Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5](I)=[C:4]([O:9][CH3:10])[CH:3]=1.[N:11]1([C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])[CH2:16][CH2:15][NH:14][CH2:13][CH2:12]1.CC(C)([O-])C.[Na+].CC1(C)C2C(=C(P(C3C=CC=CC=3)C3C=CC=CC=3)C=CC=2)OC2C(P(C3C=CC=CC=3)C3C=CC=CC=3)=CC=CC1=2>C1(C)C=CC=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.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([N:14]2[CH2:13][CH2:12][N:11]([C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])[CH2:16][CH2:15]2)=[C:4]([O:9][CH3:10])[CH:3]=1
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Reactant: COc1cc(Br)ccc1I
Agent: [Pd]
Agent: CC(C)(C)[O-]
Agent: CC1(C)c2cccc(P(c3ccccc3)c3ccccc3)c2Oc2c(P(c3ccccc3)c3ccccc3)cccc21
Solvent: Cc1ccccc1
Product: COc1cc(Br)ccc1N1CCN(C(=O)OC(C)(C)C)CC1
Temperature: 45 °C
Reaction time: 18 h

Procedure:
4-bromo-1-iodo-2-methoxybenzene (647 mg, 2.07 mmol), tert-butyl piperazine-1-carboxylate (350 mg, 1.88 mmol), sodium tert-butoxide (541 mg, 5.6 mmol), Pd2(dba)3 (52 mg, 0.056 mmol) and XantPhos (98 mg, 0.17 mmol) were taken up in toluene (18 mL) under Ar. The reaction mixture was stirred for 18 h and was then heated to 45° C. After an additional 2.5 h, the temperature was increased to 65° C. After an additional 3 h, the reaction mixture was cooled and partitioned between water and EtOAc. The phases were separated, and the organic phase was dried over Na2SO4, filtered, and concentrated. The crude residue was purified by silica gel chromatography (0-25% EtOAc in hexanes) to afford tert-butyl 4-(4-bromo-2-methoxyphenyl)piperazine-1-carboxylate 7.09. LCMS-ESI+ (m/z): [M-41]+ calcd for C16H24BrN2O3: 371.1; found: 370.8.
Reaction SMILES: [CH2:1]([C@@H:8]1[CH2:12][O:11][C:10](=[O:13])[N:9]1[C:14]([C@@H:16]([CH2:21][CH:22]=[CH2:23])[CH2:17][C:18]([OH:20])=O)=[O:15])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(Cl)CCl.C1C=CC2N(O)N=NC=2C=1.CCN(C(C)C)C(C)C.[Cl:47][C:48]1[CH:55]=[CH:54][C:51]([CH2:52][NH2:53])=[CH:50][CH:49]=1>ClCCl.CN(C1C=CN=CC=1)C>[CH2:1]([C@@H:8]1[CH2:12][O:11][C:10](=[O:13])[N:9]1[C:14]([C@@H:16]([CH2:21][CH:22]=[CH2:23])[CH2:17][C:18]([NH:53][CH2:52][C:51]1[CH:54]=[CH:55][C:48]([Cl:47])=[CH:49][CH:50]=1)=[O:20])=[O:15])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: NCc1ccc(Cl)cc1
Reactant: C=CC[C@@H](CC(=O)O)C(=O)N1C(=O)OC[C@H]1Cc1ccccc1
Agent: CN(C)c1ccncc1
Agent: On1nnc2ccccc21
Solvent: ClCCCl
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: C=CC[C@@H](CC(=O)NCc1ccc(Cl)cc1)C(=O)N1C(=O)OC[C@H]1Cc1ccccc1
Yield: 77.3 %

Procedure:
A solution of compound 3a (0.402 g, 1.3 mmol), EDC (0.364 g, 1.9 mmol), HOBT (0.256 g, 1.9 mmol), and Hunig's base (0.662 mL, 3.8 mmol) in dichloromethane (17 mL) was cooled to 0° C. and stirred for half an hour. To this solution 4-chlorobenzylamine (0.174 mL, 1.43 mmol) and a catalytic amount of DMAP were added. The reaction was stirred overnight and the reaction progress was monitored by TLC. The dichloromethane was removed in vacuo and the reaction mixture quenched with aqueous NH4Cl. The solution was washed with water and brine, dried over Na2SO4, and concentrated under reduced pressure to give well formed white crystals of 4a (0.443 g, 79%). 1H NMR (500 MHz, CDCl3): δ ppm 7.31-7.36 (m, 2H) 7.21-7.29 (m, 5H) 7.17-7.21 (m, 2H) 6.09 (t, J=5.6 Hz, 1H) 5.73-5.82 (m, 1H) 5.04-5.10 (m, 2H) 4.65 (ddd, J=13.3, 6.7, 3.4 Hz 1H) 4.41 (dd, J=15.2, 5.9 Hz, 1H) 4.34 (dd, J=14.9, 5.9 Hz, 1H) 4.23-4.30 (m, 1H) 4.23-4.30 (m, 1H) 4.14-4.18 (m, 2H) 3.28 (dd, J=13.7, 2.9 Hz, 1H) 2.66-2.80 (m, 2H) 2.41-2.51 (m, 2H) 2.22-2.29 (m, 1H); 13C NMR (126 MHz, CDCl3): δ 175.1, 171.0, 153.4, 137.1, 135.7, 134.8, 133.4, 129.7, 129.3, 129.1, 129.0, 127.5, 118.1, 66.3, 55.7, 43.1, 40.1, 38.0, 37.8, 36.3. HRMS calcd. for C24H25ClN2O4 (M+H) m/z 441.1581, found 441.1581.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([C:16]([NH:18][CH2:19][C:20]2[C:21](=[O:28])[NH:22][C:23]([CH3:27])=[CH:24][C:25]=2[CH3:26])=[O:17])[C:5]2[CH:6]=[N:7][N:8]([CH:11]3[CH2:15][CH2:14][CH2:13][CH2:12]3)[C:9]=2[CH:10]=1.[CH:29]1([S:32]([OH:34])=[O:33])[CH2:31][CH2:30]1.CNCCNC.CNCCNC>FC(F)(F)S([O-])(=O)=O.[Cu+2].FC(F)(F)S([O-])(=O)=O.CS(C)=O>[CH:11]1([N:8]2[C:9]3[CH:10]=[C:2]([S:32]([CH:29]4[CH2:31][CH2:30]4)(=[O:34])=[O:33])[CH:3]=[C:4]([C:16]([NH:18][CH2:19][C:20]4[C:21](=[O:28])[NH:22][C:23]([CH3:27])=[CH:24][C:25]=4[CH3:26])=[O:17])[C:5]=3[CH:6]=[N:7]2)[CH2:15][CH2:14][CH2:13][CH2:12]1
Reactant: O=S(O)C1CC1
Reactant: Cc1cc(C)c(CNC(=O)c2cc(Br)cc3c2cnn3C2CCCC2)c(=O)[nH]1
Agent: [Cu+2]
Agent: CNCCNC
Agent: O=S(=O)([O-])C(F)(F)F
Solvent: CS(C)=O
Product: Cc1cc(C)c(CNC(=O)c2cc(S(=O)(=O)C3CC3)cc3c2cnn3C2CCCC2)c(=O)[nH]1
Yield: 60.8 %

Procedure:
To a 10-mL microwave tube were added 6-bromo-1-cyclopentyl-N-[(4,6-dimethyl-2-oxo-1,2-dihydro-3-pyridinyl)methyl]-1H-indazole-4-carboxamide (70 mg, 0.158 mmol), cyclopropanesulfinic acid (40.8 mg, 0.316 mmol), dimethyl sulfoxide (3 mL), N,N′-dimethyl-1,2-ethanediamine methyl[2-(methylamino)ethyl]amine (55.7 mg, 0.632 mmol), and copper(II) trifluoromethanesulfonate (57.1 mg, 0.158 mmol), and the mixture was degassed for 5 min by bubbling nitrogen. The tube was sealed and the mixture irradiated at 120° C. (microwave) for 3 h. The mixture was filtered and the DMSO solution was purified using reverse-phase HPLC to give 45 mg of product. The product was collected as an off-white solid. 1H NMR (400 MHz, DMSO-d6) δ ppm 1.00-1.12 (m, 2H), 1.15-1.31 (m, 2H), 1.67-1.79 (m, 2H), 1.84-1.94 (m, 2H), 1.96-2.08 (m, 2H), 2.12-2.28 (m, 8H), 2.93-3.05 (m, 1H), 4.38 (d, J=5.05 Hz, 2H), 5.43 (quin, J=7.01 Hz, 1H), 5.90 (s, 1H), 8.01 (d, J=1.26 Hz, 1H), 8.44 (s, 1H), 8.52 (s, 1H), 8.83 (t, J=4.93 Hz, 1H), 11.57 (s, 1H); LCMS: (M+H)+=469.0
Reaction SMILES: [CH2:1]([O:3][C:4]1[C:13]([NH:14][C:15](=[O:23])OC2C=CC=CC=2)=[N:12][C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[N:5]=1)[CH3:2].[F:24][C:25]1[CH:26]=[C:27]([N:32]2[CH2:37][CH2:36][NH:35][CH2:34][CH2:33]2)[CH:28]=[C:29]([F:31])[CH:30]=1>>[CH2:1]([O:3][C:4]1[C:13]([NH:14][C:15]([N:35]2[CH2:34][CH2:33][N:32]([C:27]3[CH:26]=[C:25]([F:24])[CH:30]=[C:29]([F:31])[CH:28]=3)[CH2:37][CH2:36]2)=[O:23])=[N:12][C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[N:5]=1)[CH3:2]
Reactant: CCOc1nc2ccccc2nc1NC(=O)Oc1ccccc1
Reactant: Fc1cc(F)cc(N2CCNCC2)c1
Product: CCOc1nc2ccccc2nc1NC(=O)N1CCN(c2cc(F)cc(F)c2)CC1
Yield: 78.6 %

Procedure:
Phenyl N-(2-ethoxyquinoxalin-3-yl)carbamate and 1-(3,5-difluorophenyl)piperazine were reacted by the same way with the example 36 to obtain the titled compound.
Reaction SMILES: [H-].[Na+].Cl[CH:4](Cl)[C:5]([OH:7])=[O:6].[Cl:9][C:10]1[CH:15]=[CH:14][C:13]([C:16]([CH3:24])([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[OH:17])=[C:12]([OH:25])[CH:11]=1.[OH-].[Na+]>O1CCOCC1>[Cl:9][C:10]1[CH:15]=[CH:14][C:13]2[C:16]([CH3:24])([C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)[O:17][CH:4]([C:5]([OH:7])=[O:6])[O:25][C:12]=2[CH:11]=1
Reactant: O=C(O)C(Cl)Cl
Reactant: CC(O)(c1ccccc1)c1ccc(Cl)cc1O
Agent: [H-]
Agent: [Na+]
Agent: [OH-]
Solvent: C1COCCO1
Product: CC1(c2ccccc2)OC(C(=O)O)Oc2cc(Cl)ccc21
Temperature: 95 °C
Yield: 109.4 %

Procedure:
A mixture of 9.85 g of sodium hydride as a 50% oil suspension, 100 ml of dioxane, 0.73 g of dibenzo-18-courone-6 was stirred and a solution of 11.31 g of dichloroacetic acid in 120 ml of dioxane was added thereto at room temperature with stirring. Then, a solution of 14.550 g of 4-chloro-2-hydroxy-α-methyl-α-phenyl benzene methanol in 200 ml dioxane was added thereto dropwise and the mixture was then refluxed for 6 hours at 95° C. and then returned to room temperature. The reaction mixture was poured into ice and 10 ml of 2 N sodium hydroxide were added thereto. The aqueous phase was washed with 300 ml of ether, was acidified with 20 ml of concentrated hydrochloric acid and then was extracted 3 times with 250 ml of ether. The ether extracts were washed twice with 100 ml of water and the acid of the organic phase was extracted twice with 250 ml of a 5% aqueous solution of sodium bicarbonate. The aqueous phase was washed with 100 ml of ether and was acidified again with 50 ml of concentrated hydrochloric acid. The acid was again extracted 4 times with 250 ml of ether, and the decanted organic phase was washed 3 times with 100 ml of water, dried over magnesium sulfate, treated with activated carbon, filtered and evaporated to dryness under reduced pressure to obtain 19.5 g of 7-chloro-4-methyl-4-phenyl-[4H]-1,3-benzodioxin-2-carboxylic acid (mixture of two racemates of diastereoisomers).
Reaction SMILES: [CH2:1]([C:3]1[CH:24]=[CH:23][CH:22]=[CH:21][C:4]=1[CH2:5][NH:6][C:7]1[C:8]2[N:9]([C:16]([CH3:20])=[C:17]([CH3:19])[N:18]=2)[CH:10]=[C:11]([C:13](N)=[O:14])[CH:12]=1)[CH3:2].[OH-:25].[Na+]>C(O)C>[CH2:1]([C:3]1[CH:24]=[CH:23][CH:22]=[CH:21][C:4]=1[CH2:5][NH:6][C:7]1[C:8]2[N:9]([C:16]([CH3:20])=[C:17]([CH3:19])[N:18]=2)[CH:10]=[C:11]([C:13]([OH:14])=[O:25])[CH:12]=1)[CH3:2]
Reactant: CCc1ccccc1CNc1cc(C(N)=O)cn2c(C)c(C)nc12
Reactant: [OH-]
Agent: [Na+]
Solvent: CCO
Product: CCc1ccccc1CNc1cc(C(=O)O)cn2c(C)c(C)nc12
Yield: 99.8 %

Procedure:
8-(2-ethylbenzylamino)-2,3-dimethylimidazo[1,2-a]pyridine-6-carboxamide (1.0 g, 0.0031 mol) and sodium hydroxide (1.2 g, 0.031 mol) were solved in ethanol (95%)(30 ml) and was refluxed overnight. The solvent was evaporated under reduced pressure and to the residue was added water. The pH was adjusted to 7 by addition of conc HCl (2.6 ml) and the solid that precipitated was isolated by filtration, washed with water and dried to give 1.0 g (99%) of the title compound.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([C:8]2[CH:13]=[CH:12][C:11]([CH2:14][C@H:15]([NH:19][C:20]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21])[C:16]([OH:18])=[O:17])=[CH:10][CH:9]=2)[CH:5]=[C:4]([O:27][C@@H:28]([C:33]2[CH:38]=[CH:37][C:36](Br)=[CH:35][CH:34]=2)[C:29]([F:32])([F:31])[F:30])[N:3]=1.[F:40][C:41]([F:52])([F:51])[C:42]1[CH:47]=[CH:46][N:45]=[CH:44][C:43]=1B(O)O.C(#N)C.C(=O)([O-])[O-].[Na+].[Na+]>Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.O>[NH2:1][C:2]1[N:7]=[C:6]([C:8]2[CH:13]=[CH:12][C:11]([CH2:14][C@H:15]([NH:19][C:20]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21])[C:16]([OH:18])=[O:17])=[CH:10][CH:9]=2)[CH:5]=[C:4]([O:27][C@@H:28]([C:33]2[CH:38]=[CH:37][C:36]([C:43]3[CH:44]=[N:45][CH:46]=[CH:47][C:42]=3[C:41]([F:52])([F:51])[F:40])=[CH:35][CH:34]=2)[C:29]([F:32])([F:31])[F:30])[N:3]=1
Reactant: OB(O)c1cnccc1C(F)(F)F
Reactant: CC(C)(C)OC(=O)N[C@@H](Cc1ccc(-c2cc(O[C@@H](c3ccc(Br)cc3)C(F)(F)F)nc(N)n2)cc1)C(=O)O
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: CC#N
Product: CC(C)(C)OC(=O)N[C@@H](Cc1ccc(-c2cc(O[C@@H](c3ccc(-c4cnccc4C(F)(F)F)cc3)C(F)(F)F)nc(N)n2)cc1)C(=O)O
Temperature: 150 °C
Yield: 12.8 %

Procedure:
A microwave vial (2 ml) was charged with (S)-3-(4-{2-amino-6-[(S)-1-(4-bromo-phenyl)-2,2,2-trifluoro-ethoxy]-pyrimidin-4-yl}-phenyl)-2-tert-butoxycarbonylamino-propionic acid (139 mg, 0.23 mmol), 4-trifluoromethylpyridine-3-boronic acid (61 mg, 0.3 mmol), 1 ml of acetonitrile, and 0.7 ml of water. To this mixture was added 0.4 ml of aqueous sodium carbonate (1M), followed by 14 mg of dichlorobis(triphenylphosphine)-palladium(II). The reaction vessel was sealed and heated to 150° C. for 5 minutes with microwave irradiation. After cooling, the reaction mixture was evaporated to dryness, the residue was dissolved in 2.5 ml of methanol and was purified by preparative HPLC to give 20 mg of (S)-3-[4-(2-amino-6-{(S)-2,2,2-trifluoro-1-[4-(4-trifluoromethyl-pyridin-3-yl)-phenyl]-ethoxy}-pyrimidin-4-yl)-phenyl]-2-tert butoxycarbonylamino-propionic acid
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][C:6]([OH:10])=[CH:7][CH:8]=2)[CH:3]=[N:2]1.Br[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=1[N+:18]([O-:20])=[O:19].C(=O)([O-])[O-].[K+].[K+].O>CN(C)C=O>[N+:18]([C:13]1[CH:14]=[CH:15][CH:16]=[CH:17][C:12]=1[O:10][C:6]1[CH:5]=[C:4]2[C:9](=[CH:8][CH:7]=1)[NH:1][N:2]=[CH:3]2)([O-:20])=[O:19]
Reactant: O=[N+]([O-])c1ccccc1Br
Reactant: Oc1ccc2[nH]ncc2c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: O=[N+]([O-])c1ccccc1Oc1ccc2[nH]ncc2c1
Temperature: 120 °C
Reaction time: 6 h
Yield: 10 %

Procedure:
To a solution of the 1H-indazol-5-ol (300 mg, 2.24 mmol) obtained in Reference Example 4 in N,N-dimethylformamide (6 ml) were added 2-bromonitrobenzene (497 mg, 2.46 mmol) and potassium carbonate (402 mg, 2.91 mmol), and the resulting mixture was heated to 120° C. After 6 hours, the mixture was poured into water (20 ml) and extracted with ethyl acetate (20 ml×2). The organic layer was dried over anhydrous magnesium sulfate. The organic layer dried was concentrated under reduced pressure and the resulting residue was purified by a silica gel column chromatography (eluent: hexane/ethyl acetate) to obtain 5-(2-nitrophenoxy)-1H-indazole (57 mg, 10%).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[NH:8][NH2:9].[C:10]1([C:16](=O)[C:17]([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)=[O:18])[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1>>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[NH:8][N:9]=[C:16]([C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)[C:17]([C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)=[O:18]
Reactant: O=C(C(=O)c1ccccc1)c1ccccc1
Reactant: NNc1ccccc1Cl
Product: O=C(C(=NNc1ccccc1Cl)c1ccccc1)c1ccccc1

Procedure:
1,2-Diphenylethane-1,2-dione (2-chlorophenyl)hydrazone was prepared from 2-chlorophenyl hydrazine and 1,2-diphenyl-ethane-1,2-dione according to the procedure of Step 1 Example 2. MS m/z 335;
Reaction SMILES: [CH3:1][C:2]([CH3:13])([O:4][C:5]([NH:7][CH2:8][C:9]([O:11][CH3:12])=[O:10])=[O:6])[CH3:3].[H-].[Na+].[Br:16][CH2:17][C:18]1[CH:23]=[CH:22][CH:21]=[C:20]([CH2:24]Br)[CH:19]=1>O1CCCC1>[Br:16][CH2:17][C:18]1[CH:19]=[C:20]([CH2:24][N:7]([C:5]([O:4][C:2]([CH3:13])([CH3:1])[CH3:3])=[O:6])[CH2:8][C:9]([O:11][CH3:12])=[O:10])[CH:21]=[CH:22][CH:23]=1
Reactant: BrCc1cccc(CBr)c1
Reactant: COC(=O)CNC(=O)OC(C)(C)C
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: COC(=O)CN(Cc1cccc(CBr)c1)C(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
A solution of the product from step (i) (5 g) in tetrahydrofuran (10 ml) was added dropwise to a suspension of sodium hydride (1.1 g) in tetrahydrofuran (40 ml) at 0° C. The mixture was warmed to room temperature and stirred for 30 minutes then added dropwise to a solution of α,α′-dibromo-m-xylene (10.56 g) in tetrahydrofuran (40 ml). The mixture was stirred at room temperature for 2 hours, quenched with aqueous ammonium chloride and partitioned between ethyl and acetate and water. The organic phase was dried (MgSO4) and evaporated. Purified by chromatography eluting with 10% ethyl acetate in isohexane. Yield 2.8 g.
Reaction SMILES: [OH:1]/[N:2]=[C:3](/[C:32]1[CH:37]=[CH:36][C:35](=[O:38])[N:34]([CH3:39])[CH:33]=1)\[CH2:4][C@H:5]([C:13]1[CH:18]=[CH:17][C:16]([CH:19]2[CH2:24][CH2:23][N:22](C(OC(C)(C)C)=O)[CH2:21][CH2:20]2)=[CH:15][CH:14]=1)[C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=1[CH3:12].Cl.O1CCOCC1.C(=O)([O-])O.[Na+]>C(O)C>[OH:1]/[N:2]=[C:3](/[C:32]1[CH:37]=[CH:36][C:35](=[O:38])[N:34]([CH3:39])[CH:33]=1)\[CH2:4][C@H:5]([C:13]1[CH:18]=[CH:17][C:16]([CH:19]2[CH2:20][CH2:21][NH:22][CH2:23][CH2:24]2)=[CH:15][CH:14]=1)[C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=1[CH3:12]
Reactant: Cc1ccccc1[C@H](C/C(=N\O)c1ccc(=O)n(C)c1)c1ccc(C2CCN(C(=O)OC(C)(C)C)CC2)cc1
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCO
Solvent: C1COCCO1
Product: Cc1ccccc1[C@H](C/C(=N\O)c1ccc(=O)n(C)c1)c1ccc(C2CCNCC2)cc1
Yield: 49.3 %

Procedure:
(R,E)-tert-Butyl 4-(4-(3-(hydroxyimino)-3-(1-methyl-6-oxo-1,6-dihydropyridin-3-yl)-1-o-tolylpropyl)phenyl)piperidine-1-carboxylate (example 506, 30 mg) was dissolved in ethanol (0.8 mL) and hydrochloric acid solution (4.0 M in 1,4-dioxane (170 μl, 680 μmol) was added, then after 14 h the reaction mixture was poured onto aq. sat. sodium hydrogencarbonate solution and extracted 2 times with dichloromethane. The combined organic layers were washed with brine dried over magnesium sulfate, filtered and evaporated. The residue was triturated with ethyl acetate/heptane to afford the title compound (12 mg, 41%). Light yellow solid; MS (ESI+): m/z=: 430.5 [M+H]+).
Reaction SMILES: C(=O)([O-])[O-].[Na+].[Na+].[ClH:7].[N:8]12[CH2:15][CH2:14][CH:11]([CH2:12][CH2:13]1)[C@@H:10]([NH:16][C:17]([C:19]1[O:20][C:21]3[C:27](Br)=[CH:26][CH:25]=[CH:24][C:22]=3[CH:23]=1)=[O:18])[CH2:9]2.[OH:29][CH2:30][C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][C:32]=1B(O)O>CN(C=O)C.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2]>[ClH:7].[N:8]12[CH2:15][CH2:14][CH:11]([CH2:12][CH2:13]1)[C@@H:10]([NH:16][C:17]([C:19]1[O:20][C:21]3[C:27]([C:32]4[CH:33]=[CH:34][CH:35]=[CH:36][C:31]=4[CH2:30][OH:29])=[CH:26][CH:25]=[CH:24][C:22]=3[CH:23]=1)=[O:18])[CH2:9]2
Reactant: OCc1ccccc1B(O)O
Reactant: O=C(N[C@H]1CN2CCC1CC2)c1cc2cccc(Br)c2o1
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: Cl
Solvent: CN(C)C=O
Product: O=C(N[C@H]1CN2CCC1CC2)c1cc2cccc(-c3ccccc3CO)c2o1
Temperature: 90 °C

Procedure:
0.64 ml of 2 M aqueous sodium carbonate solution and 17.5 mg (0.02 mmol) of PdCl2(dppf) are added to a mixture of 150 mg (0.43 mmol) of N-[(3R)-1-azabicyclo[2.2.2]oct-3-yl]-7-bromo-1-benzofuran-2-carboxamide hydrochloride (Example 30A) and 65.3 mg (0.43 mmol) of 2-(hydroxymethyl)phenylboronic acid in 1.5 ml of DMF. The reaction mixture is heated at 90° C. for 18 h and then filtered through kieselguhr and evaporated to dryness. Purification of the crude product by preparative HPLC, subsequent addition of a 3:1 mixture of acetonitrile and 1N hydrochloric acid, concentration and drying under high vacuum result in 13 mg (7.1% of theory) of the title compound.
Reaction SMILES: [CH3:1][C:2]1([C:7]2[O:11][C:10]([CH2:12][N:13]3[CH:17]=[C:16]([NH2:18])[CH:15]=[N:14]3)=[CH:9][CH:8]=2)[O:6]CCO1.[F:19][C:20]([F:37])([F:36])[O:21][C:22]1[CH:27]=[CH:26][C:25]([C:28]2[O:32][CH:31]=[N:30][C:29]=2[C:33](O)=[O:34])=[CH:24][CH:23]=1>>[C:2]([C:7]1[O:11][C:10]([CH2:12][N:13]2[CH:17]=[C:16]([NH:18][C:33]([C:29]3[N:30]=[CH:31][O:32][C:28]=3[C:25]3[CH:24]=[CH:23][C:22]([O:21][C:20]([F:36])([F:19])[F:37])=[CH:27][CH:26]=3)=[O:34])[CH:15]=[N:14]2)=[CH:9][CH:8]=1)(=[O:6])[CH3:1]
Reactant: CC1(c2ccc(Cn3cc(N)cn3)o2)OCCO1
Reactant: O=C(O)c1ncoc1-c1ccc(OC(F)(F)F)cc1
Product: CC(=O)c1ccc(Cn2cc(NC(=O)c3ncoc3-c3ccc(OC(F)(F)F)cc3)cn2)o1

Procedure:
Following general procedure B followed by T, starting from 1-[5-(2-methyl-[1,3]dioxolan-2-yl)-furan-2-ylmethyl]-1H-pyrazol-4-ylamine and 5-(4-trifluoromethoxy-phenyl)-oxazole-4-carboxylic acid. LC-MS-conditions 01b: tR=1.01 min; [M+H]+=461.11.
Reaction SMILES: [CH:1]([C:3]1[CH:8]=[CH:7][C:6]([CH2:9][CH2:10][C:11]([OH:13])=[O:12])=[CH:5][CH:4]=1)=O.[CH3:14][C:15]1([CH3:28])[C@@H:17]2[CH2:18][C:19]3[C:23]([C@H:16]12)=[C:22]([CH3:24])[S:21][C:20]=3[C:25](=[O:27])[CH3:26].[OH-].[K+].Cl>CO.O>[O:27]=[C:25]([C:20]1[S:21][C:22]([CH3:24])=[C:23]2[C:19]=1[CH2:18][C@H:17]1[C:15]([CH3:28])([CH3:14])[C@H:16]12)[CH:26]=[CH:1][C:3]1[CH:8]=[CH:7][C:6]([CH2:9][CH2:10][C:11]([OH:13])=[O:12])=[CH:5][CH:4]=1
Reactant: O=Cc1ccc(CCC(=O)O)cc1
Reactant: CC(=O)c1sc(C)c2c1C[C@@H]1[C@H]2C1(C)C
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: Cc1sc(C(=O)C=Cc2ccc(CCC(=O)O)cc2)c2c1[C@H]1[C@@H](C2)C1(C)C
Yield: 41.1 %

Procedure:
A solution of 3-(4-formyl-phenyl)-propionic acid (142 mg, 0.80 mmol), (1aS,5aR)-1-(1,1,2-trimethyl-1,1a,5,5a-tetrahydro-3-thia-cyclopropa[a]pentalen-4-yl)-ethanone (176 mg, 0.80 mmol), KOH (2.8 g, 50 mmol) in methanol (25 mL) is stirred at 70° C. for 1 h. The reaction mixture is diluted with water (400 mL) and acidified by adding 2 N aq. HCl. The mixture is extracted twice with DCM, the organic extracts are combined, dried over Na2SO4 and evaporated. The crude product is purified by prep. HPLC (Waters Xterra MS18 30×75 mm, 10 to 95% acetonitrile in water containing 0.5% formic acid) to give 3-{4-[3-oxo-3-((1aS,5aR)-1,1,2-trimethyl-1,1a,5,5a-tetrahydro-3-thia-cyclopropa[a]pentalen-4-yl)-propenyl]-phenyl}-propionic acid (125 mg) as yellow resin; LC-MS: tR=1.07 min, [M+1]+=381.18.
Reaction SMILES: [CH3:1][C:2]1[CH:17]=[CH:16][C:5]2[N:6]=[C:7]([C:10]3[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=3)[CH2:8][O:9][C:4]=2[CH:3]=1.FC(F)(F)C(O)=O.[N:25](OCCCC)=[O:26]>C(OCC)C>[CH3:1][C:2]1[CH:17]=[CH:16][C:5]2[N:6]([N:25]=[O:26])[CH:7]([C:10]3[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=3)[CH2:8][O:9][C:4]=2[CH:3]=1
Reactant: CCCCON=O
Reactant: Cc1ccc2c(c1)OCC(c1ccccc1)=N2
Solvent: CCOCC
Solvent: O=C(O)C(F)(F)F
Product: Cc1ccc2c(c1)OCC(c1ccccc1)N2N=O
Temperature: 5 °C
Reaction time: 1 h
Yield: 91.4 %

Procedure:
To a mixture of 7-methyl-3-phenyl-2H-1,4-benzoxazine (22.5 g, 99.87 mmol) in ethyl ether (300 mL) is added trifluoroacetic acid (7.7 mL, 99.87 mmol). The resulting solution is chilled to 5° C. in an ice bath and n-butyl nitrite (12.26 mL, 99.87 mmol) is added dropwise. The mixture is stirred for 1 h; solids formed during the reaction. The solids are collected by filtration and washed with ether. The filtrates are partitioned between ether and water and the organic layers are washed three times with water (500 mL), dried over magnesium sulfate, and concentrated to dryness. The combined solids gave 23.22 g (97%) of 7-methyl-4-nitroso-3-phenyl-3,4-dihydro-2H-1,4-benzoxazine.
Reaction SMILES: [C:1]1([C:7]2[C:16]3[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=3)[CH:10]=[C:9]([CH2:17][CH2:18][C:19]([OH:21])=[O:20])[N:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.S(=O)(=O)(O)O.N.[CH2:28](O)[CH3:29]>O>[C:1]1([C:7]2[C:16]3[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=3)[CH:10]=[C:9]([CH2:17][CH2:18][C:19]([O:21][CH2:28][CH3:29])=[O:20])[N:8]=2)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: O=C(O)CCc1cc2ccccc2c(-c2ccccc2)n1
Reactant: CCO
Agent: N
Agent: O=S(=O)(O)O
Solvent: O
Product: CCOC(=O)CCc1cc2ccccc2c(-c2ccccc2)n1

Procedure:
1-Phenyl-3-isoquinolinepropanoic acid (2 g) and concentrated sulphuric acid (2 cc) in absolute ethanol (20 cc) are stirred for 20 hours at room temperature (approximately 20° C.). The mixture is diluted with water (100 cc), alkalinised to pH 9 with concentrated ammonia solution and extracted with methylene chloride (3×50 cc). The organic phase is dried over magnesium sulphate, filtered and evaporated to dryness under reduced pressure. Ethyl 1-phenyl-3-isoquinolinepropionate (1.9 g) is obtained in the form of an oil, the proton NMR spectrum of which, in deuterated chloroform, has the following characteristics: