Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[CH:12]=[C:11]([CH:13]([CH:15]3[CH2:20][CH2:19][CH2:18][CH2:17][CH2:16]3)O)[C:10]([CH3:21])=[N:9]2)=[CH:4][CH:3]=1.[NH2:22][C:23]1[CH:28]=[CH:27][C:26]([C:29]([NH:31][CH2:32][CH2:33][C:34]([O:36]CC)=[O:35])=[O:30])=[CH:25][CH:24]=1>>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[CH:12]=[C:11]([CH:13]([NH:22][C:23]3[CH:24]=[CH:25][C:26]([C:29]([NH:31][CH2:32][CH2:33][C:34]([OH:36])=[O:35])=[O:30])=[CH:27][CH:28]=3)[CH:15]3[CH2:20][CH2:19][CH2:18][CH2:17][CH2:16]3)[C:10]([CH3:21])=[N:9]2)=[CH:4][CH:3]=1
Reactant: CCOC(=O)CCNC(=O)c1ccc(N)cc1
Reactant: Cc1nn(-c2ccc(Cl)cc2)cc1C(O)C1CCCCC1
Product: Cc1nn(-c2ccc(Cl)cc2)cc1C(Nc1ccc(C(=O)NCCC(=O)O)cc1)C1CCCCC1
Yield: 57.3 %

Procedure:
Using [1-(4-chlorophenyl)-3-methyl-1H-pyrazol-4-yl](cyclohexyl)methanol (0.46 g) synthesized above and ethyl 3-{[(4-aminophenyl)carbonyl]amino}propanoate (0.35 g) synthesized in Example 1(2) and in the same manner as in Example 1(7), the title object compound (0.42 g, 57%) was obtained as a white solid.
Reaction SMILES: C([O:4][C:5]1[CH:10]=[CH:9][C:8]([CH2:11][N:12]2[CH2:17][CH2:16][O:15][CH2:14][CH2:13]2)=[CH:7][CH:6]=1)(=O)C.O[Li].O>CO.O>[O:15]1[CH2:14][CH2:13][N:12]([CH2:11][C:8]2[CH:9]=[CH:10][C:5]([OH:4])=[CH:6][CH:7]=2)[CH2:17][CH2:16]1
Reactant: CC(=O)Oc1ccc(CN2CCOCC2)cc1
Agent: [Li]O
Solvent: CO
Solvent: O
Product: Oc1ccc(CN2CCOCC2)cc1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of 4-(morpholinomethyl)phenyl acetate (1.9 g, 8.1 mmol) in 1:1 methanol/water (40 mL) at 0° C. was added LiOH.H2O (339 mg, 8.1 mmol). The reaction was stirred at RT for 2 h. The mixture was concentrated to remove methanol, and the aqueous layer acidified with 3 N HCl. The aqueous layer was extracted with ethyl acetate (4×30 mL) and the organics dried and concentrated to give 454 mg recovered starting material. The aqueous layer was then made basic again (to pH 9) with 1 N NaOH and extracted with ethyl acetate (7×20 mL). These combined organics were washed with brine, dried with Na2SO4, and concentrated to give a white solid.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:12]3[CH2:13][CH2:14][CH:15]([C:17]([OH:19])=[O:18])[CH2:16][C:11]=3[O:10][N:9]=2)=[CH:4][CH:3]=1.[CH:20]([N-]C(C)C)(C)C.[Li+].C([Li])CCC.C(NC(C)C)(C)C.CI.Cl>O1CCCC1.CCCCCC.O>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[C:12]3[CH2:13][CH2:14][C@@H:15]([C:17]([OH:19])=[O:18])[C@H:16]([CH3:20])[C:11]=3[O:10][N:9]=2)=[CH:6][CH:7]=1
Reactant: CC(C)[N-]C(C)C
Reactant: O=C(O)C1CCc2c(-c3ccc(Cl)cc3)noc2C1
Agent: Cl
Agent: [Li+]
Agent: [Li]CCCC
Solvent: CCCCCC
Solvent: CC(C)NC(C)C
Solvent: O
Product: C[C@@H]1c2onc(-c3ccc(Cl)cc3)c2CC[C@H]1C(=O)O
Temperature: 20 °C
Reaction time: 0.25 h

Procedure:
A solution of 3.46 g (0.0125 mol) of racemic 3-(4-chlorophenyl)-4,5,6,7-tetrahydro-1,2-benzisoxazole-6-carboxylic acid in 50 ml of dry tetrahydrofuran was added slowly at -70° C. to a solution of lithium diisopropylamide prepared by adding 10 ml of a 2.5M solution of n-butyllithium in hexane to 2.53 g (0.025 mol) of diisopropyl amine in 25 ml of dry tetrahydrofuran at -70° C. After 15 minutes, 2 g (0.014 mol) of methyl iodide were added and the mixture was allowed to warm to 20° C. over a period of 1.5 hours. The mixture was added to water, acidified with 2N hydrochloric acid and extracted with diethyl ether. The resulting mixture of cis- and trans-3-(4-chlorophenyl)-4,5,6,7-tetrahydro-7-methyl-1,2-benzisoxazole-6-carboxylic acids was separated by repeated crystallization from acetic acid. The cis-3-(4-chlorophenyl)-4,5,6,7-tetrahydro-7-methyl-1,2-benzisoxazole-6-carboxylic acid separated first, there being obtained 0.78 g of melting point 238°-241° C. The mother liquor yielded 0.79 g of trans-3-(4-chlorophenyl)-4,5,6,7-tetrahydro-7-methyl-1,2-benzisoxazole-6-carboxylic acid of melting point 183°-186° C.
Reaction SMILES: O=[C:2]1[CH2:6][CH2:5][N:4](C(OC(C)(C)C)=O)[CH2:3]1.[N:14]1([C:20]([O:22][CH2:23][C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)=[O:21])[CH2:19][CH2:18][NH:17][CH2:16][CH2:15]1.C([BH3-])#N.[Na+].O>C(O)C.CC(C)[O-].CC(C)[O-].CC(C)[O-].CC(C)[O-].[Ti+4]>[NH:4]1[CH2:5][CH2:6][CH:2]([N:17]2[CH2:16][CH2:15][N:14]([C:20]([O:22][CH2:23][C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=3)=[O:21])[CH2:19][CH2:18]2)[CH2:3]1
Reactant: O=C(OCc1ccccc1)N1CCNCC1
Reactant: CC(C)(C)OC(=O)N1CCC(=O)C1
Agent: [Ti+4]
Agent: CC(C)[O-]
Agent: [BH3-]C#N
Solvent: O
Solvent: CCO
Product: O=C(OCc1ccccc1)N1CCN(C2CCNC2)CC1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
A mixture of tert-butyl 3-oxopyrrolidine-1-carboxylate 45-1 (0.32 g, 1.73 mmol)), benzyl piperazine-1-carboxylate 45-2 (0.38 g, 1.73 mmol) and titanium tetraisopropoxide (0.61 g, 2.16 mmol) were stirred at 25° C. for 1 hour. Then the viscous solution was diluted with 2 mL of absolute ethanol and sodium cyanoborohydride (0.073 g, 1.16 mmol) was added. After stirring for 18 hours at 25° C., 1 mL of water was added and the solids filtered off. The filtrate was then dried under reduced pressure, redissolved in ethyl acetate, refiltered and evaporated. This material was purified on a silica column and then treated with trifluoroacetic acid to afford 45-3. 1H-NMR (CDCl3): 7.36(m, 5H); 5.13(s, 2H); 3.55(m, 4H); 3.26(m, 1H); 3.08(m, 1H); 2.80(m, 1H); 2.62(m, 1H); 2.49(m, 2H); 2.41(m, 2H); 2.08(m, 2H); 1.75(m, 1H).
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([CH2:10][C:11]#[N:12])[CH:7]=[CH:8][CH:9]=1)([O-:3])=[O:2].C1(C)C=CC(S(O)(=O)=O)=CC=1.[CH2:24](N)[CH2:25][NH2:26].[OH-].[Na+].[ClH:30]>>[ClH:30].[N+:1]([C:4]1[CH:5]=[C:6]([CH:7]=[CH:8][CH:9]=1)[CH2:10][C:11]1[NH:26][CH2:25][CH2:24][N:12]=1)([O-:3])=[O:2]
Reactant: NCCN
Reactant: N#CCc1cccc([N+](=O)[O-])c1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: Cl
Agent: [Na+]
Product: O=[N+]([O-])c1cccc(CC2=NCCN2)c1
Temperature: 100 °C

Procedure:
A mixture of 30.7 mmol (5 g) of 3-nitrophenylacetonitrile and 30 mmol (7.2 g) of ethylenediamine para-toluenesulphonate is heated at 100° C. for 1 hour. After cooling to 20° C., the mixture is hydrolysed with 100 ml of a 5M aqueous solution of sodium hydroxide and then extracted with dichloromethane. The organic phases are dried over magnesium sulphate and concentrated. The residue obtained is converted into the hydrochloride by the action of an ethanolic HCl solution to yield the expected product.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2([CH3:36])[C:12]([C:14]3[CH:19]=[CH:18][C:17]([Cl:20])=[CH:16][CH:15]=3)([CH3:13])[N:11]([C:21](Cl)=[O:22])[C:10]([C:24]3[CH:29]=[C:28]([CH:30]4[CH2:32][CH2:31]4)[CH:27]=[CH:26][C:25]=3[O:33][CH2:34][CH3:35])=[N:9]2)=[CH:4][CH:3]=1.Cl.Cl.[CH3:39][S:40]([CH2:43][CH2:44][CH2:45][N:46]1[CH2:51][CH2:50][NH:49][CH2:48][CH2:47]1)(=[O:42])=[O:41]>>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C@@:8]2([CH3:36])[C@:12]([C:14]3[CH:15]=[CH:16][C:17]([Cl:20])=[CH:18][CH:19]=3)([CH3:13])[N:11]([C:21]([N:49]3[CH2:48][CH2:47][N:46]([CH2:45][CH2:44][CH2:43][S:40]([CH3:39])(=[O:41])=[O:42])[CH2:51][CH2:50]3)=[O:22])[C:10]([C:24]3[CH:29]=[C:28]([CH:30]4[CH2:32][CH2:31]4)[CH:27]=[CH:26][C:25]=3[O:33][CH2:34][CH3:35])=[N:9]2)=[CH:4][CH:3]=1
Reactant: CCOc1ccc(C2CC2)cc1C1=NC(C)(c2ccc(Cl)cc2)C(C)(c2ccc(Cl)cc2)N1C(=O)Cl
Reactant: CS(=O)(=O)CCCN1CCNCC1
Agent: Cl
Product: CCOc1ccc(C2CC2)cc1C1=N[C@@](C)(c2ccc(Cl)cc2)[C@@](C)(c2ccc(Cl)cc2)N1C(=O)N1CCN(CCCS(C)(=O)=O)CC1

Procedure:
In a manner analogous to the method described in example 5, rac-(4S*,5R*)-4,5-bis-(4-chloro-phenyl)-2-(5-cyclopropyl-2-ethoxy-phenyl)-4,5-dimethyl-4,5-dihydro-imidazole1-carbonyl chloride was reacted with 1-(3-methanesulfonyl-propyl)-piperazine dihydrochloride (prepared as described in Fotouhi, N. et al. WO 2005110996) to give the title compound as a racemic mixture. The enantiomers were separated by supercritical fluid chromatography (Berger Instrument Multi-Gram II, Daicel ChiralPak OD-H 3×25 cm, 35° C. at 100 bar, eluting with 30% isopropanol in carbon dioxide) gave the title compound. HR-MS (ES, m/z) calculated for C37H44N4O4SCl2 [(M+H)+] 711.2533, observed 711.2536.
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([C:10]2[N:11]=[C:12]([C@@H:15]3[CH2:19][CH2:18][CH2:17][N:16]3[C:20](=[O:28])[CH2:21][C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=3)[NH:13][CH:14]=2)=[CH:6][CH:5]=1)([O-])=O.CO.O1CCCC1.[Cl-].[NH4+]>O.[Fe]>[NH2:1][C:4]1[CH:9]=[CH:8][C:7]([C:10]2[N:11]=[C:12]([C@@H:15]3[CH2:19][CH2:18][CH2:17][N:16]3[C:20](=[O:28])[CH2:21][C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=3)[NH:13][CH:14]=2)=[CH:6][CH:5]=1
Reactant: O=C(Cc1ccccc1)N1CCC[C@H]1c1nc(-c2ccc([N+](=O)[O-])cc2)c[nH]1
Agent: [Fe]
Agent: [Cl-]
Agent: [NH4+]
Solvent: C1CCOC1
Solvent: O
Solvent: CO
Product: Nc1ccc(-c2c[nH]c([C@@H]3CCCN3C(=O)Cc3ccccc3)n2)cc1
Temperature: 75 °C
Reaction time: 1 h

Procedure:
To a solution of the Product from Example 1I (0.137 g, 0.36 mmol) in a mixture of water (0.75 mL), methanol (1.5 mL) and tetrahydrofuran (1.5 mL) was added iron (0.102 g, 1.82 mmol) and ammonium chloride (0.030 g, 0.54 mmol) and the resulting mixture was heated with vigorous stirred at 75° C. for one hour. The warm reaction mixture was filtered through celite and rinsed well with methanol and tetrahydrofuran. The filtrate was concentrated and partitioned between 10% NaHCO3 solution and ethyl acetate. The organic layer was dried over sodium sulfate, filtered, and concentrated to give a waxy solid that was used without purification (97%).
Reaction SMILES: O[C:2]1([C:14]([O:16]CC)=O)[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)=[CH:4][CH2:3]1.[H-].C([Al+]CC(C)C)C(C)C.C1C[O:32]CC1>C1(C)C=CC=CC=1>[OH:16][CH2:14][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[CH:12][C:11]([OH:32])=[CH:10][CH:9]=2)=[CH:4][CH:3]=1
Reactant: C1CCOC1
Reactant: CCOC(=O)C1(O)C=CC(c2ccccc2)=CC1
Agent: CC(C)C[Al+]CC(C)C
Agent: [H-]
Solvent: Cc1ccccc1
Product: OCc1ccc(-c2ccc(O)cc2)cc1
Reaction time: 2 h

Procedure:
15.0 g (60.7 mmol) of ethyl 4-hydroxybiphenyl-4-carboxylate are dissolved in 500 ml of THF, and 200 ml of a 1 M solution of diisobutylaluminium hydride in toluene are added at −70° C. The cooling is subsequently removed, and the batch is stirred at room temp. for 2 h. After addition of 5 ml of isopropanol, the solution is added to water, extracted three times with MTB ether, and the combined org. phases are washed with water and dried over sodium sulfate. The solvent is removed in vacuo, and the residue is filtered through silica gel with toluene/ethyl acetate, giving 4′-hydroxymethyl-4-biphenylol as a colourless solid.
Reaction SMILES: [CH3:1][N:2]([CH3:25])[CH2:3][CH2:4][NH:5][S:6]([CH:9]1[CH2:14][CH2:13][N:12]([C:15](OCC2C=CC=CC=2)=O)[CH2:11][CH2:10]1)(=[O:8])=[O:7].ClC1[N:32]=[C:31]([N:33]2[CH2:38][CH2:37][O:36][CH2:35][CH2:34]2)[N:30]=[C:29]([N:39]2[C:43]3[CH:44]=[CH:45][CH:46]=[C:47]([O:48][CH3:49])[C:42]=3[N:41]=[C:40]2[CH:50]([F:52])[F:51])[N:28]=1.CCN(C(C)C)C(C)C>CO.C1COCC1.[Pd]>[F:52][CH:50]([F:51])[C:40]1[N:39]([C:29]2[N:30]=[C:31]([N:33]3[CH2:34][CH2:35][O:36][CH2:37][CH2:38]3)[N:32]=[C:15]([N:12]3[CH2:11][CH2:10][CH:9]([S:6]([NH:5][CH2:4][CH2:3][N:2]([CH3:1])[CH3:25])(=[O:7])=[O:8])[CH2:14][CH2:13]3)[N:28]=2)[C:43]2[CH:44]=[CH:45][CH:46]=[C:47]([O:48][CH3:49])[C:42]=2[N:41]=1
Reactant: CN(C)CCNS(=O)(=O)C1CCN(C(=O)OCc2ccccc2)CC1
Reactant: COc1cccc2c1nc(C(F)F)n2-c1nc(Cl)nc(N2CCOCC2)n1
Agent: [Pd]
Solvent: CCN(C(C)C)C(C)C
Solvent: CO
Solvent: C1CCOC1
Product: COc1cccc2c1nc(C(F)F)n2-c1nc(N2CCOCC2)nc(N2CCC(S(=O)(=O)NCCN(C)C)CC2)n1

Procedure:
The above carbamate was hydrogenated over 5% Pd on carbon in MeOH. After removal of the solvent, the residue was combined with 0.48 g (1.2 mmol) 1-[4-chloro-6-(4-morpholinyl)-1,3,5-triazin-2-yl]-2-(difluoromethyl)-4-methoxy-1H-benzimidazole (Example 2) and 0.35 g (2.7 mmol) DIPEA in THF. The mixture was heated under reflux for 1 hr and the solvent was concentrated. After dilution with water, the resulting solid was collected and dried. Chromatography on alumina, eluting with EtOAc, gave 1-[4-[2-(difluoromethyl)-4-methoxy-1H-benzimidazol-1-yl]-6-(4-morpholinyl)-1,3,5-triazin-2-yl]-N-[2-(dimethylamino)ethyl]-4-piperidinesulfonamide: mp (MeOH) 231-234° C.; 1H NMR (CDCl3) δ 7.87 (dd, J=8.4, 0.6 Hz, 1H), 7.47 (t, JHF=53.5 Hz, 1H), 7.35 (t, J=8.2 Hz, 1H), 6.81 (d, J=7.8 Hz, 1H), 4.91 (br d, J=13.3 Hz, 2H), 4.04 (s, 3H), 3.88 (m, 4H), 3.78 (m, 4H), 3.25-3.17 (m, 3H), 3.00 (m, 2H), 2.45 (br t, J=5.7 Hz, 2H), 2.27 (m, 2H), 2.23 (s, 6H), 1.83 (dq, J=12.5, 4.4 Hz, 2H); Anal. Calcd. for C25H35F2N9O4S: C, 50.4; H, 5.9; N, 21.2. Found: C, 50.2; H, 5.7; N, 21.3%.
Reaction SMILES: [CH2:1]([OH:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[H-].[Na+].[C:11]([O:15][C:16]([N:18]1[CH2:23][CH2:22][CH:21]([O:24][C:25]2[CH:26]=[C:27]3[C:32](=[CH:33][CH:34]=2)[C:31](Cl)=[N:30][CH:29]=[CH:28]3)[CH2:20][CH2:19]1)=[O:17])([CH3:14])([CH3:13])[CH3:12]>CC(N(C)C)=O>[C:11]([O:15][C:16]([N:18]1[CH2:23][CH2:22][CH:21]([O:24][C:25]2[CH:26]=[C:27]3[C:32](=[CH:33][CH:34]=2)[C:31]([O:8][CH2:1][C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)=[N:30][CH:29]=[CH:28]3)[CH2:20][CH2:19]1)=[O:17])([CH3:14])([CH3:13])[CH3:12]
Reactant: CC(C)(C)OC(=O)N1CCC(Oc2ccc3c(Cl)nccc3c2)CC1
Reactant: OCc1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: CC(=O)N(C)C
Product: CC(C)(C)OC(=O)N1CCC(Oc2ccc3c(OCc4ccccc4)nccc3c2)CC1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
0.70 g (6.49 mmol) of benzyl alcohol were dissolved in 10 mL of dimethyl acetamide. 260 mg (6.49 mmol) of sodium hydride (60%) were added and the solution was stirred at room temperature. After 30 min a solution of 1.57 g (4.33 mmol) of 4-(1-chloro-isoquinolin-6-yloxy)-piperidine-1-carboxylic acid tert-butyl ester (10) in 10 mL of dimethyl acetamide was added and the resulting mixture was heated at 90° C. (bath temperature). After 8 h and standing at room temperature overnight 1.0 additional equivalents of benzyl alcohol and sodium hydride were added and heating at 90° C. was continued for 8 h. For workup, the solvent was removed i. vac. and the residue was dissolved in dichloromethane. The organic solution was washed twice with water, dried with MgSO4 and evaporated. The resulting crude product was purified by preparative HPLC. Rt=2.13 min (Method C). Detected mass: 435.2 (M+H+).
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][C:8]([O:14][CH2:15][CH2:16][CH2:17][N:18]3[CH2:22][CH2:21][CH2:20][CH2:19]3)=[C:9]([O:12][CH3:13])[CH:10]=2)[N:5]=[CH:4][N:3]=1.[OH:23][C:24]1[CH:25]=[CH:26][C:27]2[O:32][CH2:31][C:30](=[O:33])[NH:29][C:28]=2[CH:34]=1>>[CH3:13][O:12][C:9]1[CH:10]=[C:11]2[C:6](=[CH:7][C:8]=1[O:14][CH2:15][CH2:16][CH2:17][N:18]1[CH2:22][CH2:21][CH2:20][CH2:19]1)[N:5]=[CH:4][N:3]=[C:2]2[O:23][C:24]1[CH:25]=[CH:26][C:27]2[O:32][CH2:31][C:30](=[O:33])[NH:29][C:28]=2[CH:34]=1
Reactant: O=C1COc2ccc(O)cc2N1
Reactant: COc1cc2c(Cl)ncnc2cc1OCCCN1CCCC1
Product: COc1cc2c(Oc3ccc4c(c3)NC(=O)CO4)ncnc2cc1OCCCN1CCCC1
Yield: 94.3 %

Procedure:
Using a procedure analogous to that described for Example 9, 4-chloro-6-methoxy-7-(3-(pyrrolidin-1-yl)propoxy)quinazoline (0.13 g, 0.4 mmol), (prepared as described for the (starting material in Example 9), was reacted with 6-hydroxy-2H-4H-1,4-benzoxazin-3-one (83 mg, 0.5 mmol), (J. Chem. Soc. C, 1971, 2696), to give 6-methoxy-7-(3-(pyrrolidin-1-yl)propoxy)-4-(3-oxo-2H-4H-1,4-benzoxazin-6-yloxy)quinazoline (170 mg, 94%).
Reaction SMILES: C[O:2][C:3]([C:5]1([CH2:18][CH2:19][O:20][Si:21]([C:24]([CH3:27])([CH3:26])[CH3:25])([CH3:23])[CH3:22])[CH2:10][CH2:9][N:8]([C:11]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12])[CH2:7][CH2:6]1)=O.[BH4-].[Li+]>C1COCC1>[OH:2][CH2:3][C:5]1([CH2:18][CH2:19][O:20][Si:21]([C:24]([CH3:27])([CH3:26])[CH3:25])([CH3:23])[CH3:22])[CH2:6][CH2:7][N:8]([C:11]([O:13][C:14]([CH3:16])([CH3:17])[CH3:15])=[O:12])[CH2:9][CH2:10]1
Reactant: COC(=O)C1(CCO[Si](C)(C)C(C)(C)C)CCN(C(=O)OC(C)(C)C)CC1
Agent: [BH4-]
Agent: [Li+]
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1CCC(CO)(CCO[Si](C)(C)C(C)(C)C)CC1
Temperature: 25 °C
Reaction time: 48 h

Procedure:
The crude tert-butyl 4-methoxycarbonyl-4-(2-(tert-butyldimethylsilyloxy)eth-1-yl)piperidine-1-carboxylate (assumed 44 mmol) from Step A was taken up in THF (200 mL) and 2M lithium borohydride in THF (29 mL, 58 mmol) was added via syringe at room temperature. The reaction was stirred for 2 days at room temperature and then at 50° C. for 20 h after addition of more 2M lithium borohydride in THF (2.9 mL, 5.8 mmol). The mixture was then quenched with acetic acid, diluted with ether and aq. sodium bicarbonate solution, and extracted three times with ether. The combined organic layers were washed with brine, dried over sodium sulfate, filtered, and concentrated. The residue was purified by flash chromatography (20% ethyl acetate in hexanes) to afford recovered starting material (2.5 g) and the title product (7.1 g).
Reaction SMILES: COC(N1CCC(N2CCC(N3C4C=CC=CC=4NC3=O)CC2)CC1)=O.[CH3:27][O:28][C:29]([N:31]1[CH2:34][CH:33]([N:35]2[CH2:40][CH2:39][CH:38]([N:41]3[C:45]4[CH:46]=[CH:47][CH:48]=[CH:49][C:44]=4[NH:43][C:42]3=[O:50])[CH2:37][CH2:36]2)[CH2:32]1)=[O:30].C(Cl)(=O)C.[CH3:55][S:56](Cl)(=[O:58])=[O:57]>>[CH3:27][O:28][C:29]([N:31]1[CH2:34][CH:33]([N:35]2[CH2:40][CH2:39][CH:38]([N:41]3[C:45]4[CH:46]=[CH:47][CH:48]=[CH:49][C:44]=4[N:43]([S:56]([CH3:55])(=[O:58])=[O:57])[C:42]3=[O:50])[CH2:37][CH2:36]2)[CH2:32]1)=[O:30]
Reactant: CS(=O)(=O)Cl
Reactant: COC(=O)N1CC(N2CCC(n3c(=O)[nH]c4ccccc43)CC2)C1
Agent: COC(=O)N1CCC(N2CCC(n3c(=O)[nH]c4ccccc43)CC2)CC1
Solvent: CC(=O)Cl
Product: COC(=O)N1CC(N2CCC(n3c(=O)n(S(C)(=O)=O)c4ccccc43)CC2)C1

Procedure:
Example 12 was repeated except that 1-[1-(1-methoxycarbonylpiperidin-4-yl) piperidin-4-yl]-1,3-dihydro-2H-benzimidazol-2-one was replaced with 1-[1-(1-methoxycarbonylazetidin-3-yl)-piperidin-4-yl]-1,3-dihydro-2H-benzimidazol-2-one which was prepared by the method of Referential Example 3, and the acetyl chloride was replaced with methanesulfonyl chloride. The title compound was obtained as a colorless oil.
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][C:5]2[O:9][CH:8]=[C:7]([CH3:10])[C:6]=2[CH:11]=1.[CH2:12]([CH:14]([CH2:18][CH3:19])[C:15](Cl)=[O:16])[CH3:13].[Cl-].[Al+3].[Cl-].[Cl-].O>[N+](C)([O-])=O>[CH2:12]([CH:14]([CH2:18][CH3:19])[C:15]([C:8]1[O:9][C:5]2[CH:4]=[CH:3][C:2]([F:1])=[CH:11][C:6]=2[C:7]=1[CH3:10])=[O:16])[CH3:13]
Reactant: Cc1coc2ccc(F)cc12
Reactant: CCC(CC)C(=O)Cl
Agent: [Al+3]
Agent: [Cl-]
Solvent: O
Solvent: C[N+](=O)[O-]
Product: CCC(CC)C(=O)c1oc2ccc(F)cc2c1C
Reaction time: 1.5 h
Yield: 85 %

Procedure:
To a solution of 5-fluoro-3-methyl-1-benzofuran (12.0 g) synthesized in Example A67(2), 2-ethylbutyrylchloride (9.58 g) in nitromethane (240 mL) was added aluminum chloride (anhydrous) (12.94 g) at 0° C., and the mixture was stirred for 1.5 hr. Water was added to the reaction mixture and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, and dried over anhydrous magnesium sulfate. After filtration, the filtrate was concentrated. The residue was subjected to silica gel column chromatography (hexane-ethyl acetate 100:0-90:10, v/v) to give the title compound (15.02 g, 93%) as a yellow oil.
Reaction SMILES: [F:1][C:2]1([CH2:8][OH:9])[CH2:7][CH2:6][O:5][CH2:4][CH2:3]1.[H-].[Na+].F[C:13]1[CH:18]=[CH:17][C:16]([S:19]([NH2:22])(=[O:21])=[O:20])=[CH:15][C:14]=1[S:23]([C:26]([F:29])([F:28])[F:27])(=[O:25])=[O:24].Cl>O1CCCC1.ClCCl>[F:1][C:2]1([CH2:8][O:9][C:13]2[CH:18]=[CH:17][C:16]([S:19]([NH2:22])(=[O:21])=[O:20])=[CH:15][C:14]=2[S:23]([C:26]([F:27])([F:29])[F:28])(=[O:25])=[O:24])[CH2:7][CH2:6][O:5][CH2:4][CH2:3]1
Reactant: OCC1(F)CCOCC1
Reactant: NS(=O)(=O)c1ccc(F)c(S(=O)(=O)C(F)(F)F)c1
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: ClCCl
Solvent: C1CCOC1
Product: NS(=O)(=O)c1ccc(OCC2(F)CCOCC2)c(S(=O)(=O)C(F)(F)F)c1
Reaction time: 0.5 h

Procedure:
To a solution of EXAMPLE 37C (0.500 g) in tetrahydrofuran (5 mL) was added sodium hydride (0.596 g). Additional tetrahydrofuran (25 mL) was added and the mixture stirred for 30 minutes, then 4-fluoro-3-(trifluoromethylsulfonyl)benzenesulfonamide (1.145 g) was added as a solution in tetrahydrofuran (5 mL). After stirring for 2 hours, the reaction mixture was partioned between 1N aqueous HCl (50 mL) and dichloromethane (200 mL). The organic layer was dried over magnesium sulfate, filtered, and concentrated. The resulting solid was chromatographed over silica gel (Reveleris 80 g) eluting with a gradient of 0.5% to 7.5% methanol/dichloromethane over 30 minutes (flow=40 mL/min) to provide the title compound.
Reaction SMILES: [O:1]1[C:5]([C:6]2[CH:11]=[CH:10][C:9]([NH:12][C:13]3[N:14]=[C:15]([N:23]([C:27]4[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=4)[CH2:24][CH2:25][OH:26])[C:16]4[CH2:22][NH:21][CH2:20][CH2:19][C:17]=4[N:18]=3)=[CH:8][CH:7]=2)=[CH:4][N:3]=[CH:2]1.C(O)(=O)C.[CH:37](=O)[CH2:38][CH3:39].C([BH3-])#N.[Na+]>CO>[O:1]1[C:5]([C:6]2[CH:11]=[CH:10][C:9]([NH:12][C:13]3[N:14]=[C:15]([N:23]([C:27]4[CH:28]=[CH:29][CH:30]=[CH:31][CH:32]=4)[CH2:24][CH2:25][OH:26])[C:16]4[CH2:22][N:21]([CH2:37][CH2:38][CH3:39])[CH2:20][CH2:19][C:17]=4[N:18]=3)=[CH:8][CH:7]=2)=[CH:4][N:3]=[CH:2]1
Reactant: OCCN(c1ccccc1)c1nc(Nc2ccc(-c3cnco3)cc2)nc2c1CNCC2
Reactant: CCC=O
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CO
Solvent: CC(=O)O
Product: CCCN1CCc2nc(Nc3ccc(-c4cnco4)cc3)nc(N(CCO)c3ccccc3)c2C1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 22.3 %

Procedure:
2-((2-(4-(Oxazol-5-yl)phenylamino)-5,6,7,8-tetrahydropyrido[4,3-d]pyrimidin-4-yl)(phenyl)amino)ethanol (25 mg, 0.06 mmol, Example 1) was dissolved in methanol (1 mL). Acetic acid (0.013 mL, 0.23 mmol) and propionaldehyde (4.25 μL, 0.06 mmol) was added and the reaction mixture was stirred at room temperature for 10 minutes. Sodium cyanoborohydride (3.67 mg, 0.06 mmol) was added and after 15 minutes the solvent was evaporated under reduced pressure. The crude was dissolved in few drops of dimethylformamide and acetonitrile, filtered and purified by preparative HPLC yielding 2-((2-(4-(oxazol-5-yl)phenylamino)-6-propyl-5,6,7,8-tetrahydropyrido[4,3-d]pyrimidin-4-yl)(phenyl)amino)ethanol (6.3 mg, 22.95%).
Reaction SMILES: C([O:3][C:4]([CH:6]1[CH2:11][CH2:10][N:9]([C:12]2[CH:17]=[C:16]([C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)[N:15]=[C:14]3[CH:24]=[CH:25][S:26][C:13]=23)[CH2:8][CH2:7]1)=O)C.[CH2:27]([NH2:29])[CH3:28].[Na]>CO>[CH2:27]([NH:29][C:4]([CH:6]1[CH2:7][CH2:8][N:9]([C:12]2[CH:17]=[C:16]([C:18]3[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=3)[N:15]=[C:14]3[CH:24]=[CH:25][S:26][C:13]=23)[CH2:10][CH2:11]1)=[O:3])[CH3:28]
Reactant: CCN
Reactant: CCOC(=O)C1CCN(c2cc(-c3ccccc3)nc3ccsc23)CC1
Agent: [Na]
Solvent: CO
Product: CCNC(=O)C1CCN(c2cc(-c3ccccc3)nc3ccsc23)CC1
Yield: 39 %

Procedure:
A solution of 1-(5-phenylthieno[3,2-b]pyridin-7-yl)-4-piperidinecarboxylic acid ethyl ester (50 mg, 0.14 mmole), ethylamine (2 mL), and a catalytic amount of sodium cynide in MeOH (10 mL) is heated in a sealed tube at 70° C. oil bath for 48 hours. The solvent is removed on rotary-evaporator. The resulting residue is purified on a preparative tlc plate to give N-Ethyl 1-(5-phenylthieno[3,2-b]pyridin-7-yl)-4 piperidinecarboxamide (20 mg, 39% yield) as a colorless oil. This material is dissolved in ethyl acetate (1 mL), diluted with HCl saturated ethyl acetate (2 mL), and concentrated to afford N-ethyl 1-(6-phenylthieno[2,3-b]pyridin-4-yl)-4-piperidinecarboxamide hydrochloride (compound 1, 26 mg) as greasy oil. The salt is solidified with ether, collected by filtration, washed with ether, and dried in vacuo. m.p. >270° C. (dec).