Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[C:2]([O:4][CH2:5][CH3:6])=[O:3].[CH2:7]([O:9][C:10](=[O:59])[C@H:11]([CH2:51][C:52]1[CH:57]=[CH:56][C:55]([OH:58])=[CH:54][CH:53]=1)[NH:12][C:13]([C:15]1([CH2:20][C@H:21]([C:44]([O:46][C:47]([CH3:50])([CH3:49])[CH3:48])=[O:45])[CH2:22][NH:23][C:24](=[O:43])[C@H:25]([CH2:31][CH2:32][CH2:33][CH2:34][NH:35][C:36]([O:38][C:39]([CH3:42])([CH3:41])[CH3:40])=[O:37])[NH:26][S:27]([CH3:30])(=[O:29])=[O:28])[CH2:19][CH2:18][CH2:17][CH2:16]1)=[O:14])[CH3:8].C(N(CC)CC)C>CN(C)C1C=CN=CC=1.ClCCl>[CH2:7]([O:9][C:10](=[O:59])[C@H:11]([CH2:51][C:52]1[CH:53]=[CH:54][C:55]([O:58][C:2]([O:4][CH2:5][CH3:6])=[O:3])=[CH:56][CH:57]=1)[NH:12][C:13]([C:15]1([CH2:20][C@H:21]([C:44]([O:46][C:47]([CH3:48])([CH3:49])[CH3:50])=[O:45])[CH2:22][NH:23][C:24](=[O:43])[C@H:25]([CH2:31][CH2:32][CH2:33][CH2:34][NH:35][C:36]([O:38][C:39]([CH3:42])([CH3:41])[CH3:40])=[O:37])[NH:26][S:27]([CH3:30])(=[O:29])=[O:28])[CH2:19][CH2:18][CH2:17][CH2:16]1)=[O:14])[CH3:8]
Reactant: CCOC(=O)[C@H](Cc1ccc(O)cc1)NC(=O)C1(C[C@@H](CNC(=O)[C@H](CCCCNC(=O)OC(C)(C)C)NS(C)(=O)=O)C(=O)OC(C)(C)C)CCCC1
Reactant: CCOC(=O)Cl
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCOC(=O)Oc1ccc(C[C@H](NC(=O)C2(C[C@@H](CNC(=O)[C@H](CCCCNC(=O)OC(C)(C)C)NS(C)(=O)=O)C(=O)OC(C)(C)C)CCCC2)C(=O)OCC)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 47.6 %

Procedure:
Ethyl chloroformate (0.1093 g, 1.007 mmol) was added to an ice-cooled solution of N-{1-[3-(N2 -methanesulphonyl-N6 -t-butyloxycarbonyl-(S)-lysylamino)-2-(S)-t-butyloxycarbonylpropyl]-1-cyclopentanecarbony}-(S)-tyrosine-ethyl ester (0.7041 g, 0.916 mmol), triethylamine (0.2781 g, 2.75 mmol and 4-dimethylaminopyridine (0.0112 g in dry dichloromethane (20 ml). After 30 minutes the ice-cooling was removed and the reaction stirred overnight at room temperature. The solvent was then evaporated under reduced pressure and the residual oil partitioned between ethyl acetate (50 ml) and 2N hydrochloric acid (50 ml). The phases were separated and the organic phase washed with saturated sodium bicarbonate solution (50 ml), then with saturated brine, (50 ml) and was finally dried over magnesium sulphate, before removing the solvent under reduced pressure to give the crude product as an oil. Chromatography over silica gel, eluting with mixtures of dichloromethane and diethyl ether gave the title compound as a white foam (0.367 g, 48%). Found: C,56.68; H,7.36; N,6.65. C39H64N4O13S requires C,56.50; H,7.78; N,6.76%.
Reaction SMILES: Cl[C:2]1[N:13]=[C:12]([C:14]([F:17])([F:16])[F:15])[CH:11]=[CH:10][C:3]=1[C:4]([N:6]([O:8][CH3:9])[CH3:7])=[O:5].[CH3:18][Si:19]([C:22]#[CH:23])([CH3:21])[CH3:20]>>[CH3:9][O:8][N:6]([CH3:7])[C:4](=[O:5])[C:3]1[CH:10]=[CH:11][C:12]([C:14]([F:17])([F:16])[F:15])=[N:13][C:2]=1[C:23]#[C:22][Si:19]([CH3:21])([CH3:20])[CH3:18]
Reactant: C#C[Si](C)(C)C
Reactant: CON(C)C(=O)c1ccc(C(F)(F)F)nc1Cl
Product: CON(C)C(=O)c1ccc(C(F)(F)F)nc1C#C[Si](C)(C)C
Yield: 60 %

Procedure:
2-Chloro-N-methoxy-N-methyl-6-trifluoromethyl-nicotinamide (1.2 g, 4.52 mmol) was reacted with (trimethylsilyl)acetylene (0.689 ml, 4.97 mmol) to give N-methoxy-N-methyl-6-trifluoromethyl-2-trimethylsilanylethynyl-nicotinamide (896 mg, 60%).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][CH:9]=1)[CH:5]=[O:6].[C:10](#[N:12])[CH3:11]>>[Br:1][C:2]1[CH:3]=[C:4]([CH:5]([OH:6])[CH2:11][C:10]#[N:12])[CH:7]=[CH:8][CH:9]=1
Reactant: O=Cc1cccc(Br)c1
Reactant: CC#N
Product: N#CCC(O)c1cccc(Br)c1

Procedure:
Alkylation of 3-bromobenzaldehyde with acetonitrile following the method described in Example 50 gave 3-(3-bromophenyl)-3-hydroxypropanenitrile as a light yellow oil. Yield (2.75 g, 81%): 1H NMR (400 MHz, DMSO-d6) δ 7.60 (t, J=1.6 Hz, 1H), 7.46 (ddd, J=7.6, 2.0, 1.2 Hz, 1H), 7.40 (dd, J=7.6, 2.0 Hz, 1H), 7.31 (t, J=7.6 Hz, 1H), 6.05 (d, J=4.8 Hz, 1H), 2.94-2.80 (m, 2H).
Reaction SMILES: [C:1]1([CH:7]([O:14][C:15]([C:17]23[C:28]4([CH:30]=[O:31])[CH2:29][CH:20]([C:21]2([CH2:33][O:34][C:35]25[CH:44]([O:45][Si:46]([C:49]([CH3:52])([CH3:51])[CH3:50])([CH3:48])[CH3:47])[CH:41]6[CH:42]([OH:43])[CH:37]([CH:38]([O:40]6)[O:39]2)[O:36]5)[CH2:22][CH:23]2[CH:27]4[CH2:26][CH2:25][CH:24]2[CH3:32])[CH:19]=[C:18]3[CH:53]([CH3:55])[CH3:54])=[O:16])[C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[H-].[Na+].Br[CH2:59][CH:60]=[C:61]([CH3:63])[CH3:62]>CN(C)C=O>[C:1]1([CH:7]([O:14][C:15]([C:17]23[C:28]4([CH:30]=[O:31])[CH2:29][CH:20]([C:21]2([CH2:33][O:34][C:35]25[CH:44]([O:45][Si:46]([C:49]([CH3:52])([CH3:51])[CH3:50])([CH3:48])[CH3:47])[CH:41]6[CH:42]([O:43][CH2:59][CH:60]=[C:61]([CH3:63])[CH3:62])[CH:37]([CH:38]([O:40]6)[O:39]2)[O:36]5)[CH2:22][CH:23]2[CH:27]4[CH2:26][CH2:25][CH:24]2[CH3:32])[CH:19]=[C:18]3[CH:53]([CH3:55])[CH3:54])=[O:16])[C:8]2[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: CC(C)=CCBr
Reactant: CC(C)C1=CC2CC3(C=O)C4CCC(C)C4CC2(COC24OC5OC(C(O)C5O2)C4O[Si](C)(C)C(C)(C)C)C13C(=O)OC(c1ccccc1)c1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CC(C)=CCOC1C2OC3(OCC45CC6C(C)CCC6C6(C=O)CC4C=C(C(C)C)C65C(=O)OC(c4ccccc4)c4ccccc4)OC2OC1C3O[Si](C)(C)C(C)(C)C
Reaction time: 0.25 h

Procedure:
50 mg of compound (6) was dissolved in 0.4 ml of dry dimethylformamide under a nitrogen atmosphere and mixed with about 5 mg of sodium hydride under cooling with ice. After 15 minutes, 37.4 ml of 4-bromo-2-methyl2-butene was added, and the reaction solution was stirred under cooling with ice for 50 minutes. The reaction solution was allowed to react at room temperature for another 20 minutes under stirring. Then, the reaction solution was charged onto a silica gel column (Kieselgel 60, Merck, 1.5φ×19 cm) and eluted with n-hexane-ethyl acetate (10:1) to give 34.4 mg of compound (42) as a colorless oily substance.
Reaction SMILES: [Cl:1][C:2]1[S:6][C:5]([C:7]([OH:9])=O)=[CH:4][CH:3]=1.C(Cl)(=O)C([Cl:13])=O>ClCCl>[Cl:1][C:2]1[S:6][C:5]([C:7]([Cl:13])=[O:9])=[CH:4][CH:3]=1
Reactant: O=C(O)c1ccc(Cl)s1
Reactant: O=C(Cl)C(=O)Cl
Solvent: ClCCl
Product: O=C(Cl)c1ccc(Cl)s1

Procedure:
480 mg (2.95 mmol) of 5-chlorothiophene-2-carboxylic acid are dissolved in 24 ml of dichloromethane, and 2.4 ml (27.5 mmol) of oxalyl chloride are added. The mixture is heated under reflux for 16 h. It is then concentrated in vacuo, and the residue is again mixed with dichloromethane and concentrated once again. A viscous oil remains and is dried under high vacuum. 534 mg (quant.) of the target compound are obtained and are reacted further without further purification and characterization.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([O:23][CH3:24])=[C:6]([CH:22]=1)[C:7]([NH:9][C:10]1[S:11][C:12]2[C:17]([CH3:19])([CH3:18])[O:16][C:15]([CH3:21])([CH3:20])[C:13]=2[N:14]=1)=[O:8].CC(C)([O-])C.[K+].Br[CH2:32][C:33]1[CH:38]=[CH:37][C:36]([F:39])=[CH:35][C:34]=1[F:40]>CN(C)C=O.O1CCCC1.C(OCC)(=O)C>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([O:23][CH3:24])=[C:6]([CH:22]=1)[C:7](/[N:9]=[C:10]1\[S:11][C:12]2[C:17]([CH3:18])([CH3:19])[O:16][C:15]([CH3:20])([CH3:21])[C:13]=2[N:14]\1[CH2:32][C:33]1[CH:38]=[CH:37][C:36]([F:39])=[CH:35][C:34]=1[F:40])=[O:8]
Reactant: COc1ccc(Cl)cc1C(=O)Nc1nc2c(s1)C(C)(C)OC2(C)C
Reactant: Fc1ccc(CBr)c(F)c1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: COc1ccc(Cl)cc1C(=O)/N=c1\sc2c(n1Cc1ccc(F)cc1F)C(C)(C)OC2(C)C
Temperature: 80 °C
Reaction time: 8 h
Yield: 5.1 %

Procedure:
To a solution of Example 2A (0.3 g, 0.8 mmol) in N,N-dimethylformamide/tetrahydrofuran (1:4, 10 mL) were added potassium t-butoxide (0.11 g, 1.0 mmol) and 1-(bromomethyl)-2,4-difluorobenzene (Aldrich) (0.21 g, 1.0 mmol). The reaction was stirred at 80° C. overnight and then diluted with ethyl acetate (10 mL). The mixture was washed with 1M NaHCO3 and this aqueous layer was extracted with ethyl acetate (2×20 mL). The combined organic extracts were dried (Na2SO4), filtered and concentrated. The residue was purified by column chromatography using an Analogix® IT280™ (SiO2, 0-100% ethyl acetate in hexanes) to afford 20 mg (5%) of the title compound. 1H NMR (300 MHz, DMSO-d6) δ ppm 1.47 (s, 6H) 1.52 (s, 6H) 3.72 (s, 3H) 5.35 (s, 2H) 7.07 (d, 3H) 7.32 (d, 1H) 7.37 (d, J=2.71 Hz, 1H) 7.40-7.50 (m, J=8.81 Hz, 1H); MS (ESI+) m/z 493 (M+H)+.
Reaction SMILES: [O:1]=[C:2]1[N:8]([CH:9]2[CH2:14][CH2:13][N:12]([C:15]([O:17][C@H:18]([CH2:35][C:36]3[CH:41]=[C:40]([CH3:42])[C:39]([O:43]CC4C=CC=CC=4)=[C:38]([CH3:51])[CH:37]=3)[C:19]([N:21]3[CH2:26][CH2:25][N:24]([CH:27]4[CH2:32][CH2:31][S:30](=[O:34])(=[O:33])[CH2:29][CH2:28]4)[CH2:23][CH2:22]3)=[O:20])=[O:16])[CH2:11][CH2:10]2)[CH2:7][CH2:6][C:5]2[CH:52]=[CH:53][CH:54]=[CH:55][C:4]=2[NH:3]1.[H][H]>CO.[Pd]>[O:1]=[C:2]1[N:8]([CH:9]2[CH2:14][CH2:13][N:12]([C:15]([O:17][C@H:18]([CH2:35][C:36]3[CH:37]=[C:38]([CH3:51])[C:39]([OH:43])=[C:40]([CH3:42])[CH:41]=3)[C:19]([N:21]3[CH2:26][CH2:25][N:24]([CH:27]4[CH2:28][CH2:29][S:30](=[O:33])(=[O:34])[CH2:31][CH2:32]4)[CH2:23][CH2:22]3)=[O:20])=[O:16])[CH2:11][CH2:10]2)[CH2:7][CH2:6][C:5]2[CH:52]=[CH:53][CH:54]=[CH:55][C:4]=2[NH:3]1
Reactant: [H][H]
Reactant: Cc1cc(C[C@@H](OC(=O)N2CCC(N3CCc4ccccc4NC3=O)CC2)C(=O)N2CCN(C3CCS(=O)(=O)CC3)CC2)cc(C)c1OCc1ccccc1
Agent: [Pd]
Solvent: CO
Product: Cc1cc(C[C@@H](OC(=O)N2CCC(N3CCc4ccccc4NC3=O)CC2)C(=O)N2CCN(C3CCS(=O)(=O)CC3)CC2)cc(C)c1O

Procedure:
A solution of 45 mg (0.06 mmol) (R)-1-(4-benzyloxy-3,5-dimethyl-benzyl)-2-[4-(1,1-dioxo-hexahydro-1λ6-thiopyran-4-yl)-piperazin-1-yl]-2-oxo-ethyl 4-(2-oxo-1,2,4,5-tetrahydro-1,3-benzodiazepin-3-yl)-piperidine-1-carboxylate in 10 mL MeOH was combined with 10 mg 10% Pd/C and hydrogenated at RT and 3 bar hydrogen pressure until the reaction came to an end. The catalyst was removed by suction filtering and the residue was purified by HPLC. The fractions containing the product were combined and lyophilised.
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]([C:13]2[O:17][N:16]=[C:15]([C:18]3[CH:26]=[CH:25][CH:24]=[C:23]4[C:19]=3[CH2:20][CH2:21][CH:22]4[N:27]3[CH2:30][CH:29]([C:31]([O:33]C)=[O:32])[CH2:28]3)[N:14]=2)[CH:6]=[CH:7][C:8]=1[O:9][CH:10]([CH3:12])[CH3:11])#[N:2].[OH-].[Na+]>CS(C)=O>[C:1]([C:3]1[CH:4]=[C:5]([C:13]2[O:17][N:16]=[C:15]([C:18]3[CH:26]=[CH:25][CH:24]=[C:23]4[C:19]=3[CH2:20][CH2:21][CH:22]4[N:27]3[CH2:30][CH:29]([C:31]([OH:33])=[O:32])[CH2:28]3)[N:14]=2)[CH:6]=[CH:7][C:8]=1[O:9][CH:10]([CH3:12])[CH3:11])#[N:2]
Reactant: COC(=O)C1CN(C2CCc3c(-c4noc(-c5ccc(OC(C)C)c(C#N)c5)n4)cccc32)C1
Agent: [Na+]
Agent: [OH-]
Solvent: CS(C)=O
Product: CC(C)Oc1ccc(-c2nc(-c3cccc4c3CCC4N3CC(C(=O)O)C3)no2)cc1C#N
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of methyl 1-(4-(5-(3-cyano-4-isopropoxyphenyl)-1,2,4-oxadiazol-3-yl)-2,3-dihydro-1H-inden-1-yl)azetidine-3-carboxylate (6.8 mg, 0.02 mmol) was added 5N NaOH (20 μL). The mixture was stirred at room temperature for 2 hours, dissolved in 250 μL of 1:1 DMSO: MeOH and purified by preparative HPLC. LCMS-ESI (m/z) calculated for C25H24N4O4: 444.5. found 445.1 [M+H]+, tR=6.52 min (Method 2).
Reaction SMILES: [C:1]([C:9]1[CH:13]=[C:12]([CH3:14])[N:11]([CH:15]([CH3:18])[CH2:16][OH:17])[C:10]=1[CH3:19])(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:20](Cl)(=[O:27])[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1.C(N(CC)CC)C.C(Cl)(Cl)Cl>C(Cl)Cl>[C:20]([O:17][CH2:16][CH:15]([N:11]1[C:12]([CH3:14])=[CH:13][C:9]([C:1](=[O:8])[C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=2)=[C:10]1[CH3:19])[CH3:18])(=[O:27])[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1
Reactant: O=C(Cl)c1ccccc1
Reactant: Cc1cc(C(=O)c2ccccc2)c(C)n1C(C)CO
Solvent: ClC(Cl)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: Cc1cc(C(=O)c2ccccc2)c(C)n1C(C)COC(=O)c1ccccc1
Temperature: 25 °C
Reaction time: 20 h
Yield: 77.8 %

Procedure:
In 10 ml of methylene chloride were dissolved 140 mg (0.54 mmole) of 2-(3-benzoyl-2,5-dimethylpyrrol-1-yl) 2-methylethanol and 383 mg (2.75 mmoles) of benzoyl chloride. Triethylamine (1 ml) was added to the solution, and the mixture was stirred at room temperature for 20 hours. Chloroform was added to the reaction mixture. The mixture was washed with dilute hydrochloric acid and then with an aqueous solution of sodium hydrogen carbonate, and the resulting extract was dried over anhydrous magnesium sulfate, and concentrated to afford 860 mg of a crude product. The product was chromatographed on a column of silica gel using cyclohexane/ethyl acetate (3/1) as an eluent to afford compound (314) (150 mg, 0.42 mmole, 77.8%).
Reaction SMILES: C(Cl)(=O)C(Cl)=O.CS(C)=O.[OH:11][CH:12]1[CH2:17][CH2:16][CH2:15][N:14]([C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])[CH:13]1[CH3:25].C(N(CC)C(C)C)(C)C>ClCCl>[CH3:25][CH:13]1[C:12](=[O:11])[CH2:17][CH2:16][CH2:15][N:14]1[C:18]([O:20][C:21]([CH3:22])([CH3:24])[CH3:23])=[O:19]
Reactant: CC1C(O)CCCN1C(=O)OC(C)(C)C
Agent: O=C(Cl)C(=O)Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: CS(C)=O
Solvent: ClCCl
Product: CC1C(=O)CCCN1C(=O)OC(C)(C)C
Temperature: -78 °C
Reaction time: 0.17 h

Procedure:
A solution of oxalyl chloride (4.06 mL, 46.5 mmol) in 50 mL of dichloromethane was cooled to −78° C. and 4.95 mL (69.8 mmol) of dimethyl sulfoxide was added slowly and the mixture was stirred at −78° C. for 10 min. Then a solution of 5.00 g (23.3 mmol) of tert-butyl 3-hydroxy-2-methylpiperidine-1-carboxylate (Step B) in 5 mL of dichloromethane was added dropwise to above mixture. The mixture was stirred at −78° C. for 20 min, then 40.5 mL (232 mmol) of N,N-diisopropylethylamine was added to the mixture. The reaction was warmed to ambient temperature and continued to stir at ambient temperature for 1 h. The mixture was partitioned between dichloromethane and water. The aqueous phase was extracted with three potions of dichloromethane. The combined organic layers were washed with brine, dried over magnesium sulfate, and concentrated. Purification by flash chromatography on a Biotage®D system (silica gel, eluting with 10% ethyl acetate/hexane to 30% ethyl acetate/hexane) gave the title compound. LC/MS 214 (M+1).
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1([C:9]2[CH:14]=[CH:13][C:12]([C:15]3[CH:20]=[CH:19][C:18]([C:21]4[O:25][N:24]=[C:23]([CH3:26])[C:22]=4[CH:27]4[CH2:29][O:28]4)=[CH:17][CH:16]=3)=[CH:11][CH:10]=2)[CH2:8][CH2:7]1)=[O:5])[CH3:2].[CH2:30]([OH:37])[C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1>>[CH2:1]([O:3][C:4]([C:6]1([C:9]2[CH:14]=[CH:13][C:12]([C:15]3[CH:16]=[CH:17][C:18]([C:21]4[O:25][N:24]=[C:23]([CH3:26])[C:22]=4[CH:27]([OH:28])[CH2:29][O:37][CH2:30][C:31]4[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=4)=[CH:19][CH:20]=3)=[CH:11][CH:10]=2)[CH2:8][CH2:7]1)=[O:5])[CH3:2]
Reactant: OCc1ccccc1
Reactant: CCOC(=O)C1(c2ccc(-c3ccc(-c4onc(C)c4C4CO4)cc3)cc2)CC1
Product: CCOC(=O)C1(c2ccc(-c3ccc(-c4onc(C)c4C(O)COCc4ccccc4)cc3)cc2)CC1

Procedure:
Prepared according to the procedure described in Example 14, Step 4, using 1-[4′-(3-methyl-4-oxiranyl-isoxazol-5-yl)-biphenyl-4-yl]-cyclopropanecarboxylic acid ethyl ester and benzyl alcohol.
Reaction SMILES: [OH:1][CH2:2][CH2:3][N:4]([C:13]([C:15]1[CH:16]=[N:17][N:18]([C:20]2[CH:25]=[CH:24][C:23]([O:26][CH2:27][CH2:28][CH2:29][N:30]3[CH2:34][CH2:33][CH2:32][C@H:31]3[CH3:35])=[CH:22][CH:21]=2)[CH:19]=1)=[O:14])[CH2:5][C:6]([O:8]C(C)(C)C)=[O:7].Cl>O1CCOCC1.C(OCC)(=O)C>[OH:1][CH2:2][CH2:3][N:4]([C:13]([C:15]1[CH:16]=[N:17][N:18]([C:20]2[CH:25]=[CH:24][C:23]([O:26][CH2:27][CH2:28][CH2:29][N:30]3[CH2:34][CH2:33][CH2:32][C@H:31]3[CH3:35])=[CH:22][CH:21]=2)[CH:19]=1)=[O:14])[CH2:5][C:6]([OH:8])=[O:7]
Reactant: C[C@@H]1CCCN1CCCOc1ccc(-n2cc(C(=O)N(CCO)CC(=O)OC(C)(C)C)cn2)cc1
Agent: Cl
Solvent: C1COCCO1
Solvent: CCOC(C)=O
Product: C[C@@H]1CCCN1CCCOc1ccc(-n2cc(C(=O)N(CCO)CC(=O)O)cn2)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 38.9 %

Procedure:
To a solution of tert-butyl N-(2-hydroxyethyl)-N-{[1-(4-{3-[(2R)-2-methylpyrrolidin-1-yl]propoxy}phenyl)-1H-pyrazol-4-yl]carbonyl}glycinate prepared in Example 67-(3) (0.218 g) in 1,4-dioxane (4.0 ml), a solution of hydrochloric acid in ethyl acetate (4 M, 4.0 ml) was added and stirred at room temperature for 1 hour. The reaction mixture was concentrated under reduced pressure, and the resulting residue was purified by octadecylsilyl (ODS) column chromatography (eluting solvent: acetonitrile:water=95:5) to give the titled compound (0.075 g) as a colorless amorphous substance.
Reaction SMILES: CS(O[CH2:6][CH2:7][C:8]1[O:9][C:10]2[CH:16]=[CH:15][C:14]([C:17]3[CH:22]=[CH:21][C:20]([C:23]#[N:24])=[CH:19][CH:18]=3)=[CH:13][C:11]=2[CH:12]=1)(=O)=O.[CH2:25]([NH:27][CH2:28][CH3:29])[CH3:26]>>[CH2:25]([N:27]([CH2:28][CH3:29])[CH2:6][CH2:7][C:8]1[O:9][C:10]2[CH:16]=[CH:15][C:14]([C:17]3[CH:22]=[CH:21][C:20]([C:23]#[N:24])=[CH:19][CH:18]=3)=[CH:13][C:11]=2[CH:12]=1)[CH3:26]
Reactant: CS(=O)(=O)OCCc1cc2cc(-c3ccc(C#N)cc3)ccc2o1
Reactant: CCNCC
Product: CCN(CC)CCc1cc2cc(-c3ccc(C#N)cc3)ccc2o1

Procedure:
The product from Example 1C and diethylamine were processed as described in Example 1D to provide the titled compound. 1H NMR (300 MHz, CD3OD) δ 7.75 (m, 1H), 7.80 (m, 4H), 7.60 (m, 2H), 6.85 (s, 1H), 3.6 (t, J=7.5 Hz, 2H), 3.25-3.5 (m, 6H), (t, 6H, J=6.6 Hz); MS (DCI) m/z 319 (M+H)+;
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH2:11][CH:10]([C:14]([O:16]C/C=C\C)=[O:15])[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].C[Si](C)(C)[N-][Si](C)(C)C.[Li+].C[Si](Cl)(C)C.[OH-].[Na+]>O1CCCC1.O>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH2:11][C:10]([CH:11]([CH3:12])[CH:10]=[CH2:9])([C:14]([OH:16])=[O:15])[CH2:9]1)=[O:7])([CH3:2])([CH3:3])[CH3:4]
Reactant: C/C=C\COC(=O)C1CCCN(C(=O)OC(C)(C)C)C1
Agent: C[Si](C)(C)Cl
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: C1CCOC1
Solvent: O
Product: C=CC(C)C1(C(=O)O)CCCN(C(=O)OC(C)(C)C)C1
Temperature: 0 °C
Reaction time: 0.42 h
Yield: 124.5 %

Procedure:
To a solution of piperidine-1,3-dicarboxylic acid 3-((Z)-but-2-enyl)ester 1-tert-butyl ester (68.3 g) in tetrahydrofuran (700 ml) cooled to −74° C. was added lithium hexamethyl disilazide (1.6M tetrahydrofuran solution, 166 ml). The reaction mixture was warmed to 0° C. over 35 minutes, stirred at the same temperature for additional 25 minutes, and cooled to −74° C. again. To the mixture was added trimethylsilyl chloride (39.6 ml). The reaction mixture was warmed to room temperature over 70 minutes, and stirred at the same temperature for additional 4 hours. To the mixture were sequentially added water (600 ml), 2M aqueous sodium hydroxide solution (70 ml), and the mixture was washed with n-hexane (600 ml). The separated aqueous layer was acidified by 2M aqueous hydrochloric acid solution, followed by extracted with ethyl acetate (300 ml, 200 ml, 150 ml) three times. The combined organic layer was washed with saturated aqueous sodium chloride solution, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The resulting residue was slurry-washed with n-hexane/ethyl acetate solution (10/1) to give the titled compound (42.5 g).
Reaction SMILES: [CH2:1]=[C:2]1[CH2:6][CH2:5][CH2:4][CH2:3]1.B1C2CCCC1CCC2.[CH2:16]([O:23][C:24]1[CH:29]=[C:28](I)[CH:27]=[CH:26][C:25]=1[N:31]1[S:35](=[O:37])(=[O:36])[NH:34][C:33](=[O:38])[CH2:32]1)[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1.B.C([O-])([O-])=O.[Na+].[Na+]>C1COCC1.COCCOC>[CH2:16]([O:23][C:24]1[CH:29]=[C:28]([CH2:1][CH:2]2[CH2:6][CH2:5][CH2:4][CH2:3]2)[CH:27]=[CH:26][C:25]=1[N:31]1[S:35](=[O:37])(=[O:36])[NH:34][C:33](=[O:38])[CH2:32]1)[C:17]1[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=1
Reactant: O=C1CN(c2ccc(I)cc2OCc2ccccc2)S(=O)(=O)N1
Reactant: C=C1CCCC1
Agent: B
Agent: B1C2CCCC1CCC2
Agent: O=C([O-])[O-]
Solvent: COCCOC
Solvent: C1CCOC1
Product: O=C1CN(c2ccc(CC3CCCC3)cc2OCc2ccccc2)S(=O)(=O)N1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
To a solution of methylenecyclopentane (246 mg, 3 mmol) in THF (7.5 mL) is added 9-BBN (7.5 mL, 0.5M in THF, 3 mmol) and the mixture is stirred at RT for 18 h. A mixture of 5-(2-benzyloxy-4-iodophenyl)-1,1-dioxo-1,2,5-thiadiazolidin-3-one (200 mg, 0.45 mmol), 3.38 mL of the borane solution previously prepared (0.675 mmol), resin-bound PPh3Pd (100 mg) and Na2CO3 (0.9 mL, 2M) in DME (5 mL) is heated in a microwave apparatus at 110° C. for 15 min. The mixture is filtered and the solvent removed under reduced pressure to give the title compound which is used directly in the next step.
Reaction SMILES: [S:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[C:2]1[O:10][C:11]1[CH:19]=[C:18]2[C:14]([CH:15]=[C:16]([CH2:20][OH:21])[NH:17]2)=[CH:13][CH:12]=1>C(Cl)(Cl)Cl.O=[Mn]=O>[S:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[C:2]1[O:10][C:11]1[CH:19]=[C:18]2[C:14]([CH:15]=[C:16]([CH:20]=[O:21])[NH:17]2)=[CH:13][CH:12]=1
Reactant: OCc1cc2ccc(Oc3nc4ccccc4s3)cc2[nH]1
Agent: O=[Mn]=O
Solvent: ClC(Cl)Cl
Product: O=Cc1cc2ccc(Oc3nc4ccccc4s3)cc2[nH]1
Temperature: 80 °C
Yield: 49.9 %

Procedure:
To a solution of [6-(benzothiazol-2-yloxy)-1H-indol-2-yl]-methanol (97 mg, 0.32 mmol) in CHCl3 (5 mL) was added MnO2 (280 mg, 3.2 mmol) and heated (80° C., 2 h). The reaction mixture was cooled (rt), filtered (Celite®) and washed with EtOAc (100 mL). The organic layer was washed with brine (50 mL), dried, filtered and concentrated in vacuo. The resulting residue was purified by silica gel flash chromatography using EtOAc:hexane (0-50%) to provide the title compound as beige solid (47 mg, 49%). MS (ESI): mass calcd. for C16H10N2O2S, 294.1; m/z found, 295.0 [M+H]+. 1H NMR (400 MHz, CDCl3): 9.80 (s, 1H), 9.80 (s, 1H), 7.79 (d, J=8.8, 1H), 7.73 (d, J=8.1, 1H), 7.68 (d, J=8.0, 1H), 7.49 (s, 1H), 7.40 (dd, J=11.3, 4.1, 1H), 7.31-7.24 (m, 2H), 7.15 (dd, J=8.8, 2.1, 1H).
Reaction SMILES: [NH2:1][C:2]1[CH:15]=[CH:14][C:5]([C:6]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)=[O:7])=[CH:4][CH:3]=1.[C:16](Cl)(=[O:25])[C:17]1[CH:22]=[CH:21][CH:20]=[C:19]([O:23][CH3:24])[CH:18]=1.C(N(CC)CC)C>C1COCC1>[C:6]([C:5]1[CH:4]=[CH:3][C:2]([NH:1][C:16](=[O:25])[C:17]2[CH:22]=[CH:21][CH:20]=[C:19]([O:23][CH3:24])[CH:18]=2)=[CH:15][CH:14]=1)(=[O:7])[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1
Reactant: COc1cccc(C(=O)Cl)c1
Reactant: Nc1ccc(C(=O)c2ccccc2)cc1
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: COc1cccc(C(=O)Nc2ccc(C(=O)c3ccccc3)cc2)c1
Yield: 94.1 %

Procedure:
Reaction of 4-aminobenzophenone (100 mg, 0.51 mmol) in THF (6 mL) with m-anisoyl chloride (136 mg, 0.65 mmol) in presence of triethylamine (90 μL, 0.65 mmol) according to method A gave N-(4-benzoyl-phenyl)-3-methoxy-benzamide (160 mg, 0.48 mmol, 94% yield) as a white powder after purification by chromatography on silica gel (eluent EtOAc/DCM 0/100 to 5/95.
Reaction SMILES: [NH2:1][C@@H:2]1[CH2:6][CH2:5][N:4]([C:7]([O:9][C:10]([CH3:13])([CH3:12])[CH3:11])=[O:8])[CH2:3]1.C(N(CC)CC)C.Cl[C:22]([O:24][C@H:25]1[CH2:29][CH2:28][O:27][CH2:26]1)=[O:23]>C(Cl)Cl>[C:10]([O:9][C:7]([N:4]1[CH2:5][CH2:6][C@@H:2]([NH:1][C:22](=[O:23])[O:24][C@H:25]2[CH2:29][CH2:28][O:27][CH2:26]2)[CH2:3]1)=[O:8])([CH3:13])([CH3:12])[CH3:11]
Reactant: CC(C)(C)OC(=O)N1CC[C@@H](N)C1
Reactant: O=C(Cl)O[C@H]1CCOC1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N1CC[C@@H](NC(=O)O[C@H]2CCOC2)C1
Temperature: 25 °C

Procedure:
To a solution of (R)-tert-butyl 3-aminopyrrolidine-1-carboxylate (500 mg, 2.6 mmol) in 5 mL CH2Cl2 was added triethylamine (0.73 mL, 5.2 mmol), and the reaction was cooled to −20° C. (S)-tetrahydrofuran-3-yl chloroformate (525 mg, 3.48 mmol) was added in portions over a period of 10 minutes to the above reaction mixture. After allowing the reaction to warm to room temperature, it was quenched with water and extracted twice with CH2Cl2. The combined organic layers were dried over MgSO4, filtered, and concentrated to afford (S)-tetrahydrofuran-3-yl(R)-1-(tert-butoxycarbonyl)pyrrolidin-3-ylcarbamate. Purification via silica gel chromatography using 0-20% EtOAc in CH2Cl2 gave (S)-tetrahydrofuran-3-yl(R)-1-(tert-butoxycarbonyl)pyrrolidin-3-ylcarbamate (490 mg, 63%). LC/MS: m/z 301.3 (M+H)+ at 2.35 min (10%-99% CH3CN (0.035% TFA)/H2O (0.05% TFA)).