Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: S(C1C=CC(C)=CC=1)([O-])(=O)=O.[C:12]([C:16]1[CH:17]=[C:18]([CH:22]=[C:23]([C:26]([CH3:29])([CH3:28])[CH3:27])[C:24]=1[OH:25])[CH2:19][CH2:20]O)([CH3:15])([CH3:14])[CH3:13].[N:30]1([C:36]2[CH:41]=[CH:40][C:39]([CH2:42][C:43]([O:45][CH2:46][CH2:47][CH2:48][CH3:49])=[O:44])=[CH:38][CH:37]=2)[CH2:35][CH2:34][NH:33][CH2:32][CH2:31]1.C(=O)([O-])[O-].[K+].[K+]>CC(=O)CC>[C:26]([C:23]1[CH:22]=[C:18]([CH:17]=[C:16]([C:12]([CH3:13])([CH3:15])[CH3:14])[C:24]=1[OH:25])[CH2:19][CH2:20][N:33]1[CH2:32][CH2:31][N:30]([C:36]2[CH:37]=[CH:38][C:39]([CH2:42][C:43]([O:45][CH2:46][CH2:47][CH2:48][CH3:49])=[O:44])=[CH:40][CH:41]=2)[CH2:35][CH2:34]1)([CH3:29])([CH3:27])[CH3:28]
Reactant: CC(C)(C)c1cc(CCO)cc(C(C)(C)C)c1O
Reactant: CCCCOC(=O)Cc1ccc(N2CCNCC2)cc1
Agent: Cc1ccc(S(=O)(=O)[O-])cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCC(C)=O
Product: CCCCOC(=O)Cc1ccc(N2CCN(CCc3cc(C(C)(C)C)c(O)c(C(C)(C)C)c3)CC2)cc1

Procedure:
A mixture of 20.2 g. (50 mmole) of the tosylate of 3,5-di-tert.-butyl-4-hydroxyphenethyl alcohol, 13.8 g. (50 mmole) n-butyl 4-(piperazin-1-yl)-phenylacetate, 6.9 g. (50 mmole) powdered anhydrous potassium carbonate and 200 ml. butan-2-one is maintained at reflux temperature for 24 hours, then suction filtered hot and the filtrate evaporated in a vacuum. The residue is taken up in diethyl ether, the ether phase is extracted twice with water, then dried with anhydrous sodium sulphate and evaporated. By means of ligroin, the product is brought to crystallisation and recrystallised from n-butanol. Yield 14.3 g. (59% of theory); m.p. 103°-105° C.
Reaction SMILES: C(OC([N:8]1[CH2:12][CH2:11][C@@H:10]([O:13][NH:14][C:15]([C@@H:17]2[CH2:23][CH2:22][C@@H:21]3[CH2:24][N:18]2[C:19](=[O:30])[N:20]3[O:25][S:26]([O-:29])(=[O:28])=[O:27])=[O:16])[CH2:9]1)=O)(C)(C)C.C([N+](CCCC)(CCCC)CCCC)CCC.FC(F)(F)C(O)=O>C(Cl)Cl>[O:30]=[C:19]1[N:18]2[CH2:24][C@@H:21]([CH2:22][CH2:23][C@H:17]2[C:15]([NH:14][O:13][C@@H:10]2[CH2:11][CH2:12][NH:8][CH2:9]2)=[O:16])[N:20]1[O:25][S:26]([OH:29])(=[O:28])=[O:27]
Reactant: CC(C)(C)OC(=O)N1CC[C@@H](ONC(=O)[C@@H]2CC[C@@H]3CN2C(=O)N3OS(=O)(=O)[O-])C1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: O=C(NO[C@@H]1CCNC1)[C@@H]1CC[C@@H]2CN1C(=O)N2OS(=O)(=O)O
Reaction time: 1 h

Procedure:
To a solution of N,N,N-tributylbutan-1-aminium ({[(2S,5R)-2-({[(3R)-1-(tert-butoxycarbonyl)pyrrolidin-3-yl]oxy}carbamoyl)-7-oxo-1,6-diazabicyclo[3.2.1]oct-6-yl]oxy}sulfonyl)oxidanide 6 (0.245 g, 0.35 mmol) in DCM (14 mL) was added trifluoroacetic acid (0.70 mL, 9.08 mmol) dropwise at 0° C. The reaction mixture was stirred for 1 h, then evaporated. Ether was added to the residue and the resulting white precipitate was collected by centrifugation. The solid was triturated with acetonitrile (2×) and the white solid was collected by centrifugation. The white solid was purified by HPLC on a prep-X Bridge-19×250 mm column and freeze-dried to give (2S,5R)-7-oxo-N-[(3R)-pyrrolidin-3-yloxy]-6-(sulfooxy)-1,6-diazabicyclo[3.2.1]octane-2-carboxamide Compound 1 (Table 1) (0.03 g, 25%) as a white solid.
Reaction SMILES: C(NCC1SC=C([C:11]2[CH:20]=[C:19]3[C:14]([C:15](=[O:28])[C:16]([C:23]([O:25]CC)=[O:24])=[CH:17][N:18]3[CH2:21][CH3:22])=[CH:13][C:12]=2[F:29])N=1)(=O)C>Cl>[CH2:21]([N:18]1[C:19]2[C:14](=[CH:13][C:12]([F:29])=[CH:11][CH:20]=2)[C:15](=[O:28])[C:16]([C:23]([OH:25])=[O:24])=[CH:17]1)[CH3:22]
Reactant: CCOC(=O)c1cn(CC)c2cc(-c3csc(CNC(C)=O)n3)c(F)cc2c1=O
Agent: Cl
Product: CCn1cc(C(=O)O)c(=O)c2cc(F)ccc21

Procedure:
A solution of 0.32 g (0.76 mmol) ethyl 7-[2-(acetamidomethyl)-4-thiazolyl]-1-ethyl-6-fluoro-1,4-dihydro-4-oxo-3-quinolinecarboxylate in 3 ml 6N hydrochloric acid was stirred at reflux three hours. The mixture was evaporated to dryness and the resulting solid was suspended in 5 ml water and dissolved by addition of 1N sodium hydroxide to pH 11. After filtration the product was precipitated by addition of 1N hydrochloric acid to pH 6.2, filtered, washed with water and dried to afford 0.22 g 7-[2-aminomethyl)-4-thiazolyl]-1-ethyl-6-fluoro-1,4-dihydro-4-oxo-3-quinolinecarboxylic acid, mp 249°-254° C. (dec).
Reaction SMILES: C(OC([N:6]=[S:7]([C:10]1[CH:15]=[CH:14][C:13]([NH:16][C:17]2[N:22]=[C:21]([NH:23][C@H:24]([CH2:29][OH:30])[CH2:25][CH:26]([CH3:28])[CH3:27])[C:20]([C:31]3[CH:35]=[CH:34][S:33][CH:32]=3)=[CH:19][N:18]=2)=[CH:12][CH:11]=1)([CH3:9])=[O:8])=O)C.CC[O-].[Na+]>>[OH:30][CH2:29][C@@H:24]([NH:23][C:21]1[C:20]([C:31]2[CH:35]=[CH:34][S:33][CH:32]=2)=[CH:19][N:18]=[C:17]([NH:16][C:13]2[CH:12]=[CH:11][C:10]([S:7]([CH3:9])(=[NH:6])=[O:8])=[CH:15][CH:14]=2)[N:22]=1)[CH2:25][CH:26]([CH3:28])[CH3:27]
Reactant: CCOC(=O)N=S(C)(=O)c1ccc(Nc2ncc(-c3ccsc3)c(N[C@H](CO)CC(C)C)n2)cc1
Agent: CC[O-]
Agent: [Na+]
Product: CC(C)C[C@@H](CO)Nc1nc(Nc2ccc(S(C)(=N)=O)cc2)ncc1-c1ccsc1
Yield: 36 %

Procedure:
In the reaction of (RS)—N-(ethoxycarbonyl)-S-(4-{[4-{[(S)-1-(hydroxymethyl)-3-methylbutyl]amino}-5-(3-thienyl)pyrimidine-2-yl]amino}phenyl)-S-methyl-sulfoximide (135 mg, 0.26 mmol) with sodium ethylate (70 mg, 1.0 mmol) according to procedure 14, the desired product is obtained in 36% yield (42 mg) after chromatographic purification (silica gel, dichloromethane/methanol (9/1)).
Reaction SMILES: [CH3:1][C:2]1[NH:3][CH2:4][CH2:5][N:6]=1.Cl[CH2:8][C:9](=[O:11])[CH3:10]>CC(C)=O>[O:11]=[C:9]([CH3:10])[CH2:8][N:6]1[CH2:5][CH2:4][N:3]=[C:2]1[CH3:1]
Reactant: CC1=NCCN1
Reactant: CC(=O)CCl
Solvent: CC(C)=O
Product: CC(=O)CN1CCN=C1C

Procedure:
A mixture of 8.4 g. of 2-methyl-2-imidazoline and 9.25 g. of chloroacetone is refluxed in 100 ml. of acetone for two hours. The solvent is removed in vacuo, and the residue is taken up in water and neutralized with 1N sodium hydroxide. Extracting with chloroform, drying and removing the solvent in vacuo gives 1-(2-oxopropyl)-2-methyl-2-imidazoline.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([NH:14][C:15](=[O:22])[C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][N:17]=2)[CH:5]=[CH:6][C:7]=1[N:8]1[CH2:13][CH2:12][NH:11][CH2:10][CH2:9]1.[C:23](O)(=[O:26])[CH2:24][CH3:25].CCN=C=NCCCN(C)C.Cl.CCN(CC)CC.OC1C2N=NNC=2C=CC=1>C(Cl)Cl>[Cl:1][C:2]1[CH:3]=[C:4]([NH:14][C:15](=[O:22])[C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][N:17]=2)[CH:5]=[CH:6][C:7]=1[N:8]1[CH2:13][CH2:12][N:11]([C:23](=[O:26])[CH2:24][CH3:25])[CH2:10][CH2:9]1
Reactant: O=C(Nc1ccc(N2CCNCC2)c(Cl)c1)c1ccccn1
Reactant: CCC(=O)O
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: Oc1cccc2[nH]nnc12
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCC(=O)N1CCN(c2ccc(NC(=O)c3ccccn3)cc2Cl)CC1
Yield: 73.7 %

Procedure:
According to Scheme 5 Step 5 Method A: A solution of N-(3-chloro-4-(piperazin-1-yl)phenyl)picolinamide (0.19 mmol, 60 mg), propionic acid (0.19 mmol, 14 μL), EDCI.HCl (0.28 mmol, 54 mg), Et3N (0.38 mmol, 53 μL) and of hydroxybenzotriazole (0.21 mmol, 32 mg) in DCM (5 mL) was stirred at room temperature for 1 day. The solution was quenched with water. The aqueous phase was extracted with DCM. The organic phase was washed with brine, was dried over Na2SO4, was filtered and was concentrated under reduced pressure. The solid was triturated with water and finally with iPr2O to afford N-(3-chloro-4-(4-propionylpiperazin-1-yl)phenyl)picolinamide (0.14 mmol, 51 mg, 72%) as a yellow solid.
Reaction SMILES: C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].[CH3:15][O:16][C:17]1[C:30]2[CH2:29][CH2:28][C@H:27]3[C@@H:22]([CH2:23][CH2:24][CH2:25][NH:26]3)[C:21]=2[CH:20]=[CH:19][CH:18]=1.[C:31]1([C:37]2[CH:50]=[CH:49][C:40]([C:41]([NH:43][CH2:44][CH2:45][CH2:46][CH:47]=O)=[O:42])=[CH:39][CH:38]=2)[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1.C([O-])([O-])=O.[K+].[K+]>ClCCl>[CH3:15][O:16][C:17]1[C:30]2[CH2:29][CH2:28][C@H:27]3[C@@H:22]([CH2:23][CH2:24][CH2:25][N:26]3[CH2:47][CH2:46][CH2:45][CH2:44][NH:43][C:41](=[O:42])[C:40]3[CH:49]=[CH:50][C:37]([C:31]4[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=4)=[CH:38][CH:39]=3)[C:21]=2[CH:20]=[CH:19][CH:18]=1
Reactant: O=CCCCNC(=O)c1ccc(-c2ccccc2)cc1
Reactant: COc1cccc2c1CC[C@@H]1NCCC[C@@H]21
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: ClCCl
Product: COc1cccc2c1CC[C@H]1[C@H]2CCCN1CCCCNC(=O)c1ccc(-c2ccccc2)cc1
Reaction time: 6 h

Procedure:
Sodium triacetoxyborohydride 0.83 g, 3.9 mmol) was added to a stirred mixture of trans-7-methoxy-1,2,3,4,4a,5,6,10b-octahydrobenzo[f]quinoline (D6a, 0.57 g, 2.6 mmol) and 4-(4-phenylbenzoylamino)butyraldehyde (0.77 g, 2.9 mmol) in dichloromethane (50 ml) at room temperature. After stirring for 6 h, the mixture was poured onto saturated aqueous K2CO3 (40 ml) and extracted with dichloromethane (3×20 ml). The combined organic extracts were washed with brine, dried (Na2SO4) and concentrated in vacuo to afford a white solid which was chromatographed on silica using 40-100% ethyl acetate/pentane as elution gradient. The title compound was obtained as a white solid (1.2 g, 99%).
Reaction SMILES: [Cl:1][C:2]1[CH:26]=[N:25][C:5]2[NH:6][C:7]3[C:12]([C:4]=2[CH:3]=1)=[C:11]([C:13]1[CH:18]=[CH:17][CH:16]=[C:15]([S:19]([CH2:22][CH3:23])(=[O:21])=[O:20])[CH:14]=1)[CH:10]=[CH:9][C:8]=3[OH:24].C(S(C1C=C(C2C=C[C:44]([O:47]CCO)=[C:43]3C=2C2C=C(C)C=NC=2N3)C=CC=1)(=O)=O)C>>[Cl:1][C:2]1[CH:26]=[N:25][C:5]2[NH:6][C:7]3[C:12]([C:4]=2[CH:3]=1)=[C:11]([C:13]1[CH:18]=[CH:17][CH:16]=[C:15]([S:19]([CH2:22][CH3:23])(=[O:21])=[O:20])[CH:14]=1)[CH:10]=[CH:9][C:8]=3[O:24][CH2:43][CH2:44][OH:47]
Reactant: CCS(=O)(=O)c1cccc(-c2ccc(O)c3[nH]c4ncc(Cl)cc4c23)c1
Reactant: CCS(=O)(=O)c1cccc(-c2ccc(OCCO)c3[nH]c4ncc(C)cc4c23)c1
Product: CCS(=O)(=O)c1cccc(-c2ccc(OCCO)c3[nH]c4ncc(Cl)cc4c23)c1

Procedure:
The title compound was prepared from Compound 218 by using an analogous procedure to that outlined in the preparation of Compound 215. 1H NMR (400 MHz, Methanol-d4) δ 8.39 (s, 1H) 8.14 (m, 1H) 8.06 (m, 1H) 8.00 (m, 1H) 7.87 (t, J=8.0 Hz, 1H) 7.71 (d, J=4.0 Hz, 1H) 7.21 (d, J=8.0 Hz, 1H) 7.16 (d, J=8.0 Hz, 1H) 4.36 (t, J=4 Hz, 2H) 4.07 (t, J=4 Hz, 2H) 3.30 (q, J=7.5 Hz, 2H) 1.31 (t, J=7.5 Hz, 3H). [M+H] calc'd for C21H20ClN2O4S, 431; found, 431.
Reaction SMILES: [C:1]([C:4]1[CH:9]=[C:8]([Cl:10])[CH:7]=[C:6]([CH3:11])[C:5]=1[OH:12])(=[O:3])[CH3:2].[CH:13]1([C:19](OC)=[O:20])[CH2:18][CH2:17][CH2:16][CH2:15][CH2:14]1.[H-].[Na+].Cl>C1(C)C=CC=CC=1.O>[Cl:10][C:8]1[CH:7]=[C:6]([CH3:11])[C:5]([OH:12])=[C:4]([C:1](=[O:3])[CH2:2][C:19]([CH:13]2[CH2:18][CH2:17][CH2:16][CH2:15][CH2:14]2)=[O:20])[CH:9]=1
Reactant: CC(=O)c1cc(Cl)cc(C)c1O
Reactant: COC(=O)C1CCCCC1
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: Cc1ccccc1
Solvent: O
Product: Cc1cc(Cl)cc(C(=O)CC(=O)C2CCCCC2)c1O

Procedure:
2-Acetyl-4-chloro-6-methylphenol (1.84 g) and methyl cyclohexanecarboxylate (1.7 g) were dissolved in toluene (36 ml) and to the solution was added 60% sodium hydride (0.96 g). Then, the mixture was heated under reflux for 16 hours. The mixture was poured into cold water. Diluted hydrochloric acid was added and crystals precipitated were filtered and recrystallized from methanol to obtain the title compound, yield 1.54 g (52.2%). The melting point and IR and NMR spectra were identical with those of the compound of Reference Example 5.
Reaction SMILES: [C:1]([C:3]([C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)([C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)[CH:4]([CH3:8])[C:5](Cl)=[O:6])#[N:2].[CH:21]([NH:24][CH:25]([CH3:27])[CH3:26])([CH3:23])[CH3:22].C(C(C1C=CC=CC=1)(C1C=CC=CC=1)C(CC)C(N(C)C)=O)#N>O>[C:1]([C:3]([C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)([C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)[CH:4]([CH3:8])[C:5]([N:24]([CH:25]([CH3:27])[CH3:26])[CH:21]([CH3:23])[CH3:22])=[O:6])#[N:2]
Reactant: CC(C)NC(C)C
Reactant: CC(C(=O)Cl)C(C#N)(c1ccccc1)c1ccccc1
Agent: CCC(C(=O)N(C)C)C(C#N)(c1ccccc1)c1ccccc1
Solvent: O
Product: CC(C)N(C(=O)C(C)C(C#N)(c1ccccc1)c1ccccc1)C(C)C
Reaction time: 8 h

Procedure:
0.1 Mol of 3-cyano-3,3-diphenyl-2-methylpropionyl chloride were added dropwise while cooling and stirring to 50 g (0.5 mol) of diisopropylamine. The mixture was left standing at room temperature overnight and heated at 40°-50° C. for 30 minutes. The mixture was poured into water and isolated as described above for the preparation of 3-cyano-3,3-diphenyl-2-ethyl-N,N-dimethyl-propanamide. The amide was crystallized from a mixture of toluen and ether. Yield: 25 g (50%), melting at 195°-205° C.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[CH:4][C:5]2[C:6](=O)[C:7]3[C:12]([N:13]([CH2:17][CH2:18][CH2:19][Br:20])[C:14]=2[C:15]=1[CH3:16])=[CH:11][CH:10]=[CH:9][CH:8]=3.[CH3:22][Li].O>O1CCCC1.C(OCC)C>[CH3:1][C:2]1[CH:3]=[CH:4][C:5]2[C:6](=[CH2:22])[C:7]3[C:12]([N:13]([CH2:17][CH2:18][CH2:19][Br:20])[C:14]=2[C:15]=1[CH3:16])=[CH:11][CH:10]=[CH:9][CH:8]=3
Reactant: [Li]C
Reactant: Cc1ccc2c(=O)c3ccccc3n(CCCBr)c2c1C
Solvent: C1CCOC1
Solvent: O
Solvent: CCOCC
Product: C=C1c2ccccc2N(CCCBr)c2c1ccc(C)c2C
Reaction time: 1 h

Procedure:
0.1 g of 3,4-dimethyl-10-(3-bromopropyl)-9-acridone was dissolved in 5 ml of dry tetrahydrofuran. Then 0.36 ml of methyllithium (a 1.4 M solution in diethyl ether) was added dropwise at −78° C. After stirring at the same temperature for 1 hr, water was added to the liquid reaction mixture followed by extraction with ethyl acetate. The organic layer was washed with water and dried over anhydrous magnesium sulfate. After evaporating the solvent under reduced pressure, the residue was purified by silica gel column chromatography to give 0.1 g of the title compound.
Reaction SMILES: C[C:2]1[CH:8]=[C:7]([N+:9]([O-:11])=[O:10])[C:5]([NH2:6])=[C:4]([N+:12]([O-])=O)[CH:3]=1.[CH2:15](O)C>O>[CH3:15][NH:6][C:5]1[C:7]([N+:9]([O-:11])=[O:10])=[CH:8][CH:2]=[CH:3][C:4]=1[NH2:12]
Reactant: CCO
Reactant: Cc1cc([N+](=O)[O-])c(N)c([N+](=O)[O-])c1
Solvent: O
Product: CNc1c(N)cccc1[N+](=O)[O-]
Temperature: 28 °C
Yield: 85 %

Procedure:
The procedure of Gillespie et al., J. Org. Chem. 25:942 (1960) was adopted as follows. A dark black solution of 4-methyl-2,6-dinitroaniline (0.100 g, 0.561 mmol, Aldrich, used as received) in 6.66% aq. (NH4)2S (3.3 mL, prepared from 20% aq.(NH4)2S solution supplied by Aldrich) and ethanol (3.5 mL) was refluxed for 45 min. It was then cooled to 28° C. and the solvents were removed as much as possible under vacuum (inside the hood to avoid the stench of ammonium sulfide). The slurry so obtained was diluted with water (10 mL) and the -resulting red solid was filtered and dried under vacuum to obtain 0.072 g (85%) solid as a red powder, which was used as such for the next reaction. 1H NMR (acetone-dip: 2.205 (s, 3H), 6.342 for s, 2H), 6.622 (s, 1H), 7.571 (s, 1H).
Reaction SMILES: C([O:5][C:6](=[O:28])[C@H:7]([CH2:21][C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)[NH:8][C:9]([O:11][C:12]1[CH:17]=[CH:16][C:15]([N+:18]([O-:20])=[O:19])=[CH:14][CH:13]=1)=[O:10])(C)(C)C.FC(F)(F)C(O)=O>>[N+:18]([C:15]1[CH:14]=[CH:13][C:12]([O:11][C:9]([NH:8][C@H:7]([C:6]([OH:28])=[O:5])[CH2:21][C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)=[O:10])=[CH:17][CH:16]=1)([O-:20])=[O:19]
Reactant: CC(C)(C)OC(=O)[C@H](Cc1ccccc1)NC(=O)Oc1ccc([N+](=O)[O-])cc1
Solvent: O=C(O)C(F)(F)F
Product: O=C(N[C@@H](Cc1ccccc1)C(=O)O)Oc1ccc([N+](=O)[O-])cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 96 %

Procedure:
In a nitrogen atmosphere, 193 mg (0.5 mmol) of the N-(4-nitrophenoxycarbonyl)phenylalanine t-butyl ester and 5 mL of trifluoroacetic acid were introduced into a round-bottom flask having a capacity of 10 mL. The contents were stirred at room temperature for 1 hour. This reaction mixture was concentrated under reduced pressure with a vacuum pump and then analyzed by NMR spectroscopy using dioxane as an internal reference. As a result, it was found that N-(4-nitrophenoxycarbonyl)phenylalanine had been obtained in a yield of 96%. Furthermore, this reaction mixture was subjected to column isolation to obtain N-(4-nitrophenoxycarbonyl)phenylalanine in an amount of 160 mg (isolation yield, 97%).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([NH:9][C:10]2[C:19]3[C:14](=[CH:15][CH:16]=[C:17]([C:20]([N:22](C)[CH2:23][C:24]([F:27])([F:26])[F:25])=[O:21])[CH:18]=3)[N:13]=[C:12]([C:29]3[CH:30]=[N:31][CH:32]=[CH:33][CH:34]=3)[N:11]=2)[CH:5]=[CH:6][C:7]=1[F:8].FC(F)(F)CNC>>[Cl:1][C:2]1[CH:3]=[C:4]([NH:9][C:10]2[C:19]3[C:14](=[CH:15][CH:16]=[C:17]([C:20]([NH:22][CH2:23][C:24]([F:27])([F:25])[F:26])=[O:21])[CH:18]=3)[N:13]=[C:12]([C:29]3[CH:30]=[N:31][CH:32]=[CH:33][CH:34]=3)[N:11]=2)[CH:5]=[CH:6][C:7]=1[F:8]
Reactant: CN(CC(F)(F)F)C(=O)c1ccc2nc(-c3cccnc3)nc(Nc3ccc(F)c(Cl)c3)c2c1
Agent: CNCC(F)(F)F
Product: O=C(NCC(F)(F)F)c1ccc2nc(-c3cccnc3)nc(Nc3ccc(F)c(Cl)c3)c2c1

Procedure:
4-(3-chloro-4-fluorophenylamino)-2-(pyridin-3-yl)-N-(2,2,2-trifluoroethyl)quinazoline-6-carboxamide was synthesized in a similar manner to that described for 4-(3-chloro-4-fluorophenylamino)-N-methyl-2-(pyridin-3-yl)-N-(2,2,2-trifluoroethyl)quinazoline-6-carboxamide substituting 2,2,2-trifluoroethylamine for 2,2,2-trifluoro-N-methylethylamine. The resulting product was analyzed. LCMS: r.t=1.934 min, [M+1]+=476.0. 1H-NMR (400 MHz, DMSO-d6): δ 10.43 (s, 1H), 9.54 (s, 1H), 9.32 (t, J=6.1 Hz, 1H), 9.14 (s, 1H), 8.72 (d, J=4.6 Hz, 1H), 8.68 (d, J=8.0 Hz, 1H), 8.32 (d, J=8.7 Hz, 1H), 8.27 (dd, J=6.7, 2.2 Hz, 1H), 7.98 (d, J=8.7 Hz, 1H), 7.96-7.90 (m, 1H), 7.62-7.51 (m, 2H), 4.27-4.14 (m, 2H).
Reaction SMILES: [NH2:1][C:2]1[C:7]([C:8]([O:10][CH3:11])=[O:9])=[CH:6][CH:5]=[CH:4][N:3]=1.C(=O)([O-])[O-].[Ca+2].[CH3:17][NH:18][S:19](Cl)(=[O:21])=[O:20]>C(#N)C>[CH3:17][NH:18][S:19]([NH:1][C:2]1[C:7]([C:8]([O:10][CH3:11])=[O:9])=[CH:6][CH:5]=[CH:4][N:3]=1)(=[O:21])=[O:20]
Reactant: CNS(=O)(=O)Cl
Reactant: COC(=O)c1cccnc1N
Agent: O=C([O-])[O-]
Agent: [Ca+2]
Solvent: CC#N
Product: CNS(=O)(=O)Nc1ncccc1C(=O)OC
Reaction time: 15 h

Procedure:
Methyl 2-amino-3-pyridine carboxylate (15.2 grams; 0.1 mole), calcium carbonate (13.0 grams; 0.1 mole) and methylsulfamoyl chloride (13.0 grams; 0.1 mole) were mixed with 200 ml of acetonitrile and the resulting reaction mixture stirred at ambient temperatures for a period of about 15 hours. Following the reaction period, the reaction mixture was filtered and the solvent removed in vacuo. The semi-solid residue thus obtained was extracted with ethanol. A white crystalline precipitate, obtained by filtering the extract solution, was recrystallized from ethanol and the desired title compound having a melting point of 133° C.-139° C. was obtained.
Reaction SMILES: [Cl:1][C:2]1[CH:14]=[C:13]([N+:15]([O-])=O)[CH:12]=[CH:11][C:3]=1[C:4]([O:6][C:7]([CH3:10])([CH3:9])[CH3:8])=[O:5].C(OCC)(=O)C>C(O)C.[Pt]>[NH2:15][C:13]1[CH:12]=[CH:11][C:3]([C:4]([O:6][C:7]([CH3:9])([CH3:10])[CH3:8])=[O:5])=[C:2]([Cl:1])[CH:14]=1
Reactant: CC(C)(C)OC(=O)c1ccc([N+](=O)[O-])cc1Cl
Agent: [Pt]
Solvent: CCOC(C)=O
Solvent: CCO
Product: CC(C)(C)OC(=O)c1ccc(N)cc1Cl
Temperature: 25 °C
Yield: 96.3 %

Procedure:
To a solution of tert-butyl 2-chloro-4-nitro-benzoate (2.05 g, 7.98 mmol) in ethanol 12 mL) and ethyl acetate (108 mL) was added platinum on activated charcoal (5%, 295 mg), and the mixture was stirred under at room temperature under a hydrogen atmosphere (1 bar). After filtration through a pad of diatomaceous earth, the filtrate was evaporated to afford tert-butyl 4-amino-2-chlorobenzoate (1.75 g, 96%). Orange solid, MS (EI)=227.2 (M+).
Reaction SMILES: [OH-].[Na+].C([O:11][CH2:12][CH:13]([CH2:32][CH:33]([O:35][C:36](=[O:43])[C:37]1[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=1)[CH3:34])[CH2:14][S:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH3:31])(=O)C1C=CC=CC=1>CO.O1CCCC1>[C:36]([O:35][CH:33]([CH3:34])[CH2:32][CH:13]([CH2:14][S:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH3:31])[CH2:12][OH:11])(=[O:43])[C:37]1[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=1
Reactant: CCCCCCCCCCCCCCCCSCC(COC(=O)c1ccccc1)CC(C)OC(=O)c1ccccc1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Product: CCCCCCCCCCCCCCCCSCC(CO)CC(C)OC(=O)c1ccccc1
Yield: 62.8 %

Procedure:
Using 6.89 ml (13.78 mM) of 2N aqueous sodium hydroxide, 4.017 g (6.89 mM) of 2-(2-benzoyloxypropan-1-yl)-3-hexadecylthio-propyl benzoate m11 in 38 ml of methanol and 43 ml of tetrahydrofuran is converted to 2.071 g (62.8% yield) of the titled compound m12 by the same procedure as described in (125).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[NH:8][C:7](=[O:12])[C:6]([C:13]1[O:17][N:16]=[C:15]([CH:18]=O)[CH:14]=1)=[C:5]2[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1.[N:26]1([CH2:32][CH2:33][NH2:34])[CH2:31][CH2:30][O:29][CH2:28][CH2:27]1>>[Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[NH:8][C:7](=[O:12])[C:6]([C:13]1[O:17][N:16]=[C:15]([CH2:18][NH:34][CH2:33][CH2:32][N:26]3[CH2:31][CH2:30][O:29][CH2:28][CH2:27]3)[CH:14]=1)=[C:5]2[C:20]1[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=1
Reactant: NCCN1CCOCC1
Reactant: O=Cc1cc(-c2c(-c3ccccc3)c3cc(Cl)ccc3[nH]c2=O)on1
Product: O=c1[nH]c2ccc(Cl)cc2c(-c2ccccc2)c1-c1cc(CNCCN2CCOCC2)no1
Yield: 37 %

Procedure:
From 5-(6-chloro-2-oxo-4-phenyl-1,2-dihydro-quinolin-3-yl)-isoxazole-3-carboxaldehyde and 2-morpholin-4-yl-ethylamine according to procedure 24. Yield 37%.
Reaction SMILES: [C:1]1([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][N:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[Br:13]Br>[Fe].C(Cl)(Cl)Cl>[Br:13][C:6]1[CH:5]=[CH:4][CH:3]=[CH:2][C:1]=1[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][N:8]=1
Reactant: c1ccc(-c2ccccn2)cc1
Reactant: BrBr
Agent: [Fe]
Solvent: ClC(Cl)Cl
Product: Brc1ccccc1-c1ccccn1
Temperature: 90 °C
Yield: 35.4 %

Procedure:
2-Phenylpyridine 3 g(19.3 mmol) and iron powder 40 mg(0.716 mmol) were mixed and stirred. Bromine 4.0 g (25 mmol) was added dropwise with stirring at 0° C., avoiding the rising temperature. Then the mixture was heated up to 90° C. and keep the temperature for ten hours with stirring. After the completion of the reaction, this reaction mixture was dissolved into chloroform solution and washed with 5% aqueous sodium thiosulfate solution. After dried by sodium sulufate, the organic solution was concentrated by an evaporator. The residue obtainedwas purifiedbyuse of silica gel column chromatography. 1.6 g (6.83 mmol) of 2-(bromophenyl)pyridine was obtained and the yield was 35.4%. Analysis: M+=234.0 By FD-MS.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([N:8]2[C:17]3[C:12](=[CH:13][C:14]([OH:18])=[CH:15][CH:16]=3)[CH2:11][CH2:10][CH2:9]2)[CH:5]=[CH:4][N:3]=1.[NH2:19][C:20]1[CH:25]=[CH:24][C:23]([S:26]([NH:29][CH2:30][CH:31]2[CH2:33][CH2:32]2)(=[O:28])=[O:27])=[CH:22][CH:21]=1.C1(C)C=CC(S(O)(=O)=O)=CC=1>CN(C=O)C>[CH:31]1([CH2:30][NH:29][S:26]([C:23]2[CH:22]=[CH:21][C:20]([NH:19][C:2]3[N:7]=[C:6]([N:8]4[C:17]5[C:12](=[CH:13][C:14]([OH:18])=[CH:15][CH:16]=5)[CH2:11][CH2:10][CH2:9]4)[CH:5]=[CH:4][N:3]=3)=[CH:25][CH:24]=2)(=[O:28])=[O:27])[CH2:32][CH2:33]1
Reactant: Oc1ccc2c(c1)CCCN2c1ccnc(Cl)n1
Reactant: Nc1ccc(S(=O)(=O)NCC2CC2)cc1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: CN(C)C=O
Product: O=S(=O)(NCC1CC1)c1ccc(Nc2nccc(N3CCCc4cc(O)ccc43)n2)cc1
Temperature: 90 °C
Reaction time: 8 h
Yield: 54.4 %

Procedure:
The reaction flask containing 2,4-dichloropyrimidine (372 mg, 2.5 mmol), 6-methoxy-1,2,3,4-tetrahydroquinoline (489 mg, 3 mmol) and diisopropylethylamine (0.52 mL, 3 mmol) in n-butanol (10 mL) was heated at 40° C. overnight. The solvent was evaporated, and the residue was purified by flash column chromatography to give 2-Chloro-4-(6-methoxy-3,4-dihydroquinolin-1(2H)-yl)pyrimidine (551 mg, 80%). This intermediate (250 mg, 0.91 mmol) was then dissolved in dichloromethane and treated with BBr3 (1 M in dichloromethane) (1 mL, 1 mmol) at −78° C. The reaction mixture was slowly warmed up to room temperature and stirred for 1 hr, poured into water, extracted with dichloromethane. The combined organics were dried over anhydrous Na2SO4 and concentrated. The residue was purified by flash column chromatography to give 2-Chloro-4-(6-hydroxy-3,4-dihydroquinolin-1(2H)-yl)pyrimidine (154 mg, 65%). To a stirred solution of 2-chloro-4-(6-hydroxy-3,4-dihydroquinolin-1(2H)-yl)pyrimidine (29 mg, 0.11 mmol) and 4-amino-N-(cyclopropylmethyl)benzenesulfonamide (27 mg, 0.12 mmol) in DMF (0.5 mL) was added p-toluenesulfonic acid (2 M in dioxane) (55 μL, 0.11 mmol). The reaction mixture was stirred at 90° C. overnight, then purified by HPLC to give the title compound (27 mg, 56%).