Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([O:32][C:33]2[CH:38]=[C:37]([F:39])[C:36]([S:40](=[O:59])(=[O:58])[N:41](CC3C=CC(OC)=CC=3OC)[C:42]3[S:46][N:45]=[CH:44][N:43]=3)=[CH:35][C:34]=2[F:60])=[C:6]([C:8]2[CH:9]=[CH:10][C:11]3[O:15][N:14]=[C:13]([N:16](C(OC(C)(C)C)=O)C(OC(C)(C)C)=O)[C:12]=3[CH:31]=2)[CH:7]=1.FC(F)(F)C(O)=O>ClCCl>[NH2:16][C:13]1[C:12]2[CH:31]=[C:8]([C:6]3[CH:7]=[C:2]([Cl:1])[CH:3]=[CH:4][C:5]=3[O:32][C:33]3[C:34]([F:60])=[CH:35][C:36]([S:40]([NH:41][C:42]4[S:46][N:45]=[CH:44][N:43]=4)(=[O:58])=[O:59])=[C:37]([F:39])[CH:38]=3)[CH:9]=[CH:10][C:11]=2[O:15][N:14]=1
Reactant: COc1ccc(CN(c2ncns2)S(=O)(=O)c2cc(F)c(Oc3ccc(Cl)cc3-c3ccc4onc(N(C(=O)OC(C)(C)C)C(=O)OC(C)(C)C)c4c3)cc2F)c(OC)c1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: Nc1noc2ccc(-c3cc(Cl)ccc3Oc3cc(F)c(S(=O)(=O)Nc4ncns4)cc3F)cc12
Temperature: 25 °C
Reaction time: 4 h
Yield: 63 %

Procedure:
To a solution of di-tert-butyl [5-(5-chloro-2-{4-[(2,4-dimethoxybenzyl)(1,2,4-thiadiazol-5-yl)sulfamoyl]-2,5-difluorophenoxy}phenyl)-1,2-benzoxazol-3-yl]imidodicarbonate (1.70 g, 1.92 mmol) in dichloromethane (25 mL) was added trifluoroacetic acid (10 mL). The reaction mixture was stirred at ambient temperature for 4 h and concentrated in vacuo. The residue was taken up in methanol (15 mL) and filtered. The filtrate was concentrated in vacuo and triturated with dichloromethane/diethyl ether (2:1 v/v, 15 mL) to afford 4-(2-(3-aminobenzo[d]isoxazol-5-yl)-4-chlorophenoxy)-2,5-difluoro-N-(1,2,4-thiadiazol-5-yl)benzenesulfonamide as a colorless solid in 63% yield (0.65 g): 1H NMR (300 MHz, DMSO-d6) δ8.49 (s, 1H), 7.95 (s, 1H), 7.72-7.66 (m, 1H), 7.62-7.59 (m, 2H), 7.49-7.42 (m, 2H), 7.26-7.24 (d, J=8.4 Hz, 1H), 7.14-7.08 (m, 1H), 6.47-6.40 (br s, 2H); MS (ES+) m/z 535.8 (M+1), 537.8 (M+1).
Reaction SMILES: [CH2:1]([OH:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.O=S(Cl)Cl.[CH:13]1[CH:18]=[C:17]([OH:19])[CH:16]=[C:15]([CH2:20][C@H:21]([NH2:25])[C:22](O)=[O:23])[CH:14]=1>CCOC(C)=O>[NH2:25][CH:21]([CH2:20][C:15]1[CH:14]=[CH:13][CH:18]=[C:17]([OH:19])[CH:16]=1)[C:22]([O:8][CH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1)=[O:23]
Reactant: OCc1ccccc1
Reactant: N[C@@H](Cc1cccc(O)c1)C(=O)O
Solvent: CCOC(C)=O
Solvent: O=S(Cl)Cl
Product: NC(Cc1cccc(O)c1)C(=O)OCc1ccccc1
Temperature: -5 °C
Reaction time: 0.08 h
Yield: 59 %

Procedure:
To 10 mL of benzyl alcohol at −5° C. was added, with stirring, 0.2 mL of SOCl2 slowly. The clear colorless solution was cooled to −5° C. and 490 mg of meta-Tyrosine was added. After 5 min, the resulting solution was heated to 120° C. overnight. 100 ml of AcOEt are added. The organic phase are washed with saturated NaHCO3 and brine then dried over Na2SO4, filtered and concentrated to afford 170 as a white solid (430 mg, 59%). 1H NMR (DMSO): δ 1.90 (s, 3H), 2.87 (dd, 1H, J=13.1, 6.5 Hz), 2.94 (dd, 1H, J=13.1, 6.5 Hz), 3.73 (t, 1H, J=6.5 Hz), 5.19 (s, 2H), 6.70 (d, 1H, J=7.7 Hz), 6.75 (s, 1H), 7.17 (t, 1H, J=7.7 Hz), 7.41 (d, 1H, J=7.0 Hz), 7.48 (m, 5H), 9.37 (s, 1H).
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([CH2:10][CH2:11][C:12]([OH:14])=O)=[CH:6][CH:5]=1)([O-:3])=[O:2].C(Cl)(=O)C([Cl:18])=O>C(Cl)Cl.CN(C=O)C>[N+:1]([C:4]1[CH:9]=[CH:8][C:7]([CH2:10][CH2:11][C:12]([Cl:18])=[O:14])=[CH:6][CH:5]=1)([O-:3])=[O:2]
Reactant: O=C(Cl)C(=O)Cl
Reactant: O=C(O)CCc1ccc([N+](=O)[O-])cc1
Solvent: CN(C)C=O
Solvent: ClCCl
Product: O=C(Cl)CCc1ccc([N+](=O)[O-])cc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
3-(4-Nitrophenyl)propanoic acid prepared in Example DD (12.5 g, 64 mmol) was suspended in CH2Cl2 (300 mL) and treated with oxalyl chloride (7.4 mL, 85 mmol) and DMF (5 drops). The solution was stirred overnight at room temperature. The solution was concentrated, and the residue was dissolved in CH2Cl2 and re-concentrated. The crude product was used as is in the next step.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([C:8]2[C:16]3[C:11](=[N:12][CH:13]=[CH:14][N:15]=3)[NH:10][N:9]=2)[CH:5]=[CH:4][CH:3]=1.[NH:17]1[CH2:22][CH2:21][NH:20][CH2:19][CH2:18]1>CN1C(=O)CCC1.CCOC(C)=O>[N:17]1([C:2]2[N:7]=[C:6]([C:8]3[C:16]4[C:11](=[N:12][CH:13]=[CH:14][N:15]=4)[NH:10][N:9]=3)[CH:5]=[CH:4][CH:3]=2)[CH2:22][CH2:21][NH:20][CH2:19][CH2:18]1
Reactant: C1CNCCN1
Reactant: Clc1cccc(-c2n[nH]c3nccnc23)n1
Solvent: CCOC(C)=O
Solvent: CN1CCCC1=O
Product: c1cc(-c2n[nH]c3nccnc23)nc(N2CCNCC2)c1
Temperature: 150 °C
Yield: 11 %

Procedure:
A mixture of 3-(6-chloro-2-pyridyl)-1H-pyrazolo[3,4-b]pyrazine (150 mg, 0.6476 mmol) and piperazine (167.4 mg, 1.943 mmol) in NMP (1.5 mL) was heated in microwave at 150° C. for a total of 1.5 h. Mixture cooled to ambient, diluted with EtOAc and washed with sat. NaHCO3 solution (1×), water (2×), brine (1×), dried (MgSO4), filtered and concentrated in vacuo. Crude product purified by ISCO companion (24 g SiO2, 0.5 to 10% MeOH (containing 10% ammonium hydroxide), pure fractions combined and concentrated in vacuo. Product re-dissolved in MeCN/H2O and freeze-dried to leave title compound as a yellow solid (20 mg, 11%). 1H NMR (DMSO-d6) δ2.82 (t, 4H), 3.56 (t, 4H), 6.85 (d, 1H), 7.69 (t, 1H), 7.77 (d, 1H), 8.65 (d, 1H) and 8.73 (d, 1H). ES+281.9.
Reaction SMILES: [I:1][C:2]1[C:7]([CH3:8])=[CH:6][N:5]=[C:4]([OH:9])[C:3]=1[CH3:10].FS([C:15]([F:20])([F:19])C(O)=O)(=O)=O.S([O-])([O-])(=O)=O.[Na+].[Na+].C(=O)(O)[O-].[Na+]>C(#N)C>[F:19][CH:15]([F:20])[O:9][C:4]1[C:3]([CH3:10])=[C:2]([I:1])[C:7]([CH3:8])=[CH:6][N:5]=1
Reactant: O=C(O)C(F)(F)S(=O)(=O)F
Reactant: Cc1cnc(O)c(C)c1I
Agent: O=C([O-])O
Agent: O=S(=O)([O-])[O-]
Agent: [Na+]
Solvent: CC#N
Product: Cc1cnc(OC(F)F)c(C)c1I
Temperature: 25 °C
Reaction time: 3.5 h

Procedure:
4-iodo-3,5-dimethylpyridin-2-ol (350 mg), 2-(fluorosulfonyl)difluoroacetic acid (0.17 mL), and sodium sulfate (39.9 mg) were added to acetonitrile (5.7 mL). The mixture was stirred at room temperature for 3.5 hours. A saturated aqueous sodium bicarbonate solution was added to the reaction mixture, followed by extraction with ethyl acetate. The organic layer was concentrated under reduced pressure to give the title compound (378.6 mg).
Reaction SMILES: S(=O)(=O)(O)O.C([Si](C)(C)[O:11][CH2:12][C:13]1[CH:18]=[CH:17][C:16]([CH:19]=[CH:20][C:21]2[CH:26]=[CH:25][CH:24]=[C:23]([CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][C:32]([CH3:41])([O:34]C3CCCCO3)[CH3:33])[CH:22]=2)=[CH:15][CH:14]=1)(C)(C)C>C1COCC1.O>[OH:11][CH2:12][C:13]1[CH:14]=[CH:15][C:16]([CH:19]=[CH:20][C:21]2[CH:22]=[C:23]([CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][C:32]([CH3:41])([OH:34])[CH3:33])[CH:24]=[CH:25][CH:26]=2)=[CH:17][CH:18]=1
Reactant: CC(C)(CCCCCc1cccc(C=Cc2ccc(CO[Si](C)(C)C(C)(C)C)cc2)c1)OC1CCCCO1
Agent: O=S(=O)(O)O
Solvent: C1CCOC1
Solvent: O
Product: CC(C)(O)CCCCCc1cccc(C=Cc2ccc(CO)cc2)c1

Procedure:
In a manner similar to Example 25(d), by reacting 0.2 ml of concentrated sulphuric acid with 1 g (1.86 mmol) of tert-butyldimethyl-[4-(2-{3-[6-methyl-6-(tetrahydropyran-2-yloxy)heptyl]phenyl}vinyl)benzyloxy]silane in 20 ml of THF and 10 ml of water, after purification on a silica column (ethyl acetate 50-heptane 50), white crystals (m=350 mg; Y=56%) are obtained. m.p.=105-7° C.
Reaction SMILES: [C:1]([OH:8])(=[O:7])/[CH:2]=[CH:3]/[C:4]([OH:6])=[O:5].C(O)(=O)/C=C/C(O)=O.[CH3:17][N:18]1[C:22]2([CH2:27][CH2:26][CH2:25][CH2:24][CH2:23]2)[CH:21]([NH2:28])[CH2:20][CH2:19]1.[OH-].[Na+].[C:31](Cl)(=[O:38])[C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1.C(O)(=O)/C=C/C(O)=O>C(#N)C>[C:1]([OH:8])(=[O:7])/[CH:2]=[CH:3]/[C:4]([OH:6])=[O:5].[CH3:17][N:18]1[C:22]2([CH2:23][CH2:24][CH2:25][CH2:26][CH2:27]2)[CH:21]([NH:28][C:31](=[O:38])[C:32]2[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=2)[CH2:20][CH2:19]1
Reactant: CN1CCC(N)C12CCCCC2
Reactant: O=C(Cl)c1ccccc1
Agent: O=C(O)/C=C/C(=O)O
Agent: [Na+]
Agent: [OH-]
Solvent: CC#N
Product: CN1CCC(NC(=O)c2ccccc2)C12CCCCC2
Reaction time: 24 h
Yield: 25.7 %

Procedure:
To a stirring suspension of 3.5 g (0.021 mole) of 1-methyl-4-amino-1-azaspiro[4.5]decane of Example 2 and 150 ml of 10% NaOH was added dropwise 3.1 g (0.022 mole) of benzoyl chloride. The reaction was stirred vigorously for 24 hours, the aqueous solution was decanted and the remaining oil was dissolved in ethyl acetate and dried over Na2SO4. The solvent was then evaporated to give a solid which was recrystallized from hexane to give 2.5 g. The solid was dissolved in 10 ml of acetonitrile and 1.1 g of fumaric acid was added. The suspension was stirred until the amine salt precipitated from solution. The compound was filtered and recrystallized twice from ethanol-ether to give 2.1 g (25.7%) of 1-methyl-4-benzamido-1-azaspiro[4.5]decane fumarate, m.p. 171°-173° C.
Reaction SMILES: OC1CC[N:5]([C:8]([NH:10][C:11]2[NH:15][C:14]3[CH:16]=[CH:17][C:18]([O:20][S:21]([C:24]4[CH:29]=[CH:28][C:27]([N:30]5[CH2:35][CH2:34][CH:33]([OH:36])[CH2:32][CH2:31]5)=[CH:26][CH:25]=4)(=[O:23])=[O:22])=[CH:19][C:13]=3[N:12]=2)=[O:9])[CH2:4][CH2:3]1.NC[CH:39]1[O:44][CH2:43][CH2:42][NH:41][CH2:40]1>O1CCCC1.CN1CCCC1=O>[N:41]1([CH2:3][CH2:4][NH:5][C:8](=[O:9])[NH:10][C:11]2[NH:15][C:14]3[CH:16]=[CH:17][C:18]([O:20][S:21]([C:24]4[CH:25]=[CH:26][C:27]([N:30]5[CH2:35][CH2:34][CH:33]([OH:36])[CH2:32][CH2:31]5)=[CH:28][CH:29]=4)(=[O:23])=[O:22])=[CH:19][C:13]=3[N:12]=2)[CH2:42][CH2:43][O:44][CH2:39][CH2:40]1
Reactant: O=C(Nc1nc2cc(OS(=O)(=O)c3ccc(N4CCC(O)CC4)cc3)ccc2[nH]1)N1CCC(O)CC1
Reactant: NCC1CNCCO1
Solvent: CN1CCCC1=O
Solvent: C1CCOC1
Product: O=C(NCCN1CCOCC1)Nc1nc2cc(OS(=O)(=O)c3ccc(N4CCC(O)CC4)cc3)ccc2[nH]1
Yield: 33.1 %

Procedure:
A solution of 4-(4-hydroxy-piperidin-1-yl)-benzenesulfonic acid 2-[(4-hydroxy-piperidine-1-carbonyl)-amino]-1H-benzoimidazol-5-yl ester (example 79, 20 mg) and 2-(aminomethyl)-morpholine (50 mg) in tetrahydrofuran (1 ml) and N-methylpyrrolidinone (0.2 ml) was heated at 95° C. for 22 hours. The reaction mixture was then evaporated and purified by triggered LC/MS to give 4-(4-hydroxy-piperidin-1-yl)-benzenesulfonic acid 2-[3-(2-morpholin-4-yl-ethyl)-ureido]-1H-benzoimidazol-5-yl ester as an off-white solid (7 mg). Mass spectrum: 545 [M+H]+; retention time=5.47 minutes.
Reaction SMILES: [C:1]([C:9]1[CH:41]=[CH:40][C:12]2[N:13]([CH2:17][CH2:18][O:19][C:20]3[CH:25]=[CH:24][C:23]([CH2:26][CH:27]([NH:32][C:33]([O:35][C:36]([CH3:39])([CH3:38])[CH3:37])=[O:34])[C:28]([O:30][CH3:31])=[O:29])=[CH:22][CH:21]=3)[C:14](=[O:16])[S:15][C:11]=2[CH:10]=1)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:42]I.[H-].[Na+].Cl>CN(C=O)C>[C:1]([C:9]1[CH:41]=[CH:40][C:12]2[N:13]([CH2:17][CH2:18][O:19][C:20]3[CH:25]=[CH:24][C:23]([CH2:26][CH:27]([N:32]([C:33]([O:35][C:36]([CH3:37])([CH3:38])[CH3:39])=[O:34])[CH3:42])[C:28]([O:30][CH3:31])=[O:29])=[CH:22][CH:21]=3)[C:14](=[O:16])[S:15][C:11]=2[CH:10]=1)(=[O:8])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: COC(=O)C(Cc1ccc(OCCn2c(=O)sc3cc(C(=O)c4ccccc4)ccc32)cc1)NC(=O)OC(C)(C)C
Reactant: CI
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COC(=O)C(Cc1ccc(OCCn2c(=O)sc3cc(C(=O)c4ccccc4)ccc32)cc1)N(C)C(=O)OC(C)(C)C

Procedure:
Dissolve the compound obtained in Step C of Example 10 (1 eq.) and CH3I (2 eq.): in 55 ml of anhydrous DMF and place in an ice bath at 0° C. Add NaH (1.5 eq.) in portions. Allow to return to ambient temperature. Hydrolyse, acidify with 1N HCl and filter. Purify the resulting crude product by chromatography on silica gel (eluant:diethyl ether/toluene 2/8).
Reaction SMILES: [CH3:1][N:2]([CH:4](OC)OC)[CH3:3].[CH3:9][C:10]1[CH:18]=[CH:17][C:13]([C:14]([OH:16])=[O:15])=[CH:12][C:11]=1[N+:19]([O-:21])=[O:20]>CN(C)C=O>[CH3:3][N:2]([CH3:1])[CH:4]=[CH:9][C:10]1[CH:18]=[CH:17][C:13]([C:14]([OH:16])=[O:15])=[CH:12][C:11]=1[N+:19]([O-:21])=[O:20]
Reactant: Cc1ccc(C(=O)O)cc1[N+](=O)[O-]
Reactant: COC(OC)N(C)C
Solvent: CN(C)C=O
Product: CN(C)C=Cc1ccc(C(=O)O)cc1[N+](=O)[O-]
Temperature: 140 °C
Reaction time: 2 h
Yield: 71.6 %

Procedure:
DMF-DMA (45.4 g; 2.3 equiv.) was added under a nitrogen atmosphere to a solution of 4-methyl-3-nitrobenzoic acid (30 g; 1 equiv.) in dimethylformamide (150 ml). The resulting reaction mixture was heated for 17 h at 140° C. When the conversion was complete, the DMF was distilled off; 150 ml of methanol were added to the residue, and the mixture was stirred for 2 hours at room temperature and then crystallised overnight at 0-4° C. The resulting solid was filtered out and washed with ice-cold methanol and then with hexane. Drying yielded 4-(2-(dimethylamino)vinyl)-3-nitrobenzoic acid (28 g; 71.79%) in the form of a red solid.
Reaction SMILES: [C:1]12([CH2:9][CH:8]([NH:10][C:11](=[O:19])OC3C=CC=CC=3)[C:7]3[CH:20]=[CH:21][CH:22]=[CH:23][C:6]=3[O:5]1)[CH2:4][CH2:3][CH2:2]2.NC[C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][N:27]=1.[CH2:32]([N:34](CC)CC)C.O>CS(C)=O>[C:1]12([CH2:9][CH:8]([NH:10][C:11]([NH:34][CH2:32][C:29]3[CH:28]=[N:27][CH:26]=[CH:31][CH:30]=3)=[O:19])[C:7]3[CH:20]=[CH:21][CH:22]=[CH:23][C:6]=3[O:5]1)[CH2:2][CH2:3][CH2:4]2
Reactant: NCc1ccccn1
Reactant: CCN(CC)CC
Reactant: O=C(NC1CC2(CCC2)Oc2ccccc21)Oc1ccccc1
Solvent: O
Solvent: CS(C)=O
Product: O=C(NCc1cccnc1)NC1CC2(CCC2)Oc2ccccc21

Procedure:
A solution of phenyl 3,4-dihydro-spiro[2H-1-benzopyran-2,1′-cyclobutan]-4-ylcarbamate (1 mmol) and 2-(amino methyl)pyridine (1 mmol) in dimethylsulfoxide was stirred at room temperature in the presence of a base such as triethylamine (2 mmol). Few drops of water were added in the reaction mixture. Product precipitated out, was filtered and washed with water. It was then purified by column chromatography to afford the desired urea as a white solid.
Reaction SMILES: C(N(C(C)C)CC)(C)C.N1(OC(N(C)C)=[N+](C)C)C2C=CC=CC=2N=N1.F[B-](F)(F)F.[Cl:32][C:33]1[CH:34]=[C:35]([S:40]([NH:43][C:44]2[CH:45]=[C:46]3[C:51](=[CH:52][CH:53]=2)[C:50]([C:54]([OH:56])=O)=[CH:49][CH:48]=[CH:47]3)(=[O:42])=[O:41])[CH:36]=[C:37]([Cl:39])[CH:38]=1.[CH2:57]([NH2:64])[C:58]1[CH:63]=[CH:62][CH:61]=[CH:60][CH:59]=1>CN(C)C=O.O>[CH2:57]([NH:64][C:54]([C:50]1[C:51]2[C:46](=[CH:45][C:44]([NH:43][S:40]([C:35]3[CH:34]=[C:33]([Cl:32])[CH:38]=[C:37]([Cl:39])[CH:36]=3)(=[O:42])=[O:41])=[CH:53][CH:52]=2)[CH:47]=[CH:48][CH:49]=1)=[O:56])[C:58]1[CH:63]=[CH:62][CH:61]=[CH:60][CH:59]=1
Reactant: O=C(O)c1cccc2cc(NS(=O)(=O)c3cc(Cl)cc(Cl)c3)ccc12
Reactant: NCc1ccccc1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Solvent: O
Product: O=C(NCc1ccccc1)c1cccc2cc(NS(=O)(=O)c3cc(Cl)cc(Cl)c3)ccc12
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
1.50 ml diisopropylethylamine and 2.81 g O-(benzotriazol-1-yl)-1,1,3,3-tetramethyluronium-tetrafluoroborate are added to 3.47 g 6-(3,5-dichloro-phenylsulphonylamino)-naphthalene-1-carboxylic acid in 15 ml N,N-dimethylformamide. The reaction mixture is stirred for 15 minutes at ambient temperature, then 0.97 ml benzylamine and 1.50 ml diisopropylethylamine are added and the mixture is stirred for a further two hours at ambient temperature. For working up the reaction mixture is mixed with water and extracted with ethyl acetate. The combined organic extracts are washed with 1N hydrochloric acid, 1N sodium hydroxide solution and saturated sodium chloride solution, dried on magnesium sulphate and evaporated down. The foam-like flask residue is stirred overnight with cyclohexane/ethyl acetate and the resulting crystalline precipitate is suction filtered, washed with cyclohexane and dried.
Reaction SMILES: C(O[C:6]([N:8]1[CH2:12][C:11](=[N:13][O:14][CH3:15])[CH2:10][C@H:9]1[C:16]([OH:18])=[O:17])=[O:7])(C)(C)C.[CH3:19][O:20][C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=1[C:27]1[CH:32]=[CH:31][C:30](C(O)=O)=[CH:29][CH:28]=1.[CH3:36]O>>[CH3:19][O:20][C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=1[C:27]1[CH:32]=[CH:31][C:30]([C:6]([N:8]2[CH2:12][C:11](=[N:13][O:14][CH3:15])[CH2:10][C@H:9]2[C:16]([O:18][CH3:36])=[O:17])=[O:7])=[CH:29][CH:28]=1
Reactant: CON=C1C[C@@H](C(=O)O)N(C(=O)OC(C)(C)C)C1
Reactant: CO
Reactant: COc1ccccc1-c1ccc(C(=O)O)cc1
Product: CON=C1C[C@@H](C(=O)OC)N(C(=O)c2ccc(-c3ccccc3OC)cc2)C1

Procedure:
Following the general method as outlined in Example 11, starting from (2S,4EZ)-1-(tert-butoxycarbonyl)4-(methoxyimino)-2-pyrrolidinecarboxylic acid, 2′-methoxy[1,1′-biphenyl]-4-carboxylic-acid, and methanol, the title compound was isolated as a mixture of two isomers in 92.1% purity by HPLC.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]2[C:11]3[S:12][C:13]([C:15]([OH:17])=O)=[CH:14][C:10]=3[CH2:9][CH2:8][O:7][C:6]=2[CH:18]=1.[Si]([O:26][CH2:27][CH2:28][NH:29][C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][C:31]=1[Cl:36])(C(C)(C)C)(C)C>>[Br:1][C:2]1[CH:3]=[CH:4][C:5]2[C:11]3[S:12][C:13]([C:15]([N:29]([C:30]4[CH:35]=[CH:34][CH:33]=[CH:32][C:31]=4[Cl:36])[CH2:28][CH2:27][OH:26])=[O:17])=[CH:14][C:10]=3[CH2:9][CH2:8][O:7][C:6]=2[CH:18]=1
Reactant: O=C(O)c1cc2c(s1)-c1ccc(Br)cc1OCC2
Reactant: CC(C)(C)[Si](C)(C)OCCNc1ccccc1Cl
Product: O=C(c1cc2c(s1)-c1ccc(Br)cc1OCC2)N(CCO)c1ccccc1Cl
Yield: 25 %

Procedure:
Following Example 16, 8-bromo-4,5-dihydrobenzo[b]thieno[2,3-d]oxepine-2-carboxylic acid was converted to the acid chloride and reacted with N-(2-(tert-butyldimethylsilyloxy)ethyl)-2-chloroaniline. Desilylation gave 233 (yield 25%). MS: (ESI+)
Reaction SMILES: C(C1[CH:8]=[CH:7][C:6]([C:9]2[C:13]3[CH:14]=[C:15]([CH2:18][C:19]([O:21]C)=[O:20])[CH:16]=[CH:17][C:12]=3[O:11][CH:10]=2)=[CH:5][CH:4]=1)#N.[CH2:23]([OH:25])[CH3:24].[OH-:26].[Na+]>O>[C:23]([C:24]1[CH:8]=[CH:7][C:6]([C:9]2[C:13]3[CH:14]=[C:15]([CH2:18][C:19]([OH:21])=[O:20])[CH:16]=[CH:17][C:12]=3[O:11][CH:10]=2)=[CH:5][CH:4]=1)([OH:26])=[O:25]
Reactant: CCO
Reactant: [OH-]
Reactant: COC(=O)Cc1ccc2occ(-c3ccc(C#N)cc3)c2c1
Agent: [Na+]
Solvent: O
Product: O=C(O)Cc1ccc2occ(-c3ccc(C(=O)O)cc3)c2c1

Procedure:
To a suspension of 5 g. of the product of step A in 20 ml. of ethanol is added 50 ml. of 30 percent sodium hydroxide solution, and the mixture is refluxed for 30 minutes, 75 ml. of water is added, and the mixture is refluxed for an additional three hours. The mixture is decanted into 125 ml. of 6N hydrochloric acid, the solid is separated by filtration then recrystallized from acetic acid to provide 3-(4-carboxyphenyl)benzofuran-5-acetic acid, m.p. 278°-281° C.
Reaction SMILES: [CH3:1][O:2][CH2:3][O:4][C:5]1[C:9]([C:10]([O:12][CH2:13][CH3:14])=[O:11])=[CH:8][N:7](C(OC(C)(C)C)=O)[N:6]=1.O.[OH-].[Li+].O1CCCC1.CO>O>[CH3:1][O:2][CH2:3][O:4][C:5]1[C:9]([C:10]([O:12][CH2:13][CH3:14])=[O:11])=[CH:8][NH:7][N:6]=1
Reactant: CCOC(=O)c1cn(C(=O)OC(C)(C)C)nc1OCOC
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Solvent: O
Product: CCOC(=O)c1c[nH]nc1OCOC
Temperature: 25 °C
Yield: 76.7 %

Procedure:
A mixture of 4-ethyl 1-tert-butyl 3-(methoxymethoxy)-1H-pyrazole-1,4-dicarboxylate (3.52 g), lithium hydroxide monohydrate (1.47 g), tetrahydrofuran (60 mL), methanol (30 mL) and water (30 mL) was stirred at room temperature for hrs. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate and concentrated. The residue was subjected to silica gel column chromatography and eluted with ethyl acetate-hexane (1:9-4:1, v/v) to give ethyl 3-(methoxymethoxy)-1H-pyrazole-4-carboxylate as a colorless solid (1.80 g, yield 77%).
Reaction SMILES: [CH2:1]([N:3]1[C:7]2=[N:8][CH:9]=[C:10]([C:15]([OH:17])=O)[C:11]([C:12](O)=[O:13])=[C:6]2[CH:5]=[N:4]1)[CH3:2].CCN=C=NCCCN(C)C.Cl.C1C=CC2N(O)[N:37]=[N:36]C=2C=1.C(N(CC)CC)C.NN>C1COCC1.O>[CH2:1]([N:3]1[C:7]2[N:8]=[CH:9][C:10]3[C:15](=[O:17])[NH:36][NH:37][C:12](=[O:13])[C:11]=3[C:6]=2[CH:5]=[N:4]1)[CH3:2]
Reactant: CCn1ncc2c(C(=O)O)c(C(=O)O)cnc21
Reactant: On1nnc2ccccc21
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: NN
Solvent: CCN(CC)CC
Solvent: O
Solvent: C1CCOC1
Product: CCn1ncc2c3c(=O)[nH][nH]c(=O)c3cnc21
Temperature: 25 °C
Reaction time: 5 h

Procedure:
An alternative method could be used by starting with 1-ethyl-1H-pyrazolo[3,4-b]pyridine-4,5-dicarboxylic acid. The diacid was dissolved in anhydrous THF with EDAC.HCl (1.2 eq), HOBT (1.2 eq), and triethylamine (5.0 eq). To this solution was added anhydrous hydrazine (2.0 eq). The resulting solution was stirred at rt for 5 h and then diluted with water. The precipitated solid was collected by filtration to afford the title compound as a white solid.
Reaction SMILES: [CH:1](=O)[C:2]1[O:6][CH:5]=[CH:4][CH:3]=1.[CH:8]1[CH2:12][CH:11]=[CH:10][CH:9]=1>C(NCC)C.CO>[O:6]1[CH:5]=[CH:4][CH:3]=[C:2]1[C:1]1[C:9](=[CH2:10])[CH:8]=[CH:12][CH:11]=1
Reactant: C1=CCC=C1
Reactant: O=Cc1ccco1
Solvent: CO
Solvent: CCNCC
Product: C=C1C=CC=C1c1ccco1

Procedure:
About equal molar amounts of furfural and cyclopentadiene are reacted in the presence of diethylamine catalyst and about 33% methanol solvent according to the method suggested by C. Schmidt, Chem, Ber., Volume 90, p. 1352, 1957. A viscous dark material is separated from the water layer.
Reaction SMILES: [NH2:1][CH2:2][C:3]1[CH:12]=[C:11]2[C:6]([C:7]([C:25]3[CH:30]=[CH:29][C:28]([CH3:31])=[C:27]([CH3:32])[CH:26]=3)=[C:8]([CH:15]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])[C:16]([O:18][CH3:19])=[O:17])[N:9]([CH3:14])[C:10]2=[O:13])=[CH:5][CH:4]=1.[CH2:33]([N:35]=[C:36]=[O:37])[CH3:34]>C1(C)C=CC=CC=1>[C:21]([O:20][CH:15]([C:8]1[N:9]([CH3:14])[C:10](=[O:13])[C:11]2[C:6]([C:7]=1[C:25]1[CH:30]=[CH:29][C:28]([CH3:31])=[C:27]([CH3:32])[CH:26]=1)=[CH:5][CH:4]=[C:3]([CH2:2][NH:1][C:36]([NH:35][CH2:33][CH3:34])=[O:37])[CH:12]=2)[C:16]([O:18][CH3:19])=[O:17])([CH3:22])([CH3:23])[CH3:24]
Reactant: CCN=C=O
Reactant: COC(=O)C(OC(C)(C)C)c1c(-c2ccc(C)c(C)c2)c2ccc(CN)cc2c(=O)n1C
Solvent: Cc1ccccc1
Product: CCNC(=O)NCc1ccc2c(-c3ccc(C)c(C)c3)c(C(OC(C)(C)C)C(=O)OC)n(C)c(=O)c2c1
Temperature: 70 °C
Reaction time: 2 h
Yield: 59 %

Procedure:
A solution of methyl 2-(7-(aminomethyl)-4-(3,4-dimethylphenyl)-2-methyl-1-oxo-1,2-dihydroisoquinolin-3-yl)-2-(tert-butoxy)acetate (17 mg, 0.039 mmol) in Toluene (750 μl) was treated with ethyl isocyanate (9.25 μl, 0.117 mmol) and stirred at 70° C. for 2 hours. The reaction was cooled to rt, concentrated, and purified with column chromatography (0-10% MeOH/DCM) to afford methyl 2-(tert-butoxy)-2-(4-(3,4-dimethylphenyl)-7-((3-ethylureido)methyl)-2-methyl-1-oxo-1,2-dihydroisoquinolin-3-yl)acetate (11.8 mg, 0.023 mmol, 59.7% yield). The methyl ester was then hydrolyzed in a manner similar to that described in Example 165 Step C and purified by reverse phase HPLC to afford 2-(tert-butoxy)-2-(4-(3,4-dimethylphenyl)-7-((3-ethylureido)methyl)-2-methyl-1-oxo-1,2-dihydroisoquinolin-3-yl)acetic acid (9.1 mg, 0.018 mmol, 86% yield) as a white solid: 1H NMR (400 MHz, CHLOROFORM-d) δ ppm 8.35 (s, 1 H), 7.56-7.42 (m, 1 H), 7.37-7.28 (m, 1 H), 7.25-7.20 (m, 1 H), 7.12 (dd, J=8.5, 11.0 Hz, 1 H), 7.08-6.97 (m, 1 H), 5.32 (d, J=3.1 Hz, 1 H), 4.46 (s, 2 H), 3.69 (s, 3 H), 3.18 (q, J=7.1 Hz, 2 H), 2.36 (s, 3 H), 2.30 (d, J=9.4 Hz, 3 H), 1.13 (t, J=7.2 Hz, 3 H), 1.04 (d, J=5.1 Hz, 9 H); LCMS (m/z) ES+=494 (M+1).