Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[C:4]([F:9])[C:3]=1[NH:10][S:11]([CH2:14][C:15]([OH:17])=O)(=[O:13])=[O:12].[OH:18][CH:19]([CH:22]1[CH2:26][O:25][C:24]([CH3:28])([CH3:27])[O:23]1)[CH2:20][NH2:21].OC1C2N=NNC=2C=CC=1.C1(N=C=NC2CCCCC2)CCCCC1>CN(C=O)C>[OH:18][CH:19]([CH:22]1[CH2:26][O:25][C:24]([CH3:28])([CH3:27])[O:23]1)[CH2:20][NH:21][C:15](=[O:17])[CH2:14][S:11](=[O:12])(=[O:13])[NH:10][C:3]1[C:4]([F:9])=[CH:5][C:6]([F:8])=[CH:7][C:2]=1[F:1]
Reactant: O=C(O)CS(=O)(=O)Nc1c(F)cc(F)cc1F
Reactant: CC1(C)OCC(C(O)CN)O1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: Oc1cccc2[nH]nnc12
Solvent: CN(C)C=O
Product: CC1(C)OCC(C(O)CNC(=O)CS(=O)(=O)Nc2c(F)cc(F)cc2F)O1
Temperature: -10 °C
Reaction time: 1 h

Procedure:
1.38 g (3.16 mmol) of 2-[N-(2,4,6-trifluorophenyl)sulfamoyl] acetic acid is dissolved in 20 ml of DMF with exclusion of moisture and under argon atmosphere, 509 mg (3.16 mmol) of 2-hydroxy-2-(2,2-dimethyl-1,3-dioxolan-4-yl)-ethylamine and 484 mg (3.16 mmol) of hydroxybenzotriazole are added and the solution is cooled to -10° C. 652 mg (3.16 mmol) of dicyclohexylcarbodiimide is added to the cooled solution, it is stirred for one hour at -10° C and for 12 more hours at room temperature. The turbid reaction solution is then filtered and the clear filtrate is evaporated to dryness in a vacuum. The residue is dissolved in 100 ml of ethyl acetate and the solution is shaken out five times with saturated sodium bicarbonate solution and twice with water. The ethyl acetate solution is dried on sodium sulfate, filtered and evaporated to dryness. The residue is chromatographed on silica gel 60 (Merck) with ethyl acetate/methylene chloride 8:2. The corresponding fractions together contain 0.62 g (1.42 mmol)=45% of the theoretical yield of product is obtained as an amorphous solid.
Reaction SMILES: [SH:1][C:2]1[NH:3][C:4]2[CH:10]=[C:9]([C:11]([O:13][CH2:14][CH3:15])=[O:12])[CH:8]=[CH:7][C:5]=2[N:6]=1.C(=O)([O-])[O-].[K+].[K+].[C:22]([C:25]1[CH:30]=[CH:29][C:28]([S:31][CH2:32][CH2:33][CH2:34][CH2:35]Br)=[C:27]([CH2:37][CH2:38][CH3:39])[C:26]=1[OH:40])(=[O:24])[CH3:23].Cl>CN(C)C=O>[C:22]([C:25]1[CH:30]=[CH:29][C:28]([S:31][CH2:32][CH2:33][CH2:34][CH2:35][S:1][C:2]2[NH:3][C:4]3[CH:10]=[C:9]([C:11]([O:13][CH2:14][CH3:15])=[O:12])[CH:8]=[CH:7][C:5]=3[N:6]=2)=[C:27]([CH2:37][CH2:38][CH3:39])[C:26]=1[OH:40])(=[O:24])[CH3:23]
Reactant: CCOC(=O)c1ccc2nc(S)[nH]c2c1
Reactant: CCCc1c(SCCCCBr)ccc(C(C)=O)c1O
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCCc1c(SCCCCSc2nc3ccc(C(=O)OCC)cc3[nH]2)ccc(C(C)=O)c1O
Temperature: 65 °C
Reaction time: 0.5 h
Yield: 89.8 %

Procedure:
A mixture of ethyl 2-mercaptobenzimidazole-5-carboxylate (1.29 g), anhydrous potassium carbonate (960 mg) in N,N-dimethylformamide (20 ml) was stirred at 60-70 ° C. for 30 minutes. To this mixture was added a solution of 4-(4-acetyl-3-hydroxy-2-propylphenylthio)butylbromide (2.00 g) in N,N-dimethylformamide (10 ml) dropwise during 10 minutes and stirred at the same temperature for 30 minutes. The reaction mixture was poured into ice-water, made acidic with concentrated hydrochloric acid and extracted with ethyl acetate. The organic layer was washed with water, dried over anhydrous sodium sulfate and evaporated. The resulting residue was purified by silica gel column chromatography, eluting with dichloromethane-ethyl acetate 10:1), to give the title compound (2.53 g, 89.8%) as pale yellow oil.
Reaction SMILES: CC([O-])(C)C.[K+].CC1C=CC(S([CH2:17][N+:18]#[C-])(=O)=O)=CC=1.[CH:20]([C:22]1[C:30]([O:31][CH3:32])=[CH:29][C:28]([CH3:33])=[C:27]2[C:23]=1[CH:24]=[CH:25][N:26]2C(OC(C)(C)C)=O)=O.CO>C1COCC1>[CH3:32][O:31][C:30]1[C:22]([CH2:20][C:17]#[N:18])=[C:23]2[C:27](=[C:28]([CH3:33])[CH:29]=1)[NH:26][CH:25]=[CH:24]2
Reactant: [C-]#[N+]CS(=O)(=O)c1ccc(C)cc1
Reactant: COc1cc(C)c2c(ccn2C(=O)OC(C)(C)C)c1C=O
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: CO
Solvent: C1CCOC1
Product: COc1cc(C)c2[nH]ccc2c1CC#N
Reaction time: 0.25 h

Procedure:
To a suspension of KOtBu (6.98 g, 62.2 mmol) in THF (50.0 mL) at −78° C. was added TOSMIC (8.10 g, 41.5 mmol) in THF (50.0 mL). The mixture was stirred at −78° for 15 minutes. To the mixture at −78° C. was then added a solution of tert-butyl 4-formyl-5-methoxy-7-methyl-1H-indole-1-carboxylate (Example 19-D) (6 g, 20.74 mmol) in THF (50 mL). The reaction was stirred at −78° C. for 1.5 hours. MeOH (10 ml) was then added and the reaction was removed from the dry ice bath. After 30 minutes the reaction was placed in a 40° C. water bath for 30 minutes. At this point, the reaction was cooled in an ice bath and was quenched with a saturated solution of ammonium chloride and then diluted with water and EtOAc. The layers were separated and the organics layer was dried, concentrated and absorbed onto silica to purify via FCC (0-50% EtOAc:heptanes) to afford the title compound. MS (ESI+) m/z 201.2 (M+H).
Reaction SMILES: [OH:1][C:2]1[N:7]=[C:6]([O:8][C:9]2[N:13]([CH3:14])[N:12]=[C:11]([C:15]([F:18])([F:17])[F:16])[CH:10]=2)[CH:5]=[C:4]([CH3:19])[CH:3]=1.[F:20][C:21]([F:27])([F:26])[CH:22]=[CH:23][CH2:24]O.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OCC)=O)=NC(OCC)=O>O1CCOCC1.CCCCC.C(OCC)(=O)C>[CH3:14][N:13]1[C:9]([O:8][C:6]2[CH:5]=[C:4]([CH3:19])[CH:3]=[C:2]([O:1][CH2:24]/[CH:23]=[CH:22]/[C:21]([F:27])([F:26])[F:20])[N:7]=2)=[CH:10][C:11]([C:15]([F:18])([F:17])[F:16])=[N:12]1
Reactant: Cc1cc(O)nc(Oc2cc(C(F)(F)F)nn2C)c1
Reactant: OCC=CC(F)(F)F
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1COCCO1
Solvent: CCCCC
Solvent: CCOC(C)=O
Product: Cc1cc(OC/C=C/C(F)(F)F)nc(Oc2cc(C(F)(F)F)nn2C)c1
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 99.4 %

Procedure:
A mixture of 6-hydroxy-2-(l-methyl-3-trifluoromethylpyrazol-5-yloxy)-4-methylpyridine (0.8 g, 2.93 mmol), 4,4,4-trifluorobut-2-en-1-ol (0.44 g, 3.5 mmol), triphenylphosphine (0.92 g, 3.51 mmol) and diethyl azodicarboxylate (0.61 g, 3.51 mmol) in dry dioxane (3 ml) is stirred for 1.5 h at ambient temperature. The reaction mixture is diluted with pentane/ethyl acetate (by volume ration 1/1) and filtered through a bed of silica gel. The filtrate is washed with water. The organic layer is dried with anhydrous magnesium sulfate, filtered and evaporated in vacuo. Purification by flash chromatography (silica gel: pentane/ethyl acetate 9/1 v/v) yields the title compound (1.11 g, 70 % yield) as an colorless oil.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[C:17]3[O:16][CH:15]([CH2:18][NH2:19])[CH2:14][C:13]=3[CH:12]=[CH:11][CH:10]=2)=[CH:5][CH:4]=1.C(N(C(C)C)CC)(C)C.Cl[C:30]([O:32][CH2:33][C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1)=[O:31]>>[CH2:33]([O:32][C:30](=[O:31])[NH:19][CH2:18][CH:15]1[CH2:14][C:13]2[CH:12]=[CH:11][CH:10]=[C:9]([C:6]3[CH:7]=[CH:8][C:3]([O:2][CH3:1])=[CH:4][CH:5]=3)[C:17]=2[O:16]1)[C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1
Reactant: O=C(Cl)OCc1ccccc1
Reactant: COc1ccc(-c2cccc3c2OC(CN)C3)cc1
Solvent: CCN(C(C)C)C(C)C
Product: COc1ccc(-c2cccc3c2OC(CNC(=O)OCc2ccccc2)C3)cc1
Yield: 84.6 %

Procedure:
Treatment of 1-[7-(4-methoxyphenyl)-2,3-dihydro-1-benzofuran-2-yl]methanamine (0.727 g, 2.49 mmol) with diisopropylethylamine (0.483 g, 3.73) and benzyl chloroformate (0.510 g, 2.99 mmol) generally according to the procedure described for Intermediate 12 provided 0.820 g of (±)-benzyl[7-(4-methoxyphenyl)-2,3-dihydro-1-benzofuran-2-yl]methylcarbamate as a colorless oil. Rf=0.48 (silica, ethyl acetate:hexanes 1:5); Anal. calcd. for C24H23NO4: C, 74.02; H, 5.95; N, 3.60. Found: C, 73.66H, 6.13; N, 3.42. Chiral HPLC separation of (±)-benzyl[7-(4-methoxyphenyl)-2,3-dihydro-1-benzofuran-2-yl]methylcarbamate (Chiralcel AD, methanol) provided two fractions. Fraction 1 (Rt=7.386 min, Chiralcel AD, methanol); Fraction 2 (Rt=10.882 min, Chiralcel AD, methanol).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:13]=[C:12]([C:14]([OH:16])=O)[CH:11]=[CH:10][CH:9]=2)=[CH:4][CH:3]=1.[CH2:17]([O:19][C:20](=[O:30])[CH2:21][O:22][C:23]1[CH:28]=[CH:27][CH:26]=[C:25]([NH2:29])[CH:24]=1)[CH3:18]>CCOC(C)=O>[CH2:17]([O:19][C:20](=[O:30])[CH2:21][O:22][C:23]1[CH:28]=[CH:27][CH:26]=[C:25]([NH:29][C:14]([C:12]2[CH:11]=[CH:10][CH:9]=[C:8]([C:5]3[CH:4]=[CH:3][C:2]([Cl:1])=[CH:7][CH:6]=3)[N:13]=2)=[O:16])[CH:24]=1)[CH3:18]
Reactant: O=C(O)c1cccc(-c2ccc(Cl)cc2)n1
Reactant: CCOC(=O)COc1cccc(N)c1
Solvent: CCOC(C)=O
Product: CCOC(=O)COc1cccc(NC(=O)c2cccc(-c3ccc(Cl)cc3)n2)c1

Procedure:
Carboxylic acid (149) (50 mg, 0.21 mmol) was coupled to aniline (64) (42 mg, 0.21 mmol) using Method C. During this reaction, partial hydrolysis occurred. The residue was re-dissolved in EtOAc (2 ml) and the organic layer was washed with 1M HCl (2×1 ml), dried (Na2SO4), filtered and the solvent removed in vacuo to give a mixture of acid and ester, which was used without further purification.
Reaction SMILES: [C:1]1([C:7]2[O:8][C:9]([C:30]([F:33])([F:32])[F:31])=[C:10]([C:12]([NH:14][C:15]3[CH:16]=[CH:17][C:18]([N:21]4[CH2:26][CH2:25][CH:24]([C:27](O)=[O:28])[CH2:23][CH2:22]4)=[N:19][CH:20]=3)=[O:13])[N:11]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH3:34][S:35]([NH2:38])(=[O:37])=[O:36].CCN=C=NCCCN(C)C>C(Cl)Cl.CN(C)C1C=CN=CC=1>[CH3:34][S:35]([NH:38][C:27]([CH:24]1[CH2:25][CH2:26][N:21]([C:18]2[CH:17]=[CH:16][C:15]([NH:14][C:12]([C:10]3[N:11]=[C:7]([C:1]4[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=4)[O:8][C:9]=3[C:30]([F:33])([F:31])[F:32])=[O:13])=[CH:20][N:19]=2)[CH2:22][CH2:23]1)=[O:28])(=[O:37])=[O:36]
Reactant: CS(N)(=O)=O
Reactant: O=C(Nc1ccc(N2CCC(C(=O)O)CC2)nc1)c1nc(-c2ccccc2)oc1C(F)(F)F
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Product: CS(=O)(=O)NC(=O)C1CCN(c2ccc(NC(=O)c3nc(-c4ccccc4)oc3C(F)(F)F)cn2)CC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 36.1 %

Procedure:
To a suspension of 5′-[(2-phenyl-5-trifluoromethyl-oxazole-4-carbonyl)-amino]-3,4,5,6-tetrahydro-2H-[1,2′]bipyridinyl-4-carboxylic acid (39.4 mg, 0.085 mmol) in methylene chloride (5 mL) was added methanesulfonamide (8.2 mg, 0.086 mmol). Then 4-dimethylaminopyridine (10.45 mg, 0.085 mmol) and EDCI (16.4 mg, 0.085 mmol) was added. The mixture was stirred at room temperature overnight. Solvents were evaporated and the residue was purified by flash column chromatography using a linear gradient of ethyl acetate containing 1% acetic acid in hexanes (20% to 100% in 15 minutes) to give the desired compound as a pale yellow solid (16.5 mg). 1H-NMR is consistent with the desired structure. LRMS for C23H22F3N5O5S (m/e) calcd 537.13, obsd 538.1 (M+1).
Reaction SMILES: [O:1]=[C:2]1[CH:7]=[CH:6][N:5]([C:8]([O:10][CH3:11])=[O:9])[CH:4]([CH2:12][CH2:13][C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[CH2:3]1>CCOC(C)=O.[Pd]>[O:1]=[C:2]1[CH2:7][CH2:6][N:5]([C:8]([O:10][CH3:11])=[O:9])[CH:4]([CH2:12][CH2:13][C:14]2[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=2)[CH2:3]1
Reactant: COC(=O)N1C=CC(=O)CC1CCc1ccccc1
Agent: [Pd]
Solvent: CCOC(C)=O
Product: COC(=O)N1CCC(=O)CC1CCc1ccccc1
Yield: 101 %

Procedure:
Methyl 4-oxo-2-phenethyl-3,4-dihydropyridine-1(2H)-carboxylate (21.7 g, ca 75 mmol) was hydrogenated over Pd/C (5%) in EtOAc at 5 bar for 20 h. The mixture was filtered through a silica plug and then evaporated to give the product as an oil (19.8 g). 1H NMR (600 MHz, cdcl3) δ 1.69 (m, 1H), 1.80 (m, 1H), 2.26 (m, 2H), 2.41 (m, 1H), 2.47-2.70 (m, 3H), 3.16 (m, 1H), 3.69 (m, 3H), 4.15-4.48 (br m, 2H), 7.14-7.30 (m, 5H). MS 262 m/z (M+H)+.
Reaction SMILES: C([NH:11][CH2:12][CH2:13][CH2:14][C@H:15]([C:32]([NH:34][C@H:35]([C:38]1[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=1)[CH2:36][OH:37])=[O:33])[NH:16][C:17](=[O:31])[CH:18]([C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1)[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)(OCC1C=CC=CC=1)=O.[ClH:44]>[Pd].CO>[ClH:44].[C:25]1([CH:18]([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[C:17]([NH:16][C@@H:15]([C:32]([NH:34][C@H:35]([C:38]2[CH:39]=[CH:40][CH:41]=[CH:42][CH:43]=2)[CH2:36][OH:37])=[O:33])[CH2:14][CH2:13][CH2:12][NH2:11])=[O:31])[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=1
Reactant: O=C(NCCC[C@@H](NC(=O)C(c1ccccc1)c1ccccc1)C(=O)N[C@@H](CO)c1ccccc1)OCc1ccccc1
Agent: [Pd]
Agent: Cl
Solvent: CO
Product: NCCC[C@@H](NC(=O)C(c1ccccc1)c1ccccc1)C(=O)N[C@@H](CO)c1ccccc1

Procedure:
Prepared according to the method described in Example 1(e) above from a batch of (R)-N5 -(Cbz)-N2 -(diphenylacetyl)-(R)-N-(2-hydroxy-1-phenyl-ethyl)ornithine amide (2.5 g; from step (c) above), 10% Pd/C (200 mg), 100 mL of MeOH and 1.0 mL of concentrated HCl, yielding 1.8 g of the sub-title compound as a white foam.
Reaction SMILES: C([O:8][C:9]1[C:17]([C:18](=[O:25])[NH:19][CH2:20][C:21]([F:24])([F:23])[F:22])=[CH:16][C:15]([F:26])=[CH:14][C:10]=1[C:11]([OH:13])=[O:12])C1C=CC=CC=1>C(O)C.[C].[Pd]>[F:26][C:15]1[CH:16]=[C:17]([C:18](=[O:25])[NH:19][CH2:20][C:21]([F:23])([F:24])[F:22])[C:9]([OH:8])=[C:10]([CH:14]=1)[C:11]([OH:13])=[O:12]
Reactant: O=C(O)c1cc(F)cc(C(=O)NCC(F)(F)F)c1OCc1ccccc1
Agent: [Pd]
Solvent: CCO
Product: O=C(O)c1cc(F)cc(C(=O)NCC(F)(F)F)c1O
Reaction time: 1 h

Procedure:
5.2 g (14 mmol) of 2-benzyloxy-5-fluoro-3-(2,2,2-trifluoroethylcarbamoyl)-benzoic acid is dissolved in 30 ml of ethanol. 250 mg of palladium-carbon (10%) is added and is hydrogenated in 1 hour at normal temperature. The catalyst is then filtered off and the filtrate is evaporated to dryness in a vacuum. The residue is chromatographed on silica gel 60 (Merck) with dichloromethane/methanol. 3.03 g (11.34 mmol)=81% of the theoretical yield of the compound is obtained as an amorphous solid.
Reaction SMILES: [CH3:1][C@H:2]1[CH2:7][CH2:6][CH2:5][C@@H:4]([CH3:8])[C:3]1=[N:9]O.C(=O)([O-])[O-:12].[K+].[K+]>C1(C)C(C)=CC=CC=1>[CH3:1][C@H:2]1[CH2:7][CH2:6][CH2:5][C@@H:4]([CH3:8])[NH:9][C:3]1=[O:12]
Reactant: O=C([O-])[O-]
Reactant: C[C@@H]1CCC[C@H](C)C1=NO
Agent: [K+]
Solvent: Cc1ccccc1C
Product: C[C@@H]1CCC[C@H](C)C(=O)N1
Temperature: 100 °C
Reaction time: 10 h

Procedure:
3.1 g of cis-2,6-dimethylcyclohexanoneoxime and 12 g of poly phosphoric acid were added to 40 ml of xylene and stirred at 100° C. for 10 hours. Then the reaction mixture which was cooled to about room temperature was added to ice-water. Potassium carbonate was added to it, and extracted with ethyl acetate three times. The organic layers were joined, washed with saturated aqueous solution of sodium chloride, dried with anhydrous magnesium sulfate, and concentrated. The residue was subjected to silica gel column chromatography to obtain 2.5 g of hexahydro-cis-3,7-dimethylazepin-2-one.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:11]([O:12][CH3:13])=[C:10]([O:14][CH3:15])[CH:9]=[C:8]2[C:4]=1[C:5](=[O:17])C(=O)[NH:7]2.[OH-:18].[Na+].OO.Cl>C(O)(=O)C>[NH2:7][C:8]1[C:4]([C:5]([OH:17])=[O:18])=[C:3]([O:2][CH3:1])[C:11]([O:12][CH3:13])=[C:10]([O:14][CH3:15])[CH:9]=1
Reactant: [OH-]
Reactant: COc1cc2c(c(OC)c1OC)C(=O)C(=O)N2
Agent: Cl
Agent: OO
Agent: [Na+]
Solvent: CC(=O)O
Product: COc1cc(N)c(C(=O)O)c(OC)c1OC
Reaction time: 0.17 h
Yield: 28.2 %

Procedure:
A solution of 4,5,6-tris(methyloxy)-1H-indole-2,3-dione (10 g, 42.2 mmol) in 33% aqueous NaOH (70.5 ml, 582 mmol) at 100° C. was treated with 30% aqueous hydrogen peroxide (12.9 ml, 126 mmol) dropwise over 30 min, at a rate to prevent the foaming mixture from overflowing the flask. After addition was complete, the mixture was stirred for 10 minutes before being cooled and diluted by the addition of ice. The mixture was adjusted to pH 8 by addition of concentrated HCl (70 mL) and then acidified to pH 3 with the addition of glacial acetic acid. The solid that formed was collected by filtration, washed with water, and dried under vacuum to give 6-amino-2,3,4-tris(methyloxy)benzoic acid (2.7 g, 28%) as a tan solid. MS (m/z) 228.0 (M+H+).
Reaction SMILES: C[O:2][C:3](=[O:25])[C:4]1[CH:9]=[CH:8][C:7]([CH:10]([O:16][C:17]2[CH:18]=[N:19][C:20]([Cl:24])=[C:21]([CH3:23])[CH:22]=2)[CH2:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[CH:6][CH:5]=1.[OH-].[Na+]>CO>[Cl:24][C:20]1[N:19]=[CH:18][C:17]([O:16][CH:10]([C:7]2[CH:6]=[CH:5][C:4]([C:3]([OH:25])=[O:2])=[CH:9][CH:8]=2)[CH2:11][C:12]([CH3:13])([CH3:14])[CH3:15])=[CH:22][C:21]=1[CH3:23]
Reactant: COC(=O)c1ccc(C(CC(C)(C)C)Oc2cnc(Cl)c(C)c2)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: Cc1cc(OC(CC(C)(C)C)c2ccc(C(=O)O)cc2)cnc1Cl
Reaction time: 5 h
Yield: 97.9 %

Procedure:
To the solution of 4-[1-(6-chloro-5-methyl-pyridin-3-yloxy)-3,3-dimethyl-butyl]-benzoic acid methyl ester (440 mg) in methanol (30 mL) is added sodium hydroxide (5 N aqueous, 2 mL) and stirred for 5 h. The reaction mixture is concentrated and acidified by 5 N HCl (2 mL), extracted with ethyl acetate. Combined organic layers are washed with water and brine, dried over sodium sulfate. Concentration gives the titled compound (414 mg).
Reaction SMILES: [N:1]([CH2:4][CH:5]1[C:13]2[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=2)[C:7](=[C:14]2[C:22]3[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=3)[NH:16][C:15]2=[O:23])[O:6]1)=[C:2]=[O:3].[OH:24][CH2:25][CH2:26][NH2:27]>C1COCC1>[OH:24][CH2:25][CH2:26][NH:27][C:2]([NH:1][CH2:4][CH:5]1[C:13]2[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=2)[C:7](=[C:14]2[C:22]3[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=3)[NH:16][C:15]2=[O:23])[O:6]1)=[O:3]
Reactant: NCCO
Reactant: O=C=NCC1OC(=C2C(=O)Nc3ccccc32)c2ccccc21
Solvent: C1CCOC1
Product: O=C(NCCO)NCC1OC(=C2C(=O)Nc3ccccc32)c2ccccc21
Temperature: 60 °C
Yield: 20.5 %

Procedure:
A solution of 3-(3-isocyanatomethyl-3H-isobenzofuran-1-ylidene)-1,3-dihydro-indol-2-one (75 mg, 0.24 mmol) and 2-hydroxyethylamine (44.4 μl, 0.74 mmol) in THF (2.0 ml) was stirred at room temperature for 25 minutes and then heated at 60° C. for 5 minutes. The reaction was partitioned between EtOAc and water. The organic layer was washed with water, brine, dried with anhydrous Na2SO4, and rotary evaporated to result in a brown-yellow solid. The brown-yellow solid was chromatographed through silica gel column (CHCl3 to 5% MeOH/CHCl3 gradient) to give 1-(2-hydroxy-ethyl)-3-[3-(2-oxo-1,2-dihydro-indol-3-ylidene)-1,3-dihydro-isobenzofuran-1-ylmethyl]-urea as a yellow solid (18 mg, 20%).
Reaction SMILES: [Br:1][C:2]1[CH:11]=[C:10]2[C:5]([CH:6]=[N:7][NH:8][C:9]2=[O:12])=[CH:4][CH:3]=1.Cl.Cl[CH2:15][C:16]1[CH:17]=[N:18][CH:19]=[CH:20][CH:21]=1>>[Br:1][C:2]1[CH:11]=[C:10]2[C:5]([CH:6]=[N:7][N:8]([CH2:15][C:16]3[CH:17]=[N:18][CH:19]=[CH:20][CH:21]=3)[C:9]2=[O:12])=[CH:4][CH:3]=1
Reactant: ClCc1cccnc1
Reactant: O=c1[nH]ncc2ccc(Br)cc12
Agent: Cl
Product: O=c1c2cc(Br)ccc2cnn1Cc1cccnc1

Procedure:
The titled compound was prepared from 7-bromo-1 (2H)-phthalazinone and 3-chloromethylpyridine hydrochloride in the same manner as in Example 10 (1) a).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[SH:8].C(N(CC)CC)C.[CH3:16][O:17][C:18](=[O:23])[CH2:19][C:20](Cl)=O>C(OCC)C>[CH3:16][O:17][C:18](=[O:23])[CH2:19][C:20]1[S:8][C:3]2[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=2[N:1]=1
Reactant: Nc1ccccc1S
Reactant: COC(=O)CC(=O)Cl
Solvent: CCN(CC)CC
Solvent: CCOCC
Product: COC(=O)Cc1nc2ccccc2s1
Temperature: 25 °C
Reaction time: 2 h
Yield: 82 %

Procedure:
3.2 mL (30 mmol) 2-Amino-thiophenol are dissolved in 100 mL diethylether and treated with 4.17 mL (1 eq.) triethylamine to yield a suspension, to which 3.21 mL (1 eq.) chlorocarbonyl-acetic methyl ester in 10 mL diethylether is added dropwise within 20 min. The resulting suspension is stirred and additional 2 h at room temperature, and the precipitate removed by filtration. The filtrate is evaporated and column chromatographed (silica gel, ethyl acetate/petroleum ether 1:2) to yield the desired product as a yellowish liquid (5.1 g, 82%).
Reaction SMILES: C([N-]C(C)C)(C)C.[Li+].[CH2:9]([N:16]1[CH2:21][CH2:20][N:19]([CH2:22][CH2:23][CH2:24][C:25]([O:27][CH2:28][CH3:29])=[O:26])[CH2:18][CH2:17]1)[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1.CN(P(N(C)C)(N(C)C)=O)C.[I:41][CH2:42][CH2:43][CH2:44][CH2:45]I>O1CCCC1>[CH2:9]([N:16]1[CH2:17][CH2:18][N:19]([CH2:22][CH2:23][CH:24]([CH2:45][CH2:44][CH2:43][CH2:42][I:41])[C:25]([O:27][CH2:28][CH3:29])=[O:26])[CH2:20][CH2:21]1)[C:10]1[CH:11]=[CH:12][CH:13]=[CH:14][CH:15]=1
Reactant: ICCCCI
Reactant: CCOC(=O)CCCN1CCN(Cc2ccccc2)CC1
Agent: CC(C)[N-]C(C)C
Agent: [Li+]
Solvent: CN(C)P(=O)(N(C)C)N(C)C
Solvent: C1CCOC1
Product: CCOC(=O)C(CCCCI)CCN1CCN(Cc2ccccc2)CC1
Temperature: -50 °C
Reaction time: 1 h

Procedure:
To a stirred solution of lithium diisopropylamide (2 M, 32.0 ml, 6.36 mmol) in tetrahydrofuran (420 ml) was added ethyl 4-(4-benzyl-1-piperazinyl)-butanoate (6.47 g, 21.2 mmol) (Preparation 1) at −78° C. and the mixture was stirred for 1 h at the same temperature. To this mixture was added HMPA (19.4 ml) and the resultant mixture was added to a solution of 1,4-diiodobutane (13.2 g, 4.25 mmol) in tetrahydrofuran (22 ml) at −78° C. After 1 h, the temperature was raised to −50° C. and the mixture was stirred for 1 hour. The reaction was quenched by adding AcOH (0.230 ml). After the mixture was basified with aq. saturated NaHCO3, then the mixture was extracted with ethyl acetate. The extract was washed with brine, dried over Na2SO4, filtered and concentrated in vacuo. The residue was purified by column chromatography (SiO2, 200-350 mesh/500 g/hexane:ethyl acetate=2:1) to provide a yellow oil (6.3 g/63%).
Reaction SMILES: [CH:1]1([O:6][C:7]2[C:8]([O:22][CH3:23])=[CH:9][C:10]([CH:20]=[O:21])=[C:11]([CH:19]=2)[C:12]([N:14]([CH2:17][CH3:18])[CH2:15][CH3:16])=[O:13])[CH2:5][CH2:4][CH2:3][CH2:2]1.[CH2:24]([Mg]Br)[CH3:25]>>[CH2:15]([N:14]([CH2:17][CH3:18])[C:12](=[O:13])[C:11]1[CH:19]=[C:7]([O:6][CH:1]2[CH2:2][CH2:3][CH2:4][CH2:5]2)[C:8]([O:22][CH3:23])=[CH:9][C:10]=1[CH:20]([OH:21])[CH2:24][CH3:25])[CH3:16]
Reactant: CC[Mg]Br
Reactant: CCN(CC)C(=O)c1cc(OC2CCCC2)c(OC)cc1C=O
Product: CCC(O)c1cc(OC)c(OC2CCCC2)cc1C(=O)N(CC)CC
Yield: 76 %

Procedure:
Operating analogously to example 31 using 5-cyclopentyloxy-N,N-diethyl-2-formyl-4-methoxy-benzamide, obtained as described in example 4, product B, and ethyl-magnesium bromide the title product was obtained (yield 76%).
Reaction SMILES: [CH:1]1([NH:8][C:9]([NH2:11])=[S:10])[CH2:7][CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.Br[C:13]1([C:17](OCC)=[O:18])[CH2:16][CH2:15][CH2:14]1>C(N(CC)C(C)C)(C)C.C(O)C>[CH:1]1([NH:8][C:9]2[S:10][C:13]3([C:17](=[O:18])[N:11]=2)[CH2:16][CH2:15][CH2:14]3)[CH2:7][CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: CCOC(=O)C1(Br)CCC1
Reactant: NC(=S)NC1CCCCCC1
Solvent: CCO
Solvent: CCN(C(C)C)C(C)C
Product: O=C1N=C(NC2CCCCCC2)SC12CCC2
Temperature: 155 °C
Reaction time: 1.5 h

Procedure:
A mixture of 1-cycloheptylthiourea (0.255 g, 1.48 mmol) and ethyl 1-bromocyclobutanecarboxylate (0.25 mL, 1.48 mmol, Aldrich) in N,N-diisopropylethylamine (0.5 mL) and ethanol (1.0 mL) was heated in a sealed tube in a microwave oven (Emrys Optimizer from Personal Chemistry) at 155° C. for 2 h, then at 170° C. for 1.5 h. After removing the low-boiling solvents in vacuo, the residue was partitioned between EtOAc and water. The organic portion was separated, washed with brine, and conc. in vacuo. The residue was purified by flash column chromatography (0 to 35% of EtOAc in hexanes) to give the title compound as a tan solid. MS m/z: 253.2 (M+H)+