Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[S:6][C:5]([C:7]2[N:11]([C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=3[Cl:18])[N:10]=[C:9]([C:19]([OH:28])([C:24]([F:27])([F:26])[F:25])[C:20]([F:23])([F:22])[F:21])[CH:8]=2)=[CH:4][CH:3]=1.[CH3:29][S:30]([C:33]1[CH:34]=[C:35](B(O)O)[CH:36]=[CH:37][CH:38]=1)(=[O:32])=[O:31].C([O-])([O-])=O.[K+].[K+]>>[Cl:18][C:13]1[CH:14]=[CH:15][CH:16]=[CH:17][C:12]=1[N:11]1[C:7]([C:5]2[S:6][C:2]([C:37]3[CH:36]=[CH:35][CH:34]=[C:33]([S:30]([CH3:29])(=[O:32])=[O:31])[CH:38]=3)=[CH:3][CH:4]=2)=[CH:8][C:9]([C:19]([OH:28])([C:24]([F:27])([F:25])[F:26])[C:20]([F:21])([F:23])[F:22])=[N:10]1
Reactant: OC(c1cc(-c2ccc(Br)s2)n(-c2ccccc2Cl)n1)(C(F)(F)F)C(F)(F)F
Reactant: CS(=O)(=O)c1cccc(B(O)O)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Product: CS(=O)(=O)c1cccc(-c2ccc(-c3cc(C(O)(C(F)(F)F)C(F)(F)F)nn3-c3ccccc3Cl)s2)c1
Temperature: 80 °C
Reaction time: 3 h
Yield: 34.4 %

Procedure:
A mixture of 2-[5-(5-bromothiophen-2-yl)-1-(2-chlorophenyl)-1H-pyrazol-3-yl]-1,1,1,3,3,3-hexafluoro-propan-2-ol (84 mg, 0.17 mmol), 3-methanesulfonyl-phenylboronic acid (42 mg, 0.21 mmol), K2CO3 (70 mg, 0.51 mmol), Cl2Pd(dppf).DCM (21 mg, 15 mol %) and H2O (0.2 mL) in dioxane (2 mL) was sparged with Argon for 5 min and then heated at 80° C. as a sealed flask. After 3 h the reaction mixture was allowed to cool to ambient temperature, filtered (Celite™) and the filter agent rinsed with EtOAc. The combined filtrates were concentrated under reduced pressure and purified by chromatography (silica, EtOAc/Hex, 0:100 to 50:50) to give the title compound (34 mg) as a white solid. 1H-NMR (DCM-d2): δ 8.03 (m, 1H), 7.83 (m, 1H), 7.76 (m, 1H), 7.55-7.62 (m, 4H), 7.49-7.54 (m, 1H), 7.29 (d, 1H), 6.91 (d, 1H), 6.86 (s, 1H), 5.10 (s, 1H), 3.05 (s, 3H); MS(ES): 581 [M+H]+.
Reaction SMILES: Cl[S:2]([C:5]1[N:13]=[C:12]2[N:7]([C:8]([O:15][CH3:16])=[N:9][C:10]([CH3:14])=[CH:11]2)[N:6]=1)(=[O:4])=[O:3].[NH2:17][C:18]1[CH:19]=[N:20][CH:21]=[CH:22][C:23]=1[O:24][CH2:25][CH3:26].ClCCl>N1C=CC=CC=1>[CH2:25]([O:24][C:23]1[CH:22]=[CH:21][N:20]=[CH:19][C:18]=1[NH:17][S:2]([C:5]1[N:13]=[C:12]2[N:7]([C:8]([O:15][CH3:16])=[N:9][C:10]([CH3:14])=[CH:11]2)[N:6]=1)(=[O:4])=[O:3])[CH3:26]
Reactant: COc1nc(C)cc2nc(S(=O)(=O)Cl)nn12
Reactant: CCOc1ccncc1N
Solvent: ClCCl
Solvent: c1ccncc1
Product: CCOc1ccncc1NS(=O)(=O)c1nc2cc(C)nc(OC)n2n1

Procedure:
2-Chlorosulfonyl-5-methoxy-7-methyl[1,2,4]triazolo[1,5-c]pyrimidine (1.5 g, 5.7 mmol) was added to a solution of 0.8 g (5.7 mmol) of 3-amino-4-ethoxypyridine in 30 mL of dry pyridine in portions over 10 minutes with stirring. After 16 hours the reaction mixture was poured into 400 mL of dichloromethane. The resulting mixture was washed with 150 mL of water, dried over magnesium smlfate, and filtered. The liltrate was combined with 5 g of silica gel and the mixture was concentrated by evaporation under reduced pressure. The resulting silica plug was placed onto a 200 g silica gel column and eluted with dichloromethane containing increasing amount of ethanol. The product fractions were combined and concentrated by evaporation under reduced pressure and the solid obtained was dried to obtain 0.75 g (36 percent of theory) of the title compound as a white solid melting at 184°-186° C.
Reaction SMILES: [Br:1][C:2]1[C:3]([OH:16])=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]([C:12](=[O:14])[CH3:13])[C@@H:7]([CH3:15])[CH2:6][CH2:5]2.Br[CH:18]1[CH2:20][CH2:19]1.[I-].[Na+].C(=O)([O-])[O-].[Cs+].[Cs+]>CN(C=O)C.C(OCC)(=O)C>[Br:1][C:2]1[C:3]([O:16][CH:18]2[CH2:20][CH2:19]2)=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]([C:12](=[O:14])[CH3:13])[C@@H:7]([CH3:15])[CH2:6][CH2:5]2
Reactant: BrC1CC1
Reactant: CC(=O)N1c2ccc(Br)c(O)c2CC[C@@H]1C
Agent: O=C([O-])[O-]
Agent: [Cs+]
Agent: [I-]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CC(=O)N1c2ccc(Br)c(OC3CC3)c2CC[C@@H]1C
Temperature: 180 °C
Yield: 97.7 %

Procedure:
A solution of (S)-1-(6-bromo-5-hydroxy-2-methyl-3,4-dihydroquinolin-1(2H)-yl)ethanone (17.05 mg, 0.06 mmol) in DMF (500 μL) was added to a microwave reaction vial equipped with a magnetic stir bar. Bromocyclopropane (150 μL, 1.87 mmol), sodium iodide (8.99 mg, 0.060 mmol) and cesium carbonate (98 mg, 0.300 mmol) were then added and the reaction was sealed. The reaction was heated in the microwave at 180° C. for 6 h. The mixture was diluted with ethyl acetate and washed with brine. The organic layer was dried over anhydrous sodium sulfate, filtered, and concentrated to afford (S)-1-(6-bromo-5-cyclopropoxy-2-methyl-3,4-dihydroquinolin-1(2H)-yl)ethanone (0.019 g, 100%) which was used without further purification. MS (ESI, pos. ion) m/z 324, 326 [M+H]+.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([NH:11][CH:12]([CH2:27]OS(C)(=O)=O)[C:13]([NH:15][C:16]2[CH:21]=[CH:20][CH:19]=[C:18]([C:22]([O:24][CH2:25][CH3:26])=[O:23])[CH:17]=2)=[O:14])(=[O:10])=[O:9])=[CH:4][CH:3]=1.[NH:33]1[CH:37]=[CH:36][N:35]=[CH:34]1>>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([NH:11][CH:12]([CH2:27][N:33]2[CH:37]=[CH:36][N:35]=[CH:34]2)[C:13]([NH:15][C:16]2[CH:21]=[CH:20][CH:19]=[C:18]([C:22]([O:24][CH2:25][CH3:26])=[O:23])[CH:17]=2)=[O:14])(=[O:10])=[O:9])=[CH:4][CH:3]=1
Reactant: c1c[nH]cn1
Reactant: CCOC(=O)c1cccc(NC(=O)C(COS(C)(=O)=O)NS(=O)(=O)c2ccc(Cl)cc2)c1
Product: CCOC(=O)c1cccc(NC(=O)C(Cn2ccnc2)NS(=O)(=O)c2ccc(Cl)cc2)c1

Procedure:
The procedure described in Example 79 was repeated, except that (RS)-2-(4-chlorobenzenesulfonylamino)-N-(3-ethoxycarbonylphenyl)-3-methanesulfonyloxypropanamide (163.3 mg) was reacted with imidazole to obtain the desired (RS)-2-(4-chlorobenzenesulfonylamino)-N-(3-ethoxycarbonylphenyl)-3-(1H-imidazol-1-yl)propanamide (63.5 mg) together with a less polar by-product. The by-product was not investigated further.
Reaction SMILES: C[O:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[C:9]1[N:10]=[C:11]([N:18]2[CH2:23][CH2:22][N:21]([C:24]([O:26][CH2:27][CH:28]([CH3:30])[CH3:29])=[O:25])[CH2:20][CH2:19]2)[C:12]2[S:17][CH:16]=[CH:15][C:13]=2[N:14]=1.B(Br)(Br)Br.C([O-])(O)=O.[Na+]>C(Cl)Cl>[OH:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[C:9]1[N:10]=[C:11]([N:18]2[CH2:19][CH2:20][N:21]([C:24]([O:26][CH2:27][CH:28]([CH3:30])[CH3:29])=[O:25])[CH2:22][CH2:23]2)[C:12]2[S:17][CH:16]=[CH:15][C:13]=2[N:14]=1
Reactant: COc1ccccc1-c1nc(N2CCN(C(=O)OCC(C)C)CC2)c2sccc2n1
Agent: BrB(Br)Br
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Product: CC(C)COC(=O)N1CCN(c2nc(-c3ccccc3O)nc3ccsc23)CC1
Temperature: 25 °C

Procedure:
A solution of isobutyl 4-(2-(2-methoxyphenyl)thieno[3,2-d]pyrimidin-4-yl)piperazine-1-carboxylate (0.11 g, 0.26 mmol) in CH2Cl2 (2 mL) was cooled to −50° C., and a solution of BBr3 in CH2Cl2 (1 M, 1.5 mL, 1.5 mmol) was slowly added. The reaction was allowed to gradually warm to room temperature over 16 h, and saturated aqueous NaHCO3 was slowly added. The organic layer was separated, washed with water, dried over Na2SO4, and concentrated under vacuum. The residue was purified by preparative reverse phase HPLC using 10%-99% CH3CN (0.035% TFA)/H2O (0.05% TFA) to give isobutyl 4-(2-(2-hydroxyphenyl)thieno[3,2-d]pyrimidin-4-yl)piperazine-1-carboxylate. LC/MS: m/z 413.3 (M+H)+ at 3.33 min (10%-99% CH3CN (0.035% TFA)/H2O (0.05% TFA)).
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[C:6]([N:8]2[CH2:13][CH2:12][O:11][CH2:10][CH2:9]2)[CH:5]=[C:4]([CH3:14])[C:3]=1[NH2:15].[CH:16]1([CH2:21][C:22](Cl)=[O:23])[CH2:20][CH2:19][CH2:18][CH2:17]1.O>C(#N)C>[CH:16]1([CH2:21][C:22]([NH:15][C:3]2[C:2]([CH3:1])=[CH:7][C:6]([N:8]3[CH2:13][CH2:12][O:11][CH2:10][CH2:9]3)=[CH:5][C:4]=2[CH3:14])=[O:23])[CH2:20][CH2:19][CH2:18][CH2:17]1
Reactant: O=C(Cl)CC1CCCC1
Reactant: Cc1cc(N2CCOCC2)cc(C)c1N
Solvent: CC#N
Solvent: O
Product: Cc1cc(N2CCOCC2)cc(C)c1NC(=O)CC1CCCC1
Temperature: 150 °C
Yield: 20 %

Procedure:
2,6-Dimethyl-4-morpholin-4-yl-phenylamine (0.50 g) and cyclopentylacetyl chloride (0.53 mL) were dissolved in acetonitrile (5 mL) and heated to 150° C. for 10 minutes in a sealed microwave process vial. Water (25 mL) was added and the product was extracted with ethyl acetate (3×25 mL). The organic phases were washed with brine (50 mL), dried over magnesium sulfate and concentrated in vacuo. The crude product was purified by flash chromatography to furnish 0.138 g (20%) of the title compound as an off-white solid. LC-MS-TOF (m/z) 317 (MH+); tR=1.93, (UV, ELSD) 95%, 100%. 1H NMR (500 MHz, DMSO-d6): 1.21 (m, 2H), 1.52 (m, 2H), 1.61 (m, 2H), 1.76 (m, 2H), 2.07 (s, 6H), 2.11 (m, 1H), 2.25 (d, 2H), 3.05 (dd, 4H), 3.71 (dd, 4H), 6.63 (s, 2H), 8.94 (s, 1H).
Reaction SMILES: [C:1]([N:4]1[C:13]2[C:8](=[CH:9][C:10]([C:14]3[CH:15]=[CH:16][C:17]([C:20]([O:22]C)=[O:21])=[N:18][CH:19]=3)=[CH:11][CH:12]=2)[C@H:7]([NH:24][C:25]2[CH:30]=[CH:29][C:28]([C:31]#[N:32])=[CH:27][N:26]=2)[CH2:6][C@@H:5]1[CH3:33])(=[O:3])[CH3:2].O.[OH-].[Li+].C(O)(=O)C>O1CCOCC1>[C:1]([N:4]1[C:13]2[C:8](=[CH:9][C:10]([C:14]3[CH:15]=[CH:16][C:17]([C:20]([OH:22])=[O:21])=[N:18][CH:19]=3)=[CH:11][CH:12]=2)[C@H:7]([NH:24][C:25]2[CH:30]=[CH:29][C:28]([C:31]#[N:32])=[CH:27][N:26]=2)[CH2:6][C@@H:5]1[CH3:33])(=[O:3])[CH3:2]
Reactant: COC(=O)c1ccc(-c2ccc3c(c2)[C@H](Nc2ccc(C#N)cn2)C[C@H](C)N3C(C)=O)cn1
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1COCCO1
Solvent: CC(=O)O
Product: CC(=O)N1c2ccc(-c3ccc(C(=O)O)nc3)cc2[C@H](Nc2ccc(C#N)cn2)C[C@@H]1C
Temperature: 25 °C
Reaction time: 1 h
Yield: 68.3 %

Procedure:
Methyl 5-((2S,4R)-1-acetyl-4-((5-cyanopyridin-2-yl)amino)-2-methyl-1,2,3,4-tetrahydroquinolin-6-yl)picolinate (for a preparation see Intermediate 33)(2.94 g, 6.66 mmol) was dissolved in anhydrous 1,4-dioxane (20 ml). Water (20.0 ml) was added followed by lithium hydroxide (0.319 g, 13.32 mmol) and reaction mixture stirred at r.t. After 1 h, the 1,4-dioxane was removed in vacuo and aqueous residue was treated with acetic acid (1.144 ml, 19.98 mmol). The resulting orange precipitate was stirred for 20 min, isolated by filtration, washed with water and dried under vacuum overnight to give 5-((2S,4R)-1-acetyl-4-((5-cyanopyridin-2-yl)amino)-2-methyl-1,2,3,4-tetrahydroquinolin-6-yl)picolinic acid (2.16 g, 4.55 mmol, 68.3% yield) as a brown solid. LCMS (Formate, 2 min), Rt=0.68 min, MH+=428.
Reaction SMILES: C(OC(=O)[NH:7][C:8]1[C:9]([C:13]2[CH:18]=[CH:17][C:16]([CH2:19][CH2:20][C:21]3[CH:26]=[CH:25][C:24]([S:27]([CH3:30])(=[O:29])=[O:28])=[CH:23][CH:22]=3)=[CH:15][CH:14]=2)=[N:10][O:11][CH:12]=1)(C)(C)C.Cl>O1CCOCC1>[CH3:30][S:27]([C:24]1[CH:23]=[CH:22][C:21]([CH2:20][CH2:19][C:16]2[CH:17]=[CH:18][C:13]([C:9]3[C:8]([NH2:7])=[CH:12][O:11][N:10]=3)=[CH:14][CH:15]=2)=[CH:26][CH:25]=1)(=[O:28])=[O:29]
Reactant: CC(C)(C)OC(=O)Nc1conc1-c1ccc(CCc2ccc(S(C)(=O)=O)cc2)cc1
Agent: Cl
Solvent: C1COCCO1
Product: CS(=O)(=O)c1ccc(CCc2ccc(-c3nocc3N)cc2)cc1
Temperature: 25 °C
Reaction time: 24.5 h

Procedure:
(3-{4-[2-(4-Methanesulfonyl-phenyl)-ethyl]-phenyl}-isoxazol-4-yl)-carbamic acid tert-butyl ester (88 mg, 0.2 mmol) was dissolved in dioxane (2 mL) and 4N HCl in dioxane (4 mL) was added dropwise. The reaction mixture was stirred at rt for 24.5 h and 3-{4-[2-(4-methanesulfonyl-phenyl)-ethyl]-phenyl}-isoxazol-4-ylamine hydrochloride (53 mg, 71%) was collected by filtration as a white solid. HRMS: 343.111 (M+1)
Reaction SMILES: [NH:1]([C:29]([O:31][CH2:32][C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1)=[O:30])[CH2:2][CH2:3][C:4]([NH:6][C@H:7]([C:18]([N:20]1[CH2:28][CH2:27][CH2:26][C@H:21]1[C:22]([O:24]C)=[O:23])=[O:19])[CH2:8][CH2:9][CH2:10][NH:11][C:12](=[NH:17])[NH:13][N+:14]([O-:16])=[O:15])=[O:5].[OH-].[Na+]>CC(C)=O>[NH:1]([C:29]([O:31][CH2:32][C:33]1[CH:34]=[CH:35][CH:36]=[CH:37][CH:38]=1)=[O:30])[CH2:2][CH2:3][C:4]([NH:6][C@H:7]([C:18]([N:20]1[CH2:28][CH2:27][CH2:26][C@H:21]1[C:22]([OH:24])=[O:23])=[O:19])[CH2:8][CH2:9][CH2:10][NH:11][C:12](=[NH:17])[NH:13][N+:14]([O-:16])=[O:15])=[O:5]
Reactant: COC(=O)[C@@H]1CCCN1C(=O)[C@H](CCCNC(=N)N[N+](=O)[O-])NC(=O)CCNC(=O)OCc1ccccc1
Agent: [Na+]
Agent: [OH-]
Solvent: CC(C)=O
Product: N=C(NCCC[C@H](NC(=O)CCNC(=O)OCc1ccccc1)C(=O)N1CCC[C@H]1C(=O)O)N[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 2 h

Procedure:
In 30 ml. of acetone was dissolved 2.82 g. of Z-β-Ala-Arg(NO2)-Pro-OMe and, under cooling with ice, 10.7 ml. of 1N aqueous sodium hydroxide was added. The mixture was stirred at room temperature for 2 hours. After the mixture was neutralized with 11 ml. of 1N hydrochloric acid, the acetone was distilled off under reduced pressure. To the oily residue was added 30 ml. of cold water and the water was removed by decantation. The residue was washed once with cold water and dried. It was then chromatographed on a column of silica gel (90 g.) with a developer solvent, ethyl acetate-pyridine-acetic acid-water(60:20:6:11). The fractions rich in the contemplated compound were pooled and concentrated to dryness under reduced pressure. The residue was washed with ether and collected by filtration. Yield 2.62 g., melting point: 65°-67° C; [α]D22 -27.5° (c=1.07 %, DMF).
Reaction SMILES: [Na].CO.[Cl:4][C:5]1[CH:6]=[C:7]([N:12]2[CH:16]=[N:15][C:14]([OH:17])=[N:13]2)[CH:8]=[CH:9][C:10]=1[Cl:11].Br[CH:19]([CH3:25])[C:20]([O:22][CH2:23][CH3:24])=[O:21]>CS(C)=O>[Cl:4][C:5]1[CH:6]=[C:7]([N:12]2[CH:16]=[N:15][C:14]([O:17][CH:19]([C:20]([O:22][CH2:23][CH3:24])=[O:21])[CH3:25])=[N:13]2)[CH:8]=[CH:9][C:10]=1[Cl:11]
Reactant: Oc1ncn(-c2ccc(Cl)c(Cl)c2)n1
Reactant: CCOC(=O)C(C)Br
Agent: [Na]
Solvent: CS(C)=O
Solvent: CO
Product: CCOC(=O)C(C)Oc1ncn(-c2ccc(Cl)c(Cl)c2)n1
Yield: 67.1 %

Procedure:
The process was carried out essentially like that of Example 5, using 0.8 g of sodium, 20 ml of methanol, 100 ml of dimethylsulfoxide, 8 g of 1-(3,4-dichlorophenyl)-3-hydroxy-1,2,4-1H-triazole and 6.3 g of ethyl 2-bromopropionate. The product was 7.7 g of the desired product, m.p. 69°-71°.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:16]=[CH:15][C:12]([CH:13]=[O:14])=[CH:11][C:10]=1[OH:17])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(=O)([O-])[O-].[K+].[K+].[CH:24]1(Br)[CH2:28][CH2:27][CH2:26][CH2:25]1.O>C(OCC)C>[CH2:1]([O:8][C:9]1[CH:16]=[CH:15][C:12]([CH:13]=[O:14])=[CH:11][C:10]=1[O:17][CH:24]1[CH2:28][CH2:27][CH2:26][CH2:25]1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: BrC1CCCC1
Reactant: O=Cc1ccc(OCc2ccccc2)c(O)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOCC
Solvent: O
Product: O=Cc1ccc(OCc2ccccc2)c(OC2CCCC2)c1
Temperature: 25 °C
Reaction time: 0.75 h

Procedure:
A stirred solution of 4-benzyloxy-3-hydroxybenzaldehyde (60.9 g; that is prepared as described in Reference Example 36) in dry dimethylformanide (270 mL) under nitrogen is treated portionwise with potassium carbonate (79.5 g). After stirring at room temperature for 45 minutes, it is treated with cyclopentyl bromide (34.3 mL), and the resulting suspension is heated at 60° C. for 8 hours. After cooling, the solution is evaporated to low bulk under reduced pressure, to give an oil. This oil is treated with water (250 mL) and diethyl ether (300 mL), and the aqueous layer is washed with further quantities of diethyl ether (2×50 mL). The combined ethereal extracts are washed with brine (1×50 mL) and with water (3×50 mL), dried over magnesium sulfate and evaporated. The resulting residue is crystallized from methanol, to give 4-benzyloxy-3-cyclopentyloxybenzaldehyde (79 g), m.p. 55-56° C. [Elemental analysis: C,77.1; H,6.9%; calculated: C,77.0; H,6.8%].
Reaction SMILES: [C:1]1([N:7]=[C:8]([S:15][CH:16]([CH3:18])[CH3:17])[CH2:9][CH2:10][Si](C)(C)C)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C(=O)([O-])[O-].[K+].[K+].[Cl-].[Na+]>CO>[C:1]1([N:7]=[C:8]([S:15][CH:16]([CH3:17])[CH3:18])[CH2:9][CH3:10])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: CC(C)SC(CC[Si](C)(C)C)=Nc1ccccc1
Agent: O=C([O-])[O-]
Agent: [Cl-]
Agent: [K+]
Solvent: CO
Product: CCC(=Nc1ccccc1)SC(C)C
Yield: 92.7 %

Procedure:
Isopropyl N-phenyl-3-(trimethylsilyl)thiopropioimidate (1.6 g) was dissolved to methanol (50 ml), small amount of potassium carbonate was added thereto under ice-cooling, then stirred for minutes. The reaction solution was poured into aqueous solution of sodium chloride, and it was extracted with ethyl acetate. The organic layer was washed with water, dried and distilled off the solvent to obtain isopropyl N-phenyl-thiopropioimidate (1.1 g).
Reaction SMILES: [CH2:1](COC)OC.C([Zn]CC)C.C(I)I.C(B1O[C@@H](C(N(C)C)=O)[C@H](C(N(C)C)=O)O1)CCC.[Br:34][C:35]1[CH:36]=[CH:37][C:38]([O:45][CH2:46][CH:47]2[CH2:49][CH2:48]2)=[C:39](/[CH:41]=[CH:42]/[CH2:43][OH:44])[CH:40]=1.[NH4+].[Cl-]>C(Cl)Cl.C(OCC)C>[Br:34][C:35]1[CH:36]=[CH:37][C:38]([O:45][CH2:46][CH:47]2[CH2:48][CH2:49]2)=[C:39]([C@H:41]2[CH2:1][C@@H:42]2[CH2:43][OH:44])[CH:40]=1
Reactant: OC/C=C/c1cc(Br)ccc1OCC1CC1
Reactant: COCCOC
Agent: CCCCB1O[C@@H](C(=O)N(C)C)[C@H](C(=O)N(C)C)O1
Agent: CC[Zn]CC
Agent: [Cl-]
Solvent: CCOCC
Solvent: ICI
Solvent: ClCCl
Product: OC[C@H]1C[C@@H]1c1cc(Br)ccc1OCC1CC1
Temperature: -15 °C
Reaction time: 0.17 h
Yield: 91.6 %

Procedure:
Following a published procedure for asymmetric allylic cyclopropanation: To dimethoxyethane (DME) (1.39 g, 1.60 mL, 15.4 mmol, 1.90 equiv) in CH2Cl2 (50 mL) in a flame-dried round-bottom flask under a N2 atmosphere cooled in an ethyleneglycol/CO2 bath at −15 ° C. was added diethylzinc (2.01 g, 1.67 mL, 16.3 mmol, 2.00 equiv), while maintaining the bath temperature between −15 and −10 ° C. CH2I2 (8.70 g, 2.62 mL, 32.5 mmol, 4.00 equiv) was added dropwise over 20 minutes at −15 ° C. The reaction mixture was stirred at −15 ° C. for 10 minutes. A solution of (4R,5R)-2-butyl-N,N,N′,N′-tetramethyl-1,3,2-dioxaborolane-4,5-dicarboxamide (2.63 g, 2.46 mL, 9.75 mmol, 1.20 equiv) in CH2Cl2 (10 mL) from a separate flame-dried round-bottom flask under a N2 atmosphere was added over 5 minutes via syringe. A solution of (E)-3-(5-bromo-2-(cyclopropylmethoxy)phenyl)prop-2-en-1-ol (S7) (2.30 g, 8.12 mmol, 1.00 equiv) in CH2Cl2 (10 mL) from a separate flame-dried round-bottom flask under a N2 atmosphere was added over 5 minutes via syringe. The reaction mixture was allowed to warm to 23 ° C. and stirred for 20 hours. Saturated aqueous NH4Cl solution (10 mL) and 1M HC1 (50 mL) were added to the reaction mixture. The reaction mixture was transferred to a separatory funnel. Diethyl ether (200 mL) was added and the separatory funnel was shaken and the organic phase was separated. The aqueous phase was extracted from with diethyl ether (200 mL) and then again with diethyl ether (100 mL). The combined organic phases were transferred to an Erlenmeyer flask. 2 M NaOH solution (60 mL) and 30% H2O2 solution (15 mL) were added. The reaction mixture was stirred vigorously for 5 minutes. The reaction mixture was transferred into a separatory funnel and partitioned. The organic phase was washed with 1.0 M aqueous HC1 (75 mL), saturated aqueous Na2CO3 solution (75 mL), saturated aqueous NaHCO3 solution (75 mL) and brine (75 mL). The organic phase was dried with MgSO4, and concentrated in vacuo. The residue was purified by chromatography on silica gel, eluting with a gradient of 10-30% EtOAc in hexanes (v/v) to afford 2.21 g of the title compound as a colorless oil (92% yield and 96% ee as determined on a Chiracel ODH column with 5% isopropanol/hexanes eluent (see FIG. 2A). Racemic S8 was synthesized using the above procedures omitting the addition of (4R,5R)-2-butyl-N,N,N′,N′-tetramethyl-1,3,2-dioxaborolane-4,5-dicarboxamide. Absolute stereochemistry was assigned by analogy.
Reaction SMILES: [CH3:1][CH:2]([OH:9])[CH2:3][NH:4][CH2:5][CH:6]([OH:8])[CH3:7].[C:10](OC)(=O)[CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH3:21].CO>>[CH3:1][CH:2]1[O:9][C:21]2([CH2:20][CH2:19][CH2:18][CH2:17][CH2:16][CH2:15][CH2:14][CH2:13][CH2:12][CH2:11][CH3:10])[O:8][CH:6]([CH3:7])[CH2:5][N:4]2[CH2:3]1
Reactant: CC(O)CNCC(C)O
Reactant: CCCCCCCCCCCC(=O)OC
Solvent: CO
Product: CCCCCCCCCCCC12OC(C)CN1CC(C)O2
Temperature: 230 °C
Reaction time: 5.5 h

Procedure:
To a 1 liter stirred reactor, equipped with a distillation column, condenser, and graduated receiver, the following constituents were added: 261.2 g of diisopropanol amine (DIPA) and 432.0 g (98%) of methyl laurate. The contents were heated slowly to 230° C. under a nitrogen blanket. After 5.5 hours, 57 ml of methanol (0.72 equivalent) had come overhead. The pressure was then slowly lowered to strip out unreacted DIPA. At a batch temperature of 180° C. and a pressure of 293 Pa, a cut consisting of 79.7 g of DIPA and 87.8 g of methyl laurate was removed. The batch temperature was then raised to 200° C. and the pressure dropped to 267 Pa. During this period, a cut of 140.9 g of the amide acetal was recovered. This represents a 35.7% conversion of the methyl laurate to amide acetal.
Reaction SMILES: CC1N=CSC=1.C([Mg]Br)C.[Mg].C(Br)C.[Cl:15][C:16]1[CH:21]=[CH:20][C:19]([C:22]2(C#N)[CH2:25][CH2:24][CH2:23]2)=[CH:18][CH:17]=1.[OH-].[Na+].Cl.ClC1C=CC(C2([C:42]([C:44]3[S:45][CH:46]=[C:47]([CH3:49])[N:48]=3)=[NH:43])CCC2)=CC=1.[BH4-].[Na+]>CCOCC.O.C1(C)C=CC=CC=1.O1CCCC1>[Cl:15][C:16]1[CH:17]=[CH:18][C:19]([C:22]2([NH:43][CH2:42][C:44]3[S:45][CH:46]=[C:47]([CH3:49])[N:48]=3)[CH2:23][CH2:24][CH2:25]2)=[CH:20][CH:21]=1
Reactant: Cc1csc(C(=N)C2(c3ccc(Cl)cc3)CCC2)n1
Reactant: N#CC1(c2ccc(Cl)cc2)CCC1
Agent: CC[Mg]Br
Agent: Cc1cscn1
Agent: Cl
Solvent: CCOCC
Solvent: O
Solvent: Cc1ccccc1
Product: Cc1csc(CNC2(c3ccc(Cl)cc3)CCC2)n1
Temperature: 90 °C

Procedure:
A solution of 4-methylthiazole (4.95 g) in ether (5 ml) was added to ethylmagnesium bromide prepared under nitrogen from magnesium turnings (1.2 g) and ethyl bromide (5.5 g) in ether (40 ml). A yellow precipitate was formed which dissolved when the ether was replaced by tetrahydrofuran (70 ml). 1-(4-Chlorophenyl)cyclobutanecarbonitrile (6.0 g) was added and the solvent replaced by toluene and the mixture heated at 90° C. for two hours. Water and 2N sodium hydroxide solution were added and the reaction mixture extracted with ether. The extract was dried and the solvents removed by evaporation. The residue was dissolved in ether and hydrogen chloride gas was passed into the solution to give a pale yellow solid which is believed to be [1-(4-chlorophenyl)cyclobutyl](4-methylthiazol2-yl)methanimine hydrochloride. This salt was heated at 95° C. for two hours with a solution of sodium borohydride (2 g) in diethyleneglycoldimethylether (100 ml). Water and 2N sodium hydroxide solution were added and the reaction mixture extracted with ether. The extract was dried and the solvents removed by evaporation. The residue was dissolved in ether and hydrogen chloride gas was passed into the solution to give a yellow solid. This solid was converted into the free base which was purified by column chromatography on a florisil column eluted with a mixture of ether and cyclohexane to give [1-(4-chlorophenyl)cyclobutyl](4-methylthiazol-2-yl)methylamine which was converted into a hydrochloride salt [m.p. 230°-232° C. (dec)]containing 1.5 moles of hydrochloride by dissolving the free base in ether and passing hydrogen chloride gas through the solution.
Reaction SMILES: C[O:2][C:3](=[O:21])[C:4]1[CH:9]=[CH:8][C:7]([O:10]C)=[C:6]([NH:12][C:13]2[CH:18]=[C:17]([Cl:19])[CH:16]=[C:15]([Cl:20])[CH:14]=2)[CH:5]=1.Br.[OH-].[NH4+]>C(O)(=O)C>[Cl:19][C:17]1[CH:18]=[C:13]([NH:12][C:6]2[CH:5]=[C:4]([CH:9]=[CH:8][C:7]=2[OH:10])[C:3]([OH:21])=[O:2])[CH:14]=[C:15]([Cl:20])[CH:16]=1
Reactant: COC(=O)c1ccc(OC)c(Nc2cc(Cl)cc(Cl)c2)c1
Agent: Br
Agent: [NH4+]
Agent: [OH-]
Solvent: CC(=O)O
Product: O=C(O)c1ccc(O)c(Nc2cc(Cl)cc(Cl)c2)c1
Temperature: 25 °C
Reaction time: 144 h
Yield: 90.3 %

Procedure:
A solution of 3-(3,5-dichlorophenylamino)-4-methoxybenzoic acid methyl ester (4.48 g, 13.74 mmol), 100 mL of concentrated HBr, and 60 mL of acetic acid was heated to reflux. After 6 days, the reaction was cooled to room temperature and concentrated aqueous ammonium hydroxide was added in portions until the pH=4. The mixture was extracted with ethyl acetate three times, and the combined extracts were washed with brine (2×) and H2O (2×) then dried over MgSO4 and stripped of solvent in vacuo. The residue was triturated with 5% ether/hexane, filtered off and dried to afford the product (3.7 g); m.p. 166-167° C.