Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:11]=[CH:10][CH:9]=[C:8]([CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH3:26])[C:4]=1[C:5](Cl)=[O:6].[NH2:27][C:28]1[CH:35]=[CH:34][C:31]([C:32]#[N:33])=[C:30]([C:36]([F:39])([F:38])[F:37])[CH:29]=1.C(N(CC)CC)C>ClCCl>[C:32]([C:31]1[CH:34]=[CH:35][C:28]([NH:27][C:5](=[O:6])[C:4]2[C:8]([CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH3:26])=[CH:9][CH:10]=[CH:11][C:3]=2[O:2][CH3:1])=[CH:29][C:30]=1[C:36]([F:37])([F:38])[F:39])#[N:33]
Reactant: N#Cc1ccc(N)cc1C(F)(F)F
Reactant: CCCCCCCCCCCCCCCc1cccc(OC)c1C(=O)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCCCCCCCCCCCCCCc1cccc(OC)c1C(=O)Nc1ccc(C#N)c(C(F)(F)F)c1

Procedure:
2-Methoxy-6-pentadecyl-benzoyl chloride was condensed with 4-Amino-2-trifluromethyl benzonitrile in dichloromethane in presence of triethylamine as acid scavenger to yield N-(4-Cyano-3-trifluoromethyl-phenyl)-2-methoxy-6-pentadecyl-benzamide. The reaction mixture was then concentrated in vacuo and the residue was extracted into ethyl acetate. The ethyl acetate layer was washed with water and with cold aqueous hydrochloric acid, then dried over sodium sulphate and finally concentrated in vacuo. The residue obtained was chromatographed over silica gel to afford the desired product.
Reaction SMILES: [CH:1]([C:4]1[S:5][CH:6]=[C:7](/[CH:9]=[CH:10]/[C:11]([O:13][CH2:14]C)=[O:12])[N:8]=1)([CH3:3])[CH3:2].CO.[Mg].C(C1(CCC(OC)=O)NC=CS1)(C)C>C1COCC1>[CH:1]([C:4]1[S:5][CH:6]=[C:7]([CH2:9][CH2:10][C:11]([O:13][CH3:14])=[O:12])[N:8]=1)([CH3:3])[CH3:2]
Reactant: CCOC(=O)/C=C/c1csc(C(C)C)n1
Agent: COC(=O)CCC1(C(C)C)NC=CS1
Agent: [Mg]
Solvent: CO
Solvent: C1CCOC1
Product: COC(=O)CCc1csc(C(C)C)n1

Procedure:
A solution of 225 mg (1 mmol) of (E)-ethyl 3-(2-isopropyl-4-thiazolyl)propenoate in 10 ml of freshly distilled (from calcium hydride) methanol and 1 ml of dry THF was treated with 49 mg (2 mmol) of magnesium turnings. The mixture was stirred for 20 min, during which the magnesium was consumed. The resulting solution was poured over cold aqueous HCl, basified to pH 8 with NaHCO3, extracted with ethyl acetate, dried over Na2SO4, and concentrated. Silica gel chromatography using 10% ethyl acetate in hexane provided a mixture of the desired compound and methyl 3-(2-isopropyl-4-thiazolinyl)propanoate.
Reaction SMILES: [F:1][C:2]1[CH:32]=[CH:31][C:5]([C:6]([C:8]2[CH:30]=[CH:29][C:11]([O:12][CH2:13][C:14]#[C:15][C:16]3[CH:21]=[CH:20][C:19]([CH2:22][C@H:23]([O:27][CH3:28])[C:24]([OH:26])=[O:25])=[CH:18][CH:17]=3)=[CH:10][CH:9]=2)=O)=[CH:4][CH:3]=1.[NH2:33][OH:34].N1C=CC=CC=1>C(O)C>[F:1][C:2]1[CH:32]=[CH:31][C:5]([C:6](=[N:33][OH:34])[C:8]2[CH:30]=[CH:29][C:11]([O:12][CH2:13][C:14]#[C:15][C:16]3[CH:21]=[CH:20][C:19]([CH2:22][C@H:23]([O:27][CH3:28])[C:24]([OH:26])=[O:25])=[CH:18][CH:17]=3)=[CH:10][CH:9]=2)=[CH:4][CH:3]=1
Reactant: CO[C@@H](Cc1ccc(C#CCOc2ccc(C(=O)c3ccc(F)cc3)cc2)cc1)C(=O)O
Reactant: NO
Solvent: CCO
Solvent: c1ccncc1
Product: CO[C@@H](Cc1ccc(C#CCOc2ccc(C(=NO)c3ccc(F)cc3)cc2)cc1)C(=O)O
Reaction time: 8 h

Procedure:
(2S)-3-(4-{3-[4-(4-Fluoro-benzoyl)-phenoxy]-prop-1-ynyl}-phenyl)-2-methoxy-propionic acid from Example 12 (0.01 mmol, 1 eq) was mixed with Hydroxylamine chlorydrate (4 eq), pyridine (10 eq) and Ethanol (2 ml) and the mixture reaction was stirred overnight. The ethanol was evaporated under vacuo and HCl 0.5% was added to the residue to pH=3. Extracted with Ethyl Acetate and concentrated to give the title product as a mixture of two oximes. MS(ES) for C26H22FNO5 [M+H]+: 448.2, [M−H]−: 446.2.
Reaction SMILES: [F:1][C:2]1[CH:16]=[CH:15][C:5]([CH2:6][NH:7][CH:8]([C:12]([NH2:14])=[O:13])[C:9]([NH2:11])=[O:10])=[CH:4][CH:3]=1.[CH:17](OCC)(OCC)OCC.CC1C=CC(S(O)(=O)=O)=CC=1>C(O)C>[OH:13][C:12]1[N:14]=[CH:17][N:7]([CH2:6][C:5]2[CH:4]=[CH:3][C:2]([F:1])=[CH:16][CH:15]=2)[C:8]=1[C:9]([NH2:11])=[O:10]
Reactant: CCOC(OCC)OCC
Reactant: NC(=O)C(NCc1ccc(F)cc1)C(N)=O
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: CCO
Product: NC(=O)c1c(O)ncn1Cc1ccc(F)cc1

Procedure:
16.05 g (71.04 mmol) of 2-(4-fluorobenzylamino)malonamide are refluxed with 71 ml of triethyl orthoformate, i.e. 6 equivalents, and a catalytic amount of PTSA (250 mg) in 535 ml of absolute ethanol, in a round-bottomed flask placed under argon.
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][NH:4][CH2:3][CH2:2]1.C([C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1[S:15][N:16]1[CH2:21]CNCC1)#N>C(O)(C)C>[N:1]1([C:21]2[C:11]3[CH:12]=[CH:13][CH:14]=[CH:9][C:10]=3[S:15][N:16]=2)[CH2:6][CH2:5][NH:4][CH2:3][CH2:2]1
Reactant: N#Cc1ccccc1SN1CCNCC1
Reactant: C1CNCCN1
Solvent: CC(C)O
Product: c1ccc2c(N3CCNCC3)nsc2c1
Temperature: 90 °C
Yield: 55 %

Procedure:
Anhydrous piperazine (17.2 g, 0.20 mol) and isopropanol (3.0 mL) were charged to a round bottom flask equipped with a mechanical stirrer, thermometer, condenser topped with a nitrogen inlet, and an addition funnel. Once the flask was purged and then maintained under nitrogen, the mixture was heated to 90° C. to afford a solution. A solution of 1-(2-cyanophenylthio)piperazine (4.38 g, 20.0 mmol) in isopropanol (2.0 mL) was slowly added to the warm piperazine solution over 1 hour. Once the addition was complete, the solution was heated to reflux (118° C.) for 24 hours. The reddish solution was cooled to room temperature and then analyzed by HPLC. 3-(1-Piperazinyl)-1,2-benzisothiazole was formed in 55% yield by HPLC assay.
Reaction SMILES: Br[C:2]1[O:6][C:5]([C:7]([O:9][CH2:10][CH3:11])=[O:8])=[CH:4][CH:3]=1.C(#N)C.[C:15]([Si:17]([CH3:20])([CH3:19])[CH3:18])#[CH:16].P([O-])(O)(O)=O.[Na+]>[Cu](I)I.C(N(CC)CC)C>[CH3:18][Si:17]([C:15]#[C:16][C:2]1[O:6][C:5]([C:7]([O:9][CH2:10][CH3:11])=[O:8])=[CH:4][CH:3]=1)([CH3:20])[CH3:19]
Reactant: CCOC(=O)c1ccc(Br)o1
Reactant: C#C[Si](C)(C)C
Agent: I[Cu]I
Agent: O=P([O-])(O)O
Agent: [Na+]
Solvent: CC#N
Solvent: CCN(CC)CC
Product: CCOC(=O)c1ccc(C#C[Si](C)(C)C)o1

Procedure:
A solution of 5 g of the product of Stage A, 15 ml of acetonitrile, 15 ml of triethylamine, 4.5 ml of ethynyltrimethylsilane, 170 mg of (triphenylphosphine)palladium chloride and 30 mg of copper iodide was heated at 40° C. for 2 and a half hours and then allowed to return to room temperature and was poured into an aqueous sodium dihydrogenphosphate solution. The mixture was extracted with ethyl acetate and the extract was washed with water and dried. The solvent was evaporated to obtain after chromatography on silica (eluent: 95/5 hexane/ethyl acetate) 4.75 g of the expected product.
Reaction SMILES: C1(O[C:8](=[O:26])[NH:9][C:10]2[C:11]([O:19][C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)=[N:12][C:13]([CH3:18])=[C:14]([CH2:16][CH3:17])[CH:15]=2)C=CC=CC=1.[C:27]([O:30][C:31]1[CH:32]=[C:33]([N:37]2[CH2:42][CH2:41][NH:40][CH2:39][CH2:38]2)[CH:34]=[CH:35][CH:36]=1)(=[O:29])[CH3:28]>>[CH2:16]([C:14]1[CH:15]=[C:10]([NH:9][C:8]([N:40]2[CH2:39][CH2:38][N:37]([C:33]3[CH:34]=[CH:35][CH:36]=[C:31]([O:30][C:27](=[O:29])[CH3:28])[CH:32]=3)[CH2:42][CH2:41]2)=[O:26])[C:11]([O:19][C:20]2[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=2)=[N:12][C:13]=1[CH3:18])[CH3:17]
Reactant: CC(=O)Oc1cccc(N2CCNCC2)c1
Reactant: CCc1cc(NC(=O)Oc2ccccc2)c(Oc2ccccc2)nc1C
Product: CCc1cc(NC(=O)N2CCN(c3cccc(OC(C)=O)c3)CC2)c(Oc2ccccc2)nc1C
Yield: 83 %

Procedure:
Phenyl-N-(5-ethyl-6-methyl-2-phenoxypyridin-3-yl)carbamate and 1-(3-acetoxyphenyl)piperazine were reacted by the same way with the example 1 to obtain the titled compound.
Reaction SMILES: [CH3:1][C:2]1[N:6]([C:7]([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[CH:5]=[N:4][C:3]=1[CH2:26][CH2:27][C:28]([C:30]1[C:38]2[C:33](=[CH:34][CH:35]=[CH:36][CH:37]=2)[NH:32][CH:31]=1)=[O:29].[H-].[Na+].[CH3:41][N:42]([CH3:46])[C:43](Cl)=[O:44].O>CN(C=O)C>[CH3:41][N:42]([CH3:46])[C:43]([N:32]1[C:33]2[C:38](=[CH:37][CH:36]=[CH:35][CH:34]=2)[C:30]([C:28](=[O:29])[CH2:27][CH2:26][C:3]2[N:4]=[CH:5][N:6]([C:7]([C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=3)([C:8]3[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=3)[C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)[C:2]=2[CH3:1])=[CH:31]1)=[O:44]
Reactant: Cc1c(CCC(=O)c2c[nH]c3ccccc23)ncn1C(c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: CN(C)C(=O)Cl
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: Cc1c(CCC(=O)c2cn(C(=O)N(C)C)c3ccccc23)ncn1C(c1ccccc1)(c1ccccc1)c1ccccc1
Reaction time: 20 h

Procedure:
A solution of 3-[5-methyl-1-(triphenylmethyl)-1H-imidazol-4-yl]-1-(1H-indol-3-yl)-1-propanone (500 mg) in dry DMF (3 ml) was added dropwise to a stirred suspension of sodium hydride (73% dispersion in oil; 40 mg) in dry DMF (1 ml) under nitrogen. After 15 min. dimethylcarbamyl chloride (0.11 ml) was added and the mixture was stirred for 20 h. Water (50 ml) was added and the suspension was extracted with dichloromethane (3×25 ml). The combined, dried organic extracts were evaporated to give an oil (815 mg) which was purified by FCC (column made up in ethyl acetate:triethylamine 99:1) eluting with ethyl acetate to give the title compound (445 mg) as a foam, t.l.c. on triethylamine impregnated silica (ethyl acetate) Rf 0.20.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([S:8][CH:9]2[CH2:15][CH:14]3[N:16](C)[CH:11]([CH2:12][CH2:13]3)[CH2:10]2)=[CH:4][CH:3]=1.Cl[C:19]([O:21][CH2:22][C:23]([Cl:26])([Cl:25])[Cl:24])=[O:20].C(=O)([O-])[O-].[K+].[K+]>C1C=CC=CC=1>[F:1][C:2]1[CH:3]=[CH:4][C:5]([S:8][CH:9]2[CH2:15][CH:14]3[N:16]([C:19]([O:21][CH2:22][C:23]([Cl:26])([Cl:25])[Cl:24])=[O:20])[CH:11]([CH2:12][CH2:13]3)[CH2:10]2)=[CH:6][CH:7]=1
Reactant: O=C(Cl)OCC(Cl)(Cl)Cl
Reactant: CN1C2CCC1CC(Sc1ccc(F)cc1)C2
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: c1ccccc1
Product: O=C(OCC(Cl)(Cl)Cl)N1C2CCC1CC(Sc1ccc(F)cc1)C2

Procedure:
A mixture of 3-(4-fluorophenylsulfanyl)-8-methyl-8-azabicyclo-(3.2.1)-octane (the compound of Preparation 36, 8.20 g, 32.65 mmol), 2,2,2-trichloroethyl chloroformate (4.94 mL, 35.92 mmol), and potassium carbonate (4.96 g, 35.92 mmol) in benzene (140 mL) was refluxed overnight. The solvent was removed at reduced pressure and the residue was taken up in ethyl acetate. The organic phase was washed with aqueous bicarbonate and brine, dried over calcium sulfate and concentrated. The residue was flash chromatographed on silica gel (3×4 inches) with elution proceeding as follows: hexane (350 mL), nil; 10% ethyl acetate/hexane (400 mL), discarded forerun; 10% ethyl acetate/hexane (600 mL), 20% ethyl acetate/hexane (500 mL), and 30% ethyl acetate/hexane (250 mL), 10.32 g (77%) of 3-(4-fluorophenylsulfanyl)-8-(2,2,2-trichloroethoxycarbonyl)-8-azabicyclo-(3.2.1)-octane as an off white solid which had: mp 65-67° C.; NMR δ 7.40 (dd, J=5.5, 9 Hz, 2 H), 6.98 (long range coupled t, J=8.5 Hz, 2 H), 4.72 (ABq, Δv1-3 =60 Hz, J=12 Hz, 2 H), 4.35 (sym m, 2 H), 3.32 (septet, J=6 Hz, 1 H), 2.10-1.94 (m, 2 H), 1.94-1.58 (m, 6 H).
Reaction SMILES: FC(F)(F)C(O)=O.[NH:8]([C:15]1[CH:27]=[CH:26][C:18]([C:19]([O:21]C(C)(C)C)=[O:20])=[C:17]([NH:28][C:29]([C:31]2[CH:32]=[N:33][CH:34]=[C:35]([C:37]3[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=3)[CH:36]=2)=[O:30])[CH:16]=1)[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1>>[NH:8]([C:15]1[CH:27]=[CH:26][C:18]([C:19]([OH:21])=[O:20])=[C:17]([NH:28][C:29]([C:31]2[CH:32]=[N:33][CH:34]=[C:35]([C:37]3[CH:38]=[CH:39][CH:40]=[CH:41][CH:42]=3)[CH:36]=2)=[O:30])[CH:16]=1)[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1
Reactant: CC(C)(C)OC(=O)c1ccc(Nc2ccccc2)cc1NC(=O)c1cncc(-c2ccccc2)c1
Solvent: O=C(O)C(F)(F)F
Product: O=C(Nc1cc(Nc2ccccc2)ccc1C(=O)O)c1cncc(-c2ccccc2)c1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
Trifluoroacetic acid (3.0 mL) was added to the obtained tert-butyl 4-anilino-2-(5-phenylpyridine-3-carboxamido)benzoate, followed by stirring at room temperature for 1 hour and 30 minutes. The solvent was evaporated under reduced pressure, and diisopropyl ether was added to the obtained residue. The solid substance was collected by filtration. Dioxane (3.0 mL) and a 2 mol/L aqueous solution of sodium hydroxide (0.068 mL) were sequentially added to the obtained solid substance, followed by stirring at room temperature for 1 hour and 30 minutes. A 10% aqueous solution of citric acid was added to the reaction mixture, and the solid substance was collected by filtration to obtain 73 mg of 4-anilino-2-(5-phenylpyridine-3-carboxamido)benzoic acid as a yellow solid.
Reaction SMILES: OO.C1(=O)OC(=[O:7])C=C1.[Cl:10][C:11]1[N:16]=[C:15]([NH:17][C:18]([O:20][CH3:21])=[O:19])[N:14]=[C:13]([NH:22][C:23]([O:25][CH3:26])=[O:24])[CH:12]=1>C(Cl)Cl.C1C=CC=CC=1>[Cl:10][C:11]1[N:16]=[C:15]([NH:17][C:18]([O:20][CH3:21])=[O:19])[N+:14]([O-:7])=[C:13]([NH:22][C:23]([O:25][CH3:26])=[O:24])[CH:12]=1
Reactant: COC(=O)Nc1cc(Cl)nc(NC(=O)OC)n1
Reactant: O=C1C=CC(=O)O1
Agent: OO
Solvent: ClCCl
Solvent: c1ccccc1
Product: COC(=O)Nc1cc(Cl)nc(NC(=O)OC)[n+]1[O-]

Procedure:
A mixture of 18.7 g (0.385 mol) of 70 percent hydrogen peroxide and 400 ml of methylene chloride, stirred under argon and cooled to about 0°, is treated with 49.0 g (0.5 mol) of maleic acid anhydride. The mixture is stirred at 0° for 5 minutes and subsequently treated dropwise over a period of 15 minutes with a solution of 13.0 g (0.05 mol) of dimethyl 6-chloro-2,4-pyrimidinedicarbamate in 1500 ml of methylene chloride in such a manner that the temperature does not exceed 2°. The cooling bath is removed, the mixture is stirred for a further 15.5 hours, cooled to 3° and filtered. The white solid residue is subsequently washed with 400 ml of semi-saturated ice-cold sodium carbonate solution and then with 100 ml of ice-water. The material obtained is taken up in 150 ml of benzene and evaporated. This procedure is repeated once more and then the residue is dried at 60° under vacuum. There is obtained dimethyl 6-chloro-2,4-pyrimidinedicarbamate 3-oxide as a white solid of melting point 224°-225°.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[O:11][C:10]3[CH:12]=[CH:13][C:14]([Cl:16])=[CH:15][C:9]=3[N:8]=[C:7]([C:17]3[CH2:18][CH2:19][N:20](C)[CH2:21][CH:22]=3)[C:6]=2[CH:24]=1.[H-].[Al+3].[Li+].[H-].[H-].[H-]>CCOCC>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[O:11][C:10]3[CH:12]=[CH:13][C:14]([Cl:16])=[CH:15][C:9]=3[NH:8][CH:7]([C:17]3[CH:22]=[CH:21][N:20]=[CH:19][CH:18]=3)[C:6]=2[CH:24]=1
Reactant: CN1CC=C(C2=Nc3cc(Cl)ccc3Oc3ccc(Cl)cc32)CC1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: CCOCC
Product: Clc1ccc2c(c1)NC(c1ccncc1)c1cc(Cl)ccc1O2

Procedure:
A 20.0 g. portion of 2,8-dichloro-11-(4-pyridyl)-dibenz[b,f][1,4]oxazepine (Example 2), 10.0 g. of lithium aluminum hydride and 800 ml. of ether are reacted as described in Example 3, yielding 2,8-dichloro-10,11-dihydro-11-(4-pyridyl)-dibenz[b,f][1,4]oxazepine, mp. 202°-205° C.
Reaction SMILES: [C:1]([N:9]1[C:17]2[C:12](=[CH:13][C:14]([N+:18]([O-])=O)=[CH:15][CH:16]=2)[CH:11]=[C:10]1[C:21]([O:23][CH2:24][CH3:25])=[O:22])(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1>C1COCC1.[Pd]>[NH2:18][C:14]1[CH:13]=[C:12]2[C:17](=[CH:16][CH:15]=1)[N:9]([C:1](=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1)[C:10]([C:21]([O:23][CH2:24][CH3:25])=[O:22])=[CH:11]2
Reactant: CCOC(=O)c1cc2cc([N+](=O)[O-])ccc2n1C(=O)c1ccccc1
Agent: [Pd]
Solvent: C1CCOC1
Product: CCOC(=O)c1cc2cc(N)ccc2n1C(=O)c1ccccc1
Yield: 96.1 %

Procedure:
A solution of 3.2 (1.86 g, 5.5 mmol) and 10% Pd/C (440 mg) in dry THF (30 ml) was stirred under H2 for 16 hrs. The resulting mixture was filtered through celite which was washed with EtOAc (40 ml) and the filtrate was concentrated. The residue was purified by chromatography (SiO2, 0 to 40% EtOAc in hexanes) to afford 3.3 (1.63 g, 96%) as a bright yellow oil. 1H NMR (250 MHz, CDCl3) δ ppm 7.40-7.72 (m, 6H), 7.18 (s, 1H), 6.92 (d, 1H), 6.82 (dd, 1H), 3.92 (q, 2H), 3.68 (br s, 2H), 1.06 (t, 3H); FABMS: (NBA/NaI) m/z 308 (M+H+ expected 308).
Reaction SMILES: [CH:1]12[NH:8][CH:5]([CH2:6][CH2:7]1)[CH2:4][CH:3]([O:9][CH2:10][C:11]1[C:12]([C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=3[O:25][CH:26]([F:28])[F:27])=[N:13][O:14][C:15]=1[CH:16]1[CH2:18][CH2:17]1)[CH2:2]2.[F:29][C:30]1[CH:31]=[C:32]([CH:35]=[CH:36][C:37]=1F)[C:33]#[N:34]>>[CH:16]1([C:15]2[O:14][N:13]=[C:12]([C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=3[O:25][CH:26]([F:27])[F:28])[C:11]=2[CH2:10][O:9][CH:3]2[CH2:2][CH:1]3[N:8]([C:37]4[CH:36]=[CH:35][C:32]([C:33]#[N:34])=[CH:31][C:30]=4[F:29])[CH:5]([CH2:6][CH2:7]3)[CH2:4]2)[CH2:17][CH2:18]1
Reactant: FC(F)Oc1ccccc1-c1noc(C2CC2)c1COC1CC2CCC(C1)N2
Reactant: N#Cc1ccc(F)c(F)c1
Product: N#Cc1ccc(N2C3CCC2CC(OCc2c(-c4ccccc4OC(F)F)noc2C2CC2)C3)c(F)c1

Procedure:
4-(3-((5-cyclopropyl-3-(2-(difluoromethoxy)phenyl)isoxazol-4-yl)methoxy)-8-azabicyclo[3.2.1]octan-8-yl)-3-fluorobenzonitrile (26-A) was prepared from 4-((8-azabicyclo[3.2.1]octan-3-yloxy)methyl)-5-cyclopropyl-3-(2-(difluoromethoxy)phenyl)isoxazole and 3,4-difluorobenzonitrile according to the procedure described for the preparation of example 23.
Reaction SMILES: [CH3:1][C:2]([NH:12]C=O)([CH3:11])[CH2:3][C:4]1[CH:5]=[C:6]([CH3:10])[CH:7]=[CH:8][CH:9]=1.Cl.C(=O)([O-])[O-].[K+].[K+]>O>[CH3:11][C:2]([NH2:12])([CH3:1])[CH2:3][C:4]1[CH:5]=[C:6]([CH3:10])[CH:7]=[CH:8][CH:9]=1
Reactant: Cc1cccc(CC(C)(C)NC=O)c1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Product: Cc1cccc(CC(C)(C)N)c1
Temperature: 0 °C

Procedure:
1.80 g (9.41 mmol) N-(1,1-dimethyl-2-m-tolylethyl)-formamide, 20 mL water and 20 mL conc. hydrochloric acid were refluxed for 2 h. The reaction mixture was diluted with 20 mL ice water and made alkaline with saturated potassium carbonate solution. The aqueous phase was extracted with DCM (2×20 mL). The organic phase was washed with water, dried on sodium sulphate and evaporated down i. vac. The residue was co-evaporated with toluene (2×).
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[C:8](=[O:12])[NH:7][N:6]=[C:5]2[Cl:13].[CH3:14][O:15][C:16]1[CH:17]=[C:18]([CH:21]=[C:22]([O:24][CH3:25])[CH:23]=1)[CH2:19][NH2:20].C1C=CC(P(C2C(C3C(P(C4C=CC=CC=4)C4C=CC=CC=4)=CC=C4C=3C=CC=C4)=C3C(C=CC=C3)=CC=2)C2C=CC=CC=2)=CC=1.CC([O-])(C)C.[Na+]>CC(N(C)C)=O.CCOC(C)=O.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]>[Cl:13][C:5]1[C:4]2[C:9](=[CH:10][CH:11]=[C:2]([NH:20][CH2:19][C:18]3[CH:21]=[C:22]([O:24][CH3:25])[CH:23]=[C:16]([O:15][CH3:14])[CH:17]=3)[CH:3]=2)[C:8](=[O:12])[NH:7][N:6]=1
Reactant: O=c1[nH]nc(Cl)c2cc(Br)ccc12
Reactant: COc1cc(CN)cc(OC)c1
Agent: [Pd]
Agent: CC(C)(C)[O-]
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: CCOC(C)=O
Solvent: CC(=O)N(C)C
Product: COc1cc(CNc2ccc3c(=O)[nH]nc(Cl)c3c2)cc(OC)c1
Yield: 2.1 %

Procedure:
A mixture 6-bromo-4-chloro-2H-phthalazin-1-one (105 mg, 0.405 mmol), 3,5-dimethoxybenzylamine (0.64 mL, 0.424 mmol), Pd2(dba)3 (25 mg, 0.027 mmol), rac-BINAP (78 mg, 0.125 mmol) and NaOt-Bu (92 mg, 0.963 mmol) in DMA (6 mL) was heated at 80° C. for 45 minutes. The mixture was allowed to cool, diluted with EtOAc and washed with water. The organic layer was washed with sat.aq. NaHCO3, brine and dried (Na2SO4). Chromatography on silica (EtOAc/hexanes) afforded 4-chloro-6-(3,5-dimethoxy-benzylamino)-2H-phthalazin-1-one (3 mg) as a brown solid, 1H (400 MHz, CDCl3) δ: 3.65 (d, 6H), 4.28 (s, 2H), 6.25 (m, 1H), 6.42 (m, 2H), 6.81 (m, 1H), 6.95 (m, 2H), 8.00 (m, 1H), ppm. m/z (M+1) 345.92.
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])[C:9]([CH2:15][CH2:16][CH3:17])=[N:8][C:7]([OH:18])=[CH:6]2.Cl.Cl[CH2:21][C:22]1[C:23]([NH:37][CH2:38][CH2:39][NH:40][C:41](=[O:43])[CH3:42])=[N:24][C:25]2[C:30]([CH:31]=1)=[CH:29][C:28]([O:32][CH2:33][CH:34]1[CH2:36][CH2:35]1)=[CH:27][CH:26]=2.[Li+].[OH-]>C1COCC1>[CH:34]1([CH2:33][O:32][C:28]2[CH:29]=[C:30]3[C:25](=[CH:26][CH:27]=2)[N:24]=[C:23]([NH:37][CH2:38][CH2:39][NH:40][C:41](=[O:43])[CH3:42])[C:22]([CH2:21][C:6]2[C:5]4[C:10](=[CH:11][C:12]([O:13][CH3:14])=[C:3]([O:2][CH3:1])[CH:4]=4)[C:9]([CH2:15][CH2:16][CH3:17])=[N:8][C:7]=2[OH:18])=[CH:31]3)[CH2:35][CH2:36]1
Reactant: CC(=O)NCCNc1nc2ccc(OCC3CC3)cc2cc1CCl
Reactant: CCCc1nc(O)cc2cc(OC)c(OC)cc12
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Product: CCCc1nc(O)c(Cc2cc3cc(OCC4CC4)ccc3nc2NCCNC(C)=O)c2cc(OC)c(OC)cc12
Temperature: 160 °C
Reaction time: 1.5 h

Procedure:
To a solution of 6,7-dimethoxy-1-propylisoquinolin-3-ol RBO 35134 (151 mg, 0.6 mmol) in THF (13 mL) in a 20 mL microwave vial equipped with a magnetic stirrer was added N-(2-(3-(chloromethyl)-6-(cyclopropylmethoxy)quinolin-2-ylamino)ethyl)-acetamide hydrochloride SLA 47096B (235 mg, 0.6 mmol) followed by a 2 N aq. LiOH solution (0.612 mL, 1.2 mmol) and the mixture was stirred at 160° C. for 1.5 h under microwave irradiation. After cooling to RT, THF was removed at 40° C. under vacuum and the residue was taken up in CH2Cl2 (50 mL). The organic solution was washed with brine (10 mL), dried over Na2SO4, filtered, and concentrated under vacuum. Purification by column chromatography (SiO2, eluent CH2Cl2:MeOH=100:0 to 94:6) provided N-(2-(6-(cyclopropylmethoxy)-3-((3-hydroxy-6,7-dimethoxy-1-propylisoquinolin-4-yl)methyl)quinolin-2-ylamino)ethyl)acetamide. The free base was dissolved in MeOH (2 mL) in a 10 mL round-bottomed flask equipped with a magnetic stirrer before addition of a 0.149 M HCl solution in MeOH (2.0 mL). The reaction mixture was stirred for 5 min at RT and concentrated at 40° C. under vacuum to afford N-(2-(6-(cyclopropylmethoxy)-3-((3-hydroxy-6,7-dimethoxy-1-propylisoquinolin-4-yl)methyl)quinolin-2-ylamino)ethyl)acetamide dihydrochloride 83 as a brown solid (41 mg, 11% yield).
Reaction SMILES: [CH:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][C:2]=1[NH:11][N:12]=[C:13]([C:16]#[N:17])[C:14]#[N:15].NC1C=CC2C(=CC=CC=2)C=1.C(#N)CC#N.O.[NH2:35][NH2:36]>>[NH2:15][C:14]1[C:13](=[N:12][NH:11][C:2]2[CH:3]=[CH:4][C:5]3[C:10](=[CH:9][CH:8]=[CH:7][CH:6]=3)[CH:1]=2)[C:16]([NH2:17])=[N:36][N:35]=1
Reactant: N#CC(C#N)=NNc1ccc2ccccc2c1
Reactant: NN
Agent: Nc1ccc2ccccc2c1
Solvent: O
Solvent: N#CCC#N
Product: NC1=NN=C(N)C1=NNc1ccc2ccccc2c1
Yield: 67 %

Procedure:
The title compound was prepared using 110 mg (0.5 mmol) of 2-[(naphthalen-2-yl)hydrazono]malononitrile, which was derived from 2-aminonaphthalene (143 mg, 1.0 mmol) and malononitrile (1.5 mmol) as described in Example 8, and hydrazine hydrate. The hydrazine hydrate was added to the solution at a temperature of 75° C. despite the fact that the starting material had not fully dissolved. The solution cleared briefly and then a precipitate formed. The resulting solid was isolated by filtration, washed with ethanol, and dried to yield 86 mg (67%) of the title compound as a tan coloured solid.
Reaction SMILES: [CH2:1]([C:8]1[CH:13]=[CH:12][C:11]([C:14]2[CH:15]=[N:16][N:17]3[C:22]([OH:23])=[C:21](C(O)=O)[CH:20]=[N:19][C:18]=23)=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.NC1C=CC=CC=1.Cl>>[CH2:1]([C:8]1[CH:9]=[CH:10][C:11]([C:14]2[CH:15]=[N:16][N:17]3[C:22]([OH:23])=[CH:21][CH:20]=[N:19][C:18]=23)=[CH:12][CH:13]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=C(O)c1cnc2c(-c3ccc(Cc4ccccc4)cc3)cnn2c1O
Agent: Cl
Solvent: Nc1ccccc1
Product: Oc1ccnc2c(-c3ccc(Cc4ccccc4)cc3)cnn12
Temperature: 0 °C
Reaction time: 7 h
Yield: 83.2 %

Procedure:
A mixture of 3-(4-benzylphenyl)-6-carboxy-7-hydroxypyrazolo[1,5-a]pyrimidine (1.24 g) and aniline (11 ml) was stirred at 100° C. to 110° C. for 7 hours, and ice-water was put into the reaction mixture. After adding hydrochloric acid to adjust to acid, the reaction mixture was stirred at 0° C. for 1 hour. The precipitate was separated by filtration, washed with methanol-water (1:3)(50 ml), and dried to give the title compound (0.90 g).