Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH:17]([C:18]([OH:20])=O)[CH2:16][C:15]2[CH:14]=[C:13]3[O:21][CH2:22][C@H:23]([C:25]4[CH:30]=[CH:29][C:28]([O:31][CH2:32][C:33]5[CH:38]=[CH:37][C:36]([Cl:39])=[C:35]([Cl:40])[CH:34]=5)=[CH:27][CH:26]=4)[O:24][C:12]3=[CH:11][C:10]=2[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH3:41][O:42][C:43](=[O:62])[C@:44]([NH2:61])([CH3:60])[CH2:45][C:46]1[CH:51]=[CH:50][C:49]([C:52]2[CH:57]=[CH:56][C:55]([C:58]#[N:59])=[CH:54][CH:53]=2)=[CH:48][CH:47]=1>>[C:1]([O:5][C:6]([N:8]1[CH:17]([C:18](=[O:20])[NH:61][C@@:44]([C:43]([O:42][CH3:41])=[O:62])([CH3:60])[CH2:45][C:46]2[CH:47]=[CH:48][C:49]([C:52]3[CH:57]=[CH:56][C:55]([C:58]#[N:59])=[CH:54][CH:53]=3)=[CH:50][CH:51]=2)[CH2:16][C:15]2[CH:14]=[C:13]3[O:21][CH2:22][C@H:23]([C:25]4[CH:30]=[CH:29][C:28]([O:31][CH2:32][C:33]5[CH:38]=[CH:37][C:36]([Cl:39])=[C:35]([Cl:40])[CH:34]=5)=[CH:27][CH:26]=4)[O:24][C:12]3=[CH:11][C:10]=2[CH2:9]1)=[O:7])([CH3:3])([CH3:2])[CH3:4]
Reactant: CC(C)(C)OC(=O)N1Cc2cc3c(cc2CC1C(=O)O)OC[C@H](c1ccc(OCc2ccc(Cl)c(Cl)c2)cc1)O3
Reactant: COC(=O)[C@@](C)(N)Cc1ccc(-c2ccc(C#N)cc2)cc1
Product: COC(=O)[C@](C)(Cc1ccc(-c2ccc(C#N)cc2)cc1)NC(=O)C1Cc2cc3c(cc2CN1C(=O)OC(C)(C)C)O[C@@H](c1ccc(OCc2ccc(Cl)c(Cl)c2)cc1)CO3
Yield: 72.3 %

Procedure:
(S)-3-[4-(3,4-dichloro-benzyloxy)-phenyl]-2,3,8,9-tetrahydro-6H-[1,4]dioxino[2,3-g]isoquinoline-7,8-dicarboxylic acid 7-tert-butyl ester (100 mg) was coupled with (S)-2-amino-3-(4′-cyano-biphenyl-4-yl)-2-methyl-propionic acid methyl ester (50 mg) according to General Procedure L to give (S)-8-[(S)-2-(4′-Cyano-biphenyl-4-yl)-1-methoxycarbonyl-1-methyl-ethyl-carbamoyl]-3-[4-(3,4-dichloro-benzyloxy)-phenyl]-2,3,8,9-tetrahydro-6H-[1,4]dioxino[2,3-g]-isoquinoline-7-carboxylic acid tert-butyl ester (106 mg). This intermediate was deprotected according to General Procedure C to give (S)-3-(4′-cyano-biphenyl-4-yl)-2-({(S)-3-[4-(3,4-dichloro-benzyloxy)-phenyl]-2,3,6,7,8,9-hexahydro-[1,4]dioxino[2,3-g]isoquinoline-8-carbonyl}-amino)-2-methyl-propionic acid methyl ester hydrochloride. This compound (40 mg) was further reacted with 2-acetylamino-4-methyl-thiazole-5-sulfonyl chloride to give (S)-2-({(S)-7-(2-acetylamino-4-methyl-thiazole-5-sulfonyl)-3-[4-(3,4-dichloro-benzyloxy)-phenyl]-2,3,6,7,8,9-hexahydro-[1,4]dioxino[2,3-g]isoquinoline-8-carbonyl}-amino)-3-(4′-cyano-biphenyl-4-yl)-2-methyl-propionic acid methyl ester according to General Procedure E. This product (25 mg) was hydrolyzed according to General Procedure B to give the title. LCMS (m/z): 966.
Reaction SMILES: C[O:2][C:3](=O)[CH2:4][C:5]1[C:6]([N+:18]([O-:20])=[O:19])=[N:7][CH:8]=[C:9]([N:11]2[CH2:16][CH2:15][N:14]([CH3:17])[CH2:13][CH2:12]2)[CH:10]=1.[NH4+:22].[OH-]>>[CH3:17][N:14]1[CH2:15][CH2:16][N:11]([C:9]2[CH:10]=[C:5]([CH2:4][C:3]([NH2:22])=[O:2])[C:6]([N+:18]([O-:20])=[O:19])=[N:7][CH:8]=2)[CH2:12][CH2:13]1
Reactant: COC(=O)Cc1cc(N2CCN(C)CC2)cnc1[N+](=O)[O-]
Reactant: [NH4+]
Agent: [OH-]
Product: CN1CCN(c2cnc([N+](=O)[O-])c(CC(N)=O)c2)CC1

Procedure:
A solution of [5-(4-Methyl-piperazin-1-yl)-2-nitro-pyridin-3-yl]-acetic acid methyl ester (222 mg, 0.75 mmol) in 33% aq. NH4OH (100 mL) is stirred for 16 h at 50° C. in a sealed autoclave. TLC analysis indicated complete consumption of starting material. The solvent is evaporated at reduced pressure to afford the title compound as a yellow solid in a 3:2 mixture with the corresponding carboxylic acid. 1H NMR (d6-DMSO 400 MHz): δ 2.18 (s, 3H), 2.36-2.44 (m, 4H), 3.36-3.44 (m, 4H), 3.77 (s, 2H), 6.92 (bs, 1H), 7.34 (d, J=2 Hz, 1H), 7.44 (bs, 1H), 8.07 (d, J=2 Hz, 1H). ES+−MS: 280.4 [M+H]+.
Reaction SMILES: C(OC(=O)[NH:7][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=1[NH:14][C:15]([C:17]1[CH:26]=[CH:25][C:20]2[N:21]=[C:22](N)[S:23][C:19]=2[CH:18]=1)=[O:16])(C)(C)C.[F:28][C:29]([F:40])([F:39])[O:30][C:31]1[CH:38]=[CH:37][C:34](C=O)=[CH:33][CH:32]=1.C([Sn](Cl)(Cl)CCCC)CCC.C1([SiH3])C=CC=CC=1>C1COCC1>[NH2:7][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=1[NH:14][C:15]([C:17]1[CH:26]=[CH:25][C:20]2[N:21]=[C:22]([C:34]3[CH:33]=[CH:32][C:31]([O:30][C:29]([F:28])([F:39])[F:40])=[CH:38][CH:37]=3)[S:23][C:19]=2[CH:18]=1)=[O:16]
Reactant: O=Cc1ccc(OC(F)(F)F)cc1
Reactant: CC(C)(C)OC(=O)Nc1ccccc1NC(=O)c1ccc2nc(N)sc2c1
Agent: CCCC[Sn](Cl)(Cl)CCCC
Agent: [SiH3]c1ccccc1
Solvent: C1CCOC1
Product: Nc1ccccc1NC(=O)c1ccc2nc(-c3ccc(OC(F)(F)F)cc3)sc2c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 93.7 %

Procedure:
To a solution of 115 (300 mg, 0.78 mmol), 4-(trifluoromethoxy)benzaldehyde (123 μl, 0.86 mmol), and dibutyltin dichloride (24 mg, 0.08 mmol) in THF was added phenylsilane (106 μl, 0.86 mmol). The mixture was stirred overnight at room temperature under nitrogen, additional aldehyde and phenylsilane were added and the stirring continued until no more starting material was present. The THF was evaporated off the mixture and the residue was purified by flash column chromatography (EtOAc/hexane 30/70, then 50/50), to give the title compound 116 (314 mg, 72%). 1H-NMR (DMSO) δ: 9.77 (s, 1H), 8.89 (t, J=5.7 Hz, 1H); 8.69 (s, 1H); 8.29 (d, J=1.8 Hz, 1H); 7.84 (dd, J=8.4, 1.8 Hz, 1H); 7.50 (m, 5H); 7.37 (d, J=7.8 Hz, 2H); 7.17 (m, 2H); 4.69 (d, J=5.7 Hz, 2H); 1.47 (s, 9H).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:33]=[CH:34][CH:35]=1)[CH2:5][O:6][C:7]1[CH:12]=[CH:11][C:10]([NH:13][C:14]2[C:23]3[C:18](=[CH:19][CH:20]=[C:21]([C:24]4[O:25][C:26]([CH2:29][CH2:30][NH2:31])=[CH:27][CH:28]=4)[CH:22]=3)[N:17]=[CH:16][N:15]=2)=[CH:9][C:8]=1[Cl:32].[CH3:36][S:37]([CH2:40][C:41](O)=[O:42])(=[O:39])=[O:38].Cl.CN(C)CCCN=C=NCC.C(N(CC)C(C)C)(C)C>>[F:1][C:2]1[CH:3]=[C:4]([CH:33]=[CH:34][CH:35]=1)[CH2:5][O:6][C:7]1[CH:12]=[CH:11][C:10]([NH:13][C:14]2[C:23]3[C:18](=[CH:19][CH:20]=[C:21]([C:24]4[O:25][C:26]([CH2:29][CH2:30][NH:31][C:41](=[O:42])[CH2:40][S:37]([CH3:36])(=[O:39])=[O:38])=[CH:27][CH:28]=4)[CH:22]=3)[N:17]=[CH:16][N:15]=2)=[CH:9][C:8]=1[Cl:32]
Reactant: NCCc1ccc(-c2ccc3ncnc(Nc4ccc(OCc5cccc(F)c5)c(Cl)c4)c3c2)o1
Reactant: CS(=O)(=O)CC(=O)O
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Product: CS(=O)(=O)CC(=O)NCCc1ccc(-c2ccc3ncnc(Nc4ccc(OCc5cccc(F)c5)c(Cl)c4)c3c2)o1

Procedure:
Preparation according to Procedure (I) utilizing (4-(3-fluorobenzyloxy)-3-chlorophenyl)-(6-(5-(2-aminoethyl)-furan-2-yl)-quinazolin-4-yl)-amine (26 mg, 0.0537 mmol), methanesulfonylacetic acid (22.2 mg, 0.161 mmol), 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (30.0 mg, 0.161 mmol) and N,N-diisopropylethylamine (0.028 mL, 0.161 mmol). 1H (DMSO) 9.84 (s, 1H), 8.65 (s, 1H), 8.49 (s, 1H), 8.10 (d, 1H), 7.96 (d, 1H), 7.73 (d, 1H), 7.69 (m, 1H), 7.41 (m, 1H), 7.22-7.29 (m, 3H), 7.13 (m, 1H), 6.98 (d, 1H), 6.35 (d, 1H), 5.21 (s, 2H), 4.02 (s, 2H), 3.07 (t, 2H), 3.05 (s, 3H), 2.87 (t, 2H). Electrospray m/z 609 (MH+).
Reaction SMILES: [F:1][C:2]1[C:3]([NH:12][C:13]2[CH:18]=[CH:17][C:16]([C:19]#[C:20][Si](C)(C)C)=[CH:15][C:14]=2[F:25])=[C:4]([CH:8]=[CH:9][C:10]=1[F:11])[C:5]([OH:7])=[O:6].C([O-])([O-])=O.[K+].[K+]>CO>[F:1][C:2]1[C:3]([NH:12][C:13]2[CH:18]=[CH:17][C:16]([C:19]#[CH:20])=[CH:15][C:14]=2[F:25])=[C:4]([CH:8]=[CH:9][C:10]=1[F:11])[C:5]([OH:7])=[O:6]
Reactant: C[Si](C)(C)C#Cc1ccc(Nc2c(C(=O)O)ccc(F)c2F)c(F)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CO
Product: C#Cc1ccc(Nc2c(C(=O)O)ccc(F)c2F)c(F)c1
Temperature: 25 °C
Reaction time: 15 h
Yield: 99 %

Procedure:
The product of Step B, 3,4-difluoro-2-[[2-fluoro-4-(trimethylsilylethynyl)phenyl]amino]benzoic acid (3.99 g, 11.0 mmol), was dissolved in MeOH (200 mL), to which was added K2CO3 (3.03 g, 22.0 mmol). This mixture was stirred at room temperature for 15 hours, then the reaction solvent removed under reduced pressure. The resulting residue was dissolved in water (50 mL), to which was added 1 M HCl until the pH=4. The resulting pale brown precipitate was collected by filtration and dried to afford the desired product (3.17 g, 99%); m.p. (EtOAc/hexanes) 160–162° C. 1H NMR [400 MHz, (CD3)2SO] δ 13.70 (br s, 1 H), 9.24 (br s, 1 H), 7.82 (ddd, J=9.2, 6.1, 2.1 Hz, 1 H), 7.38 (dd, J=12.0, 1.9, 1 H), 7.21 (ddd, J=8.4, 1.9, 0.8 Hz, 1 H), 7.16 (td, J=9.5, 7.3 Hz, 1 H), 6.96 (ddd, J=8.9, 8.4, 5.4 Hz, 1 H), 4.15 (s, 1 H). Anal. Calcd for C15H8F3NO2: C, 62.4; H, 3.1; N, 4.7. Found: C, 62.4; H, 3.2; N, 4.6.
Reaction SMILES: F[C:2]1[CH:7]=[CH:6][C:5]([C:8]([F:11])([F:10])[F:9])=[CH:4][C:3]=1[C:12]([F:15])([F:14])[F:13].[NH:16]1[CH2:21][CH2:20][CH:19]([CH2:22][OH:23])[CH2:18][CH2:17]1.C(=O)([O-])[O-].[K+].[K+].O.C(OCC)(=O)C>CN(C)C=O>[F:13][C:12]([F:15])([F:14])[C:3]1[CH:4]=[C:5]([C:8]([F:11])([F:10])[F:9])[CH:6]=[CH:7][C:2]=1[N:16]1[CH2:21][CH2:20][CH:19]([CH2:22][OH:23])[CH2:18][CH2:17]1
Reactant: Fc1ccc(C(F)(F)F)cc1C(F)(F)F
Reactant: OCC1CCNCC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: OCC1CCN(c2ccc(C(F)(F)F)cc2C(F)(F)F)CC1
Temperature: 80 °C
Reaction time: 8 h
Yield: 87 %

Procedure:
To a solution of 1-fluoro-2,4-bis(trifluoromethyl)benzene (1.5 g) in N,N-dimethylformamide (10 mL) were added 4-piperidinemethanol (1.49 g) and potassium carbonate (1.79 g), and the mixture was stirred at 80° C. overnight. Water/ethyl acetate were added to the reaction mixture, and the organic layer was separated, washed with water and saturated brine, dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure to give the title compound (1.84 g).
Reaction SMILES: [C:1]1(=O)[O:5][CH2:4][CH2:3][O:2]1.[I:7][C:8]1[CH:13]=[CH:12]C(O)=[CH:10][CH:9]=1.C(=O)([O-])[O-].[K+].[K+].Cl.[OH-].[Na+]>>[OH:5][CH2:4][CH2:3][O:2][C:1]1[CH:12]=[CH:13][C:8]([I:7])=[CH:9][CH:10]=1
Reactant: Oc1ccc(I)cc1
Reactant: O=C1OCCO1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Product: OCCOc1ccc(I)cc1
Temperature: 90 °C
Reaction time: 3 h
Yield: 26.6 %

Procedure:
A melt of ethylene carbonate (6.5 g, 74 mmol) in a small flask under Argon was treated with 4-iodophenol (0.400 g, 1.82 mmol) and powdered potassium carbonate (1.26 g, 9.1 mmol) and was stirred at 90° C. for 3 hr. The mixture was treated with cold dilute hydrochloric acid to decompose the excess potassium carbonate and excess aqueous sodium hydroxide solution was slowly added and the mixture was stirred over night. The suspension was extracted with methylene chloride, was washed with water and brine, was dried over sodium sulfate and was stripped to afford a white solid, which was purified by flash chromatography on silica gel (20 mL) with methylene chloride to afford (0.128 g, 27%) of the titled intermediate as a white solid, mp 76°-77.5° C.
Reaction SMILES: C1(P(C2C=CC=CC=2)(C2C=CC=CC=2)=[C:8]([C:10]([O:12][CH2:13][CH3:14])=[O:11])[CH3:9])C=CC=CC=1.[N+:27]([C:30]1[CH:37]=[CH:36][C:33]([CH:34]=O)=[CH:32][CH:31]=1)([O-:29])=[O:28]>>[CH3:9][C:8](=[CH:34][C:33]1[CH:36]=[CH:37][C:30]([N+:27]([O-:29])=[O:28])=[CH:31][CH:32]=1)[C:10]([O:12][CH2:13][CH3:14])=[O:11]
Reactant: CCOC(=O)C(C)=P(c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: O=Cc1ccc([N+](=O)[O-])cc1
Product: CCOC(=O)C(C)=Cc1ccc([N+](=O)[O-])cc1
Yield: 56 %

Procedure:
The title compound was prepared from triphenyl(1-[ethoxycarbonyl]ethylidene)phosphorane and 4-nitrobenzaldehyde, substantially according to Preparation 5. The product was obtained in 56% yield, as an orange-yellow solid, m.p. 70.5°-73° C.
Reaction SMILES: [CH:1]1([C:4]2[C:5]([NH:30][S:31]([CH3:34])(=[O:33])=[O:32])=[CH:6][C:7]3[O:11][C:10]([C:12]4[CH:17]=[CH:16][C:15]([O:18][C:19]5[CH:24]=[CH:23][C:22]([F:25])=[CH:21][CH:20]=5)=[CH:14][CH:13]=4)=[C:9]([C:26]([OH:28])=O)[C:8]=3[CH:29]=2)[CH2:3][CH2:2]1.C1N=C[N:37](C(N2C=NC=C2)=O)[CH:36]=1.Cl.CN.CCN(C(C)C)C(C)C>CN(C=O)C>[CH3:36][NH:37][C:26]([C:9]1[C:8]2[CH:29]=[C:4]([CH:1]3[CH2:3][CH2:2]3)[C:5]([NH:30][S:31]([CH3:34])(=[O:33])=[O:32])=[CH:6][C:7]=2[O:11][C:10]=1[C:12]1[CH:13]=[CH:14][C:15]([O:18][C:19]2[CH:24]=[CH:23][C:22]([F:25])=[CH:21][CH:20]=2)=[CH:16][CH:17]=1)=[O:28]
Reactant: CS(=O)(=O)Nc1cc2oc(-c3ccc(Oc4ccc(F)cc4)cc3)c(C(=O)O)c2cc1C1CC1
Reactant: O=C(n1ccnc1)n1ccnc1
Agent: CN
Agent: Cl
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CNC(=O)c1c(-c2ccc(Oc3ccc(F)cc3)cc2)oc2cc(NS(C)(=O)=O)c(C3CC3)cc12
Temperature: 25 °C
Reaction time: 2 h
Yield: 80.5 %

Procedure:
step 1—To a solution of 28 (0.51 g, 1.07 mmol) in dry DMF (5 mL) was added CDI (0.19 g, 1.17 mmol) and the solution stirred at RT for 2 h. Methyl amine hydrochloride (0.72 g, 10.7 mmol) and DIPEA (1.4 g, 10.7 mmol) were added and the resulting solution heated at 85° C. for 3 h. The solution was cooled and partitioned between EtOAc and H2O. The organic phase was dried (Na2SO4), filtered and concentrated. The crude product was purified by SiO2 chromatography eluting with an EtOAc/hexane gradient (0 to 40% EtOAc) to afford 0.426 g of 5-cyclopropyl-2-[4-(4-fluoro-phenoxy)-phenyl]-6-methanesulfonylamino-benzofuran-3-carboxylic acid methylamide (30).
Reaction SMILES: ClC1C=C(C=CC=1)C(OO)=[O:6].[C:12]([NH:22][C@@H:23]([CH2:26][CH:27]([CH3:29])[CH3:28])[CH:24]=[CH2:25])([O:14][CH2:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)=[O:13].ClCCl>C(Cl)(Cl)Cl>[C:12]([NH:22][C@@H:23]([CH2:26][CH:27]([CH3:29])[CH3:28])[CH:24]1[O:6][CH2:25]1)([O:14][CH2:15][C:16]1[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=1)=[O:13]
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: C=C[C@H](CC(C)C)NC(=O)OCc1ccccc1
Solvent: ClCCl
Solvent: ClC(Cl)Cl
Product: CC(C)C[C@H](NC(=O)OCc1ccccc1)C1CO1
Reaction time: 16 h
Yield: 44.3 %

Procedure:
To a solution of 600 mg of 3-chloroperoxybenzoic acid in 5 ml of dry chloroform was added a solution of 850 mg of (3S)-3-carbobenzoxyamino-5-methyl-1-hexene in 5 ml of dry chloroform under ice-cooling, and the mixture was stirred for 16 hours. Dichloromethane was added to the reaction mixture, and the mixture was successively washed with an aqueous sodium thiosulfate solution, a 5% aqueous sodium bicarbonate solution and a saturated sodium chloride aqueous solution, dried over anhydrous magnesium sulfate, and evaporated under reduced pressure. The residue was purified by silica gel flash column chromatography (eluent: benzene/hexane=1/1 by volume) to obtain 401 mg of (3S)-3-carbobenzoxyamino-5-methyl-1,2-epoxyhexane as a colorless oil.
Reaction SMILES: [NH:1]1[C:5](=[O:6])[CH2:4][CH2:3][C@H:2]1[C:7]([OH:9])=[O:8].[CH2:10](O)[CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH3:19].C1(N=C=NC2CCCCC2)CCCCC1>ClCCl.CN(C)C1C=CN=CC=1>[NH:1]1[C:5](=[O:6])[CH2:4][CH2:3][C@H:2]1[C:7]([O:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH3:19])=[O:8]
Reactant: CCCCCCCCCCO
Reactant: O=C1CC[C@@H](C(=O)O)N1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Product: CCCCCCCCCCOC(=O)[C@@H]1CCC(=O)N1
Temperature: 0 °C
Reaction time: 2 h

Procedure:
To an ice cold suspension of pyroglutamic acid (1.3 g) and n-decanol (1.6 g) in dichloromethane (50 ml), dicyclohexylcarbodiimide (2.1 g) and 4-dimethylaminopyridine (0.1 g) were added. After stirring at ice bath temperature for 2 hours, the cooling bath was removed and the mixture was stirred at room temperature overnight. The dichloromethane was evaporated off. The residue was taken in ether and filtered. The filtrate was washed with 1 N HCl, water, aqueous bicarbonate and water. It was then dried over Na2SO4 and evaporated. The residue weighed 2.75 g. It was chromatographed over silica gel. The pure decyl ester was eluted with ethylacetate-chloroform (1:4), 2 3 g m.p. 34°-35°.
Reaction SMILES: [F:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:7]([F:11])[C:3]=1[C:4](Cl)=[O:5].[C:12]([O:16][C:17](=[O:39])[CH2:18][N:19]1[C:23]2[CH:24]=[CH:25][C:26]([NH:28][CH2:29][C:30]3[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=3)=[CH:27][C:22]=2[N:21]=[C:20]1[CH2:36][CH2:37][CH3:38])([CH3:15])([CH3:14])[CH3:13].CCN(C(C)C)C(C)C>CN(C1C=CN=CC=1)C.C(Cl)Cl.Cl>[C:12]([O:16][C:17](=[O:39])[CH2:18][N:19]1[C:23]2[CH:24]=[CH:25][C:26]([N:28]([CH2:29][C:30]3[CH:31]=[CH:32][CH:33]=[CH:34][CH:35]=3)[C:4](=[O:5])[C:3]3[C:2]([F:1])=[CH:10][CH:9]=[CH:8][C:7]=3[F:11])=[CH:27][C:22]=2[N:21]=[C:20]1[CH2:36][CH2:37][CH3:38])([CH3:15])([CH3:14])[CH3:13]
Reactant: O=C(Cl)c1c(F)cccc1F
Reactant: CCCc1nc2cc(NCc3ccccc3)ccc2n1CC(=O)OC(C)(C)C
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CCCc1nc2cc(N(Cc3ccccc3)C(=O)c3c(F)cccc3F)ccc2n1CC(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 8 h

Procedure:
2,6-Difluoro-benzoyl chloride (45 μL, 0.36 mmol) was added to a solution of (5-benzylamino-2-propyl-benzoimidazol-1-yl)-acetic acid tert-butyl ester (45 mg, 0.12 mmol), DIEA (41 μL, 0.24 mmol) and DMAP (15 mg, 0.12 mmol) in CH2Cl2 (1 mL), and stirred overnight at room temperature. The reaction solution was diluted with aqueous HCl (1.0 M) and filtered through an Extrelut column. The Extrelut column was washed with CH2Cl2, and the filtrate was concentrated to afford the subtitle compound that was used without further purification. MS calculated for C30H31F2N3O3+H: 520, observed: 520.
Reaction SMILES: [CH:1]([O:3][CH2:4][CH3:5])=[CH2:2].C1(C)C=CC(S([O-])(=O)=O)=CC=1.[NH+]1C=CC=CC=1.[C:23]([O:26][CH:27]1[CH:39]=[CH:38][CH:37]([CH3:40])[CH:36]([C:41]([CH3:63])=[CH:42][CH:43]=[CH:44][CH:45]([CH3:62])[CH2:46][CH:47]2[O:61][CH:48]2[CH:49]([CH3:60])[CH:50]([O:53][C:54](=[O:59])[CH2:55][O:56][CH2:57][CH3:58])[CH2:51][CH3:52])[O:35][C:33](=[O:34])[CH2:32][CH:31]([O:64][Si:65]([C:68]([CH3:71])([CH3:70])[CH3:69])([CH3:67])[CH3:66])[CH2:30][CH2:29][C:28]1([OH:73])[CH3:72])(=[O:25])[CH3:24]>ClCCl.C(OCC)(=O)C>[C:23]([O:26][CH:27]1[C:28]([O:73][CH:1]([O:3][CH2:4][CH3:5])[CH3:2])([CH3:72])[CH2:29][CH2:30][CH:31]([O:64][Si:65]([C:68]([CH3:69])([CH3:70])[CH3:71])([CH3:66])[CH3:67])[CH2:32][C:33]([O:35][CH:36](/[C:41](/[CH3:63])=[CH:42]/[CH:43]=[CH:44]/[CH:45]([CH3:62])[CH2:46][CH:47]2[O:61][CH:48]2[CH:49]([CH3:60])[CH:50]([O:53][C:54](=[O:59])[CH2:55][O:56][CH2:57][CH3:58])[CH2:51][CH3:52])[CH:37]([CH3:40])[CH:38]=[CH:39]1)=[O:34])(=[O:25])[CH3:24]
Reactant: CCOCC(=O)OC(CC)C(C)C1OC1CC(C)C=CC=C(C)C1OC(=O)CC(O[Si](C)(C)C(C)(C)C)CCC(C)(O)C(OC(C)=O)C=CC1C
Reactant: C=COCC
Agent: CCOCC(=O)OC(CC)C(C)C1OC1CC(C)/C=C/C=C(\C)C1OC(=O)CC(O[Si](C)(C)C(C)(C)C)CCC(C)(OC(C)OCC)C(OC(C)=O)/C=C/C1C
Agent: Cc1ccc(S(=O)(=O)[O-])cc1
Agent: c1cc[nH+]cc1
Solvent: ClCCl
Solvent: CCOC(C)=O
Product: CCOCC(=O)OC(CC)C(C)C1OC1CC(C)/C=C/C=C(\C)C1OC(=O)CC(O[Si](C)(C)C(C)(C)C)CCC(C)(OC(C)OCC)C(OC(C)=O)C=CC1C
Temperature: 25 °C
Reaction time: 17 h

Procedure:
Ethyl vinyl ether (82 mg, 1.1 mmol) and pyridinium p-toluenesulfonate (9.2 mg, 0.036 mmol) were added to a solution of 7-acetoxy-3-t-butyldimethylsiloxy-21-ethoxyacetoxy-6-hydroxy-6,10,12,16,20-pentamethyl-18,19-epoxytricosa-8,12,14-trien-11-olide (27 mg, 0.036 mmol) in dichloromethane (1.5 mL) at room temperature. The mixture was stirred at room temperature for 17 hours. The reaction solution was diluted with ethyl acetate, washed with brine, dried over anhydrous magnesium sulfate and evaporated. The resulting crude product was purified by silica gel column chromatography (Kanto silica gel 60N, spherical, neutral, 40 to 100 μm, eluate; hexane:ethyl acetate=80:20) to obtain the title compound (16 mg, 54%) as a colorless oil.
Reaction SMILES: [CH3:1][N:2]1[C:6]([NH:7][CH2:8][CH2:9][CH2:10][O:11][C:12]2[CH:17]=[CH:16][CH:15]=[C:14]([CH2:18][N:19]3[CH2:24][CH2:23][CH2:22][CH2:21][CH2:20]3)[CH:13]=2)=[N:5][C:4]([CH:25]=[N:26]O)=[N:3]1.C(=O)(O)[O-].[Na+]>C(OC(=O)C)(=O)C>[CH3:1][N:2]1[C:6]([NH:7][CH2:8][CH2:9][CH2:10][O:11][C:12]2[CH:17]=[CH:16][CH:15]=[C:14]([CH2:18][N:19]3[CH2:20][CH2:21][CH2:22][CH2:23][CH2:24]3)[CH:13]=2)=[N:5][C:4]([C:25]#[N:26])=[N:3]1
Reactant: Cn1nc(C=NO)nc1NCCCOc1cccc(CN2CCCCC2)c1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC(=O)OC(C)=O
Product: Cn1nc(C#N)nc1NCCCOc1cccc(CN2CCCCC2)c1
Yield: 42 %

Procedure:
A solution of 1-methyl-5-[[3-[3-(1-piperidinylmethyl)phenoxy]propyl]amino]-1H-1,2,4-triazole-3-carboxaldehyde oxime (0.75 g) in acetic anhydride (4 ml) was heated at 100° for 10 hours. The mixture was poured onto aqueous sodium bicarbonate and extracted with toluene. The extract was dried (Na2SO4), filtered, and evaporated to give a solid, which was crystallized from diethyl ether and petroleum ether (b.p. 60°-80°) to give the title compound (0.3 g) as a white powder, m.p. 66°-7°.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([C:8]([CH3:13])([CH3:12])[C:9]([O-:11])=[O:10])[CH:5]=[N:6][CH:7]=1.[K+].[CH3:15][N:16]1[C:25]2[C:20](=[CH:21][C:22](B3OC(C)(C)C(C)(C)O3)=[CH:23][CH:24]=2)[CH2:19][CH2:18][C:17]1=[O:35].C([O-])([O-])=O.[Na+].[Na+]>C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.Cl[Pd]Cl>[CH3:12][C:8]([C:4]1[CH:5]=[N:6][CH:7]=[C:2]([C:22]2[CH:21]=[C:20]3[C:25](=[CH:24][CH:23]=2)[N:16]([CH3:15])[C:17](=[O:35])[CH2:18][CH2:19]3)[CH:3]=1)([CH3:13])[C:9]([OH:11])=[O:10]
Reactant: CC(C)(C(=O)[O-])c1cncc(Br)c1
Reactant: CN1C(=O)CCc2cc(B3OC(C)(C)C(C)(C)O3)ccc21
Agent: Cl[Pd]Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Product: CN1C(=O)CCc2cc(-c3cncc(C(C)(C)C(=O)O)c3)ccc21

Procedure:
In analogy to the procedure described for the preparation of example 59 [C], potassium 2-(5-bromopyridin-3-yl)-2-methylpropanoate (example 72 [B]) was reacted with 1-methyl-6-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-3,4-dihydro-1H-quinolin-2-one (intermediate A-1) in presence of bis(triphenylphosphine)palladium(II)chloride and Na2CO3 (1M aq. solution) to give the title compound as a brown foam. MS: 325.4 (M+H+).
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].Br[C:8]1[CH:13]=[CH:12][C:11]([Br:14])=[CH:10][C:9]=1I.[C:16]([O:22][CH3:23])(=[O:21])[CH2:17][C:18]([CH3:20])=[O:19]>C1COCC1.CCOC(C)=O.[Cu]I>[CH3:23][O:22][C:16]([C:17]1[C:9]2[CH:10]=[C:11]([Br:14])[CH:12]=[CH:13][C:8]=2[O:19][C:18]=1[CH3:20])=[O:21]
Reactant: Brc1ccc(Br)c(I)c1
Reactant: COC(=O)CC(C)=O
Agent: [Cu]I
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: COC(=O)c1c(C)oc2ccc(Br)cc12
Temperature: 100 °C
Reaction time: 5 h

Procedure:
To a stirred mixture of 100 mg (0.525 mmol) copper(I)iodide and 1.90 g (13.7 mmol) potassium carbonate in 10 mL THF was added 1.75 g (4.84 mmol) 1,4-dibromo-2-iodo-benzene and 520 μL methyl acetoacetate under argon atmosphere. Then the mixture was stirred at 100° C. for 5 h under reflux. The reaction mixture was diluted with EtOAc and extracted with water. The combined organic phases were dried over sodium sulfate, filtered and concentrated in vacuo. The crude material was purified by flash chromatography (PE/EtOAc=9/1).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][N:5]2[C:8]([C:11]([NH:13][C:14]3[CH:22]=[CH:21][CH:20]=[C:19]4[C:15]=3[C:16]([CH2:31][CH3:32])=[N:17][N:18]4[CH2:23][C:24]3[CH:29]=[CH:28][CH:27]=[C:26]([CH3:30])[N:25]=3)=[O:12])=[CH:9][N:10]=[C:4]2[CH:3]=1.[N:33]1[CH:34]=[CH:35][N:36]2[CH2:41][CH2:40][N:39](C(OC(C)(C)C)=O)[CH2:38][C:37]=12.C([O-])([O-])=O.[K+].[K+]>CN(C=O)C.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C([O-])(=O)C.C([O-])(=O)C.[Pd+2]>[CH2:31]([C:16]1[C:15]2[C:19](=[CH:20][CH:21]=[CH:22][C:14]=2[NH:13][C:11]([C:8]2[N:5]3[CH:6]=[CH:7][C:2]([C:35]4[N:36]5[CH2:41][CH2:40][NH:39][CH2:38][C:37]5=[N:33][CH:34]=4)=[CH:3][C:4]3=[N:10][CH:9]=2)=[O:12])[N:18]([CH2:23][C:24]2[CH:29]=[CH:28][CH:27]=[C:26]([CH3:30])[N:25]=2)[N:17]=1)[CH3:32]
Reactant: CCc1nn(Cc2cccc(C)n2)c2cccc(NC(=O)c3cnc4cc(Br)ccn34)c12
Reactant: CC(C)(C)OC(=O)N1CCn2ccnc2C1
Agent: [Pd+2]
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: CC(=O)[O-]
Solvent: CN(C)C=O
Product: CCc1nn(Cc2cccc(C)n2)c2cccc(NC(=O)c3cnc4cc(-c5cnc6n5CCNC6)ccn34)c12
Temperature: 140 °C
Yield: 26.3 %

Procedure:
7-Bromo-N-(3-ethyl-1-((6-methylpyridin-2-yl)methyl)-1H-indazol-4-yl)imidazo[1,2-a]pyridine-3-carboxamide (prepared as in Example 127, Step A; 50 mg, 0.10 mmol) in DMF (4 mL) was added tert-butyl 5,6-dihydroimidazo[1,2-a]pyrazine-7(8H)-carboxylate (68 mg, 0.31 mmol), Pd(PPh3)4 (12 mg, 0.01 mmol), palladium diacetate (2.3 mg, 0.010 mmol) and K2CO3 (42 mg, 0.31 mmol). The reaction mixture was purged with argon and the reaction vial was sealed and the mixture was heated to 140° C. for 3 hours. The mixture was cooled to ambient temperature and diluted with DCM (20 mL). The solution was washed with H2O, dried (Na2SO4) and concentrated under reduced pressure. The residue was purified by silica gel chromatography (DCM/MeOH/NH4OH 10:1:0.1) to provide the final product (14 mg). MS (ES+APCI) m/z=532 (M+H).