Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]12([C:11]3[CH:12]=[C:13]([C:25]4[CH:37]=[CH:36][C:28](/[CH:29]=[CH:30]/[C:31]([O:33][CH2:34][CH3:35])=[O:32])=[CH:27][C:26]=4[CH3:38])[CH:14]=[CH:15][C:16]=3[O:17]CC3C=CC=CC=3)[CH2:10][CH:5]3[CH2:6][CH:7]([CH2:9][CH:3]([CH2:4]3)[CH2:2]1)[CH2:8]2.B(Br)(Br)Br.CCOC(C)=O.CCCCCC>C(Cl)Cl>[C:1]12([C:11]3[CH:12]=[C:13]([C:25]4[CH:37]=[CH:36][C:28](/[CH:29]=[CH:30]/[C:31]([O:33][CH2:34][CH3:35])=[O:32])=[CH:27][C:26]=4[CH3:38])[CH:14]=[CH:15][C:16]=3[OH:17])[CH2:8][CH:7]3[CH2:9][CH:3]([CH2:4][CH:5]([CH2:6]3)[CH2:10]1)[CH2:2]2
Reactant: CCOC(=O)/C=C/c1ccc(-c2ccc(OCc3ccccc3)c(C34CC5CC(CC(C5)C3)C4)c2)c(C)c1
Agent: BrB(Br)Br
Solvent: CCCCCC
Solvent: ClCCl
Solvent: CCOC(C)=O
Product: CCOC(=O)/C=C/c1ccc(-c2ccc(O)c(C34CC5CC(CC(C5)C3)C4)c2)c(C)c1
Reaction time: 2 h

Procedure:
A mixture of 1.44 g (2.84 mmol) of ethyl (E)-4-[3-(1-adamantyl)-4-benzyloxyphenyl]-3-methylcinnamate was stirred in 10 ml of CH2Cl2 at −78° C. under Ar while 8.0 ml of 1.0 M BBr3 in CH2Cl2 was added slowly over a period of 0.5 hour. The reaction mixture was stirred for 2 hours more, at which time the reaction was complete. The mixture was extracted with EtOAc, washed with brine and water, dried (MgSO4), filtered, and concentrated. Flash column chromatography (20% EtOAc/hexane) yielded a pale-yellow solid (0.86 g, 73%: m.p. 193-195° C.; Rf0.47 (20% EtOAc/hexane); 1H NMR (300 MHz, CDCl3) δ 1.78, 2.14 (2 s, 12, AdCH2), 2.09 (s, 3, AdCH), 1.35 (t, J=7.2 Hz, 3 CH3), 2.31 (s, 3, ArCH3), 4.27 (q, J=7.6 Hz, 2, CH2), 4.94 (s, 1, OH), 6.46 (d, J=16.4 Hz, 1, HC═CCO), 6.71 (d, J=8.4 Hz, 1, ArH), 7.03 (dd, J=8.4, 1.6 Hz, 1, ArH), 7.16 (d, J=2.8 Hz, 1, ArH), 7.25 (s, 1, ArH), 7.39 (dd, J=9.2, 2.4 Hz, 1, ArH), 7.41 (s, 1, ArH), 7.71 ppm (d, J=16.0 Hz, 1, C═CHCO).
Reaction SMILES: [OH:1][CH:2]1[CH2:20][CH:19]2[N:4]([C:5](=[O:39])[CH:6]([NH:31][C:32]([O:34][C:35]([CH3:38])([CH3:37])[CH3:36])=[O:33])[CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH:12]=[CH:13][CH:14]3[C:16]([C:22]([NH:24][S:25]([CH:28]4[CH2:30][CH2:29]4)(=[O:27])=[O:26])=[O:23])([NH:17][C:18]2=[O:21])[CH2:15]3)[CH2:3]1.[C:40](Cl)(=[O:47])[C:41]1[CH:46]=[CH:45][CH:44]=[N:43][CH:42]=1>>[C:40]([O:1][CH:2]1[CH2:20][CH:19]2[N:4]([C:5](=[O:39])[CH:6]([NH:31][C:32]([O:34][C:35]([CH3:36])([CH3:38])[CH3:37])=[O:33])[CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH:12]=[CH:13][CH:14]3[C:16]([C:22]([NH:24][S:25]([CH:28]4[CH2:30][CH2:29]4)(=[O:27])=[O:26])=[O:23])([NH:17][C:18]2=[O:21])[CH2:15]3)[CH2:3]1)(=[O:47])[C:41]1[CH:46]=[CH:45][CH:44]=[N:43][CH:42]=1
Reactant: CC(C)(C)OC(=O)NC1CCCCCC=CC2CC2(C(=O)NS(=O)(=O)C2CC2)NC(=O)C2CC(O)CN2C1=O
Reactant: O=C(Cl)c1cccnc1
Product: CC(C)(C)OC(=O)NC1CCCCCC=CC2CC2(C(=O)NS(=O)(=O)C2CC2)NC(=O)C2CC(OC(=O)c3cccnc3)CN2C1=O
Yield: 7.6 %

Procedure:
Prepared by way of method I using 18-hydroxy-14-tert-butoxycarbonylamino-4-cyclopropylsulfonylaminocarbonyl-2,15-dioxo-3,16-diazatricyclo[14.3.0.04,6]-nonadec-7-ene (100 mg, 0.175 mmol) and nicotinoyl chloride (94 mg, 0.53 mmol). The final trituration (diethyl ether/hexane) and filtration gave 9.0 mg (8.0%) of 18-(nicotinoyloxy)-14-tert-butoxycarbonylamino-4-cyclopropylsulfonylaminocarbonyl-2,15-dioxo-3,16-diazatricyclo-[14.3.0.04,6]-nonadec-7-ene as a white powder: 95.0% pure (HPLC), MS m/z 672 (M−H)−, HRMS: calcd. 674.2860 and found 674.2855 (M+H)+, mp 157-159° C.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[CH:10]=[CH:9][C:8]([OH:11])=[CH:7][N:6]=1)=[O:4].C(=O)([O-])[O-].[K+].[K+].[F:18][C:19]([F:33])([C:29]([F:32])([F:31])[F:30])[CH2:20]OS(C(F)(F)F)(=O)=O>>[CH3:1][O:2][C:3]([C:5]1[CH:10]=[CH:9][C:8]([O:11][CH2:20][C:19]([F:33])([F:18])[C:29]([F:32])([F:31])[F:30])=[CH:7][N:6]=1)=[O:4]
Reactant: COC(=O)c1ccc(O)cn1
Reactant: O=S(=O)(OCC(F)(F)C(F)(F)F)C(F)(F)F
Agent: O=C([O-])[O-]
Agent: [K+]
Product: COC(=O)c1ccc(OCC(F)(F)C(F)(F)F)cn1

Procedure:
In a manner analogous to that described in example 30a), the alkylation of the 5-hydroxy-pyridine-2-carboxylic acid methyl ester with potassium carbonate and trifluoro-methanesulphonic acid 2,2,3,3,3-pentafluoropropyl ester yielded the 5-(2,2,3,3,3-pentafluoro-propoxy)-pyridine-2-carboxylic acid methyl ester as a light yellow oil. MS (ISP): m/z=285 [M]+. b) In a manner analogous to that described in example 30b), the hydrolysis of the 5-(2,2,3,3,3-pentafluoro-propoxy)-pyridine-2-carboxylic acid methyl ester with lithium hydroxide yielded the 5-(2,2,3,3,3-pentafluoro-propoxy)-pyridine-2-carboxylic acid as a white solid. MS (ISP): m/z=271 [M+H]+.
Reaction SMILES: C(O)(=O)C.C(OC([NH:15][C:16]1[CH:20]=[C:19]([C:21]([O:23][C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)=[O:22])[N:18]([C:30]2[C:35]([Cl:36])=[CH:34][CH:33]=[CH:32][N:31]=2)[N:17]=1)=O)C1C=CC=CC=1>[H][H].[Pd]>[NH2:15][C:16]1[CH:20]=[C:19]([C:21]([O:23][C:24]2[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=2)=[O:22])[N:18]([C:30]2[C:35]([Cl:36])=[CH:34][CH:33]=[CH:32][N:31]=2)[N:17]=1
Reactant: O=C(Nc1cc(C(=O)Oc2ccccc2)n(-c2ncccc2Cl)n1)OCc1ccccc1
Reactant: [H][H]
Agent: [Pd]
Solvent: CC(=O)O
Product: Nc1cc(C(=O)Oc2ccccc2)n(-c2ncccc2Cl)n1
Yield: 52.3 %

Procedure:
0.6 g of a 10% Pd—C powder was added to an acetic acid (50 ml) solution comprising 3.0 g of phenyl 3-benzyloxycarbonylamino-1-(3-chloropyridin-2-yl)-1H-5-pyrazolecarboxylate obtained by repeatedly carrying out the above step (5), followed by stirring in hydrogen atmosphere at room temperature for 12 hours. The reaction solution was subjected to filtration with celite, and then the filtrate and the liquid obtained after washing the celite were concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: ethyl acetate) to obtain 1.1 g of crystals of the desired product (melting point: 140.4° C.).
Reaction SMILES: [CH3:1][N:2]([CH3:5])[CH2:3][CH3:4].[Br:6][CH2:7][CH2:8][O:9][CH2:10][CH2:11][O:12][CH3:13]>C(#N)C>[Br-:6].[CH3:1][N+:2]([CH3:5])([CH2:3][CH3:4])[CH2:7][CH2:8][O:9][CH2:10][CH2:11][O:12][CH3:13]
Reactant: CCN(C)C
Reactant: COCCOCCBr
Solvent: CC#N
Product: CC[N+](C)(C)CCOCCOC
Product: [Br-]
Temperature: 80 °C
Reaction time: 24 h
Yield: 100 %

Procedure:
A mixture of 5.12 g (0.070 mol) of dimethylethylamine, 14.2 g (0.070 mol) of 1-bromo-2-(methoxyethoxy)ethane and 10.2 g of acetonitrile was stirred at 80° C. for 24 hours for reaction thereof. After completion of the reaction, the resulted reaction mixture was concentrated, and the residue was dried under reduced pressure to obtain 18.4 g (0.070 mol) of N,N-dimethyl-N-ethyl-N-methoxyethoxyethylammonium bromide.
Reaction SMILES: Cl[C:2](Cl)([O:4]C(=O)OC(Cl)(Cl)Cl)Cl.[NH2:13][C:14]1[CH:15]=[C:16]([CH:22]=[CH:23][CH:24]=1)[C:17]([O:19][CH2:20][CH3:21])=[O:18].C(N(CC)CC)C.[C:32]([C:36]([CH2:38][N:39]1[C:45]2[CH:46]=[C:47]([CH3:50])[CH:48]=[CH:49][C:44]=2[N:43]([CH:51]2[CH2:56][CH2:55][CH2:54][CH2:53][CH2:52]2)[CH2:42][CH:41]([NH2:57])[C:40]1=[O:58])=[O:37])([CH3:35])([CH3:34])[CH3:33]>O1CCCC1>[C:32]([C:36]([CH2:38][N:39]1[C:45]2[CH:46]=[C:47]([CH3:50])[CH:48]=[CH:49][C:44]=2[N:43]([CH:51]2[CH2:56][CH2:55][CH2:54][CH2:53][CH2:52]2)[CH2:42][CH:41]([NH:57][C:2]([NH:13][C:14]2[CH:24]=[CH:23][CH:22]=[C:16]([C:17]([O:19][CH2:20][CH3:21])=[O:18])[CH:15]=2)=[O:4])[C:40]1=[O:58])=[O:37])([CH3:35])([CH3:33])[CH3:34]
Reactant: Cc1ccc2c(c1)N(CC(=O)C(C)(C)C)C(=O)C(N)CN2C1CCCCC1
Reactant: CCOC(=O)c1cccc(N)c1
Reactant: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CCOC(=O)c1cccc(NC(=O)NC2CN(C3CCCCC3)c3ccc(C)cc3N(CC(=O)C(C)(C)C)C2=O)c1
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 164.3 %

Procedure:
Triphosgene (122 mg) was added to a solution of ethyl 3-aminobenzoate (182 mg) in tetrahydrofuran (10 ml) under ice-cooling, triethylamine (98 μl) was added thereto five times (total: 490 μl), the mixture was stirred at room temperature for 5 minutes. A solution of 1-tert-butylcarbonylmethyl-2-oxo-3-amino-5-cyclohexyl-8-methyl-1,3,4,5-tetrahydro-2H-1,5-benzodiazepine (393 mg) in anhydrous tetrahydrofuran (5 ml) was added to the mixture under ice-cooling, stirred at room temperature for 30 minutes. Ice-water was added to the reaction mixture, extracted with methylene chloride. The organic layer was washed with saturated brine and dried over anhydrous sodium sulfate, the solvent was evaporated under reduced pressure, and a mixed solvent of n-hexane and ethyl acetate(n-hexane:ethyl acetate=1:1) was added to the residue for crystallization, collected by filtration, to thereby obtain 380 mg of the title compound.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]2[C:10](=[CH:11][CH:12]=1)[C:9](=[O:13])[NH:8][C:7]2=[O:14])([O-:3])=[O:2].Br[CH2:16][C:17]([O:19][CH2:20][C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)=[O:18].C([O-])([O-])=O.[K+].[K+]>CN(C=O)C>[N+:1]([C:4]1[CH:5]=[C:6]2[C:10](=[CH:11][CH:12]=1)[C:9](=[O:13])[N:8]([CH2:16][C:17]([O:19][CH2:20][C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)=[O:18])[C:7]2=[O:14])([O-:3])=[O:2]
Reactant: O=C(CBr)OCc1ccccc1
Reactant: O=C1NC(=O)c2cc([N+](=O)[O-])ccc21
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: O=C(CN1C(=O)c2ccc([N+](=O)[O-])cc2C1=O)OCc1ccccc1
Yield: 78 %

Procedure:
A solution of 5-nitroisoindoline-1,3-dione (1.00 g, 5.20 mmol), benzyl 2-bromoacetate (1.225 ml, 7.81 mmol) and K2CO3 (1.079 g, 7.81 mmol) in DMF (10 ml) was heated at 90° C. for 2 hours. The insoluble inorganic salts were filtered off, and the filtrate was diluted with ethyl acetate and washed with 1N HCl and with brine. The organic layer was dried over Na2SO4 and the solvent was removed under vacuum. The residue was purified by crystallization from MeOH to afford benzyl 2-(5-nitro-1,3-dioxoisoindolin-2-yl)acetate (1.39 g, 4.08 mmol, 78% yield, MS/ESI+ not detectable [MH]+).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:12]3[CH2:13][C:14]4[S:15][CH:16]=[CH:17][C:18]=4[C:11]=3[N:10]([CH2:19][O:20][CH2:21][CH2:22][Si:23]([CH3:26])([CH3:25])[CH3:24])[N:9]=2)=[CH:4][CH:3]=1.[CH3:27][O:28][C:29]1[CH:34]=[CH:33][C:32](B2OC(C)(C)C(C)(C)O2)=[CH:31][N:30]=1.[C:44]([O-])([O-])=[O:45].[Na+].[Na+]>C1(C)C=CC=CC=1.C(O)C.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>[CH3:44][O:45][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:12]3[CH2:13][C:14]4[S:15][C:16]([C:32]5[CH:31]=[N:30][C:29]([O:28][CH3:27])=[CH:34][CH:33]=5)=[CH:17][C:18]=4[C:11]=3[N:10]([CH2:19][O:20][CH2:21][CH2:22][Si:23]([CH3:26])([CH3:25])[CH3:24])[N:9]=2)=[CH:4][CH:3]=1
Reactant: O=C([O-])[O-]
Reactant: COc1ccc(B2OC(C)(C)C(C)(C)O2)cn1
Reactant: C[Si](C)(C)CCOCn1nc(-c2ccc(Br)cc2)c2c1-c1ccsc1C2
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Na+]
Solvent: Cc1ccccc1
Solvent: CCO
Product: COc1ccc(-c2nn(COCC[Si](C)(C)C)c3c2Cc2sc(-c4ccc(OC)nc4)cc2-3)cc1
Temperature: 100 °C
Yield: 75 %

Procedure:
A mixture of the corresponding 6-(4-Bromo-phenyl)-4-(2-trimethylsilanyl-ethoxymethyl)-4,7-dihydro-1-thia-4,5-diaza-cyclopenta[a]pentalene (0.68 g, 1.4 mmol), 2-Methoxy-5-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-pyridine (0.33 g, 2.1 mmol), Na2CO3 (2 M, 3.3 mL), and Pd(PPh3)2Cl2 (13 mg, 1.1 mmol) in toluene/ethanol (1:1, 8 mL) was heated at 100° C. for 8 hr. The solution was cooled to room temperature and extracted with ethyl acetate. The target product was purified by gravity column chromatography (20% EtOAc in hexane) to give 6-(4-Methoxy-phenyl)-2-(6-methoxy-pyridin-3-yl)-4-(2-trimethylsilanyl-ethoxymethyl)-4,7-dihydro-1-thia-4,5-diaza-cyclopenta[a]pentalene as orange solid in 75% yield.
Reaction SMILES: C([Li])CCC.[CH2:6]([N:13]1[CH:17]=[CH:16][N:15]=[CH:14]1)[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1.[C:18]([C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1)(=[O:25])[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1>C1COCC1.C(=O)([O-])[O-].[Na+].[Na+]>[CH2:6]([N:13]1[CH:17]=[CH:16][N:15]=[C:14]1[C:18]([C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)([C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1)[OH:25])[C:7]1[CH:8]=[CH:9][CH:10]=[CH:11][CH:12]=1
Reactant: c1ccc(Cn2ccnc2)cc1
Reactant: O=C(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [Li]CCCC
Agent: [Na+]
Solvent: C1CCOC1
Product: OC(c1ccccc1)(c1ccccc1)c1nccn1Cc1ccccc1
Temperature: 23 °C
Reaction time: 0.33 h

Procedure:
A solution of n-butyllithium in hexanes (1.6 M, 45.0 mL, 72.0 mmol, 1.14 equiv) was added to a solution of 1-benzylimidazole (1-1, 10.0 g, 63.2 mmol, 1 equiv) in THF (200 mL) at −78° C. and the resulting mixture was stirred for 20 min. A solution of benzophenone (15.5 mL, 95.0 mmol, 1.50 equiv) in THF (30 mL) was added and the reaction mixture was stirred at −78° C. for 1 h, then warmed to 23° C. The mixture was partitioned between saturated ammonium chloride solution (200 mL) and ethyl acetate (400 mL), and the organic layer was separated, dried over magnesium sulfate and concentrated to give a yellow oil. The oil was suspended in saturated aqueous sodium carbonate solution and the resulting precipitate was filtered, washed with water (200 mL) then ethyl ether (2×100 mL) and air dried to afford (1-benzyl-1H-imidazol-2-yl)(diphenyl)methanol (1-2) as a white solid. 1H NMR (300 MHz, DMSO) δ 7.25 (m, 12H), 7.04 (m, 2H), 6.93 (s, 2H), 6.78 (s, 1H), 5.02 (s, 2H). LRMS m/z (M-OH) 323.1 found, 323.2 required.
Reaction SMILES: [CH2:1]1[CH2:5][O:4][CH2:3][CH2:2]1.[Cl:6][C:7]1[CH:12]=[CH:11][C:10]([OH:13])=[CH:9][CH:8]=1.C(O[CH2:17][CH3:18])C>>[Cl:6][C:7]1[CH:12]=[CH:11][C:10]([O:13][C@H:18]2[CH:17]=[CH:5][C:1]3[C:2](=[CH:5][CH:1]=[CH:2][CH:3]=3)[C@@H:3]2[OH:4])=[CH:9][CH:8]=1
Reactant: CCOCC
Reactant: C1CCOC1
Reactant: Oc1ccc(Cl)cc1
Product: O[C@H]1c2ccccc2C=C[C@@H]1Oc1ccc(Cl)cc1
Temperature: 80 °C
Yield: 89 %

Procedure:
To a flame dried round-bottomed flask, [Rh(COD)Cl]2 (1.7 mg, 0.0035 mmol), (S)-(R)-PPF-PtBu2 (3.8 mg, 0.0069 mmol) and 1 (100 mg, 0.694 mmol) were added followed by addition of THF (2.5 mL) and 4-chlorophenol (446 mg, 3.47 mmol). The mixture was heated at 80° C. for 6 hours, then poured into diethyl ether and extracted 3 times with 10% aqueous sodium hydroxide solution. The aqueous extracts were combined and back-extracted three times with diethyl ether. The combined ether extracts were washed with brine and dried with anhydrous sodium sulfate. The solvents were removed in vacuo, yielding a solid which was purified by flash chromatography on silica gel (5% ethyl acetate in hexanes) giving a white crystalline solid 8 (169 mg, 89%). The ee was determined to be 92% by formation of Mosher's ester. Rf=0.47 on silica (20% ethyl acetate in hexanes); mp 125-125.5° C. (Et2O); [α]25D+150° (c=10.6, CHCl3). IR (KBr, cm−1) 3302 (br), 3064 (w), 2874 (w), 1590 (m), 1489 (s), 1362 (w), 1230 (s), 1052 (m), 890 (w), 846 (m), 778 (s), 663 (m); 1H NMR (400 MHz, CDCl3): δ7.65-7.64 (1H, m), 7.33-7.26 (4H, m), 7.16-7.13 (1H, m), 6.91(1H, ddd, J=2.0, 2.0, 8.9 Hz), 6.55 (1H, dd, J=1.8, 9.9 Hz), 5.99 (1H, dd, J=2.2, 9.9 Hz), 5.19 (1H, dd, J=3.8, 10.0 Hz), 5.07 (1H, ddd, J=2.0, 2.0, 10.1 Hz), 2.56 (1H, d, J=4.0 Hz); 13C NMR (400 MHz, CDCl3): δ155.8, 135.2, 131.7, 129.5, 129.3, 128.2, 128.1, 126.5, 126.2, 125.3, 125.2, 116.9, 79.2, 72.1. HRMS calcd for (M-H2O)+ (C16H11OCl): 254.0498. Found: 254.0499.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([CH:18]=[CH:19][CH:20]=1)[CH2:5][N:6]([CH2:15][CH2:16][CH3:17])[C:7](=[O:14])[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1.[CH:21]([C:23]1[CH:28]=[CH:27][C:26](B(O)O)=[CH:25][CH:24]=1)=[O:22]>>[CH:21]([C:23]1[CH:28]=[CH:27][C:26]([C:2]2[CH:20]=[CH:19][CH:18]=[C:4]([CH2:5][N:6]([CH2:15][CH2:16][CH3:17])[C:7](=[O:14])[C:8]3[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=3)[CH:3]=2)=[CH:25][CH:24]=1)=[O:22]
Reactant: O=Cc1ccc(B(O)O)cc1
Reactant: CCCN(Cc1cccc(Br)c1)C(=O)c1ccccc1
Product: CCCN(Cc1cccc(-c2ccc(C=O)cc2)c1)C(=O)c1ccccc1
Yield: 52 %

Procedure:
In a manner similar to that of Example 1(e), by reacting 1.4 g (4.2 mmol) of N-(3-bromo benzyl)-N-propylbenzamide with 940 mg (6.2 mmol) of 4-formylbenzene boronic acid, 780 mg (53%) of the expected product are obtained.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([F:8])[C:3]=1B(O)O.COCCOC.[Cl:18][C:19]1[CH:24]=[C:23](Cl)[N:22]=[CH:21][N:20]=1>O>[Cl:18][C:19]1[CH:24]=[C:23]([C:3]2[C:2]([F:1])=[CH:7][CH:6]=[CH:5][C:4]=2[F:8])[N:22]=[CH:21][N:20]=1
Reactant: Clc1cc(Cl)ncn1
Reactant: OB(O)c1c(F)cccc1F
Solvent: O
Solvent: COCCOC
Product: Fc1cccc(F)c1-c1cc(Cl)ncn1
Temperature: 80 °C
Reaction time: 5 h
Yield: 16.7 %

Procedure:
A reaction vessel was charged with [1,1′-bis(diphenylphosphino)ferrocene dichloropalladium]methylene chloride complex, 1.007 g of 2,6-difluorophenylboronic acid, and 2.707 g of tripotassium phosphate n-hydrate, to which 16 ml of 1,2-dimethoxyethane, 4 ml of water, and 0.95 g of 4,6-dichloropyrimidine were added, followed by stirring at 80° C. under an atmosphere of a nitrogen gas for 5 hours. The reaction mixture was then left for cooling to room temperature, and water was added to the reaction mixture, which was extracted with ethyl acetate. The organic layer was washed with a saturated aqueous sodium chloride solution, dried over anhydrous magnesium sulfate, and then concentrated. The residue was subjected to silica gel column chromatography to give 0.241 g of 4-chloro-6-(2,6-difluorophenyl)pyrimidine.
Reaction SMILES: O[Li:2].O.[NH2:4][C:5]1[N:14]=[CH:13][C:12]([Cl:15])=[CH:11][C:6]=1[C:7]([O:9]C)=[O:8]>O.CO>[NH2:4][C:5]1[N:14]=[CH:13][C:12]([Cl:15])=[CH:11][C:6]=1[C:7]([O-:9])=[O:8].[Li+:2]
Reactant: [Li]O
Reactant: COC(=O)c1cc(Cl)cnc1N
Solvent: O
Solvent: CO
Product: Nc1ncc(Cl)cc1C(=O)[O-]
Product: [Li+]
Temperature: 70 °C
Reaction time: 24 h
Yield: 114.3 %

Procedure:
A solution of LiOH.H2O (1.38 g, 33 mmol) in water (33 mL) was added in one portion to a suspension of methyl 2-amino-5-chloronicotinate (6.08 g, 27 mmol) in MeOH (110 mL). The reaction mixture was stirred at 70° C. for 24 hours, and gradually became homogeneous. The solvents were removed under reduced pressure, and after the resulting white solid was dried under vacuum (<1 mmHg) to constant weight, 5.51 g (95%) of lithium 2-amino-5-chloronicotinate was obtained.
Reaction SMILES: Cl.[CH2:2]([N:4]1[CH2:13][CH2:12][C@@:11]2([C:14]3[CH:19]=[CH:18][CH:17]=[C:16]([O:20][CH3:21])[CH:15]=3)[C@@H:6]([CH2:7][CH2:8][C:9](=O)[CH2:10]2)[CH2:5]1)C.[CH2:23]([NH:30][C:31](=[O:44])[C:32](=[N:36]NC1C=CC=CC=1)[C:33](=O)[CH3:34])[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1>[Zn].C(O)(=O)C>[CH2:23]([NH:30][C:31]([C:32]1[NH:36][C:9]2[CH2:10][C@@:11]3([C:14]4[CH:19]=[CH:18][CH:17]=[C:16]([O:20][CH3:21])[CH:15]=4)[C@H:6]([CH2:7][C:8]=2[C:33]=1[CH3:34])[CH2:5][N:4]([CH3:2])[CH2:13][CH2:12]3)=[O:44])[C:24]1[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=1
Reactant: CC(=O)C(=NNc1ccccc1)C(=O)NCc1ccccc1
Reactant: CCN1CC[C@]2(c3cccc(OC)c3)CC(=O)CC[C@H]2C1
Agent: Cl
Agent: [Zn]
Solvent: CC(=O)O
Product: COc1cccc([C@@]23CCN(C)C[C@H]2Cc2c([nH]c(C(=O)NCc4ccccc4)c2C)C3)c1

Procedure:
1 g (3.3 mmol) of (±)-trans-2-ethyl-4a-(3-methoxyphenyl)-6-oxo-1,2,3,4,4a,5,6,7,8,8a-decahydroisoquinoline hydrochloride, 2.95 g (10 mmol) of N-benzyl-2-phenylhydrazono-3-oxobutyramide, 0.82 g (10 mmol) of CH3 COONa, 2.6 g (40 mmol) of zinc dust and 5 ml of glacial acetic acid were treated as described in example 1. The residue was crystallised from AcOEt yielding 0.65 g of the title compound. M. p.=162°-164° C.
Reaction SMILES: [OH:1][C:2]1[CH:11]=[CH:10][C:9]2[C:4](=[CH:5][C:6]([OH:12])=[CH:7][CH:8]=2)[C:3]=1[N:13]=O.[S:15]([O-:18])([OH:17])=[O:16].[Na+].S(=O)(O)[O-].Cl>O>[OH:1][C:2]1[CH:11]=[C:10]([S:15]([OH:18])(=[O:17])=[O:16])[C:9]2[C:4](=[CH:5][C:6]([OH:12])=[CH:7][CH:8]=2)[C:3]=1[NH2:13]
Reactant: O=Nc1c(O)ccc2ccc(O)cc12
Reactant: O=S([O-])O
Agent: Cl
Agent: [Na+]
Solvent: O
Product: Nc1c(O)cc(S(=O)(=O)O)c2ccc(O)cc12

Procedure:
In the second reaction stage, the 2,7-dihydroxy-1-nitrosonaphthalene (I), which as a rule is still moist with water and reacts in the tautomeric oxime form (Ia), is first suspended, according to Boninger, Chem. Ber. 27, 3050 (1894), in commercially-available 37% aqueous sodium hydrogen sulfite solution and stirred at about 20°-25° C. until it is completely dissolved. The bisulfite addition compound (IIa) thus formed is not isolated, but the brown reaction solution is acidified with hydrochloric acid and heated to about 25°-60° C., 2,7-dihydroxy-1-aminonaphthalene-4-sulfonic acid (II) being formed by reduction of the nitroso group and aromatization of the cycloaliphatic ring system. The aminonaphtholsulfonic acid (II) is isolated by filtering off with suction the light-gray crystals formed, washing the crystals on the suction filter, first with water and then with methanol and, if desired, drying them. The reaction product thus prepared is used without further purification, if appropriate while still moist, for the next reaction stage. The yield of reaction product II is about 90-95% of theory.
Reaction SMILES: [C:1]([NH2:4])(=[O:3])[CH3:2].[CH2:5]([O:7][C:8](=[O:14])[CH2:9][C:10]([CH2:12]Cl)=O)[CH3:6].C(=O)([O-])O.[Na+].Cl>C(O)(=O)C>[CH3:2][C:1]1[O:3][C:9]([C:8]([O:7][CH2:5][CH3:6])=[O:14])=[C:10]([CH3:12])[N:4]=1
Reactant: CCOC(=O)CC(=O)CCl
Reactant: CC(N)=O
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC(=O)O
Product: CCOC(=O)c1oc(C)nc1C
Reaction time: 10 h

Procedure:
800 mmol of acetoamide and 400 mmol of ethylchloroaceto acetate were dissolved into 146 g of anhydrous acetic acid. Reaction was carried out for 10 hours at 130° C. The reacted liquid was alkalized with saturated sodium hydrogen carbonate and then the product was extracted into an organic phase using ethyl acetate. The organic phase was dried under sodium sulfate and then the solvent was evaporated out, obtaining a black liquid. To this black liquid 6N hydrochloric acid aqueous solution was added to make it alkaline. Then the product was extracted into organic phase using ethyl acetate. The thus obtained solid substance was dissolved in hexane. Insoluble matter was eliminated and solvent was evaporated out, obtaining ethyl 2,4-dimethyl-1,3-oxazole-5-carboxylate, an yellowish white solid (yield: 30%).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([CH:9]=[CH:10][CH:11]=1)[C:5]([NH:7][CH3:8])=[O:6].Br[CH:13]([C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)[C:14]([O:16][CH2:17][CH3:18])=[O:15].CCN(C(C)C)C(C)C>C(#N)C>[CH3:8][NH:7][C:5]([C:4]1[CH:3]=[C:2]([NH:1][CH:13]([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[C:14]([O:16][CH2:17][CH3:18])=[O:15])[CH:11]=[CH:10][CH:9]=1)=[O:6]
Reactant: CNC(=O)c1cccc(N)c1
Reactant: CCOC(=O)C(Br)c1ccccc1
Solvent: CCN(C(C)C)C(C)C
Solvent: CC#N
Product: CCOC(=O)C(Nc1cccc(C(=O)NC)c1)c1ccccc1
Temperature: 100 °C
Reaction time: 1 h
Yield: 92.7 %

Procedure:
3-Amino-N-methylbenzamide (371 mg, 2.47 mmol), ethyl 2-bromo-2-phenylacetate (0.29 ml, 1.64 mmol), and DIPEA (0.43 ml, 2.47 mmol) were dissolved in acetonitrile (5 ml) and stirred under microwave irradiation into a sealed vial at 100° C. for 60 minutes (UPLC-MS: complete conversion). Acetonitrile was evaporated, and the crude residue was purified by flash chromatography (DCM/EtOAc=8/2) to obtain ethyl 2-(3-(methylcarbamoyl)phenylamino)-2-phenylacetate (475 mg, 92% yield).