Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3]([CH:5](P(OC)(OC)=O)[NH:6][C:7]([O:9][CH2:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)=[O:8])=[O:4].[CH3:23][C:24]1[CH:28]=[CH:27][S:26][C:25]=1[CH:29]=O.C1CCN2C(=NCCC2)CC1>ClCCl>[CH2:10]([O:9][C:7]([NH:6]/[C:5](=[CH:29]\[C:25]1[S:26][CH:27]=[CH:28][C:24]=1[CH3:23])/[C:3]([O:2][CH3:1])=[O:4])=[O:8])[C:11]1[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=1
Reactant: Cc1ccsc1C=O
Reactant: COC(=O)C(NC(=O)OCc1ccccc1)P(=O)(OC)OC
Solvent: C1CCC2=NCCCN2CC1
Solvent: ClCCl
Product: COC(=O)/C(=C/c1sccc1C)NC(=O)OCc1ccccc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 81.3 %

Procedure:
A stirred solution of N-(benzyloxycarbonyl)-α-phosphonoglycine trimethyl ester (5.01 g, 15.1 mmol) and 3-methylthiophene-2-carbaldehyde (7.5:1 mixture with 4-methylthiophene-2-carbaldehyde, 2.48 g, 19.6 mmol) in dry dichloromethane (100 mL), was cooled to 0° C. and treated dropwise with DBU (2.76 g, 18.1 mmol). The mixture was warmed to ambient temperature and stirred overnight. The solution was concentrated, taken up in ethyl acetate (150 mL) and washed with 5% hydrochloric acid (2×75 mL). The organic extract was washed with saturated aqueous sodium bicarbonate (2×75 mL), water (75 mL), dried (magnesium sulfate), filtered and evaporated. The residue was purified by flash chromatography (20-40% ethyl acetate/hexanes gradient) to afford the title compound (4.07 g, 81%) as an orange oil. The product is a mixture of 3- and 4-methylthiophene isomers (6.8:1). 1H NMR major isomer: (300 MHz, d6-DMSO) δ2.33 (s, 3H), 3.72, (s, 3H), 5.13 (bs, 2H), 7.01 (d, 1H, J=5.3 Hz), 7.18-7.52 (m, 5H), 7.60-7.85 (m, 2H), 8.83 (s, 1H). MS APCI, m/z=354(M+Na). LC/MS: 2.43 min.
Reaction SMILES: C([O:5][C:6](=[O:18])[CH2:7][O:8][C:9]1[CH:14]=[CH:13][C:12]([Cl:15])=[CH:11][C:10]=1[C:16]#[CH:17])(C)(C)C.[F:19][C:20]1[CH:25]=[CH:24][C:23]([S:26]([CH3:29])(=[O:28])=[O:27])=[CH:22][C:21]=1I.C(N(CC)CC)C>C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2].C1COCC1>[Cl:15][C:12]1[CH:13]=[CH:14][C:9]([O:8][CH2:7][C:6]([OH:5])=[O:18])=[C:10]([C:16]#[C:17][C:21]2[CH:22]=[C:23]([S:26]([CH3:29])(=[O:27])=[O:28])[CH:24]=[CH:25][C:20]=2[F:19])[CH:11]=1
Reactant: C#Cc1cc(Cl)ccc1OCC(=O)OC(C)(C)C
Reactant: CS(=O)(=O)c1ccc(F)c(I)c1
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: c1ccc(P(c2ccccc2)[c-]2cccc2)cc1
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CS(=O)(=O)c1ccc(F)c(C#Cc2cc(Cl)ccc2OCC(=O)O)c1
Temperature: 60 °C
Reaction time: 60 h

Procedure:
A mixture of (4-chloro-2-ethynyl-phenoxy)-acetic acid tert-butyl ester (Intermediate 3, 164 mg; 0.61 mmol), 1-fluoro-2-iodo-4-(methylsulfonyl)benzene (Intermediate 58, 184 mg; 0.61 mmol), 1,1′-bis(diphenylphosphino)ferrocenedichloro palladium(ii) (27 mg; 0.04 mmol) and cuprous iodide (7 mg; 0.04 mmol) was degassed during two minutes under nitrogen then anhydrous THF (3 mL) and triethylamine (170 μL; 1.23 mmol) were added and reaction mixture was stirred at 60° C. for 60 hours. The solvent was evaporated and the residue was treated with an HCl solution (4 N in dioxane, 3.7 mL). After stirring for 16 hours, the solvents were removed under vacuum and the crude product purified by preparative HPLC. The title compound was obtained as a brown solid.
Reaction SMILES: [CH:1]1[C:13]2[CH:12]([CH2:14][O:15][C:16]([N:18]3[CH2:23][CH2:22][O:21][CH2:20][C@H:19]3[C:24](O)=[O:25])=[O:17])[C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[C:5]=2[CH:4]=[CH:3][CH:2]=1.CCN=C=NCCCN(C)C.C1C=CC2N(O)N=NC=2C=1.[C:48]([O:52][C:53](=[O:65])[NH:54][CH2:55][C:56]1[CH:61]=[CH:60][C:59]([Cl:62])=[CH:58][C:57]=1[CH2:63][NH2:64])([CH3:51])([CH3:50])[CH3:49]>C(Cl)Cl>[CH:1]1[C:13]2[CH:12]([CH2:14][O:15][C:16]([N:18]3[CH2:23][CH2:22][O:21][CH2:20][C@H:19]3[C:24](=[O:25])[NH:64][CH2:63][C:57]3[CH:58]=[C:59]([Cl:62])[CH:60]=[CH:61][C:56]=3[CH2:55][NH:54][C:53]([O:52][C:48]([CH3:51])([CH3:49])[CH3:50])=[O:65])=[O:17])[C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[C:5]=2[CH:4]=[CH:3][CH:2]=1
Reactant: O=C(O)[C@@H]1COCCN1C(=O)OCC1c2ccccc2-c2ccccc21
Reactant: CC(C)(C)OC(=O)NCc1ccc(Cl)cc1CN
Agent: CCN=C=NCCCN(C)C
Agent: On1nnc2ccccc21
Solvent: ClCCl
Product: CC(C)(C)OC(=O)NCc1ccc(Cl)cc1CNC(=O)[C@@H]1COCCN1C(=O)OCC1c2ccccc2-c2ccccc21
Temperature: 25 °C
Reaction time: 5 h

Procedure:
To a solution of (S)-4-[{(9H-Fluoren-9-yl)methoxy}carbonyl]morpholine-3-carboxylic acid (2.96 g, 8.39 mmol, 1.0 eq) in CH2Cl2 (10 mL), EDCI (3.20 g, 16.68 mmol, 2 eq.), HOBT (2.20 g, 16.28 mmol) and tert-butyl[2-(aminomethyl)-4-chlorobenzyl]carbamate (2.20 g, 8.39 mmol) were added at 0° C. The resulting mixture was stirred for 5 h at room temperature. The reaction mixture was diluted with CH2Cl2 (50 mL) and washed sequentially with saturated NaHCO3 solution (20 mL) and 0.5 M aqueous HCl (20 mL). The organic layer was separated, washed with brine solution (20 mL), dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure. The residue was purified by column chromatography (silica gel; eluent: 40% EtOAc/hexanes) to afford the title compound as pale yellow semi solid (4.10 g)
Reaction SMILES: [F:1][C:2]1[C:11]([F:12])=[CH:10][C:9]([CH:13]=O)=[C:8]2[C:3]=1[C:4](=[O:16])[CH:5]=[C:6]([CH3:15])[O:7]2.[C:17]([CH:19]=[C:20]([O-])[CH3:21])#[N:18].[Na+].[NH2:24]/[C:25](/[CH3:34])=[CH:26]\[C:27]([O:29][CH:30]1[CH2:33][CH2:32][CH2:31]1)=[O:28].C(O)(=O)C>CC(O)C>[C:17]([C:19]1[CH:13]([C:9]2[CH:10]=[C:11]([F:12])[C:2]([F:1])=[C:3]3[C:8]=2[O:7][C:6]([CH3:15])=[CH:5][C:4]3=[O:16])[C:26]([C:27]([O:29][CH:30]2[CH2:33][CH2:32][CH2:31]2)=[O:28])=[C:25]([CH3:34])[NH:24][C:20]=1[CH3:21])#[N:18]
Reactant: C/C(N)=C/C(=O)OC1CCC1
Reactant: Cc1cc(=O)c2c(F)c(F)cc(C=O)c2o1
Reactant: CC([O-])=CC#N
Agent: [Na+]
Solvent: CC(C)O
Solvent: CC(=O)O
Product: CC1=C(C#N)C(c2cc(F)c(F)c3c(=O)cc(C)oc23)C(C(=O)OC2CCC2)=C(C)N1

Procedure:
A solution of 100 mg (0.45 mmol) of 5,6-difluoro-2-methyl-4-oxo-4H-chromene-8-carbaldehyde in 5 ml of 2-propanol is mixed with 46.9 mg (0.45 mmol) of sodium 1-cyanoprop-1-en-2-olate, 69.23 mg (0.45 mmol) of cyclobutyl 3-aminocrotonate and 0.04 ml (0.67 mmol) of acetic acid and stirred under reflux for 3 h. After cooling, the mixture is concentrated. The residue is taken up in dichloromethane and washed with water. The organic phase is dried over sodium sulfate and concentrated. The resulting residue is crystallized from diethyl ether. The yellow crystals are filtered off with suction and dried in a vacuum drying oven at 40° C. 104.4 mg (54.9% of theory) of the title compound are obtained.
Reaction SMILES: [C:1]1([CH2:7][N:8]2[C:12]([NH:13][C:14]3[C:15](=[CH:19][CH:20]=[CH:21][CH:22]=3)[C:16](O)=O)=[CH:11][CH:10]=[N:9]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[NH4+].[OH-].O=P(Cl)(Cl)[Cl:27]>>[C:1]1([CH2:7][N:8]2[C:12]3=[N:13][C:14]4[C:15]([C:16]([Cl:27])=[C:11]3[CH:10]=[N:9]2)=[CH:19][CH:20]=[CH:21][CH:22]=4)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: O=C(O)c1ccccc1Nc1ccnn1Cc1ccccc1
Reactant: O=P(Cl)(Cl)Cl
Agent: [NH4+]
Agent: [OH-]
Product: Clc1c2ccccc2nc2c1cnn2Cc1ccccc1
Temperature: 0 °C

Procedure:
A mixture of N-(1-phenylmethylpyrazol-5-yl) anthranilic acid (6 g) and POCl3 (60 ml) was heated on a steam bath overnight. The reaction mixture was poured into ice-water, neutralized with NH4OH and the precipitate which formed was collected by filtration, washed with water and dried to afford 5 g of 1-phenylmethyl-4-chloro-1H-pyrazolo[3,4-b]quinoline, as a light brown powder.
Reaction SMILES: [N+:1]([N:4]=[C:5]1[NH:9][CH2:8][CH2:7][NH:6]1)([O-:3])=[O:2].[CH:10]([O-:15])([O-])[O:11][CH2:12][CH3:13].CN1[CH2:21][CH2:20]N(C)C1=O>O>[CH2:20]([O:15][CH:10]([O:11][CH2:12][CH3:13])[N:6]1[CH2:7][CH2:8][NH:9][C:5]1=[N:4][N+:1]([O-:3])=[O:2])[CH3:21]
Reactant: CN1CCN(C)C1=O
Reactant: O=[N+]([O-])N=C1NCCN1
Reactant: CCOC([O-])[O-]
Solvent: O
Product: CCOC(OCC)N1CCNC1=N[N+](=O)[O-]
Temperature: 25 °C

Procedure:
A mixture of 25 g of 2-nitroiminoimidazolidine, 100 g of ethyl orthoformate and 25 ml of 1,3-dimethyl-2-imidazolidinone was heated under reflux for 3 hours. After cooling to room temperature, the mixture was poured into water, followed by extraction with ethyl acetate. After washing with water, the extract was dried with anhydrous magnesium sulfate, after which the solvent was distilled off under reduced pressure. The resultant crystals were sludged with ether to give 32 g of 1-diethoxymethyl-2-nitroiminoimidazolidine.
Reaction SMILES: CC(P(C(C)(C)C)C1C(C2C=CC=CC=2)=CC=CC=1)(C)C.C(N(CC)CC)C.[C:29]1([CH3:43])[CH:34]=[CH:33][C:32]([C:35]#[C:36][P:37](=[O:42])([OH:41])[O:38][CH2:39][CH3:40])=[CH:31][CH:30]=1.[Cl:44][CH2:45][CH2:46][CH2:47][C:48]#[CH:49]>[Au].ClC(Cl)C>[C:29]1([CH3:43])[CH:30]=[CH:31][C:32]([C:35]#[C:36][P:37](=[O:41])([O:42][C:48]([CH2:47][CH2:46][CH2:45][Cl:44])=[CH2:49])[O:38][CH2:39][CH3:40])=[CH:33][CH:34]=1
Reactant: CCOP(=O)(O)C#Cc1ccc(C)cc1
Reactant: C#CCCCCl
Agent: [Au]
Agent: CC(C)(C)P(c1ccccc1-c1ccccc1)C(C)(C)C
Solvent: CC(Cl)Cl
Solvent: CCN(CC)CC
Product: C=C(CCCCl)OP(=O)(C#Cc1ccc(C)cc1)OCC
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 69.9 %

Procedure:
A gold (Ag(I)) catalyst {[Au(JohnPhos)NCCH3]+SbF6—} [JohnPhos:(2-biphenyl)di-tert-butylphosphine] (11.3 mg, 0.015 mmol) and triethylamine (Et3N) (3.0 mg, 0.03 mmol) were put into a reaction container, and dichloroethane (0.4 mL) was put thereinto. After stirring at room temperature for 5 minutes, ethyl hydrogen p-tolylethynylphosphonate (67.3 mg, 0.3 mmol) diluted with 0.5 mL of dichloroethane was added thereto, and finally, 5-chloropent-1-yne (61.5 mg, 0.6 mmol) was put thereinto. Then, when all of the starting materials disappeared in the TLC, the reaction was allowed to be completed. After the solvent was removed under low atmospheric pressure, the product was separated by chromatography to obtain ethyl 5-chloropent-1-en-2-yl p-tolylethynylphosphonate (68.5 mg, 70%) which is a title compound.
Reaction SMILES: [CH2:1]([O:8][C@@H:9]1[C@@H:14]([O:15][CH2:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[C@H:13]([O:23][CH2:24][C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)[C@@H:12]([CH2:31][O:32][CH2:33][C:34]2[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=2)[O:11][CH:10]1[C:40]1[C:48]2[O:47][CH2:46][CH2:45][C:44]=2[C:43]([Cl:49])=[C:42]([CH2:50]Br)[CH:41]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C([O-])([O-])=O.[K+].[K+].[CH3:58][O:59][C:60]1[CH:65]=[CH:64][C:63](B(O)O)=[CH:62][CH:61]=1>CC(C)=O.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>[Cl:49][C:43]1[C:44]2[CH2:45][CH2:46][O:47][C:48]=2[C:40]([CH:10]2[C@H:9]([O:8][CH2:1][C:2]3[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=3)[C@@H:14]([O:15][CH2:16][C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)[C@H:13]([O:23][CH2:24][C:25]3[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=3)[C@@H:12]([CH2:31][O:32][CH2:33][C:34]3[CH:35]=[CH:36][CH:37]=[CH:38][CH:39]=3)[O:11]2)=[CH:41][C:42]=1[CH2:50][C:63]1[CH:64]=[CH:65][C:60]([O:59][CH3:58])=[CH:61][CH:62]=1
Reactant: Clc1c(CBr)cc(C2O[C@H](COCc3ccccc3)[C@@H](OCc3ccccc3)[C@H](OCc3ccccc3)[C@H]2OCc2ccccc2)c2c1CCO2
Reactant: COc1ccc(B(O)O)cc1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Solvent: O
Product: COc1ccc(Cc2cc(C3O[C@H](COCc4ccccc4)[C@@H](OCc4ccccc4)[C@H](OCc4ccccc4)[C@H]3OCc3ccccc3)c3c(c2Cl)CCO3)cc1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 63 %

Procedure:
To a mixture of compound 49 (623 mg, 0.81 mmol), K2CO3 (447 mg, 3.24 mmol) and 4-methoxyphenyl boronic acid (306 mg, 2.02 mmol) in acetone (7.5 mL) and H2O (2.5 mL) was added bis(triphenylphosphine)palladium chloride (56 mg, 0.08 mmol) at 0° C. under atmosphere of nitrogen. The mixture was stirred at 0° C. for 30 min and then, stirred at room temperature for 16 hours. The mixture was partitioned between EtOAc and water. The organic layer was washed with brine, dried over MgSO4, filtered and concentrated in vacuo. The residue was purified by silica gel column chromatography to provide the product 50 (407 mg, 62%) as colorless oil.
Reaction SMILES: CS(O[CH2:6][C:7]1[N:15]=[C:14]2[C:10]([N:11]=[CH:12][N:13]2[C@H:16]2[C@H:20]([OH:21])[C@H:19]([OH:22])[C@@H:18]([CH2:23][O:24][CH3:25])[O:17]2)=[C:9]([NH:26][CH2:27][CH:28]([C:35]2[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=2)[C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)[N:8]=1)(=O)=O.[NH2:41][CH2:42][C:43]([N:45]([CH:49]([CH3:51])[CH3:50])[CH:46]([CH3:48])[CH3:47])=[O:44].C(N(C(C)C)C(C)C)C>>[OH:21][C@@H:20]1[C@H:19]([OH:22])[C@@H:18]([CH2:23][O:24][CH3:25])[O:17][C@H:16]1[N:13]1[CH:12]=[N:11][C:10]2[C:14]1=[N:15][C:7]([CH2:6][NH:41][CH2:42][C:43]([N:45]([CH:46]([CH3:48])[CH3:47])[CH:49]([CH3:50])[CH3:51])=[O:44])=[N:8][C:9]=2[NH:26][CH2:27][CH:28]([C:29]1[CH:30]=[CH:31][CH:32]=[CH:33][CH:34]=1)[C:35]1[CH:36]=[CH:37][CH:38]=[CH:39][CH:40]=1
Reactant: CC(C)N(C(=O)CN)C(C)C
Reactant: COC[C@H]1O[C@@H](n2cnc3c(NCC(c4ccccc4)c4ccccc4)nc(COS(C)(=O)=O)nc32)[C@H](O)[C@@H]1O
Solvent: CCN(C(C)C)C(C)C
Product: COC[C@H]1O[C@@H](n2cnc3c(NCC(c4ccccc4)c4ccccc4)nc(CNCC(=O)N(C(C)C)C(C)C)nc32)[C@H](O)[C@@H]1O
Yield: 11.3 %

Procedure:
The title compound was prepared by a similar method to example 40 using {9-[(2R,3R,4S,5R)-3,4-dihydroxy-5-(methoxymethyl)tetrahydro-2-furanyl]-6-[(2,2-diphenylethyl)amino]-9H-purin-2-yl}methyl methanesulfonate (preparation 25) (374 mg, 0.66 mmol), 2-amino-N,N-diisopropylacetamide (520 mg, 3.3 mmol) (preparation 22) and N-ethyl-N-isopropyl-2-propanamine (170 mg, 1.32 mmol). The compound was purified by column chromatography on silica gel eluting with a solvent gradient of dichloromethane:methanol:ammonia (95:5:0.5) increasing in polarity to (90:10:1). The solvent was removed under reduced pressure to give a residue which was triturated with diethyl ether to give the title compound (47 mg) as a solid. MS: 632 (MH+).
Reaction SMILES: [C:1](=[O:14])([O-])[O:2][C:3]1[CH:8]=CC=C[C:4]=1C(C)(C)C.[NH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][NH2:22].[CH2:23](O)C>>[C:1]([NH:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][NH2:22])([O:2][C:3]([CH3:4])([CH3:8])[CH3:23])=[O:14]
Reactant: NCCCCCCN
Reactant: CCO
Reactant: CC(C)(C)c1ccccc1OC(=O)[O-]
Product: CC(C)(C)OC(=O)NCCCCCCN
Temperature: 25 °C

Procedure:
Tert-butylphenyl carbonate (6.37 mL, 14.7 mmol) was added dropwise to a solution of 1,6 diaminohexane (4 g, 14.7 mmol) in ethanol (20 mL) at 80° C. The reaction mixture was refluxed overnight. The reaction mixture was then cooled to room temperature leaving a yellow solution. The solution was concentrated to 15 mL and diluted with water (30 mL). The solution pH was adjusted to 3 with 2M HCl followed by an extraction with dichloromethane (3×50 mL). The water solution pH was then adjusted to pH 12 followed by extraction with dichloromethane (3×50 mL). The organic solutions were combined, washed with sodium bicarbonate (2×50 mL), dried with sodium sulfate, and concentrated to a yellow oil. Characterization matched previously published values (M. Pittelkow, et al., “Mono Carbamate Protection of Aliphatic Diamines Using Alkyl Phenyl Carbonates,” Organic Syntheses (2007) 84, pg 207).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:20])[C:4]1[CH:9]=[CH:8][C:7]([N+:10]([O-])=O)=[C:6]([O:13][CH2:14][CH2:15][CH2:16][N:17]([CH3:19])[CH3:18])[CH:5]=1>CO.[Cl-].[NH4+].C(OCC)(=O)C.[Zn]>[CH3:1][O:2][C:3](=[O:20])[C:4]1[CH:9]=[CH:8][C:7]([NH2:10])=[C:6]([O:13][CH2:14][CH2:15][CH2:16][N:17]([CH3:18])[CH3:19])[CH:5]=1
Reactant: COC(=O)c1ccc([N+](=O)[O-])c(OCCCN(C)C)c1
Agent: [Cl-]
Agent: [NH4+]
Agent: [Zn]
Solvent: CCOC(C)=O
Solvent: CO
Product: COC(=O)c1ccc(N)c(OCCCN(C)C)c1
Reaction time: 12 h
Yield: 88 %

Procedure:
To a stirred, cooled (about 0° C.) solution of 3-(3-dimethylamino-propoxy)-4-nitro-benzoic acid methyl ester (282 mg, 1.0 mmol) in methanol (2 mL) and saturated aqueous ammonium chloride (1 mL) was added zinc dust (2.0 mmol). After stirring for 12 hours, the reaction was diluted with 30 mL of ethyl acetate and washed with 30 mL of 10% aqueous sodium carbonate (2×30. mL), brine (1×30 mL), then dried (MgSO4), and filtered. The filtered solution was concentrated under reduced pressure to yield the desired product as a tan solid (88% yield). 1H-NMR (400 MHz, CDCl3) δ 7.52 (d, 1H), 7.48 (s, 1H), 7.25 (s, 1H), 6.65 (d, 1H), 4,29 (br s, 1H), 4.09 (t, 2H), 3.85 (s, 3H), 2.49 (t, 2H), 2.25 (s, 6H), 2.00 (m, 2H).
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([O:8][CH2:9][C:10]([F:13])([F:12])[F:11])[N:5]=[C:4]([NH:14][C:15]2[CH:27]=[CH:26][C:18]([C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])=[CH:17][CH:16]=2)[N:3]=1.CCN(C(C)C)C(C)C.[NH2:37][CH2:38][C:39]1[CH:44]=[CH:43][C:42]([OH:45])=[CH:41][CH:40]=1>C1COCC1>[OH:45][C:42]1[CH:43]=[CH:44][C:39]([CH2:38][NH:37][C:2]2[CH:7]=[C:6]([O:8][CH2:9][C:10]([F:13])([F:12])[F:11])[N:5]=[C:4]([NH:14][C:15]3[CH:27]=[CH:26][C:18]([C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])=[CH:17][CH:16]=3)[N:3]=2)=[CH:40][CH:41]=1
Reactant: CC(C)(C)OC(=O)c1ccc(Nc2nc(Cl)cc(OCC(F)(F)F)n2)cc1
Reactant: NCc1ccc(O)cc1
Solvent: CCN(C(C)C)C(C)C
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)c1ccc(Nc2nc(NCc3ccc(O)cc3)cc(OCC(F)(F)F)n2)cc1
Temperature: 120 °C
Yield: 78.6 %

Procedure:
To a solution of tert-butyl 4-((4-chloro-6-(2,2,2-trifluoroethoxy)pyrimidin-2-yl)amino)benzoate (30 mg, 0.07 mmol), and Hunig's Base (0.026 mL, 0.15 mmol) in THF (1 mL) was added 4-(aminomethyl)phenol (33 mg, 0.27 mmol). The resulting mixture was stirred at 120° C. for 30 hs. The solvent was removed and the crude product was purified by silica gel chromatography using 20% -40% of EtOAc/Hexanes to give tert-butyl 4-((4-((4-hydroxybenzyl)amino)-6-(2,2,2-trifluoroethoxy)pyrimidin-2-yl)amino)benzoate (27 mg, 74%) as white solid.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[O:8][C:7]([C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)=[CH:6][C:5]2=[O:18].Br[CH2:20][CH2:21][CH2:22][CH2:23][CH2:24]Cl.[OH:26][CH:27]1[CH2:32][CH2:31][NH:30][CH2:29][CH2:28]1>>[OH:26][CH:27]1[CH2:32][CH2:31][N:30]([CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][O:1][C:2]2[CH:11]=[CH:10][C:9]3[O:8][C:7]([C:12]4[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=4)=[CH:6][C:5](=[O:18])[C:4]=3[CH:3]=2)[CH2:29][CH2:28]1
Reactant: O=c1cc(-c2ccccc2)oc2ccc(O)cc12
Reactant: OC1CCNCC1
Reactant: ClCCCCCBr
Product: O=c1cc(-c2ccccc2)oc2ccc(OCCCCCN3CCC(O)CC3)cc12

Procedure:
The compound was prepared by a method similar to Example 3 from 6-hydroxyflavone, 1-bromo-5-chloropentane and 4-hydroxypiperidine: mp 128°-129° C.
Reaction SMILES: [C:1](CC(O)=O)#[N:2].[CH2:7]([NH:10][C:11]([NH2:13])=[O:12])[CH2:8][CH3:9].C(O[C:18](=[O:20])[CH3:19])(=O)C>>[NH2:2][C:1]1[N:10]([CH2:7][CH2:8][CH3:9])[C:11](=[O:12])[NH:13][C:18](=[O:20])[CH:19]=1
Reactant: CC(=O)OC(C)=O
Reactant: N#CCC(=O)O
Reactant: CCCNC(N)=O
Product: CCCn1c(N)cc(=O)[nH]c1=O
Reaction time: 1 h

Procedure:
To a solution of 47 g. (0.55 mol) cyanoacetic acid and 100 ml of acetic anhydride was added 50 g (0.49 mol) of n-propylurea. The solution was stirred at 60°-70° C. for 1 hour. After cooling, white crystals were filtered off and washed with ethanol. Yield 56.2 g (68%) (I). This was stirred in 100 ml of hot water and 60 ml of 2 N NaOH was added in portions so the solution the whole time was basic. The reaction mixture was refluxed for 20 minutes and then neutralized with 5 N HCl. After cooling, white crystals were filtered off. Yield 34.3 g (61%) (II) NMR.
Reaction SMILES: [CH3:1][N:2]1[CH2:15][CH2:14][C:5]2[NH:6][C:7]3[CH:8]=[CH:9][C:10]([CH3:13])=[CH:11][C:12]=3[C:4]=2[CH2:3]1.[OH-].[K+].[C:18]1([NH2:24])[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1.[CH2:25](Cl)Cl>O>[CH3:1][N:2]1[CH2:15][CH2:14][C:5]2[N:6]([CH2:25][NH:24][C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)[C:7]3[CH:8]=[CH:9][C:10]([CH3:13])=[CH:11][C:12]=3[C:4]=2[CH2:3]1
Reactant: Cc1ccc2[nH]c3c(c2c1)CN(C)CC3
Reactant: ClCCl
Reactant: Nc1ccccc1
Agent: [K+]
Agent: [OH-]
Solvent: O
Product: Cc1ccc2c(c1)c1c(n2CNc2ccccc2)CCN(C)C1
Temperature: 85 °C
Reaction time: 2 h

Procedure:
To a solution of 2,8-dimethyl-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indole (200 mg, 1.0 mmol) in DCM (4 mL) were added powdered KOH (392 mg, 7.0 mmol) and phenylamine (111 mg, 1.2 mmol). The reaction mixture was stirred at 85° C. for 2 h. The reaction mixture was diluted with water (20 mL) and extracted with DCM (3×20 mL). The combined organic layer was washed with water (3×30 mL), dried over anhydrous sodium sulfate and concentrated under reduced pressure to afford crude material, which was purified by silica gel column chromatography (3% MeOH-DCM), followed by reverse phase HPLC to yield (2,8-dimethyl-1,2,3,4-tetrahydro-pyrido[4,3-b]indol-5-ylmethyl)-phenyl-amine (20 mg). 1H NMR (CD3OD, freebase) δ (ppm): 7.4 (d, 1H), 7.07 (s, 1H), 7.0 (t, 2H), 6.97 (d, 1H), 6.67 (d, 2H), 6.6 (t, 1H), 5.42 (s, 2H), 3.7 (s, 2H), 3.07 (t, 2H), 2.9 (t, 2H), 2.58 (s, 3H), 2.4 (s, 3H).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[C:9]1[N:14]=[C:13]([NH:15][CH3:16])[C:12]([C:17]#[N:18])=[CH:11][C:10]=1[C:19]1[CH:24]=[CH:23][C:22]([Cl:25])=[CH:21][CH:20]=1.C[Mg+].[Br-].[C:29](Cl)(=[O:33])[CH2:30][CH2:31][CH3:32]>>[Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[C:9]1[N:14]=[C:13]([N:15]([CH3:16])[C:29](=[O:33])[CH2:30][CH2:31][CH3:32])[C:12]([C:17]#[N:18])=[CH:11][C:10]=1[C:19]1[CH:24]=[CH:23][C:22]([Cl:25])=[CH:21][CH:20]=1
Reactant: CNc1nc(-c2ccc(Cl)cc2Cl)c(-c2ccc(Cl)cc2)cc1C#N
Reactant: CCCC(=O)Cl
Agent: C[Mg+]
Agent: [Br-]
Product: CCCC(=O)N(C)c1nc(-c2ccc(Cl)cc2Cl)c(-c2ccc(Cl)cc2)cc1C#N

Procedure:
The product of Step D Example 1 was reacted with MeMgBr followed by butyryl chloride using the procedure of EXAMPLE 42 Step A to afford the title compound.
Reaction SMILES: Cl[C:2]1[N:7]2[N:8]=[C:9]([CH3:11])[CH:10]=[C:6]2[N:5]=[C:4]([NH:12][C:13]([CH:15]2[CH2:17][CH:16]2[C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)=[O:14])[CH:3]=1.[CH3:24][O:25][C:26]1[CH:31]=[CH:30][C:29](B(O)O)=[CH:28][CH:27]=1.O1CCOCC1>CO.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2]>[CH3:24][O:25][C:26]1[CH:31]=[CH:30][C:29]([C:2]2[N:7]3[N:8]=[C:9]([CH3:11])[CH:10]=[C:6]3[N:5]=[C:4]([NH:12][C:13]([CH:15]3[CH2:17][CH:16]3[C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)=[O:14])[CH:3]=2)=[CH:28][CH:27]=1
Reactant: COc1ccc(B(O)O)cc1
Reactant: Cc1cc2nc(NC(=O)C3CC3c3ccccc3)cc(Cl)n2n1
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: c1ccc(P(c2ccccc2)[c-]2cccc2)cc1
Solvent: C1COCCO1
Solvent: CO
Product: COc1ccc(-c2cc(NC(=O)C3CC3c3ccccc3)nc3cc(C)nn23)cc1
Temperature: 100 °C
Yield: 68.9 %

Procedure:
A suspension of N-(7-chloro-2-methylpyrazolo[1,5-a]pyrimidin-5-yl)-2-phenylcyclopropanecarboxamide (8C, 200 mg, 0.612 mmol), 4-methoxyphenylboronic acid (186 mg, 1.22 mmol), and [1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium(II) (35 mg, 49 μmol) in 2:1 1,4-dioxane/saturated aqueous NaHCO3 (660 microliters of 1,4-dioxane and 330 microliters of saturated aqueous NaHCO3) was prepared in a 2 mL microwave reaction vessel and the sealed reaction vessel warmed to 100° C. for 10 minutes. The reaction mixture was cooled to rt, diluted with methanol, filtered, and purified via preparative HPLC (70-75% MeCN/H2O gradient+0.01% TFA). Lyophilization of the combined fractions gave the titled compound as a yellow solid (168 mg, 69%). 1H NMR (DMSO-d6) δ: 11.23 (s, 1H), 8.01-8.18 (m, 2H), 7.89 (s, 1H), 7.26-7.37 (m, 2H), 7.08-7.26 (m, 5H), 6.30 (s, 1H), 3.87 (s, 3H), 2.42-2.48 (m, 1H), 2.26-2.43 (m, 4H), 1.49-1.59 (m, 1H), 1.39-1.47 (m, 1H). ESI-MS: m/z 399.0 (M+H)+.