Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:9]2[CH2:15][C:14](=[O:16])[O:13][C:11](=[O:12])[CH2:10]2)[CH:5]=[CH:6][C:7]=1[Cl:8].[NH:17]1[C:26]2[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=2)[CH2:20][CH2:19][CH2:18]1.C(N(CC)CC)C>C(Cl)Cl>[Cl:1][C:2]1[CH:3]=[C:4]([CH:9]([CH2:10][C:11](=[O:12])[CH:18]2[CH2:19][CH2:20][C:21]3[C:26](=[CH:25][CH:24]=[CH:23][CH:22]=3)[NH:17]2)[CH2:15][C:14]([OH:13])=[O:16])[CH:5]=[CH:6][C:7]=1[Cl:8]
Reactant: c1ccc2c(c1)CCCN2
Reactant: O=C1CC(c2ccc(Cl)c(Cl)c2)CC(=O)O1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: O=C(O)CC(CC(=O)C1CCc2ccccc2N1)c1ccc(Cl)c(Cl)c1
Temperature: 0 °C
Reaction time: 2 h

Procedure:
3-(3,4-Dichlorophenyl)glutaric anhydride (10 g, Example 1, Step C) in CH2Cl2 (300 mL) at 0° C. was treated sequentially with 1,2,3,4-tetrahydroquinoline (5.6 mL), triethylamine (6.3 mL) and N,N-dimethylaminopyridine (472 mg). The mixture was stirred at 0° C. for two hours then allowed to warm to room temperature and stirred for 12 hours. The reaction mixture was diluted with CH2Cl2 (500 mL) and washed with 1N HCl (1×200 mL) and water (1×200 mL). The organic layers were dried over MgSO4, filtered and concentrated to afford the title compound (14.3 g).
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]2[O:17][C:16]3[C:11](=[CH:12][C:13]([OH:18])=[CH:14][CH:15]=3)[CH:10]3[CH2:19]S[CH2:21][CH:9]23)=[CH:4][CH:3]=1.O[O:23][S:24]([O-:26])=O.[K+].[O-]S([O-])=O.[Na+].[Na+]>CO.O.CCOC(C)=O>[OH:1][C:2]1[CH:3]=[CH:4][C:5]([C@@H:8]2[O:17][C:16]3[C:11](=[CH:12][C:13]([OH:18])=[CH:14][CH:15]=3)[C@@H:10]3[CH2:19][S:24](=[O:26])(=[O:23])[CH2:21][C@H:9]23)=[CH:6][CH:7]=1
Reactant: Oc1ccc(C2Oc3ccc(O)cc3C3CSCC32)cc1
Reactant: O=S([O-])OO
Agent: O=S([O-])[O-]
Agent: [K+]
Agent: [Na+]
Solvent: CO
Solvent: O
Solvent: CCOC(C)=O
Product: O=S1(=O)C[C@H]2[C@@H](C1)c1cc(O)ccc1O[C@H]2c1ccc(O)cc1
Yield: 75.8 %

Procedure:
To a solution of enantiomer A of 4-(4-hydroxy-phenyl)-1,3a,4,9b-tetrahydro-3H-5-oxa-2-thia-cyclopenta[a]naphthalen-8-ol 11d (10 mg, 0.033 mmol) in MeOH/H2O (1:1, 3 mL) add oxone (40 mg, 0.066 mmol). Stir the reaction at 50° C. for 2 hours. Add 1.0 M Na2SO3 and stir the reaction for 5 minutes. Dilute with EtOAc and wash with saturated sodium bicarbonate. Extract aqueous layer with EtOCAc (2×). Combine organic extracts, dry (Na2SO4), filter and concentrate to afford 4-(4-Hydroxy-phenyl)-2,2-dioxo-1,2,3,3a,4,9b-hexahydro-5-oxa-2λ6-thia-cyclopenta[a]naphthalen-8-ol 14 (8.5 mg, 0.025 mmol, 77%). 1H NMR (δ, 400 MHz, MeOD) 7.47 (d, 2H, J=8.3 Hz), 6.87-6.74 (m, 4H), 6.67 (dd, 1H, J=8.6, 2.4 Hz), 5.25 (s, 1H), 4.12-4.01 (m, 2H), 3.00 (m, 1H), 2.72 (dt, 1H, J=6.8, 12.8 Hz), 2.63-2.53 (m, 1H), 2.52-2.42 (m, 1H). HPLC (Zorbax C18 column; 10 to 100% CH3CN/H2O for 10 min then 100% CH3CN for 5 min; 1 mL/min; tr 7.68 min).
Reaction SMILES: COC1C=C(NC2N=CC3CC(=O)NC4C=C(I)C=CC=4C=3N=2)C=CC=1OC.CNCC#C.[CH3:34][O:35][C:36]1[CH:37]=[C:38]([NH:44][C:45]2[N:46]=[CH:47][C:48]3[CH2:54][C:53](=[O:55])[NH:52][C:51]4[CH:56]=[C:57]([C:60]#[C:61][CH2:62][NH:63][CH3:64])[CH:58]=[CH:59][C:50]=4[C:49]=3[N:65]=2)[CH:39]=[CH:40][C:41]=1[O:42][CH3:43].Cl>>[CH3:34][O:35][C:36]1[CH:37]=[C:38]([NH:44][C:45]2[N:46]=[CH:47][C:48]3[CH2:54][C:53](=[O:55])[NH:52][C:51]4[CH:56]=[C:57]([CH2:60][CH2:61][CH2:62][NH:63][CH3:64])[CH:58]=[CH:59][C:50]=4[C:49]=3[N:65]=2)[CH:39]=[CH:40][C:41]=1[O:42][CH3:43]
Reactant: CNCC#Cc1ccc2c(c1)NC(=O)Cc1cnc(Nc3ccc(OC)c(OC)c3)nc1-2
Agent: C#CCNC
Agent: COc1ccc(Nc2ncc3c(n2)-c2ccc(I)cc2NC(=O)C3)cc1OC
Agent: Cl
Product: CNCCCc1ccc2c(c1)NC(=O)Cc1cnc(Nc3ccc(OC)c(OC)c3)nc1-2

Procedure:
In a manner similar to that described for Method O, 2-(3,4-dimethoxy-phenylamino)-9-iodo-5H,7H-benzo[b]pyrimido[4,5-d]azepin-6-one (I-30) and N-methylprop-2-yn-1-amine were converted to 2-(3,4-dimethoxy-phenylamino)-9-(3-methylamino-prop-1-ynyl)-5H,7H-benzo[b]pyrimido[4,5-d]azepin-6-one. The crude product (unstable) was carried on in a similar manner to that described for Method P to give I-87, which was converted to the HCl salt (40%): MS Rt=0.98 min, m/z=434 (M+H).
Reaction SMILES: I[CH2:2][CH2:3][CH2:4][CH3:5].[CH3:6][O:7][C:8]1[CH:16]=[C:15]([CH:17]=[C:18]([CH3:20])[CH3:19])[CH:14]=[CH:13][C:9]=1[C:10](Cl)=[O:11]>C1C=CC=CC=1.CN(C)C=O.[Cu].[Zn].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>[CH3:6][O:7][C:8]1[CH:16]=[C:15]([CH:17]=[C:18]([CH3:20])[CH3:19])[CH:14]=[CH:13][C:9]=1[C:10](=[O:11])[CH2:2][CH2:3][CH2:4][CH3:5]
Reactant: COc1cc(C=C(C)C)ccc1C(=O)Cl
Reactant: CCCCI
Agent: [Cu]
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [Zn]
Solvent: CN(C)C=O
Solvent: c1ccccc1
Product: CCCCC(=O)c1ccc(C=C(C)C)cc1OC
Temperature: 60 °C
Reaction time: 2 h
Yield: 60.1 %

Procedure:
A mixture of 1-iodobutane (185 mg) and zinc-copper couple (101 mg) in benzene (3 ml) and N,N-dimethylformamide (0.2 ml) was stirred at 60° C. for 2 hours. To the mixture, a solution of tetrakis(triphenylphosphine)palladium (31 mg) and 2-methoxy-4-(2-methyl-1-propenyl)benzoyl chloride (prepared from 138 mg of 2-methoxy-4-(2-methyl-1propenyl)benzoic acid and 0.07 ml of oxalyl chloride) in benzene (2 ml) was added, and the reaction mixture was stirred at room temperature for 30 minutes. The mixture was filtered and the filtrate was concentrated. The residue was dissolved in ethyl acetate and the organic solution was washed with water and brine, dried over magnesium sulfate and concentrated. The residue was chromatographed on silica gel column eluting with a mixture of hexane and ethyl acetate (9:1) to give 2'-methoxy-4'-(2-methyl-1-propenyl)valerophenone (91 mg) 10 as an oil.
Reaction SMILES: [NH:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[C:6]([O:8][CH2:9][CH3:10])=[O:7].[Al+3].[Cl-].[Cl-].[Cl-].[CH3:15][O:16]C(Cl)Cl>ClCCCl.[N+](C)([O-])=O>[CH:15]([C:4]1[CH:3]=[C:2]([C:6]([O:8][CH2:9][CH3:10])=[O:7])[NH:1][CH:5]=1)=[O:16]
Reactant: CCOC(=O)c1ccc[nH]1
Reactant: COC(Cl)Cl
Agent: [Al+3]
Agent: [Cl-]
Solvent: ClCCCl
Solvent: C[N+](=O)[O-]
Product: CCOC(=O)c1cc(C=O)c[nH]1
Reaction time: 1 h
Yield: 90 %

Procedure:
To a mixture of ethyl pyrrole-2-carboxylate (8.1 g, 58.3 mmol) and AlCl3 (15.5 g, 2 equiv) in 1,2-dichloroethane-nitromethane (1:1, 120 ml) was added α,α,-dichloromethyl methyl ether (6.4 mL, 2 equiv) dropwise at −20° C. Stirring was continued for 1 h at −20° C. and the reaction mixture was stored at −20° C. overnight. It was then poured into ice. Organic layer was separated and aqueous layer was extracted with DCM. The combined organic layers were washed with water, aqueous NH4OH and water and dried over Na2SO4. Evaporation of solvent afforded ethyl 4-formylpyrrole-2-carboxylate as a solid (8.8 g, 90%). 1H-NMR(CDCl3): δ 10.40 (1H, s), 8.95 (1H, s), 7.60 (1H, dd), 7.33 (1H, dd), 4.36 (2H, q), 1.39 (3H, t).
Reaction SMILES: [Br:1][C:2]1[S:6][C:5]([C:7]([OH:9])=O)=[CH:4][CH:3]=1.C(Cl)(=O)C(Cl)=O.[Cl:16][C:17]1[CH:23]=[CH:22][CH:21]=[CH:20][C:18]=1[NH2:19].CCN(C(C)C)C(C)C.Cl.[Cl-].[Na+].O>C(Cl)Cl.CC(=O)OCC.CN(C=O)C>[Br:1][C:2]1[S:6][C:5]([C:7]([NH:19][C:18]2[CH:20]=[CH:21][CH:22]=[CH:23][C:17]=2[Cl:16])=[O:9])=[CH:4][CH:3]=1
Reactant: Nc1ccccc1Cl
Reactant: O=C(O)c1ccc(Br)s1
Agent: Cl
Agent: O=C(Cl)C(=O)Cl
Agent: [Cl-]
Solvent: ClCCl
Solvent: CCOC(C)=O
Solvent: O
Product: O=C(Nc1ccccc1Cl)c1ccc(Br)s1
Reaction time: 2 h
Yield: 92 %

Procedure:
A mixture of 5-bromo-thiophene-2-carboxylic acid (5) (207 mg, 1 mmol), oxalyl chloride (420 μl) and catalytic amount of DMF in 5 ml DCM was stirred at r.t for 2 h before evaporation to dryness. The resulting solid residue was dissolved in 5 ml DCM and to which were added 2-chloroaniline (209 μl, 2 eq) and DIEA (522 μl). The reaction mixture was stirred at r.t for overnight before worked up with EA/aq. HCl/brine. The org. phase was concentrated and then purified on a flash silica gel column to give 291 mg (5-bromo(2-thienyl))-N-(2-chlorophenyl)carboxamide (7) as light yellow solid. (yield: 92%, purity>90%).
Reaction SMILES: [NH:1]1[CH2:5][CH:4]=[CH:3][CH2:2]1.CCN(CC)CC.[C:13](Cl)([O:15][CH2:16][CH:17]1[C:29]2[C:24](=[CH:25][CH:26]=[CH:27][CH:28]=2)[C:23]2[C:18]1=[CH:19][CH:20]=[CH:21][CH:22]=2)=[O:14]>C(Cl)Cl>[CH:28]1[C:29]2[CH:17]([CH2:16][O:15][C:13]([N:1]3[CH2:5][CH:4]=[CH:3][CH2:2]3)=[O:14])[C:18]3[C:23](=[CH:22][CH:21]=[CH:20][CH:19]=3)[C:24]=2[CH:25]=[CH:26][CH:27]=1
Reactant: O=C(Cl)OCC1c2ccccc2-c2ccccc21
Reactant: C1=CCNC1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: O=C(OCC1c2ccccc2-c2ccccc21)N1CC=CC1
Temperature: 0 °C
Reaction time: 1 h
Yield: 94.4 %

Procedure:
To a solution of 3-pyrroline (25.0 g, 0.36 mol) in CH2Cl2 (500 mL) at 0° C. was added Et3N (60 mL, 0.42 mol), followed by Fmoc-Cl (103 g, 0.39 mole) at 0° C. The reaction mixture was stirred at 0° C. for 1 h, then 30 minutes at it. The reaction mixture was partitioned between H2O (250 mL) and CH2Cl2 (150 mL×3). The organic phase was washed with brine and dried over Na2SO4. The solvent was evaporated, and the residue was purified on silica gel using 5 to 70% EtOAc in hexanes as eluting solvents to afford 2,5-dihydro-pyrrole-1-carboxylic acid 9H-fluoren-9-ylmethyl ester (99 g, 95%) as a white solid. MS m/z 314.0 ([M+Na]+).
Reaction SMILES: C(=O)([O-])[O-].[Na+].[Na+].[CH3:7][CH:8]([O:10][C:11]1[CH:16]=[CH:15][C:14](B(O)O)=[CH:13][CH:12]=1)[CH3:9].Br[C:21]1[C:22]([NH2:27])=[N:23][CH:24]=[CH:25][CH:26]=1>COCCOC.O.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>[CH3:7][CH:8]([O:10][C:11]1[CH:16]=[CH:15][C:14]([C:21]2[C:22]([NH2:27])=[N:23][CH:24]=[CH:25][CH:26]=2)=[CH:13][CH:12]=1)[CH3:9]
Reactant: CC(C)Oc1ccc(B(O)O)cc1
Reactant: Nc1ncccc1Br
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: COCCOC
Product: CC(C)Oc1ccc(-c2cccnc2N)cc1
Temperature: 80 °C
Reaction time: 8 h
Yield: 90.6 %

Procedure:
A mixture of sodium carbonate (906 mg), tetrakis(triphenylphosphine)palladium(0) (247 mg), 4-(1-methylethoxy)phenylboronic acid (1000 mg) and 3-bromopyridin-2-amine (0.739 g) in 1,2-dimethoxyethane (50 mL) and water (10 mL) was stirred under a nitrogen atmosphere at 80° C. overnight. The reaction mixture was added to water, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate/hexane) to give the title compound (883 mg) as a pale-yellow solid.
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5](=[O:24])[N:6]([CH2:8][CH2:9][CH2:10][C:11]2[CH:12]=[C:13]([CH:21]=[CH:22][CH:23]=2)[O:14][CH2:15][C:16]([O:18][CH2:19][CH3:20])=[O:17])[CH:7]=1.[C:25]1([C:34]2[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=2)[C:26](B(O)O)=[CH:27][CH:28]=[CH:29][CH:30]=1.C([O-])([O-])=O.[Na+].[Na+].O>[Cl-].[Na+].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.C1(C)C=CC=CC=1>[C:25]1([C:34]2[CH:35]=[CH:36][CH:37]=[CH:38][CH:39]=2)[CH:26]=[CH:27][CH:28]=[CH:29][C:30]=1[C:2]1[CH:3]=[CH:4][C:5](=[O:24])[N:6]([CH2:8][CH2:9][CH2:10][C:11]2[CH:12]=[C:13]([CH:21]=[CH:22][CH:23]=2)[O:14][CH2:15][C:16]([O:18][CH2:19][CH3:20])=[O:17])[CH:7]=1
Reactant: CCOC(=O)COc1cccc(CCCn2cc(Br)ccc2=O)c1
Reactant: OB(O)c1ccccc1-c1ccccc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Cl-]
Solvent: O
Solvent: Cc1ccccc1
Product: CCOC(=O)COc1cccc(CCCn2cc(-c3ccccc3-c3ccccc3)ccc2=O)c1
Temperature: 100 °C
Reaction time: 3 h
Yield: 82.7 %

Procedure:
A mixture of ethyl {3-[3-(5-bromo-2-oxopyridin-1(2H)-yl) propyl]phenoxy}acetate (187.5 mg), 2-biphenylboronic acid (104 mg), Na2CO3(504 mg), Pd(PPh3)4 (27 mg), water (4 mL) and toluene (8 mL) were stirred under N2 gas atmosphere at 100° C. for 3 hours. The reaction mixture was cooled to ambient temperature, diluted with 5% aqueous sodium chloride solution and extracted with EtOAc. The organic layer was washed with brine, dried over anhydrous MgSO4, filtered and evaporated in vacuo. The residue was purified by silica gel column chromatography (n-hexane:EtOAc=70:30-50:50). to give ethyl {3-[3-(5-biphenyl-2-yl-2-oxopyridin-1(2H)-yl)propyl]phenoxy}acetate (184 mg) as a colorless oil.
Reaction SMILES: Cl.[CH3:2][NH:3][CH:4]1[CH2:9][CH2:8][O:7][CH2:6][CH2:5]1.FC(F)(F)S([O-])(=O)=O.[N:18]1([S:23](N2C=C[NH+](C)C2)(=[O:25])=[O:24])[CH:22]=[CH:21][N:20]=[CH:19]1>>[CH3:2][N:3]([CH:4]1[CH2:9][CH2:8][O:7][CH2:6][CH2:5]1)[S:23]([N:18]1[CH:22]=[CH:21][N:20]=[CH:19]1)(=[O:25])=[O:24]
Reactant: C[NH+]1C=CN(S(=O)(=O)n2ccnc2)C1
Reactant: CNC1CCOCC1
Agent: Cl
Agent: O=S(=O)([O-])C(F)(F)F
Product: CN(C1CCOCC1)S(=O)(=O)n1ccnc1

Procedure:
Imidazole-1-sulfonic acid methyl-(tetrahydro-pyran-4-yl)-amide was prepared in accordance with step A of the general method described in example 76 from methyl-(tetrahydro-pyran-4-yl)amine hydrochloride and 3-(1H-imidazol-1-ylsulfonyl)-1-methyl-1H-imidazolium trifluoromethanesulfonate; MS: m/e=246.8 (M+H+).
Reaction SMILES: Cl.[NH:2]1[CH2:7][CH2:6][CH:5]([N:8]2[N:12]=[C:11]([CH2:13][O:14][C:15]3[CH:16]=[CH:17][C:18]([N:21]4[CH:25]=[N:24][N:23]=[N:22]4)=[N:19][CH:20]=3)[CH:10]=[N:9]2)[CH2:4][CH2:3]1.[C:26]1([CH2:32][S:33](Cl)(=[O:35])=[O:34])[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1>>[CH2:32]([S:33]([N:2]1[CH2:3][CH2:4][CH:5]([N:8]2[N:12]=[C:11]([CH2:13][O:14][C:15]3[CH:16]=[CH:17][C:18]([N:21]4[CH:25]=[N:24][N:23]=[N:22]4)=[N:19][CH:20]=3)[CH:10]=[N:9]2)[CH2:6][CH2:7]1)(=[O:35])=[O:34])[C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1
Reactant: c1cc(-n2cnnn2)ncc1OCc1cnn(C2CCNCC2)n1
Reactant: O=S(=O)(Cl)Cc1ccccc1
Agent: Cl
Product: O=S(=O)(Cc1ccccc1)N1CCC(n2ncc(COc3ccc(-n4cnnn4)nc3)n2)CC1

Procedure:
The title compound was synthesized using Intermediate 15 and phenylmethanesulfonyl chloride in a similar manner as described in Example 39. 1H NMR (DMSO-d6): δ 10.07 (1H, s), 8.41 (1H, d), 8.00 (1H, d), 7.96 (1H, s), 7.86 (1H, dd), 7.36 (5H, m), 5.35 (2H, s), 4.68 (1H, m), 4.43 (2H, s) 3.54 (2H, m), 2.99 (2H, m), 2.12 (2H, m), 1.91 (2H, m).
Reaction SMILES: [F:1][C:2]1[CH:10]=[C:9]([OH:11])[CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=[O:5].[C:12](Cl)(=[O:25])[CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH3:24].CN(C1C=CC=CN=1)C.Cl>ClCCl.C(N(CC)CC)C>[F:1][C:2]1[CH:10]=[C:9]([O:11][C:12](=[O:25])[CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH3:24])[CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=[O:5]
Reactant: CCCCCCCCCCCCC(=O)Cl
Reactant: O=C(O)c1ccc(O)cc1F
Agent: CN(C)c1ccccn1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCCCCCCCCCCCC(=O)Oc1ccc(C(=O)O)c(F)c1
Temperature: 25 °C
Reaction time: 20 h
Yield: 59.4 %

Procedure:
To a solution of 2-fluoro-4-hydroxybenzoic acid (1.4 g) and triethylamine (1.0 g) in dichloromethane (40 ml) were added tridecanoyl chloride (2.0 g) and dimethylaminopyridine (0.2 g). The solution was stirred at room temperature for about 20 hours and thereto was added dilute aqueous hydrochloric acid solution. The organic layer was separated by a funnel and distilled to remove the solvent. The residue was washed with n-hexane and dried to obtain the titled compound (about 1.8 g).
Reaction SMILES: C(OC([NH:8][C:9]1[C:14]([F:15])=[C:13]([C:16]2[CH:21]=[CH:20][C:19]([Cl:22])=[C:18]([F:23])[CH:17]=2)[N:12]=[C:11]([C:24]([O:26][CH3:27])=[O:25])[C:10]=1[CH:28]=[CH2:29])=O)(C)(C)C.FC(F)(F)C(O)=O>ClC(Cl)C>[NH2:8][C:9]1[C:14]([F:15])=[C:13]([C:16]2[CH:21]=[CH:20][C:19]([Cl:22])=[C:18]([F:23])[CH:17]=2)[N:12]=[C:11]([C:24]([O:26][CH3:27])=[O:25])[C:10]=1[CH:28]=[CH2:29]
Reactant: C=Cc1c(C(=O)OC)nc(-c2ccc(Cl)c(F)c2)c(F)c1NC(=O)OC(C)(C)C
Solvent: O=C(O)C(F)(F)F
Solvent: CC(Cl)Cl
Product: C=Cc1c(C(=O)OC)nc(-c2ccc(Cl)c(F)c2)c(F)c1N
Reaction time: 4 h
Yield: 95.5 %

Procedure:
Methyl 4-(tert-butoxycarbonylamino)-6-(4-chloro-3-fluorophenyl)-5-fluoro-3-vinylpicolinate (0.966 g, 2.274 mmol) was dissolved in dichloroethane (11 mL) and trifluoroacetic acid (3.50 mL, 45.5 mmol) was added. After 4 h at room temperature, the reaction mixture was concentrated under vacuum then coevaporated with additional dichloroethane twice more. The residue was purified by flash chromatography (SiO2, eluting with 7-60% ethyl acetate in hexanes) to provide the title compound as a white solid (0.705 g, 95%).
Reaction SMILES: Br[C:2]1[N:18]([C@@H:19]2[CH2:23][CH2:22][N:21]([C:24]([O:26][C:27]([CH3:30])([CH3:29])[CH3:28])=[O:25])[CH2:20]2)[C:5]2[N:6]=[CH:7][N:8]=[C:9]([NH:10]C(OC(C)(C)C)=O)[C:4]=2[C:3]=1[C:31]1[CH:36]=[CH:35][C:34]([O:37][C:38]2[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=2)=[CH:33][CH:32]=1.[O:44]1[CH:48]=[CH:47][N:46]=[CH:45]1.CC([O-])(C)C.[K+]>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>[NH2:10][C:9]1[C:4]2[C:3]([C:31]3[CH:36]=[CH:35][C:34]([O:37][C:38]4[CH:39]=[CH:40][CH:41]=[CH:42][CH:43]=4)=[CH:33][CH:32]=3)=[C:2]([C:45]3[O:44][CH:48]=[CH:47][N:46]=3)[N:18]([C@@H:19]3[CH2:23][CH2:22][N:21]([C:24]([O:26][C:27]([CH3:30])([CH3:29])[CH3:28])=[O:25])[CH2:20]3)[C:5]=2[N:6]=[CH:7][N:8]=1
Reactant: c1cocn1
Reactant: CC(C)(C)OC(=O)Nc1ncnc2c1c(-c1ccc(Oc3ccccc3)cc1)c(Br)n2[C@@H]1CCN(C(=O)OC(C)(C)C)C1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: C1COCCO1
Product: CC(C)(C)OC(=O)N1CC[C@@H](n2c(-c3ncco3)c(-c3ccc(Oc4ccccc4)cc3)c3c(N)ncnc32)C1
Temperature: 100 °C
Yield: 37.1 %

Procedure:
To a suspension of (R)-tert-butyl 3-(6-bromo-4-(tert-butoxycarbonylamino)-5-(4-phenoxyphenyl)-7H-pyrrolo[2,3-d]pyrimidin-7-yl)pyrrolidine-1-carboxylate (119) (100 mg, 0.15 mmol), oxazole (52 mg, 0.75 mmol), t-BuOK (35 mg, 0.3 mmol) in dioxane (4 mL) was added tetrakis (36 mg, 0.03 mmol). The resulting mixture was purged with N2 (2×) before heated to 100° C. under N2 atmosphere for 30 hrs. The mixture was cooled down to r.t and concentrated under reduced pressure. The residue was purified by flash chromatography (silica gel, 0 to 50% EA in PE) to afford (R)-tert-butyl 3-(4-amino-6-(oxazol-2-yl)-5-(4-phenoxyphenyl)-7H-pyrrolo[2,3-d]pyrimidin-7-yl)pyrrolidine-1-carboxylate (123) (30 mg, 42% yield) as a white solid. LC-MS (ESI): m/z (M+1) 539.1.
Reaction SMILES: C1(CN2C(=O)C(CO)=CC(C3C=CC4OCCC=4C=3)=N2)CC1.[C:23]([C:26]1[C:27](=[O:49])[N:28]([CH2:41][C:42]2[CH:47]=[CH:46][C:45]([F:48])=[CH:44][CH:43]=2)[N:29]=[C:30]([C:32]2[CH:33]=[CH:34][C:35]3[O:39][CH2:38][CH2:37][C:36]=3[CH:40]=2)[CH:31]=1)(O)=[O:24]>>[F:48][C:45]1[CH:44]=[CH:43][C:42]([CH2:41][N:28]2[C:27](=[O:49])[C:26]([CH2:23][OH:24])=[CH:31][C:30]([C:32]3[CH:33]=[CH:34][C:35]4[O:39][CH2:38][CH2:37][C:36]=4[CH:40]=3)=[N:29]2)=[CH:47][CH:46]=1
Reactant: O=C(O)c1cc(-c2ccc3c(c2)CCO3)nn(Cc2ccc(F)cc2)c1=O
Agent: O=c1c(CO)cc(-c2ccc3c(c2)CCO3)nn1CC1CC1
Product: O=c1c(CO)cc(-c2ccc3c(c2)CCO3)nn1Cc1ccc(F)cc1
Yield: 43.4 %

Procedure:
The general procedure of Example 1 (4) was carried out by use of 4-carboxy-2-(4-fluorobenzyl)-6-(2,3-dihydro-1-benzofuran-5-yl)-2H-pyridazin-3-one, to thereby yield the title compound as a yellow oil (yield: 43.4%).
Reaction SMILES: Cl[C:2]1[N:7]=[CH:6][C:5]([C:8]([N:10]2[C:16]3[CH:17]=[CH:18][CH:19]=[CH:20][C:15]=3[CH2:14][N:13]3[CH:21]=[CH:22][CH:23]=[C:12]3[CH2:11]2)=[O:9])=[CH:4][CH:3]=1.[C:24]1(B(O)O)[C:33]2[C:28](=[CH:29][CH:30]=[CH:31][CH:32]=2)[CH:27]=[CH:26][CH:25]=1.C(O)C.C(=O)([O-])[O-].[Na+].[Na+]>C1(C)C=CC=CC=1.C(OCC)(=O)C.O.C([O-])(=O)C.[Pd+]>[C:32]1([C:2]2[N:7]=[CH:6][C:5]([C:8]([N:10]3[C:16]4[CH:17]=[CH:18][CH:19]=[CH:20][C:15]=4[CH2:14][N:13]4[CH:21]=[CH:22][CH:23]=[C:12]4[CH2:11]3)=[O:9])=[CH:4][CH:3]=2)[C:33]2[C:28](=[CH:27][CH:26]=[CH:25][CH:24]=2)[CH:29]=[CH:30][CH:31]=1
Reactant: OB(O)c1cccc2ccccc12
Reactant: O=C(c1ccc(Cl)nc1)N1Cc2cccn2Cc2ccccc21
Agent: [Pd+]
Agent: CC(=O)[O-]
Agent: O=C([O-])[O-]
Solvent: O
Solvent: CCO
Solvent: Cc1ccccc1
Product: O=C(c1ccc(-c2cccc3ccccc23)nc1)N1Cc2cccn2Cc2ccccc21
Yield: 22.8 %

Procedure:
A suspension of (6-chloro-pyridin-3-yl)-[10,11-dihydro-5H-pyrrolo{2,1-c][1,4]benzodiazepin-10-yl]methanone of Step A (0.645 g, 1.9 mmol) and naphthalene boronic acid (0.372 g, 2.1 mmol) in a mixture of toluene (1.2 mL), ethanol (2 mL) and 1M aqueous sodium carbonate (0.4 mL) was sparged with nitrogen for 10 minutes. To this was added palladium(I) acetate (0.026 g, 0.1 mmol). The mixture was heated at reflux under a static pressure of nitrogen for 48 hrs. The reaction was diluted with ethyl acetate and water. The organic layer was washed with saturated aqueous sodium bicarbonate then water. The sample was dried over anhydrous magnesium sulfate, filtered and concentrated in vacuo to a brown oil. Flash chromatography of the residue on silica gel eluting with 20–50% ethyl acetate in hexane, yielded 0.180 g of a solid which was recrystallized from chloroform to provide the title compound as off white crystals, m.p. 155–158° C.
Reaction SMILES: [F:1][C:2]([F:16])([F:15])[O:3][C:4]1[CH:9]=[CH:8][C:7]([C:10]([CH3:14])([CH3:13])[CH2:11][OH:12])=[CH:6][CH:5]=1.[O:17]([C:24]1[CH:25]=[C:26]([CH:29]=[CH:30][C:31]=1[F:32])[CH2:27]Br)[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1.[OH-].[Na+]>[Br-].C([N+](CC)(CC)CC1C=CC=CC=1)C.O>[F:1][C:2]([F:15])([F:16])[O:3][C:4]1[CH:5]=[CH:6][C:7]([C:10]([CH3:13])([CH3:14])[CH2:11][O:12][CH2:27][C:26]2[CH:29]=[CH:30][C:31]([F:32])=[C:24]([O:17][C:18]3[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=3)[CH:25]=2)=[CH:8][CH:9]=1
Reactant: Fc1ccc(CBr)cc1Oc1ccccc1
Reactant: CC(C)(CO)c1ccc(OC(F)(F)F)cc1
Agent: CC[N+](CC)(CC)Cc1ccccc1
Agent: [Br-]
Agent: [Na+]
Solvent: O
Product: CC(C)(COCc1ccc(F)c(Oc2ccccc2)c1)c1ccc(OC(F)(F)F)cc1
Temperature: 25 °C
Reaction time: 3 h
Yield: 77 %

Procedure:
1.4 g of 2-(4-trifluoromethoxyphenyl)-2-methylpropyl alcohol prepared in the above step (1), 2.6 g of 3-phenoxy-4-fluorobenzyl bromide and 0.6 g of triethylbenzylammonium bromide were added to 20 ml of a 50% aqueous NaOH solution and the mixture was stirred at room temperature for 3 h. Water was added thereto. After extracting with benzene, the benzene solution was washed with a dilute hydrochloric acid solution and then water and dried. Benzene was distilled off under reduced pressure and 3.6 g of an oily product thus obtained was purified according to column chromatography [silica gel, developer: toluene/hexane (1:4)] to obtain 2.0 g of 3-phenoxy-4-fluorobenzyl 2-(4-trifluoromethoxyphenyl)-2-methylpropyl ether.
Reaction SMILES: [F:1][C:2]([F:11])([F:10])[C:3]1[CH:8]=[CH:7][C:6]([OH:9])=[CH:5][CH:4]=1.[Cl:12][C:13]1[C:14](F)=[CH:15][C:16]2[O:21][CH:20]([C:22]([F:25])([F:24])[F:23])[C:19]([C:26]([O:28]CC)=[O:27])=[CH:18][C:17]=2[CH:31]=1>>[Cl:12][C:13]1[C:14]([O:9][C:6]2[CH:5]=[CH:4][C:3]([C:2]([F:10])([F:11])[F:1])=[CH:8][CH:7]=2)=[CH:15][C:16]2[O:21][CH:20]([C:22]([F:24])([F:23])[F:25])[C:19]([C:26]([OH:28])=[O:27])=[CH:18][C:17]=2[CH:31]=1
Reactant: CCOC(=O)C1=Cc2cc(Cl)c(F)cc2OC1C(F)(F)F
Reactant: Oc1ccc(C(F)(F)F)cc1
Product: O=C(O)C1=Cc2cc(Cl)c(Oc3ccc(C(F)(F)F)cc3)cc2OC1C(F)(F)F

Procedure:
The title compound was prepared from 4-(trifluoromethyl)phenol and ethyl 6-chloro-7-fluoro-2-(trifluoromethyl)-2H-1-benzopyran-3-carboxylate (Example 183, Step 2) via a procedure similar to that described in Example 183, Steps 3 and 4: mp 230.9-232.0° C. 1H NMR (acetone-d6/300 MHz) 7.93 (s, 1H), 7.77 (m, 3H), 7.27 (d, 2H, J=8.7 Hz), 6.86 (s, 1H), 5.87 (q, 1H, J=7.0 Hz). 19F NMR (acetone-d6/282 MHz)−62.8 (s, 3F), −79.4 (d, 3F, J=7.2 Hz). ESLRMS m/z 437 (M−H). ESHRMS m/z 437.0008 (M−H, Calc'd 437.0015). Anal. Calc'd for C18H9ClF6O4: C, 49.28; H, 2.07; Cl, 8.08. Found: C, 49.25; H, 2.08; Cl, 8.24.