Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1][C:2]1[C:6]2[O:7][C:8]([N:12]3[CH2:17][CH2:16][O:15][CH2:14][CH2:13]3)=[CH:9][C:10](=[O:11])[C:5]=2[S:4][CH:3]=1.[C:18]1(I)[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1.[F-].[K+]>[N+]([O-])([O-])=O.[Ag+].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.CS(C)=O>[Br:1][C:2]1[C:6]2[O:7][C:8]([N:12]3[CH2:17][CH2:16][O:15][CH2:14][CH2:13]3)=[CH:9][C:10](=[O:11])[C:5]=2[S:4][C:3]=1[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1
Reactant: Ic1ccccc1
Reactant: O=c1cc(N2CCOCC2)oc2c(Br)csc12
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Ag+]
Agent: O=[N+]([O-])[O-]
Solvent: CS(C)=O
Product: O=c1cc(N2CCOCC2)oc2c(Br)c(-c3ccccc3)sc12
Temperature: 120 °C

Procedure:
A 2 mL conical microwave vial was charged with a magnetic stirring bar, 3-bromo-5-morpholino-7H-thieno[3,2-b]pyran-7-one (103) (50 mg, 158 μmol), phenyl iodide (27 mg, 132 μmol), potassium fluoride (11.5 mg, 198 μmol), silver nitrate (34 mg, 198 μmol), anhydrous dimethyl sulfoxide (1 mL), and dichlorobis(triphenylphosphine)palladium (II) (4.6 mg, 6.6 mop. The reaction mixture was sealed, and the reaction mixture was magnetically stirred and heated under microwave irradiation to 120° C. for 15 minutes to give 3-bromo-5-morpholino-2-phenyl-7H-thieno[3,2-b]pyran-7-one (76).
Reaction SMILES: [OH:1][C:2]1[CH:8]=[CH:7][CH:6]=[C:5]([N+:9]([O-:11])=[O:10])[C:3]=1[NH2:4].[OH-].[K+].[CH3:14]I>CN(C=O)C>[CH3:14][O:1][C:2]1[CH:8]=[CH:7][CH:6]=[C:5]([N+:9]([O-:11])=[O:10])[C:3]=1[NH2:4]
Reactant: Nc1c(O)cccc1[N+](=O)[O-]
Reactant: CI
Agent: [K+]
Agent: [OH-]
Solvent: CN(C)C=O
Product: COc1cccc([N+](=O)[O-])c1N
Temperature: 25 °C
Reaction time: 4 h

Procedure:
To a mixture of 2-hydroxy-6-nitroaniline (41 g; 0.266 mol) and 85% KOH (17.5 g; 0.266 mol) in anhydrous DMF (80 ml), CH3I (16.5 ml; 0.266 mol) was added dropwise. The reaction mixture was stirred at room temperature for 4 hours then poured into ice-water, the title compound precipitated as a brown solid. 40 g; m.p. 67-68° C.
Reaction SMILES: [CH:1]1[C:13]2[O:12][C:11]3[C:10]4[C:14]5[C:19]([NH:20][C:9]=4[CH:8]=[CH:7][C:6]=3[C:5]=2[CH:4]=[CH:3][CH:2]=1)=[CH:18][CH:17]=[CH:16][CH:15]=5.[H-].[Na+].Cl[C:24]1[N:29]=[C:28]([C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=2)[N:27]=[C:26]([C:36]2[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=2)[N:25]=1>CN(C)C=O.C1COCC1>[C:36]1([C:26]2[N:27]=[C:28]([C:30]3[CH:31]=[CH:32][CH:33]=[CH:34][CH:35]=3)[N:29]=[C:24]([N:20]3[C:9]4[CH:8]=[CH:7][C:6]5[C:5]6[CH:4]=[CH:3][CH:2]=[CH:1][C:13]=6[O:12][C:11]=5[C:10]=4[C:14]4[C:19]3=[CH:18][CH:17]=[CH:16][CH:15]=4)[N:25]=2)[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=1
Reactant: Clc1nc(-c2ccccc2)nc(-c2ccccc2)n1
Reactant: c1ccc2c(c1)[nH]c1ccc3c4ccccc4oc3c12
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: C1CCOC1
Product: c1ccc(-c2nc(-c3ccccc3)nc(-n3c4ccccc4c4c5oc6ccccc6c5ccc43)n2)cc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
13 g (50.5 mmol) of 7H-12-oxa-7-azaindeno[1,2-a]fluorene are dissolved in 150 ml of dimethylformamide under a protective-gas atmosphere, and 2.4 g of 60% NaH in mineral oil (60.6 mmol) are added. After 1 h at room temperature, a solution of 2-chloro-4,6-diphenyl-1,3,5-triazine (14.9 g, 55.6 mmol) in 100 ml of THF is added dropwise. The reaction mixture is stirred at room temperature for 12 h. After this time, the reaction mixture is poured onto ice and extracted three times with dichloromethane. The combined organic phases are dried over Na2SO4 and evaporated. The residue is extracted with hot toluene, recrystallised from toluene and finally sublimed in a high vacuum, the purity is 99.9%. The yield is 18.4 g (75%).
Reaction SMILES: [CH3:1][Mg]Br.[O:4]=[C:5]1[CH2:8][N:7]([C:9]([O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:10])[CH2:6]1>C1COCC1>[OH:4][C:5]1([CH3:1])[CH2:8][N:7]([C:9]([O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:10])[CH2:6]1
Reactant: C[Mg]Br
Reactant: CC(C)(C)OC(=O)N1CC(=O)C1
Solvent: C1CCOC1
Product: CC1(O)CN(C(=O)OC(C)(C)C)C1
Reaction time: 1 h
Yield: 60.4 %

Procedure:
Methyl magnesium bromide (3.0M in Diethyl ether) (1.5 mL, 4.5 mmol) was added to cold (−10° C.) solution of tert-butyl 3-oxoazetidine-1-carboxylate (650 mg, 3.8 mmol) in THF (10 mL) and stirring was continued at 20-35° C. for 1 h. After which the reaction mixture was quenched with saturated aqueous NH4Cl solution and extracted with ethylacetate. The organic layer separated was washed with water, dried over anhydrous sodium sulphate and concentrated under reduced pressure to afford the residue. The residue was purified by column chromatography (using 60-120 silica gel and 50% EtOAc in Hexane as eluent) to afford 430 mg of the title compound.
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][N:11]([S:14]([N:17]2[CH2:22][CH2:21][O:20][CH2:19][CH2:18]2)(=[O:16])=[O:15])[CH2:10][CH2:9]1)=O)(C)(C)C.[ClH:23]>O1CCOCC1>[ClH:23].[N:11]1([S:14]([N:17]2[CH2:18][CH2:19][O:20][CH2:21][CH2:22]2)(=[O:16])=[O:15])[CH2:10][CH2:9][NH:8][CH2:13][CH2:12]1
Reactant: CC(C)(C)OC(=O)N1CCN(S(=O)(=O)N2CCOCC2)CC1
Agent: Cl
Solvent: C1COCCO1
Product: O=S(=O)(N1CCNCC1)N1CCOCC1
Reaction time: 8 h

Procedure:
4-(Morpholine-4-sulfonyl)-piperazine-1-carboxylic acid tert-butyl ester (39 mg) was dissolved in 4 mL of dioxane, and 4 mL of 4.0 M hydrochloric acid in dioxane was added. After standing overnight at ambient temperature, the solvent was removed to give 4-(piperazine-1-sulfonyl)-morpholine hydrochloride as a white solid.
Reaction SMILES: I[C:2]1[CH:7]=[CH:6][C:5]([S:8]([NH:11][C:12]2[S:13][CH:14]=[CH:15][N:16]=2)(=[O:10])=[O:9])=[CH:4][CH:3]=1.[CH2:17]1[C:25]2[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=2)[CH2:19][CH:18]1[N:26]1[CH2:30][CH2:29][NH:28][C:27]1=[O:31].C(=O)([O-])[O-].[K+].[K+]>[Cu]I.CN1C(=O)CCC1>[CH2:19]1[C:20]2[C:25](=[CH:24][CH:23]=[CH:22][CH:21]=2)[CH2:17][CH:18]1[N:26]1[CH2:30][CH2:29][N:28]([C:2]2[CH:7]=[CH:6][C:5]([S:8]([NH:11][C:12]3[S:13][CH:14]=[CH:15][N:16]=3)(=[O:10])=[O:9])=[CH:4][CH:3]=2)[C:27]1=[O:31]
Reactant: O=S(=O)(Nc1nccs1)c1ccc(I)cc1
Reactant: O=C1NCCN1C1Cc2ccccc2C1
Agent: [Cu]I
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN1CCCC1=O
Product: O=C1N(c2ccc(S(=O)(=O)Nc3nccs3)cc2)CCN1C1Cc2ccccc2C1
Yield: 10.3 %

Procedure:
Synthesized according to general procedure 43. The reaction was set up with 4-iodo-N-(thiazol-2-yl)benzenesulfonamide (250 mg, 0.68 mmol), 1-(2,3-dihydro-1H-inden-2-yl)imidazolidin-2-one (138 mg, 0.68 mmol), copper(I) iodide (267 mg, 1.4 mmol), potassium carbonate (282 mg, 2.0 mmol), and NMP (1.7 mL). The dark mixture was purified via silica gel chromatography using 5% MeOH in CH2Cl2 followed by trituration with 50% Et2O in CH2Cl2 to obtain the desired urea as a white solid (32 mg, 0.07 mmol, 10% yield). 1H NMR (400 MHz, DMSO-d6) δ 12.66 (s, 1H), 7.75-7.69 (m, 4H), 7.26-7.24 (m, 3H), 7.19-7.17 (m, 2H), 6.81 (d, J=4.5 Hz, 1H), 4.74 (dd, J=1.3, 14.2 Hz, 1H), 3.81-3.77 (m, 2H), 3.34-3.27 (m, 2H), 3.12 (dd, J=7.9, 16.1 Hz, 2H), 3.00 (dd, J=6.2, 16.1 Hz, 2H). LC/MS (10%-99% CH3CN (0.035% TFA)/H2O (0.05% TFA)), m/z: M+1 obs=441.2; tR=1.45 min.
Reaction SMILES: O.[NH:2]1[C:6]([CH2:7][CH2:8][CH:9]2[CH2:18][CH2:17][CH:16]3[CH:11]([CH2:12][CH:13]([C:19]([OH:21])=[O:20])[NH:14][CH2:15]3)[CH2:10]2)=[N:5][N:4]=[N:3]1.Cl.[CH2:23](O)[CH3:24]>>[CH2:23]([O:20][C:19]([CH:13]1[CH2:12][CH:11]2[CH:16]([CH2:17][CH2:18][CH:9]([CH2:8][CH2:7][C:6]3[N:5]=[N:4][NH:3][N:2]=3)[CH2:10]2)[CH2:15][NH:14]1)=[O:21])[CH3:24]
Reactant: O=C(O)C1CC2CC(CCc3nnn[nH]3)CCC2CN1
Reactant: CCO
Agent: Cl
Solvent: O
Product: CCOC(=O)C1CC2CC(CCc3nn[nH]n3)CCC2CN1
Yield: 100 %

Procedure:
A solution of 6.0 g (21.5 mmol) of 6-[2-(1H-Tetrazol-5-yl)-ethyl]-decahydro-isoquinoline-3-carboxylic acid monohydrate in 70 mL of ethanol saturated with hydrogen chloride (g) is heated at reflux overnight. The mixture is concentrated in vacuo, suspended in diethyl ether, and again concentrated in vacuo. The residue is suspended in diethyl ether and heated at reflux for 3 hr. The solid is filtered and rinsed with diethyl ether to afford 7.4 g (100%) of the title compound.
Reaction SMILES: [CH2:1]=[C:2]1[CH:8]2[CH2:9][CH:5]([CH2:6][CH2:7]2)[C:4](=[O:10])[O:3]1.C(N(CC)CC)C.CC(C)(O)C#N.[CH3:24][S:25]([C:28]1[CH:36]=[CH:35][C:31]([C:32](Cl)=[O:33])=[C:30]([N+:37]([O-:39])=[O:38])[CH:29]=1)(=[O:27])=[O:26]>C(#N)C.C(OCC)(=O)C>[OH:3][C:2]1[CH:8]2[CH2:9][CH:5]([CH2:6][CH2:7]2)[C:4](=[O:10])[C:1]=1[C:32](=[O:33])[C:31]1[CH:35]=[CH:36][C:28]([S:25]([CH3:24])(=[O:27])=[O:26])=[CH:29][C:30]=1[N+:37]([O-:39])=[O:38]
Reactant: CS(=O)(=O)c1ccc(C(=O)Cl)c([N+](=O)[O-])c1
Reactant: C=C1OC(=O)C2CCC1C2
Agent: CC(C)(O)C#N
Solvent: CCN(CC)CC
Solvent: CC#N
Solvent: CCOC(C)=O
Product: CS(=O)(=O)c1ccc(C(=O)C2=C(O)C3CCC(C3)C2=O)c([N+](=O)[O-])c1
Reaction time: 12 h
Yield: 41.7 %

Procedure:
2.76 g (0.02 mol) of 93% 4-methylene-3-oxabicyclo[3.2.1]octan-2-one and 4.45 g (0.044 mmol) of triethylamine are stirred for 6 hours at a temperature of 20° C. in 50 ml of acetonitrile in the presence of 170 mg (2 mmol) of acetone cyanohydrin. 4.22 g (0.16 mol) of 4-methanesulfonyl-2-nitrobenzoyl chloride are then introduced and stirring is continued for a further 12 hours at a temperature of 20° C. A further 170 mg (2 mmol) of acetone cyanohydrin are then added and stirring is continued for a further 30 minutes until conversion is complete. The reaction mixture is then taken up in ethyl acetate and extracted at a pH value of 13 against water. The aqueous phase is acidified and extracted with fresh ethyl acetate, once at pH 5 and once at pH 4, dried and concentrated by evaporation. 3.05 g of 4-hydroxy-3-(4-methanesulfonyl-2-nitrobenzoyl)-bicyclo[3.2.1]oct-3-en-2-one with a good level of purity are obtained. The yield is 44.9% based on the starting material 4-methylene-3-oxabicyclo[3.2.1]octan-2-one or 52.2% based on the starting material 4-methanesulfonyl-2-nitrobenzoic acid.
Reaction SMILES: [ClH:1].[CH3:2][C:3]1([CH3:28])[CH2:8][CH2:7][C:6]([C:9]2[CH:14]=[CH:13][C:12]([O:15][CH3:16])=[CH:11][C:10]=2[N:17]2[CH2:22][CH2:21][N:20]([CH2:23][CH2:24][CH2:25][CH2:26][CH3:27])[CH2:19][CH2:18]2)=[CH:5][CH2:4]1>CO.[Pd]>[ClH:1].[CH3:2][C:3]1([CH3:28])[CH2:8][CH2:7][CH:6]([C:9]2[CH:14]=[CH:13][C:12]([O:15][CH3:16])=[CH:11][C:10]=2[N:17]2[CH2:18][CH2:19][N:20]([CH2:23][CH2:24][CH2:25][CH2:26][CH3:27])[CH2:21][CH2:22]2)[CH2:5][CH2:4]1
Reactant: CCCCCN1CCN(c2cc(OC)ccc2C2=CCC(C)(C)CC2)CC1
Agent: [Pd]
Agent: Cl
Solvent: CO
Product: CCCCCN1CCN(c2cc(OC)ccc2C2CCC(C)(C)CC2)CC1
Temperature: 25 °C
Reaction time: 17 h
Yield: 38.4 %

Procedure:
To a solution of 1-[2-(4,4-dimethylcyclohex-1-enyl)-5-methoxyphenyl]-4-pentylpiperazine hydrochloride (44 mg) prepared in Example (1f) in methanol (5 mL) was added 10% palladium on carbon (100 mg, wet), and the mixture was stirred for 17 hours under a hydrogen atmosphere at atmospheric pressure and room temperature. The reaction mixture was passed through Celite, and the filtrate was concentrated under reduced pressure. Diethyl ether was added to the residue and the mixture was filtered to give 17 mg of the title compound as a light yellow solid.
Reaction SMILES: [C:1]1([C:7]2[CH:12]=[C:11]([CH3:13])[CH:10]=[CH:9][C:8]=2[NH2:14])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[C:15](Cl)(=[O:20])[O:16][C:17]([CH3:19])=[CH2:18]>CCOC(C)=O.C([O-])(O)=O.[Na+]>[C:1]1([C:7]2[CH:12]=[C:11]([CH3:13])[CH:10]=[CH:9][C:8]=2[NH:14][C:15](=[O:20])[O:16][C:17]([CH3:19])=[CH2:18])[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: C=C(C)OC(=O)Cl
Reactant: Cc1ccc(N)c(-c2ccccc2)c1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCOC(C)=O
Product: C=C(C)OC(=O)Nc1ccc(C)cc1-c1ccccc1
Temperature: 25 °C
Reaction time: 16 h
Yield: 78 %

Procedure:
To a biphasic solution of 2-phenyl-4-methylbenzenamine (0.29 g, 1.583 mmol) in EtOAc (10 mL) and NaHCO3 (10 ml) was added prop-1-en-2-yl carbonochloridate (0.259 ml, 2.374 mmol) and mixture was stirred for 16 h at RT. The layers were separated and the aqueous layer was extracted with EtOAc (1×30 mL). The combined organics were washed with brine, dried (Na2SO4) and concentrated to provide prop-1-en-2-yl 2-phenyl-4-methylphenylcarbamate as an off-white solid (0.33 g, 78% yield). 1H NMR (400 MHz, CDCl3): δ 8.00 (brs, 1H), 7.50-7.46 (m, 2H), 7.42-7.35 (m, 3H), 7.18 (dd, J=8.4 Hz, 1.6 Hz, 1H), 7.05 (s, 1H), 6.67 (brs, 1H), 4.72 (s, 1H), 4.68 (s, 1H), 2.34 (s, 3H), 1.94 (s, 3H); MS (ESI) m/z: 290.0 (M+Na+).
Reaction SMILES: [C:1]([O:8][CH3:9])(=[O:7])[CH2:2][C:3]([O:5][CH3:6])=[O:4].[H-].[Na+].F[C:13]1[CH:18]=[CH:17][C:16]([C:19]2[CH:24]=[CH:23][CH:22]=[C:21]([NH:25][C:26](=[O:31])[C:27]([F:30])([F:29])[F:28])[CH:20]=2)=[CH:15][C:14]=1[N+:32]([O-:34])=[O:33]>CS(C)=O>[N+:32]([C:14]1[CH:15]=[C:16]([C:19]2[CH:24]=[CH:23][CH:22]=[C:21]([NH:25][C:26](=[O:31])[C:27]([F:28])([F:29])[F:30])[CH:20]=2)[CH:17]=[CH:18][C:13]=1[CH:2]([C:1]([O:8][CH3:9])=[O:7])[C:3]([O:5][CH3:6])=[O:4])([O-:34])=[O:33]
Reactant: COC(=O)CC(=O)OC
Reactant: O=C(Nc1cccc(-c2ccc(F)c([N+](=O)[O-])c2)c1)C(F)(F)F
Agent: [H-]
Agent: [Na+]
Solvent: CS(C)=O
Product: COC(=O)C(C(=O)OC)c1ccc(-c2cccc(NC(=O)C(F)(F)F)c2)cc1[N+](=O)[O-]
Temperature: 100 °C
Reaction time: 0.17 h
Yield: 50 %

Procedure:
Dimethyl malonate (9.6 mL) was added dropwise to a stirred suspension of 3.2 g of 60% sodium hydride in mineral oil in 40 mL anhydrous dimethylsulfoxide under nitrogen. The mixture was stirred for 10 minutes and 2-fluoro-5-(3-trifluoroacetamidophenyl)nitrobenzene in 20 mL dimethylsulfoxide was added. The resulting dark red mixture was heated to 100° C. for 2 hours. The reaction was quenched by pouring into 100 mL of saturated ammonium chloride solution and extracted twice with 50 mL of ethyl acetate. The organic phase was washed with 50 mL each of saturated ammonium chloride solution, water, and brine, dried over anhydrous sodium sulfate and concentrated to a yellow oil. The oil was chromatographed on a column of silica gel (ethyl acetate:hexane (1.4)) to give 4.4 g (50% yield) of dimethyl 2-[2-nitro-4-(3-trifluoroacetamidophenyl)phenyl]-malonate as a pale yellow solid.
Reaction SMILES: [C:1]([C:4]1[CH:9]=[CH:8][C:7]([N:10]=[N:11][C:12](=[C:16]2[C:25]3[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=3)[CH2:19][C:18]([CH3:27])([CH3:26])[NH:17]2)[C:13](O)=[O:14])=[CH:6][CH:5]=1)(=[O:3])[CH3:2].[CH3:28][NH:29][CH3:30].C1C=CC2N(O)N=NC=2C=1.C(N(CC)CC)C>CN(C=O)C.ClCCl>[C:1]([C:4]1[CH:9]=[CH:8][C:7]([N:10]=[N:11][C:12](=[C:16]2[C:25]3[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=3)[CH2:19][C:18]([CH3:26])([CH3:27])[NH:17]2)[C:13]([N:29]([CH3:30])[CH3:28])=[O:14])=[CH:6][CH:5]=1)(=[O:3])[CH3:2]
Reactant: CNC
Reactant: CC(=O)c1ccc(N=NC(C(=O)O)=C2NC(C)(C)Cc3ccccc32)cc1
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(=O)c1ccc(N=NC(C(=O)N(C)C)=C2NC(C)(C)Cc3ccccc32)cc1
Temperature: 25 °C

Procedure:
(4-acetyl-phenylazo)-(3,3-dimethyl-3,4-dihydro-2H-isoquinoline-1-ylidene)-acetic acid, dimethylamine, HOBt (Advanced ChemTech Corp., USA) and triethylamine are dissolved in DMF, a dichloromethane solution of HETU (Advanced ChemTech Corp., USA) is added, and then the mixture is stirred at room temperature. The stirred and blended solvent is washed with a saturated aqueous sodium chloride solution and a 5% aqueous sodium hydrogen carbonate solution. The reaction product is dried with anhydrous sodium sulfate and filtered and, then, the solvent is removed by reducing the pressure. The residue containing the reaction product is purified by column chromatography to obtain the title compound.
Reaction SMILES: [CH3:1][CH:2]1[C:11]2([CH:16]=[CH:15][N:14](C(OCC3C=CC=CC=3)=O)[CH2:13][CH2:12]2)[C:10]2[C:5](=[N:6][CH:7]=[CH:8][CH:9]=2)[NH:4][C:3]1=O>C(O)C.[Pd]>[CH3:1][C:2]1[C:11]2([CH2:16][CH2:15][NH:14][CH2:13][CH2:12]2)[C:10]2[C:5](=[N:6][CH:7]=[CH:8][CH:9]=2)[NH:4][CH:3]=1
Reactant: CC1C(=O)Nc2ncccc2C12C=CN(C(=O)OCc1ccccc1)CC2
Agent: [Pd]
Solvent: CCO
Product: CC1=CNc2ncccc2C12CCNCC2
Reaction time: 6 h

Procedure:
Benzyl 3-methyl-2-oxo-2,2′,3,3′-tetrahydro-1H,1′H-spiro[1,8-naphthyridine-4,4′-pyridine]-1′-carboxylate (73 mg, 0.20 mmol) was diluted in ethanol (10 mL) and palladium (10% on carbon; 100 mg) was added. The reaction vessel was evacuated and back-filled with nitrogen (3×), then back-filled with hydrogen (1 atm). After 6 h, the mixture was filtered with celite, washed with ethanol and methanol. The filtrate was concentrated to give the title compound. MS 232.1 (M+1).
Reaction SMILES: C1([C:7]2[CH:17]=[CH:16][CH:15]=[C:9]3[C:10]([NH:12][C:13](=[O:14])[C:8]=23)=[O:11])C=CC=CC=1.C([O-])([O-])=O.[K+].[K+].Br[CH2:25][C:26]1[N:36]([CH2:37][C:38]([CH3:41])([CH3:40])[CH3:39])[C:29]2[N:30]=[C:31]([C:34]#[N:35])[N:32]=[CH:33][C:28]=2[CH:27]=1>CN(C=O)C>[CH3:39][C:38]([CH3:41])([CH3:40])[CH2:37][N:36]1[C:29]2[N:30]=[C:31]([C:34]#[N:35])[N:32]=[CH:33][C:28]=2[CH:27]=[C:26]1[CH2:25][N:12]1[C:13](=[O:14])[C:8]2[C:9](=[CH:15][CH:16]=[CH:17][CH:7]=2)[C:10]1=[O:11]
Reactant: CC(C)(C)Cn1c(CBr)cc2cnc(C#N)nc21
Reactant: O=C1NC(=O)c2c1cccc2-c1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CC(C)(C)Cn1c(CN2C(=O)c3ccccc3C2=O)cc2cnc(C#N)nc21
Reaction time: 2 h
Yield: 67.7 %

Procedure:
To a solution of 500 mg (1.63 mmoles) of phenylphthalimide in 20 ml of DMF, 315 mg (2.28 mmoles) of K2CO3 and 500 mg (1.63 mmoles) of 6-bromomethyl-7-(2,2-dimethyl-propyl)-7H-pyrrolo[2,3-d]pyrimidine-2-carbonitrile are added successively and the mixture is stireed for 2 hours at ambient temperature. The reaction mixture is quenched with ice-water and extracted with AcOEt. The combined extracts are washed with H2O, brine and dried over MgSO4. Chromatography on silica gel (eluent: n-Hexane:AcOEt=2:1) give 412 mg of desired 7-(2,2-dimethyl-propyl)-6-(1,3-dioxo-1,3-dihydro-isoindol-2-ylmethyl)-7H-pyrrolo[2,3-d]pyrimidine-2-carbonitrile in 68% yield.
Reaction SMILES: [F:1][C:2]1[CH:15]=[CH:14][C:5]([O:6][C:7]2[CH:13]=[CH:12][CH:11]=[CH:10][C:8]=2[NH2:9])=[C:4]([O:16][CH3:17])[CH:3]=1.Cl[C:19]([C:21]1[CH:30]=[CH:29][C:24]([C:25]([O:27][CH3:28])=[O:26])=[CH:23][CH:22]=1)=[O:20].N1C=CC=CC=1>C1C=CC=CC=1.CN(C1C=CN=CC=1)C>[F:1][C:2]1[CH:15]=[CH:14][C:5]([O:6][C:7]2[CH:13]=[CH:12][CH:11]=[CH:10][C:8]=2[NH:9][C:19]([C:21]2[CH:30]=[CH:29][C:24]([C:25]([O:27][CH3:28])=[O:26])=[CH:23][CH:22]=2)=[O:20])=[C:4]([O:16][CH3:17])[CH:3]=1
Reactant: COc1cc(F)ccc1Oc1ccccc1N
Reactant: COC(=O)c1ccc(C(=O)Cl)cc1
Agent: CN(C)c1ccncc1
Solvent: c1ccccc1
Solvent: c1ccncc1
Product: COC(=O)c1ccc(C(=O)Nc2ccccc2Oc2ccc(F)cc2OC)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 94.1 %

Procedure:
To a slurry of title compound 91 (4 g, 17.15 mmol) and methyl 4-(chlorocarbonyl)benzoate (3.58 g, 18.01 mmol) in benzene (60 mL) at 0° C. was added pyridine (4.85 mL, 60.0 mmol) drop wise followed by a single crystal of DMAP. The temperature was raised to room temperature and the reaction mixture was left to stir for 1 h. The reaction mixture was filtered and the filtrate was diluted with 5% aq HCl and ethyl acetate. The organic layer was washed with 5% aq HCl, water and brine then left in the fridge over the weekend. The precipitated solid was filtered, washed with water and hexanes to afford title compound 92 (6.38 g, 94%) as an off-white solid. LRMS (ESI): (calc) 395.12. (found) 396.4 (MH)+.
Reaction SMILES: I[C:2]1[N:3]=[N:4][C:5]([C:8]#[C:9][C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)=[CH:6][CH:7]=1.[CH3:16][C:17]1([CH3:24])[CH2:22][CH2:21][NH:20][C:19](=[O:23])[CH2:18]1.C1(P(C2C=CC=CC=2)C2C3OC4C(=CC=CC=4P(C4C=CC=CC=4)C4C=CC=CC=4)C(C)(C)C=3C=CC=2)C=CC=CC=1>C1(C)C=CC=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[CH3:16][C:17]1([CH3:24])[CH2:22][CH2:21][N:20]([C:2]2[N:3]=[N:4][C:5]([C:8]#[C:9][C:10]3[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=3)=[CH:6][CH:7]=2)[C:19](=[O:23])[CH2:18]1
Reactant: CC1(C)CCNC(=O)C1
Reactant: Ic1ccc(C#Cc2ccccc2)nn1
Agent: [Pd]
Agent: CC1(C)c2cccc(P(c3ccccc3)c3ccccc3)c2Oc2c(P(c3ccccc3)c3ccccc3)cccc21
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: Cc1ccccc1
Product: CC1(C)CCN(c2ccc(C#Cc3ccccc3)nn2)C(=O)C1
Yield: 22.6 %

Procedure:
To a well stirred suspension of 3-iodo-6-(phenylethynyl)pyridazine (Example 151, step 1) (80 mg, 261 μmol), 4,4-dimethylpiperidin-2-one (66.5 mg, 314 μmol, 1.2 equiv.) and 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene (xantphos) (6.05 mg, 10.5 μmol, 0.04 equiv.) in 2 ml of toluene were added under argon atmosphere tris(dibenzylideneacetone)dipalladium(0) (Pd2(dba)3), (4.79 mg, 5.23 μmol, 0.02 equiv.) and the mixture was stirred for 4 hours at 100° C. The crude mixture was directly purified by flash chromatography over a 20 g silicagel column using a heptane to 50% ethyl acetate in heptane gradient, and yielded 18 mg (23% yield) of the title compound as a white solid, MS: m/e=306.2 (M+H+).
Reaction SMILES: [CH:1]([C@H:4]1[CH2:8][O:7][C:6](=[O:9])[N:5]1[C:10]1[CH:15]=[CH:14][N:13]=[C:12]([NH:16][C@H:17]([C:19]2[CH:40]=[CH:39][C:22]([CH2:23][N:24]3[CH2:29][CH2:28][N:27](C(OC(C)(C)C)=O)[C:26]([CH3:38])([CH3:37])[CH2:25]3)=[CH:21][CH:20]=2)[CH3:18])[N:11]=1)([CH3:3])[CH3:2].C(O)(C(F)(F)F)=O.CC[NH+](CC)CC.CC[NH+](CC)CC.C([O-])([O-])=O>C(Cl)Cl>[CH3:38][C:26]1([CH3:37])[NH:27][CH2:28][CH2:29][N:24]([CH2:23][C:22]2[CH:39]=[CH:40][C:19]([C@@H:17]([NH:16][C:12]3[N:11]=[C:10]([N:5]4[C@@H:4]([CH:1]([CH3:2])[CH3:3])[CH2:8][O:7][C:6]4=[O:9])[CH:15]=[CH:14][N:13]=3)[CH3:18])=[CH:20][CH:21]=2)[CH2:25]1
Reactant: CC(C)[C@H]1COC(=O)N1c1ccnc(N[C@@H](C)c2ccc(CN3CCN(C(=O)OC(C)(C)C)C(C)(C)C3)cc2)n1
Agent: CC[NH+](CC)CC
Agent: O=C([O-])[O-]
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CC(C)[C@H]1COC(=O)N1c1ccnc(N[C@@H](C)c2ccc(CN3CCNC(C)(C)C3)cc2)n1
Temperature: 25 °C
Reaction time: 1 h
Yield: 36.3 %

Procedure:
To a solution of tert-butyl 4-(4-((S)-1-(4-((S)-4-isopropyl-2-oxooxazolidin-3-yl)pyrimidin-2-ylamino)ethyl)benzyl)-2,2-dimethylpiperazine-1-carboxylate (78 mg, 0.14 mmol) in DCM (1 mL) was added TFA (1 mL, 12 mmol) slowly at −78° C. The reaction was stirred at room temperature for 1 h then was concentrated and diluted with DCM (10 mL). The solution was stirred with 3 eq. of MP-carbonate resin (3.28 mmol/g, Biotage) for 1 h at room temperature. The resin was removed by filtration and washed (2×5 mL) with DCM. The filtrate was concentrated and purified through HPLC to give (S)-3-(2-(((S)-1-(4-((3,3-dimethylpiperazin-1-yl)methyl)phenyl)ethyl)amino)pyrimidin-4-yl)-4-isopropyloxazolidin-2-one as a white solid (23 mg, 36% yield).
Reaction SMILES: [CH2:1]([O:4][C@@H:5]1[CH2:25][C@@H:24]2[C@:11]([CH3:29])([CH2:12][C@H:13]([OH:28])[C@H:14]3[C@H:23]2[CH2:22][CH2:21][C:20]2[C@:15]3([CH3:27])[CH2:16][CH2:17][C:18](=[O:26])[CH:19]=2)[C@@:6]1([OH:30])[C:7](=[O:10])[CH2:8][Cl:9])[CH:2]=[CH2:3].ClC1C=CC=C(C(OO)=[O:39])C=1>ClCCl>[Cl:9][CH2:8][C:7](=[O:10])[C@:6]1([OH:30])[C@:11]2([CH3:29])[C@H:24]([C@H:23]3[C@H:14]([C@@H:13]([OH:28])[CH2:12]2)[C@:15]2([CH3:27])[C:20](=[CH:19][C:18](=[O:26])[CH2:17][CH2:16]2)[CH2:21][CH2:22]3)[CH2:25][C@H:5]1[O:4][CH2:1][CH:2]1[CH2:3][O:39]1
Reactant: C=CCO[C@@H]1C[C@H]2[C@@H]3CCC4=CC(=O)CC[C@]4(C)[C@H]3[C@@H](O)C[C@]2(C)[C@@]1(O)C(=O)CCl
Reactant: O=C(OO)c1cccc(Cl)c1
Solvent: ClCCl
Product: C[C@]12CCC(=O)C=C1CC[C@@H]1[C@@H]2[C@@H](O)C[C@@]2(C)[C@H]1C[C@@H](OCC1CO1)[C@]2(O)C(=O)CCl

Procedure:
A solution of 16α-allyloxy-21-chloro-11β,17-dihydroxypregn-4-ene-3,20-dione (3.8 mmoles) in 50 ml of dichloromethane is stirred with 0.76 g of m-chloroperbenzoic acid for 19 hours at room temperature. The resulting solution is washed with a mixture of 10% potassium carbonate solution and 10% sodium sulfite solution, dried, and evaporated in vacuo to yield the title compound.