Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:17]3[C:12](=[CH:13][C:14]([F:20])=[C:15](F)[C:16]=3[F:18])[C:11](=[O:21])[C:10]([C:22]([OH:24])=[O:23])=[CH:9]2)=[CH:4][CH:3]=1.[NH2:25][C:26]1[CH:34]=[CH:33][CH:32]=[C:31]2[C:27]=1[CH2:28][NH:29][CH2:30]2.C1CCN2C(=NCCC2)CC1>CN(C=O)C>[NH2:25][C:26]1[CH:34]=[CH:33][CH:32]=[C:31]2[C:27]=1[CH2:28][N:29]([C:15]1[C:16]([F:18])=[C:17]3[C:12]([C:11](=[O:21])[C:10]([C:22]([OH:24])=[O:23])=[CH:9][N:8]3[C:5]3[CH:6]=[CH:7][C:2]([F:1])=[CH:3][CH:4]=3)=[CH:13][C:14]=1[F:20])[CH2:30]2
Reactant: O=C(O)c1cn(-c2ccc(F)cc2)c2c(F)c(F)c(F)cc2c1=O
Reactant: Nc1cccc2c1CNC2
Solvent: CN(C)C=O
Solvent: C1CCC2=NCCCN2CC1
Product: Nc1cccc2c1CN(c1c(F)cc3c(=O)c(C(=O)O)cn(-c4ccc(F)cc4)c3c1F)C2
Yield: 43.1 %

Procedure:
170 mg of 1-(4-fluorophenyl)-6,7,8-trifluoro-1,4- dihydro-4-oxoquinoline-3-carboxylic acid, 81 mg of 4-amino isoindoline, 137 mg of DBU, and 1.5 ml of anhydrous DMF were processed in the same manner as in Example 20 to produce 98 mg of the target compound.
Reaction SMILES: O1CCN(S(F)(F)[F:8])CC1.[C:11]1([C:17]2([C:34]3[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=3)[C@H:25]3[C@H:21]([CH2:22][N:23]([C:26]([O:28][C:29]([CH3:32])([CH3:31])[CH3:30])=[O:27])[CH2:24]3)[C@@H:20](O)[CH2:19][CH2:18]2)[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1>ClCCl>[C:11]1([C:17]2([C:34]3[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=3)[CH2:18][CH2:19][C@@H:20]([F:8])[C@@H:21]3[C@H:25]2[CH2:24][N:23]([C:26]([O:28][C:29]([CH3:32])([CH3:31])[CH3:30])=[O:27])[CH2:22]3)[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1
Reactant: CC(C)(C)OC(=O)N1C[C@H]2[C@@H](C1)C(c1ccccc1)(c1ccccc1)CC[C@@H]2O
Reactant: FS(F)(F)N1CCOCC1
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N1C[C@@H]2[C@H](F)CCC(c3ccccc3)(c3ccccc3)[C@@H]2C1
Reaction time: 4 h

Procedure:
A solution of 3.5 cm3 of morpholinosulphur trifluoride in 50 cm3 of dichloromethane is added to a solution, cooled to +5° C., of 9.4 g of (3aR,4S,7aR)-7,7-diphenyl-2-tert-butyloxycarbonyl-4-perhydroisoindolol in 250 cm3 of dry dichloromethane. The reaction mixture is stirred for 4 hours at +5° C. and then diluted with 300 cm3 of dichloromethane, washed with 250 cm3 of an aqueous solution of sodium hydrogen carbonate, dried over magnesium sulphate, filtered and concentrated to dryness under reduced pressure (2.7 kPa). The residue is chromatographed on a silica gel column (particle size 0.04-0.06 mm, diameter 3.5 cm, height 42 cm), eluting under a nitrogen pressure of 0.5 bar with a cyclohexane and ethyl acetate mixture (90/10 by volume) and collecting fractions of 120 cm3. Fractions 13 to 17 are pooled and concentrated to dryness under reduced pressure (2.7 kPa). The residue is crystallized from cyclohexane. 2.55 g of (3aR,7R,7aR)-4,4-diphenyl-7-fluoro-2-tert-butyloxycarbonylperhydroisoindole are obtained in the form of white crystals; melting point 202° C.
Reaction SMILES: [CH3:1][S:2]([C:5]1[CH:6]=[CH:7][C:8]([O:11][C:12]2[CH:13]=[C:14]3[C:18](=[C:19]([O:21][CH:22]4[CH2:27][CH2:26][O:25][CH2:24][CH2:23]4)[CH:20]=2)[NH:17][C:16]([C:28]([O:30]CC)=[O:29])=[CH:15]3)=[N:9][CH:10]=1)(=[O:4])=[O:3].[OH-].[Na+].O1CCCC1>C(O)C>[CH3:1][S:2]([C:5]1[CH:6]=[CH:7][C:8]([O:11][C:12]2[CH:13]=[C:14]3[C:18](=[C:19]([O:21][CH:22]4[CH2:23][CH2:24][O:25][CH2:26][CH2:27]4)[CH:20]=2)[NH:17][C:16]([C:28]([OH:30])=[O:29])=[CH:15]3)=[N:9][CH:10]=1)(=[O:4])=[O:3]
Reactant: CCOC(=O)c1cc2cc(Oc3ccc(S(C)(=O)=O)cn3)cc(OC3CCOCC3)c2[nH]1
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: C1CCOC1
Product: CS(=O)(=O)c1ccc(Oc2cc(OC3CCOCC3)c3[nH]c(C(=O)O)cc3c2)nc1
Temperature: 50 °C
Reaction time: 0.83 h
Yield: 109.1 %

Procedure:
A mixture of ethyl 5-{[5-(methylsulfonyl)pyridin-2-yl]oxy}-7-(tetrahydro-2H-pyran-4-yloxy)-1H-indole-2-carboxylate (4.0 g), 1M aqueous sodium hydroxide solution (13 mL), tetrahydrofuran (20 mL), and ethanol (20 mL) was stirred at 50° C. for 50 min. The reaction solution was concentrated under reduced pressure, and the residue was dissolved in water. 1M Hydrochloric acid (13.2 mL) was added and the precipitated yellow solid was collected by filtration. The obtained solid was washed with water and diethyl ether to give the title compound (4.1 g, yield 100%) as a yellow solid.
Reaction SMILES: [Cl:1][C:2]1[C:10]([C:11]#[N:12])=[CH:9][CH:8]=[C:7]2[C:3]=1[CH:4]=[C:5]([CH:13]([F:15])[F:14])[NH:6]2.Br[CH2:17][C:18]#[N:19].C([O-])([O-])=O.[Cs+].[Cs+]>>[Cl:1][C:2]1[C:10]([C:11]#[N:12])=[CH:9][CH:8]=[C:7]2[C:3]=1[CH:4]=[C:5]([CH:13]([F:14])[F:15])[N:6]2[CH2:17][C:18]#[N:19]
Reactant: N#CCBr
Reactant: N#Cc1ccc2[nH]c(C(F)F)cc2c1Cl
Agent: O=C([O-])[O-]
Agent: [Cs+]
Product: N#CCn1c(C(F)F)cc2c(Cl)c(C#N)ccc21

Procedure:
Synthesized as described in Example 4 using 4-chloro-2-(difluoromethyl)-1H-indole-5-carbonitrile, bromoacetonitrile (2 eq) and Cs2CO3 (2 eq): MS (ES) m/z 264 (M−1).
Reaction SMILES: P(=O)(O)(O)O.[Cl-].[Na+].[CH2:8]([OH:30])[C@H:9]1[O:14][C@H:13]([O:15][C@H]2[C@H](O)[C@@H](O)[C@H](O)O[C@@H]2CO)[C@H:12]([OH:27])[C@@H:11]([OH:28])[C@@H:10]1[OH:29]>O>[O:15]=[CH:13][C@@H:12]([C@H:11]([C@@H:10]([C@@H:9]([CH2:8][OH:30])[OH:14])[OH:29])[OH:28])[OH:27]
Reactant: OC[C@H]1O[C@H](O[C@H]2[C@H](O)[C@@H](O)[C@H](O)O[C@@H]2CO)[C@H](O)[C@@H](O)[C@@H]1O
Agent: O=P(O)(O)O
Agent: [Cl-]
Agent: [Na+]
Solvent: O
Product: O=C[C@H](O)[C@@H](O)[C@H](O)[C@H](O)CO

Procedure:
To 1 ml of a buffer solution (pH 6.5) containing 20 mM phosphoric acid and 6.7 mM sodium chloride, 300 mg of maltose (Wako Pure Chemical Industries Ltd. product) were dissolved, and then, 10 mg of α-amylase (saccharification type, Seikakagaku Corporation product by using Bacillus subtilis) and 1 mg of ε-poly-L-lysine hydrochloride were added and dissolved. To this solution, 103 cells of Bacillus stearothermophilus were inoculated and then, were allowed to react at 60° C. for 24 hrs. After the reaction was completed, the reaction solution was heated in a boiled water to stop the enzyme reaction, and filtered through a 0.45 μm membrane filter. The quantity of glucose in the filtrate was measured by a high speed liquid chromatographic method. The quantity of glucose thus obtained was 260 mg.
Reaction SMILES: [CH3:1][N:2]1[CH2:7][CH2:6][C:5](=[C:8]2[C:14]3[CH:15]=[C:16]([C:19]([OH:21])=[O:20])[CH:17]=[CH:18][C:13]=3[CH:12]=[CH:11][C:10]3[CH:22]=[CH:23][CH:24]=[CH:25][C:9]2=3)[CH2:4][CH2:3]1.B(F)(F)F.[CH3:30][CH2:31]OCC>C(O)C>[CH3:1][N:2]1[CH2:7][CH2:6][C:5](=[C:8]2[C:14]3[CH:15]=[C:16]([C:19]([O:21][CH2:30][CH3:31])=[O:20])[CH:17]=[CH:18][C:13]=3[CH:12]=[CH:11][C:10]3[CH:22]=[CH:23][CH:24]=[CH:25][C:9]2=3)[CH2:4][CH2:3]1
Reactant: CN1CCC(=C2c3ccccc3C=Cc3ccc(C(=O)O)cc32)CC1
Reactant: CCOCC
Agent: FB(F)F
Solvent: CCO
Product: CCOC(=O)c1ccc2c(c1)C(=C1CCN(C)CC1)c1ccccc1C=C2

Procedure:
Racemic 5-(1-methyl-4-piperidylidene)-5H-dibenzo[a,d]cycloheptene-3-carboxylic acid (0.03 mole) and an equal molar amount of boron trifluoride etherate in 60 ml of absolute ethanol was refluxed overnight. The solution was evaporated to dryness and the residue was partitioned between ether and a saturated aqueous solution of sodium bicarbonate. The ether was separated and dried over MgSO4. The resulting ethyl ester, crystallized from acetonitrile, had m.p. 102°-103° C.
Reaction SMILES: [NH2:1][N:2]1[CH:6]=[CH:5][C:4]([Br:7])=[C:3]1[C:8]([NH:10][C:11]1[CH:16]=[C:15]([Cl:17])[CH:14]=[C:13]([Cl:18])[CH:12]=1)=[O:9].CCN(C(C)C)C(C)C.[C:28]([O:32][C:33]([NH:35][C@@H:36]([CH3:40])[C:37](O)=[O:38])=[O:34])([CH3:31])([CH3:30])[CH3:29].C(P1(=O)OP(CCC)(=O)OP(CCC)(=O)O1)CC>CN(C=O)C.O>[Br:7][C:4]1[CH:5]=[CH:6][N:2]([NH:1][C:37](=[O:38])[C@@H:36]([NH:35][C:33](=[O:34])[O:32][C:28]([CH3:30])([CH3:29])[CH3:31])[CH3:40])[C:3]=1[C:8](=[O:9])[NH:10][C:11]1[CH:16]=[C:15]([Cl:17])[CH:14]=[C:13]([Cl:18])[CH:12]=1
Reactant: C[C@H](NC(=O)OC(C)(C)C)C(=O)O
Reactant: Nn1ccc(Br)c1C(=O)Nc1cc(Cl)cc(Cl)c1
Agent: CCCP1(=O)OP(=O)(CCC)OP(=O)(CCC)O1
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Solvent: O
Product: C[C@H](NC(=O)OC(C)(C)C)C(=O)Nn1ccc(Br)c1C(=O)Nc1cc(Cl)cc(Cl)c1
Temperature: 0 °C
Reaction time: 8 h
Yield: 47.1 %

Procedure:
To a solution of 1.58 g (4.53 mmol) of 1-amino-3-bromo-N-(3,5-dichlorophenyl)-1H-pyrrole-2-carboxamide in 30 mL DMF were added 2.60 mL (14.93 mmol) of DIEA and 0.94 g (4.97 mmol) of (S)-2-(tert-butoxycarbonylamino)propanoic acid. The solution was cooled to 0° C. and 4 mL of T3P® (50% solution in DMF, 6.78 mmol) were added dropwise. The mixture was stirred at room temperature overnight and an additional 2.60 mL (14.93 mmol) of DIEA, 0.94 g (4.97 mmol) of (S)-2-(tert-butoxycarbonylamino)propanoic acid and 4 mL of T3P® (50% solution in DMF, 6.78 mmol) were added. The stirring was kept for 24 hours more and water was added to the reaction mixture. The product was extracted three times with ethyl acetate and the combined organic extracts were washed with water and brine, dried over magnesium sulphate, filtered and the solvents evaporated in vacuum. The product was purified by flash chromatography (0% to 50% hexane/AcOEt) to give 1.11 g (47% yield) of the title compound as a beige solid.
Reaction SMILES: [CH3:1][NH2:2].[NH2:3][C:4]1[C:5]([F:29])=[CH:6][C:7]([F:28])=[C:8]([N:10]2[C:19]3[C:14](=[CH:15][C:16]([F:23])=[C:17](F)[C:18]=3[O:20][CH3:21])[C:13](=[O:24])[C:12]([C:25]([OH:27])=[O:26])=[CH:11]2)[CH:9]=1>N1C=CC=CC=1>[NH2:3][C:4]1[C:5]([F:29])=[CH:6][C:7]([F:28])=[C:8]([N:10]2[C:19]3[C:14](=[CH:15][C:16]([F:23])=[C:17]([NH:2][CH3:1])[C:18]=3[O:20][CH3:21])[C:13](=[O:24])[C:12]([C:25]([OH:27])=[O:26])=[CH:11]2)[CH:9]=1
Reactant: COc1c(F)c(F)cc2c(=O)c(C(=O)O)cn(-c3cc(N)c(F)cc3F)c12
Reactant: CN
Solvent: c1ccncc1
Product: CNc1c(F)cc2c(=O)c(C(=O)O)cn(-c3cc(N)c(F)cc3F)c2c1OC
Temperature: 50 °C
Reaction time: 25 h

Procedure:
Pyridine (200 mg) and a 40% aqueous solution (200 mg) of methylamine were added to 1-(5-amino-2,4-difluorophenyl)-6,7-difluoro-8-methoxy-4-oxo-1,4-dihydroquinoline-3-carboxylic acid (100 mg), and the mixture was stirred at 50° C. for 25 hours. The solvent was distilled off, and ethanol was added to the residue. The resultant mixture was stirred, and solids were collected by filtration and washed with ethanol and diethyl ether to obtain the title compound (33 mg) as a yellow powder.
Reaction SMILES: Cl[C:2]1[N:10]=[C:9]2[C:5]([N:6]=[CH:7][NH:8]2)=[C:4]([N:11]2[CH2:16][CH2:15][O:14][CH2:13][CH2:12]2)[N:3]=1.[CH3:17][C@H:18]1[O:23][C@@H:22]([CH3:24])[CH2:21][NH:20][CH2:19]1.CCN(C(C)C)C(C)C.O>CC(N(C)C)=O>[CH3:24][C@@H:22]1[O:23][C@H:18]([CH3:17])[CH2:19][N:20]([C:2]2[N:10]=[C:9]3[C:5]([N:6]=[CH:7][NH:8]3)=[C:4]([N:11]3[CH2:16][CH2:15][O:14][CH2:13][CH2:12]3)[N:3]=2)[CH2:21]1
Reactant: Clc1nc(N2CCOCC2)c2nc[nH]c2n1
Reactant: C[C@@H]1CNC[C@H](C)O1
Solvent: O
Solvent: CCN(C(C)C)C(C)C
Solvent: CC(=O)N(C)C
Product: C[C@@H]1CN(c2nc(N3CCOCC3)c3nc[nH]c3n2)C[C@H](C)O1
Temperature: 130 °C
Reaction time: 40 h
Yield: 98.3 %

Procedure:
To the solution of 2-chloro-6-morpholin-4-yl-9H-purine (1.5 g, 6.26 mmol) in DMA (5 mL) was added cis-2,6 dimethylmorpholine (1.42 g, 12.52 mmol), followed by DIPEA (2.1 mL, 12.02 mmol). The mixture was stirred at 130° C. for 40 hours. Upon completion of the reaction, the solution was poured into water. The aqueous layer was extracted with EtOAc three times. The combined organic layers were dried over Na2SO4, filtered and the solvent was removed under reduced pressure to provide 2-((2S,6R)-2,6-dimethyl-morpholin-4-yl)-6-morpholin-4-yl-9H-purine (1.96 g, 98%) as a yellow solid. LC/MS analysis method 7, mass (ES+) m/z 319.2 1HNMR (DMSO-d6): 12.37 (1H, s), 7.76 (1H, s), 4.38 (2H, d), 4.12 (4H, brs), 3.69 (4H, m), 3.54 (2H, m), 2.40 (2H, m), 1.14 (6H, d).
Reaction SMILES: [CH3:1][N:2]([CH3:32])[C:3]([C:5]1[N:26]([CH:27]2[CH2:31][CH2:30][CH2:29][CH2:28]2)[C:8]2[N:9]=[C:10]([NH:13][C:14]3[CH:19]=[CH:18][C:17]([N:20]4[CH2:25][CH2:24][NH:23][CH2:22][CH2:21]4)=[CH:16][N:15]=3)[N:11]=[CH:12][C:7]=2[CH:6]=1)=[O:4].Br[CH2:34][CH:35]([CH3:37])[CH3:36]>>[CH3:1][N:2]([CH3:32])[C:3]([C:5]1[N:26]([CH:27]2[CH2:31][CH2:30][CH2:29][CH2:28]2)[C:8]2[N:9]=[C:10]([NH:13][C:14]3[CH:19]=[CH:18][C:17]([N:20]4[CH2:21][CH2:22][N:23]([CH2:34][CH:35]([CH3:37])[CH3:36])[CH2:24][CH2:25]4)=[CH:16][N:15]=3)[N:11]=[CH:12][C:7]=2[CH:6]=1)=[O:4]
Reactant: CN(C)C(=O)c1cc2cnc(Nc3ccc(N4CCNCC4)cn3)nc2n1C1CCCC1
Reactant: CC(C)CBr
Product: CC(C)CN1CCN(c2ccc(Nc3ncc4cc(C(=O)N(C)C)n(C5CCCC5)c4n3)nc2)CC1
Yield: 39.9 %

Procedure:
Following General Procedure D, 7-cyclopentyl-2-(5-piperazin-1-yl-pyridin-2-ylamino)-7H-pyrrolo[2,3-d]pyrimidine-6-carboxylic acid dimethylamide (100 mg, 0.230 mmol) and 1-bromo-2-methyl propane (94 mg, 0.690 mmol) gave 7-cyclopentyl-2-[5-(4-isobutyl-piperazin-1-yl)-pyridin-2-ylamino]-7H-pyrrolo[2,3-d]pyrimidine-6-carboxylic acid dimethylamide (45 mg, 41%). MS (ESI) m/z 491.3 (M+H)+
Reaction SMILES: [OH:1][C:2]1[N:6]([CH:7]2[CH2:9][CH2:8]2)[N:5]=[CH:4][C:3]=1[C:10]([C:12]1[CH:17]=[CH:16][C:15]([S:18]([CH3:21])(=[O:20])=[O:19])=[C:14]([CH:22]=[CH2:23])[C:13]=1[O:24][CH3:25])=[O:11].O=S(Cl)Cl.[CH3:30]S(C1C=CC(C(O)=O)=C(OC)C=1C=C)(=O)=O.C1(N2C=CC(=O)N2)CC1.C([O-])([O-])=O.[K+].[K+]>C1(C)C=CC=CC=1.COCCOC>[CH3:30][O:1][C:2]1[N:6]([CH:7]2[CH2:8][CH2:9]2)[N:5]=[CH:4][C:3]=1[C:10]([C:12]1[CH:17]=[CH:16][C:15]([S:18]([CH3:21])(=[O:20])=[O:19])=[C:14]([CH:22]=[CH2:23])[C:13]=1[O:24][CH3:25])=[O:11]
Reactant: C=Cc1c(S(C)(=O)=O)ccc(C(=O)c2cnn(C3CC3)c2O)c1OC
Reactant: C=Cc1c(S(C)(=O)=O)ccc(C(=O)O)c1OC
Agent: O=C([O-])[O-]
Agent: O=c1ccn(C2CC2)[nH]1
Agent: [K+]
Solvent: Cc1ccccc1
Solvent: O=S(Cl)Cl
Solvent: COCCOC
Product: C=Cc1c(S(C)(=O)=O)ccc(C(=O)c2cnn(C3CC3)c2OC)c1OC
Temperature: 25 °C
Reaction time: 8 h

Procedure:
5-Hydroxy-1-cyclopropyl-1H-pyrazol-4-yl-(4-methylsulfonyl-2-methoxy-3-vinylphenyl)methanone SOCl2 (1.2 g, 10 mmol) was added to a solution of 4-methylsulfonyl-2-methoxy-3-vinylbenzoic acid (1.6 g, 6 mmol) in toluene (60 ml), and the mixture was heated at reflux for 2 h. The mixture was then concentrated, and the product was added to a solution of N-cyclopropylpyrazolone (6 mmol), K2CO3 (1.6 g, 11.6 mmol) in DME (30 ml), and the mixture was stirred at RT overnight. The mixture was subsequently heated at reflux for 2 h and concentrated, and the residue was dissolved in H2O. The H2O phase was extracted 3× with CH2Cl2, and the combined organic phases were dried over MgSO4 and concentrated.
Reaction SMILES: [C:1]([O:5][C:6]([CH:8]1[CH2:13][CH2:12][C:11]([CH:14]2[C:22]3[C:17](=[CH:18][C:19]([Cl:23])=[CH:20][CH:21]=3)[NH:16][C:15]2=[O:24])=[CH:10][NH:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[Cl:25][C:26]1[CH:27]=[C:28]([CH:31]=[CH:32][CH:33]=1)[CH2:29]Br.[I-].[K+].C(=O)([O-])[O-].[K+].[K+]>CC(C)=O.C(OCC)(=O)C>[C:1]([O:5][C:6]([CH:8]1[CH2:13][CH2:12][C:11]([C:14]2([CH2:29][C:28]3[CH:31]=[CH:32][CH:33]=[C:26]([Cl:25])[CH:27]=3)[C:22]3[C:17](=[CH:18][C:19]([Cl:23])=[CH:20][CH:21]=3)[NH:16][C:15]2=[O:24])=[CH:10][NH:9]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: Clc1cccc(CBr)c1
Reactant: CC(C)(C)OC(=O)C1CCC(C2C(=O)Nc3cc(Cl)ccc32)=CN1
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CC(C)=O
Product: CC(C)(C)OC(=O)C1CCC(C2(Cc3cccc(Cl)c3)C(=O)Nc3cc(Cl)ccc32)=CN1
Temperature: 60 °C

Procedure:
A mixture of 5-[6-chloro-2-oxo-2,3-dihydro-1H-indol-3-yl]-3,4-dihydro-2H-pyridine-carboxylic acid tert-butyl ester (1.4 g, 4.00 mmol) (from Example 20a supra), 3-chlorobenzyl bromide (0.97 g, 4.67 mmol) (Aldrich), potassium iodide (0.79 g, 4.73 mmol) and potassium carbonate (1.2 g, 8.60 mmol) in acetone (30 mL) was heated at 60° C. for 12 hours in a capped pressure tube. After cooling, mixture was diluted with ethyl acetate and washed with water and brine. Aqueous layers were back washed with ethyl acetate. The organic layers were combined, dried over Na2SO4 and concentrated. The residue was purified by chromatography (ethyl acetate-dichloromethane, 1:9, V/V) to give rac-5-[6-chloro-3-(3-chloro-benzyl)-2-oxo-2,3-dihydro-1H-indol-3-yl]-3,4-dihydro-2H-pyridine-carboxylic acid tert-butyl ester as a brown solid. (Yield 1.5 g, 79%).
Reaction SMILES: [CH3:1][C:2]1[N:3]([C:12]2[CH:17]=[CH:16][CH:15]=[C:14]([C:18]([F:21])([F:20])[F:19])[CH:13]=2)[C:4](=[O:11])[C:5]([C:8](O)=[O:9])=[N:6][CH:7]=1.[CH3:22][N:23](C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)[CH3:24].F[P-](F)(F)(F)(F)F.CCN(CC)CC.Cl.CNC>CN(C=O)C.O>[CH3:22][N:23]([CH3:24])[C:8]([C:5]1[C:4](=[O:11])[N:3]([C:12]2[CH:17]=[CH:16][CH:15]=[C:14]([C:18]([F:20])([F:21])[F:19])[CH:13]=2)[C:2]([CH3:1])=[CH:7][N:6]=1)=[O:9]
Reactant: Cc1cnc(C(=O)O)c(=O)n1-c1cccc(C(F)(F)F)c1
Reactant: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: CNC
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: O
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: Cc1cnc(C(=O)N(C)C)c(=O)n1-c1cccc(C(F)(F)F)c1
Reaction time: 2 h

Procedure:
A mixture of 5-methyl-3-oxo-4-[3-(trifluoromethyl)phenyl]-3,4-dihydropyrazine-2-carboxylic acid (0.21 g, 0.7 mmol), HATU (0.266 g, 0.7 mmol) and Et3N (0.293 g, 2.9 mmol) in DMF (2 ml) was reacted with dimethylamine HCl. After 2 h, the reaction mixture was diluted with water and extracted with ethyl acetate (3×5 ml). The organic phase was dried (MgSO4), filtered and evaporated. No further purification was performed.
Reaction SMILES: Cl[C:2]1[N:9]=[CH:8][C:7]([F:10])=[CH:6][C:3]=1[C:4]#[N:5].O.[NH2:12][NH2:13]>C(O)CCC>[F:10][C:7]1[CH:6]=[C:3]2[C:4]([NH2:5])=[N:13][NH:12][C:2]2=[N:9][CH:8]=1
Reactant: N#Cc1cc(F)cnc1Cl
Reactant: NN
Solvent: O
Solvent: CCCCO
Product: Nc1n[nH]c2ncc(F)cc12
Temperature: 25 °C
Yield: 89.9 %

Procedure:
To a solution of compound 4 (50 g, 321.7 mmol) in 1-butanol (1 L) was added hydrazine monohydrate (150 mL, 3.2 mol), and the mixture was refluxed for 4 h. The mixture was cooled to room temperature and concentrated. The precipitate was successively washed on filter with water (2×) and Et2O (2×) and dried in vacuo overnight to give compound 5 (44 g, 88%) as a yellow solid. 1H NMR (DMSO-d6, 300 MHz): δ 5.53 (s, 2H); 7.94 (dd, 1H); 8.35 (dd, 1H); 12.02 (s, 1H).
Reaction SMILES: [N:1]1([C:6]2[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=2[C:12]#[N:13])[CH:5]=[N:4][CH:3]=[N:2]1>[Pd].C(O)C>[N:1]1([C:6]2[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=2[CH2:12][NH2:13])[CH:5]=[N:4][CH:3]=[N:2]1
Reactant: N#Cc1ccccc1-n1cncn1
Agent: [Pd]
Solvent: CCO
Product: NCc1ccccc1-n1cncn1

Procedure:
A solution of 2-(1,2,4-triazol-1-yl)cyanobenzene (508 mg, 2.99 mmol) and 25% by weight of palladium on carbon, 10% catalyst (134 mg) in ethanol (75 ml) was placed on a PARR Hydrogenation Apparatus under a hydrogen atmosphere at 55 psi. overnight. The mixture was filtered through celite and concentrated to give 2-(1,2,4-triazol-1-yl)-benzylamine; 1H NMR (CD3OD) δ 8.80 (s, 1H), 8.22 (s, 1H), 7.64–7.43 (m, 4H), 3.66 (s, 2H).
Reaction SMILES: [NH2:1][C:2]1[NH:6][N:5]=[C:4]([NH:7][C:8]2[CH:13]=[CH:12][CH:11]=[C:10]([Cl:14])[CH:9]=2)[C:3]=1[C:15]#[N:16].[F:17][C:18]([F:28])([F:27])[C:19]1[CH:24]=[CH:23][C:22]([CH:25]=O)=[CH:21][CH:20]=1>CCO.N1CCCCC1>[Cl:14][C:10]1[CH:9]=[C:8]([NH:7][C:4]2[C:3]([C:15]#[N:16])=[C:2]([N:1]=[CH:25][C:22]3[CH:21]=[CH:20][C:19]([C:18]([F:17])([F:27])[F:28])=[CH:24][CH:23]=3)[NH:6][N:5]=2)[CH:13]=[CH:12][CH:11]=1
Reactant: O=Cc1ccc(C(F)(F)F)cc1
Reactant: N#Cc1c(Nc2cccc(Cl)c2)n[nH]c1N
Solvent: CCO
Solvent: C1CCNCC1
Product: N#Cc1c(Nc2cccc(Cl)c2)n[nH]c1N=Cc1ccc(C(F)(F)F)cc1
Yield: 42 %

Procedure:
5-amino-3-((3-chlorophenyl)amino)-1H-pyrazole-4-carbonitrile (100 mg) was suspended in EtOH (4 mL) and alpha,alpha,alpha-Trifluoro-p-tolualdehyde (1 eq.) and piperidine (1 drop) were added. Stirred at reflux until intermediate was absent (HPLC). After reaction was complete (18 hrs) it was brought to room temperature and filtered to obtain A15 as a yellow powder. Powder was washed with EtOH. Product was allowed to dry under vacuum for 1 hr (71 mg, 42% yield).
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([CH2:7][CH2:8][C:9]([OH:11])=[O:10])[CH:2]=1.[CH:12](N=C=NC(C)C)(C)C.C([O-])(O)=O.[Na+]>C(Cl)Cl.CO.CN(C1C=CN=CC=1)C>[N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([CH2:7][CH2:8][C:9]([O:11][CH3:12])=[O:10])[CH:2]=1
Reactant: O=C(O)CCc1cccnc1
Reactant: CC(C)N=C=NC(C)C
Agent: CN(C)c1ccncc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: CO
Product: COC(=O)CCc1cccnc1
Temperature: 23 °C
Reaction time: 2 h
Yield: 99.1 %

Procedure:
To a solution of 3-(3-pyridinyl)propanoic acid (2.50 g, 16.5 mmol) in CH2Cl2 (110 mL) and MeOH (1 mL) was added DMAP (0.010 g, 0.082 mmol) and diisopropylcarbodiimide (4.17 g, 33.1 mmol). The reaction was stirred for 2 hours at 23° C. then saturated aqueous NaHCO3 (100 mL) was added. The mixture was extracted with CH2Cl2 (100 mL) and the combined extracts were dried over Na2SO4, filtered, and evaporated in vacuo. The residue was purified by flash chromatography on silica gel (elution with 60% EtOAc/hexanes) to provide 2.70 g (99%) of the desired product. MS (DCI/NH3) m/z 166 (M+H)30 .
Reaction SMILES: [C:1]([OH:9])(=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl.[C:11]1([CH:17]2[O:22][CH2:21][CH2:20][NH:19][CH2:18]2)[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1.C([N:25](CC)CC)C.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>C(#N)C.ClCCl>[NH2:25][C:5]1[CH:6]=[CH:7][C:2]([C:1]([N:19]2[CH2:20][CH2:21][O:22][CH:17]([C:11]3[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=3)[CH2:18]2)=[O:9])=[CH:3][CH:4]=1
Reactant: c1ccc(C2CNCCO2)cc1
Reactant: CCN(CC)CC
Reactant: O=C(O)c1ccccc1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CC#N
Solvent: ClCCl
Product: Nc1ccc(C(=O)N2CCOC(c3ccccc3)C2)cc1
Temperature: 25 °C
Reaction time: 16 h
Yield: 85 %

Procedure:
To a stirred suspension of benzoic acid (160 mg, 1 mmol) and 2-phenylmorpholine hydrochloride (300 mg, 1.5 mmol) in acetonitrile (10 ml) was added triethylamine (0.4 ml, 3 mmol) followed by HATU and the reaction mixture was stirred at room temperature for 16 hours. The reaction was diluted with dichloromethane (25 ml) and washed with sodium hydrogen carbonate (25 ml, saturated solution). The organics were collected, dried over magnesium sulfate and concentrated in vacuo. The residue was purified by flash chromatography on silica gel, eluting with ethylacetate to afford the title compound as a clear oil (240 mg, 84% yield). HPLC retention time 5.05 min. Mass spectrum (ES+) m/z 283 (M+H).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:6]=[CH:7][C:8]=1[O:9][C:10]1[C:19]2[C:14](=[CH:15][C:16]([O:22][CH2:23][CH2:24][CH2:25][N:26]3[CH2:31][CH2:30][O:29][CH2:28][CH2:27]3)=[C:17]([O:20][CH3:21])[CH:18]=2)[N:13]=[CH:12][CH:11]=1)[NH2:5].C(N(CC)CC)C.ClC(Cl)(O[C:43](=[O:49])OC(Cl)(Cl)Cl)Cl.[F:51][C:52]1[CH:53]=[C:54]([CH:59]([NH2:61])[CH3:60])[CH:55]=[CH:56][C:57]=1[F:58]>C(Cl)(Cl)Cl>[F:51][C:52]1[CH:53]=[C:54]([CH:59]([NH:61][C:43]([NH:5][C:4]2[CH:6]=[CH:7][C:8]([O:9][C:10]3[C:19]4[C:14](=[CH:15][C:16]([O:22][CH2:23][CH2:24][CH2:25][N:26]5[CH2:31][CH2:30][O:29][CH2:28][CH2:27]5)=[C:17]([O:20][CH3:21])[CH:18]=4)[N:13]=[CH:12][CH:11]=3)=[C:2]([F:1])[CH:3]=2)=[O:49])[CH3:60])[CH:55]=[CH:56][C:57]=1[F:58]
Reactant: CC(N)c1ccc(F)c(F)c1
Reactant: COc1cc2c(Oc3ccc(N)cc3F)ccnc2cc1OCCCN1CCOCC1
Reactant: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Solvent: ClC(Cl)Cl
Solvent: CCN(CC)CC
Product: COc1cc2c(Oc3ccc(NC(=O)NC(C)c4ccc(F)c(F)c4)cc3F)ccnc2cc1OCCCN1CCOCC1
Temperature: 25 °C
Reaction time: 0.42 h
Yield: 34.3 %

Procedure:
3-Fluoro-4-{[6-methoxy-7-(3-morpholinopropoxy)-4-quinolyl]oxy}-aniline (30 mg) was dissolved in chloroform (3 ml) and triethylamine (0.3 ml) to prepare a solution. A solution of triphosgene (17 mg) in chloroform (0.2 ml) was then added to the solution, and the mixture was stirred at room temperature for 25 min. Next, a solution of 1-(3,4-difluorophenyl)ethylamine (14 mg) in chloroform (0.2 ml) was added thereto, and the mixture was stirred at room temperature for 5 hr. The stirred mixture was purified by chromatography on silica gel using chloroform/methanol for development to give the title compound (12 mg, yield 29%).