Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]1[O:6][C:5]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)=[N:4][C:3]=1[CH2:13][CH2:14][O:15][C:16]1[CH:43]=[CH:42][C:19]([CH2:20][CH:21]([C:32]([O:34][CH2:35][C:36]2[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=2)=[O:33])[C:22]([O:24][CH2:25][C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)=[O:23])=[CH:18][CH:17]=1.[H-].[Na+].Br[CH2:47][C:48]([O:50][CH2:51][CH3:52])=[O:49].S([O-])(O)(=O)=O.[Na+]>O1CCCC1.O>[CH2:51]([O:50][C:48]([CH2:47][C:21]([CH2:20][C:19]1[CH:42]=[CH:43][C:16]([O:15][CH2:14][CH2:13][C:3]2[N:4]=[C:5]([C:7]3[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=3)[O:6][C:2]=2[CH3:1])=[CH:17][CH:18]=1)([C:32]([O:34][CH2:35][C:36]1[CH:37]=[CH:38][CH:39]=[CH:40][CH:41]=1)=[O:33])[C:22]([O:24][CH2:25][C:26]1[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=1)=[O:23])=[O:49])[CH3:52]
Reactant: Cc1oc(-c2ccccc2)nc1CCOc1ccc(CC(C(=O)OCc2ccccc2)C(=O)OCc2ccccc2)cc1
Reactant: CCOC(=O)CBr
Agent: O=S(=O)([O-])O
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: CCOC(=O)CC(Cc1ccc(OCCc2nc(-c3ccccc3)oc2C)cc1)(C(=O)OCc1ccccc1)C(=O)OCc1ccccc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 101 %

Procedure:
Dibenzyl 2-[4-[2-(5-methyl-2-phenyl-4-oxazolyl)ethoxy]benzyl]malonate (26.0 g, 45.2 mmol) synthesized according to the method described in WO95/18125 was dissolved in tetrahydrofuran (250 ml), and sodium hydride (60% in oil, 2.2 g, 54.2 mmol) was added at 0° C., which was followed by stirring at room temperature for 30 min. To the reaction mixture was added a solution of ethyl bromoacetate (15.3 ml, 135.6 mmol) in tetrahydrofuran (50 ml) at room temperature. After stirring for 1 hr, sodium hydride (60% in oil, 1.1 g, 27.1 mmol) and ethyl bromoacetate (5.1 ml, 45.2 mmol) were added. After stirring for 1 hr, sodium hydride (60% in oil, 2.2 g, 54.2 mmol) was added and the mixture was stirred for 1 hr. Water and 1N aqueous sodium hydrogensulfate solution were added to the reaction mixture and extracted three times with ethyl acetate (200 ml). The extracted organic layers were combined, washed with brine, dried over sodium sulfate and concentrated. The residue was purified by silica gel column chromatography (developing solvent; hexane:ethyl acetate=5:1→3:1) to give the title compound (30.2 g, yield 100%) as an oil.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[C:15](=[O:16])[C:14]2[C:9](=[C:10]([Cl:38])[C:11]([NH:18][CH2:19][CH:20]([OH:37])[CH2:21][O:22][CH:23]3[CH2:26][N:25](C(OCC4C=CC=CC=4)=O)[CH2:24]3)=[C:12]([F:17])[CH:13]=2)[N:8]([C:39]2[C:44]([F:45])=[CH:43][C:42]([F:46])=[C:41]([NH2:47])[N:40]=2)[CH:7]=1)=[O:5])[CH3:2]>CO.[Pd]>[CH2:1]([O:3][C:4]([C:6]1[C:15](=[O:16])[C:14]2[C:9](=[C:10]([Cl:38])[C:11]([NH:18][CH2:19][CH:20]([OH:37])[CH2:21][O:22][CH:23]3[CH2:26][NH:25][CH2:24]3)=[C:12]([F:17])[CH:13]=2)[N:8]([C:39]2[C:44]([F:45])=[CH:43][C:42]([F:46])=[C:41]([NH2:47])[N:40]=2)[CH:7]=1)=[O:5])[CH3:2]
Reactant: CCOC(=O)c1cn(-c2nc(N)c(F)cc2F)c2c(Cl)c(NCC(O)COC3CN(C(=O)OCc4ccccc4)C3)c(F)cc2c1=O
Agent: [Pd]
Solvent: CO
Product: CCOC(=O)c1cn(-c2nc(N)c(F)cc2F)c2c(Cl)c(NCC(O)COC3CNC3)c(F)cc2c1=O
Reaction time: 1 h
Yield: 93.6 %

Procedure:
To a slurry of 10% Pd on carbon (2.1 g) in MeOH (20 mL) was added a solution of 11 (13.7 g, 20.3 mmol) in MeOH (230 mL). The mixture was hydrogenated at 1 atm. for 1 h, filtered over Hyflo and evaporated yielding 12 as beige crystals (10.3 g, 93%). Mp. 148-152° C.; 1H NMR (300 MHz, DMSO-d6): δ 1.27 (3H, t, J=7.1 Hz), 3.27 (1H, d, J=5.0 Hz), 3.28-3.80 (10H, m), 4.19 (1H, br. s), 4.21 (2H, q, J=7.1 Hz), 5.86 (1H, s), 6.74 (2H, s), 7.84 (1H, d, J=13.8 Hz), 7.94 (1H, dd, J=9.7, 9.0 Hz), 8.43 (1H, s); 13C NMR (75 MHz, CDCl3): δ 14.1, 48.4 (d, JF=10 Hz), 53.6, 60.2, 68.4, 70.4 (d, JF=4 Hz), 72.1, 106.4 (d, JF=6 Hz), 111.0, 111.3 (d, JF=23 Hz), 113.6 (dd, JF=23, 21 Hz), 118.9 (d, JF=6 Hz), 133.8 (d, JF=13 Hz), 134.2, 139.5 (d, JF=12 Hz), 143.3 (dd, JF=248, 4 Hz), 145.0 (dd, JF=259, 5 Hz), 145.6 (d, JF=14 Hz), 149.3 (d, JF=245 Hz), 149.5, 163.5, 171.0; IR: (KBr) 1697, 1614, 1496, 1457 cm-1; ES-HRMS m/z: (M++1H) Calcd. for C23H24ClF3N5O5 542.1413. Found 542.1391.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([CH3:8])=[CH:4][C:3]=1[F:9].C1(C)C=CC=CC=1.[CH3:17][N:18](C=O)C>[C-]#N.[C-]#N.[Zn+2].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>[C:17]([C:2]1[CH:7]=[CH:6][C:5]([CH3:8])=[CH:4][C:3]=1[F:9])#[N:18]
Reactant: CN(C)C=O
Reactant: Cc1ccc(Br)c(F)c1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [C-]#N
Agent: [Zn+2]
Solvent: Cc1ccccc1
Product: Cc1ccc(C#N)c(F)c1
Temperature: 100 °C
Reaction time: 18 h

Procedure:
To a deoxygenated solution of 4-bromo-3-fluorotoluene (25.0 g, 132 mmol) in DMF (500 mL) was added Zn(CN)2 (10.1 g, 86 mmol) and Pd(PPh3)4 (15 g, 13 mmol). The reaction was stirred at 100° C. for 18 hours, then cooled to room temperature. The solution was poured into toluene (1 L), washed with 30% aqueous NH4OH (2×1 L), then brine (800 mL), then dried (Na2SO4), filtered, and concentrated in vacuo to provide the crude product. Purification by silica gel chromatography, eluting with a gradient of hexane −0% to 7% EtOAc, yielded the titled product.
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][N:5]=[C:4]2[NH:8][CH:9]=[CH:10][C:3]=12.[Br:11][C:12]1[C:13]([CH3:17])=[N:14][NH:15][CH:16]=1>>[Br:11][C:12]1[C:13]([CH3:17])=[N:14][N:15]([C:2]2[CH:7]=[CH:6][N:5]=[C:4]3[NH:8][CH:9]=[CH:10][C:3]=23)[CH:16]=1
Reactant: Clc1ccnc2[nH]ccc12
Reactant: Cc1n[nH]cc1Br
Product: Cc1nn(-c2ccnc3[nH]ccc23)cc1Br
Temperature: 130 °C
Yield: 87.5 %

Procedure:
A mixture of 4-chloro-1H-pyrrolo[2,3-b]pyridine (0.050 g, 0.00033 mol) and 4-bromo-3-methyl-1H-pyrazole (0.10 g, 0.00066 mol) was heated at 130° C. overnight. The reaction mixture then was subjected to column chromatography (eluting with 5% MeOH/DCM, 0.5% NH4OH, on silica gel) to give 80 mg pale yellow solid which was triturated with MeOH (1.5 mL) to yield the product as a pale yellow solid (44 mg, 44% yield).
Reaction SMILES: CN(C)C=O.[CH2:6]([CH:8]1[O:10][CH2:9]1)Br.C(=O)([O-])[O-].[K+].[K+].[NH2:17][C:18]1[CH:37]=[CH:36][C:21]([O:22][C:23]2[C:32]3[C:27](=[CH:28][C:29]([OH:35])=[C:30]([C:33]#[N:34])[CH:31]=3)[N:26]=[CH:25][CH:24]=2)=[CH:20][C:19]=1[F:38]>C(OCC)(=O)C.O>[NH2:17][C:18]1[CH:37]=[CH:36][C:21]([O:22][C:23]2[C:32]3[C:27](=[CH:28][C:29]([O:35][CH2:6][CH:8]4[CH2:9][O:10]4)=[C:30]([C:33]#[N:34])[CH:31]=3)[N:26]=[CH:25][CH:24]=2)=[CH:20][C:19]=1[F:38]
Reactant: BrCC1CO1
Reactant: N#Cc1cc2c(Oc3ccc(N)c(F)c3)ccnc2cc1O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: O
Solvent: CN(C)C=O
Product: N#Cc1cc2c(Oc3ccc(N)c(F)c3)ccnc2cc1OCC1CO1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
After adding dimethylformamide (6 ml), epibromohydrin (1.3 ml) and potassium carbonate (380 mg) to 4-(4-amino-3-fluorophenoxy)-6-cyano-7-hydroxyquinoline (400 mg), the mixture was stirred overnight at room temperature. Water was added to the reaction solution, extraction was performed with ethyl acetate, and then the organic layer was washed with water and saturated saline in that order and dried over anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure to obtain the title compound (400 mg).
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6]2[CH:8]=[C:9]([C:11]([OH:13])=O)[NH:10][C:5]2=[CH:4][CH:3]=1.[C:14]([O-:17])([O-])=O.[Cs+].[Cs+].CS([O:24][CH2:25][C:26]1[CH:31]=[C:30]([Cl:32])[CH:29]=[C:28]([CH2:33][O:34][Si:35]([C:48]([CH3:51])([CH3:50])[CH3:49])([C:42]2[CH:47]=[CH:46][CH:45]=[CH:44][CH:43]=2)[C:36]2[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=2)[CH:27]=1)(=O)=O>CN(C=O)C.O>[Si:35]([O:17][CH2:14][C:26]1[CH:27]=[C:28]([CH:29]=[C:30]([Cl:32])[CH:31]=1)[CH2:33][N:10]1[C:5]2[C:6](=[N:7][C:2]([Cl:1])=[CH:3][CH:4]=2)[CH:8]=[C:9]1[C:11]([O:24][CH2:25][C:26]1[CH:31]=[C:30]([Cl:32])[CH:29]=[C:28]([CH2:33][O:34][Si:35]([C:48]([CH3:51])([CH3:50])[CH3:49])([C:42]2[CH:47]=[CH:46][CH:45]=[CH:44][CH:43]=2)[C:36]2[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=2)[CH:27]=1)=[O:13])([C:48]([CH3:51])([CH3:49])[CH3:50])([C:42]1[CH:47]=[CH:46][CH:45]=[CH:44][CH:43]=1)[C:36]1[CH:37]=[CH:38][CH:39]=[CH:40][CH:41]=1
Reactant: O=C([O-])[O-]
Reactant: CC(C)(C)[Si](OCc1cc(Cl)cc(COS(C)(=O)=O)c1)(c1ccccc1)c1ccccc1
Reactant: O=C(O)c1cc2nc(Cl)ccc2[nH]1
Agent: [Cs+]
Solvent: O
Solvent: CN(C)C=O
Product: CC(C)(C)[Si](OCc1cc(Cl)cc(COC(=O)c2cc3nc(Cl)ccc3n2Cc2cc(Cl)cc(CO[Si](c3ccccc3)(c3ccccc3)C(C)(C)C)c2)c1)(c1ccccc1)c1ccccc1

Procedure:
5-Chloro-1H-pyrrolo[3,2-b]pyridine-2-carboxylic acid (0.645 g, 3.28 mmol, from Example 99, Step 1) and Cs2CO3 (3.2 g, 9.8 mmol) were added to a solution of 3-({[tert-butyl(diphenyl)silyl]oxy}methyl)-5-chlorobenzyl methanesulfonate (3.88 g, 7.93 mmol, from Step 3) in DMF (13 mL). Concurrently, a separate batch of 5-chloro-1H-pyrrolo[3,2-b]pyridine-2-carboxylic acid (0.558 g, 2.81 mmol) was treated with the same reagents under the same conditions. After stirring each reaction overnight, the reactions were combined, diluted with water and extracted with three portions of EtOAc. The combined organic extracts were washed sequentially with water and brine, dried over sodium sulfate, filtered and concentrated. The product was purified by flash chromatography, eluting with a gradient from 0-50% EtOAc in hexanes. Yield: (3.11 g, 52%).
Reaction SMILES: [F:1][CH:2]([F:37])[C:3]1[N:7]([C:8]2[N:13]=[C:12]([N:14]3[CH2:19][CH2:18][O:17][CH2:16][CH2:15]3)[N:11]=[C:10]([N:20]3[CH2:25][CH2:24][N:23]([S:26]([CH:29]=[CH2:30])(=[O:28])=[O:27])[CH2:22][CH2:21]3)[N:9]=2)[C:6]2[CH:31]=[CH:32][CH:33]=[C:34]([O:35][CH3:36])[C:5]=2[N:4]=1.[CH2:38]([NH:40][CH2:41][CH3:42])[CH3:39].O1CCOCC1>C1COCC1>[F:37][CH:2]([F:1])[C:3]1[N:7]([C:8]2[N:13]=[C:12]([N:14]3[CH2:15][CH2:16][O:17][CH2:18][CH2:19]3)[N:11]=[C:10]([N:20]3[CH2:21][CH2:22][N:23]([S:26]([CH2:29][CH2:30][N:40]([CH2:41][CH3:42])[CH2:38][CH3:39])(=[O:28])=[O:27])[CH2:24][CH2:25]3)[N:9]=2)[C:6]2[CH:31]=[CH:32][CH:33]=[C:34]([O:35][CH3:36])[C:5]=2[N:4]=1
Reactant: CCNCC
Reactant: C=CS(=O)(=O)N1CCN(c2nc(N3CCOCC3)nc(-n3c(C(F)F)nc4c(OC)cccc43)n2)CC1
Solvent: C1CCOC1
Solvent: C1COCCO1
Product: CCN(CC)CCS(=O)(=O)N1CCN(c2nc(N3CCOCC3)nc(-n3c(C(F)F)nc4c(OC)cccc43)n2)CC1
Temperature: 25 °C
Reaction time: 17 h
Yield: 31.6 %

Procedure:
A mixture of 2-(difluoromethyl)-4-methoxy-1-{4-(4-morpholinyl)-6-[4-(vinylsulfonyl)-1-piperazinyl]-1,3,5-triazin-2-yl}-1H-benzimidazole (Example 3) (150 mg, 0.280 mmol) and N,N-diethylamine (0.14 mL, 1.35 mmol) in THF (20 mL) was stirred at room temperature for 17 hrs, refluxed for 1 hr, and then stirred at room temperature for 4 hrs. 1,4-Dioxane (20 mL) was added and the mixture was refluxed for 21 hrs. Additional N,N-diethylamine (0.14 mL, 1.35 mmol) was then added and the mixture was refluxed for another 4.5 hrs. The reaction mixture was cooled to room temperature and the solvents were removed under vacuum. The residue was diluted with water and extracted with CH2Cl2 (2×). The organic layers were combined, dried (Na2SO4), and concentrated under vacuum. Chromatography on silica, eluting with CH2Cl2/MeOH (100:0 to 98:2), gave N-[2-({4-[4-[2-(difluoromethyl)-4-methoxy-1H-benzimidazol-1-yl]-6-(4-morpholinyl)-1,3,5-triazin-2-yl]-1-piperazinyl}sulfonyl)ethyl]-N,N-diethylamine (54 mg, 53%).
Reaction SMILES: [NH2:1][C@@H:2]1[CH2:7][CH2:6][CH2:5][CH2:4][C@H:3]1[OH:8].[OH-].[Na+].[OH-].[K+].[CH2:13](Cl)[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1>C1(C)C(C)=CC=CC=1.C(O)CCC.O>[CH2:13]([O:8][CH:3]1[CH2:4][CH2:5][CH2:6][CH2:7][CH:2]1[NH2:1])[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1
Reactant: ClCc1ccccc1
Reactant: N[C@@H]1CCCC[C@H]1O
Agent: [K+]
Agent: [Na+]
Agent: [OH-]
Solvent: Cc1ccccc1C
Solvent: O
Solvent: CCCCO
Product: NC1CCCCC1OCc1ccccc1

Procedure:
0.2 mol of trans-2-aminocyclohexanol are dissolved in 600 ml of xylene isomer mixture and 100 ml of n-butanol and heated to reflux. 0.2 mol of a 50% sodium hydroxide or potassium hydroxide solution in water is added dropwise to this solution over 15 minutes. In the course of this, the water which has been introduced and which forms is distilled off immediately. After the addition has ended, the water present in the reaction solution and then the n-butanol is distilled off until a transition temperature of 140-141° C. is attained. Thereafter, 0.2 mol of benzyl chloride is added dropwise over 30 minutes and the solution is stirred further under reflux for two hours. After aqueous workup, the desired 2-benzyloxycyclohexylamine is obtained in 93% (GC area%) yield in the case of sodium hydroxide, and in 92% (GC area%) yield in the case of potassium hydroxide.
Reaction SMILES: [N:1]1([CH2:6][CH2:7][N:8]2[C:16]3[C:11](=[CH:12][C:13]([NH2:17])=[CH:14][CH:15]=3)[CH:10]=[N:9]2)[CH2:5][CH2:4][CH2:3][CH2:2]1.[O:18]([C:25]1[CH:26]=[C:27]([CH2:31][C:32](O)=[O:33])[CH:28]=[CH:29][CH:30]=1)[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1>>[O:18]([C:25]1[CH:26]=[C:27]([CH2:31][C:32]([NH:17][C:13]2[CH:12]=[C:11]3[C:16](=[CH:15][CH:14]=2)[N:8]([CH2:7][CH2:6][N:1]2[CH2:5][CH2:4][CH2:3][CH2:2]2)[N:9]=[CH:10]3)=[O:33])[CH:28]=[CH:29][CH:30]=1)[C:19]1[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=1
Reactant: O=C(O)Cc1cccc(Oc2ccccc2)c1
Reactant: Nc1ccc2c(cnn2CCN2CCCC2)c1
Product: O=C(Cc1cccc(Oc2ccccc2)c1)Nc1ccc2c(cnn2CCN2CCCC2)c1

Procedure:
1-(2-pyrrolidin-1-yl-ethyl)-1H-indazol-5-ylamine and (3-phenoxy-phenyl)-acetic acid were processed as described in Example 17 to provide the title compound. MS (DCI/NH3) MS m/z 441 (M+H)+; 1H NMR (500 MHz, DMSO-d6) δ ppm 1.83 (m, 2 H), 1.99 (m, 2 H), 3.04 (m, 2 H), 3.52 (m, 2 H), 3.65 (s, 2 H), 3.71 (q, J=5.61 Hz, 2 H), 4.74 (t, J=6.24 Hz, 2 H), 6.89 (m, 1 H), 7.02 (m, 3 H), 7.14 (m, 2 H), 7.37 (m, 3 H), 7.51 (m, 1 H), 7.68 (m, 1 H), 8.12 (m, 2 H), 9.68 (br s, N H).
Reaction SMILES: C(OC(=O)[NH:7][C:8]1[CH:13]=[C:12]([C:14]([F:17])([F:16])[F:15])[CH:11]=[C:10]([C:18](=[O:34])[N:19]([CH3:33])[C:20]2[CH:21]=[N:22][CH:23]=[CH:24][C:25]=2[C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][C:27]=2[CH3:32])[CH:9]=1)(C)(C)C>CCCCCCC.CCOC(C)=O>[NH2:7][C:8]1[CH:9]=[C:10]([CH:11]=[C:12]([C:14]([F:17])([F:15])[F:16])[CH:13]=1)[C:18]([N:19]([CH3:33])[C:20]1[CH:21]=[N:22][CH:23]=[CH:24][C:25]=1[C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][C:27]=1[CH3:32])=[O:34]
Reactant: Cc1ccccc1-c1ccncc1N(C)C(=O)c1cc(NC(=O)OC(C)(C)C)cc(C(F)(F)F)c1
Solvent: CCCCCCC
Solvent: CCOC(C)=O
Product: Cc1ccccc1-c1ccncc1N(C)C(=O)c1cc(N)cc(C(F)(F)F)c1

Procedure:
The title compound was prepared in analogy to example 85, intermediate a, from {3-[methyl-(4-o-tolyl-pyridin-3-yl)-carbamoyl]-5-trifluoromethyl-phenyl}-carbamic acid tert-butyl ester and using a gradient of n-heptane:EtOAc (100:0 to 0:100) for the chromatographic purification. Colorless solid (94%). MS (ESI): m/z=386.147 [M+H]+.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6](B(O)O)=[CH:5][CH:4]=1.[SH:12][CH2:13][CH:14]([CH2:34][C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1)[C:15]([NH:17][C@H:18]([C:31]([OH:33])=[O:32])[CH2:19][C:20]1[CH:25]=[CH:24][C:23](C2SC=CC=2)=[CH:22][CH:21]=1)=[O:16].C(=O)(O)[O-].[K+]>C1(C)C=CC=CC=1>[SH:12][CH2:13][CH:14]([CH2:34][C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1)[C:15]([NH:17][C@H:18]([C:31]([OH:33])=[O:32])[CH2:19][C:20]1[CH:25]=[CH:24][C:23]([C:6]2[CH:7]=[CH:8][C:3]([O:2][CH3:1])=[CH:4][CH:5]=2)=[CH:22][CH:21]=1)=[O:16]
Reactant: O=C(N[C@@H](Cc1ccc(-c2cccs2)cc1)C(=O)O)C(CS)Cc1ccccc1
Reactant: COc1ccc(B(O)O)cc1
Agent: O=C([O-])O
Agent: [K+]
Solvent: Cc1ccccc1
Product: COc1ccc(-c2ccc(C[C@H](NC(=O)C(CS)Cc3ccccc3)C(=O)O)cc2)cc1

Procedure:
The operation is carried out as in Stage 1 of Example 10 using 4-methoxy benzeneboronic acid instead of thiophene-2-boronic acid, starting with 351.6 mg of methyl ester of N-[(1,1-dimethylethoxy) carbonyl]-O-[(trifluoromethyl) sulphonyl]-L-tyrosine (prepared as indicated in Stage 1 of Example 10), 10 ml of toluene, 250 mg of 4-methoxybenzene boronic acid, 170.3 mg of potassium bicarbonate and 190.17 mg of 5-tetrakis (triphenyl phosphine) Pd(O). In this way 199 mg of expected product is obtained.
Reaction SMILES: C[N:2]([CH:4]=[N:5][C:6]([C:8]1[N:9]([CH3:31])[C:10]([CH2:29][CH3:30])=[C:11]([C:27]#[N:28])[C:12]=1[C:13]1[CH:18]=[CH:17][C:16]([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=2[C:25]#[N:26])=[CH:15][CH:14]=1)=O)C.O.[NH2:33]N>C(O)(=O)C>[C:25]([C:20]1[CH:21]=[CH:22][CH:23]=[CH:24][C:19]=1[C:16]1[CH:17]=[CH:18][C:13]([C:12]2[C:11]([C:27]#[N:28])=[C:10]([CH2:29][CH3:30])[N:9]([CH3:31])[C:8]=2[C:6]2[NH:5][CH:4]=[N:2][N:33]=2)=[CH:14][CH:15]=1)#[N:26]
Reactant: NN
Reactant: CCc1c(C#N)c(-c2ccc(-c3ccccc3C#N)cc2)c(C(=O)N=CN(C)C)n1C
Solvent: O
Solvent: CC(=O)O
Product: CCc1c(C#N)c(-c2ccc(-c3ccccc3C#N)cc2)c(-c2nnc[nH]2)n1C
Temperature: 90 °C
Yield: 38.8 %

Procedure:
Dissolve 4-cyano-3-(2′-cyano-biphenyl-4-yl)-5-ethyl-1-methyl-1H-pyrrole-2-carboxylic acid dimethylaminomethyleneamide (183 mg, 0.45 mmol, prepared in preparation 47) in 2 mL of glacial acetic acid, add hydrazine monohydrate (0.70 mmol) and heat to 90° C. under nitrogen. After 90 minutes cool the reaction slightly, pour into 50 mL of ice-water and stir for twenty minutes. Filter off the resulting solid and rinse with 10 mL of water. Vacuum-dry overnight to give the title compound (66 mg, 39%). MS(ES+, m/e)=379 (M++1).
Reaction SMILES: [C:1]1(=[O:8])[NH:7][CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[CH2:9]=O.[CH:11](=[O:15])[CH:12]([CH3:14])[CH3:13].Cl.[OH-].[Na+]>>[CH3:13][C:12]([CH3:9])([CH:11]=[O:15])[CH2:14][N:7]1[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2][C:1]1=[O:8]
Reactant: C=O
Reactant: CC(C)C=O
Reactant: O=C1CCCCCN1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Product: CC(C)(C=O)CN1CCCCCC1=O
Reaction time: 8 h

Procedure:
In a round-bottom flask with a mounted reflux condenser and under nitrogen atmosphere, 80.5 g (0.71 mol) of ε-caprolactam, 59.3 g (0.71 mol) of 36% aqueous formaldehyde, and 56.4 g (0.78 mol) of isobutyraldehyde were introduced while being stirred vigorously, mixed with 13.4 g of concentrated hydrochloric acid (slight exothermicity). After that, the mixture was heated to boiling in an oil bath (100° C.) and was kept boiling overnight. The clear, yellowish reaction mixture was neutralized with 2N NaOH, extracted twice with ethyl acetate, the combined organic phases were washed with brine, dried on MgSO4 and completely concentrated by evaporation in a rotary evaporator. The yellow oil that was obtained was fractionated in a vacuum. The product distilled at an overhead temperature of 98° C. and a pressure of 4·10−2 mbar. Yield: 20.7 g (15% of theory) of colorless and odorless liquid, which crystallized when left to stand.
Reaction SMILES: [Cl:1][C:2]1[N:10]=[CH:9][CH:8]=[CH:7][C:3]=1[C:4](O)=[O:5].C(N(CC)CC)C.C(OC(Cl)=O)C.[N-:24]=[N+:25]=[N-:26].[Na+]>CC(C)=O.O>[N:24]([C:4]([C:3]1[C:2]([Cl:1])=[N:10][CH:9]=[CH:8][CH:7]=1)=[O:5])=[N+:25]=[N-:26]
Reactant: O=C(O)c1cccnc1Cl
Reactant: [N-]=[N+]=[N-]
Agent: CCOC(=O)Cl
Agent: [Na+]
Solvent: O
Solvent: CC(C)=O
Solvent: CCN(CC)CC
Product: [N-]=[N+]=NC(=O)c1cccnc1Cl
Temperature: 0 °C
Reaction time: 1 h
Yield: 47.4 %

Procedure:
To a solution of 2-chloronicotinic acid (1.0 g, 6.35 mmol) in a mixture of acetone (14 mL) and water (6 mL) was added triethylamine (0.97 mL, 6.98 mmol). The mixture was cooled to 0° C. in a ice-bath. Ethylchloroformate (1.03 g, 9.5 mmol) was then added and the resulting mixture was stirred for 1.0 hour at 0° C. To the mixture was added sodium azide (0.70 g, 10.8 mmol), and the mixture was stirred for another 3 hours. The mixture was concentrated, the residue was diluted with dichloromethane and washed with water. The organic layer was dried over MgSO4 and concentrated to give desired product (550 mg, 48%). 1HNMR (CDCl3) (δ) 8.57 (d, 1H), 8.22 (d, 1H), 7.37 (t, 1H).
Reaction SMILES: [Cl:1][CH2:2][CH2:3][CH2:4][C:5](Cl)=[O:6].[CH3:8][Si:9]([C:12]#[C:13][Si](C)(C)C)([CH3:11])[CH3:10].[Cl-].[Al+3].[Cl-].[Cl-]>C(Cl)Cl>[CH3:8][Si:9]([CH3:11])([CH3:10])[C:12]#[C:13][C:5](=[O:6])[CH2:4][CH2:3][CH2:2][Cl:1]
Reactant: O=C(Cl)CCCCl
Reactant: C[Si](C)(C)C#C[Si](C)(C)C
Agent: [Al+3]
Agent: [Cl-]
Solvent: ClCCl
Product: C[Si](C)(C)C#CC(=O)CCCCl
Reaction time: 0.33 h

Procedure:
To a stirred solution of 16.8 grams of 4-chlorobutyryl chloride and 20.4 grams of bis-trimethylsilylacetylene in 300 ml of dry methylene chloride, cooled in an ice bath, is added powdered anhydrous aluminum chloride, portionwise, over a period of 20 minutes. The mixture is stirred for 5 minutes, then the cooling bath is removed and the mixture stirred at room temperature for 4 hours. The mixture is poured into 500 ml of ice-water. The organic layer is separated, washed with water and brine, dried over anhydrous sodium sulfate and filtered through diatomaceous earth. The mother liquor is evaporated to dryness giving a brownish residue. The residue is Kugelrohr-distilled to give a colorless liquid.
Reaction SMILES: C([O:3][C:4]([CH:6]1[CH:8]([CH:9]=[C:10]([C:17]([F:20])([F:19])[F:18])[C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[C:7]1([CH3:22])[CH3:21])=[O:5])C.[OH-].[Na+]>C(O)C.O>[CH3:21][C:7]1([CH3:22])[CH:8]([CH:9]=[C:10]([C:17]([F:19])([F:20])[F:18])[C:11]2[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=2)[CH:6]1[C:4]([OH:5])=[O:3]
Reactant: CCOC(=O)C1C(C=C(c2ccccc2)C(F)(F)F)C1(C)C
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: CC1(C)C(C=C(c2ccccc2)C(F)(F)F)C1C(=O)O
Yield: 36.8 %

Procedure:
21 g (0.067 mol) of 2,2-dimethyl-3-(2-trifluoromethyl-2-phenyl-vinyl)-cyclopropanecarboxylic acid ethyl ester were dissolved in 100 ml of ethanol, a solution of 3.1 g of sodium hydroxide in 75 ml of water was then added and the mixture was heated to the reflux temperature for 4 hours, while stirring. The ethanol was then distilled off under a waterpump vacuum, the residue was taken up in 300 ml of water and the aqueous mixture was extracted once with 300 ml of methylene chloride. The aqueous phase was separated off, acidified with concentrated hydrochloric acid and then extracted twice with 300 ml of methylene chloride. The organic phases were then separated off, dried over magnesium chloride, and the solvent was distilled off under a waterpump vacuum. Last residues of solvent were removed by brief incipient distillation at a bath temperature of 60° C. under 2 mbar. 7 g (36.8% of theory) of 2,2-dimethyl-3-(2-trifluoromethyl-2-phenyl-vinyl)-cyclopropanecarboxylic acid were then obtained as a very viscous light yellow oil.
Reaction SMILES: C([O:3][C:4]([CH2:6][C:7](=[O:39])[CH2:8][C@H:9]1[CH2:14][CH2:13][C@H:12]([O:15][C:16]([N:18]2[CH2:27][CH2:26][C:25]3[C:20](=[CH:21][CH:22]=[C:23]([NH:28][C:29]([NH:31][C:32]4[CH:37]=[CH:36][CH:35]=[CH:34][C:33]=4[F:38])=[O:30])[CH:24]=3)[CH2:19]2)=[O:17])[CH2:11][CH2:10]1)=O)C.Cl.[NH2:41]O>C(O)C>[OH:3][C:4]1[CH:6]=[C:7]([CH2:8][C@H:9]2[CH2:10][CH2:11][C@H:12]([O:15][C:16]([N:18]3[CH2:27][CH2:26][C:25]4[C:20](=[CH:21][CH:22]=[C:23]([NH:28][C:29]([NH:31][C:32]5[CH:37]=[CH:36][CH:35]=[CH:34][C:33]=5[F:38])=[O:30])[CH:24]=4)[CH2:19]3)=[O:17])[CH2:13][CH2:14]2)[O:39][N:41]=1
Reactant: NO
Reactant: CCOC(=O)CC(=O)C[C@H]1CC[C@H](OC(=O)N2CCc3cc(NC(=O)Nc4ccccc4F)ccc3C2)CC1
Agent: Cl
Solvent: CCO
Product: O=C(Nc1ccc2c(c1)CCN(C(=O)O[C@H]1CC[C@H](Cc3cc(O)no3)CC1)C2)Nc1ccccc1F
Temperature: 80 °C

Procedure:
To a mixture of trans-6-[3-(2-fluoro-phenyl)-ureido]-3,4-dihydro-1H-isoquinoline-2-carboxylic acid 4-(3-ethoxycarbonyl-2-oxo-propyl)-cyclohexyl ester (127 mg) obtained in Example (42a) and ethanol (3 mL), hydroxylamine hydrochloride (164 mg) was added at room temperature in the same way as in Example (42b). The reaction mixture was heated at 80° C. for 12 hours and concentrated. The residue was purified by column chromatography (dichloromethane/ethyl acetate). The obtained solid was purified by PTLC (dichloromethane/ethyl acetate=1:1) to obtain the title compound (34 mg, 28%) as an orange solid.