Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C([O:3][C:4]([CH2:6][N:7]1[C:13]2[CH:14]=[CH:15][CH:16]=[CH:17][C:12]=2[N:11]([C:18](=[O:41])[C:19]2[CH:24]=[CH:23][C:22]([NH:25][C:26](=[O:40])[C:27]3[CH:32]=[CH:31][CH:30]=[CH:29][C:28]=3[C:33]3[CH:38]=[CH:37][C:36]([CH3:39])=[CH:35][CH:34]=3)=[CH:21][CH:20]=2)[CH2:10][CH2:9][C:8]1=[O:42])=[O:5])C.[OH-].[Na+]>C(O)C>[C:4]([CH2:6][N:7]1[C:13]2[CH:14]=[CH:15][CH:16]=[CH:17][C:12]=2[N:11]([C:18](=[O:41])[C:19]2[CH:20]=[CH:21][C:22]([NH:25][C:26](=[O:40])[C:27]3[CH:32]=[CH:31][CH:30]=[CH:29][C:28]=3[C:33]3[CH:38]=[CH:37][C:36]([CH3:39])=[CH:35][CH:34]=3)=[CH:23][CH:24]=2)[CH2:10][CH2:9][C:8]1=[O:42])([OH:5])=[O:3]
Reactant: CCOC(=O)CN1C(=O)CCN(C(=O)c2ccc(NC(=O)c3ccccc3-c3ccc(C)cc3)cc2)c2ccccc21
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: Cc1ccc(-c2ccccc2C(=O)Nc2ccc(C(=O)N3CCC(=O)N(CC(=O)O)c4ccccc43)cc2)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 95.2 %

Procedure:
The mixture of 1-ethoxycarbonylmethyl-5-{4-[2-(4methylphenyl)benzoylamino]benzoyl}-1,3,4,5-tetrahydro-1,5-benzodiazepin-2(2H)-one (240 mg), 1N sodium hydroxide aqueous solution (2 ml) and ethanol (5 ml) was stirred for 1 hour at ambient temperature. The reaction was quenched with 1N hydrochloric acid (2 ml) and ethanol was removed. The residue was diluted with ethyl acetate and the solution was washed with brine, and the solution was dried over magnesium sulfate. Filtering and the removal of solvents afforded a crude product. The crude product was triturated with a mixture of diisopropyl ether and diethyl ether (1:1) to give 1-carboxymethyl-5-{4-[2-(4methylphenyl)benzoylamino]benzoyl}-1,3,4,5-tetrahydro-1,5-benzodiazepin-2(2H)-one (217 mg) as a white powder.
Reaction SMILES: [CH3:1][NH:2][CH2:3][CH2:4][CH2:5][O:6][C:7]1[CH:12]=[CH:11][C:10]([CH:13]2[CH2:18][CH2:17][N:16]([C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])[CH2:15][CH:14]2[O:26][CH2:27][C:28]2[CH:37]=[CH:36][C:35]3[C:30](=[CH:31][CH:32]=[CH:33][CH:34]=3)[CH:29]=2)=[CH:9][CH:8]=1.[CH2:38](Br)[C:39]1[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=1>>[CH2:38]([N:2]([CH3:1])[CH2:3][CH2:4][CH2:5][O:6][C:7]1[CH:12]=[CH:11][C:10]([CH:13]2[CH2:18][CH2:17][N:16]([C:19]([O:21][C:22]([CH3:23])([CH3:24])[CH3:25])=[O:20])[CH2:15][CH:14]2[O:26][CH2:27][C:28]2[CH:37]=[CH:36][C:35]3[C:30](=[CH:31][CH:32]=[CH:33][CH:34]=3)[CH:29]=2)=[CH:9][CH:8]=1)[C:39]1[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=1
Reactant: BrCc1ccccc1
Reactant: CNCCCOc1ccc(C2CCN(C(=O)OC(C)(C)C)CC2OCc2ccc3ccccc3c2)cc1
Product: CN(CCCOc1ccc(C2CCN(C(=O)OC(C)(C)C)CC2OCc2ccc3ccccc3c2)cc1)Cc1ccccc1

Procedure:
In an analogous manner to that described in Example 44 (e), by alkylating tert-butyl (3RS,4RS)-4-[4-(3-methylamino-propoxy)-phenyl]-3-(naphthalen-2-ylmethoxy)-piperidine-1-carboxylate [Example 57 (e)] with benzyl bromide there was obtained tert-butyl (3RS,4RS)-4-[4-[3-(benzyl-methyl-amino)-propoxy]-phenyl]-3-(naphthalen-2-ylmethoxy)-piperidine-1-carboxylate as a colourless solid; MS: 595 (M+H)+.
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[CH2:10][C:11]([OH:13])=O)([O-:3])=[O:2].[NH2:14][CH:15]1[CH2:20][CH2:19][N:18]([CH2:21][C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)[CH2:17][CH2:16]1.ON1C2C=CC=CC=2N=N1.CN(C)CCCN=C=NCC.C(N(CC)CC)C>C(OCC)(=O)C>[CH2:21]([N:18]1[CH2:19][CH2:20][CH:15]([NH:14][C:11](=[O:13])[CH2:10][C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N+:1]([O-:3])=[O:2])[CH2:16][CH2:17]1)[C:22]1[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=1
Reactant: NC1CCN(Cc2ccccc2)CC1
Reactant: O=C(O)Cc1ccccc1[N+](=O)[O-]
Agent: CCN=C=NCCCN(C)C
Agent: On1nnc2ccccc21
Solvent: CCOC(C)=O
Solvent: CCN(CC)CC
Product: O=C(Cc1ccccc1[N+](=O)[O-])NC1CCN(Cc2ccccc2)CC1
Temperature: 40 °C
Reaction time: 2 h
Yield: 98.7 %

Procedure:
(2-Nitro-phenyl)-acetic acid (2.0 g, 11.04 mmol), 4-amino-1-benzylpiperidine (2.25 mL, 10.03 mmol), 1-hydroxybenzotriazole (1.49 g, 11.04 mmol) and 1-(3-dimethylaminopropyl)-3-ethyl carbodiimide (2.3 g, 12.03 mmol) were combined in ethyl acetate (25 mL). To this solution was added triethylamine (4.2 mL. 30.1 mmol) and the reaction mixture stirred at 40° C. for 2 h. After cooling to room temperature, the mixture was diluted with ethyl acetate and washed with water (2×), 5% sodium bicarbonate, brine (2×), dried over sodium sulfate, and concentrated to afford 3.5 g (98%) of the desired product. LC/MS: tR=1.24 min, 354.30 (MH)+.
Reaction SMILES: [CH2:1]([N:4]1[CH2:7][CH:6]([C:8]2[CH:13]=[CH:12][C:11]([NH2:14])=[CH:10][CH:9]=2)[CH2:5]1)[CH2:2][CH3:3].[F:15][CH2:16][C@@H:17]([C:19]1[CH:24]=[CH:23][C:22]([S:25](Cl)(=[O:27])=[O:26])=[CH:21][CH:20]=1)[CH3:18]>C(Cl)Cl.N1C=CC=CC=1>[F:15][CH2:16][C@@H:17]([C:19]1[CH:24]=[CH:23][C:22]([S:25]([NH:14][C:11]2[CH:10]=[CH:9][C:8]([CH:6]3[CH2:5][N:4]([CH2:1][CH2:2][CH3:3])[CH2:7]3)=[CH:13][CH:12]=2)(=[O:27])=[O:26])=[CH:21][CH:20]=1)[CH3:18]
Reactant: C[C@@H](CF)c1ccc(S(=O)(=O)Cl)cc1
Reactant: CCCN1CC(c2ccc(N)cc2)C1
Solvent: c1ccncc1
Solvent: ClCCl
Product: CCCN1CC(c2ccc(NS(=O)(=O)c3ccc([C@@H](C)CF)cc3)cc2)C1
Yield: 4.9 %

Procedure:
Following the same procedure as described in example 55, 4-(1-propyl-azetidin-3-yl)phenylamine (150 mg, 0.78 mmol) in CH2Cl2/pyridine 1:1 (12 ml) was treated with 4-((R)-2-fluoro-1-methyl-ethyl)-benzenesulfonyl chloride (242 mg, 1.02 mmol). Purification of the crude product by chromatography on reversed phase silica gel (H2O+0.1% acetic acid:CH3CN+0.1% acetic acid, 75:25) provided the title compound (15 mg, 5%) as a colourless gum.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:9]=[N:10][C:11]3[N:12]([C:14]([C:17]4([C:20]5[CH:21]=[C:22]6[C:27](=[CH:28][CH:29]=5)[N:26]=[CH:25][CH:24]=[CH:23]6)[CH2:19][CH2:18]4)=[N:15][N:16]=3)[N:13]=2)=[CH:4][CH:3]=1.[NH:30]1[CH:34]=[CH:33][CH:32]=[N:31]1.P([O-])([O-])([O-])=O.[K+].[K+].[K+].CNC1CCCCC1NC>O1CCOCC1.CO.[Cu]I>[N:30]1([C:2]2[CH:7]=[CH:6][C:5]([C:8]3[CH:9]=[N:10][C:11]4[N:12]([C:14]([C:17]5([C:20]6[CH:21]=[C:22]7[C:27](=[CH:28][CH:29]=6)[N:26]=[CH:25][CH:24]=[CH:23]7)[CH2:19][CH2:18]5)=[N:15][N:16]=4)[N:13]=3)=[CH:4][CH:3]=2)[CH:34]=[CH:33][CH:32]=[N:31]1
Reactant: Brc1ccc(-c2cnc3nnc(C4(c5ccc6ncccc6c5)CC4)n3n2)cc1
Reactant: c1cn[nH]c1
Agent: [Cu]I
Agent: CNC1CCCCC1NC
Agent: O=P([O-])([O-])[O-]
Solvent: CO
Solvent: C1COCCO1
Product: c1cnc2ccc(C3(c4nnc5ncc(-c6ccc(-n7cccn7)cc6)nn45)CC3)cc2c1
Temperature: 150 °C

Procedure:
A mixture of 6-{1-[6-(4-bromophenyl)[1,2,4]triazolo[4,3-b][1,2,4]triazin-3-yl]cyclopropyl}quinoline (20 mg, 0.04 mmol, Example 41), 1H-pyrazole (4.6 mg, 0.068 mmol), potassium phosphate (20 mg, 0.095 mmol), N,N′-dimethylcyclohexane-1,2-diamine (1.4 μL), and copper(I) iodide (1.7 mg) in 1,4-dioxane (500 μL) was heated at 150° C. for 2 h. After cooling, the mixture was diluted with methanol and filtered. The filtrate was purified by RP-HPLC (pH=10) to afford the desired product. Analytical LCMS: (M+H)+=431.1.
Reaction SMILES: [OH:1][C:2]1(/[CH:15]=[CH:16]/[CH2:17][C:18]([F:21])([F:20])[F:19])[CH2:7][CH2:6][N:5](C(OC(C)(C)C)=O)[CH2:4][CH2:3]1>Cl.O1CCOCC1>[F:21][C:18]([F:19])([F:20])[CH2:17]/[CH:16]=[CH:15]/[C:2]1([OH:1])[CH2:3][CH2:4][NH:5][CH2:6][CH2:7]1
Reactant: CC(C)(C)OC(=O)N1CCC(O)(/C=C/CC(F)(F)F)CC1
Agent: Cl
Solvent: C1COCCO1
Product: OC1(/C=C/CC(F)(F)F)CCNCC1

Procedure:
A solution of (E)-tert-butyl 4-hydroxy-4-(4,4,4-trifluorobut-1-enyl)piperidine-1-carboxylate (200 mg, 0.65 mmol) in 3M HCl/1,4-dioxane (5 mL) was stirred at room temperature for 2 hours. The solution was evaporated to dryness under reduced pressure to give the product which was used in the next step without further purification. LC-MS: m/z 210.2 (M+H)+.
Reaction SMILES: [CH:1]1([C:4]([C:6]2[CH:7]=[N:8][C:9]3[C:14]([C:15]=2[NH:16][C:17]2[CH:18]=[CH:19][C:20]([N:23]4[CH2:28][CH2:27][CH2:26][C@H:25]([NH:29]C(=O)OC(C)(C)C)[CH2:24]4)=[N:21][CH:22]=2)=[CH:13][C:12]([C:37]2[CH:42]=[C:41]([Cl:43])[C:40]([OH:44])=[C:39]([Cl:45])[CH:38]=2)=[CH:11][CH:10]=3)=[O:5])[CH2:3][CH2:2]1.Cl>C(OCC)(=O)C>[ClH:43].[NH2:29][C@H:25]1[CH2:26][CH2:27][CH2:28][N:23]([C:20]2[N:21]=[CH:22][C:17]([NH:16][C:15]3[C:14]4[C:9](=[CH:10][CH:11]=[C:12]([C:37]5[CH:38]=[C:39]([Cl:45])[C:40]([OH:44])=[C:41]([Cl:43])[CH:42]=5)[CH:13]=4)[N:8]=[CH:7][C:6]=3[C:4]([CH:1]3[CH2:3][CH2:2]3)=[O:5])=[CH:18][CH:19]=2)[CH2:24]1
Reactant: CC(C)(C)OC(=O)N[C@H]1CCCN(c2ccc(Nc3c(C(=O)C4CC4)cnc4ccc(-c5cc(Cl)c(O)c(Cl)c5)cc34)cn2)C1
Agent: Cl
Solvent: CCOC(C)=O
Product: N[C@H]1CCCN(c2ccc(Nc3c(C(=O)C4CC4)cnc4ccc(-c5cc(Cl)c(O)c(Cl)c5)cc34)cn2)C1
Temperature: 40 °C
Yield: 182.6 %

Procedure:
(S)-tert-Butyl 1-(5-(3-(cyclopropanecarbonyl)-6-(3,5-dichloro-4-hydroxyphenyl)quinolin-4-ylamino)pyridin-2-yl)piperidin-3-ylcarbamate (5.7 g, 8.8 mmol) was reacted HCl (100 mL, 1.25M in methanol). The mixture was heated to 40° C. for 16 h. The reaction was diluted with ethyl acetate (100 mL). The resultant solid was filtered and washed with ethyl acetate. The solids were dissolved in a mixture of water, methanol, and acetonitrile. The solution was concentrated by lyophilization to obtain desired product (4.7 g, 81%) as an orange solid: 1H NMR (500 MHz, CD3OD) δ 9.36 (s, 1H), 8.32-8.22 (m, 3H), 8.08 (d, J=9.2 Hz, 1H), 7.90 (dd, J=9.5, 2.6 Hz, 1H), 7.48 (s, 2H), 7.36 (d, J=9.5 Hz, 1H), 4.51-4.45 (m, 1H), 4.11-4.03 (m, 1H), 3.53-3.36 (m, 3H), 2.87-2.78 (m, 1H), 2.27-2.20 (m, 1H), 2.06-1.97 (m, 1H), 1.85-1.72 (m, 2H), 1.25-1.10 (m, 4H); ESI MS m/z 548 [C29H27Cl2N5O2+H]+; HPLC 98.8% (AUC), tR=9.51 min.
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])[N:9]=[CH:8][CH:7]=[C:6]2[O:15][C:16]1[CH:22]=[CH:21][C:19]([NH2:20])=[C:18]([F:23])[CH:17]=1.C(O)C.[Cl:27][C:28]1[CH:29]=[C:30]([C:34]([N:36]=[C:37]=[S:38])=[O:35])[CH:31]=[CH:32][CH:33]=1>C1(C)C=CC=CC=1>[Cl:27][C:28]1[CH:29]=[C:30]([CH:31]=[CH:32][CH:33]=1)[C:34]([NH:36][C:37]([NH:20][C:19]1[CH:21]=[CH:22][C:16]([O:15][C:6]2[C:5]3[C:10](=[CH:11][C:12]([O:13][CH3:14])=[C:3]([O:2][CH3:1])[CH:4]=3)[N:9]=[CH:8][CH:7]=2)=[CH:17][C:18]=1[F:23])=[S:38])=[O:35]
Reactant: O=C(N=C=S)c1cccc(Cl)c1
Reactant: COc1cc2nccc(Oc3ccc(N)c(F)c3)c2cc1OC
Solvent: Cc1ccccc1
Solvent: CCO
Product: COc1cc2nccc(Oc3ccc(NC(=S)NC(=O)c4cccc(Cl)c4)c(F)c3)c2cc1OC
Temperature: 25 °C
Reaction time: 2 h
Yield: 93 %

Procedure:
4-[(6,7-Dimethoxy-4-quinolyl)oxy]-2-fluoroaniline (50 mg) was dissolved in toluene (5 ml) and ethanol (1 ml) to prepare a solution. Commercially available 3-chloro-1-benzenecarbonyl isothiocyanate (50 μl) was then added to the solution, and the mixture was stirred at room temperature for 2 hr. The reaction solution was concentrated, and the residue was purified by chromatography on silica gel using chloroform/acetone for development to give the title compound (76 mg, yield 93%).
Reaction SMILES: S(S([O-])=O)([O-])=O.[Na+].[Na+].[NH2:9][C:10]1[C:11]([CH3:16])=[CH:12][CH:13]=[CH:14][CH:15]=1.C(=O)([O-])O.[Na+].[Br:22][C:23]([F:32])([F:31])[C:24](Br)([F:29])[C:25]([F:28])([F:27])[F:26].C(=O)([O-])[O-].[Na+].[Na+]>S([O-])(O)(=O)=O.C([N+](CCCC)(CCCC)CCCC)CCC.COC(C)(C)C.O>[CH3:16][C:11]1[CH:12]=[C:13]([C:24]([F:29])([C:25]([F:28])([F:27])[F:26])[C:23]([Br:22])([F:32])[F:31])[CH:14]=[CH:15][C:10]=1[NH2:9]
Reactant: Cc1ccccc1N
Reactant: FC(F)(F)C(F)(Br)C(F)(F)Br
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: O=C([O-])O
Agent: O=C([O-])[O-]
Solvent: O
Solvent: COC(C)(C)C
Product: Cc1cc(C(F)(C(F)(F)F)C(F)(F)Br)ccc1N
Temperature: 40 °C
Reaction time: 18 h

Procedure:
First 154.36 g (0.887 mol) of sodium dithionite and then 50 g (0.467 mol) of o-toluidine (2-methylaniline) were added at room temperature to a mixture of 900 ml of water, 350 ml of tert-butyl methyl ether, 74.48 g (0.887 mol) of sodium hydrogencarbonate and 12.68 g of tetra-n-butylammonium hydrogensulphate. Subsequently, a solution of 274.684 g of 1,2-dibromo-1,1,2,3,3,3-hexafluoropropane in 100 ml of tert-butyl methyl ether was added dropwise at 35–40° C. and, on completion of addition, the mixture was stirred at 40° C. for a further 18 h. If necessary, sodium carbonate was used to adjust to a pH of 5 and the organic phase was removed, dried and concentrated. The remaining residue is incipiently distilled under reduced pressure at 0.3 mbar up to an internal temperature of 100° C.
Reaction SMILES: Cl.[NH2:2][CH2:3][C:4]1[C:13](=[O:14])[C:12]2[C:7](=[N:8][C:9]([C:15]([F:18])([F:17])[F:16])=[CH:10][CH:11]=2)[N:6]([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[C:5]=1[C:25]([O:27][CH3:28])=[O:26].[CH3:29][N:30]1[N:34]=[N:33][C:32]([C:35]2[CH:43]=[CH:42][C:38]([C:39](O)=[O:40])=[CH:37][CH:36]=2)=[N:31]1>>[CH3:28][O:27][C:25]([C:5]1[N:6]([C:19]2[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=2)[C:7]2[C:12]([C:13](=[O:14])[C:4]=1[CH2:3][NH:2][C:39](=[O:40])[C:38]1[CH:42]=[CH:43][C:35]([C:32]3[N:33]=[N:34][N:30]([CH3:29])[N:31]=3)=[CH:36][CH:37]=1)=[CH:11][CH:10]=[C:9]([C:15]([F:16])([F:17])[F:18])[N:8]=2)=[O:26]
Reactant: Cn1nnc(-c2ccc(C(=O)O)cc2)n1
Reactant: COC(=O)c1c(CN)c(=O)c2ccc(C(F)(F)F)nc2n1-c1ccccc1
Agent: Cl
Product: COC(=O)c1c(CNC(=O)c2ccc(-c3nnn(C)n3)cc2)c(=O)c2ccc(C(F)(F)F)nc2n1-c1ccccc1

Procedure:
3-{[4-(2-Methyl-2H-tetrazol-5-yl)-benzoylamino]-methyl}-4-oxo-1-phenyl-7-trifluoromethyl-1,4-dihydro-[1,8]-naphthyridine-2-carboxylic acid methyl ester was prepared starting from intermediate J and 4-(2-methyl-2H-tetrazol-5-yl)-benzoic acid. 1H NMR (300 MHz, DMSO-d6) δ ppm 8.91 (d, J=8.15 Hz, 1H) 8.71 (br. s., 1H) 8.07-8.17 (m, 2H) 7.90-8.03 (m, 3H) 7.52-7.62 (m, 3H) 7.39-7.50 (m, 2H) 4.48 (d, J=4.83 Hz, 2H) 4.44 (s, 3H) 3.41 (s, 3H). LCMS calcd. for C27H20F3N7O4 [(M+H)+] 563.1, obsd. 564.1.
Reaction SMILES: [CH3:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH:7]=[CH2:8].[CH2:9]([O:11][SiH:12]([O:16][CH2:17][CH3:18])[O:13][CH2:14][CH3:15])[CH3:10].C(OC(=O)C)(=O)C.C([Si](C=C)(C)O[Si](C)(C)C)=C>C1(C)C=CC=CC=1>[CH2:8]([Si:12]([O:16][CH2:17][CH3:18])([O:13][CH2:14][CH3:15])[O:11][CH2:9][CH3:10])[CH2:7][CH2:6][CH2:5][CH2:4][CH2:3][CH2:2][CH3:1]
Reactant: CCO[SiH](OCC)OCC
Reactant: C=CCCCCCC
Agent: C=C[Si](C)(C=C)O[Si](C)(C)C
Solvent: CC(=O)OC(C)=O
Solvent: Cc1ccccc1
Product: CCCCCCCC[Si](OCC)(OCC)OCC
Temperature: 50 °C
Yield: 14.3 %

Procedure:
224 mg Of octene-1, 328 mg of triethoxysilane, and 56 mg of toluene were placed in a glass reaction tube and 0.01 ml of acetic anhydride was added to this mixture. Then, 0.001 ml of a toluene solution of a 0-valent platinum complex of divinyltetramethyldisiloxane (platinum content: 0.4 wt %) was added to this mixture. The reaction tube was sealed with Teflon tape and heated for 30 minutes in an oil bath at 50° C. When the contents were analyzed by GC-MS following cooling, the conversion rate of octene-1 was 16.5%, and n-octyltriethoxysilane was produced at a yield of 14.3%.
Reaction SMILES: [CH3:1][C:2]1[N:6]([C:7]2[CH:12]=[CH:11][C:10]([C:13]([F:16])([F:15])[F:14])=[CH:9][CH:8]=2)[N:5]=[CH:4][C:3]=1[C:17](Cl)=[O:18].[NH2:20][C:21]1[CH:28]=[CH:27][C:26]([N:29]2[CH2:34][CH2:33][CH:32]([N:35]3[CH2:40][CH2:39][O:38][CH2:37][CH2:36]3)[CH2:31][CH2:30]2)=[CH:25][C:22]=1[C:23]#[N:24]>>[C:23]([C:22]1[CH:25]=[C:26]([N:29]2[CH2:34][CH2:33][CH:32]([N:35]3[CH2:40][CH2:39][O:38][CH2:37][CH2:36]3)[CH2:31][CH2:30]2)[CH:27]=[CH:28][C:21]=1[NH:20][C:17]([C:3]1[CH:4]=[N:5][N:6]([C:7]2[CH:12]=[CH:11][C:10]([C:13]([F:16])([F:15])[F:14])=[CH:9][CH:8]=2)[C:2]=1[CH3:1])=[O:18])#[N:24]
Reactant: Cc1c(C(=O)Cl)cnn1-c1ccc(C(F)(F)F)cc1
Reactant: N#Cc1cc(N2CCC(N3CCOCC3)CC2)ccc1N
Product: Cc1c(C(=O)Nc2ccc(N3CCC(N4CCOCC4)CC3)cc2C#N)cnn1-c1ccc(C(F)(F)F)cc1
Yield: 39.9 %

Procedure:
By the reaction and treatment in the same manner as in Example 150 using 5-methyl-1-(4-trifluoromethylphenyl)pyrazole-4-carboxylic chloride (0.9 g) and 2-amino-5-(4-morpholinopiperidin-1-yl)benzonitrile (0.9 g), the title compound (0.67 g) was obtained, melting point: 210–212° C.
Reaction SMILES: N[C:2]1[C:10]([Cl:11])=[CH:9][C:5]([C:6]([OH:8])=[O:7])=[C:4]([O:12][CH3:13])[CH:3]=1.F[B-](F)(F)F.[H+].N([O-])=[O:21].[Na+]>O>[Cl:11][C:10]1[C:2]([OH:21])=[CH:3][C:4]([O:12][CH3:13])=[C:5]([CH:9]=1)[C:6]([OH:8])=[O:7]
Reactant: COc1cc(N)c(Cl)cc1C(=O)O
Reactant: O=N[O-]
Agent: F[B-](F)(F)F
Agent: [H+]
Agent: [Na+]
Solvent: O
Product: COc1cc(O)c(Cl)cc1C(=O)O
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 12.3 %

Procedure:
To a suspension of 4-amino-5-chloro-2-methoxybenzoic acid (25 g; 0.12 mol) in 125 ml of water was added tetrafluoroboric acid (40.5 ml of 48% aqueous solution). The white cake was then cooled to 0° C. and NaNO2 (9.41 g in 75 mL of H2O) was added drop wise and the whole stirred at that temperature for 30 minutes. The white precipitate was collected by filtration. The diazonium salt was suspended in glacial AcOH (1250 mL) and the resulting suspension was stirred at 100° C. for 1 hour (it became a brown solution). It was allowed to stand at RT for two more hours. The solvent was removed under reduced pressure and the brown oily residue suspended in brine (1250 ml) and extracted with EtOAC (3×400 ml). The combined organic layers were dried over magnesium sulphate, filtered and evaporated under reduced pressure to give brown oil. Purification by preparative reversed-phase HPLC (Et2O/EtOH 0/100 to 40/60) afforded 3.0 g (13%) of a red solid.
Reaction SMILES: C[O:2][C:3](=[O:27])[C@H:4]([CH2:21][C:22]1[N:26]=[CH:25][NH:24][CH:23]=1)[NH:5][C:6](=[O:20])[C@H:7]([C@H:16]([CH2:18][CH3:19])[CH3:17])[NH:8][C:9]([O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:10].[OH-].[Li+].[ClH:30]>CO>[ClH:30].[C:12]([O:11][C:9]([NH:8][C@H:7]([C:6]([NH:5][C@H:4]([C:3]([OH:27])=[O:2])[CH2:21][C:22]1[N:26]=[CH:25][NH:24][CH:23]=1)=[O:20])[C@H:16]([CH2:18][CH3:19])[CH3:17])=[O:10])([CH3:14])([CH3:15])[CH3:13]
Reactant: CC[C@H](C)[C@H](NC(=O)OC(C)(C)C)C(=O)N[C@@H](Cc1c[nH]cn1)C(=O)OC
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Product: CC[C@H](C)[C@H](NC(=O)OC(C)(C)C)C(=O)N[C@@H](Cc1c[nH]cn1)C(=O)O
Reaction time: 3 h

Procedure:
29.4 g of t-butoxycarbonylisoleucylhistidine methyl ester is dissolved in 150 ml of methanol. To this solution is added 308 ml of 1 N lithium hydroxide. The reaction mixture is stirred for three hours, then neutralized with 1 N hydrochloride acid to pH 3. The solvent is removed by vacuum and the residue is dissolved in N,N-dimethylformamide. The solution is filtered and the solvent removed by vacuum. The residue is dissolved in methanol/2-propanol. The alcohol solution is added to 2 liters of cold rapidly stirring ethyl ether. The white precipitate is filtered and dried in vacuo to afford t-butoxycarbonylisoleucylhistidine hydrochloride.
Reaction SMILES: [NH2:1][C:2]1[C:11]2[C:6](=[CH:7][C:8](Br)=[CH:9][CH:10]=2)[CH:5]=[CH:4][N:3]=1.[C:13]([O:17][C:18]([N:20]1[CH2:25][CH2:24][CH2:23][CH:22]([NH2:26])[CH2:21]1)=[O:19])([CH3:16])([CH3:15])[CH3:14].C(P(C(C)(C)C)C1C=CC=CC=1C1C=CC=CC=1)(C)(C)C.CC(C)([O-])C.[Na+]>O1CCOCC1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[C:13]([O:17][C:18]([N:20]1[CH2:25][CH2:24][CH2:23][CH:22]([NH:26][C:8]2[CH:7]=[C:6]3[C:11](=[CH:10][CH:9]=2)[C:2]([NH2:1])=[N:3][CH:4]=[CH:5]3)[CH2:21]1)=[O:19])([CH3:16])([CH3:14])[CH3:15]
Reactant: CC(C)(C)OC(=O)N1CCCC(N)C1
Reactant: Nc1nccc2cc(Br)ccc12
Agent: [Pd]
Agent: CC(C)(C)P(c1ccccc1-c1ccccc1)C(C)(C)C
Agent: CC(C)(C)[O-]
Solvent: C1COCCO1
Product: CC(C)(C)OC(=O)N1CCCC(Nc2ccc3c(N)nccc3c2)C1
Temperature: 120 °C

Procedure:
To a degassed solution of 1-amino-6-bromoisoquinolin (554 mg), prepared as described in WO 98/47876 (Akzo Nobel N.V.), 3-aminopiperidine-1-carboxylic acid tert-butyl ester (823 mg), 2-(di-tert-butylphosphino)biphenyl and sodium tert-butoxide (367 mg) in dioxane (10 ml) under argon, was added tris(dibenzylidene-acetone)dipalladium(0). The mixture was further degassed with argon then heated at 120° C. for 90 minutes. The mixture was cooled to room temperature then diluted with methanol. The crude mixture was loaded onto a pre-acidified SCX column and the basic products eluted with 2M ammonia in methanol to give a crude residue (700 mg). The residue was purified by preparative HPLC to give 3-(1-aminoisoquinolin-6-ylamino)piperidin-1-carboxylic acid tert-butyl ester. A mixture of the 3-(1-aminoisoquinolin-6-ylamino)-piperidin-1-carboxylic acid tert-butyl ester in dichloromethane (6 ml) and trifluoroacetic acid (3 ml) were stirred at ambient temperature for 3 h. The mixture was concentrated then purified by preparative HPLC followed by loading onto a pre-acidified SCX column and the free base eluted with 2M ammonia in methanol to give 6-(piperidin-3-ylamino)-isoquinolin-1-ylamine, El-MS: m/z=243.7 [M+H]+.
Reaction SMILES: [Br:1][C:2]1[CH:11]=[C:10]2[C:5]([C:6](=[O:21])[N:7]3[CH2:20][CH2:19][C:14]4(OCC[O:15]4)[CH2:13][CH2:12][C:8]3=[N:9]2)=[CH:4][CH:3]=1.Cl>C1COCC1>[Br:1][C:2]1[CH:11]=[C:10]2[C:5]([C:6](=[O:21])[N:7]3[CH2:20][CH2:19][C:14](=[O:15])[CH2:13][CH2:12][C:8]3=[N:9]2)=[CH:4][CH:3]=1
Reactant: O=c1c2ccc(Br)cc2nc2n1CCC1(CC2)OCCO1
Agent: Cl
Solvent: C1CCOC1
Product: O=C1CCc2nc3cc(Br)ccc3c(=O)n2CC1
Temperature: 25 °C

Procedure:
A solution of 3-bromo-9,10-dihydro-6H-spiro[azepino[2,1-b]quinazoline-8,2′-[1,3]dioxolan]-12(7H)-one (0.5 g, 1.43 mmol) and 4N HCl (4 mL) in THF (20 mL) was heated at reflux for 4 h. After it was cooled to rt, the reaction mixture was quenched with aq. Na2CO3 and extracted with ethyl acetate (3×50 mL). The combined organic layers were dried over Na2SO4. After filtration and concentration, the residue was purified by silica gel chromatography to give the desired product.
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].F[C:8]1[CH:15]=[CH:14][C:11]([C:12]#[N:13])=[CH:10][CH:9]=1.[C:16]1([C@H:26]([N:28]([CH2:36][C@@H:37]2[C@@H:41]([C:42]3[CH:47]=[CH:46][CH:45]=[CH:44][CH:43]=3)[CH2:40][NH:39][CH2:38]2)[C:29](=[O:35])[O:30][C:31]([CH3:34])([CH3:33])[CH3:32])[CH3:27])[C:25]2[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=2)[CH:19]=[CH:18][CH:17]=1.CS(C)=O>C(OCC)(=O)C>[C:12]([C:11]1[CH:14]=[CH:15][C:8]([N:39]2[CH2:40][C@H:41]([C:42]3[CH:47]=[CH:46][CH:45]=[CH:44][CH:43]=3)[C@@H:37]([CH2:36][N:28]([C@@H:26]([C:16]3[C:25]4[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=4)[CH:19]=[CH:18][CH:17]=3)[CH3:27])[C:29](=[O:35])[O:30][C:31]([CH3:34])([CH3:33])[CH3:32])[CH2:38]2)=[CH:9][CH:10]=1)#[N:13]
Reactant: C[C@H](c1cccc2ccccc12)N(C[C@H]1CNC[C@@H]1c1ccccc1)C(=O)OC(C)(C)C
Reactant: N#Cc1ccc(F)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CS(C)=O
Product: C[C@H](c1cccc2ccccc12)N(C[C@H]1CN(c2ccc(C#N)cc2)C[C@@H]1c1ccccc1)C(=O)OC(C)(C)C
Temperature: 110 °C
Reaction time: 8 h
Yield: 58.6 %

Procedure:
A 650 mg portion of potassium carbonate and 339 mg of 4-fluorobenzonitrile were added to a mixture of 1.0 g of tert-butyl [(1R)-1-(1-naphthyl)ethyl]{[(3R,4S)-4-phenylpyrrolidin-3-yl]methyl}carbamate and 10 ml of DMSO and stirred overnight at 110° C. After cooling down to room temperature, the reaction solution was mixed with ethyl acetate, washed with water and saturated brine in that order and dried with anhydrous sodium sulfate. The solvent was evaporated under a reduced pressure, and the thus obtained residue was purified by a silica gel column chromatography (hexane-ethyl acetate) to obtain 723 mg of tert-butyl {[(3R,4S)-1-(4-cyanophenyl)-4-phenylpyrrolidin-3-yl]methyl}[(1R)-1-(1-naphthyl)ethyl]carbamate as a colorless amorphous substance. EP: 532.