Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][S:2]([C:5]1[CH:10]=[CH:9][C:8](B(O)O)=[CH:7][CH:6]=1)(=[O:4])=[O:3].C(=O)([O-])[O-].[K+].[K+].Br[C:21]1[CH:22]=[C:23]([C:29]2[N:33]([CH3:34])[C:32]([C:35]([O:37][CH3:38])=[O:36])=[CH:31][C:30]=2[CH3:39])[CH:24]=[CH:25][C:26]=1[O:27][CH3:28].C(O)C>C1(C)C=CC=CC=1>[CH3:28][O:27][C:26]1[C:25]([C:8]2[CH:9]=[CH:10][C:5]([S:2](=[O:4])(=[O:3])[NH2:1])=[CH:6][CH:7]=2)=[CH:24][C:23]([C:29]2[N:33]([CH3:34])[C:32]([C:35]([O:37][CH3:38])=[O:36])=[CH:31][C:30]=2[CH3:39])=[CH:22][CH:21]=1
Reactant: COC(=O)c1cc(C)c(-c2ccc(OC)c(Br)c2)n1C
Reactant: NS(=O)(=O)c1ccc(B(O)O)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCO
Solvent: Cc1ccccc1
Product: COC(=O)c1cc(C)c(-c2ccc(OC)c(-c3ccc(S(N)(=O)=O)cc3)c2)n1C
Temperature: 97.5 °C
Yield: 62.4 %

Procedure:
4-aminosulfonylbenzene boronic acid (0.72 g, 3.57 mmol) and potassium carbonate (0.89 g, 6.50 mmol) were added to a solution of methyl 5-(3-bromo-4-methoxyphenyl)-1,4-dimethyl-1H-pyrrole-2-carboxylate (10a, 1.1 g, 3.25 mmol) in a mixture of toluene:ethanol (5:15 ml) in a tube at 25° C. Nitrogen gas was bubbled through the reaction mixture for 15 minutes. Tetrakis(triphenylphosphine)(0) palladium (0.18 g, 0.16 mmol) was then added to the reaction mixture under nitrogen atmosphere and the tube was sealed. The reaction mixture was heated at 95-100° C. for 1 hr under stirring. The progress of the reaction was monitored by TLC. The reaction mixture was then cooled to 25° C. and filtered through celite. The celite cake was washed with 10% methanol in DCM (30 ml). The combined filtrate was concentrated under reduced pressure to obtain a crude product, which was then purified by column chromatography using 40% ethyl acetate in hexanes as an eluent to obtain the title compound 10b (0.84 g, 62.6%).
Reaction SMILES: [CH2:1]([N:3]([CH2:6]C)[CH2:4]C)C.Cl.[F:9][C:10]([F:27])([S:23]([O-:26])(=[O:25])=[O:24])[CH:11]([O:16][C:17](=[O:22])[C:18]([CH3:21])([CH3:20])[CH3:19])[C:12]([F:15])([F:14])[F:13].[Na+].ClCCl>O>[F:27][C:10]([F:9])([S:23]([O-:26])(=[O:24])=[O:25])[CH:11]([O:16][C:17](=[O:22])[C:18]([CH3:20])([CH3:21])[CH3:19])[C:12]([F:13])([F:15])[F:14].[CH3:1][NH+:3]([CH3:6])[CH3:4]
Reactant: CCN(CC)CC
Agent: CC(C)(C)C(=O)OC(C(F)(F)F)C(F)(F)S(=O)(=O)[O-]
Agent: Cl
Agent: [Na+]
Solvent: O
Solvent: ClCCl
Product: C[NH+](C)C

Procedure:
Triethylamine was dissolved in cold water. To the solution, hydrochloric acid was added, and sodium 1,1,3,3,3-pentafluoro-2-(pivaloyloxy)propanesulfonate prepared in Synthesis Example 27 and dichloromethane were added, whereupon the mixture was stirred. The organic layer was separated and washed with water. From the organic layer as washed, the dichloromethane was distilled off in vacuum. Diethyl ether was added to the residue for recrystallization. The crystals were filtered and dried, obtaining the target compound in a yield of 75%.
Reaction SMILES: [CH:1]([C:4]1[CH:8]=[C:7]([CH:9]([CH3:11])[CH3:10])[N:6]([CH:12]2[CH2:17][CH2:16][C:15](=[O:18])[CH2:14][CH2:13]2)[N:5]=1)([CH3:3])[CH3:2].[BH4-].[Na+].Cl>CO.CCOC(C)=O>[CH:1]([C:4]1[CH:8]=[C:7]([CH:9]([CH3:11])[CH3:10])[N:6]([C@H:12]2[CH2:13][CH2:14][C@H:15]([OH:18])[CH2:16][CH2:17]2)[N:5]=1)([CH3:2])[CH3:3].[CH:1]([C:4]1[CH:8]=[C:7]([CH:9]([CH3:11])[CH3:10])[N:6]([C@@H:12]2[CH2:13][CH2:14][C@H:15]([OH:18])[CH2:16][CH2:17]2)[N:5]=1)([CH3:2])[CH3:3]
Reactant: CC(C)c1cc(C(C)C)n(C2CCC(=O)CC2)n1
Agent: Cl
Agent: [BH4-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CO
Product: CC(C)c1cc(C(C)C)n([C@H]2CC[C@@H](O)CC2)n1
Product: CC(C)c1cc(C(C)C)n([C@H]2CC[C@H](O)CC2)n1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of 4-(3,5-diisopropyl-pyrazol-1-yl)-cyclohexanone (236 mg, 0.95 mmol) in methanol (10 mL) was added NaBH4 (38 mg, 1 mmol). The reaction was stirred at room temperature overnight followed by acidification with HCl (10% aqueous). The reaction was diluted with EtOAc and extracted with water, brine, dried over MgSO4 and concentrated. The residue was purified on silica gel (100% hexane to 4:1 hexane:EtOAc) to give trans-4-(3,5-diisopropyl-pyrazol-1-yl)-cyclohexanol (yield 43.3 mg) and cis-4-(3,5-diisopropyl-pyrazol-1-yl)-cyclohexanol (yield 121 mg) as colorless solids. LC-MS (C15H26N2O calculated 250) m/z 251 (M+H).
Reaction SMILES: [CH3:1][OH:2].O=S(Cl)Cl.[Br:7][C:8]1[C:9]([NH:21][C:22]2[CH:26]=[C:25]([CH:27]3[CH2:29][CH2:28]3)[NH:24][N:23]=2)=[N:10][C:11]([C:14]2[S:18][C:17](C#N)=[CH:16][CH:15]=2)=[N:12][CH:13]=1.[OH-:30].[Na+]>CO.C1COCC1>[Br:7][C:8]1[C:9]([NH:21][C:22]2[CH:26]=[C:25]([CH:27]3[CH2:29][CH2:28]3)[NH:24][N:23]=2)=[N:10][C:11]([C:14]2[S:18][C:17]([C:1]([OH:30])=[O:2])=[CH:16][CH:15]=2)=[N:12][CH:13]=1
Reactant: [OH-]
Reactant: CO
Reactant: N#Cc1ccc(-c2ncc(Br)c(Nc3cc(C4CC4)[nH]n3)n2)s1
Agent: [Na+]
Solvent: O=S(Cl)Cl
Solvent: C1CCOC1
Product: O=C(O)c1ccc(-c2ncc(Br)c(Nc3cc(C4CC4)[nH]n3)n2)s1
Temperature: 0 °C
Reaction time: 1 h
Yield: 38.9 %

Procedure:
A 100 mL round bottomed flask was charged with anhydrous methanol (50 mL). Then, SOCl2 (20 mL) was added dropwise with ice bath. After addition, the mixture was stirred for 1 h at 0° C. Then, the ice bath was removed and 5-(5-bromo-4-(5-cyclopropyl-1H-pyrazol-3-ylamino)pyrimidin-2-yl)thiophene-2-carbonitrile (800 mg, 2.1 mmol, 1.0 equiv.) was added. The mixture was stirred overnight at rt and the solvent was removed. Then, methanol (10 mL) and 1 N HCl aqueous (5 mL) was added. The mixture was stirred for 1 h and the solvent was removed to give a residue, which was purified by silica gel column chromatography (PE/EA/MeOH=2:1:0.06 as eluant) to give a yellow solid. This solid and NaOH (6N, 3 mL) was dissolved in methanol/THF (10 mL/10 mL). The mixture was stirred for 2 h. The solvent was removed and water (10 mL) was added. Then, 1 N HCl was added until the pH of the solution reach 2-3. The mixture was filtered and the solid was collected as acid 5-(5-bromo-4-(5-cyclopropyl-1H-pyrazol-3-ylamino)pyrimidin-2-yl)thiophene-2-carboxylic acid (332.5 mg, yield: 38.9%). LC-MS (m/z)=407.1 [M+H]+.
Reaction SMILES: [CH2:1]([O:3][C:4]([CH:6]1[C:11](=[O:12])[CH2:10][CH2:9][N:8]([C:13]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14])[CH2:7]1)=[O:5])[CH3:2].CN(C=O)C.[CH2:25](Br)[C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1>>[CH2:1]([O:3][C:4]([C:6]1([CH2:25][C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)[C:11](=[O:12])[CH2:10][CH2:9][N:8]([C:13]([O:15][C:16]([CH3:18])([CH3:17])[CH3:19])=[O:14])[CH2:7]1)=[O:5])[CH3:2]
Reactant: BrCc1ccccc1
Reactant: CCOC(=O)C1CN(C(=O)OC(C)(C)C)CCC1=O
Solvent: CN(C)C=O
Product: CCOC(=O)C1(Cc2ccccc2)CN(C(=O)OC(C)(C)C)CCC1=O
Temperature: 60 °C
Reaction time: 20 h
Yield: 34.4 %

Procedure:
To a solution of 4-oxo-piperidine-1,3-dicarboxylic acid 1-tert-butyl ester 3-ethyl ester (73.36 g, 0.27 mol) in DMF (734 mL) lithium carbonate (50 g, 0.676 mol) was added, followed by benzyl bromide (55.44 g, 0.324 mol). The mixture was heated to about 60° C. and stirred for about 20 hours. The reaction mixture was then cooled to room temperature and extracted with IPE, washed with water and dried over magnesium sulfate. After filtration and concentration in vacuo a solid was obtained. Recrystallization of the crude product in hexane afforded a white solid (33.6 g, yield 38.2%).
Reaction SMILES: [Cl:1][CH2:2][C:3](Cl)=[O:4].[CH2:6]([C:9]1[CH:10]=[CH:11][CH:12]=[C:13]2[C:18]=1[NH:17][C:16](=[O:19])[CH:15]=[CH:14]2)[CH2:7][CH3:8]>>[Cl:1][CH2:2][C:3]([C:11]1[CH:12]=[C:13]2[C:18](=[C:9]([CH2:6][CH2:7][CH3:8])[CH:10]=1)[NH:17][C:16](=[O:19])[CH:15]=[CH:14]2)=[O:4]
Reactant: CCCc1cccc2ccc(=O)[nH]c12
Reactant: O=C(Cl)CCl
Product: CCCc1cc(C(=O)CCl)cc2ccc(=O)[nH]c12

Procedure:
By using chloroacetyl chloride and 8-propylcarbostyril, there was obtained 6-chloroacetyl-8-propylcarbostyril as a white powder having a melting point of 244°-247° C.
Reaction SMILES: C([Li])CCC.[CH2:6]([C@H:13]1[CH2:17][O:16][C:15](=[O:18])[NH:14]1)[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1.[CH:19]1([CH2:25][CH2:26][CH2:27][CH2:28][C:29](Cl)=[O:30])[CH2:24][CH2:23][CH2:22][CH2:21][CH2:20]1>O1CCCC1>[CH2:6]([C@H:13]1[CH2:17][O:16][C:15](=[O:18])[N:14]1[C:29](=[O:30])[CH2:28][CH2:27][CH2:26][CH2:25][CH:19]1[CH2:24][CH2:23][CH2:22][CH2:21][CH2:20]1)[C:7]1[CH:8]=[CH:9][CH:10]=[CH:11][CH:12]=1
Reactant: O=C(Cl)CCCCC1CCCCC1
Reactant: O=C1N[C@@H](Cc2ccccc2)CO1
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: O=C(CCCCC1CCCCC1)N1C(=O)OC[C@@H]1Cc1ccccc1
Temperature: 25 °C
Reaction time: 0.75 h
Yield: 94.3 %

Procedure:
A solution of n-butyllithium (100 ml, 250 mmol, 2.5M in hexanes) was added via a cannula to a solution of (4S)-4-benzyl-1,3-oxazolidin-2-one (44.30 g, 250 mmol) in anhydrous tetrahydrofuran (400 ml) at −78° C. The yellow solution was then stirred for 45 minutes. A solution of 5-cyclohexylpentanoyl chloride (55.5 g, 275 mmol) in tetrahydrofuran (100 ml) was then added over 1 hour. The mixture was stirred at −78° C. for 30 minutes then warmed to room temperature over 1 hour. The mixture was quenched with an aqueous solution of ammonium chloride (20% w/v, 400 ml) and extracted with ethyl acetate. The layers were separated and the organic layer was washed with brine, dried over anhydrous sodium sulphate and the solvent removed under reduced pressure. The solid was recrystallised from hexane (500 ml) to afford the title compound as a white solid (81.0 g).
Reaction SMILES: [C:1]([C:5]1[CH:10]=[CH:9][C:8]([OH:11])=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2].[CH2:12]([S:14]SCC)[CH3:13].C(S)C>C(O)CC.CCCO.CCCO.CCCO.CCCO.[Zr].[Zr]>[CH2:12]([S:14][C:9]1[CH:10]=[C:5]([C:1]([CH3:4])([CH3:2])[CH3:3])[CH:6]=[CH:7][C:8]=1[OH:11])[CH3:13]
Reactant: CC(C)(C)c1ccc(O)cc1
Reactant: CCSSCC
Agent: [Zr]
Solvent: CCS
Solvent: CCCO
Product: CCSc1cc(C(C)(C)C)ccc1O
Temperature: 194 °C
Yield: 48.3 %

Procedure:
To 4-t-Butylphenol (10.0 g, 0.067 moles) was added 2.8 g zirconium n-propoxide in n-propanol consisting of 21.6% zirconium (0.007 mole) and 10.8% free propanol. The mixture was distilled at atmospheric pressure removing 1.8 g of n-propanol. To the mixture was added ethyl disulfide (8.2 g, 0.067 moles). The mixture was heated under nitrogen while ethyl mercaptan was removed continuously by distillation. Heating under nitrogen was continued for a total of 142 hours during which temperature slowly increased to 194° C. The mixture was cooled, hydrolyzed by addition of water, and made acid with concentrated HCl. The mixture was extracted with ether. The ether extracts were dried over magnesium sulfate, filtered, and concentrated on a rotary flash evaporator. GC analysis of the concentrate indicated only two major components, 2.5 g of 4-t-butylphenol and 6.8 g of 2-ethylthio-4-t-butylphenol (49% yield).
Reaction SMILES: [I-].[CH3:2][S+](C)(C)=O.[OH-].[K+].C(O[C@@H:13]1[C@H:18]2[C@H:19]3[C@H:29]([CH2:30][CH2:31][C@:16]2([CH3:17])[C:15](=[O:34])[CH2:14]1)[C@:27]1([CH3:28])[C:22]([CH:23]=[C:24]([O:32][CH3:33])[CH2:25][CH2:26]1)=[CH:21][CH2:20]3)(=O)C.O>CS(C)=O>[CH2:2]1[C@@H:14]2[C:15](=[O:34])[C@:16]3([CH2:31][CH2:30][C@H:29]4[C@@H:19]([CH2:20][CH:21]=[C:22]5[C@:27]4([CH3:28])[CH2:26][CH2:25][C:24]([O:32][CH3:33])=[CH:23]5)[C@@H:18]3[C@H:13]12)[CH3:17]
Reactant: COC1=CC2=CC[C@H]3[C@@H]4[C@@H](OC(C)=O)CC(=O)[C@@]4(C)CC[C@@H]3[C@@]2(C)CC1
Reactant: C[S+](C)(C)=O
Agent: [I-]
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: CS(C)=O
Product: COC1=CC2=CC[C@H]3[C@@H]4[C@@H]5C[C@@H]5C(=O)[C@@]4(C)CC[C@@H]3[C@@]2(C)CC1
Reaction time: 1 h

Procedure:
64.8 g of trimethylsulfoxonium iodide is dissolved in 900 ml of dimethyl sulfoxide under nitrogen atmosphere with stirring and to this solution 27.55 g of potassium hydroxide is added at 25-30° C. The reaction mixture is stirred for 1 hour, then 81.1 g of 15α-acetoxy-3-methoxy-androst-3,5-diene-17-one is added and stirring is continued at 25-30° C. until the reaction is finished (about additional 6 hours). The solution is slowly added to 4500 ml of water, the precipitate is compacted by stirring (30 minutes), filtered, washed with water until it is neutral and dried in vacuo to constant weight below 40° C. The title compound is crystallized from methanol.
Reaction SMILES: C(N(C(C)C)CC)(C)C.C1(O[C:17](=[O:29])[NH:18][C:19]2[CH:24]=[CH:23][CH:22]=[C:21]([S:25]([CH3:28])(=[O:27])=[O:26])[CH:20]=2)C=CC=CC=1.[NH2:30][C:31]1[CH:54]=[CH:53][C:34]([O:35][C:36]2[C:45]3[C:40](=[CH:41][C:42]([O:48][CH2:49][CH2:50][O:51][CH3:52])=[C:43]([C:46]#[N:47])[CH:44]=3)[N:39]=[CH:38][CH:37]=2)=[CH:33][CH:32]=1>>[C:46]([C:43]1[CH:44]=[C:45]2[C:40](=[CH:41][C:42]=1[O:48][CH2:49][CH2:50][O:51][CH3:52])[N:39]=[CH:38][CH:37]=[C:36]2[O:35][C:34]1[CH:33]=[CH:32][C:31]([NH:30][C:17]([NH:18][C:19]2[CH:24]=[CH:23][CH:22]=[C:21]([S:25]([CH3:28])(=[O:26])=[O:27])[CH:20]=2)=[O:29])=[CH:54][CH:53]=1)#[N:47]
Reactant: COCCOc1cc2nccc(Oc3ccc(N)cc3)c2cc1C#N
Reactant: CS(=O)(=O)c1cccc(NC(=O)Oc2ccccc2)c1
Solvent: CCN(C(C)C)C(C)C
Product: COCCOc1cc2nccc(Oc3ccc(NC(=O)Nc4cccc(S(C)(=O)=O)c4)cc3)c2cc1C#N
Yield: 75.5 %

Procedure:
Diisopropylethylamine (0.057 ml, 0.328 mmol) and phenylN-[3-(methylsulfonyl)phenyl]carbamate (96 mg, 0.328 mmol) were reacted with 4-(4-aminophenoxy)-7-(2-methoxyethoxy)-6-cyanoquinoline (100 mg, 0.298 mmol), and the title compound (120 mg, 0.225 mmol, 75.6%) was obtained as white crystals by the same procedure as in Example 34.
Reaction SMILES: [N:1]12[CH2:8][CH2:7][CH:4]([CH2:5][CH2:6]1)[C@@H:3]([O:9][C:10]1[N:15]=[N:14][C:13]([C:16]3[CH:17]=[C:18]4[C:22](=[CH:23][CH:24]=3)[NH:21][CH:20]=[CH:19]4)=[CH:12][CH:11]=1)[CH2:2]2.CC(O)=O.[Br:29]N1C(=O)CCC1=O>CC#N>[Br:29][C:19]1[C:18]2[C:22](=[CH:23][CH:24]=[C:16]([C:13]3[N:14]=[N:15][C:10]([O:9][C@@H:3]4[CH:4]5[CH2:7][CH2:8][N:1]([CH2:6][CH2:5]5)[CH2:2]4)=[CH:11][CH:12]=3)[CH:17]=2)[NH:21][CH:20]=1
Reactant: O=C1CCC(=O)N1Br
Reactant: c1cc2cc(-c3ccc(O[C@H]4CN5CCC4CC5)nn3)ccc2[nH]1
Solvent: CC(=O)O
Solvent: CC#N
Product: Brc1c[nH]c2ccc(-c3ccc(O[C@H]4CN5CCC4CC5)nn3)cc12
Temperature: 25 °C
Reaction time: 1 h

Procedure:
The product of Example 9B (160 mg, 0.5 mmol) was dissolved in MeCN (10 mL) and treated with HOAc (Sigma, 60 mg, 1 mmol) for 10 min. N-bromosuccinimide (Aldrich, 110 mg, 0.6 mmol) in MeCN (Aldrich, 5 mL) was slowly added over 5 min. The mixture was stirred for 1 hour at ambient temperature and concentrated under vacuum. The title compound was purified by chromatography (SiO2, CH2Cl2:MeOH:NH3.H2O, 90:10:1, Rf. 0.15) as a solid (70 mg, yield, 35%). 1H NMR (300 MHz, CD3OD) δ 1.55-1.62 (m, 1H), 1.70-1.96 (m, 2H), 2.05-2.20 (m, 1H), 2.29-2.43 (m, 1H), 2.74-3.13 (m, 5H), 3.42-3.66 (m, 1H, 5.24-5.46 (m, 1H), 7.27 (d, J=9.2 Hz, 1H), 7.38 (s, 1H), 7.53 (d, J=8.5 Hz, 1H), 7.82 (dd, J=8.5, 1.7 Hz, 1H), 8.05 (s, 1H), 8.11 (d, J=9.5 Hz, 1H) ppm. MS (DCI/NH3): 399 (M+H)+, 401 (M+H)+.
Reaction SMILES: [NH2:1][CH2:2][C:3]1[N:11]=[C:10]2[C:6]([N:7]=[CH:8][N:9]2[C@H:12]2[C@H:16]([OH:17])[C@H:15]([OH:18])[C@@H:14]([CH2:19][O:20][CH3:21])[O:13]2)=[C:5]([NH:22][CH2:23][CH:24]([C:31]2[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=2)[C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)[N:4]=1.[CH3:37][O:38][CH2:39][CH2:40][S:41](Cl)(=[O:43])=[O:42].C(N(CC)CC)C>O1CCCC1>[OH:17][C@@H:16]1[C@H:15]([OH:18])[C@@H:14]([CH2:19][O:20][CH3:21])[O:13][C@H:12]1[N:9]1[CH:8]=[N:7][C:6]2[C:10]1=[N:11][C:3]([CH2:2][NH:1][S:41]([CH2:40][CH2:39][O:38][CH3:37])(=[O:43])=[O:42])=[N:4][C:5]=2[NH:22][CH2:23][CH:24]([C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1)[C:25]1[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=1
Reactant: COC[C@H]1O[C@@H](n2cnc3c(NCC(c4ccccc4)c4ccccc4)nc(CN)nc32)[C@H](O)[C@@H]1O
Reactant: COCCS(=O)(=O)Cl
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: COCCS(=O)(=O)NCc1nc(NCC(c2ccccc2)c2ccccc2)c2ncn([C@@H]3O[C@H](COC)[C@@H](O)[C@H]3O)c2n1
Yield: 74.9 %

Procedure:
The title compound was prepared by a similar method to example 3 using (2R,3R,4S,5R)-2-{2-(aminomethyl)-6-[(2,2-diphenylethyl)amino}-9H-purin-9-yl}-5-(methoxymethyl)tetrahydro-3,4-furandiol (example 1) (250 mg, 0.49 mmol), 2-methoxy-1-ethanesulfonyl chloride (J. Org. Chem. 2633, 26, 1961) (77 mg, 0.49 mmol), triethylamine (150 mg, 1.5 mmol) in tetrahydrofuran (23 ml). The crude product was purified by column chromatography on silica gel eluting with a solvent system of dichloromethane:methanol:ammonia (96:4:0.2) gave the title compound (225 mg) as an oil. MS: 614 (MH+).
Reaction SMILES: [NH2:1][C@H:2]([CH:17]1[CH2:22][CH2:21][CH2:20][CH2:19][CH2:18]1)[C:3]([C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)([C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1)[OH:4].C[B:24]1[O:29]B(C)OB(C)O1.O1CCC[CH2:33]1>>[CH:17]1([C@@H:2]2[C:3]([C:11]3[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=3)([C:5]3[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=3)[O:4][B:24]([O:29][CH3:33])[NH:1]2)[CH2:22][CH2:21][CH2:20][CH2:19][CH2:18]1
Reactant: CB1OB(C)OB(C)O1
Reactant: C1CCOC1
Reactant: N[C@H](C1CCCCC1)C(O)(c1ccccc1)c1ccccc1
Product: COB1N[C@H](C2CCCCC2)C(c2ccccc2)(c2ccccc2)O1
Reaction time: 1.5 h

Procedure:
(R)-2-amino-2-cyclohexyl-1,1-diphenylethanol (59 mg, 0.2 mmol), dry tetrahydrofuran (2 mL) and trimethylboroxine (27.2 μL, 0.24 mmol) were added to a dry flask under an atmosphere of nitrogen, then stirred for 1.5 hr to form a solution of (R)-4-cyclohexyl-5,5-diphenyl-2-methoxy-1,3,2-oxazaborolidine. Borane dimethylsulfide complex (100 μL, 1.0 mmol) was added and the reaction stirred for 30 minutes. Then, a solution of bromoacetophenone (199 mg, 1.0 mmol) in dry tetrahydrofuran (4 mL) was added at the rate of 9 mL/hr by means of a syringe pump. After 1.5 hr, methanol was added to quench the reaction and then, the solvent was removed by evaporation. The resulting residue was chromatographed on silica gel (hexane/ethyl acetate 20:1) and combination of the like fractions, followed by removal of the solvent gave (R)-2-bromo-1-phenylethanol (130 mg, 98.7% ee). The enantiomeric excess was measured by HPLC (Chiralcel OD-H column, mobile phase, hexane/2-propanol 9:1, flow rate=0.7 mL/min).
Reaction SMILES: [C:1](Cl)(=[O:6])[C:2]([CH3:5])([CH3:4])[CH3:3].[CH3:8][O:9][C:10]1[CH:16]=[CH:15][CH:14]=[CH:13][C:11]=1[NH2:12].C(N(CC)CC)C.O>O1CCOCC1>[CH3:8][O:9][C:10]1[CH:16]=[CH:15][CH:14]=[CH:13][C:11]=1[NH:12][C:1](=[O:6])[C:2]([CH3:5])([CH3:4])[CH3:3]
Reactant: CC(C)(C)C(=O)Cl
Reactant: COc1ccccc1N
Solvent: O
Solvent: C1COCCO1
Solvent: CCN(CC)CC
Product: COc1ccccc1NC(=O)C(C)(C)C
Temperature: 25 °C
Reaction time: 2 h
Yield: 95.5 %

Procedure:
Pivaloyl chloride (120 g, 1 mol) was added dropwise at ambient temperature to a stirred solution of 2-methoxyaniline (123 g, 1 mol) and triethylamine (111 g, 1.1 mol) in 1,4-dioxane (1200 ml), the mixture was stirred at ambient temperature for 2 hours, then it was poured into water (3000 ml). The product was extracted into ethyl acetate (3×300 ml), then the combined extracts were dried (MgSO4) and the solvents were removed in vacuo to give N-(2-methoxyphenyl)pivalamide (198 g; 96%) as a low-melting solid which was used without further purification.
Reaction SMILES: [CH2:1]([N:3]([CH2:22][CH3:23])[C:4]([C:6]1[CH:11]=[CH:10][C:9]([CH:12]([OH:21])[C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=2[O:19][CH3:20])=[CH:8][CH:7]=1)=[O:5])[CH3:2].[C:24](OC(=O)C)(=[O:26])[CH3:25].CO>N1C=CC=CC=1>[C:24]([O:21][CH:12]([C:9]1[CH:8]=[CH:7][C:6]([C:4](=[O:5])[N:3]([CH2:1][CH3:2])[CH2:22][CH3:23])=[CH:11][CH:10]=1)[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=1[O:19][CH3:20])(=[O:26])[CH3:25]
Reactant: CCN(CC)C(=O)c1ccc(C(O)c2ccccc2OC)cc1
Reactant: CC(=O)OC(C)=O
Solvent: c1ccncc1
Solvent: CO
Product: CCN(CC)C(=O)c1ccc(C(OC(C)=O)c2ccccc2OC)cc1
Temperature: 25 °C
Reaction time: 15 h

Procedure:
1-(4-Diethylcarbamoylphenyl)-1-(2-methoxyphenyl)methyl alcohol (14.14 g) was dissolved in pyridine (280 ml), added with acetic anhydride (140 ml) with ice cooling and stirred at room temperature for 15 hours. After the reaction mixture was added with methanol (140 ml) with ice cooling and stirred at room temperature for 10 minutes, the solvent was evaporated under reduced pressure to obtain 1-(4-diethylcarbamoylphenyl)-1-(2-methoxyphenyl)methyl acetate.
Reaction SMILES: [Cl:1][C:2]1[C:13]([Cl:14])=[C:12]([C:15](=[O:19])[CH2:16][CH2:17][CH3:18])[CH:11]=[CH:10][C:3]=1[O:4][CH2:5][CH2:6][C:7]([OH:9])=[O:8].Cl.[CH3:21]NC.C=O.C(O)(=O)C>CN(C)C=O>[Cl:1][C:2]1[C:13]([Cl:14])=[C:12]([C:15](=[O:19])[C:16](=[CH2:21])[CH2:17][CH3:18])[CH:11]=[CH:10][C:3]=1[O:4][CH2:5][CH2:6][C:7]([OH:9])=[O:8]
Reactant: CCCC(=O)c1ccc(OCCC(=O)O)c(Cl)c1Cl
Reactant: CNC
Agent: C=O
Agent: Cl
Solvent: CN(C)C=O
Solvent: CC(=O)O
Product: C=C(CC)C(=O)c1ccc(OCCC(=O)O)c(Cl)c1Cl
Temperature: 0 °C
Reaction time: 1.5 h

Procedure:
3-(2,3-Dichloro-4-butyrylphenoxy)propionic acid (6.65 g, 0.022 mole), dimethylamine hydrochloride (12 g, 0.15 mole), paraformaldehyde (2.3 g, 0.077 equiv.) and acetic acid (1 ml) were mixed and stirred while heating on a steam bath for 2.5 hours. N,N-dimethylformamide (25 ml) was added to the mixture and stirring and heating continued for another 1.5 hours. The mixture was poured into ice water (600 ml) and the precipitate that formed removed by filtration, washed with water and dried. After recrystallization from butyl chloride, 58 g 3-[2,3-dichloro-4-(2-methylenebutyryl)phenoxy]propionic acid remained.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([F:30])[C:5]([C:24]2[N:28]=[C:27]([CH3:29])[O:26][N:25]=2)=[C:6]([C:8]2[CH:9]=[C:10]3[C:14](=[CH:15][CH:16]=2)[C@@H:13]([NH:17][C:18]([C:20]2([NH2:23])[CH2:22][CH2:21]2)=[O:19])[CH2:12][CH2:11]3)[CH:7]=1.[CH3:31][O:32][C:33]1[N:38]=[CH:37][C:36]([C:39](O)=[O:40])=[CH:35][N:34]=1>>[Cl:1][C:2]1[CH:3]=[C:4]([F:30])[C:5]([C:24]2[N:28]=[C:27]([CH3:29])[O:26][N:25]=2)=[C:6]([C:8]2[CH:9]=[C:10]3[C:14](=[CH:15][CH:16]=2)[C@@H:13]([NH:17][C:18]([C:20]2([NH:23][C:39]([C:36]4[CH:35]=[N:34][C:33]([O:32][CH3:31])=[N:38][CH:37]=4)=[O:40])[CH2:21][CH2:22]2)=[O:19])[CH2:12][CH2:11]3)[CH:7]=1
Reactant: Cc1nc(-c2c(F)cc(Cl)cc2-c2ccc3c(c2)CC[C@@H]3NC(=O)C2(N)CC2)no1
Reactant: COc1ncc(C(=O)O)cn1
Product: COc1ncc(C(=O)NC2(C(=O)N[C@H]3CCc4cc(-c5cc(Cl)cc(F)c5-c5noc(C)n5)ccc43)CC2)cn1

Procedure:
In analogy to the procedures described for the preparation of intermediate A-1 [B], 1-amino-cyclopropanecarboxylic acid{(S)-5-[5-chloro-3-fluoro-2-(5-methyl-[1,2,4]oxadiazol-3-yl)-phenyl]-indan-1-yl}-amide (example 24) was coupled with 2-methoxy-pyrimidine-5-carboxylic acid to yield the title compound as light yellow solid. MS: 563.2 (MH+, 1Cl).
Reaction SMILES: [CH3:1][C:2]1([CH3:21])[CH:11]=[C:10]([CH3:12])[C:9]2[C:4](=[CH:5][CH:6]=[C:7](OS(C(F)(F)F)(=O)=O)[CH:8]=2)[NH:3]1.[CH3:22][O:23][C:24]1[CH:29]=[CH:28][C:27](B(O)O)=[CH:26][CH:25]=1.[C:33]1([CH2:39][CH2:40][SH:41])[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1>>[CH3:22][O:23][C:24]1[CH:29]=[CH:28][C:27]([C:7]2[CH:8]=[C:9]3[C:4](=[CH:5][CH:6]=2)[NH:3][C:2]([CH3:1])([CH3:21])[CH:11]=[C:10]3[CH2:12][S:41][CH2:40][CH2:39][C:33]2[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=2)=[CH:26][CH:25]=1
Reactant: SCCc1ccccc1
Reactant: CC1=CC(C)(C)Nc2ccc(OS(=O)(=O)C(F)(F)F)cc21
Reactant: COc1ccc(B(O)O)cc1
Product: COc1ccc(-c2ccc3c(c2)C(CSCCc2ccccc2)=CC(C)(C)N3)cc1

Procedure:
Trifluoromethanesulfonic acid 2,2,4-trimethyl-1,2-dihydroquinolin-6-yl ester was coupled with 4-methoxyphenylboronic acid. Bromination and coupling reaction with 2-phenylethanethiol gave 15 mg of the title compound.