Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: COC(C)(C)C.CCCCCC.[CH2:13]([O:20][C:21]([NH:23][C:24]1([C:31]([O:33][CH2:34][CH3:35])=[O:32])[CH2:29][C:28](=[O:30])[NH:27][C:25]1=[O:26])=[O:22])[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1>P([O-])([O-])([O-])=O.O1CCCC1>[CH2:13]([O:20][C:21]([NH:23][C@:24]1([C:31]([O:33][CH2:34][CH3:35])=[O:32])[CH2:29][C:28](=[O:30])[NH:27][C:25]1=[O:26])=[O:22])[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1
Reactant: CCOC(=O)C1(NC(=O)OCc2ccccc2)CC(=O)NC1=O
Agent: O=P([O-])([O-])[O-]
Solvent: CCCCCC
Solvent: C1CCOC1
Solvent: COC(C)(C)C
Product: CCOC(=O)[C@@]1(NC(=O)OCc2ccccc2)CC(=O)NC1=O
Yield: 36 %

Procedure:
0.5 g of esterase (PLE (21 kU/g); manufactured by Sigma-Aldrich Corporation, lyophilized powder) were dissolved in 200 mL of 0.07 mol/L phosphate buffer solution of which pH value was adjusted to 6-5 and thereto, a solution in which 10 g of 2-benzyloxycarbonylamino-2-ethoxycarbonyl succinimide were dissolved in 20 g of tetrahydrofuran was added. The resultant mixture was stirred at 30° C. for 48 hours and thereto, 100 mL of t-butyl methyl ether were added. Thereafter, the resultant mixture was filtered with Celite (No. 545) and washed with 50 mL of t-butyl methyl ether. After the filtrate was removed, the organic phase was washed with 100 ml, of water several times and the solvent was distilled off under reduced pressure. Thereafter, the product was recrystallized in ethyl acetate and hexane to thereby obtaining 3.6 g (yield: 36%) of (R)-2-benzyloxycarbonylamino-2-ethoxycarbonyl succinimide having an optical purity of 98.9% e.e. (enantiomeric excess) as a white crystal.
Reaction SMILES: CON(C)[C:4]([CH:6]1[CH2:11][CH2:10][NH:9][C:8](=[O:12])[CH2:7]1)=[O:5].C[Mg+].[Br-].[CH3:17]COCC>C1COCC1>[C:4]([CH:6]1[CH2:11][CH2:10][NH:9][C:8](=[O:12])[CH2:7]1)(=[O:5])[CH3:17]
Reactant: CCOCC
Reactant: CON(C)C(=O)C1CCNC(=O)C1
Agent: C[Mg+]
Agent: [Br-]
Solvent: C1CCOC1
Product: CC(=O)C1CCNC(=O)C1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
A solution of N-methoxy-N-methyl-2-oxopiperidine-4-carboxamide (2.72 g, 9.79 mmol) in THF (30 ml) was immersed in an ice-bath. MeMgBr (3M) in Et2O (4.57 ml, 13.70 mmol) was added slowly and the remaining white suspension was stirred for 1 h in an ice-bath and over night at room temperature. The reaction mixture was quenched carefully with aqueous saturated NaHCO3 and extracted with DCM. The organic layers were washed with brine, combined, dried over Na2SO4, filtered and concentrated in vacuo to obtain the title compound as yellow-brown oil. The crude product was directly used in the next step.
Reaction SMILES: [CH:1]([C:3]1[CH:10]=[CH:9][C:6]([C:7]#[N:8])=[CH:5][C:4]=1[C:11]([F:14])([F:13])[F:12])=O.[F:15][C:16]([F:28])([F:27])[C:17]1[CH:18]=[C:19]([NH:23][C:24]([NH2:26])=[O:25])[CH:20]=[CH:21][CH:22]=1.[C:29]([O:35][CH2:36][CH3:37])(=[O:34])[CH2:30][C:31]([CH3:33])=O.P(OCC)(OCC)(OCC)=O.O=P12OP3(OP(OP(O3)(O1)=O)(=O)O2)=O>C1COCC1>[CH3:33][C:31]1[N:23]([C:19]2[CH:20]=[CH:21][CH:22]=[C:17]([C:16]([F:27])([F:28])[F:15])[CH:18]=2)[C:24](=[O:25])[NH:26][CH:1]([C:3]2[CH:10]=[CH:9][C:6]([C:7]#[N:8])=[CH:5][C:4]=2[C:11]([F:14])([F:13])[F:12])[C:30]=1[C:29]([O:35][CH2:36][CH3:37])=[O:34]
Reactant: NC(=O)Nc1cccc(C(F)(F)F)c1
Reactant: CCOC(=O)CC(C)=O
Reactant: N#Cc1ccc(C=O)c(C(F)(F)F)c1
Agent: O=P12OP3(=O)OP(=O)(O1)OP(=O)(O2)O3
Solvent: C1CCOC1
Solvent: CCOP(=O)(OCC)OCC
Product: CCOC(=O)C1=C(C)N(c2cccc(C(F)(F)F)c2)C(=O)NC1c1ccc(C#N)cc1C(F)(F)F

Procedure:
The reaction was carried out under argon. 4-Formyl-3-(trifluoromethyl)benzonitrile (996 mg, 5.0 mmol; for the preparation cf. WO 98/37058), 1-[3-(trifluoromethyl)phenyl]urea (1.02 g, 5.0 mmol) and ethyl acetoacetate (651 mg, 5.0 mmol) were added successively to a solution of ethyl polyphosphate (2.0 g; prepared from triethyl phosphate and diphosphorus pentoxide analogously to the process in Example 18A) in THF (25 ml). The mixture was stirred under reflux for 19 h and then concentrated. Ethyl acetate (150 ml) was added to the residue, and the mixture was washed successively with water (50 ml), saturated sodium bicarbonate solution (50 ml) and saturated sodium chloride solution (50 ml). The organic phase was dried over sodium sulphate and concentrated. The residue was purified by silica gel chromatography (mobile phase: cyclohexane→cyclohexane/ethyl acetate 2:1). This gave 1.55 g (62% of theory) of the target product.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([O:8][C:9]2[C:10]([CH3:18])=[C:11]([CH2:16][OH:17])[CH:12]=[N:13][C:14]=2[CH3:15])[CH:5]=[CH:4][N:3]=1.[OH-].[Na+].[O-:21][Mn](=O)(=O)=O.[K+]>ClCCl>[Cl:1][C:2]1[CH:7]=[C:6]([O:8][C:9]2[C:14]([CH3:15])=[N:13][CH:12]=[C:11]([C:10]=2[CH3:18])[C:16]([OH:21])=[O:17])[CH:5]=[CH:4][N:3]=1
Reactant: Cc1ncc(CO)c(C)c1Oc1ccnc(Cl)c1
Reactant: O=[Mn](=O)(=O)[O-]
Agent: [K+]
Agent: [Na+]
Agent: [OH-]
Solvent: ClCCl
Product: Cc1ncc(C(=O)O)c(C)c1Oc1ccnc(Cl)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 50.5 %

Procedure:
(5-(2-chloropyridin-4-yloxy)-4,6-dimethylpyridin-3-yl)methanol (5.00 g, 18.9 mmol) was charged with NaOH (0.1N in H20, 19 ml, 1.9 mmol). Aqueous KMnO4 (3%, 119 mL, 22.7 mmol) was then added. The reaction stirred at ambient temperature overnight. The solution was diluted with dichloromethane, filtered through celite, and acidified with citric acid. The organic layer was separated and the aqueous layer was extracted with DCM. The combined organic layers were dried and concentrated to give the title compound (2.66 g, 51%).
Reaction SMILES: [O:1]=[C:2]1[N:6]([CH2:7][C:8]([OH:10])=[O:9])[CH2:5][CH2:4][O:3]1.C(=O)([O-])[O-].[K+].[K+].[CH2:17](Br)[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1>CN(C=O)C>[O:1]=[C:2]1[N:6]([CH2:7][C:8]([O:10][CH2:17][C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)=[O:9])[CH2:5][CH2:4][O:3]1
Reactant: O=C(O)CN1CCOC1=O
Reactant: BrCc1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: O=C(CN1CCOC1=O)OCc1ccccc1
Reaction time: 3 h
Yield: 30.8 %

Procedure:
To a stirred solution of 1.0 g (6.9 mmol) of (2-oxo-1,3-oxazolidin-3-yl)acetic acid in 10 mL of anhydrous DMF was added 1.0 g (7.6 mmol) of potassium carbonate followed by 1.0 mL (8.3 mmol) of benzyl bromide. The reaction mixture was stirred for 3 h then quenched with water. The aqueous phase was extracted with ethyl acetate (3×25 mL) and the combined organics were washed with water (2×10 mL), brine (10 mL), dried over magnesium sulfate, filtered and evaporated in vacuo. The crude residue was purified by silica gel chromatography eluting with 50% ethyl acetate in hexanes to afford the title compound as a white solid 0.50 g (31%). LC-MS: m/z (ES) 236 (MH)+.
Reaction SMILES: P(CCCC)(CCCC)CCCC.CCN(CC)CC.[CH2:21]([OH:26])[CH:22]([OH:25])[CH:23]=[CH2:24].I[C:28]1[CH:33]=[CH:32][C:31]([CH3:34])=[CH:30][CH:29]=1>CN(C=O)C.O>[OH:26][CH2:21][C:22](=[O:25])[CH2:23][CH2:24][C:28]1[CH:33]=[CH:32][C:31]([CH3:34])=[CH:30][CH:29]=1
Reactant: C=CC(O)CO
Reactant: Cc1ccc(I)cc1
Agent: CCCCP(CCCC)CCCC
Solvent: O
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: Cc1ccc(CCC(=O)CO)cc1
Temperature: 100 °C
Reaction time: 1.5 h
Yield: 73.3 %

Procedure:
To a stirred solution of Pd (OAc)2 (40 mg, 0.18 mmol), nBu3P (71 mg, 0.35 mmol), and Et3N (232 mg, 2.29 mmol) in DMF (5 ml) was added 3-butene-1,2-diol (155 mg, 1.76 mmol) followed by 4-iodotoluene (500 mg, 2.29 mmol), and the reaction mixture was stirred at 100° C. for 1.5 h. The reaction mixture was poured into water (50 ml) and extracted with ethyl acetate. The organic layer was washed with brine, dried (magnesium sulfate) and evaporated in vacuo. The residue was purified by silica gel (10 g) column chromatography eluting with toluene/ethyl acetate (50:1) to give 1-hydroxy-4-(p-tolyl)butan-2-one (230 mg, 73.4%) as a pale yellow solid.
Reaction SMILES: [C:1]1([C:7]2[C:16]3[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=3)[C:10](=[O:17])[NH:9][N:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[H-].[Na+].[H][H].Br[CH2:23][CH2:24][C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1.[OH-].[Na+]>CS(C)=O.O>[C:1]1([C:7]2[C:16]3[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=3)[C:10](=[O:17])[N:9]([CH2:23][CH2:24][C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=3)[N:8]=2)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: O=c1[nH]nc(-c2ccccc2)c2ccccc12
Reactant: [H][H]
Reactant: BrCCc1ccccc1
Agent: [H-]
Agent: [Na+]
Agent: [OH-]
Solvent: CS(C)=O
Solvent: O
Product: O=c1c2ccccc2c(-c2ccccc2)nn1CCc1ccccc1
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 95.1 %

Procedure:
Eighty-five grams (0.38 moles) of 4-phenyl-1(2H)-phthalazinone was added to 18.4 g (0.47 moles) of sodium hydride in 1 L of DMSO in four portions. The mixture was stirred for two hours at room temperature until evolution of hydrogen had ceased, and 95.5 g (0.52 moles) of 2-bromoethylbenzene was added. The mixture was stirred 1.5 hours at room temperature, 1 L of 2N NaOH was added and the slurry was poured into 1 L of water. The product was filtered off and dried to yield 118 g (95%) of 4-phenyl-2-(2-phenylethyl)-1(2H)-phthalazinone, mp 135-138.
Reaction SMILES: [C:1]([OH:6])(=[O:5])[C:2]([OH:4])=[O:3].[F:7][C:8]1[CH:13]=[CH:12][C:11]([CH2:14][N:15]2[C:19]3[CH:20]=[CH:21][CH:22]=[CH:23][C:18]=3[N:17]=[C:16]2[NH:24][CH:25]2[CH2:30][CH2:29][N:28]([CH2:31][CH2:32]NC3N(C)C4C=NC=CC=4N=3)[CH2:27][CH2:26]2)=[CH:10][CH:9]=1.O1C=CC=C1C[N:50]1C2C=CC=C[C:53]=2[N:52]=[C:51]1[NH:59][CH:60]1[CH2:65][CH2:64][N:63](CCN=C=S)[CH2:62][CH2:61]1>>[C:1]([OH:6])(=[O:5])[C:2]([OH:4])=[O:3].[F:7][C:8]1[CH:9]=[CH:10][C:11]([CH2:14][N:15]2[C:19]3[CH:20]=[CH:21][CH:22]=[CH:23][C:18]=3[N:17]=[C:16]2[NH:24][CH:25]2[CH2:30][CH2:29][N:28]([CH2:31][CH2:32][CH2:53][NH:52][C:51]3[NH:59][C:60]4[CH:61]=[CH:62][N:63]=[CH:64][C:65]=4[N:50]=3)[CH2:27][CH2:26]2)=[CH:12][CH:13]=1
Reactant: Cn1c(NCCN2CCC(Nc3nc4ccccc4n3Cc3ccc(F)cc3)CC2)nc2ccncc21
Reactant: S=C=NCCN1CCC(Nc2nc3ccccc3n2Cc2ccco2)CC1
Agent: O=C(O)C(=O)O
Product: Fc1ccc(Cn2c(NC3CCN(CCCNc4nc5cnccc5[nH]4)CC3)nc3ccccc32)cc1

Procedure:
N-[2-[4-[[1-[(4-fluorophenyl)methyl]-1H-benzimidazol-2-yl]amino]-1-piperidinyl]ethyl]-3-methyl-3H-imidazo[4,5-c]pyridin-2-amine ethanedioate(1:3) monohydrate; mp. 242.3° C. (compound 123).
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:9](=[N:10][CH:11]=1)[NH:8][C:7](=[O:12])[CH2:6][CH2:5]2.[CH3:13][N:14]([CH3:33])[CH2:15][CH2:16][N:17]1[C:25]2[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=2)[C:19]([CH2:26][N:27]([CH3:32])[C:28](=[O:31])[CH:29]=[CH2:30])=[CH:18]1.C1(C)C=CC=CC=1P(C1C=CC=CC=1C)C1C=CC=CC=1C.C(N(C(C)C)CC)(C)C>C(#N)CC.CC([O-])=O.CC([O-])=O.[Pd+2]>[CH3:33][N:14]([CH3:13])[CH2:15][CH2:16][N:17]1[C:25]2[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=2)[C:19]([CH2:26][N:27]([CH3:32])[C:28](=[O:31])/[CH:29]=[CH:30]/[C:2]2[CH:11]=[N:10][C:9]3[NH:8][C:7](=[O:12])[CH2:6][CH2:5][C:4]=3[CH:3]=2)=[CH:18]1
Reactant: C=CC(=O)N(C)Cc1cn(CCN(C)C)c2ccccc12
Reactant: O=C1CCc2cc(Br)cnc2N1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: Cc1ccccc1P(c1ccccc1C)c1ccccc1C
Solvent: CCC#N
Solvent: CCN(C(C)C)C(C)C
Product: CN(C)CCn1cc(CN(C)C(=O)/C=C/c2cnc3c(c2)CCC(=O)N3)c2ccccc21

Procedure:
A solution of 6-bromo-3,4-dihydro-1H-1,8-naphthyridin-2-one (0.61 g, 2.70 mmole), N-[1-(2-dimethylaminoethyl)-1H-indol-3-ylmethyl]-N-methyl-acrylamide (1.00 g, 3.50 mmole), Pd(OAc)2 (0.08 g, 0.35 mmole), tri-ortho-tolylphosphine (0.21 g, 0.70 mmole), and diisopropylethylamine (0.91 mL, 5.25 mmole) in propionitrile (70 mL) was deoxygenated, then was and heated to reflux under a N2 overnight. The dark mixture was filtered through a pad of celite®, and the filter pad was rinsed with acetonitrile (250 mL).
Reaction SMILES: [CH3:1][O:2][C:3]([C@@H:5]1[CH2:9][CH2:8][C:7](=[O:10])[N:6]1[C:11]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12])=[O:4].[C:18](OC(=O)C)(=[O:20])[CH3:19].CCN(CC)CC>C1COCC1.C1(C)C=CC=CC=1.CN(C)C1C=CN=CC=1>[CH3:1][O:2][C:3]([C@@H:5]1[CH2:9][CH2:8][CH:7]([O:10][C:18](=[O:20])[CH3:19])[N:6]1[C:11]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12])=[O:4]
Reactant: COC(=O)[C@@H]1CCC(=O)N1C(=O)OC(C)(C)C
Reactant: CC(=O)OC(C)=O
Agent: CN(C)c1ccncc1
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Solvent: Cc1ccccc1
Product: COC(=O)[C@@H]1CCC(OC(C)=O)N1C(=O)OC(C)(C)C
Temperature: -78 °C
Reaction time: 1 h

Procedure:
To a solution of (S)-5-oxo-pyrrolidine-1,2-dicarboxylic acid 1-tert-butyl ester 2-methyl ester (prepared according to J. Org. Chem. 2003, 60, 7219) (1.9 g, 7.8 mmol) in THF (25 mL), cooled to −78° C., was slowly added DibalH (1 M in toluene; 11.0 mL, 11.0 mmol) under an argon atmosphere, followed by stirring of the solution at −78° C. for 1 h. The reaction was quenched by addition of a saturated aqueous solution of NH4Cl (30 mL). The mixture was allowed to warm up to RT, and a 10% aqueous Na2CO3 solution (20 mL) and CH2Cl2 (70 mL) were subsequently added. The layers were separated and the aqueous phase was extracted with CH2Cl2 (2×50 mL). The combined organics were dried (Na2SO4) and concentrated in vacuo. The residue was dissolved in CH2Cl2 (25 mL), acetic anhydride (2.21 mL, 23.4 mmol), NEt3 (3.26 mL, 23.4 mmol) and 4-dimethylaminopyridine (0.2 g, 1.6 mmol) were subsequently added and the reaction mixture was stirred at RT overnight. The organics were washed with a saturated aqueous NaHCO3 solution (10 mL) and 1M aqueous HCl, dried (Phase separator) and concentrated in vacuo. The residue was purified by flash column chromatography on silica gel (c-hexane/EtOAc gradient 3:1 to 1:1) to give the title compound. TLC, Rf (c-hexane/EtOAc 1:1)=0.5; MS: 310.0 [M+Na]+, 597.3 [2M+Na]+.
Reaction SMILES: O.[C:2]1(=[O:8])[CH2:7][CH2:6][CH2:5][CH2:4][CH2:3]1.N1C[CH2:12][CH2:11][CH2:10]1.C(Br)C=C>C1(C)C=CC=CC=1>[CH2:12]([CH:3]1[CH2:4][CH2:5][CH2:6][CH2:7][C:2]1=[O:8])[CH:11]=[CH2:10]
Reactant: C1CCNC1
Reactant: O=C1CCCCC1
Solvent: O
Solvent: C=CCBr
Solvent: Cc1ccccc1
Product: C=CCC1CCCCC1=O

Procedure:
Into a 2 liter round bottom flask, equipped with Dean-Stark water separator, cyclohexanone (186 g, 1.90 moles, Aldrich) was dissolved in 1 liter toluene, and then pyrrolidine (292 g, 4.1 moles) was added. The mixture was brought to reflux overnight, during which 55 mL of water was collected. After switching to a distillation head, excess pyrrolindine and toluene were distilled off (1.2 liter). When most of the volatiles had been removed, aspirator vacuum was applied to assist in removal of residual toluene. In the same flask, the residue was dissolved in 1.2 liter of acetonitrile. Allyl bromide (305 g, 2.5 moles) was added dropwise. The mixture was heated slowly to gentle reflux overnight. After distilling off most of the acetonitrile and cooling, 1.2 liter of water was added and heated to reflux for 30 minutes. Extracted with ether after the mixture was cooled (200 mL×3). Combined ether layer was dried over sodium sulfate. The crude product, after removing the solvent, was purified by vacuum distillation: 73-78° C., 6.7 mmHg, Yield: 156 grams (59% for two steps). See also, Stork et al., J. American Chem. Soc., 85:207-222 (1963), and Johnson et al., J. American Chem. Soc., 88:149-159 (1966).
Reaction SMILES: ClC1C=C2C([CH:6]=[C:7]([C:11]3[C:12]([OH:31])=[C:13]([C:22]4[CH:27]=[CH:26][CH:25]=[C:24]([N+]([O-])=O)[CH:23]=4)[CH:14]=[C:15]([C:17]4[NH:21][N:20]=[N:19][N:18]=4)[CH:16]=3)N2)=CC=1C(N)=N.[N+:35](C1C=C(B(O)O)C=CC=1)([O-:37])=[O:36].C([O-])([O-])=[O:48].[Na+].[Na+].Cl>C(O)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.C1(C)C=CC=CC=1>[OH:31][CH:12]1[C:11]([C:7](=[O:48])[CH3:6])([N+:35]([O-:37])=[O:36])[CH:16]=[C:15]([C:17]2[NH:18][N:19]=[N:20][N:21]=2)[CH:14]=[C:13]1[C:22]1[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=1
Reactant: O=C([O-])[O-]
Reactant: O=[N+]([O-])c1cccc(B(O)O)c1
Reactant: N=C(N)c1cc2cc(-c3cc(-c4nnn[nH]4)cc(-c4cccc([N+](=O)[O-])c4)c3O)[nH]c2cc1Cl
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: Cl
Agent: [Na+]
Solvent: CCO
Solvent: Cc1ccccc1
Product: CC(=O)C1([N+](=O)[O-])C=C(c2nnn[nH]2)C=C(c2ccccc2)C1O
Temperature: 25 °C

Procedure:
A solution of 1-[3-bromo-2-hydroxy-5-(1H-tetrazol-5-yl)-phenyl]-ethanone (1, 1.07 g, 3.78 mmoles) and 3-nitrophenylboronic acid (0.69 g, 5.67 mmoles) in ethanol (8 mL) was mixes with toluene (25 mL), 2M Na2CO3 (2.8 mL) and the resulting mixture flushed with nitrogen. The nitrogen flushed reaction mixture then was combined with Pd(PPh3)4 (0.44 g, 0.38 mmoles) and the resulting solution was refluxed from about 8 to about 16 hours. The reaction mixture then was cooled to ambient temperature, acidified with 1N HCl and extracted with EtOAc (2×150 mL). The combined organic extracts were washed with brine, dried over anhydrous sodium sulfate and concentrated to afford compound 2 product as a colorless oil (1.22, 100%). MS (ESI, M++1): Calc. 325.08; Found 325.9.
Reaction SMILES: Cl[C:2]1[C:3](=[O:15])[N:4]([CH:10]([CH2:13][CH3:14])[CH2:11][CH3:12])[C:5]([CH3:9])=[C:6]([Cl:8])[N:7]=1.[Cl:16][C:17]1[CH:18]=[C:19]([O:26][CH3:27])[CH:20]=[C:21]2[C:25]=1[NH:24][CH2:23][CH2:22]2.C[Si](C)(C)[N-][Si](C)(C)C.[Na+].C([O-])(O)=O.[Na+]>C1COCC1>[Cl:8][C:6]1[N:7]=[C:2]([N:24]2[C:25]3[C:21](=[CH:20][C:19]([O:26][CH3:27])=[CH:18][C:17]=3[Cl:16])[CH2:22][CH2:23]2)[C:3](=[O:15])[N:4]([CH:10]([CH2:13][CH3:14])[CH2:11][CH3:12])[C:5]=1[CH3:9]
Reactant: CCC(CC)n1c(C)c(Cl)nc(Cl)c1=O
Reactant: COc1cc(Cl)c2c(c1)CCN2
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1CCOC1
Product: CCC(CC)n1c(C)c(Cl)nc(N2CCc3cc(OC)cc(Cl)c32)c1=O
Temperature: 25 °C
Reaction time: 8 h
Yield: 17 %

Procedure:
Part C: A solution 3,5-dichloro-1-(1-ethylpropyl)-6-methyl-2(1H)-pyrazinone from Part B (80 mg, 0.321 mmol) and 7-chloro-5-methoxyindoline (61.9 mg, 0.337 mmol) in THF (1.6 mL) was cooled to 0° C. and was treated with sodium hexamethyldisilazide (353 μL, 0.353 mmol, 1 M in THF). The reaction mixture was allowed to warm up to room temperature and was stirred overnight. The mixture was transferred to a separatory funnel containing saturated NaHCO3 and the aqueous layer was extracted with EtOAc (3×20 mL). The combined organic layers were washed with brine, dried over MgSO4, filtered and concentrated. The residue was purified by column chromatography on silica gel (10% EtOAc in hexanes→40% EtOAc in hexanes) to provide the target compound (22 mg, 17% yield) as a brown oil: 1H NMR (CDCl3) δ 6.72 (s, 2 H), 4.27 (t, J=7.88 Hz, 2 H), 4.00-3.95 (m, 1 H), 3.77 (s, 3 H), 3.09 (t, J=7.8 Hz, 2H), 2.48-2.38 (m, 2 H), 2.42 (s, 3 H), 1.95-1.81 (m, 2 H), 0.87 (t, J=7.5 Hz, 6 H); HRMS (ESI) m/z 396.1259 [(M+H)+, calcd for C19H24N3O2Cl2 396.1246].
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[N:9]=[CH:8][CH:7]=[C:6]2[O:15][C:16]1[C:22]([CH3:23])=[CH:21][C:19]([NH2:20])=[C:18]([CH3:24])[CH:17]=1.Cl[C:26](Cl)([O:28][C:29](=[O:35])OC(Cl)(Cl)Cl)Cl.OC1[CH:45]=[CH:44][C:41]([C:42]#[N:43])=[CH:40][CH:39]=1.C(=O)(O)[O-].[Na+]>C(Cl)Cl.C(N(CC)CC)C.C1(C)C=CC=CC=1>[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[N:9]=[CH:8][CH:7]=[C:6]2[O:15][C:16]1[C:22]([CH3:23])=[CH:21][C:19]([NH:20][C:29](=[O:35])[O:28][C:26]2[CH:45]=[CH:44][C:41]([C:42]#[N:43])=[CH:40][CH:39]=2)=[C:18]([CH3:24])[CH:17]=1
Reactant: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Reactant: N#Cc1ccc(O)cc1
Reactant: COc1cc2nccc(Oc3cc(C)c(N)cc3C)c2cc1OC
Agent: O=C([O-])O
Agent: [Na+]
Solvent: Cc1ccccc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COc1cc2nccc(Oc3cc(C)c(NC(=O)Oc4ccc(C#N)cc4)cc3C)c2cc1OC
Yield: 55.3 %

Procedure:
4-[(6,7-Dimethoxy-4-quinolyl)oxy]-2,5-dimethylaniline (50 mg) was added to toluene (5 ml) and triethylamine (0.5 ml), and the mixture was heated under reflux to prepare a solution. A solution of triphosgene (68 mg) in methylene chloride was then added thereto, and the mixture was heated under reflux for 10 min. Next, 4-hydroxybenzonitrile (27 mg) was added thereto, and the mixture was further stirred with heating under reflux for 3 hr. A saturated aqueous sodium bicarbonate solution was added to stop the reaction, and the reaction solution was then extracted with chloroform, followed by washing with a 1 N aqueous hydrochloric acid solution, water, and saturated brine in that order. The extract was dried over sodium sulfate and was then concentrated. The residue was purified on a column using chloroform/methanol to give the title compound (40 mg, yield 53%).
Reaction SMILES: [CH3:1][N:2]([CH3:6])[C:3](Cl)=[O:4].[C:7]([O:11][C:12](=[O:18])[NH:13][C@H:14]([CH3:17])[CH2:15][OH:16])([CH3:10])([CH3:9])[CH3:8].N1C=CC=CC=1>CN(C)C1C=CN=CC=1.C(Cl)Cl.CCOC(C)=O>[CH3:1][N:2]([CH3:6])[C:3](=[O:4])[O:16][CH2:15][C@H:14]([NH:13][C:12]([O:11][C:7]([CH3:10])([CH3:8])[CH3:9])=[O:18])[CH3:17]
Reactant: C[C@H](CO)NC(=O)OC(C)(C)C
Reactant: CN(C)C(=O)Cl
Agent: CN(C)c1ccncc1
Solvent: c1ccncc1
Solvent: ClCCl
Solvent: CCOC(C)=O
Product: C[C@H](COC(=O)N(C)C)NC(=O)OC(C)(C)C
Reaction time: 8 h

Procedure:
N,N-Dimethylcarbamoyl chloride (0.12 mL, 0.0013 mol) was added to a solution of tert-butyl[(1R)-2-hydroxy-1-methylethyl]carbamate (0.150 g, 0.856 mmol), 4-dimethylaminopyridine (0.02 g, 0.2 mmol) and pyridine (0.14 g, 1.7 mmol) in methylene chloride (3.0 mL). The mixture was stirred overnight, diluted with EtOAc and washed with 1N HCl, saturated NaHCO3 and brine. The organic layers were dried over Na2SO4, filtered, and concentrated. The residue was purified by chromatography on silica gel with EtOAc in hexanes (0-30%) to afford the desired product.
Reaction SMILES: [OH:1][N:2]=[C:3]([CH:6]=[CH:7][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:4]#[N:5].C(=NO)C=CC1C=CC=CC=1.[CH3:25][S:26](Cl)(=[O:28])=[O:27].C(N(CC)CC)C>O1CCCC1.O>[CH3:25][S:26]([O:1][N:2]=[C:3]([CH:6]=[CH:7][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:4]#[N:5])(=[O:28])=[O:27]
Reactant: N#CC(C=Cc1ccccc1)=NO
Reactant: CS(=O)(=O)Cl
Agent: ON=CC=Cc1ccccc1
Solvent: O
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CS(=O)(=O)ON=C(C#N)C=Cc1ccccc1
Temperature: 0 °C
Reaction time: 2 h
Yield: 54.7 %

Procedure:
3.44 g (0.02 mol) of 2-hydroxyimino-4-phenyl-but-3-enenitrile, (mp 127-129° C., prepared from cinnamaldoxime according to C. Trione et al, J. Org. Chem. 1993, 58, 2075) are dissolved in 20 ml of anhydrous tetrahydrofuran and cooled to 0° C. Methanesulfonyl chloride (1.7 ml, 0.022 mol) is added at once, followed by triethylamine (4.2 ml, 0.03 mol) dropwise over 15 min, keeping the temperature of the mixture at 5° C. The mixture is then stirred at 25° C. for two hours, and poured into 150 ml of iced water. The off-white precipitate is washed with ether, dried and recrystallyzed from 70 ml of ethanol, yielding 2.74 g (55%) of 2-methylsulfonyloxyimino-4-phenyl-but-3-enenitrile as colorless crystals, mp. 144-148° C. No attempt is made to recover more material from the ether extract.
Reaction SMILES: CN.[C:3]([O:7][CH2:8][CH3:9])(=[O:6])[CH:4]=[CH2:5].[CH:10]([N:13](C(C)C)CC)(C)C.Cl[C:20](=[O:27])[CH2:21][C:22]([O:24][CH2:25][CH3:26])=[O:23]>C(O)C.CN(C1C=CN=CC=1)C.ClCCl>[CH2:8]([O:7][C:3](=[O:6])[CH2:4][CH2:5][N:13]([C:20](=[O:27])[CH2:21][C:22]([O:24][CH2:25][CH3:26])=[O:23])[CH3:10])[CH3:9]
Reactant: CCN(C(C)C)C(C)C
Reactant: C=CC(=O)OCC
Reactant: CCOC(=O)CC(=O)Cl
Agent: CN
Agent: CN(C)c1ccncc1
Solvent: CCO
Solvent: ClCCl
Product: CCOC(=O)CCN(C)C(=O)CC(=O)OCC
Temperature: 0 °C
Reaction time: 2 h

Procedure:
To a cold (0° C.) solution of methylamine in ethanol (400 mL; 33% wt), ethyl acrylate (39.7 g, 0.397 mol) was added over a period of 20 minutes. The reaction mixture was stirred at 0° C. for 2 hours, and concentrated under vacuum. The crude product was used without further purification. The above crude product (21.8 g, 0.166 mol), diisopropylethylamine (28.9 mL, 0.166 mol), and 4-(N,N-dimethylamino)pyridine (2 g, 16 mmol) was dissolved in dichloromethane (300 mL) and cooled to 0° C. The mixture was treated with ethyl 3-chloro-3-oxopropionate (21.3 mL, 0.166 mol) and stirred at 0° C. for one hour. The mixture was allowed to warm up to room temperature and stirred overnight. The reaction mixture was partitioned with aq HCl (400 mL, 1M). The organic extract was washed with brine, dried over anhydrous magnesium sulfate, filtered, and concentrated under vacuum to provide the title compound as yellow oil