Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]1([O:6][C:7]2[CH:8]=[C:9]([CH:15]([N:20]3[C:28](=[O:29])[C:27]4[C:22](=[CH:23][CH:24]=[CH:25][C:26]=4[NH:30][C:31](=[O:33])[CH3:32])[C:21]3=[O:34])[CH2:16][CH:17]([OH:19])[CH3:18])[CH:10]=[CH:11][C:12]=2[O:13][CH3:14])[CH2:5][CH2:4][CH2:3][CH2:2]1.[Cr](Cl)([O-])(=O)=O.[NH+]1C=CC=CC=1>C(Cl)Cl>[CH:1]1([O:6][C:7]2[CH:8]=[C:9]([CH:15]([N:20]3[C:28](=[O:29])[C:27]4[C:22](=[CH:23][CH:24]=[CH:25][C:26]=4[NH:30][C:31](=[O:33])[CH3:32])[C:21]3=[O:34])[CH2:16][C:17](=[O:19])[CH3:18])[CH:10]=[CH:11][C:12]=2[O:13][CH3:14])[CH2:2][CH2:3][CH2:4][CH2:5]1
Reactant: COc1ccc(C(CC(C)O)N2C(=O)c3cccc(NC(C)=O)c3C2=O)cc1OC1CCCC1
Agent: O=[Cr](=O)([O-])Cl
Agent: c1cc[nH+]cc1
Solvent: ClCCl
Product: COc1ccc(C(CC(C)=O)N2C(=O)c3cccc(NC(C)=O)c3C2=O)cc1OC1CCCC1
Temperature: 25 °C
Reaction time: 5 h
Yield: 85.6 %

Procedure:
A mixture of N-{2-[1-(3-cyclopentyloxy-4-methoxyphenyl)-3-hydroxybutyl]-1,3-dioxoisoindolin-4-yl}acetamide (1.28 g, 2.74 mmol), pyridinium chlorochromate (1.18 g, 5.48 mmol) and celite (0.6 g) in methylene chloride (35 mL) was stirred at room temperature for 5 hours. The mixture was filtered through celite and the filtrate was washed with water (30 mL), brine (30 mL) and dried over magnesium sulfate. The solvent was removed in vacuo and the residue was purified by chromatography (Silica gel, methylene chloride:ethyl acetate 9:1) to give N-{2-[1-(3-cyclopentyloxy-4-methoxyphenyl)-3-oxobutyl]-1,3-dioxoisoindolin-4-yl}acetamide (1.09 g, 85%) as a white solid: mp 145-147° C.; 1H NMR (CDCl3) δ 9.53 (s, 1H), 8.70 (d, J=8.4 Hz, 1H), 7.62 (t, J=7.6 Hz, 1H), 7.46 (d, J=7.3 Hz, 1H), 7.07-7.01 (m, 2H), 6.81 (d, J=8.2 Hz, 1H), 5.73-5.67 (dd, J=5.1, 9.8 Hz, 1H), 4.77 (m, 1H), 4.04-3.93 (dd, J=10.0, 18.1 Hz, 1H), 3.80 (s, 3H), 3.28-3.19 (dd, J=5.1, 18.0 Hz, 1H), 2.26 (s, 3H), 2.18 (s, 3H), 1.97-1.61 (m, 8H); 13C NMR (CDCl3) δ 205.22, 170.03, 169.15, 167.82, 149.83, 147.70, 137.33, 135.77, 131.23, 124.63, 119.88, 117.87, 115.28, 114.57, 111.72, 80.46, 55.99, 49.94, 44.82, 32.75, 30.14, 24.92, 24.05; Anal. Calcd. for C26H28N2O6; C, 67.23; H, 6.08; N, 6.03. Found: C, 66.96; H, 6.06; N, 5.89.
Reaction SMILES: C[O:2][C:3]([C:5]1[CH:10]=[CH:9][C:8]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=2[C:17]([F:20])([F:19])[F:18])=[C:7]([CH3:21])[CH:6]=1)=[O:4].[OH-].[Na+].Cl>O1CCCC1>[CH3:21][C:7]1[CH:6]=[C:5]([C:3]([OH:4])=[O:2])[CH:10]=[CH:9][C:8]=1[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=1[C:17]([F:18])([F:19])[F:20]
Reactant: COC(=O)c1ccc(-c2ccccc2C(F)(F)F)c(C)c1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Product: Cc1cc(C(=O)O)ccc1-c1ccccc1C(F)(F)F
Yield: 90.6 %

Procedure:
To a solution of (2-methyl-2′-trifluoromethyl-[1,1′-biphenyl]-4-yl)-carboxylic acid methyl ester of Step B (1.9 g, 6.5 mmol) in tetrahydrofuran (30 mL) was added 1 N sodium hydroxide (13 mL, 13 mmol). The reaction mixture was heated at reflux overnight, then cooled and acidified with 2 N hydrochloric acid. The aqueous layer was extracted with ethyl acetate and the combined extracts were dried over anhydrous sodium sulfate, filtered and concentrated in vacuo to give 1.65 g of the title compound as a white solid, m.p. 171–174° C.
Reaction SMILES: [CH3:1][C:2]1[CH:18]=[CH:17][C:5]([N:6]=[CH:7][C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=2[N+:14]([O-:16])=[O:15])=[CH:4][CH:3]=1.B(F)(F)F.CCOCC.[CH2:28]=[C:29]([CH3:31])[CH3:30]>C(#N)C>[CH3:28][C:29]1([CH3:31])[C:4]2[C:5](=[CH:17][CH:18]=[C:2]([CH3:1])[CH:3]=2)[NH:6][CH:7]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=2[N+:14]([O-:16])=[O:15])[CH2:30]1
Reactant: Cc1ccc(N=Cc2ccccc2[N+](=O)[O-])cc1
Reactant: C=C(C)C
Agent: FB(F)F
Solvent: CC#N
Solvent: CCOCC
Product: Cc1ccc2c(c1)C(C)(C)CC(c1ccccc1[N+](=O)[O-])N2
Temperature: 90 °C
Reaction time: 8 h
Yield: 85.4 %

Procedure:
To a suspension of 4-methyl-N-(2-nitrobenzylidene)aniline (10 g) and boron trifluoride etherate (3 mL) in anhydrous acetonitrile was added isobutene (70 mL, pre-cooled to −78° C.) at ice-bath. After addition, the resulting mixture was stirred at 90° C. in sealed tube overnight. The solvent was removed under reduced pressure. The residue was purified by silica gel column chromatography to give 4,4,6-trimethyl-2-(2-nitrophenyl)-1,2,3,4-tetrahydroquinoline (10.5 g, yield 85.4%). LC/MS m/e obsd. (ESI+) [(M+H)+] 297.2.
Reaction SMILES: Cl.[CH3:2][C:3]1([OH:8])[CH2:7][CH2:6][NH:5][CH2:4]1.C(=O)([O-])[O-].[K+].[K+].[F:15][C:16]1[CH:17]=[C:18]([CH:21]=[C:22]([F:24])[CH:23]=1)[CH2:19]Br>C(#N)C>[F:15][C:16]1[CH:17]=[C:18]([CH:21]=[C:22]([F:24])[CH:23]=1)[CH2:19][N:5]1[CH2:6][CH2:7][C:3]([CH3:2])([OH:8])[CH2:4]1
Reactant: CC1(O)CCNC1
Reactant: Fc1cc(F)cc(CBr)c1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: CC1(O)CCN(Cc2cc(F)cc(F)c2)C1
Reaction time: 12 h

Procedure:
According to Example 15, 3-methylpyrrolidin-3-ol hydrochloride was synthesized. To a 100 mL reaction flask were added 3-methylpyrrolidin-3-ol hydrochloride (1 g, 7.2 mmol), anhydrous potassium carbonate (2.5 g, 18 mmol) and acetonitrile (15 mL). To the resulting mixture was slowly added a solution of 3,5-difluorobenzyl bromide (1.64 g, 7.9 mmol) in acetonitrile dropwisely at 85° C. The reaction was conducted for 12 hours. After the completion of reaction monitored by TLC, the resulting mixture was evaporated under reduced pressure to remove acetonitrile. To the residue was added a mixed solution of dichloromethane and water for extraction. The organic phase was dried over anhydrous sodium sulfate, and evaporated to remove the solvent to produce a crude product of 1-(3,5-difluorobenzyl)-3-methylpyrrolidin-3-ol (1.8 g), which was directly used in the next step.
Reaction SMILES: [C:1]1([CH2:7][CH2:8][CH2:9][CH:10]([NH:20][C:21]([CH:23]2[CH2:28][CH2:27][N:26]([C:29](=[O:33])[CH2:30][CH:31]=[CH2:32])[CH2:25][CH2:24]2)=[O:22])[CH2:11][CH2:12][CH2:13][C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.ClC1C=CC=C(C(OO)=[O:42])C=1.[O-]S([O-])=O.[Na+].[Na+]>C(Cl)Cl>[C:1]1([CH2:7][CH2:8][CH2:9][CH:10]([NH:20][C:21]([CH:23]2[CH2:28][CH2:27][N:26]([C:29](=[O:33])[CH2:30][CH:31]3[CH2:32][O:42]3)[CH2:25][CH2:24]2)=[O:22])[CH2:11][CH2:12][CH2:13][C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: C=CCC(=O)N1CCC(C(=O)NC(CCCc2ccccc2)CCCc2ccccc2)CC1
Reactant: O=C(OO)c1cccc(Cl)c1
Agent: O=S([O-])[O-]
Agent: [Na+]
Solvent: ClCCl
Product: O=C(NC(CCCc1ccccc1)CCCc1ccccc1)C1CCN(C(=O)CC2CO2)CC1
Temperature: 25 °C
Reaction time: 72 h

Procedure:
1-(3-Butenoyl)-piperidine-4-carboxylic acid [4-phenyl-1-(3-phenyl-propyl)-butyl]-amide (27) (1.00 g; 2.24 mmol) and m-chloroperbenzoic acid (Aldrich Chemical Company; 71% by assay; 0.65 g; 2.91 mmol) are combined in 10 mL of methylene chloride and refluxed for 24 hours. The solution is stirred at ambient temperature for 72 hours, diluted with methylene chloride (50 mL) and shaken with 10% aqueous Na2SO3 (50 mL). The methylene chloride layer is separated and washed successively with saturated aqueous NaHCO3 solution and brine. The organic layer is dried over MgSO4, filtered and concentrated in vacuo. The residue is purified by chromatography on silica gel using a gradient elution (80%→90% ethyl acetate in hexanes, then 50%→60% acetone in hexanes) affording 28 as a solid. CIMS (NH3CI): 463 (MH+)
Reaction SMILES: [CH3:1][C:2]1([C:7]2[N:12]=[C:11]([CH2:13][N:14]3[N:18]=[C:17]([NH2:19])[CH:16]=[N:15]3)[CH:10]=[CH:9][CH:8]=2)[O:6]CCO1.[C:20]1([C:26]2[O:30][CH:29]=[N:28][C:27]=2[C:31](O)=[O:32])[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1>>[C:2]([C:7]1[N:12]=[C:11]([CH2:13][N:14]2[N:18]=[C:17]([NH:19][C:31]([C:27]3[N:28]=[CH:29][O:30][C:26]=3[C:20]3[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=3)=[O:32])[CH:16]=[N:15]2)[CH:10]=[CH:9][CH:8]=1)(=[O:6])[CH3:1]
Reactant: O=C(O)c1ncoc1-c1ccccc1
Reactant: CC1(c2cccc(Cn3ncc(N)n3)n2)OCCO1
Product: CC(=O)c1cccc(Cn2ncc(NC(=O)c3ncoc3-c3ccccc3)n2)n1

Procedure:
Following general procedure A followed by B, starting from 2-[6-(2-methyl-[1,3]dioxolan-2-yl)-pyridin-2-ylmethyl]-2H-[1,2,3]triazol-4-ylamine and 5-phenyl-oxazole-4-carboxylic acid.
Reaction SMILES: [S:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[C:6]([OH:8])=O.[F:9][C:10]([F:21])([F:20])[O:11][C:12]1[CH:17]=[CH:16][C:15]([CH2:18][NH2:19])=[CH:14][CH:13]=1>>[F:9][C:10]([F:20])([F:21])[O:11][C:12]1[CH:17]=[CH:16][C:15]([CH2:18][NH:19][C:6]([C:2]2[S:1][CH:5]=[CH:4][CH:3]=2)=[O:8])=[CH:14][CH:13]=1
Reactant: O=C(O)c1cccs1
Reactant: NCc1ccc(OC(F)(F)F)cc1
Product: O=C(NCc1ccc(OC(F)(F)F)cc1)c1cccs1

Procedure:
Prepared in a similar manner as described in example 4 from thiophene-2-carboxylic acid and (4-(trifluoromethoxy)phenyl)methanamine. MS (M+H, 303).
Reaction SMILES: Br[C:2]1C(Cl)=NC(Cl)=N[CH:7]=1.[Br:10][C:11]1[C:12]([NH:18][CH:19]([CH:29]([CH3:31])C)[CH2:20][NH:21][C:22](=[O:28])[O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[N:13][C:14]([Cl:17])=[N:15][CH:16]=1>>[Br:10][C:11]1[C:12]([NH:18][C:19]2([CH2:20][NH:21][C:22](=[O:28])[O:23][C:24]([CH3:25])([CH3:26])[CH3:27])[CH2:29][CH2:31][CH2:7][CH2:2]2)=[N:13][C:14]([Cl:17])=[N:15][CH:16]=1
Reactant: CC(C)C(CNC(=O)OC(C)(C)C)Nc1nc(Cl)ncc1Br
Reactant: Clc1ncc(Br)c(Cl)n1
Product: CC(C)(C)OC(=O)NCC1(Nc2nc(Cl)ncc2Br)CCCC1

Procedure:
tert-butyl N-[[1-[(5-bromo-2-chloro-pyrimidin-4-yl)amino]cyclopentyl]methyl]carbamate was synthesized using 5-bromo-2,4-dichloro-pyrimidine and Intermediate L using analogous reaction conditions as described for tert-butyl N-[2-[(5-bromo-2-chloro-pyrimidin-4-yl)amino]-3-methyl-butyl]carbamate. 1H NMR (600 MHz, DMSO-d6) δ ppm 1.34 (s, 9H) 1.50-1.58 (m, 2H) 1.63-1.78 (m, 4H) 1.96-2.06 (m, 2H) 3.25 (d, J=6.15 Hz, 2H) 6.71 (s, 1H) 7.18 (t, J=6.29 Hz, 1H) 8.20 (s, 1H). LCMS (ESI) 405 (M+H).
Reaction SMILES: [CH2:1]([C:3]1[CH:4]=[C:5]([NH:15][C:16]([NH:18][CH2:19][C@@H:20]2[CH2:25][CH2:24][CH2:23][N:22]([CH2:26][C:27]([C:29]3[CH:34]=[CH:33][C:32]([F:35])=[CH:31][CH:30]=3)=[O:28])[CH2:21]2)=[O:17])[CH:6]=[C:7]([C:9]2[N:13]([CH3:14])[N:12]=[N:11][N:10]=2)[CH:8]=1)[CH3:2].[BH4-].[Na+].O>CO>[CH2:1]([C:3]1[CH:4]=[C:5]([NH:15][C:16]([NH:18][CH2:19][C@@H:20]2[CH2:25][CH2:24][CH2:23][N:22]([CH2:26][CH:27]([C:29]3[CH:30]=[CH:31][C:32]([F:35])=[CH:33][CH:34]=3)[OH:28])[CH2:21]2)=[O:17])[CH:6]=[C:7]([C:9]2[N:13]([CH3:14])[N:12]=[N:11][N:10]=2)[CH:8]=1)[CH3:2]
Reactant: CCc1cc(NC(=O)NC[C@@H]2CCCN(CC(=O)c3ccc(F)cc3)C2)cc(-c2nnnn2C)c1
Agent: [BH4-]
Agent: [Na+]
Solvent: O
Solvent: CO
Product: CCc1cc(NC(=O)NC[C@@H]2CCCN(CC(O)c3ccc(F)cc3)C2)cc(-c2nnnn2C)c1
Temperature: 25 °C
Reaction time: 3 h
Yield: 90.8 %

Procedure:
A solution of (S)-1-[3-ethyl-5-(1-methyl-1H-tetrazol-5-yl)-phenyl]-3-{1-[2-(4-fluorophenyl)-2-oxo-ethyl]-piperidin-3-ylmethyl}-urea (23 mg, 48 μmol) in methanol (1.0 mL) was treated with sodium borohydride (4.5 mg, 120 μmol) and the mixture was stirred at room temperature. After 3 hours and again after 5 hours, additional sodium borohydride (ca. 2 mg) was added. After a total of 7 hours, water (0.5 mL) was added, and the mixture was concentrated under vacuum. The residue was purified by flash column chromatography, eluting with 3% methanol in dichloromethane containing 0.3% aqueous ammonia, to provide a white glassy solid (21 mg, 91%). This material was a 1:1 mixture of epimers at the hydroxyl group. 1H NMR (300 MHz, CDCl3) δ8.25+8.16 (2s, 1H), 7.75+7.70 (2s, 1H), 7.54 (s, 1H), 7.30 (m, 2H), 7.05 (s, 1H), 7.00 (t, J=9 Hz, 2H), 6.21+6.13 (2 bt, 1H), 4.71 (m, 1H), 4.15+4.14 (2 s, 3H), 3.3-3.1 (m, 3H), 3.0-2.7 (m, 3H), 2.60 (q, J=8 Hz, 2H), 2.5-2.3 (m, 3H), 2.3-2.1 (2m, 1H), 1.9-1.5 (m, 4H), 1.20+1.19 (2 t, J=8 Hz, 3H) Mass spec (ES+) m/z 482.4 (M+H+).
Reaction SMILES: [Cl-].[NH4+:2].C[Al](C)C.CO[C:9](=[O:38])[C:10]1[CH:15]=[CH:14][C:13]([OH:16])=[C:12]([NH:17][C:18](=[O:37])[CH2:19][O:20][C:21]2[CH:26]=[CH:25][C:24]([C:27]34[CH2:36][CH:31]5[CH2:32][CH:33]([CH2:35][CH:29]([CH2:30]5)[CH2:28]3)[CH2:34]4)=[CH:23][CH:22]=2)[CH:11]=1.Cl>C1(C)C=CC=CC=1>[C:27]12([C:24]3[CH:25]=[CH:26][C:21]([O:20][CH2:19][C:18]([NH:17][C:12]4[CH:11]=[C:10]([CH:15]=[CH:14][C:13]=4[OH:16])[C:9]([NH2:2])=[O:38])=[O:37])=[CH:22][CH:23]=3)[CH2:28][CH:29]3[CH2:35][CH:33]([CH2:32][CH:31]([CH2:30]3)[CH2:36]1)[CH2:34]2
Reactant: [NH4+]
Reactant: COC(=O)c1ccc(O)c(NC(=O)COc2ccc(C34CC5CC(CC(C5)C3)C4)cc2)c1
Agent: C[Al](C)C
Agent: Cl
Agent: [Cl-]
Solvent: Cc1ccccc1
Product: NC(=O)c1ccc(O)c(NC(=O)COc2ccc(C34CC5CC(CC(C5)C3)C4)cc2)c1
Temperature: 80 °C
Reaction time: 0.25 h

Procedure:
Ammonium chloride (6.5 mg, 0.12 mmol) in anhydrous toluene 2 ml was treated with trimethyl aluminium (in 2.0 M Hexane, 0.26 ml, 0.51 mmol) under nitrogen. After 0.25 h, It was added 3-[2-(4-adamantan-1-yl-phenoxy)-acetylamino]-4-hydroxy-benzoic acid methyl ester (50.1 mg, 0.12 mmol) in toluene 4 ml. The mixture was stirred for 3 h at 80° C. After cooling, the reaction mixture was treated with diluted HCl until no foaming more. The reaction mixture was separated with ethyl acetate and sodium bicarbonate. The organic phase was washed by brine, dried (MgSO4 anh), and concentrated. The residue was purified by preparative TLC(CH2Cl2:MeOH=15:1) to give 3-[2-(4-adamantan-1-yl-phenoxy)-acetylamino]-4-hydroxy-benzamide as a white-solid (12.9 mg, 25.6%-yield).
Reaction SMILES: [IH:1].[CH2:2]([N:4]=[C:5](SC)[NH:6][NH2:7])[CH3:3].[CH2:10]([NH2:17])[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1>O>[IH:1].[NH2:7][NH:6][C:5]([NH:4][CH2:2][CH3:3])=[N:17][CH2:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1
Reactant: CCN=C(NN)SC
Reactant: NCc1ccccc1
Agent: I
Solvent: O
Product: CCNC(=NCc1ccccc1)NN

Procedure:
A solution of 25.0 g. of methyl N-ethylthiocarbazimidate hydroiodide and 10.2 g. of benzylamine in 150 ml. of water is heated on a steam bath for one hour and then evaporated under reduced pressure. The residue is dissolved in ethanol, treated with activated charcoal, filtered and evaporated under reduced pressure. The residue is dissolved in methylene chloride and the solution is passed through hydrous sodium magnesium silicate and concentrated under reduced pressure, giving the desired product as a residual red oil.
Reaction SMILES: [F:1][CH:2]([F:27])[CH2:3][N:4]1[C:8]([N:9]2[CH2:15][CH:14](O)[CH2:13][N:12]([C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])[CH2:11][CH2:10]2)=[C:7]([N+:24]([O-:26])=[O:25])[CH:6]=[N:5]1.COCCN(S(F)(F)[F:38])CCOC.C([O-])(O)=O.[Na+]>C(Cl)Cl.C1COCC1>[F:1][CH:2]([F:27])[CH2:3][N:4]1[C:8]([N:9]2[CH2:15][CH:14]([F:38])[CH2:13][N:12]([C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])[CH2:11][CH2:10]2)=[C:7]([N+:24]([O-:26])=[O:25])[CH:6]=[N:5]1
Reactant: CC(C)(C)OC(=O)N1CCN(c2c([N+](=O)[O-])cnn2CC(F)F)CC(O)C1
Reactant: COCCN(CCOC)S(F)(F)F
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1CCOC1
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N1CCN(c2c([N+](=O)[O-])cnn2CC(F)F)CC(F)C1
Temperature: 25 °C
Reaction time: 18 h
Yield: 74 %

Procedure:
To a solution of tert-butyl 4-(1-(2,2-difluoroethyl)-4-nitro-1H-pyrazol-5-yl)-6-hydroxy-1,4-diazepane-1-carboxylate (370 mg, 0.95 mmol) in DCM (10 mL) was added deoxo-Fluor® (50% solution in THF, 1.0 mL, 2.37 mmol) and the mixture was stirred at room temperature for 18 hr. Saturated aqueous NaHCO3 solution (10 mL) was added slowly and the mixture was stirred for 15 min. The aqueous layer was extracted with DCM (10 mL), the combined organic layers were passed through a phase separation cartridge and the solvent was removed under reduced pressure. Purification via silica gel column chromatography gave tert-butyl 4-(1-(2,2-difluoroethyl)-4-nitro-1H-pyrazol-5-yl)-6-fluoro-1,4-diazepane-1-carboxylate as a pale green gum (366 mg, 74%). 1H NMR (400 MHz, CDCl3) δ 8.12 (s, 1H), 6.34-6.00 (m, 1H), 5.08-2.75 (m, 11H), 1.48 (s, 9H).
Reaction SMILES: [NH2:1][C:2]([NH2:4])=[NH:3].CO[C:7]1[CH:12]([C:13](OCC)=[O:14])[CH2:11][CH:10]([CH2:18][O:19][Si:20]([C:23]([CH3:26])([CH3:25])[CH3:24])([CH3:22])[CH3:21])[CH2:9][N:8]=1>O>[NH2:3][C:2]1[N:4]=[C:13]([OH:14])[C:12]2[CH2:11][CH:10]([CH2:18][O:19][Si:20]([C:23]([CH3:25])([CH3:24])[CH3:26])([CH3:22])[CH3:21])[CH2:9][NH:8][C:7]=2[N:1]=1
Reactant: CCOC(=O)C1CC(CO[Si](C)(C)C(C)(C)C)CN=C1OC
Reactant: N=C(N)N
Solvent: O
Product: CC(C)(C)[Si](C)(C)OCC1CNc2nc(N)nc(O)c2C1
Temperature: 90 °C
Yield: 73.1 %

Procedure:
A mixture of 9.8 g of guanidine free base and 13.8 g of 2-methoxy-3-carboethoxy-5-[t-butyl(dimethyl)silyloxymethyl]-3,4,5,6-tetrahydropyridine was heated at 90° C. under nitrogen for 18 hours. The mixture was cooled to room temperature, and water was added to give a white precipitate. This was filtered to give 9.5 g of the title compound: MS m/z 311 (M+ +1), 310 (M+); 300-MHz 1H NMR (DMSO-d6) δ0.03 (s, 6 H), 0.85 (S, 9 H), 1.70-1.88 (m, 2 H), 2.27-2.38 (m, 1 H), 2.78-2.88 (m, 1 H), 3.16-3.27 (m, 1 H), 3.37-3.45 (m, 1 H), 3.49-3.58 (m, 1 H), 5.92 (b s, 2 H), 6.21 (b s, 1 H), 9.67 (b s, 1 H).
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:10]=[C:11]([S:22][CH2:23][CH2:24]C(OC)=O)[CH:12]=[N:13][C:14]=1[NH:15][C:16]1[S:17][CH:18]=[C:19]([CH3:21])[N:20]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.CC([O-])(C)C.[K+].[Cl:35]CC1[CH:42]=[CH:41][C:40]([O:43][CH3:44])=[CH:39][CH:38]=1.Cl>>[ClH:35].[CH3:44][O:43][C:40]1[CH:41]=[CH:42][C:24]([CH2:23][S:22][C:11]2[CH:10]=[C:9]([O:8][CH2:1][C:2]3[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=3)[C:14]([NH:15][C:16]3[S:17][CH:18]=[C:19]([CH3:21])[N:20]=3)=[N:13][CH:12]=2)=[CH:38][CH:39]=1
Reactant: COc1ccc(CCl)cc1
Reactant: COC(=O)CCSc1cnc(Nc2nc(C)cs2)c(OCc2ccccc2)c1
Agent: CC(C)(C)[O-]
Agent: Cl
Agent: [K+]
Product: COc1ccc(CSc2cnc(Nc3nc(C)cs3)c(OCc3ccccc3)c2)cc1
Yield: 77.6 %

Procedure:
Methyl 3-(5-(benzyloxy)-6-(4-methylthiazol-2-ylamino)pyridin-3-ylthio)propanoate (prepared according to Example 42; 70 mg, 0.17 mmol), KOtBu (0.59 mL, 0.59 mmol) and 1-(chloromethyl)-4-methoxybenzene (0.023 mL, 0.17 mmol) were reacted according to the method of Example 43 to afford 5-(4-methoxybenzylthio)-3-(benzyloxy)-N-(4-methylthiazol-2-yl)pyridin-2-amine hydrochloride (64.1 mg, 78.3% yield) as a white solid after HCl salt formation. 1H NMR (d6-DMSO) δ 7.82 (d, 1H), 7.60-7.54 (m, 3H), 7.45-7.34 (m, 3H), 7.13 (m, 2H), 6.82 (m, 3H), 5.30 (s, 2H), 4.14 (s, 2H), 3.70 (s, 3H), 2.30 (d, 3H); Mass spectrum (apci) m/z=450.0 (M+H-HCl).
Reaction SMILES: [O:1]=[C:2]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[C:4](=[O:11])[N:3]1[O:12][C:13](=[CH2:17])[C:14]([OH:16])=[O:15].[C:18]1([C:24]([C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)=[N+]=[N-])[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1>C(#N)C>[O:1]=[C:2]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[C:4](=[O:11])[N:3]1[O:12][C:13](=[CH2:17])[C:14]([O:16][CH:24]([C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)[C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1)=[O:15]
Reactant: C=C(ON1C(=O)c2ccccc2C1=O)C(=O)O
Reactant: [N-]=[N+]=C(c1ccccc1)c1ccccc1
Solvent: CC#N
Product: C=C(ON1C(=O)c2ccccc2C1=O)C(=O)OC(c1ccccc1)c1ccccc1
Yield: 70.3 %

Procedure:
2-[(1,3-Dioxo-2H-isoindol-2-yl)oxy]-2-propenoic acid (39.6 g, 0.17 mole) was dissolved in 800 ml of acetonitrile and a solution of diphenyldiazomethane (43.4 g, 0.224 mole/1000 ml acetonitrile) was added dropwise over 3 hours at 0° C. The reaction solution was evaporated to a solid which was triturated with hexane. The resulting solid was dissolved in dichloromethane and filtered through a pad of silica gel (Kieselgel 60). Addition of hexane produced 47.7 g of the title compound.
Reaction SMILES: [C:1]([O:5][C:6](=[O:26])[NH:7][C:8]1[CH:13]=[C:12]([O:14][CH3:15])[C:11]([N:16]2[CH:20]=[CH:19][CH:18]=[C:17]2[C:21]([CH3:24])([CH3:23])[CH3:22])=[CH:10][C:9]=1[NH2:25])([CH3:4])([CH3:3])[CH3:2].CC1(C)[O:33][C:32]([C:34]2[CH:35]=[C:36]([CH:39]=[CH:40][CH:41]=2)[C:37]#[N:38])=[CH:31][C:30](=O)[O:29]1>>[C:1]([O:5][C:6](=[O:26])[NH:7][C:8]1[CH:13]=[C:12]([O:14][CH3:15])[C:11]([N:16]2[CH:20]=[CH:19][CH:18]=[C:17]2[C:21]([CH3:24])([CH3:23])[CH3:22])=[CH:10][C:9]=1[NH:25][C:30](=[O:29])[CH2:31][C:32]([C:34]1[CH:41]=[CH:40][CH:39]=[C:36]([C:37]#[N:38])[CH:35]=1)=[O:33])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC1(C)OC(=O)C=C(c2cccc(C#N)c2)O1
Reactant: COc1cc(NC(=O)OC(C)(C)C)c(N)cc1-n1cccc1C(C)(C)C
Product: COc1cc(NC(=O)OC(C)(C)C)c(NC(=O)CC(=O)c2cccc(C#N)c2)cc1-n1cccc1C(C)(C)C

Procedure:
The title compound was prepared from [2-amino-4-(2-tert.-butyl-pyrrol-1-yl)-5-methoxy-phenyl]-carbamic acid tert.-butyl ester (Example J5) (89 mg, 0.25 mmol) and 3-(2,2-dimethyl-6-oxo-6H-[1,3]dioxin-4-yl)-benzonitrile (Example L1) (63 mg, 0.275 mmol) according to the general procedure M. Obtained as an off-white solid (72 mg).
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[CH:10]=[CH:9][C:8](B(O)O)=[CH:7][CH:6]=1)=[O:4].Br[C:15]1[CH:20]=[CH:19][C:18]([CH3:21])=[CH:17][N:16]=1>>[CH3:21][C:18]1[CH:19]=[CH:20][C:15]([C:8]2[CH:9]=[CH:10][C:5]([C:3]([O:2][CH3:1])=[O:4])=[CH:6][CH:7]=2)=[N:16][CH:17]=1
Reactant: Cc1ccc(Br)nc1
Reactant: COC(=O)c1ccc(B(O)O)cc1
Product: COC(=O)c1ccc(-c2ccc(C)cn2)cc1

Procedure:
Repeating the operations of Production Example 14 using 4-(methoxycarbonyl)phenylboronic acid and 2-bromo-5-methylpyridine, methyl 4-(5-methyl-2-pyridyl)benzoate was obtained. Hydrolyzing the same with 5N aqueous sodium hydroxide solution, the title compound was obtained as white solid.
Reaction SMILES: [O:1]1[CH2:5][CH2:4][CH:3]([C:6]([OH:8])=O)[CH2:2]1.[CH2:9]([C@H:16]1[CH2:20][NH:19][C@H:18]([C:21]([NH:23][C:24]2[CH:29]=[CH:28][C:27]([O:30][C:31]3[CH:36]=[CH:35][C:34]([F:37])=[CH:33][CH:32]=3)=[CH:26][CH:25]=2)=[O:22])[CH2:17]1)[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1>>[CH2:9]([C@H:16]1[CH2:20][N:19]([C:6]([CH:3]2[CH2:4][CH2:5][O:1][CH2:2]2)=[O:8])[C@H:18]([C:21]([NH:23][C:24]2[CH:29]=[CH:28][C:27]([O:30][C:31]3[CH:32]=[CH:33][C:34]([F:37])=[CH:35][CH:36]=3)=[CH:26][CH:25]=2)=[O:22])[CH2:17]1)[C:10]1[CH:11]=[CH:12][CH:13]=[CH:14][CH:15]=1
Reactant: O=C(Nc1ccc(Oc2ccc(F)cc2)cc1)[C@@H]1C[C@@H](Cc2ccccc2)CN1
Reactant: O=C(O)C1CCOC1
Product: O=C(Nc1ccc(Oc2ccc(F)cc2)cc1)[C@@H]1C[C@@H](Cc2ccccc2)CN1C(=O)C1CCOC1
Yield: 28.3 %

Procedure:
Proceeding as in Example 1, but substituting tetrahydrofuran-3-carboxylic acid and (2S,4R)-4-benzyl-N-(4-(4-fluorophenoxy)phenyl)pyrrolidine-2-carboxamide, gave Compound 36, (2S,4R)-4-benzyl-N-(4-(4-fluorophenoxy)phenyl)-1-(tetrahydrofuran-3-carbonyl)pyrrolidine-2-carboxamide (8.3 mg, 28.3%). 1H-NMR (400 MHz, DMSO-D6): σ 9.95 (s, 1H), 7.56 (m, 2H), 7.27 (m, 2H), 7.19 (m, 5H), 6.92 (m, 4H), 4.46 (m, 1H), 3.86 (m, 1H), 3.66 (m, 4H), 3.31 (m, 2H), 2.63 (m, 3H), 1.94 (m, 4H). MS (EI) for C29H29FN2O4: 489.5 (MH+).
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[CH2:7][OH:8].I[CH:10]([CH3:12])[CH3:11].[BH4-].[Na+]>CO.O>[CH3:11][CH:10]([N:1]1[CH2:6][CH2:5][CH2:4][CH2:3][CH:2]1[CH2:7][OH:8])[CH3:12]
Reactant: CC(C)I
Reactant: OCc1ccccn1
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Solvent: O
Product: CC(C)N1CCCCC1CO
Temperature: 25 °C
Reaction time: 3 h
Yield: 12.9 %

Procedure:
In a closed stainless steel tube were heated pyridine-2-methanol (3.27 g, 30 mmol) and 2-iodopropane (3.59 ml, 36 mmol) at 120° C. for 20 hours. A reaction product was dissolved in a methanol-water (10:1) mixture 23 ml) followed by addition of sodium borohydride (1.14 g, 30 mmol). After stirring at room temperature for 3 hours, a reaction solution was concentrated to dryness. To the residue was added water followed by extraction with ethyl acetate. The organic layer was dried over anhydrous magnesium sulfate, and the solvent was removed under reduced pressure. The crude product thus obtained was purified by column chromatography on silica gel (SiO2 : 90 g, CHCl3) to give 0.61 g of a product (yield 13%). The substance was then subjected to catalytic hydrogenation (2.7 kg/cm2, 1 hour) at room temperature in ethanol (20 ml) using platinum oxide (0.07 g) as a catalyst. The catalyst was removed by filtration, and the filtrate was concentrated under reduced pressure to give 0.58 g of the title compound.