Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C([N-]C(C)C)(C)C.[Li+].[CH2:9]([O:11][C:12](=[O:17])[CH2:13][O:14][CH2:15][CH3:16])[CH3:10].[CH2:18]([O:25][C:26]1[CH:33]=[CH:32][C:29]([CH:30]=[O:31])=[C:28]([CH3:34])[CH:27]=1)[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1>C1COCC1.CCCCCCC.O1CCCC1>[CH2:9]([O:11][C:12](=[O:17])[CH:13]([O:14][CH2:15][CH3:16])[CH:30]([C:29]1[CH:32]=[CH:33][C:26]([O:25][CH2:18][C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)=[CH:27][C:28]=1[CH3:34])[OH:31])[CH3:10]
Reactant: CCOCC(=O)OCC
Reactant: Cc1cc(OCc2ccccc2)ccc1C=O
Agent: CC(C)[N-]C(C)C
Agent: [Li+]
Solvent: C1CCOC1
Solvent: CCCCCCC
Product: CCOC(=O)C(OCC)C(O)c1ccc(OCc2ccccc2)cc1C
Reaction time: 0.5 h
Yield: 102.7 %

Procedure:
To a −78° C. cold 2 M solution of lithium diisopropylamide (305 mmol) in THF/n-heptane (152.4 ml) was added a solution of ethoxy-acetic acid ethyl ester (45.2 ml, 331 mmol) in tetrahydrofuran (240 ml) within 1.5 h under an argon atmosphere. The mixture was stirred for 30 min. A solution of 4-benzyloxy-2-methyl-benzaldehyde (30 g, 132.6 mmol) in tetrahydrofuran (420 ml) was added dropwise over a period of 50 min. The reaction mixture was stirred 2 h at −78° C., poured onto ice water/aqueous ammonium chloride solution 1/1 and extracted two times with ethyl acetate. The combined extracts were washed three times with ice water/brine 1/1 and dried over sodium sulfate. The solvent was removed under reduced pressure and the residue purified by column chromatography (silica gel, n-heptane/AcOEt) to give 48.8 g (136.2 mmol) of the title compound as a mixture of stereoisomers as yellow oil.
Reaction SMILES: C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N1C=CN=C1.[I:25]I.[CH2:27]([O:34][C:35](=[O:41])[NH:36][C@H:37]([CH3:40])[CH2:38]O)[C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1>C(Cl)Cl.O>[CH2:27]([O:34][C:35](=[O:41])[NH:36][C@H:37]([CH3:40])[CH2:38][I:25])[C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1
Reactant: II
Reactant: C[C@H](CO)NC(=O)OCc1ccccc1
Agent: c1c[nH]cn1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Solvent: O
Product: C[C@H](CI)NC(=O)OCc1ccccc1
Temperature: 0 °C
Reaction time: 3 h

Procedure:
Triphenylphospine (24 g, 91.8 mmol) was added to a solution of imidazole (12.5 g, 184 mmol) in CH2Cl2 (231 ml), then was cooled to 0 degrees C. Iodine (23.3 g, 91.8 mmol) was added to the suspension. The reaction mixture turned yellow, then faintly brown. After 5 minutes ((R)-2-hydroxy-1-methyl-ethyl)-carbamic acid benzyl ester (9.59 g, 45.9 mmol) was added and the reaction mixture was warmed to RT then stirred for 3 h. Then, H2O (7 ml) was added and the reaction mixture was partitioned between CH2Cl2 (300 ml) and H2O (600 ml). The aqueous layer was extracted again with CH2Cl2 (200 ml). The combined organic layer was then washed with a solution of 1:9 aq. saturated Na2S2O3: H2O (140 ml), then brine (400 ml). The combined organics were dried with MgSO4, filtered, concentrated in vacuo, then filtered through a plug of silica gel washing with 15% EtOAc/hexanes (1.5 liter). The solution was concentrated in vacuo, then the solid was washed with hexane and the resultant white solid was used in the next reaction without further purification (11 g, 75%).
Reaction SMILES: [N+]([C:4]1[CH:12]=[CH:11][C:7]2[N:8]=[CH:9][S:10][C:6]=2[CH:5]=1)([O-])=O.[OH-].[K+].ClC[C:17](=O)[CH2:18][C:19]([O:21][CH2:22][CH3:23])=[O:20].Cl>CCO>[S:10]1[C:6]2[CH:5]=[CH:4][CH:12]=[CH:11][C:7]=2[NH:8]/[C:17](=[CH:18]/[C:19]([O:21][CH2:22][CH3:23])=[O:20])/[CH2:9]1
Reactant: CCOC(=O)CC(=O)CCl
Reactant: O=[N+]([O-])c1ccc2ncsc2c1
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Product: CCOC(=O)/C=C1\CSc2ccccc2N1
Temperature: 0 °C
Reaction time: 1 h
Yield: 4.5 %

Procedure:
steps 1 and 2—To a solution of 6-nitrobenzothiazole (10, 10.2 g, 57 mmol) in EtOH (500 mL) was added KOH (7.0 g, 125 mmol). The reaction was heated at reflux for 15 min then cooled to 0° C. Ethyl chloroacetoacetate (9.3 g, 57 mmol) was added and the mixture stirred at RT for 1 h. The reaction mixture was poured into 1N HCl (500 mL) and the resulting solid was collected. The solid was dissolved in EtOAc. The organic phase was washed with brine, dried (MgSO4) and the solvent was removed under reduced pressure. The product was purified by SiO2 chromatography eluting with 10% EtOAc/hexane to afford 0.61 g (70%) of 12a: LCMS RT 3.48 min, M+H.
Reaction SMILES: [CH3:1][O:2][CH2:3][CH2:4][O:5][CH2:6]Cl.[C:8]([O:12][C:13]([N:15]1[CH2:20][CH2:19][CH:18]([OH:21])[CH2:17][CH2:16]1)=[O:14])([CH3:11])([CH3:10])[CH3:9].C(N(C(C)C)CC)(C)C>O1CCCC1>[C:8]([O:12][C:13]([N:15]1[CH2:20][CH2:19][CH:18]([O:21][CH2:6][O:5][CH2:4][CH2:3][O:2][CH3:1])[CH2:17][CH2:16]1)=[O:14])([CH3:11])([CH3:9])[CH3:10]
Reactant: CC(C)(C)OC(=O)N1CCC(O)CC1
Reactant: COCCOCCl
Solvent: CCN(C(C)C)C(C)C
Solvent: C1CCOC1
Product: COCCOCOC1CCN(C(=O)OC(C)(C)C)CC1
Temperature: 0 °C
Reaction time: 1 h
Yield: 58.7 %

Procedure:
10 ml of a tetrahydrofuran (THF) solution of 1.37 g (11 mmol) of 2-methoxyethoxymethyl chloride was added dropwise to 10 ml of a THF solution of 2.01 g (10 mmol) of N-t-butoxycarbonyl-4-hydroxypiperidine (manufactured by Aldrich) and 2.58 g (20 mmol) of diisopropylethylamine at 0° C. in a nitrogen atmosphere. After the addition, the reaction solution was allowed to reach room temperature, and stirred for one hour. After confirming disappearance of the raw materials by thin-layer chromatography (TLC), the reaction solution was cooled to 0° C. The reaction was then terminated by adding water. The reaction solution was subjected to an extraction operation three times using water and ethyl acetate. The resulting organic layer was washed once with a saturated ammonium chloride solution, washed once with water, washed once with a saturated sodium chloride aqueous solution, and dried over anhydrous sodium sulfate. After evaporating the solvent under reduced pressure, the product was purified by column chromatography to obtain 1.7 g of N-t-butoxycarbonyl-4-[(2-methoxyethoxy)methoxy]piperidine as a colorless liquid (hereinafter referred to as “compound (A-1)”) (yield: 60%).
Reaction SMILES: C(OC([NH:8][C@@H:9]1[C:15](=[O:16])[N:14]([CH2:17][C:18]2[CH:23]=[CH:22][C:21]([CH:24]([CH3:26])[CH3:25])=[CH:20][CH:19]=2)[C:13]2[CH:27]=[CH:28][CH:29]=[CH:30][C:12]=2[O:11][CH2:10]1)=O)(C)(C)C.[ClH:31]>C(OCC)(=O)C>[ClH:31].[NH2:8][C@@H:9]1[C:15](=[O:16])[N:14]([CH2:17][C:18]2[CH:23]=[CH:22][C:21]([CH:24]([CH3:26])[CH3:25])=[CH:20][CH:19]=2)[C:13]2[CH:27]=[CH:28][CH:29]=[CH:30][C:12]=2[O:11][CH2:10]1
Reactant: CC(C)c1ccc(CN2C(=O)[C@@H](NC(=O)OC(C)(C)C)COc3ccccc32)cc1
Agent: Cl
Solvent: CCOC(C)=O
Product: CC(C)c1ccc(CN2C(=O)[C@@H](N)COc3ccccc32)cc1
Reaction time: 2 h

Procedure:
55 g of (S)-3-(tert-butoxycarbonylamino)-5-(p-isopropylbenzyl)-2,3,4,5-tetrahydro-1,5-benzoxazepin-4-one are dissolved in 180 ml of approximately 5 hydrochloric acid in ethyl acetate, foaming occurring. After stirring for two hours, the ochre-coloured suspension is concentrated and recrystallised from ether. The hygroscopic product has a m.p. of 215° C. (decomp.).
Reaction SMILES: O[N:2]=[C:3]([C:5]1[CH:14]=[CH:13][C:8]([C:9]([O:11][CH3:12])=[O:10])=[CH:7][C:6]=1[CH3:15])[CH3:4].[ClH:16]>CO.[Pd]>[ClH:16].[NH2:2][CH:3]([C:5]1[CH:14]=[CH:13][C:8]([C:9]([O:11][CH3:12])=[O:10])=[CH:7][C:6]=1[CH3:15])[CH3:4]
Reactant: COC(=O)c1ccc(C(C)=NO)c(C)c1
Agent: [Pd]
Agent: Cl
Solvent: CO
Product: COC(=O)c1ccc(C(C)N)c(C)c1
Reaction time: 8 h
Yield: 99.8 %

Procedure:
To a degassed solution of methyl 4-[N-hydroxyethanimidoyl]-3-methylbenzoate (0.348 g, 1.68 mmol) and 12.0 M aqueous hydrochloric acid (0.35 mL, 4.20 mmol) in methanol (15 mL) was added 10% palladium on carbon (0.11 g, 0.101 mmol). The reaction mixture was stirred under a balloon atmosphere of H2 overnight. All insolubles were then removed via filtration through celite and the filtrate was evaporated to dryness. The residue was redissolved in methanol/toluene and concentrated under reduced pressure to afford a white solid (0.385 g, 100%). LC-MS: (FA) ES+ 195; 1H NMR (300 MHz, DMSO) δ 7.15 (m Hz, 2H), 6.73 (d, J=8.1 Hz, 1H), 6.45-6.26 (m, 1H), 3.96 (dd, J=13.7, 6.9 Hz, 1H), 3.10 (s, 3H), 1.67 (s, 3H), 0.80 (d, J=6.8 Hz, 3H).
Reaction SMILES: [CH:1]([NH2:4])([CH3:3])[CH3:2].Br[CH2:6][CH2:7][N:8]1[C:12]2=[N:13][CH:14]=[CH:15][CH:16]=[C:11]2[O:10][C:9]1=[O:17]>C(#N)C>[CH:1]([NH:4][CH2:6][CH2:7][N:8]1[C:12]2=[N:13][CH:14]=[CH:15][CH:16]=[C:11]2[O:10][C:9]1=[O:17])([CH3:3])[CH3:2]
Reactant: CC(C)N
Reactant: O=c1oc2cccnc2n1CCBr
Solvent: CC#N
Product: CC(C)NCCn1c(=O)oc2cccnc21

Procedure:
0.1 mol of isopropylamine and 0.01 mol of 3-(2-bromoethyl)-3H-oxazolo[4,5-b]pyridin-2-one, dissolved beforehand in 40 cm3 of acetonitrile, are introduced into a 100-cm3 ground-necked round-bottomed flask equipped with a reflux condenser. The mixture is heated to reflux for 15 hours. After cooling, the precipitate obtained is drained, dried and recrystallized.
Reaction SMILES: C[O:2][C:3](=[O:13])[CH:4]=[CH:5][CH2:6][N:7]1[CH2:12][CH2:11][CH2:10][CH2:9][CH2:8]1.[ClH:14]>>[ClH:14].[N:7]1([CH2:6][CH:5]=[CH:4][C:3]([OH:13])=[O:2])[CH2:12][CH2:11][CH2:10][CH2:9][CH2:8]1
Reactant: COC(=O)C=CCN1CCCCC1
Agent: Cl
Product: O=C(O)C=CCN1CCCCC1
Yield: 17 %

Procedure:
4-Piperidin-1-yl-but-2-enoic acid methyl ester (2.05 g, 11.2 mmol) and concentrated hydrochloric acid (10 mL) were combined in dioxanes (30 mL) and heated to reflux overnight. The mixture was concentrated in vacuo. The residue was crystallized from IPA to yield the desired product (390 mg, 17%). 400 MHz 1H NMR (DMSO-d6) δ 6.80 (dt, 1H, J=15.6, 7.1 Hz), 6.14 (d, 1H, J=15.6 Hz), 3.85 (d, 1H, J=7.1 Hz), 2.89 (m, 4H), 1.54 (m, 6H). MS m/z 170 (M+1).
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([N:7]2[C:15]3[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=3)[CH:9]=[CH:8]2)[CH:2]=1.[Cl-].[CH2:17]([O:19][C:20](=[O:27])[CH2:21][CH2:22][CH2:23][C:24](O)=[O:25])[CH3:18].[OH-].[NH4+]>C(Cl)Cl>[O:25]=[C:24]([C:9]1[C:10]2[C:15](=[CH:14][CH:13]=[CH:12][CH:11]=2)[N:7]([C:3]2[CH:2]=[N:1][CH:6]=[CH:5][CH:4]=2)[CH:8]=1)[CH2:23][CH2:22][CH2:21][C:20]([O:19][CH2:17][CH3:18])=[O:27]
Reactant: CCOC(=O)CCCC(=O)O
Reactant: c1cncc(-n2ccc3ccccc32)c1
Agent: [Cl-]
Agent: [NH4+]
Agent: [OH-]
Solvent: ClCCl
Product: CCOC(=O)CCCC(=O)c1cn(-c2cccnc2)c2ccccc12
Reaction time: 8 h

Procedure:
To a mixture of 10.0 g of N-(3-pyridyl)-indole (J. Chem. Soc. (C), 85, 1970) and 13.8 g of glutaric acid monoethyl ester chloride in 90 ml of methylene chloride is added dropwise over a period of 3 hours a solution of 20.1 g of stannic chloride in 60 ml of methylene chloride. The reaction mixture is stirred at room temperative overnight. The reaction mixture is cooled to 10°-15° and 150 ml of 14% aqueous ammonium hydroxide is added. The organic layer is separated, washed with water and dried over sodium sulfate to yield 3-(1-oxo-4-ethoxycarbonylbutyl)-N-(3-pyridyl)indole, melting at 95°-97°.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:10]=[CH:9][C:6]([CH2:7][NH2:8])=[CH:5][CH:4]=1.[CH:11](=O)[C:12]1[CH:17]=[CH:16][C:15]([O:18][CH3:19])=[CH:14][CH:13]=1>>[CH3:1][O:2][C:3]1[CH:10]=[CH:9][C:6]([CH2:7][N:8]=[CH:11][C:12]2[CH:17]=[CH:16][C:15]([O:18][CH3:19])=[CH:14][CH:13]=2)=[CH:5][CH:4]=1
Reactant: COc1ccc(CN)cc1
Reactant: COc1ccc(C=O)cc1
Product: COc1ccc(C=NCc2ccc(OC)cc2)cc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 131 %

Procedure:
4-Methoxybenzylamine (40 g, 290 mmol) was cooled to 0° C., and p-anisaldehyde (39.7 g, 292 mmol) was added dropwise. The reaction was stirred at ambient temperature for two hours, concentrated under reduced pressure, and further dried under high vacuum overnight to provide 97 g of N-(4-methoxybenzyl)-N-[(4-methoxyphenyl)methylidene]amine as a white, waxy solid.
Reaction SMILES: Br[C:2]1[N:3]=[CH:4][C:5]([C:8]([N:10]2[CH2:15][CH2:14][N:13]([C:16]3[C:21]([CH3:22])=[CH:20][C:19]([CH3:23])=[CH:18][N:17]=3)[CH2:12][CH2:11]2)=[O:9])=[N:6][CH:7]=1.[CH3:24][C@@H:25]1[CH2:29][O:28][C:27](=[O:30])[NH:26]1>>[CH3:22][C:21]1[C:16]([N:13]2[CH2:14][CH2:15][N:10]([C:8]([C:5]3[N:6]=[CH:7][C:2]([N:26]4[C@H:25]([CH3:24])[CH2:29][O:28][C:27]4=[O:30])=[N:3][CH:4]=3)=[O:9])[CH2:11][CH2:12]2)=[N:17][CH:18]=[C:19]([CH3:23])[CH:20]=1
Reactant: C[C@@H]1COC(=O)N1
Reactant: Cc1cnc(N2CCN(C(=O)c3cnc(Br)cn3)CC2)c(C)c1
Product: Cc1cnc(N2CCN(C(=O)c3cnc(N4C(=O)OC[C@H]4C)cn3)CC2)c(C)c1
Yield: 80.3 %

Procedure:
Using (5-bromopyrazin-2-yl) [4-(3,5-dimethylpyridin-2-yl)piperazin-1-yl]methanone (130 mg) described in Preparation Example 232 and (R)-4-methyloxazolidin-2-one (35 mg) and by the reaction and treatment in the same manner as in Example 1, the title compound (110 mg) was obtained.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([CH2:9][CH2:10][CH2:11][NH:12][C:13](=[O:27])[CH2:14][C:15]2[CH:20]=[CH:19][C:18]([O:21][CH2:22][CH2:23][NH2:24])=[C:17]([O:25][CH3:26])[CH:16]=2)[CH:5]=[CH:6][C:7]=1[CH3:8].[C:28]([O:31][C:32]1[C:33](=[CH:37][CH:38]=[CH:39][CH:40]=1)[C:34](O)=[O:35])(=[O:30])[CH3:29].ON1C2C=CC=CC=2N=N1>C(#N)C.CN(C)C=O>[CH3:1][C:2]1[CH:3]=[C:4]([CH2:9][CH2:10][CH2:11][NH:12][C:13](=[O:27])[CH2:14][C:15]2[CH:20]=[CH:19][C:18]([O:21][CH2:22][CH2:23][NH:24][C:34](=[O:35])[C:33]3[CH:37]=[CH:38][CH:39]=[CH:40][C:32]=3[O:31][C:28](=[O:30])[CH3:29])=[C:17]([O:25][CH3:26])[CH:16]=2)[CH:5]=[CH:6][C:7]=1[CH3:8]
Reactant: CC(=O)Oc1ccccc1C(=O)O
Reactant: COc1cc(CC(=O)NCCCc2ccc(C)c(C)c2)ccc1OCCN
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: CC#N
Product: COc1cc(CC(=O)NCCCc2ccc(C)c(C)c2)ccc1OCCNC(=O)c1ccccc1OC(C)=O
Yield: 62.6 %

Procedure:
0.27 g (0.66 mmol) of N-{3-(3,4-dimethylphenyl)propyl}-4-(2-aminoethoxy)-3-methoxyphenylacetamide obtained in Step 5 of Example 3, 0.17 g (0.94 mmol) of acetylsalicylic acid and 0.10 g (0.74 mmol) of 1-hydroxylbenzotriazole were dissolved in 15 ml of a mixture of acetonitrile and dimethylformamide(1:2). 0.19 g (0.92 mmol) of dicyclohexanecarbodiimide was added thereto and the resultant mixture was stirred at a room temperature for 2 days. White precipitates were removed and the remaining solution was diluted with 30 ml of dichloromethane, which was washed with water and dried. After removing the solvent under a reduced pressure, the residue was subjected to silica gel chromatography to obtain 0.22 g of the title compound (yield: 63%).
Reaction SMILES: C(OC([N:8](C(OC(C)(C)C)=O)[C:9]1[N:17]=[C:16]2[C:12]([N:13]=[CH:14][N:15]2[O:18][CH2:19][C@H:20]([O:40][CH2:41][P:42]([O:47][CH2:48][CH3:49])([O:44][CH2:45][CH3:46])=[O:43])[CH2:21][O:22][Si](C(C)(C)C)(C2C=CC=CC=2)C2C=CC=CC=2)=[C:11]([O:50][CH3:51])[N:10]=1)=O)(C)(C)C>FC(F)(F)C(O)=O>[NH2:8][C:9]1[N:17]=[C:16]2[C:12]([N:13]=[CH:14][N:15]2[O:18][CH2:19][C@H:20]([O:40][CH2:41][P:42]([O:44][CH2:45][CH3:46])([O:47][CH2:48][CH3:49])=[O:43])[CH2:21][OH:22])=[C:11]([O:50][CH3:51])[N:10]=1
Reactant: CCOP(=O)(CO[C@@H](COn1cnc2c(OC)nc(N(C(=O)OC(C)(C)C)C(=O)OC(C)(C)C)nc21)CO[Si](c1ccccc1)(c1ccccc1)C(C)(C)C)OCC
Solvent: O=C(O)C(F)(F)F
Product: CCOP(=O)(CO[C@H](CO)COn1cnc2c(OC)nc(N)nc21)OCC
Yield: 69.2 %

Procedure:
A solution of (S)-2-[bis-(t-butyloxycarbonyl)amino]-9-[3-(t-butyldiphenylsilyloxy)-2-(diethoxyphosphorylmethoxy)propoxy]-6-methoxypurine (300 mg, 0.36 mmol) in 67% aqueous trifluoroacetic acid (3 ml) was kept at ambient temperature for 3 hours. The solution was washed with hexane (3×10 ml) and the aqueous phase evaporated to dryness. The residue obtained was chromatographed on silica gel (dichloromethane: methanol 95:5 as eluant, then 90:10) to give (R)-2-amino-9-[2-(diethoxyphosphorylmethoxy)-3-hydroxypropoxy]-6-methoxypurine as a pale yellow glass (101 mg, 70%). 1H NMR: δH [(CD3)2SO] 1.23 (6H, t, J=7.1 Hz, (OCH2CH3)2), 3.5-3.65 (2H, m, CH2), 3.70-3.80 (1H, m, CH), 3.96 (3H, s, OCH3), 3.98-4.10 (6H, m, (OCH2CH3)2, OCH2P), 4.31 (1H, dd, J=11.27 Hz, J=6.87 Hz, NOCHB), 4.45 (1H, dd, J=11.27 Hz, J=3.02 Hz, NOCHA), 4.85 (1H, t, J=5.50 Hz, D2O exchangeable OH), 6.60 (2H, s, D2O exchangeable NH2), 8.14 (1H, s, H-8). m/z: (FAB+ve ion, thioglycerol) 406 (MH+, 100%).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]([CH2:14][C:15]1[CH:20]=[C:19]([C:21]([O:23][CH2:24][CH3:25])=[O:22])[CH:18]=[CH:17][N:16]=1)[CH2:9][CH2:10][CH2:11][CH:12]=O)=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH2:26]([NH:33][CH:34]1[CH2:36][CH2:35]1)[C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1>>[CH2:26]([N:33]([CH:34]1[CH2:35][CH2:36]1)[CH2:12][CH2:11][CH2:10][CH2:9][N:8]([CH2:14][C:15]1[CH:20]=[C:19]([C:21]([O:23][CH2:24][CH3:25])=[O:22])[CH:18]=[CH:17][N:16]=1)[C:6]([O:5][C:1]([CH3:4])([CH3:3])[CH3:2])=[O:7])[C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1
Reactant: CCOC(=O)c1ccnc(CN(CCCC=O)C(=O)OC(C)(C)C)c1
Reactant: c1ccc(CNC2CC2)cc1
Product: CCOC(=O)c1ccnc(CN(CCCCN(Cc2ccccc2)C2CC2)C(=O)OC(C)(C)C)c1

Procedure:
By General Procedure A from ethyl 2-({[(tert-butoxy)carbonyl](4-oxobutyl)amino}methyl)pyridine-4-carboxylate and N-benzylcyclopropanamine. Purification by column chromatography (5% MeOH/DCM) gave the title compound as colorless oil. 1H-NMR (300 MHz, CDCl3): δ 8.60 (d, 1H), 7.70 (s, 1H), 7.60 (d, 1H), 7.10 (m, 5H), 4.50 (d, 2H), 4.40 (q, 2H), 3.50 (m, 2H), 3.15 (m, 2H), 2.50 (m, 2H), 1.60 (m, 1H), 1.45 (m, 16H), 0.4 (m, 4H) ppm.
Reaction SMILES: [NH:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[C:2]1[NH:10][CH:11]1[CH2:16][CH2:15][N:14]([C:17]([O:19][CH2:20][CH3:21])=[O:18])[CH2:13][CH2:12]1.Cl[CH2:23][C:24]1[O:28][C:27]([C:29]([O:31][CH2:32][CH3:33])=[O:30])=[CH:26][CH:25]=1.C(=O)([O-])[O-].[Na+].[Na+].CN(C)C=O>O>[CH2:32]([O:31][C:29]([C:27]1[O:28][C:24]([CH2:23][N:1]2[C:5]3[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=3[N:3]=[C:2]2[NH:10][CH:11]2[CH2:16][CH2:15][N:14]([C:17]([O:19][CH2:20][CH3:21])=[O:18])[CH2:13][CH2:12]2)=[CH:25][CH:26]=1)=[O:30])[CH3:33]
Reactant: CCOC(=O)c1ccc(CCl)o1
Reactant: CCOC(=O)N1CCC(Nc2nc3ccccc3[nH]2)CC1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CCOC(=O)c1ccc(Cn2c(NC3CCN(C(=O)OCC)CC3)nc3ccccc32)o1
Yield: 70.8 %

Procedure:
A mixture of 28.8 parts of ethyl 4-(1H-benzimidazol-2-ylamino)-1-piperidinecarboxylate (as prepared in Example XIV of U.S. Pat. No. 4,219,559), 33.9 parts of ethyl 5-chloromethyl-2-furancarboxylate, 15.9 parts of sodium carbonate and 282 parts of N,N-dimethylformamide was stirred for 2 nights at 70° C. The reaction mixture was poured into water and the product was extracted with methylbenzene. The extract was washed with water, dried, filtered and evaporated. The residue was purified by column chromatography (silica gel; CHCl3 /CH3OH 97:3). The eluent of the desired fraction was evaporated and the residue was stirred in 1,1'-oxybisethane. The precipitate was filtered off and dried, yielding 31.2 parts (70.8%) of ethyl 4-[[1-[[5-(ethoxycarbonyl)-2-furanyl]-methyl]-1H-benzimidazol-2-yl]amino]-1-piperidinecarboxylate; mp. 136.0° C. (interm. 1).
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([NH:10][C:11]2[CH:16]=[CH:15][C:14]([N:17]3[CH2:22][CH2:21][N:20]([CH:23]4[CH2:26][O:25][CH2:24]4)[CH2:19][C@H:18]3[CH3:27])=[CH:13][N:12]=2)[C:5](=[O:9])[N:6]([CH3:8])[CH:7]=1.[C:28]([O:31][CH2:32][C:33]1[C:38](B2OC(C)(C)C(C)(C)O2)=[CH:37][C:36]([F:48])=[CH:35][C:34]=1[N:49]1[C:61](=[O:62])[C:60]2[S:59][C:58]3[CH2:57][CH2:56][CH2:55][CH2:54][C:53]=3[C:52]=2[CH:51]=[N:50]1)(=[O:30])[CH3:29]>>[C:28]([O:31][CH2:32][C:33]1[C:34]([N:49]2[C:61](=[O:62])[C:60]3[S:59][C:58]4[CH2:57][CH2:56][CH2:55][CH2:54][C:53]=4[C:52]=3[CH:51]=[N:50]2)=[CH:35][C:36]([F:48])=[CH:37][C:38]=1[C:2]1[CH:3]=[C:4]([NH:10][C:11]2[CH:16]=[CH:15][C:14]([N:17]3[CH2:22][CH2:21][N:20]([CH:23]4[CH2:26][O:25][CH2:24]4)[CH2:19][C@H:18]3[CH3:27])=[CH:13][N:12]=2)[C:5](=[O:9])[N:6]([CH3:8])[CH:7]=1)(=[O:30])[CH3:29]
Reactant: C[C@@H]1CN(C2COC2)CCN1c1ccc(Nc2cc(Br)cn(C)c2=O)nc1
Reactant: CC(=O)OCc1c(B2OC(C)(C)C(C)(C)O2)cc(F)cc1-n1ncc2c3c(sc2c1=O)CCCC3
Product: CC(=O)OCc1c(-c2cc(Nc3ccc(N4CCN(C5COC5)C[C@H]4C)cn3)c(=O)n(C)c2)cc(F)cc1-n1ncc2c3c(sc2c1=O)CCCC3
Yield: 47.9 %

Procedure:
Following the procedure in Example 102 and starting with (R)-5-bromo-1-methyl-3-(5-(2-methyl-4-(oxetan-3-yl)piperazin-1-yl)pyridin-2-ylamino)pyridin-2(1H)-one 115f (217 mg, 0.50 mmol) and 117e (249 mg, 0.50 mmol) afforded 117f as a yellow solid (174 mg, 48%). MS: [M+H]+ 726.
Reaction SMILES: [CH3:1][NH:2][C@H:3]1[CH2:7][CH2:6][N:5]([CH2:8][C:9]2[CH:14]=[CH:13][N:12]=[C:11]([C:15]3[CH:20]=[C:19]([O:21][CH3:22])[C:18]([O:23][CH3:24])=[C:17]([O:25][CH3:26])[CH:16]=3)[CH:10]=2)[CH2:4]1.Cl[CH2:28][C:29]1[CH:34]=[CH:33][N:32]=[C:31]([C:35]2[CH:40]=[C:39]([O:41][CH3:42])[C:38]([O:43][CH3:44])=[C:37]([O:45][CH3:46])[CH:36]=2)[CH:30]=1>>[CH3:1][N:2]([C@H:3]1[CH2:7][CH2:6][N:5]([CH2:8][C:9]2[CH:14]=[CH:13][N:12]=[C:11]([C:15]3[CH:16]=[C:17]([O:25][CH3:26])[C:18]([O:23][CH3:24])=[C:19]([O:21][CH3:22])[CH:20]=3)[CH:10]=2)[CH2:4]1)[CH2:28][C:29]1[CH:34]=[CH:33][N:32]=[C:31]([C:35]2[CH:40]=[C:39]([O:41][CH3:42])[C:38]([O:43][CH3:44])=[C:37]([O:45][CH3:46])[CH:36]=2)[CH:30]=1
Reactant: CN[C@H]1CCN(Cc2ccnc(-c3cc(OC)c(OC)c(OC)c3)c2)C1
Reactant: COc1cc(-c2cc(CCl)ccn2)cc(OC)c1OC
Product: COc1cc(-c2cc(CN3CC[C@H](N(C)Cc4ccnc(-c5cc(OC)c(OC)c(OC)c5)c4)C3)ccn2)cc(OC)c1OC

Procedure:
(3S)-3-methylamino-1-[[2-(3,4,5-trimethoxyphenyl)pyridin-4-yl]methyl]pyrrolidine (104 mg) and 4-chloromethyl-2-(3,4,5-trimethoxyphenyl)pyridine (85 mg) was condensed in the same manner as described in Example 2. Yellow syrup obtained was converted to a tetrahydrochloride by the usual method giving the title compound as yellow powder.
Reaction SMILES: [S:1]1[C:5]([C:6]2[CH:11]=[CH:10][N:9]=[C:8]([NH:12][CH:13]3[CH2:18][CH2:17][N:16]([CH2:19][CH2:20][C:21]#[N:22])[CH2:15][CH2:14]3)[N:7]=2)=[CH:4][C:3]2[CH:23]=[CH:24][CH:25]=[CH:26][C:2]1=2.[H-].[H-].[H-].[H-].[Li+].[Al+3]>C1COCC1>[NH2:22][CH2:21][CH2:20][CH2:19][N:16]1[CH2:15][CH2:14][CH:13]([NH:12][C:8]2[N:7]=[C:6]([C:5]3[S:1][C:2]4[CH:26]=[CH:25][CH:24]=[CH:23][C:3]=4[CH:4]=3)[CH:11]=[CH:10][N:9]=2)[CH2:18][CH2:17]1
Reactant: N#CCCN1CCC(Nc2nccc(-c3cc4ccccc4s3)n2)CC1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Product: NCCCN1CCC(Nc2nccc(-c3cc4ccccc4s3)n2)CC1

Procedure:
Compound of Example 151 was reduced with LAH in THF at 60° C. analogous to Example 53.
Reaction SMILES: N[C@@H:2]([CH:6](C)C)[C@H:3](O)[CH3:4].[NH2:9][C@@H:10]([CH:19]([CH3:21])[CH3:20])[C@@H:11]([C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)[OH:12].C([O-])([O-])=O.[Na+].[Na+].C([O-])([O-])=O.[K+].[K+]>CCOC(C)=O.CCCCCC>[CH3:20][CH:19]([CH3:21])[C@H:10]([N:9]1[CH2:4][CH2:3][CH2:2][CH2:6]1)[C@@H:11]([C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)[OH:12]
Reactant: CC(C)[C@H](N)[C@@H](C)O
Reactant: CC(C)[C@H](N)[C@H](O)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Agent: [Na+]
Solvent: CCCCCC
Solvent: CCOC(C)=O
Product: CC(C)[C@@H]([C@H](O)c1ccccc1)N1CCCC1
Yield: 86 %

Procedure:
Repeat Step (a) of EXAMPLE 1, but replace (2R,3S)-3-amino-4-methylpentan-2-ol with (1R,2S)-2-amino-3-methyl-1-phenylbutan-1-ol, and replace Na2CO3 (1.16 g, 11.0 mmol) with K2CO3 (1.52 g, 11.0 mmol). Column chromatography (Silica gel, eluent is n-Hexane:EtOAc=10:1) is used to purify the coarse product and a slightly-yellow liquid (1.00 g) is obtained. The yield is 86% and the other analysis includes:
Reaction SMILES: [Si:1]([O:8][C@H:9]1[CH2:18][C:17]([CH3:20])([CH3:19])[CH2:16][C:15]2[N:14]=[C:13]([CH:21]([CH3:23])[CH3:22])[C:12]3[C@@H:24]([C:33]4[C:38]([F:39])=[CH:37][C:36]([C:40]([F:43])([F:42])[F:41])=[CH:35][N:34]=4)[O:25][C:26]4([CH2:31][CH2:30][O:29][CH2:28][CH:27]4I)[C:11]=3[C:10]1=2)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2]>[OH-].[OH-].[Pd+2]>[Si:1]([O:8][C@H:9]1[CH2:18][C:17]([CH3:19])([CH3:20])[CH2:16][C:15]2[N:14]=[C:13]([CH:21]([CH3:23])[CH3:22])[C:12]3[C@@H:24]([C:33]4[C:38]([F:39])=[CH:37][C:36]([C:40]([F:42])([F:43])[F:41])=[CH:35][N:34]=4)[O:25][C:26]4([CH2:31][CH2:30][O:29][CH2:28][CH2:27]4)[C:11]=3[C:10]1=2)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:2])[CH3:3]
Reactant: CC(C)c1nc2c(c3c1[C@@H](c1ncc(C(F)(F)F)cc1F)OC31CCOCC1I)[C@@H](O[Si](C)(C)C(C)(C)C)CC(C)(C)C2
Agent: [Pd+2]
Agent: [OH-]
Product: CC(C)c1nc2c(c3c1[C@@H](c1ncc(C(F)(F)F)cc1F)OC31CCOCC1)[C@@H](O[Si](C)(C)C(C)(C)C)CC(C)(C)C2

Procedure:
Obtained by starting from (3S,9S)-9-(tert-butyldimethylsilyloxy)-3-(3-fluoro-5-(trifluoromethyl)pyridin-2-yl)-3′-iodo-4-isopropyl-7,7-dimethyl-2′,3′,5′,6,6′,7,8,9-octahydro-3H-spiro[furo[3,4-c]quinoline-1,4′-pyran]. 10% palladiumhydroxide on charcoal is used instead of 10% palladium on charcoal.