Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:10]2[N:11]=[C:12](O)[C:13]3[C:18]([CH:19]=2)=[CH:17][C:16]([O:20][CH3:21])=[CH:15][CH:14]=3)[CH:5]=[CH:6][C:7]=1[O:8][CH3:9].O=P(Cl)(Cl)[Cl:25]>>[Cl:25][C:12]1[C:13]2[C:18](=[CH:17][C:16]([O:20][CH3:21])=[CH:15][CH:14]=2)[CH:19]=[C:10]([C:4]2[CH:5]=[CH:6][C:7]([O:8][CH3:9])=[C:2]([Cl:1])[CH:3]=2)[N:11]=1
Reactant: COc1ccc2c(O)nc(-c3ccc(OC)c(Cl)c3)cc2c1
Reactant: O=P(Cl)(Cl)Cl
Product: COc1ccc2c(Cl)nc(-c3ccc(OC)c(Cl)c3)cc2c1
Yield: 94.5 %

Procedure:
A solution of 3-(3-chloro-4-methoxyphenyl)-6-methoxyisoquinolin-1-ol (1.2 g, 3.80 mmol) in POCl3 (5.31 ml, 57.0 mmol) was refluxed for 4 h. The reaction mixture was concentrated. The residue was dissolved in DCM and the pH was adjusted to 7 with 4N NaOH. The organic phase was collected and dried over sodium sulfate, filtered, then concentrated under vacuum to give 1-chloro-3-(3-chloro-4-methoxyphenyl)-6-methoxyisoquinoline (1.2 g, 95% yield). δ ppm 1H NMR (400 MHz, CHLOROFORM-d) δ 8.22 (d, J=9.3 Hz, 1H), 8.15 (d, J=2.3 Hz, 1H), 8.02 (dd, J=8.7, 2.4 Hz, 1H), 7.27-7.24 (m, 1H), 7.13 (d, J=2.5 Hz, 1H), 7.05 (d, J=8.5 Hz, 1H), 3.99 (s, 6H); MS: MS m/z 334.1 (M++1).
Reaction SMILES: [CH:1]1[CH2:6][CH2:5][CH2:4][CH2:3][CH:2]=1.[Cl:7][BH2:8].CSC>[Hg].C(OCC)C>[CH:1]1([B:8]([CH:1]2[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]2)[Cl:7])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: C1=CCCCC1
Reactant: BCl
Agent: [Hg]
Solvent: CSC
Solvent: CCOCC
Product: ClB(C1CCCCC1)C1CCCCC1
Temperature: 0 °C
Reaction time: 2 h
Yield: 80 %

Procedure:
A 250-mL round bottom flask fitted with a rubber septum, a magnetic stirring bar, and a connecting tube attached to a mercury bubbler was cooled in an ice bath and charged with diethyl ether (90 mL) under inert atmosphere. Cyclohexene (21.2 mL, 210 mmol) was added, followed by the slow addition of monochloroborane-methyl sulfide (11.6 mL, 100 mmol). The mixture was stirred at 0° C. for 2 h. The solvent was removed under reduced pressure (25° C., 12 Torr). Distillation provided pure dicyclohexylchloroborane (δ76 ppm in hexane), 16.85 g, 80% yield, bp 104°-105° C. (0.5 mm). Synthesis of this product by this process can readily be carried out on a molar scale.
Reaction SMILES: [CH3:1][N:2]([CH2:4][C:5]#[C:6][C:7]1[C:13]2[CH:14]=[C:15]([Cl:18])[CH:16]=[CH:17][C:12]=2[S:11][C:10]2[CH:19]=[CH:20][CH:21]=[CH:22][C:9]=2[CH:8]=1)[CH3:3].ClC1C=CC=C(C(OO)=[O:31])C=1>C(Cl)(Cl)Cl>[CH3:1][N+:2]([O-:31])([CH2:4][C:5]#[C:6][C:7]1[C:13]2[CH:14]=[C:15]([Cl:18])[CH:16]=[CH:17][C:12]=2[S:11][C:10]2[CH:19]=[CH:20][CH:21]=[CH:22][C:9]=2[CH:8]=1)[CH3:3]
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: CN(C)CC#CC1=Cc2ccccc2Sc2ccc(Cl)cc21
Solvent: ClC(Cl)Cl
Product: C[N+](C)([O-])CC#CC1=Cc2ccccc2Sc2ccc(Cl)cc21
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
A solution of 2 g. of N,N-dimethyl-3-(8-chloro-dibenzo[ b,f] thiepin-10-yl)-2-propynylamine in 100 ml of chloroform is treated at -50° C. with 1.2 g of m-chloroperbenzoic acid. The solution is stirred for 15 minutes at this temperature. warmed to room temperature and chromatographed on basic aluminum oxide using chloroform/methanol (9:1) as the eluant, whereby there is obtained N,N-dimethyl-3-(8-chloro-dibenzo[ b,f] thiepin-10-yl)-2-propynylamine N-oxide, which melts at 68°-69° C. after recrystallization from ethyl acetate/petroleum ether.
Reaction SMILES: [CH3:1][N:2]([CH3:11])[C:3]1[CH:10]=[CH:9][C:6]([CH:7]=O)=[CH:5][CH:4]=1.[Cl-:12].[NH2:13][N+:14]1[CH:18]=[CH:17][N:16]([NH2:19])[C:15]=1[C:20]1[CH:25]=[CH:24][C:23]([O:26][CH3:27])=[CH:22][CH:21]=1>C(O)(=O)C>[Cl-:12].[CH3:1][N:2]([CH3:11])[C:3]1[CH:10]=[CH:9][C:6]([CH:7]=[N:19][N+:16]2[CH:17]=[CH:18][N:14]([N:13]=[CH:7][C:6]3[CH:9]=[CH:10][C:3]([N:2]([CH3:11])[CH3:1])=[CH:4][CH:5]=3)[C:15]=2[C:20]2[CH:25]=[CH:24][C:23]([O:26][CH3:27])=[CH:22][CH:21]=2)=[CH:5][CH:4]=1
Reactant: CN(C)c1ccc(C=O)cc1
Reactant: COc1ccc(-c2n(N)cc[n+]2N)cc1
Agent: [Cl-]
Solvent: CC(=O)O
Product: COc1ccc(-c2n(N=Cc3ccc(N(C)C)cc3)cc[n+]2N=Cc2ccc(N(C)C)cc2)cc1
Temperature: 25 °C
Reaction time: 48 h

Procedure:
131 mg of 4-(dimethylamino)benzaldehyde are added to a solution of 90 mg of 1,3-diamino-2-(4-methoxyphenyl) imidazolium chloride in 2 ml of glacial acetic acid. After stirring at room temperature for 48 hours, the dark yellow solution is evaporated. The residue is placed on a column loaded with 8 g of silica gel, whereupon the product is eluted with dichloromethane/ethanol (9:1) and recrystallized from ethanol/ether. There is obtained 1,3-bis[[p-(dimethylamino)benzylidene]amino]-2-(p-methoxyphenyl)imidazolium chloride of melting point 250°.
Reaction SMILES: C(OC(=O)[NH:7][C@H:8]([CH2:31][NH:32][C:33]([C:35]1[C:40]([NH2:41])=[N:39][C:38]([NH2:42])=[C:37]([Cl:43])[N:36]=1)=[O:34])[CH2:9][CH2:10][CH2:11][CH2:12][NH:13][C:14](=[O:30])[CH2:15][C:16]1[CH:21]=[CH:20][C:19]([O:22][CH2:23][C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)=[CH:18][CH:17]=1)(C)(C)C.[C:45]([OH:51])([C:47]([F:50])([F:49])[F:48])=[O:46]>C(Cl)Cl>[F:48][C:47]([F:50])([F:49])[C:45]([OH:51])=[O:46].[NH2:7][C@@H:8]([CH2:9][CH2:10][CH2:11][CH2:12][NH:13][C:14](=[O:30])[CH2:15][C:16]1[CH:17]=[CH:18][C:19]([O:22][CH2:23][C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)=[CH:20][CH:21]=1)[CH2:31][NH:32][C:33]([C:35]1[C:40]([NH2:41])=[N:39][C:38]([NH2:42])=[C:37]([Cl:43])[N:36]=1)=[O:34]
Reactant: CC(C)(C)OC(=O)N[C@@H](CCCCNC(=O)Cc1ccc(OCc2ccccc2)cc1)CNC(=O)c1nc(Cl)c(N)nc1N
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: Nc1nc(N)c(C(=O)NC[C@@H](N)CCCCNC(=O)Cc2ccc(OCc3ccccc3)cc2)nc1Cl

Procedure:
A solution of ((S)-5-[2-(4-benzyloxy-phenyl)-acetylamino]-1-{[(3,5-diamino-6-chloro-pyrazine-2-carbonyl)-amino]-methyl}-pentyl)-carbamic acid tert-butyl ester (0.1 g, 0.16 mmol) in DCM (3 mL) and TFA (1 mL) is stirred at RT for 6 h. The solvent is removed in vacuo and the resulting residue is dissolved in DMSO and purified by reverse phase column chromatography (Isolute™ C18, 0-100% acetonitrile in water-0.1% TFA) to afford the title compound. [M+H]+ 526. 1H NMR (500 MHz, DMSO-d6) δ 8.16 (1H, t), 8.05 (1H, t), 7.94 (4H, br), 7.42 (2H, d), 7.37 (2H, dd), 7.31 (1H, dd), 7.16 (2H, d), 7.04 (2H, br), 6.92 (2H, d), 5.05 (2H, s), 3.38 (2H, m), 3.31 (2H, s), 3.18 (1H, m), 3.02 (2H, m), 1.52 (2H, m), 1.38 (4H, m).
Reaction SMILES: [CH2:1]([N:8]1[CH2:13][CH2:12][N:11]([C:14]([C@@H:16]2[CH2:21][CH2:20][CH2:19][CH2:18][N:17]2[C:22](OC(C)(C)C)=O)=O)[CH2:10][CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[H-].[Al+3].[Li+].[H-].[H-].[H-]>C1COCC1>[CH2:1]([N:8]1[CH2:9][CH2:10][N:11]([CH2:14][C@@H:16]2[CH2:21][CH2:20][CH2:19][CH2:18][N:17]2[CH3:22])[CH2:12][CH2:13]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CC(C)(C)OC(=O)N1CCCC[C@H]1C(=O)N1CCN(Cc2ccccc2)CC1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Product: CN1CCCC[C@H]1CN1CCN(Cc2ccccc2)CC1
Yield: 95.2 %

Procedure:
A solution of (S)-tert-butyl 2-(4-benzylpiperazine-1-carbonyl)piperidine-1-carboxylate 1.23 g (3.18 mmol) in THF (10 ml) was added slowly to a solution of 1M lithium aluminum hydride in THF 9.6 ml in THF (8 ml) at 0° C. under argon protection. The reaction mixture was refluxed for 2 hours, cooled down, quenched with water and extracted with ethyl ether 2×50 ml. The combined organic solution was washed with brine, dried over sodium sulfate and concentrated to give 0.87 g of desired product 95% yield.
Reaction SMILES: [CH3:1][C:2]([CH3:7])([CH2:5][OH:6])[CH2:3][OH:4].[N+:8]([C:11]1[CH:18]=[CH:17][CH:16]=[C:15]([N+]([O-])=O)[C:12]=1[C:13]#[N:14])([O-:10])=[O:9]>>[OH:4][CH2:3][C:2]([CH3:7])([CH3:1])[CH2:5][O:6][C:15]1[CH:16]=[CH:17][CH:18]=[C:11]([N+:8]([O-:10])=[O:9])[C:12]=1[C:13]#[N:14]
Reactant: N#Cc1c([N+](=O)[O-])cccc1[N+](=O)[O-]
Reactant: CC(C)(CO)CO
Product: CC(C)(CO)COc1cccc([N+](=O)[O-])c1C#N
Yield: 73 %

Procedure:
Prepared as in Example 215c from 2,2-dimethylpropane-1,3-diol and 2,6-dinitrobenzonitrile in 73% yield. 1H NMR (400 MHz, DMSO-d6) δ 0.94 (s, 6H), 3.29-3.31 (m, 2H), 3.95 (s, 2H), 4.69 (t, J=5.6 Hz, 1H), 7.69-7.71 (m, 1H), 7.84-7.90 (m, 2H).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]2[C:10](B3OC(C)(C)C(C)(C)O3)=[CH:9][N:8]([S:20]([C:23]3[CH:28]=[CH:27][C:26]([CH3:29])=[CH:25][CH:24]=3)(=[O:22])=[O:21])[C:5]2=[N:6][CH:7]=1.Cl[C:31]1[N:36]=[C:35]([NH:37][C@H:38]2[CH2:43][CH2:42][CH2:41][C@:40]([CH2:45][C:46]#[N:47])([OH:44])[CH2:39]2)[C:34]([F:48])=[CH:33][N:32]=1.C([O-])([O-])=O.[Na+].[Na+].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>C(COC)OC.[Pd]>[F:48][C:34]1[C:35]([NH:37][C@H:38]2[CH2:43][CH2:42][CH2:41][C@:40]([CH2:45][C:46]#[N:47])([OH:44])[CH2:39]2)=[N:36][C:31]([C:10]2[C:4]3[C:5](=[N:6][CH:7]=[C:2]([F:1])[CH:3]=3)[N:8]([S:20]([C:23]3[CH:24]=[CH:25][C:26]([CH3:29])=[CH:27][CH:28]=3)(=[O:21])=[O:22])[CH:9]=2)=[N:32][CH:33]=1
Reactant: Cc1ccc(S(=O)(=O)n2cc(B3OC(C)(C)C(C)(C)O3)c3cc(F)cnc32)cc1
Reactant: N#CC[C@]1(O)CCC[C@H](Nc2nc(Cl)ncc2F)C1
Agent: [Pd]
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: COCCOC
Product: Cc1ccc(S(=O)(=O)n2cc(-c3ncc(F)c(N[C@H]4CCC[C@@](O)(CC#N)C4)n3)c3cc(F)cnc32)cc1
Temperature: 120 °C

Procedure:
A solution of 5-fluoro-1-(p-tolylsulfonyl)-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyrrolo[2,3-b]pyridine, 44a, (0.23 g, 0.55 mmol), 2-((1S,3S)-3-(2-chloro-5-fluoropyrimidin-4-ylamino)-1-hydroxycyclohexyl)-ethanenitrile, 69a, (0.14 g, 0.50 mmol) and Na2CO3 (0.75 mL of 2M solution, 1.50 mmol) in dimethoxyethane (15 mL) was degassed with nitrogen for 30 min. To the reaction mixture was added palladium; triphenylphosphane (0.03 g, 0.03 mmol) and continued to degas the solution for 15 min. The reaction mixture was heated at 120° C. in a pressure tube for 45 min. The reaction mixture was filtered through celite and the filtrate was removed under reduced pressure. The resulting residue was purified by silica gel chromatography (40% EtOAc/Hexanes) to afford 150 mg of desired product: LCMS RT=3.55 (M+H) 539.42.
Reaction SMILES: C([O:4][CH:5]([CH:9]([O:32]C(=O)C)[C:10]([NH:12][CH2:13][C:14]1[CH:27]=[CH:26][C:25]2[O:24][C:23]3[C:18]4=[C:19]([C:28](=[O:31])[NH:29][N:30]=[C:17]4[C:16]=2[CH:15]=1)[CH:20]=[CH:21][CH:22]=3)=[O:11])[C:6]([OH:8])=[O:7])(=O)C.[OH-].[Na+]>O.O1CCOCC1>[OH:4][CH:5]([CH:9]([OH:32])[C:10]([NH:12][CH2:13][C:14]1[CH:27]=[CH:26][C:25]2[O:24][C:23]3[C:18]4=[C:19]([C:28](=[O:31])[NH:29][N:30]=[C:17]4[C:16]=2[CH:15]=1)[CH:20]=[CH:21][CH:22]=3)=[O:11])[C:6]([OH:8])=[O:7]
Reactant: CC(=O)OC(C(=O)O)C(OC(C)=O)C(=O)NCc1ccc2c(c1)-c1n[nH]c(=O)c3cccc(c13)O2
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: C1COCCO1
Product: O=C(O)C(O)C(O)C(=O)NCc1ccc2c(c1)-c1n[nH]c(=O)c3cccc(c13)O2
Temperature: 40 °C
Reaction time: 8 h
Yield: 25 %

Procedure:
Compound 51 was dissolved in a solution of NaOH (2.5 equivalent) in H2O/Dioxane. The reaction mixture was stirred overnight at 40° C., then was acidified to pH=3. Aqueous layer was extracted with ethyl acetate. Organic layer was dried with MgSO4. Solvent was removed in vacuo to afford a white solid 52 in 25% yield. MS: (ES+): 398; Mp: 181-185° C.; 1H-NMR (DMSO-d6, 400 MHz): 12.54 (s, 1H), 8.32 (t, J=6.2 Hz, 1H), 7.93 (d, J=2.0 Hz, 1H), 7.90-7.80 (m, 2H), 7.62 (dd, J=7.5 and 2.0 Hz, 1H), 7.40 (dd, J=8.5 and 2.0 Hz, 1H), 7.25 (d, J=8.5 Hz, 1H), 4.30-4.19 (m, 4H); Anal. Calcd for C19H15N3O7.(3H2O): C, 50.56; H, 4.69; N, 9.31. Found: C, 50.59; H, 4.07; N, 9.28.
Reaction SMILES: [F:1][C:2]1[CH:10]=[CH:9][C:5]([CH2:6][CH2:7][OH:8])=[CH:4][CH:3]=1.Cl[CH2:12][C:13]([OH:15])=[O:14].CC1CCCCC1>>[F:1][C:2]1[CH:10]=[CH:9][C:5]([CH2:6][CH2:7][O:8][CH2:12][C:13]([OH:15])=[O:14])=[CH:4][CH:3]=1
Reactant: OCCc1ccc(F)cc1
Reactant: O=C(O)CCl
Solvent: CC1CCCCC1
Product: O=C(O)COCCc1ccc(F)cc1
Yield: 78.8 %

Procedure:
7.0 g of 4-fluorophenethyl alcohol were reacted with 4.73 g of chloroacetic acid in a manner analogous to that described in Example 1(a) to give 7.8 g (79%) of 2-(4-fluorophenyl)ethoxyacetic acid of melting point 82°-85° C. (from methylcyclohexane).
Reaction SMILES: [Cl:1][C:2]1[C:3]2[NH:10][CH:9]=[CH:8][C:4]=2[N:5]=[CH:6][N:7]=1.C(=O)([O-])[O-].[K+].[K+].Cl[CH2:18][C:19]1[O:23][C:22]([C:24]([O:26][CH2:27][CH3:28])=[O:25])=[CH:21][CH:20]=1>CN(C)C=O.O>[Cl:1][C:2]1[C:3]2[N:10]([CH2:18][C:19]3[O:23][C:22]([C:24]([O:26][CH2:27][CH3:28])=[O:25])=[CH:21][CH:20]=3)[CH:9]=[CH:8][C:4]=2[N:5]=[CH:6][N:7]=1
Reactant: CCOC(=O)c1ccc(CCl)o1
Reactant: Clc1ncnc2cc[nH]c12
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: CCOC(=O)c1ccc(Cn2ccc3ncnc(Cl)c32)o1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 82.9 %

Procedure:
To a suspension of 4-chloro-5H-pyrrolo[3,2-d]pyrimidine (500 mg) in N,N-dimethylformamide (6.5 mL) was added potassium carbonate (541 mg) under ice-cooling, and the mixture was stirred for 15 min. while warming to room temperature. Ethyl 5-(chloromethyl)-2-furoate (737 mg) was added to the reaction mixture, and the mixture was stirred at room temperature for 16 hrs. The reaction mixture was diluted with water (20 mL), and extracted with a mixed solvent (40 mL×3) of ethyl acetate/tetrahydrofuran (1/1). The organic layer washed with saturated brine (20 mL×3) and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure, and the obtained residue was subjected to silica gel column chromatography (silica gel, eluent:hexane/ethyl acetate=80/20→10/90). The object fraction was concentrated under reduced pressure and dried to give the title compound (825 mg) as a pale-yellow solid.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]([S:15]([C:18]2[CH:23]=[CH:22][C:21]([O:24][CH3:25])=[C:20]([O:26][CH3:27])[CH:19]=2)(=[O:17])=[O:16])[C@H:9]([C:11]([O:13]C)=[O:12])[CH3:10])=[C:4]([CH2:28][C:29]2[C:34]([F:35])=[CH:33][CH:32]=[CH:31][C:30]=2[F:36])[CH:3]=1.O.[OH-].[Li+]>C(O)C>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]([S:15]([C:18]2[CH:23]=[CH:22][C:21]([O:24][CH3:25])=[C:20]([O:26][CH3:27])[CH:19]=2)(=[O:16])=[O:17])[C@H:9]([C:11]([OH:13])=[O:12])[CH3:10])=[C:4]([CH2:28][C:29]2[C:34]([F:35])=[CH:33][CH:32]=[CH:31][C:30]=2[F:36])[CH:3]=1
Reactant: COC(=O)[C@H](C)N(c1ccc(Cl)cc1Cc1c(F)cccc1F)S(=O)(=O)c1ccc(OC)c(OC)c1
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: COc1ccc(S(=O)(=O)N(c2ccc(Cl)cc2Cc2c(F)cccc2F)[C@@H](C)C(=O)O)cc1OC
Reaction time: 18 h
Yield: 36.9 %

Procedure:
To 1.373 g of methyl N-[4-chloro-2-(2,6-difluorobenzyl)phenyl]-N-[(3,4-dimethoxyphenyl)sulfonyl]alaninate dissolved in 20 ml of ethanol is added 0.52 g of lithium hydroxide monohydrate, and the mixture is left at room temperature for 18 hours. The medium is concentrated and the residue is taken up in ethyl acetate and washed with 5% potassium hydrogen sulfate solution. The organic phase is dried over anhydrous sodium sulfate and concentrated. The residue is chromatographed on a column of silica gel, eluting with a 90/10 (v/v) dichloromethane/methanol mixture to give 0.494 g of the expected product.
Reaction SMILES: Br[C:2]1[CH:10]=[C:9]2[C:5]([C:6]3[CH2:15][CH2:14][N:13]([C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])[CH2:12][C:7]=3[N:8]2[CH3:11])=[CH:4][CH:3]=1.[N:23]1[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=1[CH2:29][CH2:30][N:31]1[CH2:36][CH2:35][NH:34][C:33](=[O:37])[CH2:32]1>>[CH3:11][N:8]1[C:9]2[C:5](=[CH:4][CH:3]=[C:2]([N:34]3[CH2:35][CH2:36][N:31]([CH2:30][CH2:29][C:24]4[CH:25]=[CH:26][CH:27]=[CH:28][N:23]=4)[CH2:32][C:33]3=[O:37])[CH:10]=2)[C:6]2[CH2:15][CH2:14][N:13]([C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])[CH2:12][C:7]1=2
Reactant: Cn1c2c(c3ccc(Br)cc31)CCN(C(=O)OC(C)(C)C)C2
Reactant: O=C1CN(CCc2ccccn2)CCN1
Product: Cn1c2c(c3ccc(N4CCN(CCc5ccccn5)CC4=O)cc31)CCN(C(=O)OC(C)(C)C)C2
Yield: 17.7 %

Procedure:
tert-Butyl 7-bromo-9-methyl-3,4-dihydro-1H-pyrido[3,4-b]indole-2(9H)-carboxylate (820 mg, 2.25 mmol) and 4-(2-(pyridin-2-yl)ethyl)piperazin-2-one (426 mg, 2.08 mmol) were reacted according to Example 2 (step f) to provide the title compound (180 mg, 16%) as a yellow oil: ESI MS m/z 490 [M+H]+.
Reaction SMILES: [F:1][C:2]1[CH:22]=[CH:21][C:5]([CH2:6][CH:7]2[CH2:16][C:15]3[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=3)[CH2:9][N:8]2[CH2:17][CH2:18][CH2:19][NH2:20])=[CH:4][CH:3]=1.[CH3:23][O:24][C:25]1[CH:26]=[C:27]([N:31]=[C:32]=[O:33])[CH:28]=[CH:29][CH:30]=1>>[F:1][C:2]1[CH:22]=[CH:21][C:5]([CH2:6][CH:7]2[CH2:16][C:15]3[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=3)[CH2:9][N:8]2[CH2:17][CH2:18][CH2:19][NH:20][C:32]([NH:31][C:27]2[CH:28]=[CH:29][CH:30]=[C:25]([O:24][CH3:23])[CH:26]=2)=[O:33])=[CH:4][CH:3]=1
Reactant: NCCCN1Cc2ccccc2CC1Cc1ccc(F)cc1
Reactant: COc1cccc(N=C=O)c1
Product: COc1cccc(NC(=O)NCCCN2Cc3ccccc3CC2Cc2ccc(F)cc2)c1

Procedure:
The reaction and treatment were carried out in the same manner as in Example 208 using 3-[3-(4-fluorobenzyl)-3,4-dihydroisoquinolin-2(1H)-yl]propanamine obtained in Example 214-b) as a starting material, and using 3-methoxyphenyl isocyanate instead of phenyl isocyanate to obtain a title compound as a pale yellow amorphous substance.
Reaction SMILES: [H-].[H-].[H-].[H-].[Li+].[Al+3].[OH:7][CH:8]1[CH2:13][CH2:12][CH2:11][N:10]([CH2:14][C:15]#[N:16])[CH2:9]1>C1COCC1>[NH2:16][CH2:15][CH2:14][N:10]1[CH2:11][CH2:12][CH2:13][CH:8]([OH:7])[CH2:9]1
Reactant: N#CCN1CCCC(O)C1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Product: NCCN1CCCC(O)C1
Temperature: 25 °C
Yield: 63.2 %

Procedure:
LiAlH4 (2.44 g, 64.2 mmol) was added to dry THF (20 mL) at 0° C. in a three-neck round bottom flask under N2. The solution was stirred for 15 min. before the 3-hydroxypiperidin-1-yl-acetonitrile (3 g, 21.4 mmol), diluted in dry THF (5 mL), was added slowly via syringe. The reaction mixture was then refluxed 5 h before allowing the solution to cool to RT. Excess of LiAlH4 was destroyed by dropwise addition of 2.4 mL of H2O, 2.4 mL of NaOH (15%) and finally EtOAc was added dropwise until no effervesence was observed. The formed granular precipitate (lithium hydroxide and aluminium hydroxide) was filtered off and washed several times with CH2Cl2 and EtOAc. The organic layer was dried (MgSO4) and the solvent was removed in vacuo to yield a thick yellowish oil. The title-compound was purified by kugelrohr distillation (172° C., 0.05 mbar) and obtained as a straw coloured oil (1.95 g, 63%). δH (250 MHz;
Reaction SMILES: O/[N:2]=[C:3](/[C:5]1[CH:6]=[C:7]2[C:11](=[CH:12][CH:13]=1)[NH:10][C:9](=[O:14])[CH2:8]2)\[CH3:4].[OH-].[NH4+]>[Ni].CO>[NH2:2][CH:3]([C:5]1[CH:6]=[C:7]2[C:11](=[CH:12][CH:13]=1)[NH:10][C:9](=[O:14])[CH2:8]2)[CH3:4]
Reactant: C/C(=N\O)c1ccc2c(c1)CC(=O)N2
Agent: [Ni]
Agent: [NH4+]
Agent: [OH-]
Solvent: CO
Product: CC(N)c1ccc2c(c1)CC(=O)N2
Reaction time: 9 h

Procedure:
To a MeOH (30 ml) solution of 5-[(1E)-N-hydroxyethanimidoyl]-1,3-dihydro-2H-indol-2-one (0.5 g, 2.6 mmol; WO 2004108133), Raney Nickel and aqueous solution of ammonium hydroxide (10 ml) were added and the mixture was stirred for 9 hours under hydrogen (4.0 kgf/cm2). Then, the reaction was filtered off and the filtrate was evaporated to give 5-(1-aminoethyl)-1,3-dihydro-2H-indol-2-one as a free form. Then, the amine was treated with MeOH solution of 10% of chloride and recrystallized from MeOH/diethyl ether to give the title compound as a white solid. MS (ESI) m/z 177 (M+H)+
Reaction SMILES: [CH3:1][O:2][C:3](=[O:11])[C:4]1[CH:9]=[C:8](I)[CH:7]=[CH:6][N:5]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C([O:33][CH:34](OCC)[C:35]#[CH:36])C>[Cu]I.C([O-])(=O)C.[Pd+2].C([O-])(=O)C.C(N(CC)CC)C>[CH3:1][O:2][C:3]([C:4]1[CH:9]=[C:8]([CH2:36][CH2:35][CH2:34][OH:33])[CH:7]=[CH:6][N:5]=1)=[O:11]
Reactant: C#CC(OCC)OCC
Reactant: COC(=O)c1cc(I)ccn1
Agent: [Cu]I
Agent: [Pd+2]
Agent: CC(=O)[O-]
Solvent: CCN(CC)CC
Product: COC(=O)c1cc(CCCO)ccn1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To a dry flask were added intermediate 11b prepared in general method P (2.98 g, 11.33 mmol, 1 equiv), triphenylphosphine (238 mg, 0.91 mmol, 0.08 equiv), copper(I) iodide (172.6 mg, 0.91 mmol, 0.08 equiv), palladium acetate (101.6 mg, 0.45 mmol, 0.04 equiv) and triethylamine (42 mL). The mixture was deaerated with nitrogen, followed by addition of 3,3-Diethoxy-propyne (Aldrich) (2.90 g, 22.7 mmol, 2 equiv). The mixture was stirred at rt for 3 h. The solvent was removed under vacuum to give a dark residue. The residue was purified by chromatography to give a yellow oil 11c (R9′=3,3-Diethoxy-prop-1-ynyl) (3 g, 100%): 1H NMR (300 MHz, CDCl3) δ 8.69 (dd, J=0.8, 5.0, 1), 8.15 (d, J=0.8, 1.4, 1), 7.49 (dd, J=1.7, 5.0, 1), 5.48 (s, 1), 3.99 (s, 3), 3.82-3.73 (m, 2), 3.71-3.62 (m, 2), 1.26 (t, J=7.2, 6). MS (ESPOS): 264.6 [M+H]+.
Reaction SMILES: [C:1]([NH2:9])(=[NH:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:10](OC)(=[O:16])[CH2:11][C:12](OC)=[O:13]>CS(C)=O>[C:2]1([C:1]2[N:9]=[C:12]([OH:13])[CH:11]=[C:10]([OH:16])[N:8]=2)[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: COC(=O)CC(=O)OC
Reactant: N=C(N)c1ccccc1
Solvent: CS(C)=O
Product: Oc1cc(O)nc(-c2ccccc2)n1
Reaction time: 24 h

Procedure:
A mixture of benzamidine (7.42 g) and dimethyl malonate (8.09 g) in dry dimethyl sulfoxide (7 mL) was allowed to stand at room temperature for 24 h. The precipitated product was collected and washed with water and ether to afford 2-Phenyl-4,6-dihydroxy-pyrimidine as a white solid.
Reaction SMILES: [N+:1]([C:4]1[CH:19]=[CH:18][C:7]([CH2:8][C:9]2[CH:17]=[CH:16][C:12]([C:13](O)=[O:14])=[CH:11][CH:10]=2)=[CH:6][CH:5]=1)([O-:3])=[O:2].C(Cl)(=O)C([Cl:23])=O>CN(C)C=O>[Cl:23][C:13]([C:12]1[CH:16]=[CH:17][C:9]([CH2:8][C:7]2[CH:18]=[CH:19][C:4]([N+:1]([O-:3])=[O:2])=[CH:5][CH:6]=2)=[CH:10][CH:11]=1)=[O:14]
Reactant: O=C(O)c1ccc(Cc2ccc([N+](=O)[O-])cc2)cc1
Reactant: O=C(Cl)C(=O)Cl
Solvent: CN(C)C=O
Product: O=C(Cl)c1ccc(Cc2ccc([N+](=O)[O-])cc2)cc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
4-(4-Nitrobenzyl)-benzoic acid (1.03 g, 4 mmol) was dissolved in dichlorormethane (40 mL). Oxalyl chloride (0.42 mL, 1.2 eq) was added to the mixture, followed by 1 drop of N,N-dimethylformamide. The mixture was stirred for 1 hour at room temperature and the solvents evaporated to give 4-(4-chlorocarbonylbenzyl)-nitrobenzene (1.10 g) as a pale yellow solid.
Reaction SMILES: [Cl:1][C:2]1[C:3]([NH:20][CH:21]2[CH2:35][CH:24]3[CH2:25][N:26](C(OC(C)(C)C)=O)[CH2:27][CH:23]3[CH2:22]2)=[N:4][C:5]([NH:8][C:9]2[CH:10]=[CH:11][C:12]3[C:16]([CH:17]=2)=[N:15][N:14]([CH3:18])[C:13]=3[CH3:19])=[N:6][CH:7]=1.Cl.CCOC(C)=O>C(Cl)Cl>[Cl:1][C:2]1[C:3]([NH:20][CH:21]2[CH2:22][CH:23]3[CH2:27][NH:26][CH2:25][CH:24]3[CH2:35]2)=[N:4][C:5]([NH:8][C:9]2[CH:10]=[CH:11][C:12]3[C:16]([CH:17]=2)=[N:15][N:14]([CH3:18])[C:13]=3[CH3:19])=[N:6][CH:7]=1
Reactant: Cc1c2ccc(Nc3ncc(Cl)c(NC4CC5CN(C(=O)OC(C)(C)C)CC5C4)n3)cc2nn1C
Agent: Cl
Solvent: ClCCl
Solvent: CCOC(C)=O
Product: Cc1c2ccc(Nc3ncc(Cl)c(NC4CC5CNCC5C4)n3)cc2nn1C
Temperature: 25 °C
Reaction time: 8 h
Yield: 49.7 %

Procedure:
To a solution of tert-butyl 5-((5-chloro-2-((2,3-dimethyl-2H-indazol-6-yl)amino)pyrimidin-4-yl)amino)hexahydrocyclopenta[c]pyrrole-2(1H)-carboxylate (452.1 mg, 0.908 mmol) in DCM (10 mL) was added a solution of HCl in EtOAc (10 mL, 40 mmol). The reaction mixture was stirred at rt overnight and concentrated in vacuo. The residue was dissolved in water (30 mL) and adjusted to pH=10 with a saturated Na2CO3 aqueous solution, then extracted with DCM (250 mL×3). The combined organic phases were washed with brine (250 mL), dried over anhydrous Na2SO4, filtered and concentrated in vacuo. The residue was purified by silica gel column chromatography (MeOH/DCM (v/v)=1/5) to give the title compound as a beige solid (179.6 mg, 49.7%).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[N:10]=[C:11](O)[C:12]3[CH:13]=[CH:14][CH:15]=[N:16][C:17]=3[CH:18]=2)=[CH:5][CH:4]=1.O=P(Cl)(Cl)[Cl:22]>>[Cl:22][C:11]1[N:10]=[C:9]([C:6]2[CH:7]=[CH:8][C:3]([O:2][CH3:1])=[CH:4][CH:5]=2)[CH:18]=[C:17]2[C:12]=1[CH:13]=[CH:14][CH:15]=[N:16]2
Reactant: COc1ccc(-c2cc3ncccc3c(O)n2)cc1
Reactant: O=P(Cl)(Cl)Cl
Product: COc1ccc(-c2cc3ncccc3c(Cl)n2)cc1
Yield: 98.5 %

Procedure:
7-(4-Methoxyphenyl)-[1,6]naphthyridin-5-ol (13 g) and POCl3 (275 mL) was heated to 135° C. for 26 hours in a sealed tube. The mixture was cooled and the POCl3 was evaporated. The residue was poured onto ice and neutralized with 2M Na2CO3 and the precipitate was filtered and washed with H2O to yield 13.8 g of the title compound (98.5%), mp 126-127° C.