Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:9]=[C:10]3[CH:15]=[CH:14][C:13]([N:16]4[CH2:21][CH2:20][N:19]([CH3:22])[CH2:18][CH2:17]4)=[N:12][N:11]3[C:23]=2[C:24]2[CH:29]=[CH:28][N:27]=[C:26](F)[CH:25]=2)=[CH:4][CH:3]=1.[CH3:31][NH:32][CH3:33]>O>[F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:9]=[C:10]3[CH:15]=[CH:14][C:13]([N:16]4[CH2:17][CH2:18][N:19]([CH3:22])[CH2:20][CH2:21]4)=[N:12][N:11]3[C:23]=2[C:24]2[CH:29]=[CH:28][N:27]=[C:26]([N:32]([CH3:33])[CH3:31])[CH:25]=2)=[CH:4][CH:3]=1
Reactant: CN1CCN(c2ccc3nc(-c4ccc(F)cc4)c(-c4ccnc(F)c4)n3n2)CC1
Reactant: CNC
Solvent: O
Product: CN1CCN(c2ccc3nc(-c4ccc(F)cc4)c(-c4ccnc(N(C)C)c4)n3n2)CC1
Temperature: 150 °C

Procedure:
0.10 g (0.25 mmol) of 2-(4-fluorophenyl)-3-(2-fluoropyrid-4-yl)-6-(4-methylpiperazin-1-yl)imidazo[1,2-b]pyridazine and 10 mL of dimethylamine are introduced into an autoclave. The mixture is heated at 150° C. overnight and then cooled and poured into water. The product is extracted with chloroform, and the organic phase is dried over sodium sulfate and then concentrated under reduced pressure to give a solid. This solid is crystallized and recrystallized from acetonitrile to give 0.028 g of a white powder after cooling, filtering off and drying.
Reaction SMILES: O[C:2]1[C:7]([C:8]#[N:9])=[CH:6][N:5]=[C:4]2[C:10]3[CH:16]=[CH:15][CH:14]=[CH:13][C:11]=3[O:12][C:3]=12.CCCCCC.P(Cl)(Cl)([Cl:25])=O>>[Cl:25][C:2]1[C:7]([C:8]#[N:9])=[CH:6][N:5]=[C:4]2[C:10]3[CH:16]=[CH:15][CH:14]=[CH:13][C:11]=3[O:12][C:3]=12
Reactant: O=P(Cl)(Cl)Cl
Reactant: N#Cc1cnc2c(oc3ccccc32)c1O
Solvent: CCCCCC
Product: N#Cc1cnc2c(oc3ccccc32)c1Cl
Temperature: 25 °C
Yield: 65 %

Procedure:
A mixture of 2.10 g (11.0 mmol) of 4-hydroxybenzo[4,5]furo[3,2-b]pyridine-3-carbonitrile in 15 mL of phosphorous oxychloride is heated at reflux temperature for 1.5 hours, then cooled to room temperature. Hexane is added and the solid is collected by filtration, dissolved in ethyl acetate and washed with cold 1 N NaOH. The organic layer is dried over sodium sulfate, filtered through a pad of diatomaceous earth and concentrated in vacuo to give 1.55 g (65%) of a red solid, mp 229–231° C.
Reaction SMILES: CS([Cl:5])(=O)=O.[CH2:6]([O:9][C:10]1[CH:15]=[CH:14][C:13]([CH2:16]O)=[CH:12][CH:11]=1)[CH:7]=[CH2:8].C(N(CC)CC)C>ClCCl>[CH2:6]([O:9][C:10]1[CH:15]=[CH:14][C:13]([CH2:16][Cl:5])=[CH:12][CH:11]=1)[CH:7]=[CH2:8]
Reactant: CS(=O)(=O)Cl
Reactant: C=CCOc1ccc(CO)cc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: C=CCOc1ccc(CCl)cc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
7.67 g (67.0 mmol) methanesulfonyl chloride were given at 0° C. to a solution of 10.0 g (60.9 mmol) (4-allyloxy-phenyl)-methanol and 9.34 ml (67.0 mmol) triethylamine in 35 ml dichloromethane and stirred at r.t. overnight. The mixture was poured in ice water, extracted with dichloromethane and the organic phase dried over Na2SO4. After removal of solvents the residue was purified by chromatography on silica gel (ethyl acetate/n-heptane 1:5) to yield 3.12 g (28%) pale yellow oil.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C:9]([CH3:14])([CH3:13])[C:10]([OH:12])=O)=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH2:15]([O:22][C:23]([N:25]1[CH2:30][CH2:29][NH:28][CH2:27][CH2:26]1)=[O:24])[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1.ON1C2C=CC=CC=2N=N1.Cl.C(N=C=NCCCN(C)C)C>O1CCCC1.O>[CH2:15]([O:22][C:23]([N:25]1[CH2:30][CH2:29][N:28]([C:10](=[O:12])[C:9]([NH:8][C:6]([O:5][C:1]([CH3:2])([CH3:3])[CH3:4])=[O:7])([CH3:14])[CH3:13])[CH2:27][CH2:26]1)=[O:24])[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1
Reactant: O=C(OCc1ccccc1)N1CCNCC1
Reactant: CC(C)(C)OC(=O)NC(C)(C)C(=O)O
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: O
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)NC(C)(C)C(=O)N1CCN(C(=O)OCc2ccccc2)CC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 67.7 %

Procedure:
To a solution of 2-(tert-butoxycarbonylamino)-2-methylpropionic acid (10 g) in tetrahydrofuran (20 mL) were added 1-(benzyloxycarbonyl)piperazine (16.3 g), 1-hydroxybenzotriazole (8.02 g) and 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (11.4 g), and the mixture was stirred at room temperature overnight. The reaction mixture was poured into water, and the resulting mixture was extracted with ethyl acetate. The extract was washed with water and brine, and dried over anhydrous sodium sulfate. The solvent was removed under reduced pressure. The residue was dissolved in a mixed solvent of n-hexane and ethyl acetate (1/1) (40 mL) at 60° C. with heating, and the solution was stirred at room temperature overnight. To the mixture was added the same solvent (30 mL), and the mixture was further stirred overnight. The precipitated crystals were collected by filtration, and washed with the same solvent and dried under reduced pressure to give 4-benzyloxycarbonyl-1-[2-(tert-butoxycarbonylamino)-2-methylpropionyl]piperazine (13.5 g). To a solution of the obtained 4-benzyloxycarbonyl-1-[2-(tert-butoxycarbonylamino)-2-methylpropionyl]piperazine (5 g) in tetrahydrofuran (30 mL) was added hydrochloric acid (4 mol/L 1,4-dioxane solution, 40 mL), and the mixture was stirred at room temperature overnight. The precipitated crystals were collected by filtration. The obtained crystals were dissolved in ethyl acetate and a saturated aqueous sodium hydrogen carbonate solution. The organic layer was separated, and the organic layer was washed with brine and dried over anhydrous sodium sulfate. The solvent was removed under reduced pressure to give the title compound (3.65 g).
Reaction SMILES: [H-].[Al+3].[Li+].[H-].[H-].[H-].[Cl:7][C:8]1[CH:22]=[CH:21][C:11]([CH2:12][CH:13]2[NH:19][C:18](=O)[CH2:17][CH2:16][CH2:15][CH2:14]2)=[CH:10][CH:9]=1>O1CCCC1>[Cl:7][C:8]1[CH:22]=[CH:21][C:11]([CH2:12][CH:13]2[CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][NH:19]2)=[CH:10][CH:9]=1
Reactant: O=C1CCCCC(Cc2ccc(Cl)cc2)N1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Product: Clc1ccc(CC2CCCCCN2)cc1
Temperature: 0 °C
Yield: 68.3 %

Procedure:
Add 0.5 g of lithium aluminum hydride to a solution of 2.8 g 7-(4-chlorobenzyl)-perhydroazepin -2-one in 30 ml of tetrahydrofurane. Boil the mixture under reflux for 16 hours, cool it and then carefully treat it with ice-water. After extraction with diethyl ether, dry the extract over sodium sulfate concentrate the oily residue and distill in a vacuum to obtain 1.8 g of the title compound with a BP of 90° to 92° at 0.05 mm Hg.
Reaction SMILES: [CH2:1]([N:4]1[C:9](=[O:10])[C:8]([C:11]2[CH:16]=[CH:15][C:14](=[O:17])[NH:13][CH:12]=2)=[C:7]([C:18]2[CH:23]=[CH:22][CH:21]=[C:20]([F:24])[CH:19]=2)[N:6]=[C:5]1[NH2:25])[CH:2]=[CH2:3].[C:26](=O)([O-])[O-].[K+].[K+].IC>CS(C)=O>[CH2:1]([N:4]1[C:9](=[O:10])[C:8]([C:11]2[CH:16]=[CH:15][C:14](=[O:17])[N:13]([CH3:26])[CH:12]=2)=[C:7]([C:18]2[CH:23]=[CH:22][CH:21]=[C:20]([F:24])[CH:19]=2)[N:6]=[C:5]1[NH2:25])[CH:2]=[CH2:3]
Reactant: O=C([O-])[O-]
Reactant: C=CCn1c(N)nc(-c2cccc(F)c2)c(-c2ccc(=O)[nH]c2)c1=O
Agent: [K+]
Solvent: CI
Solvent: CS(C)=O
Product: C=CCn1c(N)nc(-c2cccc(F)c2)c(-c2ccc(=O)n(C)c2)c1=O
Temperature: 50 °C
Reaction time: 16 h

Procedure:
To a solution of 3-allyl-2-amino-6-(3-fluorophenyl)-5-(6-oxo-1,6-dihydro-3-pyridinyl)-3,4-dihydro-4-pyrimidinone in dimethyl sulfoxide were added potassium carbonate (2 equivalents) and iodomethane (4 equivalents), followed by stirring at 50° C. for 16 hours. After filtering off the insoluble matters, the filtrate was purified by HPLC, to give the title compound.
Reaction SMILES: [CH3:1][NH:2][CH2:3][CH2:4][OH:5].CO[C:8]([C:10]1[C:14]([NH:15][C:16]([C:18]2[C:23]([NH:24][C:25]3[CH:26]=[N:27][CH:28]=[N:29][CH:30]=3)=[CH:22][CH:21]=[C:20]([CH:31]3[CH2:33][CH2:32]3)[N:19]=2)=[O:17])=[CH:13][N:12]([CH3:34])[N:11]=1)=[O:9]>>[OH:5][CH2:4][CH2:3][N:2]([CH3:1])[C:8]([C:10]1[C:14]([NH:15][C:16]([C:18]2[C:23]([NH:24][C:25]3[CH:26]=[N:27][CH:28]=[N:29][CH:30]=3)=[CH:22][CH:21]=[C:20]([CH:31]3[CH2:32][CH2:33]3)[N:19]=2)=[O:17])=[CH:13][N:12]([CH3:34])[N:11]=1)=[O:9]
Reactant: COC(=O)c1nn(C)cc1NC(=O)c1nc(C2CC2)ccc1Nc1cncnc1
Reactant: CNCCO
Product: CN(CCO)C(=O)c1nn(C)cc1NC(=O)c1nc(C2CC2)ccc1Nc1cncnc1
Yield: 13 %

Procedure:
According to the general method described in step 5 of example 27, reaction of 2-methylamino-ethanol with 4-{[6-cyclopropyl-3-(pyrimidin-5-ylamino)-pyridine-2-carbonyl]-amino}-1-methyl-1H-pyrazole-3-carboxylic acid methyl ester provided the title compound (13%) as amorphous yellow solid.
Reaction SMILES: [Cl:1][C:2]1[C:7]([N+:8]([O-:10])=[O:9])=[CH:6][N:5]=[C:4]([OH:11])[CH:3]=1.O[CH2:13][C@@H:14]([NH:16][C:17](=[O:23])[O:18][C:19]([CH3:22])([CH3:21])[CH3:20])[CH3:15].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(C)C=CC=CC=1.N(C(OC(C)C)=O)=NC(OC(C)C)=O>C1COCC1>[Cl:1][C:2]1[C:7]([N+:8]([O-:10])=[O:9])=[CH:6][N:5]=[C:4]([O:11][CH2:15][C@@H:14]([NH:16][C:17](=[O:23])[O:18][C:19]([CH3:20])([CH3:22])[CH3:21])[CH3:13])[CH:3]=1
Reactant: C[C@@H](CO)NC(=O)OC(C)(C)C
Reactant: O=[N+]([O-])c1cnc(O)cc1Cl
Agent: CC(C)OC(=O)N=NC(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: Cc1ccccc1
Solvent: C1CCOC1
Product: C[C@@H](COc1cc(Cl)c([N+](=O)[O-])cn1)NC(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 45.2 %

Procedure:
To a solution of 4-chloro-5-nitropyridin-2-ol (1.00 g), tert-butyl ((2S)-1-hydroxypropan-2-yl)carbamate (1.51 g) and triphenylphosphine (2.25 g) in THF (10 mL) was added dropwise diisopropyl azodicarboxylate toluene solution (1.9 M, 4.52 mL), and the mixture was stirred at room temperature for 30 min. The reaction mixture was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (NH, hexane/ethyl acetate) to give the title compound (860 mg).
Reaction SMILES: F[CH2:2][C:3]([C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1)=O.[NH2:11][NH2:12].C(Cl)Cl>C(O)CO>[CH3:2][C:3]1[C:5]2[C:10](=[CH:9][CH:8]=[CH:7][CH:6]=2)[NH:12][N:11]=1
Reactant: NN
Reactant: O=C(CF)c1ccccc1
Solvent: ClCCl
Solvent: OCCO
Product: Cc1n[nH]c2ccccc12
Temperature: 25 °C
Reaction time: 2 h
Yield: 75.7 %

Procedure:
To a stirring solution of 36.2 g (0.26 mol) of 2-Fluoroacetophenone in 120 mL of ethylene glycol is added 8.6 mL (0.27 mol, 1.05 equiv.) of hydrazine. The resulting solution is stirred 2 h at RT and then heated at 165° C. for 40 h. The solution is cooled to RT, poured into CH2Cl2 (200 mL) and extracted with H2O (2×200 mL). The organic layers were combined, dried (MgSO4), and the solvent removed in vacuo. Purification of the crude material by recrystallization form hexane/CHCl3 afforded 26 g of 3-Methylindazole as a light tan solid: 1H NMR (CDCl3, 300 MHz) δ7.73 (d, 1H, J=8.1), 7.44 (m, 2H), 7.19 (dd, 1H, J=7.0,7.0), 2.67 (s, 3H).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C@H:8]([O:10][C:11](=[O:26])[NH:12][C:13]1[C:14]([CH3:25])=[N:15][O:16][C:17]=1[C:18]1[CH:23]=[CH:22][C:21](Br)=[CH:20][CH:19]=1)[CH3:9].[CH2:27]([O:29][C:30](=[O:49])[C:31]([CH3:48])([C:33]1[CH:38]=[CH:37][C:36](B2OC(C)(C)C(C)(C)O2)=[CH:35][CH:34]=1)[CH3:32])[CH3:28]>>[CH2:27]([O:29][C:30](=[O:49])[C:31]([C:33]1[CH:38]=[CH:37][C:36]([C:21]2[CH:22]=[CH:23][C:18]([C:17]3[O:16][N:15]=[C:14]([CH3:25])[C:13]=3[NH:12][C:11]([O:10][C@@H:8]([C:3]3[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=3[F:1])[CH3:9])=[O:26])=[CH:19][CH:20]=2)=[CH:35][CH:34]=1)([CH3:48])[CH3:32])[CH3:28]
Reactant: CCOC(=O)C(C)(C)c1ccc(B2OC(C)(C)C(C)(C)O2)cc1
Reactant: Cc1noc(-c2ccc(Br)cc2)c1NC(=O)O[C@H](C)c1ccccc1F
Product: CCOC(=O)C(C)(C)c1ccc(-c2ccc(-c3onc(C)c3NC(=O)O[C@H](C)c3ccccc3F)cc2)cc1

Procedure:
Following the procedure described in Example 36, Step 6, [5-(4-bromo-phenyl)-3-methyl-isoxazol-4-yl]-carbamic acid (R)-1-(2-fluoro-phenyl)-ethyl ester and 2-methyl-2-[4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-phenyl]-propionic acid ethyl ester were reacted to provide 2-(4′-{4-[(R)-1-(2-Fluoro-phenyl)-ethoxycarbonylamino]-3-methyl-isoxazol-5-yl}-biphenyl-4-yl)-2-methyl-propionic acid ethyl ester, which was hydrolyzed to the acid as described in Example 17, Step 3.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[C:9]1[C:18]([C:19]2[CH:24]=[CH:23][C:22]([Cl:25])=[CH:21][CH:20]=2)=[CH:17][C:12]([C:13]([O:15][CH3:16])=[O:14])=[C:11](Cl)[N:10]=1.[Cl:27][C:28]1[CH:29]=[N:30][CH:31]=[C:32]([OH:34])[CH:33]=1>>[Cl:25][C:22]1[CH:23]=[CH:24][C:19]([C:18]2[C:9]([C:3]3[CH:4]=[CH:5][C:6]([Cl:8])=[CH:7][C:2]=3[Cl:1])=[N:10][C:11]([O:34][C:32]3[CH:31]=[N:30][CH:29]=[C:28]([Cl:27])[CH:33]=3)=[C:12]([CH:17]=2)[C:13]([O:15][CH3:16])=[O:14])=[CH:20][CH:21]=1
Reactant: Oc1cncc(Cl)c1
Reactant: COC(=O)c1cc(-c2ccc(Cl)cc2)c(-c2ccc(Cl)cc2Cl)nc1Cl
Product: COC(=O)c1cc(-c2ccc(Cl)cc2)c(-c2ccc(Cl)cc2Cl)nc1Oc1cncc(Cl)c1

Procedure:
Using the procedure described in Example 84, methyl 6-(2,4-dichlorophenyl)-5-(4-chlorophenyl)-2-chloro-nicotinate Example 83 was reacted with 3-chloro-5-hydroxypyridine to afford the title compound: m/e=521 (M+3); Rt=4.65 min
Reaction SMILES: [Cl:1][CH:2]=[C:3]1[C:7]([CH2:9][CH3:10])([CH3:8])[CH2:6][CH2:5][O:4]1.[ClH:11]>>[Cl:1][CH2:2][C:3](=[O:4])[C:7]([CH2:9][CH3:10])([CH3:8])[CH2:6][CH2:5][Cl:11]
Reactant: CCC1(C)CCOC1=CCl
Reactant: Cl
Product: CCC(C)(CCCl)C(=O)CCl
Reaction time: 2 h
Yield: 81 %

Procedure:
64 g (0.4 mole) of 2-chloromethylene-3-ethyl-3-methyl-tetrahydrofuran are saturated with hydrogen chloride gas at 10° to 20° C., while cooling with ice. After the mixture has been left to stand at room temperature for 2 hours, excess hydrogen chloride is stripped off and the residue is distilled. 60 g (81% of theory) of 1,5-dichloro-3-ethyl-3-methyl-2-pentanone of boiling point 92°-101° C./0.05 mbar are obtained. ##STR102##
Reaction SMILES: S(=O)(=O)(O)O.[CH3:6]O.[C:8]([OH:17])(=[O:16])[CH2:9][CH2:10][CH2:11][CH2:12][CH:13]([CH3:15])[CH3:14]>C1(C)C=CC=CC=1>[CH3:6][O:16][C:8](=[O:17])[CH2:9][CH2:10][CH2:11][CH2:12][CH:13]([CH3:15])[CH3:14]
Reactant: CO
Reactant: CC(C)CCCCC(=O)O
Agent: O=S(=O)(O)O
Solvent: Cc1ccccc1
Product: COC(=O)CCCCC(C)C
Yield: 95 %

Procedure:
2 g concentrated sulfuric acid were added to a solution of 32 g (1 mol) methanol and 144 g (1 mol) "isooctanoic acid" (isomeric mixture from Ruhrchemie A. G. Oberhausen) in 200 ml toluene and heated to boiling with hater separation until the equimolar amount of water separates (about 2 hours). After cooling it was washed with water and then with 10% sodium bicarbonate solution. The solvent was distilled off under reduced pressure. The remaining end-product after distillation over a 15 cm Vigreux column gave 150 g (95%) isooctanoic acid methylester as an easily mobile liquid with a fruity smell.
Reaction SMILES: C1C=CC(C2C=CC=CC=2)=CC=1.C1C=CC(OC2C=CC=CC=2)=CC=1.[Br:26][C:27]1[CH:32]=[CH:31][C:30]([NH:33][CH:34]=[C:35]([S:41]([CH3:44])(=[O:43])=[O:42])[C:36]([O:38]CC)=O)=[CH:29][CH:28]=1>>[Br:26][C:27]1[CH:28]=[C:29]2[C:30](=[CH:31][CH:32]=1)[N:33]=[CH:34][C:35]([S:41]([CH3:44])(=[O:42])=[O:43])=[C:36]2[OH:38]
Reactant: CCOC(=O)C(=CNc1ccc(Br)cc1)S(C)(=O)=O
Solvent: c1ccc(Oc2ccccc2)cc1
Solvent: c1ccc(-c2ccccc2)cc1
Product: CS(=O)(=O)c1cnc2ccc(Br)cc2c1O
Temperature: 25 °C
Reaction time: 2 h
Yield: 61.2 %

Procedure:
To Dowtherm at 250° C. was added ethyl 3-(4-bromophenylamino)-2-(methylsulfonyl)acrylate (1.08 g, 3.10 mmol) portionwise and the reaction mixture was stirred for 2 h. The reaction mixture was cooled to room temperature, diluted with hexanes and the resulting precipitate was filtered to afford the desired product (573 mg, 61%) as a tan solid: ESI MS m/z 302 [C10H8BrNO3S+H]+.
Reaction SMILES: [C:1]([O:5]/[N:6]=[C:7](\[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][N:17]=1)/[C:8]1[CH:13]=[C:12](Br)[CH:11]=[CH:10][C:9]=1[OH:15])([CH3:4])([CH3:3])[CH3:2].C(N)[CH2:23][NH2:24]>CN(C=O)C.O>[C:1]([O:5]/[N:6]=[C:7](\[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][N:17]=1)/[C:8]1[CH:13]=[C:12]([C:23]#[N:24])[CH:11]=[CH:10][C:9]=1[OH:15])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)O/N=C(\c1ccccn1)c1cc(Br)ccc1O
Reactant: NCCN
Solvent: CN(C)C=O
Solvent: O
Product: CC(C)(C)O/N=C(\c1ccccn1)c1cc(C#N)ccc1O
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
(Z)-2-(5-bromo-2-hydroxybenzoyl)pyridine O-t-butyloxime (12.7 g) was dissolved in DMF (100 ml). To the solution was added cuprous cyanide (4.64 g), and the mixture was heated, under argon atmosphere, for 3 hours under reflux. To the reaction mixture was added a solution of ethylenediamine (30 ml) in water (20 ml). The mixture was stirred for 30 minutes at room temperature, followed by extraction with ethyl acetate. The organic layer was dried (anhydrous magnesium sulfate), then the solvent was distilled off. The residue was purified by means of a silica gel column chromatography, eluting with ethyl acetate/hexane, to give (Z)-2-(5-cyano-2-hydroxybenzoyl)pyridine O-t-butyloxime (4.31 g) (Compound 76).
Reaction SMILES: [C:1]([C:3]1[CH:4]=[N:5][CH:6]=[CH:7][CH:8]=1)#[CH:2].Br[C:10]1[C:18]([N+:19]([O-:21])=[O:20])=[CH:17][CH:16]=[C:15]2[C:11]=1/[C:12](=[CH:23]/[C:24]1[NH:25][CH:26]=[CH:27][C:28]=1[O:29][CH3:30])/[C:13](=[O:22])[NH:14]2>C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.[Cu]I.CN(C=O)C.CCN(CC)CC>[CH3:30][O:29][C:28]1[CH:27]=[CH:26][NH:25][C:24]=1/[CH:23]=[C:12]1\[C:13](=[O:22])[NH:14][C:15]2[C:11]\1=[C:10]([C:2]#[C:1][C:3]1[CH:4]=[N:5][CH:6]=[CH:7][CH:8]=1)[C:18]([N+:19]([O-:21])=[O:20])=[CH:17][CH:16]=2
Reactant: COc1cc[nH]c1/C=C1\C(=O)Nc2ccc([N+](=O)[O-])c(Br)c21
Reactant: C#Cc1cccnc1
Agent: [Cu]I
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: COc1cc[nH]c1/C=C1\C(=O)Nc2ccc([N+](=O)[O-])c(C#Cc3cccnc3)c21

Procedure:
Using Method D above, 3-ethynyl pyridine (0.14 g, 1.38 mmol) (see Example 64) was coupled with (Z)-4-bromo-1,3-dihydro-3-[(3-methoxy-1H-pyrrol-2-yl)methylene]-5-nitro-2H-indol-2-one (0.2 g, 0.55 mmol) (Starting Material 3) using (Ph3P)4Pd (31.8 mg) (Aldrich) and CuI (5.3 mg) (Aldrich) as catalyst in DMF (6 mL) and Et3N (6 mL) as solvent and at 85° C. for 18 h, yielding (Z)-1,3-dihydro-3-[(3-methoxy-1H-pyrrol-2-yl)methylene]-5-nitro-4-[(3-pyridinyl)ethynyl]-2H-indol-2-one. (Yield 0.16 g, 71%).
Reaction SMILES: [Cl:1][C:2]1[CH:9]=[C:6]([CH:7]=[O:8])[C:5]([OH:10])=[CH:4][CH:3]=1.[CH3:11][C:12]1([CH3:25])[CH2:17][CH:16](OS(C)(=O)=O)[CH2:15][C:14]([CH3:24])([CH3:23])[O:13]1.C([O-])([O-])=O.[K+].[K+]>CN(C)C=O>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([O:10][CH:16]2[CH2:15][C:14]([CH3:24])([CH3:23])[O:13][C:12]([CH3:25])([CH3:11])[CH2:17]2)=[C:6]([CH:9]=1)[CH:7]=[O:8]
Reactant: CC1(C)CC(OS(C)(=O)=O)CC(C)(C)O1
Reactant: O=Cc1cc(Cl)ccc1O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CC1(C)CC(Oc2ccc(Cl)cc2C=O)CC(C)(C)O1

Procedure:
In a manner similar to the method described in example 4a, 5-chlorosalicylaldehyde (4.6 g, 30 mmol) (Aldrich) reacted with methanesulfonic acid 2,2,6,6-tetramethyl-tetrahydro-pyran-4-yl ester (8 g, 34 mmol) and K2CO3 in N,N-dimethylformamide to give 5-chloro-2-(2,2,6,6-tetramethyl-tetrahydro-pyran-4-yloxy)-benzaldehyde as a off white solid (Yield 0.94 g, 10%).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[NH:8][C:9]([C:12]1[S:25][C:15]2[C:16]3[CH:24]=[N:23][CH:22]=[CH:21][C:17]=3[O:18][CH2:19][CH2:20][C:14]=2[CH:13]=1)=[N:10][NH2:11].[CH2:26](OC(OCC)OCC)C>>[S:25]1[C:15]2[C:16]3[CH:24]=[N:23][CH:22]=[CH:21][C:17]=3[O:18][CH2:19][CH2:20][C:14]=2[CH:13]=[C:12]1[C:9]1[N:8]([C:3]2[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=2[Cl:1])[CH:26]=[N:11][N:10]=1
Reactant: NN=C(Nc1ccccc1Cl)c1cc2c(s1)-c1cnccc1OCC2
Reactant: CCOC(OCC)OCC
Product: Clc1ccccc1-n1cnnc1-c1cc2c(s1)-c1cnccc1OCC2
Temperature: 85 °C
Yield: 38 %

Procedure:
A mixture of N-(2-chlorophenyl)-4,5-dihydropyrido[4,3-b]thieno[2,3-d]oxepine-2-carbohydrazonamide (44 mg, 0.12 mmol) and 3 ml of triethylorthoformate was heated at 85° C. for 4 hours. The mixture was concentrated in vacuum and triturated with diethylether. The precipitate was collected, washed with diethylether and purified by flash chromatography eluting with 60% of ethyl acetate in hexane to give 320 (17 mg, 38%). MS: (ESI+) 381.1
Reaction SMILES: [O:1]1[CH2:3][C@H:2]1[CH2:4][O:5][C:6]1[CH:14]=[CH:13][CH:12]=[C:11]2[C:7]=1[CH:8]=[CH:9][NH:10]2.[Cl:15][C:16]1[CH:17]=[C:18]2[C:22](=[CH:23][CH:24]=1)[NH:21][CH:20]=[C:19]2[CH:25]1[CH2:30][CH2:29][NH:28][CH2:27][CH2:26]1.C(O)C>CS(C)=O>[Cl:15][C:16]1[CH:17]=[C:18]2[C:22](=[CH:23][CH:24]=1)[NH:21][CH:20]=[C:19]2[CH:25]1[CH2:30][CH2:29][N:28]([CH2:3][C@H:2]([OH:1])[CH2:4][O:5][C:6]2[CH:14]=[CH:13][CH:12]=[C:11]3[C:7]=2[CH:8]=[CH:9][NH:10]3)[CH2:27][CH2:26]1
Reactant: c1cc(OC[C@@H]2CO2)c2cc[nH]c2c1
Reactant: Clc1ccc2[nH]cc(C3CCNCC3)c2c1
Solvent: CCO
Solvent: CS(C)=O
Product: O[C@H](COc1cccc2[nH]ccc12)CN1CCC(c2c[nH]c3ccc(Cl)cc23)CC1

Procedure:
The title compound was prepared in a fashion similar to that described in Example 1 using (S)-(+)-4-(oxiranylmethoxy)-1H-indole and 5-chloro-3-(piperidin-4-yl)-1H-indole using ethanol as the reaction solvent. Yield 0.380 g (42%) as a yellowish foam. mp 109°-114° C. (dec) FDMS m/e=423 (M+ of free base). α[D]589 =+6.5 (c=1.04, dimethylsulfoxide).
Reaction SMILES: [CH3:1][N:2]([O:7][CH3:8])[C:3](=[O:6])[CH2:4]Br.[C:9]([NH:12][C:13]1[CH:18]=[CH:17][C:16]([OH:19])=[CH:15][CH:14]=1)(=[O:11])[CH3:10].C(=O)([O-])[O-].[Cs+].[Cs+]>C(#N)C>[CH3:1][N:2]([O:7][CH3:8])[C:3](=[O:6])[CH2:4][O:19][C:16]1[CH:15]=[CH:14][C:13]([NH:12][C:9](=[O:11])[CH3:10])=[CH:18][CH:17]=1
Reactant: CON(C)C(=O)CBr
Reactant: CC(=O)Nc1ccc(O)cc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CC#N
Product: CON(C)C(=O)COc1ccc(NC(C)=O)cc1
Yield: 74 %

Procedure:
This bromoacetamide was dissolved in acetonitrile and to the solution were added 10.75 gm (71.15 mMol) 4-acetamidophenol followed by 23.10 gm (71.1 mMol) cesium carbonate. The reaction mixture was heated at reflux for 3 hours and then concentrated under reduced pressure. The residue was partitioned between dichloromethane and 1N aqueous sodium hydroxide. The organic phase was separated, washed sequentially with water and saturated aqueous sodium chloride, dried over magnesium sulfate and concentrated under reduced pressure. The residue was subjected to silica gel chromatography, eluting with ethyl acetate. Fractions containing product were combined and concentrated under reduced pressure to provide 10.34 gm (74%) of the desired compound.
Reaction SMILES: [F:1][CH2:2][C:3]([CH3:13])([CH3:12])[C:4](=[O:11])[CH2:5][N:6]1[CH:10]=[N:9][CH:8]=[N:7]1.[OH-].[K+].[CH3:16]I.[ClH:18]>CS(C)=O.O>[ClH:18].[F:1][CH2:2][C:3]([CH3:13])([CH3:12])[C:4](=[O:11])[CH:5]([N:6]1[CH:10]=[N:9][CH:8]=[N:7]1)[CH3:16]
Reactant: CI
Reactant: CC(C)(CF)C(=O)Cn1cncn1
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: CS(C)=O
Product: CC(C(=O)C(C)(C)CF)n1cncn1
Temperature: 25 °C
Reaction time: 24 h
Yield: 71.7 %

Procedure:
37.2 g (0.2 mol) of 1-fluoro-2,2-dimethyl-4-(1,2,4-triazol-1-yl)-butan-3-one were dissolved in 200 ml of dimethylsulphoxide, 11.2 g (0.2 mol) of potassium hydroxide, dissolved in 24 ml of water, were added and 28.4 g (0.2 mol) of methyl iodide were added dropwise at 20° C., whilst cooling. The reaction mixture was subsequently stirred at room temperature for 24 hours and poured onto 1,000 ml of water, the mixture was extracted twice with 200 ml of methylene chloride each time, the combined organic phases were washed five times with 100 ml of water each time and dried over sodium sulphate, the solvent was distilled off, the residue was taken up in 100 ml of acetone, the mixture was filtered and the solvent was distilled off from the mother liquor. The residue was taken up in 150 ml of ethyl acetate, and 14.4 g (0.2 mol) of hydrogen chloride were passed in. Thereafter, the mixture was allowed to crystallise out. 33.8 g (72% of theory) of 1-fluoro-2,2-dimethyl-4-(1,2,4-triazol-1-yl)-pentan-3-one hydrochloride of melting point 142° C. were obtained. ##STR62##