Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[C:10]([CH2:17][C@@H:18]([C:30]([O:32][C:33]([CH3:36])([CH3:35])[CH3:34])=[O:31])[N:19]2[CH:24]=[CH:23][CH:22]=[C:21]([C:25]([O:27]C)=[O:26])[C:20]2=[O:29])=[CH:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[OH-].[Li+].Cl>O1CCOCC1.O>[C:1]([O:5][C:6]([N:8]1[C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[C:10]([CH2:17][C@@H:18]([C:30]([O:32][C:33]([CH3:36])([CH3:35])[CH3:34])=[O:31])[N:19]2[CH:24]=[CH:23][CH:22]=[C:21]([C:25]([OH:27])=[O:26])[C:20]2=[O:29])=[CH:9]1)=[O:7])([CH3:3])([CH3:4])[CH3:2]
Reactant: COC(=O)c1cccn([C@@H](Cc2cn(C(=O)OC(C)(C)C)c3ccccc23)C(=O)OC(C)(C)C)c1=O
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: C1COCCO1
Solvent: O
Product: CC(C)(C)OC(=O)[C@H](Cc1cn(C(=O)OC(C)(C)C)c2ccccc12)n1cccc(C(=O)O)c1=O
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of (S)-3-[2-tert-Butoxycarbonyl-2-(3-methoxycarbonyl-2-oxo-2H-pyridin-1-yl)-ethyl]-indole-1-carboxylic acid tert-butyl ester (2.3 g, 4.7 mmol) in dioxane (60 ml) was added a lithium hydroxide (115 mg, 4.7 mmol) in water (30 ml). The mixture was stirred overnight at room temperature. The mixture was diluted with water, acidified to pH-3 with 1M HCl and extracted with ethylacetate. The organic layer was washed with brine, dried (MgSO4), filtered and evaporated to afford the crude product as a white solid was used in the next stage without further purification (1.9 g, 85%); 1H NMR (400 MHz, CDCl3) δ 1.45 (9H, s), 1.74 (9H, s), 3.50 (2H, m), 5.65 (1H, br s), 6.08 (1H, t), 7.2-7.5 (5H, m), 8.15 (2H, m);
Reaction SMILES: Cl[C:2]1[N:23]=[C:5]2[C:6]([NH:10][C:11]3[C:12]([N:17]([CH3:22])[S:18]([CH3:21])(=[O:20])=[O:19])=[N:13][CH:14]=[CH:15][CH:16]=3)=[CH:7][CH:8]=[CH:9][N:4]2[N:3]=1.[CH3:24][N:25]1[CH2:30][CH2:29][N:28]([C:31]2[CH:32]=[C:33]([CH:35]=[CH:36][CH:37]=2)[NH2:34])[CH2:27][CH2:26]1.C1(P(C2CCCCC2)C2C=CC=CC=2C2C=CC=CC=2P(C2CCCCC2)C2CCCCC2)CCCCC1>>[CH3:22][N:17]([C:12]1[C:11]([NH:10][C:6]2[C:5]3[N:4]([N:3]=[C:2]([NH:34][C:33]4[CH:35]=[CH:36][CH:37]=[C:31]([N:28]5[CH2:27][CH2:26][N:25]([CH3:24])[CH2:30][CH2:29]5)[CH:32]=4)[N:23]=3)[CH:9]=[CH:8][CH:7]=2)=[CH:16][CH:15]=[CH:14][N:13]=1)[S:18]([CH3:21])(=[O:20])=[O:19]
Reactant: CN1CCN(c2cccc(N)c2)CC1
Reactant: CN(c1ncccc1Nc1cccn2nc(Cl)nc12)S(C)(=O)=O
Agent: c1ccc(P(C2CCCCC2)C2CCCCC2)c(-c2ccccc2P(C2CCCCC2)C2CCCCC2)c1
Product: CN1CCN(c2cccc(Nc3nc4c(Nc5cccnc5N(C)S(C)(=O)=O)cccn4n3)c2)CC1

Procedure:
N-Methyl-N-(3-{2-[3-(4-methyl-piperazin-1-yl)-phenylamino]-[1,2,4]triazolo[1,5-a]pyridin-8-ylamino}-pyridin-2-yl)-methanesulfonamide was prepared from N-[3-(2-chloro-[1,2,4]triazolo[1,5-a]pyridin-8-ylamino)-pyridin-2-yl]-N-methyl-methanesulfonamide (75.0 mg, 0.212 mmol) and 3-(4-methylpiperazin-1-yl)aniline (45.0 mg, 0.235 mmol) with 2,2′-bis-dicyclohexylphosphanyl-biphenyl (23.0 mg, 0.0421 mmol) as the ligand in a manner analogous to Example 2d. Product isolated as a brown foam (0.017 g, 16%). 1H NMR (400 MHz, CDCl3, δ, ppm): 8.11-8.06 (m, 2H), 7.78 (d, J=7.5 Hz, 1H), 7.52 (s, 1H), 7.28-7.19 (m, 3H), 7.12 (d, J=7.5 Hz, 1H), 7.06 (d, J=7.9 Hz, 1H), 6.84 (s, 1H), 6.78-6.73 (m, 1H), 6.57 (d, J=8.0 Hz, 1H), 3.32 (s, 3H), 3.29-3.24 (m, 4H), 3.09 (s, 3H), 2.62-2.57 (m, 4H), 2.36 (s, 3H). MS=518 (MH)+.
Reaction SMILES: N(OCCC(C)C)=O.N[C:10]1[C:15]([O:16][C:17]2[C:18]([O:23][CH2:24][C:25]([O:27][CH3:28])=[O:26])=[N:19][CH:20]=[CH:21][CH:22]=2)=[CH:14][C:13]([NH:29][C:30](=[O:32])[CH3:31])=[C:12]([F:33])[CH:11]=1.[ClH:34]>C(#N)C.[Cu]Cl.[Cu](Cl)Cl>[Cl:34][C:10]1[C:15]([O:16][C:17]2[C:18]([O:23][CH2:24][C:25]([O:27][CH3:28])=[O:26])=[N:19][CH:20]=[CH:21][CH:22]=2)=[CH:14][C:13]([NH:29][C:30](=[O:32])[CH3:31])=[C:12]([F:33])[CH:11]=1
Reactant: COC(=O)COc1ncccc1Oc1cc(NC(C)=O)c(F)cc1N
Reactant: Cl
Agent: Cl[Cu]
Agent: Cl[Cu]Cl
Agent: CC(C)CCON=O
Solvent: CC#N
Product: COC(=O)COc1ncccc1Oc1cc(NC(C)=O)c(F)cc1Cl
Reaction time: 1 h

Procedure:
A solution of 2.01 g of isoamyl nitrite in 1 ml of acetonitrile was added to a mixture of 2.0 g of N-[4-amino-2-fluoro-5-{2-(methoxycarbonyl)methoxy-3-pyridyl oxy}phenyl]acetamide, 1.13 g of copper(I) chloride, 2.31 g of copper(II) chloride and 20 ml of acetonitrile dropwise at room temperature, and the mixture was stirred for 1 hour. This reaction solution was poured into 2% hydrochloric acid, and extracted with ethyl acetate. The organic layer was washed with saturated saline, dried over anhydrous magnesium sulfate, and concentrated. The residue was subjected to silica gel column chromatography to obtain 1.04 g of N-[4-chloro-2-fluoro-5-{2-(methoxycarbonyl)methoxy-3-pyridyloxy}phenyl]acetamide.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:8]2[CH:16]=[CH:15][CH:14]=[C:13]3[C:9]=2[CH2:10][C:11](=[O:17])[NH:12]3)[CH:5]=[CH:6][CH:7]=1.[N:18]1([CH2:23][CH2:24][NH:25][C:26]([C:28]2[C:32]([CH3:33])=[C:31]([CH:34]=O)[NH:30][C:29]=2[CH3:36])=[O:27])[CH2:22][CH2:21][CH2:20][CH2:19]1>C(O)C.N1CCCCC1>[N:18]1([CH2:23][CH2:24][NH:25][C:26]([C:28]2[C:32]([CH3:33])=[C:31]([CH:34]=[C:10]3[C:9]4[C:13](=[CH:14][CH:15]=[CH:16][C:8]=4[C:4]4[CH:5]=[CH:6][CH:7]=[C:2]([Cl:1])[CH:3]=4)[NH:12][C:11]3=[O:17])[NH:30][C:29]=2[CH3:36])=[O:27])[CH2:22][CH2:21][CH2:20][CH2:19]1
Reactant: O=C1Cc2c(cccc2-c2cccc(Cl)c2)N1
Reactant: Cc1[nH]c(C=O)c(C)c1C(=O)NCCN1CCCC1
Solvent: C1CCNCC1
Solvent: CCO
Product: Cc1[nH]c(C=C2C(=O)Nc3cccc(-c4cccc(Cl)c4)c32)c(C)c1C(=O)NCCN1CCCC1
Temperature: 25 °C
Reaction time: 72 h
Yield: 61.3 %

Procedure:
To a solution of 4-(3-chloro-phenyl)-1,3-dihydro-indol-2-one (60.9 mg, 0.25 mmol) and 5-formyl-2,4-dimethyl-1H-pyrrole-3-carboxylic acid (2-pyrrolidin-1-yl-ethyl)-amide (68.5 mg, 0.26 mmol) in ethanol (2 mL) was added piperidine (3 drops). The reaction mixture was stirred at room temperature for three days. The reaction solution was evaporated, and purified on a silica gel column eluting with MeOH—CH2Cl2 5:95 to provide pure product 5-[4-(3-chloro-phenyl)-2-oxo-1,2-dihydro-indol-3-ylidenemethyl]-2,4-dimethyl-1H-pyrrole-3-carboxylic acid (2-pyrrolidin-1-yl-ethyl)-amide as a yellow solid (75 mg, 61%).
Reaction SMILES: [Br:1][C:2]1[CH:11]=[CH:10][C:9]([Cl:12])=[CH:8][C:3]=1[C:4]([O:6][CH3:7])=[O:5].OS(O)(=O)=O.[N+:18]([O-])([OH:20])=[O:19]>CCOC(C)=O>[Br:1][C:2]1[C:11]([N+:18]([O-:20])=[O:19])=[CH:10][C:9]([Cl:12])=[CH:8][C:3]=1[C:4]([O:6][CH3:7])=[O:5]
Reactant: O=[N+]([O-])O
Reactant: COC(=O)c1cc(Cl)ccc1Br
Agent: O=S(=O)(O)O
Solvent: CCOC(C)=O
Product: COC(=O)c1cc(Cl)cc([N+](=O)[O-])c1Br
Temperature: 0 °C
Reaction time: 1.5 h
Yield: 101.9 %

Procedure:
A solution of methyl 2-bromo-5-chlorobenzoate (10 g, 40 mmol) in concentrated H2SO4 (48 ml, 910 mmol) was cooled to −5° C. in an acetone/ice bath in air. A mixture of concentrated nitric acid (3.35 ml, 52 mmol) and concentrated H2SO4 (3.4 ml, 64 mmol) was added dropwise to the reaction mixture at 0° C. over 30 minutes. The yellow reaction mixture was stirred at 0° C. for 1.5 hours before being poured onto ice. EtOAc (150 ml) was added and the phases were separated. The organic phase was washed with deionized water (3×50 ml) followed by brine (50 ml). The organic phase was dried over MgSO4, filtered and concentrated under reduced pressure to give 12.0 g (60%) of the title compound material as a pale yellow oil which solidified upon standing. This material contained 40% of the 6-nitro isomer. This material was used without further purification. LC-MS 91%, m/z=no ionisation, 1H NMR (500 MHz, Chloroform-d) δ 7.86 (1H, d, J=2.52 Hz), 7.77 (1H, d, J=2.52 Hz), 3.99 (3H, s).
Reaction SMILES: [F:1][C:2]1([F:14])[CH2:8][CH2:7][C:6]2[CH:9]=[C:10]([NH2:13])[CH:11]=[CH:12][C:5]=2[CH2:4][CH2:3]1.Cl[C:16]1[N:21]=[C:20]([NH:22][C@@H:23]2[CH2:28][CH2:27][CH2:26][CH2:25][C@H:24]2[NH:29][S:30]([CH3:33])(=[O:32])=[O:31])[C:19]([Cl:34])=[CH:18][N:17]=1.C(O)(C)C.Cl.O1CCOCC1>>[Cl:34][C:19]1[C:20]([NH:22][C@@H:23]2[CH2:28][CH2:27][CH2:26][CH2:25][C@H:24]2[NH:29][S:30]([CH3:33])(=[O:32])=[O:31])=[N:21][C:16]([NH:13][C:10]2[CH:11]=[CH:12][C:5]3[CH2:4][CH2:3][C:2]([F:14])([F:1])[CH2:8][CH2:7][C:6]=3[CH:9]=2)=[N:17][CH:18]=1
Reactant: CS(=O)(=O)N[C@@H]1CCCC[C@H]1Nc1nc(Cl)ncc1Cl
Reactant: Nc1ccc2c(c1)CCC(F)(F)CC2
Agent: Cl
Solvent: C1COCCO1
Solvent: CC(C)O
Product: CS(=O)(=O)N[C@@H]1CCCC[C@H]1Nc1nc(Nc2ccc3c(c2)CCC(F)(F)CC3)ncc1Cl
Reaction time: 0.17 h
Yield: 50 %

Procedure:
Into a microwave vial was placed 7,7-difluoro-6,7,8,9-tetrahydro-5H-benzocyclohepten-2-ylamine (79 mg, 0.00040 mol) and N-[(1R,2R)-2-(2,5-dichloro-pyrimidin-4-ylamino)-cyclohexyl]-methanesulfonamide (100 mg, 0.0003 mol) in isopropyl alcohol (4 mL, 0.05 mol) with 4N HCl-dioxane (0.04 g, 0.0003 mol). The reaction was subjected to microwaves at 120° C. for 10 min. HPLC and LCMS indicated trace starting material remaining. The reaction mixture was resubjected to microwaves for an additional 10 min. A tan solid had precipitated out of solution and was collected by filtration. The solid was redissolved in methylene chloride (5 mL) and washed with sat. sodium bicarbonate (1×5 mL) and water (2×5 mL). The organic phase was dried over magnesium sulfate, filtered and concentrated in vacuo to give N-{(1R,2R)-2-[5-Chloro-2-(7,7-difluoro-6,7,8,9-tetrahydro-5H-benzocyclohepten-2-ylamino)-pyrimidin-4-ylamino]-cyclohexyl}-methanesulfonamide as a brown solid (75 mg, 40%). MP: 118-128° C.; 1HNMR (400 MHz, DMSO-d6) δ 9.16 (s, 1H), 7.93 (s, 1H), 7.62 (s, 1H), 7.46 (d, 1H, J=8 Hz), 7.18 (d, 1H, J=8 Hz), 7.07 (d, 1H, J=8 Hz), 6.71 (d, 1H, J=8 Hz), 3.84 (m, 1H), 2.94 (s, 3H), 2.70 (m, 4H), 1.99-2.09 (m, 6H), 1.71 (m, 2H), 1.18-1.39 (m, 5H); MS (m/e) 500 (M+1).
Reaction SMILES: C(O[C:4](=[C:11]1[C:19]2[C:14](=[CH:15][CH:16]=[C:17]([N+:20]([O-:22])=[O:21])[CH:18]=2)[NH:13][C:12]1=[O:23])[C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1)C.[CH3:24][CH:25]1[CH2:30][CH2:29][N:28]([CH2:31][C:32]2[CH:38]=[CH:37][C:35]([NH2:36])=[CH:34][CH:33]=2)[CH2:27][CH2:26]1>CN(C=O)C>[CH3:24][CH:25]1[CH2:30][CH2:29][N:28]([CH2:31][C:32]2[CH:33]=[CH:34][C:35]([NH:36]/[C:4](=[C:11]3\[C:12](=[O:23])[NH:13][C:14]4[C:19]\3=[CH:18][C:17]([N+:20]([O-:22])=[O:21])=[CH:16][CH:15]=4)/[C:5]3[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=3)=[CH:37][CH:38]=2)[CH2:27][CH2:26]1
Reactant: CC1CCN(Cc2ccc(N)cc2)CC1
Reactant: CCOC(=C1C(=O)Nc2ccc([N+](=O)[O-])cc21)c1ccccc1
Solvent: CN(C)C=O
Product: CC1CCN(Cc2ccc(N/C(=C3\C(=O)Nc4ccc([N+](=O)[O-])cc43)c3ccccc3)cc2)CC1

Procedure:
Prepared analogously to Example 89 from 3-(1-ethoxy-1-phenyl-methylidene)-5-nitro-2-indolinone and 4-(4-methylpiperidinomethyl)-aniline in DMF.
Reaction SMILES: O=[C:2]([CH2:8][CH2:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)[C:3]([O:5][CH2:6][CH3:7])=[O:4].[NH2:16][C@H:17]([C:19]([N:21]1[CH2:28][CH2:27][CH2:26][C@H:22]1[C:23]([OH:25])=[O:24])=[O:20])[CH3:18].C([BH3-])#N.[Na+]>C(O)C.O>[CH2:6]([O:5][C:3]([CH:2]([NH:16][C@H:17]([C:19]([N:21]1[CH2:28][CH2:27][CH2:26][C@H:22]1[C:23]([OH:25])=[O:24])=[O:20])[CH3:18])[CH2:8][CH2:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)=[O:4])[CH3:7]
Reactant: C[C@H](N)C(=O)N1CCC[C@H]1C(=O)O
Reactant: CCOC(=O)C(=O)CCc1ccccc1
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: O
Solvent: CCO
Product: CCOC(=O)C(CCc1ccccc1)N[C@@H](C)C(=O)N1CCC[C@H]1C(=O)O
Yield: 65.1 %

Procedure:
Ethyl 2-oxo-4-phenylbutyrate (1.03 g) and L-alanyl-L-proline (0.19 g) are dissolved in a 1:1 ethanol-water solvent. A solution of sodium cyanoborohydride (0.19 g) in ethanol-water is added dropwise at room temperature over the course of two hours. When reaction is complete, the product is absorbed on strong acid ion-exchange resin and eluted with 2% pyridine in water. The product-rich cuts are freeze dried to give 0.25 g of crude N-(1-ethoxycarbonyl-3-phenylpropyl)-L-alanyl-L-proline. The mass spectrum shows a molecular ion at 448 m/e for the monosilylated species. Chromatography affords the desired isomer.
Reaction SMILES: [CH3:1][N:2]([S:15]([C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=1[C:24]([F:27])([F:26])[F:25])(=[O:17])=[O:16])[C:3]1[CH:4]=[CH:5][CH:6]=[C:7]2[C:11]=1[NH:10][C:9]([C:12](O)=[O:13])=[CH:8]2.C[N:29](C)C=O.Cl.CN(C)CCCN=C=NCC>C(OCC)(=O)C>[CH3:1][N:2]([S:15]([C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=1[C:24]([F:26])([F:27])[F:25])(=[O:16])=[O:17])[C:3]1[CH:4]=[CH:5][CH:6]=[C:7]2[C:11]=1[NH:10][C:9]([C:12]([NH2:29])=[O:13])=[CH:8]2
Reactant: CN(c1cccc2cc(C(=O)O)[nH]c12)S(=O)(=O)c1ccccc1C(F)(F)F
Reactant: CN(C)C=O
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: CCOC(C)=O
Product: CN(c1cccc2cc(C(N)=O)[nH]c12)S(=O)(=O)c1ccccc1C(F)(F)F
Temperature: 25 °C
Yield: 98 %

Procedure:
To a mixture of 7-(methyl{[2-(trifluoromethyl)phenyl]sulfonyl}amino)-1H-indole-2-carboxylic acid (2.65 g), 1H-1,2,3-benzotriazol-1-ol-ammonia complex (1.3 g) and N,N-dimethylformamide (30 mL) was added N-[3-(dimethylamino)propyl]-N′-ethylcarbodiimide hydrochloride (1.7 g) under ice-cooling, and the mixture was stirred from under ice-cooling to room temperature for 18 hr. The reaction solution was diluted with ethyl acetate, washed with water, aqueous sodium hydrogencarbonate solution and saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The obtained colorless crystals were washed with ethyl acetate-hexane to give the title compound (2.6 g, yield 98%) as colorless crystals. MS: 398 (MH+). melting point 223-224° C.
Reaction SMILES: [C:1]([N:4]1[C:12]2[CH:11]=[CH:10][CH:9]=[C:8]3[CH:13]4[O:16][CH:14]4[CH2:15][CH:6]([C:7]=23)[CH:5]1[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=1[F:23])(=[O:3])[CH3:2].[Br-].[Mg+2].[Br-]>C1(C)C=CC=CC=1.O>[C:1]([N:4]1[C:12]2[CH:11]=[CH:10][CH:9]=[C:8]3[CH2:13][C:14](=[O:16])[CH2:15][CH:6]([C:7]=23)[CH:5]1[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=1[F:23])(=[O:3])[CH3:2]
Reactant: CC(=O)N1c2cccc3c2C(CC2OC32)C1c1ccccc1F
Agent: [Br-]
Agent: [Mg+2]
Solvent: O
Solvent: Cc1ccccc1
Product: CC(=O)N1c2cccc3c2C(CC(=O)C3)C1c1ccccc1F
Yield: 103.8 %

Procedure:
A portion (0.53 g) of the compound obtained in Example 250 was dissolved in anhydrous toluene (100 ml) and to the solution was added magnesium bromide etherate (5.54 g). The mixture was heated to reflux for 4 hours and allowed to cool. The reaction mixture was diluted with water and extracted twice with ethyl acetate. The organic layers were combined, washed with saturated aqueous solution of sodium chloride and dried over anhydrous sodium sulfate. Then, the solvent was distilled off under reduced pressure to yield 0.55 g of the titled compound as a crude yellow solid. The compound was used in the subsequent reaction without further purification.
Reaction SMILES: [C:1]([C:4]1[N:5]=[C:6]([CH2:9][CH:10]([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[CH2:11][C:12]([O:14][CH2:15][CH3:16])=[O:13])[O:7][CH:8]=1)([OH:3])=O.C(N1C=CN=C1)(N1C=CN=C1)=O.CCN(CC)CC.Cl.Cl.[NH2:44][CH2:45][CH2:46][CH2:47][NH:48][C:49]1[CH:54]=[CH:53][CH:52]=[CH:51][N:50]=1>C(Cl)Cl>[C:17]1([CH:10]([CH2:9][C:6]2[O:7][CH:8]=[C:4]([C:1]([NH:44][CH2:45][CH2:46][CH2:47][NH:48][C:49]3[CH:54]=[CH:53][CH:52]=[CH:51][N:50]=3)=[O:3])[N:5]=2)[CH2:11][C:12]([O:14][CH2:15][CH3:16])=[O:13])[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1
Reactant: NCCCNc1ccccn1
Reactant: CCOC(=O)CC(Cc1nc(C(=O)O)co1)c1ccccc1
Agent: Cl
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCOC(=O)CC(Cc1nc(C(=O)NCCCNc2ccccn2)co1)c1ccccc1
Reaction time: 2 h
Yield: 90.9 %

Procedure:
To a solution of ethyl (±)-4-(4-carboxy-1,3-oxazol-2-yl)-3-phenylbutanoate (100 mg, 0.33 mmole) in CH2Cl2 (2 mL) was added 1,1′-carbonyldiimidazole (80 mg, 0.49 mmole). After 2 hr, Et3N (0.14 mL, 0.98 mmole) and 2-[(3-amino-1-propyl)amino]pyridine dihydrochloride (110 mg, 0.49 mmole) were added. After 4 h, the mixture was concentrated under reduced pressure. The residue was chromatographed on silica gel (75% EtOAc/hexanes) to give the title compound (131 mg, 91%) as a yellow oil: MS (ES) m/e 437 (M+H)+.
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](=[O:25])[C:14]2[CH:19]=[CH:18][C:17]([C:20]([CH3:24])([CH3:23])[CH2:21][OH:22])=[CH:16][CH:15]=2)[CH:3]=1.[C:26]1(B(O)O)[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1>CO.Cl[Pd]Cl.C1(P(C2C=CC=CC=2)[C-]2C=CC=C2)C=CC=CC=1.[C-]1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=C1.[Fe+2]>[OH:22][CH2:21][C:20]([C:17]1[CH:18]=[CH:19][C:14]([C:13]([NH:12][C:4]2[CH:3]=[C:2]([C:26]3[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=3)[N:7]3[N:8]=[C:9]([CH3:11])[CH:10]=[C:6]3[N:5]=2)=[O:25])=[CH:15][CH:16]=1)([CH3:24])[CH3:23]
Reactant: Cc1cc2nc(NC(=O)c3ccc(C(C)(C)CO)cc3)cc(Cl)n2n1
Reactant: OB(O)c1ccccc1
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: c1ccc(P(c2ccccc2)[c-]2cccc2)cc1
Solvent: CO
Product: Cc1cc2nc(NC(=O)c3ccc(C(C)(C)CO)cc3)cc(-c3ccccc3)n2n1
Temperature: 110 °C
Yield: 49 %

Procedure:
A suspension of N-(7-chloro-2-methylpyrazolo[1,5-a]pyrimidin-5-yl)-4-(1-hydroxy-2-methylpropan-2-yl)benzamide (4G, 44 mg, 1.0 equivalent), phenylboronic acid (1.5 equivalents) and [1,1′-bis(diphenylphosphino)ferrocene] dichloropalladium(II) (0.09 equivalents) in 2:1 dioxane/saturated aqueous NaHCO3 (0.125 M with respect to 4G) was warmed to 110° C. in a microwave reactor. The reaction mixture was cooled to room temperature, diluted with methanol, filtered, and purified via preparative HPLC to afford the title compound (49%) as a yellow solid. 1H NMR (400 MHz, DMSO-d6) δ ppm 1.26 (s, 6 H), 2.40 (s, 3 H), 3.47 (s, 2 H), 4.76 (br. s., 1 H), 6.40 (s, 1 H), 7.53 (d, J=8.59 Hz, 2 H), 7.58-7.68 (m, 3 H), 7.94-8.04 (m, 3 H), 8.04-8.10 (m, 2 H), 11.19 (s, 1 H). ESI-MS: m/z 401.1 (M+H)+.
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][CH:4]([CH2:7][N:8]2[CH2:20][CH2:19][C:18]3[C:17]4[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=4)[NH:11][C:10]=3[CH2:9]2)[CH2:3][CH2:2]1.C(N(CC)CC)C.Cl[C:29]([O:31][CH2:32][CH3:33])=[O:30]>C(Cl)(Cl)Cl>[CH2:9]1[C:10]2[NH:11][C:12]3[C:17]([C:18]=2[CH2:19][CH2:20][N:8]1[CH2:7][CH:4]1[CH2:5][CH2:6][N:1]([C:29]([O:31][CH2:32][CH3:33])=[O:30])[CH2:2][CH2:3]1)=[CH:16][CH:15]=[CH:14][CH:13]=3
Reactant: c1ccc2c3c([nH]c2c1)CN(CC1CCNCC1)CC3
Reactant: CCOC(=O)Cl
Solvent: CCN(CC)CC
Solvent: ClC(Cl)Cl
Product: CCOC(=O)N1CCC(CN2CCc3c([nH]c4ccccc34)C2)CC1

Procedure:
7.06 g (26.2 mmol) of 2-[(4-piperidyl)methyl]-1,2,3,4-tetrahydro-9H-pyrido[3,4-b]indole, 70 ml of chloroform and 4 ml (26.2 mmol) of triethylamine are introduced under an argon atmosphere into a Keller flask, and 2.8 ml (26.2 mmol) of ethyl chloroformate are added.
Reaction SMILES: [O:1]1[CH2:6][CH2:5][N:4]([CH2:7][CH2:8][NH2:9])[CH2:3][CH2:2]1.[Cl:10][C:11]1[CH:16]=[C:15](Cl)[CH:14]=[CH:13][C:12]=1[N+:18]([O-:20])=[O:19].C([O-])([O-])=O.[Cs+].[Cs+]>C(#N)C>[Cl:10][C:11]1[CH:16]=[C:15]([CH:14]=[CH:13][C:12]=1[N+:18]([O-:20])=[O:19])[NH:9][CH2:8][CH2:7][N:4]1[CH2:5][CH2:6][O:1][CH2:2][CH2:3]1
Reactant: O=[N+]([O-])c1ccc(Cl)cc1Cl
Reactant: NCCN1CCOCC1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CC#N
Product: O=[N+]([O-])c1ccc(NCCN2CCOCC2)cc1Cl
Temperature: 25 °C
Yield: 50.4 %

Procedure:
A suspension of 2-morpholinoethanamine (5.34 g, 41 mmol), 2,4-dichloro-1-nitrobenzene (7.87 g, 41 mmol) and Cs2CO3 (26.73 g, 82 mmol) in acetonitrile (100 mL) was refluxed for 6 h under N2, then cooled to rt, filtered and concentrated in vacuo. The residue was purified by a silica gel column chromatography (PE/EtOAc (V/V)=4:1) to give the title compound as a yellow solid (5.90 g, 50%).
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][N:11]([S:14]([C:17]2[CH:18]=[C:19]3[C:24](=[CH:25][CH:26]=2)[CH:23]=[N:22][CH:21]=[CH:20]3)(=[O:16])=[O:15])[CH2:10][CH2:9]1)=O)(C)(C)C.[ClH:27].O1CCOCC1>ClCCl>[ClH:27].[ClH:27].[N:11]1([S:14]([C:17]2[CH:18]=[C:19]3[C:24](=[CH:25][CH:26]=2)[CH:23]=[N:22][CH:21]=[CH:20]3)(=[O:16])=[O:15])[CH2:12][CH2:13][NH:8][CH2:9][CH2:10]1
Reactant: CC(C)(C)OC(=O)N1CCN(S(=O)(=O)c2ccc3cnccc3c2)CC1
Agent: Cl
Solvent: ClCCl
Solvent: C1COCCO1
Product: O=S(=O)(c1ccc2cnccc2c1)N1CCNCC1

Procedure:
150 mg of 6-(4-tert-butoxycarbonylpiperazin-1-ylsulfonyl)isoquinoline was dissolved in 10 mL of dichloromethane, and 1 mL of 4 M hydrochloric acid-dioxane solution was added dropwise thereto with stirring and then reacted at room temperature for 3 hours. From the reaction solution, the solvent was distilled off, and the obtained residue was dissolved in 0.5 mL of methanol. Then, 5 mL of ethyl acetate was added with vigorous stirring, and the deposited white crystal was collected by filtration and dried to obtain 35 mg of the compound of interest as a white crystal (25%).
Reaction SMILES: [CH2:1]1[C:9]2[C:8]3[CH:10]=[CH:11][CH:12]=[CH:13][C:7]=3[O:6][C:5]=2[CH2:4][CH2:3][CH:2]1[NH2:14].[N+:15]([C:18]1[CH:26]=[CH:25][C:21]([C:22](Cl)=[O:23])=[CH:20][CH:19]=1)([O-:17])=[O:16].C(N(CC)CC)C>O1CCCC1>[N+:15]([C:18]1[CH:19]=[CH:20][C:21]([C:22]([NH:14][C:2]2[CH:3]=[CH:4][C:5]3[O:6][C:7]4[CH2:13][CH2:12][CH2:11][CH2:10][C:8]=4[C:9]=3[CH:1]=2)=[O:23])=[CH:25][CH:26]=1)([O-:17])=[O:16]
Reactant: O=C(Cl)c1ccc([N+](=O)[O-])cc1
Reactant: NC1CCc2oc3ccccc3c2C1
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: O=C(Nc1ccc2oc3c(c2c1)CCCC3)c1ccc([N+](=O)[O-])cc1
Yield: 81.3 %

Procedure:
Following the procedure of Example 1, tetrahydro-dibenzofuran-2-ylamine (2.8 g, 15 mmol), 4-nitrobenzoyl chloride (3.0 g, 16 mmol), and triethylamine (6.4 mL, 45 mmol) in tetrahydrofuran (60 mL) provided 4-nitro-N-(6,7,8,9-tetrahydro-dibenzofuran-2-yl)-benzamide (4.1 g). Mp 279-280° C.;Anal. Calcd. for C19H16N2O4: C, 67.85; H, 4.79; N, 8.33; Found: C, 67.69; H, 4.61; N, 8.26.
Reaction SMILES: [C:1]([C:5]1[CH:50]=[CH:49][C:8]2[N:9]([CH2:41][O:42][CH2:43][CH2:44][Si:45]([CH3:48])([CH3:47])[CH3:46])[C:10]([CH2:12][CH2:13][CH2:14][CH2:15][NH:16][CH2:17][C@@H:18]3[C@H:22]4[O:23][C:24]([CH3:27])([CH3:26])[O:25][C@H:21]4[C@H:20]([N:28]4[C:32]5[N:33]=[CH:34][N:35]=[C:36]([NH:37][CH:38]6[CH2:40][CH2:39]6)[C:31]=5[CH:30]=[CH:29]4)[CH2:19]3)=[N:11][C:7]=2[CH:6]=1)([CH3:4])([CH3:3])[CH3:2].CCN(CC)CC.[CH3:58][S:59](Cl)(=[O:61])=[O:60]>C(Cl)Cl>[CH:38]1([NH:37][C:36]2[C:31]3[CH:30]=[CH:29][N:28]([C@H:20]4[C@@H:21]5[O:25][C:24]([CH3:27])([CH3:26])[O:23][C@@H:22]5[C@@H:18]([CH2:17][N:16]([CH2:15][CH2:14][CH2:13][CH2:12][C:10]5[N:9]([CH2:41][O:42][CH2:43][CH2:44][Si:45]([CH3:48])([CH3:47])[CH3:46])[C:8]6[CH:49]=[CH:50][C:5]([C:1]([CH3:2])([CH3:3])[CH3:4])=[CH:6][C:7]=6[N:11]=5)[S:59]([CH3:58])(=[O:61])=[O:60])[CH2:19]4)[C:32]=3[N:33]=[CH:34][N:35]=2)[CH2:40][CH2:39]1
Reactant: CC1(C)O[C@@H]2[C@@H](CNCCCCc3nc4cc(C(C)(C)C)ccc4n3COCC[Si](C)(C)C)C[C@@H](n3ccc4c(NC5CC5)ncnc43)[C@@H]2O1
Reactant: CS(=O)(=O)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC1(C)O[C@@H]2[C@@H](CN(CCCCc3nc4cc(C(C)(C)C)ccc4n3COCC[Si](C)(C)C)S(C)(=O)=O)C[C@@H](n3ccc4c(NC5CC5)ncnc43)[C@@H]2O1
Reaction time: 3 h
Yield: 48.5 %

Procedure:
7-[(3aS,4R,6R,6aR)-6-({[4-(5-tert-Butyl-1-{[2-(trimethylsilyl)ethoxy]methyl}-1H-1,3-benzodiazol-2-yl)butyl]amino}methyl)-2,2-dimethyl-hexahydrocyclopenta[d][1,3]dioxol-4-yl]-N-cyclopropyl-7H-pyrrolo[2,3-d]pyrimidin-4-amine (0.052 g, 0.074 mmol) was dissolved in dry DCM (1 ml) and dry Et3N (0.02 ml, 0.148 mmol) and methanesulfonyl chloride (0.01 ml, 0.089 mmol) was added dropwise at r.t. under N2. The reaction was left for 3 hrs after which time LCMS analysis showed the reaction had gone to −80% completion. The reaction was concentrated in vacuo and purified by UV directed prep HPLC to give the product as a white solid (0.028 g, 48%): MS (ESI+) for C40H61N7O5SSi m/z 391.3 [M+2H]2+, 780.1 [M+H]+; LC purity 83% (UV), 100% ELS (ret. time, 1.80 min); 1H NMR (500 MHz, CDCl3) δ 8.29 (s, 1H), 7.59-7.79 (m, 1H), 7.29-7.45 (m, 2H), 6.97 (d, J=3.63 Hz, 1H), 6.64 (br. s., 1H), 5.50 (s, 2H), 4.88-5.06 (m, 2H), 4.58 (br. s., 1H), 3.51-3.60 (m, 2H), 3.39-3.51 (m, 1H), 3.32 (br. s., 3H), 2.98 (br. s., 3H), 2.84-2.92 (m, 3H), 2.46 (br. s., 2H), 2.16 (d, J=11.66 Hz, 1H), 1.90-2.02 (m, 2H), 1.77-1.89 (m, 2H), 1.48-1.58 (m, 3H), 1.33-1.44 (m, 9H), 1.20-1.32 (m, 4H), 0.83-0.99 (m, 4H), 0.61-0.78 (m, 2H), −0.12-0.03 (m, 9H).