Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]2[NH:11][C:10](=[O:12])[CH2:9][O:8][C:7]([CH2:18][CH3:19])([C:13]3[S:14][CH:15]=[CH:16][CH:17]=3)[C:6]=2[CH:20]=1.Br[C:22]1[CH:23]=[C:24]([C:27]#[N:28])[O:25][CH:26]=1>>[CH2:18]([C:7]1([C:13]2[S:14][CH:15]=[CH:16][CH:17]=2)[C:6]2[CH:20]=[C:2]([C:22]3[CH:23]=[C:24]([C:27]#[N:28])[O:25][CH:26]=3)[CH:3]=[CH:4][C:5]=2[NH:11][C:10](=[O:12])[CH2:9][O:8]1)[CH3:19]
Reactant: CCC1(c2cccs2)OCC(=O)Nc2ccc(Br)cc21
Reactant: N#Cc1cc(Br)co1
Product: CCC1(c2cccs2)OCC(=O)Nc2ccc(-c3coc(C#N)c3)cc21

Procedure:
Prepared from 7-bromo-5-ethyl-5-thien-2-yl-1,5-dihydro-4,1-benzoxazepin-2(3H)-one and 4-bromo-2-cyanofuran generally according to the procedures described in examples 82 and 1. A white solid: mp 99-100° C.; 1H NMR (DMSO-d6): δ 10.04 (s, 1H), 8.60 (s, 1H), 8.17 (s, 1H), 7.54-7.61 (m, 3H), 7.22 (d, J=8.45 Hz, 1H), 6.99 (dd, J=4.99, 3.60 Hz, 1H), 6.90 (dd, J=3.48, 1.02 Hz, 1H), 4.40, (d, J=15.42, 1H), 3.94 (d, J=15.47 Hz, 1H), 2.5 (m, 2H), 0.76 (t, J=7.02 Hz, 3H); MS (ESI) m/z 365 ([M+H]+); MS (ESI) m/z 363 ([M−H]−); Anal. calcd for C20H16N2O3S: C, 65.92; H, 4.43; N, 7.69. Found: C, 64.84; H, 4.59; N, 6.98.
Reaction SMILES: [CH2:1]([O:8][C@H:9]([C@H:11]([N:15]1[CH:19]=[C:18]([C:20]([NH2:22])=[O:21])[N:17]=[CH:16]1)[CH2:12][CH2:13][OH:14])[CH3:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:23][S:24](Cl)(=[O:26])=[O:25].C(N(CC)CC)C>ClCCl>[CH2:1]([O:8][C@H:9]([C@H:11]([N:15]1[CH:19]=[C:18]([C:20]([NH2:22])=[O:21])[N:17]=[CH:16]1)[CH2:12][CH2:13][O:14][S:24]([CH3:23])(=[O:26])=[O:25])[CH3:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CS(=O)(=O)Cl
Reactant: C[C@H](OCc1ccccc1)[C@@H](CCO)n1cnc(C(N)=O)c1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: C[C@H](OCc1ccccc1)[C@@H](CCOS(C)(=O)=O)n1cnc(C(N)=O)c1
Reaction time: 1 h
Yield: 103.4 %

Procedure:
To a stirred mixture of 1-[(2S,3R)-2-benzyloxy-5-hydroxy-3-pentyl]imidazole-4-carboxamide (330 mg, 1.09 mmol) and methanesulfonyl chloride (249 mg, 2.18 mmol) in dichloromethane (10 ml) was added dropwise triethylamine (220 mg, 2.18 mmol) at ice-bath temperature. After 1 hour, the reaction mixture was partitioned between dichloromethane and water. The organic layer was washed with brine, dried (magnesium sulfate), and concentrated in vacuo to give 1-[(2S,3R)-2-benzyloxy-5-methanesulfonyloxy-3-pentyl]imidazole-4-carboxamide (430 mg, 103%) as an oil. This material was used for the next reaction without further purification.
Reaction SMILES: C[O:2][C:3](=[O:19])[C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([CH2:10][O:11][C:12]2[CH:17]=[CH:16][C:15](I)=[CH:14][CH:13]=2)[CH:5]=1.[CH3:20][O:21][CH2:22][C:23]1[CH:24]=[C:25](B(O)O)[CH:26]=[CH:27][CH:28]=1>>[CH3:20][O:21][CH2:22][C:23]1[CH:28]=[C:27]([C:15]2[CH:16]=[CH:17][C:12]([O:11][CH2:10][C:6]3[CH:5]=[C:4]([CH:9]=[CH:8][CH:7]=3)[C:3]([OH:2])=[O:19])=[CH:13][CH:14]=2)[CH:26]=[CH:25][CH:24]=1
Reactant: COCc1cccc(B(O)O)c1
Reactant: COC(=O)c1cccc(COc2ccc(I)cc2)c1
Product: COCc1cccc(-c2ccc(OCc3cccc(C(=O)O)c3)cc2)c1

Procedure:
3-(3′-Methoxymethyl-biphenyl-4-yloxymethyl)-benzoic acid was prepared using the procedure described above for the preparation of Example 12 from 3-(4-iodo -phenoxymethyl)-benzoic acid methyl ester (of Intermediate 1) and 3-methoxymethylphenylboronic acid (available from Digital Specialty Chemicals, Inc., Dublin, N.H.). Mass spectrum MH+=349.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:10]2([C:27]([F:30])([F:29])[F:28])[CH2:14][CH2:13][N:12]([C:15]3[S:16][C:17]([C:24](O)=[O:25])=[C:18]([C:20]([F:23])([F:22])[F:21])[N:19]=3)[CH2:11]2)[CH:5]=[C:6]([Cl:9])[C:7]=1[Cl:8].S(Cl)(Cl)=O>CN(C)C=O.ClCCCl>[Cl:1][C:2]1[CH:3]=[C:4]([C:10]2([C:27]([F:30])([F:28])[F:29])[CH2:14][CH2:13][N:12]([C:15]3[S:16][C:17]([CH2:24][OH:25])=[C:18]([C:20]([F:23])([F:22])[F:21])[N:19]=3)[CH2:11]2)[CH:5]=[C:6]([Cl:9])[C:7]=1[Cl:8]
Reactant: O=C(O)c1sc(N2CCC(c3cc(Cl)c(Cl)c(Cl)c3)(C(F)(F)F)C2)nc1C(F)(F)F
Solvent: ClCCCl
Solvent: CN(C)C=O
Solvent: O=S(Cl)Cl
Product: OCc1sc(N2CCC(c3cc(Cl)c(Cl)c(Cl)c3)(C(F)(F)F)C2)nc1C(F)(F)F
Yield: 51.4 %

Procedure:
2-[3-(3,4,5-Trichlorophenyl)-3-(trifluoromethyl)pyrrolidin-1-yl]-4-(trifluoro-methyl)-1,3-thiazole-5-carboxylic acid (2.2 g) was added to 1,2-dichloroethane (50 mL). Thionyl chloride (1.0 g) and one drop of N,N-dimethylformamide were added to the mixture, which was then refluxed under heating for 5 hours. After removing the solvent by evaporation, the residues were dissolved in 1,4-dioxane (20 mL), and then added dropwise to the mixture solution comprising water (30 mL), 1,4-dioxane (30 mL), and sodium borohydride (0.5 g) under ice cooling. After the dropwise addition was completed, the reaction solution was refluxed under heating for one hour. After cooling, the reaction solution was poured over ice water, and then extracted with ethyl acetate. After cooling, the extraction was again carried out by adding water and ethyl acetate. The organic layer was dried over magnesium sulfate. The solvent was evaporated off under reduced pressure, and the residue was then purified by a silica gel chromatography to obtain the title compound (1.1 g, 65%).
Reaction SMILES: [CH2:1]([N:8]1[CH2:13][CH2:12][CH2:11][CH:10]([NH:14][C:15]2[CH:27]=[CH:26][C:18]([C:19]([N:21]([CH2:24][CH3:25])[CH2:22][CH3:23])=[O:20])=[CH:17][CH:16]=2)[CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.O>C1(C)C=CC=CC=1.CC([O-])=O.CC([O-])=O.[Cu+2]>[CH2:1]([N:8]1[CH2:13][CH2:12][CH2:11][CH:10]([N:14]([C:15]2[CH:16]=[CH:17][C:18]([C:19]([N:21]([CH2:22][CH3:23])[CH2:24][CH3:25])=[O:20])=[CH:26][CH:27]=2)[C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)[CH2:9]1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CCN(CC)C(=O)c1ccc(NC2CCCN(Cc3ccccc3)C2)cc1
Agent: [Cu+2]
Agent: CC(=O)[O-]
Solvent: Cc1ccccc1
Solvent: O
Product: CCN(CC)C(=O)c1ccc(N(c2ccccc2)C2CCCN(Cc3ccccc3)C2)cc1
Temperature: 110 °C
Yield: 137.6 %

Procedure:
A mixture of 4-[N-(1-benzyl-piperidin-3-yl)-amino]-N,N-diethyl benzamide (compound 13) (0.29 mg, 0.79 mmol), Ph3Bi (0.87 g, 1.98 mmol), and Cu(OAc)2 (0.36 g, 1.98 mmol) in toluene (5 mL) was heated at 110° C. for 12 h and allowed to cool to room temperature. Water (5 mL) was added and the mixture filtered through Celite®. The layers in the filtrate were separated and the organic phase washed with water, brine, dried over Na2SO4 and concentrated. Chromatography of the residue (9:1 EtOAc/heptane) gave the title compound 14 (0.24 g, 67%) as a pale yellow viscous oil.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:16]=[CH:17][CH:18]=1)[CH2:5][C:6]1[CH:7]=[C:8]([CH:13]=[CH:14][CH:15]=1)[C:9]([O:11]C)=[O:10].[OH-].[Li+]>O.C1COCC1>[F:1][C:2]1[CH:3]=[C:4]([CH:16]=[CH:17][CH:18]=1)[CH2:5][C:6]1[CH:7]=[C:8]([CH:13]=[CH:14][CH:15]=1)[C:9]([OH:11])=[O:10]
Reactant: COC(=O)c1cccc(Cc2cccc(F)c2)c1
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: O=C(O)c1cccc(Cc2cccc(F)c2)c1
Temperature: 60 °C
Yield: 79 %

Procedure:
A mixture of methyl 3-(3-fluorobenzyl)benzoate and lithium hydroxide (0.227 g; 5.42 mmol) in water (5 mL) and THF (5 mL) was heated at 60° C. for 3 hours and concentrated under reduced pressure. The resulting aqueous solution was acidified with a 6N solution of hydrochloric acid in water. The resulting precipitate was filtered off to give 0.198 g (79%) of 3-(3-fluorobenzyl)benzoic acid which was used without further purification.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[C:6]([NH:8][C:9]2[CH:14]=[CH:13][C:12]([C:15]([F:18])([F:17])[F:16])=[CH:11][CH:10]=2)[N:5]2[N:19]=[C:20](S(C)(=O)=O)[N:21]=[C:4]2[N:3]=1.[O-:26][CH2:27][CH3:28].[Na+]>C(O)C>[CH2:27]([O:26][C:20]1[N:21]=[C:4]2[N:3]=[C:2]([CH3:1])[CH:7]=[C:6]([NH:8][C:9]3[CH:14]=[CH:13][C:12]([C:15]([F:18])([F:17])[F:16])=[CH:11][CH:10]=3)[N:5]2[N:19]=1)[CH3:28]
Reactant: CC[O-]
Reactant: Cc1cc(Nc2ccc(C(F)(F)F)cc2)n2nc(S(C)(=O)=O)nc2n1
Agent: [Na+]
Solvent: CCO
Product: CCOc1nc2nc(C)cc(Nc3ccc(C(F)(F)F)cc3)n2n1
Temperature: 120 °C

Procedure:
Intermediate 16 (0.14 g, 0.377 mmol) was added to sodium ethoxide (ALDRICH, 0.077 g, 1.131 mmol) in ethanol (3 mL). The mixture was heated under microwave irradiation at 120° C. for 30 minutes. Solvent was removed under vacuum to yield a yellowish residue which was purified by flash chromatography (Si, eluting with a 90:10% DCM: MeOH mixture) to yield the title compound as a beige solid.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([NH:9][C:10](=[O:12])[CH3:11])=[CH:5][CH:4]=1.[Br:13]Br>C(O)(=O)C>[Br:13][C:4]1[CH:5]=[C:6]([NH:9][C:10](=[O:12])[CH3:11])[CH:7]=[CH:8][C:3]=1[O:2][CH3:1]
Reactant: COc1ccc(NC(C)=O)cc1
Reactant: BrBr
Solvent: CC(=O)O
Product: COc1ccc(NC(C)=O)cc1Br
Temperature: 65 °C
Yield: 45.1 %

Procedure:
To a solution of N-(4-methoxyphenyl)acetamide II (7.50 g, 45.40 mmol) in acetic acid (50 mL) was added a solution of Br2 (4.70 mL, 90.80 mmol) in acetic acid (10.0 mL). The resulting reaction mixture was then heated to 65° C. for 4 h. After the completion of the reaction (TLC monitoring), acetic acid was distilled off, cooled the residue to 0° C. and then basified with aqueous NH3 till pH 12 followed by extraction with EtOAc (2×500.0 mL). The combined organics was washed with brine, dried (Na2SO4), filtered and concentrated under reduced pressure. The crude residue was purified over silica gel (60-120 M, 25-30% EtOAc-Hexane) to obtain the desired product (5.0 g, 45%). 1H NMR (400 MHz, DMSO-d6): δ 2.0 (s, 3H), 3.79 (s, 3H), 7.06 (d, J=8.80 Hz, 1H), 7.44 (dd, J=2.40 and 8.80 Hz, 1H), 7.91 (d, J=2.40 Hz, 1H) and 9.92 (br s, 1H). MS: 244.15 (M+H)+.
Reaction SMILES: Br[C:2]1[C:10]2[N:9]3[CH2:11][CH2:12][CH2:13][NH:14][C:15](=[O:16])[C:8]3=[CH:7][C:6]=2[CH:5]=[C:4]([CH3:17])[CH:3]=1.[CH3:18][O:19][C:20]1[CH:25]=[CH:24][C:23](B(O)O)=[CH:22][CH:21]=1>>[CH3:18][O:19][C:20]1[CH:25]=[CH:24][C:23]([C:2]2[C:10]3[N:9]4[CH2:11][CH2:12][CH2:13][NH:14][C:15](=[O:16])[C:8]4=[CH:7][C:6]=3[CH:5]=[C:4]([CH3:17])[CH:3]=2)=[CH:22][CH:21]=1
Reactant: COc1ccc(B(O)O)cc1
Reactant: Cc1cc(Br)c2c(c1)cc1n2CCCNC1=O
Product: COc1ccc(-c2cc(C)cc3cc4n(c23)CCCNC4=O)cc1

Procedure:
The title compound, off-white solid (33 mg, 60%), MS (ISP) m/z=321.5 [(M+H)+], mp 208° C., was prepared in accordance with the general method of example 1 from 7-bromo-9-methyl-2,3,4,5-tetrahydro-[1,4]diazepino[1,2-a]indol-1-one (intermediate 11) (50 mg, 0.17 mmol) and commercially available 4-methoxy-phenylboronic acid (33.7 mg, 0.22 mmol).
Reaction SMILES: Br[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:5](=[O:12])[C:4](=[O:13])[CH:3]=1.[Cl:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=1B(O)O.C1(C)C=CC=CC=1P(C1C=CC=CC=1C)C1C=CC=CC=1C.C([O-])([O-])=O.[K+].[K+].[Br-]>C1COCC1.O.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd].C(OCC)(=O)C>[Cl:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=1[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:5](=[O:12])[C:4](=[O:13])[CH:3]=1
Reactant: OB(O)c1ccccc1Cl
Reactant: O=C1C=C(Br)c2ccccc2C1=O
Agent: [Pd]
Agent: Cc1ccccc1P(c1ccccc1C)c1ccccc1C
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: O
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: O=C1C=C(c2ccccc2Cl)c2ccccc2C1=O
Temperature: 25 °C

Procedure:
To a solution of 4-bromo-[1,2]naphthoquinone (350 mg, 1.48 mmol) in THF (20 mL) and H2O (5 mL) was added 2-chlorophenylboronic acid (231 mg. 1.48 mmol). followed by tri-o-tolylphosphine (45 mg, 148 μmol) and K2CO3 (614 mg, 4.44 mmol). The mixture was deoxygenated with bubbling N2 for about ten minutes, at which time the N3 line was removed and tris(dibenzylideneacetone)dipalladium(0) (68 mg, 74 μmol) was added. The resultant mixture was heated to reflux for 2 hours under N2, at which point no starting bromide was detectable by TLC (hexanes:ethyl acetate, 1:1, v/v). The mixture was cooled to room temperature and the THF evaporated under reduced pressure. The dried material was dissolved in ethyl acetate, washed sequentially with saturated aqueous ammonium chloride, H2O and brine, dried over Na2SO4, filtered, and evaporated under reduced pressure. The isolated material was chromatographed on silica gel (hexanes-ethyl acetate, 4:1, v/v) and dried to yield the product, 4-(2-chloro-phenyl)-[1,2]naphthoquinone, as an orange solid. 1H NMR (300 MHz, CDCl3) δ 8.21 (1H, dd, J=6.9, 2.1 Hz), 7.56-7.52 (3H, m), 7.48-7.44(2H, m), 7.44 (1H, m), 6.91 (1H, dd, J=2, 6 Hz), 6.39 (1H, s); HPLC: 7.45 min.
Reaction SMILES: [C:1]([C:4]1[CH:5]=[CH:6][C:7]([OH:14])=[C:8]([CH:13]=1)[C:9]([O:11][CH3:12])=[O:10])(=[O:3])[CH3:2].I[CH2:16][CH2:17][CH3:18].C(=O)([O-])[O-].[K+].[K+]>CC(=O)CC>[C:1]([C:4]1[CH:5]=[CH:6][C:7]([O:14][CH2:16][CH2:17][CH3:18])=[C:8]([CH:13]=1)[C:9]([O:11][CH3:12])=[O:10])(=[O:3])[CH3:2]
Reactant: COC(=O)c1cc(C(C)=O)ccc1O
Reactant: CCCI
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCC(C)=O
Product: CCCOc1ccc(C(C)=O)cc1C(=O)OC
Reaction time: 24 h
Yield: 56.3 %

Procedure:
A stirred mixture of methyl 5-acetyl-2-hydroxy-benzoate (10 g, 0.0515 mol), 1-iodopropane (10.5 g, 0.0618 mol), anhydrous potassium carbonate (14.2 g, 0.103 mol) and 2-butanone (200 ml) was heated under reflux for 18 hours. A further quantity of 1-iodopropane (10.5 g, 0.0618 mol) was then added and heating under reflux continued for a further 24 hours. The solvent was removed by evaporation under vacuum and the residue partitioned between water (200 ml) and ethyl acetate (200 ml). The aqueous phase was extracted with ethyl acetate (2×100 ml), then the organic solutions combined, dried (Na2SO4) and evaporated under vacuum. The residue was chromatographed on silica gel (120 g) using a methanol in dichloromethane elution gradient (0-1%), then crystallization of the product from ethyl acetate-hexane gave the title compound as white crystals (6.85 g, 56%), m.p. 49° C.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([N+:8]([O-])=O)[CH:5]=[CH:4][C:3]=1[Si:11]([CH3:14])([CH3:13])[CH3:12]>CO.[C].[Pd]>[F:1][C:2]1[CH:7]=[C:6]([CH:5]=[CH:4][C:3]=1[Si:11]([CH3:14])([CH3:13])[CH3:12])[NH2:8]
Reactant: C[Si](C)(C)c1ccc([N+](=O)[O-])cc1F
Agent: [Pd]
Solvent: CO
Product: C[Si](C)(C)c1ccc(N)cc1F
Temperature: 25 °C
Reaction time: 3.5 h
Yield: 68.3 %

Procedure:
A mixture of (2-fluoro-4-nitrophenyl)trimethylsilane (3.22 g, 15.10 mmol) and 10% palladium-carbon (1.0 g, 0.47 mmol, 50%, wet) in MeOH (65 mL) was stirred at room temperature for 3.5 hr under hydrogen atmosphere (1 atm). The catalyst was removed by filtration, and the filtrate was concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (solvent gradient; 2→15% MeOH/ethyl acetate) to give 3-fluoro-4-(trimethylsilyl)aniline (1.89 g, 10.31 mmol, 68.3%) as a colorless oil.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:16]3[C:11]([CH:12]=[N:13][C:14]([S:17][CH3:18])=[N:15]3)=[CH:10][CH:9]=2)=[C:4]([N+:19]([O-])=O)[CH:3]=1.[Cl-].[NH4+].C(O)C.O>[Fe]>[CH3:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:16]3[C:11]([CH:12]=[N:13][C:14]([S:17][CH3:18])=[N:15]3)=[CH:10][CH:9]=2)=[C:4]([NH2:19])[CH:3]=1
Reactant: CSc1ncc2ccc(-c3ccc(C)cc3[N+](=O)[O-])n2n1
Agent: [Fe]
Agent: [Cl-]
Agent: [NH4+]
Solvent: CCO
Solvent: O
Product: CSc1ncc2ccc(-c3ccc(C)cc3N)n2n1
Temperature: 100 °C
Yield: 86.5 %

Procedure:
A mixture of 7-(4-Methyl-2-nitro-phenyl)-2-methylsulfanyl-pyrrolo[2,1-f][1,2,4]triazine (620 mg, 2.1 mmol), iron (346 mg, 6.19 mmol), ammonium chloride (55.2 mg, 1.03 mmol) in ethanol (12.0 mL, 206 mmol) and water (8 mL, 400 mmol) was heated at 100° C. The mixture was cooled, solvent was evaporated and was diluted with water and EtOAc. It was filtered through a pad of celite, extracted from EtOAc, combined organic was washed with brine. After drying, solvent was evaporated to give 5-Methyl-2-(2-methylsulfanyl-pyrrolo[2,1-f][1,2,4]triazin-7-yl)-phenylamine as a solid (491 mg, 88%). LCMS (E/I+) 271. The product was taken to the next step without further purification.
Reaction SMILES: ClC1C=C(Cl)C=CC=1C1N=C(CC)C(N[C@@H]2C3C(=CC=CC=3)C[C@@H]2O)=NC=1CC.Br[C:31]1[N:32]=[C:33]([CH2:52][CH3:53])[C:34]([NH:39][CH:40]2[C:49]3[C:44](=[CH:45][CH:46]=[C:47]([O:50][CH3:51])[CH:48]=3)[CH2:43][CH2:42][CH2:41]2)=[N:35][C:36]=1[CH2:37][CH3:38].[Cl:54][C:55]1[CH:60]=[C:59]([O:61][CH3:62])[CH:58]=[CH:57][C:56]=1B(O)O>>[Cl:54][C:55]1[CH:60]=[C:59]([O:61][CH3:62])[CH:58]=[CH:57][C:56]=1[C:31]1[N:32]=[C:33]([CH2:52][CH3:53])[C:34]([NH:39][CH:40]2[C:49]3[C:44](=[CH:45][CH:46]=[C:47]([O:50][CH3:51])[CH:48]=3)[CH2:43][CH2:42][CH2:41]2)=[N:35][C:36]=1[CH2:37][CH3:38]
Reactant: CCc1nc(NC2CCCc3ccc(OC)cc32)c(CC)nc1Br
Reactant: COc1ccc(B(O)O)c(Cl)c1
Agent: CCc1nc(-c2ccc(Cl)cc2Cl)c(CC)nc1N[C@@H]1c2ccccc2C[C@@H]1O
Product: CCc1nc(-c2ccc(OC)cc2Cl)c(CC)nc1NC1CCCc2ccc(OC)cc21

Procedure:
Following the procedure for the preparation of (1R,2S)-1-{[5-(2,4-dichlorophenyl)-3,6-diethylpyrazin-2-yl]amino}-2,3-dihydro-1H-inden-2-ol but substituting 5-bromo-3,6-diethyl-N-(7-methoxy-1,2,3,4-tetrahydronaphthalen-1-yl)pyrazin-2-amine and 2-chloro-4-methoxyphenylboronic acid, and making non-critical variations provided the title compound as a oil: 1H NMR (400 MHz, CDCl3) δ 7.29, 7.11, 7.04, 6.99, 6.91, 6.84, 5.47, 4.64, 3.86, 3.78, 2.83, 2.68, 2.55, 2.15, 1.91, 1.74, 1.27, 1.21; 13C NMR (100 MHz, CDCl3) δ 160.08, 158.37, 151.72, 150.71, 140.19, 139.72, 138.22, 136.12, 135.06, 132.59, 131.63, 130.50, 130.39, 115.13, 114.20, 113.41, 55.99, 55.74, 49.29, 30.08, 29.16, 27.66, 26.50, 20.66, 13.35, 11.82; HRMS (FAB) calcd for C26H30ClN3O2+H 452.2104, found 452.2097.
Reaction SMILES: [H-].[Al+3].[Li+].[H-].[H-].[H-].[CH3:7][C:8]1[CH:20]=[CH:19][C:11]([O:12][CH2:13][CH2:14][NH:15][C:16](=O)[CH3:17])=[CH:10][CH:9]=1>CCOCC>[CH2:16]([NH:15][CH2:14][CH2:13][O:12][C:11]1[CH:10]=[CH:9][C:8]([CH3:7])=[CH:20][CH:19]=1)[CH3:17]
Reactant: CC(=O)NCCOc1ccc(C)cc1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: CCOCC
Product: CCNCCOc1ccc(C)cc1
Temperature: 25 °C
Reaction time: 24 h

Procedure:
To a chilled suspension of 0.49 g (013 mol) lithium aluminium hydride in 50 mL anhydrous ether, add 5.0 g (025 mol) N-[2-(4-methylphenoxy)ethyl]acetamide at a rate which maintains the reaction temperature below 10° C. Allow to warm to room temperature and stir at ambient temp. for 24 hrs. After this time, quench the mixture with H2O and filter the salts. Concentrate the filtrate to obtain the title compound.
Reaction SMILES: [CH3:1][C:2]([CH:4]1[CH2:7][CH2:6][CH2:5]1)=O.Br.BrBr.[CH2:11]([O:13][P:14]([CH2:19][C:20]([NH2:22])=[S:21])(=[O:18])[O:15][CH2:16][CH3:17])[CH3:12].[OH-].[NH4+]>C(O)(=O)C.C(OCC)(=O)C.CO.O.CO>[CH2:11]([O:13][P:14]([CH2:19][C:20]1[S:21][CH:1]=[C:2]([CH:4]2[CH2:7][CH2:6][CH2:5]2)[N:22]=1)(=[O:18])[O:15][CH2:16][CH3:17])[CH3:12]
Reactant: CCOP(=O)(CC(N)=S)OCC
Reactant: CC(=O)C1CCC1
Agent: Br
Agent: BrBr
Agent: [NH4+]
Solvent: O
Solvent: CC(=O)O
Solvent: CCOC(C)=O
Product: CCOP(=O)(Cc1nc(C2CCC2)cs1)OCC
Temperature: 5 °C
Reaction time: 1.25 h
Yield: 100 %

Procedure:
A 250-mL round-bottom flask equipped with a thermometer, drying tube (calcium chloride) was charged with 10.0 g (0.1019 mol) of cyclobutyl methyl ketone (SEA C Lot 01) and 80 mL of methanol. The mixture was cooled to 5° C., and 0.8 mL of a 30% solution of hydrogen bromide in acetic acid was added, followed by 5.0 mL (0.09705 mol) of bromine, during a period of 10 min, while the temperature of the slight exotherm was maintained at about 5° C. The mixture was stirred for 4 hours at 5° C. (Decolorization from dark brown to light orange occurred after 75 minutes). To this mixture was added dropwise 10.0 mL of water, with cooling in an ice bath (the temperature rose from 5° to 10° C.). After the addition, the mixture was stirred at room temperature for a period of 45 minutes. To this mixture was added 20.45 g (0.0968 mol) of crude compound of Example 1 as a powdered solid which dissolved gradually with concomitant decolorization of the yellow solution. The reaction temperature during the addition of the compound of Example 1 was maintained at 30° C. by an ice bath. The mixture was stirred at room temperature overnight. At that time, the compound of Example 1 was no longer detectable (TLC, Merck silica gel 60, F-254; 95:5 ethyl acetate-methanol). The mixture was rendered basic with concentrated ammonium hydroxide solution while the temperature was maintained at 20° C. with an ice bath and was then evaporated. The residue was taken up in 150 mL of ethyl acetate. This solution was washed with 100 mL of water and the aqueous phase was reextracted with 75 mL of ethyl acetate. 50 mL of brine was used to wash, in succession, the first and the second ethyl acetate solutions. The ethyl acetate solutions were combined and dried over sodium sulfate. After solvent evaporation and drying at 60° C. at 10 torr, there was obtained 28 g of crude [(4-cyclobutyl-2-thiazolyl)methyl]phosphonic acid diethyl ester as a dark oil, 99.83% pure (HPLC); 100% yield based on the compound of Example 1 used.
Reaction SMILES: C(OC(=O)[NH:7][C:8]1[CH:13]=[C:12]([O:14][CH2:15][CH3:16])[C:11]([C:17]([F:20])([F:19])[F:18])=[CH:10][C:9]=1[NH:21][C:22](=[O:40])[CH2:23][C:24]([C:26]1[CH:31]=[CH:30][CH:29]=[C:28]([C:32]2[C:33]([CH2:38][CH3:39])=[N:34][CH:35]=[CH:36][CH:37]=2)[CH:27]=1)=O)(C)(C)C.C(O)(C(F)(F)F)=O>C(Cl)Cl>[CH2:15]([O:14][C:12]1[C:11]([C:17]([F:20])([F:19])[F:18])=[CH:10][C:9]2[NH:21][C:22](=[O:40])[CH2:23][C:24]([C:26]3[CH:31]=[CH:30][CH:29]=[C:28]([C:32]4[C:33]([CH2:38][CH3:39])=[N:34][CH:35]=[CH:36][CH:37]=4)[CH:27]=3)=[N:7][C:8]=2[CH:13]=1)[CH3:16]
Reactant: CCOc1cc(NC(=O)OC(C)(C)C)c(NC(=O)CC(=O)c2cccc(-c3cccnc3CC)c2)cc1C(F)(F)F
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CCOc1cc2c(cc1C(F)(F)F)NC(=O)CC(c1cccc(-c3cccnc3CC)c1)=N2

Procedure:
The title compound was prepared from (5-ethoxy-2-{3-[3-(2-ethyl-pyridin-3-yl)-phenyl]-3-oxo-propionylamino}-4-trifluoromethyl-phenyl)-carbamic acid tert-butyl ester (Example M215) (255 mg, 0.45 mmol) by treatment with TFA in CH2Cl2 according to the general procedure N. Obtained as a light yellow solid (148 mg, 73%).
Reaction SMILES: [N+:1]([C:4]1[CH:17]=[CH:16][CH:15]=[C:14]2[C:5]=1[C:6](=[O:19])[C:7]1[CH2:8][CH2:9][CH2:10][CH2:11][C:12]=1[C:13]2=[O:18])([O-])=O.[H][H].[OH-].[Na+]>[Pd].C(O)C>[NH2:1][C:4]1[C:5]2[C:6](=[O:19])[C:7]3[C:12](=[CH:11][CH:10]=[CH:9][CH:8]=3)[C:13](=[O:18])[C:14]=2[CH:15]=[CH:16][CH:17]=1
Reactant: O=C1C2=C(CCCC2)C(=O)c2c1cccc2[N+](=O)[O-]
Reactant: [H][H]
Agent: [Pd]
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: Nc1cccc2c1C(=O)c1ccccc1C2=O

Procedure:
2.6 Grams of 5% palladium on carbon catalyst was added to a mixture of 260 grams of 5-nitrotetrahydroanthraquinone and 24,000 grams of ethanol, into which was injected hydrogen for absorption in the 5-nitro compound in an amount of 2 mols per mol of the 5-nitro compound at normal (ambient) temperature and under normal atmospheric pressure. The solution which was first pale yellow turned reddish brown in color as the reaction proceeded and a small amount of precipitate appeared in the solution. When the hydrogenation was continued, the solution became almost transparent and dark reddish brown upon completion of the reaction. The hydrogen in the reactor was replaced by nitrogen, to which was added 400 grams of a 20% sodium hydroxide solution and the color of the resultant solution turned dark yellowish brown immediately after the addition of the alkali during which a small amount of glossy crystals were precipitated. The reaction was completed immediately, dark yellowish brown being the color of leuco-1-aminoanthraquinone which is obtained by catalytical hydrogenation of 1-aminoanthraquinone or by having 1 mol of hydrogen absorbed in 1 mol of 1-aminoanthraquinone under the same reaction conditions, and then air was fed into the solution for oxidation. Upon determination, it was found that 0.5 mol of oxygen was absorbed per mol of the 5-nitro compound. As a result, the reaction solution turned reddish orange with a precipitate of a reddish orange color. The resultant solution was subjected to filtration, followed by extraction of the cake with acetone for separation of the catalyst. The resultant filtrate was dried up to obtain 220 grams of 1-aminoanthraquinone having a purity of 98%.