Azzindani/Open_Reaction_Data huggingface dataset:
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.[CH3:14][CH:15]1[C:24]2[C:19](=[CH:20][C:21]([C:25]3[CH:30]=[CH:29][N:28]=[CH:27][CH:26]=3)=[CH:22][CH:23]=2)[CH2:18][CH2:17][NH:16]1>>[Br:1][C:2]1[CH:3]=[N:4][C:5]2[N:6]([N:8]=[C:9]([C:11]([N:16]3[CH2:17][CH2:18][C:19]4[C:24](=[CH:23][CH:22]=[C:21]([C:25]5[CH:30]=[CH:29][N:28]=[CH:27][CH:26]=5)[CH:20]=4)[CH:15]3[CH3:14])=[O:13])[CH:10]=2)[CH:7]=1
Reactant: CC1NCCc2cc(-c3ccncc3)ccc21
Reactant: O=C(O)c1cc2ncc(Br)cn2n1
Product: CC1c2ccc(-c3ccncc3)cc2CCN1C(=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 1-Methyl-6-pyridin-4-yl-1,2,3,4-tetrahydro-isoquinoline to provide the title compound in moderate yield.
Reaction SMILES: [C:1]([C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=1[S:12]([N:15]=[C:16]=[O:17])(=[O:14])=[O:13])([O:3][CH2:4][CH3:5])=[O:2].[NH2:18][C:19]1[N:24]=[C:23]([NH:25][CH3:26])[N:22]=[C:21]([O:27][C:28]([F:31])([F:30])[F:29])[N:20]=1>C(Cl)Cl>[CH3:26][NH:25][C:23]1[N:22]=[C:21]([O:27][C:28]([F:31])([F:29])[F:30])[N:20]=[C:19]([NH:18][C:16]([NH:15][S:12]([C:7]2[CH:8]=[CH:9][CH:10]=[CH:11][C:6]=2[C:1]([O:3][CH2:4][CH3:5])=[O:2])(=[O:13])=[O:14])=[O:17])[N:24]=1
Reactant: CNc1nc(N)nc(OC(F)(F)F)n1
Reactant: CCOC(=O)c1ccccc1S(=O)(=O)N=C=O
Solvent: ClCCl
Product: CCOC(=O)c1ccccc1S(=O)(=O)NC(=O)Nc1nc(NC)nc(OC(F)(F)F)n1
Temperature: 22 °C
Reaction time: 30 h

Procedure:
3.1 g (0.012 mol) of 2-carboethoxybenzenesulfonyl isocyanate in 3 ml of methylene chloride were added over the course of 10 minutes to a stirred mixture of 2.5 g (0.012 mol) of 2-amino-4-methylamino-6-trifluoromethoxy-1,3,5-triazine and 150 ml of methylene chloride at 22° C., and the mixture was stirred at 22° C. for 30 hours. It was then concentrated under reduced pressure, stirred with methyl tert-butyl ether and filtered off with suction. Further washing with methanol and drying resulted in 3.8 g (67.4% of theory) of the title compound of melting point 182°-184° C. (decomposition).
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[C:6]([C:8]2[CH:13]=[CH:12][C:11]([NH2:14])=[C:10]([CH3:15])[CH:9]=2)[CH:5]=[CH:4][C:3]=1[NH2:16].[OH-].[K+].CCCCC[CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH3:30].I[C:32]1[CH:37]=[CH:36][C:35]([CH3:38])=[CH:34][CH:33]=1>[Cu](I)I.O>[CH3:38][C:35]1[CH:36]=[CH:37][C:32]([N:16]([C:28]2[CH:27]=[CH:26][C:25]([CH3:24])=[CH:30][CH:29]=2)[C:3]2[CH:4]=[CH:5][C:6]([C:8]3[CH:13]=[CH:12][C:11]([N:14]([C:13]4[CH:8]=[CH:9][C:10]([CH3:15])=[CH:11][CH:12]=4)[C:5]4[CH:6]=[CH:7][C:2]([CH3:1])=[CH:3][CH:4]=4)=[C:10]([CH3:15])[CH:9]=3)=[CH:7][C:2]=2[CH3:1])=[CH:33][CH:34]=1
Reactant: Cc1ccc(I)cc1
Reactant: Cc1cc(-c2ccc(N)c(C)c2)ccc1N
Reactant: CCCCCCCCCCCC
Agent: I[Cu]I
Agent: [K+]
Agent: [OH-]
Solvent: O
Product: Cc1ccc(N(c2ccc(C)cc2)c2ccc(-c3ccc(N(c4ccc(C)cc4)c4ccc(C)cc4)c(C)c3)cc2C)cc1
Temperature: 180 °C
Reaction time: 5 h
Yield: 75.7 %

Procedure:
In a round flask were charged 3.14 g (13.8 mmol) of o-tolidine, 40 g of potassium hydroxide, 400 mg of copper iodide, and 30 ml of n-dodecane, and the mixture was heated at 180° C. in a nitrogen stream. To the mixture was added dropwise 24.0 g (110 mmol) of 4-iodotoluene, and the heating at 180° C. was continued for 5 hours. Water was added to the reaction mixture, and the mixture was extracted with toluene. In order to assure completion of the reaction, the solvent was once removed by distillation, and 40 g of potassium hydroxide, 400 mg of copper iodide, and 24.0 g (110 mmol) of 4-iodotoluene were added to the residue, followed by allowing to react at 180° C. for 5 hours in a nitrogen stream. Water was added, and the mixture was extracted with toluene. The extract was dried over sodium sulfate and then treated with activated clay. The solvent was removed by distillation to obtain 5.98 g (yield: 75.7%) of N,N,N',N'-tetrakis-(4-methylphenyl)-3,3'-dimethylbenzidine, which was recrystallized from a mixed solvent of toluene/acetone/hexane to obtain 4.32 g (final yield: 54.7%) of a white crystal having a melting point of 174°-175° C. Analysis by high performance liquid chromatography revealed that the product has a high purity of 99.9%.
Reaction SMILES: [CH3:1][C:2]1[C:3]([C@H:8]2[CH2:13][CH2:12][CH2:11][C@@H:10]([C:14]3[C:19]([CH3:20])=[CH:18][CH:17]=[CH:16][N:15]=3)[NH:9]2)=[N:4][CH:5]=[CH:6][CH:7]=1.[CH2:21]([O:23][C:24](=[O:31])[CH2:25][CH2:26][CH2:27][CH2:28][CH2:29]Br)[CH3:22].CCN(C(C)C)C(C)C>CC#N>[CH2:21]([O:23][C:24](=[O:31])[CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][N:9]1[C@H:8]([C:3]2[C:2]([CH3:1])=[CH:7][CH:6]=[CH:5][N:4]=2)[CH2:13][CH2:12][CH2:11][C@@H:10]1[C:14]1[C:19]([CH3:20])=[CH:18][CH:17]=[CH:16][N:15]=1)[CH3:22]
Reactant: CCOC(=O)CCCCCBr
Reactant: Cc1cccnc1[C@@H]1CCC[C@H](c2ncccc2C)N1
Solvent: CCN(C(C)C)C(C)C
Solvent: CC#N
Product: CCOC(=O)CCCCCN1[C@@H](c2ncccc2C)CCC[C@H]1c1ncccc1C
Reaction time: 23 h
Yield: 90.2 %

Procedure:
A solution of (2′R,6′S)-3,3″-dimethyl-1′,2′,3′,4′,5′,6′-hexahydro-[2,2′;6′,2″]terpyridine (308 mg, 1.15 mmol), 6-bromo-hexanoic acid ethyl ester (283 mg, 1.27 mmol), DIPEA (260 μL, 1.49 mmol) and KI (10 mg, 0.060 mmol) in CH3CN (12 mL) was warmed to 60° C. and stirred for 23 h according to General Procedure A. Purification by flash chromatography on silica gel using CH2Cl2/MeOH/NH4OH (94:5:1) afforded 6-((2′R,6′S)-3,3″-dimethyl-3′,4′,5′,6′-tetrahydro-2′H-[2,2′;6′,2″]terpyridin-1′-yl)-hexanoic acid ethyl ester (425 mg, 90%) as a yellow oil. 1H NMR (CDCl3) δ 0.60-0.68 (m, 2H), 0.79-0.85 (m, 1H), 1.13-1.25 (m, 5H), 1.58-1.70 (m, 3H), 1.94-1.98 (m, 4H), 2.08-2.25 (m, 7H), 2.48 (bs, 6H), 1.50-2.63 (m, 2H), 4.03 (q, 2H, J=7.1 Hz), 7.05-7.08 (m, 2H), 7.43 (d, 2H, J=7.3 Hz), 8.47 (bs, 2H).
Reaction SMILES: C1(=[CH:9][C:10]([O:12][CH2:13]C)=[O:11])CCCCCCC1.[H-].C([Al+][CH2:21][CH:22]([CH3:24])[CH3:23])C(C)C.[CH3:25][CH2:26][CH2:27][CH2:28][CH2:29]C.Cl>O1CCCC1>[C:10]([O:12][CH2:13][CH:24]=[C:22]1[CH2:21][CH2:29][CH2:28][CH2:27][CH2:26][CH2:25][CH2:23]1)(=[O:11])[CH3:9]
Reactant: CC(C)C[Al+]CC(C)C
Reactant: CCOC(=O)C=C1CCCCCCC1
Reactant: CCCCCC
Agent: Cl
Agent: [H-]
Solvent: C1CCOC1
Product: CC(=O)OCC=C1CCCCCCC1
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
To an ice-cooled solution of ethyl cyclooctylideneacetate (4.82 g) in tetrahydrofuran (25 mL) was added 1M diisobutylaluminum hydride/hexane (73.8 mL) dropwise over 15 minutes. After stirring the reaction solution under ice cooling for 30 minutes, 2N hydrochloric acid (50 mL) was added. After allowing the solution for its temperature rise to room temperature, it was stirred for additional 30 minutes. The reaction solution was extracted with ethyl acetate. The organic layer was dried over anhydrous sodium sulfate and dried over under reduced pressure. To the resulting residue were added pyridine (22 mL), acetic anhydride (10.1 mL) and N,N-dimethylaminopyridine (0.26 g) sucessively. The solution was stirred at room temperature for 18 hours. The reaction solution was diluted with ethyl acetate, washed in turn with 2N hydrochloric acid, saturated aqueous sodium bicarbonate solution and saturated aqueous sodium chloride solution. The organic layer was dried over anhydrous sodium sulfate and concentrated under reduced pressure. The resulting residue was purified by chromatography [silica gel, hexane-ethyl acetate (97:3)] to give the title compound (3.41 g).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([O:29][CH:30]([F:32])[F:31])=[C:6]([C:8]2[C:12]([NH:13][C:14]([C:16]3[CH:17]=[N:18][N:19]4[CH:24]=[CH:23][CH:22]=[N:21][C:20]=34)=[O:15])=[CH:11][N:10]([CH2:25][C:26](O)=[O:27])[N:9]=2)[CH:7]=1.Cl.[NH:34]1[CH2:39][CH2:38][CH:37]([C:40]([O:42][CH2:43][CH2:44][N:45]2[CH2:50][CH2:49][O:48][CH2:47][CH2:46]2)=[O:41])[CH2:36][CH2:35]1.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>CN(C=O)C>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([O:29][CH:30]([F:32])[F:31])=[C:6]([C:8]2[C:12]([NH:13][C:14]([C:16]3[CH:17]=[N:18][N:19]4[CH:24]=[CH:23][CH:22]=[N:21][C:20]=34)=[O:15])=[CH:11][N:10]([CH2:25][C:26]([N:34]3[CH2:35][CH2:36][CH:37]([C:40]([O:42][CH2:43][CH2:44][N:45]4[CH2:50][CH2:49][O:48][CH2:47][CH2:46]4)=[O:41])[CH2:38][CH2:39]3)=[O:27])[N:9]=2)[CH:7]=1
Reactant: O=C(OCCN1CCOCC1)C1CCNCC1
Reactant: O=C(O)Cn1cc(NC(=O)c2cnn3cccnc23)c(-c2cc(Cl)ccc2OC(F)F)n1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: O=C(Nc1cn(CC(=O)N2CCC(C(=O)OCCN3CCOCC3)CC2)nc1-c1cc(Cl)ccc1OC(F)F)c1cnn2cccnc12
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of {3-(5-Chloro-2-difluoromethoxyphenyl)-4-[(pyrazolo[1,5-a]pyrimidine-3-carbonyl)amino]pyrazol-1-yl}acetic acid (150 mg, 0.26 mmol) in DMF (2 mL) was added 2-(morpholin-4-yl)ethyl piperidine-4-carboxylate hydrochloride (140 mg, 0.50 mmol), DIEA (101 mg, 0.78 mmol), HATU (119 mg, 0.31 mmol). The resulting solution was stirred at room temperature overnight and concentrated under vacuum. The residue was passed through a short pad of silica gel eluting with 10% MeOH in DCM. The crude product was purified by Prep-HPLC with the following conditions (Prep-HPLC-005): Column, XBridge Prep C18 OBD Column, 5 um, 19*150 mm; mobile phase, water with 0.05% FA and MeCN (31.0% MeCN up to 38.0% in 10 min, up to 95.0% in 1 min, hold 95.0% in 1 min, down to 31.0% in 2 min); Detector, UV 254/220 nm. This resulted in 35.6 mg (20%) of the formic acid salt of 2-(morpholin-4-yl)ethyl 1-(2-[3-[5-chloro-2-(difluoromethoxy)phenyl]-4-[pyrazolo[1,5-a]pyrimidine-3-amido]-1H-pyrazol-1-yl]acetyl)piperidine-4-carboxylate as a off-white solid. LCMS (Method 28) [M+H]+=687.2, RT=0.86 min. 1H NMR (400 MHz, DMSO-d6) δ: (ppm) 9.76 (s, 1H), 9.34 (dd, 1H, J=1.6, 7.2 Hz), 8.69-8.68 (m, 2H), 8.32 (s, 1H), 7.63 (dd, 1H, J=2.4, 8.8 Hz), 7.55 (d, 1H, J=2.8 Hz), 7.46 (d, 1H, J=8.8 Hz), 7.29 (dd, 1H, J=4.4, 6.8 Hz), 7.08 (t, 1H, J=73.2 Hz), 5.27-5.22 (m, 2H), 4.20-4.15 (m, 3H), 3.89-3.82 (m, 1H), 3.58-3.55 (m, 4H), 3.26-3.17 (m, 1H), 2.89-2.78 (m, 1H), 2.69-2.59 (m, 1H), 2.53-2.51 (m, 2H), 2.40-2.32 (m, 4H), 1.91-1.80 (m, 2H), 1.69-1.41 (m, 2H).
Reaction SMILES: [Cl:1][C:2]1[CH:15]=[C:14]([Cl:16])[CH:13]=[CH:12][C:3]=1[CH2:4][C:5]1[N:10]=[N:9][C:8]([OH:11])=[CH:7][CH:6]=1.[CH3:17][N:18]([C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)[C:19](Cl)=[O:20].N12CCN(CC1)CC2.O>CN(C)C=O>[Cl:1][C:2]1[CH:15]=[C:14]([Cl:16])[CH:13]=[CH:12][C:3]=1[CH2:4][C:5]1[N:10]=[N:9][C:8]([O:11][C:19](=[O:20])[N:18]([CH3:17])[C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)=[CH:7][CH:6]=1
Reactant: CN(C(=O)Cl)c1ccccc1
Reactant: Oc1ccc(Cc2ccc(Cl)cc2Cl)nn1
Agent: C1CN2CCN1CC2
Solvent: O
Solvent: CN(C)C=O
Product: CN(C(=O)Oc1ccc(Cc2ccc(Cl)cc2Cl)nn1)c1ccccc1
Yield: 80.7 %

Procedure:
A solution of 6-(2,4-dichlorobenzyl)-3-pyridazinol (98 mg, 0.38 mmol), N-methyl-N-phenylcarbamoyl chloride (65 mg, 0.38 mmol) and 1,4-diazabicyclo[2.2.2]octane (43 mg, 0.38 mmol) in dimethylformamide (10 ml) was stirred at room temperature for 2 hours. Water was added and the solution was extracted twice with dichloromethane. The combined organic layers were dried over sodium sulphate, filtered and evaporated in vacuo. The residue was purified by flash column chromatography (SiO2, ethyl acetate:heptane (40:60)) yielding the title compound (119 mg, 80% yield) as a yellow oil.
Reaction SMILES: [CH3:1]C([O-])(C)C.[K+].[CH3:7][C:8]1[CH:9]=[C:10]([C:19]([O:21]CC)=[O:20])[C:11]([C:14](OCC)=O)=[N:12][CH:13]=1.[NH2:24][C:25]([CH3:32])([CH2:29][CH2:30]C)[C:26]([NH2:28])=[O:27].O>C1(C)C=CC=CC=1>[CH:29]([C:25]1([CH3:32])[NH:24][C:14]([C:11]2[C:10]([C:19]([OH:21])=[O:20])=[CH:9][C:8]([CH3:7])=[CH:13][N:12]=2)=[N:28][C:26]1=[O:27])([CH3:1])[CH3:30]
Reactant: CCCC(C)(N)C(N)=O
Reactant: CC(C)(C)[O-]
Reactant: CCOC(=O)c1cc(C)cnc1C(=O)OCC
Agent: [K+]
Solvent: Cc1ccccc1
Solvent: O
Product: Cc1cnc(C2=NC(=O)C(C)(C(C)C)N2)c(C(=O)O)c1
Temperature: 80 °C
Yield: 68.4 %

Procedure:
With stirring, 116 g (1.034 moles) of potassium tert-butylate are added in portions to a solution of 123 g (0.519 mole) of diethyl 5-methyl-2,3-pyridinedicarboxylate and 67.5 g (0.519 mole) of 2-amino-2,4-dimethylbutyramide in 600 ml of toluene. During the addition of potassium tert-butylate the mixture exotherms to 60° C. When the addition of potassium tert-butylate is complete, the reaction mixture is heated to 80° C. and stirred overnight. Then 800 ml of water are added to the mixture which has cooled to room temperature, and the layers are separated. The aqueous phase is adjusted to pH 3 by addition of 85 ml of 37% hydrochloric acid, cooled to 0° C. and filtered. The product is dried, affording 97.8 g (69% of theory) of 2-(5-isopropyl-5-methyl-4-oxoimidazolin-2-yl)-5-methyl-3-pyridinecarboxylic acid of m.p. 200°-202° C.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6](Cl)[CH:5]=[CH:4][N:3]=1.[C:9]([CH2:11][C:12]1([N:25]2[CH:29]=[C:28](B3OC(C)(C)C(C)(C)O3)[CH:27]=[N:26]2)[CH2:17][CH2:16][N:15]([C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])[CH2:14][CH2:13]1)#[N:10].P([O-])([O-])([O-])=O.[K+].[K+].[K+]>O1CCOCC1.O.CCOC(C)=O.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[Cl:1][C:2]1[N:7]=[C:6]([C:28]2[CH:27]=[N:26][N:25]([C:12]3([CH2:11][C:9]#[N:10])[CH2:13][CH2:14][N:15]([C:18]([O:20][C:21]([CH3:22])([CH3:23])[CH3:24])=[O:19])[CH2:16][CH2:17]3)[CH:29]=2)[CH:5]=[CH:4][N:3]=1
Reactant: CC(C)(C)OC(=O)N1CCC(CC#N)(n2cc(B3OC(C)(C)C(C)(C)O3)cn2)CC1
Reactant: Clc1ccnc(Cl)n1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CCOC(C)=O
Solvent: C1COCCO1
Product: CC(C)(C)OC(=O)N1CCC(CC#N)(n2cc(-c3ccnc(Cl)n3)cn2)CC1
Temperature: 100 °C
Yield: 81 %

Procedure:
A mixture of 2,4-dichloropyrimidine (1.00 g, 6.71 mmol), tert-butyl 4-(cyanomethyl)-4-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazol-1-yl)piperidine-1-carboxylate (2.8 g, 6.7 mol), tetrakis(triphenylphosphine)palladium (0.5 g, 0.4 mmol), and potassium phosphate (4.3 g, 20 mmol) in 1,4-dioxane (20 mL) and water (2 mL) was heated at 100° C. overnight. After cooling to room temperature, the mixture was diluted with EtOAc, washed with water, brine, dried over MgSO4, and concentrated. The residue was purified on silica gel, eluting with 0 to 100% EtOAc in hexanes, to give the desired product (2.19 g, 82%). LCMS (M+H) 403.0.
Reaction SMILES: [CH:1]1([C:4](=O)[CH:5]=[CH:6][C:7]2[CH:12]=[CH:11][C:10]([CH3:13])=[CH:9][CH:8]=2)[CH2:3][CH2:2]1.[N+:15]([CH2:18][CH3:19])([O-:17])=[O:16].[Na].C[OH:22]>>[CH:1]1([CH2:4][C:5](=[O:22])[CH:6]([C:7]2[CH:12]=[CH:11][C:10]([CH3:13])=[CH:9][CH:8]=2)[CH:18]([N+:15]([O-:17])=[O:16])[CH3:19])[CH2:3][CH2:2]1
Reactant: CC[N+](=O)[O-]
Reactant: Cc1ccc(C=CC(=O)C2CC2)cc1
Reactant: CO
Agent: [Na]
Product: Cc1ccc(C(C(=O)CC2CC2)C(C)[N+](=O)[O-])cc1

Procedure:
The procedure of Example IX using 32.1 g of 1-cyclopropyl-3-(p-methylphenyl)prop-2-en-1-one, 16.5 ml of nitroethane and 2.1 g of sodium in 170 ml of methanol gives 32 g of 1-cyclopropyl-3-(p-methylphenyl)-4-nitropentanone which is used in the crude state for the remainder of the operations.
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]([CH:9]=[CH:10][C:11]=1[O:12][CH:13]([CH3:15])[CH3:14])[C:6](Cl)=[O:7])#[N:2].O[NH:17][C:18](=[NH:38])[C:19]1[CH:28]=[CH:27][CH:26]=[C:25]2[C:20]=1[CH:21]=[CH:22][N:23]=[C:24]2[CH2:29][CH2:30][C:31]([O:33][C:34]([CH3:37])([CH3:36])[CH3:35])=[O:32].C(N(CC)CC)C>CN(C=O)C>[C:1]([C:3]1[CH:4]=[C:5]([C:6]2[O:7][N:17]=[C:18]([C:19]3[CH:28]=[CH:27][CH:26]=[C:25]4[C:20]=3[CH:21]=[CH:22][N:23]=[C:24]4[CH2:29][CH2:30][C:31]([O:33][C:34]([CH3:37])([CH3:36])[CH3:35])=[O:32])[N:38]=2)[CH:9]=[CH:10][C:11]=1[O:12][CH:13]([CH3:15])[CH3:14])#[N:2]
Reactant: CC(C)(C)OC(=O)CCc1nccc2c(C(=N)NO)cccc12
Reactant: CC(C)Oc1ccc(C(=O)Cl)cc1C#N
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: CC(C)Oc1ccc(-c2nc(-c3cccc4c(CCC(=O)OC(C)(C)C)nccc34)no2)cc1C#N
Temperature: 25 °C
Reaction time: 0.75 h

Procedure:
A solution of 3-cyano-4-[(1-methylethyl)oxy]benzoyl chloride (WO2008128951; 89 mg, 0.4 mmol) in dry DMF (1.5 ml) was added to a stirred solution of 1,1-dimethylethyl 3-{5-[(hydroxyamino)(imino)methyl]-1-isoquinolinyl}propanoate (D36; 114 mg, 0.360 mmol) and triethylamine (0.084 mL, 0.600 mmol) in dry DMF (1.5 ml) at 0° and the mixture was allowed to warm to room temperature and stirred for 45 min.
Reaction SMILES: CO[C:3]1[CH:12]=[C:11]2[C:6]([CH:7]=[CH:8][CH:9]=[C:10]2[CH2:13][O:14][NH:15][C:16](=[O:18])[CH3:17])=[CH:5][CH:4]=1.[CH3:19][O:20]C1C=CC2C(=CC=CC=2)C=1CON>>[CH3:19][O:20][C:9]1[CH:8]=[CH:7][C:6]2[C:11](=[CH:12][CH:3]=[CH:4][CH:5]=2)[C:10]=1[CH2:13][O:14][NH:15][C:16](=[O:18])[CH3:17]
Reactant: COc1ccc2ccccc2c1CON
Reactant: COc1ccc2cccc(CONC(C)=O)c2c1
Product: COc1ccc2ccccc2c1CONC(C)=O

Procedure:
By carrying out the procedure in the same manner as for the synthesis of the compound of Example 1, but using the O-[(2-methoxynaphth-1-yl)methyl]hydroxylamine of preparation 6, the title compound is obtained.
Reaction SMILES: [Br:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([NH2:8])=[S:7])=[CH:4][CH:3]=1.Br[CH:12]([CH:19]=O)[CH2:13][C:14]([O:16][CH2:17][CH3:18])=[O:15]>C(O)C>[CH2:17]([O:16][C:14](=[O:15])[CH2:13][C:12]1[S:7][C:6]([C:5]2[CH:9]=[CH:10][C:2]([Br:1])=[CH:3][CH:4]=2)=[N:8][CH:19]=1)[CH3:18]
Reactant: NC(=S)c1ccc(Br)cc1
Reactant: CCOC(=O)CC(Br)C=O
Solvent: CCO
Product: CCOC(=O)Cc1cnc(-c2ccc(Br)cc2)s1

Procedure:
A mixture of 4-bromothiobenzamide (2.16 g., 0.01 mole) and ethyl 3-bromo-4-oxobutyrate (3.2 g., 0.015 mole) in ethanol (50 ml.) is heated at reflux for 6 hours. On cooling and partial evaporation there is obtained 2-(4-bromophenyl)thiazol-5-ylacetic acid ethyl ester. Reaction of this product with ammonia according to the procedure of Example 3 gives 2-(4-bromophenyl)thiazol-5-ylacetamide, which on reaction with diethyl oxalate and base in dimethylformamide, according to the general procedure of Example 6, affords the title compound.
Reaction SMILES: [C:1]([OH:6])(=[O:5])[C@H:2]([CH3:4])[OH:3].[NH2:7][C:8]1[N:13]=[CH:12][CH:11]=[CH:10][N:9]=1>CO>[C:1]([O-:6])(=[O:5])[C@H:2]([CH3:4])[OH:3].[NH2:7][C:8]1[N:13]=[CH:12][CH:11]=[CH:10][NH+:9]=1
Reactant: C[C@H](O)C(=O)O
Reactant: Nc1ncccn1
Solvent: CO
Product: C[C@H](O)C(=O)[O-]
Product: Nc1nccc[nH+]1

Procedure:
(S)-Lactic acid (3.0 g; 28 mmol) was dissolved in methanol (5 cm3) and added to a solution of 2-aminopyrimidine (2.7 g; 28 mmol) in methanol (5 cm3). The resulting white product was collected by filtration, recrystallized from water, and dried in vacuo. Found: C, 58.0%; H, 5.4%; N, 16.8%. Calculated for C12H13N3O3 : C, 58.28%; N, 5.31%; N, 17.00%. M.pt. 125°-127° C.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:12])[CH2:4][C:5]1[S:6][CH:7]=[C:8]([CH2:10]Cl)[CH:9]=1.[C-:13]#[N:14].[K+]>CN(C=O)C>[CH3:1][O:2][C:3](=[O:12])[CH2:4][C:5]1[S:6][CH:7]=[C:8]([CH2:10][C:13]#[N:14])[CH:9]=1
Reactant: [C-]#N
Reactant: COC(=O)Cc1cc(CCl)cs1
Agent: [K+]
Solvent: CN(C)C=O
Product: COC(=O)Cc1cc(CC#N)cs1
Temperature: 50 °C
Yield: 77.8 %

Procedure:
A solution of (4-chloromethyl-thiophen-2-yl)-acetic acid methyl ester (0.58 g, 2.83 mmol) and potassium cyanide (0.39 g, 5.95 mmol) in DMF (15 mL) is stirred at room temperature for 14 h then heated to 50° C. for 0.5 h. The mixture is quenched with saturated aq NaCl and extracted with CHCl3 (3×). The combined organic layers are washed with saturated aq NaCl, dried over Na2SO4, filtered and concentrated in vacuo. The residue is purified by chromatography (silica gel, 10% ethyl acetate in heptane) to give (4-cyanomethyl-thiophen-2-yl)-acetic acid methyl ester (0.43 g, 78%) as a colorless oil: 1H NMR (CDCl3, 300 MHz) δ 7.10 (s, 1 H), 6.95 (s, 1 H), 3.80 (s, 2 H), 3.72 (s, 3 H), 3.65 (s, 2 H).
Reaction SMILES: [C:1]([O:5][C:6]([CH2:8][NH:9][C@H:10]([CH3:33])[C@@H:11]([C:20]1[CH:25]=[CH:24][C:23]([O:26][C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)=[CH:22][CH:21]=1)[CH2:12][CH2:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[O:34]1[C@@H:38]([C:39]([O:41][C:42]([CH3:45])([CH3:44])[CH3:43])=[O:40])[C@H:37]([C:46]([O-])=[O:47])[O:36][C:35]1([C:54]([O:56][CH2:57][CH3:58])=[O:55])[C:49]([O:51][CH2:52][CH3:53])=[O:50].C(N(CC)CC)C.[Cl-].ClC1N(C)CC[NH+]1C>C(Cl)(Cl)Cl.O>[C:1]([O:5][C:6]([CH2:8][N:9]([C@H:10]([CH3:33])[C@@H:11]([C:20]1[CH:25]=[CH:24][C:23]([O:26][C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)=[CH:22][CH:21]=1)[CH2:12][CH2:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)[C:46]([C@H:37]1[C@H:38]([C:39]([O:41][C:42]([CH3:45])([CH3:43])[CH3:44])=[O:40])[O:34][C:35]([C:49]([O:51][CH2:52][CH3:53])=[O:50])([C:54]([O:56][CH2:57][CH3:58])=[O:55])[O:36]1)=[O:47])=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: C[C@@H](NCC(=O)OC(C)(C)C)[C@H](CCc1ccccc1)c1ccc(Oc2ccccc2)cc1
Reactant: CCOC(=O)C1(C(=O)OCC)O[C@@H](C(=O)[O-])[C@H](C(=O)OC(C)(C)C)O1
Agent: CN1CC[NH+](C)C1Cl
Agent: [Cl-]
Solvent: ClC(Cl)Cl
Solvent: O
Solvent: CCN(CC)CC
Product: CCOC(=O)C1(C(=O)OCC)O[C@@H](C(=O)OC(C)(C)C)[C@H](C(=O)N(CC(=O)OC(C)(C)C)[C@H](C)[C@H](CCc2ccccc2)c2ccc(Oc3ccccc3)cc2)O1
Reaction time: 1 h
Yield: 95 %

Procedure:
860 mg of N-(tert-butoxycarbonylmethyl)-{(1R,2R)-1-methyl-2-(4-phenoxyphenyl)-4-phenylbutyl}amine obtained in Example 50, 1.04 g of 5-tert-butyl 2,2-diethyl (4R,5R)-1,3-dioxolane-2,2,4,5-tetracarboxylate obtained in Example 68, and 2.02 ml of triethylamine, were dissolved in 20 ml of chloroform, and a solution of 816 mg of 2-chloro-1,3-dimethylimidazolinium chloride in 10 ml of chloroform, was added under cooling with ice, followed by stirring at the same temperature for 1 hour. The reaction solution was poured into water and extracted with ethyl acetate. The extract solution was washed with a saturated sodium chloride aqueous solution and then, dried over anhydrous sodium sulfate. The drying agent was filtered off and then, the solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography (hexane/ethyl acetate=5/1) to obtain 1.45 g (yield: 95%) of the above identified compound as a colorless oily substance.
Reaction SMILES: [F:1][C:2]([F:16])([F:15])[C:3]([NH:5][C@H:6]([C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)[CH2:7][OH:8])=[O:4].[Li][CH2:18][CH2:19][CH2:20]C.CN1C(=O)N(C)CCC1.C(Br)C=C>C1COCC1>[CH2:20]([O:8][CH2:7][C@H:6]([NH:5][C:3](=[O:4])[C:2]([F:15])([F:16])[F:1])[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)[CH:19]=[CH2:18]
Reactant: O=C(N[C@@H](CO)c1ccccc1)C(F)(F)F
Reactant: [Li]CCCC
Solvent: C1CCOC1
Solvent: C=CCBr
Solvent: CN1CCCN(C)C1=O
Product: C=CCOC[C@H](NC(=O)C(F)(F)F)c1ccccc1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 73.7 %

Procedure:
Step Q (2): (R)-2,2,2-Trifluoro-N-(2-hydroxy-1-phenylethyl)acetamide from step Q (1) (3.34 g, 14.3 mmol) was dissolved in THF (30 mL) and chilled to −78° C. n-BuLi (12 mL, 29 mmol, 2.5 M in hexanes) and DMPU (3.45 mL, 29 mmol) were added to the mixture. After 10 min, allyl bromide (12 mL, 143 mmol) was added. The mixture was warmed to rt and then heated to reflux for 16 h. The mixture was quenched with saturated NH4Cl, diluted with 1 N NaOH, and extracted with EtOAc. The combined organic layers were dried over Na2SO4, filtered, and concentrated in vacuo. Purification by silica-gel column chromatography (0-25% EtOAc/Hexanes) afforded 2.88 g (73% yield) of (R)-N-(2-(allyloxy)-1-phenylethyl)-2,2,2-trifluoroacetamide as a yellow residue. LC-MS (M+H)+=274.06. 1H NMR (300 MHz, CDCl3) δ ppm 3.66-3.79 (m, 2H) 3.95-4.01 (m, 2H) 5.07-5.26 (m, 3H) 5.73-5.89 (m, 1H) 6.95-7.06 (m, 1H) 7.24-7.37 (m, 4H).