Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1][C@:2]([C:32]1[CH:36]=[C:35]([CH3:37])[O:34][N:33]=1)([CH3:31])[C:3]#[C:4][C:5]1[CH:6]=[CH:7][C:8]2[O:14][CH2:13][CH2:12][N:11]3[C:15]([C:21]([NH:23]C4CCOCC4)=[O:22])=[C:16]([C:18]([NH2:20])=[O:19])[N:17]=[C:10]3[C:9]=2[CH:30]=1.[F:38][C:39]1[CH:40]=[C:41]([CH:44]=[CH:45][CH:46]=1)[CH2:42]N>>[F:38][C:39]1[CH:40]=[C:41]([CH:44]=[CH:45][CH:46]=1)[CH2:42][NH:20][C:18]([C:16]1[N:17]2[CH2:12][CH2:13][O:14][C:8]3[CH:7]=[CH:6][C:5]([C:4]#[C:3][C@@:2]([OH:1])([C:32]4[CH:36]=[C:35]([CH3:37])[O:34][N:33]=4)[CH3:31])=[CH:30][C:9]=3[C:10]2=[N:11][C:15]=1[C:21]([NH2:23])=[O:22])=[O:19]
Reactant: Cc1cc([C@](C)(O)C#Cc2ccc3c(c2)-c2nc(C(N)=O)c(C(=O)NC4CCOCC4)n2CCO3)no1
Reactant: NCc1cccc(F)c1
Product: Cc1cc([C@](C)(O)C#Cc2ccc3c(c2)-c2nc(C(N)=O)c(C(=O)NCc4cccc(F)c4)n2CCO3)no1

Procedure:
Prepared as described for (R)-10-(3-hydroxy-3-(5-methylisoxazol-3-yl)but-1-yn-1-yl)-N3-(tetrahydro-2H-pyran-4-yl)-5,6-dihydrobenzo[f]imidazo[1,2-d][1,4]oxazepine-2,3-dicarboxamide replacing oxan-4-amine hydrochloride with 3-fluorobenzylamine. off-white solid (45.4 mg, 5%).
Reaction SMILES: [NH2:1][C:2]1[C:3](=[O:14])[N:4]([CH2:12][CH3:13])[C:5](=[O:11])[N:6]([CH2:9][CH3:10])[C:7]=1[NH2:8].[CH2:15]([O:19][C:20]1[CH:30]=[CH:29][C:23]([CH:24]=[CH:25][C:26](O)=O)=[CH:22][CH:21]=1)[CH2:16][CH2:17][CH3:18]>>[CH2:15]([O:19][C:20]1[CH:21]=[CH:22][C:23](/[CH:24]=[CH:25]/[C:26]2[NH:1][C:2]3[C:3](=[O:14])[N:4]([CH2:12][CH3:13])[C:5](=[O:11])[N:6]([CH2:9][CH3:10])[C:7]=3[N:8]=2)=[CH:29][CH:30]=1)[CH2:16][CH2:17][CH3:18]
Reactant: CCn1c(N)c(N)c(=O)n(CC)c1=O
Reactant: CCCCOc1ccc(C=CC(=O)O)cc1
Product: CCCCOc1ccc(/C=C/c2nc3c([nH]2)c(=O)n(CC)c(=O)n3CC)cc1
Yield: 52.6 %

Procedure:
Substantially the same procedure as in Example 7 was repeated using 3.00 g (15.1 mmol) of 5,6-diamino-1,3-diethyluracil and 3.67 g (16.7 mmol) of 4-butoxycinnamic acid. Then, the resultant crude crystals were recrystallized from dioxane/water to give 3.04 g (yield 53%) of Compound 104 as pale yellow needles.
Reaction SMILES: [C:1]1([C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=2)[CH:6]=[CH:5][C:4]([C:7]2[N:8]([CH2:19][CH2:20][CH2:21][NH:22]C(=O)OC(C)(C)C)[C:9](=[N:12][C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=3)[S:10][CH:11]=2)=[CH:3][CH:2]=1.Cl.O>O1CCOCC1>[NH2:22][CH2:21][CH2:20][CH2:19][N:8]1[C:7]([C:4]2[CH:5]=[CH:6][C:1]([C:30]3[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=3)=[CH:2][CH:3]=2)=[CH:11][S:10][C:9]1=[N:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1
Reactant: CC(C)(C)OC(=O)NCCCn1c(-c2ccc(-c3ccccc3)cc2)csc1=Nc1ccccc1
Agent: Cl
Solvent: C1COCCO1
Solvent: O
Product: NCCCn1c(-c2ccc(-c3ccccc3)cc2)csc1=Nc1ccccc1
Yield: 100 %

Procedure:
A mixture of t-butyl 3-[4-(1,1′-biphenyl-4-yl)-2-(phenylimino)-thiazol-3(2H)-yl]propylcarbamate (233 mg) and a 4N solution of hydrogen chloride in dioxane (2 ml) was stirred at room temperature for one hour. To the reaction mixture was added water, and the mixture was washed with diethyl ether. The aqueous layer was basified with a saturated aqueous sodium hydrogen carbonate solution, and the mixture was extracted with chloroform. The organic layer was washed with a saturated brine, and dried over sodium sulfate, and the solvent was evaporated under reduced pressure to give the title compound (185 mg).
Reaction SMILES: [N+](C1C=CC([O:10][C:11](=O)[NH:12][CH2:13][CH:14]2[CH2:19][CH2:18][C:17]([N:26]([CH3:28])[CH3:27])([C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)[CH2:16][CH2:15]2)=CC=1)([O-])=O.[NH:30]1[CH2:35][CH:34]=[C:33]([C:36]2[C:44]3[C:39](=[CH:40][CH:41]=[CH:42][CH:43]=3)[NH:38][CH:37]=2)[CH2:32][CH2:31]1>O1CCOCC1>[CH3:27][N:26]([CH3:28])[C:17]1([C:20]2[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=2)[CH2:16][CH2:15][CH:14]([CH2:13][NH:12][C:11]([N:30]2[CH2:31][CH:32]=[C:33]([C:36]3[C:44]4[C:39](=[CH:40][CH:41]=[CH:42][CH:43]=4)[NH:38][CH:37]=3)[CH2:34][CH2:35]2)=[O:10])[CH2:19][CH2:18]1
Reactant: C1=C(c2c[nH]c3ccccc23)CCNC1
Reactant: CN(C)C1(c2ccccc2)CCC(CNC(=O)Oc2ccc([N+](=O)[O-])cc2)CC1
Solvent: C1COCCO1
Product: CN(C)C1(c2ccccc2)CCC(CNC(=O)N2CC=C(c3c[nH]c4ccccc34)CC2)CC1
Yield: 28.4 %

Procedure:
The diastereoisomer mixture of (4-dimethylamino-4-phenylcyclohexylmethyl)-carbamic acid-4-nitro-phenyl ester (825.5 mg, 2.08 mmole) was added to a solution of 3-(1,2,3,6-tetrahydropyridine-4-yl)-1H-indole (411.8 mg, 2.08 mmole) in dioxane (10 ml). The reaction mixture formed a clear, reddish-brown solution above 60° C. The solution was boiled under reflux for 12 hours. The solution was worked up by distilling off the solvent in vacuo. The residue contained, apart from nitrophenol, also the two diastereoisomers of 4-(1H-indol-3-yl)-3,6-dihydro-2H-pyridine-1-carboxylic acid-(4-dimethylamino-4-phenylcyclohexylmethyl)-amide. The diastereoisomers were separated and purified by flash chromatography on silica gel (120 g). Methanol (2000 ml) was used as eluent. The non-polar diastereoisomer (351 mg, m.p. 204°-206° C., 37%) and the polar diastereoisomer of 4-(1H-indol-3-yl)-3,6-dihydro-2H-pyridine-1-carboxylic acid-(4-dimethylamino-4-phenylcyclohexylmethyl)-amide (270 mg, m.p. 112°-115° C., 28%) were thereby obtained as pale yellow solids.
Reaction SMILES: [Cl:1][S:2]([C:5]1[C:15]([CH3:16])=[CH:14][C:8]([O:9][CH2:10][C:11](Cl)=[O:12])=[CH:7][C:6]=1[CH3:17])(=[O:4])=[O:3].[CH2:18]([OH:25])[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1.CCN(CC)CC.Cl>C1COCC1.CN(C1C=CN=CC=1)C>[Cl:1][S:2]([C:5]1[C:15]([CH3:16])=[CH:14][C:8]([O:9][CH2:10][C:11]([O:25][CH2:18][C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)=[O:12])=[CH:7][C:6]=1[CH3:17])(=[O:4])=[O:3]
Reactant: OCc1ccccc1
Reactant: Cc1cc(OCC(=O)Cl)cc(C)c1S(=O)(=O)Cl
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: Cc1cc(OCC(=O)OCc2ccccc2)cc(C)c1S(=O)(=O)Cl
Temperature: -78 °C
Reaction time: 5 h
Yield: 16 %

Procedure:
Referring to FIG. 37, to a solution of 2-(4-(chlorosulfonyl)-3,5-dimethylphenoxy)acetyl chloride (6 g, 20.3 mmol) in THF (60 mL) were added dropwise a solution of BnOH (2.2 g, 20.3 mmol), Et3N (3.44 mL, 24.3 mmol) and DMAP (25 mg, 0.2 mmol) in THF (30 mL) at −78° C. The reaction mixture was stirred for 5 h at −78° C. and then poured into HCl solution (1 N, 100 mL). The resulting mixture was extracted with ethyl acetate (100 mL×2). The combined extracts were washed with brine, dried over anhydrous Na2SO4 and concentrated under reduced pressure. The residue was purified by flash column chromatography (petroleum ether/EtOAc=60:1) to give product as a white powder (1.2 g, 16% yield). 2-(4-(Chlorosulfonyl)-3,5-dimethylphenoxy)acetyl chloride (2.0 g) was recovered. 1H NMR (CDCl3, 300 MHz): δ 7.42-7.32 (m, 5H), 6.67 (s, 2H), 5.32 (s, 2H), 4.74 (s, 2H) 2.72 (s, 6H).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][C:11]=1[O:12][CH3:13])[C:8](=O)[CH:7]=[CH:6]2.[NH:15]1[CH2:19][CH2:18][CH2:17][CH2:16]1.O=P12OP3(OP(OP(O3)(O1)=O)(=O)O2)=O>C1(C)C=CC=CC=1>[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][C:11]=1[O:12][CH3:13])[CH2:8][CH:7]=[C:6]2[N:15]1[CH2:19][CH2:18][CH2:17][CH2:16]1
Reactant: C1CCNC1
Reactant: COc1cc2c(cc1OC)C(=O)C=C2
Agent: O=P12OP3(=O)OP(=O)(O1)OP(=O)(O2)O3
Solvent: Cc1ccccc1
Product: COc1cc2c(cc1OC)C(N1CCCC1)=CC2
Temperature: 25 °C
Yield: 45.6 %

Procedure:
5,6-Dimethoxy-1-indenone (5.1 g, 26.53 mmol) was dissolved in 120 mL of toluene. To this solution 17.7 mL (212 mmol) of pyrrolidine was added followed by 0.5 g of P2O5. The reaction mixture was refluxed for about 20 hours in a flask equipped with a Dean-Stark adapter. The flask was cooled to room temperature and the solvent was evaporated in vacuum leaving a brown-red solid. This solid was extracted with 50 mL of ether and filtered. The ether was evaporated leaving a brown solid. This solid was extracted with 120 mL of hot hexane and filtered. The hexane was removed and solid was dissolved in a mixture of 30 mL of toluene and 60 mL of hexane and filtered. The red solution was cooled to −27° C. overnight. The resulting solid was recovered by decantation, washed with cold hexane and dried under reduced pressure to give 2.97 g of 1-(5,6-dimethoxy-1H-inden-3-yl)pyrrolidine. Yield was 46 percent.
Reaction SMILES: [C:1]1([CH:7]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[C:8]#[N:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH2:16]=[O:17]>N1C=CC=CC=1.O>[OH:17][CH2:16][C:7]([C:1]1[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1)([C:10]1[CH:11]=[CH:12][CH:13]=[CH:14][CH:15]=1)[C:8]#[N:9]
Reactant: C=O
Reactant: N#CC(c1ccccc1)c1ccccc1
Solvent: O
Solvent: c1ccncc1
Product: N#CC(CO)(c1ccccc1)c1ccccc1
Temperature: 23 °C
Reaction time: 40 h
Yield: 79.2 %

Procedure:
To a suspension of 2,2-diphenylacetonitrile (2.0 g, 10.35 mmol) and paraformaldehyde (1.242 g, 41.399 mmol) in pyridine (18 mL) was added Triton B (40% solution in water, 1.022 mL, 2.587 mmol) at 0° C. The suspension instantaneously changed color. The cooling bath was removed and the reaction was stirred at 23° C. for ˜40 hours. The reaction was then acidified with acetic acid (2 mL) and poured into water (150 mL). The aqueous phase was extracted with diethyl ether (2×) and the combined organic extracts were washed with water (2×), 1N HCl (2×) and saturated sodium bicarbonate. The organic phase was dried over anhydrous magnesium sulfate, filtered and concentrated. The residue was purified on silica gel Biotage chromatography (ethyl acetate/hexane 10% to 50%) to give the title material (1.83 g, 100%) as an oil. HPLC ret. time (Condition A): 1.682 min. 1H NMR (400 MHz, CDCl3) δ ppm: 2.21 (1H, t, J=7.20 Hz), 4.37 (2H, d, J=6.82 Hz), 7.35-7.44 (10H, m).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][C:5]2[O:9][C:8]([CH:10]([NH:17][C:18]3[CH:23]=[CH:22][C:21]([C:24]([N:26]([CH3:34])[CH2:27][CH2:28][C:29]([O:31][CH2:32][CH3:33])=[O:30])=[O:25])=[CH:20][CH:19]=3)[CH:11]3[CH2:16][CH2:15][CH2:14][CH2:13][CH2:12]3)=[C:7]([CH3:35])[C:6]=2[CH:36]=1.C(N(CC)CC)C.[C:44](OC(=O)C)(=[O:46])[CH3:45].C(=O)([O-])O.[Na+]>O1CCCC1>[C:44]([NH:1][C:2]1[CH:3]=[CH:4][C:5]2[O:9][C:8]([CH:10]([NH:17][C:18]3[CH:23]=[CH:22][C:21]([C:24]([N:26]([CH3:34])[CH2:27][CH2:28][C:29]([O:31][CH2:32][CH3:33])=[O:30])=[O:25])=[CH:20][CH:19]=3)[CH:11]3[CH2:12][CH2:13][CH2:14][CH2:15][CH2:16]3)=[C:7]([CH3:35])[C:6]=2[CH:36]=1)(=[O:46])[CH3:45]
Reactant: CC(=O)OC(C)=O
Reactant: CCOC(=O)CCN(C)C(=O)c1ccc(NC(c2oc3ccc(N)cc3c2C)C2CCCCC2)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CCOC(=O)CCN(C)C(=O)c1ccc(NC(c2oc3ccc(NC(C)=O)cc3c2C)C2CCCCC2)cc1
Temperature: 25 °C
Reaction time: 60 h
Yield: 70 %

Procedure:
To a solution (10 mL) of ethyl 3-{[(4-{[(5-amino-3-methyl-1-benzofuran-2-yl)(cyclohexyl)methyl]amino}phenyl)carbonyl](methyl)amino}-propanoate (480 mg) synthesized above in tetrahydrofuran were added triethylamine (204 μL) and acetic anhydride (138 μL), and the mixture was stirred at room temperature for 2.5 days. Saturated aqueous sodium hydrogen carbonate solution was added to quench the reaction, and the reaction mixture was extracted with ethyl acetate. The extract was washed with saturated brine, dried over magnesium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (90% ethyl acetate/hexane) to give the title object compound (366 mg, 70%) as a pale-brown oil
Reaction SMILES: [CH3:1][S:2][C:3]1[CH:8]=[C:7]([C:9]2[S:10][C:11]3[CH:19]=[CH:18][CH:17]=[CH:16][C:12]=3[C:13](=[O:15])[N:14]=2)[CH:6]=[CH:5][N:4]=1.ClC1C=CC=C(C(OO)=[O:28])C=1>C(Cl)(Cl)Cl>[CH3:1][S:2]([C:3]1[CH:8]=[C:7]([C:9]2[S:10][C:11]3[CH:19]=[CH:18][CH:17]=[CH:16][C:12]=3[C:13](=[O:15])[N:14]=2)[CH:6]=[CH:5][N:4]=1)=[O:28]
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: CSc1cc(-c2nc(=O)c3ccccc3s2)ccn1
Solvent: ClC(Cl)Cl
Product: CS(=O)c1cc(-c2nc(=O)c3ccccc3s2)ccn1
Temperature: 25 °C
Reaction time: 1 h
Yield: 31.7 %

Procedure:
2-[2-(Methylthio)-4-pyridyl]-4H-1,3-benzothiazine-4-one (0.28 g, 1.00 mmol) was dissolved in chloroform (30 ml), and a solution of 3-chloroperbenzoic acid (ca. 77%, 0.23 g, 1.00 mmol) in chloroform (10 ml) was added dropwise thereto. The mixture was stirred at room temperature for 1 hr. The solvent was evaporated, and the residue was recrystallized from ethanol to give the titled compound (0.096 g, 32%) as pale yellow crystals.
Reaction SMILES: [CH:1]([C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)/[C:9](=[N:13]/[OH:14])/[CH2:8][CH2:7][CH2:6]2)=[CH2:2].C([N-]C(C)C)(C)C.[Li+].[F:23][C:24]([F:36])([F:35])[C:25]1[CH:26]=[C:27]([CH:32]=[CH:33][CH:34]=1)[C:28](OC)=O.S(=O)(=O)(O)O>O.C1(C)C=CC=CC=1>[F:23][C:24]([F:35])([F:36])[C:25]1[CH:26]=[C:27]([C:28]2[O:14][N:13]=[C:9]3[C:10]4[C:5]([CH2:6][CH2:7][C:8]=23)=[CH:4][C:3]([CH:1]=[CH2:2])=[CH:12][CH:11]=4)[CH:32]=[CH:33][CH:34]=1
Reactant: COC(=O)c1cccc(C(F)(F)F)c1
Reactant: C=Cc1ccc2c(c1)CCC/C2=N\O
Agent: CC(C)[N-]C(C)C
Agent: O=S(=O)(O)O
Agent: [Li+]
Solvent: Cc1ccccc1
Solvent: O
Product: C=Cc1ccc2c(c1)CCc1c-2noc1-c1cccc(C(F)(F)F)c1
Temperature: 0 °C
Reaction time: 0.17 h
Yield: 81.4 %

Procedure:
To 6-vinyl-3,4-dihydronaphthalen-1(2H)-one oxime (Intermediate 1, 0.151 g, 0.808 mmol) was added 5 mL of toluene and the contents were concentrated under reduced pressure. The resulting solid was kept under high vacuum for 10 min. The white solid was cooled to 0° C. and lithium diisopropylamide (2.0 M, 0.8 mL, 1.61 mmol) was added drop wise over a period of 3 min. The reaction mixture was stirred at 0° C. for 20 min., then methyl 3-(trifluoromethyl)benzoate (0.087 mL, 0.539 mmol) was added dropwise over a period of 1 min. at 0° C. After 10 min. at 0° C., concentrated sulfuric acid (0.2 mL) was added dropwise at 0° C. and the reaction was stirred for 20 minutes. Water (2 mL) was added and the homogenous solution was heated at 60° C. for ˜2 hr. The reaction mixture was stirred overnight at room temperature. The contents were concentrated under reduced pressure. Next, 5 mL of dioxane was added and the contents were heated at 100° C. for 1.5 hr. The reaction mixture was concentrated under reduced pressure and partitioned between ethyl acetate (20 mL) and sat. aq. sodium bicarbonate (10 mL). The ethyl acetate layer was dried over sodium sulfate, concentrated under reduced pressure, and purified by silica gel column chromatography (hexane/ethyl acetate). Fractions corresponding to the product were collected and concentrated to yield 3-(3-(trifluoromethyl)phenyl)-7-vinyl-4,5-dihydronaphtho[1,2-c]isoxazole (0.15 g, 0.439 mmol, 82% yield) as a pale yellow solid. LC/MS M+1=342.
Reaction SMILES: [CH2:1]([O:3][CH2:4][C:5]1[N:6]([CH2:18][CH2:19][CH2:20][C:21]2([OH:27])[CH2:26][CH2:25][CH2:24][CH2:23][CH2:22]2)[C:7]2[C:16]3[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=3[N:10]=[CH:9][C:8]=2[N:17]=1)[CH3:2].C1C=C(Cl)C=C(C(OO)=O)C=1.[OH-].[NH4+:40].C1(C)C=CC(S(Cl)(=O)=O)=CC=1>C(Cl)(Cl)Cl>[NH2:40][C:9]1[C:8]2[N:17]=[C:5]([CH2:4][O:3][CH2:1][CH3:2])[N:6]([CH2:18][CH2:19][CH2:20][C:21]3([OH:27])[CH2:22][CH2:23][CH2:24][CH2:25][CH2:26]3)[C:7]=2[C:16]2[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=2[N:10]=1
Reactant: [NH4+]
Reactant: CCOCc1nc2cnc3ccccc3c2n1CCCC1(O)CCCCC1
Agent: Cc1ccc(S(=O)(=O)Cl)cc1
Agent: O=C(OO)c1cccc(Cl)c1
Agent: [OH-]
Solvent: ClC(Cl)Cl
Product: CCOCc1nc2c(N)nc3ccccc3c2n1CCCC1(O)CCCCC1
Temperature: 0 °C
Reaction time: 1.5 h
Yield: 53 %

Procedure:
To a solution of 1-{3-[2-(ethoxymethyl)-1H-imidazo[4,5-c]quinolin-1-yl]propyl}cyclohexanol (1.10 g, 2.99 mmol) in chloroform (15 mL) at rt was added m-CPBA (0.96 g, 3.89 mmol) in portions. The reaction was stirred for 1.5 h, then was cooled to 0° C. and concentrated ammonium hydroxide (5 mL) was added followed by portionwise addition of p-toluenesulfonyl chloride (0.630 g, 3.29 mmol). The mixture was stirred at 0° C. for 1 h, then was filtered. The filtrate was diluted with dichloromethane (30 mL) and saturated aqueous sodium bicarbonate (30 mL). The layers were separated and the aqueous layer was extracted with dichloromethane (20 mL). The organic layers were combined, dried over MgSO4, filtered, and concentrated to afford an orange solid, which was purified by HPFC (silica gel, eluted with 0-35% CMA/chloroform). The appropriate fractions were concentrated to afford a tan solid that was crystallized from chloroform/hexanes and dried at 75° C. under vacuum to afford 1-{3-[4-amino-2-(ethoxymethyl)-1H-imidazo[4,5-c]quinolin-1-yl]propyl}cyclohexanol as white crystals (600 mg, 53%), mp 175-176° C. Anal. calcd for C22H30N4O2: C, 69.08; H, 7.91; N, 14.65.
Reaction SMILES: [NH2:1][CH:2]([C:7]1[CH:8]=[C:9]([C:13]2[CH:20]=[CH:19][C:16]([C:17]#[N:18])=[C:15]([CH3:21])[CH:14]=2)[CH:10]=[N:11][CH:12]=1)[C:3]([F:6])([F:5])[F:4].C(N(CC)CC)C.[CH2:29]([S:31](Cl)(=[O:33])=[O:32])[CH3:30]>C(Cl)Cl>[C:17]([C:16]1[CH:19]=[CH:20][C:13]([C:9]2[CH:8]=[C:7]([CH:2]([NH:1][S:31]([CH2:29][CH3:30])(=[O:33])=[O:32])[C:3]([F:4])([F:6])[F:5])[CH:12]=[N:11][CH:10]=2)=[CH:14][C:15]=1[CH3:21])#[N:18]
Reactant: CCS(=O)(=O)Cl
Reactant: Cc1cc(-c2cncc(C(N)C(F)(F)F)c2)ccc1C#N
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCS(=O)(=O)NC(c1cncc(-c2ccc(C#N)c(C)c2)c1)C(F)(F)F
Temperature: 25 °C
Reaction time: 16 h
Yield: 15.8 %

Procedure:
To a solution of 4-(5-(1-amino-2,2,2-trifluoroethyl)pyridin-3-yl)-2-methylbenzonitrile (322 mg, 1.105 mmol) in CH2Cl2 (5.5 mL) at 0° C. was added triethylamine (462 μl, 3.32 mmol) and ethanesulfonyl chloride (115 μl, 1.216 mmol). The mixture was stirred for 16 h at room temperature. The mixture was quenched with saturated NaHCO3 and extracted with EtOAc two times, dried over magnesium sulfate, filtered, concentrated. The residue was purified via Biotage (10-50% EtOAc/heptane; SNAP25 column) giving the title compound (67 mg, 16%). LC-MS (M+1) 384.1. 1H NMR (400 MHz, MeOD) δ ppm 1.28 (t, J=7.33 Hz, 3H) 2.63 (s, 3H) 2.96-3.19 (m, 2H) 5.47 (q, J=7.89 Hz, 1H) 7.66-7.72 (m, 1H) 7.76-7.79 (m, 1H) 7.81 (d, J=8.02 Hz, 1H) 8.24-8.43 (m, 1H) 8.76 (d, J=2.27 Hz, 1H) 8.93 (d, J=2.21 Hz, 1H).
Reaction SMILES: [N:1]12[CH2:9][CH:5]([C:6](=[O:8])[CH2:7]1)[CH2:4][CH2:3][CH2:2]2.[C:10]12([CH2:20][S:21]([OH:24])(=[O:23])=[O:22])[C:17]([CH3:19])([CH3:18])[CH:14]([CH2:15][CH2:16]1)[CH2:13][C:11]2=[O:12]>C(O)C>[C:10]12([CH2:20][S:21]([OH:24])(=[O:22])=[O:23])[C:17]([CH3:19])([CH3:18])[CH:14]([CH2:15][CH2:16]1)[CH2:13][C:11]2=[O:12].[N:1]12[CH2:9][C@@H:5]([C:6](=[O:8])[CH2:7]1)[CH2:4][CH2:3][CH2:2]2
Reactant: O=C1CN2CCCC1C2
Agent: CC1(C)C2CCC1(CS(=O)(=O)O)C(=O)C2
Solvent: CCO
Product: O=C1CN2CCC[C@H]1C2
Temperature: 70 °C

Procedure:
To a solution of (±)1-azabicyclo[3.2.1]octan-6-one (124 g, 1 mol) in ethanol (100 ml) was added a solution of (+)camphorsulfonic acid (232 g, 1.0 mol) in 200 ml ethanol. The mixture was heated to 70° C. and slowly cooled over 2 hours to 5° C. The precipitated crystals were collected by filtration and washed with cold ethanol (3×40 ml). The crude compound was crystallized from ethanol (150 ml) giving the title compound in 57.3 g yield. M.p. 267°-268° C. (decomp.). [α]D =+48° (water).
Reaction SMILES: [CH2:1]([N:3]1[C:12]2[C:7](=[CH:8][CH:9]=[C:10]([C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][N:14]=3)[CH:11]=2)[C:6](=[O:19])[C:5]([C:20]([OH:22])=O)=[CH:4]1)[CH3:2].FC1C=CC([N:30]2C3C(=CC=C(C4C=CN=CC=4)C=3)C(=O)C(C(N)=O)=C2)=CC=1>>[CH2:1]([N:3]1[C:12]2[C:7](=[CH:8][CH:9]=[C:10]([C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][N:14]=3)[CH:11]=2)[C:6](=[O:19])[C:5]([C:20]([NH2:30])=[O:22])=[CH:4]1)[CH3:2]
Reactant: CCn1cc(C(=O)O)c(=O)c2ccc(-c3ccccn3)cc21
Reactant: NC(=O)c1cn(-c2ccc(F)cc2)c2cc(-c3ccncc3)ccc2c1=O
Product: CCn1cc(C(N)=O)c(=O)c2ccc(-c3ccccn3)cc21

Procedure:
[I; R=H, R1C2H5, R2H, R6H, R7 -pyridinyl] was prepared from 2.94 g 1-ethyl-1,4-dihydro-4-oxo-7-(2-pyridinyl)-3-quinolinecarboxylic acid (U.S. Pat No. 3,753,993) according to the procedure of Example 1, part (h), and was obtained (2.66 g) in the form of a light-tan solid, m.p. 245°-246° C.
Reaction SMILES: [ClH:1].Cl.[Cl:3][C:4]1C(C2SC3C=CC=C(C(N)=O)C=3C=2)=NC(NCCC2CCN(C)CC2)=NC=1.[CH:32]1([NH:35][C:36]([C:38]2[C:46]3[CH:45]=[C:44]([C:47]4[C:52]([CH3:53])=[CH:51][N:50]=[C:49]([NH:54][CH2:55][CH2:56][CH2:57][N:58]5[CH2:63][CH2:62][NH:61][CH2:60][C@@H:59]5[CH3:64])[N:48]=4)[S:43][C:42]=3[CH:41]=[CH:40][CH:39]=2)=[O:37])[CH2:34][CH2:33]1>>[ClH:3].[ClH:1].[ClH:3].[CH:32]1([NH:35][C:36]([C:38]2[C:46]3[CH:45]=[C:44]([C:47]4[C:52]([CH3:53])=[CH:51][N:50]=[C:49]([NH:54][CH2:55][CH2:56][CH2:57][N:58]5[CH2:63][CH2:62][N:61]([CH3:4])[CH2:60][C@@H:59]5[CH3:64])[N:48]=4)[S:43][C:42]=3[CH:41]=[CH:40][CH:39]=2)=[O:37])[CH2:33][CH2:34]1
Reactant: CN1CCC(CCNc2ncc(Cl)c(-c3cc4c(C(N)=O)cccc4s3)n2)CC1
Reactant: Cc1cnc(NCCCN2CCNC[C@@H]2C)nc1-c1cc2c(C(=O)NC3CC3)cccc2s1
Agent: Cl
Product: Cc1cnc(NCCCN2CCN(C)C[C@@H]2C)nc1-c1cc2c(C(=O)NC3CC3)cccc2s1

Procedure:
Using the method of 2-{5-chloro-2-[2-(1-methylpiperidin-4-yl)-ethylamino]-pyrimidin-4-yl}-benzo[b]thiophene-4-carboxylic acid amide di-hydrochloride, the title compound is synthesized from (S)-2{5-methyl-2-[3-(2-methylpiperazin-1-yl)-propylamino]-pyrimidin-4-yl}-benzo[b]thiophene-4-carboxylic acid cyclopropylamide and isolated as a yellow solid. ES+(m/z) 479 [M(free base)+H].
Reaction SMILES: [C:1]([O:5][C:6]([N:8]([CH2:21][C:22]1[N:23]=[CH:24][S:25][CH:26]=1)[C@H:9]([C:17]([O:19]C)=[O:18])[CH2:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].O[Li].O>C1COCC1.O>[C:1]([O:5][C:6]([N:8]([CH2:21][C:22]1[N:23]=[CH:24][S:25][CH:26]=1)[C@H:9]([C:17]([OH:19])=[O:18])[CH2:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: COC(=O)[C@H](Cc1ccccc1)N(Cc1cscn1)C(=O)OC(C)(C)C
Agent: [Li]O
Solvent: O
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N(Cc1cscn1)[C@@H](Cc1ccccc1)C(=O)O
Temperature: 25 °C
Yield: 83.1 %

Procedure:
Ester 34.8.D (2.75 g, 7.3 mmol) was dissolved in THF/H2O. LiOH hydrate (646 mg, 15.4 mmol) was added and the mixture was stirred at room temperature. The THF was removed on a rotavap and the resulting aqueous layer was acidified with 1.0 N HCl and then conc. HCl. A white sticky solid formed which was extracted with EtOAc. The organic layers were dried with sodium sulfate, filtered, and concentrated to yield 34.8.E as a sticky foam (2.20 g).
Reaction SMILES: F[C:2]1[CH:11]=[CH:10][C:5]([C:6]([O:8][CH3:9])=[O:7])=[CH:4][C:3]=1[N+:12]([O-:14])=[O:13].[NH2:15][C:16]1[CH:21]=[CH:20][CH:19]=[C:18]([CH3:22])[CH:17]=1.C(=O)([O-])[O-].[K+].[K+]>C(#N)C>[N+:12]([C:3]1[CH:4]=[C:5]([CH:10]=[CH:11][C:2]=1[NH:15][C:16]1[CH:17]=[C:18]([CH3:22])[CH:19]=[CH:20][CH:21]=1)[C:6]([O:8][CH3:9])=[O:7])([O-:14])=[O:13]
Reactant: COC(=O)c1ccc(F)c([N+](=O)[O-])c1
Reactant: Cc1cccc(N)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: COC(=O)c1ccc(Nc2cccc(C)c2)c([N+](=O)[O-])c1
Yield: 73.3 %

Procedure:
The compound obtained in Step 1 (1.30 g, 6.53 mmol), m-toluidine (1.40 g, 13.1 mmol), and potassium carbonate (870 mg, 6.53 mmol) were dissolved in acetonitrile, and then stirred under reflux for 12 hours. The solvent was removed by concentration under reduced pressure, and then the precipitate generated by adding hexane thereto was filtered and washed with hexane, to obtain methyl 3-nitro-4-(m-tolylamino)benzoate as an orange solid (1.37 g, 73%).
Reaction SMILES: [C:1]([NH:5][C:6]([NH:8][CH2:9][CH2:10]Cl)=[O:7])([CH3:4])([CH3:3])[CH3:2].[H-].[Na+]>C1COCC1>[C:1]([N:5]1[CH2:10][CH2:9][NH:8][C:6]1=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)NC(=O)NCCCl
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CC(C)(C)N1CCNC1=O
Temperature: 25 °C
Reaction time: 1 h
Yield: 74.8 %

Procedure:
A 0° C. solution of 1-(tert-butyl)-3-(2-chloroethyl)urea (2.00 g, 11.19 mmol) in THF (20 mL) was treated with NaH (60% in mineral oil, 0.800 g, 33.3 mmol), stirred at RT for 1 h, then heated at 65° C. overnight. The mixture was cooled to RT, concentrated to dryness, treated with satd. NH4Cl, extracted with EtOAc (3×) and the combined organics were dried over Na2SO4 and concentrated to dryness to afford 1-(tert-butyl)imidazolidin-2-one (1.19 g, 75%). MS (ESI) m/z: 143.1 (M+H+).
Reaction SMILES: [C:1]([O:6][CH2:7][CH3:8])(=[O:5])/[CH:2]=[CH:3]/[CH3:4].[CH2:9]([NH2:16])[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1>>[CH2:9]([NH:16][CH:3]([CH3:4])[CH2:2][C:1]([O:6][CH2:7][CH3:8])=[O:5])[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1
Reactant: C/C=C/C(=O)OCC
Reactant: NCc1ccccc1
Product: CCOC(=O)CC(C)NCc1ccccc1
Yield: 68.9 %

Procedure:
A solution of ethyl crotonate (5.0 ml, 40 mmol) and benzyl amine (4.8 ml, 44 mmol) was heated to 100° C. for 18 hs. The reaction was allowed to cool and the product was distilled at 90° C. at 200 mtorr pressure to give the ethyl 3-(benzylamino)butanoate (6.1 g, 69%) as a clear oil, MS (M+H)+=222.