Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([C:4]1[CH:9]=[C:8]([Cl:10])[C:7]([NH:11][C:12]2[C:21]3[CH:20]=[CH:19][NH:18][C:17](=[O:22])[C:16]=3[C:15]3[CH:23]=[C:24]([Br:27])[CH:25]=[CH:26][C:14]=3[N:13]=2)=[C:6]([Cl:28])[CH:5]=1)(=[O:3])[CH3:2].[BH4-].[Na+]>CO>[Br:27][C:24]1[CH:25]=[CH:26][C:14]2[N:13]=[C:12]([NH:11][C:7]3[C:6]([Cl:28])=[CH:5][C:4]([CH:1]([OH:3])[CH3:2])=[CH:9][C:8]=3[Cl:10])[C:21]3[CH:20]=[CH:19][NH:18][C:17](=[O:22])[C:16]=3[C:15]=2[CH:23]=1
Reactant: CC(=O)c1cc(Cl)c(Nc2nc3ccc(Br)cc3c3c(=O)[nH]ccc23)c(Cl)c1
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Product: CC(O)c1cc(Cl)c(Nc2nc3ccc(Br)cc3c3c(=O)[nH]ccc23)c(Cl)c1
Reaction time: 0.5 h

Procedure:
To a solution of 5-[(4-acetyl-2,6-dichlorophenyl)amino]-9-bromobenzo[c]-2,6-naphthyridin-1(2H)-one (700 mg, 1.47 mmol) in methanol (10 mL) was added sodium borohydride (444 mg, 11.7 mmol) at 0° C. and the reaction mixture was stirred for 30 min. The solution was extracted with EtOAc and water, dried over MgSO4, filtered, and concentrated to afford the crude material. Purification by column chromatography on silica gel (100% CH2Cl2 to 70% CH2Cl2/30% MeOH) afforded the title compound.
Reaction SMILES: C[O:2][C:3]1[CH:4]=[CH:5][C:6]2[C:18](=[O:19])[C:17]3[C:16]4[C:11](=[CH:12][C:13]([C:20]#[N:21])=[CH:14][CH:15]=4)[NH:10][C:9]=3[C:8]([CH3:23])([CH3:22])[C:7]=2[CH:24]=1>Cl.N1C=CC=CC=1>[OH:2][C:3]1[CH:4]=[CH:5][C:6]2[C:18](=[O:19])[C:17]3[C:16]4[C:11](=[CH:12][C:13]([C:20]#[N:21])=[CH:14][CH:15]=4)[NH:10][C:9]=3[C:8]([CH3:22])([CH3:23])[C:7]=2[CH:24]=1
Reactant: COc1ccc2c(c1)C(C)(C)c1[nH]c3cc(C#N)ccc3c1C2=O
Agent: Cl
Solvent: c1ccncc1
Product: CC1(C)c2cc(O)ccc2C(=O)c2c1[nH]c1cc(C#N)ccc21
Temperature: 170 °C
Reaction time: 13 h
Yield: 94 %

Procedure:
8-Methoxy-6,6-dimethyl-11-oxo-6,11-dihydro-5H-benzo[b]carbazole-3-carbonitrile (Compound A5-2, 6.58 g, 20.8 mmol) was dissolved in pyridine hydrochloric acid salt (25.0 g), and stirred at 170° C. for 13 hours. The reaction mixture was partitioned in ethyl acetate (400 mL) and distilled water (400 mL), and the aqueous layer was extracted one more time with ethyl acetate (400 mL). The combined organic layer was washed twice with distilled water (100 mL) and once with saturated brine (100 mL) in order, and dried over anhydrous sodium sulfate. The organic layer was concentrated under reduced pressure to yield a product, which was suspended and washed with a small amount of CPME to obtain the title compound as a colorless crystal (5.91 g, 93%).
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][N:5]=[C:4]2[N:8]=[C:9]([CH2:11][CH2:12][CH3:13])[NH:10][C:3]=12.[H-].[Na+].[C:16]([C:18]1[C:23]([C:24]2[CH:29]=[CH:28][C:27]([CH2:30]Br)=[CH:26][CH:25]=2)=[CH:22][CH:21]=[CH:20][N:19]=1)#[N:17].[NH4+].[Cl-]>CN(C=O)C.[Cl-].[Na+].O>[CH3:1][C:2]1[CH:7]=[CH:6][N:5]=[C:4]2[N:8]([CH2:30][C:27]3[CH:26]=[CH:25][C:24]([C:23]4[C:18]([C:16]#[N:17])=[N:19][CH:20]=[CH:21][CH:22]=4)=[CH:29][CH:28]=3)[C:9]([CH2:11][CH2:12][CH3:13])=[N:10][C:3]=12
Reactant: CCCc1nc2nccc(C)c2[nH]1
Reactant: N#Cc1ncccc1-c1ccc(CBr)cc1
Agent: [Cl-]
Agent: [H-]
Agent: [NH4+]
Solvent: CN(C)C=O
Solvent: O
Product: CCCc1nc2c(C)ccnc2n1Cc1ccc(-c2cccnc2C#N)cc1
Temperature: 25 °C
Reaction time: 0.33 h

Procedure:
To a solution of 7-Methyl-2-propylimidazo[4,5-b]pyridine (320 mg, 1.83 mmol) from Example 1 Step B in DMF (9 mL) at rt was added NaH (82 mg of an 80% dispersion in oil, 2.74 mmol). After 20 min., 2-cyano-3-(4-bromomethyl- phenyl)pyridine (600 mg, 2.19 mmol) was added and the mixture was stirred at rt for 3 h. Brine (100 mL) and aqueous NH4Cl (40 mL) were added and the product was extracted with EtOAc. Purification by flash chromatography (100% EtOAc) gave the above titled compound.
Reaction SMILES: [OH:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=O)=[C:4]([NH:11][C:12](=O)[CH:13]([CH3:15])[CH3:14])[CH:3]=1.[NH2:17][C:18]1[CH:25]=[CH:24][C:21]([C:22]#[N:23])=[CH:20][CH:19]=1.C(C#N)(C)=O.P(Cl)(Cl)Cl.[OH-].[Na+]>O>[OH:1][C:2]1[CH:3]=[C:4]2[C:5]([C:6](=[O:8])[N:17]([C:18]3[CH:25]=[CH:24][C:21]([C:22]#[N:23])=[CH:20][CH:19]=3)[C:12]([CH:13]([CH3:15])[CH3:14])=[N:11]2)=[CH:9][CH:10]=1
Reactant: N#Cc1ccc(N)cc1
Reactant: CC(C)C(=O)Nc1cc(O)ccc1C(=O)O
Agent: CC(=O)C#N
Agent: [Na+]
Agent: [OH-]
Solvent: ClP(Cl)Cl
Solvent: O
Product: CC(C)c1nc2cc(O)ccc2c(=O)n1-c1ccc(C#N)cc1
Temperature: 22 °C
Reaction time: 20 h
Yield: 75.2 %

Procedure:
A 2-L Argonaut reactor, equipped with pitched-blade impeller, RTD sensor, reflux condenser, addition funnel, and nitrogen inlet-outlet, was charged with 54.90 g (246.0 mmol) of 4-hydroxy-2-isobutyrylamino-benzoic acid (5), 31.96 g (270.6 mmol) of 4-aminobenzonitrile (6) and 919.2 g (1.177 L) of AcCN. The suspension was stirred at 22±3° C. for 30 min with an efficient mixing, and 70.97 g (45.09 mL, 516.7 mmol) of PCl3 were added while maintaining an internal temperature of 22±10° C. The suspension was then warmed to an internal temperature of 60±3° C. over 1 h, and the mixture was stirred at 60±3° C. for 20 h with an efficient mixing. The suspension was cooled to an internal temperature of 15±3° C. over 30 min, and then 54.275 g (1356.87 mmol) of NaOH in 220 g of water were added while maintaining an internal temperature of 15±10° C. The suspension was warmed to an internal temperature of 75±5° C. over 1 h, then the mixture was stirred at this temperature for 30 min. Then the mixture was cooled to an internal temperature of 30±5° C. over 45 min, and the organic layer was separated off. The organic layer was then line-filtered by pressure (300 to 500 mbar) and the solvent was concentrated under vacuum (100-50 torr) at an internal temperature of 20-30° C. to collect ˜950 mL of solvent (batch volume ˜200 mL). 875 mL of water were added to the concentrate. Again the solvent was concentrated under vacuum (200-150 torr) at an internal temperature of 20-30° C. to collect ˜200 mL of solvent (batch volume ˜820 mL). The remaining suspension was stirred at 20±3° C. for 2 h, and the solid was removed by filtration over a polypropylene filter paper in a Büchner funnel with suction. The filter cake was washed with 2×100 mL of H2O. The solid was dried under vacuum (100-150 mbar) at 50±5° C. with nitrogen bleeding until ≦1% LOD (15 h) to obtain 56.5 g of 4-(7-hydroxy-2-isopropyl-4-oxo-4H-quinazoline-3-yl)-benzonitrile (7) as a white solid.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][C:4]([C:7]2[N:8]=[N:9][C:10]([C:13]([O:15]CC)=[O:14])=[CH:11][N:12]=2)=[CH:3][CH:2]=1.[OH-].[Na+]>O1CCCC1.CO>[N:1]1[CH:6]=[CH:5][C:4]([C:7]2[N:8]=[N:9][C:10]([C:13]([OH:15])=[O:14])=[CH:11][N:12]=2)=[CH:3][CH:2]=1
Reactant: CCOC(=O)c1cnc(-c2ccncc2)nn1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Product: O=C(O)c1cnc(-c2ccncc2)nn1
Reaction time: 0.08 h

Procedure:
Ethyl 3-(pyridin-4-yl)-1,2,4-triazin-6-carboxylate (200 mg) was dissolved in a mixed solvent of tetrahydrofuran (5 ml) and methanol (5 ml) at room temperature. A 1N aqueous solution (1.00 ml) of sodium hydroxide was added to the reaction mixture in one portion. After stirring for 5 minutes, the reaction mixture was distilled under reduced pressure to remove tetrahydrofuran and methanol, followed by neutralization with 1N hydrochloric acid. The reaction mixture was concentrated to dryness, whereby 3-(pyridin-4-yl)-1,2,4-triazine-6-carboxylic acid was obtained as a crudely purified product.
Reaction SMILES: [H-].[Na+].[O:3]1[C:11]2[CH:10]=[CH:9][NH:8][C:7](=[O:12])[C:6]=2[CH:5]=[CH:4]1.C([O:15][CH:16]([O:19]CC)[CH2:17]Br)C.O>CN(C=O)C>[OH:15][CH:16]([OH:19])[CH2:17][N:8]1[CH:9]=[CH:10][C:11]2[O:3][CH:4]=[CH:5][C:6]=2[C:7]1=[O:12]
Reactant: O=c1[nH]ccc2occc12
Reactant: CCOC(CBr)OCC
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: O=c1c2ccoc2ccn1CC(O)O
Temperature: 0 °C

Procedure:
Sodium hydride (60% in oil, 0.36 g) was suspended in DMF (10 ml), and was cooled to 0° C. in an ice water bath. 5H-Furo[3,2-c]pyridin-4-one (1.0 g) was added thereto at the same temperature, and the mixture was stirred at 0° C. for an hour. Bromoacetaldehyde diethylacetal (2.6 ml) was added thereto, and the mixture was stirred at 80° C. for 5 hours. Water was added to the reaction liquid, followed by extraction by ethyl acetate. The organic layer was dried over sodium sulfate, and condensed under reduced pressure. A 3N-hydrochrolic acid (5.8 ml) was added to an acetone solution (20 ml) of the residue, and the liquid was stirred at 60° C. for 5 hours. Water was added to the reaction liquid and stirred at room temperature. The precipitated insoluble matter was separated, washed with water, and dried to give the title compound (0.90 g) as a white solid.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH2:19][C:20]([CH3:28])([CH3:27])[CH2:21][C:22]([O:24]CC)=[O:23])[CH:5]=[CH:6][C:7]=1[O:8][CH2:9][CH2:10][CH2:11][NH:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][N:14]=1.FC(F)(F)C(O)=O>CO.[OH-].[Na+]>[F:1][C:2]1[CH:3]=[C:4]([CH2:19][C:20]([CH3:28])([CH3:27])[CH2:21][C:22]([OH:24])=[O:23])[CH:5]=[CH:6][C:7]=1[O:8][CH2:9][CH2:10][CH2:11][NH:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][N:14]=1
Reactant: CCOC(=O)CC(C)(C)Cc1ccc(OCCCNc2ccccn2)c(F)c1
Agent: [Na+]
Agent: [OH-]
Solvent: O=C(O)C(F)(F)F
Solvent: CO
Product: CC(C)(CC(=O)O)Cc1ccc(OCCCNc2ccccn2)c(F)c1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
The product of STEP 8 (370 mg, 0.95 mmol) was dissolved in 20 ml methanol and 20 ml 1N sodium hydroxide solution . The reaction was stirred at room temperature for 16 h, and acidified with trifluoroacetic acid (3 ml). Solvents were evaporated and residue was purified on HPLC using acetonitrile gradient 10-50% in 30 min to yield 300 mg. FAB-MS: (MH+)=361. H NMR(CDCl3) δ1.03 (s, 6H), 2.20 (s, 2H), 2.22 (p, 2H), 2.62 (s, 2IH), 3.58 (q, 2H), 4.14 (t, 2H), 6.72 (t, 1H), 6.86-6.98 (m, 4H), 7.70 (m, 2H); Anal. Calcd. for C20H25N2O3F plus 1.4 CF3COOH: C, 52.66; H, 5.12; N, 5.39. Found: C, 52.56; H, 5.23; N, 5.09.
Reaction SMILES: ClC1C=C(Cl)C=CC=1C1N=C(CC)C(N[C@@H:18]2[C:26]3[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=3)[CH2:20][C@@H:19]2[O:27][CH2:28][CH3:29])=NC=1CC.[CH3:32][N:33]([CH3:62])[C:34]1[N:39]=[CH:38][C:37]([C:40]2[N:41]=[C:42]([CH2:59][CH3:60])[C:43]([NH:48][C@@H]3C4C(=CC=CC=4)C[C@@H]3O)=[N:44][C:45]=2[CH2:46][CH3:47])=[C:36]([CH3:61])[CH:35]=1>>[CH3:62][N:33]([CH3:32])[C:34]1[N:39]=[CH:38][C:37]([C:40]2[N:41]=[C:42]([CH2:59][CH3:60])[C:43]([NH:48][C@@H:18]3[C:26]4[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=4)[CH2:20][C@@H:19]3[O:27][CH2:28][CH3:29])=[N:44][C:45]=2[CH2:46][CH3:47])=[C:36]([CH3:61])[CH:35]=1
Reactant: CCO[C@H]1Cc2ccccc2[C@H]1Nc1nc(CC)c(-c2ccc(Cl)cc2Cl)nc1CC
Reactant: CCc1nc(-c2cnc(N(C)C)cc2C)c(CC)nc1N[C@@H]1c2ccccc2C[C@@H]1O
Product: CCO[C@H]1Cc2ccccc2[C@H]1Nc1nc(CC)c(-c2cnc(N(C)C)cc2C)nc1CC

Procedure:
Following the procedure for the preparation of 5-(2,4-dichlorophenyl)-N-[(1R,2S)-2-ethoxy-2,3-dihydro-1H-inden-1-yl]-3,6-diethylpyrazin-2-amine but substituting (1R,2S)-1-({5-[6-(dimethylamino)-4-methylpyridin-3-yl]-3,6-diethylpyrazin-2-yl}amino)-2,3-dihydro-1H-inden-2-ol and making non-critical variations provided the title compound as a light golden amorphous solid. IR (diffuse reflectance) 3446, 2969, 2931, 2893, 2874, 1604, 1562, 1517, 1487, 1392, 1372, 1208, 1174, 1123, 1089 cm−1; OAMS supporting ions at: ESI+ 446.3; MS (EI) m/z 445 (M+); HRMS (FAB) calcd for C27H35N5O+H1 446.2920, found 446.2915. [α]25D=−89 (c 0.47, methylene chloride); Anal. Calcd for C27H35N5O: C, 72.78; H, 7.92; N, 15.72. Found: C, 72.58; H, 7.94; N, 15.59.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([CH:21]=[CH:22][C:23]=1[CH3:24])[O:5][C:6]1[CH:7]=[CH:8][C:9]2[N:10]([CH:12]=[C:13]([NH:15][C:16]([CH:18]3[CH2:20][CH2:19]3)=[O:17])[N:14]=2)[N:11]=1.[C:25]1([C:30](O)=[O:31])[CH2:29][CH2:28][CH2:27][CH:26]=1.ON1C2C=CC=CC=2N=N1.C(N(CC)C(C)C)(C)C>CN(C)C(=O)C>[CH:18]1([C:16]([NH:15][C:13]2[N:14]=[C:9]3[CH:8]=[CH:7][C:6]([O:5][C:4]4[CH:21]=[CH:22][C:23]([CH3:24])=[C:2]([NH:1][C:30]([C:25]5[CH2:29][CH2:28][CH2:27][CH:26]=5)=[O:31])[CH:3]=4)=[N:11][N:10]3[CH:12]=2)=[O:17])[CH2:20][CH2:19]1
Reactant: O=C(O)C1=CCCC1
Reactant: Cc1ccc(Oc2ccc3nc(NC(=O)C4CC4)cn3n2)cc1N
Agent: On1nnc2ccccc21
Solvent: CC(=O)N(C)C
Solvent: CCN(C(C)C)C(C)C
Product: Cc1ccc(Oc2ccc3nc(NC(=O)C4CC4)cn3n2)cc1NC(=O)C1=CCCC1
Yield: 26.7 %

Procedure:
Using N-[6-(3-amino-4-methylphenoxy)imidazo[1,2-b]pyridazin-2-yl]cyclopropanecarboxamide (200 mg, 0.62 mmol), N,N-dimethylacetamide (4.0 mL), 1-cyclopentenecarboxylic acid (139 mg, 1.24 mmol), O-(benzotriazol-1-yl)-N,N,N′N′-tetramethyluronium hexafluorophosphate (704 mg, 1.86 mmol), 1-hydroxybenzotriazole (251 mg, 1.86 mmol) and N,N-diisopropylethylamine (323 μL, 1.86 mmol), and in the same manner as in Example 219, the title compound (69 mg, 21%) was obtained as a white powder.
Reaction SMILES: [C:1]([O:5][C:6](=[O:36])[NH:7][C:8]1([C:12]2[CH:17]=[CH:16][C:15](C3C(=O)C4C(=CC=C(F)C=4)OC=3C3C=CC=CC=3)=[CH:14][CH:13]=2)[CH2:11][CH2:10][CH2:9]1)([CH3:4])([CH3:3])[CH3:2].[Cl:37][C:38]1[N:39]=[CH:40][CH:41]=[C:42]2[C:47](=[O:48])[C:46](I)=[C:45]([C:50]3[CH:55]=[CH:54][CH:53]=[CH:52][CH:51]=3)[O:44][C:43]=12>>[C:1]([O:5][C:6](=[O:36])[NH:7][C:8]1([C:12]2[CH:13]=[CH:14][C:15]([C:46]3[C:47](=[O:48])[C:42]4[C:43]([O:44][C:45]=3[C:50]3[CH:55]=[CH:54][CH:53]=[CH:52][CH:51]=3)=[C:38]([Cl:37])[N:39]=[CH:40][CH:41]=4)=[CH:16][CH:17]=2)[CH2:9][CH2:10][CH2:11]1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)NC1(c2ccc(-c3c(-c4ccccc4)oc4ccc(F)cc4c3=O)cc2)CCC1
Reactant: O=c1c(I)c(-c2ccccc2)oc2c(Cl)nccc12
Product: CC(C)(C)OC(=O)NC1(c2ccc(-c3c(-c4ccccc4)oc4c(Cl)nccc4c3=O)cc2)CCC1
Yield: 20 %

Procedure:
Following the procedure used to prepare {1-[4-(6-fluoro-4-oxo-2-phenyl-4H-chromen-3-yl)-phenyl]-cyclobutyl}-carbamic acid tert-butyl ester, 8-chloro-3-iodo-2-phenyl-pyrano[2,3-c]pyridin-4-one was reacted to give the title compound (30 mg, 20%) as a white solid. LCMS (Method A): RT=4.88 min, [M+Na]+=525/527.
Reaction SMILES: [C:1]1([S:7]([N:10]2[CH2:12][CH:11]2[C:13]([N:15]2[CH2:20][CH2:19][N:18]([C:21]3[CH:26]=[C:25]([CH3:27])[CH:24]=[CH:23][C:22]=3[CH3:28])[CH2:17][CH2:16]2)=[O:14])(=[O:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[I-].[Na+].[Cl:31][C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][C:33]=1[N:38]=[C:39]=[O:40]>>[C:1]1([S:7]([N:10]2[CH2:12][CH:11]([C:13]([N:15]3[CH2:16][CH2:17][N:18]([C:21]4[CH:26]=[C:25]([CH3:27])[CH:24]=[CH:23][C:22]=4[CH3:28])[CH2:19][CH2:20]3)=[O:14])[N:38]([C:33]3[CH:34]=[CH:35][CH:36]=[CH:37][C:32]=3[Cl:31])[C:39]2=[O:40])(=[O:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: O=C=Nc1ccccc1Cl
Reactant: Cc1ccc(C)c(N2CCN(C(=O)C3CN3S(=O)(=O)c3ccccc3)CC2)c1
Agent: [I-]
Agent: [Na+]
Product: Cc1ccc(C)c(N2CCN(C(=O)C3CN(S(=O)(=O)c4ccccc4)C(=O)N3c3ccccc3Cl)CC2)c1

Procedure:
In analogy to example 2, (RS)-(1-benzenesulfonyl-aziridin-2-yl)-[4-(2,5-dimethyl-phenyl)-piperazin-1-yl]-methanone (example 2, step 3) was reacted with sodium iodide and 2-chlorophenyl isocyanate to give the title compound as a colorless solid. MS: 553.3 ([M+H]+)
Reaction SMILES: [CH2:1]([CH:7]1[O:9][C:8]1([C:15]([O:17][CH2:18][CH3:19])=[O:16])[C:10](OCC)=[O:11])[CH2:2][CH2:3][CH2:4][CH2:5][CH3:6].[NH3:20]>C(O)C>[NH2:20][C:10]([C:8]1([C:15]([O:17][CH2:18][CH3:19])=[O:16])[CH:7]([CH2:1][CH2:2][CH2:3][CH2:4][CH2:5][CH3:6])[O:9]1)=[O:11]
Reactant: CCCCCCC1OC1(C(=O)OCC)C(=O)OCC
Reactant: N
Solvent: CCO
Product: CCCCCCC1OC1(C(N)=O)C(=O)OCC
Reaction time: 48 h

Procedure:
A solution of 8.0 g of 2A in 10 ml of ethanol was saturated with ammonia (gas) and the mixture was allowed to stand for 2 days at room temperature. The precipitate that formed was collected and recrystallized from pentane to give 2, as white crystals, mp: 58°-60° C.
Reaction SMILES: [N:1]1([CH:6]=[CH:7][C:8]2[O:9][C:10]3[CH:16]=[C:15]([NH2:17])[CH:14]=[CH:13][C:11]=3[N:12]=2)[CH2:5][CH2:4][CH2:3][CH2:2]1.C([BH3-])#N.[Na+]>CO>[N:1]1([CH2:6][CH2:7][C:8]2[O:9][C:10]3[CH:16]=[C:15]([NH2:17])[CH:14]=[CH:13][C:11]=3[N:12]=2)[CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: Nc1ccc2nc(C=CN3CCCC3)oc2c1
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CO
Product: Nc1ccc2nc(CCN3CCCC3)oc2c1

Procedure:
To a solution of 2-(2-pyrrolidin-1-yl-vinyl)-benzooxazol-6-ylamine (3.2 mmol) in MeOH (40 mL) is added sodium cyanoborohydride (6.4 mmol) at room temperature. The reaction mixture is heated to reflux for 18 hours. The mixture is concentrated and the residue is dissolved in DCM. The solution is washed with water and brine, and dried (MgSO4). A small amount of activated carbon is added to the solution, and the mixture is filtered. The filtrate is concentrated to afford 2-(2-pyrrolidin-1-yl-ethyl)-benzooxazol-6-ylamine as a solid. 1H NMR (300 MHz, CDCl3): δ 1.79 (m, 4H), 2.61 (m, 4H), 3.00-3.18 (m, 4H), 4.78 (broad, 2N—H), 6.68 (q, H), 6.80 (d, H), 7.43 (d, H).
Reaction SMILES: [C:1]1([C:11]2[CH:16]=[CH:15][CH:14]=[C:13]([CH3:17])[C:12]=2[C:18]2[CH:19]=[C:20]3[C:25](=[CH:26][CH:27]=2)[N:24]=[C:23]([NH2:28])[C:22]([N:29]2[CH2:34][CH2:33][O:32][CH2:31][CH2:30]2)=[CH:21]3)[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH2:4][CH2:3][N:2]=1.[BH4-].[Na+].Cl>CO>[CH3:17][C:13]1[CH:14]=[CH:15][CH:16]=[C:11]([CH:1]2[C:10]3[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=3)[CH2:4][CH2:3][NH:2]2)[C:12]=1[C:18]1[CH:19]=[C:20]2[C:25](=[CH:26][CH:27]=1)[N:24]=[C:23]([NH2:28])[C:22]([N:29]1[CH2:34][CH2:33][O:32][CH2:31][CH2:30]1)=[CH:21]2
Reactant: Cc1cccc(C2=NCCc3ccccc32)c1-c1ccc2nc(N)c(N3CCOCC3)cc2c1
Agent: Cl
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Product: Cc1cccc(C2NCCc3ccccc32)c1-c1ccc2nc(N)c(N3CCOCC3)cc2c1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A suspension of 6-(2-(3,4-dihydroisoquinolin-1-yl)-6-methylphenyl)-3-morpholinoquinolin-2-amine (0.0075 g, 0.017 mmol) in MeOH (0.50 mL) was treated with NaBH4 (25.0 mg, 0.661 mmol) and stirred at ambient temperature overnight. On following day, reaction mixture treated with 2N HCl and stirred for 2 h. The mixture was filtered and the filtrate was purified directly by reverse phase HPLC (1-90% acetonitrile/H2O, TFA modifier, 20 min). Single fraction freeze-dried to afford 6-(2-methyl-6-(1,2,3,4-tetrahydroisoquinolin-1-yl)phenyl)-3-morpholinoquinolin-2-amine (2,2,2-trifluoroacetate salt). MS (ESI, pos. ion) m/z: 451 (M+1).
Reaction SMILES: [CH3:1][O:2][C:3]1(O)[CH2:8][CH2:7][CH2:6][CH2:5][CH2:4]1.S([O-])(O)=[O:11].[Na+].S(=O)(=O)(O)O.C(=O)([O-])[O-].[Na+].[Na+]>>[CH3:1][O:2][C@H:3]1[CH2:8][CH2:7][CH2:6][CH2:5][C:4]1=[O:11]
Reactant: COC1(O)CCCCC1
Reactant: O=S([O-])O
Agent: O=C([O-])[O-]
Agent: O=S(=O)(O)O
Agent: [Na+]
Product: CO[C@H]1CCCCC1=O

Procedure:
Reaction was carried out in the same manner as in Example 16. After the peak due to (S)-2)-methoxycyclohexanol had disappeared, the reaction solution was given 2 g of sodium hydrogensulfite with stirring so that the reaction solution did not change potassium iodide starch paper into purple any longer. The reaction solution was adjusted to pH 2 or below with 10% sulfuric acid, followed by stirring at 20-25° C. for 1 hour. The reaction solution was adjusted to pH 7.5-8 with an aqueous solution of sodium carbonate, followed by stirring at 20-25° C. for 1 hour. The reaction solution was adjusted again to pH 2 or below with 10% sulfuric acid, followed by stirring at 20-25° C. for 2 hours. The reaction solution was extracted three times with 100 g of toluene. The toluene layers were combined together and washed with a saturated aqueous solution of sodium chloride. After concentration and distillation in the same manner as in Example 1, there was obtained 10.3 g (80 mmol) of (S)-2-methoxycyclohexanone having a chemical purity of 99.3% and an optical purity of 99.6% ee. This product was heated at 60° C. for 48 hours in the same manner as in Example 16; it decreased in optical purity to 99.0% ee.
Reaction SMILES: [NH2:1][C@@H:2]([CH2:11][CH3:12])[C@H:3]([OH:10])[C:4]([NH:6][CH:7]1[CH2:9][CH2:8]1)=[O:5].N[C@@H:14](CCC)C(O)=O>>[NH2:1][C@@H:2]([CH2:11][CH2:12][CH3:14])[C@H:3]([OH:10])[C:4]([NH:6][CH:7]1[CH2:8][CH2:9]1)=[O:5]
Reactant: CC[C@H](N)[C@H](O)C(=O)NC1CC1
Reactant: CCC[C@H](N)C(=O)O
Product: CCC[C@H](N)[C@H](O)C(=O)NC1CC1

Procedure:
The title compound was prepared in analogy to (2S,3S)-3-amino-N-cyclopropyl-2-hydroxypentanamide, Representative Procedure B, using (S)-2-aminopentanoic acid in the first step (step B1).
Reaction SMILES: [NH2:1][CH2:2][CH2:3][CH2:4][NH:5][CH2:6][CH2:7][CH2:8][CH2:9][NH:10][CH2:11][CH2:12][CH2:13][NH2:14].C(O[C:23]1[CH:28]=[C:27]([O:29][CH2:30][C:31]2[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=2)[CH:26]=[CH:25][C:24]=1[CH2:37][C:38](OC1C=CC([N+]([O-])=O)=CC=1)=[O:39])C1C=CC=CC=1>>[CH2:30]([O:29][CH:37]([C:24]1[CH:23]=[CH:28][C:27]([O:29][CH2:30][C:31]2[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=2)=[CH:26][CH:25]=1)[C:38]([NH:14][CH2:13][CH2:12][CH2:11][NH:10][CH2:9][CH2:8][CH2:7][CH2:6][NH:5][CH2:4][CH2:3][CH2:2][NH2:1])=[O:39])[C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1
Reactant: O=C(Cc1ccc(OCc2ccccc2)cc1OCc1ccccc1)Oc1ccc([N+](=O)[O-])cc1
Reactant: NCCCNCCCCNCCCN
Product: NCCCNCCCCNCCCNC(=O)C(OCc1ccccc1)c1ccc(OCc2ccccc2)cc1
Yield: 126.9 %

Procedure:
To a solution of spermine (1,4-bis [{(3-amino) propyl}amino]butane, 460 mg) in N,N-dimethylformamide anhydride (5 ml) is added a solution of para-nitrophenyl 2,4-dibenzyloxyphenylacetate (100 mg) in N,N-dimethylformamide anhydride (5 ml). The resulting solution is concentrated to dryness under reduced pressure and thereto are added 5 % aqueous sodium hydrogencarbonate solution (0.1 ml) and then water (30 ml). The resulting precipitate is filtered and washed thoroughly with water, followed by drying, to yield crude 2,4-dibenzyloxyphenylacetylspermine (72 mg, yield 64%). 3) To a solution of crude 2,4-dibenzyloxyphenylacetylspermine (72 mg) in acetic acid (5 ml) is added 10% palladium-carbon (50 mg) and then catalytic reduction is carried out in a hydrogen stream for one and half hours. After the reaction is over, the catalyst is removed by filtration and the filtrate is concentrated to dryness under reduced pressure. The residue is subjected to separation and purification by high-performance liquid chromatography (reversed-phase partition column TSK gel ODS-120T manufactured by Toyo Soda Mfg., CO., Ltd.; inner diameter of the column: 7.8 mm, length: 30 mm; resin diameter; 3 μm; column temperature: 40° C.; eluent: water/acetonitrile mixed solvent (98/2, V/V) to which trifluoroacetic acid has been added to final concentration of 0.05% by volume). The solvent is distilled off to yield 2,4-dihydroxyphenylacetyl-spermine trifluoroacetic acid salt (3.0 mg, yield 4.2%).
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([C:8]([F:11])([F:10])[F:9])[N:5]=[C:4]([S:12][CH3:13])[N:3]=1.[CH3:14][S:15][C:16]1[CH:21]=[CH:20][C:19](B(O)O)=[CH:18][CH:17]=1.C(=O)([O-])[O-].[Na+].[Na+]>COCCOC.O>[CH3:13][S:12][C:4]1[N:3]=[C:2]([C:19]2[CH:20]=[CH:21][C:16]([S:15][CH3:14])=[CH:17][CH:18]=2)[CH:7]=[C:6]([C:8]([F:11])([F:10])[F:9])[N:5]=1
Reactant: CSc1nc(Cl)cc(C(F)(F)F)n1
Reactant: CSc1ccc(B(O)O)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: COCCOC
Product: CSc1ccc(-c2cc(C(F)(F)F)nc(SC)n2)cc1
Reaction time: 24 h
Yield: 83.9 %

Procedure:
A mixture of 4-chloro-2-methylthio-6-(trifluoromethyl)pyrimidine (ButtPark Ltd, 2.86 g, 14.55 mmol), 4-(methylthio)phenylboronic acid (Aldrich, 2.83 g, 1.1 eq), tetrakistriphenylphosphine palladium (0) (0.2 g) and sodium carbonate (4.04 g, 2.6 eq) in DME (200 ml) and water (100 ml) was heated under reflux with stirring under N2 for 24 h. The reaction mixture was concentrated in vacuo and the resultant mixture partitioned between ethyl acetate and water. The organic phase was separated, washed with water, dried (Na2SO4) and concentrated in vacuo to a purple solid. Purification by flash column chromatography with cyclohexane:ethyl acetate as (6:1) as eluant gave the title compound as a yellow crystalline solid (3.86 g, 84%).