Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C([O:3][CH:4](OCC)[CH2:5][O:6][C:7](=[O:16])[C:8]1[CH:13]=[CH:12][C:11]([O:14][CH3:15])=[CH:10][CH:9]=1)C.C(O)(C(F)(F)F)=O.O>C(Cl)Cl>[O:3]=[CH:4][CH2:5][O:6][C:7](=[O:16])[C:8]1[CH:13]=[CH:12][C:11]([O:14][CH3:15])=[CH:10][CH:9]=1
Reactant: CCOC(COC(=O)c1ccc(OC)cc1)OCC
Solvent: O
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: COc1ccc(C(=O)OCC=O)cc1
Temperature: 25 °C
Reaction time: 3.5 h
Yield: 100 %

Procedure:
A solution of 4-methoxybenzoic acid 2,2-diethoxy-ethyl ester (2b, 7.5 g, 28 mmol) in Cl2CH2 (75 ml) was treated with TFA (16.7 g, 11.3 ml, 140 mmol) and water (7.5 g, 7.5 ml, 28 mmol). The homogeneous solution was stirred for 3.5 hours at room temperature until GC showed complete reaction. The solution was concentrated in vacuo at 40° C. and then diluted with hexane and concentrated in vacuo several times to remove traces of TFA. The product, 4-methoxybenzoic acid 2-oxo-ethyl ester (2c, 5.9 g, 28 mmol, 100%) was isolated as an amorphous white solid and was used in the next step without any further purification. GC (Rt=11.0 min, 95%); 1H-NMR (CDCl3) δ: 9.72 (1H, s, HCO—), 8.06 (2H, d, J=8.8, ArH), 6.95 (2H, d, J=8.8, ArH), 4.87 (2H, s, HCOCH2O—), 3.87 (3H, s, OCH3).
Reaction SMILES: C(O)(C(F)(F)F)=O.C(O[C:13]([N:15](C)[C@H:16]1[C:24]2[C:19](=[CH:20][CH:21]=[C:22]([C:25]([O:27][CH3:28])=[O:26])[CH:23]=2)[CH2:18][CH2:17]1)=O)(C)(C)C>C(Cl)Cl>[CH3:13][NH:15][C@H:16]1[C:24]2[C:19](=[CH:20][CH:21]=[C:22]([C:25]([O:27][CH3:28])=[O:26])[CH:23]=2)[CH2:18][CH2:17]1
Reactant: COC(=O)c1ccc2c(c1)[C@H](N(C)C(=O)OC(C)(C)C)CC2
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CN[C@@H]1CCc2ccc(C(=O)OC)cc21
Reaction time: 1 h
Yield: 92 %

Procedure:
TFA (25 ml) was added dropwise at 0° C. to a solution of (R)-methyl 3-(tert-butoxycarbonyl-(methyl)amino)-2,3-dihydro-1H-indene-5-carboxylate (11.0 g, 36.60 mmol, 1.0 eq.) in DCM (100 ml) and stirring was carried out for 1 hour at RT. After monitoring by TLC, the reaction solution was concentrated under reduced pressure and the residue was taken up in sat. sodium hydrogen carbonate solution and extracted with ethyl acetate (3×1000 ml). The combined org. phases were dried over sodium sulfate, concentrated and used in the next stage without being purified further. Yield: 92% (6.8 g, 33.17 mmol).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:40])[C@@H:4]([NH:32][C:33](OC(C)(C)C)=O)[CH2:5][C:6]1[CH:31]=[CH:30][C:9]2[O:10][C@@H:11]([C:14]3[CH:19]=[CH:18][C:17]([O:20][CH2:21][C:22]4[CH:27]=[CH:26][C:25]([Cl:28])=[C:24]([Cl:29])[CH:23]=4)=[CH:16][CH:15]=3)[CH2:12][O:13][C:8]=2[CH:7]=1.[C:41]1([C@H:47](O)[CH2:48][CH2:49][CH3:50])[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=1.ClC1C=C(C=CC=1Cl)COC1C=CC([C@H]2COC3=CC4C[C@@H](C(O)=O)N([C@H](C5C=CC=CC=5)CCC)CC=4C=C3O2)=CC=1>>[CH3:1][O:2][C:3]([C@@H:4]1[CH2:5][C:6]2[CH:7]=[C:8]3[O:13][CH2:12][C@H:11]([C:14]4[CH:15]=[CH:16][C:17]([O:20][CH2:21][C:22]5[CH:27]=[CH:26][C:25]([Cl:28])=[C:24]([Cl:29])[CH:23]=5)=[CH:18][CH:19]=4)[O:10][C:9]3=[CH:30][C:31]=2[CH2:33][N:32]1[C@H:47]([C:41]1[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=1)[CH2:48][CH2:49][CH3:50])=[O:40]
Reactant: CCC[C@@H](O)c1ccccc1
Reactant: COC(=O)[C@H](Cc1ccc2c(c1)OC[C@H](c1ccc(OCc3ccc(Cl)c(Cl)c3)cc1)O2)NC(=O)OC(C)(C)C
Agent: CCC[C@@H](c1ccccc1)N1Cc2cc3c(cc2C[C@H]1C(=O)O)OC[C@H](c1ccc(OCc2ccc(Cl)c(Cl)c2)cc1)O3
Product: CCC[C@@H](c1ccccc1)N1Cc2cc3c(cc2C[C@H]1C(=O)OC)OC[C@H](c1ccc(OCc2ccc(Cl)c(Cl)c2)cc1)O3

Procedure:
(3S,8S)-3-[4-(3,4-Dichloro-benzyloxy)-phenyl]-7-((S)-1-phenyl-butyl)-2,3,6,7,8,9-hexahydro-[1,4]dioxino[2,3-g]isoquinoline-8-carboxylic acid methyl ester was synthesized from (S)-2-tert-butoxycarbonylamino-3-{(S)-2-[4-(3,4-dichloro-benzyloxy)-phenyl]-2,3-dihydro-benzo[1,4]dioxin-6-yl}-propionic acid methyl ester and (R)-1-phenyl-butane-1-ol according to General Procedure AC. This ester was converted to (3S,8S)-3-[4-(3,4-dichloro-benzyloxy)-phenyl]-7-((S)-1-phenyl-butyl)-2,3,6,7,8,9-hexahydro-[1,4]dioxino[2,3-g]isoquinoline-8-carboxylic acid according to General Procedure AB.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]([OH:11])=[C:6]([C:8](=[O:10])[CH3:9])[CH:7]=1.[CH:12](=O)[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1>C(O)C.O>[Br:1][C:2]1[CH:7]=[C:6]2[C:5](=[CH:4][CH:3]=1)[O:11][CH:12]([C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)[CH2:9][C:8]2=[O:10]
Reactant: CC(=O)c1cc(Br)ccc1O
Reactant: O=Cc1ccccc1
Solvent: O
Solvent: CCO
Product: O=C1CC(c2ccccc2)Oc2ccc(Br)cc21
Yield: 20.8 %

Procedure:
A mixture of 1-(5-bromo-2-hydroxy-phenyl)-ethanone (29 g, 0.135 mol), benzaldehyde (14.3 g, 0.135 mol) and borax (51.5 g, 0.135 mol) in ethanol (180 mL) and H2O (300 mL) was refluxed for one day. The reaction mixture was cooled, diluted with an equal volume of H2O and extracted with ethyl acetate. The organic layer was dried over anhydrous Na2SO4, filtered, and evaporated to give 6-bromo-2-phenyl-chroman-4-one (8.5 g, 21%). 1H-NMR (CDCl3): 2.89 (dd, 1H), 3.06 (dd, 1H), 5.46 (dd, 1H), 6.95 (d, 1H), 7.37-7.46 (m, 5H), 7.58 (d, 1H), 8.02 (d, 1H).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:8](=[C:9]([NH:11][CH:12]3[CH2:16][CH2:15][CH2:14][CH2:13]3)[CH:10]=1)[NH:7][C:6]([C:17]1[S:18][CH2:19][C@@H:20]([CH2:22][C:23]([OH:25])=O)[N:21]=1)=[CH:5]2.[NH2:26][CH2:27][CH2:28][CH2:29][N:30]1[CH2:35][CH2:34][O:33][CH2:32][CH2:31]1>>[Cl:1][C:2]1[CH:3]=[C:4]2[C:8](=[C:9]([NH:11][CH:12]3[CH2:16][CH2:15][CH2:14][CH2:13]3)[CH:10]=1)[NH:7][C:6]([C:17]1[S:18][CH2:19][C@@H:20]([CH2:22][C:23]([NH:26][CH2:27][CH2:28][CH2:29][N:30]3[CH2:35][CH2:34][O:33][CH2:32][CH2:31]3)=[O:25])[N:21]=1)=[CH:5]2
Reactant: O=C(O)C[C@@H]1CSC(c2cc3cc(Cl)cc(NC4CCCC4)c3[nH]2)=N1
Reactant: NCCCN1CCOCC1
Product: O=C(C[C@@H]1CSC(c2cc3cc(Cl)cc(NC4CCCC4)c3[nH]2)=N1)NCCCN1CCOCC1
Yield: 35 %

Procedure:
The compound (50 mg, 0.13 mmol) prepared in Example 27 and 4-(3-aminopropyl)morpholine instead of morpholine were reacted according to the same procedure as Example 73 to give the title compound (23 mg, Yield 35%).
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]([C:9]2[N:18]=[CH:17][CH:16]=[CH:15][C:10]=2[C:11]([O:13]C)=[O:12])[CH:6]=[CH:7][CH:8]=1)#[N:2].O.[OH-].[Li+]>CO.O>[C:1]([C:3]1[CH:4]=[C:5]([C:9]2[N:18]=[CH:17][CH:16]=[CH:15][C:10]=2[C:11]([OH:13])=[O:12])[CH:6]=[CH:7][CH:8]=1)#[N:2]
Reactant: COC(=O)c1cccnc1-c1cccc(C#N)c1
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: N#Cc1cccc(-c2ncccc2C(=O)O)c1
Reaction time: 20 h
Yield: 92.7 %

Procedure:
Methyl 2-(3′-cyanophenyl)nicotinate (1.21 g, 5.1 mmol) was partially dissolved in MeOH (40 mL), and lithium hydroxide monohydrate (234 mg dissolved in 6 mL H2O, 5.6 mmol) was added. After 20 hours, the resulting solution was diluted with water and extracted with CHCl3. The aqueous was acidified to pH 4 with 1 M HCl and extracted several times with CHCl3. Solid sodium chloride was added to the aqueous solution and the solution was extracted with 5-10% MeOH/CHCl3. The organic extracts were combined, dried over Na2SO4, filtered, and evaporated to yield a white solid (1.06 g, 93%). 1H NMR (CDCl3): δ8.85 (dd, 1H, J=5.1, J′=1.5), 8.35 (dd, 1H, J=7.6, J′=1.4), 7.84 (s, 1H), 7.75 (m, 2H), 7.55 (t, 1H, J=7.7), 7.47 (m, 1H).
Reaction SMILES: [C:1]1([N:7]2[CH2:12][CH2:11][NH:10][CH2:9][CH2:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.Cl[CH2:14][CH2:15][CH:16]([OH:29])[CH2:17][O:18][C:19]1[CH:24]=[CH:23][CH:22]=[C:21]([C:25]([F:28])([F:27])[F:26])[CH:20]=1.C(=O)([O-])[O-].[Na+].[Na+]>C(O)CCC>[F:26][C:25]([F:27])([F:28])[C:21]1[CH:20]=[C:19]([CH:24]=[CH:23][CH:22]=1)[O:18][CH2:17][CH:16]([OH:29])[CH2:15][CH2:14][N:10]1[CH2:11][CH2:12][N:7]([C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=2)[CH2:8][CH2:9]1
Reactant: c1ccc(N2CCNCC2)cc1
Reactant: OC(CCCl)COc1cccc(C(F)(F)F)c1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCCCO
Product: OC(CCN1CCN(c2ccccc2)CC1)COc1cccc(C(F)(F)F)c1
Yield: 42.3 %

Procedure:
This compound was prepared according to the procedure of Example 78. A mixture of 2.4 g (0.015 mole) of 1-phenylpiperazine, 4.0 g (0.015 mole) of 4-chloro-1-(3-trifluoromethylphenoxy)-2-butanol and 5.3 g (0.05 mole) of anhydrous sodium carbonate in 100 ml of 1-butanol gave 2.5 g (42%) of a tan powder, m.p. 73°-74° C. Recrystallizing solvent used was ligroin.
Reaction SMILES: [C:1]1([C:7]2[CH:11]=[C:10]([C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=3)[N:9]([CH2:18][C:19]3[CH:28]=[CH:27][C:22]([C:23](OC)=[O:24])=[CH:21][C:20]=3[O:29][CH:30]([CH3:32])[CH3:31])[N:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[H-].[Al+3].[Li+].[H-].[H-].[H-].O.O.O.O.O.O.O.O.O.O.S([O-])([O-])(=O)=O.[Na+].[Na+]>O1CCCC1>[C:1]1([C:7]2[CH:11]=[C:10]([C:12]3[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=3)[N:9]([CH2:18][C:19]3[CH:28]=[CH:27][C:22]([CH2:23][OH:24])=[CH:21][C:20]=3[O:29][CH:30]([CH3:32])[CH3:31])[N:8]=2)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: COC(=O)c1ccc(Cn2nc(-c3ccccc3)cc2-c2ccccc2)c(OC(C)C)c1
Agent: O=S(=O)([O-])[O-]
Agent: [Al+3]
Agent: [H-]
Solvent: O
Solvent: C1CCOC1
Product: CC(C)Oc1cc(CO)ccc1Cn1nc(-c2ccccc2)cc1-c1ccccc1
Temperature: 0 °C
Yield: 90.9 %

Procedure:
To a solution of methyl 4-[(3,5-diphenyl-1H-pyrazol-1-yl)methyl]-3-isopropoxybenzoate (0.59 g, 1.38 mmol) in tetrahydrofuran (12 mL) was added lithium aluminum hydride (52 mg, 1.38 mmol) under stirring at 0° C., and the mixture was stirred at the same temperature for 2.5 hr. After completion of the reaction, sodium sulfate decahydrate (0.89 g, 2.76 mmol) was added to the reaction mixture, and the mixture was stirred at room temperature for 2 hr. The insoluble material was filtered off, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (hexane/ethyl acetate=5/1-hexane/ethyl acetate=1/1) to give the title compound (0.50 g, yield 92%) as a colorless oil.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][C:10]2[C:18]([O:19][CH3:20])=[CH:17][CH:16]=[CH:15][C:11]=2[C:12]([OH:14])=[O:13])[CH:5]=[CH:6][CH:7]=1.[H][H]>[Pd].[O-]S([O-])(=O)=O.[Ba+2].CO>[Cl:1][C:2]1[CH:3]=[C:4]([CH2:8][CH2:9][C:10]2[C:18]([O:19][CH3:20])=[CH:17][CH:16]=[CH:15][C:11]=2[C:12]([OH:14])=[O:13])[CH:5]=[CH:6][CH:7]=1
Reactant: [H][H]
Reactant: COc1cccc(C(=O)O)c1C=Cc1cccc(Cl)c1
Agent: [Pd]
Agent: O=S(=O)([O-])[O-]
Agent: [Ba+2]
Solvent: CO
Product: COc1cccc(C(=O)O)c1CCc1cccc(Cl)c1
Yield: 87 %

Procedure:
For the synthesis of the title compound, 6.0 g of 2-[2-(3-chlorophenyl)-vinyl]-3-methoxybenzoic acid, 0.6 g of Pd/BaSO4 (5%), 4 l of hydrogen and 150 ml of methanol are employed in method J (variant 1). Yield: 87%; m.p.: 91° C.; C16H15ClO3 (Mr=290.75)
Reaction SMILES: C([O:3][C:4](=[O:24])[CH2:5][CH:6]1[O:10][B:9]([OH:11])[C:8]2[CH:12]=[C:13]([O:17][C:18]3[S:22][N:21]=[C:20]([Cl:23])[N:19]=3)[CH:14]=[C:15]([CH3:16])[C:7]1=2)C.[Li+].[OH-].Cl>C1COCC1.O>[Cl:23][C:20]1[N:19]=[C:18]([O:17][C:13]2[CH:14]=[C:15]([CH3:16])[C:7]3[CH:6]([CH2:5][C:4]([OH:24])=[O:3])[O:10][B:9]([OH:11])[C:8]=3[CH:12]=2)[S:22][N:21]=1
Reactant: CCOC(=O)CC1OB(O)c2cc(Oc3nc(Cl)ns3)cc(C)c21
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: Cc1cc(Oc2nc(Cl)ns2)cc2c1C(CC(=O)O)OB2O
Temperature: 25 °C
Reaction time: 2 h
Yield: 11.7 %

Procedure:
To a solution of [6-(3-chloro-[1,2,4]thiadiazol-5-yloxy)-1-hydroxy-4-methyl-1,3-dihydro-benzo[c][1,2]oxaborol-3-yl]-acetic acid ethyl ester (135 mg, 0.502 mmol) in THF (5 mL) and H2O (2 mL) was added LiOH (0.105 g, 2.50 mmol). The resulting solution was stirred at room temperature for 2 hrs. The mixture was diluted with H2O and acidified to pH 3 with 1N HCl at 0° C. The resulting mixture was extracted with ethyl acetate. The organic phase was separated, dried (Na2SO4), and concentrated. The crude mixture was purified by prep HPLC to give title compound (20 mg, 18%) as a white solid. 1H NMR (CD3OD) δ7.42 (d, 1H), 7.29 (d, 1H), 5.66 (dd, 1H), 3.20 (dd, 1H), 2.40 (s, 3H), 2.36 (dd, 1H). MS found: (M+H)+: 341.
Reaction SMILES: [NH2:1][CH2:2][CH:3]1[CH2:8][N:7]2[N:9]=[C:10]([C:15]3[CH:20]=[CH:19][C:18]([O:21][C:22]4[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=4)=[CH:17][CH:16]=3)[C:11]([C:12]([NH2:14])=[O:13])=[C:6]2[NH:5][CH2:4]1.[C:28](Cl)(=[O:31])[CH:29]=[CH2:30]>>[C:28]([NH:1][CH2:2][CH:3]1[CH2:8][N:7]2[N:9]=[C:10]([C:15]3[CH:20]=[CH:19][C:18]([O:21][C:22]4[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=4)=[CH:17][CH:16]=3)[C:11]([C:12]([NH2:14])=[O:13])=[C:6]2[NH:5][CH2:4]1)(=[O:31])[CH:29]=[CH2:30]
Reactant: C=CC(=O)Cl
Reactant: NCC1CNc2c(C(N)=O)c(-c3ccc(Oc4ccccc4)cc3)nn2C1
Product: C=CC(=O)NCC1CNc2c(C(N)=O)c(-c3ccc(Oc4ccccc4)cc3)nn2C1

Procedure:
The desired product was prepared form 6-(aminomethyl)-2-(4-phenoxyphenyl)-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrimidine-3-carboxamide and acryloyl chloride using the procedure similar to that for compound 8. 1H NMR (400 MHz, DMSO-d6) δ 8.31 (t, J=5.6 Hz, 1H), 7.51 (d, J=8.8 Hz, 2H), 7.46-7.38 (m, 2H), 7.17 (t, J=7.6 Hz, 1H), 7.08 (d, J=7.6 Hz, 2H), 7.04 (d, J=8.8 Hz, 2H), 6.61 (s, 1H), 6.25 (dd, J=17.1, 10.1 Hz, 1H), 6.11 (dd, J=17.1, 2.2 Hz, 1H), 5.62 (dd, J=10.1, 2.2 Hz, 1H), 4.07 (dd, J=12.4, 6.0 Hz, 1H), 3.73 (dd, J=12.4, 8.0 Hz, 1H), 3.41-3.34 (m, 1H), 3.27-3.21 (m, 2H), 3.09-2.96 (m, 1H), 2.37-2.24 (m, 1H). MS (ESI) m/e [M+1]+ 417.9.
Reaction SMILES: [C:1]([C:4]1[CH:5]=[C:6]([N:15]2[CH2:20][CH2:19][O:18][CH2:17][CH2:16]2)[CH:7]=[C:8]([O:13][CH3:14])[C:9]=1[N+:10]([O-])=O)([CH3:3])=[CH2:2]>CO>[CH:1]([C:4]1[CH:5]=[C:6]([N:15]2[CH2:20][CH2:19][O:18][CH2:17][CH2:16]2)[CH:7]=[C:8]([O:13][CH3:14])[C:9]=1[NH2:10])([CH3:3])[CH3:2]
Reactant: C=C(C)c1cc(N2CCOCC2)cc(OC)c1[N+](=O)[O-]
Solvent: CO
Product: COc1cc(N2CCOCC2)cc(C(C)C)c1N
Reaction time: 16 h

Procedure:
A solution of 4-(3-isopropenyl-5-methoxy-4-nitro-phenyl)-morpholine (3.0 g, 10.7 mmol) in methanol (170 ml) is degassed and flushed with argon for 20 min. To the reaction mixture is added 10% palladium on carbon (1.1 g) and the resulting mixture is hydrogenated in a par shaker (50 psi) for 16 h. After completion of reaction (monitored by TLC), the mixture is filtered through a pad of celite. The filtrate is concentrated in vacuo yielding (2-isopropyl-6-methoxy-4-morpholin-4-yl-phenyl)-amine. The crude material is used in the next step without further purification (2.3 g, 9.2 mmol, 86%).
Reaction SMILES: [F:1][C:2]1[C:10]([O:11][C:12]2[C:21]3[C:16](=[CH:17][C:18]([O:24][CH2:25][CH2:26][CH2:27][N:28]4[CH2:33][CH2:32][NH:31][CH2:30][CH2:29]4)=[C:19]([O:22][CH3:23])[CH:20]=3)[N:15]=[CH:14][N:13]=2)=[CH:9][CH:8]=[C:7]2[C:3]=1[CH:4]=[C:5]([CH3:34])[NH:6]2.FC(F)(F)S(O[CH2:41][C:42]([F:45])([F:44])[F:43])(=O)=O>CO>[F:1][C:2]1[C:10]([O:11][C:12]2[C:21]3[C:16](=[CH:17][C:18]([O:24][CH2:25][CH2:26][CH2:27][N:28]4[CH2:33][CH2:32][N:31]([CH2:41][C:42]([F:45])([F:44])[F:43])[CH2:30][CH2:29]4)=[C:19]([O:22][CH3:23])[CH:20]=3)[N:15]=[CH:14][N:13]=2)=[CH:9][CH:8]=[C:7]2[C:3]=1[CH:4]=[C:5]([CH3:34])[NH:6]2
Reactant: COc1cc2c(Oc3ccc4[nH]c(C)cc4c3F)ncnc2cc1OCCCN1CCNCC1
Reactant: O=S(=O)(OCC(F)(F)F)C(F)(F)F
Solvent: CO
Product: COc1cc2c(Oc3ccc4[nH]c(C)cc4c3F)ncnc2cc1OCCCN1CCN(CC(F)(F)F)CC1
Yield: 44 %

Procedure:
Using an analogous procedure to that described for the preparation of Example 14, 4-[(4-fluoro-2-methyl-1H-indol-5-yl)oxy]-6-methoxy-7-(3-piperazin-1-ylpropoxy)quinazoline (250 mg, 0.54 mmol) was reacted with 2,2,2-trifluoroethyl trifluoromethanesulphonate (128 mg, 0.59 mmol) and purified by column chromatography, eluting with 5% methanol/methylene chloride to give a sticky solid. The sticky solid was dissolved in methanol and absorbed onto an Isolute SCX column. The column was washed with methanol and eluted with 7N ammonia in methanol. The product was triturated in ether/isohexane and filtered to give 4-[(4-fluoro-2-methyl-1H-indol-5-yl)oxy]-6-methoxy-7-{3-[4-(2,2,2-trifluoroethyl)piperazin-1-yl]propoxy}quinazoline (130 mg, 44%).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][NH:11][C:10]([CH2:16][C:17]2[CH:22]=[CH:21][C:20]([F:23])=[CH:19][C:18]=2[F:24])([CH:14]=O)[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[O-]S([O-])(=O)=O.[Mg+2].CN.CC([O-])=O.[Na+].[BH3-][C:39]#[N:40].[Na+]>COCCOC.CO>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][NH:11][C:10]([CH2:16][C:17]2[CH:22]=[CH:21][C:20]([F:23])=[CH:19][C:18]=2[F:24])([CH2:14][NH:40][CH3:39])[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)OC(=O)N1CCNC(C=O)(Cc2ccc(F)cc2F)C1
Reactant: [BH3-]C#N
Agent: CC(=O)[O-]
Agent: CN
Agent: O=S(=O)([O-])[O-]
Solvent: COCCOC
Solvent: CO
Product: CNCC1(Cc2ccc(F)cc2F)CN(C(=O)OC(C)(C)C)CCN1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of the aldehyde of Example 198, Step A (340 mg, 1 mmol) in dry DME (10 mL) was added about 250 mg MgSO4 followed by methyl amine (1 mL of a 2.0 M solution in MeOH, 2 equiv). The reaction was monitored by MS for the consumption of aldehyde and formation of the corresponding imine (+APcl (M+1)+ 354). Once imine formation was complete, NaOAc (820 mg, 10 mmol) and NaCNBH3 (248 mg, 4 mmol) were added and the mixture was stirred at room temperature for 1 h. The mixture was filtered through Celite® and the filtrate was concentrated. The resulting residue was taken up in EtOAc (25 mL) and washed with 1 N NaOH and brine solutions, respectively. The organic phase was dried over MgSO4 and concentrated to deliver the crude amine (306 mg). Purification by flash chromatography (SiO2 gel, 3:1:0.2 EtOAc:Hexane:EtOH) delivered 210 mg (59%) of the diamine of Example 198, Step B: +APcl MS (M+1)+ 356, (M−tBu+1)+ 300, (M−Boc+1)+ 256; 1H NMR=400 MHz (CDCl3) δ: 7.21 (m, 1H), 6.81 (m, 2H), 2.51 (br s, 3H), 1.42 (s, 9H).
Reaction SMILES: [CH3:1][C:2]1[C:6]([CH2:7][N:8]2[CH:12]=[C:11]([N:13]3[C:17](=[O:18])[CH2:16][NH:15][C:14]3=[O:19])[CH:10]=[N:9]2)=[C:5]([CH3:20])[O:4][N:3]=1.[F:21][C:22]1[CH:30]=[CH:29][CH:28]=[CH:27][C:23]=1[CH2:24][CH2:25]Br>>[CH3:1][C:2]1[C:6]([CH2:7][N:8]2[CH:12]=[C:11]([N:13]3[C:17](=[O:18])[CH2:16][N:15]([CH2:25][CH2:24][C:23]4[CH:27]=[CH:28][CH:29]=[CH:30][C:22]=4[F:21])[C:14]3=[O:19])[CH:10]=[N:9]2)=[C:5]([CH3:20])[O:4][N:3]=1
Reactant: Fc1ccccc1CCBr
Reactant: Cc1noc(C)c1Cn1cc(N2C(=O)CNC2=O)cn1
Product: Cc1noc(C)c1Cn1cc(N2C(=O)CN(CCc3ccccc3F)C2=O)cn1
Yield: 24 %

Procedure:
Prepared as in example 10-52 from 3-(1-((3,5-dimethylisoxazol-4-yl)methyl)-1H-pyrazol-4-yl)imidazolidine-2,4-dione (example 10-1) and 2-fluorophenethyl bromide. Yield: 24%. MS M+H calculated 398.16. Found 398.1. The title compound was shown to inhibit hT2R08 bitter receptor and had an IC50 of 0.13 μM.
Reaction SMILES: [F:1][C:2]1[CH:8]=[CH:7][C:5]([NH2:6])=[CH:4][CH:3]=1.CO[CH:11]1[CH2:15][CH2:14][CH:13](OC)O1>C(O)(=O)C>[F:1][C:2]1[CH:8]=[CH:7][C:5]([N:6]2[CH:11]=[CH:15][CH:14]=[CH:13]2)=[CH:4][CH:3]=1
Reactant: Nc1ccc(F)cc1
Reactant: COC1CCC(OC)O1
Solvent: CC(=O)O
Product: Fc1ccc(-n2cccc2)cc1
Temperature: 0 °C
Yield: 72.4 %

Procedure:
4-Fluoroaniline (117 g) and 2,5-dimethoxytetrahydrofuran (139 g) were added to acetic acid (120 ml), stirred at reflux temperature for an hour and then the reaction solution was poured into ice water (1 l). The precipitated solid was filtered, dissolved in methanol and water was added therein. The precipitated solid was collected again by filtration to give 1-(4-fluorophenyl)pyrrole (122.7 g).
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].[NH:7]1[CH:11]=[CH:10][N:9]=[CH:8]1.Br[CH2:13][C:14]1[CH:21]=[CH:20][C:17]([C:18]#[N:19])=[C:16]([CH3:22])[CH:15]=1>C1COCC1>[N:7]1([CH2:13][C:14]2[CH:21]=[CH:20][C:17]([C:18]#[N:19])=[C:16]([CH3:22])[CH:15]=2)[CH:11]=[CH:10][N:9]=[CH:8]1
Reactant: c1c[nH]cn1
Reactant: Cc1cc(CBr)ccc1C#N
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1CCOC1
Product: Cc1cc(Cn2ccnc2)ccc1C#N
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 58 %

Procedure:
To the suspension of potassium carbonate (2.16 g, 15.7 mmol) in THF at room temperature was added imidazole (4.27 g, 62.8 mmol). The mixture was stirred at room temperature for 10 minutes then 4-(bromomethyl)-2-methylbenzonitrile (CAS 1001055-64-6) (6.6 g, 31.4 mmol) was added and refluxed for 24 hours. The mixture was then cooled to room temperature. Potassium carbonate was filtered off. The filtrate was concentrated and residue was redissolved in dichloromethane. The dichloromethane phase was washed with water (three times) and then HCl (three times). To the combined HCl phase was added sodium carbonate (solid) and extracted with ethyl acetate. Ethyl acetate phase was washed with water and brine, dried over sodium sulfate and concentrated. Column chromatography (10% methanol/ethyl acetate) gave 4-((1H-imidazol-1-yl)methyl)-2-methylbenzonitrile (3.59 g, 58%) as a white solid.
Reaction SMILES: [CH:1]12[CH2:6][CH:5]1[CH2:4][N:3]([C:7]1[N:12]=[C:11]([NH:13][CH2:14][C:15]3[CH:20]=[CH:19][C:18]([O:21][CH3:22])=[C:17]([Cl:23])[CH:16]=3)[C:10]([C:24]([OH:26])=O)=[CH:9][N:8]=1)[CH2:2]2.[OH:27][C@H:28]1[CH2:33][CH2:32][C@H:31]([NH2:34])[CH2:30][CH2:29]1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C>C1COCC1>[CH:1]12[CH2:6][CH:5]1[CH2:4][N:3]([C:7]1[N:12]=[C:11]([NH:13][CH2:14][C:15]3[CH:20]=[CH:19][C:18]([O:21][CH3:22])=[C:17]([Cl:23])[CH:16]=3)[C:10]([C:24]([NH:34][C@H:31]3[CH2:32][CH2:33][C@H:28]([OH:27])[CH2:29][CH2:30]3)=[O:26])=[CH:9][N:8]=1)[CH2:2]2
Reactant: COc1ccc(CNc2nc(N3CC4CC4C3)ncc2C(=O)O)cc1Cl
Reactant: N[C@H]1CC[C@H](O)CC1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: C1CCOC1
Solvent: CCN(C(C)C)C(C)C
Product: COc1ccc(CNc2nc(N3CC4CC4C3)ncc2C(=O)N[C@H]2CC[C@H](O)CC2)cc1Cl
Reaction time: 8 h

Procedure:
In THF (20 mL) were dissolved 2-(3-azabicyclo[3.1.0]hexan-3-yl)-4-((3-chloro-4-methoxybenzyl)amino)pyrimidine-5-carboxylic acid (180 mg, 0.48 mmol), trans-4-hydroxycyclohexylamine (66 mg, 0.58 mmol) and HATU (220 mg, 0.58 mmol). The solution was cooled in an ice bath and DIEA (0.25 mL, 1.44 mmol) was added then. The reaction was conducted at ambient temperature for 8 h, followed by concentration, addition of water and extraction with ethyl acetate. The organic phase was dried, concentrated and purified by silica gel column chromatography (DCM/methanol=20/1) to give 2-(3-azabicyclo[3.1.0]hexan-3-yl)-4-((3-chloro-4-methoxybenzyl)amino)-N-(trans-4-hydroxycyclohexanyl)pyrimidine-5-formamide (141 mg, 62% yield).
Reaction SMILES: Cl.Cl.[NH2:3][CH2:4][C:5]([C:7]1[CH:8]=[CH:9][CH:10]=[C:11]2[C:16]=1[N:15]=[CH:14][CH:13]=[C:12]2[C:17]([NH:19][CH3:20])=[O:18])=[CH2:6].[H][H]>CO.[Pd]>[NH2:3][CH2:4][CH:5]([C:7]1[CH:8]=[CH:9][CH:10]=[C:11]2[C:16]=1[N:15]=[CH:14][CH:13]=[C:12]2[C:17]([NH:19][CH3:20])=[O:18])[CH3:6]
Reactant: [H][H]
Reactant: C=C(CN)c1cccc2c(C(=O)NC)ccnc12
Agent: [Pd]
Agent: Cl
Solvent: CO
Product: CNC(=O)c1ccnc2c(C(C)CN)cccc12
Yield: 79.8 %

Procedure:
As shown in step 9-viii of Scheme 9, 8-[1-(aminomethyl)vinyl]-N-methyl-quinoline-4-carboxamide, dihydrochloride (compound 2036, 168.8 g, 537 mmol) was stirred in MeOH (1.688 L) and TEA (114.2 g, 157.3 mL, 1.129 mol) was added, followed by the addition of 5% Pd on BaSO4 (22.88 g, 10.75 mmol). The atmosphere of the reaction mixture was replaced with hydrogen gas and the reaction stirred at under 1 atmosphere of hydrogen atmosphere for 16 hours. After this time, the hydrogen atmosphere was removed and the mixture filtered through diatomaceous earth, concentrated under reduced pressure, and treated with 800 mL water and 250 mL DCM. The resulting biphasic mixture was stirred vigorously until most of the solids had dissolved, resulting in a thick mixture that separates on standing. The pH of the aqueous layer was checked and found to be pH=8. This layer was washed with 3×500 mL DCM, the pH adjusted to 14 with 500 mL 6N NaOH, and extracted with an additional 500 mL DCM. The aqueous solution was then treated with 500 g NaCl and it was extracted with an additional 500 mL DCM. The combined organics were dried over Na2SO4, filtered, and concentrated under reduced pressure to provide 8-(1-aminopropan-2-yl)-N-methylquinoline-4-carboxamide [compound 2037 (racemic mixture) 104.2 g, 80% yield]: LC-MS=244.43 (M+H); 1H NMR (300 MHz, methanol-d4) δ 8.94 (d, J=4.3 Hz, 1H), 8.02 (dd, J=8.3, 1.6 Hz, 1H), 7.72-7.59 (m, 2H), 7.50 (d, J=4.3 Hz, 1H), 4.30 (h, J=7.0 Hz, 1H), 3.04 (dd, J=12.7, 7.0 Hz, 1H), 3.01 (s, 3H), 2.90 (dd, J=12.7, 6.9 Hz, 1H), 1.40 (d, J=7.1 Hz, 3H).