Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6]([C:9]2[CH:43]=[CH:42][C:12]3[N:13]([CH2:38][CH:39]4[CH2:41][CH2:40]4)[C:14]([CH2:16][O:17][CH2:18][C:19]4([C:32]5[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=5)[CH2:24][CH2:23][N:22]([C:25](OC(C)(C)C)=O)[CH2:21][CH2:20]4)=[N:15][C:11]=3[CH:10]=2)=[CH:5][CH:4]=1)#[N:2].C=O.C(O)=O>C(OCC)(=O)C>[CH:39]1([CH2:38][N:13]2[C:12]3[CH:42]=[CH:43][C:9]([C:6]4[CH:7]=[CH:8][C:3]([C:1]#[N:2])=[CH:4][CH:5]=4)=[CH:10][C:11]=3[N:15]=[C:14]2[CH2:16][O:17][CH2:18][C:19]2([C:32]3[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=3)[CH2:24][CH2:23][N:22]([CH3:25])[CH2:21][CH2:20]2)[CH2:41][CH2:40]1
Reactant: CC(C)(C)OC(=O)N1CCC(COCc2nc3cc(-c4ccc(C#N)cc4)ccc3n2CC2CC2)(c2ccccc2)CC1
Agent: C=O
Solvent: O=CO
Solvent: CCOC(C)=O
Product: CN1CCC(COCc2nc3cc(-c4ccc(C#N)cc4)ccc3n2CC2CC2)(c2ccccc2)CC1
Temperature: 70 °C
Yield: 50 %

Procedure:
tert-Butyl 4-(((5-(4-cyanophenyl)-1-(cyclopropylmethyl)-1H-benzo[d]imidazol-2-yl)methoxy)methyl)-4-phenylpiperidine-1-carboxylate (23 mg, 0.04 mmol) was combined with aqueous formaldehyde (37%, 0.5 mL, 168 equiv) and formic acid (0.5 mL, 329 equiv) and heated at 70° C. for 64 h. At the end, after adjusting the pH of the reaction mixture to 6.0 extractive work up with ethyl acetate followed by evaporation of the organic layer in vacuo gave the crude product. The crude product was purified by preparative HPLC (HPLC method 12). Fractions containing the required product were combined and evaporated in vacuo. The residue obtained was purified by silica gel chromatography using a linear gradient of 1.2%-20% methanol in dichloromethane to obtain 12 mg (50% yield) as a TFA salt. 1H-NMR (500 MHz, CD3OD) δ 7.92 (s, 1H), 7.86 (d, JAB=8.5 Hz, 2 H), 7.81 (d, JAB=8.5 Hz, 2 H), 7.67-7.65 (m, 1 H), 7.63 (d, J=8.2 Hz, 1 H), 7.39-7.32 (m, 4 H), 7.24 (m, 1 H), 4.75 (s, 2 H), 3.84 (d, J=6.7 Hz, 2 H), 3.60 (s, 2 H), 3.08 (m, 2 H), 2.67 (m, 2 H), 2.55 (s, 3 H), 2.42 (m, 2 H), 2.12 (m, 2 H), 1.05 (m, 1 H), 0.51-0.48 (m, 2 H), 0.35-0.32 (m, 2 H). 13C NMR (126 MHz, CD3OD) δ 151.8, 146.5, 142.2, 136.1, 134.4, 132.8, 128.8, 128.0, 127.2, 126.8, 123.0, 118.9, 117.6, 111.6, 110.4, 65.5, 51.5, 43.7, 40.4, 30.6, 11.0, 3.6. Mass Spec.: 491(MH)+.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([Cl:8])[C:3]=1[CH2:9][C:10]([OH:12])=O.CN(C=O)C.S(Cl)([Cl:20])=O>C1(C)C=CC=CC=1>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([Cl:8])[C:3]=1[CH2:9][C:10]([Cl:20])=[O:12]
Reactant: O=S(Cl)Cl
Reactant: O=C(O)Cc1c(Cl)cccc1Cl
Solvent: Cc1ccccc1
Solvent: CN(C)C=O
Product: O=C(Cl)Cc1c(Cl)cccc1Cl
Temperature: 25 °C
Reaction time: 12 h

Procedure:
To a mixture of 2,6-dichlorophenyl acetic acid (100 g, 487 mmol) and DMF (1.5 mL) in toluene (600 mL) was added thionyl chloride (116 g, 974 mmol). The resulting mixture was stirred at rt. After 12 h, the solution was concentrated to provide 2,6-dichloro-phenylacetyl chloride as colorless oil. MS (ESI): mass calcd. for C8H5Cl3O, 221.94; m/z found, 223.0 [M+H]+. 1H NMR (CDCl3): 7.33 (d, J=8.1 Hz, 2H), 7.29-7.24 (m, 1H), 4.56 (s, 2H). A suspension of the crude 2,6-dichloro-phenylacetyl chloride and 4,6-dichloro-pyrimidin-5-ylamine (76 g, 463 mmol) was heated neat to 130° C. After 1 h, the resulting solid was cooled, collected by filtration, and washed with cold MeOH (400 mL) to provide the title compound as a solid (135 g, 84%). MS (ESI): mass calcd. for C12H7Cl4N3O, 348.9; m/z found, 350.0 [M+H]+. 1H NMR ((CD3)2SO): 10.59 (s, 1H), 8.86 (s, 1H), 7.50 (d, J=8.0 Hz, 2H), 7.37-7.33 (m, 1H), 4.13 (s, 2H).
Reaction SMILES: [Na].[C:2](=O)([O:5]C)[O:3][CH3:4].[CH2:8]([N:10]1[C:18]2[C:13](=[CH:14][C:15]([C:19]3([CH3:24])[O:23][CH2:22][CH2:21][O:20]3)=[CH:16][CH:17]=2)[CH2:12][C:11]1=[O:25])[CH3:9]>CO>[CH3:4][O:3][C:2]([CH:12]1[C:13]2[C:18](=[CH:17][CH:16]=[C:15]([C:19]3([CH3:24])[O:20][CH2:21][CH2:22][O:23]3)[CH:14]=2)[N:10]([CH2:8][CH3:9])[C:11]1=[O:25])=[O:5]
Reactant: CCN1C(=O)Cc2cc(C3(C)OCCO3)ccc21
Reactant: COC(=O)OC
Agent: [Na]
Solvent: CO
Product: CCN1C(=O)C(C(=O)OC)c2cc(C3(C)OCCO3)ccc21

Procedure:
Sodium (2.68 g, 112 mmol) was added to methanol (110 mL) in a 3-neck flask fitted with a reflux condenser, while controlling the temperature with an ice-bath. After dissolution dimethyl carbonate (9.4 mL, 112 mmol) was added followed by 1-ethyl-5-(2-methyl-[1,3]dioxolan-2-yl)-1,3-dihydro-indol-2-one (U.S. Pat. No. 4,686,224, 9.2 g, 37 mmol). The mixture was heated to reflux for 70 hours, then cooled, concentrated to about 25 mL, diluted with water, acidified to pH 7 with acetic acid and extracted twice with ethyl acetate. The combined extracts were washed with brine, dried over magnesium sulfate and concentrated in vacuo to an oily solid which was triturated in isopropyl ether, collected and dried (7.9 g, 70%).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)=[C:4]([CH2:14][CH2:15]O)[CH:3]=1.P(Br)(Br)[Br:18].O>C1(C)C=CC=CC=1>[Br:18][CH2:15][CH2:14][C:4]1[CH:3]=[C:2]([Cl:1])[CH:7]=[CH:6][C:5]=1[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1
Reactant: OCCc1cc(Cl)ccc1-c1ccccc1
Reactant: BrP(Br)Br
Solvent: O
Solvent: Cc1ccccc1
Product: Clc1ccc(-c2ccccc2)c(CCBr)c1
Reaction time: 20 h
Yield: 119.4 %

Procedure:
To a solution, maintained at 5° C., of 710 mg (3.05 mmol) of 2-(4-chlorobiphenyl-2-yl)ethanol, prepared in Example 51, in 10 ml of toluene are added 97 μl (1.02 mmol) of PBr3, and the reaction medium is allowed to return to room temperature. After stirring for 20 hours, the reaction medium is poured into 100 ml of water and extracted with ethyl acetate. The organic phase is washed with water, dried over Na2SO4 and then concentrated under vacuum to give a yellow liquid, which is purified by flash chromatography on a column of silica, in dichloromethane. 360 mg of a pale yellow oil are obtained.
Reaction SMILES: [C:1]1([CH2:7][CH2:8][CH2:9][NH:10][C:11](=[O:25])[C@H:12]([CH2:14][CH2:15][CH2:16][NH:17]C(OC(C)(C)C)=O)[NH2:13])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C(O)(=O)C.[C:30]1([CH2:36][CH:37]=O)[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1.C([BH3-])#N.[Na+]>CO>[C:1]1([CH2:7][CH2:8][CH2:9][NH:10][C:11](=[O:25])[C@H:12]([CH2:14][CH2:15][CH2:16][NH2:17])[NH:13][CH2:37][CH2:36][C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=2)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: O=CCc1ccccc1
Reactant: CC(C)(C)OC(=O)NCCC[C@H](N)C(=O)NCCCc1ccccc1
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CO
Product: NCCC[C@H](NCCc1ccccc1)C(=O)NCCCc1ccccc1
Reaction time: 0.5 h
Yield: 86.8 %

Procedure:
A cold solution (0° C.) of the above amine (3 g, 8.6 mmol), in methanol (20 ml), was treated sequentially with acetic acid (345 μl, 6 mmol) and phenylacetaldehyde (1.2 ml, 10 mmol). Then a solution of sodium cyanoborohydride (2.7 g, 43 mmol) in methanol (10 ml) was added to the mixture slowly. The reaction was stirred for additional 30 minutes and the solvent was removed in vacuo. The residue was dissolved in ethyl acetate and washed with aqueous sodium bicarbonate, and purified by chromatography (silica gel, hexane/ethyl acetate) to afford Nα-(phenethyl)ornithine 3-phenylpropylamide (2.64 g): 1H NMR (400 MHz, CD3OD) δ1.4 (s, 9H), 1.45-1.8 (m, 6H), 2.6 (t, J=6.4 Hz, 2H), 2.65-2.8 (m, 4H), 3.02-3.2 (m, 5H), and 7.1-7.3 (m, 10H).
Reaction SMILES: FC(F)(F)C(O)=O.C(OC(=O)[NH:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=1[N:21]1[C:25](=[O:26])[NH:24][C:23]([CH:27]([C:41]2[CH:46]=[C:45]([CH2:47][CH3:48])[CH:44]=[C:43]([O:49][CH2:50][C:51](=[O:55])[N:52]([CH3:54])[CH3:53])[C:42]=2[F:56])[NH:28][C:29]2[CH:34]=[CH:33][C:32]([C:35]3[N:39]=[C:38]([CH3:40])[O:37][N:36]=3)=[CH:31][CH:30]=2)=[N:22]1)(C)(C)C>ClCCl>[NH2:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=1[N:21]1[C:25](=[O:26])[NH:24][C:23]([CH:27]([NH:28][C:29]2[CH:30]=[CH:31][C:32]([C:35]3[N:39]=[C:38]([CH3:40])[O:37][N:36]=3)=[CH:33][CH:34]=2)[C:41]2[C:42]([F:56])=[C:43]([CH:44]=[C:45]([CH2:47][CH3:48])[CH:46]=2)[O:49][CH2:50][C:51]([N:52]([CH3:54])[CH3:53])=[O:55])=[N:22]1
Reactant: CCc1cc(OCC(=O)N(C)C)c(F)c(C(Nc2ccc(-c3noc(C)n3)cc2)c2nn(-c3ccccc3NC(=O)OC(C)(C)C)c(=O)[nH]2)c1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CCc1cc(OCC(=O)N(C)C)c(F)c(C(Nc2ccc(-c3noc(C)n3)cc2)c2nn(-c3ccccc3N)c(=O)[nH]2)c1
Temperature: 25 °C
Reaction time: 4 h
Yield: 86.7 %

Procedure:
After adding 2 ml of trifluoroacetic acid to a solution of 0.135 g of [2-(3-{(3-dimethylcarbamoylmethoxy-5-ethyl-2-fluorophenyl)-[4-(5-methyl-[1,2,4]oxadiazol-3-yl)phenylamino]methyl}-5-oxo-4,5-dihydro-1H-[1,2,4]triazol-1-yl)phenyl]carbamic acid t-butyl ester in 10 ml of dichloromethane, the reaction mixture was stirred at room temperature for 4 hours, and the solvent was removed under reduced pressure. Next, 50 ml of ethyl acetate and 5 ml of 5% aqueous potassium carbonate were added to the residue, and the organic layer was washed with 20 ml of water and 20 ml of saturated aqueous sodium chloride in that order. The aqueous layer was extracted with 50 ml of ethyl acetate, and then the organic layers were combined and dried over anhydrous magnesium sulfate, the desiccating agent was filtered off and the filtrate was concentrated under reduced pressure. The title compound (0.100 g) was obtained as a white solid.
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: CCC(C)=O
Solvent: 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: [NH2:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:7]2[C:3]=1[C:4](=[O:20])[N:5]([CH:12]1[CH2:17][CH2:16][C:15](=[O:18])[NH:14][C:13]1=[O:19])[C:6]2=[O:11].[Cl:21][CH2:22][C:23](Cl)=[O:24]>C1COCC1>[O:19]=[C:13]1[CH:12]([N:5]2[C:4](=[O:20])[C:3]3[C:7](=[CH:8][CH:9]=[CH:10][C:2]=3[NH:1][C:23](=[O:24])[CH2:22][Cl:21])[C:6]2=[O:11])[CH2:17][CH2:16][C:15](=[O:18])[NH:14]1
Reactant: Nc1cccc2c1C(=O)N(C1CCC(=O)NC1=O)C2=O
Reactant: O=C(Cl)CCl
Solvent: C1CCOC1
Product: O=C1CCC(N2C(=O)c3cccc(NC(=O)CCl)c3C2=O)C(=O)N1
Yield: 95.5 %

Procedure:
To a stirred suspension of 4-amino-2-(2,6-dioxo(3-piperidyl))isoindoline-1,3-dione (1.37 g, 5.00 mmol) in THF (30 ml) was added chloroacetyl chloride-(0.62 g, 5.5 mmol). The mixture was heated to reflux for 30 minutes. The solvent was evaporated in vacuo and the resulting solid was slurried in diethyl ether (20 ml) and filtered to give 1.67 g (96%) of product as an off-white solid: 1H NMR (DMSO-d6) δ 11.18 (s, 1H), 10.31 (s, 1H), 8.54 (d, J=8.4 Hz, 1H), 7.88 (t, J=7.7 Hz, 1H), 7.68 (d, J=7.3 Hz, 1H), 5.17 (dd, J=5.2 and 12.7 Hz, 1H), 4.54 (s, 2H), 2.90-2.85 (m, 1H), 2.65-2.51 (m, 2H), 2.10-2.06 (m, 1H).
Reaction SMILES: C(O)=O.[CH3:4][O:5][C:6]1[CH:7]=[C:8]([CH:11]=[CH:12][C:13]=1[O:14][CH3:15])[CH:9]=O.[CH3:16][C:17]1([CH3:25])[O:24][C:22](=[O:23])[CH2:21][C:19](=[O:20])[O:18]1.Cl>C(N(CC)CC)C>[CH3:4][O:5][C:6]1[CH:7]=[C:8]([CH:11]=[CH:12][C:13]=1[O:14][CH3:15])[CH2:9][CH:21]1[C:22](=[O:23])[O:24][C:17]([CH3:25])([CH3:16])[O:18][C:19]1=[O:20]
Reactant: COc1ccc(C=O)cc1OC
Reactant: CC1(C)OC(=O)CC(=O)O1
Agent: Cl
Solvent: O=CO
Solvent: CCN(CC)CC
Product: COc1ccc(CC2C(=O)OC(C)(C)OC2=O)cc1OC
Temperature: 25 °C
Reaction time: 18 h
Yield: 88.2 %

Procedure:
Under ice-cooling, to formic acid (20 mL) was added dropwise triethylamine (29.6 mL). Then, 3,4-dimethoxybenzaldehyde (9.22 g) and Meldrum's acid (8.00 g) were added under ice-cooling, and the mixture was stirred at room temperature for 18 hr. The reaction mixture was poured into a mixture of ice (80 g) and 1 mol/L hydrochloric acid (50 mL), and the precipitate was collected by filtration to give the title compound (14.4 g) as a white solid.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[NH:9][CH:10]=[CH:11][C:12]=2[C:13]2[CH:18]=[CH:17][C:16]([F:19])=[CH:15][CH:14]=2)=[CH:4][CH:3]=1.O.[F:21][C:22]([F:26])([F:25])[CH:23]=[O:24]>C1(C)C=CC=CC=1>[F:19][C:16]1[CH:17]=[CH:18][C:13]([C:12]2[CH:11]=[C:10]([CH:23]([C:22]([F:26])([F:25])[F:21])[OH:24])[NH:9][C:8]=2[C:5]2[CH:6]=[CH:7][C:2]([F:1])=[CH:3][CH:4]=2)=[CH:14][CH:15]=1
Reactant: Fc1ccc(-c2cc[nH]c2-c2ccc(F)cc2)cc1
Reactant: O=CC(F)(F)F
Solvent: Cc1ccccc1
Solvent: O
Product: OC(c1cc(-c2ccc(F)cc2)c(-c2ccc(F)cc2)[nH]1)C(F)(F)F
Yield: 53.8 %

Procedure:
A mixture of 2.55 g (0.01 mole) of 2,3-bis(4-fluorophenyl)-1H-pyrrole and 1.3 g (0.011 mole) of trifluoroacetaldehyde hydrate in 75 ml toluene was heated at reflux for 3.5 hours. The mixture was concentrated on a rotary evaporator. The residue was purified by chromatography on silica gel to give 1.9 g of product, m.p. 121°-122°.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([S:8](Cl)(=[O:10])=[O:9])[CH:5]=[CH:6][CH:7]=1.[F-:12].[K+]>C(#N)C.C1OCCOCCOCCOCCOCCOC1>[Br:1][C:2]1[CH:3]=[C:4]([S:8]([F:12])(=[O:10])=[O:9])[CH:5]=[CH:6][CH:7]=1
Reactant: O=S(=O)(Cl)c1cccc(Br)c1
Reactant: [F-]
Agent: C1COCCOCCOCCOCCOCCO1
Agent: [K+]
Solvent: CC#N
Product: O=S(=O)(F)c1cccc(Br)c1
Temperature: 25 °C
Reaction time: 18 h
Yield: 80.9 %

Procedure:
To a stirred solution of 3-bromophenylsulfonyl chloride (5 g, 0.0196 mol) in acetonitrile (20 ml) was added potassium fluoride (2.27 g, 0.0391 mol) followed by 18-crown-6 ether (0.08 g) and the reaction stirred at room temperature for 18 h. The reaction mixture was then washed with water (60 ml), extracted with ethyl acetate (3×80 ml) and the combined organic extracts dried (Na2SO4). Solvents were evaporated in vacuo to give a yellow oil (3.79 g, 81%).
Reaction SMILES: [S:1](=[O:4])(=[O:3])=[O:2].O1CCOCC1.S(=O)(=O)=O.[CH2:15]([OH:19])[CH:16]([CH3:18])[CH3:17]>ClC(Cl)C>[CH2:15]([O:19][S:1](=[O:3])(=[O:2])[OH:4])[CH:16]([CH3:18])[CH3:17]
Reactant: O=S(=O)=O
Reactant: CC(C)CO
Solvent: C1COCCO1
Solvent: CC(Cl)Cl
Product: CC(C)COS(=O)(=O)O

Procedure:
609 g sulfur trioxide-dioxane addition product, which contained 143.9 g (1.8 mols) sulfur trioxide and was dissolved in 400 g dichloroethane, was reacted with 137.1 g (1.85 mols) isobutanol, and a solution of sulfuric acid monoisobutylester in dichloroethane was obtained. 66 g of this solution, which contained 49 g (0.32 mol) sulfuric acid monoisobutylester, was added dropwise within 1 hour to 59.5 g (0.33 mol) dichlorophenylphosphane. The whole was initially heated for a short while to 30° C. and then cooled with water to maintain the reaction temperature at 20° C. Next, the reaction mixture was stirred for 4 hours at room temperature, stripped under a vacuum of 1 mm mercury and at a temperature of up to 30° C. 79 g of a brown, medium-viscous crude product was obtained. 31P-NMR-spectroscopy indicated that 41% of the phosphorus used was present in the crude product in the form of benzenephosphonic acid isobutylester chloride.
Reaction SMILES: [F:1][C:2]1([F:11])[CH2:7][CH2:6][C:5]([CH2:9][OH:10])([CH3:8])[CH2:4][CH2:3]1.C(=O)([O-])[O-].[Cs+].[Cs+].[Cl:18][C:19]1[C:20](F)=[CH:21][C:22]([F:32])=[C:23]([CH:31]=1)[C:24]([O:26][C:27]([CH3:30])([CH3:29])[CH3:28])=[O:25]>CS(C)=O.C(OCC)(=O)C>[Cl:18][C:19]1[C:20]([O:10][CH2:9][C:5]2([CH3:8])[CH2:4][CH2:3][C:2]([F:11])([F:1])[CH2:7][CH2:6]2)=[CH:21][C:22]([F:32])=[C:23]([CH:31]=1)[C:24]([O:26][C:27]([CH3:28])([CH3:29])[CH3:30])=[O:25]
Reactant: CC1(CO)CCC(F)(F)CC1
Reactant: CC(C)(C)OC(=O)c1cc(Cl)c(F)cc1F
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CCOC(C)=O
Solvent: CS(C)=O
Product: CC1(COc2cc(F)c(C(=O)OC(C)(C)C)cc2Cl)CCC(F)(F)CC1
Temperature: 70 °C
Reaction time: 16 h
Yield: 50.6 %

Procedure:
A mixture of (4,4-difluoro-1-methylcyclohexyl)methanol (3.05 g, 18.56 mmol)(PCT Int. Appl., WO2012025857, 2012), cesium carbonate (12.09 g, 37.12 mmol), and tert-butyl 5-chloro-2,4-difluorobenzoate (6.0 g, 24.13 mmol) in dimethylsulfoxide (70 mL) was stirred at 70° C. for 16 hours, cooled to ambient temperature and diluted with ethyl acetate (150 mL); washed with water (2×300 mL), brine (150 mL); dried over anhydrous magnesium sulfate, filtered, and concentrated in vacuo. Purification of the residue by column chromatography eluting with a gradient of ethyl acetate in hexanes (0-5%) afforded the title compound (3.69 g, 51%) as colorless oil: MS (ES+) m/z 393.1 (M+1).
Reaction SMILES: [NH2:1][C:2]1[CH:23]=[CH:22][C:5]([O:6][C:7]2[CH:12]=[CH:11][N:10]=[C:9]([NH2:13])[C:8]=2[C:14]#[C:15][C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][N:17]=2)=[C:4]([F:24])[CH:3]=1.[F:25][C:26]1[CH:31]=[CH:30][C:29]([CH2:32][C:33]([N:35]=[C:36]=[O:37])=[O:34])=[CH:28][CH:27]=1.COC1C=CC(CNC2N=CN=C(OC3C=CC(NC(NC(=O)CC4C=CC(F)=CC=4)=O)=CC=3F)C=2)=CC=1.C(O)(C(F)(F)F)=O.[ClH:83]>>[ClH:83].[ClH:83].[NH2:13][C:9]1[C:8]([C:14]#[C:15][C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][N:17]=2)=[C:7]([O:6][C:5]2[CH:22]=[CH:23][C:2]([NH:1][C:36]([NH:35][C:33](=[O:34])[CH2:32][C:29]3[CH:30]=[CH:31][C:26]([F:25])=[CH:27][CH:28]=3)=[O:37])=[CH:3][C:4]=2[F:24])[CH:12]=[CH:11][N:10]=1
Reactant: O=C=NC(=O)Cc1ccc(F)cc1
Reactant: Nc1ccc(Oc2ccnc(N)c2C#Cc2ccccn2)c(F)c1
Agent: COc1ccc(CNc2cc(Oc3ccc(NC(=O)NC(=O)Cc4ccc(F)cc4)cc3F)ncn2)cc1
Agent: Cl
Solvent: O=C(O)C(F)(F)F
Product: Nc1nccc(Oc2ccc(NC(=O)NC(=O)Cc3ccc(F)cc3)cc2F)c1C#Cc1ccccn1
Yield: 40 %

Procedure:
The title compound was prepared from 4-(4-amino-2-fluorophenoxy)-3-(2-(pyridin-2-yl)ethynyl)pyridin-2-amine (25 mg, 0.078 mmol) and a 0.3 M solution of 2-(4-fluorophenyl)acetyl isocyanate in toluene (Compound D of Example 11, 0.26 mL, 0.078 mmol) in the same manner as Step E of Example 11. The crude product was prepared by preparative HPLC (Column B). The TFA salt was converted to the hydrochloride in the same manner as in Step E of Example 36 to give the title compound (18 mg, 40%) as a brown solid. 1H NMR (DMSO-d6) δ 11.06 (s, 1H), 10.63 (s, 1H), 8.62 (d, 1H, J=4.6 Hz), 8.23 (s, 1H), 7.99 (d, 1H, J=7.1 Hz), 7.94-7.84 (m, 3H), 7.87-7.76 (m, 1H), 7.51-7.42 (m, 3H), 7.39-7.32 (m, 2H), 7.21-7.13 (m, 2H), 6.30 (d, 1H, J=7.1 Hz), 3.74 (s, 2H) MS (ESI+): m/z 498.11 (M+H)+.
Reaction SMILES: C([Mg]Cl)(C)(C)C.CO[C:9](=[O:34])[CH2:10][C@H:11]([O:23][C:24](=[O:33])[CH:25](Br)[CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH3:31])[CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH3:22].C1COCC1.C([Mg]Cl)(C)(C)C.C1COCC1>C(OCC)(=O)C>[CH2:26]([C:25]1[C:24](=[O:33])[O:23][C@H:11]([CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH3:22])[CH2:10][C:9]=1[OH:34])[CH2:27][CH2:28][CH2:29][CH2:30][CH3:31]
Reactant: CCCCCCCCCCC[C@H](CC(=O)OC)OC(=O)C(Br)CCCCCC
Agent: CC(C)(C)[Mg]Cl
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: CCCCCCCCCCC[C@@H]1CC(O)=C(CCCCCC)C(=O)O1
Temperature: 0 °C
Yield: 78.5 %

Procedure:
In a 500 mL 3-necked round bottom flask fitted with a Claisen head with N2 inlet, a West condenser, a thermocouple-J-KEM controller and an addition funnel was added a solution of tert-butylmagnesium chloride (341 mL of a 1.0 M solution, 341 mmole, 3 equiv.) at about 60° C. Methyl-(R)-3-(2′-bromo-1′-oxooctyloxy)tetradecanoate (52.6.0 g, 113.5 mmole, 1 equiv.) (“bromodiester”) and 25 mL of dry THF were added to an addition funnel. The bromodiester mixture was slowly added to the t-BuMgCl/THF mixture at reflux over about one hour. The reaction mixture was sampled at 1 and 2 hours at about 60° C. (resulting in 90 and 91% area normalized gas chromatography (AN GC) analysis, respectively). After 2 hours the resulting reaction mixture was cooled and concentrated on a roto-evaporator to about ⅓ to about ½ the original volume. The resulting syrupy mixture was taken up in about 250 mL of toluene (or an ether, such as methyl tert-butyl ether and the like; a hydrocarbon, such as hexane, heptane, and the like; or mixtures thereof) and added to a mixture containing 250 mL of toluene, 75 mL of 10% HCl in a 1 L jacketed flask keeping the quenched solution below 30° C. The aqueous layer was removed. The organic layer washed one time with 50 mL of 1.0 N HCl solution. The aqueous layer was removed, the organic layer washed one time with 50 mL of water, dried over magnesium sulfate, filtered and concentrated. This resulted in a gel-like solid residue. The residue was dissolved in 250 mL of ethyl acetate at 40° C. The ethyl acetate was removed on the roto-evaporator. The resulting crude off-white solid (42.4 g) was slurried up in about 100 mL of hexane and cooled to 0° C., filtered and rinsed with 50 mL of cold hexane followed by another 25 mL of cold hexane. The isolated white solids were air dried under vacuum for about 1 to 2 hours resulting in 31.4 g of (6R)-3-hexyl-5,6-dihydro-4-hydroxy-6-undecyl-pyran-2-one (78.4% yield).
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([C:22]([OH:28])([CH3:27])[C:23]([F:26])([F:25])[F:24])[CH:5]=[CH:6][C:7]=1[N:8]1[CH2:13][CH2:12][N:11]([S:14]([C:17]2[S:18][CH:19]=[CH:20][CH:21]=2)(=[O:16])=[O:15])[CH2:10][CH2:9]1.C(NC(C)C)(C)C.C[Si](C)(C)[C:38]#[C:39][C:40]1([CH3:44])[CH2:43][O:42][CH2:41]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.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd].[Cu]I.CN(C=O)C>[F:24][C:23]([F:26])([F:25])[C:22]([C:4]1[CH:5]=[CH:6][C:7]([N:8]2[CH2:13][CH2:12][N:11]([S:14]([C:17]3[S:18][CH:19]=[CH:20][CH:21]=3)(=[O:16])=[O:15])[CH2:10][CH2:9]2)=[C:2]([C:38]#[C:39][C:40]2([CH3:44])[CH2:43][O:42][CH2:41]2)[CH:3]=1)([OH:28])[CH3:27]
Reactant: CC1(C#C[Si](C)(C)C)COC1
Reactant: CC(O)(c1ccc(N2CCN(S(=O)(=O)c3cccs3)CC2)c(Br)c1)C(F)(F)F
Agent: [Cu]I
Agent: [Pd]
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: CC(C)NC(C)C
Solvent: CN(C)C=O
Product: CC1(C#Cc2cc(C(C)(O)C(F)(F)F)ccc2N2CCN(S(=O)(=O)c3cccs3)CC2)COC1
Temperature: 100 °C
Reaction time: 12 h

Procedure:
A 20 mL vial was charged with 2-(3-bromo-4-(4-(thiophen-2-ylsulfonyl)piperazin-1-yl)phenyl)-1,1,1-trifluoro-2-propanol (0.500 g, 1.00 mmol), diisopropylamine (2.14 mL, 15.0 mmol), 2 mL of DMF, tetrakis(triphenylphosphine)palladium (0) (0.116 g, 0.100 mmol, Strem Chemical Inc, Newburyport, Mass.), copper (I) iodide (0.019 g, 0.100 mmol, Strem Chemical Inc, Newburyport, Mass.), and trimethyl((3-methyloxetan-3-yl)ethynyl)silane (0.506 g, 3.00 mmol, published PCT patent application no. WO2010030954). The vial was sealed and heated at 100° C. for 3 h. After that time, an additional 20 mol % of both tetrakis(triphenylphosphine)palladium (0) and copper (I) iodide were added and heating was continued for an additional 12 h. The mixture was concentrated and purified by column chromatography (40 g of silica, 0 to 60% EtOAc in hexanes) to give 1,1,1-trifluoro-2-(3-((3-methyl-3-oxetanyl)ethynyl)-4-(4-(2-thiophenylsulfonyl)-1-piperazinyl)phenyl)-2-propanol (0.150 g) as a mixture of two enantiomers.