Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([N:3]([CH2:35][CH3:36])[CH2:4]/[CH:5]=[CH:6]\C1C=C(F)C=CC=1S(NC1C(C(OC)=O)=C2C(C3C=COC=3CO2)=CC=1)(=O)=O)[CH3:2].Br[C:38]1[CH:43]=[C:42]([F:44])[CH:41]=[CH:40][C:39]=1[S:45]([NH:48][C:49]1[C:58]([C:59]([O:61][CH3:62])=[O:60])=[C:57]2[C:52]([CH:53]3[C:63]([F:65])([F:64])[CH:54]3[CH2:55][O:56]2)=[CH:51][CH:50]=1)(=[O:47])=[O:46].C(N(CC)C/C=C\[Sn](CCCC)(CCCC)CCCC)C>>[CH2:1]([N:3]([CH2:35][CH3:36])[CH2:4]/[CH:5]=[CH:6]\[C:38]1[CH:43]=[C:42]([F:44])[CH:41]=[CH:40][C:39]=1[S:45]([NH:48][C:49]1[C:58]([C:59]([O:61][CH3:62])=[O:60])=[C:57]2[C:52]([CH:53]3[C:63]([F:65])([F:64])[CH:54]3[CH2:55][O:56]2)=[CH:51][CH:50]=1)(=[O:47])=[O:46])[CH3:2]
Reactant: CCN(CC)C/C=C\c1cc(F)ccc1S(=O)(=O)Nc1ccc2c(c1C(=O)OC)OCc1occc1-2
Reactant: COC(=O)c1c(NS(=O)(=O)c2ccc(F)cc2Br)ccc2c1OCC1C2C1(F)F
Agent: CCCC[Sn](/C=C\CN(CC)CC)(CCCC)CCCC
Product: CCN(CC)C/C=C\c1cc(F)ccc1S(=O)(=O)Nc1ccc2c(c1C(=O)OC)OCC1C2C1(F)F

Procedure:
Prepared by proceeding in a similar manner to Intermediate 9, starting from methyl (1aRS,7bSR)-5-(2-bromo-4-fluorobenzenesulfonylamino)-1,1-difluoro-1,1a,2,7b-tetrahydro-cyclopropa[c]chromene-4-carboxylate (Intermediate 60) and N,N-diethyl-N—((Z)-1-tributylstannanylprop-1-en-3-yl)amine (Intermediate 11) as a pale yellow gum.
Reaction SMILES: [CH:1]1([C:4]2[N:8]([C:9]3[CH:18]=[CH:17][CH:16]=[C:15]4[C:10]=3[CH:11]=[CH:12][CH:13]=[N:14]4)[N:7]=[CH:6][C:5]=2[C:19]([OH:21])=O)[CH2:3][CH2:2]1.S(Cl)([Cl:24])=O>>[CH:1]1([C:4]2[N:8]([C:9]3[CH:18]=[CH:17][CH:16]=[C:15]4[C:10]=3[CH:11]=[CH:12][CH:13]=[N:14]4)[N:7]=[CH:6][C:5]=2[C:19]([Cl:24])=[O:21])[CH2:3][CH2:2]1
Reactant: O=S(Cl)Cl
Reactant: O=C(O)c1cnn(-c2cccc3ncccc23)c1C1CC1
Product: O=C(Cl)c1cnn(-c2cccc3ncccc23)c1C1CC1

Procedure:
combining 5-cyclopropyl-1-quinolin-5-yl-1H-pyrazole4-carboxylic acid and thionyl chloride to form 5-cyclopropyl-1-quinolin-5-yl-1H-pyrazole4-carboxylic acid chloride;
Reaction SMILES: C[O:2][C:3](=O)[C:4]([CH3:22])([C:6]1[N:7]=[C:8]([C:12]2[CH:17]=[CH:16][C:15]([C:18]([F:21])([F:20])[F:19])=[CH:14][CH:13]=2)[O:9][C:10]=1[CH3:11])[CH3:5].[H-].[Al+3].[Li+].[H-].[H-].[H-]>C1COCC1>[CH3:22][C:4]([C:6]1[N:7]=[C:8]([C:12]2[CH:13]=[CH:14][C:15]([C:18]([F:20])([F:21])[F:19])=[CH:16][CH:17]=2)[O:9][C:10]=1[CH3:11])([CH3:5])[CH2:3][OH:2]
Reactant: COC(=O)C(C)(C)c1nc(-c2ccc(C(F)(F)F)cc2)oc1C
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Product: Cc1oc(-c2ccc(C(F)(F)F)cc2)nc1C(C)(C)CO
Reaction time: 2 h
Yield: 89.8 %

Procedure:
To a solution of 2-methyl-2-[5-methyl-2-(4-trifluoromethyl-phenyl)-oxazol-4-yl]-propionic acid methyl ester (2.8 g) from step B in THF (14 mL) is added a solution of lithium aluminum hydride in THF (1.0 M, 13 mL) at 0° C. After 2 hrs, the reaction is quenched by water and sodium hydroxide, filtered, concentrated. Chromatography on silica gel gave 2-Methyl-2-[5-methyl-2-(4-trifluoromethyl-phenyl)-oxazol-4-yl]-propan-1-ol (2.3 g).
Reaction SMILES: [CH2:1]([Li])[CH2:2][CH2:3]C.[CH2:6]([C:13]([OH:22])([C:18]([CH3:21])([CH3:20])C)C(C)(C)C)[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1.C(=O)C1C=CC=CC=1.CN(P(N(C)C)(N(C)C)=O)C>CCCCC.C1COCC1.[Cl-].[Cl-].[Zn+2].C(OCC)C>[C:18]1([CH:13]([OH:22])[CH2:6][C:7]2[CH:8]=[CH:9][CH:10]=[CH:11][CH:12]=2)[CH:20]=[CH:3][CH:2]=[CH:1][CH:21]=1
Reactant: [Li]CCCC
Reactant: CC(C)(C)C(O)(Cc1ccccc1)C(C)(C)C
Agent: [Cl-]
Agent: [Zn+2]
Solvent: C1CCOC1
Solvent: CCOCC
Solvent: CCCCC
Product: OC(Cc1ccccc1)c1ccccc1
Temperature: 70 °C
Reaction time: 0.5 h

Procedure:
1.33 ml of a 1.6-molar solution of n-butyllithium (2.13 mmol) in pentane were added dropwise at room temperature under argon for 2 minutes to a stirred solution of 500 mg (2.13 mmol) 3-benzyl-2,2,4,4-tetramethyl-3-pentanol in 4 ml THF. The solution obtained was stirred for 30 minutes, then 275 μl (2.13 mmol) benzaldehyde, 290 mg (2.13 mmol) ZnCl2 and 2 ml HMPA were added. The reaction mixture was heated to 70° C. and stirred for 4 hours at this temperature. Subsequently, it was cooled to room temperature and processed analogous to Example 1. The raw product obtained was cleaned by means of a silica column with 35% diethyl ether/light gasoline. There was obtained the alcohol as a colorless oil.
Reaction SMILES: [C:1]([C:5]1[O:9][N:8]=[C:7]([NH:10][C:11]([NH:13][C:14]2[CH:19]=[CH:18][CH:17]=[C:16]([SH:20])[CH:15]=2)=[O:12])[CH:6]=1)([CH3:4])([CH3:3])[CH3:2].Cl[C:22]1[C:31]2[C:26](=[CH:27][C:28]([O:34][CH2:35][CH3:36])=[C:29]([O:32][CH3:33])[CH:30]=2)[N:25]=[CH:24][N:23]=1.C([O-])([O-])=O.[Cs+].[Cs+]>C(O)(C)C>[C:1]([C:5]1[O:9][N:8]=[C:7]([NH:10][C:11]([NH:13][C:14]2[CH:19]=[CH:18][CH:17]=[C:16]([S:20][C:22]3[C:31]4[C:26](=[CH:27][C:28]([O:34][CH2:35][CH3:36])=[C:29]([O:32][CH3:33])[CH:30]=4)[N:25]=[CH:24][N:23]=3)[CH:15]=2)=[O:12])[CH:6]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)c1cc(NC(=O)Nc2cccc(S)c2)no1
Reactant: CCOc1cc2ncnc(Cl)c2cc1OC
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CC(C)O
Product: CCOc1cc2ncnc(Sc3cccc(NC(=O)Nc4cc(C(C)(C)C)on4)c3)c2cc1OC
Temperature: 70 °C
Yield: 48 %

Procedure:
A mixture of 1-(5-tert-butylisoxazol-3-yl)-3-(3-mercaptophenyl)urea described in Example 44A (0.146 g 0.5 mmol), 4-chloro-7-ethoxy-6-methoxyquinazoline from Example 6B Step 1 (0.12 g, 0.5 mmol), and Cs2CO3 (0.161 mg, 0.5 mmol) in isopropanol (10 mL) was heated at 70° C. for 7 hours. It was quenched with water and extracted with CH2Cl2. Extracts were dried over MgSO4 and concentrated under reduced pressure. It was purified by silica gel chromatography with EtOAc/hexane as eluant to afford 1-(5-tert-butylisoxazol-3-yl)-3-[3-(7-ethoxy-6-methoxyquinazolin-4-ylthio)phenyl]urea as solid (0.118 g, 48%). 1H NMR (300 MHz, CDCl3) δ 9.3 (br, 1H), 8.74 (s, 1H), 8.05 (s, 1H), 7.86 (s, 1H), 7.62 (d, 1H), 7.37 (m, 3H), 7.25 (1H), 5.91 (s, 1H), 4.29 (q, 2H), 4.06 (s, 3H), 1.58 (t, 3H), 1.32 (s, 9H); LC-MS (ESI) m/z 494 (M+H)+.
Reaction SMILES: I[C:2]1[CH:7]=[C:6]([CH2:8][CH2:9][CH3:10])[CH:5]=[CH:4][C:3]=1[OH:11].Cl[C:13]1[C:14](I)=[C:15]([OH:20])C=C(Cl)C=1>>[CH2:8]([C:6]1[CH:5]=[CH:4][C:3]2[O:11][C:14]([CH2:15][OH:20])=[CH:13][C:2]=2[CH:7]=1)[CH2:9][CH3:10]
Reactant: CCCc1ccc(O)c(I)c1
Reactant: Oc1cc(Cl)cc(Cl)c1I
Product: CCCc1ccc2oc(CO)cc2c1

Procedure:
When the product of Step A was substituted for 3,5-dichloro-2-iodophenol in Example 8, Step E, the similar process afforded the title compound in 31%, as off-white oil. 1H-NMR (CDCl3) 0.93 (m, 3H); 1.58-1.73 (m, 2H); 1.9 (tr, 1H, J=6 Hz); 2.65 (tr, 2H, J=6 Hz); 4.76 (d, 2H, J=6 Hz); 6.58 (s, 1H); 7.08 (dd, 1H, J=3, 9 Hz); 7.3-7.37 (m, 2H).
Reaction SMILES: C(C1C=C(C=CC=1CC)C(C1C=CC=CC=1)=O)C.[CH2:19]([C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=1[CH2:27][CH3:28])[CH3:20].[Cl-].[Al+3].[Cl-].[Cl-].[CH3:33][O:34][C:35]1[CH:36]=[C:37]([CH:41]=[CH:42][C:43]=1[O:44][CH3:45])[C:38](Cl)=[O:39]>>[CH2:19]([C:21]1[CH:26]=[C:25]([C:38](=[O:39])[C:37]2[CH:41]=[CH:42][C:43]([O:44][CH3:45])=[C:35]([O:34][CH3:33])[CH:36]=2)[CH:24]=[CH:23][C:22]=1[CH2:27][CH3:28])[CH3:20]
Reactant: CCc1ccccc1CC
Reactant: COc1ccc(C(=O)Cl)cc1OC
Agent: CCc1ccc(C(=O)c2ccccc2)cc1CC
Agent: [Al+3]
Agent: [Cl-]
Product: CCc1ccc(C(=O)c2ccc(OC)c(OC)c2)cc1CC

Procedure:
3',4'-Diethyl-3,4-dimethoxybenzophenone was prepared analogously to 3,4-diethylbenzophenone using diethylbenzene (2.5 mL, 15 mmol), aluminum chloride (2.2 g, 16.5 mmol) and 3,4-dimethoxybenzoyl chloride (3 g, 15 mmol) with a reaction time of 3 hours at reflux. The crude product was purified by flash column chromatography (silica gel, 1.5% ethyl acetate/hexane) to afford 0.84 g (20%) of the product as an orange solid: mp 60-61° C.; 1H NMR (CDCl3) δ 7.74-7.15 (m, 5 H), 7.00-6.80 (m, 1 H) 3.96 (s, 3 H), 3.94 (s, 3 H), 2.93-2.60 (m, 4 H), 1.43-1.15 (m, 6 H); 13C NMR (CDCl3) δ 195.5, 152.7, 148.8, 146.3, 141.7, 135.9, 130.6, 129.8, 128.0, 127.7, 125.1, 112.2, 109.7, 56.0, 25.6, 25.4, 15.1, 15.0; Anal. Calcd for C19H22O3. Theoretical: C, 76.48; H, 7.43. Found: C, 76.53; H, 7.34.
Reaction SMILES: F[C:2]1[N:7]=[C:6]([C:8]([NH:10][C:11]2[CH:19]=[C:18]([C:20]3[CH:28]=[CH:27][CH:26]=[C:25]4[C:21]=3[CH:22]=[CH:23][NH:24]4)[CH:17]=[C:16]3[C:12]=2[CH:13]=[N:14][NH:15]3)=[O:9])[CH:5]=[CH:4][CH:3]=1.[CH3:29][N:30]1[CH2:35][CH2:34][CH:33]([NH2:36])[CH2:32][CH2:31]1.CCN(C(C)C)C(C)C>CS(C)=O.CO>[NH:24]1[C:25]2[C:21](=[C:20]([C:18]3[CH:17]=[C:16]4[C:12]([CH:13]=[N:14][NH:15]4)=[C:11]([NH:10][C:8]([C:6]4[CH:5]=[CH:4][CH:3]=[C:2]([NH:36][CH:33]5[CH2:34][CH2:35][N:30]([CH3:29])[CH2:31][CH2:32]5)[N:7]=4)=[O:9])[CH:19]=3)[CH:28]=[CH:27][CH:26]=2)[CH:22]=[CH:23]1
Reactant: CN1CCC(N)CC1
Reactant: O=C(Nc1cc(-c2cccc3[nH]ccc23)cc2[nH]ncc12)c1cccc(F)n1
Solvent: CCN(C(C)C)C(C)C
Solvent: CO
Solvent: CS(C)=O
Product: CN1CCC(Nc2cccc(C(=O)Nc3cc(-c4cccc5[nH]ccc45)cc4[nH]ncc34)n2)CC1
Temperature: 160 °C
Yield: 43 %

Procedure:
6-Fluoro-N-[6-(1H-indol-4-yl)-1H-indazol-4-yl]-2-pyridinecarboxamide (50 mg, 0.14 mmol) and 1-methyl-4-piperidinamine (30.7 mg, 0.27 mmol) were dissolved in DMSO (0.5 ml) in a microwave vial. DIPEA (0.141 ml) was added and the mixture was heated at 160° C. for 4 h under microwave irradiation. The reaction mixture was diluted with MeOH (0.5 ml) and was purified by Mass Directed Automated Preparative HPLC (Method C). Fractions containing product were blown to dryness and the residue dissolved in methanol. This solution was loaded onto a 1 g aminopropyl column which was eluted with MeOH (1 column volume). The solvent removed under a stream of nitrogen to give the title compound (28 mg) as a cream solid.
Reaction SMILES: C(OC(=O)C1C=CC(NC2CCCCC2)=C(NC(C2C=C3C(=CC=2)N=C(C2C(C4C=CC(Cl)=CC=4)=CC=C(C(N4CCCC4)=O)C=2)C=C3)=O)C=1)C.ClC1C=CC([C:57]2[C:62]([C:63]3[CH:72]=[CH:71][C:70]4[C:65](=[CH:66][CH:67]=[C:68]([C:73]5[N:77]([CH:78]6[CH2:83][CH2:82][CH2:81][CH2:80][CH2:79]6)[C:76]6[CH:84]=[CH:85][C:86]([C:88]([OH:90])=[O:89])=[CH:87][C:75]=6[N:74]=5)[CH:69]=4)[N:64]=3)=[CH:61][C:60]([C:91]([N:93]3[CH2:97][CH2:96][CH2:95][CH2:94]3)=[O:92])=[CH:59][CH:58]=2)=CC=1.C(C1C=CC=CC=1)(=O)C>>[CH:78]1([N:77]2[C:76]3[CH:84]=[CH:85][C:86]([C:88]([OH:90])=[O:89])=[CH:87][C:75]=3[N:74]=[C:73]2[C:68]2[CH:69]=[C:70]3[C:65](=[CH:66][CH:67]=2)[N:64]=[C:63]([C:62]2[CH:57]=[CH:58][CH:59]=[C:60]([C:91]([N:93]4[CH2:97][CH2:96][CH2:95][CH2:94]4)=[O:92])[CH:61]=2)[CH:72]=[CH:71]3)[CH2:83][CH2:82][CH2:81][CH2:80][CH2:79]1
Reactant: O=C(O)c1ccc2c(c1)nc(-c1ccc3nc(-c4cc(C(=O)N5CCCC5)ccc4-c4ccc(Cl)cc4)ccc3c1)n2C1CCCCC1
Agent: CCOC(=O)c1ccc(NC2CCCCC2)c(NC(=O)c2ccc3nc(-c4cc(C(=O)N5CCCC5)ccc4-c4ccc(Cl)cc4)ccc3c2)c1
Solvent: CC(=O)c1ccccc1
Product: O=C(O)c1ccc2c(c1)nc(-c1ccc3nc(-c4cccc(C(=O)N5CCCC5)c4)ccc3c1)n2C1CCCCC1

Procedure:
The title compound was synthesized in four steps as described for Compound 13, Compound 25, Compound 27 Q=ethyl and Compound 204, respectively, except the product of the previous step was used in the first step, instead of acetophenone.
Reaction SMILES: Br[C:2]1[CH:10]=[C:9]([Cl:11])[CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=[O:5].[CH2:12]([N:19]1[CH2:24][CH2:23][C:22](=O)[CH2:21][CH2:20]1)[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.O.C(OCC)C>O1CCCC1.CCCCCC.C([Li])CCC>[CH2:12]([N:19]1[CH2:24][CH2:23][C:22]2([C:2]3[CH:10]=[C:9]([Cl:11])[CH:8]=[CH:7][C:3]=3[C:4](=[O:5])[O:6]2)[CH2:21][CH2:20]1)[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1
Reactant: O=C1CCN(Cc2ccccc2)CC1
Reactant: O=C(O)c1ccc(Cl)cc1Br
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: O
Solvent: CCOCC
Product: O=C1OC2(CCN(Cc3ccccc3)CC2)c2cc(Cl)ccc21
Temperature: -78 °C
Reaction time: 3 h
Yield: 37.2 %

Procedure:
To a solution of 2-bromo-4-chlorobenzoic acid (2.35 g, 10.0 mmol) in tetrahydrofuran (THF) (15 mL) was added, a 1.6 M solution in hexane, n-butyllithium (Parham, W. E; Egberg, D. C.; Sayed, Y. A; Thraikill, R. W; Keyser, G. E; William, M. N; Montgomery, M. C; Jones, L. D., J. Org. Chem., 1976, 41, 2628-2633) (20 mL, 32.0 mmol) slowly at −78° C. under nitrogen. After addition was complete the reaction mixture was stirred at −78° C. for 3 hours (h). Then a solution of 1-benzylpiperidin-4-one (3.78 g, 20.0 mmol) in THF (10 mL) was added slowly to the reaction mixture at −78° C. After addition was complete the reaction temperature was raised to room temperature and the reaction mixture was stirred at room temperature overnight. The reaction mixture was poured into a mixture of water (H2O) (60 mL) and diethyl ether (60 mL), layers were separated. The aqueous layer was extracted with diethyl ether (2×20 mL). The aqueous layer was acidified with aq 6 M HCl to pH 2 and boiled for 1 h, cooled to 0° C., pH was adjusted to 10 by addition of aqueous sodium hydroxide (NaOH) (6M) and rapidly extracted with trichloromethane (CHCl3). The organic layer was washed with H2O, dried over sodium sulphate (Na2SO4), filtered and concentrated in vacuo to give sub-titled compound (1.22 g) and it was pure enough for the next step.
Reaction SMILES: CS(Cl)(=O)=O.[Br:6][C:7]1[CH:12]=[C:11]([F:13])[C:10]([CH2:14]O)=[C:9]([F:16])[CH:8]=1.C(N(CC)CC)C.[NH:24]1[CH2:29][CH2:28][CH2:27][CH2:26][CH2:25]1.C(=O)([O-])[O-].[K+].[K+]>C(Cl)Cl.C(#N)C>[Br:6][C:7]1[CH:12]=[C:11]([F:13])[C:10]([CH2:14][N:24]2[CH2:29][CH2:28][CH2:27][CH2:26][CH2:25]2)=[C:9]([F:16])[CH:8]=1
Reactant: C1CCNCC1
Reactant: OCc1c(F)cc(Br)cc1F
Agent: CS(=O)(=O)Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: Fc1cc(Br)cc(F)c1CN1CCCCC1
Temperature: 25 °C
Reaction time: 2 h
Yield: 94.6 %

Procedure:
Methane sulfonyl chloride (0.38 mL, 4.93 mmol) was added dropwise to a cooled (0° C.) solution of (4-bromo-2,6-difluorophenyl)-methanol (1.00 g, 4.48 mmol) and triethylamine (0.75 mL, 5.38 mmol) in DCM (50 mL). The reaction mixture was allowed to warm to ambient temperature and stirred for 2 h. The mixture was diluted with DCM (30 mL) and washed with water (20 mL). The organic phase was separated, dried over anhydrous sodium sulfate, filtered and evaporated in vacuo to afford a colourless oil. The oil was dissolved in acetonitrile (30 mL), piperidine (0.53 mL, 5.38 mmol) and potassium carbonate (0.93 g, 6.72 mmol) were added and the reaction mixture was heated at 50° C. for 90 minutes. The reaction mixture was allowed to cool to ambient temperature and the solid removed by filtration. The filtrate was evaporated in vacuo and the resultant residue purified by flash column chromatography (silica, 12 g column, ISCO, 0-40% ethyl acetate in cyclohexane) to afford the title compound as a colourless oil (1.23 g, 99%). 1H NMR (CDCl3, 300 MHz): 7.07 (d, J=6.6 Hz, 2H), 3.62 (t, J=1.7 Hz, 2H), 2.41 (t, J=5.1 Hz, 4H), 1.59-1.50 (m, 4H), 1.42-1.33 (m, 2H). LCMS (Method B): RT=1.67 min, M+H+=290/292.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([CH2:9][C:10]#[N:11])=[CH:5][CH:4]=1.[C:12](OCC)(=[O:18])[C:13]([O:15][CH2:16][CH3:17])=[O:14]>[O-]CC.[Na+]>[C:10]([CH:9]([C:6]1[CH:7]=[CH:8][C:3]([O:2][CH3:1])=[CH:4][CH:5]=1)[C:12](=[O:18])[C:13]([O:15][CH2:16][CH3:17])=[O:14])#[N:11]
Reactant: COc1ccc(CC#N)cc1
Reactant: CCOC(=O)C(=O)OCC
Agent: CC[O-]
Agent: [Na+]
Product: CCOC(=O)C(=O)C(C#N)c1ccc(OC)cc1

Procedure:
Following the procedures outlined in Examples 1 and 3, p-methoxyphenylacetonitrile is reacted with diethyl oxalate in alcoholic sodium ethoxide solution to give ethyl 3-cyano-3-(p-methoxyphenyl)-pyruvate which is then similarly reacted with phenylacetonitrile to yield 2-(p-methoxyphenyl)-5-phenyl-3,4-dioxoadiponitrile, m.p. 256°-258° C.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH2:9][OH:10])[CH:5]=[CH:6][C:7]=1I.[C:11]([O:15][CH3:16])(=[O:14])[CH:12]=[CH2:13].C(=O)([O-])[O-].[K+].[K+].C(OCC)(=O)C>CCCC[N+](CCCC)(CCCC)CCCC.[Cl-].CN(C)C=O.[Cl-].[Na+].O.C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[Br:1][C:2]1[CH:3]=[C:4]([CH2:9][OH:10])[CH:5]=[CH:6][C:7]=1/[CH:13]=[CH:12]/[C:11]([O:15][CH3:16])=[O:14]
Reactant: C=CC(=O)OC
Reactant: OCc1ccc(I)c(Br)c1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Solvent: CN(C)C=O
Solvent: O
Solvent: CCOC(C)=O
Product: COC(=O)/C=C/c1ccc(CO)cc1Br
Temperature: 50 °C
Reaction time: 20 h

Procedure:
A mixture of (3-bromo-4-iodophenyl)methanol (5.3 g, 17 mmol), methyl acrylate (1.97 mL, 21.8 mmol), tetra-N-butylammonium chloride (4.7 g, 17 mmol), palladium acetate (80 mg, 0.03 mmol) and finely grounded potassium carbonate (5.85 g, 42.3 mmol) in N,N-dimethylformamide (20 mL) was stirred at 50° C. for 20 h. The reaction mixture was cooled to room temperature. Ethyl acetate (200 mL) and brine (50 mL) were added, and the mixture was filtered under suction. The filtrate was collected, and aqueous layer was extracted with ethyl acetate twice. The combined organic layers were dried over sodium sulfate, filtered, and concentrated. The residue was purified by silica gel chromatography (5% to 40% ethyl acetate/hexane) to give oil (3.6 g, 90% purity, 70%). 1H NMR (400 MHz, CDCl3): δ 8.03 (d, J=18.2 Hz, 1H), 7.60 (m, 2H), 7.32 (d, J=8.0 Hz, 1H), 6.39 (d, J=16.0 Hz, 1H), 4.71 (d, J=5.5 Hz, 1H). LCMS found for C11H12BrO3 (M+H)+: m/z=271, 273.
Reaction SMILES: [OH:1][C@H:2]1[CH2:7][CH2:6][C@H:5]([C:8]([O:10][CH3:11])=[O:9])[CH2:4][CH2:3]1.N1C=CN=C1.[C:17]([Si:21](Cl)([CH3:23])[CH3:22])([CH3:20])([CH3:19])[CH3:18]>CN(C=O)C>[Si:21]([O:1][C@H:2]1[CH2:3][CH2:4][C@H:5]([C:8]([O:10][CH3:11])=[O:9])[CH2:6][CH2:7]1)([C:17]([CH3:20])([CH3:19])[CH3:18])([CH3:23])[CH3:22]
Reactant: COC(=O)[C@H]1CC[C@H](O)CC1
Reactant: CC(C)(C)[Si](C)(C)Cl
Agent: c1c[nH]cn1
Solvent: CN(C)C=O
Product: COC(=O)[C@H]1CC[C@H](O[Si](C)(C)C(C)(C)C)CC1
Temperature: 25 °C
Reaction time: 14 h

Procedure:
A 500-mL round-bottom flask, purged and maintained with an inert atmosphere of nitrogen, was charged with a solution of methyl trans-4-hydroxycyclohexane-1-carboxylate (16.6 g, 104.93 mmol, 1.00 equiv) and imidazole (14.28 g, 180.53 mmol, 1.72 equiv) in distilled DMF (25 mL). Tert-butyl(chloro)dimethylsilane (28.3 g, 187.76 mmol, 1.79 equiv) was added slowly and the resulting solution was stirred for 14 hrs at room temperature. After completion, the reaction was then quenched with water and extracted with 3×200 mL of ethyl acetate. The combined organic layers were washed with water, brine and dried over sodium sulfate. After concentration under reduced pressure, the residue was applied onto a silica gel column with ethyl acetate/petroleum ether (10:1) to give the desired methyl trans-4-[(tert-butyldimethylsilyl)oxy]cyclohexane-1-carboxylate (27.4 g, 96%) as a colorless oil.
Reaction SMILES: [C:1]([O:4][C@@H:5]1[N:8]([S:9]([O-:12])(=[O:11])=[O:10])[C:7](=[O:13])[C@H:6]1[NH:14][C:15](=[O:32])[C:16]([C:22]1[N:23]=[C:24]([NH:27]C(=O)CCl)[S:25][CH:26]=1)=[N:17][O:18][CH:19]([CH3:21])[CH3:20])(=[O:3])[CH3:2].[Na+:33].CSC(=S)N.[Na]>O>[C:1]([O:4][C@@H:5]1[N:8]([S:9]([O-:12])(=[O:11])=[O:10])[C:7](=[O:13])[C@H:6]1[NH:14][C:15](=[O:32])[C:16]([C:22]1[N:23]=[C:24]([NH2:27])[S:25][CH:26]=1)=[N:17][O:18][CH:19]([CH3:21])[CH3:20])(=[O:3])[CH3:2].[Na+:33]
Reactant: CC(=O)O[C@H]1[C@H](NC(=O)C(=NOC(C)C)c2csc(NC(=O)CCl)n2)C(=O)N1S(=O)(=O)[O-]
Agent: CSC(N)=S
Agent: [Na+]
Agent: [Na]
Solvent: O
Product: CC(=O)O[C@H]1[C@H](NC(=O)C(=NOC(C)C)c2csc(N)n2)C(=O)N1S(=O)(=O)[O-]
Temperature: 25 °C
Reaction time: 1 h
Yield: 71.4 %

Procedure:
To a solution of 0.250 g sodium (3S,4S)-4-acetoxy-3-[2-(2-chloroacetamidothiazol-4-yl)-2-isopropoxyiminoacetamido]-2-oxoazetidine-1-sulfonate in 4 ml of water is added 73 mg of sodium monomethyldithiocarbamate under ice-cooling and the mixture is stirred at room temperature for one hour. The insolubles are filtered off and the filtrate is purified on a column of XAD-II. The above procedure gives 0.153 g of sodium (3S,4S)-4-acetoxy-3-[2-(2-aminothiazol-4-yl)-2-isopropoxyiminoacetamido]-2-oxoazetidine-1-sulfonate.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([O:8][C:9]2[C:14]3[N:15]=[CH:16][C:17](=[O:19])[NH:18][C:13]=3[N:12]=[CH:11][CH:10]=2)[CH:5]=[CH:4][C:3]=1[NH:20][C:21](=[O:29])OC1C=CC=CC=1.[C:30]([C:34]1[CH:38]=[C:37]([NH2:39])[N:36]([C:40]2[CH:41]=[N:42][C:43]([CH3:46])=[CH:44][CH:45]=2)[N:35]=1)([CH3:33])([CH3:32])[CH3:31]>>[C:30]([C:34]1[CH:38]=[C:37]([NH:39][C:21]([NH:20][C:3]2[CH:4]=[CH:5][C:6]([O:8][C:9]3[C:14]4[N:15]=[CH:16][C:17](=[O:19])[NH:18][C:13]=4[N:12]=[CH:11][CH:10]=3)=[CH:7][C:2]=2[F:1])=[O:29])[N:36]([C:40]2[CH:41]=[N:42][C:43]([CH3:46])=[CH:44][CH:45]=2)[N:35]=1)([CH3:33])([CH3:32])[CH3:31]
Reactant: O=C(Nc1ccc(Oc2ccnc3[nH]c(=O)cnc23)cc1F)Oc1ccccc1
Reactant: Cc1ccc(-n2nc(C(C)(C)C)cc2N)cn1
Product: Cc1ccc(-n2nc(C(C)(C)C)cc2NC(=O)Nc2ccc(Oc3ccnc4[nH]c(=O)cnc34)cc2F)cn1
Yield: 16.7 %

Procedure:
Method F4 was used with 65 mg (0.17 mmol) of phenyl 2-fluoro-4-(3-oxo-3,4-dihydropyrido[3,2-b]pyrazin-8-yloxy)phenylcarbamate and 45 mg (0.2 mmol) of 3-tert-butyl-1-(6-methylpyridin-3-yl)-1H-pyrazol-5-amine (Regan, J. et al., J. Med. Chem. 2002, 45, 2994-3008). Obtained 15 mg, 17% yield of the title compound.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:11]=[CH:10][C:6]([C:7]([OH:9])=O)=[CH:5][C:4]=1/[CH:12]=[CH:13]/[C:14]1[CH:19]=[CH:18][C:17]([O:20][C:21]([F:24])([F:23])[F:22])=[CH:16][CH:15]=1.[NH2:25][CH:26]([CH2:29][OH:30])[CH2:27][OH:28]>>[OH:28][CH2:27][CH:26]([NH:25][C:7](=[O:9])[C:6]1[CH:10]=[CH:11][C:3]([O:2][CH3:1])=[C:4](/[CH:12]=[CH:13]/[C:14]2[CH:19]=[CH:18][C:17]([O:20][C:21]([F:23])([F:22])[F:24])=[CH:16][CH:15]=2)[CH:5]=1)[CH2:29][OH:30]
Reactant: NC(CO)CO
Reactant: COc1ccc(C(=O)O)cc1/C=C/c1ccc(OC(F)(F)F)cc1
Product: COc1ccc(C(=O)NC(CO)CO)cc1/C=C/c1ccc(OC(F)(F)F)cc1

Procedure:
The captioned compound was synthesized from 4-methoxy-3-[(E)-2-(4-trifluoromethoxyphenyl)vinyl]benzoic acid obtained in step B of Example 2-2-1 and 2-amino-1,3-propanediol in accordance with the same procedure as in the methods described in step C of Example 1-2-3.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:8]([CH2:10][C:11]([OH:13])=[O:12])[NH2:9])[CH:5]=[CH:6][CH:7]=1.C(N(CC)CC)C.[C:21]1([CH2:27][C:28](Cl)=[O:29])[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1>O.CC(C)=O>[C:21]1([CH2:27][C:28]([NH:9][CH:8]([C:4]2[CH:5]=[CH:6][CH:7]=[C:2]([Cl:1])[CH:3]=2)[CH2:10][C:11]([OH:13])=[O:12])=[O:29])[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1
Reactant: NC(CC(=O)O)c1cccc(Cl)c1
Reactant: O=C(Cl)Cc1ccccc1
Solvent: CCN(CC)CC
Solvent: O
Solvent: CC(C)=O
Product: O=C(O)CC(NC(=O)Cc1ccccc1)c1cccc(Cl)c1
Temperature: -5 °C
Reaction time: 2 h

Procedure:
To a solution, in a 3/1 mixture of water/acetone, of 10 mmol of (±)-3-(3-chlorophenyl)-β-alanine described in Step A of Example 1 there are added 24 mmol of triethylamine and then, at −5° C., 13 mmol of phenylacetyl chloride. After stirring for 2 hours at −5° C. and then for 3 hours at ambient temperature, the solution is filtered; the acetone is evaporated off, the aqueous phase is washed with ether and is then acidified to pH=1 and extracted with ethyl acetate. The combined organic phases are dried and then evaporated. The residue obtained is washed with hexane, precipitated in a minimum of ether and then filtered to yield the expected product.
Reaction SMILES: [H-].[Na+].[CH3:3][O:4][C:5](=[O:11])[C:6]([CH3:10])([CH3:9])[CH2:7][OH:8].[CH2:12](OS(C1C=CC(C)=CC=1)(=O)=O)[CH3:13]>CN(C)C=O.O.CCCCCC>[CH3:3][O:4][C:5](=[O:11])[C:6]([CH3:10])([CH3:9])[CH2:7][O:8][CH2:12][CH3:13]
Reactant: COC(=O)C(C)(C)CO
Reactant: CCOS(=O)(=O)c1ccc(C)cc1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CCCCCC
Solvent: CN(C)C=O
Product: CCOCC(C)(C)C(=O)OC
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 34 %

Procedure:
1 mol of sodium hydride was added to the solvent dimethylformamide, and 1 mol of hydroxypivalic acid methyl ester was added thereto while the temperature of the solution did not exceed 30° C. The solution was stirred at room temperature for 90 minutes. Then, 1.2 mol of p-toluenesulfonic acid ethyl ester was added to the solution while the temperature of the solution did not exceed 30° C. Then, a water/hexane mixture having the same mass as that of the dimethylformamide was added to and mixed with the solution, after which water was removed therefrom. The resulting organic material was concentrated, and the residue was fractionated at atmospheric pressure and 108-111° C., thereby obtaining the intermediate 3-ethoxy-2,2-dimethylpropionic acid methyl ester at a yield of 34%.