Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH-].[NH4+:2].F[C:4]1[CH:5]=[CH:6][C:7]([C:12]([F:15])([F:14])[F:13])=[C:8]([CH:11]=1)[C:9]#[N:10]>O1CCOCC1>[NH2:2][C:4]1[CH:5]=[CH:6][C:7]([C:12]([F:15])([F:14])[F:13])=[C:8]([CH:11]=1)[C:9]#[N:10]
Reactant: [NH4+]
Reactant: N#Cc1cc(F)ccc1C(F)(F)F
Agent: [OH-]
Solvent: C1COCCO1
Product: N#Cc1cc(N)ccc1C(F)(F)F

Procedure:
Ammonium hydroxide solution (50 mL) was added to a stirred solution of 5-fluoro-2-(trifluoromethyl)benzonitrile (commercially available, for example from Alfa Aesar, Ward Hill, Mass., USA, 2.0 g, 10.6 mmol) in 1,4-dioxane (10 mL) and the reaction mixture was heated to 130° C. for 20 h under 200 psi pressure in a steel bomb. The reaction mixture was evaporated to dryness, and the residue was diluted with DCM and washed with water. The organic layer was dried over anhydrous Na2SO4 and concentrated under reduced pressure to afford the crude product. This was purified by column chromatography (100-200 mesh silica gel), eluting with 20%-40% EtOAc/petroleum ether, to give the title compound (1.2 g).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([F:8])=[CH:4][C:3]=1[C:9]1[S:13][C:12]([CH2:20][CH2:21][CH2:22][NH:23][C:24](=[O:30])[O:25][C:26]([CH3:29])([CH3:28])[CH3:27])([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[NH:11][N:10]=1.[N:31]1([C:36](N2C=CN=C2)=[S:37])C=CN=C1.[NH2:43]N>C1COCC1>[C:26]([O:25][C:24]([NH:23][CH2:22][CH2:21][CH2:20][C:12]1([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[N:11]([C:36](=[S:37])[NH:31][NH2:43])[N:10]=[C:9]([C:3]2[CH:4]=[C:5]([F:8])[CH:6]=[CH:7][C:2]=2[F:1])[S:13]1)=[O:30])([CH3:27])([CH3:29])[CH3:28]
Reactant: S=C(n1ccnc1)n1ccnc1
Reactant: NN
Reactant: CC(C)(C)OC(=O)NCCCC1(c2ccccc2)NN=C(c2cc(F)ccc2F)S1
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)NCCCC1(c2ccccc2)SC(c2cc(F)ccc2F)=NN1C(=S)NN
Temperature: 70 °C
Reaction time: 1 h
Yield: 25 %

Procedure:
To a solution of tert-butyl 3-(5-(2,5-difluorophenyl)-2-phenyl-2,3-dihydro-1,3,4-thiadiazol-2-yl)propylcarbamate (0.123 g, 0.284 mmol) in THF (2 mL) was added di(1H-imidazol-1-yl)methanethione (0.061 g, 0.340 mmol). After heating to 70° C. for 2 hours, the reaction mixture was cooled to room temperature and treated with hydrazine (0.027 g, 0.851 mmol). After stirring for 1 hour, the mixture was concentrated under reduced pressure and chromatographed (10:1 hexanes/ethyl acetate) to provide the product (0.036 g, 25%).
Reaction SMILES: C(OC(=O)CC(N1C=CC(C2C=CC=CC=2)=C1)C(NC1CC2=CN(C3C2=CC=CC=3)CCOCCNC1=O)=O)C1C=CC=CC=1.CO[CH:48]1[CH:52]([CH2:53][C:54]([O:56][CH3:57])=[O:55])[CH2:51][CH:50](OC)O1.[F:60][C:61]1[CH:67]=[CH:66][C:64]([NH2:65])=[CH:63][CH:62]=1.FC(F)(F)C(O)=O>ClCCCl>[CH3:57][O:56][C:54](=[O:55])[CH2:53][C:52]1[CH:51]=[CH:50][N:65]([C:64]2[CH:66]=[CH:67][C:61]([F:60])=[CH:62][CH:63]=2)[CH:48]=1
Reactant: Nc1ccc(F)cc1
Reactant: COC(=O)CC1CC(OC)OC1OC
Agent: O=C(CC(C(=O)NC1Cc2cn(c3ccccc23)CCOCCNC1=O)n1ccc(-c2ccccc2)c1)OCc1ccccc1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCCl
Product: COC(=O)Cc1ccn(-c2ccc(F)cc2)c1
Reaction time: 16 h
Yield: 80.9 %

Procedure:
According to the procedure described in Example 1(c) for the preparation of N-(8-oxo-4-oxa-1,7-diaza-tricyclo[9.6.1.012,17]octadeca-11(18),12,14,16-tetraen-9-yl)-3(3-phenyl-1H-pyrrol-1-yl)succinamic acid benzyl ester, to a mixture of crude methyl 2-(2,5-dimethoxy-tetrahydrofuran-3-yl)-acetate (120 mg, ˜0.58 mmol) and 4-fluoroaniline (50 μL, 0.53 mmol) in 1,2-dichloroethane (10 mL) was added trifluoroacetic acid (0.2 mL, 0.26 mmol). After 16 hours at 80° C., the resultant mixture was partitioned between EtOAc and 1M pH 7 phosphate buffer. The separated aqueous layer was extracted with EtOAc. The combined organic layers were washed with brine, dried over Na2SO4, and concentrated to a crude oil, which was purified via flash column chromatography with 0-15% EtOAc/hex gradient eluant to yield 100 mg (77%) of 2-[1-(4-fluorophenyl)-1H-pyrrol-3-yl]-acetic acid methyl ester as an oil. 1H NMR: δ 7.34-7.30 (m, 2H), 7.10 (t, 2H, J=8.6 Hz), 6.96-6.94 (m, 2H), 6.28 (t, 1H, J=2.2 Hz), 3.72 (s, 3H), 3.56 (s, 2H). Anal. Calculated for C13H12NO2F•0.6 H2O: C, 63.98; H, 5.45; N, 5.74. Found: C, 64.01; H, 5.04; N, 5.65.
Reaction SMILES: [C:1]1(=[O:7])[NH:5][C:4](=[O:6])[CH:3]=[CH:2]1.[C:8]1([C:14]([O:16][CH2:17][CH3:18])=[O:15])[CH2:13][CH2:12][CH:11]=[CH:10][CH:9]=1.C(C1C=C(O)C(=CC=1)O)(C)(C)C>C1(C)C=CC=CC=1>[CH2:17]([O:16][C:14]([C:8]12[CH2:13][CH2:12][CH:11]([CH:10]=[CH:9]1)[CH:3]1[CH:2]2[C:1](=[O:7])[NH:5][C:4]1=[O:6])=[O:15])[CH3:18]
Reactant: O=C1C=CC(=O)N1
Reactant: CCOC(=O)C1=CC=CCC1
Agent: CC(C)(C)c1ccc(O)c(O)c1
Solvent: Cc1ccccc1
Product: CCOC(=O)C12C=CC(CC1)C1C(=O)NC(=O)C12

Procedure:
13.5 g (0.138 mol) of maleimide and 25.3 g (0.17 mol) of ethyl 1,3-cyclohexadiene-1-carboxylate are heated under reflux with 1.4 g of 4-(tertbutyl)-pyrocatechol in 275 ml of toluene overnight. The mixture is concentrated and the residue is recrystallized from isopropanol.
Reaction SMILES: [NH:1]1[CH2:5][CH2:4][CH2:3][C@@H:2]1[C:6]([NH:8][C@H:9]([C:11]1[CH:20]=[CH:19][C:14]([C:15]([O:17][CH3:18])=[O:16])=[CH:13][CH:12]=1)[CH3:10])=[O:7].[F:21][C:22]([F:32])([F:31])[C:23]1[CH:30]=[CH:29][C:26]([CH2:27]Br)=[CH:25][CH:24]=1.C([O-])([O-])=O.[Na+].[Na+]>>[F:21][C:22]([F:31])([F:32])[C:23]1[CH:30]=[CH:29][C:26]([CH2:27][N:1]2[CH2:5][CH2:4][CH2:3][C@@H:2]2[C:6]([NH:8][C@H:9]([C:11]2[CH:12]=[CH:13][C:14]([C:15]([O:17][CH3:18])=[O:16])=[CH:19][CH:20]=2)[CH3:10])=[O:7])=[CH:25][CH:24]=1
Reactant: FC(F)(F)c1ccc(CBr)cc1
Reactant: COC(=O)c1ccc([C@H](C)NC(=O)[C@H]2CCCN2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Product: COC(=O)c1ccc([C@H](C)NC(=O)[C@H]2CCCN2Cc2ccc(C(F)(F)F)cc2)cc1

Procedure:
The title compound (D144) (60 mg) was prepared according to the general procedure for substituted benzyl amines preparation starting from methyl 4-((S)-1-((R)-pyrrolidine-2-carboxamido)ethyl)benzoate (D103) (50 mg) and and 4-(trifluoromethyl)-benzylbromide (0.056 ml). (Na2CO3; reaction time: 5 hrs; 70° C.).
Reaction SMILES: [OH:1][N:2]1[C:6]2[CH:7]=[C:8]([CH:11]=[CH2:12])[CH:9]=[CH:10][C:5]=2[N:4]=[N:3]1.C(N(CC)CC)C.[CH:20]([C:22]1[CH:27]=[CH:26][C:25]([S:28](Cl)(=[O:30])=[O:29])=[CH:24][CH:23]=1)=[CH2:21]>C1C=CC=CC=1>[CH:20]([C:22]1[CH:23]=[CH:24][C:25]([S:28]([O:1][N:2]2[C:6]3[CH:7]=[C:8]([CH:11]=[CH2:12])[CH:9]=[CH:10][C:5]=3[N:4]=[N:3]2)(=[O:30])=[O:29])=[CH:26][CH:27]=1)=[CH2:21]
Reactant: C=Cc1ccc(S(=O)(=O)Cl)cc1
Reactant: C=Cc1ccc2nnn(O)c2c1
Solvent: c1ccccc1
Solvent: CCN(CC)CC
Product: C=Cc1ccc(S(=O)(=O)On2nnc3ccc(C=C)cc32)cc1
Temperature: 10 °C
Yield: 44.2 %

Procedure:
In benzene (200 ml) are dissolved 1-hydroxy-6-vinyl-1,2,3-benzotriazole (31.2 g) and triethylamine (20 g) under stirring and thereto is added dropwise a solution of p-vinylbenzenesulfonyl chloride (39.2 g) in benzene (70 ml) under ice-cooling to 10° C. The mixture is stirred at room temperature for 3.5 hours. The reaction mixture is poured onto ice-water (1 liter) and the mixture is extracted with ethyl acetate (500 ml, three times). The combined extracts are washed with an aqueous sodium hydrogen carbonate and then water, dried over anhydrous magnesium sulfate, treated with charcoal, and then concentrated under a reduced pressure till about 150 ml. To the mixture is added n-hexane and the mixture is allowed to stand at a cooled place. The precipitated crystals are separated by filtration to give 1-(p-vinylbenzenesulfonyloxy)-6-vinyl-1,2,3-benzotriazole (28.0 g), melting point: 85°-87° C. To the filtrate is further added n-hexane and the mixture is allowed to stand at a cooled place to give additionally the desired product (11.7 g).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]=[C:9]=[O:10])=[CH:4][C:3]=1[C:11]([F:14])([F:13])[F:12].[NH2:15][C:16]1[CH:35]=[CH:34][C:19]([O:20][C:21]2[CH:26]=[CH:25][N:24]=[C:23]([C:27]([O:29][C:30]([CH3:33])([CH3:32])[CH3:31])=[O:28])[CH:22]=2)=[CH:18][C:17]=1[F:36]>ClCCl>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9](=[O:10])[NH:15][C:16]2[CH:35]=[CH:34][C:19]([O:20][C:21]3[CH:26]=[CH:25][N:24]=[C:23]([C:27]([O:29][C:30]([CH3:32])([CH3:33])[CH3:31])=[O:28])[CH:22]=3)=[CH:18][C:17]=2[F:36])=[CH:4][C:3]=1[C:11]([F:12])([F:13])[F:14]
Reactant: O=C=Nc1ccc(Cl)c(C(F)(F)F)c1
Reactant: CC(C)(C)OC(=O)c1cc(Oc2ccc(N)c(F)c2)ccn1
Solvent: ClCCl
Product: CC(C)(C)OC(=O)c1cc(Oc2ccc(NC(=O)Nc3ccc(Cl)c(C(F)(F)F)c3)c(F)c2)ccn1
Temperature: 25 °C
Reaction time: 16 h
Yield: 79.6 %

Procedure:
At room temperature, 1-chloro-4-isocyanato-2-(trifluoromethyl)benzene (1.06 g, 4.77 mmol, 1.05 eq) was dissolved in dichloromethane (10 mL). A solution of tert-butyl 4-(4-amino-3-fluorophenoxy)picolinate (1.38 g, 4.54 mmol, 1 eq) in dichloromethane (50 mL) was added dropwise slowly. The resulted mixture was stirred at room temperature for 16 h. The solvent was removed under reduced pressure, and the resulted solid was purified by column chromatography (dichloromethane: methanol=30:1) to give the title compound (1.9 g, purity 94%, yield 80%) as a reddish-brown solid.
Reaction SMILES: [CH3:1][C:2]1([CH3:12])[C@H:4]([CH:5]=[C:6]=[CH:7][Br:8])[C@H:3]1[C:9]([OH:11])=[O:10].[O:13]([C:20]1[CH:21]=[C:22]([CH:25]=[CH:26][CH:27]=1)[CH2:23]O)[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1>>[CH3:1][C:2]1([CH3:12])[C@H:4]([CH:5]=[C:6]=[CH:7][Br:8])[C@H:3]1[C:9]([O:11][CH2:23][C:22]1[CH:25]=[CH:26][CH:27]=[C:20]([O:13][C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[CH:21]=1)=[O:10]
Reactant: OCc1cccc(Oc2ccccc2)c1
Reactant: CC1(C)[C@H](C=C=CBr)[C@H]1C(=O)O
Product: CC1(C)[C@H](C=C=CBr)[C@H]1C(=O)OCc1cccc(Oc2ccccc2)c1

Procedure:
Using the procudure of Example 1, 1.2 g of the acid of Example 29 and 1 g of 3-phenoxy-benzyl alcohol were reacted to obtain after chromatography over silica gel and elution with a 9-1 hexane-ethyl acetate mixture 1.49 g of 3-phenoxybenzyl (1R,trans) 2,2-dimethyl-3-(3-bromo-1,2-propadienyl)-cyclopropane-carboxylate with a specific rotation of [α]D20 =+15.5°±2° (c=0.5% in chloroform).
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:7]([Si:11]([CH3:14])([CH3:13])[CH3:12])[C:3]=1[C:4]([NH2:6])=[O:5].[OH-].[NH4+].[CH:17](=O)[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1.[NH:25]1[C:29]2[CH:30]=[CH:31][CH:32]=[CH:33][C:28]=2[N:27]=[N:26]1>C1(C)C=CC=CC=1>[N:25]1([CH:17]([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[NH:6][C:4](=[O:5])[C:3]2[C:7]([Si:11]([CH3:14])([CH3:13])[CH3:12])=[CH:8][CH:9]=[CH:10][C:2]=2[Cl:1])[C:29]2[CH:30]=[CH:31][CH:32]=[CH:33][C:28]=2[N:27]=[N:26]1
Reactant: c1ccc2[nH]nnc2c1
Reactant: O=Cc1ccccc1
Reactant: C[Si](C)(C)c1cccc(Cl)c1C(N)=O
Agent: [NH4+]
Agent: [OH-]
Solvent: Cc1ccccc1
Product: C[Si](C)(C)c1cccc(Cl)c1C(=O)NC(c1ccccc1)n1nnc2ccccc21
Yield: 11.5 %

Procedure:
A mixture of 2-chloro-6-trimethylsilylbenzamide (2.27 g, 10 mmol), which may be readily prepared by the reaction of the compound of Example b and ammonium hydroxide, benzaldehyde (1.1 g, 10 mmol), and benzotriazole (1.2 g, 10 mmol) was refluxed 5 days in toluene utilizing a Dean-Stark trap to remove water. The solvent was removed to yield an oil which crystallizes. Recrystallization from ethyl acetate yielded 0.5 g of the title compound. m.p. 184°-186° C.
Reaction SMILES: [CH:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][C:2]=1[CH:11]=O.[NH2:13][C:14]1[CH:19]=[N:18][C:17]([Br:20])=[CH:16][N:15]=1.[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+]>ClC(Cl)C.C(O)(=O)C.ClCCl>[Br:20][C:17]1[N:18]=[CH:19][C:14]([NH:13][CH2:11][C:2]2[CH:3]=[CH:4][C:5]3[C:10](=[CH:9][CH:8]=[CH:7][CH:6]=3)[CH:1]=2)=[N:15][CH:16]=1
Reactant: O=Cc1ccc2ccccc2c1
Reactant: Nc1cnc(Br)cn1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CC(Cl)Cl
Solvent: ClCCl
Solvent: CC(=O)O
Product: Brc1cnc(NCc2ccc3ccccc3c2)cn1
Yield: 48.7 %

Procedure:
2-Napthaldehyde (0.6 g, 3.84 mmol) and 2-amino-5-bromopyrazine (0.56 g, 3.201 mmol) were treated with Na(OAc)3BH (1.02 g, 4.802 mmol) in dichloroethane (15.0 mls) and acetic acid (0.5 mls) for 18 hours at room temperature. The mixture was diluted with dichloromethane, washed with 1.0 N NaOH, washed with brine, dried over MgSO4, and concentrated. Chromatography (SiO2, EtOAc:Hex, 1:1) gave 0.49 g 5-bromo-N-(naphthalen-2-ylmethyl)pyrazin-2-amine.
Reaction SMILES: [NH2:1][CH2:2][C:3]1[C:4]([NH:20][C@H:21]([C:24]2[CH:29]=[CH:28][C:27]([F:30])=[CH:26][CH:25]=2)[CH2:22][OH:23])=[N:5][C:6]([NH:10][C:11]2[CH:15]=[C:14]([O:16][CH:17]([CH3:19])[CH3:18])[NH:13][N:12]=2)=[C:7]([F:9])[CH:8]=1.[C:31](O)(=[O:33])[CH3:32]>C1COCC1.C(Cl)Cl>[F:9][C:7]1[CH:8]=[C:3]([CH2:2][NH:1][C:31](=[O:33])[CH3:32])[C:4]([NH:20][C@H:21]([C:24]2[CH:29]=[CH:28][C:27]([F:30])=[CH:26][CH:25]=2)[CH2:22][OH:23])=[N:5][C:6]=1[NH:10][C:11]1[CH:15]=[C:14]([O:16][CH:17]([CH3:19])[CH3:18])[NH:13][N:12]=1
Reactant: CC(C)Oc1cc(Nc2nc(N[C@@H](CO)c3ccc(F)cc3)c(CN)cc2F)n[nH]1
Reactant: CC(=O)O
Solvent: C1CCOC1
Solvent: ClCCl
Product: CC(=O)NCc1cc(F)c(Nc2cc(OC(C)C)[nH]n2)nc1N[C@@H](CO)c1ccc(F)cc1
Temperature: 0 °C
Reaction time: 0.75 h
Yield: 39 %

Procedure:
(R)-2-(3-(Aminomethyl)-5-fluoro-6-(5-isopropoxy-1H-pyrazol-3-ylamino)pyridin-2-ylamino)-2-(4-fluorophenyl)ethanol (Example 13; 0.175 g, 0.42 mmol) and acetic acid loaded TFP resin (1.4 mmol/g loading, 0.42 mmol) were placed in a THF-DCM solution (1:1, 5 ml) at 0° C. The resulting solution was shaken vigorously at 0° C. for 45 min and filtered. The resulting resin was washed with a THF-DCM solution (1:1, 3×5 ml for 30 min. each). The resulting organic layers were combined and concentrated. The resulting solid was purified by reverse-phase column chromatography (5-50% CH3CN in H2O over 400 ml) to give the title compound (0.075 g, 39%). 1H NMR (400 MHz, CD3OD) δ 7.42-7.39 (m, 2H), 7.17 (d, J=10.7 Hz, 1H), 7.05-7.01 (m, 2H), 5.26 (s, 1H), 5.02-4.95 (m, 1H), 4.55-4.53 (m, 1H), 4.36 (d, J=15.0 Hz, 1H), 4.22 (d, J=15.0 Hz, 1H), 3.84-3.72 (m, 2H), 2.01 (s, 3H), 1.31 (d, J=6.0 Hz, 6H). MS: Calcd.: 460. Found: [M+H]+ 461.
Reaction SMILES: C1C=CC=CC=1.[CH2:7]([O:9][C:10](=[O:27])[C:11]([CH3:26])=[CH:12][C:13]1[CH:18]=[C:17]2[CH:19]=[CH:20][C:21]([N+:23]([O-])=O)=[CH:22][C:16]2=[CH:15][CH:14]=1)[CH3:8]>[Fe].O>[CH2:7]([O:9][C:10](=[O:27])[C:11]([CH3:26])=[CH:12][C:13]1[CH:18]=[C:17]2[CH:19]=[CH:20][C:21]([NH2:23])=[CH:22][C:16]2=[CH:15][CH:14]=1)[CH3:8]
Reactant: CCOC(=O)C(C)=Cc1ccc2cc([N+](=O)[O-])ccc2c1
Agent: [Fe]
Solvent: O
Solvent: c1ccccc1
Product: CCOC(=O)C(C)=Cc1ccc2cc(N)ccc2c1
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 78.3 %

Procedure:
Into 30 ml of benzene, 2.0 g (7 mmol) of 3-(2-nitro-benzo[d]phenyl)-2-methyl-2-propenoic acid ethyl ester were dissolved; and, with 1.73 g of iron powder (Koso Chem. Co.) and 2.5 ml of distilled water being added thereto under stirring at room temperature, temperature was raised, so that a reaction was carried out for 1.5 hours at 70° C. After the completion of the reaction, insoluble matters were filtered out, and the filtrate was added to 100 ml of water. The resulting solution was extracted twice with 100 ml of ethyl acetate; and thus obtained ethyl acetate solution was successively washed with water, an aqueous sodium hydrogencarbonate solution, and a saturated aqueous sodium chloride solution. The washed solution was dried on sodium sulfate anhydride; and, after sodium sulfate was filtered out, the filtrate was concentrated. Thus obtained oily product was refined by a silica gel column chromatography (silica gel; developing solvent: ethyl acetate/hexane=1/5), whereby 1.4 g of the aimed compound were obtained as an oily product (yield: 77%).
Reaction SMILES: [Br:1][C:2]1[CH:8]=[CH:7][C:6]([Br:9])=[CH:5][C:3]=1[NH2:4].N1C=CC=CC=1.[F:16][C:17]1[CH:25]=[C:24]([S:26]([CH3:29])(=[O:28])=[O:27])[CH:23]=[CH:22][C:18]=1[C:19](Cl)=[O:20]>C(Cl)Cl.O>[Br:1][C:2]1[CH:8]=[CH:7][C:6]([Br:9])=[CH:5][C:3]=1[NH:4][C:19](=[O:20])[C:18]1[CH:22]=[CH:23][C:24]([S:26]([CH3:29])(=[O:28])=[O:27])=[CH:25][C:17]=1[F:16]
Reactant: Nc1cc(Br)ccc1Br
Reactant: CS(=O)(=O)c1ccc(C(=O)Cl)c(F)c1
Solvent: O
Solvent: c1ccncc1
Solvent: ClCCl
Product: CS(=O)(=O)c1ccc(C(=O)Nc2cc(Br)ccc2Br)c(F)c1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 98.8 %

Procedure:
2-Fluoro-4-(methylsulfonyl)benzoic acid (1 g, 4.6 mmol) dissolved in DCM (15 ml), cooled to 0° C. and added oxalyl chloride (0.6 ml, 6.9 mmol). Catalytic amount of DMF was added to this mixture and stirred at rt for 30 mins. After 30 mins, DCM removed on rotavapour and co-distilled the residue two times with DCM to obtain 2-fluoro-4-(methylsulfonyl)benzoyl chloride quantitatively. 2,5-Dibromoaniline (0.9 g, 3.59 mmol) dissolved in DCM (10 ml) and added Pyridine (0.34 g, 4.30 mmol) under nitrogen atmosphere. This mixture stirred at rt for 30 mins and added 2-fluoro-4-(methylsulfonyl)benzoyl chloride (1.01 g, 3.59 mmol). After continuing stirring at rt for 15 mins, reaction mass diluted with water and extracted with DCM. DCM layer washed with aq. NaHCO3 and DCM removed on rotavapour to obtain the solid. Solid was triturated with Et2O and Petether mixture (4:1) to obtain the titled compound (1.6 g) as a brown solid. 1H-NMR (δ ppm, DMSO-d6, 400 MHz): 10.34 (s, 1H), 8.34-7.99 (m, 1H), 7.98-7.93 (m, 2H), 7.92-7.89 (m, 1H), 7.68 (d, J 8.6, 1H), 7.43 (dd, J 2.4, 8.6, 1H), 3.33 (s, 3H).
Reaction SMILES: [OH-:1].[Li+].[CH:3]1[C:15]2[CH2:14][C:13]3[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=3)[C:7]=2[CH:6]=[CH:5][C:4]=1[O:16][CH:17]1[CH2:21][CH:20]([C:22]([O:24]C)=[O:23])[NH:19][C:18]1=[O:26].Cl>O.O1CCCC1>[CH:3]1[C:15]2[CH2:14][C:13]3[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=3)[C:7]=2[CH:6]=[CH:5][C:4]=1[O:16][CH:17]([C:18]([OH:26])=[O:1])[CH2:21][C@@H:20]([C:22]([OH:24])=[O:23])[NH2:19]
Reactant: COC(=O)C1CC(Oc2ccc3c(c2)Cc2ccccc2-3)C(=O)N1
Reactant: [OH-]
Agent: Cl
Agent: [Li+]
Solvent: O
Solvent: C1CCOC1
Product: N[C@@H](CC(Oc1ccc2c(c1)Cc1ccccc1-2)C(=O)O)C(=O)O
Temperature: 60 °C
Reaction time: 3.3 h

Procedure:
A mixture of lithium hydroxide (0.117 g) in water (1.5 ml) and tetrahydrofuran (4.7 ml) was treated with methyl 3-(2-fluorenoxy)-2-pyrrolidone-5-carboxylate (0.526 g), and heated to 60° C. After about 3.3 hours, the reaction mixture was allowed to cool to room temperature. The reaction mixture was treated with 5N HCl (976 ml). The resulting colloidal suspension was sonicated for ten minutes. The insolubles were collected by filtration, washed with 1:1 THF:water (10 ml), THF (10 ml), and water (10 ml). The insolubles were dried overnight in at vacuum oven at 60° C. to afford the title compound.
Reaction SMILES: C[O:2][C:3](=[O:36])[C:4]1[CH:9]=[CH:8][C:7]([CH2:10][O:11][C:12]2[C:17]([C:18]3[N:22]([CH2:23][CH:24]4[CH2:29][CH2:28][CH2:27][CH2:26][CH2:25]4)[C:21]4[CH:30]=[C:31]([F:35])[C:32]([F:34])=[CH:33][C:20]=4[N:19]=3)=[CH:16][CH:15]=[CH:14][N:13]=2)=[CH:6][CH:5]=1.O.[OH-].[Li+]>O1CCCC1.O>[CH:24]1([CH2:23][N:22]2[C:21]3[CH:30]=[C:31]([F:35])[C:32]([F:34])=[CH:33][C:20]=3[N:19]=[C:18]2[C:17]2[C:12]([O:11][CH2:10][C:7]3[CH:8]=[CH:9][C:4]([C:3]([OH:36])=[O:2])=[CH:5][CH:6]=3)=[N:13][CH:14]=[CH:15][CH:16]=2)[CH2:29][CH2:28][CH2:27][CH2:26][CH2:25]1
Reactant: COC(=O)c1ccc(COc2ncccc2-c2nc3cc(F)c(F)cc3n2CC2CCCCC2)cc1
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: O=C(O)c1ccc(COc2ncccc2-c2nc3cc(F)c(F)cc3n2CC2CCCCC2)cc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 26 %

Procedure:
A solution of 4-[3-(1-cyclohexylmethyl-5,6-difluoro-1H-benzoimidazol-2-yl)-pyridin-2-yloxymethyl]-benzoic acid methyl ester (84 mg, 0.17 mmol) in tetrahydrofuran (20 ml) and water (10 ml) was treated with an aqueous solution of lithium hydroxide monohydrate (36 mg, 0.86 mmol) and stirred at 25° C. for 2 h. The solvent removed in vacuo, the resulting crude material diluted with water (5 ml) and acidified with 2M aqueous hydrochloric acid solution. The aqueous layer was extracted with ethyl acetate, washed with water, brine, dried over sodium sulfate, filtered and evaporated under reduced pressure. The crude product was purified by column chromatography over silica gel (50% ethyl acetate/n-hexane) to afford the final compound as an off-white powder (26%). MS (Turbo Spray): m/z=478.4 (M+H).
Reaction SMILES: [NH2-:1].[Na+].C(O)(=O)CCCCCCC/C=C\CCCCCCCC.[N:23]1[C:32]2[C:27](=[CH:28][CH:29]=[CH:30][CH:31]=2)[CH:26]=[CH:25][CH:24]=1>C1(C)C=CC=CC=1>[NH2:1][C:24]1[CH2:25][CH2:26][C:27]2[C:32](=[CH:31][CH:30]=[CH:29][CH:28]=2)[N:23]=1
Reactant: [NH2-]
Reactant: c1ccc2ncccc2c1
Agent: CCCCCCCC/C=C\CCCCCCCC(=O)O
Agent: [Na+]
Solvent: Cc1ccccc1
Product: NC1=Nc2ccccc2CC1
Reaction time: 2 h
Yield: 39.3 %

Procedure:
A mixture of 46.8 g (1.2 moles) of sodamide. 400 cc of toluene containing 0.5 cc of oleic acid and 129.2 g (1.0 mole) of quinoline was placed in a liter Magne Drive, equipped as described in Example 15. The autoclave was closed and purged of air with ammonia, pressurized to 30 psig with ammonia and then to 200 psig with nitrogen. The pressure relief valve was set at 350 psig. Cooling water was turned on the reflux condenser. The autoclave was heated with stirring for 2 hours within a range of 138°-148° C. No hydrogen evolution was observed. The autoclave was cooled and vented to atmospheric pressure. The reaction mixture was carefully hydrolyzed (external cooling) with 150 cc of water. The maximum temperature was 30° C. The hydrolyzed mixture contained organic crystalline material. In order to dissolve the crystals, 200 cc of 4-picoline was added and the mixture thoroughly stirred. The aqueous phase was allowed to settle and was removed. The organic phase was placed under vacuum at 40° C. to remove most of the residual ammonia. It was then treated with dry ice and filtered to remove carbonates. The filtrate was topped to a liquid temperature of 110° C. at 50 mm Hg. To the residue was added about 2 parts of toluene and the solution was allowed to crystallize. The mixture was filtered to give 57.4 g of 2-amino-3,4-dihydroquinoline, m.p. of 134.9°-136.3° C. The dihydroquinoline was hydrolyzed in boiling water to give 3,4-dihydrocarbostyril m.p. 165.7°-167.1° C. It is reported in Tetsuji et al., J. Heterocycle Chem., 2, 330 (1965) that the Chichibabin amination of quinoline in toluene at atmospheric pressure gave only 2-aminoquinoline. Derivatives of 3,4-dihydrocarbostryril have anti-inflammatory and blood platelet coagulation activities as claimed by Nakagawa et al., Japan. Kokai 77 73,866.
Reaction SMILES: [N:1]([CH2:4][C@@H:5]([F:17])[C@H:6]([O:9][CH2:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)[CH:7]=C)=[N+:2]=[N-:3].C(O)(C(F)(F)F)=[O:19].[OH2:25]>CC(O)=O.CCOC(C)=O>[N:1]([CH2:4][C@@H:5]([F:17])[C@H:6]([O:9][CH2:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)[C:7]([OH:19])=[O:25])=[N+:2]=[N-:3]
Reactant: C=C[C@@H](OCc1ccccc1)[C@H](F)CN=[N+]=[N-]
Reactant: O
Reactant: O=C(O)C(F)(F)F
Solvent: CCOC(C)=O
Solvent: CC(=O)O
Product: [N-]=[N+]=NC[C@@H](F)[C@H](OCc1ccccc1)C(=O)O
Temperature: 40 °C

Procedure:
To a stirring solution of 4 (9.1 g, 4.76 mmol) in AcOH (19.8 mL) was added TFA (1.8 mL of a 3:1 TFA:water solution), and the reaction was heated at 40° C. for 45 min. Additional TFA (0.45 mL of a 3:1 TFA:water solution) was added and the reaction was heated for 1.5 hr. The reaction was then cooled to room temperature, diluted with EtOAc (200 mL) and washed with sat. aq. NaHCO3 (3×200 mL) and brine (200 mL). The organic layer was dried over Na2SO4, filtered and concentrated to dryness to yield compound 5 (8.7 g, 3.43 mmol), which was carried through to the next step without further purification. MS m/z calcd for C99H111N5O25Si2 (M+Na+) 1848.7. found 1848.3.