Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: I[C:2]1[C:10]2[C:5](=[CH:6][CH:7]=[C:8]([C:11]3[O:15][C:14]([NH:16][CH:17]([CH3:19])[CH3:18])=[N:13][N:12]=3)[CH:9]=2)[N:4]([S:20]([C:23]2[CH:29]=[CH:28][C:26]([CH3:27])=[CH:25][CH:24]=2)(=[O:22])=[O:21])[CH:3]=1.[CH3:30][O:31][C:32]1[CH:53]=[CH:52][C:35]([CH2:36][O:37][C:38]2[CH:43]=[C:42]([Sn](C)(C)C)[N:41]=[C:40]([S:48]([CH3:51])(=[O:50])=[O:49])[N:39]=2)=[CH:34][CH:33]=1>CN(C=O)C.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.[Cu]I>[CH:17]([NH:16][C:14]1[O:15][C:11]([C:8]2[CH:9]=[C:10]3[C:5](=[CH:6][CH:7]=2)[N:4]([S:20]([C:23]2[CH:24]=[CH:25][C:26]([CH3:27])=[CH:28][CH:29]=2)(=[O:22])=[O:21])[CH:3]=[C:2]3[C:42]2[CH:43]=[C:38]([O:37][CH2:36][C:35]3[CH:34]=[CH:33][C:32]([O:31][CH3:30])=[CH:53][CH:52]=3)[N:39]=[C:40]([S:48]([CH3:51])(=[O:50])=[O:49])[N:41]=2)=[N:12][N:13]=1)([CH3:18])[CH3:19]
Reactant: Cc1ccc(S(=O)(=O)n2cc(I)c3cc(-c4nnc(NC(C)C)o4)ccc32)cc1
Reactant: COc1ccc(COc2cc([Sn](C)(C)C)nc(S(C)(=O)=O)n2)cc1
Agent: [Cu]I
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: CN(C)C=O
Product: COc1ccc(COc2cc(-c3cn(S(=O)(=O)c4ccc(C)cc4)c4ccc(-c5nnc(NC(C)C)o5)cc34)nc(S(C)(=O)=O)n2)cc1
Temperature: 100 °C
Yield: 62.5 %

Procedure:
A glass microwave reaction vessel was charged with 5-(3-iodo-1-tosyl-1H-indol-5-yl)-N-isopropyl-1,3,4-oxadiazol-2-amine (800 mg, 1.532 mmol) and 4-((4-methoxybenzyl)oxy)-2-(methylsulfonyl)-6-(trimethylstannyl)pyrimidine (875 mg, 1.914 mmol) in DMF (5 mL) followed by Pd(PPh3)4 (88 mg, 0.077 mmol) and CuI (72.9 mg, 0.383 mmol). The reaction mixture was stirred and heated in an Initiator microwave reactor (Personal Chemistry, Biotage AB, Inc., Upssala, Sweden) at 100° C. for 1 h. The mixture was filtered through a plug of celite and washed with DCM. The filtrate was washed with water (25 mL×3) and the organic layer was dried, filtered and concentrated. The residue was purified with silica gel chromatography (eluting with 10-20% EtOAc in DCM with 1% MeOH) to give N-isopropyl-5-(3-(6-((4-methoxybenzyl)oxy)-2-(methylsulfonyl)pyrimidin-4-yl)-1-tosyl-1H-indol-5-yl)-1,3,4-oxadiazol-2-amine (660 mg, 0.958 mmol, 62.6% yield) as a brown solid. MS (ESI, pos. ion) m/z: 688.8 (M+1).
Reaction SMILES: FC(F)(F)C(OC(=O)C(F)(F)F)=O.[Br:14][CH2:15][CH2:16][C:17]([OH:19])=[O:18].[C:20]([C:24]([C:27]([O:30][C:31]([C:37]([O:40][C:41]([CH2:47]O)([C:43]([F:46])([F:45])[F:44])[F:42])([F:39])[F:38])([C:33]([F:36])([F:35])[F:34])[F:32])([F:29])[F:28])([F:26])[F:25])([F:23])([F:22])[F:21]>O>[Br:14][CH2:15][CH2:16][C:17]([O:19][CH2:47][C:41]([O:40][C:37]([C:31]([O:30][C:27]([C:24]([C:20]([F:21])([F:22])[F:23])([F:25])[F:26])([F:28])[F:29])([C:33]([F:36])([F:35])[F:34])[F:32])([F:39])[F:38])([C:43]([F:46])([F:45])[F:44])[F:42])=[O:18]
Reactant: O=C(O)CCBr
Reactant: OCC(F)(OC(F)(F)C(F)(OC(F)(F)C(F)(F)C(F)(F)F)C(F)(F)F)C(F)(F)F
Solvent: O=C(OC(=O)C(F)(F)F)C(F)(F)F
Solvent: O
Product: O=C(CCBr)OCC(F)(OC(F)(F)C(F)(OC(F)(F)C(F)(F)C(F)(F)F)C(F)(F)F)C(F)(F)F
Reaction time: 0.5 h
Yield: 76.3 %

Procedure:
A mixture comprising trifluoroacetic anhydride (25.6 g) and 3-bromopropionic acid (17.9 g) was stirred at room temperature under a nitrogen stream for 1 hour. CF3CF2CF2OCF(CF3)CF2OCF(CF3)CH2OH (55.9 g) was added dropwise thereto while cooling with water so that the internal temperature would be maintained to be 30° C. or lower over a period of 30 minutes. 3 hours later, the reaction liquid was directly concentrated and purified by silica gel column chromatography (eluent: mixed solvent comprising hexane (10): ethyl acetate (1)) to obtain the title compound (54.6 g). The yield: 80%.
Reaction SMILES: [CH2:1]([O:7][C:8]1[CH:13]=[CH:12][C:11]([CH2:14][CH2:15][C:16](=[O:18])[CH3:17])=[CH:10][CH:9]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH3:6].C(NC(C)C)(C)C.[Li].[CH2:27]([O:34][C:35]1[CH:40]=[CH:39][C:38]([CH2:41][CH2:42][CH:43]=[O:44])=[CH:37][CH:36]=1)[C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1>>[CH2:27]([O:34][C:35]1[CH:36]=[CH:37][C:38]([CH2:41][CH2:42][CH:43]([OH:44])[CH2:17][C:16](=[O:18])[CH2:15][CH2:14][C:11]2[CH:10]=[CH:9][C:8]([O:7][CH2:1][CH2:2][CH2:3][CH2:4][CH2:5][CH3:6])=[CH:13][CH:12]=2)=[CH:39][CH:40]=1)[C:28]1[CH:29]=[CH:30][CH:31]=[CH:32][CH:33]=1
Reactant: CCCCCCOc1ccc(CCC(C)=O)cc1
Reactant: O=CCCc1ccc(OCc2ccccc2)cc1
Agent: [Li]
Solvent: CC(C)NC(C)C
Product: CCCCCCOc1ccc(CCC(=O)CC(O)CCc2ccc(OCc3ccccc3)cc2)cc1

Procedure:
In a manner similar to Example 3, 2.48 g (10 mmol) of 4-(4-hexyloxyphenyl)-butan-2-one was treated with 15 mmol of lithium diisopropylamine, followed by 3 g (12 mmol) of 3-(4-benzyloxyphenyl)-propan-1-al to give, after purification (silica gel dry column, hexane: ethyl acetate, 2:1), 0.7 g of the title compound pound as a pale yellow oil. MS(EI): 488 (m+), 470 (m+ -H2O) Using the method described hereinabove, the following examples further illustrate the invention:
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH2:8][CH2:9][C:10]([OH:12])=O.S(Cl)([Cl:15])=O>C1(C)C=CC=CC=1>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH2:8][CH2:9][C:10]([Cl:15])=[O:12]
Reactant: O=S(Cl)Cl
Reactant: O=C(O)CCc1ccccc1Cl
Solvent: Cc1ccccc1
Product: O=C(Cl)CCc1ccccc1Cl

Procedure:
A mixture of 3-(2-chlorophenyl)propanoic acid (5.0 g, 27.1 mmole), thionyl chloride (10.9 ml, 149 mmole) and toluene (75 ml) was refluxed for two hours. Concentration in vacuo gave 3-(2-chlorophenyl)propanoyl chloride which was taken up in methylene chloride and used in the next step without further purification.
Reaction SMILES: [C:1]1([C:7]2[N:8]=[CH:9][O:10][CH:11]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[Cl:12][S:13](O)(=[O:15])=[O:14]>ClCCl>[O:10]1[CH:11]=[C:7]([C:1]2[CH:2]=[CH:3][C:4]([S:13]([Cl:12])(=[O:15])=[O:14])=[CH:5][CH:6]=2)[N:8]=[CH:9]1
Reactant: c1ccc(-c2cocn2)cc1
Reactant: O=S(=O)(O)Cl
Solvent: ClCCl
Product: O=S(=O)(Cl)c1ccc(-c2cocn2)cc1
Temperature: 2.5 °C
Reaction time: 0.33 h
Yield: 23 %

Procedure:
4-Phenyl-oxazole (Intermediate 25, 550 mg, 3.79 mmol) was dissolved in a minimum of dichloromethane and was added slowly to chlorosulfonic acid (2.537 mL, 37.9 mmol) at 0° C. The reaction mixture was stirred for 20 min 0-5° C. then warmed to room temperature then to 45° C. and stirred for 2 h. The reaction mixture was cooled to room temperature and cautiously poured on ice water. The aqueous layer was extracted with ethyl acetate, dried over sodium sulfate, and concentrated to crude 4-oxazol-4-yl-benzenesulfonyl chloride. The starting material and product have Rf values in 20% EtOAc/heptane of Rf=0.47 and Rf=0.23, respectively. The crude product was purifed by chromatography on a Biotage 25M column eluting ethyl acetate/heptane to yield 4-oxazol-4-yl-benzenesulfonyl chloride (212 mg, 0.870 mmol). MH+=244.2.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([CH:11]2[CH2:16][CH2:15][NH:14][CH2:13][CH2:12]2)(=[O:10])=[O:9])=[CH:4][CH:3]=1.Br[CH2:18][C:19]([C:21]1[CH:26]=[CH:25][C:24]([F:27])=[CH:23][CH:22]=1)=[O:20].C(=O)([O-])[O-].[K+].[K+]>C(#N)C>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([S:8]([CH:11]2[CH2:16][CH2:15][N:14]([CH2:18][C:19]([C:21]3[CH:26]=[CH:25][C:24]([F:27])=[CH:23][CH:22]=3)=[O:20])[CH2:13][CH2:12]2)(=[O:9])=[O:10])=[CH:6][CH:7]=1
Reactant: O=S(=O)(c1ccc(Br)cc1)C1CCNCC1
Reactant: O=C(CBr)c1ccc(F)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: O=C(CN1CCC(S(=O)(=O)c2ccc(Br)cc2)CC1)c1ccc(F)cc1
Temperature: 25 °C
Reaction time: 17 h

Procedure:
4-(4-Bromophenylsulphonyl)piperidine (Example 1 Step d, 0.9 g, 0.003 mol) was added to a mixture of 2-bromo-4′-fluoroacetophenone (0.7 g, 0.0033 mol) and potassium carbonate (0.84 g, 0.006 mol) in acetonitrile (5 ml) and the resulting slurry stirred at room temperature for 17 h. The insolubles were removed by filtration and the solvent evaporated to give a gum which was purified by column chromatography (SiO2, CH2Cl2:MeOH 2.21-2.26 (2H, m),2.90-2.98 (1H, m), 3.07-3.10 (2H, m), 3.77 (2H, s), 7.42 (2H, d, 8 Hz), 7.56 (2H, t, 8 Hz), 7.65-7.69 (1H, m), 7.86-7.93 (4H, m).
Reaction SMILES: O[C:2]([CH3:18])([CH3:17])[C:3]#[C:4][C:5]([C:7]1[CH:8]=[CH:9][C:10]([O:15][CH3:16])=[C:11]([CH:14]=1)[C:12]#[N:13])=[O:6].C(NCC)C.C([OH:26])C>>[CH3:17][C:2]1([CH3:18])[O:6][C:5]([C:7]2[CH:8]=[CH:9][C:10]([O:15][CH3:16])=[C:11]([CH:14]=2)[C:12]#[N:13])=[CH:4][C:3]1=[O:26]
Reactant: CCO
Reactant: COc1ccc(C(=O)C#CC(C)(C)O)cc1C#N
Solvent: CCNCC
Product: COc1ccc(C2=CC(=O)C(C)(C)O2)cc1C#N
Reaction time: 1 h
Yield: 100 %

Procedure:
To a stirred solution of 5-(4-hydroxy-4-methylpent-2-ynoyl)-2-methoxybenzonitrile (0.9 g, 3.70 mmol) in ethanol (10 mL), a solution of diethyl amine (0.38 mL, 3.70 mmol) in EtOH (2.0 mL) was added dropwise at RT and the reaction mixture was stirred for additional 1 h. The ethanol was then was removed, and the mixture diluted with EtOAc (40 mL). The combined organic layers were washed with water (5 mL) and brine (10 mL), dried over Na2SO4, filtered, and concentrated in vacuo to afford 5-(5,5-dimethyl-4-oxo-4,5-dihydrofuran-2-yl)-2-methoxybenzonitrile (0.9 g, 100%) as a yellow semi solid.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:10])[C:4]([C:6]([F:9])([F:8])[F:7])=[CH2:5].O([CH2:13][N:14]([CH2:20][C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)[CH2:15][Si](C)(C)C)C.FC(F)(F)C(O)=O>ClCCl>[CH3:1][O:2][C:3]([C:4]1([C:6]([F:9])([F:8])[F:7])[CH2:5][CH2:13][N:14]([CH2:20][C:21]2[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=2)[CH2:15]1)=[O:10]
Reactant: C=C(C(=O)OC)C(F)(F)F
Reactant: COCN(Cc1ccccc1)C[Si](C)(C)C
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: COC(=O)C1(C(F)(F)F)CCN(Cc2ccccc2)C1
Temperature: 25 °C
Reaction time: 8 h
Yield: 76.2 %

Procedure:
To a stirred cold solution (0° C.) of 2-trifluoromethyl-acrylic acid methyl ester (308 mg, 2 mmol) and N-(methoxylmethyl)-N-(trimethylsilylmethyl)benzylamine (529 μl, 4.8 mmol) in dichloromethane (3 ml) was added slowly trifluoroacetic acid (31 μl). The resulting solution was allowed to stir at rt overnight and directly purified by column chromatography eluting with ethyl acetate in hexane (1:4) to provide 1-benzyl-3-trifluoromethyl-pyrrolidine-3-carboxylic acid methyl ester as oil (438 mg, 76%).
Reaction SMILES: [F:1][C:2]1[CH:29]=[CH:28][C:5]([CH2:6][NH:7][C:8]([C:10]2([CH2:23][CH2:24][CH2:25][CH2:26]Br)[C:22]3[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=3[C:16]3[C:11]2=[CH:12][CH:13]=[CH:14][CH:15]=3)=[O:9])=[CH:4][CH:3]=1.[CH3:30][C@H:31]1[NH:36][C@@H:35]([CH3:37])[CH2:34][N:33]([C:38]2[O:39][C:40]3[CH:46]=[CH:45][CH:44]=[CH:43][C:41]=3[N:42]=2)[CH2:32]1>>[F:1][C:2]1[CH:29]=[CH:28][C:5]([CH2:6][NH:7][C:8]([C:10]2([CH2:23][CH2:24][CH2:25][CH2:26][N:36]3[C@H:35]([CH3:37])[CH2:34][N:33]([C:38]4[O:39][C:40]5[CH:46]=[CH:45][CH:44]=[CH:43][C:41]=5[N:42]=4)[CH2:32][C@@H:31]3[CH3:30])[C:22]3[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=3[C:16]3[C:11]2=[CH:12][CH:13]=[CH:14][CH:15]=3)=[O:9])=[CH:4][CH:3]=1
Reactant: O=C(NCc1ccc(F)cc1)C1(CCCCBr)c2ccccc2-c2ccccc21
Reactant: C[C@@H]1CN(c2nc3ccccc3o2)C[C@H](C)N1
Product: C[C@@H]1CN(c2nc3ccccc3o2)C[C@H](C)N1CCCCC1(C(=O)NCc2ccc(F)cc2)c2ccccc2-c2ccccc21

Procedure:
Prepared analogously to Example 1 from 9-(4-bromo-butyl)-9H-fluorene-9-carboxylic acid-4-fluoro-benzylamide and 2-(cis-3,5-dimethyl-piperazin-1-yl)-benzoxazole.
Reaction SMILES: [F:1][C:2]1[CH:3]=[N:4][C:5]([O:12][C:13]2[CH:18]=[CH:17][C:16]([F:19])=[CH:15][CH:14]=2)=[C:6]([CH:11]=1)[C:7]([O:9]C)=[O:8].[OH-].[Na+].Cl>CO.O>[F:1][C:2]1[CH:3]=[N:4][C:5]([O:12][C:13]2[CH:18]=[CH:17][C:16]([F:19])=[CH:15][CH:14]=2)=[C:6]([CH:11]=1)[C:7]([OH:9])=[O:8]
Reactant: COC(=O)c1cc(F)cnc1Oc1ccc(F)cc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: O=C(O)c1cc(F)cnc1Oc1ccc(F)cc1
Temperature: 40 °C
Reaction time: 3 h
Yield: 90.9 %

Procedure:
To a stirred solution of methyl 5-fluoro-2-(4-fluorophenoxy)nicotinate (step 1, 2.63 g, 9.9 mmol) in methanol (50 mL) was added 2 N sodium hydroxide aqueous solution (10 mL). The reaction mixture was stirred at 40° C. for 3 h. After cooling, the pH value was adjusted to 4.0 by the addition of 2 N hydrochloric acid. The mixture was diluted with water (100 mL), and extracted with dichloromethane (100 mL×3). The combined organic layer was washed with brine (100 mL), dried (sodium sulfate), and concentrated to afford 2.26 g (91%) of the title compound as off white solids: 1H-NMR (CDCl3) δ 8.25 (1H, dd, J=7.5, 3.1 Hz), 8.16 (1H, d, J=3.1 Hz), 7.16–7.13 (4H, m); MS (ESI) m/z 252 (M+H)+.
Reaction SMILES: [ClH:1].[O:2]=[C:3]1[NH:9][C:8]2[C:10]([C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=3)=[CH:11][CH:12]=[CH:13][C:7]=2[O:6][CH2:5][C@@H:4]1[NH:20]C(=O)OC(C)(C)C.C(OC(C)C)(C)C>O1CCOCC1>[ClH:1].[NH2:20][C@@H:4]1[C:3](=[O:2])[NH:9][C:8]2[C:10]([C:14]3[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=3)=[CH:11][CH:12]=[CH:13][C:7]=2[O:6][CH2:5]1
Reactant: CC(C)(C)OC(=O)N[C@H]1COc2cccc(-c3ccccc3)c2NC1=O
Agent: Cl
Solvent: C1COCCO1
Solvent: CC(C)OC(C)C
Product: N[C@H]1COc2cccc(-c3ccccc3)c2NC1=O
Temperature: 25 °C
Reaction time: 4 h

Procedure:
2 mL of dioxane and 1.8 mL of a solution of hydrochloric acid in dioxane (4M) are added to a 25 mL round-bottomed flask containing 85 mg of 43 (0.24 mmol). The mixture is stirred for 4 h at RT under argon. The dioxane is concentrated, and taken up in 10 mL of isopropyl ether. The solid formed is disintegrated with isopropyl ether. 60 mg of amine 44 (cream-coloured solid) are obtained after filtration in the hydrochloride form.
Reaction SMILES: [CH:1]1([NH2:4])[CH2:3][CH2:2]1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].[I:19][C:20]1[CH:25]=[CH:24][C:23]([C:26](=O)[CH3:27])=[CH:22][CH:21]=1.C(=O)([O-])O.[Na+]>C(Cl)(Cl)Cl.C(O)(=O)C>[I:19][C:20]1[CH:25]=[CH:24][C:23]([CH:26]([NH:4][CH:1]2[CH2:3][CH2:2]2)[CH3:27])=[CH:22][CH:21]=1
Reactant: CC(=O)c1ccc(I)cc1
Reactant: NC1CC1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClC(Cl)Cl
Solvent: CC(=O)O
Product: CC(NC1CC1)c1ccc(I)cc1
Temperature: 25 °C
Reaction time: 24 h
Yield: 92.8 %

Procedure:
Cyclopropylamine (0.85 g), acetic acid (0.89 g), and sodium triacetoxyborohydride (3.2 g) were added to a chloroform (20 mL) solution of 1-(4-iodophenyl)ethanone (1.2 g), and the mixture was stirred in a nitrogen atmosphere for 24 hours at room temperature. A saturated aqueous solution of sodium hydrogen carbonate was added to the reaction mixture, and then the mixture was extracted with chloroform. Then, the organic layer was washed with brine, and dried over anhydrous magnesium sulfate. Then, the desiccant was filtered out, and the solvent was distilled off under reduced pressure. The resulting residue was purified by OH type silica gel chromatography (hexane/ethyl acetate=80/20) to obtain N-[1-(4-iodophenyl)ethyl]cyclopropylamine (colorless oil) (1.3 g, 95%).
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH2:3][CH2:2]1.[C:10](OC(=O)C)(=[O:12])[CH3:11]>>[C:10]([N:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH2:3][CH2:2]1)(=[O:12])[CH3:11]
Reactant: c1ccc2c(c1)CCN2
Reactant: CC(=O)OC(C)=O
Product: CC(=O)N1CCc2ccccc21
Temperature: 0 °C

Procedure:
To a 3-neck 500 ml round bottom flask containing 108.5 g (0.911 mol) indoline was added acetic anhydride at a rate such as to maintain a temperature below 25° C. After addition (one hour), the reddish sludge was poured into ice water, filtered and washed several times with water. It was allowed to dry overnight and recrystallized from 700 ml of ethanol and gave 116.6 g (72.4% by weight yield) of N-acetylindoline.
Reaction SMILES: O[C:2]1[NH:6][C:5]2[CH:7]=[CH:8][CH:9]=[CH:10][C:4]=2[N:3]=1.[OH-].[NH4+].P(Cl)(Cl)([Cl:15])=O>>[Cl:15][C:2]1[NH:6][C:5]2[CH:7]=[CH:8][CH:9]=[CH:10][C:4]=2[N:3]=1
Reactant: O=P(Cl)(Cl)Cl
Reactant: Oc1nc2ccccc2[nH]1
Agent: [NH4+]
Agent: [OH-]
Product: Clc1nc2ccccc2[nH]1
Temperature: 0 °C

Procedure:
2-Hydroxy-1H-benzimidazole (62 g, 0.46 mole) was added to phosphorous oxychloride (200 mL) and the mixture was refluxed for 4.5 hours. The resulting solution was poured over 4 L of ice and the mixture was made strongly basic with ammonium hydroxide. The resulting solid was isolated by filtration, washed with water and dried to provide crude 2-chloro-1H-benzimidazole.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[C:18]([C:19]3[CH:24]=[CH:23][C:22]([O:25][CH3:26])=[CH:21][CH:20]=3)=[CH:17][C:16]3[C:11](=[CH:12][CH:13]=[C:14]([C:27]([O:29]CC)=[O:28])[CH:15]=3)[N:10]=2)=[CH:5][CH:4]=1.[OH-].[Na+]>CO.O>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]([C:9]2[C:18]([C:19]3[CH:24]=[CH:23][C:22]([O:25][CH3:26])=[CH:21][CH:20]=3)=[CH:17][C:16]3[C:11](=[CH:12][CH:13]=[C:14]([C:27]([OH:29])=[O:28])[CH:15]=3)[N:10]=2)=[CH:7][CH:8]=1
Reactant: CCOC(=O)c1ccc2nc(-c3ccc(OC)cc3)c(-c3ccc(OC)cc3)cc2c1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: COc1ccc(-c2cc3cc(C(=O)O)ccc3nc2-c2ccc(OC)cc2)cc1
Temperature: 50 °C
Reaction time: 3 h
Yield: 77.8 %

Procedure:
A solution of ethyl 2,3-bis(4-methoxyphenyl)quinoline-6-carboxylate (83 mg, 0.20 mmol, 1.00 equiv) and sodium hydroxide (40 mg, 1.00 mmol, 5.00 equiv) in methanol (10 mL) and water (1 mL) were placed in a 25-mL round-bottom flask and stirred for 3 h at 50° C. in an oil bath. The resulting mixture was concentrated under vacuum, diluted with 10 mL of H2O, and the pH adjusted to 4-5 with 1N HCl. The resulting solids were collected by filtration and dried in an oven under reduced pressure. The crude product (80 mg) was purified by Flash-Prep-HPLC (CH3CN/H2O; Detector, UV 254 nm), affording 60 mg (78%) of 2,3-bis(4-methoxyphenyl)quinoline-6-carboxylic acid as a yellow solid.
Reaction SMILES: Cl.Cl[C:3]1[CH:8]=[C:7]([C:9]2[CH:14]=[CH:13][CH:12]=[C:11]([Cl:15])[CH:10]=2)[N:6]=[C:5]2[CH2:16][CH2:17][CH2:18][C:4]=12.[NH2:19][C:20]1[CH:25]=[CH:24][C:23]([CH2:26][CH2:27][CH2:28][C:29]([O:31][CH3:32])=[O:30])=[CH:22][CH:21]=1>>[Cl:15][C:11]1[CH:10]=[C:9]([C:7]2[N:6]=[C:5]3[CH2:16][CH2:17][CH2:18][C:4]3=[C:3]([NH:19][C:20]3[CH:21]=[CH:22][C:23]([CH2:26][CH2:27][CH2:28][C:29]([O:31][CH3:32])=[O:30])=[CH:24][CH:25]=3)[CH:8]=2)[CH:14]=[CH:13][CH:12]=1
Reactant: Clc1cccc(-c2cc(Cl)c3c(n2)CCC3)c1
Reactant: COC(=O)CCCc1ccc(N)cc1
Agent: Cl
Product: COC(=O)CCCc1ccc(Nc2cc(-c3cccc(Cl)c3)nc3c2CCC3)cc1
Temperature: 150 °C
Yield: 79 %

Procedure:
An 18-mL test tube was charged with 4-chloro-2-(3-chlorophenyl)-6,7-dihydro-5H-cyclopenta[b]pyridine HCl salt (10 mg, 0.033 mmol, 1 eq. Synthesis of this compound was described in step 1 of EXAMPLE 1) and methyl 4-(4-aminophenyl)butanoate (17 mg, 0.088 mmol, 2.7 eq.). The resulting mixture was heated at 150° C. under Ar for 1 hr. After cooling to room temperature, the mixture was partitioned between NaHCO3 aq. (10 ml) and dichloromethane (10 ml). The organic layer was collected and concentrated on a rotary evaporator. The residue was purified by chromatography on silica gel using dichloromethane followed by 5% of ethyl acetate in dichloromethane as eluent to give methyl 4-[4-[[2-(3-chlorophenyl)-6,7-dihydro-5H-cyclopenta[b]pyridin-4-yl]amino]phenyl]butanoate (11 mg, 79% yield).
Reaction SMILES: [CH3:1][O:2][CH2:3][CH2:4][O:5][C:6]1[CH:7]=[C:8]([O:12][CH2:13][C@@H:14]2[CH2:18][CH2:17][CH2:16][NH:15]2)[CH:9]=[N:10][CH:11]=1.C=O.[C:21]([O-])(O)=O.[Na+]>C(O)=O>[CH3:1][O:2][CH2:3][CH2:4][O:5][C:6]1[CH:7]=[C:8]([O:12][CH2:13][C@@H:14]2[CH2:18][CH2:17][CH2:16][N:15]2[CH3:21])[CH:9]=[N:10][CH:11]=1
Reactant: COCCOc1cncc(OC[C@@H]2CCCN2)c1
Reactant: O=C([O-])O
Agent: C=O
Agent: [Na+]
Solvent: O=CO
Product: COCCOc1cncc(OC[C@@H]2CCCN2C)c1
Temperature: 50 °C
Yield: 85 %

Procedure:
To 5-methoxyethoxy-3-(2-(S)-pyrrolidinylmethoxy)pyridine from Example 197f (450 mg, 1.78 mmol) was added formaldehyde (37%, 8 mL) and formic acid (88%, 4 mL), and the mixture was heated at 50° C. for 4 h and then allowed cool to room temperature. The mixture was basified with saturated NaHCO3 and then extracted with Et2O. The organic layer was dried over Na2SO4 and concentrated. The residue was chromatographed (silica gel; hexane/EtOAc, 2:1) to afford the title compound (402 mg, 85%): 1H NMR (CDCl3, 300 MHz) δ 2.00-2.08 (m, 4H), 2.45 (m, 1H), 3.05 (s, 3H), 3.45 (s, 3H), 3.65 (t, 2H, J=6.0 Hz), 3.85 (t, 2H, J=6.0 Hz), 4.15 (m, 1H), 4.30-4.35 (m, 2H), 4.52 (m, 1H), 7.25 (t, 1H, J=3.0 Hz), 8.02 (br s, 2H); MS (CI/NH3) m/z 267 (M+H)+.
Reaction SMILES: [NH2:1][CH:2]([C:33]1[CH:38]=[CH:37][C:36]([O:39][CH2:40][CH2:41][O:42][C:43]([CH3:46])([CH3:45])[CH3:44])=[CH:35][CH:34]=1)[C:3]([NH:5][C@H:6]([C:15]1[NH:16][C:17]([C:20]2[CH:25]=[CH:24][C:23]([C:26]#[C:27][Si](C)(C)C)=[CH:22][C:21]=2[F:32])=[CH:18][N:19]=1)[C@H:7]([C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)[CH3:8])=[O:4].[F-].C([N+](CCCC)(CCCC)CCCC)CCC.C(OCC)(=O)C>O1CCCC1>[NH2:1][CH:2]([C:33]1[CH:38]=[CH:37][C:36]([O:39][CH2:40][CH2:41][O:42][C:43]([CH3:44])([CH3:46])[CH3:45])=[CH:35][CH:34]=1)[C:3]([NH:5][C@H:6]([C:15]1[NH:16][C:17]([C:20]2[CH:25]=[CH:24][C:23]([C:26]#[CH:27])=[CH:22][C:21]=2[F:32])=[CH:18][N:19]=1)[C@H:7]([C:9]1[CH:10]=[CH:11][CH:12]=[CH:13][CH:14]=1)[CH3:8])=[O:4]
Reactant: C[C@@H](c1ccccc1)[C@H](NC(=O)C(N)c1ccc(OCCOC(C)(C)C)cc1)c1ncc(-c2ccc(C#C[Si](C)(C)C)cc2F)[nH]1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: C#Cc1ccc(-c2cnc([C@@H](NC(=O)C(N)c3ccc(OCCOC(C)(C)C)cc3)[C@@H](C)c3ccccc3)[nH]2)c(F)c1
Reaction time: 2 h

Procedure:
To a solution of 2-amino-2-[4-(2-tert-butoxy-ethoxy)-phenyl]-N-{(1S,2S)-1-[5-(2-fluoro-4-trimethylsilanylethynyl-phenyl)-1H-imidazol-2-yl]-2-phenyl-propyl}-acetamide (290 mg, 0.45 mmol) in tetrahydrofuran (10 mL) at room temperature under an atmosphere of nitrogen was added 1.0 M tetrabutylammonium fluoride in tetrahydrofuran (680 μL, 0.68 mmol) and the resulting solution was allowed to stir for 2 hours. The reaction was poured into ethyl acetate (50 mL), washed with water (2×20 mL), brine, dried over sodium sulfate, filtered and concentrated in vacuo to give 2-amino-2-[4-(2-tert-butoxy-ethoxy)-phenyl]-N-{(1S,2S)-1-[5-(4-ethynyl-2-fluoro-phenyl)-1H-imidazol-2-yl]-2-phenyl-propyl}-acetamide which was used without further purification (250 mg, 97%).
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[C:5]([O:10][CH2:11][C@@H:12]3[CH2:16][CH2:15][CH2:14][N:13]3C(OC(C)(C)C)=O)[CH:6]=[CH:7][CH:8]=2)[CH:3]=[N:2]1.[H-].[Na+].[C:26]1([S:32](Cl)(=[O:34])=[O:33])[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1.[F:36][C:37]([F:42])([F:41])[C:38]([OH:40])=[O:39]>CN(C)C=O>[F:36][C:37]([F:42])([F:41])[C:38]([OH:40])=[O:39].[C:26]1([S:32]([N:1]2[C:9]3[C:4](=[C:5]([O:10][CH2:11][C@@H:12]4[CH2:16][CH2:15][CH2:14][NH:13]4)[CH:6]=[CH:7][CH:8]=3)[CH:3]=[N:2]2)(=[O:34])=[O:33])[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1
Reactant: O=S(=O)(Cl)c1ccccc1
Reactant: CC(C)(C)OC(=O)N1CCC[C@H]1COc1cccc2[nH]ncc12
Agent: [H-]
Agent: [Na+]
Solvent: O=C(O)C(F)(F)F
Solvent: CN(C)C=O
Product: O=S(=O)(c1ccccc1)n1ncc2c(OC[C@@H]3CCCN3)cccc21
Reaction time: 0.17 h

Procedure:
A solution of t-butyl (2S)-2-[(1H-indazol-4-yloxy)methyl]pyrrolidine-1-carboxylate (0.317 g, 1.0 mmol) in dimethylformamide is treated with sodium hydride (0.08 g, 2.0 mmol, 60% in mineral oil) at room temperature, stirred for 10 min, treated with benzenesulfonyl chloride (0.264 g, 1.5 mmol), stirred for 18 h under nitrogen at room temperature, quenched with water and diluted with ether. The organic phase is separated, washed sequentially with water and brine, dried over MgSO4 and concentrated in vacuo to give a white foam residue. The residue is purified by chromatography (silica gel, EtOAc:hexanes, 15:85) to give a white solid. This solid is dissolved in trifluoroacetic acid at 0° C., stirred at room temperature for 90 min and concentrated in vacuo. The resultant residue is triturated under ether to afford the title compound as a white solid, 300 mg, mp 218-219° C., identified by NMR and mass spectral analyses.