Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C[O:2][C:3]([C:5]1[N:13]=[C:12]2[C:8]([N:9]=[CH:10][N:11]2[C@@H:14]2[CH2:18][C@H:17]([N:19]([C:24]([O:26][C:27]([CH3:30])([CH3:29])[CH3:28])=[O:25])C(=O)CC)[C@@H:16]([OH:31])[C@H:15]2[OH:32])=[C:7]([NH:33][CH2:34][CH:35]([C:42]2[CH:47]=[CH:46][CH:45]=[CH:44][CH:43]=2)[C:36]2[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=2)[N:6]=1)=O.[CH2:48]([NH2:51])[CH2:49][NH2:50]>>[C:27]([O:26][C:24](=[O:25])[NH:19][C@H:17]1[CH2:18][C@@H:14]([N:11]2[CH:10]=[N:9][C:8]3[C:12]2=[N:13][C:5]([C:3](=[O:2])[NH:50][CH2:49][CH2:48][NH2:51])=[N:6][C:7]=3[NH:33][CH2:34][CH:35]([C:42]2[CH:47]=[CH:46][CH:45]=[CH:44][CH:43]=2)[C:36]2[CH:37]=[CH:38][CH:39]=[CH:40][CH:41]=2)[C@H:15]([OH:32])[C@@H:16]1[OH:31])([CH3:28])([CH3:30])[CH3:29]
Reactant: CCC(=O)N(C(=O)OC(C)(C)C)[C@H]1C[C@@H](n2cnc3c(NCC(c4ccccc4)c4ccccc4)nc(C(=O)OC)nc32)[C@H](O)[C@@H]1O
Reactant: NCCN
Product: CC(C)(C)OC(=O)N[C@H]1C[C@@H](n2cnc3c(NCC(c4ccccc4)c4ccccc4)nc(C(=O)NCCN)nc32)[C@H](O)[C@@H]1O
Temperature: 90 °C

Procedure:
A solution comprising 9-[(1R,2S,3R,4S)-4-(tert-butoxycarbonyl-propionyl-amino)-2,3-dihydroxy-cyclopentyl]-6-(2,2-diphenyl-ethylamino)-9H-purine-2-carboxylic acid methyl ester (3.00 g, 4.66 mmol) in ethylenediamine (5 ml, 75 mmol) is heated at 90° C. for 1 hour. After cooling to room temperature, the ethylenediamine is removed in vacuo and purification by C-18 reverse phase column chromatography eluting with water (100%) followed by MeOH (100%) yields the title compound.
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([C:10]2([C:15]([OH:17])=O)[CH2:14][CH2:13][CH2:12][CH2:11]2)=[CH:6][CH:5]=1)([O-:3])=[O:2].C(Cl)(=O)C([Cl:21])=O>ClCCl.CN(C)C=O>[N+:1]([C:4]1[CH:9]=[CH:8][C:7]([C:10]2([C:15]([Cl:21])=[O:17])[CH2:14][CH2:13][CH2:12][CH2:11]2)=[CH:6][CH:5]=1)([O-:3])=[O:2]
Reactant: O=C(Cl)C(=O)Cl
Reactant: O=C(O)C1(c2ccc([N+](=O)[O-])cc2)CCCC1
Solvent: CN(C)C=O
Solvent: ClCCl
Product: O=C(Cl)C1(c2ccc([N+](=O)[O-])cc2)CCCC1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
A stirred suspension of 1-(4-nitro-phenyl)-cyclopentanecarboxylic acid (8.85 g) in dry dichloromethane (100 mL) was treated with oxalyl chloride (5.0 mL) and catalytic amount dry dimethylformamide (5 drops). The mixture was stirred at room temperature, under anhydrous conditions, for 16 hours then evaporated to give the title compound as an off white solid (100%), which was used without further purification.
Reaction SMILES: [C:1]([NH:3][C:4](=[N:7][CH:8]1[C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[CH2:11][CH2:10][CH2:9]1)SC)#[N:2].[CH2:18]([NH2:22])[CH:19]([CH3:21])[CH3:20]>C(#N)C>[C:1]([N:3]=[C:4]([NH:7][CH:8]1[C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[CH2:11][CH2:10][CH2:9]1)[NH:22][CH2:18][CH:19]([CH3:21])[CH3:20])#[N:2]
Reactant: CC(C)CN
Reactant: CSC(=NC1CCCc2ccccc21)NC#N
Solvent: CC#N
Product: CC(C)CNC(=NC#N)NC1CCCc2ccccc21
Reaction time: 100 h

Procedure:
A solution of 12.3 g of N-cyano-N'-(1,2,3,4-tetrahydro-1-naphthyl)-S-methylisothiourea and 20 ml of isobutylamine in 100 ml of acetonitrile was heated at reflux with stirring for 100 hours. The solvent was then removed by evaporation in vacuo. The residual oil was dissolved in methylene chloride and the solution was washed with three 80 ml portions of 3N hydrochloric acid and then dried over anhydrous sodium sulfate. The sodium sulfate was removed by filtration, and the methylene chloride was removed from the filtrate by evaporation in vacuo, leaving N"-cyano-N-isobutyl-N'-(1,2,3,4-tetrahydro-1-naphthyl)guanidine as 11.6 g of a pale yellow, viscous oil.
Reaction SMILES: [OH:1][C:2]1[N:6]([C:7]2[CH:12]=[C:11]([C:13]#[N:14])[CH:10]=[CH:9][N:8]=2)[N:5]=[CH:4][CH:3]=1.[CH:15]1([C:18]2[CH:23]=[CH:22][C:21]([CH2:24]O)=[C:20]([F:26])[CH:19]=2)[CH2:17][CH2:16]1>>[CH:15]1([C:18]2[CH:23]=[CH:22][C:21]([CH2:24][O:1][C:2]3[N:6]([C:7]4[CH:12]=[C:11]([C:13]#[N:14])[CH:10]=[CH:9][N:8]=4)[N:5]=[CH:4][CH:3]=3)=[C:20]([F:26])[CH:19]=2)[CH2:17][CH2:16]1
Reactant: N#Cc1ccnc(-n2nccc2O)c1
Reactant: OCc1ccc(C2CC2)cc1F
Product: N#Cc1ccnc(-n2nccc2OCc2ccc(C3CC3)cc2F)c1

Procedure:
The title compound was prepared from 2-(5-hydroxy-1H-pyrazol-1-yl)pyridine-4-carbonitrile and (4-cyclopropyl-2-fluorophenyl)methanol according to the procedure for the preparation of Example 39, part C. 1H NMR (800 MHz, CDCl3): δ 0.68-0.73 (2H, m), 0.99-1.04 (2H, m), 1.86-1.92 (1H, m), 5.24 (2H, s), 5.80 (1H, d, J=4.0 Hz), 6.78 (1H, dd, J=4.0 Hz, 23.2 Hz), 6.88 (1H, dd, J=3.2 Hz, 16.0 Hz), 7.30-7.34 (1H, m), 7.39 (1H, dd, J=1.6 Hz, 9.6 Hz), 7.57 (1H, d, J=3.2 Hz), 8.00 (1H, s), 8.69 (1H, d, J=9.6 Hz). [M+H] Calc'd for C19H15FN4O, 335. Found, 335.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[CH:4][C:3]=1[CH2:9][NH:10][CH:11]1[CH2:16][CH2:15][N:14]([CH2:17][C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[CH2:13][CH2:12]1.[C:24](C1NC=CN=1)(C1NC=CN=1)=[O:25]>O1CCCC1>[CH2:17]([N:14]1[CH2:13][CH2:12][CH:11]([N:10]2[CH2:9][C:3]3[C:2](=[CH:7][CH:6]=[C:5]([OH:8])[CH:4]=3)[NH:1][C:24]2=[O:25])[CH2:16][CH2:15]1)[C:18]1[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=1
Reactant: O=C(c1ncc[nH]1)c1ncc[nH]1
Reactant: Nc1ccc(O)cc1CNC1CCN(Cc2ccccc2)CC1
Solvent: C1CCOC1
Product: O=C1Nc2ccc(O)cc2CN1C1CCN(Cc2ccccc2)CC1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 58.1 %

Procedure:
A stirred solution of 4-amino-3-[(1-benzyl-piperidin-4-yl-amino)-methyl]-phenol (0.16 g, 0.51 mmol) in tetrahydrofuran (3 mL) at 0° C. was treated with carbonyl diimidazole (52 mg, 0.51 mmol). The reaction was stirred for 30 min at 0° C. and at reflux for 1 h. After cooling to room temperature, the solvent was evaporated and the residue purified by column to afford 100 mg (57%) of the desired product. LC/MS: tR=1.09 min, 338.28 (MH)+.
Reaction SMILES: [CH2:1]1[O:11][CH:2]1[CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH3:10].[CH2:12]([NH2:15])[CH2:13][NH2:14]>C(O)C>[CH2:12]([NH:15][CH2:1][CH:2]([OH:11])[CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH3:10])[CH2:13][NH:14][CH2:1][CH:2]([OH:11])[CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH3:10]
Reactant: CCCCCCCCC1CO1
Reactant: NCCN
Solvent: CCO
Product: CCCCCCCCC(O)CNCCNCC(O)CCCCCCCC

Procedure:
In a manner similar to that of Example 1, condensation of 1-decene oxide (100 g.) and ethylenediamine (19.2 g.) and recrystallization of a portion (20 g.) of the resulting solid (45 g.) from ethanol gave N,N'-ethylenebis[2-hydroxydecylamine] (I: R = CH3 (CH2)7, R' = H, X = (CH2)2, Z = H) (13.6 g., m.p. 140.0°-145.8° C.).
Reaction SMILES: [NH2:1][C:2]1[N+:7]([O-:8])=[C:6]([NH2:9])[CH:5]=[C:4]([N:10]2[CH2:15][CH:14]=[CH:13][CH2:12][CH2:11]2)[N:3]=1.[CH3:16][O:17][C:18](Cl)=[O:19].[OH-].[Na+]>C(Cl)Cl.O>[NH2:1][C:2]1[N+:7]([O-:8])=[C:6]([NH:9][C:18]([O:17][CH3:16])=[O:19])[CH:5]=[C:4]([N:10]2[CH2:11][CH:12]=[CH:13][CH2:14][CH2:15]2)[N:3]=1
Reactant: COC(=O)Cl
Reactant: Nc1cc(N2CC=CCC2)nc(N)[n+]1[O-]
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: ClCCl
Product: COC(=O)Nc1cc(N2CC=CCC2)nc(N)[n+]1[O-]

Procedure:
20 G. of 2,4-diamino-6-[3,6-dihydro-1(2H)-pyridyl]-pyrimidine-3-oxide are suspended and stirred in 140 ml. of methylene chloride and 120 ml. of water. While cooling, there are simultaneously added dropwise 8 ml. of chloroformic acid methyl ester in 20 ml. of methylene chloride and sufficient 28% sodium hydroxide so that the pH value is held between 7.0 and 7.5. After completion of the addition, the mixture is stirred for a further 1 hour and the residue is subsequently filtered off. The two phases obtained are separated and the organic phase is treated for 1 hour while stirring at 0° C. with 150 ml. of 1-N sodium hydroxide. The mixture obtained is treated with 20 ml. of methanol and the two phases are separated. The aqueous phase is extracted twice with 200 ml. of methylene chloride and the combined organic extracts are dried over sodium sulfate. By evaporation of the solvent there is obtained pure methyl 2-amino-6-[3,6-dihydro-1(2H)-pyridyl]-4-pyrimidinecarbamate-3-oxide having a melting point of 174°-176° C.
Reaction SMILES: Br[CH2:2][CH2:3][CH2:4][CH2:5][C:6]12[CH2:17][CH2:16][CH2:15][C:13]3[C:14]1=[C:9]([CH:10]=[CH:11][CH:12]=3)[NH:8][C:7]2=[O:18].[N:19]1[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=1[N:25]1[CH2:30][CH2:29][NH:28][CH2:27][CH2:26]1.C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O>[N:19]1[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=1[N:25]1[CH2:26][CH2:27][N:28]([CH2:2][CH2:3][CH2:4][CH2:5][C:6]23[CH2:17][CH2:16][CH2:15][C:13]4[C:14]2=[C:9]([CH:10]=[CH:11][CH:12]=4)[NH:8][C:7]3=[O:18])[CH2:29][CH2:30]1
Reactant: c1ccc(N2CCNCC2)nc1
Reactant: O=C1Nc2cccc3c2C1(CCCCBr)CCC3
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: O=C1Nc2cccc3c2C1(CCCCN1CCN(c2ccccn2)CC1)CCC3
Yield: 100 %

Procedure:
2a-(4-Bromobutyl)-2a,3,4,5-tetrahydrobenz[cd]indole-2(1H)-one (147 mg, 0.48 mmol), 1-(2-pyridyl)piperazine (86 mg, 0.53 mmol) and potassium carbonate (99 mg, 0.72 mmol) were stirred overnight in anhydrous N,N-dimethylformamide (2 ml) at 60° C. The solvent was evaporated under a reduced pressure, and the thus obtained residue was mixed with ethyl acetate and water. The reaction product was extracted with ethyl acetate, washed with saturated brine and dried with anhydrous sodium sulfate, the solvent was evaporated under a reduced pressure and then the thus obtained substance was separated and purified by a silica gel column chromatography to obtain 190 mg of the title compound (0.48 mmol, 100% in yield).
Reaction SMILES: [CH:1]([C:3]1[CH:17]=[CH:16][C:6]([O:7][CH2:8][CH2:9][CH2:10][C:11]([O:13]CC)=[O:12])=[C:5]([N+:18]([O-:20])=[O:19])[CH:4]=1)=[O:2].C(=O)([O-])[O-].[K+].[K+]>CO.O>[CH:1]([C:3]1[CH:17]=[CH:16][C:6]([O:7][CH2:8][CH2:9][CH2:10][C:11]([OH:13])=[O:12])=[C:5]([N+:18]([O-:20])=[O:19])[CH:4]=1)=[O:2]
Reactant: CCOC(=O)CCCOc1ccc(C=O)cc1[N+](=O)[O-]
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CO
Product: O=Cc1ccc(OCCCC(=O)O)c([N+](=O)[O-])c1
Yield: 69.1 %

Procedure:
4-(4-Formyl-2-nitrophenoxy)butanoic acid, ethyl ester (135 mg, 0.48 mmol) is dissolved in 3 mL of methanol/water (3:2) and treated with 232 mg (1.68 mmol) of potassium carbonate according to the procedure described for Example 4 to give 84 mg (69%) of 4-(4-formyl-2-nitrophenoxy)butanoic acid as a yellow powder: m.p. 136°-139°; the 1H NMR (300 MHz, CDCl3) is consistent with the desired product; IR (KBr) 3400, 1730, 1700, 1650, 1600, 1570 cm-1 ; MS (CI) m/e 254, 236, 224, 208, 196, 168.
Reaction SMILES: [C:1]([Si:5]([CH3:17])([CH3:16])[O:6][C:7]1[CH:15]=[C:14]2[C:10]([CH:11]=[CH:12][NH:13]2)=[CH:9][CH:8]=1)([CH3:4])([CH3:3])[CH3:2].C(=O)([O-])[O-].[Cs+].[Cs+].[C:24]([O:28][C:29](=[O:32])[CH2:30]Br)([CH3:27])([CH3:26])[CH3:25]>CN(C=O)C>[C:24]([O:28][C:29](=[O:32])[CH2:30][N:13]1[C:14]2[C:10](=[CH:9][CH:8]=[C:7]([O:6][Si:5]([C:1]([CH3:4])([CH3:3])[CH3:2])([CH3:17])[CH3:16])[CH:15]=2)[CH:11]=[CH:12]1)([CH3:27])([CH3:26])[CH3:25]
Reactant: CC(C)(C)[Si](C)(C)Oc1ccc2cc[nH]c2c1
Reactant: CC(C)(C)OC(=O)CBr
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)Cn1ccc2ccc(O[Si](C)(C)C(C)(C)C)cc21
Temperature: 25 °C
Reaction time: 14 h
Yield: 75.4 %

Procedure:
To an ice cold solution of 6-(tert-butyl-dimethyl-silanyloxy)-1H-indole (13 g, 52.5 mmol) and cesium carbonate (18.8 g, 57.8 mmol) in DMF (130 ml) under an argon atmosphere was added bromo-acetic acid tert-butyl ester (8.5 ml, 57.8 mmol). The mixture was naturally warmed to room temperature, stirred for 14 h, poured onto 2 N HCl/ice water 1/1 and extracted two times with ethyl acetate. The combined organic layers were washed with water and dried over sodium sulfate. The solvent was removed under reduced pressure and the residue purified by column chromatography (silica gel, heptane/AcOEt) to give 14.3 g (39.6 mmol, 75%) of the title compound as yellow oil.
Reaction SMILES: [CH3:1][N:2]1[C:11]([OH:12])=[C:5]2[N:6]=[CH:7][N:8]=[C:9]([SH:10])[C:4]2=[N:3]1.C(=O)([O-])[O-].[K+].[K+].Cl[CH2:20][C:21]([O:23][CH3:24])=[O:22]>CO>[CH3:1][N:2]1[C:11]([OH:12])=[C:5]2[N:6]=[CH:7][N:8]=[C:9]([S:10][CH2:20][C:21]([O:23][CH3:24])=[O:22])[C:4]2=[N:3]1
Reactant: COC(=O)CCl
Reactant: Cn1nc2c(S)ncnc2c1O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CO
Product: COC(=O)CSc1ncnc2c(O)n(C)nc12
Temperature: 60 °C

Procedure:
1.5 g of 2-methyl-3-hydroxy-7-mercapto-pyrazolo [4,3-d]pyrimidine was suspended in 35 ml of methanol, and 1.25 g of anhydrous potassium carbonate and 1.07 g of methyl chloroacetate were sequentially added. The mixture was heated at 60° C. for 18 hours. Then, the solvent was distilled off. Water was added to the residue, and the residue was dissolved. Chloroform-soluble substances were extracted with chloroform and removed. Then, the aqueous layer was acidified with 1:1 hydrochloric acid, and the precipitated solid was extracted with chloroform. This chloroform layer was washed with water, and dried over anhydrous magnesium sulfate. Then, the solvent was distilled off. The remaining solid was recrystallized from acetone-chloroform.
Reaction SMILES: [OH-].[Na+].[CH3:3][O:4][C:5]([C:7]1[NH:8][CH:9]=[C:10]([S:12][C:13]#N)[CH:11]=1)=[O:6].BrC[CH2:17][C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1>O.CC(O)(C)C>[CH2:13]([S:12][C:10]1[CH:11]=[C:7]([C:5]([O:4][CH3:3])=[O:6])[NH:8][CH:9]=1)[CH2:17][C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1
Reactant: COC(=O)c1cc(SC#N)c[nH]1
Reactant: BrCCc1ccccc1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CC(C)(C)O
Product: COC(=O)c1cc(SCCc2ccccc2)c[nH]1
Temperature: 60 °C
Reaction time: 2 h
Yield: 85.9 %

Procedure:
A solution of sodium hydroxide (88.0 mg, 2.20 mmol) in degassed H2O (0.500 mL) was added to a mixture of 2-methoxycarbonyl-4-thiocyanopyrrole (0.200 g, 1.10 mmol), prepared according to the procedure described in J. Chem. Soc. Perkin Trans. 2 1990, 699, and (2-bromoethyl)benzene (0.165 mL, 1.21 mmol) in degassed t-BuOH (2.0 mL). The reaction mixture was stirred at 60° C. for 2 h, cooled to rt and concentrated. The residue was dissolved in CH2Cl2 (50 mL) washed with H2O (2×25 mL), dried over anhydrous Na2SO4, concentrated and purified by chromatography on silica gel with MeOH and CH2Cl2 (0-10% gradient) as the mobile phases to afford 0.247 g of the title compound as a light yellow oil: 1H NMR (500 MHz, CDCl3) δ 2.83-2.88 (m, 2H), 2.89-2.95 (m, 2H), 3.87 (s, 3H), 6.94-6.97 (m, 1H), 7.00 (dd, J=2.7, 1.6 Hz, 1H), 7.14-7.22 (m, 3H), 7.26-7.30 (m, 2H), 9.30 (br. s., 1H); HPLC a) column: Phenomenex Luna 5μ 4.6×50 mm, 4 min gradient, 10% MeOH/90% H2O/0.1% H3PO4 to 90% MeOH/10% H2O/0.1% H3PO4; 1 min hold, 4 mL/min UV detection at 220 nm, 3.561 min retention time, (>95%); HPLC b) column: Phenomenex Luna C18 4.6×50 mm, 4 min gradient, 10% MeOH/90% H2O/0.1% TFA to 90% MeOH/10% H2O/0.1% TFA, 1 min hold; 4 mL/min, UV detection at 220 nm, 3.535 min retention time; MS (ES) 262 [M+H]+.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([Cl:8])[C:3]=1[C:9]1[C:29]([NH2:30])=[N:28][C:12]2[N:13]=[C:14]([NH:17][CH2:18][CH2:19][CH2:20][N:21]3[CH2:26][CH2:25][N:24]([CH3:27])[CH2:23][CH2:22]3)[N:15]=[CH:16][C:11]=2[CH:10]=1.[Br:31][C:32]1[CH:37]=[CH:36][C:35]([N:38]=[C:39]=[O:40])=[CH:34][CH:33]=1>CO.CC#N>[Br:31][C:32]1[CH:37]=[CH:36][C:35]([NH:38][C:39]([NH:30][C:29]2[C:9]([C:3]3[C:4]([Cl:8])=[CH:5][CH:6]=[CH:7][C:2]=3[Cl:1])=[CH:10][C:11]3[CH:16]=[N:15][C:14]([NH:17][CH2:18][CH2:19][CH2:20][N:21]4[CH2:26][CH2:25][N:24]([CH3:27])[CH2:23][CH2:22]4)=[N:13][C:12]=3[N:28]=2)=[O:40])=[CH:34][CH:33]=1
Reactant: CN1CCN(CCCNc2ncc3cc(-c4c(Cl)cccc4Cl)c(N)nc3n2)CC1
Reactant: O=C=Nc1ccc(Br)cc1
Solvent: CO
Solvent: CC#N
Product: CN1CCN(CCCNc2ncc3cc(-c4c(Cl)cccc4Cl)c(NC(=O)Nc4ccc(Br)cc4)nc3n2)CC1
Yield: 67.7 %

Procedure:
6-(2,6-Dichlorophenyl)-N2 -[3-(4-methyl-piperazin-1-yl)-propyl]-pyrido[2,3-d]pyrimidine-2,7-diamine (1.0 g) from Example 36 was reacted with 0.44 g of 4-bromophenyl isocyanate according to the general procedure of Example 37 to give 0.97 g of 1-(4-Bromo-phenyl)-3-{6-(2,6-dichlorophenyl)-2-[3-(4-methylpiperazin-1-yl)-propylamino]-pyrido[2,3-d]pyrimidin-7-yl}-urea, ESMS (20/80 MeOH/CH3CN+0.1% AcOH+DMSO): M+ +H=645; mp 171-175° C.
Reaction SMILES: [OH:1][C@:2]1([CH2:9][NH:10][C:11]([C:13]2[C:14]3[CH:15]=[CH:16][C:17](Cl)=[N:18][C:19]=3[CH:20]=[CH:21][C:22]=2[Cl:23])=[O:12])[CH2:7][CH2:6][CH2:5][C@@H:4]([CH3:8])[CH2:3]1.CCN(C(C)C)C(C)C.[F:34][CH:35]1[CH2:39][NH:38][CH:37]([CH2:40][OH:41])[CH2:36]1>>[OH:1][C@:2]1([CH2:9][NH:10][C:11]([C:13]2[C:14]3[CH:15]=[CH:16][C:17]([N:38]4[CH2:39][CH:35]([F:34])[CH2:36][CH:37]4[CH2:40][OH:41])=[N:18][C:19]=3[CH:20]=[CH:21][C:22]=2[Cl:23])=[O:12])[CH2:7][CH2:6][CH2:5][C@@H:4]([CH3:8])[CH2:3]1
Reactant: C[C@@H]1CCC[C@](O)(CNC(=O)c2c(Cl)ccc3nc(Cl)ccc23)C1
Reactant: OCC1CC(F)CN1
Solvent: CCN(C(C)C)C(C)C
Product: C[C@@H]1CCC[C@](O)(CNC(=O)c2c(Cl)ccc3nc(N4CC(F)CC4CO)ccc23)C1

Procedure:
The title compound was synthesized according to the procedure described in example 1 using 2,6-dichloro-quinoline-5-carboxylic acid ((1R,3R)-1-hydroxy-3methyl-cyclohexylmethyl)-amide, DIPEA and 4-fluoro-2-(hydroxymethyl) pyrrolidine. 1H NMR (400 MHz, DMSO-d6) δ ppm 8.75 (1H), 7.85 (m, 1H), 7.58 (2H), 7.05 (1H), 5.43-5.56 (1H), 5.07 (m, 1H), 4.31 (m, 1H), 4.16 (s, 1H), 3.89 (m, 1H), 3.70 (m, 2H), 3.55 (m, 1H), 3.26 (m, 2H), 2.44 (m, 2H), 2.06 (m, 2H), 1.85 (m, 2H), 1.74-1.76 (m, 5H), 1.27-1.32 (m, 1H), 0.83 (d, 3H), 0.74 (m, 1H). m/z: 450 [M+H]
Reaction SMILES: O[C:2]1([CH3:11])[CH:6]([CH2:7][CH:8]=[CH2:9])[C:5](=[O:10])[CH:4]=[CH:3]1.[Na+].[Cl-].[OH2:14]>[Cl-].[Cl-].[Zn+2]>[CH2:7]([C:6]1[C:5](=[O:10])[CH2:4][CH:3]([OH:14])[C:2]=1[CH3:11])[CH:8]=[CH2:9]
Reactant: C=CCC1C(=O)C=CC1(C)O
Reactant: O
Agent: [Cl-]
Agent: [Na+]
Agent: [Zn+2]
Product: C=CCC1=C(C)C(O)CC1=O

Procedure:
Into a reaction vessel, a solution of 4-hydroxy-4-methyl-5-allyl-2-cyclopentenone (3 g) and ZnCl2 (5 g) in water (120 ml) was charged, and the temperature was elevated up to 100° C. The contents were refluxed for 15 hours while stirring. After cooling, NaCl (40 g) was added to the reaction mixture, and the resulting mixture was extracted with toluene (120 ml) 4 times. The extracts were combined together and concentrated at 50° C. under reduced pressure to give an oily substance (2.5 g). The oily substance was chromatographed on silica gel (30 g), followed by development with a solvent mixture of ethyl acetate and hexane (1:2 by volume) to give 2-allyl-3-methyl-4-hydroxy-2cyclopentenone (2.4 g). Yield, 80%.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[C:4]([C:9]([CH3:11])=[O:10])[CH:3]=1.[Br:12][C:13]1[C:20]([O:21][CH3:22])=[C:19]([O:23][CH3:24])[CH:18]=[CH:17][C:14]=1[CH:15]=O>>[Br:12][C:13]1[C:20]([O:21][CH3:22])=[C:19]([O:23][CH3:24])[CH:18]=[CH:17][C:14]=1/[CH:15]=[CH:11]/[C:9]([C:4]1[CH:3]=[C:2]([CH3:1])[CH:7]=[CH:6][C:5]=1[OH:8])=[O:10]
Reactant: COc1ccc(C=O)c(Br)c1OC
Reactant: CC(=O)c1cc(C)ccc1O
Product: COc1ccc(/C=C/C(=O)c2cc(C)ccc2O)c(Br)c1OC
Yield: 65.1 %

Procedure:
2-Hydroxy-5-methylacetophenone (85 mg, 0.57 mmol) and 2-bromo-3,4-dimethoxybenzaldehyde (166 mg, 0.68 mmol) were reacted according to the same procedure as Preparation 1 to give 140 mg (Yield 54.6%) of the title compound.
Reaction SMILES: Cl.Cl.[NH2:3][C@@H:4]([C@H:20]([O:22][CH3:23])[CH3:21])[CH2:5][S:6]([CH2:9][C:10]1[CH:11]=[N:12][C:13]2[C:18]([CH:19]=1)=[CH:17][CH:16]=[CH:15][CH:14]=2)(=[O:8])=[O:7].Br[CH2:25][C:26]#[N:27].C(N(C(C)C)C(C)C)C>C(#N)C>[C:26]([CH2:25][NH:3][C@@H:4]([C@H:20]([O:22][CH3:23])[CH3:21])[CH2:5][S:6]([CH2:9][C:10]1[CH:11]=[N:12][C:13]2[C:18]([CH:19]=1)=[CH:17][CH:16]=[CH:15][CH:14]=2)(=[O:7])=[O:8])#[N:27]
Reactant: CO[C@H](C)[C@H](N)CS(=O)(=O)Cc1cnc2ccccc2c1
Reactant: N#CCBr
Agent: Cl
Solvent: CC#N
Solvent: CCN(C(C)C)C(C)C
Product: CO[C@H](C)[C@@H](CS(=O)(=O)Cc1cnc2ccccc2c1)NCC#N

Procedure:
A mixture of (2S,3R)-2-amino-3-methoxy-1-(3-quinolylmethanesulfonyl)butane dihydrochloride (0.93 g), bromoacetonitrile (0.41 ml) and N-ethyldiisopropylamine (1.7 ml) in acetonitrile (15 ml) was refluxed for 16 h, cooled and evaporated. The residue was partitioned between MDC (15 ml) and saturated sodium hydrogen carbonate solution (15 ml). The organic phase was collected and the aqueous re-extracted with MDC (15 ml). The combined MDC phases were dried (MgSO4) and evaporated. The residue was flash chromatographed (silica gel, step gradient: 70–100% EtOAc/hexane) to give the subtitle compound (0.59 g). MS (APCI+ve ion) 348(MH+); 1H NMR δ(CDCl3): 8.91 (1H, m), 8.3 (1H, d, J=2 Hz), 8.14 (1H, d, J=8 Hz), 7.78 (1H, d, J=8 Hz), 7.78 (1H, t, J=8 Hz), 7.60 (1H, t, J=8 Hz), 4.55 (2H, s), 3.4–3.88 (4H, m), 3.33 (3H, s), 2.93–3.28 (2H, m), 2.18 (1H, m), 0.93 (3H, d, J=6.3 Hz).
Reaction SMILES: [CH3:1][N:2]1[CH2:15][C:14]([CH3:17])([CH3:16])[C:5]2[NH:6][C:7]3[CH:8]=[CH:9][C:10]([CH3:13])=[CH:11][C:12]=3[C:4]=2[CH2:3]1.[H-].[Na+].[O:20]1[CH2:22][CH:21]1[C:23]1[CH:28]=[CH:27][N:26]=[CH:25][CH:24]=1>CN(C=O)C>[N:26]1[CH:27]=[CH:28][C:23]([CH:21]([OH:20])[CH2:22][N:6]2[C:7]3[CH:8]=[CH:9][C:10]([CH3:13])=[CH:11][C:12]=3[C:4]3[CH2:3][N:2]([CH3:1])[CH2:15][C:14]([CH3:17])([CH3:16])[C:5]2=3)=[CH:24][CH:25]=1
Reactant: c1cc(C2CO2)ccn1
Reactant: Cc1ccc2[nH]c3c(c2c1)CN(C)CC3(C)C
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: Cc1ccc2c(c1)c1c(n2CC(O)c2ccncc2)C(C)(C)CN(C)C1
Reaction time: 4 h
Yield: 58.7 %

Procedure:
2,4,4,8-Tetramethyl-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indole (1.0 gm, 4.385 mmol) was dissolved in DMF (8 mL) and sodium hydride (0.526 g, 13.15 mmol) was added portionwise under nitrogen. 4-Oxiranyl-pyridine (0.9 g, 7.45 mmol) was diluted in DMF (2 mL) and added dropwise at RT and stirred for 4 h. After consumption of starting material (by monitoring TLC & LCMS), the reaction mixture was poured in to ice water, product was precipitated and filtered, and the residue was washed with water & hexane, dried under reduced pressure and crystallized in EtOH (10 mL) and diethyl ether (50 mL) to obtain 900 mg of 1-pyridin-4-yl-2-(2,4,4,8-tetramethyl-1,2,3,4-tetrahydro-pyrido[4,3-b]indol-5-yl)-ethanol. 1H NMR (CDCl3, freebase) δ (ppm): 8.62 (d, 2H), 7.37 (d, 2H), 7.31 (d, 1H), 7.19 (s, 1H), 7.01 (d, 1H), 5.22 (t, 1H), 4.32 (d, 1H), 3.6 (d, 1H), 3.48 (d, 1H), 2.65 b (s, 1H), 2.44 (s, 3H), 1.47 (s, 3H), 1.28 (s, 3H). Separation by chiral HPLC provides enantiomers 71a and 71b.
Reaction SMILES: Cl[C:2]1[C:3](=[O:16])[N:4]([CH:9]([CH:12]2[CH2:15][CH2:14][CH2:13]2)[CH2:10][CH3:11])[CH:5]=[C:6]([Cl:8])[N:7]=1.[Br:17][C:18]1[C:23]2[NH:24][CH2:25][CH2:26][O:27][C:22]=2[CH:21]=[C:20]([O:28][CH3:29])[CH:19]=1>>[Br:17][C:18]1[C:23]2[N:24]([C:2]3[C:3](=[O:16])[N:4]([CH:9]([CH:12]4[CH2:15][CH2:14][CH2:13]4)[CH2:10][CH3:11])[CH:5]=[C:6]([Cl:8])[N:7]=3)[CH2:25][CH2:26][O:27][C:22]=2[CH:21]=[C:20]([O:28][CH3:29])[CH:19]=1
Reactant: COc1cc(Br)c2c(c1)OCCN2
Reactant: CCC(C1CCC1)n1cc(Cl)nc(Cl)c1=O
Product: CCC(C1CCC1)n1cc(Cl)nc(N2CCOc3cc(OC)cc(Br)c32)c1=O

Procedure:
Prepared in a similar fashion as described for Example 556 using 3,5-dichloro-1-(1-cyclobutylpropyl)-2(1H)-pyrazinone and 5-bromo-7-methoxy-3,4-dihydro-2H-1,4-benzoxazine as the starting materials to give a brown oil. 1H NMR (300 MHz, CDCl3): δ 6.73 (d, J=2.9 Hz, 1H), 6.72 (s, 1H), 6.45 (d, J=2.6 Hz, 1H), 4.90–4.85 (m, 1H), 4.50–3.88 (m, 4H), 3.76 (s, 3H), 2.58–2.50 (m, 1H), 2.18–2.13 (m, 1H), 1.85–1.65 (m, 6H), 1.50–1.40 (m, 1H), 0.83 (t, J=7.4 Hz, 3H), HRMS (ESI) m/z 468.0665 [M+, calcd for C20H24N3O3BrCl 468.0690].