Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([SiH:6]([CH2:9][CH3:10])[CH2:7][CH3:8])([CH2:4][CH3:5])([CH3:3])[CH3:2].[Mg].Cl[C:13](C)(CCC)C.Cl[SiH](Cl)Cl>>[CH2:7]([SiH:6]([CH2:9][CH3:10])[C:1]([CH3:3])([CH2:4][CH2:5][CH3:13])[CH3:2])[CH3:8]
Reactant: CCCC(C)(C)Cl
Reactant: CC[SiH](CC)C(C)(C)CC
Agent: Cl[SiH](Cl)Cl
Agent: [Mg]
Product: CCCC(C)(C)[SiH](CC)CC

Procedure:
The procedure of synthesizing Compound 34a was repeated, except that 2-methylpentan-2-ylmagnesium chloride THF solution (100 mL), which had been prepared from magnesium (2.43 g, 100 mmol) and 2-chloro-2-methylpentane (12.0 g, 99.0 mmol); trichlorosilane (9.70 mL, 96.1 mmol); and ethylmagnesium chloride THF solution (0.93M, 200 mL, 1.86 mmol) were employed, whereby the Compound 42a was obtained as a colorless liquid (boiling point; 40 mmHg, 100 to 103° C. fraction, 6.62 g, 40%).
Reaction SMILES: C[O:2][C:3]([C:5]1[C:6]([C:24]2[CH:29]=[CH:28][C:27]([C:30](O)=[O:31])=[CH:26][CH:25]=2)=[CH:7][CH:8]=[C:9]([C:11]2[S:12][CH:13]=[C:14]([C:16]3[CH:21]=[CH:20][C:19]([Cl:22])=[C:18]([Cl:23])[CH:17]=3)[N:15]=2)[CH:10]=1)=[O:4].[NH2:33][CH:34]1[CH2:38][CH2:37][O:36][CH2:35]1>>[Cl:23][C:18]1[CH:17]=[C:16]([C:14]2[N:15]=[C:11]([C:9]3[CH:10]=[C:5]([C:3]([OH:2])=[O:4])[C:6]([C:24]4[CH:29]=[CH:28][C:27]([C:30](=[O:31])[NH:33][CH:34]5[CH2:38][CH2:37][O:36][CH2:35]5)=[CH:26][CH:25]=4)=[CH:7][CH:8]=3)[S:12][CH:13]=2)[CH:21]=[CH:20][C:19]=1[Cl:22]
Reactant: NC1CCOC1
Reactant: COC(=O)c1cc(-c2nc(-c3ccc(Cl)c(Cl)c3)cs2)ccc1-c1ccc(C(=O)O)cc1
Product: O=C(NC1CCOC1)c1ccc(-c2ccc(-c3nc(-c4ccc(Cl)c(Cl)c4)cs3)cc2C(=O)O)cc1
Yield: 119.2 %

Procedure:
Using the conditions of General Procedure E for Amide Coupling in Parallel Mode, 4-[4-(3,4-dichloro-phenyl)-thiazol-2-yl]-biphenyl-2,4′-dicarboxylic acid 2-methyl ester (which may be prepared as described for Intermediate 8; 100 mg, 0.21 mmol) was reacted with 3-aminotetrahydrofuran (available from Aldrich Chemical Company, Inc.; 54 mg, 0.62 mmol). The resulting ester was hydrolyzed and the acid was purified using HPLC Purification Conditions B to give 4-[4-(3,4-dichloro-phenyl)-thiazol-2-yl]-4′-(tetrahydro-furan-3-ylcarbamoyl)-biphenyl-2-carboxylic acid (135 mg, 121%). 1H NMR (400 MHz, DMSO-d6) δ ppm 13.20 (br s, 1H), 8.62 (d, J=6.5 Hz, 1H), 8.48 (s, 1H), 8.39 (d, J=2.0 Hz, 1H), 8.34 (d, J=2.0 Hz, 1H), 8.25 (dd, J=8.0, 2.0 Hz, 1H), 8.10 (dd, J=8.5, 2.0 Hz, 1H), 7.93 (d, J=8.3 Hz, 2H), 7.77 (d, J=8.5 Hz, 1H), 7.59 (d, J=8.0 Hz, 1H), 7.48 (d, J=8.3 Hz, 2H), 4.43-4.54 (m, 1H), 3.84-3.92 (m, 2H), 3.69-3.77 (m, 1H), 3.61 (dd, J=8.9, 4.4 Hz, 1H), 2.12-2.22 (m, 1H), 1.90-2.00 (m, 1H).
Reaction SMILES: [CH2:1]([O:3][C@@H:4]([CH2:10][C:11]1[CH:16]=[CH:15][C:14]([O:17][CH2:18][CH2:19][C:20]2[CH:25]=[CH:24][C:23]([O:26][S:27]([CH3:30])(=[O:29])=[O:28])=[CH:22][CH:21]=2)=[CH:13][CH:12]=1)[C:5]([O:7]CC)=[O:6])[CH3:2].C1COCC1.O.[OH-].[Li+]>CCOC(C)=O>[CH2:1]([O:3][C@@H:4]([CH2:10][C:11]1[CH:12]=[CH:13][C:14]([O:17][CH2:18][CH2:19][C:20]2[CH:21]=[CH:22][C:23]([O:26][S:27]([CH3:30])(=[O:28])=[O:29])=[CH:24][CH:25]=2)=[CH:15][CH:16]=1)[C:5]([OH:7])=[O:6])[CH3:2]
Reactant: CCOC(=O)[C@H](Cc1ccc(OCCc2ccc(OS(C)(=O)=O)cc2)cc1)OCC
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: CCO[C@@H](Cc1ccc(OCCc2ccc(OS(C)(=O)=O)cc2)cc1)C(=O)O
Temperature: 25 °C
Reaction time: 2.5 h

Procedure:
To the oil of ethyl (S)-2-ethoxy-3-[4(2-{4-methanesulfonyloxyphenyl}ethoxy)phenyl]propanoate (723 g (71.2% assay), 1.18 mol. 1.0 eq) was added THF (3900 ml). When a homogenous solution was formed, water (900 ml) was added. The mixture was cooled to +10° C. Lithium hydroxide solution (390 ml, 4 M, 1.32 eq) was added over 1 hour. The temperature was then raised to +30° C. and the reaction allowed to proceed at this temperature for 2-3 hours. The reaction was stopped when the conversion was >99%. EtOAc (500 ml) was added and the mixture cooled to room temperature. The solution was stirred for about 30 minutes and the THF was evaporated off. When about 80-90% of the THF was evaporated, water (1900 ml) was added. The evaporation was continued until no THF remained in the mixture. The alkaline water solution was then washed with EtOAc (1000 ml, 2×1250 ml, and 950 ml). The pH of the water solution of (S)-2-ethoxy-3-[4(2-{4-methanesulfonyloxyphenyl}ethoxy)phenyl]propanoic acid was then adjusted to 2.0-2.5 with HCl (aq) (550 ml, 3.0 M). EtOAc (2500 ml) was added and the phases separated. The ethyl acetate solution of (S)-2-ethoxy-3-[4-(2-{4-methanesulfonyloxyphenyl}ethoxy)phenyl]propanoic acid was then washed with water (700 ml) and after separation evaporated to dryness. The remaining oil was then used in the following crystallisation.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]2[S:8][CH:9]=[CH:10][C:5]2=[N:4][C:3]=1[C:11]([O:13][CH2:14][CH3:15])=[O:12].C[Si]([N-][Si](C)(C)C)(C)C.[K+].[C:26]1(C)[CH:31]=CC=C[CH:27]=1.IC(C)C>C1COCC1.CCO>[CH:26]([NH:1][C:2]1[N:7]=[C:6]2[S:8][CH:9]=[CH:10][C:5]2=[N:4][C:3]=1[C:11]([O:13][CH2:14][CH3:15])=[O:12])([CH3:31])[CH3:27]
Reactant: CCOC(=O)c1nc2ccsc2nc1N
Reactant: Cc1ccccc1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [K+]
Solvent: C1CCOC1
Solvent: CCO
Solvent: CC(C)I
Product: CCOC(=O)c1nc2ccsc2nc1NC(C)C
Temperature: -78 °C
Yield: 35.3 %

Procedure:
Ethyl 3-aminothieno[2,3-b]pyrazine-2-carboxylate (0.500 g, 2.24 mmol) was dissolved in 15 ml THF under nitrogen. The solution was cooled to -78° C and dropwise treated with 4.9 ml 0.5M KHMDS in toluene (2.46 mmol). The resulting purple reaction mixture was allowed to warm to rt, treated with 2-iodopropane (0.46 s g, 2.69 mmol) and then brought to reflux for 48h. After the addition of 1 ml EtOH, the reaction mixture was concentrated and applied directly to a silica gel column. Elution with a solvent gradient from 10:1 to 4:1 hexanes: ethyl acetate gave the title compound (0.210 g, 35%). 1H NMR (300 MHz, CDCl3) δ1.30 (d, 6H), 1.40 (t, 3H), 4.37 (q, 2H), 5.27 (dh, 1H), 7.42 (br d, 1H), 8.55 (d, 1H), 8.58 (d, 1H). MS (DCI/NH3) m/e 266 (M+H).
Reaction SMILES: [C:1]([C:5]1[CH:49]=[CH:48][C:8]([C:9]([NH:11][C:12]2[CH:28]=[C:27]([NH:29][C:30](=[O:47])[C@H:31]([CH2:40][C:41]3[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=3)[NH:32]C(OC(C)(C)C)=O)[CH:26]=[CH:25][C:13]=2[C:14]([NH:16][C:17]2[CH:22]=[CH:21][C:20]([O:23][CH3:24])=[CH:19][CH:18]=2)=[O:15])=[O:10])=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2].[F:50][C:51]([F:56])([F:55])[C:52]([OH:54])=[O:53]>C(Cl)Cl>[F:50][C:51]([F:56])([F:55])[C:52]([OH:54])=[O:53].[C:1]([C:5]1[CH:6]=[CH:7][C:8]([C:9]([NH:11][C:12]2[CH:28]=[C:27]([NH:29][C:30](=[O:47])[C@H:31]([CH2:40][C:41]3[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=3)[NH2:32])[CH:26]=[CH:25][C:13]=2[C:14]([NH:16][C:17]2[CH:22]=[CH:21][C:20]([O:23][CH3:24])=[CH:19][CH:18]=2)=[O:15])=[O:10])=[CH:48][CH:49]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: COc1ccc(NC(=O)c2ccc(NC(=O)[C@H](Cc3ccccc3)NC(=O)OC(C)(C)C)cc2NC(=O)c2ccc(C(C)(C)C)cc2)cc1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: COc1ccc(NC(=O)c2ccc(NC(=O)[C@@H](N)Cc3ccccc3)cc2NC(=O)c2ccc(C(C)(C)C)cc2)cc1
Reaction time: 1.5 h
Yield: 124.8 %

Procedure:
To a solution of 2-(4-tert-butylbenzoylamino)-4-[[N-(tert-butyloxycarbonyl)-L-phenylalanyl]amino]-N-(4-methoxyphenyl)benzamide (112 mg, 0.17 mmol) in methylene chloride (5 mL) was added trifluoroacetic acid (0.065 mL, 0.84 mmol). After 1.5 h, an additional portion of trifluoroacetic acid (0.50 mL, 6.5 mmol) was added and the resulting mixture stirred for 1 h. The mixture was concentrated in vacuo to give 144 mg (100%) of the title compound as a tan solid.
Reaction SMILES: [NH2:1][C:2]1[C:3]([C:9]([OH:11])=O)=[N:4][C:5]([I:8])=[CH:6][N:7]=1.C1CN([P+](ON2N=NC3C=CC=CC2=3)(N2CCCC2)N2CCCC2)CC1.F[P-](F)(F)(F)(F)F.Cl.[CH3:46][NH:47][O:48][CH3:49]>CN(C=O)C.C(N(CC)C(C)C)(C)C>[CH3:49][O:48][N:47]([CH3:46])[C:9]([C:3]1[C:2]([NH2:1])=[N:7][CH:6]=[C:5]([I:8])[N:4]=1)=[O:11]
Reactant: Nc1ncc(I)nc1C(=O)O
Reactant: CNOC
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Agent: c1ccc2c(c1)nnn2O[P+](N1CCCC1)(N1CCCC1)N1CCCC1
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CON(C)C(=O)c1nc(I)cnc1N
Temperature: 80 °C
Yield: 57.4 %

Procedure:
27.50 g (0.104 mol) of 3-amino-6-iodo-pyrazine-2-carboxylic acid, 63.0 g (0.125 mol) of PyBOP (1-benzotriazolyloxy-tris(pyrrolidino)phosphonium hexafluorophosphate) and 18.70 g (0.193 mol) of N,O-dimethylhydroxylamine hydrochloride were placed in a nitrogen flushed flask and then dissolved in a mixture of 100 ml of anhydrous DMF and 27 ml of N,N-di-iso-propylethylamine. The mixture was heated to 80° C. for 16 hours. The solvent was evaporated at 50-60° C. under reduced pressure to afford a dark oil. The oil was extracted three to four times with 300 ml of toluene. The toluene phases were combined and evaporated. The resulting oil was purified via chromatography on silica gel using a gradient of ethyl acetate in hexanes to afford 18.40 g (59.72 mmol; 58%) of 3-amino-6-iodo-pyrazine-2-carboxylic acid methoxy-methyl-amide as a yellow solid. 1H-NMR (d6-DMSO) δ: 8.28 [1H] s, 6.78 [2H] s, 3.66 [3H] s, 3.25 [3H] s. MS: m/z 309 [MH+].
Reaction SMILES: BrC1C=CC(O)=C(C2C=[CH:16][C:15]3[C:10](=[CH:11][CH:12]=[C:13]([C:18]4[N:22]([CH:23]5[CH2:28][CH2:27][CH2:26][CH2:25][CH2:24]5)[C:21]5[CH:29]=[CH:30][C:31]([C:33]([OH:35])=[O:34])=[CH:32][C:20]=5[N:19]=4)[CH:14]=3)[N:9]=2)C=1.[OH:37][C:38]1[C:46]2[O:45][C:44]([C:47](=O)[CH3:48])=[CH:43][C:42]=2[CH:41]=[CH:40][CH:39]=1.[OH-].[K+]>C(O)C>[CH:23]1([N:22]2[C:21]3[CH:29]=[CH:30][C:31]([C:33]([OH:35])=[O:34])=[CH:32][C:20]=3[N:19]=[C:18]2[C:13]2[CH:14]=[C:15]3[C:10](=[CH:11][CH:12]=2)[N:9]=[C:47]([C:44]2[O:45][C:46]4[C:38]([OH:37])=[CH:39][CH:40]=[CH:41][C:42]=4[CH:43]=2)[CH:48]=[CH:16]3)[CH2:24][CH2:25][CH2:26][CH2:27][CH2:28]1
Reactant: CC(=O)c1cc2cccc(O)c2o1
Reactant: O=C(O)c1ccc2c(c1)nc(-c1ccc3nc(-c4cc(Br)ccc4O)ccc3c1)n2C1CCCCC1
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Product: O=C(O)c1ccc2c(c1)nc(-c1ccc3nc(-c4cc5cccc(O)c5o4)ccc3c1)n2C1CCCCC1
Yield: 20 %

Procedure:
Following the procedure and workup for Compound 354, Compound 354e (100 mg, 0.256 mmol) was reacted with 1-(7-hydroxy-benzofuran-2-yl)-ethanone (0.256 mmol) in ethanol (2 mL) using 10% w/v KOH in ethanol (506 μL, 0.64 mmol) to produce the title compound (19 mg, 20% yield). MS: 504.22 (M+H+); HPLC Procedure A, retention time=12.20 min.
Reaction SMILES: [CH3:1][Si](C=[N+]=[N-])(C)C.CCCCCC.[OH:14][CH2:15][C:16]([NH:19][C:20](=[O:29])[C:21]1[CH:26]=[CH:25][C:24]([F:27])=[CH:23][C:22]=1[F:28])([CH3:18])[CH3:17].B(F)(F)F.CCOCC.Cl>C(Cl)Cl>[CH3:1][O:14][CH2:15][C:16]([NH:19][C:20](=[O:29])[C:21]1[CH:26]=[CH:25][C:24]([F:27])=[CH:23][C:22]=1[F:28])([CH3:18])[CH3:17]
Reactant: C[Si](C)(C)C=[N+]=[N-]
Reactant: CC(C)(CO)NC(=O)c1ccc(F)cc1F
Agent: Cl
Agent: FB(F)F
Solvent: CCOCC
Solvent: ClCCl
Solvent: CCCCCC
Product: COCC(C)(C)NC(=O)c1ccc(F)cc1F
Temperature: 25 °C
Reaction time: 8 h
Yield: 60 %

Procedure:
A solution of 2M trimethylsilyldiazomethane in hexane (3.9 ml, 7.8 mmol) was added dropwise to a solution of N-(2-hydroxy-1,1-dimethylethyl)-2,4-difluorobenzamide obtained in Example 27 (0.59 g, 2.6 mmol) and boron trifluoride diethyl etherate (43 mg, 0.3 mmol) in methylene chloride (6 ml), and stirred at room temperature overnight. To the reaction mixture was added 1N hydrochloric acid (5 ml) dropwise, and the resulting mixture was concentrated and extracted with ethyl acetate. The extract was washed with brine, dried over MgSO4 and concentrated under a reduced pressure. The residue was purified by silica gel column chromatography (hexane/ethyl acetate=10/1) to give the title compound (0.38 g; 60%).
Reaction SMILES: [CH2:1]([C@H:8]1[CH2:12][O:11][C:10](=[O:13])[N:9]1[C:14]1[CH:23]=[CH:22][C:17]([C:18](OC)=[O:19])=[CH:16][CH:15]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:24][C:25]1[CH:30]=[C:29]([CH3:31])[CH:28]=[CH:27][C:26]=1[N:32]1[CH2:37][CH2:36][NH:35][CH2:34][CH2:33]1>>[CH2:1]([C@H:8]1[CH2:12][O:11][C:10](=[O:13])[N:9]1[C:14]1[CH:15]=[CH:16][C:17]([C:18]([N:35]2[CH2:36][CH2:37][N:32]([C:26]3[CH:27]=[CH:28][C:29]([CH3:31])=[CH:30][C:25]=3[CH3:24])[CH2:33][CH2:34]2)=[O:19])=[CH:22][CH:23]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: Cc1ccc(N2CCNCC2)c(C)c1
Reactant: COC(=O)c1ccc(N2C(=O)OC[C@@H]2Cc2ccccc2)cc1
Product: Cc1ccc(N2CCN(C(=O)c3ccc(N4C(=O)OC[C@@H]4Cc4ccccc4)cc3)CC2)c(C)c1
Yield: 47.5 %

Procedure:
By reaction and treatment in the same manner as in Example 34 and using methyl (S)-4-(4-benzyl-2-oxooxazolidin-3-yl)benzoate (142 mg) described in Preparation Example 197 and 1-(2,4-dimethylphenyl)piperazine (87 mg), the title compound (101.8 mg) was obtained.
Reaction SMILES: [CH3:1][NH:2][CH2:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.[NH2:10][C:11](N)=[O:12]>>[CH3:1][N:2]([CH2:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1)[C:11]([NH2:10])=[O:12]
Reactant: NC(N)=O
Reactant: CNCc1ccccc1
Product: CN(Cc1ccccc1)C(N)=O
Temperature: 118 °C
Reaction time: 4 h
Yield: 74.9 %

Procedure:
To N-methylbenzylamine (12.1 g, 0.1 mol) was added urea (6.0 g, 0.1 mol). After stirred at 118° C. for 4 h, the mixture was cooled to room temperature. The solidified mixture was ground to a powder, washed with n-hexane and recrystallized with ethyl acetate to afford N-methyl-N-benzylurea (12.3 g, 75% yield): mp 125°-129° C.
Reaction SMILES: [NH2:1][CH:2]([C:11]1[C:16]([O:17][CH3:18])=[CH:15][CH:14]=[CH:13][C:12]=1[O:19][CH3:20])[CH2:3][CH:4]([CH3:10])[C:5]([O:7]CC)=O.[CH:21]1[C:29]2[C:28]3[CH:30]=[CH:31][CH:32]=[CH:33][C:27]=3[O:26][C:25]=2[CH:24]=[CH:23][C:22]=1[CH:34]=O>>[CH:21]1[C:29]2[C:28]3[CH:30]=[CH:31][CH:32]=[CH:33][C:27]=3[O:26][C:25]=2[CH:24]=[CH:23][C:22]=1[CH2:34][N:1]1[CH:2]([C:11]2[C:12]([O:19][CH3:20])=[CH:13][CH:14]=[CH:15][C:16]=2[O:17][CH3:18])[CH2:3][CH:4]([CH3:10])[C:5]1=[O:7]
Reactant: O=Cc1ccc2oc3ccccc3c2c1
Reactant: CCOC(=O)C(C)CC(N)c1c(OC)cccc1OC
Product: COc1cccc(OC)c1C1CC(C)C(=O)N1Cc1ccc2oc3ccccc3c2c1

Procedure:
Prepared according to the described general procedure 2 (GP2) by reaction of ethyl 4-amino-4-(2,6-dimethoxyphenyl)-2-methylbutanoate with commercially available dibenzo[b,d]furan-2-carbaldehyde. Subsequent purification by preparative HPLC afforded the target compound. LC-MS (conditions A): tR=0.96 min.; [M+H]+: 416.03 g/mol.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH2:8][C:9]([CH3:20])([CH3:19])[CH2:10][NH:11]C(=O)OC(C)(C)C)[CH:5]=[CH:6][CH:7]=1.[ClH:21].CCOC(C)=O>CCOC(C)=O>[ClH:21].[Br:1][C:2]1[CH:3]=[C:4]([CH2:8][C:9]([CH3:20])([CH3:19])[CH2:10][NH2:11])[CH:5]=[CH:6][CH:7]=1
Reactant: CC(C)(CNC(=O)OC(C)(C)C)Cc1cccc(Br)c1
Agent: Cl
Solvent: CCOC(C)=O
Product: CC(C)(CN)Cc1cccc(Br)c1
Temperature: 25 °C
Reaction time: 2.5 h

Procedure:
tert-Butyl 3-(3-bromophenyl)-2,2-dimethylpropylcarbamate (72) (3.2 g, 9.35 mmol) was dissolved in EtOAc (55 mL), and a solution of HCl-EtOAc (˜4.2 M, 20 mL, 84 mmol) was added. The reaction was vented with a needle and stirred at room temperature for 2.5 h. The reaction was then diluted with hexanes and the white solid was collected on a fritted glass funnel The mother liquor was concentrated under reduced pressure, suspended in ˜5-10% EtOAc-hexanes, and the white solid was collected and combined with the first batch. The solid was dried in a vacuum oven at room temperature overnight to give pure 3-(3-bromophenyl)-2,2-dimethylpropan-1-amine hydrochloride as a white solid. Yield (1.52 g): 1H NMR (400 MHz, CDCl3) δ 8.53 (br s, 2H), 7.37 (dq, J=1.2 and 8.0 Hz, 1H), 7.31 (t, J=1.6 Hz, 1H), 7.13 (t, J=7.7 Hz, 1H), 7.08 (dt, J=8.0, 1.6 Hz, 1H), 2.83-2.84 (m, 2H), 2.67 (s, 2H), 1.09 (s, 6H).
Reaction SMILES: [CH:1]([C:3]1([C:12](Cl)=[O:13])[CH2:11][C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH2:4]1)=[CH2:2].[CH2:15](OC(=O)CC(O)=O)C.C(O[Mg])C.S(=O)(=O)(O)O>C(OCCCC)CCC>[CH:1]([C:3]1([C:12](=[O:13])[CH3:15])[CH2:11][C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH2:4]1)=[CH2:2]
Reactant: CCOC(=O)CC(=O)O
Reactant: C=CC1(C(=O)Cl)Cc2ccccc2C1
Agent: CCO[Mg]
Agent: O=S(=O)(O)O
Solvent: CCCCOCCCC
Product: C=CC1(C(C)=O)Cc2ccccc2C1

Procedure:
1-(2,3-Dihydro-2-vinyl-1H-inden-2-yl)-ethanone was prepared by treating 2,3-dihydro-2-vinyl-1H-indene-2-carboxylic acid chloride with ethoxy magnesium malonic acid ethyl ester in dibutylether and after that with sulfuric acid according to the method of Reynolds, G. A. and Hauser, C. B., Org. Synth. 30 (1957) 70.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:12]([C:13]3[CH:18]=[CH:17][C:16]([N+:19]([O-])=O)=[CH:15][CH:14]=3)=[CH:11][CH:10]=[C:9]2[C:22]2[CH:27]=[CH:26][C:25]([N+:28]([O-])=O)=[CH:24][CH:23]=2)=[CH:4][CH:3]=1.[Cl-].[NH4+].O>C(O)C.C1COCC1.[Fe]>[F:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:9]([C:22]3[CH:27]=[CH:26][C:25]([NH2:28])=[CH:24][CH:23]=3)=[CH:10][CH:11]=[C:12]2[C:13]2[CH:18]=[CH:17][C:16]([NH2:19])=[CH:15][CH:14]=2)=[CH:4][CH:3]=1
Reactant: O=[N+]([O-])c1ccc(-c2ccc(-c3ccc([N+](=O)[O-])cc3)n2-c2ccc(F)cc2)cc1
Agent: [Fe]
Agent: [Cl-]
Agent: [NH4+]
Solvent: O
Solvent: CCO
Solvent: C1CCOC1
Product: Nc1ccc(-c2ccc(-c3ccc(N)cc3)n2-c2ccc(F)cc2)cc1
Yield: 127.2 %

Procedure:
To a solution of example 19A (1.017 g, 2.496 mmol) in ethanol (15 mL) and THF (15 mL) was added iron powder (0.836 g, 14.98 mmol) followed by ammonium chloride (0.401 g, 7.49 mmol) and water (3.75 mL). Reaction mixture was refluxed for 45 minutes. Slurry filtered through celite, washed with ethanol, combined filtrate was concentrated and the residue purified by column chromatography (gradient elution from 30% to 50% EtOAc:hexanes) to provide 1.09 g (77%) of the title compound.
Reaction SMILES: [Cl:1][C:2]1[CH:15]=[C:14]([F:16])[C:13]([N:17]2[C:22](=[O:23])[CH:21]=[C:20]([C:24]([F:27])([F:26])[F:25])[N:19]([CH3:28])[C:18]2=[O:29])=[CH:12][C:3]=1[O:4][C:5]1[C:6]([OH:11])=[N:7][NH:8][C:9]=1[CH3:10].[C:30]([O:35][CH3:36])(=[O:34])[C@@H:31]([CH3:33])O.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OC(C)C)=O)=NC(OC(C)C)=O>C(OCC)(=O)C.C1(C)C=CC=CC=1.CCCCCC>[CH3:36][O:35][C:30]([C@@H:31]([O:11][C:6]1[C:5]([O:4][C:3]2[CH:12]=[C:13]([N:17]3[C:22](=[O:23])[CH:21]=[C:20]([C:24]([F:26])([F:27])[F:25])[N:19]([CH3:28])[C:18]3=[O:29])[C:14]([F:16])=[CH:15][C:2]=2[Cl:1])=[C:9]([CH3:10])[NH:8][N:7]=1)[CH3:33])=[O:34]
Reactant: Cc1[nH]nc(O)c1Oc1cc(-n2c(=O)cc(C(F)(F)F)n(C)c2=O)c(F)cc1Cl
Reactant: COC(=O)[C@@H](C)O
Agent: CC(C)OC(=O)N=NC(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: Cc1ccccc1
Solvent: CCCCCC
Solvent: CCOC(C)=O
Product: COC(=O)[C@H](C)Oc1n[nH]c(C)c1Oc1cc(-n2c(=O)cc(C(F)(F)F)n(C)c2=O)c(F)cc1Cl
Temperature: 25 °C
Reaction time: 3 h
Yield: 51.4 %

Procedure:
To a solution of 0.13 g of 4-{2-chloro-4-fluoro-5-[3-methyl-2,6-dioxo-4-(trifluoromethyl)-1,2,3,6-tetrahydropyrimidin-1-yl]phenoxy}-3-hydroxy-5-methylpyrazole in 2.0 ml of ethyl acetate were added 0.10 g of (R)-(+)-methyl lactate, 0.26 g of triphenylphosphine and 0.5 ml of a 40% solution of diisopropyl azodicarboxylate in toluene, and the mixture was stirred for 3 hours at room temperature. 6 ml of n-hexane was poured into this reaction solution, and the precipitated insoluble substance was filtrated off. This solution was subjected to silica gel column chromatography to obtain 0.08 g of (S)-3-{1-(methoxycarbonyl)ethoxy}-4-{2-chloro-4-fluoro-5-[3-methyl-2,6-dioxo-4-(trifluoromethyl)-1,2,3,6-tetrahydropyrimidin-1-yl]phenoxy}-5-methylpyrazole [S optical isomer of present compound 5-12, hereinafter, represented as 5-12-S].
Reaction SMILES: [N+](=[C:3]([C:17](=[O:28])[C@@H:18]([C@@H:20]1[C@@H:23]([C@H:24]([OH:26])[CH3:25])[C:22](=[O:27])[NH:21]1)[CH3:19])[C:4]([O:6][CH2:7][C:8]1[CH:13]=[CH:12][C:11]([N+:14]([O-:16])=[O:15])=[CH:10][CH:9]=1)=[O:5])=[N-]>ClC(Cl)C.C1C=CC=CC=1.C([O-])(=O)C.[Rh+2].C([O-])(=O)C>[OH:26][C@@H:24]([C@H:23]1[C:22](=[O:27])[N:21]2[C@@H:20]1[C@@H:18]([CH3:19])[C:17](=[O:28])[CH:3]2[C:4]([O:6][CH2:7][C:8]1[CH:13]=[CH:12][C:11]([N+:14]([O-:16])=[O:15])=[CH:10][CH:9]=1)=[O:5])[CH3:25]
Reactant: C[C@@H](O)[C@H]1C(=O)N[C@@H]1[C@@H](C)C(=O)C(=[N+]=[N-])C(=O)OCc1ccc([N+](=O)[O-])cc1
Agent: [Rh+2]
Agent: CC(=O)[O-]
Solvent: c1ccccc1
Solvent: CC(Cl)Cl
Product: C[C@@H](O)[C@H]1C(=O)N2C(C(=O)OCc3ccc([N+](=O)[O-])cc3)C(=O)[C@H](C)[C@H]12

Procedure:
To a solution of 4-nitrobenzyl (4R)-2-diazo-4-[(2R, 3S)-3-{(1R)-1-hydroxyethyl}-4-oxoazetidin-2-yl]-3-oxopentanoate (1.0 g) in dichloroethane (50 ml) was added rhodium (II) acetate (2 mg) under refluxing. After refluxing for 1 hour, the reaction mixture was evaporated in vacuo to give a residue. The residue was dissolved in anhydrous benzene (10 ml) and then evaporated. This operation was repeated once again to give 4-nitrobenzyl (4R,5R,6S)-6-[(1R)-1-hydroxyethyl]-4-methyl-3,7-dioxo-1-azabicyclo[3.2.0]heptane-2-carboxylate. The compound obtained above was dissolved in anhydrous acetonitrile (20 ml) and cooled to 0° C. under an atmosphere of nitrogen. To this solution were added N,N-diisopropyl-N-ethylamine (0.59 ml) and diphenyl phosphorochloridate (0.61 ml) successively, and the solution was stirred at 0°-5° C. for 40 minutes. To the resulting solution were added a solution of (2S,4S)-2-(2-aminothiazol-4-yl)-4-mercapto-1-(4-nitrobenzyloxycarbonyl)pyrrolidine (1.07 g) in acetonitrile and N,N-diisopropyl-N-ethylamine (0.59 ml) and the stirring was continued at the same temperature for 2 hours. The reaction mixture was poured into ethyl acetate (60 ml) and washed with 0.1N hydrochloric acid, saturated aqueous sodium bicarbonate and brine successively. The dried organic layer was evaporated and the oily residue was chromatographed on silica gel (60 g) eluting with a mixture of dichloromethane and acetone (5:2 V/V) to give 4-nitrobenzyl (4R,5S,6S)-3-[(2S,4S)-2-(2-aminothiazol-4-yl)-1-(4-nitrobenzyloxycarbonyl)pyrrolidin-4-ylthio]-6-[(1R)-1-hydroxyethyl]-4-methyl-7-oxo-1-azabicyclo[3.2.0]hept-2-ene-2-carboxylate (900 mg).
Reaction SMILES: Br[CH2:2][C:3]1[CH:19]=[CH:18][C:6]2[S:7][CH:8]=[C:9]([C:10](=[CH:15][O:16][CH3:17])[C:11]([O:13][CH3:14])=[O:12])[C:5]=2[CH:4]=1.[C:20]1([OH:26])[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1.C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O>[O:26]([CH2:2][C:3]1[CH:19]=[CH:18][C:6]2[S:7][CH:8]=[C:9]([C:10](=[CH:15][O:16][CH3:17])[C:11]([O:13][CH3:14])=[O:12])[C:5]=2[CH:4]=1)[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1
Reactant: Oc1ccccc1
Reactant: COC=C(C(=O)OC)c1csc2ccc(CBr)cc12
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: COC=C(C(=O)OC)c1csc2ccc(COc3ccccc3)cc12
Temperature: 50 °C

Procedure:
A mixture of 1 g of methyl α-(5-bromomethyl-3-benzo[b]-thienyl)-β-methoxyacrylate (see Example 11 ), 0.28 g of phenol and 2 g of potassium carbonate in 20 ml of dimethylformamide is heated for 2 hours at 50° C. The mixture is cooled to room temperature and filtered, and the filtrate is then concentrated under reduced pressure, and the crude product is purified by chromatography on silica gel using diethyl ether/n-hexane (1:1). Recrystallization from methylene chloride/n-hexane gives methyl α-(5-phenoxymethyl-3-benzo[b]thienyl)-β-methoxyacrylate as colourless crystals, m.p. 130° C.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[CH:6][C:5]([C:8]2[O:12][C:11]([C:13]([O:15]C)=O)=[N:10][N:9]=2)=[C:4]([NH:17][CH:18]([CH3:20])[CH3:19])[CH:3]=1.[NH:21]1[CH2:26][CH2:25][O:24][CH2:23][CH2:22]1>CO>[Cl:1][C:2]1[N:7]=[CH:6][C:5]([C:8]2[O:12][C:11]([C:13]([N:21]3[CH2:26][CH2:25][O:24][CH2:23][CH2:22]3)=[O:15])=[N:10][N:9]=2)=[C:4]([NH:17][CH:18]([CH3:20])[CH3:19])[CH:3]=1
Reactant: COC(=O)c1nnc(-c2cnc(Cl)cc2NC(C)C)o1
Reactant: C1COCCN1
Solvent: CO
Product: CC(C)Nc1cc(Cl)ncc1-c1nnc(C(=O)N2CCOCC2)o1

Procedure:
A solution of methyl 5-(6-chloro-4-(isopropylamino)pyridin-3-yl)-1,3,4-oxadiazole-2-carboxylate (66) (150 mg, 0.51 mmol) in morpholine (1 mL) and MeOH (1 mL) was heated at 80° C. for 2 h. The reaction mass was concentrated under reduced pressure. The crude material obtained was triturated with diethyl ether and filtered to get the desired compound, (5-(6-chloro-4-(isopropylamino)pyridin-3-yl)-1,3,4-oxadiazol-2-yl)(morpholino)methanone. LC/MS: Acquity BEH C18 2.1×50 mm, 1.8 micron; Solvent A=0.1% TFA in water; Solvent B=0.1% TFA in ACN; gradient 0-100% B over 2 min; retention time: 0.88 min; LCMS (ES-API), m/z 352.7 (M+H).