Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: I[C:2]1[CH:10]=[CH:9][CH:8]=[C:7]2[C:3]=1/[C:4](=[CH:12]/[C:13]1[NH:14][CH:15]=[CH:16][CH:17]=1)/[C:5](=[O:11])[NH:6]2.C([O-])([O-])=O.[Na+].[Na+].O.[NH2:25][C:26]1[CH:27]=[C:28](B(O)O)[CH:29]=[CH:30][CH:31]=1>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.COCCOC>[NH2:25][C:26]1[CH:31]=[C:30]([C:2]2[CH:10]=[CH:9][CH:8]=[C:7]3[C:3]=2/[C:4](=[CH:12]/[C:13]2[NH:14][CH:15]=[CH:16][CH:17]=2)/[C:5](=[O:11])[NH:6]3)[CH:29]=[CH:28][CH:27]=1
Reactant: Nc1cccc(B(O)O)c1
Reactant: O=C1Nc2cccc(I)c2/C1=C/c1ccc[nH]1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: COCCOC
Product: Nc1cccc(-c2cccc3c2/C(=C/c2ccc[nH]2)C(=O)N3)c1
Temperature: 100 °C
Yield: 91.3 %

Procedure:
A solution of (Z)-1,3-dihydro-4-iodo-3-[(1H-pyrrol-2-yl)methylene]-2H-indol-2-one (500 mg, 1.49 mmol) (Starting Material 1), 2M aqueous Na2CO3 solution (1.49 mL, 2.98 mmol), (Ph3P)4Pd (86 mg, 0.074 mmol) (Aldrich), and 3-aminophenylboronic acid monohydrate (253 mg, 1.63 mmol) (Lancaster) in 10 mL of a 3:1 mixture of 1,2-dimethoxyethane:distilled water was heated at 100° C. under a nitrogen atmosphere for 96 h. The reaction mixture was allowed to cool to room temperature and then directly purified by flash chromatography (Merck Silica gel 60, 230-400 mesh, 35% ethyl acetate-hexanes elution) to yield pure (Z)-4-(3-aminophenyl)-1,3-dihydro-3-[(1H-pyrrol-2-yl)methylene]-2H-indol-2-one (410 mg, 91%) as a yellow solid (mp 92-94° C.) (solid to gel).
Reaction SMILES: C(O[C@@H:5]1[NH:8][C:7](=[O:9])[C@H:6]1[NH:10][C:11]([C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1)([C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)(=O)C.[N-:30]=[N+:31]=[N-:32].[Na+]>CO.O>[N:30]([C@H:5]1[NH:8][C:7](=[O:9])[C@H:6]1[NH:10][C:11]([C:18]1[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=1)([C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1)[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)=[N+:31]=[N-:32]
Reactant: [N-]=[N+]=[N-]
Reactant: CC(=O)O[C@@H]1NC(=O)[C@H]1NC(c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Na+]
Solvent: O
Solvent: CO
Product: [N-]=[N+]=N[C@H]1NC(=O)[C@H]1NC(c1ccccc1)(c1ccccc1)c1ccccc1
Reaction time: 2 h
Yield: 35.2 %

Procedure:
To a solution of 3.0 g of (3S,4S)-4-acetoxy-3-tritylamino-2-oxoazetidine in 50 ml of methanol is added a solution of 0.65 g of sodium azide in 5 ml of water under ice-cooling, following by stirring for two hours at 40°-50° C. The solvent is distilled off under reduced pressure. To the residue is added ethyl acetate, and the organic layer is separated, which is washed with water and concentrated. The residue is purified on a silica-gel column (ethyl acetate:n-hexane=1:1) to give 1.01 g of (3S,4R)-4-azido-3-tritylamino-2-oxoazetidine.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][N:5]=[C:4]([O:8][CH3:9])[CH:3]=1.[C:10]1(/[CH:16]=[CH:17]/B(O)O)[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1.C([O-])([O-])=O.[K+].[K+]>CS(C)=O>[CH3:9][O:8][C:4]1[CH:3]=[C:2](/[CH:17]=[CH:16]/[C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[CH:7]=[CH:6][N:5]=1
Reactant: OB(O)/C=C/c1ccccc1
Reactant: COc1cc(Br)ccn1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CS(C)=O
Product: COc1cc(/C=C/c2ccccc2)ccn1
Temperature: 90 °C
Yield: 92.8 %

Procedure:
4-Bromo-2-methoxypyridine (1.85 g, 9.84 mmol), (E)-phenylvinylboronic acid (4.3 g, 30 mmol), K2CO3 (4.0 g, 30 mmol) and [1,1′-Bis-(diphosphenylphosphino)ferrocene]dichloropalladium(II) (PdCl2dppf) (400 mg, 0.5 mmol) were stirred in DMSO (15 mL) under vacuum for 30 min. The flask was flushed with nitrogen and the mixture was heated at 90° C. for 30 min. Upon cooling, the mixture was diluted with methylene chloride and washed with 5% lithium chloride solution (5×), dried, concentrated, and the residue was purified by column chromatography (silica gel, hexanes/ethyl acetate, 97:3 to 75:25) to provide the title compound (1.93 g, 93%) as an orange oil: 1H NMR (300 MHz, CDCl3) δ 8.12 (d, J=5.2 Hz, 1H), 7.51 (m, 2H), 7.40-7.22 (m, 4H), 7.02-6.94 (m, 2H), 6.78 (s, 1H), 3.95 (s, 3H).
Reaction SMILES: [CH:1]1([CH2:4][CH2:5][CH2:6][NH:7][C:8]([C:10]2[N:11]=[N:12][C:13]([Cl:16])=[CH:14][CH:15]=2)=[O:9])[CH2:3][CH2:2]1.[NH:17]1[CH2:22][CH2:21][CH:20]([NH:23][C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=2[C:30]([F:33])([F:32])[F:31])[CH2:19][CH2:18]1>>[ClH:16].[CH:1]1([CH2:4][CH2:5][CH2:6][NH:7][C:8]([C:10]2[N:11]=[N:12][C:13]([N:17]3[CH2:18][CH2:19][CH:20]([NH:23][C:24]4[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=4[C:30]([F:31])([F:32])[F:33])[CH2:21][CH2:22]3)=[CH:14][CH:15]=2)=[O:9])[CH2:3][CH2:2]1
Reactant: O=C(NCCCC1CC1)c1ccc(Cl)nn1
Reactant: FC(F)(F)c1ccccc1NC1CCNCC1
Product: Cl
Product: O=C(NCCCC1CC1)c1ccc(N2CCC(Nc3ccccc3C(F)(F)F)CC2)nn1
Yield: 38 %

Procedure:
Following the procedure as described in Example 1, making variations only as required to use 6-chloropyridazine-3-carboxylic acid (3-cyclopropylpropyl)amide in place of 6-chloropyridazine-3-carboxylic acid (2-cyclopropylethyl)amide to react with piperidin-4-yl-(2-trifluoromethylphenyl)amine, the title compound was obtained as a white powder in 38% yield. m.p. 117-121° C. 1H NMR (300 MHz, DMSO-d6) δ 8.73 (br., s, 1H), 7.90 (d, J=9.3 Hz, 1H), 7.62 (d, J=9.6 Hz, 1H), 7.46-7.37 (m, 2H), 6.99 (d, J=8.4 Hz, 1H), 6.68 (t, J=7.5 Hz, 1H), 4.42 (d, J=13.2 Hz, 2H), 3.82 (br., s, 2H), 3.29-3.22 (m, 3H), 1.98 (d, J=11.7 Hz, 2H), 1.61-1.54 (m, 4H), 1.20-1.13 (m, 2H), 0.65-0.63 (m, 1H), 0.33-0.26 (m, 2H), −0.03-−0.05 (m, 2H). 13C NMR (75 MHz, DMSO-d6) δ 162.1, 157.4, 144.4, 144.1, 133.6, 126.4, 126.3, 116.3, 115.6, 113.0, 112.0, 48.9, 44.4, 31.4, 30.6, 29.2, 10.4, 4.3. MS (ES+) m/z 448.0 (M+1-HCl).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[N:9]1[CH2:14][CH2:13][N:12]([CH2:15][CH2:16][CH2:17][NH:18][C:19]2[N:29]=[CH:28][CH:27]=[CH:26][C:20]=2[C:21]([N:23]([CH3:25])[CH3:24])=[O:22])[CH2:11][CH2:10]1.Cl.[Br:31]N1C(=O)CCC1=O>C(Cl)Cl.CO.O.C([O-])([O-])=O.[K+].[K+]>[Br:31][C:7]1[CH:6]=[CH:5][C:4]([N:9]2[CH2:10][CH2:11][N:12]([CH2:15][CH2:16][CH2:17][NH:18][C:19]3[N:29]=[CH:28][CH:27]=[CH:26][C:20]=3[C:21]([N:23]([CH3:25])[CH3:24])=[O:22])[CH2:13][CH2:14]2)=[C:3]([O:2][CH3:1])[CH:8]=1
Reactant: O=C1CCC(=O)N1Br
Reactant: COc1ccccc1N1CCN(CCCNc2ncccc2C(=O)N(C)C)CC1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CO
Solvent: O
Solvent: ClCCl
Product: COc1cc(Br)ccc1N1CCN(CCCNc2ncccc2C(=O)N(C)C)CC1
Temperature: 25 °C
Reaction time: 24 h
Yield: 75.5 %

Procedure:
2-{3-[4-(2-Methoxyphenyl)piperazin-1-yl]propylamino}-N,N-dimethylnicotinamide (0.21 g, 0.53 mmol), prepared as in Example 21, was dissolved in methylene chloride and the solution was treated with excess hydrochloric acid in methanol and concentrated under reduced pressure. The residue was dissolved in 6 mL of DMF and N-bromosuccinimide (0.101 g, 0.57 mmol) was added. The mixture was stirred at room temperature for approximately 24 hours, diluted with water and basified with K2CO3. The basified mixture was extracted with ethyl acetate and the ethyl acetate layer was washed with brine, dried (MgSO4), filtered and concentrated. The residue was purified on silica gel by column chromatography eluting with 5% methanol/methylene chloride to give 2-{3-[4-(4-bromo-2-methoxyphenyl)piperazin-1-yl]propylamino}-N,N-dimethylnicotinamide (0.19 g, 0.40 mmol) as an oil.
Reaction SMILES: [CH3:1][C:2]([C:4]([CH3:6])=[CH2:5])=[CH2:3].[CH3:7][Si:8]([C:11]#[CH:12])([CH3:10])[CH3:9]>ClCCl.[Zn+2].[I-].[I-].C1(P(CC)C2C=CC=CC=2)C=CC=CC=1>[CH3:3][C:2]1[CH2:1][CH:12]=[C:11]([Si:8]([CH3:10])([CH3:9])[CH3:7])[CH2:5][C:4]=1[CH3:6]
Reactant: C#C[Si](C)(C)C
Reactant: C=C(C)C(=C)C
Agent: CCP(c1ccccc1)c1ccccc1
Agent: [I-]
Agent: [Zn+2]
Solvent: ClCCl
Product: CC1=C(C)CC([Si](C)(C)C)=CC1
Temperature: 30 °C
Reaction time: 0.5 h
Yield: 52.9 %

Procedure:
In a four-necked flask, 0.54 g (2.5 mmol) of CoBr2, 2.62 g (8.2 mmol) of ZnI2 and 1.09 g (2.7 mmol) of diphenylphosphinoethane were dissolved in 120 ml of dichloromethane and the mixture was stirred for 0.5 hour at 30° C. Subsequently, 27.5 ml (244 mmol) of 2,3-dimethyl-1,3-butadiene, 21.5 g (219 mol) of trimethylsilylacetylene and 0.69 g (2.7 mmol) of Bu4NBH4 were added thereto, and the mixture was allowed to react for one hour at 30° C. After dichloromethane was evaporated under reduced pressure, 23.3 g of the title compound was obtained at a yield of 59.0% (GC purity 89%).
Reaction SMILES: [N:1]1[O:2][N:3]=[C:4]2[CH:9]=[C:8](B(O)O)[CH:7]=[CH:6][C:5]=12.I[C:14]1[C:22]2[C:17](=[N:18][CH:19]=[N:20][C:21]=2[NH2:23])[N:16]([CH:24]([CH3:26])[CH3:25])[N:15]=1.C([O-])([O-])=O.[Na+].[Na+]>CCO.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>[N:3]1[O:2][N:1]=[C:5]2[CH:6]=[CH:7][C:8]([C:14]3[C:22]4[C:17](=[N:18][CH:19]=[N:20][C:21]=4[NH2:23])[N:16]([CH:24]([CH3:26])[CH3:25])[N:15]=3)=[CH:9][C:4]=12
Reactant: CC(C)n1nc(I)c2c(N)ncnc21
Reactant: OB(O)c1ccc2nonc2c1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCO
Solvent: COCCOC
Product: CC(C)n1nc(-c2ccc3nonc3c2)c2c(N)ncnc21
Temperature: 80 °C

Procedure:
A solution of Benzo[c][1,2,5]oxadiazole-5-boronic acid (18 mg, 0.11 mmol) in EtOH (3.3 mL) was added to a solution of 3-iodo-1-isopropyl-1H-pyrazolo[3,4-d]pyrimidin-4-amine (30 mg, 0.10 mmol) in DME (12 mL). Pd(PPh3)4 (30 mg, 0.03 mmol) and saturated Na2CO3 (1.9 mL) were added and the reaction was heated to 80° C. under an argon atmosphere overnight. After cooling, the reaction was extracted with saturated NaCl and CH2Cl2. Organic phases were combined, concentrated in vacuo and purified by RP-HPLC (MeCN:H2O:0.1% TFA) to yield BA44. ESI-MS (M+H)+ m/z calcd 296.1, found 296.1.
Reaction SMILES: [CH2:1]([O:8][CH2:9][C@@H:10]1[CH2:13][C@H:12]([OH:14])[CH2:11]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[H-].[Na+].I[CH3:18]>O1CCCC1>[CH3:18][O:14][C@H:12]1[CH2:13][C@@H:10]([CH2:9][O:8][CH2:1][C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)[CH2:11]1
Reactant: O[C@H]1C[C@@H](COCc2ccccc2)C1
Reactant: CI
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CO[C@H]1C[C@@H](COCc2ccccc2)C1
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
To a solution of cis-3-benzyloxymethylcyclobutanol (Albany Molecular Research Institute, 1.0 g, 5.2 mmol) in 10 mL of tetrahydrofuran at 0° C. was added NaH (0.62 g, 15.6 mmol). The mixture stirred for 15 minutes then iodomethane (0.49 mL, 7.8 mmol) was added and the mixture was allowed to warm to ambient temperature and stir for 16 hours. Some starting material remained by TLC so additional NaH (0.21, 5.2 mmol) and iodomethane (0.32 mL, 5.2 mmol) were added and the mixture stirred for an additional 2 hours. The mixture was quenched with 10 mL of NH4Cl and diluted with 10 mL of ethyl acetate. The layers were separated and the aqueous layer was extracted 2×5 mL of ethyl acetate. The combined organic extracts were dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure. Purification via column chromatography (SiO2, 75% hexanes in ethyl acetate) afforded the title compound. MS (DCI/NH3) m/z 207 (M+H)+.
Reaction SMILES: [CH:1]([C:4]1[N:9]=[C:8]([C:10]2[CH:15]=[CH:14][C:13]([CH3:16])=[CH:12][N:11]=2)[CH:7]=[C:6]([C:17]([OH:19])=O)[CH:5]=1)([CH3:3])[CH3:2].[F:20][C:21]([F:32])([F:31])[C:22]1[N:27]=[CH:26][C:25]([C@H:28]([NH2:30])[CH3:29])=[CH:24][N:23]=1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C(N(C(C)C)CC)(C)C>CN(C=O)C>[CH:1]([C:4]1[N:9]=[C:8]([C:10]2[CH:15]=[CH:14][C:13]([CH3:16])=[CH:12][N:11]=2)[CH:7]=[C:6]([C:17]([NH:30][C@@H:28]([C:25]2[CH:24]=[N:23][C:22]([C:21]([F:32])([F:31])[F:20])=[N:27][CH:26]=2)[CH3:29])=[O:19])[CH:5]=1)([CH3:2])[CH3:3]
Reactant: C[C@@H](N)c1cnc(C(F)(F)F)nc1
Reactant: Cc1ccc(-c2cc(C(=O)O)cc(C(C)C)n2)nc1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: Cc1ccc(-c2cc(C(=O)N[C@H](C)c3cnc(C(F)(F)F)nc3)cc(C(C)C)n2)nc1
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 79.8 %

Procedure:
To a solution of 6-isopropyl-5′-methyl-2,2′-bipyridine-4-carboxylic acid (25.0 mg, 0.07 mmol) in DMF (0.3 mL) were added hydrochloride salt of (1R)-1-[2-(trifluoromethyl)pyrimidin-5-yl]ethanamine (22.1 mg, 0.08 mmol), HATU (38.2 mg, 0.10 mmol) and diisopropylethylamine (58.5 μL, 0.34 mmol). The mixture was stirred at ambient temperature. After 20 min, the mixture was purified by reverse phase chromatography (C-18, 95% water/acetonitrile→25% water/acetonitrile with 0.1% trifluoroacetic acid) gave the title compound (24 mg), HRMS 430.1850 (M+1). 1H NMR (400 MHz, CDCl3): δ 8.96 (s, 2H), 8.48 (s, 1H), 8.43 (d, 8.1 Hz, 1H), 8.37 (s, 1H), 7.67 (d, J=8.2 Hz, 1H), 7.63 (s, 1H), 6.96 (d, J=6.7 Hz, 1H), 5.44-5.35 (m, 1H), 3.24-3.14 (m, 1H), 2.42 (s, 3H), 1.74 (d, J=7.2 Hz, 3H), 1.37 (d, J=6.9 Hz, 6H).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH:9]=[C:10]([NH:12][CH:13]2[CH2:17][CH2:16][CH2:15][CH2:14]2)[CH:11]=1)[C:5]([O:7][CH3:8])=[O:6].[C:18](=O)([O-])[O-].[Cs+].[Cs+].[CH2:24](I)[CH3:25]>CN(C=O)C>[Br:1][C:2]1[CH:11]=[C:10]([N:12]([CH:13]2[CH2:17][CH2:16][CH2:15][CH2:14]2)[CH2:24][CH3:25])[C:9]([CH3:18])=[C:4]([CH:3]=1)[C:5]([O:7][CH3:8])=[O:6]
Reactant: COC(=O)c1cc(Br)cc(NC2CCCC2)c1
Reactant: O=C([O-])[O-]
Reactant: CCI
Agent: [Cs+]
Solvent: CN(C)C=O
Product: CCN(c1cc(Br)cc(C(=O)OC)c1C)C1CCCC1
Temperature: 80 °C
Yield: 45.9 %

Procedure:
To a stirred solution of methyl 3-bromo-5-(cyclopentylamino)benzoate (0.3 g, 0.96 mmol) in DMF (5 mL), cesium carbonate (0.628 g, 1.92 mmol) and ethyl iodide (0.748 g, 4.8 mmol) were added; resulting reaction mass was heated at 80° C. for 24 h. On completion, reaction mass was cooled to room temperature and filtered, residue was washed with ethyl acetate and filtrate was concentrated and then purified by column chromatography to afford desired compound (0.150 g, 46%).
Reaction SMILES: [NH2:1][C:2]1[C:7]([CH2:8][OH:9])=[C:6]([NH:10][CH2:11][CH2:12][NH:13][C:14](=[O:20])[O:15][C:16]([CH3:19])([CH3:18])[CH3:17])[CH:5]=[C:4]([C:21]2[C:26]([O:27][CH2:28][C:29]3[CH:34]=[CH:33][C:32]([O:35][CH3:36])=[CH:31][CH:30]=3)=[CH:25][CH:24]=[CH:23][C:22]=2[O:37][CH2:38][CH:39]2[CH2:41][CH2:40]2)[N:3]=1.CCN(CC)CC.Cl[C:50](Cl)([O:52]C(=O)OC(Cl)(Cl)Cl)Cl>C1COCC1>[CH:39]1([CH2:38][O:37][C:22]2[CH:23]=[CH:24][CH:25]=[C:26]([O:27][CH2:28][C:29]3[CH:30]=[CH:31][C:32]([O:35][CH3:36])=[CH:33][CH:34]=3)[C:21]=2[C:4]2[CH:5]=[C:6]([NH:10][CH2:11][CH2:12][NH:13][C:14](=[O:20])[O:15][C:16]([CH3:18])([CH3:19])[CH3:17])[C:7]3[CH2:8][O:9][C:50](=[O:52])[NH:1][C:2]=3[N:3]=2)[CH2:40][CH2:41]1
Reactant: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Reactant: COc1ccc(COc2cccc(OCC3CC3)c2-c2cc(NCCNC(=O)OC(C)(C)C)c(CO)c(N)n2)cc1
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: COc1ccc(COc2cccc(OCC3CC3)c2-c2cc(NCCNC(=O)OC(C)(C)C)c3c(n2)NC(=O)OC3)cc1
Temperature: 0 °C
Reaction time: 1 h
Yield: 138.5 %

Procedure:
To a cold (0° C.) solution of tert-butyl 2-{[2-amino-6-{2-(cyclopropylmethoxy)-6-[(4-methoxybenzyl)oxy]phenyl}-3-(hydroxymethyl)-4-pyridinyl]amino}ethylcarbamate (0.050 g, 0.089 mmol) and Et3N (0.074 mL, 0.531 mmol) in THF (10 mL) was added triphosgene (0.013 g, 0.044 mmol) in one portion. The mixture was stirred at 0° C. for 1 hr, and then partitioned between ethyl acetate and water. The organic phase was washed with brine, dried over Na2SO4, filtered, and concentrated under reduced pressure. Purification by column chromatography on silica gel (ethyl acetate) gave tert-butyl 2-[(7-{2-(cyclopropylmethoxy)-6-[(4-methoxybenzyl)-oxy]phenyl}-2-oxo-1,4-dihydro-2H-pyrido[2,3-d][1,3]oxazin-5-yl)amino]ethylcarbamate as colorless oil (0.036 g, yield; 69%).
Reaction SMILES: [OH-].[K+].C([O-])C.C[O:7][C:8]([C:10]1[N:11]([CH3:33])[C:12](=[O:32])[N:13]2[C:19]3[CH:20]=[CH:21][C:22]([Cl:24])=[CH:23][C:18]=3[C:17]([C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=3[Cl:31])=[N:16][CH2:15][C:14]=12)=[O:9]>O.CO>[Cl:24][C:22]1[CH:21]=[CH:20][C:19]2[N:13]3[C:12](=[O:32])[N:11]([CH3:33])[C:10]([C:8]([OH:9])=[O:7])=[C:14]3[CH2:15][N:16]=[C:17]([C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=3[Cl:31])[C:18]=2[CH:23]=1
Reactant: COC(=O)c1c2n(c(=O)n1C)-c1ccc(Cl)cc1C(c1ccccc1Cl)=NC2
Agent: CC[O-]
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: Cn1c(C(=O)O)c2n(c1=O)-c1ccc(Cl)cc1C(c1ccccc1Cl)=NC2

Procedure:
Potassium hydroxide, 1.3 g (0.02 mole), was dissolved in 1 ml of water and added to a suspension of 4 g (0.0097 mole) of 8-chloro-6-(2-chlorophenyl)-1,2-dihydro-2-methyl-1-oxo-4H-imidazo[1,5-a][1,4]benzodiazepin-3-carboxylic acid methyl ester ethanolate in 200 ml of methanol. The solution was refluxed under argon for 3 hrs, concentrated at reduced pressure, diluted with cold water and acidified with acetic acid to give an off-white solid. The solid was washed with water and air dried on the funnel overnight to give crude end product. Recrystallization from ethanol/methylene chloride gave white crystals with mp 265°-267° (dec).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[C:6]([C:8]2[CH2:12][CH2:11][C:10](=[O:13])[CH:9]=2)[CH:5]=[CH:4][C:3]=1[NH:14][C:15](=[O:21])[O:16][C:17]([CH3:20])([CH3:19])[CH3:18].CN(C)[C@@H]1CCN(CC2C=CC(C(O)=O)=CC=2)C1.[C:40]([O:43][C:44]1[CH:52]=[CH:51][C:47]([C:48](O)=[O:49])=[CH:46][CH:45]=1)(=[O:42])[CH3:41]>CCOC(C)=O>[C:40]([O:43][C:44]1[CH:52]=[CH:51][C:47]([C:48](=[O:49])[NH:1][C:2]2[CH:7]=[C:6]([C:8]3[CH2:12][CH2:11][C:10](=[O:13])[CH:9]=3)[CH:5]=[CH:4][C:3]=2[NH:14][C:15]([O:16][C:17]([CH3:18])([CH3:20])[CH3:19])=[O:21])=[CH:46][CH:45]=1)(=[O:42])[CH3:41]
Reactant: CC(C)(C)OC(=O)Nc1ccc(C2=CC(=O)CC2)cc1N
Reactant: CC(=O)Oc1ccc(C(=O)O)cc1
Agent: CN(C)[C@@H]1CCN(Cc2ccc(C(=O)O)cc2)C1
Solvent: CCOC(C)=O
Product: CC(=O)Oc1ccc(C(=O)Nc2cc(C3=CC(=O)CC3)ccc2NC(=O)OC(C)(C)C)cc1
Yield: 30 %

Procedure:
Following the same procedure as described in Example 1, step 6 (scheme 1), but substituting compound 4 for compound 258 and compound 7 for 4-acetoxybenzoic acid, title compound 259 was obtained as a yellow oil in 30% yield [after flash chromatography (eluent: 30% AcOEt in hexanes)].
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([N+:8]([O-])=O)[C:3]=1[C:11]1[CH2:16][C:15]([CH3:18])([CH3:17])[CH2:14][C:13]([CH3:20])([CH3:19])[CH:12]=1.[Cl-].[NH4+].O>C(O)C.[Fe]>[F:1][C:2]1[C:3]([C:11]2[CH2:16][C:15]([CH3:18])([CH3:17])[CH2:14][C:13]([CH3:20])([CH3:19])[CH:12]=2)=[C:4]([NH2:8])[CH:5]=[CH:6][CH:7]=1
Reactant: CC1(C)C=C(c2c(F)cccc2[N+](=O)[O-])CC(C)(C)C1
Agent: [Fe]
Agent: [Cl-]
Agent: [NH4+]
Solvent: O
Solvent: CCO
Product: CC1(C)C=C(c2c(N)cccc2F)CC(C)(C)C1
Temperature: 90 °C
Reaction time: 2 h
Yield: 31.5 %

Procedure:
To a solution of 1-fluoro-3-nitro-2-(3,3,5,5-tetramethylcyclohex-1-enyl)benzene (2.25 g, 8.11 mmol) produced in Example (97b) in ethanol (45 mL) were added ammonium chloride (150 mg, 2.8 mmol), water (15 mL) and iron powder (1.6 g, 28.65 mmol), followed by stirring for 2 hours at an external temperature of 90° C. The reaction mixture was filtered and the filtrate was concentrated under reduced pressure. Ethyl acetate and water were added to the obtained residue and extraction was performed with ethyl acetate. The separated organic layer was washed with brine and then dried over anhydrous sodium sulfate. The desiccant was filtered off and the filtrate was concentrated under reduced pressure. The resultant residue was purified by NH silica gel column chromatography (ethyl acetate/heptane) to give 632 mg of the title compound as a light yellow oil.
Reaction SMILES: [C:1]([NH:4][C:5]1[CH:10]=[CH:9][C:8]([CH:11]([CH3:16])[C:12]([O:14]C)=[O:13])=[CH:7][CH:6]=1)(=[S:3])[NH2:2].Br[CH2:18][C:19](=O)[C:20]([CH3:23])([CH3:22])[CH3:21]>>[C:20]([C:19]1[N:2]=[C:1]([NH:4][C:5]2[CH:10]=[CH:9][C:8]([CH:11]([CH3:16])[C:12]([OH:14])=[O:13])=[CH:7][CH:6]=2)[S:3][CH:18]=1)([CH3:23])([CH3:22])[CH3:21]
Reactant: CC(C)(C)C(=O)CBr
Reactant: COC(=O)C(C)c1ccc(NC(N)=S)cc1
Product: CC(C(=O)O)c1ccc(Nc2nc(C(C)(C)C)cs2)cc1
Yield: 57 %

Procedure:
Following the same procedure described for 1 and starting from methyl 2-[4-(carbamothioylamino)phenyl]propanoate (2.49 g, 10 mmol) and 1-bromopinacolone (1.75 ml, 13 mmol), after workup and methyl ester hydrolysis, pure compound 6 (1.75 g, 5.7 mmol) was isolated by filtration (38% overall yield from methyl 2-[4-(carbamothioylamino)phenyl]propanoate).
Reaction SMILES: [Ag-:1]=O.[C:3]([OH:14])(=[O:13])[CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][C:9]([CH3:12])([CH3:11])[CH3:10].OO.[Ag]>C(O)C>[C:3]([O-:14])(=[O:13])[CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][C:9]([CH3:10])([CH3:11])[CH3:12].[Ag+:1]
Reactant: O=[Ag-]
Reactant: CC(C)(C)CCCCCC(=O)O
Agent: [Ag]
Agent: OO
Solvent: CCO
Product: CC(C)(C)CCCCCC(=O)[O-]
Product: [Ag+]

Procedure:
Silver neodecanoate was prepared according to the procedure as disclosed in Armstrong, U.S. Pat. No. 4,555,501 herein incorporated by reference, from silver (I) oxide and neodecanoic acid. A slurry of 5 ml neodecanoic acid and 5 ml absolute ethanol was heated to 80° C. in an oil bath. Approximately 1.7 grams Ag2O was added slowly and the resulting solution was heated for approximately 5 minutes. One drop of 30 percent by weight H2O2 was added to the resulting solution to oxidize any prereduced silver metal. After the addition of H2O2 the solution was clear yellow. Absolute ethanol was added to the solution to precipitate white silver neodecanoate. The precipitate was filtered and reslurried twice in absolute ethanol. An amount of the dye, 3,3'-di(3-acetoxypropyl-11-diphenylamino-10,12-ethylene-5,5',6,6'-dibenzothiatricarbocyanine perchlorate) was added to a methylene chloride solution to provide a 0.01 molar solution. To this solution was added 1 weight percent silver neodecanoate and 1 weight percent polystyrene, based upon the weight of the solution. This solution was spin-coated onto a glass substrate to provide an active layer approximately 1 μm thick.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH:9]=[CH:10][CH:11]=1)[C:5](=[O:8])[CH2:6]Br.[N-:12]=[N+:13]=[N-:14].[Na+]>CO>[Br:1][C:2]1[CH:3]=[C:4]([CH:9]=[CH:10][CH:11]=1)[C:5](=[O:8])[CH2:6][N:12]=[N+:13]=[N-:14]
Reactant: [N-]=[N+]=[N-]
Reactant: O=C(CBr)c1cccc(Br)c1
Agent: [Na+]
Solvent: CO
Product: [N-]=[N+]=NCC(=O)c1cccc(Br)c1
Yield: 99.3 %

Procedure:
A solution of 20.2 g (73 mmol) of 3-bromophenacyl bromide and 5.42 g (83 mmol) of sodium azide was stirred at RT for 90 min in methanol. The solvent was removed under reduced pressure and the crude product was partitioned between ethyl acetate (200 ml) and water (100 mL). The organic layer was separated, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure to afford the title compound (17.4 g, 99%) as a light yellow solid. 1H NMR (400 MHz, d6-DMSO): δ 8.10 (d, J=1.0, 1H), 7.90–7.97 (m, 2H), 7.22 (t, J=7.9, 1H), 4.93 (s, 2H).
Reaction SMILES: [CH:1]([C:4]1[O:8][N:7]=[C:6]([C:9](OCC)=[O:10])[CH:5]=1)([CH3:3])[CH3:2].[BH4-].[Na+].O>C(O)C>[CH:1]([C:4]1[O:8][N:7]=[C:6]([CH2:9][OH:10])[CH:5]=1)([CH3:3])[CH3:2]
Reactant: CCOC(=O)c1cc(C(C)C)on1
Agent: [BH4-]
Agent: [Na+]
Solvent: CCO
Solvent: O
Product: CC(C)c1cc(CO)no1
Temperature: 25 °C
Reaction time: 10 h
Yield: 94.6 %

Procedure:
20.76 g of ethyl 5-i-propyl-isoxazole-3-carboxylate was dissolved in 200 ml of ethanol, and 4.20 g of sodium borohydride was then added. The mixture was stirred at room temperature for 10 hours. After 50 ml of water was added, the reaction mixture was concentrated to 50 ml under reduced pressure. The concentrated solution was extracted with ethyl acetate. The organic layer was dried over anhydrous magnesium sulfate, filtered and then concentrated under reduced pressure. The residue was subjected to silica gel column chromatography to obtain 15.13 g of (5-i-propyl-isoxazol-3-yl)methanol.