Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]1[N:7]=[C:6]([C:8]2[CH:13]=[CH:12][CH:11]=[C:10]([C:14]3[CH:15]=[C:16]([S:20](Cl)(=[O:22])=[O:21])[CH:17]=[CH:18][CH:19]=3)[N:9]=2)[CH:5]=[C:4]([C:24]2[CH:29]=[CH:28][C:27]([C:30]([F:33])([F:32])[F:31])=[CH:26][CH:25]=2)[CH:3]=1.[NH:34]1[CH2:38][CH2:37][CH2:36][CH2:35]1>C1COCC1.CCOC(C)=O>[CH3:1][C:2]1[N:7]=[C:6]([C:8]2[CH:13]=[CH:12][CH:11]=[C:10]([C:14]3[CH:19]=[CH:18][CH:17]=[C:16]([S:20]([N:34]4[CH2:38][CH2:37][CH2:36][CH2:35]4)(=[O:22])=[O:21])[CH:15]=3)[N:9]=2)[CH:5]=[C:4]([C:24]2[CH:29]=[CH:28][C:27]([C:30]([F:33])([F:32])[F:31])=[CH:26][CH:25]=2)[CH:3]=1
Reactant: Cc1cc(-c2ccc(C(F)(F)F)cc2)cc(-c2cccc(-c3cccc(S(=O)(=O)Cl)c3)n2)n1
Reactant: C1CCNC1
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: Cc1cc(-c2ccc(C(F)(F)F)cc2)cc(-c2cccc(-c3cccc(S(=O)(=O)N4CCCC4)c3)n2)n1
Yield: 71.7 %

Procedure:
The title compound was prepared from 3-[6′-methyl-4′-(4-trifluoromethyl-phenyl)-[2,2′]bipyridinyl-6-yl]-benzenesulfonyl chloride (example I.2) (0.300 g, 0.613 mmol) by treatment with pyrrolidine (0.131 mg, 1.84 mmol) in THF (5 mL) at 23° C. for 16 h. Diluted with EtOAc, washed with 5% citric acid, sat. NaHCO3-sol. and brine, dried organic layer over Na2SO4. Removal of the solvent in vacuum left a crude product, which was purified by silica gel column chromatography with EtOAc followed by trituration with diethyl ether/heptane to give the title compound (0.230 g, 71%) as a white solid. MS (ISP) 524.3 [(M+H)+]; mp 174° C.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][CH3:9])=[CH:4][C:3]=1/[CH:10]=[C:11](\[SH:15])/[C:12]([OH:14])=[O:13].II.S(S([O-])=O)([O-])(=O)=O.[Na+].[Na+].CCOCC>C(COC)OC>[F:1][C:2]1[C:3]2[CH:10]=[C:11]([C:12]([OH:14])=[O:13])[S:15][C:4]=2[C:5]([O:8][CH3:9])=[CH:6][CH:7]=1
Reactant: COc1ccc(F)c(/C=C(\S)C(=O)O)c1
Agent: II
Agent: O=S([O-])S(=O)(=O)[O-]
Agent: [Na+]
Solvent: COCCOC
Solvent: CCOCC
Product: COc1ccc(F)c2cc(C(=O)O)sc12
Temperature: 25 °C
Yield: 58.5 %

Procedure:
(2Z)-3-(2-Fluoro-5-methoxyphenyl)-2-mercapto-2-propenoic acid (1.00 g, 4.38 mmol) was added in one portion to a solution of iodine (1.66 g, 6.56 mmol) in dimethoxyethane (10 mL). This was heated in the microwave with 300W at 160° C. for 10 mins. After this time the reaction was allowed to cool to room temperature and poured onto saturated sodium metabisulphite (200 mL) and ether (400 mL). Ether layer was separated and product extracted with aqueous sodium hydroxide (2 N, 2×100 mL). This was then acidified to pH 2 with aqueous hydrochloric acid (2 N, 250 mL), and product extracted with ether (2×150 mL). The combined organic extracts were dried (MgSO4) and concentrated in vacuo to give a white solid (580 mg, 30%); δH (300 MHz, CD3OD) 8.00 (1H, s, Ar), 7.30-7.19 (1H, m, Ar), 7.10-7.00 (1H, m, Ar), 3.95 (3H, s, OCH3).
Reaction SMILES: [OH:1][C:2]1[CH:15]=[CH:14][C:5]([C:6]([O:8][CH2:9][CH:10]([CH3:13])[CH2:11][CH3:12])=[O:7])=[CH:4][CH:3]=1.N1C=CC=CC=1.[C:22]([O:32][C:33]1[CH:41]=[CH:40][C:36]([C:37](Cl)=[O:38])=[CH:35][CH:34]=1)([O:24][CH2:25][C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1)=[O:23]>O1CCCC1>[C:22]([O:32][C:33]1[CH:34]=[CH:35][C:36]([C:37]([O:1][C:2]2[CH:3]=[CH:4][C:5]([C:6]([O:8][CH2:9][CH:10]([CH3:13])[CH2:11][CH3:12])=[O:7])=[CH:14][CH:15]=2)=[O:38])=[CH:40][CH:41]=1)([O:24][CH2:25][C:26]1[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=1)=[O:23]
Reactant: O=C(OCc1ccccc1)Oc1ccc(C(=O)Cl)cc1
Reactant: CCC(C)COC(=O)c1ccc(O)cc1
Solvent: C1CCOC1
Solvent: c1ccncc1
Product: CCC(C)COC(=O)c1ccc(OC(=O)c2ccc(OC(=O)OCc3ccccc3)cc2)cc1
Reaction time: 8 h
Yield: 62.7 %

Procedure:
A solution of 16 mmol (3.3 g) of the 2-methylbutyl p-hydroxybenzoate obtained in 1.(2) in a solvent mixture of 20 ml of THF (tetrahydrofuran) and 40 ml of pyridine was cooled, and to the solution was added dropwise a THF solution of 10 mmol (2/9 g) of the 4-carbobenzoxyoxybenzoyl chloride obtained in 1.(4). The temperature was gradually returned to room temperature, and then the mixture was stirred for 8 hours. After conclusion of the reaction, the reaction solution and purified by column chromatography to obtain 2.9 g of 2-methylbutyl 4-(4'-carbobenzoxyoxybenzoyloxy)benzoate [m.p.: 64.4°-65.4° C⟧ (Yield: 63%)
Reaction SMILES: [Cl:1][C:2]1[N:10]=[C:9]2[C:5]([N:6]=[CH:7][N:8]2[CH:11]2[CH2:15][CH2:14][CH2:13][CH2:12]2)=[C:4](Cl)[N:3]=1.[F:17][C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=1[NH:24][NH2:25]>C(N(CC)CC)C>[Cl:1][C:2]1[N:10]=[C:9]2[C:5]([N:6]=[CH:7][N:8]2[CH:11]2[CH2:15][CH2:14][CH2:13][CH2:12]2)=[C:4]([NH:25][NH:24][C:19]2[CH:20]=[CH:21][CH:22]=[CH:23][C:18]=2[F:17])[N:3]=1
Reactant: Clc1nc(Cl)c2ncn(C3CCCC3)c2n1
Reactant: NNc1ccccc1F
Solvent: CCN(CC)CC
Product: Fc1ccccc1NNc1nc(Cl)nc2c1ncn2C1CCCC1

Procedure:
2-Chloro-6-[2-fluorophenylhydrazino]-9-cyclopentylpurine is prepared from 2,6-dichloro-9-cyclopentylpurine, 2-fluorophenylhydrazine, and triethylamine essentially as described above in Example 1, Scheme A, step b.
Reaction SMILES: [NH2:1][C:2]1[CH:23]=[CH:22][C:5]([O:6][C:7]2[C:16]3[C:11](=[CH:12][C:13]([O:19][CH3:20])=[C:14]([O:17][CH3:18])[CH:15]=3)[N:10]=[C:9]([NH2:21])[CH:8]=2)=[C:4]([F:24])[CH:3]=1.COC1C=C2C(=CC=1OC)N=C(SC)C=C2OC1C=CC(N[C:49]([C:51]2([C:54]([NH:56][C:57]3[CH:62]=[CH:61][C:60]([F:63])=[CH:59][CH:58]=3)=[O:55])[CH2:53][CH2:52]2)=[O:50])=CC=1F>>[NH2:21][C:9]1[CH:8]=[C:7]([O:6][C:5]2[CH:22]=[CH:23][C:2]([NH:1][C:49]([C:51]3([C:54]([NH:56][C:57]4[CH:62]=[CH:61][C:60]([F:63])=[CH:59][CH:58]=4)=[O:55])[CH2:53][CH2:52]3)=[O:50])=[CH:3][C:4]=2[F:24])[C:16]2[C:11](=[CH:12][C:13]([O:19][CH3:20])=[C:14]([O:17][CH3:18])[CH:15]=2)[N:10]=1
Reactant: COc1cc2nc(N)cc(Oc3ccc(N)cc3F)c2cc1OC
Reactant: COc1cc2nc(SC)cc(Oc3ccc(NC(=O)C4(C(=O)Nc5ccc(F)cc5)CC4)cc3F)c2cc1OC
Product: COc1cc2nc(N)cc(Oc3ccc(NC(=O)C4(C(=O)Nc5ccc(F)cc5)CC4)cc3F)c2cc1OC

Procedure:
N-(4-{[2-amino-6,7-bis(methyloxy)quinolin-4-yl]oxy}-3-fluorophenyl)-N′-(4-fluorophenyl)cyclopropane-1,1-dicarboxamide was synthesized from 4-(4-amino-2-fluoro-phenoxy)-6,7-dimethoxy-quinolin-2-ylamine in a similar manner as N-(4-{[6,7-bis(methyloxy)-2-(methylthio)quinolin-4-yl]oxy}-3-fluorophenyl)-N′-(4-fluorophenyl)cyclopropane-1,1-dicarboxamide. It was purified by preparatory HPLC using ammonium acetate and isolated as a white solid (4.0% yield). 1H NMR (DMSO-d6) δ 10.34 (s, 1H), 9.95 (s, 1H), 7.82 (d, 1H), 7.58 (m, 2H), 7.44 (d, 1H), 7.33 (t, 1H), 7.25 (s, 1H), 7.09 (t, 2H), 7.07 (s, 1H), 6.17 (br s, 2H), 5.66 (s, 1H), 3.79 (s, 3H), 3.77 (s, 3H), 1.40 (d, 4H). LCMS: m/z 535 (M+H)+.
Reaction SMILES: Cl[CH2:2][C:3](=[CH2:16])[CH2:4][CH:5]1[O:9][C:8](=[O:10])[CH:7]=[C:6]1[N:11]1[CH2:15][CH2:14][CH2:13][CH2:12]1.[Cl:17][C:18]1[N:23]=[CH:22][C:21]([CH2:24][NH2:25])=[CH:20][CH:19]=1.C(N(C(C)C)C(C)C)C>C(#N)C>[Cl:17][C:18]1[N:23]=[CH:22][C:21]([CH2:24][NH:25][CH2:2][C:3](=[CH2:16])[CH2:4][CH:5]2[O:9][C:8](=[O:10])[CH:7]=[C:6]2[N:11]2[CH2:15][CH2:14][CH2:13][CH2:12]2)=[CH:20][CH:19]=1
Reactant: C=C(CCl)CC1OC(=O)C=C1N1CCCC1
Reactant: NCc1ccc(Cl)nc1
Solvent: CCN(C(C)C)C(C)C
Solvent: CC#N
Product: C=C(CNCc1ccc(Cl)nc1)CC1OC(=O)C=C1N1CCCC1
Yield: 75.3 %

Procedure:
At 60° C., 600 mg (2.48 mmol) of 5-[2-(chloromethyl)prop-2-en-1-yl]-4-pyrrolidin-1-ylfuran-2(5H)-one (V-1a), 354 mg (2.48 mmol) of 1-(6-chloropyridin-3-yl)methanamine and 0.43 ml (2.48 mmol) of N-ethyl-N-isopropylpropan-2-amine in 10 ml of acetonitrile are stirred for 21 hours. Concentration under reduced pressure and purification of the residue by column chromatography on silica gel (silica gel 60, Merck, particle size: 0.04 to 0.063 mm) using the mobile phase mixture dichloromethane:methanol (98:2 to 90:10) gives 650 mg (73% of theory) of 5-[2-({[(6-chloropyridin-3-yl)methyl]amino}methyl)prop-2-en-1-yl]-4-pyrrolidin-1-ylfuran-2(5H)-one.
Reaction SMILES: [OH:1][C@H:2]([C@@H:4]1[C@@H:7]([S:8][CH3:9])[N:6]([C:10](=[C:15]([CH3:17])[CH3:16])[C:11]([O:13][CH3:14])=[O:12])[C:5]1=[O:18])[CH3:3].Cl[C:20]([O:22][CH2:23][C:24]1[CH:29]=[CH:28][C:27]([N+:30]([O-:32])=[O:31])=[CH:26][CH:25]=1)=[O:21]>CN(C)C1C=CN=CC=1.ClCCl.C(OCC)(=O)C>[CH3:16][C:15]([CH3:17])=[C:10]([N:6]1[C@H:7]([S:8][CH3:9])[C@@H:4]([C@@H:2]([O:1][C:20]([O:22][CH2:23][C:24]2[CH:25]=[CH:26][C:27]([N+:30]([O-:32])=[O:31])=[CH:28][CH:29]=2)=[O:21])[CH3:3])[C:5]1=[O:18])[C:11]([O:13][CH3:14])=[O:12]
Reactant: COC(=O)C(=C(C)C)N1C(=O)[C@H]([C@H](C)O)[C@H]1SC
Reactant: O=C(Cl)OCc1ccc([N+](=O)[O-])cc1
Agent: CN(C)c1ccncc1
Solvent: CCOC(C)=O
Solvent: ClCCl
Product: COC(=O)C(=C(C)C)N1C(=O)[C@H]([C@H](C)OC(=O)OCc2ccc([N+](=O)[O-])cc2)[C@H]1SC
Temperature: 0 °C
Reaction time: 1 h
Yield: 90.9 %

Procedure:
To a solution of methyl 2-[(3S,4R)-3-{(1S)-1-hydroxyethyl}-4-methylthio-2-oxoazetidin-1-yl]-3-methylbut-2-enoate (376 mg) and 4-dimethylaminopyridine (336 mg) in dichloromethane (3 ml) was added p-nitrobenzyl chloroformate (358 mg) at -30° C. under a nitrogen atmosphere. After stirring for one hour at 0° C., the mixture was diluted with ethyl acetate and washed with dilute hydrochloric acid, water, a dilute aqueous sodium bicarbonate, and brine. Drying over magnesium sulfate and the removal of the solvent left an oil (635 mg), which was chromatographed on silica gel (25 g) eluting with 10-25% ethyl acetate in hexane to afford methyl 3-methyl-2-[(3S,4R)-4-methylthio-3-{(1S)-1-(p-nitrobenzyloxycarbonyloxy)ethyl}-2-oxoazetidin-1-yl]-but-2-enoate (566 mg) as an oil.
Reaction SMILES: Br[C:2]1[CH:11]=[CH:10][C:5]([C:6]([O:8][CH3:9])=[O:7])=[CH:4][C:3]=1[CH3:12].B([C:16]1[CH:24]=[CH:23][C:19]([C:20]([OH:22])=[O:21])=[CH:18][CH:17]=1)(O)O.C(N(CC)CC)C>CN(C=O)C>[CH3:9][O:8][C:6]([C:5]1[CH:10]=[CH:11][C:2]([C:16]2[CH:24]=[CH:23][C:19]([C:20]([OH:22])=[O:21])=[CH:18][CH:17]=2)=[C:3]([CH3:12])[CH:4]=1)=[O:7]
Reactant: O=C(O)c1ccc(B(O)O)cc1
Reactant: COC(=O)c1ccc(Br)c(C)c1
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: COC(=O)c1ccc(-c2ccc(C(=O)O)cc2)c(C)c1
Temperature: 100 °C
Yield: 38.7 %

Procedure:
A stirred solution of methyl 4-bromo-3-methylbenzoate (EP 0533268 A1) (1.0 g, 0.0044 mole) in dry DMF (10 ml) under argon was treated with 4-boronobenzoic acid (0.73 g, 0.0044 mole) and tetrakis (triphenylphosphine)palladium(0) (80 mg), followed by triethylamine (1.8 ml, 0.016 mole). The mixture was heated at 100° C. for 18 hours, then concentrated in vacuo. The residue was treated with ethyl acetate and extracted with 10% NaHCO3 solution. The basic extract was acidified with dil. HCl and extracted with ethyl acetate. The extract was dried (Na2SO4) and concentrated in vacuo to afford the title compound as a white solid (0.46 g, 39%).
Reaction SMILES: [CH3:1][C:2]1[NH:11][C:10](=[O:12])[C:9]2[C:4](=[CH:5][C:6]3[CH2:15][CH2:14][CH:13]([N:16]([C:20]4[CH:37]=[CH:36][C:23]([C:24](N[C@H](C(O)=O)CCC(O)=O)=[O:25])=[CH:22][CH:21]=4)[CH2:17][C:18]#[CH:19])[C:7]=3[CH:8]=2)[N:3]=1.CC1NC(=O)C2C(=CC3CCC(N(C4C=CC(C(O)=O)=CC=4)CC#C)C=3C=2)N=1.[F:66][C:67]1[C:72]([OH:73])=[C:71]([F:74])[C:70]([F:75])=[C:69]([F:76])[C:68]=1[F:77]>>[CH3:1][C:2]1[NH:11][C:10](=[O:12])[C:9]2[C:4](=[CH:5][C:6]3[CH2:15][CH2:14][CH:13]([N:16]([C:20]4[CH:37]=[CH:36][C:23]([C:24]([O:73][C:72]5[C:71]([F:74])=[C:70]([F:75])[C:69]([F:76])=[C:68]([F:77])[C:67]=5[F:66])=[O:25])=[CH:22][CH:21]=4)[CH2:17][C:18]#[CH:19])[C:7]=3[CH:8]=2)[N:3]=1
Reactant: C#CCN(c1ccc(C(=O)N[C@@H](CCC(=O)O)C(=O)O)cc1)C1CCc2cc3nc(C)[nH]c(=O)c3cc21
Reactant: Oc1c(F)c(F)c(F)c(F)c1F
Agent: C#CCN(c1ccc(C(=O)O)cc1)C1CCc2cc3nc(C)[nH]c(=O)c3cc21
Product: C#CCN(c1ccc(C(=O)Oc2c(F)c(F)c(F)c(F)c2F)cc1)C1CCc2cc3nc(C)[nH]c(=O)c3cc21

Procedure:
Using an analogous procedure to that described in section (3) of Example 5 p-[N-((6RS)-2-methyl-4-oxo-3,4,7,8-tetrahydro-6H-cyclopenta[g]quinazolin-6-yl)-N-(prop-2-ynyl)amino]benzoic acid was reacted with pentafluorophenol to give pentafluorophenyl p-[N-((6RS)-2-methyl-4-oxo-3,4,7,8-tetrahydro-6H-cyclopenta-[g]quinazolin-6-yl)-N-(prop-2-ynyl)amino]benzoate.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[CH2:7][CH2:8][CH2:9][CH:10]1[CH2:15][CH2:14][N:13]([CH2:16][C@@H:17]2[C@@H:21]([C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=3)[CH2:20][N:19]([C@H:28]([CH:41]3[CH2:46][CH2:45][CH2:44][CH2:43][CH2:42]3)[C:29]([O:31]CC3C=CC(OC)=CC=3)=[O:30])[CH2:18]2)[CH2:12][CH2:11]1.C(Cl)Cl.CO.[NH4+].[OH-]>>[N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[CH2:7][CH2:8][CH2:9][CH:10]1[CH2:11][CH2:12][N:13]([CH2:16][C@@H:17]2[C@@H:21]([C:22]3[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=3)[CH2:20][N:19]([C@H:28]([CH:41]3[CH2:46][CH2:45][CH2:44][CH2:43][CH2:42]3)[C:29]([OH:31])=[O:30])[CH2:18]2)[CH2:14][CH2:15]1
Reactant: COc1ccc(COC(=O)[C@@H](C2CCCCC2)N2C[C@H](CN3CCC(CCCc4ccccn4)CC3)[C@@H](c3ccccc3)C2)cc1
Agent: [NH4+]
Agent: [OH-]
Solvent: ClCCl
Solvent: CO
Product: O=C(O)[C@@H](C1CCCCC1)N1C[C@H](CN2CCC(CCCc3ccccn3)CC2)[C@@H](c2ccccc2)C1
Yield: 93.9 %

Procedure:
The title compound was prepared from 58 mg (0.093 mmol) of 2-(R)-(3-(S)-((4-(3-(2-pyridyl)propyl)piperidin-1-yl)methyl)-4-(S)-phenylpyrrolidin-1-yl)-2-(cyclohexyl)acetic acid, (4-methoxy)benzyl ester (from EXAMPLE 72, Step C) using a procedure analogous to that described in EXAMPLE 10, Step F. Flash chromatography using 90:10:1 v/v/v CH2Cl2/MeOH/NH4OH as the eluant afforded 44 mg (94%) of the title compound: 1H NMR (500 MHz) δ 0.82-3.90 (35H), 7.07-7.58 (8H), 8.49 (d, J=4.8 Hz, 11H); ESI-MS 504 (M+H).
Reaction SMILES: C(O[C:6](=O)[N:7]([CH:9]1[CH2:14][CH2:13][CH:12]([NH:15][CH2:16][C:17]2[CH:22]=[C:21]([C:23]3[CH:28]=[CH:27][N:26]=[C:25]([F:29])[CH:24]=3)[CH:20]=[CH:19][C:18]=2[O:30][CH3:31])[CH2:11][CH2:10]1)C)(C)(C)C.[Cl:33][C:34]1[C:35]2[C:45]([F:46])=[CH:44][CH:43]=[CH:42][C:36]=2[S:37][C:38]=1[C:39](Cl)=[O:40]>>[F:29][C:25]1[CH:24]=[C:23]([C:21]2[CH:20]=[CH:19][C:18]([O:30][CH3:31])=[C:17]([CH:22]=2)[CH2:16][N:15]([CH:12]2[CH2:11][CH2:10][CH:9]([NH:7][CH3:6])[CH2:14][CH2:13]2)[C:39]([C:38]2[S:37][C:36]3[CH:42]=[CH:43][CH:44]=[C:45]([F:46])[C:35]=3[C:34]=2[Cl:33])=[O:40])[CH:28]=[CH:27][N:26]=1
Reactant: O=C(Cl)c1sc2cccc(F)c2c1Cl
Reactant: COc1ccc(-c2ccnc(F)c2)cc1CNC1CCC(N(C)C(=O)OC(C)(C)C)CC1
Product: CNC1CCC(N(Cc2cc(-c3ccnc(F)c3)ccc2OC)C(=O)c2sc3cccc(F)c3c2Cl)CC1

Procedure:
Following the synthetic protocol described in Method D′; 3-Chloro-4-fluoro-benzo[b]thiophene-2-carboxylic acid [5-(2-fluoro-pyridin-4-yl)-2-methoxy-benzyl]-(4-methylamino-cyclohexyl)-amide is prepared starting from {4-[5-(2-Fluoro-pyridin-4-yl)-2-methoxy-benzylamino]-cyclohexyl}-methyl-carbamic acid tert-butyl ester and 3-Chloro-4-fluoro-benzo[b]thiophene-2-carbonyl chloride. The desired product is isolated in 49%.
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][C:5]2[O:14][CH2:13][C:12]3[C:8]4[C:9](=[N:24][CH:25]=[CH:26][C:7]=4[C:6]=2[CH:27]=1)[N:10]([CH2:16][O:17][CH2:18][CH2:19][Si:20]([CH3:23])([CH3:22])[CH3:21])[C:11]=3I.CC1(C)C(C)(C)OB([C:36]2[CH2:41][CH2:40][N:39]([C:42]([O:44][C:45]([CH3:48])([CH3:47])[CH3:46])=[O:43])[CH2:38][CH:37]=2)O1.C(=O)(O)[O-].[Na+]>CN(C)C=O.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[F:1][C:2]1[CH:3]=[CH:4][C:5]2[O:14][CH2:13][C:12]3[C:8]4[C:9](=[N:24][CH:25]=[CH:26][C:7]=4[C:6]=2[CH:27]=1)[N:10]([CH2:16][O:17][CH2:18][CH2:19][Si:20]([CH3:23])([CH3:22])[CH3:21])[C:11]=3[C:36]1[CH2:41][CH2:40][N:39]([C:42]([O:44][C:45]([CH3:48])([CH3:47])[CH3:46])=[O:43])[CH2:38][CH:37]=1
Reactant: CC(C)(C)OC(=O)N1CC=C(B2OC(C)(C)C(C)(C)O2)CC1
Reactant: C[Si](C)(C)CCOCn1c(I)c2c3c(ccnc31)-c1cc(F)ccc1OC2
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N1CC=C(c2c3c4c(ccnc4n2COCC[Si](C)(C)C)-c2cc(F)ccc2OC3)CC1
Temperature: 80 °C

Procedure:
A mixture of Example 14H (200 mg, 0.403 mmol), tert-butyl 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-5,6-dihydropyridine-1(2H)-carboxylate (137 mg, 0.443 mmol), tetrakis(triphenylphosphine)palladium(0) (23.28 mg, 0.020 mmol), and sodium bicarbonate solution (1.5 mL, 0.403 mmol) in N,N-dimethylformamide (6 mL) was degassed and heated at 80° C. for 5 hours. After cooling, the mixture was filtered, treated with water and brine and extracted with ethyl acetate (twice). The combined organic layers were washed with brine, dried over magnesium sulfate, filtered, concentrated, and purified on silica using the ISCO Companion flash system eluting with ethyl acetate/heptanes (15:85 to 20:80) to provide the title compound. MS (ESI+) m/z 552.0 (M+H)+.
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]([O:10][CH2:11][CH:12]([CH3:14])[CH3:13])=[C:6]([CH:9]=1)[C:7]#[N:8].[B:15](OC(C)C)([O:20]C(C)C)[O:16]C(C)C.Cl>C1COCC1.C1(C)C=CC=CC=1>[C:7]([C:6]1[CH:9]=[C:2]([B:15]([OH:20])[OH:16])[CH:3]=[CH:4][C:5]=1[O:10][CH2:11][CH:12]([CH3:14])[CH3:13])#[N:8]
Reactant: CC(C)OB(OC(C)C)OC(C)C
Reactant: CC(C)COc1ccc(Br)cc1C#N
Agent: Cl
Solvent: C1CCOC1
Solvent: Cc1ccccc1
Product: CC(C)COc1ccc(B(O)O)cc1C#N
Temperature: 25 °C

Procedure:
5-Bromo-2-isobutoxybenzonitrile and triisopropyl borate were dissolved in a mixed solvent of THF and toluene and an n-butyllithium-hexane solution was added dropwise to the solution at a temperature below −60° C. After the temperature was elevated to −20° C., 1M hydrochloric acid was added, followed by stirring at room temperature to obtain (3-cyano-4-isobutoxyphenyl)boronic acid. F: 220.
Reaction SMILES: C([O:3][C:4](=[O:26])[CH2:5][N:6]1[C:10]([C:11]([O:13]CC)=[O:12])=[C:9]2[O:16][CH2:17][CH2:18][CH2:19][O:20][C:8]2=[C:7]1[C:21]([O:23]CC)=[O:22])C.O.[OH-].[K+]>CC(C)=O>[C:4]([CH2:5][N:6]1[C:7]([C:21]([OH:23])=[O:22])=[C:8]2[O:20][CH2:19][CH2:18][CH2:17][O:16][C:9]2=[C:10]1[C:11]([OH:13])=[O:12])([OH:26])=[O:3]
Reactant: CCOC(=O)Cn1c(C(=O)OCC)c2c(c1C(=O)OCC)OCCCO2
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: CC(C)=O
Product: O=C(O)Cn1c(C(=O)O)c2c(c1C(=O)O)OCCCO2

Procedure:
To a 100-mL round-bottom flask was added diethyl 7-(2-ethoxy-2-oxoethyl)-2,3,4,7-tetrahydro-[1,4]dioxepino[2,3-c]pyrrole-6,8-dicarboxylate (17.56 g, 47.5 mmol), DI water (45 mL), acetone (25 mL), and potassium hydroxide (13.34 g, 238 mmol). The reaction mixture was bubbled with argon for 20 minutes, then refluxed for 2.5 hours, resulting in a deep brown solution. The organic volatiles were removed in vacuo and the remaining aqueous layer was chilled in an ice bath. To the mixture was added concentrated sulfuric acid until a pH of 6 was reached, whereupon a white solid precipitate formed. This precipitate was filtered from the red aqueous solution and washed with several portions of DI water, and after drying weighed 13.55 g (100%). To confirm the structure NMR analysis was performed on the fully deprotonated version by dissolving into a NaOD/D2O solution. 1H NMR (300 MHz, D2O/NaOD): δ 5.17 (s, 2H), 4.13-4.09 (m, 4H), 2.19 (p, 2H, J=5.7 Hz). 13C NMR (75 MHz, CDCl3): δ 180.9, 171.0, 141.9, 120.3, 74, 9, 51.9, 36.3. The product was used in the subsequent reaction without further purification.
Reaction SMILES: [C:1]([CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][N+:9]1[C:17]2[C:12](=[C:13]([F:19])[CH:14]=[C:15]([F:18])[CH:16]=2)[C:11]([CH3:21])([CH3:20])[C:10]=1[CH3:22])([OH:3])=[O:2].Cl.[C:24]1([N:30]=[CH:31][CH2:32][CH:33]=NC2C=CC=CC=2)[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1.C(OC(=O)C)(=O)C>C(O)(=O)C>[F:19][C:13]1[CH:14]=[C:15]([F:18])[CH:16]=[C:17]2[C:12]=1[C:11]([CH3:21])([CH3:20])/[C:10](=[CH:22]\[CH:33]=[CH:32]\[CH:31]=[N:30]\[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1)/[N:9]2[CH2:8][CH2:7][CH2:6][CH2:5][CH2:4][C:1]([OH:3])=[O:2]
Reactant: C(CC=Nc1ccccc1)=Nc1ccccc1
Reactant: CC1=[N+](CCCCCC(=O)O)c2cc(F)cc(F)c2C1(C)C
Agent: Cl
Solvent: CC(=O)O
Solvent: CC(=O)OC(C)=O
Product: CC1(C)/C(=C\C=C\C=N\c2ccccc2)N(CCCCCC(=O)O)c2cc(F)cc(F)c21
Temperature: 120 °C

Procedure:
To 1-(5-carboxypentyl)-4,6-difluoro-2,3,3-trimethyl-3H-indolium (50 mg) was added malonaldehyde bis(phenylimine) monohydrochloride (37.6 mg), acetic anhydride (2 ml) and acetic acid (1 ml). This mixture was heated to 120° C. for 1 hour after which time it was cooled to room temperature. This crude reaction mixture (ca. 32 mg/ml product) was used without purification as further described.
Reaction SMILES: CS(O[CH2:6][CH2:7][CH:8]1[CH2:13][CH2:12][N:11]([C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])[CH2:10][CH2:9]1)(=O)=O.[C:21]([CH2:23][C:24]([O:26][CH2:27][CH3:28])=[O:25])#[N:22].[O-]CC.[Na+].S([O-])(=O)(=O)C.C(O)(=O)C>CCO>[C:21]([CH:23]([C:24]([O:26][CH2:27][CH3:28])=[O:25])[CH2:6][CH2:7][CH:8]1[CH2:13][CH2:12][N:11]([C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])[CH2:10][CH2:9]1)#[N:22]
Reactant: CCOC(=O)CC#N
Reactant: CC(C)(C)OC(=O)N1CCC(CCOS(C)(=O)=O)CC1
Agent: CC[O-]
Agent: CS(=O)(=O)[O-]
Agent: [Na+]
Solvent: CCO
Solvent: CC(=O)O
Product: CCOC(=O)C(C#N)CCC1CCN(C(=O)OC(C)(C)C)CC1
Temperature: 37.5 °C

Procedure:
Combine tert-butyl 4-(2-methylsulfonyloxyethyl)piperidine-1-carboxylate (5.26 kg, 17.1 mol), ethyl cyanoacetate (7 kg, 62 mol), 21% sodium ethoxide in EtOH (8.25 L, 24.75 mol) and EtOH (35 L) in a 50 L reactor under a nitrogen atmosphere. Heat the mixture at 35-40° C. for 18 h at which time NMR analysis shows 20% of the mesylate remaining Continue heating the mixture at 35-40° C. for 24 h at which time NMR analysis shows only a small amount of mesylate. Slowly cool the reaction to RT and add glacial acetic acid (1422 mL, 22.68 mol) over 30 min. Concentrate the mixture using vacuum distillation and then partition between water (25 L) and EtOAc (35 L). Separate the layers and extract the aqueous phase with EtOAc (10 L). Combine the organic portions, wash with brine (15 L), and concentrate to a red oil. Purify the oil using silica gel chromatography (75 kg silica gel, 65-250 mesh), eluting with hexane (40 L) and then 20% EtOAc/hexane to provide a fraction (7.8 kg) that is 30% ethyl cyanoacetate/70% desired product. Concentrate the material by wipe film distillation at 100° C. and 210 mtorr vacuum, collecting the non-volatile fraction to provide the title compound (4.54 kg, 82%).
Reaction SMILES: [NH:1]1[CH2:7][C:5](=[O:6])[NH:4][C:2]1=[O:3].[CH:8](=O)[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1.C([O-])(=O)C.[NH4+]>C(O)(=O)C>[CH:8](=[C:7]1[NH:1][C:2](=[O:3])[NH:4][C:5]1=[O:6])[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1
Reactant: O=C1CNC(=O)N1
Reactant: O=Cc1ccccc1
Agent: CC(=O)[O-]
Agent: [NH4+]
Solvent: CC(=O)O
Product: O=C1NC(=O)C(=Cc2ccccc2)N1
Temperature: 25 °C
Reaction time: 4 h
Yield: 81 %

Procedure:
Similar to the procedure of U.S. Pat. No. 4,345,072, a mixture comprising hydantoin (25 g, 0.25 mole), benzaldehyde (29.3 g, 0.275 mole), ammonium acetate (19.3 g, 0.25 mole) and glacial acetic acid (60 g) were placed in a round bottom flask fitted with stirrer, condenser, thermometer and heating mantle. The white solids became yellow on heating. All the solids dissolved when the temperature reached between 120° C. and 134° C. The mixture was refluxed for one-half hour (125° to 134° C.) and then held at 120° C. for 4 hours with stirring. Solids crystallized out on cooling to room temperature. The solid was suction filtered, water washed and then ethanol washed. After air drying, the yellow orange solid had a weight of 38.0 g for an 81% yield. The melting point of the 5-benzalhydantoin obtained was determined to be 218°-220° C. which corresponds to the melting point reported in BIOCHEM J. 29, 542 (1935).
Reaction SMILES: [C:1]1(C)C=CC(S(O)(=O)=O)=CC=1.[NH:12]([C:14]([C:16]1[CH:24]=[CH:23][C:19]([C:20]([OH:22])=[O:21])=[CH:18][CH:17]=1)=[O:15])[NH2:13].C(OC(OCC)OCC)C>O>[O:15]1[CH:1]=[N:13][N:12]=[C:14]1[C:16]1[CH:24]=[CH:23][C:19]([C:20]([OH:22])=[O:21])=[CH:18][CH:17]=1
Reactant: NNC(=O)c1ccc(C(=O)O)cc1
Reactant: Cc1ccc(S(=O)(=O)O)cc1
Solvent: O
Solvent: CCOC(OCC)OCC
Product: O=C(O)c1ccc(-c2nnco2)cc1
Temperature: 100 °C
Yield: 379.7 %

Procedure:
Hydrazine hydrate was added to a solution of terephthalic acid monomethyl ester (1 g, 5.5 mmol) in MeOH (10 mL) and stirring was continued for 1 hr. The reaction mixture was concentrated to afford 900 mg (90.09% Yield) of 4-hydrazinocarbonyl-benzoic acid. p-Toluene sulfonic acid (48 mg, 0.277 mmol) was added to a solution of 4-hydrazinocarbonyl-benzoic acid (500 mg, 2.77 mmol) in triethylorthoformate (7.5 mL, 44.0 mmol) and stirring was continued with heating at 100° C. for 3 hrs. The reaction mixture was diluted with water, the solid was collected to afford 200 mg (37.9% Yield) of 4-[1,3,4]oxadiazol-2-yl-benzoic acid.