Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C([O:3][C:4](=O)[CH:5](O)[CH:6]([C:13]1[CH:18]=[CH:17][C:16]([O:19][CH:20]2[CH2:25][CH2:24][CH2:23][CH2:22][CH2:21]2)=[CH:15][CH:14]=1)[C:7](=O)[CH2:8][CH2:9][CH2:10][CH3:11])C.O.[NH2:29][NH2:30]>C(O)(=O)C>[CH2:8]([C:7]1[C:6]([C:13]2[CH:18]=[CH:17][C:16]([O:19][CH:20]3[CH2:25][CH2:24][CH2:23][CH2:22][CH2:21]3)=[CH:15][CH:14]=2)=[CH:5][C:4](=[O:3])[NH:29][N:30]=1)[CH2:9][CH2:10][CH3:11]
Reactant: NN
Reactant: CCCCC(=O)C(c1ccc(OC2CCCCC2)cc1)C(O)C(=O)OCC
Solvent: O
Solvent: CC(=O)O
Product: CCCCc1n[nH]c(=O)cc1-c1ccc(OC2CCCCC2)cc1
Temperature: 100 °C

Procedure:
To a stirred solution of the octanoic acid ethyl ester (105 mmol, 39.5 g) in glacial acetic acid (25.5 mL) was added hydrazine hydrate (525 mmol, 25.5 mL), and the reaction was heated at 100° C. for 12 h. After cooling, the volatiles were removed in vacuo, the residue was dissolved in ethyl acetate (300 mL). The organic layer was washed with water (100 mL), saturated NaHCO3 (3×100 mL), brine (100 mL), dried (Na2SO4), filtered, and concentrated under reduced pressure. The residue was recrystallized from a mixture of ethyl acetate (200 mL) and hexanes (300 mL) to afford 6-butyl-5-(4-cyclohexyloxy-phenyl)-2H-pyridazin-3-one.
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.[CH2:26]([S:30](Cl)(=[O:32])=[O:31])[CH2:27][CH2:28][CH3:29]>>[CH2:26]([S:30]([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:32])=[O:31])[CH2:27][CH2:28][CH3:29]
Reactant: CCCCS(=O)(=O)Cl
Reactant: c1cc(-n2cnnn2)ncc1OCc1cnn(C2CCNCC2)n1
Agent: Cl
Product: CCCCS(=O)(=O)N1CCC(n2ncc(COc3ccc(-n4cnnn4)nc3)n2)CC1

Procedure:
The title compound was synthesized using Intermediate 15 and 1-butanesulfonyl chloride in a similar manner as described in Example 39. 1H NMR (DMSO-d6): δ 10.08 (1H, s), 8.41 (1H, d), 8.00 (1H, d), 7.96 (1H, s), 7.86 (1H, dd), 5.36 (2H, s), 4.71 (1H, m), 3.63 (2H, m), 3.01 (4H, m), 2.2 (2H, m), 1.99 (2H, m), 1.64 (2H, m), 1.39 (2H, m), 0.89 (3H, t).
Reaction SMILES: [NH2:1][C:2]1[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[CH:4][C:3]=1I.O=[C:12]([CH3:16])[C:13]([OH:15])=[O:14].C1N2CCN(CC2)C1>CN(C=O)C.CC([O-])=O.CC([O-])=O.[Pd+2]>[C:6]([C:5]1[CH:4]=[C:3]2[C:2](=[CH:9][CH:8]=1)[NH:1][C:12]([C:13]([OH:15])=[O:14])=[CH:16]2)#[N:7]
Reactant: CC(=O)C(=O)O
Reactant: N#Cc1ccc(N)c(I)c1
Agent: [Pd+2]
Agent: C1CN2CCN1CC2
Agent: CC(=O)[O-]
Solvent: CN(C)C=O
Product: N#Cc1ccc2[nH]c(C(=O)O)cc2c1
Temperature: 105 °C
Reaction time: 1 h
Yield: 59.1 %

Procedure:
A suspension of 4-amino-3-iodobenzonitrile (2.44 g), 2-oxopropanoic acid (2.64 g), DABCO (3.36 g), and Pd(OAc)2 in DMF (30 mL) was heated to 105° C. and stirred at that temperature for 1 hour. The solvent was evaporated. EtOAc (200 mL) was added and the resulting solution was washed with water (100 mL) and aqueous NaOH solution (20 mL). The combined aqueous solution was extracted with EtOAc (3×150 mL). The organic fractions were combined. The combined solution was dried over anhydrous magnesium sulfate. The dried solution was concentrated. The residue was triturated to afford 5-cyano-1H-indole-2-carboxylic acid (D20) (1.1 g) as a brown solid.
Reaction SMILES: [NH2:1][CH2:2][CH:3]([C:5]1[CH:10]=[CH:9][CH:8]=[C:7]([F:11])[CH:6]=1)[OH:4].O=[C:13]([CH3:27])[CH2:14][O:15][C:16]1[CH:21]=[CH:20][C:19]([CH2:22][C:23]([O:25][CH3:26])=[O:24])=[CH:18][CH:17]=1.C1C=CC=CC=1.C([BH3-])#N.[Na+]>CO>[CH3:26][O:25][C:23]([CH2:22][C:19]1[CH:18]=[CH:17][C:16]([O:15][CH2:14][CH:13]([NH:1][CH2:2][CH:3]([C:5]2[CH:10]=[CH:9][CH:8]=[C:7]([F:11])[CH:6]=2)[OH:4])[CH3:27])=[CH:21][CH:20]=1)=[O:24]
Reactant: NCC(O)c1cccc(F)c1
Reactant: COC(=O)Cc1ccc(OCC(C)=O)cc1
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: c1ccccc1
Solvent: CO
Product: COC(=O)Cc1ccc(OCC(C)NCC(O)c2cccc(F)c2)cc1
Yield: 25.3 %

Procedure:
Following a procedure similar to that described in Example 6, but using 2 g of 2-amino-1-(3-fluorophenyl)ethanol (prepared as described in Preparation 13), 3.44 g of methyl 4-(2-oxopropoxy)phenylacetate (prepared as described in Preparation 3), 60 ml of benzene, 60 ml of absolute methanol and 3.6 g of sodium cyanoborohydride, 1.18 g of the title compound were obtained as crystals, melting at 52° C.
Reaction SMILES: [BH4-].[Na+].[C:3]1([C:9]2[O:10][CH:11]=[C:12]([CH2:14][O:15][C:16]3[CH:23]=[CH:22][C:19]([CH:20]=[O:21])=[CH:18][CH:17]=3)[N:13]=2)[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.CO.Cl>O>[C:3]1([C:9]2[O:10][CH:11]=[C:12]([CH2:14][O:15][C:16]3[CH:17]=[CH:18][C:19]([CH2:20][OH:21])=[CH:22][CH:23]=3)[N:13]=2)[CH:4]=[CH:5][CH:6]=[CH:7][CH:8]=1
Reactant: O=Cc1ccc(OCc2coc(-c3ccccc3)n2)cc1
Agent: Cl
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Solvent: O
Product: OCc1ccc(OCc2coc(-c3ccccc3)n2)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 91 %

Procedure:
Sodium borohydride (0.36 g) was added to a mixture of 4-(2-phenyl-4-oxazolylmethoxy)benzaldehyde (2.65 g) and methanol (50 ml) under ice-cooling, which was stirred at room temperature for 1 hour. Dilute hydrochloric acid and water were added to the reaction mixture, which was extracted with ethyl acetate. The ethyl acetate layer was washed with saturated aqueous sodium chloride solution, dried (MgSO4) and concentrated to obtain 4-(2-phenyl-4-oxazolylmethoxy)benzyl alcohol (2.43 g, yield 91%) as colorless crystals. This was recrystallized from ethyl acetate-hexane. Melting point: 141–142° C.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([NH:10][C:11]2[C:20]3[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=3)[C:14]3=[N:21][N:22]=[C:23]([C:24]4[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=4[CH3:30])[N:13]3[N:12]=2)[CH:7]=[CH:8][CH:9]=1)([O-])=O.Cl.O.O.[Sn](Cl)(Cl)(Cl)Cl>C(O)(=O)C>[CH3:30][C:25]1[CH:26]=[CH:27][CH:28]=[CH:29][C:24]=1[C:23]1[N:13]2[N:12]=[C:11]([NH:10][C:6]3[CH:7]=[CH:8][CH:9]=[C:4]([NH2:1])[CH:5]=3)[C:20]3[C:15]([C:14]2=[N:21][N:22]=1)=[CH:16][CH:17]=[CH:18][CH:19]=3
Reactant: Cc1ccccc1-c1nnc2c3ccccc3c(Nc3cccc([N+](=O)[O-])c3)nn12
Agent: Cl
Agent: Cl[Sn](Cl)(Cl)Cl
Solvent: O
Solvent: CC(=O)O
Product: Cc1ccccc1-c1nnc2c3ccccc3c(Nc3cccc(N)c3)nn12
Temperature: 90 °C
Reaction time: 48 h
Yield: 84.8 %

Procedure:
To a suspension of (3-nitro-phenyl)-(3-o-tolyl-[1,2,4]triazolo[3,4-a]-phthalazin-6-yl)-amine (compound B10) (263 mg, 0.66 mmol) in a 2:1 mixture of glacial acetic acid and 37% hydrochloric acid (18 ml) is added tin chloride dihydrate (450 mg, 1.99 mmol). The mixture is stirred at 90° C. for 2 days. Upon cooling, the precipitate is filtered and the filtrate concentrated. Purification of residue by column chromatography (CH2Cl2/MeOH, 95:5) gives 205 mg of an off-white solid which is triturated with a 1:1 mixture of isopropanol and petroleum ether to yield 77 mg of the title compound as off-white needles.
Reaction SMILES: [Br:1][C:2]1[C:3]2[C:4]3[CH2:23][CH2:22][N:21](C(OC(C)(C)C)=O)[CH2:20][CH2:19][C:5]=3[N:6]([CH2:11][C:12]([O:14][CH2:15][CH:16]([CH3:18])[CH3:17])=[O:13])[C:7]=2[CH:8]=[CH:9][CH:10]=1.FC(F)(F)C(O)=O>C(Cl)Cl>[Br:1][C:2]1[C:3]2[C:4]3[CH2:23][CH2:22][NH:21][CH2:20][CH2:19][C:5]=3[N:6]([CH2:11][C:12]([O:14][CH2:15][CH:16]([CH3:18])[CH3:17])=[O:13])[C:7]=2[CH:8]=[CH:9][CH:10]=1
Reactant: CC(C)COC(=O)Cn1c2c(c3c(Br)cccc31)CCN(C(=O)OC(C)(C)C)CC2
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CC(C)COC(=O)Cn1c2c(c3c(Br)cccc31)CCNCC2
Temperature: 25 °C
Reaction time: 2.5 h
Yield: 79.8 %

Procedure:
tert-butyl 10-bromo-6-(2-isobutoxy-2-oxoethyl)-1,4,5,6-tetrahydroazepino[4,5-b]indole-3(2H)-carboxylate (0.0412 g, 0.0859 mmol) was dissolved in CH2Cl2 (2 mL) and trifluoroacetic acid (1.0 mL, 1.48 g, 13.0 mmol, 151 equiv.) was added. The resulting solution was stirred at rt for 2.5 h. The reaction mixture was concentrated to dryness. The residue was taken up in EtOAc (2 mL), then treated with 1N HCl in Et2O. Hydrochloride salt formation did not occur and the resulting solution were concentrated to dryness. The residue was partitioned between EtOAc and 1N NaOH. The layers were separated, and the aqueous layer was extracted with EtOAc. The combined organic layers were washed with brine, dried over MgSO4, filtered and concentrated. The crude isobutyl (10-bromo-2,3,4,5-tetrahydroazepino[4, 5-b]indol-6(1H)-yl)acetate (0.0260 g) was obtained in 80% yield. 1H NMR (300 MHz, CD3OD) δ 0.85, 1.86, 2.98-3.03, 3.11-3.14, 3.53-3.56, 3.91, 5.02, 6.94, 7.18, 7.25; MS (ESI+) for C18H23BrN2O2 m/z 379.0 (M+H)+.
Reaction SMILES: [H-].[Na+].[Br:3][C:4]1[CH:13]=[CH:12][C:7]([O:8][CH2:9][CH2:10][OH:11])=[CH:6][CH:5]=1.[CH2:14](Br)[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1.O>CN(C)C=O>[CH2:14]([O:11][CH2:10][CH2:9][O:8][C:7]1[CH:12]=[CH:13][C:4]([Br:3])=[CH:5][CH:6]=1)[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1
Reactant: OCCOc1ccc(Br)cc1
Reactant: BrCc1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: Brc1ccc(OCCOCc2ccccc2)cc1

Procedure:
Sodium hydride (60% in mineral oil, 0.500 g) was added to a solution of 2-(4-bromophenoxy)ethanol (2.25 g) in N,N-dimethylformamide (15 mL) at room temperature with stirring. After being stirred for 20 minutes, benzyl bromide (1.42 mL) was added at that temperature, and the mixture was stirred for additional 13 hrs. Water was added to the reaction mixture, and the resulting mixture was extracted with ethyl acetate. The organic layer was washed with water and brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure, and the residue was purified by medium-pressure silica gel column chromatography (eluent: ethyl acetate/n-hexane=1/9) to afford 1-(2-benzyloxyethoxy)-4-bromobenzene (2.51 g).
Reaction SMILES: C[O:2][C:3](=[O:32])[CH:4]([O:21][C:22]1[CH:27]=[CH:26][CH:25]=[C:24]([C:28]([CH3:31])([CH3:30])[CH3:29])[CH:23]=1)[C:5]1[CH:10]=[CH:9][C:8]([O:11][CH2:12][O:13][C:14]2[CH:19]=[CH:18][C:17]([Cl:20])=[CH:16][CH:15]=2)=[CH:7][CH:6]=1.[OH-].[K+].Cl>C(O)C.O>[C:28]([C:24]1[CH:23]=[C:22]([CH:27]=[CH:26][CH:25]=1)[O:21][CH:4]([C:5]1[CH:10]=[CH:9][C:8]([O:11][CH2:12][O:13][C:14]2[CH:15]=[CH:16][C:17]([Cl:20])=[CH:18][CH:19]=2)=[CH:7][CH:6]=1)[C:3]([OH:32])=[O:2])([CH3:31])([CH3:29])[CH3:30]
Reactant: COC(=O)C(Oc1cccc(C(C)(C)C)c1)c1ccc(OCOc2ccc(Cl)cc2)cc1
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: CC(C)(C)c1cccc(OC(C(=O)O)c2ccc(OCOc3ccc(Cl)cc3)cc2)c1
Yield: 91.2 %

Procedure:
To a solution of 9.5 g of methyl(m-tert.-butylphenoxy){p-[(p-chlorophenoxy)methoxy]phenyl}acetate in 60 ml of ethanol is added a solution of 7 g of potassium hydroxide in 60 ml of water. The mixture is stirred and refluxed for 18 hours and while hot is acidified with 11.5 ml of concentrated HCl. The mixture is chilled immediately. The supernatant is decanted from the oil which separates. Water is added and decanted. The gummy material is dissolved in dichloromethane, dried (MgSO4) and the solvent removed under reduced pressure to give 8.4 g of a gum. The gum is triturated with hexane containing a small amount of dichloromethane to give 5.7 g of yellow crystals. The crystals are dissolved in 25 ml of dichloromethane and the solution diluted with 50 ml of hexane. Chilling gives 4.4 g of product as pale yellow crystals, mp 122°-124° C.
Reaction SMILES: Br.Br[CH:3]([C:5]1[CH:6]=[C:7]([C:23]([N:25]([CH3:27])[CH3:26])=[O:24])[CH:8]=[C:9]2[C:14]=1[O:13][C:12]([N:15]1[CH2:20][CH2:19][O:18][C@H:17]([CH3:21])[CH2:16]1)=[CH:11][C:10]2=[O:22])[CH3:4].[F:28][C:29]1[CH:30]=[C:31]([CH:33]=[C:34]([F:36])[CH:35]=1)[NH2:32]>CC(N(C)C)=O>[F:28][C:29]1[CH:30]=[C:31]([NH:32][CH:3]([C:5]2[CH:6]=[C:7]([C:23]([N:25]([CH3:27])[CH3:26])=[O:24])[CH:8]=[C:9]3[C:14]=2[O:13][C:12]([N:15]2[CH2:20][CH2:19][O:18][C@H:17]([CH3:21])[CH2:16]2)=[CH:11][C:10]3=[O:22])[CH3:4])[CH:33]=[C:34]([F:36])[CH:35]=1
Reactant: Nc1cc(F)cc(F)c1
Reactant: CC(Br)c1cc(C(=O)N(C)C)cc2c(=O)cc(N3CCO[C@H](C)C3)oc12
Agent: Br
Solvent: CC(=O)N(C)C
Product: CC(Nc1cc(F)cc(F)c1)c1cc(C(=O)N(C)C)cc2c(=O)cc(N3CCO[C@H](C)C3)oc12
Yield: 58.9 %

Procedure:
8-(1-bromoethyl)-N,N-dimethyl-2-((R)-2-methylmorpholino)-4-oxo-4H-chromene-6-carboxamide hydrobromide (1 g, 1.98 mmol) and 3,5-difluoroaniline (1.024 g, 7.93 mmol) in DMA (5 mL) were reacted as described in Example 9.0 to give 8-(1-(3,5-difluorophenylamino)ethyl)-N,N-dimethyl-2-((R)-2-methylmorpholino)-4-oxo-4H-chromene-6-carboxamide (0.550 g, 57%). Mass Spectrum: M+H+ 472. NMR Spectrum (DMSOd6): 1.16 (d, 3H), 1.52 (d, 3H), 2.74 (bs, 3H), 2.75-2.84 (m, 1H), 2.95 (bs, 3H), 3.08-3.16 (m, 1H), 3.56-3.68 (m, 2H), 3.86-4.04 (m, 3H), 4.97-5.08 (m, 1H), 5.62 (s, 1H), 6.12-6.19 (m, 2H), 6.22 (t, 1H), 6.93 (d, 0.5H), 6.94 (d, 0.5H), 6.54 (d, 0.5H), 6.55 (d, 0.5H), 7.81 (s, 1H).
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([C:14]2[C:15]([O:25][C:26]([CH3:29])([CH3:28])[CH3:27])=[N:16][C:17]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[N:18][CH:19]=2)[CH:5]=[C:6]([C:10]([CH3:13])([CH3:12])[CH3:11])[C:7]=1[O:8][CH3:9].CC1(C)C(C)(C)OB([C:38]2[CH:46]=[C:45]3[C:41]([C:42]([CH2:47][NH:48][S:49]([CH3:52])(=[O:51])=[O:50])=[CH:43][CH2:44]3)=[CH:40][CH:39]=2)O1>>[C:10]([C:6]1[C:7]([O:8][CH3:9])=[C:2]([C:38]2[CH:46]=[C:45]3[C:41]([C:42]([CH2:47][NH:48][S:49]([CH3:52])(=[O:50])=[O:51])=[CH:43][CH2:44]3)=[CH:40][CH:39]=2)[CH:3]=[C:4]([C:14]2[C:15]([O:25][C:26]([CH3:27])([CH3:28])[CH3:29])=[N:16][C:17]([O:20][C:21]([CH3:23])([CH3:24])[CH3:22])=[N:18][CH:19]=2)[CH:5]=1)([CH3:12])([CH3:11])[CH3:13]
Reactant: CC1(C)OB(c2ccc3c(c2)CC=C3CNS(C)(=O)=O)OC1(C)C
Reactant: COc1c(Br)cc(-c2cnc(OC(C)(C)C)nc2OC(C)(C)C)cc1C(C)(C)C
Product: COc1c(-c2ccc3c(c2)CC=C3CNS(C)(=O)=O)cc(-c2cnc(OC(C)(C)C)nc2OC(C)(C)C)cc1C(C)(C)C

Procedure:
The product from Example 2 Part A (55.9 mg, 0.12 mmol) and N-((6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-inden-3-yl)methyl)methanesulfonamide (41.9 mg, 0.120 mmol) were reacted in the same manner as Example 2 Part B. The crude product was purified by silica gel flash chromatography eluting with ethyl acetate/hexane (5% to 25%) to give the title compound.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[CH:4][C:5]2[C:9]([O:10][C:11]3[CH:16]=[CH:15][C:14](/[CH:17]=[CH:18]/[C:19]([OH:21])=[O:20])=[CH:13][CH:12]=3)=[C:8]([C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=3[CH:28]([CH3:30])[CH3:29])[S:7][C:6]=2[CH:31]=1.[Si:32](Cl)([C:35]([CH3:38])([CH3:37])[CH3:36])([CH3:34])[CH3:33].C(N(CC)C(C)C)(C)C.C([O-])([O-])=O.[K+].[K+]>C(Cl)Cl>[Si:32]([O:1][C:2]1[CH:3]=[CH:4][C:5]2[C:9]([O:10][C:11]3[CH:12]=[CH:13][C:14](/[CH:17]=[CH:18]/[C:19]([OH:21])=[O:20])=[CH:15][CH:16]=3)=[C:8]([C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=3[CH:28]([CH3:29])[CH3:30])[S:7][C:6]=2[CH:31]=1)([C:35]([CH3:38])([CH3:37])[CH3:36])([CH3:34])[CH3:33]
Reactant: CC(C)(C)[Si](C)(C)Cl
Reactant: CC(C)c1ccccc1-c1sc2cc(O)ccc2c1Oc1ccc(/C=C/C(=O)O)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)c1ccccc1-c1sc2cc(O[Si](C)(C)C(C)(C)C)ccc2c1Oc1ccc(/C=C/C(=O)O)cc1
Temperature: 25 °C
Reaction time: 18 h
Yield: 94.8 %

Procedure:
To a solution of (E)-3-(4-((6-hydroxy-2-(2-isopropylphenyl)benzo[b]thiophen-3-yl)oxy)phenyl)acrylic acid (100 mg, 0.232 mmol) in DCM (3 mL) at room temperature were added tert-butyldimethylsilyl chloride (88 mg, 0.581 mmol) and N,N-diisopropylethylamine (0.122 mL, 0.697 mmol). The resulting mixture was stirred at room temperature for 18 h after which time the reaction was quenched by addition of water and extracted with EtOAc (2×). The combined organic layers were dried over anhydrous Na2SO4, filtered and concentrated in vacuo and the resulting crude material was then dissolved in THF (wet) and K2CO3 (32.1 mg, 0.232 mmol) was added and the mixture was stirred at room temperature for 2 h. Upon completion the reaction was quenched by addition of 1N HCl and extracted with EtOAc (2×), the combined organic layers were washed with brine, dried over anhydrous Na2SO4, filtered and concentrated in vacuo to afford (E)-3-(4-((6-((tert-butyldimethylsilyl)oxy)-2-(2-isopropylphenyl)benzo[b]thiophen-3-yl)oxy)phenyl)acrylic acid (120 mg, 0.220 mmol, 95% yield). 1H NMR (400 MHz, CDCl3) δ ppm 7.66 (d, J=16.0 Hz, 1H), 7.37 (d, J=8.8 Hz, 2H), 7.34-7.24 (m, 5H), 7.17-7.09 (m, 1H), 6.90-6.82 (m, 3H), 6.26 (d, J=15.9 Hz, 1H), 3.24 (p, J=6.7 Hz, 1H), 1.17 (d, J=6.7 Hz, 6H), 1.01 (s, 9 H), 0.24 (s, 6H).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:9]=[C:10]3[N:14]([C:15]=2I)[CH:13]=[CH:12][O:11]3)=[CH:4][CH:3]=1.[F:17][C:18]1[CH:19]=[C:20](B2OC(C)(C)C(C)(C)O2)[CH:21]=[CH:22][C:23]=1[N+:24]([O-:26])=[O:25].C([O-])([O-])=O.[Cs+].[Cs+].COCCOC>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.O>[F:17][C:18]1[CH:19]=[C:20]([C:15]2[N:14]3[C:10]([O:11][CH:12]=[CH:13]3)=[N:9][C:8]=2[C:5]2[CH:6]=[CH:7][C:2]([F:1])=[CH:3][CH:4]=2)[CH:21]=[CH:22][C:23]=1[N+:24]([O-:26])=[O:25]
Reactant: CC1(C)OB(c2ccc([N+](=O)[O-])c(F)c2)OC1(C)C
Reactant: Fc1ccc(-c2nc3occn3c2I)cc1
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: [Cs+]
Solvent: O
Solvent: COCCOC
Product: O=[N+]([O-])c1ccc(-c2c(-c3ccc(F)cc3)nc3occn23)cc1F
Temperature: 100 °C
Yield: 83.4 %

Procedure:
A mixture of 6-(4-fluorophenyl)-5-iodo-imidazo[2,1-b]oxazole (10.0 g, 27.4 mmol; Preparation #A.1), 2-(3-fluoro-4-nitrophenyl)-4,4,5,5-tetramethyl-[1,3,2]dioxaborolane (11.9 g, 41.1 mmol; Preparation #B.1), Cs2CO3 (28.6 g, 87.8 mmol), tetrakis(triphenylphosphine)palladium(0) (3.17 g, 2.74 mmol; Strem), DME (150 mL) and water (30.0 mL) was added to a flask with screw-thread top. The flask was sealed and heated at about 100° C. for about 16 h. After cooling to ambient temperature the reaction was concentrated under reduced pressure to remove organic solvent. The resulting mixture was diluted with water (200 mL) and EtOAc (200 mL) then filtered to remove insoluble material. The layers were separated and the aqueous layer was extracted with additional EtOAc (2×200 mL). The combined organic layers were washed with brine, dried over Na2SO4, decanted, and concentrated. The crude material was purified by silica gel chromatography using DCM to give the title compound (7.80 g, 78%): LC/MS (Table 1, Method b) Rt=2.19 min; MS m/z: 342.1 (M+H)+.
Reaction SMILES: [CH3:1][C:2]([C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1)([CH3:6])[C:3]([OH:5])=O.S(Cl)(Cl)=O.[NH2:17][C:18]1[CH:23]=[CH:22][C:21]([N:24]2[C:30](=[O:31])[CH2:29][C:28](=[O:32])[NH:27][C:26]3[C:33]4[C:38]([CH:39]=[CH:40][C:25]2=3)=[CH:37][CH:36]=[CH:35][CH:34]=4)=[CH:20][CH:19]=1>>[CH3:6][C:2]([C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1)([CH3:1])[C:3]([NH:17][C:18]1[CH:23]=[CH:22][C:21]([N:24]2[C:30](=[O:31])[CH2:29][C:28](=[O:32])[NH:27][C:26]3[C:33]4[C:38]([CH:39]=[CH:40][C:25]2=3)=[CH:37][CH:36]=[CH:35][CH:34]=4)=[CH:20][CH:19]=1)=[O:5]
Reactant: Nc1ccc(N2C(=O)CC(=O)Nc3c2ccc2ccccc32)cc1
Reactant: CC(C)(C(=O)O)c1ccccc1
Solvent: O=S(Cl)Cl
Product: CC(C)(C(=O)Nc1ccc(N2C(=O)CC(=O)Nc3c2ccc2ccccc32)cc1)c1ccccc1
Yield: 49.6 %

Procedure:
2-Methyl-2-phenylpropionic acid (33 mg, 0.2 mmol) was treated with thionyl chloride in the same manner as that of Example 13, and then by using the resultant together with 5-(4-aminophenyl)-1H-naphtho[1,2-b][1,4]diazepine-2,4(3H,5H)-dione (32 mg, 0.1 mmol) obtained in Example 1, (3), the title compound (23 mg, yield 50%) was obtained as slightly brown powder in the same manner as that of Example 1, (4).
Reaction SMILES: [K].[O-:2][CH2:3][CH2:4]CC.Cl[C:8]1[N:16]=[CH:15][CH:14]=[CH:13][C:9]=1[C:10]([OH:12])=[O:11]>C(O)C>[CH2:3]([O:2][C:8]1[C:9]([C:10]([OH:12])=[O:11])=[CH:13][CH:14]=[CH:15][N:16]=1)[CH3:4]
Reactant: CCCC[O-]
Reactant: O=C(O)c1cccnc1Cl
Agent: [K]
Solvent: CCO
Product: CCOc1ncccc1C(=O)O
Temperature: 170 °C
Yield: 86.3 %

Procedure:
A solution of potassium ten-butoxide (44.9 g, 0.40 mol) in absolute ethanol (300 ml) was added slowly to a solution of 2-chloronicotinic acid (30 g, 0.19 mol) in ethanol (100 ml), and the reaction heated in a sealed vessel at 170° C. for 20 hours. The solvent was removed under reduced pressure, the residue dissolved in water (200 ml) and acidified to pH 3 with aqueous hydrochloric acid. The aqueous solution was extracted with dichloromethane (4×200 ml), the combined organic layers were dried over Na2SO4, filtered and concentrated under reduced pressure to afford the title compound as a white solid (27.4 g).
Reaction SMILES: [O:1]1[C:3]2([CH2:8][CH2:7][N:6]([C:9]([O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:10])[CH2:5][CH2:4]2)[CH2:2]1.[N-:16]=[N+:17]=[N-:18].[Na+]>O1CCOCC1.O>[N:16]([CH2:2][C:3]1([OH:1])[CH2:8][CH2:7][N:6]([C:9]([O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:10])[CH2:5][CH2:4]1)=[N+:17]=[N-:18]
Reactant: [N-]=[N+]=[N-]
Reactant: CC(C)(C)OC(=O)N1CCC2(CC1)CO2
Agent: [Na+]
Solvent: O
Solvent: C1COCCO1
Product: CC(C)(C)OC(=O)N1CCC(O)(CN=[N+]=[N-])CC1
Yield: 94.7 %

Procedure:
To a solution of the compound prepared in Example 255 (0.500 g) in dioxane (31 mL) and water (3 mL) was treated with sodium azide (0.143 g) at room temperature. The mixture was refluxed overnight. The solvent was evaporated in vacuo and the residue was distributed between ethyl acetate and water. The aqueous layer was extracted with more ethyl acetate, dried and evaporated in vacuo to obtain the title compound (0.534 g) having the following physical data.
Reaction SMILES: [Br:1][C:2]1[CH:11]=[C:10]2[C:5]([C:6]([NH:13][CH2:14][CH:15]([CH3:17])[CH3:16])=[C:7]([NH2:12])[CH:8]=[N:9]2)=[CH:4][CH:3]=1.[CH2:18]([O:20][CH2:21][C:22](Cl)=O)[CH3:19]>N1C=CC=CC=1>[Br:1][C:2]1[CH:3]=[CH:4][C:5]2[C:6]3[N:13]([CH2:14][CH:15]([CH3:17])[CH3:16])[C:19]([CH2:18][O:20][CH2:21][CH3:22])=[N:12][C:7]=3[CH:8]=[N:9][C:10]=2[CH:11]=1
Reactant: CC(C)CNc1c(N)cnc2cc(Br)ccc12
Reactant: CCOCC(=O)Cl
Solvent: c1ccncc1
Product: CCOCc1nc2cnc3cc(Br)ccc3c2n1CC(C)C
Temperature: 25 °C
Reaction time: 3.5 h
Yield: 41.1 %

Procedure:
A solution of 7-bromo-N4-isobutylquinoline-3,4-diamine (85 g, prepared according to Part F of Example 1) in anhydrous pyridine (413 mL) was immersed in an ice bath, and ethoxyacetyl chloride (36.9 g, 300 mmol) was added. The reaction was allowed to warm to room temperature and was then heated in an oil bath held at 85° C. for 3.5 h. The reaction mixture was concentrated under vacuum, and the residue was taken up in diethyl ether and washed with 2M Na2CO3 (2×) followed by H2O (1×). The organic layer was dried (MgSO4), filtered, and concentrated. Recrystallization of the resulting solid from boiling 15% ethyl acetate in hexanes afforded 43.0 g of 7-bromo-2-ethoxymethyl-1-isobutyl-1H-imidazo[4,5-c]quinoline as brown crystals.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:8]2[CH:9]=[CH:10][C:11]([F:27])=[C:12]([C@:14]3([CH3:26])[C:20]([F:22])([F:21])[C:19]([CH3:24])([CH3:23])[O:18][CH2:17][C:16](=O)[NH:15]3)[CH:13]=2)[CH:5]=[N:6][CH:7]=1.COC1C=CC(P2(SP(C3C=CC(OC)=CC=3)(=S)S2)=[S:37])=CC=1>O1CCOCC1>[Cl:1][C:2]1[CH:3]=[C:4]([C:8]2[CH:9]=[CH:10][C:11]([F:27])=[C:12]([C@:14]3([CH3:26])[C:20]([F:22])([F:21])[C:19]([CH3:24])([CH3:23])[O:18][CH2:17][C:16](=[S:37])[NH:15]3)[CH:13]=2)[CH:5]=[N:6][CH:7]=1
Reactant: CC1(C)OCC(=O)N[C@](C)(c2cc(-c3cncc(Cl)c3)ccc2F)C1(F)F
Reactant: COc1ccc(P2(=S)SP(=S)(c3ccc(OC)cc3)S2)cc1
Solvent: C1COCCO1
Product: CC1(C)OCC(=S)N[C@](C)(c2cc(-c3cncc(Cl)c3)ccc2F)C1(F)F
Yield: 86.3 %

Procedure:
The reaction of (R)-5-[5-(5-chloro-pyridin-3-yl)-2-fluoro-phenyl]-6,6-difluoro-5,7,7-trimethyl-[1,4]oxazepan-3-one (235 mg, 589 μmol) with Lawesson's reagent (238 mg, 589 μmol) in 1,4-dioxane (19.6 ml) yielded the (R)-5-[5-(5-chloro-pyridin-3-yl)-2-fluoro-phenyl]-6,6-difluoro-5,7,7-trimethyl-[1,4]oxazepan-3-thione (211 mg, 86% yield) as a white solid. MS (ISP): m/z=415.1 [M+H]+ and 417.1 [M+2+H]+.