Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1][C:2]1[C:3]([C:13]([O:15]CC)=[O:14])=CC2[C:10]([CH:11]=1)=[CH:9]C=C(O)C=2.[I-].C(=O)([O-])[O-:20].[K+].[K+].O>CN(C)C=O.C(OCC)(=O)C>[CH3:9][C:10]([CH2:11][C:2]([CH2:3][C:13]([OH:15])=[O:14])=[O:1])=[O:20]
Reactant: O=C([O-])[O-]
Reactant: CCOC(=O)c1cc2cc(O)ccc2cc1O
Agent: [I-]
Agent: [K+]
Solvent: O
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CC(=O)CC(=O)CC(=O)O
Temperature: 55 °C

Procedure:
A solution of ethyl 3,7-dihydroxy-2-naphthoate (62 mg, 0.26 mmole) (the acid was obtained from Aldrich and it was converted to the ester using standard techniques) 2 mg, and iodide 2 (242 mg) in dimethylforamide (0.5 ml) was heated at 55° C. with potassium carbonate (175 mg) for 4 hours. An additional amount of the iodide 2 (80 mg) was added to the mixture which was heated at 55° C. overnight. The mixture was worked up with water (50 ml) and ethyl acetate (2×75 ml). The ethyl acetate extracts were washed with brine (30 ml), dried over sodium sulfate, filtered and concentrated. The crude product was purified on a silica gel column (hexane:ethyl acetate, 1.5:1) to provide the triacetate of 17 (130 mg, 65% yield).
Reaction SMILES: Br[C:2]1[CH:3]=[N:4][CH:5]=[C:6]([CH:12]=1)[C:7]([O:9][CH2:10][CH3:11])=[O:8].[CH2:13]([C:15]1[CH:20]=[CH:19][C:18](B(O)O)=[CH:17][CH:16]=1)[CH3:14]>>[CH2:13]([C:15]1[CH:20]=[CH:19][C:18]([C:2]2[CH:12]=[C:6]([C:7]([O:9][CH2:10][CH3:11])=[O:8])[CH:5]=[N:4][CH:3]=2)=[CH:17][CH:16]=1)[CH3:14]
Reactant: CCc1ccc(B(O)O)cc1
Reactant: CCOC(=O)c1cncc(Br)c1
Product: CCOC(=O)c1cncc(-c2ccc(CC)cc2)c1

Procedure:
According to General Method 1A, 29 g (126 mmol) of ethyl 5-bromonicotinate and 23 g (152 mmol, 1.2 eq.) of 4-ethylphenylboronic acid were reacted. Yield: 32 g (82% of theory)
Reaction SMILES: O[CH2:2][CH2:3][NH:4][C:5]([C:7]1[NH:11][C:10]2[CH:12]=[CH:13][CH:14]=[CH:15][C:9]=2[N:8]=1)=[O:6].S(Cl)(Cl)=O>CN(C=O)C>[C:5]1(=[O:6])[C:7]2=[N:11][C:10]3[CH:12]=[CH:13][CH:14]=[CH:15][C:9]=3[N:8]2[CH2:2][CH2:3][NH:4]1
Reactant: O=C(NCCO)c1nc2ccccc2[nH]1
Solvent: O=S(Cl)Cl
Solvent: CN(C)C=O
Product: O=C1NCCn2c1nc1ccccc12
Temperature: 0 °C
Yield: 52.5 %

Procedure:
A 100-mL single-neck round-bottomed flask equipped with a magnetic stirrer and reflux condenser was purged with nitrogen and charged with 152a (1.41 g, 6.84 mmol) and DMF (10 mL), and the reaction mixture was cooled to 0° C. A solution of thionyl chloride (896 mg, 7.53 mmol) in DMF (5 mL) was added dropwise. The reaction was heated at 150° C. for 2 h. After this time, the solvent was removed under reduced pressure. The resulting residue was partitioned between water (20 mL) and methylene chloride (20 mL). The layers were separated, and the aqueous phase was extracted with methylene chloride (2×20 mL). The organic extracts were combined, dried over sodium sulfate, filtered and concentrated under reduced pressure. The resulting residue was purified by flash chromatography to afford a 52% yield (672 mg) of 152b as a brown solid: mp>250° C.; 1H NMR (500 MHz, DMSO-d6) d 8.53 (s, 1H), 7.76 (d, 1H, J=9.0 Hz), 7.66 (d, 1H, J=9.0 Hz), 7.40 (t, 1H, J=9.0 Hz), 7.31 (t, 1H, J=9.0 Hz), 4.41 (t, 2H, J=6.0 Hz), 3.71 (m, 2H); MS (APCI+) m/z 188.4 (M+H).
Reaction SMILES: COC([N:5]1[CH2:10][CH2:9][CH:8]([C:11]2[C:19]3[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=3)[NH:13][N:12]=2)[CH2:7][CH2:6]1)=N.C(O)(=O)C>O>[NH:5]1[CH2:6][CH2:7][CH:8]([C:11]2[C:19]3[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=3)[NH:13][N:12]=2)[CH2:9][CH2:10]1
Reactant: COC(=N)N1CCC(c2n[nH]c3ccccc23)CC1
Solvent: CC(=O)O
Solvent: O
Product: c1ccc2c(C3CCNCC3)n[nH]c2c1
Yield: 46.4 %

Procedure:
A solution of 4.7 g of 4-(1H-indazol-3-yl)piperidine-1-carboximidic acid methyl ester and 80% of acetic acid was heated under reflux for 48 hrs. The reaction mixture was cooled and poured into water. The aqueous phase was extracted with ether and then made basic by the slow addition of a 50% aqueous sodium hydroxide soluton. A solid separated from the solution. The solid was collected and dried. Recrystallization from ethanol yielded 1.7 g (46%) of product. Concentration of the mother liquors from this and another experiment gave additional product, mp 213°-215° C.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][N:5]2[C:8]3[CH2:14][N:13]([C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])[CH2:12][CH2:11][C:9]=3[N:10]=[C:4]2[CH:3]=1.[F:22][C:23]([F:38])([F:37])[C:24]1[CH:29]=[CH:28][C:27]([C:30]2[CH:35]=[CH:34][NH:33][C:32](=[O:36])[CH:31]=2)=[CH:26][CH:25]=1>>[O:36]=[C:32]1[CH:31]=[C:30]([C:27]2[CH:28]=[CH:29][C:24]([C:23]([F:37])([F:22])[F:38])=[CH:25][CH:26]=2)[CH:35]=[CH:34][N:33]1[C:2]1[CH:7]=[CH:6][N:5]2[C:8]3[CH2:14][N:13]([C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])[CH2:12][CH2:11][C:9]=3[N:10]=[C:4]2[CH:3]=1
Reactant: CC(C)(C)OC(=O)N1CCc2nc3cc(Br)ccn3c2C1
Reactant: O=c1cc(-c2ccc(C(F)(F)F)cc2)cc[nH]1
Product: CC(C)(C)OC(=O)N1CCc2nc3cc(-n4ccc(-c5ccc(C(F)(F)F)cc5)cc4=O)ccn3c2C1
Yield: 63.5 %

Procedure:
tert-Butyl 7-bromo-3,4-dihydropyrido[4′,3′:4,5]imidazo[1,2-a]pyridine-2(1H)-carboxylate (150 mg, 0.426 mmol) and 4-(4-(trifluoromethyl)phenyl)pyridin-2(1H)-one (103 mg, 0.426 mmol) were reacted according to Example 18 (step g) to provide the title compound (138 mg, 64%) as a yellow solid: ESI MS m/z 511 [M+H]+.
Reaction SMILES: [Na].Cl[C:3]1[CH:8]=[CH:7][C:6]([N+:9]([O-:11])=[O:10])=[CH:5][C:4]=1[C:12]([F:15])([F:14])[F:13].[CH3:16][OH:17]>>[CH3:16][O:17][C:3]1[CH:8]=[CH:7][C:6]([N+:9]([O-:11])=[O:10])=[CH:5][C:4]=1[C:12]([F:15])([F:14])[F:13]
Reactant: CO
Reactant: O=[N+]([O-])c1ccc(Cl)c(C(F)(F)F)c1
Agent: [Na]
Product: COc1ccc([N+](=O)[O-])cc1C(F)(F)F
Yield: 99 %

Procedure:
Sodium (11.78 g, 0.512 mol) was dissolved in dry methanol (1 l) and to the resulting solution was added a solution of 1-chloro-4-nitro-2-trifluoromethyl-benzene (96.22 g, 0.427 mol) in methanol (100 ml). The reaction mixture was refluxed for 3 h then cooled and evaporated in vacuo. The residue was partitioned between water (500 ml) and dichloromethane (3×400 ml). The combined organic extracts were dried (Na2SO4) and evaporated to give the title compound (93.76 g, 99%) as a white solid.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2([CH:12]([N:21]([CH3:23])[CH3:22])[CH2:13][CH2:14][CH2:15][O:16][CH2:17][C:18](=[O:20])[CH3:19])[CH2:11][CH2:10][CH2:9]2)=[CH:4][CH:3]=1.[BH4-].[Na+].CC(O)C>O>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2([CH:12]([N:21]([CH3:23])[CH3:22])[CH2:13][CH2:14][CH2:15][O:16][CH2:17][CH:18]([OH:20])[CH3:19])[CH2:9][CH2:10][CH2:11]2)=[CH:6][CH:7]=1
Reactant: CC(=O)COCCCC(N(C)C)C1(c2ccc(Cl)cc2)CCC1
Agent: [BH4-]
Agent: [Na+]
Solvent: CC(C)O
Solvent: O
Product: CC(O)COCCCC(N(C)C)C1(c2ccc(Cl)cc2)CCC1

Procedure:
A mixture of 1-{4-[1-(4-chlorophenyl)cyclobutyl]-4-dimethylaminobutoxy}propan-2-one (1.4 g prepared as described in Example 214) sodium borohydride (1.5 g) and propan-2-ol (30 ml) was heated under reflux for 4.25 hours. The mixture was cooled and poured into water. The aqueous mixture was extracted with ether. The extract was dried and evaporated to give a residue which was heated at 90°/20 mm to leave 1-{4-[1-(4-chlorophenyl)cyclobutyl]-4-dimethylaminobutoxy}propan-2-ol as an oil the boiling point of which was not determined.
Reaction SMILES: [CH2:1]([O:8][C:9]([N:11]1[CH2:16][CH2:15][CH:14]([O:17][C:18]2[CH:23]=[CH:22][C:21]([CH2:24][C@H:25]([NH:36][S:37]([C:40]3[CH:45]=[CH:44][C:43](I)=[CH:42][CH:41]=3)(=[O:39])=[O:38])[CH2:26][O:27][C:28]3[CH:29]=[C:30]([CH:33]=[CH:34][CH:35]=3)[C:31]#[N:32])=[CH:20][CH:19]=2)[CH2:13][CH2:12]1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:47]([O:51][CH2:52][CH3:53])(=[O:50])[CH:48]=[CH2:49].C1(C)C=CC=CC=1P(C1C=CC=CC=1C)C1C=CC=CC=1C.C(N(CCCC)CCCC)CCC>C(#N)C.C([O-])(=O)C.[Pd+2].C([O-])(=O)C.ClCCl>[CH2:1]([O:8][C:9]([N:11]1[CH2:16][CH2:15][CH:14]([O:17][C:18]2[CH:23]=[CH:22][C:21]([CH2:24][C@H:25]([NH:36][S:37]([C:40]3[CH:45]=[CH:44][C:43](/[CH:49]=[CH:48]/[C:47]([O:51][CH2:52][CH3:53])=[O:50])=[CH:42][CH:41]=3)(=[O:39])=[O:38])[CH2:26][O:27][C:28]3[CH:35]=[CH:34][CH:33]=[C:30]([C:31]#[N:32])[CH:29]=3)=[CH:20][CH:19]=2)[CH2:13][CH2:12]1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: N#Cc1cccc(OC[C@H](Cc2ccc(OC3CCN(C(=O)OCc4ccccc4)CC3)cc2)NS(=O)(=O)c2ccc(I)cc2)c1
Reactant: C=CC(=O)OCC
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: Cc1ccccc1P(c1ccccc1C)c1ccccc1C
Solvent: ClCCl
Solvent: CC#N
Solvent: CCCCN(CCCC)CCCC
Product: CCOC(=O)/C=C/c1ccc(S(=O)(=O)N[C@H](COc2cccc(C#N)c2)Cc2ccc(OC3CCN(C(=O)OCc4ccccc4)CC3)cc2)cc1

Procedure:
738 mg (1.00 mmol)) of 3-[(2S)-3-[4-[1-(benzyloxycarbonyl)-4-piperidyloxy]phenyl]-2-(4-iodobenzenesulfonylamino)propoxy]benzonitrile was dissolved in 5 ml of acetonitrile. 0.22 ml (2.0 mmol) of ethyl acrylate, 11 mg (0.05 mmol) of palladium acetate, 91 mg (0.3 mmol) of tris-o-tolylphosphine and 0.48 ml (2.0 mmol) of tributylamine were added to the solution, and they were heated under reflux for 15 hours. After the same isolation process as that of step 1 in Example 1 with dichloromethane as the extractant, the crude product was obtained, which was purified by the silica gel column chromatography to obtain the title compound.
Reaction SMILES: [CH:1]([CH:3]1[CH2:8][CH2:7][N:6]([C:9]([O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:10])[CH2:5][CH2:4]1)=[O:2].[CH3:16]C([O-])(C)C.[K+].CI>C(Cl)Cl.[Cl-].[Na+].O>[CH:1]([C:3]1([CH3:16])[CH2:8][CH2:7][N:6]([C:9]([O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:10])[CH2:5][CH2:4]1)=[O:2]
Reactant: CC(C)(C)OC(=O)N1CCC(C=O)CC1
Reactant: CC(C)(C)[O-]
Agent: [Cl-]
Agent: [K+]
Agent: [Na+]
Solvent: CI
Solvent: O
Solvent: ClCCl
Product: CC1(C=O)CCN(C(=O)OC(C)(C)C)CC1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 37.5 %

Procedure:
To a solution of tert-butyl 4-formylpiperidine-1-carboxylate (4.5 g, 21.10 mmol) in CH2Cl2 (50 mL) at 0° C. was added t-BuOK (3.08 g, 27.4 mmol) followed by MeI (3.96 mL, 63.3 mmol) at 0° C. The resulting mixture was stirred 30 min, and then warmed to room temp and stirred for 1.5 h. The reaction mixture was then poured into brine and the mixture was extracted with dichloromethane, dried (Na2SO4), filtered and concentrated. The residue was then purified by Biotage (0-20% EtOAc/hexane) to afford tert-butyl 4-formyl-4-methylpiperidine-1-carboxylate (1.8 g, 7.92 mmol, 37.5% yield) as colorless oil. 1H NMR (500 MHz, CDCl3) δ 9.48 (s, 1H), 3.71-3.66 (m, 2H), 3.19-3.05 (m, 2H), 1.93 (dt, J=13.7, 4.1 Hz, 2H), 1.47 (s, 9H), 1.46-1.37 (m, 2H), 1.10 (s, 3H). LCMS (M+H)=228.1.
Reaction SMILES: [N:1]1([C:6]2[CH:11]=[CH:10][C:9]([OH:12])=[CH:8][CH:7]=2)[CH:5]=[CH:4][N:3]=[CH:2]1.Cl[CH2:14][CH2:15][CH2:16][OH:17].C(=O)([O-])[O-].[K+].[K+]>C(C(C)=O)C>[N:1]1([C:6]2[CH:11]=[CH:10][C:9]([O:12][CH2:14][CH2:15][CH2:16][OH:17])=[CH:8][CH:7]=2)[CH:5]=[CH:4][N:3]=[CH:2]1
Reactant: Oc1ccc(-n2ccnc2)cc1
Reactant: OCCCCl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCC(C)=O
Product: OCCCOc1ccc(-n2ccnc2)cc1

Procedure:
A stirred mixture of 4(1H-imidazol-1-yl)phenol (16.0 g, 0.10 mole), 3-chloropropanol (19.0 g, 0.20 mole), potassium carbonate (28 g, 0.20 mole) and methyl ethyl ketone (100 ml) was heated at reflux temperature for 24 hr. The reaction mixture was cooled, filtered, and the filtrate concentrated. The residue was partitioned between ethyl acetate and 0.01N sodium hydroxide solution. The ethyl acetate layer was dried (magnesium sulfate), diluted with ether, and the solid precipitate collected. The solid was recrystallized from methyl isobutyl ketone to obtain 10.0 g (46%), mp 76°-78° C.
Reaction SMILES: C1(C(C2C=CC=CC=2)(C2C=CC=CC=2)[N:8]2[CH:12]=[C:11]([CH2:13][CH2:14][CH2:15][O-:16])[N:10]=[CH:9]2)C=CC=CC=1.[Na+].[Cl-].[CH3:31][C:32]1[CH:37]=[CH:36][C:35]([CH2:38][CH2:39][CH3:40])=[CH:34][CH:33]=1>>[CH3:31][C:32]1[CH:37]=[CH:36][C:35]([CH2:38][CH2:39][CH2:40][O:16][CH2:15][CH2:14][CH2:13][C:11]2[N:10]=[CH:9][NH:8][CH:12]=2)=[CH:34][CH:33]=1
Reactant: [O-]CCCc1cn(C(c2ccccc2)(c2ccccc2)c2ccccc2)cn1
Reactant: CCCc1ccc(C)cc1
Agent: [Cl-]
Agent: [Na+]
Product: Cc1ccc(CCCOCCCc2c[nH]cn2)cc1

Procedure:
5 mmol of sodium 3-(1-triphenylmethyl-1H-imidazol-4-yl)propanolate and 5 mmol of 3-(4-methylphenyl)propane chloride are treated as described in Example 5.
Reaction SMILES: [NH2:1][C:2]1[C:3](S(O)(=O)=O)=[CH:4][CH:5]=[CH:6][CH:7]=1.[NH2:12][C:13]1[CH:18]=[CH:17][CH:16]=[C:15](S(O)(=O)=O)[CH:14]=1.[CH2:23]=O>>[CH:15]1[C:16]([CH2:23][C:5]2[CH:6]=[CH:7][C:2]([NH2:1])=[CH:3][CH:4]=2)=[CH:17][CH:18]=[C:13]([NH2:12])[CH:14]=1
Reactant: C=O
Reactant: Nc1ccccc1S(=O)(=O)O
Reactant: Nc1cccc(S(=O)(=O)O)c1
Product: Nc1ccc(Cc2ccc(N)cc2)cc1

Procedure:
An 2-anilinesulfonic acid derivative (e.g. sodium 2-anilinesulfonate) or an 3-anilinesulfonic acid derivative (e.g. sodium 3-anilinesulfonate) is treated with formalin under acidic conditions to give the corresponding 4,4′-diaminodiphenylmethane derivative. This is diazotized using sodium nitrite under acidic conditions in the presence of hydrochloric acid, followed by reaction with sodium azide, to give the desired product.
Reaction SMILES: Cl.[F:2][CH2:3][CH2:4][NH2:5].Cl[C:7]1[C:16]([C:17]([C:19](=[CH:25]N(C)C)[C:20]([O:22][CH2:23][CH3:24])=[O:21])=[O:18])=[CH:15][C:14]2[C:9](=[CH:10][C:11]([Cl:30])=[C:12]([F:29])[CH:13]=2)[N:8]=1>C(N(CC)CC)C>[Cl:30][C:11]1[C:12]([F:29])=[CH:13][C:14]2[C:9]([CH:10]=1)=[N:8][C:7]1[N:5]([CH2:4][CH2:3][F:2])[CH:25]=[C:19]([C:20]([O:22][CH2:23][CH3:24])=[O:21])[C:17](=[O:18])[C:16]=1[CH:15]=2
Reactant: NCCF
Reactant: CCOC(=O)C(=CN(C)C)C(=O)c1cc2cc(F)c(Cl)cc2nc1Cl
Agent: Cl
Solvent: CCN(CC)CC
Product: CCOC(=O)c1cn(CCF)c2nc3cc(Cl)c(F)cc3cc2c1=O
Temperature: 75 °C
Reaction time: 16 h
Yield: 57 %

Procedure:
2.7 cm3 of triethylamine are added to a suspension of 1.9 g of 2-fluoroethylamine hydrochloride in 25 cm3 of trichlorcmethane. 3.5 g of ethyl 2-(2,7-dichloro-6-fluoroquinoline-3-carbonyl)-3-dimethylaminoacrylate are added to the solution obtained at about 20° C. After stirring at this temperature for 16 hours, the solution is concentrated to dryness under reduced pressure (20 kPa) at about 50° C. The residue is taken up in 20 cm3 of ethanol and 3 cm3 of triethylamine and heat at about 75° C., with stirring, for 2 hours. After cooling to about 20° C. the insoluble matter is drained and washed with twice 10 cm3 of ethanol and twice 10 cm3 of diisopropyl ether. 1.9 g of 8-chloro-3-ethoxycarbonyl-7-fluoro-1-(2-fluoro-ethyl)-4-oxo-1,4-dihydro-benzo[b][1,8]naphthyridine are obtained in the form of a yellow solid melting at 268° C., which is used for the subsequent steps without further purification.
Reaction SMILES: [C:1](=O)([O-])[O-].[K+].[K+].[C:7]([O:11][C:12]([NH:14][C@H:15]([C:28]([OH:30])=[O:29])[CH2:16][C:17]1[C:25]2[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=2)[N:19]([CH:26]=[O:27])[CH:18]=1)=[O:13])([CH3:10])([CH3:9])[CH3:8].IC>CN(C=O)C>[C:7]([O:11][C:12]([NH:14][C@H:15]([C:28]([O:30][CH3:1])=[O:29])[CH2:16][C:17]1[C:25]2[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=2)[N:19]([CH:26]=[O:27])[CH:18]=1)=[O:13])([CH3:10])([CH3:8])[CH3:9]
Reactant: CC(C)(C)OC(=O)N[C@@H](Cc1cn(C=O)c2ccccc12)C(=O)O
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: CI
Solvent: CN(C)C=O
Product: COC(=O)[C@H](Cc1cn(C=O)c2ccccc12)NC(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 1 h
Yield: 86.4 %

Procedure:
To DMF (50 mL) suspension of potassium carbonate (6.2 g) was added dropwise DMF (70 mL) solution of Nα-tert-butoxycarbonyl-1-formyl-L-tryptophan (10.0 g) at 0° C., and the mixture was stirred for 1 hour at room temperature. Next, DMF (25 mL) solution of iodomethane (2.8 mL) was added dropwise at 0° C., and the mixture was stirred for 20 hours at room temperature. The reaction mixture was poured into ice water and extracted with ethyl acetate. The organic layer was dried over anhydrous sodium sulfate, and thereafter the residue obtained by distilling off the solvent under a reduced pressure was purified with silica gel column chromatography (BZ-127ZH, n-hexane:ethyl acetate=7:3), to give the captioned compound (9.0 g, 86%) as crystals.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[NH:8][C:9](=[O:37])[C:10]1[CH:15]=[CH:14][C:13]([CH2:16]NC2N=C(NCCC3C=CC(OC)=C(OC)C=3)C=CN=2)=[CH:12][CH:11]=1.COC1C=C(CCNC2C=CN=C(NCC3C=CC(C(O)=O)=CC=3)N=2)C=CC=1OC.[O:68]=[C:69]1[NH:73][C:72](=[O:74])[CH:71](CC2C=CC(C(O)=O)=CC=2)[S:70]1>>[NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[NH:8][C:9](=[O:37])[C:10]1[CH:11]=[CH:12][C:13]([CH2:16][CH:71]2[S:70][C:69](=[O:68])[NH:73][C:72]2=[O:74])=[CH:14][CH:15]=1
Reactant: O=C1NC(=O)C(Cc2ccc(C(=O)O)cc2)S1
Reactant: COc1ccc(CCNc2ccnc(NCc3ccc(C(=O)Nc4ccccc4N)cc3)n2)cc1OC
Agent: COc1ccc(CCNc2ccnc(NCc3ccc(C(=O)O)cc3)n2)cc1OC
Product: Nc1ccccc1NC(=O)c1ccc(CC2SC(=O)NC2=O)cc1
Yield: 51 %

Procedure:
Following the procedure described for the synthesis of compound 10a (scheme 2, Example 2) but replacing acid 9 by the acid 352, title compound was obtained in 51% yield. 1H NMR: (400 MHz, DMSO-d6, δ (ppm): 12.04 (br s, 1H), 9.62 (s, 1H), 7.90 (d, j=8.2 Hz, 2H), 7.36 (d, j=8.2, 2H), 7.16 (d (dd) J=8.4, 1H), 7.13 (d (dd), J=6.7, 1H), 6.95 (dd, J=1.6 Hz, J=7.8 Hz, 1H), 6.75 (dd, j=1.4 Hz, j=8.0 Hz, 1H), 6.57 (dd, j=1.4 Hz, 7.6 Hz, 1H), 4.99 (dd, J=4.7 Hz, J=9.0 Hz, 1H), 4.96 (br s, 2H), 3.45 (dd, J=4.5 Hz, J=14.1 Hz, 1H), 3.22 (dd, J=9.0 Hz, J=14.3 Hz, 1H). LRMS: 341.3 (calcd.), 342.3 [MH]+ (found).
Reaction SMILES: [C:1]([N:8]1[C@H:13]([CH3:14])[CH2:12][NH:11][CH2:10][C@@H:9]1[CH3:15])([O:3][C:4]([CH3:7])(C)C)=[O:2].[Cl:16][C:17]1[CH:24]=[CH:23]C(CCl)=[CH:19][CH:18]=1>>[ClH:16].[Cl:16][C:17]1[CH:24]=[CH:23][C:7]([CH2:4][O:3][C:1]([N:8]2[C@H:9]([CH3:15])[CH2:10][NH:11][CH2:12][C@@H:13]2[CH3:14])=[O:2])=[CH:19][CH:18]=1
Reactant: ClCc1ccc(Cl)cc1
Reactant: C[C@@H]1CNC[C@H](C)N1C(=O)OC(C)(C)C
Product: C[C@@H]1CNC[C@H](C)N1C(=O)OCc1ccc(Cl)cc1
Product: Cl

Procedure:
Prepared in analogy to Example 25 with cis-N-Boc-2,6-dimethyl-piperazine and 4-chloro-benzyl chloride. Colourless powder, 1H-NMR (d6-DMSO): 1.30 d 7.2 Hz, 6H; 3.0–3.25 m, 4H and 4.2–4.4 m, 2H; 5.11 s, 2H; 7.35–7.55 AB-system, 4H; 9.5 br, 2H. MS (ISP): 283.1 (M+H)+.
Reaction SMILES: [OH:1][C:2]1[C:11]2[C:6](=[CH:7][C:8]([CH3:12])=[CH:9][CH:10]=2)[N:5]=[CH:4][C:3]=1[C:13]([O:15]CC)=[O:14].Cl>[OH-].[Na+]>[OH:1][C:2]1[C:11]2[C:6](=[CH:7][C:8]([CH3:12])=[CH:9][CH:10]=2)[N:5]=[CH:4][C:3]=1[C:13]([OH:15])=[O:14]
Reactant: CCOC(=O)c1cnc2cc(C)ccc2c1O
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Product: Cc1ccc2c(O)c(C(=O)O)cnc2c1
Temperature: 25 °C
Yield: 99.9 %

Procedure:
Ethyl 4-hydroxy-7-methyl-3-quinolinecarboxylate (32 g, 138 mmol) was suspended in sodium hydroxide (500 mL of 10% aqueous) and then heated at reflux for about 30 minutes. The reaction mixture was allowed to cool to ambient temperature and then it was acidified with concentrated hydrochloric acid. The resulting precipitate was isolated by filtration, rinsed well with water and then oven dried to provide 4-hydroxy-7-methyl-3-quinolinecarboxylic acid (28 g). A portion (2 g) was recrystallized twice from N,N-dimethylformamide to give a fluffy white solid, m.p. 264-265° C. Analysis: Calculated for C11H9NO3: %C, 65.02; %H, 4.46; %N, 6.89; Found: %C, 65.22; %H, 4.42; %N, 6.88.
Reaction SMILES: [C:1]([C:9]1[CH:26]=[CH:25][CH:24]=[CH:23][C:10]=1[NH:11][CH:12]1[CH2:17][CH2:16][N:15]([C:18]([O:20][CH2:21][CH3:22])=[O:19])[CH2:14][CH2:13]1)(=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl[CH2:28][C:29](Cl)=[O:30].[I-].[Na+].C(=O)([O-])[O-].[NH4+:38].[NH4+]>>[CH2:21]([O:20][C:18]([N:15]1[CH2:16][CH2:17][CH:12]([N:11]2[C:10]3[CH:23]=[CH:24][CH:25]=[CH:26][C:9]=3[C:1]([C:2]3[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=3)=[N:38][CH2:28][C:29]2=[O:30])[CH2:13][CH2:14]1)=[O:19])[CH3:22]
Reactant: CCOC(=O)N1CCC(Nc2ccccc2C(=O)c2ccccc2)CC1
Reactant: [NH4+]
Reactant: O=C(Cl)CCl
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [Na+]
Product: CCOC(=O)N1CCC(N2C(=O)CN=C(c3ccccc3)c3ccccc32)CC1

Procedure:
The reactions are performed as in the method of Example 23 (d) and (e). Thus ethyl 4-(2-benzoylanilino)piperidine-1-carboxylate (2.56 g) is reacted successively with 2-chloro-acetyl chloride, sodium iodide and ammonium carbonate, whereby 1,3-dihydro-1-(1-ethoxycarbonyl-4-piperidinyl)-5-phenyl-2H-1,4-benzodiazepin-2-one (2.27 g) is obtained as a powder.
Reaction SMILES: Cl[C:2]1[N:28]=[CH:27][CH:26]=[CH:25][C:3]=1[C:4]([NH:6][C:7]1[CH:12]=[CH:11][C:10]([C:13]([F:16])([F:15])[F:14])=[C:9]([O:17][CH2:18][CH2:19][N:20]2[CH2:24][CH2:23][CH2:22][CH2:21]2)[CH:8]=1)=[O:5].CCN(C(C)C)C(C)C.[F:38][C:39]1[CH:46]=[CH:45][C:42]([CH2:43][NH2:44])=[CH:41][CH:40]=1>CCOCC>[F:38][C:39]1[CH:46]=[CH:45][C:42]([CH2:43][NH:44][C:2]2[N:28]=[CH:27][CH:26]=[CH:25][C:3]=2[C:4]([NH:6][C:7]2[CH:12]=[CH:11][C:10]([C:13]([F:16])([F:15])[F:14])=[C:9]([O:17][CH2:18][CH2:19][N:20]3[CH2:24][CH2:23][CH2:22][CH2:21]3)[CH:8]=2)=[O:5])=[CH:41][CH:40]=1
Reactant: O=C(Nc1ccc(C(F)(F)F)c(OCCN2CCCC2)c1)c1cccnc1Cl
Reactant: NCc1ccc(F)cc1
Solvent: CCOCC
Solvent: CCN(C(C)C)C(C)C
Product: O=C(Nc1ccc(C(F)(F)F)c(OCCN2CCCC2)c1)c1cccnc1NCc1ccc(F)cc1
Temperature: 130 °C

Procedure:
2-Chloro-N-[3-(2-pyrrolidin-1-yl-ethoxy)-4-trifluoromethyl-phenyl]-nicotinamide (199.1 mg), DIEA (252 μL) and 4-fluorobenzylamine (193 μL) were combined in a sealed tube and heated to 130° C. for 2 h. The mixture was purified on silica gel chromatography (2-3.5% MeOH/CH2Cl2). The desired fractions were concentrated in vacuo, and the residue was dissolved in Et2O and hexanes were added until the solution became cloudy. The solids were filtered, and dried. Additional material was obtained from the filtrate upon additional rounds of concentration, dissolving in Et2O and treatment with hexanes. M+H 503.4, Calc'd for C26H26N4O2F4-502.2.
Reaction SMILES: C([O:9][C:10]1[C:19](=[O:20])[C:18]2[C:13](=[CH:14][C:15]([CH3:21])=[CH:16][CH:17]=2)[N:12]([CH3:22])[CH:11]=1)(=O)C1C=CC=CC=1.N1CCCCC1>ClCCl>[OH:9][C:10]1[C:19](=[O:20])[C:18]2[C:13](=[CH:14][C:15]([CH3:21])=[CH:16][CH:17]=2)[N:12]([CH3:22])[CH:11]=1
Reactant: Cc1ccc2c(=O)c(OC(=O)c3ccccc3)cn(C)c2c1
Solvent: ClCCl
Solvent: C1CCNCC1
Product: Cc1ccc2c(=O)c(O)cn(C)c2c1
Temperature: 25 °C
Reaction time: 72 h

Procedure:
A mixture of 1,7-dimethyl-4-oxo-1,4-dihydroquinol-3-yl benzoate (1.45 g), piperidine (0.49 ml) and dichloromethane (14 ml) was stirred at ambient temperature under nitrogen for 3 days. Further piperidine (0.13 ml) was added and the mixture stirred overnight. The solvent was removed by distillation and the residue triturated with diethyl ether (20 ml) to give the novel compound 3-hydroxy-1,7- dimethyl-4quinolone, m.p. 268°.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH2:11][CH2:10][CH:9]1[CH2:14][NH2:15])=[O:7])([CH3:4])([CH3:3])[CH3:2].CS[C:18]1[O:19][C:20]2[CH:26]=[CH:25][CH:24]=[N:23][C:21]=2[N:22]=1>>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH2:11][CH2:10][CH:9]1[CH2:14][NH:15][C:18]1[O:19][C:20]2[CH:26]=[CH:25][CH:24]=[N:23][C:21]=2[N:22]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)OC(=O)N1CCCCC1CN
Reactant: CSc1nc2ncccc2o1
Product: CC(C)(C)OC(=O)N1CCCCC1CNc1nc2ncccc2o1

Procedure:
The title compound (0.7 g) was prepared from (RS)-2-aminomethyl-piperidine-1-carboxylic acid tert-butyl ester (0.64 g) and 2-methylthio-4-azabenzoxazole Chu-Moyeret al J. Org Chem. (1995), 60(17), 5721-5. (0.5 g) according to the method of D30.
Reaction SMILES: CC[N:3]([CH:7]([CH3:9])C)[CH:4]([CH3:6])C.Cl[C:11]1[N:16]=[C:15]([Cl:17])[C:14]([C:18]([F:21])([F:20])[F:19])=[CH:13][N:12]=1.C[N:23]([CH:25]=O)C>>[Cl:17][C:15]1[C:14]([C:18]([F:21])([F:20])[F:19])=[CH:13][N:12]=[C:11]([NH:23][CH2:25][C:9]2[CH:7]=[N:3][CH:4]=[CH:6][C:14]=2[C:18]([F:21])([F:20])[F:19])[N:16]=1
Reactant: CCN(C(C)C)C(C)C
Reactant: FC(F)(F)c1cnc(Cl)nc1Cl
Reactant: CN(C)C=O
Product: FC(F)(F)c1ccncc1CNc1ncc(C(F)(F)F)c(Cl)n1
Temperature: 0 °C
Reaction time: 8 h
Yield: 17.2 %

Procedure:
(4-(Trifluoromethyl)pyridin-3-yl)methanamine, HCl (1.0 equiv.) was placed in a round bottom flask with DIEA (2.5 M) and DMF (0.6 M). The flask was cooled to 0° C. and 2,4-dichloro-5-(trifluoromethyl)pyrimidine (1.0 equiv.) was slowly added portion-wise. The reaction mixture was stirred overnight and allowed to warm to room temperature. The reaction mixture was loaded directly onto a silica gel column and purified using 0-20% ethyl acetate in hexanes followed by 20% ethyl acetate in hexanes. Fractions containing the desired isomer (lower Rf spot by thin layer chromatography) were combined and volatile organic solvents were removed under reduced pressure to give 4-chloro-5-(trifluoromethyl)-N-((4-(trifluoromethyl)pyridin-3-yl)methyl)pyrimidin-2-amine (17.2% yield) as a white solid. MS (ESI) m/z 357.2 [M+1]+