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][C:3]=1[O:10][CH3:11].[CH3:12][O:13][C:14]1[CH:21]=[CH:20][C:17]([CH2:18]Cl)=[CH:16][CH:15]=1.C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O>[CH3:11][O:10][C:3]1[CH:4]=[C:5]([CH:8]=[CH:9][C:2]=1[O:1][CH2:18][C:17]1[CH:20]=[CH:21][C:14]([O:13][CH3:12])=[CH:15][CH:16]=1)[CH:6]=[O:7]
Reactant: COc1cc(C=O)ccc1O
Reactant: COc1ccc(CCl)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: COc1ccc(COc2ccc(C=O)cc2OC)cc1
Temperature: 25 °C
Yield: 84.6 %

Procedure:
A mixture of 4-hydroxy-3-methoxybenzaldehyde (22.6 g, 149 mmol), 4-methoxybenzyl chloride (23.3 g, 149 mmol) and potassium carbonate (30.8 g, 223 mmol) was stirred in N,N-dimethylformamide (DMF) (150 mL) at 90 C for 2 hours. The solution was filtered hot, and cooled to room temperature. The filtrate was concentrated and dissolved ethyl acetate (300 mL) and extracted with aqueous sodium bicarbonate and water. The organics were dried with magnesium sulfate, filtered and concentrated. The crude product was recrystalized with ethyl acetate and hexanes to give product as an off-white solid (34.2 g, 126 mmol). 1H NMR (300 MHz, d6-DMSO): δ 9.86 (s, 1H), 7.58 (d, J=8.2 Hz, 1H), 7.44-7.40 (m, 3H), 7.30 (d, J=8.4 Hz, 1H), 6.98 (d, J=8.7 Hz, 2H), 5.15 (s, 2H), 3.84 (s, 3H), 3.78 (s, 3H). MS (ES+, m/z)=273 (M+H).
Reaction SMILES: [CH3:1][O:2][CH2:3][C@@H:4]1[CH2:8][CH2:7][CH2:6][N:5]1[S:9]([C:12]1[CH:13]=[C:14]2[C:18](=[CH:19][CH:20]=1)[NH:17][C:16](=O)[C:15]12[O:26]CCCO1)(=[O:11])=[O:10].Cl[CH2:28][C:29]1([C:35]#[N:36])[CH2:34][CH2:33][CH2:32][CH2:31][CH2:30]1>>[CH3:1][O:2][CH2:3][C@@H:4]1[CH2:8][CH2:7][CH2:6][N:5]1[S:9]([C:12]1[CH:20]=[CH:19][C:18]2[N:17]3[CH2:28][C:29]4([CH2:34][CH2:33][CH2:32][CH2:31][CH2:30]4)[CH2:35][N:36]=[C:16]3[C:15](=[O:26])[C:14]=2[CH:13]=1)(=[O:11])=[O:10]
Reactant: N#CC1(CCl)CCCCC1
Reactant: COC[C@@H]1CCCN1S(=O)(=O)c1ccc2c(c1)C1(OCCCO1)C(=O)N2
Product: COC[C@@H]1CCCN1S(=O)(=O)c1ccc2c(c1)C(=O)C1=NCC3(CCCCC3)CN12

Procedure:
The title compound was prepared as a yellow foam from 5′-{[(2S)-2-(methoxymethyl)pyrrolidin-1-yl]sulfonyl}spiro[1,3-dioxane-2,3′-indol]-2′(1′H)-one and 1-chloromethyl-cyclohexanecarbonitrile (Syn. Comm. 20(12) 1757, 1990) using a procedure similar to that of steps 3-5 of Example 12. NMR (400 Mz, DMSO-d6): consistent. MS: (ES−) m/z 430 [M−H].
Reaction SMILES: Br.C[O:3][C:4]1[CH:9]=[CH:8][C:7]([CH2:10][C:11](=[O:13])[CH3:12])=[CH:6][CH:5]=1>O>[OH:3][C:4]1[CH:5]=[CH:6][C:7]([CH2:10][C:11](=[O:13])[CH3:12])=[CH:8][CH:9]=1
Reactant: COc1ccc(CC(C)=O)cc1
Agent: Br
Solvent: O
Product: CC(=O)Cc1ccc(O)cc1
Temperature: 30 °C
Reaction time: 0.03 h

Procedure:
Hydrobromic acid (48%, 250 mL) was heated to approximately 120° C. Over a period of two minutes, a 9.85 g sample of 4-methoxyphenylacetone was added dropwise. After 15 minutes, the reaction mixture was chilled to 30° C. and diluted to 500 mL with distilled water. The resulting mixture was extracted twice with 250 mL portions of diethyl ether. The combined organic extracts were washed with brine, dried over magnesium sulfate, and the solvent was removed in vacuo. The resulting oil was purified immediately by column chromatography over silica gel, using 40% ethyl acetate and 60% hexane. Appropriate fractions were pooled and solvents removed in vacuo to yield a thick yellow oil.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([F:8])=[CH:4][N:3]=1.[C:9]1([Mg]Br)[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1>O1CCCC1.CCOC(C)=O>[F:8][C:5]1[CH:6]=[CH:7][C:2]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)=[N:3][CH:4]=1
Reactant: Fc1ccc(Br)nc1
Reactant: Br[Mg]c1ccccc1
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: Fc1ccc(-c2ccccc2)nc1
Reaction time: 0.17 h
Yield: 69.1 %

Procedure:
To a solution of 2-bromo-5-fluoropyridine (10.0 g, 56.82 mmol, Aldrich) in tetrahydrofuran (100 ml) was added tetrakis (triphenylphosphine)Pd complex and stirred for 10 min. Then, phenylmagnesium bromide (68.2 ml, 1.00 M in THF, 68.19 mmol) was added drop-wise at 0° C. The mixture was stirred overnight. Then the reaction was diluted with EtOAc (600 ml), and filtered. The filtrate was concentrated and purified by flash chromatography by eluting with 2% EtOAc-Hexane to obtain 6.8 g (69%) of 5-fluoro-2-phenylpyridine.
Reaction SMILES: [CH3:1][NH:2][CH3:3].[C:4]([N:9]=[C:10]=[O:11])(=[O:8])[C:5]([CH3:7])=[CH2:6]>C(Cl)(Cl)Cl.ClCCCl>[C:4]([NH:9][C:10]([N:2]([CH3:3])[CH3:1])=[O:11])(=[O:8])[C:5]([CH3:7])=[CH2:6]
Reactant: C=C(C)C(=O)N=C=O
Reactant: CNC
Solvent: ClCCCl
Solvent: ClC(Cl)Cl
Product: C=C(C)C(=O)NC(=O)N(C)C
Yield: 99.9 %

Procedure:
To a solution of dimethylamine (0.45 g; 10 mmol) in chloroform (20 ml), a solution of methacryloyl isocyanate (1.11 g; 10 mmol) in 1,2-dichloroethane (20 ml) was dropwise added under nitrogen stream while cooling with ice. After completion of the addition, chloroform and 1,2-dichloroethane were evaporated under reduced pressure to give 1-methacryloyl-3,3-dimethylurea (1.56 g) as a colorless oil.
Reaction SMILES: [CH3:1][C:2]1[C:6]([CH2:7][N:8]2[CH:12]=[C:11]([N:13]3[C:17](=[O:18])[CH2:16][N:15]([CH2:19][C:20]4[CH:21]=[C:22]([CH:26]=[CH:27][CH:28]=4)[C:23]([OH:25])=O)[C:14]3=[O:29])[CH:10]=[N:9]2)=[C:5]([CH3:30])[O:4][N:3]=1.Cl.CN.[CH2:34]([N:36](CC)CC)C.C(Cl)CCl>C(#N)C.Cl>[CH3:1][C:2]1[C:6]([CH2:7][N:8]2[CH:12]=[C:11]([N:13]3[C:17](=[O:18])[CH2:16][N:15]([CH2:19][C:20]4[CH:21]=[C:22]([CH:26]=[CH:27][CH:28]=4)[C:23]([NH:36][CH3:34])=[O:25])[C:14]3=[O:29])[CH:10]=[N:9]2)=[C:5]([CH3:30])[O:4][N:3]=1
Reactant: CCN(CC)CC
Reactant: Cc1noc(C)c1Cn1cc(N2C(=O)CN(Cc3cccc(C(=O)O)c3)C2=O)cn1
Agent: CN
Agent: Cl
Solvent: ClCCCl
Solvent: CC#N
Product: CNC(=O)c1cccc(CN2CC(=O)N(c3cnn(Cc4c(C)noc4C)c3)C2=O)c1
Yield: 24.7 %

Procedure:
3-((3-(1-((3,5-dimethylisoxazol-4-yl)methyl)-1H-pyrazol-4-yl)-2,4-dioxoimidazolidin-1-yl)methyl)benzoic acid (100 mg, 0.24 mmol) (example 10-8), methylamine hydrochloride (67 mg, 1 mmol), triethylamine (155 mg, 1.5 mmol), and EDC (57 mg, 0.3 mmol) in acetonitrile (3 mL) were irradiated in the microwave reactor at 80° C. for 10 minutes. The reaction was cooled, diluted with aqueous 1N HCl (100 mL) and extracted with ethyl acetate (3×, 75 mL). The combined organic extracts were dried over sodium sulfate, filtered and concentrated. The crude product was dissolved in MeOH (3 mL) and purified by reversed phase HPLC (5 to 95% acetonitrile in H2O: 25 minute gradient) to afford 3-((3-(1-((3,5-dimethylisoxazol-4-yl)methyl)-1H-pyrazol-4-yl)-2,4-dioxoimidazolidin-1-yl)methyl)-N-methylbenzamide (25 mg, 25%) as white solid. MS M+H calculated 423.17; found 423.2. The title compound was shown to inhibit hT2R08 bitter receptor and had an IC50 of 0.14 μM.
Reaction SMILES: [CH3:1][C:2]1[N:29]=[C:5]2[NH:6][C:7](=[O:28])[C:8]([CH2:13][C:14]3[CH:19]=[CH:18][C:17]([C:20]4[C:21]([C:26]#[N:27])=[CH:22][CH:23]=[CH:24][CH:25]=4)=[CH:16][CH:15]=3)=[C:9]([CH2:10][CH2:11][CH3:12])[N:4]2[N:3]=1.I[CH:31]([CH2:33][CH3:34])[CH3:32].C(=O)([O-])[O-].[K+].[K+].CN(C)C(=O)C>C(OCC)(=O)C>[CH3:1][C:2]1[N:29]=[C:5]2[N:6]([CH:31]([CH3:32])[CH2:33][CH3:34])[C:7](=[O:28])[C:8]([CH2:13][C:14]3[CH:19]=[CH:18][C:17]([C:20]4[C:21]([C:26]#[N:27])=[CH:22][CH:23]=[CH:24][CH:25]=4)=[CH:16][CH:15]=3)=[C:9]([CH2:10][CH2:11][CH3:12])[N:4]2[N:3]=1
Reactant: CCCc1c(Cc2ccc(-c3ccccc3C#N)cc2)c(=O)[nH]c2nc(C)nn12
Reactant: CCC(C)I
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CC(=O)N(C)C
Product: CCCc1c(Cc2ccc(-c3ccccc3C#N)cc2)c(=O)n(C(C)CC)c2nc(C)nn12
Temperature: 100 °C
Reaction time: 16 h
Yield: 22 %

Procedure:
A mixture of 4′-[(2-methyl-5-oxo-7-propyl-4,5-dihydro[1,2,4]triazolo[1,5-a]pyrimidin-6-yl)methyl]biphenyl-2-carbonitrile (1.5 g), 2-iodobutane (1.4 mL), potassium carbonate (1 g) and N,N-dimethylacetamide (15 mL) was stirred at 100° C. for 16 hr. The reaction mixture was diluted with ethyl acetate, washed with 5% aqueous potassium hydrogensulfate solution and then with saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure, and the residue was purified by silica gel column chromatography to give the title compound as a colorless solid (0.36 g, 22%).
Reaction SMILES: [H-].[Na+].C(OP([CH2:11][C:12]#[N:13])(OCC)=O)C.[CH:14](=O)[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1.O>O1CCCC1>[C:12](#[N:13])[CH:11]=[CH:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1
Reactant: CCOP(=O)(CC#N)OCC
Reactant: O=Cc1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: N#CC=Cc1ccccc1
Reaction time: 1 h
Yield: 71.4 %

Procedure:
Four grams of 60% sodium hydride was suspended in 100 ml tetrahydrofuran, and 17.1 g of diethylphosphonoacetonitrile was added with ice cooling. To the resulting solution, was added dropwise a solution of 10.6 g benzaldehyde in 80 ml tetrahydrofuran, and the mixture was stirred for one hour. After admixing 50 ml water, the organic layer was collected, dried over anhydrous sodium sulfate and concentrated. Distillation of the concentrate under reduced pressure (102°-106° C./6 mmHg) gave 8.9 g (yield: 69.0%) of cinnamonitrile.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]([O:23][CH2:24][C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)=[C:6]([CH:22]=1)[CH2:7][NH:8][C:9]1[CH:21]=[CH:20][C:12]([C:13]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14])=[CH:11][CH:10]=1.[CH3:31][O:32][C:33](=[O:42])[C:34]1[CH:39]=[CH:38][C:37]([CH2:40]Br)=[CH:36][CH:35]=1.C(=O)([O-])[O-].[K+].[K+].O>CN(C)C=O>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([O:23][CH2:24][C:25]2[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=2)=[C:6]([CH:22]=1)[CH2:7][N:8]([C:9]1[CH:21]=[CH:20][C:12]([C:13]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14])=[CH:11][CH:10]=1)[CH2:40][C:37]1[CH:36]=[CH:35][C:34]([C:33]([O:32][CH3:31])=[O:42])=[CH:39][CH:38]=1
Reactant: CC(C)(C)OC(=O)c1ccc(NCc2cc(Br)ccc2OCc2ccccc2)cc1
Reactant: COC(=O)c1ccc(CBr)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: COC(=O)c1ccc(CN(Cc2cc(Br)ccc2OCc2ccccc2)c2ccc(C(=O)OC(C)(C)C)cc2)cc1
Temperature: 25 °C
Reaction time: 24 h

Procedure:
tert-Butyl 4-[5-bromo-2-benzyloxybenzylamino]benzoate (16.9 g) and methyl-4-bromomethylbenzoate were dissolved in in dimethylformamide (30 ml) and potassium carbonate (18 g) added. The mixture was stirred at ambient temperature for 24 hours and then poured into water (300 ml). The reaction mixture was extracted with ether (4×100 ml). The combined ether extracts were washed with water (3×100 ml) and brine (1×100 ml), dried over magnesium sulphate and evaporated. The residue was purified by MPLC eluting with 1:1 dichloromethane/hexane to give tert-butyl 4-[N-(5-bromo-2-benzyloxybenzyl)-N-(4-methoxycarbonylbenzyl)amino]benzoate (3.6 g) m.p. 154°-155° C.
Reaction SMILES: F[C:2]1[CH:3]=[CH:4][C:5]([N+:9]([O-:11])=[O:10])=[C:6]([CH3:8])[CH:7]=1.[F:12][C:13]1[CH:14]=[CH:15][C:16]([OH:21])=[C:17]([CH:20]=1)[C:18]#[N:19].C(=O)([O-])[O-].[K+].[K+].O>CN(C)C(=O)C>[F:12][C:13]1[CH:14]=[CH:15][C:16]([O:21][C:3]2[CH:2]=[CH:7][C:6]([CH3:8])=[C:5]([N+:9]([O-:11])=[O:10])[CH:4]=2)=[C:17]([CH:20]=1)[C:18]#[N:19]
Reactant: Cc1cc(F)ccc1[N+](=O)[O-]
Reactant: N#Cc1cc(F)ccc1O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CC(=O)N(C)C
Product: Cc1ccc(Oc2ccc(F)cc2C#N)cc1[N+](=O)[O-]
Temperature: 100 °C
Reaction time: 8 h
Yield: 95.1 %

Procedure:
In a 3-necked 5 L flask, equipped with a mechanic stirrer, a condenser, and a J-Kem temperature probe, a solution of 5-fluoro-2-nitrotoluene (158 g, 1.02 mol) in N,N-dimethylacetamide (500 mL) was added to a mixture of 5-fluoro-2-hydroxybenzonitrile (147 g, 1.07 mol) and potassium carbonate (163 g, 1.2 mol) in N,N-dimethylacetamide (573 mL) at room temperature. The mixture was heated to 100° C. After 8 hours, the reaction mixture was cooled to room temperature and water (3400 mL) was added in an ice bath. The precipitate was filtered, washed with water (1073 mL×2), and dried in vacuum (40° C.) to give (264 g, 90%) of the desired compound as a brown solid. MS (APCI−) m/z 272 (M−1) was detected. 1H NMR (400 MHz, CDCl3) δ 8.10 (d, 1H, J=9 Hz), 7.41-7.48 (m, 1H), 7.38 (m, 1H), 7.07-7.14 (m, 1H), 6.88-7.10 (m, 1H), 2.63 (s, 3H).
Reaction SMILES: [H-].[Na+].[NH:3]1[CH:7]=[CH:6][N:5]=[CH:4]1.Br[CH2:9][C:10]1[CH:22]=[CH:21][C:13]([CH:14]=[CH:15][C:16]([O:18][CH2:19][CH3:20])=[O:17])=[CH:12][CH:11]=1>C(#N)C>[NH:3]1[CH:7]=[CH:6][N:5]=[C:4]1[CH2:9][C:10]1[CH:22]=[CH:21][C:13]([CH:14]=[CH:15][C:16]([O:18][CH2:19][CH3:20])=[O:17])=[CH:12][CH:11]=1
Reactant: c1c[nH]cn1
Reactant: CCOC(=O)C=Cc1ccc(CBr)cc1
Agent: [H-]
Agent: [Na+]
Solvent: CC#N
Product: CCOC(=O)C=Cc1ccc(Cc2ncc[nH]2)cc1
Reaction time: 0.5 h
Yield: 69.5 %

Procedure:
To a suspension of 0.96 g of 50% sodium hydride in 50 ml of dry acetonitrile was added 1.3 g of imidazole at room temperature, and then the mixture was stirred for 30 min. A solution of 5.38 g of ethyl p-bromomethylcinnamate in 20 ml of dry acetonitrile was added to the mixture at room temperature for 10 min, and then the mixture was stirred at the same temperature for 1 hr. After concentration under reduced pressure, the residue was dissolved in 100 ml of benzene and washed with water and dried. The solvent was evaporated and the residual oil was chromatographed on silica gel using chloroform, and the resulting crystals were recrystallized from diethyl ether to give 3.4 g of ethyl 4-(1-imidazolylmethyl)cinnamate. This compound was added to 30 ml of 80% aqueous ethanol containing 0.8 g of sodium hydroxide and the mixture was stirred for 4 hr at room temperature. After concentration and reduced pressure, 25 ml of water was added to the residue and the mixture was washed with diethyl ether. The mixture was adjusted to pH 1 to 2 by an addition of concentrated hydrochloric acid and the acidic solution was concentrated under reduced pressure. To the residue, 30 ml of 2-methyl-2-propanol was added and the mixture was evaporated again, and the residue was dissolved in 80 ml of ethanol and the insoluble materials were filtered off. The filtrate was evaporated to obtain 3.4 g of crude 4-(1-imidazolylmethyl)cinnamic acid hydrochloride.
Reaction SMILES: [H-].[Na+].[Br:3][C:4]1[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[NH:6][C:5]=1[CH3:13].[CH2:14]([O:16][CH2:17][CH2:18]Br)[CH3:15].[I-].[Na+]>CN(C)C=O>[Br:3][C:4]1[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[N:6]([CH2:15][CH2:14][O:16][CH2:17][CH3:18])[C:5]=1[CH3:13]
Reactant: CCOCCBr
Reactant: Cc1[nH]c2ccccc2c1Br
Agent: [H-]
Agent: [I-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCOCCn1c(C)c(Br)c2ccccc21
Reaction time: 1 h
Yield: 74.4 %

Procedure:
Under ice-cooling, sodium hydride (60% in oil, 1.44 g, 36.0 mmol) was added to a solution of 3-bromo-2-methyl-1H-indole (6.30 g, 30.0 mmol) in N,N-dimethylformamide (30 mL) by small portions, and the mixture was stirred under a nitrogen atmosphere at the same temperature for 1 hr. 2-Bromoethyl ethyl ether (5.07 mL, 45.0 mmol) and sodium iodide (0.747 g, 4.50 mmol) were added to the reaction mixture, and the mixture was stirred at 70° C. for 6 hr. The reaction mixture was concentrated under reduced pressure, water was added and the mixture was extracted with ethyl acetate. The extract was washed with saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (hexane-25% ethyl acetate/hexane) to give the title compound (6.30 g, yield 74%) as a dark-purple oil. MS m/z 282 (MH+).
Reaction SMILES: [NH2:1][C:2]1[S:3][C:4]([C:10]([CH3:13])([CH3:12])[CH3:11])=[CH:5][C:6]=1[C:7]([NH2:9])=[O:8].[C:14]1([CH3:23])[CH:19]=[CH:18][C:17]([N:20]=[C:21]=[O:22])=[CH:16][CH:15]=1>C1(C)C=CC=CC=1>[C:7]([C:6]1[CH:5]=[C:4]([C:10]([CH3:13])([CH3:12])[CH3:11])[S:3][C:2]=1[NH:1][C:21]([NH:20][C:17]1[CH:18]=[CH:19][C:14]([CH3:23])=[CH:15][CH:16]=1)=[O:22])(=[O:8])[NH2:9]
Reactant: Cc1ccc(N=C=O)cc1
Reactant: CC(C)(C)c1cc(C(N)=O)c(N)s1
Solvent: Cc1ccccc1
Product: Cc1ccc(NC(=O)Nc2sc(C(C)(C)C)cc2C(N)=O)cc1
Yield: 39.7 %

Procedure:
A solution of 2-amino-5-tert-butylthiophene-3-carboxamide (0.14 g, 0.7 mmol) and p-tolyl isocyanate (0.093 g, 0.7 mmol) in toluene (5 mL) was stirred at 60° C. overnight. The reaction mixture was separated between with water (10 mL) and EtOAc (10 mL). The aqueous phase was back-extracted with EtOAc (3×10 mL), and the combined organic phases were washed with a saturated NaCl solution (25 mL), dried (Na2SO4), and concentrated under reduced pressure. The residue was purified by chromatography (SiO2; gradient from 20% EtOAc/80% pet. ether to 30% EtOAc/70% pet ether) to give N-(3-carbamoyl-5-tert-butyl-2-thienyl)-N′-(4-methylphenyl)urea (0.092 g, 40%): 1H-NMR (CDCl3) δ1.38 (s, 9H), 2.32 (s, 3H), 5.58 (br s, 2H), 6.53 (s, 1H), 7.13 (app d, 2H), 7.35 (app d, 2H), 7.45 (br, 1H), 11.23 (br s, 1H).
Reaction SMILES: [OH-].[K+].[N+:3]([CH:6]=[C:7](SC)[S:8]([CH3:10])=O)([O-:5])=[O:4].Cl.[NH2:14][CH2:15][C:16](=O)[CH3:17]>CO>[CH3:10][S:8][C:7]1[NH:14][CH:15]=[C:16]([CH3:17])[C:6]=1[N+:3]([O-:5])=[O:4]
Reactant: CC(=O)CN
Reactant: CSC(=C[N+](=O)[O-])S(C)=O
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: CO
Product: CSc1[nH]cc(C)c1[N+](=O)[O-]
Reaction time: 0.08 h
Yield: 16.8 %

Procedure:
Crushed potassium hydroxide (5.7 g, 0.1 mol) was added portionwise to a refluxing solution of 1-nitro-2-methylthio-2-methylsulphinylethylene (9.3 g, 0.05 mol) and aminoacetone hydrochloride (5.6 g, 0.05 mol) in methanol (100 ml). Reflux was continued for 5 minutes, and then the mixture was cooled and the solvent removed in vacuo. Water was added to the residue, and the solid was recrystallised from chloroform/methanol/petroleum ether to give 2-methylthio-3-nitro-4-methylpyrrole (1.45 g, 16%) m.p. 216-216-5.
Reaction SMILES: [C:1]([O:4][C:5]1[CH:6]=[C:7]2[C:12](=[CH:13][CH:14]=1)[N:11]=[C:10]([C:15]1[CH:20]=[CH:19][CH:18]=[C:17]([N+:21]([O-:23])=[O:22])[CH:16]=1)[N:9]=[C:8]2Cl)(=[O:3])[CH3:2].[NH2:25][C:26]1[CH:27]=[C:28]2[C:32](=[CH:33][CH:34]=1)[N:31]([C:35]([O:37][C:38]([CH3:41])([CH3:40])[CH3:39])=[O:36])[N:30]=[CH:29]2>CC(O)C>[C:1]([O:4][C:5]1[CH:6]=[C:7]2[C:12](=[CH:13][CH:14]=1)[N:11]=[C:10]([C:15]1[CH:20]=[CH:19][CH:18]=[C:17]([N+:21]([O-:23])=[O:22])[CH:16]=1)[N:9]=[C:8]2[NH:25][C:26]1[CH:27]=[C:28]2[C:32](=[CH:33][CH:34]=1)[N:31]([C:35]([O:37][C:38]([CH3:41])([CH3:40])[CH3:39])=[O:36])[N:30]=[CH:29]2)(=[O:3])[CH3:2]
Reactant: CC(C)(C)OC(=O)n1ncc2cc(N)ccc21
Reactant: CC(=O)Oc1ccc2nc(-c3cccc([N+](=O)[O-])c3)nc(Cl)c2c1
Solvent: CC(C)O
Product: CC(=O)Oc1ccc2nc(-c3cccc([N+](=O)[O-])c3)nc(Nc3ccc4c(cnn4C(=O)OC(C)(C)C)c3)c2c1
Temperature: 95 °C
Yield: 92.5 %

Procedure:
A mixture of 4-chloro-2-(3-nitrophenyl)quinazolin-6-yl acetate (1.63 g, 4.74 mmol) and tert-butyl 5-amino-1H-indazole-1-carboxylate (1.16 g, 4.28 mmol) in IPA (80 mL) were heated at 95° C. for 5 h. The mixture was allowed to cool to RT, the yellow solid was collected via filtration and washed with Et2O to give the product tert-butyl 5-(6-acetoxy-2-(3-nitrophenyl)quinazolin-4-ylamino)-1H-indazole-1-carboxylate (2.14 g, 3.96 mmol, 84%). HPLC retention time 9.649 min.
Reaction SMILES: [NH2:1][CH2:2][C@H:3]1[CH2:7][CH2:6][N:5]([C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9])[CH2:4]1.[Br:15][C:16]1[CH:17]=[C:18]([C:22](O)=[O:23])[NH:19][C:20]=1[Br:21]>>[C:11]([O:10][C:8]([N:5]1[CH2:6][CH2:7][C@H:3]([CH2:2][NH:1][C:22]([C:18]2[NH:19][C:20]([Br:21])=[C:16]([Br:15])[CH:17]=2)=[O:23])[CH2:4]1)=[O:9])([CH3:14])([CH3:13])[CH3:12]
Reactant: CC(C)(C)OC(=O)N1CC[C@H](CN)C1
Reactant: O=C(O)c1cc(Br)c(Br)[nH]1
Product: CC(C)(C)OC(=O)N1CC[C@H](CNC(=O)c2cc(Br)c(Br)[nH]2)C1

Procedure:
60.1 Using general procedure E, (R)-3-aminomethyl-1-N-tert-butoxycarbonyl-pyrrolidine was coupled with 4,5-dibromo-1H-pyrrole-2-carboxylic acid to give (R)-3-{[(4,5-dibromo-1H-pyrrole-2-carbonyl)-amino]-methyl}-pyrrolidine-1-carboxylic acid tert-butyl ester. Pale yellow solid. MS449.9 ([M−H]−)
Reaction SMILES: [NH2:1][C:2]1[S:3][CH:4]=[C:5]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)[N:6]=1.[C:13](Cl)(Cl)=[O:14]>N1C=CC=CC=1>[C:7]1([C:5]2[N:6]=[C:2]([NH:1][C:13]([NH:1][C:2]3[S:3][CH:4]=[C:5]([C:7]4[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=4)[N:6]=3)=[O:14])[S:3][CH:4]=2)[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1
Reactant: Nc1nc(-c2ccccc2)cs1
Reactant: O=C(Cl)Cl
Solvent: c1ccncc1
Product: O=C(Nc1nc(-c2ccccc2)cs1)Nc1nc(-c2ccccc2)cs1
Temperature: 5 °C
Reaction time: 8 h
Yield: 105.5 %

Procedure:
Into 50 ml of a dry pyridine solution containing 7.5 g of 2-amino-4-phenylthiazole, 4.8 g of phosgene was absorbed under cooling (about 5° C.). The temperature of the mixture was then allowed to rise to room temperature. To this solution, 7.5 g of 2-amino-4-phenylthiazole was added further. The mixture was stirred overnight. The pyridine was removed under reduced pressure and the residue was converted to powder in methyl alcohol. The powder was then recrystallized from an N,N-dimethylformamide/methyl alcohol mixed solvent to obtain 8.5 g of N,N'-bis(4-phenylthiazol-2-yl)urea.
Reaction SMILES: Br[C:2]1[CH:10]=[C:9]2[C:5]([CH2:6][C:7]3([CH2:15][CH:14]([O:16][CH3:17])[CH:13]([O:18][CH3:19])[CH2:12]3)[C:8]2=[O:11])=[CH:4][CH:3]=1.[C:20]([C:22]1[CH:23]=[C:24](B(O)O)[CH:25]=[CH:26][CH:27]=1)#[N:21].C(=O)([O-])[O-].[Cs+].[Cs+]>O1CCOCC1.O.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>[CH3:19][O:18][CH:13]1[CH:14]([O:16][CH3:17])[CH2:15][C:7]2([CH2:6][C:5]3[C:9](=[CH:10][C:2]([C:26]4[CH:27]=[C:22]([CH:23]=[CH:24][CH:25]=4)[C:20]#[N:21])=[CH:3][CH:4]=3)[C:8]2=[O:11])[CH2:12]1
Reactant: COC1CC2(Cc3ccc(Br)cc3C2=O)CC1OC
Reactant: N#Cc1cccc(B(O)O)c1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: C1COCCO1
Solvent: O
Product: COC1CC2(Cc3ccc(-c4cccc(C#N)c4)cc3C2=O)CC1OC
Temperature: 110 °C
Yield: 73 %

Procedure:
In a microwave vial was placed 6′-bromo-3,4-dimethoxyspiro[cyclopentane-1,2′-inden]-1′(3′H)-one 1st isomer (51 mg, 0.157 mmol), 3-cyanobenzeneboronic acid (30 mg, 0.204 mmol), PdCl2(PPh3)2 (11 mg, 0.016 mmol) and cesium carbonate (128 mg, 0.393 mmol). This solid mixture was dissolved in a Dioxane/water mixture (2.0 mL, 6:1 ratio, respectively). The solution was purged with a N2 stream for 30 seconds. The vessel was placed in the μwave and heated to 110° C. for 30 minutes. After that time, the mixture was filtered through a Celite plug. The plug was rinsed with dichloromethane (4 mL) and water (4 mL). The phases in the filtrate were separated. The aqueous phase was back-extracted with dichloromethane (2 mL). The combined organic phases were washed with brine, dried over MgSO4, filtered and concentrated under reduce pressure. The crude material was purified by flash chromatography (ISCO, 12 g SiO2 cartridge, ethyl acetate/hexanes as the eluents). The corresponding fractions were combined and concentrated under reduce pressure yielding 3-(3,4-dimethoxy-1′-oxo-1′,3′-dihydrospiro[cyclopentane-1,2′-indene]-6′-yl)benzonitrile 1st isomer (40 mg, 0.115 mmol, 73% yield).
Reaction SMILES: [NH2:1][CH:2]([C:14]1[C:22]([CH2:23][CH3:24])=[CH:21][C:20]([CH3:25])=[C:19]2[C:15]=1[CH:16]=[CH:17][NH:18]2)[C:3]1[NH:7][C:6]2[CH:8]=[CH:9][C:10]([C:12]#[N:13])=[CH:11][C:5]=2[N:4]=1.[CH:26](C1C=C(C)C2N(S(C3C=CC(C)=CC=3)(=O)=O)C=CC=2C=1C=O)(C)C>>[NH2:1][CH:2]([C:14]1[C:22]([CH:23]([CH3:26])[CH3:24])=[CH:21][C:20]([CH3:25])=[C:19]2[C:15]=1[CH:16]=[CH:17][NH:18]2)[C:3]1[NH:7][C:6]2[CH:8]=[CH:9][C:10]([C:12]#[N:13])=[CH:11][C:5]=2[N:4]=1
Reactant: Cc1ccc(S(=O)(=O)n2ccc3c(C=O)c(C(C)C)cc(C)c32)cc1
Reactant: CCc1cc(C)c2[nH]ccc2c1C(N)c1nc2cc(C#N)ccc2[nH]1
Product: Cc1cc(C(C)C)c(C(N)c2nc3cc(C#N)ccc3[nH]2)c2cc[nH]c12

Procedure:
The title compound was synthesized following the same procedures that led to 2-(amino(5-ethyl-7-methyl-1H-indol-4-yl)methyl)-1H-benzo[d]imidazole-5-carbonitrile (Example 96) starting from 5-Isopropyl-7-methyl-1-tosyl-1H-indole-4-carbaldehyde (Example 50-A). 1H NMR (400 MHz, ACETONITRILE-d3 with about 5 μL TFA) δ ppm 9.50 (br. s., 1H), 8.00 (s, 1H), 7.60 (d, J=8.30 Hz, 1H), 7.56 (dd, J=1.50, 8.30 Hz, 1H), 7.05-7.20 (m, 2H), 6.55 (s, 1H), 5.71-5.88 (m, 1H), 3.33-3.48 (m, 1H), 2.52 (s, 3H), 1.36 (d, J=6.82 Hz, 3H), 1.21-1.33 (m, 3H). HRMS calcd. for C21H21N5 (M+H)+ 344.1870. found 344.1865.