Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(NC(C)C)(C)C.C([Li])CCC.[Li+].CC([N-]C(C)C)C.[CH2:21]([N:23]([CH2:34][CH3:35])[C:24](=[O:33])[C:25]1[CH:30]=[C:29]([F:31])[CH:28]=[CH:27][C:26]=1[CH3:32])[CH3:22].[CH2:36]([O:43][C:44]1[CH:55]=[CH:54][C:47]([C:48](N(OC)C)=[O:49])=[CH:46][CH:45]=1)[C:37]1[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=1.C(N)(=O)C1C=CC=CC=1>C1COCC1.CCCCCC.CCOCC>[CH2:36]([O:43][C:44]1[CH:45]=[CH:46][C:47]([C:48](=[O:49])[CH2:32][C:26]2[CH:27]=[CH:28][C:29]([F:31])=[CH:30][C:25]=2[C:24]([N:23]([CH2:21][CH3:22])[CH2:34][CH3:35])=[O:33])=[CH:54][CH:55]=1)[C:37]1[CH:38]=[CH:39][CH:40]=[CH:41][CH:42]=1
Reactant: CCN(CC)C(=O)c1cc(F)ccc1C
Reactant: CON(C)C(=O)c1ccc(OCc2ccccc2)cc1
Agent: CC(C)[N-]C(C)C
Agent: NC(=O)c1ccccc1
Agent: [Li+]
Solvent: CCOCC
Solvent: C1CCOC1
Solvent: CC(C)NC(C)C
Product: CCN(CC)C(=O)c1cc(F)ccc1CC(=O)c1ccc(OCc2ccccc2)cc1
Temperature: -10 °C
Reaction time: 0.17 h
Yield: 68.1 %

Procedure:
To a solution of diisopropylamine (3.8 mL, 27 mmol) in THF (85 mL) in a −10° C. bath was added a solution of butyllithium (17.0 mL of a 1.4 M solution in hexane, 23.8 mmol). After stirring at −10° C. for 10 minutes, the cooling bath was further cooled to −78° C. The resulting solution of LDA was then treated with a mixture of N,N-diethyl-5-fluoro-2-methyl-benzamide (3.48 g, 16.6 mmol) and 4-benzyloxy-N-methoxy-N-methylbenzamide (4.51 g, 16.6 mmol) as a solution in THF (25 mL) by cannula addition over ˜8 minutes. The flask and cannula containing the benzamide mixture solution was then rinsed with additional THF (10 mL) which was added to the reaction to insure complete transfer. TLC analysis of the deep purple reaction solution after stirring for 15 minutes at −78° C. showed one main product spot. After stirring for 30 minutes at −78° C. the reaction was quenched by the addition of saturated aqueous NH4Cl (50 mL). The cooling bath was removed and the suspension was allowed to slowly warm to ambient temperature. After warming to ambient temperature, H2O was added to dissolve the solids that had formed, the reaction was diluted with Et2O (400 mL), and transferred to a separatory funnel. The resulting layers were separated, and the aqueous layer was extracted with Et2O (3×75 mL). The organic layers were combined, washed with saturated aqueous sodium chloride (100 mL), dried over Na2SO4, filtered and concentrated under reduced pressure to afford a pale yellow oil. The crude oil was purified by silica gel column chromatography eluting with a gradient from 0% to 30% EtOAc/hexane. Product-containing fractions from the column were combined and concentrated to afford 2-[2-(4-benzyloxyphenyl)-2-oxo-ethyl]-N,N-diethyl-5-fluoro-benzamide (4.74 g, 68% yield) as a pale yellow oil. 1H NMR analysis showed some impurities present.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][C:4]1[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[NH:6][CH:5]=1.[C:13]1(=O)[O:18][C:16](=[O:17])[C:15]2=[CH:19][CH:20]=[CH:21][CH:22]=[C:14]12>O>[NH:6]1[C:7]2[C:12](=[CH:11][CH:10]=[CH:9][CH:8]=2)[C:4]([CH2:3][CH2:2][N:1]2[C:16](=[O:17])[C:15]3[C:14](=[CH:22][CH:21]=[CH:20][CH:19]=3)[C:13]2=[O:18])=[CH:5]1
Reactant: NCCc1c[nH]c2ccccc12
Reactant: O=C1OC(=O)c2ccccc21
Solvent: O
Product: O=C1c2ccccc2C(=O)N1CCc1c[nH]c2ccccc12

Procedure:
Tryptamine (3.04 g, 19.0 mmol) and phthalic anhydride (3.00 g, 20.0 mmol) were boiled for 12 h in a water separator. The solvent was distilled off i. vac. and the residue was dissolved in methylene chloride. Product was precipitated out by addition of cyclohexane and the precipitate was filtered off with suction and dried. Yield: 4.46 g (Ind-1; 87%)
Reaction SMILES: [CH2:1]([O:15][C:16]1[CH:21]=[CH:20][C:19]([CH2:22][C:23]([OH:25])=O)=[CH:18][CH:17]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH3:14].CN(C)[CH:28]=[O:29].C(Cl)(=O)C(Cl)=O>C(Cl)Cl>[OH:29][CH2:28][C:23](=[O:25])[CH2:22][C:19]1[CH:18]=[CH:17][C:16]([O:15][CH2:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH3:14])=[CH:21][CH:20]=1
Reactant: CN(C)C=O
Reactant: CCCCCCCCCCCCCCOc1ccc(CC(=O)O)cc1
Agent: O=C(Cl)C(=O)Cl
Solvent: ClCCl
Product: CCCCCCCCCCCCCCOc1ccc(CC(=O)CO)cc1
Temperature: 95 °C

Procedure:
To a suspension of about 60.0 g of (4-tetradecyloxyphenyl)acetic acid in about 400 ml of methylene chloride containing about 0.63 ml of dimethylformamide was added, over about 10 minutes about 27.31 g of oxalyl chloride. After about 2 hours the solvent was removed, the residue was dissolved in hexane and filtered through celite. The solvent was removed and the residue dried in vacuo. An about 110.82 g portion of tris-trimethylsilyloxyethylene was added and the solution was heated at about 95° C., under argon, for about 5 hours. The solution was poured into a mixture of about 30 ml of concentrated hydrochloric acid (about 12N) about 170 ml of water and about 200 ml of tetrahydrofuran with stirring and heat. This mixture was refluxed about 10 minutes, ethyl acetate was added, the warm organic layer separated and washed with brine, saturated sodium bicarbonate solution, then brine, dried and the solvent removed, giving, after recrystallization from hexane, about 52 g of the desired title compound as a white solid, mp. 84°-85° C.
Reaction SMILES: [NH:1]([C:28]([O:30][C:31]([CH3:34])([CH3:33])[CH3:32])=[O:29])[C@H:2]([C:11]([NH:13][C@@H:14]([C:19]([NH:21][CH2:22][C:23]([O:25]CC)=[O:24])=[O:20])[CH2:15][CH2:16][S:17][CH3:18])=[O:12])[CH2:3][C:4]1[CH:9]=[CH:8][C:7]([OH:10])=[CH:6][CH:5]=1.[OH-].[Na+].Cl.CN(C=O)C>CO>[NH:1]([C:28]([O:30][C:31]([CH3:34])([CH3:33])[CH3:32])=[O:29])[C@H:2]([C:11]([NH:13][C@@H:14]([C:19]([NH:21][CH2:22][C:23]([OH:25])=[O:24])=[O:20])[CH2:15][CH2:16][S:17][CH3:18])=[O:12])[CH2:3][C:4]1[CH:9]=[CH:8][C:7]([OH:10])=[CH:6][CH:5]=1
Reactant: CCOC(=O)CNC(=O)[C@@H](CCSC)NC(=O)[C@H](Cc1ccc(O)cc1)NC(=O)OC(C)(C)C
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CN(C)C=O
Solvent: CO
Product: CSCC[C@@H](NC(=O)[C@H](Cc1ccc(O)cc1)NC(=O)OC(C)(C)C)C(=O)NCC(=O)O
Temperature: 25 °C
Reaction time: 1 h
Yield: 87.1 %

Procedure:
In 30 ml of MeOH is dissolved 2.8 g of BOC-Tyr-(D)-Met-Gly-OEt. After cooling, 12 ml of N-aqueous sodium hydroxide solution is added, and the mixture is stirred at room temperature for 1 hour. After cooling, 60 ml of0.2 N-aqueous hydrochloric acid solution is added, and the precipitated crystals are collected by filtration, followed by washing with cold water.Thus obtained is 2.3 g of the desired product, m.p. 184°-186°C., Rf1 =0.24, [α]D21 +13.3° (c=0.46, DMF)
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][C:5]([OH:11])=[C:6]([C:8](=[O:10])[CH3:9])[CH:7]=1.Br[CH2:13][CH2:14][OH:15].C(=O)([O-])[O-].[K+].[K+].[I-].[Na+]>CN(C)C=O>[C:8]([C:6]1[CH:7]=[C:2]([F:1])[CH:3]=[CH:4][C:5]=1[O:11][CH2:13][CH2:14][OH:15])(=[O:10])[CH3:9]
Reactant: CC(=O)c1cc(F)ccc1O
Reactant: OCCBr
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CC(=O)c1cc(F)ccc1OCCO
Temperature: 100 °C
Reaction time: 8 h

Procedure:
5′-Fluoro-2′-hydroxyacetophenone 5.0 g, 2-bromoethanol 6.08 g, potassium carbonate 13.4 g and sodium iodide 7.28 g were dissolved in N,N-dimethylformamide 108 ml and stirred at 100° C. overnight. The reaction mixture was cooled and then partitioned by adding water and ethyl acetate. The organic layer was washed with water and then with brine, dried over magnesium sulfate anhydride, and evaporated. The residue was purified by silica gel column chromatography (hexane/ethyl acetate system), whereby the title compound 1.66 g, 26% was obtained as a brown oil.
Reaction SMILES: [CH2:1]([N:3]([CH2:6][CH2:7][NH:8][C:9](=[O:23])[C:10]1[CH:15]=[C:14]([NH:16][S:17]([CH3:20])(=[O:19])=[O:18])[CH:13]=[CH:12][C:11]=1[O:21][CH3:22])[CH2:4][CH3:5])[CH3:2].S(OC)(O[CH3:28])(=O)=O.C(=O)([O-])[O-].[K+].[K+]>CC(C)=O>[CH2:1]([N:3]([CH2:6][CH2:7][NH:8][C:9](=[O:23])[C:10]1[CH:15]=[C:14]([N:16]([CH3:28])[S:17]([CH3:20])(=[O:18])=[O:19])[CH:13]=[CH:12][C:11]=1[O:21][CH3:22])[CH2:4][CH3:5])[CH3:2]
Reactant: CCN(CC)CCNC(=O)c1cc(NS(C)(=O)=O)ccc1OC
Reactant: COS(=O)(=O)OC
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: CCN(CC)CCNC(=O)c1cc(N(C)S(C)(=O)=O)ccc1OC

Procedure:
To a solution of N-(diethylaminoethyl)-5-methanesulfonamido-2-methoxybenzamide in acetone are added dimethyl sulfate and potassium carbonate. The resultant mixture is refluxed for 2 hours. After evaporating the solvent, the residue is mixed with water and shaken with methylene chloride. The organic layer is washed with water, dried over anhydrous sodium sulfate, and concentrated in vacuum. The residue is washed with isopropyl ether to give N-(diethylaminoethyl)-2-methoxy-5-(N-methyl-methanesulfonamido)benzamide as crystals melting at 48°-50° C.
Reaction SMILES: [CH:1]1[CH:2]=[CH:3][C:4]2[NH:9][C:8]([OH:10])=[C:7]([C:11]3[C:19](=O)[C:18]4[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=4[N:12]=3)[C:5]=2[CH:6]=1.[Cl-].[OH:22][NH3+:23].O>N1C=CC=CC=1>[CH:1]1[CH:2]=[CH:3][C:4]2[NH:9][C:8]([OH:10])=[C:7]([C:11]3[NH:12][C:13]4[CH:14]=[CH:15][CH:16]=[CH:17][C:18]=4[C:19]=3[N:23]=[O:22])[C:5]=2[CH:6]=1
Reactant: [NH3+]O
Reactant: O=C1C(c2c(O)[nH]c3ccccc23)=Nc2ccccc21
Agent: [Cl-]
Solvent: O
Solvent: c1ccncc1
Product: O=Nc1c(-c2c(O)[nH]c3ccccc23)[nH]c2ccccc12
Temperature: 25 °C
Yield: 90.2 %

Procedure:
Indirubin (0.64 g, 2.4 mmol) was dissolved in anhydrous pyridine (25 mL), and hydroxylammonium chloride (1.67 g, 24 mmol) was added to the solution. The reaction liquid was heated and refluxed for 2.5 hours and then cooled to room temperature. The reaction liquid was poured into water (100 mL), and the precipitated crude crystals were collected by suction filtration. The resulting crude crystals were recrystallized from methanol/water to give red needle-shaped crystals of indirubin-3′-oxime (0.60 g, 89%).
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:14]=[CH:13][C:12]([C@@H:15]([OH:18])[CH2:16][Br:17])=[CH:11][C:10]=1[N+:19]([O-])=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:22](OC(=O)C)(=[O:24])C.C(O)=O>C1COCC1.C1(C)C=CC=CC=1.O=[Pt]=O>[CH2:1]([O:8][C:9]1[CH:14]=[CH:13][C:12]([C@@H:15]([OH:18])[CH2:16][Br:17])=[CH:11][C:10]=1[NH:19][CH:22]=[O:24])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=[N+]([O-])c1cc([C@@H](O)CBr)ccc1OCc1ccccc1
Reactant: CC(=O)OC(C)=O
Agent: O=[Pt]=O
Solvent: C1CCOC1
Solvent: O=CO
Solvent: Cc1ccccc1
Product: O=CNc1cc([C@@H](O)CBr)ccc1OCc1ccccc1
Temperature: 0 °C
Reaction time: 2 h
Yield: 78.3 %

Procedure:
(R)-1-[4-(Benzyloxy)-3-nitrophenyl]-2-bromoethanol (0.2 g, 5.7 mmol) in THF:toluene (1:1, 5 mL) was reacted with PtO2 (1% w/w) on a Parr shaker at 45 psi at rt overnight. The next morning the PtO2 was removed by filtration over celite. The filtered solution was cooled to 0° C. and a solution of acetic anhydride (0.161 mL, 0.569 mmol) and formic acid (0.043 mL, 1.140 mmol) was added dropwise to a stirred solution. After 30 min the reaction was warmed to rt and stirred for 2 h. The reaction mixture was concentrated to near dryness and water was added. The aqueous layer was extracted with EtOAc (3×25 mL). The combined organic layers were washed with NaHCO3, brine, dried over Na2SO4 (s), and concentrated. Chromatography (1:1 Hexanes/EtOAc) gave the title compound (156 mg, 78% 2 steps). ES/MS calcd. C16H17BrNO3+ 350.0. Found m/z=350 (M+H)+.
Reaction SMILES: CC(C)(OC([NH:7][C@H:8]([C:28]([N:30]1[CH2:35][CH2:34][CH:33]([CH2:36][CH3:37])[CH2:32][CH2:31]1)=[O:29])[CH2:9][CH2:10][CH2:11][CH:12]1[CH2:17][CH2:16][N:15]([C:18]([O:20][CH2:21][C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)=[O:19])[CH2:14][CH2:13]1)=O)C.[ClH:39]>ClCCl>[ClH:39].[NH2:7][C@H:8]([C:28]([N:30]1[CH2:35][CH2:34][CH:33]([CH2:36][CH3:37])[CH2:32][CH2:31]1)=[O:29])[CH2:9][CH2:10][CH2:11][CH:12]1[CH2:17][CH2:16][N:15]([C:18]([O:20][CH2:21][C:22]2[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=2)=[O:19])[CH2:14][CH2:13]1
Reactant: CCC1CCN(C(=O)[C@H](CCCC2CCN(C(=O)OCc3ccccc3)CC2)NC(=O)OC(C)(C)C)CC1
Agent: Cl
Solvent: ClCCl
Product: CCC1CCN(C(=O)[C@@H](N)CCCC2CCN(C(=O)OCc3ccccc3)CC2)CC1
Reaction time: 3 h
Yield: 100 %

Procedure:
A solution of 1.54 g (3.0 mmol) of phenylmethyl (S)-4-[4-[[(1,1-dimethylethoxy)carbonyl]amino]-5-(4-ethylpiperid-1-yl)-5-oxopentyl]piperidine-1-carboxylate in 60 ml of dichloromethane is treated for 5 min at 0° C. with a stream of hydrogen chloride. After 3 hours at 0° C., the mixture is concentrated under reduced pressure. The resulting product is used without further purification in the following step. 1.35 g of phenylmethyl (S)-4-[4-amino-5-(4-ethylpiperid-1-yl)-5-oxopentyl]piperidine-1-carboxylate hydrochloride are thus obtained in the form of a viscous oil.
Reaction SMILES: [CH3:1][C:2]1[O:6][N:5]=[C:4]([C:7]([NH:9][C@@H:10]2[C:24](=[O:25])[N:23]3[CH2:26][C@H:27]([O:29]C(=O)C4C=CC([N+]([O-])=O)=CC=4)[CH2:28][C@H:22]3[C:21](=[O:41])[NH:20][C@:19]3([C:43]([O:45][CH2:46][CH3:47])=[O:44])[CH2:42][CH:18]3[CH:17]=[CH:16][CH2:15][CH2:14][CH2:13][CH2:12][CH2:11]2)=[O:8])[CH:3]=1.[Li+].[OH-].Cl>C1COCC1.ClCCl>[OH:29][C@H:27]1[CH2:26][N:23]2[C:24](=[O:25])[C@@H:10]([NH:9][C:7]([C:4]3[CH:3]=[C:2]([CH3:1])[O:6][N:5]=3)=[O:8])[CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH:16]=[CH:17][CH:18]3[CH2:42][C@@:19]3([C:43]([O:45][CH2:46][CH3:47])=[O:44])[NH:20][C:21](=[O:41])[C@@H:22]2[CH2:28]1
Reactant: CCOC(=O)[C@@]12CC1C=CCCCCC[C@H](NC(=O)c1cc(C)on1)C(=O)N1C[C@H](OC(=O)c3ccc([N+](=O)[O-])cc3)C[C@H]1C(=O)N2
Agent: CCOC(=O)[C@@]12CC1/C=C\CCCCC[C@H](NC(=O)c1cc(C)on1)C(=O)N1C[C@H](O)C[C@H]1C(=O)N2
Agent: CCOC(=O)[C@@]12CC1/C=C\CCCCC[C@H](NC(=O)c1cc(C)on1)C(=O)N1C[C@H](OC(=O)c3ccc([N+](=O)[O-])cc3)C[C@H]1C(=O)N2
Agent: Cl
Solvent: ClCCl
Solvent: C1CCOC1
Product: CCOC(=O)[C@@]12CC1C=CCCCCC[C@H](NC(=O)c1cc(C)on1)C(=O)N1C[C@H](O)C[C@H]1C(=O)N2
Reaction time: 1 h

Procedure:
To a solution of (2R,6S,14aR,16aS,Z)-ethyl 6-(5-methylisoxazole-3-carboxamido)-2-(4-nitrobenzoyloxy)-5,16-dioxo-1,2,3,5,6,7,8,9,10,11,13a,14,14a,15,16,16a-hexadecahydrocyclopropa[e]pyrrolo[1,2-a][1,4]diazacyclopentadecine-14a-carboxylate (10 g) in THF (110 mL) at 0° C. was added a solution of 0.5 M LiOH (33.8 mL). After 1 h, the reaction was diluted with dichloromethane (150 mL) and neutralized with 1N HCl (50 mL). The organic layer was extracted and washed with 5% NaHCO3 (50 mL) twice and once with a 5% aq. NaCl solution (50 mL). The dichloromethane layer was evaporated under reduced pressure to an oil (8.0 g, 100% yield).
Reaction SMILES: [Br:1][C:2]1[C:3]([CH3:11])=[CH:4][CH:5]=[C:6]2[C:10]=1[NH:9][N:8]=[CH:7]2.[C:12]([O-])([O-])=O.[Cs+].[Cs+].CI>C(#N)C>[Br:1][C:2]1[C:10]2[C:6](=[CH:7][N:8]([CH3:12])[N:9]=2)[CH:5]=[CH:4][C:3]=1[CH3:11]
Reactant: O=C([O-])[O-]
Reactant: Cc1ccc2cn[nH]c2c1Br
Agent: [Cs+]
Solvent: CI
Solvent: CC#N
Product: Cc1ccc2cn(C)nc2c1Br
Temperature: 80 °C

Procedure:
To a solution of 7-bromo-6-methyl-1H-indazole (1 equiv.) in acetonitrile, Cs2CO3 (1.3 equiv.) and MeI (3 eq.) was added and reaction was heated at 80° C. for 1.5 h. On completion, it was cooled and quenched by addition of water. Extraction was carried out using ethyl acetate. Organic layer was dried over Na2SO4 and crude compound was column purified to afford the title compound. (Polar isomer confirmed as N-2-Methyl and non-polar isomer confirmed as N-1-Methyl by NOE experimentation).
Reaction SMILES: [Cl:1][C:2]1[CH:25]=[CH:24][C:5]([C:6]([NH:8][CH:9]([CH2:13][CH:14]2[C:22]3[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=3)[NH:16][C:15]2=[O:23])[C:10]([OH:12])=[O:11])=[O:7])=[CH:4][CH:3]=1.S(Cl)(Cl)=O.[CH3:30]O>>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:6]([NH:8][CH:9]([CH2:13][CH:14]2[C:22]3[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=3)[NH:16][C:15]2=[O:23])[C:10]([O:12][CH3:30])=[O:11])=[O:7])=[CH:24][CH:25]=1
Reactant: O=C(NC(CC1C(=O)Nc2ccccc21)C(=O)O)c1ccc(Cl)cc1
Reactant: CO
Solvent: O=S(Cl)Cl
Product: COC(=O)C(CC1C(=O)Nc2ccccc21)NC(=O)c1ccc(Cl)cc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
19 Grams of 2-(4-chlorobenzoylamino)-3-(oxindol3-yl)propionic acid 1/4-hydrate prepared in Example 3 was dissolved in 30 ml of methanol, then to this solution was added dropwise 9.4 g of thionyl chloride under an ice-cooled condition, then the reaction mixture was stirred at a room temperature overnight. Methanol was removed by evaporation, the residue thus obtained was extracted with chloroform, and the extract was dried with anhydrous sodium sulfate, then the solvent was removed by evaporation. The resulting residue was purified by means of a silica gel column chromatography (eluting agent: chloroform/methanol=40/1) to obtain 10.5 g of methyl 2-(4-chlorobenzoylamino)-3-(oxindol-3-yl)propionate. The chemical structure of this product was determined by means of NMR method.
Reaction SMILES: Cl.[NH2:2][OH:3].CC([O-])(C)C.[K+].[Cl:10][C:11]1[CH:12]=[C:13]([C:18]2([C:32]([F:35])([F:34])[F:33])[O:22][N:21]=[C:20]([C:23]3[CH:30]=[CH:29][C:26]([C:27]#[N:28])=[C:25]([CH3:31])[CH:24]=3)[CH2:19]2)[CH:14]=[C:15]([Cl:17])[CH:16]=1>CS(C)=O>[Cl:10][C:11]1[CH:12]=[C:13]([C:18]2([C:32]([F:33])([F:35])[F:34])[O:22][N:21]=[C:20]([C:23]3[CH:30]=[CH:29][C:26]([C:27]([NH:2][OH:3])=[NH:28])=[C:25]([CH3:31])[CH:24]=3)[CH2:19]2)[CH:14]=[C:15]([Cl:17])[CH:16]=1
Reactant: Cc1cc(C2=NOC(c3cc(Cl)cc(Cl)c3)(C(F)(F)F)C2)ccc1C#N
Reactant: NO
Agent: CC(C)(C)[O-]
Agent: Cl
Agent: [K+]
Solvent: CS(C)=O
Product: Cc1cc(C2=NOC(c3cc(Cl)cc(Cl)c3)(C(F)(F)F)C2)ccc1C(=N)NO
Temperature: 80 °C
Reaction time: 5 h
Yield: 61 %

Procedure:
A solution hydroxylamine hydrochloride (8.70 g) in DMSO was cooled to 15° C., before KOtBu was added in small portions. This mixture was added to a solution of 4-[5-(3,5-Dichloro-phenyl)-5-trifluoromethyl-4,5-dihydro-isoxazol-3-yl]-2-methyl-benzonitrile (5.00 g) in DMSO (20 mL) at room temperature and stirred at 80° C. for 5 h. After completion of the reaction, the mixture was poured onto ice-water and the resulting solid was collected by filtration, washed with water and dried. Chromatography on silica gel yielded the title compound (3.3 g, 61%).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([N+:15]([O-])=O)[CH:6]=[C:7]([O:13][CH3:14])[C:8]=1[O:9][CH2:10][CH2:11][OH:12]>[Pd].C(O)C>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:6]=[C:7]([O:13][CH3:14])[C:8]=1[O:9][CH2:10][CH2:11][OH:12])[NH2:15]
Reactant: COc1cc([N+](=O)[O-])cc(OC)c1OCCO
Agent: [Pd]
Solvent: CCO
Product: COc1cc(N)cc(OC)c1OCCO
Reaction time: 16 h
Yield: 92 %

Procedure:
A slurry of potassium 2,6-dimethoxy-4-nitrophenolate [Collins, R. P. and Davis, M. J. Chem. Soc. (1961), 1986] (38 g, 160 mmol) in DMF (600 ml) was treated with 2-bromoethanol (25 ml, 353 mmol) and hexamethylphosphorus triamide (31 ml, 176 mmol) and the reaction heated at 115° for 6 h. After cooling, the reaction was poured onto 1M hydrochloric acid (1.5 l) and extracted with ethyl acetate (5×500 ml). The organics were washed with 1M sodium hydroxide (4×700 ml), brine (200 ml) and drfied (MgSO4). Concentration in vacuo gave 3,5-dimethoxy-4-(2-hydroxyethoxy)nitrobenzene as an off white solid (31 g) δH (CDCl3) 7.52 (2H, s), 4.21 (2H, t, J 2.9 Hz), 3.94 (3H, s), 3.76 (2H, m) and 2.94 (1H, br s). MS (ES+) 266 (MNa+, 50%), 244 (MH+, 100%). A mixture of this nitrobenzene (750 mg, 3.16 mmol) and 10% palladium on carbon (75 mg) in ethanol (50 ml) was degassed and then subjected to an atmosphere of hydrogen (balloon) for 16 h. at 200. Dichloromethane was added and the solution filtered and solvent removed in vacuo to give 3,5-dimethoxy-4-(2-hydroxyethoxy)aniline as a grey solid (620 mg) after trituration with diethyl ether. δH (CDCl3+DMSO) 5.84 (2H, s), 3.87-3.84 (2H, m), 3.64 (6H, s) and 3.52-3.49 (2H, m). MS (ES+) 214 (MH+, 100%.
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][O:4][C:3]2[CH:7]=[N:8][CH:9]=[CH:10][C:2]1=2.[Cl:11][C:12]1[CH:13]=[C:14]([CH:18]=[CH:19][C:20]=1[O:21][CH3:22])[C:15](Cl)=[O:16].C(N(CC)CC)C.Cl>ClCCl>[Cl:11][C:12]1[CH:13]=[C:14]([C:15]([N:1]2[CH2:6][CH2:5][O:4][C:3]3[CH:7]=[N:8][CH:9]=[CH:10][C:2]2=3)=[O:16])[CH:18]=[CH:19][C:20]=1[O:21][CH3:22]
Reactant: c1cc2c(cn1)OCCN2
Reactant: COc1ccc(C(=O)Cl)cc1Cl
Agent: Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COc1ccc(C(=O)N2CCOc3cnccc32)cc1Cl
Temperature: 25 °C
Reaction time: 2 h
Yield: 99.7 %

Procedure:
In a 10 ml flask, 2,3-dihydro-1H-pyrido[3,4-b][1,4]oxazine (60 mg, 0.441 mmol) and 3-chloro-4-methoxy-benzoyl chloride (108 mg, 0.529 mmol) were dissolved in dichloromethane (3 ml). Triethylamine (0.12 ml, 0.881 mmol) was added thereto and then stirred at room temperature for 2 hours. After neutralizing with 1N hydrochloric acid solution, the mixture was extracted with dichloromethane, and the combined organic layer was dried over anhydrous sodium sulfate (Na2SO4), filtered and evaporated under reduced pressure. The residue was purified by column chromatography on silica eluting with a solvent of ethyl acetate:n-hexane=1:1. The fractions containing the product were collected and evaporated to obtain white solid (134 mg, 99.8%).
Reaction SMILES: [C:1]([Cu])#[N:2].[CH3:4][O:5][C:6]([C@H:8]1[N:12]2[C:13](=[O:35])[C:14](Br)=[C:15]([CH2:23][C:24]3[C:33]4[C:28](=[CH:29][CH:30]=[CH:31][CH:32]=4)[CH:27]=[CH:26][CH:25]=3)[C:16]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)=[C:11]2[S:10][CH2:9]1)=[O:7]>CN1C(=O)CCC1>[CH3:4][O:5][C:6]([C@H:8]1[N:12]2[C:13](=[O:35])[C:14]([C:1]#[N:2])=[C:15]([CH2:23][C:24]3[C:33]4[C:28](=[CH:29][CH:30]=[CH:31][CH:32]=4)[CH:27]=[CH:26][CH:25]=3)[C:16]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)=[C:11]2[S:10][CH2:9]1)=[O:7]
Reactant: N#C[Cu]
Reactant: COC(=O)[C@@H]1CSc2c(-c3ccccc3)c(Cc3cccc4ccccc34)c(Br)c(=O)n21
Solvent: CN1CCCC1=O
Product: COC(=O)[C@@H]1CSc2c(-c3ccccc3)c(Cc3cccc4ccccc34)c(C#N)c(=O)n21
Temperature: 220 °C
Yield: 81 %

Procedure:
CuCN (120 mg, 1.3 mmol) was added to a stirred solution of 5a (150 mg, 0.30 mmol) in NMP (1.0 mL) at rt. The reaction mixture was heated at 220° C. for 20 min using microwave irradiation and the solvent was then removed by lyophilisation from deionised water. The residue was thoroughly extracted with CH2Cl2, dried and concentrated. Purification by silica gel chromatography (heptane:EtOAc, 1:1) gave 6a as a white foam (110 mg, 82%)[α]D −83 (c 1.0, CHCl3); IR λ 3012, 2956, 2217, 1751, 1654, 1486, 1442, 1369 cm−1; 1H NMR (400 MHz, CDCl3) δ 7.79 (d, J=7.8, 1H), 7.70 (d, J=8.1, 1H), 7.62 (d, J=8.2, 1H), 7.47-7.29 (m, 3H), 7.19-6.92 (m, 5H), 6.87 (d, J=7.3, 1H), 5.79 (dd, J=8.9, 2.3, 1H), 4.41-4.27 (m, 2H), 3.89 (s, 3H), 3.75 (dd, J=11.9, 8.9, 1H), 3.52 (dd, J=11.9, 2.3, 1H); 13C NMR (100 MHz, CDCl3) δ 167.6, 160.7, 158.7, 155.2, 134.4, 133.6, 132.4, 131.4, 129.7, 129.2, 128.8 (broad and splitted), 128.6, 127.6, 126.1, 125.7, 125.3, 125.2, 122.7, 117.1, 115.2, 101.3, 64.4, 53.7, 35.3, 31.8; HRMS (EI+) calcd for C27H20N2O3S 452.1195, obsd 452.1192.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[C:6]([CH:8]([CH3:10])[CH3:9])[CH:5]=[CH:4][C:3]=1[N:11]1[C:19]2[C:14](=[C:15]([CH3:21])[CH:16]=[C:17]([CH3:20])[N:18]=2)[C:13]([C:22]#[N:23])=[CH:12]1.[C:24]([CH2:32][C:33](=O)C)(=O)[C:25]1C=CC=C[CH:26]=1.C1(C)C(C)=CC=CC=1>O>[Br:1][C:2]1[CH:7]=[C:6]([CH:8]([CH3:10])[CH3:9])[CH:5]=[CH:4][C:3]=1[N:11]1[C:19]2[C:14](=[C:15]([CH3:21])[CH:16]=[C:17]([C:20]3[CH:33]=[CH:32][CH:24]=[CH:25][CH:26]=3)[N:18]=2)[C:13]([C:22]#[N:23])=[CH:12]1.[Br:1][C:2]1[CH:7]=[C:6]([CH:8]([CH3:10])[CH3:9])[CH:5]=[CH:4][C:3]=1[N:11]1[C:19]2[C:14](=[C:15]([CH3:21])[CH:16]=[C:17]([CH3:20])[N:18]=2)[C:13]([C:22]#[N:23])=[CH:12]1
Reactant: CC(=O)CC(=O)c1ccccc1
Agent: Cc1cc(C)c2c(C#N)cn(-c3ccc(C(C)C)cc3Br)c2n1
Solvent: O
Solvent: Cc1ccccc1C
Product: Cc1cc(-c2ccccc2)nc2c1c(C#N)cn2-c1ccc(C(C)C)cc1Br

Procedure:
A mixture of 737 mg (2.00 mmole) of the product from Example 64 (Part B), 324 mg (2.00 mmole) of benzoylacetone and 25 mL of xylene was heated in a flask equipped with a water separator for 2 hours. The solvent was removed by evaporation, and the residue chromatographed on silica gel, eluting in step gradients with 0, 5, 10; and 15% ethyl acetate in hexane. Both 1-(2-bromo-4-isopropylphenyl)-3-cyano-4-methyl-6-phenyl-7-azaindole and 1-(2-bromo-4-isopropylphenyl)-3-cyano-6-methyl-4-methyl-7-azaindole were obtained. The Rf values were respectively 0.38 and 0.28 (silica gel with 80:20 hexane-ethyl acetate). The assignment of the structures was based on the nmr data of the de-cyanylated compounds in Example 67.