Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([O:5][C:6]([N:8]([CH:20]1[CH2:26][C:25]2[CH:27]=[C:28]([C:31]([OH:33])=O)[CH:29]=[CH:30][C:24]=2[CH2:23][CH2:22][CH2:21]1)[CH2:9][C@H:10]([OH:19])[CH2:11][O:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].Cl.[CH3:35][N:36](C)CCCN=C=NCC.ON1C2C=CC=CC=2N=N1.CN>ClCCl.O1CCCC1>[OH:19][C@H:10]([CH2:11][O:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)[CH2:9][N:8]([CH:20]1[CH2:21][CH2:22][CH2:23][C:24]2[CH:30]=[CH:29][C:28]([C:31](=[O:33])[NH:36][CH3:35])=[CH:27][C:25]=2[CH2:26]1)[C:6]([O:5][C:1]([CH3:4])([CH3:3])[CH3:2])=[O:7]
Reactant: CCN=C=NCCCN(C)C
Reactant: CC(C)(C)OC(=O)N(C[C@H](O)COc1ccccc1)C1CCCc2ccc(C(=O)O)cc2C1
Agent: CN
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: ClCCl
Solvent: C1CCOC1
Product: CNC(=O)c1ccc2c(c1)CC(N(C[C@H](O)COc1ccccc1)C(=O)OC(C)(C)C)CCC2
Temperature: 25 °C
Reaction time: 8 h
Yield: 42.1 %

Procedure:
To a mixture of 8-[N-tert-butoxycarbonyl-N-[(2S)-2-hydroxy-3-phenoxypropyl]amino]-6,7,8,9-tetrahydro-5H-benzocycloheptene-2-carboxylic acid (0.30 g), 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (0.15 g) and 1-hydroxybenzotriazole (0.11 g) in dichloromethane (6 ml) was added a solution of methylamine in tetrahydrofuran (2.0M, 0.40 ml). The reaction mixture was stirred at room temperature overnight, and partitioned between ethyl acetate and aqueous sodium bicarbonate solution. The organic layer was separated, washed with brine, dried over magnesium sulfate and evaporated in vacuo. The residue was purified by column chromatography on silica gel eluting with a mixture of chloroform and methanol (100:1 to 10:1) to afford N-[(2S)-2-hydroxy-3-phenoxypropyl]-N-tert-butoxycarbonyl-(3-methylcarbamoyl-6,7,8,9-tetrahydro-5H-benzocyclohepten-6-yl)amine (0.13 g).
Reaction SMILES: [C:1](Cl)(=[O:5])[C:2](Cl)=O.C(Cl)Cl.[CH2:10]([O:12][C:13]([C:15]1[NH:16][C:17]2[C:22](C=1)=[CH:21][C:20]([Br:24])=[CH:19][CH:18]=2)=[O:14])[CH3:11].C([O-])(O)=O.[Na+]>CN(C=O)C>[CH2:10]([O:12][C:13]([C:15]1[NH:16][C:17]2[C:18]([C:2]=1[CH:1]=[O:5])=[CH:19][C:20]([Br:24])=[CH:21][CH:22]=2)=[O:14])[CH3:11]
Reactant: O=C(Cl)C(=O)Cl
Reactant: CCOC(=O)c1cc2cc(Br)ccc2[nH]1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: ClCCl
Product: CCOC(=O)c1[nH]c2ccc(Br)cc2c1C=O
Temperature: 25 °C
Reaction time: 0.33 h

Procedure:
Oxalyl chloride (3.43 mL, 39.9 mmol) was added with stirring to DMF (30 mL) and CH2Cl2 (80 mL) at 0° C. After 20 min at 0° C., 5-bromoindole-2-carboxylic acid ethyl ester (10 g, 37.3 mmol) in DMF (80 mL), was added. The mixture was stirred at rt for 24 h and poured into NaHCO3 (aq, sat) and extracted with CH2Cl2. The combined extracts were washed with H2O and brine, dried (Na2SO4) and concentrated. Crystallisation from EtOH gave the sub-title compound. Yield 8.9 g (81%).
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([C:8]2[N:13]=[C:12]([C:14]3[CH:19]=[CH:18][C:17]([Cl:20])=[CH:16][C:15]=3[Cl:21])[CH:11]=[C:10]([C:22]([F:25])([F:24])[F:23])[N:9]=2)[CH:5]=[CH:6][CH:7]=1.[C:26]([NH:30][S:31]([C:34]1[CH:35]=[C:36](B(O)O)[CH:37]=[CH:38][CH:39]=1)(=[O:33])=[O:32])([CH3:29])([CH3:28])[CH3:27]>>[C:26]([NH:30][S:31]([C:34]1[CH:39]=[C:38]([C:2]2[CH:7]=[CH:6][CH:5]=[C:4]([C:8]3[N:13]=[C:12]([C:14]4[CH:19]=[CH:18][C:17]([Cl:20])=[CH:16][C:15]=4[Cl:21])[CH:11]=[C:10]([C:22]([F:23])([F:25])[F:24])[N:9]=3)[CH:3]=2)[CH:37]=[CH:36][CH:35]=1)(=[O:33])=[O:32])([CH3:29])([CH3:27])[CH3:28]
Reactant: FC(F)(F)c1cc(-c2ccc(Cl)cc2Cl)nc(-c2cccc(Br)c2)n1
Reactant: CC(C)(C)NS(=O)(=O)c1cccc(B(O)O)c1
Product: CC(C)(C)NS(=O)(=O)c1cccc(-c2cccc(-c3nc(-c4ccc(Cl)cc4Cl)cc(C(F)(F)F)n3)c2)c1

Procedure:
3′-[4-(2,4-dichloro-phenyl)-6-trifluoromethyl-pyrimidin-2-yl]-biphenyl-3-sulfonic acid tert-butylamide was prepared from 2-(3-bromo-phenyl)-4-(2,4-dichloro-phenyl)-6-trifluoromethyl-pyrimidine (example E.106) (0.45 g, 1.0 mmol) and commercially available 3-(tert.-butylsulfamoyl)-phenylboronic acid (0.31 g, 1.2 mmol) according to the general procedure VI. Obtained as an off-white solid (0.36 g), which was subsequently deprotected.
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]([C:8]([O:10][CH3:11])=[O:9])=[N:6][CH:7]=1.[CH:12]([Sn](CCCC)(CCCC)CCCC)=[CH2:13]>O1CCOCC1.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[CH:12]([C:2]1[CH:3]=[CH:4][C:5]([C:8]([O:10][CH3:11])=[O:9])=[N:6][CH:7]=1)=[CH2:13]
Reactant: C=C[Sn](CCCC)(CCCC)CCCC
Reactant: COC(=O)c1ccc(Br)cn1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Solvent: C1COCCO1
Product: C=Cc1ccc(C(=O)OC)nc1
Temperature: 100 °C
Yield: 66.3 %

Procedure:
The title compound was prepared by following general procedure 2. Methyl 5-bromopyridine-2-carboxylate (4.0 g, 18.5 mmol) was dissolved in 160 mL dioxane. Vinyltributyltin (11.7 g, 37 mmol) was added to this solution at 25° C., followed by addition of dichlorobis(triphenylphosphine)palladium (1.5 g, mmol). The reaction mixture was degassed and purged with nitrogen for 5 min. and then heated at 100° C. for 2 h. The reaction mixture was evaporated under reduced pressure and the residue was purified by SiO2 chromatography (100-200 mesh, eluent: hexane-50% ethyl acetate-hexane gradient). The requisite fractions were concentrated below 40° C. under reduced pressure to obtain 2 g of methyl 5-vinylpyridine-2-carboxylate as a pale yellow oil (solid at −20° C.). TLC Rf 0.3 in 40% Ethyl acetate:Hexane.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:18]=[C:17]2[C:12]([C:13](Cl)=[C:14]([N+:19]([O-:21])=[O:20])[CH:15]=[N:16]2)=[CH:11][CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(N(CC)CC)C.[NH2:30][CH2:31][C:32]([CH3:35])([OH:34])[CH3:33]>ClCCl>[CH2:1]([O:8][C:9]1[CH:18]=[C:17]2[C:12]([C:13]([NH:30][CH2:31][C:32]([CH3:35])([OH:34])[CH3:33])=[C:14]([N+:19]([O-:21])=[O:20])[CH:15]=[N:16]2)=[CH:11][CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CC(C)(O)CN
Reactant: O=[N+]([O-])c1cnc2cc(OCc3ccccc3)ccc2c1Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(C)(O)CNc1c([N+](=O)[O-])cnc2cc(OCc3ccccc3)ccc12
Temperature: 25 °C
Reaction time: 3 h
Yield: 77.8 %

Procedure:
7-Benzyloxy-4-chloro-3-nitroquinoline (66.4 g, 0.21 mol) was dissolved in a mixture of dichloromethane (1.5 L) and triethylamine (59 mL, 0.422 mol). A solution of 1-amino-2-methyl-2-propanol (22.5 g, 0.25 mol) in dichloromethane (100 mL) was added dropwise. The reaction was stirred at ambient temperature for 3 hours and then quenched with 1% aqueous sodium carbonate solution. A precipitate formed which was filtered to provide 60 g of crude 1-(7-benzyloxy-3-nitroquinolin-4-ylamino)-2-methylpropan-2-ol as a yellow-brown solid.
Reaction SMILES: CO[CH:3](OC)[N:4]([CH3:6])[CH3:5].[CH3:9][C:10]1[C:15]([N+:16]([O-:18])=[O:17])=[CH:14][CH:13]=[CH:12][C:11]=1[C:19]([F:22])([F:21])[F:20].O>CN(C)C=O>[CH3:5][N:4]([CH3:6])/[CH:3]=[CH:9]/[C:10]1[C:11]([C:19]([F:22])([F:21])[F:20])=[CH:12][CH:13]=[CH:14][C:15]=1[N+:16]([O-:18])=[O:17]
Reactant: COC(OC)N(C)C
Reactant: Cc1c([N+](=O)[O-])cccc1C(F)(F)F
Solvent: CN(C)C=O
Solvent: O
Product: CN(C)/C=C/c1c([N+](=O)[O-])cccc1C(F)(F)F
Temperature: 110 °C

Procedure:
3.5 ml of DMF-DMA (N,N-dimethylformamide-dimethyl acetal) are added to a solution of 1 g of 2-methyl-3-nitrobenzotrifluoride in 6 ml of N,N-dimethylformamide. The reaction medium is heated at 110° C. until the starting material has disappeared, then poured into water and extracted with ethyl acetate. The organic phases are washed successively with a 10% sodium bicarbonate solution, a 10% ammonium chloride solution and a saturated sodium chloride solution, dried over magnesium sulfate and filtered. The filtrate is concentrated under reduced pressure so as to give 1.2 g of dimethyl[(E)-2-(2-nitro-6-trifluoromethylphenyl)vinyl]amine in the form of an oil which is used in the next step.
Reaction SMILES: I[CH2:2][CH:3]([NH:14][C:15](=[O:21])[O:16][C:17]([CH3:20])([CH3:19])[CH3:18])[CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH3:13].[N-:22]=[N+:23]=[N-:24].[Na+]>CN(C=O)C>[N:22]([CH2:2][CH:3]([NH:14][C:15](=[O:21])[O:16][C:17]([CH3:20])([CH3:19])[CH3:18])[CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH3:13])=[N+:23]=[N-:24]
Reactant: [N-]=[N+]=[N-]
Reactant: CCCCCCCCCCC(CI)NC(=O)OC(C)(C)C
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCCCCCCCCCC(CN=[N+]=[N-])NC(=O)OC(C)(C)C
Temperature: 110 °C
Reaction time: 12 h
Yield: 50.4 %

Procedure:
tert-Butyl N-[1-(R/S)-(iodomethyl)undecyl]carbamate 62 (250 mg, 0.608 mmol) was dissolved in abs. DMF (10 ml). Sodium azide (79.0 mg, 1.22 mmol) was added to the solution, which was subsequently stirred at 110° C. for 12 hours. Following evaporation, the residue was taken up in CH2Cl2 (50 ml) and was washed with NaHCO3(sat, aq) (1×50 ml). The organic phase was dried over MgSO4, filtered and evaporated. The residue was purified by column chromatography in hexane:ether 10:1 (v/v) to give 63 (100 mg, 54%).
Reaction SMILES: C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N1C=CN=C1.[I-:25].[NH:26]([C:34]([O:36][CH2:37][C:38]1[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=1)=[O:35])[C@H:27]([C:30]([O:32][CH3:33])=[O:31])[CH2:28]O>C(Cl)Cl>[CH2:37]([O:36][C:34]([NH:26][C@@H:27]([CH2:28][I:25])[C:30]([O:32][CH3:33])=[O:31])=[O:35])[C:38]1[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=1
Reactant: [I-]
Reactant: COC(=O)[C@H](CO)NC(=O)OCc1ccccc1
Agent: c1c[nH]cn1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Product: COC(=O)[C@H](CI)NC(=O)OCc1ccccc1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 5.7 %

Procedure:
A mixture of triphenylphosphine (23.3 g, 0.890 mol) and imidazole (6.0 g, 0.89 mol) in DCM (100 mL) was cooled to 0° C. and iodide (22.6 g, 0.890 mol) was added in small portions over 0.5 h. The cooling bath was removed and the mixture was stirred for 0.5 h. After the mixture was re-cooled to 0° C., a solution of Cbz-L-Ser-OMe 15.0 g, 0.590 mol) in DCM (100 mL) was added dropwise. After the addition, the cooling bath was removed and the mixture was allowed to warm to ambient temperature and stirred for 1.5 h. The mixture was filtered and the filtrate was concentrated to remove most of the solvent. MTBE (400 mL) was added to the residue and the mixture was filtered to remove triphenylphosphine oxide. The filtrate was concentrated and the residue was purified by flash column chromatography on silica gel (petroleum ether/EtOAc=50:1 to 10:1) to afford (R)-methyl 2-(benzyloxycarbonylamino)-3-iodopropanoate (12.3 g, 57% yield) as a colorless solid.
Reaction SMILES: C(OC([C:8]1[S:12][C:11]2[CH:13]=[C:14]([OH:19])[C:15]([O:17][CH3:18])=[CH:16][C:10]=2[C:9]=1[OH:20])=O)CCC.[OH-].[Na+]>>[OH:20][C:9]1[C:10]2[CH:16]=[C:15]([O:17][CH3:18])[C:14]([OH:19])=[CH:13][C:11]=2[S:12][CH:8]=1
Reactant: CCCCOC(=O)c1sc2cc(O)c(OC)cc2c1O
Agent: [Na+]
Agent: [OH-]
Product: COc1cc2c(O)csc2cc1O
Yield: 63 %

Procedure:
2.96 g (10 mmol) XVI and 6.00 g NaOH were heated under reflux for 3.5 h in 100 ml degassed water. The still hot solution was then acidified with concentrated HCl to pH 1. The compound XVII precipitating on cooling in an ice bath was removed and washed with a little n-hexane. A yield of 1.23 g XVII (6.3 mmol, 63%) was obtained.
Reaction SMILES: [Cl:1][C:2]1[C:6]([Cl:7])=[C:5]([CH3:8])[NH:4][C:3]=1[C:9]([OH:11])=O.O=S(Cl)[Cl:14]>>[Cl:1][C:2]1[C:6]([Cl:7])=[C:5]([CH3:8])[NH:4][C:3]=1[C:9]([Cl:14])=[O:11]
Reactant: Cc1[nH]c(C(=O)O)c(Cl)c1Cl
Reactant: O=S(Cl)Cl
Product: Cc1[nH]c(C(=O)Cl)c(Cl)c1Cl

Procedure:
A solution of 3,4-dichloro-5-methyl-1H-pyrrole-2-carboxylic acid (Intermediate 3) in 50 ml SOCl2 was heated at reflux for 30 min. Solvent was removed and the residue was dried in vacuo.
Reaction SMILES: [F:1][C:2]([F:14])([F:13])[O:3][C:4]1[CH:12]=[CH:11][CH:10]=[CH:9][C:5]=1[C:6](O)=[O:7]>C1COCC1>[F:1][C:2]([F:13])([F:14])[O:3][C:4]1[CH:12]=[CH:11][CH:10]=[CH:9][C:5]=1[CH2:6][OH:7]
Reactant: O=C(O)c1ccccc1OC(F)(F)F
Solvent: C1CCOC1
Product: OCc1ccccc1OC(F)(F)F
Temperature: 25 °C
Reaction time: 14 h

Procedure:
To a stirred solution of 2-trifluoromethoxybenzoic acid (1.0 g, 5.2 mmol) in THF (25 mL) at 0° C. was added borane-THF complex (15 mL of a 1.0 M solution in THF, 15 mmol). The solution was warmed to ambient temperature and stirred for 14 h. The solvent was removed under reduced pressure and the residue was partitioned between EtOAc (75 mL) and saturated aqueous NaHCO3 (75 mL). The organic phase was dried (MgSO4), filtered and the solvent was removed under reduced pressure to give 2-trifluoromethoxybenzyl alcohol as a colorless liquid (TLC Rf =0.2 (1:3 EtOAc-hexanes)).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:34])[C:4]([C:16]1[CH:21]=[CH:20][C:19]([O:22][C:23]2[CH:28]=[CH:27][C:26]([CH2:29][CH2:30][C:31](=[O:33])[NH2:32])=[CH:25][CH:24]=2)=[CH:18][CH:17]=1)=[CH:5][C:6]1[CH:11]=[C:10]([O:12][CH3:13])[CH:9]=[C:8]([O:14][CH3:15])[CH:7]=1.C([N-]C(C)C)(C)C.[Li+].Cl[C:44]([O:46][CH2:47][CH3:48])=[O:45]>C1COCC1>[CH3:1][O:2][C:3](=[O:34])[C:4]([C:16]1[CH:21]=[CH:20][C:19]([O:22][C:23]2[CH:24]=[CH:25][C:26]([CH2:29][CH2:30][C:31]([NH:32][C:44]([O:46][CH2:47][CH3:48])=[O:45])=[O:33])=[CH:27][CH:28]=2)=[CH:18][CH:17]=1)=[CH:5][C:6]1[CH:11]=[C:10]([O:12][CH3:13])[CH:9]=[C:8]([O:14][CH3:15])[CH:7]=1
Reactant: CCOC(=O)Cl
Reactant: COC(=O)C(=Cc1cc(OC)cc(OC)c1)c1ccc(Oc2ccc(CCC(N)=O)cc2)cc1
Agent: CC(C)[N-]C(C)C
Agent: [Li+]
Solvent: C1CCOC1
Product: CCOC(=O)NC(=O)CCc1ccc(Oc2ccc(C(=Cc3cc(OC)cc(OC)c3)C(=O)OC)cc2)cc1
Temperature: -78 °C
Reaction time: 0.17 h

Procedure:
2-{4-[4-(2-Carbamoyl-ethyl)-phenoxy]-phenyl }-3-(3,5-dimethoxyphenyl)-acrylic acid methyl ester (7) was obtained as a byproduct in the synthesis of 3-(3,5-dimethoxy-phenyl)-2-{4-[4-(2,4-dioxothiazolidin-5-ylmethyl)-phenoxy]-phenyl}-acrylic acid methyl ester, performed essentially as shown in PCT/US99/09982 (WO 99/58127). 7 (460 mg, 1.0 mmol) was taken up in dry THF (6 mL) and cooled to −78° C. To this solution, lithium diisopropyl amide (LDA) (2M, 0.55 mL, 1.1 mmol) was added and stirred for 10 min. Ethyl chloroformate (0.11 mL, 1.2 mmol) was added and stirred overnight at room temperature. The reaction was quenched with saturated aqueous ammonium chloride solution and ethyl acetate (50 mL) was added. The organic layer was washed with brine (2×20 mL), dried on anhydrous magnesium sulfate and evaporated under reduced pressure. The crude product was purified by silica gel chromatography and eluted with hexane-ethyl acetate (7:3). Yield: 264 mg, 49.8%.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH2:9][C:10]2[N:11]=[C:12]([NH:26][C:27](=[O:29])[CH3:28])[S:13][C:14]=2[CH2:15][C:16]2[CH:21]=[CH:20][C:19]([S:22]([CH3:25])(=[O:24])=[O:23])=[CH:18][CH:17]=2)=[CH:4][CH:3]=1.CS[C:32]1[S:33][CH2:34][CH2:35][N:36]=1.Cl.C([O-])(O)=O.[Na+]>COCCO>[S:33]1[CH2:34][CH2:35][N:36]=[C:32]1[NH:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:8][CH2:9][C:10]2[N:11]=[C:12]([NH:26][C:27](=[O:29])[CH3:28])[S:13][C:14]=2[CH2:15][C:16]2[CH:21]=[CH:20][C:19]([S:22]([CH3:25])(=[O:24])=[O:23])=[CH:18][CH:17]=2)=[CH:6][CH:7]=1
Reactant: CC(=O)Nc1nc(CCc2ccc(N)cc2)c(Cc2ccc(S(C)(=O)=O)cc2)s1
Reactant: CSC1=NCCS1
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: COCCO
Product: CC(=O)Nc1nc(CCc2ccc(NC3=NCCS3)cc2)c(Cc2ccc(S(C)(=O)=O)cc2)s1
Temperature: 120 °C
Reaction time: 1.3 h
Yield: 58.4 %

Procedure:
A mixture of N-{4-[2-(4-aminophenyl)ethyl]-5-[4-(methylsulfonyl)benzyl]-1,3-thiazol-2-yl}-acetamide (200 mg), 2-(methylsulfanyl)-4,5-dihydro-1,3-thiazole (62 mg), concentrated HCl (0.064 ml) and 2-methoxyethanol (3 ml) was stirred at 120° C. for 1.3 hours under N2 atmosphere. After cooled to r.t., the reaction mixture was made basic with saturated NaHCO3. The mixture was extracted with AcOEt. The organic layer was dried over anhydrous MgSO4, and concentrated in vacuo. The residue was purified by preparative silica gel chromatography with CHCl3/MeOH (10:1) as an eluent to give N-{4-{2-[4-(4,5-dihydro-1,3-thiazol-2-ylamino)phenyl]ethyl}-5-[4-(methylsulfonyl)benzyl]-1,3-thiazol-2-yl}acetamide (139.8 mg) as a pale yellow amorphous substance.
Reaction SMILES: C([O:3][C:4]([C:6]1[CH:7]=[N:8][N:9]([C:11]2[N:20](COCC[Si](C)(C)C)[C:19](=[O:29])[C:18]3[C:13](=[CH:14][CH:15]=[C:16](I)[CH:17]=3)[N:12]=2)[CH:10]=1)=[O:5])C.[Cl:31][C:32]1[CH:33]=[C:34](B(O)O)[CH:35]=[CH:36][CH:37]=1>>[Cl:31][C:32]1[CH:37]=[C:36]([C:16]2[CH:17]=[C:18]3[C:13](=[CH:14][CH:15]=2)[N:12]=[C:11]([N:9]2[CH:10]=[C:6]([C:4]([OH:3])=[O:5])[CH:7]=[N:8]2)[NH:20][C:19]3=[O:29])[CH:35]=[CH:34][CH:33]=1
Reactant: OB(O)c1cccc(Cl)c1
Reactant: CCOC(=O)c1cnn(-c2nc3ccc(I)cc3c(=O)n2COCC[Si](C)(C)C)c1
Product: O=C(O)c1cnn(-c2nc3ccc(-c4cccc(Cl)c4)cc3c(=O)[nH]2)c1

Procedure:
The titled compound was prepared in a manner analogous to Example 69, steps C-E, using 1-[6-iodo-4-oxo-3-(2-trimethylsilanyl-ethoxymethyl)-3,4-dihydro-quinazolin-2-yl]-1H-pyrazole-4-carboxylic acid ethyl ester (Example 69 product from step B) and 3-chlorophenylboronic acid in step C. MS (ESI): mass calcd. for C18H11ClN4O3, 366.1; m/z found, 367.0 [M+H]+. 1H NMR (600 MHz, DMSO-d6): 13.00 (br s, 2H), 8.98 (s, 1H), 8.36 (d, J=2.2 Hz, 1H), 8.28 (s, 1H), 8.20 (dd, J=8.5, 2.3 Hz, 1H), 7.85 (t, J=1.9 Hz, 1H), 7.81-7.75 (m, 2H), 7.55 (t, J=7.9 Hz, 1H), 7.49 (ddd, J=8.0, 2.0, 1.0 Hz, 1H).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[O:9][C:10]3[CH:20]=[CH:19][C:18]([C:21]4[CH:22]=[C:23]([CH:27]=[CH:28][CH:29]=4)[C:24](O)=[O:25])=[CH:17][C:11]=3[C:12]=2[C:13](=[O:16])[NH:14][CH3:15])=[CH:4][CH:3]=1.CCN=C=NCCCN(C)C.Cl.[C:42]([S:46]([NH2:49])(=[O:48])=[O:47])([CH3:45])([CH3:44])[CH3:43].ClCCCl>CN(C1C=CN=CC=1)C.CN(C=O)C>[C:42]([S:46]([NH:49][C:24]([C:23]1[CH:22]=[C:21]([C:18]2[CH:19]=[CH:20][C:10]3[O:9][C:8]([C:5]4[CH:6]=[CH:7][C:2]([F:1])=[CH:3][CH:4]=4)=[C:12]([C:13]([NH:14][CH3:15])=[O:16])[C:11]=3[CH:17]=2)[CH:29]=[CH:28][CH:27]=1)=[O:25])(=[O:48])=[O:47])([CH3:45])([CH3:44])[CH3:43]
Reactant: CC(C)(C)S(N)(=O)=O
Reactant: CNC(=O)c1c(-c2ccc(F)cc2)oc2ccc(-c3cccc(C(=O)O)c3)cc12
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: ClCCCl
Solvent: CN(C)C=O
Product: CNC(=O)c1c(-c2ccc(F)cc2)oc2ccc(-c3cccc(C(=O)NS(=O)(=O)C(C)(C)C)c3)cc12
Yield: 30.6 %

Procedure:
In a 1 dram vial with stir bar were combined 3-(2-(4-fluorophenyl)-3-(methylcarbamoyl)benzofuran-5-yl)benzoic acid (35 mg, 0.090 mmol), DMAP (33 mg, 0.27 mmol), EDC hydrochloride (26 mg, 0.14 mmol), and tert-butylsulfonamide (37 mg, 0.27 mmol). 1,2-Dichloroethane (1 mL) and DMF (0.3 mL) were added, the vial was capped, and the reaction was stirred at r.t. overnight. The reaction was concentrated, filtered, purified by prep HPLC, and concentrated on a speedvac to give 14 mg (31% yield) of the title compound as a white powder. 1H NMR (500 MHz, CDCl3) δ ppm 8.12 (s, 1H) 7.97 (s, 1H) 7.91 (dd, J=8.55, 5.19 Hz, 2H) 7.84 (d, J=7.63 Hz, 1H) 7.79 (d, J=7.32 Hz, 1H) 7.46-7.59 (m, 3H) 7.19 (t, J=8.55 Hz, 2H) 6.04 (br. s., 1H) 2.99 (d, J=4.58 Hz, 3H) 1.54 (s, 9H). LC/MS was performed by using Shimadzu-VP instrument with UV detection at 220 nm and Waters Micromass. LC/MS method: solvent A=10% CH3CN/90% H2O/0.1% TFA, solvent B=90% CH3CN/10% H2O/0.1% TFA, start % B=0, final % B=100, gradient time=2 min, stop time=3 min, flow rate=4 ml/min, column: Sunfire C18 5 μm 4.6×50 mm; HPLC Rt=1.71 min, (ES+) m/z (MH+)=509. Analytical HPLC were performed using a Shimadzu-VP instrument with UV detection at 220 nm and 254 nm. Analytical HPLC method: solvent A=5% CH3OH/95% H2O/10 mM NH4HCO3, solvent B=95% CH3OH/5% H2O/10 mM NH4HCO3, start % B=10, final % B=100, gradient time=15 min, stop time=18 min, flow rate=1 ml/min. Column: Phenomenex Gemini C18, 4.6 mm, 3 μm, Rt=16.49 min, purity=100%; column: Waters Xbridge Phenyl 4.6×150 mm, 3.5 μm, Rt=15.35 min, purity=100%.
Reaction SMILES: FC(F)(F)C(O)=O.[CH2:8]([O:10][C:11]([C:13]1[C:14]([C:44]([O:46][CH2:47][CH3:48])=[O:45])=[C:15]([CH2:41][CH2:42][CH3:43])[N:16]2[C:21]=1[C:20]([C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)=[CH:19][C:18]([N:28]1[CH2:33][CH2:32][N:31](C(OC(C)(C)C)=O)[CH2:30][CH2:29]1)=[N:17]2)=[O:12])[CH3:9]>C(Cl)Cl>[CH2:8]([O:10][C:11]([C:13]1[C:14]([C:44]([O:46][CH2:47][CH3:48])=[O:45])=[C:15]([CH2:41][CH2:42][CH3:43])[N:16]2[C:21]=1[C:20]([C:22]1[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=1)=[CH:19][C:18]([N:28]1[CH2:29][CH2:30][NH:31][CH2:32][CH2:33]1)=[N:17]2)=[O:12])[CH3:9]
Reactant: CCCc1c(C(=O)OCC)c(C(=O)OCC)c2c(-c3ccccc3)cc(N3CCN(C(=O)OC(C)(C)C)CC3)nn12
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CCCc1c(C(=O)OCC)c(C(=O)OCC)c2c(-c3ccccc3)cc(N3CCNCC3)nn12
Temperature: 25 °C
Reaction time: 1 h

Procedure:
Trifluoroacetic acid (2 mL) was added to a solution of 2-(4-t-butoxycarbonyl-piperazin-1-yl)-4-phenyl-7-propyl-pyrrolo[1,2-b]pyridazine-5,6-dicarboxylic acid diethyl ester (101) (105 mg, 0.186 mmol) in CH2Cl2 (5 mL). The reaction mixture was stirred for 1 h at ambient temperature and concentrated. Purification by flash chromatography (silica gel, 10% methanol/CHCl3) provided the title compound. 1H NMR (DMSO-d6) δ 1.05-1.11 (m, 6H), 1.39 (t, 3H, J=7.2 Hz), 3.34 (t, 2H, J=7.4 Hz), 3.40-3.42 (m, 4H), 3.72 (q, 2H, J=7.0 Hz), 3.92-3.95 (m, 4H), 4.35 (q, 2H, J=7.1 Hz), 6.99 (s, 1H), 7.57-7.67 (m, 5H), 8.94 (brs, 2H). Mass Spectrum (ES+) m/e=465.1 (M+1-114 (CF3CO2H)).
Reaction SMILES: Cl[CH2:2][C:3]1[CH:8]=[CH:7][C:6]([N:9]2[C:17]3[CH2:16][CH2:15][CH2:14][CH2:13][C:12]=3[C:11]([C:18]([F:21])([F:20])[F:19])=[N:10]2)=[CH:5][CH:4]=1.[CH2:22]([NH:24][C:25](=[O:27])[CH3:26])[CH3:23]>>[CH2:22]([N:24]([CH2:2][C:3]1[CH:8]=[CH:7][C:6]([N:9]2[C:17]3[CH2:16][CH2:15][CH2:14][CH2:13][C:12]=3[C:11]([C:18]([F:21])([F:20])[F:19])=[N:10]2)=[CH:5][CH:4]=1)[C:25](=[O:27])[CH3:26])[CH3:23]
Reactant: FC(F)(F)c1nn(-c2ccc(CCl)cc2)c2c1CCCC2
Reactant: CCNC(C)=O
Product: CCN(Cc1ccc(-n2nc(C(F)(F)F)c3c2CCCC3)cc1)C(C)=O

Procedure:
The title compound was prepared from 1-[4-(chloromethyl)phenyl]-3-(trifluoromethyl)-4,5,6,7-tetrahydro-1H-indazole and N-ethylacetamide using a similar procedure to that described for Description 15.
Reaction SMILES: Br[CH2:2][C:3]([N:5]1[CH2:10][CH2:9][N:8]([C:11]2[CH:16]=[CH:15][C:14]([C:17]([O:26]COC)([C:22]([F:25])([F:24])[F:23])[C:18]([F:21])([F:20])[F:19])=[CH:13][C:12]=2[CH2:30][CH2:31][CH3:32])[CH2:7][C@H:6]1[CH3:33])=[O:4].[O:34]1[C:38]2[CH:39]=[CH:40][C:41]([C:43]3([CH3:50])[NH:47][C:46](=[O:48])[NH:45][C:44]3=[O:49])=[CH:42][C:37]=2[CH2:36][CH2:35]1>>[O:34]1[C:38]2[CH:39]=[CH:40][C:41]([C:43]3([CH3:50])[NH:47][C:46](=[O:48])[N:45]([CH2:2][C:3]([N:5]4[CH2:10][CH2:9][N:8]([C:11]5[CH:16]=[CH:15][C:14]([C:17]([OH:26])([C:18]([F:19])([F:21])[F:20])[C:22]([F:24])([F:25])[F:23])=[CH:13][C:12]=5[CH2:30][CH2:31][CH3:32])[CH2:7][C@H:6]4[CH3:33])=[O:4])[C:44]3=[O:49])=[CH:42][C:37]=2[CH2:36][CH2:35]1
Reactant: CCCc1cc(C(OCOC)(C(F)(F)F)C(F)(F)F)ccc1N1CCN(C(=O)CBr)[C@H](C)C1
Reactant: CC1(c2ccc3c(c2)CCO3)NC(=O)NC1=O
Product: CCCc1cc(C(O)(C(F)(F)F)C(F)(F)F)ccc1N1CCN(C(=O)CN2C(=O)NC(C)(c3ccc4c(c3)CCO4)C2=O)[C@H](C)C1

Procedure:
(R)-2-bromo-1-(4-{4-[1,1,1,3,3,3-hexafluoro-2-(methoxymethoxy)propan-2-yl]-2-propylphenyl}-2-methylpiperazin-1-yl)ethanone and 5-(2,3-dihydrobenzofuran-5-yl)-5-methylimidazolidine-2,4-dione were used for a similar reaction and treatment as Examples 14-1 and 15-1, and the title compound was obtained as a yellow oil.