Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(OC(C1C(O)=C2C=C(C3C=CC(F)=CC=3)N(C3C=CC=CC=3)C2=CN=1)=O)C.[CH2:29]([O:31][C:32]([C:34]1[C:35]([OH:55])=[C:36]2[C:42](Br)=[C:41]([C:44]([CH3:47])([CH3:46])[CH3:45])[N:40]([C:48]3[CH:53]=[CH:52][C:51]([F:54])=[CH:50][CH:49]=3)[C:37]2=[CH:38][N:39]=1)=[O:33])[CH3:30]>>[CH2:29]([O:31][C:32]([C:34]1[C:35]([OH:55])=[C:36]2[CH:42]=[C:41]([C:44]([CH3:47])([CH3:46])[CH3:45])[N:40]([C:48]3[CH:49]=[CH:50][C:51]([F:54])=[CH:52][CH:53]=3)[C:37]2=[CH:38][N:39]=1)=[O:33])[CH3:30]
Reactant: CCOC(=O)c1ncc2c(c1O)c(Br)c(C(C)(C)C)n2-c1ccc(F)cc1
Agent: CCOC(=O)c1ncc2c(cc(-c3ccc(F)cc3)n2-c2ccccc2)c1O
Product: CCOC(=O)c1ncc2c(cc(C(C)(C)C)n2-c2ccc(F)cc2)c1O

Procedure:
Prepared in analogy to that of 2-(4-fluoro-phenyl)-4-hydroxy-1-phenyl-1H-pyrrolo[2,3-c]pyridine-5-carboxylic acid ethyl ester from 3-bromo-2-tert-butyl-1-(4-fluoro-phenyl)-4-hydroxy-1H-pyrrolo[2,3-c]pyridine-5-carboxylic acid ethyl ester. The title compound, ESI MS (m/z): 357 (M+H+).
Reaction SMILES: [Cl:1][C:2]1[C:3]([C:10](=O)[CH2:11][N:12]2[C:16](=[O:17])[C:15]3=[CH:18][CH:19]=[CH:20][CH:21]=[C:14]3[C:13]2=[O:22])=[N:4][CH:5]=[C:6]([O:8][CH3:9])[CH:7]=1.Cl.[CH3:25][O:26][NH2:27].N1C=CC=CC=1>C(O)C>[Cl:1][C:2]1[C:3]([C:10](=[N:27][O:26][CH3:25])[CH2:11][N:12]2[C:16](=[O:17])[C:15]3=[CH:18][CH:19]=[CH:20][CH:21]=[C:14]3[C:13]2=[O:22])=[N:4][CH:5]=[C:6]([O:8][CH3:9])[CH:7]=1
Reactant: CON
Reactant: COc1cnc(C(=O)CN2C(=O)c3ccccc3C2=O)c(Cl)c1
Agent: Cl
Solvent: CCO
Solvent: c1ccncc1
Product: CON=C(CN1C(=O)c2ccccc2C1=O)c1ncc(OC)cc1Cl
Temperature: 80 °C
Reaction time: 6 h
Yield: 77.4 %

Procedure:
To a solution of 120 mg of N-[2-(3-chloro-5-methoxypyridin-2-yl)-2-oxoethyl]phthalimide and 60 mg of methoxyamine hydrochloride in 5 ml of ethanol, 85 mg of pyridine was added, and the mixture was stirred at 80° C. for 6 hours. After completion of the reaction, the solvent was evaporated under reduced pressure, and the resulting residue was purified by silica gel column chromatography using ethyl acetate-hexane (with a gradient of from 1:9 to 3:7) as the eluent to obtain 101 mg of the desired product as a pale yellow oil.
Reaction SMILES: [CH3:1][C:2]1[N:7]=[C:6]([C:8]2[CH:13]=[CH:12][N:11]=[C:10]([C:14]3[CH:15]=[C:16]([S:20](Cl)(=[O:22])=[O:21])[CH:17]=[CH:18][CH:19]=3)[CH:9]=2)[CH:5]=[C:4]([C:24]2[CH:29]=[CH:28][C:27]([C:30]([F:33])([F:32])[F:31])=[CH:26][CH:25]=2)[CH:3]=1.[NH:34]1[CH2:39][CH2:38][O:37][CH2:36][CH2:35]1>C1COCC1.CCOC(C)=O>[CH3:1][C:2]1[N:7]=[C:6]([C:8]2[CH:13]=[CH:12][N:11]=[C:10]([C:14]3[CH:19]=[CH:18][CH:17]=[C:16]([S:20]([N:34]4[CH2:39][CH2:38][O:37][CH2:36][CH2:35]4)(=[O:22])=[O:21])[CH:15]=3)[CH:9]=2)[CH:5]=[C:4]([C:24]2[CH:29]=[CH:28][C:27]([C:30]([F:33])([F:32])[F:31])=[CH:26][CH:25]=2)[CH:3]=1
Reactant: Cc1cc(-c2ccc(C(F)(F)F)cc2)cc(-c2ccnc(-c3cccc(S(=O)(=O)Cl)c3)c2)n1
Reactant: C1COCCN1
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: Cc1cc(-c2ccc(C(F)(F)F)cc2)cc(-c2ccnc(-c3cccc(S(=O)(=O)N4CCOCC4)c3)c2)n1
Temperature: 25 °C
Yield: 68 %

Procedure:
The title compound was prepared from the above described solution of 3-[6-methyl-4-(4-trifluoromethyl-phenyl)-[2,4′]bipyridinyl-2′-yl]-benzenesulfonyl chloride (ca. 0.2 g, 0.41 mmol) by treatment with excess morpholine in THF (5 mL) at 50° C. for 16 h. Cooled to rt, diluted with EtOAc, washed with 1 N HCl, dried organic layer over Na2SO4. Removal of the solvent in vacuum left a crude product, which was purified by silica gel column chromatography with n-heptane/EtOAc followed by trituration with n-heptane/diethyl ether to give the title compound (0.150 g, 68%) as a white solid. MS (ISP) 539.9 [(M+H)+]; mp 115° C.
Reaction SMILES: [CH3:1][C:2]1[N:3]=[C:4]([NH:19]C(=O)C)[S:5][C:6]=1[C:7]1[N:8]=[C:9]([NH:12][C:13]2[CH:14]=[N:15][CH:16]=[CH:17][CH:18]=2)[S:10][CH:11]=1.Cl.C([O-])(O)=O.[Na+]>C(O)C>[CH3:1][C:2]1[N:3]=[C:4]([NH2:19])[S:5][C:6]=1[C:7]1[N:8]=[C:9]([NH:12][C:13]2[CH:14]=[N:15][CH:16]=[CH:17][CH:18]=2)[S:10][CH:11]=1
Reactant: CC(=O)Nc1nc(C)c(-c2csc(Nc3cccnc3)n2)s1
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCO
Product: Cc1nc(N)sc1-c1csc(Nc2cccnc2)n1

Procedure:
N-[4′-Methyl-2-(pyridin-3-ylamino)-[4,5′]bithiazolyl-2′-yl]-acetamide (0.9 g) is refluxed in a mixture of ethanol (30 ml) and concentrated hydrochloric acid (3 ml) for 18 hours then additional hydrochloric acid is added (1.5 ml). After a further 24 hours at reflux the reaction mixture is cooled and the pH adjusted to 8-9 by the addition of 5% aqueous NaHCO3. The title compound is collected by filtration, washed with water and dried to give a light brown solid.
Reaction SMILES: Cl.[CH:2]([O:5][C:6]1[CH:11]=[CH:10][C:9]([CH:12]=[C:13]([N+]([O-])=O)[CH3:14])=[CH:8][CH:7]=1)([CH3:4])[CH3:3].[O:18]1CCCC1>[Fe]>[CH:2]([O:5][C:6]1[CH:11]=[CH:10][C:9]([CH2:12][C:13](=[O:18])[CH3:14])=[CH:8][CH:7]=1)([CH3:4])[CH3:3]
Reactant: C1CCOC1
Reactant: CC(=Cc1ccc(OC(C)C)cc1)[N+](=O)[O-]
Agent: [Fe]
Agent: Cl
Product: CC(=O)Cc1ccc(OC(C)C)cc1

Procedure:
Concentrated hydrochloric acid (90 ml) was added dropwise, over 45 minutes, to a stirred mixture of iron powder (17.5 g) and 1-(4-isopropoxyphenyl)-2-nitroprop1-ene (16.0 g) in tetrahydrofuran (50 ml) at reflux. The mixture was heated under reflux for a further hour, cooled, filtered through diatomaecous earth and the tetrahydrofuran removed under reduced pressure. The residue was diluted with water, extracted with diethyl ether, washed with brine, dried (magnesium sulphate), filtered and evaporated to dryness. Distillation of the residue gave the title compound, bp 120°-6°/1.5 mm.
Reaction SMILES: [CH3:1][N:2]([CH3:15])[C:3]1([C:13]#N)[CH2:12][CH2:11][C:6]2([O:10][CH2:9][CH2:8][O:7]2)[CH2:5][CH2:4]1.[Cl-].[NH4+]>O1CCCC1.C([Mg]Cl)C1C=CC=CC=1>[CH2:13]([C:3]1([N:2]([CH3:15])[CH3:1])[CH2:12][CH2:11][C:6]2([O:10][CH2:9][CH2:8][O:7]2)[CH2:5][CH2:4]1)[C:3]1[CH:12]=[CH:11][CH:6]=[CH:5][CH:4]=1
Reactant: CN(C)C1(C#N)CCC2(CC1)OCCO2
Agent: Cl[Mg]Cc1ccccc1
Agent: [Cl-]
Agent: [NH4+]
Solvent: C1CCOC1
Product: CN(C)C1(Cc2ccccc2)CCC2(CC1)OCCO2
Temperature: 25 °C
Reaction time: 8 h

Procedure:
50 g 8-dimethylamino-1,4-dioxaspiro[4.5]decane-8-carbonitrile were dissolved in 400 ml analytical grade tetrahydrofuran, 214 ml 2.0 molar benzylmagnesium chloride solution in THF were added under a nitrogen atmosphere and the mixture was stirred overnight at room temperature. For working up, 200 ml saturated ammonium chloride solution were added, while cooling with ice, the phases were separated, the aqueous phase was extracted twice with 250 ml diethyl ether each time, the combined organic phases were dried over sodium sulfate, filtered and concentrated and the residue was largely freed from solvent residues in vacuo. The crude (8-benzyl-1,4-dioxaspiro[4.5]dec-8-yl)-dimethylamine obtained (78.4 g) was stirred, without further purification, with a mixture of 200 ml conc. hydrochloric acid (32 per cent by weight) and 120 ml water for 24 hours at room temperature. The reaction mixture was then first washed three times with 100 ml diethyl ether each time, then rendered alkaline by addition of sodium hydroxide solution (32 per cent by weight), while cooling with ice, and extracted three times with 100 ml methylene chloride each time, the combined methylene chloride extracts were dried over sodium sulfate, filtered and concentrated and the residue was largely freed from solvent residues in vacuo. 50.4 g 4-benzyl-4-dimethylaminocyclohexanone were obtained as a brownish solid.
Reaction SMILES: [CH2:1]([NH2:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Br[CH2:10][C:11]1[CH:12]=[C:13]([CH:18]=[CH:19][C:20]=1[CH2:21]Br)[C:14]([O:16][CH3:17])=[O:15].C(N(CC)CC)C>O1CCCC1>[CH2:1]([N:8]1[CH2:10][C:11]2[C:20](=[CH:19][CH:18]=[C:13]([C:14]([O:16][CH3:17])=[O:15])[CH:12]=2)[CH2:21]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: COC(=O)c1ccc(CBr)c(CBr)c1
Reactant: NCc1ccccc1
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: COC(=O)c1ccc2c(c1)CN(Cc1ccccc1)C2
Temperature: 25 °C
Reaction time: 3 h

Procedure:
Benzylamine (3.21 g, 30.0 mmol) in anhydrous tetrahydrofuran (25 ml) was added to a stirred mixture of methyl 3,4-bis-(bromomethyl)benzoate (9.66 g, 30.0 mmol) (obtained from Fluorochem) and triethylamine (9 ml, 64.7 mmol) in anhydrous tetrahydrofuran (50 ml) and the resulting mixture was stirred at room temperature for 3 hours. The solvent was removed in vacuo at 40° C. and the residue partitioned between ethyl acetate (100 ml) and water (100 ml). The organic layer was washed with a further portion of water (100 ml), separated and the solvent removed in vacuo at 40° C. to afford methyl 2-benzyl-2,3-dihydro-1H-isoindole-5-carboxylate as a pale orange solid that was used immediately without further purification as described below. 1H NMR (DMSO-d6) 7.82 (2H, m), 7.40-7.25 (6H, m), 3.90 (3H, s), 3.88 (2H, s), 3.84 (4H, s). MS: [M+H]+ 268.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([NH:8][CH2:9][CH:10]2[CH2:15][CH2:14][N:13]([C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])[CH2:12][CH2:11]2)[C:5](I)=[CH:4][N:3]=1.[CH3:24][O:25][CH2:26]/[CH:27]=[CH:28]/B1OC(C)(C)C(C)(C)O1.C(=O)([O-])[O-].[Na+].[Na+]>C(#N)C.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[Cl:1][C:2]1[CH:7]=[C:6]([NH:8][CH2:9][CH:10]2[CH2:15][CH2:14][N:13]([C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])[CH2:12][CH2:11]2)[C:5](/[CH:28]=[CH:27]/[CH2:26][O:25][CH3:24])=[CH:4][N:3]=1
Reactant: CC(C)(C)OC(=O)N1CCC(CNc2cc(Cl)ncc2I)CC1
Reactant: COC/C=C/B1OC(C)(C)C(C)(C)O1
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: [Na+]
Solvent: CC#N
Product: COC/C=C/c1cnc(Cl)cc1NCC1CCN(C(=O)OC(C)(C)C)CC1
Yield: 65.4 %

Procedure:
A solution of tert-butyl 4-((2-chloro-5-iodopyridin-4-ylamino)methyl)piperidine-1-carboxylate (Synthesis 170-B) (0.100 g, 0.22 mmol), (E)-2-(3-methoxyprop-1-enyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (0.044 g, 0.22 mmol), sodium carbonate (0.5 M, 0.66 mL) and tetrakis(triphenylphosphine)palladium(0) (0.013 g, 0.01 mmol) in acetonitrile (2.00 mL) was heated under microwave irradiation for 20 min at 100° C. The solvent was removed in vacuo and the crude product was purified by silica column chromatography, eluting with ethyl acetate and hexane (1/1). to give the title compound as a colourless oil (0.057 g, 65%).
Reaction SMILES: [N:1]1([CH:10]([C:16]([O:18]CC)=[O:17])[C:11]([O:13]CC)=[O:12])[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH:3]=[CH:2]1.[OH-].[K+]>C(O)C>[N:1]1([CH:10]([C:11]([OH:13])=[O:12])[C:16]([OH:18])=[O:17])[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH:3]=[CH:2]1
Reactant: CCOC(=O)C(C(=O)OCC)n1ccc2ccccc21
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Product: O=C(O)C(C(=O)O)n1ccc2ccccc21
Reaction time: 8 h

Procedure:
To a solution of diethyl (1H-indol-1-yl)malonate (0.02 mole) in 25 ml of absolute ethanol is added 25 ml (0.02 mole) of 0.8 N ethanolic potassium hydroxide. This solution is stirred overnight. The solvent is flash evaporated and the residue is dissolved in 25 ml of water and washed twice with 50 ml of ether. The aqueous phase is separated, acidified to pH of 2.5, saturated with sodium chloride and extracted twice with 80 ml of ether. The ether extracts are combined, dried and evaporated to give the monoethyl ester of (1H-indol-1-yl)malonic acid.
Reaction SMILES: [I:1]I.[C:3]1([C:9]([C:13]2[CH:18]=[CH:17][N:16]=[CH:15][CH:14]=2)([OH:12])[C:10]#[CH:11])[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.[OH-].[Na+]>CO.O>[I:1][C:11]#[C:10][C:9]([C:3]1[CH:4]=[CH:5][CH:6]=[CH:7][CH:8]=1)([C:13]1[CH:18]=[CH:17][N:16]=[CH:15][CH:14]=1)[OH:12]
Reactant: C#CC(O)(c1ccccc1)c1ccncc1
Reactant: II
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: OC(C#CI)(c1ccccc1)c1ccncc1
Reaction time: 3 h
Yield: 79.1 %

Procedure:
50.8 g (0.2 mol) of iodine were gradually introduced into a suspension of 42 g (0.2 mol) of 3-phenyl-3-pyridin-4-yl-1-propyn-3-ol in 500 ml of methanol at room temperature, while simultaneously adding 80 ml of concentrated sodium hydroxide solution dropwise. An almost clear solution was thereby obtained. After stirring the solution at room temperture for three hours, it was diluted with a large amount of water and the crystals which had separated out were filtered off, washed with water and dried in vacuo. After recrystallization from methanol, 53 g (79.2% of theory) of 1-iodo-3-phenyl-3-pyridin-4-yl-1-propyn-3-ol were obtained as colorless crystals of melting point 175° C. (decomposition).
Reaction SMILES: [CH3:1][C:2]1[C:6]([C:7]2[CH:8]=[C:9]([C:19]([C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][N:22]=3)=[O:20])[C:10]3[N:14]=[C:13]([O:15][CH2:16][CH3:17])[NH:12][C:11]=3[CH:18]=2)=[C:5]([CH3:27])[O:4][N:3]=1.[CH:28]1([Mg]Cl)[CH2:31][CH2:30][CH2:29]1>C1COCC1>[CH:28]1([C:19]([C:9]2[C:10]3[N:14]=[C:13]([O:15][CH2:16][CH3:17])[NH:12][C:11]=3[CH:18]=[C:7]([C:6]3[C:2]([CH3:1])=[N:3][O:4][C:5]=3[CH3:27])[CH:8]=2)([C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][N:22]=2)[OH:20])[CH2:31][CH2:30][CH2:29]1
Reactant: Cl[Mg]C1CCC1
Reactant: CCOc1nc2c(C(=O)c3ccccn3)cc(-c3c(C)noc3C)cc2[nH]1
Solvent: C1CCOC1
Product: CCOc1nc2c(C(O)(c3ccccn3)C3CCC3)cc(-c3c(C)noc3C)cc2[nH]1
Temperature: 0 °C
Reaction time: 0.17 h

Procedure:
(6-(3,5-dimethylisoxazol-4-yl)-2-ethoxy-1H-benzo[d]imidazol-4-yl)(pyridin-2-yl)methanone (50 mg, 0.14 mmol) was dissolved in dry THF (1.4 mL) and cooled to 0° C. Cylobutylmagnesium chloride (0.5 M, 1.1 mL, 0.55 mmol) was added dropwise and the reaction was allowed to stir for 10 mins and then quenched with water. Reaction was extracted three times with EtOAc and combined organic layers were washed once with water, concentrated, and purified by reverse-phase HPLC to give cyclobutyl(6-(3,5-dimethylisoxazol-4-yl)-2-ethoxy-1H-benzo[d]imidazol-4-yl)(pyridin-2-yl)methanol intermediate. The intermediate was taken up in EtOH (1.5 mL) and 4.0 M HCl/dioxane and heated to 65° C. for 2 hours, concentrated and purified by reverse-phase HPLC to afford the desired product as a white powder.
Reaction SMILES: [O:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]([NH:11][C:12]2[O:13][CH2:14][C:15]3[CH:21]=[C:20]([NH2:22])[CH:19]=[CH:18][C:16]=3[N:17]=2)[CH2:3][CH2:2]1.[CH:23]1([C:26](Cl)=[O:27])[CH2:25][CH2:24]1>>[O:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]([NH:11][C:12]2[O:13][CH2:14][C:15]3[CH:21]=[C:20]([NH:22][C:26]([CH:23]4[CH2:25][CH2:24]4)=[O:27])[CH:19]=[CH:18][C:16]=3[N:17]=2)[CH2:3][CH2:2]1
Reactant: Nc1ccc2c(c1)COC(NC1CCOc3ccccc31)=N2
Reactant: O=C(Cl)C1CC1
Product: O=C(Nc1ccc2c(c1)COC(NC1CCOc3ccccc31)=N2)C1CC1
Yield: 50 %

Procedure:
Prepared from rac-N2-chroman-4-yl-4H-benzo[d][1,3]oxazine-2,6-diamine (Example 75) (295 mg, 1.0 mmol, HPLC 0.699 min) and cyclopropanecarbonyl chloride (115 mg, 0.55 mmol) according to the procedure described for Example 27. Obtained the title compound as an off-white foam (100 mg, 28%, HPLC 1.353 min), MS (ISP) m/e=364.3 [(M+H)+].
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([C:8]2[N:17]=[C:16]([NH:18][C:19]3[CH:20]=[C:21]4[C:25](=[CH:26][CH:27]=3)[N:24]([C:28]([O:30][C:31]([CH3:34])([CH3:33])[CH3:32])=[O:29])[N:23]=[CH:22]4)[C:15]3[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=3)[N:9]=2)[CH:5]=[CH:6][CH:7]=1.Cl[CH2:36][C:37]([NH:39][CH2:40][CH2:41][N:42]([CH3:44])[CH3:43])=[O:38].C([O-])([O-])=O.[K+].[K+]>CN(C=O)C>[CH3:43][N:42]([CH3:44])[CH2:41][CH2:40][NH:39][C:37](=[O:38])[CH2:36][O:1][C:2]1[CH:3]=[C:4]([C:8]2[N:17]=[C:16]([NH:18][C:19]3[CH:20]=[C:21]4[C:25](=[CH:26][CH:27]=3)[N:24]([C:28]([O:30][C:31]([CH3:34])([CH3:33])[CH3:32])=[O:29])[N:23]=[CH:22]4)[C:15]3[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=3)[N:9]=2)[CH:5]=[CH:6][CH:7]=1
Reactant: CC(C)(C)OC(=O)n1ncc2cc(Nc3nc(-c4cccc(O)c4)nc4ccccc34)ccc21
Reactant: CN(C)CCNC(=O)CCl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CN(C)CCNC(=O)COc1cccc(-c2nc(Nc3ccc4c(cnn4C(=O)OC(C)(C)C)c3)c3ccccc3n2)c1
Reaction time: 16 h

Procedure:
A suspension of tert-butyl 5-(2-(3-hydroxyphenyl)quinazolin-4-ylamino)-1H-indazole-1-carboxylate (80 mg, 0.18 mmol), 2-chloro-N-(2-(dimethylamino)-ethyl)acetamide (40 mg, 0.25 mmol), K2CO3 (162 mg, 1.17 mmol), in DMF (5 mL). Stirred at RT for 4 h upon which 2 equivalents each of 2-chloro-N-(2-(dimethylamino)-ethyl)acetamide and K2CO3 were added. Continued to stir for 16 h. Concentrated in vacuo to afford the crude tert-butyl 5-(2-(3-(2-(2-(dimethylamino)-ethylamino)-2-oxoethoxy)phenyl)quinazolin-4-ylamino)-1H-indazole-1-carboxylate. (0.18 mmol).
Reaction SMILES: [C:1]1([CH3:7])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[Cl-].[Al+3].[Cl-].[Cl-].[CH2:12]([SiH:15]([Cl:17])[Cl:16])[CH:13]=[CH2:14].[Cl-].[Na+]>>[CH3:7][C:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[CH:13]([CH3:14])[CH2:12][SiH:15]([Cl:17])[Cl:16]
Reactant: Cc1ccccc1
Reactant: C=CC[SiH](Cl)Cl
Agent: [Al+3]
Agent: [Cl-]
Agent: [Na+]
Product: Cc1ccccc1C(C)C[SiH](Cl)Cl
Temperature: 50 °C
Yield: 71 %

Procedure:
In the same apparatus and procedures as EXAMPLE 1, 19.3 g (210 mmol) of toluene and 0.9 g (7.0 mmol) of aluminum chloride were placed and reacted with 10.0 g (70 mmol) of allyldichlorosilane under the dry nitrogen atmosphere for 30 min. After stirring the solution for another an hour, 2.0 g (30 mmol) of sodium chloride was added to reaction mixture, warmed up to 50° C. and stirred for two hours to deactivate the catalyst. Vacuum distillation of the reaction products gave 11.7 g (bp, 73°-76° C./0.5 mmHg) of of 3-(methylphenyl)-1,1-dichloro-1-silabutane in 71% yield.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:14]=[CH:13][C:12]([C:15](OC)=[C:16]([C:19]#[N:20])[C:17]#[N:18])=[CH:11][CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.O.[NH2:24][NH2:25]>CCO>[NH2:18][C:17]1[NH:25][N:24]=[C:15]([C:12]2[CH:13]=[CH:14][C:9]([O:8][CH2:1][C:2]3[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=3)=[CH:10][CH:11]=2)[C:16]=1[C:19]#[N:20]
Reactant: NN
Reactant: COC(=C(C#N)C#N)c1ccc(OCc2ccccc2)cc1
Solvent: CCO
Solvent: O
Product: N#Cc1c(-c2ccc(OCc3ccccc3)cc2)n[nH]c1N
Yield: 87.7 %

Procedure:
Compound 31C (3.1 g, 10.68 mmol) was dissolved in EtOH (20 mL). To this solution was added hydrazine hydrate (0.622 mL, 12.81 mmol). The reaction was heated under reflux for 2 hours. The solvent was removed, and the residue was taken up into EtOAc. It was then washed with water, brine, dried over MgSO4, and concentrated under reduced pressure to provide 2.72 g of the desired product: 1H NMR (DMSO-d6): δ 12.64 and 11.99 (s, 1H), 7.71-7.74 (m, 2H), 7.32-7.48 (m, 5H), 7.09-7.10 (br, 2H), 6.38 (s, 2H), 5.15 (s, 2H). MS (DCI(+)): m/z 291 (M+H).
Reaction SMILES: [OH:1][CH:2]1[C:10]2[C:9]3[O:11][C@@:12]45[CH2:22][CH2:21][C@H:20]([OH:23])[C:19]([CH3:25])([CH3:24])[C@@H:18]4[CH2:17][CH2:16][C@H:15]([CH3:26])[C@@:13]5([CH3:27])[CH2:14][C:8]=3[C:7]([OH:28])=[CH:6][C:5]=2[C:4](=[O:29])[NH:3]1.[C:30]1(C)[CH:35]=CC(S([O-])(=O)=O)=C[CH:31]=1.[NH+]1C=CC=CC=1.C(OCC)(=O)C>C(O)CC>[OH:28][C:7]1[C:8]2[CH2:14][C@:13]3([CH3:27])[C@@H:15]([CH3:26])[CH2:16][CH2:17][C@H:18]4[C:19]([CH3:25])([CH3:24])[C@@H:20]([OH:23])[CH2:21][CH2:22][C@@:12]34[O:11][C:9]=2[C:10]2[CH:2]([O:1][CH2:31][CH2:30][CH3:35])[NH:3][C:4](=[O:29])[C:5]=2[CH:6]=1
Reactant: C[C@H]1CC[C@H]2C(C)(C)[C@@H](O)CC[C@]23Oc2c(c(O)cc4c2C(O)NC4=O)C[C@]13C
Reactant: Cc1ccc(S(=O)(=O)[O-])cc1
Agent: c1cc[nH+]cc1
Solvent: CCCO
Solvent: CCOC(C)=O
Product: CCCOC1NC(=O)c2cc(O)c3c(c21)O[C@@]12CC[C@H](O)C(C)(C)[C@@H]1CC[C@H](C)[C@@]2(C)C3
Temperature: 25 °C
Reaction time: 1 h
Yield: 207.7 %

Procedure:
To a solution of Compound (30a) (33 mg, 0.08 mmol) in 3.0 ml of 1-propanol was added 6 mg of pyridinium p-toluenesulfonate, and the mixture stirred at room temperature for one hour. To the reaction was added 20 ml of ethyl acetate. The mixture was washed with saturated brine, and dried over anhydrous sodium sulfate. After concentration under reduced pressure, the residue was purified by a column chromatography (Merck, Lobar column, size A; ethyl acetate), and by crystallization from ethyl acetate to give 22 mg (60%) of Compound (30c).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][CH:6]=[CH:5]2.[OH-].[Na+].[CH3:13]I>CS(C)=O.O>[Br:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[N:7]([CH3:13])[CH:6]=[CH:5]2
Reactant: Brc1ccc2[nH]ccc2c1
Reactant: CI
Agent: [Na+]
Agent: [OH-]
Solvent: CS(C)=O
Solvent: O
Product: Cn1ccc2cc(Br)ccc21
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
A solution of 5-bromo-1H-indole (1.530 mmol) in dimethyl sulfoxide (10 mL) was treated with NaOH (2.295 mmol) and stirred at room temperature for 30 min. The solution was then treated with methyl iodide (4.59 mmol) and was stirred for 3 days at room temperature. The solution was diluted with water (100 mL) and was extracted with ethyl acetate. The combined organic phases were washed with water, washed with brine, dried over magnesium sulfate, filtered, and concentrated in vacuo. The yellow oil was used without further purification. MS(ES)+ m/e 210/212 [M+H]+ (bromide isotope pattern).
Reaction SMILES: Cl.[Cl:2][C:3]1[CH:23]=[CH:22][C:6]([CH2:7][C:8]2[N:9]=[C:10]([C:16]3[CH:21]=[CH:20][N:19]=[CH:18][CH:17]=3)[S:11][C:12]=2[C:13](=[NH:15])[NH2:14])=[CH:5][CH:4]=1.C(=O)([O-])[O-].[Na+].[Na+].Br[CH2:31][C:32](=O)[CH2:33][N:34]1C(=O)C2C(=CC=CC=2)C1=O>CN(C=O)C.C(OCC)(=O)C.O>[Cl:2][C:3]1[CH:4]=[CH:5][C:6]([CH2:7][C:8]2[N:9]=[C:10]([C:16]3[CH:21]=[CH:20][N:19]=[CH:18][CH:17]=3)[S:11][C:12]=2[C:13]2[NH:14][CH:31]=[C:32]([CH2:33][NH2:34])[N:15]=2)=[CH:22][CH:23]=1
Reactant: N=C(N)c1sc(-c2ccncc2)nc1Cc1ccc(Cl)cc1
Reactant: O=C(CBr)CN1C(=O)c2ccccc2C1=O
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: NCc1c[nH]c(-c2sc(-c3ccncc3)nc2Cc2ccc(Cl)cc2)n1
Yield: 40.2 %

Procedure:
To a mixture of 4-(4-chlorobenzyl)-2-(pyridin-4-yl)thiazole-5-carboximidamide hydrochloride (112 mg, 0.306 mmol) in DMF (2.96 mL) was added sodium carbonate (162 mg, 1.53 mmol) and 2-(3-bromo-2-oxopropyl)isoindoline-1,3-dione (95.0 mg, 0.337 mmol) and the resulting mixture was heated at 100 degrees for 4 hours. The reaction was cooled and taken up in ethyl acetate (30 mL) and water (5 mL). The layers were separated and the organic layer was washed with water (3×5 mL). The organic layer was dried, filtered and concentrated in vacuo. The residue was purified by silica gel chromatography (MeOH/DCM=0/100→10/90) to give 47 mg (30% yield) of the title compound. LC/MS (FA) ES+ 512. 514. 1H NMR (300 MHz, DMSO-d6) δ: 12.67 (bs, 1H), 8.69-8.67 (m, 2H), 7.91-7.79 (m, 6H), 7.27-7.24 (m, 3H), 7.11-7.08 (m, 2H), 4.77 (s, 2H), 4.45 (s, 2H).
Reaction SMILES: [OH-].[Li+].[Br:3][C:4]1[N:5]([C:17]2[C:26]3[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=3)[C:20]([CH:27]3[CH2:29][CH2:28]3)=[CH:19][CH:18]=2)[C:6]([S:9]CCC(OCC)=O)=[N:7][N:8]=1.Cl>C1COCC1.CO>[Br:3][C:4]1[N:5]([C:17]2[C:26]3[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=3)[C:20]([CH:27]3[CH2:29][CH2:28]3)=[CH:19][CH:18]=2)[C:6]([SH:9])=[N:7][N:8]=1
Reactant: CCOC(=O)CCSc1nnc(Br)n1-c1ccc(C2CC2)c2ccccc12
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Product: Sc1nnc(Br)n1-c1ccc(C2CC2)c2ccccc12
Temperature: 25 °C
Reaction time: 2 h
Yield: 77.1 %

Procedure:
Aqueous lithium hydroxide solution (1M, 437 μL, 0.437 mmol, 3 eq.) was added to a solution of ethyl 3-(5-bromo-4-(4-cyclopropylnaphthalen-1-yl)-4H-1,2,4-triazol-3-ylthio)propanoate (65 mg, 0.146 mmol) in THF (1.5 mL) and methanol (1 mL). The mixture was stirred at room temperature for ˜2 hours, and HCl (1N, 584 μL, 0.584 mmol, 4 eq.) added. The mixture was concentrated, a little water added, sonicated and the off-white solids isolated by filtration. The isolated material was placed into small amount of methanol, sonicated again, and then filtered to give 5-bromo-4-(4-cyclopropylnaphthalen-1-yl)-4H-1,2,4-triazole-3-thiol as an off-white solid (39 mg, 78%).