Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: CC1C=C(C)C=C(C)C=1S(O[C:14]1[C:19]([CH2:20][C:21]2[CH:26]=[CH:25][C:24]([O:27][CH2:28][CH2:29][O:30][CH2:31][CH2:32][C:33]([P:36]([O:41][CH2:42][CH3:43])([O:38][CH2:39][CH3:40])=[O:37])([F:35])[F:34])=[CH:23][C:22]=2[O:44][CH3:45])=[C:18]([CH3:46])[N:17]=[C:16]([NH2:47])[N:15]=1)(=O)=O.C(O)(C(F)(F)F)=O.[CH2:55]([NH2:60])[CH2:56][CH2:57][CH2:58][CH3:59]>CCOC(C)=O>[NH2:47][C:16]1[N:17]=[C:18]([CH3:46])[C:19]([CH2:20][C:21]2[CH:26]=[CH:25][C:24]([O:27][CH2:28][CH2:29][O:30][CH2:31][CH2:32][C:33]([P:36](=[O:37])([O:38][CH2:39][CH3:40])[O:41][CH2:42][CH3:43])([F:35])[F:34])=[CH:23][C:22]=2[O:44][CH3:45])=[C:14]([NH:60][CH2:55][CH2:56][CH2:57][CH2:58][CH3:59])[N:15]=1
Reactant: CCOP(=O)(OCC)C(F)(F)CCOCCOc1ccc(Cc2c(C)nc(N)nc2OS(=O)(=O)c2c(C)cc(C)cc2C)c(OC)c1
Reactant: CCCCCN
Solvent: CCOC(C)=O
Solvent: O=C(O)C(F)(F)F
Product: CCCCCNc1nc(N)nc(C)c1Cc1ccc(OCCOCCC(F)(F)P(=O)(OCC)OCC)cc1OC
Temperature: 100 °C
Yield: 76 %

Procedure:
To a solution of 2-amino-5-(4-(2-(3-(diethoxyphosphoryl)-3,3-difluoropropoxy)ethoxy)-2-methoxybenzyl)-6-methylpyrimidin-4-yl 2,4,6-trimethylbenzenesulfonate (1 equiv.) in EtOAc (0.20 M) was added TFA (1.1 equiv.) and amylamine (3.3 equiv.). The reaction mixture was then heated to 100° C. for 18 h. At this point the reaction mixture was allowed to cool to room temperature and the volatiles were removed in vacuo. The resulting residue was purified by a COMBIFLASH™ system using a gradient of 0-10% MeOH/DCM to provide the title compound (76%) as a solid.
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][CH2:4][CH2:3][C:2]1=[O:7].C(N(CC)CC)C.[O:15](C(OC(C)(C)C)=O)[C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=O>C(#N)C.CN(C1C=CN=CC=1)C>[O:7]=[C:2]1[CH2:3][CH2:4][CH2:5][CH2:6][N:1]1[C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:15]
Reactant: CC(C)(C)OC(=O)OC(=O)OC(C)(C)C
Reactant: O=C1CCCCN1
Agent: CN(C)c1ccncc1
Solvent: CC#N
Solvent: CCN(CC)CC
Product: CC(C)(C)OC(=O)N1CCCCC1=O
Reaction time: 0.17 h
Yield: 63.3 %

Procedure:
A solution of piperidin-2-one (25 g, 252.2 mmol) in acetonitrile (250 ml) was cooled to 0° C. and added DMAP (6.1 g, 50.4 mmol) and triethyl amine (25.5 g, 252.2 mmol) and stirred for 10 min at same temperature then added (BOC)2O (66 g, 302.6 mmol) and continue stirring for 2 h at room temperature. After completion of starting material, solvent was removed and residue was re-dissolved in ethyl acetate and washed with water, brine and dried over Na2SO4 and concentration to afford crude product as brown liquid (31.8 g) which was used directly for the next step. 1H NMR (300 MHz, CDCl3) δ 3.66-3.62 (2H, m), 2.52-2.47 (2H, m), 1.83-1.79 (4H, m), 1.52 (9H, s) ppm.
Reaction SMILES: [CH3:1][NH:2][C:3]1[CH:26]=[CH:25][C:6]([O:7][C:8]2[CH:13]=[CH:12][N:11]=[C:10]([NH:14][C:15](=[O:24])[CH2:16][N:17]3[CH2:22][CH2:21][CH:20]([CH3:23])[CH2:19][CH2:18]3)[CH:9]=2)=[CH:5][C:4]=1[N+:27]([O-])=O>[Pd]>[NH2:27][C:4]1[CH:5]=[C:6]([CH:25]=[CH:26][C:3]=1[NH:2][CH3:1])[O:7][C:8]1[CH:13]=[CH:12][N:11]=[C:10]([NH:14][C:15](=[O:24])[CH2:16][N:17]2[CH2:18][CH2:19][CH:20]([CH3:23])[CH2:21][CH2:22]2)[CH:9]=1
Reactant: CNc1ccc(Oc2ccnc(NC(=O)CN3CCC(C)CC3)c2)cc1[N+](=O)[O-]
Agent: [Pd]
Product: CNc1ccc(Oc2ccnc(NC(=O)CN3CCC(C)CC3)c2)cc1N

Procedure:
N-{4-[4-(methylamino)-3-nitrophenoxy] (2-pyridyl)}-2-(4-methylpiperidyl)acetamide was hydrogenated in the presence of Pd C for 4 hours. The catalyst was removed via filtration and filtrate was concentrated to give N-{4-[3-amino-4-(methylamino)phenoxy](2-pyridyl)}-2-(4-methylpiperidyl)acetamide. MS: MH+=370.2.
Reaction SMILES: [C:1](Cl)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[NH2:10][CH2:11][CH:12]1[C:21]([C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)([C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)[CH2:20][CH2:19][CH2:18][C:13]21[O:17][CH2:16][CH2:15][O:14]2.C(N(CC)CC)C>ClCCl>[C:1]([NH:10][CH2:11][CH:12]1[C:21]([C:28]2[CH:29]=[CH:30][CH:31]=[CH:32][CH:33]=2)([C:22]2[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=2)[CH2:20][CH2:19][CH2:18][C:13]21[O:14][CH2:15][CH2:16][O:17]2)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C(Cl)c1ccccc1
Reactant: NCC1C2(CCCC1(c1ccccc1)c1ccccc1)OCCO2
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: O=C(NCC1C2(CCCC1(c1ccccc1)c1ccccc1)OCCO2)c1ccccc1
Reaction time: 4 h
Yield: 74.7 %

Procedure:
A solution of benzoyl chloride (7.7 g) in anhydrous dichloromethane (10 cc) is added dropwise, in the course of 40 minutes and while the temperature of the reaction mixture is maintained at +5° C., to a solution, cooled to +5° C., of (RS)-6-aminomethyl-7,7-diphenyl-1,4-dioxaspiro[4.5]decane (16.2 g) and triethylamine (5.6 g) in anhydrous dichloromethane (150 cc). The reaction mixture is then stirred for 4 hours at +25° C., thereafter washed with distilled water (125 cc) cooled to +5° C., dried over magnesium sulphate, filtered and concentrated to dryness under reduced pressure (2.7 kPa). The residue is recrystallized in a mixture (50 cc) of acetonitrile and isopropyl ether (50:50 by volume). The crystals are drained and dried. (RS)-6-Benzamidomethyl-7,7-diphenyl-1,4-dioxaspiro[4.5]decane (16 g) is obtained in the form of white crystals. M.p. 162° C.
Reaction SMILES: Br[CH2:2][C:3]([C:5]1[S:6][CH:7]=[CH:8][CH:9]=1)=O.[C:10]([CH2:12][C:13]([NH2:15])=[S:14])#[N:11]>>[S:6]1[CH:7]=[CH:8][CH:9]=[C:5]1[C:3]1[N:15]=[C:13]([CH2:12][C:10]#[N:11])[S:14][CH:2]=1
Reactant: O=C(CBr)c1cccs1
Reactant: N#CCC(N)=S
Product: N#CCc1nc(-c2cccs2)cs1
Yield: 49 %

Procedure:
This compound was synthesized from 2-bromo-1-(thiophen-2-yl)ethanone and 2-cyanothioacetamide as described in example 1 step 1 (0.25 g, yield 49%): 1H NMR (400 MHz, CDCl3) δ 7.47 (d, J=3.4 Hz, 1H), 7.36 (s, 1H), 7.33 (d, J=5.1 Hz, 1H), 7.09 (t, J=4.2 Hz, 1H), 4.17 (s, 2H). MS (ESI) m/z: Calculated for C9H6N2S2: 206.00. found: 207.0 (M+H)+.
Reaction SMILES: [OH:1][C:2]1[N:7]=[C:6]([SH:8])[N:5]=[C:4]2[NH:9][N:10]=[C:11]([CH3:12])[C:3]=12.[OH-].[Na+].[CH3:15]I>O>[OH:1][C:2]1[N:7]=[C:6]([S:8][CH3:15])[N:5]=[C:4]2[NH:9][N:10]=[C:11]([CH3:12])[C:3]=12
Reactant: CI
Reactant: Cc1n[nH]c2nc(S)nc(O)c12
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: CSc1nc(O)c2c(C)n[nH]c2n1
Temperature: 5 °C
Reaction time: 0.29 h

Procedure:
4-hydroxy-6-mercapto-3-methylpyrazolo[3,4-d]pyrimidine (14 g) was dissolved in a solution of 10 g. of sodium hydroxide in 300 ml. of water. The solution was cooled to 5° C. and shaken with 12 g. of methyl iodide. After 15-20 minutes, the solution was charcoaled, filtered and acidified with acetic acid to yield 12 g. of crude product. Recrystallization in acidic acid gave the product. MS (ES+): 197.0 (M+1)+.
Reaction SMILES: P(Cl)(Cl)([Cl:3])=O.[CH3:6][O:7][C:8]1[CH:9]=[C:10]2[C:15](=[CH:16][C:17]=1[O:18][CH3:19])[N:14]=[CH:13][CH2:12][C:11]2=O.[OH-].[Na+]>C1(C)C=CC=CC=1>[Cl:3][C:11]1[C:10]2[C:15](=[CH:16][C:17]([O:18][CH3:19])=[C:8]([O:7][CH3:6])[CH:9]=2)[N:14]=[CH:13][CH:12]=1
Reactant: COc1cc2c(cc1OC)C(=O)CC=N2
Reactant: O=P(Cl)(Cl)Cl
Agent: [Na+]
Agent: [OH-]
Solvent: Cc1ccccc1
Product: COc1cc2nccc(Cl)c2cc1OC
Reaction time: 1 h
Yield: 80.6 %

Procedure:
Toluene (3 L) and phosphorus oxychloride (1300 g) were added to 6,7-dimethoxy-4-quinolone (1056 g), and the mixture was heated under reflux with stirring for one hr. The reaction solution was neutralized with an aqueous sodium hydroxide solution at 0° C. The resultant precipitate was collected by filtration and was slurried in water (10 L) for washing. The slurry was filtered, and the filtered product was then dried under the reduced pressure to give 4-chloro-6,7-dimethoxyquinoline (928 g, yield 87.6%).
Reaction SMILES: [NH2:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][NH2:8].C(N(CC)CC)C.[C:16]([O:20][C:21](ON=C(C1C=CC=CC=1)C#N)=[O:22])([CH3:19])([CH3:18])[CH3:17]>C(Cl)(Cl)Cl>[C:16]([O:20][C:21]([NH:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][NH2:8])=[O:22])([CH3:19])([CH3:18])[CH3:17]
Reactant: CC(C)(C)OC(=O)ON=C(C#N)c1ccccc1
Reactant: NCCCCCCN
Solvent: CCN(CC)CC
Solvent: ClC(Cl)Cl
Product: CC(C)(C)OC(=O)NCCCCCCN
Reaction time: 7 h
Yield: 77 %

Procedure:
In this synthesis CDTAMA is reacted with the monoprotected diamine N-(t-butyoxycarbonyl)-1,6-diaminohexane to give the corresponding amide. The t-Boc protecting group is then hydrolyzed to give the product. To prepare the monoprotected diamine N-(t-butyoxycarbonyl)-1,6-diaminohexane, first 9.4 g (81.2 mmol) of 1,6-diaminohexane is dissolved in 60 ml dry chloroform and 0.85 ml (6.1 mmol) triethylamine is added. To this solution is added dropwise 1 g (4.1 mmol) [2-(tert-butoxycarbonyloxyimino)-2-phenylacetonitrile (BOC-ON) dissolved in 20 ml dry chloroform. This solution is stirred 7 hr, filtered and the filtrate evaporated to an oil. This oil is vacuum distilled to remove the excess 1,6-diaminohexane. The residue in the distillation flask is dissolved in acetone and purified on a silica gel chromatography column (eluted with acetone) to give 0.68 g (77%) of N-(t-butoxycarbonyl)-1,6-diaminohexane as a yellow oil.
Reaction SMILES: [Cl:1][C:2]1[N:6]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)[N:5]=[C:4]([CH3:13])[C:3]=1[CH:14]=O.[NH:16]1[C:20]2=[N:21][CH:22]=[CH:23][CH:24]=[C:19]2[CH:18]=[CH:17]1>>[Cl:1][C:2]1[N:6]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)[N:5]=[C:4]([CH3:13])[C:3]=1[CH2:14][C:18]1[C:19]2[C:20](=[N:21][CH:22]=[CH:23][CH:24]=2)[NH:16][CH:17]=1
Reactant: c1cnc2[nH]ccc2c1
Reactant: Cc1nn(-c2ccccc2)c(Cl)c1C=O
Product: Cc1nn(-c2ccccc2)c(Cl)c1Cc1c[nH]c2ncccc12

Procedure:
3-((5-chloro-3-methyl-1-phenyl-1H-pyrazol-4-yl)methyl)-1H-pyrrolo[2,3-b]pyridine P-0080 was synthesized in 2 steps from 5-chloro-3-methyl-1-phenyl-1H-pyrazole-4-carbaldehyde 100 and 7-azaindole 1 as shown in Scheme 38.
Reaction SMILES: C1N=CN([C:6](N2C=NC=C2)=[S:7])C=1.[OH:13][CH2:14][C:15]([NH:18][C:19]1[S:20][CH:21]=[C:22]([C:24]2[CH:31]=[CH:30][C:27]([C:28]#[N:29])=[CH:26][CH:25]=2)[N:23]=1)([CH3:17])[CH3:16]>O1CCCC1>[CH3:16][C:15]1([CH3:17])[CH2:14][O:13][C:6](=[S:7])[N:18]1[C:19]1[S:20][CH:21]=[C:22]([C:24]2[CH:25]=[CH:26][C:27]([C:28]#[N:29])=[CH:30][CH:31]=2)[N:23]=1
Reactant: CC(C)(CO)Nc1nc(-c2ccc(C#N)cc2)cs1
Reactant: S=C(n1ccnc1)n1ccnc1
Solvent: C1CCOC1
Product: CC1(C)COC(=S)N1c1nc(-c2ccc(C#N)cc2)cs1
Temperature: 25 °C
Reaction time: 2 h
Yield: 11.4 %

Procedure:
1,1-Thiocarbonyldiimidazole (652 mg, 3.6 mmol) was added to a solution of 4-{2-[(2-hydroxy-1,1-dimethylethyl)amino]-1,3-thiazol-4-yl}benzonitrile (1.0 g, 3.6 mmol), prepared in the previous step, in 60 mL of dry tetrahydrofuran at 0° C. The solution was allowed to warm to room temperature. After 2 h, starting material remained. The reaction was heated to reflux. After 12 h, the reaction was cooled to room temperature and concentrated under reduced pressure. Purification of the residue by reverse phase HPLC using a continuous gradient of 70-83% acetonitrile-water over 10 min gave the title compound (130 mg, 11%) as a tan solid. mp>240° C. (dec.)
Reaction SMILES: [C:1]([OH:10])(=[O:9])[C:2]1[C:3](=[CH:5][CH:6]=[CH:7][CH:8]=1)[NH2:4].[CH2:11]=[C:12]1[O:16][C:14](=O)[CH2:13]1.C(OC(=O)C)(=O)C>CC(C)=O.O1CCCC1>[O:16]=[C:12]([CH3:11])[CH2:13][C:14]1[O:9][C:1](=[O:10])[C:2]2[CH:8]=[CH:7][CH:6]=[CH:5][C:3]=2[N:4]=1
Reactant: Nc1ccccc1C(=O)O
Reactant: C=C1CC(=O)O1
Solvent: CC(C)=O
Solvent: C1CCOC1
Solvent: CC(=O)OC(C)=O
Product: CC(=O)Cc1nc2ccccc2c(=O)o1
Temperature: 25 °C
Reaction time: 16 h
Yield: 57.2 %

Procedure:
To a solution of anthranilic acid (290 g, 2.1 mol) in acetone (1000 mL), diketene (460 mL, 6.0 mol) was added dropwise at room temperature. The mixture was stirred at room temperature for 16 hours. The resulting crystals were collected by filtration, washed with acetone and diethylether, and air dried (170 g). The crude crystals were suspended in a mixture of acetic anhydride (320 mL, 3.4 mol) and tetrahydrofuran (1000 mL), and the mixture was heated and stirred at 80° C. for 12 hours. After the mixture was cooled to room temperature, the reaction solvents were evaporated under reduced pressure, and the resulting crude crystals were filtered. The crystals were washed with acetonitrile and air dried to give the title compound (244 g, 57% yield).
Reaction SMILES: Br[CH2:2][C@@H:3]([C:5]1[O:9][N:8]=[C:7]([Br:10])[CH:6]=1)[OH:4].C(=O)([O-])[O-].[K+].[K+]>CC(C)=O>[Br:10][C:7]1[CH:6]=[C:5]([C@@H:3]2[CH2:2][O:4]2)[O:9][N:8]=1
Reactant: O[C@@H](CBr)c1cc(Br)no1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: Brc1cc([C@@H]2CO2)on1
Temperature: 25 °C
Reaction time: 48 h
Yield: 76.7 %

Procedure:
A mixture of (1R)-2-bromo-1-(3-bromoisoxazole-5-yl)ethanol (which was obtained in Example 119) (1.44 g, 5.31 mmol), potassium carbonate (1.46 g, 10.62 mmol) and acetone (30 mL) was stirred at ambient temperature for 48 hours. The reaction mixture was filtered, and the solvent was removed in vacuo. The residue was purified by flash chromatography (hexanes/chloroform/isopropyl alcohol 8/1.8/0.2) to give a colorless oil (0.774 g, 53% yield); 1H NMR (300 MHz, CDCl3) δ 3.17 (m, 1H), 3.21 (m, 1H), 3.99 (m, 1H), 6.38 (s, 1H).
Reaction SMILES: Cl.Cl.Cl.[O:4]1[C:8]2=[C:9]([N:13]3[CH2:18][CH2:17][N:16]([CH2:19][CH2:20][C@H:21]4[CH2:26][CH2:25][C@H:24]([NH2:27])[CH2:23][CH2:22]4)[CH2:15][CH2:14]3)[N:10]=[CH:11][CH:12]=[C:7]2[CH2:6][CH2:5]1.[CH3:28][O:29][CH2:30][C:31](O)=[O:32]>>[O:4]1[C:8]2=[C:9]([N:13]3[CH2:18][CH2:17][N:16]([CH2:19][CH2:20][C@H:21]4[CH2:26][CH2:25][C@H:24]([NH:27][C:31](=[O:32])[CH2:30][O:29][CH3:28])[CH2:23][CH2:22]4)[CH2:15][CH2:14]3)[N:10]=[CH:11][CH:12]=[C:7]2[CH2:6][CH2:5]1
Reactant: N[C@H]1CC[C@H](CCN2CCN(c3nccc4c3OCC4)CC2)CC1
Reactant: COCC(=O)O
Agent: Cl
Product: COCC(=O)N[C@H]1CC[C@H](CCN2CCN(c3nccc4c3OCC4)CC2)CC1

Procedure:
The title compound, white solid (92 mg, 76%), MS (ISP) m/z=403.5 [(M+H)+], mp 126.5° C., was prepared in accordance with the general method of example 6 from trans-4-{2-[4-(2,3-dihydro-furo[2,3-c]pyridin-7-yl)-piperazin-1-yl]-ethyl}-cyclohexylamine trihydrochloride (intermediate B) (132 mg, 0.3 mmol) and methoxy-acetic acid.
Reaction SMILES: [CH3:1][O:2][C:3]([N:5]=[C:6]=[O:7])=[O:4].[NH2:8][C:9]1[S:10][C:11]2[CH:17]=[CH:16][CH:15]=[C:14]([Cl:18])[C:12]=2[N:13]=1>O1CCOCC1>[Cl:18][C:14]1[C:12]2[N:13]=[C:9]([NH:8][C:6](=[O:7])[NH:5][C:3]([O:2][CH3:1])=[O:4])[S:10][C:11]=2[CH:17]=[CH:16][CH:15]=1
Reactant: COC(=O)N=C=O
Reactant: Nc1nc2c(Cl)cccc2s1
Solvent: C1COCCO1
Product: COC(=O)NC(=O)Nc1nc2c(Cl)cccc2s1
Temperature: 25 °C
Reaction time: 8 h
Yield: 45 %

Procedure:
Five and one half parts by weight of methoxycarbonyl isocyanate was added gradually with stirring to a solution at room temperature of nine parts by weight of 2-amino-4-chlorobenzothiazole dissolved in 200 parts by weight of dioxane. After stirring the reaction mixture at room temperature overnight, a product was isolated by filtration giving a 45% yield of methyl 4-[4-chlorobenzothiazol-2-yl]allophanate having a melting point of 319°-20° C.
Reaction SMILES: [Cl:1][C:2]1[C:7]([F:8])=[CH:6][CH:5]=[C:4]([Cl:9])[C:3]=1[CH:10]([O:12][C:13]1[C:14]([NH2:31])=[N:15][CH:16]=[C:17]([C:19]2[CH:24]=[CH:23][C:22]([P:25]([CH3:28])([CH3:27])=[O:26])=[CH:21][C:20]=2[O:29]C)[CH:18]=1)[CH3:11].Cl.N1C=CC=CC=1>>[NH2:31][C:14]1[N:15]=[CH:16][C:17]([C:19]2[CH:24]=[CH:23][C:22]([P:25]([CH3:28])([CH3:27])=[O:26])=[CH:21][C:20]=2[OH:29])=[CH:18][C:13]=1[O:12][CH:10]([C:3]1[C:4]([Cl:9])=[CH:5][CH:6]=[C:7]([F:8])[C:2]=1[Cl:1])[CH3:11]
Reactant: COc1cc(P(C)(C)=O)ccc1-c1cnc(N)c(OC(C)c2c(Cl)ccc(F)c2Cl)c1
Agent: Cl
Solvent: c1ccncc1
Product: CC(Oc1cc(-c2ccc(P(C)(C)=O)cc2O)cnc1N)c1c(Cl)ccc(F)c1Cl
Temperature: -205 °C

Procedure:
A mixture of 3-[1-(2,6-dichloro-3-fluoro-phenyl)ethoxy]-5-(4-dimethylphosphoryl-2-methoxy-phenyl)pyridin-2-amine (30 mg) and pyridine HCl salt (0.5 g) was heated to −205° C. for 30 minutes under N2. The reaction mixture was cooled down to room temperature and purified by reverse phase HPLC (water/methanol, 10-100%) as a gummy solid (4 mg); ESMS: m/z 469 (M+H)+.
Reaction SMILES: C(NC(C)C)(C)C.C([Li])CCC.[C:13]1(=[O:18])[O:17][CH2:16][CH2:15][CH2:14]1.[CH2:19](Br)[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1.CN(C)P(N(C)C)(N(C)C)=O>O1CCCC1>[CH2:19]([CH:14]1[CH2:15][CH2:16][O:17][C:13]1=[O:18])[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1
Reactant: BrCc1ccccc1
Reactant: O=C1CCCO1
Agent: [Li]CCCC
Solvent: CN(C)P(=O)(N(C)C)N(C)C
Solvent: C1CCOC1
Solvent: CC(C)NC(C)C
Product: O=C1OCCC1Cc1ccccc1
Temperature: -78 °C

Procedure:
To a solution of diisopropylamine (15.18 g, 0.15 mol) in dry tetrahydrofuran (200 ml) at −78° C. under a nitrogen atmosphere, n-butyllithium (1.6 M in hexanes, 94 ml, 0.15 mol) was added dropwise. After twenty minutes of stirring at −78° C., γ-butyrolactone (12.91 g, 0.15 mol) was added dropwise, such that the reaction temperature was maintained below −70° C. After twenty minutes of stirring at −78° C., a mixture of benzyl bromide (25.65 g, 0.15 mol) and hexamethylphosphoramide (26.85 g, 0.15 mol) was added dropwise to the reaction mixture. The reaction mixture was then permitted to warm to −30° C. and stirred at this temperature for two hours.
Reaction SMILES: [Cl:1][C:2]1[C:7]([O:8][CH3:9])=[CH:6][C:5]([O:10][CH3:11])=[C:4]([Cl:12])[C:3]=1[C:13]1[CH:14]=[C:15]2[C:20](=[CH:21][CH:22]=1)[N:19]=[C:18]([NH:23][C@H:24]1[C@@H:29]([NH2:30])[CH2:28][CH2:27][O:26][CH2:25]1)[N:17]=[CH:16]2.CCN(C(C)C)C(C)C.[C:40](Cl)(=[O:43])[CH:41]=[CH2:42]>C(Cl)Cl>[Cl:12][C:4]1[C:5]([O:10][CH3:11])=[CH:6][C:7]([O:8][CH3:9])=[C:2]([Cl:1])[C:3]=1[C:13]1[CH:14]=[C:15]2[C:20](=[CH:21][CH:22]=1)[N:19]=[C:18]([NH:23][C@H:24]1[C@@H:29]([NH:30][C:40](=[O:43])[CH:41]=[CH2:42])[CH2:28][CH2:27][O:26][CH2:25]1)[N:17]=[CH:16]2
Reactant: COc1cc(OC)c(Cl)c(-c2ccc3nc(N[C@@H]4COCC[C@@H]4N)ncc3c2)c1Cl
Reactant: C=CC(=O)Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: C=CC(=O)N[C@H]1CCOC[C@H]1Nc1ncc2cc(-c3c(Cl)c(OC)cc(OC)c3Cl)ccc2n1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 60.4 %

Procedure:
(3S,4S)—N3-(6-(2,6-dichloro-3,5-dimethoxyphenyl)quinazolin-2-yl)tetrahydro-2H-pyran-3,4-diamine (0.060 g, 0.134 mmol) was taken up in CH2Cl2 (2 ml) and cooled to 0° C., followed by addition of DIEA (0.023 ml, 0.134 mmol) and then acryloyl chloride (0.012 ml, 0.147 mmol) slowly. The reaction was stirred at 0° C. for 30 minutes, then the mixture was loaded directly onto silica and purified by flash chromotography using 0-10% CH2Cl2/MeOH. N-((3S,4S)-3-((6-(2,6-dichloro-3,5-dimethoxyphenyl)quinazolin-2-yl)amino)tetrahydro-2H-pyran-4-yl)acrylamide (0.041 g, 0.081 mmol, 61% yield) was recovered as an off white solid. MS (ES+) C24H24Cl2N4O4 requires: 502, found: 503 [M+H]+.
Reaction SMILES: [CH2:1]([N:4]1[CH2:9][CH2:8][CH2:7][CH2:6][CH2:5]1)[C:2]#[CH:3].[F:10][C:11]1[C:12](I)=[C:13]2[C:17](=[CH:18][CH:19]=1)[NH:16][C:15](=[O:20])/[C:14]/2=[CH:21]\[C:22]1[NH:26][CH:25]=[N:24][C:23]=1[CH3:27]>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.[Cu]I.CN(C=O)C.CCN(CC)CC>[F:10][C:11]1[C:12]([C:3]#[C:2][CH2:1][N:4]2[CH2:9][CH2:8][CH2:7][CH2:6][CH2:5]2)=[C:13]2[C:17](=[CH:18][CH:19]=1)[NH:16][C:15](=[O:20])/[C:14]/2=[CH:21]\[C:22]1[NH:26][CH:25]=[N:24][C:23]=1[CH3:27]
Reactant: Cc1nc[nH]c1/C=C1\C(=O)Nc2ccc(F)c(I)c21
Reactant: C#CCN1CCCCC1
Agent: [Cu]I
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: Cc1nc[nH]c1/C=C1\C(=O)Nc2ccc(F)c(C#CCN3CCCCC3)c21

Procedure:
Using Method C above, 1-(2-propynyl)-piperidine (41.3 mg, 0.34 mmol) (prepared according to Kano et al. supra) was coupled with (Z)-1,3-dihydro-5-fluoro-4-iodo-3-[(4-methyl-1H-imidazol-5-yl)methylene]-2H-indol-2-one (Starting Material 3 supra) (50 mg, 0.135 mmol) using (Ph3P)4Pd (16 mg) and CuI (3 mg) as catalyst in DMF (3 mL) and Et3N (3 mL) as solvent at 80° C. for 5 h to give (Z)-1,3-dihydro-5-fluoro-3-[(4-methyl-1H-imidazol-5-yl)methylene]-4-[3-(1-pipendinyl)-1-propynyl]-2H-indol-2-one. (Yield 15 mg, 31%).
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][CH:11]([C:14]2[CH:19]=[CH:18][C:17]([F:20])=[C:16]([NH:21][C:22](=[O:40])[CH2:23][CH2:24][C:25]3[CH:30]=[CH:29][C:28]([O:31][C:32]4[CH:37]=[CH:36][C:35]([F:38])=[C:34]([F:39])[CH:33]=4)=[CH:27][CH:26]=3)[CH:15]=2)[CH2:10][CH2:9]1)=O)(C)(C)C.FC(F)(F)C(O)=O>C(Cl)Cl>[F:39][C:34]1[CH:33]=[C:32]([CH:37]=[CH:36][C:35]=1[F:38])[O:31][C:28]1[CH:29]=[CH:30][C:25]([CH2:24][CH2:23][C:22]([NH:21][C:16]2[CH:15]=[C:14]([CH:11]3[CH2:10][CH2:9][NH:8][CH2:13][CH2:12]3)[CH:19]=[CH:18][C:17]=2[F:20])=[O:40])=[CH:26][CH:27]=1
Reactant: CC(C)(C)OC(=O)N1CCC(c2ccc(F)c(NC(=O)CCc3ccc(Oc4ccc(F)c(F)c4)cc3)c2)CC1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: O=C(CCc1ccc(Oc2ccc(F)c(F)c2)cc1)Nc1cc(C2CCNCC2)ccc1F
Reaction time: 0.17 h
Yield: 95.3 %

Procedure:
Into a solution of tert-butyl-4-[3-({3-[4-(3,4-difluorophenoxy)phenyl]propanoyl}amino)-4-fluorophenyl]-1-piperidinecarboxylate (85.0 mg, 0.150 mmol) in CH2Cl2 (2.0 mL) was added trifluoroacetic acid (170 mg, 1.50 mmol) at room temperature. The reaction mixture was stirred for 10 min and concentrated in vacuo. The residue was dissolved in CHCl3/i-PrOH (3:1, 10 mL) and was basified to pH 11 with 5% KOH solution. The organic layer was extracted and the aqueous layer was extracted with CHCl3/i-PrOH (3:1, 3×10 mL). The combined organic extracts were washed with brine, dried over MgSO4, filtered and concentrated in vacuo to afford 3-[4-(3,4-difluorophenoxy)phenyl]-N-[2-fluoro-5-(4-piperidinyl)phenyl]propanamide (65.0 mg, 92%): 1H NMR (400 MHz, CD3OD) δ 8.27-8.12 (m, 1H), 7.39 (s, 1H), 7.33-7.17 (m, 2H), 7.17-7.06 (m, 1H), 7.06-6.97 (m, 1H), 6.97-6.87 (m, 3H), 6.86-6.74 (m, 1H), 6.74-6.62 (m, 1H), 6.15-5.63 (br, 1H), 3.55-3.31 (m, 2H), 3.15-2.97 (m, 2H), 2.97-2.79 (m, 2H), 2.79-2.59 (m, 3H), 2.05-1.79 (m, 4H); ESMS m/e: 455.2 (M+H)+.
Reaction SMILES: Br[C:2]1[N:3]=[C:4]2[C:10]3[CH:11]=[CH:12][CH:13]=[CH:14][C:9]=3[NH:8][C:7]3[N:15]=[CH:16][CH:17]=[CH:18][C:6]=3[N:5]2[C:19]=1[C:20]1[CH:25]=[CH:24][C:23]([C:26]2([NH:30][C:31](=[O:37])[O:32][C:33]([CH3:36])([CH3:35])[CH3:34])[CH2:29][CH2:28][CH2:27]2)=[CH:22][CH:21]=1.C([Sn](CCCC)(CCCC)[C:43]1[O:44][C:45]2[CH:51]=[CH:50][CH:49]=[CH:48][C:46]=2[N:47]=1)CCC.[F-].[Cs+]>O1CCOCC1.O.CC(C)([P](C(C)(C)C)([Pd][P](C(C)(C)C)(C(C)(C)C)C(C)(C)C)C(C)(C)C)C>[O:44]1[C:45]2[CH:51]=[CH:50][CH:49]=[CH:48][C:46]=2[N:47]=[C:43]1[C:2]1[N:3]=[C:4]2[C:10]3[CH:11]=[CH:12][CH:13]=[CH:14][C:9]=3[NH:8][C:7]3[N:15]=[CH:16][CH:17]=[CH:18][C:6]=3[N:5]2[C:19]=1[C:20]1[CH:25]=[CH:24][C:23]([C:26]2([NH:30][C:31](=[O:37])[O:32][C:33]([CH3:36])([CH3:35])[CH3:34])[CH2:29][CH2:28][CH2:27]2)=[CH:22][CH:21]=1
Reactant: CC(C)(C)OC(=O)NC1(c2ccc(-c3c(Br)nc4n3-c3cccnc3Nc3ccccc3-4)cc2)CCC1
Reactant: CCCC[Sn](CCCC)(CCCC)c1nc2ccccc2o1
Agent: CC(C)(C)[P]([Pd][P](C(C)(C)C)(C(C)(C)C)C(C)(C)C)(C(C)(C)C)C(C)(C)C
Agent: [Cs+]
Agent: [F-]
Solvent: C1COCCO1
Solvent: O
Product: CC(C)(C)OC(=O)NC1(c2ccc(-c3c(-c4nc5ccccc5o4)nc4n3-c3cccnc3Nc3ccccc3-4)cc2)CCC1
Temperature: 130 °C
Yield: 21.2 %

Procedure:
A mixture of tert-butyl {1-[4-(2-bromo-9H-imidazo[1,2-d]pyrido[2,3-b][1,4]benzodiazepin-3-yl)phenyl]cyclobutyl}carbamate (50.0 mg, 0.0895 mmol), 2-(tributylstannyl)-1,3-benzoxazole (81.2 mg, 0.179 mmol), bis (tri-tert-butylphosphine)palladium(0) (9.15 mg, 0.0179 mmol) and cesium fluoride (88.4 mg, 0.582 mmol) in 1,4-dioxane (1.00 mL) was heated at 130° C. under microwave irradiation for 2 hours under nitrogen. After cooling to room temperature, the mixture was diluted with water and extracted with EtOAc (×3). The combined organic layer was dried over anhydrous Na2SO4 and concentrated. The residue was purified by PTLC (EtOAc/hexane=1:1, DCM/EtOAc=1:1) to afford desired product (11.3 mg, 21.2%) as white solid. 1HNMR (CDCl3) 500 MHz δ: 8.27 (dd, J=7.7, 1.7 Hz, 1H), 8.08-8.02 (m, 1H), 7.75-7.68 (m, 1H), 7.52-7.38 (m, 5H), 7.37-7.25 (m, 3H), 7.20-7.14 (m, 1H), 6.98 (d, J=8.0 Hz, 1H), 6.92-6.81 (m, 1H), 6.63 (dd, J=8.0, 4.6 Hz, 1H), 6.45 (s, 1H), 5.20 (s, 1H), 2.68-2.25 (m, 4H), 2.22-2.09 (m, 1H), 1.97-1.86 (m, 1H), 1.54-1.11 (m, 9H).