Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1][C:2]([CH3:35])([CH3:34])[CH2:3][C@@:4]1([C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)[O:9][C:8](=[O:10])[N:7]([C@H:11]([C:13]2[CH:18]=[CH:17][C:16](B3OC(C)(C)C(C)(C)O3)=[CH:15][CH:14]=2)[CH3:12])[CH2:6][CH2:5]1.Br[C:37]1[CH:38]=[CH:39][C:40]([C:43]2([S:46]([CH3:49])(=[O:48])=[O:47])[CH2:45][CH2:44]2)=[N:41][CH:42]=1>>[OH:1][C:2]([CH3:34])([CH3:35])[CH2:3][C@@:4]1([C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)[O:9][C:8](=[O:10])[N:7]([C@H:11]([C:13]2[CH:14]=[CH:15][C:16]([C:37]3[CH:42]=[N:41][C:40]([C:43]4([S:46]([CH3:49])(=[O:48])=[O:47])[CH2:45][CH2:44]4)=[CH:39][CH:38]=3)=[CH:17][CH:18]=2)[CH3:12])[CH2:6][CH2:5]1
Reactant: C[C@@H](c1ccc(B2OC(C)(C)C(C)(C)O2)cc1)N1CC[C@](CC(C)(C)O)(c2ccccc2)OC1=O
Reactant: CS(=O)(=O)C1(c2ccc(Br)cn2)CC1
Product: C[C@@H](c1ccc(-c2ccc(C3(S(C)(=O)=O)CC3)nc2)cc1)N1CC[C@](CC(C)(C)O)(c2ccccc2)OC1=O
Yield: 58 %

Procedure:
The title compound was prepared from (S)-6-(2-hydroxy-2-methylpropyl)-6-phenyl-3-{(S)-1-[4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]-ethyl}-1,3-oxazinan-2-one and 5-bromo-2-(1-methanesulfonyl-cyclopropyl)-pyridine following a procedure analogous to that described in Example 1. Yield: 58% of theory; LC (method 1): tR=1.86 min; Mass spectrum (ESI+): m/z=549 [M+H]+.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([N:8]2[CH2:12][CH2:11][C@:10]([CH:15]3[CH2:17][CH2:16]3)([C:13]#[N:14])[C:9]2=[O:18])[CH:5]=[CH:4][N:3]=1.[NH2:19][C:20]1[CH:21]=[N:22][N:23]([C:25]([CH3:29])([CH3:28])[CH2:26][OH:27])[CH:24]=1.C(O)(=O)C>C(O)C>[CH:15]1([C@:10]2([C:13]#[N:14])[CH2:11][CH2:12][N:8]([C:6]3[CH:5]=[CH:4][N:3]=[C:2]([NH:19][C:20]4[CH:21]=[N:22][N:23]([C:25]([CH3:29])([CH3:28])[CH2:26][OH:27])[CH:24]=4)[N:7]=3)[C:9]2=[O:18])[CH2:17][CH2:16]1
Reactant: CC(C)(CO)n1cc(N)cn1
Reactant: N#C[C@@]1(C2CC2)CCN(c2ccnc(Cl)n2)C1=O
Solvent: CCO
Solvent: CC(=O)O
Product: CC(C)(CO)n1cc(Nc2nccc(N3CC[C@@](C#N)(C4CC4)C3=O)n2)cn1
Yield: 41.3 %

Procedure:
A solution of (3S)-1-(2-chloropyrimidin-4-yl)-3-cyclopropyl-2-oxopyrrolidine-3-carbonitrile (11.5 g) obtained in Step E of Example 103, 2-(4-amino-1H-pyrazol-1-yl)-2-methylpropan-1-ol (7.1 g) obtained in Step H of Example 103 and acetic acid (2.6 mL) in ethanol (200 mL) was stirred in a sealed tube reactor at 150° C. for 1 hr, and the solvent was evaporated under reduced pressure. The reaction mixture was neutralized with saturated aqueous sodium bicarbonate, and extracted with ethyl acetate. The obtained organic layer was washed with saturated brine, and dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (hexane/ethyl acetate), and recrystallized (diisopropyl ether/ethyl acetate) to give the title compound (6.9 g).
Reaction SMILES: [H-].[Na+].[F:3][C:4]1[CH:5]=[N:6][CH:7]=[C:8]([F:11])[C:9]=1[NH2:10].[Cl:12][C:13]1[CH:21]=[C:20]([C:22]#[N:23])[CH:19]=[C:18]([Cl:24])[C:14]=1[C:15](Cl)=[O:16]>CN(C=O)C>[Cl:12][C:13]1[CH:21]=[C:20]([C:22]#[N:23])[CH:19]=[C:18]([Cl:24])[C:14]=1[C:15]([NH:10][C:9]1[C:8]([F:11])=[CH:7][N:6]=[CH:5][C:4]=1[F:3])=[O:16]
Reactant: N#Cc1cc(Cl)c(C(=O)Cl)c(Cl)c1
Reactant: Nc1c(F)cncc1F
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: N#Cc1cc(Cl)c(C(=O)Nc2c(F)cncc2F)c(Cl)c1
Reaction time: 1.5 h
Yield: 53.5 %

Procedure:
NaH (461 mg, 11.54 mmol) was added portionwise to a solution of 3,5-difluoropyridin-4-ylamine (1.0 g, 7.69 mmol) in DMF (20 mL) at 0° C. under a nitrogen atmosphere. A solution of 2,6-dichloro-4-cyano-benzoyl chloride (1.98 g, 8.46 mmol) in DMF (15 mL) was then added whilst maintaining the internal temperature below 10° C. Stirring was continued for 1.5 hours. The reaction mixture was quenched by addition of a saturated solution of NH4Cl and partitioned between water and EtOAc. The aqueous phase was further extracted with EtOAc (×2) and the combined organic layers were washed with water, then with brine, dried (MgSO4) and concentrated under reduced pressure. The resultant residue was combined with the crude reaction mixture obtained following the same method starting from 3,5-difluoro-pyridin-4-ylamine (100 mg, 0.77 mmol) and purified by column chromatography on silica gel eluting with 0-50% EtOAc in cyclohexane to afford the title compound as an off-white solid (1.35 g, 49% yield). LCMS (Method D): RT=3.02 min, m/z: 328 [M+H+].
Reaction SMILES: COC(CCC/C=[C:9]1/[C:10](=[O:17])[CH:11]2[CH:15]([CH2:16]/1)[CH2:14][CH2:13][CH2:12]2)=O.[OH-].[Li+].C(O)(=O)C>CO>[CH:11]12[CH2:12][CH2:13][CH2:14][CH:15]1[CH2:16][CH2:9][C:10]2=[O:17]
Reactant: COC(=O)CCC/C=C1\CC2CCCC2C1=O
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Solvent: CC(=O)O
Product: O=C1CCC2CCCC12
Temperature: 10 °C
Reaction time: 3.3 h
Yield: 148 %

Procedure:
A stirred solution of 6-[(E)-(mixture of 3β and 3β)-hydroxyoct-1-enyl]-3-[(E)-4-methoxycarbonylbutylidene]bicyclo[3,3,0]octan-2-one (90 mg), prepared as described in Example 4 and predominantly in the 6β-configuration, otherwise known as (±)-methyl(5E,13E)-(9S),[mixture of (15R) and (15S)]-6a-oxo-6,9-methano-15-hydroxyprosta-5,13-dienoate, in methanol (2 ml) at 5° C. was treated with aqueous lithium hydroxide solution (1.5 ml; 1.0N). The resulting solution was stirred for 3.3 hours at 10° C. and was then treated with glacial acetic acid (0.1 ml). The methanol was removed in vacuo and the residue was diluted with ethyl acetate (10 ml), washed with hydrochloric acid (2N), then with water, and then with saturated aqueous sodium chloride solution, dried over anhydrous sodium sulphate and concentrated in vacuo, to give 3-[(E)-4-carboxybutylidene]-6-[(E)-(mixture of 3α and 3β)-hydroxyoct-1-enyl]bicyclo[3,3,0]octan-2-one (70.0 mg), thought to be in the 6β-configuration, otherwise known as (±)-(5E,13E)-(9S),[mixture of (15R) and (15S)]-6a-oxo-6,9-methano-15-hydroxyprosta-5,13-dienoic acid [NMR in deuterochloroform: multiplets at 6.6, 5.5, 4.8-3.7, 3.0-1.1, 1.1-0.7 p.p.m⟧
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[CH:4][N:3]=1.Cl.[N:12]1([C:18]([O:20][CH2:21][C:22]([NH:24][CH3:25])=[O:23])=[O:19])[CH2:17][CH2:16][NH:15][CH2:14][CH2:13]1.C(N(CC)C(C)C)(C)C>ClCCCl>[N+:8]([C:5]1[CH:6]=[CH:7][C:2]([N:15]2[CH2:14][CH2:13][N:12]([C:18]([O:20][CH2:21][C:22]([NH:24][CH3:25])=[O:23])=[O:19])[CH2:17][CH2:16]2)=[N:3][CH:4]=1)([O-:10])=[O:9]
Reactant: CNC(=O)COC(=O)N1CCNCC1
Reactant: O=[N+]([O-])c1ccc(Cl)nc1
Agent: Cl
Solvent: ClCCCl
Solvent: CCN(C(C)C)C(C)C
Product: CNC(=O)COC(=O)N1CCN(c2ccc([N+](=O)[O-])cn2)CC1
Temperature: 70 °C
Yield: 89 %

Procedure:
1.84 g (11.6 mmol) of 2-chloro-5-nitropyridine are added to a solution of 2.05 g (8.62 mmol) of 2-(methylamino)-2-oxoethyl 1-piperazinecarboxylate hydrochloride, obtained in step 5.2., and 3.85 ml (22.4 mmol) of N,N diisopropylethylamine in 55 ml of 1,2-dichloroethane. This reaction mixture is maintained at 70° C. for 5 hours. The mixture is allowed to cool to room temperature and concentrated under reduced pressure, and the residue thus obtained is purified by chromatography on silica gel, eluting with a 98/2 mixture of dichloromethane and methanol. 2.48 g of product are obtained in the form of a pale yellow solid, and are used without further purification in the following step.
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3]([C:10]2[N:11]=[N:12][N:13]([C:15]3[CH:23]=[CH:22][C:18]([C:19](O)=[O:20])=[CH:17][CH:16]=3)[CH:14]=2)=[N:2]1.[CH3:24][N:25]([CH3:31])[CH:26]1[CH2:30][CH2:29][NH:28][CH2:27]1>>[NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3]([C:10]2[N:11]=[N:12][N:13]([C:15]3[CH:16]=[CH:17][C:18]([C:19]([N:28]4[CH2:29][CH2:30][CH:26]([N:25]([CH3:31])[CH3:24])[CH2:27]4)=[O:20])=[CH:22][CH:23]=3)[CH:14]=2)=[N:2]1
Reactant: O=C(O)c1ccc(-n2cc(-c3n[nH]c4ccccc34)nn2)cc1
Reactant: CN(C)C1CCNC1
Product: CN(C)C1CCN(C(=O)c2ccc(-n3cc(-c4n[nH]c5ccccc45)nn3)cc2)C1

Procedure:
The title compound was obtained following procedure described for example 26, but starting from 4-[4-(1H-indazol-3-yl)-1H-1,2,3-triazol-1-yl]benzoic acid (100 mg; 0.33 mmol; 1.0 eq.) and 3-dimethylamino pyrrolidine (56 mg, 0.49, 1.5 eq.). Purification by flash chomatography on silica (DCM:MeOH:NH4OH, gradient from 100:0:0 to 90:10:0.1) afforded the title compound as a yellow powder. 1H NMR (300 Mz, DMSO-d6) δ 13.37 (s, 1H), 9.39 (s, 1H), 8.36 (d, J=8.2 Hz, 1H), 8.13 (d, J=8.3 Hz, 2H), 7.83-7.72 (m, 2H), 7.61 (d, J=8.4 Hz, 1H), 7.53-7.36 (m, 1H), 7.33-7.19 (m, 1H), 3.77-3.18 (m, 5H), 2.78-2.60 (m, 1H), 2.24-1.92 (m, 6H), 1.82-1.69 (m, 1H). HPLC (Condition A): Rt 2.20 min (purity 90.1%). MS (ESI+): 402.3, MS (ESI−): 400.3.
Reaction SMILES: [OH:1][C:2]1([CH2:17][CH:18]=O)[CH2:6][CH2:5][CH2:4][CH:3]1[C:7]([O:9][CH2:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)=[O:8].[C:20](=[O:27])([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])[NH2:21].C([SiH](CC)CC)C.FC(F)(F)C(O)=O>C(#N)C>[C:23]([O:22][C:20]([NH:21][CH2:18][CH2:17][C:2]1([OH:1])[CH2:6][CH2:5][CH2:4][CH:3]1[C:7]([O:9][CH2:10][C:11]1[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=1)=[O:8])=[O:27])([CH3:26])([CH3:25])[CH3:24]
Reactant: O=CCC1(O)CCCC1C(=O)OCc1ccccc1
Reactant: CC(C)(C)OC(N)=O
Agent: CC[SiH](CC)CC
Solvent: CC#N
Solvent: O=C(O)C(F)(F)F
Product: CC(C)(C)OC(=O)NCCC1(O)CCCC1C(=O)OCc1ccccc1
Temperature: 25 °C
Reaction time: 3 h
Yield: 42.2 %

Procedure:
To a solution of benzyl 2-hydroxy-2-(2-oxoethyl)cyclopentanecarboxylate (from step C, 120 mg, 0.457 mmol) in acetonitrile (2 mL) was added tert-butyl carbamate (214 mg, 1.830 mmol), triethylsilane (213 mg, 1.830 mmol) and trifluoroacetic acid (0.070 mL, 0.915 mmol). The resulting mixture was stirred at room temperature for 3 hours. The reaction mixture was concentrated and subjected to preparative HPLC(Shimadzu VP-ODS 20×100 mm, 8 min. gradient, Solvent A: 10% MeOH, 90% H2O, 0.1% TFA; Solvent B: 90% MeOH, 10% H2O, 0.1% TFA; wavelength: 220 nM). The desired fractions were concentrated and freeze dried to yield benzyl 2-(2-(tert-butoxycarbonylamino)ethyl)-2-hydroxycyclopentanecarboxylate (70 mg, 0.193 mmol, 42.1% yield) as a solid. MS (ESI+)=386 (M+Na)+
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([NH:8][C:9](=[O:17])[CH2:10][C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[CH:5]=[CH:6][CH:7]=1.C([O:20][C:21](=O)[C:22](OCC)=[O:23])C.CC(C)([O-])C.[K+]>O>[Cl:1][C:2]1[CH:3]=[C:4]([N:8]2[C:9](=[O:17])[C:10]([C:11]3[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=3)=[C:22]([OH:23])[C:21]2=[O:20])[CH:5]=[CH:6][CH:7]=1
Reactant: O=C(Cc1ccccc1)Nc1cccc(Cl)c1
Reactant: CCOC(=O)C(=O)OCC
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: O
Product: O=C1C(O)=C(c2ccccc2)C(=O)N1c1cccc(Cl)c1
Reaction time: 3 h

Procedure:
After the addition of anhydride THF (20 ml) to compound 5c (1.55 g, 7.34 mmol), the temperature was adjusted to 0° C. Diethyloxalate (1.45 g, 9.50 mmol) and potassium t-butoxide (1.35 g, 11.9 mmol) were added thereto and the agitation for 3 hours was carried out. After the identification of the reaction progress with TLC, the solution was poured into the distilled water and acidified with 1N HCL aqueous solution. Three times extractions were carried out with EA and three times washings were carried out with brine. Water was removed by using Na2SO4, solvents were removed and then, the suspension was carried out by EA/HX (⅓).
Reaction SMILES: [Br:1][C:2]1[C:3]([Cl:9])=[N:4][C:5]([CH3:8])=[CH:6][CH:7]=1.OO.NC(N)=[O:14].FC(F)(F)C(OC(=O)C(F)(F)F)=O>C(Cl)Cl>[Br:1][C:2]1[C:3]([Cl:9])=[N+:4]([O-:14])[C:5]([CH3:8])=[CH:6][CH:7]=1
Reactant: NC(N)=O
Reactant: Cc1ccc(Br)c(Cl)n1
Agent: OO
Solvent: O=C(OC(=O)C(F)(F)F)C(F)(F)F
Solvent: ClCCl
Product: Cc1ccc(Br)c(Cl)[n+]1[O-]
Temperature: 25 °C
Yield: 102.2 %

Procedure:
To a solution of 3-bromo-2-chloro-6-methylpyridine (1 g, 4.84 mmol) and urea hydrogen peroxide (911 mg, 9.69 mmol) in DCM (24 mL) at 0° C. was added trifluoroacetic anhydride (1.4 mL, 9.69 mmol). After warming to 25° C. over 12 h, the solution was partitioned between H2O-DCM. The aqueous phase was washed several times with DCM and the combined organic fractions were dried over Na2SO4, concentrated and purified via column chromatography (silica, 1% MeOH in DCM) yielding the title compound (1.1 g, quant.) as a white solid: LCMS (ES) m/z=223 (M+H)+.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[CH:5][CH:6]=[C:7]2[C:11]=1[CH:10]([N:12]1[C:17]3[N:18]=[C:19]([S:22][CH3:23])[N:20]=[CH:21][C:16]=3[CH:15]=[CH:14][C:13]1=[O:24])[CH2:9][CH2:8]2.ClC1C=CC=C(C(OO)=[O:33])C=1>ClCCl>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][CH:6]=[C:7]2[C:11]=1[CH:10]([N:12]1[C:17]3[N:18]=[C:19]([S:22]([CH3:23])=[O:33])[N:20]=[CH:21][C:16]=3[CH:15]=[CH:14][C:13]1=[O:24])[CH2:9][CH2:8]2
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: COc1cccc2c1C(n1c(=O)ccc3cnc(SC)nc31)CC2
Solvent: ClCCl
Product: COc1cccc2c1C(n1c(=O)ccc3cnc(S(C)=O)nc31)CC2
Temperature: 25 °C
Reaction time: 5 h
Yield: 112.3 %

Procedure:
To a solution of 8-(7-methoxy-2,3-dihydro-1H-inden-1-yl)-2-(methylthio)pyrido[2,3-d]pyrimidin-7(8H)-one (0.32 g, 0.94 mmol) in dichloromethane (3 mL) was added 3-chloroperbenzoic acid (70%, 0.18 g, 0.73 mmol) and the mixture was stirred at room temperature for 5 h. The reaction mixture was extracted with saturated sodium bicarbonate solution (2×1.5 mL), the organic layer was dried over sodium sulfate, then filtered and evaporated to give 8-(7-methoxy-2,3-dihydro-1H-inden-1-yl)-2-(methylsulfinyl)pyrido[2,3-d]pyrimidin-7(8H)-one as a light brown oil (0.29 g, 0.82 mmol, 87%). ESMS m/z 356 (M+H)+.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][N:5]([C:8]2[CH:9]=[CH:10][C:11]3[N:15]=[C:14]([CH:16]4[CH2:18][CH:17]4[C:19]([OH:22])([CH3:21])[CH3:20])[N:13]([CH3:23])[C:12]=3[CH:24]=2)[C:4](=[O:25])[CH:3]=1.[Cl:26][C:27]1[CH:28]=[CH:29][C:30]([CH2:33]O)=[N:31][CH:32]=1.C(P(CCCC)CCCC)CCC.N(C(N1CCCCC1)=O)=NC(N1CCCCC1)=O>CCOC(C)=O.C1COCC1>[Cl:26][C:27]1[CH:28]=[CH:29][C:30]([CH2:33][O:1][C:2]2[CH:7]=[CH:6][N:5]([C:8]3[CH:9]=[CH:10][C:11]4[N:15]=[C:14]([CH:16]5[CH2:18][CH:17]5[C:19]([OH:22])([CH3:20])[CH3:21])[N:13]([CH3:23])[C:12]=4[CH:24]=3)[C:4](=[O:25])[CH:3]=2)=[N:31][CH:32]=1
Reactant: OCc1ccc(Cl)cn1
Reactant: Cn1c(C2CC2C(C)(C)O)nc2ccc(-n3ccc(O)cc3=O)cc21
Agent: CCCCP(CCCC)CCCC
Agent: O=C(N=NC(=O)N1CCCCC1)N1CCCCC1
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: Cn1c(C2CC2C(C)(C)O)nc2ccc(-n3ccc(OCc4ccc(Cl)cn4)cc3=O)cc21
Temperature: 60 °C
Reaction time: 2 h
Yield: 49.9 %

Procedure:
To a mixture of 4-hydroxy-1-(2-((1RS,2SR)-2-(2-hydroxypropan-2-yl)cyclopropyl)-1-methyl-1H-benzimidazol-6-yl)pyridin-2(1H)-one (100 mg), (5-chloropyridin-2-yl)methanol (85 mg), tributylphosphine (0.219 ml) and THF (10 ml) was added 1,1′-(azodicarbonyl)dipiperidine (223 mg), and the mixture was stirred at 60° C. for 2 h. The reaction mixture was diluted with EtOAc, quenched with water, and extracted with EtOAc. The organic layer was separated, washed with water and brine successively, dried over MgSO4, filtered through silica pad, and concentrated in vacuo. The residue was purified by column chromatography (hexane/EtOAc then EtOAc/MeOH), followed by recrystallization from IPA-IPE to give the title compound (68.4 mg) as an off-white solid.
Reaction SMILES: Br[CH2:2][C:3]1[CH:12]=[CH:11][C:6]([C:7]([O:9][CH3:10])=[O:8])=[CH:5][CH:4]=1.C([O-])([O-])=O.[K+].[K+].[C:19]1([OH:25])[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1.O>CN(C=O)C>[CH3:10][O:9][C:7](=[O:8])[C:6]1[CH:11]=[CH:12][C:3]([CH2:2][O:25][C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)=[CH:4][CH:5]=1
Reactant: COC(=O)c1ccc(CBr)cc1
Reactant: Oc1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: COC(=O)c1ccc(COc2ccccc2)cc1
Reaction time: 8 h
Yield: 87.7 %

Procedure:
To a stirred mixture of 5.72 g (25.0 mmol, 1.0 eq.) of methyl 4-bromomethylbenzoate (Aldrich) and 3.80 g (27.5 mmol, 1.1 eq.) of K2CO3 in 10 mL of DMF at ambient temperature was added a solution of 2.59 g (27.5 mmol, 1.1 eq.) of phenol in 10 mL of DMF dropwise and the mixture stirred overnight. The reaction mixture was poured into 100 mL of water and extracted with 3×100 mL portions of 25% CH2Cl2 -hexanes. The combined organic phases were extracted with 3×100 mL portions of water, dried (MgSO4), filtered and concentrated in vacuo. The solid residue was recrystallized from ~50 mL of hexanes to give 5.31 g (88%) of the title compound as a white, crystalline solid. 1H NMR (300 MHz, CDCl3) δ8.05 (d, 2H), 7.51 (d, 2H), 7.26-7.33 (m, 2H), 6.95-7.02 (m, 3H), 5.13 (s, 2H), 3.92 (s, 3H). MS (DCl) m/e 260 (M+NH4)+.
Reaction SMILES: C[O:2][CH2:3][C@H:4]([CH3:35])[O:5][C:6]1[CH:7]=[C:8]([C:23]2[NH:27][C:26]([C:28]3[O:29][C@@H:30]([CH2:33][OH:34])[CH2:31][N:32]=3)=[CH:25][CH:24]=2)[CH:9]=[C:10]([O:12][C:13]2[CH:18]=[N:17][C:16]([S:19]([CH3:22])(=[O:21])=[O:20])=[CH:15][N:14]=2)[CH:11]=1.B(Br)(Br)Br.C(=O)([O-])O.[Na+]>C(Cl)Cl>[OH:34][CH2:33][C@@H:30]1[O:29][C:28]([C:26]2[NH:27][C:23]([C:8]3[CH:7]=[C:6]([CH:11]=[C:10]([O:12][C:13]4[CH:18]=[N:17][C:16]([S:19]([CH3:22])(=[O:21])=[O:20])=[CH:15][N:14]=4)[CH:9]=3)[O:5][C@@H:4]([CH3:35])[CH2:3][OH:2])=[CH:24][CH:25]=2)=[N:32][CH2:31]1
Reactant: COC[C@H](C)Oc1cc(Oc2cnc(S(C)(=O)=O)cn2)cc(-c2ccc(C3=NC[C@H](CO)O3)[nH]2)c1
Agent: BrB(Br)Br
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Product: C[C@@H](CO)Oc1cc(Oc2cnc(S(C)(=O)=O)cn2)cc(-c2ccc(C3=NC[C@H](CO)O3)[nH]2)c1
Reaction time: 1 h
Yield: 65.3 %

Procedure:
{(5R)-2-[5-(3-[(1S)-2-Methoxy-1-methylethoxy]-5-{[5-(methylsulfonyl)pyrazin-2-yl]oxy}phenyl)-1H-pyrrol-2-yl]-4,5-dihydro-1,3-oxazol-5-yl}methanol (105 mg, 0.21 mmol) synthesized in Example (101d) was dissolved in methylene chloride (10 mL), and boron tribromide (1.0 mol/L methylene chloride solution, 315 μL, 0.315 mmol) was added at −78° C. under nitrogen atmosphere, and subsequently the temperature was brought back to room temperature, followed by stirring for 1 hour. To the reaction solution, a saturated aqueous sodium hydrogencarbonate solution was added, and extraction was carried out with methylene chloride. The organic layer was washed with saturated brine, and subsequently dried over sodium sulfate. The solvent was distilled off under reduced pressure, and the resulting residue was purified using silica gel column chromatography (elution solvent: methanol/methylene chloride=0%-7.5%) to afford the desired compound (67 mg, yield 66%) as a white solid.
Reaction SMILES: [F:1][C:2]([F:19])([CH:16]([F:18])[F:17])[CH2:3][O:4][C:5]1[CH:6]=[C:7]([CH:12]=[CH:13][C:14]=1C)S([O-])(=O)=O.[OH:20][C:21]1C=C(C=CC=1)C=O.C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O>[F:19][C:2]([F:1])([CH:16]([F:17])[F:18])[CH2:3][O:4][C:5]1[CH:6]=[C:7]([CH:12]=[CH:13][CH:14]=1)[CH:21]=[O:20]
Reactant: Cc1ccc(S(=O)(=O)[O-])cc1OCC(F)(F)C(F)F
Reactant: O=Cc1cccc(O)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: O=Cc1cccc(OCC(F)(F)C(F)F)c1
Temperature: 20 °C

Procedure:
Combine 3-(2,2,3,3-tetrafluoropropoxy)tosylate (5.72 g, 17.2 mmol), 3-hydroxybenzaldehyde (2.44 g, 20.0 mmol), dimethylformamide (36 ml) and powdered potassium carbonate (3.03 g) and heat at 110° C. for 10 h. Cool to 20° C. Pass through a bed of aluminium-oxide-90 (57.2 g, 70–230 mesh, grade II–III, Brockmann: Merck # 1.01097) and elute with toluene (120 ml). Wash the eluted organic phase with 1N HCl (36 ml) and then water. Evaporate the organic layer under reduced pressure to give the title compound.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[CH2:11][CH:10](Cl)[C:9]3[CH:13]=[C:14]([F:17])[CH:15]=[CH:16][C:8]=3[S:7][C:6]=2[CH:18]=1.[C:19]([N:24]1[CH2:29][CH2:28][NH:27][CH2:26][CH2:25]1)([O:21][CH2:22][CH3:23])=[O:20]>C(Cl)(Cl)Cl>[C:19]([N:24]1[CH2:29][CH2:28][N:27]([CH:10]2[C:9]3[CH:13]=[C:14]([F:17])[CH:15]=[CH:16][C:8]=3[S:7][C:6]3[CH:18]=[C:2]([Cl:1])[CH:3]=[CH:4][C:5]=3[CH2:11]2)[CH2:26][CH2:25]1)([O:21][CH2:22][CH3:23])=[O:20]
Reactant: Fc1ccc2c(c1)C(Cl)Cc1ccc(Cl)cc1S2
Reactant: CCOC(=O)N1CCNCC1
Solvent: ClC(Cl)Cl
Product: CCOC(=O)N1CCN(C2Cc3ccc(Cl)cc3Sc3ccc(F)cc32)CC1

Procedure:
38.8 G. of 3,10-dichloro-10,11-dihydro-8-fluoro-dibenzo[b,f]thiepin into 100 ml. of chloroform are heated with 82 g. of 1-carbethoxypiperazine for 24 hours under reflux conditions. The reaction mixture is poured on ice water and equilibrated with chloroform. The organic phase is dried over magnesium sulfate and evaporated under reduced pressure. Raw 1-carbethoxy-4-(3-chloro-10,11-dihydro-8-fluoro-dibenzo[b,f]thiepin-10-yl)-piperazine is obtained as a yellow oil.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([NH:8][CH2:9][CH:10]2[CH2:15][CH2:14][N:13]([C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])[CH2:12][CH2:11]2)[C:5](I)=[CH:4][N:3]=1.[CH3:24][O:25][CH2:26]/[CH:27]=[CH:28]/B1OC(C)(C)C(C)(C)O1.C(=O)([O-])[O-].[Na+].[Na+]>C(#N)C.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[Cl:1][C:2]1[CH:7]=[C:6]([NH:8][CH2:9][CH:10]2[CH2:15][CH2:14][N:13]([C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])[CH2:12][CH2:11]2)[C:5](/[CH:28]=[CH:27]/[CH2:26][O:25][CH3:24])=[CH:4][N:3]=1
Reactant: COC/C=C/B1OC(C)(C)C(C)(C)O1
Reactant: CC(C)(C)OC(=O)N1CCC(CNc2cc(Cl)ncc2I)CC1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CC#N
Product: COC/C=C/c1cnc(Cl)cc1NCC1CCN(C(=O)OC(C)(C)C)CC1
Yield: 65.4 %

Procedure:
A solution of tert-butyl 4-((2-chloro-5-iodopyridin-4-ylamino)methyl)piperidine-1-carboxylate (Synthesis 170-B) (0.100 g, 0.22 mmol), (E)-2-(3-methoxyprop-1-enyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (0.044 g, 0.22 mmol), sodium carbonate (0.5 M, 0.66 mL) and tetrakis(triphenylphosphine)palladium(0) (0.013 g, 0.01 mmol) in acetonitrile (2.00 mL) was heated under microwave irradiation for 20 min at 100° C. The solvent was removed in vacuo and the crude product was purified by silica column chromatography, eluting with ethyl acetate and hexane (1/1). to give the title compound as a colourless oil (0.057 g, 65%).
Reaction SMILES: Cl.C(N(CC)CC)C.[N-:9]=[N+:10]=[N-:11].[Na+].[C:13]([C:15]1[CH:16]=[C:17]([CH:20]=[CH:21][CH:22]=1)[CH:18]=[O:19])#[N:14]>CN1CCCC1=O>[NH:9]1[C:13]([C:15]2[CH:16]=[C:17]([CH:20]=[CH:21][CH:22]=2)[CH:18]=[O:19])=[N:14][N:11]=[N:10]1
Reactant: N#Cc1cccc(C=O)c1
Reactant: [N-]=[N+]=[N-]
Agent: Cl
Agent: [Na+]
Solvent: CN1CCCC1=O
Solvent: CCN(CC)CC
Product: O=Cc1cccc(-c2nnn[nH]2)c1
Temperature: 110 °C

Procedure:
5.8 g (42.1 mmol) of triethylamine hydrochloride and 6.0 g (92.3 mmol) of sodium azide are added to a solution of 4.0 g (30.5 mmol) of 3cyano-benzaldehyde in 100 ml of 1-methyl-2-pyrrolidone and heated at 110° C. for 1.5 hours (argon atmosphere). When cool the reaction mixture is poured into 0.6 liter of ice/37% HCl (20:1) and stirred thoroughly to complete the reaction. Extraction with 3 portions of ethyl acetate, washing the organic phases with 3× water and brine, drying (Na2SO4), concentration by evaporation and stirring in diethyl ether yield 3-(tetrazol-5-yl)-benzaldehyde; m.p. 185-189° C.; TLC: Rf=0.13 (CHCl3/methanol/H2O/acetic acid=85:13:1.5:0.5).
Reaction SMILES: [OH:1][C:2]1[N:6]([CH3:7])[N:5]=[C:4]([C:8]([O:10][CH3:11])=[O:9])[CH:3]=1.C(=O)([O-])[O-].[K+].[K+].Cl[CH:19]([F:21])[F:20].O>CN(C)C=O>[F:20][CH:19]([F:21])[O:1][C:2]1[N:6]([CH3:7])[N:5]=[C:4]([C:8]([O:10][CH3:11])=[O:9])[CH:3]=1
Reactant: FC(F)Cl
Reactant: COC(=O)c1cc(O)n(C)n1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: COC(=O)c1cc(OC(F)F)n(C)n1
Temperature: 70 °C
Reaction time: 1.5 h

Procedure:
67.6 g (0.43 mol) 5-Hydroxy-3-methoxycarbonyl-1-methylpyrazole and 299.2 g (2.17 mol) potassium carbonate was dissolved in 1500 ml dimethylformamide and heated to 70° C. At this temperature chlorodifluoromethane was introduced over 2 hours and the mixture stirred at 80° C. for 1.5 hours. The reaction mixture was added to water and extracted 6 times with ethyl acetate. The combined organic phases were washed with saturated aqueous sodium chloride and dried over magnesium sulfate. The reaction solution was concentrated.