Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C([Mg]Br)C.[C:5]([C:7]1[CH:8]=[N:9][CH:10]=[N:11][CH:12]=1)#[CH:6].[Cl:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=1[C:20]1[O:24][N:23]=[C:22]([CH2:25][O:26][CH:27]2[CH2:32][CH2:31][CH2:30][CH2:29][O:28]2)[C:21]=1[CH:33]=[O:34]>C(OCC)C.C1COCC1>[Cl:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=1[C:20]1[O:24][N:23]=[C:22]([CH2:25][O:26][CH:27]2[CH2:32][CH2:31][CH2:30][CH2:29][O:28]2)[C:21]=1[CH:33]([OH:34])[C:6]#[C:5][C:7]1[CH:8]=[N:9][CH:10]=[N:11][CH:12]=1
Reactant: C#Cc1cncnc1
Reactant: O=Cc1c(COC2CCCCO2)noc1-c1ccccc1Cl
Agent: CC[Mg]Br
Solvent: CCOCC
Solvent: C1CCOC1
Product: OC(C#Cc1cncnc1)c1c(COC2CCCCO2)noc1-c1ccccc1Cl
Yield: 40.1 %

Procedure:
Add 3M ethylmagnesium bromide (36 mL, 109 mmol) in diethyl ether to a 0° C. solution of 5-ethynyl-pyrimidine (8.1 g, 77 mmol) in THF (75 mL). Add 5-(2-chloro-phenyl)-3-(tetrahydro-pyran-2-yloxymethyl)-isoxazole-4-carbaldehyde (10 g, 31 mmol) in THF (75 mL) and stir 15 h at RT. Quench the reaction with 1N HCl and extract with diethyl ether (2×150 mL). Wash the organic phase with brine (150 mL), dry over sodium sulfate, filter and concentrate under reduced pressure. Purification by flash chromatography (silica gel, 1:1 to 3:7 hexanes/EtOAc) gives the title compound (5.3 g, 40%): 1H NMR (300 MHz, CDCl3) δ 9.18 (s, 1H), 8.35 (s, 2H), 7.44–7.62 (m, 4H), 5.65 (t, J=14 Hz, 1H), 5.08–5.28 (m, 1H), 4.80–4.95 (m, 2H), 4.42–4.60 (m, 1H), 3.80–4.01 (m, 1H), 3.51–3.68 (m, 1H), 1.54–1.90 (m, 6H); TLC Rf=0.20 (3:7 Hexanes:EtOAc).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([OH:21])([C:15]2[CH:16]=[N:17][CH:18]=[CH:19][CH:20]=2)[CH2:9][C:10](OCC)=[O:11])=[CH:4][CH:3]=1.[NH3:22]>C(O)C>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([OH:21])([C:15]2[CH:16]=[N:17][CH:18]=[CH:19][CH:20]=2)[CH2:9][C:10]([NH2:22])=[O:11])=[CH:4][CH:3]=1
Reactant: N
Reactant: CCOC(=O)CC(O)(c1ccc(Br)cc1)c1cccnc1
Solvent: CCO
Product: NC(=O)CC(O)(c1ccc(Br)cc1)c1cccnc1

Procedure:
0.8 g (2.5 mmole) of ethyl 3-(4-bromophenyl)-3-hydroxy-3-(3-pyridyl)-propanoate, 50 ml of aqueous ammonia and 10 ml of absolute ethanol was stirred at room temperature for 24 hours. The white precipitate obtained was collected by filtration. Recrystallization from isopropyl alcohol gave 0.45 g (56%), m.p. 213°-214° C. The formula C14H13BrN2O2 was verified through elemental analysis, C calculated 52.4, found 51.9. ##STR29##
Reaction SMILES: S(OC)(O[CH3:5])(=O)=O.[CH:8]1[C:16]2[C:15]3[CH:17]=[C:18]4[C:23](=[CH:24][C:14]=3[CH:13]=[CH:12][C:11]=2[NH:10][C:9]=1[C:25]([O:27][CH2:28][CH3:29])=[O:26])[CH:22]=[CH:21][CH:20]=[CH:19]4>CCOC(C)=O.CCCCCC>[CH3:5][N:10]1[C:11]2[CH:12]=[CH:13][C:14]3[CH:24]=[C:23]4[C:18](=[CH:17][C:15]=3[C:16]=2[CH:8]=[C:9]1[C:25]([O:27][CH2:28][CH3:29])=[O:26])[CH:19]=[CH:20][CH:21]=[CH:22]4
Reactant: CCOC(=O)c1cc2c(ccc3cc4ccccc4cc32)[nH]1
Reactant: COS(=O)(=O)OC
Solvent: CCCCCC
Solvent: CCOC(C)=O
Product: CCOC(=O)c1cc2c3cc4ccccc4cc3ccc2n1C
Yield: 97 %

Procedure:
Using the procedure described in Example 34A except that dimethyl sulfate was used as the alkylating agent, ethyl 3H-naphth[2,3-e]indole-2-carboxylate (H. G. Pars Pharmaceutical Laboratories, Inc.) gave a 97% yield of ethyl 3-methyl-3H-naphth[2,3-e]indole-2-carboxylate, mp 141°-144°, (EtOAc/hexane), (C,H,N).
Reaction SMILES: F[C:2]1[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[CH:4][C:3]=1[C:10]([F:13])([F:12])[F:11].[OH:14][C:15]([C@H:18]1[CH2:22][CH2:21][NH:20][C@H:19]1[CH3:23])([CH3:17])[CH3:16].C(=O)([O-])[O-].[Li+].[Li+]>>[OH:14][C:15]([C@H:18]1[CH2:22][CH2:21][N:20]([C:2]2[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[CH:4][C:3]=2[C:10]([F:13])([F:12])[F:11])[C@H:19]1[CH3:23])([CH3:17])[CH3:16]
Reactant: N#Cc1ccc(F)c(C(F)(F)F)c1
Reactant: C[C@@H]1NCC[C@@H]1C(C)(C)O
Agent: O=C([O-])[O-]
Agent: [Li+]
Product: C[C@H]1[C@@H](C(C)(C)O)CCN1c1ccc(C#N)cc1C(F)(F)F

Procedure:
Using 4-fluoro-3-(trifluoromethyl)benzonitrile (300 mg), (2S,3S)-3-(1-hydroxy-1-methylethyl)-2-methylpyrrolidine 1/2 oxalate (359 mg) and lithium carbonate (140 mg), the title compound was obtained as a colorless solid (yield: 180 mg) by an operation similar to that in Example 3.
Reaction SMILES: C([NH:8][C@H:9]1[CH2:13][CH2:12][C@@H:11]([C:14]2[C:22]3[C:17](=[CH:18][CH:19]=[C:20]([F:23])[CH:21]=3)[NH:16][CH:15]=2)[CH2:10]1)C1C=CC=CC=1.C([O-])=O.[NH4+]>CO.[Pd]>[F:23][C:20]1[CH:21]=[C:22]2[C:17](=[CH:18][CH:19]=1)[NH:16][CH:15]=[C:14]2[C@@H:11]1[CH2:12][CH2:13][C@H:9]([NH2:8])[CH2:10]1
Reactant: Fc1ccc2[nH]cc([C@@H]3CC[C@H](NCc4ccccc4)C3)c2c1
Agent: [Pd]
Agent: O=C[O-]
Agent: [NH4+]
Solvent: CO
Product: N[C@H]1CC[C@@H](c2c[nH]c3ccc(F)cc23)C1

Procedure:
A mixture of cis-benzyl-3-(5-fluoro-1H-indol-3-yl)-cyclopentylamine (0.45 g, 1.46 mmol), 0.2 g 10% Pd/C and ammonium formate (1.0 g, 15.9 mmol) in methanol (30 mL) were refluxed under nitrogen for 4 hours. The reaction mixture was cooled, filtered through celite, and concentrated. The residue was diluted with 1 N aqueous NaOH (50 mL) and extracted with ethyl acetate (3×50 mL). The combined organic layers were washed with water (50 mL) and brine (50 mL), then were dried over anhydrous sodium sulfate, filtered and concentrated to give 0.28 g (quant.) of the title compound as a thick oil: MS (ESI) m/z 219 [M+H]+.
Reaction SMILES: [CH2:1]([C:10]1[CH:11]=[N:12][C:13]([C:16]2[CH:21]=[CH:20][C:19]([OH:22])=[CH:18][CH:17]=2)=[N:14][CH:15]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH3:9].[CH2:23]([C@H:28]1[CH2:33][CH2:32][C@H:31]([CH2:34][CH2:35][CH2:36]Br)[CH2:30][CH2:29]1)[CH2:24][CH2:25][CH2:26][CH3:27].C(=O)([O-])[O-].[K+].[K+].CC(=O)CC>O>[CH2:23]([C@H:28]1[CH2:33][CH2:32][C@H:31]([CH2:34][CH2:35][CH2:36][O:22][C:19]2[CH:18]=[CH:17][C:16]([C:13]3[N:14]=[CH:15][C:10]([CH2:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH3:9])=[CH:11][N:12]=3)=[CH:21][CH:20]=2)[CH2:30][CH2:29]1)[CH2:24][CH2:25][CH2:26][CH3:27]
Reactant: CCCCC[C@H]1CC[C@H](CCCBr)CC1
Reactant: CCCCCCCCCc1cnc(-c2ccc(O)cc2)nc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CCC(C)=O
Product: CCCCCCCCCc1cnc(-c2ccc(OCCC[C@H]3CC[C@H](CCCCC)CC3)cc2)nc1

Procedure:
A mixture of 0.5 g of 4-(5-nonyl-2-pyrimidinyl)phenol, 0.55 g of 3-(trans-4-pentylcyclohexyl)-1-propyl bromide, 0.91 g of potassium carbonate and 50 ml of absolute butanone was heated under reflux overnight. Subsequently, the cooled reaction mixture was poured into water and extracted three times with 50 ml of diethyl ether each time. The combined organic phases were washed with 500 ml of water, dried over magnesium sulfate, filtered and concentrated. Chromatography of the residue on silica gel with toluene and recrystallization from ethanol gave pure 2-(4-[3-(trans-4-pentylcyclohexyl)-1-propyloxy]phenyl-5-nonylpyrimidine with m.p. (C--SC) 83° C., transition SC --N 103° C., cl.p. (N-I) 133° C.
Reaction SMILES: [C:1](Cl)(=[O:6])[C:2]([CH3:5])([CH3:4])[CH3:3].[CH2:8]([O:15][C@@H:16]1[C@@H:29]([OH:30])[C@@H:28]([O:31][CH2:32][C:33]2[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=2)[C@@H:27]([CH2:39][OH:40])[O:26][C@H:17]1[O:18][CH2:19][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1.CO>N1C=CC=CC=1>[CH2:8]([O:15][C@@H:16]1[C@@H:29]([OH:30])[C@@H:28]([O:31][CH2:32][C:33]2[CH:34]=[CH:35][CH:36]=[CH:37][CH:38]=2)[C@@H:27]([CH2:39][O:40][C:1](=[O:6])[C:2]([CH3:5])([CH3:4])[CH3:3])[O:26][C@H:17]1[O:18][CH2:19][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)[C:9]1[CH:10]=[CH:11][CH:12]=[CH:13][CH:14]=1
Reactant: CC(C)(C)C(=O)Cl
Reactant: OC[C@H]1O[C@@H](OCc2ccccc2)[C@H](OCc2ccccc2)[C@@H](O)[C@H]1OCc1ccccc1
Solvent: CO
Solvent: c1ccncc1
Product: CC(C)(C)C(=O)OC[C@H]1O[C@@H](OCc2ccccc2)[C@H](OCc2ccccc2)[C@@H](O)[C@H]1OCc1ccccc1
Reaction time: 1.17 h
Yield: 90.2 %

Procedure:
Under nitrogen gas atmosphere, pivaloyl chloride (4.2 ml, 35.7 mmol) was added to a solution of Compound 13 (7.3 g, 16.2 mmol) in pyridine (50 ml) at 0° C., and the mixture was stirred for 70 minutes. Methanol was added to the reaction mixture, and the mixture was stirred for 40 minutes, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (toluene:ethyl acetate=6:1) to obtain Compound 14 (7.81 g, 90%).
Reaction SMILES: [CH:1]([C:3]1[C:11]2[C:6](=[CH:7][C:8]([C:12]([O:14][CH3:15])=[O:13])=[CH:9][CH:10]=2)[N:5]([CH3:16])[N:4]=1)=O.[C:17]([N:36]1[CH:40]=[CH:39][N:38]=[C:37]1[NH2:41])([C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1)([C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1)[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].O>C1(C)C=CC=CC=1>[CH3:16][N:5]1[C:6]2[C:11](=[CH:10][CH:9]=[C:8]([C:12]([O:14][CH3:15])=[O:13])[CH:7]=2)[C:3]([CH2:1][NH:41][C:37]2[N:36]([C:17]([C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)([C:30]3[CH:31]=[CH:32][CH:33]=[CH:34][CH:35]=3)[C:24]3[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=3)[CH:40]=[CH:39][N:38]=2)=[N:4]1
Reactant: COC(=O)c1ccc2c(C=O)nn(C)c2c1
Reactant: Nc1nccn1C(c1ccccc1)(c1ccccc1)c1ccccc1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: O
Solvent: Cc1ccccc1
Product: COC(=O)c1ccc2c(CNc3nccn3C(c3ccccc3)(c3ccccc3)c3ccccc3)nn(C)c2c1
Temperature: 25 °C
Reaction time: 24 h

Procedure:
The product of Step A (204 mg, 1 mmol) is dissolved in toluene (10 mL) with N-trityl-2-aminoimidazole (357 mg, 1.1 mmol) and heated to reflux with a Dean-Stark trap. Four aliquots of toluene (3 mL each) are removed via distillation at 1.5 hour intervals, being replaced by dry toluene each time, and then the solution is left to reflux for 18 hours. The reaction is cooled to room temperature and sodium triacetoxyborohydride (1 gram, 5 mmol) is added in one portion. The reaction is stirred at room temperature for 24 hours, poured into water, and the layers separated. The aqueous layer is extracted with ethyl acetate and the combined organic layers are washed with saturated bicarbonate, water, and brine, dried over magnesium sulfate, concentrated, and purified by flash chromatography to afford the product.
Reaction SMILES: [Br:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH:8]=[CH2:9].[CH:10]([O:12][C:13]1[CH:18]=[CH:17][C:16]([O:19]C)=[CH:15][CH:14]=1)=C>>[Br:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7]/[CH:8]=[CH:9]\[O:19][C:16]1[CH:17]=[CH:18][C:13]([O:12][CH3:10])=[CH:14][CH:15]=1
Reactant: C=CCCCCCCBr
Reactant: C=COc1ccc(OC)cc1
Product: COc1ccc(O/C=C\CCCCCCBr)cc1
Reaction time: 16 h
Yield: 69.5 %

Procedure:
Following the general procedure, 8-bromooct-1-ene (50.0 mg, 0.262 mmol) was treated with p-methoxyphenyl vinyl ether (79.0 mg, 0.5 23 mmol) and 1.2 mol % of in situ-generated complex 1a (31.0 μL, 0.10 M, 3.14 μmol; final substrate concentration=8.45 M) and allowed to stir for 16 h. The unpurified product is >98% Z (as determined by 400 MHz 1H NMR analysis). Excess p-methoxyphenyl vinyl ether was removed by vacuum distillation (1.0 torr, 80° C.). The resulting oil was purified by neutral alumina chromatography (100% hexanes to 100:1 hexanes:Et2O) to afford 10b (56.9 mg, 0.182 mmol, 69.0% yield, >98% Z isomer) as a colorless oil. IR (neat): 2924 (s), 2854 (m), 1665 (m), 1503 (s), 1463 (m), 1441 (m), 1389 (w), 1214 (s), 1180 (m), 1102 (m), 1040 (s); 1H NMR (400 MHz, CDCl3): δ 6.95-6.90 (2H, m), 6.86-6.82 (2H, m), 6.28 (1H, dt, J=6.0, 1.5 Hz), 4.73 (1H, td, J=7.4, 6.0 Hz), 3.78 (3H, s), 3.40 (2H, t, J=7.0 Hz), 2.24-2.17 (2H, m), 1.90-1.81 (2H, m), 1.49-1.32 (6H, m); 13C NMR (100 MHz, CDCl3): δ 155.2, 151.8, 141.4, 117.5, 114.8, 112.0, 55.8, 34.1, 33.0, 29.4, 28.4, 28.1, 23.9; HRMS (ESI+) [M+H]+ calcd for C15H22BrO2: 313.0803, found: 313.0800
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][N:5]([CH3:27])[C:6]2[C:7]=1[CH:8]=[CH:9][C:10]1[N:19]([C:20]3[CH:25]=[CH:24][C:23]([F:26])=[CH:22][CH:21]=3)[CH2:18][CH:17]=[C:12]3[NH:13][C:14](=[O:16])[C:15]=2[C:11]=13.C(N(CC)C(C)C)(C)C.[Br:37][C:38]1[CH:43]=[CH:42][C:41]([F:44])=[CH:40][C:39]=1[CH2:45][C:46](O)=[O:47].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>CN(C)C(=O)C>[Br:37][C:38]1[CH:43]=[CH:42][C:41]([F:44])=[CH:40][C:39]=1[CH2:45][C:46]([NH:1][C:2]1[CH:3]=[CH:4][N:5]([CH3:27])[C:6]2[C:7]=1[CH:8]=[CH:9][C:10]1[N:19]([C:20]3[CH:21]=[CH:22][C:23]([F:26])=[CH:24][CH:25]=3)[CH2:18][CH:17]=[C:12]3[NH:13][C:14](=[O:16])[C:15]=2[C:11]=13)=[O:47]
Reactant: O=C(O)Cc1cc(F)ccc1Br
Reactant: CN1C=CC(N)=c2ccc3c4c([nH]c(=O)c-4c21)=CCN3c1ccc(F)cc1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CC(=O)N(C)C
Solvent: CCN(C(C)C)C(C)C
Product: CN1C=CC(NC(=O)Cc2cc(F)ccc2Br)=c2ccc3c4c([nH]c(=O)c-4c21)=CCN3c1ccc(F)cc1
Yield: 24 %

Procedure:
A stock solution of Example 23e and N,N-diisopropylethylamine (0.14 M and 0.40 M in N,N-dimethylacetamide, respectively, 287 μL) and 2-(2-bromo-5-fluorophenyl)acetic acid (0.4 M in N,N-dimethylacetamide, 124 μL), and 2-(3H-[1,2,3]triazolo[4,5-b]pyridin-3-yl)-1,1,3,3-tetramethylisouronium hexafluorophosphate(V) (0.21 M in N,N-dimethylacetamide, 287 μL) were aspirated from their respective source vials, mixed through a perfluoroalkoxy mixing tube (0.2 mm inner diameter), and loaded into an injection loop. The reaction segment was injected into the flow reactor (Hastelloy coil, 0.75 mm inner diameter, 1.8 mL internal volume) set at 100° C. and passed through the reactor at 180 μL per minute (10 minute residence time). Upon exiting the reactor, the reaction mixture was loaded directly into an injection loop and purified by reverse phase HPLC(C8, acetonitrile/water (0.1% ammonium acetate), 5-100%) to give 0.0058 g (24%) of the title compound. 1H NMR (400 MHz, DMSO-d6/D2O) δ 8.14 (d, J=2.44 Hz, 1H), 7.68 (dd, J=8.85, 5.49 Hz, 1H), 7.65 (s, 1H), 7.42 (dd, J=8.54, 2.44 Hz, 1H), 7.36 (dd, J=9.61, 3.20 Hz, 1H), 7.21 (d, J=8.54 Hz, 1H), 7.14 (td, J=8.54, 3.36 Hz, 1H), 7.04 (s, 1H), 6.82 (m, 2H), 6.49 (m, 2H), 5.02 (d, J=15.87 Hz, 1H), 4.18 (d, J=16.78 Hz, 1H), 4.03 (s, 3H), 3.92 (s, 2H). MS (APCI+) m/z 575.1 (M+H)+.
Reaction SMILES: OC(C(F)(F)F)=O.[NH:8]1[CH2:11][CH:10]([NH:12][C:13](=[O:29])[CH2:14][NH:15][C:16]2[C:20]3[CH:21]=[C:22]([C:25]([F:28])([F:27])[F:26])[CH:23]=[CH:24][C:19]=3[O:18][N:17]=2)[CH2:9]1.[CH:30]([CH:33]1[CH2:38][CH2:37][C:36](=O)[CH2:35][CH2:34]1)([CH3:32])[CH3:31]>>[CH:30]([CH:33]1[CH2:38][CH2:37][CH:36]([N:8]2[CH2:11][CH:10]([NH:12][C:13](=[O:29])[CH2:14][NH:15][C:16]3[C:20]4[CH:21]=[C:22]([C:25]([F:27])([F:26])[F:28])[CH:23]=[CH:24][C:19]=4[O:18][N:17]=3)[CH2:9]2)[CH2:35][CH2:34]1)([CH3:32])[CH3:31]
Reactant: CC(C)C1CCC(=O)CC1
Reactant: O=C(CNc1noc2ccc(C(F)(F)F)cc12)NC1CNC1
Solvent: O=C(O)C(F)(F)F
Product: CC(C)C1CCC(N2CC(NC(=O)CNc3noc4ccc(C(F)(F)F)cc34)C2)CC1

Procedure:
The title compound was prepared as a white solid from reaction of (N-Azetidin-3-yl-2-(5-trifluoromethyl-benzo[d]isoxazol-3-ylamino)-acetamide TFA salt (as prepared in Example 1, Step D) and 4-isopropyl-cyclohexanone using the procedure described in Step E of Example 1.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[N:8]1[C:20]2[C:19]3[CH:18]=[CH:17][CH:16]=[C:15]([O:21][CH2:22][C:23]([F:29])([F:28])[C:24]([F:27])([F:26])[F:25])[C:14]=3[N:13]=[C:12](Cl)[C:11]=2[CH:10]=[CH:9]1.[NH2:31][CH2:32][CH2:33][CH2:34][OH:35]>>[CH3:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[N:8]1[C:20]2[C:19]3[CH:18]=[CH:17][CH:16]=[C:15]([O:21][CH2:22][C:23]([F:29])([F:28])[C:24]([F:27])([F:26])[F:25])[C:14]=3[N:13]=[C:12]([NH:31][CH2:32][CH2:33][CH2:34][OH:35])[C:11]=2[CH:10]=[CH:9]1
Reactant: Cc1ccccc1-n1ccc2c(Cl)nc3c(OCC(F)(F)C(F)(F)F)cccc3c21
Reactant: NCCCO
Product: Cc1ccccc1-n1ccc2c(NCCCO)nc3c(OCC(F)(F)C(F)(F)F)cccc3c21

Procedure:
1-(2-Methylphenyl)-4-chloro-6-β,β,γ,γ,γ-pentafluoropropyloxypyrrolo[3,2-c]quinoline(600 mg, 1.4 mmol) was dissolved in 3-amino-1-propanol(5.0 ml), and reacted at the same condition of Step 3 in the Example 59 to obtain 610 mg of desired compound as solid in 94% of yield.
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([C:8]([Cl:11])([Cl:10])[Cl:9])[CH:5]=[C:4]([Cl:12])[N:3]=1.[Na].[CH3:14][O:15][CH2:16][CH2:17][OH:18]>>[Cl:12][C:4]1[CH:5]=[C:6]([C:8]([Cl:11])([Cl:10])[Cl:9])[CH:7]=[C:2]([O:18][CH2:17][CH2:16][O:15][CH3:14])[N:3]=1
Reactant: COCCO
Reactant: Clc1cc(C(Cl)(Cl)Cl)cc(Cl)n1
Agent: [Na]
Product: COCCOc1cc(C(Cl)(Cl)Cl)cc(Cl)n1
Reaction time: 5 h

Procedure:
To a solution of 26.54 grams (0.10 mole) of 2,6-dichloro-4-(trichloromethyl)pyridine dissolved in 150 milliliters (ml) of 2-methoxyethanol was added over a 35 minute period, a solution composed of 2.53 grams (0.11 mole) of sodium metal dissolved in 100 ml of 2-methoxyethanol. The mixture was stirred for 5 hours at 65°-75° C. The insoluble by-products were removed by filtration and the 2-methoxyethanol was removed by evaporation under reduced pressure. The resulting oily product was diluted with water and extracted with methylene chloride and dried with sodium sulfate. The methylene chloride was then removed leaving the 2-chloro-6-(2-methoxyethoxy)-4-(trichloromethyl)pyridine as an oil. The product was recovered in a yield of 25.6 grams (84 percent of theoretical) and had a refractive index of n 25/d = 1.5440. Upon analysis, the compound was found to have carbon, hydrogen and nitrogen contents of 35.48, 2.99 and 4.72 percent, respectively, as compared with the theoretical contents of 35.44, 2.97 and 4.59 percent, respectively, as calculated for the above named structure.
Reaction SMILES: [BH4-].[Na+].[CH3:3][O:4][C:5](=[O:28])[CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][N:12]1[CH:17]([CH2:18][CH2:19][C:20](=[O:26])[CH2:21][CH2:22][CH2:23][CH2:24][CH3:25])[CH2:16][CH2:15][CH2:14][C:13]1=[O:27]>CO.C(Cl)Cl>[CH3:3][O:4][C:5](=[O:28])[CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][N:12]1[C:13](=[O:27])[CH2:14][CH2:15][CH2:16][CH:17]1[CH2:18][CH2:19][CH:20]([OH:26])[CH2:21][CH2:22][CH2:23][CH2:24][CH3:25]
Reactant: CCCCCC(=O)CCC1CCCC(=O)N1CCCCCCC(=O)OC
Agent: [BH4-]
Agent: [Na+]
Solvent: ClCCl
Solvent: CO
Product: CCCCCC(O)CCC1CCCC(=O)N1CCCCCCC(=O)OC
Temperature: 25 °C
Reaction time: 4 h
Yield: 60.1 %

Procedure:
Sodium borohydride (24 mg, 0.63 mmol), followed by MeOH (2 drops), was added to a solution of 7-[2-oxo-6-(3-oxo-octyl)-piperidin-1-yl]-heptanoic acid methyl ester (23 mg, 0.063 mmol) in CH2Cl2 (1.0 mL) at 0° C. The mixture was allowed to warm to rt. After 4 h at rt, the reaction was quenched with HCl (11.0M aqueous) and extracted with EtOAc (3×10 mL). The combined organic phase was washed with saturated aqueous NaHCO3 (15 mL) and brine (15 mL) then dried (Na2SO4), filtered and concentrated in vacuo. Purification of the residue by flash column chromatography on silica gel (CH2Cl2→3% MeOH/CH2Cl2, gradient) afforded 14 mg (61%) of the title compound.
Reaction SMILES: [CH2:1]([N:8]1[C:16]2[C:11](=[CH:12][C:13]([Cl:17])=[CH:14][CH:15]=2)[CH:10]=[C:9]1[CH:18]([NH2:22])[CH:19]([CH3:21])[CH3:20])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(O[BH-](O[C:33](=[O:35])[CH3:34])OC(=O)C)(=O)C.[Na+].[OH-].[Na+]>C(Cl)Cl>[NH2:8][CH2:1][CH2:2][CH2:3][N:22]([CH:18]([C:9]1[N:8]([CH2:1][C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=2)[C:16]2[C:11]([CH:10]=1)=[CH:12][C:13]([Cl:17])=[CH:14][CH:15]=2)[CH:19]([CH3:20])[CH3:21])[C:33](=[O:35])[C:34]1[CH:19]=[CH:18][CH:9]=[CH:10][CH:11]=1
Reactant: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Reactant: CC(C)C(N)c1cc2cc(Cl)ccc2n1Cc1ccccc1
Agent: [Na+]
Agent: [OH-]
Solvent: ClCCl
Product: CC(C)C(c1cc2cc(Cl)ccc2n1Cc1ccccc1)N(CCCN)C(=O)c1ccccc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 38.4 %

Procedure:
To a solution of 1-(1-benzyl-5-chloro-1H-indole-2-yl)-2-methylpropan-1-amine (0.44 mmol) in 10 mL of anhydrous DCM, was added aldehyde (0.44 mmol) and sodium triacetoxyborohydride (0.44 mmol) at 0° C. The mixture was stirred at room temperature overnight. The solution was poured into 10% aq. NaOH, and extracted with EtOAc (×3). The organic layers were combined, washed with H2O (×3), brine (×3), dried (Na2SO4), filtered, and the filtrate was concentrated. The material was purified by flash chromatography (20% EtOAc:hexane) to yield 40 mg of title compound.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][N:5]=[C:4]2[CH:8]=[CH:9][NH:10][C:3]=12.[Cl:11][CH2:12][CH2:13][C@H:14]([C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)O>>[Cl:1][C:2]1[CH:7]=[CH:6][N:5]=[C:4]2[CH:8]=[CH:9][N:10]([C@H:14]([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)[CH2:13][CH2:12][Cl:11])[C:3]=12
Reactant: O[C@H](CCCl)c1ccccc1
Reactant: Clc1ccnc2cc[nH]c12
Product: ClCC[C@@H](c1ccccc1)n1ccc2nccc(Cl)c21

Procedure:
7-Chloro-1-(3-chloro-1-(S)-phenyl-propyl)-1H-pyrrolo[3,2-b]pyridine was prepared from 7-chloro-1H-pyrrolo[3,2-b]pyridine and 3-chloro-1-(R)-phenyl-propan-1-ol following the procedure of steps 1 and 2 of Example 11 (20% yield, 40 mg).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:10]=[C:9]([CH2:11][CH:12]=[O:13])[CH:8]=[CH:7][C:4]=1[C:5]#[N:6].[CH3:14][Mg]Br>ClCCl.C1COCC1>[OH:13][CH:12]([CH3:14])[CH2:11][C:9]1[CH:8]=[CH:7][C:4]([C:5]#[N:6])=[C:3]([O:2][CH3:1])[CH:10]=1
Reactant: COc1cc(CC=O)ccc1C#N
Reactant: C[Mg]Br
Solvent: C1CCOC1
Solvent: ClCCl
Product: COc1cc(CC(C)O)ccc1C#N
Temperature: 25 °C
Reaction time: 12 h

Procedure:
To a stirred solution of 2-methoxy-4-(2-oxoethyl)benzonitrile (1.5 g, 8.5 mmol) in dichloromethane (30 mL) at 0° C. was added 2.8 mL (8.5 mmol) of a 3.0 M solution of methylmagnesium bromide in THF. The reaction mixture was allowed to warm up to rt and stirred for 12 h. The reaction was then quenched by the addition of 10 mL of 1 N hydrochloric acid and extracted with dichloromethane (2×30 mL). The combined organic extracts were dried with magnesium sulfate, filtered, and concentrated in vacuo. The crude residue was purified on silica (30% EtOAc/hexanes as eluent) to afford 4-(2-hydroxypropyl)-2-methoxybenzonitrile.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH:10]([C:12]2[CH:17]=[CH:16][C:15]([C:18]#[C:19][Si:20]([CH:27]([CH3:29])[CH3:28])([CH:24]([CH3:26])[CH3:25])[CH:21]([CH3:23])[CH3:22])=[CH:14][CH:13]=2)O)[CH:5]=[CH:6][C:7]=1[O:8][CH3:9].C([SiH](CC)CC)C.FC(F)(F)C(O)=O>ClCCl>[Br:1][C:2]1[CH:3]=[C:4]([CH:5]=[CH:6][C:7]=1[O:8][CH3:9])[CH2:10][C:12]1[CH:13]=[CH:14][C:15]([C:18]#[C:19][Si:20]([CH:27]([CH3:28])[CH3:29])([CH:24]([CH3:26])[CH3:25])[CH:21]([CH3:22])[CH3:23])=[CH:16][CH:17]=1
Reactant: COc1ccc(C(O)c2ccc(C#C[Si](C(C)C)(C(C)C)C(C)C)cc2)cc1Br
Agent: CC[SiH](CC)CC
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: COc1ccc(Cc2ccc(C#C[Si](C(C)C)(C(C)C)C(C)C)cc2)cc1Br
Reaction time: 4 h

Procedure:
A solution of 8.0 g (3-bromo-4-methoxy-phenyl)-{4-[(triisopropylsilyl)-ethynyl]-phenyl}-methanol and 5.7 mL triethylsilane in 80 mL dichloromethane is cooled in an ice bath. Then 6.5 mL trifluoroacetic acid are added dropwise, and the solution is stirred for 4 h in the cooling bath. The solution is diluted with dichloromethane and washed with aqueous sodium hydrogen carbonate solution. After drying over sodium sulfate the solvent is removed to give the product.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:20])[C:5]([O:8][C:9]1[C:18]2[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=2)[CH:12]=[C:11]([OH:19])[CH:10]=1)([CH3:7])[CH3:6])[CH3:2].[CH3:21][C:22]1[C:27]([CH2:28][CH2:29]O)=[CH:26][CH:25]=[C:24]([C:31]2[CH:36]=[CH:35][C:34]([C:37]([F:40])([F:39])[F:38])=[CH:33][CH:32]=2)[N:23]=1>>[CH2:1]([O:3][C:4](=[O:20])[C:5]([CH3:7])([O:8][C:9]1[C:18]2[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=2)[CH:12]=[C:11]([O:19][CH2:29][CH2:28][C:27]2[C:22]([CH3:21])=[N:23][C:24]([C:31]3[CH:36]=[CH:35][C:34]([C:37]([F:40])([F:38])[F:39])=[CH:33][CH:32]=3)=[CH:25][CH:26]=2)[CH:10]=1)[CH3:6])[CH3:2]
Reactant: CCOC(=O)C(C)(C)Oc1cc(O)cc2ccccc12
Reactant: Cc1nc(-c2ccc(C(F)(F)F)cc2)ccc1CCO
Product: CCOC(=O)C(C)(C)Oc1cc(OCCc2ccc(-c3ccc(C(F)(F)F)cc3)nc2C)cc2ccccc12

Procedure:
A] In analogy to the procedures described in example 4D] and 4E], 2-(3-hydroxy-naphthalen-1-yloxy)-2-methyl-propionic acid ethyl ester (example 14C]) was reacted with 2-[2-methyl-6-(4-trifluoromethyl-phenyl)-pyridin-3-yl]-ethanol (example 4K]) to give 2-methyl-2-(3-{2-[2-methyl-6-(4-trifluoromethyl-phenyl)-pyridin-3-yl]-ethoxy}-naphthalen-1-yloxy)-propionic acid ethyl ester, which was subsequently saponified to yield the title compound as light yellow solid.