Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][Si:2]([CH3:42])([CH3:41])[CH2:3][CH2:4][O:5][CH2:6][N:7]([CH2:33][O:34][CH2:35][CH2:36][Si:37]([CH3:40])([CH3:39])[CH3:38])[C:8]1[N:13]2[N:14]=[CH:15][CH:16]=[C:12]2[N:11]=[C:10]([C:17]2[CH2:24][CH:23]3[N:25]([C:26]([O:28][C:29]([CH3:32])([CH3:31])[CH3:30])=[O:27])[CH:19]([CH2:20][O:21][CH2:22]3)[CH:18]=2)[CH:9]=1.[H][H]>CCOC(C)=O.[Pd]>[CH3:40][Si:37]([CH3:38])([CH3:39])[CH2:36][CH2:35][O:34][CH2:33][N:7]([CH2:6][O:5][CH2:4][CH2:3][Si:2]([CH3:1])([CH3:42])[CH3:41])[C:8]1[N:13]2[N:14]=[CH:15][CH:16]=[C:12]2[N:11]=[C:10]([CH:17]2[CH2:18][CH:19]3[N:25]([C:26]([O:28][C:29]([CH3:32])([CH3:31])[CH3:30])=[O:27])[CH:23]([CH2:22][O:21][CH2:20]3)[CH2:24]2)[CH:9]=1
Reactant: [H][H]
Reactant: CC(C)(C)OC(=O)N1C2C=C(c3cc(N(COCC[Si](C)(C)C)COCC[Si](C)(C)C)n4nccc4n3)CC1COC2
Agent: [Pd]
Solvent: CCOC(C)=O
Product: CC(C)(C)OC(=O)N1C2COCC1CC(c1cc(N(COCC[Si](C)(C)C)COCC[Si](C)(C)C)n3nccc3n1)C2
Yield: 86.1 %

Procedure:
tert-butyl 7-(7-(bis((2-(trimethylsilyl)ethoxy)methyl)amino)pyrazolo[1,5-a]pyrimidin-5-yl)-3-oxa-9-azabicyclo[3.3.1]non-6-ene-9-carboxylate (1.27 g, 2.06 mmol) in EtOAc (50 mL) was hydrogenated at 50° C. using 10% Pd/C catalyst (200 mg) and 1 atmospheric hydrogen pressure for 16 h. After filtering off the catalyst, the solvent was evaporated off under reduced pressure and crude material was purified by column chromatography (0-40% hexane-ethyl acetate) to give product tert-butyl 7-(7-(bis((2-(trimethylsilyl)ethoxy)methyl)amino)pyrazolo[1,5-a]pyrimidin-5-yl)-3-oxa-9-azabicyclo[3.3.1]nonane-9-carboxylate (1.1 g) as syn- and anti-mixture. HPLC-MS tR=3.15 min (UV254 nm). Mass calculated for formula C30H53N5O5Si2 619.3; observed MH+ (LCMS) 620.2 (m/z).
Reaction SMILES: [CH3:1][O:2][CH2:3][CH2:4][CH2:5][O:6][C:7]1[CH:14]=[C:13]([CH3:15])[CH:12]=[CH:11][C:8]=1[CH:9]=[O:10].[BH4-].[Na+].O>CO>[CH3:1][O:2][CH2:3][CH2:4][CH2:5][O:6][C:7]1[CH:14]=[C:13]([CH3:15])[CH:12]=[CH:11][C:8]=1[CH2:9][OH:10]
Reactant: COCCCOc1cc(C)ccc1C=O
Agent: [BH4-]
Agent: [Na+]
Solvent: O
Solvent: CO
Product: COCCCOc1cc(C)ccc1CO
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a solution of the title B compound, 2-(3-methoxy-propoxy)-4-methyl-benzaldehyde (3.7 g, 17.41 mmol) in 30 mL of methanol is added portion wise sodium borohydride (1.03 g, 26.12 mmol). The reaction mixture is stirred for 30 min at room temperature. Sodium borohydride (1.03 g, 26.12 mmol) is added and the mixture further stirred overnight to complete the reaction. After addition of H2O, the aqueous layer is extracted twice with ethyl acetate. The combined organic extracts are dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue is purified by flash column chromatography on silica gel (hexane/EtOAc 4/1 to 1/2) to afford the title compound as a colorless oil: TLC, Rf (hexane/AcOEt 2/1)=0.2. Rt (HPLC, Nucleosil C18, 10:90-100:0 CH3CN/H2O+0.1% TFA within 5 min, then 100% CH3CN+0.1% TFA): 4.88 min.
Reaction SMILES: [CH:1](=[C:3]1[CH2:9][C@H:8]2[C@H:10]3[C@H:19]([CH2:20][CH2:21][C@:5]2([CH2:6][CH3:7])[C:4]1=[O:24])[C:18]1[CH:17]=[CH:16][C:15]([O:22][CH3:23])=[CH:14][C:13]=1[CH2:12][CH2:11]3)[CH3:2]>C(O)C.[Pd]>[CH2:1]([C@H:3]1[CH2:9][C@H:8]2[C@H:10]3[C@H:19]([CH2:20][CH2:21][C@:5]2([CH2:6][CH3:7])[C:4]1=[O:24])[C:18]1[CH:17]=[CH:16][C:15]([O:22][CH3:23])=[CH:14][C:13]=1[CH2:12][CH2:11]3)[CH3:2]
Reactant: CC=C1C[C@H]2[C@@H]3CCc4cc(OC)ccc4[C@H]3CC[C@]2(CC)C1=O
Agent: [Pd]
Solvent: CCO
Product: CC[C@H]1C[C@H]2[C@@H]3CCc4cc(OC)ccc4[C@H]3CC[C@]2(CC)C1=O
Yield: 99.4 %

Procedure:
A solution of 1.3 g of 16-ethylidene-3-methoxy-18-methyl-1,3,5(10)-estratrien-17-one in 180 ml of ethanol is hydrogenated, after adding 130 mg of 10% palladium charcoal, at room temperature and normal pressure. After absorbing 115 ml of hydrogen the reaction product is filtered off from the catalyst and the filtrate concentrated. Crystallization from methanol yields 1.3 g of 16β-ethyl-3-methoxy-18-methyl-1,3,5(10)-estratrien-17-one, m.p. 101°-102° C.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([F:8])[C:3]=1[N:9]1[C:14]2[N:15]=[C:16](S(C)(=O)=O)[N:17]=[C:18]([C:19]3[CH:20]=[C:21]([CH:29]=[CH:30][C:31]=3[CH3:32])[C:22]([N:24]([CH2:27][CH3:28])[CH2:25][CH3:26])=[O:23])[C:13]=2[CH2:12][NH:11][C:10]1=[O:37].[CH3:38][N:39]1[CH2:44][CH2:43][CH:42]([NH2:45])[CH2:41][CH2:40]1>C1COCC1>[F:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([F:8])[C:3]=1[N:9]1[C:14]2[N:15]=[C:16]([NH:45][CH:42]3[CH2:43][CH2:44][N:39]([CH3:38])[CH2:40][CH2:41]3)[N:17]=[C:18]([C:19]3[CH:20]=[C:21]([CH:29]=[CH:30][C:31]=3[CH3:32])[C:22]([N:24]([CH2:27][CH3:28])[CH2:25][CH3:26])=[O:23])[C:13]=2[CH2:12][NH:11][C:10]1=[O:37]
Reactant: CCN(CC)C(=O)c1ccc(C)c(-c2nc(S(C)(=O)=O)nc3c2CNC(=O)N3c2c(F)cccc2F)c1
Reactant: CN1CCC(N)CC1
Solvent: C1CCOC1
Product: CCN(CC)C(=O)c1ccc(C)c(-c2nc(NC3CCN(C)CC3)nc3c2CNC(=O)N3c2c(F)cccc2F)c1
Reaction time: 8 h

Procedure:
3-[8-(2,6-difluorophenyl)-2-(methylsulfonyl)-7-oxo-5,6,7,8-tetrahydropyrimido[4,5-d]pyrimidin-4-yl]-N,N-diethyl-4-methylbenzamide-(0.053 g, 0.1 mmol) was dissolved in THF (5 mL) and 1-methyl-4-piperidinamine (0.044 g, 0.5 mmol) was added. The reaction was stirred under argon overnight. The solvents were pumped off in vacuo, and the residue was purified by mass directed auto prep. The fractions were evaporated, and aqueous basic workup gave the title compound as a white amorphous solid. mp 165-169° C. LC-MS m/z 564 (M+H)+, 1.44 min (ret time).
Reaction SMILES: [CH3:1][CH:2]([CH3:8])[CH2:3][CH2:4][C:5](=[O:7])[CH3:6].[CH2:9]([O:11][C:12](=[O:18])[C:13](OCC)=[O:14])[CH3:10].CC[O-].[Na+]>>[CH2:9]([O:11][C:12](=[O:18])[C:13](=[O:14])[CH2:6][C:5](=[O:7])[CH2:4][CH2:3][CH:2]([CH3:8])[CH3:1])[CH3:10]
Reactant: CC(=O)CCC(C)C
Reactant: CCOC(=O)C(=O)OCC
Agent: CC[O-]
Agent: [Na+]
Product: CCOC(=O)C(=O)CC(=O)CCC(C)C
Temperature: 25 °C
Yield: 70.4 %

Procedure:
5-methyl-2-hexanone (5.0084 g, 43.9 mmol) and diethyloxalate (5.95 mL, 43.8 mmol) were mixed together, and then added to a solution of NaOEt (˜3 M, 14.6 mL) stirring in an ice bath under N2. After stirring for 15 minutes, the reaction was warmed to room temperature and stirred overnight. The reaction was quenched at 0° C. with 1N HCl and extracted 2× with CH2Cl2. The combined organics were washed with H2O, dried with Na2SO4, filtered, and concentrated to yield crude 46. The crude material was purified with 1:1 Hexanes:CH2Cl2 to obtain 6.6035 g (70.3%) of 46. 1H (CDCl3, 400 MHz): δ 6.28 (1H, s), 4.25 (2H, q, J=7.0 Hz), 2.40 (2H, t, 7.6 Hz), 1.54-1.41 (3H, m), 1.27 (3H, t, J=7.3 Hz), 0.82 (6H, d, J=6.3 Hz) ppm. 13C (CDCl3, 100 MHz): δ 203.40, 166.27, 161.85, 101.37, 62.15, 38.74, 33.39, 27.46, 21.99, 13.77 ppm. DEPT (CDCl3, 100 MHz): CH3 carbons: 21.99, 13.77; CH2 carbons: 62.15, 38.74, 33.39; CH carbons: 101.37, 27.46 ppm. HPLC: 11.038 min.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[C:7]([CH3:31])=[C:8]2[C:13](=[CH:14][C:15]=1[CH3:16])[N:12]=[C:11]([CH2:17][OH:18])[N:10]([C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=1[S:25](=[O:29])(=[O:28])[NH:26][CH3:27])[C:9]2=[O:30])=[O:5])[CH3:2].C(OC(C1C(C)=C2C(=CC=1C)N=[C:42]([CH2:48]OCC1C=CC=CC=1)[N:41](C1C=CC=CC=1S(=O)(=O)NC)[C:40]2=[O:68])=O)C.C(OCC)C>C1COCC1.[Pd]>[CH2:1]([O:3][C:4]([C:6]1[C:7]([CH3:31])=[C:8]2[C:13](=[CH:14][C:15]=1[CH3:16])[N:12]=[C:11]([CH2:17][O:18][C:40](=[O:68])[NH:41][CH2:42][CH3:48])[N:10]([C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=1[S:25](=[O:29])(=[O:28])[NH:26][CH3:27])[C:9]2=[O:30])=[O:5])[CH3:2]
Reactant: CCOC(=O)c1c(C)cc2nc(CO)n(-c3ccccc3S(=O)(=O)NC)c(=O)c2c1C
Reactant: CCOC(=O)c1c(C)cc2nc(COCc3ccccc3)n(-c3ccccc3S(=O)(=O)NC)c(=O)c2c1C
Agent: [Pd]
Solvent: C1CCOC1
Solvent: CCOCC
Product: CCNC(=O)OCc1nc2cc(C)c(C(=O)OCC)c(C)c2c(=O)n1-c1ccccc1S(=O)(=O)NC
Reaction time: 8 h
Yield: 43 %

Procedure:
Preparation of 2-Hydroxymethyl-5,7-dimethyl-3-(2-methylsulfamoyl-phenyl)-4-oxo-3,4-dihydro-quinazoline-6-carboxylic acid ethyl ester: A solution of 2-Benzyloxymethyl-5,7-dimethyl-3-(2-methylsulfamoyl-phenyl)-4-oxo-3,4-dihydro-quinazoline-6-carboxylic acid ethyl ester (15 g, 0.028 mol) in anhydrous THF (270 mL) is degassed under house vacuum. Palladium on activated charcoal (Acros, 10% Pd, 930 mg) is added and the suspension is flushed with hydrogen (balloon). The suspension is stirred under hydrogen overnight. TLC and LCMS analysis indicates that starting material remained. The reaction mixture is filtered through Celite, and the catalyst is washed sequentially with methanol, DCM and methanol. The filtrate is evaporated to give a cream solid. Trituration with diethyl ether provides a white solid which is removed by filtration and dried under high vacuum to provide the title compound (5.42 g, 0.012 mol, 43%). The ethereal filtrate, which contains un-reacted starting material, is evaporated in vacuo and the residue is subjected to a second cycle of hydrogenation (Pd—C, 920 mg): after stirring overnight under hydrogen TLC/LCMS indicated absence of starting material. The reaction mixture is worked-up as above to provide the title compound as a white solid (4.75 g, 0.01 mol, 38%). Total yield: 10.17 g, 0.022 mol, 82%.
Reaction SMILES: [C:1]1([NH:7][C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[H-].[Na+].Br.[NH2:17][C:18]1[N:19]=[C:20]([NH2:30])[C:21]2[CH:27]=[C:26]([CH2:28]Br)[CH:25]=[N:24][C:22]=2[N:23]=1>>[NH2:17][C:18]1[N:19]=[C:20]([NH2:30])[C:21]2[CH:27]=[C:26]([CH2:28][N:7]([C:1]3[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=3)[C:8]3[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=3)[CH:25]=[N:24][C:22]=2[N:23]=1
Reactant: Nc1nc(N)c2cc(CBr)cnc2n1
Reactant: c1ccc(Nc2ccccc2)cc1
Agent: Br
Agent: [H-]
Agent: [Na+]
Product: Nc1nc(N)c2cc(CN(c3ccccc3)c3ccccc3)cnc2n1

Procedure:
X=N; W=CH2; Z=non-linked hydrogens on each phenyl group; Z=CH2; m=n=0) is prepared similarly as disclosed in Example 1 above by using N,N-diphenylamine (1.3 g, 0.77 mmol), NaH (50 mg, 2.1 mmol), and 2,4-diamino-6-bromomethylpyrido[2,3-d]pyrimidine hydrobromide (100 mg, 0.3 mmol). The product can be purified by chromatography.
Reaction SMILES: [CH2:1]([O:8][C:9]1[C:14](=[O:15])[N:13]2[CH2:16][C:17](=[O:20])[N:18]([CH3:19])[C:12]2=[N:11][C:10]=1[C:21]([O:23]CC)=[O:22])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[OH-].[Na+].Cl.C(OCC)(=O)C>C(O)C.O1CCCC1>[CH2:1]([O:8][C:9]1[C:14](=[O:15])[N:13]2[CH2:16][C:17](=[O:20])[N:18]([CH3:19])[C:12]2=[N:11][C:10]=1[C:21]([OH:23])=[O:22])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CCOC(=O)c1nc2n(c(=O)c1OCc1ccccc1)CC(=O)N2C
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCOC(C)=O
Solvent: CCO
Solvent: C1CCOC1
Product: CN1C(=O)Cn2c1nc(C(=O)O)c(OCc1ccccc1)c2=O
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 95 %

Procedure:
A solution of intermediate 12, ethyl 6-benzyloxy-1-methyl-2,5-dioxo-1,2,3,5-tetrahydroimidazo[1,2-a]pyrimidine-7-carboxylate, (0.084 g, 0.24 mmol) in a mixture of ethanol (5 ml) and tetrahydrofuran (5 ml) was treated with 1.0 ml of a 1 M aqueous sodium hydroxide and the resulting mixture was stirred at 25° C. for 30 min. The reaction mixture was then acidified with 1 N hydrochloric acid and extracted with ethyl acetate. The organic phase was washed with brine, dried over anhydrous magnesium sulfate and concentrated to give 0.073 g (95% yield) of the title acid as white crystals; mp 194° C. (ethyl acetate). 1HNMR 400 MHz (DMSO-d6) δ (ppm): 3.07 (3H, s, NCH3), 4.54 (2H, s, CH2), 5.04 (2H, s, CH2), 7.3–7.5 (5H, m, aromatics), 13.8 (1H, s, OH). MS (ESI+) m/z 316 [M+H+].
Reaction SMILES: [C:1](=[O:8])([O:5][CH2:6][CH3:7])OCC.[H-].[Na+].[C:11]1([N:17]2[C:21]([C:22](=[O:24])[CH3:23])=[CH:20][CH:19]=[N:18]2)[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1>O>[O:24]=[C:22]([C:21]1[N:17]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[N:18]=[CH:19][CH:20]=1)[CH2:23][C:1]([O:5][CH2:6][CH3:7])=[O:8]
Reactant: CC(=O)c1ccnn1-c1ccccc1
Reactant: CCOC(=O)OCC
Agent: [H-]
Agent: [Na+]
Solvent: O
Product: CCOC(=O)CC(=O)c1ccnn1-c1ccccc1

Procedure:
To a mixture of diethyl carbonate (20.0 mL) and 60% NaH (0.34 g) was added 1-(1-phenyl-1H-pyrazol-5-yl)ethanone (1.30 g) at room temperature, and the mixture was heated under reflux for 2 hr. To the reaction mixture was added water, and the mixture was extracted with dichloromethane. The extract was washed with saturated brine, dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (petroleum ether/ethyl acetate) to give the title compound (1.10 g).
Reaction SMILES: [C:1]([C:5]1[N:6]=[C:7]([N:16]2[CH2:20][CH2:19][C:18]([F:22])([F:21])[CH2:17]2)[C:8]2[C:9](=[N:11][N:12]([CH2:14][CH3:15])[N:13]=2)[N:10]=1)([CH3:4])([CH3:3])[CH3:2].C(C1N=C(N2CCC(F)(F)C2)C2N=NNC=2N=1)(C)(C)C.BrCC1[CH:50]=[CH:49][CH:48]=[C:47]([F:51])[C:46]=1[Cl:52]>>[C:1]([C:5]1[N:6]=[C:7]([N:16]2[CH2:20][CH2:19][C:18]([F:21])([F:22])[CH2:17]2)[C:8]2[C:9](=[N:11][N:12]([CH2:14][C:15]3[CH:50]=[CH:49][CH:48]=[C:47]([F:51])[C:46]=3[Cl:52])[N:13]=2)[N:10]=1)([CH3:2])([CH3:3])[CH3:4]
Reactant: Fc1cccc(CBr)c1Cl
Reactant: CCn1nc2nc(C(C)(C)C)nc(N3CCC(F)(F)C3)c2n1
Agent: CC(C)(C)c1nc(N2CCC(F)(F)C2)c2nn[nH]c2n1
Product: CC(C)(C)c1nc(N2CCC(F)(F)C2)c2nn(Cc3cccc(F)c3Cl)nc2n1

Procedure:
In analogy to the procedure described for the synthesis of 5-tert-butyl-7-(3,3-difluoro-pyrrolidin-1-yl)-2-ethyl-2H-[1,2,3]triazolo[4,5-d]pyrimidine (example 3, step b), the title compound was prepared from 5-tert-butyl-7-(3,3-difluoropyrrolidin-1-yl)-3H-[1,2,3]triazolo[4,5-d]pyrimidine and 1-(bromomethyl)-2-chloro-3-fluorobenzene and isolated as light-yellow gums (4.9 mg, 28%). MS (m/e): 425.3 (MH+).
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[O:9][C:10]2[CH:18]=[CH:17][CH:16]=[CH:15][C:11]=2[C:12](=O)[N:13]=1.[NH:19]([C:21]1[CH:29]=[CH:28][C:24]([C:25]([OH:27])=[O:26])=[CH:23][CH:22]=1)[NH2:20]>CN1CCCC1=O.C(O)(=O)CC>[CH:16]1[CH:17]=[CH:18][C:10]([OH:9])=[C:11]([C:12]2[N:13]=[C:8]([C:3]3[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=3[OH:1])[N:19]([C:21]3[CH:29]=[CH:28][C:24]([C:25]([OH:27])=[O:26])=[CH:23][CH:22]=3)[N:20]=2)[CH:15]=1
Reactant: O=c1nc(-c2ccccc2O)oc2ccccc12
Reactant: NNc1ccc(C(=O)O)cc1
Solvent: CN1CCCC1=O
Solvent: CCC(=O)O
Product: O=C(O)c1ccc(-n2nc(-c3ccccc3O)nc2-c2ccccc2O)cc1
Temperature: 120 °C
Reaction time: 1 h
Yield: 90.8 %

Procedure:
A suspension of 0.7 g (2.92 mmol) of 2-(2-hydroxyphenyl)benz[e][1,3]oxazin-4-one and 0.52 g (3.44 mmol) of 4-hydrazinobenzoic acid in 5 ml of N-methylpyrrolidone and 5 ml of propionic acid is heated to 120° C. The mixture is maintained at this temperature and stirred for 1 hour. After completion of the reaction, the mixture is cooled and poured onto crushed ice. The resulting crystals are aspirated and washed with water. After drying, 0.99 g of raw deferasirox is obtained, i.e. 91% of the theory, with an HPLC content of 92.9% and a melting temperature of 250 to 261° C.
Reaction SMILES: [CH3:1][C:2]1[O:6][N:5]=[C:4]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)[C:3]=1[CH2:13][O:14][C:15]1[CH:23]=[CH:22][C:18]([C:19]([OH:21])=O)=[CH:17][N:16]=1.[CH:24]1([NH2:28])[CH2:27][CH2:26][CH2:25]1>>[CH:24]1([NH:28][C:19](=[O:21])[C:18]2[CH:22]=[CH:23][C:15]([O:14][CH2:13][C:3]3[C:4]([C:7]4[CH:8]=[CH:9][CH:10]=[CH:11][CH:12]=4)=[N:5][O:6][C:2]=3[CH3:1])=[N:16][CH:17]=2)[CH2:27][CH2:26][CH2:25]1
Reactant: NC1CCC1
Reactant: Cc1onc(-c2ccccc2)c1COc1ccc(C(=O)O)cn1
Product: Cc1onc(-c2ccccc2)c1COc1ccc(C(=O)NC2CCC2)cn1
Yield: 56 %

Procedure:
As described for example 8b, 6-(5-methyl-3-phenyl-isoxazol-4-ylmethoxy)-nicotinic acid (100 mg, 0.32 mmol) was converted, using cyclobutylamine (1 M in DMF) instead of methylamine, to the title compound (66 mg, 56%) which was obtained as a white solid. MS: m/e=364.4 [M+H]+.
Reaction SMILES: [F:1][C:2]([F:12])([F:11])[C:3]1[CH:10]=[CH:9][C:6]([CH2:7]Br)=[CH:5][CH:4]=1.[CH2:13]([O:20][C:21]1[CH:22]=[C:23]([CH:26]=[CH:27][C:28]=1[OH:29])[CH:24]=[O:25])[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1.C(=O)([O-])[O-].[Cs+].[Cs+]>CN(C)C=O.C(OCC)(=O)C>[C:14]1([CH2:13][O:20][C:21]2[CH:22]=[C:23]([CH:26]=[CH:27][C:28]=2[O:29][CH2:7][C:6]2[CH:9]=[CH:10][C:3]([C:2]([F:12])([F:11])[F:1])=[CH:4][CH:5]=2)[CH:24]=[O:25])[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1
Reactant: FC(F)(F)c1ccc(CBr)cc1
Reactant: O=Cc1ccc(O)c(OCc2ccccc2)c1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: O=Cc1ccc(OCc2ccc(C(F)(F)F)cc2)c(OCc2ccccc2)c1
Reaction time: 8 h
Yield: 100.2 %

Procedure:
4-Trifluoromethylbenzyl bromide (0.17 mL, 1.09 mmol, 1 eq) was added dropwise to a stirred solution of 3-benzyloxy-4-hydroxybenzaldehyde (250 mg, 1.09 mmol, 1 eq) and cesium carbonate (357 mg, 1.09 mmol, 1 eq) in N,N-dimethylformamide (10 mL). The reaction mixture was stirred overnight, then diluted with ethyl acetate (30 mL) and washed sequentially with water (4×30 mL), 0.5M aqueous sodium hydroxide (30 mL), 10% HCl and brine. The organic solution was dried over sodium sulfate and evaporated in vacuo to give the product as a white powder (422 mg, 99%). 1H NMR (CDCl3) δ 9.82 (s, 1H, O═C—H), 5.28 (2H, s, CH2Ar), 5.21 (s, 2H, CH2Ph).
Reaction SMILES: [N:1]1[N:2]([C:6]2[CH:7]=[C:8]([NH:12][C:13]3[C:14]([C:29]#[N:30])=[N:15][CH:16]=[C:17]([NH:19][C@@H:20]4[CH2:25][CH2:24][CH2:23][C:22]([F:27])([F:26])[C@@H:21]4[NH2:28])[N:18]=3)[CH:9]=[CH:10][CH:11]=2)[N:3]=[CH:4][CH:5]=1.[OH-].[Na+].OO.CC(O)=[O:37]>CCO.CS(C)=O>[N:1]1[N:2]([C:6]2[CH:7]=[C:8]([NH:12][C:13]3[C:14]([C:29]([NH2:30])=[O:37])=[N:15][CH:16]=[C:17]([NH:19][C@@H:20]4[CH2:25][CH2:24][CH2:23][C:22]([F:27])([F:26])[C@@H:21]4[NH2:28])[N:18]=3)[CH:9]=[CH:10][CH:11]=2)[N:3]=[CH:4][CH:5]=1
Reactant: N#Cc1ncc(N[C@@H]2CCCC(F)(F)[C@@H]2N)nc1Nc1cccc(-n2nccn2)c1
Reactant: CC(=O)O
Agent: OO
Agent: [Na+]
Agent: [OH-]
Solvent: CS(C)=O
Solvent: CCO
Product: NC(=O)c1ncc(N[C@@H]2CCCC(F)(F)[C@@H]2N)nc1Nc1cccc(-n2nccn2)c1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
The compound 3-(3-(2H-1,2,3-triazol-2-yl)phenylamino)-5-((1R,2R)-2-amino-3,3-difluorocyclohexylamino)pyrazine-2-carbonitrile (41 mg) was dissolved in EtOH (2 mL) and DMSO (1 mL), aq. 1N NaOH (1.0 mL) and aq. H2O2 (50%, 1.0 mL) were added. The mixture was stirred at room temperature for 30 min. HOAc (0.5 mL) was added. The mixture was then concentrated in vacuo. The residue was purified by HPLC to give the titled compound (38 mg). MS 430.3 (M+H); UV 202.3, 262.1, 299.7, 358.5 nm; t 0.488 min.
Reaction SMILES: [CH:1]1([CH:4]=[N:5][N:6]2[C:15]3[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=3)[C:9]([OH:16])=[C:8]([C:17]3[NH:22][C:21]4[S:23][CH:24]=[C:25]([CH2:26][O:27][CH2:28][O:29][CH3:30])[C:20]=4[S:19](=[O:32])(=[O:31])[N:18]=3)[C:7]2=[O:33])[CH2:3][CH2:2]1.CO.[BH4-].[Li+].Cl>O1CCCC1.O>[CH:1]1([CH2:4][NH:5][N:6]2[C:15]3[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=3)[C:9]([OH:16])=[C:8]([C:17]3[NH:22][C:21]4[S:23][CH:24]=[C:25]([CH2:26][O:27][CH2:28][O:29][CH3:30])[C:20]=4[S:19](=[O:31])(=[O:32])[N:18]=3)[C:7]2=[O:33])[CH2:2][CH2:3]1
Reactant: COCOCc1csc2c1S(=O)(=O)N=C(c1c(O)c3ccccc3n(N=CC3CC3)c1=O)N2
Agent: Cl
Agent: [BH4-]
Agent: [Li+]
Solvent: CO
Solvent: C1CCOC1
Solvent: O
Product: COCOCc1csc2c1S(=O)(=O)N=C(c1c(O)c3ccccc3n(NCC3CC3)c1=O)N2
Temperature: 25 °C
Reaction time: 1 h
Yield: 53 %

Procedure:
The product of Example 350F (78.9 mg, 0.16 mmol) in tetrahydrofuran (4 mL) and methanol (0.013 mL, 0.32 mmol) at 0° C. was treated dropwise with a 2.0 M solution of lithium borohydride in tetrahydrofuran (0.131 mL, 0.24 mmol). The reaction was stirred at 25° C. for 1 hour, acidified with 1N hydrochloric acid to approximately pH 2-4, diluted with water (20 mL), and the resulting precipitate was collected by filtration and dried. The crude product was chromatographed on silica gel with 2% methanol/dichloromethane to give the title compound (41.6 mg, 52.5%). The sodium salt of the title compound was prepared according to the procedure of Example 1D. 1H NMR (300 MHz, DMSO-d6) δ 0.15 (d, J=4.41 Hz, 2 H), 0.42 (d, J=8.09 Hz, 2 H), 1.01 (m, 1 H), 2.84 (d, J=6.62 Hz, 2 H), 4.64 (s, 2 H), 4.71 (s, 2 H), 6.36 (br.s, 1 H), 7.41 (m, 2 H), 7.88 (t, J=7.35 Hz, 1 H), 8.07 (d, J=8.46 Hz, 1 H), 8.16 (d, J=8.09 Hz, 1 H). MS (ESI−) m/z 489 (M−H)−.
Reaction SMILES: C[O:2][C:3](=[O:18])[C:4]1[CH:9]=[CH:8][C:7]([CH2:10][N:11]2[CH:15]=[C:14]([CH2:16][OH:17])[N:13]=[CH:12]2)=[CH:6][CH:5]=1.[H-].[Na+].[CH2:21](Br)[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1>C1COCC1.CN(C=O)C>[CH2:21]([O:17][CH2:16][C:14]1[N:13]=[CH:12][N:11]([CH2:10][C:7]2[CH:8]=[CH:9][C:4]([C:3]([OH:2])=[O:18])=[CH:5][CH:6]=2)[CH:15]=1)[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1
Reactant: COC(=O)c1ccc(Cn2cnc(CO)c2)cc1
Reactant: BrCc1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CN(C)C=O
Product: O=C(O)c1ccc(Cn2cnc(COCc3ccccc3)c2)cc1
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 3.3 %

Procedure:
To a solution of 4-(4-hydroxymethylimidazol-1-yl-methyl)benzoic acid methyl ester of Example A1 (0.4 g, 1.6 mmol) in THF/DMF (6/4) was added portionwise NaH 60% (162 mg, 4 mmol). The reaction mixture was stirred at room temperature for 1.5 h, then benzyl bromide (328 mg, 1.92 mmol) was added and the reaction was stirred overnight. The solvent was removed under reduced pressure, then water (10 ml) was added and the mixture was extracted with CH2Cl2. The aqueous phase was acidified with HCl 1 N to pH=4 and extracted with CH2Cl2. The latest organic phase was dried over MgSO4 and concentrated under vacuum. The crude product was purified by flash chromatography on silica gel (CH2Cl2/MeOH: 95/05) to give a white solid (17 mg).
Reaction SMILES: [CH3:1][N:2]1[CH:6]=[CH:5][N:4]=[C:3]1[SH:7].C[Si](C)(C)N[Si](C)(C)C.[N+:17]([C:20]1[CH:27]=[CH:26][C:23]([CH2:24]Br)=[CH:22][CH:21]=1)([O-:19])=[O:18].CN1C=CN=C1S[Si](C)(C)C>C(OCC)(=O)C.S1(C2C(=CC=CC=2)C(=O)N1)(=O)=O.CN(C)P(=O)(N(C)C)N(C)C.C1(C)C=CC=CC=1>[CH3:1][N:2]1[CH:6]=[CH:5][N:4]=[C:3]1[S:7][CH2:24][C:23]1[CH:26]=[CH:27][C:20]([N+:17]([O-:19])=[O:18])=[CH:21][CH:22]=1
Reactant: Cn1ccnc1S
Reactant: O=[N+]([O-])c1ccc(CBr)cc1
Agent: C[Si](C)(C)N[Si](C)(C)C
Agent: Cn1ccnc1S[Si](C)(C)C
Agent: O=C1NS(=O)(=O)c2ccccc21
Solvent: CCOC(C)=O
Solvent: Cc1ccccc1
Solvent: CN(C)P(=O)(N(C)C)N(C)C
Product: Cn1ccnc1SCc1ccc([N+](=O)[O-])cc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 88.9 %

Procedure:
A mixture consisting of 2.85 g (25 mmoles) of 1-methyl-2-mercaptoimidazole, 22 mg (0.12 mmoles) of saccharin, 20 ml of toluene and 5.2 ml (25 mmoles) of hexamethyldisilazane was refluxed for 1 hour and after cooling to room temperature, 5.40 g (25 mmoles) of 4-nitrobenzyl bromide and then 5 ml of hexamethylphosphoric triamide were added to the mixture which contained 1-methyl-2-(trimethylsilylthio)-imidazole. After stirring for 2 hours at room temperature, the mixture was diluted to 150 ml with ethyl acetate and the solution thus obtained was washed three times with 50 ml of a saturated sodium bicarbonate solution and then twice with 20 ml of water. The organic layer was dried, filtered and evaporated to dryness and the crystalline residue was washed with 100 ml of petroleum ether (boiling range 60°-80° C.) and then vacuum dried to obtain 5.54 g (89% yield) of 1-methyl-2-(4-nitrobenzylthio)-imidazole melting to 74°-77° C. Crystallization of a sample from ethanol raised the melting point to 77.5°-78.0° C.
Reaction SMILES: [OH-].[Na+].[C:3]([C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=1[N+:11]([O-:13])=[O:12])#[N:4].[C:14]([C:18]1[CH:23]=[CH:22][CH:21]=[C:20]([C:24]([CH3:27])([CH3:26])[CH3:25])[C:19]=1[OH:28])([CH3:17])([CH3:16])[CH3:15].Cl>CS(C)=O>[C:24]([C:20]1[CH:21]=[C:22]([C:9]2[CH:8]=[CH:7][C:6]([N+:11]([O-:13])=[O:12])=[C:5]([C:3]#[N:4])[CH:10]=2)[CH:23]=[C:18]([C:14]([CH3:17])([CH3:16])[CH3:15])[C:19]=1[OH:28])([CH3:27])([CH3:26])[CH3:25]
Reactant: N#Cc1ccccc1[N+](=O)[O-]
Reactant: CC(C)(C)c1cccc(C(C)(C)C)c1O
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CS(C)=O
Product: CC(C)(C)c1cc(-c2ccc([N+](=O)[O-])c(C#N)c2)cc(C(C)(C)C)c1O
Temperature: 80 °C
Yield: 24.5 %

Procedure:
A mixture of 30 mg (0.75 mmol) of powdered sodium hydroxide, 87 mg (0.59 mmol) of 2-cyano-1-nitrobenzene, 155 mg (0.75 mmol) of 2,6-di-t-butylphenol, and 1.0 mL of dimethylsulfoxide was heated at 80° C. for two hours and poured into 10 mL of 1N HCl, and the resulting aqueous mixture was extracted with three 10 mL portions of diethyl ether. The ether layers were combined, dried over magnesium sulfate, and concentrated. Purification of the residue by preparative thin layer chromatography and crystallization afforded 51 mg (24% yield) of 2,6-di-t-butyl-4-(3'-cyano-4'-nitrophenyl)phenol.