Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][C:5]2[O:10][CH2:9][CH2:8][N:7]([CH2:11][CH2:12][N:13]([CH3:15])[CH3:14])[C:6]=2[CH:16]=1.[CH3:17][O:18][CH:19]([O:22][CH3:23])[CH:20]=O>[Pd].C(O)C>[CH3:17][O:18][CH:19]([O:22][CH3:23])[CH2:20][NH:1][C:2]1[CH:3]=[CH:4][C:5]2[O:10][CH2:9][CH2:8][N:7]([CH2:11][CH2:12][N:13]([CH3:14])[CH3:15])[C:6]=2[CH:16]=1
Reactant: COC(C=O)OC
Reactant: CN(C)CCN1CCOc2ccc(N)cc21
Agent: [Pd]
Solvent: CCO
Product: COC(CNc1ccc2c(c1)N(CCN(C)C)CCO2)OC
Yield: 76.6 %

Procedure:
6-Amino-3,4-dihydro-4-(2-dimethylaminoethyl)-2H-1,4-benzoxazine (D3, 1.78 g, 8.1 mmol) and dimethoxyacetaldehyde (40% in MTBE, 3.1 g) were hydrogenated over 10% palladium on carbon (0.5g) in ethanol (70 ml) for 24 h. The catalyst was filtered off, and the filtrate was evaporated to dryness. The residue was dissolved in ethyl acetate, washed with water and brine, dried (Na2SO4) and evaporated to give the title compound (1.92 g, 77%) as a brown oil.
Reaction SMILES: I[C@H:2]1[C@H:19]([CH3:20])[C@@:18]2([CH3:21])[C:5]([CH2:6][CH2:7][C@@H:8]3[C@@H:17]2[CH2:16][CH2:15][C@@:13]2([CH3:14])[C@H:9]3[CH2:10][CH2:11][C:12]2=[O:22])=[CH:4][C:3]1=[O:23].C(=O)([O-])[O-].[Li+].[Li+].O>CN(C)C=O>[CH3:20][C:19]1[C@@:18]2([CH3:21])[C:5]([CH2:6][CH2:7][C@@H:8]3[C@@H:17]2[CH2:16][CH2:15][C@@:13]2([CH3:14])[C@H:9]3[CH2:10][CH2:11][C:12]2=[O:22])=[CH:4][C:3](=[O:23])[CH:2]=1
Reactant: C[C@H]1[C@H](I)C(=O)C=C2CC[C@@H]3[C@H](CC[C@]4(C)C(=O)CC[C@@H]34)[C@]21C
Agent: O=C([O-])[O-]
Agent: [Li+]
Solvent: CN(C)C=O
Solvent: O
Product: CC1=CC(=O)C=C2CC[C@@H]3[C@H](CC[C@]4(C)C(=O)CC[C@@H]34)[C@@]12C
Reaction time: 1.5 h

Procedure:
2.13 g (5 mmol) of 2β-iodo-1α-methylandrost-4-ene-3,17-dione from a) is introduced to a suspension, preheated to 130° C., of 0.73 g (10 mmol) of lithium carbonate in 10 ml of dimethylformamide and stirred at this temperature for 1.5 hours. After cooling, the reaction solution is added to 30 ml of water, extracted with ethyl acetate and after drying on sodium sulfate is concentrated by evaporation. The crude product is chromatographed on silica gel with ethyl acetate/hexane as mobile solvent. After recrystallization from ethyl acetate, 1.1 g of 1-methylandrosta-1,4-diene-3,17-dione (74% of theory) of a melting point of 169° C. is obtained.
Reaction SMILES: [C:1]([C:3]1([OH:21])[CH2:8][CH2:7][N:6]([CH3:9])[CH:5]([CH2:10][C:11]2[CH:16]=[CH:15][C:14]([O:17][CH3:18])=[CH:13][CH:12]=2)[C:4]1([CH3:20])[CH3:19])#[CH:2]>CO.[Pd]>[CH2:1]([C:3]1([OH:21])[CH2:8][CH2:7][N:6]([CH3:9])[CH:5]([CH2:10][C:11]2[CH:12]=[CH:13][C:14]([O:17][CH3:18])=[CH:15][CH:16]=2)[C:4]1([CH3:20])[CH3:19])[CH3:2]
Reactant: C#CC1(O)CCN(C)C(Cc2ccc(OC)cc2)C1(C)C
Agent: [Pd]
Solvent: CO
Product: CCC1(O)CCN(C)C(Cc2ccc(OC)cc2)C1(C)C

Procedure:
A solution of 56 g of 4-ethinyl-2-(p-methoxybenzyl)-1,3,3-trimethyl-4-piperidinol in 350 ml of methanol is subjected to hydrogenation at atmospheric pressure and room temperature, the catalyst being 5% palladium on charcoal (5 g.).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:30])[CH2:5][C:6]1[CH:11]=[CH:10][C:9]([O:12][CH3:13])=[C:8]([O:14][C:15]2[CH:20]=[CH:19][C:18]([NH2:21])=[CH:17][C:16]=2[CH2:22][S:23][C:24]2[S:25][C:26]([CH3:29])=[N:27][N:28]=2)[CH:7]=1)[CH3:2].[Cl:31][C:32]1[CH:40]=[CH:39][C:35]([C:36](Cl)=[O:37])=[CH:34][CH:33]=1>>[CH2:1]([O:3][C:4](=[O:30])[CH2:5][C:6]1[CH:11]=[CH:10][C:9]([O:12][CH3:13])=[C:8]([O:14][C:15]2[CH:20]=[CH:19][C:18]([NH:21][C:36](=[O:37])[C:35]3[CH:39]=[CH:40][C:32]([Cl:31])=[CH:33][CH:34]=3)=[CH:17][C:16]=2[CH2:22][S:23][C:24]2[S:25][C:26]([CH3:29])=[N:27][N:28]=2)[CH:7]=1)[CH3:2]
Reactant: O=C(Cl)c1ccc(Cl)cc1
Reactant: CCOC(=O)Cc1ccc(OC)c(Oc2ccc(N)cc2CSc2nnc(C)s2)c1
Product: CCOC(=O)Cc1ccc(OC)c(Oc2ccc(NC(=O)c3ccc(Cl)cc3)cc2CSc2nnc(C)s2)c1

Procedure:
As described for Example 10, [3-(2-bromomethyl-4-nitro-phenoxy)-4-methoxy-phenyl]-acetic acid ethyl ester and 5-methyl-1,3,4-thiadiazole-2-thiol were reacted to form {4-methoxy-3-[2-(5-methyl-[1,3,4]thiadiazol-2-ylsulfanylmethyl)-4-nitro-phenoxy]-phenyl}-acetic acid ethyl ester, which was reduced to {3-[4-amino-2-(5-methyl-[1,3,4]thiadiazol-2-ylsulfanylmethyl)-phenoxy]-4-methoxy-phenyl}-acetic acid ethyl ester and then treated with 4-chlorobenzoyl chloride to provide {3-[4-(4-chloro-benzoylamino)-2-(5-methyl-[1,3,4]thiadiazol-2-ylsulfanylmethyl)-phenoxy]-4-methoxy-phenyl}-acetic acid ethyl ester. Hydrolysis of the ester to the acid provided Compound 19.
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([CH:10]=[C:11]([C:16](=O)[CH3:17])[C:12]([O:14][CH3:15])=[O:13])=[CH:6][CH:5]=1)([O-:3])=[O:2].[NH2:19][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=1[SH:26]>CN(C)C=O.CCOCC>[CH3:17][C:16]1[NH:19][C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=2[S:26][CH:10]([C:7]2[CH:8]=[CH:9][C:4]([N+:1]([O-:3])=[O:2])=[CH:5][CH:6]=2)[C:11]=1[C:12]([O:14][CH3:15])=[O:13]
Reactant: Nc1ccccc1S
Reactant: COC(=O)C(=Cc1ccc([N+](=O)[O-])cc1)C(C)=O
Solvent: CCOCC
Solvent: CN(C)C=O
Product: COC(=O)C1=C(C)Nc2ccccc2SC1c1ccc([N+](=O)[O-])cc1
Temperature: 25 °C

Procedure:
A solution of 2-[(4-nitrophenyl)methylene]-3-oxobutanoic acid, methyl ester (1.295 g., 5 mmoles) in dimethylformamide (5 ml.) is treated with 2-aminothiophenol (695 mg. of 90%, 5 mmoles). After stirring the reaction at room temperature for one hour, it is heated at 60°-65° for 24 hours. The reaction is allowed to cool down to ambient temperature and diluted with ether. The resulting yellow solution is washed thoroughly with water, 1N sodium hydroxide, and brine. After drying over anhydrous magnesium sulfate, the solvent is stripped off to give a yellow foam (1.3 g.). This product is purified by flash chromatography (20% ethyl acetate in hexane) and the residue is recrystallized from isopropyl ether-dichloromethane to provide 2,5-dihydro-4-methyl-2-(4-nitrophenyl)-1,5-benzothiazepine-3-carboxylic acid, methyl ester as yellow needles; m.p. 149.5°-151.5° (sinters at 140°). TLC (silica gel; acetone:hexane, 30:70) Rf =0.30.
Reaction SMILES: C(Cl)(=O)C(Cl)=O.CS(C)=O.[CH3:11][C:12]([C:16]1[CH:21]=[CH:20][CH:19]=[C:18]([CH3:22])[CH:17]=1)([CH3:15])[CH2:13][OH:14].C(N(CC)CC)C>O1CCCC1.O>[CH3:15][C:12]([C:16]1[CH:21]=[CH:20][CH:19]=[C:18]([CH3:22])[CH:17]=1)([CH3:11])[CH:13]=[O:14]
Reactant: Cc1cccc(C(C)(C)CO)c1
Agent: O=C(Cl)C(=O)Cl
Solvent: O
Solvent: CS(C)=O
Solvent: C1CCOC1
Product: Cc1cccc(C(C)(C)C=O)c1
Temperature: 25 °C
Reaction time: 0.08 h

Procedure:
To a solution of oxalyl chloride (15.1 g, 119 mmol) in tetrahydrofuran (150 ml) was dropwise added a solution of dimethyl-sulfoxide (16.8 ml, 237 mmol) in tetrahydrofuran (50 ml) at −78° C., and the mixture was stirred for 5 min. A solution of 2-methyl-2-(3-methylphenyl)propan-1-ol (12.99 g, 79.09 mmol) in tetrahydrofuran (80 ml) was added at −78° C., and the mixture was stirred for 15 min. Triethylamine (66.1 ml, 475 mmol) was added thereto, and the mixture was warmed to room temperature. The reaction mixture was poured into water and extracted twice with ethyl acetate. The recovered organic layer was dried over anhydrous magnesium sulfate and the solvent was evaporated under reduced pressure. The obtained crude product was purified by silica gel column chromatography (hexane/ethyl acetate=15/1) to give the objective substance.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6](O)=[CH:5][CH:4]=1.[F:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=1[CH:17]([OH:41])[CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][N:23]1[CH2:28][CH2:27][CH:26]([C:29]2[CH:30]=[C:31]([NH:35][C:36](=[O:40])[CH:37]([CH3:39])[CH3:38])[CH:32]=[CH:33][CH:34]=2)[CH2:25][CH2:24]1>>[F:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=1[CH:17]([O:41][C:6]1[CH:7]=[CH:8][C:3]([O:2][CH3:1])=[CH:4][CH:5]=1)[CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][N:23]1[CH2:24][CH2:25][CH:26]([C:29]2[CH:30]=[C:31]([NH:35][C:36](=[O:40])[CH:37]([CH3:38])[CH3:39])[CH:32]=[CH:33][CH:34]=2)[CH2:27][CH2:28]1
Reactant: COc1ccc(O)cc1
Reactant: CC(C)C(=O)Nc1cccc(C2CCN(CCCCCC(O)c3ccccc3F)CC2)c1
Product: COc1ccc(OC(CCCCCN2CCC(c3cccc(NC(=O)C(C)C)c3)CC2)c2ccccc2F)cc1

Procedure:
Prepared by Procedure A and Scheme AN using 4-methoxyphenol and N-(3-{1-[6-(2-fluorophenyl)-6-hydroxyhexyl]-4-piperidinyl}phenyl)-2-methylpropanamide: ESMS m/e: 547.1 (M+H)+.
Reaction SMILES: [Cl:1][C:2]1[C:3](=[O:14])O[C:5](=[O:13])[C:6]=1[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1.Cl.[F:16][C:17]1[CH:22]=[CH:21][C:20]([NH:23][NH2:24])=[CH:19][CH:18]=1.C(N(CC)CC)C>C(Cl)Cl>[Cl:1][C:2]1[C:3](=[O:14])[N:24]([NH:23][C:20]2[CH:21]=[CH:22][C:17]([F:16])=[CH:18][CH:19]=2)[C:5](=[O:13])[C:6]=1[C:7]1[CH:8]=[CH:9][CH:10]=[CH:11][CH:12]=1
Reactant: NNc1ccc(F)cc1
Reactant: O=C1OC(=O)C(c2ccccc2)=C1Cl
Agent: Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: O=C1C(Cl)=C(c2ccccc2)C(=O)N1Nc1ccc(F)cc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
3.13 g (15 mmol) of 3-chloro-4-phenylfuran-2,5-dione and 2.44 g (15 mmol) of 4-fluorophenylhydrazine hydrochloride were initially charged in 50 ml of methylene chloride, and the mixture was, at room temperature, admixed dropwise with stirring with 1.52 g (15 mmol) of triethylamine and stirred at room temperature overnight. A further 50 ml of methylene chloride were added, and the mixture was washed three times with in each case 80 ml of water, dried over sodium sulfate and concentrated under reduced pressure. Yield: 3.9 g of a crystalline solid, m.p. 115-117° C.
Reaction SMILES: [C:1]([NH:11][CH2:12][C:13]([OH:15])=O)([O:3][CH2:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1)=[O:2].[C:16]([O:20][C:21](=[O:24])[CH2:22][NH2:23])([CH3:19])([CH3:18])[CH3:17].F[P-](F)(F)(F)(F)F.N1(O[P+](N(C)C)(N(C)C)N(C)C)C2C=CC=CC=2N=N1.C(N(CC)CC)C>C(#N)C>[C:16]([O:20][C:21](=[O:24])[CH2:22][NH:23][C:13](=[O:15])[CH2:12][NH:11][C:1]([O:3][CH2:4][C:5]1[CH:6]=[CH:7][CH:8]=[CH:9][CH:10]=1)=[O:2])([CH3:19])([CH3:18])[CH3:17]
Reactant: CC(C)(C)OC(=O)CN
Reactant: O=C(O)CNC(=O)OCc1ccccc1
Agent: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(CC)CC
Solvent: CC#N
Product: CC(C)(C)OC(=O)CNC(=O)CNC(=O)OCc1ccccc1
Yield: 77.6 %

Procedure:
N-Carbobenzyloxy-glycine (2.1 g, 10 mmol) and glycine-tert-butyl ester (1.3 g, 10 mmol) were coupled using benzotriazol-1-yloxytris(dimethylamino) phosphonium hexafluorophosphate (4.4 g, 10 mmol) and triethylamine (1.5 g, 15 mmol) in acetonitrile following the method described in Example 23 to give 2.5 g(79%) of N-carbobenzyloxy-glycylglycine-tert-butyl ester after chromatography on silica gel.
Reaction SMILES: [NH3:1].C(O[C:6]1[C:9](=[O:10])[C:8](=[O:11])[C:7]=1[C:12]1[C:21]2[C:16](=[CH:17][CH:18]=[C:19]([C:22]#[N:23])[CH:20]=2)[O:15][C:14]([CH3:25])([CH3:24])[CH:13]=1)(C)C>C(#N)C>[NH2:1][C:6]1[C:9](=[O:10])[C:8](=[O:11])[C:7]=1[C:12]1[C:21]2[C:16](=[CH:17][CH:18]=[C:19]([C:22]#[N:23])[CH:20]=2)[O:15][C:14]([CH3:24])([CH3:25])[CH:13]=1
Reactant: CC(C)Oc1c(C2=CC(C)(C)Oc3ccc(C#N)cc32)c(=O)c1=O
Reactant: N
Solvent: CC#N
Product: CC1(C)C=C(c2c(N)c(=O)c2=O)c2cc(C#N)ccc2O1
Temperature: 25 °C
Reaction time: 16 h
Yield: 35 %

Procedure:
Ammonia gas was bubbled into a solution of 361 mg (1.12 mmol) of 4-(2-isopropoxy-3,4-dioxo-cyclobut-1-enyl)-2,2-dimethyl-2H-chromene-6-carbonitrile in acetonitrile (11 ml) for 30 min. The reaction mixture was stirred at ambient temperature for 16 h. The reaction mixture was quenched with H2O (50 mL) and was extracted into 20% THF-CH2Cl2. The combined organic extracts were dried over anhydrous Na2SO4 and then concentrated and recrystallized from acetone-petroleum ether to give 110 mg of the title compound (35% yield), mp>250° C., as an off white solid: 1H-NMR (DMSO-d6 ; 400 MHz) δ9.18 (bs, 1H), 8.68 (bs, 1H), 7.79 (d, 1H), 7.67 (dd, 1H), 7.01 (d, 1H), 6.29 (s, 1H), and 1.47 ppm (s, 6H); IR (KBr) 3300, 3100, 1780, 1730, 1720, 1665, and 1610 cm-1 ; mass spectrum (PBEI), m/e 281 (M+H), 280 (M+), 252, and 209.
Reaction SMILES: [CH3:1][C:2]1([CH3:23])[O:6][C:5](=[O:7])[N:4]([C:8]2[CH:16]=[CH:15][C:11]([C:12](O)=[O:13])=[CH:10][CH:9]=2)[C@H:3]1[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1.C(N(C(C)C)C(C)C)C.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[Cl:57][C:58]1[N:59]=[N:60][C:61]([NH:64][NH2:65])=[CH:62][CH:63]=1>CN(C=O)C.O>[Cl:57][C:58]1[N:59]=[N:60][C:61]([NH:64][NH:65][C:12](=[O:13])[C:11]2[CH:10]=[CH:9][C:8]([N:4]3[C@@H:3]([C:17]4[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=4)[C:2]([CH3:23])([CH3:1])[O:6][C:5]3=[O:7])=[CH:16][CH:15]=2)=[CH:62][CH:63]=1
Reactant: CC1(C)OC(=O)N(c2ccc(C(=O)O)cc2)[C@H]1c1ccccc1
Reactant: NNc1ccc(Cl)nn1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Solvent: O
Product: CC1(C)OC(=O)N(c2ccc(C(=O)NNc3ccc(Cl)nn3)cc2)[C@H]1c1ccccc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
(S)-4-(5,5-Dimethyl-2-oxo-4-phenyloxazolidin-3-yl)benzoic acid (400 mg, 1.285 mmol) was dissolved in DMF (2.57 mL) at room temperature. To the reaction mixture, was successively added N-ethyl-N-isopropylpropan-2-amine (670 μL, 3.85 mmol), 2-(3H-[1,2,3]triazolo[4,5-b]pyridin-3-yl)-1,1,3,3-tetramethylisouronium hexafluorophosphate(V) (489 mg, 1.285 mmol, commercially available from Sigma-Aldrich, Milwaukee, Wis.) and 3-chloro-6-hydrazinylpyridazine (186 mg, 1.285 mmol). The vial was sealed and immersed in a 55° C. oil bath. After stirring overnight, LC-MS indicated complete conversion to the product. After cooling to room temperature, the reaction mixture was transferred to water in a flask in an ice/water bath. The solution was extracted w with DCM (3×50 mL). The combined organic layers were then washed with water (2×50 mL) and brine (50 mL). The organic layer was dried over Na2SO4. The solution was then filtered and concentrated under reduced pressure to give the product as a yellow solid. The product thus obtained was was used in the next step without further purification. m/z (ESI) 438.0 (M+H)+.
Reaction SMILES: [CH3:1][C:2]1[N:3]=[C:4]([C:10]2[CH:15]=[CH:14][C:13]([C:16]([F:19])([F:18])[F:17])=[CH:12][CH:11]=2)[O:5][C:6]=1[CH:7]([OH:9])[CH3:8].[H-].[Na+].C[O:23][C:24](=[O:36])[CH2:25][CH2:26][C:27]1[CH:32]=[CH:31][C:30]([CH2:33]I)=[CH:29][C:28]=1[CH3:35].Cl>[OH-].[Na+].CN(C)C=O>[CH3:35][C:28]1[CH:29]=[C:30]([CH2:33][O:9][CH:7]([C:6]2[O:5][C:4]([C:10]3[CH:15]=[CH:14][C:13]([C:16]([F:19])([F:18])[F:17])=[CH:12][CH:11]=3)=[N:3][C:2]=2[CH3:1])[CH3:8])[CH:31]=[CH:32][C:27]=1[CH2:26][CH2:25][C:24]([OH:36])=[O:23]
Reactant: Cc1nc(-c2ccc(C(F)(F)F)cc2)oc1C(C)O
Reactant: COC(=O)CCc1ccc(CI)cc1C
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: Cc1cc(COC(C)c2oc(-c3ccc(C(F)(F)F)cc3)nc2C)ccc1CCC(=O)O
Temperature: 25 °C

Procedure:
A mixture of 1-[4-Methyl-2-(4-trifluoromethyl-phenyl)-oxazol-5-yl]-ethanol (0.132 g, 0.487 mmol), sodium hydride (0.05 g, 1.25 mmol) and N,N-dimethyl formamide (5 mL) is stirred at room temperature. 3-(4-Iodomethyl-2-methyl-phenyl)-propionic acid methyl ester (0.17 g, 0.535 mmol) is added and the mixture is heated to 65 deg C., 2 hr. The reaction is cooled to room temperature and diluted with aqueous sodium hydroxide (10 mL, 5M) and stirred 1 hr. The pH is adjusted with aqueous hydrochloric acid until pH is 2–3. The product is extracted into ethyl acetate (3×25 mL). The combined extracts are dried over anhydrous magnesium sulfate, filtered and concentrated. The residue is purified via silica chromatography eluting with 7:3 hexanes:ethyl acetate to 1:1 hexanes:ethyl acetate to afford the title compound as a white solid, 0.027 g, 12%. MS M++1 448. The structure is confirmed by 1H NMR spectroscopy.
Reaction SMILES: [C:1]1([S:7]([N:10]2[C:14]3=[N:15][CH:16]=[C:17]([O:19][CH3:20])[CH:18]=[C:13]3[CH:12]=[C:11]2[C:21](OS(C2C=CC(C)=CC=2)(=O)=O)=[CH:22][CH:23]2[CH2:28][CH2:27][O:26][CH2:25][CH2:24]2)(=[O:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[F:40][C:41]([F:52])([F:51])[C:42]1[CH:47]=[CH:46][C:45](B(O)O)=[CH:44][CH:43]=1.C(=O)([O-])[O-].[Na+].[Na+]>O1CCOCC1.C(OCC)(=O)C.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:1]1([S:7]([N:10]2[C:14]3=[N:15][CH:16]=[C:17]([O:19][CH3:20])[CH:18]=[C:13]3[CH:12]=[C:11]2[C:21]([C:43]2[CH:44]=[CH:45][CH:46]=[CH:47][C:42]=2[C:41]([F:52])([F:51])[F:40])=[CH:22][CH:23]2[CH2:24][CH2:25][O:26][CH2:27][CH2:28]2)(=[O:8])=[O:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: OB(O)c1ccc(C(F)(F)F)cc1
Reactant: COc1cnc2c(c1)cc(C(=CC1CCOCC1)OS(=O)(=O)c1ccc(C)cc1)n2S(=O)(=O)c1ccccc1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: C1COCCO1
Solvent: CCOC(C)=O
Product: COc1cnc2c(c1)cc(C(=CC1CCOCC1)c1ccccc1C(F)(F)F)n2S(=O)(=O)c1ccccc1
Yield: 80.9 %

Procedure:
To a mixture of toluene-4-sulfonic acid-1-(1-benzenesulfonyl-5-methoxy-1H-pyrrolo[2,3-b]pyridin-2-yl)-2-(tetrahydro-pyran-4-yl)-vinyl ester (prepared as in Example 31, 350 mg, 0.62 mmol), 4-(trifluoromethyl)phenylboronic acid (293 mg, 1.54 mmol) and dichlorobis(triphenylphosphine)palladium (II) (43 mg, 0.06 mmol) in dioxane (5 mL) was added an aqueous sodium carbonate solution (2 M, 0.8 mL, 1.6 mmol). The resulting mixture was subjected to microwave irradiation for 2 h at 100° C. The mixture was diluted with ethyl acetate (250 mL), washed with a saturated aqueous sodium bicarbonate solution (2×50 mL), brine, dried over anhydrous sodium sulfate and then concentrated in vacuo. Purification by flash silica gel chromatography (silica gel from QingDao, 200-300 mesh, glass column from Shanghai SD company, 50% ethyl acetate/hexanes) afforded 1-benzenesulfonyl-5-methoxy-2-[2-(tetrahydro-pyran-4-yl)-1-(trifluoromethyl-phenyl)-vinyl]-1H-pyrrolo[2,3-b]pyridine (272 mg, 82%) as a light yellow solid: LC/MS m/e calcd for C28H25F3N2O4S [M+H]+ 543.58, observed 543.2.
Reaction SMILES: [CH3:1][C:2]1[O:6][N:5]=[C:4]([C:7]2[CH:12]=[CH:11][CH:10]=[C:9]([C:13]([F:16])([F:15])[F:14])[CH:8]=2)[C:3]=1[C:17]([OH:19])=O.Cl.C(N=C=NCCCN(C)C)C.OC1C2N=NNC=2C=CC=1.[N:42]1([C:48]2[CH:53]=[CH:52][C:51]([OH:54])=[CH:50][CH:49]=2)[CH2:47][CH2:46][NH:45][CH2:44][CH2:43]1>>[OH:54][C:51]1[CH:50]=[CH:49][C:48]([N:42]2[CH2:47][CH2:46][N:45]([C:17]([C:3]3[C:4]([C:7]4[CH:12]=[CH:11][CH:10]=[C:9]([C:13]([F:14])([F:15])[F:16])[CH:8]=4)=[N:5][O:6][C:2]=3[CH3:1])=[O:19])[CH2:44][CH2:43]2)=[CH:53][CH:52]=1
Reactant: Oc1ccc(N2CCNCC2)cc1
Reactant: Cc1onc(-c2cccc(C(F)(F)F)c2)c1C(=O)O
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: Oc1cccc2[nH]nnc12
Product: Cc1onc(-c2cccc(C(F)(F)F)c2)c1C(=O)N1CCN(c2ccc(O)cc2)CC1
Yield: 55.4 %

Procedure:
In a similar manner as described in Example 1, by using dimethylformimide (15 mL), 5-methyl-3-(3-(trifluoromethyl)phenyl)isoxazol-4-carboxylic acid (500 mg, 1.84 mmol), 1-ethyl-3-(dimethylaminopropyl)carbodiimide hydrochloride (388 mg, 2.02 mmol), hydroxybenzotriazole (299 mg, 2.21 mmol) and 4-(piperazine-1-yl)phenol (328 mg, 1.84 mmol), a white solid required compound (438 mg, 1.02 mmol, 55%) was obtained.
Reaction SMILES: [NH2:1][C@H:2]([C:8]([OH:10])=[O:9])[CH2:3][CH2:4][C:5]([OH:7])=O.[Na].[OH-].[Na+].[CH:14](=O)[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1.[BH4-].[Na+]>O.C(=O)C1C=CC=CC=1>[O:7]=[C:5]1[N:1]([CH2:14][C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[C@H:2]([C:8]([OH:10])=[O:9])[CH2:3][CH2:4]1
Reactant: N[C@@H](CCC(=O)O)C(=O)O
Reactant: O=Cc1ccccc1
Agent: [BH4-]
Agent: [Na+]
Agent: [Na]
Solvent: O
Product: O=C(O)[C@@H]1CCC(=O)N1Cc1ccccc1
Temperature: 10 °C
Reaction time: 0.17 h
Yield: 55 %

Procedure:
L-Glutamic acid, monosodium salt (250 g, 1.33 mol) was added at room temperature to a solution of sodium hydroxide (53.6 g, 1.34 mol) in 550 mL of water. To the resulting solution was added benzaldehyde (142.3 g, 1.34 mol). The mixture was stirred and cooled to 10° C. and sodium borohydride (15.2 g, 0.409 mol) was added in portions, keeping the temperature at 10°-15° C. The mixture was stirred for 30 min, and another portion of benzaldehyde (7.5 g, 0.07 mol) was added. After 10 min, a second portion of sodium borohydride (3.7 g, 0.10 mol) was added as before. The mixture was then allowed to stir at room temperature overnight. The solution was washed with methylene chloride (250 mL, discarded), and acidified to pH 3 with 6N HCl. The paste, consisting of N-(phenylmethyl)-L-glutamic acid, was diluted with 500 mL of H2O and heated to reflux overnight. The resulting solution was cooled to room temperature and extracted with chloroform. The combined extracts were washed with brine, dried over Na2SO4, and concentrated on a rotary evaporator to give 160 g (55% yield) of (S)-5-oxo-1-(phenylmethyl)-2-pyrrolidinecarboxylic acid as a white solid.
Reaction SMILES: [O:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[O:3][CH:2]1[CH2:10][NH2:11].[S:12](N)([NH2:15])(=[O:14])=[O:13]>O1CCOCC1>[O:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[O:3][CH:2]1[CH2:10][NH:11][S:12]([NH2:15])(=[O:14])=[O:13]
Reactant: NCC1Oc2ccccc2O1
Reactant: NS(N)(=O)=O
Solvent: C1COCCO1
Product: NS(=O)(=O)NCC1Oc2ccccc2O1

Procedure:
C-Benzo[1,3]dioxol-2-yl-methylamine (2.94 g, 19.4 mmol) and sulfamide (3.74 g, 38.9 mmol) were combined in dry dioxane (50 mL) and the solution was heated to reflux overnight. The reaction was concentrated and the residue was chromatographed (2% to 10% acetone in dichloromethane) to yield the title compound as a white solid.
Reaction SMILES: [N:1]1([CH2:6][C:7]2[CH:12]=[CH:11][C:10]([S:13]([N:16]3[CH2:21][CH2:20][N:19]([CH2:22][CH:23]4[CH2:28][CH2:27][N:26](C(OC(C)(C)C)=O)[CH2:25][CH2:24]4)[C:18](=[O:36])[CH2:17]3)(=[O:15])=[O:14])=[CH:9][CH:8]=2)[CH:5]=[CH:4][N:3]=[CH:2]1.[ClH:37]>C(OCC)(=O)C.CO>[ClH:37].[ClH:37].[N:1]1([CH2:6][C:7]2[CH:8]=[CH:9][C:10]([S:13]([N:16]3[CH2:21][CH2:20][N:19]([CH2:22][CH:23]4[CH2:28][CH2:27][NH:26][CH2:25][CH2:24]4)[C:18](=[O:36])[CH2:17]3)(=[O:14])=[O:15])=[CH:11][CH:12]=2)[CH:5]=[CH:4][N:3]=[CH:2]1
Reactant: CC(C)(C)OC(=O)N1CCC(CN2CCN(S(=O)(=O)c3ccc(Cn4ccnc4)cc3)CC2=O)CC1
Agent: Cl
Solvent: CO
Solvent: CCOC(C)=O
Product: O=C1CN(S(=O)(=O)c2ccc(Cn3ccnc3)cc2)CCN1CC1CCNCC1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To 4-[4-(1H-imidazol-1-ylmethyl)benzenesulfonyl]-1-[1-(tert-butoxycarbonyl)piperidin-4-ylmethyl]-2-piperazinone (420 mg) was added 4N hydrochloric acid in ethyl acetate (15 ml) and methanol (4 ml), and the mixture was stirred at room temperature for 30 minutes. The reaction solution was concentrated to give amorphous of the title compound (442 mg).
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6]([OH:9])=[CH:5][CH:4]=1)#[N:2].C(=O)(O[C:14]([CH3:18])([CH3:17])[C:15]#[CH:16])OC.C1CCN2C(=NCCC2)CC1>C(#N)C.C/C(/O)=C/C(C)=O.C/C(/O)=C/C(C)=O.[Cu]>[CH3:17][C:14]([O:9][C:6]1[CH:7]=[CH:8][C:3]([C:1]#[N:2])=[CH:4][CH:5]=1)([CH3:18])[C:15]#[CH:16]
Reactant: N#Cc1ccc(O)cc1
Reactant: C#CC(C)(C)OC(=O)OC
Agent: [Cu]
Agent: CC(=O)/C=C(/C)O
Solvent: C1CCC2=NCCCN2CC1
Solvent: CC#N
Product: C#CC(C)(C)Oc1ccc(C#N)cc1
Reaction time: 72 h

Procedure:
To a solution of 4-cyanophenol (3.0 g, 25.18 mmol) and methyl 1,1-dimethyl-2-propynyl carbonate (3.93 g, 27.64 mmol) in anhydrous acetonitrile (24 mL) at 0° C. under argon was added DBU (5.0 mL, 33.43 mmol). After the solution had cooled to ~0° C., copper(II) acetylacetonate (66.4 mg, 0.254 mmol) was added. After stirring at ~0° C. for 72 hours, the mixture was concentrated at reduced pressure. The residue was partitioned between 1N HCl (40 mL) and toluene (200 mL). The organic fraction was washed with 1N HCl (2×40 mL), 1N NaOH (2×40 mL), 1N NaHCO3, and brine. After drying (magnesium sulfate), the solvent was removed at reduced pressure to give crude title compound as a pale yellow oil. Distillation of the crude material (bulb to bulb) afforded the title compound as a colorless, low melting solid (4.59 g).
Reaction SMILES: [CH3:1][O:2][CH2:3][C@@H:4]([OH:6])[CH3:5].[Cl:7][C:8]1[N:13]=[C:12](Cl)[C:11]([Cl:15])=[CH:10][N:9]=1.[H-].[Na+]>C1COCC1>[Cl:7][C:8]1[N:13]=[C:12]([O:6][C@@H:4]([CH3:5])[CH2:3][O:2][CH3:1])[C:11]([Cl:15])=[CH:10][N:9]=1
Reactant: Clc1ncc(Cl)c(Cl)n1
Reactant: COC[C@H](C)O
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: COC[C@H](C)Oc1nc(Cl)ncc1Cl

Procedure:
(S)-1-Methoxypropan-2-ol (0.58 ml, 5.88 mmol) was added drop wise to a mixture of 2,4,5-trichloropyrimidine (0.63 ml, 5.34 mmol) and NaH (60% dispersion in mineral oil, 0.24 g, 5.88 mmol) in THF (10 ml) at room temperature. After 30 minutes the reaction mixture was partitioned between water and DCM, the organic layer washed with water, dried over Na2SO4 and evaporated to give the title compound as a yellow-brown oil. (UPLC-MS 7) tR 1.01; ESI-MS 237.0 and 238.9 [M+H]+.