Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[C:7]([O:9][CH:10]2[CH2:15][CH2:14][N:13]([C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])[CH2:12][CH2:11]2)[CH:6]=[CH:5][C:4]=1[CH2:23][C:24]([OH:26])=O.[CH3:27][C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][C:29]=1[N:34]1[CH2:39][CH2:38][NH:37][CH:36]([C:40]([NH2:42])=[O:41])[CH2:35]1.C(Cl)CCl.C(N(CC)CC)C>CN(C=O)C>[CH3:1][O:2][C:3]1[CH:8]=[C:7]([O:9][CH:10]2[CH2:15][CH2:14][N:13]([C:16]([O:18][C:19]([CH3:22])([CH3:20])[CH3:21])=[O:17])[CH2:12][CH2:11]2)[CH:6]=[CH:5][C:4]=1[CH2:23][C:24]([N:37]1[CH2:38][CH2:39][N:34]([C:29]2[CH:30]=[CH:31][CH:32]=[CH:33][C:28]=2[CH3:27])[CH2:35][CH:36]1[C:40]([NH2:42])=[O:41])=[O:26]
Reactant: Cc1ccccc1N1CCNC(C(N)=O)C1
Reactant: COc1cc(OC2CCN(C(=O)OC(C)(C)C)CC2)ccc1CC(=O)O
Solvent: CCN(CC)CC
Solvent: ClCCCl
Solvent: CN(C)C=O
Product: COc1cc(OC2CCN(C(=O)OC(C)(C)C)CC2)ccc1CC(=O)N1CCN(c2ccccc2C)CC1C(N)=O
Temperature: 25 °C
Reaction time: 72 h

Procedure:
2-Methoxy-4-(1-Boc-4-piperidyloxy)phenylacetic acid (331 mg, 0.91 mmol), 4-(2-methylphenyl)piperazine-2-carboxamide (200 mg, 0.91 mmol), EDC (209 mg, 1.09 mmol), and HBT (141 mg, 1.04 mmol) were combined in DMF (7 ml) under nitrogen. The mixture was adjusted to pH ca. 9 (moistened E. Merck colorpHast indicator) by addition of triethylamine (0.4 ml) and stirred at ambient temperature for 72 hours. The mixture was concentrated in vacuo and the residue was partitioned between ethyl acetate and aqueous sodium bicarbonate. The ethyl acetate layer was washed with sodium bicarbonate and with brine, dried over sodium sulfate, filtered, and evaporated to dryness in vacuo. The residue was chromatographed on silica gel eluted with 3% methanol in methylene chloride. The combined product fractions were evaporated to dryness in vacuo to give 1-(2-methoxy-4-(1-Boc-4-piperidyloxy)phenylacetyl)-4-(2-methylphenyl)piperazine-2-carboxamide.
Reaction SMILES: C([SnH](CCCC)CCCC)CCC.CC(N=NC(C#N)(C)C)(C#N)C.Br[C:27]1[C:28]([N:33]([CH2:56][O:57][CH2:58][CH2:59][Si:60]([CH3:63])([CH3:62])[CH3:61])[C:34]([C:36]2[O:55][C:39]3=[N:40][CH:41]=[C:42]([CH2:44][O:45][CH2:46][C:47]4[CH:52]=[CH:51][C:50]([O:53][CH3:54])=[CH:49][CH:48]=4)[CH:43]=[C:38]3[CH:37]=2)=[O:35])=[N:29][CH:30]=[CH:31][CH:32]=1>C1C=CC=CC=1>[CH3:54][O:53][C:50]1[CH:51]=[CH:52][C:47]([CH2:46][O:45][CH2:44][C:42]2[CH:43]=[C:38]3[CH2:37][C:36]4([C:27]5[C:28](=[N:29][CH:30]=[CH:31][CH:32]=5)[N:33]([CH2:56][O:57][CH2:58][CH2:59][Si:60]([CH3:63])([CH3:62])[CH3:61])[C:34]4=[O:35])[O:55][C:39]3=[N:40][CH:41]=2)=[CH:48][CH:49]=1
Reactant: COc1ccc(COCc2cnc3oc(C(=O)N(COCC[Si](C)(C)C)c4ncccc4Br)cc3c2)cc1
Agent: CC(C)(C#N)N=NC(C)(C)C#N
Agent: CCCC[SnH](CCCC)CCCC
Solvent: c1ccccc1
Product: COc1ccc(COCc2cnc3c(c2)CC2(O3)C(=O)N(COCC[Si](C)(C)C)c3ncccc32)cc1
Reaction time: 1 h

Procedure:
A deoxygenated solution of tributyltin hydride (0.779 g, 2.68 mmol) and AIBN (43 mg, 0.26 mmol) in benzene (44 mL) was added dropwise over 2 h to a deoxygenated solution of N-(3-bromopyridin-2-yl)-5-(((4-methoxybenzyl)oxy)methyl)-N-((2-(trimethylsilyl)ethoxy)methyl)furo[2,3-b]pyridine-2-carboxamide (0.80 g, 1.3 mmol) and AIBN (87 mg, 0.53 mmol) in benzene (86 mL) at reflux, and the heating was continued for 1 h. The excess tributyl tinhydride was quenched with thiophenol (0.5 mL) and the reaction mixture was concentrated. The residue was purified by flash chromatography on silica gel eluting with 20% ethyl acetate in petroleum ether to give the title compound as a racemic mixture. MS: m/z=520.2 (M+1).
Reaction SMILES: Cl[C:2]([Cl:12])(OC(=O)OC(Cl)(Cl)Cl)Cl.OC[CH:15]1[CH2:21][S:20][CH2:19][C:18](=[CH2:22])[CH2:17][S:16]1.C(N(CC)CC)C>ClCCl>[Cl:12][CH2:2][CH:15]1[CH2:21][S:20][CH2:19][C:18](=[CH2:22])[CH2:17][S:16]1
Reactant: C=C1CSCC(CO)SC1
Reactant: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: C=C1CSCC(CCl)SC1
Reaction time: 1 h
Yield: 198.9 %

Procedure:
Triphosgene (0.843 g, 2.84 mmoles) was dissolved in 20 mL of dichloromethane. 2-(Hydroxymethyl)-6-methylene-1,4-dithiepane (1.5 g, 8.52 mmoles) and triethyl amine (1.185 mL, 0.86 g) were dissolved in ca. 5 mL of dichloromethane and added dropwise to the triphosgene solution. After ca. one hour the reaction was largely complete. A little more triphosgene was added and the solution was stirred overnight. The reaction was worked up by evaporation of solvent, addition of water and extraction with ether. The extracts were dried and evaporated and the resulting oil was chromatographed on silica gel to give 1.1 g (67%) of clear oil.
Reaction SMILES: [Cl:1][C:2]1[N:3]=[C:4]([N:12]2[CH2:17][CH2:16][O:15][CH2:14][CH2:13]2)[C:5]2[S:10][C:9]([NH2:11])=[CH:8][C:6]=2[N:7]=1.[C:18](Cl)(=[O:21])[CH2:19][CH3:20]>>[Cl:1][C:2]1[N:3]=[C:4]([N:12]2[CH2:17][CH2:16][O:15][CH2:14][CH2:13]2)[C:5]2[S:10][C:9]([NH:11][C:18](=[O:21])[CH2:19][CH3:20])=[CH:8][C:6]=2[N:7]=1
Reactant: CCC(=O)Cl
Reactant: Nc1cc2nc(Cl)nc(N3CCOCC3)c2s1
Product: CCC(=O)Nc1cc2nc(Cl)nc(N3CCOCC3)c2s1

Procedure:
2-Chloro-4-morpholinothieno[3,2-d]pyrimidin-6-amine (35 mg) was reacted with 23 μL of propionyl chloride via General Procedure G to give N-(2-chloro-4-morpholinothieno[3,2-d]pyrimidin-6-yl)propionamide.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH2:14][C@H:13]3[N:10]([C:11](=[O:25])[C@@H:12]3[C@H:15]([O:17][Si:18]([CH2:23][CH3:24])([CH2:21][CH3:22])[CH2:19][CH3:20])[CH3:16])[C:9]=2[C:26]([O:28][CH2:29][C:30]2[CH:35]=[CH:34][C:33]([N+:36]([O-:38])=[O:37])=[CH:32][CH:31]=2)=[O:27])=[CH:4][CH:3]=1.N1C=CC=CC=1.ClC(Cl)(Cl)[C:47]([N:49]=C=O)=[O:48].C(OCC)(=O)C>ClCCl>[NH2:49][C:47]([O:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH2:14][C@H:13]3[N:10]([C:11](=[O:25])[C@@H:12]3[C@H:15]([O:17][Si:18]([CH2:23][CH3:24])([CH2:21][CH3:22])[CH2:19][CH3:20])[CH3:16])[C:9]=2[C:26]([O:28][CH2:29][C:30]2[CH:35]=[CH:34][C:33]([N+:36]([O-:38])=[O:37])=[CH:32][CH:31]=2)=[O:27])=[CH:4][CH:3]=1)=[O:48]
Reactant: CC[Si](CC)(CC)O[C@H](C)[C@H]1C(=O)N2C(C(=O)OCc3ccc([N+](=O)[O-])cc3)=C(c3ccc(O)cc3)C[C@H]12
Reactant: O=C=NC(=O)C(Cl)(Cl)Cl
Solvent: CCOC(C)=O
Solvent: c1ccncc1
Solvent: ClCCl
Product: CC[Si](CC)(CC)O[C@H](C)[C@H]1C(=O)N2C(C(=O)OCc3ccc([N+](=O)[O-])cc3)=C(c3ccc(OC(N)=O)cc3)C[C@H]12
Temperature: 0 °C
Reaction time: 1 h
Yield: 52.3 %

Procedure:
4-Nitrobenzyl (5R,6S)-3-(4-hydroxyphenyl)-7-oxo-6-{(1R)-1-[(triethylsilyl)oxy]ethyl}-1-azabicyclo[3.2.0]hept-2-ene-2-carboxylate (200 mg) prepared in the above step was dissolved in dichloromethane (4.5 ml). Thereto were added under ice cooling pyridine in a catalytic amount and trichloroacetyl isocyanate (106 mg), and the mixture was stirred for 1 hour. The reaction mixture was poured into a mixture of ice water and ethyl acetate. The mixture was extracted and separated with a separating funnel. The organic layer was washed with cold water (twice) and a cold saturated aqueous sodium chloride solution in the order, and dried over anhydrous sodium sulfate. The solvent was removed under reduced pressure. The residue was dissolved in methanol (13.5 ml) and thereto silica gel (2.7 g) was added. The mixture was stirred for 1.5 hours and then, kept in a refrigerator overnight. After the reaction mixture was diluted with chloroform, silica gel was removed by filtration. The solution was washed with chloroform/methanol (=4/1) and the solvent was removed under reduced pressure. The residue was purified by silica gel thin layer chromatography (chloroform/acetone=9/1) to give 4-nitrobenzyl (5R,6S)-3-{4-[(aminocarbonyl)oxy]phenyl}-6-{(1R)-1-[(triethylsilyl)oxy]ethyl}-7-oxo-1-azabicyclo[3.2.0]hept-2-ene-2-carboxylate (113 mg).
Reaction SMILES: [C:1]([O:5][C@@H:6]([C:12]1[C:21]([CH:22]=[CH2:23])=[CH:20][C:19]2[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=2)[C:13]=1[C:24]1[CH:29]=[CH:28][C:27]([Cl:30])=[CH:26][CH:25]=1)[C:7]([O:9]CC)=[O:8])([CH3:4])([CH3:3])[CH3:2].[OH-].[Na+].CC(O)=O>C1COCC1.CO>[C:1]([O:5][C@@H:6]([C:12]1[C:21]([CH:22]=[CH2:23])=[CH:20][C:19]2[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=2)[C:13]=1[C:24]1[CH:29]=[CH:28][C:27]([Cl:30])=[CH:26][CH:25]=1)[C:7]([OH:9])=[O:8])([CH3:2])([CH3:3])[CH3:4]
Reactant: C=Cc1cc2ccccc2c(-c2ccc(Cl)cc2)c1[C@H](OC(C)(C)C)C(=O)OCC
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Solvent: CC(=O)O
Product: C=Cc1cc2ccccc2c(-c2ccc(Cl)cc2)c1[C@H](OC(C)(C)C)C(=O)O
Temperature: 25 °C
Reaction time: 8 h
Yield: 76.7 %

Procedure:
To a solution (S)-ethyl 2-tert-butoxy-2-(1-(4-chlorophenyl)-3-vinylnaphthalen-2-yl)acetate (7.4 mg, 0.0175 mmol) in THF/MeOH (1/1, 1 mL), was added NaOH (2 N, 280 L). The reaction mixture was stirred at room temperature overnight. Then the temperature was raised to 40° C. and the reaction mixture was stirred for 4 h. The reaction was then cooled down and neutralized by adding HOAc. The reaction mixture was concentrated in vacuo and the residue was purified by reverse phase HPLC (Gemini, 5 to 100% ACN/H2O+0.1% TFA) to provide 5.3 mg of the desired product. 1H-NMR: 400 MHz, (CD3OD) δ: 8.07 (s, 1H), 7.89 (d, J=4.0 Hz, 1H), 7.60-7.54 (m, 4H), 7.48-7.44 (m, 1H), 7.35-7.31 (m, 2H), 7.25-7.22 (m, 1H), 5.76-5.71 (m, 1H), 5.29-5.26 (m, 1H), 5.21 (s, 1H), 0.98 (s, 9H). LCMS-ESI− (m/z): [M−H]− calcd for C24H23ClO3: 393.1. Found: 393.0.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[C@H:13]([C:14]([OH:16])=O)[C@H:12]2[CH2:17][C@@H:9]1[C@H:10]([OH:18])[CH2:11]2)=[O:7])([CH3:4])([CH3:3])[CH3:2].[NH:19]1[CH2:23][CH2:22][CH2:21][C@H:20]1[C:24]([NH2:26])=[O:25].O.ON1C2C=CC=CC=2N=N1.Cl.CN(C)CCCN=C=NCC.C(N(C(C)C)CC)(C)C>C(Cl)(Cl)Cl.O>[NH2:26][C:24]([C@@H:20]1[CH2:21][CH2:22][CH2:23][N:19]1[C:14]([C@@H:13]1[C@H:12]2[CH2:17][C@H:9]([C@H:10]([OH:18])[CH2:11]2)[N:8]1[C:6]([O:5][C:1]([CH3:2])([CH3:3])[CH3:4])=[O:7])=[O:16])=[O:25]
Reactant: CC(C)(C)OC(=O)N1[C@@H]2C[C@@H](C[C@H]2O)[C@H]1C(=O)O
Reactant: NC(=O)[C@@H]1CCCN1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CCN(C(C)C)C(C)C
Solvent: ClC(Cl)Cl
Solvent: O
Product: CC(C)(C)OC(=O)N1[C@@H]2C[C@@H](C[C@H]2O)[C@H]1C(=O)N1CCC[C@H]1C(N)=O
Temperature: 25 °C
Reaction time: 5 h
Yield: 83.3 %

Procedure:
To a suspension of (1R,3S,4S,6R)-2-(tert-butoxycarbonyl)-6-hydroxy-2-azabicyclo[2.2.1]heptane-3-carboxylic acid obtained in Example 42-6 (45 g) in chloroform (450 mL), were added (2S)-2-pyrrolidinecarboxamide (21 g), 1-hydroxybenzotriazole hydrate (29.5 g), 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (36.9 g) and diisopropylethylamine (45.3 g) in water bath. The mixture was stirred at room temperature for 5 hrs. The precipitate collected by vacuum filtration and washed with ethyl acetate to give the target compound as a solid (51.5 g).
Reaction SMILES: [H-].[Na+].C(OP([CH2:11][C:12]([NH:14][CH:15]([C:19]1[CH:48]=[CH:47][C:22]([O:23][CH2:24][CH2:25][O:26][CH2:27][CH2:28][O:29][CH2:30][CH2:31][N:32]([C:40]([O:42][C:43]([CH3:46])([CH3:45])[CH3:44])=[O:41])[C:33]([O:35][C:36]([CH3:39])([CH3:38])[CH3:37])=[O:34])=[CH:21][CH:20]=1)[CH2:16][CH2:17][CH3:18])=[O:13])(OCC)=O)C.[Br:49][C:50]1[N:55]=[C:54]([CH:56]=O)[CH:53]=[CH:52][CH:51]=1>O1CCCC1>[Br:49][C:50]1[N:55]=[C:54](/[CH:56]=[CH:11]/[C:12]([NH:14][CH:15]([C:19]2[CH:20]=[CH:21][C:22]([O:23][CH2:24][CH2:25][O:26][CH2:27][CH2:28][O:29][CH2:30][CH2:31][N:32]([C:40]([O:42][C:43]([CH3:44])([CH3:46])[CH3:45])=[O:41])[C:33]([O:35][C:36]([CH3:37])([CH3:39])[CH3:38])=[O:34])=[CH:47][CH:48]=2)[CH2:16][CH2:17][CH3:18])=[O:13])[CH:53]=[CH:52][CH:51]=1
Reactant: O=Cc1cccc(Br)n1
Reactant: CCCC(NC(=O)CP(=O)(OCC)OCC)c1ccc(OCCOCCOCCN(C(=O)OC(C)(C)C)C(=O)OC(C)(C)C)cc1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CCCC(NC(=O)/C=C/c1cccc(Br)n1)c1ccc(OCCOCCOCCN(C(=O)OC(C)(C)C)C(=O)OC(C)(C)C)cc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 67.5 %

Procedure:
To a suspension of NaH (52 mg 60% in mineral oil, 1.31 mmol) in tetrahydrofuran (1.0 mL) at ice bath temperature was added a solution of (2-(2-(2-(4-(1-(2-(diethoxyphosphoryl)acetamido)butyl)phenoxy)ethoxy)ethoxy)ethyl)imidodicarbonic acid, 1,3-bis-tert-butyl ester (49; 295 mg, 0.43 mmol) in tetrahydrofuran (2 mL). The resulting mixture was stirred at room temperature for 30 minutes and then treated drop-wise with 6-bromopicolinaldehyde (81 mg, 0.43 mmol) in tetrahydrofuran (2 mL). The mixture was stirred for another 30 minutes, and then carefully quenched with water. The solution was extracted with ethyl acetate (3×), and the combined organic extracts were washed with sat. brine, dried over sodium sulfate, and concentrated to an oil. Purification by flash silica gel column chromatography, eluting with 7:3 hexanes/ethyl acetate, afforded 50 (205 mg, 67%) as a clear oil: MS (ES+) m/z 706.2 (M+H)+.
Reaction SMILES: C(N(CC)CC)C.[CH3:8][N:9]([CH3:14])[S:10](Cl)(=[O:12])=[O:11].[C:15]([C:17]1([C:23]2[N:28]=[CH:27][C:26]([NH:29][C:30]([C:32]3[CH:33]=[N:34][N:35]([C:38]4[CH:43]=[CH:42][C:41]([C:44]([F:47])([F:46])[F:45])=[CH:40][N:39]=4)[C:36]=3[CH3:37])=[O:31])=[CH:25][CH:24]=2)[CH2:22][CH2:21][NH:20][CH2:19][CH2:18]1)#[N:16].ClCCl>O>[C:15]([C:17]1([C:23]2[N:28]=[CH:27][C:26]([NH:29][C:30]([C:32]3[CH:33]=[N:34][N:35]([C:38]4[CH:43]=[CH:42][C:41]([C:44]([F:47])([F:46])[F:45])=[CH:40][N:39]=4)[C:36]=3[CH3:37])=[O:31])=[CH:25][CH:24]=2)[CH2:18][CH2:19][N:20]([S:10](=[O:12])(=[O:11])[N:9]([CH3:14])[CH3:8])[CH2:21][CH2:22]1)#[N:16]
Reactant: CN(C)S(=O)(=O)Cl
Reactant: Cc1c(C(=O)Nc2ccc(C3(C#N)CCNCC3)nc2)cnn1-c1ccc(C(F)(F)F)cn1
Solvent: O
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: Cc1c(C(=O)Nc2ccc(C3(C#N)CCN(S(=O)(=O)N(C)C)CC3)nc2)cnn1-c1ccc(C(F)(F)F)cn1
Temperature: 25 °C
Reaction time: 48 h

Procedure:
Triethylamine (48 μl) and dimethylsulfamoyl chloride (37 μl) were added to a mixture of N-[6-(4-cyanopiperidin-4-yl)pyridin-3-yl]-5-methyl-1-[5-(trifluoromethyl)pyridin-2-yl]-1H-pyrazole-4-carboxamide (150 mg) described in Reference Example 169 and dichloromethane (6.6 ml) and stirred at room temperature for two days. Water was added to the reaction solution, extracted with chloroform, the organic layer was washed with saturated brine, dried over anhydrous sodium sulfate and concentrated in vacuo. The resulting residue was purified with silica gel chromatography (chloroform/methanol) to give the titled compound (135 mg) as a white solid.
Reaction SMILES: C([O:3][C:4](=[O:24])[CH2:5][NH:6][C:7]1[C:12]([NH:13][C:14](=O)[C:15]2[CH:20]=[CH:19][C:18]([O:21][CH3:22])=[CH:17][CH:16]=2)=[CH:11][CH:10]=[CH:9][N:8]=1)C.C(O)CO.[OH-].[K+]>O>[CH3:22][O:21][C:18]1[CH:19]=[CH:20][C:15]([C:14]2[N:6]([CH2:5][C:4]([OH:3])=[O:24])[C:7]3=[N:8][CH:9]=[CH:10][CH:11]=[C:12]3[N:13]=2)=[CH:16][CH:17]=1
Reactant: CCOC(=O)CNc1ncccc1NC(=O)c1ccc(OC)cc1
Agent: [K+]
Agent: [OH-]
Solvent: OCCO
Solvent: O
Product: COc1ccc(-c2nc3cccnc3n2CC(=O)O)cc1
Yield: 1.7 %

Procedure:
A mixture of N-[3-[(4-methoxybenzoyl)amino]-2-pyridinyl]glycine ethyl ester (32 g, 0.1 mole) and 167 ml of ethylene glycol was heated at reflux for 11/2 hr. After cooling, potassium hydroxide (8.4 g) in 40 ml of water was added, and the reaction mixture was heated at reflux for 1 hr. The solution was filtered to remove yellow precipitate, the filtrate was diluted with 650 ml of water, and acidified with 3N hydrochloric acid. The solid which formed, was collected by filtration, washed with water, and dried under high vacuum at 50° C. overnight to give 25.5 g (90.1% yield). A 0.5-g sample was recrystallized from ethanol, collected by filtration, washed with cold ethanol and water, and dried under high vacuum at 70° C. over 2 days to give 0.47 g of crystals, mp 260°-63° C.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([O:8][CH2:9][CH3:10])[CH:5]=[C:4]([CH3:11])[N:3]=1.[NH:12]1[CH:16]=[CH:15][N:14]=[CH:13]1>O1CCCC1>[CH2:9]([O:8][C:6]1[CH:5]=[C:4]([CH3:11])[N:3]=[C:2]([N:12]2[CH:16]=[CH:15][N:14]=[CH:13]2)[N:7]=1)[CH3:10]
Reactant: c1c[nH]cn1
Reactant: CCOc1cc(C)nc(Cl)n1
Solvent: C1CCOC1
Product: CCOc1cc(C)nc(-n2ccnc2)n1
Yield: 50.5 %

Procedure:
In anhydrous tetrahydrofuran, 173 mg of 2-chloro-4-ethoxy-6-methylpyrimidine was substituted with 68 mg of imidazole. The reaction mixture was treated according to the procedure of Example 5 to yield 103 mg of 4-ethoxy-2-(1-imidazolyl)-6-methylpyrimidine, recrystallized from a mixture of n-hexane and ethyl acetate, having a melting point of 115.5°-116° C.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([CH:8]([C:21]2[CH:26]=[CH:25][C:24]([F:27])=[CH:23][C:22]=2[F:28])[CH2:9]/[C:10](/[C:13]2[CH:14]=[CH:15][C:16](=[O:20])[N:17]([CH3:19])[CH:18]=2)=[N:11]\[OH:12])=[CH:4][CH:3]=1.[C:29]([C:32]1[CH:37]=[CH:36][C:35](B(O)O)=[CH:34][CH:33]=1)([OH:31])=[O:30]>>[F:28][C:22]1[CH:23]=[C:24]([F:27])[CH:25]=[CH:26][C:21]=1[CH:8]([C:5]1[CH:6]=[CH:7][C:2]([C:35]2[CH:36]=[CH:37][C:32]([C:29]([OH:31])=[O:30])=[CH:33][CH:34]=2)=[CH:3][CH:4]=1)[CH2:9]/[C:10](=[N:11]\[OH:12])/[C:13]1[CH:14]=[CH:15][C:16](=[O:20])[N:17]([CH3:19])[CH:18]=1
Reactant: O=C(O)c1ccc(B(O)O)cc1
Reactant: Cn1cc(/C(CC(c2ccc(Br)cc2)c2ccc(F)cc2F)=N/O)ccc1=O
Product: Cn1cc(/C(CC(c2ccc(-c3ccc(C(=O)O)cc3)cc2)c2ccc(F)cc2F)=N/O)ccc1=O

Procedure:
The title compound was prepared in analogy to example 166, from 5-{3-(4-bromo-phenyl)-3-(2,4-difluoro-phenyl)-1-[(E)-hydroxyimino]-propyl}-1-methyl-1H-pyridin-2-one (example 402) and 4-carboxyphenylboronic acid (CAS RN 14047-29-1). The compound was purified by two silica gel chromatographies using a 20 g column and a MPLC system eluting with a gradient of dichloromethane:methanol (100:0 to 70:30). Light brown foam. MS (ESI+): m/z=489.2 ([M+H]+).
Reaction SMILES: [Cl:1][C:2]1[CH:8]=[CH:7][CH:6]=[C:5]([Cl:9])[C:3]=1[NH2:4].ClCCCl.[CH3:14][O:15][C:16]1[CH:26]=[CH:25][CH:24]=[C:23]([O:27][CH3:28])[C:17]=1[C:18]([N:20]=[C:21]=[O:22])=[O:19]>C(OCC)C>[CH3:28][O:27][C:23]1[CH:24]=[CH:25][CH:26]=[C:16]([O:15][CH3:14])[C:17]=1[C:18]([NH:20][C:21]([NH:4][C:3]1[C:2]([Cl:1])=[CH:8][CH:7]=[CH:6][C:5]=1[Cl:9])=[O:22])=[O:19]
Reactant: Nc1c(Cl)cccc1Cl
Reactant: COc1cccc(OC)c1C(=O)N=C=O
Solvent: CCOCC
Solvent: ClCCCl
Product: COc1cccc(OC)c1C(=O)NC(=O)Nc1c(Cl)cccc1Cl

Procedure:
A 16.2 g. portion of 2,6-dichloroaniline (Aldrich Chemical Co., Milwaukee, Wis.) was dissolved in 200 ml. 1,2-dichloroethane in a flask under a nitrogen atmosphere at about 25° C. To this was added 25 g. of 2,6-dimethoxybenzoylisocyanate in 25 ml. 1,2-dichloroethane and the solution was warmed to 40° C. for two hours after the addition was complete. Thin layer chromatography on silica gel developed in diethyl ether indicated that no 2,6-dichloroaniline remained. The solvent was removed in vacuo and the residue slurried in methanol. The solids were collected and washed with methanol. Yield 26.5 g. (72%).
Reaction SMILES: [CH3:1][C:2]1[S:6][C:5]([C:7]([O:9][CH3:10])=[O:8])=[CH:4][C:3]=1[NH:11][S:12]([C:15]1[S:16][CH:17]=[CH:18][CH:19]=1)(=[O:14])=[O:13].[H-].[Na+].[CH3:22]I.O>CN(C)C=O>[CH3:1][C:2]1[S:6][C:5]([C:7]([O:9][CH3:10])=[O:8])=[CH:4][C:3]=1[N:11]([CH3:22])[S:12]([C:15]1[S:16][CH:17]=[CH:18][CH:19]=1)(=[O:13])=[O:14]
Reactant: COC(=O)c1cc(NS(=O)(=O)c2cccs2)c(C)s1
Reactant: CI
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: COC(=O)c1cc(N(C)S(=O)(=O)c2cccs2)c(C)s1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 99 %

Procedure:
To a solution of methyl 5-methyl-4-[(2-thienylsulfonyl)amino]thiophene-2-carboxylate (35.7 g) in N,N-dimethylformamide (200 mL) was slowly added sodium hydride (60%, oily, 5.2 g) at 0° C., and the mixture was stirred at room temperature for 30 min. Methyl iodide (8.0 mL) was added to the reaction mixture, and the mixture was stirred at room temperature for 1 hr. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The ethyl acetate layer was washed with saturated brine, dried (MgSO4) and concentrated. The residue was subjected to silica gel column chromatography to give methyl 5-methyl-4-[methyl(2-thienylsulfonyl)amino]thiophene-2-carboxylate (37.5 g, yield 99%) as yellow crystals from a fraction eluted with ethyl acetate-hexane (1:3, volume ratio).
Reaction SMILES: [NH2:1][C:2]1[CH:35]=[CH:34][CH:33]=[CH:32][C:3]=1[C:4]([N:6]([CH2:15][CH2:16][N:17]1[CH2:22][CH2:21][CH:20]([C:23](=[O:31])[C:24]2[CH:29]=[CH:28][C:27]([F:30])=[CH:26][CH:25]=2)[CH2:19][CH2:18]1)[C:7]1[CH:12]=[CH:11][CH:10]=[C:9]([O:13][CH3:14])[CH:8]=1)=[O:5].[C:36](OC(=O)C)(=[O:38])[CH3:37]>>[C:36]([NH:1][C:2]1[CH:35]=[CH:34][CH:33]=[CH:32][C:3]=1[C:4]([N:6]([CH2:15][CH2:16][N:17]1[CH2:22][CH2:21][CH:20]([C:23](=[O:31])[C:24]2[CH:25]=[CH:26][C:27]([F:30])=[CH:28][CH:29]=2)[CH2:19][CH2:18]1)[C:7]1[CH:12]=[CH:11][CH:10]=[C:9]([O:13][CH3:14])[CH:8]=1)=[O:5])(=[O:38])[CH3:37]
Reactant: COc1cccc(N(CCN2CCC(C(=O)c3ccc(F)cc3)CC2)C(=O)c2ccccc2N)c1
Reactant: CC(=O)OC(C)=O
Product: COc1cccc(N(CCN2CCC(C(=O)c3ccc(F)cc3)CC2)C(=O)c2ccccc2NC(C)=O)c1
Yield: 65.8 %

Procedure:
Using 2-amino-N-{2-[4-(4-fluorobenzoyl)piperidino]ethyl}-N-(3-methoxyphenyl)benzamide (238.0 mg, 0.50 mmol) and acetic anhydride (0.057 ml, 0.60 mmol), the procedure of Inventive Example 94 was repeated to obtain 170.4 mg (65.9%) of the title compound in a colorless amorphous form.
Reaction SMILES: [C:1]([N:4]1[C:8](=[O:9])[CH:7]=[CH:6][C:5]1=[O:10])(=[O:3])[NH2:2].[CH:11]([OH:14])([CH3:13])[CH3:12]>>[C:8]([O:14][CH:11]([CH3:13])[CH3:12])(=[O:9])/[CH:7]=[CH:6]\[C:5](=[O:10])[NH:4][C:1](=[O:3])[NH2:2]
Reactant: NC(=O)N1C(=O)C=CC1=O
Reactant: CC(C)O
Product: CC(C)OC(=O)/C=C\C(=O)NC(N)=O
Yield: 95 %

Procedure:
The addition of isopropanol to N-carbamylmaleimide under the conditions of Example C afforded a 95% yield of isopropyl maleurate. M.P.: 113°-14° C.; 1H NMR (CDCl3): δ10.6 (br s, 1H), 8.2 (br s, 1H), 6.3 (AB, 2H), 5.8 (br s, 1H), 5.2 (quintet, 1H), 1.3 (d, 6H); HPLC (20% CH3CN/H2O, C8): Rt=5.6 minutes.
Reaction SMILES: FC(F)(F)C(O)=O.C(OC(=O)[NH:14][C:15]1[CH:16]=[N:17][C:18]([Cl:23])=[C:19]([F:22])[C:20]=1[I:21])(C)(C)C>ClCCl>[Cl:23][C:18]1[N:17]=[CH:16][C:15]([NH2:14])=[C:20]([I:21])[C:19]=1[F:22]
Reactant: CC(C)(C)OC(=O)Nc1cnc(Cl)c(F)c1I
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: Nc1cnc(Cl)c(F)c1I
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 98.4 %

Procedure:
Trifluoroacetic acid (50 mL) was added to a solution of (6-chloro-5-fluoro-4-iodo-pyridin-3-yl)-carbamic acid tert-butyl ester (31 g, 83.2 mmol) in dichloromethane (150 mL) and the resultant reaction mixture was stirred at ambient temperature for 90 minutes. The solvent was evaporated and the resultant residue was treated with ice/water (200 mL), layered with diethyl ether (300 mL) and the pH of the aqueous phase was adjusted to 10 by the addition of solid potassium carbonate solution. The organic phase was separated, dried (Na2SO4), filtered and concentrated in-vacuo to afford a residue. The resultant residue was triturated with pentane:diethyl ether (9:1) to afford the title compound as a cream coloured solid (22.3 g, 98%). 1H NMR (400 MHz, CDCl3): 7.63 (s, 1H).
Reaction SMILES: [CH:1](=[N:5][OH:6])[CH:2]([CH3:4])[CH3:3].[CH2:7]([Cl:10])[C:8]#[CH:9].CCN(CC)CC.Cl([O-])=O.[Na+]>C(Cl)Cl>[Cl:10][CH2:7][C:8]1[O:6][N:5]=[C:1]([CH:2]([CH3:4])[CH3:3])[CH:9]=1
Reactant: C#CCCl
Reactant: CC(C)C=NO
Agent: [Na+]
Agent: [O-][Cl+][O-]
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(C)c1cc(CCl)on1
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 62.1 %

Procedure:
To a stirring solution of 1.0 g (11.5 mmol) of isobutyraldehyde oxime, 0.9 g (12.1 mmol) of propargyl chloride, and 0.7 mL (5.02 mmol) of Et3N in 30 mL of CH2Cl2 at 0° C. was added 125 mL of sodium chlorite solution (>4% chlorine). The ice bath was removed and stirring was continued with warming to r.t. After 1.5 h, CH2Cl2 was added, and the organic layer was washed with 20 mL of brine, dried over Na2SO4, filtered, and concentrated. Purification by flash silica gel chromatography (10% EtOAc/hexanes) provided 1.14 g of 5-(chloromethyl)-3-isopropylisoxazole as a pale yellow liquid in about 62% yield. (60%)