Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][S:2]([NH2:5])(=[O:4])=[O:3].C(N(CC)CC)C.[C:13](Cl)(=[O:17])[O:14][CH2:15][CH3:16]>CN(C1C=CN=CC=1)C.C(Cl)Cl.CCOC(C)=O>[CH3:1][S:2]([NH:5][C:13](=[O:17])[O:14][CH2:15][CH3:16])(=[O:4])=[O:3]
Reactant: CCOC(=O)Cl
Reactant: CS(N)(=O)=O
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Solvent: CCOC(C)=O
Product: CCOC(=O)NS(C)(=O)=O
Temperature: 25 °C

Procedure:
To a mixture of methanesulfonamide (1.0 g, 11 mmol), triethylamine (1.9 mL, 14 mmol), and DMAP (0.13 g, 1.1 mmol) in DCM (20 mL) cooled in an ice-water bath was added ethyl carbonochloridate (1.1 mL, 12 mmol) dropwise via a syringe under an argon atmosphere. The mixture was allowed to warm up to rt overnight. The reaction mixture was concentrated, and the residue obtained was dissolved in EtOAc (100 mL). The solution was washed with 1 N HCl (20 mL) and brine, and dried over MgSO4. The mixture was filtered and concentrated to give compound 12a as a yellow oil. 1H-NMR (400 MHz, CDCl3) δ (ppm): 7.86 (br. s., 1H), 4.28 (q, J=7.25 Hz, 2H), 3.30 (s, 3H), 1.33 (t, J=7.25 Hz, 3H).
Reaction SMILES: [CH2:1]([CH:3]1[CH2:26][NH:25][C:6]2=[N:7][C:8]([C:18]3[CH:23]=[CH:22][C:21]([CH3:24])=[CH:20][CH:19]=3)=[C:9]([C:11]3[CH:16]=[CH:15][C:14]([CH3:17])=[CH:13][CH:12]=3)[N:10]=[C:5]2[CH2:4]1)[CH3:2].O=[CH:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][C:34]([O:36][CH2:37][CH3:38])=[O:35].[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+]>ClCCCl>[CH2:1]([CH:3]1[CH2:26][N:25]([CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][C:34]([O:36][CH2:37][CH3:38])=[O:35])[C:6]2=[N:7][C:8]([C:18]3[CH:19]=[CH:20][C:21]([CH3:24])=[CH:22][CH:23]=3)=[C:9]([C:11]3[CH:16]=[CH:15][C:14]([CH3:17])=[CH:13][CH:12]=3)[N:10]=[C:5]2[CH2:4]1)[CH3:2]
Reactant: CCC1CNc2nc(-c3ccc(C)cc3)c(-c3ccc(C)cc3)nc2C1
Reactant: CCOC(=O)CCCCCC=O
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCCl
Product: CCOC(=O)CCCCCCN1CC(CC)Cc2nc(-c3ccc(C)cc3)c(-c3ccc(C)cc3)nc21
Reaction time: 0.17 h

Procedure:
To a mixture comprising 7-ethyl-2,3-di-p-tolyl-5,6,7,8-tetrahydropyrido[2,3-b]pyrazine (Intermediate D)(0.1 g, 0.291 mmol) in 1,2-dichloroethane (2 ml) was added molecular sieves followed by ethyl 7-oxoheptanoate (0.15 g, 0.874 mmol). The mixture was stirred for 10 minutes and treated with NaBH(OAc)3. After stirring at RT overnight, the reaction mixture was passed through Celite® (filter material) and partitioned between EtOAc and water. The organic layer was washed with saturated brine solution, dried over anhydrous sodium sulphate and concentrated under vacuum to afford the titled compound;
Reaction SMILES: CC[CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][C:16]([OH:18])=[O:17].CCCCCCCCCCCCCCCCCC(O)=O.CCCCCCCC/C=C\CCCCCCCC(O)=O.CCCCC/C=C\C/C=C\CCCCCCCC(O)=O>>[CH3:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][C:16]([OH:18])=[O:17]
Reactant: CCCCCCCCCCCCCCCC(=O)O
Agent: CCCCC/C=C\C/C=C\CCCCCCCC(=O)O
Agent: CCCCCCCC/C=C\CCCCCCCC(=O)O
Agent: CCCCCCCCCCCCCCCCCC(=O)O
Product: CCCCCCCCCCCCCC(=O)O

Procedure:
C16:0 56.9; C18:0 6.9; C18:1 30.9; C18:2 4 3.
Reaction SMILES: [OH:1][CH2:2][CH2:3][CH2:4][O:5][C:6]1[C:11]([CH3:12])=[CH:10][C:9]([CH2:13][CH2:14][C:15]([C:17]2[S:24][C:23]([CH3:25])=[C:22]3[C:18]=2[CH2:19][C@H:20]2[C:26]([CH3:28])([CH3:27])[C@H:21]23)=[O:16])=[CH:8][C:7]=1[CH3:29].CCN(C(C)C)C(C)C.[CH3:39][S:40](Cl)(=[O:42])=[O:41]>C(Cl)Cl>[CH3:12][C:11]1[CH:10]=[C:9]([CH2:13][CH2:14][C:15](=[O:16])[C:17]2[S:24][C:23]([CH3:25])=[C:22]3[C:18]=2[CH2:19][C@H:20]2[C:26]([CH3:27])([CH3:28])[C@H:21]23)[CH:8]=[C:7]([CH3:29])[C:6]=1[O:5][CH2:4][CH2:3][CH2:2][O:1][S:40]([CH3:39])(=[O:42])=[O:41]
Reactant: CS(=O)(=O)Cl
Reactant: Cc1cc(CCC(=O)c2sc(C)c3c2C[C@@H]2[C@H]3C2(C)C)cc(C)c1OCCCO
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: Cc1cc(CCC(=O)c2sc(C)c3c2C[C@@H]2[C@H]3C2(C)C)cc(C)c1OCCCOS(C)(=O)=O
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 833.4 %

Procedure:
To a solution of 3-[4-(3-hydroxy-propoxy)-3,5-dimethyl-phenyl]-1-((1aS,5aR)-1,1,2-trimethyl-1,1a,5,5a-tetrahydro-3-thia-cyclopropa[a]pentalen-4-yl)-propan-1-one (2.00 g, 4.85 mmol) in DCM (60 mL) and DIPEA (1.33 mL, 7.76 mmol) is added methane sulfonylchloride (0.452 mL, 582 μmol) at 0° C. The reaction mixture is stirred at 0° C. for 30 min. Another portion of methane sulfonylchloride (0.452 mL, 5.82 mmol) is added and stirring is continued for 30 min. The reaction mixture is diluted with DCM, washed with 0.1 N aq. NaOH followed by 10% aq. citric acid solution, dried over MgSO4 and evaporated to give methanesulfonic acid 3-{2,6-dimethyl-4-[3-oxo-3-((1aS,5aR)-1,1,2-trimethyl-1,1a,5,5a-tetrahydro-3-thia-cyclopropa[a]pentalen-4-yl)-propyl]-phenoxy}-propyl ester (2.38 g) as a brown oil; LC-MS: tR=1.15 min, [M+1]+=491.34.
Reaction SMILES: [N:1]1([C:7]2[CH:16]=[CH:15][CH:14]=[C:13]3[C:8]=2[C:9]([NH2:18])=[N:10][C:11]([NH2:17])=[N:12]3)[CH2:6][CH2:5][NH:4][CH2:3][CH2:2]1.[F:19][C:20]([F:31])([F:30])[O:21][C:22]1[CH:23]=[C:24]([CH:27]=[CH:28][CH:29]=1)[CH2:25]Br>>[F:19][C:20]([F:30])([F:31])[O:21][C:22]1[CH:23]=[C:24]([CH:27]=[CH:28][CH:29]=1)[CH2:25][N:4]1[CH2:5][CH2:6][N:1]([C:7]2[CH:16]=[CH:15][CH:14]=[C:13]3[C:8]=2[C:9]([NH2:18])=[N:10][C:11]([NH2:17])=[N:12]3)[CH2:2][CH2:3]1
Reactant: FC(F)(F)Oc1cccc(CBr)c1
Reactant: Nc1nc(N)c2c(N3CCNCC3)cccc2n1
Product: Nc1nc(N)c2c(N3CCN(Cc4cccc(OC(F)(F)F)c4)CC3)cccc2n1
Yield: 70 %

Procedure:
Title compound was prepared via Resin Method using 5-piperazin-1-yl-quinazoline-2,4-diamine (50 mg; 0.2 mmol) and 3-(trifluoromethoxy)benzyl bromide (94.4 mg; 0.37 mmol) to obtain 58.9 mg. (70% yield). 1H NMR (400 MHz, DMSO-d6) δ 10.0 (br s, 1H), 8.97 (br s, 1H), 7.72 (m, 2H), 7.50 (m, 2H), 7.28 (m, 1H), 7.29 (m, 4H), 3.64 (s, 2H), 3.04 (d, J=10.4 Hz, 2H), 2.93 (m, 4H), 2.32 (m, 2H). ESIMS+419.8 m/z
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[CH:6]=[C:7]([CH:11]=[C:12]([C:14]2[CH:18]=[C:17]([Cl:19])[S:16][C:15]=2[Cl:20])[CH:13]=1)[C:8]([OH:10])=O)=[O:4].[CH3:21][N:22]([CH3:26])[CH2:23][CH2:24][NH2:25].ON1C2C=CC=CC=2N=N1.C(N=C=NCCCN(C)C)C>ClCCl>[Cl:20][C:15]1[S:16][C:17]([Cl:19])=[CH:18][C:14]=1[C:12]1[CH:11]=[C:7]([C:8](=[O:10])[NH:25][CH2:24][CH2:23][N:22]([CH3:26])[CH3:21])[CH:6]=[C:5]([CH:13]=1)[C:3]([O:2][CH3:1])=[O:4]
Reactant: COC(=O)c1cc(C(=O)O)cc(-c2cc(Cl)sc2Cl)c1
Reactant: CN(C)CCN
Agent: CCN=C=NCCCN(C)C
Agent: On1nnc2ccccc21
Solvent: ClCCl
Product: COC(=O)c1cc(C(=O)NCCN(C)C)cc(-c2cc(Cl)sc2Cl)c1
Temperature: 25 °C
Reaction time: 7 h
Yield: 67.3 %

Procedure:
To a mixture of 3-methoxycarbonyl-5-(2,5-dichlorothiophen-3-yl)benzoic acid (0.7 g), N,N-dimethylethylenediamine (0.186 g) and 1-hydroxybenzotriazole (0.314 g) in dichloromethane (25 ml) was added 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide (0.446 g) under ice cooling, and the solution was stirred for 7 hours at room temperature. After evaporating the solvent, the residue was dissolved in a mixture of ethyl acetate and saturated aqueous sodium hydrogencarbonate solution with stirring. The organic layer was successively washed with water and brine, dried over magnesium sulfate and evaporated in vacuo. The residue was purified by column chromatography on silica gel eluting with a mixture of chloroform and methanol (20:1). The eluted fractions containing the desired product were collected and evaporated in vacuo to afford methyl 5-(2,5-dichlorothiophen-3-yl)-3-[(2-dimethylaminoethyl)carbamoyl]benzoate (0.57 g).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:13])[C:4]([CH3:12])([CH3:11])[CH2:5][O:6][Si](C)(C)C.[O:14]1[CH2:18][CH2:17][C:16](=O)[CH2:15]1.C([SiH](CC)CC)C.C([O-])(O)=O.[Na+]>[N+](C)([O-])=O>[CH3:1][O:2][C:3](=[O:13])[C:4]([CH3:12])([CH3:11])[CH2:5][O:6][CH:16]1[CH2:17][CH2:18][O:14][CH2:15]1
Reactant: COC(=O)C(C)(C)CO[Si](C)(C)C
Reactant: O=C1CCOC1
Agent: CC[SiH](CC)CC
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C[N+](=O)[O-]
Product: COC(=O)C(C)(C)COC1CCOC1
Temperature: 25 °C
Reaction time: 2 h
Yield: 89.5 %

Procedure:
2,2-Dimethyl-3-trimethylsilanyloxy-propionic acid methyl ester (478 mg, 2.34 mmol) was added to a solution of dihydro-furan-3-one (168 mg, 1.95 mmol) and FeCl3 (16 mg, 0.097 mmol) in nitromethane (6.0 mL) at 0° C. Triethylsilane (0.374 mL, 2.33 mmol) was added and the reaction was warmed to room temperature and stirred for 2 h. Sat. NaHCO3 was added and the reaction was extracted with dichloromethane. The organic layer was separated, washed with brine, dried over Na2SO4 and concentrated to give a pale liquid. Purification by flash column chromatography on silica gel using 30% ethyl acetate in hexanes provided dimethyl-3-(tetrahydro-furan-3-yloxy)-propionic acid methyl ester (353 mg, 75%) as a colorless liquid.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]2[N:13](CC3C=CC(OC)=CC=3)[CH2:12][CH2:11][CH2:10][CH2:9][C:8]([C:23]([O:25][CH3:26])=[O:24])=[CH:7][C:6]=2[CH:27]=1.FC(F)(F)C(O)=O>C1(C)C=CC=CC=1>[Br:1][C:2]1[CH:3]=[CH:4][C:5]2[NH:13][CH2:12][CH2:11][CH2:10][CH2:9][C:8]([C:23]([O:25][CH3:26])=[O:24])=[CH:7][C:6]=2[CH:27]=1
Reactant: COC(=O)C1=Cc2cc(Br)ccc2N(Cc2ccc(OC)cc2)CCCC1
Solvent: O=C(O)C(F)(F)F
Solvent: Cc1ccccc1
Product: COC(=O)C1=Cc2cc(Br)ccc2NCCCC1
Temperature: 80 °C
Reaction time: 7 h
Yield: 82.1 %

Procedure:
To a solution of methyl 9-bromo-1-(4-methoxybenzyl)-2,3,4,5-tetrahydro-1H-1-benzoazonin-6-carboxylate (12.5 g) in toluene (62.5 ml) was added trifluoroacetic acid (62.5 ml) and the mixture was stirred under nitrogen atmosphere at 80° C. for 7 hours. After distilling off the solvent under reduced pressure, water was added at 0° C. and the mixture was neutralized with potassium carbonate, and extracted with ethyl acetate. After washing the organic layer with aqueous saturated sodium bicarbonate solution and saturated brine, the resultant was dried with magnesium sulfate. The solvent was distilled off under reduced pressure, and the resulting residue was purified by silica gel column chromatography (hexane-ethyl acetate=9:1) and recrystallized from hexane:ethyl acetate to give methyl 9-bromo-2,3,4,5-tetrahydro-1H-1-benzoazonin-6-carboxylate (7.4 g) as yellow crystals.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[CH:10]=[CH:9][NH:8][C:5]2=[N:6][CH:7]=1.[Cl-].[Cl-].[Cl-].[Al+3].[F:15][C:16]1[C:24]([N+:25]([O-:27])=[O:26])=[CH:23][CH:22]=[CH:21][C:17]=1[C:18](Cl)=[O:19]>[N+](C)([O-])=O>[Br:1][C:2]1[CH:3]=[C:4]2[C:10]([C:18]([C:17]3[CH:21]=[CH:22][CH:23]=[C:24]([N+:25]([O-:27])=[O:26])[C:16]=3[F:15])=[O:19])=[CH:9][NH:8][C:5]2=[N:6][CH:7]=1
Reactant: Brc1cnc2[nH]ccc2c1
Reactant: O=C(Cl)c1cccc([N+](=O)[O-])c1F
Agent: [Al+3]
Agent: [Cl-]
Solvent: C[N+](=O)[O-]
Product: O=C(c1cccc([N+](=O)[O-])c1F)c1c[nH]c2ncc(Br)cc12
Temperature: 45 °C
Reaction time: 0.5 h
Yield: 16.2 %

Procedure:
5-Bromo-1H-pyrrolo[2,3-b]pyridine (4, 0.525 g, 2.66 mmol) is combined with aluminum trichloride (2.05 g, 15.4 mmol) and 10 mL of nitromethane. 2-Fluoro-3-nitro-benzoyl chloride (17, 0.521 g, 2.56 mmol) in 5 mL of nitromethane is added and the reaction is heated at 45° C. for 6 hours. The reaction is quenched by slowly adding 5 mL of methanol. The resulting precipitate is collected by filtration and combined with ethyl acetate, water and celite, then stirred for 30 minutes and filtered. The organic layer is isolated and washed with water, then brine, dried over magnesium sulfate, filtered and the filtrate is concentrated under vacuum to provide the desired compound (18, 151 mg). MS (ESI) [M−H+]−=362.4 and 364.4.
Reaction SMILES: [O:1]1[CH:5]=[CH:4][C:3]([C:6]2[CH:18]=[CH:17][C:9]([C:10]([O:12][C:13]([CH3:16])([CH3:15])[CH3:14])=[O:11])=[CH:8][CH:7]=2)=[CH:2]1>CO.[Pd]>[O:1]1[CH2:5][CH2:4][CH:3]([C:6]2[CH:18]=[CH:17][C:9]([C:10]([O:12][C:13]([CH3:14])([CH3:16])[CH3:15])=[O:11])=[CH:8][CH:7]=2)[CH2:2]1
Reactant: CC(C)(C)OC(=O)c1ccc(-c2ccoc2)cc1
Agent: [Pd]
Solvent: CO
Product: CC(C)(C)OC(=O)c1ccc(C2CCOC2)cc1
Temperature: 25 °C
Reaction time: 24 h
Yield: 85.9 %

Procedure:
To a solution of tert-butyl 4-(furan-3-yl)benzoate (400 mg, 1.64 mmol) in methanol (20 mL) was added palladium on carbon (10%, 40 mg), and the mixture was stirred for 24 hours at room temperature under hydrogen atmosphere. Insoluble matters were removed using celite, and the filtrate was concentrated in vacuum to give title product as a white solid (350 mg, 86%). LRMS (M+H+) m/z: calcd 248.14. found 248 1H NMR (300 MHz, CD3OD): δ 7.91 (m, 2H), 7.38 (d, J=8.4 Hz, 2H), 4.09 (m, 2H), 3.95 (m, 1H), 3.87 (m, 1H), 3.72 (m, 1H), 2.45 (m, 1H), 2.36 (m, 1H), 1.59 (s, 9H).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([OH:8])[C:3]=1[CH2:9][N:10]1[CH:14]=[CH:13][C:12]([NH:15][C:16](=[O:25])[C:17]2[C:22]([F:23])=[CH:21][CH:20]=[CH:19][C:18]=2[F:24])=[N:11]1.CC(C)([O-])C.[K+].Br[CH2:33][CH:34]1[CH2:37][CH2:36][CH2:35]1.C(Cl)(Cl)Cl>CS(C)=O>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([O:8][CH2:33][CH:34]2[CH2:37][CH2:36][CH2:35]2)[C:3]=1[CH2:9][N:10]1[CH:14]=[CH:13][C:12]([NH:15][C:16](=[O:25])[C:17]2[C:22]([F:23])=[CH:21][CH:20]=[CH:19][C:18]=2[F:24])=[N:11]1
Reactant: BrCC1CCC1
Reactant: O=C(Nc1ccn(Cc2c(O)cccc2Cl)n1)c1c(F)cccc1F
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: CS(C)=O
Solvent: ClC(Cl)Cl
Product: O=C(Nc1ccn(Cc2c(Cl)cccc2OCC2CCC2)n1)c1c(F)cccc1F
Temperature: 60 °C
Reaction time: 0.33 h

Procedure:
To a stirred solution of N-{1-[(2-chloro-6-hydroxyphenyl)methyl]-1H-pyrazol-3-yl}-2,6-difluorobenzamide (for a preparation see Intermediate 11)(0.047 g, 0.13 mmol) in dry DMSO (0.6 ml) in a reactivial was added potassium t-butoxide (0.0145 g, 0.13 mmol). The mixture was stirred for 20 min and then (bromomethyl)cyclobutane (0.023 g, 0.15 mmol, Aldrich) added. The mixture was stirred and heated at 60° C. for 24 h. The cooled reaction mixture was added to chloroform (about 20 ml) and this solution filtered through a hydrophobic frit and evaporated in vacuo. The residue was purified on MDAP (Method B) to give the title compound as a white solid (0.038 g); LCMS: (System 4) MH+=432, tRET=3.36 min.
Reaction SMILES: [C:1]([C@@H:3]1[CH2:7][N:6]([C:8]2[CH:13]=[CH:12][N:11]3[N:14]=[CH:15][C:16]([C:17]([N:19](CC4C=CC(OC)=CC=4)CC4C=CC(OC)=CC=4)=[O:18])=[C:10]3[CH:9]=2)[C@@H:5]([C:38]2[CH:43]=[CH:42][CH:41]=[C:40]([F:44])[CH:39]=2)[CH2:4]1)#[N:2]>C(O)(C(F)(F)F)=O.CS(C)=O>[C:1]([C@@H:3]1[CH2:7][N:6]([C:8]2[CH:13]=[CH:12][N:11]3[N:14]=[CH:15][C:16]([C:17]([NH2:19])=[O:18])=[C:10]3[CH:9]=2)[C@@H:5]([C:38]2[CH:43]=[CH:42][CH:41]=[C:40]([F:44])[CH:39]=2)[CH2:4]1)#[N:2]
Reactant: COc1ccc(CN(Cc2ccc(OC)cc2)C(=O)c2cnn3ccc(N4C[C@@H](C#N)C[C@@H]4c4cccc(F)c4)cc23)cc1
Solvent: O=C(O)C(F)(F)F
Solvent: CS(C)=O
Product: N#C[C@H]1C[C@H](c2cccc(F)c2)N(c2ccn3ncc(C(N)=O)c3c2)C1

Procedure:
A solution of 5-((2R,4S)-4-cyano-2-(3-fluorophenyl)pyrrolidin-1-yl)-N,N-bis(4-methoxybenzyl)pyrazolo[1,5-a]pyridine-3-carboxamide (I-35) (15 mg, 0.025 mmol) in TFA (0.5 mL) was heated to 60° C. for 2 hours. The reaction was reduced to dryness and the crude material was taken up in DMSO and purified by preparative LCMS and lyophilized to give 5-((2R,4S)-4-cyano-2-(3-fluorophenyl)pyrrolidin-1-yl)pyrazolo[1,5-a]pyridine-3-carboxamide (X-25). 1H NMR (400 MHz, CD3CN) δ 8.22 (d, J=7.8 Hz, 1 H), 8.05 (s, 1 H), 7.43-7.28 (m, 1 H), 7.10 (d, J=7.7 Hz, 1 H), 7.06-6.96 (m, 3 H), 6.38 (dd, J=2.8, 7.7 Hz, 1 H), 5.09 (dd, J=3.0, 8.1 Hz, 1 H), 4.18 (dd, J=7.6, 9.6 Hz, 1 H), 3.82-3.70 (m, 1 H), 3.49-3.34 (m, 1 H), 2.86-2.68 (m, 1 H), 2.38-2.28 (m, 1 H). MS m/z 350.1 (M+1)+.
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[N:5]([CH2:12][CH2:13][O:14][CH2:15][CH3:16])[C:4](=[O:17])[C:3]=1[C:18]#[N:19].[C:20]([O:24][C:25]([N:27]1[CH2:30][CH:29]([NH2:31])[CH2:28]1)=[O:26])([CH3:23])([CH3:22])[CH3:21].[H-].[Na+]>>[C:20]([O:24][C:25]([N:27]1[CH2:30][CH:29]([NH:31][C:2]2[C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[N:5]([CH2:12][CH2:13][O:14][CH2:15][CH3:16])[C:4](=[O:17])[C:3]=2[C:18]#[N:19])[CH2:28]1)=[O:26])([CH3:23])([CH3:21])[CH3:22]
Reactant: CC(C)(C)OC(=O)N1CC(N)C1
Reactant: CCOCCn1c(=O)c(C#N)c(Cl)c2ccccc21
Agent: [H-]
Agent: [Na+]
Product: CCOCCn1c(=O)c(C#N)c(NC2CN(C(=O)OC(C)(C)C)C2)c2ccccc21
Reaction time: 2 h

Procedure:
To a stirred solution of 4-Chloro-1-(2-ethoxy-ethyl)-2-oxo-1,2-dihydro-quinoline-3-carbonitrile (1 eq, 0.100 g, 0.36 mmole) in N,N′-dimethylfomamide was added commercially available 3-Amino-azetidine-1-carboxylic acid tert-butyl ester (1.1 eq, 0.068 g, 0.39 mmole) and treated with 60% NaH oil dispersion (1.5 eq, 0.013 g, 0.54 mmole). After stirring for 2 h, reaction was quenched with 10% HCl aq. (1 ml) then H2O (5 ml). A solid formed that was collected and dried. No further purification was necessary, afforded 3-[3-Cyano-1-(2-ethoxy-ethyl)-2-oxo-1,2-dihydro-quinolin-4-ylamino]-azetidine-1-carboxylic acid tert-butyl ester as a pale yellow solid (0.133 g, 90%, calc M+H 413, obs M+H 413).
Reaction SMILES: [N:1]1([CH2:7][CH2:8][NH:9][S:10]([C:13]2[CH:17]=[C:16]([C:18]([C:20]3[C:21](Cl)=[N:22][CH:23]=[CH:24][CH:25]=3)=O)[NH:15][CH:14]=2)(=[O:12])=[O:11])[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1.O.[NH2:28][NH2:29]>C(O)C>[N:1]1([CH2:7][CH2:8][NH:9][S:10]([C:13]2[CH:17]=[C:16]([C:18]3[C:20]4[C:21](=[N:22][CH:23]=[CH:24][CH:25]=4)[NH:29][N:28]=3)[NH:15][CH:14]=2)(=[O:12])=[O:11])[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1
Reactant: O=C(c1cc(S(=O)(=O)NCCN2CCOCC2)c[nH]1)c1cccnc1Cl
Reactant: NN
Solvent: CCO
Solvent: O
Product: O=S(=O)(NCCN1CCOCC1)c1c[nH]c(-c2n[nH]c3ncccc23)c1
Temperature: 80 °C

Procedure:
A mixture of 5-(2-chloro-pyridine-3-carbonyl)-1H-pyrrole-3-sulfonic acid (2-morpholin-4-yl-ethyl)-amide (100 mg) and hydrazine hydrate (excess) in ethanol (5 mL) was heated at 80° C. for 48 hours. The reaction was concentrated, diluted with water, acidified to pH 2 with 1N HCl and extracted with DCM. The aqueous layer was adjusted to pH 7 with NaHCO3, the precipitate was collected by vacuum filtration, washed with water to give the titled compound as a white solid.
Reaction SMILES: [F:1][C:2]1[CH:10]=[CH:9][C:8]([C:11]([F:14])([F:13])[F:12])=[CH:7][C:3]=1[C:4](Cl)=[O:5].C(N(CC)CC)C.[NH2:22][C:23]1[CH:24]=[CH:25][C:26]([CH3:32])=[C:27]([CH:31]=1)[C:28]([OH:30])=[O:29]>C(Cl)Cl>[F:1][C:2]1[CH:10]=[CH:9][C:8]([C:11]([F:14])([F:13])[F:12])=[CH:7][C:3]=1[C:4]([NH:22][C:23]1[CH:24]=[CH:25][C:26]([CH3:32])=[C:27]([CH:31]=1)[C:28]([OH:30])=[O:29])=[O:5]
Reactant: Cc1ccc(N)cc1C(=O)O
Reactant: O=C(Cl)c1cc(C(F)(F)F)ccc1F
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: Cc1ccc(NC(=O)c2cc(C(F)(F)F)ccc2F)cc1C(=O)O
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
To a 100 mL round-bottomed flask containing 2-fluoro-5-(trifluoromethyl)benzoyl chloride (0.44 ml, 2.9 mmol) in CH2Cl2 (30 mL) was added triethylamine (0.48 ml, 3.4 mmol). After 10 min, 5-amino-2-methylbenzoic acid (0.400 g, 2.6 mmol) was added. The solution was stirred at rt overnight. After cooling, the crude reaction mixture was concentrated to remove excess NEt3 then diluted with CH2Cl2 and washed with 1 N HCl once, and brine & salt once then dried over Na2SO4 to afford 5-(2-fluoro-5-(trifluoromethyl)benzamido)-2-methylbenzoic acid 32 as an off-white solid. MS m/z found: 342.1 (ESI, pos. ion).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:22])[CH2:5][CH:6]([C:12]1[CH:17]=[CH:16][CH:15]=[C:14]([O:18][CH3:19])[C:13]=1[O:20][CH3:21])[CH2:7][CH2:8][CH2:9][CH2:10][CH3:11])[CH3:2].[N+:23]([O-])([OH:25])=[O:24]>O>[CH2:1]([O:3][C:4](=[O:22])[CH2:5][CH:6]([C:12]1[CH:17]=[C:16]([N+:23]([O-:25])=[O:24])[CH:15]=[C:14]([O:18][CH3:19])[C:13]=1[O:20][CH3:21])[CH2:7][CH2:8][CH2:9][CH2:10][CH3:11])[CH3:2]
Reactant: O=[N+]([O-])O
Reactant: CCCCCC(CC(=O)OCC)c1cccc(OC)c1OC
Solvent: O
Product: CCCCCC(CC(=O)OCC)c1cc([N+](=O)[O-])cc(OC)c1OC
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A mixture of 1.13 g (3.66 mmol) of 3-(2, 3-dimethoxyphenyl) octanoic acid ethyl ester and 3 ml of 60% nitric acid was stirred at room temperature for 2 hours. The reaction mixture was mixed with water and extracted with ethyl acetate. The organic layer was washed with saturated saline, dried over anhydrous magnesium sulfate and the solvent evaporated in vacuo. The residue was chromatographed on a silica gel column, eluting with ethyl acetate/hexane (1/5) to give 1.15 g of 3-(2, 3-dimethoxy-5-nitropheyl) octanoic acid ethyl ester as a yellow oil. Yield, 89%. This compound showed a coupling constant of J=2.6 Hz in 1H NMR (CDCl3) spectra, suggesting meta-coupling. Further, 0.10 g of 3-(2, 3-dimethoxy-6-nitrophenyl) octanoic acid etheyl ester (yield, 7.7%) was obtained, showing a coupling constant of J=9.1 Hz in 1H NMR (CDCl3) spectra.
Reaction SMILES: [Br:1][C:2]1[CH:11]=[CH:10][CH:9]=[C:8]2[C:3]=1[CH2:4][CH2:5][CH2:6][C:7]2=[O:12].[Br:13]Br>C(Cl)Cl.CCOCC>[Br:13][CH:6]1[CH2:5][CH2:4][C:3]2[C:8](=[CH:9][CH:10]=[CH:11][C:2]=2[Br:1])[C:7]1=[O:12]
Reactant: BrBr
Reactant: O=C1CCCc2c(Br)cccc21
Solvent: ClCCl
Solvent: CCOCC
Product: O=C1c2cccc(Br)c2CCC1Br
Yield: 79.4 %

Procedure:
A clear yellow solution of 5-bromo-3,4-dihydro-1(2H)-naphthalenone(12.09 g, 53.7 mmol) in freshly opened Et2O (220 mL) under an N2 atmosphere was chilled to −5° C. HCl was bubbled in subsurface for 1 min, causing no visible change. The dropwise addition of a solution of Br2 (8.58 g, 53.7 mmol) in CH2Cl2 (20 mL) and Et2O (2 mL) to the vigorously stirring solution of 5-bromo-3,4-dihydro-1(2H)-naphthalenone over 2 h (each drop was allowed to fully decolorize before adding the next) produced a product mixture that assayed by HPLC. Peak area showed 79.4% title compound, 9.5% unreacted 5-bromo-3,4-dihydro-1(2H)-Naphthalenone, 0.6% unidentified, and 9.4% 2,2′,5-tribromo-1-tetralone. The addition of H2O produced a top light brown organic phase, and a clear, colorless bottom aqueous phase which was separated. After drying with MgSO4, the organic layer was concentrated in vacuo at room temperature to give the crude intermediate title compound as a light brown oil (16.08 g, 98.5%).
Reaction SMILES: [C:1]1([C@H:11]([NH:13][C:14]([CH:16]2[O:21][CH2:20][CH2:19][NH:18][CH2:17]2)=[O:15])[CH3:12])[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][CH:2]=1.[F:22][C:23]1[CH:28]=[CH:27][CH:26]=[C:25](I)[CH:24]=1.C([O-])([O-])=O.[Cs+].[Cs+]>C1(C)C=CC=CC=1.C(OCC)(=O)C>[F:22][C:23]1[CH:24]=[C:25]([N:18]2[CH2:19][CH2:20][O:21][CH:16]([C:14]([NH:13][C@@H:11]([C:1]3[C:10]4[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=4)[CH:4]=[CH:3][CH:2]=3)[CH3:12])=[O:15])[CH2:17]2)[CH:26]=[CH:27][CH:28]=1
Reactant: Fc1cccc(I)c1
Reactant: C[C@@H](NC(=O)C1CNCCO1)c1cccc2ccccc12
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: Cc1ccccc1
Solvent: CCOC(C)=O
Product: C[C@@H](NC(=O)C1CN(c2cccc(F)c2)CCO1)c1cccc2ccccc12
Temperature: 110 °C

Procedure:
A mixture solution of N-((R)-1-(naphthalen-1-yl)ethyl)morpholine-2-carboxamide (Intermediate-2) (300 mg, 1.056 mmol) in toluene (10 mL), bis(tri-tert butyl phosphine) Pd(0) (0.10, 54 mg), trisdibenzylidene acetone dipalladium(0) (48 mg, 0.0528 mmol), 1-fluoro-3-iodobenzene (0.15 ml, 1.26 mmol) and Cs2CO3 (516 mg, 1.58 mmol) were added. The reaction mass was heated to 110° C. and further maintained for 15 h under nitrogen atmosphere. The mixture was diluted with ethyl acetate, filtered through celite bed, and concentrated under vacuum. It was further purified by column chromatography on silica gel using a mixture of ethyl acetate and hexane as eluent to afford title compound as oily mass (250 mg), m/z: 379.2.