Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([NH:4][C:5]1[CH:13]=[CH:12][CH:11]=[C:10]2[C:6]=1[C:7](=[O:35])[N:8]([CH:15]([C:20]1[CH:25]=[CH:24][C:23]([O:26][CH:27]([F:29])[F:28])=[C:22]([O:30][CH2:31][CH:32]3[CH2:34][CH2:33]3)[CH:21]=1)[CH2:16][C:17]([OH:19])=O)[C:9]2=[O:14])(=[O:3])[CH3:2].C(N1C=CN=C1)([N:38]1C=CN=C1)=O.[OH-].[NH4+].O>O1CCCC1>[C:1]([NH:4][C:5]1[CH:13]=[CH:12][CH:11]=[C:10]2[C:6]=1[C:7](=[O:35])[N:8]([CH:15]([C:20]1[CH:25]=[CH:24][C:23]([O:26][CH:27]([F:29])[F:28])=[C:22]([O:30][CH2:31][CH:32]3[CH2:33][CH2:34]3)[CH:21]=1)[CH2:16][C:17]([NH2:38])=[O:19])[C:9]2=[O:14])(=[O:3])[CH3:2]
Reactant: O=C(n1ccnc1)n1ccnc1
Reactant: CC(=O)Nc1cccc2c1C(=O)N(C(CC(=O)O)c1ccc(OC(F)F)c(OCC3CC3)c1)C2=O
Agent: [NH4+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: CC(=O)Nc1cccc2c1C(=O)N(C(CC(N)=O)c1ccc(OC(F)F)c(OCC3CC3)c1)C2=O
Temperature: 25 °C
Reaction time: 2 h
Yield: 74.6 %

Procedure:
To a solution of 3-(4-acetylamino-1,3-dioxo-1,3-dihydro-isoindol-2-yl)-3-(3-cyclopropylmethoxy-4-difluoromethoxy-phenyl)-propionic acid (100 mg, 0.22 mmol) in tetrahydrofurane was added carbonyldiimidazole (53 mg, 0.33 mmol) at room temperature. The solution was stirred for 2 hours at room temperature. To the mixture was added ammonium hydroxide (0.05 ml, 0.66 mmol). The resulted mixture was stirred at room temperature for 2 hours. Water (5 ml) was added to the reaction mixture. THF was removed in vacuo and the resulted mixture was taken up in ethyl acetate (20 ml). The organic layer was washed with saturated sodium bicarbonate solution (3×10 ml), water (10 ml), brine (10 ml) and was dried over magnesium sulfate. The solvent was removed in vacuo. The resulted oil was purified by HPLC (acetonitrile:water=45:55) to give 3-(4-acetylamino-1,3-dioxo-1,3-dihydro-isoindol-2-yl)-3-(3-cyclopropylmethoxy-4-difluoromethoxy-phenyl)-propionamide as a white solid (80 mg, 81%): mp 77–79° C.; 1HNMR (CDCl3): δ 0.32–0.38 (m, 2H), 0.60–0.67 (m, 2H), 1.20–1.31 (m, 1H), 2.27 (s, 3H), 3.03 (dd, J=5.5, 15.5 Hz, 1H), 3.70 (dd, J=8.4, 15.5 Hz, 1H), 5.28–5.40 (m, 1H), 5.74–5.80 (m,1H), 5.79 (dd, J=5.8, 10.5 Hz, 1H), 6.60 (t, JH-F=75 Hz, 1H), 7.09–7.13 (m, 3H), 7.47 (d, J=7.3 Hz, 1H), 7.63 (t, J=7.5 Hz, 1H), 8.75 (d, J=8.5 Hz, 1H), 9.49 (s, 1H). 13C NMR (CDCl3): δ 3.8, 3.9, 10.74, 25.6, 38.1, 51.9, 474.5, 112.5, 114.8, 115.8, 116.7, 118.7, 120.8, 123.5, 125.6, 131.8, 136.7, 137.8, 138.1, 140.8, 151.2, 168.6, 169.9, 170.5, 172.1; Anal. Calcd. for C24H23F2N3O6+0.5 H2O: C, 58.06%; H, 4.87; N, 8.46. Found: C, 57.77; H, 4.60; N, 8.33; 1% H2O.
Reaction SMILES: Cl.Cl.[NH2:3][CH2:4][CH2:5][CH2:6][S:7][C:8]1[CH:13]=[CH:12][N:11]=[CH:10][CH:9]=1.C(N(CC)CC)C.[CH3:21][O:22][C:23]1[CH:24]=[C:25]([CH:29]=[C:30]([O:32][CH3:33])[CH:31]=1)[C:26](Cl)=[O:27]>C(Cl)Cl>[CH3:33][O:32][C:30]1[CH:29]=[C:25]([CH:24]=[C:23]([O:22][CH3:21])[CH:31]=1)[C:26]([NH:3][CH2:4][CH2:5][CH2:6][S:7][C:8]1[CH:13]=[CH:12][N:11]=[CH:10][CH:9]=1)=[O:27]
Reactant: COc1cc(OC)cc(C(=O)Cl)c1
Reactant: NCCCSc1ccncc1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COc1cc(OC)cc(C(=O)NCCCSc2ccncc2)c1
Yield: 87.7 %

Procedure:
To a solution of 1.00 g (4.15 mmol) of 4-(3-aminopropylthio)pyridine dihydrochloride and 2.77 ml (19.8 mmol) of triethylamine in 40 ml of methylene chloride was added 995 mg (4.96 mmol) of 3,5-dimethoxybenzoyl chloride under ice-cooling with stirring and the mixture was stirred at room temperature for 30 minutes. The reaction mixture was washed with an aqueous saturated sodium bicarbonate solution and water and dried. The solvent was distilled off. The residue was purified by column chromatography (eluent: ethyl acetate) to obtain 1.21 g of the desired compound (87.7%, pale yellow powder), mp: 110.0°-111.0° C.
Reaction SMILES: [H-].[Na+].[C:3]([O:7][C:8](=[O:41])[NH:9][CH2:10][C:11]1[CH:40]=[CH:39][C:14]2[N:15]([CH2:34][CH2:35][CH:36]([CH3:38])[CH3:37])[C:16]([CH2:18][N:19]3[C:28]4[C:23](=[CH:24][CH:25]=[CH:26][CH:27]=4)[C:22](=[O:29])[N:21]([CH:30]4[CH2:32][CH2:31]4)[C:20]3=[O:33])=[N:17][C:13]=2[CH:12]=1)([CH3:6])([CH3:5])[CH3:4].I[CH3:43]>CN(C=O)C>[C:3]([O:7][C:8](=[O:41])[N:9]([CH2:10][C:11]1[CH:40]=[CH:39][C:14]2[N:15]([CH2:34][CH2:35][CH:36]([CH3:37])[CH3:38])[C:16]([CH2:18][N:19]3[C:28]4[C:23](=[CH:24][CH:25]=[CH:26][CH:27]=4)[C:22](=[O:29])[N:21]([CH:30]4[CH2:32][CH2:31]4)[C:20]3=[O:33])=[N:17][C:13]=2[CH:12]=1)[CH3:43])([CH3:5])([CH3:4])[CH3:6]
Reactant: CI
Reactant: CC(C)CCn1c(Cn2c(=O)n(C3CC3)c(=O)c3ccccc32)nc2cc(CNC(=O)OC(C)(C)C)ccc21
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CC(C)CCn1c(Cn2c(=O)n(C3CC3)c(=O)c3ccccc32)nc2cc(CN(C)C(=O)OC(C)(C)C)ccc21
Reaction time: 8 h
Yield: 76 %

Procedure:
To a suspension of NaH (60% mineral oil, 11.2 mg, 0.28 mmol) in DMF (2 mL) at room temperature was added [2-(3-cyclopropyl-2,4-dioxo-3,4-dihydro-2H-quinazolin-1-ylmethyl)-1-(3-methyl-butyl)-1H-benzoimidazol-5-ylmethyl]-carbamic acid tert-butyl ester (50 mg, 0.094 mmol). After stirring for 5 min iodomethane (47 μL, 0.75 mmol) was added. The mixture was stirred overnight under a nitrogen atmosphere and partitioned between water and ethyl acetate. The aqueous phase was extracted with ethyl acetate and the combined organic phases washed with 5% sodium meta-bisulfite and brine. After drying over MgSO4 the residue was purified by flash chromatography (eluent 2% MeOH in CH2Cl2) to give [2-(3-cyclopropyl-2,4-dioxo-3,4-dihydro-2H-quinazolin-1-ylmethyl)-1-(3-methyl-butyl)-1H-benzoimidazol-5-ylmethyl]-methyl-carbamic acid tert-butyl ester (39 mg, 76%) as a white solid:
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[N:9]1[C:17](=[O:18])[C:16]2[C@H:15]3[C:19]([CH3:21])([CH3:20])[C@:12]([CH3:22])([CH2:13][CH2:14]3)[C:11]=2[NH:10]1.[F:23][C:24]1[CH:31]=[CH:30][C:27]([CH2:28]Br)=[CH:26][CH:25]=1>[I-].C([N+](CCCC)(CCCC)CCCC)CCC.CN(C)C=O>[F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[N:9]1[C:17](=[O:18])[C:16]2[C@H:15]3[C:19]([CH3:21])([CH3:20])[C@:12]([CH3:22])([CH2:13][CH2:14]3)[C:11]=2[N:10]1[CH2:28][C:27]1[CH:30]=[CH:31][C:24]([F:23])=[CH:25][CH:26]=1
Reactant: Fc1ccc(CBr)cc1
Reactant: CC1(C)[C@H]2CC[C@]1(C)c1[nH]n(-c3ccc(F)cc3F)c(=O)c12
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [I-]
Solvent: CN(C)C=O
Product: CC1(C)[C@H]2CC[C@]1(C)c1c2c(=O)n(-c2ccc(F)cc2F)n1Cc1ccc(F)cc1
Yield: 81 %

Procedure:
A solution of (4R,7S)-2-(2,4-difluoro-phenyl)-7,8,8-trimethyl-1,2,4,5,6,7-hexahydro-4,7-methano-indazol-3-one (Intermediate 42; 152 mg, 0.5 mmol), tetrabutylammonium iodide (195 mg, 0.52 mmol) and 4-fluorobenzyl bromide (0.33 mL, 2.57 mmol) in dimethylformamide (1 mL) was heated at 100° C. in a sealed tube for 9 h. The solvent was evaporated and ethyl acetate was added. The solution was washed with 10% aqueous sodium thiosulfate and brine, dried (sodium sulfate), filtered, evaporated, and purified using an Analogix Intelliflash 280 system (Analogix, Inc. Burlington, Wis.) with a RS-12G silica gel column, eluting with 20-100% ethyl acetate/hexanes, to give (4R,7S)-2-(2,4-difluoro-phenyl)-1-(4-fluoro-benzyl)-7,8,8-trimethyl-1,2,4,5,6,7-hexahydro-4,7-methano-indazol-3-one (167 mg, 81%) as an off-white solid. ES(+)-MS (M+H) 395.
Reaction SMILES: [CH3:1][S:2](Cl)(=[O:4])=[O:3].[C:6]([NH2:14])([CH2:9][C:10]([CH3:13])([CH3:12])[CH3:11])([CH3:8])[CH3:7].C(N(CC)CC)C.Cl>ClCCl>[CH3:7][C:6]([NH:14][S:2]([CH3:1])(=[O:4])=[O:3])([CH3:8])[CH2:9][C:10]([CH3:13])([CH3:12])[CH3:11]
Reactant: CS(=O)(=O)Cl
Reactant: CC(C)(C)CC(C)(C)N
Agent: Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(C)(C)CC(C)(C)NS(C)(=O)=O
Temperature: 25 °C
Reaction time: 1 h

Procedure:
Methanesulfonyl chloride (46 mL, 0.6 mol) in dichloromethane (100 mL) was added dropwise over 45 minutes to a solution of tert-octylamine (80 mL, 0.5 mol) and triethylamine (84 mL, 0.6 mol) in dichloromethane (400 mL) at 0° C. The mixture was stirred for a further 1 hour at room temperature then 1M HCl (1 L) was added in one portion. The mixture was extracted with dichloromethane (2×1 L). The organic solution was dried over MgSO4, filtered and concentrated in vacuo to afford N-(1,1,3,3-tetramethyl-butyl)-methanesulfonamide as a yellow oil (100.8g, 97%).
Reaction SMILES: [C:1]1([CH3:20])[CH:6]=[CH:5][C:4]([C:7]2[N:8]=[C:9]3[CH:14]=[CH:13][C:12]([C:15]([O:17][CH3:18])=[O:16])=[CH:11][N:10]3[CH:19]=2)=[CH:3][CH:2]=1.O.[C:22]([OH:26])(=[O:25])[CH:23]=[O:24]>ClCCl>[OH:24][CH:23]([C:7]1([C:4]2[CH:3]=[CH:2][C:1]([CH3:20])=[CH:6][CH:5]=2)[N:8]2[CH:11]=[C:12]([C:15]([O:17][CH3:18])=[O:16])[CH:13]=[CH:14][C:9]2=[N:10][CH2:19]1)[C:22]([OH:26])=[O:25]
Reactant: O=CC(=O)O
Reactant: COC(=O)c1ccc2nc(-c3ccc(C)cc3)cn2c1
Solvent: ClCCl
Solvent: O
Product: COC(=O)C1=CN2C(=NCC2(c2ccc(C)cc2)C(O)C(=O)O)C=C1
Temperature: 25 °C
Yield: 87 %

Procedure:
To a suspension of methyl 2-(4-tolyl)imidazo[1,2-a]pyridine-6-carboxylate 3 (13.31 g, 50 mmol) in dichloromethane (100 ml) was added solid glyoxylic acid monohydrate (6 g) and the mixture was heated at reflux for 4 h. The mixture was then cooled to room temperature and the white solid filtered, washed by dichloromethane, and dried under vacuum to give (14.9 g, 87%) of 2-hydroxy-2-[6-methoxycarbonyl-3-(4-tolyl)imidazo[1,2-a]pyridine-3-yl]acetic acid 4 as a white solid.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[Br:8].[Li]CCCC.Cl[Sn:15]([CH2:24][CH2:25][CH2:26][CH3:27])([CH2:20][CH2:21][CH2:22][CH3:23])[CH2:16][CH2:17][CH2:18][CH3:19]>C1COCC1.CCCCCC>[Br:8][C:3]1[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=1[Sn:15]([CH2:20][CH2:21][CH2:22][CH3:23])([CH2:24][CH2:25][CH2:26][CH3:27])[CH2:16][CH2:17][CH2:18][CH3:19]
Reactant: Brc1ccccc1Br
Reactant: CCCC[Sn](Cl)(CCCC)CCCC
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CCCCCC
Product: CCCC[Sn](CCCC)(CCCC)c1ccccc1Br
Reaction time: 0 h
Yield: 81 %

Procedure:
A microsystem composed of three T-shaped micromixers (M1, M2 and M3) and two microtube reactors (R1 and R2) was used. The whole microsystem was dipped in a cooling bath (−78° C.). A solution of o-dibromobenzene (0.27 M) in THF (flow rate: 6 mL/min, 1.62 mmol/min) and a solution of n-BuLi (1.5 M) in n-hexane (flow rate: 1.2 mL/min, 1.8 mmol/min) were introduced to the first T-shaped mixer M1 (inner diameter: 250 μm) by using syringe pumps. The resulting solution was passed through the tube reactor R1 and was mixed with chlorotributylstannane (Bu3SnCl) (0.32 M) in THF (flow rate: 6 mL/min, 1.92 mmol/min) in the second T-shaped mixer M2 (inner diameter: 500 μm). The resulting solution was passed through the tube reactor R2 and was introduced to the third T-shaped mixer M3 (inner diameter: 500 μm), where the solution was quenched with methanol (neat, flow rate=3.0 mmol/min). The residence time of the tube reactor R1 (inner diameter: 500 μm, length=50 cm) was 0.82 second. The residence time of the tube reactor R2 (inner diameter: 1,000 μm, length=50 cm) was 1.78 second. After finishing the reaction, an aliquot of the product solution was taken (15 sec) and was concentrated, then the residue was subjected to silica gel column chromatography (hexane) to refine, 2-bromophenyltributylstannane was obtained as colorless oil in 81% yield, 146.6 mg. 1H NMR (400 MHz, CDCl3) δ: 0.88 (t, J=7.2 Hz, 9H), 1.12-1.17 (m, 6H), 1.27-1.38 (m, 6H), 1.51-1.60 (m, 6H), 7.10-7.15 (dt, J=7.6, 1.6 Hz, 1H), 7.18-7.23 (dt, J=7.6, 1.2 Hz, 1H), 7.27-7.31 (dd, J=7.6, 1.6 Hz, 1H), 7.44-7.50 (dd, J=7.6, 1.6 Hz, 1H); 13C NMR (100 MHz, CDCl3) δ: 11.0, 13.8, 27.4, 29.1, 126.1, 129.8, 131.5, 133.2, 137.8, 146.5. HRMS (EI) m/z: calcd. for C14H22BrSn (M+-C4H9) 388.9927, found 388.9925.
Reaction SMILES: CS(C)=O.CS(O[CH2:10][CH2:11][C:12]1[CH:17]=[C:16]([CH2:18][O:19][Si:20]([C:23]([CH3:26])([CH3:25])[CH3:24])([CH3:22])[CH3:21])[C:15]([Cl:27])=[C:14]([Cl:28])[CH:13]=1)(=O)=O.[C-:29]#[N:30].[K+]>CCOCC>[Cl:28][C:14]1[CH:13]=[C:12]([CH2:11][CH2:10][C:29]#[N:30])[CH:17]=[C:16]([CH2:18][O:19][Si:20]([C:23]([CH3:26])([CH3:25])[CH3:24])([CH3:22])[CH3:21])[C:15]=1[Cl:27]
Reactant: [C-]#N
Reactant: CC(C)(C)[Si](C)(C)OCc1cc(CCOS(C)(=O)=O)cc(Cl)c1Cl
Agent: [K+]
Solvent: CS(C)=O
Solvent: CCOCC
Product: CC(C)(C)[Si](C)(C)OCc1cc(CCC#N)cc(Cl)c1Cl
Temperature: 80 °C
Reaction time: 4 h

Procedure:
To a DMSO (0.4 M) solution of 2-[3,4-dichloro-5-({[(1,1-dimethylethyl)(dimethyl)silyl]oxy}methyl)phenyl]ethyl methanesulfonate (1 eq.) from the previous step was added potassium cyanide (1.3 eq.). The resulting solution was stirred at 80° C. for 4 h. The reaction was then diluted with ether and quenched with water. The aqueous layer was separated and back-extracted with ether. The combined organic extracts were washed further with water and brine, dried over Na2SO4, filtered and the filtrate concentrated in vacuo to give the title compound as a pink oil.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:19](=[CH:20][CH:21]=1)[C:9]1[O:10][C:11]3([CH2:17][S:18][C:8]=1[C:7](=[O:22])[C:6]2=[O:23])[CH2:16][CH2:15][NH:14][CH2:13][CH2:12]3.[C:24]([C:28]1[CH:38]=[CH:37][C:31]([O:32][CH2:33][C@H:34]2[CH2:36][O:35]2)=[CH:30][CH:29]=1)([CH3:27])([CH3:26])[CH3:25]>>[C:24]([C:28]1[CH:38]=[CH:37][C:31]([O:32][CH2:33][C@H:34]([OH:35])[CH2:36][N:14]2[CH2:15][CH2:16][C:11]3([O:10][C:9]4[C:19]5[C:5]([C:6](=[O:23])[C:7](=[O:22])[C:8]=4[S:18][CH2:17]3)=[CH:4][C:3]([O:2][CH3:1])=[CH:21][CH:20]=5)[CH2:12][CH2:13]2)=[CH:30][CH:29]=1)([CH3:25])([CH3:26])[CH3:27]
Reactant: CC(C)(C)c1ccc(OC[C@H]2CO2)cc1
Reactant: COc1ccc2c(c1)C(=O)C(=O)C1=C2OC2(CCNCC2)CS1
Product: COc1ccc2c(c1)C(=O)C(=O)C1=C2OC2(CCN(C[C@@H](O)COc3ccc(C(C)(C)C)cc3)CC2)CS1

Procedure:
Compound 201 was synthesized using 8-methoxyspiro[naphtho[1,2-b][1,4]oxathiine-2,4′-piperidine]-5,6-dione, (2R)-2-[(4-tert-butylphenoxy)methyl]oxirane and conditions outlined in procedure Y. M.p.=188-190° C.; 400 MHz 1H NMR (DMSO-d6) δ: 7.73 (d, J=8.6 Hz, 1H), 7.38 (d, J=7.6 Hz, 1H), 7.34 (d, J=2.8 Hz, 1H), 7.31 (d, J=3.0 Hz, 1H), 7.28 (d, J=8.0 Hz, 2H), 6.85 (d, J=9.0 Hz, 1H), 4.86 (d, J=4.7 Hz, 1H), 4.00-3.81 (m, 1H), 3.87 (s, 3H), 3.05 (s, 2H), 2.86-2.73 (m, 2H), 2.54-2.38 (m, 2H), 2.02-1.95 (m, 2H), 1.86-1.74 (m, 2H), 1.25 (s, 9H). LCMS: 538 [M+H].
Reaction SMILES: [C:1](Cl)(Cl)=[O:2].[CH3:5][C:6]1[CH:11]=[CH:10][C:9]([NH2:12])=[C:8]([NH2:13])[CH:7]=1.[OH-].[Na+]>O>[CH3:5][C:6]1[CH:11]=[CH:10][C:9]2=[N:12][C:1](=[O:2])[N:13]=[C:8]2[CH:7]=1
Reactant: O=C(Cl)Cl
Reactant: Cc1ccc(N)c(N)c1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: Cc1ccc2c(c1)=NC(=O)N=2
Yield: 98.5 %

Procedure:
53 g (0.54 mol) of phosgene are passed into 61 g (0.5 mol) of 4-methyl-1,2-diaminobenzene in 450 ml of water and the pH is simultaneously kept constant at 7.2 with 86 g (1.08 mol) of 50% strength aqueous sodium hydroxide solution. After cooling, 72 g of precipitated 5-methyl-benzimidazol-2-one of melting point 290° C. are obtained, which corresponds to a yield of 97% of theory.
Reaction SMILES: [Si:1]([O:18][CH2:19][CH2:20][C:21]1[CH:22]=[C:23]([CH:27]=[CH:28][CH:29]=1)[C:24](O)=[O:25])([C:14]([CH3:17])([CH3:16])[CH3:15])([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(Cl)Cl.ClC(N(C)C)=C(C)C.[NH2:41][C:42]1[S:43][C:44]2[CH2:71][CH2:70][CH2:69][CH2:68][C:45]=2[C:46]=1[C:47]([NH:49][C:50]1[CH:55]=[CH:54][C:53]([CH2:56][CH2:57][C:58]2[CH:67]=[CH:66][C:61]([C:62]([O:64][CH3:65])=[O:63])=[CH:60][CH:59]=2)=[CH:52][CH:51]=1)=[O:48]>N1C=CC=CC=1>[Si:1]([O:18][CH2:19][CH2:20][C:21]1[CH:22]=[C:23]([CH:27]=[CH:28][CH:29]=1)[C:24]([NH:41][C:42]1[S:43][C:44]2[CH2:71][CH2:70][CH2:69][CH2:68][C:45]=2[C:46]=1[C:47]([NH:49][C:50]1[CH:51]=[CH:52][C:53]([CH2:56][CH2:57][C:58]2[CH:59]=[CH:60][C:61]([C:62]([O:64][CH3:65])=[O:63])=[CH:66][CH:67]=2)=[CH:54][CH:55]=1)=[O:48])=[O:25])([C:14]([CH3:16])([CH3:17])[CH3:15])([C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1)[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1
Reactant: COC(=O)c1ccc(CCc2ccc(NC(=O)c3c(N)sc4c3CCCC4)cc2)cc1
Reactant: CC(C)(C)[Si](OCCc1cccc(C(=O)O)c1)(c1ccccc1)c1ccccc1
Agent: CC(C)=C(Cl)N(C)C
Solvent: c1ccncc1
Solvent: ClCCl
Product: COC(=O)c1ccc(CCc2ccc(NC(=O)c3c(NC(=O)c4cccc(CCO[Si](c5ccccc5)(c5ccccc5)C(C)(C)C)c4)sc4c3CCCC4)cc2)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 97.6 %

Procedure:
To a mixture of 480 mg of 3-(2-{[tert-butyl(diphenyl)silyl]oxy}ethyl)benzoic acid and 10 ml of methylene chloride was added 160 mg of 1-chloro-N,N,2-trimethylpropenylamine under ice cooling, followed by stirring for 1 hour at room temperature. 10 ml of a methylene chloride solution containing 450 mg of methyl 4-[2-(4-{[(2-amino-4,5,6,7-tetrahydro-1-benzothiophen-3-yl)carbonyl]amino}phenyl)ethyl]benzoate and 0.20 mL of pyridine was added to the reaction mixture under ice cooling, followed by stirring for 1 hour under ice cooling and then for 4 days at room temperature. The reaction mixture was concentrated under reduced pressure, ethyl acetate and water were added thereto, and the organic layer was separated. The organic layer was washed with a 5% aqueous citric acid solution, a saturated aqueous sodium hydrogen carbonate solution, and saturated brine in this order and dried over anhydrous sodium sulfate, and the solvent was removed under reduced pressure. The residue was purified by silica gel column chromatography (hexane:ethyl acetate=1:1), thereby obtaining 830 mg of methyl 4-[2-(4-{[(2-{[3-(2-{[tert-butyl(diphenyl)silyl]oxy}ethyl)benzoyl]amino}-4,5,6,7-tetrahydro-1-benzothiophen-3-yl)carbonyl]amino}phenyl)ethyl]benzoate.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([C@@H:8]([N:10]2[CH2:15][CH2:14][C@:13]([CH2:22][C:23]([OH:26])([CH3:25])[CH3:24])([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)[O:12][C:11]2=[O:27])[CH3:9])=[CH:4][CH:3]=1.[N:28]1[CH:33]=[CH:32][CH:31]=[CH:30][C:29]=1B(O)O>>[OH:26][C:23]([CH3:25])([CH3:24])[CH2:22][C@@:13]1([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[O:12][C:11](=[O:27])[N:10]([C@H:8]([C:5]2[CH:6]=[CH:7][C:2]([C:29]3[CH:30]=[CH:31][CH:32]=[CH:33][N:28]=3)=[CH:3][CH:4]=2)[CH3:9])[CH2:15][CH2:14]1
Reactant: C[C@@H](c1ccc(Br)cc1)N1CC[C@](CC(C)(C)O)(c2ccccc2)OC1=O
Reactant: OB(O)c1ccccn1
Product: C[C@@H](c1ccc(-c2ccccn2)cc1)N1CC[C@](CC(C)(C)O)(c2ccccc2)OC1=O

Procedure:
The title compound was prepared from (S)-3-((S)-1-(4-bromophenyl)ethyl)-6-(2-hydroxy-2-methylpropyl)-6-phenyl-1,3-oxazinan-2-one and pyridine-2-boronic acid following procedures analogous to those described in Example 75 Step 1. LC-MS Method 2 tR=1.542 min, m/z=430.23; 1H NMR (CDCl3) 1.02-1.15 (d, 6H), 1.50 (d, 3H), 2.09-2.21 (m, 6H), 2.32 (m, 1H), 2.78 (m, 1H), 5.65 (m, 1H), 6.98 (d, 2H), 7.15-7.30 (m, 6H), 7.55 (m, 1H), 7.70 (d, 1H), 8.60 (d, 1H).
Reaction SMILES: [C:1]([NH:4][C:5]1[CH:10]=[CH:9][C:8]([OH:11])=[CH:7][CH:6]=1)(=[O:3])[CH3:2].[CH3:12][O:13][C:14]([C:16]1[CH:21]=[CH:20][C:19](B(O)O)=[CH:18][CH:17]=1)=[O:15]>C(Cl)Cl.C([O-])(=O)C.[Cu+2].C([O-])(=O)C>[C:1]([NH:4][C:5]1[CH:10]=[CH:9][C:8]([O:11][C:19]2[CH:20]=[CH:21][C:16]([C:14]([O:13][CH3:12])=[O:15])=[CH:17][CH:18]=2)=[CH:7][CH:6]=1)(=[O:3])[CH3:2]
Reactant: CC(=O)Nc1ccc(O)cc1
Reactant: COC(=O)c1ccc(B(O)O)cc1
Agent: [Cu+2]
Agent: CC(=O)[O-]
Solvent: ClCCl
Product: COC(=O)c1ccc(Oc2ccc(NC(C)=O)cc2)cc1
Yield: 75.1 %

Procedure:
Dry air is bubbled through a solution of 4-acetamidophenol (320 mg, 2.1 mmol), copper(II) acetate (384 mg, 2.1 mmol), TEA (1.5 mL, 10.5 mol), (4-methoxycarbonylphenyl)boronic acid (760 mg, 4.2 mmol), and powdered molecular sieves (2 g) in CH2Cl2 (21 mL) for 16 hours at room temperature. The resulting material is concentrated and purified by flash column chromatography (25-50% EtOAc in heptane) to give the desired product (450 mg, 75%). 1H NMR (300 MHz, DMSO) δ8.01, 7.54, 7.27, 7.05, 6.98, 3.92, 2.22.
Reaction SMILES: [CH2:1]([N:8]1[CH2:15][CH2:14][CH2:13][C@H:9]1[C:10]([OH:12])=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C[N:17]1[CH2:22][CH2:21]O[CH2:19][CH2:18]1.ClC(OCC(C)C)=O.N1CCCC1>ClCCl>[N:17]1([C:10]([CH:9]2[CH2:13][CH2:14][CH2:15][N:8]2[CH2:1][C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=2)=[O:12])[CH2:22][CH2:21][CH2:19][CH2:18]1
Reactant: CN1CCOCC1
Reactant: O=C(O)[C@@H]1CCCN1Cc1ccccc1
Agent: CC(C)COC(=O)Cl
Solvent: ClCCl
Solvent: C1CCNC1
Product: O=C(C1CCCN1Cc1ccccc1)N1CCCC1
Temperature: 25 °C
Reaction time: 1 h
Yield: 53.9 %

Procedure:
A solution of 1-benzyl-L-proline (50 g) in dichloromethane (300 ml) is cooled with ice. To the solution is added N-methylmorpholine (22.5 g), and then further thereto is added dropwise isobutyl chloroformate (30 g). The mixture is stirred at the same temperature for about one hour, and thereto is added dropwise pyrrolidine (18.8 ml) at the same temperature. The mixture is warmed to room temperature, and stirred for two days. The mixture is washed twice with water (250 ml), and dried over magnesium sulfate. The mixture is concentrated under reduced pressure, and the residue is recrystallized from ethyl acetate-n-hexane to give 2-(1-pyrrolidinyl)carbonyl-1-benzylpyrrolidine (31 g), as white powder.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:19])[CH:5]([O:16][CH2:17][CH3:18])[CH2:6][C:7]1[CH:12]=[CH:11][C:10]([OH:13])=[C:9]([O:14][CH3:15])[CH:8]=1)[CH3:2].[C:20]([C:24]1[CH:29]=[CH:28][C:27]([C:30]2[S:31][C:32]([CH3:38])=[C:33]([CH2:35][CH2:36]O)[N:34]=2)=[CH:26][CH:25]=1)([CH3:23])([CH3:22])[CH3:21].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OCC)=O)=NC(OCC)=O>O1CCCC1>[CH2:1]([O:3][C:4](=[O:19])[CH:5]([O:16][CH2:17][CH3:18])[CH2:6][C:7]1[CH:12]=[CH:11][C:10]([O:13][CH2:36][CH2:35][C:33]2[N:34]=[C:30]([C:27]3[CH:26]=[CH:25][C:24]([C:20]([CH3:21])([CH3:23])[CH3:22])=[CH:29][CH:28]=3)[S:31][C:32]=2[CH3:38])=[C:9]([O:14][CH3:15])[CH:8]=1)[CH3:2]
Reactant: Cc1sc(-c2ccc(C(C)(C)C)cc2)nc1CCO
Reactant: CCOC(=O)C(Cc1ccc(O)c(OC)c1)OCC
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: CCOC(=O)C(Cc1ccc(OCCc2nc(-c3ccc(C(C)(C)C)cc3)sc2C)c(OC)c1)OCC

Procedure:
In analogy to the procedure described in example 1 d], [rac]-2-ethoxy-3-(4-hydroxy-3-methoxy-phenyl)-propionic acid ethyl ester was reacted with 2-[2-(4-tert-butyl-phenyl)-5-methyl-thiazol-4-yl]-ethanol (example 12 b]) in tetrahydrofuran in the presence of triphenylphosphine and DEAD (diethyl azodicarboxylate) to yield [rac]-3-(4-{2-[2-(4-tert-butyl-phenyl)-5-methyl-thiazol-4-yl]-ethoxy}-3-methoxy-phenyl)-2-ethoxy-propionic acid ethyl ester, which was further saponified in analogy to the procedure described in example 4 e], to yield [rac]-3-(4-{2-[2-(4-tert-butyl-phenyl)-5-methyl-thiazol-4-yl]-ethoxy}-3-methoxy-phenyl)-2-ethoxy-propionic acid as light yellow amorphous solid.
Reaction SMILES: [CH2:1]([C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[N:9]=[C:10]=[S:11])[CH3:2].Cl.C([O:15][C:16](=O)[CH2:17][NH:18][CH3:19])C.C(N(CC)CC)C>C(Cl)(Cl)Cl>[CH2:1]([C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[N:9]1[C:16](=[O:15])[CH2:17][N:18]([CH3:19])[C:10]1=[S:11])[CH3:2]
Reactant: CCc1ccccc1N=C=S
Reactant: CCOC(=O)CNC
Agent: Cl
Solvent: CCN(CC)CC
Solvent: ClC(Cl)Cl
Product: CCc1ccccc1N1C(=O)CN(C)C1=S
Yield: 87.4 %

Procedure:
The title compound was prepared by the procedure described in Example 1 using 16.3 g of 2-ethylphenyl-isothiocyanate, 15.3 g of sarcosine ethyl ester hydrochloride, 20.2 g of triethyl amine, and 300 mL of chloroform. The title compound (20.4 g) was obtained as an off-white solid, m.p. 135°-137° C. Anal. Calcd. for C12H14N2O S: C, 61.51; H, 6.02; N,11.96. Found: C, 61.11; H, 5.92; N, 11.71. Mass spectrum (El, M.+) m/z 234.