Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][CH2:4][CH:3]([CH2:7][NH:8][C:9]([C:11]2[S:15][C:14]([C:16]3[CH:21]=[CH:20][C:19]([Cl:22])=[CH:18][CH:17]=3)=[N:13][C:12]=2[CH3:23])=[O:10])[CH2:2]1.[CH3:24][O:25][C:26]([C:28]1[CH:29]=[C:30](OB(O)O)[CH:31]=[CH:32][CH:33]=1)=[O:27].C(N(CC)CC)C>ClCCl.C([O-])(=O)C.[Cu+2].C([O-])(=O)C>[Cl:22][C:19]1[CH:18]=[CH:17][C:16]([C:14]2[S:15][C:11]([C:9]([NH:8][CH2:7][CH:3]3[CH2:4][CH2:5][CH2:6][N:1]([C:32]4[CH:33]=[C:28]([CH:29]=[CH:30][CH:31]=4)[C:26]([O:25][CH3:24])=[O:27])[CH2:2]3)=[O:10])=[C:12]([CH3:23])[N:13]=2)=[CH:21][CH:20]=1
Reactant: Cc1nc(-c2ccc(Cl)cc2)sc1C(=O)NCC1CCCNC1
Reactant: COC(=O)c1cccc(OB(O)O)c1
Agent: [Cu+2]
Agent: CC(=O)[O-]
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COC(=O)c1cccc(N2CCCC(CNC(=O)c3sc(-c4ccc(Cl)cc4)nc3C)C2)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 37 %

Procedure:
N-(Piperidin-3-yl methyl)-2-(4-chlorophenyl)-4-methylthiazole-5-carboxamide (172 mg, 0.492 mmol), 3-(methoxycarbonyl)phenylboric acid (177 mg, 0.984 mmol) and molecular sieves 4 Å (400 mg) were suspended in dichloromethane (10 mL). To this suspension, copper (II) acetate (188 mg, 0.984 mmol) and triethylamine (0.344 mL, 2.46 mmol) were added and the mixture was stirred at room temperature for 8 hours. Subsequently, the reaction mixture was filtered through Celite, followed by addition of a saturated aqueous sodium bicarbonate solution. The mixture was then extracted with ethyl acetate and the extract washed with brine, followed by drying over magnesium sulfate and evaporation of the solvent. Purification of the residue by silica gel column chromatography (hexane:ethyl acetate=20:1->2:1) gave 88.2 mg (37%) of the desired compound as a colorless powder.
Reaction SMILES: C([O:8][C:9]1[CH:14]=[CH:13][C:12]([CH2:15][CH2:16][NH2:17])=[CH:11][C:10]=1[O:18][CH3:19])C1C=CC=CC=1.[H][H]>[Pd].O1CCCC1>[NH2:17][CH2:16][CH2:15][C:12]1[CH:13]=[CH:14][C:9]([OH:8])=[C:10]([O:18][CH3:19])[CH:11]=1
Reactant: COc1cc(CCN)ccc1OCc1ccccc1
Reactant: [H][H]
Agent: [Pd]
Solvent: C1CCOC1
Product: COc1cc(CCN)ccc1O

Procedure:
0.5 g of palladium on charcoal (10%) were added to 5 g (19.5 mmol) of 2-[4-(benzyloxy)-3-methoxyphenyl]ethylamine [cf.: Heterocycles, Vol. 28, 297-298 (1989)] in 100 ml of tetrahydrofuran and the mixture was hydrogenated under atmospheric pressure. After the uptake of hydrogen had ended, the mixture was filtered and the filtrate was freed from the solvent.
Reaction SMILES: C1C2C3C=CC=CC=3CCCCC=2C(CO)=CC=1.ClC(C(F)(F)F)=C[C@@H]1[C@H](C(Cl)=O)C1(C)C.[Cl:34][C:35]([C:62]([F:65])([F:64])[F:63])=[CH:36][C@@H:37]1[C@H:39]([C:40]([O:42][CH2:43][C:44]2[C:49]3[CH2:50][CH2:51][CH2:52][CH2:53][C:54]4[CH:59]=[CH:58][CH:57]=[CH:56][C:55]=4[C:48]=3[CH:47]=[CH:46][CH:45]=2)=[O:41])[C:38]1([CH3:61])[CH3:60]>>[Cl:34][C:35]([C:62]([F:63])([F:64])[F:65])=[CH:36][CH:37]1[CH:39]([C:40]([O:42][CH2:43][C:44]2[C:49]3[CH2:50][CH2:51][CH2:52][CH2:53][C:54]4[CH:59]=[CH:58][CH:57]=[CH:56][C:55]=4[C:48]=3[CH:47]=[CH:46][CH:45]=2)=[O:41])[C:38]1([CH3:61])[CH3:60]
Reactant: CC1(C)[C@H](C=C(Cl)C(F)(F)F)[C@@H]1C(=O)OCc1cccc2c1CCCCc1ccccc1-2
Agent: CC1(C)[C@H](C=C(Cl)C(F)(F)F)[C@@H]1C(=O)Cl
Agent: OCc1cccc2c1CCCCc1ccccc1-2
Product: CC1(C)C(C=C(Cl)C(F)(F)F)C1C(=O)OCc1cccc2c1CCCCc1ccccc1-2

Procedure:
In the manner of Example I, but substituting 5,6,7,8-tetrahydrodibenzo[a,c]cyclooctene-4-methanol and cis-3-(2-chloro-3,3,3-trifluoropropenyl)-2,2-dimethylcyclopropanecarbonyl chloride, (5,6,7,8-tetrahydrodibenzo[a,c]cycloocten-4-yl)-methyl cis-3-(2-chloro-3,3,3-trifluoropropenyl)-2,2-dimethylcyclopropanecarboxylate was prepared.
Reaction SMILES: [CH3:1][C:2]1[C:7](=[O:8])[C@@H:6]([OH:9])[CH2:5][C:4]([CH3:11])([CH3:10])[C:3]=1[C:12]#[C:13][C:14]([CH3:18])=[CH:15][CH:16]=[O:17].[O:19]([CH2:26][C:27](Cl)=[O:28])[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1.O>N1C=CC=CC=1>[CH3:1][C:2]1[C:7](=[O:8])[C@@H:6]([O:9][C:27](=[O:28])[CH2:26][O:19][C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[CH2:5][C:4]([CH3:10])([CH3:11])[C:3]=1[C:12]#[C:13][C:14]([CH3:18])=[CH:15][CH:16]=[O:17]
Reactant: O=C(Cl)COc1ccccc1
Reactant: CC(C#CC1=C(C)C(=O)[C@@H](O)CC1(C)C)=CC=O
Solvent: O
Solvent: c1ccncc1
Product: CC(C#CC1=C(C)C(=O)[C@@H](OC(=O)COc2ccccc2)CC1(C)C)=CC=O
Temperature: 0 °C
Reaction time: 1 h

Procedure:
13.5 g of the ketoaldehyde of formula XII obtained in Example 20 are dissolved in 100 ml of pyridine. 10 g of phenoxyacetic acid chloride are added dropwise to the solution at 0° C. The mixture is stirred for 1 hour at 0° C. and then poured into water and extracted with diethyl ether. The ether extract is washed with 5% strength aqueous sulfuric acid and then with water. The 5-[2,6,6-trimethyl-3-oxo-4(S)-(phenoxyacetoxy)-cyclohex-1-en-1-yl]-3-methyl-penta-2-en-4-yn-1-al (XIV) isolated from the extract is further reacted as follows:
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6]([NH:9][C:10]2[N:15]=[C:14]([NH:16][CH2:17][CH2:18][CH3:19])[C:13]([C:20]([NH:22][C:23]3[CH:24]=[C:25]([NH:29][C:30](=[O:42])[C@@H:31]([N:33]([CH3:41])[C:34](=[O:40])[O:35][C:36]([CH3:39])([CH3:38])[CH3:37])[CH3:32])[CH:26]=[CH:27][CH:28]=3)=[O:21])=[CH:12][N:11]=2)=[CH:5][CH:4]=1)#[N:2].[OH2:43]>C(O)C.CS(C)=O.[OH-].[Na+].OO>[C:1]([C:3]1[CH:8]=[CH:7][C:6]([NH:9][C:10]2[N:15]=[C:14]([NH:16][CH2:17][CH2:18][CH3:19])[C:13]([C:20]([NH:22][C:23]3[CH:24]=[C:25]([NH:29][C:30](=[O:42])[C@@H:31]([N:33]([CH3:41])[C:34](=[O:40])[O:35][C:36]([CH3:39])([CH3:38])[CH3:37])[CH3:32])[CH:26]=[CH:27][CH:28]=3)=[O:21])=[CH:12][N:11]=2)=[CH:5][CH:4]=1)(=[O:43])[NH2:2]
Reactant: CCCNc1nc(Nc2ccc(C#N)cc2)ncc1C(=O)Nc1cccc(NC(=O)[C@H](C)N(C)C(=O)OC(C)(C)C)c1
Reactant: O
Agent: OO
Agent: [Na+]
Agent: [OH-]
Solvent: CS(C)=O
Solvent: CCO
Product: CCCNc1nc(Nc2ccc(C(N)=O)cc2)ncc1C(=O)Nc1cccc(NC(=O)[C@H](C)N(C)C(=O)OC(C)(C)C)c1
Reaction time: 1 h

Procedure:
To a solution of (S)-tert-butyl (1-((3-(2-((4-cyanophenyl)amino)-4-(propylamino)pyrimidine-5-carboxamido)phenyl)amino)-1-oxopropan-2-yl)(methyl)carbamate (C8, 173 mg) in ethanol (4 mL) and dimethyl sulfoxide (2 mL), 2.0 mol/L aqueous sodium hydroxide (0.45 mL) and 35% aqueous hydrogen peroxide (87 μL) were added at room temperature, and the mixture was stirred at the same temperature for 1 hour. To the reaction mixture, water (15 mL) was added. The solid matter was taken by filtration, washed successively with water and ethyl acetate, and then dried under reduced pressure to obtain (S)-tert-butyl (1-((3-(2-((4-carbamoylphenyl)amino)-4-(propylamino)pyrimidine-5-carboxamido)phenyl)amino)-1-oxopropan-2-yl)(methyl)carbamate (C7, 102 mg) as white solid.
Reaction SMILES: Cl[S:2]([C:5]1[CH:14]=[CH:13][C:12]2[NH:11][C:10](=[O:15])[C:9]3[NH:16][CH:17]=[C:18]([C:19]([OH:21])=[O:20])[C:8]=3[C:7]=2[CH:6]=1)(=[O:4])=[O:3].[Cl:22][C:23]1[CH:24]=[C:25]([CH:27]=[CH:28][CH:29]=1)[NH2:26]>>[Cl:22][C:23]1[CH:24]=[C:25]([NH:26][S:2]([C:5]2[CH:14]=[CH:13][C:12]3[NH:11][C:10](=[O:15])[C:9]4[NH:16][CH:17]=[CH:18][C:8]=4[C:7]=3[CH:6]=2)(=[O:3])=[O:4])[CH:27]=[CH:28][CH:29]=1.[CH2:18]([C:19]([O-:21])=[O:20])[CH3:17]
Reactant: O=C(O)c1c[nH]c2c(=O)[nH]c3ccc(S(=O)(=O)Cl)cc3c12
Reactant: Nc1cccc(Cl)c1
Product: CCC(=O)[O-]
Product: O=c1[nH]c2ccc(S(=O)(=O)Nc3cccc(Cl)c3)cc2c2cc[nH]c12
Yield: 14.6 %

Procedure:
This compound is prepared according to synthesis 25, from 150 mg (0.46 mmol) of 8-chlorosulfonyl-4-oxo-4,5-dihydro-3H-pyrrolo[2,3-c]quinoline-1-carboxylic acid (synthesis 2) and 59 μL (0.55 mmol) of 3-chloro-aniline. After purification by chromatography on silica (eluent dichloromethane/methanol 95/5) then trituration in diethyl ether, 15 mg (7%) of 8-(3-chlorophenylsulfamoyl)-4-oxo-4,5-dihydro-3H-pyrrolo[2,3-c]quinoline-1-ethyl carboxylate is obtained in the form of a white solid.
Reaction SMILES: [I:1][C:2]1[CH:3]=[C:4]([OH:8])[CH:5]=[CH:6][CH:7]=1.CN[C:11]1[N:16]=[C:15]([CH2:17][CH2:18]O)[CH:14]=[CH:13][CH:12]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[N:39]([C:46](OCC)=O)=NC(OCC)=O>C1COCC1>[I:1][C:2]1[CH:3]=[C:4]([CH:5]=[CH:6][CH:7]=1)[O:8][CH2:18][CH2:17][C:15]1[N:16]=[C:11]([CH2:46][NH2:39])[CH:12]=[CH:13][CH:14]=1
Reactant: CNc1cccc(CCO)n1
Reactant: CCOC(=O)N=NC(=O)OCC
Reactant: Oc1cccc(I)c1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: NCc1cccc(CCOc2cccc(I)c2)n1
Temperature: 25 °C
Reaction time: 8 h
Yield: 73.7 %

Procedure:
To a stirring solution of 3-iodophenol (1.11 g, 5.1 mmol), 2-[6-(Methylamino)-2-pyridyl]ethan-1-ol (700 mg, 4.6 mmol), triphenylphosphine (1.3 g, 5.1 mmol), and THF (20 ml), was added diethyl azodicarboxylate (0.80 ml, 5.1 mmol) at 0° C. After stirring overnight under argon at room temperature, the solvent was evaporated under vacuum. The crude product was chromatographed over silica gel to yield 1.2 g (74%) of {6-[2-(3-Iodophenoxy)ethyl](2-pyridyl)}methylamine. NMR 1H Cl3CD δ: 7.40 (t, 1H, J=8.0 Hz), 7.26 (m, 2H), 6.96 (t, 1H, J=8.0 Hz), 6.87 (m, 1H), 6.52 (d, 1H, J=8.0 Hz), 6.25 (d, 1H, J=4.0 Hz), 4.51 (br s, 1H), 4.29 (t, 2H, J=6.8 Hz), 3.07 (t, 2H, J=6.8 Hz), 2.90 (d, 3H, J=8Hz).
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[N:4][CH:5]=[C:6]([CH:16]=1)[C:7]([NH:9][CH:10]1[CH2:15][CH2:14][NH:13][CH2:12][CH2:11]1)=[O:8].[CH2:17]([O:19][C:20]1[CH:21]=[C:22]([CH:25]=[CH:26][C:27]=1[OH:28])[CH:23]=O)[CH3:18]>>[CH2:17]([O:19][C:20]1[CH:21]=[C:22]([CH:25]=[CH:26][C:27]=1[OH:28])[CH2:23][N:13]1[CH2:12][CH2:11][CH:10]([NH:9][C:7](=[O:8])[C:6]2[CH:16]=[C:2]([CH3:1])[CH:3]=[N:4][CH:5]=2)[CH2:15][CH2:14]1)[CH3:18]
Reactant: Cc1cncc(C(=O)NC2CCNCC2)c1
Reactant: CCOc1cc(C=O)ccc1O
Product: CCOc1cc(CN2CCC(NC(=O)c3cncc(C)c3)CC2)ccc1O
Yield: 100 %

Procedure:
The title compound (37 mg, 100%) was prepared analogously to example 30 from 5-methyl-N-(piperidin-4-yl)-nicotinamide and 3-ethoxy-4-hydroxy-benzaldehyde. MS: 370.5 (MH+).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][NH:11][CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[Cl:14][C:15]1[N:19](Cl)[S:18][NH:17][CH:16]=1>CN(C)C=O.C(OCC)C>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]([C:16]2[C:15]([Cl:14])=[N:19][S:18][N:17]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: ClC1=CNSN1Cl
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Solvent: CCOCC
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N1CCN(c2nsnc2Cl)CC1
Temperature: 25 °C
Reaction time: 24 h

Procedure:
Piperazine-1-carboxylic acid tert-butyl ester (10 g, 0.054 m) was dissolved in anhydrous dimethylformamide (DMF, 50 mL) under nitrogen in a single-necked round bottomed flask. The clear solution was placed in a preheated oil bath (50 C-60 C). 4,5-Dichloro-[1,2,5]thiadiazole (5.0 mL, 0.054 m) was added and the reaction mixture was allowed to stir for 24 h. A yellow solution containing a white solid was observed. After cooling to room temperature, the mixture was diluted with an equal volume of anhydrous ethyl ether and stirred for 5 minutes. The solid was removed by filtration and the yellow filtrate was concentrated under aspirator vacuum to remove ether and then evaporated under oil pump vacuum to remove DMF. The yellow residue was dried at oil pump vacuum overnight to give 9.91 g of 4-(4-chloro-[1,2,5]thiadiazol-3-yl)piperazine-1-carboxylic acid tert-butyl ester. Two recrystallizations of crude product from hexane gave white crystals: mp 83-86° C.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[C@@H:9]([CH2:13][CH2:14]O)[NH:8][CH2:7][CH2:6]2.[F:16][C:17]([F:22])([F:21])[C:18]([NH2:20])=[O:19].C(Br)(Br)(Br)[Br:24].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>ClCCl>[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[C@@H:9]([CH2:13][CH2:14][Br:24])[NH:8][CH2:7][CH2:6]2.[F:16][C:17]([F:22])([F:21])[C:18]([NH2:20])=[O:19]
Reactant: COc1ccc2c(c1)CCN[C@@H]2CCO
Reactant: BrC(Br)(Br)Br
Agent: NC(=O)C(F)(F)F
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Product: COc1ccc2c(c1)CCN[C@@H]2CCBr
Yield: 93.4 %

Procedure:
To a solution of 6-methoxy-1-(R)-(2-hydroxyethyl)-3,4-dihydro-1H-isoquinoline-trifluoroacetamide (330mg, 1.09 mmol) obtained in step (b) of Example 190 and carbon tetrabromide (542 mg, 1.63 mmol) in dichloromethane (5 ml) was added gradually triphenyl phosphine (343 mg, 1.31 mmol) with stirring under cooling in a water bath. The resulting mixture was further stirred at room temperature, and after confirming the disappearance of the starting material by thin layer chromatography, the reaction mixture was evaporated in vacuo. The residue obtained was purified by chromatography on a silica gel column using a mixed solvent of hexane and ethyl acetate (80:20) as the eluent to afford the title compound (390 mg, yield: 98%) as a colorless oil.
Reaction SMILES: [OH:1][CH:2]([CH2:15][N:16]1[CH:20]=[CH:19][N:18]=[C:17]1[N+:21]([O-:23])=[O:22])[CH2:3][N:4]1C(=O)C2C(=CC=CC=2)C1=O.NN>C(O)C.O>[NH2:4][CH2:3][CH:2]([OH:1])[CH2:15][N:16]1[CH:20]=[CH:19][N:18]=[C:17]1[N+:21]([O-:23])=[O:22]
Reactant: O=C1c2ccccc2C(=O)N1CC(O)Cn1ccnc1[N+](=O)[O-]
Agent: NN
Solvent: O
Solvent: CCO
Product: NCC(O)Cn1ccnc1[N+](=O)[O-]
Yield: 83.3 %

Procedure:
Compound 8 (5 g, 15.8 mmol) was added to a solution of pure hydrazine (608 mg, 18.97 mmol, 1.2 equivalent) in 50 ml of ethyl alcohol and 4 ml of water. The mixture was refluxed for 2 h and then held at room temperature. The white solid (phthalhydrazide) was filtered. The filtrate was concentrated and the residue was redistributed in ethyl acetate and water. The water phase was extracted two times with ethyl acetate and the combined ethyl acetate phase was dried to give a yellowish solid as the HCl salt (9, 2.45 g, 70% yield). 1H NMR (D2O, δppm)(HCl salt): 2.91 (dd, 1H, NH2—CHa, J=13.2 Hz, 9.9 Hz), 3.21 (dd, 1H, NH2—CHb, J=13.2 Hz, 2.7 Hz), 4.19 (tt, 1H, HO—CH—, J=9.0 Hz, 3.0 Hz), 4.28 (dd, 1H, imidazole-CHa—, J=13.8 Hz, 8.7 Hz), 4.57 (dd, 1H, imidazole-CHb—, J=13.8 Hz, 2.7 Hz), 7.09 (d, 1H, J=0.9 Hz, —CH═), 7.35 (d, 1H, J=0.9 Hz, —CH═). 13C NMR (D2O, δppm): 42.06, 53.00, 66.86, 128.06, 128.92, 144.73.
Reaction SMILES: [Cl:1][C:2]1[N:3]=[N:4][C:5]([NH:8][NH2:9])=[CH:6][CH:7]=1.[C:10](O)(=O)[CH2:11][OH:12].CC1C=CC(S(O)(=O)=O)=CC=1.O>C1(C)C=CC=CC=1>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]2[N:4]([C:10]([CH2:11][OH:12])=[N:9][N:8]=2)[N:3]=1
Reactant: O=C(O)CO
Reactant: NNc1ccc(Cl)nn1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: O
Solvent: Cc1ccccc1
Product: OCc1nnc2ccc(Cl)nn12

Procedure:
A mixture of 3-chloro-6-hydrazinopyridazine (1.44 g, 9.96 mmol), glycolic acid (0.76 g, 10 mmol) and p-TsOH.H2O (2.37 g, 12.4 mmol) in toluene was refluxed overnight. Some oil formed at the bottom of the flask. LC-MS of this oil showed the desired product was formed. Toluene was decanted off, and the oil residue was suspended in water (10 mL), then basified with 3N aq. NaOH to pH=10, the resulting off-white solid was collected, and dried to give the title compound. LC-MS (ES+): 185/187 (3/1) [MH+]. 1H NMR (CDCl3): δ=2.96 (br s, 1H, —OH), 5.25 (s, 2H), 7.17 (d, J=9.6 Hz, 1H), 8.11 (d, J=9.6 Hz, 1H).
Reaction SMILES: [N:1]1[CH:6]=[CH:5][C:4]([C:7]2[C:15]3[C:10](=[CH:11][CH:12]=[C:13]([C:16]([NH2:18])=[O:17])[CH:14]=3)[N:9](C(C3C=CC=CC=3)(C3C=CC=CC=3)C3C=CC=CC=3)[N:8]=2)=[CH:3][CH:2]=1.C([SiH](CC)CC)C.[C:45]([OH:51])([C:47]([F:50])([F:49])[F:48])=[O:46]>CN(C=O)C>[C:45]([OH:51])([C:47]([F:50])([F:49])[F:48])=[O:46].[N:1]1[CH:6]=[CH:5][C:4]([C:7]2[C:15]3[C:10](=[CH:11][CH:12]=[C:13]([C:16]([NH2:18])=[O:17])[CH:14]=3)[NH:9][N:8]=2)=[CH:3][CH:2]=1
Reactant: NC(=O)c1ccc2c(c1)c(-c1ccncc1)nn2C(c1ccccc1)(c1ccccc1)c1ccccc1
Agent: CC[SiH](CC)CC
Solvent: O=C(O)C(F)(F)F
Solvent: CN(C)C=O
Product: NC(=O)c1ccc2[nH]nc(-c3ccncc3)c2c1

Procedure:
N—((R)-1-((S or R)-2-(Dimethylamino)-1-(2-fluorophenyl)-2-oxoethyl)piperidin-3-yl)-3-(pyridin-4-yl)-1-trityl-1H-indazole-5-carboxamide (53 mg, 0.071 mmol) was stirred in TFA (0.5 mL) at room temperature for 30 minutes. triethylsilane (0.015 mL, 0.093 mmol) was added and the reaction mixture diluted with DMF (1 mL). The solution was purified by reverse-phase, mass-triggered prep-HPLC. The product fraction was lyophilized to give the bis TFA salt of N—((R)-1-((S or R)-2-(dimethylamino)-1-(2-fluorophenyl)-2-oxoethyl)piperidin-3-yl)-3-(pyridin-4-yl)-1H-indazole-5-carboxamide as a white solid.
Reaction SMILES: [NH2:1][C:2]1[CH:11]=[C:10]([NH2:12])[CH:9]=[CH:8][C:3]=1[C:4]([O:6][CH3:7])=[O:5].P(Cl)(Cl)Cl.[C:17]([OH:26])(=O)[C:18]1[C:19](=[CH:21][CH:22]=[CH:23][CH:24]=1)[OH:20]>N1C=CC=CC=1>[C:17]([NH:1][C:2]1[CH:11]=[C:10]([NH:12][C:17](=[O:26])[C:18]2[C:19](=[CH:21][CH:22]=[CH:23][CH:24]=2)[OH:20])[CH:9]=[CH:8][C:3]=1[C:4]([O:6][CH3:7])=[O:5])(=[O:26])[C:18]1[C:19](=[CH:21][CH:22]=[CH:23][CH:24]=1)[OH:20]
Reactant: COC(=O)c1ccc(N)cc1N
Reactant: O=C(O)c1ccccc1O
Solvent: c1ccncc1
Solvent: ClP(Cl)Cl
Product: COC(=O)c1ccc(NC(=O)c2ccccc2O)cc1NC(=O)c1ccccc1O
Temperature: 90 °C
Reaction time: 1 h
Yield: 54.7 %

Procedure:
In 200 ml of pyridine was dissolved 8.3 g of methyl 2,4-diaminobenzoate, and to the solution was added a solution of 4.4 ml of phosphorus trichloride in 30 ml of pyridine under cooling with ice, followed by stirring at 50° to 70°C for one hour. To the mixture was added 21 g of salicylic acid was added, followed by heating at 90°C for three hours. After the cooling of the mixture by allowing it to stand, undissolved substances were filtered off and the filtrate was subjected to concentrate under reduced pressure. The concentrate was added to cold diluted hydrochloric acid to precipitate crystals. The crystals were recovered by filtration, washed with water and recrystallized from an acetone-dioxane-water mixture to obtain 11.1 g of methyl 2,4-bis(salicylamido)-benzoate having a melting point between 259° - 260°C. It was confirmed that the product was identical to that obtained in Example 7.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C:29]2[C:30]([C:35]#[N:36])=[CH:31][CH:32]=[CH:33][CH:34]=2)[CH:5]=[CH:6][C:7]=1[CH2:8][C:9]1[C:10](=[O:28])[N:11]([C@H:21]2[CH2:26][CH2:25][C@H:24]([OH:27])[CH2:23][CH2:22]2)[C:12]2[N:13]([N:18]=[CH:19][N:20]=2)[C:14]=1[CH2:15][CH2:16][CH3:17].[N+](=CC(OCC)=[O:41])=[N-].[C:45]1([CH3:51])[CH:50]=CC=C[CH:46]=1>C([O-])(=O)C.[Rh+]>[F:1][C:2]1[CH:3]=[C:4]([C:29]2[C:30]([C:35]#[N:36])=[CH:31][CH:32]=[CH:33][CH:34]=2)[CH:5]=[CH:6][C:7]=1[CH2:8][C:9]1[C:10](=[O:28])[N:11]([C@H:21]2[CH2:26][CH2:25][C@H:24]([O:27][CH2:46][C:45]([OH:41])([CH3:51])[CH3:50])[CH2:23][CH2:22]2)[C:12]2[N:13]([N:18]=[CH:19][N:20]=2)[C:14]=1[CH2:15][CH2:16][CH3:17]
Reactant: CCOC(=O)C=[N+]=[N-]
Reactant: CCCc1c(Cc2ccc(-c3ccccc3C#N)cc2F)c(=O)n([C@H]2CC[C@H](O)CC2)c2ncnn12
Reactant: Cc1ccccc1
Agent: [Rh+]
Agent: CC(=O)[O-]
Product: CCCc1c(Cc2ccc(-c3ccccc3C#N)cc2F)c(=O)n([C@H]2CC[C@H](OCC(C)(C)O)CC2)c2ncnn12
Reaction time: 1 h

Procedure:
To a mixture of 3′-fluoro-4′-{[4-(trans-4-hydroxycyclohexyl)-5-oxo-7-propyl-4,5-dihydro[1,2,4]triazolo[1,5-a]pyrimidin-6-yl]methyl}biphenyl-2-carbonitrile (0.71 g), rhodium(I) acetate (0.006 g) and toluene (30 mL) was added dropwise ethyl diazoacetate (0.71 mL) at 80° C., and the mixture was stirred at the same temperature for 1 hr. The reaction mixture was concentrated under reduced pressure, and the obtained residue was purified by silica gel column chromatography. The obtained residue was dissolved in tetrahydrofuran (15 mL), and methylmagnesium bromide (1.0 M tetrahydrofuran solution, 2.2 mL) was added at room temperature. The reaction mixture was stirred for 1 hr, 1 N hydrochloric acid was added, and the mixture was extracted with ethyl acetate. The obtained ethyl acetate layer was washed with saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure. The obtained residue was purified by silica gel column chromatography to give the title compound as a colorless solid (0.18 g, 22%).
Reaction SMILES: [CH3:1][C:2]([O:5][C:6](=[O:26])[NH:7][CH2:8][CH2:9][C@@H:10]([O:16][C:17]1[CH:22]=[C:21]([Cl:23])[CH:20]=[CH:19][C:18]=1[C:24]#[N:25])[C:11]1[S:12][CH:13]=[CH:14][N:15]=1)([CH3:4])[CH3:3].[H-].[Na+].IC.[C:31](OCC)(=O)C>O1CCCC1.CCCC(C)C>[CH3:4][C:2]([O:5][C:6](=[O:26])[N:7]([CH2:8][CH2:9][C@@H:10]([O:16][C:17]1[CH:22]=[C:21]([Cl:23])[CH:20]=[CH:19][C:18]=1[C:24]#[N:25])[C:11]1[S:12][CH:13]=[CH:14][N:15]=1)[CH3:31])([CH3:1])[CH3:3]
Reactant: CC(C)(C)OC(=O)NCC[C@@H](Oc1cc(Cl)ccc1C#N)c1nccs1
Reactant: CCOC(C)=O
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CI
Solvent: CCCC(C)C
Product: CN(CC[C@@H](Oc1cc(Cl)ccc1C#N)c1nccs1)C(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 98 %

Procedure:
To a solution of [(3R)-3-(5-chloro-2-cyanophenoxy)-3-(2-thiazolyl)propyl]-carbamic acid 1,1-dimethylethyl ester (200 mg, 0.51 mmol) in dry tetrahydrofuran (10 ml), was added sodium hydride (56 mg, 60% dispersion in oil, 1.41 mmol) and stirred at room temperature for 15 minutes. Iodomethane (1.325 g, 0.58 ml, 4.7 mmol) was added. The reaction was stirred at room temperature for 18 h, quenched with saturated ammonium chloride solution and partitioned between ethyl acetate and water. The combined extracts were washed with water (3×25 ml) and saturated brine solution, dried (magnesium sulphate) and concentrated in vacuo to leave a crude yellow gum. Flash chromatography (silica, 25% ethyl acetate in isohexane) afforded 175 mg of an opaque oil (98%).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([NH:14][C:15]2[CH:20]=[CH:19][C:18]([Cl:21])=[CH:17][C:16]=2[CH2:22][CH2:23][C:24]([O:26]CC)=[O:25])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[OH-].[Na+]>CO.O>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([NH:14][C:15]2[CH:20]=[CH:19][C:18]([Cl:21])=[CH:17][C:16]=2[CH2:22][CH2:23][C:24]([OH:26])=[O:25])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CCOC(=O)CCc1cc(Cl)ccc1NC1CCN(C(=O)OC(C)(C)C)CC1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: CC(C)(C)OC(=O)N1CCC(Nc2ccc(Cl)cc2CCC(=O)O)CC1
Temperature: 25 °C
Yield: 73.3 %

Procedure:
4-[4-Chloro-2-(2-ethoxycarbonyl-ethyl)-phenylamino]-piperidine-1-carboxylic acid tert-butyl ester (5.7 g, 13.9 mmol) was set stirring in MeOH (40 mL). A solution of NaOH (1.4 g, 34.7 mmol) in water (10 mL) was added and the mixture stirred at room temperature. After 3 h the mixture was acidified to pH 7 and MeOH was evaporated. The aqueous layer was extracted with CH2Cl2 (3×100 mL). The organics were combined, dried over Na2SO4 and concentrated to afford 3.9 g (73%) of the desired product. TLC (silica, 50% EtOAc/hexanes): Rf=0.4. MS (electrospray): exact mass calculated for C19H27ClN2O4, 382.17; m/z found, 381.1 [M31 −H].
Reaction SMILES: Cl.[CH2:2]([O:4][C:5](=[O:8])[CH2:6][NH2:7])[CH3:3].C(=O)(O)[O-].[Na+].[CH2:14]([C:16]1([C:24](Cl)=[O:25])[CH2:23][CH2:22][CH2:21][CH2:20][CH2:19][CH2:18][CH2:17]1)[CH3:15]>O.CCOCC>[CH2:2]([O:4][C:5](=[O:8])[CH2:6][NH:7][C:24]([C:16]1([CH2:14][CH3:15])[CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23]1)=[O:25])[CH3:3]
Reactant: CCC1(C(=O)Cl)CCCCCCC1
Reactant: CCOC(=O)CN
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: CCOCC
Product: CCOC(=O)CNC(=O)C1(CC)CCCCCCC1

Procedure:
Glycine ethyl ester hydrochloride (0.04 mole) and sodium bicarbonate (0.08 mole) were dissolved in water (50 ml.). 1-Ethylcyclooctanecarbonyl chloride (1 g. 0.04 mole) in ether (20 ml.) was then added with stirring. The ether layer was separated, dried (MgSO4) and concentrated. The residue was recrystallised from 40°-60° petroleum ether to give N-(1-ethylcyclooctanecarbonyl) glycine ethyl ester mp. 65°-7°