Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]([C:4]1[C:10]([F:11])=[CH:9][CH:8]=[C:7]([CH:12]([CH3:14])[CH3:13])[C:5]=1[NH2:6])([CH3:3])[CH3:2].C(N(CC)C1C=CC=CC=1)C.[Br:26][CH2:27][C:28](Br)=[O:29]>O>[Br:26][CH2:27][C:28]([NH:6][C:5]1[C:7]([CH:12]([CH3:14])[CH3:13])=[CH:8][CH:9]=[C:10]([F:11])[C:4]=1[CH:1]([CH3:3])[CH3:2])=[O:29]
Reactant: CC(C)c1ccc(F)c(C(C)C)c1N
Reactant: O=C(Br)CBr
Solvent: O
Solvent: CCN(CC)c1ccccc1
Product: CC(C)c1ccc(F)c(C(C)C)c1NC(=O)CBr
Temperature: 25 °C
Reaction time: 2 h
Yield: 82 %

Procedure:
To a solution of 2,6-diisopropyl-3-fluoroaniline (synthesized by the method described in the Japanese Patent Application Laid open No. Sho. 63-208556) (550 mg, 2.82 mmol) indichloromethane (20 ml) were added N,N-diethylaniline (478 mg, 3.94 mmol) and bromoacetyl bromide (649 mg, 3.22 mmol) successively with ice-cooling, and stirred at room temperature for 2 hours. The reaction solution was diluted with water and extracted with chloroform. The organic layer was washed with a saturated sodium chloride solution, dried over anhydrous sodium sulfate and concentrated in vacuo. The resulting residue was purified by a silica gel column chromatography (silica gel 50 g, developing solvent; hexane:ethyl acetate=7:1 3:1) to provide 730 mg (yield 82%) of 2-bromo-N-(2,6-diisopropyl-3-fluorophenyl)acetamide as colorless prisms.
Reaction SMILES: [CH3:1][O:2][N:3]([CH3:33])[C:4](=[O:32])[CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][N:16]1[C:28]2[C:27]3[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=3[N:21]=[CH:20][C:19]=2[N:18]=[C:17]1[CH2:29][CH2:30][CH3:31].C1C=C(Cl)C=C(C(OO)=[O:42])C=1>>[CH3:1][O:2][N:3]([CH3:33])[C:4](=[O:32])[CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][N:16]1[C:28]2[C:27]3[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=3[N+:21]([O-:42])=[CH:20][C:19]=2[N:18]=[C:17]1[CH2:29][CH2:30][CH3:31]
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: CCCc1nc2cnc3ccccc3c2n1CCCCCCCCCCCC(=O)N(C)OC
Product: CCCc1nc2c[n+]([O-])c3ccccc3c2n1CCCCCCCCCCCC(=O)N(C)OC

Procedure:
The general methods described in Steps 9 and 10 of Example 1 and Step 7 of Example 16 was used to aminate N-methoxy-N-methyl-12-(2-propyl-1H-imidazo[4,5-c]quinolin-1-yl)dodecanamide (4.01 g, 8.86 mmol) by reaction with m-CPBA (6.13 g) to provide N-methoxy-N-methyl-12-(5-oxido-2-propyl-1H-imidazo[4,5-c]quinolin-1-yl)dodecanamide followed by reaction with p-toluenesulfonyl chloride (2.53 g, 13.3 mmol) and ammonium hydroxide solution (40 mL) to provide 2-(4-amino-2-propyl-1H-imidazo[4,5-c]quinolin-1-yl)-N-methoxy-N-methyldodecanamide hydrochloride as an off-white solid after recrystallizationof the hydrochloride salt from isopropanol, mp 156-158° C.
Reaction SMILES: C[O:2][CH:3](OC)[CH2:4][S:5]([C:7]1[S:8][C:9]([C:20]2[CH:25]=[CH:24][C:23]([O:26][CH3:27])=[CH:22][CH:21]=2)=[C:10]([C:12]2[CH:17]=[CH:16][C:15]([O:18][CH3:19])=[CH:14][CH:13]=2)[N:11]=1)=[O:6].S(=O)(=O)(O)O.O>C(O)(=O)C.C(Cl)Cl>[CH3:19][O:18][C:15]1[CH:16]=[CH:17][C:12]([C:10]2[N:11]=[C:7]([S:5]([CH2:4][CH:3]=[O:2])=[O:6])[S:8][C:9]=2[C:20]2[CH:25]=[CH:24][C:23]([O:26][CH3:27])=[CH:22][CH:21]=2)=[CH:13][CH:14]=1
Reactant: COc1ccc(-c2nc(S(=O)CC(OC)OC)sc2-c2ccc(OC)cc2)cc1
Agent: O=S(=O)(O)O
Solvent: O
Solvent: ClCCl
Solvent: CC(=O)O
Product: COc1ccc(-c2nc(S(=O)CC=O)sc2-c2ccc(OC)cc2)cc1
Temperature: 0 °C

Procedure:
5.75 g of 2-[4,5-bis-(p-methoxyphenyl)-thiazol-2-ylsulphinyl]-acetaldehyde-dimethylacetal are dissolved in 5 ml of acetic acid. Then, while stirring, 30 ml of a mixture of 2 parts acetic acid, 1 part sulphuric acid and 1 part water are added dropwise over a period of 5 minutes. The mixture is stirred at room temperature for 30 minutes, diluted with 100 ml of methylene chloride and poured into 200 ml of ice-water. The organic layer is removed and washed with 200 ml of ice-water. The aqueous phase is extracted by shaking three times with 50 ml of methylene chloride each time. The organic phases are combined, dried over magnesium sulphate and concentrated to dryness by evaporation. The crude product is dissolved in 200 ml of methylene chloride and stirred with 5 g of silica gel. The mixture is filtered, concentrated to dryness by evaporation and dried under reduced pressure. 2-[4,5-bis-(p-methoxyphenyl)-thiazol-2-ylsulphinyl]-acetaldehyde is obtained in the form of a highly viscous oil, IR-spectrum: νC=O =1720 cm-1, νS=O =1080 cm-1 (CCl4).
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[N:7]2[N:13]=[C:12]([C:14]3[CH:19]=[CH:18][CH:17]=[C:16]([N+:20]([O-])=O)[CH:15]=3)[C:11]([C:23]3[CH:28]=[CH:27][N:26]=[CH:25][CH:24]=3)=[C:8]2[S:9][CH:10]=1)=[O:5])[CH3:2].[Cl-].[NH4+].C([O-])(O)=O.[Na+]>O1CCOCC1.O.O.[Zn]>[CH2:1]([O:3][C:4]([C:6]1[N:7]2[N:13]=[C:12]([C:14]3[CH:19]=[CH:18][CH:17]=[C:16]([NH2:20])[CH:15]=3)[C:11]([C:23]3[CH:24]=[CH:25][N:26]=[CH:27][CH:28]=3)=[C:8]2[S:9][CH:10]=1)=[O:5])[CH3:2]
Reactant: CCOC(=O)c1csc2c(-c3ccncc3)c(-c3cccc([N+](=O)[O-])c3)nn12
Agent: O=C([O-])O
Agent: [Cl-]
Agent: [NH4+]
Solvent: C1COCCO1
Solvent: O
Product: CCOC(=O)c1csc2c(-c3ccncc3)c(-c3cccc(N)c3)nn12
Temperature: 100 °C
Yield: 44.3 %

Procedure:
6-(3-Nitrophenyl)-7-pyridin-4-yl-pyrazolo[5,1-b]thiazole-3-carboxylic acid ethyl ester (200 mg, 0.508 mmol) was dissolved in a 5:1 dioxane/water mixture (3 mL). Zinc powder (133 mg, 2.03 mmol, 4 eq) and ammonium chloride (271 mg, 5.08 mmol, 10 eq) were added and the mixture was stirred at 100° C. After 4 hours an addition of Zinc powder was made (37 mg) and heating was continued for 1.5 more hours. It was then diluted with water, made basic by addition of saturated aqueous NaHCO3 and extracted with ethyl acetate (3×20 mL). Combined organic layers were washed with sat. aq. NaHCO3 and brine, dried over Na2SO4 and concentrated under reduced pressure. 82 mg of 6-(3-amino-phenyl)-7-pyridin-4-yl-pyrazolo[5,1-b]thiazole-3-carboxylic acid ethyl ester were obtained as off-white solid, which was used without purification in the following step.
Reaction SMILES: C([BH3-])#N.[Na+].[NH2:5][CH2:6][C:7]1[CH:8]=[N:9][C:10]([Cl:13])=[CH:11][CH:12]=1.[C:14]1(=O)[CH2:19][CH2:18][CH2:17][CH2:16][CH2:15]1.C(O)(=O)C.C([O-])([O-])=O.[K+].[K+]>CO.O>[Cl:13][C:10]1[N:9]=[CH:8][C:7]([CH2:6][NH:5][CH:14]2[CH2:19][CH2:18][CH2:17][CH2:16][CH2:15]2)=[CH:12][CH:11]=1
Reactant: O=C1CCCCC1
Reactant: NCc1ccc(Cl)nc1
Agent: O=C([O-])[O-]
Agent: [BH3-]C#N
Agent: [K+]
Solvent: CC(=O)O
Solvent: O
Solvent: CO
Product: Clc1ccc(CNC2CCCCC2)cn1
Temperature: 25 °C
Reaction time: 8 h
Yield: 90.9 %

Procedure:
Under a nitrogen atmosphere, add sodium cyanoborohydride (3.53 g, 56 mmol) to a solution of 3-aminomethyl-6-chloro-pyridine (2 g, 14 mmol), cyclohexanone (1.38 g, 14 mmol) and acetic acid (168 mg, 0.2 mmol) in methanol (20 mL) at 0° C. Warm the mixture to room temperature and stir overnight. Add water (100 mL) and saturated aqueous K2CO3. Extract three times with DCM and wash the combined organic extracts with water and brine. Dry over Na2SO4, filter, and concentrate in vacuo. Purify by chromatography on silica gel (150 g) eluting with 9:1 DCM/(chloroform:methanol:concentrated NH4OH 80:18:2) to obtain the desired intermediate (2.86 g, 91%). MS (APCI+) m/z: 225 (M+H)+.
Reaction SMILES: Br[C:2]1[O:6][C:5]([CH:7]=[C:8]2[C:16]3[C:11](=[CH:12][CH:13]=[C:14]([Cl:17])[CH:15]=3)[NH:10][C:9]2=[O:18])=[CH:4][CH:3]=1.C([O-])([O-])=O.[Cs+].[Cs+].[O:25]1[CH2:30][CH2:29][N:28]([CH2:31][CH2:32][NH:33][C:34]2[CH:39]=[CH:38][C:37](B3OC(C)(C)C(C)(C)O3)=[CH:36][N:35]=2)[CH2:27][CH2:26]1>O1CCOCC1.O>[Cl:17][C:14]1[CH:15]=[C:16]2[C:11](=[CH:12][CH:13]=1)[NH:10][C:9](=[O:18])[C:8]2=[CH:7][C:5]1[O:6][C:2]([C:37]2[CH:36]=[N:35][C:34]([NH:33][CH2:32][CH2:31][N:28]3[CH2:29][CH2:30][O:25][CH2:26][CH2:27]3)=[CH:39][CH:38]=2)=[CH:3][CH:4]=1
Reactant: CC1(C)OB(c2ccc(NCCN3CCOCC3)nc2)OC1(C)C
Reactant: O=C1Nc2ccc(Cl)cc2C1=Cc1ccc(Br)o1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: C1COCCO1
Solvent: O
Product: O=C1Nc2ccc(Cl)cc2C1=Cc1ccc(-c2ccc(NCCN3CCOCC3)nc2)o1
Temperature: 120 °C

Procedure:
To 3-((5-bromofuran-2-yl)methylene)-5-chloroindolin-2-one (50 mg, 0.155 mmol) in dioxane/water (5% water) was added Cs2CO3 (152 mg, 0.466 mmol) and N-(2-morpholinoethyl)-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridin-2-amine (62 mg, 0.186 mmol). The mixture was degassed with nitrogen for 5 minutes then heated in microwave for 20 minutes at 120° C. The solution was diluted with water and the solid formed was isolated by filtration. The solid was purified by HPLC to yield 5-chloro-3-((5-(6-(2-morpholinoethylamino)pyridin-3-yl)furan-2-yl)methylene)indolin-2-one. LCMS (M+1=451).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]2[C:7]3[N:15]=[C:14]([C:16]4[CH:21]=[CH:20][C:19]([O:22][CH3:23])=[CH:18][CH:17]=4)[N:13]=[C:12]([C:24]([O:26]C)=O)[C:8]=3[NH:9][C:10]=2[CH:11]=1.[NH3:28]>CO>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]2[C:7]3[N:15]=[C:14]([C:16]4[CH:21]=[CH:20][C:19]([O:22][CH3:23])=[CH:18][CH:17]=4)[N:13]=[C:12]([C:24]([NH2:28])=[O:26])[C:8]=3[NH:9][C:10]=2[CH:11]=1
Reactant: COC(=O)c1nc(-c2ccc(OC)cc2)nc2c1[nH]c1cc(OC)ccc12
Reactant: N
Solvent: CO
Product: COc1ccc(-c2nc(C(N)=O)c3[nH]c4cc(OC)ccc4c3n2)cc1
Temperature: 80 °C

Procedure:
A suspension of methyl 7-methoxy-2-(4-methoxyphenyl)-5H-pyrimido[5,4-b]indole-4-carboxylate (97 mg, 0.27 mmol) in a 7 N solution of ammonia in MeOH (10 mL) in a sealed microwave vial was heated at 80° C. overnight. The solvent was removed and the residue was suspended in EtOAc. Filtration gave 7-methoxy-2-(4-methoxyphenyl)-5H-pyrimido[5,4-b]indole-4-carboxamide (58 mg) as a yellow solid. MS (ESI) m/z 349.0 (M+H). 1H NMR (DMSO-d6) δ ppm 11.68 (1H, br. s.), 8.59-8.73 (3H, m), 8.20 (1H, d, J=8.85 Hz), 8.05 (1H, s), 7.29 (1H, d, J=2.14 Hz), 7.08 (2H, d, J=8.85 Hz), 6.96 (1H, dd, J=8.70, 2.29 Hz), 3.90 (3H, s), 3.87 (3H, s).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH2:8][C:9]([OH:11])=[O:10].[CH3:12][O:13][C:14]1[C:15]([NH2:20])=[CH:16][CH:17]=[CH:18][CH:19]=1>>[CH3:12][O:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=1[NH:20][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH2:8][C:9]([OH:11])=[O:10]
Reactant: COc1ccccc1N
Reactant: O=C(O)Cc1ccccc1Br
Product: COc1ccccc1Nc1ccccc1CC(=O)O

Procedure:
In the manner described in example 3, 2-bromophenylacetic acid is condensed with o-anisidine to yield 2-[(2-methoxyphenyl)amino]phenylacetic acid.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:34])[CH:5]([O:30][CH:31]([CH3:33])[CH3:32])[CH:6]([C:8]1[C:13]2[S:14][CH:15]=[CH:16][C:12]=2[C:11]([O:17][CH2:18][CH2:19][C:20]2[N:21]=[C:22]([C:26]([CH3:29])([CH3:28])[CH3:27])[O:23][C:24]=2[CH3:25])=[CH:10][CH:9]=1)O)[CH3:2].C([SiH](CC)CC)C>FC(F)(F)C(O)=O>[CH2:1]([O:3][C:4](=[O:34])[CH:5]([O:30][CH:31]([CH3:33])[CH3:32])[CH2:6][C:8]1[C:13]2[S:14][CH:15]=[CH:16][C:12]=2[C:11]([O:17][CH2:18][CH2:19][C:20]2[N:21]=[C:22]([C:26]([CH3:27])([CH3:28])[CH3:29])[O:23][C:24]=2[CH3:25])=[CH:10][CH:9]=1)[CH3:2]
Reactant: CCOC(=O)C(OC(C)C)C(O)c1ccc(OCCc2nc(C(C)(C)C)oc2C)c2ccsc12
Agent: CC[SiH](CC)CC
Solvent: O=C(O)C(F)(F)F
Product: CCOC(=O)C(Cc1ccc(OCCc2nc(C(C)(C)C)oc2C)c2ccsc12)OC(C)C
Reaction time: 2 h
Yield: 76.7 %

Procedure:
0.434 g of the above prepared 3-{4-[2-(2-tert-butyl-5-methyl-oxazol-4-yl)-ethoxy]-benzo[b]thiophen-7-yl}-3-hydroxy-2-isopropoxy-propionic acid ethyl ester (0.886 mmol) was dissolved in 4.5 ml of trifluoroacetic acid, treated at 0° with 1.408 ml of triethylsilane (10 eq.) and then kept for 2 h at 0° under vigorous stirring, when TLC indicated the disappearance of starting material. The reaction mixture was then poured onto crashed ice/AcOEt/NaHCO3, the organic layer washed with water (pH of aq. phase˜8), dried over sodium sulfate, and evaporated to dryness. Flash chromatography (SiO2, hexane/AcOEt=8/2) yielded 0.322 g of the title compound as colorless oil.
Reaction SMILES: [CH2:1]([C:8]1([OH:19])[CH2:11][N:10](C(OC(C)(C)C)=O)[CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[ClH:20]>>[ClH:20].[CH2:1]([C:8]1([OH:19])[CH2:11][NH:10][CH2:9]1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CC(C)(C)OC(=O)N1CC(O)(Cc2ccccc2)C1
Agent: Cl
Product: OC1(Cc2ccccc2)CNC1
Temperature: 25 °C
Reaction time: 3 h
Yield: 90 %

Procedure:
tert-butyl 3-benzyl-3-hydroxyazetidine-1-carboxylate 3 (2.0 gm, 7.59 mmol) was taken into a round bottomed flask and was added methanolic-HCl (25 mL, 20%) and was stirred for 3 h at room temperature. After completion of the reaction (monitored by TLC), the solvent was removed under vacuum to get a white solid as a crude product. The crude product was washed with ethyl acetate repeatedly and then dried well to obtain compound 4 as a white solid (1.36 gm, 90%) which was used without further purification.
Reaction SMILES: CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[F:25][C:26]1[CH:31]=[CH:30][C:29]([C:32]2[O:55][C:35]3=[N:36][C:37]([NH:49][CH2:50][C:51]([F:54])([F:53])[F:52])=[C:38]([C:40]4[CH:41]=[C:42]([CH:46]=[CH:47][CH:48]=4)[C:43](O)=[O:44])[CH:39]=[C:34]3[C:33]=2[C:56](=[O:59])[NH:57][CH3:58])=[CH:28][CH:27]=1.C(N(C(C)C)C(C)C)C.Cl.[O:70]1[CH:74]=[N:73][C:72]([C:75]([NH2:78])([CH3:77])[CH3:76])=[N:71]1>CN(C=O)C>[O:70]1[CH:74]=[N:73][C:72]([C:75]([NH:78][C:43]([C:42]2[CH:41]=[C:40]([C:38]3[CH:39]=[C:34]4[C:33]([C:56]([NH:57][CH3:58])=[O:59])=[C:32]([C:29]5[CH:30]=[CH:31][C:26]([F:25])=[CH:27][CH:28]=5)[O:55][C:35]4=[N:36][C:37]=3[NH:49][CH2:50][C:51]([F:53])([F:52])[F:54])[CH:48]=[CH:47][CH:46]=2)=[O:44])([CH3:77])[CH3:76])=[N:71]1
Reactant: CC(C)(N)c1ncon1
Reactant: CNC(=O)c1c(-c2ccc(F)cc2)oc2nc(NCC(F)(F)F)c(-c3cccc(C(=O)O)c3)cc12
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CNC(=O)c1c(-c2ccc(F)cc2)oc2nc(NCC(F)(F)F)c(-c3cccc(C(=O)NC(C)(C)c4ncon4)c3)cc12
Temperature: 25 °C
Reaction time: 1 h
Yield: 48.8 %

Procedure:
2-(3H-[1,2,3]triazolo[4,5-b]pyridin-3-yl)-1,1,3,3-tetramethylisouronium hexafluorophosphate(V) (117 mg, 0.308 mmol) was added to stirring solution of 3-(2-(4-fluorophenyl)-3-(methylcarbamoyl)-6-((2,2,2-trifluoroethyl)amino)furo[2,3-b]pyridin-5-yl)benzoic acid (100 mg, 0.205 mmol), N-ethyl-N-isopropylpropan-2-amine (0.11 mL, 0.62 mmol) and 2-(1,2,4-oxadiazol-3-yl)propan-2-amine hydrochloride (50 mg, 0.31 mmol) in DMF (1 mL) at rt. The mixture was allowed to stir at rt for 1 h. The reaction mixture was then purified by preparative reverse phase HPLC on a C18 column using a suitably buffered H2O/CH3CN gradient, and concentrated to give the expected product 5-(3-((2-(1,2,4-oxadiazol-3-yl)propan-2-yl)carbamoyl)phenyl)-2-(4-fluorophenyl)-N-methyl-6-((2,2,2-trifluoroethyl)amino)furo[2,3-b]pyridine-3-carboxamide (61 mg, 0.10 mmol, 49% yield)) consistent by LCMS and NMR. LC-MS retention time: 1.73 min; m/z (MH+): 597. LC data was recorded on a Shimadzu LC-10AS liquid chromatograph equipped with a Phenomenex-Luna 3u C18 2.0×30 mm column using a SPD-10AV UV-Vis detector at a detector wave length of 220 nM. The elution conditions employed a flow rate of 1 mL/min, a gradient of 100% solvent A/0% solvent B to 0% solvent A/100% solvent B, a gradient time of 2 min, a hold time of 1 min, and an analysis time of 3 min where solvent A was 10% acetonitrile/90% H2O/0.1% trifluoroacetic acid and solvent B was 10% H2O/90% acetonitrile/0.1% trifluoroacetic acid. MS data was determined using a Micromass Platform for LC in electrospray mode. 1H NMR (400 MHz, DMSO-d6) δ 9.43 (s, 1H), 8.70 (s, 1H), 8.40-8.32 (m, 1H), 8.01-7.94 (m, 2H), 7.93 (s, 1H), 7.90-7.85 (m, 1H), 7.69 (s, 1H), 7.64-7.57 (m, 2H), 7.38-7.31 (m, 2H), 6.63 (t, J=6.4 Hz, 1H), 4.26-4.12 (m, 2H), 2.80 (d, J=4.8 Hz, 3H), 1.70 (s, 6H).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:34])[CH:5]([C:10]1[CH:11]=[C:12]([C:24]2[CH:29]=[CH:28][C:27]([C:30]([F:33])([F:32])[F:31])=[CH:26][CH:25]=2)[CH:13]=[C:14](OS(C(F)(F)F)(=O)=O)[CH:15]=1)[CH2:6][CH:7]([CH3:9])[CH3:8])[CH3:2].C(P(C(C)(C)C)C1C=CC2C(=CC=CC=2)C=1C1C2C(=CC=CC=2)C=CC=1)(C)(C)C.[CH3:64][C:65]1[CH:77]=[CH:76][CH:75]=[CH:74][C:66]=1[CH2:67][CH:68]1[CH2:73][CH2:72][CH2:71][CH2:70][NH:69]1.CC([O-])(C)C.[Na+]>C1(C)C=CC=CC=1.CC([O-])=O.CC([O-])=O.[Pd+2]>[CH2:1]([O:3][C:4](=[O:34])[CH:5]([C:10]1[CH:11]=[C:12]([C:24]2[CH:25]=[CH:26][C:27]([C:30]([F:32])([F:33])[F:31])=[CH:28][CH:29]=2)[CH:13]=[C:14]([N:69]2[CH2:70][CH2:71][CH2:72][CH2:73][CH:68]2[CH2:67][C:66]2[CH:74]=[CH:75][CH:76]=[CH:77][C:65]=2[CH3:64])[CH:15]=1)[CH2:6][CH:7]([CH3:9])[CH3:8])[CH3:2]
Reactant: Cc1ccccc1CC1CCCCN1
Reactant: CCOC(=O)C(CC(C)C)c1cc(OS(=O)(=O)C(F)(F)F)cc(-c2ccc(C(F)(F)F)cc2)c1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: CC(C)(C)P(c1ccc2ccccc2c1-c1cccc2ccccc12)C(C)(C)C
Solvent: Cc1ccccc1
Product: CCOC(=O)C(CC(C)C)c1cc(-c2ccc(C(F)(F)F)cc2)cc(N2CCCCC2Cc2ccccc2C)c1
Temperature: 100 °C

Procedure:
To a solution of 4-methyl-2-(5-trifluoromethanesulfonyloxy-4′-trifluoromethyl-biphenyl-3-yl)-pentanoic acid ethyl ester (1g) (190 mg, 0.37 mmol) in toluene (2.5 mL) in a sealed tube was added racemic-2-(di-t-butylphosphino)-1,1′-binaphthyl (44 mg, 0.11 mmol), Pd(OAc)2 (83 mg, 0.37 mmol), 2-(2-methyl-benzyl)-piperidine (98 mg, 0.52 mmol). The system was flushed with nitrogen. To this was added NaOtBu (53 mg, 0.56 mmol) and heated to 100° C. for 1 h. The reaction was cooled to room temperature and quenched by slow addition of water. The mixture was extracted with EtOAc (3×20 mL). The organic phase was washed with saturated NaHCO3 solution and brine. The organic fraction was dried (MgSO4) and concentrated in vacuo. The crude mixture was purified by ISCO column chromatography to obtain 4-methyl-2-{5-[2-(2-methyl-benzyl)-piperidin-1-yl]-4′-trifluoromethyl-biphenyl-3-yl}-pentanoic acid ethyl ester. Calcd for C34H40F3NO2 (M+H) 552.68, Found 552.41.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2([C:26]3[CH:31]=[CH:30][C:29]([F:32])=[CH:28][CH:27]=3)[CH2:12][CH2:11][N:10]([CH2:13][C:14](=[O:24])[N:15]3[CH2:23][C@H:22]4[C@H:17]([NH:18][CH2:19][CH2:20][CH2:21]4)[CH2:16]3)[C:9]2=[O:25])=[CH:4][CH:3]=1.[F:33][C:34]([F:44])([F:43])[C:35]1[CH:36]=[C:37]([CH:40]=[CH:41][CH:42]=1)[CH:38]=O.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>ClC(Cl)C.C(O)(=O)C.ClCCl>[F:32][C:29]1[CH:28]=[CH:27][C:26]([C:8]2([C:5]3[CH:6]=[CH:7][C:2]([F:1])=[CH:3][CH:4]=3)[CH2:12][CH2:11][N:10]([CH2:13][C:14](=[O:24])[N:15]3[CH2:23][C@H:22]4[C@H:17]([N:18]([CH2:38][C:37]5[CH:40]=[CH:41][CH:42]=[C:35]([C:34]([F:33])([F:43])[F:44])[CH:36]=5)[CH2:19][CH2:20][CH2:21]4)[CH2:16]3)[C:9]2=[O:25])=[CH:31][CH:30]=1
Reactant: O=Cc1cccc(C(F)(F)F)c1
Reactant: O=C(CN1CCC(c2ccc(F)cc2)(c2ccc(F)cc2)C1=O)N1C[C@@H]2CCCN[C@@H]2C1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CC(Cl)Cl
Solvent: ClCCl
Product: O=C(CN1CCC(c2ccc(F)cc2)(c2ccc(F)cc2)C1=O)N1C[C@@H]2CCCN(Cc3cccc(C(F)(F)F)c3)[C@@H]2C1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
To a solution of product from Example 210A (0.2 g, 0.455 mmol) in dichloroethane (10 mL) was added 3-(trifluoromethyl)benzaldehyde (0.135 g, 0.774 mmol), sodium triacetoxyborohydride (0.145 g, 0.683 mmol), and a few drops of acetic acid. The reaction mixture was stirred at room temperature for 16 hours, then diluted with dichloromethane and washed with saturated aqueous NaHCO3 solution. The organic layer was separated, dried over MgSO4, concentrated and purified by silica gel chromatography eluting with 2-5% methanol/dichloromethane. 1H NMR (400 MHz, pyridine-d5, temperature 90° C.) δ ppm 7.63-7.72 (m, 1H), 7.55-7.63 (m, 4H), 7.47-7.58 (m, 2H), 7.33-7.45 (m, 1H), 7.00-7.08 (m, 4H), 4.13-4.33 (m, 2H), 3.66-3.77 (m, 1H), 3.51-3.65 (m, 3H), 3.27-3.65 (m, 4H), 2.87-3.15 (m, 1H), 2.73-2.80 (m, 2H), 2.45-2.57 (m, 1H), 2.06-2.26 (m, 2H), 1.23-1.56 (m, 4H); MS (ESI+) m/z 599 (M+H)+.
Reaction SMILES: C([O:8][C:9]1[CH:10]=[C:11]2[C:15](=[CH:16][C:17]=1[O:18][CH2:19][CH2:20][CH2:21][CH3:22])[NH:14][CH:13]=[CH:12]2)C1C=CC=CC=1.[H][H].C(O)C>[Pd].C(Cl)Cl>[CH2:19]([O:18][C:17]1[CH:16]=[C:15]2[C:11]([CH:12]=[CH:13][NH:14]2)=[CH:10][C:9]=1[OH:8])[CH2:20][CH2:21][CH3:22]
Reactant: CCCCOc1cc2[nH]ccc2cc1OCc1ccccc1
Reactant: [H][H]
Agent: [Pd]
Solvent: CCO
Solvent: ClCCl
Product: CCCCOc1cc2[nH]ccc2cc1O
Yield: 54.5 %

Procedure:
5-Benzyloxy 6-butoxy indole (0.5 g, 0.0017 mole) is hydrogenated under 50 atmospheres of hydrogen in a reactor with 5 ml of absolute ethanol and 70 mg of 10% palladium on carbon for 2 hours. After filtration and evaporation of the solvent, the residue is purified by chromatography on silica 60 (eluent: CH2Cl2, to obtain 6-butoxy 5-hydroxy indole (0.19 g, beige powder, yield 55%).
Reaction SMILES: [C:1]([NH:4][C:5]1[CH:6]=[C:7]([C:11]2[CH:16]=[N:15][CH:14]=[C:13](Cl)[N:12]=2)[CH:8]=[CH:9][CH:10]=1)(=[O:3])[CH3:2].[CH2:18]1[O:27][C:26]2[CH:25]=[CH:24][C:22]([NH2:23])=[CH:21][C:20]=2[O:19]1>>[CH2:18]1[O:27][C:26]2[CH:25]=[CH:24][C:22]([NH:23][C:13]3[CH:14]=[N:15][CH:16]=[C:11]([C:7]4[CH:8]=[CH:9][CH:10]=[C:5]([NH:4][C:1](=[O:3])[CH3:2])[CH:6]=4)[N:12]=3)=[CH:21][C:20]=2[O:19]1
Reactant: CC(=O)Nc1cccc(-c2cncc(Cl)n2)c1
Reactant: Nc1ccc2c(c1)OCO2
Product: CC(=O)Nc1cccc(-c2cncc(Nc3ccc4c(c3)OCO4)n2)c1
Yield: 73.1 %

Procedure:
Using Method F with 200 mg (0.33 mmol) 4a and 138 mg (1.0 mmol) 3,4-methylendioxyaniline, 84 mg (29.0%) pure title compound were obtained after preparative HPLC (eluent: AcOEt) purification of the whole batch. Reaction time: 18 hours. 1H-NMR (DMSO), δ (ppm), J (Hz): 2.08 (s, 3H, CH3CO), 5.99 (s, 2H, OCH2O), 6.91 (d, 1H, Harom 5, J=8.40), 7.32 (q, 1H, Harom 6, Jo=8.43, Jm=1.99), 7.40 (d, 1H, Harom 2, J=1.85), 7.43 (t, 1H, Harom 5′, J=7.87), 7.65 (d, 1H, Harom 4′ or 6′, J=8.93), 7.68 (d, 1H, Harom 6′ or 4′, J=7.83), 8.12 (s, 1H, HP5), 8.30 (s, 1H, Harom 2′), 8.35 (s, 1H, HP3), 9.42 (s, 1H, NHamino), 10.09 (s, 1H, NHamido); MS, (C19H16N4O3), m/z: 349.1 [M++1, 100].
Reaction SMILES: ICI.[CH2:4]([N:11]([C@@H:29]([C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1)[CH3:30])[C@@H:12]1[C@H:17]([N:18]2[C:26](=[O:27])[C:25]3[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=3)[C:19]2=[O:28])[CH2:16][CH:15]=[CH:14][CH2:13]1)[C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1.[CH2:37]([Zn]CC)C.C(=O)([O-])O.[Na+]>CO.C(Cl)Cl>[CH2:4]([N:11]([C@@H:29]([C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1)[CH3:30])[C@H:12]1[CH2:13][CH:14]2[CH:15]([CH2:37]2)[CH2:16][C@H:17]1[N:18]1[C:19](=[O:28])[C:20]2[C:25](=[CH:24][CH:23]=[CH:22][CH:21]=2)[C:26]1=[O:27])[C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1
Reactant: C[C@H](c1ccccc1)N(Cc1ccccc1)[C@H]1CC=CC[C@H]1N1C(=O)c2ccccc2C1=O
Reactant: CC[Zn]CC
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CO
Solvent: ICI
Solvent: ClCCl
Product: C[C@H](c1ccccc1)N(Cc1ccccc1)[C@H]1CC2CC2C[C@H]1N1C(=O)c2ccccc2C1=O
Reaction time: 15 h

Procedure:
A methylene chloride (3 ml) solution containing diiodomethane (0.2 ml) and a methylene chloride solution (3 ml) containing 2-((1R,6S)-6-(benzyl ((R)-1-phenylethyl)amino)-3-cyclohexen-1-yl)isoindolin-1,3-dione (0.36 g) obtained in the 1st step were added to a methylene chloride solution (10 ml) containing diethyl zinc (1M in hexane) (2.47 ml), followed by stirring for 15 hours. Methanol and sodium hydrogen carbonate were added to the reaction solution. The reaction solution was filtered through Celite. The filtrate was extracted with ethyl acetate. The organic layers were washed with water and saturated saline and dried over anhydrous sodium sulfate. The solvent was distilled away under reduced pressure and the obtained residue was purified by silica gel chromatography (n-hexane:ethyl acetate=1:0 to 1:0.2). A 2-((3R,4S)-4-(benzyl ((R)-1-phenylethyl)amino)bicyclo[4.1.0]heptan-3-yl)isoindolin-1,3-dione (0.20 g) was thus obtained.
Reaction SMILES: C[O:2][C:3]([CH2:5][CH2:6][CH2:7][CH2:8][C:9]1[CH:10]=[CH:11][C:12]2[N:13]([CH:15]=[N:16][CH:17]=2)[CH:14]=1)=[O:4]>C(O)C.[OH-].[Na+].O>[C:3]([CH2:5][CH2:6][CH2:7][CH2:8][C:9]1[CH:10]=[CH:11][C:12]2[N:13]([CH:15]=[N:16][CH:17]=2)[CH:14]=1)([OH:4])=[O:2]
Reactant: COC(=O)CCCCc1ccc2cncn2c1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: O=C(O)CCCCc1ccc2cncn2c1

Procedure:
A solution of 6-(4-methoxycarbonylbutyl)-imidazo[1,5-a]pyridine in 0.3 ml of ethanol and 0.8 ml of 1N sodium hydroxide, is refluxed gently for 2 hours, cooled, diluted with 2 ml of water and extracted with ethyl acetate (5 ml). The aqueous phase is brought to pH=6 and is extracted with chloroform. The extracts are dried and evaporated to yield 6-(4-carboxybutyl)-imidazo[1,5-a]pyridine, melting at 168°-171°.