Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [ClH:1].Cl.[F:3][C:4]1[CH:5]=[C:6]([CH:8]=[C:9]([CH2:17][NH:18][CH3:19])[C:10]=1[O:11][C@@H:12]1[CH2:16][CH2:15][O:14][CH2:13]1)[NH2:7].CCN(C(C)C)C(C)C.[CH2:29]([O:36][C:37]([O:39]N1C(=O)CCC1=O)=O)[C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1>CN(C=O)C>[ClH:1].[NH2:7][C:6]1[CH:5]=[C:4]([F:3])[C:10]([O:11][C@@H:12]2[CH2:16][CH2:15][O:14][CH2:13]2)=[C:9]([CH:8]=1)[CH2:17][N:18]([CH3:19])[C:37](=[O:39])[O:36][CH2:29][C:30]1[CH:31]=[CH:32][CH:33]=[CH:34][CH:35]=1
Reactant: CNCc1cc(N)cc(F)c1O[C@@H]1CCOC1
Reactant: O=C(OCc1ccccc1)ON1C(=O)CCC1=O
Agent: Cl
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CN(Cc1cc(N)cc(F)c1O[C@@H]1CCOC1)C(=O)OCc1ccccc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 76.1 %

Procedure:
To 38B (200 mg, 0.639 mmol) and DIEA (0.445 ml, 2.55 mmol) in DMF (10 mL), was added N-(benzyloxycarbonyloxy) succinimide (167 mg, 0.671 mmol). The mixture was stirred at rt for 1 h, then quenched with H2O. The mixture was extracted with EtOAc (3×) and the organic layer was washed with 1N HCl, sat. NaHCO3, brine, and dried over Na2SO4. The crude was purified by flash column chromatography (0-60% EtOAc/hexanes) to give 38C (182 mg, 0.486 mmol, 76% yield). MS (ESI) m/z: 375.3 (M+H)+.
Reaction SMILES: Cl[C:2]1[CH:11]=[C:10]([C:12]([F:15])([F:14])[F:13])[C:5]([C:6]([O:8][CH3:9])=[O:7])=[CH:4][N:3]=1.[F:16][C:17]([F:38])([F:37])[C:18]1[CH:19]=[C:20]([C:28]2([C:33]([F:36])([F:35])[F:34])[CH2:32][CH2:31][NH:30][CH2:29]2)[CH:21]=[C:22]([C:24]([F:27])([F:26])[F:25])[CH:23]=1.C(=O)([O-])[O-].[K+].[K+].O>CN(C)C=O.C(OCC)(=O)C>[F:26][C:24]([F:25])([F:27])[C:22]1[CH:21]=[C:20]([C:28]2([C:33]([F:36])([F:34])[F:35])[CH2:32][CH2:31][N:30]([C:2]3[CH:11]=[C:10]([C:12]([F:15])([F:14])[F:13])[C:5]([C:6]([O:8][CH3:9])=[O:7])=[CH:4][N:3]=3)[CH2:29]2)[CH:19]=[C:18]([C:17]([F:16])([F:37])[F:38])[CH:23]=1
Reactant: FC(F)(F)c1cc(C(F)(F)F)cc(C2(C(F)(F)F)CCNC2)c1
Reactant: COC(=O)c1cnc(Cl)cc1C(F)(F)F
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: COC(=O)c1cnc(N2CCC(c3cc(C(F)(F)F)cc(C(F)(F)F)c3)(C(F)(F)F)C2)cc1C(F)(F)F
Temperature: 80 °C
Yield: 65.3 %

Procedure:
Methyl 6-chloro-4-(trifluoromethyl)nicotinate (2.39 g), 3-[3,5-bis(trifluoromethyl)-phenyl]-3-(tri-fluoromethyl)pyrrolidine (2.98 g) and potassium carbonate (1.8 g) were suspended in dimethylformamide (50 ml). The reaction mixture was heated for 8 hours at 80° C. Water and ethyl acetate were added and the extraction was carried out. The extract was dried over magnesium sulfate, filtered and concentrated under reduced pressure. The target compound (3.07 g) was obtained by purification with silica gel column chromatography.
Reaction SMILES: [CH3:1][NH:2][C:3]([NH:5][C:6]1[S:10][N:9]=[C:8]([C:11]([Cl:14])([Cl:13])[Cl:12])[N:7]=1)=[O:4].[C:15]([N:23]=[C:24]=[O:25])(=[O:22])[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1.NC(N)=O>C1C=CC=CC=1>[C:15]([NH:23][C:24]([N:2]([CH3:1])[C:3]([NH:5][C:6]1[S:10][N:9]=[C:8]([C:11]([Cl:12])([Cl:14])[Cl:13])[N:7]=1)=[O:4])=[O:25])(=[O:22])[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1
Reactant: CNC(=O)Nc1nc(C(Cl)(Cl)Cl)ns1
Reactant: O=C=NC(=O)c1ccccc1
Agent: NC(N)=O
Solvent: c1ccccc1
Product: CN(C(=O)NC(=O)c1ccccc1)C(=O)Nc1nc(C(Cl)(Cl)Cl)ns1
Temperature: 145 °C
Yield: 35.5 %

Procedure:
A glass pressure vessel was charged with 5.5 grams (0.02 mole) 1-methyl-3-(3-trichloromethyl-1,2,4-thiadiazol-5-yl)urea, 3.2 grams (0.02 mole) benzoyl isocyanate and 50 milliliters benzene. A magnetic stirring bar was added and the vessel sealed. The stirred reaction mixture was heated at 145° C. for 1.5 hours and then allowed to cool to room temperature where 4.5 grams of starting urea precipitates. The urea was removed by filtration and the filtrate concentrated in vacuo to leave 3.0 grams of residue. Extraction of the residue with hot cyclohexane, followed by cooling the extract yielded 0.2 grams (11% selectivity) of pure product; m.p. 70° C.
Reaction SMILES: [N:1]([C:4]1[CH:17]=[CH:16][C:7]([O:8][CH2:9][CH2:10][N:11]2[CH2:15]CC[CH2:12]2)=[CH:6][CH:5]=1)=[C:2]=[S:3].CN(C)CCOC1C=CC(N)=CC=1>>[N:1]([C:4]1[CH:17]=[CH:16][C:7]([O:8][CH2:9][CH2:10][N:11]([CH3:12])[CH3:15])=[CH:6][CH:5]=1)=[C:2]=[S:3]
Reactant: S=C=Nc1ccc(OCCN2CCCC2)cc1
Agent: CN(C)CCOc1ccc(N)cc1
Product: CN(C)CCOc1ccc(N=C=S)cc1

Procedure:
The title compound is prepared as described in Example 1 for 1-[2-(4-isothiocyanato-phenoxy)-ethyl]-pyrrolidine but using 4-(2-dimethylamino-ethoxy)-phenylamine. Title compound: ES-MS: 223.0 [M+H]+; single peak at tR=6.52 min (System 1).
Reaction SMILES: [CH:1]([CH:3]1[CH2:7][N:6]([C:8]2[C:12]([NH:13][C:14](=[O:20])[O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[CH:11][N:10]([CH3:21])[N:9]=2)[C:5](=[O:22])[C:4]1([CH3:24])[CH3:23])=O.[CH3:25][NH:26][CH3:27].C1COCC1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].C(=O)([O-])O.[Na+]>C1COCC1.C(O)(=O)C>[CH3:25][N:26]([CH2:1][CH:3]1[CH2:7][N:6]([C:8]2[C:12]([NH:13][C:14](=[O:20])[O:15][C:16]([CH3:18])([CH3:19])[CH3:17])=[CH:11][N:10]([CH3:21])[N:9]=2)[C:5](=[O:22])[C:4]1([CH3:23])[CH3:24])[CH3:27]
Reactant: Cn1cc(NC(=O)OC(C)(C)C)c(N2CC(C=O)C(C)(C)C2=O)n1
Reactant: CNC
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CC(=O)O
Product: CN(C)CC1CN(c2nn(C)cc2NC(=O)OC(C)(C)C)C(=O)C1(C)C
Temperature: 25 °C
Reaction time: 16 h

Procedure:
To a solution of tert-butyl (3-(4-formyl-3,3-dimethyl-2-oxopyrrolidin-1-yl)-1-methyl-1H-pyrazol-4-yl)carbamate (173 mg) obtained in Step D of Example 4, 2M dimethylamine THF solution (0.39 mL) and acetic acid (30 μL) in THF (5.0 mL) was added sodium triacetoxyborohydride (220 mg). The reaction mixture was stirred at room temperature for 16 hr, saturated aqueous sodium hydrogen carbonate solution was added thereto, and the mixture was extracted with ethyl acetate. The extract was washed with saturated brine, and dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (NH, ethyl acetate/hexane), and then HPLC (C18, mobile phase: water/acetonitrile (containing 0.1% TFA)), and the obtained fraction was concentrated under reduced pressure to give the title compound (112 mg).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:8]2[O:12][N:11]=[C:10]([C:13](=[O:15])[CH3:14])[CH:9]=2)[CH:5]=[CH:6][CH:7]=1.[BH4-].[Na+]>CO>[Cl:1][C:2]1[CH:3]=[C:4]([C:8]2[O:12][N:11]=[C:10]([CH:13]([OH:15])[CH3:14])[CH:9]=2)[CH:5]=[CH:6][CH:7]=1
Reactant: CC(=O)c1cc(-c2cccc(Cl)c2)on1
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Product: CC(O)c1cc(-c2cccc(Cl)c2)on1
Yield: 109.3 %

Procedure:
In a screw cap vial equipped with stir bar added the title compound of Example 6.1 (100 mg, 0.45 mmol), sodium borohydride (34 mg, 0.90 mmol) and methanol (3 mL). The resulting mixture was stirred at room temperature for 3 h. The reaction was quenched with water (30 mL) and brine (30 mL), extracted with dichloromethane (3 times 30 mL). The combined organic phase was dried (sodium sulfate), filtered and concentrated, in vacuo to isolate the title compound as a white solid (110 mg).
Reaction SMILES: C(OC(=O)C([C@H](CC1C=CC=CC=1)COC)(N)[C@@H](C(OC(C)(C)C)=O)C(N)=O)C1C=CC=CC=1.[C:35]1([C:50]2[CH:55]=[CH:54][CH:53]=[CH:52][CH:51]=2)[CH:40]=[CH:39][C:38]([C:41]2[O:42][C:43]([CH2:46][C:47]([OH:49])=O)=[CH:44][CH:45]=2)=[CH:37][CH:36]=1.FC(F)(F)C(O)=O.[CH3:63][NH:64][C:65](=[O:72])[C@H:66]([C:68]([CH3:71])([CH3:70])[CH3:69])[NH2:67].F[P-](F)(F)(F)(F)F.N1(O[P+](N(C)C)(N(C)C)N(C)C)C2C=CC=CC=2N=N1>CO.C(Cl)Cl>[CH3:69][C:68]([CH3:71])([CH3:70])[C@H:66]([NH:67][C:47](=[O:49])[CH2:46][C:43]1[O:42][C:41]([C:38]2[CH:37]=[CH:36][C:35]([C:50]3[CH:55]=[CH:54][CH:53]=[CH:52][CH:51]=3)=[CH:40][CH:39]=2)=[CH:45][CH:44]=1)[C:65](=[O:72])[NH:64][CH3:63]
Reactant: CNC(=O)[C@@H](N)C(C)(C)C
Reactant: O=C(O)Cc1ccc(-c2ccc(-c3ccccc3)cc2)o1
Agent: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Agent: COC[C@@H](Cc1ccccc1)C(N)(C(=O)OCc1ccccc1)[C@H](C(N)=O)C(=O)OC(C)(C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: ClCCl
Solvent: CO
Solvent: O=C(O)C(F)(F)F
Product: CNC(=O)[C@@H](NC(=O)Cc1ccc(-c2ccc(-c3ccccc3)cc2)o1)C(C)(C)C
Yield: 58 %

Procedure:
According to the procedure described in Example 1(f) for the preparation of N-(1(S)-benzyl-2-methoxy-ethyl-3(R)-t-butoxycarbonyl-amino-succinamic acid benzyl ester, 2-(2-biphenyl-4-yl-furan-5-yl)-acetic acid was coupled to L-t-leucine N-methylamide trifluoroacetic acid salt with BOP. Flash column chromatography with 0-5% MeOH/CH2Cl2 gradient eluant provided in 58% yield N-[2,2-dimethyl-1(S)-(N-methyl-carbamoyl)-propyl)-2-(2-biphenyl-4-yl-furan-5-yl)-acetamide as an orange foam, which decomposed >75° C. and was used without further purification. 1H NMR (acetone-d6): δ 7.72 (d, 2H, J=8.5 Hz), 7.61 (d, 4H, J=7.7 Hz), 7.45 (t, 2H, J=7.5 Hz), 7.35 (t, 1H, J=7.4 Hz), 6.65 (d, 1H, J=3.3 Hz), 6.56 (d, 1H, J=9.2 Hz), 6.36 (d, 1H, J=3.3 Hz), 5.9 (bs, 1H), 4.22 (d, 1H, J=9.2 Hz), 3.71 (s, 2H), 2.79 (d, 3H, J=4.5 Hz), 0.94 (s, 9H). Anal. Calculated for C25H28N2O3.0.6 H2O.0.1 MTBE: C, 72.21; H, 7.23; N, 6.61. Found: C, 72.10; H, 6.97; N, 6.39.
Reaction SMILES: C1(OC2C=CC=CC=2)C=CC=CC=1.C(O[C:17]([C:19]([C:33](=[O:35])[CH3:34])=[CH:20][NH:21][C:22]1[CH:32]=[CH:31][C:25]([C:26]([O:28][CH2:29][CH3:30])=[O:27])=[CH:24][CH:23]=1)=[O:18])C>CCCCCC>[C:33]([C:19]1[C:17](=[O:18])[C:23]2[C:22](=[CH:32][CH:31]=[C:25]([C:26]([O:28][CH2:29][CH3:30])=[O:27])[CH:24]=2)[NH:21][CH:20]=1)(=[O:35])[CH3:34]
Reactant: CCOC(=O)C(=CNc1ccc(C(=O)OCC)cc1)C(C)=O
Solvent: CCCCCC
Solvent: c1ccc(Oc2ccccc2)cc1
Product: CCOC(=O)c1ccc2[nH]cc(C(C)=O)c(=O)c2c1
Temperature: 225 °C
Reaction time: 0.5 h
Yield: 98.8 %

Procedure:
Diphenyl ether (150 ml, 943 mmol) was heated to boiling and ethyl 4-((2-(ethoxycarbonyl)-3-oxobut-1-en-1-yl)amino)benzoate (6.84 g, 22.40 mmol) was added slowly. After the addition, the reaction was allowed to stir at 200-250° C. for another 30 min. After cooling, the reaction was diluted with hexane, filtered, and the precipitate was washed with hexane/diethyl ether, collected and dried to give ethyl 3-acetyl-4-oxo-1,4-dihydroquinoline-6-carboxylate (5.74 g, 22.14 mmol, 99% yield) as tan solid. LCMS: (M+H)+: 260.0.
Reaction SMILES: [Cl:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:5]([OH:12])=[CH:4][N:3]=1.Cl[C:14]1[CH:21]=[CH:20][C:17]([C:18]#[N:19])=[CH:16][N:15]=1.C([O-])([O-])=O.[K+].[K+]>CN(C=O)C>[Cl:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:5]([O:12][C:14]2[CH:21]=[CH:20][C:17]([C:18]#[N:19])=[CH:16][N:15]=2)=[CH:4][N:3]=1
Reactant: Oc1cnc(Cl)c2ccccc12
Reactant: N#Cc1ccc(Cl)nc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: N#Cc1ccc(Oc2cnc(Cl)c3ccccc23)nc1
Temperature: 70 °C

Procedure:
To a solution of 1-chloro-4-hydroxyisoquinoline (1.0 g, 5.6 mmol) in DMF (16 mL), was added 6-chloronicotinonitrile (0.55 g, 4.0 mmol) and K2CO3 (1.65 g, 11.9 mmol). The reaction mixture was heated at 70° C. for 6.5 h. Solvent was removed in vacuo and residue partitioned between EtOAc (100 mL), THF (100 mL) and water (60 mL). The organic phase was washed with water (2×60 mL), 1M NaOH (2×40 mL), brine (40 mL) and dried (MgSO4). Solvent was removed in vacuo to give the title compound: RT=3.66 min; m/z (ES+)=282.0 [M+H]+.
Reaction SMILES: [NH:1]1[CH:5]=[CH:4][C:3]([C:6]2[CH:11]=[CH:10][N:9]3[C:12]([C:15]([OH:17])=O)=[CH:13][N:14]=[C:8]3[CH:7]=2)=[N:2]1.[NH2:18][C:19]1[CH:20]=[C:21]([C:26]2[N:30]=[C:29]([CH:31]3[CH2:34][N:33]([C:35]([O:37][CH3:38])=[O:36])[CH2:32]3)[O:28][N:27]=2)[CH:22]=[CH:23][C:24]=1[CH3:25].CCCP(=O)=O>C(OCC)(=O)C>[NH:1]1[CH:5]=[CH:4][C:3]([C:6]2[CH:11]=[CH:10][N:9]3[C:12]([C:15]([NH:18][C:19]4[CH:20]=[C:21]([C:26]5[N:30]=[C:29]([CH:31]6[CH2:34][N:33]([C:35]([O:37][CH3:38])=[O:36])[CH2:32]6)[O:28][N:27]=5)[CH:22]=[CH:23][C:24]=4[CH3:25])=[O:17])=[CH:13][N:14]=[C:8]3[CH:7]=2)=[N:2]1
Reactant: O=C(O)c1cnc2cc(-c3cc[nH]n3)ccn12
Reactant: COC(=O)N1CC(c2nc(-c3ccc(C)c(N)c3)no2)C1
Agent: CCCP(=O)=O
Solvent: CCOC(C)=O
Product: COC(=O)N1CC(c2nc(-c3ccc(C)c(NC(=O)c4cnc5cc(-c6cc[nH]n6)ccn45)c3)no2)C1
Temperature: 80 °C

Procedure:
To a stirring solution of 7-(1H-pyrazol-3-yl)imidazo[1,2-a]pyridine-3-carboxylic acid (63) (31.7 mg, 0.14 mmol), and methyl (3-(3-amino-4-methylphenyl)-1,2,4-oxadiazol-5-yl)methylcarbamate (31) (52 mg, 0.18 mmol) in ethyl acetate (0.1 mL) was added propylphosphonic anhydride (50 wt % in ethyl acetate 0.41 mL). The reaction was heated at 80° C. for 12 hours. The resulting mixture was diluted in ethyl acetate and washed with 1N Na2CO3. After aqueous workup, the residue was purified by reverse phase HPLC to afford methyl 3-(3-(3-(7-(1H-pyrazol-3-yl)imidazo[1,2-a]pyridine-3-carboxamido)-4-methylphenyl)-1,2,4-oxadiazol-5-yl)azetidine-1-carboxylate (F68). MS (m/z) 499.1 (M+1)+.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[CH:10]=[N:9][C:8]([CH3:11])=[CH:7][N:6]=1)=[O:4].C1C(=O)N([Br:19])C(=O)C1.C(OOC(=O)C1C=CC=CC=1)(=O)C1C=CC=CC=1>C(Cl)(Cl)(Cl)Cl>[CH3:1][O:2][C:3]([C:5]1[CH:10]=[N:9][C:8]([CH2:11][Br:19])=[CH:7][N:6]=1)=[O:4]
Reactant: COC(=O)c1cnc(C)cn1
Reactant: O=C1CCC(=O)N1Br
Agent: O=C(OOC(=O)c1ccccc1)c1ccccc1
Solvent: ClC(Cl)(Cl)Cl
Product: COC(=O)c1cnc(CBr)cn1
Temperature: 25 °C
Reaction time: 1 h
Yield: 29.6 %

Procedure:
To a solution of 5-methyl-pyrazine-2-carboxylic acid methyl ester (2.0 g, 13.146 mmol) in CCl4 (25 mL0 was added NBS (2.57 g, 14.461 mmol) and benzoyl peroxide (0.318 g, 1.314 mmol) and the solution was heated at 70 C. for 1 h. Upon cooling to RT, the organic layer was washed with NaHCO3, water, dried (Na2SO4), and concentrated under reduced pressure to give 0.900 g 5-Bromomethyl-pyrazine-2-carboxylic acid methyl ester.
Reaction SMILES: C(OC([N:11]1[CH2:15][CH2:14][CH2:13][C@H:12]1[C:16]1[N:17]=[C:18]([C:21]2[CH:26]=[CH:25][C:24]([CH:27]3[CH2:32][CH2:31][CH:30]([C:33]4[N:34]=[C:35]([C@@H:38]5[CH2:42][CH2:41][CH2:40][N:39]5C(OCC5C=CC=CC=5)=O)[NH:36][CH:37]=4)[CH2:29][CH2:28]3)=[CH:23][CH:22]=2)[NH:19][CH:20]=1)=O)C1C=CC=CC=1.C(Cl)(=O)C.[Cl-].[Al+3].[Cl-].[Cl-].Cl>ClCCl.C(OCC)(=O)C>[NH:39]1[CH2:40][CH2:41][CH2:42][C@H:38]1[C:35]1[NH:36][CH:37]=[C:33]([CH:30]2[CH2:31][CH2:32][CH:27]([C:24]3[CH:25]=[CH:26][C:21]([C:18]4[NH:19][CH:20]=[C:16]([C@@H:12]5[CH2:13][CH2:14][CH2:15][NH:11]5)[N:17]=4)=[CH:22][CH:23]=3)[CH2:28][CH2:29]2)[N:34]=1
Reactant: O=C(OCc1ccccc1)N1CCC[C@H]1c1c[nH]c(-c2ccc(C3CCC(c4c[nH]c([C@@H]5CCCN5C(=O)OCc5ccccc5)n4)CC3)cc2)n1
Agent: Cl
Agent: [Al+3]
Agent: [Cl-]
Solvent: ClCCl
Solvent: CCOC(C)=O
Solvent: CC(=O)Cl
Product: c1cc(C2CCC(c3c[nH]c([C@@H]4CCCN4)n3)CC2)ccc1-c1nc([C@@H]2CCCN2)c[nH]1
Temperature: 25 °C
Reaction time: 8 h
Yield: 202.9 %

Procedure:
To a solution of A5 (19.2 g) in dichloromethane (500 mL) at −20° C. was added acetyl chloride (16.8 mL), followed by aluminum chloride (43 g). The reaction was allowed to warm up to rt. After overnight stirring, the reaction was poured into a mixture of ethyl acetate (800 mL), 1M HCl (800 mL) along with some ice. After separating the organic layer, the aqueous layer was extracted with ethyl acetate (3×300 mL). The combined organic layers were washed with brine, H2O, dried over Na2SO4, filtered, and concentrated to afford A6 (24 g), which was used for next reaction without further purification.
Reaction SMILES: [NH2:1][C:2]1[C:3]([CH3:9])=[C:4]([OH:8])[CH:5]=[CH:6][CH:7]=1.[C:10]([O:14][C:15](=O)[O:16]C(C)(C)C)([CH3:13])([CH3:12])[CH3:11]>C1COCC1>[C:10]([O:14][C:15]([NH:1][C:2]1[C:3]([CH3:9])=[C:4]([OH:8])[CH:5]=[CH:6][CH:7]=1)=[O:16])([CH3:13])([CH3:12])[CH3:11]
Reactant: Cc1c(N)cccc1O
Reactant: CC(C)(C)OC(=O)OC(C)(C)C
Solvent: C1CCOC1
Product: Cc1c(O)cccc1NC(=O)OC(C)(C)C
Yield: 69 %

Procedure:
3-Amino-2-methylphenol (2.0 g; 16 mmol) and di-t-butylcarbonate were dissolved in THF (20 mL) and refluxed overnight. Evaporation of the solvent followed by flash chromatography (SiO2; EtOAc 5-30% in isohexane) afforded 2.48 g (69%) of the sub-title compound.
Reaction SMILES: [C:1]([C:4]1[CH:17]=[C:16]([O:18][CH3:19])[CH:15]=[CH:14][C:5]=1[CH:6]=[C:7]1[S:11]C(=S)N[C:8]1=[O:13])([OH:3])=O.[OH-:20].[Na+].Cl>>[CH3:19][O:18][C:16]1[CH:15]=[CH:14][C:5]2[CH:6]=[C:7]([C:8]([OH:20])=[O:13])[S:11][C:1](=[O:3])[C:4]=2[CH:17]=1
Reactant: COc1ccc(C=C2SC(=S)NC2=O)c(C(=O)O)c1
Reactant: [OH-]
Agent: Cl
Agent: [Na+]
Product: COc1ccc2cc(C(=O)O)sc(=O)c2c1

Procedure:
A solution of the benzylidenerhodanine of Example 7 in 18 ml. of 15% NaOH is refluxed for 0.75 hour and poured into dilute HCl, whereupon a yellow solid forms. The solid is collected and recrystallized from ethanol to give 7-methoxy-1-oxo-1H-2-benzothiopyran-3-carboxylic acid as pale yellow needles, m.p. 291°-292°.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=2[CH2:14][N:15]2[CH2:20][CH2:19][N:18](C(OC(C)(C)C)=O)[CH2:17][CH2:16]2)=[CH:4][CH:3]=1.Cl>O1CCOCC1>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=2[CH2:14][N:15]2[CH2:16][CH2:17][NH:18][CH2:19][CH2:20]2)=[CH:4][CH:3]=1
Reactant: CC(C)(C)OC(=O)N1CCN(Cc2ccccc2-c2ccc(Cl)cc2)CC1
Agent: Cl
Solvent: C1COCCO1
Product: Clc1ccc(-c2ccccc2CN2CCNCC2)cc1
Reaction time: 8 h

Procedure:
A solution of EXAMPLE 22B (1.00 g, 2.59 mmol) in dioxane (20 mL) at room temperature was treated with 4N HCl in dioxane (19.4 mL, 77.7 mmol), stirred overnight. Solvent was removed under reduced pressure. The residue was further dried under vacuum and used for the next step without further purification.
Reaction SMILES: [F-:1].[K+].Cl[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[N+:10]([O-:12])=[O:11].C1(C)C(C)=CC=CC=1>[Cl-].C[N+](C)(C)C>[F:1][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[N+:10]([O-:12])=[O:11]
Reactant: O=[N+]([O-])c1ccccc1Cl
Reactant: [F-]
Agent: C[N+](C)(C)C
Agent: [Cl-]
Agent: [K+]
Solvent: Cc1ccccc1C
Product: O=[N+]([O-])c1ccccc1F
Temperature: 180 °C
Reaction time: 21 h

Procedure:
In a 2-liter flange flask fitted with a distillation bridge and impeller stirrer, 278.4 g (4.8 mol) of potassium fluoride and 23.5 g (0.21 mol) of tetramethylammonium chloride were introduced at 120° C. into the melt of 939 g (6.0 mol) of 2-chloronitrobenzene. Subsequently, 4 g (0.38 mol) of xylene were added and the reaction suspension was heated to 180° C., the xylene was removed under reduced pressure and the mixture was stirred for 21 hours at this temperature. Amount of 2-fluoronitrobenzene formed, according to GC analysis:
Reaction SMILES: [Cl-].C[SiH](C)C.[Cl:6][C:7]1[CH:14]=[CH:13][CH:12]=[CH:11][C:8]=1[CH2:9]Br.[Cl:15][C:16]1[CH:21]=[C:20](Cl)[N:19]=[CH:18][N:17]=1.O>O1CCCC1.BrC(Br)C.[Zn]>[Cl:15][C:16]1[CH:21]=[C:20]([CH2:9][C:8]2[CH:11]=[CH:12][CH:13]=[CH:14][C:7]=2[Cl:6])[N:19]=[CH:18][N:17]=1
Reactant: Clc1ccccc1CBr
Reactant: Clc1cc(Cl)ncn1
Agent: CC(Br)Br
Agent: C[SiH](C)C
Agent: [Cl-]
Solvent: O
Solvent: C1CCOC1
Product: Clc1cc(Cc2ccccc2Cl)ncn1
Reaction time: 0.33 h
Yield: 34.9 %

Procedure:
In 10 ml of tetrahydrofuran was suspended 1.3 g of zinc (powder), to which dibromoethane (2 drops) was added. The mixture was heated under reflux for 5 minutes, to which trimethylsilane chloride was added. The mixture was further heated under reflux for 5 minutes, to which a solution of 2.1 g of 2-chlorobenzyl bromide dissolved in 20 ml of tetrahydrofuran was slowly added with heating under reflux, followed by stirring for 20 minutes. (The solution thus obtained is referred to as solution C). In 10 ml of tetrahydrofuran were suspended 1.5 g of 4,6-dichloropyrimidine and 0.1 g of dichlorobistriphenylphosphine palladium, to which the above solution C was added, followed by heating under reflux for 3 hours and further stirring at room temperature for 12 hours. The reaction mixture was then poured into water and extracted three times with ethyl acetate. The organic layers were combined, washed with water, dried over anhydrous magnesium sulfate, and then concentrated. The residue was subjected to silica gel column chromatography to give 0.84 g of 4-chloro-6-(2-chlorobenzyl)pyrimidine.
Reaction SMILES: [CH3:1][NH2:2].C(O[C:6](=[C:8]([C:11]#[N:12])[C:9]#[N:10])[CH3:7])C>CCOCC>[CH3:1][NH:2][C:6](=[C:8]([C:11]#[N:12])[C:9]#[N:10])[CH3:7]
Reactant: CN
Reactant: CCOC(C)=C(C#N)C#N
Solvent: CCOCC
Product: CNC(C)=C(C#N)C#N
Temperature: 25 °C

Procedure:
Add methylamine (1120 mL, 2.6 Eq.) to 2-(1-ethoxy-ethylidene)-malononitrile (115 g, 0.84 mol) in ether dropwise while stirring at room temperature under a nitrogen atmosphere. Stir at this temperature for 2 hours and then concentrate under reduced vacuum. Triturate the resulting solid in ethyl acetate (400 mL) and filter to produce 102 g of the title compound as a tan solid. Mass spectrum (m/e): 122.0 (M*+1): (Bruker 300)
Reaction SMILES: [CH3:1][N:2]1[C:7](=[O:8])[C:6]([C:9]2[CH2:13][CH:12]([C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=3)[O:11][N:10]=2)=[CH:5][C:4]([C:20]([OH:22])=O)=[N:3]1.[F:23][C:24]1[CH:29]=[CH:28][C:27]([CH2:30][NH2:31])=[CH:26][C:25]=1[O:32][CH3:33].C(N(C(C)C)C(C)C)C.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>CN(C=O)C>[F:23][C:24]1[CH:29]=[CH:28][C:27]([CH2:30][NH:31][C:20]([C:4]2[CH:5]=[C:6]([C:9]3[CH2:13][CH:12]([C:14]4[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=4)[O:11][N:10]=3)[C:7](=[O:8])[N:2]([CH3:1])[N:3]=2)=[O:22])=[CH:26][C:25]=1[O:32][CH3:33]
Reactant: COc1cc(CN)ccc1F
Reactant: Cn1nc(C(=O)O)cc(C2=NOC(c3ccccc3)C2)c1=O
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: COc1cc(CNC(=O)c2cc(C3=NOC(c4ccccc4)C3)c(=O)n(C)n2)ccc1F
Temperature: 25 °C
Reaction time: 16 h
Yield: 41.2 %

Procedure:
To a solution of 1-methyl-6-oxo-5-(5-phenyl-4,5-dihydroisoxazol-3-yl)-1,6-dihydropyridazine-3-carboxylic acid (150 mg, 0.501 mmol, Preparation #34) in DMF (4 mL) was added (4-fluoro-3-methoxyphenyl)methanamine (93 mg, 0.601 mmol, WO 2008/083056), N-ethyl-N-isopropylpropan-2-amine (194 mg, 1.504 mmol, Spectrochem) and followed by HATU (286 mg, 0.752 mmol, Molekule). The reaction mixture was stirred at RT for 16 h. and was quenched with ice cold water (10 mL). The product was extracted with EtOAc (3×20 mL). The combined organic layers were dried over sodium sulphate and evaporated to dryness under vacuum. The residue obtained was purified by silica gel column chromatography by eluenting with 40-60% EtOAc in hexane. The relevant fractions containing the product were combined and evaporated under reduced pressure to afford N-(4-fluoro-3-methoxybenzyl)-1-methyl-6-oxo-5-(5-phenyl-4,5-dihydroisoxazol-3-yl)-1,6-dihydropyridazine-3-carboxamide 90 mg, (41.1%) as pale yellow solids. 1H NMR (400 MHz, DMSO) δ 9.159-9.127 (m, 1H), 8.143 (s, 1H), 7.422-7.331 (m, 5H), 7.167-7.117 (m, 2H), 6.886-6.849 (m, 1H), 5.812-5.763 (m, 1H), 4.436-4.420 (d, J=6.4 Hz, 2H), 3.964-3.892 (m, 1H) 3.819 (s, 3H), 3.781 (s, 3H), 3.508-3.443 (m, 1H). MS m/z 437.3 (M+H)+;
Reaction SMILES: [ClH:1].[N+:2]([C:5]1[CH:10]=[CH:9][C:8]([CH2:11][CH:12]=[C:13]2[CH:18]3[CH2:19][CH2:20][N:15]([CH2:16][CH2:17]3)[CH2:14]2)=[CH:7][CH:6]=1)([O-])=O.[Sn].Cl.[OH-].[Na+]>O>[ClH:1].[ClH:1].[NH2:2][C:5]1[CH:10]=[CH:9][C:8]([CH2:11][CH:12]=[C:13]2[CH:18]3[CH2:17][CH2:16][N:15]([CH2:20][CH2:19]3)[CH2:14]2)=[CH:7][CH:6]=1
Reactant: O=[N+]([O-])c1ccc(CC=C2CN3CCC2CC3)cc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: Nc1ccc(CC=C2CN3CCC2CC3)cc1
Reaction time: 1 h

Procedure:
To 7.75 g (0.03 mole) of 3-[2-(4-nitrophenyl)ethylidene]-1-azabicyclo[2.2.2]octane hydrochloride and 7.12 g (0.06 mole) of mossy tin suspended in 50 ml of water add 30 ml (0.36 mole) of concentrated hydrochloric acid in six portions with good mixing. Maintain the reaction just near the boiling point, cooling if necessary. After the reaction slows heat the mixture at 80°-90° C. with good stirring for 1 hour. Follow the progress of the reaction by thin-layer chromatography on silica gel (acetonitrile:ammonium hydroxide, 95:5). At the completion of the reaction cool the mixture to 0°-5° C. Add 20% sodium hydroxide to bring the mixture to pH>12. Filter any solids if necessary and wash the solids well with methylene chloride solution. Extract the aqueous mixture with four 100 ml portions of methylene chloride. Combine the methylene chloride washes and extracts, and wash them with 50 ml of water and 50 ml of saturated sodium chloride solution. Dry the methylene chloride solution over anhydrous sodium sulfate, filter and remove the solvent in vacuo to provide the title compound as the free base.