Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: O.[OH-].[Li+].[CH3:4][O:5][C:6]1[CH:11]=[CH:10][C:9]([C@@H:12]2[CH2:21][CH2:20][CH2:19][C@H:18]3[N:13]2[C:14](=[O:30])[CH:15](P(=O)(OCC)OCC)[CH2:16][CH2:17]3)=[CH:8][CH:7]=1.[CH3:31][O:32][C:33]1[CH:34]=[C:35]([CH:38]=[CH:39][C:40]=1[N:41]1[CH:45]=[C:44]([CH3:46])[N:43]=[CH:42]1)[CH:36]=O.C(OCC)(=O)C>O1CCCC1.C(O)C.[Cl-].[Na+].O>[CH3:31][O:32][C:33]1[CH:34]=[C:35]([CH:38]=[CH:39][C:40]=1[N:41]1[CH:45]=[C:44]([CH3:46])[N:43]=[CH:42]1)/[CH:36]=[C:15]1\[CH2:16][CH2:17][C@H:18]2[N:13]([C:14]\1=[O:30])[C@@H:12]([C:9]1[CH:8]=[CH:7][C:6]([O:5][CH3:4])=[CH:11][CH:10]=1)[CH2:21][CH2:20][CH2:19]2
Reactant: COc1cc(C=O)ccc1-n1cnc(C)c1
Reactant: CCOP(=O)(OCC)C1CC[C@H]2CCC[C@@H](c3ccc(OC)cc3)N2C1=O
Agent: [Cl-]
Agent: [Li+]
Agent: [Na+]
Solvent: CCO
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: COc1ccc([C@H]2CCC[C@H]3CC/C(=C\c4ccc(-n5cnc(C)c5)c(OC)c4)C(=O)N32)cc1
Temperature: 25 °C
Reaction time: 3 h
Yield: 69.6 %

Procedure:
Lithium hydroxide monohydrate (11 mg) was added to a mixed solution of diethyl [(6S*,9aR*)-6-(4-methoxyphenyl)-4-oxooctahydroquinolizin-3-yl]phosphonate (35 mg) and 3-methoxy-4-(4-methyl-1H-imidazol-1-yl)benzaldehyde (19 mg) in tetrahydrofuran (2 mL) and ethanol (0.5 mL), and the reaction solution was stirred at room temperature for three hours. Ethyl acetate and brine were added to the reaction solution, and the organic layer was separated. The resulting organic layer was dried over magnesium sulfate and then concentrated under reduced pressure. The residue was purified by silica gel column chromatography (carrier: Chromatorex NH; elution solvent: heptane:ethyl acetate=1:1->ethyl acetate) to obtain 28 mg of the title compound. The property values of the compound are as follows.
Reaction SMILES: [CH3:1][N:2]1[C:6]([S:7][CH2:8][C:9]2[CH2:10][S:11][C@@H:12]3[CH:19]([NH:20][C:21](=[O:36])[C:22]([C:24]4[N:25]=[C:26]([NH:29][S:30]([CH2:33][CH2:34][CH3:35])(=[O:32])=[O:31])[S:27][CH:28]=4)=[O:23])[C:18](=[O:37])[N:13]3[C:14]=2[C:15]([OH:17])=[O:16])=[N:5][N:4]=[N:3]1.CO.[OH-].[Na+].[BH4-].[Na+]>C(O)C>[CH3:1][N:2]1[C:6]([S:7][CH2:8][C:9]2[CH2:10][S:11][C@@H:12]3[CH:19]([NH:20][C:21](=[O:36])[CH:22]([OH:23])[C:24]4[N:25]=[C:26]([NH:29][S:30]([CH2:33][CH2:34][CH3:35])(=[O:32])=[O:31])[S:27][CH:28]=4)[C:18](=[O:37])[N:13]3[C:14]=2[C:15]([OH:17])=[O:16])=[N:5][N:4]=[N:3]1
Reactant: CCCS(=O)(=O)Nc1nc(C(=O)C(=O)NC2C(=O)N3C(C(=O)O)=C(CSc4nnnn4C)CS[C@H]23)cs1
Agent: CCCS(=O)(=O)N=c1[nH]c(C(=O)C(=O)NC2C(=O)N3C(C(=O)O)=C(CSc4nnnn4C)CS[C@H]23)cs1
Agent: [BH4-]
Agent: [Na+]
Solvent: CCO
Solvent: CO
Product: CCCS(=O)(=O)Nc1nc(C(O)C(=O)NC2C(=O)N3C(C(=O)O)=C(CSc4nnnn4C)CS[C@H]23)cs1

Procedure:
To a mixture of 3-(1-methyl-1H-tetrazol-5-yl)thiomethyl-7-[2-(2-propanesulfonylamino-1,3-thiazol-4-yl)glyoxylamido]-3-cephem-4-carboxylic acid, which can be represented as 3-(1-methyl-1H-tetrazol-5-yl)thiomethyl-7-[2-(2-propanesulfonylimino-2,3-dihydro-1,3-thiazol-4-yl)glyoxylamido]-3-cephem-4-carboxylic acid, (8.0 g.), methanol (160 ml.) and 1 N sodium hydroxide aqueous solution (13.6 ml.) was dropwise added a mixture of sodium borohydride (0.26 g.) and ethanol (15 ml.) over 20 minutes under stirring and ice-cooling. The mixture was further stirred for 1 hour, and then methanol was distilled off. The residue was dissolved in water, and the solution was washed with ethyl acetate. To the aqueous solution was added ethyl acetate, and the mixture was adjusted to pH 2 with 10% hydrochloric acid, and then the ethyl acetate layer was separated from the mixture. The remaining aqueous layer was saturated with sodium chloride and then extracted with ethyl acetate. The ethyl acetate extract was combined with the separated ethyl acetate layer, washed with a saturated aqueous solution of sodium chloride and then dried. The solvent was distilled off, and the residue was washed with diethyl ether and then dried to give 3-(1-methyl-1H-tetrazol-5-yl)thiomethyl-7-[2-hydroxy-2-(2-propanesulfonylamino-1,3-thiazol-4-yl)acetamido]-3-cephem-4-carboxylic acid, which can be represented as 3-(1-methyl-1H-tetrazol-5-yl)thiomethyl-7-[2-hydroxy-2-(2-propanesulfonylimino-2,3-dihydro-1,3-thiazol-4-yl)acetamido]-3-cephem-4-carboxylic acid, (5.5 g.), mp. 160° to 170° C. (dec.).
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[N:3]=1.[CH:14](=O)[C:15]1[CH:22]=[CH:21][CH:20]=[C:17]([CH:18]=[O:19])[CH:16]=1>[Cl-].[Zn+2].[Cl-]>[C:8]1([C:4]2[N:3]=[C:2]([CH:1]=[CH:14][C:15]3[CH:16]=[C:17]([CH:20]=[CH:21][CH:22]=3)[CH:18]=[O:19])[CH:7]=[CH:6][CH:5]=2)[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1
Reactant: O=Cc1cccc(C=O)c1
Reactant: Cc1cccc(-c2ccccc2)n1
Agent: [Cl-]
Agent: [Zn+2]
Product: O=Cc1cccc(C=Cc2cccc(-c3ccccc3)n2)c1
Temperature: 160 °C

Procedure:
A mixture of 2-methyl-6-phenylpyridine (525 mg) (step 2), isophthalaldehyde (630 mg) and dry zinc chloride (40 mg) was heated at 160° C. under N2 for 3 hours. The resulting mixture was partitioned between 25% aqueous NH40Ac (20 cc) and ethyl acetate (20 cc) The organic layer was washed with H2O (10 cc), brine and solvent as removed in vacuo. The residue was purified by chromatography to afford the title compound.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH3:16])[CH:5]=[C:6]([N:13]([CH3:15])[CH3:14])[C:7]=1[C:8]([O:10][CH2:11][CH3:12])=[O:9].[N+:17]([O-])([OH:19])=[O:18].O>S(=O)(=O)(O)O>[Cl:1][C:2]1[C:3]([N+:17]([O-:19])=[O:18])=[C:4]([CH3:16])[CH:5]=[C:6]([N:13]([CH3:14])[CH3:15])[C:7]=1[C:8]([O:10][CH2:11][CH3:12])=[O:9]
Reactant: O=[N+]([O-])O
Reactant: CCOC(=O)c1c(Cl)cc(C)cc1N(C)C
Agent: O=S(=O)(O)O
Solvent: O
Product: CCOC(=O)c1c(N(C)C)cc(C)c([N+](=O)[O-])c1Cl
Temperature: 25 °C
Reaction time: 8 h

Procedure:
Ethyl 6-chloro-4,N,N-trimethylanthranilate (compound 1) (3 g) was added dropwise with stirring to a solution of nitric acid (SG 1.43) (3 ml) in conc sulphuric acid (10 ml) at room temperature. The mixture was stirred overnight at room temperature, then poured into water (200 ml). The yellow product was extracted into chloroform, and the extracts were dried by filtration after washing with water. The solvent was removed and the residue crystallised from ethanol to give ethyl 6-chloro-4,N,N-trimethyl-5-nitroanthranilate (2 g) as yellow needles, mp 76° C.
Reaction SMILES: [CH2:1]([C:7]1[CH:8]=[C:9]([C:13]2[N:17]([CH3:18])[C:16]([C:19]([OH:21])=O)=[C:15]([I:22])[N:14]=2)[CH:10]=[CH:11][CH:12]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH3:6].[N:23]1([CH2:30][CH2:31][OH:32])[CH2:29][CH2:28][CH2:27][NH:26][CH2:25][CH2:24]1>>[CH2:1]([C:7]1[CH:8]=[C:9]([C:13]2[N:17]([CH3:18])[C:16]([C:19]([N:26]3[CH2:27][CH2:28][CH2:29][N:23]([CH2:30][CH2:31][OH:32])[CH2:24][CH2:25]3)=[O:21])=[C:15]([I:22])[N:14]=2)[CH:10]=[CH:11][CH:12]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH3:6]
Reactant: OCCN1CCCNCC1
Reactant: CCCCCCc1cccc(-c2nc(I)c(C(=O)O)n2C)c1
Product: CCCCCCc1cccc(-c2nc(I)c(C(=O)N3CCCN(CCO)CC3)n2C)c1

Procedure:
In analogy to the procedure described for example 1, 2-(3-hexyl-phenyl)-5-iodo-3-methyl-3H-imidazole-4-carboxylic acid (intermediate 1) and 2-[1,4]diazepan-1-yl-ethanol gave the title compound as light yellow oil. MS: 539.3 (MH+).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:28]([F:31])([F:30])[F:29])=[C:6]([CH:27]=1)[CH2:7][N:8]1[CH2:13][CH2:12][NH:11][C:10]2[N:14]=[CH:15][C:16]([C:18]3[CH:19]=[C:20]([CH:24]=[CH:25][CH:26]=3)[C:21](O)=[O:22])=[CH:17][C:9]1=2.[N:32]1[CH:37]=[CH:36][CH:35]=[N:34][C:33]=1[N:38]1[CH2:43][CH2:42][NH:41][CH2:40][CH2:39]1>>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:28]([F:29])([F:31])[F:30])=[C:6]([CH:27]=1)[CH2:7][N:8]1[CH2:13][CH2:12][NH:11][C:10]2[N:14]=[CH:15][C:16]([C:18]3[CH:19]=[C:20]([C:21]([N:41]4[CH2:42][CH2:43][N:38]([C:33]5[N:32]=[CH:37][CH:36]=[CH:35][N:34]=5)[CH2:39][CH2:40]4)=[O:22])[CH:24]=[CH:25][CH:26]=3)=[CH:17][C:9]1=2
Reactant: O=C(O)c1cccc(-c2cnc3c(c2)N(Cc2cc(Cl)ccc2C(F)(F)F)CCN3)c1
Reactant: c1cnc(N2CCNCC2)nc1
Product: O=C(c1cccc(-c2cnc3c(c2)N(Cc2cc(Cl)ccc2C(F)(F)F)CCN3)c1)N1CCN(c2ncccn2)CC1

Procedure:
3-{1-[5-chloro-2-(trifluoromethyl)benzyl]-1,2,3,4-tetrahydropyrido[2,3-b]pyrazin-7-yl}benzoic acid was reacted with 1-(2-pyrimidinyl)piperazine as in General Procedure 10 to give the title compound. LCMS: m/z=593.97 (M+H+); retention time=0.84 minutes.
Reaction SMILES: [CH3:1][N:2]1[C:6]([NH:7][C:8]2[N:9]=[CH:10][C:11]3[CH2:17][CH2:16][N:15](C(OC(C)(C)C)=O)[CH2:14][C:12]=3[N:13]=2)=[CH:5][CH:4]=[N:3]1.Cl.O1CCOCC1.N.CO>C(Cl)Cl.CCO>[CH3:1][N:2]1[C:6]([NH:7][C:8]2[N:9]=[CH:10][C:11]3[CH2:17][CH2:16][NH:15][CH2:14][C:12]=3[N:13]=2)=[CH:5][CH:4]=[N:3]1
Reactant: Cn1nccc1Nc1ncc2c(n1)CN(C(=O)OC(C)(C)C)CC2
Agent: Cl
Agent: N
Solvent: C1COCCO1
Solvent: ClCCl
Solvent: CCO
Product: Cn1nccc1Nc1ncc2c(n1)CNCC2
Reaction time: 18 h
Yield: 57.6 %

Procedure:
To a solution of tert-butyl 2-(1-methyl-1H-pyrazol-5-ylamino)-5,6-dihydropyrido[3,4-d]pyrimidine-7(8H)-carboxylate (0.556 g, 1.68 mmol) in DCM/EtOH 5 mL, 1:1) was added 4N HCl in dioxane (4.21 ml, 16.8 mmol) and the solution stirred for 18 h. The reaction was concentrated to afford an orange solid that was neutralized by stirring with 7N NH3/MeOH and washed with DCM. The precipitate was filtered and purified by SiO2 chromatography (SNAP 25) eluting with a MeOH/DCM gradient (0 to 20% MeOH) to afford 0.223 g (75% purity, 44% yield) of N-(1-methyl-1H-pyrazol-5-yl)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-2-amine (184) as a light yellow solid: MS m/z (APCI-pos) M+1=231.2.
Reaction SMILES: [CH3:1][C:2]1[N:3]([CH2:16][CH:17]([CH3:19])[CH3:18])[C:4]2[C:13]3[CH:12]=[CH:11][C:10]([OH:14])=[CH:9][C:8]=3[N:7]=[CH:6][C:5]=2[N:15]=1.I[CH2:21][CH2:22][CH:23]1[CH2:28][CH2:27][N:26]([C:29]([O:31][C:32]([CH3:35])([CH3:34])[CH3:33])=[O:30])[CH2:25][CH2:24]1>>[CH3:1][C:2]1[N:3]([CH2:16][CH:17]([CH3:19])[CH3:18])[C:4]2[C:13]3[CH:12]=[CH:11][C:10]([O:14][CH2:21][CH2:22][CH:23]4[CH2:24][CH2:25][N:26]([C:29]([O:31][C:32]([CH3:33])([CH3:35])[CH3:34])=[O:30])[CH2:27][CH2:28]4)=[CH:9][C:8]=3[N:7]=[CH:6][C:5]=2[N:15]=1
Reactant: CC(C)(C)OC(=O)N1CCC(CCI)CC1
Reactant: Cc1nc2cnc3cc(O)ccc3c2n1CC(C)C
Product: Cc1nc2cnc3cc(OCCC4CCN(C(=O)OC(C)(C)C)CC4)ccc3c2n1CC(C)C

Procedure:
The general method described in Part L of Example 2 was used to treat 2-methyl-1-(2-methylpropyl)-1H-imidazo[4,5-c]quinolin-7-ol with tert-butyl 4-(2-iodoethyl)piperidine-1-carboxylate. After chromatographic purification, tert-butyl 4-(2-{[2-methyl-1-(2-methylpropyl)-1H-imidazo[4,5-c]quinolin-7-yl]oxy}ethyl)piperidine-1-carboxylate was isolated as a viscous, orange oil.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:29])[CH2:4][C:5]1[CH:6]=[C:7]([C:13]2[CH:18]=[CH:17][C:16]([C:19]([F:22])([F:21])[F:20])=[CH:15][C:14]=2[CH2:23]NCC(=O)N)[C:8]([O:11][CH3:12])=[CH:9][CH:10]=1.C[O:31][C:32](=[O:54])[CH2:33]C1C=C(C2C=CC(C(F)(F)F)=CC=2CO)C(OC)=CC=1.C(N(CC)CC)C.C(Cl)(=O)C>C(Cl)Cl.O>[CH3:1][O:2][C:3](=[O:29])[CH2:4][C:5]1[CH:6]=[C:7]([C:13]2[CH:18]=[CH:17][C:16]([C:19]([F:22])([F:20])[F:21])=[CH:15][C:14]=2[CH2:23][O:54][C:32](=[O:31])[CH3:33])[C:8]([O:11][CH3:12])=[CH:9][CH:10]=1
Reactant: COC(=O)Cc1ccc(OC)c(-c2ccc(C(F)(F)F)cc2CNCC(N)=O)c1
Reactant: COC(=O)Cc1ccc(OC)c(-c2ccc(C(F)(F)F)cc2CO)c1
Solvent: ClCCl
Solvent: CCN(CC)CC
Solvent: O
Product: COC(=O)Cc1ccc(OC)c(-c2ccc(C(F)(F)F)cc2COC(C)=O)c1
Temperature: 25 °C
Reaction time: 0.75 h

Procedure:
To a mixture of {2′-[(carbamoylmethyl-amino)-methyl]-6-methoxy-4′-trifluoromethyl-biphenyl-3-yl}-acetic acid methyl ester and (2′-hydroxymethyl-6-methoxy-4′-trifluoromethyl-biphenyl-3-yl)-acetic acid methyl ester (0.223 g, 0.54 mmol) in CH2Cl2 (2.2 mL) was added triethylamine (0.11 mL, 0.82 mmol), followed by acetyl chloride (0.06 mL, 0.82 mmol), and the reaction was stirred at room temperature for 45 minutes. The mixture was worked up with CH2Cl2 and H2O, and the crude material was purified by silica gel chromatography (0-100% EtOAc in hexanes, then 5% MeOH in CH2Cl2) to give the title compound.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@@H:9]([C:18]([OH:20])=O)[CH2:10][CH2:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].Cl.[CH3:22][O:23][CH2:24][NH2:25].C1CN([P+](Br)(N2CCCC2)N2CCCC2)CC1.F[P-](F)(F)(F)(F)F.C(N(C(C)C)CC)(C)C>C(OCC)(=O)C.ClCCl>[CH3:22][O:23][CH2:24][NH:25][C:18](=[O:20])[C@@H:9]([CH2:10][CH2:11][C:12]1[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=1)[NH:8][C:6]([O:5][C:1]([CH3:2])([CH3:3])[CH3:4])=[O:7]
Reactant: COCN
Reactant: CC(C)(C)OC(=O)N[C@H](CCc1ccccc1)C(=O)O
Agent: Br[P+](N1CCCC1)(N1CCCC1)N1CCCC1
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: ClCCl
Solvent: CCOC(C)=O
Solvent: CCN(C(C)C)C(C)C
Product: COCNC(=O)[C@@H](CCc1ccccc1)NC(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 10 h
Yield: 196 %

Procedure:
A mixture of N-tert-butoxycarbonyl-D-homophenylalanine (3.0 g, 10.7 mmol), methoxymethylamine hydrochloride (1.15 g, 1.1 eq.), PyBrop (5 g, 1 eq.), diisopropylethylamine (5.6 mL, 3 eq.) and dichloromethane (10 mL) was stirred at 25° C. for 10 hours, and the reaction mixture was poured into ethyl acetate and washed successively with water, 1 N HCl, sat. sodium bicarbonate and brine. The combined extracts was dried (Na2SO4) and concentrated in vacuo. Further purification by chromatography over silica gel (45% ethyl acetate/hexane) afforded the title compound (6.76 g) as a white solid: 1H NMR (400 MHz, CDCl3) δ 1.46 (s, 9H), 1.85 (m, 1H), 2.04 (m, 1H), 2.72 (m, 2H), 3.17 (s, 3H), 3.63 (s, 3H), 4.69 (m, 1H), 5.25 (bd, 1H, NH), 7.20 (m, 3H) and 7.28 (m, 2H).
Reaction SMILES: [CH3:1][CH2:2][CH2:3][C:4]1[C:9]([OH:10])=[C:8]([C:11]([CH3:13])=[O:12])[CH:7]=[CH:6][C:5]=1[OH:14].[N+](C(OCC)=O)(C(OCC)=O)=[N-].[CH:27]1[CH2:32][CH2:31][CH2:30][CH2:29][C:28]=1O.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>O1CCCC1>[C:11]([C:8]1[CH:7]=[CH:6][C:5]([O:14][CH:32]2[CH2:31][CH2:30][CH2:29][CH:28]=[CH:27]2)=[C:4]([CH2:3][CH2:2][CH3:1])[C:9]=1[OH:10])(=[O:12])[CH3:13]
Reactant: OC1=CCCCC1
Reactant: CCCc1c(O)ccc(C(C)=O)c1O
Agent: CCOC(=O)[N+](=[N-])C(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: CCCc1c(OC2C=CCCC2)ccc(C(C)=O)c1O
Temperature: 25 °C
Reaction time: 18 h

Procedure:
To a mixture of 2,4-dihydroxy-3-propylacetophenone, 40 g, diethyl diazodicarboxylate, 51 g, and cyclohexen-2-ol, 20 g, in tetrahydrofuran, 1.5 L, cooled at 0° C., was added slowly a solution of triphenylphosphine, 80 g, in THF, 0.5 L. The mixture was stirred at room temperature for 18 hours. The volatiles were removed in vacuo. The residue was dissolved in a minimum amount of CH2Cl2 and placed on a silica gel column. Elution with 1% EtOAc/hexane yielded 20 g of the title compound as an oil. NMR (ppm) (CDCl3): 12.75 (1H, s, phenolic OH), 7.60 (1H, d, J-9 Hz, H ortho to acetyl), 6.53 (1H, d, J-9 Hz, H meta to acetyl), 5.90 (2H, m, olefinic proton), 4.87 (1H, m, CHOAc), 2.60 (3H, s, CH3).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:23]=[CH:22][C:6]([CH2:7][NH:8][S:9]([C:12]2[CH:21]=[CH:20][C:15]([C:16]([O:18]C)=[O:17])=[CH:14][CH:13]=2)(=[O:11])=[O:10])=[CH:5][CH:4]=1.Br[CH2:25][C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][C:27]=1[F:32]>>[F:32][C:27]1[CH:28]=[CH:29][CH:30]=[CH:31][C:26]=1[CH2:25][N:8]([CH2:7][C:6]1[CH:22]=[CH:23][C:3]([O:2][CH3:1])=[CH:4][CH:5]=1)[S:9]([C:12]1[CH:13]=[CH:14][C:15]([C:16]([OH:18])=[O:17])=[CH:20][CH:21]=1)(=[O:10])=[O:11]
Reactant: COC(=O)c1ccc(S(=O)(=O)NCc2ccc(OC)cc2)cc1
Reactant: Fc1ccccc1CBr
Product: COc1ccc(CN(Cc2ccccc2F)S(=O)(=O)c2ccc(C(=O)O)cc2)cc1

Procedure:
Prepared as in example 5-10 from Methyl 4-(N-(4-methoxybenzyl)sulfamoyl)-benzoate (Example 5-10b) and 1-(bromomethyl)-2-fluorobenzene. 1H NMR (400 MHz, DMSO-d6): δ, ppm: 3.66(s, 3H), 4.29 (s, 2H), 4.37(s, 2H), 6.72 (d, 2H, J=8 Hz), 7.01-7.03 (m, 6H), 7.93 (d, 2H, J=8 Hz), 8.08 (d, 2H, J=8 Hz).
Reaction SMILES: [CH:1]1([NH:7][C:8](=[O:11])[CH:9]=[CH2:10])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.Cl.NC(N)=[S:15].[OH-].[Na+]>O>[CH:1]1([NH:7][C:8](=[O:11])[CH2:9][CH2:10][SH:15])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: NC(N)=S
Reactant: C=CC(=O)NC1CCCCC1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: O=C(CCS)NC1CCCCC1
Temperature: 60 °C
Yield: 90.4 %

Procedure:
A mixture of N-cyclohexylacrylamide (15.3 g), concentrated hydrochloric acid (19.4 g, 37.6%), thiourea (7.6 g) and water (10 g) was heated to 60° C. for 2 hours, cooled to 20° C. and sodium hydroxide (50%, 16 g) was slowly added under nitrogen keeping the temperature below 30° C. The resulting mixture was heated to 60° C. for 1 hour and extracted with methylene chloride (2×50 ml). Removal of the solvent afforded N-cyclohexyl-3-mercaptopropionamide (16.9 g) which was purified by vacuum distillation at 0.05 mm and 130° C. to yield 13.7 g of N-cyclohexyl-3-mercaptopropionamide; m.p. 73.5°-75.5° C.
Reaction SMILES: C([O-])([O-])=O.[Na+].[Na+].[N+](C1C=CC(C([O:16][C@H:17]2[C:21]3[N:22]=[CH:23][N:24]=[C:25](Cl)[C:20]=3[C@H:19]([CH3:27])[CH2:18]2)=O)=CC=1)([O-])=O.B1([C:39]2[CH2:44][CH2:43][N:42]([C:45]([O:47][C:48]([CH3:51])([CH3:50])[CH3:49])=[O:46])[CH2:41][CH:40]=2)OC(C)(C)C(C)(C)O1.[Li+].[OH-]>O1CCOCC1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2].O>[OH:16][C@H:17]1[C:21]2[N:22]=[CH:23][N:24]=[C:25]([C:39]3[CH2:44][CH2:43][N:42]([C:45]([O:47][C:48]([CH3:51])([CH3:50])[CH3:49])=[O:46])[CH2:41][CH:40]=3)[C:20]=2[C@H:19]([CH3:27])[CH2:18]1
Reactant: CC(C)(C)OC(=O)N1CC=C(B2OC(C)(C)C(C)(C)O2)CC1
Reactant: C[C@@H]1C[C@@H](OC(=O)c2ccc([N+](=O)[O-])cc2)c2ncnc(Cl)c21
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: O=C([O-])[O-]
Solvent: O
Solvent: C1COCCO1
Product: C[C@@H]1C[C@@H](O)c2ncnc(C3=CCN(C(=O)OC(C)(C)C)CC3)c21
Temperature: 120 °C
Reaction time: 18 h
Yield: 67 %

Procedure:
A solution of Na2CO3 (2 mL, 2M) was added to a solution of (5R,7R)-4-chloro-5-methyl-6,7-dihydro-5H-cyclopenta[d]pyrimidin-7-yl 4-nitrobenzoate (334 mg, 1.00 mmol), 3,6-dihydro-2H-pyridine-1-tert-butoxycarbonyl-4-boronic acid, pinacol ester (340 mg, 1.10 mmol) in 1,4-dioxane (6 mL). The mixture was sparged with N2 for 2 minutes. The catalyst Pd(dppf)Cl2 (65 mg, 0.08 mmol) was added in one portion. The reaction vial was sealed and heated in microwave to 120° C. for 20 minutes. A solution of LiOH (0.7 mL, 3M) was added. The mixture was stirred at room temperature for 18 hours. Water (30 mL) was added to the mixture, extracted with DCM (3×20 mL). The combined organics were dried (Na2SO4), filtered and concentrated. The crude product was purified by flash chromatography (0-5% MeOH/DCM gradient elution) to give tert-butyl 4-((5R,7R)-7-hydroxy-5-methyl-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-yl)-5,6-dihydropyridine-1(2H)-carboxylate as an oil (221 mg, 67%). 1H NMR (CDCl3, 400 MHz) δ 9.01 (s, 1H), 6.44 (s, 1H), 5.30 (m, 1H), 4.16-4.11 (m, 2H), 3.71-3.55 (m, 3H), 2.83-2.78 (m, 1H), 2.50-2.30 (m, 1H), 2.28-2.24 (m, 2H), 1.50 (s, 9H), 1.28-1.22 (m, 3H).
Reaction SMILES: [CH:1]1([C:5]([N:7]([C:14]2[CH:19]=[C:18]([O:20][C:21]3[CH:26]=[CH:25][C:24]([N+:27]([O-])=O)=[CH:23][CH:22]=3)[CH:17]=[CH:16][N:15]=2)C(C2CCC2)=O)=[O:6])[CH2:4][CH2:3][CH2:2]1.[Cl-].[NH4+].CN(C)C=O.C(O)C>[Fe].O>[NH2:27][C:24]1[CH:25]=[CH:26][C:21]([O:20][C:18]2[CH:17]=[CH:16][N:15]=[C:14]([NH:7][C:5]([CH:1]3[CH2:4][CH2:3][CH2:2]3)=[O:6])[CH:19]=2)=[CH:22][CH:23]=1
Reactant: O=C(C1CCC1)N(C(=O)C1CCC1)c1cc(Oc2ccc([N+](=O)[O-])cc2)ccn1
Agent: [Fe]
Agent: [Cl-]
Agent: [NH4+]
Solvent: O
Solvent: CCO
Solvent: CN(C)C=O
Product: Nc1ccc(Oc2ccnc(NC(=O)C3CCC3)c2)cc1
Yield: 25.2 %

Procedure:
N1-Cyclobutanecarbonyl-N1-[4-(4-nitrophenoxy)-2-pyridyl]-1-cyclobutanecarboxamide (720 mg), iron powder (1.4 g), ammonium chloride (2.4 g), dimethylformamide (52 ml), ethanol (2 ml) and water (2 ml) were stirred at 100° C. for 15 minutes. The mixture was filtered with celite, and then water and ethyl acetate were added for extraction. The organic layer was washed 5 times with aqueous ammonium chloride solution and then dried over magnesium sulfate. The drying agent was filtered off, the solvent was distilled off under reduced pressure, ethyl acetate and hexane were added to the residue and the precipitated solid was filtered out to obtain 130 mg of a solid.
Reaction SMILES: [OH:1][CH2:2][C:3]1[CH:7]=[C:6]([CH3:8])[O:5][N:4]=1.[Si:9](Cl)([C:12]([CH3:15])([CH3:14])[CH3:13])([CH3:11])[CH3:10].C(N(CC)CC)C.O>C(Cl)Cl.CN(C)C1C=CN=CC=1>[Si:9]([O:1][CH2:2][C:3]1[CH:7]=[C:6]([CH3:8])[O:5][N:4]=1)([C:12]([CH3:15])([CH3:14])[CH3:13])([CH3:11])[CH3:10]
Reactant: Cc1cc(CO)no1
Reactant: CC(C)(C)[Si](C)(C)Cl
Agent: CN(C)c1ccncc1
Solvent: CCN(CC)CC
Solvent: O
Solvent: ClCCl
Product: Cc1cc(CO[Si](C)(C)C(C)(C)C)no1
Temperature: 25 °C
Reaction time: 48 h
Yield: 82.3 %

Procedure:
To a chilled (5° C.) solution of 3-hydroxymethyl -5-methylisoxazole (16.8 g, 148 mmol) and tert-butyldimethylsilyl chloride (24.6 g, 163 mmol) in dry methylene chloride (100 mL) was added over 15 minutes a solution of triethylamine (22.7 mL, 163 mmol) in methylene chloride (25 mL). 4-Dimethylaminopyridine (1.81 g, 14.8 mmol) was added and the thick reaction mixture was stirred at room temperature for 48 hours. Water (100 mL) was added and the aqueous layer extracted with methylene chloride (3x). The combined organic phases were washed with brine, dried (MgSO4), filtered through a pad composed of a layer of Florisil and a layer of Silica Gel 60, and concentrated in vacuo. The yellow oil obtained (36.6 g) was purified by chromatography (Silica Gel 60, 2% ethyl acetate in hexanes) to give 27.7 g (81.9%) of pure title compound as a pale yellow oil.
Reaction SMILES: C([O:5][C:6](=[O:30])[CH2:7][O:8][CH2:9][CH:10]([O:21][C:22](=O)[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)[CH2:11][O:12][C:13](=O)[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)(C)(C)C.FC(F)(F)C(O)=O>ClCCl>[CH2:22]([O:21][CH:10]([CH2:11][O:12][CH2:13][C:14]1[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=1)[CH2:9][O:8][CH2:7][C:6]([OH:30])=[O:5])[C:23]1[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=1
Reactant: CC(C)(C)OC(=O)COCC(COC(=O)c1ccccc1)OC(=O)c1ccccc1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: O=C(O)COCC(COCc1ccccc1)OCc1ccccc1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
130 g (336.4 mmol) of the title compound of Example 7a is dissolved in 200 ml of dichloromethane, and 100 ml of trifluoroacetic acid is added at 0° C. It is stirred for 4 hours at room temperature and then evaporated to the dry state. The residue is crystallized from pentane/diethyl ether.
Reaction SMILES: CCO.CO.[BH4-].[Na+].[CH3:8][O:9][C:10]([C:12]1[C:13]2[C:14](/[CH:35]=[CH:36]/[N+:37]([O-:39])=[O:38])=[C:15]([C:22]3[CH:27]=[CH:26][C:25]([CH2:28][N:29]([C:31]([O:33][CH3:34])=[O:32])[CH3:30])=[CH:24][CH:23]=3)[NH:16][C:17]=2[CH:18]=[C:19]([F:21])[CH:20]=1)=[O:11]>O.C(O)(=O)C>[CH3:8][O:9][C:10]([C:12]1[C:13]2[C:14]([CH2:35][CH2:36][N+:37]([O-:39])=[O:38])=[C:15]([C:22]3[CH:27]=[CH:26][C:25]([CH2:28][N:29]([C:31]([O:33][CH3:34])=[O:32])[CH3:30])=[CH:24][CH:23]=3)[NH:16][C:17]=2[CH:18]=[C:19]([F:21])[CH:20]=1)=[O:11]
Reactant: COC(=O)c1cc(F)cc2[nH]c(-c3ccc(CN(C)C(=O)OC)cc3)c(/C=C/[N+](=O)[O-])c12
Agent: [BH4-]
Agent: [Na+]
Solvent: O
Solvent: CO
Solvent: CC(=O)O
Product: COC(=O)c1cc(F)cc2[nH]c(-c3ccc(CN(C)C(=O)OC)cc3)c(CC[N+](=O)[O-])c12
Temperature: 15 °C
Reaction time: 0.25 h
Yield: 45 %

Procedure:
EtOH (900 ml) and MeOH (90 ml) were added to a 2 L flask. Powdered sodium borohydride (20.5 g, 0.55 mol) was then added. The suspension was cooled to 15° C. Nitroalkene 12 (49.0 g, 0.11 mol) was added in portions over 45 minutes while the temperature was maintained at ˜15° C. After addition was complete, additional EtOH (800 ml) was added. The reaction mixture was stirred for 15 minutes. TLC analysis indicated the completion of the reaction. A mixture of acetic acid (40 ml) and water (40 ml) was added slowly to quench the excess of sodium borohydride. A reddish suspension was obtained. Solvent was removed in a rotovap. The residue was partitioned between EtOAc (600 ml) and water (300 ml). Aqueous phase was separated. The solid in organic layer was collected by filtration and dried to afford 21.94 g of product 13 (45% yield). The organic filtrate was concentrated to dryness. The residue was then reslurried with EtOAC (70 ml)/heptane (200 ml). The solid was collected by filtration and dried to afford second crop of product (21.74 g, 44% yield). The combined yield for this step is 89%. 1H NMR (300 MHz, DMSO-d6) δ 2.87 (s, 3H), 3.584 (t, 2H, J=7.8 Hz), 3.661 (s, 3H), 3.903 (s, 3H), 4.519 (s, 2H), 4.607 (t, 2H, J=7.8 Hz), 7.41 (m, 4H), 7.58 (d, 2H, J=8.10 Hz), 12.0 (s, br, 1H). Exact mass calculated for C22H23FN3O6: 444.1571. Found: 444.1559.