Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C([O:3][C:4]([CH:6]([C:15](OCC)=[O:16])[CH:7]([CH2:9][CH2:10][CH2:11][CH2:12][CH2:13]C)C)=O)C.[H-].[Al+3].[Li+].[H-].[H-].[H-]>>[CH2:7]([CH:6]([CH2:4][OH:3])[CH2:15][OH:16])[CH2:9][CH2:10][CH2:11][CH2:12][CH3:13]
Reactant: CCCCCCC(C)C(C(=O)OCC)C(=O)OCC
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Product: CCCCCCC(CO)CO

Procedure:
Quantities: compound from Example 2 (72.2 g, 0.3 mol) and lithium aluminum hydride (20 g, 0.53 mol). The experimental procedure was as described in Example 6. The pure product isolated by distillation under reduced pressure.
Reaction SMILES: [F:1][C:2]1[C:10]([CH3:11])=[C:9]([F:12])[C:8]([F:13])=[C:7]([N+:14]([O-:16])=[O:15])[C:3]=1[C:4](O)=[O:5].S(Cl)([Cl:19])=O>C1C=CC=CC=1>[F:1][C:2]1[C:10]([CH3:11])=[C:9]([F:12])[C:8]([F:13])=[C:7]([N+:14]([O-:16])=[O:15])[C:3]=1[C:4]([Cl:19])=[O:5]
Reactant: Cc1c(F)c(F)c([N+](=O)[O-])c(C(=O)O)c1F
Reactant: O=S(Cl)Cl
Solvent: c1ccccc1
Product: Cc1c(F)c(F)c([N+](=O)[O-])c(C(=O)Cl)c1F

Procedure:
2,4,5-Trifluoro-3-methyl-6-nitrobenzoic acid was suspended in 490 ml of benzene to which was subsequently added dropwise 30.4 ml (0.42 mol) of thionyl chloride at room temperature. After completion of the dropwise addition, the reaction solution was heated under reflux for 22 hours. After evaporation of benzene, the resulting residue was subjected twice to azeotropic treatment with 200 ml of benzene to yield crude 2,4,5-trifluoro-3-methyl-6-nitrobenzoyl chloride. A 6.13 g (0.25 mol) portion of magnesium was mixed with 200 ml of ethanol. Thereto was added dropwise 10 ml of carbon tetrachloride at room temperature, followed by 6 hours of stirring at the same temperature. When magnesium was dissolved, 44 ml (0.29 mol) of diethyl malonate dissolved in 150 ml of tetrahydrofuran was added dropwise thereto, spending 1 hour. After completion of the dropwise addition, the mixture was stirred for 2 hours at room temperature. After completion of the reaction, the solvent was evaporated and the resulting residue was dried under a reduced pressure. The thus obtained solid matter was mixed with 300 ml of tetrahydrofuran to which was subsequently added dropwise 150 ml of tetrahydrofuran solution of the acid chloride obtained above in 1.5 hours. After completion of the dropwise addition, the reaction solution was stirred for 2 hours at room temperature. After completion of the reaction, the reaction solution was mixed with 400 ml of ethyl acetate and washed with 10% citric acid (500 ml×1), water (500 ml×1) and saturated brine (500 ml×1) in that order. The organic layer was dried over anhydrous sodium sulfate and the solvent was evaporated. The resulting residue was mixed with 1.5 liters of water and 1.5 g of p-toluenesulfonic acid, and heated under reflux for 1.5 hours. After completion of the reaction, the reaction solution was spontaneously cooled and extracted with benzene (500 ml×5). The organic layers were combined, washed with 500 ml of saturated brine and dried over anhydrous sodium sulfate. After evaporation of the solvent, the resulting residue was subjected to a silica gel column chromatography to yield 37.65 g (44%) of the title compound from the eluate of hexane:ethyl acetate=95:5.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[C:6]([O:8]C)[CH:5]=[C:4]([NH2:10])[C:3]=1[N+:11]([O-:13])=[O:12].O>Br>[NH2:10][C:4]1[CH:5]=[C:6]([OH:8])[CH:7]=[C:2]([NH2:1])[C:3]=1[N+:11]([O-:13])=[O:12]
Reactant: COc1cc(N)c([N+](=O)[O-])c(N)c1
Agent: Br
Solvent: O
Product: Nc1cc(O)cc(N)c1[N+](=O)[O-]

Procedure:
1 g of 2,6-diamino-4-methoxynitrobenzene prepared as in example 1 was heated in 3 ml of 66% hydrobromic acid for 15 minutes over a boiling water bath. Upon addition of water the desired product precipitated as the hydrobromate. This was taken up into suspension in water then dissolved by addition of concentrated soda in order to enable elimination of an insoluble impurity by filtration in the presence of animal charcoal. The desired product precipitated from the filtrate on addition of concentrated hydrochloric acid. After filtration and vacuum drying in the presence of P2O5, the product decomposed at 264° C.
Reaction SMILES: [Si]([O:8][CH:9]1[C:14]2[CH:15]=[C:16]([C:18](=[N:20][OH:21])[NH2:19])[S:17][C:13]=2[CH2:12][CH2:11][CH2:10]1)(C(C)(C)C)(C)C.[CH2:22]([C:26]1[CH:34]=[CH:33][C:29]([C:30](O)=O)=[CH:28][CH:27]=1)[CH:23]([CH3:25])[CH3:24].C1(N=C=NC2CCCCC2)CCCCC1.[F-].C([N+](CCCC)(CCCC)CCCC)CCC>>[CH2:22]([C:26]1[CH:27]=[CH:28][C:29]([C:30]2[O:21][N:20]=[C:18]([C:16]3[S:17][C:13]4[CH2:12][CH2:11][CH2:10][CH:9]([OH:8])[C:14]=4[CH:15]=3)[N:19]=2)=[CH:33][CH:34]=1)[CH:23]([CH3:25])[CH3:24]
Reactant: CC(C)Cc1ccc(C(=O)O)cc1
Reactant: CC(C)(C)[Si](C)(C)OC1CCCc2sc(C(N)=NO)cc21
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Product: CC(C)Cc1ccc(-c2nc(-c3cc4c(s3)CCCC4O)no2)cc1

Procedure:
The crude product of the title compound was synthesized by conducting the similar reaction to that mentioned in Example 2 (2c) using 4-{[t-butyl(dimethyl)silyl]oxy}-N′-hydroxy-4,5,6,7-tetrahydro-1-benzothiophene-2-carboximidamide (0.15 g, 0.50 mmol) that was obtained in Example 8 (8e), 4-isobutylbenzoic acid (89 mg, 0.50 mmol), N,N′-dicyclohexylcarbodiimide (0.11 g, 0.55 mmol), and a 1.0 M solution of tetrabutylammonium fluoride (0.75 ml, 0.75 mmol). Subsequently, the crude product of the title compound thus obtained was purified by chromatography on a silica gel column using a mixed solvent of ethyl acetate and hexane (1:1) as the eluent to afford the title compound (92 mg) in a yield of 52% as a colourless oily product.
Reaction SMILES: Cl.[NH2:2][C:3]([NH2:5])=[NH:4].[H-].[Na+].Cl[C:9]1[C:18]2[C:13](=[CH:14][CH:15]=[C:16]([S:19](=[O:28])(=[O:27])[NH:20][C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=3)[CH:17]=2)[CH:12]=[CH:11][N:10]=1>CS(C)=O>[NH:4]([C:9]1[C:18]2[C:13](=[CH:14][CH:15]=[C:16]([S:19](=[O:28])(=[O:27])[NH:20][C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=3)[CH:17]=2)[CH:12]=[CH:11][N:10]=1)[C:3]([NH2:5])=[NH:2]
Reactant: O=S(=O)(Nc1ccccc1)c1ccc2ccnc(Cl)c2c1
Reactant: N=C(N)N
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: CS(C)=O
Product: N=C(N)Nc1nccc2ccc(S(=O)(=O)Nc3ccccc3)cc12
Temperature: 60 °C
Yield: 13.6 %

Procedure:
Guanidine hydrochloride (100 mg, 1.05 mmol) was added in one portion to a suspension of sodium hydride (NaH) (30 mg, 80% dispersion by wt. in mineral oil, 1.0 mmol) in dimethylsulphoxide (DMSO) (3.5 mL) and the mixture was heated at 60° C. under nitrogen (N2) for 30 minutes. 1-Chloro-7-phenylsulphamoylisoquinoline (110 mg, 0.345 mmol) was added and the mixture was heated at 100° C. for 3 d. The solvents were evaporated in vacuo and the residue was purified by column chromatography (silica gel using CH2Cl2-methanol-0.880NH3 (97:3:0.3 to 90:10:1) as eluant) to give 1-guanidino-7-phenylsulphamoylisoquinoline (16 mg, 0.047 mmol) as an off-white solid.
Reaction SMILES: [C:1]1([CH:8]=[CH:7][C:5]([OH:6])=[CH:4][CH:3]=1)[OH:2].[C:9](Cl)(=[O:19])[C:10]1[C:11](=[CH:15][CH:16]=[CH:17][CH:18]=1)[C:12](Cl)=[O:13]>CCO>[OH:2][C:1]1[C:8]2[C:12](=[O:13])[C:11]3[C:10](=[CH:18][CH:17]=[CH:16][CH:15]=3)[C:9](=[O:19])[C:7]=2[C:5]([OH:6])=[CH:4][CH:3]=1
Reactant: Oc1ccc(O)cc1
Reactant: O=C(Cl)c1ccccc1C(=O)Cl
Solvent: CCO
Product: O=C1c2ccccc2C(=O)c2c(O)ccc(O)c21
Yield: 64.9 %

Procedure:
The method was the same as in Example 1, but using 11.0 g (0.1 mols) of hydroquinone and 20.1 g (0.1 mols) of phthalic acid dichloride. The product was 15.6 g (65% yield) of 1,4-dihydroxy-9,10-anthraquinone (2), m.p.=199° C. (literature 200°-202° C. EtOH).
Reaction SMILES: [CH3:1][O:2][C:3]1[C:17]([CH2:18][OH:19])=[CH:16][C:6]2[N:7]=[C:8]([C:10]3[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=3)[S:9][C:5]=2[CH:4]=1>CC(CC(C)C)=O.[O-2].[O-2].[Mn+4]>[CH3:1][O:2][C:3]1[C:17]([CH:18]=[O:19])=[CH:16][C:6]2[N:7]=[C:8]([C:10]3[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=3)[S:9][C:5]=2[CH:4]=1
Reactant: COc1cc2sc(-c3ccccc3)nc2cc1CO
Agent: [Mn+4]
Agent: [O-2]
Solvent: CC(=O)CC(C)C
Product: COc1cc2sc(-c3ccccc3)nc2cc1C=O
Yield: 22.3 %

Procedure:
A solution of 10.94 grams (40.4 mmol) 6-methoxy-2-phenyl-5-hydroxymethylbenzothiazole (as part of a mixture of regioisomeric alcohols) in 600 mL of methylisobutyl ketone was treated with 42 grams (484 mmol) of manganese dioxide. The mixture was heated under reflux for 1.5 hours and was then filtered through Celite®. The filtrate was evaporated in vacuo and the residue was chromatographed on silica (elution with 9/1 hexane/ethyl acetate). Mixed fractions were rechromatographed on silica using 95/5 hexane/ethyl acetate to afford a total of 2.43 grams of the desired aldehyde.
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].[Cl:7][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=1[CH:14]1NN=[C:16]([CH:19]2[CH2:21][CH2:20]2)[CH2:15]1>C(O)CO>[Cl:7][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=1[CH:14]1[CH2:15][CH:16]1[CH:19]1[CH2:21][CH2:20]1
Reactant: Clc1ccccc1C1CC(C2CC2)=NN1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: OCCO
Product: Clc1ccccc1C1CC1C1CC1
Temperature: 100 °C
Reaction time: 2 h
Yield: 89.8 %

Procedure:
To a solution of 50 g (0.36 mol) of potassium carbonate in 600 g of ethylene glycol there are added at 190° C., in the course of 2 hours, 201.5 g of 5-(2-chlorophenyl)-3-cyclopropyl-4,5-dihydro-1H-pyrazole, prepared as described under A2. Stirring is then carried out for 2 hours at 190° C. The end of the reaction is indicated by cessation of the evolution of gas. The reaction mixture is then cooled to 100° C., whereupon phase separation occurs and the upper, product phase is separated off. 158 g of 2-(2-chlorophenyl)bicyclopropyl are obtained as crude product, which may be further purified, for example by distillation.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][C:5]2[C:11](=[O:12])[C:10]3[CH:13]=[CH:14][C:15]([N+:17]([O-:19])=[O:18])=[CH:16][C:9]=3[CH2:8][O:7][C:6]=2[CH:20]=1.Cl[C:22]1[CH:27]=[CH:26][C:25]([C:28]([F:31])([F:30])[F:29])=[CH:24][C:23]=1[N+:32]([O-:34])=[O:33].C1(P(C2CCCCC2)C2C=CC=CC=2C2C(C(C)C)=CC(C(C)C)=CC=2C(C)C)CCCCC1.CC([O-])(C)C.[K+]>C1(C)C=CC=CC=1.CC([O-])=O.CC([O-])=O.[Pd+2].CC(O)(C)C>[N+:17]([C:15]1[CH:14]=[CH:13][C:10]2[C:11](=[O:12])[C:5]3[CH:4]=[CH:3][C:2]([NH:1][C:22]4[CH:27]=[CH:26][C:25]([C:28]([F:31])([F:29])[F:30])=[CH:24][C:23]=4[N+:32]([O-:34])=[O:33])=[CH:20][C:6]=3[O:7][CH2:8][C:9]=2[CH:16]=1)([O-:19])=[O:18]
Reactant: O=[N+]([O-])c1cc(C(F)(F)F)ccc1Cl
Reactant: Nc1ccc2c(c1)OCc1cc([N+](=O)[O-])ccc1C2=O
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: CC(C)(C)[O-]
Solvent: Cc1ccccc1
Solvent: CC(C)(C)O
Product: O=C1c2ccc([N+](=O)[O-])cc2COc2cc(Nc3ccc(C(F)(F)F)cc3[N+](=O)[O-])ccc21
Temperature: 100 °C

Procedure:
In accordance with general method Z, 0.70 g (2.60 mmol) of (6), 0.55 g (3.05 mmol) of 4-chloro-3-nitro-benzotrifluoride, 2 spatula tips of Pd(OAc)2, 0.10 g of 2-(dicyclohexylphosphino)-2′,4′,6′-triisopropylbiphenyl (phosphine ligand), 0.50 g of KOt-Bu, 2.0 ml of t-BuOH are weighed out and dissolved in 10 ml of toluene (anhydrous). The mixture is refluxed at 100° C. under an argon atmosphere for 4 h. The crude product is purified by chromatography over silica gel with n-hexane/ethyl acetate (5/2). Yield: 0.047 g (3.9%);
Reaction SMILES: C([Li])CCC.[CH2:6]([O:16][C:17]1[C:21]([O:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH3:32])=[CH:20][S:19][CH:18]=1)[CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH3:15].[CH2:33]([Sn:37](Cl)([CH2:42][CH2:43][CH2:44][CH3:45])[CH2:38][CH2:39][CH2:40][CH3:41])[CH2:34][CH2:35][CH3:36]>C1COCC1>[CH2:42]([Sn:37]([CH2:33][CH2:34][CH2:35][CH3:36])([CH2:38][CH2:39][CH2:40][CH3:41])[C:18]1[S:19][CH:20]=[C:21]([O:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH3:32])[C:17]=1[O:16][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH3:15])[CH2:43][CH2:44][CH3:45]
Reactant: CCCC[Sn](Cl)(CCCC)CCCC
Reactant: CCCCCCCCCCOc1cscc1OCCCCCCCCCC
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: CCCCCCCCCCOc1csc([Sn](CCCC)(CCCC)CCCC)c1OCCCCCCCCCC
Temperature: -40 °C
Reaction time: 1 h
Yield: 99 %

Procedure:
n-Butyllithium (1.8 mL, 4.5 mmol, 2.5 M solution in hexane) was added dropwise at -78° C. to a solution of 3,4-didecyloxythiophene (1.86 g, 4.69 mmol) in anhydrous THF (200 mL) under nitrogen. The solution was stirred for 1 h and warmed to -40° C. Tributylstannyl chloride (1.47 g, 4.52 mmol) was added and the entire solution was finally allowed to warm to room temperature. At room temperature the mixture was filtered using Celite and the solvent was stripped. The organo-tin compound was vacuum dried to give 2-(tributylstannyl)-3,4-didecyloxythiophene, obtained as a light yellow liquid, yield=99%. MS(EI) m/z (rel int): 629 [(M)+ --C4H9, 22%], 396 [(M+ --C12H27Sn), 8.5%], 256 [(M+ --C22H47Sn), 3%] and 116 [(M+ --C32H67Sn), 43%].
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[O:12][N:11]=[CH:10][C:9]=2[C:13]([OH:15])=O)=[CH:4][CH:3]=1.[CH2:16]([NH:23][CH2:24][C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1)[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1>>[CH2:24]([N:23]([CH2:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)[C:13]([C:9]1[CH:10]=[N:11][O:12][C:8]=1[C:5]1[CH:4]=[CH:3][C:2]([CH3:1])=[CH:7][CH:6]=1)=[O:15])[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1
Reactant: c1ccc(CNCc2ccccc2)cc1
Reactant: Cc1ccc(-c2oncc2C(=O)O)cc1
Product: Cc1ccc(-c2oncc2C(=O)N(Cc2ccccc2)Cc2ccccc2)cc1

Procedure:
The title compound was prepared from 5-(4-methylphenyl)isoxazole-4-carboxylic acid (10.2 mg, 0.050 mmol) and dibenzylamine (11.8 mg, 0.060 mmol) as described in synthetic method B and thereafter purified by preparative HPLC method B to give a solid (2.6 mg). Calcd for C25H22N2O2: 382.1681, found 382.1684.
Reaction SMILES: [CH2:1]([N:8]1[C:17]2[C:12](=[CH:13][C:14]([OH:18])=[CH:15][CH:16]=2)[CH2:11][CH2:10][CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[H-].[Na+].[Cl:21][C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=1[N:28]=[C:29]=[O:30]>O1CCCC1>[CH2:1]([N:8]1[C:17]2[C:12](=[CH:13][C:14]([O:18][C:29](=[O:30])[NH:28][C:23]3[CH:24]=[CH:25][CH:26]=[CH:27][C:22]=3[Cl:21])=[CH:15][CH:16]=2)[CH2:11][CH2:10][CH2:9]1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=C=Nc1ccccc1Cl
Reactant: Oc1ccc2c(c1)CCCN2Cc1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: O=C(Nc1ccccc1Cl)Oc1ccc2c(c1)CCCN2Cc1ccccc1
Reaction time: 0.33 h

Procedure:
A solution of 1-benzyl-1, 2, 3, 4-tetrahydro-quinolin-6-ol (0.239 g., 1 mmol) in dry tetrahydrofuran (5 ml) was added to a stirred suspension of sodium hydride (0.024 g, 1 mmol) in dry tetrahydrofuran (5 ml) at −10° C. during 5 min. The reaction mixture was stirred for 20 min. Then 2-chloro-phenyl isocyanate was added (0.184 g., 1.2 mmol) was added to the stirring reaction mixture. Stirring was continued for additional 2.5 hours during which the temperature was allowed to rise to room temperature (34° C.). The reaction mixture was quenched with water (0.2 ml), concentrated under vaccum, diluted with water (5 ml), extracted with chloroform (2×5 ml) and dried over sodium sulphate. The combined fractions of chloroform were concentrated under vaccum. The residue was chromatographed on silica gel using chloroform: hexane (20:80) as eluant to give 2i; yield: 0.20 g. (50.9%), m.p. 130° C., C23H21ClN2O2; 1H NMR δ ppm (CDCl3): 1.90-2.02 (m, 2H), 2.82 (t, 2H), 3.30-3.35 (m, 2H), 4.46 (s, 2H), 6.43-6.48 (m, 1H), 6.74-6.82 (m, 2H), 7.20-7.25 (m, 5H), 7.44-7.46 (m, 4H); IR vmax (KBr) (cm−1): 534, 754, 807, 882, 1018, 1059, 1193, 1245, 1303, 1352, 1432, 1506, 1597, 1718, 1749, 2371, 2830, 2922, 3418, 3760.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:8]=[C:9]([F:11])[CH:10]=1)[C:5]([OH:7])=O.[O:12]([CH2:19][C:20]1[O:21][C:22]2[CH2:23][NH:24][CH2:25][CH2:26][C:27]=2[N:28]=1)[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.Cl.CN(C)CCCN=C=NCC.ON1C2C=CC=CC=2N=N1.C(N(CC)C(C)C)(C)C>CN(C=O)C.O>[F:11][C:9]1[CH:8]=[C:4]([CH:3]=[C:2]([F:1])[CH:10]=1)[C:5]([N:24]1[CH2:25][CH2:26][C:27]2[N:28]=[C:20]([CH2:19][O:12][C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=3)[O:21][C:22]=2[CH2:23]1)=[O:7]
Reactant: c1ccc(OCc2nc3c(o2)CNCC3)cc1
Reactant: O=C(O)c1cc(F)cc(F)c1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Solvent: O
Product: O=C(c1cc(F)cc(F)c1)N1CCc2nc(COc3ccccc3)oc2C1
Temperature: 25 °C
Reaction time: 16 h
Yield: 54 %

Procedure:
3,5-Difluorobenzoic acid (0.082 g, 0.52 mmol) was added to a stirred solution of 4,5,6,7-tetrahydro-2-(phenoxymethyl)-oxazolo[5,4-c]pyridine (0.10 g, 0.43 mmol), 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (0.10 g, 0.52 mmol), 1-hydroxybenzotriazole (0.070 g, 0.52 mmol) and N,N-diisopropylethylamine (0.15 mL, 0.87 mmol) in anhydrous DMF (2.2 mL) under N2. The reaction mixture was stirred at room temperature for 16 hours, diluted with H2O and extracted with AcOEt. The organic layer was separated, extracted with brine, dried (Na2SO4), filtered and the solvent evaporated in vacuo. The crude product was purified by flash column chromatography (silica; 7 N solution of ammonia in MeOH in DCM 0/100 to 5/95). The desired fractions were collected and the solvents evaporated in vacuo to yield 5-(3,5-difluorobenzoyl)-4,5,6,7-tetrahydro-2-(phenoxymethyl)-oxazolo[5,4-c]pyridine (0.086 g, 53% yield) as a colorless oil. C20H16F2N2O3. (mixture of rotamers 65:35) 1H NMR (500 MHz, CDCl3) δ ppm 2.71 (br. s., 1.3 H), 2.79 (br. s., 0.7 H), 3.66 (br. s., 1.3 H), 4.02 (br. s., 0.7 H), 4.50 (br. s., 0.7 H), 4.80 (br. s., 1.3 H), 5.13 (br. s., 2 H), 6.82-6.95 (m, 1 H), 6.95-7.09 (m, 5 H), 7.31 (t, J=7.8 Hz, 2 H).
Reaction SMILES: Br[C:2](Br)=[CH:3][C:4]1[S:8][C:7]([C:9]2[S:10][CH:11]=[CH:12][CH:13]=2)=[CH:6][CH:5]=1.[Li]CCCC>C1COCC1>[C:3]([C:4]1[S:8][C:7]([C:9]2[S:10][CH:11]=[CH:12][CH:13]=2)=[CH:6][CH:5]=1)#[CH:2]
Reactant: BrC(Br)=Cc1ccc(-c2cccs2)s1
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: C#Cc1ccc(-c2cccs2)s1
Temperature: -78 °C
Yield: 88 %

Procedure:
Anhydrous 5-(2,2-dibromo-ethenyl)-2,2'-bithiophene was dissolved in anhydrous THF and stirred at -78° C. After n-BuLi was added into the solution and stirred for 1 hour, the temperature was raised to 25° C. and stirred for further 1 hour. The solution was monitored by thin layer chromatography to determine whether the reaction was completed. The reaction solution was then extracted with ether and washed with water. After the solution was washed with saturated NaCl solution and dried over anhydrous magnesium sulfate. After removal of ether, the crude product was purified by column chromatography and the oily product was obtained. The yield is 88%.
Reaction SMILES: [OH:1]/[N:2]=[C:3](/[C:9](=[O:11])[CH3:10])\[C:4]([O:6][CH2:7][CH3:8])=[O:5].[CH3:12][O:13][C@H:14]1[CH2:19][CH2:18][CH2:17][CH2:16][C@H:15]1O>>[CH3:12][O:13][C@@H:14]1[CH2:19][CH2:18][CH2:17][CH2:16][C@H:15]1[O:1]/[N:2]=[C:3](/[C:9](=[O:11])[CH3:10])\[C:4]([O:6][CH2:7][CH3:8])=[O:5]
Reactant: CO[C@H]1CCCC[C@H]1O
Reactant: CCOC(=O)/C(=N\O)C(C)=O
Product: CCOC(=O)/C(=N\O[C@@H]1CCCC[C@H]1OC)C(C)=O

Procedure:
Ethyl (Z)-2-hydroxyimino-3-oxobutyrate (0.98 g) was alkylated with cis-2-methoxycyclohexanol (0.89 g) as described in Example 4, method 3. The pure title compound was obtained as a colourless oil (0.3 g). νmax (film) 1745, 1695, and 1595 cm-1 ; δH (CDCl3) 1.30-2.30 (13H, m), 2.39 (3H, s), 3.42 (3H, s), and 4.20-4.60 (3H, m). [Mass spectrum: CI MH+ (272)].
Reaction SMILES: [C:1]([NH:4][C:5]1[C:10]([C:11]2[C:16]([CH3:17])=[CH:15][C:14]([O:18][CH2:19][C:20]3([OH:28])[CH2:25][CH2:24][S:23](=[O:27])(=[O:26])[CH2:22][CH2:21]3)=[CH:13][C:12]=2[CH3:29])=[CH:9][C:8]([CH2:30][NH:31][C:32]2[CH:37]=[CH:36][C:35]([CH2:38][CH2:39][C:40]([OH:42])=[O:41])=[C:34]([F:43])[CH:33]=2)=[CH:7][CH:6]=1)(=[O:3])[CH3:2].[OH-].[Na+].[Cl-].[Ca+2:47].[Cl-]>CO>[Ca+2:47].[C:1]([NH:4][C:5]1[C:10]([C:11]2[C:16]([CH3:17])=[CH:15][C:14]([O:18][CH2:19][C:20]3([OH:28])[CH2:21][CH2:22][S:23](=[O:27])(=[O:26])[CH2:24][CH2:25]3)=[CH:13][C:12]=2[CH3:29])=[CH:9][C:8]([CH2:30][NH:31][C:32]2[CH:37]=[CH:36][C:35]([CH2:38][CH2:39][C:40]([O-:42])=[O:41])=[C:34]([F:43])[CH:33]=2)=[CH:7][CH:6]=1)(=[O:3])[CH3:2].[C:1]([NH:4][C:5]1[C:10]([C:11]2[C:16]([CH3:17])=[CH:15][C:14]([O:18][CH2:19][C:20]3([OH:28])[CH2:21][CH2:22][S:23](=[O:27])(=[O:26])[CH2:24][CH2:25]3)=[CH:13][C:12]=2[CH3:29])=[CH:9][C:8]([CH2:30][NH:31][C:32]2[CH:37]=[CH:36][C:35]([CH2:38][CH2:39][C:40]([O-:42])=[O:41])=[C:34]([F:43])[CH:33]=2)=[CH:7][CH:6]=1)(=[O:3])[CH3:2]
Reactant: CC(=O)Nc1ccc(CNc2ccc(CCC(=O)O)c(F)c2)cc1-c1c(C)cc(OCC2(O)CCS(=O)(=O)CC2)cc1C
Agent: [Ca+2]
Agent: [Cl-]
Agent: [Na+]
Solvent: CO
Product: CC(=O)Nc1ccc(CNc2ccc(CCC(=O)[O-])c(F)c2)cc1-c1c(C)cc(OCC2(O)CCS(=O)(=O)CC2)cc1C
Yield: 44.3 %

Procedure:
To a solution of 3-{4-[({6-(acetylamino)-4′-[(4-hydroxy-1,1-dioxidotetrahydro-2H-thiopyran-4-yl)methoxy]-2′,6′-dimethylbiphenyl-3-yl}methyl)amino]-2-fluorophenyl}propanoic acid (86.3 mg, 0.14 mmol) in methanol (1 mL) was added 1 M sodium hydroxide solution (0.14 mL). Successively, an aqueous solution of calcium chloride (8.7 mg, 0.07 mmol) was gradually added. The precipitated solid was collected by filtration, washed with water, and vacuum dried to give the title compound (39.2 mg, yield 44%) as a colorless amorphous powder.
Reaction SMILES: [NH2:1][CH:2]1[N:8]=[C:7]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[C:6]2[CH:15]=[CH:16][CH:17]=[CH:18][C:5]=2[N:4]([CH3:19])[C:3]1=[O:20].[C:21]1([CH2:27][N:28]=[C:29]=[O:30])[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1>O1CCCC1>[CH3:19][N:4]1[C:5]2[CH:18]=[CH:17][CH:16]=[CH:15][C:6]=2[C:7]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)=[N:8][CH:2]([NH:1][C:29]([NH:28][CH2:27][C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)=[O:30])[C:3]1=[O:20]
Reactant: O=C=NCc1ccccc1
Reactant: CN1C(=O)C(N)N=C(c2ccccc2)c2ccccc21
Solvent: C1CCOC1
Product: CN1C(=O)C(NC(=O)NCc2ccccc2)N=C(c2ccccc2)c2ccccc21
Reaction time: 8 h

Procedure:
Equimolar amounts of 3(R,S)-amino-1,3-dihydro-1-methyl-5-phenyl-2H-1,4-benzodiazepin-2-one and phenylmethylisocyanate were mixed in 8 ml of dry tetrahydrofuran at room temperature. The reaction mixture was allowed to stand for 8 hours and was then filtered. The collected solids were washed with tetrahydrofuran and dried in vacuo over P2O5 to give the analytical product: 240°-242° C.
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6]([C:9](=[O:11])[CH3:10])=[CH:5][CH:4]=1)#[CH:2].[Cl:12][C:13]1[C:14]([C:20]#[N:21])=[N:15][CH:16]=[C:17](Cl)[CH:18]=1.CN(C=O)C.C(N(CC)CC)C>C(OCC)(=O)C.C(=O)(O)[O-].[Na+].Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.[Cu](I)I>[C:9]([C:6]1[CH:7]=[CH:8][C:3]([C:1]#[C:2][C:17]2[CH:18]=[C:13]([Cl:12])[C:14]([C:20]#[N:21])=[N:15][CH:16]=2)=[CH:4][CH:5]=1)(=[O:11])[CH3:10]
Reactant: N#Cc1ncc(Cl)cc1Cl
Reactant: C#Cc1ccc(C(C)=O)cc1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: I[Cu]I
Agent: O=C([O-])O
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CC(=O)c1ccc(C#Cc2cnc(C#N)c(Cl)c2)cc1

Procedure:
To a solution of 1-(4-ethynylphenyl)ethanone (commercially available) (1 eq) 3,5-dichloropicolinonitrile (1 eq), dichlorobis(triphenylphosphine)-palladium (II) (20 mol %), copper iodide (10 mol %) and DMF:Triethylamine (10:1) (0.13 M) was stirred at ambient temperature overnight. The reaction mixture was then diluted with ethyl acetate and sodium bi-carbonate solution. The two phases were separated, and the aqueous phase was extracted twice with ethyl acetate. The combined organic layers were washed with brine, dried over sodium sulfate, and concentrated en vacuo. The crude material was purified by flash chromatography on a COMBIFLASH® system (ISCO) using 0-100% ethyl acetate in hexane and 5-((4-acetylphenyl)ethynyl)-3-chloropicolinonitrile was isolated as a yellow solid