Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(OC(CCCCC)CCI)(C)(C)C.C(OC(CCC)CCI)(C)(C)C.[C:27]([O:31][CH:32]([C:37]#[C:38][CH2:39][CH2:40][CH3:41])[CH2:33][CH2:34][Mg:35][I:36])([CH3:30])([CH3:29])[CH3:28].C(OC(C#CCCC)CCI)(C)(C)C>>[C:27]([O:31][CH:32]([CH2:37][CH2:38][CH2:39][CH2:40][CH3:41])[CH2:33][CH2:34][Mg:35][I:36])([CH3:30])([CH3:29])[CH3:28].[C:27]([O:31][CH:32]([CH2:37][CH2:38][CH3:39])[CH2:33][CH2:34][Mg:35][I:36])([CH3:30])([CH3:29])[CH3:28]
Reactant: CCCC#CC(CC[Mg]I)OC(C)(C)C
Agent: CCCC#CC(CCI)OC(C)(C)C
Agent: CCCC(CCI)OC(C)(C)C
Agent: CCCCCC(CCI)OC(C)(C)C
Product: CCCC(CC[Mg]I)OC(C)(C)C
Product: CCCCCC(CC[Mg]I)OC(C)(C)C

Procedure:
Treatment of the cyclopentenones designated in the table below with the designated Grignard reagents by the procedure of Example 493 is productive of the alkyl 9-oxo-15-t-butoxy-8ξ-prostanoates and prostenoates of the table. 3-t-Butoxyoctylmagnesium iodide was prepared from 3-t-butoxy-1-iodooctane (Example 492); 3-t-butoxyhexyl magnesium iodide was prepared from 3-t-butoxy-1-iodohexane (Example 502), 3-t-butoxy-4-octynyl magnesium iodide was prepared from 3-t-butoxy-1-iodo-4-octyne (Example 500); and 3-t-butoxy-4-cis-octenyl magnesium iodide was prepared from 3-t-butoxy-1-iodo-4-cis-octene (Example 501).
Reaction SMILES: [NH2:1][C:2]1[CH:12]=[CH:11][C:5]([C:6]([O:8][CH2:9][CH3:10])=[O:7])=[CH:4][CH:3]=1.CS(O[CH2:18][CH2:19][C:20]1[S:21][CH:22]=[CH:23][CH:24]=1)(=O)=O.CN(C)P(N(C)C)(N(C)C)=O.C(O)C>O>[S:21]1[CH:22]=[CH:23][CH:24]=[C:20]1[CH2:19][CH2:18][NH:1][C:2]1[CH:3]=[CH:4][C:5]([C:6]([O:8][CH2:9][CH3:10])=[O:7])=[CH:11][CH:12]=1
Reactant: CS(=O)(=O)OCCc1cccs1
Reactant: CCOC(=O)c1ccc(N)cc1
Solvent: CCO
Solvent: CN(C)P(=O)(N(C)C)N(C)C
Solvent: O
Product: CCOC(=O)c1ccc(NCCc2cccs2)cc1

Procedure:
A mixture of 33.0 g. of ethyl p-aminobenzoate, 21.8 g. of 2-(2-thienyl)ethanol O-methanesulfonate (prepared as described in Example 49) and 100 ml. of hexamethylphosphoramide is heated in an oil bath at 125° C. for 16 hours. The mixture is chilled, diluted with 15 ml. of ethanol and 150 ml. of water. The mixture is extracted with ether and the ether extracts washed with water, dried over magnesium sulfate and concentrated in vacuo to give a crude oil. A sample of this oil is chromatographed over silica gel and the fractions containing the product are combined and recrystallized from hexane to give ethyl 4-[2-(2-thienyl)ethylamino]benzoate as yellow-tan crystals, m.p. 93°-95° C.
Reaction SMILES: [CH3:1][C:2]([CH3:23])([CH3:22])[CH2:3][CH2:4][CH2:5][C:6]1[CH:7]=[C:8]([C:13]2[CH:18]=[C:17]([O:19][CH3:20])[CH:16]=[CH:15][C:14]=2[F:21])[CH:9]=[CH:10][C:11]=1[OH:12].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[CH:43]1([CH:46]([C:53]2[CH:58]=[CH:57][CH:56]=[C:55]([CH2:59]O)[CH:54]=2)[CH2:47][C:48]([O:50][CH2:51][CH3:52])=[O:49])[CH2:45][CH2:44]1.N(C(OCC)=O)=NC(OCC)=O>C1COCC1.C1(C)C=CC=CC=1>[CH:43]1([CH:46]([C:53]2[CH:58]=[CH:57][CH:56]=[C:55]([CH2:59][O:12][C:11]3[CH:10]=[CH:9][C:8]([C:13]4[CH:18]=[C:17]([O:19][CH3:20])[CH:16]=[CH:15][C:14]=4[F:21])=[CH:7][C:6]=3[CH2:5][CH2:4][CH2:3][C:2]([CH3:23])([CH3:22])[CH3:1])[CH:54]=2)[CH2:47][C:48]([O:50][CH2:51][CH3:52])=[O:49])[CH2:45][CH2:44]1
Reactant: CCOC(=O)CC(c1cccc(CO)c1)C1CC1
Reactant: COc1ccc(F)c(-c2ccc(O)c(CCCC(C)(C)C)c2)c1
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: Cc1ccccc1
Solvent: C1CCOC1
Product: CCOC(=O)CC(c1cccc(COc2ccc(-c3cc(OC)ccc3F)cc2CCCC(C)(C)C)c1)C1CC1
Yield: 78.5 %

Procedure:
To a solution of 3-(4,4-dimethylpentyl)-2′-fluoro-5′-methoxy-[1,1′-biphenyl]-4-ol (280 mg) in THF (5.0 mL) were added triphenylphosphine (348 mg), ethyl 3-cyclopropyl-3-(3-(hydroxymethyl)phenyl)propanoate (330 mg) and a 40% solution of diethyl azodicarboxylate in toluene (600 μL), and the mixture was stirred at room temperature for 2 hr. The reaction mixture was concentrated under reduced pressure and the residue was purified by silica gel column chromatography (ethyl acetate/hexane) to give the title compound (380 mg) as a colorless oil.
Reaction SMILES: [C:1]1([N:7]2[C:11]([C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=3)=[CH:10][CH:9]=[C:8]2[C:18]2[CH:19]=[C:20]3[C:25](=[CH:26][CH:27]=2)[CH:24]=[C:23]([OH:28])[CH:22]=[CH:21]3)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH3:29][O:30][C:31](=[O:48])[CH:32](OS(C(F)(F)F)(=O)=O)[CH2:33][C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1.C(=O)([O-])[O-].[Cs+].[Cs+]>>[C:1]1([N:7]2[C:11]([C:12]3[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=3)=[CH:10][CH:9]=[C:8]2[C:18]2[CH:19]=[C:20]3[C:25](=[CH:26][CH:27]=2)[CH:24]=[C:23]([O:28][CH:32]([CH2:33][C:34]2[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=2)[C:31]([O:30][CH3:29])=[O:48])[CH:22]=[CH:21]3)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: Oc1ccc2cc(-c3ccc(-c4ccccc4)n3-c3ccccc3)ccc2c1
Reactant: COC(=O)C(Cc1ccccc1)OS(=O)(=O)C(F)(F)F
Agent: O=C([O-])[O-]
Agent: [Cs+]
Product: COC(=O)C(Cc1ccccc1)Oc1ccc2cc(-c3ccc(-c4ccccc4)n3-c3ccccc3)ccc2c1
Reaction time: 0.5 h
Yield: 72.6 %

Procedure:
In a similar manner as described in step 1 of Example 7, the title compound was prepared from 6-(1,5-diphenyl-1H-pyrrol-2-yl)-2-naphthol (0.300 g, 0.676 mmol), prepared in step 2 of Example 11, 3-phenyl-2-trifluoromethanesulfonyloxypropionic acid methyl ester (0.317 g, 1.02 mmol) and cesium carbonate (0.441 g, 1.35 mmol) with the exception that this reaction was complete after 30 minutes at ambient temperature. Purification on a Biotage Horizon™ system with a KP-Sil Flash 25+M column (40 g Silica Gel, 60 Å) using 25% to 65% methylene chloride in hexane as the eluent gave methyl 2-{[6-(1,5-diphenyl-1H-pyrrol-2-yl)-2-naphthyl]oxy}-3-phenylpropanoate as a white solid (0.257 g, 89%), mp 178–179° C. Elemental Analysis for C36H29NO3 Calc'd: C, 82.58; H, 5.58; N, 2.67. Found: C; 81.87; H, 5.10; N, 2.50.
Reaction SMILES: [NH2:1][C:2]1[CH:10]=[C:9]([C:11]2[C:16]([C:17]([F:20])([F:19])[F:18])=[CH:15][CH:14]=[CH:13][N:12]=2)[CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=O.[CH:21]([NH2:23])=O>O>[F:18][C:17]([F:20])([F:19])[C:16]1[C:11]([C:9]2[CH:10]=[C:2]3[C:3]([C:4]([OH:6])=[N:23][CH:21]=[N:1]3)=[CH:7][CH:8]=2)=[N:12][CH:13]=[CH:14][CH:15]=1
Reactant: NC=O
Reactant: Nc1cc(-c2ncccc2C(F)(F)F)ccc1C(=O)O
Solvent: O
Product: Oc1ncnc2cc(-c3ncccc3C(F)(F)F)ccc12
Temperature: 25 °C

Procedure:
Stir the mixture of 2-amino-4-(3-trifluoromethyl-pyridin-2-yl)-benzoic acid (1.95 mmol) in HCONH2 (10 mL) for 4 hours at 145° C. Cool to room temperature, dilute with 20 ml of water, and collect the precipitate to give 7-(3-trifluoromethyl-pyridin-2-yl)-quinazolin-4-ol.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:12])[C:5]1[CH:10]=[CH:9][C:8]([NH2:11])=[CH:7][CH:6]=1)[CH3:2].[N+:13]([O-:16])([OH:15])=[O:14].[N:17]#[C:18][NH2:19]>C(O)C>[N+:13]([O-:16])([OH:15])=[O:14].[CH2:1]([O:3][C:4](=[O:12])[C:5]1[CH:10]=[CH:9][C:8]([NH:11][C:18]([NH2:19])=[NH:17])=[CH:7][CH:6]=1)[CH3:2]
Reactant: CCOC(=O)c1ccc(N)cc1
Reactant: N#CN
Solvent: CCO
Solvent: O=[N+]([O-])O
Product: CCOC(=O)c1ccc(NC(=N)N)cc1
Temperature: 25 °C
Reaction time: 24 h

Procedure:
4-aminobenzoic acid ethyl ester (20 g, 0.121 mol), nitric acid (7.26 g, 0.121 mol), cyanamide (50%, 14 ml 0.182 mol) were mixed under reflux with ethanol (50 ml). After 24 hr, the mixture was cooled to RT, and then washed with ethanol to give the titled compound as crystalline solid.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([F:8])[C:5]([N:9]2[C:14](=[O:15])[CH:13]=[C:12]([C:16]([F:19])([F:18])[F:17])[N:11]([CH3:20])[C:10]2=[O:21])=[C:4]([CH2:22][C:23]([CH3:25])=[CH2:24])[C:3]=1[OH:26].C(=O)([O-])[O-].[K+].[K+].Br[CH2:34][C:35]([O:37][CH3:38])=[O:36].O>CN(C)C=O>[Cl:1][C:2]1[CH:7]=[C:6]([F:8])[C:5]([N:9]2[C:14](=[O:15])[CH:13]=[C:12]([C:16]([F:18])([F:19])[F:17])[N:11]([CH3:20])[C:10]2=[O:21])=[C:4]([CH2:22][C:23]([CH3:25])=[CH2:24])[C:3]=1[O:26][CH2:34][C:35]([O:37][CH3:38])=[O:36]
Reactant: C=C(C)Cc1c(O)c(Cl)cc(F)c1-n1c(=O)cc(C(F)(F)F)n(C)c1=O
Reactant: COC(=O)CBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: C=C(C)Cc1c(OCC(=O)OC)c(Cl)cc(F)c1-n1c(=O)cc(C(F)(F)F)n(C)c1=O
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
First, 1.0 g of 1-[4-chloro-6-fluoro-3-hydroxy-2-(2-methyl-2-propenyl)phenyl]-3-methyl-4-trifluoromethyl-1,2,3,6-tetrahydropyrimidine-2,6-dione was dissolved in 15 ml of N,N-dimethylformamide, to which 0.43 g of potassium carbonate and 0.4 ml of methyl bromoacetate were added, and the mixture was stirred at room temperature for 30 minutes. After completion of the reaction, the reaction mixture was poured into water and extracted with diethyl ether. The organic layer was dried and concentrated. The residue was subjected to silica gel chromatography, which afforded 1.0 g of 1-[4-chloro-6-fluoro-3-methoxycarbonylmethyloxy-2-(2-methyl-2-propenyl)phenyl]-3-methyl-4-trifluoromethyl-1,2,3,6-tetrahydropyrimidine-2,6-dione.
Reaction SMILES: [CH3:1][O:2][C:3]([NH:5][C@H:6]([C:10]([OH:12])=O)[CH:7]([CH3:9])[CH3:8])=[O:4].CCN=C=NCCCN(C)C.C1C=CC2N(O)N=NC=2C=1.CN1CCOCC1.[CH2:41]([NH:48][NH2:49])[C:42]1[CH:47]=[CH:46][CH:45]=[CH:44][CH:43]=1.CCN(CC)CC>>[CH3:1][O:2][C:3](=[O:4])[NH:5][C@H:6]([C:10]([NH:49][NH:48][CH2:41][C:42]1[CH:47]=[CH:46][CH:45]=[CH:44][CH:43]=1)=[O:12])[CH:7]([CH3:9])[CH3:8]
Reactant: NNCc1ccccc1
Reactant: COC(=O)N[C@H](C(=O)O)C(C)C
Agent: CCN=C=NCCCN(C)C
Agent: On1nnc2ccccc21
Solvent: CCN(CC)CC
Solvent: CN1CCOCC1
Product: COC(=O)N[C@H](C(=O)NNCc1ccccc1)C(C)C
Yield: 65 %

Procedure:
The general procedure for the preparation of hydrazides described above was followed using N-(methoxycarbonyl)-(L)-valine (J. Med. Chem., 39, 3203-3216, 1996) (2.11 g, 12.0 mmol), EDAC (2.41 g, 12.6 mmol), HOBT (1.70 g, 12.6 mmol), NMM (1.38 mL, 12.6 mmol), benzylhydrazine×2HCl (2.45 g, 12.6 mmol) and Et3N (3.52 mL, 25.0 mmol), which gave the title compound (2.08 g, 65%) as a light yellow solid.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2([C:13]([OH:15])=O)[CH2:12][CH2:11][CH2:10][CH2:9]2)=[CH:4][CH:3]=1.[NH2:16][CH2:17][CH2:18][CH2:19][N:20]1[CH2:25][CH2:24][CH:23]([C:26]2[CH:27]=[C:28]([NH:32][C:33](=[O:37])[CH:34]([CH3:36])[CH3:35])[CH:29]=[CH:30][CH:31]=2)[CH2:22][CH2:21]1.C(Cl)(Cl)Cl>CN(C=O)C>[F:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2([C:13]([NH:16][CH2:17][CH2:18][CH2:19][N:20]3[CH2:25][CH2:24][CH:23]([C:26]4[CH:31]=[CH:30][CH:29]=[C:28]([NH:32][C:33](=[O:37])[CH:34]([CH3:35])[CH3:36])[CH:27]=4)[CH2:22][CH2:21]3)=[O:15])[CH2:9][CH2:10][CH2:11][CH2:12]2)=[CH:6][CH:7]=1
Reactant: O=C(O)C1(c2ccc(F)cc2)CCCC1
Reactant: CC(C)C(=O)Nc1cccc(C2CCN(CCCN)CC2)c1
Solvent: ClC(Cl)Cl
Solvent: CN(C)C=O
Product: CC(C)C(=O)Nc1cccc(C2CCN(CCCNC(=O)C3(c4ccc(F)cc4)CCCC3)CC2)c1

Procedure:
Example 36 was prepared from 1-(4-fluoro phenyl)cyclopentanecarboxylic acid and N-{3-[1-(3-aminopropyl)-4-piperidinyl]phenyl}-2-methylpropanamide according to the procedures described in Scheme 9: 1H NMR (400 MHz, CDCl3) δ 7.53 (s, 1H), 7.33 (dd, 2H, J=5.8, 3.6 Hz,), 7.29–7.26 (m, 2H), 7.25–7.20 (m, 1H), 7.02–6.95 (m, 2H), 6.93 (d, 1H, J=7.1 Hz), 6.54–6.49 (m, 1H), 3.26 (q, 2H, J=6.5 Hz), 3.22–3.14 (m, 1H), 2.90 (d, 1H, J=12.0 Hz), 2.55–2.37 (m, 4H), 2.29 (t, 2H, J=6.5 Hz), 2.06 (s, 4H), 2.00–1.90 (m, 3H), 1.82–1.75 (m, 4H), 1.73–1.66 (m, 3H), 1.65–1.57 (m, 4H), 1.25 (d, 6H, J=6.7 Hz); ESMS m/e: 494.3 (M+H)+; Anal. Calc. for C30H40FN3O2.0.10 CHCl3.0.650 DMF: C, 70.92; H, 8.27; N, 8.64. Found: C, 70.83; H, 8.11; N, 8.93.
Reaction SMILES: [C:1]([O:4][C:5]1[C:14]2[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=2)[C:8]([O:15][C:16](=[O:18])[CH3:17])=[C:7]([Cl:19])[C:6]=1[O:20][C:21]1[CH:26]=[CH:25][C:24](N)=[CH:23][CH:22]=1)(=[O:3])[CH3:2].[BrH:28].[N+]([O-])([O-])=O.[Na+].[C:34]([O:38][CH2:39][CH2:40][CH2:41][CH3:42])(=[O:37])[CH:35]=[CH2:36]>>[Br:28][CH:35]([CH2:36][C:24]1[CH:25]=[CH:26][C:21]([O:20][C:6]2[C:7]([Cl:19])=[C:8]([O:15][C:16](=[O:18])[CH3:17])[C:9]3[C:14](=[CH:13][CH:12]=[CH:11][CH:10]=3)[C:5]=2[O:4][C:1](=[O:3])[CH3:2])=[CH:22][CH:23]=1)[C:34]([O:38][CH2:39][CH2:40][CH2:41][CH3:42])=[O:37]
Reactant: CC(=O)Oc1c(Cl)c(Oc2ccc(N)cc2)c(OC(C)=O)c2ccccc12
Reactant: C=CC(=O)OCCCC
Reactant: Br
Agent: O=[N+]([O-])[O-]
Agent: [Na+]
Product: CCCCOC(=O)C(Br)Cc1ccc(Oc2c(Cl)c(OC(C)=O)c3ccccc3c2OC(C)=O)cc1

Procedure:
Following a procedure similar to that described in Preparation 1(d), 8.3 g of 1,4-diacetoxy-2-(4-aminophenoxy)-3-chloronaphthalene [prepared as described in step (c) above] were arylated using 15 g of a 47% w/v aqueous solution of hydrobromic acid, 1.9 g of sodium nitrate, 27 g of butyl acrylate and 0.5 g of cupric bromide, to give 5.8 g of the title compound as a pale yellow oil.
Reaction SMILES: C[Si](Cl)(C)C.[C:6]1(=[O:13])[CH2:11][CH2:10][CH2:9][C:8](=[O:12])[CH2:7]1.[CH:14]([C:16]1[CH:23]=[CH:22][C:19]([C:20]#[N:21])=[CH:18][CH:17]=1)=O.[F:24][C:25]([F:37])([F:36])[C:26]1[CH:31]=[C:30]([NH:32][C:33]([NH2:35])=[O:34])[CH:29]=[CH:28][N:27]=1>CN(C)C=O.C(#N)C.O>[C:20]([C:19]1[CH:22]=[CH:23][C:16]([CH:14]([C:7]2[C:8](=[O:12])[CH2:9][CH2:10][CH2:11][C:6]=2[OH:13])[NH:35][C:33]([NH:32][C:30]2[CH:29]=[CH:28][N:27]=[C:26]([C:25]([F:24])([F:36])[F:37])[CH:31]=2)=[O:34])=[CH:17][CH:18]=1)#[N:21]
Reactant: NC(=O)Nc1ccnc(C(F)(F)F)c1
Reactant: O=C1CCCC(=O)C1
Reactant: N#Cc1ccc(C=O)cc1
Agent: C[Si](C)(C)Cl
Solvent: CN(C)C=O
Solvent: CC#N
Solvent: O
Product: N#Cc1ccc(C(NC(=O)Nc2ccnc(C(F)(F)F)c2)C2=C(O)CCCC2=O)cc1
Temperature: 25 °C
Reaction time: 1.5 h

Procedure:
Trimethylsilyl chloride (187 μL, 1.47 mmol) is added to a solution of cyclohexane-1,3-dione (150 mg, 1.34 mmol), 4-formylbenzonitrile (175 mg, 1.34 mmol) and 1-(2-(trifluoromethyl)pyridin-4-yl)urea (274 mg, 1.34 mmol) in a mixture of N,N-dimethyl-formamide (1.0 mL) and acetonitrile (1.8 mL), and the mixture is stirred at room temperature for 1.5 h. The reaction mixture is cooled to room temperature and poured into a mixture of water and ice. The mixture is filtered, and the precipitate is washed with water and dried under reduced pressure. Yield: 410 mg; ESI mass spectrum [M+H]+=431, Retention time HPLC: 0.60 min (V011_S01).
Reaction SMILES: Br[C:2]1[C:10]2[C:9](=[O:11])[N:8]([CH3:12])[C:7](=[O:13])[N:6]([CH2:14][CH:15]([CH3:17])[CH3:16])[C:5]=2[S:4][C:3]=1[CH2:18][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=1[C:25]([F:28])([F:27])[F:26].CC[Mg+].[Br-].[F:33][C:34]1[CH:41]=[CH:40][CH:39]=[CH:38][C:35]=1[CH:36]=[O:37]>O1CCCC1>[F:33][C:34]1[CH:41]=[CH:40][CH:39]=[CH:38][C:35]=1[CH:36]([OH:37])[C:2]1[C:10]2[C:9](=[O:11])[N:8]([CH3:12])[C:7](=[O:13])[N:6]([CH2:14][CH:15]([CH3:17])[CH3:16])[C:5]=2[S:4][C:3]=1[CH2:18][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=1[C:25]([F:28])([F:27])[F:26]
Reactant: O=Cc1ccccc1F
Reactant: CC(C)Cn1c(=O)n(C)c(=O)c2c(Br)c(Cc3ccccc3C(F)(F)F)sc21
Agent: CC[Mg+]
Agent: [Br-]
Solvent: C1CCOC1
Product: CC(C)Cn1c(=O)n(C)c(=O)c2c(C(O)c3ccccc3F)c(Cc3ccccc3C(F)(F)F)sc21

Procedure:
5-Bromo-1-isobutyl-3-methyl-6-[2-(trifluoromethyl)benzyl]thieno[2,3-d]pyrimidine-2,4(1H,3H)-dione (Example 1 part c)) (100 mg) was dissolved in tetrahydrofuran (2 ml) and EtMgBr (210 ul of a 1M solution in tetrahydrofuran) was added. After 10 min 2-fluorobenzaldehyde (210 μl of a 1M solution in tetrahydrofuran) was added. After 1 hr the reaction was quenched via addition of water. The reaction was concentrated in vacuo and extracted into dichloromethane, concentrated in vacuo and purified by chromatography eluting with 0-75% diethyl ether in isohexane to yield 5-[(2-fluorophenyl)hydroxymethyl]-3-methyl-1-(2-methylpropyl)-6-[[2-(trifluoromethyl)phenyl]methyl]-thieno[2,3-d]pyrimidine-2,4(1H,3H)-dione. This was redissolved in dichloromethane (1 ml) and added to a mixture of oxalyl chloride (50 ul) and dimethyl sulphoxide (100 μl) in dichloromethane (1 ml) at −78° C. After 30 mins triethylamine (260 ul) was added and the reaction allowed to warm to room temperature. The reaction was then washed with water and evaporated to dryness before the residue was purified by chromatography eluting with 0-75% diethyl ether in hexane to yield the title compound (11 mg).
Reaction SMILES: [CH:1]1([CH2:4][O:5][C:6]2[CH:11]=[CH:10][C:9]([C:12]3[O:13][C:14]4[CH:20]=[C:19]([O:21][CH2:22][C@@H:23]([NH:25][C:26](=[O:32])OC(C)(C)C)[CH3:24])[CH:18]=[CH:17][C:15]=4[N:16]=3)=[CH:8][C:7]=2[F:33])[CH2:3][CH2:2]1.[CH3:34][N:35]=C=O>>[CH:1]1([CH2:4][O:5][C:6]2[CH:11]=[CH:10][C:9]([C:12]3[O:13][C:14]4[CH:20]=[C:19]([O:21][CH2:22][C@@H:23]([NH:25][C:26]([NH:35][CH3:34])=[O:32])[CH3:24])[CH:18]=[CH:17][C:15]=4[N:16]=3)=[CH:8][C:7]=2[F:33])[CH2:3][CH2:2]1
Reactant: CN=C=O
Reactant: C[C@@H](COc1ccc2nc(-c3ccc(OCC4CC4)c(F)c3)oc2c1)NC(=O)OC(C)(C)C
Product: CNC(=O)N[C@@H](C)COc1ccc2nc(-c3ccc(OCC4CC4)c(F)c3)oc2c1

Procedure:
Using tert-butyl ((2S)-1-((2-(4-(cyclopropylmethoxy)-3-fluorophenyl)-1,3-benzoxazol-6-yl)oxy)propan-2-yl)carbamate and methyl isocyanate, and in the same manner as in Example 10, the title compound was obtained.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([C:8]([F:11])([F:10])[F:9])=[CH:4][C:3]=1[C:12]1[CH:17]=[CH:16][N:15]=[CH:14][CH:13]=1.[B:18](OC(C)C)([O:23]C(C)C)[O:19]C(C)C.C([Li])CCC>C(OCC)C>[N:15]1[CH:16]=[CH:17][C:12]([C:3]2[CH:4]=[C:5]([C:8]([F:11])([F:10])[F:9])[CH:6]=[CH:7][C:2]=2[B:18]([OH:23])[OH:19])=[CH:13][CH:14]=1
Reactant: FC(F)(F)c1ccc(Br)c(-c2ccncc2)c1
Reactant: CC(C)OB(OC(C)C)OC(C)C
Agent: [Li]CCCC
Solvent: CCOCC
Product: OB(O)c1ccc(C(F)(F)F)cc1-c1ccncc1
Reaction time: 0.5 h

Procedure:
A round bottom flask was charged with 4-(2-bromo-5-(trifluoromethyl)phenyl)pyridine (2.0 g, 6.62 mmol), diethyl ether (50.9 ml), and triisopropyl borate (1.845 ml, 7.94 mmol). The flask was cooled to −78° C. for 10 minutes after which butyllithium (1.7 M in hexanes) (4.67 ml, 7.94 mmol) was added dropwise. The reaction was stirred for 30 minutes. The dry-ice bath was removed and 2N aqueous NaOH solution (50 mL) was added. The resulting biphasic mixture was stirred vigorously for one hour. The mixture was diluted with water, and the layers were separated. The diethyl ether was then extracted with water (×2) and the water layers were combined and washed twice with diethyl ether. The aqueous layer was neutralized to about pH 7 with 1N aqueous HCl solution and extracted with ethyl acetate (three times). The combined organic layers were dried over sodium sulfate, filtered and concentrated to afford (2-(pyridin-4-yl)-4-(trifluoromethyl)phenyl)boronic acid as an off-white solid. m/z (ESI) 268.1 (M+H)+.
Reaction SMILES: [Cl:1][C:2]1[N:10]=[C:9]2[C:5]([N:6]=[CH:7][N:8]2[CH:11]([CH2:14][CH3:15])[CH2:12][CH3:13])=[C:4]([NH:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[N:3]=1.[NH2:23][C@H:24]1[CH2:29][CH2:28][C@H:27]([NH2:30])[CH2:26][CH2:25]1>O.C(OCC)(=O)C>[ClH:1].[ClH:1].[NH2:23][C@H:24]1[CH2:29][CH2:28][C@H:27]([NH:30][C:2]2[N:10]=[C:9]3[C:5]([N:6]=[CH:7][N:8]3[CH:11]([CH2:14][CH3:15])[CH2:12][CH3:13])=[C:4]([NH:16][C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)[N:3]=2)[CH2:26][CH2:25]1
Reactant: N[C@H]1CC[C@H](N)CC1
Reactant: CCC(CC)n1cnc2c(Nc3ccccc3)nc(Cl)nc21
Solvent: CCOC(C)=O
Solvent: O
Product: CCC(CC)n1cnc2c(Nc3ccccc3)nc(N[C@H]3CC[C@H](N)CC3)nc21
Product: Cl
Reaction time: 4 h

Procedure:
The operation is carried out as in Stage 3 of Example 3 starting from 97 mg of the product obtained in Stage 1 above and 350 mg of trans-1,4-diaminocyclohexane and the reaction medium is taken to a temperature of 140 to 150° C. for approximately 4 hours then cooled down to 70–80° C. and diluted with 20 ml of water/ethyl acetate in a proportion of 50/50, left to settle, followed by washing with 10 ml of water and 5 ml of an aqueous solution of sodium chloride, drying and evaporating to dryness. After purification on silica eluting with methanol/ammonium hydroxide (NH4OH) in a proportion of 98/2 and salification with 1.4 N hydrochloric acid in ethanol, 66 mg of expected product is obtained in the form of crystals.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9]([NH:11][C:12]2[CH:17]=[CH:16][C:15]([OH:18])=[CH:14][CH:13]=2)=[O:10])=[CH:4][C:3]=1[C:19]([F:22])([F:21])[F:20].CC(C)([O-])C.[K+].Cl[C:30]1[CH:35]=[CH:34][N:33]=[C:32]([C:36]([NH:38][CH3:39])=[O:37])[CH:31]=1>CN(C)C=O.C(OCC)(=O)C.C(#N)C>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9](=[O:10])[NH:11][C:12]2[CH:13]=[CH:14][C:15]([O:18][C:30]3[CH:35]=[CH:34][N:33]=[C:32]([C:36]([NH:38][CH3:39])=[O:37])[CH:31]=3)=[CH:16][CH:17]=2)=[CH:4][C:3]=1[C:19]([F:20])([F:21])[F:22]
Reactant: CNC(=O)c1cc(Cl)ccn1
Reactant: O=C(Nc1ccc(O)cc1)Nc1ccc(Cl)c(C(F)(F)F)c1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Solvent: CC#N
Product: CNC(=O)c1cc(Oc2ccc(NC(=O)Nc3ccc(Cl)c(C(F)(F)F)c3)cc2)ccn1
Temperature: 25 °C
Reaction time: 2.5 h
Yield: 64.9 %

Procedure:
1-(4-chloro-3-(trifluoromethyl)phenyl)-3-(4-hydroxyphenyl)urea (35 g, 0.1060 mol) was dissolved in dry N,N-dimethyl formamide (100 ml) and potassium tert-butoxide (14.28 g, 0.1272 mol) was added in one lot at room temperature. The reaction mass was stirred at ambient temperature for 2-3 hours and 4-chloro-N-methyl picolinamide (18.09 g, 0.1060 mol) was added in one lot. The reaction mass was maintained at 60-70° C. for 2-3 hours and cooled to room temperature. It was then diluted with ethyl acetate and the organic layer was washed with water followed by 1N HCl and finally with brine. The organic layer was separated, dried over sodium sulfate and degassed to obtain solid. The obtained solid was stripped with ethyl acetate, finally slurried in acetonitrile (350 ml) at room temperature, filtered and vacuum dried to give 4-(4-{3-[4-Chloro-3-(trifluoromethyl)phenyl]ureido}phenoxy)-N2-methylpyridine-2-carboxamide (sorafenib) (32 g).
Reaction SMILES: [C:1]1([CH:7]([O:14][C:15]([C@@H:17]2[N:21]3[C:22](=[O:35])[C@@H:23]([NH:24]C(=O)COC4C=CC=CC=4)[C@H:20]3[S@@:19](=O)[C:18]2([CH3:38])[CH3:37])=[O:16])[C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.N1C=[CH:43][CH:42]=[CH:41][CH:40]=1.C(Br)(=O)C.[O:49]1[CH2:54][CH2:53][O:52][CH2:51][CH2:50]1>>[C:8]1([CH:7]([O:14][C:15]([C:17]2[N:21]3[C:22](=[O:35])[C@@H:23]([NH:24][C:54](=[O:49])[CH2:53][O:52][C:51]4[CH:50]=[CH:43][CH:42]=[CH:41][CH:40]=4)[C@H:20]3[S:19][CH2:37][C:18]=2[CH3:38])=[O:16])[C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1
Reactant: c1ccncc1
Reactant: CC1(C)[C@H](C(=O)OC(c2ccccc2)c2ccccc2)N2C(=O)[C@@H](NC(=O)COc3ccccc3)[C@H]2[S@]1=O
Reactant: C1COCCO1
Agent: CC(=O)Br
Product: CC1=C(C(=O)OC(c2ccccc2)c2ccccc2)N2C(=O)[C@@H](NC(=O)COc3ccccc3)[C@H]2SC1
Temperature: 100 °C
Reaction time: 0.25 h

Procedure:
(1S,3S,5R,6R) 2,2-Dimethyl-6-phenoxyacetamidopenam-3-carboxylic acid-1-oxide diphenylmethyl ester (25.00 gms, 45.41 mmoles) was dissolved in sieve-dried, peroxide-free dioxane (250 mls) at 25° C. with good agitation. To this solution, in order, were added pyridine (10.99 mls, 10.78 gms, 136.22 mmoles), acetyl bromide (0.67 mls, 1.12 gms, 9.08 mmoles) and dimethylsilyl diisocyanate (16.14 gms, 113.51 mmoles), and the slurry was heated to reflux (ca. 100° C.) for 4 hours. The dioxane slurry was then cooled to 25° C., filtered, and concentrated in vacuo at 50° C. to a heavy oil. The oil was taken up in methylene chloride (400 mls), stirred for 15 minutes at 25° C., filtered, and concentrated in vacuo to dryness. The residue was dissolved in hot 1-butanol (500 mls, ca. 90°-95° C.) and allowed to cool to 25° C. The slurry was cooled to 0°-5° C. for 16 hours, filtered, washed with cold butanol (0°-5° C., 100 mls), then with Skellysolve B (200 mls), and oven-dried at 45° C. to constant weight. Yield: 20.2 gms, 86.4% of snow-white crystalline title compound. The NMR spectrum was clean and consistent for the desired structure, as follows: 80 MHz H' NMR, δ(CD2Cl2) 2.08 (3H,s,CH3), 3.04-3.62 (2H, m, CH2, JAB =18.1 Hz), 4.55 (2H, s, CH2), 4.99-5.05 (1H, d, β-lactam H, JA =4.7 Hz), 5.74-5.91 (1 H, m, β-lactam H, J=4.7 Hz), 6.75-7.50 (17H, m, aromatic CH, and NH).