Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([OH:5])(=[O:4])[CH:2]=O.[C:6]([C:9]1[O:10][CH:11]=[CH:12][CH:13]=1)(=[O:8])[CH3:7]>C(#N)C>[O:10]1[CH:11]=[CH:12][CH:13]=[C:9]1[C:6](=[O:8])[CH:7]=[CH:2][C:1]([OH:5])=[O:4]
Reactant: CC(=O)c1ccco1
Reactant: O=CC(=O)O
Solvent: CC#N
Product: O=C(O)C=CC(=O)c1ccco1
Yield: 21.7 %

Procedure:
A mixture of 14.8 g of glyoxylic acid (in 18.5 cc of water) and 22 g of 2-acetylfuran is heated at 125°-135° C. for about 5 hours; the water is removed as it forms via a Dean Stark tube. The mass cyrstallizes over about a 16 hour period and is dissolved in 600 cc of ethyl acetate and extracted into 600 cc of 10% sodium carbonate. The aqueous solution is treated with activated charcoal and a filter aid, and then filtered. It is made strongly acid with 20% HCl and the solid which precipitates is extracted with ethyl acetate. The ethyl acetate is dried over MgSO4 and removed to yield a solid residue which is dissolved in 100 cc hot acetonitrile and allowed to cool for about 16 hours. The solid is filtered to yield 7.2 g of the title compound, melting point 153°-155° C.
Reaction SMILES: C([O:8][CH2:9][CH2:10][CH2:11][C:12]1[N:13]([CH2:29][C:30]2[CH:35]=[CH:34][N:33]=[CH:32][CH:31]=2)[C:14]([S:20][C:21]2[CH:26]=[C:25]([Cl:27])[CH:24]=[C:23]([Cl:28])[CH:22]=2)=[C:15]([CH:17]([CH3:19])[CH3:18])[N:16]=1)C1C=CC=CC=1.Cl.C(=O)([O-])O.[Na+]>>[Cl:27][C:25]1[CH:26]=[C:21]([S:20][C:14]2[N:13]([CH2:29][C:30]3[CH:35]=[CH:34][N:33]=[CH:32][CH:31]=3)[C:12]([CH2:11][CH2:10][CH2:9][OH:8])=[N:16][C:15]=2[CH:17]([CH3:19])[CH3:18])[CH:22]=[C:23]([Cl:28])[CH:24]=1
Reactant: CC(C)c1nc(CCCOCc2ccccc2)n(Cc2ccncc2)c1Sc1cc(Cl)cc(Cl)c1
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Product: CC(C)c1nc(CCCO)n(Cc2ccncc2)c1Sc1cc(Cl)cc(Cl)c1
Temperature: 110 °C
Yield: 76 %

Procedure:
In 50 ml of tetrahydrofuran was dissolved 5.0 g (11.5 mmol.) of imidazole (101e), followed by addition of 5 ml of water and 1.84 g (46 mmol) of sodium hydroxide, and then, 250 mg (0.8 mmol) of n-tetrabutylammonium bromide and 2.3 g (14 mmol) of 4-chloromethylpyridine hydrochloride were further added. The mixture was stirred under heating at 50° C. for 8 hours. After cooling, the reaction mixture was diluted with water and extracted with ethyl acetate. The extract was washed with water, dried over sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (5% methanol-ethyl acetate) to provide 2-(3-benzyloxypropyl)-5-(3,5-dichlorophenylthio)-4-isopropyl-1-(pyridin-4-yl)methyl-1H-imidazole (136c) as oil. To thus-obtained oil (136c) was added 27 ml of concentrated hydrochloric acid and the mixture was heated at 110° C. for 2 hours. After cooling, the mixture was neutralized with sodium hydrogen carbonate and extracted with ethyl acetate. The extract was washed with water, dried over sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (5% methanol-ethyl acetate) and recrystallized from ethyl acetate-n-hexane to provide 3.8 g (yield 76%) of 3-(5-(3,5-dichlorophenylthio)-4-isopropyl-1-(pyridin-4-ylmethyl)-1H-imidazol-2-yl)-propan-1-ol (137c) as crystals. mp 106-107° C.
Reaction SMILES: [OH:1][CH2:2][CH2:3][C:4]1[CH:5]=[C:6]([CH:17]=[CH:18][C:19]=1[O:20][CH3:21])[CH2:7][CH:8]([C:13]([O:15][CH3:16])=[O:14])[C:9]([O:11][CH3:12])=[O:10].[CH3:22][O:23][C:24]1[CH:29]=[CH:28][C:27]([N:30]=[C:31]=[O:32])=[CH:26][CH:25]=1>>[CH3:21][O:20][C:19]1[CH:18]=[CH:17][C:6]([CH2:7][CH:8]([C:9]([O:11][CH3:12])=[O:10])[C:13]([O:15][CH3:16])=[O:14])=[CH:5][C:4]=1[CH2:3][CH2:2][O:1][C:31]([NH:30][C:27]1[CH:28]=[CH:29][C:24]([O:23][CH3:22])=[CH:25][CH:26]=1)=[O:32]
Reactant: COC(=O)C(Cc1ccc(OC)c(CCO)c1)C(=O)OC
Reactant: COc1ccc(N=C=O)cc1
Product: COC(=O)C(Cc1ccc(OC)c(CCOC(=O)Nc2ccc(OC)cc2)c1)C(=O)OC

Procedure:
Using dimethyl 2-[3-(2-hydroxyethyl)-4-methoxybenzyl]malonate and 4-methoxyphenylisocyanate, the title compound was obtained in the same manner as described in Example 192b).
Reaction SMILES: [N:1]12[CH2:8][CH2:7][CH:4]([CH2:5][CH2:6]1)[CH:3]([NH:9][C:10](=[O:27])[C:11]1[CH:16]=[C:15]([Cl:17])[C:14]([NH:18][C:19](=[O:21])[CH3:20])=[CH:13][C:12]=1[O:22][CH2:23][CH:24]1[CH2:26][CH2:25]1)[CH2:2]2.C(O)(=[O:30])C>OO>[N:1]12[CH2:6][CH2:5][CH:4]([CH2:7][CH2:8]1)[CH:3]([NH+:9]([O-:30])[C:10](=[O:27])[C:11]1[CH:16]=[C:15]([Cl:17])[C:14]([NH:18][C:19](=[O:21])[CH3:20])=[CH:13][C:12]=1[O:22][CH2:23][CH:24]1[CH2:25][CH2:26]1)[CH2:2]2
Reactant: CC(=O)O
Reactant: CC(=O)Nc1cc(OCC2CC2)c(C(=O)NC2CN3CCC2CC3)cc1Cl
Agent: OO
Product: CC(=O)Nc1cc(OCC2CC2)c(C(=O)[NH+]([O-])C2CN3CCC2CC3)cc1Cl
Temperature: 80 °C
Reaction time: 15 h

Procedure:
To a solution of N-(1-azabicyclo[2.2.2]oct-3-yl)-2-cyclopropylmethoxy-4-acetamido-5-chlorobenzamide (2.6 g; 0.007 moles) in acetic acid (20 ml), 30% hydrogen peroxide (1.8 ml) was added and the resulting solution was stirred at 80° C. for 15 hours. The solvent was removed in vacuo, the residue was treated with water, alcalinized with sodium hydroxide aqueous solution, saturated with sodium chloride and extracted with methylene chloride. The organic solution was dried (Na2SO4), the solvent removed in vacuo and the residual yellow solid treated with diethyl ether and collected. After washing with acetonitrile and diethyl ether, N-(1-azabicyclo[2.2.2]oct-3-yl)-2-cyclopropylmethoxy-4-acetamido-5-chlorobenzamide N-oxide was obtained as a white solid, which was dried at 50° C. to give 1.4 g; m.p. 234°-236° C. (d).
Reaction SMILES: [CH2:1]([O:8][C:9](=[O:34])[CH2:10][C@@H:11]([NH:26][C:27]([O:29][C:30]([CH3:33])([CH3:32])[CH3:31])=[O:28])[C:12]([NH:14][C@@H:15](CC1C=CC=CC=1)[CH2:16][O:17]C)=[O:13])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.N[C@H:36](CO)[C:37](C)([CH3:39])[CH3:38].F[P-](F)(F)(F)(F)F.N1(O[P+](N(C)C)(N(C)C)N(C)C)C2C=CC=CC=2N=N1>>[CH2:1]([O:8][C:9](=[O:34])[CH2:10][C@@H:11]([NH:26][C:27]([O:29][C:30]([CH3:32])([CH3:33])[CH3:31])=[O:28])[C:12]([NH:14][C@H:15]([CH2:16][OH:17])[C:37]([CH3:39])([CH3:38])[CH3:36])=[O:13])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CC(C)(C)[C@H](N)CO
Reactant: COC[C@H](Cc1ccccc1)NC(=O)[C@@H](CC(=O)OCc1ccccc1)NC(=O)OC(C)(C)C
Agent: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Agent: F[P-](F)(F)(F)(F)F
Product: CC(C)(C)OC(=O)N[C@H](CC(=O)OCc1ccccc1)C(=O)N[C@H](CO)C(C)(C)C
Yield: 90 %

Procedure:
As described in Example 1(f) for the preparation of N-(1(S)-benzyl-2-methoxyethyl)-3(R)-(t-butoxycarbonylamino)succinamic acid benzyl ester, N-t-butoxycarbonyl-D-aspartic acid β-benzyl ester (1.00 g, 3.10 mmol) and L-t-leucinol (400 mg, 3.40 mrnol) were coupled with BOP to afford 1.20 g (90%) of 3(R)-(t-butoxycarbonylamino)-N-(1(S)-hydroxymethyl-2,2-dimethyl-propyl)succinamic acid benzyl ester as a white powder, mp 186-7° C.
Reaction SMILES: [N+:1]([O-:4])(O)=[O:2].[CH3:5][N:6]1[C:12]2[CH:13]=[CH:14][CH:15]=[CH:16][C:11]=2[C:10]([CH3:18])([CH3:17])[CH2:9][CH2:8][C:7]1=[O:19]>C(OC(=O)C)(=O)C.C(O)(=O)C>[CH3:5][N:6]1[C:12]2[CH:13]=[CH:14][C:15]([N+:1]([O-:4])=[O:2])=[CH:16][C:11]=2[C:10]([CH3:17])([CH3:18])[CH2:9][CH2:8][C:7]1=[O:19]
Reactant: CN1C(=O)CCC(C)(C)c2ccccc21
Reactant: O=[N+]([O-])O
Solvent: CC(=O)O
Solvent: CC(=O)OC(C)=O
Product: CN1C(=O)CCC(C)(C)c2cc([N+](=O)[O-])ccc21
Reaction time: 72 h

Procedure:
2.0 ml of 65% nitric acid were cautiously added dropwise to 7.1 ml of acetic anhydride at 0° C. This solution was added to a solution of 3.14 g of 2,3,4,5-tetrahydro-1,5,5-trimethyl-2-oxo-1H-1-benzazepine in 9.0 ml of acetic anhydride and 2.8 ml of glacial acetic acid. The reaction mixture was left to stand at room temperature for 3 days and then poured on ice, washed in succession with water, soda solution and water, dried and evaporated. Recrystallization from ethyl acetate/hexane yielded 3.39 g of 2,3,4,5-tetrahydro-1,5,5-trimethyl-7-nitro-2-oxo-1H-1-benzazepine, 113°-115° C.
Reaction SMILES: [C:1](Cl)(Cl)=[O:2].[CH3:5][C:6]1[CH:11]=[CH:10][C:9]([NH2:12])=[C:8]([NH2:13])[CH:7]=1.[OH-].[Na+]>O>[CH3:5][C:6]1[CH:11]=[CH:10][C:9]2=[N:12][C:1](=[O:2])[N:13]=[C:8]2[CH:7]=1
Reactant: Cc1ccc(N)c(N)c1
Reactant: O=C(Cl)Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: Cc1ccc2c(c1)=NC(=O)N=2
Yield: 98.5 %

Procedure:
53 g (0.54 mol) of phosgene are passed into 61 g (0.5 mol) of 4-methyl-1,2-diaminobenzene in 450 ml of water and the pH is simultaneously kept constant at 7.2 with 86 g (1.08 mol) of 50% strength aqueous sodium hydroxide solution. After cooling, 72 g of precipitated 5-methyl-benzimidazol-2-one of melting point 290° C. are obtained, which corresponds to a yield of 97% of theory.
Reaction SMILES: [ClH:1].[Cl:2][C:3]1[CH:16]=[CH:15][C:6]([C:7]([CH:9]2[CH2:14][CH2:13][NH:12][CH2:11][CH2:10]2)=[O:8])=[CH:5][CH:4]=1.[C:17](=[O:20])(O)[O-].[Na+]>C(O)CCC>[ClH:2].[Cl:2][C:3]1[CH:4]=[CH:5][C:6]([C:7]([CH:9]2[CH2:14][CH2:13][N:12]([CH2:7][CH2:9][CH2:10][C:17](=[O:20])[C:3]3[CH:16]=[CH:15][C:6]([Cl:1])=[CH:5][CH:4]=3)[CH2:11][CH2:10]2)=[O:8])=[CH:15][CH:16]=1
Reactant: O=C(c1ccc(Cl)cc1)C1CCNCC1
Reactant: O=C([O-])O
Agent: Cl
Agent: [Na+]
Solvent: CCCCO
Product: O=C(CCCN1CCC(C(=O)c2ccc(Cl)cc2)CC1)c1ccc(Cl)cc1
Reaction time: 0.5 h

Procedure:
A mixture of 4-(p-chlorobenzoyl)piperidine hydrochloride (10.5 g.; 0.04 mole), 2-(p-chlorophenyl)-2-(ω-chloropropyl)-1,3-dioxolane (10.5 g.; 0.04 mole) and sodium bicarbonate (13.5 g.; 0.16 mole) of n-butanol was refluxed for twenty hours. The hot mixture was filtered, the filtrate was concentrated at reduced pressure and the residual material was dissolved in a mixture of ethanol and 6N hydrochloric acid. The mixture was stirred 0.5 hour and hydrochloride salt which separated was collected by filtration. The salt was recrystallized from isopropanol-methanol (charcoal) to give 9.2 g. (57%) of the hydrochloride salt which melted at 253°-256° C.
Reaction SMILES: [C:1]([O:4][C:5]1[CH:14]=[C:13]([O:15][C:16](=[O:18])[CH3:17])[CH:12]=[C:11]2[C:6]=1[C:7](=[O:28])[C:8]([C:20]1[CH:25]=[CH:24][C:23]([O:26][CH3:27])=[CH:22][CH:21]=1)=[C:9]([CH3:19])[O:10]2)(=[O:3])[CH3:2].[Br:29]N1C(=O)CCC1=O>C(Cl)(Cl)(Cl)Cl.C(OOC(=O)C1C=CC=CC=1)(=O)C1C=CC=CC=1>[C:1]([O:4][C:5]1[CH:14]=[C:13]([O:15][C:16](=[O:18])[CH3:17])[CH:12]=[C:11]2[C:6]=1[C:7](=[O:28])[C:8]([C:20]1[CH:21]=[CH:22][C:23]([O:26][CH3:27])=[CH:24][CH:25]=1)=[C:9]([CH2:19][Br:29])[O:10]2)(=[O:3])[CH3:2]
Reactant: COc1ccc(-c2c(C)oc3cc(OC(C)=O)cc(OC(C)=O)c3c2=O)cc1
Reactant: O=C1CCC(=O)N1Br
Agent: O=C(OOC(=O)c1ccccc1)c1ccccc1
Solvent: ClC(Cl)(Cl)Cl
Product: COc1ccc(-c2c(CBr)oc3cc(OC(C)=O)cc(OC(C)=O)c3c2=O)cc1
Yield: 111.9 %

Procedure:
A solution of 5,7-diacetoxy-4'-methoxy-2-methylisoflavone (2 g), benzoyl peroxide (0.1 g) and N-bromosuccinimide (1.4 g) in 120 ml carbon tetrachloride was heated under reflux for 20 hours, the solvent was distilled off under reduced pressure, and the solid residue was treated with water. The crude product collected by filtration was recrystallized from methanol, affording 2.7 g of 5,7-diacetoxy-4'-methoxy-2-bromomethylisoflavone.
Reaction SMILES: [N+:1]([C:4]1[NH:8][N:7]=[C:6]([C:9]2[O:13][N:12]=[C:11]([C:14]3[CH:19]=[CH:18][C:17]([O:20][C:21]([F:24])([F:23])[F:22])=[CH:16][CH:15]=3)[N:10]=2)[CH:5]=1)([O-])=O>C(OCC)(=O)C.[Pd]>[NH2:1][C:4]1[NH:8][N:7]=[C:6]([C:9]2[O:13][N:12]=[C:11]([C:14]3[CH:15]=[CH:16][C:17]([O:20][C:21]([F:22])([F:24])[F:23])=[CH:18][CH:19]=3)[N:10]=2)[CH:5]=1
Reactant: O=[N+]([O-])c1cc(-c2nc(-c3ccc(OC(F)(F)F)cc3)no2)n[nH]1
Agent: [Pd]
Solvent: CCOC(C)=O
Product: Nc1cc(-c2nc(-c3ccc(OC(F)(F)F)cc3)no2)n[nH]1
Yield: 103.5 %

Procedure:
A solution of 5-(5-nitro-1H-pyrazol-3-yl)-3-[4-(trifluoromethoxy)phenyl]-1,2,4-oxadiazole (Intermediate F, 342 mg, 1.0 mmol) in ethyl acetate (43 mL) was subjected to hydrogenation using an H-Cube flow reactor (Thales Nano, Budapest, Hungary) (10% Pd/C, 30×4 mm, 1 bar H2, 25° C., 1 mL/min). After evaporation of the solvent, the crude product was purified by MPLC (silica, cyclohexane/ethyl acetate 1:1) affording the title compound as a solid (322 mg, 93%): 1H NMR (400 MHz, DMSO-d6) δ 12.49 (s, 1H), 8.19 (d, 2H), 7.49 (d, 2H), 5.93 (s, 1H), 5.44 (s, 2H); ES-MS m/z 312 (MH)+; HPLC RT (Method E) 1.76 min.
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[C:9]1[CH:14]=[CH:13][C:12]([CH:15]([OH:26])[C:16]([O:18]CC2C=CC=CC=2)=[O:17])=[CH:11][CH:10]=1)#[N:2].Cl.[H][H]>[Pd].[C].C(O)(=O)C>[C:1]([C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[C:9]1[CH:14]=[CH:13][C:12]([CH:15]([OH:26])[C:16]([OH:18])=[O:17])=[CH:11][CH:10]=1)#[N:2]
Reactant: [H][H]
Reactant: N#Cc1ccccc1-c1ccc(C(O)C(=O)OCc2ccccc2)cc1
Agent: [Pd]
Agent: Cl
Solvent: CC(=O)O
Product: N#Cc1ccccc1-c1ccc(C(O)C(=O)O)cc1

Procedure:
A solution of 0.01 moles of benzyl 2'-cyano-4-biphenylylglycolate dissolved in 100 ml. of acetic acid and containing 0.01 mole of hydrogen chloride is shaken with hydrogen over a 5% Pd carbon catalyst until 0.01 moles of hydrogen is absorbed. The catalyst is then filtered and the solution is evaporated to dryness and crystallized to obtain 2'-cyano-4-biphenylylglycolic acid.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([Cl:8])=[CH:4][C:3]=1[NH:9][CH:10]1[CH2:15][CH2:14][N:13]([CH2:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[CH2:12][CH2:11]1.[C:23](N1C=CN=C1)(N1C=CN=C1)=[O:24]>C(#N)C>[CH2:16]([N:13]1[CH2:12][CH2:11][CH:10]([N:9]2[C:3]3[CH:4]=[C:5]([Cl:8])[CH:6]=[CH:7][C:2]=3[NH:1][C:23]2=[O:24])[CH2:15][CH2:14]1)[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1
Reactant: Nc1ccc(Cl)cc1NC1CCN(Cc2ccccc2)CC1
Reactant: O=C(n1ccnc1)n1ccnc1
Solvent: CC#N
Product: O=c1[nH]c2ccc(Cl)cc2n1C1CCN(Cc2ccccc2)CC1
Yield: 64.7 %

Procedure:
A mixture of 12.71 g of the compound obtained in step B) and 8.9 g of 1,1'-carbonyldiimidazole in 130 ml of acetonitrile is refluxed for 3 hours. The solvent is evaporated off under vacuum, the residue is taken up with water, extracted with DCM, washed with a saturated solution of NaHCO3 and with water and dried over Na2SO4 and the solvent is evaporated off under vacuum. The residue is chromatographed on silica using a DCM/MeOH mixture (92/8; v/v) as the eluent. 8.9 g of the expected product are obtained after recrystallization from absolute ethanol. M.p.=204°-206° C.
Reaction SMILES: C([O:4][C:5]1[CH:6]=[C:7]([CH3:11])[CH:8]=[CH:9][CH:10]=1)(=O)C.[Al+3].[Cl-].[Cl-].[Cl-].Cl.[CH3:17][CH2:18][O:19]CC>>[CH3:11][C:7]1[CH:8]=[CH:9][C:10]([C:18]([CH3:17])=[O:19])=[C:5]([OH:4])[CH:6]=1
Reactant: CCOCC
Reactant: CC(=O)Oc1cccc(C)c1
Agent: Cl
Agent: [Al+3]
Agent: [Cl-]
Product: CC(=O)c1ccc(C)cc1O
Temperature: 165 °C

Procedure:
To 50 g (0.33 mol) of 3-acetoxytoluene from Step 1 was added AlCl3 (60 g, 0.45 mol) and the resulting mixture was heated at 165° C. for 20 min., then cooled at 0° C. and HCl 1N was carefully added followed by Et2O. The aqueous phase was extracted 5× with Et2O and the combined organic phase wash washed with brine, dried over MgSO4 and evaporated. The residue was distilled under vacuum to give 42.2 (84%.) of the title compound.
Reaction SMILES: [C:1](N1[C@@H](C2C=CC=CC=2)COC1=O)(=O)/C=C/CC.[C:19]([CH2:21][C@@H:22]1[N:26]([C:27]2[CH:32]=[CH:31][C:30]([OH:33])=[CH:29][CH:28]=2)[N:25]=[C:24]([C:34]2[CH:41]=[CH:40][C:37]([C:38]#[N:39])=[CH:36][CH:35]=2)[C@H:23]1[CH3:42])#[N:20]>>[C:19]([CH2:21][C@@H:22]1[N:26]([C:27]2[CH:28]=[CH:29][C:30]([OH:33])=[CH:31][CH:32]=2)[N:25]=[C:24]([C:34]2[CH:35]=[CH:36][C:37]([C:38]#[N:39])=[CH:40][CH:41]=2)[C@H:23]1[CH2:42][CH3:1])#[N:20]
Reactant: C[C@@H]1C(c2ccc(C#N)cc2)=NN(c2ccc(O)cc2)[C@H]1CC#N
Reactant: CC/C=C/C(=O)N1C(=O)OC[C@@H]1c1ccccc1
Product: CC[C@@H]1C(c2ccc(C#N)cc2)=NN(c2ccc(O)cc2)[C@H]1CC#N

Procedure:
4-((4S,5S)-5-(Cyanomethyl)-4-ethyl-1-(4-hydroxyphenyl)-4,5-dihydro-1H-pyrazol-3-yl)benzonitrile was prepared from (S,E)-3-(pent-2-enoyl)-4-phenyloxazolidin-2-one following the procedure for the preparation of 4-((4S,5S)-5-(cyanomethyl)-1-(4-hydroxyphenyl)-4-methyl-4,5-dihydro-1H-pyrazol-3-yl)benzonitrile (91G): LC-MS [M+H] 331.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[C:9]1[CH:14]=[CH:13][C:12]([C:15]([O:17]C)=[O:16])=[CH:11][C:10]=1[CH3:19].[OH-].[Na+]>CCO.O>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[C:9]1[CH:14]=[CH:13][C:12]([C:15]([OH:17])=[O:16])=[CH:11][C:10]=1[CH3:19]
Reactant: COC(=O)c1ccc(-c2ccccc2OC)c(C)c1
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: COc1ccccc1-c1ccc(C(=O)O)cc1C
Temperature: 60 °C
Reaction time: 1 h

Procedure:
To solution of methyl 2′-methoxy-2-methylbiphenyl-4-carboxylate, prepared in Step 1 (2 g; 7.80 mmol; 1 eq.) in EtOH (60 mL), was added at RT an aqueous solution of sodium hydroxide (4.68 mL; 5 M; 23.41 mmol; 3 eq.). The reaction mixture was stirred at 60° C. for one hour. The reaction mixture was concentrated under vacuum to give an orange solid. It was taken up in water (400 mL) and the aqueous phase was washed twice with EtOAc (200 mL). Aqueous phase was acidified with concentrated HCl (2 mL) to pH 2. Then it was concentrated under vacuum until a precipitate was formed. (⅕ of volume). The suspension was filtered off and dried under vacuum to afford the title compound as a brown solid. 1H NMR: (DMSO-d6, 300 MHz) δ 12.89 (s, 1H), 7.86 (s, 1H), 7.82-7.79 (dd, J=7.99 Hz, J=1.23 Hz, 1H), 7.46-7.40 (m, 1H), 7.26-7.23 (d, J=7.68 Hz, 1H), 7.16-7.04 (m, 3H), 3.75 (s, 3H), 2.13 (s, 3H). LC/MS (Method A): 240.9 (M−H)−. HPLC (Method A) Rt 4.05 min (Purity: 98.5%).
Reaction SMILES: [C@H:1]1([NH:11][C:12]2[O:13][CH2:14][C:15]3[CH:21]=[C:20]([NH2:22])[CH:19]=[CH:18][C:16]=3[N:17]=2)[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH2:4][CH2:3][CH2:2]1.[CH3:23][N:24]1[CH2:29][CH2:28][N:27]([S:30](Cl)(=[O:32])=[O:31])[CH2:26][CH2:25]1>>[C@H:1]1([NH:11][C:12]2[O:13][CH2:14][C:15]3[CH:21]=[C:20]([NH:22][S:30]([N:27]4[CH2:28][CH2:29][N:24]([CH3:23])[CH2:25][CH2:26]4)(=[O:32])=[O:31])[CH:19]=[CH:18][C:16]=3[N:17]=2)[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH2:4][CH2:3][CH2:2]1
Reactant: Nc1ccc2c(c1)COC(N[C@@H]1CCCc3ccccc31)=N2
Reactant: CN1CCN(S(=O)(=O)Cl)CC1
Product: CN1CCN(S(=O)(=O)Nc2ccc3c(c2)COC(N[C@@H]2CCCc4ccccc42)=N3)CC1
Yield: 60.5 %

Procedure:
Prepared from (R)-N2-(1,2,3,4-tetrahydro-naphthalen-1-yl)-4H-benzo[d][1,3]oxazine-2,6-diamine (Example 33) (100 mg, 0.341 mmol) and 4-methyl-piperazine-1-sulfonyl chloride (CAS 1688-95-5) (74 mg, 0.375 mmol) according to the procedure described for Example 27. Obtained the title compound as a light brown oil (94 mg, 61%), MS (ISP) m/e=456.3 [(M+H)+].
Reaction SMILES: I[C:2]1[CH:14]=[CH:13][C:5]([C:6]([O:8][C:9]([CH3:12])([CH3:11])[CH3:10])=[O:7])=[CH:4][CH:3]=1.[CH2:15]([OH:19])[CH2:16][C:17]#[CH:18]>C(N(CC)CC)C.ClCCl.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.Cl[Pd]Cl.[Cu]I>[OH:19][CH2:15][CH2:16][C:17]#[C:18][C:2]1[CH:14]=[CH:13][C:5]([C:6]([O:8][C:9]([CH3:12])([CH3:11])[CH3:10])=[O:7])=[CH:4][CH:3]=1
Reactant: CC(C)(C)OC(=O)c1ccc(I)cc1
Reactant: C#CCCO
Agent: Cl[Pd]Cl
Agent: [Cu]I
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(C)(C)OC(=O)c1ccc(C#CCCO)cc1
Temperature: 25 °C
Reaction time: 18 h
Yield: 145.8 %

Procedure:
A mixture of 1,1-dimethylethyl 4-iodobenzoate (1.1 g, 3.62 mmol, e.g. which can be preparable e.g. according to E. C. Taylor, J. Org. Chem., 1995, 60(24), 7947), 3-butyn-1-ol (0.36 ml, 4.70 mmol, 1.3 equivalents), bis(triphenylphosphine)palladium(II)dichloride [(PPh3)2PdCl2] (0.13 g, 018 mmol, 5 mol %) and copper(I)iodide (0.014 g, 0.07 mmol, 2 mol %) in triethylamine (5 ml) was stirred at room temperature for 18 hours. The mixture was diluted with dichloromethane (50 ml) and washed with water (50 ml). The organic phase was collected by passing through a hydrophobic frit and evaporated to give a dark brown oil (1.3 g). This was purified by flash chromatography on silica gel (100 g silica cartridge, FlashMaster II), eluting with a gradient of 0 to 100% ethyl acetate in cyclohexane over 20 minutes. Fractions containing product (obtained from 4:1 cyclohexane:ethyl acetate eluant) were pooled and evaporated to dryness to give the title compound as a brown gummy oil (0.9 g). 1H NMR (400 MHz, chloroform-d) δ (delta) ppm 1.60 (9H, s), 1.85 (1H, t, J=6.27 Hz), 2.73 (2H, t, J=6.27 Hz), 3.85 (2H, q, J=6.27 Hz), 7.45 (2H, d, J=8.53 Hz), 7.92 (2H, d, J=8.53 Hz).
Reaction SMILES: [NH2:1][C:2]1[CH:6]=[CH:5][S:4][C:3]=1[C:7]([O:9][CH3:10])=[O:8].[OH-].[K+].ClC(OC(Cl)(Cl)Cl)=[O:15]>O>[NH:1]1[C:2]2[CH:6]=[CH:5][S:4][C:3]=2[C:7](=[O:8])[O:9][C:10]1=[O:15]
Reactant: O=C(Cl)OC(Cl)(Cl)Cl
Reactant: COC(=O)c1sccc1N
Agent: [K+]
Agent: [OH-]
Solvent: O
Product: O=c1[nH]c2ccsc2c(=O)o1
Temperature: 90 °C
Reaction time: 4 h
Yield: 84.2 %

Procedure:
Methyl 3-aminothiophene-2-carboxylate (31.0 g, 0.20 mol) was added to a solution of potassium hydroxide (22.68 g, 0.40 mol) in 1 L water. The solution was heated at 90° C. for 2 hours. The solution was then cooled to 0° C. and trichloromethyl chloroformate (35.7 mL, 0.30 mol) was added slowly, maintaining the temperature between 0° C. and 10° C. The solution was stirred at 0° C. for 4 hours, and then allowed to warm up gradually to room temperature and stirred for another 3 hours. The precipitated solid product was collected by vacuum filtration to give 28.5 g (85% yield) 1H-thieno[3,2-d][1,3]oxazine-2,4-dione. 1H-NMR (DMSO-d6) δ 6.94 (d, J=5.0 Hz, 1H), 8.24 (d, J=5.0 Hz, 1H), 12.26 (b, 1H) ppm; EIMS m/z 170 (M+1).
Reaction SMILES: [N:1]1([C:5]([C:7]2[CH:8]=[C:9]([Cl:37])[C:10]([O:13][C:14]3[CH:15]=[C:16]([C:26]4[NH:30][C:29]([C:31]([NH:33][CH2:34][CH2:35]Cl)=[O:32])=[CH:28][CH:27]=4)[CH:17]=[C:18]([O:20][C@@H:21]([CH3:25])[CH2:22][O:23][CH3:24])[CH:19]=3)=[N:11][CH:12]=2)=[O:6])[CH2:4][CH2:3][CH2:2]1.[H-].[Na+].[Cl-].[NH4+]>O1CCCC1>[N:1]1([C:5]([C:7]2[CH:8]=[C:9]([Cl:37])[C:10]([O:13][C:14]3[CH:19]=[C:18]([O:20][C@@H:21]([CH3:25])[CH2:22][O:23][CH3:24])[CH:17]=[C:16]([C:26]4[NH:30][C:29]([C:31]5[O:32][CH2:35][CH2:34][N:33]=5)=[CH:28][CH:27]=4)[CH:15]=3)=[N:11][CH:12]=2)=[O:6])[CH2:2][CH2:3][CH2:4]1
Reactant: COC[C@H](C)Oc1cc(Oc2ncc(C(=O)N3CCC3)cc2Cl)cc(-c2ccc(C(=O)NCCCl)[nH]2)c1
Agent: [Cl-]
Agent: [H-]
Agent: [NH4+]
Solvent: C1CCOC1
Product: COC[C@H](C)Oc1cc(Oc2ncc(C(=O)N3CCC3)cc2Cl)cc(-c2ccc(C3=NCCO3)[nH]2)c1
Temperature: 25 °C
Reaction time: 7.5 h
Yield: 61.2 %

Procedure:
5-(3-{[5-(Azetidin-1-ylcarbonyl)-3-chloropyridin-2-yl]oxy}-5-[(1S)-2-methoxy-1-methylethoxy]phenyl)-N-(2-chloroethyl)-1H-pyrrole-2-carboxamide (210 mg, 0.384 mmol) synthesized in Example (73a) was dissolved in tetrahydrofuran (10.0 mL), and sodium hydride (60%, 80 mg, 2.00 mmol) was added, followed by stirring at room temperature for 7.5 hours under nitrogen atmosphere. To the reaction solution, a saturated aqueous ammonium chloride solution (30 mL) was added, and extraction was carried out with dichloromethane (30 mL). The organic layer was washed with saturated brine, and subsequently dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure, and the resulting residue was purified using silica gel column chromatography (elution solvent: ethyl acetate) to afford the desired compound (120 mg, yield 62%) as a white solid.
Reaction SMILES: Cl.O.[C:3]([O:8][C:9]1[CH:14]=[C:13]([CH:15]([CH3:17])[CH3:16])[CH:12]=[CH:11][C:10]=1[C:18]1([NH:32][C:33](=[O:37])[CH2:34][CH2:35][CH3:36])[C:26](=[O:27])[C:25]2[C:20](=[CH:21][CH:22]=[CH:23][C:24]=2[N+:28]([O-])=O)[C:19]1=[O:31])(=[O:7])[CH2:4][CH2:5][CH3:6]>C(O)C.[Fe]>[C:3]([O:8][C:9]1[CH:14]=[C:13]([CH:15]([CH3:16])[CH3:17])[CH:12]=[CH:11][C:10]=1[C:18]1([NH:32][C:33](=[O:37])[CH2:34][CH2:35][CH3:36])[C:26](=[O:27])[C:25]2[C:20](=[CH:21][CH:22]=[CH:23][C:24]=2[NH2:28])[C:19]1=[O:31])(=[O:7])[CH2:4][CH2:5][CH3:6]
Reactant: CCCC(=O)NC1(c2ccc(C(C)C)cc2OC(=O)CCC)C(=O)c2cccc([N+](=O)[O-])c2C1=O
Agent: [Fe]
Agent: Cl
Solvent: CCO
Solvent: O
Product: CCCC(=O)NC1(c2ccc(C(C)C)cc2OC(=O)CCC)C(=O)c2cccc(N)c2C1=O
Yield: 86.3 %

Procedure:
Iron powder (0.07 g, 1.3 mmol), conc. HCl (0.05 ml), and water (1 ml) were added in that order to a solution of 2-(2-butyramido-4-nitro-1,3-dioxo-2,3-dihydro-1H-inden-2-yl)-5-isopropylphenyl butyrate (90 mg, 0.18 mmol) in ethanol (5 ml). The reaction mixture was heated for 1 hrs under reflux. After filtration at high temperature, the filtrate was concentrated in a vacuum and purified using column chromatography (ethylacetate:hexane=1:4 to 1:2) to afford the title compound (70 mg, 83%).