Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C([C:3]([C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][N:27]=1)([C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][N:21]=1)[CH2:4][CH2:5][N:6]1[CH2:11][CH2:10][N:9]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=2[O:18][CH3:19])[CH2:8][CH2:7]1)#N.S(=O)(=O)(O)O.O.[OH-].[Na+]>C(OCC)(=O)C>[N:21]1[CH:22]=[CH:23][CH:24]=[CH:25][C:20]=1[CH:3]([C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][N:27]=1)[CH2:4][CH2:5][N:6]1[CH2:11][CH2:10][N:9]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=2[O:18][CH3:19])[CH2:8][CH2:7]1
Reactant: COc1ccccc1N1CCN(CCC(C#N)(c2ccccn2)c2ccccn2)CC1
Agent: O=S(=O)(O)O
Agent: [Na+]
Agent: [OH-]
Solvent: CCOC(C)=O
Solvent: O
Product: COc1ccccc1N1CCN(CCC(c2ccccn2)c2ccccn2)CC1
Temperature: 125 °C
Reaction time: 1.5 h
Yield: 81.6 %

Procedure:
A mixture of 2.44 g of compound of Example 6 and 12 mL of 70% sulphuric acid was stirred for 1.5 h at 125° C. The obtained reaction mixture was then cooled to room temperature, followed by careful pouring into 100 g of ice, dilution with water, alkalinization with 35% sodium hydroxide, and extraction with ethyl acetate (3×40 mL). The combined organic phases were then washed with water, dried on anhydrous sodium sulphate, and then evaporated to complete dryness under vacuum. The obtained crude was then purified by flash chromatography (ethyl acetate-2.2 N solution of ammonia in methanol 9.6:0.4). The recovered fractions were then evaporated to complete dryness, affording 1.87 g of the title product (82%).
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=O)=[C:4]([O:11][CH2:12][CH3:13])[CH:3]=1.C(OC([NH:21][CH2:22][C:23]1[CH:24]=[C:25]([CH2:31][CH:32]([O:36][CH:37]([CH3:39])[CH3:38])[C:33]([O-:35])=[O:34])[CH:26]=[CH:27][C:28]=1[O:29][CH3:30])=O)(C)(C)C>>[Cl:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([NH:21][CH2:22][C:23]2[CH:24]=[C:25]([CH2:31][CH:32]([O:36][CH:37]([CH3:39])[CH3:38])[C:33]([OH:35])=[O:34])[CH:26]=[CH:27][C:28]=2[O:29][CH3:30])=[O:8])=[C:4]([O:11][CH2:12][CH3:13])[CH:3]=1
Reactant: COc1ccc(CC(OC(C)C)C(=O)[O-])cc1CNC(=O)OC(C)(C)C
Reactant: CCOc1cc(Cl)ccc1C(=O)O
Product: CCOc1cc(Cl)ccc1C(=O)NCc1cc(CC(OC(C)C)C(=O)O)ccc1OC

Procedure:
Using 4-chloro-2-ethoxybenzoic acid and 3-[3-([(tert-butoxycarbonyl)amino)methyl]-4-methoxyphenyl]-2-isopropoxypropanoate, 3-(3-[(4-chloro-2-ethoxybenzoyl)amino]methyl-4-methoxyphenyl)-2-isopropoxypropanoic acid was obtained in the same method as in Example 38).
Reaction SMILES: [C:1]([C:4]1([O:9]/[N:10]=[C:11](/[C:16]2[O:17][CH:18]=[CH:19][CH:20]=2)\[C:12]([O:14][CH3:15])=[O:13])[CH2:8][CH2:7][CH2:6][CH2:5]1)([OH:3])=O.Cl.[O:22]([NH2:29])[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1>>[O:17]1[CH:18]=[CH:19][CH:20]=[C:16]1/[C:11](=[N:10]/[O:9][C:4]1([C:1](=[O:3])[NH:29][O:22][C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)[CH2:8][CH2:7][CH2:6][CH2:5]1)/[C:12]([O:14][CH3:15])=[O:13]
Reactant: NOc1ccccc1
Reactant: COC(=O)/C(=N\OC1(C(=O)O)CCCC1)c1ccco1
Agent: Cl
Product: COC(=O)/C(=N\OC1(C(=O)NOc2ccccc2)CCCC1)c1ccco1
Yield: 44 %

Procedure:
This compound prepared from methyl Z-2-(carboxycyclopent-1-yloxyimino)-2-(fur-2-yl)acetate and phenoxyamine hydrochloride as described in Preparation 7(c), was purified by chromatography on silica gel plates in ethyl acetate-light petroleum b.p. 40°-60° (3:1 v/v). τ(DMSO d6) 2.5-3.1 (phenyl), 7.7-8.1, 8.1-8.5 (cyclopentyl), 2.0, 3.28, 3.02 (furyl), 6.03 (methyl). Yield 44%
Reaction SMILES: [OH:1][C:2]1[C:10]2[N:9]=[C:8]([CH3:11])[N:7]([CH3:12])[C:6]=2[CH:5]=[C:4]([C:13]([N:15]([CH3:17])[CH3:16])=[O:14])[CH:3]=1.Cl[CH:19]1[C:28]2[C:23](=[CH:24][CH:25]=[CH:26][CH:27]=2)[CH2:22][O:21][CH2:20]1>>[CH2:22]1[C:23]2[C:28](=[CH:27][CH:26]=[CH:25][CH:24]=2)[CH:19]([O:1][C:2]2[C:10]3[N:9]=[C:8]([CH3:11])[N:7]([CH3:12])[C:6]=3[CH:5]=[C:4]([C:13]([N:15]([CH3:16])[CH3:17])=[O:14])[CH:3]=2)[CH2:20][O:21]1
Reactant: ClC1COCc2ccccc21
Reactant: Cc1nc2c(O)cc(C(=O)N(C)C)cc2n1C
Product: Cc1nc2c(OC3COCc4ccccc43)cc(C(=O)N(C)C)cc2n1C
Yield: 12 %

Procedure:
The title compound was prepared as a white solid in 12% yield (38 mg) from 4-hydroxy-N,N,1,2-tetramethyl-1H-benzimidazole-6-carboxamide (0.20 g, 0.85 mmol, WO 2004054984) and 4-chloro-3,4-dihydro-1H-isochromene (0.20 g, 1.2 mmol, STEP 1) by the same manner in STEP 1 of Example 1:
Reaction SMILES: [C:1]([CH:3]=[C:4]1[CH2:7][C:6]([C:14]([O:16][CH:17]([CH3:19])[CH3:18])=[O:15])([C:8]([O:10][CH:11]([CH3:13])[CH3:12])=[O:9])[CH2:5]1)#[N:2].[NH:20]1[CH:24]=[C:23]([C:25]2[C:26]3[CH:33]=[CH:32][N:31]([CH2:34][O:35][CH2:36][CH2:37][Si:38]([CH3:41])([CH3:40])[CH3:39])[C:27]=3[N:28]=[CH:29][N:30]=2)[CH:22]=[N:21]1.N12CCCN=C1CCCCC2>C(#N)C>[C:1]([CH2:3][C:4]1([N:20]2[CH:24]=[C:23]([C:25]3[C:26]4[CH:33]=[CH:32][N:31]([CH2:34][O:35][CH2:36][CH2:37][Si:38]([CH3:41])([CH3:40])[CH3:39])[C:27]=4[N:28]=[CH:29][N:30]=3)[CH:22]=[N:21]2)[CH2:5][C:6]([C:8]([O:10][CH:11]([CH3:12])[CH3:13])=[O:9])([C:14]([O:16][CH:17]([CH3:19])[CH3:18])=[O:15])[CH2:7]1)#[N:2]
Reactant: C[Si](C)(C)CCOCn1ccc2c(-c3cn[nH]c3)ncnc21
Reactant: CC(C)OC(=O)C1(C(=O)OC(C)C)CC(=CC#N)C1
Solvent: C1CCC2=NCCCN2CC1
Solvent: CC#N
Product: CC(C)OC(=O)C1(C(=O)OC(C)C)CC(CC#N)(n2cc(-c3ncnc4c3ccn4COCC[Si](C)(C)C)cn2)C1
Temperature: 50 °C
Yield: 17.2 %

Procedure:
Diisopropyl 3-(cyanomethylene)cyclobutane-1,1-dicarboxylate (2.65 g, 0.00999 mol) was combined with 4-(1H-pyrazol-4-yl)-7-[2-(trimethylsilyl)ethoxy]methyl-7H-pyrrolo[2,3-d]pyrimidine (1 g, 0.003 mol) in acetonitrile (10 mL) and 1,8-diazabicyclo[5.4.0]undec-7-ene (0.5 mL, 0.003 mol) was added under N2. The mixture was heated at 50° C. overnight. The reaction was concentrated and purified with Combiflash (silica gel, 0-50% EtOAc/Hex) to give the desired product (0.3 g) as colorless oil. LCMS calculated for C29H41N6O5Si(M+H): 581.3; Found: 581.4.
Reaction SMILES: [CH3:1][C:2]([O:5][C:6]([N:8]1[CH2:13][CH:12]=[C:11]([C:14]2[CH:19]=[CH:18][C:17]([NH2:20])=[CH:16][C:15]=2[F:21])[CH2:10][CH2:9]1)=[O:7])([CH3:4])[CH3:3]>CO.[Pd]>[CH3:4][C:2]([O:5][C:6]([N:8]1[CH2:9][CH2:10][CH:11]([C:14]2[CH:19]=[CH:18][C:17]([NH2:20])=[CH:16][C:15]=2[F:21])[CH2:12][CH2:13]1)=[O:7])([CH3:1])[CH3:3]
Reactant: CC(C)(C)OC(=O)N1CC=C(c2ccc(N)cc2F)CC1
Agent: [Pd]
Solvent: CO
Product: CC(C)(C)OC(=O)N1CCC(c2ccc(N)cc2F)CC1
Reaction time: 2 h

Procedure:
A mixture of 3,6-dihydro-4-[4-amino-2-fluorophenyl]-1(2H)-pyridinecarboxylic acid 1,1-dimethylethyl ester (EXAMPLE 20, Step 3, 11.44 g) and 10% palladium-on-carbon (4 g) in methanol (400 mL) in four Parr bottles is shaken on the Parr apparatus under a hydrogen atmosphere at 40 psi for two hours, the catalyst is removed by filtration through Celite, and the filtrate is concentrated under reduced pressure to give the 4-[4-amino-2-fluorophenyl]-1-piperidinecarboxylic acid 1,1-dimethylethyl ester intermediate. A mixture of this intermediate (11.17 g) and sodium bicarbonate (6.57 g) in dry tetrahydrofuran (390 mL) is treated with benzyl chloroformate (5.86 mL), and the resulting mixture is stirred at ambient temperature for 15 hours and washed with water (200 mL). The aqueous phase is extracted with methylene chloride (150 mL), and the combined organic phase is washed with saline (50 mL), dried over anhydrous sodium sulfate and concentrated under reduced pressure to give the crude product which is chromatographed on silica gel (70 - 230 mesh, 800 g), eluting with a gradient of ethyl acetate/hexane (15/85 - 25/75). Pooling and concentration of those fractions with an Rf =0.38 by TLC (ethyl acetate/hexane, 25/75) gives the title compound, mp 96-98° C.
Reaction SMILES: [Cl-].[Mg+2].[Cl-].[C:4]([O:10][CH3:11])(=[O:9])[CH2:5][C:6]([CH3:8])=[O:7].N1C=CC=CC=1.[Cl:18][C:19]1[CH:27]=[CH:26][CH:25]=[C:24]([F:28])C=1C(Cl)=O.S(=O)(=O)(O)O>C1(C)C=CC=CC=1.O.C(#N)C>[Cl:18][C:19]1[CH:27]=[CH:26][CH:25]=[C:24]([F:28])[C:8]=1[C:6](=[O:7])[CH2:5][C:4]([O:10][CH3:11])=[O:9]
Reactant: O=C(Cl)c1c(F)cccc1Cl
Reactant: COC(=O)CC(C)=O
Agent: O=S(=O)(O)O
Agent: [Cl-]
Agent: [Mg+2]
Solvent: CC#N
Solvent: Cc1ccccc1
Solvent: c1ccncc1
Product: COC(=O)CC(=O)c1c(F)cccc1Cl
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 78.1 %

Procedure:
To 7.4 g (77.7 mmol) of magnesium chloride and 9.02 g (116.1 mmol) of methyl acetoacetate was added 30 mL acetonitrile. The mixture was cooled in an ice bath and 12.6 mL (155.4 mmol) of pyridine was slowly added while keeping the temperature below 5° C. The reaction was removed from the ice bath and was stirred for 30 min. at room temperature. A solution of 15.0 g (77.7 mmol) 2-chloro-6-fluorobenzoyl chloride in 20 mL toluene was added to the reaction and the mixture was subsequently refluxed for four hours. The reaction was then cooled to room temperature and carefully treated with 6.5 mL (98.1 mmol) of concentrated sulfuric acid. The reaction was diluted with water and the layers were separated. The aqueous layer was extracted with dichloromethane and the combined organic layers were dried over sodium sulfate and concentrated to a residue. The residue was purified by flash chromatography eluting with 15% ethyl acetate/hexanes mixture to give 14.0 g (78%) of the title compound as a reddish-pink oil.
Reaction SMILES: [CH:1]([N:4]1[C:8]2[CH:9]=[CH:10][C:11]([C:13](O)=[O:14])=[CH:12][C:7]=2[N:6]=[C:5]1[NH:16][C:17]1[S:18][C:19]2[CH:25]=[C:24]([O:26][C:27]([F:30])([F:29])[F:28])[CH:23]=[CH:22][C:20]=2[N:21]=1)([CH3:3])[CH3:2].CN.[CH3:33][N:34](C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C>CN(C=O)C>[CH3:33][NH:34][C:13]([C:11]1[CH:10]=[CH:9][C:8]2[N:4]([CH:1]([CH3:3])[CH3:2])[C:5]([NH:16][C:17]3[S:18][C:19]4[CH:25]=[C:24]([O:26][C:27]([F:28])([F:29])[F:30])[CH:23]=[CH:22][C:20]=4[N:21]=3)=[N:6][C:7]=2[CH:12]=1)=[O:14]
Reactant: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Reactant: CC(C)n1c(Nc2nc3ccc(OC(F)(F)F)cc3s2)nc2cc(C(=O)O)ccc21
Agent: CN
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CNC(=O)c1ccc2c(c1)nc(Nc1nc3ccc(OC(F)(F)F)cc3s1)n2C(C)C
Yield: 42.7 %

Procedure:
1-Isopropyl-2-(6-trifluoromethoxy-benzothiazol-2-ylamino)-1H-benzoimidazole-5-carboxylic acid methylamide (44.0 mg) was prepared by following General Procedure F starting from 1-isopropyl-2-(6-trifluoromethoxy-benzothiazol-2-ylamino)-1H-benzo-imidazole-5-carboxylic acid (100.0 mg), methylamine (2.0 M solution in THF, 0.5 mL), HBTU (130.0 mg) and DIEA (0.1 mL) in DMF (1.0 mL). LCMS: m/z 451; and 1H NMR (DMSO-d6, 400 MHz): δ 8.40 (1H, m), 8.10 (1H, m), 7.92 (1H, m), 7.75-7.68 (2H, m), 7.37-7.35 (1H, m), 5.17-5.12 (1H, m), 2.82-2.80 (3H, s), 1.58-1.57 (6H, d), 2 —NH proton signals were not observed.
Reaction SMILES: [O:1]=[C:2]1[CH2:7][C:6]2([C:16]([O:18][CH3:19])=[O:17])[N:8]([C:9]([O:11][C:12]([CH3:15])(C)C)=[O:10])[CH:3]1[CH2:4][CH2:5]2.C(O)(C(F)(F)F)=O.C(Cl)(OC[C:31]1[CH:36]=[CH:35]C=[CH:33][CH:32]=1)=O>C(Cl)Cl>[O:1]=[C:2]1[CH2:7][C:6]2([C:16]([O:18][CH3:19])=[O:17])[N:8]([C:9]([O:11][CH2:12][C:15]3[CH:35]=[CH:36][CH:31]=[CH:32][CH:33]=3)=[O:10])[CH:3]1[CH2:4][CH2:5]2
Reactant: COC(=O)C12CCC(C(=O)C1)N2C(=O)OC(C)(C)C
Reactant: O=C(Cl)OCc1ccccc1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: COC(=O)C12CCC(C(=O)C1)N2C(=O)OCc1ccccc1
Reaction time: 12 h
Yield: 30 %

Procedure:
A mixture of O7-tert-butyl O4-methyl 2-oxo-7-azabicyclo[2.2.1]heptane-4,7-dicarboxylate (prepared according to the literature: Org. Lett., Vol. 9, No. 7, 2007 p 1235-p 1238) (0.34 g, 1.27 mmol), TFA (1.5 ml) in DCM was stirred for 2 hours. After removal of solvent and TFA under reduced pressure, the residue was dissolved into DCM (5 mL). To it was added TEA (0.51 g, 5.08 mmol) and CbzCl (0.43 g, 2.54 mmol). After 12 hours, the mixture was concentrated under reduced pressure. The residue was purified by flash chromatography to give O7-benzyl O4-methyl 2-oxo-7-azabicyclo[2.2.1]heptane-4,7-dicarboxylate 148b. Yield:30%. MS: calc'd (MH +) 304, measured (MH +) 304.
Reaction SMILES: [CH3:1][N:2]1[C:10]([CH2:11][N:12]2[CH2:17][CH2:16][CH:15]([C:18]([OH:21])([CH3:20])[CH3:19])[CH2:14][CH2:13]2)=[N:9][C:8]2[C:3]1=[N:4][C:5]([Sn](CCCC)(CCCC)CCCC)=[N:6][C:7]=2[N:22]1[CH2:27][CH2:26][O:25][CH2:24][CH2:23]1.Br[C:42]1[C:43]2[N:44]([CH:48]=[N:49][CH:50]=2)[CH:45]=[CH:46][CH:47]=1>O1CCOCC1.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.S1C=CC=C1C([O-])=O.[Cu+]>[CH:50]1[N:49]=[CH:48][N:44]2[CH:45]=[CH:46][CH:47]=[C:42]([C:5]3[N:4]=[C:3]4[C:8]([N:9]=[C:10]([CH2:11][N:12]5[CH2:13][CH2:14][CH:15]([C:18]([OH:21])([CH3:20])[CH3:19])[CH2:16][CH2:17]5)[N:2]4[CH3:1])=[C:7]([N:22]4[CH2:27][CH2:26][O:25][CH2:24][CH2:23]4)[N:6]=3)[C:43]=12
Reactant: Brc1cccn2cncc12
Reactant: CCCC[Sn](CCCC)(CCCC)c1nc(N2CCOCC2)c2nc(CN3CCC(C(C)(C)O)CC3)n(C)c2n1
Agent: [Cu+]
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])c1cccs1
Solvent: C1COCCO1
Product: Cn1c(CN2CCC(C(C)(C)O)CC2)nc2c(N3CCOCC3)nc(-c3cccn4cncc34)nc21
Temperature: 150 °C
Yield: 59.1 %

Procedure:
A mixture of 2-[1-(9-methyl-6-morpholin-4-yl-2-(tributylstannanyl)-9H-purin-8-ylmethyl)piperidin-4-yl]propan-2-ol (135 mg, 0.20 mmol), 8-bromoimidazo[1,5-a]pyridine (44 mg, 0.22 mmol), Pd(PPh3)4 (24 mg, 10 mol %) and copper(I)-thiophene-2-carboxylate (8 mg, 20 mol %) in dioxane (2 mL) was purged with argon gas then heated at 150° C., for 20 min, in a microwave reactor. The reaction mixture was loaded onto an Isolute® SCX-2 cartridge, washed with MeOH then the desired product eluted with 2 M NH3 in MeOH. The resulting residue was purified by column chromatography (Si—PCC, 0-10% MeOH in DCM) to give 222 as a yellow solid (58 mg, 58%). LCMS (Method G): RT=4.86 min, [M+H]+ 491.4. 1H NMR (400 MHz, CHCl3-d): δ 8.42 (s, 1 H), 8.19 (s, 1 H), 8.02 (d, J=6.9 Hz, 1 H), 7.95 (dd, J=6.9, 0.9 Hz, 1 H), 6.74-6.67 (m, 1 H), 4.38 (m, 4 H), 3.96 (s, 3 H), 3.91-3.87 (m, 4 H), 3.80-3.66 (m, 2 H), 2.97 (d, J=11.0 Hz, 2 H), 2.22-1.99 (m, 2 H), 1.75 (d, J=11.0 Hz, 2 H), 1.44-1.26 (m, 4 H), 1.20-1.17 (s, 6 H)
Reaction SMILES: [Cl:1][C:2]1[C:3]([F:21])=[C:4]([F:20])[C:5]([NH:11][C:12]2[CH:17]=[CH:16][C:15]([I:18])=[CH:14][C:13]=2[Cl:19])=[C:6]([CH:10]=1)[C:7]([OH:9])=O.C(N(C(C)C)CC)(C)C.[CH3:31][C:32]1([CH3:40])[O:36][C@H:35]([CH2:37][O:38][NH2:39])[CH2:34][O:33]1.ON1C2C=CC=CC=2N=N1.F[P-](F)(F)(F)(F)F.N1(O[P+](N(C)C)(N(C)C)N(C)C)C2C=CC=CC=2N=N1>O1CCCC1>[Cl:1][C:2]1[C:3]([F:21])=[C:4]([F:20])[C:5]([NH:11][C:12]2[CH:17]=[CH:16][C:15]([I:18])=[CH:14][C:13]=2[Cl:19])=[C:6]([CH:10]=1)[C:7]([NH:39][O:38][CH2:37][C@@H:35]1[CH2:34][O:33][C:32]([CH3:40])([CH3:31])[O:36]1)=[O:9]
Reactant: O=C(O)c1cc(Cl)c(F)c(F)c1Nc1ccc(I)cc1Cl
Reactant: CC1(C)OC[C@@H](CON)O1
Agent: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Agent: F[P-](F)(F)(F)(F)F
Agent: On1nnc2ccccc21
Solvent: C1CCOC1
Solvent: CCN(C(C)C)C(C)C
Product: CC1(C)OC[C@@H](CONC(=O)c2cc(Cl)c(F)c(F)c2Nc2ccc(I)cc2Cl)O1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 90.3 %

Procedure:
A 1 L single necked round-bottomed flask equipped with a magnetic stirrer was charged with a solution of 5-chloro-2-(2-chloro-4-iodo-phenylamino)-3,4-difluoro-benzoic acid (59.6 g, 135 mmol) in dry tetrahydrofuran (300 mL). The solution was cooled to 0° C. in an ice-acetone bath. To this solution was added diisopropylethylamine (34.8 g, 270 mmol), (S)-O-(2,2-dimethyl-[1,3]dioxolan-4-ylmethyl)-hydroxylamine (29.7 g, 202 mmol), 1-hydroxybenzotriazole (30.93 g, 202 mmol), and benzotriazol-1-yloxy-tris(dimethylamino)phosphonium hexafluorophosphate (BOP) (89.32 g, 202 mmol). After 30 minutes, the cooling bath was removed, and the reaction was stirred at ambient temperature for 18 hrs. The solvent was evaporated in vacuo, and the residue was dissolved in diethyl ether. The organic solution was washed with 10% aqueous sodium hydroxide (3×500 mL) and brine, and dried (MgSO4). The solution was concentrated to afford 5-chloro-2-(2-chloro-4-iodo-phenylamino)-N-((S)-2,2-dimethyl-[1,3]dioxolan-4-ylmethoxy)-3,4-difluoro-benzamide (69.9 g) as a pale yellow solid that was used directly in the next hydrolysis reaction.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([S:8][C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][N:10]=2)=[CH:4][C:3]=1[N:15]([CH3:23])[C:16](=[O:22])[O:17][C:18]([CH3:21])([CH3:20])[CH3:19].[O:24]=[C:25]1[NH:29][C:28](=[O:30])[CH:27]([CH2:31][C:32]2[CH:42]=[CH:41][C:35]([O:36][CH2:37][C:38](O)=[O:39])=[CH:34][CH:33]=2)[S:26]1.C(P(=O)(OCC)OCC)#N.C(N(CC)CC)C>O1CCCC1>[O:24]=[C:25]1[NH:29][C:28](=[O:30])[CH:27]([CH2:31][C:32]2[CH:33]=[CH:34][C:35]([O:36][CH2:37][C:38]([NH:1][C:2]3[CH:7]=[CH:6][C:5]([S:8][C:9]4[CH:14]=[CH:13][CH:12]=[CH:11][N:10]=4)=[CH:4][C:3]=3[N:15]([CH3:23])[C:16](=[O:22])[O:17][C:18]([CH3:19])([CH3:20])[CH3:21])=[O:39])=[CH:41][CH:42]=2)[S:26]1
Reactant: CN(C(=O)OC(C)(C)C)c1cc(Sc2ccccn2)ccc1N
Reactant: O=C(O)COc1ccc(CC2SC(=O)NC2=O)cc1
Agent: CCOP(=O)(C#N)OCC
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CN(C(=O)OC(C)(C)C)c1cc(Sc2ccccn2)ccc1NC(=O)COc1ccc(CC2SC(=O)NC2=O)cc1
Yield: 48.6 %

Procedure:
In a similar manner to that described in Example (2-1), a reaction was carried out using t-butyl N-[2-amino-5-(pyridine-2-ylthio)phenyl]-N-methylcarbamate (0.78 g), 4-(2,4-dioxothiazolidin-5-ylmethyl)phenoxyacetic acid (1.06 g), diethyl cyanophosphonate (0.61 g), triethylamine (0.38 g) and anhydrous tetrahydrofuran (20 ml) and the reaction mixture was purified to give the desired product (0.68 g).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[C:4](F)[CH:3]=1.[OH:12][C:13]1[CH:14]=[C:15]([C@@H:19]([NH:21][C:22](=[O:28])[O:23][C:24]([CH3:27])([CH3:26])[CH3:25])[CH3:20])[CH:16]=[CH:17][CH:18]=1.C(=O)([O-])[O-].[K+].[K+].CN(C)C=O>O>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[C:4]([CH:3]=1)[O:12][C:13]1[CH:14]=[C:15]([C@@H:19]([NH:21][C:22](=[O:28])[O:23][C:24]([CH3:27])([CH3:26])[CH3:25])[CH3:20])[CH:16]=[CH:17][CH:18]=1
Reactant: C[C@H](NC(=O)OC(C)(C)C)c1cccc(O)c1
Reactant: O=[N+]([O-])c1ccc(Cl)cc1F
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: C[C@H](NC(=O)OC(C)(C)C)c1cccc(Oc2cc(Cl)ccc2[N+](=O)[O-])c1
Temperature: 100 °C
Reaction time: 1 h
Yield: 70.7 %

Procedure:
A mixture of 4-chloro-2-fluoronitrobenzene (10.4 g, 59.2 mmols), tert-butyl(1S)-1-(3-hydroxyphenyl)ethylcarbamate (13.4 g, 56.5 mmols), potassium carbonate (9.4 g, 68 mmols) and N,N-dimethylformamide (150 ml) was stirred at 100° C. for 1 hour. The reaction mixture was cooled, poured into water, and extracted with ethyl acetate. The extract was washed with water and brine, and then dried with anhydrous magnesium sulfate, and the solvent was evaporated away. The residue was purified through silica gel column chromatography, and the resulting crystal was re-crystallized from hexane/ethyl acetate to give a crystal of tert-butyl(1S)-(-)-1-[3-(5-chloro-2-nitrophenoxy)phenyl]ethylcarbamate (15.7 g, 71%).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[C:11]3[N:12]=[C:13]([NH:16][C:17]4[CH:22]=[CH:21][C:20](I)=[CH:19][CH:18]=4)[N:14]=[CH:15][C:10]=3[CH2:9][C:8](=[O:24])[NH:7][C:6]=2[CH:25]=1.[CH2:26]([N:29]1[CH2:33][CH2:32][CH2:31][CH2:30]1)[C:27]#[CH:28]>>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[C:11]3[N:12]=[C:13]([NH:16][C:17]4[CH:22]=[CH:21][C:20]([C:28]#[C:27][CH2:26][N:29]5[CH2:33][CH2:32][CH2:31][CH2:30]5)=[CH:19][CH:18]=4)[N:14]=[CH:15][C:10]=3[CH2:9][C:8](=[O:24])[NH:7][C:6]=2[CH:25]=1
Reactant: O=C1Cc2cnc(Nc3ccc(I)cc3)nc2-c2ccc(Cl)cc2N1
Reactant: C#CCN1CCCC1
Product: O=C1Cc2cnc(Nc3ccc(C#CCN4CCCC4)cc3)nc2-c2ccc(Cl)cc2N1

Procedure:
In a manner similar to that described for Method O, 9-chloro-2-(4-iodo-phenylamino)-5H,7H-benzo[b]pyrimido[4,5-d]azepin-6-one (I-36) and 1-(prop-2-ynyl)pyrrolidine were converted to I-47 (52%): HRMS Calcd. for C25H22ClN5O: 444.1591, Found 444.1589.
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:10]=1[NH:9][CH:8]=[CH:7]2.[C:11]([O:15][CH3:16])(=[O:14])[CH:12]=[CH2:13].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C(N(CC)C(C)C)(C)C>C([O-])(=O)C.[Pd+2].C([O-])(=O)C.CN(C)C=O>[NH:9]1[C:10]2[C:6](=[CH:5][CH:4]=[CH:3][C:2]=2/[CH:13]=[CH:12]/[C:11]([O:15][CH3:16])=[O:14])[CH:7]=[CH:8]1
Reactant: C=CC(=O)OC
Reactant: Brc1cccc2cc[nH]c12
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: COC(=O)/C=C/c1cccc2cc[nH]c12
Temperature: 70 °C
Reaction time: 18 h
Yield: 67.4 %

Procedure:
7-Bromoindole (5.0 g, 25.5 mmol), methyl acrylate (4.6 ml, 51.1 mmol), triphenylphosphine (0.55 g, 2.10 mmol), N,N-diisopropylethylamine (5.8 ml, 42.3 mmol), and palladium (II) acetate (0.25 g, 1.11 mmol) were added to N,N-dimethylformamide (50 ml), and the mixture was stirred at 70° C. for 18 hours under a stream of nitrogen. After cooling to room temperature, methyl acrylate (4.6 ml, 51.1 mmol), triphenylphosphine (0.55 g, 2.10 mmol), and palladium (II) acetate (0.25 g, 1.11 mmol) were added to the reaction mixture, and the mixture was stirred at 75° C. for 47 hours under a stream of nitrogen. After cooling to room temperature, methyl acrylate (7.0 ml, 77.7 mmol), triphenylphosphine (0.88 g, 3.36 mmol), and palladium (II) acetate (0.40 g, 1.78 mmol) were added to the reaction mixture, and the mixture was stirred at 100° C. for 95 hours under a stream of nitrogen. After cooling to room temperature, the reaction mixture was concentrated under reduced pressure. To the obtained residue, a hexane/ethyl acetate mixed solution (1:1, 300 ml) was added, and the organic layer was washed with water. The obtained aqueous layer was subjected to extraction with a hexane/ethyl acetate (1:1) mixed solution, and the combined organic layer was washed with saturated saline. The obtained organic layer was dried over anhydrous magnesium sulfate and then concentrated under reduced pressure. The obtained residue was purified by silica gel chromatography (eluent; hexane:ethyl acetate=6:1) to obtain 2 (E)-methyl 3-(1H-indol-7-yl)acrylate (3.46 g, 67%) as a pale yellow-brown solid. ESI-MS: m/z 202 [M+H]+. 1H-NMR (CDCl3) δ: 3.85 (3H, s), 6.52 (1H, d, J=16.0 Hz), 6.62 (1H, dd, J=2.9, 2.0 Hz), 7.16 (1H, t, J=7.6 Hz), 7.28 (1H, t, J=2.9 Hz), 7.43 (1H, d, J=7.6 Hz), 7.71 (1H, d, J=7.6 Hz), 8.04 (1H, d, J=16.0 Hz), 8.59 (1H, br s).
Reaction SMILES: N1C2C(=CC=C3C=2N=CC=C3)C=CC=1.C(=O)([O-])[O-].[Cs+].[Cs+].Cl.Cl[C:23]1[C:28]([NH:29][C:30](=[O:41])[C:31]2[CH:36]=[C:35]([CH3:37])[C:34]([O:38][CH3:39])=[C:33]([CH3:40])[CH:32]=2)=[CH:27][CH:26]=[C:25]([Cl:42])[N:24]=1>O1CCCC1.[Cu]I>[Cl:42][C:25]1[N:24]=[C:23]2[O:41][C:30]([C:31]3[CH:36]=[C:35]([CH3:37])[C:34]([O:38][CH3:39])=[C:33]([CH3:40])[CH:32]=3)=[N:29][C:28]2=[CH:27][CH:26]=1
Reactant: COc1c(C)cc(C(=O)Nc2ccc(Cl)nc2Cl)cc1C
Agent: [Cu]I
Agent: Cl
Agent: O=C([O-])[O-]
Solvent: C1CCOC1
Product: COc1c(C)cc(-c2nc3ccc(Cl)nc3o2)cc1C
Temperature: 140 °C

Procedure:
In a microwaveable vessel, 1.03 g of N-(2,6-dichloropyridin-3-yl)-4-methoxy-3,5-dimethylbenzamide were dissolved in 15 ml of dry tetrahydrofuran, and 30 mg of copper(I) iodide, 57 mg of 1,10-phenanthroline and 1.54 g of cesium carbonate were added. In a microwave sunthesizer, the reaction mixture was then heated at 140° C. for 2 h. For work-up, the mixture was added to 10 ml of a 0.5 M aqueous hydrochloric acid solution. The mixture was extracted twice with ethyl acetate. The collected organic phases were combined and the solvent was removed under reduced pressure. This gave 0.88 g (98%) of the product, which was reacted further without any further purification.