Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]1[CH:6]=[C:5]([CH3:7])[NH:4][C:3]=1/[CH:8]=[C:9]1\[C:10](=[O:25])[N:11]([C:18](N2C=CN=C2)=[O:19])[C:12]2[C:17]\1=[CH:16][CH:15]=[CH:14][CH:13]=2.[OH:26][C:27]1[CH:35]=[CH:34][C:30]([C:31]([OH:33])=[O:32])=[CH:29][CH:28]=1>C(N(CC)CC)C.C1COCC1>[C:31]([C:30]1[CH:34]=[CH:35][C:27]([O:26][C:18]([N:11]2[C:12]3[C:17](=[CH:16][CH:15]=[CH:14][CH:13]=3)/[C:9](=[CH:8]/[C:3]3[NH:4][C:5]([CH3:7])=[CH:6][C:2]=3[CH3:1])/[C:10]2=[O:25])=[O:19])=[CH:28][CH:29]=1)([OH:33])=[O:32]
Reactant: O=C(O)c1ccc(O)cc1
Reactant: Cc1cc(C)c(/C=C2\C(=O)N(C(=O)n3ccnc3)c3ccccc32)[nH]1
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: Cc1cc(C)c(/C=C2\C(=O)N(C(=O)Oc3ccc(C(=O)O)cc3)c3ccccc32)[nH]1
Temperature: 25 °C
Reaction time: 8 h
Yield: 37.3 %

Procedure:
A reaction mixture of 3-[1-(3,5-dimethyl-1H-pyrrol-2-yl)-meth-(Z)-ylidene]-1-(imidazol-1-ylcarbonyl)-1,3-dihydro-indol-2-one (332 mg, 1.0 mmol), 4-hydroxybenzoic acid (138 mg, 1.0 mmol), and 2 drops of triethylamine in 3.0 mL of THF was stirred at room temperature overnight and concentrated. The residue was then purified on a silica gel column eluting with ethyl acetate-hexane (1:3) and 0.5% of acetic acid in ethyl acetate-dichloromethane (2:1) to afford 150 mg (37%) of 3-[1-(3,5-dimethyl-1H-pyrrol-2-yl)-meth-(Z)-ylidene]-2-oxo-2,3-dihydro-indole-1-carboxylic acid 4-carboxy-phenyl ester. 1H NMR (400 MHz, DMSO-d6) δ 12.65 (s, vbr, 1H, COOH), 12.60 (s, br, 1H, NH-1′), 8.12 (d, J=7.39 Hz, 2H), 7.86-7.88 (m, 1H), 7.64 (s, vbr, 1H), 7.51 (s, 1H, H-vinyl), 7.43 (d, J=7.39 Hz, 2H), 7.21-7.23 (m, 2H), 6.09 (s, br, 1H, H-4′), 2.40 (s, 3H, CH3), and 2.38 (s, 3H, CH3).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:17][CH2:16][C:15]2[C:10](=[C:11]([C:18](O)=[O:19])[CH:12]=[CH:13][CH:14]=2)[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[S:21]1[C:25]2[CH:26]=[CH:27][CH:28]=[CH:29][C:24]=2[N:23]=[C:22]1[NH2:30].CCN=C=NCCCN(C)C>C(Cl)Cl.CN(C1C=CN=CC=1)C>[S:21]1[C:25]2[CH:26]=[CH:27][CH:28]=[CH:29][C:24]=2[N:23]=[C:22]1[NH:30][C:18]([C:11]1[CH:12]=[CH:13][CH:14]=[C:15]2[C:10]=1[CH2:9][N:8]([C:6]([O:5][C:1]([CH3:4])([CH3:3])[CH3:2])=[O:7])[CH2:17][CH2:16]2)=[O:19]
Reactant: Nc1nc2ccccc2s1
Reactant: CC(C)(C)OC(=O)N1CCc2cccc(C(=O)O)c2C1
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N1CCc2cccc(C(=O)Nc3nc4ccccc4s3)c2C1
Temperature: 25 °C
Reaction time: 8 h
Yield: 84.7 %

Procedure:
To a solution of 2-(tert-butoxycarbonyl)-1,2,3,4-tetrahydroisoquinoline-8-carboxylic acid (6.8 g, 24.5 mmol) and benzo[d]thiazol-2-amine (5.52 g, 36.8 mmol) in DCM (80 mL) was added EDCI (9.4 g, 49.04 mmol) and DMAP (6 g, 49 mmol). The mixture was stirred at rt overnight. The reaction mixture was diluted with DCM (400 mL), washed with 5% aq. HCl, water, brine, dried over Na2SO4, and concentrated under reduced pressure to provide 8.5 g of the desired product tert-butyl 8-(benzo[d]thiazol-2-ylcarbamoyl)-3,4-dihydroisoquinoline-2(1H)-carboxylate (1A): 1H NMR (300 MHz, CDCl3) δ ppm 7.83 (1H, m), 7.48 (1H, d), 7.34 (4H, m), 7.19 (1H, t), 4.91 (2H, m), 3.67 (2H, t), 2.92 (2H, t), 1.47 (9H, m). MS (ESI(+)): m/z 410 (M+H).
Reaction SMILES: Cl[C:2]1C=C(Cl)C=C(Cl)C=1O.C([Zn]CC)C.C(I)I.[Br:19][C:20]1[CH:25]=[CH:24][C:23]([C:26]([O:28][CH3:29])=[CH2:27])=[CH:22][CH:21]=1>C(Cl)Cl.CCCCC>[Br:19][C:20]1[CH:21]=[CH:22][C:23]([C:26]2([O:28][CH3:29])[CH2:2][CH2:27]2)=[CH:24][CH:25]=1
Reactant: Oc1c(Cl)cc(Cl)cc1Cl
Reactant: C=C(OC)c1ccc(Br)cc1
Agent: CC[Zn]CC
Solvent: ICI
Solvent: ClCCl
Solvent: CCCCC
Product: COC1(c2ccc(Br)cc2)CC1
Temperature: -40 °C
Reaction time: 0.33 h
Yield: 60.3 %

Procedure:
To a solution of 2,4,6-trichlorophenol (1.90 g, 9.64 mmol) in methylene chloride (70 ml) at −40° C. was added diethyl zinc (9.64 ml, 1M solution in hexane, 9.64 mmol). The mixture was stirred at −40° C. for 20 min and then CH2I2 (778 μl, 9.64 mmol) was added. After stirring for an additional 20 min, 1-bromo-4-(1-methoxyvinyl)-benzene (1.37 g, 6.43 mmol) was added. The reaction mixture was slowly warmed to RT and stirring was continued for 16 h. Pentane was added and the mixture was washed with 1M HCl, sat. NaHCO3, sat. Na2SO3 and brine. The organic layer was dried (MgSO4), filtered, concentrated in vacuo to give a crude residue which was purified by flash column chromatography (2% ethyl acetate in cyclohexane-10% ethyl acetate in cyclohexane) to give 1-bromo-4-(1-methoxycyclopropyl)-benzene (880 mg, 60%) as a yellow oil. 1H NMR (CDCl3, 300 MHz): δ 7.46 (d, J=8.5 Hz, 2H), 7.18 (d, J=8.5 Hz, 2H), 3.21 (s, 3H), 1.21-1.17 (m, 2H), 0.95-0.91 (m, 2H).
Reaction SMILES: [N:1]1[CH:2]=[CH:3][N:4]2[C:10]=1[CH2:9][C:8]1[CH:11]=[CH:12][CH:13]=[CH:14][C:7]=1[NH:6][C:5]2=[O:15].[CH3:16][N:17]1[CH2:23][CH2:22][CH2:21][NH:20][CH2:19][CH2:18]1>C(Cl)Cl>[NH:4]1[CH:3]=[CH:2][N:1]=[C:10]1[CH2:9][C:8]1[CH:11]=[CH:12][CH:13]=[CH:14][C:7]=1[NH:6][C:5]([N:20]1[CH2:21][CH2:22][CH2:23][N:17]([CH3:16])[CH2:18][CH2:19]1)=[O:15]
Reactant: CN1CCCNCC1
Reactant: O=C1Nc2ccccc2Cc2nccn21
Solvent: ClCCl
Product: CN1CCCN(C(=O)Nc2ccccc2Cc2ncc[nH]2)CC1
Temperature: 25 °C
Reaction time: 24 h

Procedure:
To a suspension of 0.76 g of 11H-imidazo[1,2-c][1,3]benzodiazepin-5-(6H)-one in 9 ml of methylene chloride is added at once 0.41 g of N-methylhomopiperazine and the mixture is stirred at room temperature for 24 hours. The reaction mixture is filtered and the filtrate is evaporated to dryness. Recrystallization of the residue from methylene chloride-ether gave 1-[2-(2-imidazolylmethyl)phenylcarbamoyl]-4-methylhomopiperazine, the compound of formula VI wherein R1, R2, R4 -R7 are hydrogen, CnH2n is (CH2)3, R3 is methyl and Z is oxygen, melting at 139°-143°.
Reaction SMILES: C[O-].[Na+].Cl[CH:5]([N:21]1[CH:25]=[N:24][CH:23]=[N:22]1)[CH:6]([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=1[F:20])[C:7]1[CH:12]=[CH:11][C:10]([F:13])=[CH:9][CH:8]=1.O>CO.[I-].[K+]>[N:21]1([CH:5]=[C:6]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=2[F:20])[C:7]2[CH:8]=[CH:9][C:10]([F:13])=[CH:11][CH:12]=2)[CH:25]=[N:24][CH:23]=[N:22]1
Reactant: Fc1ccc(C(c2ccccc2F)C(Cl)n2cncn2)cc1
Agent: C[O-]
Agent: [I-]
Agent: [K+]
Solvent: O
Solvent: CO
Product: Fc1ccc(C(=Cn2cncn2)c2ccccc2F)cc1
Yield: 89.3 %

Procedure:
28.6 g of sodium methylate and 0.2 g of potassium iodide are added to a solution of 84.7 g of 1-chloro-1(1,2,4-triazol-1-yl)-2-(2-fluorophenyl)-2-(4-fluorophenyl)-ethane in 500 ml of methanol. After the reaction mixture has been refluxed for one hour, 300 ml of water are added to the solution, which is extracted several times by shaking with methyl tert-butyl ether. The organic phase separated off is washed twice with water, then dried over sodium sulfate and evaporated down, 67 g (89%) of 1-(1,2,4-triazol-1-yl)-2-(2-fluorophenyl)-2-(4-fluorophenyl)-ethene being obtained in the form of an oil.
Reaction SMILES: [CH2:1]([O:8][C:9](=[O:52])[CH:10]([CH2:36][CH2:37][C:38](=[O:51])[NH:39]CC1C=CC(OC)=CC=1OC)[CH2:11][C:12]1([C:17](=[O:35])[NH:18][C@H:19]2[CH2:24][CH2:23][C@@H:22]([C:25]([O:27][CH2:28][C:29]3[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=3)=[O:26])[CH2:21][CH2:20]2)[CH2:16][CH2:15][CH2:14][CH2:13]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.O.C(=O)([O-])O.[Na+]>FC(F)(F)C(O)=O>[CH2:1]([O:8][C:9](=[O:52])[CH:10]([CH2:36][CH2:37][C:38](=[O:51])[NH2:39])[CH2:11][C:12]1([C:17](=[O:35])[NH:18][C@H:19]2[CH2:20][CH2:21][C@@H:22]([C:25]([O:27][CH2:28][C:29]3[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=3)=[O:26])[CH2:23][CH2:24]2)[CH2:13][CH2:14][CH2:15][CH2:16]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: COc1ccc(CNC(=O)CCC(CC2(C(=O)N[C@H]3CC[C@@H](C(=O)OCc4ccccc4)CC3)CCCC2)C(=O)OCc2ccccc2)c(OC)c1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O=C(O)C(F)(F)F
Solvent: O
Product: NC(=O)CCC(CC1(C(=O)N[C@H]2CC[C@@H](C(=O)OCc3ccccc3)CC2)CCCC1)C(=O)OCc1ccccc1
Temperature: 25 °C
Reaction time: 18 h
Yield: 37.6 %

Procedure:
3-{1-[(cis-4-Benzyloxycarbonyl-cyclohexyl)carbamoyl]-cyclopentyl}-2-{2-[(2,4-dimethoxyphenyl)methylcarbamoyl]ethyl}propanoic acid benzyl ester (Example 164) (0.37 g, 0.52 mmole) was dissolved in trifluoroacetic acid (10 ml). After stirring for 18 hours at room temperature the deep pink reaction mixture was poured into iced water which was basified with sodium hydrogen carbonate and extracted with dichloromethane. The combined extracts were dried (Na2SO4) and evaporated under vacuum. The residue was purified by column chromatography on silica gel eluting with dichloromethane-diethyl ether and methanoldichloromethane mixtures to yield the title ester (110 mg, 38%). Rf 0.25 (silica; ethylacetate).
Reaction SMILES: [CH2:1]([N:8]1[C:13](=[O:14])[C:12]([CH3:15])=[C:11]([CH3:16])[N:10]=[C:9]1[C@H:17]([NH:21][C:22](=[O:30])[C:23]1[CH:28]=[CH:27][C:26]([CH3:29])=[CH:25][CH:24]=1)[CH:18]([CH3:20])[CH3:19])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[H-].[Na+].Cl[CH2:34][CH2:35][N:36]1[CH2:40][CH2:39][CH2:38][CH2:37]1>CN(C=O)C>[CH2:1]([N:8]1[C:13](=[O:14])[C:12]([CH3:15])=[C:11]([CH3:16])[N:10]=[C:9]1[C@H:17]([N:21]([CH2:34][CH2:35][N:36]1[CH2:40][CH2:39][CH2:38][CH2:37]1)[C:22](=[O:30])[C:23]1[CH:28]=[CH:27][C:26]([CH3:29])=[CH:25][CH:24]=1)[CH:18]([CH3:20])[CH3:19])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: ClCCN1CCCC1
Reactant: Cc1ccc(C(=O)N[C@@H](c2nc(C)c(C)c(=O)n2Cc2ccccc2)C(C)C)cc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: Cc1ccc(C(=O)N(CCN2CCCC2)[C@@H](c2nc(C)c(C)c(=O)n2Cc2ccccc2)C(C)C)cc1
Temperature: 25 °C
Yield: 44.4 %

Procedure:
To N-[(R)-1-(1-benzyl-4,5-dimethyl-6-oxo-1,6-dihydro-pyrimidin-2-yl)-2-methyl-propyl]-4-methyl-benzamide (50 mg, 0.123 Mmol) in DMF was added sodium hydride (5 mg, 0.147 Mmol). The reaction stirred for 15 at RT then 1-(2-chloro-ethyl)-pyrrolidine (20 mg, 0.135 mmol) (Tilford et al.; J. Am. Chem. Soc.; 70; 1948; 4001). was added. The reaction was stirred at RT for 24 h, quenched with water and extracted with ethyl acetate (3×20 mL). The combined organic layers were washed with water (1×20 ml), brine (1×20 mL), dried (Na2SO4), filtered, and evaporated to yield the title compound (30 mg, 49%) as a colorless oil: MS (ES) m/e 501.4 (M+H)+.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:9]=[C:10]3[CH:15]=[CH:14][C:13]([I:16])=[CH:12][N:11]3[CH:17]=2)=[CH:4][CH:3]=1.C(=O)([O-])[O-].[K+].[K+].Br[CH2:25][CH2:26][CH2:27][F:28].O>CN(C)C=O.C(Cl)(Cl)Cl>[F:28][CH2:27][CH2:26][CH2:25][O:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[N:9]=[C:10]3[CH:15]=[CH:14][C:13]([I:16])=[CH:12][N:11]3[CH:17]=2)=[CH:6][CH:7]=1
Reactant: FCCCBr
Reactant: Oc1ccc(-c2cn3cc(I)ccc3n2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: ClC(Cl)Cl
Solvent: O
Product: FCCCOc1ccc(-c2cn3cc(I)ccc3n2)cc1
Temperature: 25 °C
Reaction time: 24 h
Yield: 44.1 %

Procedure:
673 mg (corresponding to 2.0 mmol) of 2-(4′-hydroxyphenyl)-6-iodoimidazo[1,2-a]pyridine was dissolved in 25 mL of N,N-dimethylformamide, and 831 mg (corresponding to 6.0 mmol) of potassium carbonate was added thereto. 275 μL (corresponding to 3.0 mmol) of 1-bromo-3-fluoropropane was added to the resulting solution, and the solution was stirred for 24 hours at room temperature. After the completion of the reaction, the reaction solution was poured into water, and extracted three times with chloroform. The combined chloroform layer was washed with water and a saturated sodium chloride solution, dried over anhydrous sodium sulfate, filtered and concentrated. The resulting crude product was purified by flash silica gel column chromatography (elution solvent: chloroform), and further purified by recycle preparative HPLC (HPLC apparatus: LC-908 (under trade name; manufactured by Japan Analytical Industry Co., Ltd.); column: two of JAIGEL 2H (under trade name; manufactured by Japan Analytical Industry Co., Ltd.) connected together; mobile phase: chloroform), to obtain 349 mg (corresponding to 0.881 mmol) of 2-[4′-(3″-fluoropropoxy)phenyl]-6-iodoimidazo[1,2-a]pyridine (FIG. 5, Step 3).
Reaction SMILES: [NH2:1][C:2]1[C:7]([CH:8]=[O:9])=[C:6]([CH:10]2[CH2:15][CH2:14][CH2:13][N:12](C(OC(C)(C)C)=O)[CH2:11]2)[CH:5]=[C:4]([C:23]2[C:28]([OH:29])=[CH:27][CH:26]=[CH:25][C:24]=2[O:30][CH2:31][C:32]2[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=2)[N:3]=1.[ClH:38]>O1CCOCC1>[ClH:38].[NH2:1][C:2]1[N:3]=[C:4]([C:23]2[C:28]([OH:29])=[CH:27][CH:26]=[CH:25][C:24]=2[O:30][CH2:31][C:32]2[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=2)[CH:5]=[C:6]([CH:10]2[CH2:15][CH2:14][CH2:13][NH:12][CH2:11]2)[C:7]=1[CH:8]=[O:9]
Reactant: CC(C)(C)OC(=O)N1CCCC(c2cc(-c3c(O)cccc3OCc3ccccc3)nc(N)c2C=O)C1
Agent: Cl
Solvent: C1COCCO1
Product: Nc1nc(-c2c(O)cccc2OCc2ccccc2)cc(C2CCCNC2)c1C=O
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a stirred solution of tert-butyl 3-{2-amino-6-[2-(benzyloxy)-6-hydroxyphenyl]-3-formyl-4-pyridinyl}-1-piperidinecarboxylate (0.090 g, 0.183 mmol) in 1,4-dioxane (2 mL) was added 4N HCl in dioxane (2 mL). The mixture was stirred at room temperature for 2 hrs. The resulting precipitate was collected by filtration, washed with acetonitril, and dried under reduced pressure to give 2-amino-6-[2-(benzyloxy)-6-hydroxyphenyl]-4-(3-piperidinyl)nicotinaldehyde hydrochloride. (0.103 g, yield quant.)
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][CH2:9][CH2:10][N:11]2[CH2:16][CH2:15][CH2:14][CH2:13][CH2:12]2)=[CH:4][C:3]=1[NH:17][C:18](=[O:28])/[C:19](/[CH3:27])=[CH:20]/C1C=CC=CC=1.[Cl-].[Cl-].[Cl-].[Al+3]>ClC1C=CC=CC=1.O>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][CH2:9][CH2:10][N:11]2[CH2:12][CH2:13][CH2:14][CH2:15][CH2:16]2)=[C:4]2[C:3]=1[NH:17][C:18](=[O:28])[C:19]([CH3:20])=[CH:27]2
Reactant: C/C(=C\c1ccccc1)C(=O)Nc1cc(OCCN2CCCCC2)ccc1Cl
Agent: [Al+3]
Agent: [Cl-]
Solvent: O
Solvent: Clc1ccccc1
Product: Cc1cc2c(OCCN3CCCCC3)ccc(Cl)c2[nH]c1=O
Temperature: 125 °C
Reaction time: 2 h
Yield: 39 %

Procedure:
(E)-N-(2-chloro-5-(2-(piperidin-1-yl)ethoxy)phenyl)-2-methyl-3-phenylacrylamide (100 mg, 0.2 mmol, 1 eq.) was placed in chlorobenzene (500 μL), in the presence of aluminium trichloride (201 mg, 1.5 mmol, 6 eq.). The reaction mixture was heated at 125° C. and stirred for 2 hours. After cooling down to room temperature, it was diluted with a water and ice mixture and extracted with ethyl acetate. The organic phase was dried over MgSO4, filtered and concentrated under reduced pressure. The resulting residue was purified by column chromatography on silica gel to afford 8-chloro-3-methyl-5-(2-(piperidin-1-yl)ethoxy)quinolin-2(1H)-one (25 mg, 31%).
Reaction SMILES: [Si:1]([O:18][CH2:19][C:20]1[C:21]([N:35]2[CH2:40][C@H:39]([CH3:41])[O:38][C@H:37]([CH3:42])[CH2:36]2)=[C:22]([F:34])[C:23]([F:33])=[C:24]([C:26](=O)[C:27]([O:29][CH2:30][CH3:31])=[O:28])[CH:25]=1)([C:14]([CH3:17])([CH3:16])[CH3:15])([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl.[NH2:44][OH:45]>N1C=CC=CC=1>[Si:1]([O:18][CH2:19][C:20]1[C:21]([N:35]2[CH2:36][C@H:37]([CH3:42])[O:38][C@H:39]([CH3:41])[CH2:40]2)=[C:22]([F:34])[C:23]([F:33])=[C:24]([C:26](=[N:44][OH:45])[C:27]([O:29][CH2:30][CH3:31])=[O:28])[CH:25]=1)([C:14]([CH3:15])([CH3:16])[CH3:17])([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CCOC(=O)C(=O)c1cc(CO[Si](c2ccccc2)(c2ccccc2)C(C)(C)C)c(N2C[C@@H](C)O[C@@H](C)C2)c(F)c1F
Reactant: NO
Agent: Cl
Solvent: c1ccncc1
Product: CCOC(=O)C(=NO)c1cc(CO[Si](c2ccccc2)(c2ccccc2)C(C)(C)C)c(N2C[C@@H](C)O[C@@H](C)C2)c(F)c1F
Temperature: 115 °C
Reaction time: 16 h

Procedure:
Ethyl 2-(5-((tert-butyldiphenylsilyloxy)methyl)-4-((2R,6S)-2,6-dimethylmorpholino)-2,3-difluorophenyl)-2-oxoacetate (Intermediate 114, 2.808 g, 4.71 mmol) and hydroxylamine hydrochloride (0.360 g, 5.18 mmol) were dissolved in pyridine (40 ml) and stirred at 115° C. for 16 hours. The reaction was concentrated to remove excess pyridine. The residue was dissolved in ethyl acetate and washed with water and brine 3×. The organic layer was dried over MgSO4 and concentrated. The residue was purified by silica gel column chromatography using a gradient of hexanes to ethyl acetate to give the title compound as a mixture of oxime isomers (1.924 g, 3.15 mmol, 66.8%).
Reaction SMILES: [F:1][CH2:2][C:3]([N:10]1[C:14](=[O:15])[C:13]2=[CH:16][CH:17]=[CH:18][CH:19]=[C:12]2[C:11]1=[O:20])([CH2:6][CH2:7][CH2:8][OH:9])[C:4]#[N:5].N1C=CC=CC=1.[CH3:27][S:28](Cl)(=[O:30])=[O:29]>ClCCl>[F:1][CH2:2][C:3]([N:10]1[C:14](=[O:15])[C:13]2=[CH:16][CH:17]=[CH:18][CH:19]=[C:12]2[C:11]1=[O:20])([CH2:6][CH2:7][CH2:8][O:9][S:28]([CH3:27])(=[O:30])=[O:29])[C:4]#[N:5]
Reactant: CS(=O)(=O)Cl
Reactant: N#CC(CF)(CCCO)N1C(=O)c2ccccc2C1=O
Solvent: ClCCl
Solvent: c1ccncc1
Product: CS(=O)(=O)OCCCC(C#N)(CF)N1C(=O)c2ccccc2C1=O
Reaction time: 8 h
Yield: 86.5 %

Procedure:
A mixture of 2-fluoromethyl-2-phthalimido-5-hydroxy-valeronitrile (42.8 g), dry pyridine (170 ml), and dry dichloromethane (350 ml) is stirred and cooled with ice/salt mixture. Freshly distilled methanesulfonylchloride (15.7 g) in dichloromethane (200 ml) is slowly added, and stirring is continued at room temperature overnight. The mixture is then poured onto ice/2 N HCl, and the organic phase is extracted subsequently with 1 N HCl, water, 10% sodium bicarbonate, and water (3×). Drying (MgSO4), treatment with charcoal (room temperature), and evaporation gives the title compound as a brown oil (42 g).
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[C:9]2[CH:10]=[CH:11][C:12]([O:14][Si](C(C)C)(C(C)C)C(C)C)=[CH:13][C:8]=2[O:7][CH:6]=1)=[O:4].O.O.O.[F-].C([N+](CCCC)(CCCC)CCCC)CCC.CCOC(C)=O.O>CN(C=O)C>[CH3:1][O:2][C:3]([C:5]1[C:9]2[CH:10]=[CH:11][C:12]([OH:14])=[CH:13][C:8]=2[O:7][CH:6]=1)=[O:4]
Reactant: COC(=O)c1coc2cc(O[Si](C(C)C)(C(C)C)C(C)C)ccc12
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: CCOC(C)=O
Solvent: O
Solvent: CN(C)C=O
Product: COC(=O)c1coc2cc(O)ccc12
Reaction time: 0.5 h

Procedure:
17.9 g (51.4 mMol) 6-Triisopropylsilanyloxy-benzofuran-3-carboxylic acid methyl ester are dissolved in 200 ml DMF. Then 34 g (108 mMol) tetrabutylammoniumfluorid trihydrate are added. After 30 min, the mixture is poured into 400 ml EtOAc and 600 ml water, the aq. phase is separated off and extracted 3 times with EtOAc. The organic layers are washed 4 times with water, brine and dried (Na2SO4). Then char coal is added and the mixture filtered. Partial concentration of the filtrate gives the crystalline title compound, which is filtered off and washed with ether and hexane: m.p.: 200-201° C. More product can be isolated from the filtrate by addition of 280 g SiO2, concentration, application to a chromatography column (SiO2; hexane/EtOAc 3: 1) and eluation with hexane/EtOAc 3:1.
Reaction SMILES: [CH3:1][N:2]1[C:6]2[CH:7]=[C:8]([N:11]3[CH:16]=[CH:15][C:14]([OH:17])=[CH:13][C:12]3=[O:18])[CH:9]=[CH:10][C:5]=2[N:4]=[C:3]1[CH3:19].[F:20][C:21]([F:30])([F:29])[C:22]1[CH:23]=[C:24]([CH2:27]O)[S:25][CH:26]=1.N(C(N1CCCCC1)=O)=NC(N1CCCCC1)=O.C(P(CCCC)CCCC)CCC>C1COCC1>[CH3:1][N:2]1[C:6]2[CH:7]=[C:8]([N:11]3[CH:16]=[CH:15][C:14]([O:17][CH2:27][C:24]4[S:25][CH:26]=[C:22]([C:21]([F:30])([F:29])[F:20])[CH:23]=4)=[CH:13][C:12]3=[O:18])[CH:9]=[CH:10][C:5]=2[N:4]=[C:3]1[CH3:19]
Reactant: OCc1cc(C(F)(F)F)cs1
Reactant: Cc1nc2ccc(-n3ccc(O)cc3=O)cc2n1C
Agent: CCCCP(CCCC)CCCC
Agent: O=C(N=NC(=O)N1CCCCC1)N1CCCCC1
Solvent: C1CCOC1
Product: Cc1nc2ccc(-n3ccc(OCc4cc(C(F)(F)F)cs4)cc3=O)cc2n1C
Temperature: 50 °C
Reaction time: 8 h
Yield: 39.3 %

Procedure:
To a suspension of 1-(1,2-dimethyl-1H-benzimidazol-6-yl)-4-hydroxypyridin-2(1H)-one (200 mg) in THF (5 ml) were added (4-(trifluoromethyl)thiophen-2-yl)methanol (157 mg), 1,1′-(azodicarbonyl)dipiperidine (257 mg) and tributylphosphine (0.25 ml) at room temperature, and the mixture was stirred at 50° C. overnight. After cooling, the mixture was purified by NH silica gel column chromatography (EtOAc/MeOH), followed by preparative HPLC (C18, mobile phase: H2O/CH3CN (0.1% TFA included)). The desired fraction was neutralized with saturated NaHCO3 solution, and extracted with EtOAc. The organic layer was separated, dried over MgSO4 and concentrated in vacuo to give the title compound (129 mg) as white crystals.
Reaction SMILES: [CH:1]1([C:6]([N:8]2[CH2:13][CH:12]([C:14]3[CH:19]=[CH:18][C:17]([CH2:20][CH3:21])=[CH:16][CH:15]=3)[CH2:11][CH:10]([C:22]([OH:24])=O)[CH2:9]2)=[O:7])[CH2:5][CH2:4][CH2:3][CH2:2]1.O[N:26]=[C:27]([NH2:29])[CH3:28]>>[CH:1]1([C:6]([N:8]2[CH2:9][CH:10]([C:22]3[O:24][N:29]=[C:27]([CH3:28])[N:26]=3)[CH2:11][CH:12]([C:14]3[CH:19]=[CH:18][C:17]([CH2:20][CH3:21])=[CH:16][CH:15]=3)[CH2:13]2)=[O:7])[CH2:2][CH2:3][CH2:4][CH2:5]1
Reactant: CC(N)=NO
Reactant: CCc1ccc(C2CC(C(=O)O)CN(C(=O)C3CCCC3)C2)cc1
Product: CCc1ccc(C2CC(c3nc(C)no3)CN(C(=O)C3CCCC3)C2)cc1

Procedure:
66 mg (0.20 mmol) of 1-(cyclopentylcarbonyl)-5-(4-ethylphenyl)piperidine-3-carboxylic acid (Example 7A) and 24 mg (0.22 mmol, 1.1 eq.) of N′-hydroxyethanimidamide were reacted according to the General Method 1. Yield: 58 mg (79% of theory)
Reaction SMILES: [O:1]1[C:5]2[CH:6]=[CH:7][C:8]([CH2:10][NH:11][C:12]([C:14]3[N:19]=[CH:18][N:17]=[C:16]([C:20]([NH:22][CH2:23][C:24]4[CH:33]=[CH:32][C:27]([C:28]([O:30]C)=[O:29])=[CH:26][CH:25]=4)=[O:21])[CH:15]=3)=[O:13])=[CH:9][C:4]=2[CH2:3][CH2:2]1.[OH-].[Na+]>O1CCCC1.O>[O:1]1[C:5]2[CH:6]=[CH:7][C:8]([CH2:10][NH:11][C:12]([C:14]3[N:19]=[CH:18][N:17]=[C:16]([C:20]([NH:22][CH2:23][C:24]4[CH:25]=[CH:26][C:27]([C:28]([OH:30])=[O:29])=[CH:32][CH:33]=4)=[O:21])[CH:15]=3)=[O:13])=[CH:9][C:4]=2[CH2:3][CH2:2]1
Reactant: COC(=O)c1ccc(CNC(=O)c2cc(C(=O)NCc3ccc4c(c3)CCO4)ncn2)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: O=C(O)c1ccc(CNC(=O)c2cc(C(=O)NCc3ccc4c(c3)CCO4)ncn2)cc1
Temperature: 25 °C
Reaction time: 24 h

Procedure:
6.28 g (14 mmol) of methyl 4-[({6-[(2,3-dihydrobenzofuran-5-ylmethyl)-carbamoyl]pyrimidine-4-carbonyl}amino)methyl]benzoate (see 5b) were suspended in 150 ml of tetrahydrofuran and 70 ml of water, after which 16.9 ml of a 1N aqueous solution of NaOH were added and the reaction mixture was then stirred at room temperature for 24 hours.
Reaction SMILES: Cl[C:2]1[N:6]2[CH:7]=[CH:8][C:9]([C:11]3C=NC=C[CH:16]=3)=[CH:10][C:5]2=[N:4][C:3]=1[NH:17][C:18]([NH:20][CH2:21][CH3:22])=[O:19].N.C([OH:26])C>>[C:11]([C:9]1[CH:8]=[CH:7][N:6]2[CH:2]=[C:3]([NH:17][C:18]([NH:20][CH2:21][CH3:22])=[O:19])[N:4]=[C:5]2[CH:10]=1)(=[O:26])[CH3:16]
Reactant: CCNC(=O)Nc1nc2cc(-c3cccnc3)ccn2c1Cl
Reactant: CCO
Agent: N
Product: CCNC(=O)Nc1cn2ccc(C(C)=O)cc2n1
Reaction time: 3 h
Yield: 74 %

Procedure:
To a suspension of diester 2 (10.9 g, 31.9 mmol) in 50 mL ethanol was added 50 mL of 7M methanolic ammonia at 23° C. After 3 h, the copious precipitate was collected by vacuum filtration and dried under a stream of air to give 7.45 g (74%) of amide 3 as a white solid.
Reaction SMILES: [CH2:1]=[CH:2][CH:3]=[CH2:4].[CH2:5]([Li])[CH2:6][CH2:7][CH3:8].CN(CCN(C)C)C>CCCCCC>[CH2:1]=[CH:2][CH:3]=[CH2:4].[CH2:1]=[CH:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1
Reactant: [Li]CCCC
Agent: C=CC=C
Agent: CN(C)CCN(C)C
Solvent: CCCCCC
Product: C=Cc1ccccc1
Temperature: 85 °C
Reaction time: 0.25 h

Procedure:
In this experiment, a styrene-butadiene polymer was synthesized utilizing the continuous polymerization procedure of this invention over a period of six days without any evidence of reactor fouling. A three-reactor system which consisted of a 1-gallon first reactor, a 2-gallon second reactor and a 2-gallon third reactor was utilized with the polymerization temperature being maintained at about 85° C. In the procedure used, 1,3-butadiene was charged into the first reactor at a rate of 117.55 grams per minute, n-butyl lithium was charged into the first reactor as a 0.25 M solution at a rate of 1.2769 grams per minute and TMEDA was charged into the first reactor as a 0.25 M solution at a rate of 1.2067 grams per minute. The 1,3-butadiene monomer was charged into the reactor as a 16 weight percent premix solution in hexane. The residence time in the first reactor was 0.25 hour.