Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][CH2:2][CH2:3][CH2:4][OH:5].Br[CH2:7][C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9]>ClCCl>[C:11]([O:10][C:8](=[O:9])[CH2:7][NH:1][CH2:2][CH2:3][CH2:4][OH:5])([CH3:14])([CH3:13])[CH3:12]
Reactant: CC(C)(C)OC(=O)CBr
Reactant: NCCCO
Solvent: ClCCl
Product: CC(C)(C)OC(=O)CNCCCO
Temperature: 0 °C
Reaction time: 3 h

Procedure:
196 ml of 3-aminopropanol (2.56 mol) were diluted in 250 ml of dichloromethane and the whole was cooled to 0° C. on an ice bath. 20 g of tert-butyl bromoacetate (102.5 mmol), solubilized in 200 ml of dichloromethane, were then added dropwise while the reaction mixture was maintained at 0° C. At the end of the addition (2 hours later), the reaction mixture was left at room temperature for 3 hours.
Reaction SMILES: [Cl:1][C:2]1[C:3]([NH:13][C@@H:14]2[CH2:19][CH2:18][CH2:17][N:16]([CH2:20][CH:21]3[CH2:26][CH2:25][CH2:24][CH2:23][CH2:22]3)[CH2:15]2)=[N:4][CH:5]=[C:6]([CH:12]=1)[C:7](OCC)=[O:8].[Li].O.O.O.O.C(C(C(C([O-])=O)O)O)([O-])=O.[Na+].[K+]>O1CCCC1>[Cl:1][C:2]1[CH:12]=[C:6]([CH2:7][OH:8])[CH:5]=[N:4][C:3]=1[NH:13][C@@H:14]1[CH2:19][CH2:18][CH2:17][N:16]([CH2:20][CH:21]2[CH2:22][CH2:23][CH2:24][CH2:25][CH2:26]2)[CH2:15]1
Reactant: CCOC(=O)c1cnc(N[C@@H]2CCCN(CC3CCCCC3)C2)c(Cl)c1
Agent: O=C([O-])C(O)C(O)C(=O)[O-]
Agent: [K+]
Agent: [Li]
Solvent: C1CCOC1
Solvent: O
Product: OCc1cnc(N[C@@H]2CCCN(CC3CCCCC3)C2)c(Cl)c1
Reaction time: 3 h
Yield: 73.6 %

Procedure:
To a stirred solution of ethyl 5-chloro-6-{[(3R)-1-(cyclohexylmethyl)-3-piperidinyl]amino}nicotinate (321 mg) in tetrahydrofuran (6 mL) was added lithium aluminumhydride (80.2 mg) portionwise in an ice bath and the resulting suspension was stirred at the same temperature for three hours. To this was added saturated aqueous potassium sodium (+)-tartrate tetrahydrate solution portionwise at the same temperature and the mixture was stirred at ambient temperature for one hour. The mixture was extracted with ethyl acetate and the aqueous phase was removed. The organic layer was washed with brine, dried over anhydrous sodium sulfate, filtered and concentrated in vacuo. The residue was purified by flash chromatography eluting with ethylacetate-hexane 1:1 (v/v) to afford (5-chloro-6-{[(3R)-1-(cyclohexylmethyl)-3-piperidinyl]amino}-3-pyridinyl)methanol (210 mg) as a colorless oil.
Reaction SMILES: N[C:2]1[CH:12]=[CH:11][C:10]2[CH:9]3[CH2:13][CH:5]([CH2:6][N:7]([C:14](=[O:19])[C:15]([F:18])([F:17])[F:16])[CH2:8]3)[C:4]=2[CH:3]=1.N([O-])=O.[Na+].[ClH:24]>O.Cl[Cu]>[Cl:24][C:2]1[CH:12]=[CH:11][C:10]2[CH:9]3[CH2:13][CH:5]([CH2:6][N:7]([C:14](=[O:19])[C:15]([F:18])([F:17])[F:16])[CH2:8]3)[C:4]=2[CH:3]=1
Reactant: Nc1ccc2c(c1)C1CC2CN(C(=O)C(F)(F)F)C1
Reactant: Cl
Agent: Cl[Cu]
Agent: O=N[O-]
Agent: [Na+]
Solvent: O
Product: O=C(N1CC2CC(C1)c1cc(Cl)ccc12)C(F)(F)F
Temperature: 60 °C
Yield: 95 %

Procedure:
1-(4-Amino-10-aza-tricyclo[6.3.1.02,7]dodeca-2(7),3,5-trien-10-yl)-2,2,2-trifluoro-ethanone (460 mg, 1.7 mmol) was dissolved in H2O (2 mL) and concentrated HCl solution (1 mL) then cooled to 0° C. and treated with a solution of sodium nitrite (NaNO2) (275 mg) in H2O (1 mL) dropwise. To the resulting solution was added a CuCl (202 mg, prepared as described above, 2.04 mmol) in concentrated HCl solution (2 mL) over 10 minutes (gas evolution observed). The resulting solution was warmed to 60° C. for 15 minutes, then was cooled to room temperature and extracted with ethyl acetate (4×30 mL). After drying over Na2SO4, the solution was filtered and concentrated to an oil which was filtered through a Silica pad to remove baseline material eluting with 50% ethyl acetate/hexanes to give an oil (470 mg, 95%).
Reaction SMILES: Cl.[CH2:2]([O:4][C:5](=[O:8])[CH2:6][NH2:7])[CH3:3].C(N(CC)CC)C.[Cl:16][C:17]1[CH:18]=[C:19]2[C:24](=[CH:25][CH:26]=1)[CH:23]=[C:22]([S:27](Cl)(=[O:29])=[O:28])[CH:21]=[CH:20]2.Cl>C(Cl)Cl>[Cl:16][C:17]1[CH:18]=[C:19]2[C:24](=[CH:25][CH:26]=1)[CH:23]=[C:22]([S:27]([NH:7][CH2:6][C:5]([O:4][CH2:2][CH3:3])=[O:8])(=[O:29])=[O:28])[CH:21]=[CH:20]2
Reactant: CCOC(=O)CN
Reactant: O=S(=O)(Cl)c1ccc2cc(Cl)ccc2c1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCOC(=O)CNS(=O)(=O)c1ccc2cc(Cl)ccc2c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 101.4 %

Procedure:
Glycine ethyl ester hydrochloride (9.88 g) was suspended in methylene chloride (500 ml), and triethylamine (20.2 ml) and then 6-chloronaphthalene-2-sulfonyl chloride (17.6 g) were added to the suspension under cooling with ice. After stirring at room temperature for 1 hour and adjusting the mixture to pH 2 by addition of 1N hydrochloric acid, the mixture was extracted with methylene chloride. The methylene chloride layer was washed with saturated sodium chloride solution and dried over anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure. After washing the resulting crystals in n-hexane, the crystals were collected by filtration and air-dried to obtain the title compound (22.4 g).
Reaction SMILES: [H-].[Na+].[CH2:3]([NH:6][C:7](=[O:13])[O:8][C:9]([CH3:12])([CH3:11])[CH3:10])[C:4]#[CH:5].[CH2:14](I)[CH3:15]>CN(C=O)C.O>[CH2:14]([N:6]([CH2:3][C:4]#[CH:5])[C:7](=[O:13])[O:8][C:9]([CH3:10])([CH3:12])[CH3:11])[CH3:15]
Reactant: C#CCNC(=O)OC(C)(C)C
Reactant: CCI
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: C#CCN(CC)C(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 1 h
Yield: 46.5 %

Procedure:
A suspension of sodium hydride (354 mg, 14.2 mmol) in DMF (33 mL) at room temperature was treated with a solution of Example 516A (2.0 g, 12.9 mmol) in DMF (10 mL) and stirred for one hour at room temperature. The solution was cooled to 0° C., treated with ethyl iodide (1.24 mL, 15.5 mmol), stirred for one hour at 0° and overnight at room temperature. The solution was diluted with water (25 mL), extracted with diethyl ether (2×50 mL) and the combined organic layers were washed with brine (30 mL0, dried (MgSO4), filtered and concentrated. The residue was purified by flash chromatography on silica gel using 5-10% ethyl acetate/hexanes to give the 1.1 g (47% yield) of the desired product. MS (ESI(+)) m/e 184 (M+H)+.
Reaction SMILES: Br[CH2:2][C:3]1[N:7]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[N:6]=[C:5]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[N:4]=1.[C-:20]#[N:21].[K+].O>CS(C)=O>[C:8]1([N:7]2[C:3]([CH2:2][C:20]#[N:21])=[N:4][C:5]([C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=3)=[N:6]2)[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1
Reactant: BrCc1nc(-c2ccccc2)nn1-c1ccccc1
Reactant: [C-]#N
Agent: [K+]
Solvent: CS(C)=O
Solvent: O
Product: N#CCc1nc(-c2ccccc2)nn1-c1ccccc1
Temperature: 60 °C
Yield: 114.4 %

Procedure:
A mixture of 5-(bromomethyl)-1,3-diphenyl-1H-1,2,4-triazole (265 mg, 843 μmol) and potassium cyanide (62.3 mg, 928 μmol) in DMSO (5 mL) was heated at 60° C. for 1.5 h. The reaction mixture was cooled to RT, poured into water (25 mL) and extracted with ethyl acetate (2×50 mL). The organic phases were washed with water (2×25 mL) and brine (1×25 mL), and the combined organic layer was dried over MgSO4 and concentrated in vacuo to give 251 mg of crude product. The product was obtained after purification by flash chromatography (using silica gel and an ethyl acetate/heptane gradient) as light yellow waxy solid (120 mg, 461 μmol, 54.7%).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:14]=[C:15]([N+:19]([O-:21])=[O:20])[C:16]=1[O:17][CH3:18])[CH:6]([OH:13])[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1.[Cr](Cl)([O-])(=O)=O.[NH+]1C=CC=CC=1>C(Cl)Cl>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:14]=[C:15]([N+:19]([O-:21])=[O:20])[C:16]=1[O:17][CH3:18])[C:6]([C:7]1[CH:8]=[CH:9][CH:10]=[CH:11][CH:12]=1)=[O:13]
Reactant: COc1cc(C(O)c2ccccc2)cc([N+](=O)[O-])c1OC
Agent: O=[Cr](=O)([O-])Cl
Agent: c1cc[nH+]cc1
Solvent: ClCCl
Product: COc1cc(C(=O)c2ccccc2)cc([N+](=O)[O-])c1OC
Temperature: 25 °C
Reaction time: 2 h

Procedure:
2.5 g of 3,4-dimethoxy-5-nitrobenzhydrol dissolved in 50 ml of methylene chloride are treated with 2.2 g of pyridinium chlorochromate, whereupon the mixture is stirred at room temperature for 2 hours. The insoluble constituents are subsequently filtered. The filtrate is evaporated and the residue is chromatographed on 60 g of silica gel with methylene chloride. After crystallization from methylene chloride/hexane there is obtained 3,4-dimethoxy-5-nitrobenzophenone of m.p. 78°-80°.
Reaction SMILES: [C:1]([C:3]1[CH:8]=[C:7]([Br:9])[C:6]([OH:10])=[C:5]([Br:11])[CH:4]=1)#[N:2].C1(C)C=CC=CC=1.C(N(CC)CC)C.[Cl:26][CH:27]([O:31][N:32]=[CH:33][C:34]1[C:39]([Cl:40])=[CH:38][CH:37]=[CH:36][CH:35]=1)[C:28](Cl)=[O:29]>CCCCCCC.C(O)(C)C>[Cl:26][CH:27]([O:31][N:32]=[CH:33][C:34]1[C:39]([Cl:40])=[CH:38][CH:37]=[CH:36][CH:35]=1)[C:28]([O:10][C:6]1[C:5]([Br:11])=[CH:4][C:3]([C:1]#[N:2])=[CH:8][C:7]=1[Br:9])=[O:29]
Reactant: O=C(Cl)C(Cl)ON=Cc1ccccc1Cl
Reactant: N#Cc1cc(Br)c(O)c(Br)c1
Solvent: CC(C)O
Solvent: CCN(CC)CC
Solvent: CCCCCCC
Product: N#Cc1cc(Br)c(OC(=O)C(Cl)ON=Cc2ccccc2Cl)c(Br)c1

Procedure:
A mixture of 2.1 gm. (0.0076 mole) of 4-cyano-2,6-dibromophenol (m.p. 190.0°-191.5° C.), 40 ml. of toluene and 0.8 gm. (0.008 mole) of triethylamine was stirred in a system protected from atmospheric moisture by a `drying tube`, and to it there were added, in portions, a total of 2.0 grams (0.0075 mole) of 2,6-dichlorobenzylideneaminooxyacetyl chloride. The reaction mixture was then heated for an hour on the steambath; it was filtered hot, washing the triethylamine hydrochloride on the filter with hot toluene, then discarding it. The combined filtrates were evaporated to dryness under reduced pressure, and the residue was triturated with cold methanol, then filtered. The filter-cake was then washed with cold methanol and air-dried to obtain 3.3 gm. (85.6%) of colorless solid, m.p. 166°-168° C. This material was treated with boiling isopropyl alcohol and n-heptane mixture, and was then cooled in ice bath. The solid present was removed by filration, washed on the filter with n-hexane and dried in air to obtain 3.1 gm. of crystalline product melting at 168.0°-170.5° C. (uncorrected).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]2[C:17]3[C:12](=[CH:13][C:14]([C:18]4[N:23]=[N:22][C:21]([N:24](C)[C:25](=O)OC(C)(C)C)=[CH:20][CH:19]=4)=[CH:15][CH:16]=3)[CH2:11][N:10](C)[CH2:9]2)=[CH:4][CH:3]=1.CN(C1C2C(N(C)C)=CC=CC=2C=CC=1)C.ClC(OC(Cl)C)=O>ClCCCl>[F:1][C:2]1[CH:3]=[CH:4][C:5]([CH:8]2[C:17]3[C:12](=[CH:13][C:14]([C:18]4[N:23]=[N:22][C:21]([NH:24][CH3:25])=[CH:20][CH:19]=4)=[CH:15][CH:16]=3)[CH2:11][NH:10][CH2:9]2)=[CH:6][CH:7]=1
Reactant: CN1Cc2cc(-c3ccc(N(C)C(=O)OC(C)(C)C)nn3)ccc2C(c2ccc(F)cc2)C1
Agent: CC(Cl)OC(=O)Cl
Agent: CN(C)c1cccc2cccc(N(C)C)c12
Solvent: ClCCCl
Product: CNc1ccc(-c2ccc3c(c2)CNCC3c2ccc(F)cc2)nn1
Temperature: 25 °C
Yield: 20.2 %

Procedure:
To a mixture of the product from Step A (428 mg, 0.96 mmol) and proton sponge (102 mg, 0.50 mmol) in 1,2-dichloroethane (3 mL) was added 1-chloroethyl chloroformate (208 μL, 1.91 mmol) at 0° C. under a nitrogen atmosphere. The reaction mixture was allowed to warm to ambient temperature over a weekend and concentrated in vacuo. The intermediate 2-chloroethylcarbamate was purified by flash column chromatography (dichloromethane) and refluxed in methanol for 3 hours. The resulting solution was concentrated under reduced pressure and treated with trifluoroacetic acid (5 mL) in dichloromethane (5 mL) for 1 hour. After concentration in vacuo, the residue was partitioned between dichloromethane (30 mL) and 2N aqueous sodium hydroxide (10 mL). The organic layer was washed with brine, dried over sodium sulfate, and concentrated in vacuo to give the crude material which was purified by flash column chromatography (90:10 to 50:50 ethyl acetate/ethyl acetate:methanol:ammonium hydroxide) to give 6-(4-(4-fluorophenyl)-1,2,3,4-tetrahydroisoquinolin-7-yl)-N-methylpyridazin-3-amine (65 mg, 20%) as a colorless oil: [α]D=+18.0° (0.05, methanol): 1H NMR (CDCl3, 300 MHz) δ 7.76 (d, J=1.2 Hz, 1H), 7.66 (dd, J=8.1 Hz, 1.8 Hz, 1H), 7.58 (d, J=9.6 Hz, 1H), 7.12-7.06 (m, 2H), 7.03-6.95 (m, 2H), 6.99 (t, J=8.4 Hz, 1H), 6.72 (d, J=9.3 Hz, 1H), 4.95 (d, J=5.1 Hz, 1H), 4.26-4.09 (m, 2H), 3.42 (dd, J=12.9 Hz, 5.1 Hz, 1H), 3.11-3.05 (m, 4H), 1.96 (br s, 2H); ESI MS m/z 335 [M+H]+.
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]([O:23][CH3:24])=[C:6]([NH:8][S:9]([C:12]2[CH:17]=[CH:16][C:15]([C:18]3[S:19][CH:20]=[CH:21][CH:22]=3)=[CH:14][CH:13]=2)(=[O:11])=[O:10])[CH:7]=1.[CH3:25][N:26]1[C@H:31]([CH3:32])[CH2:30][NH:29][CH2:28][C@@H:27]1[CH3:33].CC(C)([O-])C.[Na+].C1(P(C2CCCCC2)C2C=CC=CC=2C2C=CC=CC=2N(C)C)CCCCC1>O1CCOCC1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[CH3:24][O:23][C:5]1[CH:4]=[CH:3][C:2]([N:29]2[CH2:30][C@H:31]([CH3:32])[N:26]([CH3:25])[C@H:27]([CH3:33])[CH2:28]2)=[CH:7][C:6]=1[NH:8][S:9]([C:12]1[CH:17]=[CH:16][C:15]([C:18]2[S:19][CH:20]=[CH:21][CH:22]=2)=[CH:14][CH:13]=1)(=[O:11])=[O:10]
Reactant: C[C@@H]1CNC[C@H](C)N1C
Reactant: COc1ccc(Br)cc1NS(=O)(=O)c1ccc(-c2cccs2)cc1
Agent: [Pd]
Agent: CC(C)(C)[O-]
Agent: CN(C)c1ccccc1-c1ccccc1P(C1CCCCC1)C1CCCCC1
Solvent: C1COCCO1
Product: COc1ccc(N2C[C@@H](C)N(C)[C@@H](C)C2)cc1NS(=O)(=O)c1ccc(-c2cccs2)cc1
Temperature: 25 °C

Procedure:
The product of Step 2 (200 mg, 0.47 mmol), cis-1,2,6-trimethyl piperazine (118 mg, 0.94 mmol), sodium tert-butoxide (90 mg, 0.94 mmol), tris(dibenzylideneacetone)dipalladium(0) (22 mg, 0.024 mmol) and 2-dicyclohexylphosphino-2′-(N,N-dimethylamino)biphenyl (28 mg, 0.071 mmol) in dioxane (10 ml) was heated at reflux for 16 hours. After cooling to room temperature the solution was concentrated in vacuo. The residue was applied to an SCX ion exchange cartridge (Varian bond-elute) and washed with methanol and 2M ammonia in methanol. The combined basic fractions were concentrated in vacuo and the residue purified by mass directed autoprep to afford the title product (E277). MS (ES+) 472 [M+H]+.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([N+:13]([O-])=O)[CH:5]=[C:6]([CH:9]([F:12])[CH2:10][CH3:11])[C:7]=1[Cl:8].CO.C(#N)C.O>Cl.[Cl-].[Cl-].[Cl-].[Ti+3]>[Br:1][C:2]1[CH:3]=[C:4]([CH:5]=[C:6]([CH:9]([F:12])[CH2:10][CH3:11])[C:7]=1[Cl:8])[NH2:13]
Reactant: CCC(F)c1cc([N+](=O)[O-])cc(Br)c1Cl
Agent: [Ti+3]
Agent: Cl
Agent: [Cl-]
Solvent: CO
Solvent: O
Solvent: CC#N
Product: CCC(F)c1cc(N)cc(Br)c1Cl
Temperature: 25 °C
Reaction time: 3 h
Yield: 85.6 %

Procedure:
6.54 g (22.1 mmol) of 3-bromo-4-chloro-5-(1-fluoropropyl)-1-nitrobenzene was dissolved in a solvent mixture comprising 30 ml of methanol and 90 ml of acetonitrile, followed by the addition of 120 ml of a 20% solution of titanium trichloride in diluted hydrochloric acid under a nitrogen stream under cooling with ice. The obtained mixture was stirred at room temperature for 3 hours and then poured into water. The resulting mixture was extracted with ethyl acetate. The ethyl acetate phase was washed with a saturated aqueous solution of sodium hydrogen carbonate and a saturated brine successively, dried and distilled to remove the solvent. The residue was purified by silica gel column chromatography to give 5.04 g of the title compound (yield: 86%).
Reaction SMILES: CON(C)[C:4](=[O:15])[C:5]1[CH:10]=[CH:9][C:8]([N+:11]([O-:13])=[O:12])=[CH:7][C:6]=1[F:14].[H-].C([Al+]CC(C)C)C(C)C.C1(C)C=CC=CC=1.Cl>O1CCCC1>[N+:11]([C:8]1[CH:9]=[CH:10][C:5]([CH:4]=[O:15])=[C:6]([F:14])[CH:7]=1)([O-:13])=[O:12]
Reactant: CON(C)C(=O)c1ccc([N+](=O)[O-])cc1F
Agent: CC(C)C[Al+]CC(C)C
Agent: Cl
Agent: [H-]
Solvent: Cc1ccccc1
Solvent: C1CCOC1
Product: O=Cc1ccc([N+](=O)[O-])cc1F
Yield: 86.9 %

Procedure:
Compound 14a (860 mg) was dissolved in tetrahydrofuran (10.0 ml), and the reaction mixture was ice-cooled. Diisobutylaluminum hydride/toluene solution (0.98 mol/l, 5.0 ml) was added thereto, and the mixture was stirred under ice-cooling for 1 hour. After adding a 1N hydrochloric acid aqueous solution, the reaction mixture was returned to room temperature and extracted with ethyl acetate. The organic layer was washed with a 1N hydrochloric acid aqueous solution and saturated sodium-hydrogencarbonate aqueous solution, and then dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure. The obtained residue was recrystallized with a mixed solvent of tert-butylmethylether and n-heptane to obtain Compound 14b (554 mg, 86%) as a white solid.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:20])[C:4]1[CH:9]=[CH:8][C:7](B2OC(C)(C)C(C)(C)O2)=[C:6]([CH3:19])[CH:5]=1.FC(F)(F)S(O[C:27]1[CH:32]([C:33]([CH3:36])([CH3:35])[CH3:34])[CH2:31][CH2:30][CH2:29][CH:28]=1)(=O)=O>>[CH3:1][O:2][C:3](=[O:20])[C:4]1[CH:9]=[CH:8][C:7]([C:31]2[CH:32]([C:33]([CH3:36])([CH3:35])[CH3:34])[CH2:27][CH2:28][CH2:29][CH:30]=2)=[C:6]([CH3:19])[CH:5]=1
Reactant: COC(=O)c1ccc(B2OC(C)(C)C(C)(C)O2)c(C)c1
Reactant: CC(C)(C)C1CCCC=C1OS(=O)(=O)C(F)(F)F
Product: COC(=O)c1ccc(C2=CCCCC2C(C)(C)C)c(C)c1
Yield: 84.9 %

Procedure:
3-Methyl-4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-benzoic acid methyl ester of Example 28, Step A (1.00 g, 3.62 mmol) and 6-tert-butyl-cyclohex-1-en-1-yl trifluoromethanesulfonate (1.24 g, 4.34 mmol) were reacted in the manner of Example 1, Step F. Purification by flash column chromatography on silica gel, eluting with a solvent gradient of from 0 to 5% ethyl acetate in hexane, afforded the title compound (0.880 g) as a light yellow oil.
Reaction SMILES: N1C=CC=CC=1.FC(F)(F)C(OC(=O)C(F)(F)F)=O.[C:20]1([C:26]2([C:38]3[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=3)[CH2:34][C:33]3[NH:32][N:31]=[C:30]([C:35]([NH2:37])=O)[C:29]=3[CH:28]=[CH:27]2)[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1>O1CCOCC1>[C:38]1([C:26]2([C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)[CH2:34][C:33]3[NH:32][N:31]=[C:30]([C:35]#[N:37])[C:29]=3[CH:28]=[CH:27]2)[CH:39]=[CH:40][CH:41]=[CH:42][CH:43]=1
Reactant: NC(=O)c1n[nH]c2c1C=CC(c1ccccc1)(c1ccccc1)C2
Solvent: O=C(OC(=O)C(F)(F)F)C(F)(F)F
Solvent: C1COCCO1
Solvent: c1ccncc1
Product: N#Cc1n[nH]c2c1C=CC(c1ccccc1)(c1ccccc1)C2
Temperature: 20 °C
Reaction time: 20 h
Yield: 77.1 %

Procedure:
0.845 cm3 of pyridine and 0.74 cm3 of trifluoroacetic anhydride are successively added dropwise to a solution, cooled to a temperature in the region of 5° C., of 1.1 g of 6,6-diphenyl-6,7-dihydro-1H-indazole-3-carboxamide in 100 cm3 of dioxane. After warming to a temperature in the region of 20° C., the reaction mixture is stirred for about 20 hours at this temperature. 2 cm3 of pyridine and 2 cm3 of trifluoroacetic anhydride are added to the solution and the reaction mixture is refluxed for about 4 hours. After cooling to a temperature in the region of 20° C., the mixture is concentrated to dryness under reduced pressure (13 kPa). The residue is taken up in 50 cm3 of water and 150 cm3 of ethyl acetate; the pH of the mixture is brought to the region of 8 by addition of sodium bicarbonate. After separation of the phases by settling, the aqueous phase is extracted with three times 50 cm3 of ethyl acetate, and the combined organic phases are washed with three times 50 cm3 of water and then dried over magnesium sulphate, filtered and concentrated to dryness under reduced pressure (13 kPa). The residue is purified by flash chromatography on a column of silica [eluent: dichloromethane/ethyl acetate (90/10 by volume)]. 0.8 g of 6,6-diphenyl-6,7-dihydro-1H-indazole-3-carbonitrile is thus obtained in the form of a white powder, the characteristics of which are as follows:
Reaction SMILES: [CH2:1]1[CH:6]2[C:7]3[CH:19]=[CH:18][CH:17]=[CH:16][C:8]=3[CH2:9][C:10]3[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=3[N:5]2[CH2:4][CH2:3][NH:2]1.[C:20]([O:24][CH2:25][CH3:26])(=[O:23])[CH:21]=[CH2:22]>C(O)C>[CH2:1]1[CH:6]2[C:7]3[CH:19]=[CH:18][CH:17]=[CH:16][C:8]=3[CH2:9][C:10]3[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=3[N:5]2[CH2:4][CH2:3][N:2]1[CH2:22][CH2:21][C:20]([O:24][CH2:25][CH3:26])=[O:23]
Reactant: C=CC(=O)OCC
Reactant: c1ccc2c(c1)Cc1ccccc1N1CCNCC21
Solvent: CCO
Product: CCOC(=O)CCN1CCN2c3ccccc3Cc3ccccc3C2C1
Yield: 88 %

Procedure:
A mixture of 2.50 g of 1,2,3,4,10,14b-hexahydrodibenzo[c,f]pyrazino[1,2-a]azepine and 1.20 g of ethyl acrylate in 13 ml of ethanol was refluxed for 3 hrs. The reaction mixture was concentrated and the residue was chromatographed on silica gel using a mixture of n-hexane and ethyl acetate (1:1) as an eluent to give 3.08 g of colorless crystals, which were recrystallized from isopropyl ether to give colorless needles, mp 159°-160° C.
Reaction SMILES: [CH3:1][N:2]1[CH2:7][CH2:6][N:5]([C:8]2[CH:9]=[C:10]([CH:17]=[CH:18][C:19]=2[O:20][CH3:21])[CH2:11][NH:12][O:13][CH:14]=[C:15]=[O:16])[CH2:4][CH2:3]1.[Cl:22][C:23]1[C:24](=[O:30])[NH:25][N:26]=[CH:27][C:28]=1Cl.C(N(CC)CC)C.C(O)C>O>[Cl:22][C:23]1[C:24](=[O:30])[NH:25][N:26]=[CH:27][C:28]=1[N:12]([O:13][CH:14]=[C:15]=[O:16])[CH2:11][C:10]1[CH:17]=[CH:18][C:19]([O:20][CH3:21])=[C:8]([N:5]2[CH2:6][CH2:7][N:2]([CH3:1])[CH2:3][CH2:4]2)[CH:9]=1
Reactant: COc1ccc(CNOC=C=O)cc1N1CCN(C)CC1
Reactant: O=c1[nH]ncc(Cl)c1Cl
Solvent: O
Solvent: CCN(CC)CC
Solvent: CCO
Product: COc1ccc(CN(OC=C=O)c2cn[nH]c(=O)c2Cl)cc1N1CCN(C)CC1
Reaction time: 8 h
Yield: 47.9 %

Procedure:
A mixture comprising 1.16 g of 3-(4-methylpiperazin-1-yl)-carbonylmethoxy-4-methoxybenzylamine, 0.5 g of 4,5-dichloro-3(2H)-pyridazinone, 0.46 g of triethylamine, 10 ml of ethanol and 10 ml of water, was refluxed under heating with stirring overnight. The solvent was distilled off under reduced pressure, and an aqueous potassium carbonate solution was added to the residue. The mixture was extracted with chloroform. The extract solution was washed with water and a saturated sodium chloride aqueous solution and then dried over anhydrous sodium sulfate. Then, the solvent was distilled off. The obtained residue was purified by silica gel column chromatography and then crystallized from chloroform/diethyl ether to obtain 0.61 g of the above-identified compound as white crystals.
Reaction SMILES: [CH:1]1[C:6]2=[N:7][S:8][N:9]=[C:5]2[C:4]([NH:10][C:11]2[NH:15][CH2:14][CH2:13][N:12]=2)=[C:3]([Cl:16])[CH:2]=1.[CH:17]([OH:19])=[O:18]>C(O)(C)C>[CH:1]1[C:6]2=[N:7][S:8][N:9]=[C:5]2[C:4]([NH:10][C:11]2[NH:15][CH2:14][CH2:13][N:12]=2)=[C:3]([Cl:16])[CH:2]=1.[CH:17]([O-:19])=[O:18]
Reactant: O=CO
Agent: Clc1ccc2nsnc2c1NC1=NCCN1
Solvent: CC(C)O
Product: O=C[O-]
Temperature: 2.5 °C

Procedure:
3.0 g of the tizanidine base (99.15% HPLC) and 1.9 g of 99% formic acid are added to 5 ml of isopropyl alcohol; after short heating to boil a yellowish solution results, from which a precipitated product starts to separate. After cooling to 0-5° C. and aspiration 3.09 g of tizanidine formate are obtained.
Reaction SMILES: [F:1][C@H:2]1[C@H:8]([NH:9]C(=O)OC(C)(C)C)[CH2:7][CH2:6][C@@H:5]([C:17]2[N:21]([CH3:22])[N:20]=[CH:19][C:18]=2[N+:23]([O-])=O)[O:4][CH2:3]1.[F:26][C:27]1[CH:32]=[C:31]([C:33]2([OH:37])[CH2:36][CH2:35][CH2:34]2)[CH:30]=[C:29]([F:38])[C:28]=1[C:39]1[N:44]=[C:43]([C:45](O)=[O:46])[CH:42]=[CH:41][C:40]=1[F:48]>>[NH2:9][C@H:8]1[C@H:2]([F:1])[CH2:3][O:4][C@H:5]([C:17]2[N:21]([CH3:22])[N:20]=[CH:19][C:18]=2[NH:23][C:45](=[O:46])[C:43]2[CH:42]=[CH:41][C:40]([F:48])=[C:39]([C:28]3[C:29]([F:38])=[CH:30][C:31]([C:33]4([OH:37])[CH2:34][CH2:35][CH2:36]4)=[CH:32][C:27]=3[F:26])[N:44]=2)[CH2:6][CH2:7]1
Reactant: Cn1ncc([N+](=O)[O-])c1[C@@H]1CC[C@@H](NC(=O)OC(C)(C)C)[C@H](F)CO1
Reactant: O=C(O)c1ccc(F)c(-c2c(F)cc(C3(O)CCC3)cc2F)n1
Product: Cn1ncc(NC(=O)c2ccc(F)c(-c3c(F)cc(C4(O)CCC4)cc3F)n2)c1[C@@H]1CC[C@@H](N)[C@H](F)CO1

Procedure:
Following the procedure for Example 111 starting from tert-butyl ((3S,4R,7S)-3-fluoro-7-(1-methyl-4-nitro-1H-pyrazol-5-yl)oxepan-4-yl)carbamate (Intermediate 80), and replacing 5-((tert-butoxycarbonyl)amino)-2-(2,6-difluorophenyl)thiazole-4-carboxylic acid with 6-(2,6-difluoro-4-(1-hydroxycyclobutyl)phenyl)-5-fluoropicolinic acid (see US2012/225062) gave 198. 1H NMR (400 MHz, DMSO-d6) δ 10.19 (s, 1H), 8.29 (dd, J=8.7, 4.0 Hz, 1H), 8.14 (t, J=8.8 Hz, 1H), 7.90 (s, 1H), 7.35 (d, J=9.5 Hz, 2H), 5.89 (br, 1H), 4.80 (dd, J=10.5, 3.7 Hz, 1H), 4.32-4.07 (m, 1H), 4.07-3.84 (m, 2H), 3.75 (s, 3H), 3.11-3.00 (m, 1H), 2.50-2.39 (m, 2H), 2.38-2.26 (m, 2H), 2.09-1.88 (m, 2H), 1.84-1.68 (m, 2H), 1.67-1.57 (m, 2H). LCMS (ES+) m/z 534 (M+1).