Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1][C:2]1[CH:9]=[CH:8][C:5]([CH:6]=[O:7])=[CH:4][CH:3]=1.[CH2:10](I)[CH2:11][CH:12]([CH3:14])[CH3:13].C(=O)([O-])[O-].[K+].[K+].O>CN(C)C=O>[CH3:13][CH:12]([CH3:14])[CH2:11][CH2:10][O:1][C:2]1[CH:9]=[CH:8][C:5]([CH:6]=[O:7])=[CH:4][CH:3]=1
Reactant: CC(C)CCI
Reactant: O=Cc1ccc(O)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: CC(C)CCOc1ccc(C=O)cc1
Temperature: 25 °C
Reaction time: 48 h
Yield: 94.5 %

Procedure:
A mixture of 1.00 g of p-hydroxybenzaldehyde, 1.46 g of isoamyl iodide and 1.80 g of potassium carbonate in 15 ml of N,N-dimethylformamide was stirred at room temperature for 2 days. Water was added to the reaction mixture, and the product was extracted with ethyl acetate. The ethyl acetate layer was washed in sequence with 1N sodium hydroxide, water and saturated aqueous solution of sodium chloride, dried over anhydrous magnesium sulfate and concentrated under reduced pressure to give 1.34 g of p-(3-methylbutoxy)benzaldehyde.
Reaction SMILES: [CH3:1][C:2]1([C:8]2[CH:9]=[C:10]([NH:14][S:15]([CH3:18])(=[O:17])=[O:16])[CH:11]=[CH:12][CH:13]=2)[CH:7]2[CH:3]1[CH2:4][NH:5][CH2:6]2.C(=O)([O-])O.[Na+].Br[CH2:25]/[CH:26]=[CH:27]/[C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1.C(OCC)C>CN(C)C=O.O>[NH3:5].[CH3:1][C:2]1([C:8]2[CH:9]=[C:10]([NH:14][S:15]([CH3:18])(=[O:17])=[O:16])[CH:11]=[CH:12][CH:13]=2)[CH:7]2[CH:3]1[CH2:4][N:5]([CH2:25]/[CH:26]=[CH:27]/[C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1)[CH2:6]2
Reactant: BrC/C=C/c1ccccc1
Reactant: CC1(c2cccc(NS(C)(=O)=O)c2)C2CNCC21
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCOCC
Solvent: CN(C)C=O
Solvent: O
Product: CC1(c2cccc(NS(C)(=O)=O)c2)C2CN(C/C=C/c3ccccc3)CC21
Product: N
Temperature: 50 °C
Reaction time: 0.08 h
Yield: 23.5 %

Procedure:
To a solution of the hydrochloride salt of N-[3-(6-methyl-3-azabicyclo[3.1.0]hex-6-yl)phenyl]methanesulfonamide (Preparation 53, 200 mg, 0.89 mmol) in N,N-dimethylformamide (8 ml) was added sodium hydrogen carbonate (3 g, 36 mmol) and 1-[(E)-3-bromo-1-propenyl]benzene (0.13 ml, 0.89 mmol) and the reaction mixture was heated at 50° C. for 20 h. After cooling, diethyl ether (15 ml) and water (15 ml) were added and the reaction mixture was stirred vigorously for 5 min. The phases were separated and the aqueous layer was further extracted with diethyl ether (2×15 ml). The combined organic extracts were dried (Na2SO4), filtered and concentrated in vacuo. The residual oil was purified by flash column chromatography using a Sep-Pak™ cartridge packed with silica gel (10 g) eluting with dichloromethane:ethanol:0.88 ammonia solution (200:8:1) to afford the title compound as an oil (40 mg, 12%).
Reaction SMILES: [Br:1][CH2:2][CH2:3][OH:4].[CH2:5]=[C:6]1[O:10][C:8](=[O:9])[CH2:7]1>ClCCl.CN(C)C1C=CN=CC=1.CC(C)=O>[C:8]([O:4][CH2:3][CH2:2][Br:1])(=[O:9])[CH2:7][C:6]([CH3:5])=[O:10]
Reactant: C=C1CC(=O)O1
Reactant: OCCBr
Agent: CN(C)c1ccncc1
Solvent: CC(C)=O
Solvent: ClCCl
Product: CC(=O)CC(=O)OCCBr
Reaction time: 1 h

Procedure:
250 g of 2-bromoethanol are dissolved in 1.3 l of dichloromethane, and 1.2 g of 4-dimethylaminopyridine are added. 400 ml of a 50% strength diketene solution in acetone are added dropwise with vigorous stirring, so that the solvent boils moderately. After the dropwise addition, stirring is continued for a further 1 h at the boiling point and the mixture is then left to stand overnight. After the solvent has been evaporated off in a rotary evaportor in vacuo, the residue is distilled. 402 g of the title compound of b.p. 80°-83° C./0.04 mbar are obtained.
Reaction SMILES: [H-].[Al+3].[Li+].[H-].[H-].[H-].[CH2:7]([N:14]1[C:18](=O)[CH2:17][CH:16]([C:20](OC)=[O:21])[CH2:15]1)[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1.O>C1COCC1>[CH2:7]([N:14]1[CH2:18][CH2:17][CH:16]([CH2:20][OH:21])[CH2:15]1)[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1
Reactant: COC(=O)C1CC(=O)N(Cc2ccccc2)C1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: O
Solvent: C1CCOC1
Product: OCC1CCN(Cc2ccccc2)C1
Temperature: -5 °C
Yield: 95.2 %

Procedure:
A suspension of lithium aluminum hydride (7.50 g) in 150 ml THF was cooled to -5° C. A solution of methyl 1-benzyl-5-oxo-3-pyrrolidine carboxylate (0.064 moles, 15.0 g) in THF was added dropwise. The mixture was heated to 40° C. for 16 hours. Water (25 ml) was added. The mixture was filtered and extracted with ether. The organic phase was washed with water, dried over sodium sulfate and concentrated to yield 11.65 g of N-benzyl-3-hydroxymethylpyrrolidine. (MS) The alcohol (0.06 moles, 11.5 g) in 75 ml 2N sulfuric acid was added dropwise to a stirred solution of chromium dioxide (0.15 moles, 15.0 g) in 100 ml 2N sulfuric acid. The solution was stirred at room temperature for 16 hours. The solution was treated with barium hydroxide hydrate (0.317 mmoles, 100 g) in 250 ml hot water. The solid was filtered and washed with water. The aqueous solution was extracted with ether. Carbon dioxide was bubbled through the solution until the pH was 7.0. The solution was filtered and concentrated to yield 4.5 g of N-benzyl-3-pyrrolidinecarboxylic acid. (MS) The oil was dissolved in 50 ml methanol. Dry HC1 gas was bubbled through the solution. The solution was heated to near reflux for 4 hours and concentrated. The residue was neutralized with aqueous sodium bicarbonate. The product was extracted with ether, dried and concentrated to yield 3.0 g of methyl N-benzyl-3-pyrrolidinecarboxylate.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:17][C:16]([CH3:19])([CH3:18])[C:15]2[C:10](=[CH:11][C:12]([NH:20][C:21]([C:23]3[C:24](F)=[N:25][CH:26]=[CH:27][CH:28]=3)=[O:22])=[CH:13][CH:14]=2)[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].Cl.[NH:31]1[C:35]2=[N:36][CH:37]=[CH:38][C:39]([CH2:40][NH2:41])=[C:34]2[CH2:33][CH2:32]1.CCN(C(C)C)C(C)C>>[C:1]([O:5][C:6]([N:8]1[CH2:17][C:16]([CH3:19])([CH3:18])[C:15]2[C:10](=[CH:11][C:12]([NH:20][C:21]([C:23]3[C:24]([NH:41][CH2:40][C:39]4[CH:38]=[CH:37][N:36]=[C:35]5[NH:31][CH2:32][CH2:33][C:34]=45)=[N:25][CH:26]=[CH:27][CH:28]=3)=[O:22])=[CH:13][CH:14]=2)[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)OC(=O)N1Cc2cc(NC(=O)c3cccnc3F)ccc2C(C)(C)C1
Reactant: NCc1ccnc2c1CCN2
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)(C)OC(=O)N1Cc2cc(NC(=O)c3cccnc3NCc3ccnc4c3CCN4)ccc2C(C)(C)C1

Procedure:
A mixture of 7-[(2-fluoro-pyridine-3-carbonyl)-amino]-4,4-dimethyl-3,4-dihydro-1H-isoquinoline-2-carboxylic acid tert-butyl ester (0.187 g), C-(2,3-dihydro-1H-pyrrolo[2,3-b]pyridin-4-yl)-methylamine HCl salt (0.098 g, step B), DIEA (1.0 mL) and IpOH (1.5 mL) was subjected to a Microwave condition (170° C., 1000 s). Solvent was removed and the residue was purified by chromatography through silica gel (70 g, 1-4% MeOH/CH2Cl2 with 1% NH4OH, stepwise gradient) to afford 7-({2-[(2,3-dihydro-1H-pyrrolo[2,3-b]pyridin-4-ylmethyl)-amino]-pyridine-3-carbonyl}-amino)-4,4-dimethyl-3,4-dihydro-1H-isoquinoline-2-carboxylic acid tert-butyl ester as cream color solid. MS: (ES+) 529 (M+H). Calc'd. for C30H36N6O3—528.65.
Reaction SMILES: [C:1]1([CH:7]([OH:10])[CH2:8][OH:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.N1C=CN=C1.[C:16]([Si:20](Cl)([CH3:22])[CH3:21])([CH3:19])([CH3:18])[CH3:17]>CN(C=O)C.C(OCC)(=O)C>[Si:20]([O:9][CH2:8][CH:7]([C:1]1[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1)[OH:10])([C:16]([CH3:19])([CH3:18])[CH3:17])([CH3:22])[CH3:21]
Reactant: OCC(O)c1ccccc1
Reactant: CC(C)(C)[Si](C)(C)Cl
Agent: c1c[nH]cn1
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CC(C)(C)[Si](C)(C)OCC(O)c1ccccc1
Temperature: 0 °C
Reaction time: 1.5 h

Procedure:
A mixture of 1-phenyl-1,2-ethanediol (1.38 g, 10 mmole), immidazole (817 mg, 12 mmole), and tert-butylchlorodimethylsilane (1.81 g, 12 mmole) in DMF 15 (ml) was stirred at 0° C. for 1.5 hrs and then at room temperature overnight. The resulting mixture was diluted with ethyl acetate, washed with water, brine, and dried over sodium sulfate. After removal of the solvent, the residue was purified by silica gel column chromatography using ethyl acetate-hexane (1:4) as eluent. 2-(tert-butyidimethylsilyl)oxy-1-phenylethanol was obtained as an oil (2.6 g, 100% yield).
Reaction SMILES: [CH:1]1[C:6]([NH2:7])=[CH:5][CH:4]=[C:3]([OH:8])[CH:2]=1.[C:9]1(=O)[O:14][C:12](=[O:13])[CH:11]=[CH:10]1.O=P12OP3(OP(OP(O3)(O1)=O)(=O)O2)=O.CN(C)C=O>O>[OH:8][C:3]1[CH:4]=[CH:5][C:6]([N:7]2[C:12](=[O:13])[CH:11]=[CH:10][C:9]2=[O:14])=[CH:1][CH:2]=1
Reactant: Nc1ccc(O)cc1
Reactant: O=C1C=CC(=O)O1
Agent: O=P12OP3(=O)OP(=O)(O1)OP(=O)(O2)O3
Solvent: CN(C)C=O
Solvent: O
Product: O=C1C=CC(=O)N1c1ccc(O)cc1
Temperature: 15 °C
Reaction time: 2 h
Yield: 48.4 %

Procedure:
In a reactor, 30.0 g (0.275 moles of p-aminophenol, 29.7 g (0.303 moles) of maleic anhydride, 39.0 g (0.275 moles) of phosphorus pentoxide and 100 g of dimethylformamide were charged and stirred at 15° C. for 2 hours. The reaction mixture was then gradually heated to 60° C., at which temperature the reaction was further continued for 2.5 hours. After cooling to room temperature, the resulting reaction mixture was admixed with water to precipitate N-(p-hydroxyphenyl)maleimide in the form of crystals. The crystals were separated by filtration, washed with water and then dried to obtain 25.1 g (0.133 moles) of N-(p-hydroxyphenyl)maleimide (yield 48.2%).
Reaction SMILES: [NH2:1][C:2]1[CH:10]=[CH:9][C:8]([Cl:11])=[CH:7][C:3]=1[C:4]([OH:6])=[O:5].[Cl:12][CH2:13][C:14](Cl)=[O:15].C(=O)([O-])[O-].[K+].[K+].Cl>C(#N)C>[Cl:12][CH2:13][C:14]([NH:1][C:2]1[CH:10]=[CH:9][C:8]([Cl:11])=[CH:7][C:3]=1[C:4]([OH:6])=[O:5])=[O:15]
Reactant: O=C(Cl)CCl
Reactant: Nc1ccc(Cl)cc1C(=O)O
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: O=C(CCl)Nc1ccc(Cl)cc1C(=O)O

Procedure:
12.5 g (73 mmol) of 2-amino-5-chlorobenzoic acid are initially introduced into 500 ml of acetonitrile and treated with 9.0 g (80 mmol) of chloroacetyl chloride with stirring, the temperature being kept at 20°-25° C. (ice-bath). 22 g (0.16 mol) of finely pulverized potassium carbonate are then introduced and the mixture is stirred overnight at room temperature. The batch is adjusted to pH 2 with dilute hydrochloric acid and the acetonitrile is stripped off on a rotary evaporator. The precipitate is filtered off with suction and washed well with water. The crude product is treated with sodium bicarbonate solution and stirred. Insoluble matter is filtered off with suction and the filtrate acidified with dilute hydrochloric acid to pH 2. The precipitated product is filtered off with suction and dried. Yield: 7 g (77.3% of theory) M.p.: 188° C.
Reaction SMILES: [C:1]([CH:4]([N:8]1[CH:11]([S:12][N:13]2[C:17](=[O:18])[C:16]3=[CH:19][CH:20]=[CH:21][CH:22]=[C:15]3[C:14]2=[O:23])[CH:10]([NH:24][C:25](=[O:33])[CH2:26][C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)[C:9]1=[O:34])[C:5]([CH3:7])=[CH2:6])([OH:3])=[O:2].[N+](=[CH2:37])=[N-].C(OC(=O)C)C.C1(C)C=CC=CC=1>C(OCC)C>[CH3:37][O:2][C:1]([CH:4]([N:8]1[CH:11]([S:12][N:13]2[C:14](=[O:23])[C:15]3=[CH:22][CH:21]=[CH:20][CH:19]=[C:16]3[C:17]2=[O:18])[CH:10]([NH:24][C:25](=[O:33])[CH2:26][C:27]2[CH:28]=[CH:29][CH:30]=[CH:31][CH:32]=2)[C:9]1=[O:34])[C:5]([CH3:7])=[CH2:6])=[O:3]
Reactant: C=C(C)C(C(=O)O)N1C(=O)C(NC(=O)Cc2ccccc2)C1SN1C(=O)c2ccccc2C1=O
Reactant: C=[N+]=[N-]
Solvent: CCOCC
Solvent: Cc1ccccc1
Solvent: CCOC(C)=O
Product: C=C(C)C(C(=O)OC)N1C(=O)C(NC(=O)Cc2ccccc2)C1SN1C(=O)c2ccccc2C1=O
Yield: 62 %

Procedure:
14 g (purity 70%; 20 mmoles) of 1-(1-carboxy-2-methylprop-2-enyl)-3-phenylacetamido-4-phthalimidothio-azetidin-2-one was treated with a diazomethane solution in diethyl ether. After evaporation of the reaction mixture to dryness, benzene was added. After filtering off the phthalimide, the filtrate was concentrated and chromatographed [silica gel; toluene - ethyl acetate 4:1 (v/v] to obtain 6.24 g (62% yield) of 1-(1-methoxycarbonyl-2-methylprop-2-enyl)-3-phenylacetamido-4-phthalimidothio-azetidin-2-one.
Reaction SMILES: [C:1]([CH:4]([N:8]1[CH:11]([S:12][N:13]2[C:17](=[O:18])[C:16]3=[CH:19][CH:20]=[CH:21][CH:22]=[C:15]3[C:14]2=[O:23])[CH:10]([NH:24][C:25](=[O:33])[CH2:26][C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)[C:9]1=[O:34])[C:5]([CH3:7])=[CH2:6])([OH:3])=[O:2].[N+](=[CH2:37])=[N-].C(O)(=O)C>O1CCCC1.C(OCC)C>[CH3:37][O:2][C:1]([CH:4]([N:8]1[CH:11]([S:12][N:13]2[C:14](=[O:23])[C:15]3=[CH:22][CH:21]=[CH:20][CH:19]=[C:16]3[C:17]2=[O:18])[CH:10]([NH:24][C:25](=[O:33])[CH2:26][C:27]2[CH:28]=[CH:29][CH:30]=[CH:31][CH:32]=2)[C:9]1=[O:34])[C:5]([CH3:7])=[CH2:6])=[O:3]
Reactant: C=C(C)C(C(=O)O)N1C(=O)C(NC(=O)Cc2ccccc2)C1SN1C(=O)c2ccccc2C1=O
Reactant: C=[N+]=[N-]
Solvent: CCOCC
Solvent: C1CCOC1
Solvent: CC(=O)O
Product: C=C(C)C(C(=O)OC)N1C(=O)C(NC(=O)Cc2ccccc2)C1SN1C(=O)c2ccccc2C1=O

Procedure:
To a suspension of 14 g (29 mmoles) of 1-(1-carboxy-2-methylprop-2-enyl)-3-phenylacetamido-4-phthalimidothio-azetidin-2-one (prepared as described in Example 5 B) in 100 ml of tetrahydrofuran a solution of 35 mmoles of diazomethane in diethyl ether was added. The clear solution was treated with acetic acid to remove excess diazomethane and evaporated to dryness. After addition of 100 ml of benzene the solution was filtered, concentrated and chromatographed on a column containing 500 g of silica gel using a 4:1 (v/v) mixture of toluene and ethyl acetate as an eluent. There was obtained 1-(1-methoxycarbonyl-2-methylprop-2-enyl)-3-phenylacetamido-4-phthalimidothio-azetidin-2-one.
Reaction SMILES: [CH3:1][N:2]1[CH:6]2[CH2:7][CH:8]([OH:10])[CH2:9][CH:3]1[CH2:4][CH2:5]2.C(N(CC)CC)C.[CH3:18][S:19](Cl)(=[O:21])=[O:20].C(=O)([O-])[O-].[K+].[K+]>ClCCl.O>[CH3:1][N:2]1[CH:6]2[CH2:7][CH:8]([O:10][S:19]([CH3:18])(=[O:21])=[O:20])[CH2:9][CH:3]1[CH2:4][CH2:5]2
Reactant: CS(=O)(=O)Cl
Reactant: CN1C2CCC1CC(O)C2
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CN1C2CCC1CC(OS(C)(=O)=O)C2
Temperature: 20 °C
Reaction time: 0.5 h
Yield: 78.1 %

Procedure:
Tropine (50 g) and triethylamine (60 mL, 43.56 g) in dichloromethane (1 L) were cooled to −10° C. Methane sulphonyl chloride (36 mL, 53.28 g) in dichloromethane (0.2 L) was added over 1 h at −5+/−2° C. After 0.5 h a solution of potassium carbonate (150 g) in water (0.4 L) was added and the mixture warmed to 20° C. The phases were separated and the aqueous phase extracted with further dichloromethane (1×0.2 L). The combined dichloromethane solution was concentrated by distillation collecting 1 L. n-Heptane (0.875 L) was added and the mixture stirred for 0.5 h. The solution was decanted off and then concentrated by distillation at 610 to 650 mbar until a solution temperature of 63° C. was reached. The solution was cooled to 0° C. with crystallization occurring during the cooling. The mixture was stirred for 1 h, the product isolated by filtration, washed and dried at <30° C. to give the title compound (60.62 g, 78.1%).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][C:11]=1[C:12](O)=[O:13])[N:8]=[CH:7][N:6]=[C:5]2[NH:15][CH:16]([C:18]1[NH:22][C:21]2[CH:23]=[CH:24][C:25]([Cl:27])=[CH:26][C:20]=2[N:19]=1)[CH3:17].FC1C(OC(N(C)C)=[N+](C)C)=C(F)C(F)=C(F)C=1F.F[P-](F)(F)(F)(F)F.C(N(C(C)C)CC)(C)C.[NH:63]1[CH2:68][CH2:67][CH2:66][CH2:65][CH:64]1[C:69]([O:71][CH2:72][CH3:73])=[O:70]>CS(C)=O>[Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][C:11]=1[C:12]([N:63]1[CH2:68][CH2:67][CH2:66][CH2:65][CH:64]1[C:69]([O:71][CH2:72][CH3:73])=[O:70])=[O:13])[N:8]=[CH:7][N:6]=[C:5]2[NH:15][CH:16]([C:18]1[NH:22][C:21]2[CH:23]=[CH:24][C:25]([Cl:27])=[CH:26][C:20]=2[N:19]=1)[CH3:17]
Reactant: CCOC(=O)C1CCCCN1
Reactant: CC(Nc1ncnc2cc(C(=O)O)c(Cl)cc12)c1nc2cc(Cl)ccc2[nH]1
Agent: CN(C)C(Oc1c(F)c(F)c(F)c(F)c1F)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CS(C)=O
Solvent: CCN(C(C)C)C(C)C
Product: CCOC(=O)C1CCCCN1C(=O)c1cc2ncnc(NC(C)c3nc4cc(Cl)ccc4[nH]3)c2cc1Cl

Procedure:
Prepared analogously to Example 37a from 6-chloro-4-[1-(5-chloro-1H-benzimidazol-2-yl)-ethylamino]-7-hydroxycarbonyl-quinazoline, pentafluorophenyl-tetramethyluronium-hexafluorophosphate (PFTU), diisopropylethylamine and ethyl piperidine-2-carboxylate in DMSO at ambient temperature.
Reaction SMILES: CCOC(/N=N/C(OCC)=O)=O.O[CH2:14][CH2:15][C:16]1[C:21]([C:22]([NH:24][CH2:25][C:26]2[CH:31]=[CH:30][C:29]([O:32][CH3:33])=[CH:28][CH:27]=2)=[O:23])=[CH:20][N:19]=[CH:18][CH:17]=1.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.CO>C1COCC1.C(Cl)(Cl)Cl>[CH3:33][O:32][C:29]1[CH:30]=[CH:31][C:26]([CH2:25][N:24]2[CH2:14][CH2:15][C:16]3[C:21](=[CH:20][N:19]=[CH:18][CH:17]=3)[C:22]2=[O:23])=[CH:27][CH:28]=1
Reactant: COc1ccc(CNC(=O)c2cnccc2CCO)cc1
Agent: CCOC(=O)/N=N/C(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CO
Solvent: ClC(Cl)Cl
Solvent: C1CCOC1
Product: COc1ccc(CN2CCc3ccncc3C2=O)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 49.8 %

Procedure:
DEAD (1.094 g, 6.286 mmol) was added drop wise to a solution of 4-(2-hydroxyethyl)-N-(4-methoxybenzyl)nicotinamide (I-65d: 1.5 g, 5.238 mmol) and PPh3 (2.784 g, 10.477 mmol) in THF (40 mL) at 0° C. and the resulting reaction mass was stirred at room temperature for 1 hour. The reaction was monitored by TLC (10% methanol in CHCl3). The reaction mass was concentrated under reduced pressure and the crude residue was purified by column chromatography on silica gel (3% methanol in DCM) to afford 700 mg of the product (49.82% yield).
Reaction SMILES: [Br:1][C:2]1[C:3]([OH:9])=[N:4][CH:5]=[C:6]([Cl:8])[CH:7]=1.[CH2:10](Br)[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1>C1(C)C=CC=CC=1.C(=O)([O-])[O-].[Ag+2]>[CH2:10]([O:9][C:3]1[C:2]([Br:1])=[CH:7][C:6]([Cl:8])=[CH:5][N:4]=1)[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1
Reactant: Oc1ncc(Cl)cc1Br
Reactant: BrCc1ccccc1
Agent: [Ag+2]
Agent: O=C([O-])[O-]
Solvent: Cc1ccccc1
Product: Clc1cnc(OCc2ccccc2)c(Br)c1

Procedure:
3-Bromo-5-chloro-2-pyridinol (7.0 g, 33.6 mmol) was stirred in toluene (160 ml) and silver carbonate (10.23 g, 36.9 mmol) added, followed by benzyl bromide (6.32 g, 4.39 ml, 36.9 mmol). The mixture was heated to reflux for 1 hour. After cooling, the mixture was filtered, washed with water (×2), dried (MgSO4) and evaporated. The residue was triturated with isohexane and the pale yellow solid filtered and dried. (8.36 g).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([OH:9])[CH:5]=[CH:6][C:7]=1[F:8].C([Mg]Cl)(C)C.[CH:15]([N:28]1[C:38]2[C:33](=[CH:34][CH:35]=[CH:36][CH:37]=2)[C:31](=[O:32])[C:29]1=[O:30])([C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1>O1CCCC1>[F:1][C:2]1[C:7]([F:8])=[CH:6][C:5]([C:31]2([OH:32])[C:33]3[C:38](=[CH:37][CH:36]=[CH:35][CH:34]=3)[N:28]([CH:15]([C:16]3[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=3)[C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=3)[C:29]2=[O:30])=[C:4]([OH:9])[CH:3]=1
Reactant: O=C1C(=O)N(C(c2ccccc2)c2ccccc2)c2ccccc21
Reactant: Oc1ccc(F)c(F)c1
Agent: CC(C)[Mg]Cl
Solvent: C1CCOC1
Product: O=C1N(C(c2ccccc2)c2ccccc2)c2ccccc2C1(O)c1cc(F)c(F)cc1O
Temperature: 25 °C
Reaction time: 3 h
Yield: 62.1 %

Procedure:
To a solution of 3,4-difluorophenol (10.33 g, 79.4 mmol) in anhydrous tetrahydrofuran (60 mL) at 0° C. under nitrogen was added isopropyl magnesium chloride (39.7 mL, 79.4 mmol), and the solution was stirred at ambient temperature for 3 h. Tetrahydrofuran was removed by rotary evaporation, and the residue was redissolved in anhydrous dichloromethane (140 mL). The solution was cooled to 0° C. under nitrogen, then N-benzhydryl isatin (13.77 g, 43.9 mmol) was added and the reaction mixture was allowed to warm to ambient temperature. After 3 days, the reaction was quenched with aqueous saturated ammonium chloride (60 mL) and concentrated in vacuo. The residue was re-dissolved in ethyl acetate (150 mL) and washed with water (2×100 mL) and brine (100 mL), dried over sodium sulfate, filtered, and concentrated. The residue was precipitated from diethyl ether to yield 3-(4,5-difluoro-2-hydroxyphenyl)-1-(diphenylmethyl)-3-hydroxy-1,3-dihydro-2H-indol-2-one (12.08 g, 61%) as a colorless solid: 1H NMR (300 MHz, CDCl3) δ 9.23 (brs, 1H), 7.47-7.44 (m, 1H), 7.35-7.21 (m, 9H), 7.18-7.11 (m, 2H), 6.90 (s, 1H), 6.83 (dd, J=11.2, 6.9 Hz, 1H), 6.67 (dd, J=11.2, 8.7 Hz, 1H), 6.56-6.51 (m, 1H), 4.13 (brs, 1H); MS (ES+) m/z 426.2 (M−17).
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]([CH2:10][C:11]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12])[CH:6]=[CH:7][C:8]=1F)#[N:2].[OH:18][C:19]1[CH:28]=[CH:27][C:22]([C:23]([O:25][CH3:26])=[O:24])=[CH:21][CH:20]=1.C([O-])([O-])=O.[K+].[K+].CS(C)=O>O.CCOC(C)=O>[C:14]([O:13][C:11](=[O:12])[CH2:10][C:5]1[CH:6]=[CH:7][C:8]([O:18][C:19]2[CH:20]=[CH:21][C:22]([C:23]([O:25][CH3:26])=[O:24])=[CH:27][CH:28]=2)=[C:3]([C:1]#[N:2])[CH:4]=1)([CH3:17])([CH3:16])[CH3:15]
Reactant: COC(=O)c1ccc(O)cc1
Reactant: CC(C)(C)OC(=O)Cc1ccc(F)c(C#N)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: O
Solvent: CS(C)=O
Product: COC(=O)c1ccc(Oc2ccc(CC(=O)OC(C)(C)C)cc2C#N)cc1
Temperature: 90 °C
Reaction time: 1 h
Yield: 78.9 %

Procedure:
A flask was charged with tert-butyl 2-(3-cyano-4-fluorophenyl)acetate (9.410 g, 40.00 mmol), methyl 4-hydroxybenzoate (7.303 g, 48.00 mmol), K2CO3 (6.634 g, 48.00 mmol), and DMSO (160 mL). The mixture was heated to 90° C. under a nitrogen atmosphere for 17 hours. The mixture was cooled to ambient temperature and poured into a mixture of EtOAc (250 mL) and 10% K2CO3 solution (250 mL). The resulting insoluble residue was dissolved in water and added to the EtOAc-aqueous mixture. The mixture was stirred for 1 hour and layers were separated. The aqueous layer was extracted with EtOAc, and the combined extracts were washed with saturated K2CO3, water, and brine, dried over MgSO4, filtered through a Celite pad, and concentrated under reduced pressure to give 14.7 g of crude product as an oil. The crude material was purified by silica gel chromatography to provide methyl 4-(4-(2-tert-butoxy-2-oxoethyl)-2-cyanophenoxy)benzoate (11.6 g, 79%) as a white solid.
Reaction SMILES: Cl[C:2]([O:4]CC)=[O:3].[CH3:7][O:8][C:9]1[CH:10]=[CH:11][C:12]2[CH:13]([CH3:21])[CH:14]3[CH2:18][NH:17][CH2:16][CH:15]3[C:19]=2[CH:20]=1>C1COCC1.O>[CH2:16]([NH:17][C:2](=[O:3])[O-:4])[CH3:15].[CH3:7][O:8][C:9]1[CH:10]=[CH:11][C:12]2[CH:13]([CH3:21])[CH:14]3[CH2:18][NH:17][CH2:16][CH:15]3[C:19]=2[CH:20]=1
Reactant: CCOC(=O)Cl
Agent: COc1ccc2c(c1)C1CNCC1C2C
Solvent: C1CCOC1
Solvent: O
Product: CCNC(=O)[O-]
Temperature: 25 °C
Reaction time: 8 h

Procedure:
Hydrogen sodium carbonate (11.7 g, 139 mmol) and ethyl chloroformate (3.2 mL, 33.4 mmol) were added to a solution of 5-methoxy-8-methyl-1,2,3,3a,8,8a-hexahydroindeno[1,2-c]pyrrole (from Example 1, Step E) (5.6 g, 27.8 mmol) in THF/H2O (140 mL, 1/1, v/v), and stirred overnight at room temperature. The reaction mixture was quenched by addition of an aqueous HCl solution (200 mL, 1.0 M) and the product was extracted with EtOAc (3×100 mL). The combined organic extracts were dried over MgSO4 and concentrated. The crude product was purified by column chromatography (SiO2) using a 0-35% ethyl acetate-hexanes gradient to afford 2.7 g (35%) of the subtitle compound. 1H NMR (CDCl3 300 MHz) * 7.07 (d, 1H), 6.78 (m, 2H), 4.09 (m, 2H), 3.79 (m, 5H), 3.63 (m, 1H), 3.52 (m, 1H), 3.32 (m, 1H), 3.07 (m, 1H), 2.95 (m, 1H), 1.26 (m, 6H) ppm. MS calculated for C16H21NO3+H: 276, observed: 276.
Reaction SMILES: [Na].[C:2]([C:4]1[CH:9]=[CH:8][N:7]=[CH:6][CH:5]=1)#[N:3].[Cl-:10].[NH4+:11].C(OCC)C>CO>[ClH:10].[C:2]([C:4]1[CH:9]=[CH:8][N:7]=[CH:6][CH:5]=1)(=[NH:11])[NH2:3]
Reactant: N#Cc1ccncc1
Reactant: [NH4+]
Reactant: [Cl-]
Agent: [Na]
Solvent: CCOCC
Solvent: CO
Product: Cl
Product: N=C(N)c1ccncc1
Reaction time: 6 h
Yield: 93 %

Procedure:
To a solution of 0.23 g sodium in 40 ml methanol was added 10.62 g 4-cyanopyridine at room temperature. Stirring was continued for 6 h followed by the addition of 5.9 g ammoniumchloride and stirring was continued for another 10 h. Then 120 ml diethylether was added and the precipitate was filtered off after 30 min and washed once with 20 ml of diethylether. The product was dried under high vacuum. 14.95 g 4-amidino-pyridine hydrochloride was obtained as a white powder.