Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [S:1]1[CH:5]=[CH:4][C:3]2[C:6](=[O:10])[CH2:7][CH2:8][CH2:9][C:2]1=2.[N+:11]([O-])([OH:13])=[O:12]>S(=O)(=O)(O)O>[N+:11]([C:5]1[S:1][C:2]2[CH2:9][CH2:8][CH2:7][C:6](=[O:10])[C:3]=2[CH:4]=1)([O-:13])=[O:12]
Reactant: O=C1CCCc2sccc21
Reactant: O=[N+]([O-])O
Agent: O=S(=O)(O)O
Product: O=C1CCCc2sc([N+](=O)[O-])cc21
Temperature: 0 °C
Reaction time: 1 h
Yield: 88 %

Procedure:
6,7-Dihydrobenzo[b]thiophen-4(5H)-one (5 g, 32.9 mmol) was dissolved in concentrated sulphuric acid (30 mL) and cooled to 0° C. in an ice/salt bath. Concentrated nitric acid (3.5 mL) in concentrated sulphuric acid (20 mL) was added drop-wise keeping the temperature of the reaction below 0° C. The reaction mixture was stirred at 0-5° C. for 1 hr. The solution was poured onto ice and the resulting solid filtered, washed with water and dried in a vacuum oven, affording the title compound (5.68 g, 88%).
Reaction SMILES: [NH2:1][C:2]1[CH:13]=[CH:12][C:5]2[N:6]=[C:7](SC)[CH2:8][O:9][C:4]=2[C:3]=1[C:14]([O:16][CH3:17])=[O:15].[CH3:18][O:19][CH:20]([O:23][CH3:24])[CH2:21][NH2:22]>C(O)C>[NH2:1][C:2]1[CH:13]=[CH:12][C:5]2[N:6]=[C:7]([NH:22][CH2:21][CH:20]([O:23][CH3:24])[O:19][CH3:18])[CH2:8][O:9][C:4]=2[C:3]=1[C:14]([O:16][CH3:17])=[O:15]
Reactant: COC(CN)OC
Reactant: COC(=O)c1c(N)ccc2c1OCC(SC)=N2
Solvent: CCO
Product: COC(=O)c1c(N)ccc2c1OCC(NCC(OC)OC)=N2
Yield: 115.1 %

Procedure:
A solution of methyl 7-amino-3-methylsulfanyl-2H-benzo[1,4]oxazine-8-carboxylate (Intermediate 28, 0.645 g) and aminoacetaldehyde dimethylacetal (0.403 g) in ethanol (15 mL) was heated to reflux for 4 days. After cooling, the mixture was concentrated in vacuo to give methyl 7-amino-3-(2,2-dimethoxyethylamino)-2H-benzo[1,4]oxazine-8-carboxylate (0.910 g) as a brown oil.
Reaction SMILES: [O:1]=[C:2]1[CH2:10][C:9]2[C:4](=[C:5]([O:11][C:12]3[CH:17]=[C:16]([O:18][CH3:19])[C:15]([O:20][CH3:21])=[C:14]([O:22][CH3:23])[CH:13]=3)[CH:6]=[CH:7][CH:8]=2)[NH:3]1.[OH-].[Na+].[O:26]1CCOCC1>O>[NH2:3][C:4]1[C:5]([O:11][C:12]2[CH:17]=[C:16]([O:18][CH3:19])[C:15]([O:20][CH3:21])=[C:14]([O:22][CH3:23])[CH:13]=2)=[CH:6][CH:7]=[CH:8][C:9]=1[CH2:10][C:2]([OH:26])=[O:1]
Reactant: COc1cc(Oc2cccc3c2NC(=O)C3)cc(OC)c1OC
Reactant: C1COCCO1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: COc1cc(Oc2cccc(CC(=O)O)c2N)cc(OC)c1OC

Procedure:
A mixture of 2-oxo-7-(3,4,5-trimethoxyphenoxy)indoline (3.2 g.), sodium hydroxide (1 g.), dioxane (20 ml.) and water (20 ml.) was refluxed under heating for 36 hours with stirring. After cooling, the reaction mixture was washed with diethyl ether. Ethyl acetate was added to the aqueous solution and adjusted to pH 4.0 with 5% sulfuric acid. The ethyl acetate layer was separated, washed with water and dried over magnesium sulfate and the solvent was distilled off under reduced pressure. The residue was pulverized with diethyl ether to give 2-[2-amino-3-(3,4,5-trimethoxyphenoxy)phenyl]acetic acid (2.5 g.).
Reaction SMILES: Cl.[C:2]1([CH3:10])[CH:7]=[CH:6][C:5]([NH:8][NH2:9])=[CH:4][CH:3]=1.[CH2:11]([O:13][C:14](=[O:23])[CH2:15][CH:16]([C:20](=O)[CH3:21])[C:17](=O)[CH3:18])[CH3:12].C([O-])(=O)C.[Na+]>C(O)C>[CH2:11]([O:13][C:14](=[O:23])[CH2:15][C:16]1[C:17]([CH3:18])=[N:9][N:8]([C:5]2[CH:6]=[CH:7][C:2]([CH3:10])=[CH:3][CH:4]=2)[C:20]=1[CH3:21])[CH3:12]
Reactant: Cc1ccc(NN)cc1
Reactant: CCOC(=O)CC(C(C)=O)C(C)=O
Agent: CC(=O)[O-]
Agent: Cl
Agent: [Na+]
Solvent: CCO
Product: CCOC(=O)Cc1c(C)nn(-c2ccc(C)cc2)c1C
Yield: 89 %

Procedure:
8.0 grams p-tolylhydrazine-hydrochloride, 9.3 grams 3,3-diacetyl-propionic acid-ethyl ester, 4.1 grams anhydrous sodium acetate and 70 milliliters ethanol were mixed and the mixture was heated to the boiling temperature under reflux for 1.5 hour. The reaction mixture was worked up as described in Example (3a). After distillation, 12.1 grams 3,5-dimethyl-1-(p-tolyl)pyrazol-4-acetic acid-ethyl ester were obtained as a viscous oil having a Kp0.001 of 145°-146° C., representing a yield of 89%. For analysis, the product was redistilled resulting in an nD20 1.5455.
Reaction SMILES: [O:1]=[C:2]1[CH2:7][CH2:6][S:5][CH2:4][C:3]1=[CH:8][C:9]1[CH:14]=[CH:13][C:12]([CH:15]([CH3:23])[C:16]([O:18]C(C)(C)C)=[O:17])=[CH:11][CH:10]=1.FC(F)(F)C(O)=O>C(Cl)(Cl)Cl>[O:1]=[C:2]1[CH2:7][CH2:6][S:5][CH2:4][C:3]1=[CH:8][C:9]1[CH:14]=[CH:13][C:12]([CH:15]([CH3:23])[C:16]([OH:18])=[O:17])=[CH:11][CH:10]=1
Reactant: CC(C(=O)OC(C)(C)C)c1ccc(C=C2CSCCC2=O)cc1
Solvent: ClC(Cl)Cl
Solvent: O=C(O)C(F)(F)F
Product: CC(C(=O)O)c1ccc(C=C2CSCCC2=O)cc1
Temperature: 25 °C
Reaction time: 4 h
Yield: 87.5 %

Procedure:
tert-Butyl 2-[4-(4-oxothian-3-ylidenemethyl)phenyl]propionate (220 mg) obtained in Example 1 was dissolved in chloroform (2.0 ml), to the solution was added trifluoroacetic acid (2.0 ml), and the mixture was stirred at room temperature for 4 hours. The reaction mixture was quenched with water, and extracted with chloroform. The organic layer was washed with water and saturated brine, and then dried over sodium sulfate. The solvent was evaporated under reduced pressure, and then the residue was purified by silica gel column chromatography (hexane/ethyl acetate=3/2) to give the title compound (160 mg, 87%).
Reaction SMILES: [Br:1][C:2]1[N:7]=[C:6]([C:8]2[C:16]3[C:11](=[N:12][CH:13]=[CH:14][CH:15]=3)[NH:10][N:9]=2)[CH:5]=[CH:4][CH:3]=1.[H-].[Na+].[C:19](Cl)([C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1)([C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1)[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1>CN(C=O)C>[Br:1][C:2]1[N:7]=[C:6]([C:8]2[C:16]3[C:11](=[N:12][CH:13]=[CH:14][CH:15]=3)[N:10]([C:19]([C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)([C:32]3[CH:33]=[CH:34][CH:35]=[CH:36][CH:37]=3)[C:26]3[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=3)[N:9]=2)[CH:5]=[CH:4][CH:3]=1
Reactant: Brc1cccc(-c2n[nH]c3ncccc23)n1
Reactant: ClC(c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: Brc1cccc(-c2nn(C(c3ccccc3)(c3ccccc3)c3ccccc3)c3ncccc23)n1
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
A stirred suspension of 3-(6-bromo-2-pyridyl)-1H-pyrazolo[5,4-b]pyridine (3.00 g, 10.90 mmol) in dry DMF (30.00 mL) was cooled in an ice-bath. Sodium hydride (479.6 mg, 11.99 mmol) was added in one portion and the resulting mixture changed to a yellow solution and was stirred at 0° C. for 30 minutes. Trityl chloride (3.189 g, 11.44 mmol) was added in one portion and the resulting yellow suspension was stirred at RT for 60 minutes, by which time it was a bright yellow suspension. Analysis by LCMS showed presence of desired product.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:10]=[CH:9][C:6]([CH:7]=O)=[CH:5][C:4]=1[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1.[NH:17]1[C:25]2[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=2)[CH2:19][C:18]1=[O:26]>>[CH3:1][O:2][C:3]1[C:4]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)=[CH:5][C:6]([CH:7]=[C:19]2[C:20]3[C:25](=[CH:24][CH:23]=[CH:22][CH:21]=3)[NH:17][C:18]2=[O:26])=[CH:9][CH:10]=1
Reactant: COc1ccc(C=O)cc1-c1ccccc1
Reactant: O=C1Cc2ccccc2N1
Product: COc1ccc(C=C2C(=O)Nc3ccccc32)cc1-c1ccccc1

Procedure:
4-Methoxy-3-phenylbenzaldehyde was condensed with 2-oxindole to give 0.3 g of 3-(6-methoxybiphenyl-3-ylmethylene)-1,3-dihydroindol-2-one as a yellow-orange solid.
Reaction SMILES: [CH2:1]([OH:4])[CH2:2][CH3:3].Cl[P:6]([C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1.N>>[C:13]1([P:6]([C:7]2[CH:8]=[CH:9][CH:10]=[CH:11][CH:12]=2)[O:4][CH2:1][CH2:2][CH3:3])[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=1
Reactant: ClP(c1ccccc1)c1ccccc1
Reactant: CCCO
Agent: N
Product: CCCOP(c1ccccc1)c1ccccc1
Yield: 62.8 %

Procedure:
915 g (15.25 mol) of n-propanol are cooled to -15° C. with stirring under a nitrogen atmosphere. 330 g (1.5 mol) of chloro(diphenyl)phosphine are then added dropwise at this temperature with vigorous stirring in one hour and 15 minutes. 38 g (2.24 mol) of ammonia gas are then introduced at this temperature with further vigorous stirring. The mixture is then stirred for a further ten hours without cooling. After filtering off the ammonium chloride by suction, the filtrate is freed from propanol and excess ammonia in vacuo. The remaining residue is distilled (boiling point 122° C. at 0.4m bar). 230 g of propyl diphenylphosphinite are obtained. This corresponds to a yield of 63% of theory.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[N:9]=[C:8]([CH3:15])[C:7]([C:16]([O:18][CH2:19][CH3:20])=[O:17])=[C:6]2[C:21]1[CH:26]=[CH:25][C:24]([O:27][CH3:28])=[C:23]([O:29][CH3:30])[CH:22]=1.[Br:31]N1C(=O)CCC1=O>C(Cl)(Cl)(Cl)Cl>[Br:31][CH2:15][C:8]1[C:7]([C:16]([O:18][CH2:19][CH3:20])=[O:17])=[C:6]([C:21]2[CH:26]=[CH:25][C:24]([O:27][CH3:28])=[C:23]([O:29][CH3:30])[CH:22]=2)[C:5]2[C:10](=[CH:11][C:12]([O:13][CH3:14])=[C:3]([O:2][CH3:1])[CH:4]=2)[N:9]=1
Reactant: CCOC(=O)c1c(C)nc2cc(OC)c(OC)cc2c1-c1ccc(OC)c(OC)c1
Reactant: O=C1CCC(=O)N1Br
Solvent: ClC(Cl)(Cl)Cl
Product: CCOC(=O)c1c(CBr)nc2cc(OC)c(OC)cc2c1-c1ccc(OC)c(OC)c1
Yield: 58.2 %

Procedure:
A mixture of ethyl 6,7-dimethoxy-4-(3,4-dimethoxyphenyl)-2-methylquinoline-3-carboxylate (411 mg), N-bromosuccinimide (214 mg), 2,2-azobis(isobutyronitrile)(10 mg) and carbon tetrachloride (10 ml) was stirred under reflux for 5 hours. The reaction mixture was washed with water, dried over magnesium sulfate. The solvent was evaporated under reduced pressure, and the residue was subjected to column chromatography on silica gel. The fractions eluted with chloroform/ethyl acetate (10/1, v/v) gave ethyl 2-bromomethyl-6,7-dimethoxy-4-(3,4-dimethoxyphenyl)quinoline-3-carboxylate (285 mg, 58%) which was then recrystallized from ethyl acetate-hexane. Colorless prisms. mp. 135°-136° C.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5](F)=[C:6]([CH:9]=1)[CH:7]=[O:8].[OH:11][C:12]1[CH:21]=[CH:20][C:15]([C:16]([O:18][CH3:19])=[O:17])=[CH:14][CH:13]=1.C([O-])([O-])=O.[K+].[K+]>CN(C)C(=O)C>[CH3:19][O:18][C:16](=[O:17])[C:15]1[CH:20]=[CH:21][C:12]([O:11][C:5]2[CH:4]=[CH:3][C:2]([Cl:1])=[CH:9][C:6]=2[CH:7]=[O:8])=[CH:13][CH:14]=1
Reactant: COC(=O)c1ccc(O)cc1
Reactant: O=Cc1cc(Cl)ccc1F
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(=O)N(C)C
Product: COC(=O)c1ccc(Oc2ccc(Cl)cc2C=O)cc1
Yield: 80.7 %

Procedure:
In a manner similar to the method described in Example 50a, 5-chloro-2-fluorobenzaldehyde (4.2 g, 26 mmol) (Alfa) was reacted with methyl 4-hydroxybenzoate (4 g, 28 mmol)(Aldrich) and K2CO3 in N,N-dimethylacetamide to give 4-(4-chloro-2-formyl-phenoxy)-benzoic acid methyl ester as a white solid (Yield 6.1 g, 80%).
Reaction SMILES: [F:1][C:2]([F:6])=[C:3]([F:5])I.I[C:8]1[CH:13]=[CH:12][C:11]([CH:14]2[CH2:19][CH2:18][CH:17]([CH:20]3[CH2:25][CH2:24][CH:23]([CH2:26][CH2:27][CH3:28])[CH2:22][CH2:21]3)[CH2:16][CH2:15]2)=[CH:10][CH:9]=1>[Zn].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.C1COCC1>[CH2:26]([CH:23]1[CH2:22][CH2:21][CH:20]([CH:17]2[CH2:18][CH2:19][CH:14]([C:11]3[CH:12]=[CH:13][C:8]([C:3]([F:5])=[C:2]([F:6])[F:1])=[CH:9][CH:10]=3)[CH2:15][CH2:16]2)[CH2:25][CH2:24]1)[CH2:27][CH3:28]
Reactant: FC(F)=C(F)I
Reactant: CCCC1CCC(C2CCC(c3ccc(I)cc3)CC2)CC1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [Zn]
Solvent: C1CCOC1
Product: CCCC1CCC(C2CCC(c3ccc(C(F)=C(F)F)cc3)CC2)CC1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A mixture of 5.0 g (77 mmol) of zinc powder, 50 ml of THF and 13.5 g (65 mmol) of trifluoroiodoethylene is stirred overnight, initially with ice cooling, later at room temperature. 20.5 g (50 mmol) of 1-iodo-4-[4-(4-propylcyclohexyl)cyclohexyl]benzene and 1.1 g-of tetrakis(triphenylphosphine)palladium are then added.
Reaction SMILES: [F:1][C:2]([F:27])([C:22](=[O:26])[CH2:23][CH2:24][CH3:25])[CH2:3][CH2:4][CH2:5][C@H:6]1[C@H:13]([O:14][CH:15]2[CH2:20][CH2:19][CH2:18][CH2:17][O:16]2)[CH2:12][C@H:11]2[C@@H:7]1[CH2:8][C:9](=[O:21])[O:10]2.[BH4-].[Na+]>CO>[F:27][C:2]([F:1])([CH:22]([OH:26])[CH2:23][CH2:24][CH3:25])[CH2:3][CH2:4][CH2:5][C@H:6]1[C@H:13]([O:14][CH:15]2[CH2:20][CH2:19][CH2:18][CH2:17][O:16]2)[CH2:12][C@H:11]2[C@@H:7]1[CH2:8][C:9](=[O:21])[O:10]2
Reactant: CCCC(=O)C(F)(F)CCC[C@@H]1[C@H]2CC(=O)O[C@H]2C[C@H]1OC1CCCCO1
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Product: CCCC(O)C(F)(F)CCC[C@@H]1[C@H]2CC(=O)O[C@H]2C[C@H]1OC1CCCCO1
Reaction time: 0.17 h

Procedure:
To a solution of (1S, 5R,6R,7R)-6-(4,4-difluoro-5-oxooctyl)-7-tetrahydropyranyloxy-2-oxabicyclo[3.3.0]octan-3-one (32) (5.48 g) in methanol was added sodium borohydride (0.800 g) at 0° C. and the resulting mixture was stirred for 10 minutes. The reaction mixture was treated in the conventional manner and the obtained crude product was subjected to column chromatography to give the title compound (33). Yield: 5.46 g (99.5%).
Reaction SMILES: [NH:1]1[CH:5]=[C:4]([C:6]([C:8]2[CH:9]=[CH:10][CH:11]=[C:12]3[C:17]=2[N:16]=[CH:15][CH:14]=[CH:13]3)=[CH2:7])[N:3]=[CH:2]1.[H][H]>FC(F)(F)C(O)=O.[Pd]>[NH:1]1[CH:5]=[C:4]([CH:6]([C:8]2[CH:9]=[CH:10][CH:11]=[C:12]3[C:17]=2[N:16]=[CH:15][CH:14]=[CH:13]3)[CH3:7])[N:3]=[CH:2]1
Reactant: C=C(c1c[nH]cn1)c1cccc2cccnc12
Reactant: [H][H]
Agent: [Pd]
Solvent: O=C(O)C(F)(F)F
Product: CC(c1c[nH]cn1)c1cccc2cccnc12
Yield: 86.2 %

Procedure:
The vinyl compound, 8-[1-(1H-imidazol-4-yl)-vinyl]-quinoline (0.23 g) in trifluoroacetic acid:TFA (15 mL) was reduced by the action of 10% Pd/C (58 mg) under 50 psi of hydrogen for 18 h at rt. The mixture was filtered through Celite and basified with NH3-MeOH. The solvent was removed under vacuum. The residue was purified by chromatography on silica gel with 4% NH3-MeOH:CH2Cl2 to give 8-[1-(1H-imidazol-4-yl)-ethyl]-quinoline (Intermediate C2) 0.2 g.
Reaction SMILES: [CH3:1][C:2]1[O:6][N:5]=[C:4]([CH:7]2[CH2:12][CH2:11][CH2:10][CH2:9][N:8]2C(OC(C)(C)C)=O)[N:3]=1.[ClH:20]>ClCCl.O1CCOCC1>[ClH:20].[CH3:1][C:2]1[O:6][N:5]=[C:4]([CH:7]2[CH2:12][CH2:11][CH2:10][CH2:9][NH:8]2)[N:3]=1
Reactant: Cc1nc(C2CCCCN2C(=O)OC(C)(C)C)no1
Agent: Cl
Solvent: C1COCCO1
Solvent: ClCCl
Product: Cc1nc(C2CCCCN2)no1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a cooled solution of tert-butyl 2-(5-methyl-1,2,4-oxadiazol-3-yl)piperidine-1-carboxylate (55 mg, 0.21 mmol; which may be prepared as described in Step 2) in dichloromethane (1.7 mL) was added dropwise HCl 4N in dioxane (1.3 mL). The solution was warmed to room temperature and stirred for 2 h. The solvent was evaporated under reduced pressure to give the title compound (47 mg, quantitative) as a white powder.
Reaction SMILES: [NH2:1][CH2:2][C:3]([C:6]1[C:14]2[NH:13][C:12]([C:15]3[CH:20]=[CH:19][C:18]([O:21][CH3:22])=[CH:17][CH:16]=3)=[N:11][C:10]=2[CH:9]=[CH:8][CH:7]=1)([CH3:5])[CH3:4].ClCCl.[C:26](Cl)(=[O:30])[CH:27]([CH3:29])[CH3:28]>C(N(CC)CC)C>[CH:27]([C:26]([NH:1][CH2:2][C:3]([C:6]1[CH:7]=[CH:8][C:9]2[N:13]=[C:12]([C:15]3[CH:20]=[CH:19][C:18]([O:21][CH3:22])=[CH:17][CH:16]=3)[NH:11][C:10]=2[CH:14]=1)([CH3:4])[CH3:5])=[O:30])([CH3:29])[CH3:28]
Reactant: COc1ccc(-c2nc3cccc(C(C)(C)CN)c3[nH]2)cc1
Reactant: CC(C)C(=O)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COc1ccc(-c2nc3ccc(C(C)(C)CNC(=O)C(C)C)cc3[nH]2)cc1
Reaction time: 10 h

Procedure:
1.9 g. 4-(2-Aminomethylpropan-2-yl)-2-(4-methoxyphenyl)-benzimidazole (obtained in Example 6) in 200 ml. dichloromethane are reacted with 2.5 ml. triethylamine and 0.82 g. isobutyric acid chloride at ambient temperature. After 10 hours, the solvent is removed in a vacuum and the residue is digested with water and 2N aqueous ammonia solution. The reaction mixture is extracted 4 times with dichloromethane and the organic phase is dried over anhydrous sodium sulphate, filtered and evaporated. Ethyl acetate is added thereto, a part thereof is distilled off with the dichloromethane and left to crystallise and the product is filtered with suction. The product is recrystallised from ethyl acetate to give 0.6 g. of the title compound; m.p. 218°-220° C.
Reaction SMILES: C(OC(=O)[NH:7][C:8]1[CH:13]=[C:12]([CH3:14])[C:11]([CH2:15][NH:16][C:17]([C:19]2[N:20]=[N:21][N:22]([CH2:24][C:25]3[CH:30]=[CH:29][C:28]([C:31]4[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=4)=[CH:27][CH:26]=3)[CH:23]=2)=[O:18])=[C:10]([CH3:37])[N:9]=1)(C)(C)C.C(O)(C(F)(F)F)=O>C(Cl)Cl>[NH2:7][C:8]1[N:9]=[C:10]([CH3:37])[C:11]([CH2:15][NH:16][C:17]([C:19]2[N:20]=[N:21][N:22]([CH2:24][C:25]3[CH:30]=[CH:29][C:28]([C:31]4[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=4)=[CH:27][CH:26]=3)[CH:23]=2)=[O:18])=[C:12]([CH3:14])[CH:13]=1
Reactant: Cc1cc(NC(=O)OC(C)(C)C)nc(C)c1CNC(=O)c1cn(Cc2ccc(-c3ccccc3)cc2)nn1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: Cc1cc(N)nc(C)c1CNC(=O)c1cn(Cc2ccc(-c3ccccc3)cc2)nn1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A mixture of (5-{[(1-Biphenyl-4-ylmethyl-1H-[1,2,3]triazole-4-carbonyl)-amino]-methyl}-4,6-dimethyl-pyridin-2-yl)-carbamic acid tert-butyl ester (27 mg, 0.053 mmol), 1 mL TFA and 2 mL DCM was stirred at room temperature for 2 h. The mixture was evaporated in vacuo to yield the final product (TFA salt). 1H-NMR (DMSO-d6, 400 MHz) 13.24 (bs, 1H), 8.87 (t, 1H), 8.70 (s, 1H), 7.65-7.69 (m, 4H), 7.43-7.52 (m, 6H), 7.36-7.40 (t, 1H), 6.62 (s, 1H), 5.70 (s, 2H), 4.43 (d, 2H), 2.52 (s, 3H), 2.40 (s, 3H); LCMS (method A) RtA=1.317 min; [M+H]+=413.0.
Reaction SMILES: FC(F)(F)C(O)=O.[CH:8]([N:11]1[C:15]([C:16]2[N:25]=[C:24]3[N:18]([CH2:19][CH2:20][O:21][C:22]4[CH:29]=[C:28]([CH:30]5[CH2:35][CH2:34][NH:33][CH2:32][CH2:31]5)[CH:27]=[CH:26][C:23]=43)[CH:17]=2)=[N:14][CH:13]=[N:12]1)([CH3:10])[CH3:9].[CH3:36][N:37]([CH3:43])[S:38]([CH:41]=[CH2:42])(=[O:40])=[O:39]>>[CH:8]([N:11]1[C:15]([C:16]2[N:25]=[C:24]3[C:23]4[CH:26]=[CH:27][C:28]([CH:30]5[CH2:35][CH2:34][N:33]([CH2:42][CH2:41][S:38]([N:37]([CH3:43])[CH3:36])(=[O:40])=[O:39])[CH2:32][CH2:31]5)=[CH:29][C:22]=4[O:21][CH2:20][CH2:19][N:18]3[CH:17]=2)=[N:14][CH:13]=[N:12]1)([CH3:10])[CH3:9]
Reactant: C=CS(=O)(=O)N(C)C
Reactant: CC(C)n1ncnc1-c1cn2c(n1)-c1ccc(C3CCNCC3)cc1OCC2
Solvent: O=C(O)C(F)(F)F
Product: CC(C)n1ncnc1-c1cn2c(n1)-c1ccc(C3CCN(CCS(=O)(=O)N(C)C)CC3)cc1OCC2

Procedure:
2-(2-isopropyl-2H-[1,2,4]triazol-3-yl)-8-piperidin-4-yl-4,5-dihydro-6-oxa-1,3a-diaza-benzo[e]azulene trifluoroacetic acid salt was reacted with N,N-dimethylethenesulfonamide to give 249 as a white solid. 1H NMR δ (ppm) (DMSO-d6): 8.28 (1 H, d, J=8.29 Hz), 7.86 (1 H, d, J=0.63 Hz), 7.85 (1 H, s), 7.01 (1 H, dd, J=8.37, 1.77 Hz), 6.85 (1 H, d, J=1.72 Hz), 5.88-5.80 (1 H, m), 4.48-4.42 (4 H, m), 3.23-3.15 (2 H, m), 2.95 (2 H, d, J=11.09 Hz), 2.74 (6 H, s), 2.68-2.60 (2 H, m), 2.09-1.98 (2 H, m), 1.73 (2 H, d, J=12.61 Hz), 1.64-1.55 (2 H, m), 1.43 (6 H, d, J=6.61 Hz). 1 Proton obscured by solvent peak. LCMS: RT=2.90 M+H+=513
Reaction SMILES: [F:1][C:2]1[CH:9]=[CH:8][C:5]([CH2:6][NH2:7])=[CH:4][CH:3]=1.[CH3:10][O:11][C:12](=[O:31])[C:13]1[CH:18]=[CH:17][C:16]([C:19]2[N:20]=[C:21](Cl)[C:22]3[CH:27]=[C:26]([CH2:28][CH3:29])[S:25][C:23]=3[N:24]=2)=[CH:15][CH:14]=1>>[CH3:10][O:11][C:12](=[O:31])[C:13]1[CH:14]=[CH:15][C:16]([C:19]2[N:20]=[C:21]([NH:7][CH2:6][C:5]3[CH:8]=[CH:9][C:2]([F:1])=[CH:3][CH:4]=3)[C:22]3[CH:27]=[C:26]([CH2:28][CH3:29])[S:25][C:23]=3[N:24]=2)=[CH:17][CH:18]=1
Reactant: NCc1ccc(F)cc1
Reactant: CCc1cc2c(Cl)nc(-c3ccc(C(=O)OC)cc3)nc2s1
Product: CCc1cc2c(NCc3ccc(F)cc3)nc(-c3ccc(C(=O)OC)cc3)nc2s1

Procedure:
The reaction procedure as above wherein 4-fluorobenzylamine is reacted with 4-(4-chloro-6-ethyl-thieno-[2,3-d]-pyrimidin-2-yl)-benzoic acid methylester yields 4-[4-(4-fluorobenzylamino)-6-ethyl-thieno-[2,3-d]-pyrimidin-2-yl]-benzoic acid methylester.
Reaction SMILES: [C:1]([C:5]1[CH:13]=[CH:12][C:8]([C:9](O)=[O:10])=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2].S(Cl)([Cl:16])=O>>[C:1]([C:5]1[CH:13]=[CH:12][C:8]([C:9]([Cl:16])=[O:10])=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: O=S(Cl)Cl
Reactant: CC(C)(C)c1ccc(C(=O)O)cc1
Product: CC(C)(C)c1ccc(C(=O)Cl)cc1

Procedure:
A mixture of 4-tert-butylbenzoic acid (1000 g, 5.6 mol) in sulfurous dichloride (1.5 L) was refluxed for 3 hours. Then the mixture was concentrated in vacuo, and the crude 101a was used in next step without further purification.
Reaction SMILES: [N:1]1([C:7]2[N:12]=[C:11]([C:13]3[CH:18]=[CH:17][C:16]([NH:19][C:20](=[O:28])[NH:21][C:22]4[CH:27]=[CH:26][N:25]=[CH:24][CH:23]=4)=[CH:15][CH:14]=3)[N:10]=[C:9]([NH:29][CH:30]3[CH2:33][N:32](C(OC(C)(C)C)=O)[CH2:31]3)[N:8]=2)[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1.C(O)(C(F)(F)F)=O>C(Cl)Cl>[NH:32]1[CH2:31][CH:30]([NH:29][C:9]2[N:8]=[C:7]([N:1]3[CH2:6][CH2:5][O:4][CH2:3][CH2:2]3)[N:12]=[C:11]([C:13]3[CH:14]=[CH:15][C:16]([NH:19][C:20]([NH:21][C:22]4[CH:23]=[CH:24][N:25]=[CH:26][CH:27]=4)=[O:28])=[CH:17][CH:18]=3)[N:10]=2)[CH2:33]1
Reactant: CC(C)(C)OC(=O)N1CC(Nc2nc(-c3ccc(NC(=O)Nc4ccncc4)cc3)nc(N3CCOCC3)n2)C1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: O=C(Nc1ccncc1)Nc1ccc(-c2nc(NC3CNC3)nc(N3CCOCC3)n2)cc1
Reaction time: 24 h

Procedure:
To a stirred solution of tert-butyl 3-[(4-morpholin-4-yl-6-{4-[(pyridine-4-ylcarbamoyl)amino]phenyl}-1,3,5-triazin-2-yl)amino]azetidine-1-carboxylate 40 mg (0.073 mmoles) in DCM, (20 ml) TFA (1.5 ml) was added at room temperature and stirred for 24 hours. At the end, reaction mixture was concentrated and purified by Gilson HPLC, using ACN/water and TFA. Yield: 26 (81%); (M+H) 448.5.
Reaction SMILES: [F:1][C:2]1([C:10]2[N:14]([CH3:15])[N:13]=[CH:12][C:11]=2[N+:16]([O-:18])=[O:17])[CH2:9][CH2:8][CH:7]2[CH:5]([O:6]2)[CH2:4][CH2:3]1.[Cl-].[NH4+].[N-:21]=[N+:22]=[N-:23].[Na+]>CN(C=O)C.O>[N:21]([CH:7]1[CH2:8][CH2:9][C:2]([F:1])([C:10]2[N:14]([CH3:15])[N:13]=[CH:12][C:11]=2[N+:16]([O-:18])=[O:17])[CH2:3][CH2:4][CH:5]1[OH:6])=[N+:22]=[N-:23]
Reactant: [N-]=[N+]=[N-]
Reactant: Cn1ncc([N+](=O)[O-])c1C1(F)CCC2OC2CC1
Agent: [Cl-]
Agent: [NH4+]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: Cn1ncc([N+](=O)[O-])c1C1(F)CCC(O)C(N=[N+]=[N-])CC1
Temperature: 100 °C
Yield: 47.7 %

Procedure:
A solution of 5-(4-fluoro-8-oxabicyclo[5.1.0]octan-4-yl)-1-methyl-4-nitro-1H-pyrazole (260 mg, 1.02 mmol) in DMF/water (10 mL/1 mL) was treated with ammonium chloride (135 mg, 2.55 mmol) and sodium azide (332 mg, 5.1 mmol) and the mixture was heated at 100° C. for 48 hrs. The reaction mixture was extracted with EtOAc (100 mL) and the organic layer was washed with water (7×20 mL), washed with brine (20 mL), separated, dried over MgSO4, and concentrated under reduced pressure. Purification via silica gel column chromatography (40% EtOAc/isohexane) gave 2-azido-5-fluoro-5-(1-methyl-4-nitro-1H-pyrazol-5-yl)cycloheptanol as a white solid (145 mg, 48%). 1H NMR (400 MHz, CDCl3) δ 8.06 and 8.05 (2s, 1H), 4.08 and 4.06 (2s, 3H), 3.83 (dd, J=10.7, 8.2 Hz, 1H), 3.65-3.58 (m, 1H), 2.87-2.55 (m, 2H), 2.33-2.21 (m, 2H), 2.17-1.98 (m, 3H), 1.98-1.84 (m, 2H).
Reaction SMILES: [Cl:1][C:2]1[C:3]([C:8]([C:10]([F:13])([F:12])[F:11])=[CH2:9])=[N:4][CH:5]=[CH:6][CH:7]=1.[Si:14]([O:21][C:22](=[CH2:28])/[CH:23]=[CH:24]/[N:25]([CH3:27])[CH3:26])([C:17]([CH3:20])([CH3:19])[CH3:18])([CH3:16])[CH3:15]>C1(C)C=CC=CC=1>[Si:14]([O:21][C:22]1[CH2:28][CH2:9][C:8]([C:3]2[C:2]([Cl:1])=[CH:7][CH:6]=[CH:5][N:4]=2)([C:10]([F:11])([F:13])[F:12])[CH:24]([N:25]([CH3:27])[CH3:26])[CH:23]=1)([C:17]([CH3:20])([CH3:19])[CH3:18])([CH3:16])[CH3:15]
Reactant: C=C(/C=C/N(C)C)O[Si](C)(C)C(C)(C)C
Reactant: C=C(c1ncccc1Cl)C(F)(F)F
Solvent: Cc1ccccc1
Product: CN(C)C1C=C(O[Si](C)(C)C(C)(C)C)CCC1(c1ncccc1Cl)C(F)(F)F
Reaction time: 0.5 h
Yield: 61.4 %

Procedure:
A solution of Example 26A (612 mg, 2.95 mmol) and (E)-3-(tert-butyldimethylsilyloxy)-N,N-dimethylbuta-1,3-dien-1-amine (966 mg, 4.25 mmol) in toluene (2.5 mL) was heated on a microwave at 60° C. for 30 minutes, and then 70° C. for 30 minutes. Purified by silica gel chromatography (AnaLogix® SF25-40G; 50 micron silica; elution with 0-50% ethyl acetate in hexane at 30 mL/min) to provide the title compound (787 mg, 1.81 mmol, 61.4% yield) as a light yellow oil. MS (DCI/NH3) m/e 435 (M+H)+.