Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]1(/[CH:6]=[C:7](\[C:16]2[CH:21]=[CH:20][C:19]([S:22]([CH3:25])(=[O:24])=[O:23])=[CH:18][CH:17]=2)/[C:8]([NH:10][C:11]2[S:12][CH:13]=[CH:14][N:15]=2)=[O:9])[CH2:5][CH2:4][CH2:3][CH2:2]1.[Br:26]N1C(=O)CCC1=O.C(OOC(=O)C1C=CC=CC=1)(=O)C1C=CC=CC=1>C(Cl)(Cl)(Cl)Cl>[Br:26][C:13]1[S:12][C:11]([NH:10][C:8](=[O:9])/[C:7](/[C:16]2[CH:21]=[CH:20][C:19]([S:22]([CH3:25])(=[O:24])=[O:23])=[CH:18][CH:17]=2)=[CH:6]/[CH:1]2[CH2:5][CH2:4][CH2:3][CH2:2]2)=[N:15][CH:14]=1
Reactant: O=C1CCC(=O)N1Br
Reactant: CS(=O)(=O)c1ccc(/C(=C\C2CCCC2)C(=O)Nc2nccs2)cc1
Agent: O=C(OOC(=O)c1ccccc1)c1ccccc1
Solvent: ClC(Cl)(Cl)Cl
Product: CS(=O)(=O)c1ccc(/C(=C\C2CCCC2)C(=O)Nc2ncc(Br)s2)cc1
Temperature: 90 °C
Reaction time: 8 h
Yield: 21.6 %

Procedure:
A suspension of (E)-3-cyclopentyl-2-(4-methanesulfonyl-phenyl)-N-thiazol-2-yl-acrylamide (prepared in Example 3, 0.44 g, 1.17 mmol) and N-bromosuccinimide (0.20 g, 1.17 mmol) in carbon tetrachloride (4 mL) at 25° C. was treated with benzoyl peroxide (14.17 mg, 0.058 mmol). The resulting reaction mixture was heated to 90° C. where it was stirred overnight at this temperature. The reaction mixture was allowed to cool to 25° C. and then concentrated in vacuo. The residue was dissolved in ethyl acetate (50 mL). The organic phase was then washed with water (1×50 mL) and a saturated aqueous sodium chloride solution (1×50 mL), dried over anhydrous magnesium sulfate, filtered, and concentrated in vacuo. Biotage chromatography (FLASH 40M, Silica, 4/1 to 1/1 hexanes/ethyl acetate) afforded (E)-N-(5-bromo-thiazol-2-yl)-3-cyclopentyl-2-(4-methanesulfonyl-phenyl)-acrylamide (115 mg, 22%) as white solid: mp 202-205° C.
Reaction SMILES: C([C@@H:6]([C@H:8]([C:10]([O:12][CH2:13]C)=O)[OH:9])O)(OCC)=O.C(OO)(C)(C)C.[F:21][C:22]1[CH:27]=[C:26]([F:28])[CH:25]=[CH:24][C:23]=1C(=C)[C@H](O)C.[OH-].[Na+].[O-]S([O-])(=O)=O.[Mg+2]>C(Cl)Cl.CC(C)[O-].[Ti+4].CC(C)[O-].CC(C)[O-].CC(C)[O-]>[F:21][C:22]1[CH:27]=[C:26]([F:28])[CH:25]=[CH:24][C:23]=1[C@@:10]1([O:12][CH2:13]1)[C@H:8]([OH:9])[CH3:6]
Reactant: C=C(c1ccc(F)cc1F)[C@@H](C)O
Reactant: CCOC(=O)[C@H](O)[C@@H](O)C(=O)OCC
Agent: [Ti+4]
Agent: CC(C)(C)OO
Agent: CC(C)[O-]
Solvent: ClCCl
Product: C[C@@H](O)[C@]1(c2ccc(F)cc2F)CO1
Temperature: -5 °C
Reaction time: 0.42 h

Procedure:
To a solution of diethyl L(+)-tartrate (8 ml, 0.047 mole) in dry CH2Cl2 (1.2 L) is added activated 3A° molecular sieve powder (300 g) and cooled the mixture to -5 ° C. Added a solution of titanium (IV) isopropoxide (30 ml, 0.10 mole) followed by t-butyl hydroperoxide (78 ml of 5-6M solution in decane) and continue to stir at -5° C. for 25 minutes. To this mixture, a solution of crude 6b, in CH2Cl2 (100 ml) is added and stirred for 12 hours at 5° C. Cooled the reaction mixture to -40° C., added 70 ml of 30% aq. NaOH solution saturated with NaCI and the mixture is allowed to warm to 10° C. Added 60 g of MgSO4, 20 g of celite and continued to stir at 10° C. for 30 minutes. The mixture is suction-filtered over celite. To the filtrate toluene (1 L), and 700 ml of ether are added and insoluble material removed by filtration. The filtrate is evaporated under reduced pressure to give the crude 7c as a light brown oil.
Reaction SMILES: Cl.[NH2:2][C@@H:3]1[CH2:8][CH2:7][C@H:6]([NH:9][C:10]([C:12]2[C:16]3[N:17]=[CH:18][N:19]=[C:20]([C:21]4[C:29]5[O:28][CH2:27][O:26][C:25]=5[CH:24]=[CH:23][C:22]=4[O:30][CH2:31][CH:32]4[CH2:34][CH2:33]4)[C:15]=3[NH:14][C:13]=2[CH3:35])=[O:11])[CH2:5][CH2:4]1.C([O:39][CH2:40][C:41](Cl)=[O:42])(=O)C>>[CH:32]1([CH2:31][O:30][C:22]2[CH:23]=[CH:24][C:25]3[O:26][CH2:27][O:28][C:29]=3[C:21]=2[C:20]2[C:15]3[NH:14][C:13]([CH3:35])=[C:12]([C:10]([NH:9][C@H:6]4[CH2:7][CH2:8][C@@H:3]([NH:2][C:40](=[O:39])[CH2:41][OH:42])[CH2:4][CH2:5]4)=[O:11])[C:16]=3[N:17]=[CH:18][N:19]=2)[CH2:34][CH2:33]1
Reactant: CC(=O)OCC(=O)Cl
Reactant: Cc1[nH]c2c(-c3c(OCC4CC4)ccc4c3OCO4)ncnc2c1C(=O)N[C@H]1CC[C@@H](N)CC1
Agent: Cl
Product: Cc1[nH]c2c(-c3c(OCC4CC4)ccc4c3OCO4)ncnc2c1C(=O)N[C@H]1CC[C@@H](NC(=O)CO)CC1

Procedure:
Starting from N-(cis-4-aminocyclohexyl)-4-[5-(cyclopropylmethoxy)-1,3-benzodioxol-4-yl]-6-methyl-5H-pyrrolo[3,2-d]pyrimidine-7-carboxamide hydrochloride (example D.f3) and commercially available 2-chloro-2-oxoethyl acetate the title compound is obtained as colorless solid.
Reaction SMILES: [O:1]=[C:2]1[C:6]2([CH2:11][CH2:10][N:9]([CH2:12][CH2:13][CH2:14][N:15]3[C:19]4[CH:20]=[CH:21][CH:22]=[CH:23][C:18]=4[NH:17][C:16]3=[O:24])[CH2:8][CH2:7]2)[N:5]([C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)[CH2:4][N:3]1[CH:31]([C:39]1[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=1)[CH2:32][CH2:33][CH2:34][C:35]([O:37]C)=[O:36].O.[OH-].[Li+]>CO.O>[O:1]=[C:2]1[C:6]2([CH2:7][CH2:8][N:9]([CH2:12][CH2:13][CH2:14][N:15]3[C:19]4[CH:20]=[CH:21][CH:22]=[CH:23][C:18]=4[NH:17][C:16]3=[O:24])[CH2:10][CH2:11]2)[N:5]([C:25]2[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=2)[CH2:4][N:3]1[CH:31]([C:39]1[CH:40]=[CH:41][CH:42]=[CH:43][CH:44]=1)[CH2:32][CH2:33][CH2:34][C:35]([OH:37])=[O:36]
Reactant: COC(=O)CCCC(c1ccccc1)N1CN(c2ccccc2)C2(CCN(CCCn3c(=O)[nH]c4ccccc43)CC2)C1=O
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: O=C(O)CCCC(c1ccccc1)N1CN(c2ccccc2)C2(CCN(CCCn3c(=O)[nH]c4ccccc43)CC2)C1=O
Temperature: 25 °C
Reaction time: 24 h

Procedure:
To a solution of methyl 5-(4-oxo-8-(3-(2-oxo-2,3-dihydro-1H-benzo[d]imidazol-1-yl)propyl)-1-phenyl-1,3,8-triazaspiro[4.5]decan-3-yl)-5-phenylpentanoate (0.13 g, 0.22 mmol) in methanol (3 mL) was added lithium hydroxide monohydrate (0.018 g, 0.44 mmol) in water (1 mL). After stirring at room temperature for 24 h, the reaction mixture was concentrated in vacuo and isolated by reverse phase HPLC to obtain the title compound as an acetate salt (0.075 g, 56%); 1H NMR (DMSO-d6): δ 1.41-1.58 (m, 4H), 1.81 (t, 2H, J=6.8 Hz), 1.97-2.11 (m, 2H), 2.26-2.35 (m, 4H), 2.49-2.53 (m, 2H), 2.61-2.67 (m, 5H), 3.84 (t, 2H, J=6.8 Hz), 4.26 (d, 1H, J=5.6 Hz), 4.74 (d, 1H, J=5.6 Hz), 5.15-5.19 (m, 1H), 6.76 (t, 1H, J=6.8 Hz), 6.86 (d, 2H, J=8 Hz), 6.96 (d, 3H, J=3.6 Hz), 7.17-7.24 (m, 3H), 7.29-7.32 (m, 1H), 7.35-7.38 (m, 3H), 10.80 (s, 1H), 12.07 (br, 1H); MS for C34H39N5O4 m/z 582.12 (M+H)+.
Reaction SMILES: [OH:1][CH:2]1[CH2:7][CH2:6][NH:5][CH2:4][CH2:3]1.[C:8]1(=O)[CH2:11][CH2:10][CH2:9]1.C(O)(=O)C.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>O1CCCC1>[CH:8]1([N:5]2[CH2:6][CH2:7][CH:2]([OH:1])[CH2:3][CH2:4]2)[CH2:11][CH2:10][CH2:9]1
Reactant: OC1CCNCC1
Reactant: O=C1CCC1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CC(=O)O
Product: OC1CCN(C2CCC2)CC1
Temperature: 0 °C
Reaction time: 1 h
Yield: 66.9 %

Procedure:
4-Hydroxypiperidine (2.41 g, 23.8 mmol), cyclobutanone (5 g, 71.4 mmol) and acetic acid (1.36 ml, 23.8 mmol) were stirred in tetrahydrofuran (35 ml) at 0° C. for 1.5 hours. Sodium triacetoxyborohydride (10.1 g, 47.7 mmol) was then added at 0° C. and the reaction mixture stirred at 0° C. for 1 hour. The mixture was warmed to room temperature and stirred for 1 hour, then heated to 40° C. for 18 hours. The reaction was concentrated in vacuo. The residue was taken up in water (30 ml). The aqueous layer was basified to pH 9 with ammonia and extracted with diethyl ether (3×50 ml). The organics were combined, dried over magnesium sulphate, filtered and concentrated in vacuo. The crude product was purified by flash chromatography on silica gel eluting with dichloromethane:methanol:ammonia (100:0:0 to 93:7:0.7 by volume) to provide the title compound (2.47 g, 67%) as an oil. LRMS APCI+ m/z 156 [MH]+.
Reaction SMILES: [NH2:1][C:2]1[C:3]([C:10]([O:12][CH3:13])=[O:11])=[N:4][C:5](Br)=[C:6]([F:8])[CH:7]=1.[F:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=1B(O)O>C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2].C(Cl)Cl>[NH2:1][C:2]1[C:3]([C:10]([O:12][CH3:13])=[O:11])=[N:4][C:5]([C:16]2[CH:17]=[CH:18][CH:19]=[CH:20][C:15]=2[F:14])=[C:6]([F:8])[CH:7]=1
Reactant: COC(=O)c1nc(Br)c(F)cc1N
Reactant: OB(O)c1ccccc1F
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: c1ccc(P(c2ccccc2)[c-]2cccc2)cc1
Solvent: ClCCl
Product: COC(=O)c1nc(-c2ccccc2F)c(F)cc1N
Yield: 99 %

Procedure:
Method 1 was followed using methyl 3-amino-6-bromo-5-fluoropicolinate (1.0 equiv.) and 2-fluoro-phenylboronic acid (1.5 equiv.) and Pd(dppf)Cl2-DCM (0.05 equiv.) to give methyl 3-amino-5-fluoro-6-(2-fluorophenyl)picolinate in >99% yield. LC/MS=265.0 (M+H), Rt=0.77 min.
Reaction SMILES: [C:1]([C:4]1[CH:11]=[C:10]([Cl:12])[C:7]([C:8]#[N:9])=[C:6](I)[C:5]=1[O:14][CH2:15][CH3:16])(=[O:3])[CH3:2].[NH:17]1[CH2:21][CH2:20][CH2:19][CH2:18]1.C(=O)([O-])[O-].[Cs+].[Cs+]>CN(C)C=O.C(OCC)(=O)C>[C:1]([C:4]1[CH:11]=[C:10]([Cl:12])[C:7]([C:8]#[N:9])=[C:6]([N:17]2[CH2:21][CH2:20][CH2:19][CH2:18]2)[C:5]=1[O:14][CH2:15][CH3:16])(=[O:3])[CH3:2]
Reactant: CCOc1c(C(C)=O)cc(Cl)c(C#N)c1I
Reactant: C1CCNC1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CCOc1c(C(C)=O)cc(Cl)c(C#N)c1N1CCCC1
Temperature: 120 °C
Yield: 27 %

Procedure:
The 4-acetyl-6-chloro-3-ethoxy-2-iodobenzonitrile (0.20 g, 0.57 mmol) was combined with pyrrolidine (0.052 mL, 0.63 mmol) in N,N-dimethylformamide (2.0 mL) with cesium carbonate (0.19 g, 0.57 mmol) and heated to 120° C. in a sealed tube. After heating for 18 hrs the reaction was allowed to cool, taken up in ethyl acetate, washed with water, brine, dried over magnesium sulfate and concentrated to give the crude product as a dark oil. The product was purified by FCC on silica gel eluting with hexane:ethyl acetate gradient to give 4-acetyl-6-chloro-3-ethoxy-2-pyrrolidin-1-ylbenzonitrile as an oil (0.045 g, 27%). LCMS calculated for C15H18ClN2O2(M+H)+: m/z=293.1; found 293.1.
Reaction SMILES: [CH2:1]([NH:3][CH2:4][CH3:5])[CH3:2].[Cl:6][C:7]1[CH:12]=[CH:11][C:10]([CH2:13]/[CH:14]=[CH:15]/[CH2:16]Cl)=[CH:9][CH:8]=1.ClC1C=CC(CC(Cl)C=C)=CC=1>Cl>[Cl:6][C:7]1[CH:12]=[CH:11][C:10]([CH2:13]/[CH:14]=[CH:15]/[CH2:16][N:3]([CH2:4][CH3:5])[CH2:1][CH3:2])=[CH:9][CH:8]=1
Reactant: CCNCC
Reactant: ClC/C=C/Cc1ccc(Cl)cc1
Agent: C=CC(Cl)Cc1ccc(Cl)cc1
Agent: Cl
Product: CCN(CC)C/C=C/Cc1ccc(Cl)cc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
Add 30 ml diethylamine to 10.0 g (0.05 mole) of a 7:3 mixture of (E)-1-chloro-4-(4-chloro-2-butenyl)benzene and 1-chloro-4-(2-chloro-3-butenyl)benzene and stir at room temperature overnight. Dissolve reaction mixture in 100 ml 1N HCl and wash with 50 ml ethyl acetate. Extract ethyl acetate layer with 50 ml 1N HCl. Combine aqueous layers and add cold 4N NaOH until solution has pH=9. Extract aqueous phase with 5×60 ml Et2O. Dry ethereal extracts over Na2SO4 and then filter. Evaporate solvent to provide the title compound.
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([C:12]3[CH:17]=[CH:16][C:15]([F:18])=[CH:14][CH:13]=3)[CH:10]=2)[N:5]=[CH:4][N:3]=1.[CH2:19]([NH2:23])[CH2:20][CH2:21][CH3:22]>>[CH2:19]([NH:23][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([C:12]3[CH:17]=[CH:16][C:15]([F:18])=[CH:14][CH:13]=3)[CH:10]=2)[N:5]=[CH:4][N:3]=1)[CH2:20][CH2:21][CH3:22]
Reactant: CCCCN
Reactant: Fc1ccc(-c2ccc3ncnc(Cl)c3c2)cc1
Product: CCCCNc1ncnc2ccc(-c3ccc(F)cc3)cc12
Yield: 68 %

Procedure:
This compound was synthesized from 4-chloro-6-(4-fluorophenyl)-quinazoline and n-butylamine in 68% yield, using the procedure described for example 37. The product was characterized by its mass spectrum as follows: MS (m/z): 296 ([M+H]+, 100).
Reaction SMILES: [CH2:1]([O:8][C:9]1[C:14]([C:15]2[CH:20]=[CH:19][C:18]([C:21]([F:24])([F:23])[F:22])=[CH:17][CH:16]=2)=[CH:13][C:12]([C@@H:25]2[CH2:27][C@H:26]2[NH:28][CH2:29][CH2:30]Cl)=[CH:11][CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[NH:32]1[CH2:36][CH2:35][C@@H:34]([NH:37][C:38](=[O:44])[O:39][C:40]([CH3:43])([CH3:42])[CH3:41])[CH2:33]1>CN(C=O)C>[CH2:1]([O:8][C:9]1[C:14]([C:15]2[CH:20]=[CH:19][C:18]([C:21]([F:24])([F:23])[F:22])=[CH:17][CH:16]=2)=[CH:13][C:12]([C@@H:25]2[CH2:27][C@H:26]2[NH:28][CH2:29][CH2:30][N:32]2[CH2:36][CH2:35][C@@H:34]([NH:37][C:38](=[O:44])[O:39][C:40]([CH3:42])([CH3:41])[CH3:43])[CH2:33]2)=[CH:11][CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: FC(F)(F)c1ccc(-c2cc([C@@H]3C[C@H]3NCCCl)ccc2OCc2ccccc2)cc1
Reactant: CC(C)(C)OC(=O)N[C@@H]1CCNC1
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N[C@@H]1CCN(CCN[C@@H]2C[C@H]2c2ccc(OCc3ccccc3)c(-c3ccc(C(F)(F)F)cc3)c2)C1
Temperature: 25 °C
Reaction time: 48 h
Yield: 60 %

Procedure:
To a solution of (trans)-2-(6-(benzyloxy)-4′-(trifluoromethyl)biphenyl-3-yl)-N-(2-chloroethyl)cyclopropanamine (500 mg, 1.12 mmol) in dry DMF (5 mL), (R)-tert-butyl pyrrolidin-3-ylcarbamate (438 mg, 2.3 mmol) was added and stirred at RT for 48 h. After completion, the reaction mixture was poured into ice water (20 mL), extracted with EtOAc (2×20 mL). The combined extracts were washed with water (25 mL), brine, dried over anhydrous Na2SO4, filtered and evaporated. The crude residue was purified by column chromatography (SiO2) using MeOH: CHCl3 (4:96) to get tert-butyl(R)-1-(2-((trans)-2-(6-(benzyloxy)-4′-(trifluoromethyl)biphenyl-3-yl)cyclopropylamino)ethyl)pyrrolidin-3-ylcarbamate (400 mg, 60.6%) as a white solid.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]2[N:6]([CH:18]3[CH2:24][CH:23]4[N:25](C)[CH:20]([CH2:21][CH2:22]4)[CH2:19]3)[C:7]3[C:12]([S:13][C:14]=2[CH:15]=1)=[C:11]([O:16][CH3:17])[CH:10]=[CH:9][CH:8]=3.BrC1C=CC2N(C3CC4N(C)C(CC4)C3)C3C(SC=2C=1)=CC=CC=3>>[CH:23]12[NH:25][CH:20]([CH2:21][CH2:22]1)[CH2:19][CH:18]([N:6]1[C:5]3[CH:4]=[CH:3][C:2]([Br:1])=[CH:15][C:14]=3[S:13][C:12]3[C:7]1=[CH:8][CH:9]=[CH:10][C:11]=3[O:16][CH3:17])[CH2:24]2
Reactant: COc1cccc2c1Sc1cc(Br)ccc1N2C1CC2CCC(C1)N2C
Agent: CN1C2CCC1CC(N1c3ccccc3Sc3cc(Br)ccc31)C2
Product: COc1cccc2c1Sc1cc(Br)ccc1N2C1CC2CCC(C1)N2

Procedure:
Using an adaptation of the method described in Procedure 21, substituting 3-bromo-6-methoxy-10-(8-methyl-8-aza-bicyclo[3.2.1]oct-3-yl)-10H-phenothiazine, 3cc for 3-bromo-10-(8-methyl-8-aza-bicyclo[3.2.1]oct-3-yl)-10H-phenothiazine, 31, the title compound 10-(8-aza-bicyclo[3.2.1]oct-3-yl)-3-bromo-6-methoxy-10H-phenothiazine, 4cc was obtained a mixture of endo and exo isomers.
Reaction SMILES: [CH:1]1([C:4]([N:6]2[CH2:9][CH:8]([O:10][C:11]3[CH:16]=[C:15]([CH3:17])[C:14]([C:18]4[CH:23]=[CH:22][CH:21]=[C:20]([CH2:24][O:25][C:26]5[CH:39]=[CH:38][C:29]6[C@H:30]([CH2:33][C:34]([O:36]C)=[O:35])[CH2:31][O:32][C:28]=6[CH:27]=5)[CH:19]=4)=[C:13]([CH3:40])[CH:12]=3)[CH2:7]2)=[O:5])[CH2:3][CH2:2]1.[OH-].[Li+]>CO>[CH:1]1([C:4]([N:6]2[CH2:9][CH:8]([O:10][C:11]3[CH:16]=[C:15]([CH3:17])[C:14]([C:18]4[CH:23]=[CH:22][CH:21]=[C:20]([CH2:24][O:25][C:26]5[CH:39]=[CH:38][C:29]6[C@H:30]([CH2:33][C:34]([OH:36])=[O:35])[CH2:31][O:32][C:28]=6[CH:27]=5)[CH:19]=4)=[C:13]([CH3:40])[CH:12]=3)[CH2:7]2)=[O:5])[CH2:3][CH2:2]1
Reactant: COC(=O)C[C@@H]1COc2cc(OCc3cccc(-c4c(C)cc(OC5CN(C(=O)C6CC6)C5)cc4C)c3)ccc21
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Product: Cc1cc(OC2CN(C(=O)C3CC3)C2)cc(C)c1-c1cccc(COc2ccc3c(c2)OC[C@H]3CC(=O)O)c1
Reaction time: 3 h
Yield: 42.1 %

Procedure:
The crude (S)-methyl 2-(6-((4′-((1-(cyclopropanecarbonyl)azetidin-3-yl)oxy)-2′,6′-dimethylbiphenyl-3-yl)methoxy)-2,3-dihydrobenzofuran-3-yl)acetate 15b (46 mg, 0.09 mmol) was dissolved in 3 mL of methanol, followed by addition of 1M aqueous lithium hydroxide solution (0.5 mL, 0.50 mmol). The reaction solution was stirred for 3 hours. The resulting solution was concentrated under reduced pressure, 1M hydrochloric acid was added dropwise to adjust the pH to 3, 3 mL of water were added, and then the solution was extracted with ethyl acetate (20 mL×2). The combined organic extracts were washed with saturated sodium chloride solution (30 mL), dried with anhydrous magnesium sulphate, and filtered. The filtrate was concentrated under reduced pressure to obtain the title compound (S)-2-(6-((4′-((1-(cyclopropanecarbonyl)azetidin-3-yl)oxy)-2′,6′-dimethylbiphenyl-3-yl)methoxy)-2,3-dihydrobenzofuran-3-yl)acetic acid 15 (20 mg, yield 44.0%) as a yellow solid.
Reaction SMILES: [H-].[Al+3].[Li+].[H-].[H-].[H-].N1C2C(=CC=CC=2)C(CC[CH2:18][C:19]([N:21](CC(N)=O)[CH2:22][CH2:23][C:24]2[C:32]3[C:27](=[CH:28][CH:29]=[CH:30][CH:31]=3)[NH:26][CH:25]=2)=O)=C1.O>O1CCCC1>[CH2:19]([NH:21][CH2:22][CH2:23][C:24]1[C:32]2[C:27](=[CH:28][CH:29]=[CH:30][CH:31]=2)[NH:26][CH:25]=1)[CH3:18]
Reactant: NC(=O)CN(CCc1c[nH]c2ccccc12)C(=O)CCCc1c[nH]c2ccccc12
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: O
Solvent: C1CCOC1
Product: CCNCCc1c[nH]c2ccccc12
Temperature: 0 °C
Yield: 185.2 %

Procedure:
Lithium aluminum hydride in tetrahydrofuran (1M, 30 mL) was added dropwise to a stirring solution of N-[2-(1H-indol-3-yl)ethylacetyltryptamineacetamide (2.02 g) in tetrahydrofuran (10 mL) at 0° C. The solution was then heated at reflux overnight. The solution was cooled to 0° C. and water was very carefully added dropwise. The white solid was filtered and rinsed with ether/methanol (9:1, 2×25 mL). The solvent was removed from the filtrate, giving N-ethyl-2-(1H-indol-3-yl)ethanamine as a viscous-pale yellow oil (1.75 g, 93%).
Reaction SMILES: [OH:1][CH:2]([CH2:6][CH3:7])[C:3]([OH:5])=[O:4].Br[CH:9]([CH3:13])[C:10](Br)=[O:11]>>[CH2:6]([CH:2]1[C:3](=[O:5])[O:4][CH:9]([CH3:13])[C:10](=[O:11])[O:1]1)[CH3:7]
Reactant: CC(Br)C(=O)Br
Reactant: CCC(O)C(=O)O
Product: CCC1OC(=O)C(C)OC1=O
Yield: 53 %

Procedure:
3-ethyl-6-methyl-2,5-dioxane-1,4-dione was synthesized from 2-hydroxybutyric acid and 2-bromopropionyl bromide. It was purified by distillation (45° C./50 mtorr) to give a colorless oil. Yield: 53% 1H NMR (CDCl3) δ5.03 (q), 4.99 (q, 1H for signal at 5.03 and 4.99 ppm), 4.86 (dd), 4.83 (dd, 1H for signal at 4.86 and 4.83), 1.90-2.20 (m, 2H), 1.69 (d), 1.66 (d, 3H for signals at 1.69 and 1.66 ppm). 1.15 (t). 1.14 (t, 3H for signals at 1.15 and 1.14 ppm). 13C NMR (CDCl3) δ167.6, 166.8, 166.3, 165.6, 77.7, 76.6, 72.5, 72.2, 25.3, 23.3, 17.5, 15.7, 9.1, 8.7, MS (m/q) 159.4 (M+1). The product is approximately a 3:1 mixture of the R,R/S,S and R,S diastereomers.
Reaction SMILES: [Si:1]([O:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][C:16]#[C:17][C:18]1(O)[C:27]2[C:22](=[CH:23][C:24]([O:28][CH2:29][O:30][CH3:31])=[CH:25][CH:26]=2)[O:21][CH2:20][C:19]1([C:33]1[CH:38]=[CH:37][C:36]([O:39][CH2:40][O:41][CH3:42])=[CH:35][CH:34]=1)[CH3:32])([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].C([BH3-])#N.[Na+].O.CCCCCC>ClCCCl.C(OCC)(=O)C>[Si:1]([O:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][C:16]#[C:17][CH:18]1[C:27]2[C:22](=[CH:23][C:24]([O:28][CH2:29][O:30][CH3:31])=[CH:25][CH:26]=2)[O:21][CH2:20][C:19]1([C:33]1[CH:38]=[CH:37][C:36]([O:39][CH2:40][O:41][CH3:42])=[CH:35][CH:34]=1)[CH3:32])([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:2])[CH3:3]
Reactant: COCOc1ccc(C2(C)COc3cc(OCOC)ccc3C2(O)C#CCCCCCCCO[Si](C)(C)C(C)(C)C)cc1
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: ClCCCl
Solvent: O
Solvent: CCOC(C)=O
Product: COCOc1ccc(C2(C)COc3cc(OCOC)ccc3C2C#CCCCCCCCO[Si](C)(C)C(C)(C)C)cc1
Temperature: 25 °C
Reaction time: 4 h
Yield: 52 %

Procedure:
To a solution of 4-[9-(t-butyldimethylsilyloxy)-1-nonynyl]4-hydroxy-7-methoxymethoxy-3-(4-methoxymethoxyphenyl)-3-methylchroman (116 g, 1.9 mmol) in 1,2-dichloroethane (50 ml) were added zinc iodide(II) (0.7 g) and sodium cyanoborohydride (0.6 g), which was then stirred at room temperature for 4 hours. After the reaction was completed, the reaction mixture was poured into water and extracted with chloroform. The organic layer was dried over anhydrous magnesium sulfate, and concentrated under reduced pressure to give a crude product. This crude product thus obtained was subjected to silica gel column chromatography (n-hexane:ethyl acetate=5:1) to give 4-[9-(t-butyldimethylsilyloxy)-1-nonynyl]-7-methoxymethoxy-3-(4-methoxymethoxyphenyl)-3-methylchroman (a mixture of (3RS,4RS) and (3RS,4SR), (3RS,4RS)/(3RS,4SR)=about 6/1) (590 mg, yield 52%). Then, this compound thus obtained was dissolved in methanol (50 ml) and tetrahydrofuran (10 ml), 10% palladium on carbon (0.23%) was added thereto, and the resulting mixture was stirred at room temperature under hydrogen for 20 hours. The reaction solution was filtered through cellite and concentrated under reduced pressure to give 4-(9-(t-butyldimethylsilyloxy)-nonyl)-7-methoxymethoxy-3-(4-methoxymethoxyphenyl)-3-methylchroman (crude product, 640 mg, stoichiometric yield, a mixture of (3RS,4RS) and (3RS,4SR), (3RS,4RS)/(3RS,4SR)=about 6/1).
Reaction SMILES: [C:1]1([C:7]2[CH:31]=[CH:30][C:10]([C:11]([NH:13][C:14]3[CH:23]=[C:22]4[C:17]([CH2:18][CH2:19][CH2:20][N:21]4C(=O)C(F)(F)F)=[CH:16][CH:15]=3)=[O:12])=[CH:9][N:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C(=O)([O-])[O-].[K+].[K+]>O.CO>[NH:21]1[C:22]2[C:17](=[CH:16][CH:15]=[C:14]([NH:13][C:11](=[O:12])[C:10]3[CH:30]=[CH:31][C:7]([C:1]4[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=4)=[N:8][CH:9]=3)[CH:23]=2)[CH2:18][CH2:19][CH2:20]1
Reactant: O=C(Nc1ccc2c(c1)N(C(=O)C(F)(F)F)CCC2)c1ccc(-c2ccccc2)nc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CO
Solvent: O
Product: O=C(Nc1ccc2c(c1)NCCC2)c1ccc(-c2ccccc2)nc1

Procedure:
6-Phenyl-N-(1-trifluoroacetyl-1,2,3,4-tetrahydroquinolin-7-yl)nicotinamide (Example 25) (155 mg, 0.364 mmol) and potassium carbonate (252 mg, 1.82 mmol) in water (2 ml) and methanol (8 ml) was stirred at ambient temperature for 40 mins. The resulting suspension was filtered and the solid was washed with water then dried in vacuo to give the title compound as a white solid. 1H NMR (250 MHz, CDCl3) δ (ppm): 9.11 (m, 1H), 8.22 (dd, 1H), 8.03 (m, 2H), 7.82 (d, 1H), 7.75 (br, 1H), 7.48 (m, 3H), 7.06 (d, 1H), 6.91 (d, 1H), 6.62 (dd, 1H), 3.95 (br, 1H), 3.30 (m, 2H), 2.73 (t, 2H), 1.93 (m, 2H).
Reaction SMILES: [O:1]=[C:2]1[CH2:10][C:9]2[C:4](=[C:5]([Cl:18])[CH:6]=[CH:7][C:8]=2[O:11][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[NH:3]1.[OH-:19].[Na+:20]>O.O1CCOCC1>[NH2:3][C:4]1[C:5]([Cl:18])=[CH:6][CH:7]=[C:8]([O:11][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[C:9]=1[CH2:10][C:2]([O-:19])=[O:1].[Na+:20]
Reactant: [OH-]
Reactant: O=C1Cc2c(Oc3ccccc3)ccc(Cl)c2N1
Agent: [Na+]
Solvent: O
Solvent: C1COCCO1
Product: Nc1c(Cl)ccc(Oc2ccccc2)c1CC(=O)[O-]
Yield: 37.1 %

Procedure:
A mixture of 2-oxo-4-phenoxy-7-chloroindoline (4.2 g) and sodium hydroxide (1.3 g) in water (40 ml) and dioxane (10 ml) was refluxed for 24 hrs. After cooling, the reaction mixture was filtered, and the filtrate was evaporated in vacuo. The residue was dissolved in ethanol under heating, and the solution was filtered. The filtrate was allowed to stand under ice-cooling, and the precipitating crystals were collected by filtration, washed with ethanol and dried to give sodium 2-(2-amino-3-chloro-6-phenoxyphenyl)acetate (1.8 g). The same product (2.3 g) was obtained from the mother liquid. Total yield 4.1 g. mp>240° C.
Reaction SMILES: [CH2:1]([N:8]1[CH2:13][CH2:12][CH2:11][C@@:10]([CH2:15][OH:16])([CH3:14])[CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Br[CH2:18][CH2:19][O:20][CH:21]1[CH2:26][CH2:25][CH2:24][CH2:23][O:22]1.O>[Br-].C([N+](CCCC)(CCCC)CCCC)CCC.[OH-].[Na+].[Cl-].[Na+].O>[CH2:1]([N:8]1[CH2:13][CH2:12][CH2:11][C@:10]([CH3:14])([CH2:15][O:16][CH2:18][CH2:19][O:20][CH:21]2[CH2:26][CH2:25][CH2:24][CH2:23][O:22]2)[CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: C[C@]1(CO)CCCN(Cc2ccccc2)C1
Reactant: BrCCOC1CCCCO1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [Br-]
Agent: [Cl-]
Solvent: O
Product: C[C@]1(COCCOC2CCCCO2)CCCN(Cc2ccccc2)C1
Temperature: 60 °C
Reaction time: 4 h
Yield: 55.6 %

Procedure:
(S)-(1-Benzyl-3-methylpiperidin-3-yl)methanol (1.29 g, 5.9 mmol) and tetrabutylammonium bromide (0.19 g, 0.59 mmol) were stirred in 50% NaOH (40 ml) for 15 min. The mixture was then heated to 60° C. and 2-(2-bromoethoxy)tetrahydropyran (2.7 ml, 17.7 mmol) was slowly added (2 h) from a dropping funnel. Stirring was then continued for 4 h at 60° C. Water (40 ml) and brine (20 ml) were added to the cooled mixture, which was extracted with toluene (3×50 ml). The combined extracts were washed twice with water and brine, dried, filtered and evaporated to give 3.0 g of the crude product mixture, which was subjected to flash chromatography on silica. Elution with heptane/EtOAc (80:20) gave 1.14 g of the title compound as a colorless oil.