Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(Cl)(=O)[C:2](Cl)=[O:3].[NH2:7][C:8]1[N:13]=[C:12]([O:14][CH2:15][C:16]([F:19])([F:18])[F:17])[CH:11]=[C:10]([O:20][CH2:21][C:22]([F:25])([F:24])[F:23])[N:9]=1.NC1N=CC=CN=1>O1CCOCC1>[N:7]([C:8]1[N:9]=[C:10]([O:20][CH2:21][C:22]([F:25])([F:23])[F:24])[CH:11]=[C:12]([O:14][CH2:15][C:16]([F:18])([F:19])[F:17])[N:13]=1)=[C:2]=[O:3]
Reactant: O=C(Cl)C(=O)Cl
Reactant: Nc1nc(OCC(F)(F)F)cc(OCC(F)(F)F)n1
Agent: Nc1ncccn1
Solvent: C1COCCO1
Product: O=C=Nc1nc(OCC(F)(F)F)cc(OCC(F)(F)F)n1
Temperature: 90 °C
Reaction time: 6 h
Yield: 81.5 %

Procedure:
Oxalyl chloride (42.0 mL, 481 mmol) was dissolved in anhydrous 1,4-dioxane (400 mL) under an N2 atmosphere. The resulting solution was heated to 90° C. To the hot solution was slowly added a solution of 2-amino-4,6-bis(2,2,2-trifluoroethoxy)pyrimidine (14.0 g, 48 mmol) in anhydrous 1,4-dioxane (50 mL). After addition of the aminopyrimidine solution was complete, heating was continued for 6 h, the heat removed, and the solution cooled to room temperature. The solution was concentrated and the residue distilled at reduced pressure to afford the product as a clear oil (12.4 g, 82% yield): bp 53-54° C. (ca.0.1 to 0.2 mm Hg): 1H NMR (CDCl3) δ 6.19 (s, 1H), 4.82-4.74 (q, 2H, J=8.2 Hz).
Reaction SMILES: F[C:2]1[CH:3]=[CH:4][C:5]([N+:9]([O-:11])=[O:10])=[C:6]([OH:8])[CH:7]=1.[OH:12][C:13]1[CH:18]=[CH:17][C:16]([CH2:19][C:20]([O:22]C)=[O:21])=[CH:15][CH:14]=1.C([O-])([O-])=O.[K+].[K+]>CN(C=O)C>[OH:8][C:6]1[CH:7]=[C:2]([CH:3]=[CH:4][C:5]=1[N+:9]([O-:11])=[O:10])[O:12][C:13]1[CH:14]=[CH:15][C:16]([CH2:19][C:20]([OH:22])=[O:21])=[CH:17][CH:18]=1
Reactant: O=[N+]([O-])c1ccc(F)cc1O
Reactant: COC(=O)Cc1ccc(O)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: O=C(O)Cc1ccc(Oc2ccc([N+](=O)[O-])c(O)c2)cc1
Temperature: 110 °C
Reaction time: 12 h

Procedure:
To 4.0 g (4.0 mmol) of resin-bound 5-fluoro-2-nitro-phenol prepared as generally described in Example 37 in 8.0 mL of DMF were added 1.34 g (8.0 mmol) of methyl 4-hydroxyphenylacetate, and 1.20 g (8.0 mmol) of K2CO3. The mixture was heated to 110° C. for 12 h. The resin was washed with H2O, DMF, MeOH, DCM three times of each, and was hydrolyzed by LiOH/H2O/THF/ethanol at rt for 12 h to give the resin-bound [4-(3-hydroxy-4-nitro-phenoxy)-phenyl]-acetic acid.
Reaction SMILES: [CH2:1]([N:8]=[C:9]=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[OH:11][C:12]1[C:18]([C:19]([F:22])([F:21])[F:20])=[CH:17][CH:16]=[CH:15][C:13]=1[NH2:14]>CN(C=O)C>[OH:11][C:12]1[C:18]([C:19]([F:20])([F:21])[F:22])=[CH:17][CH:16]=[CH:15][C:13]=1[NH:14][C:9]([NH:8][CH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1)=[O:10]
Reactant: O=C=NCc1ccccc1
Reactant: Nc1cccc(C(F)(F)F)c1O
Solvent: CN(C)C=O
Product: O=C(NCc1ccccc1)Nc1cccc(C(F)(F)F)c1O
Temperature: 80 °C
Reaction time: 16 h
Yield: 80.6 %

Procedure:
To a solution of benzylisocyanate (74.56 mg, 0.56 mmol) in DMF (1.0 ml), 2-hydroxy-3-trifluoromethylaniline (100 mg, 0.56 mmol) was added. The reaction mixture was stirred at 80° C. for 16 hours. Chromatography of the resulting liquid on silica gel gave desired product (140 mg, 80%). EI-MS m/z 311.1 (M+).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:20])[CH2:4][CH2:5][N:6]([CH2:12][C:13]1[CH:18]=[CH:17][C:16]([Cl:19])=[CH:15][CH:14]=1)[CH:7]1[CH2:11][CH2:10][NH:9][CH2:8]1.C(=O)([O-])[O-].[K+].[K+].Br[CH2:28][CH2:29]/[CH:30]=[C:31]1/[C:32]2[CH:45]=[C:44]([C:46]([OH:49])([CH3:48])[CH3:47])[CH:43]=[CH:42][C:33]=2[O:34][CH2:35][C:36]2[N:41]=[CH:40][CH:39]=[CH:38][C:37]/1=2>C(#N)C.O>[CH3:1][O:2][C:3](=[O:20])[CH2:4][CH2:5][N:6]([CH2:12][C:13]1[CH:14]=[CH:15][C:16]([Cl:19])=[CH:17][CH:18]=1)[CH:7]1[CH2:11][CH2:10][N:9]([CH2:28][CH2:29][CH:30]=[C:31]2[C:37]3[CH:38]=[CH:39][CH:40]=[N:41][C:36]=3[CH2:35][O:34][C:33]3[CH:42]=[CH:43][C:44]([C:46]([OH:49])([CH3:48])[CH3:47])=[CH:45][C:32]2=3)[CH2:8]1
Reactant: COC(=O)CCN(Cc1ccc(Cl)cc1)C1CCNC1
Reactant: CC(C)(O)c1ccc2c(c1)/C(=C/CCBr)c1cccnc1CO2
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Solvent: O
Product: COC(=O)CCN(Cc1ccc(Cl)cc1)C1CCN(CCC=C2c3cc(C(C)(C)O)ccc3OCc3ncccc32)C1
Temperature: 50 °C
Reaction time: 24 h

Procedure:
To a solution of 3-[(4-chloro-benzyl)-pyrrolidin-3-yl-amino]-propionic acid methyl ester (0.06 g, 0.2 mmol) in acetonitrile:water (3:1) was added potassium carbonate (0.056 g, 0.4 mmol) and (E)-2-[5-(3-bromo-propylidene)-5,11-dihydro-10-oxa-1-aza-dibenzo[a,d]cyclohepten-7-yl]-propan-2-ol (0.065 g, 0.17 mmol) and reaction stirred at 50° C. for 24 h. The reaction mixture was concentrated in vacuo, diluted with ethyl acetate and dried over sodium sulfate. The crude product was purified by flash chromatography on silica using ethyl acetate/methanol (5%). 1H-NMR (CDCl3) δ: 1.40 (6H, s), 1.60 (1H, m), 1.80 (1H, m), 2.10-2.60 (8H, m), 3.20-3.40 (6H, m), 3.50 (2H, m; 2H, s), 5.20 (2H, br s), 6.15 (1H, t), 6.70 (1H, t), 7.18-7.42 (7H, m), 7.70 (1H, dd), 8.50 (1H, dd). ESI-MS m/z: 590 (M+1), UV retention time: 1.51 min.
Reaction SMILES: Br[C:2]12[CH2:11][CH:6]3[CH2:7][CH:8]([CH2:10][CH:4]([CH2:5]3)[CH2:3]1)[CH2:9]2.C1COCC1.[C:17]1([Mg]Br)[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1>CCCCC>[C:17]1([C:2]23[CH2:11][CH:6]4[CH2:7][CH:8]([CH2:10][CH:4]([CH2:5]4)[CH2:3]2)[CH2:9]3)[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1
Reactant: BrC12CC3CC(CC(C3)C1)C2
Reactant: Br[Mg]c1ccccc1
Solvent: CCCCC
Solvent: C1CCOC1
Product: c1ccc(C23CC4CC(CC(C4)C2)C3)cc1

Procedure:
1-Bromoadamantane (215.4 mg, 1.0 mmol) and a THF solution (1.55 mL, 0.97 M, 1.50 mmol) of phenylmagnesium bromide were used as starting materials, and reacted as in Entry 1. Conditions: The THF solution of phenylmagnesium bromide was added dropwise at 40° C. over 3 hours. After silica gel column chromatography (pentane), the title compound was obtained as a white solid (0.173 g, yield 81%).
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].Cl[C:8]1[C:15]([F:16])=[CH:14][C:11]([C:12]#[N:13])=[C:10]([NH:17][C:18]2[CH:19]=[C:20]3[C:25](=[CH:26][CH:27]=2)[N:24]=[CH:23][CH:22]=[CH:21]3)[N:9]=1.[NH2:28][C@H:29]([CH2:42][CH3:43])[CH2:30][N:31]1[C:39](=[O:40])[C:38]2[C:33](=[CH:34][CH:35]=[CH:36][CH:37]=2)[C:32]1=[O:41].C(=O)([O-])O.[Na+]>O1CCOCC1>[O:41]=[C:32]1[C:33]2[C:38](=[CH:37][CH:36]=[CH:35][CH:34]=2)[C:39](=[O:40])[N:31]1[CH2:30][C@H:29]([NH:28][C:8]1[C:15]([F:16])=[CH:14][C:11]([C:12]#[N:13])=[C:10]([NH:17][C:18]2[CH:19]=[C:20]3[C:25](=[CH:26][CH:27]=2)[N:24]=[CH:23][CH:22]=[CH:21]3)[N:9]=1)[CH2:42][CH3:43]
Reactant: N#Cc1cc(F)c(Cl)nc1Nc1ccc2ncccc2c1
Reactant: CC[C@@H](N)CN1C(=O)c2ccccc2C1=O
Agent: O=C([O-])O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1COCCO1
Product: CC[C@H](CN1C(=O)c2ccccc2C1=O)Nc1nc(Nc2ccc3ncccc3c2)c(C#N)cc1F
Temperature: 140 °C
Yield: 19.7 %

Procedure:
Potassium carbonate (146 mg) and 6-chloro-5-fluoro-2-(quinolin-6-ylamino)nicotinonitrile (63 mg) were added to a tube containing a 1,4-dioxane (2 ml) solution containing (R)-2-(2-aminobutyl)isoindoline-1,3-dione (60 mg) and the tube was sealed, followed by stirring with heating at 140° C. for 13 hours. The reaction solution was cooled, and a saturated aqueous sodium hydrogen carbonate solution was added, followed by extraction with ethyl acetate. The organic layer was dried over anhydrous sodium sulfate, the solvent was distilled away under reduced pressure. The residue was purified by silica gel chromatography (n-hexane:ethyl acetate=3:2), and a yellow solid of (R)-6-((1-(1,3-dioxoisoindolin-2-yl)butan-2-yl)amino)-5-fluoro-2-(quinolin-6-ylamino)nicotinonitrile (20 mg) was thus obtained.
Reaction SMILES: [Br:1][C:2]1[C:3]([NH:9][C:10]2[CH:19]=[CH:18][CH:17]=[CH:16][C:11]=2[C:12]([NH:14][CH3:15])=[O:13])=[N:4][C:5](Cl)=[N:6][CH:7]=1.[NH2:20][C:21]1[C:22]([O:34][CH3:35])=[CH:23][C:24]2[N:30]([CH3:31])[C:29](=[O:32])[O:28][CH2:27][CH2:26][C:25]=2[CH:33]=1>>[Br:1][C:2]1[C:3]([NH:9][C:10]2[CH:19]=[CH:18][CH:17]=[CH:16][C:11]=2[C:12]([NH:14][CH3:15])=[O:13])=[N:4][C:5]([NH:20][C:21]2[C:22]([O:34][CH3:35])=[CH:23][C:24]3[N:30]([CH3:31])[C:29](=[O:32])[O:28][CH2:27][CH2:26][C:25]=3[CH:33]=2)=[N:6][CH:7]=1
Reactant: CNC(=O)c1ccccc1Nc1nc(Cl)ncc1Br
Reactant: COc1cc2c(cc1N)CCOC(=O)N2C
Product: CNC(=O)c1ccccc1Nc1nc(Nc2cc3c(cc2OC)N(C)C(=O)OCC3)ncc1Br
Yield: 24 %

Procedure:
In an analogous manner to Example 1503, the product was prepared from 2-(5-Bromo-2-chloro-pyrimidin-4-ylamino)-N-methyl-benzamide and 2-Amino-3-methoxy-5-methyl-8,9-dihydro-5H-7-oxa-5-aza-benzocyclohepten-6-one. Product isolated as a yellow solid (25 mg, 24%). mp: 227-228° C., MS (ESI+): 527, 529 (M+H), 1H-NMR (CDCl3, 400 MHz) δ 11.35 (s, 1H), 8.73 (br d, 1H), 8.48 (d, 1H), 8.25 (s, 1H), 8.24 (s, 1H), 7.71 (m, 2H), 7.35 (t, 1H), 7.10 (t, 1H), 7.04 (s, 1H), 4.31 (t, 2H), 3.82 (s, 3H), 3.37 (s, 3H), 2.82 (t, 2H), 2.80 (s, 3H).
Reaction SMILES: [Cl:1][C:2]1[C:7]([CH3:8])=[CH:6][CH:5]=[CH:4][C:3]=1[CH3:9].C1C(=O)N([Br:17])C(=O)C1.C(OOC(=O)C1C=CC=CC=1)(=O)C1C=CC=CC=1>C(Cl)(Cl)(Cl)Cl>[Br:17][CH2:9][C:3]1[CH:4]=[CH:5][CH:6]=[C:7]([CH3:8])[C:2]=1[Cl:1]
Reactant: O=C1CCC(=O)N1Br
Reactant: Cc1cccc(C)c1Cl
Agent: O=C(OOC(=O)c1ccccc1)c1ccccc1
Solvent: ClC(Cl)(Cl)Cl
Product: Cc1cccc(CBr)c1Cl
Temperature: 25 °C

Procedure:
A solution of 2-chloro-m-xylene (5.00 g, 35.60 mmol), NBS (5.70 g, 32.03 mmol), and a catalytic amount of benzoyl peroxide (100 mg) in CCl4 was refluxed for 1 hour. After cooling to room temperature the resulting mixture was filtered and the filtrate was distilled off. Purification by column chromatography using pentane as the eluant followed by distillation afforded the title compound. Spectroscopic data: 1H NMR (300 MHz, CDCl3.) δ 2.39 (s, 3H), 4.61 (s, 2H), 7.08-7.23 (m, 2H), 7.25-7.30 (m, 1H).
Reaction SMILES: [NH2:1][C:2]1[C:10]([Cl:11])=[CH:9][CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=[O:5].Cl[C:13](Cl)([O:15]C(=O)OC(Cl)(Cl)Cl)Cl.N1C=CC=CC=1>C(#N)C.C(Cl)Cl>[Cl:11][C:10]1[C:2]2[NH:1][C:13](=[O:15])[O:5][C:4](=[O:6])[C:3]=2[CH:7]=[CH:8][CH:9]=1
Reactant: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Reactant: Nc1c(Cl)cccc1C(=O)O
Solvent: ClCCl
Solvent: CC#N
Solvent: c1ccncc1
Product: O=c1[nH]c2c(Cl)cccc2c(=O)o1
Temperature: 55 °C
Reaction time: 0.17 h

Procedure:
To a stirred solution of 2-amino-3-chlorobenzoic acid (0.86 g, 5.00 mmol) in anhydrous acetonitrile (10 mL), a solution of triphosgene (0.49 g, 1.65 mmol) in anhydrous CH2Cl2 (5 mL) and anhydrous pyridine (0.79 g, 10.0 mmol) were added, drop-wise at 55° C., simultaneously over a period of 10 minutes. After the addition was complete, the reaction mixture was stirred at 55° C. for another 2 hours. The solvents were removed under vacuum and water (50 mL) was added. The separated solid was filtered, washed with water, followed by chilled CH2Cl2 (10 mL) and dried under vacuum to give 8-chloro-1H-benzo[d][1,3]oxazine-2,4-dione as an off-white solid. Yield 0.82 g (83%).
Reaction SMILES: [NH2:1][C:2]1[C:10]([Cl:11])=[CH:9][C:5]([C:6]([OH:8])=O)=[C:4]([O:12][CH3:13])[CH:3]=1.C(OC(Cl)=O)C.[NH2:20][CH:21]1[CH2:25][N:24]([CH3:26])[N:23]([CH3:27])[CH2:22]1.C(=O)(O)[O-].[Na+]>C(Cl)Cl.C(N(CC)CC)C>[NH2:1][C:2]1[C:10]([Cl:11])=[CH:9][C:5]([C:6]([NH:20][CH:21]2[CH2:25][N:24]([CH3:26])[N:23]([CH3:27])[CH2:22]2)=[O:8])=[C:4]([O:12][CH3:13])[CH:3]=1
Reactant: CN1CC(N)CN1C
Reactant: COc1cc(N)c(Cl)cc1C(=O)O
Agent: CCOC(=O)Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COc1cc(N)c(Cl)cc1C(=O)NC1CN(C)N(C)C1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A stirred solution of equal molar amounts of 4-amino-5-chloro-2-methoxybenzoic acid and triethylamine in methylene chloride (0°-5° C.) was treated dropwise with a slight excess of ethylchlorocarbonate. After 1.0 hour a solution of 4-amino-1,2-dimethylpyrazolidine in methylene chloride was added and the mixture stirred for about two hours at room temperature. An aqueous solution of sodium bicarbonate was added to the reaction mixture, the organic phase separated and concentrated to give the product which melted at 169°-171° C.
Reaction SMILES: [C:1]([NH:9][C:10](=[S:29])[NH:11][C:12]1[S:21][C:15]2[CH2:16][O:17][CH:18]([CH3:20])[CH2:19][C:14]=2[C:13]=1[C:22]([O:24]C(C)(C)C)=[O:23])(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.FC(F)(F)C(O)=O>ClCCl>[C:1]([NH:9][C:10](=[S:29])[NH:11][C:12]1[S:21][C:15]2[CH2:16][O:17][CH:18]([CH3:20])[CH2:19][C:14]=2[C:13]=1[C:22]([OH:24])=[O:23])(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CC1Cc2c(sc(NC(=S)NC(=O)c3ccccc3)c2C(=O)OC(C)(C)C)CO1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CC1Cc2c(sc(NC(=S)NC(=O)c3ccccc3)c2C(=O)O)CO1
Temperature: 25 °C
Reaction time: 4 h
Yield: 44.6 %

Procedure:
To tert-butyl 2-(3-benzoylthioureido)-5-methyl-5,7-dihydro-4H-thieno[2,3-c]pyran-3-carboxylate (0.028 g, 0.065 mmol, 1 eq.) was added a 40% v/v solution of trifluoroacetic acid in dichloromethane (2.5 mL). After stirring the solution for 4 hours at rt, the solvent was evaporated in vacuo, and the residue purified by reverse-phase chromatography to yield the product as a white semi-solid (0.011 g, 0.029 mmol, 46% yield). 1H NMR (400 MHz, Acetone) δ 8.07 (d, J=7.4, 2H), 7.68 (t, J=7.0, 1H), 7.56 (t, J=7.5, 2H), 4.76 (q, J=14.7, 2H), 3.82-3.68 (m, 1H), 3.05 (d, 1H), 1.47 (d, J=6.5, 1H), 1.32 (d, J=6.1, 3H). 13C NMR (126 MHz, Acetone) δ 175.37, 166.92, 165.37, 161.89, 148.65, 134.12, 133.28, 131.39, 129.62, 129.28, 126.49, 71.61, 65.11, 35.05, 21.82. LCMS retention time: 3.095 min; Purity at 214 nm=93.3%. HRMS m/z calculated for C17H17N2O4S2 [M++1] 377.0624. found 377.0622.
Reaction SMILES: [CH3:1][C:2]1([CH3:10])[CH2:7][CH2:6][CH:5]([CH:8]=O)[CH2:4][CH2:3]1.[CH2:11]([NH2:18])[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1.C(O)(=O)C.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>CO>[CH3:1][C:2]1([CH3:10])[CH2:7][CH2:6][CH:5]([CH2:8][NH:18][CH2:11][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[CH2:4][CH2:3]1
Reactant: CC1(C)CCC(C=O)CC1
Reactant: NCc1ccccc1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CO
Product: CC1(C)CCC(CNCc2ccccc2)CC1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
A solution of 4,4-dimethylcyclohexanecarbaldehyde (6.6 g, 0.047 mol), benzylamine (5.0 g, 0.047 mol) and acetic acid (1 mL) in methanol (60 mL) was stirred for 30 min at room temperature. Sodium triacetoxyborohydride (10.0 g, 0.047 mol) was added in one portion and the mixture was stirred at room temperature for 16 hr. The reaction mixture was concentrated in vacuo and partitioned between dichloromethane and water. The organic phase was washed with brine, silica gel was added and the mixture was concentrated in vacuo. The residue was purified by flash chromatography (CH2Cl2/MeOH), affording [(4,4-dimethyl cyclohexyl)methyl](phenylmethyl)amine as a white solid. (M+H) 232, 1.76 min. (LC/MS method B).
Reaction SMILES: [CH:1]([C:4]1[NH:8][C:7]2[CH:9]=[CH:10][CH:11]=[CH:12][C:6]=2[N:5]=1)([CH3:3])[CH3:2].Br[CH2:14][C:15]1[CH:34]=[CH:33][C:18]2/[C:19](=[C:29](/[CH3:32])\[C:30]#[N:31])/[C:20]3[CH:27]=[CH:26][C:25]([F:28])=[CH:24][C:21]=3[O:22][CH2:23][C:17]=2[CH:16]=1>>[F:28][C:25]1[CH:26]=[CH:27][C:20]2=[C:21]([CH:24]=1)[O:22][CH2:23][C:17]1[CH:16]=[C:15]([CH2:14][N:8]3[C:7]4[CH:9]=[CH:10][CH:11]=[CH:12][C:6]=4[N:5]=[C:4]3[CH:1]([CH3:3])[CH3:2])[CH:34]=[CH:33][C:18]=1/[C:19]/2=[C:29](/[CH3:32])\[C:30]#[N:31]
Reactant: CC(C)c1nc2ccccc2[nH]1
Reactant: C/C(C#N)=C1/c2ccc(CBr)cc2COc2cc(F)ccc21
Product: C/C(C#N)=C1/c2ccc(Cn3c(C(C)C)nc4ccccc43)cc2COc2cc(F)ccc21
Yield: 98 %

Procedure:
Using 2-isopropyl-1H-benzo[d]imidazole (Angewandte Chemie, International Edition, 2010, vol. 9, p 1656; 89 mg, 0.56 mmol) and (E)-2-[8-(bromomethyl)-3-fluorodibenzo[b,e]oxepin-11(6H)-ylidene]propanenitrile (200 mg, 0.56 mmol) obtained in Reference Example 1, and in the same manner as in Reference Example 1A, the title compound (240 mg, 98%) was obtained.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([OH:8])[CH:5]=[CH:6][CH:7]=1.C(=O)([O-])[O-].[K+].[K+].[CH2:15](Br)[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1>CN(C=O)C>[CH2:15]([O:8][C:4]1[CH:3]=[C:2]([Br:1])[CH:7]=[CH:6][CH:5]=1)[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1
Reactant: BrCc1ccccc1
Reactant: Oc1cccc(Br)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: Brc1cccc(OCc2ccccc2)c1
Temperature: 25 °C
Reaction time: 20 h
Yield: 95.7 %

Procedure:
A mixture of 3-bromophenol (10.0 g, 57.8 mmol) and 325 mesh potassium carbonate (8.79 g, 63.6 mmol) in DMF (100 mL) is treated dropwise with benzyl bromide (9.89 g, 57.8 mmol) and then stirred 20 hours at rt under N2. The reaction is filtered, and the filtrate is acidified with 1 N HCl. The mixture is then diluted with water and extracted with Et2O. The organic layer is dried (Na2SO4), and the solvent is removed in vacuo to afford crude product that is absorbed on silica gel and purified by flash chromatography using 10/1 hexanes/ethyl acetate to afford 14.55 g (96%) of the titled compound. Rf=0.86 (4/1 hexanes/EtOAc). 1H NMR (400 MHz, CDCl3).
Reaction SMILES: [F:1][C:2]([F:56])([F:55])[C:3]1[CH:4]=[C:5]([C@H:13]([N:15]([CH3:54])[C:16]([N:18]2[CH2:23][CH2:22][C@@:21]([CH2:31][CH:32]=[C:33]([O:38][Si](C(C)(C)C)(C)C)[C:34]([O:36][CH3:37])=[O:35])([NH:24][S:25]([C:27]([CH3:30])([CH3:29])[CH3:28])=[O:26])[CH2:20][C@@H:19]2[C:46]2[CH:51]=[CH:50][C:49]([F:52])=[CH:48][C:47]=2[CH3:53])=[O:17])[CH3:14])[CH:6]=[C:7]([C:9]([F:12])([F:11])[F:10])[CH:8]=1.C(O)(=O)C.[F-].[Cs+].C([O-])(O)=O.[Na+]>C(#N)C>[F:56][C:2]([F:1])([F:55])[C:3]1[CH:4]=[C:5]([C@H:13]([N:15]([CH3:54])[C:16]([N:18]2[CH2:23][CH2:22][C@@:21]([CH2:31][CH2:32][C:33](=[O:38])[C:34]([O:36][CH3:37])=[O:35])([NH:24][S:25]([C:27]([CH3:29])([CH3:30])[CH3:28])=[O:26])[CH2:20][C@@H:19]2[C:46]2[CH:51]=[CH:50][C:49]([F:52])=[CH:48][C:47]=2[CH3:53])=[O:17])[CH3:14])[CH:6]=[C:7]([C:9]([F:11])([F:12])[F:10])[CH:8]=1
Reactant: COC(=O)C(=CC[C@@]1(NS(=O)C(C)(C)C)CCN(C(=O)N(C)[C@H](C)c2cc(C(F)(F)F)cc(C(F)(F)F)c2)[C@@H](c2ccc(F)cc2C)C1)O[Si](C)(C)C(C)(C)C
Agent: O=C([O-])O
Agent: [Cs+]
Agent: [F-]
Solvent: CC(=O)O
Solvent: CC#N
Product: COC(=O)C(=O)CC[C@@]1(NS(=O)C(C)(C)C)CCN(C(=O)N(C)[C@H](C)c2cc(C(F)(F)F)cc(C(F)(F)F)c2)[C@@H](c2ccc(F)cc2C)C1
Temperature: 25 °C
Reaction time: 5 h
Yield: 74.8 %

Procedure:
To a solution of Methyl 4-[(2R,4R)-1-{[{(1R)-1-[3,5-bis(trifluoromethyl)phenyl]ethyl}(methyl)amino]carbonyl}-4-{[(1,1-dimethylethyl)sulfinyl]amino}-2-(4-fluoro-2-methylphenyl)-4-piperidinyl]-2-{[(1,1-dimethylethyl)(dimethyl)silyl]oxy}-2-butenoate (intermediate 5, 100 mg, 0.119 mmol) and Acetic acid (0.014 mL, 0.239 mmol) in Acetonitrile (2 mL) was added Cesium Fluoride (58.0 mg, 0.382 mmol, Aldrich) and the reaction mixture was stirred at 25° C. for 5 hrs. NaHCO3 saturated solution was added very carefully and the mixture was extracted with EtOAc (3×). The combined organic phases were dried (Na2SO4) and evaporated to dryness. The crude was purified by flash chromatography on silica with SP1 (Biotage) system (from 1:0 to 0:1 Cyclohexane/EtOAc) to give the title compound (64.4 mg, 0.089 mmol, 75% yield) as a white foam. 1H NMR (400 MHz, DMSO-d6) δ ppm 7.97 (s, 1H) 7.58-7.72 (m, 2H) 7.08-7.22 (m, 1H) 6.88 (d, 1H) 6.70 (t, 1H) 5.25-5.38 (m, 1H) 5.03 (s, 1H) 4.35-4.50 (m, 1 H) 3.72 (s, 3H) 2.86-3.22 (m, 4H) 2.65 (s, 3H) 2.36 (s, 3H) 1.44 (d, 3H) 1.32-2.12 (m, 6H) 1.19 (s, 9H). The sample consists of two species ratio ˜70:30 (see signals of OMe at 3.71 ppm, 3.66 ppm). UPLC: 2 peaks Rt 0.87 and 0.93 mins with the expected mass m/z=724 [M+H]+.
Reaction SMILES: [O:1]1[C:5]2[CH:6]=[CH:7][C:8]([CH:10]=O)=[CH:9][C:4]=2[CH:3]=[CH:2]1.[S:12]1[CH2:16][C:15](=[O:17])[NH:14][C:13]1=[O:18]>>[O:1]1[C:5]2[CH:6]=[CH:7][C:8]([CH:10]=[C:16]3[S:12][C:13](=[O:18])[NH:14][C:15]3=[O:17])=[CH:9][C:4]=2[CH:3]=[CH:2]1
Reactant: O=C1CSC(=O)N1
Reactant: O=Cc1ccc2occc2c1
Product: O=C1NC(=O)C(=Cc2ccc3occc3c2)S1

Procedure:
Following the general method as outlined in Example 1, starting from 1-benzofuran-5-carbaldehyde (intermediate 1) and 1,3-thiazolidine-2,4-dione, the title compound was obtained.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[NH:7][C:8]2[C:13]([CH:14]=1)=[CH:12][C:11]([N+:15]([O-])=O)=[CH:10][CH:9]=2)=[O:5])[CH3:2].O.C([O-])=O.[NH4+]>[Pd].CO>[CH2:1]([O:3][C:4]([C:6]1[NH:7][C:8]2[C:13]([CH:14]=1)=[CH:12][C:11]([NH2:15])=[CH:10][CH:9]=2)=[O:5])[CH3:2]
Reactant: CCOC(=O)c1cc2cc([N+](=O)[O-])ccc2[nH]1
Agent: [Pd]
Agent: O=C[O-]
Agent: [NH4+]
Solvent: O
Solvent: CO
Product: CCOC(=O)c1cc2cc(N)ccc2[nH]1
Temperature: 90 °C
Reaction time: 0.17 h
Yield: 94.5 %

Procedure:
5 g of 5-nitro-1H-indole-2-carboxylic acid ethyl ester is introduced into 170 ml of methanol and 0.5 ml of water, mixed with 6.73 g of ammonium formate and with 50 mg of palladium on carbon (10%) and refluxed for 1 hour at 90° C. Then, it is suctioned off on Celite and rewashed with warm methanol. After the solvent is removed, the residue is mixed with 100 ml of water, stirred for 10 minutes, and the precipitated solid is suctioned off on a G4 frit. The thus obtained solid is dried in a vacuum. In this way, 4.12 g of the title compound is obtained.
Reaction SMILES: [NH2:1][C@H:2]1[CH2:7][CH2:6][C@H:5]([CH2:8][C:9]([NH:11][C@H:12]2[CH2:17][C:16]3[CH:18]=[CH:19][CH:20]=[C:21]([C:22]([OH:24])=[O:23])[C:15]=3[O:14][B:13]2[OH:25])=[O:10])[CH2:4][CH2:3]1.[CH:26]([CH:28]1[CH2:33][CH2:32][N:31](C(OC(C)(C)C)=O)[CH2:30][CH2:29]1)=O>>[OH:25][B:13]1[C@@H:12]([NH:11][C:9](=[O:10])[CH2:8][C@H:5]2[CH2:6][CH2:7][C@H:2]([NH:1][CH2:26][CH:28]3[CH2:33][CH2:32][NH:31][CH2:30][CH2:29]3)[CH2:3][CH2:4]2)[CH2:17][C:16]2[CH:18]=[CH:19][CH:20]=[C:21]([C:22]([OH:24])=[O:23])[C:15]=2[O:14]1
Reactant: CC(C)(C)OC(=O)N1CCC(C=O)CC1
Reactant: N[C@H]1CC[C@H](CC(=O)N[C@H]2Cc3cccc(C(=O)O)c3OB2O)CC1
Product: O=C(C[C@H]1CC[C@H](NCC2CCNCC2)CC1)N[C@H]1Cc2cccc(C(=O)O)c2OB1O

Procedure:
Prepared from (R)-3-(2-(trans-4-aminocyclohexyl)acetamido)-2-hydroxy-3,4-dihydro-2H-benzo[e][1,2]oxaborinine-8-carboxylic acid (Example 6) and tert-butyl 4-formylpiperidine-1-carboxylate following the procedure in Example 27. Boc group was removed by treatment with 4N HCl in dioxane. The product was purified using reverse phase HPLC to afford the titled compound. ESI-MS m/z 444 (MH)+.
Reaction SMILES: [CH3:1][N:2]1[C:10]2[N:9]=[CH:8][NH:7][C:6]=2[C:5](=[O:11])[NH:4][C:3]1=[O:12].C(=O)([O-])[O-].[K+].[K+].[Cl:19][C:20]1[CH:35]=[CH:34][C:23]([C:24]([C:26]2[CH:33]=[CH:32][C:29]([CH2:30]Br)=[CH:28][CH:27]=2)=[O:25])=[CH:22][CH:21]=1.O>CN(C=O)C.C(OCC)(=O)C>[Cl:19][C:20]1[CH:21]=[CH:22][C:23]([C:24]([C:26]2[CH:33]=[CH:32][C:29]([CH2:30][N:7]3[C:6]4[C:5](=[O:11])[NH:4][C:3](=[O:12])[N:2]([CH3:1])[C:10]=4[N:9]=[CH:8]3)=[CH:28][CH:27]=2)=[O:25])=[CH:34][CH:35]=1
Reactant: O=C(c1ccc(Cl)cc1)c1ccc(CBr)cc1
Reactant: Cn1c(=O)[nH]c(=O)c2[nH]cnc21
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Solvent: O
Product: Cn1c(=O)[nH]c(=O)c2c1ncn2Cc1ccc(C(=O)c2ccc(Cl)cc2)cc1
Temperature: 25 °C
Reaction time: 24 h
Yield: 9.5 %

Procedure:
To a solution of 3-methylxanthine (1.06 g) in DMF (26 ml) were added potassium carbonate (1.06 g) and 4-(4-chlorobenzoyl)benzyl bromide (1.98 g) and the mixture was stirred at room temperature for 24 hours. To this reaction mixture were added water and ethyl acetate and the floating matter was filtered off and the filtrate aqueous solution was diluted with 1N-hydrochloric acid and extracted with chloroform. The extract was washed with saturated aqueous NaCl solution and dried over anhydrous sodium sulfate. The solvent was then distilled off and the residue was washed with ethyl acetate to provide the title compound as colorless powder (239 mg, 10%). 1H-NMR (CDC13) 8: 3.54(3H,s), 3.57(3H,s), 7.41-7.52(4H,m), 7.68-7.81(5H,m).