Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([O:5][C@@H:6]([C:11]1[C:40]([CH3:41])=[CH:39][C:38]2=[N:42][C:35]3=[CH:36][N:37]2[C:12]=1[N:13]1[CH2:48][CH2:47][C:16]([CH3:49])([O:17][CH2:18][CH2:19][CH2:20][CH2:21][C@H:22]([CH3:46])[O:23][C:24]2[CH:25]=[C:26]([CH3:45])[C:27]([CH3:44])=[CH:28][C:29]=2[C:30]2[CH:43]=[C:34]3[CH:33]=[CH:32][CH:31]=2)[CH2:15][CH2:14]1)[C:7]([O:9]C)=[O:8])([CH3:4])([CH3:3])[CH3:2].C(O[C@@H](C1C(C)=CC2=NC3=C([Cl:91])N2C=1N1CCC(C)(OCCCC[C@H](C)OC2C=CC(C)=CC=2C2C=C3C=CC=2)CC1)C(O)=O)(C)(C)C>>[C:1]([O:5][C@@H:6]([C:11]1[C:40]([CH3:41])=[CH:39][C:38]2=[N:42][C:35]3=[C:36]([Cl:91])[N:37]2[C:12]=1[N:13]1[CH2:48][CH2:47][C:16]([CH3:49])([O:17][CH2:18][CH2:19][CH2:20][CH2:21][C@H:22]([CH3:46])[O:23][C:24]2[CH:25]=[C:26]([CH3:45])[C:27]([CH3:44])=[CH:28][C:29]=2[C:30]2[CH:43]=[C:34]3[CH:33]=[CH:32][CH:31]=2)[CH2:15][CH2:14]1)[C:7]([OH:9])=[O:8])([CH3:4])([CH3:3])[CH3:2]
Reactant: COC(=O)[C@@H](OC(C)(C)C)c1c(C)cc2nc3cn2c1N1CCC(C)(CC1)OCCCC[C@H](C)Oc1cc(C)c(C)cc1-c1cccc-3c1
Reactant: Cc1ccc2c(c1)-c1cccc(c1)-c1nc3cc(C)c([C@H](OC(C)(C)C)C(=O)O)c(n3c1Cl)N1CCC(C)(CC1)OCCCC[C@H](C)O2
Product: Cc1cc2c(cc1C)-c1cccc(c1)-c1nc3cc(C)c([C@H](OC(C)(C)C)C(=O)O)c(n3c1Cl)N1CCC(C)(CC1)OCCCC[C@H](C)O2
Yield: 61 %

Procedure:
Prepared in 61% yield from methyl(2S)-2-(tert-butoxy)-2-[(22S)-4,17,18,22,28-pentamethyl-21,27-dioxa-1,7,34-triazahexacyclo[26.2.2.16,9.110,14.02,7.015,20]tetratriaconta-2,4,6(34),8,10(33),11,13,15(20),16,18-decaen-3-yl]acetate following the procedure for (2S)-2-(tert-butoxy)-2-[(22S)-8-chloro-4,17,22,28-tetramethyl-21,27-dioxa-1,7,34-triazahexacyclo[26.2.2.16,9.110,14.02,7.015,20]tetratriaconta-2,4,6(34),8,10(33),11,13,15(20),16,18-decaen-3-yl]acetic acid. 1H NMR (500 MHz, DMSO-d6) δ 8.29 (s, 1H), 7.79 (d, J=7.7 Hz, 1H), 7.54 (t, J=7.7 Hz, 1H), 7.39 (d, J=7.3 Hz, 1H), 7.33 (s, 1H), 7.09 (s, 1H), 7.02 (s, 1H), 5.79 (br. s., 1H), 4.60 (d, J=4.8 Hz, 1H), 4.02-3.86 (m, 2H), 3.51 (br. s., 1H), 3.36 (br. s., 1H), 2.55 (s, 1H), 2.43 (br. s., 3H), 2.36 (br. s., 1H), 2.25 (s, 3H), 2.19 (s, 3H), 2.00-1.52 (m, 10H), 1.20 (br. s., 3H), 1.17 (s, 9H), 1.03 (d, J=5.5 Hz, 3H); LCMS (ESI, M): 687.3.
Reaction SMILES: CC([O-])(C)C.[K+].[CH3:7]/[CH:8]=[CH:9]\[CH3:10].[Li]CCCC.C([O:19][B:20](OC(C)C)[O:21]C(C)C)(C)C.C([K])/C=C\C.Cl.[Na+].[Cl-].[C:37]([C@@H:43]([C@H:45]([C:47]([O:49][CH:50]([CH3:52])[CH3:51])=[O:48])[OH:46])[OH:44])([O:39][CH:40]([CH3:42])[CH3:41])=[O:38]>CCOCC.C1COCC1>[CH2:7]([B:20]([OH:21])[OH:19])/[CH:8]=[CH:9]\[CH3:10].[C:47]([C@@H:45]([C@H:43]([C:37]([O:39][CH:40]([CH3:42])[CH3:41])=[O:38])[OH:44])[OH:46])([O:49][CH:50]([CH3:51])[CH3:52])=[O:48]
Reactant: CC(C)OB(OC(C)C)OC(C)C
Reactant: C/C=C\C
Agent: C/C=C\C[K]
Agent: CC(C)(C)[O-]
Agent: CC(C)OC(=O)[C@H](O)[C@@H](O)C(=O)OC(C)C
Solvent: CCOCC
Solvent: C1CCOC1
Product: C/C=C\CB(O)O
Temperature: -78 °C

Procedure:
An oven-dried 1 L three-neck round bottom flask equipped with a magnetic stir bar and a −100° C. thermometer was charged with 206 mL of anhydrous THF and KOtBu (28.2 g, 250 mmol). This mixture was flushed with Ar and cooled to −78° C., then cis-2-butene (23 mL, 250 mmol), condensed from a gas lecture bottle into a rubber-stoppered round bottom flask immersed in a −78° C. dry ice-acetone bath, was poured into the reaction mixture. n-BuLi (100 mL, 2.5 M in hexane) was then added dropwise via cannula over 1.5 h. After completion of the addition, the cooling bath was removed and the reaction mixture was allowed to warm to −20 to −25° C. for 30 min before being recooled to −78° C. Triisopropylborate (57.8 mL, 250 mmol) was added drop-wise via cannula to the (Z)-crotylpotassium solution over 2 h. After addition, the reaction mixture was maintained at −78° C. for 30 min and then rapidly poured into a 2 L separatory funnel containing 470 mL of 1 N HCl saturated with NaCl. The aqueous layer was adjusted to pH 1 by using 1 N HCl (100–150 mL), and then a solution of (R,R)-diisopropyl tartrate (52.8 g, 250 mmol) in 88 mL of Et2O was added. The phases were separated, and the aqueous layer was extracted with additional Et2O (4×120 mL). The combined extracts were dried over MgSO4 for 1 h then vacuum filtered through a fritted glass funnel under Ar blanket into an oven-dried round-bottom flask. The filtrate was concentrated in vacuo, and pumped to constant weight at under vacuum. Anhydrous toluene (170 mL) was added to the flask make a 1M solution.
Reaction SMILES: [C:1]1([C:7]2[O:8][CH:9]=[C:10]([CH2:12][OH:13])[N:11]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[O:14]1[CH2:18]CC[CH2:15]1.[H-].[Na+].COCCl>O>[CH3:15][O:14][CH2:18][O:13][CH2:12][C:10]1[N:11]=[C:7]([C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)[O:8][CH:9]=1
Reactant: C1CCOC1
Reactant: OCc1coc(-c2ccccc2)n1
Agent: COCCl
Agent: [H-]
Agent: [Na+]
Solvent: O
Product: COCOCc1coc(-c2ccccc2)n1
Temperature: 25 °C
Reaction time: 1 h
Yield: 56 %

Procedure:
To a mixture of (2-phenyl-4-oxazolyl)methanol (15.60 g) and tetrahydrofuran (300 mL) was added sodium hydride (60%, oil, 4.28 g) under ice-cooling, and the mixture was stirred at room temperature for 1 hr. Chloromethyl methyl ether (9.34 g) was added to the reaction mixture under ice-cooling, and the mixture was stirred at room temperature for 15 hrs. To the reaction mixture was added water and the mixture was extracted with ethyl acetate. The organic layer was washed successively with water and saturated brine, dried over anhydrous magnesium sulfate and concentrated. The obtained residue was subjected to silica gel column chromatography to give 4-methoxymethoxymethyl-2-phenyloxazole as a colorless oil (10.86 g, 56%) from a fraction eluted with ethyl acetate-hexane (1:8, v/v).
Reaction SMILES: [CH3:1][CH:2]([CH:6]([NH:15][CH2:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)[CH:7]([C:11]([O:13][CH3:14])=[O:12])[CH:8]([OH:10])[CH3:9])[C:3](O)=[O:4].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C(N(CC)CC)C.N(C(OCC)=O)=NC(OCC)=O>C1(C)C=CC=CC=1>[CH3:9][CH:8]1[CH:7]([C:11]([O:13][CH3:14])=[O:12])[CH:6]([NH:15][CH2:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[CH:2]([CH3:1])[C:3](=[O:4])[O:10]1
Reactant: COC(=O)C(C(C)O)C(NCc1ccccc1)C(C)C(=O)O
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CCN(CC)CC
Solvent: Cc1ccccc1
Product: COC(=O)C1C(C)OC(=O)C(C)C1NCc1ccccc1
Reaction time: 1 h
Yield: 17.2 %

Procedure:
(2RS,3RS,4SR,5SR)-2-Methyl-3-benzylamino-4-methoxycarbonyl-5-hydroxyhexanoic acid (340 mg; 1.1 mmole) and triphenylphosphine (393 mg; 1.5 mmole) were dissolved in dry toluene (6 ml). After addition of triethylamine (151.5 mg; 1.5 mmole), the resultant mixture was cooled to -15° C. Diethyl azodicarboxylate (261 mg; 1.5 mmole) was added thereto, and the mixture was stirred at -10° to -5° C. for 1 hour. The solvent was removed under reduced pressure, and the residue was purified by silica gel column chromatography to give methyl (2RS,3SR,4RS,5RS)-tetrahydro-2,5-dimethyl6-oxo-4-benzylamino-2H-pyrane-3-c (190 mg) and methyl (2SR,3SR,4RS,5RS)-tetrahydro-2,5-dimethyl-6-oxo-4-benzylamino-2H-pyrane-3-carboxylate (55 mg). (2RS,3SR,4RS,5RS) isomer:
Reaction SMILES: C(O[C:6]([N:8]1[CH2:13][CH2:12][N:11]([C:14]2[C:19]([Cl:20])=[N:18][CH:17]=[CH:16][N:15]=2)[CH2:10][CH2:9]1)=[O:7])(C)(C)C.Cl.O1CCOCC1.C(N(CC)CC)C.[N:35]([C:38]1[CH:43]=[C:42]([C:44]([F:47])([F:46])[F:45])[CH:41]=[C:40]([C:48]([F:51])([F:50])[F:49])[CH:39]=1)=C=O>CCOC(C)=O.ClCCl>[F:45][C:44]([F:46])([F:47])[C:42]1[CH:43]=[C:38]([NH:35][C:6]([N:8]2[CH2:9][CH2:10][N:11]([C:14]3[C:19]([Cl:20])=[N:18][CH:17]=[CH:16][N:15]=3)[CH2:12][CH2:13]2)=[O:7])[CH:39]=[C:40]([C:48]([F:49])([F:51])[F:50])[CH:41]=1
Reactant: O=C=Nc1cc(C(F)(F)F)cc(C(F)(F)F)c1
Reactant: CC(C)(C)OC(=O)N1CCN(c2nccnc2Cl)CC1
Agent: Cl
Solvent: C1COCCO1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: O=C(Nc1cc(C(F)(F)F)cc(C(F)(F)F)c1)N1CCN(c2nccnc2Cl)CC1
Temperature: 25 °C
Reaction time: 1 h
Yield: 99.5 %

Procedure:
To a solution of 3′-chloro-2,3,5,6-tetrahydro-[1,2′]bipyrazinyl-4-carboxylic acid tert-butyl ester (3.7 g, 12.4 mmol, prepared in Example 5a) and dichloromethane (20 mL) was added anhydrous 4M HCl/Dioxane (20 mL). The solution was stirred for 1 h until complete de-protection was evident by LCMS. The solution was concentrated in vacuo, which was then re-dissolved in dichloromethane (50 mL). Triethylamine (3.78 g, 37.4 mmol) was added and the solution was cooled to 0° C. before dropwise addition of 1-isocyanato-3,5-bis-trifluoromethyl-benzene (3.70 g, 14.5 mmol) with stirring. After completion of addition the solution was allowed to warm up to room temperature and stirred for 1 h. The reaction mixture was diluted with EtOAc (150 mL), then washed with saturated sodium bicarbonate, and brine. The organic phase was dried over MgSO4 and concentrated in vacuo to yield 3′-chloro-2,3,5,6-tetrahydro-[1,2′]bipyrazinyl-4-carboxylic acid (3,5-bis-trifluoromethyl-phenyl)-amide (5.6 g, 100%) as a white solid.
Reaction SMILES: [H-].[Na+].C(OP([CH2:11][C:12]([O:14][CH3:15])=[O:13])(OCC)=O)C.[CH2:16]([O:23][C:24]1[CH:25]=[CH:26][C:27]([CH:46]=O)=[C:28]([CH:45]=1)[O:29][CH:30]([C:38]1[CH:43]=[CH:42][CH:41]=[CH:40][C:39]=1[CH3:44])[CH2:31][CH2:32][C:33]([O:35][CH2:36][CH3:37])=[O:34])[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1.O>O1CCCC1>[CH3:44][C:39]1[CH:40]=[CH:41][CH:42]=[CH:43][C:38]=1[CH:30]([O:29][C:28]1[CH:45]=[C:24]([O:23][CH2:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[CH:25]=[CH:26][C:27]=1/[CH:46]=[CH:11]/[C:12]([O:14][CH3:15])=[O:13])[CH2:31][CH2:32][C:33]([O:35][CH2:36][CH3:37])=[O:34]
Reactant: CCOP(=O)(CC(=O)OC)OCC
Reactant: CCOC(=O)CCC(Oc1cc(OCc2ccccc2)ccc1C=O)c1ccccc1C
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: CCOC(=O)CCC(Oc1cc(OCc2ccccc2)ccc1/C=C/C(=O)OC)c1ccccc1C
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
A stirred suspension of sodium hydride (0.272 g; 60% w/v dispersion in mineral oil; 6.8 mmol) in tetrahydrofuran (100 mL) at 0° C. under nitrogen is treated, dropwise, with methyl (diethylphosphono)acetate (1.43 g) and stirred for 15 minutes. It is then treated with a solution of ethyl (RS)-4-(5-benzyloxy-2-formylphenoxy)-4-(2-methylphenyl)butanoate (1.96 g) in tetrahydrofuran (5 mL) in one portion, and the reaction mixture is stirred at ambient temperature for 15 minutes. The mixture is treated with water (100 mL) and extracted with ethyl acetate (3×100 mL), and the combined organic extracts are washed with brine (50 mL), dried over magnesium sulphate, and filtered and the solvent is removed in vacuo, to give ethyl (E)-(RS)-4-(2-methylphenyl)-4-[2-(2-methoxycarbonylethenyl)-5-benzyloxyphenoxy]butanoate, in the form of a yellow oil.
Reaction SMILES: C([O:8][C:9]1[CH:10]=[C:11]2[C:15](=[CH:16][CH:17]=1)[NH:14][CH:13]=[CH:12]2)C1C=CC=CC=1.[H-].[Na+].[CH:20]([Si:23](Cl)([CH:27]([CH3:29])[CH3:28])[CH:24]([CH3:26])[CH3:25])([CH3:22])[CH3:21]>O1CCCC1>[CH:20]([Si:23]([CH:27]([CH3:29])[CH3:28])([CH:24]([CH3:26])[CH3:25])[N:14]1[C:15]2[C:11](=[CH:10][C:9]([OH:8])=[CH:17][CH:16]=2)[CH:12]=[CH:13]1)([CH3:22])[CH3:21]
Reactant: CC(C)[Si](Cl)(C(C)C)C(C)C
Reactant: c1ccc(COc2ccc3[nH]ccc3c2)cc1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CC(C)[Si](C(C)C)(C(C)C)n1ccc2cc(O)ccc21

Procedure:
5-Benzyloxy-indole (1.0 g) was treated with NaH (135 mg) and triisopropylsilyl chloride (1.0 g) in tetrahydrofuran for 1 hour, purified by flash chromatography (98/2 ethyl acetate/hexanes), then debenzylated in ethanol (35 mL) using Pearlman's catalyst (0.19 g) and a hydrogen balloon.
Reaction SMILES: [C:1]1([N:7]2[C:11]([CH3:12])=[C:10]([C:13]([OH:15])=O)[CH:9]=[N:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[NH2:16][C:17]1[CH:18]=[CH:19][C:20]([N:25]2[CH2:30][CH2:29][CH:28]([N:31]3[CH2:36][CH2:35][O:34][CH2:33][CH2:32]3)[CH2:27][CH2:26]2)=[C:21]([CH:24]=1)[C:22]#[N:23]>>[C:22]([C:21]1[CH:24]=[C:17]([NH:16][C:13]([C:10]2[CH:9]=[N:8][N:7]([C:1]3[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=3)[C:11]=2[CH3:12])=[O:15])[CH:18]=[CH:19][C:20]=1[N:25]1[CH2:30][CH2:29][CH:28]([N:31]2[CH2:32][CH2:33][O:34][CH2:35][CH2:36]2)[CH2:27][CH2:26]1)#[N:23]
Reactant: Cc1c(C(=O)O)cnn1-c1ccccc1
Reactant: N#Cc1cc(N)ccc1N1CCC(N2CCOCC2)CC1
Product: Cc1c(C(=O)Nc2ccc(N3CCC(N4CCOCC4)CC3)c(C#N)c2)cnn1-c1ccccc1
Yield: 20.3 %

Procedure:
By the reaction and treatment in the same manner as in Example 64 using 1-phenyl-5-methylpyrazole-4-carboxylic acid (0.6 g) and 5-amino-2-(4-morpholinopiperidin-1-yl)benzonitrile (0.6 g), the title compound (0.2 g) was obtained, melting point: 223° C.
Reaction SMILES: [Cl:1][C:2]1[C:14]([Cl:15])=[C:13]([CH2:16][CH2:17][CH:18]([OH:34])[C:19]2[S:20][CH:21]=[C:22]([C:24]3[CH:29]=[CH:28][C:27]([C:30]([F:33])([F:32])[F:31])=[CH:26][CH:25]=3)[CH:23]=2)[CH:12]=[CH:11][C:3]=1[O:4][C:5]([CH3:10])([CH3:9])[C:6]([OH:8])=[O:7].[H-].[Na+].[CH2:37](Br)[C:38]1[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=1>>[CH2:37]([O:34][CH:18]([C:19]1[S:20][CH:21]=[C:22]([C:24]2[CH:25]=[CH:26][C:27]([C:30]([F:31])([F:32])[F:33])=[CH:28][CH:29]=2)[CH:23]=1)[CH2:17][CH2:16][C:13]1[CH:12]=[CH:11][C:3]([O:4][C:5]([CH3:9])([CH3:10])[C:6]([OH:8])=[O:7])=[C:2]([Cl:1])[C:14]=1[Cl:15])[C:38]1[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=1
Reactant: CC(C)(Oc1ccc(CCC(O)c2cc(-c3ccc(C(F)(F)F)cc3)cs2)c(Cl)c1Cl)C(=O)O
Reactant: BrCc1ccccc1
Agent: [H-]
Agent: [Na+]
Product: CC(C)(Oc1ccc(CCC(OCc2ccccc2)c2cc(-c3ccc(C(F)(F)F)cc3)cs2)c(Cl)c1Cl)C(=O)O

Procedure:
2-(4-(3-(Benzyloxy)-3-(4-(4-(trifluoromethyl)phenyl)thien-2-yl)propyl)-2,3-dichlorophenoxy)-2-methylpropanoic acid is prepared from 2-(2,3-dichloro-4-(3-hydroxy-3-(4-(4-(trifluoromethyl)phenyl)thien-2-yl)propyl)phenoxy)-2-methylpropanoic acid using 2.2 equivalents of sodium hydride and 2.2 equivalents of benzyl bromide according to general procedure H.
Reaction SMILES: [O:1]([C:8]1[CH:9]=[C:10]([CH:13]=[CH:14][CH:15]=1)[CH2:11]Cl)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[F-:16].[K+]>[Br-].C([P+](CCCC)(CCCC)CCCCCCCCCCCCCCCC)CCC.O>[O:1]([C:8]1[CH:9]=[C:10]([CH:13]=[CH:14][CH:15]=1)[CH2:11][F:16])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: ClCc1cccc(Oc2ccccc2)c1
Reactant: [F-]
Agent: CCCCCCCCCCCCCCCC[P+](CCCC)(CCCC)CCCC
Agent: [Br-]
Agent: [K+]
Solvent: O
Product: FCc1cccc(Oc2ccccc2)c1
Temperature: 130 °C
Yield: 48.5 %

Procedure:
3-Phenoxybenzyl chloride (4.37 g), potassium fluoride (5.8 g), tri-n-butylhexadecylphosphonium bromide (1.2 g) and water (10 ml) were stirred for a period of 8 hours in a pressure bottle heated at a temperature of 130° C. The oil was separated and the aqueous phase was diluted with water and extracted with ethylene dichloride. The oil and ethylene dichloride extract were combined and the phosphonium salt was removed by chromatography over silica gel (15 g). The eluate was concentrated and distilled to give 3-phenoxybenzyl fluoride (1.96 g; 49%) b.p. 92°-95° C. at 0.3 mm Hg. (The product was stabilized by the addition of a small amount of anhydrous calcium carbonate to prevent acid catalysed polymerization).
Reaction SMILES: [O:1]1[CH2:6][CH2:5][N:4]([C:7]2[CH:12]=[CH:11][C:10]([NH:13][C:14]3[N:19]=[CH:18][C:17]([CH2:20][C:21]([NH2:23])=[O:22])=[C:16]([NH:24][CH2:25][CH:26]4[CH2:30][CH2:29][CH2:28][NH:27]4)[CH:15]=3)=[CH:9][CH:8]=2)[CH2:3][CH2:2]1.C=O.[C:33](O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].C(=O)(O)[O-].[Na+]>C(Cl)Cl.O.C(O)(=O)C>[CH3:33][N:27]1[CH2:28][CH2:29][CH2:30][CH:26]1[CH2:25][NH:24][C:16]1[CH:15]=[C:14]([NH:13][C:10]2[CH:11]=[CH:12][C:7]([N:4]3[CH2:3][CH2:2][O:1][CH2:6][CH2:5]3)=[CH:8][CH:9]=2)[N:19]=[CH:18][C:17]=1[CH2:20][C:21]([NH2:23])=[O:22]
Reactant: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Reactant: NC(=O)Cc1cnc(Nc2ccc(N3CCOCC3)cc2)cc1NCC1CCCN1
Agent: C=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: CC(=O)O
Solvent: ClCCl
Product: CN1CCCC1CNc1cc(Nc2ccc(N3CCOCC3)cc2)ncc1CC(N)=O
Temperature: 25 °C
Reaction time: 2 h
Yield: 70.2 %

Procedure:
37.9 mg of 6-[(4-morpholinophenyl)amino]-4-[(pyrrolidin-2-ylmethyl)amino]pyridine-3-carboxyamide (the compound of Example 358) was dissolved in 2 mL of methylene chloride, to which, under ice cooling, 19.4 mg of 37% formaldehyde in water, 40.5 mg of sodium triacetoxyborohydride and acetic acid were sequentially added, and stirred at room temperature for 2 hours. To the reaction mixture, saturated sodium bicarbonate in water was added, extracted with chloroform:methanol=10:1, the extract washed with saturated saline, and dried on anhydrous sodium sulfate. The solvent was evaporated, and the residue was recrystallized from chloroform-ether to obtain 27.5 mg (70%) of the title compound as a light yellow crystalline powder.
Reaction SMILES: [OH-].[CH2:2]([N+:6]([CH2:15][CH2:16][CH2:17][CH3:18])([CH2:11][CH2:12][CH2:13][CH3:14])[CH2:7][CH2:8][CH2:9][CH3:10])[CH2:3][CH2:4][CH3:5].[C:19]([OH:30])(=[O:29])[C:20]1[CH:28]=[CH:27][C:23]([C:24]([OH:26])=[O:25])=[CH:22][CH:21]=1.C(O)C>C1C=CC=CC=1>[C:19]([O-:30])(=[O:29])[C:20]1[CH:28]=[CH:27][C:23]([C:24]([O-:26])=[O:25])=[CH:22][CH:21]=1.[CH2:15]([N+:6]([CH2:2][CH2:3][CH2:4][CH3:5])([CH2:7][CH2:8][CH2:9][CH3:10])[CH2:11][CH2:12][CH2:13][CH3:14])[CH2:16][CH2:17][CH3:18].[CH2:15]([N+:6]([CH2:2][CH2:3][CH2:4][CH3:5])([CH2:7][CH2:8][CH2:9][CH3:10])[CH2:11][CH2:12][CH2:13][CH3:14])[CH2:16][CH2:17][CH3:18]
Reactant: O=C(O)c1ccc(C(=O)O)cc1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [OH-]
Solvent: CCO
Solvent: c1ccccc1
Product: O=C([O-])c1ccc(C(=O)[O-])cc1
Temperature: 25 °C

Procedure:
To a clean, dry 500 mL round bottom flask equipped with a stir bar, Dean-Starke adapter, condenser, drying tube, and nitrogen inlet, was added 10.0 mL (0.015411 mol) of a 40 wt % aqueous solution of tetrabutylammonium hydroxide, 1.2801 (0.007705 mol) terephthalic acid, 100 mL ethanol, and 150 mL benzene. Lowered apparatus into an oil bath and heated to reflux for 6 hours. The azeotrope distilled at 64.9° C. and the reaction was allowed to remove water overnight. The reaction was cooled to room temperature, and the solvent was removed via rotary evaporation. A sample of the crude product was shown to be very soluble in water, and an NMR was taken which showed the absence of terephthalic acid. The wax-like solid was recrystallized from ethanol/ether to give white crystals, 3.9104 g (78%). Calculated for C40H76N2O4: C, 740219%; H, 11.8019%; N, 4.3161%. Found: C, 69.16; H, 11.74%; N, 4.02%. 1H NMR (CDCl3 300 MHZ): δ 0.92(t 24H), δ 1.30-1.50 (mm 32H), δ 3.10 (t 16H), 6 8.00 (m 4H). Melting point 135-137° C.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:15]=[CH:16][CH:17]=1)[CH2:5][NH:6][C:7]1[CH:8]=[C:9]([CH2:13][OH:14])[N:10]([CH3:12])[N:11]=1>[O-2].[Mn+4].[O-2].ClCCl>[Cl:1][C:2]1[CH:3]=[C:4]([CH:15]=[CH:16][CH:17]=1)[CH2:5][NH:6][C:7]1[CH:8]=[C:9]([CH:13]=[O:14])[N:10]([CH3:12])[N:11]=1
Reactant: Cn1nc(NCc2cccc(Cl)c2)cc1CO
Agent: [Mn+4]
Agent: [O-2]
Solvent: ClCCl
Product: Cn1nc(NCc2cccc(Cl)c2)cc1C=O
Temperature: 25 °C
Reaction time: 8 h
Yield: 59.2 %

Procedure:
[5-(3-Chloro-benzylamino)-2-methyl-2H-pyrazol-3-yl]-methanol (647, 0.821 g, 3.26 mmol) was combined with dichloromethane (70 mL) and manganese(IV) oxide (4 g). The reaction was stirred at room temperature overnight under an atmosphere of nitrogen. The mixture was filtered through Celite and concentrated. Purification by silica gel column chromatography eluting with a gradient of ethyl acetate (10-100%) in hexane gave the desired aldehyde (648, 0.482 g, 60%).
Reaction SMILES: Cl[CH2:2][C:3]1[C:4]([S:9][CH:10]([CH3:12])[CH3:11])=[N:5][CH:6]=[CH:7][CH:8]=1.[CH2:13]([O:15][C:16](=[O:27])[CH:17]([CH3:26])[CH2:18][C:19]1[CH:24]=[CH:23][C:22]([OH:25])=[CH:21][CH:20]=1)[CH3:14]>>[CH2:13]([O:15][C:16](=[O:27])[CH:17]([CH3:26])[CH2:18][C:19]1[CH:20]=[CH:21][C:22]([O:25][CH2:2][C:3]2[C:4]([S:9][CH:10]([CH3:12])[CH3:11])=[N:5][CH:6]=[CH:7][CH:8]=2)=[CH:23][CH:24]=1)[CH3:14]
Reactant: CC(C)Sc1ncccc1CCl
Reactant: CCOC(=O)C(C)Cc1ccc(O)cc1
Product: CCOC(=O)C(C)Cc1ccc(OCc2cccnc2SC(C)C)cc1
Yield: 53.5 %

Procedure:
3-Chloromethyl-2-isopropylsulfanyl-pyridine (0.063 g, 0.31 mmol) obtained in Step C of Preparation Example 1 and 3-(4-hydroxy-phenyl)-2-methyl-propionic acid ethyl ester (0.065 g, 0.31 mmol) obtained in Step B of Preparation Example 3 were reacted in the same manner as in Step A of Example 1 to obtain the title compound (0.062 g, 53%).
Reaction SMILES: [CH2:1]([O:8][C:9](=[O:16])[NH:10][CH:11]1[CH2:14][CH2:13][C:12]1=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[NH:17]1[CH2:21][CH2:20][CH2:19][CH2:18]1>>[CH2:1]([O:8][C:9](=[O:16])[NH:10][CH:11]1[CH2:14][CH2:13][CH:12]1[N:17]1[CH2:21][CH2:20][CH2:19][CH2:18]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: C1CCNC1
Reactant: O=C(NC1CCC1=O)OCc1ccccc1
Product: O=C(NC1CCC1N1CCCC1)OCc1ccccc1

Procedure:
The title compound, colorless oil, MS: m/e=275.1 [(M+H)+], were prepared in accordance with the general method of example 1 and 2 from (2-oxo-cyclobutyl)-carbamic acid benzyl ester (CAS 406951-43-7) and pyrrolidine. The 2 diastereomers were not separated.
Reaction SMILES: [CH3:1][O:2][CH:3]([O:16][CH3:17])[C:4]1[C:13]([CH:14]=O)=[CH:12][C:11]2[CH2:10][CH2:9][CH2:8][NH:7][C:6]=2[N:5]=1.[CH3:18][N:19]([CH3:23])[CH2:20][CH2:21][NH2:22].CC(O)=O>C(Cl)Cl>[CH3:1][O:2][CH:3]([O:16][CH3:17])[C:4]1[C:13]([CH2:14][NH:22][CH2:21][CH2:20][N:19]([CH3:23])[CH3:18])=[CH:12][C:11]2[CH2:10][CH2:9][CH2:8][NH:7][C:6]=2[N:5]=1
Reactant: COC(OC)c1nc2c(cc1C=O)CCCN2
Reactant: CN(C)CCN
Solvent: CC(=O)O
Solvent: ClCCl
Product: COC(OC)c1nc2c(cc1CNCCN(C)C)CCCN2
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of 2-(dimethoxymethyl)-5,6,7,8-tetrahydro-1,8-naphthyridine-3-carbaldehyde (intermediate 41, 1.5 g, 6.35 mmol) in DCM (40 ml) at room temperature was added 2-dimethylaminoethylamine (1.387 ml, 12.70 mmol) and AcOH (0.472 mL, 8.25 mmol), followed by Na(AcO)3BH (2.69 g, 12.70 mmol) and the reaction mixture was allowed to stir at room temperature overnight. The reaction mixture was diluted with DCM, quenched with saturated aqueous NaHCO3 and stirred for 20 min. Phases were separated and the water phase was extracted with DCM. Organic phases were combined, dried using Na2SO4, filtered and concentrated. The crude product was purified via silica gel column chromatography eluting with a gradient of MeOH (0-15%) in DCM. Fractions containing the product were combined and concentrated to yield the title compound.
Reaction SMILES: [CH3:1][C:2]1[CH:10]=[C:9]([N+:11]([O-:13])=[O:12])[C:8]2[CH2:7][CH2:6][CH2:5][C:4]=2[C:3]=1[OH:14].C1N2CCN(CC2)C1.[CH3:23][N:24]([CH3:28])[C:25](Cl)=[S:26].O>CN(C)C=O>[CH3:23][N:24]([CH3:28])[C:25](=[S:26])[O:14][C:3]1[C:2]([CH3:1])=[CH:10][C:9]([N+:11]([O-:13])=[O:12])=[C:8]2[C:4]=1[CH2:5][CH2:6][CH2:7]2
Reactant: Cc1cc([N+](=O)[O-])c2c(c1O)CCC2
Reactant: CN(C)C(=S)Cl
Agent: C1CN2CCN1CC2
Solvent: CN(C)C=O
Solvent: O
Product: Cc1cc([N+](=O)[O-])c2c(c1OC(=S)N(C)C)CCC2
Temperature: 25 °C
Yield: 79.9 %

Procedure:
5-Methyl-7-nitroindan-4-ol (5.0 g) was dissolved in N,N-dimethylformamide (50 mL). After adding triethylenediamine (5.8 g) and dimethylthiocarbamoyl chloride (4.8 g) with stirring at room temperature, the mixture was stirred at 75° C. for 5 hours. The reaction mixture was cooled to room temperature. Water (100 mL) was added to the reaction mixture. The insoluble material was collected by filtration, washed with diethyl ether and dried to give the title compound (5.80 g).
Reaction SMILES: [NH2:1][CH2:2][C@H:3]1[C@H:8]([CH3:9])[CH2:7][CH2:6][CH2:5][N:4]1[C:10]([C:12]1N=C(C)S[C:16]=1[C:17]1[CH:22]=[CH:21][C:20](F)=C[CH:18]=1)=[O:11].CC1C=CC([N:35]2[N:39]=[CH:38][CH:37]=[N:36]2)=C(C=1)C(O)=O>>[NH2:1][CH2:2][C@H:3]1[C@H:8]([CH3:9])[CH2:7][CH2:6][CH2:5][N:4]1[C:10]([C:12]1[CH:16]=[C:17]([CH3:18])[CH:22]=[CH:21][C:20]=1[N:35]1[N:39]=[CH:38][CH:37]=[N:36]1)=[O:11]
Reactant: Cc1nc(C(=O)N2CCC[C@@H](C)[C@@H]2CN)c(-c2ccc(F)cc2)s1
Reactant: Cc1ccc(-n2nccn2)c(C(=O)O)c1
Product: Cc1ccc(-n2nccn2)c(C(=O)N2CCC[C@@H](C)[C@@H]2CN)c1

Procedure:
The title compound was prepared following the same general protocol as described for rac-trans-(2-(aminomethyl)-3-methylpiperidin-1-yl)(5-(4-fluorophenyl)-2-methylthiazol-4-yl)methanone in Example A65 using 5-methyl-2-(2H-1,2,3-triazol-2-yl)benzoic acid. MS (ESI) 314 (M+H).