Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [H-].[Na+].CN(C=O)C.[CH:8]1([N:11]2[C:20]3[C:15](=[CH:16][C:17]([F:24])=[C:18]([F:23])[C:19]=3[O:21][CH3:22])[C:14](=[O:25])[C:13]([C:26]([OH:28])=[O:27])=[CH:12]2)[CH2:10][CH2:9]1.[C:29]1([CH2:35]Cl)[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1>CO.O>[CH2:35]([O:27][C:26]([C:13]1[C:14](=[O:25])[C:15]2[C:20](=[C:19]([O:21][CH3:22])[C:18]([F:23])=[C:17]([F:24])[CH:16]=2)[N:11]([CH:8]2[CH2:9][CH2:10]2)[CH:12]=1)=[O:28])[C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1
Reactant: COc1c(F)c(F)cc2c(=O)c(C(=O)O)cn(C3CC3)c12
Reactant: ClCc1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: CO
Solvent: O
Solvent: CN(C)C=O
Product: COc1c(F)c(F)cc2c(=O)c(C(=O)OCc3ccccc3)cn(C3CC3)c12
Temperature: 100 °C
Reaction time: 0.17 h
Yield: 75.1 %

Procedure:
NaH (2.6 g, 0.065 mol) was suspended and dissolved into DMF (dimethylformamide; 25 ml) and the reaction solution was stirred for about 10 minutes. A DMF solution (100 ml) of 1-cyclopropyl-6,7-difluoro-1,4-dihydro-8-methoxy-4-oxo-3-quinolinecarboxylic acid (I) (14 g, 0.047 mol) was slowly dropped therein. After the completion of adding, the reaction mixture was stirred at room temperature for about 10 minutes and further PhCH2Cl (benzylchloride; 6.0 ml, 0.052 mol) was dropped therein. The reaction mixture was heated on an oil bath at 100° C. for 6 hours. After the completion of heating, the reaction mixture was poured into water (500 ml) slowly to separate crystals. Separated crystals were washed with water three times and then with MeOH to obtain 1-cyclopropyl-6,7-difluoro-1,4-dihydro-8-methoxy-4-oxo-3-quinolinecarboxylic acid benzyl ester (II) (13.6 g, yield: 74%).
Reaction SMILES: N1([C:6]([O:8][C@:9]([C:38]2[CH:43]=[CH:42][C:41]([F:44])=[CH:40][C:39]=2[F:45])([CH2:32][N:33]2[CH:37]=[N:36][CH:35]=[N:34]2)[C@H:10]([S:12][C@@H:13]2[CH2:18][O:17][C@@H:16](/[CH:19]=[CH:20]/[CH:21]=[CH:22]/[C:23]3[CH:28]=[CH:27][C:26]([C:29]#[N:30])=[CH:25][C:24]=3[F:31])[O:15][CH2:14]2)[CH3:11])=[O:7])C=CN=C1.[Si:46]([O:63][CH2:64][CH2:65][OH:66])([C:59]([CH3:62])([CH3:61])[CH3:60])([C:53]1[CH:58]=[CH:57][CH:56]=[CH:55][CH:54]=1)[C:47]1[CH:52]=[CH:51][CH:50]=[CH:49][CH:48]=1.P([O-])([O-])([O-])=O>ClCCl.CC(C)([O-])C.[K+]>[C:6](=[O:7])([O:8][C@:9]([C:38]1[CH:43]=[CH:42][C:41]([F:44])=[CH:40][C:39]=1[F:45])([CH2:32][N:33]1[CH:37]=[N:36][CH:35]=[N:34]1)[C@H:10]([S:12][C@@H:13]1[CH2:18][O:17][C@@H:16](/[CH:19]=[CH:20]/[CH:21]=[CH:22]/[C:23]2[CH:28]=[CH:27][C:26]([C:29]#[N:30])=[CH:25][C:24]=2[F:31])[O:15][CH2:14]1)[CH3:11])[O:66][CH2:65][CH2:64][O:63][Si:46]([C:59]([CH3:62])([CH3:61])[CH3:60])([C:53]1[CH:54]=[CH:55][CH:56]=[CH:57][CH:58]=1)[C:47]1[CH:52]=[CH:51][CH:50]=[CH:49][CH:48]=1
Reactant: C[C@@H](S[C@H]1CO[C@H](/C=C/C=C/c2ccc(C#N)cc2F)OC1)[C@@](Cn1cncn1)(OC(=O)n1ccnc1)c1ccc(F)cc1F
Reactant: CC(C)(C)[Si](OCCO)(c1ccccc1)c1ccccc1
Agent: CC(C)(C)[O-]
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Solvent: ClCCl
Product: C[C@@H](S[C@H]1CO[C@H](/C=C/C=C/c2ccc(C#N)cc2F)OC1)[C@@](Cn1cncn1)(OC(=O)OCCO[Si](c1ccccc1)(c1ccccc1)C(C)(C)C)c1ccc(F)cc1F
Yield: 72.7 %

Procedure:
(1R,2R)-2-[[trans-2-[(1E,3E)-4-(4-Cyano-2-fluorophenyl)-1,3-butadienyl]-1,3-dioxan-5-yl]thio]-1-(2,4-difluorophenyl)-1-[(1H-1,2,4-triazol-1-yl)methyl]propyl imidazole-1-carboxylate (637 mg, 1.00 mmol) obtained from Example 15-(1) and the crude 2-[(tert-butyldiphenylsilyl)oxy]ethanol (315 mg, ca. 1.05 mmol) obtained from Example 15-(2) were dissolved in dichloromethane (3 ml), and potassium tert-butoxide (5 mg) was added thereto. The mixture was heated under reflux for 15 minutes with stirring. After cooling, a phosphate buffer solution (pH 7) was poured into the mixture, and the reaction product was extracted with ethyl acetate. The organic layer was dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. The residue was purified by recycle preparative HPLC [LC-908; Japan Analytical Industry Co., Ltd.; GPC column JAIGEL-1H (20 mm i.d.×600 mm) and JAIGEL-2H (20 mm i.d.×600 mm) connected in series for use; solvent, chloroform] to afford the title compound (631.4 mg, 73% yield) as a colorless amorphous solid.
Reaction SMILES: Cl.C(N=C=NCCCN(C)C)C.ON1C2C=CC=CC=2N=N1.[C:23]([O:27][C:28]([NH:30][C@H:31]([CH2:35][C:36]1[CH:41]=[CH:40][C:39]([O:42][CH3:43])=[CH:38][CH:37]=1)[C:32]([OH:34])=O)=[O:29])([CH3:26])([CH3:25])[CH3:24].FC(F)(F)C(O)=O.[CH2:51]([O:58][CH2:59][CH2:60][CH2:61][CH2:62][O:63][C:64]1([C:68]2[CH:73]=[CH:72][CH:71]=[CH:70][C:69]=2[CH3:74])[CH2:67][NH:66][CH2:65]1)[C:52]1[CH:57]=[CH:56][CH:55]=[CH:54][CH:53]=1.C(N(CC)C(C)C)(C)C.[OH-].[Na+]>CN(C)C=O>[CH2:51]([O:58][CH2:59][CH2:60][CH2:61][CH2:62][O:63][C:64]1([C:68]2[CH:73]=[CH:72][CH:71]=[CH:70][C:69]=2[CH3:74])[CH2:67][N:66]([C:32](=[O:34])[C@H:31]([NH:30][C:28](=[O:29])[O:27][C:23]([CH3:24])([CH3:25])[CH3:26])[CH2:35][C:36]2[CH:41]=[CH:40][C:39]([O:42][CH3:43])=[CH:38][CH:37]=2)[CH2:65]1)[C:52]1[CH:57]=[CH:56][CH:55]=[CH:54][CH:53]=1
Reactant: Cc1ccccc1C1(OCCCCOCc2ccccc2)CNC1
Reactant: COc1ccc(C[C@@H](NC(=O)OC(C)(C)C)C(=O)O)cc1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Solvent: O=C(O)C(F)(F)F
Product: COc1ccc(C[C@@H](NC(=O)OC(C)(C)C)C(=O)N2CC(OCCCCOCc3ccccc3)(c3ccccc3C)C2)cc1
Reaction time: 0.25 h
Yield: 56.3 %

Procedure:
778 mg (4 mmol) of 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride and 544 mg (4 mmol) of N-hydroxybenzotriazole are successively added to a solution of 1 g (3.36 mmol) of (R)-2-tert-butoxycarbonylamino-3-(4-methoxyphenyl)propanoic acid dissolved in 10 ml of N,N-dimethylformamide. After stirring for 15 minutes, 1.5 g (3.36 mmol) of 3-(4-benzyloxybutoxy)-3-o-tolylazetidine trifluoroacetate are added and stirring is continued for 15 minutes at room temperature. 2.34 ml (13.4 mmol) of N,N-diisopropylethylamine are added and the mixture is stirred at room temperature for 2 hours. Aqueous 1N sodium hydroxide solution is added and the reaction medium is extracted twice with ethyl acetate. The organic phase is then washed with aqueous 1N sodium hydroxide and then with aqueous 1N hydrochloric acid solution, dried over magnesium sulfate, filtered and concentrated under reduced pressure. The crude residue obtained is purified by chromatography on silica gel eluted with a heptane/ethyl acetate mixture, the polarity being increased from 100/0 to 70/40. 1.14 g of tert-butyl [(R)-2-[3-(4-benzyloxybutoxy)-3-o-tolylazetidin-1-yl]-1-(4-methoxybenzyl)-2-oxoethyl]carbamate are obtained in the form of a colourless resin, in a yield of 53%.
Reaction SMILES: [C:1]([C:5]1[CH:6]=[C:7]([NH:17][C:18](=[O:40])[C:19]([C:21]2[C:30]3[C:25](=[CH:26][CH:27]=[CH:28][CH:29]=3)[C:24]([O:31][CH2:32][CH2:33][N:34]3[CH2:39][CH2:38][O:37][CH2:36][CH2:35]3)=[CH:23][CH:22]=2)=O)[N:8]([C:10]2[CH:15]=[CH:14][C:13]([CH3:16])=[CH:12][CH:11]=2)[N:9]=1)([CH3:4])([CH3:3])[CH3:2].Cl.[NH2:42][OH:43].N1C=CC=CC=1>CCO>[C:1]([C:5]1[CH:6]=[C:7]([NH:17][C:18](=[O:40])[C:19](=[N:42][OH:43])[C:21]2[C:30]3[C:25](=[CH:26][CH:27]=[CH:28][CH:29]=3)[C:24]([O:31][CH2:32][CH2:33][N:34]3[CH2:35][CH2:36][O:37][CH2:38][CH2:39]3)=[CH:23][CH:22]=2)[N:8]([C:10]2[CH:15]=[CH:14][C:13]([CH3:16])=[CH:12][CH:11]=2)[N:9]=1)([CH3:3])([CH3:2])[CH3:4]
Reactant: Cc1ccc(-n2nc(C(C)(C)C)cc2NC(=O)C(=O)c2ccc(OCCN3CCOCC3)c3ccccc23)cc1
Reactant: NO
Agent: Cl
Solvent: CCO
Solvent: c1ccncc1
Product: Cc1ccc(-n2nc(C(C)(C)C)cc2NC(=O)C(=NO)c2ccc(OCCN3CCOCC3)c3ccccc23)cc1
Temperature: 45 °C
Reaction time: 12 h
Yield: 60 %

Procedure:
Compound 13 (10 mg, 0.018 mmol) and hydroxylamine hydrochloride (50 eqv., 0.92 mmol, 64 mg) were dissolved in 2 mL of EtOH. Pyridine (0.1 mL) was added and the mixture was stirred at 45° C. for 12 h. The solvent was then removed in vacuo and the crude solid was purified via LCMS to yield 6 mg of a white solid (58% yield; mixture of isomers). Expected mass=555. Observed mass=556.
Reaction SMILES: [CH2:1]([N:5]=[C:6]=[O:7])[CH2:2][CH2:3][CH3:4].[CH3:8][O:9][C:10]1[CH:11]=[C:12]2[C:17](=[CH:18][C:19]=1[O:20][CH3:21])[N:16]=[CH:15][N:14]=[C:13]2[N:22]1[CH2:27][CH2:26][CH:25]([CH2:28][NH2:29])[CH2:24][CH2:23]1.Cl>C(Cl)(Cl)Cl>[CH3:8][O:9][C:10]1[CH:11]=[C:12]2[C:17](=[CH:18][C:19]=1[O:20][CH3:21])[N:16]=[CH:15][N:14]=[C:13]2[N:22]1[CH2:27][CH2:26][CH:25]([CH2:28][NH:29][C:6]([NH:5][CH2:1][CH2:2][CH2:3][CH3:4])=[O:7])[CH2:24][CH2:23]1
Reactant: COc1cc2ncnc(N3CCC(CN)CC3)c2cc1OC
Reactant: CCCCN=C=O
Agent: Cl
Solvent: ClC(Cl)Cl
Product: CCCCNC(=O)NCC1CCN(c2ncnc3cc(OC)c(OC)cc23)CC1
Temperature: 25 °C
Reaction time: 3 h
Yield: 49.7 %

Procedure:
n-Butylisocyanate (1.8 g.) was added to a stirred solution of 6,7-dimethoxy-4-[4-(aminomethyl)piperidino]- quinazoline (5 g.) in dry chloroform (100 ml.). The mixture was then stirred at room temperature for 3 hours, then left standing for 72 hours. An equal volume of 1 N hydrochloric acid was added, the organic phase separated, and the aqueous phase basified to pH 10 with aqueous potassium carbonate solution. The mixture was extracted with chloroform (2×100 ml.), the extracts combined, dried (MgSO4), and taken to dryness in vacuo. The resultant solid was recrystallized twice from acetonitrile and then once from a mixture of isopropanol and ether to yield 6,7-dimethoxy-4-[4-(3-n-butylureidomethyl) piperidino]quinazoline (3.3 g.), m.p. 141°-143° C.
Reaction SMILES: [C:1]1([C:7]2[CH:16]=[CH:15][C:14]3[C:9](=[CH:10][C:11]([C:17]4[N:18]=[C:19]([CH2:27][CH:28]5[CH2:33][CH2:32][NH:31][CH2:30][CH2:29]5)[N:20]5[CH:25]=[CH:24][N:23]=[C:22]([NH2:26])[C:21]=45)=[CH:12][CH:13]=3)[N:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.CCN(C(C)C)C(C)C.[Cl:43][CH2:44][C:45](Cl)=[O:46]>C(Cl)Cl>[NH2:26][C:22]1[C:21]2[N:20]([C:19]([CH2:27][CH:28]3[CH2:33][CH2:32][N:31]([C:45](=[O:46])[CH2:44][Cl:43])[CH2:30][CH2:29]3)=[N:18][C:17]=2[C:11]2[CH:10]=[C:9]3[C:14]([CH:15]=[CH:16][C:7]([C:1]4[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=4)=[N:8]3)=[CH:13][CH:12]=2)[CH:25]=[CH:24][N:23]=1
Reactant: O=C(Cl)CCl
Reactant: Nc1nccn2c(CC3CCNCC3)nc(-c3ccc4ccc(-c5ccccc5)nc4c3)c12
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: Nc1nccn2c(CC3CCN(C(=O)CCl)CC3)nc(-c3ccc4ccc(-c5ccccc5)nc4c3)c12
Reaction time: 0.17 h

Procedure:
1-(2-phenylquinolin-7-yl)-3-(piperidin-4-ylmethyl)-imidazo-[1,5-a]-pyrazin-8-amine (110.00 mg, 0.25 mmol) in a dried 15 mL round bottom flask was dissolved in 2.00 mL of methylene chloride and was charged with PS-DIEA (150 mg, 0.46 mmol). Chloroacetyl chloride (10 μL, 0.42 equiv) was added in one portion. After 10 min., another 5 μL of chloroacetyl chloride (0.21 equiv) was added. After another 10 min., another 2.5 μL of methoxylacetyl (0.11 equiv) was added. The reaction was filtered through a fritted funnel, and the resins were rinsed multiple times with methylene chloride. The crude product was purified by a 5 g Jones silica gel (dry loaded with silica, wetted with 100% ethyl acetate and eluted with 5% NH3 in MeOH/Ethyl Acetate) and afforded the desired product; 1H NMR (400 MHz, CHLOROFORM-d) δ 8.74 (1H, s), 8.30 (1H, d, J=8.68), 8.21 (2H, d, J=7.01), 7.98 (2H, m), 7.86 (1H, dd, J=1.70, J=1.70), 7.53 (3H, m), 7.24 (1H, d, J=5.34), 7.08 (1H, d, J=5.31), 4.63 (1H, d, J=13.24), 3.90 (1H, d, J=13.2), 3.15 (1H, t), 2.97 (2H, d, J=5.64), 2.70 (1H, t), 2.34 (1H, m), 2.05 (2H, s), 1.92 (2H, t), 1.42 (2H, m); MS (ES+): m/z 511.06/513.02 (50/25) [MH+]; HPLC: tR=2.20 min (OpenLynx, polar—5 min).
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][C:6]([NH:10][CH:11]3[CH2:16][CH2:15][C:14](=O)[CH2:13][CH2:12]3)=[CH:7][CH:8]=2)[CH:3]=[N:2]1.[CH:18]1([NH2:24])[CH2:23][CH2:22][CH2:21][CH2:20][CH2:19]1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].Cl.CO>CO>[CH:18]1([NH:24][CH:14]2[CH2:15][CH2:16][CH:11]([NH:10][C:6]3[CH:5]=[C:4]4[C:9](=[CH:8][CH:7]=3)[NH:1][N:2]=[CH:3]4)[CH2:12][CH2:13]2)[CH2:23][CH2:22][CH2:21][CH2:20][CH2:19]1
Reactant: O=C1CCC(Nc2ccc3[nH]ncc3c2)CC1
Reactant: NC1CCCCC1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: Cl
Agent: [Na+]
Solvent: CO
Product: c1cc2[nH]ncc2cc1NC1CCC(NC2CCCCC2)CC1
Temperature: 25 °C
Reaction time: 18 h
Yield: 28.3 %

Procedure:
4-(1H-5-Indazolylamino)-1-cyclohexanone (intermediate 3) (57 mg) and cyclohexylamine (50 mg) were dissolved in methanol (1 ml), and sodium triacetoxyborohydride (105 mg) was added by portions to the solution at room temperature. The reaction mixture was stirred at room temperature for 18 hr. Hydrochloric acid-methanol was then added thereto, and the reaction mixture was stirred and was then concentrated. The residue was purified by HPLC [0.5% aqueous trifluoroacetic acid solution/acetonitrile]. A saturated aqueous sodium hydrogencarbonate solution (2 ml) was then added to fractions containing respective compounds, followed by extraction with chloroform-propanol (3/1). The organic layers were dried over anhydrous sodium sulfate, and the solvent was removed by distillation under the reduced pressure to give an antiform compound (22 mg) and a syn-form compound (23 mg).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[C:9]([C:27]2[CH:32]=[CH:31][C:30]([Cl:33])=[CH:29][CH:28]=2)=[CH:10][CH:11]([C:15](=[O:26])[CH2:16][CH:17]([C:19]2[CH:24]=[CH:23][CH:22]=[C:21]([F:25])[CH:20]=2)[OH:18])[C:12](=O)[N:13]=1.C1(C)C=CC(S(O)(=O)=O)=CC=1>C1(C)C=CC=CC=1.CCOC(C)=O>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[N:13]=[C:12]2[O:18][CH:17]([C:19]3[CH:24]=[CH:23][CH:22]=[C:21]([F:25])[CH:20]=3)[CH2:16][C:15](=[O:26])[C:11]2=[CH:10][C:9]=1[C:27]1[CH:32]=[CH:31][C:30]([Cl:33])=[CH:29][CH:28]=1
Reactant: O=C(CC(O)c1cccc(F)c1)C1C=C(c2ccc(Cl)cc2)C(c2ccccc2Cl)=NC1=O
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: Cc1ccccc1
Solvent: CCOC(C)=O
Product: O=C1CC(c2cccc(F)c2)Oc2nc(-c3ccccc3Cl)c(-c3ccc(Cl)cc3)cc21
Temperature: 120 °C

Procedure:
The product of step A (200 mg, 0.42 mmol) was dissolved in toluene (2 mL) and p-toluenesulfonic acid (30 mg, 0.16 mmol) was added. The reaction was heated at 120° C. for 4 h and allowed to cool overnight. The reaction was diluted with EtOAc and washed with a saturated solution of NaHCO3, brine, dried (Na2SO4), filtered and concentrated The residue was purified by flash chromatography on silica gel gradient eluted with 0-30% EtOAc in hexane to afford the title compound. (LC-2) HPLC/MS: 464.2 (M+1), 466.2 (M+3); Rt=2.61 min.
Reaction SMILES: [NH2:1][C:2]1[C:3]([NH:10][C:11]2[CH:16]=[CH:15][C:14]([Br:17])=[CH:13][C:12]=2[F:18])=[CH:4][C:5](=[O:9])[N:6]([CH3:8])[CH:7]=1.[CH:19]1([S:22](Cl)(=[O:24])=[O:23])[CH2:21][CH2:20]1>>[Br:17][C:14]1[CH:15]=[CH:16][C:11]([NH:10][C:3]2[C:2]([NH:1][S:22]([CH:19]3[CH2:21][CH2:20]3)(=[O:24])=[O:23])=[CH:7][N:6]([CH3:8])[C:5](=[O:9])[CH:4]=2)=[C:12]([F:18])[CH:13]=1
Reactant: Cn1cc(N)c(Nc2ccc(Br)cc2F)cc1=O
Reactant: O=S(=O)(Cl)C1CC1
Product: Cn1cc(NS(=O)(=O)C2CC2)c(Nc2ccc(Br)cc2F)cc1=O

Procedure:
5-Amino-4-(2-fluoro-4-bromophenylamino)-1-methylpyridin-2(1H)-one was reacted with cyclopropanesulfonyl chloride using the same procedure as described in step f of example 1 above, and purified by HPLC.
Reaction SMILES: [NH2:1][CH2:2][C:3]([OH:5])=[O:4].C1(C[C:13](=O)[C:14]([O-:16])=[O:15])C=CC=CC=1.N[C@H](C(O)=O)CC1C=CC=CC=1>>[NH2:1][C@H:2]([C:3]([OH:5])=[O:4])[CH2:13][C:14]([OH:16])=[O:15]
Reactant: O=C([O-])C(=O)Cc1ccccc1
Reactant: NCC(=O)O
Agent: N[C@@H](Cc1ccccc1)C(=O)O
Product: N[C@@H](CC(=O)O)C(=O)O
Reaction time: 120 h
Yield: 30 %

Procedure:
Additionally, the strains were inoculated into 100 ml of a similar medium containing glycine instead of the aspartic acid. The cultures were inoculated at 30° C. on a shaking machine for 5 days. Samples were taken after 3 and 5 days. 7 strains from the cultures tested converted phenylpyruvate into phenylalanine in a yield of 30% to 60%, and these were therefore suitable for further adaptation.
Reaction SMILES: [Cl:1][C:2]1[C:7]([Cl:8])=[C:6]([Cl:9])[N:5]=[C:4]([C:10](Cl)=[O:11])[CH:3]=1.[NH2:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=1[OH:20].C(N(CC)CC)C>ClCCl>[OH:20][C:15]1[CH:16]=[CH:17][CH:18]=[CH:19][C:14]=1[NH:13][C:10]([C:4]1[CH:3]=[C:2]([Cl:1])[C:7]([Cl:8])=[C:6]([Cl:9])[N:5]=1)=[O:11]
Reactant: O=C(Cl)c1cc(Cl)c(Cl)c(Cl)n1
Reactant: Nc1ccccc1O
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: O=C(Nc1ccccc1O)c1cc(Cl)c(Cl)c(Cl)n1
Temperature: 25 °C
Yield: 97.6 %

Procedure:
A solution of 4,5,6-trichloropyridine-2-carbonyl chloride (1.0 g, 4.1 mmol) in dichloromethane (10 mL) was added dropwise to a solution of 2-aminophenol (0.45 g, 4.1 mmol) and triethylamine (0.6 mL) in dichloromethane (30 mL) at 0° C. The reaction mixture was allowed to warm to room temperature and stirred for an additional thirty minutes. The solvents were removed and the residue partitioned between 20% tetrahydrofuran/ethyl acetate and 1M hydrochloric acid. The organic layer was separated, washed with saturated sodium bicarbonate, brine, dried (MgSO4) and concentrated to provide N-(2-hydroxyphenyl)-4,5,6-trichloropyridine-2-carboxamide (1.26 g, 4.0 mmol), mp 240° C. (dec).
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([C:11]2[C:15]3[CH:16]=[CH:17][CH:18]=[CH:19][C:14]=3[O:13][C:12]=2[C:20]2[CH:25]=[CH:24][C:23]([CH3:26])=[CH:22][CH:21]=2)(=[O:10])=[O:9])=[CH:4][CH:3]=1.[CH2:27]([N:29]([CH2:33][CH3:34])[CH2:30][CH2:31]Cl)[CH3:28]>>[CH2:27]([N:29]([CH2:33][CH3:34])[CH2:30][CH2:31][O:1][C:2]1[CH:3]=[CH:4][C:5]([S:8]([C:11]2[C:15]3[CH:16]=[CH:17][CH:18]=[CH:19][C:14]=3[O:13][C:12]=2[C:20]2[CH:21]=[CH:22][C:23]([CH3:26])=[CH:24][CH:25]=2)(=[O:10])=[O:9])=[CH:6][CH:7]=1)[CH3:28]
Reactant: Cc1ccc(-c2oc3ccccc3c2S(=O)(=O)c2ccc(O)cc2)cc1
Reactant: CCN(CC)CCCl
Product: CCN(CC)CCOc1ccc(S(=O)(=O)c2c(-c3ccc(C)cc3)oc3ccccc23)cc1

Procedure:
Reaction of 3-(4-hydroxyphenylsulfonyl)-2-(4-tolyl)benzofuran with 2-diethylaminoethyl chloride according to the procedure of Example 1 gives the title compound.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:18])[C:4]1[CH:9]=[C:8]([C:10]2[CH:15]=[CH:14][C:13]([CH3:16])=[CH:12][N:11]=2)[CH:7]=[C:6]([NH2:17])[CH:5]=1.[F:19][C:20]([F:25])([CH3:24])[C:21](O)=[O:22].CCN=C=NCCCN(C)C.C1C=CC2N(O)N=NC=2C=1.CN1CCOCC1>C(#N)C>[CH3:1][O:2][C:3](=[O:18])[C:4]1[CH:9]=[C:8]([C:10]2[CH:15]=[CH:14][C:13]([CH3:16])=[CH:12][N:11]=2)[CH:7]=[C:6]([NH:17][C:21](=[O:22])[C:20]([F:25])([F:19])[CH3:24])[CH:5]=1
Reactant: CC(F)(F)C(=O)O
Reactant: COC(=O)c1cc(N)cc(-c2ccc(C)cn2)c1
Agent: CCN=C=NCCCN(C)C
Agent: On1nnc2ccccc21
Solvent: CN1CCOCC1
Solvent: CC#N
Product: COC(=O)c1cc(NC(=O)C(C)(F)F)cc(-c2ccc(C)cn2)c1
Temperature: 25 °C
Reaction time: 21 h
Yield: 65.2 %

Procedure:
3-Amino-5-(5-methyl-pyridin-2-yl)-benzoic acid methyl ester (0.7 g, 2.89 mmol, from Preparation 2), 2,2-difluoropropionic acid (0.370 g, 2.89 mmol), EDCI (4.34 mmol), and HOBt (4.34 mmol) and NMM (14.45 mmol) were added to 25 mL of acetonitrile. The reaction mixture was stirred at room temperature for 21 hours, after which the acetonitrile was removed under reduced pressure. The residue was partitioned between water and EtOAc, and the combined organic layers were washed with water, dried (MgSO4), filtered and concentrated under reduced pressure. The residue was purified by flash chromatography (EtOAc/hexanes 35:1) to give 0.630 g of 3-(2,2-difluoro-propionylamino)-5-(5-methyl-pyridin-2-yl)-benzoic acid methyl ester as a white solid, MS (M+H)=335.
Reaction SMILES: C([O:3][CH:4](OCC)[CH2:5][N:6]([CH2:9][CH3:10])[CH2:7][CH3:8])C.Cl.[OH:15][S:16]([O-:18])=[O:17].[Na+:19].C(O)C>O>[CH2:7]([N:6]([CH2:9][CH3:10])[CH2:5][CH:4]([OH:3])[S:16]([O-:18])(=[O:17])=[O:15])[CH3:8].[Na+:19]
Reactant: O=S([O-])O
Reactant: CCOC(CN(CC)CC)OCC
Agent: Cl
Agent: [Na+]
Solvent: O
Solvent: CCO
Product: CCN(CC)CC(O)S(=O)(=O)[O-]
Reaction time: 2 h

Procedure:
2,2-diethoxy-N,N-diethylethanamine (140 mg, 0.75 mmol) was added in 0.1 mL H2O. Concentrated HCl (190 mg) was added dropwise in an ice bath. The solution was stirred for 2 hours at 40 degree. NaHSO3 (350 mg, 3.36 mmol) in 0.6 mL H2O was added to the reaction solution in an ice bath and stirred for 1 hour at room temperature, then 0.6 ml ethanol was added and stirred for 1 hour at room temperature. This reaction solution was concentrated, the resulting residue was used directly for the next step.
Reaction SMILES: [S:1](S([O-])=O)([O-:4])(=[O:3])=[O:2].[Na+].[Na+].[O:10]([C:17]1[CH:18]=[C:19]([CH:22]=[CH:23][CH:24]=1)[CH:20]=[O:21])[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1.CO>O.C(OC(C)C)(C)C>[S:1](=[O:2])([OH:4])[O-:3].[O:10]([C:17]1[CH:18]=[C:19]([CH:22]=[CH:23][CH:24]=1)[CH:20]=[O:21])[C:11]1[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=1
Reactant: O=S([O-])S(=O)(=O)[O-]
Agent: O=Cc1cccc(Oc2ccccc2)c1
Agent: [Na+]
Solvent: CO
Solvent: CC(C)OC(C)C
Solvent: O
Product: O=S([O-])O
Reaction time: 3 h

Procedure:
A solution of 200 g of sodium metabisulfite in 800 ml of water was added to a solution of 200 g of m-phenoxy-benzaldehyde in 800 ml of isopropyl ether and after the addition of 250 ml of methanol, the mixture was stirred for 3 hours and was vacuum filtered. The recovered precipitate was washed with 1--1 water-methanol mixture and then with isopropyl ether and was dried to obtain 295 g of the combination bisulfite of m-phenoxy-benzaldehyde (titer of 95.5% mobile hydrogen). The product was crystallized from 4 volumes of ethyl acetate to obtain a 97.6% yield of the product with a titer of mobile hydrogen of 98%.
Reaction SMILES: [C:1]12([CH2:11][NH:12][C:13]([C:15]3[N:20]4[CH:21]=[C:22]([CH2:24][N:25]5[CH2:29][CH2:28][C@@H:27]([NH:30]C(=O)OC(C)(C)C)[CH2:26]5)[N:23]=[C:19]4[CH:18]=[CH:17][CH:16]=3)=[O:14])[CH2:10][CH:5]3[CH2:6][CH:7]([CH2:9][CH:3]([CH2:4]3)[CH2:2]1)[CH2:8]2.[ClH:38].O1C=COC=C1>CO>[C:1]12([CH2:11][NH:12][C:13]([C:15]3[N:20]4[CH:21]=[C:22]([CH2:24][N:25]5[CH2:29][CH2:28][C@@H:27]([NH2:30])[CH2:26]5)[N:23]=[C:19]4[CH:18]=[CH:17][CH:16]=3)=[O:14])[CH2:8][CH:7]3[CH2:9][CH:3]([CH2:4][CH:5]([CH2:6]3)[CH2:10]1)[CH2:2]2.[ClH:38]
Reactant: CC(C)(C)OC(=O)N[C@@H]1CCN(Cc2cn3c(C(=O)NCC45CC6CC(CC(C6)C4)C5)cccc3n2)C1
Agent: C1=COC=CO1
Agent: Cl
Solvent: CO
Product: N[C@@H]1CCN(Cc2cn3c(C(=O)NCC45CC6CC(CC(C6)C4)C5)cccc3n2)C1

Procedure:
A solution of tert-butyl [(3R)-1-({5-[(adamantan-1-ylmethyl)carbamoyl]imidazo[1,2-a]pyridin-2-yl}methyl)pyrrolidin-3-yl]carbamate (411 mg, 0.81 mmol) in MeOH (4 mL) is treated with 2 mL of HCl solution in 1,4-dioxine (4.0 M, 8 mmol) for 16 h at RT. The solvent is removed in vacuo to give the title compound as its HCl salt.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:12]([C:13]3[CH:18]=[CH:17][N:16]=[C:15]([C:19]([O-:21])=[O:20])[CH:14]=3)=[CH:11][NH:10][N:9]=2)=[CH:4][CH:3]=1.[OH-].[Na+]>C(O)C.O>[F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:12]([C:13]3[CH:18]=[CH:17][N:16]=[C:15]([C:19]([OH:21])=[O:20])[CH:14]=3)=[CH:11][NH:10][N:9]=2)=[CH:4][CH:3]=1
Reactant: O=C([O-])c1cc(-c2c[nH]nc2-c2ccc(F)cc2)ccn1
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: O=C(O)c1cc(-c2c[nH]nc2-c2ccc(F)cc2)ccn1
Yield: 73 %

Procedure:
To a solution of 4-[3-(4-fluorophenyl)-1H-pyrazol-4-yl]-2-pyridinecarboxylate prepared as set forth in Example A-224 (0.90 g, 0.003 mol) in 10 mL of ethanol was added a solution of sodium hydroxide (0.24 g, 0.006 mol) in 5 mL of water. The reaction mixture was heated at reflux for 10 hours. After the removal of solvent, the residue was dissolved in water and acidified with citric acid solution to pH 5. Then the aqueous phase was extracted with ethyl acetate and the organic phase was dried over magnesium sulfate and concentrated. The crude was purified by treating with ether to give 0.62 g of 4-[3-(4-fluorophenyl)-1H-pyrazol-4-yl]-2-pyridinecarboxylic acid as a white solid (73% yield), mp: 245° C.(dec). Anal Calc'd for C15H10FN3O+0.2H2O: C, 62.80; H, 3.65; N, 14.65. Found: C, 62.77; H, 3.42; N, 14.58.