Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2([C:30]#[N:31])[CH2:13][CH2:12][C:11]([N:14]3[CH2:19][CH2:18][CH:17]([N:20]4[C:24]5[CH:25]=[CH:26][CH:27]=[CH:28][C:23]=5[NH:22][C:21]4=[O:29])[CH2:16][CH2:15]3)=[CH:10][CH2:9]2)=[CH:4][CH:3]=1.C[O-].[Na+].[BH4-].[Na+]>CO>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2([C:30]#[N:31])[CH2:13][CH2:12][CH:11]([N:14]3[CH2:15][CH2:16][CH:17]([N:20]4[C:24]5[CH:25]=[CH:26][CH:27]=[CH:28][C:23]=5[NH:22][C:21]4=[O:29])[CH2:18][CH2:19]3)[CH2:10][CH2:9]2)=[CH:4][CH:3]=1
Reactant: N#CC1(c2ccc(Cl)cc2)CC=C(N2CCC(n3c(=O)[nH]c4ccccc43)CC2)CC1
Agent: C[O-]
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Product: N#CC1(c2ccc(Cl)cc2)CCC(N2CCC(n3c(=O)[nH]c4ccccc43)CC2)CC1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a stirred mixture of 11 parts of 1-(4-chlorophenyl)-4-[4-(2,3-dihydro-2-oxo-1H-benzimidazol-1-yl)-1-piperidinyl]-3-cyclohexene-1-carbonitrile, 5 parts of sodium methoxide solution 30% and 320 parts of methanol are added portionwise 3 parts of sodium borohydride. Upon completion, stirring is continued first for one hour at reflux temperature and further overnight at room temperature. The reaction mixture is poured onto water. The precipitated product is filtered off and boiled in methanol. The product is filtered off and dried, yielding 5.3 parts of 1-(4-chlorophenyl)-4-[4-(2,3-dihydro-2-oxo-1H-benzimidazol-1-yl)-1-piperidinyl]cyclohexanecarbonitrile; mp. 299° C.
Reaction SMILES: [Cl:1][C:2]1[C:17]([Cl:18])=[CH:16][CH:15]=[CH:14][C:3]=1[CH2:4][CH:5]([C:8](=O)[C:9]([F:12])([F:11])[F:10])[C:6]#[N:7].O.[NH2:20][NH2:21]>C(O)C>[Cl:1][C:2]1[C:17]([Cl:18])=[CH:16][CH:15]=[CH:14][C:3]=1[CH2:4][C:5]1[C:8]([C:9]([F:10])([F:11])[F:12])=[N:20][NH:21][C:6]=1[NH2:7]
Reactant: N#CC(Cc1cccc(Cl)c1Cl)C(=O)C(F)(F)F
Reactant: NN
Solvent: CCO
Solvent: O
Product: Nc1[nH]nc(C(F)(F)F)c1Cc1cccc(Cl)c1Cl
Temperature: 25 °C
Yield: 15.3 %

Procedure:
To a solution of 2-(2,3-dichlorobenzyl)-4,4,4-trifluoro-3-oxobutanenitrile (10.0 g, 33.77 mmol) in ethanol (800 mL) was added hydrazine hydrate (1.86 g, 37.15 mmol) and the resulting solution was stirred under reflux for 16 h. The mixture was cooled to room temperature and concentrated. The residue was purified by silica gel column (petroleum ether/ethyl acetate=2/1) and reverse-phase Prep-HPLC to provide the titled compound (1.6 g, 15%) as a yellow oil; LC/MS: MS (ES+) m/e 310 (MH+); 1H NMR (300 MHz, DMSO-d6) δ ppm 3.85 (s, 2H), 6.78 (dd, J=1.2, 7.8 Hz, 1H), 7.25 (t, J=7.8 Hz, 1H), 7.47 (dd, J=1.2, 7.8 Hz, 1H).
Reaction SMILES: [CH3:1][C:2]12[O:11][C:5]([CH3:12])([CH:6]([N+:8]([O-:10])=[O:9])[CH2:7]1)[CH:4]=[CH:3]2.[H][H]>C.[Pd].C(O)C>[CH3:12][C:5]12[O:11][C:2]([CH3:1])([CH2:3][CH2:4]1)[CH2:7][CH:6]2[N+:8]([O-:10])=[O:9]
Reactant: [H][H]
Reactant: CC12C=CC(C)(O1)C([N+](=O)[O-])C2
Agent: [Pd]
Solvent: CCO
Product: CC12CCC(C)(O1)C([N+](=O)[O-])C2
Yield: 86.2 %

Procedure:
5.5 g of 1,4-dimethyl-5-nitro-7-oxabicyclo[2.2.1]hept-2-ene was placed in a 1/2 liter Parr bomb with 50 ml of ethanol and 10% palladium on powdered charcoal catalyst. The bomb was charged with hydrogen gas under 50 lb pressure. After using 3 lb of hydrogen gas, the reaction mixture was removed from the bomb, filtered to remove the catalyst, and stripped. The residue taken up in ether, was washed with water, dried (MgSO4), filtered and stripped to yield 4.8 g of the desired product as a brownish oil.
Reaction SMILES: [CH:1]1([CH2:6][CH:7]([C:11]2[CH:16]=[CH:15][C:14]([C:17]#[C:18][CH2:19][N:20]3[CH2:25][CH2:24][O:23][CH2:22][CH2:21]3)=[CH:13][CH:12]=2)[C:8]([OH:10])=O)[CH2:5][CH2:4][CH2:3][CH2:2]1.F[P-](F)(F)(F)(F)F.N1(O[P+](N(C)C)(N(C)C)N(C)C)C2C=CC=CC=2N=N1.C(N(CC)CC)C.[NH2:60][C:61]1[S:62][CH:63]=[CH:64][N:65]=1>C(Cl)Cl>[CH:1]1([CH2:6][CH:7]([C:11]2[CH:12]=[CH:13][C:14]([C:17]#[C:18][CH2:19][N:20]3[CH2:21][CH2:22][O:23][CH2:24][CH2:25]3)=[CH:15][CH:16]=2)[C:8]([NH:60][C:61]2[S:62][CH:63]=[CH:64][N:65]=2)=[O:10])[CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: Nc1nccs1
Reactant: O=C(O)C(CC1CCCC1)c1ccc(C#CCN2CCOCC2)cc1
Agent: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: O=C(Nc1nccs1)C(CC1CCCC1)c1ccc(C#CCN2CCOCC2)cc1
Yield: 71.3 %

Procedure:
A solution of 3-cyclopentyl-2-[4-(3-morpholin-4-yl-prop-1-ynyl)-phenyl]-propionic acid (171 mg, 0.50 mmol), benzotriazol-1-yloxytris(dimethylamino)phosphonium hexafluorophosphate (332 mg, 0.75 mmol), triethylamine (0.21 mL, 1.50 mmol) and 2-aminothiazole (86 mg, 0.86 mmol) in methylene chloride (5 mL) was stirred at 25° C. for 2 h. At this time, the reaction was diluted with methylene chloride (10 mL). This solution was washed with water (1×10 mL), a 1N aqueous sodium hydroxide solution (1×10 mL), and a half-saturated aqueous sodium chloride solution (1×10 mL). The aqueous layers were back extracted with methylene chloride (1×10 mL). The combined organic extracts were dried over sodium sulfate, filtered, and concentrated in vacuo. Flash chromatography (Merck Silica gel 60, 230-400 mesh, 98/2 ethyl acetate/methanol) afforded 3-cyclopentyl-2-[4-(3-morpholin-4-yl-prop-1-ynyl)-phenyl]-N-thiazol-2-yl-propionamide (151 mg, 71.2%) as a white foam: EI-HRMS m/e calcd for C24H29N3O2S (M+) 423.1980, found 423.1980.
Reaction SMILES: C([O:5][C:6](=[O:46])[C:7]([O:10]/[N:11]=[C:12](/[C:33]1[N:34]=[C:35]([NH:38]C(OC(C)(C)C)=O)[S:36][CH:37]=1)\[C:13]([NH:15][C@H:16]1[C@@H:19]([CH2:20][N:21]2[CH2:26][CH2:25][CH2:24][CH2:23][C:22]2=[O:27])[N:18]([S:28]([OH:31])(=[O:30])=[O:29])[C:17]1=[O:32])=[O:14])([CH3:9])[CH3:8])(C)(C)C.C(O)(C(F)(F)F)=O>C(Cl)Cl>[NH2:38][C:35]1[S:36][CH:37]=[C:33](/[C:12](=[N:11]/[O:10][C:7]([CH3:9])([CH3:8])[C:6]([OH:46])=[O:5])/[C:13](=[O:14])[NH:15][C@H:16]2[C@@H:19]([CH2:20][N:21]3[CH2:26][CH2:25][CH2:24][CH2:23][C:22]3=[O:27])[N:18]([S:28]([OH:31])(=[O:29])=[O:30])[C:17]2=[O:32])[N:34]=1
Reactant: CC(C)(C)OC(=O)Nc1nc(/C(=N/OC(C)(C)C(=O)OC(C)(C)C)C(=O)N[C@@H]2C(=O)N(S(=O)(=O)O)[C@@H]2CN2CCCCC2=O)cs1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CC(C)(O/N=C(\C(=O)N[C@@H]1C(=O)N(S(=O)(=O)O)[C@@H]1CN1CCCCC1=O)c1csc(N)n1)C(=O)O
Yield: 19.9 %

Procedure:
Followed the general procedure for the acid mediated deprotection using (3S,4R)-3-((Z)-2-(((1-(tert-butoxy)-2-methyl-1-oxopropan-2-yl)oxy)imino)-2-(2-((tert-butoxycarbonyl)amino)thiazol-4-yl)acetamido)-2-oxo-4-((2-oxopiperidin-1-yl)methyl)azetidine-1-sulfonic acid (34 mg, 0.049 mmol), DCM (494 μL) and TFA (228 μl, 2.96 mmol). The crude residue purified by reverse phase prep HPLC (XSelect CSH, 30×100 mm, 5 μm, C18 column; ACN-water with 0.1% formic acid modifier, 60 mL/min), affording the title compound (5.2 mg, 17%) as a white powder. LCMS: Rt=0.63 min, m/z=533.1 (M+1) Method 2m_acidic_polar; 1H NMR (400 MHz, D2O) δ 7.02 (s, 1H), 5.27 (d, J=5.5 Hz, 1H), 4.59-4.48 (m, 1H), 3.61 (d, J=4.7 Hz, 2H), 3.48-3.37 (m, 1H), 3.32 (d, J=5.9 Hz, 1H), 2.34-2.13 (m, 2H), 1.78-1.57 (m, 4H), 1.39 (br s, 6H).
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].[CH3:7][C:8]1[C:14]([OH:15])=[CH:13][CH:12]=[CH:11][C:9]=1[OH:10].[CH2:16](Cl)[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1>CN(C)C=O>[CH2:16]([O:10][C:9]1[C:8]([CH3:7])=[C:14]([OH:15])[CH:13]=[CH:12][CH:11]=1)[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1
Reactant: ClCc1ccccc1
Reactant: Cc1c(O)cccc1O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: Cc1c(O)cccc1OCc1ccccc1
Temperature: 80 °C
Yield: 22.8 %

Procedure:
Anhydrous potassium carbonate (30.4 g.) was added to a stirred solution of 2-methylresorcinol (24.8 g) in N,N-dimethylformamide (DMF, 250 ml) and benzyl chloride (25.3 g) was added over 15 minutes. The mixture was heated to 80° C. and maintained at this temperature overnight with continued stirring. On cooling the DMF was removed in vacuo to give an oil which was partitioned between water and ether. The dried ethereal phase was evaporated and chromatographed on silica eluting with chloroform to give 9.78 g (23%) of the title compound of mp 58°-59° C. (Found; C, 78.16; H, 6.63; C14H14O2 requires C, 78.48, H, 6.58%).
Reaction SMILES: Br[CH:2]1[S:6][C:5](=[O:7])[NH:4][C:3]1=[O:8].[CH3:9][C:10]1[CH:15]=[CH:14][CH:13]=[C:12]([SH:16])[N:11]=1>>[CH3:9][C:10]1[CH:15]=[CH:14][CH:13]=[C:12]([S:16][CH:2]2[S:6][C:5](=[O:7])[NH:4][C:3]2=[O:8])[N:11]=1
Reactant: O=C1NC(=O)C(Br)S1
Reactant: Cc1cccc(S)n1
Product: Cc1cccc(SC2SC(=O)NC2=O)n1

Procedure:
This compound was prepared from 5-bromo-thiazolidine-2,4-dione and 2-methyl-6-mercaptopyridine (A. D. Dunn, R. Norfie, J. L'Hostis,and S. Marjot J.Prak. Chem.-Chem. Zt. 1992, 334, 119-125) according to the procedure described in Example 1: mp 114-115.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1/[CH:7]=[CH:8]/[CH2:9][CH2:10][C:11]([OH:13])=[O:12].[CH3:14][C:15]1(C)C2(CS(O)(=O)=O)C(CC1CC2)=O>C(O)C>[N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1/[CH:7]=[CH:8]/[CH2:9][CH2:10][C:11]([O:13][CH2:14][CH3:15])=[O:12]
Reactant: CC1(C)C2CCC1(CS(=O)(=O)O)C(=O)C2
Reactant: O=C(O)CC/C=C/c1ccccn1
Solvent: CCO
Product: CCOC(=O)CC/C=C/c1ccccn1
Reaction time: 2 h
Yield: 99.3 %

Procedure:
To a solution of (4E)-5-(2-pyridyl)-4-pentenoic acid (1.6 g) in ethanol (50 ml) was added d-camphor-10-sulfonic acid (2.3 g), and the mixture was heated under reflux with a reflux condenser containing 3 Å molecular sieves. After 2 hours, the mixture was evaporated, diluted with saturated aqueous sodium bicarbonate and then extracted with ethyl acetate. The organic layers were washed with brine, dried over sodium sulfate and evaporated in vacuo to give ethyl (4E)-5-(2-pyridyl)-4-pentenoate (1.84 g).
Reaction SMILES: Cl[C:2]1[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[C:4]([N+:10]([O-:12])=[O:11])[CH:3]=1.[O:13]1[CH2:18][CH2:17][CH2:16][CH2:15][CH:14]1[N:19]1[C:23](B2OC(C)(C)C(C)(C)O2)=[CH:22][CH:21]=[N:20]1.C(=O)([O-])[O-].[Na+].[Na+].O>CN(C=O)C.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.Cl[Pd]Cl>[N+:10]([C:4]1[CH:3]=[C:2]([C:23]2[N:19]([CH:14]3[CH2:15][CH2:16][CH2:17][CH2:18][O:13]3)[N:20]=[CH:21][CH:22]=2)[CH:9]=[CH:8][C:5]=1[C:6]#[N:7])([O-:12])=[O:11]
Reactant: N#Cc1ccc(Cl)cc1[N+](=O)[O-]
Reactant: CC1(C)OB(c2ccnn2C2CCCCO2)OC1(C)C
Agent: Cl[Pd]Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: N#Cc1ccc(-c2ccnn2C2CCCCO2)cc1[N+](=O)[O-]
Temperature: 90 °C
Yield: 72.4 %

Procedure:
To a solution of 4-chloro-2-nitrobenzonitrile (15 g, 82 mmol) and 1-(tetrahydro-2H-pyran-2-yl)-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (27.4 g, 99 mmol) in 300 ml of DMF were added bis(triphenylphosphine)palladium (II) chloride (1.12 g; 1.64 mmol), sodium carbonate (22.7 g; 0.16 mol) and water (30 ml). The reaction mixture was heated at 90° C. for 4.5 h, cooled and poured into 500 ml of water. The water phase was extracted twice with EtOAc, and the combined organic fractions were washed with saturated NaHCO3— solution and brine, dried over Na2SO4 and evaporated. The evaporation residual was suspended to EtOH (100 ml) and the remaining solids were filtered to give 17.7 g (72%) of the title compound. 1H-NMR (400 MHz; d6-DMSO): δ 1.52-1.68 (m, 3H), 1.78-1.87 (m, 1H), 1.91-2.00 (m, 1H), 2.31-2.47 (m, 1H), 3.67-3.76 (m, 1H), 3.99-4.06 (m, 1H), 5.32 (dd, 1H), 6.84 (d, 1H), 7.69 (d, 1H), 8.13 (dd, 1H), 8.32 (d, 1H), 8.60 (d, 1H).
Reaction SMILES: C([O:3][CH2:4][CH2:5][CH2:6][N:7]1[C:12](=[O:13])[C:11]2[C:14]([CH2:25][CH2:26][CH:27]([CH3:29])[CH3:28])=[C:15]([C:18]3[CH:23]=[CH:22][CH:21]=[C:20]([Cl:24])[CH:19]=3)[N:16]=[CH:17][C:10]=2[N:9]([CH3:30])[C:8]1=[O:31])=O.O[Li].O>C1COCC1.O.CC(=O)OCC>[Cl:24][C:20]1[CH:19]=[C:18]([C:15]2[N:16]=[CH:17][C:10]3[N:9]([CH3:30])[C:8](=[O:31])[N:7]([CH2:6][CH2:5][CH2:4][OH:3])[C:12](=[O:13])[C:11]=3[C:14]=2[CH2:25][CH2:26][CH:27]([CH3:29])[CH3:28])[CH:23]=[CH:22][CH:21]=1
Reactant: CC(C)CCc1c(-c2cccc(Cl)c2)ncc2c1c(=O)n(CCCOC=O)c(=O)n2C
Agent: [Li]O
Solvent: O
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: CC(C)CCc1c(-c2cccc(Cl)c2)ncc2c1c(=O)n(CCCO)c(=O)n2C
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 54 %

Procedure:
To a solution of 3-(6-(3-chlorophenyl)-5-isopentyl-1-methyl-2,4-dioxo-1,2-dihydropyrido[3,4-d]pyrimidin-3(4H)-yl)propyl formate (14 mg, 0.0316 mmol) in THF (0.5 mL) and H2O (0.5 mL) was added LiOH.H2O (2.46 mg, 0.058 mmol). The reaction was stirred at RT for 30 min then diluted with EA (5 mL). The organic layer was washed with brine (5 mL) dried over Na2SO4 and concentrated to a residue which was purified by Prep HPLC to give 6-(3-chlorophenyl)-3-(3-hydroxypropyl)-5-isopentyl-1-methylpyrido[3,4-d]pyrimidine-2,4(1H,3H)-dione (7.1 mg, 54% yield) as a white solid. 1H NMR (CDCl3) δ: 8.65 (s, 1H), 7.46-7.37 (m, 3H), 7.31-7.27 (m, 1H), 4.28 (t, J=6.1 Hz, 2H), 3.72 (s, 3H), 3.66-3.53 (m, 2H), 3.24-3.13 (m, 2H), 3.07 (s, 1H), 2.02-1.89 (m, 2H), 1.54 (td, J=13.2, 6.6 Hz, 1H), 1.40-1.30 (m, 2H), 0.78 (d, J=6.6 Hz, 6H). LCMS: MH+ 416 and TR=3.048 min.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:12][CH:11]([O:13]CC2C=CC=CC=2)[CH2:10][CH:9]1[C:21]([CH3:29])([CH3:28])[O:22][SiH2:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:7])([CH3:4])([CH3:3])[CH3:2]>C(OCC)(=O)C>[C:1]([O:5][C:6]([N:8]1[CH2:12][CH:11]([OH:13])[CH2:10][CH:9]1[C:21]([CH3:29])([CH3:28])[O:22][SiH2:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)OC(=O)N1CC(OCc2ccccc2)CC1C(C)(C)O[SiH2]C(C)(C)C
Solvent: CCOC(C)=O
Product: CC(C)(C)OC(=O)N1CC(O)CC1C(C)(C)O[SiH2]C(C)(C)C
Reaction time: 12 h

Procedure:
The 4-benzyloxy-2-(t-butyl-dimethyl-silanyloxymethyl)-pyrrolidine-1-carboxylic acid t-butyl ester (267.49 mg, 0.63 mmol) was taken up in ethyl acetate in a Paar vessel. The solution was flushed with argon and Pd/C (100 mg) was added to the vessel. The argon atmosphere was replaced by hydrogen at 50 psi. The vessel was shaken for 12 h. The hydrogen atmosphere was replaced by argon and the solution was filtered through a celite pad. The pad was washed twice with ethyl acetate. The solvent was removed under reduced pressure. The product was used without further purification. Yield 192.15 mg. C16H33NO4Si ms m/e=3.32.2 (M+H).
Reaction SMILES: C[O:2][CH:3](OC)[CH2:4][CH2:5][N:6]1[CH:11]=[C:10]([C:12]2[CH:17]=[CH:16][CH:15]=[C:14]([F:18])[N:13]=2)[C:9](=[O:19])[NH:8][C:7]1=[O:20]>C1COCC1>[F:18][C:14]1[N:13]=[C:12]([C:10]2[C:9](=[O:19])[NH:8][C:7](=[O:20])[N:6]([CH2:5][CH2:4][CH:3]=[O:2])[CH:11]=2)[CH:17]=[CH:16][CH:15]=1
Reactant: COC(CCn1cc(-c2cccc(F)n2)c(=O)[nH]c1=O)OC
Solvent: C1CCOC1
Product: O=CCCn1cc(-c2cccc(F)n2)c(=O)[nH]c1=O
Temperature: 25 °C
Reaction time: 2 h
Yield: 111.4 %

Procedure:
1-(3,3-Dimethoxy-propyl)-5-(6-fluoro-pyridin-2-yl)-1H-pyrimidine-2,4-dione (Prep76, 179 mg, 0.58 mmol) was dissolved in THF (4 ml) and 2N HClaq (0.5 ml) was added. The solution was then stirred at room temperature for 2 hours. THF was evaporated under vacuum and the aqueous residue was lyophilized to give 170 mg of a yellow powder that was used in the next step without further purification (quantitative yield).
Reaction SMILES: C([O:8][C:9]1[C:10]2[N:11]([C:18]([CH3:22])=[C:19]([CH3:21])[N:20]=2)[CH:12]=[C:13]([CH2:15][O:16][CH3:17])[CH:14]=1)C1C=CC=CC=1>C(O)C.[Pd]>[OH:8][C:9]1[C:10]2[N:11]([C:18]([CH3:22])=[C:19]([CH3:21])[N:20]=2)[CH:12]=[C:13]([CH2:15][O:16][CH3:17])[CH:14]=1
Reactant: COCc1cc(OCc2ccccc2)c2nc(C)c(C)n2c1
Agent: [Pd]
Solvent: CCO
Product: COCc1cc(O)c2nc(C)c(C)n2c1
Yield: 57.6 %

Procedure:
A solution of 3.0 g (10.1 mmol) 8-benzyloxy-6-methoxymethyl-2,3-dimethyl-imidazo[1,2-a]pyridine in 50 ml ethanol is hydrogenated over 0.3 g 10% Pd/C (1 bar H2) for 1 h. The catalyst is filtered off and the filtrate is evaporated. The residue is crystallized from methanol/diethyl ether to give 1.2 g (57%) of the title compound as a colourless solid (m.p. 164-165° C.).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH2:9][CH2:10][NH2:11])[CH:6]=[CH:7][CH:8]=1.C(N(CC)CC)C.[CH3:19][CH2:20][O:21][C:22](Cl)=[O:23]>ClCCl>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH2:9][CH2:10][NH:11][C:22](=[O:23])[O:21][CH2:20][CH3:19])[CH:6]=[CH:7][CH:8]=1
Reactant: CCOC(=O)Cl
Reactant: COc1cccc(CCN)c1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCOC(=O)NCCc1cccc(OC)c1
Reaction time: 1 h
Yield: 108.3 %

Procedure:
To a solution of {2-[3-(methyloxy)phenyl]ethyl}amine (20 g, 132.3 mmol) and triethylamine (20 g, 198 mmol) in dichloromethane (150 mL) was added ethyl chloridocarbonate (17.7 g, 163 mmol) dropwise at 0° C. After being stirred for 1 h the solvent was removed under vacuum and the residue was washed with ethyl acetate. Following filtration, the filtrate was concentrated to afford ethyl {2-[3-(methyloxy)phenyl]ethyl}carbamate (32 g, crude, 100%). 1H NMR(CDCl3) δ: 7.15-7.25 (1H), 6.7-6.8 (3H), 4.72 (1H), 3.75 (3H), 3.4 (2H), 2.75 (2H), 2.0 (3H), 1.15-1.3(2H).
Reaction SMILES: Br.[F:2][C:3]1[CH:4]=[C:5]([C@:10]2([OH:18])[O:15][CH2:14][C@@H:13]([CH3:16])[NH:12][C@H:11]2[CH3:17])[CH:6]=[CH:7][C:8]=1[F:9].C(O)C.O.[BH4-].[Na+].Cl>O>[F:2][C:3]1[CH:4]=[C:5]([C@@H:10]([OH:18])[C@@H:11]([NH:12][C@H:13]([CH3:16])[CH2:14][OH:15])[CH3:17])[CH:6]=[CH:7][C:8]=1[F:9]
Reactant: C[C@@H]1CO[C@@](O)(c2ccc(F)c(F)c2)[C@H](C)N1
Agent: Br
Agent: Cl
Agent: [BH4-]
Solvent: CCO
Solvent: O
Product: C[C@H](CO)N[C@@H](C)[C@H](O)c1ccc(F)c(F)c1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
To a solution of (2S,3S,5R)-2-(3,4-difluorophenyl)-3,5-dimethyl-2-morpholinol hydrobromide (25.4 g, 0.078 mole) in 50--50 ethanol-water (300 ml) was added a solution of sodium borohydride (11.9 g, 0.31 mole) in water (120 ml) at 0° C. The resulting mixture was stirred for 16 hours at room temperature. The reaction mixture was treated with concentrated hydrochloric acid and concentrated under reduced pressure. The residue was dissolved in water, basified (40% aqueous sodium hydroxide), and extracted with dichloromethane. The organic layers were combined, washed with brine and dried (potassium carbonate) to give a solution of (1R,2S)-1-(3,4-difluorophenyl)-2-[[(1R)-2-hydroxy-1-methylethyl]amino]propanol in dichlomethane (500 ml). 50 ml of the solution was concentrated under reduced pressure to yield 1.9 g of the free base as a white solid. The free base was dissolved in diethyl ether and treated with ethereal hydrogen chloride. The hydrochloride salt was recrystallized from ethanol-diethyl ether mixtures to give 1.1 g of (1R,2S)-1-(3,4-difluorophenyl)-2-[[(1R)-2-hydroxy-1-methylethyl]amino]propanol hydrochloride as a white solid. m.p. 116°-117° C.
Reaction SMILES: [CH2:1]([O:5][C:6]1[CH:11]=[C:10](Cl)[N:9]=[CH:8][N:7]=1)[C:2]#[C:3][CH3:4].C(=O)([O-])[O-].[K+].[K+].Cl.[CH3:20][CH:21]1[CH:25]([CH3:26])[CH2:24][NH:23][CH2:22]1.[Cl-].[NH4+]>C(#N)C>[CH2:1]([O:5][C:6]1[CH:11]=[C:10]([N:23]2[CH2:24][CH:25]([CH3:26])[CH:21]([CH3:20])[CH2:22]2)[N:9]=[CH:8][N:7]=1)[C:2]#[C:3][CH3:4]
Reactant: CC1CNCC1C
Reactant: CC#CCOc1cc(Cl)ncn1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Cl-]
Solvent: CC#N
Product: CC#CCOc1cc(N2CC(C)C(C)C2)ncn1
Temperature: 70 °C
Reaction time: 4 h
Yield: 104.2 %

Procedure:
Into 3 ml of acetonitrile were added 0.30 g of 4-(2-butynyloxy)-6-chloropyrimidine, 0.68 g of potassium carbonate and 0.33 g of 3,4-dimethylpyrrolidine hydrochloride (cis and trans diastereomer mixture), and the mixture was stirred for 4 hours at 70° C. The reaction mixture was cooled to near room temperature, a saturated ammonium chloride aqueous solution was added therein, and the mixture was extracted with tert-butyl methyl ether three times. The organic layers were washed with a saturated sodium chloride aqueous solution, dried over anhydrous magnesium sulfate and concentrated. The residue was subjected to silica gel column chromatography to obtain 0.42 g of 4-(2-butynyloxy)-6-(3,4-dimethylpyrrolidin-1-yl) pyrimidine (hereinafter, referred to as Compound (37)).
Reaction SMILES: [NH2:1][C:2]1[O:3][CH2:4][C@:5]2([C:19]3[C:14](=[N:15][CH:16]=[C:17]([C:20]#[C:21][C:22]([OH:25])([CH3:24])[CH3:23])[CH:18]=3)[O:13][C:12]3[C:7]2=[CH:8][C:9]([OH:26])=[CH:10][CH:11]=3)[N:6]=1.CO.[CH3:29]S(O)(=O)=O.C(=O)([O-])[O-].[K+].[K+]>>[NH2:1][C:2]1[O:3][CH2:4][C@:5]2([C:19]3[C:14](=[N:15][CH:16]=[C:17]([C:20]#[C:21][C:22]([O:25][CH3:29])([CH3:23])[CH3:24])[CH:18]=3)[O:13][C:12]3[C:7]2=[CH:8][C:9]([OH:26])=[CH:10][CH:11]=3)[N:6]=1
Reactant: CS(=O)(=O)O
Reactant: CC(C)(O)C#Cc1cnc2c(c1)[C@]1(COC(N)=N1)c1cc(O)ccc1O2
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CO
Product: COC(C)(C)C#Cc1cnc2c(c1)[C@]1(COC(N)=N1)c1cc(O)ccc1O2

Procedure:
A vessel was charged with (S)-2′-amino-3-(3-hydroxy-3-methylbut-1-ynyl)-5′H-spiro[chromeno[2,3-b]pyridine-5,4′-oxazol]-7-ol (0.512 g, 1.457 mmol) in methanol (17.73 mL, 437 mmol). Methane sulfonic acid (0.945 mL, 14.57 mmol) was added, and the vial was sealed and placed in a 55° C. oil bath overnight. Potassium carbonate was added to quench the acid, and the mixture was filtered with the aid of DCM. The filtrate was evaporated, and the residue was soluble in MeOH/DCM, but some potassium carbonate still came through. The residue was purified by chromatography on a 50-g SNAP column, eluting with 0-100% of a 90:10:1 mixture of DCM/MeOH/NH4OH in DCM. The material thus obtained was rechromatographed to under the same conditions to give (S)-2′-amino-3-(3-methoxy-3-methylbut-1-ynyl)-5′H-spiro[chromeno[2,3-b]pyridine-5,4′-oxazol]-7-ol as a pale-yellow solid.
Reaction SMILES: [CH:1]([C@@H:3]1[CH2:8][C@H:7]([N:9]([C:14]([C:16]2[N:20]([CH2:21][CH2:22][CH2:23][CH2:24][O:25][CH3:26])[C:19]3[CH:27]=[CH:28][CH:29]=[CH:30][C:18]=3[N:17]=2)=[O:15])[CH2:10][CH:11]([CH3:13])[CH3:12])[CH2:6][N:5]([C:31]([O:33][C:34]([CH3:37])([CH3:36])[CH3:35])=[O:32])[CH2:4]1)=[O:2].[Cl-].[NH4+].[CH2:40]1COCC1>>[OH:2][CH:1]([C@@H:3]1[CH2:8][C@H:7]([N:9]([C:14]([C:16]2[N:20]([CH2:21][CH2:22][CH2:23][CH2:24][O:25][CH3:26])[C:19]3[CH:27]=[CH:28][CH:29]=[CH:30][C:18]=3[N:17]=2)=[O:15])[CH2:10][CH:11]([CH3:12])[CH3:13])[CH2:6][N:5]([C:31]([O:33][C:34]([CH3:35])([CH3:37])[CH3:36])=[O:32])[CH2:4]1)[CH3:40]
Reactant: COCCCCn1c(C(=O)N(CC(C)C)[C@H]2C[C@@H](C=O)CN(C(=O)OC(C)(C)C)C2)nc2ccccc21
Reactant: C1CCOC1
Agent: [Cl-]
Agent: [NH4+]
Product: COCCCCn1c(C(=O)N(CC(C)C)[C@H]2C[C@@H](C(C)O)CN(C(=O)OC(C)(C)C)C2)nc2ccccc21
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of tert-butyl (3R,5S)-3-formyl-5-[{[1-(4-methoxybutyl)-1H-benzimidazol-2-yl]carbonyl}(2-methylpropyl)amino]piperidine-1-carboxylate (150 mg) in THF (10 ml) was added 3M-methyl magnesium bromide-ether solution (0.3 ml), and the mixture was stirred at room temperature for 1 hr. The reaction mixture was poured into saturated aqueous ammonium chloride solution, and the mixture was extracted with ethyl acetate. The extract was washed with saturated brine, and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure. The residue was subjected to silica gel column chromatography, and a fraction eluted with ethyl acetate-hexane (1:1-1:0) was concentrated under reduced pressure to give the object product (100 mg).
Reaction SMILES: [CH2:1]([NH:3][CH:4]1[CH2:9][C:8]([CH3:11])([CH3:10])S[C:6]2[S:12][C:13]([S:15]([NH2:18])(=[O:17])=[O:16])=[CH:14][C:5]1=2)[CH3:2].Cl.OO[S:22]([O-:24])=[O:23].[K+]>CO.O>[CH2:1]([NH:3][CH:4]1[CH2:9][C:8]([CH3:11])([CH3:10])[S:22](=[O:24])(=[O:23])[C:6]2[S:12][C:13]([S:15]([NH2:18])(=[O:16])=[O:17])=[CH:14][C:5]1=2)[CH3:2]
Reactant: O=S([O-])OO
Reactant: CCNC1CC(C)(C)Sc2sc(S(N)(=O)=O)cc21
Agent: Cl
Agent: [K+]
Solvent: O
Solvent: CO
Product: CCNC1CC(C)(C)S(=O)(=O)c2sc(S(N)(=O)=O)cc21

Procedure:
A solution of 5,6-dihydro-4-ethylamino-6,6-dimethyl-4H thieno[2,3-b]thiopyran-2-sulfonamide (3.95 g, 0.013 mol) in methanol (85 ml) was acidified with 6.25N methanolic hydrogen chloride (2.1 ml). With stirring, a solution of `OXONE` (11.68 g, 0.019 mol) in water (65 ml) was added over 15 minutes. After stirring at ambient temperature for 17.5 hours, the mixture was filtered and the solid was washed with methanol. The combined filtrate and washings were concentrated in vacuo below 55° C. to remove methanol and the cloudy aqueous solution was basified with saturated sodium bicarbonate solution. The mixture was extracted with ethyl acetate (150 ml and 2×100 ml), and the combined extracts were washed twice with water, dried over sodium sulfate and evaporated in vacuo. The amorphous residue was converted to the crystalline hydrochloride salt using ethanolic hydrogen chloride to yield 2.16 g (44%) of analytically pure product melting at 255°-255.5° C.