Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl.Cl[CH2:3][CH2:4][N:5]1[CH2:10][CH2:9][O:8][CH2:7][CH2:6]1.[C:11]([C:13]1([NH:16][C:17]([C@@H:19]2[CH2:24][CH2:23][CH2:22][CH2:21][C@H:20]2[C:25]([N:27]2[CH2:40][CH2:39][C:30]3[NH:31][C:32]4[C:33]([OH:38])=[CH:34][CH:35]=[CH:36][C:37]=4[C:29]=3[CH2:28]2)=[O:26])=[O:18])[CH2:15][CH2:14]1)#[N:12].C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C>[C:11]([C:13]1([NH:16][C:17]([C@@H:19]2[CH2:24][CH2:23][CH2:22][CH2:21][C@H:20]2[C:25]([N:27]2[CH2:40][CH2:39][C:30]3[NH:31][C:32]4[C:33]([O:38][CH2:3][CH2:4][N:5]5[CH2:10][CH2:9][O:8][CH2:7][CH2:6]5)=[CH:34][CH:35]=[CH:36][C:37]=4[C:29]=3[CH2:28]2)=[O:26])=[O:18])[CH2:15][CH2:14]1)#[N:12]
Reactant: ClCCN1CCOCC1
Reactant: N#CC1(NC(=O)[C@@H]2CCCC[C@H]2C(=O)N2CCc3[nH]c4c(O)cccc4c3C2)CC1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: N#CC1(NC(=O)[C@@H]2CCCC[C@H]2C(=O)N2CCc3[nH]c4c(OCCN5CCOCC5)cccc4c3C2)CC1
Temperature: 25 °C
Reaction time: 45 h

Procedure:
Following on from Example 34, 4-(2-Chloroethyl)morpholine hydrochloride (90 mg, 0.48 mmol) was added to (1R,2R)-N-(1-cyanocyclopropyl)-2-(6-hydroxy-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indole-2-carbonyl)cyclohexanecarboxamide (131 mg, 0.32 mmol) and potassium carbonate (134 mg, 0.97 mmol) in DMF (5 ml) at 25° C. under air. The resulting solution was stirred at room temperature for 45 hours, to yield after purification a cream solid. (4.00 mg, 2.4%).
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][N:5]=[C:4]([CH:8]=C)[C:3]=1[CH2:10][O:11][CH:12]1[CH2:17][CH2:16][CH2:15][CH2:14][O:13]1.[BH4-].[Na+].C[OH:21]>C(Cl)Cl>[CH3:1][C:2]1[CH:7]=[CH:6][N:5]=[C:4]([CH2:8][OH:21])[C:3]=1[CH2:10][O:11][CH:12]1[CH2:17][CH2:16][CH2:15][CH2:14][O:13]1
Reactant: CO
Reactant: C=Cc1nccc(C)c1COC1CCCCO1
Agent: [BH4-]
Agent: [Na+]
Solvent: ClCCl
Product: Cc1ccnc(CO)c1COC1CCCCO1
Temperature: -50 °C

Procedure:
4-Methyl-3-(tetrahydro-pyran-2-yloxymethyl)-2-vinyl-pyridine (300 mg. 1.29 mmol) was dissolved in DCM (36 mL) and cooled to −50° C. A gentle flow of ozone was bubbled through the reaction mixture until the colour of the solution changed to slight blue. NaBH4 (486 mg. 12.9 mmol) dissolved in MeOH (15 mL) was added and the reaction was allowed to warm to RT over a period of 1 h. The solvents were removed in vacuo and the residue pardoned between water (20 mL) and EtOAc (20 mL) extracted with EtOAc (3×20 mL). The combined organic fractions were washed with brine and dried over Na2SO4 filtered and concentrated in vacuo. The residue was purified by flash chromatography on silica gel (elution with DCM/MeOH 40:1→20:1) to give the title compound. MS (m/z): 238.0 [M+H+].
Reaction SMILES: [F:1][C:2]([F:20])([F:19])[C:3]([NH:5][CH2:6][C@@H:7]1[CH2:11][CH2:10][N:9](C(OC(C)(C)C)=O)[CH2:8]1)=[O:4].C(O)(C(F)(F)F)=O>C(Cl)Cl>[F:20][C:2]([F:1])([F:19])[C:3]([NH:5][CH2:6][C@@H:7]1[CH2:11][CH2:10][NH:9][CH2:8]1)=[O:4]
Reactant: CC(C)(C)OC(=O)N1CC[C@@H](CNC(=O)C(F)(F)F)C1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: O=C(NC[C@@H]1CCNC1)C(F)(F)F
Reaction time: 2 h
Yield: 94.8 %

Procedure:
To a stirred solution of 1,1-dimethylethyl(3S)-3{[(trifluoroacetyl)amino]methyl}-1-pyrrolidinecarboxylate (2.96 g, 10.0 mmole), in CH2Cl2 (50 mL) at RT was added TFA (25 mL). After 2 h, the reaction contents were concentrated under vacuum. The remaining residue was dissolved in (CHCl3/i-PrOH, 10:1) and washed with saturated aqueous NaHCO3. The organic phase was separated and dried over Na2SO4. Concentration under vacuum afforded the title compound (1.86 g, 95%) as a yellow oil: LC-MS (ES) m/e 197 (M+H)+.
Reaction SMILES: [CH3:1][O:2][CH:3]([CH2:17][CH3:18])[CH2:4][CH2:5][CH2:6][CH2:7][CH:8]1[CH2:15][CH2:14][CH:13]2[CH:9]1[CH2:10][C:11](=[O:16])[CH2:12]2.[CH3:19]OC(CC)CCCCC1CCC2C1CC(=O)C2.C([Mg]Br)C>CCOCC>[CH3:1][O:2][CH:3]([CH2:17][CH3:18])[CH2:4][CH2:5][CH2:6][CH2:7][CH:8]1[CH2:15][CH2:14][CH:13]2[CH:9]1[CH2:10][C:11]([CH3:19])([OH:16])[CH2:12]2
Reactant: CCC(CCCCC1CCC2CC(=O)CC12)OC
Agent: CC[Mg]Br
Solvent: CCOCC
Product: CCC(CCCCC1CCC2CC(C)(O)CC12)OC
Yield: 39.9 %

Procedure:
2-(5-Methoxyhept-1-yl)bicyclo[3.3.0]octan-7-one hexahydro-4-(5-methoxyheptyl)-2(1H)-pentalenone, (4 g, 0.0158 moles) diluted in ether is added dropwise to a stirring solution of ethyl magnesium bromide (0.0158 moles) dissolved with diethyl ether. The mixture is cooled in an ice bath during the addition. The ice bath is removed and the solution stirred for an additional hour. The reaction is quenched with water and a 15% sulfuric acid solution. The organic phase is separated and the solvent removed under vacuum. The aqueous layer is extracted (2×200 ml) and the extracts are combined with the organic layer and dried over anhydrous sodium sulfate. The solid is filtered off and the remaining solvent removed leaving a clear, pale yellow oil. The crude product is subsequently chromatographed on silica gel yielding desired product as a clear colorless oil (1.7 g, 6.3 mmoles).
Reaction SMILES: [O:1]1[C:5]2([CH2:10][CH2:9][NH:8][CH2:7][CH2:6]2)[O:4][CH2:3][CH2:2]1.Cl.Cl[C:13]1[CH:18]=[CH:17][N:16]=[CH:15][CH:14]=1.C(N(CC)CC)C.[OH-].[Na+]>C(O)C>[N:16]1[CH:17]=[CH:18][C:13]([N:8]2[CH2:9][CH2:10][C:5]3([O:4][CH2:3][CH2:2][O:1]3)[CH2:6][CH2:7]2)=[CH:14][CH:15]=1
Reactant: Clc1ccncc1
Reactant: C1CC2(CCN1)OCCO2
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: CCN(CC)CC
Product: c1cc(N2CCC3(CC2)OCCO3)ccn1
Yield: 74.5 %

Procedure:
A mixture of 1,4-dioxa-8-azaspiro[4.5]decane (150 g), 4-chloropyridine hydrochloride (190 g) and triethylamine (320 g) in ethanol (800 ml) was reacted in a sealed tube at 150° C. for 15 hours. The reaction mixture was concentrated to obtain a residue, which was made alkaline by an addition of a 6N aqueous solution of sodium hydroxide, and then extracted with dichloromethane. After drying and concentrating, the resultant residue was triturated from hexane, collected by filtration and then dried to obtain 8-(4-pyridyl)-1,4-dioxa-8-azaspiro[4.5]decane (172 g) as a pale yellow solid.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([CH2:8][C:9]([OH:11])=[O:10])[CH:5]=[CH:6][CH:7]=1.O.[C:13]1(C)C=CC(S(O)(=O)=O)=C[CH:14]=1>C(O)C>[OH:1][C:2]1[CH:3]=[C:4]([CH2:8][C:9]([O:11][CH2:13][CH3:14])=[O:10])[CH:5]=[CH:6][CH:7]=1
Reactant: O=C(O)Cc1cccc(O)c1
Reactant: Cc1ccc(S(=O)(=O)O)cc1
Solvent: O
Solvent: CCO
Product: CCOC(=O)Cc1cccc(O)c1

Procedure:
A solution of 3-Hydroxyphenylacetic acid (25 g, 164.31 mmol) and p-Toluenesulfonic acid monohydrate (3.49 g, 18.3 mmol) in abs ethanol (250 ml) was refluxed for 4 hours or until all the starting material is consumed. The reaction mixture was concentrated, diluted with ethyl acetate and washed with water. The organic layer was dried over Na2SO4, filtered, concentrated, and purified by flash chromatography on a silica gel column (hex:ethyl acetate 2:1) to give the title compound.
Reaction SMILES: [OH:1][C:2]([C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1)([C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1)[CH:3]1[CH2:8][CH2:7][N:6]([CH2:9][CH2:10][CH2:11][CH:12]([C:14]2[CH:19]=[CH:18][C:17]([C:20]([CH3:27])([CH3:26])[C:21](OCC)=[O:22])=[CH:16][CH:15]=2)[OH:13])[CH2:5][CH2:4]1.[H-].[Al+3].[Li+].[H-].[H-].[H-].[OH-].[Na+].S([O-])([O-])(=O)=O.[Na+].[Na+]>O1CCCC1.O>[C:28]1([C:2]([C:34]2[CH:35]=[CH:36][CH:37]=[CH:38][CH:39]=2)([CH:3]2[CH2:8][CH2:7][N:6]([CH2:9][CH2:10][CH2:11][CH:12]([C:14]3[CH:15]=[CH:16][C:17]([C:20]([CH3:27])([CH3:26])[CH2:21][OH:22])=[CH:18][CH:19]=3)[OH:13])[CH2:5][CH2:4]2)[OH:1])[CH:29]=[CH:30][CH:31]=[CH:32][CH:33]=1
Reactant: CCOC(=O)C(C)(C)c1ccc(C(O)CCCN2CCC(C(O)(c3ccccc3)c3ccccc3)CC2)cc1
Agent: O=S(=O)([O-])[O-]
Agent: [Al+3]
Agent: [H-]
Solvent: C1CCOC1
Solvent: O
Product: CC(C)(CO)c1ccc(C(O)CCCN2CCC(C(O)(c3ccccc3)c3ccccc3)CC2)cc1
Reaction time: 3 h

Procedure:
A suspension of 2.15 g (0.0038 mole) of ethyl 4-[4-[4-(hydroxydiphenylmethyl)-1-piperidinyl]-1-hydroxybutyl]-α,α-dimethylbenzeneacetate in 50 ml of tetrahydrofuran was slowly added to a suspension of 0.7 g (0.0184 mole) of lithium aluminum hydride in 60 ml of tetrahydrofuran under a nitrogen atmosphere with stirring at such a rate to moderate the foaming. The mixture is stirred and heated at boiling for about 3 hours after which 30 ml of tetrahydrofuran is added. The mixture is refluxed for 4 hours and let stand overnight (about 16 hours). Stirring the mixture under a nitrogen atmosphere, 2 ml of water is added cautiously followed by 2 ml of 10% sodium hydroxide, 2 ml of water and 4 g of sodium sulfate. The mixture is warmed to 50°-55° C. and stirred for 45 minutes, filtered and the solid material is washed with tetrahydrofuran. The combined filtrates are evaporated in vacuo, and the residue is recrystallized from ethanol to give α,α-diphenyl-1-[4-[4-hydroxy-tert-butyl)phenyl]-4-hydroxybutyl]-4-piperidinemthanol, M.P. 134°-136° C.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:16]=[CH:15][C:14]([C:17]3[N:18]([C:33]([O:35][C:36]([CH3:39])([CH3:38])[CH3:37])=[O:34])[C:19]4[C:24]([CH:25]=3)=[CH:23][C:22]([CH2:26][N:27]3[CH2:32][CH2:31][CH2:30][CH2:29][CH2:28]3)=[CH:21][CH:20]=4)=[C:13]3[C:9]=2[CH2:10][NH:11][C:12]3=[O:40])=[CH:4][CH:3]=1.[S:41](Cl)(=[O:44])(=[O:43])[NH2:42].O>CN(C)C(=O)C>[S:41]([O:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[CH:16]=[CH:15][C:14]([C:17]3[N:18]([C:33]([O:35][C:36]([CH3:37])([CH3:39])[CH3:38])=[O:34])[C:19]4[C:24]([CH:25]=3)=[CH:23][C:22]([CH2:26][N:27]3[CH2:32][CH2:31][CH2:30][CH2:29][CH2:28]3)=[CH:21][CH:20]=4)=[C:13]3[C:9]=2[CH2:10][NH:11][C:12]3=[O:40])=[CH:6][CH:7]=1)(=[O:44])(=[O:43])[NH2:42]
Reactant: NS(=O)(=O)Cl
Reactant: CC(C)(C)OC(=O)n1c(-c2ccc(-c3ccc(O)cc3)c3c2C(=O)NC3)cc2cc(CN3CCCCC3)ccc21
Solvent: O
Solvent: CC(=O)N(C)C
Product: CC(C)(C)OC(=O)n1c(-c2ccc(-c3ccc(OS(N)(=O)=O)cc3)c3c2C(=O)NC3)cc2cc(CN3CCCCC3)ccc21
Temperature: 25 °C
Reaction time: 17 h
Yield: 55.9 %

Procedure:
4-(4-Hydroxyphenyl)-7-[1-(tert-butoxycarbonyl)-5-(piperidinomethyl)indol-2-yl]isoindolinone (56.2 mg, 0.105 mmol) was dissolved in N,N-dimethylacetoamide (3.9 mL), and the solution was added with sulfamoyl chloride (61 mg, 0.53 mmol), followed by stirring at room temperature for 17 hours. The reaction mixture was added with water and extracted with ethyl acetate and chloroform. The organic layer was washed with saturated brine and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure and the residue was purified by preparative thin-layer chromatography (chloroform/methanol=5/1) to obtain 4-(4-sulfamoyloxyphenyl)-7-[1-(tert-butoxycarbonyl)-5-(piperidinomethyl)indol-2-yl]isoindolinone (36.2 mg, yield 56%).
Reaction SMILES: [O:1]1[CH2:6][CH2:5][C:4](=[O:7])[CH2:3][CH2:2]1.Cl[CH2:9][C:10]#[N:11].CC(C)([O-])C.[K+]>C(O)(C)(C)C>[O:7]1[C:4]2([CH2:5][CH2:6][O:1][CH2:2][CH2:3]2)[CH:9]1[C:10]#[N:11]
Reactant: O=C1CCOCC1
Reactant: N#CCCl
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: CC(C)(C)O
Product: N#CC1OC12CCOCC2
Temperature: 25 °C
Reaction time: 1 h
Yield: 90.3 %

Procedure:
Tetrahydro-4H-pyran-4-one (2.50 g, 25.0 mmol) and chloroacetonitrile (1.58 mL, 25.0 mmol) were dissolved in tert-butanol (5.0 mL). To this, a tert-butanol solution (25 mL) of potassium tert-butoxide (2.81 g, 25.0 mmol) was added dropwise and the mixture was stirred at room temperature for 1 hour. The reaction was stopped by successive addition of ice and a 1 mol/L aqueous hydrogen chloride solution (30 mL) to the reaction mixture, and extraction with ether was performed, followed by washing with brine and drying over anhydrous magnesium sulfate. The solvent was evaporated off under reduced pressure, and the residue was purified by silica gel column chromatography (hexane/ethyl acetate=7/3) to give 1,6-dioxaspiro[2.5]octane-2-carbonitrile (3.14 g, yield: 90%).
Reaction SMILES: Cl[C:2]1[CH:11]=[CH:10][N:9]=[C:8]2[C:3]=1[CH:4]=[CH:5][C:6]([CH3:12])=[N:7]2.[NH2:13][C:14]1[CH:27]=[C:26]([CH3:28])[CH:25]=[CH:24][C:15]=1[O:16][C:17]1[CH:22]=[CH:21][C:20]([OH:23])=[CH:19][CH:18]=1>>[CH3:28][C:26]1[CH:25]=[CH:24][C:15]([O:16][C:17]2[CH:18]=[CH:19][C:20]([OH:23])=[CH:21][CH:22]=2)=[C:14]([NH:13][C:2]2[C:3]3[C:8](=[N:7][C:6]([CH3:12])=[CH:5][CH:4]=3)[N:9]=[CH:10][CH:11]=2)[CH:27]=1
Reactant: Cc1ccc(Oc2ccc(O)cc2)c(N)c1
Reactant: Cc1ccc2c(Cl)ccnc2n1
Product: Cc1ccc(Oc2ccc(O)cc2)c(Nc2ccnc3nc(C)ccc23)c1

Procedure:
The product from Example 1d (278 mg, 1.56 mmol) was reacted with the product from Example 122b (336 mg, 1.56 mmol) for 18 h following the procedure from Example 1g giving the crude title compound which was purified by HPLC with TFA providing the product as a trifluoroacetic acid (226 mg, 31%). 1H NMR (300 MHz, DMSO-d6) δ ppm: 2.34 (s, 3H) 2.74 (s, 3H) 6.56 (d, J=6.99 Hz, 1H) 6.64-6.71 (m, 2H) 6.75-6.81 (m, 2H) 6.89 (d, J=8.46 Hz, 1H) 7.26 (dd, J=8.46, 1.84 Hz, 1H) 7.31 (s, 1H) 7.76 (d, J=8.82 Hz, 1H) 8.48 (d, J=6.99 Hz, 1H) 8.95 (d, J=8.46 Hz, 1H) 9.34 (s, 1H) 10.91 (s, 1H) 14.36 (s, 1H); MS (ESI+) m/z 358 (M+H−TFA)+.
Reaction SMILES: [CH2:1]([O:8][C:9]1[C:14]2[N:15]=[C:16](Cl)[N:17]=[C:18]([N:19]3[CH2:24][CH2:23][S:22](=[O:25])[CH2:21][CH2:20]3)[C:13]=2[N:12]=[CH:11][N:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[NH:27]1[CH2:32][CH2:31][NH:30][CH2:29][CH2:28]1>>[CH2:1]([O:8][C:9]1[C:14]2[N:15]=[C:16]([N:27]3[CH2:32][CH2:31][NH:30][CH2:29][CH2:28]3)[N:17]=[C:18]([N:19]3[CH2:24][CH2:23][S:22](=[O:25])[CH2:21][CH2:20]3)[C:13]=2[N:12]=[CH:11][N:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=S1CCN(c2nc(Cl)nc3c(OCc4ccccc4)ncnc23)CC1
Reactant: C1CNCCN1
Product: O=S1CCN(c2nc(N3CCNCC3)nc3c(OCc4ccccc4)ncnc23)CC1

Procedure:
This compound was prepared analogous to Example 1 from 8-benzyloxy-2-chloro-4-(1-oxido-thiomorpholino)-pyrimido-[5,4-d]-pyrimidine (m.p.: 227°-229° C.) and piperazine.
Reaction SMILES: [NH2:1][OH:2].C1COCC1.C[O:9][C:10](=O)[CH:11]([N:16]([CH3:31])[C:17]([C:19]1[CH:24]=[CH:23][C:22]([C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)=[CH:21][CH:20]=1)=[O:18])[C:12]([NH:14][CH3:15])=[O:13]>C(O)C>[C:22]1([C:25]2[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=2)[CH:21]=[CH:20][C:19]([C:17]([N:16]([CH3:31])[CH:11]([C:12]([NH:14][CH3:15])=[O:13])[C:10]([NH:1][OH:2])=[O:9])=[O:18])=[CH:24][CH:23]=1
Reactant: CNC(=O)C(C(=O)OC)N(C)C(=O)c1ccc(-c2ccccc2)cc1
Reactant: NO
Solvent: CCO
Solvent: C1CCOC1
Product: CNC(=O)C(C(=O)NO)N(C)C(=O)c1ccc(-c2ccccc2)cc1
Temperature: 25 °C
Reaction time: 4 h
Yield: 59 %

Procedure:
A 50% aqueous solution (0.20 mL) of hydroxylamine was added to a THF (0.25 mL)-ethanol (0.20 mL) solution of 4-{[1-methoxy-3-(methylamino)-1,3-dioxopropan-2-yl](methyl)carbamoyl}biphenyl (30 mg) as obtained in Example 1-(1), and the mixture was stirred for 4 hours at room temperature. The solvents were distilled off under reduced pressure, and the resulting residue was purified by preparative silica gel thin-layer chromatography (chloroform/methanol=8/1). Upon addition of IPE, the precipitated solid was separated by filtration, and dried to obtain 2-[(biphenyl-4-ylcarbonyl)(methyl)amino]-N-hydroxy-N′-methylpropanediamide (Compound 1, light yellow solid) (17 mg, 59%).
Reaction SMILES: [CH2:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH2:4][CH2:3][CH2:2]1.C([CH:23]1[CH2:27][CH2:26][CH2:25][S:24]1)CCCCCCCCCCC>>[CH2:9]1[C:10]2[C:5](=[CH:4][CH:3]=[CH:2][CH:1]=2)[CH2:6][CH2:7][CH2:8]1.[S:24]1[CH:25]=[CH:26][CH:27]=[CH:23]1
Reactant: CCCCCCCCCCCCC1CCCS1
Solvent: c1ccc2c(c1)CCCC2
Product: c1ccsc1

Procedure:
A sample of the C16 alkylate of tetralin (0.5999 g) and 2-n-dodecyltetrahydrothiophene (0.0482 g) was added to the synthetic wax isomerate base oil (29.3522 g) of Example 7 and the mixture was stirred to give a homogeneous solution (2.0 wt % tetralin and 0.16 wt % thiophene (0.02 wt % sulfur)). A 25 gram aliquot was oxidized in the copper catalyzed IP306 oxidation test, previously described. The total oxidation products were determined to be 0.71 wt %.
Reaction SMILES: Cl.Cl.Cl.[O:4]1[C:12]2[CH:11]=[CH:10][N:9]=[C:8]([N:13]3[CH2:18][CH2:17][N:16]([CH2:19][CH2:20][C@H:21]4[CH2:26][CH2:25][C@H:24]([NH2:27])[CH2:23][CH2:22]4)[CH2:15][CH2:14]3)[C:7]=2[CH2:6][CH2:5]1.[F:28][C:29]([F:35])([F:34])[CH2:30][C:31](O)=[O:32]>>[O:4]1[C:12]2[CH:11]=[CH:10][N:9]=[C:8]([N:13]3[CH2:18][CH2:17][N:16]([CH2:19][CH2:20][C@H:21]4[CH2:26][CH2:25][C@H:24]([NH:27][C:31](=[O:32])[CH2:30][C:29]([F:35])([F:34])[F:28])[CH2:23][CH2:22]4)[CH2:15][CH2:14]3)[C:7]=2[CH2:6][CH2:5]1
Reactant: N[C@H]1CC[C@H](CCN2CCN(c3nccc4c3CCO4)CC2)CC1
Reactant: O=C(O)CC(F)(F)F
Agent: Cl
Product: O=C(CC(F)(F)F)N[C@H]1CC[C@H](CCN2CCN(c3nccc4c3CCO4)CC2)CC1

Procedure:
The title compound, white solid (89 mg, 81%), MS (ISP) m/z=441.3 [(M+H)+], mp 195.5° C., was prepared in accordance with the general method of example 32 from trans-4-{2-[4-(2,3-dihydrofuro[3,2-c]pyridin-4-yl)-piperazin-1-yl]-ethyl}-cyclohexanamine trihydrochloride (intermediate C) (110 mg, 0.25 mmol) and 3,3,3-trifluoro-propionic acid.
Reaction SMILES: Br[CH2:2][C:3]1[CH:4]=[C:5]([C:10]2[N:14]=[C:13]([C:15]3[S:16][CH:17]=[CH:18][C:19]=3[Cl:20])[O:12][N:11]=2)[CH:6]=[CH:7][C:8]=1[Cl:9].[NH:21]1[CH2:25][CH2:24][CH2:23][CH2:22]1.CCN(CC)CC>ClCCl>[Cl:9][C:8]1[CH:7]=[CH:6][C:5]([C:10]2[N:14]=[C:13]([C:15]3[S:16][CH:17]=[CH:18][C:19]=3[Cl:20])[O:12][N:11]=2)=[CH:4][C:3]=1[CH2:2][N:21]1[CH2:25][CH2:24][CH2:23][CH2:22]1
Reactant: C1CCNC1
Reactant: Clc1ccc(-c2noc(-c3sccc3Cl)n2)cc1CBr
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: Clc1ccc(-c2noc(-c3sccc3Cl)n2)cc1CN1CCCC1
Yield: 95.6 %

Procedure:
A solution of 3-(3-bromomethyl-4-chloro-phenyl)-5-(3-chlorothiophen-2-yl)-[1,2,4]oxadiazol (0.030 g, 0.077 mmol), pyrrolidine (0.013 mL, 0.16 mmol), Et3N (0.054 mL, 0.39 mmol) and dichloromethane (8.0 mL) was stirred at room temperature for 20 h. The solution was diluted with dichloromethane (30 mL), washed with 10% Na2CO3 (25 mL), dried over Na2SO4, and concentrated. The product was azeotroped with dichloromethane (3×5 mL) and hexanes (2×5 mL) to give 0.028 g (96%) of the title compound as a white solid. 1H NMR (CDCl3): 8.27 (d, 1H, J=1.7 Hz), 7.98 (dd, 1H, J=8.2 and 1.9 Hz), 7.61 (d, 1H, J=5.2 Hz), 7.49 (d, 1H, J=8.5 Hz), 7.13 (d, 1H, J=5.2 Hz), 3.85 (s, 2H), 2.67 (br s, 4H), 1.84 (br s, 4H).
Reaction SMILES: COC1C=CC(C[N:8]2[C@H](C34CC(OCC3)CCCC=CCCC(C)=CC(=O)N4)CSC2=O)=CC=1.C[O:36][C@:37]1([C@@H:56]2[CH2:60][S:59][C:58](=[O:61])[N:57]2CC2C=CC(OC)=CC=2)[CH2:52][C@H:51]2[CH2:53][C@@H:39]([CH2:40][CH2:41][CH2:42][CH:43]=[CH:44][CH2:45][CH2:46][C:47]([CH3:55])=[CH:48][C:49](=O)[O:50]2)[O:38]1>>[OH:36][C@:37]1([C@@H:56]2[CH2:60][S:59][C:58](=[O:61])[NH:57]2)[CH2:52][C@H:51]2[CH2:53][C@@H:39]([CH2:40][CH2:41][CH2:42][CH:43]=[CH:44][CH2:45][CH2:46][C:47]([CH3:55])=[CH:48][C:49](=[O:50])[NH:8]2)[O:38]1
Reactant: COc1ccc(CN2C(=O)SC[C@H]2C23CCOC(CCCC=CCCC(C)=CC(=O)N2)C3)cc1
Reactant: COc1ccc(CN2C(=O)SC[C@H]2[C@@]2(OC)C[C@H]3C[C@@H](CCCC=CCCC(C)=CC(=O)O3)O2)cc1
Agent: C/C1=C/C(=O)N[C@@H]2C[C@@H](CCC/C=C\CC1)O[C@@](O)([C@@H]1CSC(=O)N1)C2
Agent: COc1ccc(CN2C(=O)SC[C@H]2[C@@]2(OC)C[C@H]3C[C@@H](CCC/C=C\CC/C(C)=C\C(=O)O3)O2)cc1
Product: CC1=CC(=O)N[C@@H]2C[C@@H](CCCC=CCC1)O[C@@](O)([C@@H]1CSC(=O)N1)C2

Procedure:
Application of the method shown in Example 46, with the modification that (1R,4Z,8Z,13R,15R)-15-methoxy-15-(((R)-3-(4-methoxybenzyl)-2-oxothiazolidin-4-yl)-5-methyl-14-oxa-2-aza-bicyclo[11.3.1]heptadeca-4,8-dien-3-one was substituted for (R)-4-((1R,4Z,8Z,13R,15R)-15-methoxy-5-methyl-3-oxo-2,14-dioxa-bicyclo[11.3.1]heptadeca-4,8-dien-15-yl)-3-(4-methoxybenzyl)thiazolidin-2-one, afforded the title compound, together with the 8E-isomer.
Reaction SMILES: [BH4-].[Na+].[CH3:3][O:4][C:5](=[O:19])[C:6]1[CH:11]=[CH:10][C:9]([C:12]2[S:13][C:14]([CH:17]=[O:18])=[CH:15][CH:16]=2)=[CH:8][CH:7]=1>CO.ClCCl>[CH3:3][O:4][C:5](=[O:19])[C:6]1[CH:11]=[CH:10][C:9]([C:12]2[S:13][C:14]([CH2:17][OH:18])=[CH:15][CH:16]=2)=[CH:8][CH:7]=1
Reactant: COC(=O)c1ccc(-c2ccc(C=O)s2)cc1
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Solvent: ClCCl
Product: COC(=O)c1ccc(-c2ccc(CO)s2)cc1
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 78.6 %

Procedure:
Sodium borohydride (155 mg, 4.1 mmol) is added to a solution of 4-(5-formylthiophen-2-yl)benzoic acid methyl ester (1.01 g, 4.1 mmol) in methanol/dichloromethane (16 ml/4 ml) and the resulting solution is stirred for 90 minutes at room temperature. The reaction is quenched by the addition of saturated aqueous ammonium chloride solution (100 ml) and extracted with dichloromethane (100 ml). The organic layer is washed with brine, dried over magnesium sulphate, filtered and concentrated in vacuo to give 4-(5-hydroxymethyl-thiophen-2-yl)benzoic acid methyl ester (800 mg)
Reaction SMILES: [CH:1]([NH:4][C:5]([C:7]1[C:15]2[C:10](=[N:11][CH:12]=[C:13]([C:16]3[C:24]4[C:19](=[CH:20][C:21]([F:25])=[CH:22][CH:23]=4)[N:18]([CH:26]4[CH2:29][O:28][CH2:27]4)[N:17]=3)[N:14]=2)[N:9](COCC[Si](C)(C)C)[CH:8]=1)=[O:6])([CH3:3])[CH3:2].C(O)(C(F)(F)F)=O>C(Cl)Cl>[CH:1]([NH:4][C:5]([C:7]1[C:15]2[C:10](=[N:11][CH:12]=[C:13]([C:16]3[C:24]4[C:19](=[CH:20][C:21]([F:25])=[CH:22][CH:23]=4)[N:18]([CH:26]4[CH2:27][O:28][CH2:29]4)[N:17]=3)[N:14]=2)[NH:9][CH:8]=1)=[O:6])([CH3:3])[CH3:2]
Reactant: CC(C)NC(=O)c1cn(COCC[Si](C)(C)C)c2ncc(-c3nn(C4COC4)c4cc(F)ccc34)nc12
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CC(C)NC(=O)c1c[nH]c2ncc(-c3nn(C4COC4)c4cc(F)ccc34)nc12
Temperature: 25 °C
Reaction time: 3 h
Yield: 42.3 %

Procedure:
To a solution of 2-(6-fluoro-1-oxetan-3-yl-1H-indazol-3-yl)-5-(2-trimethylsilanylethoxymethyl)-5H-pyrrolo[2,3-b]pyrazine-7-carboxylic acid isopropylamide (98 mg, 0.18 mmol) in CH2Cl2 (1.5 mL) was added TFA (0.5 mL). The reaction mixture was stirred at room temperature for 3 h then concentrated. The residue was redissolved in 10:90:0.5 MeOH/CH2Cl2/NH4OH (3 mL) and stirred at room temperature for 3 h then concentrated. The residue was portioned between water and 10% MeOH/CH2Cl2. The aqueous layer was extracted with 10% MeOH/CH2Cl2 (3×). The combined organics were concentrated and the residue was purified by silica gel chromatography with 0% to 5% MeOH/CH2Cl2 (0.5% NH4OH) to afford 30 mg (41%) of 2-(6-fluoro-1-oxetan-3-yl-1H-indazol-3-yl)-5H-pyrrolo[2,3-b]pyrazine-7-carboxylic acid isopropylamide as a white solid. MS (M+Na)+=417; 1H NMR (DMSO-d6, 300 MHz): δ (ppm) 12.87 (br. s., 1H), 9.20 (s, 1H), 8.45-8.51 (m, 1H), 8.44 (s, 1H), 8.04 (d, J=7.6 Hz, 1H), 7.73 (dd, J=9.8, 1.9 Hz, 1H), 7.22 (td, J=9.1, 1.9 Hz, 1H), 6.13 (quin, J=7.0 Hz, 1H), 5.11-5.20 (m, 2H), 4.99-5.10 (m, 2H), 4.21 (dq, J=13.5, 6.4 Hz, 1H), 1.30 (d, J=6.4 Hz, 6H).
Reaction SMILES: [CH2:1]1[C:7]2[CH:8]=[CH:9][C:10]([O:12][C:13]3[CH:21]=[CH:20][C:16]([C:17]([NH2:19])=[O:18])=[CH:15][N:14]=3)=[CH:11][C:6]=2[CH2:5][CH2:4][CH2:3][NH:2]1.C([O-])([O-])=O.[K+].[K+].Br[CH2:29][CH2:30][CH2:31][CH2:32][CH3:33].C(OCC)(=O)C>CN(C=O)C>[CH2:29]([N:2]1[CH2:3][CH2:4][CH2:5][C:6]2[CH:11]=[C:10]([O:12][C:13]3[CH:21]=[CH:20][C:16]([C:17]([NH2:19])=[O:18])=[CH:15][N:14]=3)[CH:9]=[CH:8][C:7]=2[CH2:1]1)[CH2:30][CH2:31][CH2:32][CH3:33]
Reactant: CCCCCBr
Reactant: NC(=O)c1ccc(Oc2ccc3c(c2)CCCNC3)nc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CCCCCN1CCCc2cc(Oc3ccc(C(N)=O)cn3)ccc2C1
Temperature: 100 °C

Procedure:
Mix 6-(2,3,4,5-tetrahydro-1H-benzo[c]azepin-7-yloxy)nicotinamide (Example 447, Part E, 0.300 g, 1.06 mmol), K2CO3 (0.366 g, 2.65 mmol), and 1-bromopentane (0.176 g, 1.16 mmol) in DMF (5.3 mL). Beat at 70° C. overnight and then increase the temperature to 100° C. for additional two hours. Cool the reaction mixture to room temperature and add ethyl acetate (150 mL). Wash with 1.0 N NaOH (1×50 mL), brine (1×50 mL), dry the organic layer over Na2SO4, filter and concentrate. Purify by flash chromatography eluting with 7% to 15% (2.0 M NH3 in methanol) in ethyl acetate to give the title compound : MS ES+354.2 (M+H)+, HRMS calcd for C21H28N3O2 354.2182 (M+H)+, found 354.2188, time 0.53 min; Anal. Calcd for C21H27N3O2: C, 71.36; H, 7.70 N, 11.89. Found: C, 71.14; H, 7.60; N, 11.79.