Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]1([C:6]2[S:14][C:13]3[C:12]([C:15]#[N:16])=[CH:11][N:10]=[C:9]([NH:17][CH2:18][C:19]4[CH:24]=[CH:23][C:22]([O:25][CH3:26])=[CH:21][CH:20]=4)[C:8]=3[CH:7]=2)[CH2:5][CH2:4][CH2:3][CH:2]=1.[OH-].[K+].C([OH:33])(C)(C)C>C(Cl)Cl>[C:1]1([C:6]2[S:14][C:13]3[C:12]([C:15]([NH2:16])=[O:33])=[CH:11][N:10]=[C:9]([NH:17][CH2:18][C:19]4[CH:24]=[CH:23][C:22]([O:25][CH3:26])=[CH:21][CH:20]=4)[C:8]=3[CH:7]=2)[CH2:5][CH2:4][CH2:3][CH:2]=1
Reactant: COc1ccc(CNc2ncc(C#N)c3sc(C4=CCCC4)cc23)cc1
Reactant: CC(C)(C)O
Agent: [K+]
Agent: [OH-]
Solvent: ClCCl
Product: COc1ccc(CNc2ncc(C(N)=O)c3sc(C4=CCCC4)cc23)cc1

Procedure:
2-Cyclopent-1-enyl-4-(4-methoxy-benzylamino)-thieno[3,2-c]pyridine-7-carbonitrile 32 (0.020 g, 0.055 mmol), crushed KOH (0.10 g) and tert-butanol (1.5 mL) was brought to reflux for 45 minutes. The reaction mixture was diluted with CH2Cl2 (20 mL) and extracted with H2O (5 mL). The organic layer was concentrated in vacuo to provide 33. 1H NMR (400 MHz, CDCl3) δ 8.37 (s, 1H), 7.34 (d, J=8 Hz, 2H), 6.91 (m, 3H), 6.24 (m 1H), 5.93 (bs, 2H), 5.37 (t, J=5 Hz,1H), 4.78 (d, J=5 Hz, 2H), 3.83 (s, 3H), 2.73 (m, 2H), 2.57 (m, 2H), 2.04 (p, J=7 Hz, 2H).
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][C:6]([CH:10]=[CH:11][CH2:12]O)=[CH:7][CH:8]=2)[CH:3]=[CH:2]1.C(N(C(C)C)C(C)C)C.[NH2:23][C:24]1[S:25][C:26]2[CH2:27][CH2:28][NH:29][CH2:30][CH2:31][C:32]=2[N:33]=1>C(Cl)(Cl)Cl.C(Cl)Cl>[NH2:23][C:24]1[S:25][C:26]2[CH2:27][CH2:28][N:29]([CH2:12][CH:11]=[CH:10][C:6]3[CH:5]=[C:4]4[C:9](=[CH:8][CH:7]=3)[NH:1][CH:2]=[CH:3]4)[CH2:30][CH2:31][C:32]=2[N:33]=1
Reactant: OCC=Cc1ccc2[nH]ccc2c1
Reactant: Nc1nc2c(s1)CCNCC2
Solvent: ClC(Cl)Cl
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: Nc1nc2c(s1)CCN(CC=Cc1ccc3[nH]ccc3c1)CC2
Temperature: -5 °C
Reaction time: 15 h

Procedure:
At -15° C., a solution of 63 mg (0.55 mmol) of methanesulphochloride in 6 ml of chloroform is added dropwise to a stirred solution of 95 mg (0.55 mmol) of 3-(5-indolyl)allyl alcohol and 142 mg (1.10 mmol) of N-ethyl-N,N-diisopropylamine in 6 ml of anhydrous methylene chloride and the resulting mixture is stirred for 15 hours at -5° C. It is evaporated down in vacuo at 20° C., the evaporation residue is dissolved in 3 ml of anhydrous dimethylformamide, 370 mg (2.20 mmol) of 2-amino-4,5,7,8-tetrahydro-6H-thiazolo[5,4-d]azepine are added and the mixture is stirred for 4 hours at 50° C. and for 3 hours at 70° C. The mixture is then evaporated down in vacuo, distributed between chloroform and water and the dried and filtered chloroform solution is evaporated down in vacuo. The evaporation residue is purified by triple column chromatography on neutral aluminium oxide (toluene/ethyl acetate/ethanol=4:1:0.5). Yield: 8 mg (4.5% of theory), Melting point: 60°-65° C. (foamy). Molecular peak (m/z) Calculated: 324 Found: 324
Reaction SMILES: [Cl:1][C:2]1[S:3][C:4]([CH:9]2[C@H:14]([O:15][CH2:16][C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)[C@@H:13]([O:23][CH2:24][C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=3)[C@H:12]([O:31][CH2:32][C:33]3[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=3)[C@@H:11]([CH2:39][O:40][CH2:41][C:42]3[CH:47]=[CH:46][CH:45]=[CH:44][CH:43]=3)[O:10]2)=[CH:5][C:6]=1[CH2:7][OH:8].CCN(CC)CC.[C:55](Cl)(=[O:62])[C:56]1[CH:61]=[CH:60][CH:59]=[CH:58][CH:57]=1>C(Cl)Cl>[C:55]([O:8][CH2:7][C:6]1[CH:5]=[C:4]([C@H:9]2[C@H:14]([O:15][CH2:16][C:17]3[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=3)[C@@H:13]([O:23][CH2:24][C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=3)[C@H:12]([O:31][CH2:32][C:33]3[CH:34]=[CH:35][CH:36]=[CH:37][CH:38]=3)[C@@H:11]([CH2:39][O:40][CH2:41][C:42]3[CH:43]=[CH:44][CH:45]=[CH:46][CH:47]=3)[O:10]2)[S:3][C:2]=1[Cl:1])(=[O:62])[C:56]1[CH:61]=[CH:60][CH:59]=[CH:58][CH:57]=1
Reactant: O=C(Cl)c1ccccc1
Reactant: OCc1cc(C2O[C@H](COCc3ccccc3)[C@@H](OCc3ccccc3)[C@H](OCc3ccccc3)[C@H]2OCc2ccccc2)sc1Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: O=C(OCc1cc([C@@H]2O[C@H](COCc3ccccc3)[C@@H](OCc3ccccc3)[C@H](OCc3ccccc3)[C@H]2OCc2ccccc2)sc1Cl)c1ccccc1
Temperature: 25 °C
Reaction time: 15 h
Yield: 101.5 %

Procedure:
To a solution of alcohol 35 (5.2 g, 7.75 mmol) in CH2Cl2 (50 mL) were added Et3N (3.5 mL, 23.3 mmol) and benzoyl chloride (1.2 mL, 10.1 mmol) at 0° C. The mixture was allowed to slowly warm to room temperature and stirred at room temperature for 15 hours. The mixture was washed with aq. saturated NaHCO3 solution. The organic layer was dried over MgSO4, filtered, and concentrated in vacuo. The residue was purified by silica column chromatography (Biotage) to provide the mixture of anomers of the title compound (6.1 g). The anomeric mixture of 36 was recrystallized with EtOH (50 mL). The precipitate was collected by filtration and washed with cold EtOH (30 mL) and dried under high vacuum to obtain β-anomer of the title compound 36 (4.64 g, 77%).
Reaction SMILES: Cl[C:2]1[CH:11]=[CH:10][N:9]=[C:8]2[C:3]=1[C:4]1[CH:16]=[CH:15][CH:14]=[CH:13][C:5]=1[C:6](=[O:12])[NH:7]2.[NH2:17][C:18]1[CH:23]=[CH:22][C:21]([OH:24])=[C:20]([F:25])[CH:19]=1.C(=O)([O-])[O-].[Cs+].[Cs+]>CN(C=O)C.O>[NH2:17][C:18]1[CH:23]=[CH:22][C:21]([O:24][C:2]2[CH:11]=[CH:10][N:9]=[C:8]3[C:3]=2[C:4]2[CH:16]=[CH:15][CH:14]=[CH:13][C:5]=2[C:6](=[O:12])[NH:7]3)=[C:20]([F:25])[CH:19]=1
Reactant: Nc1ccc(O)c(F)c1
Reactant: O=c1[nH]c2nccc(Cl)c2c2ccccc12
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Solvent: O
Product: Nc1ccc(Oc2ccnc3[nH]c(=O)c4ccccc4c23)c(F)c1
Temperature: 120 °C
Reaction time: 0.5 h
Yield: 89.9 %

Procedure:
Compound 83 (250 mg, 1.08 mmol), 4-amino-2-fluoro-phenol (276 mg, 2.17 mmol), and cesium carbonate (1.41 g, 4.34 mmol) were suspended in DMF (5 mL), and stirred for 30 minutes at 120° C. in microwave. The reaction mixture was diluted with H2O. The resulting precipitate was filtered. The precipitate was tritturated with MeOH, filtered, washed with MeOH, and dried under vacuum to provide 182 (312 mg, 90% yield) as a solid. LC-MS (M+H=322, obsd.=322).
Reaction SMILES: [OH:1][C:2]1[N:7]=[C:6]([SH:8])[N:5]=[C:4]2[NH:9][N:10]=[C:11]([CH3:12])[C:3]=12.[OH-].[Na+].CI.[CH3:17]C(O)=O>O>[OH:1][C:2]1[N:7]=[C:6]([S:8][CH3:17])[N:5]=[C:4]2[NH:9][N:10]=[C:11]([CH3:12])[C:3]=12
Reactant: Cc1n[nH]c2nc(S)nc(O)c12
Reactant: CC(=O)O
Agent: [Na+]
Agent: [OH-]
Solvent: CI
Solvent: O
Product: CSc1nc(O)c2c(C)n[nH]c2n1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a mixture of 4-hydroxy-6-mercapto-3-methylpyrazolo[3,4-d]pyrimidine (A-1) (2.86 g, 11.8 mmol) and NaOH (0.8 g, 20 mmol) in water (20 mL) at 5° C., was added CH3I (2.0 g, 14.2 mmol). After stirred at ambient temperature for 30 min, the solution was acidified with HOAc to give the crude product of the title compound (A-2), which used in next step without further purification. MS-ESI (m/z): 197.0 (M+H)+.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][CH3:9])=[CH:4][CH:3]=1.CN(CCN(CCN(C)C)C)C.C([Li])CCC.B(OC)(OC)[O:28]C.OO>O.C(O)(=O)C.C1COCC1>[F:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][CH3:9])=[CH:4][C:3]=1[OH:28]
Reactant: COB(OC)OC
Reactant: COc1ccc(F)cc1
Agent: CN(C)CCN(C)CCN(C)C
Agent: OO
Agent: [Li]CCCC
Solvent: O
Solvent: C1CCOC1
Solvent: CC(=O)O
Product: COc1ccc(F)c(O)c1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To a 200 ml THF solution containing 50.1 g of 1-fluoro-4-methoxybenzene and 70 g of N,N,N′,N′,N″-pentamethyldiethylenetriamine there was added dropwise 150 ml of n-butyllithium (2.66 M, hexane solution) at −74° C. over a period of 30 minutes, under a nitrogen atmosphere. After stirring between −74° C. and −70° C. for 3 hours, 100 ml of trimethyl borate was added. The temperature of the reaction mixture was then slowly raised to room temperature. Next, 70 ml of acetic acid and 75 ml of a 30% hydrogen peroxide aqueous solution were added and the reaction mixture was stirred overnight at room temperature. After the addition of water to the reaction mixture, it was extracted with a hexane/ethyl acetate mixture and dried over anhydrous magnesium sulfate. The desiccant was filtered out, and the filtrate was concentrated under reduced pressure to obtain a crude product of 1-fluoro-2-hydroxy-4-methoxybenzene (65.59 g) as a colorless solid.
Reaction SMILES: Cl[CH:2]([O:5][CH3:6])[CH2:3][Cl:4].[P:7]([O:14]CC)([O:11][CH2:12][CH3:13])[O:8][CH2:9][CH3:10]>>[CH2:9]([O:8][P:7]([CH:2]([O:5][CH3:6])[CH2:3][Cl:4])(=[O:14])[O:11][CH2:12][CH3:13])[CH3:10]
Reactant: COC(Cl)CCl
Reactant: CCOP(OCC)OCC
Product: CCOP(=O)(OCC)C(CCl)OC
Yield: 57.8 %

Procedure:
0.9 mole of methyl 1,2-dichloroethyl ether was added dropwise to 1 mole of triethyl phosphite at 120° C., under a N2 atmosphere. After a reaction time of 8 hours, the mixture was fractionated. 120 g of 1-methoxy-2-chloroethane-phosphonic acid diethyl ester were obtained.
Reaction SMILES: [CH3:1][O:2][C:3]1[N:8]=[CH:7][C:6](B(O)O)=[CH:5][CH:4]=1.Cl[C:13]1[CH:14]=[C:15]([C:28]2[N:33]=[C:32]([CH3:34])[N:31]=[C:30]([N:35]([CH2:45][C:46]3[CH:51]=[CH:50][C:49]([O:52][CH3:53])=[CH:48][CH:47]=3)[CH2:36][C:37]3[CH:42]=[CH:41][C:40]([O:43][CH3:44])=[CH:39][CH:38]=3)[N:29]=2)[C:16]([NH:19][C:20]2[CH:21]=[N:22][C:23]([O:26][CH3:27])=[CH:24][CH:25]=2)=[N:17][CH:18]=1.C1(P(C2CCCCC2)C2C=CC=CC=2C2C(C(C)C)=CC(C(C)C)=CC=2C(C)C)CCCCC1.C(=O)([O-])[O-].[Na+].[Na+].[OH-].[Na+]>C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd].O1CCOCC1>[CH3:44][O:43][C:40]1[CH:41]=[CH:42][C:37]([CH2:36][N:35]([CH2:45][C:46]2[CH:51]=[CH:50][C:49]([O:52][CH3:53])=[CH:48][CH:47]=2)[C:30]2[N:31]=[C:32]([CH3:34])[N:33]=[C:28]([C:15]3[CH:14]=[C:13]([C:6]4[CH:7]=[N:8][C:3]([O:2][CH3:1])=[CH:4][CH:5]=4)[CH:18]=[N:17][C:16]=3[NH:19][C:20]3[CH:21]=[N:22][C:23]([O:26][CH3:27])=[CH:24][CH:25]=3)[N:29]=2)=[CH:38][CH:39]=1
Reactant: COc1ccc(B(O)O)cn1
Reactant: COc1ccc(CN(Cc2ccc(OC)cc2)c2nc(C)nc(-c3cc(Cl)cnc3Nc3ccc(OC)nc3)n2)cc1
Agent: [Pd]
Agent: CC(C)c1cc(C(C)C)c(-c2ccccc2P(C2CCCCC2)C2CCCCC2)c(C(C)C)c1
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: C1COCCO1
Product: COc1ccc(CN(Cc2ccc(OC)cc2)c2nc(C)nc(-c3cc(-c4ccc(OC)nc4)cnc3Nc3ccc(OC)nc3)n2)cc1
Temperature: 140 °C

Procedure:
A mixture of 6-methoxypyridin-3-ylboronic acid (0.039 g, 0.256 mmol), 4-(5-chloro-2-(6-methoxypyridin-3-ylamino)pyridin-3-yl)-N,N-bis(4-methoxybenzyl)-6-methyl-1,3,5-triazin-2-amine (0.1244 g, 0.213 mmol), Pd2dba3 (7.80 mg, 8.52 μmol), and dicyclohexyl(2′,4′,6′-triisopropylbiphenyl-2-yl)phosphine (8.12 mg, 0.017 mmol) was purged with argon. The mixture were treated with dioxane (2.0 mL) and sodium carbonate (0.27 mL, 0.53 mmol) and heated in a Biotage Initiator microwave at 140° C. for 30 min. The cooled reaction mixture was treated with 1 N NaOH and extracted with EtOAc (30 mL), washed with brine, dried over MgSO4, filtered and concentrated. The crude product was used directly in the next reaction. m/z (ESI, +ve ion) 657.0 (M+H)+.
Reaction SMILES: [C:1]1([Li])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.Br[C:9]1[CH:10]=[C:11]([CH:15]2[C:20]([CH3:22])([CH3:21])[O:19][C:18]([NH:23][C@H:24]([C:35]3[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=3)[CH2:25][CH2:26][O:27][Si](C(C)(C)C)(C)C)=[N:17][S:16]2(=[O:42])=[O:41])[CH:12]=[CH:13][CH:14]=1.O.C(OCC)(=O)C>C1COCC1.C(OCCCC)CCC.[Cl-].[Zn+2].[Cl-].C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2]>[C:9]1([C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=2)[CH:14]=[CH:13][CH:12]=[C:11]([CH:15]2[C:20]([CH3:22])([CH3:21])[O:19][C:18]([NH:23][C@H:24]([C:35]3[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=3)[CH2:25][CH2:26][OH:27])=[N:17][S:16]2(=[O:41])=[O:42])[CH:10]=1
Reactant: [Li]c1ccccc1
Reactant: CC1(C)OC(N[C@@H](CCO[Si](C)(C)C(C)(C)C)c2ccccc2)=NS(=O)(=O)C1c1cccc(Br)c1
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: [Cl-]
Solvent: CCOC(C)=O
Solvent: O
Solvent: C1CCOC1
Product: CC1(C)OC(N[C@@H](CCO)c2ccccc2)=NS(=O)(=O)C1c1cccc(-c2ccccc2)c1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
Under inert gas, 2.58 ml of a 0.5 N zinc chloride solution in THF were cooled to −78° C., and 0.48 ml of a 1.8 N phenyllithium solution in dibutyl ether was added dropwise. The reaction solution was allowed to come to room temperature and stirred for 30 minutes. Then this solution was added to a solution of 100 mg of [5-(3-bromophenyl)-6,6-dimethyl-4,4-dioxo-5,6-dihydro-4H-4lambda6-1,4,3-oxathiazin-2-yl]-[(S)-3-(tert-butyldimethylsilanyloxy)-1-phenylpropyl]amine and 14.1 mg of dichloro[1,1′-bis(diphenylphosphino)ferrocene]palladium in 2 ml of THF. After stirring at 60° C. for 45 minutes, the reaction was allowed to cool to room temperature, 10 ml of water and 10 ml of ethyl acetate were added, and the organic phase was dried over MgSO4 and concentrated by rotary evaporation. The residue was dissolved in 1.5 ml of methanol, 0.15 ml of concentrated hydrochloric acid was added and the mixture was stirred at room temperature for 16 hours. The reaction solution was diluted with ethyl acetate and washed with saturated aqueous sodium chloride solution, dried over MgSO4 and concentrated by rotary evaporation. The residue was purified in a purification laboratory by means of preparative HPLC. The product-containing fractions were combined, the acetonitrile was removed under reduced pressure, and the aqueous residue was basified with saturated aqueous sodium hydrogencarbonate solution and extracted with dichloromethane. The organic phase was dried over MgSO4 and concentrated by rotary evaporation, and the residue was taken up again in a mixture of acetonitrile and water and lyophilized. This gave the product (57.8 mg) with a molecular weight of 464.6 g/mol (C26H28N2O4S); MS (ESI): m/e=565 (M+H+).
Reaction SMILES: [F:1][C:2]1[CH:11]=[C:10]([C:12]2[N:16]=[C:15]([C:17]3[CH:22]=[CH:21][C:20]([C:23]4[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=4[CH3:29])=[C:19]([CH2:30][OH:31])[CH:18]=3)[O:14][N:13]=2)[CH:9]=[CH:8][C:3]=1[C:4]([O:6][CH3:7])=[O:5].CCN(C(C)C)C(C)C.[CH3:41][S:42](Cl)(=[O:44])=[O:43].O>C(Cl)Cl>[F:1][C:2]1[CH:11]=[C:10]([C:12]2[N:16]=[C:15]([C:17]3[CH:22]=[CH:21][C:20]([C:23]4[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=4[CH3:29])=[C:19]([CH2:30][O:31][S:42]([CH3:41])(=[O:44])=[O:43])[CH:18]=3)[O:14][N:13]=2)[CH:9]=[CH:8][C:3]=1[C:4]([O:6][CH3:7])=[O:5]
Reactant: CS(=O)(=O)Cl
Reactant: COC(=O)c1ccc(-c2noc(-c3ccc(-c4ccccc4C)c(CO)c3)n2)cc1F
Solvent: CCN(C(C)C)C(C)C
Solvent: O
Solvent: ClCCl
Product: COC(=O)c1ccc(-c2noc(-c3ccc(-c4ccccc4C)c(COS(C)(=O)=O)c3)n2)cc1F
Temperature: 25 °C
Yield: 97 %

Procedure:
At 0° C., into a solution of methyl 2-fluoro-4-{5-[2-(hydroxymethyl)-2′-methylbiphenyl-4-yl]-1,2,4-oxadiazol-3-yl}benzoate, prepared as in example 58, step 1, (500 mg; 1.19 mmol) in DCM (15 mL) was added DIEA (610 μL; 3.58 mmol) and methanesulfonyl chloride (139 μL; 1.79 mmol). The reaction was allowed to warm to RT for 2 h30. Water (5 mL) was added and the DCM extract was rapidly washed twice more with water. The organic layer was then dried over magnesium sulfate, filtered and concentrated to afford the title compound as a yellow foam (573 mg; 97%). 1H NMR (DMSO-d6, 300 MHz) δ 8.47 (d, J=1.8 Hz, 1H), 8.30 (dd, J=8.0, 1.8 Hz, 1H), 8.18-8.13 (m, 1H), 8.09 (dd, J=8.1, 1.5 Hz, 1H), 8.02 (dd, J=11.2, 1.4 Hz, 1H), 7.54 (d, J=8.0 Hz, 1H), 7.40-7.29 (m, 3H), 7.19 (d, J=7.0 Hz, 1H), 5.11 (d, J=11.4 Hz, 1H), 5.05 (d, J=11.4 Hz, 1H), 3.92 (s, 3H), 3.04 (s, 3H), 2.05 (s, 3H). LC/MS (Method B): 497.3 (M+H)+. HPLC (Method A) Rt 5.52 min (Purity: 96.7%).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:16]=[CH:15][C:6]([CH2:7][O:8][CH2:9][CH2:10][CH:11]([OH:14])[CH2:12][OH:13])=[CH:5][CH:4]=1.[Si:17](Cl)([C:20]([CH3:23])([CH3:22])[CH3:21])([CH3:19])[CH3:18].C(N(CC)CC)C>CN(C)C1C=CN=CC=1.CN(C=O)C>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]([CH2:7][O:8][CH2:9][CH2:10][CH:11]([OH:14])[CH2:12][O:13][Si:17]([C:20]([CH3:23])([CH3:22])[CH3:21])([CH3:19])[CH3:18])=[CH:15][CH:16]=1
Reactant: COc1ccc(COCCC(O)CO)cc1
Reactant: CC(C)(C)[Si](C)(C)Cl
Agent: CN(C)c1ccncc1
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: COc1ccc(COCCC(O)CO[Si](C)(C)C(C)(C)C)cc1
Temperature: 25 °C
Yield: 80.5 %

Procedure:
Combine 4-(p-methoxybenzyloxy)-1,2-butandiol (42.43 g, 187.5 mmol) with DMF (700 mL) and cool in an ice bath before adding t-butyldimethylsilyl chloride (31.1 g, 206 mmol), triethylamine (31.4 mL, 225 mmol), and 4-dimethylaminopyridine (5.8 g, 47 mmol). Stir the mixture in the ice bath for 5 minutes and then allow to warm to ambient temperature and stir for sixteen hours. Filter and wash the filter cake with diethyl ether. Separate the aqueous layer and extract twice with ether. Combine the organic layers extract with water and saturated sodium chloride solution, dry over MgSO4, filter and concentrate in vacuo. Chromatograph on silica gel eluting with 2/8 ethyl acetate/hexane to give 51.4 g of the title compound the as an oil. Rf =0.25; silica gel, 2/8 ethyl acetate/hexane.
Reaction SMILES: [F:1][C:2]1([F:13])[C:11](=[O:12])[N:5]2C(C)(C)[O:7][CH2:8][C@H:4]2[CH2:3]1>O.O1CCOCC1>[F:1][C:2]1([F:13])[CH2:3][C@H:4]([CH2:8][OH:7])[NH:5][C:11]1=[O:12]
Reactant: CC1(C)OC[C@H]2CC(F)(F)C(=O)N21
Solvent: O
Solvent: C1COCCO1
Product: O=C1N[C@@H](CO)CC1(F)F
Temperature: 115 °C
Yield: 89 %

Procedure:
To a solution consisting of (R)-6,6-difluoro-3,3-dimethyltetrahydropyrrolo[1,2-c]oxazol-5(3H)-one (intermediate 6, 12.5 g, 65.4 mmol) in water-1,4-dioxane (300 mL, 1:1 v/v) was added Amberlite IR-120H*(6.23 g). The reaction mixture was heated to 115° C. for 6 hours and was subsequently filtered through Celite and washed with methanol. The filtrate was concentrated under reduced pressure, using toluene and ethanol additives to help drive off water, to provide a residue. The residue was washed with diethyl ether to afford the title compound as a tan solid (8.8 g; 89%), which was carried on without further purification; TLC Rf 0.25 (solvent system: 70:30 v/v ethyl acetate:hexanes). *Amberlite IR-120H ion-exchange resin, strongly acid gel-type resin with sulfonic acid functionality, CAS: 39389-20-3.75 g of Amberlite was washed and decanted three times with deionized water. The fourth wash was filtered using suction filtration and the semi-dry resin was quickly washed with 2-propanol then diethyl ether. The resin was dried to give 54 g of free flowing dark brown bead resin.
Reaction SMILES: [C:1]([C:3]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][C:10]=2[O:12][CH2:13][CH:14]2[O:16][CH2:15]2)[NH:5][CH:4]=1)#[N:2].C(O)CCC.[O:22]([CH:26]([CH3:34])[CH2:27][C:28]([NH:30][CH2:31][CH2:32][NH2:33])=[O:29])[N+:23]([O-:25])=[O:24].[C:35]([OH:42])(=[O:41])/[CH:36]=[CH:37]/[C:38]([OH:40])=[O:39]>CO>[C:35]([OH:42])(=[O:41])/[CH:36]=[CH:37]/[C:38]([OH:40])=[O:39].[C:1]([C:3]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][C:10]=2[O:12][CH2:13][CH:14]([OH:16])[CH2:15][NH:33][CH2:32][CH2:31][NH:30][C:28](=[O:29])[CH2:27][CH:26]([O:22][N+:23]([O-:25])=[O:24])[CH3:34])[NH:5][CH:4]=1)#[N:2]
Reactant: N#Cc1c[nH]c2cccc(OCC3CO3)c12
Reactant: CC(CC(=O)NCCN)O[N+](=O)[O-]
Agent: O=C(O)/C=C/C(=O)O
Solvent: CCCCO
Solvent: CO
Product: CC(CC(=O)NCCNCC(O)COc1cccc2[nH]cc(C#N)c12)O[N+](=O)[O-]

Procedure:
4.2 g. 1-(3-cyanoindol-4-yloxy)-2,3-epoxypropane (see European patent specification No. 0,045,910) are suspended in 100 ml. n-butanol, mixed with 11.5 g. 2-(3-nitroxybutanoylamino)-ethylamine and stirred for 2 days at ambient temperature. After removal of the solvent, the residue is chromatographed on silica gel with methylene chloride/methanol (95:5 v/v) and methylene chloride/methanolic ammonia solution (95:5 v/v). From the appropriate fractions, after removal of the solvent, there are obtained 4.6 g. of base. By dissolving in methanol and adding the calculated amount of fumaric acid, there are obtained, after suction filtration, 3.9 g. (40% of theory) of the desired fumarate; m.p. 155°-156° C.
Reaction SMILES: [F:1][C:2]1[C:7](F)=[CH:6][CH:5]=[CH:4][C:3]=1[CH2:9][S:10]([C:13]1[N:22]=[C:21]([NH:23][C@H:24]([CH3:27])[CH2:25][OH:26])[C:20]2[N:19]=[CH:18][C:17](=[O:28])[NH:16][C:15]=2[N:14]=1)(=O)=O.FC1C=CC=CC=1CS>>[F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH2:9][S:10][C:13]1[N:22]=[C:21]([NH:23][C@H:24]([CH3:27])[CH2:25][OH:26])[C:20]2[N:19]=[CH:18][C:17](=[O:28])[NH:16][C:15]=2[N:14]=1
Reactant: C[C@H](CO)Nc1nc(S(=O)(=O)Cc2cccc(F)c2F)nc2[nH]c(=O)cnc12
Agent: Fc1ccccc1CS
Product: C[C@H](CO)Nc1nc(SCc2ccccc2F)nc2[nH]c(=O)cnc12
Yield: 50.7 %

Procedure:
The titled compound (0.089 g) was prepared by the method of Example 13, step (c) using the product from Example 13, step (a) (0.20 g) and 2-fluorobenzylmercaptan (0.083 g).
Reaction SMILES: [CH2:1]([O:3][C:4]1[C:13]([O:14][CH3:15])=[CH:12][C:11]2[C:10]([C:16]3[CH:24]=[CH:23][C:19]([C:20](O)=[O:21])=[CH:18][CH:17]=3)=[N:9][C@@H:8]3[CH2:25][CH2:26][S:27][CH2:28][C@@H:7]3[C:6]=2[CH:5]=1)[CH3:2].Cl.[CH3:30][C:31]1[S:35][C:34]([CH2:36][N:37]2[C:42]3[CH:43]=[C:44]([C:46]4[CH:51]=[CH:50][CH:49]=[CH:48][CH:47]=4)[S:45][C:41]=3[C:40](=[O:52])[N:39]([CH:53]3[CH2:58][CH2:57][NH:56][CH2:55][CH2:54]3)[C:38]2=[O:59])=[N:33][CH:32]=1.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C>C(Cl)Cl>[CH2:1]([O:3][C:4]1[C:13]([O:14][CH3:15])=[CH:12][C:11]2[C:10]([C:16]3[CH:17]=[CH:18][C:19]([C:20]([N:56]4[CH2:57][CH2:58][CH:53]([N:39]5[C:40](=[O:52])[C:41]6[S:45][C:44]([C:46]7[CH:47]=[CH:48][CH:49]=[CH:50][CH:51]=7)=[CH:43][C:42]=6[N:37]([CH2:36][C:34]6[S:35][C:31]([CH3:30])=[CH:32][N:33]=6)[C:38]5=[O:59])[CH2:54][CH2:55]4)=[O:21])=[CH:23][CH:24]=3)=[N:9][C@@H:8]3[CH2:25][CH2:26][S:27][CH2:28][C@@H:7]3[C:6]=2[CH:5]=1)[CH3:2]
Reactant: Cc1cnc(Cn2c(=O)n(C3CCNCC3)c(=O)c3sc(-c4ccccc4)cc32)s1
Reactant: CCOc1cc2c(cc1OC)C(c1ccc(C(=O)O)cc1)=N[C@@H]1CCSC[C@H]21
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CCOc1cc2c(cc1OC)C(c1ccc(C(=O)N3CCC(n4c(=O)c5sc(-c6ccccc6)cc5n(Cc5ncc(C)s5)c4=O)CC3)cc1)=N[C@@H]1CCSC[C@H]21
Reaction time: 12 h

Procedure:
The title compound is prepared analogously as described for example 1 (however, stirring is performed for 12 h at RT) using 4-[(4aR,10bR)-9-ethoxy-8-methoxy-3,4,4a,10b-tetrahydro-1H-thiopyrano[4,3-c]isoquinolin-6-yl]benzoic acid (159 mg; compound C10), 1-[(5-methyl-1,3-thiazol-2-yl)methyl]-6-phenyl-3-(piperidin-4-yl)thieno[3,2-d]pyrimidine-2,4(1H,3H)-dione hydrochloride (190 mg; compound B37), HBTU (167 mg), DIPEA (207 mg) and DCM (10 ml). The crude product is purified by flash column chromatography for three times [amino phase silica gel, eluation gradient: cyclohexane/EtOAc, 100/0 to 0/100 (v/v)] to yield the title compound as a solid.
Reaction SMILES: [OH:1][CH2:2][CH:3]1[CH2:8][CH2:7][N:6]([C:9]([O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:10])[CH2:5][CH2:4]1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OC(C)C)=O)=NC(OC(C)C)=O.[CH2:49]([O:56][C:57]1[CH:81]=[CH:80][C:79](O)=[CH:78][C:58]=1[C:59]([NH:61][C:62]1[CH:71]=[C:70]([C:72]2[CH:77]=[CH:76][CH:75]=[CH:74][CH:73]=2)[CH:69]=[CH:68][C:63]=1[C:64]([O:66][CH3:67])=[O:65])=[O:60])[C:50]1[CH:55]=[CH:54][CH:53]=[CH:52][CH:51]=1>O1CCCC1>[CH2:49]([O:56][C:57]1[CH:81]=[CH:80][C:79]([O:1][CH2:2][CH:3]2[CH2:8][CH2:7][N:6]([C:9]([O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:10])[CH2:5][CH2:4]2)=[CH:78][C:58]=1[C:59]([NH:61][C:62]1[CH:71]=[C:70]([C:72]2[CH:73]=[CH:74][CH:75]=[CH:76][CH:77]=2)[CH:69]=[CH:68][C:63]=1[C:64]([O:66][CH3:67])=[O:65])=[O:60])[C:50]1[CH:51]=[CH:52][CH:53]=[CH:54][CH:55]=1
Reactant: CC(C)(C)OC(=O)N1CCC(CO)CC1
Reactant: COC(=O)c1ccc(-c2ccccc2)cc1NC(=O)c1cc(O)ccc1OCc1ccccc1
Agent: CC(C)OC(=O)N=NC(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: COC(=O)c1ccc(-c2ccccc2)cc1NC(=O)c1cc(OCC2CCN(C(=O)OC(C)(C)C)CC2)ccc1OCc1ccccc1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
Tert-butyl 4-(hydroxymethyl)piperidine-1-carboxylate (0.26 g), triphenylphosphine (0.35 g), and diisopropyl azodicarboxylate (0.26 mL) were added to a tetrahydrofuran (5.0 mL) solution of methyl 2-(2-(benzyloxy)-5-hydroxybenzamido)-4-phenylbenzoate (0.50 g), followed by stirring at room temperature for 30 minutes. Triphenylphosphine (0.35 g) and diisopropyl azodicarboxylate (0.26 mL) were added to the reaction mixture, followed by stirring at room temperature for 30 minutes. Triphenylphosphine (0.35 g) and diisopropyl azodicarboxylate (0.26 mL) were added to the reaction mixture, followed by stirring at room temperature for 30 minutes. The solvent was evaporated under reduced pressure, and the obtained residue was purified by silica gel column chromatography [Kanto Chemical Co., Inc., silica gel 60 (spherical), eluent: 95-70% hexane/ethyl acetate] to obtain methyl 2-(2-(benzyloxy)-5-((1-(tert-butoxycarbonyl)piperidin-4-yl)methoxy)benzamido)-4-phenylbenzoate as a yellow oily substance.