Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([CH:4]([S:8]([CH2:11][C@@H:12]([C:14]([OH:16])=[O:15])[NH2:13])(=[O:10])=[O:9])[CH2:5][CH2:6][CH3:7])[CH2:2][CH3:3].[C:17](NC(=O)CCC(N)=O)([O:19][CH2:20][C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)=[O:18]>C(Cl)Cl>[CH2:20]([O:19][C:17]([NH:13][C@H:12]([C:14]([OH:16])=[O:15])[CH2:11][S:8]([CH:4]([CH2:5][CH2:6][CH3:7])[CH2:1][CH2:2][CH3:3])(=[O:9])=[O:10])=[O:18])[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1
Reactant: CCCC(CCC)S(=O)(=O)C[C@H](N)C(=O)O
Reactant: NC(=O)CCC(=O)NC(=O)OCc1ccccc1
Solvent: ClCCl
Product: CCCC(CCC)S(=O)(=O)C[C@H](NC(=O)OCc1ccccc1)C(=O)O
Temperature: 0 °C
Reaction time: 4 h
Yield: 109.5 %

Procedure:
A 250 ml round bottom flask equipped with magnetic stir bar and N2 inlet was charged with 7.8 g (27 mmole) 3-[(1-propylbutyl)sulfonyl]alanine and 7.4 g (30 mmole) N-Cbz succinamide in 100 ml methylene chloride. The reaction was cooled to 0° C., and 6.9 g NMK was added dropwise. The reaction was allowed to warm to room temperature and stirred for 4 hours at which point HPLC analysis indicated complete reaction. The reaction was concentrated in vacuo and partitioned between ethyl acetate and 1 N HCl. The organic layer was washed with water, brine, dried over sodium sulfate, and concentrated in vacuo to give 11.4 g of N-[(benzyloxy)carbonyl]-3-[(1-propylbutyl)sulfonyl]alanine that was used without further purification. M+H=386.
Reaction SMILES: [F:1][C:2]1[C:7]([CH:8]=[O:9])=[C:6]([I:10])[CH:5]=[CH:4][N:3]=1.[CH2:11](O)[CH2:12][OH:13].C1(C)C=CC(S(O)(=O)=O)=CC=1>C1(C)C=CC=CC=1>[O:9]1[CH2:11][CH2:12][O:13][CH:8]1[C:7]1[C:2]([F:1])=[N:3][CH:4]=[CH:5][C:6]=1[I:10]
Reactant: OCCO
Reactant: O=Cc1c(I)ccnc1F
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: Cc1ccccc1
Product: Fc1nccc(I)c1C1OCCO1
Temperature: 25 °C

Procedure:
In a three-necked flask equipped with a Dean Stark apparatus, a mixture of 5.1 g (20.3 mmol) of 2-fluoro-4-iodo-3-pyridinecarbaldehyde, 1.4 g (22.3 mmol) of ethane-1,2-diol, and 50 mg of para-toluenesulphonic acid in 100 ml of toluene is heated at reflux. When the theoretical amount of water has been collected, the reaction mixture is cooled to room temperature, washed with a saturated sodium hydrogen carbonate solution and dried over magnesium sulphate. The expected product is obtained by concentration.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([N:11]([CH2:16][C@H:17]2[O:21][C:20]([CH3:23])([CH3:22])[N:19]([C:24]([O:26][C@H:27]3[C@H:34]4[C@H:30]([O:31][CH2:32][CH2:33]4)[O:29][CH2:28]3)=[O:25])[C@H:18]2[CH2:35][C:36]2[CH:41]=[CH:40][C:39]([OH:42])=[CH:38][CH:37]=2)[CH2:12][CH:13]([CH3:15])[CH3:14])(=[O:10])=[O:9])=[CH:4][CH:3]=1.C(=O)([O-])[O-].[Cs+].[Cs+].Br[CH2:50][C:51]1[CH:52]=[C:53]([CH:56]=[CH:57][CH:58]=1)[C:54]#[N:55].CCOCC>CN(C)C=O>[NH2:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([N:11]([CH2:16][C@H:17]2[O:21][C:20]([CH3:22])([CH3:23])[N:19]([C:24]([O:26][C@H:27]3[C@H:34]4[C@H:30]([O:31][CH2:32][CH2:33]4)[O:29][CH2:28]3)=[O:25])[C@H:18]2[CH2:35][C:36]2[CH:37]=[CH:38][C:39]([O:42][CH2:50][C:51]3[CH:58]=[CH:57][CH:56]=[C:53]([C:54]#[N:55])[CH:52]=3)=[CH:40][CH:41]=2)[CH2:12][CH:13]([CH3:15])[CH3:14])(=[O:9])=[O:10])=[CH:4][CH:3]=1
Reactant: N#Cc1cccc(CBr)c1
Reactant: CC(C)CN(C[C@H]1OC(C)(C)N(C(=O)O[C@@H]2CO[C@H]3OCC[C@H]32)[C@H]1Cc1ccc(O)cc1)S(=O)(=O)c1ccc(N)cc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CCOCC
Solvent: CN(C)C=O
Product: CC(C)CN(C[C@H]1OC(C)(C)N(C(=O)O[C@@H]2CO[C@H]3OCC[C@H]32)[C@H]1Cc1ccc(OCc2cccc(C#N)c2)cc1)S(=O)(=O)c1ccc(N)cc1
Temperature: 25 °C
Reaction time: 12 h
Yield: 81.5 %

Procedure:
To a stirred mixture of (3S,3aS,6aR)-hexahydrofuro[2,3-b]furan-3-yl (4S,5R)-5-{[[(4-aminophenyl)sulfonyl](isobutyl)amino]methyl}-4-(4-hydroxybenzyl)-2,2-dimethyl-1,3-oxazolidine-3-carboxylate (40 mg, 0.07 mmol) and cesium carbonate (22 mg, 0.07 mmol) in 1.5 mL of N,N-dimethylformamide was added 3-bromomethylbenzonitrile (13 mg, 0.07 mmol). The mixture was stirred at room temperature for 12 hours followed by dilution with 25 mL of ether. The ether was extracted with water (5×15 mL). The organic phase was dried with magnesium sulfate, filtered, and concentrated under reduced pressure. The residue was purified on silica gel using ethyl acetate-hexanes (8.5:1.5) as eluent to provide 41 mg (85%) of the title compound. 1H-NMR (DMSO-d6): δ 0.80-0.86 (6H,dd), 1.37 (3H,s), 1.48,1.55 (3H,s)*, 1.75 (2H,m), 1.94 (1H,m), 2.58-2.78 (6H,m), 2.92-3.09 (2H,m), 3.15-3.21 (1H,m), 3.61 (2H,m), 3.81 (1H,m), 4.14 (1H,m), 4.74 (1H,q), 5.17 (2H,s), 5.53,5.57 (1H,d)*, 5.99 (2H,s,b), 6.58 (2H,d), 6.95 (2H,d), 7.11,7.14 (2H,d)*, 7.22,7.28 (2H,d)*, 7.60 (1H,t), 7.80 (2H,m,b), 7.91 (1H,s).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]([CH3:34])[CH2:9][CH2:10][N:11]1[C:15]2[CH:16]=[CH:17][C:18]([C:20](O)=[O:21])=[CH:19][C:14]=2[N:13]=[C:12]1[NH:23][C:24]1[S:25][C:26]2[CH:32]=[C:31]([Cl:33])[CH:30]=[CH:29][C:27]=2[N:28]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[NH2:35][CH2:36][CH2:37][O:38][CH2:39][CH2:40][OH:41].CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C>CN(C=O)C>[C:1]([O:5][C:6](=[O:7])[N:8]([CH2:9][CH2:10][N:11]1[C:15]2[CH:16]=[CH:17][C:18]([C:20](=[O:21])[NH:35][CH2:36][CH2:37][O:38][CH2:39][CH2:40][OH:41])=[CH:19][C:14]=2[N:13]=[C:12]1[NH:23][C:24]1[S:25][C:26]2[CH:32]=[C:31]([Cl:33])[CH:30]=[CH:29][C:27]=2[N:28]=1)[CH3:34])([CH3:2])([CH3:4])[CH3:3]
Reactant: NCCOCCO
Reactant: CN(CCn1c(Nc2nc3ccc(Cl)cc3s2)nc2cc(C(=O)O)ccc21)C(=O)OC(C)(C)C
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CN(CCn1c(Nc2nc3ccc(Cl)cc3s2)nc2cc(C(=O)NCCOCCO)ccc21)C(=O)OC(C)(C)C
Yield: 42.9 %

Procedure:
(2-{2-(6-Chloro-benzothiazol-2-ylamino)-5-[2-(2-hydroxy-ethoxy)-ethylcarbamoyl]-benzoimidazol-1-yl}-ethyl)-methyl-carbamic acid tert-butyl ester (73 mg) was prepared by following General Procedure F starting from 1-[2-(tert-butoxycarbonyl-methyl-amino)-ethyl]-2-(6-chloro-benzothiazol-2-ylamino)-1H-benzoimidazole-5-carboxylic acid (145 mg), 2-(2-amino-ethoxy)-ethanol (35 mg), HBTU (125 mg), and DIEA (100 uL) in DMF (1 mL).
Reaction SMILES: [C:1]([NH:5][C:6](=[O:29])[CH2:7][N:8]1[C:14]2[CH:15]=[CH:16][CH:17]=[CH:18][C:13]=2[CH:12]([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[CH2:11][CH:10]([N:25]=[N+]=[N-])[C:9]1=[O:28])([CH3:4])([CH3:3])[CH3:2]>C(O)C.[Pd]>[C:1]([NH:5][C:6](=[O:29])[CH2:7][N:8]1[C:14]2[CH:15]=[CH:16][CH:17]=[CH:18][C:13]=2[CH:12]([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[CH2:11][CH:10]([NH2:25])[C:9]1=[O:28])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)NC(=O)CN1C(=O)C(N=[N+]=[N-])CC(c2ccccc2)c2ccccc21
Agent: [Pd]
Solvent: CCO
Product: CC(C)(C)NC(=O)CN1C(=O)C(N)CC(c2ccccc2)c2ccccc21

Procedure:
A solution of 5.80 grams (14.3 retool) N-tert-butyl-2-(3-azido-2-oxo-5-phenyl-2,3,4,5-tetrahydro-1H-(1)benzazepin-1-yl) ethanoic acid amide in 70 mL ethanol (with methylene chloride as necessary to aid dissolution) was treated with 600 mg 10% palladium on carbon under hydrogen (42 to 39 psi) for 20.5 hours. The reaction was filtered through Celite® with ethanol and methylene chloride and evaporated to a foam, 5.44 grams (100%).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:12]([C:13]3[CH:18]=[CH:17][C:16]([O:19][CH3:20])=[C:15]([O:21][C@@H:22]4[CH2:26][CH2:25][O:24][CH2:23]4)[CH:14]=3)=[CH:11][CH:10]=[N:9]2)=[CH:4][CH:3]=1.C(=O)([O-])[O-].[Na+].[Na+].COCCOC.[CH3:39][O:40][C:41]1[CH:46]=[CH:45][C:44](B(O)O)=[CH:43][N:42]=1>Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.C(OCC)(=O)C.O.C(O)C>[CH3:39][O:40][C:41]1[CH:46]=[CH:45][C:44]([C:2]2[CH:7]=[CH:6][C:5]([N:8]3[C:12]([C:13]4[CH:18]=[CH:17][C:16]([O:19][CH3:20])=[C:15]([O:21][C@@H:22]5[CH2:26][CH2:25][O:24][CH2:23]5)[CH:14]=4)=[CH:11][CH:10]=[N:9]3)=[CH:4][CH:3]=2)=[CH:43][N:42]=1
Reactant: COc1ccc(-c2ccnn2-c2ccc(Br)cc2)cc1O[C@@H]1CCOC1
Reactant: COc1ccc(B(O)O)cn1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCO
Solvent: CCOC(C)=O
Solvent: COCCOC
Product: COc1ccc(-c2ccc(-n3nccc3-c3ccc(OC)c(O[C@@H]4CCOC4)c3)cc2)cn1
Temperature: 140 °C
Reaction time: 0.01 h
Yield: 81.2 %

Procedure:
1-(4-Bromophenyl)-5-{4-methoxy-3-[(3R)-tetrahydrofuran-3-yloxy]phenyl}-1H-pyrazole (52.0 mg, 0.125 mmol), bis(triphenylphosphine)palladium(II) chloride (20 mg, 0.02 mmol), 0.1 mL of 2.00 M aqueous sodium carbonate, 2 mL of a mixture of DME, water and ethanol in a 7:3:2 ratio, and 2-methoxy-5-pyridineboronic acid (21.1 mg, 0.138 mmol) were combined in a 2.0-5.0 mL Smith Process vial. This was sealed and placed into a Personal Chemistry Emrys Optimizer, stirred for 30 seconds, and then heated to 140° C. for 300 seconds. Upon cooling, 10 mL of water and 10 mL of ethyl acetate were added and the organic layer was separated, dried over sodium sulfate, filtered and approximately 1 g of silica gel was added and the mixture was evaporated to dryness under reduced pressure. The residue was purified by column chromatography on silica gel eluting with 10% ethyl acetate in hexanes for 3 minutes, then with a linear gradient to 100% ethyl acetate over 18 minutes and then with 100% ethyl acetate for an additional 10 minutes to give 2-methoxy-5-[4-(5-{4-methoxy-3-[(3R)-tetrahydrofuran-3-yloxy]phenyl}-1H-pyrazol-1-yl)phenyl]pyridine-(45 mg, 82%) as a yellow oil. LC/MS (EI) tR 4.3 (Method C), m/z 444.1 (M++1). 1H NMR (CDCl3 300 MHz) δ 1.9 (m, 2H); 3.7-3.9 (m, 4H); 3.9 (s, 3H); 4.0 (s, 3H); 4.8 (m, 1H) 6.5 (s, 1H); 6.6 (s, 1H); 6.9 (m, 2H); 7.0 (d, 2H); 7.4 (d, 2H); 7.5 (d, 2H); 7.8 (t, 2H); 8.3 (2, 1H).
Reaction SMILES: [CH3:1][Si:2]([CH3:31])([CH3:30])[CH2:3][CH2:4][O:5][CH2:6][N:7]1[CH:11]=[CH:10][N:9]=[C:8]1[CH2:12][CH:13]([CH2:16][C:17]1[N:18]([CH2:22][O:23][CH2:24][CH2:25][Si:26]([CH3:29])([CH3:28])[CH3:27])[CH:19]=[CH:20][N:21]=1)[CH2:14][NH2:15].[CH2:32]([N:36]1[CH2:54][CH2:53][C:39]2([CH2:43][N:42]([CH2:44][C:45]3[CH:52]=[CH:51][C:48]([CH:49]=O)=[CH:47][CH:46]=3)[CH2:41][CH2:40]2)[CH2:38][CH2:37]1)[CH:33]([CH3:35])[CH3:34]>>[CH2:32]([N:36]1[CH2:54][CH2:53][C:39]2([CH2:43][N:42]([CH2:44][C:45]3[CH:46]=[CH:47][C:48]([CH2:49][NH:15][CH2:14][CH:13]([CH2:16][C:17]4[N:18]([CH2:22][O:23][CH2:24][CH2:25][Si:26]([CH3:28])([CH3:27])[CH3:29])[CH:19]=[CH:20][N:21]=4)[CH2:12][C:8]4[N:7]([CH2:6][O:5][CH2:4][CH2:3][Si:2]([CH3:1])([CH3:30])[CH3:31])[CH:11]=[CH:10][N:9]=4)=[CH:51][CH:52]=3)[CH2:41][CH2:40]2)[CH2:38][CH2:37]1)[CH:33]([CH3:35])[CH3:34]
Reactant: C[Si](C)(C)CCOCn1ccnc1CC(CN)Cc1nccn1COCC[Si](C)(C)C
Reactant: CC(C)CN1CCC2(CC1)CCN(Cc1ccc(C=O)cc1)C2
Product: CC(C)CN1CCC2(CC1)CCN(Cc1ccc(CNCC(Cc3nccn3COCC[Si](C)(C)C)Cc3nccn3COCC[Si](C)(C)C)cc1)C2
Yield: 43.3 %

Procedure:
Except for using the compound (200 mg) produced in Example 29 in place of 8-isobutyl-2,8-diazaspiro[4.5]decane and using the compound (135 mg) produced in Example 27 in place of 4-(diethoxymethyl)benzaldehyde, the same operation as in Example 26 was performed to obtain the title compound (142 mg) having the following physical properties.
Reaction SMILES: C([O:8][CH2:9][C:10]1([CH3:56])[CH2:18][C:17]2[N:16]([CH2:19][O:20][CH2:21][CH2:22][Si:23]([CH3:26])([CH3:25])[CH3:24])[N:15]=[C:14]([C:27]3[N:28]([CH2:48][O:49][CH2:50][CH2:51][Si:52]([CH3:55])([CH3:54])[CH3:53])[C:29]4[C:34]([CH:35]=3)=[CH:33][CH:32]=[C:31]([N:36]([CH3:47])[C:37](=[O:46])[CH2:38][N:39]3[CH2:44][CH2:43][CH2:42][CH2:41][C:40]3=[O:45])[CH:30]=4)[C:13]=2[CH2:12][CH2:11]1)C1C=CC=CC=1.CO>[OH-].[Pd+2].[OH-].[C].O1CCCC1>[OH:8][CH2:9][C:10]1([CH3:56])[CH2:18][C:17]2[N:16]([CH2:19][O:20][CH2:21][CH2:22][Si:23]([CH3:24])([CH3:26])[CH3:25])[N:15]=[C:14]([C:27]3[N:28]([CH2:48][O:49][CH2:50][CH2:51][Si:52]([CH3:53])([CH3:55])[CH3:54])[C:29]4[C:34]([CH:35]=3)=[CH:33][CH:32]=[C:31]([N:36]([CH3:47])[C:37](=[O:46])[CH2:38][N:39]3[CH2:44][CH2:43][CH2:42][CH2:41][C:40]3=[O:45])[CH:30]=4)[C:13]=2[CH2:12][CH2:11]1
Reactant: CN(C(=O)CN1CCCCC1=O)c1ccc2cc(-c3nn(COCC[Si](C)(C)C)c4c3CCC(C)(COCc3ccccc3)C4)n(COCC[Si](C)(C)C)c2c1
Agent: [Pd+2]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Product: CN(C(=O)CN1CCCCC1=O)c1ccc2cc(-c3nn(COCC[Si](C)(C)C)c4c3CCC(C)(CO)C4)n(COCC[Si](C)(C)C)c2c1
Reaction time: 4 h
Yield: 85.6 %

Procedure:
To a solution of N-(2-{6-benzyloxymethyl-6-methyl-1-[2-(trimethylsilyl)ethoxymethyl]-4,5,6,7-tetrahydro-1H-indazol-3-yl}-1-[2-(trimethylsilyl)ethoxymethyl]-1H-indol-6-yl)-N-methylamine (150 mg, 0.23 mmol) in N,N-dimethylformamide (3 ml) were added (2-oxopiperidin-1-yl)acetic acid obtained in Reference Example 6 (43 mg, 0.27 mmol), 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (52 mg, 0.27% mmol) and 1-hydroxybenzotriazole monohydrate (37 mg, 0.27 mmol), and the mixture was stirred at room temperature overnight. To the reaction mixture were added ethyl acetate and water, and the organic layer was separated, washed successively with water and saturated brine, and dried over sodium sulfate. Sodium sulfate was removed by filtration, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel chromatography to give N-(2-{6-benzyloxymethyl-6-methyl-1-[2-(trimethylsilyl)ethoxymethyl]-4,5,6,7-tetrahydro-1H-indazol-3-yl}-1-[2-(trimethylsilyl)ethoxymethyl]-1H-indol-6-yl)-N-methyl-2-(2-oxopiperidin-1-yl)acetamide (158 mg). Under a nitrogen atmosphere, to a solution of the obtained N-(2-{6-benzyloxymethyl-6-methyl-1-[2-(trimethylsilyl)ethoxymethyl]-4,5,6,7-tetrahydro-1H-indazol-3-yl}-1-[2-(trimethylsilyl)ethoxymethyl]-1H-indol-6-yl)-N-methyl-2-(2-oxopiperidin-1-yl)acetamide (158 mg) in a mixed solvent of methanol (0.8 ml) and tetrahydrofuran (0.8 ml) was added 20% palladium hydroxide-carbon (150 mg) at room temperature, and the mixture was stirred under a hydrogen atmosphere at normal pressure for 4 hr. The reaction mixture was filtered through celite, and the filtrate was concentrated under reduced pressure to give the title compound (120 mg, yield 75%).
Reaction SMILES: CO[C:3]([C:5]1[C:6]([OH:31])=[C:7]2[C:12](=[CH:13][N:14]=1)[N:11]([CH2:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)[C:10](=[O:22])[C:9]([C:23]1[CH:28]=[CH:27][C:26]([O:29][CH3:30])=[CH:25][CH:24]=1)=[CH:8]2)=[O:4].[NH2:32][CH2:33][CH2:34][C:35]([OH:37])=[O:36].C[O-].[Na+]>>[CH2:15]([N:11]1[C:12]2[C:7](=[C:6]([OH:31])[C:5]([C:3]([NH:32][CH2:33][CH2:34][C:35]([OH:37])=[O:36])=[O:4])=[N:14][CH:13]=2)[CH:8]=[C:9]([C:23]2[CH:24]=[CH:25][C:26]([O:29][CH3:30])=[CH:27][CH:28]=2)[C:10]1=[O:22])[C:16]1[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=1
Reactant: NCCC(=O)O
Reactant: COC(=O)c1ncc2c(cc(-c3ccc(OC)cc3)c(=O)n2Cc2ccccc2)c1O
Agent: C[O-]
Agent: [Na+]
Product: COc1ccc(-c2cc3c(O)c(C(=O)NCCC(=O)O)ncc3n(Cc3ccccc3)c2=O)cc1
Temperature: 25 °C
Yield: 73.3 %

Procedure:
A mixture of 1-benzyl-5-hydroxy-3-(4-methoxy-phenyl)-2-oxo-1,2-dihydro-[1,7]naphthyridine-6-carboxylic acid methyl ester (30 mg, 0.072 mmol), β-alanine (854 mg, 9.6 mmol) and NaOMe solution (14.4 mL, 7.2 mmol, 0.5 M in MeOH) was refluxed for 16 h. After the mixture was cooled to r.t., the solvent was evaporated in vacuo. The residue was dissolved in saturated NaHCO3 and washed several times with ether. The aqueous layer was acidified to pH about 2 with 6 M HCl, and the resulting precipitate was isolated by filtration to give 25 mg of the title compound. MS: (+) m/z 474.30 (M+1).
Reaction SMILES: [F:1][C:2]1[C:15]([CH3:16])=[C:14]([F:17])[C:13]([F:18])=[CH:12][C:3]=1[C:4]([CH2:6][C:7]([O:9][CH2:10][CH3:11])=[O:8])=[O:5].[CH:19]([O-])([O-])[O:20][CH2:21][CH3:22].C(OC(=O)C)(=O)C>>[F:1][C:2]1[C:15]([CH3:16])=[C:14]([F:17])[C:13]([F:18])=[CH:12][C:3]=1[C:4]([C:6](=[CH:19][O:20][CH2:21][CH3:22])[C:7]([O:9][CH2:10][CH3:11])=[O:8])=[O:5]
Reactant: CCOC([O-])[O-]
Reactant: CCOC(=O)CC(=O)c1cc(F)c(F)c(C)c1F
Solvent: CC(=O)OC(C)=O
Product: CCOC=C(C(=O)OCC)C(=O)c1cc(F)c(F)c(C)c1F
Reaction time: 6 h
Yield: 100.1 %

Procedure:
A mixture of ethyl 2-(2,4,5-trifluoro-3-methylbenzoyl)acetate (3.0 g), ethyl orthoformate (2.6 g) and acetic anhydride (2.9 g) was stirred at 87° to 93° C. for 6 hours and then concentrated under reduced pressure to give the title compound (3.65 g) as orange oil.
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[C:8]([CH:10]=[CH:11][C:12]2[N:16]=[C:15]([CH2:17][CH2:18][CH3:19])[O:14][N:13]=2)[CH:7]=[CH:6][C:5]=1[OH:20])([O-])=O.[OH-].[Na+]>C(OCC)(=O)C>[NH2:1][C:4]1[CH:9]=[C:8]([CH:10]=[CH:11][C:12]2[N:16]=[C:15]([CH2:17][CH2:18][CH3:19])[O:14][N:13]=2)[CH:7]=[CH:6][C:5]=1[OH:20]
Reactant: CCCc1nc(C=Cc2ccc(O)c([N+](=O)[O-])c2)no1
Agent: [Na+]
Agent: [OH-]
Solvent: CCOC(C)=O
Product: CCCc1nc(C=Cc2ccc(O)c(N)c2)no1
Temperature: 25 °C
Reaction time: 12 h

Procedure:
2-Nitro-4-[2-(5-propyl-[1,2,4]oxadiazol-3-yl)-vinyl]-phenol (compound of Example 11; 0.2 g, 0.72 mmol) was dissolved in ethyl acetate (5 mL) to which stannous chloride was added and the reaction mixture was stirred at room temperature for 12 h. The reaction mixture was cooled to 0° C. followed by addition of aqueous sodium hydroxide solution to adjust pH to 10. The reaction mixture was extracted with ethyl acetate (2×5 mL). The combined organic layers were washed with water (2×10 mL) and brine (10 mL). The organic phase obtained was dried over anhydrous sodium sulfate and concentrated to obtain a crude product, which was purified by column chromatography (silica gel, 0.5 methanol in chloroform) to afford the title compound.
Reaction SMILES: C([O:4][C:5]1[CH2:9][CH2:8][CH2:7][C:6]=1[CH2:10][CH2:11][CH2:12][CH2:13][C:14]([CH3:22])([CH3:21])[CH2:15][C:16]([O:18]CC)=[O:17])(=O)C.C(=O)([O-])[O-].[Ca+2].[Br-]>C(Cl)(Cl)(Cl)Cl.CN(C)C(=O)C.C(Cl)(Cl)Cl.O>[C:16]([CH2:15][C:14]([CH3:22])([CH3:21])[CH2:13][CH2:12][CH2:11][CH2:10][C:6]1[C:5](=[O:4])[CH2:9][CH2:8][CH:7]=1)([OH:18])=[O:17]
Reactant: CCOC(=O)CC(C)(C)CCCCC1=C(OC(C)=O)CCC1
Agent: O=C([O-])[O-]
Agent: [Br-]
Agent: [Ca+2]
Solvent: O
Solvent: CC(=O)N(C)C
Solvent: ClC(Cl)Cl
Product: CC(C)(CCCCC1=CCCC1=O)CC(=O)O
Reaction time: 0.5 h

Procedure:
To a rapidly stirred mixture of 1-acetoxy-2-(6-carbethoxy-5,5-dimethylhexyl)cyclopent-1-ene (35 g., 0.113 mole) chloroform (95 ml.), water (125 ml.) and calcium carbonate (11.8 g.) cooled in an ice-bath is added dropwise over a period of 30 minutes a solution of bromide (18.8 g.) in carbon tetrachloride (31 ml.). After stirring in the cold for an additional 45 minutes the orange colored chloroform layer is separated and washed with dilute sodium bisulfite and saturated saline solution, dried over magnesium sulfate and taken to dryness in vacuo (bath temperature: 35°-40°) leaving an amber colored oil. A slurry of 100 ml. of N,N-dimethylacetamide and 16.5 g. of CaCO3 is stirred and heated to reflux under nitrogen flow. The above dried oil is added from a dropping funnel rapidly, maintaining reflux and nitrogen flow for 30 minutes. The cooled reaction mixture is filtered, and the precipitate is washed with ether. The filtrate is poured into two liters ice-cold water and is extracted with ether. The combined extracts and washing is washed with water, saturated saline, treated with decolorizing charcoal, filtered. The solvent evaporated in vacuo to give 24 g. (77%) of subject product.
Reaction SMILES: Cl[C:2]1[C:3]([C:22]2[C:27]([CH3:28])=[CH:26][C:25]([CH3:29])=[CH:24][N:23]=2)=[CH:4][C:5]([N:8]2[CH2:13][CH2:12][N:11]([C:14](=[O:21])[CH2:15][CH2:16][S:17]([CH3:20])(=[O:19])=[O:18])[CH2:10][CH2:9]2)=[N:6][CH:7]=1.[NH4+].[OH-]>[Pd].CO.O>[CH3:28][C:27]1[C:22]([C:3]2[CH:2]=[CH:7][N:6]=[C:5]([N:8]3[CH2:9][CH2:10][N:11]([C:14](=[O:21])[CH2:15][CH2:16][S:17]([CH3:20])(=[O:18])=[O:19])[CH2:12][CH2:13]3)[CH:4]=2)=[N:23][CH:24]=[C:25]([CH3:29])[CH:26]=1
Reactant: Cc1cnc(-c2cc(N3CCN(C(=O)CCS(C)(=O)=O)CC3)ncc2Cl)c(C)c1
Agent: [Pd]
Agent: [NH4+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: Cc1cnc(-c2ccnc(N3CCN(C(=O)CCS(C)(=O)=O)CC3)c2)c(C)c1
Temperature: 25 °C
Reaction time: 12 h
Yield: 89.4 %

Procedure:
To 1-[4-(5′-chloro-3,5-dimethyl-2,4′-bipyridin-2′-yl)piperazin-1-yl]-3-(methylsulfonyl)propan-1-one (44 mg, 0.10 mmol) was added MeOH/Water 6:1 (5 mL, 0.02M), then 10% Pd/C (25 μL=20 w/w % relative to substrate) followed by NH4OH (1.0 mL, 5 eq, 0.5M solution in MeOH). The reaction of mixture was stirred at ambient temperature at 25° C. under balloon H2 for 12 hrs. After filtering off catalyst through celite, the concentrated crude product was diluted with EtOAc (25 mL), washed with water (10 mL), then brine (10 mL), dried over MgSO4, filtered. The solution was concentrated in vacuo. The residue was purified by chromatography on silica gel (EtOAc/heptane=1:3) to give the title compound (36 mg, 90%) as a yellow solid. 1H NMR (400 MHz, CDCl3) δ ppm 8.36 (s, 1 H) 8.24-8.29 (m, 1 H) 7.42 (s, 1 H) 6.79-6.84 (m, 2 H) 3.75-3.81 (m, 4 H) 3.58-3.66 (m, 4 H) 3.47 (t, J=7.33 Hz, 2 H) 3.00 (s, 3H) 2.93-2.99 (m, 2 H) 2.37 (s, 3 H) 2.33 (s, 3 H); m/z for C20H26N4O3S 403.1 (M+H)+.
Reaction SMILES: [CH2:1]([OH:4])[C:2]#[CH:3].[C:5]([Si:9]([O:22][CH2:23][C:24]1[CH:29]=[C:28](Br)[CH:27]=[C:26](Br)[CH:25]=1)([C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)([CH3:8])([CH3:7])[CH3:6]>C(N(CC)CC)C.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[OH:4][CH2:1][C:2]#[C:3][C:26]1[CH:25]=[C:24]([CH2:23][O:22][Si:9]([C:5]([CH3:7])([CH3:6])[CH3:8])([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[CH:29]=[C:28]([C:3]#[C:2][CH2:1][OH:4])[CH:27]=1
Reactant: C#CCO
Reactant: CC(C)(C)[Si](OCc1cc(Br)cc(Br)c1)(c1ccccc1)c1ccccc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: CCN(CC)CC
Product: CC(C)(C)[Si](OCc1cc(C#CCO)cc(C#CCO)c1)(c1ccccc1)c1ccccc1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 88.9 %

Procedure:
Pd(Ph3P)4 (520 mg), CuBrSMe2 (200 mg) and propargyl alcohol (3.08 ml, 35.1 mmol) are added successively to a solution of tert-butyl-(3,5-dibrombenzyloxy)diphenylsilane (A1, 5.0 g, 9.9 mmol) in triethylamine (50 ml), and the mixture is stirred at RT for 10 min and then under reflux at 80° C. for 2.5 h. After cooling, the reaction mixture is filtered off with suction through kieselguhr, and the filter cake is washed with ethyl acetate (20 ml). The organic phase is concentrated under reduced pressure. Further purification is carried out by chromatography [toluene/acetone (8:2)] on a silica gel column. This gives the title compound (4.0 g) as a colorless solid. TLC, silica gel (glass plates), [toluene/acetone (8:2)], Rf=0.48.
Reaction SMILES: Cl[C:2]1[C:7]([CH:8]=[O:9])=[C:6]([NH:10][C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=2[Cl:17])[N:5]=[C:4]([S:18][CH3:19])[N:3]=1.[F:20][C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=1B(O)O>>[F:20][C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=1[C:2]1[C:7]([CH:8]=[O:9])=[C:6]([NH:10][C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=2[Cl:17])[N:5]=[C:4]([S:18][CH3:19])[N:3]=1
Reactant: CSc1nc(Cl)c(C=O)c(Nc2ccccc2Cl)n1
Reactant: OB(O)c1ccccc1F
Product: CSc1nc(Nc2ccccc2Cl)c(C=O)c(-c2ccccc2F)n1

Procedure:
Prepared as described above in Example 11 starting from 4-chloro-6-(2-chloro-phenylamino)-2-methylsulfanyl-pyrimidine-5-carbaldehyde and 2-fluorophenylboronic acid to give the title compound 4-(2-fluoro-phenyl)-6-(2-chloro-phenylamino)-2-methylsulfanyl-pyrimidine-5-carbaldehyde. 1H-NMR: δ 2.60 (s, 3H), 6.99-7.68 (m, 7H), 8.47 (d, 1H, J=4.7 Hz), 9.78 (s, 1H), 11.59 (br s, 1H). LC MS (m/e)=374 (MH+).