Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl.[NH2:2][CH:3]1[CH2:8][CH2:7][CH2:6][O:5][CH2:4]1.[N:9]1[O:10][N:11]=[C:12]2[CH:17]=[C:16]([C:18](Cl)=[O:19])[CH:15]=[CH:14][C:13]=12>>[O:5]1[CH2:6][CH2:7][CH2:8][CH:3]([NH:2][C:18]([C:16]2[CH:15]=[CH:14][C:13]3=[N:9][O:10][N:11]=[C:12]3[CH:17]=2)=[O:19])[CH2:4]1
Reactant: NC1CCCOC1
Reactant: O=C(Cl)c1ccc2nonc2c1
Agent: Cl
Product: O=C(NC1CCCOC1)c1ccc2nonc2c1

Procedure:
N-(Tetrahydro-2H-pyran-3-yl)-[2,1,3]-benzoxadiazole-5-carboxamide was prepared from 3-aminotetrahydropyran hydrochloride and [2,1,3]-benzoxadiazole-5-carbonylchloride using the procedure described for Example 7. Mp=204-205° C., 1H NMR (300 MHz, CDCl3) δ 8.24-8.10 (m, 1H), 7.93 (dd, 1H, J=9.0 and 0.9 Hz); 7.84 (dd, 1H, J=9.0 and 1.2 Hz); 6.70-6.60 (m, NH, 1H); 4.24-4.22 (m, 1H), 3.86-3.60 (m, 4H) and 1.97-1.61 ppm (m, 4H).
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]2[C:8](=[C:9]([NH:11][CH:12]3[CH2:17][CH2:16][NH:15][CH2:14][CH2:13]3)[CH:10]=1)[NH:7][C:6]([C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)=[CH:5]2.[CH3:24][S:25](Cl)(=[O:27])=[O:26]>>[CH3:24][S:25]([N:15]1[CH2:14][CH2:13][CH:12]([NH:11][C:9]2[CH:10]=[C:2]([CH3:1])[CH:3]=[C:4]3[C:8]=2[NH:7][C:6]([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)=[CH:5]3)[CH2:17][CH2:16]1)(=[O:27])=[O:26]
Reactant: CS(=O)(=O)Cl
Reactant: Cc1cc(NC2CCNCC2)c2[nH]c(-c3ccccc3)cc2c1
Product: Cc1cc(NC2CCN(S(C)(=O)=O)CC2)c2[nH]c(-c3ccccc3)cc2c1

Procedure:
(5-Methyl-2-phenyl-1H-indol-7-yl)-piperidin-4-yl-amine prepared in Example 90 and methanesulfonylchloride were reacted according to the same procedure as Example 22 to give the title compound.
Reaction SMILES: [CH2:1]([O:4][CH2:5][CH2:6][CH:7]([NH:16]C(=O)C(F)(F)F)[C:8]1[CH:13]=[CH:12][CH:11]=[C:10]([O:14][CH3:15])[CH:9]=1)[CH:2]=[CH2:3].C(=O)([O-])[O-].[K+].[K+].CO>O>[CH2:1]([O:4][CH2:5][CH2:6][CH:7]([C:8]1[CH:13]=[CH:12][CH:11]=[C:10]([O:14][CH3:15])[CH:9]=1)[NH2:16])[CH:2]=[CH2:3]
Reactant: C=CCOCCC(NC(=O)C(F)(F)F)c1cccc(OC)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CO
Product: C=CCOCCC(N)c1cccc(OC)c1
Yield: 91.8 %

Procedure:
Step R (3): N-(3-(Allyloxy)-1-(3-methoxyphenyl)propyl)-2,2,2-trifluoroacetamide from step R (2) (610 mg, 1.92 mmol), potassium carbonate (1.33 g, 9.26 mmol), methanol (50 mL) and H2O (4 mL) were heated to reflux for 16 h. The mixture was concentrated in vacuo. H2O was added, and the aqueous layer was extracted several times with EtOAc. The combined organics were washed with brine, dried over Na2SO4, and concentrated in vacuo to afford 390 mg (92% yield) of 3-(allyloxy)-1-(3-methoxyphenyl)propan-1-amine as a pale-yellow oil. The crude mixture was used without further purification. LC-MS (M+H)+=222.95; 1H NMR (300 MHz, CDCl3) δ ppm 1.82-2.18 (m, 2H) 3.23-3.54 (m, 3H) 3.72-3.82 (m, 3H) 3.83-4.00 (m, 2H) 4.14 (t, J=6.95 Hz, 1H) 5.08-5.31 (m, 2H) 5.76-5.95 (m, 1H) 6.71-6.86 (m, 1H) 6.86-6.97 (m, 1H) 7.14-7.29 (m, 2H).
Reaction SMILES: [C:1]([CH:5]1[CH2:10][CH2:9][CH:8]([O:11][C:12]2[CH:13]=[C:14]3[C:19](=[CH:20][CH:21]=2)[N:18]=[C:17]([C:22](=O)[CH3:23])[CH:16]=[CH:15]3)[CH2:7][CH2:6]1)([CH3:4])([CH3:3])[CH3:2].[CH3:25][O:26][C:27]([CH:29]1[CH2:32][NH:31][CH2:30]1)=[O:28].C(O)C.C([BH3-])#N.[Na+]>>[C:1]([C@H:5]1[CH2:10][CH2:9][C@H:8]([O:11][C:12]2[CH:13]=[C:14]3[C:19](=[CH:20][CH:21]=2)[N:18]=[C:17]([CH:22]([N:31]2[CH2:32][CH:29]([C:27]([O:26][CH3:25])=[O:28])[CH2:30]2)[CH3:23])[CH:16]=[CH:15]3)[CH2:7][CH2:6]1)([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(=O)c1ccc2cc(OC3CCC(C(C)(C)C)CC3)ccc2n1
Reactant: COC(=O)C1CNC1
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CCO
Product: COC(=O)C1CN(C(C)c2ccc3cc(O[C@H]4CC[C@H](C(C)(C)C)CC4)ccc3n2)C1
Temperature: 25 °C

Procedure:
1-[6-(4-tert-Butyl-cyclohexyloxy)-quinolin-2-yl]-ethanone (68 mg, 0.00021 mol) and Azetidine-3-carboxylic acid methyl ester (23.9 mg, 0.000207 mol) was dissolved in Ethanol (0.50 mL, 0.0086 mol) and was heated to reflux for 2 hours. After cooling down to rt, Sodium cyanoborohydride (32.4 mg, 0.000516 mol) was added and was heated to reflux for 1 hour. After cooling down to rt and concentration, the mixture was dissolved into DCM and quenched with NEt3 and concentrated. The residue was chromatographed with MeOH/CH2Cl2 to give product (57.2 mg, 65%). LCMS 1.66 min, at m/z 425.30 ([M+1], 100%).
Reaction SMILES: C(N(CC)CC)C.[F:8][C:9]1[CH:16]=[CH:15][C:12]([CH2:13]Cl)=[CH:11][CH:10]=1.[Cl:17][SiH:18]([Cl:20])[Cl:19]>>[F:8][C:9]1[CH:16]=[CH:15][C:12]([CH2:13][Si:18]([Cl:20])([Cl:19])[Cl:17])=[CH:11][CH:10]=1
Reactant: Fc1ccc(CCl)cc1
Reactant: Cl[SiH](Cl)Cl
Solvent: CCN(CC)CC
Product: Fc1ccc(C[Si](Cl)(Cl)Cl)cc1
Yield: 24.6 %

Procedure:
In the same apparatus and procedure as Example 1 above, 0.044 g (0.40 mmol) of triethylamine, 0.60 g (4.0 mmol) of 4-fluorobenzyl chloride, and 2.71 g (20.0 mmol) of trichlorosilane were reacted at 150° C. for 40 hrs. The resulting mixture was distilled to give 0.24 g of (4-fluorobenzyl)trichlorosilane (yield; 24%).
Reaction SMILES: [C:1](Cl)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[NH2:10][CH2:11][CH2:12][C:13]1[CH:18]=[CH:17][C:16]([C:19]([NH:22][CH2:23][CH2:24][CH2:25][N:26]2[CH:30]=[CH:29][N:28]=[CH:27]2)([CH3:21])[CH3:20])=[CH:15][CH:14]=1>ClCCl>[N:26]1([CH2:25][CH2:24][CH2:23][NH:22][C:19]([C:16]2[CH:17]=[CH:18][C:13]([CH2:12][CH2:11][NH:10][C:1](=[O:8])[C:2]3[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=3)=[CH:14][CH:15]=2)([CH3:21])[CH3:20])[CH:30]=[CH:29][N:28]=[CH:27]1
Reactant: O=C(Cl)c1ccccc1
Reactant: CC(C)(NCCCn1ccnc1)c1ccc(CCN)cc1
Solvent: ClCCl
Product: CC(C)(NCCCn1ccnc1)c1ccc(CCNC(=O)c2ccccc2)cc1
Temperature: 0 °C

Procedure:
A solution of benzoyl chloride (0.2 g) in dichloromethane (3 ml) was added dropwise to a solution of N-{1-[4-(2-aminoethyl)phenyl]-1-methylethyl}-3-(imidazol-1-yl)propylamine (0.4 g) in dichloromethane (7 ml) with stirring at 0° C. The mixture was treated in a similar manner to Example 55 to give N-[2-(4-{1-[3-(imidazol-1-yl)propylamino]-1-methylethyl}phenyl)-ethyl]benzamide as an oil.
Reaction SMILES: [C:1]([OH:7])([C:3]([F:6])([F:5])[F:4])=[O:2].C([O:12][C:13](=[O:24])[NH:14][C@H:15]([CH3:23])[CH2:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][N:18]=1)(C)(C)C>C(Cl)Cl>[F:4][C:3]([F:6])([F:5])[C:1]([OH:7])=[O:2].[CH3:23][C@@H:15]([NH:14][C:13](=[O:12])[OH:24])[CH2:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][N:18]=1
Reactant: C[C@H](Cc1ccccn1)NC(=O)OC(C)(C)C
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: C[C@H](Cc1ccccn1)NC(=O)O
Reaction time: 2 h

Procedure:
TFA (4 mL) was added to a CH2Cl2 solution (10 mL) of 7-3 (120 mg, 0.48 mmol) and the solution stirred under ambient conditions for 2 h and concentrated to dryness. The residue was azeotroped with toluene (3×25 mL) to provide 7-4 as a light-yellow semi-solid.
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[C:6]([C:7]([OH:9])=O)[C:5]([OH:11])=[CH:4][CH:3]=1.[F:12][C:13]1[C:19]([F:20])=[C:18]([F:21])[C:17]([F:22])=[C:16]([F:23])[C:14]=1[NH2:15]>>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([OH:11])=[C:6]([CH:10]=1)[C:7]([NH:15][C:14]1[C:16]([F:23])=[C:17]([F:22])[C:18]([F:21])=[C:19]([F:20])[C:13]=1[F:12])=[O:9]
Reactant: Nc1c(F)c(F)c(F)c(F)c1F
Reactant: O=C(O)c1cc(Cl)ccc1O
Product: O=C(Nc1c(F)c(F)c(F)c(F)c1F)c1cc(Cl)ccc1O
Yield: 58.6 %

Procedure:
Using 5-chlorosalicylic acid and 2,3,4,5,6-pentafluoroaniline as the raw materials, the same operation as the example 16 gave the title compound.
Reaction SMILES: C(=O)(O)[O-].[Na+].[CH2:6]([NH:13][CH2:14][CH2:15][C:16]1[CH:31]=[CH:30][C:19]([O:20][C:21]2[CH:29]=[CH:28][C:24]([C:25]([NH2:27])=[O:26])=[CH:23][N:22]=2)=[CH:18][CH:17]=1)[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1.Br[CH2:33][CH2:34][C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1.CN(C=O)C>O>[CH2:6]([N:13]([CH2:33][CH2:34][C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1)[CH2:14][CH2:15][C:16]1[CH:31]=[CH:30][C:19]([O:20][C:21]2[CH:29]=[CH:28][C:24]([C:25]([NH2:27])=[O:26])=[CH:23][N:22]=2)=[CH:18][CH:17]=1)[C:7]1[CH:8]=[CH:9][CH:10]=[CH:11][CH:12]=1
Reactant: NC(=O)c1ccc(Oc2ccc(CCNCc3ccccc3)cc2)nc1
Reactant: BrCCc1ccccc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: NC(=O)c1ccc(Oc2ccc(CCN(CCc3ccccc3)Cc3ccccc3)cc2)nc1
Temperature: 25 °C
Yield: 386.6 %

Procedure:
Add sodium bicarbonate (0.0823 g, 0.0980 mmol) to a stirred solution of 6-[4-(2-benzylamino-ethyl)-phenoxy]-nicotinamide (0.3061 g, 0.0881 mmol), (2-bromoethyl)benzene (0.135 mL, 0.988 mmol), and DMF (5 mL). Heat the reaction to reflux for 3 h under nitrogen and then cool to room temperature. Pour the reaction into water (50 mL) and extract with diethyl ether (3×50 mL). Dry the diethyl ether extracts over magnesium sulfate and then filter off the magnesium sulfate. Concentrate on a rotary evaporator and purify the crude product by flash chromatography on silica gel eluting with 90% ethyl acetate/hexanes to yield 0.1538 g (39%) of 6-{4-[2-(benzyl-phenethyl-amino)-ethyl]-phenoxy}-nicotinamide: mass spectrum (ion spray): m/z=452.1 (M+1); 1H NMR (CDCl3): 8.55 (d, 1H), 8.13 (dd, 1H), 7.29-7.11 (m, 14H), 7.01 (d, 2H), 6.92 (d, 1H), 3.71 (s, 1H), 2.94-2.77 (m, 9H).
Reaction SMILES: [N:1]12[CH2:8][CH2:7][N:4]([CH2:5][CH2:6]1)[CH2:3][CH:2]2[CH2:9][NH:10][C:11]1[N:12]=[CH:13][C:14]([C:17]2[N:18]=[C:19]([N:27]3[CH2:32][CH2:31][C@@H:30]([NH:33][C:34]([C:36]4[NH:37][C:38]([CH3:43])=[C:39]([Cl:42])[C:40]=4[Cl:41])=[O:35])[C@@H:29]([O:44][CH3:45])[CH2:28]3)[S:20][C:21]=2[C:22]([O:24]CC)=[O:23])=[N:15][CH:16]=1.O.[OH-].[Li+]>CO.O>[N:1]12[CH2:8][CH2:7][N:4]([CH2:5][CH2:6]1)[CH2:3][CH:2]2[CH2:9][NH:10][C:11]1[N:12]=[CH:13][C:14]([C:17]2[N:18]=[C:19]([N:27]3[CH2:32][CH2:31][C@@H:30]([NH:33][C:34]([C:36]4[NH:37][C:38]([CH3:43])=[C:39]([Cl:42])[C:40]=4[Cl:41])=[O:35])[C@@H:29]([O:44][CH3:45])[CH2:28]3)[S:20][C:21]=2[C:22]([OH:24])=[O:23])=[N:15][CH:16]=1
Reactant: CCOC(=O)c1sc(N2CC[C@@H](NC(=O)c3[nH]c(C)c(Cl)c3Cl)[C@@H](OC)C2)nc1-c1cnc(NCC2CN3CCN2CC3)cn1
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: CO[C@H]1CN(c2nc(-c3cnc(NCC4CN5CCN4CC5)cn3)c(C(=O)O)s2)CC[C@H]1NC(=O)c1[nH]c(C)c(Cl)c1Cl
Temperature: 25 °C
Reaction time: 16 h
Yield: 70.3 %

Procedure:
Ethyl 4-{5-[(1,4-diazabicyclo[2.2.2]oct-2-ylmethyl)amino]pyrazin-2-yl}-2-[(3S,4R)-4-{[(3,4-dichloro-5-methyl-1H-pyrrol-2-yl)carbonyl]amino}-3-methoxypiperidin-1-yl]-1,3-thiazole-5-carboxylate (Example 194, 100 mg, 0.14 mmol) was dissolved in methanol (3 mL) and water (1 mL). Lithium hydroxide monohydrate (18 mg, 0.44 mmol) was added and the reaction mixture was stirred at room temperature for 16 h. The methanol was completely evaporated. The resulting crude product was taken in water (20 mL) and acidified to pH 6 with 2N hydrochloric acid (1.0 mL). The aqueous layer was concentrated to a residue, which was purified by preparative thin layer chromatography to afford 64 mg (66.8%) of 4-{5-[(1,4-diazabicyclo[2.2.2]oct-2-ylmethyl)amino]pyrazin-2-yl}-2-[(3S,4R)-4-{[(3,4-dichloro-5-methyl-1H-pyrrol-2-yl)carbonyl]amino}-3-methoxypiperidin-1-yl]-1,3-thiazole-5-carboxylic acid as a light yellow solid.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH2:10][CH2:11][C:12]2([CH:20]3[CH2:24][CH2:23][CH2:22][CH2:21]3)[O:17][C:16](=[O:18])[CH2:15][C:14](=[O:19])[CH2:13]2)[CH:5]=[CH:6][C:7]=1[O:8][CH3:9].[CH2:25]1CCN2C(=NCCC2)CC1.IC>CN(C=O)C>[Cl:1][C:2]1[CH:3]=[C:4]([CH2:10][CH2:11][C:12]2([CH:20]3[CH2:24][CH2:23][CH2:22][CH2:21]3)[O:17][C:16](=[O:18])[CH:15]=[C:14]([O:19][CH3:25])[CH2:13]2)[CH:5]=[CH:6][C:7]=1[O:8][CH3:9]
Reactant: C1CCC2=NCCCN2CC1
Reactant: COc1ccc(CCC2(C3CCCC3)CC(=O)CC(=O)O2)cc1Cl
Solvent: CI
Solvent: CN(C)C=O
Product: COC1=CC(=O)OC(CCc2ccc(OC)c(Cl)c2)(C2CCCC2)C1
Temperature: 25 °C
Reaction time: 8 h
Yield: 13.2 %

Procedure:
To a solution of 6-[2-(3-Chloro-4-methoxy-phenyl)-ethyl]-6-cyclopentyl-dihydro-pyran-2,4-dione (60 mg, 0.17 mmol) from Example B(87), dissolved in DMF (1.5 mL), were added DBU (0.028 mL, 0.188 mmol) and iodomethane (0.011 mL, 0.17 mmol). The reaction was stirred at room temperature overnight, and then was quenched with water. The reaction was extracted with EtOAc, and the organic layers were combined. After washing with saturated NaCl, the organic layer was dried over Na2SO4. The solids were removed by filtration, and the liquid was concentrated by rotary evaporation. Purification by preparatory HPLC gave the desired product (8.2 mg, 13% yield).
Reaction SMILES: S(Cl)(Cl)=O.[NH2:5][C:6]1[CH:14]=[CH:13][C:12]([CH3:15])=[CH:11][C:7]=1[C:8]([OH:10])=[O:9].[CH3:16]O>>[CH3:16][O:9][C:8](=[O:10])[C:7]1[CH:11]=[C:12]([CH3:15])[CH:13]=[CH:14][C:6]=1[NH2:5]
Reactant: CO
Reactant: Cc1ccc(N)c(C(=O)O)c1
Solvent: O=S(Cl)Cl
Product: COC(=O)c1cc(C)ccc1N
Yield: 61 %

Procedure:
Thionyl chloride (2.88 mL, 39.69 mmol) was added drop wise to a solution of 2-amino-5-methyl-benzoic acid (3.0 g, 19.84 mmol) in methanol (10 mL) at 0° C. and refluxed for 16 hr. The reaction mixture was concentrated to dryness and the residue dissolved in chloroform (100 mL). The organic layer was washed with sodium bicarbonate solution (5×30 mL), water (3×30 mL), brine (3×30 mL) and dried over anhydrous sodium sulphate. The residue was concentrated under vacuum to yield the crude compound, which was purified by column chromatography over silica gel (100-200 mesh) using 2% ethyl acetate in pet ether as eluent to afford 2-amino-5-methyl-benzoic acid methyl ester (2.0 g, 61%) as a pale yellow semi solid.
Reaction SMILES: C([O:8][C:9](=[O:30])[CH2:10][C@H:11]([NH:22][C:23]([O:25][C:26]([CH3:29])([CH3:28])[CH3:27])=[O:24])[CH2:12][N:13]1[C:18](=[O:19])[CH2:17][CH2:16][CH:15]([CH3:20])[C:14]1=[O:21])C1C=CC=CC=1.[H][H]>CO.[Pd]>[C:26]([O:25][C:23]([NH:22][C@H:11]([CH2:12][N:13]1[C:18](=[O:19])[CH2:17][CH2:16][CH:15]([CH3:20])[C:14]1=[O:21])[CH2:10][C:9]([OH:30])=[O:8])=[O:24])([CH3:29])([CH3:27])[CH3:28]
Reactant: CC1CCC(=O)N(C[C@H](CC(=O)OCc2ccccc2)NC(=O)OC(C)(C)C)C1=O
Reactant: [H][H]
Agent: [Pd]
Solvent: CO
Product: CC1CCC(=O)N(C[C@H](CC(=O)O)NC(=O)OC(C)(C)C)C1=O
Yield: 34.6 %

Procedure:
(S)-3-t-butoxycarbonylamino-4-(3-methyl-2,6-dioxo-piperidin-1-yl)-butyric acid benzyl ester (218 mg, 0.52 mmol) synthesized in Section (1) was dissolved in methanol and 10% Pd/C (22 mg, 0.1 eq) was added thereto, followed by stirring for 1 hour under 1 atm hydrogen gas. After the reaction was complete, Pd on charcoal was removed by celite filtration. The residue was purified by prep-TLC to afford 59 mg (yield: 35%) of the title compound.
Reaction SMILES: [CH3:1][C:2]12[CH2:12][CH:6]3[CH2:7][C:8]([CH3:11])([CH2:10][C:4]([C:13]4(O)[CH:18]=[CH:17][CH:16]=[CH:15][CH2:14]4)([CH2:5]3)[CH2:3]1)[CH2:9]2.N1C=CC=CC=1.[F:26][C:27]([F:40])([F:39])[S:28]([O:31]S(C(F)(F)F)(=O)=O)(=[O:30])=[O:29].[Cl-].[Na+]>C(OCC)(=O)C>[CH3:11][C:8]12[CH2:7][CH:6]3[CH2:12][C:2]([CH3:1])([CH2:3][C:4]([C:13]4[CH:14]=[CH:15][C:16]([O:31][S:28]([C:27]([F:40])([F:39])[F:26])(=[O:30])=[O:29])=[CH:17][CH:18]=4)([CH2:5]3)[CH2:10]1)[CH2:9]2
Reactant: CC12CC3CC(C)(C1)CC(C1(O)C=CC=CC1)(C3)C2
Reactant: O=S(=O)(OS(=O)(=O)C(F)(F)F)C(F)(F)F
Agent: [Cl-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: c1ccncc1
Product: CC12CC3CC(C)(C1)CC(c1ccc(OS(=O)(=O)C(F)(F)F)cc1)(C3)C2
Temperature: -15 °C
Yield: 88 %

Procedure:
Into a 100 ml four-necked flask equipped with a thermometer, an inlet for nitrogen gas and a stirrer, 4.0 g (0.0157 moles) of 4-(1-(3,5-dimethyladamantyl)phenol obtained above and 20 ml of pyridine were placed. A stream of nitrogen gas was introduced into the flask, and a solution was prepared under stirring. The obtained solution was cooled at −15° C. in an ice/methanol bath. Using a dropping funnel, trifluoromethanesulfonic acid anhydride was added dropwise. After the addition was completed, the obtained mixture was stirred at the room temperature for 2 hours. To the reaction fluid, 100 ml of ethyl acetate and 100 ml of a saturated aqueous solution of sodium chloride were added, and the obtained mixture was transferred to a separation funnel. The layer of ethyl acetate was taken out and washed twice with 100 ml of a saturated aqueous solution of sodium chloride. Then, ethyl acetate was removed by distillation under a reduced pressure using a rotary evaporator, and 5.4 g of 1-(1-(3,5-dimethyladamantyl)-4-trifluoromethane-sulfonyloxybenzene was obtained (the yield: 88%).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([CH:9]=[CH:10][C:11]=1[CH:12](O)[CH:13]([CH3:18])[C:14](OC)=[O:15])[C:5]([O:7][CH3:8])=[O:6].Cl>O1CCOCC1>[CH3:18][C:13]1[C:14](=[O:15])[NH:1][C:2]2[C:11]([CH:12]=1)=[CH:10][CH:9]=[C:4]([C:5]([O:7][CH3:8])=[O:6])[CH:3]=2
Reactant: COC(=O)c1ccc(C(O)C(C)C(=O)OC)c(N)c1
Agent: Cl
Solvent: C1COCCO1
Product: COC(=O)c1ccc2cc(C)c(=O)[nH]c2c1

Procedure:
Methyl 3-amino-4-(1-hydroxy-3-methoxy-2-methyl-3-oxopropyl)benzoate was treated with hydrochloric acid in 1,4-dioxane to obtain methyl 3-methyl-2-oxo-1,2-dihydroquinolin-7-carboxylate.
Reaction SMILES: [C:1]([NH:9][C:10]1[CH:22]=[C:21]([C:23]2[CH:28]=[CH:27][C:26]([OH:29])=[CH:25][CH:24]=2)[CH:20]=[CH:19][C:11]=1[C:12]([O:14]C(C)(C)C)=[O:13])(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1>FC(F)(F)C(O)=O>[C:1]([NH:9][C:10]1[CH:22]=[C:21]([C:23]2[CH:24]=[CH:25][C:26]([OH:29])=[CH:27][CH:28]=2)[CH:20]=[CH:19][C:11]=1[C:12]([OH:14])=[O:13])(=[O:8])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CC(C)(C)OC(=O)c1ccc(-c2ccc(O)cc2)cc1NC(=O)c1ccccc1
Solvent: O=C(O)C(F)(F)F
Product: O=C(Nc1cc(-c2ccc(O)cc2)ccc1C(=O)O)c1ccccc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
10 mL of trifluoroacetic acid was added to the obtained tert-butyl 2-(benzamido)-4-(4-hydroxyphenyl)benzoate and stirred at room temperature for 1 hour. The solvent was evaporated under reduced pressure and the obtained residue was purified with reversed-phase silica gel column chromatography [eluent; 55-90% acetonitrile /0.1% trifluoroacetic acid aqueous solution] to obtain 1.9 mg of 2-(benzamido)-4-(4-hydroxyphenyl)benzoic acid as while solid.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[C:4]([Cl:9])[C:3]=1[C:10]1[C:18]2[O:17][CH:16]([CH2:19][NH2:20])[CH2:15][C:14]=2[CH:13]=[CH:12][CH:11]=1.C(N(C(C)C)CC)(C)C.Cl[C:31]([O:33][CH2:34][C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1)=[O:32]>>[Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[C:4]([Cl:9])[C:3]=1[C:10]1[C:18]2[O:17][CH:16]([CH2:19][NH:20][C:31](=[O:32])[O:33][CH2:34][C:35]3[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=3)[CH2:15][C:14]=2[CH:13]=[CH:12][CH:11]=1
Reactant: O=C(Cl)OCc1ccccc1
Reactant: NCC1Cc2cccc(-c3c(Cl)cc(Cl)cc3Cl)c2O1
Solvent: CCN(C(C)C)C(C)C
Product: O=C(NCC1Cc2cccc(-c3c(Cl)cc(Cl)cc3Cl)c2O1)OCc1ccccc1
Yield: 96.9 %

Procedure:
Treatment of (±)-{[7-(2,4,6-trichlorophenyl)-2,3-dihydro-1-benzofuran-2-yl]methyl}amine (1.1 g, 3.57 mmol) with diisopropylethylamine (0.69 g, 5.35 mmol) and benzyl chloroformate (0.0.82 g, 4.28 mmol) generally according to the procedure described for Intermediate 12 provided 1.6 g (99%) of (±)-benzyl {[7-(2,4,6-trichlorophenyl)-2,3-dihydro-1-benzofuran-2-yl]methyl}carbamate as a colorless oil.
Reaction SMILES: Br[CH2:2][C:3]1[C:8]([Cl:9])=[CH:7][CH:6]=[CH:5][C:4]=1[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1.C1N2CN3CN(C2)CN1C3.C(O)(=[O:28])C.[Cl-].[Na+]>C(Cl)(Cl)Cl.O>[Cl:9][C:8]1[CH:7]=[CH:6][CH:5]=[C:4]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[C:3]=1[CH:2]=[O:28]
Reactant: Clc1cccc(-c2ccccc2)c1CBr
Reactant: CC(=O)O
Agent: C1N2CN3CN1CN(C2)C3
Agent: [Cl-]
Agent: [Na+]
Solvent: ClC(Cl)Cl
Solvent: O
Product: O=Cc1c(Cl)cccc1-c1ccccc1

Procedure:
A stirred solution of 2-bromomethyl-3-chloro-[1,1'-biphenyl] (18.7 g, 0.067 mole) and hexamethylenetetraamine (9.3 g, 0.067 mole) in 200 ml of chloroform was heated at reflux for 221/2 hours. The reaction mixture was cooled and the solvent evaporated under reduced pressure to give a residue. To the residue was added 250 ml of a 1:1 solution of concentrated acetic acid:water. The mixture was heated at reflux for approximately 22 hours, then cooled. The mixture was saturated with sodium chloride and extracted with four 200 ml portions of methylene chloride. The extracts were combined, washed with saturated aqueous sodium chloride solution, followed by saturated aqueous sodium bicarbonate solution, and dried over anhydrous potassium carbonate. The mixture was filtered and the filtrate evaporated under reduced pressure to give a residue. The residue was subjected to column chromatography on silica gel, elution first with toluene:n-heptane (9:1), followed by toluene:methylene chloride (1:1), and finally methylene chloride to give 3-chloro-[1,1'-biphenyl]-2-carboxaldehyde (3.4 g) as an oil.
Reaction SMILES: C(Cl)C=C.C(O[SiH](OCC)OCC)C.[Cl:15][CH2:16][CH2:17][CH2:18][Si:19]([O:26][CH2:27]C)([O:23][CH2:24]C)[O:20][CH2:21]C.CO[SiH](OC)OC>>[Cl:15][CH2:16][CH2:17][CH2:18][Si:19]([O:26][CH3:27])([O:20][CH3:21])[O:23][CH3:24]
Reactant: CCO[Si](CCCCl)(OCC)OCC
Agent: CCO[SiH](OCC)OCC
Agent: CO[SiH](OC)OC
Solvent: C=CCCl
Product: CO[Si](CCCCl)(OC)OC
Yield: 70 %

Procedure:
A potentially more economical route is the direct hydrosilation reaction of triethoxysilane and allyl chloride. Platinum is the most widely used hydrosilation catalyst and its use for the hydrosilation reaction of allyl chloride and triethoxysilane has been reported. According to U.S. Pat. No. 3,795,656, a 70% yield was obtained for the Pt-catalyzed hydrosilation reaction of allyl chloride and triethoxysilane. Belyakova et al., Obshch. Khim 1974, 44, 2439-2442, describes the Pt-catalyzed hydrosilation reaction of silanes with allyl chloride and reports a 14% yield for chloropropyltriethoxysilane. As disclosed in Japanese Patent No. 11,199,588, the Pt-catalyzed hydrosilation reaction of trimethoxysilane and allyl chloride resulted in a 70% yield of chloropropyltrimethoxysilane.
Reaction SMILES: Br[C:2]1[N:3]([CH:17]([CH3:19])[CH3:18])[C:4]2[CH:5]=[C:6]([Cl:16])[CH:7]=[C:8]([C:12]([O:14][CH3:15])=[O:13])[C:9]=2[C:10]=1[CH3:11].[C:20]([O:24][C:25]([NH:27][CH2:28][CH2:29][B-](F)(F)F)=[O:26])([CH3:23])([CH3:22])[CH3:21].[K+].C([O-])([O-])=O.[Cs+].[Cs+].CC(OC1C=CC=C(OC(C)C)C=1C1C(P(C2CCCCC2)C2CCCCC2)=CC=CC=1)C>C1(C)C=CC=CC=1.O.CCOC(C)=O.C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[C:20]([O:24][C:25]([NH:27][CH2:28][CH2:29][C:2]1[N:3]([CH:17]([CH3:19])[CH3:18])[C:4]2[CH:5]=[C:6]([Cl:16])[CH:7]=[C:8]([C:12]([O:14][CH3:15])=[O:13])[C:9]=2[C:10]=1[CH3:11])=[O:26])([CH3:23])([CH3:22])[CH3:21]
Reactant: CC(C)(C)OC(=O)NCC[B-](F)(F)F
Reactant: COC(=O)c1cc(Cl)cc2c1c(C)c(Br)n2C(C)C
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: CC(C)Oc1cccc(OC(C)C)c1-c1ccccc1P(C1CCCCC1)C1CCCCC1
Solvent: O
Solvent: Cc1ccccc1
Solvent: CCOC(C)=O
Product: COC(=O)c1cc(Cl)cc2c1c(C)c(CCNC(=O)OC(C)(C)C)n2C(C)C
Temperature: 95 °C
Reaction time: 18 h
Yield: 33.7 %

Procedure:
To a stirred mixture of methyl 2-bromo-6-chloro-1-isopropyl-3-methyl-1H-indole-4-carboxylate (0.37 g, 1.074 mmol), potassium (2-((tert-butoxycarbonyl)amino)ethyl)trifluoroborate (0.30 g, 1.195 mmol) and Cs2CO3 (1.0 g, 3.07 mmol) (purged with N2) in toluene (12 mL) and water (4 mL) was added palladium(II) acetate (20 mg, 0.089 mmol) and RuPhos (80 mg, 0.171 mmol). The reaction was heated to 95° C. and stirred for 18 hr under N2. LCMS still showed SM. Another portion of palladium(II) acetate (20 mg, 0.089 mmol) and RuPhos (80 mg, 0.171 mmol) was added and the reaction stirred at 95° C. for another 18 hr. LCMS showed that the reaction was now mostly done. The reaction was diluted with EtOAc and water, and filtered to remove insolubles. The EtOAc phase was removed, dried (MgSO4), filtered, and concentrated under vacuum. The crude was purified by silica gel chromatography (Analogix, SF25-60 g, 0 to 25% EtOAc in hexanes). Three fractions were collected. The first fraction contained a significant amount of the desbromo product, the second fraction was a mixture of unknowns, and the last fraction contained product (Note; opposite order from the TLC). The product fractions were combined, evaporated to dryness under vacuum, triturated with hexanes, filtered and dried under vacuum to give the product methyl 2-(2-((tert-butoxycarbonyl)amino)ethyl)-6-chloro-1-isopropyl-3-methyl-1H-indole-4-carboxylate (148 mg, 0.362 mmol, 33.7% yield) as a white solid. 1H NMR (400 MHz, DMSO-d6) δ=7.81 (d, J=1.5 Hz, 1 H), 7.28 (d, J=1.8 Hz, 1 H), 7.00 (t, J=5.6 Hz, 1 H), 3.87 (s, 3 H), 3.07 (q, J=6.7 Hz, 2 H), 2.97-2.85 (m, 2 H), 2.13 (s, 3 H), 1.56 (d, J=7.1 Hz, 6 H), 1.36 (s, 9 H). MS(ES)+m/e 409.2 [M+H]+.