Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: S(=O)(=O)(O)O.[NH2:6][C:7]1[N:12]=[C:11]([NH:13][C@@H:14]([CH2:18][CH2:19][CH2:20][CH3:21])[CH2:15][CH2:16][OH:17])[C:10]([CH2:22][C:23]2[CH:28]=[CH:27][C:26]([CH2:29][C:30]([OH:32])=[O:31])=[CH:25][C:24]=2[F:33])=[C:9]([CH3:34])[N:8]=1.[C:35]([O-])(O)=O.[Na+]>CO.O>[NH2:6][C:7]1[N:12]=[C:11]([NH:13][C@@H:14]([CH2:18][CH2:19][CH2:20][CH3:21])[CH2:15][CH2:16][OH:17])[C:10]([CH2:22][C:23]2[CH:28]=[CH:27][C:26]([CH2:29][C:30]([O:32][CH3:35])=[O:31])=[CH:25][C:24]=2[F:33])=[C:9]([CH3:34])[N:8]=1
Reactant: CCCC[C@@H](CCO)Nc1nc(N)nc(C)c1Cc1ccc(CC(=O)O)cc1F
Reactant: O=C([O-])O
Agent: O=S(=O)(O)O
Agent: [Na+]
Solvent: CO
Solvent: O
Product: CCCC[C@@H](CCO)Nc1nc(N)nc(C)c1Cc1ccc(CC(=O)OC)cc1F
Temperature: 70 °C

Procedure:
Concentrated sulfuric acid (0.3 mL) was added to a stirred solution of the product from step (v) (0.08 g) in MeOH (1 mL) and the mixture was heated to 70° C. for 2 h. The mixture was allowed to cool, diluted with water (2 mL) and neutralised with NaHCO3. The aqueous was extracted with EtOAc and the combined organic phase was dried and evaporated. The crude product was purified by RPHPLC to give the title compound, 0.005 g.
Reaction SMILES: Cl.[NH:2]1[CH2:5][CH:4]([C:6]2[CH:27]=[CH:26][C:9]3[C:10]4[N:14]([CH2:15][CH2:16][O:17][C:8]=3[CH:7]=2)[CH:13]=[C:12]([C:18]2[N:19]([CH:23]([CH3:25])[CH3:24])[N:20]=[CH:21][N:22]=2)[N:11]=4)[CH2:3]1.Cl[CH2:29][C:30]([NH:32][CH:33]([CH3:35])[CH3:34])=[O:31].CO>O>[CH:33]([NH:32][C:30](=[O:31])[CH2:29][N:2]1[CH2:3][CH:4]([C:6]2[CH:27]=[CH:26][C:9]3[C:10]4[N:14]([CH:13]=[C:12]([C:18]5[N:19]([CH:23]([CH3:24])[CH3:25])[N:20]=[CH:21][N:22]=5)[N:11]=4)[CH2:15][CH2:16][O:17][C:8]=3[CH:7]=2)[CH2:5]1)([CH3:35])[CH3:34]
Reactant: CC(C)NC(=O)CCl
Reactant: CC(C)n1ncnc1-c1cn2c(n1)-c1ccc(C3CNC3)cc1OCC2
Agent: Cl
Solvent: O
Solvent: CO
Product: CC(C)NC(=O)CN1CC(c2ccc3c(c2)OCCn2cc(-c4ncnn4C(C)C)nc2-3)C1

Procedure:
Following the procedure for 143, 8-azetidin-3-yl-2-(2-isopropyl-2H-[1,2,4]triazol-3-yl)-4,5-dihydro-6-oxa-1,3a-diaza-benzo[e]azulene hydrochloride (Example 65) was reacted with 2-chloro-N-isopropyl acetamide. The crude product was subjected to reverse phase HPLC (Gemini C18 column gradient 0 to 70% MeOH in H2O+0.1% HCO2H) to give 200 as a white solid. 1H NMR δ (ppm) (CDCl3): 8.46 (1H, d, J=8.28 Hz), 7.85 (1H, s), 7.63 (1H, s), 7.05 (1H, dd, J=8.32, 1.82 Hz), 6.94-6.92 (1H, m), 6.00-5.90 (1H, m), 4.49-4.40 (4H, m), 4.12-4.02 (1H, m), 3.88 (2H, t, J=7.51 Hz), 3.82-3.71 (1H, m), 3.41 (2H, t, J=7.23 Hz), 3.23 (2H, s), 1.56 (6H, d, J=6.63 Hz), 1.16 (6H, d, J=6.57 Hz). 1 Exchangeable proton not seen. LCMS: RT=6.8 min, M+H+=450
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:11]=[CH:10][CH:9]=[C:8]2[C:4]=1[CH2:5][CH2:6][C:7]2([C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)O.C1(C)C=CC(S(O)(=O)=O)=CC=1>C1(C)C=CC=CC=1>[C:13]1([CH:7]2[C:8]3[C:4](=[C:3]([O:2][CH3:1])[CH:11]=[CH:10][CH:9]=3)[CH:5]=[CH:6]2)[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=1
Reactant: COc1cccc2c1CCC2(O)c1ccccc1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: Cc1ccccc1
Product: COc1cccc2c1C=CC2c1ccccc1
Yield: 66.7 %

Procedure:
To 1 L of toluene was added 14 g (0.058 mol) of 4-methoxy-1-phenyl-indan-1-ol and 100 mg of p-toluenesulfonic acid and the mixture was placed on a Rotovap® and the solvent was distilled in vacuo (40 mm) until an oil residue was obtained. The oil was chromatographed (silica, 1:1 hexane/methylene chloride followed by ether) to afford 8.6 g (60.2%) of 1-phenyl-4-methoxy-indene as a pale red oil.
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3]([CH:10]=[CH:11][C:12]2[CH:17]=[C:16]([N:18]3[CH2:23][CH2:22][O:21][CH2:20][CH2:19]3)[CH:15]=[CH:14][C:13]=2[NH2:24])=[N:2]1.C(N(CC)CC)C.[CH3:32][N:33]1[CH:37]=[CH:36][CH:35]=[C:34]1[C:38]([Cl:40])=[O:39].C(=O)([O-])O.[Na+]>C1COCC1>[ClH:40].[NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3](/[CH:10]=[CH:11]/[C:12]2[CH:17]=[C:16]([N:18]3[CH2:19][CH2:20][O:21][CH2:22][CH2:23]3)[CH:15]=[CH:14][C:13]=2[NH:24][C:38]([C:34]2[N:33]([CH3:32])[CH:37]=[CH:36][CH:35]=2)=[O:39])=[N:2]1
Reactant: Nc1ccc(N2CCOCC2)cc1C=Cc1n[nH]c2ccccc12
Reactant: Cn1cccc1C(=O)Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: Cl
Product: Cn1cccc1C(=O)Nc1ccc(N2CCOCC2)cc1/C=C/c1n[nH]c2ccccc12
Temperature: 25 °C
Reaction time: 1 h

Procedure:
2-[2-(1H-indazol-3-yl)vinyl]-4-(morpholin-4-yl)phenylamine (0.30 g, 0.94 mmol) synthesized in Example 225 was dissolved in THF (10 mL) and the solution was added with triethylamine (0.40 mL, 2.9 mmol) and N-methylpyrrolecarbonyl chloride (0.41 g, 2.8 mmol), followed by stirring at room temperature for 1 hour. The reaction mixture was added with saturated aqueous sodium hydrogencarbonate solution, extracted with ethyl acetate and the organic layer was concentrated under reduced pressure to obtain free base of Compound 226. Further, said free base was treated by 4 mol/L hydrogen chloride-methanol solution (1.0 mL) to obtain Compound 226 (0.23 g, 49%).
Reaction SMILES: N[C:2]1[C:3]([C:15]([NH:17][CH2:18][CH:19]2[CH2:21][CH2:20]2)=[O:16])=[CH:4][CH:5]=[C:6]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=2[CH3:14])[CH:7]=1.[Cl:22][C:23]1[CH:28]=[C:27]([C:29](Cl)=[O:30])[CH:26]=[CH:25][N:24]=1.C([N:34](CC)CC)C>C(Cl)Cl>[Cl:22][C:23]1[CH:28]=[C:27]([CH:26]=[CH:25][N:24]=1)[C:29]([NH:34][C:12]1[CH:13]=[C:8]([C:6]2[CH:5]=[CH:4][C:3]([C:15]([NH:17][CH2:18][CH:19]3[CH2:21][CH2:20]3)=[O:16])=[CH:2][CH:7]=2)[C:9]([CH3:14])=[CH:10][CH:11]=1)=[O:30]
Reactant: Cc1ccccc1-c1ccc(C(=O)NCC2CC2)c(N)c1
Reactant: CCN(CC)CC
Reactant: O=C(Cl)c1ccnc(Cl)c1
Solvent: ClCCl
Product: Cc1ccc(NC(=O)c2ccnc(Cl)c2)cc1-c1ccc(C(=O)NCC2CC2)cc1
Yield: 33 %

Procedure:
5-Amino-N-(cyclopropylmethyl)-2′-methyl-1,1′-biphenyl-4-carboxamide (260 mg, 0.93 mmol), 2-chloropyridine-4-carbonyl chloride (245 μl) and triethylamine (195 μl, 1.39 mmol) were stirred at room temperature in DCM (20 ml) for 72 h. The reaction was diluted with DCM (100 ml), washed with aqueous sodium hydroxide (2M, 100 ml) and dried (magnesium sulphate). The solvent was evaporated under vacuum, the residue dissolved in methanol and purified by SPE (C18, 10 g) eluting with water, water/acetonitrile (1:1) and acetonitrile. The solvent was evaporated from the product fractions under vacuum to give 2-chloro-N-(4′-{[(cyclopropylmethyl)amino]carbonyl}-6-methyl-1,1′-biphenyl-3-yl)isonicotinamide (130 mg, 33%). NMR; δH [2H6]—DMSO 10.57,(1H, s), 8.63-8.60,(2H, m), 7.99,(1H, s), 7.93,(2H, d), 7.86,(1H, dd),7.70,(1H, dd), 7.66,(1H, d), 7.44,(2H, d), 7.32,(1H, d), 3.16,(2H, t), 2.21,(3H, s), 1.05,(1H, m), 0.43,(2H, m), 0.24,(2H, m). LCMS: retention time 3.53 min, MH+420/422.
Reaction SMILES: [O:1]1[CH2:6][CH2:5][O:4][CH2:3][CH:2]1[CH2:7][N:8]1[CH2:14][CH2:13][C:12]2[CH:15]=[CH:16][C:17]([NH2:19])=[CH:18][C:11]=2[CH2:10][CH2:9]1.O1CCOCC1CN1CCC2C=C(OC)C(N)=CC=2CC1.Cl[C:42]1[N:47]=[C:46]([NH:48][C:49]2[CH:54]=[CH:53][C:52]([O:55][CH3:56])=[CH:51][C:50]=2[N:57]2[CH:61]=[CH:60][CH:59]=[N:58]2)[C:45]([Cl:62])=[CH:44][N:43]=1>>[Cl:62][C:45]1[C:46]([NH:48][C:49]2[CH:54]=[CH:53][C:52]([O:55][CH3:56])=[CH:51][C:50]=2[N:57]2[CH:61]=[CH:60][CH:59]=[N:58]2)=[N:47][C:42]([NH:19][C:17]2[CH:16]=[CH:15][C:12]3[CH2:13][CH2:14][N:8]([CH2:7][CH:2]4[CH2:3][O:4][CH2:5][CH2:6][O:1]4)[CH2:9][CH2:10][C:11]=3[CH:18]=2)=[N:43][CH:44]=1
Reactant: Nc1ccc2c(c1)CCN(CC1COCCO1)CC2
Reactant: COc1ccc(Nc2nc(Cl)ncc2Cl)c(-n2cccn2)c1
Agent: COc1cc2c(cc1N)CCN(CC1COCCO1)CC2
Product: COc1ccc(Nc2nc(Nc3ccc4c(c3)CCN(CC3COCCO3)CC4)ncc2Cl)c(-n2cccn2)c1

Procedure:
3-1,4-Dioxinan-2-ylmethyl-2,3,4,5-tetrahydro-1H-3-benzazepin-7-ylamine, prepared in a similar manner as 3-1,4-Dioxinan-2-ylmethyl-8-methoxy-2,3,4,5-tetrahydro-1H-3-benzazepin-7-ylamine of Example 636b, was reacted with (2,5-Dichloro-pyrimidin-4-yl)-(4-methoxy-2-pyrazol-1-yl-phenyl)-amine, of Example 611c, in a similar manner as Example 601b to yield desired product 5-Chloro-N*2*-(3-[1,4]dioxan-2-ylmethyl-2,3,4,5-tetrahydro-1H-benzo[d]azepin-7-yl)-N*4*-(4-methoxy-2-pyrazol-1-yl-phenyl)-pyrimidine-2,4-diamine as a lyophylate (38%); 1H NMR (400 MHz, DMSO-d6) δ 9.73 (bs, 1H), 9.36 (s, 1H), 8.24 (s, 1H), 8.10 (s, 1H), 7.96 (bd, 1H), 7.81 (s, 1H), 7.43 (s, 1H), 7.30-7.25 (m, 2H), 7.02-7.00 (m, 2H), 6.54 (s, 1H), 4.06 (m, 1H), 3.88 (s, 3H), 3.85-3.55 (m, 6H), 3.4-3.0 (m, 6H), 2.95 (m, 1H), 2.75 (m, 1H); MS (m/e) 562.15 (M+H).
Reaction SMILES: [F:1][C:2]([F:18])([F:17])[O:3][C:4]1[CH:9]=[CH:8][C:7]([C:10]2[O:14][C:13]([CH:15]=O)=[CH:12][CH:11]=2)=[CH:6][CH:5]=1.[CH3:19][CH:20]([CH3:36])[C:21]([NH:23][C:24]1[CH:29]=[CH:28][CH:27]=[C:26]([CH:30]2[CH2:35][CH2:34][NH:33][CH2:32][CH2:31]2)[CH:25]=1)=[O:22]>>[CH3:19][CH:20]([CH3:36])[C:21]([NH:23][C:24]1[CH:29]=[CH:28][CH:27]=[C:26]([CH:30]2[CH2:35][CH2:34][N:33]([CH2:15][C:13]3[O:14][C:10]([C:7]4[CH:6]=[CH:5][C:4]([O:3][C:2]([F:1])([F:17])[F:18])=[CH:9][CH:8]=4)=[CH:11][CH:12]=3)[CH2:32][CH2:31]2)[CH:25]=1)=[O:22]
Reactant: CC(C)C(=O)Nc1cccc(C2CCNCC2)c1
Reactant: O=Cc1ccc(-c2ccc(OC(F)(F)F)cc2)o1
Product: CC(C)C(=O)Nc1cccc(C2CCN(Cc3ccc(-c4ccc(OC(F)(F)F)cc4)o3)CC2)c1

Procedure:
Prepared by Procedure F and Scheme R using 5-[4-(trifluoromethoxy)phenyl]-2-furaldehyde and 2-methyl-N-[3-(4-piperidinyl)phenyl]propanamide: ESMS m/e: 487.1 (M+H)+.
Reaction SMILES: C[O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[N:10]=[CH:11][C:12]3[C:17]([CH:18]=2)=[CH:16][CH:15]=[CH:14][CH:13]=3)=[CH:5][CH:4]=1.C(O)(=O)C>I>[CH:11]1[C:12]2[C:17](=[CH:16][CH:15]=[CH:14][CH:13]=2)[CH:18]=[C:9]([C:6]2[CH:7]=[CH:8][C:3]([OH:2])=[CH:4][CH:5]=2)[N:10]=1
Reactant: COc1ccc(-c2cc3ccccc3cn2)cc1
Agent: I
Solvent: CC(=O)O
Product: Oc1ccc(-c2cc3ccccc3cn2)cc1
Temperature: 110 °C
Reaction time: 2 h
Yield: 83.9 %

Procedure:
To a solution of 2-bromobenzaldehyde (1.85 g, 10 mmol) and 4-methoxyphenyl acetylene (1.58 g, 12 mmol) in 40 mL of triethylamine were added dichlorobis(triphenylphosphine) palladium(II) (140 mg, 2 mol %) and copper (I) iodide (20 mg, 1 mol %). The reaction mixture was heated at 50° C. under nitrogen for 3 h. The reaction mixture was cooled to room temperature and the ammonium salt was removed by filtration. The filtrate was concentrated under reduced pressure. Purification of the crude compound by column chromatography (silica gel 230-400 mesh; 10% ethyl acetate in hexanes as eluent) afforded 2-(4-methoxy phenylethynyl)benzaldehyde (2.1 g, 89%). The above compound (2.06 g, 8.73 mmol) and t-butylamine (3.83 g, 52.4 mmol) were stirred under nitrogen for 24 h at room temperature. The resulting mixture was extracted with ether and the organic layer was dried over anhydrous Na2SO4, and concentrated to give the imine (2.4 g, 94%), which was used in the next step without further purification. To a solution of the above imine (2.39 g, 8.2 mmol) in 100 mL anhydrous DMF was added (0.156 g, 0.82 mmol) copper (I) iodide, and the solution was flushed with nitrogen. The reaction mixture was heated at 100° C. for 4 h. The mixture was cooled to room temperature, and diluted with ether (200 mL). The organic layer was washed with saturated aqueous ammonium chloride (3×100 mL). The organic layer was dried over anhydrous Na2SO4 and concentrated to give the crude compound as a dark colored solid. Purification by column chromatography (silica gel 230-400 mesh; 10% ethylacetate in hexanes as eluent) afforded 3-(4-methoxyphenyl)isoquinoline (1.064 g, 55%), as a white solid. The 3-(4-methoxyphenyl)isoquinoline (1.05 g, 4.47 mmol) was suspended in 30 mL hydroiodic acid and 12 mL of acetic acid was added. The reaction mixture was stirred at 110° C. for 2 h, then cooled to room temperature. The precipitate formed was filtered off, washed with acetic acid (2×5 mL) and dried under vacuum, to give a yellow solid. The crude compound was purified by triturating with 5% methanol in ether to give 4-isoquinolin-3-yl-phenol (0.83 g, 84%) as a white powder. Selected data: MS (ES) m/z: 222.89, 221.86; MP 218-219° C.
Reaction SMILES: [CH:1]1[CH:2]=[CH:3][C:4]([C:23]([OH:25])=[O:24])=[C:5]([C:7]2[C:17]3[CH:18]=[CH:19][C:20]([OH:22])=[CH:21][C:16]=3[O:15][C:14]3[C:8]=2[CH:9]=[CH:10][C:11]([CH:13]=3)=[O:12])[CH:6]=1.C(=O)([O-])[O-].[K+].[K+].[CH2:32](Cl)[C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1.[CH3:40][C:41]([CH3:43])=O>CN(C)C=O>[CH:36]1[CH:37]=[CH:38][C:33]([CH2:32][O:12][C:11]2[CH:10]=[CH:9][C:8]3[C:7]([C:5]4[C:4]([C:23]([O:25][CH2:40][C:41]5[CH:43]=[CH:5][CH:6]=[CH:1][CH:2]=5)=[O:24])=[CH:3][CH:2]=[CH:1][CH:6]=4)=[C:17]4[C:16]([O:15][C:14]=3[CH:13]=2)=[CH:21][C:20](=[O:22])[CH:19]=[CH:18]4)=[CH:34][CH:35]=1
Reactant: O=C(O)c1ccccc1-c1c2ccc(=O)cc-2oc2cc(O)ccc12
Reactant: CC(C)=O
Reactant: ClCc1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: O=C(OCc1ccccc1)c1ccccc1-c1c2ccc(=O)cc-2oc2cc(OCc3ccccc3)ccc12
Temperature: 80 °C

Procedure:
Fluorescein (40 g, 120.5 mmol) was dissolved in dimethylformamide (DMF, 500 mL) in a 2 L flask fitted with a mechanical stirrer then potassium carbonate (72 g, 521.7 mmol) was added in as a single portion. The reaction was heated to 80° C. then benzyl chloride (42 mL, 363.5 mmol) was added dropwise. After 24 h at 80° C. the reaction was cooled down to room temperature. Acetone (400 mL) was added and the product was allowed to precipitate overnight. The solid orange product was filtered, washed with acetone and dried in a vacuum oven at 50° C. The O-benzylfluorescein benzyl ester was obtained as an orange solid (36.4 g, 59%): mp 192-193° C. (Lit. 193-194° C.); 1H NMR (DMSO-d6): 4.97 (dd, 2H, J=12.2 Hz, J=15.3 Hz), 5.28 (s, 2H), 6.13 (d, 1H, J=1.9 Hz), 6.36 (dd, 1H, J=9.9 Hz), 6.77 (d, 1H, J=9.9 Hz), 6.82 6.77 (d, 1H, J=9.0 Hz), 6.90-6.98 (m, 3H), 7.14-7.27 (m, 4H), 7.33-7.52 (m, 6H), 7.78 (dt, 1H, J=1.65 Hz, J=7.4 Hz), 8.23 (dd, 1H, J=1.35 Hz, J=7.7 Hz); 13C NMR (DMSO-d6): 67.4, 70.7, 101.9, 105.2, 114.7, 115.0, 117.3, 128.3, 128.5, 128.7, 128.8, 128.9, 129.4, 130.0, 130.2, 130.6, 130.8, 131.2, 131.4, 133.8, 134.1, 135.3, 136.6, 150.1, 153.9, 158.7, 163.3, 165.5, 184.4; IR (nujol) cm−1 1728, 1643, 1595, 1517, 1462, 1377, 1261, 1211, 1081, 855. C34H24O5: Calc.(C, 79.67; H, 4.72) Found (C, 79.74; H, 4.79).
Reaction SMILES: [CH3:1][C:2]1[N:3]=[C:4]([C:9]2[CH:10]=[N:11][C:12]([C:15]([F:18])([F:17])[F:16])=[CH:13][CH:14]=2)[S:5][C:6]=1[CH2:7][OH:8].[Cl:19][C:20]1[CH:27]=[C:26](O)[CH:25]=[CH:24][C:21]=1[C:22]#[N:23].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.CCOC(/N=N/C(OCC)=O)=O.OO>O1CCCC1.C(OCC)C>[Cl:19][C:20]1[CH:27]=[C:26]([O:8][CH2:7][C:6]2[S:5][C:4]([C:9]3[CH:10]=[N:11][C:12]([C:15]([F:18])([F:16])[F:17])=[CH:13][CH:14]=3)=[N:3][C:2]=2[CH3:1])[CH:25]=[CH:24][C:21]=1[C:22]#[N:23]
Reactant: Cc1nc(-c2ccc(C(F)(F)F)nc2)sc1CO
Reactant: N#Cc1ccc(O)cc1Cl
Agent: CCOC(=O)/N=N/C(=O)OCC
Agent: OO
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CCOCC
Solvent: C1CCOC1
Product: Cc1nc(-c2ccc(C(F)(F)F)nc2)sc1COc1ccc(C#N)c(Cl)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 49 %

Procedure:
To an ice cooled solution of 2.76 g [4-Methyl-2-(6-trifluoromethyl-pyridin-3-yl)-thiazol-5-yl]-methanol, 2.06 g 2-chloro-4-hydroxybenzonitrile and 3.03 g triphenylphosphine in 30 ml tetrahydrofuran were added 1.74 ml diethylazodicarboxyate. The reaction mixture was stirred at room temperature overnight. 0.56 ml 30% H2O2 were added and the reaction mixture diluted by addition of 200 ml diethylether. The organic layer was washed with 50 ml 1N NaOH and 50 ml water, dried over MgSO4. The solvent was removed in vacuo. The resulting residue was purified by reversed phase HPLC to obtain 2.02 g 2-Chloro-4-[4-methyl-2-(6-trifluoromethyl-pyridin-3-yl)-thiazol-5-ylmethoxy]-benzonitrile as a lyophilisate.
Reaction SMILES: [CH:1]([CH:3]1[CH:8]([CH3:9])[CH:7]2[CH2:10][CH:4]1[CH2:5][CH2:6]2)=O.[C:11]([CH2:13]C(O)=O)#[N:12].[OH-].[NH4+].CN(C)C=O>C1C=CC=CC=1>[C:11]([CH2:13][CH:1]=[C:3]1[CH:8]([CH3:9])[CH:7]2[CH2:10][CH:4]1[CH2:5][CH2:6]2)#[N:12]
Reactant: CC1C2CCC(C2)C1C=O
Reactant: N#CCC(=O)O
Agent: [NH4+]
Agent: [OH-]
Solvent: CN(C)C=O
Solvent: c1ccccc1
Product: CC1C(=CCC#N)C2CCC1C2
Yield: 77 %

Procedure:
A stirred solution of 97 g (0.7 mol) of 2-formyl-3-methylbicyclo[2.2.1]heptane 65 g (0.76 mol) of cyanoacetic acid, 2 ml of ammonium hydroxide (58%), 132 ml of dimethylformamide, and 170 ml benzene was heated to reflux and the water removed with a Dean-Stark trap. The reaction was allowed to continue until the evolution of carbon dioxide ceased (approx. 24 hrs.). Upon completion, the reaction was cooled and the solvent removed under reduced pressure. The residual oil was distilled under vacuum to give 87 g (77% yield) of 2-(2-cyanoethylidene)-3-methylbicyclo[2.2.1]heptane: b.p. 72°-85° C./1 mm; ir 2940, 2870, 2220, 1610, 1450, 1380, 830, 740; nmr 0.9-1.1 (3H, m), 1.2-2.8 (9H, m), 2.85-3.2 (2H, m), 4.8-5.4 (1H, m); ms 161.
Reaction SMILES: [Cl-:1].[C:2]([O:5][C:6]1[C:7]([CH3:22])=[C:8]2[C:13](=[C:14]([CH3:17])[C:15]=1[CH3:16])[O:12][C:11]([CH3:21])([C:18](O)=[O:19])[CH2:10][CH2:9]2)(=[O:4])[CH3:3]>ClC1C=CC=CC=1>[C:2]([O:5][C:6]1[C:7]([CH3:22])=[C:8]2[C:13](=[C:14]([CH3:17])[C:15]=1[CH3:16])[O:12][C:11]([CH3:21])([C:18]([Cl:1])=[O:19])[CH2:10][CH2:9]2)(=[O:4])[CH3:3]
Reactant: [Cl-]
Reactant: CC(=O)Oc1c(C)c(C)c2c(c1C)CCC(C)(C(=O)O)O2
Solvent: Clc1ccccc1
Product: CC(=O)Oc1c(C)c(C)c2c(c1C)CCC(C)(C(=O)Cl)O2

Procedure:
To a mixture of 1.34 g. of dimethylchloroformimium chloride and 12 ml of chlorobenzene were added 2.92 g of (±)-6-acetoxy-2,5,7,8-tetramethylchroman-2-carboxylic acid. The resulting solution was heated at 110° under N2 for 40 min and stripped of solvent to give (±) 6-acetoxy-2,5,7,8 tetramethylchroman-2-carboxylic acid chloride as a light yellow, very viscous gum. To a mixture of 2.89 mmoles of this material in 4 ml of acetone was added 0.43 ml of triethylamine and 90 mg of 10% palladium on carbon catalyst. The mixture was hydrogenated at atmospheric pressure and room temperature. Uptake ceased after 1.0 hr. The suspension was filtered and the filtrate was stripped of solvent, taken up in ether, washed with saturated aqueous sodium bicarbonate solution, 2N aqueous HCl, and brine, dried over sodium sulfate and stripped of solvent. The residue was chromatographed on silica gel with 8:2 parts by volume benzene-ethyl acetate and then crystallized from 30°-60° petroleum ether to give (±)-6-acetoxy-2,5,7,8-tetramethylchroman-2-carboxaldehyde as a white solid, m.p. 92.5°-96°.
Reaction SMILES: Cl.[CH3:2][S:3]([C:6]1[CH:12]=[CH:11][C:9]([NH2:10])=[CH:8][CH:7]=1)(=[O:5])=[O:4].C[Al](C)C.[CH3:17][C:18]1[CH:19]=[CH:20][C:21]([C:24]#[N:25])=[N:22][CH:23]=1>C1(C)C=CC=CC=1.C(Cl)(Cl)Cl>[CH3:17][C:18]1[CH:19]=[CH:20][C:21]([C:24](=[NH:25])[NH:10][C:9]2[CH:11]=[CH:12][C:6]([S:3]([CH3:2])(=[O:4])=[O:5])=[CH:7][CH:8]=2)=[N:22][CH:23]=1
Reactant: Cc1ccc(C#N)nc1
Reactant: CS(=O)(=O)c1ccc(N)cc1
Agent: C[Al](C)C
Agent: Cl
Solvent: ClC(Cl)Cl
Solvent: Cc1ccccc1
Product: Cc1ccc(C(=N)Nc2ccc(S(C)(=O)=O)cc2)nc1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a suspension of 4-(methylsulfonyl)aniline hydrochloride (10 mmol) in toluene (60 ml) at 0° C., trimethylaluminum (2M solution in toluene, 10 ml, 20 mmol) is added over 10 minutes. The reaction mixture is allowed to warm to room temperature and stirred for 2 hours. A solution of 5-methyl-2-cyanopyridine (20 mmol) in toluene (100 ml) is added over 10 minutes and the mixture is heated to 85°-90° C. After 24 hours, the reaction mixture is cooled to room temperature and poured over a slurry of silica gel in chloroform. After filtration, the residue is washed with a mixture of methylene chloride and methanol and later with methanol. The combined filtrates are concentrated and the resulting solid is stirred with a mixture of hexane and ethyl acetate (1000 ml) and filtered. The product obtained is used in the next reaction without further purification.
Reaction SMILES: [C:1]([C:4]1[CH:13]=[CH:12][CH:11]=[C:10]([O:14][C:15]2[N:20]=[C:19]([O:21][CH3:22])[CH:18]=[C:17]([O:23][CH3:24])[N:16]=2)[C:5]=1[C:6]([O:8][CH3:9])=[O:7])(=O)[CH3:2].Cl.[CH2:26]([O:28][NH2:29])[CH3:27].C([O-])(=O)C.[K+].CO>O>[CH3:22][O:21][C:19]1[CH:18]=[C:17]([O:23][CH3:24])[N:16]=[C:15]([O:14][C:10]2[CH:11]=[CH:12][CH:13]=[C:4]([C:1](=[N:29][O:28][CH2:26][CH3:27])[CH3:2])[C:5]=2[C:6]([O:8][CH3:9])=[O:7])[N:20]=1
Reactant: COC(=O)c1c(Oc2nc(OC)cc(OC)n2)cccc1C(C)=O
Reactant: CCON
Agent: CC(=O)[O-]
Agent: Cl
Agent: [K+]
Solvent: O
Solvent: CO
Product: CCON=C(C)c1cccc(Oc2nc(OC)cc(OC)n2)c1C(=O)OC
Reaction time: 5 h
Yield: 67.3 %

Procedure:
1.0 g of methyl 2-acetyl-6-[(4,6-dimethoxypyrimidin-2-yl)oxy]benzoate, 1.18 g of ethoxyamine hydrochloride and 1.18 g of potassium acetate were added to 30 ml of methanol, and the resultant mixture was refluxed with stirring for 5 hours. The reaction mixture was then poured into a cold water, and was extracted with ethyl acetate. The organic layer thus formed was washed with firstly dilute hydrochloric acid, then aqueous solution of sodium hydrogencarbonate and water in sequence. The organic layer was then dried and concentrated to obtain a solid. The solid product thus obtained was washed with n-hexane to obtain 0.76 g of the aimed compound (melting point=93° to 95° C.) at a yield of 67% as a colorless transparent crystal.
Reaction SMILES: [F:1][C:2]([F:16])([C:6]1[CH:11]=[CH:10][C:9]([C:12]([O:14][CH3:15])=[O:13])=[CH:8][CH:7]=1)[C:3]([OH:5])=O.[CH3:17][O:18][C:19]1[CH:28]=[CH:27][CH:26]=[CH:25][C:20]=1[C:21]([NH:23][NH2:24])=[O:22].[Cl-].C(N=C=NCCC[NH+](C)C)C>C(Cl)Cl>[F:16][C:2]([C:6]1[CH:11]=[CH:10][C:9]([C:12]([O:14][CH3:15])=[O:13])=[CH:8][CH:7]=1)([F:1])[C:3]([NH:24][NH:23][C:21](=[O:22])[C:20]1[CH:25]=[CH:26][CH:27]=[CH:28][C:19]=1[O:18][CH3:17])=[O:5]
Reactant: COc1ccccc1C(=O)NN
Reactant: COC(=O)c1ccc(C(F)(F)C(=O)O)cc1
Agent: CCN=C=NCCC[NH+](C)C
Agent: [Cl-]
Solvent: ClCCl
Product: COC(=O)c1ccc(C(F)(F)C(=O)NNC(=O)c2ccccc2OC)cc1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
To a solution of difluoro[4-(methoxycarbonyl)phenyl]acetic acid (0.12 g, 0.52 mmol) and 2-methoxybenzohydrazide (0.13 g, 0.78 mmol) in methylene chloride (2 mL) was added 3-{[(ethylimino)methylene]amino}-N,N-dimethylpropan-1-aminium chloride (0.2 g, 1.04 mmol). The resulting solution was stirred at ambient temperature for 16 hours. The reaction was purified by flash chromatography (0-4% methanol/methylene chloride) to give methyl 4-{1,1-difluoro-2-[2-(2-methoxybenzoyl)hydrazino]-2-oxoethyl}benzoate as a white solid. ESIMS calcd 379.1 (M++H), found 379.1 (M++H).
Reaction SMILES: C(Cl)(=O)C([Cl:4])=O.[C:7]([C:9]1[N:17]=[CH:16][CH:15]=[CH:14][C:10]=1[C:11]([O-:13])=[O:12])#[N:8].[K+].[CH:19](Cl)(O)[CH:20]([Cl:22])[Cl:21].N1C=CC=CC=1>ClCCl.O>[C:7]([C:9]1[N:17]=[CH:16][CH:15]=[CH:14][C:10]=1[C:11]([O:13][CH2:19][C:20]([Cl:22])([Cl:4])[Cl:21])=[O:12])#[N:8]
Reactant: OC(Cl)C(Cl)Cl
Reactant: O=C(Cl)C(=O)Cl
Reactant: N#Cc1ncccc1C(=O)[O-]
Agent: [K+]
Solvent: O
Solvent: c1ccncc1
Solvent: ClCCl
Product: N#Cc1ncccc1C(=O)OCC(Cl)(Cl)Cl
Yield: 74 %

Procedure:
Oxalyl chloride (2.8 g; 0.022 mol) is added to a suspension of compound 3 (4.1 g; 0.022 mol) in dichloromethane (50 cc). The mixture is heated under reflux until gas evolution ceases and then treated with a solution of trichloroethanol (3.3 g; 0.022 mol) and pyridine (3.5 g; 0.044 mol) in dichloromethane (30 cc). The mixture is then treated with water and then dried. After evaporation of the solvent and crystallization in pentane, 2,2,2-tri-chloroethyl 2-cyanonicotinate (4.55 g; m.p. 103° C.) is obtained (yield=78%).
Reaction SMILES: [Br-:1].[CH2:2]([N:4]1[C:8]([C:9]2[CH:14]=[CH:13][C:12]([OH:15])=[CH:11][CH:10]=2)=[CH:7][NH+:6](CC2C=CC=CC=2)[CH2:5]1)[CH3:3].[H][H]>[Pd].C(O)C>[BrH:1].[CH2:2]([N:4]1[C:8]([C:9]2[CH:14]=[CH:13][C:12]([OH:15])=[CH:11][CH:10]=2)=[CH:7][N:6]=[CH:5]1)[CH3:3]
Reactant: [Br-]
Reactant: [H][H]
Reactant: CCN1C[NH+](Cc2ccccc2)C=C1c1ccc(O)cc1
Agent: [Pd]
Solvent: CCO
Product: Br
Product: CCn1cncc1-c1ccc(O)cc1

Procedure:
A mixture of 7 parts of 3-ethyl-4-(4-hydroxyphenyl)-1-(phenylmethyl)-1H-imidazolium bromide and 120 parts of ethanol is hydrogenated at normal pressure and at room temperature with 2 parts of palladium-on-charcoal catalyst 10%. After the calculated amount of hydrogen is taken up, the catalyst is filtered off and the filtrate is evaporated. The oily residue solidifies on scratching in 2-propanone. The product is filtered off and dried, yielding 5 parts of 4-(1-ethyl-1H-imidazol-5-yl)phenol monohydrobromide.