Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([O:5][C@@H:6]([C:12]1[C:13]([CH3:32])=[N:14][C:15]2[N:16]([N:26]=[C:27]([C:29](O)=[O:30])[CH:28]=2)[C:17]=1[C:18]1[CH2:23][CH2:22][C:21]([CH3:25])([CH3:24])[CH2:20][CH:19]=1)[C:7]([O:9]CC)=[O:8])([CH3:4])([CH3:3])[CH3:2].[F:33][C:34]1[CH:39]=[CH:38][C:37]([CH2:40][NH2:41])=[CH:36][C:35]=1[CH3:42].CCN(C(C)C)C(C)C.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[OH-].[Na+]>CN(C=O)C.CN(C1C=CN=CC=1)C.CO.O>[C:1]([O:5][C@@H:6]([C:12]1[C:13]([CH3:32])=[N:14][C:15]2[N:16]([N:26]=[C:27]([C:29](=[O:30])[NH:41][CH2:40][C:37]3[CH:38]=[CH:39][C:34]([F:33])=[C:35]([CH3:42])[CH:36]=3)[CH:28]=2)[C:17]=1[C:18]1[CH2:23][CH2:22][C:21]([CH3:25])([CH3:24])[CH2:20][CH:19]=1)[C:7]([OH:9])=[O:8])([CH3:3])([CH3:2])[CH3:4]
Reactant: Cc1cc(CN)ccc1F
Reactant: CCOC(=O)[C@@H](OC(C)(C)C)c1c(C)nc2cc(C(=O)O)nn2c1C1=CCC(C)(C)CC1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: CN(C)c1ccncc1
Agent: F[P-](F)(F)(F)(F)F
Solvent: CO
Solvent: O
Solvent: CCN(C(C)C)C(C)C
Product: Cc1cc(CNC(=O)c2cc3nc(C)c([C@H](OC(C)(C)C)C(=O)O)c(C4=CCC(C)(C)CC4)n3n2)ccc1F
Temperature: 25 °C
Reaction time: 16 h
Yield: 42.6 %

Procedure:
To a mixture of (S)-6-(1-(tert-butoxy)-2-ethoxy-2-oxoethyl)-7-(4,4-dimethylcyclohex-1-en-1-yl)-5-methylpyrazolo[1,5-a]pyrimidine-2-carboxylic acid (30 mg, 0.068 mmol) and (4-fluoro-3-methylphenyl)methanamine (18.83 mg, 0.135 mmol) in DMF (1.5 mL) was added DIEA (0.059 mL, 0.338 mmol), HATU (51.4 mg, 0.135 mmol) and DMAP (1.653 mg, 0.014 mmol) and the resulting mixture was stirred at room temp for 16 h. At this point LCMS indicated completion of reaction. Water was then added and the mixture was extracted with ether (25 mL), washed with brine (15 mL), dried (Na2SO4), filtered and concentrated. Crude was then treated with 1N NaOH (0.203 mL, 0.203 mmol) in MeOH (1.500 mL) at 60° C. for 5 h. Mixture was then cooled and purified by prep-HPLC to afford (S)-2-(tert-butoxy)-2-(7-(4,4-dimethylcyclohex-1-en-1-yl)-2-((4-fluoro-3-methylbenzyl)carbamoyl)-5-methylpyrazolo[1,5-a]pyrimidin-6-yl)acetic acid (16.5 mg, 0.029 mmol, 43.2% yield). 1H NMR (500 MHz, DMSO-d6) δ 8.58 (t, J=6.0 Hz, 1H), 7.25 (d, J=7.6 Hz, 1H), 7.19 (dd, J=8.2, 5.2 Hz, 1H), 7.12-7.06 (m, 1H), 6.92 (s, 1H), 6.33 (br. s., 0.7H), 5.85 (br. s.; 0.3H), 5.31 (br. s., 0.7H), 5.23 (br. s., 0.3H), 4.54-4.39 (m, 2H), 2.67 (br. s., 1H), 2.59 (s, 2H), 2.23 (d, J=1.5 Hz, 3H), 2.14-2.10 (m, 4H), 1.70-1.59 (m, 2H), 1.18 (br. s., 3H), 1.14 (s, 7H), 1.08 (br. s., 2H), 1.07 (br. s., 4H). LCMS (M+H)=537.5.
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][C:8]([O:15][CH2:16][CH3:17])=[C:9]([O:12][CH2:13][CH3:14])[CH:10]=2)[N:5]=[CH:4][C:3]=1[C:18]#[N:19].[NH2:20][C:21]1[CH:29]=[C:28]2[C:24]([CH:25]=[N:26][NH:27]2)=[CH:23][CH:22]=1.C(=O)([O-])[O-].[Na+].[Na+]>C(O)C>[CH2:13]([O:12][C:9]1[CH:10]=[C:11]2[C:6](=[CH:7][C:8]=1[O:15][CH2:16][CH3:17])[N:5]=[CH:4][C:3]([C:18]#[N:19])=[C:2]2[NH:20][C:21]1[CH:29]=[C:28]2[C:24]([CH:25]=[N:26][NH:27]2)=[CH:23][CH:22]=1)[CH3:14]
Reactant: CCOc1cc2ncc(C#N)c(Cl)c2cc1OCC
Reactant: Nc1ccc2cn[nH]c2c1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCO
Product: CCOc1cc2ncc(C#N)c(Nc3ccc4cn[nH]c4c3)c2cc1OCC
Temperature: 100 °C
Yield: 83 %

Procedure:
A solution of 400 mg (1.44 mM) of 4-chloro-6,7-diethoxy-quinoline-3-carbonitrile and 250 mg (1.88 mM) of 6-aminoindazole in 10 ml of ethanol was refluxed for 3 hours. To the warm solution was added 1 ml of 1M sodium carbonate and the sample was heated for 5 minutes at 100° C., then poured into 300 ml of ice water. The solid was collected, washed with water followed by ether and dried under vacuum at 80° C. to yield 448 mg of 6,7-Diethoxy-4-(1H-indazol-6-ylamino)-quinoline-3-carbonitrile as a tan solid: mass spectrum (electrospray, m/e): M+H 374.1, mp=143-145° C.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:19]=[CH:20][C:21]=1[F:22])[NH:5][C:6]1[C:15]2[C:10](=[CH:11][C:12]([O:17][CH3:18])=[C:13]([OH:16])[CH:14]=2)[N:9]=[CH:8][N:7]=1.Cl.[N:24]1([CH2:29][CH2:30][CH2:31]Cl)[CH2:28][CH2:27][CH2:26][CH2:25]1.C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C>[Cl:1][C:2]1[CH:3]=[C:4]([CH:19]=[CH:20][C:21]=1[F:22])[NH:5][C:6]1[C:15]2[C:10](=[CH:11][C:12]([O:17][CH3:18])=[C:13]([O:16][CH2:31][CH2:30][CH2:29][N:24]3[CH2:28][CH2:27][CH2:26][CH2:25]3)[CH:14]=2)[N:9]=[CH:8][N:7]=1
Reactant: COc1cc2ncnc(Nc3ccc(F)c(Cl)c3)c2cc1O
Reactant: ClCCCN1CCCC1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: COc1cc2ncnc(Nc3ccc(F)c(Cl)c3)c2cc1OCCCN1CCCC1
Temperature: 80 °C
Yield: 5.4 %

Procedure:
A mixture of 4-(3'-chloro-4'-fluoroanilino)-6-hydroxy-7-methoxyquinazoline (1.28 g), 3-(pyrrolidin-1-yl)propyl chloride hydrochloride (Chem. Abs., 82, 57736; 1.5 g), potassium carbonate (2.8 g) and DMF (20 ml) was stirred and heated to 80° C. for 5 hours. The mixture was cooled to ambient temperature and partitioned between ethyl acetate and water. The organic phase was washed with water, dried (MgSO4) and evaporated. The residue was purified by column chromatography using a 20:3 mixture of methylene chloride and methanol as eluent. The material so obtained (1.1 g) was triturated under ethyl acetate to give 4-(3'-chloro-4'-fluoroanilino)-7-methoxy-6-(3-pyrrolidin-1-ylpropoxy)quinazoline (0.094 g). The organic solution was evaporated and the residual solid was recrystallised from acetonitrile. There was thus obtained a second crop (0.85 g) of the same product. The material gave the following characterising data:
Reaction SMILES: [CH3:1][S:2]([C:5]1[CH:6]=[CH:7][C:8]([O:14][C@H:15]([CH3:20])[C:16]([F:19])([F:18])[F:17])=[C:9]([CH:13]=1)[C:10]([OH:12])=O)(=[O:4])=[O:3].[N:21]1[CH2:24][CH:23]([OH:25])[CH:22]=1>>[OH:25][CH:23]1[CH2:24][N:21]([C:10]([C:9]2[CH:13]=[C:5]([S:2]([CH3:1])(=[O:3])=[O:4])[CH:6]=[CH:7][C:8]=2[O:14][C@H:15]([CH3:20])[C:16]([F:19])([F:18])[F:17])=[O:12])[CH2:22]1
Reactant: OC1C=NC1
Reactant: C[C@@H](Oc1ccc(S(C)(=O)=O)cc1C(=O)O)C(F)(F)F
Product: C[C@@H](Oc1ccc(S(C)(=O)=O)cc1C(=O)N1CC(O)C1)C(F)(F)F
Yield: 30 %

Procedure:
Prepared in analogy to Example 1 from 5-methanesulfonyl-2-((R)-2,2,2-trifluoro-1-methyl-ethoxy)-benzoic acid (Example A3(b)) and azetin-3-ol. The crude material was purified by flash chromatography (ethyl acetate/n-heptane) to yield the title compound as a white crystalline solid (yield 30%). MS (m/e): 368.0 (M+H+, 100%).
Reaction SMILES: Cl.Cl.Cl.[O:4]1[C:12]2[CH:11]=[CH:10][N:9]=[C:8]([N:13]3[CH2:18][CH2:17][N:16]([CH2:19][CH2:20][C@H:21]4[CH2:26][CH2:25][C@H:24]([NH2:27])[CH2:23][CH2:22]4)[CH2:15][CH2:14]3)[C:7]=2[CH2:6][CH2:5]1.[F:28][C:29]([F:37])([F:36])[C@H:30]([OH:35])[CH2:31][C:32](O)=[O:33]>>[O:4]1[C:12]2[CH:11]=[CH:10][N:9]=[C:8]([N:13]3[CH2:18][CH2:17][N:16]([CH2:19][CH2:20][C@H:21]4[CH2:26][CH2:25][C@H:24]([NH:27][C:32](=[O:33])[CH2:31][C@@H:30]([OH:35])[C:29]([F:37])([F:36])[F:28])[CH2:23][CH2:22]4)[CH2:15][CH2:14]3)[C:7]=2[CH2:6][CH2:5]1
Reactant: N[C@H]1CC[C@H](CCN2CCN(c3nccc4c3CCO4)CC2)CC1
Reactant: O=C(O)C[C@@H](O)C(F)(F)F
Agent: Cl
Product: O=C(C[C@@H](O)C(F)(F)F)N[C@H]1CC[C@H](CCN2CCN(c3nccc4c3CCO4)CC2)CC1

Procedure:
The title compound, white solid (72 mg, 77%), MS (ISP) m/z=471.5 [(M+H)+], mp 207° C., was prepared in accordance with the general method of example 32 from trans-4-{2-[4-(2,3-dihydrofuro[3,2-c]pyridin-4-yl)-piperazin-1-yl]-ethyl}-cyclohexanamine trihydrochloride (intermediate C) (88 mg, 0.2 mmol) and (R)-4,4,4-trifluoro-3-hydroxybutanoic acid.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([NH:8][C@@H:9]2[CH2:14][CH2:13][CH2:12][CH2:11][C@@H:10]2[NH:15][C:16](=[O:22])[O:17][C:18]([CH3:21])([CH3:20])[CH3:19])[CH:5]=[N:4][C:3]=1[C:23]#[N:24].[CH3:25][N:26]1[C:34]2[CH:33]=[CH:32][CH:31]=[C:30]([NH2:35])[C:29]=2[CH:28]=[CH:27]1.C([O-])([O-])=O.[K+].[K+].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>O1CCOCC1.CC([O-])=O.CC([O-])=O.[Pd+2]>[C:23]([C:3]1[N:4]=[CH:5][C:6]([NH:8][C@@H:9]2[CH2:14][CH2:13][CH2:12][CH2:11][C@@H:10]2[NH:15][C:16](=[O:22])[O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[N:7][C:2]=1[NH:35][C:30]1[CH:31]=[CH:32][CH:33]=[C:34]2[C:29]=1[CH:28]=[CH:27][N:26]2[CH3:25])#[N:24]
Reactant: Cn1ccc2c(N)cccc21
Reactant: CC(C)(C)OC(=O)N[C@H]1CCCC[C@H]1Nc1cnc(C#N)c(Cl)n1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: O=C([O-])[O-]
Solvent: C1COCCO1
Product: Cn1ccc2c(Nc3nc(N[C@@H]4CCCC[C@@H]4NC(=O)OC(C)(C)C)cnc3C#N)cccc21
Reaction time: 20 h
Yield: 146 %

Procedure:
A mixture of tert-butyl (1S,2R)-2-(6-chloro-5-cyanopyrazin-2-ylamino)cyclohexylcarbamate (80 mg, 0.227 mmol), 1-methyl-1H-indol-4-amine (50 mg, 0.342 mmol), K2CO3 (65 mg, 0.471 mmol), BINAP (25 mg, 0.040 mmol) and Pd(OAc)2 (10 mg, 0.044 mmol) in dioxane (2 mL) was degassed with Ar, then was stirred at 100 C for 20 h. Water and EtOAc were added. Organic phase was separated. The aqueous phase was extracted with EtOAc again. The combined organic phases were dried over Na2SO4, concentrated in vacuo to give a crude tert-butyl (1S,2R)-2-(5-cyano-6-(1-methyl-1H-indol-4-ylamino)pyrazin-2-ylamino)cyclohexylcarbamate (153 mg).
Reaction SMILES: [C:1]([NH2:5])(=[NH:4])[CH2:2][CH3:3].[C:6]([CH:9]([CH2:15][CH2:16][C:17]([O:19][CH2:20][CH3:21])=[O:18])[C:10](OCC)=[O:11])(=O)[CH3:7]>>[CH2:2]([C:1]1[N:5]=[C:10]([OH:11])[C:9]([CH2:15][CH2:16][C:17]([O:19][CH2:20][CH3:21])=[O:18])=[C:6]([CH3:7])[N:4]=1)[CH3:3]
Reactant: CCOC(=O)CCC(C(C)=O)C(=O)OCC
Reactant: CCC(=N)N
Product: CCOC(=O)CCc1c(C)nc(CC)nc1O
Yield: 12819.8 %

Procedure:
The title compound (1.99 g) was prepared from 5.00 g of propioamidine and 15.0 mg of diethyl 2-acetylglutarate using the procedure in Example 1, 18% yield.
Reaction SMILES: [OH-].[Na+].[CH:3]1([CH:9]=O)[CH2:8][CH2:7][CH:6]=[CH:5][CH2:4]1.[F:11][C:12]1[CH:17]=[CH:16][C:15]([CH2:18][CH:19]=[O:20])=[CH:14][CH:13]=1>O.CO>[F:11][C:12]1[CH:17]=[CH:16][C:15](/[C:18](=[CH:9]/[CH:3]2[CH2:8][CH2:7][CH:6]=[CH:5][CH2:4]2)/[CH:19]=[O:20])=[CH:14][CH:13]=1
Reactant: O=CCc1ccc(F)cc1
Reactant: O=CC1CC=CCC1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: O=C/C(=C\C1CC=CCC1)c1ccc(F)cc1
Temperature: 10 °C
Reaction time: 2 h
Yield: 41 %

Procedure:
5.5 g of sodium hydroxide in 30 ml of water are added to a solution of 40 g of 3-cyclohexenecarbaldehyde in 300 ml of methanol. The reaction mixture is cooled to 10° C., and 49.7 g of 4-fluorophenylacetaldehyde are rapidly added dropwise, the temperature of the solution not exceeding 30° C. After the mixture has been stirred for 2 hours at room temperature, 200 ml of water are added to the colorless reaction solution and the resulting emulsion is extracted by shaking with methyl tert-butyl ether. The organic phase is separated off, and 34 g (41%) of Z-2-(4-fluorophenyl)-3-(3-cyclohexenyl)-propenal are obtained under 0.5 mbar and at 136°-142° C. by distillation of the remaining residue.
Reaction SMILES: [C:1]1(=[O:11])[NH:6][CH2:5][CH2:4][N:3]2[C:7](=[O:10])[CH2:8][CH:9]=[C:2]12.[C:12]1([CH3:19])[CH:17]=[CH:16][C:15](I)=[CH:14][CH:13]=1.C([O-])([O-])=O.[K+].[K+]>CN(C)C=O.[Cu]I>[C:12]1([CH3:19])[CH:17]=[CH:16][C:15]([N:6]2[CH2:5][CH2:4][N:3]3[C:7](=[O:10])[CH2:8][CH2:9][CH:2]3[C:1]2=[O:11])=[CH:14][CH:13]=1
Reactant: Cc1ccc(I)cc1
Reactant: O=C1NCCN2C(=O)CC=C12
Agent: [Cu]I
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: Cc1ccc(N2CCN3C(=O)CCC3C2=O)cc1
Yield: 29.5 %

Procedure:
A mixture of tetrahydro-pyrrolo[1,2-a]pyrazine-1,6-dione (compound of Description 15, 150 mg, 0.97 mmol), p-tolyliodide (424 mg, 1.94 mmol), CuI (62 mg, 0.32 mmol) and K2CO3 (134 mg, 0.98 mmol) in dimethylformamide (6 ml) was refluxed for 2 hours. The solvent was removed under vacuum; the residue was triturated with ethyl acetate and after filtering off the insoluble material, the organic layer was washed with brine, dried (Na2SO4) and evaporated under vacuum. The residue was purified by flash chromatography (DCM/MeOH 95/5 respectively) to give the title compound as a light brown powder (70 mg, 30% yield).
Reaction SMILES: [C:1]([C:5]1[N:9]=[C:8]([CH2:10][C:11]([O:13]CC)=[O:12])[N:7]([CH2:16][CH2:17][O:18][CH3:19])[N:6]=1)([CH3:4])([CH3:3])[CH3:2].[Li+].[OH-].Cl>CO>[C:1]([C:5]1[N:9]=[C:8]([CH2:10][C:11]([OH:13])=[O:12])[N:7]([CH2:16][CH2:17][O:18][CH3:19])[N:6]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CCOC(=O)Cc1nc(C(C)(C)C)nn1CCOC
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Product: COCCn1nc(C(C)(C)C)nc1CC(=O)O
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 79.7 %

Procedure:
Ethyl [3-tert-Butyl-1-(2-methoxyethyl)-1H-1,2,4-triazol-5-yl]acetate (Preparation 115, 23.1 g, 0.086 mol) was dissolved in methanol (150 mL), and 1.9N LiOH (68 mL, 0.13 mol) was added. The mixture was stirred at 0° C. for 30 minutes and concentrated in vacuo at 30° C. Water (70 mL) was added. The resulting mixture was washed with ether (3×100 mL) and neutralized with titrated 2.6N HCl (49.6 mL, 0.13 mol). The resulting precipitate was filtered, washed with water, hexane and dried to afford the title compound (16.54 g, 80%).
Reaction SMILES: [Cl-].[CH2:2]([NH+:9]([CH3:41])[CH2:10][CH2:11][O:12][C@H:13]1[CH2:20][N:19]2[C:21]3[CH:22]=[C:23]([C:34]([OH:36])=[O:35])[CH:24]=[CH:25][C:26]=3[C:27]([CH:28]3[CH2:33][CH2:32][CH2:31][CH2:30][CH2:29]3)=[C:18]2[C:17]2[CH:37]=[CH:38][CH:39]=[CH:40][C:16]=2[O:15][CH2:14]1)[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.[C:42](Cl)(=O)C>CO>[CH2:2]([N:9]([CH3:41])[CH2:10][CH2:11][O:12][C@H:13]1[CH2:20][N:19]2[C:21]3[CH:22]=[C:23]([C:34]([O:36][CH3:42])=[O:35])[CH:24]=[CH:25][C:26]=3[C:27]([CH:28]3[CH2:33][CH2:32][CH2:31][CH2:30][CH2:29]3)=[C:18]2[C:17]2[CH:37]=[CH:38][CH:39]=[CH:40][C:16]=2[O:15][CH2:14]1)[C:3]1[CH:4]=[CH:5][CH:6]=[CH:7][CH:8]=1
Reactant: CC(=O)Cl
Reactant: C[NH+](CCO[C@@H]1COc2ccccc2-c2c(C3CCCCC3)c3ccc(C(=O)O)cc3n2C1)Cc1ccccc1
Agent: [Cl-]
Solvent: CO
Product: COC(=O)c1ccc2c(C3CCCCC3)c3n(c2c1)C[C@H](OCCN(C)Cc1ccccc1)COc1ccccc1-3

Procedure:
A solution (0.014 M) of N-benzyl-2-{[(7S)-11-carboxy-14-cyclohexyl-7,8-dihydro-6H-indolo[1,2-e][1,5]benzoxazocin-7-yl]oxy}-N-methylethanaminium chloride in anhydrous MeOH was treated with acetyl chloride (1.1 eq.). The mixture was heated at reflux overnight. All the volatiles were removed in vacuo to afford the title compound. The product was used in the next step without further purification. (ES+) m/z 553 (M+H)+.
Reaction SMILES: [OH:1][C@H:2]([CH3:6])[C:3](N)=O.F[B-](F)(F)F.C([O+](CC)CC)C.[NH2:19][C:20]1[C:21]([NH:29][C@H:30]2[CH2:35][CH2:34][C@H:33]([CH2:36][OH:37])[CH2:32][CH2:31]2)=[C:22]2[S:28][CH:27]=[CH:26][C:23]2=[N:24][CH:25]=1>O1CCCC1.C(O)C>[OH:37][CH2:36][C@H:33]1[CH2:32][CH2:31][C@H:30]([N:29]2[C:21]3=[C:22]4[S:28][CH:27]=[CH:26][C:23]4=[N:24][CH:25]=[C:20]3[N:19]=[C:3]2[C@H:2]([OH:1])[CH3:6])[CH2:35][CH2:34]1
Reactant: Nc1cnc2ccsc2c1N[C@H]1CC[C@H](CO)CC1
Reactant: C[C@@H](O)C(N)=O
Agent: CC[O+](CC)CC
Agent: F[B-](F)(F)F
Solvent: CCO
Solvent: C1CCOC1
Product: C[C@@H](O)c1nc2cnc3ccsc3c2n1[C@H]1CC[C@H](CO)CC1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A mixture of (2R)-2-hydroxypropanamide (42 mg, 0.48 mmol) and triethyloxonium tetrafluoroborate (85 mg, 0.45 mmol) in tetrahydrofuran (0.65 mL) was stirred at room temperature for 2 h. The solvent was removed, and the residue dissolved in ethanol (0.27 mL) and added to a suspension of {trans-4-[(6-aminothieno[3,2-b]pyridin-7-yl)amino]cyclohexyl}methanol (41 mg, 0.15 mmol) in ethanol (0.99 mL). The resulting mixture was stirred at 85° C. for 1 h. The solvent was removed and the residue was purified on RP-HPLC (XBridge C18 column, eluting with a gradient of acetonitrile/water containing 0.1% ammonium hydroxide, at flow rate of 30 mL/min) to give the desired product (2.3 mg, 4.7%). LCMS calculated for C17H22N3O2S (M+H)+: m/z=332.1. Found: 332.1.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9]([CH:11]2[CH2:13][CH2:12]2)=O)=[CH:4][N:3]=1.P(Cl)(Cl)(Cl)(Cl)[Cl:15]>ClCCl>[F:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]=[C:9]([Cl:15])[CH:11]2[CH2:13][CH2:12]2)=[CH:4][N:3]=1
Reactant: O=C(Nc1ccc(F)nc1)C1CC1
Reactant: ClP(Cl)(Cl)(Cl)Cl
Solvent: ClCCl
Product: Fc1ccc(N=C(Cl)C2CC2)cn1
Temperature: 25 °C
Reaction time: 1 h
Yield: 96.1 %

Procedure:
N-(2-fluoro-5-pyridyl)-cyclopropane carboxamide (2.0 g, 0.011 mol) was added portionwise to a stirred solution of phosphorus pentachloride (2.31 g, 0.011 mol) in dichloromethane (20 ml) under a nitrogen atmosphere at room temperature. After complete addition the mixture was stirred at room temperature for one hour and then heated at reflux for a further one hour. The reaction mixture was then evaporated under vacuum to gave N-(2-fluoro-5-pyridyl)-cyclopropylmethanimidoyl chloride (2.1 g, 96%) which was used in Stage 3 without further purification or characterisation.
Reaction SMILES: CN(C)C=O.[C:6]([C:8]1[C:13]([CH3:14])=[C:12](I)[C:11]([F:16])=[C:10]([O:17][CH3:18])[C:9]=1[NH:19][C:20](=[O:25])[C:21]([F:24])([F:23])[F:22])#[N:7].[C:26]1(B(O)O)[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1.O>[Cl-].[Na+].O>[C:6]([C:8]1[C:9]([NH:19][C:20](=[O:25])[C:21]([F:24])([F:23])[F:22])=[C:10]([O:17][CH3:18])[C:11]([F:16])=[C:12]([C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)[C:13]=1[CH3:14])#[N:7]
Reactant: OB(O)c1ccccc1
Reactant: COc1c(F)c(I)c(C)c(C#N)c1NC(=O)C(F)(F)F
Agent: [Cl-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: COc1c(F)c(-c2ccccc2)c(C)c(C#N)c1NC(=O)C(F)(F)F
Temperature: 25 °C
Yield: 97.7 %

Procedure:
Under nitrogen atmosphere, tetrakistriphenylphosphine palladium(0) (288 mg, 0.25 mmol) was added to an N,N-dimethylformamide (15 ml) suspension of N-(2-cyano-5-fluoro-4-iodo-6-methoxy-3-methylphenyl)-2,2,2-trifluoroacetamide (I-35) (500 mg, 1.24 mmol), phenylboronic acid (228 mg, 1.87 mmol), potassium phosphate n-hydrate (890 mg, 3.1 mmol), followed by stirring with heating under reflux for 15 hours and a half. After cooling to room temperature, water and saturated brine were added to the reaction liquid, followed by extraction three times with ethyl acetate, the organic layer was washed with saturated ammonium chloride water, then dried over anhydrous magnesium sulfate. After filtration and concentration under reduced pressure, the resulting residue was subjected to column chromatography, and the eluate with n-hexane:ethyl acetate (5:1) was concentrated under reduced pressure to obtain the entitled compound (427 mg, 98%) as a white solid.
Reaction SMILES: F[C:2]1[CH:7]=[CH:6][C:5]([I:8])=[CH:4][N:3]=1.[C:9]([N:16]1[CH2:21][CH2:20][NH:19][CH2:18][CH2:17]1)([O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:10]>>[C:12]([O:11][C:9]([N:16]1[CH2:21][CH2:20][N:19]([C:2]2[CH:7]=[CH:6][C:5]([I:8])=[CH:4][N:3]=2)[CH2:18][CH2:17]1)=[O:10])([CH3:15])([CH3:13])[CH3:14]
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Reactant: Fc1ccc(I)cn1
Product: CC(C)(C)OC(=O)N1CCN(c2ccc(I)cn2)CC1

Procedure:
By carrying out the procedure as described in preparation 1, but using 2-fluoro-5-iodopyridine instead of 2-chloro-5-(trifluoromethyl)pyridine and N-Boc-piperazine instead of cis-2,6-dimethylpiperazine, the title compound is obtained in the form of an oil.
Reaction SMILES: [F:1][C:2]([F:16])([F:15])[CH2:3][NH:4][C:5]1[CH:6]=[C:7]([C:13]#[N:14])[C:8]([C:11]#[N:12])=[CH:9][CH:10]=1.Br[CH:18]([CH2:26][CH3:27])[C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20]>>[C:13]([C:7]1[CH:6]=[C:5]([N:4]([CH2:3][C:2]([F:15])([F:16])[F:1])[CH:18]([CH2:26][CH3:27])[C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])[CH:10]=[CH:9][C:8]=1[C:11]#[N:12])#[N:14]
Reactant: N#Cc1ccc(NCC(F)(F)F)cc1C#N
Reactant: CCC(Br)C(=O)OC(C)(C)C
Product: CCC(C(=O)OC(C)(C)C)N(CC(F)(F)F)c1ccc(C#N)c(C#N)c1

Procedure:
Synthesized in a manner similar to example 1B using 4-[(2,2,2-trifluoroethyl)amino]-1,2-benzenedicarbonitrile and tert-butyl 2-bromobutanoate: MS (ES) m/z 368 (M+1).
Reaction SMILES: [C:1]([O:10][CH2:11][CH3:12])(=[O:9])[C:2]1[C:3](=[CH:5][CH:6]=[CH:7][CH:8]=1)[OH:4].C(=O)([O-])[O-].[Cs+].[Cs+].CN(C)C=O.Cl[CH2:25][CH2:26][CH2:27][C:28]([O:30][C:31]([CH3:34])([CH3:33])[CH3:32])=[O:29]>C(OCC)(=O)C>[C:31]([O:30][C:28]([CH2:27][CH2:26][CH2:25][O:4][C:3]1[CH:5]=[CH:6][CH:7]=[CH:8][C:2]=1[C:1]([O:10][CH2:11][CH3:12])=[O:9])=[O:29])([CH3:34])([CH3:33])[CH3:32]
Reactant: CCOC(=O)c1ccccc1O
Reactant: CC(C)(C)OC(=O)CCCCl
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CCOC(=O)c1ccccc1OCCCC(=O)OC(C)(C)C
Reaction time: 12 h
Yield: 61.8 %

Procedure:
A mixture comprising ethyl salicylate (3.14 g, 18.9 mmol) and cesium carbonate (6.2 g, 18.9 mmol), dimethylformamide (25 mL) and tert-butyl 4-chlorobutyrate (4.08 g, 22.8 mmol) was heated at 70° C. and stirred for 12 hours. The mixture was partitioned between ethyl ether (100 mL) and water and the organic layer was separated and washed with additional water (3×) and saturated aqueous sodium chloride, dried over anhydrous magnesium sulfate, filtered and concentrated in vacuo to afford a colorless oil. The residue was purified by silica gel flash chromatography using pure hexane to (10:1) hexane:ethyl acetate to provide ethyl 2-(3-tert-butoxycarbonylpropoxy)benzoate (3.6 g, 62% yield) as a colorless oil; 1H NMR (300 MHz, CDCl3): 7.80 (d, 1H), 7.49 (tr, 1H), 7.00 (m, 2H), 4.40 (q, 2H), 4.10 (tr, 2H), 2.50 (tr, 2H), 2.10 (m, 2H), 1.45 (s, 9H), 1.40 (tr, 3H).
Reaction SMILES: [C:1]1([C:7]2[CH:8]=[C:9]([N:18]3[CH2:23][CH2:22][N:21]([CH2:24][CH2:25][O:26]C4CCCCO4)[CH2:20][CH2:19]3)[N:10]3[CH:16]=[CH:15][C:14](=[O:17])[CH:13]=[CH:12][C:11]=23)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1>C(Cl)(Cl)Cl.CO.Cl.C(Cl)Cl>[OH:26][CH2:25][CH2:24][N:21]1[CH2:22][CH2:23][N:18]([C:9]2[N:10]3[CH:16]=[CH:15][C:14](=[O:17])[CH:13]=[CH:12][C:11]3=[C:7]([C:1]3[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=3)[CH:8]=2)[CH2:19][CH2:20]1
Reactant: O=c1ccc2c(-c3ccccc3)cc(N3CCN(CCOC4CCCCO4)CC3)n2cc1
Agent: Cl
Solvent: CO
Solvent: ClCCl
Solvent: ClC(Cl)Cl
Product: O=c1ccc2c(-c3ccccc3)cc(N3CCN(CCO)CC3)n2cc1
Temperature: 20 °C
Reaction time: 12 h
Yield: 23.2 %

Procedure:
To a solution of 1-phenyl-3-[4-(2-tetrahydropyranyloxyethyl)-1-piperazinyl]-7H-pyrrolo[1,2-a]azepin-7-one (1.5 g) in chloroform (15 cc) and methanol (15 cc), 11.5M aqueous hydrochloric acid solution (1 cc) is added and the mixture is stirred at a temperature of about 20° C. for 12 hours. The solvents are evaporated off and the residue thereby obtained is dissolved in methylene chloride (50 cc). The solution is washed with 1N aqueous sodium hydroxide solution (25 cc) and twice with distilled water (50 cc in total), dried over anhydrous magnesium sulphate in the presence of decolorizing charcoal, filtered and evaporated to dryness under reduced pressure (20 mm Hg; 2.7 kPa) at 40° C. 3-[4-(2-Hydroxyethyl)-1-piperazinyl]-1-phenyl-7H-pyrrolo[1,2-a]azepin-7-one (0.28 g) is thereby obtained in the form of a pale yellow oil.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH2:13][CH2:12][N:11](C(OCC3C=CC=CC=3)=O)[CH2:10][CH:9]=2)=[CH:4][CH:3]=1>[Pd].CO>[NH:11]1[CH2:12][CH2:13][CH:8]([C:5]2[CH:4]=[CH:3][C:2]([OH:1])=[CH:7][CH:6]=2)[CH2:9][CH2:10]1
Reactant: O=C(OCc1ccccc1)N1CC=C(c2ccc(O)cc2)CC1
Agent: [Pd]
Solvent: CO
Product: Oc1ccc(C2CCNCC2)cc1
Yield: 94.3 %

Procedure:
Benzyl 4-(4-hydroxyphenyl)-5,6-dihydropyridine-1(2H)-carboxylate (37.7 g, 121.86 mmol) and 5% palladium on carbon (7.6 g, 3.57 mmol) in methanol (380 mL) were stirred under an atmosphere of hydrogen at 5 bar and 25° C. for 2 hours. The catalyst was removed by filtration, washed with MeOH and the solvents evaporated. The crude material was triturated with diethyl ether, then the desired product collected by filtration and dried under vacuum to afford 4-(piperidin-4-yl)phenol (20.36 g, 94%) as a solid.