Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[N+:4]([O-:27])[CH:5]=[C:6]([Cl:26])[C:7]=1[CH2:8][C@@H:9]([C:11]1[CH:16]=[CH:15][C:14]([O:17][CH:18]([F:20])[F:19])=[C:13]([O:21][CH2:22][CH:23]2[CH2:25][CH2:24]2)[CH:12]=1)[OH:10].[CH3:28][O:29][C:30]1[CH:38]=[C:37]2[C:33]([C:34](=[O:44])[C:35](=[O:43])[N:36]2[CH2:39][C:40](O)=[O:41])=[CH:32][CH:31]=1.C(Cl)CCl>CN(C1C=CN=CC=1)C.C(Cl)Cl>[Cl:1][C:2]1[CH:3]=[N+:4]([O-:27])[CH:5]=[C:6]([Cl:26])[C:7]=1[CH2:8][C@@H:9]([C:11]1[CH:16]=[CH:15][C:14]([O:17][CH:18]([F:20])[F:19])=[C:13]([O:21][CH2:22][CH:23]2[CH2:25][CH2:24]2)[CH:12]=1)[O:10][C:40](=[O:41])[CH2:39][N:36]1[C:37]2[C:33](=[CH:32][CH:31]=[C:30]([O:29][CH3:28])[CH:38]=2)[C:34](=[O:44])[C:35]1=[O:43]
Reactant: [O-][n+]1cc(Cl)c(C[C@H](O)c2ccc(OC(F)F)c(OCC3CC3)c2)c(Cl)c1
Reactant: COc1ccc2c(c1)N(CC(=O)O)C(=O)C2=O
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Solvent: ClCCCl
Product: COc1ccc2c(c1)N(CC(=O)O[C@@H](Cc1c(Cl)c[n+]([O-])cc1Cl)c1ccc(OC(F)F)c(OCC3CC3)c1)C(=O)C2=O
Temperature: 25 °C
Reaction time: 4 h
Yield: 54.6 %

Procedure:
A mixture of (S)-3,5-dichloro-4-(2-(3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenyl)-2-hydroxyethyl)pyridine 1-oxide (0.200 g, 0.476 mmol), 2-(6-methoxy-2,3-dioxoindolin-1-yl)acetic acid (0.112 g, 0.476 mmol), DMAP (0.029 g, 0.238 mmol) and EDC (0.274 g, 1.428 mmol) in DCM (10 ml) was stirred at room temperature for 4 hours; then the reaction mixture was washed with 1N HCl, aqueous 5% NaHCO3 and brine. The organic layer was dried over Na2SO4 and evaporated to dryness. The crude was purified by flash chromatography on silica gel (ethyl acetate:DCM=7:3) to give (S)-3,5-dichloro-4-(2-(3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenyl)-2-(2-(6-methoxy-2,3-dioxoindolin-1-yl)acetoxy)ethyl)pyridine 1-oxide (0.166 g, 0.260 mmol, 55% yield). MS/ESI+ 637.19 [MH]+; [αD]=+67.91 c=0.22 in DCM; 1H NMR (300 MHz, DMSO-d6) δ ppm 8.37 (s, 2H), 7.61 (d, 1H), 7.17 (d, 1H), 7.05 (d, 1H), 6.94 (dd, 1H), 7.07 (t, 1H), 6.69 (dd, 1H), 6.66 (d, 1H), 6.02 (dd, 1H), 4.60 (s, 2H), 3.89 (d, 2H), 3.86 (s, 3H), 3.38 (dd, 1H), 3.19 (dd, 1H), 1.07-1.33 (m, 1H), 0.48-0.67 (m, 2H), 0.18-0.48 (m, 2H)
Reaction SMILES: I[C:2]1[CH:7]=[CH:6][C:5]([C:8]([N:10]2[CH2:15][CH2:14][N:13]([C:16]3[C:21]([CH3:22])=[CH:20][C:19]([CH3:23])=[C:18]([CH3:24])[N:17]=3)[CH2:12][CH2:11]2)=[O:9])=[CH:4][CH:3]=1.[CH3:25][C@@H:26]1[O:30][C:29](=[O:31])[NH:28][CH2:27]1>>[CH3:25][C@@H:26]1[O:30][C:29](=[O:31])[N:28]([C:2]2[CH:7]=[CH:6][C:5]([C:8]([N:10]3[CH2:15][CH2:14][N:13]([C:16]4[C:21]([CH3:22])=[CH:20][C:19]([CH3:23])=[C:18]([CH3:24])[N:17]=4)[CH2:12][CH2:11]3)=[O:9])=[CH:4][CH:3]=2)[CH2:27]1
Reactant: Cc1cc(C)c(N2CCN(C(=O)c3ccc(I)cc3)CC2)nc1C
Reactant: C[C@H]1CNC(=O)O1
Product: Cc1cc(C)c(N2CCN(C(=O)c3ccc(N4C[C@H](C)OC4=O)cc3)CC2)nc1C
Yield: 75.5 %

Procedure:
By reaction and treatment in the same manner as in Example 149 and using (4-iodophenyl)[4-(3,5,6-trimethylpyridin-2-yl)piperazin-1-yl]methanone (435 mg) described in Preparation Example 176 and (S)-5-methyloxazolidin-2-one (121 mg) described in Preparation Example 42, the title compound (308 mg) was obtained.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][N:3]=1.Br[C:9]1[CH:10]=[CH:11][C:12]([O:29][CH2:30][CH3:31])=[C:13]([C:15]2[NH:16][C:17](=[O:28])[C:18]3[N:23]([CH3:24])[N:22]=[C:21]([CH2:25][CH2:26][CH3:27])[C:19]=3[N:20]=2)[CH:14]=1>>[CH2:30]([O:29][C:12]1[CH:11]=[CH:10][C:9]([C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][N:3]=2)=[CH:14][C:13]=1[C:15]1[NH:16][C:17](=[O:28])[C:18]2[N:23]([CH3:24])[N:22]=[C:21]([CH2:25][CH2:26][CH3:27])[C:19]=2[N:20]=1)[CH3:31]
Reactant: Brc1ccccn1
Reactant: CCCc1nn(C)c2c(=O)[nH]c(-c3cc(Br)ccc3OCC)nc12
Product: CCCc1nn(C)c2c(=O)[nH]c(-c3cc(-c4ccccn4)ccc3OCC)nc12

Procedure:
The title compound was prepared from 2-bromopyridine and 5-(5-bromo-2-ethoxyphenyl)-1-methyl-3-n-propyl-1,6-dihydro-7H-pyrazolo[4,3-d]pyrimidin-7-one, following the procedure described in Example 32, and was obtained as an off-white solid (33%), m.p. 216°-218° C. Found: C,67.71; H,5.81; N,17.63. C22H23N5O2 requires C,67.85; H,5.95; N,17.98%.
Reaction SMILES: [CH2:1]([C:8]1[N:9]([CH2:19][C:20]([OH:22])=O)[C:10]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)=[CH:11][CH:12]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(N1C=CN=C1)(N1C=CN=C1)=O.C(=O)(O)O.[NH2:39][C:40]([NH2:42])=[NH:41].C(N(CC)CC)C>CN(C=O)C>[NH2:41][C:40](=[NH:39])[NH:42][C:20](=[O:22])[CH2:19][N:9]1[C:10]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)=[CH:11][CH:12]=[C:8]1[CH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: N=C(N)N
Reactant: O=C(O)Cn1c(Cc2ccccc2)ccc1-c1ccccc1
Agent: O=C(O)O
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: N=C(N)NC(=O)Cn1c(Cc2ccccc2)ccc1-c1ccccc1
Reaction time: 1 h
Yield: 73.8 %

Procedure:
To a stirred solution of (2-benzyl-5-phenyl-1H-pyrrol-1-yl)acetic acid (155 mg, 0.53 mmol) in DMF (1.0 ml) was added 1,1′-carbonyldiimidazole (172 mg, 1.06 mmol) at room temperature. After 1 h stirring, the reaction mixture was treated with a solution of guanidine carbonate (286 mg, 1.59 mmol) in DMF (2.0 ml) and triethylamine (0.22 ml, 1.59 mmol). After stirring for 18 h, the reaction mixture was quenched with H2O (10 ml). The aqueous was extracted with EtOAc (3×30 ml). The combined organic extracts were washed with H2O (2×30 ml), brine (30 ml), dried (Na2SO4), filtered and concentrated. The crude material was purified by chromatography (silica gel; EtOAc/2M NH3 in MeOH: 97/3) to give the titled compound (130 mg, 74%) as a solid: mp 155-158° C.; MS (+) ES, 333 (M+H)+.
Reaction SMILES: C([N:4]1[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[C:6](=[C:13]([Cl:21])[C:14]2[CH:19]=[CH:18][C:17]([Br:20])=[CH:16][CH:15]=2)[C:5]1=[O:22])(=O)C.N1CCCCC1>CO>[Cl:21][C:13](=[C:6]1[C:7]2[C:12](=[CH:11][CH:10]=[CH:9][CH:8]=2)[NH:4][C:5]1=[O:22])[C:14]1[CH:15]=[CH:16][C:17]([Br:20])=[CH:18][CH:19]=1
Reactant: CC(=O)N1C(=O)C(=C(Cl)c2ccc(Br)cc2)c2ccccc21
Solvent: CO
Solvent: C1CCNCC1
Product: O=C1Nc2ccccc2C1=C(Cl)c1ccc(Br)cc1

Procedure:
Prepared from the compound obtained in (b) by reacting with 1 equivalent of piperidine in MeOH (5 hours, 40° C.)
Reaction SMILES: FC(F)(F)S([CH:6](S(C(F)(F)F)(=O)=O)[CH2:7][CH:8]([S:16]([C:19]([F:22])([F:21])[F:20])(=[O:18])=[O:17])[S:9]([C:12]([F:15])([F:14])[F:13])(=[O:11])=[O:10])(=O)=O.[C:32]1([OH:40])[C:33](C)=[CH:34][CH:35]=[CH:36][C:37]=1[CH3:38]>C(#N)C>[F:13][C:12]([F:15])([F:14])[S:9]([CH:8]([S:16]([C:19]([F:21])([F:20])[F:22])(=[O:17])=[O:18])[CH2:7][C:6]1[C:33]([CH3:34])=[C:32]([OH:40])[C:37]([CH3:38])=[CH:36][CH:35]=1)(=[O:10])=[O:11]
Reactant: O=S(=O)(C(CC(S(=O)(=O)C(F)(F)F)S(=O)(=O)C(F)(F)F)S(=O)(=O)C(F)(F)F)C(F)(F)F
Reactant: Cc1cccc(C)c1O
Solvent: CC#N
Product: Cc1ccc(CC(S(=O)(=O)C(F)(F)F)S(=O)(=O)C(F)(F)F)c(C)c1O
Reaction time: 3 h
Yield: 94 %

Procedure:
1,1,3,3-Tetrakis(trifluoromethylsulfonyl)propane [4] (143.2 mg, 0.25 mmol) was added to an acetonitrile (0.25 ml) solution of 2,6-xylenol (34.1 mg, 0.28 mmol) at room temperature. After 3 hours of stirring, the reaction solution was concentrated under a reduced pressure. An obtained residue was purified by Kugelrohr distillation (180-200° C./3 mmHg) thereby obtaining 4-(2,2-bis(trifluoromethylsulfonyl)ethyl-2,6-dimethylphenol [1d] with a yield of 94% (96.9 mg, 0.234 mmol). Further, recrystallization was performed thereby obtaining a colorless crystal from hexane.
Reaction SMILES: [CH3:1][C:2]1[CH:24]=[CH:23][CH:22]=[C:21]([CH3:25])[C:3]=1[CH2:4][O:5][C:6]1[CH:7]=[C:8]([C:12](=[O:20])[CH2:13][CH2:14][C:15]([O:17][CH2:18][CH3:19])=[O:16])[CH:9]=[CH:10][CH:11]=1.[Br:26]Br>CCOCC>[CH3:1][C:2]1[CH:24]=[CH:23][CH:22]=[C:21]([CH3:25])[C:3]=1[CH2:4][O:5][C:6]1[CH:7]=[C:8]([C:12](=[O:20])[CH:13]([Br:26])[CH2:14][C:15]([O:17][CH2:18][CH3:19])=[O:16])[CH:9]=[CH:10][CH:11]=1
Reactant: BrBr
Reactant: CCOC(=O)CCC(=O)c1cccc(OCc2c(C)cccc2C)c1
Solvent: CCOCC
Product: CCOC(=O)CC(Br)C(=O)c1cccc(OCc2c(C)cccc2C)c1
Temperature: 0 °C
Reaction time: 4 h

Procedure:
To a ice cooled solution of Ethyl 4-(3-(2,6-dimethylbenzyloxy)phenyl)-4-oxobutyrate (Step C, 3 g, 9 mmol) in dry ether (70 ml) was added dropwise bromine (0.7971 g, 9.9 mmol) diluted in ether (30 ml). After 4 hours of stirring, reaction mixture was concentrated and purified by flash chromatography on silica gel column (EtOAc:Hex, 1:4) to provide the title compound.
Reaction SMILES: [CH:1]([C:3]1[CH:4]=[C:5]([S:12][C:13]2[CH:14]=[C:15]([NH:19][S:20]([C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=3)(=[O:22])=[O:21])[CH:16]=[CH:17][CH:18]=2)[CH:6]=[CH:7][C:8]=1[N+:9]([O-:11])=[O:10])=[O:2].ClC1C=C(C(OO)=[O:37])C=CC=1.C([O-])(O)=O.[Na+]>C(Cl)(Cl)Cl>[CH:1]([C:3]1[CH:4]=[C:5]([S:12]([C:13]2[CH:14]=[C:15]([NH:19][S:20]([C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=3)(=[O:22])=[O:21])[CH:16]=[CH:17][CH:18]=2)=[O:37])[CH:6]=[CH:7][C:8]=1[N+:9]([O-:11])=[O:10])=[O:2]
Reactant: O=Cc1cc(Sc2cccc(NS(=O)(=O)c3ccccc3)c2)ccc1[N+](=O)[O-]
Reactant: O=C(OO)c1cccc(Cl)c1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClC(Cl)Cl
Product: O=Cc1cc(S(=O)c2cccc(NS(=O)(=O)c3ccccc3)c2)ccc1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 4 h

Procedure:
A mixture of N-[3-(3-formyl-4-nitro-phenylsulfanyl)-phenyl]-benzenesulfonamide (0.0034 mol) and 3-Chloro-benzenecarboperoxoic acid (also known as MCPBA or meta-chloroperbenzoic acid) (0.7 g; 75%) in CHCl3 (q.s.) was stirred for 4 hours at room temperature. Then a NaHCO3 solution was added, and the reaction mixture was stirred. The organic layer was separated, dried, and filtered, and the solvent was evaporated. The residue was purified by column chromatography over Biotage (gradient eluent: CH2Cl2:CH3OH). The purest product fractions were collected, and the solvent was evaporated to yield the title compound as a residue.
Reaction SMILES: C([O:8][C:9]1[CH:14]=[C:13]([O:15]CC2C=CC=CC=2)[C:12]([Cl:23])=[CH:11][C:10]=1[C:24]1[O:28][N:27]=[C:26]([CH2:29][NH2:30])[C:25]=1[C:31]1[CH:36]=[CH:35][C:34]([F:37])=[CH:33][CH:32]=1)C1C=CC=CC=1.[C:38](OC(=O)C)(=[O:40])[CH3:39].C(N(CC)CC)C.B(Cl)(Cl)Cl>C(Cl)Cl>[Cl:23][C:12]1[C:13]([OH:15])=[CH:14][C:9]([OH:8])=[C:10]([C:24]2[O:28][N:27]=[C:26]([CH2:29][NH:30][C:38](=[O:40])[CH3:39])[C:25]=2[C:31]2[CH:36]=[CH:35][C:34]([F:37])=[CH:33][CH:32]=2)[CH:11]=1
Reactant: CC(=O)OC(C)=O
Reactant: NCc1noc(-c2cc(Cl)c(OCc3ccccc3)cc2OCc2ccccc2)c1-c1ccc(F)cc1
Agent: ClB(Cl)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(=O)NCc1noc(-c2cc(Cl)c(O)cc2O)c1-c1ccc(F)cc1
Yield: 14 %

Procedure:
To a solution of C-[5-(2,4-Bis-benzyloxy-5-chloro-phenyl)-4-(4-fluoro-phenyl)-isoxazol-3-yl]-methylamine (100 mg, 0.19 mmol) in DCM was added acetic anhydride (130 μl, 7.0 equiv.) and triethylamine (81 μl, 3.0 equiv.). The solution was stirred at room temperature until the amine was consumed. The solvent was removed in vacuo to leave the yellow tinged oily crude benzyl protected product. This was deprotected using the standard procedure with boron trichloride described above and purified by preparative TLC and soxhlet extraction of the silica by ether gave the pure compound as a colourless solid (10 mg, 14% yield).
Reaction SMILES: [CH:1]([N:3](C)[CH:4]([C:14]1[S:15][CH:16]=[CH:17][C:18]=1[CH3:19])[CH2:5][C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=1[NH:12][CH3:13])=O.[ClH:21]>C(OCC)C.CO>[ClH:21].[ClH:21].[CH3:1][NH:3][CH:4]([C:14]1[S:15][CH:16]=[CH:17][C:18]=1[CH3:19])[CH2:5][C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=1[NH:12][CH3:13]
Reactant: CNc1ccccc1CC(c1sccc1C)N(C)C=O
Agent: Cl
Solvent: CCOCC
Solvent: CO
Product: CNc1ccccc1CC(NC)c1sccc1C

Procedure:
N-Formyl-N-methyl-2-methylamino-α-(3-methyl-2-thienyl)benzenethanamine (4.1 g) was treated with 18 ml of 3N hydrochloric acid. After refluxing for 1.5 hours the solution was decanted over ice, basified with 12 ml of a 50% aqueous sodium hydroxide solution and extracted with dichloromethane (3×60 ml). The organic phase was dried over anhydrous sodium sulfate and concentrated to an oil. Purification of the oil was accomplished by HPLC (Water's Associates Prep LC/System 500, silica gel, elution with methanol). Concentration of the appropriate fractions afforded a residue which was dissolved in diethyl ether, filtered free of insolubles, and concentrated to afford N-methyl-2-methylamino-α-(3-methyl-2-thienyl)benzeneeethanamine as an oil. The oil was dissolved in methanol and treated with ethereal hydrogen chloride. Dilution with diethyl ether precipitated 2.4 g of the corresponding dihydrochoride salt, mp 191°-192° C.
Reaction SMILES: [CH:1]1([C:5]2[CH:6]=[C:7]([CH:14]=[CH:15][CH:16]=2)[CH2:8][C@@H:9]([C:11]([OH:13])=[O:12])[NH2:10])[CH2:4][CH2:3][CH2:2]1.[ClH:17].[CH3:18][C:19](=[CH2:21])[CH3:20].OS(O)(=O)=O.Cl>O1CCOCC1>[CH:1]1([C:5]2[CH:6]=[C:7]([CH:14]=[CH:15][CH:16]=2)[CH2:8][C@@H:9]([C:11]([O:13][C:19]([CH3:21])([CH3:20])[CH3:18])=[O:12])[NH2:10])[CH2:2][CH2:3][CH2:4]1.[ClH:17]
Reactant: N[C@@H](Cc1cccc(C2CCC2)c1)C(=O)O
Reactant: C=C(C)C
Agent: Cl
Agent: O=S(=O)(O)O
Solvent: C1COCCO1
Product: CC(C)(C)OC(=O)[C@@H](N)Cc1cccc(C2CCC2)c1
Yield: 81 %

Procedure:
According to example 54, 0.65 g of 3-cyclobutyl-L-phenylalanine·HCl was treated with 25 mL of isobutylene in 25 mL of 1,4-dioxane in the presence of 0.5 mL of conc. H2SO4. Work-up in the usual manner followed by acidification of the free amine with ethereal HCl afforded 0.64 g (81%) of tert-butyl 3-cyclobutyl-L-phenylalaninate·HCl as a white powder, m.p. 173-174° C.
Reaction SMILES: [Na].[CH:2]([CH:4]([CH2:10][CH2:11][C:12]([O:14][CH2:15][CH3:16])=[O:13])[C:5]([O:7]CC)=O)=O.[C:17]1(/[CH:23]=[CH:24]/[C:25](=[NH:27])[NH2:26])[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1.CO>CCO>[OH:7][C:5]1[C:4]([CH2:10][CH2:11][C:12]([O:14][CH2:15][CH3:16])=[O:13])=[CH:2][N:27]=[C:25](/[CH:24]=[CH:23]/[C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[N:26]=1
Reactant: CCOC(=O)CCC(C=O)C(=O)OCC
Reactant: N=C(N)/C=C/c1ccccc1
Agent: [Na]
Solvent: CO
Solvent: CCO
Product: CCOC(=O)CCc1cnc(/C=C/c2ccccc2)nc1O
Yield: 59.9 %

Procedure:
Diethyl α-formylglutarate sodium salt (1 g, 4.2 mmol) and (2E)-3-phenyl-2-propenimidamide (0.61 g, 4.2 mmol), prepared in Example 126 (g), were combined in EtOH (20 mL) and MeOH (10 mL) and heated at reflux for 12 h. The solvent was removed and the resulting solid triturated with ether and filtered to give the desired product as a yellow solid (0.75 g, 56%). The mother liquor contained additional product which was not isolated. LCMS (ES+) m/z 299 (MH+).
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[C:7](=[O:11])[N:6]([C:12]1[CH:17]=[CH:16][C:15]([OH:18])=[CH:14][CH:13]=1)[C:5]2=[O:19].C(=O)([O-])[O-].[K+].[K+].[CH2:26](Br)[C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1.O>CN(C=O)C>[CH2:26]([O:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[C:7](=[O:11])[N:6]([C:12]1[CH:17]=[CH:16][C:15]([O:18][CH2:5][C:4]3[CH:8]=[CH:9][CH:10]=[CH:2][CH:3]=3)=[CH:14][CH:13]=1)[C:5]2=[O:19])[C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1
Reactant: O=C1c2ccc(O)cc2C(=O)N1c1ccc(O)cc1
Reactant: BrCc1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: O=C1c2ccc(OCc3ccccc3)cc2C(=O)N1c1ccc(OCc2ccccc2)cc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 186 %

Procedure:
To 5-hydroxy-2-(4-hydroxyphenyl)isoindoline-1,3-dione (2.08 g) in DMF (20 mL) was added potassium carbonate (4.62 g) and a solution of benzyl bromide (3.07 g) in DMF (3.0 mL) dropwise under nitrogen atmosphere. The reaction was stirred at room temperature for 2 h then heated to 80° C. for 3 h. The mixture was cooled to room temperature, poured into water (250 mL) and let sit undisturbed for 2.0 h. The white solid was collected by filtration and washed with water. The solid was dried under high vacuum at 50° C. for 18 h yielding the title compound (3.30 g) as a white solid. 1H NMR (DMSO-d6): 7.87 (d, 1H, J=8.4 Hz), 7.48-7.35 (m, 12H), 7.32 (d, 2H, J=8.7 Hz), 7.13 (d, 2H, J=8.7 Hz), 5.35 (s, 2H), 5.17 (s, 2H); MS: 436 (MH+).
Reaction SMILES: [CH3:1][C:2]1([CH3:26])[N:8]([C:9]([O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:10])[C@@H:7]([C:16]([O:18]CC2C=CC=CC=2)=[O:17])[CH2:6][CH2:5][CH2:4][O:3]1>CCO.C1COCC1.[Pd]>[C:12]([O:11][C:9]([N:8]1[C@@H:7]([C:16]([OH:18])=[O:17])[CH2:6][CH2:5][CH2:4][O:3][C:2]1([CH3:26])[CH3:1])=[O:10])([CH3:15])([CH3:13])[CH3:14]
Reactant: CC(C)(C)OC(=O)N1[C@@H](C(=O)OCc2ccccc2)CCCOC1(C)C
Agent: [Pd]
Solvent: C1CCOC1
Solvent: CCO
Product: CC(C)(C)OC(=O)N1[C@@H](C(=O)O)CCCOC1(C)C
Temperature: 25 °C
Reaction time: 4 h
Yield: 85.2 %

Procedure:
Wet 5% Pd/C (400 mg) was added to a solution of 4-benzyl 3-tert-butyl (4R)-2,2-dimethyl-1,3-oxazepane-3,4-dicarboxylate (Preparation 49, 2.5 g, 6.87 mmol) in 50% EtOH in THF (100 mL) and stirred for 4 hours at room temperature under an H2 balloon. The reaction was filtered through celite and the filtrate was concentrated under reduced pressure to afford the title compound (1.6 g, 85%).
Reaction SMILES: C([O:3][C:4]([C:6]1[NH:7][C:8]([CH:19]=O)=[C:9]([CH2:12][CH2:13][C:14]([O:16]CC)=[O:15])[C:10]=1[CH3:11])=[O:5])C.[Br:21][C:22]1[CH:23]=[C:24]2[C:28](=[CH:29][CH:30]=1)[NH:27][C:26](=[O:31])[CH2:25]2.[OH-].[K+]>N1CCCCC1.C(O)C>[C:14]([CH2:13][CH2:12][C:9]1[C:10]([CH3:11])=[C:6]([C:4]([OH:3])=[O:5])[NH:7][C:8]=1[CH:19]=[C:25]1[C:24]2[C:28](=[CH:29][CH:30]=[C:22]([Br:21])[CH:23]=2)[NH:27][C:26]1=[O:31])([OH:16])=[O:15]
Reactant: CCOC(=O)CCc1c(C=O)[nH]c(C(=O)OCC)c1C
Reactant: O=C1Cc2cc(Br)ccc2N1
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Solvent: C1CCNCC1
Product: Cc1c(C(=O)O)[nH]c(C=C2C(=O)Nc3ccc(Br)cc32)c1CCC(=O)O
Temperature: 90 °C
Reaction time: 2 h
Yield: 98.1 %

Procedure:
A mixture of 5-formyl-4-(2-ethoxycarbonylethyl)-3-methyl-1H-pyrrole-2-carboxylic acid ethyl ester (281 mg), 5-bromo-2-oxindole (220 mg), and piperidine (2 drops) in ethanol (2 mL) was stirred at 90° C. for 2 hours. Potassium hydroxide (537 mg) was added and the temperature was increased to 95° C. for 1 hour. The reaction mixture was cooled and concentrated. The residue was dissolved into water and acidified with 2 N hydrochloric acid to pH 2. The precipitate that formed was filtered, washed with water and dried in a vacuum oven overnight to give 411 mg (98%) of 4-(2-carboxyethyl)-3-methyl-5-(5-bromo-2-oxo-1,2-dihydro-indol-3-ylidenemethyl)-1H-pyrrole-2-carboxylic acid.
Reaction SMILES: [CH2:1]([C:3]1[CH:11]=[CH:10][C:6]([C:7](O)=O)=[C:5]([O:12][CH3:13])[CH:4]=1)[CH3:2].CCN=C=NCCCN(C)C.[NH2:25][NH:26][C:27]([NH2:29])=[S:28]>N1C=CC=CC=1>[CH2:1]([C:3]1[CH:11]=[CH:10][C:6]([C:7]2[NH:29][C:27](=[S:28])[NH:26][N:25]=2)=[C:5]([O:12][CH3:13])[CH:4]=1)[CH3:2]
Reactant: NNC(N)=S
Reactant: CCc1ccc(C(=O)O)c(OC)c1
Agent: CCN=C=NCCCN(C)C
Solvent: c1ccncc1
Product: CCc1ccc(-c2n[nH]c(=S)[nH]2)c(OC)c1
Temperature: 25 °C
Reaction time: 2 h
Yield: 55 %

Procedure:
To a solution of 4-ethyl-2-methoxybenzoic acid (example 18b)(1 g, 6.1 mmol) in pyridine (6 mL) was added EDCI (1.2 g, 6.3 mmol) and the suspension was stirred at r.t. for 2 h. Then thiosemicarbazide (547 mg, 6 mmol) was added and the reaction was stirred at r.t. for 24 h. The mixture was evaporated to dryness and then diluted with water. A white solid was collected and washed with water. The solid was suspended in aq. NaHCO3 (1M, 20 mL) and heated at reflux for 2 days. The suspension was filtered hot and the aqueous solution was cooled in ice and acidified to pH 3 with conc. HCl. The solid was collected washed with water and dried to give 5-(4-ethyl-2-methoxyphenyl)-2H-1,2,4-triazole-3(4H)-thione as a white powder (55%). MS (M+H, 236).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([O:10][Si](C)(C)C)=[CH2:9])=[CH:4][CH:3]=1.[F:15][C:16]1[CH:21]=[CH:20][C:19]([C:22](=[O:33])[CH:23]=[CH:24][C:25]2[CH:26]=[C:27]([CH:30]=[CH:31][CH:32]=2)[C:28]#[N:29])=[CH:18][CH:17]=1>ClCCl>[F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8](=[O:9])[CH2:10][CH:24]([C:25]2[CH:26]=[C:27]([CH:30]=[CH:31][CH:32]=2)[C:28]#[N:29])[CH2:23][C:22]([C:19]2[CH:18]=[CH:17][C:16]([F:15])=[CH:21][CH:20]=2)=[O:33])=[CH:4][CH:3]=1
Reactant: N#Cc1cccc(C=CC(=O)c2ccc(F)cc2)c1
Reactant: C=C(O[Si](C)(C)C)c1ccc(F)cc1
Solvent: ClCCl
Product: N#Cc1cccc(C(CC(=O)c2ccc(F)cc2)CC(=O)c2ccc(F)cc2)c1
Reaction time: 48 h
Yield: 96.7 %

Procedure:
1-Fluoro-4-[1-[(trimethylsilyl) oxy]ethenyl]-benzene (0.98 g, 2.86 mmol) is added to a cooled (-78° C.) solution of 3-[3-(4-fluorophenyl)-3-oxo-1-propenyl]-benzonitrile (0.6 g, 2.39 mmol) and TrSnCl5 (0.1 g, 0.19 mmol) in 70 mL of dichloromethane and stirred under nitrogen (N2) for 3 hours. The reaction mixture is diluted with additional dichloromethane, washed with a saturated solution of sodium bicarbonate, dried (MgSO4), and concentrated to an oil. The oil is taken up in 200 mL of diethyl ether and stirred with a few drops of tetrabutylammonium fluoride for 2 days. The diethyl ether is removed under vacuum and the residue columned over SiO2 eluting with dichloromethane. Pure fractions are combined, concentrated, and triturated in diethyl ether-hexane to provide 0.9 g of analytical material; mp 120°-123° C.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:15][CH2:14][CH2:13][C@H:9]1[C:10]([OH:12])=O)=[O:7])([CH3:4])([CH3:3])[CH3:2].CCN=C=NCCCN(C)C.C1C=CC2N(O)N=NC=2C=1.C(N(CC)CC)C.[NH:44]1[CH2:48][CH2:47][C@@H:46]([OH:49])[CH2:45]1>CN(C=O)C>[C:1]([O:5][C:6]([N:8]1[CH2:15][CH2:14][CH2:13][C@H:9]1[C:10]([N:44]1[CH2:48][CH2:47][C@@H:46]([OH:49])[CH2:45]1)=[O:12])=[O:7])([CH3:2])([CH3:3])[CH3:4]
Reactant: O[C@@H]1CCNC1
Reactant: CC(C)(C)OC(=O)N1CCC[C@H]1C(=O)O
Agent: CCN=C=NCCCN(C)C
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: CC(C)(C)OC(=O)N1CCC[C@H]1C(=O)N1CC[C@@H](O)C1
Temperature: 25 °C
Reaction time: 48 h
Yield: 83.2 %

Procedure:
To a mixture of N-(tert-butoxycarbonyl)-L-proline (2 g, 9.3 mmol), EDAC (3.5 g, 18 mmol), HOBt (1.35 g, 10 mmol) in DMF (20 mL) was added triethylamine (2 mL, 14 mmol) and (R)-(+)-3-pyrrolidinol (1.5 mL, 18 mmol). After stirring at room temperature for 48 h, the reaction was quenched with water and sodium bicarbonate solution. It was then extracted with 5% of methanol in dichloromethane. The residue was purified on a silica gel column eluting with 10% of methanol in dichloromethane to give 2.2 g (83%) of (S)-2-((R)-3-hydroxy-pyrrolidin-1-ylcarbonyl)-pyrrolidine-1-carboxylic acid tert-butyl ester.
Reaction SMILES: [CH:1]([N:4]1[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[C:6]([C:13]([OH:15])=O)=[N:5]1)([CH3:3])[CH3:2].[NH2:16][C@H:17]1[CH2:22][N:21]([C:23]([O:25][C:26]([CH3:29])([CH3:28])[CH3:27])=[O:24])[C@@H:20]([CH2:30][C:31]2([OH:37])[CH2:36][CH2:35][O:34][CH2:33][CH2:32]2)[CH2:19][CH2:18]1.C(N(CC)C(C)C)(C)C.C(P(=O)(OCC)OCC)#N>CN(C)C=O>[OH:37][C:31]1([CH2:30][C@H:20]2[CH2:19][CH2:18][C@@H:17]([NH:16][C:13]([C:6]3[C:7]4[C:12](=[CH:11][CH:10]=[CH:9][CH:8]=4)[N:4]([CH:1]([CH3:2])[CH3:3])[N:5]=3)=[O:15])[CH2:22][N:21]2[C:23]([O:25][C:26]([CH3:29])([CH3:28])[CH3:27])=[O:24])[CH2:36][CH2:35][O:34][CH2:33][CH2:32]1
Reactant: CC(C)n1nc(C(=O)O)c2ccccc21
Reactant: CC(C)(C)OC(=O)N1C[C@H](N)CC[C@@H]1CC1(O)CCOCC1
Agent: CCOP(=O)(C#N)OCC
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)n1nc(C(=O)N[C@@H]2CC[C@H](CC3(O)CCOCC3)N(C(=O)OC(C)(C)C)C2)c2ccccc21
Reaction time: 18 h
Yield: 94.2 %

Procedure:
To a stirred solution of 1-isopropyl-1H-indazole-3-carboxylic acid (126 mg, 0.619 mmol), tert-butyl cis-5-amino-2-[(4-hydroxytetrahydro-2H-pyran-4-yl)methyl]piperidine-1-carboxylate (234 mg, 0.743 mmol, step 5 of Example 2), N,N-diisopropylethylamine (96 mg, 0.743 mmol) in N,N-dimethylformamide (3 mL) was added diethyl cyanophosphonate (121 mg, 0.743 mmol) at room temperature, and the mixture was stirred at the same temperature for 18 h. The mixture was concentrated under reduced pressure and the resulting residue was chromatographed on a column of silica gel eluting with n-hexane/ethyl acetate (1:1) to give 292 mg (94%) of the title compound as a colorless oil.