Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1][C:2]1[CH:3]=[N:4][NH:5][CH:6]=1.[H-].[Na+].[C:9](Cl)([C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)([C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1>O1CCCC1.C(OCC)(=O)C>[Br:1][C:2]1[CH:3]=[N:4][N:5]([C:9]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)([C:22]2[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=2)[C:16]2[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=2)[CH:6]=1
Reactant: ClC(c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: Brc1cn[nH]c1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: Brc1cnn(C(c2ccccc2)(c2ccccc2)c2ccccc2)c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 94.4 %

Procedure:
A suspension of 4-bromo-1H-pyrazole (10 g) in tetrahydrofuran (230 ml) was stirred for 1 hr at room temperature. While argon gas was provided, sodium hydride was slowly added at 0° C. to the suspension, followed by stirring for 30 min and then for an additional 30 min at room temperature. Then, trityl chloride (22.8 g) was slowly added at 0° C. to the suspension with stirring for 20 min. Further stirring was conducted for 3 hrs at room temperature before the reaction was terminated. Following the removal of excess sodium hydride with distilled water (3 ml) from the reaction at 0° C., the tetrahydrofuran solvent was evaporated in a vacuum and the concentrate thus obtained was diluted in ethyl acetate (200 ml) and washed with distilled water (200 ml) and then with brine (200 ml). The resulting organic layer was dried over anhydrous magnesium sulfate and concentrated by evaporation in vacuo. The residue was diluted in methylene chloride (2 ml) and recrystallized in methanol (200 ml) to give 4-bromo-1-trityl-1H-pyrazole (25 g).
Reaction SMILES: [OH:1][CH2:2][CH2:3][CH:4]([C:9]1[CH:14]=[CH:13][C:12]([C:15]([F:18])([F:17])[F:16])=[CH:11][CH:10]=1)[CH2:5][C:6]([NH2:8])=[O:7].N1C=CN=C1.[Si:24](Cl)([C:37]([CH3:40])([CH3:39])[CH3:38])([C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1)[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1>CN(C)C=O>[Si:24]([O:1][CH2:2][CH2:3][CH:4]([C:9]1[CH:14]=[CH:13][C:12]([C:15]([F:16])([F:17])[F:18])=[CH:11][CH:10]=1)[CH2:5][C:6]([NH2:8])=[O:7])([C:37]([CH3:40])([CH3:39])[CH3:38])([C:31]1[CH:32]=[CH:33][CH:34]=[CH:35][CH:36]=1)[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1
Reactant: CC(C)(C)[Si](Cl)(c1ccccc1)c1ccccc1
Reactant: NC(=O)CC(CCO)c1ccc(C(F)(F)F)cc1
Agent: c1c[nH]cn1
Solvent: CN(C)C=O
Product: CC(C)(C)[Si](OCCC(CC(N)=O)c1ccc(C(F)(F)F)cc1)(c1ccccc1)c1ccccc1
Reaction time: 1 h

Procedure:
5-Hydroxy-3-(4-trifluoromethylphenyl)pentanoic acid amide (350 mg) was dissolved in dimethylformamide (13 mL), and imidazole (365 mg) and tert-butyldiphenylsilyl chloride (697 μL) were added at room temperature. After stirring for one hour, the reaction solution was partitioned with ethyl acetate and water. The organic layer was washed with water (twice), 1 N hydrochloric acid and brine. After drying over magnesium sulfate, concentration under reduced pressure and purification by silica gel column chromatography (mobile phase:ethyl acetate/heptane=0 to 90%) gave the title compound (680 mg).
Reaction SMILES: FC(F)(F)C(O)=O.[CH3:8][O:9][C:10]1[N:11]=[C:12]2[C:17]([N:18]=1)=[C:16]([NH2:19])[NH:15][C:14]([O:20][C@@H:21]([CH3:24])[CH2:22][CH3:23])=[N:13]2.Br[CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][Cl:31]>>[Cl:31][CH2:30][CH2:29][CH2:28][CH2:27][CH2:26][N:11]1[C:10]([O:9][CH3:8])=[N:18][C:17]2[C:12]1=[N:13][C:14]([O:20][C@@H:21]([CH3:24])[CH2:22][CH3:23])=[N:15][C:16]=2[NH2:19]
Reactant: CC[C@H](C)Oc1nc2nc(OC)nc-2c(N)[nH]1
Reactant: ClCCCCCBr
Solvent: O=C(O)C(F)(F)F
Product: CC[C@H](C)Oc1nc(N)c2nc(OC)n(CCCCCCl)c2n1

Procedure:
Prepared similarly to Intermediate 14 from 8-(methyloxy)-2-{[(1S)-1-methylpropyl]oxy}-1H-purin-6-amine trifluoroacetate and 1-bromo-5-chloropentane.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8](=[O:33])[CH2:9][NH:10][C:11]([CH2:13][N:14](C(OC(C)(C)C)=O)[CH2:15][C:16]([NH:18][CH:19]([CH:23]([CH3:25])[CH3:24])[C:20]([OH:22])=[O:21])=[O:17])=[O:12])=[CH:4][CH:3]=1.C(OC(=O)N)(C)(C)C>>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8](=[O:33])[CH2:9][NH:10][C:11]([CH2:13][NH:14][CH2:15][C:16]([NH:18][CH:19]([CH:23]([CH3:24])[CH3:25])[C:20]([OH:22])=[O:21])=[O:17])=[O:12])=[CH:4][CH:3]=1
Reactant: CC(C)C(NC(=O)CN(CC(=O)NCC(=O)c1ccc(Br)cc1)C(=O)OC(C)(C)C)C(=O)O
Agent: CC(C)(C)OC(N)=O
Product: CC(C)C(NC(=O)CNCC(=O)NCC(=O)c1ccc(Br)cc1)C(=O)O

Procedure:
2-[2-({[2-(4-Bromo-phenyl)-2-oxo-ethylcarbamoyl]-methyl}-amino)-acetylamino]-3-methyl-butyric acid was prepared using method 804 substituting 2-[2-({[2-(4-bromo-phenyl)-2-oxo-ethylcarbamoyl]-methyl}-tert-butoxycarbonyl-amino)-acetylamino]-3-methyl-butyric acid for 1-[5-(4′-{2-[1-(2-methoxycarbonylamino-3-methyl-butyryl)-pyrrolidin-2-yl]-3H-imidazol-4-yl]-biphenyl-4-yl)-1H-imidazol-2-ylmethyl]-2-oxo-piperidin-3-yl}-carbamic acid tert-butyl ester. C17H22BrN3O5 calculated 427.1 observed [M+1]+ 428.0; rt=2.39 min.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:11]([CH3:30])([CH3:29])[CH2:12][C@:13]([CH2:19][S@:20]([C:22]2[CH:27]=[CH:26][C:25]([CH3:28])=[CH:24][CH:23]=2)=O)([OH:18])[C:14]([F:17])([F:16])[F:15])[C:5]2[O:9][CH2:8][CH2:7][C:6]=2[CH:10]=1.[I-].[Na+].FC(F)(F)C(OC(=O)C(F)(F)F)=O>CC(C)=O>[Cl:1][C:2]1[CH:3]=[C:4]([C:11]([CH3:30])([CH3:29])[CH2:12][C@:13]([CH2:19][S:20][C:22]2[CH:27]=[CH:26][C:25]([CH3:28])=[CH:24][CH:23]=2)([OH:18])[C:14]([F:17])([F:15])[F:16])[C:5]2[O:9][CH2:8][CH2:7][C:6]=2[CH:10]=1
Reactant: Cc1ccc([S@](=O)C[C@](O)(CC(C)(C)c2cc(Cl)cc3c2OCC3)C(F)(F)F)cc1
Agent: [I-]
Agent: [Na+]
Solvent: O=C(OC(=O)C(F)(F)F)C(F)(F)F
Solvent: CC(C)=O
Product: Cc1ccc(SC[C@](O)(CC(C)(C)c2cc(Cl)cc3c2OCC3)C(F)(F)F)cc1
Reaction time: 0.25 h
Yield: 99.5 %

Procedure:
To a suspension of (S)-4-(5-chloro-2,3-dihydrobenzofuran-7-yl)-1,1,1-trifluoro-4-methyl-2-((R)-toluene-4-sulfinylmethyl)pentan-2-ol (1.49 g, 3.23 mmol) and sodium iodide (1.45 g, 9.70 mmol) in 25 mL of anhydrous acetone at −40° C. was added a solution of trifluoroacetic acid anhydride (2.28 mL, 16.2 mmol) in 5 mL of anhydrous acetone via a syringe dropwise over 5 minutes. A greenish brown mixture was formed instantaneously. After 15 minutes, the reaction mixture was quenched with saturated aqueous sodium sulfite solution and neutralized with saturated aqueous sodium carbonate solution. The brown color disappeared and the crude was concentrated in vacuo to remove most of the acetone solvent. The resulting material was diluted with 50 mL of water and extracted with three 100 mL portions of ether. The combined organic phases were washed with brine, dried over magnesium sulfate, filtered, and concentrated in vacuo to afford (S)-4-(5-chloro-2,3-dihydrobenzofuran-7-yl)-1,1,1-trifluoro-4-methyl-2-p-tolylsulfanylmethylpentan-2-ol as a yellow oil (1.43 g, 99%).
Reaction SMILES: C([O:5][C:6](=[O:56])[CH:7]([N:11]([CH2:23][C:24]1[CH:29]=[CH:28][C:27]([C:30](=[O:55])[NH:31][CH2:32][CH2:33][CH:34]([CH2:45][CH2:46][NH:47][C:48]([CH3:54])([CH3:53])[C:49](=[N:51][OH:52])[CH3:50])[CH2:35][CH2:36][NH:37][C:38]([CH3:44])([CH3:43])[C:39](=[N:41][OH:42])[CH3:40])=[CH:26][CH:25]=1)[S:12]([C:15]1[CH:20]=[CH:19][C:18]([O:21][CH3:22])=[CH:17][CH:16]=1)(=[O:14])=[O:13])[CH:8]([CH3:10])[CH3:9])(C)(C)C.Cl>ClCCl>[OH:52][N:51]=[C:49]([CH3:50])[C:48]([NH:47][CH2:46][CH2:45][CH:34]([CH2:35][CH2:36][NH:37][C:38]([CH3:43])([CH3:44])[C:39](=[N:41][OH:42])[CH3:40])[CH2:33][CH2:32][NH:31][C:30]([C:27]1[CH:26]=[CH:25][C:24]([CH2:23][N:11]([S:12]([C:15]2[CH:16]=[CH:17][C:18]([O:21][CH3:22])=[CH:19][CH:20]=2)(=[O:13])=[O:14])[CH:7]([CH:8]([CH3:10])[CH3:9])[C:6]([OH:56])=[O:5])=[CH:29][CH:28]=1)=[O:55])([CH3:54])[CH3:53]
Reactant: COc1ccc(S(=O)(=O)N(Cc2ccc(C(=O)NCCC(CCNC(C)(C)C(C)=NO)CCNC(C)(C)C(C)=NO)cc2)C(C(=O)OC(C)(C)C)C(C)C)cc1
Agent: Cl
Solvent: ClCCl
Product: COc1ccc(S(=O)(=O)N(Cc2ccc(C(=O)NCCC(CCNC(C)(C)C(C)=NO)CCNC(C)(C)C(C)=NO)cc2)C(C(=O)O)C(C)C)cc1

Procedure:
Dichloromethane (4 ml) was added to the tert-butyl ester (Compound 9*) (64 mg, 0.08 mmol) and to the milky coloured solution which was obtained at ambient temperature was bobbled hydrochloric acid gas for 10 minutes. The mixture was evaporated to dryness and the residue was co-evaporated with dichloromethane (5×5 ml) to afford the product as off-white solid. Yield 58 mg (97%). M+1=747.
Reaction SMILES: [CH2:1]([C:5]1[O:6][C:7]2[CH:22]=[CH:21][CH:20]=[CH:19][C:8]=2[C:9]=1[CH2:10][NH:11][C:12]1[CH:17]=[CH:16][C:15]([OH:18])=[CH:14][CH:13]=1)[CH2:2][CH2:3][CH3:4].Cl[S:24]([C:27]1[CH:35]=[CH:34][C:30]([C:31]([OH:33])=[O:32])=[C:29]([OH:36])[CH:28]=1)(=[O:26])=[O:25]>>[CH2:1]([C:5]1[O:6][C:7]2[CH:22]=[CH:21][CH:20]=[CH:19][C:8]=2[C:9]=1[CH2:10][NH:11][C:12]1[CH:13]=[CH:14][C:15]([O:18][S:24]([C:27]2[CH:35]=[CH:34][C:30]([C:31]([OH:33])=[O:32])=[C:29]([OH:36])[CH:28]=2)(=[O:26])=[O:25])=[CH:16][CH:17]=1)[CH2:2][CH2:3][CH3:4]
Reactant: CCCCc1oc2ccccc2c1CNc1ccc(O)cc1
Reactant: O=C(O)c1ccc(S(=O)(=O)Cl)cc1O
Product: CCCCc1oc2ccccc2c1CNc1ccc(OS(=O)(=O)c2ccc(C(=O)O)c(O)c2)cc1
Yield: 68.2 %

Procedure:
The title compound was prepared according to the procedure in Example 4 using 4-[(2-butyl-benzofuran-3-ylmethyl)-amino]-phenol (0.500 g, 1.69 mmol) and 4-chlorosulphonyl-2-hydroxybenzoic acid (0.401 g, 1.69 mmol). Purification on 2% H3PO4 /MeOH treated silica gel, eluting with 25% EtOAc/hexane gave 0.571 g (85%) of the title compound as a dark yellow solid, mp 75-77° C. 1H NMR (DMSO-d6) δ 0.86 (t, 3 H), 1.31 (sextet, 2 H), 1.60 (quintet, 2 H), 2.80 (t, 2 H), 4.23 (s, 2 H), 6.54 (d, 2 H), 6.72 (d, 2 H), 7.14-7.22 (m, 2 H), 7.26-7.30 (m, 2 H), 7.45 (dd, 1 H), 7.58 (dd, 1 H), 7.95 (d, 1 H). IR (KBr) 3400, 2950, 1600, 1510 and 1380 cm-1. mass spectrum (-ESI) m/z 494 (M-H).
Reaction SMILES: [NH2:1][CH2:2][CH2:3][NH:4][C:5]1[N:13]=[C:12]([Cl:14])[N:11]=[C:10]2[C:6]=1[N:7]=[CH:8][N:9]2[CH:15]1[CH2:19][CH2:18][CH2:17][CH2:16]1.CO.[CH:22](=O)[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1.C([BH3-])#N.[Na+]>CCCCCC.CCOC(C)=O.C(O)(=O)C>[Cl:14][C:12]1[N:11]=[C:10]2[C:6]([N:7]=[CH:8][N:9]2[CH:15]2[CH2:19][CH2:18][CH2:17][CH2:16]2)=[C:5]([NH:4][CH2:3][CH2:2][NH:1][CH:22]([C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)[C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)[N:13]=1
Reactant: O=Cc1ccccc1
Reactant: NCCNc1nc(Cl)nc2c1ncn2C1CCCC1
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CCCCCC
Solvent: CO
Solvent: CCOC(C)=O
Product: Clc1nc(NCCNC(c2ccccc2)c2ccccc2)c2ncn(C3CCCC3)c2n1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
The operation is carried out as in Stage 2 of Example 7 starting from 141 mg of the product obtained in Stage 1 of Example 7, 2 ml of methanol, 0.7 ml (15 eq) of benzaldehyde and 0.1 ml of acetic acid then the reaction medium is agitated at ambient temperature for approximately 3 hours. Then 55 mg of sodium cyanoborohydride (NaBH3CN) is added and the reaction medium is agitated at ambient temperature for 1 hour. 10 ml AcOEt is added, followed by washing with 2×5 ml H2O, then 5 ml of a saturated aqueous solution of NaCl, drying and evaporating the solvent. After purification by chromatography on silica eluting with methylene chloride/ethyl acetate in a proportion of 70/30, the product obtained is impasted in hexane and in this way 143 mg of expected product is obtained.
Reaction SMILES: [C-]#N.[K+].CC(C)(O)[C:6]#[N:7].[Cl:10][C:11]1[CH:12]=[C:13](/[C:18](/[C:41]([F:44])([F:43])[F:42])=[CH:19]\[C:20]([C:22]2[CH:39]=[CH:38][C:25]([C:26]([NH:28][CH2:29][C:30](=[O:37])[NH:31][CH2:32][C:33]([F:36])([F:35])[F:34])=[O:27])=[C:24]([CH3:40])[CH:23]=2)=[O:21])[CH:14]=[C:15]([Cl:17])[CH:16]=1.O>C1(C)C=CC=CC=1>[C:6]([C@@:18]([C:13]1[CH:12]=[C:11]([Cl:10])[CH:16]=[C:15]([Cl:17])[CH:14]=1)([C:41]([F:44])([F:42])[F:43])[CH2:19][C:20]([C:22]1[CH:39]=[CH:38][C:25]([C:26]([NH:28][CH2:29][C:30](=[O:37])[NH:31][CH2:32][C:33]([F:35])([F:36])[F:34])=[O:27])=[C:24]([CH3:40])[CH:23]=1)=[O:21])#[N:7]
Reactant: Cc1cc(C(=O)/C=C(\c2cc(Cl)cc(Cl)c2)C(F)(F)F)ccc1C(=O)NCC(=O)NCC(F)(F)F
Reactant: CC(C)(O)C#N
Agent: [C-]#N
Agent: [K+]
Solvent: Cc1ccccc1
Solvent: O
Product: Cc1cc(C(=O)C[C@](C#N)(c2cc(Cl)cc(Cl)c2)C(F)(F)F)ccc1C(=O)NCC(=O)NCC(F)(F)F
Reaction time: 96 h
Yield: 31.7 %

Procedure:
Potassium cyanide (0.0082 g, 0.125 mmol) and acetone cyanohydrin (0.031 ml, 0.336 mmol) were added to a solution of 4-[(E)-3-(3,5-Dichloro-phenyl)-4,4,4-trifluoro-but-2-enoyl]-2-methyl-N-[(2,2,2-trifluoro-ethylcarbamoyl)-methyl]-benzamide (0.0600 g, 0.111 mmol) in toluene (3.0 ml). To this vigorously stirred suspension was added antracen-9-yl-methyl quininium chloride (0.0153 g, 0.028 mmol). The reaction mixture was stirred at 90 C for 4 days. After this time water was added and the reaction mixture was extracted with dichloromethane (3×). The crude product was purified by flash chromatography (0% to 25% ethyl acetate in cyclohexane) to afford 4-[(R)-3-Cyano-3-(3,5-dichloro-phenyl)-4,4,4-trifluoro-butyryl]-2-methyl-N-[(2,2,2-trifluoro-ethylcarbamoyl)-methyl]-benzamide (0.020 g, 32%) as a light yellow solid. Chiral HPLC analysis (Chiralpack AS-RH, acetonitrile:water:methanol=45:5:50, 1 ml/min, retention time 8.70 minutes (major enantiomer), 11.30 minutes (minor enantiomer) indicated that the reaction proceeded with 94% enantioselectivity.
Reaction SMILES: CN(C)[C:3]1[CH:4]=[C:5]([CH2:9][OH:10])[CH:6]=[CH:7][CH:8]=1.[Br:12][C:13]1[CH:18]=[CH:17][C:16](O)=[CH:15][C:14]=1[CH3:20].CC1(C)C(C)(C)OB(C2C=NNC=2)O1>>[Br:12][C:13]1[CH:18]=[CH:17][C:16]([O:10][CH2:9][CH:5]2[CH2:6][CH2:7][CH2:8][CH2:3][CH2:4]2)=[CH:15][C:14]=1[CH3:20]
Reactant: CN(C)c1cccc(CO)c1
Reactant: Cc1cc(O)ccc1Br
Agent: CC1(C)OB(c2cn[nH]c2)OC1(C)C
Product: Cc1cc(OCC2CCCCC2)ccc1Br

Procedure:
The title compound was prepared by substituting cyclohexylmethanol for (3-(dimethylamino)phenyl)methanol and 4-bromo-3-methylphenol for 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole in EXAMPLE 34A.
Reaction SMILES: C[O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[C:9](=[O:13])[NH:8][CH2:7][CH2:6]2.Cl.[NH+]1C=CC=CC=1>O>[OH:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[C:9](=[O:13])[NH:8][CH2:7][CH2:6]2
Reactant: COc1ccc2c(c1)CCNC2=O
Agent: Cl
Agent: c1cc[nH+]cc1
Solvent: O
Product: O=C1NCCc2cc(O)ccc21
Temperature: 200 °C
Yield: 27.5 %

Procedure:
A mixture of 6-methoxy-3,4-dihydroisoquinolin-1(2H)-one (6.40 g, 35.6 mmol) and pyridinium hydrochloride (41.1 g, 356 mmol) was heated at 200° C. for 3 h. Water was added (200 mL) and the mixture was extracted with CH2Cl2 (3×200 mL), dried (MgSO4) and concentrated to yield 6-hydroxy-3,4-dihydroisoquinolin-1(2H)-one (1.60 g, 39%, 2 steps) as a yellow solid. 1H NMR (400 Mhz, acetone-d6): δ 8.91 (brs, 1H), 7.81 (d, J=8.4 Hz, 1H), 7.40 (brs, 1H), 6.77 (d, J=8.4 Hz, 1H), 6.70 (s, 1H), 3.47 (dt, J=6.8, and 3.2 Hz, 2H), 2.88 (t, J=6.6 Hz, 2H); MS (ESI) m/z: 164.0 (M+H+).
Reaction SMILES: CS(O[CH2:6][CH2:7][N:8]1[CH:12]=[C:11]([C:13]2[CH:18]=[C:17]([C:19]([O:21]C)=[O:20])[CH:16]=[CH:15][N:14]=2)[N:10]=[CH:9]1)(=O)=O.[F:23][C:24]1[CH:25]=[C:26]([CH:30]=[CH:31][CH:32]=1)[CH2:27][NH:28][CH3:29]>>[F:23][C:24]1[CH:25]=[C:26]([CH2:27][N:28]([CH3:29])[CH2:6][CH2:7][N:8]2[CH:12]=[C:11]([C:13]3[CH:18]=[C:17]([C:19]([OH:21])=[O:20])[CH:16]=[CH:15][N:14]=3)[N:10]=[CH:9]2)[CH:30]=[CH:31][CH:32]=1
Reactant: CNCc1cccc(F)c1
Reactant: COC(=O)c1ccnc(-c2cn(CCOS(C)(=O)=O)cn2)c1
Product: CN(CCn1cnc(-c2cc(C(=O)O)ccn2)c1)Cc1cccc(F)c1
Yield: 9 %

Procedure:
The title compound was prepared in 9% yield from methyl 2-(1-{2-[(methylsulfonyl)oxy]ethyl}-1H-imidazol-4-yl)pyridine-4-carboxylate (PREPARATION 6) and 3-fluoro-N-methylbenzylamine according to the procedure for the preparation of Example 58. 1HNMR (400 MHz, DMSO): δ 2.20 (3H, s), 2.71 (2H, t, J=6.2 Hz), 4.02 (1H, t, J=5.8 Hz), 4.16 (2H, t, J=6.2 Hz), 4.39 (1H, t, J=5.9 Hz), 6.93 (1H, d, J=9.8 Hz), 7.00 (2H, d, J=7.8 Hz), 7.25 (1H, m), 7.57 (1H, m), 7.74 (1H, s), 7.79 (1H, d, J=4.2 Hz), 8.30 (1H, s), 8.59 (1H, m). [M+H] Calc'd for C19H19FN4O2, 355. Found, 355.
Reaction SMILES: [Cl:1][C:2]1[CH:12]=[CH:11][CH:10]=[C:9]([Cl:13])[C:3]=1[C:4]([N:6]=[C:7]=[O:8])=[O:5].[Cl:14][C:15]1[CH:20]=[CH:19][C:18]([S:21][C:22]2[N:27]=[CH:26][C:25]([NH2:28])=[CH:24][CH:23]=2)=[CH:17][CH:16]=1>C(OCC)(=O)C>[Cl:1][C:2]1[CH:12]=[CH:11][CH:10]=[C:9]([Cl:13])[C:3]=1[C:4]([NH:6][C:7]([NH:28][C:25]1[CH:26]=[N:27][C:22]([S:21][C:18]2[CH:19]=[CH:20][C:15]([Cl:14])=[CH:16][CH:17]=2)=[CH:23][CH:24]=1)=[O:8])=[O:5]
Reactant: O=C=NC(=O)c1c(Cl)cccc1Cl
Reactant: Nc1ccc(Sc2ccc(Cl)cc2)nc1
Solvent: CCOC(C)=O
Product: O=C(NC(=O)c1c(Cl)cccc1Cl)Nc1ccc(Sc2ccc(Cl)cc2)nc1
Reaction time: 4 h

Procedure:
2,6-Dichlorobenzoyl isocyanate (2.16 grams; 0.01 mole) and 6-(4-chlorophenylthio)-3-aminopyridine (2.37 grams; 0.01 mole) were mixed in dry ethyl acetate and stirred for 4 hours. The ethyl acetate was removed in vacuo. TLC showed a 3-spot mixture. The reaction mixture was then poured over a silica column with ethyl acetate, and the major spot collected. It was crystallized from ethyl acetate-hexanes, yield 1.5 g., m.p. 160°-162° C.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[C:11](=[O:12])[N:10](CC2C=CC(OC)=CC=2)[C:9]2[CH:22]=[CH:23][S:24][C:8]=2[C:7]=1O)=[O:5])[CH3:2].C(Cl)(=O)C([Cl:29])=O>>[CH2:1]([O:3][C:4]([C:6]1[C:11](=[O:12])[NH:10][C:9]2[CH:22]=[CH:23][S:24][C:8]=2[C:7]=1[Cl:29])=[O:5])[CH3:2]
Reactant: CCOC(=O)c1c(O)c2sccc2n(Cc2ccc(OC)cc2)c1=O
Reactant: O=C(Cl)C(=O)Cl
Product: CCOC(=O)c1c(Cl)c2sccc2[nH]c1=O

Procedure:
The preferred intermediate in the preparation of compounds of structure (I), 7-chloro-5-oxo-4,5-dihydro-thieno[3,2-b]pyridine-6-carboxylic acid ethyl ester depicted by formula (4) below, was also prepared by an alternative route as shown in Scheme 34. In this method, methyl-3-amino-thiophene-2-carboxylate was reacted with 4-methoxy benzylchloride to yield methyl 3-(4-methoxybenzylamino)thiophene-2-carboxylate, depicted by formula (65). This intermediate was reacted with ethylmalonyl chloride followed by a cyclization reaction to yield 7-hydroxy-4-(4-methoxybenzyl)-5-oxo-4,5-dihydro-thieno[3,2-b]pyridine-6-carboxylic acid ethyl ester, depicted by formula (67). Chlorination of 7-hydroxy-4-(4-methoxybenzyl)-5-oxo-4,5-dihydro-thieno[3,2-b]pyridine-6-carboxylic acid ethyl ester, depicted by formula (67) by reacting with oxalyl chloride followed by deprotection yielded the intermediate 7-chloro-5-oxo-4,5-dihydro-thieno[3,2-b]pyridine-6-carboxylic acid ethyl ester, depicted by formula (4), as shown in Scheme 34.
Reaction SMILES: [C:1]([CH2:4][CH2:5][P:6]([CH2:21][C:22]1[CH:27]=[C:26]([C:28]([CH3:31])([CH3:30])[CH3:29])[C:25]([OH:32])=[C:24]([C:33]([CH3:36])([CH3:35])[CH3:34])[CH:23]=1)([CH2:8][CH2:9][C:10]([O:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH3:20])=[O:11])=[O:7])(=[O:3])N.[OH2:37]>CCCCC>[C:33]([C:24]1[CH:23]=[C:22]([CH:27]=[C:26]([C:28]([CH3:31])([CH3:30])[CH3:29])[C:25]=1[OH:32])[CH2:21][P:6]([CH2:8][CH2:9][C:10]([O:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH3:20])=[O:11])([CH2:5][CH2:4][C:1]([O:37][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH3:20])=[O:3])=[O:7])([CH3:36])([CH3:35])[CH3:34]
Reactant: O
Reactant: CCCCCCCCOC(=O)CCP(=O)(CCC(N)=O)Cc1cc(C(C)(C)C)c(O)c(C(C)(C)C)c1
Solvent: CCCCC
Product: CCCCCCCCOC(=O)CCP(=O)(CCC(=O)OCCCCCCCC)Cc1cc(C(C)(C)C)c(O)c(C(C)(C)C)c1

Procedure:
The filtrate from Example 2, containing water and pentane, is recovered and the water layer is separated. The pentane layer is then heated to strip off pentane and obtain 5.1 grams of a yellow oil which is further heated at 180° C. under a 1 mm. vacuum to remove volatile materials and obtain the desired product.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[C:17]3[C:12](=[CH:13][CH:14]=[C:15]([OH:18])[CH:16]=3)[N:11]([CH3:19])[C:10]=2[CH3:20])=[CH:5][CH:4]=1.[CH2:21]([O:23][C:24](=[O:29])[C:25](Br)([CH3:27])[CH3:26])[CH3:22]>>[CH2:21]([O:23][C:24](=[O:29])[C:25]([O:18][C:15]1[CH:16]=[C:17]2[C:12](=[CH:13][CH:14]=1)[N:11]([CH3:19])[C:10]([CH3:20])=[C:9]2[C:6]1[CH:7]=[CH:8][C:3]([O:2][CH3:1])=[CH:4][CH:5]=1)([CH3:27])[CH3:26])[CH3:22]
Reactant: CCOC(=O)C(C)(C)Br
Reactant: COc1ccc(-c2c(C)n(C)c3ccc(O)cc23)cc1
Product: CCOC(=O)C(C)(C)Oc1ccc2c(c1)c(-c1ccc(OC)cc1)c(C)n2C

Procedure:
This compound was prepared from 3-(4-methoxyphenyl)-1,2-dimethyl-1H-indole-5-ol and 2-bromo-2-methylpropanoic acid ethylester analogously to Example 10.
Reaction SMILES: C[O:2][C:3](=[O:21])[CH:4]=[CH:5][C:6]1[CH:11]=[CH:10][C:9]([C:12]([F:15])([F:14])[F:13])=[CH:8][C:7]=1[O:16][CH2:17][CH2:18][CH2:19][CH3:20].[Li+].[OH-]>C1COCC1.CO>[CH2:17]([O:16][C:7]1[CH:8]=[C:9]([C:12]([F:14])([F:13])[F:15])[CH:10]=[CH:11][C:6]=1[CH:5]=[CH:4][C:3]([OH:21])=[O:2])[CH2:18][CH2:19][CH3:20]
Reactant: CCCCOc1cc(C(F)(F)F)ccc1C=CC(=O)OC
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Product: CCCCOc1cc(C(F)(F)F)ccc1C=CC(=O)O

Procedure:
3-(2-Butoxy-4-trifluoromethyl-phenyl)-acrylic acid methyl ester (464 mg) was reacted with 1N LiOH (10 ml) in THF and CH3OH for 1 hr as described above to yield title compound
Reaction SMILES: [C:1]([NH:11][C@@H:12]([C:18]([OH:20])=O)[CH2:13][CH2:14][C:15](=[O:17])[NH2:16])([O:3][CH2:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1)=[O:2].CN1CCOCC1.ClC(OC)=O.[NH2:33][C:34]1[CH:39]=[CH:38][C:37]([C:40]2[NH:41][C:42](=[O:49])[C:43](=[CH:47][CH:48]=2)[C:44]([OH:46])=[O:45])=[CH:36][CH:35]=1.Cl[Si](C)(C)C.C(N(CC)CC)C>ClCCl.C(O)(C)C.CN(C)C(=O)C>[C:1]([NH:11][C@@H:12]([C:18]([NH:33][C:34]1[CH:35]=[CH:36][C:37]([C:40]2[NH:41][C:42](=[O:49])[C:43](=[CH:47][CH:48]=2)[C:44]([OH:46])=[O:45])=[CH:38][CH:39]=1)=[O:20])[CH2:13][CH2:14][C:15](=[O:17])[NH2:16])([O:3][CH2:4][C:5]1[CH:6]=[CH:7][CH:8]=[CH:9][CH:10]=1)=[O:2]
Reactant: Nc1ccc(-c2ccc(C(=O)O)c(=O)[nH]2)cc1
Reactant: NC(=O)CC[C@@H](NC(=O)OCc1ccccc1)C(=O)O
Agent: COC(=O)Cl
Agent: C[Si](C)(C)Cl
Solvent: CC(=O)N(C)C
Solvent: CN1CCOCC1
Solvent: ClCCl
Product: NC(=O)CC[C@@H](NC(=O)OCc1ccccc1)C(=O)Nc1ccc(-c2ccc(C(=O)O)c(=O)[nH]2)cc1
Reaction time: 0.25 h
Yield: 89.3 %

Procedure:
A solution of 4.2 g (15 mmol) of N-carbobenzoxy-D-glutamine and 50 ml of N,N-dimethylacetamide is stirred at -12° and 1.65 ml (15 mmol) of N-methylmorpholine and 1.2 ml (15 mmol) of methyl chloroformate are added. The mixture is stirred at -12° for 15 min. A suspension of 2.3 g (10 mmol) of 6-(4-aminophenyl)-1,2-dihydro-2-oxonicotinic acid is stirred in 75 ml dichloromethane at room temperature and is silylated with 3.8 ml (30 mmol) of chlorotrimethylsilane and 4.2 ml (30 mmol) of triethylamine. The solution of the silylated material is cooled to 0°-5° and is then added to the solution of the above mixed anhydride. The reaction mixture is stirred at -7° for 1 hr, then at 0°-5° for 4 hrs and at room temperature for 16 hrs and 30 ml of isopropanol is added. The bulk of the solvents is removed at reduced pressure and the residue is diluted with 250 ml cold water. The precipitate is collected, washed with cold water and dried to give 4.4 g of 6-[4-(N-carbobenzoxy-D-glutaminylamino)phenyl]-1,2-dihydro-2-oxonicotinic acid as a yellow solid; mp 250°-252° dec; [α]D23 -13.3° (cl, DMSO).
Reaction SMILES: [CH3:1][O:2][CH2:3][C:4](Cl)=O.[NH2:7][C:8]1[CH:9]=[N:10][C:11]2[C:16]([C:17]=1[SH:18])=[CH:15][CH:14]=[CH:13][CH:12]=2.[OH-].[Na+]>COCC(O)=O.O.ClCCl>[CH3:1][O:2][CH2:3][C:4]1[S:18][C:17]2[C:16]3[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=3[N:10]=[CH:9][C:8]=2[N:7]=1
Reactant: Nc1cnc2ccccc2c1S
Reactant: COCC(=O)Cl
Agent: COCC(=O)O
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: ClCCl
Product: COCc1nc2cnc3ccccc3c2s1
Temperature: 140 °C

Procedure:
Methoxyacetyl chloride (1.8 mL) was added to a mixture of 3-aminoquinoline-4-thiol (2.8 g) in methoxyacetic acid (15 mL). The reaction was heated at about 140° C. for 1 hour and then allowed to cool to ambient temperature. The reaction mixture was diluted with a small amount of water, made basic with 10% sodium hydroxide and then extracted with dichloromethane (300 mL). The extract was washed with sodium bicarbonate, washed with water, dried over magnesium sulfate and then concentrated under vacuum to provide crude product as a dark oil. The oil was dissolved in dichloromethane and then placed on a layer of silica gel. The silica gel was eluted with 1:1 hexane:ethyl acetate. The eluant was concentrated under vacuum to provide 2.3 g of 2-(methoxymethyl)thiazolo[4,5-c]quinoline as an orange solid.