Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(N(C(C)C)C(C)C)C.[NH2:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1.[CH3:17][O:18][C:19](=[O:45])[C:20]([CH3:44])([CH3:43])[CH2:21][O:22][C:23]1[N:28]=[CH:27][C:26]([C:29]2[CH:38]=[C:37]3[C:32]([C:33]([C:40](O)=[O:41])=[CH:34][C:35]([CH3:39])=[N:36]3)=[CH:31][CH:30]=2)=[CH:25][CH:24]=1>CN(C)C=O>[CH3:44][C:20]([CH3:43])([CH2:21][O:22][C:23]1[CH:24]=[CH:25][C:26]([C:29]2[CH:38]=[C:37]3[C:32]([C:33]([C:40](=[O:41])[NH:10][C:11]4[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=4)=[CH:34][C:35]([CH3:39])=[N:36]3)=[CH:31][CH:30]=2)=[CH:27][N:28]=1)[C:19]([O:18][CH3:17])=[O:45]
Reactant: COC(=O)C(C)(C)COc1ccc(-c2ccc3c(C(=O)O)cc(C)nc3c2)cn1
Reactant: Nc1ccccc1
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: COC(=O)C(C)(C)COc1ccc(-c2ccc3c(C(=O)Nc4ccccc4)cc(C)nc3c2)cn1
Reaction time: 8 h
Yield: 88 %

Procedure:
N-Ethyl-N,N-diisopropylamine (64.5 mg, 0.50 mmol) was added at room temperature to a solution of aniline (465.0 mg, 0.50 mmol), 7-(6-(3-methoxy-2,2-dimethyl-3-oxopropoxy)pyridin-3-yl)-2-methylquinoline-4-carboxylic acid B-15 (98.8 mg, 0.25 mmol) and N,N,N′N-tetramethyl-O-(7-azabenzotriazol-1-yl)uronium hexafluorophosphate (190.0 mg, 0.50 mmol) in anhydrous N,N-dimethylformamide (5.0 mL) under an atmosphere of nitrogen. The reaction mixture was stirred overnight, then partitioned between methylene chloride (30 mL) and an aqueous solution of pH 7 phosphate buffer (30 mL). The aqueous layer was extracted with methylene chloride (3×30 mL); the combined extracts were successively washed with water (30 mL), brine (30 mL), then dried over anhydrous magnesium sulfate, filtered and concentrated to dryness under reduced pressure. The crude residue was purified by flash column chromatography on silica gel (hexanes:ethyl acetate gradient) to give methyl 2,2-dimethyl-3-(5-(2-methyl-4-(phenylcarbamoyl)quinolin-7-yl)pyridin-2-yloxy)propanoate B-16 (103.4 mg, Yield=88%). 1H NMR (500 MHz, CHLOROFORM-d) δ ppm 1.37 (s, 6H), 2.83 (s, 3H), 3.73 (s, 3H), 4.42 (s, 2H), 6.90 (d, J=8.5 Hz, 1H), 7.26-7.29 (m, 1H), 7.45-7.48 (m, 3H), 7.73-7.77 (m, 2H), 7.88 (s, 1H), 7.95 (q, J=6.0 Hz, 1H), 8.23 (s, 1H), 8.32 (d, J=8.5 Hz, 1H), 8.54 (s, 1H); MS (ESI) [M+1]+ 470.
Reaction SMILES: C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.BrN1C(=O)CCC1=O.[CH:28]1([CH2:33][CH:34]([C:38]2[CH:43]=[CH:42][C:41]([C:44]([F:47])([F:46])[F:45])=[C:40]([F:48])[CH:39]=2)[C:35]([OH:37])=O)[CH2:32][CH2:31][CH2:30][CH2:29]1.[NH2:49][C:50]1[S:51][CH:52]=[CH:53][N:54]=1>C(Cl)Cl>[CH:28]1([CH2:33][CH:34]([C:38]2[CH:43]=[CH:42][C:41]([C:44]([F:45])([F:47])[F:46])=[C:40]([F:48])[CH:39]=2)[C:35]([NH:49][C:50]2[S:51][CH:52]=[CH:53][N:54]=2)=[O:37])[CH2:29][CH2:30][CH2:31][CH2:32]1
Reactant: O=C(O)C(CC1CCCC1)c1ccc(C(F)(F)F)c(F)c1
Reactant: Nc1nccs1
Agent: O=C1CCC(=O)N1Br
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Product: O=C(Nc1nccs1)C(CC1CCCC1)c1ccc(C(F)(F)F)c(F)c1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 63.5 %

Procedure:
A solution of triphenylphosphine (312 mg, 1.19 mmol) in methylene chloride (5 mL) was cooled to 0° C. and then slowly treated with N-bromosuccinimide (212 mg, 1.19 mmol). The reaction mixture was stirred at 0° C. for 30 min and then treated with 3-cyclopentyl-2-(3-fluoro-4-trifluoromethyl-phenyl)-propionic acid (300 mg, 0.99 mmol). The resulting reaction mixture was stirred at 0° C. for 15 min and then allowed to warm to 25° C. where it was stirred for 30 min. The reaction mixture was then treated with 2-aminothiazole (218 mg, 2.18 mmol). The resulting reaction mixture was stirred at 25° C. for 3 d. The crude reaction mixture was then directly purified by flash chromatography (Merck Silica gel 60, 230–400 mesh, 2/1 hexanes/ethyl acetate) to afford 3-cyclopentyl-2-(3-fluoro-4-trifluoromethyl-phenyl)-N-thiazol-2-yl-propionamide (243 mg, 64%) as a white solid: mp 194–195° C.; EI-HRMS m/e calcd for C18H18F4N2OS (M+) 386.1076, found 386.1076.
Reaction SMILES: [OH:1][CH2:2][CH2:3][NH:4][CH2:5][CH2:6][CH2:7][C:8]1[CH:15]=[CH:14][C:11]([C:12]#[N:13])=[CH:10][CH:9]=1.C(N(CC)CC)C.[S:23](Cl)([CH3:26])(=[O:25])=[O:24]>C(Cl)Cl>[C:12]([C:11]1[CH:14]=[CH:15][C:8]([CH2:7][CH2:6][CH2:5][N:4]([S:23]([CH3:26])(=[O:25])=[O:24])[CH2:3][CH2:2][O:1][S:23]([CH3:26])(=[O:25])=[O:24])=[CH:9][CH:10]=1)#[N:13]
Reactant: CS(=O)(=O)Cl
Reactant: N#Cc1ccc(CCCNCCO)cc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CS(=O)(=O)OCCN(CCCc1ccc(C#N)cc1)S(C)(=O)=O
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 59.4 %

Procedure:
To a solution of 4-[3-(2-hydroxyethylamino)propyl]benzonitrile (4 g, 0.0196 mol; see step (v) above) in dry DCM (80 mL) were added, at 0-5° C., triethylamine (5.9 g, 0.0588 mol) and mesyl chloride (5.6 g, 0.049 mol). The resulting mixture was then stirred at room temperature for 30 min, after which the reaction was quenched by addition of water (50 mL). The resulting aqueous layer was extracted with DCM (2×50 mL) and the combined organic layers were washed with brine. Solvent was removed under reduced pressure and the crude product was recrystallised from methanol to yield 4.2 g (62%) of the title compound as a white solid.
Reaction SMILES: Cl.[N:2]12[CH2:9][CH2:8][CH2:7][C:6]1([CH2:10][C:11](Cl)=[O:12])[CH2:5][CH2:4][CH2:3]2.[CH3:14][C:15]([CH2:22][CH2:23][CH:24]=[C:25]([CH3:67])[CH2:26][CH2:27][CH:28]=[C:29]([CH3:66])[CH2:30][CH2:31][CH:32]=[C:33]([CH3:65])[CH2:34][CH2:35][CH:36]=[C:37]([CH3:64])[CH2:38][CH2:39][CH:40]=[C:41]([CH3:63])[CH2:42][CH2:43][CH:44]=[C:45]([CH3:62])[CH2:46][CH2:47][CH:48]=[C:49]([CH3:61])[CH2:50][CH2:51][CH:52]=[C:53]([CH3:60])[CH2:54][CH2:55][CH:56]=[C:57]([CH3:59])[CH3:58])=[CH:16][CH2:17][S:18][CH2:19][CH2:20][NH2:21]>N1C=CC=CC=1>[CH3:14][C:15]([CH2:22][CH2:23][CH:24]=[C:25]([CH3:67])[CH2:26][CH2:27][CH:28]=[C:29]([CH3:66])[CH2:30][CH2:31][CH:32]=[C:33]([CH3:65])[CH2:34][CH2:35][CH:36]=[C:37]([CH3:64])[CH2:38][CH2:39][CH:40]=[C:41]([CH3:63])[CH2:42][CH2:43][CH:44]=[C:45]([CH3:62])[CH2:46][CH2:47][CH:48]=[C:49]([CH3:61])[CH2:50][CH2:51][CH:52]=[C:53]([CH3:60])[CH2:54][CH2:55][CH:56]=[C:57]([CH3:59])[CH3:58])=[CH:16][CH2:17][S:18][CH2:19][CH2:20][NH:21][C:11](=[O:12])[CH2:10][C:6]12[CH2:7][CH2:8][CH2:9][N:2]1[CH2:3][CH2:4][CH2:5]2
Reactant: O=C(Cl)CC12CCCN1CCC2
Reactant: CC(C)=CCCC(C)=CCCC(C)=CCCC(C)=CCCC(C)=CCCC(C)=CCCC(C)=CCCC(C)=CCCC(C)=CCCC(C)=CCSCCN
Agent: Cl
Solvent: c1ccncc1
Product: CC(C)=CCCC(C)=CCCC(C)=CCCC(C)=CCCC(C)=CCCC(C)=CCCC(C)=CCCC(C)=CCCC(C)=CCCC(C)=CCSCCNC(=O)CC12CCCN1CCC2
Temperature: 25 °C
Reaction time: 3 h
Yield: 86.5 %

Procedure:
(1-Azabicyclo[3.3.0]octan-5-yl)acetyl chloride hydrochloride (2.00 g, 8.93 mmol) was added to a solution of 2-(3,7,11,15,19,23,27,31,35,39-decamethyl-2,6,10,14,18,22,26,30,34,38-tetracontadecaen-1-ylthio)ethylamine (5.00 g, 6.61 mmol, prepared as described in Example 4) in 75 ml of pyridine at the temperature below 20° C. and the solution was stirred at 25° C. for 3 hours. (1-Azabicyclo[3.3.0]octan-5-yl)acetyl chloride hydrochloride (0.9 g, 4.02 mmol) was further added to the reaction mixture at the temperature below 20° C. and the solution was stirred at 25° C. for an hour. The solvent in the reaction mixture was evaporated in vacuo to dryness and the remaining residue was partitioned between chloroform and 10% sodium hydroxide aqueous solution. The organic layer was washed with saturated sodium chloride aqueous solution, dried over anhydrous sodium sulfate, filtered and evaporated in vacuo to dryness to give a brown residue. The residue was chromatographed on silica gel, eluting with CH2Cl2 /MeOH (10:0-10:1.5) to afford 5.2 g (86.7%) of the desired compound, as a colorless oil.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C:9]1[CH:17]=[CH:16][C:12]([C:13]([NH2:15])=[S:14])=[CH:11][N:10]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].Cl[CH:19]([C:25]([CH3:27])=O)[C:20]([O:22][CH2:23][CH3:24])=[O:21].C([O-])(=O)C.[Na+].C(=O)([O-])O.[Na+]>C(O)C.O>[C:1]([O:5][C:6]([NH:8][C:9]1[N:10]=[CH:11][C:12]([C:13]2[S:14][C:19]([C:20]([O:22][CH2:23][CH3:24])=[O:21])=[C:25]([CH3:27])[N:15]=2)=[CH:16][CH:17]=1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)Nc1ccc(C(N)=S)cn1
Reactant: CCOC(=O)C(Cl)C(C)=O
Agent: CC(=O)[O-]
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCO
Solvent: O
Product: CCOC(=O)c1sc(-c2ccc(NC(=O)OC(C)(C)C)nc2)nc1C
Yield: 27.6 %

Procedure:
A mixture of 6-tert-butoxycarbonylaminothionicotinamide (506 mg), ethyl 2-chloro-acetoacetate (492 mg) and sodium acetate (252 mg) in ethanol (20 ml) was heated for 2 hours under reflux, and to the mixture were added sodium hydrogen carbonate aqueous solution and water. The precipitated crystals were collected by filtration, and the crystals were successively washed with water, ethanol and ether to give ethyl 2-(6-tert-butoxycarbonylamino-3-pyridyl)-4-methyl-5-thiazolecarboxylate (200 mg).
Reaction SMILES: [Cl:1][CH2:2][CH2:3][CH2:4][C:5]([C:7]1[CH:12]=[C:11]([F:13])[CH:10]=[CH:9][C:8]=1[F:14])=O.[CH3:15][C:16]([S@@:19]([NH2:21])=[O:20])([CH3:18])[CH3:17]>C1COCC1.[O-]CC.[Ti+4].[O-]CC.[O-]CC.[O-]CC>[Cl:1][CH2:2][CH2:3][CH2:4]/[C:5](=[N:21]\[S@:19]([C:16]([CH3:18])([CH3:17])[CH3:15])=[O:20])/[C:7]1[CH:12]=[C:11]([F:13])[CH:10]=[CH:9][C:8]=1[F:14]
Reactant: CC(C)(C)[S@@](N)=O
Reactant: O=C(CCCCl)c1cc(F)ccc1F
Agent: [Ti+4]
Agent: CC[O-]
Solvent: C1CCOC1
Product: CC(C)(C)[S@](=O)/N=C(\CCCCl)c1cc(F)ccc1F
Temperature: 27.5 °C
Yield: 86.4 %

Procedure:
Titanium (IV) ethoxide (54.77 g, 240.13 mmol) was added to a solution of 4-chloro-1-(2,5-difluorophenyl)butan-1-one (35 g, 160.09 mmol) and (S)-2-methylpropane-2-sulfinamide (29.1 g, 240.13 mmol) in THF (400 mL) with stirring. The mixture was stirred continuously at 70° C. for 16 h. Reaction mixture was then cooled to a temperature of 20-35° C., quenched with saturated aqueous NH4Cl solution, diluted with ethylacetate and filtered. The filtrate was washed with water followed by brine solution. The organic layer was separated, dried over anhydrous sodium sulfate and concentrated under reduced pressure to afford 44.5 g of the title compound as a colourless liquid.
Reaction SMILES: [O:1]([C:8]1[CH:14]=[CH:13][C:11]([NH2:12])=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Cl:15][C:16]1=[C:17]([Cl:23])[C:18]([O:20][C:21]1=O)=[O:19]>C(O)(=O)C>[O:1]([C:8]1[CH:9]=[CH:10][C:11]([N:12]2[C:21](=[O:20])[C:16]([Cl:15])=[C:17]([Cl:23])[C:18]2=[O:19])=[CH:13][CH:14]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: Nc1ccc(Oc2ccccc2)cc1
Reactant: O=C1OC(=O)C(Cl)=C1Cl
Solvent: CC(=O)O
Product: O=C1C(Cl)=C(Cl)C(=O)N1c1ccc(Oc2ccccc2)cc1

Procedure:
A mixture of 28 g of p-phenoxyaniline and 28 g of dichloromaleic anhydride in 200 ml of glacial acetic acid was heated at reflux for 3 hours. Upon subsequent cooling, N-phenoxyphenyl-2,3 -dichloromaleimide crystallized and was collected by filtration. The 46 g (92% of theory) of crude material was washed with petroleum ether and air-dried. An analytical sample was prepared by recrystallization from glacial acetic acid, producing golden flakes of N-(p-phenoxyphenyl)-2,3-dichloromaleimide melting at 180°-181° C.
Reaction SMILES: [C:1]12([CH2:15][CH:14]([NH:16][C:17](=[O:32])[NH:18][C:19]3[CH:27]=[CH:26][CH:25]=[C:24]4[C:20]=3[CH:21]=[N:22][N:23]4C(OC)=O)[C:13]3[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=3)[O:7]1)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]2.[OH-].[Na+].O>CO>[NH:23]1[C:24]2[C:20](=[C:19]([NH:18][C:17]([NH:16][CH:14]3[C:13]4[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=4)[O:7][C:1]4([CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]4)[CH2:15]3)=[O:32])[CH:27]=[CH:26][CH:25]=2)[CH:21]=[N:22]1
Reactant: COC(=O)n1ncc2c(NC(=O)NC3CC4(CCCCC4)Oc4ccccc43)cccc21
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: O=C(Nc1cccc2[nH]ncc12)NC1CC2(CCCCC2)Oc2ccccc21
Temperature: 25 °C
Reaction time: 0.75 h

Procedure:
The product from Example 1C (4.06 mmol) was suspended in methanol (20 mL) and was treated with 5N methanolic NaOH (3.3 mL, 16.5 mmol). The mixture was stirred at room temperature for 45 min, then it was poured into H2O (100 mL). The precipitate that formed was collected by filtration and was air-dried to afford the title compound as an off-white solid, 794 mg (43%). 1H NMR (300 MHz, DMSO-d6) δ ppm 13.01 (br, 1H), 8.67 (s, 1H), 8.06 (s, 1H), 7.69 (d, J=7.5 Hz, 1H), 7.31 (d, J=7.8 Hz, 1H), 7.23 (J=7.8 Hz, 1H), 7.16 (m, 1H), 7.08 (d, J=8.5 Hz, 1H), 6.90 (td; J=7.5, 1.0 Hz; 1H), 6.80 (dd; J=7.9, 1.0 Hz; 1H), 6.72 (d, J=8.1 Hz, 1H), 4.98 (m, 1H), 2.24 (m, 1H), 1.33-1.82 (m, 11H). MS (ESI+) m/z 377 (M+H).
Reaction SMILES: [Na].[CH3:2][C:3]1([CH3:22])[S:7]C(CNC(CC2C=CC=CC=2)=O)[NH:5][CH:4]1[C:19]([OH:21])=[O:20]>>[NH2:5][C@H:4]([C:19]([OH:21])=[O:20])[C:3]([SH:7])([CH3:22])[CH3:2]
Reactant: CC1(C)SC(CNC(=O)Cc2ccccc2)NC1C(=O)O
Agent: [Na]
Product: CC(C)(S)[C@H](N)C(=O)O

Procedure:
The sodium salt of the penilloic acid is reacted with a mercuric halogenide, for example mercuric chloride, or a mercuric salt in the presence of halogen ions in aqueous solution. This results in the formation of a penicillamine-mercuric-halogenide-complex compound which is isolated by filtration and then thoroughly freed from the formed by-product penilloaldehyde and the inorganic salt by washing and suspending.
Reaction SMILES: [CH2:1](Br)[CH:2]=[CH2:3].[Cl:5][C:6]1[CH:36]=[CH:35][C:9]([CH2:10][N:11]2[C:19]3[C:14](=[CH:15][C:16]([OH:20])=[CH:17][CH:18]=3)[C:13]([S:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[C:12]2[CH2:26][C:27]([CH3:34])([CH3:33])[C:28]([O:30][CH2:31][CH3:32])=[O:29])=[CH:8][CH:7]=1>CN(C=O)C.[Cl-].[Na+].O>[Cl:5][C:6]1[CH:7]=[CH:8][C:9]([CH2:10][N:11]2[C:19]3[C:14](=[CH:15][C:16]([O:20][CH2:3][CH:2]=[CH2:1])=[CH:17][CH:18]=3)[C:13]([S:21][C:22]([CH3:23])([CH3:24])[CH3:25])=[C:12]2[CH2:26][C:27]([CH3:34])([CH3:33])[C:28]([O:30][CH2:31][CH3:32])=[O:29])=[CH:35][CH:36]=1
Reactant: C=CCBr
Reactant: CCOC(=O)C(C)(C)Cc1c(SC(C)(C)C)c2cc(O)ccc2n1Cc1ccc(Cl)cc1
Agent: [Cl-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: C=CCOc1ccc2c(c1)c(SC(C)(C)C)c(CC(C)(C)C(=O)OCC)n2Cc1ccc(Cl)cc1
Temperature: 25 °C
Reaction time: 17 h
Yield: 86.2 %

Procedure:
A mixture of allyl bromide (1.81 g, 15 mmol) potassium carbonate (4.14 g, 30 mmol) and ethyl 3-(1-(4-chlorobenzyl)-3-(t-butylthio)-5-hydroxyindol-2-yl)-2,2dimethylpropionate (7.15 g, 15 mmol), prepared as in step 3, in anhydrous DMF (40 ml) was heated at 60° C for 3 hours, and stirred at ambient temperature for 17 hours. The reaction mixture was diluted with brine and extracted with ethyl acetate. The combined organics were washed with brine, dried over MgSO4, filtered, and concentrated in vacuo to provide a white solid. The solid was triturated with hexane (100 ml), filtered and dried in vacuo dried to obtain 6.65g of ethyl 3-(1-(4-chlorobenzyl)-3-(1,1-dimethylethylthio)-5-allyloxyindol-2-yl)-2,2dimethylpropionate as a white solid.
Reaction SMILES: [CH3:1][N:2]1[CH:6]=[CH:5][C:4]([NH:7][C:8]([C:10]2[CH:15]=[C:14](B3OC(C)(C)C(C)(C)O3)[CH:13]=[C:12]([CH3:25])[N:11]=2)=[O:9])=[N:3]1.Br[C:27]1[CH:32]=[CH:31][N:30]=[C:29]([CH3:33])[CH:28]=1>>[CH3:1][N:2]1[CH:6]=[CH:5][C:4]([NH:7][C:8]([C:10]2[CH:15]=[C:14]([C:27]3[CH:32]=[CH:31][N:30]=[C:29]([CH3:33])[CH:28]=3)[CH:13]=[C:12]([CH3:25])[N:11]=2)=[O:9])=[N:3]1
Reactant: Cc1cc(Br)ccn1
Reactant: Cc1cc(B2OC(C)(C)C(C)(C)O2)cc(C(=O)Nc2ccn(C)n2)n1
Product: Cc1cc(-c2cc(C)nc(C(=O)Nc3ccn(C)n3)c2)ccn1

Procedure:
The title compound, was prepared from 6-Methyl-4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-pyridine-2-carboxylic acid (1-methyl-1H-pyrazol-3-yl)-amide in accordance with the general method of example 131, step 2 using 4-Bromo-2-methylpyridine instead of 3-Trifluoromethyl-5-bromopyridine to yield the final compound as a white amorphous, MS (ISP): m/e=308.4 (M+H)+.
Reaction SMILES: [OH:1][CH2:2][CH2:3][C@H:4]1[NH:7][C:6](=[O:8])[C@@H:5]1[C:9]([O:12][CH3:13])([CH3:11])[CH3:10].CC(C)=[O:16].OS(O)(=O)=O.O=[Cr](=O)=O.C(O)(C)C>CC(C)=O>[CH3:13][O:12][C:9]([C@H:5]1[C:6](=[O:8])[NH:7][C@@H:4]1[CH2:3][C:2]([OH:16])=[O:1])([CH3:11])[CH3:10]
Reactant: COC(C)(C)[C@H]1C(=O)N[C@@H]1CCO
Reactant: CC(C)=O
Agent: O=[Cr](=O)=O
Agent: O=S(=O)(O)O
Solvent: CC(C)O
Product: COC(C)(C)[C@H]1C(=O)N[C@@H]1CC(=O)O

Procedure:
A solution of (3S, 4R)-4-(2-hydroxyethyl)-3-(1-methoxy-1-methylethyl)azetidin-2-one (50.7 mg) in acetone (5.42 ml) was added to a solution of 2N Jones reagent (0.542 ml) in acetone (5.42 ml) at ambient temperature over a period of 30 minutes, and the mixture was stirred for an hour. After addition of an excess of isopropyl alcohol to the mixture, the solvent was removed. The residue was dissolved in chloroform and the resultant solution was washed with a saturated aqueous sodium chloride. The washings were extracted five times with chloroform. The extracts were combined, dried over magnesium sulfate, filtered and evaporated. The crystalline residue was washed with isopropyl alcohol to give 2-[(2R, 3S)-3-(1-methoxy-1-methylethyl)-4-oxoazetidin-2-yl]acetic acid (25.1 mg). The mother liquor was concentrated and the crystalline residue was washed with hexane to give a second crop of the above product (19.4 mg). Total yield is 44.5 mg.
Reaction SMILES: I[C:2]1[N:6]2[CH:7]=[CH:8][C:9]([C:11]3[N:12]=[N:13][CH:14]=[C:15]([CH3:17])[N:16]=3)=[CH:10][C:5]2=[N:4][CH:3]=1.CC1(C)C(C)(C)OB([C:26]2[CH:27]=[C:28]([NH:32][C:33]([NH:35][CH2:36][C:37]([F:40])([F:39])[F:38])=[O:34])[CH:29]=[CH:30][CH:31]=2)O1>>[CH3:17][C:15]1[N:16]=[C:11]([C:9]2[CH:8]=[CH:7][N:6]3[C:2]([C:30]4[CH:29]=[C:28]([NH:32][C:33]([NH:35][CH2:36][C:37]([F:38])([F:39])[F:40])=[O:34])[CH:27]=[CH:26][CH:31]=4)=[CH:3][N:4]=[C:5]3[CH:10]=2)[N:12]=[N:13][CH:14]=1
Reactant: CC1(C)OB(c2cccc(NC(=O)NCC(F)(F)F)c2)OC1(C)C
Reactant: Cc1cnnc(-c2ccn3c(I)cnc3c2)n1
Product: Cc1cnnc(-c2ccn3c(-c4cccc(NC(=O)NCC(F)(F)F)c4)cnc3c2)n1

Procedure:
3-Iodo-7-(5-methyl-[1,2,4]triazin-3-yl)-imidazo[1,2-a]pyridine (120 mg, 0.4 mmol, 1 equiv) and 1-[3-(4,4,5,5-Tetramethyl-[1,3,2]dioxaborolan-2-yl)-phenyl]-3-(2,2,2-trifluoro-ethyl)-urea were coupled according to procedure D4 to furnish the title compound as a yellow solid (85 mg). 1H NMR (400 MHz, DMSO-d6): 9.34 (1H, s), 8.99 (1H, s), 8.74 (1H, d), 8.67 (1H, s), 7.98 (1H, d), 7.93 (1H, s), 7.79 (1H, s), 7.55-7.43 (2H, m), 7.31 (1H, d), 6.87 (1H, t), 3.99-3.88 (2H, m), 2.65 (3H, s). MS: [M+H]+428
Reaction SMILES: C(NC(C)C)(C)C.[CH2:8]([NH:11][C:12](=[O:24])[C:13]1[CH:18]=[CH:17][C:16]([O:19][C:20]([F:23])([F:22])[F:21])=[CH:15][CH:14]=1)[CH:9]=[CH2:10]>C1COCC1>[CH:8]([NH:11][C:12](=[O:24])[C:13]1[CH:14]=[CH:15][C:16]([O:19][C:20]([F:22])([F:23])[F:21])=[CH:17][CH:18]=1)=[CH:9][CH3:10]
Reactant: C=CCNC(=O)c1ccc(OC(F)(F)F)cc1
Solvent: CC(C)NC(C)C
Solvent: C1CCOC1
Product: CC=CNC(=O)c1ccc(OC(F)(F)F)cc1
Temperature: 0 °C
Yield: 85 %

Procedure:
To a solution of diisopropylamine (6.3 mL, 45 mmol) in THF 100 mL at −78° C., was added n-butyllithilum (18 mL, 45 mmol of a 2.5M solution in hexanes). After 10 min. a solution (10 mL THF) of N-Allyl-4-trifluoromethoxy-benzamide 11 (5 g, 20 mmol) was added dropwise to the reaction mixture. The resulting dark blue reaction mixture was allowed to warm to 0° C. where it was quenched by addition of aqueous ammonium chloride. Ether was added and the organic layer was separated, dried (sodium sulfate), and concentrated. The residue was purified by silica gel chromatography (20% ether/hexanes) to provide the title compound (colorless solid 85%). 1H NMR (400 MHz, CDCl3) δ7.85 (d, J=8.8 Hz, 2 H, Ar), 7.55 (s, 1 H, NH), 7.29 (d, J=9.5 Hz, 2 H, Ar), 6.95 (m, 1 H, NHCHCH), 5.35 & 4.99 (m, 1 H, CHCHCH3), 1.72 (m, 3 H, CH3)
Reaction SMILES: [C:1]([O:5][C@@H:6]1[C@:14]2([CH2:15][CH3:16])[C@H:9]([C@@H:10]3[CH2:24][CH2:23][C:22]4[CH:21]=[C:20]([O:25][CH3:26])[CH:19]=[CH:18][C:17]=4[C:11]3=[CH:12][CH2:13]2)[CH2:8][CH2:7]1)([CH3:4])([CH3:3])[CH3:2].[H][H]>[Pd].C(OCC)(=O)C>[C:1]([O:5][C@@H:6]1[C@:14]2([CH2:15][CH3:16])[C@H:9]([C@@H:10]3[CH2:24][CH2:23][C:22]4[CH:21]=[C:20]([O:25][CH3:26])[CH:19]=[CH:18][C:17]=4[C@H:11]3[CH2:12][CH2:13]2)[CH2:8][CH2:7]1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CC[C@]12CC=C3c4ccc(OC)cc4CC[C@H]3[C@@H]1CC[C@@H]2OC(C)(C)C
Reactant: [H][H]
Agent: [Pd]
Solvent: CCOC(C)=O
Product: CC[C@]12CC[C@@H]3c4ccc(OC)cc4CC[C@H]3[C@@H]1CC[C@@H]2OC(C)(C)C

Procedure:
A mixture of 1g (2.82 mmoles) of (+)-17β-tert.butoxy-13β-ethyl-3-methoxygona-1,3,5(10),9(11)-tetraene, 0.25 g of 5% palladium on carbon and 35 ml of ethyl acetate was stirred in an atmosphere of hydrogen for 1 hr during which time a total of 74 ml of hydrogen was absorbed (70.5 ml theory). The catalyst was filtered with suction on Celite and the filter cake was washed well with ethyl acetate. Concentration of the combined filtrate and washes in vacuo gave 1.23 g of colorless solid. This material was chromatographed on 50 g of silica gel. Elution with 19:1 hexane:ether gave 0.925 g of colorless solid which was recrystallized from ethanol. This afforded 0.67 g of colorless plates, m.p. 121°-123°. [α] D25 +44.69°(c 1.016, CHCl3); uv max (95% EtOH) 278 nm (ε 2020), 287 (1860); ir (CHCl3) 1610, 1580, 1500, 1360 cm-1 ; nmr (CDCl3)δ 7.18 (m, 1), 6.68 (m, 2) 3.74 (s, 3), 3.51 (t, 1, J = Hz), 1.15 ppm (s); ms m/e 356 (M+).
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[C:6]([OH:24])=[C:7]2[C:12](=[CH:13][N:14]=1)[N:11]([CH2:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)[C:10](=[O:22])[C:9]([CH3:23])=[CH:8]2)=[O:4].[Br:25]N1C(=O)CCC1=O>>[CH3:1][O:2][C:3]([C:5]1[C:6]([OH:24])=[C:7]2[C:12](=[C:13]([Br:25])[N:14]=1)[N:11]([CH2:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)[C:10](=[O:22])[C:9]([CH3:23])=[CH:8]2)=[O:4]
Reactant: O=C1CCC(=O)N1Br
Reactant: COC(=O)c1ncc2c(cc(C)c(=O)n2Cc2ccccc2)c1O
Product: COC(=O)c1nc(Br)c2c(cc(C)c(=O)n2Cc2ccccc2)c1O
Temperature: 25 °C
Yield: 64.3 %

Procedure:
A mixture of 1-benzyl-5-hydroxy-3-methyl-2-oxo-1,2-dihydro-[1,7]naphthyridine-6-carboxylic acid methyl ester (0.62 g, 1.9 mmol) and N-bromosuccinimide (0.36 g, 2.01 mmol) was refluxed for 3 h. After the mixture was cooled to r.t., solvent was evaporated in vacuo. The residue was chromatographed (0-30% EtOAc/hexanes+2% AcOH) to give 493 mg of the title compound as a pale yellow solid. MS: (+) m/z 402.98, 404.86 (M+1, 79/81Br)
Reaction SMILES: [Cl:1][C:2]1[C:11]([N+:12]([O-:14])=[O:13])=[C:10](Cl)[C:9]2[C:4](=[CH:5][C:6]([C:16]([F:19])([F:18])[F:17])=[CH:7][CH:8]=2)[N:3]=1.C(N(CC)CC)C.[CH3:27][O:28][C:29]1[CH:35]=[CH:34][C:32]([NH2:33])=[CH:31][CH:30]=1>CN(C)C=O.Cl>[Cl:1][C:2]1[C:11]([N+:12]([O-:14])=[O:13])=[C:10]([NH:33][C:32]2[CH:34]=[CH:35][C:29]([O:28][CH3:27])=[CH:30][CH:31]=2)[C:9]2[C:4](=[CH:5][C:6]([C:16]([F:19])([F:18])[F:17])=[CH:7][CH:8]=2)[N:3]=1
Reactant: COc1ccc(N)cc1
Reactant: O=[N+]([O-])c1c(Cl)nc2cc(C(F)(F)F)ccc2c1Cl
Agent: Cl
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: COc1ccc(Nc2c([N+](=O)[O-])c(Cl)nc3cc(C(F)(F)F)ccc23)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 100 %

Procedure:
To a solution of 2,4-dichloro-3-nitro-7-trifluoromethyl-quinoline (220 mg; 0.70 mmol; 1 eq) in dimethylformamide (3.5 mL), are added successively triethylamine (105 μL; 0.76 mmol; 1.08 eq) and 4-methoxyaniline (88 mg; 712 mmol; 1.01 eq.). The reaction mixture is allowed to stir for 1 hour at room temperature until the reaction is complete on TLC. The crude solution is diluted with a 1M aqueous solution of HCl (5 mL) and then extracted with ethyl acetate (40 mL). The organic layer is separated and washed 3 times with a 1M aqueous solution of HCl (3×40 mL), dried over sodium sulfate, filtrated and concentrated under vacuum to afford the title compound as a yellow powder (280 mg; 0.70 mmol; 100%) which is used without further purification.