Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][CH:2]([CH2:4][CH2:5][CH2:6][C@H:7]([C@@H:9]1[C@:26]2([CH3:27])[C@H:12]([C@H:13]3[C@H:23]([CH2:24][CH2:25]2)[C@:21]2([CH3:22])[C:16]([CH2:17][C@@H:18]([O:28][CH2:29][CH2:30][C:31]#[C:32][CH2:33][CH2:34][O:35]C(C4C=CC=CC=4)(C4C=CC=CC=4)C4C=CC=CC=4)[CH2:19][CH2:20]2)=[CH:15][CH2:14]3)[CH2:11][CH2:10]1)[CH3:8])[CH3:3].C(O)(=O)C.O>O1CCOCC1>[CH3:3][CH:2]([CH2:4][CH2:5][CH2:6][C@H:7]([C@@H:9]1[C@:26]2([CH3:27])[C@H:12]([C@H:13]3[C@H:23]([CH2:24][CH2:25]2)[C@:21]2([CH3:22])[C:16]([CH2:17][C@@H:18]([O:28][CH2:29][CH2:30][C:31]#[C:32][CH2:33][CH2:34][OH:35])[CH2:19][CH2:20]2)=[CH:15][CH2:14]3)[CH2:11][CH2:10]1)[CH3:8])[CH3:1]
Reactant: CC(C)CCC[C@@H](C)[C@H]1CC[C@H]2[C@@H]3CC=C4C[C@@H](OCCC#CCCOC(c5ccccc5)(c5ccccc5)c5ccccc5)CC[C@]4(C)[C@H]3CC[C@]12C
Solvent: O
Solvent: C1COCCO1
Solvent: CC(=O)O
Product: CC(C)CCC[C@@H](C)[C@H]1CC[C@H]2[C@@H]3CC=C4C[C@@H](OCCC#CCCO)CC[C@]4(C)[C@H]3CC[C@]12C

Procedure:
A suspension of 6-(5-cholesten-3β-yloxy)-1-(triphenylmethyloxy)hex-3-yne (21 g) in p-dioxan (40 ml) is heated on a steam cone until dissolution. This is followed by the addition of 90% acetic acid (30 ml) until turbidity, and the reaction mixture is heated overnight at 100°. Water (15 ml) is added and the mixture is concentrated to a small volume. Ether and petroleum ether are added and crystals (triphenylmethanol) are filtered and discarded. The filtrate is concentrated to dryness and put on a silica gel column and eluted with 20% ether in petroleum ether. The desired compound, 6-(5-cholesten-3β-yloxy)hex-3-yne-1-ol, is isolated as an oil (7.0 g).
Reaction SMILES: [CH:1]1([C:6]([NH:8][C:9]2[CH:10]=[C:11]3[C:15](=[CH:16][CH:17]=2)[N:14]([CH2:18][CH2:19][CH2:20][C:21](O)=[O:22])[C:13]([CH2:24][O:25][C:26]2[CH:35]=[CH:34][C:33]4[C:28](=[CH:29][CH:30]=[CH:31][CH:32]=4)[CH:27]=2)=[C:12]3[CH:36]=[O:37])=[O:7])[CH2:5][CH2:4][CH2:3][CH2:2]1.CCN=C=NCCCN(C)C.[F:49][C:50]([F:56])([F:55])[S:51]([NH2:54])(=[O:53])=[O:52].C1COCC1>CN(C1C=CN=CC=1)C.C(OCC)(=O)C.O>[CH:36]([C:12]1[C:11]2[C:15](=[CH:16][CH:17]=[C:9]([NH:8][C:6]([CH:1]3[CH2:5][CH2:4][CH2:3][CH2:2]3)=[O:7])[CH:10]=2)[N:14]([CH2:18][CH2:19][CH2:20][C:21](=[O:22])[NH:54][S:51]([C:50]([F:56])([F:55])[F:49])(=[O:53])=[O:52])[C:13]=1[CH2:24][O:25][C:26]1[CH:35]=[CH:34][C:33]2[C:28](=[CH:29][CH:30]=[CH:31][CH:32]=2)[CH:27]=1)=[O:37]
Reactant: NS(=O)(=O)C(F)(F)F
Reactant: O=Cc1c(COc2ccc3ccccc3c2)n(CCCC(=O)O)c2ccc(NC(=O)C3CCCC3)cc12
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Solvent: O
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: O=Cc1c(COc2ccc3ccccc3c2)n(CCCC(=O)NS(=O)(=O)C(F)(F)F)c2ccc(NC(=O)C3CCCC3)cc12
Temperature: 25 °C
Reaction time: 3 h
Yield: 94 %

Procedure:
The acid (1 eq) from step 1 of Example 53A was weighed into a flask and to this was added EDCI (1.35 eq), DMAP (1.1 eq), trifluoromethanesulfonamide (1.05 eq) followed by anhydrous THF (0.026 M) and the reaction mixture was stirred at 25° C., 3 h. Worked up with ethyl acetate/water followed by washing the organic layer with 0.05N HCl, saturated bicarbonate and brine. Chromatographic purification then afforded the desired product in 94% yield.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[O:9][C:8]([C:10]3[CH:11]=[CH:12][C:13]([NH:17][CH:18]4[CH2:23][CH2:22][O:21][CH2:20][CH2:19]4)=[C:14]([CH:16]=3)[NH2:15])=[N:7][C:6]=2[CH:24]=1.[CH3:25][C:26]([NH:28][C:29]1[CH:34]=[CH:33][C:32]([CH:35]=O)=[CH:31][CH:30]=1)=[O:27].OOS([O-])=O.[K+].C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O>[C:26]([NH:28][C:29]1[CH:34]=[CH:33][C:32]([C:35]2[N:17]([CH:18]3[CH2:19][CH2:20][O:21][CH2:22][CH2:23]3)[C:13]3[CH:12]=[CH:11][C:10]([C:8]4[O:9][C:5]5[CH:4]=[CH:3][C:2]([Cl:1])=[CH:24][C:6]=5[N:7]=4)=[CH:16][C:14]=3[N:15]=2)=[CH:31][CH:30]=1)(=[O:27])[CH3:25]
Reactant: CC(=O)Nc1ccc(C=O)cc1
Reactant: Nc1cc(-c2nc3cc(Cl)ccc3o2)ccc1NC1CCOCC1
Agent: O=C([O-])[O-]
Agent: O=S([O-])OO
Agent: [K+]
Solvent: CN(C)C=O
Product: CC(=O)Nc1ccc(-c2nc3cc(-c4nc5cc(Cl)ccc5o4)ccc3n2C2CCOCC2)cc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 73.7 %

Procedure:
To a solution of 5-chloro-2-(2-(tetrahydropyran-4-yl)aminoanilin-5-yl)benzoxazole (see Working Example 100-2) (250 mg, 0.727 mmol) in dimethylformamide (3 mL) was added 4-formylacetanilide (142 mg, 0.872 mmol) and oxone (313 mg, 0.509 mmol), and this was stirred at room temperature for 2 hours. After the reaction was complete, aqueous potassium carbonate solution was added, this was filtered and washed with water. The crystals obtained were purified by silica gel column chromatography to yield the title compound (261 mg, 74% yield) as white crystals.
Reaction SMILES: [CH:1]12[C:9](=[O:10])[CH:6]([CH2:7][CH2:8]1)[CH2:5][CH:4]=[CH:3][CH2:2]2.[CH2:11](O)[CH2:12][OH:13]>C1(C)C=CC=CC=1.O.C1(C)C=CC(S(O)(=O)=O)=CC=1>[O:10]1[CH2:11][CH2:12][O:13][C:9]21[CH:6]1[CH2:7][CH2:8][CH:1]2[CH2:2][CH:3]=[CH:4][CH2:5]1
Reactant: OCCO
Reactant: O=C1C2CC=CCC1CC2
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: Cc1ccccc1
Solvent: O
Product: C1=CCC2CCC(C1)C21OCCO1
Temperature: 25 °C
Yield: 99.7 %

Procedure:
A mixture of bicyclo[4.2.1]non-3-en-9-one (10 g, 73 mmol), ethyleneglycol (12.3 ml, 220 mmol) and p-toluenesulphonic acid monohydrate (100 mg) in toluene (250 ml) was refluxed in a Dean-Stark apparatus for four hours. The reaction mixture was cooled to ambient temperature and sequentially washed with water (3×50 ml) and brine (100 ml). The organic extract was dried over MgSO4 and concentrated in vacuo, to afford spiro[bicyclo[4.2.1]non-3-ene-9,2′-[1,3]dioxolane] (13.12 g, 99.5%).
Reaction SMILES: [CH2:1]([NH:3][C:4](=[O:42])[NH:5][C:6]1[S:7][C:8]2[C:14]([NH:15][C:16](=[O:23])[C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][N:18]=3)=[CH:13][C:12]([C:24]3[CH:25]=[N:26][C:27]([N:30]4[CH2:35][CH2:34][C:33]([CH3:41])([C:36]([O:38]CC)=[O:37])[CH2:32][CH2:31]4)=[N:28][CH:29]=3)=[CH:11][C:9]=2[N:10]=1)[CH3:2].CC(C)([O-])C.[K+]>CS(C)=O>[CH2:1]([NH:3][C:4](=[O:42])[NH:5][C:6]1[S:7][C:8]2[C:14]([NH:15][C:16](=[O:23])[C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][N:18]=3)=[CH:13][C:12]([C:24]3[CH:25]=[N:26][C:27]([N:30]4[CH2:35][CH2:34][C:33]([CH3:41])([C:36]([OH:38])=[O:37])[CH2:32][CH2:31]4)=[N:28][CH:29]=3)=[CH:11][C:9]=2[N:10]=1)[CH3:2]
Reactant: CCNC(=O)Nc1nc2cc(-c3cnc(N4CCC(C)(C(=O)OCC)CC4)nc3)cc(NC(=O)c3ccccn3)c2s1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: CS(C)=O
Product: CCNC(=O)Nc1nc2cc(-c3cnc(N4CCC(C)(C(=O)O)CC4)nc3)cc(NC(=O)c3ccccn3)c2s1
Yield: 30.4 %

Procedure:
Ethyl 1-(5-(2-(3-ethylureido)-7-(picolinamido)benzo[d]thiazol-5-yl)pyrimidin-2-yl)-4-methylpiperidine-4-carboxylate (100 mg, 0.17 mmol) was dissolved in DMSO (2 ml) with stirring and potassium-t-butoxide (76 mg, 0.68 mmol) added. The reaction was stirred at rt for 2 h. The reaction mixture was filtered and purified by preparative HPLC to afford Compound 149 as a solid (29 mg, 98% purity by LC-MS) (30%). 1H NMR (DMSO-d6): δ 10.87 (1H, s), 8.84 (1H, d, J=4.78 Hz), 8.78 (2H, s), 8.25 (1H, d, J=7.82 Hz), 8.15 (1H, td, J=7.67, 1.67 Hz), 7.81 (1H, s), 7.77 (1H, dd, J=7.65, 4.87 Hz), 7.73 (1H, s), 6.86 (1H, s), 4.32 (2H, dt, J=13.67, 4.43 Hz), 3.22 (2H, p, J=6.69 Hz), 2.05 (2H, dt, J=13.55, 3.74 Hz), 1.43 (2H, ddd, J=13.38, 9.93, 3.91 Hz), 1.22 (3H, s), 1.13 (3H, t, J=7.15 Hz). MS: 561 [M+H]+.
Reaction SMILES: [S:1]([C:9]1[CH:14]=[CH:13][C:12]([OH:15])=[CH:11][CH:10]=1)[C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[CH:4][CH:3]=1.[C:16]1([S:22](Cl)(=[O:24])=[O:23])[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1>N1C=CC=CC=1>[C:16]1([S:22]([O:8][C:5]2[CH:6]=[CH:7][C:2]([S:1][C:9]3[CH:14]=[CH:13][C:12]([O:15][S:22]([C:16]4[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=4)(=[O:24])=[O:23])=[CH:11][CH:10]=3)=[CH:3][CH:4]=2)(=[O:24])=[O:23])[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1
Reactant: O=S(=O)(Cl)c1ccccc1
Reactant: Oc1ccc(Sc2ccc(O)cc2)cc1
Solvent: c1ccncc1
Product: O=S(=O)(Oc1ccc(Sc2ccc(OS(=O)(=O)c3ccccc3)cc2)cc1)c1ccccc1
Temperature: 25 °C
Reaction time: 18 h
Yield: 97.4 %

Procedure:
A 100 ml 3-necked oven dried flask is equipped with a magnetic stirring bar and a CaCl2 -Drierite drying tube and is charged with 4,4'-thiodiphenol (5.3 grams, 24.3 mmol), benzenesulfonyl chloride (6.5 ml, 50.9 mmol), 4-dimethylaminopyridene (0.59 grams, 4.8 mmol), and anhydrous pyridine (40 ml). The mixture is stirred at ambient temperature for 18 hours, and at reflux for 4 hours, then is poured into ice-cold water (100 ml) with vigorous stirring, and the yellow oil that separates is extracted into CH2Cl2 (100 ml), and washed with water (100 ml). Drying (MgSO4), filtration and concentration affords a yellow oil. Purification by filtration through a column packed with flash grade silica gel (5"×2" i.d.), eluting with CH2Cl2 (ca. 0.5 l), gives after solvent removal under vacuum 11.8 grams (98 percent yield) of the title compound as a faintly yellowish, thick glass material.
Reaction SMILES: I[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][C:8]1[CH:13]=[CH:12][CH:11]=[C:10]([O:14][CH2:15][C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[C:9]=1[O:22][CH2:23][C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1.[C:30]1([CH2:36][O:37][C:38](=[O:50])[C:39]2[CH:44]=[CH:43][C:42]([OH:45])=[C:41]([CH2:46][CH2:47][CH3:48])[C:40]=2[OH:49])[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1.C(=O)([O-])[O-].[K+].[K+]>CC(C)=O>[C:30]1([CH2:36][O:37][C:38](=[O:50])[C:39]2[CH:44]=[CH:43][C:42]([O:45][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][C:8]3[CH:13]=[CH:12][CH:11]=[C:10]([O:14][CH2:15][C:16]4[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=4)[C:9]=3[O:22][CH2:23][C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=3)=[C:41]([CH2:46][CH2:47][CH3:48])[C:40]=2[OH:49])[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1
Reactant: ICCCCCCc1cccc(OCc2ccccc2)c1OCc1ccccc1
Reactant: CCCc1c(O)ccc(C(=O)OCc2ccccc2)c1O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: CCCc1c(OCCCCCCc2cccc(OCc3ccccc3)c2OCc2ccccc2)ccc(C(=O)OCc2ccccc2)c1O
Yield: 60.1 %

Procedure:
A mixture of 1.31 g (2.6 mmol) of 1-(6-iodohexyl)-2,3-bis(phenylmethoxy)benzene, 0.74 g (2.6 mmol) of 2,4-dihydroxy-3-propylbenzoic acid phenylmethyl ester and 0.54 g (3.9 mmol) of potassium carbonate in 35 mL of acetone was stirred at reflux for 39 hours. The reaction mixture was filtered and the filtrate was concentrated under reduced pressure to an oil which was purified by HPLC using 8% ethyl acetate-hexane to give 1.03 g (60% yield) of 2-hydroxy-4-[6-[2,3-bis(phenylmethoxy)phenyl]hexyloxy]-3-propylbenzoic acid phenylmethyl ester as an oil.
Reaction SMILES: C(NC(C)C)(C)C.C([Li])CCC.[CH2:13]([SnH:17]([CH2:22][CH2:23][CH2:24][CH3:25])[CH2:18][CH2:19][CH2:20][CH3:21])[CH2:14][CH2:15][CH3:16].[CH:26]([O:29][CH2:30]Cl)([CH3:28])[CH3:27]>C1COCC1>[CH2:22]([Sn:17]([CH2:13][CH2:14][CH2:15][CH3:16])([CH2:18][CH2:19][CH2:20][CH3:21])[CH2:30][O:29][CH:26]([CH3:28])[CH3:27])[CH2:23][CH2:24][CH3:25]
Reactant: CC(C)OCCl
Reactant: CCCC[SnH](CCCC)CCCC
Agent: [Li]CCCC
Solvent: CC(C)NC(C)C
Solvent: C1CCOC1
Product: CCCC[Sn](CCCC)(CCCC)COC(C)C
Temperature: -78 °C
Reaction time: 1.5 h

Procedure:
To a solution of 4.6 mL diisopropylamine in 40 mL of dry THF at −20° C. was added dropwise first 12.0 ml of 2.5 M butyllithium and then 8.1 ml of tributyltinhydride. After 10 min this solution was cooled to −78° C., and 3.25 g of chloromethyl isopropyl ether (Molina et al, 1982 Synthesis, 944) was added dropwise. After 10 min the cooling bath was removed and the reaction mixture was stirred at ambient temperature for 1.5 h. The mixture was poured onto water and extracted with hexanes and the extracts were dried over sodium sulfate and evaporated. The crude product was distilled (0.2 mm, 110-130° C.) to afford 7.8 g of tributyl (isopropoxymethyl)tin as a colorless liquid.
Reaction SMILES: [O:1]1[C:6]2[CH:7]=[CH:8][C:9]([CH2:11][N:12]([CH:20]3[CH2:25][CH2:24][N:23]([CH2:26][CH2:27][N:28]4[C:37]5[C:32](=[C:33]([NH:38][C:39]([NH:41][CH2:42][CH3:43])=[O:40])[CH:34]=[CH:35][CH:36]=5)[CH:31]=[CH:30][C:29]4=[O:44])[CH2:22][CH2:21]3)C(=O)OC(C)(C)C)=[CH:10][C:5]=2[O:4][CH2:3][CH2:2]1.[ClH:45].O1CCOCC1>O1CCOCC1>[ClH:45].[CH2:42]([NH:41][C:39]([NH:38][C:33]1[CH:34]=[CH:35][CH:36]=[C:37]2[C:32]=1[CH:31]=[CH:30][C:29](=[O:44])[N:28]2[CH2:27][CH2:26][N:23]1[CH2:24][CH2:25][CH:20]([NH:12][CH2:11][C:9]2[CH:8]=[CH:7][C:6]3[O:1][CH2:2][CH2:3][O:4][C:5]=3[CH:10]=2)[CH2:21][CH2:22]1)=[O:40])[CH3:43]
Reactant: CCNC(=O)Nc1cccc2c1ccc(=O)n2CCN1CCC(N(Cc2ccc3c(c2)OCCO3)C(=O)OC(C)(C)C)CC1
Agent: Cl
Solvent: C1COCCO1
Product: CCNC(=O)Nc1cccc2c1ccc(=O)n2CCN1CCC(NCc2ccc3c(c2)OCCO3)CC1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To 55 mg of tert-butyl (2,3-dihydro-1,4-benzodioxin-6-ylmethyl)(1-(2-(5-(3-ethylureido)-2-oxoquinolin-1(2H)-yl)ethyl)piperidin-4-yl)carbamate, 3 mL of 1,4-dioxane and 1 mL of 4 mol/L hydrogen chloride/1,4-dioxane were added, and stirred at room temperature for 3 hours. The resulting solid was filtered to give 26 mg of 1-ethyl-3-(1-(2-(4-((2,3-dihydro-1,4-benzodioxin-6-ylmethyl)amino)piperidin-1-yl)ethyl)quinolin-2(1H)-on-5-yl)urea hydrochloride as a yellow solid.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH2:9][C:10]([NH:12][CH3:13])=[O:11])=[CH:4][C:3]=1[CH:14]=O.[CH:16]1([NH2:19])[CH2:18][CH2:17]1.[BH4-].[Na+]>CO>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH2:9][C:10]([NH:12][CH3:13])=[O:11])=[CH:4][C:3]=1[CH2:14][NH:19][CH:16]1[CH2:18][CH2:17]1
Reactant: NC1CC1
Reactant: CNC(=O)CCc1ccc(Cl)c(C=O)c1
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Product: CNC(=O)CCc1ccc(Cl)c(CNC2CC2)c1
Temperature: 25 °C
Reaction time: 2 h
Yield: 75.3 %

Procedure:
A mixture of 3-(4-chloro-3-formyl-phenyl)-N-methyl-propionamide (2.30 g, 10.2 mmol) and cyclopropylamine (1.09 mL, 15.3 mmol) in MeOH (109 mL) was stirred for 2 h. Cyclopropylamine (0.364 mL, 5.09 mmol) was added, and the mixture was heated to reflux for 4 h. The mixture was allowed to cool down to rt, and NaBH4 (771 mg, 20.4 mmol) was added by portion. The mixture was stirred for 2 h at rt. The solvents were removed under reduced pressure, and the resulting oil was diluted with EtOAc (500 mL). The resulting mixture was washed with aq. sat. NaHCO3 and brine. The org. layer was dried over MgSO4, filtered, and the solvents were removed under reduced pressure. Purification of the crude by FC (MeOH/CH2Cl2 5:95) yielded the title compound (2.05 g, 75%). LC-MS: tR=0.58 min; ES+: 267.39.
Reaction SMILES: [CH3:1]CCCCC.[H-].[Na+].[Br:9][C:10]1[CH:11]=[C:12]([CH:16]=[CH:17][C:18]=1[CH3:19])[C:13]([OH:15])=[O:14]>CN(C=O)C.CCOC(C)=O>[Br:9][C:10]1[CH:11]=[C:12]([CH:16]=[CH:17][C:18]=1[CH3:19])[C:13]([O:15][CH3:1])=[O:14]
Reactant: CCCCCC
Reactant: Cc1ccc(C(=O)O)cc1Br
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: COC(=O)c1ccc(C)c(Br)c1
Temperature: 25 °C
Yield: 63 %

Procedure:
To a mixture of hexane washed 60% disp. NaH (2.28 g, 57 mmol) in DMF (250 mL), 0 C., was added 3-bromo-4-methylbenzoic acid (10.03 g, 46.6 mmol) After 30 min, the reaction was warmed to room temperature, diluted with EtOAc (1.25 L) and washed with H2O (5×250 mL). The organic layer was MgSO4 dried and concentrated. The residue was chromatographed (˜375 g silica, 10% EtOAc/CH2Cl2) to give the desired product as a solid (16.68 g, 63%); IR(CHCl3): 1260, 1294, 1437, 1721 cm−1; NMR(300 MHz, CDCl3): 2.46 (s, 3H); 3.92 (s, 3H); 7.31 (d, 1H, J=7.8 Hz); 7.88 (d, 1H, J=7.8 Hz); 8.21 (s, 1H); MS(FD): 228.0.
Reaction SMILES: [F:1][C:2]1[N:3]([C:7]([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[CH:4]=[CH:5][N:6]=1.[C:26]([Li])(C)([CH3:28])[CH3:27].C(Br)C=C.CCOCC>C1COCC1.CCCCC>[CH2:28]([C:5]1[N:6]=[C:2]([F:1])[N:3]([C:7]([C:14]2[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=2)([C:8]2[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=2)[C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[CH:4]=1)[CH:26]=[CH2:27]
Reactant: [Li]C(C)(C)C
Reactant: Fc1nccn1C(c1ccccc1)(c1ccccc1)c1ccccc1
Solvent: C=CCBr
Solvent: CCCCC
Solvent: CCOCC
Product: C=CCc1cn(C(c2ccccc2)(c2ccccc2)c2ccccc2)c(F)n1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of 2-fluoro-1-triphenylmethylimidazole (1.31 g.) in THF (22 ml.) at -70° under argon was added t-butyl lithium (4 ml. of a 2M solution in pentane). The red solution was stirred at -70° for 2 hours and then cuprous iodide (0.78 g.) added. The resulting dark red solution was stirred at -70° for 1 hour and then allyl bromide (1.8 ml.) added. The mixture was allowed to warm to ambient temperature over 18 hours and then poured into ether (150 ml.). The mixture was washed with saturated aqueous ammonium chloride (6×50 ml.), then brine (50 ml.), treated with charcoal and dried (MgSO4). The solution was evaporated to give 4-allyl-2-fluoro-1-triphenylmethylimidazole as a pale yellow solid, m.p. 136°-138°.
Reaction SMILES: [CH3:1][C@:2]1([NH:34]C(=O)OC(C)(C)C)[CH2:6][CH2:5][N:4]([C@@H:7]([C:12]2[CH:13]=[CH:14][C:15]3[N:16]([C:18]([C:21]4[CH:30]=[CH:29][C:28]5[C:23](=[C:24]([O:32][CH3:33])[CH:25]=[C:26]([F:31])[CH:27]=5)[N:22]=4)=[N:19][N:20]=3)[CH:17]=2)[C:8]([F:11])([F:10])[F:9])[CH2:3]1.Cl>C(Cl)Cl.O1CCOCC1>[CH3:1][C@:2]1([NH2:34])[CH2:6][CH2:5][N:4]([C@@H:7]([C:12]2[CH:13]=[CH:14][C:15]3[N:16]([C:18]([C:21]4[CH:30]=[CH:29][C:28]5[C:23](=[C:24]([O:32][CH3:33])[CH:25]=[C:26]([F:31])[CH:27]=5)[N:22]=4)=[N:19][N:20]=3)[CH:17]=2)[C:8]([F:10])([F:9])[F:11])[CH2:3]1
Reactant: COc1cc(F)cc2ccc(-c3nnc4ccc([C@H](N5CC[C@](C)(NC(=O)OC(C)(C)C)C5)C(F)(F)F)cn34)nc12
Agent: Cl
Solvent: ClCCl
Solvent: C1COCCO1
Product: COc1cc(F)cc2ccc(-c3nnc4ccc([C@H](N5CC[C@](C)(N)C5)C(F)(F)F)cn34)nc12
Reaction time: 2.5 h
Yield: 92.4 %

Procedure:
To a solution of tert-butyl (S)-3-methyl-1-((S)-2,2,2-trifluoro-1-(3-(6-fluoro-8-methoxyquinolin-2-yl)-[1,2,4]triazolo[4,3-a]pyridin-6-yl)ethyl)pyrrolidin-3-ylcarbamate (0.900 g, 1.57 mmol) in DCM (8 mL) was added 4M HCl in dioxane (2 mL) and the reaction stirred for 2.5 hours. The reaction was diluted DCM (100 mL) and washed with saturated Na2CO3 (25 mL), dried (MgSO4), filtered and concentrated under reduced pressure. The residue was purified by normal phase chromatography (5% [10% NH4OH]/DCM) to give (S)-3-methyl-1-((S)-2,2,2-trifluoro-1-(3-(6-fluoro-8-methoxyquinolin-2-yl)-[1,2,4]triazolo[4,3-a]pyridin-6-yl)ethyl)pyrrolidin-3-amine (0.690 g, 1.45 mmol, 92.8% yield) MS APCI (+) m/z 475 (M+1) detected.
Reaction SMILES: [Br:1][C:2]1[C:3]([Cl:10])=[C:4]([NH2:9])[C:5]([NH2:8])=[CH:6][CH:7]=1.[OH-].[Na+].[CH:13](O)=O>>[Br:1][C:2]1[CH:7]=[CH:6][C:5]2[NH:8][CH:13]=[N:9][C:4]=2[C:3]=1[Cl:10]
Reactant: Nc1ccc(Br)c(Cl)c1N
Reactant: O=CO
Agent: [Na+]
Agent: [OH-]
Product: Clc1c(Br)ccc2[nH]cnc12
Yield: 78 %

Procedure:
A mixture of 4-bromo-3-chloro-benzene-1,2-diamine (CASRN 1008361-80-5, 27 g, 0.1221 mol) and formic acid (80 mL) was heated to reflux for 1.5 h. After the completion of the reaction, 10% NaOH was added until the solution basic. The resulting solid was filtered and washed well with water then dried over night over suction to afford 22 g (78%) of 5-bromo-4-chloro-1H-benzoimidazole (128) as pale yellow solid which was used without additional purification.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][CH:10]=1)[CH:5]([Cl:7])[Cl:6].[OH-].[Na+].C(Cl)(Cl)(Cl)[Cl:14]>CCCCCCCCCCCC[N+](C)(C)C.[Cl-]>[CH3:1][C:2]1[CH:3]=[C:4]([C:5]([Cl:14])([Cl:7])[Cl:6])[CH:8]=[CH:9][CH:10]=1
Reactant: ClC(Cl)(Cl)Cl
Reactant: Cc1cccc(C(Cl)Cl)c1
Agent: CCCCCCCCCCCC[N+](C)(C)C
Agent: [Cl-]
Agent: [Na+]
Product: Cc1cccc(C(Cl)(Cl)Cl)c1
Yield: 101.3 %

Procedure:
70.0 gms of 3-methyl benzal chloride dissolved in 286.4 gms of carbon tetrachloride was charged into a reaction vessel with 2.67 gms of Aliquat 4 (dodecyltrimethylammonium chloride in alcohol). 192 gms of 50% aqueous sodium hydroxide was added and the mixture heated to reflux for a period of about 4 hours. During this period water was continuously removed from the reaction media using a Dean Stark Trap. After completion of the reaction, the mixture was filtered, water was added to the mixture, and the organic layer was separated by phase separation. The organic layer was stripped on a rotary evaporator to give 84.9 gms of a clear yellow oil. (Yield 93.4%).
Reaction SMILES: C1(C(C2C=CC=CC=2)[C@H](O)CC=C)C=CC=CC=1.[C:19]1([CH:25]([C:34]2[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=2)[C@@H:26]([O:30][CH2:31][CH:32]=[CH2:33])[CH2:27][CH:28]=[CH2:29])[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1>CO>[C:34]1([CH:25]([C:19]2[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=2)[C@H:26]([O:30][CH2:31][CH:32]=[CH2:33])[CH2:27][CH:28]=[CH2:29])[CH:35]=[CH:36][CH:37]=[CH:38][CH:39]=1
Reactant: C=CCO[C@@H](CC=C)C(c1ccccc1)c1ccccc1
Agent: C=CC[C@@H](O)C(c1ccccc1)c1ccccc1
Solvent: CO
Product: C=CCO[C@H](CC=C)C(c1ccccc1)c1ccccc1

Procedure:
(2R)-1,1-diphenyl-pent-4-en-2-ol 25b (0.42 g, 1.75 mmol) was reacted with allyl bromide (0.63 g, 5.25 mmol) (Procedure B) to yield (2R)-1,1-Diphenyl-2-Allyloxy-Pent-4-en 26b, 0.43 g (87%, [α]D=(−)20, c=1, MeOH). The 1HNMR and 13CNMR were identical with (2R)-1,1-diphenyl-2-alluloxy-pent-4-en shown above.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[C:4](I)[CH:3]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C(NC(C)C)(C)C.[CH2:36]([N:40]1[CH2:44][CH2:43][CH2:42][C@H:41]1[CH3:45])[CH2:37][C:38]#[CH:39]>C([O-])(=O)C.[Pd+2].C([O-])(=O)C.[Cu]I.CC#N>[Br:1][C:2]1[CH:7]=[CH:6][C:5]2[O:8][C:38]([CH2:37][CH2:36][N:40]3[CH2:44][CH2:43][CH2:42][C@H:41]3[CH3:45])=[CH:39][C:4]=2[CH:3]=1
Reactant: Oc1ccc(Br)cc1I
Reactant: C#CCCN1CCC[C@H]1C
Agent: [Cu]I
Agent: [Pd+2]
Agent: CC(=O)[O-]
Solvent: CC#N
Solvent: CC(C)NC(C)C
Product: C[C@@H]1CCCN1CCc1cc2cc(Br)ccc2o1
Temperature: 25 °C
Reaction time: 72 h
Yield: 26 %

Procedure:
4-Bromo-2-iodophenol (2.99 g, 90% pure, 9 mmol), palladium (II) acetate (112 mg, 0.50 mmol), triphenylphosphine (262 mg, 1.0 mmol), copper(I) iodide (571 mg, 3.0 mmol), and diisopropylamine (14 mL, 100 mmol) were dissolved into a 0.09 M MeCN solution of (R)-1-but-3-ynyl-2-methylpyrrolidine (120 mL, 10.8 mmol) and stirred at room temperature three days, then at 80° C. overnight. The reaction mixture was cooled to room temperature, concentrated, and chromatographed through a short column of silica with 2:1 hexanes/CH2Cl2 followed by a 0 to 1% gradient of MeOH/CH2Cl2. The appropriate fractions were concentrated, and the residue extracted with MeOH. The extracts were concentrated and partitioned between CH2Cl2 and 1 M aqueous Na2CO3, worked up as usual, dried (Na2SO4), and concentrated to provide the title compound as a dark red syrup (26% yield).
Reaction SMILES: [OH:1][CH2:2][CH2:3][NH:4][CH2:5][CH2:6][OH:7].[CH2:8](Br)[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1.C(=O)([O-])[O-].[K+].[K+].O>CN(C)C=O>[OH:1][CH2:2][CH2:3][N:4]([CH2:5][CH2:6][OH:7])[CH2:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1
Reactant: BrCc1ccccc1
Reactant: OCCNCCO
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: OCCN(CCO)Cc1ccccc1
Temperature: 25 °C
Reaction time: 21 h
Yield: 75 %

Procedure:
Bis(2-hydroxyethyl)amine (5 g) was dissolved in N,N-dimethylformamide (100 ml), added with benzyl bromide (6.52 ml) and potassium carbonate (8.657 g) and stirred at room temperature for 21 hours. The reaction mixture was added with water (200 ml) and extracted twice with dichloromethane (200 ml). The organic layer was dried over anhydrous magnesium sulfate, and then the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (elution solvent: dichloromethane:methanol=20:1→10:1) to obtain 7.631 g of the title compound. Yield: 75%.