Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[C:3]([O:12][CH3:13])=[N:4][CH:5]=[C:6]([C:8]([F:11])([F:10])[F:9])[CH:7]=1.C([Li])CCC.CN(C)[CH:21]=[O:22].Cl>CCOCC.CCCCCC>[CH3:13][O:12][C:3]1[C:2]([CH:21]=[O:22])=[CH:7][C:6]([C:8]([F:11])([F:10])[F:9])=[CH:5][N:4]=1
Reactant: COc1ncc(C(F)(F)F)cc1Br
Reactant: CN(C)C=O
Agent: Cl
Agent: [Li]CCCC
Solvent: CCOCC
Solvent: CCCCCC
Product: COc1ncc(C(F)(F)F)cc1C=O
Temperature: 20 °C
Reaction time: 0.5 h

Procedure:
A solution of 5.18 g (0.020 mol) of 3-bromo-2-methoxy-5-(trifluoromethyl)pyridine in 50 ml of ether was cooled to -100° C. and blanketed with nitrogen. A solution containing 0.024 mole of butyl lithium in hexane (15.0 ml of 1.6 M) was added slowly with stirring keeping the temperature below about -95° C. and the mixture was allowed to react for another 15 min. Dimethylformamide (7.5 ml, 0.097 mol) was added to the mixture at below -95° C. and stirring continued for about 30 min. The mixture was allowed to warm to about 20° C. and was then poured onto a mixture of ice and 1N hydrochloric acid. The mixture that formed was extracted with ether and the extract was dried over sodium sulfate and concentrated by evaporation under reduced pressure. The residue was distilled in a Kugelrohr apparatus to obtain 3.6 g (86 percent of theory) of the title compound as an oil which solidified to a white crystalline solid. The proton nmr spectrum was consistent with the assigned structure.
Reaction SMILES: S(Cl)([Cl:3])=O.[C:5]1([N:11]2[C:19]3[CH2:18][CH2:17][CH2:16][CH:15]([CH2:20][CH2:21]O)[C:14]=3[CH:13]=[N:12]2)[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1>C1(C)C=CC=CC=1.C(OCC)(=O)C>[Cl:3][CH2:21][CH2:20][CH:15]1[CH2:16][CH2:17][CH2:18][C:19]2[N:11]([C:5]3[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=3)[N:12]=[CH:13][C:14]1=2
Reactant: O=S(Cl)Cl
Reactant: OCCC1CCCc2c1cnn2-c1ccccc1
Solvent: Cc1ccccc1
Solvent: CCOC(C)=O
Product: ClCCC1CCCc2c1cnn2-c1ccccc1
Temperature: 90 °C
Yield: 76 %

Procedure:
Thionyl chloride (4 mL) is slowly added at room temperature over a solution of 2-(4,5,6,7-tetrahydro-1-phenyl-1H-indazol-4-yl)ethanol (516 mg, 2.13 mmol) in 25 mL of toluene. The reaction mixture is heated at 90° C. during 2 hours. The solvent is eliminated at reduced pressure. The crude is diluted in ethyl acetate and washed twice with a NaHCO3 solution. The solvent is next evaporated at reduced pressure, to obtain 4-(2-chloroethyl)-4,5,6,7-tetrahydro-1-phenyl-1H-indazole (423 mg, 1.62 mmol, 76%, oil).
Reaction SMILES: Cl[C:2](Cl)=[CH:3][CH:4]([NH:6][C:7]([C:9]1[C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[N:11]([CH2:18][C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=2[F:25])[N:10]=1)=[O:8])[CH3:5].[CH3:27][O-:28].[Na+]>CN1CCCC1=O>[F:25][C:20]1[CH:21]=[CH:22][CH:23]=[CH:24][C:19]=1[CH2:18][N:11]1[C:12]2[C:17](=[CH:16][CH:15]=[CH:14][CH:13]=2)[C:9]([C:7]2[O:8][C:3]([CH2:2][O:28][CH3:27])=[C:4]([CH3:5])[N:6]=2)=[N:10]1
Reactant: C[O-]
Reactant: CC(C=C(Cl)Cl)NC(=O)c1nn(Cc2ccccc2F)c2ccccc12
Agent: [Na+]
Solvent: CN1CCCC1=O
Product: COCc1oc(-c2nn(Cc3ccccc3F)c3ccccc23)nc1C
Yield: 25.6 %

Procedure:
136 mg of 1,1-dichloro-3-[l-(2-fluorobenzyl)indazole-3-carboxamido]-but-1-ene (0.267 mmol) and 47 mg of sodium methylate were stirred in 0.6 ml of N-methylpyrrolidone at 100° C. under argon overnight. The crude mixture was cooled and purified directly by column chromatography (SiO2). 24 mg (20%) of 2- [1-(2-fluorobenzyl)-indazol-3-yl]-5-methoxymethyl-4-methyl-oxazole were isolated as yellowish crystals.
Reaction SMILES: [C:1]([O:5][C:6](=[O:17])[CH2:7][O:8][C:9]1[C:14](Br)=[CH:13][C:12]([Cl:16])=[CH:11][N:10]=1)([CH3:4])([CH3:3])[CH3:2].[C:18]([C:20]1[CH:25]=[CH:24][CH:23]=[C:22]([S:26]([CH2:29][CH2:30][CH3:31])(=[O:28])=[O:27])[CH:21]=1)#[CH:19].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>CCOC(C)=O.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.Cl[Pd]Cl>[C:1]([O:5][C:6](=[O:17])[CH2:7][O:8][C:9]1[C:14]([C:19]#[C:18][C:20]2[CH:25]=[CH:24][CH:23]=[C:22]([S:26]([CH2:29][CH2:30][CH3:31])(=[O:28])=[O:27])[CH:21]=2)=[CH:13][C:12]([Cl:16])=[CH:11][N:10]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: C#Cc1cccc(S(=O)(=O)CCC)c1
Reactant: CC(C)(C)OC(=O)COc1ncc(Cl)cc1Br
Agent: Cl[Pd]Cl
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CCOC(C)=O
Product: CCCS(=O)(=O)c1cccc(C#Cc2cc(Cl)cnc2OCC(=O)OC(C)(C)C)c1
Temperature: 90 °C

Procedure:
A mixture of tert-butyl[(3-bromo-5-chloropyridin-2-yl)oxy]acetate (Intermediate 182; 160 mg; 0.50 mmol), 1-ethynyl-3-(propane-1-sulfonyl)-benzene (Intermediate 42; 155 mg; 0.74 mmol), bis(triphenylphosphine)palladium (II) chloride (10 mg; 0.01 mmol) and triphenylphosphine (26 mg; 0.10 mmol) is treated with cuprous iodide (3 mg; 0.01 mmol) and TEA (1.10 ml) and heated at 90° C. in a sealed vessel for 15 hours. The mixture was diluted with EtOAc and washed with a saturated NH4Cl solution and brine. The organic phase was dried over MgSO4, concentrated to dryness under reduced pressure affording a sticky solid, which was purified by column chromatography (silica), eluting with cyclohexane containing increasing amounts of EtOAc, affording the title compound as a yellow sticky solid
Reaction SMILES: [C:1]1([OH:11])[C:10]2[CH2:9][CH2:8][CH2:7][CH2:6][C:5]=2[CH:4]=[CH:3][CH:2]=1.Br[CH2:13][CH2:14][O:15][CH:16]1[CH2:21][CH2:20][CH2:19][CH2:18][O:17]1.C(Cl)Cl.[OH-].[Na+]>S([O-])(O)(=O)=O.C([N+](CCCC)(CCCC)CCCC)CCC.O>[C:1]1([O:11][CH2:13][CH2:14][O:15][CH:16]2[CH2:21][CH2:20][CH2:19][CH2:18][O:17]2)[C:10]2[CH2:9][CH2:8][CH2:7][CH2:6][C:5]=2[CH:4]=[CH:3][CH:2]=1
Reactant: Oc1cccc2c1CCCC2
Reactant: BrCCOC1CCCCO1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: O=S(=O)([O-])O
Agent: [Na+]
Solvent: O
Solvent: ClCCl
Product: c1cc2c(c(OCCOC3CCCCO3)c1)CCCC2
Reaction time: 8 h

Procedure:
A mixture of 1.48 g (10 mmol) of 5,6,7,8-tetrahydro-1-naphthol, 0.34 g (1.0 mmol) of tetra-n-butylammonium hydrogen sulfate, 6.27 (30 mmol) of the title product of Example 57, 20 ml of methylene chloride, 9 ml of water, and 11 ml of 1N sodium hydroxide was stirred vigorously overnight at reflux. The organic layer was separated, and the solvent removed under reduced pressure. The residue was triturated with diethyl ether and filtered to remove the insolubles. The ether solution was sequentially washed with two portions of dilute aqueous sodium hydroxide, with water, and then with brine. After drying over magnesium sulfate, the solution was filtered and the solvent was removed under reduced pressure. Chromatography of the residue on silica gel, using 5% ethyl acetate/hexane as eluent gave 730 mg of the title compound.
Reaction SMILES: [C:1]([NH2:5])([CH3:4])([CH3:3])[CH3:2].[Cl:6][C:7]1[CH:8]=[C:9]([C:13](=[O:17])[CH:14](Br)[CH3:15])[CH:10]=[CH:11][CH:12]=1>>[CH3:15][CH:14]([NH:5][C:1]([CH3:4])([CH3:3])[CH3:2])[C:13]([C:9]1[CH:10]=[CH:11][CH:12]=[C:7]([Cl:6])[CH:8]=1)=[O:17]
Reactant: CC(C)(C)N
Reactant: CC(Br)C(=O)c1cccc(Cl)c1
Product: CC(NC(C)(C)C)C(=O)c1cccc(Cl)c1
Temperature: 25 °C

Procedure:
To 1 mole of m-chloroprophenone heated to 75±5° C., bromine was added dropwise under stirring, and the reaction temperature was kept at 75±5° C. during the addition and kept for 3 hours after the addition, m-chloro-α-bromopropiophenone (compound of formula (II)) was obtained. t-Butylamine was added to m-chloro-α-bromopropiophenone obtained above and the reaction mixture was refluxed for 5.5 hours. After excessive t-butylamine was evaporated below 100° C., the concentrated solution was cooled down to room temperature and then extracted with 1000 ml of toluene and 200 ml of water. The organic phase was dried with anhydrous magnesium sulfate (20 g) to obtain a solution of bupropion free base (compound III). HCl gas was bubbled into the solution of bupropion free base at room temperature until the PH value the reaction mixture was less than or equal to 4. After filtration, crude product of bupropion hydrochloride was obtained. The crude product of bupropion hydrochloride was dissolved in 1500 ml of ethyl acetate heated to 60° C., and decolorized with activated carbon (3 g) for 30 minutes and filtered. Then filtrate was cooled down, crystal bupropion hydrochloride crystallized. Wet product of bupropion hydrochloride was obtained after filtration and was dried in vacuum (−0.04˜−0.09 MPa, 60±5° C.) for 5 hours to obtain pure product. Total yields was 75% based on m-chloropropiophenone; HPLC's purify was over 99.9%.
Reaction SMILES: [CH2:1]([C:4]1([C:18]([O:20]C)=[O:19])[CH2:8][O:7][C:6]([CH3:10])([CH3:9])[N:5]1[C:11]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12])[CH:2]=C.[OH-:22].[Na+]>CO>[OH:22][CH:2]1[CH2:1][C:4]2([N:5]([C:11]([O:13][C:14]([CH3:17])([CH3:15])[CH3:16])=[O:12])[C:6]([CH3:10])([CH3:9])[O:7][CH2:8]2)[C:18](=[O:19])[O:20]1
Reactant: C=CCC1(C(=O)OC)COC(C)(C)N1C(=O)OC(C)(C)C
Reactant: [OH-]
Agent: [Na+]
Solvent: CO
Product: CC(C)(C)OC(=O)N1C(C)(C)OCC12CC(O)OC2=O
Temperature: 60 °C
Reaction time: 8 h

Procedure:
1.7 g of 3-tert-butyl 4-methyl 4-allyl-2,2-dimethyloxazolidine-3,4-dicarboxylate were dissolved in 20 ml of methanol and 8 ml of 1 N NaOH were added. The mixture was heated at 60° C. for 3 h, allowed to cool, and the methanol was removed in vacuo. The pH of the aqueous phase was adjusted to 2 with 1 N HCl, and it was extracted 3 times with 50 ml of dichloromethane each time. The combined organic phases were dried with MgSO4, and the solvent was removed in vacuo. The residue was taken up in 80 ml of dichloromethane and 10 ml of methanol. The solution was cooled to −78° C., and ozone was passed through until it assumed a pale blue color. Argon was then passed through until the blue color had completely disappeared. 3 ml of dimethyl sulfide were added, and the mixture was allowed to reach room temperature overnight. The solvents were then removed in vacuo. The crude product obtained in this way was employed directly in the next reaction.
Reaction SMILES: [OH:1][C:2]1[CH:11]=[CH:10][CH:9]=[C:8]2[C:3]=1[CH2:4][CH2:5][CH2:6][NH:7]2.[CH2:12]1[CH2:18][S:15](=[O:17])(=[O:16])[O:14][CH2:13]1>C(#N)CCC>[OH:1][C:2]1[CH:11]=[CH:10][CH:9]=[C:8]2[C:3]=1[CH2:4][CH2:5][CH2:6][N:7]2[CH2:13][CH2:12][CH2:18][S:15]([OH:17])(=[O:16])=[O:14]
Reactant: O=S1(=O)CCCO1
Reactant: Oc1cccc2c1CCCN2
Solvent: CCCC#N
Product: O=S(=O)(O)CCCN1CCCc2c(O)cccc21
Temperature: 125 °C

Procedure:
A mixture of 0.8 g (5.36 mmol) of 5-hydroxy-1,2,3,4-tetrahydroquinoline and 0.5 g 1,3-propanesultone (4.1 mmol) in 12 ml of butyronitrile was heated at 125° C. for hours. The mixture was suction filtered and the filtrate evaporated under reduced pressure. The resulting off white compound crystallized. Product washed with ethyl ether and filtered of. Yield 0.8 g (80%)
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([C:8]2[O:9][CH:10]=[CH:11][CH:12]=2)[C:5]([C:13]#[N:14])=[C:4](S(C)=O)[N:3]=1.[N:18]1[CH:23]=[CH:22][CH:21]=[C:20]([CH2:24][NH2:25])[CH:19]=1>COCCOC>[NH2:1][C:2]1[N:7]=[C:6]([C:8]2[O:9][CH:10]=[CH:11][CH:12]=2)[C:5]([C:13]#[N:14])=[C:4]([NH:25][CH2:24][C:20]2[CH:19]=[N:18][CH:23]=[CH:22][CH:21]=2)[N:3]=1
Reactant: NCc1cccnc1
Reactant: CS(=O)c1nc(N)nc(-c2ccco2)c1C#N
Solvent: COCCOC
Product: N#Cc1c(NCc2cccnc2)nc(N)nc1-c1ccco1

Procedure:
From 2-amino-4-furan-2-yl-6-methanesulfinyl-pyrimidine-5-carbonitrile and 3-picolylamine in DME. ES-MS m/e (%): 293 (M+H+, 100).
Reaction SMILES: [NH2:1][C:2]1[C:12]([CH2:13][C:14]2[CH:19]=[CH:18][CH:17]=[C:16]([C:20]([F:23])([F:22])[F:21])[C:15]=2[CH3:24])=[C:5]2[NH:6][C:7](=[O:11])[CH2:8][C:9](=[O:10])[N:4]2[N:3]=1.[C:25]1(=O)[O:30][C:28](=[O:29])[C:27]2=[CH:31][CH:32]=[CH:33][CH:34]=[C:26]12>C(#N)C>[O:29]=[C:28]1[C:27]2[C:26](=[CH:34][CH:33]=[CH:32][CH:31]=2)[C:25](=[O:30])[N:1]1[C:2]1[C:12]([CH2:13][C:14]2[CH:19]=[CH:18][CH:17]=[C:16]([C:20]([F:23])([F:21])[F:22])[C:15]=2[CH3:24])=[C:5]2[NH:6][C:7](=[O:11])[CH2:8][C:9](=[O:10])[N:4]2[N:3]=1
Reactant: O=C1OC(=O)c2ccccc21
Reactant: Cc1c(Cc2c(N)nn3c2NC(=O)CC3=O)cccc1C(F)(F)F
Solvent: CC#N
Product: Cc1c(Cc2c(N3C(=O)c4ccccc4C3=O)nn3c2NC(=O)CC3=O)cccc1C(F)(F)F
Temperature: 80 °C
Reaction time: 96 h
Yield: 48.2 %

Procedure:
To the solution of 2-amino-3-{[2-methyl-3-(trifluoromethyl)phenyl]methyl}pyrazolo[1,5-a]pyrimidine-5,7(4H,6H)-dione (1.5 g, 4.43 mmol) in acetonitrile (100 mL) was added phthalic anhydride (1.511 g, 10.20 mmol). The reaction mixture was stirred at 80° C. for 4 days. The reaction was concentrated. To the crude was added DCM (20 mL). The insoluble solid was filtered which is the pure product. The filtrate was purified on a silica column (eluting with 20-60% EtOAc/Hexane) which was combined with the solid from filtration to give the product (1.0 g, 48%). 1H NMR (400 MHz, DMSO-d6) δ ppm 2.20 (s, 3H) 3.93 (br. s., 2H) 6.89 (t, J=7.83 Hz, 1H) 7.10 (m, 1H) 7.22 (m, 1H) 7.49-7.62 (m, 1H) 7.62-7.70 (m, 1H) 7.79-7.94 (m, 4H); LC/MS: MS (ES+) m/e 469.1 [M+H]+.
Reaction SMILES: [C:1]([O:5][CH:6]1[CH:8]([C:9]2[CH:14]=[CH:13][C:12]([CH3:15])=[CH:11][N:10]=2)[CH:7]1[CH2:16][OH:17])([CH3:4])([CH3:3])[CH3:2].[H-].[Na+].[Cl:20][C:21]1[CH:26]=[C:25](Cl)[N:24]=[C:23]([CH3:28])[N:22]=1>C1COCC1>[C:1]([O:5][CH:6]1[CH:8]([C:9]2[CH:14]=[CH:13][C:12]([CH3:15])=[CH:11][N:10]=2)[CH:7]1[CH2:16][O:17][C:25]1[CH:26]=[C:21]([Cl:20])[N:22]=[C:23]([CH3:28])[N:24]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: Cc1nc(Cl)cc(Cl)n1
Reactant: Cc1ccc(C2C(CO)C2OC(C)(C)C)nc1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: Cc1ccc(C2C(COc3cc(Cl)nc(C)n3)C2OC(C)(C)C)nc1
Yield: 55.8 %

Procedure:
To a solution of (2-tert-butoxy-3-(5-methylpyridin-2-yl)cyclopropyl)-methanol (12-5) (130 mg, 0.55 mmol) in THF, sodium hydride (28 mg, 0.69 mmol) was added at 0° C. and it was allowed to stir for 30 min whereupon a solution of 4,6-dichloro-2-methylpyrimidine (113 mg, 0.69 mmol) in THF was added. The solution was heated to reflux overnight. After cooling, it was quenched with water, extracted with EtOAc, dried over sodium sulfate, concentrated under reduced pressure and purified by Pre-TLC (PE/EA=1:1) to afford the product as a white solid (111 mg, 56%). 1H NMR (500 MHz, CDCl3) δ 8.35 (s, 1H), 7.41 (d, J=6.6 Hz, 1H), 7.04 (d, J=8.1 Hz, 1H), 6.59 (s, 1H), 4.49-4.40 (m, 2H), 3.62 (dd, J=6.9, 3.6 Hz, 1H), 2.60 (s, 3H), 2.30 (s, 3H), 2.27 (m, 1H), 2.04 (dd, J=6.7, 3.7 Hz, 1H), 1.08 (s, 9H); LRMS (ES) calculated M+H for C19H25ClN3O2: 362.8. Found: 362.1.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:40])/[CH:4]=[CH:5]/[C:6]1[N:10]2[N:11]=[C:12]([C:21]3[CH:26]=[CH:25][C:24]([C:27]4([NH:31]C(OC(C)(C)C)=O)[CH2:30][CH2:29][CH2:28]4)=[CH:23][CH:22]=3)[C:13]([C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=3)=[CH:14][C:9]2=[N:8][C:7]=1[CH3:39]>Cl.O1CCOCC1>[CH3:1][O:2][C:3](=[O:40])/[CH:4]=[CH:5]/[C:6]1[N:10]2[N:11]=[C:12]([C:21]3[CH:22]=[CH:23][C:24]([C:27]4([NH2:31])[CH2:30][CH2:29][CH2:28]4)=[CH:25][CH:26]=3)[C:13]([C:15]3[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=3)=[CH:14][C:9]2=[N:8][C:7]=1[CH3:39]
Reactant: COC(=O)/C=C/c1c(C)nc2cc(-c3ccccc3)c(-c3ccc(C4(NC(=O)OC(C)(C)C)CCC4)cc3)nn12
Agent: Cl
Solvent: C1COCCO1
Product: COC(=O)/C=C/c1c(C)nc2cc(-c3ccccc3)c(-c3ccc(C4(N)CCC4)cc3)nn12
Reaction time: 1 h
Yield: 16.4 %

Procedure:
299 mg Of the crude (E)-3-{6-[4-(1-tert-butoxycarbonylamino-cyclobutyl)-phenyl]-2-methyl-7-phenyl-imidazo[1,2-b]pyridazin-3-yl}-acrylic acid methyl ester were stirred in 17.6 mL 4M hydrogen chloride in dioxane for 22 hours at room temperature. The solvent was evaporated and the residue was treated with saturated sodium bicarbonate solution (pH 9). After stirring for one hour 100 mL dichloromethane were added and stirring was continued for one hour. The organic phase was separated and the aqueous phase was extracted once more with dichloromethane (50 mL). The combined organic extracts were washed with water and brine, dried, filtrated and the solvent was evaporated. The crude product (236 mg) was purified by HPLC to yield 40 mg of the title compound.
Reaction SMILES: [CH:1](O)=[O:2].C(OC(=O)C)(=O)C.[OH:11][NH:12][CH:13]([CH2:22][S:23]([N:26]1[CH2:31][CH2:30][N:29]([C:32]2[CH:37]=[CH:36][C:35]([O:38][CH2:39][C:40]([F:43])([F:42])[F:41])=[CH:34][N:33]=2)[CH2:28][CH2:27]1)(=[O:25])=[O:24])[CH2:14][CH2:15][C:16]1[N:21]=[CH:20][CH:19]=[CH:18][N:17]=1>C(Cl)Cl>[OH:11][N:12]([C@H:13]([CH2:22][S:23]([N:26]1[CH2:27][CH2:28][N:29]([C:32]2[CH:37]=[CH:36][C:35]([O:38][CH2:39][C:40]([F:43])([F:42])[F:41])=[CH:34][N:33]=2)[CH2:30][CH2:31]1)(=[O:25])=[O:24])[CH2:14][CH2:15][C:16]1[N:17]=[CH:18][CH:19]=[CH:20][N:21]=1)[CH:1]=[O:2]
Reactant: O=S(=O)(CC(CCc1ncccn1)NO)N1CCN(c2ccc(OCC(F)(F)F)cn2)CC1
Reactant: O=CO
Solvent: ClCCl
Solvent: CC(=O)OC(C)=O
Product: O=CN(O)[C@@H](CCc1ncccn1)CS(=O)(=O)N1CCN(c2ccc(OCC(F)(F)F)cn2)CC1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 906.9 %

Procedure:
To formic acid (54 mL, 1.4 mol) at 8° C. was added acetic anhydride (11 mL, 100 mmol) and the mixture was stirred at RT for 10 minutes. The mixed anhydride was then recooled to 8° C., and added to a solution, pre-cooled to 0° C., 2-[3-(hydroxyamino)-4-({4-[5-(2,2,2-trifluoroethoxy)pyridin-2-yl]piperazin-1-yl}sulfonyl)butyl]pyrimidine (16.32 g, 33.3 mmol) in DCM (170 mL) and formic acid (65 mL, 1.7 mol). The reaction was brought to room temperature and stirred for one hour. Volatiles were then removed in vacuo, and the residue azeotroped with toluene (2×50 mL). The residue was then dissolved in MeOH/DCM (1:1, 250 mL) and stirred overnight at room temperature. The solution was then concentrated in vacuo, and partitioned between DCM (250 mL) and sat. NaHCO3 (250 mL). The DCM layer was then filtered through silica gel (20 g) washing with 5% MeOH/DCM and the volatiles removed in vacuo to give the racemic title compound as a pale yellow foam (15.68 g, 302 mmol, 91%).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]([CH3:8])=[N:6][CH:7]=1.ClC1C=C(C(OO)=[O:17])C=CC=1>C(Cl)(Cl)Cl>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([CH3:8])=[N+:6]([O-:17])[CH:7]=1
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: Cc1ccc(Br)cn1
Solvent: ClC(Cl)Cl
Product: Cc1ccc(Br)c[n+]1[O-]
Reaction time: 2 h
Yield: 104.5 %

Procedure:
To a solution of 5-Bromo-2-methyl-pyridine (1.00 g, 5.80 mmol) in chloroform (10 mL) was slowly added 3-Chloro-benzenecarboperoxoic acid (1.004 g, 6.98 mmol) at 0° C. Stirring continued for 2 hrs at room temperature and the mixture was diluted with chloroform, washed with saturated sodium bicarbonate and water, dried over anhydrous sodium sulfate, filtered and concentrated to afford the title compound (1.14 g, 100%) as a yellow solid. 1H NMR (300 MHz, CDCl3): δ 8.46 (s, 1H), 7.36 (d, 1H), 7.17 (d, 1H), 2.49 (s, 3H).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:22]=[C:21]([O:23][CH3:24])[CH:20]=[CH:19][C:4]=1[CH2:5][N:6]1[C:11](=[O:12])[C:10]2[CH:13]=[C:14]([CH2:16][CH3:17])[S:15][C:9]=2[NH:8][C:7]1=[O:18].Br[CH2:26][C:27]1[CH:32]=[CH:31][C:30]([C:33]2[C:34]([C:39]#[N:40])=[CH:35][CH:36]=[CH:37][CH:38]=2)=[CH:29][C:28]=1[F:41].C(=O)([O-])[O-].[K+].[K+]>C(#N)C>[CH3:1][O:2][C:3]1[CH:22]=[C:21]([O:23][CH3:24])[CH:20]=[CH:19][C:4]=1[CH2:5][N:6]1[C:11](=[O:12])[C:10]2[CH:13]=[C:14]([CH2:16][CH3:17])[S:15][C:9]=2[N:8]([CH2:26][C:27]2[CH:32]=[CH:31][C:30]([C:33]3[C:34]([C:39]#[N:40])=[CH:35][CH:36]=[CH:37][CH:38]=3)=[CH:29][C:28]=2[F:41])[C:7]1=[O:18]
Reactant: N#Cc1ccccc1-c1ccc(CBr)c(F)c1
Reactant: CCc1cc2c(=O)n(Cc3ccc(OC)cc3OC)c(=O)[nH]c2s1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: CCc1cc2c(=O)n(Cc3ccc(OC)cc3OC)c(=O)n(Cc3ccc(-c4ccccc4C#N)cc3F)c2s1
Temperature: 50 °C
Reaction time: 2 h
Yield: 40.5 %

Procedure:
A mixture of 3-(2,4-dimethoxybenzyl)-6-ethylthieno[2,3-d]pyrimidine-2,4(1H,3H)-dione (2 g), 4′-(bromomethyl)-3′-fluorobiphenyl-2-carbonitrile (2 g), potassium carbonate (1.2 g) and acetonitrile (50 mL) was stirred at 50° C. for 2 hr. Insoluble material was filtered off, and the solvent was evaporated under reduced pressure. The obtained residue was purified by silica gel column chromatography to give the title compound as a colorless amorphous solid (1.3 g, 41%).
Reaction SMILES: [CH2:1]([O:17][CH2:18][C:19](=[CH2:22])[CH2:20][OH:21])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH3:16].C1(N=C=NC2CCCCC2)CCCCC1.[Br:38][CH2:39][CH2:40][CH2:41][CH2:42][CH2:43][C:44](O)=[O:45]>CCOCC.CN(C)C1C=CN=CC=1>[CH2:1]([O:17][CH2:18][C:19](=[CH2:22])[CH2:20][O:21][C:44](=[O:45])[CH2:43][CH2:42][CH2:41][CH2:40][CH2:39][Br:38])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH3:16]
Reactant: C=C(CO)COCCCCCCCCCCCCCCCC
Reactant: O=C(O)CCCCCBr
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: CN(C)c1ccncc1
Solvent: CCOCC
Product: C=C(COCCCCCCCCCCCCCCCC)COC(=O)CCCCCBr
Temperature: 22 °C
Reaction time: 18 h

Procedure:
3-Hexadecyloxy-2-methylenepropan-1-ol (from Preparation 1) (1.8 g) was dissolved in ether (35 ml). Dicyclohexylcarbodiimide (1.5 g), 4-dimethylaminopyridine (0.07 g) and 6-bromohexanoic acid (1.2 g) was added, and the mixture was stirred at 22° C. for 18 hours. The reaction mixture was filtered, and the filtrate was washed with water (35 ml), 5% acetic acid in water (35 ml) and water (35 ml). The ether solution was dried over anhydrous magnesium sulfate, filtered and evaporated in vacuo. The crude product was purified by chromatography on a Waters PrepLC®/System 500A using a PrepPAK®-500/SILICA cartridge first with ether/pentane 1:4 and in a second run with methylene chloride/hexane 1:4 as eluent.
Reaction SMILES: [C:1]([O:5][C@@H:6]([C:10]1[C:32]([CH3:33])=[CH:31][C:13]2[N:14]=[C:15]([N:17]3[CH2:22][CH2:21][O:20][C:19]([C:24]4[CH:29]=[CH:28][C:27](Cl)=[CH:26][CH:25]=4)(C)[CH2:18]3)[S:16][C:12]=2[C:11]=1[C:34]1[CH:39]=[CH:38][C:37]([Cl:40])=[CH:36][CH:35]=1)[C:7]([OH:9])=[O:8])([CH3:4])([CH3:3])[CH3:2].CC1C=CC(C2(C)OCCNC2)=CC=1>>[C:1]([O:5][C@@H:6]([C:10]1[C:32]([CH3:33])=[CH:31][C:13]2[N:14]=[C:15]([N:17]3[CH2:22][CH2:21][O:20][CH:19]([C:24]4[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=4)[CH2:18]3)[S:16][C:12]=2[C:11]=1[C:34]1[CH:35]=[CH:36][C:37]([Cl:40])=[CH:38][CH:39]=1)[C:7]([OH:9])=[O:8])([CH3:4])([CH3:2])[CH3:3]
Reactant: Cc1cc2nc(N3CCOC(C)(c4ccc(Cl)cc4)C3)sc2c(-c2ccc(Cl)cc2)c1[C@H](OC(C)(C)C)C(=O)O
Agent: Cc1ccc(C2(C)CNCCO2)cc1
Product: Cc1cc2nc(N3CCOC(c4ccccc4)C3)sc2c(-c2ccc(Cl)cc2)c1[C@H](OC(C)(C)C)C(=O)O

Procedure:
(2S)-2-tert-butoxy-2-(7-(4-chlorophenyl)-5-methyl-2-(2-phenylmorpholino)benzo[d]thiazol-6-yl)acetic acid was prepared using the similar procedure as (2S)-2-tert-butoxy-2-(7-(4-chlorophenyl)-2-(2-(4-chlorophenyl)-2-methylmorpholino)-5-methylbenzo[d]thiazol-6-yl)acetic acid except 2-(4-methylphenyl)-2-methylmorpholine was used instead of 2-(4-chlorophenyl)-2-methylmorpholine. LCMS-ESI+: calc'd for C30H31ClN2O4S: 551.2, 553.2 (M+H+); found: 551.3, 553.3 (M+H+). 1H-NMR: 400 MHz, (CD3C1) δ: 7.62 (dd, J1=2.4 Hz, J2=10 Hz, 1H), 7.49 (m, 3H), 7.3-7.4 (m, 6H), 5.13 (s, 1H), 4.58 (d, J=10.8 Hz, 1H), 4.09 (m, 2H), 3.80 (m, 2H), 3.64 (m, 1H), 3.37 (m, 1H), 3.08 (dd, J1=12.8 Hz, J2=10.8 Hz, 1H. 50 (s, 3H), 2.49 (s, 3H), 0.93 (s, 9H).
Reaction SMILES: [C:1]1([NH:7][C:8]2([CH:21](C3SC=CC=3)[O:22][CH3:23])[CH2:13][CH2:12][N:11]([C:14]3[CH:19]=[CH:18]C=CC=3)[CH:10](C)[CH2:9]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1>C(OCC)(=O)C>[C:1]1([NH:7][C:8]2([CH2:21][O:22][CH3:23])[CH2:9][CH2:10][N:11]([CH2:14][C:19]3[CH:18]=[CH:3][CH:2]=[CH:1][CH:6]=3)[CH2:12][CH2:13]2)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: COC(c1cccs1)C1(Nc2ccccc2)CCN(c2ccccc2)C(C)C1
Solvent: CCOC(C)=O
Product: COCC1(Nc2ccccc2)CCN(Cc2ccccc2)CC1
Temperature: 25 °C
Reaction time: 1 h
Yield: 110.8 %

Procedure:
Raney nickel (38 g, wet, W-2, washed with ethanol, then ethyl acetate) was added to a solution of 4-phenylamino-4-(1-thiophenyl-1-methoxymethyl)-N-phenyl-methyl piperidine (3.10 g, 7.4 mmole) in ethyl acetate (100 ml). The resulting mixture was stirred at room temperature for 1 hour, filtered through a sintered glass funnel and the filtrate concentrated under vacuum. The resulting residue was chromatographed (silica gel; ethyl acetate) to yield the product, 4-phenylamino-4-methoxymethyl-N-phenylmethyl piperidine, (1.27 g, 4.1 mmole) in 55% yield as a colorless oil.