Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:9]([O:17][CH2:18][C:19]([F:22])([F:21])[F:20])=[N:10][CH:11]=[C:12]([CH:16]=2)[C:13]([OH:15])=O)=[CH:4][C:3]=1[CH3:23].[CH:24]1([C:27]2[S:28][CH:29]=[C:30]([CH2:32][NH2:33])[N:31]=2)[CH2:26][CH2:25]1>>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:9]([O:17][CH2:18][C:19]([F:22])([F:20])[F:21])=[N:10][CH:11]=[C:12]([CH:16]=2)[C:13]([NH:33][CH2:32][C:30]2[N:31]=[C:27]([CH:24]3[CH2:26][CH2:25]3)[S:28][CH:29]=2)=[O:15])=[CH:4][C:3]=1[CH3:23]
Reactant: NCc1csc(C2CC2)n1
Reactant: Cc1cc(-c2cc(C(=O)O)cnc2OCC(F)(F)F)ccc1Cl
Product: Cc1cc(-c2cc(C(=O)NCc3csc(C4CC4)n3)cnc2OCC(F)(F)F)ccc1Cl

Procedure:
The title compound was synthesized in analogy to Example 1 using 5-(4-chloro-3-methylphenyl)-6-(2,2,2-trifluoroethoxy)nicotinic acid (example BJ) and 2-cyclopropyl-4-thiazolemethanamine (CAN 1083299-53-9) as starting materials; LC-MS (UV peak area/ESI) 95.4%, 482.09 (M+H)+.
Reaction SMILES: [C:1](Cl)(=O)[C:2]([Cl:4])=[O:3].[O:7]1[CH:11]=[CH:10][CH:9]=[C:8]1[C:12]1[CH:21]=C(C(O)=O)[C:19]2[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=2)[N:13]=1>ClCl>[O:7]1[CH:11]=[CH:10][CH:9]=[C:8]1[C:12]1[CH:21]=[C:1]([C:2]([Cl:4])=[O:3])[C:19]2[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=2)[N:13]=1
Reactant: O=C(Cl)C(=O)Cl
Reactant: O=C(O)c1cc(-c2ccco2)nc2ccccc12
Agent: ClCl
Product: O=C(Cl)c1cc(-c2ccco2)nc2ccccc12
Temperature: -10 °C
Reaction time: 8 h
Yield: 100.6 %

Procedure:
5.2 ml (60.4 mmol) of oxalyl chloride were dissolved in 70 ml of CH2 Cl2. The solution was cooled at -10° C. and 8.5 g (35.5 mmol) of 2-(2-furyl)quinoline-4-carboxylic acid were added portionwise. The reaction mixture was left overnight at room temperature and then evaporated to dryness to yield 9.2 g of the title compound, used without further purification.
Reaction SMILES: [Cl:1][C:2]1[C:11]2[C:6](=[C:7]([F:14])[C:8]([F:13])=[C:9]([F:12])[CH:10]=2)[N:5]=[C:4]([O:15]CC)[CH:3]=1.Cl.C(O)(=O)C>O>[Cl:1][C:2]1[C:11]2[C:6](=[C:7]([F:14])[C:8]([F:13])=[C:9]([F:12])[CH:10]=2)[NH:5][C:4](=[O:15])[CH:3]=1
Reactant: CCOc1cc(Cl)c2cc(F)c(F)c(F)c2n1
Agent: Cl
Solvent: O
Solvent: CC(=O)O
Product: O=c1cc(Cl)c2cc(F)c(F)c(F)c2[nH]1
Temperature: 20 °C
Yield: 97.1 %

Procedure:
A suspension of 70.4 g of 4-chloro-2-ethoxy-6,7,8-trifluoroquinoline in 170 cm3 of a 35% aqueous solution of hydrochloric acid, 420 cm3 of acetic acid and 250 cm3 of water is heated, with stirring, at a temperature close to 100° C. for 2 hours and a half. After cooling to about 20° C., the reaction mixture is poured into 1,100 cm3 of water at about 5° C., the mixture is stirred for 15 minutes at this temperature and the insoluble matter is then drained and washed with 3 times 220 cm3 of water. 61 g of 4-chloro-6,7,8-trifluorocarbostyril are obtained in the form of a cream solid melting at 213° C., which is used for the subsequent steps without further purification.
Reaction SMILES: [NH2:1][CH2:2][C@H:3]1[C@H:9]([C:10]2[CH:15]=[CH:14][C:13]([Cl:16])=[C:12]([F:17])[CH:11]=2)[O:8][CH2:7][CH2:6][N:5](C(OC(C)(C)C)=O)[CH2:4]1.[F:25][C:26]1[C:27]([O:32][CH2:33][C:34](O)=[O:35])=[N:28][CH:29]=[CH:30][CH:31]=1>>[Cl:16][C:13]1[CH:14]=[CH:15][C:10]([C@@H:9]2[O:8][CH2:7][CH2:6][NH:5][CH2:4][C@H:3]2[CH2:2][NH:1][C:34](=[O:35])[CH2:33][O:32][C:27]2[C:26]([F:25])=[CH:31][CH:30]=[CH:29][N:28]=2)=[CH:11][C:12]=1[F:17]
Reactant: CC(C)(C)OC(=O)N1CCO[C@@H](c2ccc(Cl)c(F)c2)[C@H](CN)C1
Reactant: O=C(O)COc1ncccc1F
Product: O=C(COc1ncccc1F)NC[C@@H]1CNCCO[C@H]1c1ccc(Cl)c(F)c1

Procedure:
Using tert-butyl (6R,7R)-6-(aminomethyl)-7-(4-chloro-3-fluorophenyl)-1,4-oxazepane-4-carboxylate and [(3-fluoropyridin-2-yl)oxy]acetic acid, and by a method similar to that of Example 39, followed by neutralization, the title compound was obtained.
Reaction SMILES: Cl[CH:2]([C:8]([CH3:10])=[O:9])[C:3]([O:5][CH2:6][CH3:7])=[O:4].C(=O)([O-])O.[Na+].[Cl:16][C:17]1[CH:22]=[CH:21][C:20]([SH:23])=[CH:19][CH:18]=1.O>COCCOC>[CH2:6]([O:5][C:3](=[O:4])[CH:2]([S:23][C:20]1[CH:21]=[CH:22][C:17]([Cl:16])=[CH:18][CH:19]=1)[C:8](=[O:9])[CH3:10])[CH3:7]
Reactant: CCOC(=O)C(Cl)C(C)=O
Reactant: Sc1ccc(Cl)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: COCCOC
Product: CCOC(=O)C(Sc1ccc(Cl)cc1)C(C)=O
Temperature: 25 °C
Reaction time: 3 h
Yield: 54.9 %

Procedure:
To a solution of ethyl 2-chloroacetoacetate (1.58 g, 9.61 mmol) in ethylene glycol dimethyl ether (30 mL) was added sodium hydrogencarbonate (ca. 15 g) and 4-chlorothiophenol (1.39 g, 9.61 mmol). The suspension was heated to reflux and stirred for 3 hours. The reaction mixture was allowed to cool to room temperature, and water (100 mL) was added. The mixture was extracted with ethyl ether (75 mL), and the organic extract was washed with brine (150 mL). The organic phase was dried (magnesium sulfate), filtered, and concentrated to afford a yellow oil. Flash chromatography over silica (ethyl acetate/hexanes) provided 1.44 g (55%) of the product as a colorless oil: 1H NMR (CDCl3) δ 13.8 (s, 1H), 7.26-7.21 (m, 2H), 7.06-7.04 (m, 2H), 4.21 (q, J=7.1 Hz, 2H), 2.33 (s, 3H), 1.20 (t, J=7.1 Hz, 3H).
Reaction SMILES: [Br:1]Br.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.O[CH2:23][CH2:24][C:25]1[S:29][C:28]([C:30]([O:32][CH:33]([CH3:35])[CH3:34])=[O:31])=[CH:27][CH:26]=1.N1C=CC=CC=1>C(Cl)Cl>[Br:1][CH2:23][CH2:24][C:25]1[S:29][C:28]([C:30]([O:32][CH:33]([CH3:35])[CH3:34])=[O:31])=[CH:27][CH:26]=1
Reactant: BrBr
Reactant: CC(C)OC(=O)c1ccc(CCO)s1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: c1ccncc1
Solvent: ClCCl
Product: CC(C)OC(=O)c1ccc(CCBr)s1
Temperature: 25 °C
Reaction time: 1 h
Yield: 72.6 %

Procedure:
Bromine (1.74 mL, 33.9 mmol) was added slowly to a solution of triphenylphosphine (8.9 g, 33.9 mmol) in CH2Cl2 (65 mL) at −40° C. After 1 h at −40° C., a solution of the alcohol from step 1 (6.6 g, 30.8 mmol) and pyridine (2.5 mL, 30.9 mmol) in CH2Cl2 (65 mL) was added via cannula. The mixture was allowed to warm to room temperature and was stirred overnight. The reaction was concentrated in vacuo to a brown slurry. The mixture was triturated with hexanes (150 mL) and stirred vigorously. The solids were removed by filtration and the filtrate was concentrated in vacuo to afford 6.2 g (73%) of isopropyl 5-(2-bromoethyl)thiophene-2-carboxylate.
Reaction SMILES: [O:1]=[S:2]1(=[O:27])[C:6]2[CH:7]=[CH:8][CH:9]=[CH:10][C:5]=2[C:4]2[CH:11]=[C:12]([NH:15][C:16]([N:18]3[CH2:23][CH2:22][CH:21]([C:24]([OH:26])=O)[CH2:20][CH2:19]3)=[O:17])[CH:13]=[CH:14][C:3]1=2.[NH:28]1[CH2:33][CH2:32][O:31][CH2:30][CH2:29]1.CCN=C=NCCCN(C)C.O.ON1C2C=CC=CC=2N=N1>CN(C=O)C>[O:1]=[S:2]1(=[O:27])[C:6]2[CH:7]=[CH:8][CH:9]=[CH:10][C:5]=2[C:4]2[CH:11]=[C:12]([NH:15][C:16]([N:18]3[CH2:19][CH2:20][CH:21]([C:24]([N:28]4[CH2:33][CH2:32][O:31][CH2:30][CH2:29]4)=[O:26])[CH2:22][CH2:23]3)=[O:17])[CH:13]=[CH:14][C:3]1=2
Reactant: O=C(O)C1CCN(C(=O)Nc2ccc3c(c2)-c2ccccc2S3(=O)=O)CC1
Reactant: C1COCCN1
Agent: CCN=C=NCCCN(C)C
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: O
Product: O=C(Nc1ccc2c(c1)-c1ccccc1S2(=O)=O)N1CCC(C(=O)N2CCOCC2)CC1

Procedure:
5,5-Dioxo-2-(4-carboxypiperidinocarbonylamino)dibenzothiophene (Example 84; 75 mg, 0.19 mmol), DMF (2.5 ml), morpholine (16.5 mg, 0.19 mmol), EDAC (44 mg, 0.23 mmol), 1-hydroxybenzotriazole hydrate (25.65 mg, 0.19 mmol) were stirred together for 18 hours. The solvent was removed under vacuum and the residue partitioned between H2O/EtOAc. The organic layers were washed with water, saturated aqueous NaHCO3 then brine, and then dried, filtered and evaporated to an amorphous solid. NMR: 9.08 (s, 1H)) 8.21 (d, 1H), 7.93 (m, 2H), 7.79 (m, 2H), 7.65 (m, 2H), 4.14 (m, 2H), 3.52 (m, 6H), 3.45 (m, 2H), 2.92 (m, 3H), 1.68 (m, 2H), 1.53 (m, 2H); m/z 456.73.
Reaction SMILES: [CH2:1]([N:3]1[C:8](=[O:9])[C:7]([Cl:10])=[C:6](Cl)[C:5]([OH:12])=[N:4]1)[CH3:2].[CH2:13]([O:16][C:17]1[CH:18]=[C:19]([CH:22]=[CH:23][C:24]=1[O:25][CH3:26])[CH2:20][NH2:21])[CH2:14][CH3:15].O1CCOCC1>O>[CH2:1]([N:3]1[C:8](=[O:9])[C:7]([Cl:10])=[C:6]([NH:21][CH2:20][C:19]2[CH:22]=[CH:23][C:24]([O:25][CH3:26])=[C:17]([O:16][CH2:13][CH2:14][CH3:15])[CH:18]=2)[C:5]([OH:12])=[N:4]1)[CH3:2]
Reactant: CCCOc1cc(CN)ccc1OC
Reactant: CCn1nc(O)c(Cl)c(Cl)c1=O
Solvent: O
Solvent: C1COCCO1
Product: CCCOc1cc(CNc2c(O)nn(CC)c(=O)c2Cl)ccc1OC
Reaction time: 24 h

Procedure:
A mixture comprising 523 mg of 2-ethyl-4,5-dichloro-6-hydroxy-3(2H)pyridazinone prepared in Reference Example 1, 1.71 g of 3-n-propoxy-4-methoxybenzylamine, 15 ml of 1,4-dioxane and 15 ml of water, was refluxed under stirring for 24 hours, and 1.71 g of 3-n-propoxy-4-methoxybenzylamine was further added thereto, and the reaction was conducted under the same condition for 2 days. The solvent was distilled off under reduced pressure, and dilute hydrochloric acid was added to the residue thereby obtained. The mixture was extracted with ethyl acetate. The extract was washed with water and a saturated sodium chloride aqueous solution in this order, and dried over sodium sulfate. Then, the solvent was distilled off to obtain a yellow oily substance. The oily substance was purified by silica gel column chromatography, and the slightly yellow oily substance obtained by eluting with a solvent mixture of benzene-ethyl acetate (1:2 v/v) was crystallized from ethyl acetate-diethyl ether, to obtain 418 mg of the above identified compound having a melting point of from 73° to 74° C. as colorless crystals.
Reaction SMILES: [OH:1][CH:2]1[C:7](/[CH:8]=[CH:9]/[C:10]#[C:11][C:12]2[CH:22]=[CH:21][C:15]([C:16]([O:18][CH2:19][CH3:20])=[O:17])=[CH:14][CH:13]=2)=[C:6]([CH3:23])[CH2:5][CH2:4][CH2:3]1.[C:24](Cl)(=[O:28])[CH:25]([CH3:27])[CH3:26]>>[C:24]([O:1][CH:2]1[C:7](/[CH:8]=[CH:9]/[C:10]#[C:11][C:12]2[CH:22]=[CH:21][C:15]([C:16]([O:18][CH2:19][CH3:20])=[O:17])=[CH:14][CH:13]=2)=[C:6]([CH3:23])[CH2:5][CH2:4][CH2:3]1)(=[O:28])[CH:25]([CH3:27])[CH3:26]
Reactant: CC(C)C(=O)Cl
Reactant: CCOC(=O)c1ccc(C#C/C=C/C2=C(C)CCCC2O)cc1
Product: CCOC(=O)c1ccc(C#C/C=C/C2=C(C)CCCC2OC(=O)C(C)C)cc1

Procedure:
The title compound, a colorless oil, was prepared from ethyl (+)-(E)-4-(4-(6-hydroxy-2-methylcyclohex-1-enyl)but-3-en-1-ynyl)benzoate (Compound 1b, 25 mg, 0.081 mmol) and iso-butyryl chloride (0.084 mL, 0.81 mmol) as described in General Procedure C.
Reaction SMILES: C(OC([O:7][C@@H:8]([C@H:10]1[C:21](=[O:22])[N:12]2[C:13]([C:18]([O-:20])=[O:19])=[C:14]([CH2:16]O)[CH2:15][C@H:11]12)[CH3:9])=O)C=C.[OH:23][CH2:24][C:25]1[N:32]2[C:28]([S:29][CH:30]=[CH:31]2)=[CH:27][N:26]=1>>[OH:7][C@@H:8]([C@H:10]1[C:21](=[O:22])[N:12]2[C:13]([C:18]([O-:20])=[O:19])=[C:14]([CH2:16][N:26]3[CH:27]=[C:28]4[S:29][CH:30]=[CH:31][N+:32]4=[C:25]3[CH2:24][OH:23])[CH2:15][C@H:11]12)[CH3:9]
Reactant: OCc1ncc2sccn12
Reactant: C=CCOC(=O)O[C@H](C)[C@H]1C(=O)N2C(C(=O)[O-])=C(CO)C[C@H]12
Product: C[C@@H](O)[C@H]1C(=O)N2C(C(=O)[O-])=C(Cn3cc4scc[n+]4c3CO)C[C@H]12
Yield: 6.6 %

Procedure:
The same procedure as in Example 1 was repeated except that 43 mg of (5R,6S)-6-[(1R)-1-allyloxycarbonyloxyethyl]-2-hydroxymethyl-1-carbapen-2-em-3-carboxylate and 96 mg of 5-hydroxymethylimidazo[5,1-b]thiazole were used, thereby obtaining 3.3 mg of the title compound.
Reaction SMILES: [CH:1]12[CH2:8][CH:5]([CH2:6][CH2:7]1)[C:4](=[O:9])[CH2:3][C:2]2=[O:10].[Cl:11][C:12]1[CH:17]=[CH:16][C:15]([N:18]=[C:19]=[O:20])=[CH:14][C:13]=1[C:21]([F:24])([F:23])[F:22].[H-].[Na+].Cl>CN(C)C=O.O>[Cl:11][C:12]1[CH:17]=[CH:16][C:15]([NH:18][C:19]([CH:3]2[C:4](=[O:9])[CH:5]3[CH2:8][CH:1]([CH2:7][CH2:6]3)[C:2]2=[O:10])=[O:20])=[CH:14][C:13]=1[C:21]([F:22])([F:23])[F:24]
Reactant: O=C1CC(=O)C2CCC1C2
Reactant: O=C=Nc1ccc(Cl)c(C(F)(F)F)c1
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: O=C(Nc1ccc(Cl)c(C(F)(F)F)c1)C1C(=O)C2CCC(C2)C1=O

Procedure:
A solution of bicyclo[3,2,1]octane-2,4-dione (0.552 g, 4.0 mmole), 4-chloro-3-(trifluoromethyl)phenyl isocyanate (1.77 g, 8.0 mmole), and 60% sodium hydride in mineral oil (0.176 g, 4.4 mmole) in dimethylformamide (150 mL) was stirred at 0° C. for 1 hour and heated at 45–50° C. under nitrogen for 24 hours. After cooling, the mixture was diluted with H2O and treated with 2N HCl until the mixture was clear. The clear solution was then extracted with dichloromethane. The organic layer was washed with H2O again, dried over anhydrous magnesium sulfate, and concentrated on a rotary evaporator. The residue was purified by chromatography on silica gel (30% dichloromethane/hexane) to give a clear oil as the expected product. The oily product was crystallized with ethyl acetate/hexane in a dry ice bath to afford the title compound as a white solid, mp=136–137° C.; MS (−) ESI m/z=358 (M−H)−. Analysis for C16H13ClF3NO3 Calculated: C: 53.42; H, 3.64; N, 3.89. Found: C: 53.37; H, 3.57; N, 3.67.
Reaction SMILES: [CH2:1]([O:8][CH2:9][C@@:10]1([N:38]2[CH:46]=[C:44]([CH3:45])[C:42](=[O:43])[NH:41][C:39]2=[O:40])[O:37][C@H:17]([CH2:18][O:19][Si:20]([C:33]([CH3:36])([CH3:35])[CH3:34])([C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)[C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[C@@H:12]([O:13][CH2:14][CH2:15]O)[CH2:11]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C(Cl)(Cl)(Cl)[Cl:67]>CN(C=O)C>[CH2:1]([O:8][CH2:9][C@@:10]1([N:38]2[CH:46]=[C:44]([CH3:45])[C:42](=[O:43])[NH:41][C:39]2=[O:40])[O:37][C@H:17]([CH2:18][O:19][Si:20]([C:33]([CH3:36])([CH3:35])[CH3:34])([C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)[C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[C@@H:12]([O:13][CH2:14][CH2:15][Cl:67])[CH2:11]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: Cc1cn([C@@]2(COCc3ccccc3)C[C@H](OCCO)[C@@H](CO[Si](c3ccccc3)(c3ccccc3)C(C)(C)C)O2)c(=O)[nH]c1=O
Reactant: ClC(Cl)(Cl)Cl
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CN(C)C=O
Product: Cc1cn([C@@]2(COCc3ccccc3)C[C@H](OCCCl)[C@@H](CO[Si](c3ccccc3)(c3ccccc3)C(C)(C)C)O2)c(=O)[nH]c1=O

Procedure:
Compound 10 is converted to the chloroethyl derivative with triphenylphosphine and carbon tetrachloride in DMF via the procedure of Verheydan, J. P. H. and Moffatt, J. G. J. Org. Chem. 1972 37, 2289 to give the title compound, 89.
Reaction SMILES: [CH3:1][N:2]1[C:6](=[O:7])[O:5][N:4]=[C:3]1/[C:8](=[N:15]\[O:16][CH2:17][C:18]1[N:23]=[C:22]([NH:24][C:25](=[O:31])[O:26][C:27]([CH3:30])([CH3:29])[CH3:28])[CH:21]=[CH:20][CH:19]=1)/[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1.[H-].[Na+].Br[CH2:35][CH2:36][CH:37]1[CH2:42][CH2:41][CH2:40][CH2:39][CH2:38]1>CN(C)C=O>[CH:37]1([CH2:36][CH2:35][N:24]([C:22]2[CH:21]=[CH:20][CH:19]=[C:18]([CH2:17][O:16]/[N:15]=[C:8](\[C:3]3[N:2]([CH3:1])[C:6](=[O:7])[O:5][N:4]=3)/[C:9]3[CH:10]=[CH:11][CH:12]=[CH:13][CH:14]=3)[N:23]=2)[C:25](=[O:31])[O:26][C:27]([CH3:28])([CH3:30])[CH3:29])[CH2:42][CH2:41][CH2:40][CH2:39][CH2:38]1
Reactant: BrCCC1CCCCC1
Reactant: Cn1c(/C(=N\OCc2cccc(NC(=O)OC(C)(C)C)n2)c2ccccc2)noc1=O
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: Cn1c(/C(=N\OCc2cccc(N(CCC3CCCCC3)C(=O)OC(C)(C)C)n2)c2ccccc2)noc1=O
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 85.8 %

Procedure:
A solution of tert-butyl {6-[({[(Z)-(4-methyl-5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)(phenyl)methylene]amino}oxy)methyl]pyridin-2-yl}carbamate (100 mg, 0.235 mmol, 1 eq.) in N,N-dimethylformamide (2 ml) was treated with sodium hydride (10 mg, 0.259 mmol, 1.1 eq.) and stirred at room temperature for 30 minutes. (2-Bromoethyl)cyclohexane (67 mg, 0.353 mmol, 1.5 eq.) was than added and stirring was allowed overnight. The reaction was quenched by addition of water and extracted with EtOAc (3×20 ml). The organics were combined, washed with aq. sat. NaCl, dried over MgSO4 and concentrated to afford tert-butyl (2-cyclohexylethyl){6-[({[(Z)-(4-methyl-5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)(phenyl)methylene]amino}oxy)methyl]pyridin-2-yl}carbamate (108 mg, 86% yield) which was used in the next step without further purification.
Reaction SMILES: Cl.[Cl:2][C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][CH:11]=1)[NH:8][CH:7]=[C:6]2[CH2:12][CH2:13][NH2:14].C1CN([P+](ON2N=NC3C=CC=CC2=3)(N2CCCC2)N2CCCC2)CC1.F[P-](F)(F)(F)(F)F.C(N(CC)C(C)C)(C)C.[CH:57]([C:60]1[CH:65]=[CH:64][C:63]([N:66]2[CH2:70][CH2:69][CH:68]([C:71](O)=[O:72])[C:67]2=[O:74])=[CH:62][CH:61]=1)([CH3:59])[CH3:58]>CN(C=O)C>[Cl:2][C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][CH:11]=1)[NH:8][CH:7]=[C:6]2[CH2:12][CH2:13][NH:14][C:71]([CH:68]1[CH2:69][CH2:70][N:66]([C:63]2[CH:64]=[CH:65][C:60]([CH:57]([CH3:58])[CH3:59])=[CH:61][CH:62]=2)[C:67]1=[O:74])=[O:72]
Reactant: NCCc1c[nH]c2ccc(Cl)cc12
Reactant: CC(C)c1ccc(N2CCC(C(=O)O)C2=O)cc1
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Agent: c1ccc2c(c1)nnn2O[P+](N1CCCC1)(N1CCCC1)N1CCCC1
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)c1ccc(N2CCC(C(=O)NCCc3c[nH]c4ccc(Cl)cc34)C2=O)cc1
Yield: 32.3 %

Procedure:
A mixture of 2-(5-chloro-1H-indol-3-yl)ethanamine hydrochloride (0.036 g; 0.146 mmol), PyBOP (0.113 g; 0.219 mmol), N,N-diisopropylethylamine (0.075 mL; 0.437 mmol) and 1-(4-isopropylphenyl)-2-oxopyrrolidine-3-carboxylic acid (0.100 g; 0.425 mmol) was stirred in DMF (3 mL) overnight. The reaction mixture was partitioned between ethyl acetate and sodium hydrogen sulfate, the organic layer was washed with sodium carbonate, brine, dried and concentrated under reduced pressure. The crude mixture was purified flash chromatography on silica (eluent 20 to 100% ethyl acetate in heptane) to yield 0.020 g (32%) of the title compound as a white solid.
Reaction SMILES: [C:1]1([NH2:8])[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[NH2:7].C(=O)([O-])[O-].[K+].[K+].[CH2:15](Cl)[CH:16]=[CH:17][C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1.O>CN(C)C=O>[CH2:15]([NH:7][C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][C:1]=1[NH2:8])[CH:16]=[CH:17][C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1
Reactant: Nc1ccccc1N
Reactant: ClCC=Cc1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: Nc1ccccc1NCC=Cc1ccccc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 89.5 %

Procedure:
3.24 g of ortho-phenylenediamine was dissolved in 30 ml of dimethylformamide, to the solution were added 2.07 g of potassium carbonate and 1.52 g of cinnamyl chloride, and the mixture was stirred overnight at a room temperature. After adding 100 ml of water, the reaction mixture was extracted twice with 100 ml and 50 ml of chloroform, and the extract was washed with a saturated sodium chloride aqueous solution, dried over magnesium sulfate and evaporated to remove the solvent under a reduced pressure. The resulting residue was applied to a silica gel column and eluted with chloroform, to obtain 2.0 g of the title compound as light brown crystals.
Reaction SMILES: [NH2:1][C:2]1[C:11]2[C:6](=[C:7](Br)[CH:8]=[CH:9][CH:10]=2)[N:5]=[N:4][C:3]=1[C:13]([NH:15][CH2:16][CH2:17][CH3:18])=[O:14].[CH3:19][O:20][C:21]1[CH:22]=[C:23](B(O)O)[CH:24]=[CH:25][C:26]=1[O:27][CH3:28]>>[NH2:1][C:2]1[C:11]2[C:6](=[C:7]([C:24]3[CH:23]=[CH:22][C:21]([O:20][CH3:19])=[C:26]([O:27][CH3:28])[CH:25]=3)[CH:8]=[CH:9][CH:10]=2)[N:5]=[N:4][C:3]=1[C:13]([NH:15][CH2:16][CH2:17][CH3:18])=[O:14]
Reactant: COc1ccc(B(O)O)cc1OC
Reactant: CCCNC(=O)c1nnc2c(Br)cccc2c1N
Product: CCCNC(=O)c1nnc2c(-c3ccc(OC)c(OC)c3)cccc2c1N
Yield: 75.3 %

Procedure:
Using method A, 4-amino-8-bromo-N-propyl-cinnoline-3-carboxamide (100 mg, 0.33 mmol) and 3,4-dimethoxyphenyl boronic acid (148 mg, 0.97 mmol) were reacted to afford the title compound (91 mg, 77.7% yield) as a pale-yellow solid. 1H NMR (300 MHz, CDCl3) δ 8.58 (br, 1H), 7.76-7.88 (m, 2H), 7.71 (t, J=7.7 Hz, 1H), 7.29 (m, overlapped with CHCl3), 7.23 (d, J=1.9 Hz, 1H), 7.02 (d, J =8.3 Hz, 1H), 3.95 (s, 3H), 3.93 (s, 3H), 3.47 (q, J=6.7 Hz, 2H), 1.68 (m, J=7.2 Hz, 2H), 1.01 (t, J=7.4 Hz, 3H) MS APCI, m/z=367 (M+H) HPLC 1.78 min.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9](=[O:16])[CH2:10][C:11]([O:13]CC)=[O:12])=[CH:4][CH:3]=1.[OH-].[Na+].C(OCC)(=O)C>C1COCC1>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([NH:8][C:9](=[O:16])[CH2:10][C:11]([OH:13])=[O:12])=[CH:6][CH:7]=1
Reactant: CCOC(=O)CC(=O)Nc1ccc(Br)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: O=C(O)CC(=O)Nc1ccc(Br)cc1
Reaction time: 24 h

Procedure:
The product of Step 1 (16.63 g) was dissolved in THF (150 mL) and 2N NaOH (145 mL) was added over 15 minutes. The reaction was stirred for 24 hours. The reaction mixture was concentrated to remove the THF. Diethyl ether (20 mL) was added and the layers were separated. The aqueous layer was acidified to pH=2.2 with 1N HCl which resulted in the precipitation of solids. Ethyl acetate was added until the solids were dissolved and the layers were separated. The organic extract was dried with sodium sulfate, filtered and concentrated to give 14.7 g of a cake.
Reaction SMILES: F[C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=[O:7])=[CH:4][N:3]=1.[CH3:11][S-:12].[Na+].Cl>CS(C)=O.C(OCC)(=O)C>[CH3:11][S:12][C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=[O:7])=[CH:4][N:3]=1
Reactant: C[S-]
Reactant: O=C(O)c1ccc(F)nc1
Agent: Cl
Agent: [Na+]
Solvent: CS(C)=O
Solvent: CCOC(C)=O
Product: CSc1ccc(C(=O)O)cn1
Temperature: 80 °C
Reaction time: 0.25 h

Procedure:
To a solution of 6-fluoronicotinic acid (0.995 g, 7.05 mmol) in 14 mL of DMSO was added sodium thiomethoxide (1.24 g, 17.6 mmol). The mixture was heated 80° C. for 1 h, cooled to rt, and treated with concentrated hydrochloric acid (4.5 mL, 0.054 mol). After 15 min, the mixture was diluted with ethyl acetate and concentrated in vacuo to provide 6-(methylthio)nicotinic acid that gave a mass ion (ES+) of 170.1 for [M+H]+.
Reaction SMILES: [C:1]([O:4][C:5]1[CH:6]=[CH:7][C:8]2[N:9]([CH2:22][CH3:23])[C:10]3[C:15]([C:16]=2[CH:17]=1)=[CH:14][C:13]([O:18][C:19](=O)[CH3:20])=[CH:12][CH:11]=3)(=O)[CH3:2].[ClH:24].[N:25]1(CC[Cl:33])[CH2:30][CH2:29][CH2:28][CH2:27][CH2:26]1.C[O-].[Na+]>ClC1C=CC=CC=1>[ClH:33].[ClH:24].[CH2:22]([N:9]1[C:8]2[CH:7]=[CH:6][C:5]([O:4][CH2:1][CH2:2][N:25]3[CH2:30][CH2:29][CH2:28][CH2:27][CH2:26]3)=[CH:17][C:16]=2[C:15]2[C:10]1=[CH:11][CH:12]=[C:13]([O:18][CH2:19][CH2:20][N:25]1[CH2:26][CH2:27][CH2:28][CH2:29][CH2:30]1)[CH:14]=2)[CH3:23]
Reactant: ClCCN1CCCCC1
Reactant: CCn1c2ccc(OC(C)=O)cc2c2cc(OC(C)=O)ccc21
Agent: C[O-]
Agent: Cl
Agent: [Na+]
Solvent: Clc1ccccc1
Product: CCn1c2ccc(OCCN3CCCCC3)cc2c2cc(OCCN3CCCCC3)ccc21

Procedure:
A mixture of 15.5 g (0.05 mole) of N-ethyl-3,6-carbazolediol diacetate, 18.4 g (0.1 mole) of 2-piperidinoethylchloride hydrochloride, 10.8 g (0.2 mole) of sodium methoxide and 400 ml of chlorobenzene is refluxed for 24 hours. Upon cooling, the reaction mixture is filtered, and the filtrate is washed with several portions of water, dried over anhydrous magnesium sulfate, diluted with ether and acidified with ethereal HCl. The resulting precipitate is collected and recrystallized from methanol-ethyl acetate to give N-ethyl-3,6-bis(2-piperidinoethoxy)carbazole dihydrochloride, M.P. 248°-250° C.