Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].[CH3:7][N:8]([CH3:43])[C:9]1[C:18]2[C:13](=[CH:14][CH:15]=[C:16]([NH:19][C:20]3[N:25]=[C:24]([NH:26][C:27]4[CH:28]=[C:29]5[C:34](=[CH:35][CH:36]=4)[N:33]=[C:32]([CH3:37])[CH:31]=[C:30]5[N:38]([CH3:40])[CH3:39])[N:23]=[C:22](Cl)[N:21]=3)[CH:17]=2)[N:12]=[C:11]([CH3:42])[CH:10]=1.[CH3:44][N:45]([CH3:50])[CH2:46][CH2:47][CH2:48][NH2:49]>CN(C=O)C>[CH3:7][N:8]([CH3:43])[C:9]1[C:18]2[C:13](=[CH:14][CH:15]=[C:16]([NH:19][C:20]3[N:25]=[C:24]([NH:26][C:27]4[CH:28]=[C:29]5[C:34](=[CH:35][CH:36]=4)[N:33]=[C:32]([CH3:37])[CH:31]=[C:30]5[N:38]([CH3:40])[CH3:39])[N:23]=[C:22]([NH:49][CH2:48][CH2:47][CH2:46][N:45]([CH3:50])[CH3:44])[N:21]=3)[CH:17]=2)[N:12]=[C:11]([CH3:42])[CH:10]=1
Reactant: CN(C)CCCN
Reactant: Cc1cc(N(C)C)c2cc(Nc3nc(Cl)nc(Nc4ccc5nc(C)cc(N(C)C)c5c4)n3)ccc2n1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: Cc1cc(N(C)C)c2cc(Nc3nc(NCCCN(C)C)nc(Nc4ccc5nc(C)cc(N(C)C)c5c4)n3)ccc2n1
Temperature: 100 °C

Procedure:
0.5 g (0.0036 mol) of potassium carbonate, 1 g (0.00189 mol) of 2,4-bis(4-dimethylamino-2-methylquinolin-6-yl)amino-6-chloro-[1,3,5]triazine prepared according to patent W0001561 and 1 ml (0.0078 mol) of N,N-dimethyl-1,3-propanediamine are successively loaded into a 250 ml round-bottomed flask containing 50 ml of DMF, with stirring, and then the mixture is heated for 15 hours at 100° C. The reaction medium is concentrated and taken up in 100 ml of water. The precipitate formed is filtered, washed with 2×50 ml of 0.1N NaOH and then dried. There are thus obtained 1.2 g of N,N′-bis(4-dimethylamino-2-methylquinolin-6-yl)-N″-(3-dimethylaminopropyl)-[1,3,5]triazine, which is purified by flash chromatography on 30 g of silica (35-70 μm), eluting with a mixture (85/10/5) of dichloromethane, methanol and triethylamine. There is thus obtained, after drying under vacuum at 40° C., 0.45 g (41%) of 2,4-bis(4-dimethylamino-2-methylquinolin-6-yl)amino-6-(3-dimethylaminopropyl)-amino-[1,3,5]triazine, in the form of a yellow powder whose characteristics are the following:
Reaction SMILES: [NH2:1][C:2]1[S:3][C:4]([C:8]([O:10][CH2:11][CH3:12])=[O:9])=[C:5]([CH3:7])[N:6]=1.C(N(CC)CC)C.Cl.[C:21](Cl)(=[O:28])[C:22]1[CH:27]=[CH:26][N:25]=[CH:24][CH:23]=1>O1CCCC1>[C:21]([NH:1][C:2]1[S:3][C:4]([C:8]([O:10][CH2:11][CH3:12])=[O:9])=[C:5]([CH3:7])[N:6]=1)(=[O:28])[C:22]1[CH:27]=[CH:26][N:25]=[CH:24][CH:23]=1
Reactant: CCOC(=O)c1sc(N)nc1C
Reactant: O=C(Cl)c1ccncc1
Agent: Cl
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CCOC(=O)c1sc(NC(=O)c2ccncc2)nc1C
Temperature: 25 °C
Reaction time: 48 h
Yield: 90 %

Procedure:
To a mixture of ethyl 2-amino-4-methylthiazole-5-carboxylate (5.70 g, 30.60 mmol) and triethylamine (10.0 mL, 71.80 mmol) in tetrahydrofuran (100 mL) was added isonicotinoyl chloride hydrochloride (6.00 g, 32.00 mmol). The reaction mixture was stirred at ambient temperature for 2 days. The solvent was removed by evaporation and the resulting white solid was washed sequentially with water, 10% sodium bicarbonate solution, and water, then dried to afford the title compound in 90% yield (8.10 g); 1H NMR (DMSO-d6, 300 MHz) δ 8.77 (d, J=6.0 Hz, 2H), 8.77 (d, J=6.0 Hz, 2H), 4.23 (q, J=7.2 Hz, 2H), 2.34 (s, 3H). 1.27 (t, J=7.2 Hz, 3H); MS (ES+) m/z 292.0 (M+1).
Reaction SMILES: C([O:5][C:6]([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=1[C:14]1[CH:19]=[CH:18][C:17]([CH2:20][N:21]2[C:25]([C:26]([NH2:28])=[O:27])=[C:24]([CH:29]([OH:33])[CH2:30][CH2:31][CH3:32])[N:23]=[C:22]2[CH2:34][CH2:35][CH2:36][CH3:37])=[CH:16][CH:15]=1)=[O:7])(C)(C)C.Cl>O1CCOCC1>[CH2:34]([C:22]1[N:21]([CH2:20][C:17]2[CH:16]=[CH:15][C:14]([C:9]3[CH:10]=[CH:11][CH:12]=[CH:13][C:8]=3[C:6]([OH:7])=[O:5])=[CH:19][CH:18]=2)[C:25]([C:26]([NH2:28])=[O:27])=[C:24]([CH:29]([OH:33])[CH2:30][CH2:31][CH3:32])[N:23]=1)[CH2:35][CH2:36][CH3:37]
Reactant: CCCCc1nc(C(O)CCC)c(C(N)=O)n1Cc1ccc(-c2ccccc2C(=O)OC(C)(C)C)cc1
Agent: Cl
Solvent: C1COCCO1
Product: CCCCc1nc(C(O)CCC)c(C(N)=O)n1Cc1ccc(-c2ccccc2C(=O)O)cc1

Procedure:
Following a procedure similar so that described in Example 45(d), but using 0.58 g of 1-[(2'-t-butoxycarbonylbiphenyl-4-yl)methyl]-2-butyl-4-(1-hydroxybutyl)imidazole-5-carboxamide [prepared as described in step (c) above] and 13 ml of a 4N solution of hydrogen chloride in dioxane, 0.55 g of the hydrochloride of the title compound was obtained as an amorphous powder, melting at above 110° C. (with softening).
Reaction SMILES: P(Cl)(Cl)([Cl:3])=O.[CH2:6]([S:11]([O-:14])(=O)=[O:12])[CH2:7][CH2:8][CH:9]=[CH2:10].[Na+]>>[CH2:6]([S:11]([Cl:3])(=[O:14])=[O:12])[CH2:7][CH2:8][CH:9]=[CH2:10]
Reactant: O=P(Cl)(Cl)Cl
Reactant: C=CCCCS(=O)(=O)[O-]
Agent: [Na+]
Product: C=CCCCS(=O)(=O)Cl
Temperature: 0 °C
Yield: 54.5 %

Procedure:
Phosphorus oxychloride (570.02 g) was added to sodium 4-pentene-1-sulfonate (199.18 g) at room temperature. After reflux for 3 hours, the solution was cooled in an ice bath. The reaction solution was added gradually to a large amount of ice water. After extraction with diethyl ether, the organic layer was washed with brine, dried with magnesium sulfate, and concentrated under reduced pressure to obtain 4-pentene-1-sulfonyl chloride (106.31 g) as dark brown oil.
Reaction SMILES: [Br:1][C:2]1[C:3]([CH2:9][OH:10])=[CH:4][C:5]([Cl:8])=[N:6][CH:7]=1.C(N(CC)CC)C.[CH3:18][S:19](Cl)(=[O:21])=[O:20]>C(Cl)Cl>[CH3:18][S:19]([O:10][CH2:9][C:3]1[C:2]([Br:1])=[CH:7][N:6]=[C:5]([Cl:8])[CH:4]=1)(=[O:21])=[O:20]
Reactant: OCc1cc(Cl)ncc1Br
Reactant: CS(=O)(=O)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CS(=O)(=O)OCc1cc(Cl)ncc1Br
Temperature: 25 °C
Reaction time: 1 h

Procedure:
A 0° C. solution of (5-bromo-2-chloropyridin-4-yl)methanol (1.96 g, 8.81 mmol) in CH2Cl2 (25 mL) was treated with triethylamine (2.456 ml, 17.62 mmol) and methanesulfonyl chloride (0.824 ml, 10.57 mmol). The reaction was stirred at room temperature for 1 hour. The reaction was diluted with additional CH2Cl2, then washed with aqueous NaHCO3, followed by brine. The organic was dried over sodium sulfate, filtered and the filtrate evaporated. The crude was purified by silica gel chromatography to give the titled compound. 1H NMR (CDCl3, 500 MHz): δ 8.50 (s, 1H), 7.47 (s, 1H), 5.24 (s, 2H), 3.16 (s, 3H).
Reaction SMILES: [CH2:1]([O:6][C:7]1[C:15]([O:16][CH2:17][CH2:18][CH2:19][CH2:20][CH3:21])=[CH:14][CH:13]=[C:12]2[C:8]=1[CH:9](O)[N:10]([CH2:23][CH2:24][C:25]1[CH:30]=[CH:29][C:28]([N+:31]([O-:33])=[O:32])=[CH:27][CH:26]=1)[C:11]2=[O:22])[CH2:2][CH2:3][CH2:4][CH3:5].C([SiH](CC)CC)C.FC(F)(F)C(O)=O.C(=O)([O-])O.[Na+]>ClCCl>[CH2:1]([O:6][C:7]1[C:15]([O:16][CH2:17][CH2:18][CH2:19][CH2:20][CH3:21])=[CH:14][CH:13]=[C:12]2[C:8]=1[CH2:9][N:10]([CH2:23][CH2:24][C:25]1[CH:30]=[CH:29][C:28]([N+:31]([O-:33])=[O:32])=[CH:27][CH:26]=1)[C:11]2=[O:22])[CH2:2][CH2:3][CH2:4][CH3:5]
Reactant: CCCCCOc1ccc2c(c1OCCCCC)C(O)N(CCc1ccc([N+](=O)[O-])cc1)C2=O
Agent: CC[SiH](CC)CC
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CCCCCOc1ccc2c(c1OCCCCC)CN(CCc1ccc([N+](=O)[O-])cc1)C2=O
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 86.8 %

Procedure:
4,5-Dipentyloxy-3-hydroxy-2-[2-(4-nitrophenyl)ethyl]-2,3-dihydroisoindol-1-one (1.04 g, 2.2 mmol, 1.0 eq) was dissolved in dichloromethane (20 ml), and triethylsilane (0.70 ml, 4.4 mmol, 2.0 eq) was added. The mixture was stirred for 10 minutes at room temperature. Trifluoroacetic acid (2.2 ml) was added dropwise thereto, and the mixture was further stirred for 4 hours. A saturated aqueous sodium hydrogencarbonate solution (40 ml) was added to this reaction mixture, and the mixture was extracted 3 times with ethyl acetate (30 ml). The organic layers were combined, washed with saturated brine (100 ml) and dried over anhydrous sodium sulfate. The drying agent was filtered off, and the filtrate was concentrated under reduced pressure to give 4,5-dipentyloxy-2-[2-(4-nitrophenyl)ethyl]-2,3-dihydroisoindol-1-one (868 mg, 86.8%) as pale-yellow crystals.
Reaction SMILES: [Cl-].[C:2]([CH2:5][N+:6]1[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=1[CH3:12])(O)=O.[C:13](#[N:16])[CH:14]=C.CCN(CC)CC>C1(C)C=CC=CC=1.O=[Mn]=O>[CH3:12][C:7]1[N:6]2[C:11]([CH:10]=[CH:9][CH:8]=1)=[C:14]([C:13]#[N:16])[CH:2]=[CH:5]2
Reactant: Cc1cccc[n+]1CC(=O)O
Reactant: C=CC#N
Agent: O=[Mn]=O
Agent: [Cl-]
Solvent: CCN(CC)CC
Solvent: Cc1ccccc1
Product: Cc1cccc2c(C#N)ccn12
Reaction time: 12 h

Procedure:
To a solution of crude 1-Carboxymethyl-2-methyl-pyridinium chloride (7 g, 0.037 mol) in toluene (50 mL) were added acrylonitrile (7.4 mL, 0.11 mol), MnO2 (6.5 g, 0.075 mol) and Et3N (2 mL) at room temperature under nitrogen atmosphere. The solution was heated to 90 C and was stirred at the same temperature for 12 hours. The solution was cooled down and was filtered to remove the excess MnO2. The filtrate was concentrated and the residue was purified by CombiFlash with 10% EtOAc in Hexane to afford the desirable product 5-Methyl-indolizine-1-carbonitrile, CAS: 5-Methyl-indolizine-1-carbonitrile (3 g, 52%) as a white solid.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:15])[CH:5]([CH2:11][CH:12]1[CH2:14][CH2:13]1)[C:6]([O:8][CH2:9][CH3:10])=[O:7])[CH3:2].[H-].[Na+].C1C(=O)N([Br:25])C(=O)C1>C1COCC1>[CH2:9]([O:8][C:6](=[O:7])[C:5]([Br:25])([CH2:11][CH:12]1[CH2:13][CH2:14]1)[C:4]([O:3][CH2:1][CH3:2])=[O:15])[CH3:10]
Reactant: CCOC(=O)C(CC1CC1)C(=O)OCC
Reactant: O=C1CCC(=O)N1Br
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CCOC(=O)C(Br)(CC1CC1)C(=O)OCC
Temperature: 0 °C
Reaction time: 0.25 h
Yield: 87.1 %

Procedure:
To an ice-cooled solution of 2-cyclopropylmethylmalonic acid diethyl ester (1.3 g, 6.067 mmol) in THF (45 mL) was added, portionwise, sodium hydride (0.485 g, 60% in oil, 12.13 mmol). The mixture was stirred in the ice bath for 15 min, and then at RT for 15 min. The suspension was re-cooled in the ice bath and NBS (1.19 g, 6.67 mmol) was added over 5 min. The mixture was stirred in the ice bath for 10 min, and then at RT for 30 min. The reaction mixture was filtered through Celite® and the filtrate concentrated in vacuo. The resulting residue was purified by column chromatography (Si-PCC, gradient 2-8% EtOAc in cyclohexane) affording the title compound as a colourless oil (1.55 g, 87%). 1H NMR (CDCl3, 300 MHz): δ 4.33-4.22 (4H, m), 2.24 (2H, d, J=6.6 Hz) 1.30 (6H, d, J=7.1 Hz) 1.01-0.88 (1H, m), 0.54-0.48 (2H, m), 0.17-0.12 (2H, m).
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6]([C:9]2[CH:24]=[CH:23][C:12]3[C@:13]4([CH3:22])[C@@H:18]([CH2:19][CH2:20][C:11]=3[CH:10]=2)[NH:17][C:16](=[O:21])[CH2:15][CH2:14]4)=[CH:5][CH:4]=1)#[N:2].[C:25](O)(C)(C)C.CC(C)([O-])C.[K+].CI>C(OCC)(=O)C>[CH3:25][N:17]1[C@H:18]2[C@@:13]([CH3:22])([C:12]3[CH:23]=[CH:24][C:9]([C:6]4[CH:5]=[CH:4][C:3]([C:1]#[N:2])=[CH:8][CH:7]=4)=[CH:10][C:11]=3[CH2:20][CH2:19]2)[CH2:14][CH2:15][C:16]1=[O:21]
Reactant: C[C@]12CCC(=O)N[C@@H]1CCc1cc(-c3ccc(C#N)cc3)ccc12
Reactant: CC(C)(C)O
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: CI
Solvent: CCOC(C)=O
Product: CN1C(=O)CC[C@]2(C)c3ccc(-c4ccc(C#N)cc4)cc3CC[C@@H]12
Temperature: 25 °C
Reaction time: 4 h
Yield: 80 %

Procedure:
A 15 mL round bottom flask was charged with (+)-(4aR)-(10bR)-8-(4-cyanophenyl)-10b-methyl-1,2,3,4,4a,-5,6,10b-octahydrobenzo[f]quinolin-3-one (24 mg, 0.08 mmol), 0.20 mL of t-butanol, and potassium t-butoxide (26 mg, 0.24 mmol). Methyl iodide (0.014 mL, 0.24 mmol) was added and the mixture was stirred at room temperature for 4 h. The mixture was diluted with ethyl acetate, and purified by silica gel chromatography (ethyl acetate eluent) to give 20 mg (80%) of the title compound as a white solid. mp 148°-150°. FDMS: m/e=330.
Reaction SMILES: [NH2:1][C:2]1[C:11]2[O:10][CH2:9][CH2:8][O:7][C:6]=2[CH:5]=[CH:4][C:3]=1[F:12].[Cl:13]N1C(=O)CCC1=O>CN(C)C=O>[NH2:1][C:2]1[C:11]2[O:10][CH2:9][CH2:8][O:7][C:6]=2[C:5]([Cl:13])=[CH:4][C:3]=1[F:12]
Reactant: Nc1c(F)ccc2c1OCCO2
Reactant: O=C1CCC(=O)N1Cl
Solvent: CN(C)C=O
Product: Nc1c(F)cc(Cl)c2c1OCCO2
Yield: 61.4 %

Procedure:
In a flask were placed 3.05 g (0.018 mole) of 5-amino-6-fluoro-1,4-benzodioxane and 40 mL of N,N-dimethylformamide. To this solution was added in a dropwise manner a solution of 2.65 g (0.0198 mole) of N-chlorosuccinimide in N,N-dimethylformamide while maintaining the temperature at ambient conditions. The solvent was evaporated under reduced pressure, leaving a residue which was passed through a column of silica gel, eluting with methylene chloride/heptane (1:1 ). Product-containing fractions were combined and the solvent evaporated, yielding 2.25 g of 5-amino-8-chloro-6-fluoro-1,4-benzodioxane as the residue. The NMR spectrum was consistent with the proposed structure.
Reaction SMILES: C(OC([NH:6][C:7]1[CH:12]=[CH:11][C:10]([CH:13]2[CH2:18][CH2:17][N:16]([C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])[CH2:15][CH2:14]2)=[CH:9][CH:8]=1)=O)C.[CH3:26][O:27][CH2:28][CH:29]1[CH2:33]O[C:31](=[O:34])[O:30]1>N1C=CC=CC=1>[CH3:26][O:27][CH2:28][CH:29]1[O:30][C:31](=[O:34])[N:6]([C:7]2[CH:12]=[CH:11][C:10]([CH:13]3[CH2:14][CH2:15][N:16]([C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])[CH2:17][CH2:18]3)=[CH:9][CH:8]=2)[CH2:33]1
Reactant: CCOC(=O)Nc1ccc(C2CCN(C(=O)OC(C)(C)C)CC2)cc1
Reactant: COCC1COC(=O)O1
Solvent: c1ccncc1
Product: COCC1CN(c2ccc(C3CCN(C(=O)OC(C)(C)C)CC3)cc2)C(=O)O1
Yield: 58 %

Procedure:
5.5 g (15.0 mmol) of t-butyl 4-(4-ethoxycarbonylamino-phenyl)-piperidine-1-carboxylate and 20 g (0.15 mol) of (RS)-4-(methoxymethyl)-1,3-dioxolan-2-one were stirred intensively in the presence of 2.37 g of pyridine for 18 hours at an oil bath temperature of 160°. After cooling the reaction mixture it was chromatographed on 840 g of silica gel 60 with ether. 3.4 g of t-butyl (RS)-4-[4-(5-methoxymethyl-2-oxo-oxazolidin-3-yl)-phenyl]-piperidine-1-carboxylate were obtained as a yellowish oil. 1H-NMR (CDCl3) ppm: 7.48 (d,2H), 7.22 (d,2H), 4.76 (m,1H), 4.25 (bd,2H), 4.05 (t,1H), 3.92 (t,1H), 3.64 (d,2H), 3.43 (s,3H), 2.80 (t,2H), 2.64 (m,1H), 1.78 (bd,2H), 1.61 (m,2H), 1.49 (s,9H).
Reaction SMILES: [CH:1]1([CH:4]([C:36]2[CH:37]=[N:38][C:39]([O:42][CH3:43])=[CH:40][CH:41]=2)[O:5][C:6]2[CH:33]=[CH:32][C:9]([CH2:10][N:11]3[C:15]4=[N:16][CH:17]=[C:18]([C:20]5[CH:21]=[N:22][N:23]([CH3:25])[CH:24]=5)[CH:19]=[C:14]4[N:13]=[C:12]3[NH:26]C(=O)OCC)=[CH:8][C:7]=2[O:34][CH3:35])[CH2:3][CH2:2]1.[OH-].[K+]>C(O)CCC.O>[CH:1]1([CH:4]([C:36]2[CH:37]=[N:38][C:39]([O:42][CH3:43])=[CH:40][CH:41]=2)[O:5][C:6]2[CH:33]=[CH:32][C:9]([CH2:10][N:11]3[C:15]4=[N:16][CH:17]=[C:18]([C:20]5[CH:21]=[N:22][N:23]([CH3:25])[CH:24]=5)[CH:19]=[C:14]4[N:13]=[C:12]3[NH2:26])=[CH:8][C:7]=2[O:34][CH3:35])[CH2:3][CH2:2]1
Reactant: CCOC(=O)Nc1nc2cc(-c3cnn(C)c3)cnc2n1Cc1ccc(OC(c2ccc(OC)nc2)C2CC2)c(OC)c1
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: CCCCO
Product: COc1ccc(C(Oc2ccc(Cn3c(N)nc4cc(-c5cnn(C)c5)cnc43)cc2OC)C2CC2)cn1
Temperature: 130 °C
Reaction time: 16 h
Yield: 15.1 %

Procedure:
To a stirred solution of ethyl (3-(4-(cyclopropyl(6-methoxypyridin-3-yl)methoxy)-3-methoxybenzyl)-6-(1-methyl-1H-pyrazol-4-yl)-3H-imidazo[4,5-b]pyridin-2-yl)carbamate (0.44 g, 0.75 mmol) in n-butanol (4 mL) and water (4 mL) was added potassium hydroxide (0.42 g, 7.49 mmol). The mixture was heated to 130° C. After 16 h, the mixture was allowed to cool to room temperature and was diluted with water (15 mL). The mixture was extracted with ethyl acetate (2×60 mL). The combined organic phases were dried over sodium sulfate, filtered, and concentrated. The residue was purified via prep-HPLC to provide 0.058 g (15%) of the product as a white solid: 1H NMR (500 MHz, CDCl3) δ 8.24 (d, J=1.5 Hz, 1H), 8.09 (d, J=3.0 Hz, 1H), 7.78 (s, 1H), 7.70-7.68 (m, 2H), 7.64 (s, 1H), 6.78-6.23 (m, 4H), 5.21 (s, 2H), 4.85 (s, 2H), 4.50 (d, J=8.5 Hz, 1H), 3.98 (s, 3H), 3.93 (s, 3H), 3.79 (s, 3H), 1.45-1.40 (m, 1H), 0.75-0.70 (m, 1H), 0.61-0.50 (m, 2H), 0.38-0.34 (m, 1H) ppm; (M+1)=512.
Reaction SMILES: Br.[NH2:2][C:3]1[CH:8]=[C:7]([CH:9](Br)[C:10]([C:12]2[CH:17]=[CH:16][CH:15]=[C:14]([CH3:18])[CH:13]=2)=O)[CH:6]=[CH:5][N:4]=1.[F:20][C:21]1[CH:29]=[CH:28][C:24]([C:25]([NH2:27])=[S:26])=[CH:23][CH:22]=1.C(=O)([O-])O.[Na+]>CN(C)C=O>[F:20][C:21]1[CH:29]=[CH:28][C:24]([C:25]2[S:26][C:9]([C:7]3[CH:6]=[CH:5][N:4]=[C:3]([NH2:2])[CH:8]=3)=[C:10]([C:12]3[CH:17]=[CH:16][CH:15]=[C:14]([CH3:18])[CH:13]=3)[N:27]=2)=[CH:23][CH:22]=1
Reactant: Cc1cccc(C(=O)C(Br)c2ccnc(N)c2)c1
Reactant: NC(=S)c1ccc(F)cc1
Agent: Br
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CN(C)C=O
Product: Cc1cccc(-c2nc(-c3ccc(F)cc3)sc2-c2ccnc(N)c2)c1
Temperature: 25 °C
Reaction time: 16 h
Yield: 84.6 %

Procedure:
2-(2-Amino-4-pyridyl)-2-bromo-1-(3-methylphenyl)ethanone hydrobromide (5.0 g, 13 mmol) was dissolved in N,N-dimethylformamide (40 mL), to the solution was added 4-fluorothiobenzamide (2.1 g, 13 mmol) and the mixture was stirred at room temperature for 16 hours. A saturated aqueous solution of sodium hydrogencarbonate (200 mL) was added to the reaction mixture and the mixture was extracted with ethyl acetate. The extract was dried and the solvent was distilled off. The residue was recrystallized from ethanol to obtain 3.9 g (11 mmol, yield 83%) of the title compound.
Reaction SMILES: [NH2:1][C@@H:2]([CH3:20])[C:3]([NH:5][C:6]1[CH:11]=[CH:10][C:9]([F:12])=[CH:8][C:7]=1[NH:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][N:15]=1)=[O:4].Cl[C:22]1[N:30]=[CH:29][N:28]=[C:27]2[C:23]=1[N:24]=[CH:25][N:26]2C1CCCCO1.CCN(C(C)C)C(C)C>C(O)CCC>[F:12][C:9]1[CH:10]=[CH:11][C:6]([NH:5][C:3](=[O:4])[C@@H:2]([NH:1][C:22]2[N:30]=[CH:29][N:28]=[C:27]3[C:23]=2[N:24]=[CH:25][NH:26]3)[CH3:20])=[C:7]([NH:13][C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][N:15]=2)[CH:8]=1
Reactant: Clc1ncnc2c1ncn2C1CCCCO1
Reactant: C[C@H](N)C(=O)Nc1ccc(F)cc1Nc1ccccn1
Solvent: CCCCO
Solvent: CCN(C(C)C)C(C)C
Product: C[C@H](Nc1ncnc2[nH]cnc12)C(=O)Nc1ccc(F)cc1Nc1ccccn1
Temperature: 90 °C
Yield: 97.1 %

Procedure:
A mixture of (S)-2-amino-N-[4-fluoro-2-(pyridin-2-ylamino)phenyl]propionamide (190 mg, 0.69 mmol), 6-chloro-9-(tetrahydropyran-2-yl)-9H-purine (186 mg, 0.78 mmol) and DIPEA (380 μL, 2.22 mmol) in n-butanol (1.5 mL) was heated at 90° C. in a sealed vial for 65 h. After cooling to RT, the volatiles were removed in vacuo and the resulting residue loaded into an Isolute® SCX-2 cartridge then washed with MeOH followed by 2M NH3/MeOH. The product containing fractions were combined and concentrated in vacuo to afford the title compound as an orange/brown oil (263 mg, 97%). LCMS (Method C): RT 1.67 min [M+H]+ 393.3.
Reaction SMILES: [CH2:1]([N:8]1[CH2:13][CH2:12][NH:11][CH2:10][CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(=O)([O-])[O-].[Na+].[Na+].Cl[CH2:21][C:22]#[N:23]>CC(C)=O>[CH2:1]([N:8]1[CH2:13][CH2:12][N:11]([CH2:21][C:22]#[N:23])[CH2:10][CH2:9]1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: c1ccc(CN2CCNCC2)cc1
Reactant: N#CCCl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CC(C)=O
Product: N#CCN1CCN(Cc2ccccc2)CC1
Yield: 77.3 %

Procedure:
To a suspension of 1-benzylpiperazine (18 g) and sodium carbonate (8.3 g) in acetone (50 ml) was added chloroacetonitrile (12 g) under ice-cooling, and mixed at room temperature for 2 hours. The reaction solution was concentrated under reduced pressure, to the residue were added water and diethyl ether, and the organic layer was collected by separation. The organic layer was washed with water and dried over anhydrous sodium sulfate, and then concentrated under reduced pressure. The residue was purified with silica gel column (ethyl acetate) to obtain the title compound as pale yellow liquid (17 g, 80%).
Reaction SMILES: [NH2:1][C:2]1[CH:10]=[C:6]([C:7]([NH2:9])=[O:8])[C:5]([OH:11])=[CH:4][CH:3]=1.C([O-])(O)=O.[Na+].[I:17][CH2:18][C:19](Cl)=[O:20]>O>[I:17][CH2:18][C:19]([NH:1][C:2]1[CH:10]=[C:6]([C:7]([NH2:9])=[O:8])[C:5]([OH:11])=[CH:4][CH:3]=1)=[O:20]
Reactant: NC(=O)c1cc(N)ccc1O
Reactant: O=C(Cl)CI
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Product: NC(=O)c1cc(NC(=O)CI)ccc1O
Temperature: 2.5 °C
Reaction time: 1 h
Yield: 91.2 %

Procedure:
To an ice-cooled, stirred solution of 5-Aminosalicylamide (10.0 grams, 0.073 mol), in 300 mL of water containing NaHCO3 (42.0 grams, 0.5 mol), iodoacetyl chloride (18.4 grams, 0.09 mol) is added dropwise over 15 min. After stirring at 0-5° C. for 1 hr., the solution is acidified with cold 6 N HCI. The precipitate is collected and dried in vacuo over NaOH pellets, to afford 21.3 grams (96% yield) of crude 5-(iodoacetamido)salicylamide.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][CH2:4][OH:5].Br[CH2:7][C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9]>ClCCl>[C:11]([O:10][C:8](=[O:9])[CH2:7][NH:1][CH2:2][CH2:3][CH2:4][OH:5])([CH3:14])([CH3:13])[CH3:12]
Reactant: NCCCO
Reactant: CC(C)(C)OC(=O)CBr
Solvent: ClCCl
Product: CC(C)(C)OC(=O)CNCCCO
Temperature: 0 °C
Reaction time: 3 h

Procedure:
196 ml of 3-aminopropanol (2.56 mol) were diluted in 250 ml of dichloromethane and the whole was cooled to 0° C. on an ice bath. 20 g of tert-butyl bromoacetate (102.5 mmol), solubilized in 200 ml of dichloromethane, were then added dropwise while the reaction mixture was maintained at 0° C. At the end of the addition (2 hours later), the reaction mixture was left at room temperature for 3 hours.
Reaction SMILES: F[C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[CH:4][CH:3]=1.[NH:11]1[CH2:15][CH2:14][CH2:13][CH2:12]1.C(N(CC)CC)C>C(O)(C)C>[N+:8]([C:5]1[CH:6]=[CH:7][C:2]([N:11]2[CH2:15][CH2:14][CH2:13][CH2:12]2)=[CH:3][CH:4]=1)([O-:10])=[O:9]
Reactant: C1CCNC1
Reactant: O=[N+]([O-])c1ccc(F)cc1
Solvent: CCN(CC)CC
Solvent: CC(C)O
Product: O=[N+]([O-])c1ccc(N2CCCC2)cc1
Temperature: 25 °C
Yield: 85 %

Procedure:
To a solution of 4-fluoronitrobenzene (1.0 eq.) in isopropyl alcohol, pyrrolidine (2.2 eq) and triethylamine (11.0 eq) were added and reaction mixture was refluxed overnight. Reaction mixture was cooled to room temperature, product obtained was collected by filtration and dried to get the desired 1-(4-nitrophenyl)pyrrolidine. (Yield=85%)
Reaction SMILES: CN(CCN(C)C)C.[CH2:9]([Li])[CH2:10][CH2:11][CH3:12].[CH2:14]=[CH:15][CH:16]1[O:18][CH2:17]1>CCCCCC>[CH2:17]([OH:18])[CH:16]=[CH:15][CH2:14][CH2:9][CH2:10][CH2:11][CH3:12]
Reactant: C=CC1CO1
Reactant: [Li]CCCC
Agent: CN(C)CCN(C)C
Solvent: CCCCCC
Product: CCCCCC=CCO
Temperature: 0 °C

Procedure:
A solution of 258 mg of TMEDA in 1 ml of hexane was cooled to 0° C., and a hexane solution of n-butyllithium (1.1 mmol) was added dropwise thereto under a nitrogen atmosphere and stirred at 0° C. To the resultant mixture, there was added dropwise 1 ml of a hexane solution of 3,4-epoxy-butene-1 (1 mol/liter). After completion of the addition, the resultant mixture was stirred at 0° C. for 1 hour and at room temperature for 30 minutes, followed by the usual work up. After removal of the solvent, the residue was distilled to give 41 mg of 2-octen-1-ol as a colorless oily product (yield, 32%). After acetylation of the thus obtained product, gas chromatographic analysis (PEG 20M, 45 m) was effected at a temperature of 130° C. The Z/E ratio was 76.8/23.2.
Reaction SMILES: CN(C=[N:5][S:6]([CH2:9][CH:10]([CH:13]([CH3:15])[CH3:14])[CH2:11][OH:12])(=[O:8])=[O:7])C.Cl[C:17]1[C:18]([CH3:26])=[CH:19][C:20]2[N:21]([N:23]=[CH:24][N:25]=2)[N:22]=1>>[CH:13]([CH:10]([CH2:9][S:6](=[O:7])(=[O:8])[NH2:5])[CH2:11][O:12][C:17]1[C:18]([CH3:26])=[CH:19][C:20]2[N:21]([N:23]=[CH:24][N:25]=2)[N:22]=1)([CH3:14])[CH3:15]
Reactant: CC(C)C(CO)CS(=O)(=O)N=CN(C)C
Reactant: Cc1cc2ncnn2nc1Cl
Product: Cc1cc2ncnn2nc1OCC(CS(N)(=O)=O)C(C)C

Procedure:
Using 3-(N,N-dimethylaminomethylene)aminosulfonyl-2-isopropyl-1-propanol and 6-chloro-7-methyl[1,2,4]triazolo[1,5-b]pyridazine, the same reaction as in Example 6 was conducted to produce the title compound. m.p. 196°-197° C.
Reaction SMILES: C([O:3][C:4](=O)[CH2:5][CH2:6][CH2:7][NH:8][S:9]([CH3:12])(=[O:11])=[O:10])C.[NH4+:14].[OH-]>>[CH3:12][S:9]([NH:8][CH2:7][CH2:6][CH2:5][C:4]([NH2:14])=[O:3])(=[O:11])=[O:10]
Reactant: [NH4+]
Reactant: CCOC(=O)CCCNS(C)(=O)=O
Agent: [OH-]
Product: CS(=O)(=O)NCCCC(N)=O

Procedure:
A solution of 4-methanesulfonylamino-butyric acid ethyl ester (7.08 g, 33.8 mmol) in concentrated NH4OH (200 mL) was stirred at room temperature for 66 h. The reaction mixture was concentrated to afford the title compound as a white solid (6.16 g). The product was used in the next step without further purification. 1H NMR (400 MHz, CDCl3) δ 3.30 (s, 3H), 3.05-3.09 (m, 2H), 2.91 (s, 3H), 2.24-2.30 (m, 2H), 1.80-1.85 (m, 2H); MS 181 (M++1).