Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]2[C:17]([CH3:19])([CH3:18])[CH2:16][C:15]3[C:10](=[CH:11][CH:12]=[C:13]([C:20]([OH:22])=[O:21])[CH:14]=3)[NH:9]2)=[CH:4][CH:3]=1.[F:23][C:24]1[CH:29]=[CH:28][C:27]([S:30](Cl)(=[O:32])=[O:31])=[CH:26][CH:25]=1>N1C=CC=CC=1>[F:23][C:24]1[CH:29]=[CH:28][C:27]([S:30]([NH:1][C:2]2[CH:3]=[CH:4][C:5]([CH:8]3[C:17]([CH3:18])([CH3:19])[CH2:16][C:15]4[C:10](=[CH:11][CH:12]=[C:13]([C:20]([OH:22])=[O:21])[CH:14]=4)[NH:9]3)=[CH:6][CH:7]=2)(=[O:32])=[O:31])=[CH:26][CH:25]=1
Reactant: CC1(C)Cc2cc(C(=O)O)ccc2NC1c1ccc(N)cc1
Reactant: O=S(=O)(Cl)c1ccc(F)cc1
Solvent: c1ccncc1
Product: CC1(C)Cc2cc(C(=O)O)ccc2NC1c1ccc(NS(=O)(=O)c2ccc(F)cc2)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 60.3 %

Procedure:
To a solution of 2-(4-aminophenyl)-3,3-dimethyl-1,2,3,4-tetrahydroquinoline-6-carboxylic acid (80 mg, 0.27 mmol) in pyridine (5 mL) was added 4-fluorobenzene-1-sulfonyl chloride (57 mg, 0.30 mmol) with ice cooling. Upon completion of the addition, the resultant mixture was allowed to warm back to room temperature and stir overnight. LC-MS showed the reaction was complete. Pyridine was removed in vacuo and the residue was purified by preparative Thin layer chromatography to afford 74 mg of 2-(4-(4-fluorophenyl-sulfonamido)phenyl)-3,3-dimethyl-1,2,3,4-tetrahydroquinoline-6-carboxylic acid as a yellow powder. Yield: 63%; MS (ESI+APCI) M+1=455.46.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1([C:11]2[N:12]=[C:13](Cl)[C:14]3[N:15]([C:17](=[O:24])[N:18]([C:20]([CH3:23])([CH3:22])[CH3:21])[N:19]=3)[CH:16]=2)[CH2:10][CH2:9][CH2:8][CH2:7]1)=[O:5])[CH3:2].[CH:26]([NH2:29])([CH3:28])[CH3:27]>C1COCC1>[CH2:1]([O:3][C:4]([C:6]1([C:11]2[N:12]=[C:13]([NH:29][CH:26]([CH3:28])[CH3:27])[C:14]3[N:15]([C:17](=[O:24])[N:18]([C:20]([CH3:23])([CH3:22])[CH3:21])[N:19]=3)[CH:16]=2)[CH2:10][CH2:9][CH2:8][CH2:7]1)=[O:5])[CH3:2]
Reactant: CCOC(=O)C1(c2cn3c(=O)n(C(C)(C)C)nc3c(Cl)n2)CCCC1
Reactant: CC(C)N
Solvent: C1CCOC1
Product: CCOC(=O)C1(c2cn3c(=O)n(C(C)(C)C)nc3c(NC(C)C)n2)CCCC1

Procedure:
A solution of 365 mg of 1-(2-tert-butyl-8-chloro-3-oxo-2,3-dihydro-[1,2,4]triazolo[4,3-a]pyrazin-6-yl)-cyclopentanecarboxylic acid ethyl ester and 590 mg of isopropylamine in THF (5.0 mL) was heated at reflux for two h. The solvent was removed and the residue was purified by silica gel chromatography to afford 1-(2-tert-butyl-8-isopropylamino-3-oxo-2,3-dihydro-[1,2,4]triazolo[4,3-a]pyrazin-6-yl)-cyclopentanecarboxylic acid ethyl ester as an oil. MS (M+H+)=390.3.
Reaction SMILES: [CH2:1]([N:8]1[CH2:22][CH:21]([CH3:23])[N:11]2[C:12](=[O:20])[C:13]3[CH:14]=[CH:15][CH:16]=[CH:17][C:18]=3[CH2:19][CH:10]2[CH2:9]1)C1C=CC=CC=1.[H][H]>[Pd].CO>[CH3:1][N:8]1[CH2:22][C@@H:21]([CH3:23])[N:11]2[C:12](=[O:20])[C:13]3[CH:14]=[CH:15][CH:16]=[CH:17][C:18]=3[CH2:19][C@@H:10]2[CH2:9]1
Reactant: [H][H]
Reactant: CC1CN(Cc2ccccc2)CC2Cc3ccccc3C(=O)N12
Agent: [Pd]
Solvent: CO
Product: C[C@@H]1CN(C)C[C@H]2Cc3ccccc3C(=O)N21
Temperature: 40 °C
Reaction time: 4 h
Yield: 16.3 %

Procedure:
1,2,3,4,11,11a-Hexahydro-2-benzyl-4-methyl-pyrazino[1,2-b]isoquinolin-6-one (from Isomer B, 12 mg, 0.04 mmol) and 10% palladium on carbon (5 mg) in MeOH (1 ml) was stirred under a balloon of hydrogen. The catalyst was filtered off and then fresh catalyst added. After stirring an additional 4 h at 40° C. under a balloon of hydrogen, the reaction was filtered through Celite® rinsing with methanol to afford 8 mg of crude product. Column purification (Chiralcel OD, 10% 1/1 MeOH/EtOH in hexanes) afforded pure (4R,11aR)-1,2,3,4,11,11a-hexahydro-2,4-dimethyl-pyrazino[1,2-b]isoquinolin-6-one (1.5 mg, 17% yield) MS (ESI) 231 (M+H). Further elution afforded (4S,1 aS)-1,2,3,4,11,11a-hexahydro-2,4-dimethyl-pyrazino[1,2-b]isoquinolin-6-one (1.6 mg, 18% yield) MS (ESI) 231 (M+H). Further elution also provided (4R,11aR)-1,2,3,4,11,11a-hexahydro-4-methyl-pyrazino[1,2-b]isoquinolin-6-one (2.4 mg, 29% yield) and (4S,11aS)-1,2,3,4,11,11a-hexahydro-4-methyl-pyrazino[1,2-b]isoquinolin-6-one (2.2 mg, 27% yield).
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[C:9]([N+:11]([O-:13])=[O:12])[C:8]([N+:14]([O-:16])=[O:15])=[CH:7][C:3]=1[C:4]([OH:6])=O.S(Cl)(Cl)=O.[CH:21]1([NH2:24])[CH2:23][CH2:22]1>ClCCCl>[Cl:1][C:2]1[CH:10]=[C:9]([N+:11]([O-:13])=[O:12])[C:8]([N+:14]([O-:16])=[O:15])=[CH:7][C:3]=1[C:4]([NH:24][CH:21]1[CH2:23][CH2:22]1)=[O:6]
Reactant: O=C(O)c1cc([N+](=O)[O-])c([N+](=O)[O-])cc1Cl
Reactant: NC1CC1
Solvent: ClCCCl
Solvent: O=S(Cl)Cl
Product: O=C(NC1CC1)c1cc([N+](=O)[O-])c([N+](=O)[O-])cc1Cl
Temperature: 25 °C
Reaction time: 2 h
Yield: 81 %

Procedure:
2-Chloro-4,5-dinitrobenzoic acid (known from WO-A-2009/47558) (8.0 g, 32.5 mmol) was dissolved in 1,2-dichloroethane (80 ml), and thionyl chloride (20 ml) was added under nitrogen. The reaction mixture was heated under reflux for 4 h and then the solvent was removed under reduced pressure. The residue was dissolved in dichloromethane (80 ml) and, at 0° C., cyclopropylamine (2.4 ml, 39 mmol) was added. The reaction mixture was stirred at room temperature for 2 h and then the solvent was removed under reduced pressure. The residue was stirred with diethyl ether (50 ml) for 30 min and then filtered off with suction. The residue was washed with water (100 ml) and dried. 7.5 g (81% of theory) of 2-chloro-N-cyclopropyl-4,5-dinitrobenzamide were thus obtained.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:7]([O:8][CH3:9])=[CH:6][S:5][CH:4]=1.OS([O-])(=O)=O.[Na+].[CH:16](=O)[CH2:17][CH2:18][CH2:19][CH2:20]C>C1(C)C=CC=CC=1>[CH3:1][O:2][C:3]1[C:7]([O:8][CH2:9][CH2:16][CH2:17][CH2:18][CH2:19][CH3:20])=[CH:6][S:5][CH:4]=1
Reactant: CCCCCC=O
Reactant: COc1cscc1OC
Agent: O=S(=O)([O-])O
Agent: [Na+]
Solvent: Cc1ccccc1
Product: CCCCCCOc1cscc1OC

Procedure:
10 g of 3,4-dimethoxythiophene were dissolved in 10 cm3 of 1-hexanone and 30 cm3 of toluene, 0.5 g of NaHSO4 was added, and the mixture was heated to reflux. 6 cm3 of azeotrope were distilled off and the batch was then worked up as in Example 14. Fractionation gave 3.7 g of 3-methoxy-4-hexyloxythiophene, b.p. 80° to 85° C./0.1 mbar. 4 g of dihexyloxythiophene were obtained from the distillation residue by chromatography through SiO2 using CH2Cl2.
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[N:5]=[CH:4][C:3]=1[N+:12]([O-:14])=[O:13].Cl.[CH2:16]([O:18][C:19](=[O:23])[CH2:20][CH2:21][NH2:22])[CH3:17].C(N(CC)CC)C>ClCCl>[N+:12]([C:3]1[CH:4]=[N:5][C:6]2[C:11]([C:2]=1[NH:22][CH2:21][CH2:20][C:19]([O:18][CH2:16][CH3:17])=[O:23])=[CH:10][CH:9]=[CH:8][CH:7]=2)([O-:14])=[O:13]
Reactant: O=[N+]([O-])c1cnc2ccccc2c1Cl
Reactant: CCOC(=O)CCN
Agent: Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCOC(=O)CCNc1c([N+](=O)[O-])cnc2ccccc12
Yield: 98.8 %

Procedure:
The general method described in Step 1 of Example 1 was used to react 4-chloro-3-nitroquinoline (45.3 g, 217 mmol), β-alanine ethyl ester hydrochloride (40.0 g, 240 mmol), and triethylamine (54.8 g, 542 mmol) in dichloromethane for 15 hours to provide ethyl 3-(3-nitroquinolin-4-ylamino)propionate (62.0 g) as a yellow solid.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([O:11][CH2:12][CH:13]2[CH2:17][C:16]3[CH:18]=[CH:19][CH:20]=[C:21](OS(C(F)(F)F)(=O)=O)[C:15]=3[O:14]2)(=[O:10])=[O:9])=[CH:4][CH:3]=1.[Cl:30][C:31]1[CH:32]=[C:33](B(O)O)[CH:34]=[CH:35][C:36]=1[F:37].P([O-])([O-])([O-])=O.[K+].[K+].[K+]>C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[CH3:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([O:11][CH2:12][CH:13]2[CH2:17][C:16]3[CH:18]=[CH:19][CH:20]=[C:21]([C:33]4[CH:34]=[CH:35][C:36]([F:37])=[C:31]([Cl:30])[CH:32]=4)[C:15]=3[O:14]2)(=[O:9])=[O:10])=[CH:4][CH:3]=1
Reactant: OB(O)c1ccc(F)c(Cl)c1
Reactant: Cc1ccc(S(=O)(=O)OCC2Cc3cccc(OS(=O)(=O)C(F)(F)F)c3O2)cc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Product: Cc1ccc(S(=O)(=O)OCC2Cc3cccc(-c4ccc(F)c(Cl)c4)c3O2)cc1
Yield: 47.3 %

Procedure:
Treatment of (±)-(7-{[(trifluoromethyl)sulfonyl]oxy}-2,3-dihydro-1-benzofuran-2-yl)methyl 4-methylbenzenesulfonate (1.5 g, 3.32 mmol) with 3-chloro-4-fluorophenylboronic acid (0.87 g, 4.97 mmol), tetrakis(triphenylphosphine)palladium(0) (0.38 g, 0.33 mmol), and potassium phosphate (1.41 g, 6.64 mmol) generally according to the procedure described for Intermediate 50 provided 0.68 g (48%) of (±)-[7-(3-chloro-4-fluorophenyl)-2,3-dihydro-1-benzofuran-2-yl]methyl 4-methylbenzenesulfonate as a white solid. Rf=0.43 (silica, ethyl acetate:hexanes 1:3); mp 104-108° C.; Anal. calcd. for C22H18ClFO4S2: C, 61.04; H, 4.19. Found: C, 60.74; H, 4.13.
Reaction SMILES: Cl.[C:2]([N:5]1[CH2:10][CH2:9][CH:8]([NH2:11])[CH2:7][CH2:6]1)(=[O:4])[CH3:3].[F:12][C:13]1[CH:18]=[CH:17][C:16]([N:19]=[C:20]=[O:21])=[CH:15][CH:14]=1.C(N(C(C)C)CC)(C)C>ClCCl>[C:2]([N:5]1[CH2:10][CH2:9][CH:8]([NH:11][C:20]([NH:19][C:16]2[CH:17]=[CH:18][C:13]([F:12])=[CH:14][CH:15]=2)=[O:21])[CH2:7][CH2:6]1)(=[O:4])[CH3:3]
Reactant: CC(=O)N1CCC(N)CC1
Reactant: O=C=Nc1ccc(F)cc1
Agent: Cl
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CC(=O)N1CCC(NC(=O)Nc2ccc(F)cc2)CC1
Reaction time: 3 h

Procedure:
To a suspension of 1-acetyl-4-aminopiperidine hydrochloride (536 mg) in dichloromethane (5 ml) were added 4-fluorophenyl isocyanate (375 μl) and diisopropylethylamine (575 μl ) at ambient temperature. After stirring for 3 hours, the reaction mixture was diluted with dichloromethane. An organic phase was separated and an aqueous phase was extracted with dichloromethane. A combined organic phase was dried over magnesium sulfate and the solvents were removed under reduced pressure. After crystallization from diisopropyl ether and n-hexane, N-(1-acetylpiperidin-4-yl)-N′-(4-fluorophenyl)urea (448 mg) was obtained.
Reaction SMILES: [Cl:1][C:2]1[N:6]2[N:7]=[C:8]([O:11][CH3:12])[CH:9]=[CH:10][C:5]2=[N:4][C:3]=1[C:13]1[CH:14]=[CH:15][C:16]([CH3:20])=[C:17]([CH:19]=1)[NH2:18].N1C=CC=CC=1.[CH3:27][C:28]([CH3:33])([CH3:32])[C:29](Cl)=[O:30]>C(#N)C>[Cl:1][C:2]1[N:6]2[N:7]=[C:8]([O:11][CH3:12])[CH:9]=[CH:10][C:5]2=[N:4][C:3]=1[C:13]1[CH:14]=[CH:15][C:16]([CH3:20])=[C:17]([NH:18][C:29](=[O:30])[C:28]([CH3:33])([CH3:32])[CH3:27])[CH:19]=1
Reactant: COc1ccc2nc(-c3ccc(C)c(N)c3)c(Cl)n2n1
Reactant: CC(C)(C)C(=O)Cl
Solvent: c1ccncc1
Solvent: CC#N
Product: COc1ccc2nc(-c3ccc(C)c(NC(=O)C(C)(C)C)c3)c(Cl)n2n1
Temperature: 25 °C
Reaction time: 4 h
Yield: 92.8 %

Procedure:
A stirred solution of 5-(3-chloro-6-methoxyimidazo[1,2-b]pyridazin-2-yl)-2-methylaniline (0.025 g, 0.0867 mmol) in acetonitrile (1 mL) containing pyridine (0.261 mmol) is added trimethylacetylchloride (0.0867 mmol). The mixture is stirred at room temperature for 4 hours, then concentrated to dryness and purified via chromatography (hexanes to EtOAc) to afford the title compound (0.030 g, 93%) as a white solid: LCMS (m/z)=373.4, 375.3 [M+H]+, tR=2.74 min. (compound same as Example 109)
Reaction SMILES: [OH:1][CH:2]([C:8]1[CH:13]=[CH:12][C:11]([C:14]2[N:18]=[C:17]([C:19]3[O:23][N:22]=[C:21]([C:24]4[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=4)[C:20]=3[C:30]([F:33])([F:32])[F:31])[O:16][N:15]=2)=[CH:10][CH:9]=1)[C:3]([O:5]CC)=[O:4].CO.[Li+].[OH-]>C1COCC1>[OH:1][CH:2]([C:8]1[CH:13]=[CH:12][C:11]([C:14]2[N:18]=[C:17]([C:19]3[O:23][N:22]=[C:21]([C:24]4[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=4)[C:20]=3[C:30]([F:31])([F:32])[F:33])[O:16][N:15]=2)=[CH:10][CH:9]=1)[C:3]([OH:5])=[O:4]
Reactant: CCOC(=O)C(O)c1ccc(-c2noc(-c3onc(-c4ccccc4)c3C(F)(F)F)n2)cc1
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Product: O=C(O)C(O)c1ccc(-c2noc(-c3onc(-c4ccccc4)c3C(F)(F)F)n2)cc1
Reaction time: 1 h
Yield: 73.4 %

Procedure:
(R/S)-Ethyl 2-hydroxy-2-(4-(5-(3-phenyl-4-(trifluoromethyl)isoxazol-5-yl)-1,2,4-oxadiazol-3-yl)phenyl)acetate (150 mg, 0.327 mmol) was dissolved in THF (2 mL) at 0° C. and MeOH (0.5 mL) and 1N LiOH (0.327 mL, 0.327 mmol) were added. After stirring for 1 h, the solution was concentrated and then EtOAc was added. The EtOAc was washed with 1 N HCl aqueous. The organic layer was dried (MgSO4), filtered and concentrated to give (R/S)-2-hydroxy-2-(4-(5-(3-phenyl-4-(trifluoromethyl)isoxazol-5-yl)-1,2,4-oxadiazol-3-yl)phenyl)acetic acid Int-V (110 mg, 0.240 mmol, 73.4% yield): LCMS=431.9[M+H]+, 1H NMR (400 MHz, methanol-d4) δ ppm 8.19 (2 H, d, J=8.79 Hz), 7.51-7.79 (7 H, m), 5.26 (1 H, s).
Reaction SMILES: [Br:1][C:2]1[CH:15]=[CH:14][C:5]([O:6][CH:7]2[CH2:10][N:9]([C:11](Cl)=[O:12])[CH2:8]2)=[CH:4][CH:3]=1.[C:16]1([N:22]2[CH2:27][CH2:26][NH:25][CH2:24][CH2:23]2)[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1>O1CCCC1.O>[Br:1][C:2]1[CH:15]=[CH:14][C:5]([O:6][CH:7]2[CH2:10][N:9]([C:11]([N:25]3[CH2:26][CH2:27][N:22]([C:16]4[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=4)[CH2:23][CH2:24]3)=[O:12])[CH2:8]2)=[CH:4][CH:3]=1
Reactant: O=C(Cl)N1CC(Oc2ccc(Br)cc2)C1
Reactant: c1ccc(N2CCNCC2)cc1
Solvent: O
Solvent: C1CCOC1
Product: O=C(N1CCN(c2ccccc2)CC1)N1CC(Oc2ccc(Br)cc2)C1
Reaction time: 2 h
Yield: 48 %

Procedure:
A solution of 2.9 g (0.01 mole) of 3-(4-bromophenoxy)-1-azetidinecarbonyl chloride in 15 ml of tetrahydrofuran was treated while stirring with 1.6 g (0.01 mole) of 1-phenylpiperazine added all at once, a solid formed instantaneously and after stirring for 2 hr, the reaction mixture was diluted with 200 ml of water, the solid did not dissolve. The solid was removed by filtration and when triturated with chloroform, all but about 1 g of solid dissolved. The chloroform solution was dried over magnesium sulfate then concentrated in vacuo. The oily residue crystallized when triturated with ligroin. Recrystallization from benzene/ligroin yielded 2.0 g (48.1%) of fine white crystals, m.p. 160°-161° C.
Reaction SMILES: [CH2:1]([N:3]1[CH:9]=[CH:8][C:7]2[CH:10]=[CH:11][C:12]([O:14][CH3:15])=[CH:13][C:6]=2[CH2:5][C:4]1=[O:16])[CH3:2]>C(O)(=O)C.[Pd]>[CH2:1]([N:3]1[CH2:9][CH2:8][C:7]2[CH:10]=[CH:11][C:12]([O:14][CH3:15])=[CH:13][C:6]=2[CH2:5][C:4]1=[O:16])[CH3:2]
Reactant: CCN1C=Cc2ccc(OC)cc2CC1=O
Agent: [Pd]
Solvent: CC(=O)O
Product: CCN1CCc2ccc(OC)cc2CC1=O
Reaction time: 24 h
Yield: 60.7 %

Procedure:
To a solution of 3-ethyl-8-methoxy-1,3-dihydro-benzo[d]azepin-2-one (2.20 g, 0.010 mol) in acetic acid (30 mL) was added palladium 10% wt on carbon (50% wet; 200 mg). The mixture was shaken in a Parr apparatus under an atmosphere of hydrogen (50 PSI) for 1 day. The reaction mixture was filtered through Celite, concentrated, and subjected to flash chromatography on SiO2 (ethyl acetate/hexanes 20-70%) to give 3-ethyl-8-methoxy-1,3,4,5-tetrahydro-benzo[d]azepin-2-one (1.33 g, 60%), as a white solid. m.p. ° C.; 1H-NMR (CDCl3) δ 7.00 (d, J=8.3 Hz, 1H), 6.75 (d, J=8.6 Hz, 1H), 3.85 (s, 2H), 3.78 (s, 3H), 3.69 (t, J=6.1 Hz, 2H), 3.48 (q, J=7.3 HZ, 2H), 3.08 (t, J=5.8 Hz, 2H), 1.16 (t, J=7.3 Hz, 3H); LC/MS (ESI+): 220.06 (M+H).
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][C:5]([C:8]([O:10][CH3:11])=[O:9])=[CH:4][N+:3]=1[O-:12].CC#N.FC(F)(F)C(OC(=O)C(F)(F)F)=[O:19].C([O-])(O)=O.[Na+]>CO>[OH:12][N:3]1[C:2](=[O:19])[CH:7]=[CH:6][C:5]([C:8]([O:10][CH3:11])=[O:9])=[CH:4]1
Reactant: COC(=O)c1ccc(Cl)[n+]([O-])c1
Reactant: O=C(OC(=O)C(F)(F)F)C(F)(F)F
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CO
Solvent: CC#N
Product: COC(=O)c1ccc(=O)n(O)c1
Temperature: 23 °C
Reaction time: 0.08 h

Procedure:
To a 250 mL round bottom flask containing 2-chloro-5-(methoxycarbonyl)pyridine 1-oxide (2.45 g, 13.06 mmol) was added MeCN (10 mL). The resulting mixture was stirred at 23° C. for 5 min. At this time, trifluoroacetic anhydride (20 mL) was added and the reaction was stirred 1 h. Solid NaHCO3 (25 g) was added to the flask followed by MeOH (100 mL). The solid was filtered awau and the filtrate was concentrated and subjected to silica gel chromatography (80 g ISCO column, 0-5% MeOH in CHCl3) to give methyl 1-hydroxy-6-oxo-1,6-dihydropyridine-3-carboxylate as a yellow solid.
Reaction SMILES: [NH2:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:7]2[C:3]=1[C:4](=[O:20])[N:5]([CH:12]1[CH2:17][CH2:16][C:15](=[O:18])[NH:14][C:13]1=[O:19])[C:6]2=[O:11].[F:21][C:22]([F:33])([F:32])[C:23]1[CH:31]=[CH:30][C:26]([C:27](Cl)=[O:28])=[CH:25][CH:24]=1>C1COCC1.CO>[O:19]=[C:13]1[CH:12]([N:5]2[C:4](=[O:20])[C:3]3[C:7](=[CH:8][CH:9]=[CH:10][C:2]=3[NH:1][C:27](=[O:28])[C:26]3[CH:30]=[CH:31][C:23]([C:22]([F:21])([F:32])[F:33])=[CH:24][CH:25]=3)[C:6]2=[O:11])[CH2:17][CH2:16][C:15](=[O:18])[NH:14]1
Reactant: Nc1cccc2c1C(=O)N(C1CCC(=O)NC1=O)C2=O
Reactant: O=C(Cl)c1ccc(C(F)(F)F)cc1
Solvent: CO
Solvent: C1CCOC1
Product: O=C1CCC(N2C(=O)c3cccc(NC(=O)c4ccc(C(F)(F)F)cc4)c3C2=O)C(=O)N1
Yield: 76.5 %

Procedure:
A mixture of 4-amino-2-(2,6-dioxo(3-piperidyl))isoindoline-1,3-dione (0.6 g, 2.2 mmol) and 4-(trifluoromethyl)benzoyl chloride (1 g, 4.8 mmol) in THF (20 mL) was heated to reflux for 15 h. The solvent was removed in vacuo to give a solid. The solid was slurried in methanol (20 mL) for 2 h. The suspension was filtered and washed with ether (15 mL) then methanol (15 mL) to give N-[2-(2,6-dioxo-piperidin-3-yl)-1,3-dioxo-2,3-dihydro-1H-isoindol-4-yl]-4-trifluoromethyl-benzamide as a white solid (750 mg, 77% yield): mp, 213–215° C.; 1H NMR (DMSO-d6) δ 2.05–2.10 (m, 1H, CHH), 2.49–2.65 (m, 2H, CH2), 2.83–2.98 (m, 1H, CHH), 5.18 (dd, J=5.2, 12.5 Hz, 1H, NCH), 7.72 (d, J=7.2 Hz, 1H, Ar), 7.90–8.02 (m, 3H, Ar), 8.16–8.19 (m, 2H, Ar), 8.49 (d, J=8.4 Hz, 1H, Ar), 10.58 (s, 1H, NH), 11.17 (s, 1H, NH); 13C NMR (DMSO-d6) δ 21.99, 30.92, 48.99, 118.88, 119.36, 119.32, 123.76 (q, JC-F=271 Hz); 125.99 (q, JC-F=3.6 Hz), 127.10 128.37, 131.54, 132.16 (q, JC-F=32 Hz), 136.00, 136.26, 13721, 164.05, 166.59, 167.65, 169.68, 172.73; Anal Calcd for C21H14N3O5F3: C, 56.64; H, 3.17; N, 9.44; F, 12.80. Found: C, 56.25; H3.05; N, 9.32; F, 12.69.
Reaction SMILES: [F:1][C:2]([F:15])([CH:12]([F:14])[F:13])[CH2:3][O:4][C:5]1[CH:11]=[CH:10][C:8]([NH2:9])=[CH:7][CH:6]=1.Cl[CH2:17][C:18]([O:20][CH2:21][CH3:22])=[O:19].C(=O)(O)[O-].[Na+].[I-].[Na+]>CC(C)=O>[CH2:21]([O:20][C:18]([CH2:17][NH:9][C:8]1[CH:10]=[CH:11][C:5]([O:4][CH2:3][C:2]([F:15])([F:1])[CH:12]([F:13])[F:14])=[CH:6][CH:7]=1)=[O:19])[CH3:22]
Reactant: Nc1ccc(OCC(F)(F)C(F)F)cc1
Reactant: CCOC(=O)CCl
Agent: O=C([O-])O
Agent: [I-]
Agent: [Na+]
Solvent: CC(C)=O
Product: CCOC(=O)CNc1ccc(OCC(F)(F)C(F)F)cc1
Yield: 78.9 %

Procedure:
A mixture of 8.6 g of 4-(2,2,3,3-tetrafluoropropoxy)aniline, 4.8 g of ethyl chloroacetate, 4.8 g of sodium bicarbonate, 3.0 g of sodium iodide and 300 ml of acetone was refluxed for 21 hours. The solvent was distilled off under reduced pressure and 200 ml of ice water and 200 ml of dichloromethane were added to the residue to fractionate. The dichloromethane layer was washed with water, dried over anhydrous magnesium sulfate and distilled off under reduced pressure. The residue was purified by silica gel column chromatography (eluted with ethyl acetate:hexane [1:3 v/v]) to give 9.4 g of N-ethoxycarbonylmethyl-4-(2,2,3,3-tetrafluoropropoxy)aniline as pale yellow crystals.
Reaction SMILES: [CH3:1][O:2][CH:3]([O:6][CH3:7])[CH2:4][NH2:5].C(N(CC)CC)C.Br[CH2:16][C:17]#[CH:18]>C1C=CC=CC=1>[CH2:18]([NH:5][CH2:4][CH:3]([O:6][CH3:7])[O:2][CH3:1])[C:17]#[CH:16]
Reactant: COC(CN)OC
Reactant: C#CCBr
Solvent: c1ccccc1
Solvent: CCN(CC)CC
Product: C#CCNCC(OC)OC
Temperature: 25 °C
Reaction time: 1 h

Procedure:
N-(2,2-Dimethoxyethyl)amine (23 grams), triethylamine (31 ml) and benzene (100 ml) were charged into a glass reaction vessel equipped with a mechanical stirrer and thermometer. 1-Bromo-2-propyne (16.5 grams) was added dropwise with stirring to the reaction mixture at room temperature. After the addition was completed stirring was continued for a period of about 1 hour. After this time the reaction mixture was filtered and stripped of solvent. The residue was then distilled to yield the desired product N-propargyl-N-(2,2-dimethoxyethyl)amine having a boiling point of 70° C. at 1 mm of Hg pressure.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([N+:8]([O-])=O)[C:3]=1[NH2:11]>C(O)C.[Pd]>[F:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([NH2:8])[C:3]=1[NH2:11]
Reactant: Nc1c(F)cccc1[N+](=O)[O-]
Agent: [Pd]
Solvent: CCO
Product: Nc1cccc(F)c1N

Procedure:
A solution of 2-fluoro-6-nitro-phenylamine [K. L. Kirk and L. A. Cohen J. Org. Chem. 34, 384-389 (1969)] (1.05 g) in ethanol (50 ml) was hydrogenated over 10% palladium on carbon (0.5 g), filtered and evaporated to give a brown solid, used without purification.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][C:11]=1[N+:12]([O-:14])=[O:13])[NH:8][CH2:7][CH2:6]2.Cl[CH2:16][C:17]([N:19]([CH3:21])[CH3:20])=[O:18].C(=O)([O-])[O-].[K+].[K+]>C1COCC1.C(OCC)(=O)C>[CH3:20][N:19]([CH3:21])[C:17](=[O:18])[CH2:16][N:8]1[C:9]2[C:5](=[CH:4][C:3]([O:2][CH3:1])=[C:11]([N+:12]([O-:14])=[O:13])[CH:10]=2)[CH2:6][CH2:7]1
Reactant: CN(C)C(=O)CCl
Reactant: COc1cc2c(cc1[N+](=O)[O-])NCC2
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: COc1cc2c(cc1[N+](=O)[O-])N(CC(=O)N(C)C)CC2
Temperature: 65 °C
Yield: 15.9 %

Procedure:
To a solution of 5-(methyloxy)-6-nitro-2,3-dihydro-1H-indole (0.7 g, 3.61 mmol) in THF (100 mL) was added 2-chloro-N,N-dimethylacetamide (1.11 g, 10.8 mmol), and potassium carbonate (2.98 g, 21.6 mmol). After heating at 65° C. for 4 days, the reaction was diluted with ethyl acetate (100 mL) and washed with water (100 mL). The organic layer was separated, adsorbed onto silica gel, and purified by column chromatography (DCM to 2% MeOH/DCM) to provide N,N-dimethyl-2-[5-(methyloxy)-6-nitro-2,3-dihydro-1H-indol-1-yl]acetamide (0.16 g, 16%). ESIMS (M+H)+=280.
Reaction SMILES: [F:1][C:2]1[C:31]([F:32])=[CH:30][CH:29]=[CH:28][C:3]=1[CH2:4][NH:5][C:6]1[C:11]([C:12]([NH2:14])=[O:13])=[CH:10][N:9]=[C:8]([NH:15][C:16]2[CH:21]=[CH:20][C:19]([CH:22]3[CH2:27][CH2:26][NH:25][CH2:24][CH2:23]3)=[CH:18][CH:17]=2)[CH:7]=1.CCN(C(C)C)C(C)C.Br[CH2:43][CH2:44][F:45]>CN1C(=O)CCC1>[F:1][C:2]1[C:31]([F:32])=[CH:30][CH:29]=[CH:28][C:3]=1[CH2:4][NH:5][C:6]1[C:11]([C:12]([NH2:14])=[O:13])=[CH:10][N:9]=[C:8]([NH:15][C:16]2[CH:17]=[CH:18][C:19]([CH:22]3[CH2:23][CH2:24][N:25]([CH2:43][CH2:44][F:45])[CH2:26][CH2:27]3)=[CH:20][CH:21]=2)[CH:7]=1
Reactant: NC(=O)c1cnc(Nc2ccc(C3CCNCC3)cc2)cc1NCc1cccc(F)c1F
Reactant: FCCBr
Solvent: CCN(C(C)C)C(C)C
Solvent: CN1CCCC1=O
Product: NC(=O)c1cnc(Nc2ccc(C3CCN(CCF)CC3)cc2)cc1NCc1cccc(F)c1F
Temperature: 25 °C
Reaction time: 8 h
Yield: 60.9 %

Procedure:
Compound 4-(2,3-difluorobenzylamino)-6-(4-(piperidin-4-yl)phenylamino)nicotinamide (Example 209) (85 mg, 0.18 mmol) was dissolved in 3 mL NMP with DIEA (95 μL, 0.54 mmol). To it was added 1-bromo-2-fluoroethane (230 mg, 1.8 mmol). The mixture was stirred at RT for overnight. The reaction was about 70% completion. It was quenched with TFA and concentrated in vacuo. The mixture was subjected to reverse phase preparative HPLC to isolate the title compound (53 mg). MS found for C26H28F3N5O as (M+H)+ 484.4. UV: λ=256 nm. 1H NMR: (CD3OD) δ 8.19 (1H, s), 7.37 (2H, d, J=8.4 Hz), 7.25 (1H, m), 7.19-7.14 (3H, m), 7.10 (1H, m), 5.82 (1H, s), 4.97 (1H, m), 4.85 (1H, m), 4.55 (2H, s), 3.77 (2H, d, J=12.0 Hz), 3.62 (1H, m), 3.55 (1H, m), 3.28 (2H, m), 3.00 (1H, m), 2.15 (4H, m) ppm.
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([NH2:8])[C:5]([N+:9]([O-:11])=[O:10])=[C:4]([NH2:12])[CH:3]=1.C(O)=O>C(N(CC)CC)C.[Pd]>[NH2:8][C:6]1[CH:7]=[CH:2][CH:3]=[C:4]([NH2:12])[C:5]=1[N+:9]([O-:11])=[O:10]
Reactant: Nc1cc(Cl)cc(N)c1[N+](=O)[O-]
Agent: [Pd]
Solvent: CCN(CC)CC
Solvent: O=CO
Product: Nc1cccc(N)c1[N+](=O)[O-]
Temperature: 90 °C

Procedure:
68 mg of palladium at a concentration of 10% on charcoal are added to 0.016 mole (3 g) of 4-chloro-2,6-diaminonitro-benzene in 6 ml of triethylamine, and 1.32 ml of formic acid are then added dropwise. A high exothermicity is noted. The reaction medium is heated to 90° C. for 1 hour 30. After dilution of the reaction mixture with ethanol, the catalyst is removed by hot filtration. The filtrate, evaporated to dryness under reduced pressure, enables a dry extract to be obtained. After dilution of the dry extract with water, the expected product precipitates. After filtration and washing with water, followed by drying under vacuum in the presence of phosphorus pentoxide, it is recrystallized from toluene. It melts at 142° C. (literature 141° C., 145° C.).