Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]1[C:6]([C:7]2[CH:16]=[C:15]3[C:10]([C:11]([NH:18][CH:19]([CH3:23])[CH2:20][O:21][CH3:22])=[C:12]([NH2:17])[CH:13]=[N:14]3)=[CH:9][C:8]=2[O:24][CH3:25])=[C:5]([CH3:26])[O:4][N:3]=1.N1C=CC=CC=1.[O:33]1[CH2:38][CH2:37][CH:36]([C:39](Cl)=[O:40])[CH2:35][CH2:34]1>C(Cl)Cl>[CH3:1][C:2]1[C:6]([C:7]2[CH:16]=[C:15]3[C:10]([C:11]([NH:18][CH:19]([CH3:23])[CH2:20][O:21][CH3:22])=[C:12]([NH:17][C:39]([CH:36]4[CH2:37][CH2:38][O:33][CH2:34][CH2:35]4)=[O:40])[CH:13]=[N:14]3)=[CH:9][C:8]=2[O:24][CH3:25])=[C:5]([CH3:26])[O:4][N:3]=1
Reactant: COCC(C)Nc1c(N)cnc2cc(-c3c(C)noc3C)c(OC)cc12
Reactant: O=C(Cl)C1CCOCC1
Solvent: ClCCl
Solvent: c1ccncc1
Product: COCC(C)Nc1c(NC(=O)C2CCOCC2)cnc2cc(-c3c(C)noc3C)c(OC)cc12
Temperature: 25 °C
Reaction time: 3.5 h
Yield: 100 %

Procedure:
A solution of 7-(3,5-dimethylisoxazol-4-yl)-6-methoxy-N4-(1-methoxypropan-2-yl)quinoline-3,4-diamine (for a preparation see Intermediate 2) (9.1 g) in DCM (300 ml) was treated with pyridine (30 ml) and tetrahydro-2H-pyran-4-carbonyl chloride (5.0 ml) and the solution stirred under nitrogen at ambient temperature for 3.5 h and then left standing overnight (ambient temperature, under nitrogen). The volatiles were evaporated in vacuo and the residue partitioned between DCM and water. The organic phase was washed with water ×2 and the combined aqueous extracted with DCM. The combined organic phases were washed with brine, dried (hydrophobic frit) and reduced to dryness in vacuo. The combined aqueous including the brine wash (˜pH4) was basified with solid sodium hydrogen carbonate and the aqueous extracted with DCM ×2. The organic fractions were dried (hydrophobic frit), combined with the previous material and reduced to dryness in vacuo to give a brown foam. This foam was further dried in vacuo, triturated with diethyl ether, the suspension chilled (ice/water bath) and the solid isolated by filtration. The solid was washed with a little diethyl ether and air-dried to give N-(7-(3,5-dimethylisoxazol-4-yl)-6-methoxy-4-((1-methoxypropan-2-yl)amino)quinolin-3-yl)tetrahydro-2H-pyran-4-carboxamide as a beige solid (11.95 g, 100%).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]([CH3:11])=[C:6]([CH:10]=1)[C:7]([OH:9])=O.C(Cl)(=O)C(Cl)=O.[C:18]1([O:24][CH3:25])[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1.[Al+3].[Cl-].[Cl-].[Cl-]>C(Cl)Cl.CN(C=O)C>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([CH3:11])=[C:6]([CH:10]=1)[C:7]([C:21]1[CH:22]=[CH:23][C:18]([O:24][CH3:25])=[CH:19][CH:20]=1)=[O:9]
Reactant: Cc1ccc(Br)cc1C(=O)O
Reactant: COc1ccccc1
Agent: O=C(Cl)C(=O)Cl
Agent: [Al+3]
Agent: [Cl-]
Solvent: CN(C)C=O
Solvent: ClCCl
Product: COc1ccc(C(=O)c2cc(Br)ccc2C)cc1
Reaction time: 6 h
Yield: 87.4 %

Procedure:
To a stirred suspension of 5-bromo-2-methylbenzoic acid (1.29 g, 6 mmol) in 12 mL of CH2Cl2 containing oxalyl chloride (8 mmol) was added 2 drops of DMF. Once the vigorous evolution of gas ceased, the reaction was stirred 6 hr prior to removal of the volatiles using a rotary evaporator. After dissolving the crude 5-bromo-2-methylbenzoyl chloride in 15 ml of CS2, the stirred mixture was cooled to 4° prior to adding anisole (0.7 g, 6.6 mmol) followed by AlCl3 (1.7 g, 12 mmol). The reaction, after warming to 20° over 1 hr, was stirred for 15 hr prior to quenching with 1N HCl. Subsequently, the suspension was diluted with 50 ml H2O and stirred until all solids were in solution. The mixture was extracted 3× with EtOAc. The combined organic extracts were washed 1× with 1N HCl, H2O, aq NaHCO3, and brine prior to drying over Na2SO4. After removal of the volatiles, the resulting tan solid was recrystallized from 95% EtOH to yield 1.6 g of 5-bromo-2-methyl-4′-methoxybenzophenone.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][NH:9][CH2:10][CH2:11][CH2:12][SH:13])=[CH:4][N:3]=1.[N+:14]([CH:17]=[C:18](SC)SC)([O-:16])=[O:15]>C(O)C>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][N:9]2[CH2:10][CH2:11][CH2:12][S:13][C:18]2=[CH:17][N+:14]([O-:16])=[O:15])=[CH:4][N:3]=1
Reactant: SCCCNCc1ccc(Cl)nc1
Reactant: CSC(=C[N+](=O)[O-])SC
Solvent: CCO
Product: O=[N+]([O-])C=C1SCCCN1Cc1ccc(Cl)nc1
Yield: 22.9 %

Procedure:
A mixture of N-(2-chloro-5-pyridylmethyl)3-aminopropanethiol (4.3 g), 1-nitro-2,2-bis(methylthio)ethylene (3.3 g) and ethanol (40 ml) was heated under reflux for 10 hours in a stream of nitrogen. After the reaction, about 2/3 of ethanol was distilled off under reduced pressure. Ether was added little by little to the reaction mixture to precipitate crystals. The crystals were collected by filtration, and washed with a mixture of ethanol and ether to give the desired 3-(2-chloro-5-pyridylmethyl)-2-nitromethylenetetrahydro-2H-1,3-thiazine (1.3 g) as yellow crystals.
Reaction SMILES: Cl[C:2]1[O:3][C:4]([C:7]2[CH:12]=[CH:11][C:10]([C:13]([F:16])([F:15])[F:14])=[CH:9][CH:8]=2)=[CH:5][N:6]=1.[NH2:17][C:18]1[CH:19]=[C:20]([NH:24][S:25]([CH2:28][C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)(=[O:27])=[O:26])[CH:21]=[CH:22][CH:23]=1>CC(O)C>[C:29]1([CH2:28][S:25]([NH:24][C:20]2[CH:21]=[CH:22][CH:23]=[C:18]([NH:17][C:2]3[O:3][C:4]([C:7]4[CH:12]=[CH:11][C:10]([C:13]([F:16])([F:15])[F:14])=[CH:9][CH:8]=4)=[CH:5][N:6]=3)[CH:19]=2)(=[O:26])=[O:27])[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1
Reactant: Nc1cccc(NS(=O)(=O)Cc2ccccc2)c1
Reactant: FC(F)(F)c1ccc(-c2cnc(Cl)o2)cc1
Solvent: CC(C)O
Product: O=S(=O)(Cc1ccccc1)Nc1cccc(Nc2ncc(-c3ccc(C(F)(F)F)cc3)o2)c1
Temperature: 80 °C

Procedure:
A mixture of 2-chloro-5-(4-(trifluoromethyl)phenyl)oxazole 31 (0.651 g, 2.63 mmol) and N-(3-aminophenyl)-1-phenylmethanesulfonamide 26 (0.69 g, 2.63 mmol) in 2-propanol (50 mL) was heated to 80° C. for 18 h with stirring. Upon cooling, solvent was evaporated and silica column purified (Biotage) (Acetone/hexane as an eluent) to provide 1-phenyl-N-(3-((5-(4-(trifluoromethyl)phenyl)oxazol-2-yl)amino) phenyl) methane sulfonamide. 34 (0.407 g, 33% yield) as a solid. MS (ES) m/z 474 (M+H+).
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([CH2:8][C:9]([O:11][CH2:12][CH3:13])=[O:10])[CH:5]=[CH:6][CH:7]=1.F[C:15]1[CH:22]=[CH:21][C:18]([C:19]#[N:20])=[CH:17][CH:16]=1.[OH-].[K+]>CS(C)=O.O>[C:19]([C:18]1[CH:21]=[CH:22][C:15]([O:1][C:2]2[CH:3]=[C:4]([CH2:8][C:9]([O:11][CH2:12][CH3:13])=[O:10])[CH:5]=[CH:6][CH:7]=2)=[CH:16][CH:17]=1)#[N:20]
Reactant: CCOC(=O)Cc1cccc(O)c1
Reactant: N#Cc1ccc(F)cc1
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: CS(C)=O
Product: CCOC(=O)Cc1cccc(Oc2ccc(C#N)cc2)c1
Yield: 49.3 %

Procedure:
A solution of ethyl 3-hydroxyphenylacetate (28 g, 0.15 mole) and 4-fluorobenzonitrile (25 g, 0.21 mole) in dimethylsulfoxide (150 ml) was stirred with 87% potassium hydroxide (10 g, 0.15 mole) at 75°-80° C. for 80 minutes under nitrogen. The resulting mixture was allowed to cool, diluted with water (1000 ml), and extracted with diethyl ether (2×50 ml). The organic solution was washed with water (100 ml), dried (MgSO4), concentrated in vacuo and the residue eluted on silica gel (500 g) with ethyl acetate: hexane (0 to 1:6). A solution of the product in diethyl ether (125 ml) was washed with 1N NaOH (15 ml) to remove some residual phenol, dried (K2CO3 and MgSO4), and concentrated in vacuo to give ethyl 3-(4-cyanophenyloxy)phenylacetate (20.8 g). 1H NMR (DMSO-d6, 300 MHz) δ: 1.18 (t, J=7 Hz, 3H, CH3), 3.71 (s, 2H, Ar CH2) 4.08 (q, J=7 Hz 2H, ester CH2) 7.02-7 13 (m, 4H, Ar) 7.18 (d, J=8 Hz, 1H, Ar), 7.42 (t, J=8 Hz, 1H, Ar), 7.85 (d, J=9 Hz, 2H, Ar). Anal. Calculated for C17H15NO3 : C, 72.58; H, 5.37; N, 4.98. Found: C, 72.67; H, 5.43; N, 4.94.
Reaction SMILES: [C:1]([Si:5]([CH3:24])([CH3:23])[O:6][C@@H:7]1[CH2:11][CH2:10][C@H:9]([N:12]2C(=O)C3C(=CC=CC=3)C2=O)[CH2:8]1)([CH3:4])([CH3:3])[CH3:2].NN>C(O)C.O1CCCC1>[C:1]([Si:5]([CH3:24])([CH3:23])[O:6][C@@H:7]1[CH2:11][CH2:10][C@H:9]([NH2:12])[CH2:8]1)([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)[Si](C)(C)O[C@@H]1CC[C@H](N2C(=O)c3ccccc3C2=O)C1
Agent: NN
Solvent: CCO
Solvent: C1CCOC1
Product: CC(C)(C)[Si](C)(C)O[C@@H]1CC[C@H](N)C1
Reaction time: 8 h

Procedure:
To a mixture of (±)-cis-2-[3-(tert-butyl-dimethyl-silanyloxy)-cyclopentyl]-isoindole-1,3-dione (1.03 g, 2.98 mmol) (from Example 10b supra) in ethanol/tetrahydrofuran (2:1, 20 mL) was added anhydrous hydrazine (1.2 mL, 38.90 mmol) (Aldrich). After stirring overnight the reaction mixture was filtered. The solids were washed with diethyl ether (approx. 30 mL) and the combined filtrate was concentrated. The residue was treated with diethyl ether again (approx. 30 mL) and the resulting mixture was filtered again and concentrated to give (±)-cis-3-(tert-butyl-dimethyl-silanyloxy)-cyclopentylamine as a colorless oil. (Yield 570 mg, 88%).
Reaction SMILES: [C:1]1([CH3:9])[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[Mg]Br.O1CCCC1.[CH2:15]([N:22]1[CH2:27][CH2:26][C:25](=O)[CH2:24][CH2:23]1)[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1.[Cl-].[NH4+]>O1CCCC1>[CH2:15]([N:22]1[CH2:27][CH:26]=[C:25]([C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][C:1]=2[CH3:9])[CH2:24][CH2:23]1)[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1
Reactant: O=C1CCN(Cc2ccccc2)CC1
Reactant: Cc1ccccc1[Mg]Br
Agent: [Cl-]
Agent: [NH4+]
Solvent: C1CCOC1
Product: Cc1ccccc1C1=CCN(Cc2ccccc2)CC1
Temperature: 80 °C
Reaction time: 0.17 h

Procedure:
600 mL of 0.5 M o-tolylmagnesium bromide-tetrahydrofuran solution was cooled to 0° C., and 200 mL of tetrahydrofuran solution of 40.0 g of 1-benzylpiperidin-4-one was dropwise added thereto, over 10 minutes. Cooled with ice, the reaction mixture was stirred further for 30 minutes. Then, aqueous saturated ammonium chloride solution was added thereto to stop the reaction, and this was extracted three times with ethyl acetate. The organic layer was washed with saturated saline water, dried with anhydrous magnesium sulfate, and the solvent was evaporated off under reduced pressure. 300 mL of trifluoroacetic acid was added to the resulting residue, heated up to 80° C., and stirred for 2 hours. The reaction liquid was concentrated under reduced pressure, the residue was neutralized with aqueous saturated sodium hydrogencarbonate solution, and then extracted with ethyl acetate. The organic layer was washed with saturated saline water, dried with anhydrous magnesium sulfate, and the solvent was evaporated off under reduced pressure. The residue was separated and purified through silica gel column chromatography (hexane/ethyl acetate=20/1 to 10/1) to obtain 39.9 g of the entitled compound as a pale brown oily substance.
Reaction SMILES: [C:1]([Si:5]([O:8]/[C:9](/[C:12]1[CH:17]=[CH:16][CH:15]=[C:14]([Cl:18])[CH:13]=1)=[CH:10]\[CH3:11])([CH3:7])[CH3:6])([CH3:4])([CH3:3])[CH3:2].[Si](OS(C(F)(F)F)(=O)=O)([C:22](C)(C)[CH3:23])(C)C.CCN(CC)CC>C(Cl)Cl>[C:1]([Si:5]([O:8]/[C:9](/[C:12]1[CH:17]=[CH:16][CH:15]=[C:14]([Cl:18])[CH:13]=1)=[CH:10]\[CH2:11][CH2:22][CH3:23])([CH3:7])[CH3:6])([CH3:2])([CH3:3])[CH3:4]
Reactant: CC(C)(C)[Si](C)(C)OS(=O)(=O)C(F)(F)F
Reactant: C/C=C(\O[Si](C)(C)C(C)(C)C)c1cccc(Cl)c1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCC/C=C(\O[Si](C)(C)C(C)(C)C)c1cccc(Cl)c1
Yield: 96 %

Procedure:
Compound 9t was synthesized by a procedure similar to that described for 9a using 3-chloropentaphenone (8k, 2.7 g, 0.014 mol), TBDMSOTf (3.5 mL, 15 mmol), and Et3N (3.1 mL) in CH2Cl2 (25 mL). After purification, 4.18 g (96%) of the title product was isolated as colorless oil: 1H NMR (CDCl3) δ 7.47-7.44 (m, 1H), 7.38-7.32 (m, 1H), 7.30-7.28 (m, 1H), 7.25-7.22 (m, 1H), 5.18 (t, 1H, J=7.2 Hz), 2.20 (q, 2H, J=7.5 Hz), 1.54-1.38 (m, 2H), 1.02 (s, 9H), 1.00-0.90 (m, 3H), −0.05 (s, 6H); 13C NMR (CDCl3) δ 148.0, 141.8, 133.9, 129.2, 127.6, 125.9, 123.9, 113.0, 28.3, 25.8, 22.8, 14.0, 0.0, −4.01. C17H27ClOSi.
Reaction SMILES: [NH2:1][C:2]1[N:6]([C:7]([C:9]2[CH:14]=[CH:13][C:12]([CH3:15])=[CH:11][CH:10]=2)=[O:8])[N:5]=[C:4]([NH:16][C:17]2[CH:22]=[CH:21][C:20]([O:23]CC3C=CC=CC=3)=[CH:19][CH:18]=2)[N:3]=1>C1CCCCC=1.C1COCC1.[Pd]>[NH2:1][C:2]1[N:6]([C:7]([C:9]2[CH:10]=[CH:11][C:12]([CH3:15])=[CH:13][CH:14]=2)=[O:8])[N:5]=[C:4]([NH:16][C:17]2[CH:18]=[CH:19][C:20]([OH:23])=[CH:21][CH:22]=2)[N:3]=1
Reactant: Cc1ccc(C(=O)n2nc(Nc3ccc(OCc4ccccc4)cc3)nc2N)cc1
Agent: [Pd]
Solvent: C1CCOC1
Solvent: C1=CCCCC1
Product: Cc1ccc(C(=O)n2nc(Nc3ccc(O)cc3)nc2N)cc1
Temperature: 70 °C
Reaction time: 48 h
Yield: 35.3 %

Procedure:
A mixture of 5-amino-3-[4-(benzyloxy)phenylamino]-1-(4-methylphenyl)carbonyl-1H-1,2,4-triazole (Ia-3) (3.95 g, 9.89 mmol) and 10% Pd/C (0.80 g) in cyclohexene (64 mL) and THF (128 mL) was stirred and heated at 70° C. After 2 d, additional 10% Pd/C (0.80 g) was added and heating and stirring at 70° C. was continued for an additional 3 d. After cooling to ambient temperature, the mixture was filtered through diatomaceous earth and concentrated to give a yellow-brown residue. Purification by flash chromatography (95:5 methylene chloride/methanol) followed by trituration with methylene chloride afforded 5-amino-3-[4-(hydroxy)phenylamino]-1-(4-methylphenyl)carbonyl-1H-1,2,4-triazole (Ia-4) (1.08 g, 35%) as a pale yellow solid: Rf 0.36 (95:5 methylene chloride/methanol); mp 221-223° C.; 1H NMR (300 MHz, DMSO-d6) δ 8.92 (s, 1H), 8.88 (s, 1H), 8.13 (d, J=8.2 Hz, 2H), 7.74 (br s, 2H), 7.38-7.32 (m, 4H), 6.64 (d, J=8.8 Hz, 2H), 2.42 (s, 3H); 13C NMR (75 MHz, DMSO-d6) δ 166.1, 158.4, 157.3, 151.0, 142.9, 132.9, 130.6, 129.8, 128.4, 118.1, 115.1, 21.1; IR (ATR) 1697 cm−1; ESI MS m/z 310 [C16H16N6O2+H]+; HPLC (Method A) >99% (AUC), tR=11.22 min. Anal. Calcd for C16H16N6O2.0.5H2O: C, 60.47; H, 4.92; N, 22.04. Found: C, 60.27; H, 4.70; N, 21.51.
Reaction SMILES: [C:1]1([CH2:7][CH2:8][CH2:9][CH:10]([NH:20][C:21]([CH:23]2[CH2:28][CH2:27][N:26]([C:29]([CH:31]3[CH2:36][CH2:35][NH:34][CH2:33][CH2:32]3)=[O:30])[CH2:25][CH2:24]2)=[O:22])[CH2:11][CH2:12][CH2:13][C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[O:37]1[CH2:39][C@@H:38]1[CH2:40][O:41][C:42]1[CH:51]=[CH:50][CH:49]=[C:48]2[C:43]=1[CH:44]=[CH:45][CH:46]=[N:47]2>C(O)C>[C:1]1([CH2:7][CH2:8][CH2:9][CH:10]([NH:20][C:21]([CH:23]2[CH2:24][CH2:25][N:26]([C:29]([CH:31]3[CH2:36][CH2:35][N:34]([CH2:39][C@@H:38]([OH:37])[CH2:40][O:41][C:42]4[CH:51]=[CH:50][CH:49]=[C:48]5[C:43]=4[CH:44]=[CH:45][CH:46]=[N:47]5)[CH2:33][CH2:32]3)=[O:30])[CH2:27][CH2:28]2)=[O:22])[CH2:11][CH2:12][CH2:13][C:14]2[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: c1cc(OC[C@H]2CO2)c2cccnc2c1
Reactant: O=C(NC(CCCc1ccccc1)CCCc1ccccc1)C1CCN(C(=O)C2CCNCC2)CC1
Solvent: CCO
Product: O=C(NC(CCCc1ccccc1)CCCc1ccccc1)C1CCN(C(=O)C2CCN(C[C@@H](O)COc3cccc4ncccc34)CC2)CC1
Temperature: 25 °C
Yield: 58.2 %

Procedure:
1-(Piperidine-4-carbonyl)-piperidine-4-carboxylic acid [4-phenyl-1-(3-phenyl-propyl)-butyl]-amide (71) (243.4 mg; 0.497 mmol) is dissolved in ethanol (12 mL) at ambient temperature. (R)-5-Oxiranylmethoxy-quinoline (2) (100.0 mg; 0.497 mmol) is added, then the mixture is refluxed for 16 hours. After cooling to ambient temperature, the solution is concentrated in vacuo at 40° C. The residue is purified via silica gel chromatography with gradient elution (50%→100% acetone in hexanes, then 5%→20% ethanol in acetone) affording the desired product (200 mg) as a white solid. ESMS: MH+ 691.6
Reaction SMILES: [CH3:1][C:2]1([CH3:16])[CH2:10][CH2:9][C:8]([CH3:12])([CH3:11])[C:7]2[CH2:6][CH:5]([C:13](O)=[O:14])[CH2:4][C:3]1=2.[CH3:17][Li]>O1CCCC1>[CH3:17][C:13]([CH:5]1[CH2:4][C:3]2[C:2]([CH3:16])([CH3:1])[CH2:10][CH2:9][C:8]([CH3:12])([CH3:11])[C:7]=2[CH2:6]1)=[O:14]
Reactant: CC1(C)CCC(C)(C)C2=C1CC(C(=O)O)C2
Reactant: [Li]C
Solvent: C1CCOC1
Product: CC(=O)C1CC2=C(C1)C(C)(C)CCC2(C)C
Temperature: 25 °C
Reaction time: 3 h

Procedure:
7.3 g of 4,5,6,7-tetrahydro-4,4,7,7-tetramethyl-2-indanecarboxylic acid are dissolved in 150 ml of tetrahydrofuran and treated slowly while cooling with ice and stirring vigorously with 47.3 ml of methyl lithium (1.6 molar in ether). After stirring for 3 hours at room temperature, the mixture is poured on to ice, extracted with ether, washed with water, dried over sodium sulphate and evaporated. After distillation of the crude product, there are obtained 5.6 g of 2,2,5,5-tetramethyl-bicyclo[4.3.0]non-1(6)-en-8-yl methyl ketone as a colourless liquid of boiling point 53°-60° C./0.01 mm Hg.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([NH:8][C:9]2[CH:14]=[CH:13][CH:12]=[C:11]([OH:15])[CH:10]=2)[C:5]([F:16])=[CH:4][N:3]=1.[NH2:17][C:18]1[CH:23]=[CH:22][CH:21]=[C:20]([NH2:24])[CH:19]=1>>[NH2:17][C:18]1[CH:19]=[C:20]([NH:24][C:2]2[N:7]=[C:6]([NH:8][C:9]3[CH:14]=[CH:13][CH:12]=[C:11]([OH:15])[CH:10]=3)[C:5]([F:16])=[CH:4][N:3]=2)[CH:21]=[CH:22][CH:23]=1
Reactant: Oc1cccc(Nc2nc(Cl)ncc2F)c1
Reactant: Nc1cccc(N)c1
Product: Nc1cccc(Nc2ncc(F)c(Nc3cccc(O)c3)n2)c1

Procedure:
In like manner to the preparation of N4-(3-aminophenyl)-N2-[2-(methoxycarbonyl)-benzofurane-5-yl]-5-fluoro-2,4-pyrimidinediamine, 2-chloro-5-fluoro-N4-(3-hydroxyphenyl)-4-pyrimidineamine and 1,3-diaminobenzene were reacted to give N2-(3-aminophenyl)-5-fluoro-N4-(3-hydroxyphenyl)-2,4-pyrimidinediamine. LCMS: ret. time: 11.89 min.; purity: 97.6%; MS (m/e): 312.05 (MH+).
Reaction SMILES: [H-].[Na+].[Cl:3][C:4]1[CH:13]=[C:12]2[C:7]([CH:8]=[CH:9][N:10]([CH2:15][C:16]3[CH:21]=[CH:20][C:19]([O:22][CH3:23])=[CH:18][CH:17]=3)[C:11]2=[O:14])=[CH:6][C:5]=1F.O.[C:26]([O:30][C:31]([N:33]1[CH:38]2[CH2:39][CH2:40][CH:34]1[CH2:35][CH:36]([OH:41])[CH2:37]2)=[O:32])([CH3:29])([CH3:28])[CH3:27]>CC(N(C)C)=O>[C:26]([O:30][C:31]([N:33]1[CH:38]2[CH2:39][CH2:40][CH:34]1[CH2:35][CH:36]([O:41][C:5]1[CH:6]=[C:7]3[C:12](=[CH:13][C:4]=1[Cl:3])[C:11](=[O:14])[N:10]([CH2:15][C:16]1[CH:21]=[CH:20][C:19]([O:22][CH3:23])=[CH:18][CH:17]=1)[CH:9]=[CH:8]3)[CH2:37]2)=[O:32])([CH3:29])([CH3:27])[CH3:28]
Reactant: CC(C)(C)OC(=O)N1C2CCC1CC(O)C2
Reactant: COc1ccc(Cn2ccc3cc(F)c(Cl)cc3c2=O)cc1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CC(=O)N(C)C
Product: COc1ccc(Cn2ccc3cc(OC4CC5CCC(C4)N5C(=O)OC(C)(C)C)c(Cl)cc3c2=O)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 80.1 %

Procedure:
528 mg of sodium hydride (60%) were suspended in 8 mL of dimethyl acetamide and 1.00 g of 3-hydroxy-8-aza-bicyclo[3.2.1]octane-8-carboxylic acid tert-butyl ester (70), dissolved in 4 mL of dimethyl acetamide, were added dropwise. After 1 h, 1.40 g of 7-Chloro-6-fluoro-2-(4-methoxy-benzyl)-2H-isoquinolin-1-one (62), dissolved in another 8 mL of dimethyl acetamide, were added. The reaction mixture was stirred at room temperature until the reaction was complete. 30 mL of water were added, the resulting suspension extracted three times with a mixture of dichloromethane and 2-propanol (3:1) and the combined organic layers were evaporated. Water was added and the crude product was subjected to lyophilization to remove remainders of dimethyl acetamide. The obtained crude product was purified by silica gel chromatography to yield 1.85 g of the title compound as a mixture of diastereoisomers (71). Rt=1.95 min, 2.03 min (Method C). Detected mass: 525.0 (M+H+).
Reaction SMILES: C(N(CC)CC)C.C(O[C:12](=[O:14])[CH3:13])(=O)C.[NH2:15][C:16]1[C:17]([NH:31][CH2:32][CH:33]2[CH2:38][CH2:37][N:36](C(OC(C)(C)C)=O)[CH2:35][CH2:34]2)=[CH:18][C:19]([NH:22][C:23]2[CH:28]=[N:27][C:26]([C:29]#[N:30])=[CH:25][N:24]=2)=[N:20][CH:21]=1.CC1C=CC(S(O)(=O)=O)=CC=1>CN(C=O)C>[C:29]([C:26]1[N:27]=[CH:28][C:23]([NH:22][C:19]2[N:20]=[CH:21][C:16]([NH:15][C:12](=[O:14])[CH3:13])=[C:17]([NH:31][CH2:32][CH:33]3[CH2:38][CH2:37][NH:36][CH2:35][CH2:34]3)[CH:18]=2)=[N:24][CH:25]=1)#[N:30]
Reactant: CC(C)(C)OC(=O)N1CCC(CNc2cc(Nc3cnc(C#N)cn3)ncc2N)CC1
Reactant: CC(=O)OC(C)=O
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: CC(=O)Nc1cnc(Nc2cnc(C#N)cn2)cc1NCC1CCNCC1
Reaction time: 2 h
Yield: 29.7 %

Procedure:
Triethylamine (11 μL, 0.082 mmol) and acetic anhydride (8 μL, 0.082 mmol) were added to a solution of tert-butyl 4-((5-amino-2-(5-cyanopyrazin-2-ylamino)-pyridin-4-ylamino)-methyl)-piperidine-1-carboxylate (29 mg, 0.068 mmol) in DMF (1 mL) at 0° C. After 2 hours, the mixture was loaded onto a MP-TsOH SPE cartridge, and eluted with 2M ammonia in methanol. The basic fractions were combined and concentrated. Purified by preparative HPLC gave N-(6-(5-cyanopyrazin-2-ylamino)-4-(piperidin-4-ylmethylamino)pyridin-3-yl)acetamide (7.4 mg, 32%).
Reaction SMILES: Cl[C:2]1[C:7]([N+:8]([O-])=O)=[CH:6][C:5]([CH3:11])=[CH:4][N:3]=1.[CH2:12]([NH:20][C:21](=O)[CH3:22])[CH2:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1>>[CH3:22][C:21]1[N:20]([CH2:12][CH2:13][C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[C:2]2=[N:3][CH:4]=[C:5]([CH3:11])[CH:6]=[C:7]2[N:8]=1
Reactant: CC(=O)NCCc1ccccc1
Reactant: Cc1cnc(Cl)c([N+](=O)[O-])c1
Product: Cc1cnc2c(c1)nc(C)n2CCc1ccccc1
Yield: 43 %

Procedure:
Method B applied to 2-chloro-5-methyl-3-nitropyridine (86 mg, 0.5 mmol) and N-phenethyl-acetamide (98 mg, 0.6 mmol) afforded the title compound as viscous oil (54 mg, 43%). 1H NMR (DMSO) δ 2.38 (s, 3H), 2.46 (s, 3H), 3.12 (t, 2H), 4.53 (t, 2H), 7.08-7.29 (m, 5H), 7.93 (s, 1H), 8.32 (s, 1H).
Reaction SMILES: [F:1][C:2]([F:11])([F:10])[CH2:3][CH2:4][C:5](=O)[C:6]([OH:8])=[O:7].CC1[N:18]=CC(COP(O)(O)=O)=C(C=O)C=1O>P([O-])([O-])([O-])=O.[K+].[K+].[K+]>[F:1][C:2]([F:11])([F:10])[CH2:3][CH2:4][C@@H:5]([NH2:18])[C:6]([OH:8])=[O:7]
Reactant: Cc1ncc(COP(=O)(O)O)c(C=O)c1O
Reactant: O=C(O)C(=O)CCC(F)(F)F
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Product: N[C@H](CCC(F)(F)F)C(=O)O

Procedure:
A solution containing 5,5,5-trifluoro-2-oxopentanoic acid (100 mg, 0.588 mmoles), R,S-alanine (200 mg, 2.244 mmoles), and 0.02 mM pyridoxal phosphate, in 0.1 M potassium phosphate buffer, pH 7.5, was incubated with R-transaminase AT-103 from Biocatalytics (5 mg, 44units) or cloned R-transaminase from Bacillus thuringiensis SC 16569 (0.5 mL, 10 units, BMS transaminase) at 30° C. in a total volume of 5 mL in 15 mL tubes for 44 h. Reaction yields of (R)-5,5,5-trifluoro-2-aminopentanoic acid of 49% and 48% were obtained with AT-103 and BMS transaminases, respectively. Ee was 100% in both cases.
Reaction SMILES: [CH:1]1([NH:4][C:5](=[O:24])[C:6]([C:17]2[CH:22]=[CH:21][C:20]([CH3:23])=[CH:19][CH:18]=2)=[CH:7][C:8]2[CH:16]=[CH:15][C:11]([C:12](O)=[O:13])=[CH:10][CH:9]=2)[CH2:3][CH2:2]1.CN(C=O)C.[CH:30]1[CH:31]=[CH:32][C:33]2[N:38](O)N=[N:36][C:34]=2[CH:35]=1.C1(N)C=CC=CC=1N>O>[NH2:38][C:33]1[CH:32]=[CH:31][CH:30]=[CH:35][C:34]=1[NH:36][C:12](=[O:13])[C:11]1[CH:10]=[CH:9][C:8]([CH:7]=[C:6]([C:17]2[CH:18]=[CH:19][C:20]([CH3:23])=[CH:21][CH:22]=2)[C:5]([NH:4][CH:1]2[CH2:2][CH2:3]2)=[O:24])=[CH:16][CH:15]=1
Reactant: Cc1ccc(C(=Cc2ccc(C(=O)O)cc2)C(=O)NC2CC2)cc1
Reactant: On1nnc2ccccc21
Agent: Nc1ccccc1N
Solvent: O
Solvent: CN(C)C=O
Product: Cc1ccc(C(=Cc2ccc(C(=O)Nc3ccccc3N)cc2)C(=O)NC2CC2)cc1
Reaction time: 4 h
Yield: 45 %

Procedure:
To a suspension of 4-(3-(cyclopropylamino)-2-(4-methylphenyl)-3-oxoprop-1-en-1-yl)benzoic acid (0.2 g, 0.6 mmol, prepared according to the procedure described in Example 99, step I-III) in DMF (3 mL) EDCl (0.23 g, 1.1 mmol), HOBt (0.08 g, 5 mmol), o-phenylenediamine (0.08 g, 0.7 mmol), were added followed by TEA (0.23 mL, 15 mmol). The reaction mixture was stirred for 4 hours after which the mixture was added to cold water (100 mL) and kept 0° C. for 1 hour to obtain a pale yellow solid. The solid was filtered and washed with water (50 mL) dried under vacuum to afford the title compound (0.110 g, 45% yield). 1H NMR (DMSO-d6) δ (ppm): 0.51 (2H, m, —CH2), 0.63-0.65 (2H, m, —CH2), 2.33 (3H, s, —CH3), 2.67-2.75 (1H, m, —CH), 4.87 (2H, s, —NH2), 6.55-6.58 (1H, m, Ar—H), 6.74-6.76 (1H, m, Ar—H), 6.93-6.97 (1H, m, Ar—H), 7.04 (2H, d, Ar—H), 7.11 (3H, m, Ar—H), 7.19 (2H, m, Ar—H), 7.25 (1H, s, ═CH), 7.76-7.78 (3H, m, Ar—H and —NH), 9.57 (1H, s, —NH), MS m/z: 412.2 (M++1).