Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: CS(O[CH2:6][C@H:7]1[CH2:18][CH2:17][C:16]2[S:15][C:14]3[N:13]=[CH:12][N:11]=[C:10]([O:19][CH:20]4[CH2:25][CH2:24][C:23]([NH:27][C:28](=[O:34])[O:29][C:30]([CH3:33])([CH3:32])[CH3:31])([CH3:26])[CH2:22][CH2:21]4)[C:9]=3[C:8]1=2)(=O)=O.[C-:35]#[N:36].[Na+]>CS(C)=O.CN(C)C1C=CN=CC=1>[C:35]([CH2:6][C@H:7]1[CH2:18][CH2:17][C:16]2[S:15][C:14]3[N:13]=[CH:12][N:11]=[C:10]([O:19][CH:20]4[CH2:25][CH2:24][C:23]([NH:27][C:28](=[O:34])[O:29][C:30]([CH3:31])([CH3:33])[CH3:32])([CH3:26])[CH2:22][CH2:21]4)[C:9]=3[C:8]1=2)#[N:36]
Reactant: [C-]#N
Reactant: CC1(NC(=O)OC(C)(C)C)CCC(Oc2ncnc3sc4c(c23)[C@@H](COS(C)(=O)=O)CC4)CC1
Agent: CN(C)c1ccncc1
Agent: [Na+]
Solvent: CS(C)=O
Product: CC1(NC(=O)OC(C)(C)C)CCC(Oc2ncnc3sc4c(c23)[C@@H](CC#N)CC4)CC1
Temperature: 80 °C
Reaction time: 2.5 h
Yield: 96.2 %

Procedure:
To a 50-mL round-bottom flask containing a solution of tert-butyl N-(4-[[(3S)-3-[(methanesulfonyloxy)methyl]-7-thia-9,11-diazatricyclo[6.4.0.0[2,6]]dodeca-1(8),2(6),9,11-tetraen-12-yl]oxy]-1-methylcyclohexyl)carbamate (1.0 g, 1.95 mmol, 1.00 equiv) in DMSO (12 mL) was added NaCN (479 mg, 9.78 mmol, 5.00 equiv) and 4-dimethylaminopyridine (30 mg, 0.25 mmol, 0.13 equiv) and the solution was stirred for 2.5 h at 80° C. After cooling, the reaction was then quenched by the addition of water, extracted with 3×100 mL of ethyl acetate. The organic layers were combined, washed with brine, dried over sodium sulfate and concentrated under vacuum. The residue was applied onto a silica gel column with ethyl acetate/petroleum ether (1/2) to give the desired tert-butyl N-(4-[[(3R)-3-(cyanomethyl)-7-thia-9,11-diazatricyclo[6.4.0.0[2,6]]dodeca-1(8),2(6),9,11-tetraen-12-yl]oxy]-1-methylcyclohexyl)carbamate (830 mg, 96%) as a white solid.
Reaction SMILES: [C:1]([N:20]1[N:24]=[N:23][C:22]([C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=2[CH:31]2[CH2:36][CH2:35][CH:34]([CH:37]=[O:38])[CH2:33][CH2:32]2)=[N:21]1)([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.CCC(C)[BH-](C(C)CC)C(C)CC.[Li+]>C1COCC1>[C:1]([N:20]1[N:24]=[N:23][C:22]([C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=2[CH:31]2[CH2:36][CH2:35][CH:34]([CH2:37][OH:38])[CH2:33][CH2:32]2)=[N:21]1)([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)([C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1)[C:14]1[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=1
Reactant: O=CC1CCC(c2ccccc2-c2nnn(C(c3ccccc3)(c3ccccc3)c3ccccc3)n2)CC1
Agent: CCC(C)[BH-](C(C)CC)C(C)CC
Agent: [Li+]
Solvent: C1CCOC1
Product: OCC1CCC(c2ccccc2-c2nnn(C(c3ccccc3)(c3ccccc3)c3ccccc3)n2)CC1
Temperature: -25 °C
Reaction time: 1 h
Yield: 81.7 %

Procedure:
A 50 ml round-bottom flask, equipped with a magnetic stirring bar, septum, and nitrogen inlet, was charged with 220 mg (0.44 mmol, 1.0 equiv) of 1-[2-(2-trityl-tetrazol-5-yl)phenyl]-4-formylcyclohexane (from Step G) and 4 ml THF (over sieves). Into this clear solution, after being cooled down to -25° C., was added 530 μl (1.0M solution in THF, 0.53 mmol, 1.2 equiv) L-Selectride solution. After one hour, another 530 μl of L-Selectride solution was added to push the reaction to completion. The reaction was quenched after 1.5 hours with saturated aqueous sodium bicarbonate solution. Ethyl acetate was added to dissolve the organics. Layers were separated, and the aqueous layer was extracted with 5×10 ml ethyl acetate. The combined organic portion was washed with saturated aqueous sodium bicarbonate solution, dried over anhydrous sodium sulfate, filtered, concentrated, and chromatographed on a silica gel column (3 cm×31 cm, 4:6:1=hexane:methylene chloride:ethyl acetate, 1% distilled triethylamine) to afford 180 mg (82%) of the title alcohol: Rf=0.32 (4:6:1=hexane:methylene chloride:ethyl acetate, 1% distilled triethylamine); 1H NMR δ3.71-3.67 (dd, CHCH2OH from one isomer), 3.38-3.32 (dd, CHCH2OH from the other isomer), 3.10-3.00 (tt, CH2CHCH2); 13C NMR δ68.6, 40.2, 40.0, 33.2, 29.4.
Reaction SMILES: Cl.[CH3:2][O:3][C:4](=[O:17])[C@H:5]([CH2:7][C:8]1[CH:13]=[C:12]([I:14])[C:11]([OH:15])=[C:10]([I:16])[CH:9]=1)[NH2:6].[Cl:18][C:19]1[CH:20]=[C:21]([NH:26][CH:27]([C:29](O)=[O:30])[CH3:28])[CH:22]=[CH:23][C:24]=1[Cl:25].N[C@H](C(O)=O)C>>[CH3:2][O:3][C:4](=[O:17])[C@H:5]([CH2:7][C:8]1[CH:9]=[C:10]([I:16])[C:11]([OH:15])=[C:12]([I:14])[CH:13]=1)[NH:6][C:29](=[O:30])[CH:27]([CH3:28])[NH:26][C:21]1[CH:22]=[CH:23][C:24]([Cl:25])=[C:19]([Cl:18])[CH:20]=1
Reactant: CC(Nc1ccc(Cl)c(Cl)c1)C(=O)O
Reactant: COC(=O)[C@@H](N)Cc1cc(I)c(O)c(I)c1
Agent: C[C@H](N)C(=O)O
Agent: Cl
Product: COC(=O)[C@H](Cc1cc(I)c(O)c(I)c1)NC(=O)C(C)Nc1ccc(Cl)c(Cl)c1

Procedure:
Following General Procedure D and using 3,5-diiodo-L-tyrosine methyl ester hydrochloride (Bachem) and N-(3,4-dichlorophenyl)-D,L-alanine (from Example A above), the title compound was prepared as a mixture of stereoisomers about alanine. The reaction was monitored by tlc (Rf=0.29 in 10% MeOH/CH2Cl2) and purification was by flash chromatography (10% methanol/methylene chloride).
Reaction SMILES: [O:1]=[C:2]1[CH:6]([NH:7]C(=O)OCC2C=CC=CC=2)[CH2:5][CH2:4][N:3]1[CH2:18][O:19][CH2:20][CH2:21][Si:22]([CH3:25])([CH3:24])[CH3:23].C([O-])=O.[NH4+]>CO.[Pd]>[NH2:7][CH:6]1[CH2:5][CH2:4][N:3]([CH2:18][O:19][CH2:20][CH2:21][Si:22]([CH3:24])([CH3:23])[CH3:25])[C:2]1=[O:1]
Reactant: C[Si](C)(C)CCOCN1CCC(NC(=O)OCc2ccccc2)C1=O
Agent: [Pd]
Agent: O=C[O-]
Agent: [NH4+]
Solvent: CO
Product: C[Si](C)(C)CCOCN1CCC(N)C1=O
Temperature: 55 °C
Yield: 59.1 %

Procedure:
A suspension of 10% Pd/C paste (1 g, 0.4400 mmol), benzyl N-[2-oxo-1-(2-trimethylsilylethoxy-methyl)-pyrrolidin-3-yl]carbamate (which may be prepared as described in Description 40) (7.2 g, 19.8 mmol) and ammonium formate (3.7 g, 58.6 mmol) in methanol (400 mL) was heated at a block temperature of 55° C. under N2 for 2 hours. The reaction was cooled to ambient temperature and filtered through Celite under N2 and washed with MeOH (2×25 mL). The filtrate was evaporated to a colourless oil. The oil was partitioned between DCM (75 mL) and water (75 mL). The latter was re-extracted with DCM (5×50 mL) then DCM/MeOH (9:1) (2×50 mL) and the combined organic extracts were dried (Na2SO4) and evaporated to a colourless oil, which was dried at room temperature under vacuum for 14 hours to give 3-amino-1-(2-trimethylsilylethoxymethyl)pyrrolidin-2-one (D41) 2.7 g (11.7 mmol=59% yield);
Reaction SMILES: [F:1][C:2]1[CH:33]=[C:32]([N+:34]([O-])=O)[CH:31]=[CH:30][C:3]=1[O:4][C:5]1[CH:6]=[C:7]2[C:11](=[CH:12][C:13]=1[C:14]1[CH:19]=[CH:18][C:17]([S:20]([CH3:23])(=[O:22])=[O:21])=[CH:16][CH:15]=1)[N:10]([CH:24]1[CH2:29][CH2:28][CH2:27][CH2:26][O:25]1)[N:9]=[CH:8]2>CCOC(C)=O.[Pd]>[F:1][C:2]1[CH:33]=[C:32]([CH:31]=[CH:30][C:3]=1[O:4][C:5]1[CH:6]=[C:7]2[C:11](=[CH:12][C:13]=1[C:14]1[CH:15]=[CH:16][C:17]([S:20]([CH3:23])(=[O:21])=[O:22])=[CH:18][CH:19]=1)[N:10]([CH:24]1[CH2:29][CH2:28][CH2:27][CH2:26][O:25]1)[N:9]=[CH:8]2)[NH2:34]
Reactant: CS(=O)(=O)c1ccc(-c2cc3c(cnn3C3CCCCO3)cc2Oc2ccc([N+](=O)[O-])cc2F)cc1
Agent: [Pd]
Solvent: CCOC(C)=O
Product: CS(=O)(=O)c1ccc(-c2cc3c(cnn3C3CCCCO3)cc2Oc2ccc(N)cc2F)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 82.4 %

Procedure:
To a solution of 5-(2-fluoro-4-nitrophenoxy)-6-(4-(methylsulfonyl)phenyl)-1-(tetrahydro-2H-pyran-2-yl)-1H-indazole (320 mg, 0.63 mmol) in EtOAc (50 mL) is added Pd/C (10%, 100 mg). The resulting mixture is degassed by evacuation and backfilled with H2 three times. It is stirred under an atmosphere of H2 at RT overnight. The solid is removed by filtration and the filtrate is concentrated. The residue is purified by silica gel column chromatography eluting with DCM:MeOH (20:1) to give the desired product (250 mg, 83% yield). MS (m/z): 482.1 (M+H).
Reaction SMILES: Cl.[NH:2]1[CH2:7][CH2:6][CH:5]([C:8]2[C:20]3[C:19]4[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=4[C:13](=[O:21])[NH:12][C:11]=3[N:10]([CH3:22])[N:9]=2)[CH2:4][CH2:3]1.C=O.[C:25](O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>O>[CH3:25][N:2]1[CH2:3][CH2:4][CH:5]([C:8]2[C:20]3[C:19]4[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=4[C:13](=[O:21])[NH:12][C:11]=3[N:10]([CH3:22])[N:9]=2)[CH2:6][CH2:7]1
Reactant: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Reactant: Cn1nc(C2CCNCC2)c2c3ccccc3c(=O)[nH]c21
Agent: C=O
Agent: Cl
Agent: [Na+]
Solvent: O
Product: CN1CCC(c2nn(C)c3[nH]c(=O)c4ccccc4c23)CC1
Reaction time: 1 h
Yield: 54.9 %

Procedure:
1-(Piperidin-4-yl)-3-methyl-pyrazolo[3,4-c]isoquinolin-5(4H)-one hydrochloride (1.0 g) obtained in Example 227 and 35% aqueous formalin solution (0.53 g) were suspended in water (20 mL), and sodium triacetoxyborohydride (1.3 g) was added at room temperature, and the mixture was stirred for 1 hr. After the completion of the reaction, the solvent was evaporated, and aqueous potassium carbonate solution was added to the obtained residue. The mixture was extracted with a mixed solvent (chloroform:methanol=10:1), and the organic layer was dried over magnesium sulfate. The solvent was evaporated, and ethanol was added to the precipitated crystals. The precipitated crystals was collected by filtration and washed with ethyl acetate to give 1-(1-methylpiperidin-4-yl)-3-methyl-pyrazolo[3,4-c]isoquinolin-5(4H)-one (0.51 g) as pale-brown crystals.
Reaction SMILES: C(O[C:5](=[O:7])C)(=O)C.C(O)=O.[Cl:11][C:12]1[C:13]([NH2:32])=[CH:14][C:15]2[N:19]=[C:18]([CH2:20][CH3:21])[N:17]([C:22]3[CH:27]=[CH:26][C:25]([CH2:28][CH2:29][Cl:30])=[CH:24][CH:23]=3)[C:16]=2[CH:31]=1>C1COCC1>[Cl:11][C:12]1[C:13]([NH:32][CH:5]=[O:7])=[CH:14][C:15]2[N:19]=[C:18]([CH2:20][CH3:21])[N:17]([C:22]3[CH:23]=[CH:24][C:25]([CH2:28][CH2:29][Cl:30])=[CH:26][CH:27]=3)[C:16]=2[CH:31]=1
Reactant: CCc1nc2cc(N)c(Cl)cc2n1-c1ccc(CCCl)cc1
Reactant: CC(=O)OC(C)=O
Solvent: C1CCOC1
Solvent: O=CO
Product: CCc1nc2cc(NC=O)c(Cl)cc2n1-c1ccc(CCCl)cc1
Temperature: 60 °C
Reaction time: 2 h
Yield: 67 %

Procedure:
A solution of acetic anhydride (0.14 ml) in THF (5 ml) was added formic acid (0.06 ml, 1.65 mmol) at 0° C. under nitrogen and the mixture was stirred at 60° C. for 2 h. Then the mixture was recooled to 0° C. and was added 6-Chloro-1-[4-(2-chloroethyl)phenyl]-2-ethyl-1H-benzimidazol-5-ylamine (Example 110, step 6, 100 mg, 0.3 mmol) in THF (2 ml). The mixture was stirred at room temperature for 2 h. The volafile component was removed under reduced pressure, and the residue was dissolved with ethyl acetate (100 ml). The organic layer was washed with 2N aqueous NaOH (50 ml), brine (50 ml), then dried (Na2SO4). After removal of solvent, the crude product was purified by flash column chromatography eluting with hexane/ethyl acetate (1:10) to afford 68 mg (67%) of the title compound as pale yellow solids.
Reaction SMILES: C[N:2](C)[CH:3]=[CH:4][C:5]([C:7]1[C:12](=[O:13])[CH:11]=[CH:10][N:9]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=2[N:20]2[CH2:25][CH2:24][O:23][CH2:22][CH2:21]2)[N:8]=1)=O.[C:27]1([NH:33]N)[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1>CO>[N:20]1([C:15]2[CH:16]=[CH:17][CH:18]=[CH:19][C:14]=2[N:9]2[CH:10]=[CH:11][C:12](=[O:13])[C:7]([C:5]3[N:33]([C:27]4[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=4)[N:2]=[CH:3][CH:4]=3)=[N:8]2)[CH2:21][CH2:22][O:23][CH2:24][CH2:25]1
Reactant: CN(C)C=CC(=O)c1nn(-c2ccccc2N2CCOCC2)ccc1=O
Reactant: NNc1ccccc1
Solvent: CO
Product: O=c1ccn(-c2ccccc2N2CCOCC2)nc1-c1ccnn1-c1ccccc1
Yield: 5.1 %

Procedure:
To a solution of 3-[3-(dimethylamino)prop-2-enoyl]-1-(2-morpholin-4-ylphenyl)pyridazin-4(1H)-one (crude, 870 mg, 2.46 mmol) 20 mL of methanol was added phenylhydrazine (400 mg, 3.69 mmol). The mixture was refluxed for 4 h and concentrated. The residue was dissolved in dichloromethane (20 mL), washed with 1N HCl aqueous solution and brine, dried over Na2SO4, and concentrated under reduced pressure. The residue was purified by prep-HPLC to give 1-(2-morpholin-4-ylphenyl)-3-(1-phenyl-1H-pyrazol-5-yl)pyridazin-4(1H)-one (50 mg, 5% for two steps) as a yellow solid.
Reaction SMILES: [CH:1]1([CH:5]([OH:15])[C:6]2[CH:14]=[CH:13][C:9]([C:10]([OH:12])=O)=[CH:8][CH:7]=2)[CH2:4][CH2:3][CH2:2]1.Cl.[NH2:17][CH2:18][CH2:19][C:20]([O:22][CH2:23][CH3:24])=[O:21].F[P-](F)(F)(F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2N=CC=CC=2N=N1.C(N(C(C)C)CC)(C)C>CN(C)C=O>[CH:1]1([CH:5]([OH:15])[C:6]2[CH:7]=[CH:8][C:9]([C:10]([NH:17][CH2:18][CH2:19][C:20]([O:22][CH2:23][CH3:24])=[O:21])=[O:12])=[CH:13][CH:14]=2)[CH2:2][CH2:3][CH2:4]1
Reactant: O=C(O)c1ccc(C(O)C2CCC2)cc1
Reactant: CCOC(=O)CCN
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CCOC(=O)CCNC(=O)c1ccc(C(O)C2CCC2)cc1
Reaction time: 1.5 h
Yield: 104.3 %

Procedure:
N,N-dimethylformamide (9.00 mL) was added to a vial containing 4-(cyclobutyl(hydroxy)methyl)benzoic acid (370 mg, 1.79 mmol), ethyl 3-aminopropanoate hydrochloride (551 mg, 3.59 mmol) and O-(7-azabenzotriazol-1-yl)-N,N,N′,N′ tetramethyluronium hexafluorophosphate (1.36 g, 3.59 mmol). Diisopropylethylamine (1.56 mL, 8.97 mmol) was then added. The reaction was stirred for 1.5 h, and was then concentrated. Purification by column chromatography (0-50% ethyl acetate in heptane) afforded ethyl 3-(4-(cyclobutyl(hydroxy)methyl)benzamido)propanoate (570 mg, 100% yield) as a white solid. 1H NMR (400 MHz, CDCl3) δ 7.73 (d, J=8.2 Hz, 2H), 7.38 (d, J=8.2 Hz, 2H), 4.63 (d, J=7.8 Hz, 1H), 4.17 (q, J=7.2 Hz, 2H), 3.72 (q, J=6.0 Hz, 2H), 2.64 (t, J=5.9 Hz, 2H), 2.61-2.54 (m, 1H), 2.08-1.95 (m, 2H), 1.88-1.75 (m, 4H), 1.27 (t, J=7.1 Hz, 3H). MS (M+1): 306.3.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([NH:18][C:19](=O)[C:20]2[CH:25]=[CH:24][C:23]([C:26]([CH3:35])([CH3:34])[CH2:27][N:28]3[CH2:33][CH2:32][O:31][CH2:30][CH2:29]3)=[CH:22][CH:21]=2)=[C:6]([CH:17]=1)[C:7]([NH:9][C:10]1[CH:15]=[CH:14][C:13]([Cl:16])=[CH:12][N:11]=1)=[O:8].C1COCC1>Cl.O1CCOCC1>[Cl:1][C:2]1[CH:17]=[C:6]2[C:5](=[CH:4][CH:3]=1)[N:18]=[C:19]([C:20]1[CH:25]=[CH:24][C:23]([C:26]([CH3:35])([CH3:34])[CH2:27][N:28]3[CH2:33][CH2:32][O:31][CH2:30][CH2:29]3)=[CH:22][CH:21]=1)[N:9]([C:10]1[CH:15]=[CH:14][C:13]([Cl:16])=[CH:12][N:11]=1)[C:7]2=[O:8]
Reactant: CC(C)(CN1CCOCC1)c1ccc(C(=O)Nc2ccc(Cl)cc2C(=O)Nc2ccc(Cl)cn2)cc1
Agent: Cl
Solvent: C1COCCO1
Solvent: C1CCOC1
Product: CC(C)(CN1CCOCC1)c1ccc(-c2nc3ccc(Cl)cc3c(=O)n2-c2ccc(Cl)cn2)cc1
Temperature: 25 °C

Procedure:
A solution of the product from Example 197 (15.0 mg, 0.028 mmol) in 5 ml of 4N HCl in dioxane and 0.5 mL of THF was refluxed for 6 hr. The mixture was cooled to rt and purified with reverse phase HPLC to give the desired product as white solid. MS found: (M+1)+=509.1.
Reaction SMILES: [OH:1][CH2:2][CH2:3][C:4]1[CH:9]=[CH:8][C:7]([CH2:10][CH:11]([O:17][CH:18]([CH3:20])[CH3:19])[C:12]([O:14]CC)=[O:13])=[CH:6][CH:5]=1.[C:21]1([N:27]=[C:28]=[O:29])[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1>>[CH:18]([O:17][CH:11]([CH2:10][C:7]1[CH:6]=[CH:5][C:4]([CH2:3][CH2:2][O:1][C:28](=[O:29])[NH:27][C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)=[CH:9][CH:8]=1)[C:12]([OH:14])=[O:13])([CH3:19])[CH3:20]
Reactant: CCOC(=O)C(Cc1ccc(CCO)cc1)OC(C)C
Reactant: O=C=Nc1ccccc1
Product: CC(C)OC(Cc1ccc(CCOC(=O)Nc2ccccc2)cc1)C(=O)O

Procedure:
Using ethyl 3-[4-(2-hydroxyethyl)phenyl]-2-isopropoxypropanoate and phenylisocyanate, the title compound was obtained in the same manner as described in Example 148.
Reaction SMILES: [CH:1]1([C@@:4]2([OH:22])[CH2:8][CH2:7][N:6](C(OCC3C=CC=CC=3)=O)[C@H:5]2[CH:19]([CH3:21])[CH3:20])[CH2:3][CH2:2]1>[Pd].O>[CH:1]1([C@:4]2([OH:22])[CH2:8][CH2:7][NH:6][C@H:5]2[CH:19]([CH3:20])[CH3:21])[CH2:3][CH2:2]1
Reactant: CC(C)[C@@H]1N(C(=O)OCc2ccccc2)CC[C@]1(O)C1CC1
Agent: [Pd]
Solvent: O
Product: CC(C)[C@@H]1NCC[C@@]1(O)C1CC1

Procedure:
By an operation in the same manner as in Reference Example 4 and using benzyl (2S,3S)-3-cyclopropyl-3-hydroxy-2-isopropylpyrrolidine-1-carboxylate (1.98 g) and 50% water containing-10% Pd/C (0.10 g), the title compound was obtained as a colorless solid (yield: 1.22 g, yield: 88%).
Reaction SMILES: [CH:1]([O:4][C:5]([N:7]1[CH2:12][CH2:11][CH:10]([CH:13]2[O:22][C:16]3=[CH:17][N:18]=[C:19](Cl)[CH:20]=[C:15]3[CH2:14]2)[CH2:9][CH2:8]1)=[O:6])([CH3:3])[CH3:2].[CH3:23][S:24]([N:27]1[CH2:32][CH:31]=[C:30](B2OC(C)(C)C(C)(C)O2)[CH2:29][CH2:28]1)(=[O:26])=[O:25]>>[CH:1]([O:4][C:5]([N:7]1[CH2:12][CH2:11][CH:10]([CH:13]2[O:22][C:16]3=[CH:17][N:18]=[C:19]([C:30]4[CH2:31][CH2:32][N:27]([S:24]([CH3:23])(=[O:26])=[O:25])[CH2:28][CH:29]=4)[CH:20]=[C:15]3[CH2:14]2)[CH2:9][CH2:8]1)=[O:6])([CH3:3])[CH3:2]
Reactant: CC1(C)OB(C2=CCN(S(C)(=O)=O)CC2)OC1(C)C
Reactant: CC(C)OC(=O)N1CCC(C2Cc3cc(Cl)ncc3O2)CC1
Product: CC(C)OC(=O)N1CCC(C2Cc3cc(C4=CCN(S(C)(=O)=O)CC4)ncc3O2)CC1

Procedure:
The title compound is prepared from 4-(5-chloro-2,3-dihydro-furo[2,3-c]pyridin-2-yl)-piperidine-1-carboxylic acid isopropyl ester and 1-(methylsulfonyl)-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1,2,3,6-tetrahydropyridine following a procedure analogous to that described in Example 28. LC (method 7): tR=1.03 min; Mass spectrum (ESI+): m/z=450 [M+H]+.
Reaction SMILES: [C:1]([O:5][CH3:6])(=[O:4])[CH:2]=[O:3].Br[CH:8]([CH2:13][OH:14])[C:9]([O:11][CH3:12])=[O:10].C(=O)([O-])[O-].[K+].[K+].C(=O)=O>CCCCCC>[O:14]1[CH2:13][CH:8]([C:9]([O:11][CH3:12])=[O:10])[O:3][CH:2]1[C:1]([O:5][CH3:6])=[O:4]
Reactant: COC(=O)C(Br)CO
Reactant: COC(=O)C=O
Agent: O=C([O-])[O-]
Agent: O=C=O
Agent: [K+]
Solvent: CCCCCC
Product: COC(=O)C1COC(C(=O)OC)O1
Reaction time: 8 h
Yield: 21.4 %

Procedure:
Methyl glyoxylate 11.3 g (0.128 mol) and methyl 2-bromo-3-hydroxypropionate 31 g (0.129 mol) were mixed and the mildly exothermic reaction allowed to cool. The mixture was then treated with hexane (50 ml) and 17.8 g (0.129 mol) potassium carbonate. Evolution of CO2 was sluggish; the mixture was warmed to 45° and allowed to stir overnight. The work-up as described in Example 1 yielded after ether removal, 13.0 g of a light yellow liquid. Distillation in vacuo gave 5.2 g (21%) of the title compound bp 84°-86° at 0.3 mm Hg as a clear colorless liquid. Analysis by GlPC indicated >96% purity, and the pmr spectrum indicated a mixture of trans & cis isomers approximately 70-80% trans.
Reaction SMILES: Cl.[CH3:2][N:3]([CH3:24])[C:4]([C:10]1[CH:15]=[CH:14][C:13]([NH:16][C:17]([C@H:19]2[CH2:23][CH2:22][CH2:21][NH:20]2)=[O:18])=[CH:12][CH:11]=1)=[N:5][S:6]([CH3:9])(=[O:8])=[O:7].[Cl:25][C:26]1[CH:31]=[CH:30][C:29]([N:32]=[C:33]=[O:34])=[CH:28][CH:27]=1>C(Cl)Cl>[CH3:2][N:3]([CH3:24])[C:4]([C:10]1[CH:11]=[CH:12][C:13]([NH:16][C:17]([C@H:19]2[CH2:23][CH2:22][CH2:21][N:20]2[C:33]([NH:32][C:29]2[CH:30]=[CH:31][C:26]([Cl:25])=[CH:27][CH:28]=2)=[O:34])=[O:18])=[CH:14][CH:15]=1)=[N:5][S:6]([CH3:9])(=[O:8])=[O:7]
Reactant: CN(C)C(=NS(C)(=O)=O)c1ccc(NC(=O)[C@H]2CCCN2)cc1
Reactant: O=C=Nc1ccc(Cl)cc1
Agent: Cl
Solvent: ClCCl
Product: CN(C)C(=NS(C)(=O)=O)c1ccc(NC(=O)[C@H]2CCCN2C(=O)Nc2ccc(Cl)cc2)cc1
Reaction time: 8 h

Procedure:
Part F: 10.6 mg (0.028 mmol) of the hydrochloride were dissolved in 2 mL of anhydrous CH2Cl2. 2 eq of TEA and 1 eq of p-chlorophenyl isocyanate were added, and the mixture was stirred under N2 atmosphere for 8 h. Volatiles were evaporated. 3 mL of CH2Cl2 were added and the mixture was washed twice with 1 mL of water, dried over MgSO4, and concentrated. The crude product was purified by prep HPLC to give the title compound. 1H NMR (500 MHz, CDCl3) δ 9.76 (s, 1H), 7.45–7.24 (m, 8H), 6.4 (s, 1H), 4.72 (d, J=5 Hz, 1H), 3.6 (m, 1H), 3.45 (m, 1H), 3.25 (s, 3H) 2.93 (s, 3H), 2.84 (s, 3H), 2.65 (m, 1H), 2.3–1.9 (m, 3H), ppm. LC-MS (ESI) 492.15 [M+H]+, tR=4.928 min (Shimadzu Phenomenex S5 ODS 4.6×50 mm Luna flow rate 2.5 ml/mn; detection at 220 nM; Gradient elution 0% to 100% B over 8 min; (A=10% MeOH, 90% H2O, 0.2% H3PO4 & B=90% MeOH, 10% H2O, 0.2% H3PO4). HRMS (ESI) m/z calcd for C22H27N5O4SCl [M+H]+ 492.14724, found 492.1506.
Reaction SMILES: C=O.[CH3:3][C:4]1[S:13][C:12]2[NH:11][C:10]3[CH:14]=[CH:15][CH:16]=[CH:17][C:9]=3[N:8]=[C:7]([N:18]3[CH2:23][CH2:22][NH:21][C@@H:20]([CH2:24][C@@H:25]([C:27]4[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=4)[OH:26])[CH2:19]3)[C:6]=2[CH:5]=1.[C:33](O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>C(Cl)Cl.C(=O)(O)[O-].[Na+]>[CH3:33][N:21]1[CH2:22][CH2:23][N:18]([C:7]2[C:6]3[CH:5]=[C:4]([CH3:3])[S:13][C:12]=3[NH:11][C:10]3[CH:14]=[CH:15][CH:16]=[CH:17][C:9]=3[N:8]=2)[CH2:19][C@@H:20]1[CH2:24][C@@H:25]([C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1)[OH:26]
Reactant: Cc1cc2c(s1)Nc1ccccc1N=C2N1CCN[C@@H](C[C@H](O)c2ccccc2)C1
Reactant: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: C=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Product: Cc1cc2c(s1)Nc1ccccc1N=C2N1CCN(C)[C@@H](C[C@H](O)c2ccccc2)C1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 42.6 %

Procedure:
Add formaldehyde (33 μL, 0.42 mmol, 37% in water) to a solution of (S,S)-2-[4-(2-methyl-4H-3-thia-4,9-diaza-benzo[f]azulen-10-yl)-piperazin-2-yl]-1-phenyl-ethanol (160 mg, 0.38 mmol) in methylene chloride (6 mL). Stir 15 min at ambient temperature. Add sodium triacetoxyborohydride (121 mg, 0.57 mmol) and stir 2 h at ambient temperature. Dilute with saturated sodium bicarbonate solution and extract with methylene chloride. Dry the extracts with sodium sulfate, filter and concentrate the filtrate. Purify by radial silica gel chromatography using a 2 mm plate and 2N ammonia in methanol-methylene chloride (1%–5%) as the eluent to give 70 mg (42%) of the title compound: mass spectrum (ion spray): m/z=433 (M+1), 431 (M−1). HR-MS calculated for C25H29N4OS: 433.2062. Found 433.2061. 1H NMR (DMSO-d6): δ 7.60 (s, 1H), 7.36–7.17 (m, 5H), 6.88–6.75 (m, 3H), 6.68 (br d, 1H), 6.35 (s, 1H), 5.34 (br d, 1H), 4.60–4.50 (m, 1H), 3.85 (br d, 1H), 3.70 (br d, 1H), 3.04–2.92 (m, 1H), 2.85–2.66 (m, 2H), 2.29 (s, 3H), 2.17 (s, 3H), 2.20–2.10 (m, 1H) 2.08–1.98 (m, 1H), 1.97–1.85 (m, 1H), 1.66–1.52 (m, 1H).
Reaction SMILES: C(N(CC)CC)C.[CH2:8]([O:17][C:18](=[O:21])[NH:19][OH:20])[CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH3:16].O1CCOCC1.[C:28]1([S:34](Cl)(=[O:36])=[O:35])[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1>O>[CH2:8]([O:17][C:18](=[O:21])[NH:19][O:20][S:34]([C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1)(=[O:36])=[O:35])[CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH3:16]
Reactant: CCCCCCCCCOC(=O)NO
Reactant: O=S(=O)(Cl)c1ccccc1
Solvent: O
Solvent: CCN(CC)CC
Solvent: C1COCCO1
Product: CCCCCCCCCOC(=O)NOS(=O)(=O)c1ccccc1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
20.4 Parts of triethylamine are added to a stirred mixture of 40.6 parts of nonyl-N-hydroxycarbamate, 100 parts of dioxan and 35.3 parts of benzene sulphonyl chloride at 0° C keeping the pH in the range 2 to 5. The mixture is stirred for 18 hours at 25° C then added to 500 parts of water. The oily product is separated into 300 parts of toluene and the solution is washed with water, dried and evaporated at 40° l C under reduced pressure to give 72 parts of nonyl-N-benzenesulphonyloxycarbamate as a colourless oil.
Reaction SMILES: [OH-].[K+].[CH:3]([O:6][C:7]1[C:8]([CH3:17])=[N:9][CH:10]=[C:11]([CH:16]=1)[C:12]([O:14]C)=[S:13])([CH3:5])[CH3:4]>O.CO>[CH:3]([O:6][C:7]1[C:8]([CH3:17])=[N:9][CH:10]=[C:11]([CH:16]=1)[C:12]([OH:14])=[S:13])([CH3:5])[CH3:4]
Reactant: COC(=S)c1cnc(C)c(OC(C)C)c1
Agent: [K+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: Cc1ncc(C(O)=S)cc1OC(C)C
Temperature: 25 °C
Reaction time: 6 h

Procedure:
Potassium hydroxide (770 mg) in water (8 mL) is added to a solution of methyl 5-isopropyloxy-6-methylthionicotinoate (1.1 g) in methanol (15 mL) and the mixture stirred at room temperature for 6 hours. After concentrating in vacuo the residue is dissolved in water and acidified to pH 1 with concentrated aqueous hydrochloric acid. The mixture is extracted with ethyl acetate, the extracts washed with water and dried (MgSO4). The solvent is removed in vacuo to give 5-isopropyloxy-6-methylthionicotinic acid as a white solid, m.p. 154-5° C.