Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl.[CH:2]([C:4]1[C:12]2[C:7](=[CH:8][C:9]([O:13][CH3:14])=[CH:10][CH:11]=2)[N:6]([C:15](OC(C)(C)C)=O)[N:5]=1)=[O:3].[CH2:22]1CCN2C(=NCCC2)C[CH2:23]1.ICCC>O1CCOCC1.CN(C=O)C>[CH3:14][O:13][C:9]1[CH:8]=[C:7]2[C:12]([C:4]([CH:2]=[O:3])=[N:5][N:6]2[CH2:15][CH2:22][CH3:23])=[CH:11][CH:10]=1
Reactant: COc1ccc2c(C=O)nn(C(=O)OC(C)(C)C)c2c1
Reactant: C1CCC2=NCCCN2CC1
Agent: Cl
Solvent: C1COCCO1
Solvent: CN(C)C=O
Solvent: CCCI
Product: CCCn1nc(C=O)c2ccc(OC)cc21
Temperature: 25 °C
Reaction time: 8 h
Yield: 63.6 %

Procedure:
A solution of 2 M HCl in dioxane (0.47 mL, 0.94 mmol) was added to a stirred, room temperature mixture of tert-butyl 3-formyl-6-methoxy-1H-indazole-1-carboxylate (50 mg, 0.18 mmol) in dioxane (1 mL) and the mixture was stirred at room temperature for 8 hours. It was concentrated and dried under vacuum. To the residue in DMF (1.0 mL), DBU (0.08 mL, 0.54 mmol) was added and the reaction mixture was stirred for 30 minutes. Then 1-iodopropane (0.09 mL, 0.90 mmol) was added and the solution was stirred for 16 hours at room temperature. The solvent was removed in vacuo and the residue was partitioned between ethyl acetate (20 mL) and saturated sodium bicarbonate (5 mL), washed with brine, dried over sodium sulfate, filtered and concentrated under reduced pressure to give the title compound (25 mg, 63% crude yield).
Reaction SMILES: [O:1]([C:8]1[N:13]=[CH:12][C:11]([C:14]([O:16]CC)=[O:15])=[CH:10][N:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.O.[OH-].[Li+]>O1CCCC1.CO.O>[O:1]([C:8]1[N:9]=[CH:10][C:11]([C:14]([OH:16])=[O:15])=[CH:12][N:13]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CCOC(=O)c1cnc(Oc2ccccc2)nc1
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Solvent: O
Solvent: C1CCOC1
Product: O=C(O)c1cnc(Oc2ccccc2)nc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 86.7 %

Procedure:
To a solution of ethyl 2-phenoxypyrimidine-5-carboxylate (400 mg, 1.6 mmol) in mixed solution of tetrahydrofuran/methanol/water=3:1:1 (4 mL) was added lithium hydroxide monohydrate (200 mg, 8.4 mmol). The mixture was stirred at room temperature for 2 hours. The suspension was concentrated in vacuo. To the residue, was added water (50 mL) and extracted with dichloromethane (2*50 mL). The combined organic phase was separated, dried by sodium sulfate, filtered and concentrated to give a residue. The residue was purified by column chromatography (silica gel, petroleum ether/ethyl acetate=5/1) to give the product 2-phenoxypyrimidine-5-carboxylic acid (300 mg, 79%) as pale solid.
Reaction SMILES: [CH:1]1([N:4]2[C:13]3[C:8](=[CH:9][C:10]([F:20])=[C:11]([N:14]4[CH2:19][CH2:18][NH:17][CH2:16][CH2:15]4)[CH:12]=3)[C:7](=[O:21])[C:6]([C:22]([OH:24])=[O:23])=[CH:5]2)[CH2:3][CH2:2]1.CS(O[CH2:30][C@@H:31]1[O:35][C:34](=[O:36])[N:33]([C:37]2[CH:38]=[CH:39][C:40]3[S:41][CH2:42][C:43](=[O:47])[NH:44][C:45]=3[N:46]=2)[CH2:32]1)(=O)=O>>[CH:1]1([N:4]2[C:13]3[C:8](=[CH:9][C:10]([F:20])=[C:11]([N:14]4[CH2:19][CH2:18][N:17]([CH2:30][C@H:31]5[O:35][C:34](=[O:36])[N:33]([C:37]6[CH:38]=[CH:39][C:40]7[S:41][CH2:42][C:43](=[O:47])[NH:44][C:45]=7[N:46]=6)[CH2:32]5)[CH2:16][CH2:15]4)[CH:12]=3)[C:7](=[O:21])[C:6]([C:22]([OH:24])=[O:23])=[CH:5]2)[CH2:2][CH2:3]1
Reactant: CS(=O)(=O)OC[C@H]1CN(c2ccc3c(n2)NC(=O)CS3)C(=O)O1
Reactant: O=C(O)c1cn(C2CC2)c2cc(N3CCNCC3)c(F)cc2c1=O
Product: O=C1CSc2ccc(N3C[C@@H](CN4CCN(c5cc6c(cc5F)c(=O)c(C(=O)O)cn6C5CC5)CC4)OC3=O)nc2N1

Procedure:
In analogy to Example 1, starting from 1-cyclopropyl-6-fluoro-1,4-dihydro-7-(1-piperazinyl)-4-oxo-3-quinoline carboxylic acid (commercial; 166 mg) and 6-[(5R)-5-[[(methylsulfonyl)oxy]methyl]-2-oxo-3-oxazolidinyl]-2H-pyrido[3,2-b]-1,4-thiazin-3(4H)-one (prepared in analogy to its (S) enantiomer described in WO 2010/041194; 180 mg), the title compound was obtained as a beige solid after CC (DCM/MeOH 9:1) and crystallization from EtOH.
Reaction SMILES: [OH:1][C:2]([CH:7]([F:9])[F:8])([CH3:6])[C:3](O)=[O:4].S(Cl)(Cl)=O.[NH2:14][C:15]1[CH:28]=[CH:27][C:18]([C:19]([C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)=[O:20])=[CH:17][CH:16]=1.Cl.C>CC(N(C)C)=O>[C:21]1([C:19]([C:18]2[CH:17]=[CH:16][C:15]([NH:14][C:3](=[O:4])[C:2]([OH:1])([CH3:6])[CH:7]([F:9])[F:8])=[CH:28][CH:27]=2)=[O:20])[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=1
Reactant: Nc1ccc(C(=O)c2ccccc2)cc1
Reactant: CC(O)(C(=O)O)C(F)F
Agent: Cl
Solvent: CC(=O)N(C)C
Solvent: O=S(Cl)Cl
Product: CC(O)(C(=O)Nc1ccc(C(=O)c2ccccc2)cc1)C(F)F
Temperature: -10 °C
Reaction time: 1 h

Procedure:
A solution of 2-hydroxy-2-difluoromethylpropionic acid (1.07 g, 7.65 mmol) in dry dimethylacetamide (15 ml) was stirred under a nitrogen atmosphere at -10° C. Thionyl chloride (0.91 g, 7.65 mmol) was added and the resulting mixture was allowed to stir at -10° C. for 1 hour. 4-Aminobenzophenone (1.0 g, 5.1 mmol) was then added and the reaction mixture was stirred at -10° C. for a further 15 mins. The solution was then allowed to warm to room temperature where it was stirred overnight. The reaction mixture was poured into hydrochloric acid solution (1M) and extracted with ethyl acetate. The combined ethyl acetate fractions were washed with water and brine. After drying (Na2SO4) and decolorization (Charcoal) the solution was evaporated in vacuo. A off-white foam was obtained which was triturated with hexane/ethyl acetate. The crude product was filtered through a short silica gel column with chloroform and crystallized from chloroform/hexane to give the title tertiary carbinol (0.89 g, 55%) as shiny, buff-colored crystals; mp=123°-124° C. 1H--NMR (300 MHz, d6 --DMSO): 1.45 (s, 3H, CH3), 6.17 (t, J=55 Hz, 1H, CHF2), 6.77 (s, 1H, OH), 7.56 (t, 2H, ArH), 7.65-7.76 (m, 5H, ArH), 7.96 (d, J=8.7 Hz, 2H, ArH), 10.19 (s, 1H, NH). MS (CI, CH4): 320(M+1, 100).
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@@H:9]([CH2:42][C:43]1[CH:48]=[CH:47][CH:46]=[CH:45][CH:44]=1)[CH2:10][C@@H:11]1[O:15][C:14]([CH3:17])([CH3:16])[N:13]([C:18]([O:20][CH2:21][C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)=[O:19])[C@H:12]1[CH2:28][C:29]1[CH:34]=[CH:33][C:32](OC(=O)C(F)(F)F)=[CH:31][CH:30]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[Li+].[Cl-].C([Sn](CCCC)(CCCC)[C:56]1[CH:61]=[CH:60][N:59]=[CH:58][CH:57]=1)CCC>CN(C=O)C.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[C:1]([O:5][C:6]([NH:8][C@@H:9]([CH2:42][C:43]1[CH:48]=[CH:47][CH:46]=[CH:45][CH:44]=1)[CH2:10][C@@H:11]1[O:15][C:14]([CH3:16])([CH3:17])[N:13]([C:18]([O:20][CH2:21][C:22]2[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=2)=[O:19])[C@H:12]1[CH2:28][C:29]1[CH:30]=[CH:31][C:32]([C:56]2[CH:57]=[CH:58][N:59]=[CH:60][CH:61]=2)=[CH:33][CH:34]=1)=[O:7])([CH3:2])([CH3:3])[CH3:4]
Reactant: CCCC[Sn](CCCC)(CCCC)c1ccncc1
Reactant: CC(C)(C)OC(=O)N[C@@H](Cc1ccccc1)C[C@@H]1OC(C)(C)N(C(=O)OCc2ccccc2)[C@H]1Cc1ccc(OC(=O)C(F)(F)F)cc1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cl-]
Agent: [Li+]
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N[C@@H](Cc1ccccc1)C[C@@H]1OC(C)(C)N(C(=O)OCc2ccccc2)[C@H]1Cc1ccc(-c2ccncc2)cc1
Temperature: 100 °C
Yield: 48.6 %

Procedure:
A solution containing the product from Example 23I (0.64 g, 0.906 mmol) in DMF (10 mL) was treated with LiCl (0.384 g, 9.06 mmol), dichlorobis(triphenylphosphine)palladium(II) (0.19 g, 0.271 mmol), and 4(tri-n-butylstannyl)pyridine (1.0 g, 2.72 mmol), heated at 100° C. for 16 hours, cooled and partitioned between ethyl acetate and water. The organic phase was washed with brine and dried over MgSO4, filtered and concentrated. The residue was chromatographed on silica gel eluting with 0-25% ethyl acetate in dichloromethane to give the title compound (0.28 g, 49% yield).
Reaction SMILES: [CH3:1][C:2]1[CH:6]=[C:5]([NH2:7])[N:4]([C:8]2[CH:13]=[CH:12][CH:11]=[C:10]([O:14][CH2:15][CH3:16])[N:9]=2)[N:3]=1.N/C(=C\C)/C#N.C(OC1N=C(NN)C=CC=1)C.[C:34]([C:42](=[CH:48]OCC)[C:43]([O:45][CH2:46][CH3:47])=[O:44])(=[O:41])[C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1>>[C:34]([C:42](=[CH:48][NH:7][C:5]1[N:4]([C:8]2[CH:13]=[CH:12][CH:11]=[C:10]([O:14][CH2:15][CH3:16])[N:9]=2)[N:3]=[C:2]([CH3:1])[CH:6]=1)[C:43]([O:45][CH2:46][CH3:47])=[O:44])(=[O:41])[C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1
Reactant: CCOc1cccc(-n2nc(C)cc2N)n1
Reactant: CCOC=C(C(=O)OCC)C(=O)c1ccccc1
Agent: C/C=C(\N)C#N
Agent: CCOc1cccc(NN)n1
Product: CCOC(=O)C(=CNc1cc(C)nn1-c1cccc(OCC)n1)C(=O)c1ccccc1

Procedure:
Following the procedure described in Reference Example 1-1, 3-methyl-1-(6-ethoxy-2-pyridinyl)-1H-pyrazol-5-amine was prepared from aminocrotononitrile and 6-ethoxy-2-hydrazinopyridine. Following the procedure described in Reference Example 1-2, the compound was subjected to a reaction with ethyl 2-benzoyl-3-ethoxy-2-propenoate to give ethyl 2-benzoyl-3-[[3-methyl-1-(6-ethoxy-2-pyridinyl)-1H-pyrazol-5-yl]amino)-2-propenoate. The compound was treated following the method described in Example 1-4 to give the title compound (35% cyclization yield).
Reaction SMILES: [CH3:1][S:2][C:3](SC)=[CH:4][N+:5]([O-:7])=[O:6].[NH:10]1[CH2:15][CH2:14][CH2:13][CH2:12][CH2:11]1>CCO>[CH3:1][S:2][C:3]([N:10]1[CH2:15][CH2:14][CH2:13][CH2:12][CH2:11]1)=[CH:4][N+:5]([O-:7])=[O:6]
Reactant: C1CCNCC1
Reactant: CSC(=C[N+](=O)[O-])SC
Solvent: CCO
Product: CSC(=C[N+](=O)[O-])N1CCCCC1
Yield: 39.6 %

Procedure:
In 20 ml of EtOH was dissolved 1.7 g (0.01 mole) of 1,1-bis(methylthio)-2-nitroethylene under heating and 0.9 g (0.01 mole) of piperidine dissolved in 10 ml of EtCH was added dropwise in 3 portions at 30-minutes intervals under reflux. After 2 hours of reflux, the solvent was distilled off and the residue was chromatographed on a silica gel column and eluted with AcOEt-toluene (2:3). The above procedure yielded 0.8 g of the title compound as yellow prisms.
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6]([OH:9])=[CH:5][CH:4]=1)#[N:2].[OH-].[Na+].[OH-].[CH2:13]([N+](C)(C)C)[C:14]1[CH:19]=[CH:18]C=[CH:16][CH:15]=1>O.ClCCl>[CH2:19]([C:14]([CH3:13])([O:9][C:6]1[CH:7]=[CH:8][C:3]([C:1]#[N:2])=[CH:4][CH:5]=1)[C:15]#[CH:16])[CH3:18]
Reactant: C[N+](C)(C)Cc1ccccc1
Reactant: N#Cc1ccc(O)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: ClCCl
Solvent: O
Product: C#CC(C)(CC)Oc1ccc(C#N)cc1
Reaction time: 96 h

Procedure:
17.47 g of 2-chloro-2-methylpent-1-yne were added to a mixture of 11.9 g of 4-cyanophenol, 6.0 g of sodium hydroxide, 15 ml of a 40% methanolic solution of benzyltrimethylammonium hydroxide in 85 ml of water and 85 ml of dichloromethane and stirred for 4 days. The organic phase was separated, washed with 2M sodium hydroxide solution, dried over sodium sulphate and evaporated. The residue was chromatographed on silica gel using ethyl acetate/petroleum ether (1:9) for the elution to give 10.1 g of 4-(1-ethyl-1-methyl-2-propynyloxy)benzonitrile.
Reaction SMILES: [CH2:1]([O:3][C:4]([CH2:6][C:7]1[N:8]=[C:9]([S:12][CH2:13][C:14]([NH:16][CH2:17][C@H:18]2[O:23][CH2:22][CH2:21][NH:20][CH2:19]2)=[O:15])[S:10][CH:11]=1)=[O:5])[CH3:2].[Cl:24][C:25]1[CH:32]=[CH:31][C:28]([CH:29]=O)=[CH:27][CH:26]=1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].C(=O)([O-])O.[Na+]>C(Cl)Cl.C(O)(=O)C>[Cl:24][C:25]1[CH:32]=[CH:31][C:28]([CH2:29][N:20]2[CH2:21][CH2:22][O:23][C@@H:18]([CH2:17][NH:16][C:14](=[O:15])[CH2:13][S:12][C:9]3[S:10][CH:11]=[C:7]([CH2:6][C:4]([O:3][CH2:1][CH3:2])=[O:5])[N:8]=3)[CH2:19]2)=[CH:27][CH:26]=1
Reactant: O=Cc1ccc(Cl)cc1
Reactant: CCOC(=O)Cc1csc(SCC(=O)NC[C@@H]2CNCCO2)n1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: ClCCl
Product: CCOC(=O)Cc1csc(SCC(=O)NC[C@H]2CN(Cc3ccc(Cl)cc3)CCO2)n1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
The resultant product (899 mg) of (75-3) was dissolved in methylene chloride (12.5 mL), 4-chlorobenzaldehyde (387 mg) and acetic acid (143 μL) were added and the mixture was stirred at room temperature for 1 hr. Sodium triacetoxyborohydride (1.06 g) was added to the reaction mixture and the mixture was further stirred overnight at room temperature. Saturated aqueous sodium hydrogen carbonate was added to the reaction mixture, and the mixture was extracted with chloroform. The extract was washed with saturated brine, dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure. The obtained residue was purified by silica gel column chromatography using a mixed solvent of chloroform and acetone as an eluent. The solvent was evaporated from the eluent to give the title compound (1.16 g) as a pale-yellow oil.
Reaction SMILES: [C:1]([OH:5])([CH3:4])([CH3:3])[CH3:2].C([Li])CCC.[C:11]1([CH3:20])[CH:16]=[CH:15][CH:14]=[C:13]([C:17](Cl)=[O:18])[CH:12]=1>O1CCCC1>[CH3:20][C:11]1[CH:12]=[C:13]([CH:14]=[CH:15][CH:16]=1)[C:17]([O:5][C:1]([CH3:4])([CH3:3])[CH3:2])=[O:18]
Reactant: Cc1cccc(C(=O)Cl)c1
Reactant: CC(C)(C)O
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: Cc1cccc(C(=O)OC(C)(C)C)c1

Procedure:
To a solution of tert-butanol (12.2 ml) in tetrahydrofuran (300 ml) at 0° C. was added n-butyllithium (52 ml) dropwise over 10 minutes. m-Toluoyl chloride (20 g) was added and the mixture heated at reflux for 1 hours. The mixture was partitioned between ethyl acetate and water and the organic phase dried (MgSO4) and evaporated. Purified by chromatography eluting with 20% dichloromethane in isohexane. Yield 14.78 g. Used directly in the next step.
Reaction SMILES: [CH:1]1([NH:4][C:5](=[O:23])[C:6]2[CH:11]=[C:10]([C:12]3[CH:13]=[C:14]4[C:18](=[CH:19][CH:20]=3)[NH:17][N:16]=[CH:15]4)[C:9]([CH3:21])=[C:8]([F:22])[CH:7]=2)[CH2:3][CH2:2]1.[H-].[Na+].Br[CH2:27][C:28]([O:30][CH3:31])=[O:29].O>CN(C=O)C>[CH:1]1([NH:4][C:5]([C:6]2[CH:7]=[C:8]([F:22])[C:9]([CH3:21])=[C:10]([C:12]3[CH:13]=[C:14]4[C:18](=[CH:19][CH:20]=3)[N:17]([CH2:27][C:28]([O:30][CH3:31])=[O:29])[N:16]=[CH:15]4)[CH:11]=2)=[O:23])[CH2:2][CH2:3]1
Reactant: Cc1c(F)cc(C(=O)NC2CC2)cc1-c1ccc2[nH]ncc2c1
Reactant: COC(=O)CBr
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: COC(=O)Cn1ncc2cc(-c3cc(C(=O)NC4CC4)cc(F)c3C)ccc21
Reaction time: 0.33 h

Procedure:
A solution of N-cyclopropyl-3-fluoro-5-(1H-indazol-5-yl)-4-methylbenzamide (example 60) (0.35 g) in dry DMF (5 ml) was treated with sodium hydride (60% oil dispersion, 0.08 g) at room temp under nitrogen then stirred for 20 min. A solution of methyl bromoacetate (0.2 ml) in dry DMF (0.5 ml) was added and stirring was continued for 1 h. Water (30 ml) was added and the mixture was extracted with ethyl acetate (×2). The organic extracts were washed with water (×3) and brine, dried (Na2SO4) and concentrated under vacuum. The residue was purified using a Varian Bond-Elut SPE cartridge (silica, 10 g) eluting with cyclohexane:ethyl acetate (4:1 to 1:1) to give the title compound as a yellow foam (0.26 g).
Reaction SMILES: [C:1]1([CH3:17])[CH:6]=[CH:5][C:4]([S:7]([N:10]2[CH:16]3[CH:11]2[CH2:12][CH2:13][CH2:14][CH2:15]3)(=[O:9])=[O:8])=[CH:3][CH:2]=1.[CH3:18][Li]>C1COCC1.C/C(/O)=C/C(C)=O.C/C(/O)=C/C(C)=O.[Cu]>[CH3:17][C:1]1[CH:2]=[CH:3][C:4]([S:7]([NH:10][C@@H:16]2[CH2:15][CH2:14][CH2:13][CH2:12][C@H:11]2[CH3:18])(=[O:8])=[O:9])=[CH:5][CH:6]=1
Reactant: [Li]C
Reactant: Cc1ccc(S(=O)(=O)N2C3CCCCC32)cc1
Agent: [Cu]
Agent: CC(=O)/C=C(/C)O
Solvent: C1CCOC1
Product: Cc1ccc(S(=O)(=O)N[C@@H]2CCCC[C@H]2C)cc1
Reaction time: 8 h
Yield: 62 %

Procedure:
To the solution of 180 g of) 7-(Toluene-4-sulfonyl)-7-aza-bicyclo[4.1.0]heptane and 18 g of Copper(II)acetyl acetonate in 1500 ml of dry THF was added 86 ml of a 10 M solution of methyllithium dropwise over 30 min. The mixture was stirred under nitrogen atmosphere for 8 h. It was then washed with water and extracted with ethyl acetate twice. The combined organic layers were concentrated. The resulting residue was purified by chromatography (silica, hexan/ethyl acetate) to afford 120 g (62%) of 4-Methyl-N-(trans-2-methyl-cyclohexyl)-benzenesulfonamide
Reaction SMILES: [F:1][C:2]([F:23])([F:22])[C@@H:3]([OH:21])[CH2:4][N:5]1[CH2:10][CH2:9][O:8][CH:7]([C:11]2[CH:12]=[N:13][C:14]([C:17]([F:20])([F:19])[F:18])=[CH:15][CH:16]=2)[CH2:6]1.C(N(CC)CC)C.[Cl:31][C:32]1[CH:37]=[CH:36][C:35]([N:38]=[C:39]=[O:40])=[CH:34][C:33]=1[F:41]>ClCCl>[F:23][C:2]([F:1])([F:22])[C@@H:3]([O:21][C:39](=[O:40])[NH:38][C:35]1[CH:36]=[CH:37][C:32]([Cl:31])=[C:33]([F:41])[CH:34]=1)[CH2:4][N:5]1[CH2:10][CH2:9][O:8][C@H:7]([C:11]2[CH:12]=[N:13][C:14]([C:17]([F:19])([F:20])[F:18])=[CH:15][CH:16]=2)[CH2:6]1
Reactant: O=C=Nc1ccc(Cl)c(F)c1
Reactant: O[C@@H](CN1CCOC(c2ccc(C(F)(F)F)nc2)C1)C(F)(F)F
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: O=C(Nc1ccc(Cl)c(F)c1)O[C@@H](CN1CCO[C@H](c2ccc(C(F)(F)F)nc2)C1)C(F)(F)F
Temperature: 50 °C

Procedure:
In a 25 mL round-bottom flask, (2S)-1,1,1-trifluoro-3-(2-(6-(trifluoromethyl)pyridin-3-yl)morpholino)propan-2-ol (384 mg, 1.12 mmol) was combined with dichloromethane (12 ml) to give a colorless solution. Triethylamine (113 mg, 155 μl, 1.12 mmol) was added. 1-chloro-2-fluoro-4-isocyanatobenzene (211 mg, 1.23 mmol) was added. The reaction mixture was warmed at 50° C. overnight. Reaction was complete by LCMS. Two major close-running spots of similar intensity could be seen by TLC (silica 25% EtOAc in hexanes eluent), a front-running spot and a later-running spot. The crude material was purified by flash chromatography (silica gel, 80 g, 5% to 20% EtOAc in hexanes gradient). Mixed fractions were purified by flash chromatography (silica gel, 80 g, 5% to 20% EtOAc in hexanes gradient). Fractions from both columns that contained pure front-running product were concentrated, dissolved in ether and treated with 1M HCl in ether to form the HCl salt. The salt came out as a sticky semisolid, which turned yellow. The resulting residue was taken up in dichloromethane and free-based by washing with saturated NaHCO3. The aqueous phase was extracted 3 times with dichloromethane. The combined organic layers were dried over Na2SO4 and concentrated in vacuo. The crude material was purified by flash chromatography (silica gel, 40 g, 20% to 30% EtOAc in hexanes gradient) to afford (4-chloro-3-fluorophenyl)-carbamic acid (S)-2,2,2-trifluoro-1-[(R)-2-(6-trifluoromethyl-pyridin-3-yl)-morpholin-4-ylmethyl]-ethyl ester (146 mg) as a white foam. (M+H)+=516 m/e.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[C:6]([CH2:8][CH3:9])[CH:5]=[CH:4][C:3]=1[OH:10].[Br:11][C:12]1[CH:17]=[CH:16][C:15]([N:18]=[C:19]=S)=[CH:14][CH:13]=1.C(N(CC)CC)C>O1CCCC1.S([O-])([O-])(=O)=O.[Cu+2]>[Br:11][C:12]1[CH:17]=[CH:16][C:15]([NH:18][C:19]2[O:10][C:3]3[CH:4]=[CH:5][C:6]([CH2:8][CH3:9])=[CH:7][C:2]=3[N:1]=2)=[CH:14][CH:13]=1
Reactant: S=C=Nc1ccc(Br)cc1
Reactant: CCc1ccc(O)c(N)c1
Agent: [Cu+2]
Agent: O=S(=O)([O-])[O-]
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CCc1ccc2oc(Nc3ccc(Br)cc3)nc2c1
Temperature: 25 °C
Reaction time: 2 h
Yield: 46.2 %

Procedure:
To a mixture of 2-amino-4-ethylphenol (0.89 g, 0.0065 mol) in tetrahydrofuran (80 mL) was added 4-bromophenyl isothiocyanate (1.4 g, 0.0065 mol) at room temperature. The mixture was stirred for 2 hours at room temperature. Anhydrous copper sulfate (6.2 g, 0.039 mol), triethylamine (0.9 mL, 0.0065 mol) and silica gel (11.7 g) were added to the reaction mixture. The mixture was stirred for 4 hours at room temperature. The solvent was removed under reduced pressure. The mixture was filtered through silica gel pad using 25% ethyl acetate/n-heptane as a mobile phase to give brown colored solid. The solid was purified by flash column chromatography on silica using 0%-25% ethyl acetate/n-heptane as a mobile phase. The solvent was removed, and the residue was triturated with n-heptane to give N2-(4-bromophenyl)-5-ethyl-1,3-benzoxazol-2-amine (0.96 g, 0.003 mol). RP-HPLC (Delta Pak C18, 5 μm, 300A, 15 cm; 5%-95% acetonitrile—0.1M ammonium acetate over 10 min, 1 mL/min) Rt 12.1 min. MS: MH+: 318
Reaction SMILES: [CH2:1]([C:3]1[CH:16]=[CH:15][C:6]([CH2:7][C:8]2[CH:13]=[CH:12][C:11]([OH:14])=[CH:10][CH:9]=2)=[CH:5][CH:4]=1)[CH3:2].[H-].[Na+].CC1C=CC(S(O[CH2:30][CH2:31][C@@:32]2([O:71][CH3:72])[C@H:37]([O:38][CH2:39][C:40]3[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=3)[C@@H:36]([O:46][CH2:47][C:48]3[CH:53]=[CH:52][CH:51]=[CH:50][CH:49]=3)[C@H:35]([O:54][CH2:55][C:56]3[CH:61]=[CH:60][CH:59]=[CH:58][CH:57]=3)[C@@H:34]([CH2:62][O:63][CH2:64][C:65]3[CH:70]=[CH:69][CH:68]=[CH:67][CH:66]=3)[O:33]2)(=O)=O)=CC=1.[O-]C1C=CC=CC=1.C1(O)C=CC=CC=1>CN(C=O)C.CCOC(C)=O>[CH2:39]([O:38][C@@H:37]1[C@@H:36]([O:46][CH2:47][C:48]2[CH:53]=[CH:52][CH:51]=[CH:50][CH:49]=2)[C@H:35]([O:54][CH2:55][C:56]2[CH:57]=[CH:58][CH:59]=[CH:60][CH:61]=2)[C@@H:34]([CH2:62][O:63][CH2:64][C:65]2[CH:66]=[CH:67][CH:68]=[CH:69][CH:70]=2)[O:33][C@:32]1([CH2:31][CH2:30][O:14][C:11]1[CH:12]=[CH:13][C:8]([CH2:7][C:6]2[CH:15]=[CH:16][C:3]([CH2:1][CH3:2])=[CH:4][CH:5]=2)=[CH:9][CH:10]=1)[O:71][CH3:72])[C:40]1[CH:41]=[CH:42][CH:43]=[CH:44][CH:45]=1
Reactant: CO[C@@]1(CCOS(=O)(=O)c2ccc(C)cc2)O[C@H](COCc2ccccc2)[C@@H](OCc2ccccc2)[C@H](OCc2ccccc2)[C@H]1OCc1ccccc1
Reactant: CCc1ccc(Cc2ccc(O)cc2)cc1
Agent: [H-]
Agent: [Na+]
Agent: [O-]c1ccccc1
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Solvent: Oc1ccccc1
Product: CCc1ccc(Cc2ccc(OCC[C@]3(OC)O[C@H](COCc4ccccc4)[C@@H](OCc4ccccc4)[C@H](OCc4ccccc4)[C@H]3OCc3ccccc3)cc2)cc1
Temperature: 60 °C
Reaction time: 0.08 h

Procedure:
4-(4-Ethylbenzyl)phenol (3) (28 mg, 0.13 mmol) was dissolved in DMF (200 μL). NaH (5 mg, 60%/mineral oil, 0.13 mmol) was added. After 5 min, a solution of 2-((2S,3R,4S,5R,6R)-3,4,5-tris(benzyloxy)-6-(benzyloxymethyl)-2-methoxytetrahydro-2H-pyran-2-yl)ethyl 4-methylbenzenesulfonate (9) (50 mg in 200 μL DMF) was added to the phenoxide solution. After 2 h, the reaction was heated to 60° C. for 2 h, then stirred overnight at room temperature (15h). The reaction mixture was diluted with EtOAc and washed with NaHCO3 (2×). The aqueous layers were combined and back-extracted with EtOAc (2×). The organic layers were combined, dried, and concentrated provide 72 mg. 1HNMR indicated that the product was present, but with extraneous phenol contamination. The sample was purified by preparative thin-layer chromatography (SiO2, eluting with 40% EtOAc/hexanes) to provide a film (26.1 mg, approx 50%) that still had contaminating phenol present. The material was carried forward to the next step. 1H NMR (300 MHz, CDCl3) δ ppm: 6.99-7.32 (m, 25H), 6.69 (m, 3H), 4.48-4.97 (m, 8H), 4.13 (t, J=9 Hz, 1H), 3.94 (m, 1H), 3.86 (s, 2H), 3.55-3.80 (m, 6H), 3.26 (s, 3H), 2.60 (q, J=15.3, 7.8 Hz, 2H), 2.27 (m, 2H), 1.21 (t, J=8.1 Hz). LC/MS tR=6.47 min, calcd for C52H56O7: 792.4, found 815.4 (M+Na)+.