Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[C:3](=[O:18])[N:4]([CH2:9][C:10]2[CH:15]=[CH:14][C:13]([O:16][CH3:17])=[CH:12][CH:11]=2)[CH:5]=C(Cl)N=1.[CH3:19][O:20][C:21](=[O:28])[C:22]#[C:23][C:24]([O:26][CH3:27])=[O:25]>C1(C)C(C)=CC=CC=1>[Cl:1][C:2]1[C:3](=[O:18])[N:4]([CH2:9][C:10]2[CH:11]=[CH:12][C:13]([O:16][CH3:17])=[CH:14][CH:15]=2)[CH:5]=[C:22]([C:21]([O:20][CH3:19])=[O:28])[C:23]=1[C:24]([O:26][CH3:27])=[O:25]
Reactant: COC(=O)C#CC(=O)OC
Reactant: COc1ccc(Cn2cc(Cl)nc(Cl)c2=O)cc1
Solvent: Cc1ccccc1C
Product: COC(=O)c1cn(Cc2ccc(OC)cc2)c(=O)c(Cl)c1C(=O)OC
Temperature: 150 °C
Yield: 33.4 %

Procedure:
Compound (8) (2.0 g, 7.01 mmol) and 2-butynedioic acid dimethyl ester (2.99 g, 21.04 mmol) were added to xylene (40 ml). The reaction was heated at about 150° C. for about 16 h. The reaction was cooled to about 25° C. The reaction mixture was filtered through a Büchner funnel to afford the title compound (0.9 g, 2.338 mmol, 33.3% yield). LC-MS (ESI+): m/e 366 (M+H)+, Rt: 1.98 min; 1H-NMR (DMSO-d6, 400 MHz): δ=3.73 (s, 3H), 3.79 (s, 3H), 3.88 (s, 3H), 5.21 (s, 2H), 6.91 (d, 2H, J=6.8 Hz), 7.34 (d, 2H, J=6.8 Hz), 8.81 (s, 1H).
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[CH:9]=[C:8]([CH:10]=[O:11])[S:7][CH:6]=1)=[O:4].[CH2:12]([Mg]Cl)[C:13]([CH3:16])([CH3:15])[CH3:14].O>CCOCC>[CH3:1][O:2][C:3]([C:5]1[CH:9]=[C:8]([CH:10]([OH:11])[CH2:12][C:13]([CH3:16])([CH3:15])[CH3:14])[S:7][CH:6]=1)=[O:4]
Reactant: CC(C)(C)C[Mg]Cl
Reactant: COC(=O)c1csc(C=O)c1
Solvent: O
Solvent: CCOCC
Product: COC(=O)c1csc(C(O)CC(C)(C)C)c1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 44.1 %

Procedure:
A solution of 5-formyl-thiophene-3-carboxylic acid methyl ester (0.504 g, 2.96 mmol) in Et2O (30 mL) at 0° C. is treated with neopentyl magnesium chloride (7.1 mL, 0.5 M in Et2O, 3.6 mmol) and stirred for 15 min. Solution warmed to rt and additional Et2O (10 mL) added. The reaction mixture is stirred overnight at rt. after which it is poured into H2O (30 mL) and extracted with EtOAc (3×50 mL). Combined extracts washed with brine, dried over MgSO4, filtered, and concentrated. The residue is loaded onto silica gel and eluted using hexanes with an ethyl acetate gradient from 0% to 50%. The resulting mixture is then loaded onto C18 and eluted using H2O and a MeCN gradient from 15% to 100% giving (±)-5-(1-hydroxy-3,3-dimethyl-butyl)-thiophene-3-carboxylic acid methyl ester (0.316 g, 44%) as a light yellow syrup.
Reaction SMILES: O=S(Cl)Cl.[Br:5][C:6]1[CH:7]=[C:8]([CH:12]=[CH:13][C:14]=1[OH:15])[C:9]([OH:11])=O.CCN(C(C)C)C(C)C.[F:25][C:26]([F:36])([F:35])[O:27][C:28]1[CH:34]=[CH:33][C:31]([NH2:32])=[CH:30][CH:29]=1.[OH-].[Na+]>C1(C)C=CC=CC=1.C1COCC1>[Br:5][C:6]1[CH:7]=[C:8]([CH:12]=[CH:13][C:14]=1[OH:15])[C:9]([NH:32][C:31]1[CH:33]=[CH:34][C:28]([O:27][C:26]([F:25])([F:35])[F:36])=[CH:29][CH:30]=1)=[O:11]
Reactant: Nc1ccc(OC(F)(F)F)cc1
Reactant: O=C(O)c1ccc(O)c(Br)c1
Agent: [Na+]
Agent: [OH-]
Solvent: O=S(Cl)Cl
Solvent: Cc1ccccc1
Solvent: CCN(C(C)C)C(C)C
Product: O=C(Nc1ccc(OC(F)(F)F)cc1)c1ccc(O)c(Br)c1
Temperature: 80 °C
Reaction time: 2.5 h

Procedure:
SOCl2 (8.41 mL, 115 mmol) was added to a suspension of 3-bromo-4-hydroxybenzoic acid (5 g, 23.04 mmol) in toluene (50 mL) and the RM was stirred at 80° C. for 2.5 h. The solvent was evaporated off under reduced pressure and the residue was dissolved in THF (25 mL). DIPEA (8.05 mL, 46.1 mmol) was added and the RM was cooled to 0° C., treated with a solution of 4-trifluoromethoxyaniline (3.40 mL, 25.3 mmol) in THF (5 mL) and stirred for 1 h. The RM was treated with 4M NaOH (23.04 mL, 92 mmol), heated at 100° C. for 3 h and the solvent was evaporated off under reduced pressure. The residue was treated with aq. HCl (50 mL of 1M), and extracted with TBME/EtOAc (1:1). The combined extracts were washed with sat. aq. NaHCO3 and brine, dried over MgSO4 and the solvent was evaporated off under reduced pressure to give the crude product was purified by flash chromatography (Silica gel column, 100 g, DCM/EtOAc from 0% to 20EtOAc) and crystallized from cyclohexane/DCM to afford the title compound as a beige solid. UPLC-MS (Condition 1) tR=2.70 min, m/z=375.9/377.8 [M+H]+, m/z=374.0/375.9 [M−H]−; 1H-NMR (400 MHz, DMSO-d6) δ ppm 7.05 (d, J=8.6 Hz, 1H) 7.35 (d, J=8.6 Hz, 2H) 7.80-7.90 (m, 3H) 8.17 (d, J=2.2 Hz, 1H) 10.26 (s, 1H) 11.03 (s, 1H).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:12]=[CH:11][C:10]2[CH2:9][CH2:8][CH2:7][CH2:6][C:5]=2[C:4]=1[C:13]([OH:15])=O.C(Cl)(=O)C([Cl:19])=O>C(Cl)Cl.CN(C=O)C>[CH3:1][O:2][C:3]1[CH:12]=[CH:11][C:10]2[CH2:9][CH2:8][CH2:7][CH2:6][C:5]=2[C:4]=1[C:13]([Cl:19])=[O:15]
Reactant: COc1ccc2c(c1C(=O)O)CCCC2
Reactant: O=C(Cl)C(=O)Cl
Solvent: ClCCl
Solvent: CN(C)C=O
Product: COc1ccc2c(c1C(=O)Cl)CCCC2
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of 2-methoxy-5,6,7,8-tetrahydro-1-naphthalenecarboxylic acid (0.20 g, 0.97 mmol) in DCM (5 mL) was added oxalyl chloride (0.11 mL, 1.21 mmol) and 1 drop of DMF. The mixture was stirred at room temperature for 2 h. The solvent was removed in vacuo and the 2-methoxy-5,6,7,8-tetrahydro-1-naphthalenecarbonyl chloride was used without purification.
Reaction SMILES: [CH:1]1([C:4]2[C:5]([O:13][CH2:14][C:15]([F:18])([F:17])[F:16])=[CH:6][C:7]([C:10]([OH:12])=O)=[N:8][CH:9]=2)[CH2:3][CH2:2]1.[CH:19]1([CH2:22][C:23]([C:26]2[O:27][C:28]([CH3:31])=[N:29][N:30]=2)([NH2:25])[CH3:24])[CH2:21][CH2:20]1>>[CH:1]1([C:4]2[C:5]([O:13][CH2:14][C:15]([F:18])([F:17])[F:16])=[CH:6][C:7]([C:10]([NH:25][C:23]([C:26]3[O:27][C:28]([CH3:31])=[N:29][N:30]=3)([CH3:24])[CH2:22][CH:19]3[CH2:20][CH2:21]3)=[O:12])=[N:8][CH:9]=2)[CH2:2][CH2:3]1
Reactant: O=C(O)c1cc(OCC(F)(F)F)c(C2CC2)cn1
Reactant: Cc1nnc(C(C)(N)CC2CC2)o1
Product: Cc1nnc(C(C)(CC2CC2)NC(=O)c2cc(OCC(F)(F)F)c(C3CC3)cn2)o1

Procedure:
The title compound was synthesized in analogy to Example 112e, using 5-Cyclopropyl-4-(2,2,2-trifluoro-ethoxy)-pyridine-2-carboxylic acid (Example 48c) and 1-cyclopropyl-2-(5-methyl-1,3,4-oxadiazol-2-yl)propan-2-amine (example 173b) as starting materials and isolated (99 mg, 76%); MS (ESI, m/z): 425.6 (M+H+).
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6]([C:8]([F:11])([F:10])[F:9])[C:5]([C:12](Cl)=[O:13])=[CH:4][N:3]=1.[OH2:15]>>[Cl:1][C:2]1[N:7]=[C:6]([C:8]([F:11])([F:10])[F:9])[C:5]([C:12]([OH:13])=[O:15])=[CH:4][N:3]=1
Reactant: O
Reactant: O=C(Cl)c1cnc(Cl)nc1C(F)(F)F
Product: O=C(O)c1cnc(Cl)nc1C(F)(F)F
Yield: 98 %

Procedure:
A solution of 2-chloro-4-trifluoromethylpyrimidine-5-carbonyl chloride (2.1 g, 8.6 mmol) in H2O (10 mL) was stirred at 0° C. under N2 for 0.5 h. The resulting solid was filtered and dried to give the title compound (1.91 g, 98% yield); m.p. 232°-234° C. (dec.).
Reaction SMILES: CN(/[CH:4]=[C:5]1/[C:6](=O)[C:7]2[C:12]([C@H:13]([C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=3[F:21])[CH2:14]/1)=[CH:11][CH:10]=[CH:9][CH:8]=2)C.[OH:23][CH2:24][CH2:25][C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][C:27]=1[NH:32][C:33]([NH2:35])=[NH:34]>>[F:21][C:16]1[CH:17]=[CH:18][CH:19]=[CH:20][C:15]=1[C@H:13]1[C:12]2[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=2[C:6]2[N:35]=[C:33]([NH:32][C:27]3[CH:28]=[CH:29][CH:30]=[CH:31][C:26]=3[CH2:25][CH2:24][OH:23])[N:34]=[CH:4][C:5]=2[CH2:14]1
Reactant: N=C(N)Nc1ccccc1CCO
Reactant: CN(C)/C=C1\C[C@@H](c2ccccc2F)c2ccccc2C1=O
Product: OCCc1ccccc1Nc1ncc2c(n1)-c1ccccc1[C@H](c1ccccc1F)C2

Procedure:
This was synthesized by using general procedure 6 except that (R,E)-2-((dimethylamino)methylene)-4-(2-fluorophenyl)-3,4-dihydronaphthalen-1(2H)-one reacted with 1-(2-(2-hydroxyethyl)phenyl)guanidine to give (R)-2-(2-(6-(2-fluorophenyl)-5,6-dihydrobenzo[h]quinazolin-2-ylamino)phenyl)ethanol. M.p.=162-163° C. 1H NMR 400 MHz (DMSO-d6) δ 9.05 (s, 1 H), 8.23-8.21 (m, 2 H), 7.81-7.79 (d, 1 H), 7.46-7.43 (m, 2 H), 7.30-7.22 (m, 4 H), 7.06-7.02 (m, 3 H), 6.82-6.77 (m, 1 H), 5.21 (t, J=4.4 Hz, 1 H), 4.65 (t, J=6.8 Hz, 1 H), 3.70-3.66 (m, 2 H), 3.19-3.04 (m, 2 H), 2.18 (t, J=6.0 Hz, 2 H). LCMS m/e 412 (M+H).
Reaction SMILES: [ClH:1].C(OCC)(=O)C.[C:8]([O:16][CH2:17][CH2:18][O:19][CH2:20][CH2:21][N:22]1[C:30]2[C:29]([NH:31][C:32]3[CH:51]=[CH:50][C:35]([O:36][CH:37]4[CH2:42][CH2:41][N:40](C(OC(C)(C)C)=O)[CH2:39][CH2:38]4)=[C:34]([Cl:52])[CH:33]=3)=[N:28][CH:27]=[N:26][C:25]=2[CH:24]=[CH:23]1)(=[O:15])[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1>C(O)C>[ClH:52].[ClH:1].[C:8]([O:16][CH2:17][CH2:18][O:19][CH2:20][CH2:21][N:22]1[C:30]2[C:29]([NH:31][C:32]3[CH:51]=[CH:50][C:35]([O:36][CH:37]4[CH2:38][CH2:39][NH:40][CH2:41][CH2:42]4)=[C:34]([Cl:52])[CH:33]=3)=[N:28][CH:27]=[N:26][C:25]=2[CH:24]=[CH:23]1)(=[O:15])[C:9]1[CH:10]=[CH:11][CH:12]=[CH:13][CH:14]=1
Reactant: CC(C)(C)OC(=O)N1CCC(Oc2ccc(Nc3ncnc4ccn(CCOCCOC(=O)c5ccccc5)c34)cc2Cl)CC1
Agent: Cl
Solvent: CCOC(C)=O
Solvent: CCO
Product: O=C(OCCOCCn1ccc2ncnc(Nc3ccc(OC4CCNCC4)c(Cl)c3)c21)c1ccccc1
Temperature: 25 °C
Reaction time: 5 h

Procedure:
4N Hydrochloric acid/ethyl acetate solution (20 mL) and ethanol (10 mL) were added to tert-butyl 4-{4-[(5-{2-[2-(benzoyloxy)ethoxy]ethyl}-5H-pyrrolo[3,2-d]pyrimidin-4-yl)amino]-2-chlorophenoxy}piperidine-1-carboxylate (3.82 g), and the mixture was stirred at room temperature for 5 hrs. The reaction mixture was concentrated under reduced pressure, and the obtained residue was crystallized from ethanol-ethyl acetate to give the title compound (3.68 g) as a white powder.
Reaction SMILES: [O:1]=[C:2]([CH2:6][CH3:7])[CH2:3][C:4]#[N:5].[CH2:8](O)[CH2:9][OH:10].C1(C)C=CC(S(O)(=O)=O)=CC=1>C1(C)C=CC=CC=1.C(OCC)(=O)C>[CH2:6]([C:2]1([CH2:3][C:4]#[N:5])[O:10][CH2:9][CH2:8][O:1]1)[CH3:7]
Reactant: OCCO
Reactant: CCC(=O)CC#N
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: CCOC(C)=O
Solvent: Cc1ccccc1
Product: CCC1(CC#N)OCCO1

Procedure:
A solution of 3-oxo-pentanenitrile (1.582 g, 16.49 mmol), ethylene glycol (1.026 ml, 84.59 mmol) and a catalytic amount of p-Toluene Sulphonic acid (8 mg) in Toluene (10 ml) is refluxed at 150° C. for 2 days using Dean-Stark apparatus. The reaction mixture is diluted with ethyl acetate and washed with saturated sodium bicarbonate solution. The organic phase is dried over MgSO4, filtered, and the solvent evaporated to yield (2-ethyl-[1,3]dioxolan-2-yl)-acetonitrile. 1H NMR (400 MHz, CDCl3) d 4.15(2H,m), 4.05 (2H, m), 2.65 (2H, s), 1.80 (2H, q), 0.95 (3H, t)
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([O:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH3:14])[C:3]=1[F:15].C([Li])CCC.B(OC)(OC)[O:22]C.Cl>C(OCC)(=O)C.C1COCC1>[F:1][C:2]1([OH:22])[CH:7]=[CH:6][CH:5]=[C:4]([O:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH3:14])[CH:3]1[F:15]
Reactant: COB(OC)OC
Reactant: CCCCCCOc1cccc(F)c1F
Agent: Cl
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: CCCCCCOC1=CC=CC(O)(F)C1F
Temperature: 0 °C
Reaction time: 2 h
Yield: 66.3 %

Procedure:
1,2-Difluoro-3-hexyloxybenzene (s-1) (17.8 g) and THF (500 ml) were placed in a reaction vessel under an atmosphere of nitrogen, and cooled to −74° C. n-Butyllithium (1.57M; n-hexane and cyclohexane solution; 58.0 ml) was added dropwise in the temperature range of −74° C. to −70° C., and the stirring was continued for another 2 hours. Trimethyl borate (9.5 g) in a THF (50 ml) solution was added dropwise in the temperature range of −74° C. to −65° C., and the stirring was continued for 8 hours while the mixture was allowed to return to 25° C. The reaction mixture was poured into a vessel containing 1N-hydrochloric acid (100 ml) and ice-water (500 ml) and mixed with them. Ethyl acetate (300 ml) was added, and mixture was then allowed to stand until it had separated into organic and aqueous layers, and the extraction was carried out. The resulting organic layers were separated, and washed successively with water, a saturated aqueous solution of sodium hydrogencarbonate and brine, and then dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure. The residue and acetic acid (100 ml) were placed in a reaction vessel at room temperature under an atmosphere of nitrogen, and an aqueous solution of hydrogen peroxide (31%; 10.1 ml) was added dropwise in the temperature range of 25° C. to 30° C., and the stirring was continued for another 2 hours. The reaction mixture was poured into a vessel containing an aqueous solution of sodium hydrogen sulfite (100 ml) and ethyl acetate (300 ml) and mixed with them. The mixture was then allowed to stand until it had separated into organic and aqueous layers, and the extraction was carried out. The resulting organic layers were separated, and washed successively with water and brine, and then dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure to give 1,2-difluoro-3-hexyloxyphenol (s-20) (12.8 g). The yield based on the compound (s-1) was 66.6%.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[N:8]1[CH2:13][CH2:12][N:11]([CH2:14][C:15]2[CH:20]=[CH:19][C:18]([NH2:21])=[CH:17][CH:16]=2)[CH2:10][CH2:9]1.Cl[C:23]1[C:32]2[C:27](=[CH:28][C:29]([C:33]([F:36])([F:35])[F:34])=[CH:30][CH:31]=2)[N:26]=[CH:25][CH:24]=1>>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[N:8]1[CH2:13][CH2:12][N:11]([CH2:14][C:15]2[CH:20]=[CH:19][C:18]([NH:21][C:23]3[C:32]4[C:27](=[CH:28][C:29]([C:33]([F:36])([F:34])[F:35])=[CH:30][CH:31]=4)[N:26]=[CH:25][CH:24]=3)=[CH:17][CH:16]=2)[CH2:10][CH2:9]1
Reactant: FC(F)(F)c1ccc2c(Cl)ccnc2c1
Reactant: Nc1ccc(CN2CCN(c3ccccc3Cl)CC2)cc1
Product: FC(F)(F)c1ccc2c(Nc3ccc(CN4CCN(c5ccccc5Cl)CC4)cc3)ccnc2c1

Procedure:
In the manner given in Example 1C, 1-(o-chlorophenyl)-4-[(4-aminophenyl)methyl]piperazine and 4-chloro-7-(trifluoromethyl)quinoline are reacted together at reflux to give 4-[[4-[[4-(o-chlorophenyl)-1-piperazinyl]methyl]phenyl]amino]-7-(trifluoromethyl)quinoline.
Reaction SMILES: [CH2:1]([N:3]1[C:12]2[C:7](=[CH:8][C:9]([F:14])=[C:10](F)[CH:11]=2)[C:6](=[O:15])[C:5]([C:16]([OH:18])=[O:17])=[CH:4]1)[CH3:2].[NH:19]1[CH2:24][CH2:23][S:22][CH2:21][CH2:20]1.C(#N)C>CN(C)C=O>[CH2:1]([N:3]1[C:12]2[C:7](=[CH:8][C:9]([F:14])=[C:10]([N:19]3[CH2:24][CH2:23][S:22][CH2:21][CH2:20]3)[CH:11]=2)[C:6](=[O:15])[C:5]([C:16]([OH:18])=[O:17])=[CH:4]1)[CH3:2]
Reactant: C1CSCCN1
Reactant: CCn1cc(C(=O)O)c(=O)c2cc(F)c(F)cc21
Solvent: CN(C)C=O
Solvent: CC#N
Product: CCn1cc(C(=O)O)c(=O)c2cc(F)c(N3CCSCC3)cc21
Temperature: 25 °C
Yield: 65.8 %

Procedure:
A solution of 1.35 g (5.33 mmol) of 1-ethyl-6,7-difluoro-1,4-dihydro-4-oxo-3-quinolinecarboxylic acid, 1.34 ml (13.3 mmol) of thiomorpholine, 40 ml of acetonitrile, and 20 ml of N,N-dimethylformamide was heated under reflux for 21 hours. The reaction mixture was cooled to room temperature and the solid was collected by filtration, washed with water and acetonitrile, and dried to give 1.18 g of 1-ethyl-6-fluoro-1,4-dihydro-4-oxo-7-(4-thiomorpholinyl)-3-quinolinecarboxylic acid, mp 254°-6°.
Reaction SMILES: Cl[CH2:2][C:3]1[CH:8]=[CH:7][C:6]([CH:9]2[CH2:14][CH2:13][N:12]([C:15]([O:17][CH2:18][C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)=[O:16])[CH2:11][CH:10]2[O:25][CH2:26][C:27]2[CH:28]=[CH:29][C:30]3[O:35][CH2:34][CH2:33][N:32]([CH2:36][CH2:37][CH2:38][O:39][CH3:40])[C:31]=3[CH:41]=2)=[CH:5][CH:4]=1.[O:42]1[C:46]2[CH:47]=[CH:48][C:49]([OH:51])=[CH:50][C:45]=2[O:44][CH2:43]1>>[O:42]1[C:46]2[CH:47]=[CH:48][C:49]([O:51][CH2:2][C:3]3[CH:8]=[CH:7][C:6]([CH:9]4[CH2:14][CH2:13][N:12]([C:15]([O:17][CH2:18][C:19]5[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=5)=[O:16])[CH2:11][CH:10]4[O:25][CH2:26][C:27]4[CH:28]=[CH:29][C:30]5[O:35][CH2:34][CH2:33][N:32]([CH2:36][CH2:37][CH2:38][O:39][CH3:40])[C:31]=5[CH:41]=4)=[CH:5][CH:4]=3)=[CH:50][C:45]=2[O:44][CH2:43]1
Reactant: COCCCN1CCOc2ccc(COC3CN(C(=O)OCc4ccccc4)CCC3c3ccc(CCl)cc3)cc21
Reactant: Oc1ccc2c(c1)OCO2
Product: COCCCN1CCOc2ccc(COC3CN(C(=O)OCc4ccccc4)CCC3c3ccc(COc4ccc5c(c4)OCO5)cc3)cc21

Procedure:
Analogously to Method I, 0.150 g of benzyl 4-(4-chloromethylphenyl)-3-[4-(3-methoxypropyl)-3,4-dihydro-2H-benzo[1,4]oxazin-6-ylmethoxy]piperidine-1-carboxylate (Example 270b) and 0.0548 g of benzo[1,3]dioxol-5-ol are reacted. The title compound is obtained as a yellowish oil. Rf=0.18 (1:2 EtOAc-heptane); Rt=5.78.
Reaction SMILES: FC(F)(F)S(O[C:7]1[CH:16]=[C:15]2[C:10]([CH:11]([C:18]3[CH:23]=[CH:22][C:21]([Cl:24])=[CH:20][CH:19]=3)[CH2:12][N:13]([CH3:17])[CH2:14]2)=[CH:9][C:8]=1[F:25])(=O)=O.BrCC(C1C=CC(Cl)=CC=1)=O.[C:39]([C:42]1[CH:47]=[CH:46][C:45](B(O)O)=[CH:44][CH:43]=1)(=[O:41])[NH2:40].C(=O)([O-])[O-].[Cs+].[Cs+]>O.CN(C)C=O>[Cl:24][C:21]1[CH:22]=[CH:23][C:18]([CH:11]2[C:10]3[C:15](=[CH:16][C:7]([C:45]4[CH:46]=[CH:47][C:42]([C:39]([NH2:40])=[O:41])=[CH:43][CH:44]=4)=[C:8]([F:25])[CH:9]=3)[CH2:14][N:13]([CH3:17])[CH2:12]2)=[CH:19][CH:20]=1
Reactant: CN1Cc2cc(OS(=O)(=O)C(F)(F)F)c(F)cc2C(c2ccc(Cl)cc2)C1
Reactant: NC(=O)c1ccc(B(O)O)cc1
Agent: O=C(CBr)c1ccc(Cl)cc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: O
Solvent: CN(C)C=O
Product: CN1Cc2cc(-c3ccc(C(N)=O)cc3)c(F)cc2C(c2ccc(Cl)cc2)C1
Temperature: 90 °C
Yield: 31.5 %

Procedure:
A mixture of 4-(4-chlorophenyl)-6-fluoro-2-methyl-1,2,3,4-tetrahydroisoquinolin-7-yl trifluoromethanesulfonate (695 mg, 1.64 mmol) which was prepared using similar methods described in Step A to Step E of Example 26 starting from 2-bromo-1-(4-chlorophenyl)ethanone, 4-carbamoylphenylboronic acid (406 mg, 2.46 mmol) and cesium carbonate (1.6 mg, 4.92 mmol) in water (5 mL) and N,N-dimethylformamide (20 mL) was degassed with argon and then [1,1′-bis(diphenylphosphino)ferrocene]palladium(II) (59 mg, 0.08 mmol) was added. The mixture was degassed again and then heated to 90° C. for 2 hours. The mixture was partitioned between water and ethyl acetate (3×) and the combined organic extracts were washed with brine, dried over sodium sulfate, filtered, and concentrated. The residue was purified by preparative HPLC followed by preparative thin-layer chromatography (90:10:1 diethyl ether/methanol/concentrated ammonium hydroxide) to give 4-(4-(4-chlorophenyl)-6-fluoro-2-methyl-1,2,3,4-tetrahydroisoquinolin-7-yl)benzamide (204 mg, 32%) as an off-white solid: ESI MS m/z 395 [M+H]+.
Reaction SMILES: [OH:1][C:2]1[C:3]2[N:4]([C:13]([CH3:17])=[C:14]([CH3:16])[N:15]=2)[CH:5]=[C:6]([C:8]([O:10]CC)=[O:9])[CH:7]=1.[O:18]1[CH:20]2[CH2:21][C:22]3[C:27]([CH:19]12)=[CH:26][CH:25]=[CH:24][CH:23]=3.C(N(CC)CC)C.C(OCC)(=O)C>CO.O>[OH:18][C@@H:20]1[CH2:21][C:22]2[C:27](=[CH:26][CH:25]=[CH:24][CH:23]=2)[C@H:19]1[O:1][C:2]1[C:3]2[N:4]([C:13]([CH3:17])=[C:14]([CH3:16])[N:15]=2)[CH:5]=[C:6]([C:8]([OH:10])=[O:9])[CH:7]=1
Reactant: c1ccc2c(c1)CC1OC21
Reactant: CCOC(=O)c1cc(O)c2nc(C)c(C)n2c1
Solvent: CO
Solvent: CCOC(C)=O
Solvent: CCN(CC)CC
Product: Cc1nc2c(O[C@@H]3c4ccccc4C[C@H]3O)cc(C(=O)O)cn2c1C
Temperature: 50 °C
Reaction time: 0.5 h
Yield: 21.8 %

Procedure:
To a suspension of 7.3 g (31.2 mmol) ethyl 8-hydroxy-2,3-dimethyl-imidazo[1,2-a]pyridine-6-carboxylate and 7.3 g (55.2 mmol) 1,2-epoxyindane in 150 ml methanol and 15 ml water are added 8.8 ml triethylamine and the reaction mixture is heated to 50° C. for 20 h. After cooling down, 100 ml ethyl acetate are added and the precipitate is collected by filtration. A second crop of material crystallizes from the mother liquor on evaporation. The total amount of precipitate is 6.0 g, which is suspended in a mixture of 100 ml dioxane and 60 ml 2N aqueous sodium hydroxide. After boiling under reflux for 1 h, the reaction mixture is evaporated to ⅓ of its volume and diluted with 15 ml methanol. The flask is placed in an ice bath and the pH is adjusted to pH=7 by adding 6N hydrochloric acid. After 30 min, the thick suspension is diluted with 20 ml methanol and filtered by suction. A second crop of material is obtained by evaporation of the mother liquor. The total amount of crude product is 6.75 g. Further purification is achieved by filtration over silica gel using dichloromethane:methanol:acetic acid (13:1:0.2) as eluent. Crystallization from methanol/diethyl ether yields 2.3 g (22%) of the title compound as a colourless solid (m.p. 229-231° C.).
Reaction SMILES: [CH3:1][C:2]1([CH3:12])[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[NH:5][CH2:4][CH2:3]1.[N+:13]([O-])([O-:15])=[O:14].[K+].C([O-])([O-])=O.[Na+].[Na+]>OS(O)(=O)=O>[CH3:1][C:2]1([CH3:12])[C:11]2[C:6](=[CH:7][C:8]([N+:13]([O-:15])=[O:14])=[CH:9][CH:10]=2)[NH:5][CH2:4][CH2:3]1
Reactant: CC1(C)CCNc2ccccc21
Reactant: O=[N+]([O-])[O-]
Agent: O=C([O-])[O-]
Agent: O=S(=O)(O)O
Agent: [K+]
Product: CC1(C)CCNc2cc([N+](=O)[O-])ccc21
Temperature: 25 °C
Reaction time: 2 h
Yield: 50.9 %

Procedure:
To a mixture of 4,4-dimethyl-1,2,3,4-tetrahydro-quinoline (33 g, 0.2 mol) in H2SO4 (120 mL) was slowly added KNO3 (20.7 g, 0.2 mol) at 0° C. After addition, the mixture was stirred at room temperature for 2 h, carefully poured into ice water and basified with Na2CO3 to pH 8. The mixture was extracted with ethyl acetate (3×200 mL). The combined extracts were washed with water and brine, dried over Na2SO4 and concentrated to give 4,4-dimethyl-7-nitro-1,2,3,4-tetrahydro-quinoline (21 g, 50%).
Reaction SMILES: [CH:1]([C:3]1[CH:4]=[N:5][C:6]2[C:11]([CH:12]=1)=[CH:10][CH:9]=[C:8]([NH:13][C:14](=[O:23])[O:15][CH2:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)[CH:7]=2)=[O:2].C1COCC1.[BH4-].[Na+].Cl>O.CO>[OH:2][CH2:1][C:3]1[CH:4]=[N:5][C:6]2[C:11]([CH:12]=1)=[CH:10][CH:9]=[C:8]([NH:13][C:14](=[O:23])[O:15][CH2:16][C:17]1[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=1)[CH:7]=2
Reactant: O=Cc1cnc2cc(NC(=O)OCc3ccccc3)ccc2c1
Agent: Cl
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Solvent: C1CCOC1
Solvent: O
Product: O=C(Nc1ccc2cc(CO)cnc2c1)OCc1ccccc1
Temperature: 25 °C
Yield: 64.9 %

Procedure:
To a stirred mixture of benzyl 3-formylquinolin-7-ylcarbamate (2.0 g, 0.0065 mol), THF (50 mL), MeOH (50 mL), and water (50 mL) was added sodium tetrahydroborate (0.25 g, 0.0065 mol). The mixture was stirred at rt until LC-MS indicated no SM. The mixture was acidified with 1N HCl and concentrated under vacuum, and then treated with aq. NaHCO3 solution and EtOAc. The organic layer was separated and washed with brine, dried (Na2SO4), and evaporated. The residue was purified by column chromatography on silica gel using MeOH-EtOAc (0-10%) as eluent to give the product (1.3 g, 64%) as a light yellow solid. LC-MS: 1.83 min, 309.2 (M+1).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9]([C:11]2[C:12]([CH3:21])=[N:13][C:14]([C:17]([F:20])([F:19])[F:18])=[CH:15][CH:16]=2)=[O:10])=[CH:4][C:3]=1I.[NH2:23][C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][N:25]=1.CC(C)([O-])C.[K+]>C1(C)C=CC=CC=1.CCOCC.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd].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.[Fe+2]>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9]([C:11]2[C:12]([CH3:21])=[N:13][C:14]([C:17]([F:20])([F:19])[F:18])=[CH:15][CH:16]=2)=[O:10])=[CH:4][C:3]=1[NH:23][C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][N:25]=1
Reactant: Nc1ccccn1
Reactant: Cc1nc(C(F)(F)F)ccc1C(=O)Nc1ccc(Cl)c(I)c1
Agent: [Fe+2]
Agent: [Pd]
Agent: CC(C)(C)[O-]
Solvent: Cc1ccccc1
Solvent: CCOCC
Product: Cc1nc(C(F)(F)F)ccc1C(=O)Nc1ccc(Cl)c(Nc2ccccn2)c1
Temperature: 23 °C

Procedure:
N-(4-Chloro-3-iodophenyl)-6-(trifluoromethyl)-2-methylpyridine-3-carboxamide (220 mg, 0.5 mmol), 2-aminopyridine (40 mg, 0.42 mmol), potassium t-butoxide (66 mg, 0.59 mmol), Pd2(dba)3 (20 mg, 0.21 mmol), dppf (24 mg, 0.042 mmol) in toluene (2.1 mL) were heated to 100° C. for 1.5 days. The solution was cooled to 23° C., diluted with ether, filtered through celite, washed with ethyl acetate, and concentrated. Purified by reverse phase HPLC to yield N-(4-chloro-3-(pyridin-2-ylamino)phenyl)-6-(trifluoromethyl)-2-methylpyridine-3-carboxamide as a white solid: 1H NMR (CDCl3, 400 MHz) δ 11.53 (s, 1H), 9.68 (s, 1H), 8.05 (m, 2H), 7.85 (m, 2H), 7.55 (d, 1H), 7.26 (d, 1H), 7.13 (dd, 1H), 6.91 (t, 1H), 6.88 (d, 1H), 2.75 (s, 3H); MS (Q1) 407.0 (M)+.