Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(OC(=O)[NH:7][C:8]1[CH:13]=[CH:12][C:11]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=2[Cl:20])=[CH:10][C:9]=1[NH2:21])(C)(C)C.CC1(C)O[C:28]([C:30]2[CH:31]=[C:32]([CH:35]=[CH:36][CH:37]=2)[C:33]#[N:34])=[CH:27][C:26](=[O:38])O1.C(O)(C(F)(F)F)=O>C(Cl)Cl>[Cl:20][C:15]1[CH:16]=[CH:17][CH:18]=[CH:19][C:14]=1[C:11]1[CH:12]=[CH:13][C:8]2[N:7]=[C:28]([C:30]3[CH:31]=[C:32]([CH:35]=[CH:36][CH:37]=3)[C:33]#[N:34])[CH2:27][C:26](=[O:38])[NH:21][C:9]=2[CH:10]=1
Reactant: CC1(C)OC(=O)C=C(c2cccc(C#N)c2)O1
Reactant: CC(C)(C)OC(=O)Nc1ccc(-c2ccccc2Cl)cc1N
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: N#Cc1cccc(C2=Nc3ccc(-c4ccccc4Cl)cc3NC(=O)C2)c1

Procedure:
Prepared from (3-amino-2′-chloro-biphenyl-4-yl)-carbamic acid tert.-butyl ester (Example G22) and 3-(2,2-dimethyl-6-oxo-6H-[1,3]dioxin-4-yl)-benzonitrile (Example J4) according to the general procedure K. The obtained material was deprotected and cyclized by treatment with TFA in CH2Cl2 according to the general procedure M. Obtained as a white powder (43 mg).
Reaction SMILES: [F:1][C:2]1[C:3]([NH:16][C:17]2[CH:22]=[CH:21][C:20]([I:23])=[CH:19][C:18]=2[F:24])=[C:4]([C:9]([N:11]2[CH2:14][CH:13]([NH2:15])[CH2:12]2)=[O:10])[CH:5]=[CH:6][C:7]=1[F:8].C1CN([P+](ON2N=NC3C=CC=CC2=3)(N2CCCC2)N2CCCC2)CC1.F[P-](F)(F)(F)(F)F.C(N(CC)C(C)C)(C)C.[Br:67][CH2:68][C:69](O)=[O:70]>CN(C)C=O>[Br:67][CH2:68][C:69]([NH:15][CH:13]1[CH2:14][N:11]([C:9]([C:4]2[CH:5]=[CH:6][C:7]([F:8])=[C:2]([F:1])[C:3]=2[NH:16][C:17]2[CH:22]=[CH:21][C:20]([I:23])=[CH:19][C:18]=2[F:24])=[O:10])[CH2:12]1)=[O:70]
Reactant: NC1CN(C(=O)c2ccc(F)c(F)c2Nc2ccc(I)cc2F)C1
Reactant: O=C(O)CBr
Agent: F[P-](F)(F)(F)(F)F
Agent: c1ccc2c(c1)nnn2O[P+](N1CCCC1)(N1CCCC1)N1CCCC1
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: O=C(CBr)NC1CN(C(=O)c2ccc(F)c(F)c2Nc2ccc(I)cc2F)C1
Yield: 81.6 %

Procedure:
A solution of 1-({3,4-difluoro-2-[(2-fluoro-4-iodophenyl)amino]phenyl}carbonyl)azetidin-3-amine (100 mg, 0.22 mmol), PyBOP (131 mg, 0.25 mmol), N,N-diisopropylethylamine (80 μL, 0.44 mol) and bromoacetic acid (35 mg, 0.25 mmol) in dimethylformamide (1 mL) was stirred at room temperature for 15 hours. The reaction mixture was concentrated in vacuo and the resultant residue was purified by column chromatography eluting with 80% ethyl acetate in hexanes to afford 2-bromo-N-[1-({3,4-difluoro-2-[(2-fluoro-4-iodophenyl)amino]phenyl}carbonyl)azetidin-3-yl]acetamide (102 mg, 82% yield) as a white foam. MS (EI) for C18H14BrF3IN3O2: 568.
Reaction SMILES: [Li+].CCC[CH2-].Br[C:7]1[CH:8]=[C:9]2[C:14](=[CH:15][CH:16]=1)[CH:13]=[C:12]([OH:17])[CH:11]=[CH:10]2.C([Li])(C)(C)C.CN(C)P(N(C)C)(N(C)C)=O.CN(C)[CH:36]=[O:37]>C1COCC1>[OH:17][C:12]1[CH:13]=[C:14]2[C:9](=[CH:10][CH:11]=1)[CH:8]=[C:7]([CH:36]=[O:37])[CH:16]=[CH:15]2
Reactant: Oc1ccc2cc(Br)ccc2c1
Reactant: CN(C)C=O
Agent: [CH2-]CCC
Agent: [Li+]
Agent: [Li]C(C)(C)C
Solvent: CN(C)P(=O)(N(C)C)N(C)C
Solvent: C1CCOC1
Product: O=Cc1ccc2cc(O)ccc2c1
Reaction time: 0.17 h
Yield: 80.9 %

Procedure:
Step a) N-Butyllithium (35.9 mL, 89.7 mmol) was added dropwise to a cold (-78° C.) solution of 6-bromo-2-naphthol (20.0 g, 89.7 mmol) in THF (200 mL). After stirring for 10 minutes, tert-butyllithium (52.76 mL, 89.7 mmol) was added dropwise. The mixture was stirred for 30 min at -78° C., and two hours at -20° C. Then, hexamethylphosphoramide (15.6 mL, 89.7 mmol) was added to the reaction mixture. After stirring for 20 minutes. N,N-dimethylformamide (6.94 mL, 89.7 mmol) was added dropwise. The mixture was allowed to come to room temperature, stirred for 1 hour, and quenched with aqueous ammonium chloride. The mixture was poured into water, acidified with 2N HCL and extracted with EtOAc. The organic extracts were dried over MgSO4. Evaporation and purification by flash chromatography (hexane/EtOAc 3/1 ), gave a yellow solid (12.5 g, 81% yield, m.p. 173°-174° C.).
Reaction SMILES: BrC1C=C[C:5](NCC(OC)=O)=[N:6]C=1.[CH3:14][N:15]1[C:23]2[C:18](=[CH:19][CH:20]=[CH:21][C:22]=2[CH3:24])[C:17]([C:25]([O-])=O)=[CH:16]1.CN1C2C(=CC=CC=2)C(C)=C1C([O-])=O>>[CH3:14][N:15]1[C:23]2[C:18](=[CH:19][CH:20]=[CH:21][C:22]=2[CH3:24])[C:17]([CH2:25][NH:6][CH3:5])=[CH:16]1
Reactant: Cc1cccc2c(C(=O)[O-])cn(C)c12
Reactant: COC(=O)CNc1ccc(Br)cn1
Agent: Cc1c(C(=O)[O-])n(C)c2ccccc12
Product: CNCc1cn(C)c2c(C)cccc12
Yield: 98 %

Procedure:
According to the procedure of Preparation 13 (c), except substituting 1,7-dimethyl-1H-indole-3-carboxylate for the 1,3-dimethyl-1H-indole-2-carboxylate, the title compound (0.74 g, 98%) was obtained as an amber oil: MS (ES) mmole 189.2 (M+H)+.
Reaction SMILES: [CH2:1]([N:8]1[C:17]([CH:18]=[O:19])=[C:16]([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[C:15]2[C:10](=[CH:11][CH:12]=[C:13]([Br:26])[CH:14]=2)[C:9]1=[O:27])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:28][Mg]Br.O>C1COCC1>[CH2:1]([N:8]1[C:17]([CH:18]([OH:19])[CH3:28])=[C:16]([C:20]2[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=2)[C:15]2[C:10](=[CH:11][CH:12]=[C:13]([Br:26])[CH:14]=2)[C:9]1=[O:27])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=Cc1c(-c2ccccc2)c2cc(Br)ccc2c(=O)n1Cc1ccccc1
Reactant: C[Mg]Br
Solvent: C1CCOC1
Solvent: O
Product: CC(O)c1c(-c2ccccc2)c2cc(Br)ccc2c(=O)n1Cc1ccccc1
Reaction time: 0.17 h

Procedure:
To a solution of 2-benzyl-6-bromo-1-oxo-4-phenyl-1,2-dihydroisoquinoline-3-carbaldehyde (500 mg) in THF (5 ml) was added dropwise a solution of methyl magnesium bromide in THF (3M, 0.5 ml) at room temperature, and the mixture was stirred for 10 min. To the reaction mixture was added water and the mixture was extracted with ethyl acetate. The organic layer was washed with water and saturated brine, and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure and the obtained residue was crystallized from ethyl acetate-hexane to give the title compound (470 mg).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([N:9]([CH3:11])[CH3:10])[CH:5]=[C:6]([CH3:8])[CH:7]=1.C([O-])(=O)C.[NH4+].[Br:17]N1C(=O)CCC1=O.CCOC(C)=O>C(#N)C>[Br:17][C:7]1[C:6]([CH3:8])=[CH:5][C:4]([N:9]([CH3:10])[CH3:11])=[CH:3][C:2]=1[F:1]
Reactant: Cc1cc(F)cc(N(C)C)c1
Reactant: O=C1CCC(=O)N1Br
Agent: CC(=O)[O-]
Agent: [NH4+]
Solvent: CC#N
Solvent: CCOC(C)=O
Product: Cc1cc(N(C)C)cc(F)c1Br
Reaction time: 1 h
Yield: 92.7 %

Procedure:
To a solution of (3-Fluoro-5-methyl-phenyl)-dimethyl-amine (2.82 g, 18.4 mmol) in acetonitrile (28 mL) were sequentially added ammonium acetate (0.142 g, 1.84 mmol) and a solution of N-bromosuccinimide (3.27 g, 18.4 mmol) in acetonitrile (23 mL) drop-wise at 0° C. After 1 h., at r.t., the solvent was switched to EtOAc, and the solution was washed with saturated NaHCO3 (aq), dried (MgSO4), filtered, and concentrated in vacuo to give an orange, oily residue. Purification of this oil by flash chromatography (SiO2, 5% EtOAc/Hexanes) gave (4-Bromo-3-fluoro-5-methyl-phenyl)-dimethyl-amine as an ivory solid (3.96 g, 93%).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1([OH:14])[CH2:13][CH2:12][NH:11][CH2:10][CH2:9]1.N1C(C)=CC=CC=1C.[I-].[K+].Br[CH2:26][CH2:27][CH:28]=[C:29]1[C:35]2[CH:36]=[CH:37][CH:38]=[N:39][C:34]=2[CH2:33][O:32][C:31]2[CH:40]=[CH:41][C:42]([C:44]([OH:47])([CH3:46])[CH3:45])=[CH:43][C:30]1=2>C(O)(C)C>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1([OH:14])[CH2:9][CH2:10][N:11]([CH2:26][CH2:27][CH:28]=[C:29]2[C:35]3[CH:36]=[CH:37][CH:38]=[N:39][C:34]=3[CH2:33][O:32][C:31]3[CH:40]=[CH:41][C:42]([C:44]([OH:47])([CH3:46])[CH3:45])=[CH:43][C:30]2=3)[CH2:12][CH2:13]1
Reactant: OC1(c2ccccc2Cl)CCNCC1
Reactant: CC(C)(O)c1ccc2c(c1)C(=CCCBr)c1cccnc1CO2
Agent: [I-]
Agent: [K+]
Solvent: Cc1cccc(C)n1
Solvent: CC(C)O
Product: CC(C)(O)c1ccc2c(c1)C(=CCCN1CCC(O)(c3ccccc3Cl)CC1)c1cccnc1CO2
Temperature: 80 °C
Reaction time: 14 h
Yield: 51.4 %

Procedure:
To a solution of the 4-(2-chloro-phenyl)-piperidin-4-ol (0.210 g, 1.0 mmol) in isopropanol was added 2,6-lutidine (0.31 mL, 2.7 mmol) and catalytic potassium iodide. This mixture was heated to 80° C., and treated with 2-[5-(3-Bromo-propylidene)-5,11-dihydro-10-oxa-1-aza-dibenzo[a,d]cyclohepten-7-yl]-propan-2-ol (0.287 g, 0.77 mmol), added in portions over 1 h. The solution was then stirred at 80° C. for an additional 14 h. The reaction was concentrated in vacuo, then purified by Isco flash chromatography (15% methanol/85% methylene chloride) to yield the title compound (0.200 g, 52%).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:11]=1[C:10](=[O:12])[NH:9][CH:8]=[CH:7]2.[C:13](=O)([O-])[O-].[K+].[K+].CI>CN(C=O)C>[Br:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:11]=1[C:10](=[O:12])[N:9]([CH3:13])[CH:8]=[CH:7]2
Reactant: O=c1[nH]ccc2cccc(Br)c12
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: CI
Solvent: CN(C)C=O
Product: Cn1ccc2cccc(Br)c2c1=O
Reaction time: 72 h
Yield: 94.5 %

Procedure:
A solution of (b) (180 mg, 0.8 mmol) in DMF (5 ml) was treated with potassium carbonate (140 mg) and methyl iodide (0.062 ml) and stirred for 3 days then evaporated. The residue was partitioned between dilute aqueous sodium chloride solution and dichloromethane, re-extracting with dichloromethane twice more. The combined organic extracts were dried and evaporated affording a yellow solid (180 mg, 94%).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[C@@H:12]([CH2:13][CH2:14][C:15]2[CH:20]=[CH:19][C:18]([N:21]=[C:22]=[O:23])=[CH:17][CH:16]=2)[CH2:11][O:10][C:9]1([CH3:25])[CH3:24])=[O:7])([CH3:4])([CH3:3])[CH3:2].C(N(CC)C(C)C)(C)C.[Cl:35][C:36]1[CH:43]=[CH:42][C:39]([CH2:40][OH:41])=[CH:38][CH:37]=1>ClCCCl>[C:1]([O:5][C:6]([N:8]1[C@@H:12]([CH2:13][CH2:14][C:15]2[CH:20]=[CH:19][C:18]([NH:21][C:22]([O:41][CH2:40][C:39]3[CH:42]=[CH:43][C:36]([Cl:35])=[CH:37][CH:38]=3)=[O:23])=[CH:17][CH:16]=2)[CH2:11][O:10][C:9]1([CH3:25])[CH3:24])=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: OCc1ccc(Cl)cc1
Reactant: CC(C)(C)OC(=O)N1[C@@H](CCc2ccc(N=C=O)cc2)COC1(C)C
Solvent: ClCCCl
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)(C)OC(=O)N1[C@@H](CCc2ccc(NC(=O)OCc3ccc(Cl)cc3)cc2)COC1(C)C
Temperature: 110 °C
Yield: 51.4 %

Procedure:
To a stirred suspension of (S)-4-[2-(4-isocyanato-phenyl)-ethyl]-2,2-dimethyl-oxazolidine-3-carboxylic acid tert-butyl ester (240 mg) in 1,2-dichloroethane (2 ml) in a pressure tube were added sequentially N,N-diisopropylethylamine (0.24 ml) and 4-chloro-benzyl alcohol (148 mg). The tube was capped and stirring was continued while the reaction mixture was heated at 110° C. for 18 h. The mixture was then cooled to room temperature and concentrated in vacuo. The residue was purified by column chromatography (SiO2; gradient: heptane/EtOAc) to give (S)-4-{2-[4-(4-chloro-benzyloxycarbonylamino)-phenyl]-ethyl}-2,2-dimethyl-oxazolidine-3-carboxylic acid tert-butyl ester (174 mg, 51%) as a colourless amorphous solid. MS (ISP): 508.2 ([{37Cl}M+NH4]+), 506.2 ([{35Cl}M+NH4]+), 491.2 ([{37Cl}M+H]+), 489.2 ([{35Cl}M+H]+), 435.2 ([{37Cl}M+H—C4H8]+), 433.2 ([{35Cl}M+H—C4H8]+).
Reaction SMILES: [C:1]1([C:15]([OH:16])=[C:11]([N+:12]([O-:14])=[O:13])[CH:10]=[C:6]([N+:7]([O-:9])=[O:8])[CH:5]=1)[N+:2]([O-:4])=[O:3].[NH2:17][CH2:18][C:19](=O)[CH2:20][CH:21]([C:24]1[CH:29]=[CH:28][C:27]([C:30]([O:32][CH3:33])=[O:31])=[CH:26][CH:25]=1)[CH2:22][CH3:23].[NH2:35][NH:36][C:37]([NH2:39])=[O:38].[ClH:40]>CCO>[ClH:40].[C:11]1([C:15]([OH:16])=[C:1]([N+:2]([O-:4])=[O:3])[CH:5]=[C:6]([N+:7]([O-:9])=[O:8])[CH:10]=1)[N+:12]([O-:14])=[O:13].[NH2:17][CH2:18][C:19](=[N:35][NH:36][C:37]([NH2:39])=[O:38])[CH2:20][CH:21]([C:24]1[CH:29]=[CH:28][C:27]([C:30]([O:32][CH3:33])=[O:31])=[CH:26][CH:25]=1)[CH2:22][CH3:23]
Reactant: CCC(CC(=O)CN)c1ccc(C(=O)OC)cc1
Reactant: NNC(N)=O
Agent: Cl
Agent: O=[N+]([O-])c1cc([N+](=O)[O-])c(O)c([N+](=O)[O-])c1
Solvent: CCO
Product: CCC(CC(CN)=NNC(N)=O)c1ccc(C(=O)OC)cc1

Procedure:
A mixture of the amino ketone picrate ((9) 6.4 g, 0.133 mol), semicarbazide.HCl (2.6 g, 0.023 mol) and 190 ml of 70% EtOH was stirred at room temperature for 90 hours. The solid was collected and washed with 70% EtOH, and the filtrate was evaporated and similarly retreated with 1.27 g of semicarbazide.HCl in 75 ml of 70% EtOH to afford 0.76 g of yellow crystals (10), mp 200°-201° C. The original solid above was treated with 225 ml of warm EtOH and the insoluble portion collected to give 2.67 g, ml 196°-197° C. The combined mother liquors were evaporated and retreated with 0.84 g of semicarbazide.HCl in 61 ml of 70% EtOH to afford another 1.66 g of (10), mp 200°-201° C., for a total yield of (10) of 5.09 (71%).
Reaction SMILES: [C:1]([O:4][C:5]1[CH:6]=[C:7]([CH:11]=[CH:12][C:13]=1[NH:14][C:15](=[O:17])[CH3:16])[C:8]([OH:10])=[O:9])(=[O:3])[CH3:2].CC(OC(C)=O)=O.[N+:25]([O-])([OH:27])=[O:26]>O1CCOCC1>[C:1]([O:4][C:5]1[CH:6]=[C:7]([CH:11]=[C:12]([N+:25]([O-:27])=[O:26])[C:13]=1[NH:14][C:15](=[O:17])[CH3:16])[C:8]([OH:10])=[O:9])(=[O:3])[CH3:2]
Reactant: O=[N+]([O-])O
Reactant: CC(=O)Nc1ccc(C(=O)O)cc1OC(C)=O
Solvent: CC(=O)OC(C)=O
Solvent: C1COCCO1
Product: CC(=O)Nc1c(OC(C)=O)cc(C(=O)O)cc1[N+](=O)[O-]
Temperature: 0 °C
Yield: 89.9 %

Procedure:
Compound 102 (1.00 g, 4.21 mmol) was suspended with stirring in a mixture of Ac2O (8.33 mL, 8.99 g, 88.2 mmol) and dioxane (6.6 mL). This was cooled to 0° C., and a cold solution of the nitrating mixture made from Ac2O (3.33 mL, 3.59 g, 35.2 mmol) and concentrated HNO3 (3.33 mL) was slowly added to the mixture containing 102. The reaction mixture was then warmed to 30°-35° C. until the reaction was complete as evidenced by TLC. The reaction mixture was poured onto ice/water (100 mL), extracted with EtOAc (4×50 mL), dried (NaSO4), and concentrated to dryness on a rotary evaporator to give crude 104 (1.05 g, 89.9%) as an oil. Trituration with CHCl3 gave a solid: mp 196°-201° C. (dioxane/hexane).
Reaction SMILES: [S-:1][C:2]#[N:3].[K+].Br[CH2:6][C:7]1([CH3:33])[CH:11]([C:12]([O:14][CH2:15][C:16]([Cl:19])([Cl:18])[Cl:17])=[O:13])[N:10]2[C:20](=[O:32])[CH:21]([NH:22][C:23](=[O:31])[CH2:24][C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=3)[C@H:9]2[S:8]1>O.CC(C)=O>[S:1]([CH2:6][C:7]1([CH3:33])[CH:11]([C:12]([O:14][CH2:15][C:16]([Cl:17])([Cl:18])[Cl:19])=[O:13])[N:10]2[C:20](=[O:32])[CH:21]([NH:22][C:23](=[O:31])[CH2:24][C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=3)[C@H:9]2[S:8]1)[C:2]#[N:3]
Reactant: CC1(CBr)S[C@@H]2C(NC(=O)Cc3ccccc3)C(=O)N2C1C(=O)OCC(Cl)(Cl)Cl
Reactant: N#C[S-]
Agent: [K+]
Solvent: CC(C)=O
Solvent: O
Product: CC1(CSC#N)S[C@@H]2C(NC(=O)Cc3ccccc3)C(=O)N2C1C(=O)OCC(Cl)(Cl)Cl
Temperature: 25 °C
Reaction time: 5.5 h
Yield: 78.4 %

Procedure:
Potassium thiocyanate (1.17 g) was dissolved in a mixture of water (20 ml) and acetone (100 ml). To this solution was added 2,2,2-trichloroethyl 2-bromomethyl-2-methyl-6-(2-phenyl-acetamido)penam-3carboxylate (5.45 g) at room temperature and the mixture was stirred for 5.5 hours at room temperature. After removing acetone under reduced pressure at room temperature, precipitates were collected by filtration, washed with water and further washed with ethanol to give 2,2,2-trichloroethyl 2-thiocyanatomethyl-2-methyl-6-(2-phenylacetamido)penam-3-carboxylate (4.10 g). This substance was recrystallized from isopropylether containing 5% acetone to give pure compound, mp 133° to 135° C.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([OH:8])[CH:5]=[CH:6][CH:7]=1.[C:9](O)(=[O:12])[CH:10]=[CH2:11].C1C2NC3C(=CC=CC=3)SC=2C=CC=1>>[F:1][C:2]1[CH:3]=[C:4]2[C:5]([C:9](=[O:12])[CH2:10][CH2:11][O:8]2)=[CH:6][CH:7]=1
Reactant: Oc1cccc(F)c1
Reactant: C=CC(=O)O
Agent: c1ccc2c(c1)Nc1ccccc1S2
Product: O=C1CCOc2cc(F)ccc21
Temperature: -78 °C
Reaction time: 4.5 h

Procedure:
Following the same procedure established in Example 1, the reactor was charged with meta-fluorophenol (28 grams), acrylic acid (27 grams), and phenothiazine (0.02 grams). The reactor was sealed, evacuated and cooled to -78° C. before the anhydrous hydrogen fluoride (125 grams) was added. The mixture was stirred and warmed to 40° C. for one hour then to 100° C. for 4.5 hours as the pressure was recorded at 140 psig. After venting the excess hydrogen fluoride the reactor was cooled to 5° C. and the mixture washed with D.I. water. Analysis by HPLC indicated no 4-Chromanones to be present. A mixture of by-products were seen.
Reaction SMILES: ClC1N=C(C2SC(N3CCCC3)=NC=2C2C=C(NS(C3C(F)=CC=CC=3F)(=O)=O)C=CC=2)C=CN=1.[Cl:36][C:37]1[N:42]=[C:41]([CH2:43][C:44]([C:46]2[CH:47]=[C:48]([NH:52][C:53](=[O:58])[O:54][CH2:55][CH:56]=[CH2:57])[CH:49]=[CH:50][CH:51]=2)=O)[CH:40]=[CH:39][N:38]=1.[CH3:59][CH:60]([CH3:64])[C:61](=[S:63])[NH2:62]>>[Cl:36][C:37]1[N:42]=[C:41]([C:43]2[S:63][C:61]([CH:60]([CH3:64])[CH3:59])=[N:62][C:44]=2[C:46]2[CH:47]=[C:48]([NH:52][C:53](=[O:58])[O:54][CH2:55][CH:56]=[CH2:57])[CH:49]=[CH:50][CH:51]=2)[CH:40]=[CH:39][N:38]=1
Reactant: C=CCOC(=O)Nc1cccc(C(=O)Cc2ccnc(Cl)n2)c1
Reactant: CC(C)C(N)=S
Agent: O=S(=O)(Nc1cccc(-c2nc(N3CCCC3)sc2-c2ccnc(Cl)n2)c1)c1c(F)cccc1F
Product: C=CCOC(=O)Nc1cccc(-c2nc(C(C)C)sc2-c2ccnc(Cl)n2)c1
Yield: 45.9 %

Procedure:
Following a procedure analogous to the procedure described in Intermediate 6, using 2-propen-1-yl {3-[(2-chloro-4-pyrimidinyl)acetyl]phenyl}carbamate (10.0 g, 30.14 mmol), and 2-methylpropanethioamide (3.73 g, 36.17 mmol), prepared by a procedure analogous to Intermediate 1, 5.74 g of the title compound was obtained. MS (ESI): 415 [M+H]+.
Reaction SMILES: [C:1]([C@H:6]1[C@H:15]([C:16]([O:18]CC)=[O:17])[CH2:14][C:13]2[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=2)[CH2:7]1)([O:3][CH2:4][CH3:5])=[O:2].[OH-].[Na+].Cl>C(O)C.C(OCC)(=O)C>[C:1]([C@H:6]1[C@H:15]([C:16]([OH:18])=[O:17])[CH2:14][C:13]2[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=2)[CH2:7]1)([O:3][CH2:4][CH3:5])=[O:2]
Reactant: CCOC(=O)[C@@H]1Cc2ccccc2C[C@H]1C(=O)OCC
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCOC(C)=O
Solvent: CCO
Product: CCOC(=O)[C@@H]1Cc2ccccc2C[C@H]1C(=O)O
Reaction time: 16 h
Yield: 72.6 %

Procedure:
To a stirred solution of trans 2,3-dicarboethoxy-1,2,3,4-tetrahydronaphthalene (2.1 g, 7.6 mmol) in ethanol (10 mL) at room temperature under nitrogen was added 1.0 M aqueous sodium hydroxide solution (7.6 mL, 7.6 mmol). After 16 h, 1.0 M aqueous hydrochloric acid solution (10 mL) was added to quench the reaction mixture. Upon completion of addition, the reaction mixture was concentrated under vacuum to yield a residue. The residue was diluted with ethyl acetate. The organic layer was washed with 1.0 M aqueous hydrochloric acid solution, saturated aqueous ammonium chloride solution and brine, dried over anhydrous magnesium sulfate, and concentrated under vacuum to yield a residue. The residue was purified by silica gel chromatography (50% ethyl acetate in hexane was used) to yield the title compound (1.37 g, 73%). 13C NMR (400 MHz, (CD3)2CO) δ 175.7, 174.7, 135.0, 134.9, 129.3, 129.2, 127.0, 61.0, 42.8, 42.5, 32.2, 14.4. 1H NMR (400 MHz, (CD3)2CO) δ 7.02 (s, 4H), 4.03 (m, 2H), 2.74-3.09 (m, 6H), 1.13 (t, J=7.0 Hz, 6H). MS [M+Na]+, 271.
Reaction SMILES: [CH2:1]([C@H:8]1[C@@H:13]([O:14][CH2:15][C:16]2[CH:21]=[C:20]([C:22]([F:25])([F:24])[F:23])[CH:19]=[C:18]([C:26]([F:29])([F:28])[F:27])[CH:17]=2)[CH2:12][CH2:11][NH:10][CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C1C[O:33][CH2:32][CH2:31]1>C(Cl)(=O)C.CCN(CC)CC>[C:32]([N:10]1[CH2:11][CH2:12][C@H:13]([O:14][CH2:15][C:16]2[CH:17]=[C:18]([C:26]([F:29])([F:27])[F:28])[CH:19]=[C:20]([C:22]([F:23])([F:24])[F:25])[CH:21]=2)[C@H:8]([CH2:1][C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)[CH2:9]1)(=[O:33])[CH3:31]
Reactant: C1CCOC1
Reactant: FC(F)(F)c1cc(CO[C@H]2CCNC[C@H]2Cc2ccccc2)cc(C(F)(F)F)c1
Solvent: CC(=O)Cl
Solvent: CCN(CC)CC
Product: CC(=O)N1CC[C@H](OCc2cc(C(F)(F)F)cc(C(F)(F)F)c2)[C@H](Cc2ccccc2)C1
Reaction time: 1 h
Yield: 79 %

Procedure:
To a solution of the compound (0.40 g) obtained in Example 404 in THF (4 ml), acetyl chloride (0.075 ml) and Et3N (0.147 ml) were added at room temperature, and the reaction mixture was stirred at the same temperature for 1 hour. The reaction mixture was concentrated under reduced pressure, and then the residue was dissolved in ethyl acetate. The organic layer was washed with 1 N hydrogen chloride and brine, dried, and then the solvent was evaporated under reduced pressure. The obtained residue was purified by preparative thin layer chromatography to obtain the title compound as pale yellow oil (0.275 g, 79%).
Reaction SMILES: [CH2:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH2:3][NH:2]1.Br[CH2:11][CH2:12][OH:13].C(N(CC)CC)C>C1(C)C=CC=CC=1>[OH:13][CH2:12][CH2:11][N:2]1[CH2:3][C:4]2[C:9](=[CH:8][CH:7]=[CH:6][CH:5]=2)[CH2:1]1
Reactant: c1ccc2c(c1)CNC2
Reactant: OCCBr
Solvent: CCN(CC)CC
Solvent: Cc1ccccc1
Product: OCCN1Cc2ccccc2C1
Yield: 62.7 %

Procedure:
A solution of 2.85 g (0.0252 mol) of isoindoline, 2.99 g (0.0252 mol) of 2-bromoethanol and 5.09 g (0.05 mol) of triethylamine in 100 ml of dry toluene was refluxed for 12 hours. After cooling the mixture was filtered, concentrated in vacuo, dissolved in ethyl acetate and washed with water. The organic phase was dried over magnesium sulfate and concentrated in vacuo to yield 2.58 g (63%) of a dark red oil. NMR (CDCl3) δ 2.78 (2H, t), 3.52 (2H, t), 3.82 (4H, s), 7.0 (4H, s)
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]2[O:11][CH2:10][CH2:9][N:8]([C:12]([N:14]3[CH2:19][CH2:18][CH:17]([CH:20]([F:22])[F:21])[CH2:16][CH2:15]3)=[O:13])[CH2:7][C:6]=2[CH:23]=1.CC1(C)C(C)(C)OB([C:32]2[CH:37]=[CH:36][C:35]([C:38]3[NH:39][CH:40]=[CH:41][N:42]=3)=[CH:34][CH:33]=2)O1.C(=O)([O-])[O-].[Cs+].[Cs+]>O1CCOCC1.O>[F:21][CH:20]([F:22])[CH:17]1[CH2:18][CH2:19][N:14]([C:12]([N:8]2[CH2:7][C:6]3[CH:23]=[C:2]([C:32]4[CH:37]=[CH:36][C:35]([C:38]5[NH:42][CH:41]=[CH:40][N:39]=5)=[CH:34][CH:33]=4)[CH:3]=[CH:4][C:5]=3[O:11][CH2:10][CH2:9]2)=[O:13])[CH2:15][CH2:16]1
Reactant: CC1(C)OB(c2ccc(-c3ncc[nH]3)cc2)OC1(C)C
Reactant: O=C(N1CCC(C(F)F)CC1)N1CCOc2ccc(Br)cc2C1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: C1COCCO1
Solvent: O
Product: O=C(N1CCC(C(F)F)CC1)N1CCOc2ccc(-c3ccc(-c4ncc[nH]4)cc3)cc2C1
Temperature: 90 °C
Reaction time: 18 h
Yield: 4.4 %

Procedure:
A mixture of 7-bromo-4-{[4-(difluoromethyl)piperidine-1-yl]carbonyl]-2,3,4,5-tetrahydro-1,4-benzoxazepine (78 mg, 0.20 mmol) (example 2, step 3), 2-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)-1H-imidazole (0.20 mmol), cesium carbonate (325 mg, 1.00 mmol), and dichloro[1,1-bis(diphenylphosphino]ferrocenepalladium (II) dichloromethane adduct (16 mg, 0.02 mmol) in dioxane (5.0 mL) and water (0.5 mL) was degassed with nitrogen, and then stirred at 90° C. for 18 h. The reaction mixture was cooled to room temperature, diluted with ethyl acetate, and filtered through celite. The filtrate was washed with water (1×) and brine (1×), dried over sodium sulfate, filtered and concentrated. Purification by preparative reverse phase HPLC (0.1% aqueous trifluoroacetic acid-acetonitrile) provided the title compound (4 mg, 4% yield). 1H NMR (400 MHz, methanol-d4): 7.97 (d, 2H), 7.91 (d, 2H), 7.66 (s, 2H), 7.62 (d, 1H), 7.57 (dd, 1H), 7.08 (d, 1H), 5.72 (m, 1H), 4.53 (s, 2H), 4.24 (m, 2H), 3.72 (m, 4H), 2.84 (m, 2H), 2.00 (m, 1H), 1.76 (m, 2H), 1.49 (m, 2H); MS (EI) for C25H26F2N4O2: 453 (MH+).