Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9]2[CH:18]=[C:17]3[C:12]([C:13]([OH:29])=[C:14]([C:24]([O:26]CC)=O)[C:15](=[O:23])[N:16]3[CH2:19][CH2:20][O:21][CH3:22])=[N:11][CH:10]=2)=[CH:4][CH:3]=1.[NH2:30][CH2:31][CH2:32][N:33]([CH3:38])[S:34]([CH3:37])(=[O:36])=[O:35]>>[F:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:8][C:9]2[CH:18]=[C:17]3[C:12]([C:13]([OH:29])=[C:14]([C:24]([NH:30][CH2:31][CH2:32][N:33]([CH3:38])[S:34]([CH3:37])(=[O:36])=[O:35])=[O:26])[C:15](=[O:23])[N:16]3[CH2:19][CH2:20][O:21][CH3:22])=[N:11][CH:10]=2)=[CH:6][CH:7]=1
Reactant: CN(CCN)S(C)(=O)=O
Reactant: CCOC(=O)c1c(O)c2ncc(Cc3ccc(F)cc3)cc2n(CCOC)c1=O
Product: COCCn1c(=O)c(C(=O)NCCN(C)S(C)(=O)=O)c(O)c2ncc(Cc3ccc(F)cc3)cc21
Yield: 63.2 %

Procedure:
In a manner similar to that described in example 316, from ethyl 7-[(4-fluorophenyl)methyl]-4-hydroxy-1-[2-(methyloxy)ethyl]-2-oxo-1,2-dihydro-1,5-naphthyridine-3-carboxylate (10 mg, 0.025 mmol) and N-(2-aminoethyl)-N-methylmethanesulfonamide (50 mg, 0.329 mmol) was prepared 7-[(4-fluorophenyl)methyl]-4-hydroxy-N-{2-[methyl(methylsulfonyl)amino]ethyl}-1-[2-(methyloxy)ethyl]-2-oxo-1,2-dihydro-1,5-naphthyridine-3-carboxamide (8 mg, 62% yield) as a white solid after purification by reverse phase HPLC. 1H NMR (CDCl3) δ 10.36 (br s, 1 H), 8.53 (s, 1 H), 7.69 (s, 1 H), 7.16-7.13 (m, 2 H), 7.02-6.98 (m, 2 H), 4.33 (m, 2 H), 4.10 (s, 2 H), 3.68-3.61 (m, 4 H), 3.39 (m, 2 H), 3.18 (s, 3 H), 2.95 (s, 3 H), 2.82 (s, 3 H); MS m/z 507 M+1).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4](/[CH:16]=[C:17](\[CH3:30])/[CH2:18][N:19]2C(=O)C3C(=CC=CC=3)C2=O)[CH:5]=[C:6]([F:15])[C:7]=1[O:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1.O.NN>CO>[F:1][C:2]1[CH:3]=[C:4](/[CH:16]=[C:17](\[CH3:30])/[CH2:18][NH2:19])[CH:5]=[C:6]([F:15])[C:7]=1[O:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1
Reactant: C/C(=C\c1cc(F)c(Oc2ccccc2)c(F)c1)CN1C(=O)c2ccccc2C1=O
Agent: NN
Solvent: O
Solvent: CO
Product: C/C(=C\c1cc(F)c(Oc2ccccc2)c(F)c1)CN
Temperature: 50 °C
Reaction time: 8 h
Yield: 71.9 %

Procedure:
To a solution of (E)-2-(3-(3,5-difluoro-4-phenoxyphenyl)-2-methylallyl)isoindoline-1,3-dione (Intermediate 93.2, 100 mg, 0.25 mmol) in methanol (1 mL) was added hydrazine hydrate (25 mg, 0.5 mmol) and the reaction stirred at 50° C. overnight. The white solid was filtered with DCM, and the solvent removed from the filtrate. The residue was brought up in DCM and filtered. This was repeated until no further precipitate formed to give 49.5 mg of the title compound (71%) as a yellow oil, a 10 mg portion of which was diluted with 1N HCl and freeze dried to give 7.8 mg of the title compound as an HCl salt. 1H-NMR (400 MHz, d6-DMSO): δ 8.25 (s, 2H), 7.37 (t, 2H), 7.20 (d, 2H), 7.12 (t, 1H), 6.97 (s, 1H), 3.57 (s, 2H), 1.96 (s, 3H). MS (m/z): 258.96 (M-NH2).
Reaction SMILES: C(O[C:6](=[O:12])[O:7][C:8]([CH3:11])([CH3:10])[CH3:9])(C)(C)C.[NH:13]1[CH2:18][CH2:17][CH:16]([CH2:19][CH2:20][CH2:21][OH:22])[CH2:15][CH2:14]1.[OH-].[Na+]>O1CCOCC1>[C:8]([O:7][C:6]([N:13]1[CH2:18][CH2:17][CH:16]([CH2:19][CH2:20][CH2:21][OH:22])[CH2:15][CH2:14]1)=[O:12])([CH3:9])([CH3:10])[CH3:11]
Reactant: CC(C)(C)OC(=O)OC(C)(C)C
Reactant: OCCCC1CCNCC1
Agent: [Na+]
Agent: [OH-]
Solvent: C1COCCO1
Product: CC(C)(C)OC(=O)N1CCC(CCCO)CC1
Temperature: 0 °C

Procedure:
A solution of 6 g of di(tert-butyl)carbonate in 20 ml of dioxan was introduced into a solution of 3.2 g of 3-(4-piperidinyl)propanol in 50 ml of dioxan containing 25 ml of a 2N aqueous solution of sodium hydroxide, cooled at 0° C. The mixture was allowed to react for 16 hours at room temperature. The solution was then evaporated and the residue was extracted with ethylether. The organic layer was washed with a 10% solution of KHSO4 and then dried over MgSO4.
Reaction SMILES: [NH2:1][C:2]1[C:7]2[CH2:8][C:9]([CH3:12])([CH3:11])[O:10][C:6]=2[C:5]([C:13]([NH:15][CH2:16][C@@H:17]2[CH2:22][CH2:21][N:20](C(OC(C)(C)C)=O)[CH2:19][C@H:18]2[OH:30])=[O:14])=[CH:4][C:3]=1[Cl:31]>Cl.CC(O)C.CO>[NH2:1][C:2]1[C:7]2[CH2:8][C:9]([CH3:11])([CH3:12])[O:10][C:6]=2[C:5]([C:13]([NH:15][CH2:16][C@@H:17]2[CH2:22][CH2:21][NH:20][CH2:19][C@H:18]2[OH:30])=[O:14])=[CH:4][C:3]=1[Cl:31]
Reactant: CC(C)(C)OC(=O)N1CC[C@@H](CNC(=O)c2cc(Cl)c(N)c3c2OC(C)(C)C3)[C@H](O)C1
Agent: Cl
Solvent: CO
Solvent: CC(C)O
Product: CC1(C)Cc2c(N)c(Cl)cc(C(=O)NC[C@@H]3CCNC[C@H]3O)c2O1
Yield: 73 %

Procedure:
A mixture of intermediate (26) (0.011 mol) in a mixture of HCl in 2-propanol (12 ml) and methanol (100 ml) was stirred and refluxed for 30 minutes. The mixture was cooled and the solvent was evaporated. The residue was partitioned between water/NH3 and DCM. The organic layer was separated, dried, filtered and the solvent was evaporated, yielding 2.84 g (73%) of (−)-(trans)-4-amino-5-chloro-2,3-dihydro-N-[(3-hydroxy-4-piperidinyl)methyl]-2,2-dimethyl-7-benzofurancarboxamide (interm. 14). A sample (0.5 g) was crystallized from ACN with a drop of water, filtered off and dried, yielding 0.2 g of intermediate (14) [mp. 116° C.; [α]D20=−15.91° (c=25.14 mg/5 ml in CH3OH)].
Reaction SMILES: [CH:1]([N:4]1[CH2:9][CH2:8][CH2:7][CH2:6][CH2:5]1)=[CH:2][CH3:3].C(N(CC)CC)C.[CH2:17]([C@H:24]1[CH2:29][CH2:28][C@H:27]([C:30](=[O:34])[CH:31]=[CH:32]Cl)[CH2:26][CH2:25]1)[CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH3:23].O>C(OCC)C>[CH2:17]([C@H:24]1[CH2:29][CH2:28][C@H:27]([C:30](=[O:34])[CH:31]=[CH:32][C:2]([CH3:3])=[CH:1][N:4]2[CH2:9][CH2:8][CH2:7][CH2:6][CH2:5]2)[CH2:26][CH2:25]1)[CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH3:23]
Reactant: CC=CN1CCCCC1
Reactant: CCCCCCC[C@H]1CC[C@H](C(=O)C=CCl)CC1
Solvent: O
Solvent: CCN(CC)CC
Solvent: CCOCC
Product: CCCCCCC[C@H]1CC[C@H](C(=O)C=CC(C)=CN2CCCCC2)CC1

Procedure:
A mixture of 6 g of N-(1-propenyl)piperidine, 45 ml of of diethyl ether and 4.36 ml of triethylamine is treated dropwise while stirring and gassing with nitrogen at 0° C. within 1 hour with a solution of 8.5 g of trans-4-heptyl-1-(3-chloroacryloyl)cyclohexane in 20 ml of diethyl ether. The suspension is stirred at 0° C. for a further 1 hour and then treated with 120 ml of water and extracted three times with diethyl ether. The organic phases are washed twice with water, dried over sodium sulphate, filtered and concentrated, there being obtained N-[5-(trans-4-heptylcyclohexyl)-2-methyl-5-oxo-1,3-pentadienyl]piperidine.
Reaction SMILES: [C:1]([C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=1[S:11]([N:14]([CH2:16][C:17]#[N:18])[CH3:15])(=[O:13])=[O:12])(OC)=[O:2].C[O-].[Na+].CO>C1(C)C=CC=CC=1>[C:17]([C:16]1[N:14]([CH3:15])[S:11](=[O:13])(=[O:12])[C:6]2[CH:7]=[CH:8][CH:9]=[CH:10][C:5]=2[C:1]=1[OH:2])#[N:18]
Reactant: COC(=O)c1ccccc1S(=O)(=O)N(C)CC#N
Agent: C[O-]
Agent: [Na+]
Solvent: CO
Solvent: Cc1ccccc1
Product: CN1C(C#N)=C(O)c2ccccc2S1(=O)=O
Reaction time: 1 h
Yield: 75 %

Procedure:
To a solution of o-carbomethoxy-N-cyanomethyl-N-methylbenzenesulfonamide (108 g) in toluene (600 ml) was added 28% sodium methoxide-methanol solution (83 ml) with vigorous stirring. After 2 hours the solvent was evaporated to ca. 400 ml and water (800 ml) added to dissolve the viscous residue. The pH was adjusted to ca. 2 with 6N HCl. The resulting crystals were granulated for 1 hour, filtered off, washed with water and dried in vacuo to give the title product, 77.2 g (81.1%). Purified product was obtained in 75% yield by dissolving the compound (3.3 g) in isopropanol, followed by dropwise addition of water (35 ml).
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[C:4]([F:9])[C:3]=1[CH:10]([C:16]([O:18]CC)=O)[C:11]([O:13]CC)=O.C(N(CCCC)CCCC)CCC.[N:34]1[CH:39]=[CH:38][CH:37]=[CH:36][C:35]=1[C:40]([NH2:42])=[NH:41].[OH-].[Na+]>O.C(O)C>[OH:13][C:11]1[C:10]([C:3]2[C:4]([F:9])=[CH:5][C:6]([F:8])=[CH:7][C:2]=2[F:1])=[C:16]([OH:18])[N:42]=[C:40]([C:35]2[CH:36]=[CH:37][CH:38]=[CH:39][N:34]=2)[N:41]=1
Reactant: CCOC(=O)C(C(=O)OCC)c1c(F)cc(F)cc1F
Reactant: N=C(N)c1ccccn1
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Solvent: CCCCN(CCCC)CCCC
Product: Oc1nc(-c2ccccn2)nc(O)c1-c1c(F)cc(F)cc1F
Temperature: 65 °C
Reaction time: 0.5 h
Yield: 48.6 %

Procedure:
332 g (1.16 mol) of diethyl 2-(2,4,6-trifluorophenyl)malonate and 192 g (1.04 mol) of tributylamine were heated at 180° C. for eight hours together with 182 g (1.17 mol) of pyridine-2-carboxamidine. In the course of this, the ethanol produced was distilled off. The reaction mixture was then allowed to cool to 60-70° C. and was mixed with a solution of 116 g (2.89 mol) of sodium hydroxide in 1200 ml of water. After stirring for 30 min and cooling to approximately 20-25° C., the mixture was extracted with methyl tert-butyl ether (MTBE) and, after phase separation, the aqueous phase was acidified with 6N hydrochloric acid. After filtering off and drying, 180 g of the title compound were obtained.
Reaction SMILES: [C:1]1([S:7]([N:10]2[C:14]3=[N:15][CH:16]=[C:17]([N+:20]([O-:22])=[O:21])[C:18](Cl)=[C:13]3[CH:12]=[CH:11]2)(=[O:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[C:23]([O:27][C:28]([N:30]1[CH2:35][CH2:34][CH2:33][CH:32]([NH2:36])[CH2:31]1)=[O:29])([CH3:26])([CH3:25])[CH3:24].C(N(C(C)C)CC)(C)C>CC(O)C>[C:23]([O:27][C:28]([N:30]1[CH2:35][CH2:34][CH2:33][CH:32]([NH:36][C:18]2[C:17]([N+:20]([O-:22])=[O:21])=[CH:16][N:15]=[C:14]3[N:10]([S:7]([C:1]4[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=4)(=[O:9])=[O:8])[CH:11]=[CH:12][C:13]=23)[CH2:31]1)=[O:29])([CH3:26])([CH3:24])[CH3:25]
Reactant: O=[N+]([O-])c1cnc2c(ccn2S(=O)(=O)c2ccccc2)c1Cl
Reactant: CC(C)(C)OC(=O)N1CCCC(N)C1
Solvent: CCN(C(C)C)C(C)C
Solvent: CC(C)O
Product: CC(C)(C)OC(=O)N1CCCC(Nc2c([N+](=O)[O-])cnc3c2ccn3S(=O)(=O)c2ccccc2)C1
Temperature: 80 °C
Reaction time: 12 h
Yield: 86.5 %

Procedure:
A suspension of 1-benzenesulfonyl-4-chloro-5-nitro-1H-pyrrolo[2,3-b]pyridine (15.3 g, 45.4 mmol), 3-amino-piperidine-1-carboxylic acid tert-butyl ester (10.00 g, 49.9 mmol), and diisopropylethylamine (25 ml, 140 mmol) in propan-2-ol (200 ml) was heated at 80° C. for 20 h. The mixture was then cooled to 25° C. and stirred for 12 h. The resulting yellow solid was collected by vacuum filtration, washed with propan-2-ol (1×30 ml), and was air-dried to afford 3-(1-benzenesulfonyl-5-nitro-1H-pyrrolo[2,3-b]pyridin-4-ylamino)-piperidine-1-carboxylic acid tert-butyl ester (19.7 g, 87%). LCMS (Method G, ESI): RT=1.25 min, m+H=502.3. This material was used in the next step below without additional purification or characterization.
Reaction SMILES: [C:1]([O:4][C:5](=[O:7])[CH3:6])(=O)[CH3:2].CC1[CH:14]=[C:13]([N+:15]([O-:17])=[O:16])[CH:12]=[CH:11][N+:10]=1[O-]>C(O)C>[C:5]([O:4][CH2:1][C:2]1[CH:14]=[C:13]([N+:15]([O-:17])=[O:16])[CH:12]=[CH:11][N:10]=1)(=[O:7])[CH3:6]
Reactant: Cc1cc([N+](=O)[O-])cc[n+]1[O-]
Reactant: CC(=O)OC(C)=O
Solvent: CCO
Product: CC(=O)OCc1cc([N+](=O)[O-])ccn1
Temperature: 80 °C
Reaction time: 0.33 h

Procedure:
200 mL of acetic anhydride was heated to 100° C., followed by gradual addition of 2-methyl-4-nitropyridine N-oxide (25.0 g, 162 mmol). After the addition, the mixture was gradually heated, and was kept at 130° C. for 20 minutes. Then, the reaction mixture was cooled to 80° C., followed by dropwise addition of 200 mL of ethanol to stop the reaction.
Reaction SMILES: [F:1][C:2]1[CH:11]=[CH:10][C:5]([C:6]([O:8][CH3:9])=[O:7])=[C:4]([OH:12])[CH:3]=1.[CH2:13](Br)[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1.C(=O)([O-])[O-].[Cs+].[Cs+]>CN(C)C=O.CCOCC>[CH2:13]([O:12][C:4]1[CH:3]=[C:2]([F:1])[CH:11]=[CH:10][C:5]=1[C:6]([O:8][CH3:9])=[O:7])[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1
Reactant: COC(=O)c1ccc(F)cc1O
Reactant: BrCc1ccccc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Solvent: CCOCC
Product: COC(=O)c1ccc(F)cc1OCc1ccccc1

Procedure:
Methyl 4-fluoro-2-hydroxybenzoate (2.00 g), benzyl bromide (1.54 mL), and cesium carbonate (4.60 g) in N,N-dimethylformamide (50 mL) were stirred in for 24 hours. The reaction was taken up in ether and washed 3× with 1M NaOH solution and with brine, then concentrated to give the title compound.
Reaction SMILES: Br.[CH3:2][C:3]1[N:4]=[CH:5][NH:6][C:7]=1[CH3:8].[Cl:9][C:10]1[CH:17]=[CH:16][CH:15]=[CH:14][C:11]=1[CH2:12]Br.[OH-].[K+].CCOCC>CN(C=O)C.O>[Cl:9][C:10]1[CH:17]=[CH:16][CH:15]=[CH:14][C:11]=1[CH2:12][N:4]1[C:3]([CH3:2])=[C:7]([CH3:8])[N:6]=[CH:5]1
Reactant: Clc1ccccc1CBr
Reactant: Cc1nc[nH]c1C
Agent: Br
Agent: [K+]
Agent: [OH-]
Solvent: CN(C)C=O
Solvent: CCOCC
Solvent: O
Product: Cc1ncn(Cc2ccccc2Cl)c1C
Temperature: 25 °C
Reaction time: 8 h
Yield: 44.8 %

Procedure:
To a solution of 4.89 g (0.027 mol) of 4,5-dimethylimidazole hydrobromide and 5.7 g (0.028 mol) of 2-chlorobenzyl bromide in 20 ml of DMF is added 6 ml of 50% potassium hydroxide aqueous solution dropwise. Then the reaction mixture is stirred at RT under nitrogen overnight. The reaction mixture is poured into ether (100 ml)/ water (50 ml). The ether layer is separated, washed with water (10 ml×2), dried over anhydrous sodium sulfate and evaporated in vacuo. The raw material is subjected to chromatography on silica gel using dichloromethane-methanol (10:1) as eluent to give 2.67 g (44%) of 1-(2′-chlorobenzyl)-4,5-dimethylimidazole as a pale yellow oil. MS m/z (M++1) 221; 1H-NMR 400 MHz(δ, CDCl3): 2.00 (3H, s), 2.20 (3H, s), 5.07 (2H, s), 6.59 (1H, dd, J=9.2, 2 Hz), 7.17 (1H, td, J=8, 1.2 Hz), 7.23 (1H, td, J=8, 1.6 Hz), 7.38 (2H, dd, J=7.2, 1.6 Hz) ppm.
Reaction SMILES: [NH2:1][C:2]1[C:3](=[O:19])[NH:4][C:5](=[S:18])[N:6]([CH2:9][C:10]2[O:14][N:13]=[C:12]([CH:15]([CH3:17])[CH3:16])[CH:11]=2)[C:7]=1[NH2:8].[C:20](O)(=O)C.C(N)=N>>[CH:15]([C:12]1[CH:11]=[C:10]([CH2:9][N:6]2[C:7]3[N:8]=[CH:20][NH:1][C:2]=3[C:3](=[O:19])[NH:4][C:5]2=[S:18])[O:14][N:13]=1)([CH3:16])[CH3:17]
Reactant: CC(=O)O
Reactant: CC(C)c1cc(Cn2c(N)c(N)c(=O)[nH]c2=S)on1
Agent: N=CN
Product: CC(C)c1cc(Cn2c(=S)[nH]c(=O)c3[nH]cnc32)on1
Yield: 11 %

Procedure:
The title compound was prepared in accordance with the general method described in Example 12(d) by using 5,6-diamino-1-[(3-isopropylisoxazol-5-yl)methyl]-2-thioxo-2,3-dihydropyrimidin-4(1H)-one (0.070 g, 0.25 mmol, obtained from Example 15(c)) and formamidine acetate (0.040 g, 0.37 mmol) which yielded the title compound (8.0 mg, 11% yield).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[CH:8]=[C:7]([S:12]([CH2:15][C@@H:16]([OH:20])[C:17]([OH:19])=O)(=[O:14])=[O:13])[CH:6]=[CH:5]2.[NH:21]1[CH2:26][CH2:25][CH:24]([N:27]2[CH2:32][CH2:31][CH2:30][NH:29][C:28]2=[O:33])[CH2:23][CH2:22]1.C1C=CC2N(O)N=NC=2C=1.CCN=C=NCCCN(C)C>CN(C=O)C>[Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[CH:8]=[C:7]([S:12]([CH2:15][C@@H:16]([OH:20])[C:17]([N:21]1[CH2:26][CH2:25][CH:24]([N:27]3[CH2:32][CH2:31][CH2:30][NH:29][C:28]3=[O:33])[CH2:23][CH2:22]1)=[O:19])(=[O:13])=[O:14])[CH:6]=[CH:5]2
Reactant: O=C1NCCCN1C1CCNCC1
Reactant: O=C(O)[C@H](O)CS(=O)(=O)c1ccc2cc(Cl)ccc2c1
Agent: CCN=C=NCCCN(C)C
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Product: O=C([C@H](O)CS(=O)(=O)c1ccc2cc(Cl)ccc2c1)N1CCC(N2CCCNC2=O)CC1
Temperature: 25 °C
Reaction time: 15 h

Procedure:
(2S)-3-[(6-Chloronaphthalen-2-yl)sulfony]-2-hydroxypropionic acid, 1-(piperidin-4-yl)tetrahydropyrimidin-2(1H)-one, and HOBt (23.0 g) were dissolved in DMF, WSC was added thereto, and the mixture was stirred at room temperature for 15 hours. The reaction mixture was concentrated under reduced pressure, diluted with an aqueous sodium bicarbonate solution, and extracted with dichloromethane. The extract was washed with an aqueous 5% citric acid solution and saturated saline solution, and dried over sodium sulfate, and the solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate to ethyl acetate/methanol=10/1) to obtain the title compound as a colorless powder.
Reaction SMILES: CC(C)([O-])C.[K+].[Cl:7][C:8]1[CH:13]=[CH:12][C:11]([CH2:14][C:15](=[N:20]O)[C:16]([F:19])([F:18])[F:17])=[CH:10][CH:9]=1.Cl[CH:23]=[CH:24][C:25]#[N:26]>O1CCCC1.C(Cl)Cl>[Cl:7][C:8]1[CH:13]=[CH:12][C:11]([C:14]2[C:24]([C:25]#[N:26])=[CH:23][NH:20][C:15]=2[C:16]([F:19])([F:18])[F:17])=[CH:10][CH:9]=1
Reactant: N#CC=CCl
Reactant: ON=C(Cc1ccc(Cl)cc1)C(F)(F)F
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: C1CCOC1
Solvent: ClCCl
Product: N#Cc1c[nH]c(C(F)(F)F)c1-c1ccc(Cl)cc1
Temperature: 0 °C
Reaction time: 0.25 h

Procedure:
Potassium-t-butoxide (2.46 g, 0.022 mol) is added in portions to a solution of 3-(p-chlorophenyl)-1,1,1-trifluoro-2-propanone oxime, (E)-, or (Z)-(4.75 g, 0.02 mol) in tetrahydrofuran (20 mL) at such a rate that the temperature if maintained at 25°-30° C. (ice-water bath). The resulting solution is stirred for 15 minutes and then added dropwise to a solution of β-chloroacrylonitrile (1.75 g, 0.02 mol) in tetrahydrofuran (15 mL) at 15°-10° C. over 1/2 hour. The ice bath is removed and the reaction mixture is stirred for 1 hour, diluted with water, made acidic with a small amount of dilute HCl and extracted with ether. The combined ether extracts are washed with water and brine and dried (Na2SO4). Concentration in vacuo gives an oil which is dissolved in methylene chloride and filtered through a bed of flash column silica gel (30 mL size) and washed with an ethyl acetate/methylene chloride mixture (1:1). The filtrate is evaporated and the residual semi-solid is crystallized from methylene chloride/hexanes to give the title product as a yellow solid (2.10 g): mp 162.5°-164.0° C. IR (Nujol) 3200, 2250 cm-1, 1H NMR (DMSO-d6) δ7.42, 7.56 (AB, JAB =8.3 Hz, ArH), 8.03 (s, 1H, 2H); 19F NMR δ-51.2; 13C NMR δ94.2 (C-3), 115.0 (CN), 116.6 (q, 2JCF =38.3 Hz, C-5), 120.6 (q, 1JCF =268.7 Hz, CF3), 127.0 (q, 3JCF =3.5 Hz, C-4), 128.6 (C-2') 129.1 (C-1'), 129.7 (C-2), 130.8 (C-3'), 133.4 (C-4').
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:9]=[CH:10][C:11]3[O:17][CH2:16][CH2:15][C:14]([C:18](O)=[O:19])=[CH:13][C:12]=3[CH:21]=2)=[CH:4][CH:3]=1.ON1C2C=CC=CC=2N=N1.Cl.C(N=C=NCCCN(C)C)C.[NH2:44][C@H:45]1[CH2:50][CH2:49][C@H:48]([CH2:51][N:52]([CH:54]2[CH2:59][CH2:58][N:57]([C:60]([O:62][C:63]([CH3:66])([CH3:65])[CH3:64])=[O:61])[CH2:56][CH2:55]2)[CH3:53])[CH2:47][CH2:46]1>C(#N)C.C(N(CC)CC)C>[C:63]([O:62][C:60]([N:57]1[CH2:58][CH2:59][CH:54]([N:52]([CH2:51][C@H:48]2[CH2:49][CH2:50][C@H:45]([NH:44][C:18]([C:14]3[CH2:15][CH2:16][O:17][C:11]4[CH:10]=[CH:9][C:8]([C:5]5[CH:4]=[CH:3][C:2]([CH3:1])=[CH:7][CH:6]=5)=[CH:21][C:12]=4[CH:13]=3)=[O:19])[CH2:46][CH2:47]2)[CH3:53])[CH2:55][CH2:56]1)=[O:61])([CH3:66])([CH3:65])[CH3:64]
Reactant: CN(C[C@H]1CC[C@H](N)CC1)C1CCN(C(=O)OC(C)(C)C)CC1
Reactant: Cc1ccc(-c2ccc3c(c2)C=C(C(=O)O)CCO3)cc1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CCN(CC)CC
Solvent: CC#N
Product: Cc1ccc(-c2ccc3c(c2)C=C(C(=O)N[C@H]2CC[C@H](CN(C)C4CCN(C(=O)OC(C)(C)C)CC4)CC2)CCO3)cc1
Reaction time: 2 h

Procedure:
Into a suspension of 7-(4-methylphenyl)-2,3-dihydro-1-benzooxepine-4-carboxylic acid (400 mg) and 1-hydroxybenzotriazole (289 mg) in acetonitrile (20 ml) was added at room temperature 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (0.41 g), and the resulting mixture was stirred for 2 hours. Into the reaction mixture was added a solution of tert-butyl trans-4-[N-(4-aminocyclohexylmethyl)-N-methylamino]piperidine-1-carboxylate (698 mg) and triethylamine (0.4 ml) in acetonitrile (30 ml), and the resulting mixture was stirred for 20 hours. After the reaction mixture was concentrated under reduced pressure, water was added to the residue, and the resulting mixture was extracted with ethyl acetate. The organic layer was washed with an aqueous saturated solution of sodium chloride and was dried with magnesium sulfate. After the resulting organic layer was concentrated under reduced pressure to remove the solvent, the residue was subjected to purification using column chromatography (ethanol/ethyl acetate 1:3→1:2) and to recrystallization (ethyl acetate/hexane) to obtain trans-N-[4-[N-(1-tert-butoxycarbonylpiperidin-4-yl)-N-methylaminomethyl]cyclohexyl]-7-(4-methylphenyl)-2,3-dihydro-1-benzooxepine-4-carboxamide (compound 65) (560 mg) as colorless crystals.
Reaction SMILES: C(O[C:4](=[O:16])[CH2:5][NH:6][C:7](=[O:15])[CH2:8][N:9]1[CH2:13][CH2:12][CH2:11][C:10]1=[O:14])C.[NH3:17]>CO>[O:14]=[C:10]1[CH2:11][CH2:12][CH2:13][N:9]1[CH2:8][C:7]([NH:6][CH2:5][C:4]([NH2:17])=[O:16])=[O:15]
Reactant: N
Reactant: CCOC(=O)CNC(=O)CN1CCCC1=O
Solvent: CO
Product: NC(=O)CNC(=O)CN1CCCC1=O
Temperature: 25 °C
Yield: 100 %

Procedure:
17.1 g (0.075 mole) of N-(2-oxo-1-pyrrolidineacetyl)-glycine ethyl ester are dissolved in 350 ml of methanol. The solution is saturated with a current of ammonia (about 2 hours), stirring is maintained for 3 hours at ambient temperature. After the reaction mixture has been evaporated to dryness in vacuo, the residue crystallizes quickly, 14.9 g of 2-(2-oxo-1pyrrolidineacetamido)-acetamide being obtained (yield: 100% of theory); M.P. 147°-148° C.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[N:4][C:5]2[N:6]([N:8]=[C:9]([C:11]([OH:13])=O)[CH:10]=2)[CH:7]=1.[Br:14][C:15]1[CH:24]=[C:23]2[C:18]([CH2:19][CH2:20][NH:21][CH:22]2[CH3:25])=[CH:17][CH:16]=1>>[Br:14][C:15]1[CH:24]=[C:23]2[C:18]([CH2:19][CH2:20][N:21]([C:11]([C:9]3[CH:10]=[C:5]4[N:4]=[CH:3][C:2]([Br:1])=[CH:7][N:6]4[N:8]=3)=[O:13])[CH:22]2[CH3:25])=[CH:17][CH:16]=1
Reactant: CC1NCCc2ccc(Br)cc21
Reactant: O=C(O)c1cc2ncc(Br)cn2n1
Product: CC1c2cc(Br)ccc2CCN1C(=O)c1cc2ncc(Br)cn2n1

Procedure:
In close analogy to the procedure described in Example 1, 6-bromo-pyrazolo[1,5-a]pyrimidine-2-carboxylic acid is reacted with 7-Bromo-1-methyl-1,2,3,4-tetrahydro-isoquinoline to provide the title compound in moderate yield.
Reaction SMILES: Br[C:2]1[CH:3]=[N:4][C:5](=[O:35])[N:6]([CH:8]2[CH2:13][CH2:12][CH:11]([N:14]3[CH2:17][CH:16]([NH:18][C:19]([CH2:21][NH:22][C:23](=[O:34])[C:24]4[CH:29]=[CH:28][CH:27]=[C:26]([C:30]([F:33])([F:32])[F:31])[CH:25]=4)=[O:20])[CH2:15]3)[CH2:10][CH2:9]2)[CH:7]=1>CO.[Pd]>[O:35]=[C:5]1[N:4]=[CH:3][CH:2]=[CH:7][N:6]1[CH:8]1[CH2:13][CH2:12][CH:11]([N:14]2[CH2:15][CH:16]([NH:18][C:19]([CH2:21][NH:22][C:23](=[O:34])[C:24]3[CH:29]=[CH:28][CH:27]=[C:26]([C:30]([F:32])([F:33])[F:31])[CH:25]=3)=[O:20])[CH2:17]2)[CH2:10][CH2:9]1
Reactant: O=C(CNC(=O)c1cccc(C(F)(F)F)c1)NC1CN(C2CCC(n3cc(Br)cnc3=O)CC2)C1
Agent: [Pd]
Solvent: CO
Product: O=C(CNC(=O)c1cccc(C(F)(F)F)c1)NC1CN(C2CCC(n3cccnc3=O)CC2)C1

Procedure:
N-({1-[4-(5-Bromo-2-oxo-2H-pyrimidin-1-yl)-cyclohexyl]-azetidin-3-ylcarbamoyl}-methyl)-3-trifluoromethyl-benzamide (as prepared in Example 3, Step C, ˜150 mg, 0.27 mmol) in MeOH (20 mL) was driven through H-Cube® Continuous-flow Hydrogenation reactor (ThalesNano, Budapest, Hungary) under full hydrogen mode at room temperature using 10% Pd/C cartridge. The resulting solution was concentrated and purified by silica gel column on a CombiFlash® system using ethyl acetate and 7N NH3 in MeOH as eluent (from pure ethyl acetate to 5% 7N NH3 in MeOH in ethyl acetate) to afford the title compound as white solid.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[O:14]C2N=NC=CC=2C=1O)=[O:5])[CH3:2].C(O[C:19](=[O:30])[C:20]1[C:25]([O:26][CH3:27])=[CH:24][C:23]([CH3:28])=[N:22][C:21]=1Cl)C>>[CH2:1]([O:3][C:4]([C:6]1[O:14][C:21]2=[N:22][C:23]([CH3:28])=[CH:24][C:25]([O:26][CH3:27])=[C:20]2[C:19]=1[OH:30])=[O:5])[CH3:2]
Reactant: CCOC(=O)c1oc2nnccc2c1O
Reactant: CCOC(=O)c1c(OC)cc(C)nc1Cl
Product: CCOC(=O)c1oc2nc(C)cc(OC)c2c1O

Procedure:
This compound was prepared using a method analogous to that of 5-hydroxyfuro[2,3-c]pyridazine-6-carboxylic acid ethyl ester (A.2.3.1), 2-chloro-4-methoxy-6-methylnicotinic acid ethyl ester replacing 3-chloropyridazine-4-carboxylic acid ethyl ester;
Reaction SMILES: [CH3:1][O:2][C:3]1[C:10]([O:11][CH3:12])=[CH:9][CH:8]=[CH:7][C:4]=1[CH2:5][NH2:6].[N:13]1[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=1[CH2:19][CH2:20][NH2:21]>>[CH3:1][O:2][C:3]1[C:10]([O:11][CH3:12])=[CH:9][CH:8]=[CH:7][C:4]=1[CH2:5][NH:6][C:10](=[O:11])[C:3]([NH:21][CH2:20][CH2:19][C:14]1[CH:15]=[CH:16][CH:17]=[CH:18][N:13]=1)=[O:2]
Reactant: COc1cccc(CN)c1OC
Reactant: NCCc1ccccn1
Product: COc1cccc(CNC(=O)C(=O)NCCc2ccccn2)c1OC

Procedure:
Prepared in a similar manner to example 125 using 2,3-dimethoxybenzylamine, ethyl oxalyl chloride, and 2-(pyridin-2-yl)ethylamine; m/e=343 [M+1].