Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:8][C@@H:9]1[C@@H:16]([OH:17])[C@H:15]([O:18][CH2:19][C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[CH2:14][O:13][C@H:10]1[O:11][CH3:12])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[H-].[Na+].[CH3:28]I>CN(C=O)C>[CH2:1]([O:8][C@@H:9]1[C@@H:16]([O:17][CH3:28])[C@H:15]([O:18][CH2:19][C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[CH2:14][O:13][C@H:10]1[O:11][CH3:12])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CO[C@@H]1OC[C@@H](OCc2ccccc2)[C@H](O)[C@H]1OCc1ccccc1
Reactant: CI
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CO[C@@H]1OC[C@@H](OCc2ccccc2)[C@H](OC)[C@H]1OCc1ccccc1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 99.9 %

Procedure:
To a solution of methyl 2,4-di-O-benzyl-b-D-xylopyranoside (38 g, 0.11 mole) in dry DMF (500 ml) was added 60% NaH in oil (4.4 g, 0.11 mole). After stirring at 0° C. for 30 min, methyl iodide (17 g, 0.12 mole) was added and the reaction mixture was allowed to warm to room temperature. The solution was continued to stir for 1 hr and evaporated to dryness under reduced pressure. The oily residue was partitioned between ether (300 ml) and water (300 ml). The ether layer was dried over anhydrous sodium sulfate, evaporated to dryness under reduced pressure to give methyl 2,4-di-O-benzyl-3-O-methyl-b-D-xylopyranoside (39.4 g, 100% yield) as colorless oil; EI-MS: m/z 358 (M+), 254 (M+ -Bn); 1H-NMR (CDCl3)d: 3.18 (1H,dd,J=10 & 12 Hz), 3.24 (1H,dd, J=7.5 & 9 Hz), 3.29 (1H,t,J=9 Hz), 3.50 (1H,m), 3.52 (3H, s), 3.65 (3H,s), 3.9 (1H,dd,J=5.9 & 12 Hz), 4.21 (1H,d,J=7.5 Hz), 4.62 (1H,d,J=12 Hz), 4.69 (1H,d,J=11 Hz), 4.75 (1H,d,J=12 Hz), 4.85 (1H,d,11 Hz), 7.35 (10 br.s).
Reaction SMILES: C[O:2][C:3]1[CH:4]=[C:5]([CH3:13])[CH:6]=[C:7]([O:11][CH3:12])[C:8]=1[O:9][CH3:10].Cl[C:15]([CH2:17][CH2:18][CH2:19][CH2:20][C:21]([O:23]CC)=[O:22])=[O:16]>>[OH:2][C:3]1[C:8]([O:9][CH3:10])=[C:7]([O:11][CH3:12])[CH:6]=[C:5]([CH3:13])[C:4]=1[C:15]([CH2:17][CH2:18][CH2:19][CH2:20][C:21]([OH:23])=[O:22])=[O:16]
Reactant: CCOC(=O)CCCCC(=O)Cl
Reactant: COc1cc(C)cc(OC)c1OC
Product: COc1cc(C)c(C(=O)CCCCC(=O)O)c(O)c1OC

Procedure:
3,4,5-Trimethoxytoluene(formula VII wherein R=H3CO, X=H, Y=H3CO)(2.09 parts) and ethyl 5-chloroformylpentanoate (2.66 parts) were treated in the same manner as Example 4. The procedure provided 5-(2'-hydroxy-3', 4'-dimethoxy-6'methylbenzoyl)pentanoic acid (formula II-1 wherein R=H3CO, X=H, Y=OH, n=4, in the free form)(1.97 part) as pale-brown needles melting at 111°-112° C.
Reaction SMILES: [Li+].CC([N-]C(C)C)C.[Br:9][C:10]1[CH:11]=[N:12][CH:13]=[C:14]([Br:17])[C:15]=1[CH3:16].Br[CH2:19][C:20]([O:22][CH2:23][CH3:24])=[O:21].CC(O)=O>C1COCC1>[Br:9][C:10]1[CH:11]=[N:12][CH:13]=[C:14]([Br:17])[C:15]=1[CH2:16][CH2:19][C:20]([O:22][CH2:23][CH3:24])=[O:21]
Reactant: Cc1c(Br)cncc1Br
Reactant: CCOC(=O)CBr
Agent: CC(C)[N-]C(C)C
Agent: [Li+]
Solvent: C1CCOC1
Solvent: CC(=O)O
Product: CCOC(=O)CCc1c(Br)cncc1Br
Temperature: -78 °C
Reaction time: 1.5 h
Yield: 31.8 %

Procedure:
To a solution of LDA (0.308 mol) [generated from N,N-diisopropylamine (31.2 g, 0.308 mol) and n-BuLi (123 mL, 0.308 mol, 2.5M in hexane) in 800 mL THF] was added slowly a solution of 3,5-dibromo-4-methylpyridine (70 g, 0.28 mol) in THF (300 mL) while the inner temperature was maintained below −70° C. After the addition, the resulting mixture was stirred for another 30 min at −78° C. before ethyl bromoacetate (116.9 g, 0.7 mol) was slowly added and the reaction mixture was stirred at −78° C. for another 1.5 h. 10% aq. AcOH was added (resulting pH=4-5), and the reaction was allowed to warm up to room temperature. After evaporation of solvent, the residue was poured into sat. aq. NaHCO3 solution, and was extracted with EtOAc (1 L×3). The combined organic layers were washed with brine and dried over Na2SO4, filtered and concentrated in vacuo to give a crude product which was purified by column chromatography (n-pentane:EtOAc=15:1˜5:1) to afford the title compound (30 g, 32%) as a gray solid. MS: 337.7 (M+H+, 2 Br).
Reaction SMILES: [Li]CCCC.[CH3:6][N:7]1[C:11]([CH3:12])=[CH:10][CH:9]=[N:8]1.[CH3:13][C:14]1([CH3:21])[CH2:19][CH2:18][CH2:17][C:16](=[O:20])[CH2:15]1>O1CCCC1.CCOCC>[CH3:13][C:14]1([CH3:21])[CH2:19][CH2:18][CH2:17][C:16]([CH2:6][N:7]2[C:11]([CH3:12])=[CH:10][CH:9]=[N:8]2)([OH:20])[CH2:15]1
Reactant: Cc1ccnn1C
Reactant: CC1(C)CCCC(=O)C1
Agent: [Li]CCCC
Solvent: CCOCC
Solvent: C1CCOC1
Product: Cc1ccnn1CC1(O)CCCC(C)(C)C1
Temperature: 0 °C
Reaction time: 1 h

Procedure:
To a cold (−78° C.) solution of nBuLi (12.48 mL) in tetrahydrofuran (40 mL) was added a solution of 1,5-dimethyl-1H-pyrazole (3.0 g) in tetrahydrofuran (3 mL) dropwise. After stirring for 1 hour, a solution of 3,3-dimethylcyclohexanone (3.94 g) in tetrahydrofuran (3 mL) was added dropwise, and the reaction was allowed to warm to 0° C. After stirring for 1 hour, the reaction mixture was diluted with ether (100 mL), washed with water (50 mL) and brine (50 mL), dried over magnesium sulfate, filtered, and concentrated. Purification of the residue by silica gel chromatography, eluting with a gradient of 3% to 25% ethyl acetate in hexanes, gave the title compound.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4](/[CH:8]=[CH:9]/[C:10]([OH:12])=[O:11])[CH:5]=[CH:6][CH:7]=1.S(=O)(=O)(O)O.O.[CH3:19]O>>[OH:1][C:2]1[CH:3]=[C:4](/[CH:8]=[CH:9]/[C:10]([O:12][CH3:19])=[O:11])[CH:5]=[CH:6][CH:7]=1
Reactant: O=C(O)/C=C/c1cccc(O)c1
Reactant: CO
Agent: O=S(=O)(O)O
Solvent: O
Product: COC(=O)/C=C/c1cccc(O)c1
Temperature: 70 °C
Reaction time: 15 h

Procedure:
To a solution of (E)-3-(3-hydroxyphenyl)acrylic acid (15.0 g) in methanol (100 mL) was added sulfuric acid (2.0 mL), and the mixture was stirred at 70° C. for 15 hr. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The extract was washed with saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure to give the title compound (15.8 g) as white crystals. This compound was used for the next step without further purification.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:22])[C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([S:10][C:11]2[C:19]3[C:14](=[CH:15][C:16](Br)=[CH:17][CH:18]=3)[NH:13][C:12]=2[CH3:21])[CH:5]=1.[CH3:23][S:24]([O-:26])=[O:25].[Na+]>CN1C(=O)CCC1.[Cu]I>[CH3:1][O:2][C:3](=[O:22])[C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([S:10][C:11]2[C:19]3[C:14](=[CH:15][C:16]([S:24]([CH3:23])(=[O:26])=[O:25])=[CH:17][CH:18]=3)[NH:13][C:12]=2[CH3:21])[CH:5]=1
Reactant: COC(=O)c1cccc(Sc2c(C)[nH]c3cc(Br)ccc23)c1
Reactant: CS(=O)[O-]
Agent: [Cu]I
Agent: [Na+]
Solvent: CN1CCCC1=O
Product: COC(=O)c1cccc(Sc2c(C)[nH]c3cc(S(C)(=O)=O)ccc23)c1
Temperature: 140 °C
Reaction time: 8 h

Procedure:
3-(6-Bromo-2-methyl-1H-indol-3-ylsulfanyl)-benzoic acid methyl ester (0.113 g, 0.3 mmol), sodium methanesulfinate (0.138 g, 1.35 mmol), and copper(I) iodide (0.257 g, 1.35 mmol) were combined in NMP (3 mL) in a sealed reaction vessel and stirred at 140° C. for overnight. The resulting mixture was cooled to room temperature, and subjected to standard aqueous workup. The crude residue was purified by silica gel chromatography (10-100% EtOAc in hexanes) to afford the title compound.
Reaction SMILES: [CH2:1]([NH:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH3:25])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH3:12].[OH:26]O>C(O)CC>[CH2:14]([N:13]([CH2:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH3:12])[OH:26])[CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH3:25]
Reactant: OO
Reactant: CCCCCCCCCCCCNCCCCCCCCCCCC
Solvent: CCCO
Product: CCCCCCCCCCCCN(O)CCCCCCCCCCCC
Reaction time: 72 h

Procedure:
Following the general procedure of Example 5, to a solution of 50 grams (0.14 mol) of didodecylamine dissolved in 200 ml of n-propanol at 40° C. is added dropwise 9.62 grams (0.14 mol) of 50% aqueous hydrogen peroxide solution. After 72 hours at 40-45° C., the reaction mixture is filtered to give a crude product which is subsequently recrystallized from 300 ml of hexane. The above-named product is obtained in a yield of 24.8 grams (48%) as white needles melting at 90-92° C.
Reaction SMILES: [CH3:1][NH:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.[C:9](Cl)([Cl:11])=[O:10].C(=O)([O-])[O-].[K+].[K+]>C(#N)C.C1(C)C=CC=CC=1>[CH3:1][N:2]([C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1)[C:9]([Cl:11])=[O:10]
Reactant: O=C(Cl)Cl
Reactant: CNc1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: Cc1ccccc1
Solvent: CC#N
Product: CN(C(=O)Cl)c1ccccc1
Temperature: 25 °C
Reaction time: 16 h
Yield: 94 %

Procedure:
A vigorously stirred solution of 10.7 g (0.1 mole) of N-methylaniline in 100 ml of acetonitrile was added dropwise under a nitrogen atmosphere to a cold mixture of 155 ml (0.3 mole) of a 1.93M solution of phosgene in toluene and 83.0 g (0.6 mole) of anhydrous potassium carbonate in 200 ml of acetonitrile. After the final addition, the mixture was stirred at ambient temperature for 16 h, filtered, and the filtrate concentrated under reduced pressure. The residue was recrystallized from benzene/petroleum ether (60°-110° C.) to yield 15.9 g (94%) of white solid, mp 85°-86° C.
Reaction SMILES: [S:1](Cl)([C:4]1[CH:10]=[CH:9][C:7]([CH3:8])=[CH:6][CH:5]=1)(=[O:3])=[O:2].[NH2:12][C@@H:13]([C:17]([OH:19])=[O:18])[CH:14]([CH3:16])[CH3:15]>C(OCC)C.[OH-].[Na+]>[S:1]([NH:12][C@@H:13]([C:17]([OH:19])=[O:18])[CH:14]([CH3:16])[CH3:15])([C:4]1[CH:10]=[CH:9][C:7]([CH3:8])=[CH:6][CH:5]=1)(=[O:3])=[O:2]
Reactant: CC(C)[C@@H](N)C(=O)O
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: CCOCC
Product: Cc1ccc(S(=O)(=O)N[C@@H](C(=O)O)C(C)C)cc1
Reaction time: 4 h

Procedure:
A solution of tosyl chloride (20 g, 0.1 mol) in diethyl ether (100 ml) was added in drops at room temperature to a solution of D-valine (11.7 g, 0.1 mol) in 200 ml of 1N NaOH, and the two-phase mixture was stirred vigorously for 4 hours. Then, the diethyl ether phase was separated, the aqueous phase was washed twice more with diethyl ether and acidified at 0° C. by adding concentrated HCl. After 30 minutes, it was suctioned off, liberally rewashed with ice water and dried for several hours at 0.01 Torr. 18.1 g, (67%), of colorless crystals was obtained (melting point: 147° C.).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:11][CH:10]([CH3:12])[C:9]1([CH2:20][CH:21]=O)[C:13]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14])=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH2:23]([NH2:30])[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].O>O1CCCC1>[C:1]([O:5][C:6]([N:8]1[CH2:11][CH:10]([CH3:12])[C:9]1([CH2:20][CH2:21][NH:30][CH2:23][C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1)[C:13]([O:15][C:16]([CH3:17])([CH3:18])[CH3:19])=[O:14])=[O:7])([CH3:2])([CH3:3])[CH3:4]
Reactant: CC1CN(C(=O)OC(C)(C)C)C1(CC=O)C(=O)OC(C)(C)C
Reactant: NCc1ccccc1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: CC1CN(C(=O)OC(C)(C)C)C1(CCNCc1ccccc1)C(=O)OC(C)(C)C
Temperature: 0 °C
Reaction time: 2 h

Procedure:
To a solution of the residue (95.0 g) obtained in (7) in tetrahydrofuran (300 ml) was added benzylamine (34 ml) at room temperature, and the mixture was stirred for 2 hours. The mixture was cooled to 0° C. Then, thereto was added sodium triacetoxyborohydride (83.3 g), and the mixture was stirred at room temperature for 1.5 hours. To the reaction mixture was added water (300 ml), and the mixture was extracted with n-hexane/ethyl acetate (1/3, 600 ml). The separated organic layer was washed with water (300 ml) and saturated aqueous sodium chloride solution (200 ml), and then extracted with 5% aqueous citric acid solution (300 ml, 200 ml) twice and 10% aqueous citric acid solution (250 ml×3) 3 times. The combined aqueous layer was basified by 4M aqueous sodium hydroxide solution to pH 10 and extracted with chloroform (300 ml). The organic layer was washed with saturated aqueous sodium chloride solution (200 ml), dried over anhydrous magnesium sulfate and concentrated under reduced pressure to give the titled compound (46.9 g).
Reaction SMILES: [O:1]=[C:2]1[N:8]([CH2:9][C:10]([N:12]([CH:19]([CH3:21])[CH3:20])[C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)=[O:11])[C:7]2[CH:22]=[CH:23][CH:24]=[CH:25][C:6]=2[N:5]([C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)[C:4](=[O:32])[CH2:3]1.Cl[CH2:34][C:35]1[N:39]=[C:38]([C:40]2[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=2)[O:37][N:36]=1>CN(C=O)C.C1(C)C=CC=CC=1>[O:1]=[C:2]1[N:8]([CH2:9][C:10]([N:12]([CH:19]([CH3:21])[CH3:20])[C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)=[O:11])[C:7]2[CH:22]=[CH:23][CH:24]=[CH:25][C:6]=2[N:5]([C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)[C:4](=[O:32])[CH:3]1[CH2:34][C:35]1[N:39]=[C:38]([C:40]2[CH:41]=[CH:42][CH:43]=[CH:44][CH:45]=2)[O:37][N:36]=1
Reactant: ClCc1noc(-c2ccccc2)n1
Reactant: CC(C)N(C(=O)CN1C(=O)CC(=O)N(c2ccccc2)c2ccccc21)c1ccccc1
Solvent: Cc1ccccc1
Solvent: CN(C)C=O
Product: CC(C)N(C(=O)CN1C(=O)C(Cc2noc(-c3ccccc3)n2)C(=O)N(c2ccccc2)c2ccccc21)c1ccccc1
Reaction time: 0.08 h
Yield: 42.1 %

Procedure:
To a stirring solution of 200 mg (0.47 mmol) of 2-(2,4-Dioxo-5-phenyl-2,3,4,5-tetrahydro-benzo[b][1,4]diazepin-1-yl)-N-isopropyl-N-phenyl acetamide in 4 mL DMF at 0° C. is added dropwise 0.98 mL (0.49 mmol, 1.05 equiv) of a 0.5N solution of KN(TMS)2 in toluene. The resulting solution is stirred 5 min, then 100 mg (0.51 mmol, 1.1 equiv) of 3-chloromethyl-5-phenyl-[1,2,4]oxadiazole is added. The reaction mixture is stirred 30 min at 0° C. then 14 h at RT. The reaction mixture is quenched with 1 mL of H2O and the solvent removed in vacuo. The residue is dissolved in 40 mL EtOAc, washed with 40 mL H2O, and the organic layer is dried (MgSO4) and the solvent removed in vacuo. The resulting oil is purified by silica gel flash column chromatography using hexane/EtOAc 2/1 as eluent followed by further purification via reverse phase MPLC using a C-18 column and 60% acetonitrile/40% H2O with 0.1% TFA as eluent followed by lyophilization to afford 116 mg of 2-[2,4-Dioxo-5-phenyl-3-(5-phenyl-[1,2,4]oxadiazol-3-ylmethyl)-2,3,4,5-tetrahydro-benzo[b][1,4]diazepin-1-yl]-N-isopropyl-N-phenyl acetamide as a white amorphous solid: 1H NMR (CDCl3, 300 MHz) δ8.07 (d, 2H, J=6.9), 7.59-7.13 (m, 16H), 7.00 (dd, 1H, J=1.3, 8.1), 5.01 (m, 1H), 4.27 (s, br, 2H), 4.1 (t, 1H, J=6.1), 3.66 (dd, 1H, J=7.8, 17.1), 3.50 (dd, 1H, J=6.1, 17.1) 1.08 (t, 6H, J=6.9); low resolution MS (FAB) m/e 586 (MH+), 451, 277, 227, 195.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:4]([C:34]([F:37])([F:36])[F:35])=[C:5]2[C:10](=[CH:11][CH:12]=1)[C:9]([C:13]([N:15]([C:24]([O:26][CH3:27])=[O:25])[CH2:16][C:17]([O:19]C(C)(C)C)=[O:18])=[O:14])=[C:8]([O:28][CH2:29][C:30]([F:33])([F:32])[F:31])[CH:7]=[CH:6]2>C(O)=O.O>[CH3:1][O:2][C:3]1[C:4]([C:34]([F:35])([F:37])[F:36])=[C:5]2[C:10](=[CH:11][CH:12]=1)[C:9]([C:13]([N:15]([C:24]([O:26][CH3:27])=[O:25])[CH2:16][C:17]([OH:19])=[O:18])=[O:14])=[C:8]([O:28][CH2:29][C:30]([F:31])([F:32])[F:33])[CH:7]=[CH:6]2
Reactant: COC(=O)N(CC(=O)OC(C)(C)C)C(=O)c1c(OCC(F)(F)F)ccc2c(C(F)(F)F)c(OC)ccc12
Solvent: O
Solvent: O=CO
Product: COC(=O)N(CC(=O)O)C(=O)c1c(OCC(F)(F)F)ccc2c(C(F)(F)F)c(OC)ccc12
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 78.8 %

Procedure:
A suspension of N-[[6-methoxy-2-(2,2,2-trifluoroethoxy)-5-(trifluoromethyl)-1-naphthalenyl]carbonyl]-N-(methoxycarbonyl)glycine, 1,1-dimethylethyl ester (5.86 g, 10.9 mmol) in formic acid (135 mL) was stirred at room temperature under a dry nitrogen atmosphere. After 10 minutes, dissolution occurred. After 1 hour, the reaction mixture was diluted with water (1.5 L) and extracted with ether (2×400 mL). The extracts were combined and the ether was removed. The residue was suspended in water (100 mL) and filtered. The solid was washed with water (2×20 mL) and air dried. The crude product was recrystallized from chloroform to provide the title compound as a white powder (4.15 g, 79%), m.p. 186°-187° C.
Reaction SMILES: [OH:1]O.[CH3:3][C:4]1[CH:14]=[C:13]([O:15][CH2:16]/[CH:17]=[C:18](/[C:34]2[CH:39]=[CH:38][C:37]([S:40][CH3:41])=[CH:36][CH:35]=2)\[C:19]2[CH:24]=[CH:23][C:22]([C:25]#[C:26][CH2:27][N:28]3[CH2:33][CH2:32][O:31][CH2:30][CH2:29]3)=[CH:21][CH:20]=2)[CH:12]=[CH:11][C:5]=1[O:6][CH2:7][C:8]([OH:10])=[O:9]>C(O)(=O)C.O>[CH3:3][C:4]1[CH:14]=[C:13]([O:15][CH2:16]/[CH:17]=[C:18](/[C:34]2[CH:35]=[CH:36][C:37]([S:40]([CH3:41])=[O:1])=[CH:38][CH:39]=2)\[C:19]2[CH:24]=[CH:23][C:22]([C:25]#[C:26][CH2:27][N:28]3[CH2:33][CH2:32][O:31][CH2:30][CH2:29]3)=[CH:21][CH:20]=2)[CH:12]=[CH:11][C:5]=1[O:6][CH2:7][C:8]([OH:10])=[O:9]
Reactant: OO
Reactant: CSc1ccc(/C(=C/COc2ccc(OCC(=O)O)c(C)c2)c2ccc(C#CCN3CCOCC3)cc2)cc1
Solvent: CC(=O)O
Solvent: O
Product: Cc1cc(OC/C=C(\c2ccc(C#CCN3CCOCC3)cc2)c2ccc(S(C)=O)cc2)ccc1OCC(=O)O

Procedure:
30% Aqueous hydrogen peroxide (0.0613 mL, 0.6 mmol) was added to a solution of (E)-[2-methyl-4-[3-(4-methylsulfanylphenyl)-3-[4-[3-(morpholin-4-yl)propynyl]phenyl]-allyloxy]-phenoxy]acetic acid (272 mg, 0.5 mmol; example 40) in glacial acetic acid (7 mL) at 5° C. under stirring. The mixture was left to stand over night at ambient temperature, diluted with water and extracted with ethyl acetate (2×30 mL). The collected extracts were alkalized with 15% solution of ammonium hydroxide; the solution was decanted from the separated oil and the oil was and dissolved in chloroform (45 mL). The solution was washed with water (2×10 mL), dried with anhydrous magnesium sulphate and evaporated in vacuo. The residue was triturated with hexanes (3×15 mL) to yield the title compound as pale solid.
Reaction SMILES: O.[OH-].[Li+].C[O:5][C:6](=[O:37])[CH2:7][C:8]1[C:17]([CH3:18])=[C:16]([C:19]2[CH:24]=[CH:23][C:22]([S:25]([C:28]3[CH:33]=[CH:32][C:31]([F:34])=[CH:30][C:29]=3[F:35])(=[O:27])=[O:26])=[CH:21][CH:20]=2)[C:15]2[C:10](=[CH:11][CH:12]=[C:13]([Cl:36])[CH:14]=2)[CH:9]=1>C1COCC1.O>[Cl:36][C:13]1[CH:14]=[C:15]2[C:10](=[CH:11][CH:12]=1)[CH:9]=[C:8]([CH2:7][C:6]([OH:37])=[O:5])[C:17]([CH3:18])=[C:16]2[C:19]1[CH:20]=[CH:21][C:22]([S:25]([C:28]2[CH:33]=[CH:32][C:31]([F:34])=[CH:30][C:29]=2[F:35])(=[O:26])=[O:27])=[CH:23][CH:24]=1
Reactant: COC(=O)Cc1cc2ccc(Cl)cc2c(-c2ccc(S(=O)(=O)c3ccc(F)cc3F)cc2)c1C
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: Cc1c(CC(=O)O)cc2ccc(Cl)cc2c1-c1ccc(S(=O)(=O)c2ccc(F)cc2F)cc1
Temperature: 25 °C
Reaction time: 16 h
Yield: 99.5 %

Procedure:
Lithium hydroxide monohydrate (0.01 g, 0.26 mmol) was added to a stirred solution of {6-chloro-4-[4-(2,4-difluoro-benzenesulfonyl)-phenyl]-3-methyl-naphthalen-2-yl}-acetic acid methyl ester (0.032 g, 0.064 mmol) in a 3:1 THF—H2O mixture (4 mL). The reaction mixture was stirred for 16 hours at room temperature. The THF was distilled off under reduced pressure, and the crude residue was diluted with water, acidified [pH˜2] via the drop-wise addition of an aqueous solution of hydrochloric acid (6.0 N). The mixture was extracted twice with ethyl acetate. The combined organic layers were washed with water and brine, dried over anhydrous sodium sulfate and concentrated under reduced pressure to give the crude product. Trituration with hexanes afforded {6-chloro-4-[4-(2,4-difluoro-benzenesulfonyl)-phenyl]-3-methyl-naphthalen-2-yl}-acetic acid (0.031 g, 100%) as a solid. 1H NMR (400 MHz, DMSO-d6) δ ppm 12.50 (br. s, 1 H) 8.19-8.28 (m, 1 H) 8.13 (d, J=7.82 Hz, 2 H) 7.97 (d, J=8.80 Hz, 1 H) 7.92 (s, 1 H) 7.60-7.68 (m, 1 H) 7.57 (d, J=7.82 Hz, 2 H) 7.41-7.52 (m, 2 H) 6.96 (s, 1 H) 3.85 (s, 2 H) 2.03 (s, 3 H) MS calcd. for C25H16ClF2O4S [(M−H)−] 485, obsd. 485.3.
Reaction SMILES: [Cl:1][C:2]1[N:3]=[CH:4][C:5]2[NH:11][C:10](=[O:12])[CH:9]([CH3:13])[CH2:8][N:7]([CH2:14][CH:15]3[CH2:19][CH2:18][CH2:17][CH2:16]3)[C:6]=2[N:20]=1.I[CH3:22].[H-].[Na+]>CN(C)C=O>[Cl:1][C:2]1[N:3]=[CH:4][C:5]2[N:11]([CH3:22])[C:10](=[O:12])[CH:9]([CH3:13])[CH2:8][N:7]([CH2:14][CH:15]3[CH2:16][CH2:17][CH2:18][CH2:19]3)[C:6]=2[N:20]=1
Reactant: CC1CN(CC2CCCC2)c2nc(Cl)ncc2NC1=O
Reactant: CI
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CC1CN(CC2CCCC2)c2nc(Cl)ncc2N(C)C1=O
Reaction time: 2 h
Yield: 95.5 %

Procedure:
To a mixture of 1.10 g (0.00373 mole) of (rac)-2-chloro-9-cyclopentylmethyl-7-methyl-5,7,8,9-tetrahydro-pyrimido[4,5-b][1,4]diazepin-6-one (VI-55), 0.35 mL (0.0056 mole) of iodomethane and 15 mL of N,N-dimethyl-formamide at 0 degrees, was added 0.22 g (0.0056 mole) of 60% oil dispersion of sodium hydride. The mixture was stirred at 0 degrees for 2 hours, then partitioned between ethyl acetate and water. The aqueous phase was extracted with ethyl acetate. The combined organic phases were washed with water and brine, dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue was purified by silica gel chromatography eluting with hexanes-ethyl acetate (100:0-60:60) to give 1.10 g of (rac)-2-chloro-9-cyclopentylmethyl-5,7-dimethyl-5,7,8,9-tetrahydro-pyrimido[4,5-b][1,4]diazepin-6-one (VII-55) as white powder. HRMS (ES+) m/z Calcd for C15H21ClN4O+H [(M+H)+]: 309.1477. Found: 309.1476.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([CH2:14]OS(C)(=O)=O)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[H-].[Na+].[NH:22]1[CH:26]=[CH:25][N:24]=[CH:23]1>CN(C=O)C>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([CH2:14][N:22]2[CH:26]=[CH:25][N:24]=[CH:23]2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: c1c[nH]cn1
Reactant: CC(C)(C)OC(=O)N1CCC(COS(C)(=O)=O)CC1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N1CCC(Cn2ccnc2)CC1
Temperature: 60 °C
Reaction time: 16 h

Procedure:
A solution of the title compound from Step B (1.0 g, 3.408 mmoles) in DMF (15 mL) was added to a stirred solution of NaH (0.27 g, 6.817 mmoles) and imidazole (0.464 g, 6.817 mmoles) in DMF (15 mL) under nitrogen atmosphere. The mixture was stirred at 60° C. for 16 h. DMF was evaporated in vacuo. The resulting crude product was extracted with CH2Cl2 and the extract was successively washed with water and brine, and the CH2Cl2 was evaporated to leave the title residue which was chromatographed on silica gel using 3% (10% conc NH4OH in methanol)-CH2Cl2 as eluant to give the title compound (0.823 g). FABMS (M+1)=266.2, δH (CDCl3) 0.8-1.0 (m, 2H), 1.2 (s, 9H), 1.2-1.4 (m, 1H), 1.65 (m, 1H), 2.4 (dt, 2H), 3.6 (d, 2H), 4.8 (d, 2H), 6.7 (s, 1H), 6.8 (s, 1H), 7.2 (s, 1H).
Reaction SMILES: [Na].[C:2]([NH:5][C:6]#[N:7])(=[O:4])[CH3:3].[CH2:8](Cl)[CH:9]=[CH2:10]>S1(CCCC1)(=O)=O>[C:6]([N:5]([CH2:10][CH:9]=[CH2:8])[C:2](=[O:4])[CH3:3])#[N:7]
Reactant: C=CCCl
Reactant: CC(=O)NC#N
Agent: [Na]
Solvent: O=S1(=O)CCCC1
Product: C=CCN(C#N)C(C)=O

Procedure:
159.1 g (1.5 mols) of the sodium salt of acetylcyanamide and 137.8 g (1.5 mols+20% excess) of allyl chloride are reacted in 400 ml of sulfolane for 9 hours and 45 minutes at 70°-127° C. analogously to Example 1, and the mixture is worked up in accordance with Example 1. This gives 121.7 g (65.4% of theory) of a colourless distillate, boiling at 98° C./43 mbar.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[NH:11][C:10](=S)[CH2:9][N:8]=[C:7]([C:13]3[C:18]([F:19])=[CH:17][CH:16]=[CH:15][C:14]=3[F:20])[C:6]=2[CH:21]=1.[CH2:22]([NH2:26])[C:23]#[C:24][CH3:25]>O1CCCC1>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[N:11]=[C:10]([NH:26][CH2:22][C:23]#[C:24][CH3:25])[CH2:9][N:8]=[C:7]([C:13]3[C:18]([F:19])=[CH:17][CH:16]=[CH:15][C:14]=3[F:20])[C:6]=2[CH:21]=1
Reactant: Fc1cccc(F)c1C1=NCC(=S)Nc2ccc(Cl)cc21
Reactant: CC#CCN
Solvent: C1CCOC1
Product: CC#CCNC1=Nc2ccc(Cl)cc2C(c2c(F)cccc2F)=NC1

Procedure:
A mixture of 10.0 g. of 7-chloro-1,3-dihydro-5-(2,6-difluorophenyl)-2H-1,4-benzodiazepine-2-thione (V), 10.0 g. of 2-butynylamine, and 150 ml. of dry tetrahydrofuran is stirred under nitrogen at ambient temperature for about 5 hours and then concentrated in vacuo. The residue thus obtained is recrystallized from methanol to give 7-chloro-5-(2,6-difluorophenyl)-2-(2-butynylamino)-3H-1,4-benzodiazepine.