Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]([O:4][C:5]1[CH:13]=[CH:12][C:8]([C:9]([OH:11])=O)=[CH:7][CH:6]=1)([CH3:3])[CH3:2].[NH2:14][CH2:15][C:16]1[CH:17]=[C:18]([CH2:24][CH:25]([O:31][CH:32]([CH3:34])[CH3:33])[C:26]([O:28]CC)=[O:27])[CH:19]=[CH:20][C:21]=1[O:22][CH3:23]>>[CH:32]([O:31][CH:25]([CH2:24][C:18]1[CH:19]=[CH:20][C:21]([O:22][CH3:23])=[C:16]([CH2:15][NH:14][C:9](=[O:11])[C:8]2[CH:7]=[CH:6][C:5]([O:4][CH:1]([CH3:2])[CH3:3])=[CH:13][CH:12]=2)[CH:17]=1)[C:26]([OH:28])=[O:27])([CH3:34])[CH3:33]
Reactant: CC(C)Oc1ccc(C(=O)O)cc1
Reactant: CCOC(=O)C(Cc1ccc(OC)c(CN)c1)OC(C)C
Product: COc1ccc(CC(OC(C)C)C(=O)O)cc1CNC(=O)c1ccc(OC(C)C)cc1

Procedure:
Using 4-isopropoxybenzoic acid and ethyl 3-[3-(aminomethyl)-4-methoxyphenyl]-2-isopropoxypropanoate, 2-isopropoxy-3-[3-[(4-isopropoxybenzoyl)amino]methyl-4-methoxyphenyl)propanoic acid was obtained in the same manner as in Example 19d) and then in Example 19e).
Reaction SMILES: [Cl:1][C:2]1[C:7]([O:8][C:9]2[CH:14]=[CH:13][C:12]([N+:15]([O-])=O)=[CH:11][CH:10]=2)=[CH:6][C:5]([N:18]2[C:23](=[O:24])[N:22]([CH3:25])[C:21](=[O:26])[CH:20]=[N:19]2)=[C:4]([F:27])[CH:3]=1>C(O)(=O)C.O.[Fe]>[NH2:15][C:12]1[CH:13]=[CH:14][C:9]([O:8][C:7]2[C:2]([Cl:1])=[CH:3][C:4]([F:27])=[C:5]([N:18]3[C:23](=[O:24])[N:22]([CH3:25])[C:21](=[O:26])[CH:20]=[N:19]3)[CH:6]=2)=[CH:10][CH:11]=1
Reactant: Cn1c(=O)cnn(-c2cc(Oc3ccc([N+](=O)[O-])cc3)c(Cl)cc2F)c1=O
Agent: [Fe]
Solvent: O
Solvent: CC(=O)O
Product: Cn1c(=O)cnn(-c2cc(Oc3ccc(N)cc3)c(Cl)cc2F)c1=O

Procedure:
2-(4-chloro-2-fluoro-5-hydroxyphenyl)-4-methyl-1,2,4-triazine-3,5(2H,4H)-dione is reacted with potassium carbonate and 4-fluoronitrobenzene in N,N-dimethylformamide to form 2-[4-chloro-2-fluoro-5-(4-nitrophenoxy)phenyl]-4-methyl-1,2,4-triazine-3,5(2H,4H)-dione. 2-[4-chloro-2-fluoro-5-(4-nitrophenoxy)phenyl]-4-methyl-1,2,4-triazine-3,5(2H,4H)-dione is reduced with iron powder in acetic acid and water to produce 2-[5-(4-aminophenoxy)-4-chloro-2-fluorophenyl]-4-methyl-1,2,4-triazine-3,5(2H,4H)-dione. To a mixture of 2-[5-(4-aminophenoxy)-4-chloro-2-fluorophenyl]-4-methyl-1,2,4-triazine-3,5(2H,4H)-dione in hydrochloric acid is added acetone. The mixture is cooled to about 5° C., and in succession a solution of sodium nitrite in water and methyl acrylate is added. The resultant mixture is stirred for 15-30 minutes. Thereafter, copper (I) chloride is added slowly. This mixture is stirred at room temperature for approximately 30 minutes and then is poured into ice water. Extraction with an organic solvent (e.g., ethyl acetate) and subsequent purification yields methyl 2-chloro-3-[4-[2-chloro-4-fluoro-5-(4-methyl-3,5-dioxo-2H,4H-1,2,4-triazin-2-yl)-phenoxy]phenyl]-propionate.
Reaction SMILES: [CH:1]1([N:4]2[C:13]3[C:8](=[C:9]([F:17])[C:10]([F:16])=[C:11](F)[C:12]=3[F:14])[C:7](=[O:18])[C:6]([C:19]([OH:21])=[O:20])=[CH:5]2)[CH2:3][CH2:2]1.[N:22]12[CH2:32][CH2:31][CH2:30][N:29]=[C:28]1[CH2:27]CC[CH2:24][CH2:23]2.C(NCC1CCNC1)C>C(#N)C>[CH:1]1([N:4]2[C:13]3[C:8](=[C:9]([F:17])[C:10]([F:16])=[C:11]([N:29]4[CH2:28][CH2:27][CH:31]([CH2:32][NH:22][CH2:23][CH3:24])[CH2:30]4)[C:12]=3[F:14])[C:7](=[O:18])[C:6]([C:19]([OH:21])=[O:20])=[CH:5]2)[CH2:2][CH2:3]1
Reactant: C1CCC2=NCCCN2CC1
Reactant: O=C(O)c1cn(C2CC2)c2c(F)c(F)c(F)c(F)c2c1=O
Agent: CCNCC1CCNC1
Solvent: CC#N
Product: CCNCC1CCN(c2c(F)c(F)c3c(=O)c(C(=O)O)cn(C4CC4)c3c2F)C1
Temperature: 60 °C
Reaction time: 18 h
Yield: 83.3 %

Procedure:
To 1.0 g (3.32 mmol) of 1-cyclopropyl-5,6,7,8-tetrafluoro-1,4-dihydro-4-oxo-3-quinolinecarboxylic acid in 9 ml of acetonitrile was added 0.5 g (one equivalent) of 1,8-diazabicyclo[5.4.0]undec-7-ene and 0.42 g of N-ethyl-3-pyrrolidinemethanamine in 3 ml additional acetonitrile. The mixture was heated at 60° C. for four hours and stirred at 25° C. for 18 hours. The mixture was filtered and the solids washed with diethyl ether to give 1.12 g of the title compound, mp 247°-248° C.
Reaction SMILES: [CH3:1][C:2]1[C@@H:19]([OH:20])[CH2:18][C@:14]2([OH:21])[C:15]([CH3:17])([CH3:16])[C:3]=1[C@@H:4]([OH:39])[C:5]([C@@:7]1([CH3:38])[C@H:12]([C@@H:13]2[O:22][C:23]([C:25]2[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=2)=[O:24])[C@:11]2([O:33][C:34]([CH3:36])=[O:35])[CH2:31][O:32][C@@H:10]2[CH2:9][C@@H:8]1[OH:37])=[O:6].[C:40](Cl)(=[O:42])[CH3:41]>N1C=CC=CC=1>[CH3:1][C:2]1[C@@H:19]([OH:20])[CH2:18][C@:14]2([OH:21])[C:15]([CH3:16])([CH3:17])[C:3]=1[C@@H:4]([O:39][C:40]([CH3:41])=[O:42])[C:5]([C@@:7]1([CH3:38])[C@H:12]([C@@H:13]2[O:22][C:23]([C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)=[O:24])[C@:11]2([O:33][C:34]([CH3:36])=[O:35])[CH2:31][O:32][C@@H:10]2[CH2:9][C@@H:8]1[OH:37])=[O:6]
Reactant: CC(=O)O[C@@]12CO[C@@H]1C[C@H](O)[C@@]1(C)C(=O)[C@H](O)C3=C(C)[C@@H](O)C[C@@](O)([C@@H](OC(=O)c4ccccc4)[C@H]21)C3(C)C
Reactant: CC(=O)Cl
Solvent: c1ccncc1
Product: CC(=O)O[C@H]1C(=O)[C@@]2(C)[C@H]([C@H](OC(=O)c3ccccc3)[C@]3(O)C[C@H](O)C(C)=C1C3(C)C)[C@]1(OC(C)=O)CO[C@@H]1C[C@@H]2O

Procedure:
Here, 10-deacetylbaccatin III is reacted with a large excess of TES-Cl and pyridine to produce C-7 TES protected 10-deacetylbaccatin III. The product is next acylated utilizing an excess of acetyl chloride and pyridine to produce C-7 TES baccatin III.
Reaction SMILES: [CH2:1]([O:8][C:9]([NH:11][C@@H:12]([CH2:16][C:17]([CH3:20])([CH3:19])[CH3:18])[C@H:13]([OH:15])[CH3:14])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(N(CC)C(C)C)(C)C>CS(C)=O>[CH2:1]([O:8][C:9]([NH:11][C@@H:12]([CH2:16][C:17]([CH3:20])([CH3:19])[CH3:18])[C:13](=[O:15])[CH3:14])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: C[C@@H](O)[C@H](CC(C)(C)C)NC(=O)OCc1ccccc1
Solvent: CCN(C(C)C)C(C)C
Solvent: CS(C)=O
Product: CC(=O)[C@H](CC(C)(C)C)NC(=O)OCc1ccccc1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
Pyridine-SO3 complex (285 mg, 1.79 mmol) is added to a solution of the compound of Example 68A (50 mg, 0.18 mmol) and N,N-diisopropylethylamine (310 μl, 1.79 mmol) in 2 ml of DMSO at 10° C. with and the mixture is slowly warmed to RT. After 2 h, 50 ml of ice/water are added to the reaction mixture. The mixture is extracted four times with diethyl ether. The combined organic phases are washed three times with a 10% citric acid solution, then three times with water and twice with a satd. sodium chloride solution, dried over magnesium sulfate and concentrated at 20° C. on a Rotavapor. The crude product (30 mg, 60% of th.) is reacted further without additional purification.
Reaction SMILES: [I:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][C:6](=[O:11])[C:5]2=O.[O:13]1[C:17]2[CH:18]=[CH:19][C:20]([CH2:22][CH2:23][C:24]([NH:26][C:27]3[CH:32]=[CH:31][C:30]([C:33]([NH:35][NH2:36])=[O:34])=[CH:29][CH:28]=3)=[O:25])=[CH:21][C:16]=2[O:15][CH2:14]1>C(O)(=O)C>[O:13]1[C:17]2[CH:18]=[CH:19][C:20]([CH2:22][CH2:23][C:24]([NH:26][C:27]3[CH:32]=[CH:31][C:30]([C:33]([NH:35][N:36]=[C:5]4[C:4]5[C:8](=[CH:9][CH:10]=[C:2]([I:1])[CH:3]=5)[NH:7][C:6]4=[O:11])=[O:34])=[CH:29][CH:28]=3)=[O:25])=[CH:21][C:16]=2[O:15][CH2:14]1
Reactant: O=C1Nc2ccc(I)cc2C1=O
Reactant: NNC(=O)c1ccc(NC(=O)CCc2ccc3c(c2)OCO3)cc1
Solvent: CC(=O)O
Product: O=C(CCc1ccc2c(c1)OCO2)Nc1ccc(C(=O)NN=C2C(=O)Nc3ccc(I)cc32)cc1
Temperature: 100 °C
Yield: 76 %

Procedure:
Into a suspension of 5-iodo-1H-indole-2,3-dione in acetic acid was added 3-(1,3-benzodioxol-5-yl)-N-[4-(hydrazinocarbonyl)phenyl]propanamide. After stirring at 100° C. the reaction mixture was cooled to rt and a yellow solid precipitated out. Filtration on a fritté, washing with AcOH, water and drying under vacuo at 60° C. overnight gave 97 mg of the title compound (76%) as a yellow solid in 98.8% purity by HPLC (Rt: 4.33, gradient of 8 min, MaxPlot detection between 230 and 400 nm).
Reaction SMILES: [C:1]([C:5]1[N:9]=[C:8]([S:10][CH2:11][S:12]([CH3:15])(=[O:14])=[O:13])[NH:7][N:6]=1)([CH3:4])([CH3:3])[CH3:2].[CH3:16][N:17]([CH3:21])[C:18](Cl)=[O:19].C(N(CC)CC)C>O1CCCC1>[CH3:16][N:17]([CH3:21])[C:18]([N:7]1[C:8]([S:10][CH2:11][S:12]([CH3:15])(=[O:14])=[O:13])=[N:9][C:5]([C:1]([CH3:4])([CH3:2])[CH3:3])=[N:6]1)=[O:19]
Reactant: CN(C)C(=O)Cl
Reactant: CC(C)(C)c1n[nH]c(SCS(C)(=O)=O)n1
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CN(C)C(=O)n1nc(C(C)(C)C)nc1SCS(C)(=O)=O
Yield: 54.5 %

Procedure:
2 g (8.0 mmle) of 3-t-butyl-5-(methylsulfonylmethylthio)-1H-1,2,4-triazole, 0.8 ml (8.8 mmole) of dimethyl carbamoyl chloride, 1.25 ml (9.0 mmole) of triethylamine and 0.1 g (0.8 mmole) of 4-dirmthylaminopyridine were dissolved in 20 ml of tetrahydrofuran and refluxed for 4 hours. After removal of the solvent the mixture was partitioned between ether and water, dried over magnesium sulfate and concentrated under vaccum. After chromatography on silica gel, trituration with ether afforded 1.4 g of 1-dimethylcarbamoYl-3-t-butyl-5-(methyl-sulfonylmethylthio)-1H-1,2,4-triazole. m.p. 109°-110° C.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][CH:6]=[C:5]([CH3:9])[C:4]=1[OH:10].C(C1C=C(C=C(C)C=1O)[C:16]([NH:18][OH:19])=[NH:17])C>>[OH:10][C:4]1[C:5]([CH3:9])=[CH:6][C:7]([C:16]([NH:18][OH:19])=[NH:17])=[CH:8][C:3]=1[O:2][CH3:1]
Reactant: CCc1cc(C(=N)NO)cc(C)c1O
Reactant: COc1cccc(C)c1O
Product: COc1cc(C(=N)NO)cc(C)c1O

Procedure:
The title compound is prepared from commercially available 2-methoxy-6-methyl-phenol in analogy to literature procedures (e.g B. Roth et al. J. Med. Chem. 31 (1988) 122-129; and literature cited for 3-ethyl-4,N-dihydroxy-5-methyl-benzamidine); LC-MS: tR=0.50 min; [M+1]+=197.23.
Reaction SMILES: ClS(O)(=O)=O.[NH2:6][C:7]1[N:11]=[CH:10][NH:9][N:8]=1.[C:12]([CH:16]([CH2:19][CH:20]=[CH2:21])[C:17]#[N:18])(=O)[CH2:13][CH3:14]>O.CC1C=CC=CC=1C>[CH2:19]([C:16]1[C:12]([CH2:13][CH3:14])=[N:6][C:7]2[N:8]([N:9]=[CH:10][N:11]=2)[C:17]=1[NH2:18])[CH:20]=[CH2:21]
Reactant: C=CCC(C#N)C(=O)CC
Reactant: Nc1nc[nH]n1
Agent: O=S(=O)(O)Cl
Solvent: Cc1ccccc1C
Solvent: O
Product: C=CCc1c(CC)nc2ncnn2c1N
Temperature: 130 °C
Yield: 84 %

Procedure:
In a 20 l jacketed vessel fitted with reflux condenser and water separator, 14650 g of o-xylene were initially charged, and 411 g of chlorosulfonic acid were added. 2074 g of 3-amino-1,2,4-triazole and 3690 g of a solution of 2-propionylpent-4-enenitrile (87.4% in o-xylene) were added, and the mixture was heated to reflux. The mixture was stirred under reflux for 14 hours, and the water of reaction formed was removed via a phase separator. Once no more water separated off, the mixture was cooled to 130° C. and 634 g of triethylamine were added. On further cooling, the product precipitated in the form of colorless crystals. At a temperature of 100° C., 2350 g of isopropanol were added. The mixture was cooled further to 20° C., and the solid formed was separated off. The filtercake was washed with 1500 ml of a 1:1 mixture of isopropanol and water and then dried under reduced pressure. This gives 4057 g of a colorless powder. Melting point: 258° C. (decomposition), 1H-NMR: 1.35 (t, 3H); 2.88 (q, 2H); 3.45 (d, 2H); 5.09 (d, 2H); 5.20 (d, 2H); 5.6 (s, broad, 2H); 5.8-6.0 (m, 1H); 8.30 (s, 1H). Yield: 84.0%.
Reaction SMILES: [OH-].[Na+].C([O:11][CH:12]([O:14][CH2:15][C:16]1[NH:17][C:18]2[C:23]([C:24]=1[CH:25]=[O:26])=[CH:22][CH:21]=[CH:20][N:19]=2)[CH3:13])(=O)C1C=CC=CC=1>O.CO>[OH:11][CH:12]([O:14][CH2:15][C:16]1[NH:17][C:18]2[C:23]([C:24]=1[CH:25]=[O:26])=[CH:22][CH:21]=[CH:20][N:19]=2)[CH3:13]
Reactant: CC(OCc1[nH]c2ncccc2c1C=O)OC(=O)c1ccccc1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: CC(O)OCc1[nH]c2ncccc2c1C=O
Temperature: 60 °C

Procedure:
A solution of sodium hydroxide (1.33 g, 33 mmol) in water (35 ml) was added to a solution of 1-benzoyloxyethyloxymethyl-7-azaindole-3-carboxaldehyde (5.4 g, 16 mmol) in methanol (45 ml). The mixture was heated at 60° C. for 1 h, then the solvent was concentrated to half the original volume. Water was added, and the product was extracted with dichloromethane, dried over magnesium sulfate, filtered then evaporated to dryness. The product was used without further purification. Yield 2.7 g (74%)
Reaction SMILES: C(OC(=O)[NH:7][C@@H:8]1[CH2:12][CH2:11][N:10]([C:13]2[N:21]=[C:20]3[C:16]([N:17]=[CH:18][N:19]3[C@@H:22]3[CH2:26][C@H:25]([N:27]4[N:31]=[N:30][C:29]([CH2:32][CH3:33])=[N:28]4)[C@@H:24]([OH:34])[C@H:23]3[OH:35])=[C:15]([NH:36][CH2:37][CH:38]([C:46]3[CH:51]=[CH:50][C:49]([OH:52])=[CH:48][CH:47]=3)[C:39]3[CH:44]=[CH:43][C:42]([OH:45])=[CH:41][CH:40]=3)[N:14]=2)[CH2:9]1)(C)(C)C.FC(F)(F)C(O)=O.C(OC(N1CCN(C2CCN(C3N=C4C(N=CN4[C@@H]4C[C@H](N5C=C(CO)C=N5)[C@@H](O)[C@H]4O)=C(NCC(C4C=CC=CC=4)C4C=CC=CC=4)N=3)C2)CC1)=O)C1C=CC=CC=1>>[NH2:7][C@@H:8]1[CH2:12][CH2:11][N:10]([C:13]2[N:21]=[C:20]3[C:16]([N:17]=[CH:18][N:19]3[C@@H:22]3[CH2:26][C@H:25]([N:27]4[N:31]=[N:30][C:29]([CH2:32][CH3:33])=[N:28]4)[C@@H:24]([OH:34])[C@H:23]3[OH:35])=[C:15]([NH:36][CH2:37][CH:38]([C:39]3[CH:44]=[CH:43][C:42]([OH:45])=[CH:41][CH:40]=3)[C:46]3[CH:51]=[CH:50][C:49]([OH:52])=[CH:48][CH:47]=3)[N:14]=2)[CH2:9]1
Reactant: CCc1nnn([C@H]2C[C@@H](n3cnc4c(NCC(c5ccc(O)cc5)c5ccc(O)cc5)nc(N5CC[C@@H](NC(=O)OC(C)(C)C)C5)nc43)[C@H](O)[C@@H]2O)n1
Agent: O=C(OCc1ccccc1)N1CCN(C2CCN(c3nc(NCC(c4ccccc4)c4ccccc4)c4ncn([C@@H]5C[C@H](n6cc(CO)cn6)[C@@H](O)[C@H]5O)c4n3)C2)CC1
Solvent: O=C(O)C(F)(F)F
Product: CCc1nnn([C@H]2C[C@@H](n3cnc4c(NCC(c5ccc(O)cc5)c5ccc(O)cc5)nc(N5CC[C@@H](N)C5)nc43)[C@H](O)[C@@H]2O)n1

Procedure:
This compound is prepared from ((R)-1-{6-[2,2-bis-(4-hydroxy-phenyl)-ethylamino]-9-[(1R,2S,3R,4S)-4-(5-ethyl-tetrazol-2-yl)-2,3-dihydroxy-cyclopentyl]-9H-purin-2-yl}-pyrrolidin-3-yl)-carbamic acid tert-butyl ester (first step a) using a procedure analogous to that of (1R,2S,3R,5S)-3-[2-((R)-3-Amino-pyrrolidin-1-yl)-6-(2,2-diphenyl-ethylamino)-purin-9-yl]-5-(4-hydroxymethyl-pyrazol-1-yl)-cyclopentane-1,2-diol (Intermediate FB, second step b). MS (ES+) m/e 628.30 (MH+).
Reaction SMILES: [CH2:1]([C:3]1[CH:4]=[C:5]([CH2:11][C@@H:12]([NH:16][C:17]([N:19]2[CH2:24][CH2:23][CH:22]([N:25]3[CH2:31][CH2:30][C:29]4[CH:32]=[CH:33][CH:34]=[CH:35][C:28]=4[NH:27][C:26]3=[O:36])[CH2:21][CH2:20]2)=[O:18])[C:13]([OH:15])=O)[CH:6]=[CH:7][C:8]=1[CH2:9][CH3:10])[CH3:2].[F:37][C:38]1([F:50])[CH2:43][CH2:42][N:41]([CH:44]2[CH2:49][CH2:48][NH:47][CH2:46][CH2:45]2)[CH2:40][CH2:39]1>>[CH2:1]([C:3]1[CH:4]=[C:5]([CH:6]=[CH:7][C:8]=1[CH2:9][CH3:10])[CH2:11][C@@H:12]([NH:16][C:17]([N:19]1[CH2:24][CH2:23][CH:22]([N:25]2[CH2:31][CH2:30][C:29]3[CH:32]=[CH:33][CH:34]=[CH:35][C:28]=3[NH:27][C:26]2=[O:36])[CH2:21][CH2:20]1)=[O:18])[C:13]([N:47]1[CH2:48][CH2:49][CH:44]([N:41]2[CH2:40][CH2:39][C:38]([F:50])([F:37])[CH2:43][CH2:42]2)[CH2:45][CH2:46]1)=[O:15])[CH3:2]
Reactant: FC1(F)CCN(C2CCNCC2)CC1
Reactant: CCc1ccc(C[C@@H](NC(=O)N2CCC(N3CCc4ccccc4NC3=O)CC2)C(=O)O)cc1CC
Product: CCc1ccc(C[C@@H](NC(=O)N2CCC(N3CCc4ccccc4NC3=O)CC2)C(=O)N2CCC(N3CCC(F)(F)CC3)CC2)cc1CC

Procedure:
Prepared analogously to Example 9i) from 400 mg (0.81 mmol) (R)-3-(3,4-diethyl-phenyl)-2-{[4-(2-oxo-1,2,4,5-tetrahydro-1,3-benzodiazepin-3-yl)-piperidine-1-carbonyl]-amino}-propionic acid and 200 mg (0.98 mmol) 4,4-difluoro-[1,4′]bipiperidinyl.
Reaction SMILES: [O:1]=[C:2]1[C:10]2([C:22]3[C:13](=[CH:14][C:15]4[O:20][CH2:19][CH2:18][O:17][C:16]=4[CH:21]=3)[O:12][CH2:11]2)[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[N:3]1[CH2:23][C:24]1[O:28][C:27]([C:29]([O:31]C)=[O:30])=[CH:26][CH:25]=1.[OH-].[Li+].Cl>O1CCCC1.O>[O:1]=[C:2]1[C:10]2([C:22]3[C:13](=[CH:14][C:15]4[O:20][CH2:19][CH2:18][O:17][C:16]=4[CH:21]=3)[O:12][CH2:11]2)[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[N:3]1[CH2:23][C:24]1[O:28][C:27]([C:29]([OH:31])=[O:30])=[CH:26][CH:25]=1
Reactant: COC(=O)c1ccc(CN2C(=O)C3(COc4cc5c(cc43)OCCO5)c3ccccc32)o1
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: O=C(O)c1ccc(CN2C(=O)C3(COc4cc5c(cc43)OCCO5)c3ccccc32)o1
Temperature: 60 °C
Reaction time: 2 h
Yield: 102.3 %

Procedure:
A mixture of methyl 5-[(2′-oxo-2,3-dihydrospiro[furo[2,3-g][1,4]benzodioxine-8,3-indol]-1′(2′H)-yl)methyl]furan-2-carboxylate (1.38 g, 3.17 mmol) and lithium hydroxide (0.76 g, 31.7 mmol) in tetrahydrofuran (10 mL) and water (10 mL) was stirred at 60° C. for 2 h. The reaction mixture was acidified with 1 M hydrochloric acid (50 mL) and extracted with dichloromethane (3×30 mL). The combined organic solution was washed with brine (50 mL), dried over sodium sulfate, filtered and concentrated under reduced pressure to afford 5-[(2′-oxo-2,3-dihydrospiro[furo[2,3-g][1,4]benzodioxine-8,3-indol]-1′(2′H)-yl)methyl]furan-2-carboxylic acid (1.36 g, quantitative) as a colorless solid: mp 192-195° C. (diethyl ether); 1H NMR (300 MHz, CDCl3) δ8.40 (br s, 1H), 7.27 (dd, J=7.8, 7.8 Hz, 1H), 7.25 (d, J=3.3 Hz, 1H), 7.18 (d, J=7.5 Hz, 1H), 7.06 (dd, J=7.5, 7.5 Hz, 1H), 6.94 (d, J=7.8 Hz, 1H), 6.50 (s, 1H), 6.45 (d, J=3.3 Hz, 1H), 6.31 (s, 1H), 5.19 (d, J=16.5 Hz, 1H), 4.92 (d, J=9.3 Hz, 1H), 4.87 (d, J=16.5 Hz, 1H), 4.66 (d, J=9.3 Hz, 1H), 4.21-4.07 (m, 4H); 13C NMR (75 MHz, CDCl3) δ177.4, 162.8, 155.2, 154.4, 144.8, 143.7, 141.3, 138.6, 132.3, 129.1, 124.2, 124.0, 121.1, 120.9, 111.8, 110.7, 109.0, 99.5, 80.0, 64.7, 64.0, 58.2, 37.5; MS (ES+) m/z 419.9 (M+1).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:20])[CH:5]([O:17][CH2:18][CH3:19])[CH2:6][C:7]1[C:15]2[O:14][CH2:13][CH2:12][C:11]=2[C:10]([OH:16])=[CH:9][CH:8]=1)[CH3:2].Cl[CH2:22][C:23]1[N:24]=[C:25]([C:29]2[CH:34]=[CH:33][C:32]([O:35][CH:36]([CH3:38])[CH3:37])=[CH:31][CH:30]=2)[O:26][C:27]=1[CH3:28].C(=O)([O-])[O-].[K+].[K+].[I-].[K+]>>[CH2:1]([O:3][C:4](=[O:20])[CH:5]([O:17][CH2:18][CH3:19])[CH2:6][C:7]1[C:15]2[O:14][CH2:13][CH2:12][C:11]=2[C:10]([O:16][CH2:22][C:23]2[N:24]=[C:25]([C:29]3[CH:34]=[CH:33][C:32]([O:35][CH:36]([CH3:38])[CH3:37])=[CH:31][CH:30]=3)[O:26][C:27]=2[CH3:28])=[CH:9][CH:8]=1)[CH3:2]
Reactant: Cc1oc(-c2ccc(OC(C)C)cc2)nc1CCl
Reactant: CCOC(=O)C(Cc1ccc(O)c2c1OCC2)OCC
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Product: CCOC(=O)C(Cc1ccc(OCc2nc(-c3ccc(OC(C)C)cc3)oc2C)c2c1OCC2)OCC

Procedure:
In analogy to the procedure described in example 120 f], [rac]-2-ethoxy-3-(4-hydroxy-2,3-dihydro-benzofuran-7-yl)-propionic acid ethyl ester (example 125 a]) was reacted with 4-chloromethyl-2-(4-isopropoxy-phenyl)-5-methyl-oxazole (example 124 a]) in the presence of potassium carbonate and potassium iodide to yield [rac]-2-ethoxy-3-{4-[2-(4-isopropoxy-phenyl)-5-methyl-oxazol-4-ylmethoxy]-2,3-dihydro-benzofuran-7-yl}-propionic acid ethyl ester, which was further saponified in analogy to the procedure described in example 120 f] to yield [rac]-2-ethoxy-3-{4-[2-(4-isopropoxy-phenyl)-5-methyl-oxazol-4-ylmethoxy]-2,3-dihydro-benzofuran-7-yl}-propionic acid as white solid.
Reaction SMILES: [C:1]1([CH3:39])[C:2]([C:7]([CH2:9][N:10]2[C:16]3[CH:17]=[C:18]([CH3:21])[CH:19]=[CH:20][C:15]=3[N:14]([C:22]([CH:24]3[CH2:29][CH2:28][CH2:27][CH2:26][CH2:25]3)=[O:23])[CH2:13][CH:12]([NH:30]C(OC(C)(C)C)=O)[C:11]2=[O:38])=[O:8])=[CH:3][CH:4]=[CH:5][CH:6]=1>Cl.O1CCOCC1>[C:1]1([CH3:39])[C:2]([C:7]([CH2:9][N:10]2[C:16]3[CH:17]=[C:18]([CH3:21])[CH:19]=[CH:20][C:15]=3[N:14]([C:22]([CH:24]3[CH2:29][CH2:28][CH2:27][CH2:26][CH2:25]3)=[O:23])[CH2:13][CH:12]([NH2:30])[C:11]2=[O:38])=[O:8])=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: Cc1ccc2c(c1)N(CC(=O)c1ccccc1C)C(=O)C(NC(=O)OC(C)(C)C)CN2C(=O)C1CCCCC1
Agent: Cl
Solvent: C1COCCO1
Product: Cc1ccc2c(c1)N(CC(=O)c1ccccc1C)C(=O)C(N)CN2C(=O)C1CCCCC1
Temperature: 50 °C
Reaction time: 1 h
Yield: 86.2 %

Procedure:
1-(2-Toluoylmethyl)-2-oxo-3-tert-butoxycarbonylamino-5-cyclohexylcarbonyl-8-methyl-1,3,4,5-tetrahydro-2H-1,5-benzodiazepine (1.00 g) was suspended in 4N HCl-dioxane (10 ml), the suspension was stirred for one hour at 50° C. The reaction mixture was concentrated under reduced pressure, the residue was dissolved in methylene chloride (100 ml), the solution was successively washed with saturated aqueous sodium bicarbonate and saturated brine, and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure, a mixed solvent of n-hexane and diisopropyl ether was added to the residue for trituration, collected by filtration, to thereby obtain 700 mg of the titled compound (Yield: 86.2%).
Reaction SMILES: [H-].[Na+].[CH3:3][O:4][CH2:5][O:6][C:7]1[C:15]2[CH:14]=[C:13]([C:16]3[O:20][C:19](=[S:21])[NH:18][N:17]=3)[O:12][C:11]=2[CH:10]=[CH:9][CH:8]=1.[CH3:22]I>C1COCC1.CN(C=O)C>[CH3:3][O:4][CH2:5][O:6][C:7]1[C:15]2[CH:14]=[C:13]([C:16]3[O:20][C:19]([S:21][CH3:22])=[N:18][N:17]=3)[O:12][C:11]=2[CH:10]=[CH:9][CH:8]=1
Reactant: COCOc1cccc2oc(-c3n[nH]c(=S)o3)cc12
Reactant: CI
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CN(C)C=O
Product: COCOc1cccc2oc(-c3nnc(SC)o3)cc12
Temperature: 0 °C
Reaction time: 0.67 h

Procedure:
To a suspension (40 ml) of sodium hydride (0.8 g) in THF was added dropwise a solution (30 ml) of 5-(4-(methoxymethyloxy)benzo(b)furan-2-yl)-2,3-dihydro-1,3,4-oxadiazole-2-thione (4.6 g) in DMF at room temperature, and the mixture was stirred for 40 min. To this reaction mixture was added dropwise methyl iodide at room temperature, and the mixture was further stirred for 1 hr. The reaction mixture was poured into ice water and extracted with ethyl acetate. The organic layer was washed with water and dried. The solvent was evaporated under reduced pressure to give the title compound (2.5 g) as brown crystals.
Reaction SMILES: [Cl:1][C:2]1[CH:8]=[C:7]([I:9])[CH:6]=[CH:5][C:3]=1[NH2:4].C([N-]C(C)C)(C)C.[Li+].[CH3:18][O:19][C:20](=[O:36])[C:21]1[CH:26]=[C:25]([S:27](=[O:32])(=[O:31])[N:28]([CH3:30])[CH3:29])[C:24]([F:33])=[C:23]([F:34])[C:22]=1F>O1CCCC1>[CH3:18][O:19][C:20](=[O:36])[C:21]1[CH:26]=[C:25]([S:27](=[O:32])(=[O:31])[N:28]([CH3:30])[CH3:29])[C:24]([F:33])=[C:23]([F:34])[C:22]=1[NH:4][C:3]1[CH:5]=[CH:6][C:7]([I:9])=[CH:8][C:2]=1[Cl:1]
Reactant: COC(=O)c1cc(S(=O)(=O)N(C)C)c(F)c(F)c1F
Reactant: Nc1ccc(I)cc1Cl
Agent: CC(C)[N-]C(C)C
Agent: [Li+]
Solvent: C1CCOC1
Product: COC(=O)c1cc(S(=O)(=O)N(C)C)c(F)c(F)c1Nc1ccc(I)cc1Cl
Reaction time: 0.08 h
Yield: 22.6 %

Procedure:
To a stirring cold (−78° C.) solution comprised of 2-chloro-4-iodoaniline (0.143 g, 5.64×10−4 mol) in anhydrous tetrahydrofuran (5 ml) under a nitrogen atmosphere was added a commercially available lithium diisopropylamide solution (Aldrich, 2.0M in tetrahydrofuran/heptane/ethylbenzene, 0.300 ml, 6.0×10−4 mol). After stirring for 5 minutes, a solution comprised of 5-dimethylsulfamoyl-2,3,4-trifluoro-benzoic acid methyl ester (0.15 g, 5.0×10−4 mol) in tetrahydrofuran (10 ml) was added via syringe. The cold bath was removed and the reaction mixture was stirred for 2 hours. The reaction mixture was then partitioned between diethyl ether (125 ml) and saturated aqueous sodium bicarbonate (125 ml). The aqueous bicarbonate phase was extracted with an additional portion (125 ml) of diethyl ether. The combined organic phases were dried over anhydrous magnesium sulfate and concentrated in vacuo to give a yellow oil. The oil was crystallized from heptane-ethyl acetate to afford 0.060 g of an off-white powder; 23% yield; mp 154-156° C.; 1H-NMR (400 MHz; CDCl3) δ 9.74 (s, 1H), 8.30 (d, 1H, J=7.1 Hz), 7.72 (s, 1H), 7.49 (d, 1H, J=8.3 Hz), 6.73-6.69 (m, 1H), 3.92 (s, 3H), 2.84 (s, 3H), 2.83 (s, 3H); 19F-NMR (376 MHz; CDCl3) δ−123.90 (d), −139.55 (d).
Reaction SMILES: Cl[CH2:2][C:3]1[N:4]=[C:5]([C:8]2[O:9][CH:10]=[CH:11][CH:12]=2)[O:6][CH:7]=1.[O:13]=[CH:14][C:15]1[CH:23]=[CH:22][C:20]([OH:21])=[C:17]([O:18][CH3:19])[CH:16]=1.C(=O)([O-])[O-].[K+].[K+].CN(C)C=O>O>[O:9]1[CH:10]=[CH:11][CH:12]=[C:8]1[C:5]1[O:6][CH:7]=[C:3]([CH2:2][O:21][C:20]2[CH:22]=[CH:23][C:15]([CH:14]=[O:13])=[CH:16][C:17]=2[O:18][CH3:19])[N:4]=1
Reactant: COc1cc(C=O)ccc1O
Reactant: ClCc1coc(-c2ccco2)n1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: COc1cc(C=O)ccc1OCc1coc(-c2ccco2)n1
Temperature: 80 °C
Reaction time: 15 h
Yield: 91.4 %

Procedure:
A mixture of 4-chloromethyl-2-(2-furyl)-1,3-oxazole (10.0 g), vanillin (8.29 g), potassium carbonate (7.53 g) and N,N-dimethylformamide (100 mL) was stirred at 80° C. for 15 hrs. Water was poured into the reaction mixture, and the precipitated crystals were collected by filtration to give 4-{[2-(2-furyl)-1,3-oxazol-4-yl]methoxy}-3-methoxybenzaldehyde as brown crystals (14.90 g, yield 91%). Recrystallization from hexane-ethyl acetate gave pale-yellow prism crystals. melting point: 138-139° C.