Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [O:1]=[C:2]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[C:4](=[O:11])[N:3]1[O:12][C:13]([CH3:18])([CH3:17])[C:14](Cl)=[O:15].C(N(CC)CC)C.[CH3:26][C:27]([CH3:35])([O:29][C:30]([NH:32][NH:33][CH3:34])=[O:31])[CH3:28]>O1CCCC1.CN(C1C=CN=CC=1)C>[CH3:26][C:27]([CH3:35])([O:29][C:30]([NH:32][N:33]([CH3:34])[C:14](=[O:15])[C:13]([O:12][N:3]1[C:2](=[O:1])[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[C:4]1=[O:11])([CH3:18])[CH3:17])=[O:31])[CH3:28]
Reactant: CNNC(=O)OC(C)(C)C
Reactant: CC(C)(ON1C(=O)c2ccccc2C1=O)C(=O)Cl
Agent: CN(C)c1ccncc1
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CN(NC(=O)OC(C)(C)C)C(=O)C(C)(C)ON1C(=O)c2ccccc2C1=O
Temperature: 20 °C
Reaction time: 8 h
Yield: 87.4 %

Procedure:
A solution of 2-[(1,3-dihydro-1,3-dioxo-2H-isoindol-2-yl)oxy]-2-methylpropanoyl chloride (5.3 g, 22 mmole) in 40 ml of dry tetrahydrofuran was treated with triethylamine (4.10 ml, 30 mmole) and 4-(N,N-dimethylamino)pyridine (5 mg). A solution of 1-[(1,1-dimethylethoxy)carbonyl]-2-methylhydrazine (2.90 g, 20 mmole) in 20 ml of tetrahydrofuran was added dropwise at 0° C. and the resulting mixture was stirred at 20° C. overnight. The solvent was evaporated and the solid residue was partitioned between ethyl acetate and water. The organic phase was washed successively with 0.5N hydrochloric acid, 5% sodium bicarbonate, and water. Drying over magnesium sulfate and evaporation gave 6.6 g of the title compound as a colorless solid, m.p. 140°-145° C.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:14]=[CH:13][C:6](/[CH:7]=[CH:8]/[S:9](Cl)(=[O:11])=[O:10])=[CH:5][CH:4]=1.[CH3:15][NH:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1>>[CH3:1][O:2][C:3]1[CH:14]=[CH:13][C:6](/[CH:7]=[CH:8]/[S:9]([N:16]([CH3:15])[C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)(=[O:11])=[O:10])=[CH:5][CH:4]=1
Reactant: CNc1ccccc1
Reactant: COc1ccc(/C=C/S(=O)(=O)Cl)cc1
Product: COc1ccc(/C=C/S(=O)(=O)N(C)c2ccccc2)cc1
Yield: 80.9 %

Procedure:
A solution of (E)-4-methoxystyrylsulfonyl chloride (10 mmol) and N-methyl aniline (10 mmol) was subjected to General Procedure 1, part B. The title compound, melting point 126-129° C., was obtained 80.9% yield.
Reaction SMILES: C(OC(=O)[NH:7][CH:8]1[CH2:13][CH2:12][N:11]([C:14](=[O:37])[C@@H:15]([NH:24][C:25]([C:27]2[NH:36][C:30]3=[CH:31][N:32]=[C:33]([Cl:35])[CH:34]=[C:29]3[CH:28]=2)=[O:26])[CH2:16][C:17]2[CH:22]=[CH:21][C:20]([F:23])=[CH:19][CH:18]=2)[CH2:10][CH2:9]1)(C)(C)C.Cl.O1CCOCC1>CO>[NH2:7][CH:8]1[CH2:9][CH2:10][N:11]([C:14](=[O:37])[C@@H:15]([NH:24][C:25]([C:27]2[NH:36][C:30]3=[CH:31][N:32]=[C:33]([Cl:35])[CH:34]=[C:29]3[CH:28]=2)=[O:26])[CH2:16][C:17]2[CH:22]=[CH:21][C:20]([F:23])=[CH:19][CH:18]=2)[CH2:12][CH2:13]1
Reactant: CC(C)(C)OC(=O)NC1CCN(C(=O)[C@H](Cc2ccc(F)cc2)NC(=O)c2cc3cc(Cl)ncc3[nH]2)CC1
Agent: Cl
Solvent: CO
Solvent: C1COCCO1
Product: NC1CCN(C(=O)[C@H](Cc2ccc(F)cc2)NC(=O)c2cc3cc(Cl)ncc3[nH]2)CC1
Reaction time: 48 h

Procedure:
To a suspension of {1-[2-(S)-[(5-chloro-1H-pyrrolo[2,3-c]pyridine-2-carbonyl)amino]-3-(4-fluorophenyl)propionyl]piperidin-4-yl}carbamic acid tert-butyl ester (EXAMPLE 230, 500 mg, 0.92 mmol) in methanol (12 mL) was added a solution of 4M HCl in dioxane (0.69 mL, 2.76 mmol) and the reaction stirred for 48 h. The resulting precipitate was filtered and washed with ethyl acetate to give the title compound as the hydrochloride salt as a pale yellow powder. m/z (ES+)=444.16 [M+H]+; RT=2.65 min. The product was dissolved in saturated sodium bicarbonate solution. Solvent was removed in vacuo and the crude material dissolved in THF (30 mL). The solution was filtered through celite and solvent removed in vacuo to give the title compound as a yellow powder. m/z (ES+)=444.32 [M+H]+; RT=2.59 min.
Reaction SMILES: [CH3:1][S:2][C:3]1[CH:10]=[CH:9][C:6]([C:7]#[N:8])=[CH:5][CH:4]=1.[CH2:11]([C:13]1[CH:19]=[CH:18][C:16]([NH2:17])=[CH:15][CH:14]=1)[CH3:12]>>[CH2:11]([C:13]1[CH:19]=[CH:18][C:16]([NH:17][C:7]([C:6]2[CH:9]=[CH:10][C:3]([S:2][CH3:1])=[CH:4][CH:5]=2)=[NH:8])=[CH:15][CH:14]=1)[CH3:12]
Reactant: CSc1ccc(C#N)cc1
Reactant: CCc1ccc(N)cc1
Product: CCc1ccc(NC(=N)c2ccc(SC)cc2)cc1
Yield: 81.1 %

Procedure:
The title compound was prepared from 4-methylthiobenzonitrile (1.23 g, 8.2 mmol) and 4-ethylaniline (1 g, 8.2 mmol) by following the procedure described in preparation 10 (1.81 g, yield 81.1%, mp 156-158° C., purity 98.6% by HPLC). 1H-NMR (CDCl3): δ 1.22-1.26 (t, 3H), 2.51 (s, 3H), 2.60-2.66 (q, 2H), 4.70 (bs, 2H, D2O exchangeable), 6.89-6.91 (d, 2H), 7.17-7.19 (d, 2H), 7.26-7.29 (m, 2H), 7.79-7.81 (d, 2H). MS m/z:271.3 (M+).
Reaction SMILES: [CH3:1][C:2]1([CH3:14])[C@@H:4]([CH:5]=O)[C@@H:3]1[C:7]([O:9][C:10]([CH3:13])([CH3:12])[CH3:11])=[O:8].N1CCCCC1.[CH3:21][CH:22](C([O-])=O)[C:23]([O:25][CH2:26][CH3:27])=[O:24].C(OCC)C>N1C=CC=CC=1.C(OCC)(=O)C.CCCCCC>[CH3:1][C:2]1([CH3:14])[C@@H:4](/[CH:5]=[C:22](/[C:23]([O:25][CH2:26][CH3:27])=[O:24])\[CH3:21])[C@@H:3]1[C:7]([O:9][C:10]([CH3:13])([CH3:12])[CH3:11])=[O:8]
Reactant: CC(C)(C)OC(=O)[C@H]1[C@H](C=O)C1(C)C
Reactant: CCOC(=O)C(C)C(=O)[O-]
Solvent: c1ccncc1
Solvent: CCOCC
Solvent: CCCCCC
Product: CCOC(=O)/C(C)=C/[C@H]1[C@H](C(=O)OC(C)(C)C)C1(C)C
Temperature: 100 °C
Reaction time: 5 h
Yield: 85.4 %

Procedure:
Under a nitrogen atmosphere, 0.306 g of tert-butyl (±)-trans-2,2-dimethyl-3-formyl-cyclopropanecarboxylate was dissolved in 3 mL of anhydrous pyridine. Two hundred sixty-three milligrams (0.263 mg) of piperidine and 0.352 g of ethyl methylmalonate was then added thereto, and the resulting mixture was stirred at a temperature of 100° C. for a time period of 5 hours. After the mixture was allowed to cool to room temperature, 100 mL of diethyl ether was added to said mixture and the resulting mixture was washed with 3N-hydrochloric acid and then saturated brine to obtain an organic layer therefrom. The organic layer was dried over anhydrous magnesium sulfate and thereafter the solvent was evaporated under reduced pressure in order to produce a residue. The residue was subjected to silica gel column chromatography, wherein the eluent solvent was a mixture of n-hexane and ethyl acetate at a volume to volume ratio of 3:1 to give 0.372 g of tert-butyl (±)-trans-2,2-dimethyl-3-{2-ethoxycarbonyl-(E)-1-propenyl}cyclopropanecarboxylate.
Reaction SMILES: [Li]CCCC.[N:6]1[CH:11]=[CH:10][C:9]([C:12]2[N:13]3[CH2:19][CH2:18][CH2:17][C:14]3=[N:15][N:16]=2)=[CH:8][CH:7]=1.Br[CH2:21][C:22]1[N:26]=[C:25]([C:27]2[CH:32]=[CH:31][CH:30]=[C:29]([Cl:33])[CH:28]=2)[O:24][N:23]=1.[NH4+].[Cl-]>C1COCC1>[Cl:33][C:29]1[CH:28]=[C:27]([C:25]2[O:24][N:23]=[C:22]([CH2:21][CH:17]3[C:14]4=[N:15][N:16]=[C:12]([C:9]5[CH:8]=[CH:7][N:6]=[CH:11][CH:10]=5)[N:13]4[CH2:19][CH2:18]3)[N:26]=2)[CH:32]=[CH:31][CH:30]=1
Reactant: Clc1cccc(-c2nc(CBr)no2)c1
Reactant: c1cc(-c2nnc3n2CCC3)ccn1
Agent: [Cl-]
Agent: [Li]CCCC
Agent: [NH4+]
Solvent: C1CCOC1
Product: Clc1cccc(-c2nc(CC3CCn4c(-c5ccncc5)nnc43)no2)c1
Temperature: -78 °C
Reaction time: 0.5 h
Yield: 1.3 %

Procedure:
nBuLi (2.5 M, hex., 600 μl) was added to a solution of 3-pyridin-4-yl-6,7-dihydro-5H-pyrrolo[2,1-c][1,2,4]triazole (250 mg, 1.33 mmol) in THF (13 ml) at 0° C. After 10 min the reaction mixture was cooled to −78° C. and 3-(bromomethyl)-5-(3-chlorophenyl)-1,2,4-oxadiazole (400 mg, 1.46 mmol) in THF (10 ml) was added. After stirring at −78° C. for 30 min stirring was continued at 0° C. reaching r.t. o.n. Aq. sat. NH4Cl was added and the mixture was extracted with EA. The organic phase was washed with water and brine, dried and concentrated. Flash chromatography (DCM/MeOH 40:1) followed by preparative HPLC afforded 6.5 mg (1%) of the title compound. 1H NMR: 2.72 (m, 1H), 3.13 (m, 2H), 3.62 (m, 1H), 3.93 (m, 1H), 4.31 (m, 2H), 7.47 (t, 1H), 7.56 (m, 1H), 7.74 (d, 2H), 7.98 (m, 1H), 8.08 (m, 1H), 8.74 (m, 2H).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:27])[CH2:4][C@@H:5]([CH2:23][CH2:24][CH2:25][CH3:26])[C:6]([N:8]1[CH2:12][CH2:11][CH2:10][C@H:9]1[C:13]([O:15]CC1C=CC=CC=1)=[O:14])=[O:7]>C(OC(=O)C)C.[Pd]>[CH3:1][O:2][C:3](=[O:27])[CH2:4][C@@H:5]([CH2:23][CH2:24][CH2:25][CH3:26])[C:6]([N:8]1[CH2:12][CH2:11][CH2:10][C@H:9]1[C:13]([OH:15])=[O:14])=[O:7]
Reactant: CCCC[C@H](CC(=O)OC)C(=O)N1CCC[C@H]1C(=O)OCc1ccccc1
Agent: [Pd]
Solvent: CCOC(C)=O
Product: CCCC[C@H](CC(=O)OC)C(=O)N1CCC[C@H]1C(=O)O
Reaction time: 8 h

Procedure:
To a solution of mono-4-methyl 2-(R)-butylsuccinic acid, (prepared in three steps from hexanoylchloride and t-butyl bromoacetate as described below; 1 mmol) in DMF was added proline O-benzyl ester (1 mmol), DIEA (0.4 mL, 2.3 mmol), and a coupling reagent (e.g. EDCI, PyBOP, DIC, etc.; 1 mmol). The mixture was stirred overnight, then diluted with ethyl acetate and washed with aqueous HCl (1 N), water, saturated sodium bicarbonate, brine, and then dried (Na2SO4). The filtrate was concentrated and then purified on silica gel (Merck 60; ethyl acetate/hexane) to afford methyl-3-(R)-butyl-3-(2-(S)-benzyloxycarbonylpyrrolidin-1-ylcarbonyl)propionate. To this amide (0.1 mmol) in ethylacetate (10 mL) was added 10% Pd/C (100 mg) and the solution stirred under a hydrogen atmosphere for 8 h. The suspension was filtered through a Celite plug and then concentrated to afford methyl-3-(R)-butyl-3-(2-(S)-carboxypyrrolidin-1-ylcarbonyl)propionate E-2.
Reaction SMILES: [C:1]([CH2:3][NH:4][C:5](=[O:9])[C:6](Cl)=[O:7])#[N:2].[CH:10]1[C:15]([N+:16]([O-:18])=[O:17])=[CH:14][CH:13]=[C:12]([OH:19])[CH:11]=1.CN(C)C1C=CC=CC=1>C(Cl)Cl>[C:1]([CH2:3][NH:4][C:5](=[O:9])[C:6]([O:19][C:12]1[CH:11]=[CH:10][C:15]([N+:16]([O-:18])=[O:17])=[CH:14][CH:13]=1)=[O:7])#[N:2]
Reactant: N#CCNC(=O)C(=O)Cl
Reactant: O=[N+]([O-])c1ccc(O)cc1
Solvent: CN(C)c1ccccc1
Solvent: ClCCl
Product: N#CCNC(=O)C(=O)Oc1ccc([N+](=O)[O-])cc1
Reaction time: 1 h

Procedure:
50 mM of [(cyanomethyl)amino]oxoacetyl chloride dissolved in methylene chloride is added dropwise at 0° to a solution of 40 mM of p-nitrophenol and 40 mM of dimethylaniline in methylene chloride. After stirring for one hour, the reaction mixture is extracted once with dilute hydrochloric acid and twice with water. The dried methylene chloride phase is concentrated under vacuum and yields 4.2 g. of [(cyanomethyl)amino]-oxoacetic acid, 4-nitrophenyl ester as a brown oil which crystallizes upon trituration with ether. Recrystallization from toluene gives white crystals, m.p. 123-124°.
Reaction SMILES: C(OC([NH:8][S:9]([C:12]1([CH:15]([OH:22])[C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[CH2:14][CH2:13]1)(=[O:11])=[O:10])=O)(C)(C)C.Cl.C(=O)([O-])[O-].[Na+].[Na+]>C(OCC)(=O)C>[OH:22][CH:15]([C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)[C:12]1([S:9]([NH2:8])(=[O:10])=[O:11])[CH2:13][CH2:14]1
Reactant: CC(C)(C)OC(=O)NS(=O)(=O)C1(C(O)c2ccccc2)CC1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCOC(C)=O
Product: NS(=O)(=O)C1(C(O)c2ccccc2)CC1
Temperature: 65 °C
Reaction time: 8 h
Yield: 99.9 %

Procedure:
880 mg of N-tert-butyloxycarbonyl-1-(hydroxyphenylmethyl)cyclopropanesulfonamide were dissolved in 25 ml of ethyl acetate, and 13.4 ml of a 1 N aqueous hydrochloric acid were added. The reaction solution was heated to 65° C. and the completeness of the conversion was checked with LCMS. After 8 hours, the mixture was neutralized with saturated aqueous sodium carbonate solution, and the organic phase was dried over Na2SO4 and concentrated by rotary evaporation. This gave the product (610 mg) with a molecular weight of 227.3 g/mol (C10H13NO3S); MS (ESI): m/e=210 (M−H2O+H+).
Reaction SMILES: [CH3:1][CH2:2][N:3]([CH2:6][CH2:7][NH:8][C:9]([C:11]1[C:15]([CH3:16])=[C:14](/[CH:17]=[C:18]2/[C:19]3[CH:24]=[C:23]([F:25])[CH:22]=[CH:21][C:20]=3[NH:26][C:27]/2=[O:28])[NH:13][C:12]=1[CH3:29])=[O:10])[CH2:4][CH3:5].C([O:33][CH:34]([CH3:36])C)(C)C>C(O)(=O)C>[CH3:1][CH2:2][N:3]([CH2:6][CH2:7][NH:8][C:9]([C:11]1[C:15]([CH3:16])=[C:14](/[CH:17]=[C:18]2/[C:19]3[CH:24]=[C:23]([F:25])[CH:22]=[CH:21][C:20]=3[NH:26][C:27]/2=[O:28])[NH:13][C:12]=1[CH3:29])=[O:10])[CH2:4][CH3:5].[C:34]([O-:10])(=[O:33])[CH3:36]
Reactant: CC(C)OC(C)C
Agent: CCN(CC)CCNC(=O)c1c(C)[nH]c(/C=C2\C(=O)Nc3ccc(F)cc32)c1C
Solvent: CC(=O)O
Product: CC(=O)[O-]
Temperature: 20 °C
Reaction time: 0.08 h

Procedure:
Sunitinib base (1.3 g) was dissolved in acetic acid (10 ml) by stirring for 5 min at 20° C. Then diisopropyl ether (20 min) was added within 30 min with stirring. Then the solution was filtered and t-butyl methyl ether (50 ml) was added to the stirred solution within 5 min. The orange precipitate thus formed was recovered by filtration, washed with t-butyl methyl ether (50 ml) and dried on air for 12 h at 20° C. (Yield 1.425 g).
Reaction SMILES: [O:1]=[C:2]1[C:6]2([CH2:11][CH2:10][N:9]([C:12]([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13])[CH2:8][CH2:7]2)[CH2:5][CH2:4][NH:3]1.FC(F)(F)S(O[C:25]1[CH2:26][O:27][C:28](=[O:32])[C:29]=1[CH2:30][CH3:31])(=O)=O.CC1(C)C2C(=C(P(C3C=CC=CC=3)C3C=CC=CC=3)C=CC=2)OC2C(P(C3C=CC=CC=3)C3C=CC=CC=3)=CC=CC1=2.O.C(=O)([O-])[O-].[K+].[K+]>C1(C)C=CC=CC=1.C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[CH2:30]([C:29]1[C:28](=[O:32])[O:27][CH2:26][C:25]=1[N:3]1[CH2:4][CH2:5][C:6]2([CH2:11][CH2:10][N:9]([C:12]([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13])[CH2:8][CH2:7]2)[C:2]1=[O:1])[CH3:31]
Reactant: CC(C)(C)OC(=O)N1CCC2(CCNC2=O)CC1
Reactant: CCC1=C(OS(=O)(=O)C(F)(F)F)COC1=O
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: CC1(C)c2cccc(P(c3ccccc3)c3ccccc3)c2Oc2c(P(c3ccccc3)c3ccccc3)cccc21
Solvent: O
Solvent: Cc1ccccc1
Product: CCC1=C(N2CCC3(CCN(C(=O)OC(C)(C)C)CC3)C2=O)COC1=O
Temperature: 60 °C

Procedure:
A mixture of tert-butyl 1-oxo-2,8-diazaspiro[4.5]decane-8-carboxylate (200 mg, 0.786 mmol), 4-ethyl-5-oxo-2,5-dihydrofuran-3-yl trifluoromethanesulfonate (246 mg, 0.944 mmol), Xantphos (45.5, 0.079 mmol), palladium (II) acetate (8.8 mg, 0.039 mmol), water (0.043 mL, 2.4 mmol), and potassium carbonate (217 mg, 1.57 mmol) in toluene (20 mL) was heated at 60° C. for 16 h. After filtration through CELITE®, the filtrate was concentrated and the residue was purified on silica gel using ethyl acetate/hexane to give the title compound. LC/MS: (M+1)+: 365.19.
Reaction SMILES: C1(C)C=CC=CC=1.Br[C:9]1[CH:13]=[CH:12][O:11][CH:10]=1.[CH:14]([C:16]1[CH:17]=[C:18](B(O)O)[CH:19]=[CH:20][CH:21]=1)=[O:15].C([O-])([O-])=O.[K+].[K+]>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.O.CN(C=O)C>[O:11]1[CH:12]=[CH:13][C:9]([C:20]2[CH:21]=[C:16]([CH:17]=[CH:18][CH:19]=2)[CH:14]=[O:15])=[CH:10]1
Reactant: Brc1ccoc1
Reactant: O=Cc1cccc(B(O)O)c1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: Cc1ccccc1
Solvent: CN(C)C=O
Solvent: O
Product: O=Cc1cccc(-c2ccoc2)c1
Yield: 9.7 %

Procedure:
EX-601A) To a toluene (10 mL) solution of 3-bromofuran (0.54 mL, 6.0 mmol) was added 3-formylphenylboronic acid (1.00 g, 6.7 mmol) and DMF (4 mL). To the resulting solution was added K2CO3 (1.85 g, 13.4 mmol) and Pd(PPh3)4 (0.40 g, 0.35 mmol). The slurry was heated to reflux under argon for 2 h. The cooled mixture was poured into water and extracted with ethyl acetate. The organic layer was washed with brine, dried (MgSO4) and evaporated to an oil. Purification by flash chromatography on silica gel eluting with 5% ethyl acetate in hexane gave 0.10 g (10%) of the desired 3-(3-furanyl)benzaldehyde product as a yellow oil. MS: m/z=173.0 [M+H]+.
Reaction SMILES: C([O:5][C:6](=[O:18])[CH:7](C#N)[C:8]1[CH:13]=[CH:12][C:11]([CH2:14][CH3:15])=[CH:10][N:9]=1)(C)(C)C.Cl>O>[CH2:14]([C:11]1[CH:12]=[CH:13][C:8]([CH2:7][C:6]([OH:18])=[O:5])=[N:9][CH:10]=1)[CH3:15]
Reactant: CCc1ccc(C(C#N)C(=O)OC(C)(C)C)nc1
Agent: Cl
Solvent: O
Product: CCc1ccc(CC(=O)O)nc1
Temperature: 104 °C

Procedure:
Cyano-(5-ethyl-pyridin-2-yl)-acetic acid tert-butyl ester (7.3 g) was mixed with 70 mL of water and 70 mL of 12N HCl and was heated at 104° C. for 3 hours before removing the volatiles in vacuo. Water was added to dissolve the solids and the pH of the solution was adjusted to 9-10 with 2N NaOH. The solution was washed with 2-methylTHF (2×). The aqueous solution was adjusted to pH 4 with 2N HCl and was concentrated under vacuum to an oily solid. The residue was triturated with hot chloroform and heptanes to afford (5-ethylpyridin-2-yl)acetic acid (SM-1ac) as a tan solid (3.88 g, 31%, 3 steps). MS (ES+) 166.1 (M+H)+. 1H NMR (DMSO-d6) δ 1.16 (t, 3H), 2.57 (q, 2H), 3.66 (s, 2H), 7.22 (d, 1H), 7.56 (dd, 1H), 8.31 (d, 1H), 12.44 (br s, 1H).
Reaction SMILES: [CH:1]1([C:4]2[CH:9]=[CH:8][N:7]=[CH:6][C:5]=2[N:10]2[CH2:14][CH2:13][NH:12][C:11]2=[O:15])[CH2:3][CH2:2]1.Br[C:17]1[C:18]([F:26])=[CH:19][C:20]2[CH:24]=[CH:23][S:22][C:21]=2[CH:25]=1.CN[C@@H]1CCCC[C@H]1NC.P([O-])([O-])([O-])=O.[K+].[K+].[K+]>[Cu](I)I.O1CCOCC1>[CH:1]1([C:4]2[CH:9]=[CH:8][N:7]=[CH:6][C:5]=2[N:10]2[CH2:14][CH2:13][N:12]([C:17]3[C:18]([F:26])=[CH:19][C:20]4[CH:24]=[CH:23][S:22][C:21]=4[CH:25]=3)[C:11]2=[O:15])[CH2:3][CH2:2]1
Reactant: O=C1NCCN1c1cnccc1C1CC1
Reactant: Fc1cc2ccsc2cc1Br
Agent: I[Cu]I
Agent: CN[C@@H]1CCCC[C@H]1NC
Agent: O=P([O-])([O-])[O-]
Solvent: C1COCCO1
Product: O=C1N(c2cc3sccc3cc2F)CCN1c1cnccc1C1CC1
Yield: 46.1 %

Procedure:
Using analogous reagents and reaction conditions as described in Example 1 above, 1-(4-cyclopropylpyridin-3-yl)imidazolidin-2-one (I-1d: 100 mg, 0.491 mmol) was reacted with 6-bromo-5-fluoro-benzo[b]thiophene (I-27d: 136 mg, 0.5901 mmol), copper iodide (28 mg, 0.147 mmol), trans-N,N′-dimethylcyclohexane-1,2-diamine (21 mg, 0.147 mmol), potassium phosphate (313.9 mg, 1.7 mmol) and 1,4-dioxane (5 mL) to afford the crude product. Purification by column chromatography on silica gel (1% methanol in CHCl3) afforded 80 mg of the product (46% yield).
Reaction SMILES: [CH3:1][C:2]([C:5]1[CH:6]=[C:7]([CH:10]=[C:11]([C:17]([CH3:20])([CH3:19])[CH3:18])[C:12]=1[O:13][CH2:14][O:15][CH3:16])[CH2:8][NH2:9])([CH3:4])[CH3:3].[CH3:21][S:22][C:23]1[CH:24]=[C:25]([NH:29][C:30](N)=[O:31])[CH:26]=[CH:27][CH:28]=1.C(O)(=O)C>C1(C)C=CC=CC=1>[CH3:4][C:2]([C:5]1[CH:6]=[C:7]([CH2:8][NH:9][C:30]([NH:29][C:25]2[CH:26]=[CH:27][CH:28]=[C:23]([S:22][CH3:21])[CH:24]=2)=[O:31])[CH:10]=[C:11]([C:17]([CH3:20])([CH3:19])[CH3:18])[C:12]=1[O:13][CH2:14][O:15][CH3:16])([CH3:1])[CH3:3]
Reactant: COCOc1c(C(C)(C)C)cc(CN)cc1C(C)(C)C
Reactant: CSc1cccc(NC(N)=O)c1
Solvent: Cc1ccccc1
Solvent: CC(=O)O
Product: COCOc1c(C(C)(C)C)cc(CNC(=O)Nc2cccc(SC)c2)cc1C(C)(C)C
Yield: 25 %

Procedure:
The above-titled compound was prepared substantially in accordance with the procedure described in Example 6A using 5.2 g (18.5 mmol of 3,5-bis(1,1-dimethylethyl)-4-(methoxymethoxy)benzylamine, 4.62 g (25.4 mmol) of N-[3(methylthio) phenyl]urea (prepared substantially in accordance with the procedure described in Example 5), 1.06 ml of acetic acid and 180 ml of toluene. Such reaction provided 2.06 g of N[[3,5-bis(1,1-dimethylethyl)-4-(methoxymethoxy)phenyl]methyl]N'-[3-(methylthio)phenyl]urea. The methoxymethyl hydroxy protecting group was then removed, substantially in accordance with the procedure described in Example 6B, to provide 444 mg of title compound. m.p. 133°-138° C. (dec).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([N:8]2[CH:12]=[CH:11][C:10]([CH3:13])=[N:9]2)[CH:5]=[CH:4][C:3]=1[C:14]([N:16]1[C:22]2[CH:23]=[CH:24][CH:25]=[CH:26][C:21]=2[CH2:20][N:19]2[CH:27]=[CH:28][CH:29]=[C:18]2[CH2:17]1)=[O:15].C(O)(=O)C.C=O>CO>[Cl:1][C:2]1[CH:7]=[C:6]([N:8]2[CH:12]=[CH:11][C:10]([CH3:13])=[N:9]2)[CH:5]=[CH:4][C:3]=1[C:14]([N:16]1[C:22]2[CH:23]=[CH:24][CH:25]=[CH:26][C:21]=2[CH2:20][N:19]2[C:27]([CH2:14][N:16]([CH3:22])[CH3:17])=[CH:28][CH:29]=[C:18]2[CH2:17]1)=[O:15]
Reactant: Cc1ccn(-c2ccc(C(=O)N3Cc4cccn4Cc4ccccc43)c(Cl)c2)n1
Agent: C=O
Solvent: CO
Solvent: CC(=O)O
Product: Cc1ccn(-c2ccc(C(=O)N3Cc4ccc(CN(C)C)n4Cc4ccccc43)c(Cl)c2)n1
Temperature: 40 °C
Reaction time: 1 h
Yield: 39.2 %

Procedure:
To a stirred solution of [2-chloro-4-(3-methyl-pyrazol-1-yl)-phenyl]-(5H,11H-pyrrolo-[2,1-c][1,4]benzodiazepin-10-yl)-methanone (1.61 g), N, N, N′, N′, tetramethyldiamino-methane (0.82 g), and glacial acetic acid (0.48 g) in methanol (25 ml) was added a solution of 37% aqueous formaldehyde (4 ml). The mixture was warmed to 40° C. for 10 minutes. After stirring one hour at room temperature, the reaction was concentrated in vacuo, redissolved in dichloromethane, and extracted sequentially with aqueous sodium bicarbonate and water (4×). The organic phase was dried over anhydrous sodium sulfate, and filtered through a plug of silica gel, eluted with ethyl acetate. Evaporation of the solvent in vacuo afforded an oil, which on trituration with hexane yielded 0.36 g of the title compound as a colorless powder, m.p. 100-102° C.; MS (+FAB), m/z: 482 (M+Na)+, 460 (M+H)+.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[S:8][S:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=1[NH2:16].Br[C:18]([CH3:23])([CH3:22])[C:19](Cl)=[O:20]>C(#N)C>[O:20]=[C:19]1[C:18]([CH3:23])([CH3:22])[C:12]2[C:11](=[C:10]([S:9][S:8][C:3]3[CH:4]=[CH:5][CH:6]=[C:7]4[C:2]=3[NH:1][C:19](=[O:20])[C:18]4([CH3:23])[CH3:22])[CH:15]=[CH:14][CH:13]=2)[NH:16]1
Reactant: Nc1ccccc1SSc1ccccc1N
Reactant: CC(C)(Br)C(=O)Cl
Solvent: CC#N
Product: CC1(C)C(=O)Nc2c(SSc3cccc4c3NC(=O)C4(C)C)cccc21
Temperature: 40 °C
Yield: 55.2 %

Procedure:
In a stream of nitrogen, 12.4 g of bis(2-aminophenyl)disulfide was added to 100 ml of acetonitrile, and further added thereto was 18.6 g of α-bromo-α-methylpropionic acid chloride. The resulting mixture was heated under reflux for 3 hours. After removal of acetonitrile, 100 ml of ethylene chloride was added to the reaction product, and gradually added thereto was 28 g of anhydrous aluminium chloride at room temperature. After the conclusion of the additional materials, the mixture was heated for 2 hours at 40° C. with vigorous stirring. The reaction mixture was poured into 200 g of ice-cold water containing concentrated hydrochloric acid in order to decompose the aluminium chloride. After the decomposition, 100 ml of chloroform was added to the reaction mixture, and the organic phase was washed with saturated sodium chloride solution three times. The chloroform-ethylene chloride phase was removed, and concentrated to dryness. The product was purified by column chromatography on silica gel to obtain 10.6 g of bis(2-oxo-3,3-di-methyl-7-indolinyl)disulfide.
Reaction SMILES: O[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([O:12][CH3:13])[CH:10]=2)[C:5]2[O:14][C:15]3[CH:20]=[CH:19][C:18]([Cl:21])=[CH:17][C:16]=3[C:4]=2[N:3]=1.[Cl:22]C1C=C2C(C3OC4C=CC=CC=4C=3N=C2O)=CC=1>>[CH3:13][O:12][C:9]1[CH:10]=[C:11]2[C:6]([C:5]3[O:14][C:15]4[CH:20]=[CH:19][C:18]([Cl:21])=[CH:17][C:16]=4[C:4]=3[N:3]=[C:2]2[Cl:22])=[CH:7][CH:8]=1
Reactant: COc1ccc2c(c1)c(O)nc1c3cc(Cl)ccc3oc21
Reactant: Oc1nc2c3ccccc3oc2c2ccc(Cl)cc12
Product: COc1ccc2c(c1)c(Cl)nc1c3cc(Cl)ccc3oc21

Procedure:
The procedure was similar to step S19C, while the starting material was 28B in stead of 19B.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([CH:11]=[CH:12][CH:13]=1)[C:7]([NH:9][NH2:10])=[O:8])([O-:3])=[O:2].[C:14](N1C=CN=C1)(N1C=CN=C1)=[O:15].Cl.O>C1COCC1>[N+:1]([C:4]1[CH:5]=[C:6]([C:7]2[O:8][C:14](=[O:15])[NH:10][N:9]=2)[CH:11]=[CH:12][CH:13]=1)([O-:3])=[O:2]
Reactant: O=C(n1ccnc1)n1ccnc1
Reactant: NNC(=O)c1cccc([N+](=O)[O-])c1
Agent: Cl
Solvent: O
Solvent: C1CCOC1
Product: O=c1[nH]nc(-c2cccc([N+](=O)[O-])c2)o1
Temperature: 25 °C
Reaction time: 0.67 h

Procedure:
3-Nitrobenzohydrazide (2.05 g, 11.3 mmol) obtained in Step 1 was dissolved in THF (57 mL), and the mixture was stirred at room temperature for 40 minutes after adding 1,1′-carbonyldiimidazole (2.01 g, 12.4 mmol). The mixture was stirred after adding 6 mol/L hydrochloric acid (40 mL) and water (20 mL), and the precipitated solid was filtered off and dried to give 5-(3-nitrophenyl)-1,3,4-oxadiazol-2(3H)-one as a white solid. 5-(3-Nitrophenyl)-1,3,4-oxadiazol-2(3H)-one so obtained was dissolved in DMF (52 mL), and the mixture was stirred at room temperature for 40 minutes after adding potassium carbonate (2.14 g, 15.5 mmol) and methyl iodide (0.77 mL, 12.3 mmol). The mixture was stirred after adding water, and the precipitated solid was filtered off and dried to give 3-methyl-5-(3-nitrophenyl)-1,3,4-oxadiazol-2(3H)-one (2.17 g, 87%).