[CH:47]=[CH:46]/[C:43]3[CH:44]=[CH:45][C:40]([CH2:39][C:38]4[C:34]([O:33][C@@H:32]5[O:65][C@H:66]([CH2:77][O:78][C:79](=[O:81])[CH3:80])[C@@H:67]([O:73][C:74](=[O:76])[CH3:75])[C@H:68]([O:69][C:70](=[O:72])[CH3:71])[C@H:31]5[O:30][C:27](=[O:29])[CH3:28])=[N:35][NH:36][C:37]=4[CH:62]([CH3:64])[CH3:63])=[C:41]([CH3:61])[CH:42]=3)[CH2:55][CH2:54][CH2:53]2)[CH2:60][CH2:59]1)=[O:92])([CH3:85])([CH3:82])[CH3:84]
Reactant: CC(C)(C)OC(=O)NCC(=O)O
Reactant: CC(=O)OC[C@H]1O[C@@H](Oc2n[nH]c(C(C)C)c2Cc2ccc(/C=C/CCN3CCCC4(CCNCC4)C3)cc2C)[C@H](OC(C)=O)[C@@H](OC(C)=O)[C@@H]1OC(C)=O
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CC(=O)OC[C@H]1O[C@@H](Oc2n[nH]c(C(C)C)c2Cc2ccc(/C=C/CCN3CCCC4(CCN(C(=O)CNC(=O)OC(C)(C)C)CC4)C3)cc2C)[C@H](OC(C)=O)[C@@H](OC(C)=O)[C@@H]1OC(C)=O
Temperature: 25 °C
Reaction time: 2 h
Yield: 90.8 %

Procedure:
Add O-(7-azabenzotriazol-1-yl)-N,N,N′,N′ tetramethyluronium hexafluorophosphate (HATU, 543 mg, 1.43 mmol) to a solution of 4-{4-[(1E)-4-(2,9-diazaspiro[5.5]undec-2-yl)but-1-en-1-yl]-2-methylbenzyl}-5-(propan-2-yl)-1H-pyrazol-3-yl 2,3,4,6-tetra-O-acetyl-beta-D-glucopyranoside dihydrochloride (1.0 g, 1.19 mmol), N-alpha-T-Boc-glycine (317 mg, 1.79 mmol), and diisopropylethylamine (769 mg, 5.95 mmol) in dichloromethane (10 mL). Stir the mixture at room temperature for 2.0 hours. Remove the solvent under the reduced pressure. Purify the resulting residue by flash chromatography (silica gel, gradient ethyl acetate/dichloromethane from 30-85% over 20 min, 40 g column) to provide the title compound (1.0 g, 1.08 mmol). MS (m/z): 924.4 (M+1), 922.4 (M−1).
Reaction SMILES: [Si:1]([O:8][CH2:9][CH2:10][NH:11][C:12]1[C:21]2[C:16](=[CH:17][CH:18]=[CH:19][N:20]=2)[N:15]=[CH:14][C:13]=1[N+:22]([O-])=O)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2]>C(#N)C.[Pt]>[Si:1]([O:8][CH2:9][CH2:10][NH:11][C:12]1[C:21]2[C:16](=[CH:17][CH:18]=[CH:19][N:20]=2)[N:15]=[CH:14][C:13]=1[NH2:22])([C:4]([CH3:7])([CH3:5])[CH3:6])([CH3:3])[CH3:2]
Reactant: CC(C)(C)[Si](C)(C)OCCNc1c([N+](=O)[O-])cnc2cccnc12
Agent: [Pt]
Solvent: CC#N
Product: CC(C)(C)[Si](C)(C)OCCNc1c(N)cnc2cccnc12
Reaction time: 3 h
Yield: 98.2 %

Procedure:
N-(2-{[tert-Butyl(dimethyl)silyl]oxy}ethyl)-3-nitro[1,5]naphthyridin-4-amine (2.36 g, 6.78 mmol) was dissolved in 50 mL of acetonitrile and the solution was placed in a pressure bottle. Platinum on carbon (5%, 200 mg) was then added and the reaction mixture was shaken under H2 at 50 PSI (3.4×105 Pa). After 3 hours, the reaction mixture was filtered through a pad of CELITE filter agent. The pad was rinsed with acetonitrile and the combined filtrates were concentrated under reduced pressure to give 2.12 g of N4-(2-{[tert-butyl(dimethyl)silyl]oxy}ethyl)[1,5]naphthyridine-3,4-diamine as an orange solid.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([CH:12]=[CH2:13])=[C:6]([NH:8][C:9](=[O:11])[CH3:10])[CH:7]=1.Br[CH2:15][C:16]1[C:17](Cl)=[N:18][C:19]([Cl:23])=[C:20]([F:22])[CH:21]=1.C(N1C2C=CC=CC=2C=CC2N=C(Cl)C(F)=CC=2C1)(=O)C>>[C:9]([N:8]1[C:6]2[CH:7]=[C:2]([Cl:1])[CH:3]=[CH:4][C:5]=2[CH:12]=[CH:13][C:17]2[N:18]=[C:19]([Cl:23])[C:20]([F:22])=[CH:21][C:16]=2[CH2:15]1)(=[O:11])[CH3:10]
Reactant: C=Cc1ccc(Cl)cc1NC(C)=O
Reactant: Fc1cc(CBr)c(Cl)nc1Cl
Agent: CC(=O)N1Cc2cc(F)c(Cl)nc2C=Cc2ccccc21
Product: CC(=O)N1Cc2cc(F)c(Cl)nc2C=Cc2ccc(Cl)cc21

Procedure:
Compound 6D was prepared from 6C and 1B in two steps by a route analogous to that used for the preparation of 1D. HPLC Rt=3.032 min; LCMS Found: (M+H)+=337.