Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[N:3]=[C:4]2[CH:9]=[C:8]([C:10]3[CH:11]=[C:12]([CH:17]=[CH:18][CH:19]=3)[C:13]([NH:15][CH3:16])=[O:14])[CH:7]=[N:6][N:5]2[C:20]=1[C:21]1[CH:26]=[CH:25][N:24]=[C:23](Cl)[CH:22]=1.[C:28]1(B(O)O)[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1.O.C([O-])([O-])=O.[Na+].[Na+]>COCCOC.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[NH2:1][C:2]1[N:3]=[C:4]2[CH:9]=[C:8]([C:10]3[CH:11]=[C:12]([CH:17]=[CH:18][CH:19]=3)[C:13]([NH:15][CH3:16])=[O:14])[CH:7]=[N:6][N:5]2[C:20]=1[C:21]1[CH:26]=[CH:25][N:24]=[C:23]([C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)[CH:22]=1
Reactant: OB(O)c1ccccc1
Reactant: CNC(=O)c1cccc(-c2cnn3c(-c4ccnc(Cl)c4)c(N)nc3c2)c1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: COCCOC
Product: CNC(=O)c1cccc(-c2cnn3c(-c4ccnc(-c5ccccc5)c4)c(N)nc3c2)c1

Procedure:
3-[2-Amino-3-(2-Chloro-pyridin-4-yl)-imidazo-[1,2-b]-pyridazin-7-yl]-N-methyl benzamide (1 eq, 0.146 mmol, 79 mg) and phenyl boronic acid (1.5 eq, 0.219 mmol, 27.5 mg) are dissolved in DME (1.5 ml) and water (0.4 ml) and Na2CO3 (3 eq, 0.438 mmol, 46.4 mg) are added. PdCl2(PPh3)2 (0.05 eq, 0.008 mmol, 5.12 mg) is then added and the reaction mixture is heated using microwave radiation at 120° C. for 15 min. At the completion of this time the solvent is removed in vacuo and the reaction mixture is purified by flash column chromatography eluting with 9:1 DCM/MeOH to yield 3-(2-Amino-3-(2-phenyl-pyridin-4-yl)imidazo [1,2-b]pyridazin-7-yl]-N-methyl-benzamide as a yellow solid; [M+H]+=421
Reaction SMILES: [NH2:1][C:2]1[O:6][N:5]=[C:4]([CH3:7])[C:3]=1[Br:8].[C:9]1([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[CH:14]=[CH:13][CH:12]=[C:11]([S:15](Cl)(=[O:17])=[O:16])[CH:10]=1>>[Br:8][C:3]1[C:4]([CH3:7])=[N:5][O:6][C:2]=1[NH:1][S:15]([C:11]1[CH:10]=[C:9]([C:19]2[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=2)[CH:14]=[CH:13][CH:12]=1)(=[O:17])=[O:16]
Reactant: O=S(=O)(Cl)c1cccc(-c2ccccc2)c1
Reactant: Cc1noc(N)c1Br
Product: Cc1noc(NS(=O)(=O)c2cccc(-c3ccccc3)c2)c1Br
Yield: 22 %

Procedure:
N-(4-bromo-3-methyl-5-isoxazolyl)-3-biphenylsulfonamide was prepared in the same manner as described in Example 200b from 5-amino-4-bromo-3-methylisoxazole and 3-biphenylsulfonyl chloride in 22% yield. This was purified by HPLC (5% CH3CN to 100% CH3CN over 30 min.) to give a solid., m.p. 78-82° C.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@H:9]([CH2:13][C:14]#[CH:15])[C:10]([OH:12])=[O:11])=[O:7])([CH3:4])([CH3:3])[CH3:2].[C:16](=O)([O-])[O-].[Cs+].[Cs+].CI>CN(C=O)C>[CH3:16][O:11][C:10](=[O:12])[C@H:9]([NH:8][C:6]([O:5][C:1]([CH3:4])([CH3:3])[CH3:2])=[O:7])[CH2:13][C:14]#[CH:15]
Reactant: C#CC[C@@H](NC(=O)OC(C)(C)C)C(=O)O
Reactant: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Solvent: CI
Product: C#CC[C@@H](NC(=O)OC(C)(C)C)C(=O)OC
Reaction time: 3 h

Procedure:
The commercially available compound, 2-(R)-tert-butoxycarbonylaminopent-4-ynoic acid (0.321 g, 1.50 mmol) was dissolved in anhydrous DMF (5 mL). To the solution was added cesium carbonate (0.54 g, 1.65 mmol) in one portion. The mixture was stirred at room temperature for 45 min before methyl iodide (0.20 mL, 3.00 mmol) was added, and further stirred for three hours. The reaction was quenched with water (10 mL). The organics was extracted with dichloromethane (2×30 mL), washed with water (3×50 mL), and dried over anhydrous sodium sulfate. The solvent was completely removed under vacuum. The residue was further dried under high vacuum over night and used in the next reaction without further purification. The product 220 was obtained as a colorless viscous oil (0.326 g, 95% yield). 1H NMR (300 MHz, CDCl3): δ 1.48 (s, 9H), 2.08 (t, J=2.6 Hz, 1H), 2.75 (t, J=6.3 Hz, 2H), 3.78 (s, 3H), 4.46 (m, 1H), 5.32 (br s, 5H).
Reaction SMILES: [C:1]([N:3]=[C:4]([C:7]1[S:8][CH:9]=[CH:10][CH:11]=1)OC)#[N:2].[C:12]1([CH2:18][CH2:19][NH2:20])[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1>CO>[C:1]([NH:3][C:4]([C:7]1[S:8][CH:9]=[CH:10][CH:11]=1)=[N:20][CH2:19][CH2:18][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)#[N:2]
Reactant: COC(=NC#N)c1cccs1
Reactant: NCCc1ccccc1
Solvent: CO
Product: N#CNC(=NCCc1ccccc1)c1cccs1
Temperature: 25 °C
Reaction time: 1 h
Yield: 98.5 %

Procedure:
Methyl N-cyano-2-thiophenecarboximidate (0.33 g, 2.0 mmol) was dissolved in methanol (2 ml), and 2-phenylethylamine (0.27 g, 2.2 mmol) was added. The mixture was stirred at room temperature for 1 hour. After the reaction was completed, the reaction solution was concentrated under reduced pressure, and the residue thus obtained was crystallized from diethyl ether-hexane to give the title compound (0.50 g, 1.97 mmol, yield: 98%) as colorless crystals.
Reaction SMILES: O[C:2]12[CH2:11][CH:6]3[CH2:7][CH:8]([CH2:10][CH:4]([C:5]3=[O:12])[CH2:3]1)[CH2:9]2.[IH:13]>>[I:13][C:2]12[CH2:11][CH:6]3[CH2:7][CH:8]([CH2:10][CH:4]([C:5]3=[O:12])[CH2:3]1)[CH2:9]2
Reactant: I
Reactant: O=C1C2CC3CC1CC(O)(C3)C2
Product: O=C1C2CC3CC1CC(I)(C3)C2

Procedure:
Simple unit processes allow the conversion of several of the abovementioned X or X1 substituents, or others known in the art, to 5-X- or 5-X1 -adamantane-2-ones where X or X1 may be trialkylsilyloxy, iodo or cyano groups. These moities are stable under the mild conditions used in step 4 of the foregoing reaction sequence. For example, when 5-hydroxyadamantan-2-one is refluxed for 7 hours with 57% hydriodic acid, 5-iodoadamantan-2-one (m.p. 73°-76° C.) is obtained. 5-Carboxyadamantan-2-one, prepared as described in Lantvoev, J.Obshch.Khim,, 12, 2361 (1976) or Le Noble, et al., J.Org.Chem,, 48, 1101 (1983), after saponification of the methyl ester, can be converted to 5-cyanoadamantan-2-one by the three step procedure of Tabushi, et al., J.Org.Chem., 38, 3447 (1973), used for access to the isomeric 1-cyanoadamantan-2-one through the intermediacy of a keto amide. 5-Trimethylsilyloxyadamantan-2-one (m.p. 34°-38° C.), useful as a protected version of 5-hydroxyadamantan-2-one, allows the use of only one equivalent of base in step 4 of the foregoing reaction sequence to prepare the corresponding enol ether, which can then be desilylated using standard techniques.
Reaction SMILES: [Br:1][C:2]1[CH:9]=[CH:8][C:7]([OH:10])=[CH:6][C:3]=1[CH:4]=[O:5].[CH2:11](Br)[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1.C([O-])([O-])=O.[Cs+].[Cs+]>CN(C=O)C>[CH2:11]([O:10][C:7]1[CH:8]=[CH:9][C:2]([Br:1])=[C:3]([CH:6]=1)[CH:4]=[O:5])[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1
Reactant: BrCc1ccccc1
Reactant: O=Cc1cc(O)ccc1Br
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: O=Cc1cc(OCc2ccccc2)ccc1Br
Temperature: 80 °C

Procedure:
A solution of 2-bromo-5-hydroxy-benzaldehyde (5.99 g, 29.8 mmol, Preparation 13 Step A) in DMF (50 mL) was treated with benzyl bromide (7.65 g, 44.7 mmol) and Cs2CO3 (15.1 g, 44.7 mmol). The resulting mixture was heated at 80° C. for 60 min and was quenched with water (200 mL). The mixture was extracted with EtOAc (2×100 mL), dried (Na2SO4), and concentrated to a residue, which was purified on silica gel chromatography (hexanes/EtOAc 9/1) to afford 5-benzyloxy-2-bromo-benzaldehyde as white solid in quantitative yield.
Reaction SMILES: [Br:1][C:2]1[C:3](=[O:20])[NH:4][C:5](=[O:19])[N:6]([C@H:8]2[C@@:12]([F:14])([CH3:13])[C@H:11]([OH:15])[C@@:10]([F:18])([CH2:16][OH:17])[O:9]2)[CH:7]=1.C([Mg]Cl)(C)(C)C.Cl[C:28]1[C:37]2[C:32](=[CH:33][CH:34]=[CH:35][CH:36]=2)[CH:31]=[CH:30][C:29]=1[O:38][P:39](=[N:41][C@@H:42]([CH3:49])[C:43]([O:45][CH:46]([CH3:48])[CH3:47])=[O:44])=[O:40].CO>C1COCC1>[CH:46]([O:45][C:43](=[O:44])[C@@H:42]([N:41]=[P:39]([O:38][C:29]1[CH:30]=[CH:31][C:32]2[C:37](=[CH:36][CH:35]=[CH:34][CH:33]=2)[C:28]=1[O:17][CH2:16][C@:10]1([F:18])[C@@H:11]([OH:15])[C@:12]([F:14])([CH3:13])[C@H:8]([N:6]2[CH:7]=[C:2]([Br:1])[C:3](=[O:20])[NH:4][C:5]2=[O:19])[O:9]1)=[O:40])[CH3:49])([CH3:47])[CH3:48]
Reactant: CC(C)OC(=O)[C@H](C)N=[P+]([O-])Oc1ccc2ccccc2c1Cl
Reactant: C[C@]1(F)[C@H](n2cc(Br)c(=O)[nH]c2=O)O[C@](F)(CO)[C@H]1O
Agent: CC(C)(C)[Mg]Cl
Solvent: C1CCOC1
Solvent: CO
Product: CC(C)OC(=O)[C@H](C)N=[P+]([O-])Oc1ccc2ccccc2c1OC[C@@]1(F)O[C@@H](n2cc(Br)c(=O)[nH]c2=O)[C@](C)(F)[C@@H]1O
Temperature: 0 °C
Reaction time: 0.25 h
Yield: 31.9 %

Procedure:
To a solution of chiral 5-bromo-1-((2R,3R,4S,5S)-3,5-difluoro-4-hydroxy-5-hydroxymethyl-3-methyl-tetrahydro-furan-2-yl)-1H-pyrimidine-2,4-dione (92 mg, 0.26 mmol) prepared in Preparation 7 in THF (3 ml) at 0° C. was added a THF solution (Aldrich, 1 M) of tert-butylmagnesium chloride (0.64 mL, 0.64 mmol) dropwise. The mixture was stirred at 0° C. for 15 min, followed by the addition of THF solution (0.5 M) of (2S)-isopropyl 2-(chloro(naphthalen-2-yloxy)phosphorylamino)propanoate prepared in Example 3 Step B (1.29 mL, 0.64 mmol). The reaction mixture was warmed to room temperature and stirred for 2 h. Methanol (2 mL) was added to quench the reaction. The mixture was purified by flash chromatography (5-10% MeOH in DCM) to give the title compound as a white solid (56 mg, 32%).
Reaction SMILES: CC([N:5]([C@H:9]([CH3:28])[C:10]([NH:12][C:13]1[CH:18]=[CH:17][C:16]([O:19][C:20]2[CH:25]=[CH:24][CH:23]=[C:22]([O:26][CH3:27])[CH:21]=2)=[CH:15][CH:14]=1)=[O:11])C(=O)[O-])(C)C.C(O)(C(F)(F)F)=O>ClCCl>[CH3:27][O:26][C:22]1[CH:21]=[C:20]([O:19][C:16]2[CH:17]=[CH:18][C:13]([NH:12][C:10](=[O:11])[C@@H:9]([CH3:28])[NH2:5])=[CH:14][CH:15]=2)[CH:25]=[CH:24][CH:23]=1
Reactant: COc1cccc(Oc2ccc(NC(=O)[C@@H](C)N(C(=O)[O-])C(C)(C)C)cc2)c1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: COc1cccc(Oc2ccc(NC(=O)[C@@H](C)N)cc2)c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 99 %

Procedure:
To a solution of 1,1-dimethylethyl {(1R)-1-methyl-2-[(4-{[3-(methyloxy)phenyl]oxy}phenyl)amino]-2-oxoethyl}carbamate (Intermediate 1, 435 mg) in dry dichloromethane (6 mL), TFA (2 mL, 26.0 mmol) was added and the reaction mixture was stirred for 1 hour at room temperature. The solvent and the excess of TFA were evaporated and the residue was purified by SCX cartridge to afford the title compound as a yellow gum (320 mg).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9](=O)[CH2:10][CH2:11][C:12]([OH:14])=O)=[CH:5][CH:4]=1.[NH:16]([C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][N:19]=1)[NH2:17].C1(C)C=CC(S(O)(=O)=O)=CC=1.O>C1C=CC=CC=1>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]([C:9]2[CH2:10][CH2:11][C:12](=[O:14])[N:16]([C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][N:19]=3)[N:17]=2)=[CH:7][CH:8]=1
Reactant: COc1ccc(C(=O)CCC(=O)O)cc1
Reactant: NNc1ccccn1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: c1ccccc1
Solvent: O
Product: COc1ccc(C2=NN(c3ccccn3)C(=O)CC2)cc1
Temperature: 25 °C

Procedure:
In a 1 neck round bottom flask equipped with a Dean-Stark trap and condenser, 4-(4-methoxyphenyl)-4-oxo-butyric acid (5.0 g, 20 mmol), 2-hydrazinopyridine (3.9 g, 36 mmol) and p-toluene sulfonic acid (0.3 g) in 100 mL benzene were heated to reflux for 2 h while water was removed. The reaction was cooled to rt, an equal volume of Et2O was added and the product collected; Mp>300° C. This solid was dissolved in HOAc (50 mL) and heated at 100° C. for 6 h. The reaction was concentrated, dissolved in EtOAc and washed with saturated NaHCO3 solution, water, NaCl solution and dried (MgSO4). The solvent was concentrated to a thick oil; MS m/z 282 (M+H).
Reaction SMILES: Cl[C:2]1[N:11]=[C:10]2[C:5]([C:6](=[O:17])[C:7]([C:14]([OH:16])=[O:15])=[CH:8][N:9]2[CH2:12][CH3:13])=[CH:4][C:3]=1[F:18].[NH:19]1[CH2:23][CH2:22][CH:21]([CH2:24][NH2:25])[CH2:20]1>C(#N)C>[NH2:25][CH2:24][CH:21]1[CH2:22][CH2:23][N:19]([C:2]2[N:11]=[C:10]3[C:5]([C:6](=[O:17])[C:7]([C:14]([OH:16])=[O:15])=[CH:8][N:9]3[CH2:12][CH3:13])=[CH:4][C:3]=2[F:18])[CH2:20]1
Reactant: CCn1cc(C(=O)O)c(=O)c2cc(F)c(Cl)nc21
Reactant: NCC1CCNC1
Solvent: CC#N
Product: CCn1cc(C(=O)O)c(=O)c2cc(F)c(N3CCC(CN)C3)nc21
Temperature: 25 °C
Reaction time: 96 h
Yield: 66.8 %

Procedure:
A mixture of 2 00 g (7.39 mmole) of 7-chloro-1-ethyl-6-fluoro-1,4-dihydro-4-oxo-1,8 -napthyridine-3-carboxylic acid, 250 mL acetonitrile and 2.22 g (22.17 mmole) 3-pyrrolidinemethanamine [J. Org. Chem., 26, 4955 (1961)], was stirred at room temperature for four days. The reaction was filtered and the precipitate dissolved in 500 mL ammonium hydroxide at pH 10.5. This solution was filtered and the solvent removed at reduced pressure. The product was washed in 2×10 mL of water, then with ethanol/ether (1:1) until dry to give 1.65 g of 7-[3-(aminomethyl)-1-pyrrolidinyl]-1-ethyl-6-fluoro-1,4-dihydro-4-oxo -1,8-naphthyridine-3-carboxylic acid, mp 217°-218.5° C. Analysis calculated for C16H19FN4O3.1/2H2O:
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([CH3:8])[N:3]=1.[OH:9][C:10]1[C:19]2[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=2)[N:13]([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[CH2:12][C:11]=1[C:26](OCC)=[O:27]>C1(C)C=CC=CC=1>[OH:9][C:10]1[C:19]2[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=2)[N:13]([C:20]2[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=2)[CH2:12][C:11]=1[C:26]([NH:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([CH3:8])[N:3]=1)=[O:27]
Reactant: Cc1cccc(N)n1
Reactant: CCOC(=O)C1=C(O)c2ccccc2N(c2ccccc2)C1
Solvent: Cc1ccccc1
Product: Cc1cccc(NC(=O)C2=C(O)c3ccccc3N(c3ccccc3)C2)n1
Yield: 43.8 %

Procedure:
A solution of 5.49 g of 2-amino-6-methylpyridine and 10.0 g of 1,2-dihydro-4-hydroxy-1-phenyl-3-quinolinecarboxylic acid, ethyl ester in 250 ml of toluene was refluxed overnight in a soxhlet apparatus containing 10 g of 4 Å molecular sieves. Evaporation of the volatiles afforded a residue which was purified by means of high pressure liquid chromatography (silica gel: 2% ethyl acetate-dichloromethane). The resultant solution was degassed and evaporated. Recrystallization of the residue from diethyl ether yielded 5.30 g (43%) of 1,2-dihydro-4-hydroxy-N-(6-methyl-2-pyridyl)-1-phenyl-3-quinolinecarboxamide, m.p. 74°-77° C.
Reaction SMILES: C(NC(C)C)(C)C.[Cl:8][C:9]1[CH:17]=[C:16](I)[C:12]2[O:13][CH2:14][O:15][C:11]=2[C:10]=1[NH2:19].[CH3:20][Si:21]([C:24]#[CH:25])([CH3:23])[CH3:22]>C(OCC)(=O)C.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[Cl:8][C:9]1[CH:17]=[C:16]([C:25]#[C:24][Si:21]([CH3:23])([CH3:22])[CH3:20])[C:12]2[O:13][CH2:14][O:15][C:11]=2[C:10]=1[NH2:19]
Reactant: C#C[Si](C)(C)C
Reactant: Nc1c(Cl)cc(I)c2c1OCO2
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Solvent: CCOC(C)=O
Solvent: CC(C)NC(C)C
Product: C[Si](C)(C)C#Cc1cc(Cl)c(N)c2c1OCO2
Temperature: -20 °C
Reaction time: 4 h

Procedure:
Bis(triphenylphosphine)palladium(II) chloride (0.283 g), cuprous iodide (0.115 g) and diisopropylamine (0.57 ml) were added to a stirred solution of 5-chloro-7-iodo-1,3-benzodioxol-4-amine (0.600 g) and trimethylsilylacetylene (0.57 ml) in ethyl acetate (10 ml) cooled to −20° C. under a nitrogen atmosphere. The mixture was stirred for 4 hr at ambient temperature. The reaction mixture was filtered through Celite and the crude product in solution was then absorbed onto silica and purified by column chromatography using 20% dichloromethane in isohexane as eluent. There was thus obtained the title compound as an oil (0.560 g). NMR Spectrum: (CDCl3) 0.24 (s 9H), 4.03 (s, 2H), 6.02 (s, 2H), 6.91 (s, 1H); Mass Spectrum: M+H+ 268 and 270.
Reaction SMILES: [CH3:1][C:2]1[C:6]2[C:7](=[O:19])[N:8]([CH2:11][CH2:12][N:13]3[CH2:18][CH2:17][O:16][CH2:15][CH2:14]3)[CH2:9][CH2:10][C:5]=2[NH:4][C:3]=1[CH:20]=O.[F:22][C:23]1[CH:24]=[C:25]2[C:29](=[C:30]([NH2:32])[CH:31]=1)[NH:28][C:27](=[O:33])[CH2:26]2>>[NH2:32][C:30]1[CH:31]=[C:23]([F:22])[CH:24]=[C:25]2[C:29]=1[NH:28][C:27](=[O:33])[C:26]2=[CH:20][C:3]1[NH:4][C:5]2[CH2:10][CH2:9][N:8]([CH2:11][CH2:12][N:13]3[CH2:14][CH2:15][O:16][CH2:17][CH2:18]3)[C:7](=[O:19])[C:6]=2[C:2]=1[CH3:1]
Reactant: Cc1c(C=O)[nH]c2c1C(=O)N(CCN1CCOCC1)CC2
Reactant: Nc1cc(F)cc2c1NC(=O)C2
Product: Cc1c(C=C2C(=O)Nc3c(N)cc(F)cc32)[nH]c2c1C(=O)N(CCN1CCOCC1)CC2
Yield: 43.8 %

Procedure:
The title compound was prepared under the same conditions as described in Example 15 with 3-methyl-5-(2-morpholin-4-yl-ethyl)-4-oxo-4,5,6,7-tetrahydro-1H-pyrrolo[3,2-c]pyridine-2-carbaldehyde and 5-fluoro-7-amino-1,3-dihydro-indol-2-one as starting materials to give 2-(7-amino-5-fluoro-2-oxo-1,2-dihydro-indol-3-ylidenemethyl)-3-methyl-5-(2-morpholin-4-yl-ethyl)-1,5,6,7-tetrahydro-pyrrolo[3,2-c]pyridin-4-one (35 mg, 43.8%) as a red solid.
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6]([CH2:18][C:19]3[CH:24]=[CH:23][CH:22]=[C:21]([Cl:25])[CH:20]=3)([CH:12]3[CH2:17][CH2:16][CH2:15][NH:14][CH2:13]3)[C:7](=[O:11])[NH:8]2)=[CH:4][CH:3]=1.C(N(CC)CC)C.[Cl:33][C:34]1[CH:39]=[CH:38][C:37]([N:40]=[C:41]=[O:42])=[CH:36][CH:35]=1>ClCCl>[Cl:33][C:34]1[CH:39]=[CH:38][C:37]([NH:40][C:41]([N:14]2[CH2:15][CH2:16][CH2:17][CH:12]([C:6]3([CH2:18][C:19]4[CH:24]=[CH:23][CH:22]=[C:21]([Cl:25])[CH:20]=4)[C:5]4[C:9](=[CH:10][C:2]([Cl:1])=[CH:3][CH:4]=4)[NH:8][C:7]3=[O:11])[CH2:13]2)=[O:42])=[CH:36][CH:35]=1
Reactant: O=C1Nc2cc(Cl)ccc2C1(Cc1cccc(Cl)c1)C1CCCNC1
Reactant: O=C=Nc1ccc(Cl)cc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: O=C(Nc1ccc(Cl)cc1)N1CCCC(C2(Cc3cccc(Cl)c3)C(=O)Nc3cc(Cl)ccc32)C1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a solution of rac-6-chloro-3-(3-chloro-benzyl)-3-piperidin-3-yl-1,3-dihydro-indol-2-one (50 mg, 0.13 mmol) (from Example 25a supra) in dichloromethane (3 mL) was added triethylamine (20 mg, 0.19 mmol) (Aldrich), followed by the addition of 4-chloro-phenyl isocyanate (24 mg, 0.16 mmol) (Aldrich). The mixture was stirred at room temperature for 30 mins. The mixture was partitioned between dichlormethane and water. The aqueous layer was extracted with dichlormethane. The combined organic layers were washed with water, brine, dried over Na2SO4 and concentrated. The residue was purified by chromatography to give rac-3-[6-chloro-3-(3-chloro-benzyl)-2-oxo-2,3-dihydro-1H-indol-3-yl]-piperidine-1-carboxylic acid (4-chloro-phenyl)-amide as a white solid. (Yield 42 mg, 60%).
Reaction SMILES: [O:1]=[C:2]1[N:6]([C:7]2[CH:12]=[CH:11][C:10]([CH:13]3[CH2:18][CH2:17][NH:16][CH2:15][CH2:14]3)=[CH:9][CH:8]=2)[CH2:5][C@H:4]([CH2:19][NH:20][C:21](=[O:23])[CH3:22])[O:3]1.[C:24]([O:27][CH2:28][C:29](Cl)=[O:30])(=[O:26])[CH3:25].C(OCC(Cl)=O)C1C=CC=CC=1>>[O:1]=[C:2]1[N:6]([C:7]2[CH:12]=[CH:11][C:10]([C:13]3[CH2:14][CH2:15][N:16]([C:29](=[O:30])[CH2:28][O:27][C:24](=[O:26])[CH3:25])[CH2:17][CH:18]=3)=[CH:9][CH:8]=2)[CH2:5][C@H:4]([CH2:19][NH:20][C:21](=[O:23])[CH3:22])[O:3]1
Reactant: CC(=O)NC[C@H]1CN(c2ccc(C3CCNCC3)cc2)C(=O)O1
Reactant: CC(=O)OCC(=O)Cl
Agent: O=C(Cl)COCc1ccccc1
Product: CC(=O)NC[C@H]1CN(c2ccc(C3=CCN(C(=O)COC(C)=O)CC3)cc2)C(=O)O1

Procedure:
Following the general procedure of EXAMPLE 18, and making non-critical variations but substituting (S)-(−)-N-[[2-oxo-3-[4-(3,6-dihydro-2H-pyridin-4-yl)phenyl]-5-oxazolidinyl]methyl]acetamide (EXAMPLE 58) for (S)-(−)-N-[[2-oxo-3-[4-(4-piperidinyl)phenyl]-5-oxazolidinyl]methyl]acetamide and acetoxyacetyl chloride for benzyloxyacetyl chloride, the title compound is obtained, HRMS calcd for C21H25N3O6: 415.1743. Found: 415.1752.
Reaction SMILES: [F:1][C:2]([F:14])([F:13])[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[C:9](=[O:12])[CH2:10][CH3:11].[Br:15]Br>C(Cl)(Cl)(Cl)Cl>[Br:15][CH:10]([CH3:11])[C:9]([C:4]1[CH:5]=[CH:6][CH:7]=[CH:8][C:3]=1[C:2]([F:13])([F:14])[F:1])=[O:12]
Reactant: BrBr
Reactant: CCC(=O)c1ccccc1C(F)(F)F
Solvent: ClC(Cl)(Cl)Cl
Product: CC(Br)C(=O)c1ccccc1C(F)(F)F
Reaction time: 2 h
Yield: 94.9 %

Procedure:
To a solution of 2′-trifluoromethyl-propiophenone (10 g, 48 mmol) in carbon tetrachloride (50 ml) was added a solution of bromine (2.72 mL, 52.8 mmol) in carbon tetrachloride (20 mL) dropwise. After the addition was complete, stirring was continued for another 2 h. The solution was washed with satd NaHCO3 and water, dried (anhyd Na2SO4) and concentrated under reduced pressure to give 2-bromo-1-(2-trifluoromethyl-phenyl)-propan-1-one as an oil (12.8 g, 95%), which was used in the next step without purification. 1H-NMR (CDCl3): δ 7.73 (m, 2H), 7.58-7.67 (m, 2H), 4.96 (q, 1H), 1.90 (d, 3H). To a solution of 2′-trifluoromethyl-propiophenone (10 g, 48 mmol) in carbon tetrachloride (50 ml) was added a solution of bromine (2.72 mL, 52.8 mmol) in carbon tetrachloride (20 m To a suspension of NaH (60%, 2.88 g, 72 mmol) in anhyd THF (200 mL) was added methyl cyanoacetate (4.5 mL, 50 mmol). After this mixture was stirred for 3 h at 20° C., a solution of 2-bromo-1-(2-trifluoromethyl-phenyl)-propan-1-one (13.5 g, 48 mmol) was added and the mixture was stirred overnight at 20° C. The mixture was quenched with water and the organic layer was separated. The aqueous layer was extracted with EtOAc. The combined extracts were washed with brine, dried (anhyd Na2SO4) and concentrated under reduced pressure to afford the title compound as an oil (13.3 g, 93%), which was used in the next step without purification. MS (ES): 300 (MH+).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:16])[CH2:5][C:6]1[CH:11]=[CH:10][CH:9]=[C:8]([CH2:12][C:13](O)=O)[CH:7]=1)[CH3:2].[NH2:17][C:18]1[CH:23]=[CH:22][C:21]([F:24])=[C:20]([F:25])[C:19]=1[SH:26]>>[F:24][C:21]1[CH:22]=[CH:23][C:18]2[N:17]=[C:13]([CH2:12][C:8]3[CH:7]=[C:6]([CH2:5][C:4]([O:3][CH2:1][CH3:2])=[O:16])[CH:11]=[CH:10][CH:9]=3)[S:26][C:19]=2[C:20]=1[F:25]
Reactant: CCOC(=O)Cc1cccc(CC(=O)O)c1
Reactant: Nc1ccc(F)c(F)c1S
Product: CCOC(=O)Cc1cccc(Cc2nc3ccc(F)c(F)c3s2)c1
Yield: 51.8 %

Procedure:
The procedure of Example 16-i) was repeated using 1,3-phenylene diacetic acid monoethyl ester (2.87 g, 10.5 mmol) and 2-amino-5,6-difluorothiophenol (2.0 g, 11.7 mmol) to obtain ethyl 3-[(6,7-difluorobenzothiazol-2-yl)methyl]phenylacetate (1.89 g, 44%) as a pale yellow oil.
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][CH2:11][CH:10]([NH:14][C:15]2[CH:24]=[CH:23][CH:22]=[C:21]3[C:16]=2[CH:17]=[CH:18][N:19]=[CH:20]3)[CH2:9]1)=O)(C)(C)C.Cl.CCOC(C)=O.C(Cl)[Cl:33].CO>CCOC(C)=O>[ClH:33].[CH:20]1[C:21]2[C:16](=[C:15]([NH:14][CH:10]3[CH2:11][CH2:12][CH2:13][NH:8][CH2:9]3)[CH:24]=[CH:23][CH:22]=2)[CH:17]=[CH:18][N:19]=1
Reactant: CC(C)(C)OC(=O)N1CCCC(Nc2cccc3cnccc23)C1
Reactant: ClCCl
Agent: Cl
Solvent: CCOC(C)=O
Solvent: CO
Product: c1cc(NC2CCCNC2)c2ccncc2c1
Temperature: 25 °C
Reaction time: 2.5 h
Yield: 100 %

Procedure:
To a solution of 3-(isoquinolin-5-ylamino)-piperidine-1-carboxylic acid tert-butyl ester (80 g, 0.244 mol) in EtOAc (1000 mL) was added HCl-EtOAc (1000 mL) at room temperature. The mixture was stirred at room temperature for 2.5 hours. TLC (methylene chloride:methanol=10:1) showed the reaction was complete. The reaction mixture was filtered. The filtered cake was dried under vacuum to give the title compound (66 g, 100%) as a yellow solid.
Reaction SMILES: [CH3:1][N:2]1[C@H:11]2[C@@:6]([CH3:17])([C:7]3[CH:15]=[CH:14][C:13](Br)=[CH:12][C:8]=3[CH2:9][CH2:10]2)[CH2:5][CH2:4][C:3]1=[O:18].C([Sn](CCCC)(CCCC)[C:24]1[S:25][CH:26]=[CH:27][CH:28]=1)CCC>C(#N)C>[CH3:1][N:2]1[C@H:11]2[C@@:6]([CH3:17])([C:7]3[CH:15]=[CH:14][C:13]([C:24]4[S:25][CH:26]=[CH:27][CH:28]=4)=[CH:12][C:8]=3[CH2:9][CH2:10]2)[CH2:5][CH2:4][C:3]1=[O:18]
Reactant: CN1C(=O)CC[C@]2(C)c3ccc(Br)cc3CC[C@@H]12
Reactant: CCCC[Sn](CCCC)(CCCC)c1cccs1
Solvent: CC#N
Product: CN1C(=O)CC[C@]2(C)c3ccc(-c4cccs4)cc3CC[C@@H]12
Yield: 33.1 %

Procedure:
Five hundred mg of (4aR)-(10bR)-4,10b-dimethyl-8-bromo-1,2,3,4,4a,5,6,10b-octahydrobenzo[f]quinolin-3-one was combined with 730 mg of 2-(tri-n-butylstannyl)thiophene and 100 mg of bis(triphenylphosphene)palladium chloride in 6 mL of acetonitrile in a screw capped sealable tube. The mixture was flushed with argon for 5 minutes, capped and heated at 90° for 20 h. Upon cooling, the mixture was filtered and the filtrate was concentrated in vacuum. The residue was purified by chromatography on a silica gel column, eluting with ethyl acetate, and the isolated product was recrystallized from ethyl acetate/hexane/chloroform to obtain 167 mg of the desired product. mp 193°-195°. FDMS 311.