Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C@@:8]([C:27]2[CH:32]=[C:31]([O:33][C:34]([F:39])([F:38])[CH:35]([F:37])[F:36])[CH:30]=[C:29]([F:40])[CH:28]=2)([NH:16][C:17]2[S:18][C:19]([CH3:26])=[C:20]([C:22]([F:25])([F:24])[F:23])[N:21]=2)[CH2:9][C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)=[CH:4][C:3]=1[OH:41].C([O-])([O-])=O.[K+].[K+].I[CH:49]([CH3:51])[CH3:50]>CN(C=O)C>[F:1][C:2]1[CH:7]=[CH:6][C:5]([C@:8]([NH:16][C:17]2[S:18][C:19]([CH3:26])=[C:20]([C:22]([F:23])([F:25])[F:24])[N:21]=2)([C:27]2[CH:32]=[C:31]([O:33][C:34]([F:38])([F:39])[CH:35]([F:37])[F:36])[CH:30]=[C:29]([F:40])[CH:28]=2)[CH2:9][C:10]2[CH:11]=[CH:12][CH:13]=[CH:14][CH:15]=2)=[CH:4][C:3]=1[O:41][CH:49]([CH3:51])[CH3:50]
Reactant: CC(C)I
Reactant: Cc1sc(N[C@](Cc2ccccc2)(c2cc(F)cc(OC(F)(F)C(F)F)c2)c2ccc(F)c(O)c2)nc1C(F)(F)F
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: Cc1sc(N[C@](Cc2ccccc2)(c2cc(F)cc(OC(F)(F)C(F)F)c2)c2ccc(F)c(OC(C)C)c2)nc1C(F)(F)F
Temperature: 25 °C
Reaction time: 18 h
Yield: 77 %

Procedure:
To a solution of (S)-2-fluoro-5-(1-(3-fluoro-5-(1,1,2,2-tetrafluoroethoxy)phenyl)-1-(5-methyl-4-(trifluoromethyl)thiazol-2-ylamino)-2-phenylethyl)phenol (16 mg, 0.026 mmol) in DMF (0.5 mL) was added K2CO3 (8 mg, 0.058 mmol), followed by the addition of 2-iodopropane (5 mg, 0.03 mmol). The reaction vessel was sealed and stirred at room temperature for 18 h. The solid was removed by filtration and the filtrate was purified by preparative HPLC Phenomenex AXIA Luna S5 30×75 mm Ballistic column 50-100% ACN (90% in water, 0.1% TFA) gradient over 10 min with flow rate 40 mL/min and UV detection at 220 nm. (S)-N-(1-(4-fluoro-3-isopropoxyphenyl)-1-(3-fluoro-5-(1,1,2,2-tetrafluoroethoxy)phenyl)-2-phenylethyl)-5-methyl-4-(trifluoromethyl)thiazol-2-amine eluted at a retention time of 10.99 min (13 mg, 77% yield). LCMS: RT=4.38 min [M+H] 649.2 (Phenomenex Luna C18 column, 4.6×50 mm eluting with 10-90% MeOH/H2O over 4 minutes containing 0.1% TFA; 4 mL/min, monitoring at 220 nm). NMR: 400 MHz 1H (CDCl3) 7.18 ppm, 1H, m; 7.11 ppm, 3H, m; 6.97 ppm, 5H, m; 6.59 ppm, 2H, d, J=7.07 Hz; 5.86 ppm, 1H, m; 4.46 ppm, 1H, m; 3.71 ppm, 2H, s; 2.29 ppm, 3H, m; 1.24 ppm, 6H, dd, J=8.84, 6.06 Hz.
Reaction SMILES: [Cl:1][C:2]1[C:3](F)=[CH:4][C:5]([F:22])=[C:6]([S:8]([N:11](COCC)[C:12]2[CH:17]=[CH:16][N:15]=[CH:14][N:13]=2)(=[O:10])=[O:9])[CH:7]=1.ClC1C(F)=CC(F)=C(S(/N=C2/N=CN(COCC)C=C/2)(=O)=O)C=1.[NH2:47][C:48]1[CH:53]=[C:52]([C:54]2[CH:59]=[C:58]([Cl:60])[CH:57]=[CH:56][C:55]=2[OH:61])[CH:51]=[CH:50][N:49]=1>>[NH2:47][C:48]1[CH:53]=[C:52]([C:54]2[CH:59]=[C:58]([Cl:60])[CH:57]=[CH:56][C:55]=2[O:61][C:3]2[C:2]([Cl:1])=[CH:7][C:6]([S:8]([NH:11][C:12]3[CH:17]=[CH:16][N:15]=[CH:14][N:13]=3)(=[O:9])=[O:10])=[C:5]([F:22])[CH:4]=2)[CH:51]=[CH:50][N:49]=1
Reactant: Nc1cc(-c2cc(Cl)ccc2O)ccn1
Reactant: CCOCN(c1ccncn1)S(=O)(=O)c1cc(Cl)c(F)cc1F
Agent: CCOCn1cc/c(=N\S(=O)(=O)c2cc(Cl)c(F)cc2F)nc1
Product: Nc1cc(-c2cc(Cl)ccc2Oc2cc(F)c(S(=O)(=O)Nc3ccncn3)cc2Cl)ccn1

Procedure:
The title compound was prepared by analogy with the method used for Example 813 below using 5-chloro-N-(ethoxymethyl)-2,4-difluoro-N-pyrimidin-4-ylbenzenesulfonamide, 5-chloro-N-[(4E)-1-(ethoxymethyl)pyrimidin-4(1H)-ylidene]-2,4-difluorobenzenesulfonamide and 5-chloro-N-[(4E)-1-(ethoxymethyl)pyrimidin-4(1H)-ylidene]-2,4-difluorobenzenesulfonamide, (Preparation 719) used as a mixture of three regioisomers and 2-(2-aminopyridin-4-yl)-4-chlorophenol (Preparation 721).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][C:11]=1[C:12](O)=[O:13])[N:8]=[CH:7][N:6]=[C:5]2[NH:15][CH:16]([C:18]1[NH:22][C:21]2[CH:23]=[CH:24][C:25]([Cl:27])=[CH:26][C:20]=2[N:19]=1)[CH3:17].FC1C(OC(N(C)C)=[N+](C)C)=C(F)C(F)=C(F)C=1F.F[P-](F)(F)(F)(F)F.C(N(C(C)C)CC)(C)C.[CH2:63]([O:70][C:71]([CH:73]1[CH2:77][CH2:76][CH2:75][NH:74]1)=[O:72])[C:64]1[CH:69]=[CH:68][CH:67]=[CH:66][CH:65]=1>CS(C)=O>[Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][C:11]=1[C:12]([N:74]1[CH2:75][CH2:76][CH2:77][CH:73]1[C:71]([O:70][CH2:63][C:64]1[CH:65]=[CH:66][CH:67]=[CH:68][CH:69]=1)=[O:72])=[O:13])[N:8]=[CH:7][N:6]=[C:5]2[NH:15][CH:16]([C:18]1[NH:22][C:21]2[CH:23]=[CH:24][C:25]([Cl:27])=[CH:26][C:20]=2[N:19]=1)[CH3:17]
Reactant: O=C(OCc1ccccc1)C1CCCN1
Reactant: CC(Nc1ncnc2cc(C(=O)O)c(Cl)cc12)c1nc2cc(Cl)ccc2[nH]1
Agent: CN(C)C(Oc1c(F)c(F)c(F)c(F)c1F)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CS(C)=O
Solvent: CCN(C(C)C)C(C)C
Product: CC(Nc1ncnc2cc(C(=O)N3CCCC3C(=O)OCc3ccccc3)c(Cl)cc12)c1nc2cc(Cl)ccc2[nH]1

Procedure:
Prepared analogously to Example 37a from 6-chloro-4-[1-(5-chloro-1H-benzimidazol-2-yl)-ethylamino]-7-hydroxycarbonyl-quinazoline, pentafluorophenyl-tetramethyluronium-hexafluorophosphate (PFTU), diisopropylethylamine and 2-benzyloxycarbonyl-pyrrolidine in DMSO at ambient temperature.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:15])[CH:4]([CH3:14])[CH2:5][NH:6][CH2:7][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1.[C:16]([O:20][CH2:21][CH3:22])(=[O:19])[CH:17]=[CH2:18]>CO>[CH3:1][O:2][C:3]([CH:4]([CH3:14])[CH2:5][N:6]([CH2:7][C:8]1[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=1)[CH2:18][CH2:17][C:16]([O:20][CH2:21][CH3:22])=[O:19])=[O:15]
Reactant: COC(=O)C(C)CNCc1ccccc1
Reactant: C=CC(=O)OCC
Solvent: CO
Product: CCOC(=O)CCN(Cc1ccccc1)CC(C)C(=O)OC
Yield: 94.2 %

Procedure:
3-Phenylmethylamino-2-methyl-propanoic acid methyl ester (79 g, 0.38 mole) from Example and ethyl acrylate (54.2 ml, 50.06 g, 0.5 mole) were dissolved in 200 ml of methanol and then heated to reflux overnight. After being cooled, the solution was concentrated under vacuum to remove the excess of solvent and ethyl acrylate to yield the crude N-[2-(methoxycarbonyl)propyl]-N-[2-(ethoxycarbonyl)ethyl]phenylmethylamine (110 g, 95%).
Reaction SMILES: [CH2:1]([OH:4])[CH2:2][OH:3].Cl.[Cl:6][C:7]1[CH:12]=[CH:11][C:10]([C@H:13]([NH2:22])[C:14]2[CH:19]=[CH:18][C:17]([CH:20]=O)=[CH:16][CH:15]=2)=[CH:9][CH:8]=1.O.C1(C)C=CC(S(O)(=O)=O)=CC=1>C1(C)C=CC=CC=1>[Cl:6][C:7]1[CH:8]=[CH:9][C:10]([CH:13]([NH2:22])[C:14]2[CH:19]=[CH:18][C:17]([CH:20]3[O:4][CH2:1][CH2:2][O:3]3)=[CH:16][CH:15]=2)=[CH:11][CH:12]=1
Reactant: OCCO
Reactant: N[C@@H](c1ccc(Cl)cc1)c1ccc(C=O)cc1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: Cl
Solvent: Cc1ccccc1
Solvent: O
Product: NC(c1ccc(Cl)cc1)c1ccc(C2OCCO2)cc1
Reaction time: 20 h

Procedure:
Chiral (+)-{(4-chlorophenyl)[4-(1,3-dioxolan-2-yl)phenyl]methyl}amine may be obtained in the following manner: 3.95 cm3 of ethylene glycol are poured into a suspension of 18.16 g of chiral (R*)-[(4-chlorophenyl)(4-formylphenyl)methyl]amine hydrochloride, in 1000 cm3 of toluene, and 0.82 g of para-toluenesulfonic acid monohydrate is added. After stirring for 20 hours at the reflux temperature, the reaction medium is cooled, washed with a saturated aqueous sodium bicarbonate solution, with water and with a saturated aqueous sodium chloride solution. The organic phase is dried over magnesium sulfate, filtered and concentrated to dryness under reduced pressure. The residue obtained is purified on a silica gel column (particle size 0.04-0.06 mm, diameter 8.4 cm, height 21.5 cm) with, as eluent, a cyclohexane/ethyl acetate (30/70 by volume) mixture, collecting 250 cm3 fractions. Fractions 23 to 30 are concentrated to dryness under reduced pressure (2.7 kpa). 1.39 g of chiral (+)-{(4-chlorophenyl)-[4-(1,3-dioxolan-2-yl)phenyl]methyl}amine are obtained in the form of a yellow oil.
Reaction SMILES: [ClH:1].C(OC([N:9]1[CH2:14][CH2:13][CH:12]([N:15]2[CH:20]=[CH:19][C:18]([C:21]([O:23][CH3:24])=[O:22])=[C:17]([CH3:25])[C:16]2=[O:26])[CH2:11][CH2:10]1)=O)(C)(C)C.C(OC(C)C)(C)C>>[ClH:1].[CH3:25][C:17]1[C:16](=[O:26])[N:15]([CH:12]2[CH2:11][CH2:10][NH:9][CH2:14][CH2:13]2)[CH:20]=[CH:19][C:18]=1[C:21]([O:23][CH3:24])=[O:22]
Reactant: COC(=O)c1ccn(C2CCN(C(=O)OC(C)(C)C)CC2)c(=O)c1C
Agent: Cl
Solvent: CC(C)OC(C)C
Product: COC(=O)c1ccn(C2CCNCC2)c(=O)c1C
Temperature: 25 °C
Reaction time: 18 h

Procedure:
To 2M hydrogen chloride (2-propanol solution 2.85 L) was added methyl 1-(1-(tert-butoxycarbonyl)piperidin-4-yl)-3-methyl-2-oxo-1,2-dihydropyridine-4-carboxylate (200 g) at room temperature. The mixture was stirred at room temperature for 18 hours. Diisopropyl ether (11.5 L) was added to the reaction mixture and the precipitate was collected by filtration, washed with diisopropyl ether (2.86 L) to give the title compound (163.2 g).
Reaction SMILES: CS(O[CH2:6][CH2:7][O:8][CH2:9][CH:10]1[CH2:16][CH:15]2[N:17]([C:18]3[C:19]4[C:26]([C:27]5[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=5)=[C:25]([C:33](=[O:38])[NH:34][CH:35]([CH3:37])[CH3:36])[S:24][C:20]=4[N:21]=[CH:22][N:23]=3)[CH:12]([CH2:13][CH2:14]2)[CH2:11]1)(=O)=O.[N-:39]=[N+]=[N-].[Na+].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>CN1C(=O)CCC1.C(Cl)Cl>[NH2:39][CH2:6][CH2:7][O:8][CH2:9][CH:10]1[CH2:11][C@H:12]2[N:17]([C:18]3[C:19]4[C:26]([C:27]5[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=5)=[C:25]([C:33]([NH:34][CH:35]([CH3:37])[CH3:36])=[O:38])[S:24][C:20]=4[N:21]=[CH:22][N:23]=3)[C@H:15]([CH2:14][CH2:13]2)[CH2:16]1
Reactant: CC(C)NC(=O)c1sc2ncnc(N3C4CCC3CC(COCCOS(C)(=O)=O)C4)c2c1-c1ccccc1
Reactant: [N-]=[N+]=[N-]
Agent: [Na+]
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Solvent: CN1CCCC1=O
Product: CC(C)NC(=O)c1sc2ncnc(N3[C@@H]4CC[C@H]3CC(COCCN)C4)c2c1-c1ccccc1
Temperature: 150 °C
Reaction time: 8 h
Yield: 41.7 %

Procedure:
2-[[8-[6-(isopropylcarbamoyl)-5-phenyl-thieno[2,3-d]pyrimidin-4-yl]-8-azabicyclo[3.2.1]octan-3-yl]methoxy]ethyl methanesulfonate (0.3 g, 0.5 mmol) was dissolved in NMP (2 mL). Sodium azide (0.2 g, 3 mmol) was added and the reaction heated to 150° C. in the microwave for 30 minutes. The reaction mixture was diluted with DCM (20 mL), washed with water (2×20 mL), dried over Na2SO4 and concentrated in vacuo. The resulting residue was dissolved in THF (5 mL). Triphenylphosphine (0.2 g, 0.8 mmol) was added and the reaction stirred overnight at room temperature. It was heated to reflux for 5 hours. The solvent was removed at reduced pressure. The resulting residue was taken up in DCM, washed with water, dried over Na2SO4 and concentrated at reduced pressure. The resulting residue was purified by flash chromatography, eluting with a gradient of DCM to 90/10/1 DCM/MeOH/NH4OH to afford 4-[(1R,5S)-3-(2-aminoethoxymethyl)-8-azabicyclo[3.2.1]octan-8-yl]-N-isopropyl-5-phenyl-thieno[2,3-d]pyrimidine-6-carboxamide (100 mg).
Reaction SMILES: C([N:14]1[CH2:17][CH:16]([O:18][CH:19]([C:27]2[CH:32]=[CH:31][C:30]([Br:33])=[CH:29][CH:28]=2)[C:20]2[CH:25]=[CH:24][C:23]([Br:26])=[CH:22][CH:21]=2)[CH2:15]1)(C1C=CC=CC=1)C1C=CC=CC=1.Cl.[Cl:35]C1C=CC=CC=1C(OC1CNC1)C1C=CC(Cl)=CC=1>>[ClH:35].[Br:26][C:23]1[CH:24]=[CH:25][C:20]([CH:19]([O:18][CH:16]2[CH2:17][NH:14][CH2:15]2)[C:27]2[CH:28]=[CH:29][C:30]([Br:33])=[CH:31][CH:32]=2)=[CH:21][CH:22]=1
Reactant: Clc1ccc(C(OC2CNC2)c2ccccc2Cl)cc1
Reactant: Brc1ccc(C(OC2CN(C(c3ccccc3)c3ccccc3)C2)c2ccc(Br)cc2)cc1
Agent: Cl
Product: Brc1ccc(C(OC2CNC2)c2ccc(Br)cc2)cc1

Procedure:
This material was prepared from 1-benzhydryl-3-(4,4′-dibromobenzhydryloxy)azetidine (85) using the procedure described for compound (9) (1.15 mg, 30%).
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=O)=[CH:4][CH:3]=1.C(Cl)(=O)C1C=CC=CC=1.[Cl:20][C:21]1[CH:27]=[CH:26][C:24]([NH2:25])=[CH:23][CH:22]=1>[Cl-].[Cl-].[Zn+2].S(Cl)(Cl)=O>[NH2:25][C:24]1[CH:26]=[CH:27][C:21]([Cl:20])=[CH:22][C:23]=1[C:6]([C:5]1[CH:4]=[CH:3][C:2]([Cl:1])=[CH:10][CH:9]=1)=[O:8]
Reactant: O=C(O)c1ccc(Cl)cc1
Reactant: Nc1ccc(Cl)cc1
Agent: [Cl-]
Agent: [Zn+2]
Solvent: O=S(Cl)Cl
Solvent: O=C(Cl)c1ccccc1
Product: Nc1ccc(Cl)cc1C(=O)c1ccc(Cl)cc1
Temperature: 180 °C
Reaction time: 2 h
Yield: 38.3 %

Procedure:
A mixture of 21.0 g (0.135 mol) of p-chlorobenzoic acid and 20 ml of thionyl chloride were heated under reflux to give a clear solution. Removal of the excess of thionyl chloride under reduced pressure obtained white solid and immediately used for the next reaction. To the benzoyl chloride heated to 120° C. was added in portions with stirring 6.3 g (0.05 mol) of 4-chloroaniline. The mixture was heated to 180° C. and 8.5 g (0.063 mol) of ZnCl2 was added. The temperature was gradually increased to about 205° C. and kept there for 2 h. After cooling to 120° C., 60 ml of 3NHCl was added and the mixture stirred and heated to reflux. The hot acid layer was decanted and this procedure repeated two or three times. The water-insoluble residue was dissolved in 80 ml of 70% sulfuric acid and reflux for 8 h and then, after cooling poured into a large amount of ice water. The reaction mixture was neutralized with aqueous ammonia hydroxy and extracted with ethyl acetate, dried over Na2SO4. The solvent was removed and the residue was crystallized from 95% ethanol to give the title compound as golden yellow crystal 5.1 g, and yield 38.5%, m.p. 106-107° C.
Reaction SMILES: [F:1][C:2]([F:11])([F:10])[C:3]1[CH:4]=[C:5]([OH:9])[CH:6]=[CH:7][CH:8]=1.[H-].[Na+].Cl[C:15]1[CH:20]=[CH:19][N:18]=[C:17]([S:21][CH3:22])[N:16]=1>C1COCC1>[CH3:22][S:21][C:17]1[N:18]=[C:19]([O:9][C:5]2[CH:6]=[CH:7][CH:8]=[C:3]([C:2]([F:10])([F:11])[F:1])[CH:4]=2)[CH:20]=[CH:15][N:16]=1
Reactant: CSc1nccc(Cl)n1
Reactant: Oc1cccc(C(F)(F)F)c1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CSc1nccc(Oc2cccc(C(F)(F)F)c2)n1

Procedure:
In THF, a phenoxide was prepared from 3-(trifluoromethyl)phenol (4.54 g, 0.0187×1.5 mol) was mixed with NaH (1.12 g (ca. 60% in mineral oil), 0.0187×1.5 mol), and 4-chloro-2-(methylthio)pyrimidine (Compound No. VII-1) (3.0 g, 0.0187 mol) was added thereto and the mixture was refluxed for about 10 hours. The reaction solution was partitioned between ethyl acetate and aqueous saturated sodium hydrogen carbonate to separate an organic phase. The organic phase was washed with aqueous saturated sodium chloride, dried over anhydrous sodium sulfate and concentrated, then recrystallized from a methanol/water system to obtain the intermediate compound.
Reaction SMILES: [CH:1]([OH:14])([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.ON1C(=O)C2=CC=CC=C2C1=O.O=O.OO>C(#N)C>[C:1]([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)(=[O:14])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: OC(c1ccccc1)c1ccccc1
Agent: O=C1c2ccccc2C(=O)N1O
Agent: O=O
Agent: OO
Solvent: CC#N
Product: O=C(c1ccccc1)c1ccccc1
Yield: 48 %

Procedure:
A mixture of 5 mmol of benzhydrol, 0.5 mmol of N-hydroxyphthalimide, and 5 ml of acetonitrile was stirred at 75° C. in an oxygen atmosphere (1 atm) for 18 hours. An iodometric analysis of a reaction mixture revealed that hydrogen peroxide was formed in yield of 42% (selectivity: 87%). Separately, as a result of a gas chromatographic analysis of the reaction mixture, the conversion rate from benzhydrol was 48%, and benzophenone was formed in yield of 48%.
Reaction SMILES: [NH2:1][C@@H:2]([CH2:6][CH2:7][C:8]([NH:10][C@H:11]([C:14]([NH:16][CH2:17][C:18]([OH:20])=[O:19])=[O:15])[CH2:12][SH:13])=[O:9])[C:3]([OH:5])=[O:4].II>>[O:9]=[C:8]([CH2:7][CH2:6][C@@H:2]([C:3](=[O:5])[OH:4])[NH2:1])[NH:10][C@@H:11]([CH2:12][S:13][S:13][CH2:12][C@@H:11]([C:14](=[O:15])[NH:16][CH2:17][C:18](=[O:20])[OH:19])[NH:10][C:8](=[O:9])[CH2:7][CH2:6][C@@H:2]([C:3](=[O:5])[OH:4])[NH2:1])[C:14](=[O:15])[NH:16][CH2:17][C:18](=[O:20])[OH:19]
Reactant: N[C@@H](CCC(=O)N[C@@H](CS)C(=O)NCC(=O)O)C(=O)O
Agent: II
Product: N[C@@H](CCC(=O)N[C@@H](CSSC[C@H](NC(=O)CC[C@H](N)C(=O)O)C(=O)NCC(=O)O)C(=O)NCC(=O)O)C(=O)O

Procedure:
One equivalence of glutathione in saline is reacted with excess iodine to give about one-half equalivent of GSSG.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[CH:13]=[CH:12][C:11]3=[N:14][C:15]([CH2:17][O:18][C:19]4[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=4)=[CH:16][N:10]3[C:9]2=[O:25])=[CH:4][CH:3]=1>CO.[OH-].[Pd+2].[OH-]>[F:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[CH2:13][CH2:12][C:11]3=[N:14][C:15]([CH2:17][O:18][C:19]4[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=4)=[CH:16][N:10]3[C:9]2=[O:25])=[CH:4][CH:3]=1
Reactant: O=c1n(-c2ccc(F)cc2)ccc2nc(COc3ccccc3)cn12
Agent: [Pd+2]
Agent: [OH-]
Solvent: CO
Product: O=C1N(c2ccc(F)cc2)CCc2nc(COc3ccccc3)cn21
Reaction time: 6 h
Yield: 57.2 %

Procedure:
10% Palladium hydroxide (10 mg, 0.07 mmol) was added to a stirred solution of 6-(4-fluoro-phenyl)-2-phenoxymethyl-6H-imidazo[1,2-c]pyrimidin-5-one (47 mg, 0.14 mmol) in MeOH (50 mL). The mixture was hydrogenated in a Parr reactor at room temperature under H2 atmosphere for 6 hours. Then the mixture was hydrogenated other 7 cycles in a Parr reactor (50 psi) at 50° C. for 16 hours with addition of 10% palladium hydroxide (10 mg, 0.07 mmol) every cycle. The mixture was filtered through a pad of diatomaceous earth and the solvents were evaporated in vacuo. The crude product was purified by flash column chromatography (silica; AcOEt in DCM with a gradient of 0/100 to 50/50). The desired fractions were collected and the solvents evaporated in vacuo to yield 6-(4-fluoro-phenyl)-2-phenoxymethyl-7,8-dihydro-6H-imidazo[1,2-c]pyrimidin-5-one (27 mg, 57% yield) as a white solid. 1H NMR (400 MHz, CDCl3) 8 ppm 3.29 (t, J=6.7 Hz, 2H), 4.00 (t, J=6.7 Hz, 2H), 5.02 (d, J=0.7 Hz, 2H), 6.94-6.99 (m, 1H), 6.99-7.05 (m, 2H), 7.10-7.17 (m, 2H), 7.27-7.35 (m, 4H), 7.57 (s, 1H).
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[C:6]([O:8][CH3:9])[CH:5]=[CH:4][C:3]=1[N:10]1[C:22]2[C:21]3[CH:20]=[CH:19][CH:18]=[C:17]([O:23][C:24]([F:27])([F:26])[F:25])[C:16]=3[N:15]=[C:14](Cl)[C:13]=2[CH2:12][CH2:11]1.[NH2:29][CH2:30][CH2:31][CH2:32][OH:33]>>[CH3:1][C:2]1[CH:7]=[C:6]([O:8][CH3:9])[CH:5]=[CH:4][C:3]=1[N:10]1[C:22]2[C:21]3[CH:20]=[CH:19][CH:18]=[C:17]([O:23][C:24]([F:27])([F:26])[F:25])[C:16]=3[N:15]=[C:14]([NH:29][CH2:30][CH2:31][CH2:32][OH:33])[C:13]=2[CH2:12][CH2:11]1
Reactant: NCCCO
Reactant: COc1ccc(N2CCc3c(Cl)nc4c(OC(F)(F)F)cccc4c32)c(C)c1
Product: COc1ccc(N2CCc3c(NCCCO)nc4c(OC(F)(F)F)cccc4c32)c(C)c1

Procedure:
1-(2-Methyl-4-methoxyphenyl)-4-chloro-6-trifluoromethoxy-2,3-dihydropyrrolo[3,2-c]quinoline(550 mg, 1.3 mmol) was dissolved in 3-amino-1-propanol(10 ml) in the pressure tube, and reacted at the same condition of Step 3 in the Example 23 to obtain 400 mg of desired compound as solid in 67% of yield.
Reaction SMILES: [C@@H:1]12[C:10](=[O:11])[O:9][C:7](=[O:8])[C@H:2]1[CH2:3][CH2:4][CH2:5][CH2:6]2.[Cl-].[Al+3].[Cl-].[Cl-].[C:16]1([CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH3:30])[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1>>[CH2:22]([C:16]1[CH:17]=[CH:18][C:19]([C:7]([C@@H:2]2[CH2:3][CH2:4][CH2:5][CH2:6][C@H:1]2[C:10]([OH:9])=[O:11])=[O:8])=[CH:20][CH:21]=1)[CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH3:30]
Reactant: O=C1OC(=O)[C@H]2CCCC[C@H]12
Reactant: CCCCCCCCCc1ccccc1
Agent: [Al+3]
Agent: [Cl-]
Product: CCCCCCCCCc1ccc(C(=O)[C@@H]2CCCC[C@H]2C(=O)O)cc1

Procedure:
The procedure described in Example 23 is followed using trans-1,2-cyclohexanedicarboxylic anhydride (20.0 g), 1-phenylnonane (200 ml), and anhydrous aluminum chloride (38.1 g). Work-up as described provided trans-2-(4-n-nonylbenzoyl)cyclohexane1-carboxylic acid (28.5 g, m.p. 84°-86° C).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[NH:8][C:9]1[O:10][CH2:11][C:12](=[O:19])[C:13]=1[C:14]([O:16][CH2:17][CH3:18])=[O:15].[NH:20]1[C:28]2[C:23](=[CH:24][CH:25]=[CH:26][N:27]=2)[C:22]([CH:29]=O)=[CH:21]1.N1CCCCC1>C(O)C>[NH:20]1[C:28]2=[N:27][CH:26]=[CH:25][CH:24]=[C:23]2[C:22]([CH:29]=[C:11]2[O:10][C:9]([NH:8][C:3]3[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=3[F:1])=[C:13]([C:14]([O:16][CH2:17][CH3:18])=[O:15])[C:12]2=[O:19])=[CH:21]1
Reactant: CCOC(=O)C1=C(Nc2ccccc2F)OCC1=O
Reactant: O=Cc1c[nH]c2ncccc12
Solvent: CCO
Solvent: C1CCNCC1
Product: CCOC(=O)C1=C(Nc2ccccc2F)OC(=Cc2c[nH]c3ncccc23)C1=O
Yield: 27.7 %

Procedure:
To a solution of ethyl 2-[(2-fluorophenyl)amino]-4-oxo-4,5-dihydrofuran-3-carboxylate (0.10 g, 0.38 mmol) which similarly prepared according to the procedure described in the Example 4, First step and 7-azaindole-3-carboxaldehyde (0.050 g, 0.34 mmol) in ethanol (2.0 mL), piperidine (0.0034 mL, 0.034 mmol) was added at ambient temperature. The mixture was refluxed for 36 h. The precipitate was collected by filtration, washed with hot ethanol. The solid was washed with hexane then dried to afford the titled compound as solid (0.037 g, y. 27%).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:15])[C:4]1[CH:12]=[C:11]([O:13][CH3:14])[CH:10]=[C:6]([C:7]([NH2:9])=O)[CH:5]=1.N1C=CC=CC=1.FC(F)(F)C(OC(=O)C(F)(F)F)=O>ClCCl>[CH3:1][O:2][C:3](=[O:15])[C:4]1[CH:12]=[C:11]([O:13][CH3:14])[CH:10]=[C:6]([C:7]#[N:9])[CH:5]=1
Reactant: COC(=O)c1cc(OC)cc(C(N)=O)c1
Solvent: ClCCl
Solvent: c1ccncc1
Solvent: O=C(OC(=O)C(F)(F)F)C(F)(F)F
Product: COC(=O)c1cc(C#N)cc(OC)c1
Temperature: 0 °C
Reaction time: 0.33 h
Yield: 98.6 %

Procedure:
A suspension of 5-methoxy-isophthalamic acid methyl ester (4.0 g, 19.1 mmol) in a dichloromethane (80 mL) at 0° C. was treated with pyridine (6.3 mL, 77.0 mmol) and then trifluoroacetic anhydride drop-wise (6.5 mL, 46 mmol). The reaction was stirred at 0° C. for 20 min. and then stirred overnight at room temperature. The reaction mixture was washed with water, 1.0 N HCl and brine, dried over anhydrous sodium sulfate, filtered and concentrated to afford 3.6 g (98%) of 3-cyano-5-methoxy-benzoic acid methyl ester as a white solid.
Reaction SMILES: [OH:1][CH:2]([C:22]1[C:30]([S:31]([CH3:34])(=[O:33])=[O:32])=[CH:29][C:28]([CH3:35])=[C:27]2[C:23]=1[CH:24]=[CH:25][N:26]2S(C1C=CC(C)=CC=1)(=O)=O)[C:3]1[N:7](COCC[Si](C)(C)C)[C:6]2[CH:16]=[C:17]([C:20]#[N:21])[CH:18]=[CH:19][C:5]=2[N:4]=1.OC(C1C(S(C)(=O)=O)=CC(C)=C2C=1C=CN2S(C1C=CC(C)=CC=1)(=O)=O)C1N(COCC[Si](C)(C)C)C2C=CC(C#N)=CC=2N=1.F[B-](F)(F)F.[Li+].CC#N.CCN(CCOC(C1(CCC(C)C)CCCCC1)=O)CC.[OH-].[K+]>O>[OH:1][CH:2]([C:22]1[C:30]([S:31]([CH3:34])(=[O:33])=[O:32])=[CH:29][C:28]([CH3:35])=[C:27]2[C:23]=1[CH:24]=[CH:25][NH:26]2)[C:3]1[NH:4][C:5]2[CH:19]=[CH:18][C:17]([C:20]#[N:21])=[CH:16][C:6]=2[N:7]=1
Reactant: Cc1ccc(S(=O)(=O)n2ccc3c(C(O)c4nc5ccc(C#N)cc5n4COCC[Si](C)(C)C)c(S(C)(=O)=O)cc(C)c32)cc1
Agent: CCN(CC)CCOC(=O)C1(CCC(C)C)CCCCC1
Agent: Cc1ccc(S(=O)(=O)n2ccc3c(C(O)c4nc5cc(C#N)ccc5n4COCC[Si](C)(C)C)c(S(C)(=O)=O)cc(C)c32)cc1
Agent: F[B-](F)(F)F
Solvent: O
Solvent: CC#N
Product: Cc1cc(S(C)(=O)=O)c(C(O)c2nc3cc(C#N)ccc3[nH]2)c2cc[nH]c12
Temperature: 70 °C

Procedure:
To a mixture of (±)-2-(hydroxy(7-methyl-5-(methylsulfonyl)-1-tosyl-1H-indol-4-yl)methyl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-benzo[d]imidazole-6-carbonitrile and (±)-2-(hydroxy(7-methyl-5-(methylsulfonyl)-1-tosyl-1H-indol-4-yl)methyl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-benzo[d]imidazole-5-carbonitrile (100 mg, 0.150 mmol) was added a 1 M solution of lithium tetrafluoroborate in MeCN (3.0 mL, 3 mmol). Water (0.3 mL) was then added and the reaction heated to 70° C. overnight. The reaction mixture was cooled to room temperature, diluted with water and extracted with EtOAc. The organic extract was dried over MgSO4, filtered and concentrated. The resulting residue was dissolved in EtOH (1.3 mL) and isomylamine (0.3 mL, 2.6 mmol) and KOH (0.072 g, 1.3 mmol) were added. The mixture was then heated to 100° C. for 1 h using microwave irradiation. The mixture was then concentrated directly and purified using FCC eluting with DCM:MeOH:NH4OH 100:0:0 to 80:18:2 to give the title compound. 1H NMR (400 MHz, DMSO-d6) δ 13.17 (br. s., 1H), 11.50 (br. s., 1H), 7.83-8.00 (m, 1H), 7.61-7.67 (m, 1H), 7.49-7.58 (m, 2H), 7.41-7.49 (m, 1H), 7.35 (q, J=2.40 Hz, 1H), 6.91 (dd, J=4.67, 7.58 Hz, 1H), 6.58 (dt, J=1.89, 3.66 Hz, 1H), 3.46 (m, 3H), 2.53 (s, 3H). HRMS calcd. for C19H16N4O3S (M+H)+ 381.1021. found 381.1013.