Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][CH2:2][CH2:3][S:4][CH2:5][C:6]1[CH:10]=[CH:9][O:8][N:7]=1.Br.[N+:12]([CH:15]=[C:16](SC)[S:17][CH3:18])([O-:14])=[O:13]>>[N+:12]([CH:15]=[C:16]([S:17][CH3:18])[NH:1][CH2:2][CH2:3][S:4][CH2:5][C:6]1[CH:10]=[CH:9][O:8][N:7]=1)([O-:14])=[O:13]
Reactant: CSC(=C[N+](=O)[O-])SC
Reactant: NCCSCc1ccon1
Agent: Br
Product: CSC(=C[N+](=O)[O-])NCCSCc1ccon1

Procedure:
By the procedure of Example 8(i), 3-[(2-aminoethyl)-thiomethyl]isoxazole (from the hydrobromide (3.7 g)) is reacted with 1-nitro-2,2-bis-methylthioethylene (3.5 g) to give 1-nitro-2-methylthio-2-[2-(3-isoxazolylmethylthio)-ethylamino]ethylene (3.6 g) which, on reaction with methylamine by the procedure of Example 8(ii) gives the title product (3.0 g).
Reaction SMILES: [CH2:1]([C:3]1[CH:8]=[CH:7][C:6]([C:9]2[C:10]([C:17]3[CH:22]=[CH:21][N:20]=[CH:19][CH:18]=3)=[N:11][C:12]([CH:15]=O)=[CH:13][CH:14]=2)=[CH:5][CH:4]=1)[CH3:2].[NH2:23][CH2:24][CH2:25][CH2:26][P:27](=[O:30])([OH:29])[OH:28].[BH3-]C#N.[Na+]>CO>[CH2:1]([C:3]1[CH:8]=[CH:7][C:6]([C:9]2[C:10]([C:17]3[CH:22]=[CH:21][N:20]=[CH:19][CH:18]=3)=[N:11][C:12]([CH2:15][NH:23][CH2:24][CH2:25][CH2:26][P:27](=[O:28])([OH:30])[OH:29])=[CH:13][CH:14]=2)=[CH:5][CH:4]=1)[CH3:2]
Reactant: NCCCP(=O)(O)O
Reactant: CCc1ccc(-c2ccc(C=O)nc2-c2ccncc2)cc1
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CO
Product: CCc1ccc(-c2ccc(CNCCCP(=O)(O)O)nc2-c2ccncc2)cc1

Procedure:
Following General Procedure M, 3-(4-ethyl-phenyl)-[2,4′]-bipyridinyl-6-carbaldehyde (Compound 58, 50 mg, 0.17 mmol), (3-amino-propyl)-phosphonic acid (24 mg, 0.17 mmol), Bu4NOH (0.17 ml, 0.17 mmol, 1 M in MeOH) and NaCNBH3 (11 mg, 0.17 mmol) in MeOH (3 ml) were reacted to produce the title compound as a white solid.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([C:8]([O:10][CH3:11])=[O:9])[CH:5]=[N:6][CH:7]=1>[Rh].C(O)(=O)C>[CH3:11][O:10][C:8]([CH:4]1[CH2:3][CH:2]([OH:1])[CH2:7][NH:6][CH2:5]1)=[O:9]
Reactant: COC(=O)c1cncc(O)c1
Agent: [Rh]
Solvent: CC(=O)O
Product: COC(=O)C1CNCC(O)C1
Reaction time: 18 h

Procedure:
Methyl 5-hydroxypyridine-3-carboxylate (22 g, 140 mmol), acetic acid (250 mL) and rhodium on alumina (2.2 g, 21 mmol) were added to a 1 L reactor. The mixture was hydrogenated at 200 psi and 50° C. for 18 h. The reaction was allowed to cool, then filtered through a microfiber filter paper, and concentrated in vacuo which afforded a viscous colorless residue. The residue was azeotroped with toluene and dried which gave the title compound IIIa (25.4 g, 78%).
Reaction SMILES: Cl[C:2]1[N:11]=[CH:10][C:9]2[N:8]([CH3:12])[C:7](=[O:13])[C@H:6]([CH2:14][CH3:15])[N:5]([CH:16]([CH3:18])[CH3:17])[C:4]=2[N:3]=1.C[CH:20]1[CH2:24][C:23]2=[C:25]([C:30]([OH:32])=[O:31])[CH:26]=[CH:27][C:28]([NH2:29])=[C:22]2[O:21]1.Cl>C(O)C.O>[CH:16]([N:5]1[C:4]2[N:3]=[C:2]([NH:29][C:28]3[CH:27]=[CH:26][C:25]([C:30]([OH:32])=[O:31])=[C:23]4[C:22]=3[O:21][CH2:20][CH2:24]4)[N:11]=[CH:10][C:9]=2[N:8]([CH3:12])[C:7](=[O:13])[C@@H:6]1[CH2:14][CH3:15])([CH3:18])[CH3:17]
Reactant: CC[C@H]1C(=O)N(C)c2cnc(Cl)nc2N1C(C)C
Reactant: CC1Cc2c(C(=O)O)ccc(N)c2O1
Agent: Cl
Solvent: O
Solvent: CCO
Product: CC[C@H]1C(=O)N(C)c2cnc(Nc3ccc(C(=O)O)c4c3OCC4)nc2N1C(C)C
Yield: 57.9 %

Procedure:
(7S)-2-Chloro-8-isopropyl-7-ethyl-5-methyl-7H-pteridin-6-one 43d (2.50 g, 9.24 mmol) and methyl 7-amino-2,3-dihydrobenzofuran-4-carboxylateic acid 1g (1.50 g, 8.40 mmol) were dissolved in 120 mL of the mixture solvent of ethanol and water (V/V=1:2) followed by the addition of 1.5 mL of concentrated hydrochloric acid. The reaction mixture was heated to reflux for 24 hours with stirring and the precipitate was filtered. The filter cake was washed with dichloromethane (50 mL×3) and dried by heating to obtain the crude compound 7-[[(7S)-8-isopropyl-7-ethyl-5-methyl-6-oxo-7H-pteridin-2-yl]amino]-2,3-dihydrobenzofuran-4-carboxylic acid 43e (2 g) as a gray solid, which was used in the next step without further furification.
Reaction SMILES: [F:1][C:2]1[C:10]([N+:11]([O-:13])=[O:12])=[CH:9][CH:8]=[C:7]2[C:3]=1[CH2:4][CH2:5][N:6]2C(=O)C>Cl>[F:1][C:2]1[C:10]([N+:11]([O-:13])=[O:12])=[CH:9][CH:8]=[C:7]2[C:3]=1[CH2:4][CH2:5][NH:6]2
Reactant: CC(=O)N1CCc2c1ccc([N+](=O)[O-])c2F
Agent: Cl
Product: O=[N+]([O-])c1ccc2c(c1F)CCN2
Temperature: 25 °C
Yield: 76.6 %

Procedure:
A mixture of 1-(4-fluoro-5-nitro-indolin-1-yl)ethanone (0.56 g, 2.51 mmol) and concentrated hydrochloric acid (10 mL) was refluxed for 16 h. The reaction mixture was cooled to ambient temperature and partitioned between chlorofolin (100 mL) and water (100 mL). The organic layer was separated and the aqueous layer extracted with chloroform (5×30 mL). The combined organic layers were washed with water (3×20 mL), brine (3×20 mL) and dried over anhydrous sodium sulphate. Concentration in vacuo afforded 4-fluoro-5-nitro-indoline (0.35 g, 76%) as a yellow solid.
Reaction SMILES: C(O)(=O)C.[CH2:5]([O:7][C:8]1[CH:13]=[C:12]([CH:14]2[CH2:19][CH2:18][NH:17][CH2:16][CH2:15]2)[CH:11]=[CH:10][C:9]=1[NH:20][C:21](=[O:26])[C:22]([F:25])([F:24])[F:23])[CH3:6].[CH:27]([S:29]([CH3:32])(=[O:31])=[O:30])=[CH2:28].C([O-])([O-])=O.[K+].[K+]>C(Cl)Cl.CO>[CH2:5]([O:7][C:8]1[CH:13]=[C:12]([CH:14]2[CH2:19][CH2:18][N:17]([CH2:28][CH2:27][S:29]([CH3:32])(=[O:31])=[O:30])[CH2:16][CH2:15]2)[CH:11]=[CH:10][C:9]=1[NH:20][C:21](=[O:26])[C:22]([F:23])([F:24])[F:25])[CH3:6]
Reactant: C=CS(C)(=O)=O
Reactant: CCOc1cc(C2CCNCC2)ccc1NC(=O)C(F)(F)F
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: ClCCl
Solvent: CC(=O)O
Solvent: CO
Product: CCOc1cc(C2CCN(CCS(C)(=O)=O)CC2)ccc1NC(=O)C(F)(F)F
Reaction time: 3 h
Yield: 55.9 %

Procedure:
To N-[2-(ethyloxy)-4-(4-piperidinyl)phenyl]-2,2,2-trifluoroacetamide acetate (2.2 g, 5.9 mmol) and methyl vinyl sulfone (0.74 g, 7.0 mmol) in DCM (50 mL) was added K2CO3 (1.2 g, 8.8 mmol). A few drops of MeOH were added to help solubilize the reagents. The reaction was stirred in a sealed tube three h. The reaction was filtered then purified by silica gel chromatography. The desired fractions were combined, and the solvent was removed under vacuum to provide the title compound of step F as a white solid (1.4 g, 3.3 mmol, 58%). 1H NMR (400 MHz, DMSO-d6) δ 8.52 (br s, 1H), 8.18 (d, J=8.2 Hz, 1H), 6.81 (dd, J=8.2, 1.6 Hz, 1H), 6.73 (d, J=1.6 Hz, 1H), 4.11 (q, J=7.0 Hz, 2H), 3.15 (t, J=6.6 Hz, 2H), 3.02 (s, 3H), 3.00 (d, J=11.7 Hz, 2H), 2.88 (t, J=6.6 Hz, 2H), 2.52-2.42 (m, 1H), 2.18-2.10 (m, 2H), 1.84 (d, J=12.8 Hz, 2H), 1.73-1.60 (m, 2H), 1.44 (t, J=7.0 Hz, 3H).
Reaction SMILES: [CH3:1][C:2]1[N:3]=[CH:4][C:5]2[C:10]([CH:11]=1)=[CH:9][CH:8]=[CH:7][CH:6]=2.[N+:12]([O-])([O-:14])=[O:13].[K+].C(=O)([O-])[O-].[K+].[K+]>S(=O)(=O)(O)O>[CH3:1][C:2]1[N:3]=[CH:4][C:5]2[C:10]([CH:11]=1)=[C:9]([N+:12]([O-:14])=[O:13])[CH:8]=[CH:7][CH:6]=2
Reactant: O=[N+]([O-])[O-]
Reactant: Cc1cc2ccccc2cn1
Agent: O=C([O-])[O-]
Agent: O=S(=O)(O)O
Agent: [K+]
Product: Cc1cc2c([N+](=O)[O-])cccc2cn1
Temperature: 0 °C
Reaction time: 2 h

Procedure:
A solution of 3-methylisoquinoline (5.4 g, 0.038 mol) in concentrated sulfuric acid (30 ml) was cautiously added to a solution of potassium nitrate (4.25 g, 1.1 eq) in concentrated sulfuric acid (23 ml) whilst maintaining the temperature below 4° C. (ice bath). Stirring was continued for 2 h and then temperature raised to ambient. Reaction was further stirred for 3 h and then poured into ice-water slurry (500 ml). Neutralisation using solid potassium carbonate afforded a yellow solid which was filtered and washed with water. The crude product was dissolved in ethanol (200 ml), filtered and concentrated under reduced pressure to afford the title compound as a yellow solid.
Reaction SMILES: [OH:1][C:2]1[C:6](=[O:7])[O:5][CH:4]([CH2:8][CH2:9][C:10]([OH:12])=[O:11])[C:3]=1[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.S(=O)(=O)(O)O.O.Cl[CH2:26]Cl>CO>[OH:1][C:2]1[C:6](=[O:7])[O:5][CH:4]([CH2:8][CH2:9][C:10]([O:12][CH3:26])=[O:11])[C:3]=1[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1
Reactant: O=C(O)CCC1OC(=O)C(O)=C1c1ccccc1
Reactant: ClCCl
Agent: O=S(=O)(O)O
Solvent: CO
Solvent: O
Product: COC(=O)CCC1OC(=O)C(O)=C1c1ccccc1
Reaction time: 3 h

Procedure:
To a solution of 3-(4-hydroxy-5-oxo-3-phenyl2,5-dihydro-2-furyl)propionic acid (3.85 g) in dry methanol (60 ml) was added conc. sulfuric acid (3.8 ml) in one portion at 5° C. After stirring for 3 hours at ° C., the mixture was poured into a mixture of water (100 ml) and dichloromethane (50 ml). The aqueous layer was extracted with dichloromethane (50 ml) once again. The combined organic layers were washed with water three times, dried, and evaporated to dryness. To the residue was added diethyl ether and the solid was collected by filtration to yield methyl 3-(4-hydroxy-5-oxo-3-phenyl-2,5-dihydro-2-furyl)propionate (3.49 g).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][CH:6]=[C:5]2[CH:11]1[CH2:16][CH2:15][N:14]([CH3:17])[CH2:13][CH2:12]1.[CH2:18]([N:20]([CH2:24][CH3:25])[C:21](Cl)=[O:22])[CH3:19]>>[CH2:18]([N:20]([CH2:24][CH3:25])[C:21]([NH:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][CH:6]=[C:5]2[CH:11]1[CH2:16][CH2:15][N:14]([CH3:17])[CH2:13][CH2:12]1)=[O:22])[CH3:19]
Reactant: CCN(CC)C(=O)Cl
Reactant: CN1CCC(c2c[nH]c3ccc(N)cc23)CC1
Product: CCN(CC)C(=O)Nc1ccc2[nH]cc(C3CCN(C)CC3)c2c1
Yield: 87.3 %

Procedure:
Beginning with 13.0 mg (0.056 mMol) 5-amino-3-(1-methyl-piperidin-4-yl)-1H-indole and 8.0 mg (0.062 mMol) diethyl carbamoyl chloride, 16.05 mg (86%) of the title compound were recovered.
Reaction SMILES: [C:1]1([NH:7][C:8](=O)[CH:9]=[CH:10][S:11][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.S(Cl)([Cl:21])=O>CN(C)C=O>[C:1]1([N:7]=[C:8]([Cl:21])[CH:9]=[CH:10][S:11][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: O=C(C=CSc1ccccc1)Nc1ccccc1
Reactant: O=S(Cl)Cl
Solvent: CN(C)C=O
Product: ClC(C=CSc1ccccc1)=Nc1ccccc1

Procedure:
Thus, for example, IN 2003-MU444 describes the reaction of N-cyclohexyl-5-hydroxypentanamide with phosphorus pentachloride to give 5-chloro-N-cyclohexylpentaneimidoyl chloride. WO 2007/063702 provides the reaction of N-phenyl-3-(phenylsulphanyl)acrylamide with thionyl chloride and catalytical amounts of N,N-dimethylformamide to give N-phenyl-3-(phenylsulphanyl)prop-2-enimidoyl chloride.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C:10]2[CH:11]=[C:12]([C:17]([O:19][CH3:20])=[O:18])[C:13](=[O:16])[NH:14][N:15]=2)[CH:5]=[CH:6][C:7]=1[O:8][CH3:9].[Cl:21][C:22]1[CH:31]=[CH:30][C:25]([CH:26]=[CH:27][CH2:28]Cl)=[CH:24][CH:23]=1>>[Cl:21][C:22]1[CH:31]=[CH:30][C:25]([CH:26]=[CH:27][CH2:28][N:14]2[C:13](=[O:16])[C:12]([C:17]([O:19][CH3:20])=[O:18])=[CH:11][C:10]([C:4]3[CH:5]=[CH:6][C:7]([O:8][CH3:9])=[C:2]([F:1])[CH:3]=3)=[N:15]2)=[CH:24][CH:23]=1
Reactant: COC(=O)c1cc(-c2ccc(OC)c(F)c2)n[nH]c1=O
Reactant: ClCC=Cc1ccc(Cl)cc1
Product: COC(=O)c1cc(-c2ccc(OC)c(F)c2)nn(CC=Cc2ccc(Cl)cc2)c1=O
Yield: 51.1 %

Procedure:
Following the procedure of Example 1(6), 6-(3-fluoro-4-methoxyphenyl)-4-methoxycarbonyl-2H-pyridazin-3-one and 4-chlorocinnamyl chloride were reacted to yield the title compound as a pale yellow crystalline powder (yield: 51.1%).
Reaction SMILES: [CH:1]1([C:7]2[O:8][C:9]([C:23]3[CH:28]=[CH:27][C:26]([C:29]([F:32])([F:31])[F:30])=[CH:25][CH:24]=3)=[CH:10][C:11]=2[CH2:12][O:13][C:14]2[CH:22]=[CH:21][C:17]([C:18](O)=[O:19])=[CH:16][CH:15]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[CH3:33][NH:34][CH2:35][CH2:36][C:37]([O:39]CC)=[O:38]>>[CH:1]1([C:7]2[O:8][C:9]([C:23]3[CH:28]=[CH:27][C:26]([C:29]([F:32])([F:30])[F:31])=[CH:25][CH:24]=3)=[CH:10][C:11]=2[CH2:12][O:13][C:14]2[CH:22]=[CH:21][C:17]([C:18]([N:34]([CH3:33])[CH2:35][CH2:36][C:37]([OH:39])=[O:38])=[O:19])=[CH:16][CH:15]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: CCOC(=O)CCNC
Reactant: O=C(O)c1ccc(OCc2cc(-c3ccc(C(F)(F)F)cc3)oc2C2CCCCC2)cc1
Product: CN(CCC(=O)O)C(=O)c1ccc(OCc2cc(-c3ccc(C(F)(F)F)cc3)oc2C2CCCCC2)cc1
Yield: 95.3 %

Procedure:
An operation similar to that in Example 1 (4) was performed using 4-({2-cyclohexyl-5-[4-(trifluoromethyl)phenyl]-3-furyl}methoxy)benzoic acid (133 mg) as well as ethyl 3-(methylamino)propanoate (47 mg) to give the title compound (151 mg, 95%) as an amorphous compound.
Reaction SMILES: [C:1]([CH2:3][C:4]([NH2:6])=[O:5])#[N:2].C[O-].[Na+].[Cl:10][C:11]1[CH:20]=[CH:19][C:14]([CH2:15][N:16]=[N+:17]=[N-:18])=[CH:13][C:12]=1[C:21]#[N:22]>C(O)C>[NH2:2][C:1]1[N:16]([CH2:15][C:14]2[CH:19]=[CH:20][C:11]([Cl:10])=[C:12]([C:21]#[N:22])[CH:13]=2)[N:17]=[N:18][C:3]=1[C:4]([NH2:6])=[O:5]
Reactant: N#CCC(N)=O
Reactant: N#Cc1cc(CN=[N+]=[N-])ccc1Cl
Agent: C[O-]
Agent: [Na+]
Solvent: CCO
Product: N#Cc1cc(Cn2nnc(C(N)=O)c2N)ccc1Cl
Yield: 32.8 %

Procedure:
A stirred suspension of 2-cyanoacetamide (790 mg, 9.4 mmol) in absolute ethanol (40 ml) was treated with sodium methoxide (495 mg, 9.2 mmol) and refluxed 10 minutes. The mixture was cooled lightly, a solution of 4-chloro-3-cyanobenzyl azide (1.35 g, 7.0 mmol) in absolute ethanol was added, and the mixture was refluxed 2.5 hours. The mixture was filtered hot and the filtrate evaporated under vacuum. The residue was triturated with diethyl ether, filtered and washed twice with diethyl ether. The solid was crystallized from refluxing methanol, filtered, washed twice with methanol and once with diethyl ether, and dried at 65° C. under vacuum to provide 635 mg (33%) 5-amino-1-(4-chloro-3-cyanobenzyl)-1,2,3-triazole-4-carboxamide, m.p. 172°-175° C.
Reaction SMILES: [H-].[Na+].[F:3][C:4]([F:13])([F:12])[C:5]([C:7]1[NH:8][CH:9]=[CH:10][CH:11]=1)=[O:6].[CH2:14]([O:16][CH2:17][CH2:18]Br)[CH3:15]>CN(C=O)C>[CH2:14]([O:16][CH2:17][CH2:18][N:8]1[CH:9]=[CH:10][CH:11]=[C:7]1[C:5](=[O:6])[C:4]([F:3])([F:12])[F:13])[CH3:15]
Reactant: CCOCCBr
Reactant: O=C(c1ccc[nH]1)C(F)(F)F
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCOCCn1cccc1C(=O)C(F)(F)F
Temperature: 0 °C
Reaction time: 1 h

Procedure:
To a suspension of 268 mg (6.70 mmol) of NaH (60% dispersion in oil) in 20 mL DMF at 0° C. was added 1.01 g (6.19 mmol) of 2-(trifluoroacteyl)pyrrole and the mixture was stirred at 0° C. for 1 h. After this time, 765 μL (6.51 mmol) of 2-bromoethyl ethyl ether was added and the mixture was warmed to 60° C. and stirred for 16 h. After this time, the reaction mixture was allowed to cool to room temperature, quenched by the addition of a saturated aqueous solution of ammonium chloride, and extracted with EtOAc. The organic layer was washed with water and brine, dried over Na2SO4, filtered and the filtrate was concentrated. The residue was purified by chromatography on silica gel (pure hexanes grading to hexanes:EtOAc, 97:3) to give the title compound.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([CH2:7][C:8]2[C:9](=[O:16])[NH:10][C:11](SC)=[N:12][CH:13]=2)[CH:2]=1.[Br:17][C:18]1[C:19]([CH2:24][S:25][CH2:26][CH2:27][NH2:28])=[N:20][CH:21]=[CH:22][CH:23]=1>>[Br:17][C:18]1[C:19]([CH2:24][S:25][CH2:26][CH2:27][NH:28][C:11]2[NH:10][C:9](=[O:16])[C:8]([CH2:7][C:3]3[CH:2]=[N:1][CH:6]=[CH:5][CH:4]=3)=[CH:13][N:12]=2)=[N:20][CH:21]=[CH:22][CH:23]=1
Reactant: NCCSCc1ncccc1Br
Reactant: CSc1ncc(Cc2cccnc2)c(=O)[nH]1
Product: O=c1[nH]c(NCCSCc2ncccc2Br)ncc1Cc1cccnc1

Procedure:
5-(3-Pyridylmethyl)-2-methylthio-4-pyrimidone (1.27 g) was reacted with 2-(3-bromo-2-pyridylmethylthio)-ethylamine (1.35 g) according to the procedure in Example 2. The reaction mixture was triturated with hot water to give 2-[2-(3-bromo-2-pyridylmethylthio)-ethylamino]-5-(3-pyridylmethyl)-4-pyrimidone, and this product was treated with dilute hydrobromic acid to give the title compound, m.p. 217°-220.5° (ex-methanol)
Reaction SMILES: [H-].C([Al+]CC(C)C)C(C)C.C([N:14]1[C:18]([CH:19]2[CH2:21][CH2:20]2)=[CH:17][C:16]([NH:22][C:23]2[C:28](/[CH:29]=[CH:30]/[C:31](OC)=[O:32])=[CH:27][N:26]=[C:25]([C:35]3[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=3)[N:24]=2)=[N:15]1)(=O)C.[H-].[OH-].[Na+]>C1COCC1.CCCCCC>[CH:19]1([C:18]2[NH:14][N:15]=[C:16]([NH:22][C:23]3[C:28](/[CH:29]=[CH:30]/[CH2:31][OH:32])=[CH:27][N:26]=[C:25]([C:35]4[CH:36]=[CH:37][CH:38]=[CH:39][CH:40]=4)[N:24]=3)[CH:17]=2)[CH2:21][CH2:20]1
Reactant: COC(=O)/C=C/c1cnc(-c2ccccc2)nc1Nc1cc(C2CC2)n(C(C)=O)n1
Agent: CC(C)C[Al+]CC(C)C
Agent: [H-]
Agent: [Na+]
Solvent: CCCCCC
Solvent: C1CCOC1
Product: OC/C=C/c1cnc(-c2ccccc2)nc1Nc1cc(C2CC2)[nH]n1
Temperature: -78 °C
Reaction time: 1 h
Yield: 96.8 %

Procedure:
A hexane solution of diisobutylaluminum hydride (1 mL of a 1.0M solution, 1.0 mmol, 4.0 equiv.) was added to a cooled (−78° C.) solution of (E)-methyl 3-(4-(1-acetyl-5-cyclopropyl-1H-pyrazol-3-ylamino)-2-phenylpyrimidin-5-yl)acrylate (100 mg, 0.248 mmol, 1.0 equiv.) in THF (2 mL). After stirring for 1 h at −78° C., additional disobutylalumium hydride solution (0.25 mL of a 1.0M solution, 0.25 mmol, 1.0 equiv.) was added. After another 30 min, NaOH solution (1N) was added and the reaction mixture was allowed to warm slowly to room temperature for 10 min. The organic layers were separated and the aqueous phase was extracted with CH2Cl2. The combined organic layers were washed with water, brine, dried (Na2SO4) and filtered. The filtrate was concentrated to afford crude. The crude was crystallized with ethanol to afford compound (E)-3-(4-(5-cyclopropyl-1H-pyrazol-3-ylamino)-2-phenylpyrimidin-5-yl)prop-2-en-1-ol (Compound 53) (80 mg, 96%). LC-MS (m/z): 334.1 [M+H]+. 1H NMR (400 MHz, DMSO-d6) δ 0.71-0.72 (m, 2H), 0.96-0.98 (m, 2H), 1.91-1.98 (m, 1H), 4.15 (t, J=5.2 Hz, 2H), 4.87 (m, 1H), 6.34 (dt, J1=4.8 Hz, J2=15.6 Hz, 1H), 6.48 (s, 1H), 6.80 (d, J=16 Hz, 1H), 7.48-7.51 (m, 3H), 8.28-8.30 (m, 2H), 8.47 (s, 1H), 9.05 (s, 1H), 12.15 (s, 1H).
Reaction SMILES: [CH3:1][C:2]1([CH3:22])[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:5]([C:12]2[CH:17]=[CH:16][C:15]([C:18]([F:21])([F:20])[F:19])=[CH:14][CH:13]=2)=[N:4][CH2:3]1.[BH4-].[Na+]>CO>[CH3:1][C:2]1([CH3:22])[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[CH:5]([C:12]2[CH:17]=[CH:16][C:15]([C:18]([F:21])([F:19])[F:20])=[CH:14][CH:13]=2)[NH:4][CH2:3]1
Reactant: CC1(C)CN=C(c2ccc(C(F)(F)F)cc2)c2ccccc21
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Product: CC1(C)CNC(c2ccc(C(F)(F)F)cc2)c2ccccc21
Temperature: 25 °C
Reaction time: 0.75 h

Procedure:
A 50-mL round-bottomed flask was charged with 4,4-dimethyl-1-(4-(trifluoromethyl)phenyl)-3,4-dihydroisoquinoline (2.52 g, 8.3 mmol) and dry MeOH (10 mL). After cooling down to 0° C. sodium borohydride (943 mg, 24.9 mmol) was added and the mixture was stirred at RT for 45 min. Then, the solvent was removed and the residue redissolved in EtOAc, washed with sat NaHCO3, water and dried over Na2SO4. The residue was purified by silica gel chromatography (25-35% EtOAc in hexanes) to give the title compound as a white solid. MS (ESI, positive ion) m/z: 306 (M+H).
Reaction SMILES: [CH2:1]([O:5][CH:6]([O:9][CH2:10][CH2:11][CH2:12][CH3:13])[CH2:7][NH2:8])[CH2:2][CH2:3][CH3:4].Br[CH2:15][CH:16]1[O:20][CH:19]([CH3:21])[CH:18]([CH3:22])[O:17]1.C(N(CC)CC)C>C1(C)C=CC=CC=1>[CH2:10]([O:9][CH:6]([O:5][CH2:1][CH2:2][CH2:3][CH3:4])[CH2:7][NH:8][CH2:15][CH:16]1[O:20][CH:19]([CH3:21])[CH:18]([CH3:22])[O:17]1)[CH2:11][CH2:12][CH3:13]
Reactant: CCCCOC(CN)OCCCC
Reactant: CC1OC(CBr)OC1C
Solvent: Cc1ccccc1
Solvent: CCN(CC)CC
Product: CCCCOC(CNCC1OC(C)C(C)O1)OCCCC
Temperature: 25 °C

Procedure:
2,2-Dibutoxyethylamine (0.11 mole), 2-bromomethyl-4,5-dimethyl-1,3-dioxolane (0.1 mole), triethylamine (20 ml) and toluene (150 ml) are charged into a glass reaction vessel equipped with a mechanical stirrer, thermometer and reflux condenser. The reaction is heated at reflux for a period of about 12 hours. After this time the reaction mixture is allowed to cool to room temperature and is filtered. The reaction mixture is then stripped of solvent and unreacted starting materials under reduced pressure to yield the desired product N-(2,2dibutoxyethyl)-N-(4,5-dimethyl-1,3-dioxolan-2-ylmethyl)amine.
Reaction SMILES: P([O-])([O-])([O-])=O.[Na+:6].[Na+].[Na+].[N:9]1[CH:14]=[CH:13][C:12]([S:15][C:16]2[CH2:22][C@H:21]3[N:18]([C:19](=[O:40])[C@H:20]3[C:23]([CH3:39])([O:25]C(OCC3C=CC([N+]([O-])=O)=CC=3)=O)[CH3:24])[C:17]=2[C:41]([O:43]CC2C=CC([N+]([O-])=O)=CC=2)=[O:42])=[CH:11][CH:10]=1.C(=O)(O)[O-].[Na+]>[Pd].O1CCOCC1>[N:9]1[CH:14]=[CH:13][C:12]([S:15][C:16]2[CH2:22][C@H:21]3[N:18]([C:19](=[O:40])[C@H:20]3[C:23]([OH:25])([CH3:39])[CH3:24])[C:17]=2[C:41]([O-:43])=[O:42])=[CH:11][CH:10]=1.[Na+:6]
Reactant: CC(C)(OC(=O)OCc1ccc([N+](=O)[O-])cc1)[C@@H]1C(=O)N2C(C(=O)OCc3ccc([N+](=O)[O-])cc3)=C(Sc3ccncc3)C[C@H]12
Agent: [Pd]
Agent: O=C([O-])O
Agent: O=P([O-])([O-])[O-]
Solvent: C1COCCO1
Product: CC(C)(O)[C@@H]1C(=O)N2C(C(=O)[O-])=C(Sc3ccncc3)C[C@H]12
Temperature: 25 °C

Procedure:
A mixture of 5% palladium on activated charcoal (50 ml), dioxane (3.5 ml) and 1/30M sodium phosphate buffer solution (pH 7.0, 1.5 ml) was shaken for an hour under hydrogen atmosphere (40 psi) at ambient temperature. To this mixture was added a solution of 4-nitrobenzyl(5R,6R)-3-(4-pyridylthio)-6-[1-methyl-1-(4-nitrobenzyloxycarbonyloxy)ethyl]-7-oxo-1-azabicyclo[3.2.0]hept-2-ene-2-carboxylate (43 mg) in a mixture of dioxane (3.5 ml) and 1/30M sodium phosphate buffer solution (pH 7.0, 1.5 ml) at 0° C., and the resultant mixture was shaken under hydrogen atmosphere (40 psi) for 100 minutes, during which time the reaction temperature rose to ambient temperature. After addition of 1% aqueous sodium bicarbonate (0.57 ml) at 0° C., the mixture was filtered through cellulose powder. The filter-cake was washed with water (3×10 ml). The combined filtrates were concentrated to half of the original volume. The concentrate was washed with ethyl acetate (3×20 ml) and evaporated in vacuo. The residue was dissolve in water (60 ml) containing sodium chloride (1.75 g) and then chromatographed on nonionic adsorption resin "Diaion HP-20" (Trade Mark, maker: Mitsubishi Chemical Industries Ltd. (1.5×20 cm) eluting with water (100 ml) and a mixture of water and acetone (10:0 to 7:3, 200 ml). The fractions, whose UV spectra showed λmax 302 nm, were collected and lyophilized to give sodium (5R,6R)-3-(4-pyridylthio)-6-(1-hydroxy-1-methylethyl)-7-oxo-1-azabicyclo[3.2.0]-hept-2-ene-2-carboxylate (13.7 mg) as white powder.
Reaction SMILES: F.[Si]([O:9][C:10]1[CH:11]=[C:12]([CH:34]=[CH2:35])[C:13]2[O:17][C:16]([C:18]3[CH:23]=[CH:22][C:21]([O:24][Si](C(C)(C)C)(C)C)=[C:20]([F:32])[CH:19]=3)=[N:15][C:14]=2[CH:33]=1)(C(C)(C)C)(C)C.C1COCC1.C(#N)C>O>[F:32][C:20]1[CH:19]=[C:18]([C:16]2[O:17][C:13]3[C:12]([CH:34]=[CH2:35])=[CH:11][C:10]([OH:9])=[CH:33][C:14]=3[N:15]=2)[CH:23]=[CH:22][C:21]=1[OH:24]
Reactant: C=Cc1cc(O[Si](C)(C)C(C)(C)C)cc2nc(-c3ccc(O[Si](C)(C)C(C)(C)C)c(F)c3)oc12
Agent: F
Solvent: CC#N
Solvent: C1CCOC1
Solvent: O
Product: C=Cc1cc(O)cc2nc(-c3ccc(O)c(F)c3)oc12
Temperature: 65 °C
Reaction time: 8 h
Yield: 88.5 %

Procedure:
Hydrofluoric acid (48 wt. % in water, 1 mL) was added into a solution of 5-{[tert-butyl(dimethyl)silyl]oxy}-2-(4-{[tert-butyl(dimethyl)silyl]oxy}-3-fluorophenyl)-7-vinyl-1,3-benzoxazole (1.5 g, 3.0 mmol), THF (6 mL) and acetonitrile (3 mL). The reaction mixture was stirred at 65° C. for 8 h, and then poured into water. The precipitated solid was filtered off and dried. Crystallization of the product from acetone/ethyl ether gave a white solid (0.72 g, 81% yield, m.p. 249–251° C.); MS m/e 272 (M+H)+.