Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]1[CH2:6][C@H:5]([C:7]([OH:9])=[O:8])[CH2:4][CH2:3][C@H:2]1[CH2:10][NH2:11].[CH3:12][C:13]([CH3:33])([CH3:32])[C:14]([O:16][CH:17]([O:21][C:22](ON1C(=O)CCC1=O)=[O:23])[CH2:18][CH2:19][CH3:20])=[O:15]>CC(OC)(C)C.CC(C)=O.O>[CH3:32][C:13]([CH3:12])([CH3:33])[C:14]([O:16][CH:17]([O:21][C:22]([NH:11][CH2:10][C@H:2]1[CH2:3][CH2:4][C@H:5]([C:7]([OH:9])=[O:8])[CH2:6][CH2:1]1)=[O:23])[CH2:18][CH2:19][CH3:20])=[O:15]
Reactant: CCCC(OC(=O)ON1C(=O)CCC1=O)OC(=O)C(C)(C)C
Reactant: NC[C@H]1CC[C@H](C(=O)O)CC1
Solvent: CC(C)=O
Solvent: O
Solvent: COC(C)(C)C
Product: CCCC(OC(=O)NC[C@H]1CC[C@H](C(=O)O)CC1)OC(=O)C(C)(C)C

Procedure:
Following the general nucleophilic carbamoylation procedure, tranexamic acid (800 mg, 5.0 mmol) and 1-[(2,5-dioxopyrrolidinyl)oxycarbonyloxy]butyl 2,2-dimethylpropanoate (700 mg, 2.2 mmol) were reacted in the MTBE/acetone/water mixture (16 mL) to yield the title compound 38 (90 mg, 12% yield) as a white powder after work-up and mass-guided preparative HPLC purification. 1H NMR (400 MHz, DMSO-d6): δ=0.87-0.99 (m, 5H), 1.12-1.38 (br. m, 14H), 1.69-1.74 (m, 4H), 1.89-1.92 (m, 2H), 2.13 (tt, J=12, 3.2 Hz, 1H), 2.78-2.91 (m, 2H), 6.61 (t, J=5.6 Hz, 1H), 7.47 (t, J=6.0 Hz, 1H), 12.04 (s, 1H). MS (ESI) m/z 380.22 (M+Na)+; 356.18 (M−H)−.
Reaction SMILES: CO.C(=O)C.[C:6]([O:9][CH3:10])(=[O:8])[CH3:7].[C:11]([O:14][C:15](=O)[CH3:16])(=[O:13])[CH3:12]>C(O)(=O)C.C(O)C>[C:11]([O:14][CH:15]=[CH2:16])(=[O:13])[CH3:12].[C:6]([O:9][CH3:10])(=[O:8])[CH3:7]
Reactant: CC(=O)OC(C)=O
Agent: CC=O
Solvent: CC(=O)O
Solvent: COC(C)=O
Solvent: CCO
Product: C=COC(C)=O

Procedure:
Therefore, in step (a) of the process of this invention, methanol is hydrocarbonylated to C2 compounds such as ethanol, acetaldehyde, methyl acetate and dimethylacetal, and the reaction mixture containing these compounds is then freed of ethanol, acetaldehyde, methyl acetate and dimethylacetal; concurrently, in step (b), methyl acetate is carbonylated to acetic anhydride which is then freed from the reaction mixture; the mixture of acetaldehyde and dimethylacetal separated in step (a) is reacted with acetic anhydride to form a vinyl acetate precursor ethylidene diacetate (hereunder referred to as ED) and methyl acetate (step (c)), or vinyl acetate, acetic acid and methyl acetate are produced directly and simultaneously (step (c) combined with step (d)); both the methyl acetate produced in the step (c) or the combination of steps (c) and (d) and the methyl acetate produced in the step (a) are carbonylated to acetic anhydride. The above cycle is repeated. When ED is synthesized as a precursor, it is thermally decomposed (step (d)) to vinyl acetate and acetic acid. In summary, this invention accomplishes simultaneous production of vinyl acetate, acetic acid and ethanol from methanol, carbon monoxide and hydrogen.
Reaction SMILES: [Na].[CH2:2]([O:4][C:5](=[O:12])[CH2:6][C:7]([O:9][CH2:10][CH3:11])=[O:8])[CH3:3].Cl[CH2:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=1[I:21].[Cl-].[Na+].Cl>C(O)C>[CH2:2]([O:4][C:5](=[O:12])[CH:6]([CH2:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=1[I:21])[C:7]([O:9][CH2:10][CH3:11])=[O:8])[CH3:3]
Reactant: CCOC(=O)CC(=O)OCC
Reactant: ClCc1ccccc1I
Agent: Cl
Agent: [Cl-]
Agent: [Na+]
Solvent: CCO
Product: CCOC(=O)C(Cc1ccccc1I)C(=O)OCC

Procedure:
Sodium (0.19 g, 8.2 mmol) was dissolved in absolute ethanol (12 mL). The solution was cooled on an ice bath. Malonic acid diethyl ester (1.3 g, 8.1 mmol) was added. A solution of 1-chloromethyl-2-iodo-benzene (2.0 g, 7.9 mmol) in absolute ethanol (6 mL) cooled on an ice bath was added to the malonic acid diethyl ester solution. The solution, which deposited sodium chloride, was let stand at 0° C. for 4 h and at room temperature overnight. The solution was neutralised with HCl (4N). The solvent was removed in vacuo and the residue was dissolved in dichloromethane (25 mL). Water (15 mL) was added and the phases were separated. The aqueous phase was reextracted with dichloromethane (10 mL). The combined organic fractions were dried (Na2SO4), filtered and evaporated. Yield: 2.86 g, 92%.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][C:10]=1[O:11][C:12]1[CH:17]=[C:16]([C:18]2[NH:19][C:20]([C:23]3[S:24][CH:25]=[CH:26][N:27]=3)=[CH:21][CH:22]=2)[CH:15]=[C:14]([O:28][C@@H:29]([CH3:33])[CH2:30][O:31][CH3:32])[CH:13]=1)[C:5]([OH:7])=O.Cl.[CH3:35][NH:36][CH3:37].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C(N(CC)C(C)C)(C)C>O1CCCC1.[Cl-].[Na+].O>[F:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][C:10]=1[O:11][C:12]1[CH:17]=[C:16]([C:18]2[NH:19][C:20]([C:23]3[S:24][CH:25]=[CH:26][N:27]=3)=[CH:21][CH:22]=2)[CH:15]=[C:14]([O:28][C@@H:29]([CH3:33])[CH2:30][O:31][CH3:32])[CH:13]=1)[C:5]([N:36]([CH3:37])[CH3:35])=[O:7]
Reactant: CNC
Reactant: COC[C@H](C)Oc1cc(Oc2ccc(C(=O)O)cc2F)cc(-c2ccc(-c3nccs3)[nH]2)c1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: C1CCOC1
Solvent: O
Product: COC[C@H](C)Oc1cc(Oc2ccc(C(=O)N(C)C)cc2F)cc(-c2ccc(-c3nccs3)[nH]2)c1
Temperature: 25 °C
Reaction time: 4 h
Yield: 55.7 %

Procedure:
3-Fluoro-4-{3-[(1S)-2-methoxy-1-methylethoxy]-5-[5-(1,3-thiazol-2-yl)-1H-pyrrol-2-yl]phenoxy}benzoic acid (40.0 mg, 0.163 mmol) synthesized in Example (44a) was dissolved in tetrahydrofuran (5 mL), and dimethylamine hydrochloride (20.1 mg, 0.246 mmol), HATU (64.5 mg, 0.170 mmol) and N,N-diisopropylethylamine (89 μL, 0.51 mmol) were added, followed by stirring at room temperature for 4 hours under nitrogen atmosphere. To the reaction solution, saturated brine (15 mL) was added, and extraction was carried out twice with ethyl acetate (15 mL), followed by drying over sodium sulfate. The solvent was distilled off under reduced pressure, and the resulting residue was purified using silica gel column chromatography (elution solvent: ethyl acetate/hexane=0%-75%) to afford the desired compound (45 mg, yield 99%) as a pale yellow solid.
Reaction SMILES: [F:1][C:2]1[C:3]([OH:17])=[C:4]2[C:8](=[CH:9][CH:10]=1)[N:7]([CH3:11])[CH:6]=[C:5]2[CH2:12][C:13]([NH:15][CH3:16])=[O:14].Br[CH2:19][C:20]1[CH:25]=[CH:24][CH:23]=[C:22]([Cl:26])[CH:21]=1.C(=O)([O-])[O-].[Cs+].[Cs+]>C(#N)C>[Cl:26][C:22]1[CH:21]=[C:20]([CH:25]=[CH:24][CH:23]=1)[CH2:19][O:17][C:3]1[C:2]([F:1])=[CH:10][CH:9]=[C:8]2[C:4]=1[C:5]([CH2:12][C:13]([NH:15][CH3:16])=[O:14])=[CH:6][N:7]2[CH3:11]
Reactant: Clc1cccc(CBr)c1
Reactant: CNC(=O)Cc1cn(C)c2ccc(F)c(O)c12
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CC#N
Product: CNC(=O)Cc1cn(C)c2ccc(F)c(OCc3cccc(Cl)c3)c12
Temperature: 25 °C
Yield: 81.5 %

Procedure:
A mixture of 33-6 (40 mg, 0.17 mmol), 1-(bromomethyl)-3-chlorobenzene (35 mg, 0.17 mmol) and Cesium carbonate (166 mg, 0.51 mmol) in acetonitrile (20 mL) was refluxed for 2 h. After cooled to room temperature, the mixture was filtered and the filtrate was evaporated under vacuum. The resulting residue was purified by Preparative TLC (petroleum ether/ethyl acetate=1:3) to give 33-7 (50 mg, 82%) as a white solid. LRMS: calc 360.1 and found: 361.1 [M+1].
Reaction SMILES: FC(F)(F)C(O)=O.[Br:8][C:9]1[CH:18]=[CH:17][CH:16]=[C:15]2[C:10]=1[CH2:11][C@H:12]([CH2:19][OH:20])[NH:13][CH2:14]2.N1C=CN=C1.[C:26]([Si:30]([CH3:33])([CH3:32])Cl)([CH3:29])([CH3:28])[CH3:27].BrC1C=CC=C2C=1C[C@H](CO)N(C(OC(C)(C)C)=O)C2>ClCCl.CN(C)C1C=CN=CC=1>[Br:8][C:9]1[CH:18]=[CH:17][CH:16]=[C:15]2[C:10]=1[CH2:11][C@H:12]([CH2:19][O:20][Si:30]([C:26]([CH3:29])([CH3:28])[CH3:27])([CH3:33])[CH3:32])[NH:13][CH2:14]2
Reactant: OC[C@H]1Cc2c(Br)cccc2CN1
Reactant: CC(C)(C)[Si](C)(C)Cl
Agent: CC(C)(C)OC(=O)N1Cc2cccc(Br)c2C[C@@H]1CO
Agent: CN(C)c1ccncc1
Agent: c1c[nH]cn1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CC(C)(C)[Si](C)(C)OC[C@H]1Cc2c(Br)cccc2CN1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
Add trifluoroacetic acid (75.5 mL, 998.3 mmol) to solution of tert-butyl (3R)-5-bromo-3-(hydroxymethyl)-3,4-dihydro-1H-isoquinoline-2-carboxylate (15.5 g, 45.3 mmol) in dichloromethane (226 mL) at room temperature. Stir 30 min and concentrate under reduced pressure. Dry under vacuum to give [(3R)-5-bromo-1,2,3,4-tetrahydroisoquinolin-3-yl]methanol; 2,2,2-trifluoroacetic acid as a wet solid. Dissolve [(3R)-5-bromo-1,2,3,4-tetrahydroisoquinolin-3-yl]methanol; 2,2,2-trifluoroacetic acid in dichloromethane (753 mL). Add 1H-imidazole (51.3 g, 753 mmol), N,N-Dimethyl-4-pyridinamine (460 mg, 3.77 mmol), and t-butyldimethylchlorosilane (13.6 g, 90.4 mmol). Stir at room temperature overnight. Add saturated ammonium chloride solution and extract with dichloromethane. Dry the dichloromethane extracts over sodium sulfate, filter, and concentrate under reduced pressure. Combine with the crude product from a substantially same reaction run with 19.4 mmol of tert-butyl (3R)-5-bromo-3-(hydroxymethyl)-3,4-dihydro-1H-isoquinoline-2-carboxylate. Purify the residue by silica gel chromatography eluting with ethyl acetate: hexanes (5-40% gradient) to give the title compound (14.3 g, 40.1 mmol). MS (m/z): 356 (M+1).
Reaction SMILES: [CH3:1][N:2]([C:12]1[CH:13]=[N:14][CH:15]=[CH:16][CH:17]=1)[C:3]1[CH:8]=[CH:7][N:6]=[C:5]([C:9]([OH:11])=O)[CH:4]=1.[CH3:18][C:19]1[N:20]=[C:21]([NH2:24])[S:22][CH:23]=1.F[P-](F)(F)(F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2N=CC=CC=2N=N1.CCN(C(C)C)C(C)C>C(Cl)Cl.CN(C=O)C>[CH3:1][N:2]([C:12]1[CH:13]=[N:14][CH:15]=[CH:16][CH:17]=1)[C:3]1[CH:8]=[CH:7][N:6]=[C:5]([C:9]([NH:24][C:21]2[S:22][CH:23]=[C:19]([CH3:18])[N:20]=2)=[O:11])[CH:4]=1
Reactant: CN(c1cccnc1)c1ccnc(C(=O)O)c1
Reactant: Cc1csc(N)n1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: Cc1csc(NC(=O)c2cc(N(C)c3cccnc3)ccn2)n1
Yield: 26.9 %

Procedure:
Compound 12 (0.1 g, 0.4 mmol, 1 eq), 4-methylthiazol-2-amine (60 mg, 0.53 mmol, 1.2 eq), 2-(1H-7-Azabenzotriazol-1-yl)-1,1,3,3-tetramethyluronium hexafluorophosphate (348 mg, 0.915 mmol, 2.10 eq), and DIEA (160 μL, 0.915 mmol, 2.10 eq) were dissolved in CH2Cl2 (5 mL) and DMF (1 mL) and stirred rt for 48 h. The reaction was diluted with CH2Cl2 and washed with water (1×). The organics were dried (MgSO4), filtered and concentrated in vacuo. Purification by flash chromatography on silica gel afforded 35 mg (25%) of the title compound as a white solid: 1H NMR (400 MHz, CDCl3) δ 8.60 (d, J=2.3 Hz, 1H), 8.56 (dd, J=4.7, 1.1 Hz, 1H), 8.33 (d, J=4.8 Hz, 1H), 7.83 (ddd, J=8.2, 2.4, 1.5 Hz, 1H), 7.55 (dd, J=8.1, 4.7 Hz, 1H), 7.31 (s, 1H), 6.94-6.89 (m, 1H), 8.86 (s, 1H), 3.40 (s, 3H), 2.28 (s, 3H); [M+1]+: 326.2.
Reaction SMILES: CS(O[CH2:6][CH2:7][N:8]1[CH:12]=[C:11]([C:13]2[CH:18]=[C:17]([C:19]([O:21]C)=[O:20])[CH:16]=[CH:15][N:14]=2)[N:10]=[CH:9]1)(=O)=O.[Cl:23][C:24]1[CH:31]=[CH:30][C:27]([NH:28][CH3:29])=[CH:26][CH:25]=1>>[Cl:23][C:24]1[CH:31]=[CH:30][C:27]([N:28]([CH2:6][CH2:7][N:8]2[CH:12]=[C:11]([C:13]3[CH:18]=[C:17]([C:19]([OH:21])=[O:20])[CH:16]=[CH:15][N:14]=3)[N:10]=[CH:9]2)[CH3:29])=[CH:26][CH:25]=1
Reactant: COC(=O)c1ccnc(-c2cn(CCOS(C)(=O)=O)cn2)c1
Reactant: CNc1ccc(Cl)cc1
Product: CN(CCn1cnc(-c2cc(C(=O)O)ccn2)c1)c1ccc(Cl)cc1
Yield: 19 %

Procedure:
The title compound was prepared in 19% yield from methyl 2-(1-{2-[(methylsulfonyl)oxy]ethyl}-1H-imidazol-4-yl)pyridine-4-carboxylate (PREPARATION 6) and 4-chloro-N-methylaniline according to the procedure for the preparation of Example 58. 1HNMR (400 MHz, DMSO): δ 2.77 (3H, s), 3.71 (2H, t, J=6.4 Hz), 4.17 (2H, t, J=6.4 Hz), 6.71 (1H, d, J=9.0 Hz), 6.99 (1H, m), 7.15 (1H, s), 7.17 (1H, s), 7.57 (1H, m), 7.65 (1H, s), 7.78 (1H, s), 8.24 (1H, s), 8.41 (1H, d, J=5.2 Hz). [M+H] Calc'd for C18H17ClN4O2, 358. Found, 358.
Reaction SMILES: [CH2:1]([C:5]1[N:13]([CH2:14][C:15]2[CH:20]=[CH:19][C:18]([C:21]3[CH:25]=[C:24](Cl)[S:23][C:22]=3[C:27]3[NH:31][N:30]=[N:29][N:28]=3)=[CH:17][CH:16]=2)[C:8]2=[N:9][CH:10]=[CH:11][CH:12]=[C:7]2[N:6]=1)[CH2:2][CH2:3][CH3:4].[OH-].[K+]>[Pd].CO>[CH2:1]([C:5]1[N:13]([CH2:14][C:15]2[CH:16]=[CH:17][C:18]([C:21]3[CH:25]=[CH:24][S:23][C:22]=3[C:27]3[NH:31][N:30]=[N:29][N:28]=3)=[CH:19][CH:20]=2)[C:8]2=[N:9][CH:10]=[CH:11][CH:12]=[C:7]2[N:6]=1)[CH2:2][CH2:3][CH3:4]
Reactant: CCCCc1nc2cccnc2n1Cc1ccc(-c2cc(Cl)sc2-c2nnn[nH]2)cc1
Agent: [Pd]
Agent: [K+]
Agent: [OH-]
Solvent: CO
Product: CCCCc1nc2cccnc2n1Cc1ccc(-c2ccsc2-c2nnn[nH]2)cc1
Temperature: 25 °C
Reaction time: 3 h
Yield: 91.6 %

Procedure:
A mixture of 2-butyl-3-[4-[5-chloro-2-(1H-tetrazol-5-yl)-3-thienyl]benzyl]-3H-imidazo[4,5-b]pyridine (330 mg), 10% palladium on carbon (103 mg), potassium hydroxide (261 mg) and methanol (15 ml) was stirred under hydrogen atmosphere (1 atm) at ambient temperature for 3 hours. The reaction mixture was filtered through cellulose powder and the filtrate was evaporated in vacuo. The residue was dissolved in water and neutralized with 1N hydrochloric acid. The precipitate was collected by vacuum filtration to afford a white powder of 2-butyl-3-[4-[2-(1H-tetrazol-5-yl)-3-thienyl]benzyl]-3H-imidazo[4,5-b]pyridine (279 mg).
Reaction SMILES: N#N.[CH3:3][O:4][C:5](=[O:12])[CH2:6][C:7]1[S:8][CH:9]=[CH:10][CH:11]=1.[Br:13]N1C(=O)CCC1=O>C(Cl)(Cl)Cl.C(O)(=O)C>[CH3:3][O:4][C:5](=[O:12])[CH2:6][C:7]1[S:8][C:9]([Br:13])=[CH:10][CH:11]=1
Reactant: O=C1CCC(=O)N1Br
Reactant: COC(=O)Cc1cccs1
Agent: N#N
Solvent: ClC(Cl)Cl
Solvent: CC(=O)O
Product: COC(=O)Cc1ccc(Br)s1
Temperature: 25 °C
Reaction time: 72 h
Yield: 81.7 %

Procedure:
(The following reaction is carried out in an anhydrous N2 atmosphere.) Dissolve thiophene-2-yl-acetic acid methyl ester (42) (2.0 g, 12.8 mmol) in anhydrous chloroform (9.0 mL) and glacial acetic acid (9.0 mL), add N-bromosuccinimide (2.3 g, 13.0 mmol) in portions and stir the mixture for 3 d at rt. Add water to the reaction mixture, separate layers and extract the aqu. layer with dichloromethane. Wash combined organic layer several times with a 1 M aqu. NaOH and water and once with brine and dry it with Na2SO4. Purify the crude product by preparative radial chromatography (CyH/EtOAc 5+1] to obtain (5-bromo-thiophen-2-yl)-acetic acid methyl ester (43) as a yellow oil (2.46 g, 81%) which is used without any further purification. 1H NMR (400 MHz, CDCl3): 3.71 (s, 3 H); 3.75 (s, 2 H); 6.67 (d, 1 H, J=3.8 Hz); 6.88 (d, 1 H, J=3.8 Hz).
Reaction SMILES: [OH:1][CH2:2][CH2:3][CH2:4][N:5]1[C:9]2[CH:10]=[CH:11][C:12]([F:14])=[CH:13][C:8]=2[N:7]=[C:6]1[CH3:15].C(N(CC)CC)C.[CH3:23][S:24](Cl)(=[O:26])=[O:25]>C(Cl)Cl>[CH3:23][S:24]([O:1][CH2:2][CH2:3][CH2:4][N:5]1[C:9]2[CH:10]=[CH:11][C:12]([F:14])=[CH:13][C:8]=2[N:7]=[C:6]1[CH3:15])(=[O:26])=[O:25]
Reactant: Cc1nc2cc(F)ccc2n1CCCO
Reactant: CS(=O)(=O)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: Cc1nc2cc(F)ccc2n1CCCOS(C)(=O)=O
Temperature: 25 °C

Procedure:
To a stirred, cold mixture (-25° C.) of 1-(3-hydroxy-propyl)-2-methyl-5-fluoro-1H -benzimidazole (1.99 gm), triethylamine (1.47 ml) and methylenechloride (40 ml) is dropwise added a solution of methanesulfonylchloride (0.96 ml) in 15 ml CH2Cl2. After complete addition, the mixture is warmed to ambient temperature, extracted with water (2×20 ml), dried over Na2SO4 and concentrated to a thick brown oil consisting of crude 1-(3-methanesulfonyloxy-propyl)-2-methyl-5-fluoro-1H -benzimidazole.
Reaction SMILES: C[O:2][C:3]1[CH:4]=[C:5]([NH:18][C:19](=[O:27])[C:20]([OH:26])([CH3:25])[C:21]([F:24])([F:23])[F:22])[CH:6]=[CH:7][C:8]=1[S:9]([C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)(=[O:11])=[O:10].B(Br)(Br)Br>C(Cl)Cl>[OH:2][C:3]1[CH:4]=[C:5]([NH:18][C:19](=[O:27])[C:20]([OH:26])([CH3:25])[C:21]([F:24])([F:22])[F:23])[CH:6]=[CH:7][C:8]=1[S:9]([C:12]1[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=1)(=[O:10])=[O:11]
Reactant: COc1cc(NC(=O)C(C)(O)C(F)(F)F)ccc1S(=O)(=O)c1ccccc1
Agent: BrB(Br)Br
Solvent: ClCCl
Product: CC(O)(C(=O)Nc1ccc(S(=O)(=O)c2ccccc2)c(O)c1)C(F)(F)F
Temperature: 25 °C
Reaction time: 3 h
Yield: 46 %

Procedure:
To a stirred suspension of N-[3-methoxy-4-(phenylsulfonyl)phenyl]-3,3,3-trifluoro-2-hydroxy-2-methylpropanamide (0.75 g, 1.9 mmol) in dry methylene chloride (22 mL) was added boron tribromide (3.8 mL of a 1.0M solution of boron tribromide in methylene chloride, 3.8 mmol). The resulting solution was stirred at room temperature for 3 hours, diluted with methylene chloride (50 mL) and washed with water. The organic layer was dried (MgSO4) and concentrated in vacuo to yield an off-white foam. Purification by flash column chromatography (10% to 30% v/v ethyl acetate in methylene chloride) yielded the title propanamide as a white solid (0.34 g, 46%); mp 155°-156° C. 1H-NMR (250 MHz, d6 -DMSO): 1.58 (s, 3H, CH3) 7.30 (dd, 1H, J=8.8,1.8 Hz, aromatic) 7.48 (s, 1H, OH) 7.51-1.66 (m, 4H, aromatic) 7.80-7.86 (m, 3H, aromatic) 10.19 (s, 1H, NH)10.60 (s, 1H, OH). MS (CI, CH4): 390 (M+1).
Reaction SMILES: [CH:1]1([C:4]2[C:5]([CH2:17][O:18][C:19]3[CH:24]=[CH:23][C:22]([C:25]4[CH:29]=[C:28]([CH3:30])[N:27]([CH3:31])[N:26]=4)=[CH:21][C:20]=3[CH3:32])=[C:6]([N:10]3[C:14](=[O:15])[N:13]([CH3:16])[N:12]=[N:11]3)[CH:7]=[CH:8][CH:9]=2)[CH2:3][CH2:2]1.[Cl:33]N1C(=O)CCC1=O>C(Cl)(Cl)Cl>[CH:1]1([C:4]2[C:5]([CH2:17][O:18][C:19]3[CH:24]=[CH:23][C:22]([C:25]4[C:29]([Cl:33])=[C:28]([CH3:30])[N:27]([CH3:31])[N:26]=4)=[CH:21][C:20]=3[CH3:32])=[C:6]([N:10]3[C:14](=[O:15])[N:13]([CH3:16])[N:12]=[N:11]3)[CH:7]=[CH:8][CH:9]=2)[CH2:3][CH2:2]1
Reactant: Cc1cc(-c2cc(C)n(C)n2)ccc1OCc1c(C2CC2)cccc1-n1nnn(C)c1=O
Reactant: O=C1CCC(=O)N1Cl
Solvent: ClC(Cl)Cl
Product: Cc1cc(-c2nn(C)c(C)c2Cl)ccc1OCc1c(C2CC2)cccc1-n1nnn(C)c1=O
Temperature: 25 °C

Procedure:
A mixture of 1-{3-cyclopropyl-2-(2-methyl-4-(1,5-dimethyl-1H-pyrazol-3-yl)-phenoxymethyl]-phenyl}-4-methyl-1,4-dihydrotetrazole-5-one (described in Preparation example 15) (Present compound 15) 0.37 g, N-chlorosuccinimide 0.12 g and chloroform 5 ml was stirred at room temperature for twelve hours. The resulting mixture was extracted with chloroform and was washed with saturated saline. The organic layer was dried over anhydrous magnesium sulfate and was then concentrated under reduced pressure. The resulting residue was subjected to a silica gel column chromatography to give 1-{3-cyclopropyl-2-(2-methyl-4-(4-chloro-1,5-dimethyl-1H-pyrazol-3-yl)-phenoxymethyl]-phenyl}-4-methyl-1,4-dihydrotetrazole-5-one (hereinafter, referred to as “Present compound 36”) 0.13 g.
Reaction SMILES: [NH2:1][C:2]1[CH:11]=[CH:10][C:5]([C:6]([O:8][CH3:9])=[O:7])=[C:4]([N+:12]([O-:14])=[O:13])[CH:3]=1.[C:15](N1C=CC=CC1=O)(N1C=CC=CC1=O)=[S:16]>ClCCl>[CH3:9][O:8][C:6]([C:5]1[CH:10]=[CH:11][C:2]([N:1]=[C:15]=[S:16])=[CH:3][C:4]=1[N+:12]([O-:14])=[O:13])=[O:7]
Reactant: COC(=O)c1ccc(N)cc1[N+](=O)[O-]
Reactant: O=c1ccccn1C(=S)n1ccccc1=O
Solvent: ClCCl
Product: COC(=O)c1ccc(N=C=S)cc1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 3 h
Yield: 70.5 %

Procedure:
A solution of the above synthesized methyl 4-amino-2-nitrobenzoate (50 mg, 0.25 mmol) and 1,1′-thiocarbonyldi-2(1H)-pyridone (59 mg, 0.25 mmol) in dichloromethane (4.2 ml) was stirred at room temperature for 3 hours. After completion of the reaction, the solvent was evaporated, followed by purification with a silica gel column chromatography to obtain 42 mg of the desired product as a colorless oil (yield 69%).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:11][CH:10]([C:12]([OH:14])=O)[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].CCN=C=NCCCN(C)C.Cl.C1C=CC2N(O)N=NC=2C=1.C(N(CC)C(C)C)(C)C.Cl.[CH3:47][NH:48][O:49][CH3:50]>C1COCC1>[CH3:50][O:49][N:48]([CH3:47])[C:12]([CH:10]1[CH2:9][N:8]([C:6]([O:5][C:1]([CH3:2])([CH3:3])[CH3:4])=[O:7])[CH2:11]1)=[O:14]
Reactant: CNOC
Reactant: CC(C)(C)OC(=O)N1CC(C(=O)O)C1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CCN(C(C)C)C(C)C
Solvent: C1CCOC1
Product: CON(C)C(=O)C1CN(C(=O)OC(C)(C)C)C1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 98.8 %

Procedure:
To a solution of 1-(tert-butoxycarbonyl)azetidine-3-carboxylic acid (2.00 g, 9.94 mmol) in THF (50 mL) was added EDCl (2.10 g, 10.93 mmol), HOBt (1.48 g, 10.93 mmol), and N,N-diisopropylethylamine (5.19 mL, 29.82 mmol). The mixture was stirred at rt for 15 min. N,O-dimethylhydroxylamine hydrochloride (1.16 g, 11.93 mmol), was added and stirring continued for 64 h. The crude reaction was purified via ISCO® chromatography using 3:1 ethyl/hexanes to afford 2.4 g (99%) of the desired product, which was used without further characterization.
Reaction SMILES: [CH3:1][C:2]([CH3:28])([CH3:27])[CH2:3][NH:4][CH2:5][C:6]1[S:10][C:9]([C:11]([N:13]([CH3:26])[CH2:14][CH2:15][CH2:16][N:17]([CH3:25])[C:18](=[O:24])[O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:12])=[CH:8][CH:7]=1.[C:29]1([C:57]2[CH:62]=[CH:61][CH:60]=[CH:59][CH:58]=2)[CH:34]=[CH:33][CH:32]=[CH:31][C:30]=1[NH:35][C:36](=[O:56])[O:37][CH:38]1[CH2:43][CH2:42][N:41]([CH2:44][CH2:45][N:46]([CH3:55])[C:47](=[O:54])[CH2:48][CH2:49][CH2:50][CH2:51][CH:52]=O)[CH2:40][CH2:39]1>>[C:29]1([C:57]2[CH:58]=[CH:59][CH:60]=[CH:61][CH:62]=2)[CH:34]=[CH:33][CH:32]=[CH:31][C:30]=1[NH:35][C:36](=[O:56])[O:37][CH:38]1[CH2:43][CH2:42][N:41]([CH2:44][CH2:45][N:46]([C:47](=[O:54])[CH2:48][CH2:49][CH2:50][CH2:51][CH2:52][N:4]([CH2:5][C:6]2[S:10][C:9]([C:11](=[O:12])[N:13]([CH2:14][CH2:15][CH2:16][N:17]([C:18]([O:19][C:20]([CH3:21])([CH3:22])[CH3:23])=[O:24])[CH3:25])[CH3:26])=[CH:8][CH:7]=2)[CH2:3][C:2]([CH3:28])([CH3:27])[CH3:1])[CH3:55])[CH2:40][CH2:39]1
Reactant: CN(CCN1CCC(OC(=O)Nc2ccccc2-c2ccccc2)CC1)C(=O)CCCCC=O
Reactant: CN(CCCN(C)C(=O)c1ccc(CNCC(C)(C)C)s1)C(=O)OC(C)(C)C
Product: CN(CCN1CCC(OC(=O)Nc2ccccc2-c2ccccc2)CC1)C(=O)CCCCCN(Cc1ccc(C(=O)N(C)CCCN(C)C(=O)OC(C)(C)C)s1)CC(C)(C)C
Yield: 57.1 %

Procedure:
The compound (122 mg, 0.307 mol) obtained in Example 55b and the compound (171 mg, 0.368 mmol) obtained in Example 4g were used to give the title compound (181 mg; yield, 69%) as a colorless oily substance according to the method described in Example 45b.
Reaction SMILES: [Cl:1][C:2]1[C:3]([NH:20][C:21]2[CH:30]=[CH:29][CH:28]=[CH:27][C:22]=2[C:23]([NH:25][CH3:26])=[O:24])=[N:4][C:5]([NH:8][C:9]2[CH:19]=[CH:18][C:12]3[CH2:13][CH2:14][NH:15][CH2:16][CH2:17][C:11]=3[CH:10]=2)=[N:6][CH:7]=1.C=O.[C:33]([BH3-])#N.[Na+]>C(#N)C>[Cl:1][C:2]1[C:3]([NH:20][C:21]2[CH:30]=[CH:29][CH:28]=[CH:27][C:22]=2[C:23]([NH:25][CH3:26])=[O:24])=[N:4][C:5]([NH:8][C:9]2[CH:19]=[CH:18][C:12]3[CH2:13][CH2:14][N:15]([CH3:33])[CH2:16][CH2:17][C:11]=3[CH:10]=2)=[N:6][CH:7]=1
Reactant: [BH3-]C#N
Reactant: CNC(=O)c1ccccc1Nc1nc(Nc2ccc3c(c2)CCNCC3)ncc1Cl
Agent: C=O
Agent: [Na+]
Solvent: CC#N
Product: CNC(=O)c1ccccc1Nc1nc(Nc2ccc3c(c2)CCN(C)CC3)ncc1Cl
Temperature: 25 °C
Reaction time: 2 h

Procedure:
2-[5-Chloro-2-(2,3,4,5-tetrahydro-1H-benzo[d]azepin-7-ylamino)-pyrimidin-4-ylamino]-N-methyl-benzamide was suspended in acetonitrile (5 mL). Aqueous formaldehyde (37%, 325 μL/4 mmol) and sodium cyanoborohydride (210 mg/3.3 mmol) were added sequentially and the reaction stirred at room temperature for two hours. The material was concentrated onto celite and the desired product was isolated by sequential column chromatography on silica gel (eluting with 0→50% methanol/methylene chloride) followed by basic alumina (eluting with 0→40% methanol/methylene chloride). Yield 50 mg/35%. 1H NMR (400 MHz, DMSO-d6) δ 11.58 (s, 1H), 9.41 (s, 1H), 8.82-8.69 (m, 2H), 8.22 (s, 1H), 7.79 (d, J=7.8 Hz, 1H), 7.56-7.41 (m, 3H), 7.19 (dd, J=7.3, 7.3 Hz, 1H), 7.09 (d, J=8.1 Hz, 1H), 3.19-2.78 (m, 14H). LC/MS found 436 (M+H). mp 125-130° C. (dec.).
Reaction SMILES: P(Cl)(Cl)(Cl)=O.[NH:6]1[C:14]2[C:9](=[CH:10][C:11]([C:15]#[N:16])=[CH:12][CH:13]=2)[CH:8]=[CH:7]1.CN(C)[CH:19]=[O:20]>>[CH:19]([C:8]1[C:9]2[C:14](=[CH:13][CH:12]=[C:11]([C:15]#[N:16])[CH:10]=2)[NH:6][CH:7]=1)=[O:20]
Reactant: CN(C)C=O
Reactant: N#Cc1ccc2[nH]ccc2c1
Solvent: O=P(Cl)(Cl)Cl
Product: N#Cc1ccc2[nH]cc(C=O)c2c1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 84 %

Procedure:
Phosphoryl chloride (4.24 ml, 45.48 mmol) was added dropwise to dimethylformamide (3.52 ml, 45.48 mmol) and stirred for 30 mins at room temperature. A solution of 1H-indole-5-carbonitrile (5.39 g, 37.9 mmol) in dimethylformamide (10 ml) was added dropwise. A solid precipitated, further dimethylformamide (10 ml) was added to aid stirring and the reaction mixture was then stirred at room temperature for 3 hr. Water was added to quench the reaction mixture which was then stirred for 18 hr. The stirring was stopped and the reaction mixture was left to stand, after 24 hr a pink solid had precipitated in the organic layer. The layers were separated and organic layer filtered, washed with water and dried to give the desired product (5.44 g, 84%). 1H NMR (DMSO) δ 7.60-7.80 (m, 2H), 8.20-8.30 (m, 2H), 10.00 (s, 1H), 12.20-12.35 (s, br, 1H).