Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][O:14][CH:15]1[CH2:20][CH2:19][CH2:18][CH2:17][O:16]1.[CH:21]1([Mg]Br)[CH2:26][CH2:25][CH2:24][CH2:23][CH2:22]1>>[CH:21]1([CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][O:14][CH:15]2[CH2:20][CH2:19][CH2:18][CH2:17][O:16]2)[CH2:26][CH2:25][CH2:24][CH2:23][CH2:22]1
Reactant: Br[Mg]C1CCCCC1
Reactant: BrCCCCCCCCCCCCOC1CCCCO1
Product: C(CCCCCCC1CCCCC1)CCCCCOC1CCCCO1

Procedure:
57.8 g (165 millimole) of 2-[(12-bromododecyl}oxy]tetrahydro-2H-pyran and 39.6 g (247 millimole) of cyclohexyl magnesium bromide were reacted by following a procedure similar to that of Working Example 16, to give crude 2-[(12-cyclohexyldodecyl)oxy]tetrahydro-2H-pyran. This crude product was dissolved in 450 ml of methanol, to which 4.5 g of Amberlist® H-15 was added, and the resulting mixture was stirred at 45° C. for 2 hours. The resin was filtrated off, and the filtrate was concentrated to dryness under reduced pressure. The residue wa subjected to column chromatography on silica gel (1 kg), and eluted with hexane-ethyl acetate (6:1), to give the above-captioned compound as colorless solid.
Reaction SMILES: C([N:4]1[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[C:6](=[C:13](OCC)[C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[C:5]1=[O:23])(=O)C.[N:24]1([CH2:30][C:31]([N:33]([C:35]2[CH:41]=[CH:40][C:38]([NH2:39])=[CH:37][CH:36]=2)[CH3:34])=[O:32])[CH2:29][CH2:28][CH2:27][CH2:26][CH2:25]1.[OH-].[Na+]>CN(C=O)C.CO>[N:24]1([CH2:30][C:31]([N:33]([C:35]2[CH:36]=[CH:37][C:38]([NH:39]/[C:13](=[C:6]3\[C:5](=[O:23])[NH:4][C:12]4[C:7]\3=[CH:8][CH:9]=[CH:10][CH:11]=4)/[C:14]3[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=3)=[CH:40][CH:41]=2)[CH3:34])=[O:32])[CH2:29][CH2:28][CH2:27][CH2:26][CH2:25]1
Reactant: CN(C(=O)CN1CCCCC1)c1ccc(N)cc1
Reactant: CCOC(=C1C(=O)N(C(C)=O)c2ccccc21)c1ccccc1
Agent: [Na+]
Agent: [OH-]
Solvent: CN(C)C=O
Solvent: CO
Product: CN(C(=O)CN1CCCCC1)c1ccc(N/C(=C2\C(=O)Nc3ccccc32)c2ccccc2)cc1

Procedure:
Prepared analogously to Example 43 from 1-acetyl-3-(1-ethoxy-1-phenyl-methylidene)-2-indolinone and 4-(N-piperidinomethylcarbonyl-N-methyl-amino)-aniline in DMF and subsequent treatment with sodium hydroxide solution in methanol.
Reaction SMILES: [CH3:1][O:2][CH2:3][CH2:4][O:5][C:6]1[CH:7]=[C:8]([O:12][CH2:13][C@@H:14]2[CH2:18][CH2:17][CH2:16][NH:15]2)[CH:9]=[N:10][CH:11]=1.C=O.[C:21]([O-])(O)=O.[Na+]>C(O)=O>[CH3:1][O:2][CH2:3][CH2:4][O:5][C:6]1[CH:7]=[C:8]([O:12][CH2:13][C@@H:14]2[CH2:18][CH2:17][CH2:16][N:15]2[CH3:21])[CH:9]=[N:10][CH:11]=1
Reactant: O=C([O-])O
Reactant: COCCOc1cncc(OC[C@@H]2CCCN2)c1
Agent: C=O
Agent: [Na+]
Solvent: O=CO
Product: COCCOc1cncc(OC[C@@H]2CCCN2C)c1
Temperature: 50 °C
Yield: 85 %

Procedure:
To 5-methoxyethoxy-3-(2-(S)-pyrrolidinylmethoxy)pyridine from Example 197f (450 mg, 1.78 mmol) was added formaldehyde (37%, 8 mL) and formic acid (88%, 4 mL), and the mixture was heated at 50° C. for 4 h and then allowed cool to room temperature. The mixture was basified with saturated NaHCO3 and then extracted with Et2O. The organic layer was dried over Na2SO4 and concentrated. The residue was chromatographed (silica gel; hexane/EtOAc, 2:1) to afford the title compound (402 mg, 85%): 1H NMR (CDCl3, 300 MHz) δ 2.00-2.08 (m, 4H), 2.45 (m, 1H), 3.05 (s, 3H), 3.45 (s, 3H), 3.65 (t, 2H, J=6.0 Hz), 3.85 (t, 2H, J=6.0 Hz), 4.15 (m, 1H), 4.30-4.35 (m, 2H), 4.52 (m, 1H), 7.25 (t, 1H, J=3.0 Hz), 8.02 (br s, 2H); MS (CI/NH3) m/z 267 (M+H)+.
Reaction SMILES: [CH:1]1([N:7]2[CH2:15][C:14]3[C:9](=[CH:10][C:11]([N:16]4[CH2:21][CH2:20][NH:19][CH2:18][CH2:17]4)=[CH:12][CH:13]=3)[C:8]2=[O:22])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[CH:23]([O:36][C:37](N=[N+]=[N-])=[O:38])([C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1)[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1>>[CH:23]([O:36][C:37]([N:19]1[CH2:18][CH2:17][N:16]([C:11]2[CH:10]=[C:9]3[C:14]([CH2:15][N:7]([CH:1]4[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]4)[C:8]3=[O:22])=[CH:13][CH:12]=2)[CH2:21][CH2:20]1)=[O:38])([C:30]1[CH:31]=[CH:32][CH:33]=[CH:34][CH:35]=1)[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1
Reactant: O=C1c2cc(N3CCNCC3)ccc2CN1C1CCCCC1
Reactant: [N-]=[N+]=NC(=O)OC(c1ccccc1)c1ccccc1
Product: O=C(OC(c1ccccc1)c1ccccc1)N1CCN(c2ccc3c(c2)C(=O)N(C2CCCCC2)C3)CC1

Procedure:
In the same manner as in Example 28, the title compound was prepared from the compound obtained in step (e) of Example 1 and benzhydryloxycarbonyl azide.
Reaction SMILES: [CH2:1]([C:3]1[C:12]([C:13]([O:15]C)=[O:14])=[C:11]([C:17]2[CH:22]=[CH:21][C:20]([O:23][CH3:24])=[C:19]([O:25][CH3:26])[CH:18]=2)[C:10]2[C:5](=[CH:6][C:7]([O:29][CH3:30])=[C:8]([O:27][CH3:28])[CH:9]=2)[N:4]=1)[CH3:2].[OH-].[Na+].CO>O>[CH3:28][O:27][C:8]1[CH:9]=[C:10]2[C:5](=[CH:6][C:7]=1[O:29][CH3:30])[N:4]=[C:3]([CH2:1][CH3:2])[C:12]([C:13]([OH:15])=[O:14])=[C:11]2[C:17]1[CH:22]=[CH:21][C:20]([O:23][CH3:24])=[C:19]([O:25][CH3:26])[CH:18]=1
Reactant: CCc1nc2cc(OC)c(OC)cc2c(-c2ccc(OC)c(OC)c2)c1C(=O)OC
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: CCc1nc2cc(OC)c(OC)cc2c(-c2ccc(OC)c(OC)c2)c1C(=O)O
Reaction time: 14 h
Yield: 71 %

Procedure:
A mixture of methyl 2-ethyl-6,7-dimethoxy-4-(3,4-dimethoxyphenyl)quinoline-3-carboxylate (0.5 g), 4N sodium hydroxide (20 ml) and methanol was stirred for 14 hours under reflux, poured into water, made acidic and extracted with chloroform. The chloroform layer was washed with water and dried over magnesium sulfate. Evaporation of the solvent gave 6,7-dimethoxy-4-(3,4-dimethoxyphenyl)-2-ethylquinoline-3-carboxylic acid (0.343 g, 71%) which was then recrystallized from acetone-methanol. mp. 264°-267° C.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[CH2:15][CH:14]([C:16]([OH:18])=O)[N:6]3[C:7](=[O:13])[C:8](=[O:12])[NH:9][C:10]([CH:11]=1)=[C:5]23.[CH2:19]([NH2:26])[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1.C(N=C=NCCCN(C)C)C.ON1C2C=CC=CC=2N=N1.Cl>CN(C=O)C>[Br:1][C:2]1[CH:3]=[C:4]2[CH2:15][CH:14]([C:16](=[O:18])[NH:26][CH2:19][C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)[N:6]3[C:7](=[O:13])[C:8](=[O:12])[NH:9][C:10]([CH:11]=1)=[C:5]23
Reactant: NCc1ccccc1
Reactant: O=C(O)C1Cc2cc(Br)cc3[nH]c(=O)c(=O)n1c23
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Product: O=C(NCc1ccccc1)C1Cc2cc(Br)cc3[nH]c(=O)c(=O)n1c23
Temperature: 25 °C
Reaction time: 8 h
Yield: 99.9 %

Procedure:
To a solution of 8-bromo-5-carboxy-5,6-dihydro-1H-pyrrolo[1,2,3-de]quinoxaline-2,3-dione (300 mg, 0.96 mmol) and benzylamine (114 mg, 1.06 mmol) in DMF (3 mL) was added 1-ethyl-3-(3'-dimethylaminopropyl)carbodiimide (164 mg, 1.06 mmol) and N-hydroxybenztriazole (162 mg, 1.06 mmol) at 0° C. The mixture was stirred at room temperature overnight and aqueous 0.1N HCl was added. The precipitates formed were collected by filtration, washed with distilled water, and dried in vacuo to give 384 mg of the title compound (99%): mp 152.5°~153° C.; 1H NMR (270 MHz, DMSO-d6) δ12.01 (s, 1 H), 11.52 (t, 1H, J=5.6 Hz), 7.34 (m, 5H), 7.21 (d, 1H, J=1 Hz), 7.07 (d, 1H, J=1 Hz), 5.17 (dd, 1H, J=17, 10 Hz), 4.32 (d, 2H, J=5.6 Hz), 3.74 (dd, 1H, J=17, 10 Hz), 3.20 (dd, 1H, J=17, 5 Hz).
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[C@:9]1([C@@H:12](O)[CH3:13])[CH2:11][O:10]1.[F:15][C:16]([F:35])([C:31]([F:34])([F:33])[F:32])[CH2:17][O:18][C:19]1[CH:24]=[CH:23][C:22]([N:25]2[C:29](=[O:30])[NH:28][N:27]=[N:26]2)=[CH:21][CH:20]=1>>[F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[C@:9]1([O:10][CH2:11]1)[C@H:12]([N:28]1[C:29](=[O:30])[N:25]([C:22]2[CH:21]=[CH:20][C:19]([O:18][CH2:17][C:16]([F:15])([F:35])[C:31]([F:33])([F:34])[F:32])=[CH:24][CH:23]=2)[N:26]=[N:27]1)[CH3:13]
Reactant: C[C@H](O)[C@@]1(c2ccc(F)cc2F)CO1
Reactant: O=c1[nH]nnn1-c1ccc(OCC(F)(F)C(F)(F)F)cc1
Product: C[C@@H](n1nnn(-c2ccc(OCC(F)(F)C(F)(F)F)cc2)c1=O)[C@@]1(c2ccc(F)cc2F)CO1
Yield: 69.4 %

Procedure:
In the same manner as in Reference Example 5, starting from 0.962 g of (1S)-1-[(2R)-(2,4-difluorophenyl)-2-oxiranyl]ethanol and 1.19 g of 1-[4-(2,2,3,3,3-pentafluoropropoxy)phenyl]-5(1H,4H)-tetrazolone, 1.31 g of 1-[(1R,2S)-2-(2,4-difluorophenyl)-2,3-epoxy-1-methylpropyl]-4-[4-(2,2,3,3,3-pentafluoropropoxy)phenyl]-5(1H,4H)-tetrazolone was obtained as a colorless oil.
Reaction SMILES: [CH:1]1([NH:4][C:5]([NH:7][C:8]2[CH:13]=[CH:12][C:11]([O:14][C:15]3[CH:20]=[CH:19][N:18]=[C:17]4[CH:21]=[C:22]([C:24]5[CH:29]=[CH:28][C:27]([CH:30]=O)=[CH:26][N:25]=5)[S:23][C:16]=34)=[C:10]([F:32])[CH:9]=2)=[O:6])[CH2:3][CH2:2]1.[NH2:33][CH:34]1[CH2:37][N:36]([C:38]([O:40][C:41]([CH3:44])([CH3:43])[CH3:42])=[O:39])[CH2:35]1.C(O)(=O)C.[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+].C([O-])(O)=O.[Na+]>CN1C(=O)CCC1>[CH:1]1([NH:4][C:5](=[O:6])[NH:7][C:8]2[CH:13]=[CH:12][C:11]([O:14][C:15]3[CH:20]=[CH:19][N:18]=[C:17]4[CH:21]=[C:22]([C:24]5[N:25]=[CH:26][C:27]([CH2:30][NH:33][CH:34]6[CH2:35][N:36]([C:38]([O:40][C:41]([CH3:44])([CH3:43])[CH3:42])=[O:39])[CH2:37]6)=[CH:28][CH:29]=5)[S:23][C:16]=34)=[C:10]([F:32])[CH:9]=2)[CH2:3][CH2:2]1
Reactant: CC(C)(C)OC(=O)N1CC(N)C1
Reactant: O=Cc1ccc(-c2cc3nccc(Oc4ccc(NC(=O)NC5CC5)cc4F)c3s2)nc1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CN1CCCC1=O
Product: CC(C)(C)OC(=O)N1CC(NCc2ccc(-c3cc4nccc(Oc5ccc(NC(=O)NC6CC6)cc5F)c4s3)nc2)C1

Procedure:
To a suspension of the aldehyde 47 (1.0 g, 2.25 mmol, scheme 15) in NMP (12 mL) were added 3-amino-1-N-Boc-azetidine (0.600 g, 3.38 mmol) and acetic acid (0.19 mL, 3.38 mmol) at RT and stirred for 30 mill. Then NaBH(OAc)3 (1.2 g, 5.63 mmol) was added and stirred for 3 days. The reaction mixture was poured into saturated aqueous solution of NaHCO3 to form a precipitate that was collected by filtration, rinsed with water and purified via Biotage [linear gradient 2-20%, (methanol/dichloromethane; SiliaFlash 25 g cartridge]. Title compound 430 was obtained as a beige solid (960 mg, 71% yield). 1H NMR (400 MHz, DMSO-d6) δ (ppm): 8.71 (s, 1H), 8.56 (d, J=1.2 Hz, 1H), 8.51 (d, J=5.2 Hz, 1H), 8.32 (s, 1H), 8.23 (d, J=8.0 Hz, 1H), 7.89 (dd, J=8.0, 2.0 Hz, 1H), 7.73 (dd, J=13.6, 2.4 Hz, 1H), 7.38 (t, J=9.0 Hz, 1H), 7.23-7.18 (m, 1H), 6.64 (dd, J=5.2, 1.2 Hz, 1H), 6.56 (bd, J=2.4 Hz, 1H), 3.98-3.83 (m, 2H), 3.69 (s, 2H), 3.62-3.47 (m, 3H), 2.58-2.51 (m, 1H), 1.36 (s, 9H), 0.68-0.62 (m, 2H), 0.45-0.40 (m, 2H), one NH is missing. MS (m/z): 605.46 (M+H).
Reaction SMILES: [F:1][C:2]([F:36])([F:35])[C:3]1[CH:4]=[C:5]([CH:32]=[CH:33][CH:34]=1)[CH2:6][O:7][C:8]1[CH:31]=[CH:30][C:11]([NH:12][C:13]2[C:22]3[C:17](=[CH:18][CH:19]=[C:20]([C:23]4[O:27][C:26]([CH:28]=O)=[CH:25][CH:24]=4)[CH:21]=3)[N:16]=[CH:15][N:14]=2)=[CH:10][CH:9]=1.[CH3:37][S:38]([CH2:41][CH2:42][NH2:43])(=[O:40])=[O:39]>>[CH3:37][S:38]([CH2:41][CH2:42][NH:43][CH2:28][C:26]1[O:27][C:23]([C:20]2[CH:21]=[C:22]3[C:17](=[CH:18][CH:19]=2)[N:16]=[CH:15][N:14]=[C:13]3[NH:12][C:11]2[CH:10]=[CH:9][C:8]([O:7][CH2:6][C:5]3[CH:32]=[CH:33][CH:34]=[C:3]([C:2]([F:36])([F:1])[F:35])[CH:4]=3)=[CH:31][CH:30]=2)=[CH:24][CH:25]=1)(=[O:40])=[O:39]
Reactant: O=Cc1ccc(-c2ccc3ncnc(Nc4ccc(OCc5cccc(C(F)(F)F)c5)cc4)c3c2)o1
Reactant: CS(=O)(=O)CCN
Product: CS(=O)(=O)CCNCc1ccc(-c2ccc3ncnc(Nc4ccc(OCc5cccc(C(F)(F)F)c5)cc4)c3c2)o1

Procedure:
Prepared according to Procedure D from 5-(4-{4-(3-trifluoromethylbenzyloxy)anilino}-6-quinazolinyl)-furan-2-carbaldehyde (0.6 equiv) and 2-methanesulphonyl-ethylamine (1 equiv). 1H NMR 300 MHz (DMSO-d6) 11.63 (bs, 1H); 9.88 (bs, 1H); 9.59 (bs, 1H); 8.88 (s, 1H); 8.43 (d, 1H); 7.97 (d, 1H); 7.90-7.67 (m, δH); 7.34 (d, 1H); 7.19 (d, 2H); 6.89 (d, 1H); 5.30 (s, 2H); 4.45 (s, 2H); 3. 78 (m, 2H); 3.45 (m, 2H, obscured by water peak); 3.19 (s, 3H); MS m/z 597 (M+1).
Reaction SMILES: [O:1]=[C:2]1[C:6]2[CH:7]=[CH:8][CH:9]=[C:10]([CH2:11][N:12]3[CH2:17][CH2:16][N:15]([C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])[CH2:14][CH2:13]3)[C:5]=2[O:4][CH2:3]1.[NH:25]1[C:33]2[C:28](=[CH:29][CH:30]=[CH:31][N:32]=2)[C:27]([CH:34]=O)=[CH:26]1>CO.N1CCCCC1>[NH:25]1[C:33]2=[N:32][CH:31]=[CH:30][CH:29]=[C:28]2[C:27](/[CH:34]=[C:3]2\[O:4][C:5]3[C:10]([CH2:11][N:12]4[CH2:13][CH2:14][N:15]([C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])[CH2:16][CH2:17]4)=[CH:9][CH:8]=[CH:7][C:6]=3[C:2]\2=[O:1])=[CH:26]1
Reactant: O=Cc1c[nH]c2ncccc12
Reactant: CC(C)(C)OC(=O)N1CCN(Cc2cccc3c2OCC3=O)CC1
Solvent: CO
Solvent: C1CCNCC1
Product: CC(C)(C)OC(=O)N1CCN(Cc2cccc3c2O/C(=C\c2c[nH]c4ncccc24)C3=O)CC1
Temperature: 50 °C
Reaction time: 2 h
Yield: 77.4 %

Procedure:
A solution of tert-butyl 4-[(3-oxo-2,3-dihydrobenzofuran-7-yl)methyl]piperazine-1-carboxylate (0.0251 g, 0.0755 mmol) obtained in Example A56, Step 3 in methanol (2 mL) was added with 7-azaindole-3-carboxaldehyde (0.0116 g, 0.0793 mmol) and piperidine (5 drops), and the mixture was stirred at 50° C. for 2 hours. The reaction mixture was concentrated, and the resulting residue was purified by silica gel column chromatography (chloroform/methanol) to obtain tert-butyl (Z)-4-({2-[(1H-pyrrolo[2,3-b]pyridin-3-yl)methylene]-3-oxo-2,3-dihydrobenzofuran-7-yl}methyl)piperazine-1-carboxylate (0.0269 g, 77%).
Reaction SMILES: [CH:1]1([N:4]2[C:13]3[C:8](=[C:9]([F:17])[C:10]([F:16])=[C:11](F)[C:12]=3[F:14])[C:7](=[O:18])[C:6]([C:19]([OH:21])=[O:20])=[CH:5]2)[CH2:3][CH2:2]1.[N:22]1[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=1[NH:28][CH2:29][CH2:30][NH2:31].C(N(CC)CC)C>CCO>[CH:1]1([N:4]2[C:13]3[C:8](=[C:9]([F:17])[C:10]([F:16])=[C:11]([NH:31][CH2:30][CH2:29][NH:28][C:23]4[CH:24]=[CH:25][CH:26]=[CH:27][N:22]=4)[C:12]=3[F:14])[C:7](=[O:18])[C:6]([C:19]([OH:21])=[O:20])=[CH:5]2)[CH2:3][CH2:2]1
Reactant: NCCNc1ccccn1
Reactant: O=C(O)c1cn(C2CC2)c2c(F)c(F)c(F)c(F)c2c1=O
Solvent: CCO
Solvent: CCN(CC)CC
Product: O=C(O)c1cn(C2CC2)c2c(F)c(NCCNc3ccccn3)c(F)c(F)c2c1=O
Temperature: 25 °C
Yield: 56.4 %

Procedure:
A solution of 1-cyclopropyl-5,6,7,8-tetrafluoro-1,4-dihydro-4-oxoquinoline-3-carboxylic acid (3.70 g, 12.3 mmol), N-2-pyridyl-1,2-ethanediamine (1.77 g, 12.9 mmol) and triethylamine (3.50 mL) in EtOH (50 mL) was stirred at room temperature for 3 h, and refluxed for 1 h. The reaction mixture was cooled at room temperature. The resulting precipitate was combined by filtration. The cake washed with EtOH and collected by filtration and then dried to give 1-cyclopropyl-1,4-dihydro-5,6,8-trifluoro-4-oxo-7-[2-(2-pyridylamino)ethylamino]quinoline-3-carboxylic acid (2.90 g, 56%) as a pale yellow solid.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@:9]1([C:14]([OH:16])=O)[CH2:11][C@H:10]1[CH:12]=[CH2:13])=[O:7])([CH3:4])([CH3:3])[CH3:2].C(N1C=CN=C1)(N1C=CN=C1)=O.[CH3:29][O:30][CH2:31][C:32]1([S:35]([NH2:38])(=[O:37])=[O:36])[CH2:34][CH2:33]1.C1CCN2C(=NCCC2)CC1>C1COCC1>[CH:12]([C@@H:10]1[CH2:11][C@:9]1([NH:8][C:6](=[O:7])[O:5][C:1]([CH3:2])([CH3:3])[CH3:4])[C:14](=[O:16])[NH:38][S:35]([C:32]1([CH2:31][O:30][CH3:29])[CH2:34][CH2:33]1)(=[O:37])=[O:36])=[CH2:13]
Reactant: C=C[C@@H]1C[C@]1(NC(=O)OC(C)(C)C)C(=O)O
Reactant: COCC1(S(N)(=O)=O)CC1
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: C1CCC2=NCCCN2CC1
Solvent: C1CCOC1
Product: C=C[C@@H]1C[C@]1(NC(=O)OC(C)(C)C)C(=O)NS(=O)(=O)C1(COC)CC1
Temperature: 25 °C
Reaction time: 4 h
Yield: 55.2 %

Procedure:
A solution of (1R,2S)-1-[(tert-butoxycarbonyl)amino]-2-ethenylcyclopropanecarboxylic acid (132 mg) in THF (3 mL) was added 1,1′-carbonyldiimidazole (283 mg). The mixture was stirred 4 hours at reflux. The mixture was cooled to room temperature and a solution of 1-(methoxymethyl)cyclopropanesulfonamide (125 mg; Li et al., 2006, Synlett 5:725) and DBU (0.438 mL) in THF (3 mL) was added via cannula. The mixture was stirred for 40 hours at room temperature. The reaction was quenched with 1N HCl and the mixture was extracted twice with ethyl acetate. The combined organic layers were washed with brine, dried over anhydrous magnesium sulfate, filtered and concentrated under reduced pressure. The resulting residue was purified by flash chromatography (ISCO) to give the desired product (120 mg). 1H NMR (400 MHz, CDCl3): 5.71-5.62 (m, 1H), 5.29 (d, 1H), 5.16 (d, 1H), 3.36 (s, 2H), 2.15 (dt, 1H), 1.89 (dd, 1H), 1.75-1.68 (m, 2H), 1.49 (s, 9H), 1.34-1.30 (m, 1H), 1.08-1.03 (m, 2H).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C@@H:8]([CH3:12])[C:9]([OH:11])=O)=[CH:4][CH:3]=1.[NH2:13][CH2:14][CH2:15][CH2:16][N:17]1[CH2:22][CH2:21][CH:20]([C:23]2[CH:24]=[C:25]([NH:30][C:31](=[O:35])[CH:32]([CH3:34])[CH3:33])[CH:26]=[CH:27][C:28]=2[CH3:29])[CH2:19][CH2:18]1>CO>[F:1][C:2]1[CH:3]=[CH:4][C:5]([C@@H:8]([CH3:12])[C:9]([NH:13][CH2:14][CH2:15][CH2:16][N:17]2[CH2:22][CH2:21][CH:20]([C:23]3[CH:24]=[C:25]([NH:30][C:31](=[O:35])[CH:32]([CH3:34])[CH3:33])[CH:26]=[CH:27][C:28]=3[CH3:29])[CH2:19][CH2:18]2)=[O:11])=[CH:6][CH:7]=1
Reactant: Cc1ccc(NC(=O)C(C)C)cc1C1CCN(CCCN)CC1
Reactant: C[C@@H](C(=O)O)c1ccc(F)cc1
Solvent: CO
Product: Cc1ccc(NC(=O)C(C)C)cc1C1CCN(CCCNC(=O)[C@H](C)c2ccc(F)cc2)CC1

Procedure:
Example 169 was prepared from (2R)-2-(4-fluorophenyl)propanoic acid and N-{3-[1-(3-aminopropyl)-4-piperidinyl]-4-methylphenyl}-2-methylpropanamide according to the procedures described in Scheme 12; [α]D=−9.1° (C=1.65, MeOH): 1H NMR (400 MHz, CDCl3) δ 7.51 (d, 1 H, J=2.0 Hz), 7.37–7.28 (m, 2 H), 7.23–7.14 (m, 2 H), 7.08 (d, 1 H, J=8.0 Hz), 7.05–6.96 (m, 2 H), 6.90–6.82 (m, 1 H), 3.54 (q, 1 H, J=7.2 Hz), 3.43–3.23 (m, 2 H), 2.95 (ABq, 2 H), 2.73–2.59 (m, 1 H), 2.57–2.42 (m, 1 H), 2.42–2.32 (m, 2 H), 2.28 (s, 3 H), 2.07–1.91 (m, 2 H), 1.83–1.57 (m, 6 H), 1.51 (d, 3 H, J=7.2 Hz), 1.23 (d, 6 H, J=6.8 Hz); ESMS m/e: 468.3 (M+H)+.
Reaction SMILES: [C:1]1([C:6]([CH2:8][C:9]#[N:10])=[O:7])[S:5][CH:4]=[CH:3][CH:2]=1.[N-:11]=[N+:12]=[N-:13].[Na+].[Cl-].C([NH+](CC)CC)C>C1(C)C=CC=CC=1>[NH:11]1[C:9]([CH2:8][C:6]([C:1]2[S:5][CH:4]=[CH:3][CH:2]=2)=[O:7])=[N:10][N:13]=[N:12]1
Reactant: [N-]=[N+]=[N-]
Reactant: N#CCC(=O)c1cccs1
Agent: CC[NH+](CC)CC
Agent: [Cl-]
Agent: [Na+]
Solvent: Cc1ccccc1
Product: O=C(Cc1nnn[nH]1)c1cccs1
Yield: 43.5 %

Procedure:
A mixture of 2-thenoylacetonitrile (9 g, 59.3 mmol), Sodium azide (4.33 g, 66.7 mmol) and triethylammoniumchloride (9.14 g, 66.9 mmol) was stirred in dry toluene (139 mL) under argon atmosphere at 90° C. for 18 hrs. A two-phase system was formed, cooled and extracted with NaOH (2M, 3×500 mL), and the aqueous solution was poured into hydrochloric acid (4M, 300 mL) and the crude tetrazole was filtered off and recrystalised from acetonitrile. Yield: 43.5%.
Reaction SMILES: [F:1][C:2]([F:24])([F:23])[C:3]1[CH:4]=[C:5]([C:13]2[N:17]=[CH:16][N:15](/[CH:18]=[CH:19]\[C:20](O)=[O:21])[N:14]=2)[CH:6]=[C:7]([C:9]([F:12])([F:11])[F:10])[CH:8]=1.Cl.[F:26][C:27]([F:34])([F:33])[C:28]1([OH:32])[CH2:31][NH:30][CH2:29]1.C(P1(=O)OP(CCC)(=O)OP(CCC)(=O)O1)CC.CCN(C(C)C)C(C)C>C(Cl)Cl>[F:24][C:2]([F:1])([F:23])[C:3]1[CH:4]=[C:5]([C:13]2[N:17]=[CH:16][N:15](/[CH:18]=[CH:19]\[C:20]([N:30]3[CH2:31][C:28]([OH:32])([C:27]([F:34])([F:33])[F:26])[CH2:29]3)=[O:21])[N:14]=2)[CH:6]=[C:7]([C:9]([F:10])([F:11])[F:12])[CH:8]=1
Reactant: O=C(O)/C=C\n1cnc(-c2cc(C(F)(F)F)cc(C(F)(F)F)c2)n1
Reactant: OC1(C(F)(F)F)CNC1
Agent: CCCP1(=O)OP(=O)(CCC)OP(=O)(CCC)O1
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: O=C(/C=C\n1cnc(-c2cc(C(F)(F)F)cc(C(F)(F)F)c2)n1)N1CC(O)(C(F)(F)F)C1
Temperature: -30 °C
Reaction time: 0.5 h
Yield: 14.8 %

Procedure:
(Z)-3-(3-(3,5-bis(trifluoromethyl)phenyl)-1H-1,2,4-triazol-1-yl)acrylic acid (0.10 g, 1.0 eq.) and 3-(trifluoromethyl)azetidin-3-ol hydrochloride (0.055 g, 1.1 eq.) were dissolved in DCM (3.0 mL) The reaction mixture was cooled to −30° C. where T3P (0.3 mL, 1.5 eq.) and DIPEA (0.12 mL, 2.5 eq.) were added. The reaction mixture was stirred at −30° C. for 30 min. and diluted by DCM, washed with water. The combined organic layers were dried over sodium sulfate and distilled under reduce pressure (250° C., 20 mmHg) to obtain crude product. The crude product was purified by preparative TLC (70% ethyl acetate-Hexane) to yield to 0.020 g of (Z)-3-(3-(3,5-bis(trifluoromethyl)phenyl)-1H-1,2,4-triazol-1-yl)-1-(3-hydroxy-3-(trifluoromethyl)azetidin-1-yl)prop-2-en-1-one. (Yield: 14.8%). 1H NMR (400 MHz, MeOD) δ 9.20 (s, 1H), 8.65 (s, 2H), 8.09 (s, 1H), 7.40-7.43 (d, J=10 Hz, 1H), 5.95-5.93 (d, J=10.6 Hz, 1H), 4.42-4.43 (m, 2H), 4.33-4.05 (m, 2H); LCMS calcd for C17H11F9N4O2 [M+H]+474.3. Found: 475.14 Retention time: 2.872 min,
Reaction SMILES: F[C:2]1[CH:7]=[CH:6][C:5]([C:8]2[NH:9][C:10](=[O:16])[C:11](=[CH:14][CH:15]=2)[C:12]#[N:13])=[CH:4][CH:3]=1.[C:17]1([N:23]2[CH2:28][CH2:27][NH:26][CH2:25][CH2:24]2)[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1>CS(C)=O>[C:17]1([N:23]2[CH2:28][CH2:27][N:26]([C:2]3[CH:7]=[CH:6][C:5]([C:8]4[NH:9][C:10](=[O:16])[C:11](=[CH:14][CH:15]=4)[C:12]#[N:13])=[CH:4][CH:3]=3)[CH2:25][CH2:24]2)[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1
Reactant: N#Cc1ccc(-c2ccc(F)cc2)[nH]c1=O
Reactant: c1ccc(N2CCNCC2)cc1
Solvent: CS(C)=O
Product: N#Cc1ccc(-c2ccc(N3CCN(c4ccccc4)CC3)cc2)[nH]c1=O

Procedure:
From 12.9 g. of 6-(p-fluorophenyl)-1,2-dihydro-2-oxonicotinonitrile and 19.5 g. of N-phenylpiperazine in 180 ml. of dimethyl sulfoxide, there is obtained 6-[p-(4-phenyl-1-piperazinyl)phenyl]-1,2-dihydro-2-oxonicotinonitrile.
Reaction SMILES: [CH2:1]([O:3][C:4]1[CH:33]=[CH:32][C:7]2[N:8]([S:18]([C:21]3[CH:29]=[CH:28][C:24]([C:25]([OH:27])=O)=[CH:23][C:22]=3[O:30][CH3:31])(=[O:20])=[O:19])[C:9](=[O:17])[N:10]([C:11]3[CH:16]=[CH:15][CH:14]=[CH:13][N:12]=3)[C:6]=2[CH:5]=1)[CH3:2].[CH3:34][C:35]([NH2:39])([CH3:38])[CH2:36][CH3:37].CCN(C(C)C)C(C)C.F[P-](F)(F)(F)(F)F.N1(O[P+](N(C)C)(N(C)C)N(C)C)C2C=CC=CC=2N=N1>C(Cl)Cl>[CH2:1]([O:3][C:4]1[CH:33]=[CH:32][C:7]2[N:8]([S:18]([C:21]3[CH:29]=[CH:28][C:24]([C:25](=[O:27])[NH:39][C:35]([CH3:38])([CH3:34])[CH2:36][CH3:37])=[CH:23][C:22]=3[O:30][CH3:31])(=[O:20])=[O:19])[C:9](=[O:17])[N:10]([C:11]3[CH:16]=[CH:15][CH:14]=[CH:13][N:12]=3)[C:6]=2[CH:5]=1)[CH3:2]
Reactant: CCC(C)(C)N
Reactant: CCOc1ccc2c(c1)n(-c1ccccn1)c(=O)n2S(=O)(=O)c1ccc(C(=O)O)cc1OC
Agent: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CCOc1ccc2c(c1)n(-c1ccccn1)c(=O)n2S(=O)(=O)c1ccc(C(=O)NC(C)(C)CC)cc1OC
Temperature: 25 °C
Reaction time: 3 h

Procedure:
A mixture of 0.3 g of the compound obtained in EXAMPLE 111 step B), 0.5 ml of 1,1-dimethylpropylamine, 0.5 ml of DIPEA, 0.35 g of BOP and 20 ml of DCM is stirred for 3 hours at RT. The reaction mixture is concentrated under vacuum, the residue is extracted with AcOEt, washed with a 1N solution of HCl and with a 1N solution of NaOH and dried over Na2SO4 and the solvent is evaporated off under vacuum. The residue is chromatographed on silica using a DCM/AcOEt mixture (90/10; v/v) as the eluent to give 0.15 g of the expected product after crystallization from iso ether.
Reaction SMILES: C[Al](C)C.[CH3:5][O:6][C:7]1[CH:8]=[C:9]([CH2:15][CH2:16][C:17]2[CH:18]=[C:19]([NH2:22])[NH:20][N:21]=2)[CH:10]=[C:11]([O:13][CH3:14])[CH:12]=1.[CH3:23][C@H:24]1[N:29]([CH3:30])[C@@H:28]([CH3:31])[CH2:27][N:26]([C:32]2[N:37]=[CH:36][C:35]([C:38](OC)=[O:39])=[CH:34][N:33]=2)[CH2:25]1.Cl>C1(C)C=CC=CC=1.CO>[CH3:14][O:13][C:11]1[CH:10]=[C:9]([CH2:15][CH2:16][C:17]2[CH:18]=[C:19]([NH:22][C:38]([C:35]3[CH:36]=[N:37][C:32]([N:26]4[CH2:27][C@H:28]([CH3:31])[N:29]([CH3:30])[C@H:24]([CH3:23])[CH2:25]4)=[N:33][CH:34]=3)=[O:39])[NH:20][N:21]=2)[CH:8]=[C:7]([O:6][CH3:5])[CH:12]=1
Reactant: COc1cc(CCc2cc(N)[nH]n2)cc(OC)c1
Reactant: COC(=O)c1cnc(N2C[C@@H](C)N(C)[C@@H](C)C2)nc1
Agent: C[Al](C)C
Agent: Cl
Solvent: CO
Solvent: Cc1ccccc1
Product: COc1cc(CCc2cc(NC(=O)c3cnc(N4C[C@@H](C)N(C)[C@@H](C)C4)nc3)[nH]n2)cc(OC)c1
Temperature: 60 °C
Reaction time: 18 h
Yield: 39.4 %

Procedure:
Trimethylaluminium (2M in toluene, 1.04 ml, 2.08 mmol) was added dropwise to a suspension of 5-[2-(3,5-dimethoxyphenyl)ethyl]-2H-pyrazol-3-amine (205 mg, 0.83 mmol) and methyl 2-((3R,5S)-3,4,5-trimethylpiperazin-1-yl)pyrimidine-5-carboxylate (220 mg, 0.83 mmol) in toluene (5.257 ml) at 25° C. The resulting solution was stirred at 60° C. for 18 h. The reaction mixture was poured into methanol (50 mL) and acidified with HCl (2M aqueous solution, to obtain a clear freely stirring solution). The crude product was purified by ion exchange chromatography, using an SCX column. The desired product was eluted from the column using 7M NH3/MeOH and evaporated to dryness to afford impure product. The impure material was purified by preparative HPLC, using decreasingly polar mixtures of water (containing 1% NH3) and MeCN as eluents. Fractions containing the desired compound were evaporated to dryness to afford the title compound (157 mg, 39%) as a white solid.