Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([O:5][C:6]([C:8]1[C:9]([OH:26])=[N:10][C:11]2[C:16]([C:17]=1[C:18]1[CH:23]=[CH:22][CH:21]=[C:20]([Cl:24])[CH:19]=1)=[CH:15][C:14]([Cl:25])=[CH:13][CH:12]=2)=[O:7])([CH3:4])([CH3:3])[CH3:2].[H-].[Na+].Br[CH:30]([CH3:32])[CH3:31]>CN(C=O)C>[C:1]([O:5][C:6]([C:8]1[C:9]([O:26][CH:30]([CH3:32])[CH3:31])=[N:10][C:11]2[C:16]([C:17]=1[C:18]1[CH:23]=[CH:22][CH:21]=[C:20]([Cl:24])[CH:19]=1)=[CH:15][C:14]([Cl:25])=[CH:13][CH:12]=2)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)c1c(O)nc2ccc(Cl)cc2c1-c1cccc(Cl)c1
Reactant: CC(C)Br
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CC(C)Oc1nc2ccc(Cl)cc2c(-c2cccc(Cl)c2)c1C(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 65.8 %

Procedure:
To the stirred solution of 6-chloro-4-(3-chloro-phenyl)-2-hydroxy-quinoline-3-carboxylic acid tert-butyl ester (prepared as described in example 91 step B, 400 mg, 1.02 mmol) in 8 ml DMF was added NaH (60%, 65 mg, 1.54 mmol) portion wise at 0° C. and the resulting reaction mixture was stirred for 30 min at 25° C. Then the reaction mixture was cooled to 0° C. and a solution of 2-bromo-propane (0.192 ml, 2.05 mmol) was added dropwise in 2 ml DMF. The reaction mixture was stirred for 16 h at 50° C. and then quenched with saturated aqueous ammonium chloride solution (10 ml). Subsequently the mixture was diluted with water (25 ml) and extracted with ethyl acetate (3×60 ml). The organic phases were combined and was washed with brine (25 ml), dried over sodium sulfate and concentrated in vacuo to give a crude residue which was purified by column chromatography eluting with 2% ethyl acetate in hexane to yield 6-chloro-4-(3-chloro-phenyl)-2-isopropoxy-quinoline-3-carboxylic acid tert-butyl ester (290 mg, 65% yield) as an off white solid. LC-MS (ESI): 432 (M+H)+.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5](/[C:8](/[CH3:13])=[C:9](/[CH3:12])\[CH2:10][OH:11])=[CH:4][CH:3]=1.[CH2:14]([O:16][C@@H:17]([CH2:23][C:24]1[CH:29]=[CH:28][C:27](O)=[CH:26][CH:25]=1)[C:18]([O:20][CH2:21][CH3:22])=[O:19])[CH3:15]>>[Br:1][C:2]1[CH:3]=[CH:4][C:5](/[C:8](/[CH3:13])=[C:9](/[CH3:12])\[CH2:10][O:11][C:27]2[CH:26]=[CH:25][C:24]([CH2:23][C@H:17]([O:16][CH2:14][CH3:15])[C:18]([O:20][CH2:21][CH3:22])=[O:19])=[CH:29][CH:28]=2)=[CH:6][CH:7]=1
Reactant: C/C(CO)=C(\C)c1ccc(Br)cc1
Reactant: CCOC(=O)[C@H](Cc1ccc(O)cc1)OCC
Product: CCOC(=O)[C@H](Cc1ccc(OC/C(C)=C(/C)c2ccc(Br)cc2)cc1)OCC
Yield: 95.3 %

Procedure:
The title compound (0.91 g, 95% yield) was prepared from (Z)-3-(4-bromophenyl)-2-methyl-but-2-en-1-ol (0.50 g, 2.07 mmol) and (S)-ethyl 2-ethoxy-3-(4-hydroxyphenyl)-propionate (0.519 g, 2.18 mmol) by a procedure analogous to that described in example 52 c.
Reaction SMILES: [C:1]([CH2:4][O:5][C:6]1[CH:11]=[CH:10][C:9]([C:12]2[NH:13][C:14]3[C:15]([N:20]=2)=[N:16][CH:17]=[CH:18][CH:19]=3)=[C:8]([O:21]C)[CH:7]=1)([OH:3])=[O:2].Cl>>[C:1]([CH2:4][O:5][C:6]1[CH:11]=[CH:10][C:9]([C:12]2[NH:13][C:14]3[C:15]([N:20]=2)=[N:16][CH:17]=[CH:18][CH:19]=3)=[C:8]([OH:21])[CH:7]=1)([OH:3])=[O:2]
Reactant: COc1cc(OCC(=O)O)ccc1-c1nc2ncccc2[nH]1
Agent: Cl
Product: O=C(O)COc1ccc(-c2nc3ncccc3[nH]2)c(O)c1

Procedure:
2-(4-Carboxymethoxy-2-methoxyphenyl)imidazo(4,5-b)pyridine, m.p. 235°, hydrochloride, m.p. 262°
Reaction SMILES: [Si]([O:8][C@@H:9]1[C@:13]([C:15]#[C:16][Si:17]([C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=2)([C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)[C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)([OH:14])[C@@H:12]([CH2:36][OH:37])[O:11][C@H:10]1[N:38]1[CH:45]=[CH:44][C:42](=[O:43])[NH:41][C:39]1=[O:40])(C(C)(C)C)(C)C.Cl.CO>>[C:18]1([Si:17]([C:16]#[C:15][C@@:13]2([OH:14])[C@@H:12]([CH2:36][OH:37])[O:11][C@@H:10]([N:38]3[CH:45]=[CH:44][C:42](=[O:43])[NH:41][C:39]3=[O:40])[C@@H:9]2[OH:8])([C:24]2[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=2)[C:30]2[CH:31]=[CH:32][CH:33]=[CH:34][CH:35]=2)[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1
Reactant: CC(C)(C)[Si](C)(C)O[C@H]1[C@H](n2ccc(=O)[nH]c2=O)O[C@H](CO)[C@]1(O)C#C[Si](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: Cl
Solvent: CO
Product: O=c1ccn([C@@H]2O[C@H](CO)[C@](O)(C#C[Si](c3ccccc3)(c3ccccc3)c3ccccc3)[C@H]2O)c(=O)[nH]1
Temperature: 25 °C
Reaction time: 1.83 h
Yield: 88 %

Procedure:
Added to 1.3 g of 1-(2-O-(tert-butyldimethylsilyl)-3-C-triphenylsilylethynyl-β-D-ribofuranosyl)uracil obtain above were 30 ml of a 2.6% (w/v) hydrochloric acid/methanol solution, and the mixture was stirred at room temperature. After 110 minutes, the solvent was distilled off under reduced pressure, and the residue was then azeotropically distilled with ethanol, purified by column chromatography on covered silica gel (chloroform:methanol=20:1-15:1) and then suspended in hexane. The suspension was filtered to obtain 940 mg (yield: 86%) of the title compound as a pale-yellow powdered substance.
Reaction SMILES: [F:1][C:2]1[CH:55]=[CH:54][CH:53]=[CH:52][C:3]=1[CH2:4][C:5]1([NH:49][CH:50]=[O:51])[CH2:10][CH2:9][CH2:8][CH:7]([NH:11][C:12]([C:14]2[CH:15]=[C:16]3[C:20](=[CH:21][CH:22]=2)[N:19](C(C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[N:18]=[C:17]3[C:42]2[CH:47]=[CH:46][N:45]=[C:44]([CH3:48])[CH:43]=2)=[O:13])[CH2:6]1.[SiH](CC)(CC)CC>C(O)(C(F)(F)F)=O>[F:1][C:2]1[CH:55]=[CH:54][CH:53]=[CH:52][C:3]=1[CH2:4][C:5]1([NH:49][CH:50]=[O:51])[CH2:10][CH2:9][CH2:8][CH:7]([NH:11][C:12]([C:14]2[CH:15]=[C:16]3[C:20](=[CH:21][CH:22]=2)[NH:19][N:18]=[C:17]3[C:42]2[CH:47]=[CH:46][N:45]=[C:44]([CH3:48])[CH:43]=2)=[O:13])[CH2:6]1
Reactant: Cc1cc(-c2nn(C(c3ccccc3)(c3ccccc3)c3ccccc3)c3ccc(C(=O)NC4CCCC(Cc5ccccc5F)(NC=O)C4)cc23)ccn1
Agent: CC[SiH](CC)CC
Solvent: O=C(O)C(F)(F)F
Product: Cc1cc(-c2n[nH]c3ccc(C(=O)NC4CCCC(Cc5ccccc5F)(NC=O)C4)cc23)ccn1
Temperature: 25 °C
Reaction time: 0.08 h

Procedure:
N-(3-(2-fluorobenzyl)-3-formamidocyclohexyl)-3-(2-methylpyridin-4-yl)-1-trityl-1H-indazole-5-carboxamide was stirred in neat TFA at room temperature for 10 minutes, and then Et3SiH (5 equiv.) was added. The reaction mixture was stirred at room temperature for 5 minutes, and then concentrated. The product was obtained and purified by reverse phase HPLC.
Reaction SMILES: [CH3:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([N+:12]([O-:14])=[O:13])[CH:10]=2)[CH2:5][CH2:4][N:3]=1.[BH4-].[Na+].O>CO>[CH3:1][CH:2]1[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([N+:12]([O-:14])=[O:13])[CH:10]=2)[CH2:5][CH2:4][NH:3]1
Reactant: CC1=NCCc2ccc([N+](=O)[O-])cc21
Agent: [BH4-]
Agent: [Na+]
Solvent: O
Solvent: CO
Product: CC1NCCc2ccc([N+](=O)[O-])cc21
Temperature: 25 °C
Reaction time: 8 h
Yield: 82.5 %

Procedure:
1.08 g of 1-methyl-7-nitro-3,4-dihydroisoquinoline was dissolved in 10 ml of methanol, and 0.43 g of sodium borohydride was added to the solution at 0° C. The solution was stirred overnight at room temperature, and water was added to the reaction mixture. The mixture was extracted with ethyl acetate, and after washing with saturated aqueous solution of sodium chloride, the solution was dried with anhydrous sodium sulfate. The desiccant was separated by filtration, and the filtrate was purified by silica gel column chromatography to obtain 0.90 g of 1-methyl-7-nitro-1,2,3,4-tetrahydroisoquinoline, which was an oily product (yield: 82%).
Reaction SMILES: [CH3:1][N:2]1[CH:7]2[CH2:8][CH2:9][CH:3]1[CH2:4][CH:5]([N:10]1[C:18]3[C:13](=[CH:14][C:15]([NH2:19])=[CH:16][CH:17]=3)[CH:12]=[CH:11]1)[CH2:6]2.I.CS[C:23]([C:25]1[S:26][CH:27]=[CH:28][CH:29]=1)=[NH:24]>C(O)C>[CH3:1][N:2]1[CH:3]2[CH2:9][CH2:8][CH:7]1[CH2:6][CH:5]([N:10]1[C:18]3[C:13](=[CH:14][C:15]([NH:19][C:23]([C:25]4[S:26][CH:27]=[CH:28][CH:29]=4)=[NH:24])=[CH:16][CH:17]=3)[CH:12]=[CH:11]1)[CH2:4]2
Reactant: CN1C2CCC1CC(n1ccc3cc(N)ccc31)C2
Reactant: CSC(=N)c1cccs1
Agent: I
Solvent: CCO
Product: CN1C2CCC1CC(n1ccc3cc(NC(=N)c4cccs4)ccc31)C2
Temperature: 25 °C
Reaction time: 23 h
Yield: 103.8 %

Procedure:
Compound 85 (52 mg, 0.2036 mmol) is charged to a small, argon purged flask fitted with a magnetic stir bar. Anhydrous ethanol (5 mL) and thiophene-2-carboximidothioic acid methyl ester hydroiodide (87.1 mg, 0.3056 mmol) are added to the flask and the reaction was stirred under argon at ambient temperature for 23 hours, at which time the solvent was evaporated and the residue was purified via chromatography on silica gel (methanol:CH2Cl2, 1:9 to 2M NH3 in methanol:CH2Cl2, 5:95) to yield a pale yellow residue, 86 (77 mg, 100%). 1H NMR (major isomer-MeOD) δ 1.81-1.89 (m, 2H), 2.07-2.14 (m, 2H), 2.23-2.31 (m, 2H), 2.48 (s, 3H), 2.69-2.79 (m, 2H), 3.49-3.59 (m, 2H), 4.51-4.61 (m, 1H), 6.58 (d, 1H, J=3.3 Hz), 7.13 (dd, 1H, J=8.7, 1.9 Hz), 7.31-7.34 (m, 1H), 7.54-7.57 (m, 2H), 7.61 (d, 1H, J=3.5 Hz), 7.94-7.97 (m, 2H); ESI-MS (m/z, %): 365 (MH+, 15%), 183 (M++doubly charged, 100%); ESI-HRMS calculated for C21H25N4S (MH+): 365.1794, observed: 365.1784.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[O:12][N:11]=[C:10]([CH3:13])[C:9]=2[NH:14][CH:15]([CH3:24])[CH2:16][CH2:17][C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)=[CH:4][CH:3]=1.I[CH3:26]>>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[O:12][N:11]=[C:10]([CH3:13])[C:9]=2[N:14]([CH3:26])[CH:15]([CH3:24])[CH2:16][CH2:17][C:18]2[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=2)=[CH:6][CH:7]=1
Reactant: Cc1noc(-c2ccc(Br)cc2)c1NC(C)CCc1ccccc1
Reactant: CI
Product: Cc1noc(-c2ccc(Br)cc2)c1N(C)C(C)CCc1ccccc1

Procedure:
Prepared according to the procedure described in Example 123, Step 1, using [5-(4-bromo-phenyl)-3-methyl-isoxazol-4-yl]-(1-methyl-3-phenyl-propyl)-amine and iodomethane.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[CH:4][CH:3]=1.C(N(CC)CC)C.[C:16](OC(=O)C)(=[O:18])[CH3:17]>C(Cl)(Cl)Cl>[C:16]([O:8][C:5]1[CH:6]=[CH:7][C:2]([Br:1])=[CH:3][CH:4]=1)(=[O:18])[CH3:17]
Reactant: CC(=O)OC(C)=O
Reactant: Oc1ccc(Br)cc1
Solvent: CCN(CC)CC
Solvent: ClC(Cl)Cl
Product: CC(=O)Oc1ccc(Br)cc1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A solution of 4-bromophenol (25 g, 0.145 mol) in 100 ml of chloroform was added at 0° C. with triethylamine (20.1 ml) and acetic anhydride (16.4 ml) stirring at room temperature for 2 h. After that the mixture was washed with a 0.2M HCl solution, dried and the solvent was evaporated off under reduced pressure, thereby obtaining the title compound as a colourless oil (quantitative yield).
Reaction SMILES: N12CCCN=C1CCCCC2.Cl.[NH2:13][CH2:14][C:15]1[CH:23]=[CH:22][CH:21]=[C:20]2[C:16]=1[C:17](=[O:33])[N:18]([CH:25]1[CH2:30][CH2:29][C:28](=[O:31])[NH:27][C:26]1=[O:32])[C:19]2=[O:24].[CH3:34][N:35]1[C:39]([CH3:40])=[CH:38][C:37]([C:41](Cl)=[O:42])=[N:36]1>C(#N)C>[O:32]=[C:26]1[CH:25]([N:18]2[C:17](=[O:33])[C:16]3[C:20](=[CH:21][CH:22]=[CH:23][C:15]=3[CH2:14][NH:13][C:41]([C:37]3[CH:38]=[C:39]([CH3:40])[N:35]([CH3:34])[N:36]=3)=[O:42])[C:19]2=[O:24])[CH2:30][CH2:29][C:28](=[O:31])[NH:27]1
Reactant: NCc1cccc2c1C(=O)N(C1CCC(=O)NC1=O)C2=O
Reactant: Cc1cc(C(=O)Cl)nn1C
Agent: Cl
Solvent: C1CCC2=NCCCN2CC1
Solvent: CC#N
Product: Cc1cc(C(=O)NCc2cccc3c2C(=O)N(C2CCC(=O)NC2=O)C3=O)nn1C
Reaction time: 0.17 h
Yield: 36.6 %

Procedure:
1,8-Diazabicyclo[5.4.0]undec-7-ene (1.0 g, 6.6 mmol) was added to a stirred suspension of 4-aminomethyl-2-(2,6-dioxo-piperidin-3-yl)-isoindole-1,3-dione hydrochloride (0.7 g, 2.0 mmol) in acetonitrile (40 mL). After stirring for 10 minutes, 1,5-dimethyl-1H-pyrazole-3-carbonyl chloride (0.4 g, 2.6 mmol) was added. The mixture was stirred at room temperature overnight. The mixture was concentrated, and the residue was dissolved in CH2Cl2 (80 mL). The CH2Cl2 solution was washed with water (2×30 mL) and brine (30 mL), and dried (MgSO4). Solvent was removed, and the residue was purified by chromatography (SiO2, CH2Cl2: CH3OH 97.5:2.5) to give 1,5-dimethyl-1H-pyrazole-3-carboxylic acid [2-(2,6-dioxo-piperidin-3-yl)-1,3-dioxo-2,3-dihydro-1H-isoindol-4-ylmethyl]-amide (0.3 g, 38%) as a white solid: mp 213-215° C.; 1H NMR (DMSO-d6) δ 2.05-2.09 (m, 1H), 2.28 (s, 3H), 2.50-2.64 (m, 2H), 2.84-2.97 (m, 1H), 3.79 (s, 3H), 4.86 (d, J=5.9 Hz, 2H), 5.13-5.20 (dd, J=5.1 and 12.4 Hz, 1H), 6.44 (s, 1H), 7.65-7.79 (m, 3H), 8.69 (t. J=5.9 Hz, 1H), 11.15 (s, 1H); 13C NMR (DMSO-d6) δ 10.66, 21.97, 30.93, 36.39, 37.80, 48.86, 105.53, 121.71, 127.01, 131.51, 132.78, 134.70, 139.60, 140.35, 144.26, 161.91, 167.00, 167.56, 169.83, 172.75; Anal. calcd. for C20H19N5O5+0.4H2O: C, 57.66; H, 4.79; N, 16.81. Found: C, 57.85; H, 4.80; N, 16.64.
Reaction SMILES: [NH2:1][CH:2]([C:11]1[CH:12]=[C:13]([CH:19]([CH3:23])[C:20]([OH:22])=[O:21])[CH:14]=[CH:15][C:16]=1[O:17][CH3:18])[C:3]1[CH:8]=[CH:7][C:6]([O:9][CH3:10])=[CH:5][CH:4]=1.C(N(CC)CC)C.[C:31](ON1C(=O)CCC1=O)([O:33][CH2:34][CH:35]1[C:47]2[C:42](=[CH:43][CH:44]=[CH:45][CH:46]=2)[C:41]2[C:36]1=[CH:37][CH:38]=[CH:39][CH:40]=2)=[O:32]>CN(C=O)C>[C:31]([C:2]([NH2:1])([C:11]1[CH:12]=[C:13]([CH:19]([CH3:23])[C:20]([OH:22])=[O:21])[CH:14]=[CH:15][C:16]=1[O:17][CH3:18])[C:3]1[CH:8]=[CH:7][C:6]([O:9][CH3:10])=[CH:5][CH:4]=1)([O:33][CH2:34][CH:35]1[C:36]2[C:41](=[CH:40][CH:39]=[CH:38][CH:37]=2)[C:42]2[C:47]1=[CH:46][CH:45]=[CH:44][CH:43]=2)=[O:32]
Reactant: COc1ccc(C(N)c2cc(C(C)C(=O)O)ccc2OC)cc1
Reactant: O=C(OCC1c2ccccc2-c2ccccc21)ON1C(=O)CCC1=O
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: COc1ccc(C(N)(C(=O)OCC2c3ccccc3-c3ccccc32)c2cc(C(C)C(=O)O)ccc2OC)cc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
The 3-(α-amino-4-methoxybenzyl)-4-methoxyphenylpropionic acid (1.0 g,3.17 mmol) prepared in Example 4 was dissolved in 5 ml of DMF containing triethylamine (0.88 ml). To the solution, 1.28 g of Fmoc-OSu was added andthe mixture was stirred at room temperature for 1 hour. The solvent was evaporated in vacuo and 5% citric acid and ether were added to the residue. The resulting power was recrystallized from methanol and ether.
Reaction SMILES: [CH2:1]([O:3][C:4]1[CH:9]=[CH:8][C:7]([N:10]2[CH2:15][CH2:14][CH:13]([C:16]3[CH:21]=[CH:20][C:19]([C@@H:22]([NH2:24])[CH3:23])=[CH:18][CH:17]=3)[CH2:12][CH2:11]2)=[CH:6][CH:5]=1)[CH3:2].C1N=C[N:27]([C:30](N2C=NC=C2)=[O:31])[CH:26]=1.CN>CN(C=O)C>[CH2:1]([O:3][C:4]1[CH:5]=[CH:6][C:7]([N:10]2[CH2:11][CH2:12][CH:13]([C:16]3[CH:17]=[CH:18][C:19]([C@@H:22]([NH:24][C:30]([NH:27][CH3:26])=[O:31])[CH3:23])=[CH:20][CH:21]=3)[CH2:14][CH2:15]2)=[CH:8][CH:9]=1)[CH3:2]
Reactant: CCOc1ccc(N2CCC(c3ccc([C@H](C)N)cc3)CC2)cc1
Reactant: O=C(n1ccnc1)n1ccnc1
Agent: CN
Solvent: CN(C)C=O
Product: CCOc1ccc(N2CCC(c3ccc([C@H](C)NC(=O)NC)cc3)CC2)cc1
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
To 100 mg (0.31 mmol) (S)-1-{4-[1-(4-ethoxy-phenyl)-piperidin-4-yl]-phenyl}-ethylamine (XIII.1) in 2 mL DMF, 87 μL (0.62 mmol) TEA and 52 mg (0.32 mmol) CDI are added at 0° C. and the mixture is stirred for 30 min at 0° C. Subsequently 48 mg (1.54 mmol) methylamine are added and stirring is continued for 1 h at 50° C. The mixture is filtered through basic aluminum oxide and concentrated in vacuo. The residue is purified using reversed phase column chromatography (water+0.15% NH4OH; acetone) and the corresponding fractions are concentrated to yield the desired product.
Reaction SMILES: [CH3:1][CH:2]([CH2:7][CH2:8][CH3:9])[CH2:3][CH:4](O)[CH3:5].P(Br)(Br)[Br:11].BrC(CCC)C>>[Br:11][CH:4]([CH2:3][CH:2]([CH3:1])[CH2:7][CH2:8][CH3:9])[CH3:5]
Reactant: BrP(Br)Br
Reactant: CCCC(C)CC(C)O
Agent: CCCC(C)Br
Product: CCCC(C)CC(C)Br

Procedure:
17.50 g (0.135 mol) of 4-methylheptan-2-ol (3) was treated with PBr3 (13.48 g, 0.050 mol) as described above in the manufacture of 2-bromopentane (2). The product was purified by distillation at 165°-185° C. to yield 2-bromo-4methylheptane (4).
Reaction SMILES: [CH3:1][C:2]1[C:10]2[C:5](=[C:6]([CH:15]([O:17][CH2:18][C:19]3([C:25]4[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=4)[CH2:24][CH2:23][NH:22][CH2:21][CH2:20]3)[CH3:16])[CH:7]=[C:8]([C:11]([F:14])([F:13])[F:12])[CH:9]=2)[NH:4][N:3]=1.C=O.[C:33]([BH3-])#N.[Na+]>C(#N)C.C(O)(=O)C>[CH3:1][C:2]1[C:10]2[C:5](=[C:6]([CH:15]([O:17][CH2:18][C:19]3([C:25]4[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=4)[CH2:20][CH2:21][N:22]([CH3:33])[CH2:23][CH2:24]3)[CH3:16])[CH:7]=[C:8]([C:11]([F:13])([F:14])[F:12])[CH:9]=2)[NH:4][N:3]=1
Reactant: [BH3-]C#N
Reactant: Cc1n[nH]c2c(C(C)OCC3(c4ccccc4)CCNCC3)cc(C(F)(F)F)cc12
Agent: C=O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CC#N
Product: Cc1n[nH]c2c(C(C)OCC3(c4ccccc4)CCN(C)CC3)cc(C(F)(F)F)cc12
Temperature: 0 °C
Reaction time: 1 h

Procedure:
(±)-3-Methyl-7-(1-((4-phenylpiperidin-4-yl)methoxy)ethyl)-5-(trifluoromethyl)-1H-indazole (32 mg, 0.08 mmol) and formaldehyde (37 wt. % solution in water, 120 μL) were combined in acetonitrile (2 mL) and cooled to 0° C. The reaction was treated with sodium cyanoborohydride (24 mg, 0.38 mmol) and a few drops of acetic acid. The reaction was stirred at 0° C. for 30 min and at room temperature for 1 h. The solvent was removed in vacuo and the resulting crude mixture passed through a strong cation exchange column. After washing the column with several volumes of methanol, the product was eluted by washing the column with 2 M ammonia in methanol. The solvents were evaporated and the compound purified by flash chromatography on silica gel (1% ammonia/8% methanol/methylene chloride) to afford 20 mg (61%). 1H-NMR (CDCl3, 500 MHz) δ 7.95 (s, 1H), 7.30-7.40 (m, 5H), 7.21-7.44 (m, 1H), 4.40 (q, J=6.7 Hz, 1H), 3.39 (q, J=9.2 Hz, 1H), 3.33 (d, J=9.2 Hz, 1H), 2.59 (s, 3H), 2.54 (m, 2H), 2.19-2.26 (m, 4H), 2.03-2.07 (m, 2H), 1.46 (m, 3H); 13C-NMR (126 MHz, CDCl3) δ ppm 143.7, 139.0, 128.7, 127.3, 127.2, 126.7, 124.9 (q, J=272 Hz), 122.9, 122.6 (q, J=32.6 Hz), 119.7, 117.4, 78.4, 52.0, 51.9, 46.6, 40.7, 32.6, 22.0, 11.9. Mass spec.: 418.19 (MH)+. Mass spec.: 432.09 (MH)+.
Reaction SMILES: [Br:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=O)=[C:4]([S:11]([CH3:14])(=[O:13])=[O:12])[CH:3]=1.Cl.[CH2:16]([C:18]1[CH:23]=[C:22]([CH3:24])[CH:21]=[CH:20][C:19]=1[N:25]1[CH2:30][CH2:29][NH:28][CH2:27][CH2:26]1)[CH3:17].O.[Cl-].COC1N=C(OC)N=C([N+]2(C)CCOCC2)N=1.CN1CCOCC1>CO.C(Cl)(Cl)Cl>[Br:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([N:28]2[CH2:29][CH2:30][N:25]([C:19]3[CH:20]=[CH:21][C:22]([CH3:24])=[CH:23][C:18]=3[CH2:16][CH3:17])[CH2:26][CH2:27]2)=[O:8])=[C:4]([S:11]([CH3:14])(=[O:13])=[O:12])[CH:3]=1
Reactant: CS(=O)(=O)c1cc(Br)ccc1C(=O)O
Reactant: CCc1cc(C)ccc1N1CCNCC1
Agent: COc1nc(OC)nc([N+]2(C)CCOCC2)n1
Agent: Cl
Agent: [Cl-]
Solvent: CN1CCOCC1
Solvent: ClC(Cl)Cl
Solvent: CO
Product: CCc1cc(C)ccc1N1CCN(C(=O)c2ccc(Br)cc2S(C)(=O)=O)CC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 98.1 %

Procedure:
A mixture of 4-bromo-2-ethylaniline (1.4 mL), diisopropylethylamine (4.4 mL) and N,N-bis(2-chloroethyl)-4-methylbenzenesulfonamide (3 g) was refluxed for 5 hr. After cooling, the solvent was evaporated, and the residue was purified by column chromatography (chloroform) to give 1-(4-bromo-2-ethylphenyl)-4-(toluene-4-sulfonyl)piperazine (3 g). To a mixture of 1-(4-bromo-2-ethylphenyl)-4-(toluene-4-sulfonyl)piperazine (3 g), methylboronic acid (1.2 g), palladium acetate (112 mg), 2-dicyclohexylphosphino-2′,6′-dimethoxybiphenyl (411 mg) and potassium fluoride (2.3 g) was added tetrahydrofuran (30 mL), and the mixture was refluxed for 8 hr. After cooling, water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, and the solvent was evaporated. The residue was purified by column chromatography (chloroform) to give 1-(2-ethyl-4-methylphenyl)-4-(toluene-4-sulfonyl)piperazine (2.9 g). A mixture of 1-(2-ethyl-4-methylphenyl)-4-(toluene-4-sulfonyl)piperazine (2.9 g), hydrobromic acid (16 mL) and acetic acid (16 mL) was refluxed for 8 hr. After cooling, the reaction mixture was alkalified with 1N aqueous sodium hydroxide solution, and the mixture was extracted with chloroform. The organic layer was washed with saturated brine, and the solvent was evaporated. 4N hydrogen chloride/ethyl acetate (3 mL) was added and the mixture was filtered to give 1-(2-ethyl-4-methylphenyl)piperazine hydrochloride (1.7 g). To a mixture of 4-bromo-2-methanesulfonylbenzoic acid (1.1 g), 1-(2-ethyl-4-methylphenyl)piperazine hydrochloride (963 mg) and 4-(4,6-dimethoxy[1.3.5]triazin-2-yl)-4-methylmorpholinium chloride hydrate (DMT-MM) (1.5 g) were added chloroform (6 mL), methanol (6 mL) and N-methylmorpholine (440 μL), and the mixture was stirred at room temperature overnight. After evaporation of the solvent, the residue was purified by column chromatography (chloroform) to give the title compound (1.8 g).
Reaction SMILES: C([O:4][C:5]1[CH:22]=[CH:21][C:8]([C:9]([O:11][CH:12](C)[CH:13]([C:18]#[N:19])[CH2:14][CH2:15][CH2:16][CH3:17])=[O:10])=[CH:7][CH:6]=1)(=O)C.[CH2:23](N)C1C=CC=CC=1>CCOCC>[OH:4][C:5]1[CH:6]=[CH:7][C:8]([C:9]([O:11][CH2:12][C:13]([C:18]#[N:19])([CH3:23])[CH2:14][CH2:15][CH2:16][CH3:17])=[O:10])=[CH:21][CH:22]=1
Reactant: CCCCC(C#N)C(C)OC(=O)c1ccc(OC(C)=O)cc1
Reactant: NCc1ccccc1
Solvent: CCOCC
Product: CCCCC(C)(C#N)COC(=O)c1ccc(O)cc1
Temperature: 25 °C
Reaction time: 24 h
Yield: 81.6 %

Procedure:
482 mg (1.6 mM) of 2-cyano-2-methylhexyl p-acetoxybenzoate obtained in Step 1) was dissolved in 1.5 ml of dry ether, and a solution of 188 mg (1.6 mM) of benzylamine in 1 ml of ether was added thereto, followed by 24 hours of stirring at room temperature. After the reactions and distilling-off of the solvent, the product was purified by thin layer chromatography (developer solvent: ethyl acetate/methylene chloride=1:5) to obtain 339 mg of 2-cyano-2-methylhexyl p-hydroxybenzoate (yield 73.7%).
Reaction SMILES: C1(P(C2C=CC=CC=2)CCCP(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[CH3:30][O:31][C:32]1[CH:37]=[CH:36][C:35]([CH:38]2[C:46]3[C:41](=[CH:42][CH:43]=[C:44]([O:47][CH2:48][CH2:49][CH3:50])[CH:45]=3)[CH:40]([C:51]3[CH:56]=[CH:55][C:54]4[O:57][CH2:58][O:59][C:53]=4[CH:52]=3)[CH:39]2[C:60]([O-:62])=[O:61])=[C:34](OS(C(F)(F)F)(=O)=O)[CH:33]=1.[C:71]([O:75]C)(=[O:74])[CH:72]=[CH2:73].C([O-])(=O)C>C(N(CC)CC)C.C(#N)C.CN(C=O)C.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd].[Pd]>[C:71](/[CH:72]=[CH:73]/[C:34]1[CH:33]=[C:32]([O:31][CH3:30])[CH:37]=[CH:36][C:35]=1[CH:38]1[C:46]2[C:41](=[CH:42][CH:43]=[C:44]([O:47][CH2:48][CH2:49][CH3:50])[CH:45]=2)[CH:40]([C:51]2[CH:56]=[CH:55][C:54]3[O:57][CH2:58][O:59][C:53]=3[CH:52]=2)[CH:39]1[C:60]([OH:62])=[O:61])([OH:75])=[O:74]
Reactant: CCCOc1ccc2c(c1)C(c1ccc(OC)cc1OS(=O)(=O)C(F)(F)F)C(C(=O)[O-])C2c1ccc2c(c1)OCO2
Reactant: C=CC(=O)OC
Agent: [Pd]
Agent: CC(=O)[O-]
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: CC#N
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: CCCOc1ccc2c(c1)C(c1ccc(OC)cc1/C=C/C(=O)O)C(C(=O)O)C2c1ccc2c(c1)OCO2
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
1,3-bis(diphenylphosphino)propane (0.066 mmol), tris(dibenzylideneacetone)-dipalladium(0) (24 mg, 0.026) and bis(triphenylphosphine)palladium(II) choride (18 mg, 0.026 mmol), were dissolved in a 4:1 mixture of triethylamine/acetonitrile (5 mL) under argon. After 10 min at room temperature, a solution of methyl (1RS, 2SR, 3RS)-3-(4-methoxy-2-trifluoromethanesulfonyloxyphenyl)-1-(3,4-methylenedioxyphenyl)-5-(prop-1-yloxy)indane-2-carboxylate (160 mg, 0.26 mmol) and methyl acrylate (679 mg, 7.89 mmol) was added in the above solvent mixture (3 mL). The reaction mixture was heated to reflux under argon for 20 h, cooled to room temperature and a small aliquot analyzed by 1H NMR, which showed no reaction had taken place. Palladium(l) acetate (6 mg, 0.025 mmol) and methyl acrylate (679 mg, 7.89 mmol) in dry DMF (5 mL) were then added. The reaction mixture was heated to reflux overnight. On cooling the solution was filtered through a short column of silica gel and concentrated to yield an oil. The crude product was purified by flash column chromatography ( silica gel, gradient elution: 10% to 20% ethyl acetate/hexanes) to afford the title compound as a tan solid. (87 mg, 62%).