Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5](=[O:12])[N:6]([CH:8]([CH3:11])[CH2:9][OH:10])[CH:7]=1.[S:13]1[CH:17]=[CH:16][CH:15]=[C:14]1B(O)O.C([O-])([O-])=O.[Na+].[Na+]>O1CCOCC1.O.CCOC(C)=O.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2]>[OH:10][CH2:9][CH:8]([N:6]1[CH:7]=[C:2]([C:14]2[S:13][CH:17]=[CH:16][CH:15]=2)[CH:3]=[CH:4][C:5]1=[O:12])[CH3:11]
Reactant: CC(CO)n1cc(Br)ccc1=O
Reactant: OB(O)c1cccs1
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: O=C([O-])[O-]
Solvent: O
Solvent: C1COCCO1
Solvent: CCOC(C)=O
Product: CC(CO)n1cc(-c2cccs2)ccc1=O
Temperature: 90 °C
Yield: 29 %

Procedure:
To a solution of 5-bromo-1-(1-hydroxypropan-2-yl)pyridin-2(1H)-one (0.51 g, 2.2 mmol) and 2-thiopheneboronic acid (0.28 g, 2.2 mmol) in 30 mL of dioxane was added 6 mL of 1N Na2CO3 followed by 1,1′-bis(diphenylphosphino)ferrocene-palladium dichloride (0.16 g, 0.22 mmol). The reaction was heated to 90° C. for 12 hours. The mixture was then diluted with 30 mL of water and 80 mL of EtOAc. The organic phase was separated, washed with 40 mL of brine, dried over Na2SO4 and concentrated in vacuo. The residue was obtained as a greenish semi-solid (0.15 g, 29% yield). MS (ESI pos. ion) m/z (MH+): 236.0. Calc'd Exact Mass for C12H13NO2S: 235.07.
Reaction SMILES: Br[C:2]1[C:11]2[N:10]=[C:9]([NH:12][C@H:13]([CH3:17])[CH:14]([CH3:16])[CH3:15])[C:8]3[CH:18]=[CH:19][C:20]([F:22])=[CH:21][C:7]=3[C:6]=2[C:5](=[O:23])[NH:4][CH:3]=1.[S:24]1[CH:28]=[CH:27][C:26](B(O)O)=[CH:25]1>O1CCOCC1.C([O-])([O-])=O.[Na+].[Na+]>[CH3:17][C@@H:13]([NH:12][C:9]1[C:8]2[CH:18]=[CH:19][C:20]([F:22])=[CH:21][C:7]=2[C:6]2[C:5](=[O:23])[NH:4][CH:3]=[C:2]([C:26]3[CH:27]=[CH:28][S:24][CH:25]=3)[C:11]=2[N:10]=1)[CH:14]([CH3:16])[CH3:15]
Reactant: OB(O)c1ccsc1
Reactant: CC(C)[C@@H](C)Nc1nc2c(Br)c[nH]c(=O)c2c2cc(F)ccc12
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: C1COCCO1
Product: CC(C)[C@@H](C)Nc1nc2c(-c3ccsc3)c[nH]c(=O)c2c2cc(F)ccc12
Temperature: 150 °C

Procedure:
To a solution of 4-bromo-6-{[(1R)-1,2-dimethylpropyl]amino}-9-fluorobenzo[c]-1,6-naphthyridin-1(2H)-one (32 mg, 0.085 mmol) in dioxane (2 mL) and Na2CO3 (1 mL, 2.0 M) were added 3-thienylboronic acid (13 mg, 0.10 mmol) and palladium tetrakistriphenylphosphine (24 mg, 0.021 mmol). The solution was degassed by bubbling nitrogen gas and heated in a microwave reactor at 150° C. for 1 hr. The resulting solution was filtered and purified by reverse phase HPLC to produce 6-{[(1R)-1,2-dimethylpropyl]amino}-9-fluoro-4-(3-thienyl)benzo[c]-1,6-naphthyridin-1(2H)-one. 1H NMR (600 MHz, CD3OD) δ 9.63 (dd, 1H), 8.40 (m, 1H), 7.68 (m, 1H), 7.57 (s, 1H), 7.50 (m, 1H), 7.46 (d, 1H), 7.40 (m, 1H), 4.20 (br s, 1H), 1.98 (m, 1H), 1.24 (d, 3H), 0.93 (m, 6H). LRMS (ESI) calc'd for (C21H21FN3OS) [M+H]+, 382.1; found 382.1.
Reaction SMILES: [Cl:1][C:2]1[CH:11]=[C:10]2[C:5]([C:6](=[O:47])[N:7]([CH2:39][C:40]3[CH:45]=[CH:44][CH:43]=[C:42]([CH3:46])[CH:41]=3)[C:8]([CH:12]([N:18]([C:30](=[O:38])[C:31]3[CH:36]=[CH:35][C:34]([CH3:37])=[CH:33][CH:32]=3)[CH2:19][CH2:20][CH2:21][NH:22]C(=O)OC(C)(C)C)[C:13]([N:15]([CH3:17])[CH3:16])=[O:14])=[N:9]2)=[CH:4][CH:3]=1.FC(F)(F)C(O)=O>C(Cl)Cl>[NH2:22][CH2:21][CH2:20][CH2:19][N:18]([CH:12]([C:8]1[N:7]([CH2:39][C:40]2[CH:45]=[CH:44][CH:43]=[C:42]([CH3:46])[CH:41]=2)[C:6](=[O:47])[C:5]2[C:10](=[CH:11][C:2]([Cl:1])=[CH:3][CH:4]=2)[N:9]=1)[C:13]([N:15]([CH3:16])[CH3:17])=[O:14])[C:30](=[O:38])[C:31]1[CH:32]=[CH:33][C:34]([CH3:37])=[CH:35][CH:36]=1
Reactant: Cc1ccc(C(=O)N(CCCNC(=O)OC(C)(C)C)C(C(=O)N(C)C)c2nc3cc(Cl)ccc3c(=O)n2Cc2cccc(C)c2)cc1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: Cc1ccc(C(=O)N(CCCN)C(C(=O)N(C)C)c2nc3cc(Cl)ccc3c(=O)n2Cc2cccc(C)c2)cc1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of tert-butyl 3-[[1-[7-chloro-3-(3-methylbenzyl)-4-oxo-3,4-dihydroquinazolin-2-yl]-2-(dimethylamino)-2-oxoethyl](4-methylbenzoyl)amino]propylcarbamate, was added 20% solution of trifluoroacetic acid in methylene chloride at room temperature. The reaction mixture was stirred at room temperature for 2 h. The solvent was removed under reduced pressure. The crude product was purified by reverse phase HPLC to give N-(3-aminopropyl)-N-[1-[7-chloro-3-(3-methylbenzyl)-4-oxo-3,4-dihydroquinazolin-2-yl]-2-(dimethylamino)-2-oxoethyl]-4-methylbenzamide (9 mg) as TFA salt.
Reaction SMILES: C[O:2][C:3](=[O:36])[CH2:4][CH:5]1[CH2:10][CH2:9][C@H:8]([C:11]([N:13]2[CH2:18][CH2:17][N:16]([C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)[CH2:15][CH2:14]2)=[O:12])[C@@H:7]([C:25](=[O:35])[NH:26][O:27][CH2:28][C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)[CH2:6]1.O.[OH-].[Li+].Cl>C1COCC1>[CH2:28]([O:27][NH:26][C:25]([C@@H:7]1[C@@H:8]([C:11]([N:13]2[CH2:14][CH2:15][N:16]([C:19]3[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=3)[CH2:17][CH2:18]2)=[O:12])[CH2:9][CH2:10][CH:5]([CH2:4][C:3]([OH:36])=[O:2])[CH2:6]1)=[O:35])[C:29]1[CH:30]=[CH:31][CH:32]=[CH:33][CH:34]=1
Reactant: COC(=O)CC1CC[C@H](C(=O)N2CCN(c3ccccc3)CC2)[C@@H](C(=O)NOCc2ccccc2)C1
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: O=C(O)CC1CC[C@H](C(=O)N2CCN(c3ccccc3)CC2)[C@@H](C(=O)NOCc2ccccc2)C1
Temperature: 25 °C
Reaction time: 4 h
Yield: 74.3 %

Procedure:
To a solution of [3-(S)-benzyloxycarbamoyl-4-(S)-(4-phenyl-piperazine-1-carbonyl)-cyclohexyl]-acetic acid methyl ester (213 mg, 0.432 mmol) in THF (5 mL) was added water (3 mL) and lithium hydroxide (40 mg, 0.95 mmol). After stirring at ambient temperature for 4 h, the reaction mixture was acidified with 1 N HCl to a pH of ca. 5. The product was extracted with ethyl acetate (4×5 mL) and the combined organic layers were washed with brine (5 mL), dried (NaSO4), and the volatiles were removed in-vacuo to afford 154 mg (87%) of [3-(S)-benzyloxycarbamoyl-4-(S)-(4-phenyl-piperazine-1-carbonyl)-cyclohexyl]-acetic acid as a sticky oil that was used without further purification in the following coupling reaction. MS (ESI): 480 (M+H+).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:13]([C:14]3[CH:19]=[CH:18][N:17]=[CH:16][CH:15]=3)=[C:12]([C:20]3[CH:25]=[CH:24][C:23]([F:26])=[CH:22][CH:21]=3)[N:11]=[C:10]3[NH:27][N:28]=[CH:29][C:9]=23)=[CH:4][CH:3]=1.[Br:30]Br.C(#N)C>C(Cl)(Cl)Cl>[Br:30][C:29]1[C:9]2[C:10](=[N:11][C:12]([C:20]3[CH:25]=[CH:24][C:23]([F:26])=[CH:22][CH:21]=3)=[C:13]([C:14]3[CH:15]=[CH:16][N:17]=[CH:18][CH:19]=3)[C:8]=2[C:5]2[CH:6]=[CH:7][C:2]([F:1])=[CH:3][CH:4]=2)[NH:27][N:28]=1
Reactant: BrBr
Reactant: Fc1ccc(-c2nc3[nH]ncc3c(-c3ccc(F)cc3)c2-c2ccncc2)cc1
Solvent: ClC(Cl)Cl
Solvent: CC#N
Product: Fc1ccc(-c2nc3[nH]nc(Br)c3c(-c3ccc(F)cc3)c2-c2ccncc2)cc1
Temperature: 25 °C
Reaction time: 48 h
Yield: 96.3 %

Procedure:
To a suspension of 4,6-bis(4-fluorophenyl)-5-(4-pyridyl)-1H-pyrazolo[3,4-b]pyridine (1.00 g, 2.6 mmol, obtained in example 1) in CHCl3 (10 mL), a solution of Br2 (0.69 g, 4.3 mmol) in CHCl3 (3 mL) was added under argon atmosphere. Acetonitrile (4 mL) was added and the mixture was stirred at room temperature for 2 days. The residue was concentrated, dissolved in CHCl3 and washed with 1 N NaOH. A precipitate was formed, which was filtered and dissolved with MeOH. The solution was concentrated and washed with 1 N NaOH. It was extracted with EtOAc, dried over Na2SO4 and concentrated. This was treated with diethyl ether, the solvent was decanted and the product obtained was dried to afford 1.16 g of the title compound (yield: 97%).
Reaction SMILES: [C:1]12([C:11]3[CH:30]=[CH:29][C:14]([O:15][CH2:16][C:17]([NH:19][C:20]4[CH:21]=[C:22]([CH:26]=[CH:27][N:28]=4)[C:23](O)=[O:24])=[O:18])=[CH:13][CH:12]=3)[CH2:10][CH:5]3[CH2:6][CH:7]([CH2:9][CH:3]([CH2:4]3)[CH2:2]1)[CH2:8]2.[NH2:31][CH2:32][CH2:33][CH2:34][N:35]1[CH:39]=[CH:38][N:37]=[CH:36]1.C1CN([P+](ON2N=NC3C=CC=CC2=3)(N2CCCC2)N2CCCC2)CC1.F[P-](F)(F)(F)(F)F.CO>CN(C1C=CN=CC=1)C.CN(C=O)C>[C:1]12([C:11]3[CH:12]=[CH:13][C:14]([O:15][CH2:16][C:17]([NH:19][C:20]4[CH:21]=[C:22]([CH:26]=[CH:27][N:28]=4)[C:23]([NH:31][CH2:32][CH2:33][CH2:34][N:35]4[CH:39]=[CH:38][N:37]=[CH:36]4)=[O:24])=[O:18])=[CH:29][CH:30]=3)[CH2:2][CH:3]3[CH2:9][CH:7]([CH2:6][CH:5]([CH2:4]3)[CH2:10]1)[CH2:8]2
Reactant: O=C(COc1ccc(C23CC4CC(CC(C4)C2)C3)cc1)Nc1cc(C(=O)O)ccn1
Reactant: NCCCn1ccnc1
Agent: CN(C)c1ccncc1
Agent: F[P-](F)(F)(F)(F)F
Agent: c1ccc2c(c1)nnn2O[P+](N1CCCC1)(N1CCCC1)N1CCCC1
Solvent: CO
Solvent: CN(C)C=O
Product: O=C(COc1ccc(C23CC4CC(CC(C4)C2)C3)cc1)Nc1cc(C(=O)NCCCn2ccnc2)ccn1
Yield: 88.2 %

Procedure:
To solution of 2-[2-(4-adamantan-1-yl-phenoxy)-acetylamino]-isonicotinic acid (40 mg, 0.098 mmol), 1-(3-aminopropyl)imidazole (24.65 mg, 0.196 mmol) and DMAP (24.06 mg, 0.196 mmol) in DMF was added PyBOP (102.4 mg, 0.196 mmol) at room temperature, and stirred. Reaction mixture was poured onto ice cold water, diluted by methanol/MC mixture (10%). The organic phase was separated, sequentially washed with aqueous sodium bicarbonate, brine and water, dried over anhydrous MgSO4, and concentrated. The resultant crude product was purified by PLC (MeOH:MC=1:9) to afford 2-[2-(4-adamantan-1-yl-phenoxy)-acetylamino]-N-(3-imidazole-1-yl-propyl)-isonicotinamide as a colorless solid (44.4 mg, 87.85% yield).
Reaction SMILES: C(OC([NH:11][C:12]1[C:13](=[O:48])[N:14]([CH2:24][C:25]([NH:27][CH:28]([CH:45]([CH3:47])[CH3:46])[C:29](=[O:44])[C:30]([F:43])([F:42])[C:31](=[O:41])[NH:32][CH2:33][CH2:34][C:35]2[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=2)=[O:26])[C:15]([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)=[CH:16][CH:17]=1)=O)C1C=CC=CC=1.FC(F)(F)S(O)(=O)=O>ClCCl.C1(OC)C=CC=CC=1>[NH2:11][C:12]1[C:13](=[O:48])[N:14]([CH2:24][C:25]([NH:27][CH:28]([CH:45]([CH3:46])[CH3:47])[C:29](=[O:44])[C:30]([F:43])([F:42])[C:31](=[O:41])[NH:32][CH2:33][CH2:34][C:35]2[CH:36]=[CH:37][CH:38]=[CH:39][CH:40]=2)=[O:26])[C:15]([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)=[CH:16][CH:17]=1
Reactant: CC(C)C(NC(=O)Cn1c(-c2ccccc2)ccc(NC(=O)OCc2ccccc2)c1=O)C(=O)C(F)(F)C(=O)NCCc1ccccc1
Agent: O=S(=O)(O)C(F)(F)F
Solvent: ClCCl
Solvent: COc1ccccc1
Product: CC(C)C(NC(=O)Cn1c(-c2ccccc2)ccc(N)c1=O)C(=O)C(F)(F)C(=O)NCCc1ccccc1
Reaction time: 1.5 h
Yield: 33.1 %

Procedure:
To a solution of 2-(3-benzyloxycarbonylamino-2-oxo-6-phenyl-1,2-dihydro-1-pyridyl)-N-[3,3-difluoro-1-isopropyl-2-oxo-3-(N-phenethylcarbamoyl)propyl]acetamide (0.451 g) in dichloromethane (7 mL) and anisole (0.22 mL) was added trifluoromethanesulfonic acid (0.30 mL). After 1.5 h, the reaction was quenched with saturated sodium bicarbonate. The mixture was extracted with dichloromethane, and the extracts were washed (saturated sodium bicarbonate, brine), dried, and evaporated. The crude product was purified by chromatography, twice, with dichloromethane:methanol (first column: gradient, 99:1, 92:8; second column: gradient, 99:1, 92:8) as the eluent. The resulting material was crystallized from ether and petroleum ether to give the title compound (0.119 g) as a tan solid; TLC: Rf =0.27, dichloromethane:methanol (98:2); 300 MHz NMR: 9.20 (t,1), 8.42 (d,1), 7.38-7.18 (m,10), 6.51 (d,1), 5.97 (d,1), 5.15 (d,2), 4.80 (dd,1), 4.43 (broad s,2), 3.43- 3.29 (m,2), 2.76 (t,2), 2.29-2.13 (m,1), 0.85 (d,3), 0.74 (d,3); MS: m/z=525(M+1).
Reaction SMILES: C(O)C.O.[Cl:5][C:6]1[CH:7]=[C:8]([N+:26]([O-])=O)[CH:9]=[C:10]([Cl:25])[C:11]=1[O:12][CH:13]([CH3:24])[C:14]([F:23])([F:22])[C:15]([F:21])([F:20])[C:16]([F:19])([F:18])[F:17].Cl>C(O)C.[Fe]>[Cl:5][C:6]1[CH:7]=[C:8]([CH:9]=[C:10]([Cl:25])[C:11]=1[O:12][CH:13]([CH3:24])[C:14]([F:22])([F:23])[C:15]([F:20])([F:21])[C:16]([F:19])([F:18])[F:17])[NH2:26]
Reactant: CC(Oc1c(Cl)cc([N+](=O)[O-])cc1Cl)C(F)(F)C(F)(F)C(F)(F)F
Agent: [Fe]
Agent: Cl
Solvent: CCO
Solvent: O
Product: CC(Oc1c(Cl)cc(N)cc1Cl)C(F)(F)C(F)(F)C(F)(F)F
Yield: 62.3 %

Procedure:
5.29 g iron filings, 240 mL of a 2/1 ethanol-water mixture, and 8.3 g 3,5-dichloro-4-(1-methyl-2,2,3,3,4,4,4-heptafluorobutoxy)nitrobenzene was stirred vigorously and heated under reflux while 2.0 mL conc. HCl in 2 mL ethanol was added dropwise. After one hour 2.0 mL conc. HCl in 2.0 mL ethanol was added and reflux was maintained for 6 hrs. Then added 2.0 mL conc. HCl in 3.0 mL ethanol and maintained reflux overnight. The mixture was filtered hot through Celite. The filtrate was concentrated under vacuum before being partitioned in saturated sodium bicarbonate and diethyl ether. The layers were separated and the aqueous layer was extracted with diethyl ether. The combined organics were washed with brine, dried (MgSO4), filtered, and concentrated to give 4.79 g of 3,5-Dichloro-4-(1-methyl-2,2,3,3,4,4,4-heptafluorobutoxy)aniline as an amber oil. 1H NMR and MS confirm pure product. Anal. calcd C11H8Cl2F7NO: C, 35.32; H, 2.16; N, 3.74. Found: C, 36.40; H, 2.33; N, 3.98.
Reaction SMILES: [ClH:1].[C:2]([O:6][C:7]([C:9]1[C:17]2[CH:16]([N:18]=[C:19]=[O:20])[C@H:15]([CH2:21][N:22]3[C:30](=[O:31])[C:29]4[C:24](=[CH:25][CH:26]=[CH:27][CH:28]=4)[C:23]3=[O:32])[N:14](C(OC(C)(C)C)=O)[CH2:13][C:12]=2[S:11][C:10]=1[O:40][CH2:41][C:42]1[CH:47]=[CH:46][CH:45]=[CH:44][CH:43]=1)=[O:8])([CH3:5])([CH3:4])[CH3:3]>C(OCC)(=O)C>[ClH:1].[C:2]([O:6][C:7]([C:9]1[C:17]2[CH:16]([N:18]=[C:19]=[O:20])[C@H:15]([CH2:21][N:22]3[C:30](=[O:31])[C:29]4[C:24](=[CH:25][CH:26]=[CH:27][CH:28]=4)[C:23]3=[O:32])[NH:14][CH2:13][C:12]=2[S:11][C:10]=1[O:40][CH2:41][C:42]1[CH:47]=[CH:46][CH:45]=[CH:44][CH:43]=1)=[O:8])([CH3:5])([CH3:3])[CH3:4]
Reactant: CC(C)(C)OC(=O)c1c(OCc2ccccc2)sc2c1C(N=C=O)[C@H](CN1C(=O)c3ccccc3C1=O)N(C(=O)OC(C)(C)C)C2
Agent: Cl
Solvent: CCOC(C)=O
Product: CC(C)(C)OC(=O)c1c(OCc2ccccc2)sc2c1C(N=C=O)[C@H](CN1C(=O)c3ccccc3C1=O)NC2
Temperature: 25 °C
Reaction time: 48 h
Yield: 90 %

Procedure:
To a solution of 1 N hydrochloric acid in ethyl acetate (1.0 ml) was added 2-benzyloxy-carbonylamino-5-(S)-(1,3-dioxo-1,3-dihydro-isoindol-2-ylmethyl)-4,5,6,7-tetrahydro-thieno[2,3-c]pyridine-3,6-dicarboxylic acid di-tert-butyl ester (52 mg, 0.08 mmol). The solution was stirred at room temperature for 48 hours. A precipitate was filtered off which afforded 42 mg (90%) of 2-benzyloxy-carbonylamino-5-(S)-(1,3-dioxo-1,3-dihydro-isoindol-2-ylmethyl)-4,5,6,7-tetrahydro-thieno[2,3-c]pyridine-3-carboxylic acid tert-butyl ester hydrochloride as a solid.
Reaction SMILES: C(OCCO)C.[CH2:7]([C@H:10]1[CH2:15][CH2:14][C@H:13]([C:16]2[CH:21]=[CH:20][C:19]([C:22]#[N:23])=[C:18](Cl)[N:17]=2)[CH2:12][CH2:11]1)[CH2:8][CH3:9]>[Zn].O>[CH2:7]([C@H:10]1[CH2:11][CH2:12][C@H:13]([C:16]2[CH:21]=[CH:20][C:19]([C:22]#[N:23])=[CH:18][N:17]=2)[CH2:14][CH2:15]1)[CH2:8][CH3:9]
Reactant: CCC[C@H]1CC[C@H](c2ccc(C#N)c(Cl)n2)CC1
Agent: [Zn]
Solvent: O
Solvent: CCOCCO
Product: CCC[C@H]1CC[C@H](c2ccc(C#N)cn2)CC1

Procedure:
2-Ethoxyethanol (200 ml), water (40 ml) and zinc powder (20 g) were added to 2-(trans-4-n-propylcyclohexyl)-5-cyano-6-chloropyridine (17.0 g) of Example 6, followed by heating the mixture under reflux for 28 hours, cooling, thereafter filtering, adding toluene (200 ml) and water (500 ml) to the filtrate, stirring, still standing, separating the toluene layer, twice washing it with water, and carrying out the same procedure as in Example 11 to obtain the objective 2-(trans-4- n-propylcyclohexyl)-5-cyanopyridine (5 g). C-N point: 47.6° C. N-I point: 51.9° C.
Reaction SMILES: [C:1]([OH:11])(=O)[C:2]1[CH:7]=[CH:6][CH:5]=[C:4](OC)[CH:3]=1.C1CN2[C:14](=[N:15]CCC2)[CH2:13]1.C1C=CC(P(N=[N+]=[N-])(C2C=CC=CC=2)=O)=CC=1>CN(C=O)C.[Cl-].[NH4+]>[C:2]1([C:1]2[O:11][CH:13]=[CH:14][N:15]=2)[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: COc1cccc(C(=O)O)c1
Reactant: C1CN=C2CCCN2C1
Agent: [Cl-]
Agent: [N-]=[N+]=NP(=O)(c1ccccc1)c1ccccc1
Agent: [NH4+]
Solvent: CN(C)C=O
Product: c1ccc(-c2ncco2)cc1
Reaction time: 18 h
Yield: 92.7 %

Procedure:
To a mixture of methyl isooyanoacetate (7.1 g, 171 mmol), m-anisic acid (26 g, 171 mmol) and DBN (78 mL, 522 mmol) dissolved in DMF (1.1 L), was added DPPA (37 mL, 171 mmol) by dropwise addition. The reaction mixture was stirred about 18 hours, diluted with 50% saturated ammonium chloride solution (1 vol), extracted with diethyl ether, and the organic layers washed with water and brine before drying over MgSO4. Concentration and recrystallization (diethyl ether/hexanes) gave 24 23 g (58%), mp 75°-76° C. IR (KBr, cm-1) 3110, 3066, 1712, 1604, 1590, 1560, 1516, 1488, 1472, 1456, 1432, 1346, 1314, 1254, 1209, 1170, 1110, 1093, 1036, 892, 850, 786, 646. 1H NMR (300 MHz, CDCl3)δ 3.84 (3H, s), 3.92 (3H, s , 6.99 (1H, dd, J=8.1 Hz, J=2.I Hz) 7.36 (1 H, t, J=8.l Hz), 7.63 (1H, m), 7.72 (1H, Br.s), 7.88 (1H, s). 13C NMR (75 MHz, CDCl3) ppm 52.58, 55.60, 113.66, 116.97, 120.87, 126.66, 127.87, 129.76, 149.08, 155.61, 159.69, 165.54. m/e 234 (MH+).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5](F)=[C:6]([CH:11]=1)[C:7]([O:9][CH3:10])=[O:8].[F:13][C:14]1[CH:15]=[C:16]([OH:21])[CH:17]=[CH:18][C:19]=1[F:20]>>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([O:21][C:16]2[CH:17]=[CH:18][C:19]([F:20])=[C:14]([F:13])[CH:15]=2)=[C:6]([CH:11]=1)[C:7]([O:9][CH3:10])=[O:8]
Reactant: Oc1ccc(F)c(F)c1
Reactant: COC(=O)c1cc(Cl)ccc1F
Product: COC(=O)c1cc(Cl)ccc1Oc1ccc(F)c(F)c1

Procedure:
The title compound was prepared according to the procedure described in step 1 of Example 67 from methyl 5-chloro-2-fluorobenzoate and 3,4-difluorophenol: 1H-NMR (CDCl3) δ 7.92 (1H, d, J=2.8 Hz), 7.46 (1H, dd, J=8.7, 2.8 Hz), 7.11 (1H, q, J=9.1 Hz), 6.95 (1H, d, J=8.7 Hz), 6.85–6.72 (1H, m), 6.71–6.59 (1H, m), 3.83 (3H, s).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:9]=[CH:10][CH:11]=1)[C:6]([OH:8])=O.[NH2:12][C:13]1[CH:22]=[CH:21][C:20]2[C:15](=[N:16][C:17]([O:23][CH3:24])=[CH:18][CH:19]=2)[N:14]=1>O.C(#N)C>[CH3:24][O:23][C:17]1[N:16]=[C:15]2[C:20]([CH:21]=[CH:22][C:13]([NH:12][C:6](=[O:8])[C:5]3[CH:9]=[CH:10][CH:11]=[C:3]([O:2][CH3:1])[CH:4]=3)=[N:14]2)=[CH:19][CH:18]=1
Reactant: COc1ccc2ccc(N)nc2n1
Reactant: COc1cccc(C(=O)O)c1
Solvent: CC#N
Solvent: O
Product: COc1cccc(C(=O)Nc2ccc3ccc(OC)nc3n2)c1
Temperature: 4 °C
Yield: 70.4 %

Procedure:
The procedure is similar to that described in Example 1, but starting with 3-methoxybenzoic acid (9.1 g), N,N'-carbonyldiimidazole (9.7 g) and 2-amino-7-methoxy-1,8-naphthyridine (7 g). The product produced by precipitation in water (13 g; m.p. approximately 75° C.) is dissolved in 90 cc of boiling acetonitrile. After 3 hours' cooling at 4° C., the crystallised solid is separated by filtration, washed with acetonitrile (3×10 cc) and dried at 50° C. under reduced pressure (0.067 kPa). N-(7-methoxy-1,8-naphthyridin-2-yl)-3-methoxybenzamide (8.7 g) is produced, m.p. 135° C.).
Reaction SMILES: [CH3:1][CH:2]([CH3:34])[CH2:3][CH2:4][C@@H:5]([N:13]1[CH2:18][CH2:17][C@@H:16]([CH2:19][C:20]([O:22]C)=[O:21])[CH2:15][C@H:14]1[C:24]1[CH:29]=[CH:28][C:27]([C:30]([F:33])([F:32])[F:31])=[CH:26][CH:25]=1)[CH2:6][CH:7]1[CH2:12][CH2:11][O:10][CH2:9][CH2:8]1.[OH-].[Na+]>CO>[CH3:1][CH:2]([CH3:34])[CH2:3][CH2:4][C@@H:5]([N:13]1[CH2:18][CH2:17][C@@H:16]([CH2:19][C:20]([OH:22])=[O:21])[CH2:15][C@H:14]1[C:24]1[CH:25]=[CH:26][C:27]([C:30]([F:33])([F:31])[F:32])=[CH:28][CH:29]=1)[CH2:6][CH:7]1[CH2:8][CH2:9][O:10][CH2:11][CH2:12]1
Reactant: COC(=O)C[C@@H]1CCN([C@H](CCC(C)C)CC2CCOCC2)[C@H](c2ccc(C(F)(F)F)cc2)C1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: CC(C)CC[C@H](CC1CCOCC1)N1CC[C@@H](CC(=O)O)C[C@H]1c1ccc(C(F)(F)F)cc1
Yield: 83 %

Procedure:
A solution of the methyl {(2S,4R)-1-[(1R)-4-methyl-1-(tetrahydro-2H-pyran-4-ylmethyl)pentyl]-2-[4-(trifluoromethyl)phenyl]piperidin-4-yl}acetate (Step 1, 142 mg, 0.29 mmol) and aqueous NaOH (4N, 220 μl, 0.88 mmol) in MeOH (2 ml) was heated at 60° C. for 3 hrs. After cooling to RT the MeOH was removed in vacuo, and the residue was partitioned between CH2Cl2/H2O. 2N HCl (˜0.5 ml) was added. The pH of the aqueous layer was adjusted to ˜pH7 with saturated aqueous NaHCO3. The aqueous layer was extracted with CH2Cl2 (×4). The combined extracts were dried (Na2SO4), filtered and evaporated. The residue was purified by chromatography (silica, 4-8% MeOH/CH2Cl2) to give the acid (113 mg) as a colourless solid. 1H NMR (360 MHz, CD3OD): δ 0.65-0.75 (1H, m), 0.83-1.15 (11H, m), 1.18-1.55 (6H, m), 1.73-1.93 (5H, m), 2.18-2.30 (3H, m), 2.44 (1H, brt, J 12), 3.11 (1H, brd, J 12), 3.35 (1H, d, J 11), 3.43 (1H, d, J 12), 3.79 (2H, d, J 6.7), 3.88 (1H, d, J 8.0), 7.53 (2H, d, J 7.6), 7.63 (2H, d, J 8.2); M/Z (ES+) 470 (MH+).
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([CH3:8])[C:3]=1[NH:9][C:10](=[O:13])[CH2:11]Br.[F:14][C:15]1[CH:20]=[CH:19][C:18]([CH2:21][C:22]2[CH:27]=[CH:26][C:25]([N:28]3[CH2:33][CH2:32][NH:31][CH2:30][CH2:29]3)=[CH:24][CH:23]=2)=[CH:17][CH:16]=1>>[CH3:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([CH3:8])[C:3]=1[NH:9][C:10](=[O:13])[CH2:11][N:31]1[CH2:30][CH2:29][N:28]([C:25]2[CH:24]=[CH:23][C:22]([CH2:21][C:18]3[CH:19]=[CH:20][C:15]([F:14])=[CH:16][CH:17]=3)=[CH:27][CH:26]=2)[CH2:33][CH2:32]1
Reactant: Fc1ccc(Cc2ccc(N3CCNCC3)cc2)cc1
Reactant: Cc1cccc(C)c1NC(=O)CBr
Product: Cc1cccc(C)c1NC(=O)CN1CCN(c2ccc(Cc3ccc(F)cc3)cc2)CC1

Procedure:
The compound (18) synthesized in Reference Example 18 and the compound (5) synthesized in Reference Example 5 were used to produce the above compound in the same way as Example 1.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[S:12][C:11]([CH3:13])=[N:10][C:9]=2[C:14]([N:16]2[CH2:21][CH2:20][CH2:19][C@@H:18]([CH3:22])[C@H:17]2[CH2:23][N:24]2C(=O)C3C(=CC=CC=3)C2=O)=[O:15])=[CH:4][CH:3]=1.O.NN>CO>[NH2:24][CH2:23][C@@H:17]1[C@H:18]([CH3:22])[CH2:19][CH2:20][CH2:21][N:16]1[C:14]([C:9]1[N:10]=[C:11]([CH3:13])[S:12][C:8]=1[C:5]1[CH:4]=[CH:3][C:2]([F:1])=[CH:7][CH:6]=1)=[O:15]
Reactant: Cc1nc(C(=O)N2CCC[C@@H](C)[C@H]2CN2C(=O)c3ccccc3C2=O)c(-c2ccc(F)cc2)s1
Agent: NN
Solvent: O
Solvent: CO
Product: Cc1nc(C(=O)N2CCC[C@@H](C)[C@H]2CN)c(-c2ccc(F)cc2)s1

Procedure:
A mixture of 2-(((2S,3R)-1-(5-(4-fluorophenyl)-2-methylthiazole-4-carbonyl)-3-methylpiperidin-2-yl)methyl)isoindoline-1,3-dione (130 mg, 272 μmol) and hydrazine hydrate (67 μL, 1.36 mmol) in MeOH (3 mL) was heated at reflux for 2 h. The mixture was cooled and the solvent was removed in vacuo. The crude was dissolved in EtOAc and washed with 2 N NaOH (2×) and brine. The organic solution was dried over anhydrous Na2SO4. The solvent was removed to obtain the title compound which was used without further purification. MS (ESI) 348 (M+H).
Reaction SMILES: C[O:2][C:3]([C:5]1[CH:6]=[C:7]([F:36])[CH:8]=[C:9]2[C:14]=1[NH:13][CH:12]([C:15]1[CH:20]=[CH:19][CH:18]=[C:17]([N:21]3[CH2:26][CH2:25][N:24]([C:27]4[CH:32]=[CH:31][C:30]([CH3:33])=[CH:29][CH:28]=4)[CH2:23][CH2:22]3)[CH:16]=1)[CH2:11][C:10]2([CH3:35])[CH3:34])=[O:4].Cl>CO.O1CCCC1.[OH-].[Na+].O>[F:36][C:7]1[CH:8]=[C:9]2[C:14](=[C:5]([C:3]([OH:4])=[O:2])[CH:6]=1)[NH:13][CH:12]([C:15]1[CH:20]=[CH:19][CH:18]=[C:17]([N:21]3[CH2:26][CH2:25][N:24]([C:27]4[CH:28]=[CH:29][C:30]([CH3:33])=[CH:31][CH:32]=4)[CH2:23][CH2:22]3)[CH:16]=1)[CH2:11][C:10]2([CH3:35])[CH3:34]
Reactant: COC(=O)c1cc(F)cc2c1NC(c1cccc(N3CCN(c4ccc(C)cc4)CC3)c1)CC2(C)C
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: O
Solvent: C1CCOC1
Product: Cc1ccc(N2CCN(c3cccc(C4CC(C)(C)c5cc(F)cc(C(=O)O)c5N4)c3)CC2)cc1
Temperature: 60 °C
Reaction time: 12 h
Yield: 87.6 %

Procedure:
A mixture of afford 6-fluoro-4,4-dimethyl-2-[3-(4-p-tolyl-piperazin-1-yl)-phenyl]-1,2,3,4-tetrahydro-quinoline-8-carboxylic acid methyl ester (0.20 g, 0.41 mmol) in methanol (3 mL) and tetrahydrofuran (10 mL), 30% sodium hydroxide in water (1 mL). The reaction mixture was stirred at 60° C. for 12 h. The mixture was neutralized with a 3 N aqueous hydrochloric acid solution and extracted with ethyl acetate (2×50 mL), washed with water, dried over anhydrous sodium sulfate and then concentrated in vacuo to afford 6-fluoro-4,4-dimethyl-2-[3-(4-p-tolyl-piperazin-1-yl)-phenyl]-1,2,3,4-tetrahydro-quinoline-8-carboxylic acid (0.17 g, 90%) as a white solid which was used for next step without further purification: MS (ESI) M+1=474.3.