Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1]N1C(=O)CCC1=O.[NH2:9][C:10]([NH:12][C:13]1[NH:14][C:15]2[C:20]([C:21]=1[C:22]([NH2:24])=[O:23])=[CH:19][CH:18]=[C:17]([O:25][CH3:26])[CH:16]=2)=[O:11]>CN(C)C=O.O>[NH2:9][C:10]([NH:12][C:13]1[NH:14][C:15]2[C:20]([C:21]=1[C:22]([NH2:24])=[O:23])=[CH:19][C:18]([Br:1])=[C:17]([O:25][CH3:26])[CH:16]=2)=[O:11]
Reactant: O=C1CCC(=O)N1Br
Reactant: COc1ccc2c(C(N)=O)c(NC(N)=O)[nH]c2c1
Solvent: CN(C)C=O
Solvent: O
Product: COc1cc2[nH]c(NC(N)=O)c(C(N)=O)c2cc1Br
Reaction time: 1.5 h
Yield: 30 %

Procedure:
Under ice-cooling, a solution of N-bromosuccinimide (94 mg, 0.53 mmol) in anhydrous N,N-dimethylformamide (1 mL) was added to a solution of 2-aminocarbonylamino-6-methoxyindole-3-carboxamide (Compound No.1-1, 126 mg, 0.51 mmol) in anhydrous N,N-dimethylformamide (1.5 mL) and the mixture was stirred for 1.5 hours. Moreover the whole was stirred for 2 hours at room temperature and stirred for 3 hours at 50° C. After the reaction solution was diluted with water (60 mL) and extracted with ethyl acetate (50 mL), the organic layer was washed with brine (50 mL) and dried over anhydrous magnesium sulfate. After the solvent was removed under reduced pressure, the obtained solid was filtered off and washed with a mixed solvent of diethyl ether-chloroform solution (5:1, 24 mL). The solid was dried at 40° C. under reduced pressure to give the title compound (50 mg) as a gray solid (30%).
Reaction SMILES: [F:1][C:2]1[CH:13]=[CH:12][C:5]([CH2:6][NH:7][CH2:8][CH:9]([CH3:11])[CH3:10])=[CH:4][CH:3]=1.[O-]S(C(F)(F)F)(=O)=O.[N:22]1([S:27](N2C=C[N+](C)=C2)(=[O:29])=[O:28])[CH:26]=[CH:25][N:24]=[CH:23]1>CC#N>[F:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:6][N:7]([CH2:8][CH:9]([CH3:11])[CH3:10])[S:27]([N:22]2[CH:26]=[CH:25][N:24]=[CH:23]2)(=[O:29])=[O:28])=[CH:12][CH:13]=1
Reactant: C[n+]1ccn(S(=O)(=O)n2ccnc2)c1
Reactant: CC(C)CNCc1ccc(F)cc1
Agent: O=S(=O)([O-])C(F)(F)F
Solvent: CC#N
Product: CC(C)CN(Cc1ccc(F)cc1)S(=O)(=O)n1ccnc1
Yield: 32 %

Procedure:
A solution of (4-fluoro-benzyl)-isobutyl-amine (500 mg, 2.76 mmol) in MeCN (20 mL) was treated with 3-(imidazole-1-sulfonyl)-1-methyl-3H-imidazol-1-ium triflate (1.49 g, 4.14 mmol) and heated at reflux for 18 hours. The cooled reaction mixture was concentrated under vacuum and purified by silica gel chromatography (0-50% EtOAc in DCM) to afford the title compound (275 mg, 32%) as a pale yellow oil. 1H NMR (300 MHz, CDCl3) δ 7.95 (s, 1H), 7.17 (m, 4H), 7.02 (m, 2H), 4.40 (s, 2H), 3.01 (d, J=7.6 Hz, 2H), 1.77 (m, 1H), 0.80 (d, J=6.6 Hz, 6 H). LCMS (m/z, Method A) ES+ 312.0 [M+1]+.
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][C:5]([O:25][CH3:26])=[C:6]([C:8]2[CH:13]=[CH:12][N:11]=[C:10]3[NH:14][C:15]([C:17]4[CH2:18][C@@H:19]([CH2:23][OH:24])[NH:20][CH2:21][CH:22]=4)=[CH:16][C:9]=23)[CH:7]=1.C(N(C(C)C)C(C)C)C.Cl[CH2:37][C:38]([N:40]([CH3:42])[CH3:41])=[O:39]>CN(C)C=O>[F:1][C:2]1[CH:3]=[CH:4][C:5]([O:25][CH3:26])=[C:6]([C:8]2[CH:13]=[CH:12][N:11]=[C:10]3[NH:14][C:15]([C:17]4[CH2:18][C@@H:19]([CH2:23][OH:24])[N:20]([CH2:37][C:38]([N:40]([CH3:42])[CH3:41])=[O:39])[CH2:21][CH:22]=4)=[CH:16][C:9]=23)[CH:7]=1
Reactant: CN(C)C(=O)CCl
Reactant: COc1ccc(F)cc1-c1ccnc2[nH]c(C3=CCN[C@H](CO)C3)cc12
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: COc1ccc(F)cc1-c1ccnc2[nH]c(C3=CCN(CC(=O)N(C)C)[C@H](CO)C3)cc12
Temperature: 70 °C
Reaction time: 2 h

Procedure:
To a solution of Example 260H (150 mg, 0.352 mmol) in N,N-dimethylformamide (1.8 mL) was added N-ethyl-N-isopropylpropan-2-amine (227 mg, 1.759 mmol) and 2-chloro-N,N-dimethylacetamide (39.9 μL, 0.387 mmol). The mixture was stirred for 3 days at room temperature and for 2 hours at 70° C., and partitioned between water and ethyl acetate (three times). The extracts were dried over sodium sulfate, filtered, and concentrated, and the residue was purified by flash chromatography on silica gel, eluting with a gradient of 0-8% methanol/dichloromethane to afford the title compound. 1H NMR (400 MHz, DMSO-d6) δ 11.77 (s, 1H), 8.18 (d, J=5.0 Hz, 1H), 7.31-7.16 (m, 3H), 7.02 (d, J=5.0 Hz, 1H), 6.46 (s, 1H), 6.18 (d, J=1.8 Hz, 1H), 4.61 (t, J=5.3 Hz, 1H), 3.74 (s, 3H), 3.60-3.27 (m, 6H), 3.33 (s, 3H), 3.02 (s, 3H), 2.93 (dd, J=11.1, 5.7 Hz, 1H), 2.81 (s, 3H), 2.48-2.32 (m, 2H); MS (ESI+) m/z 439.0 (M+H)+.
Reaction SMILES: Br[C:2]1[N:3]=[C:4]([CH2:7][F:8])[S:5][CH:6]=1.[CH2:9]([C:13]1[N:14]=[C:15]2[CH:20]=[CH:19][C:18]([F:21])=[CH:17][N:16]2[CH:22]=1)[CH2:10][C:11]#[CH:12]>>[F:21][C:18]1[CH:19]=[CH:20][C:15]2[N:16]([CH:22]=[C:13]([CH2:9][CH2:10][C:11]#[C:12][C:2]3[N:3]=[C:4]([CH2:7][F:8])[S:5][CH:6]=3)[N:14]=2)[CH:17]=1
Reactant: C#CCCc1cn2cc(F)ccc2n1
Reactant: FCc1nc(Br)cs1
Product: FCc1nc(C#CCCc2cn3cc(F)ccc3n2)cs1
Yield: 49.8 %

Procedure:
The title compound was prepared in accordance with the general method of Example 190(F), from 4-bromo-2-(fluoromethyl)thiazole (84 mg, 0.43 mmol) and 2-(but-3-ynyl)-6-fluoro-imidazo[1,2-a]pyridine (compound 223(E), 80 mg, 0.43 mmol). The crude residue was purified over C18 chromatography (prepacked 35 g silicagel column, H2O/CH3CN: from 100/0 to 80/20 as eluent) to afford 65 mg of 6-fluoro-2-(4-(2-(fluoromethyl)thiazol-4-yl)but-3-ynyl)-imidazo[1,2-a]pyridine (Yield: 47%) as a beige powder (Mp=82-84° C.).
Reaction SMILES: [C:1]([C:3]1[C:4]([C:16]([F:19])([F:18])[F:17])=[C:5]2[C:9](=[CH:10][CH:11]=1)[N:8]([CH2:12][C:13]([OH:15])=O)[CH:7]=[CH:6]2)#[N:2].[Br:20][C:21]1[CH:22]=[C:23]([C:27]([NH:29][NH2:30])=O)[CH:24]=[N:25][CH:26]=1>>[Br:20][C:21]1[CH:22]=[C:23]([C:27]2[O:15][C:13]([CH2:12][N:8]3[C:9]4[C:5](=[C:4]([C:16]([F:19])([F:18])[F:17])[C:3]([C:1]#[N:2])=[CH:11][CH:10]=4)[CH:6]=[CH:7]3)=[N:30][N:29]=2)[CH:24]=[N:25][CH:26]=1
Reactant: NNC(=O)c1cncc(Br)c1
Reactant: N#Cc1ccc2c(ccn2CC(=O)O)c1C(F)(F)F
Product: N#Cc1ccc2c(ccn2Cc2nnc(-c3cncc(Br)c3)o2)c1C(F)(F)F

Procedure:
Synthesized as described in Example 35C from [5-cyano-4-(trifluoromethyl)-1H-indol-1-yl]acetic acid and 5-bromo-3-pyridinecarbohydrazide: MS (ES) m/z 448 and 450 (M+1 Br isotopes).
Reaction SMILES: [O:1]=[C:2]1[NH:8][CH:7]([CH2:9][CH:10]=[CH:11][C:12]2[O:16][C:15]([C:17]([O:19][CH3:20])=[O:18])=[CH:14][CH:13]=2)[CH2:6][CH2:5][CH2:4][CH2:3]1.F[B-](F)(F)F.[CH3:26][O+](C)C>C(Cl)Cl>[CH3:26][O:1][C:2]1[CH2:3][CH2:4][CH2:5][CH2:6][CH:7]([CH2:9][CH:10]=[CH:11][C:12]2[O:16][C:15]([C:17]([O:19][CH3:20])=[O:18])=[CH:14][CH:13]=2)[N:8]=1
Reactant: C[O+](C)C
Reactant: COC(=O)c1ccc(C=CCC2CCCCC(=O)N2)o1
Agent: F[B-](F)(F)F
Solvent: ClCCl
Product: COC(=O)c1ccc(C=CCC2CCCCC(OC)=N2)o1

Procedure:
The product of Example 177 is reacted with trimethyloxonium tetrafluoroborate in CH2Cl2 by the method of Example 3 to produce the title material.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6](Cl)[N:5]2[N:9]=[C:10]([C:12]3[CH:17]=[CH:16][C:15]([CH3:18])=[CH:14][CH:13]=3)[CH:11]=[C:4]2[N:3]=1.[NH:19]1[CH2:24][CH2:23][O:22][CH2:21][CH2:20]1>O1CCOCC1.O>[Cl:1][C:2]1[CH:7]=[C:6]([N:19]2[CH2:24][CH2:23][O:22][CH2:21][CH2:20]2)[N:5]2[N:9]=[C:10]([C:12]3[CH:17]=[CH:16][C:15]([CH3:18])=[CH:14][CH:13]=3)[CH:11]=[C:4]2[N:3]=1
Reactant: C1COCCN1
Reactant: Cc1ccc(-c2cc3nc(Cl)cc(Cl)n3n2)cc1
Solvent: O
Solvent: C1COCCO1
Product: Cc1ccc(-c2cc3nc(Cl)cc(N4CCOCC4)n3n2)cc1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 90 %

Procedure:
There was dissolved, in 1,4-dioxane (5 mL), 5,7-dichloro-2-(4-methylphenyl)-pyrazolo[1,5-a]pyrimidine (259 mg, 0.930 mM), morpholine (162 μL, 1.86 mM) was added to the resulting solution and then the mixture was stirred at room temperature for 15 minutes. The solvent was distilled off from the reaction mixture, the residue thus obtained was diluted with water and then extracted with methylene chloride. The extracts thus obtained were combined, dried over anhydrous sodium sulfate, the solvent was distilled off and the resulting solid was washed with methanol to thus give the title compound (274 mg, yield: 90%).
Reaction SMILES: [C:1]([N:5]1[C:9]([C:10]2[CH:15]=[CH:14][C:13]([O:16][CH3:17])=[CH:12][CH:11]=2)=[C:8]([C:18]2[S:19][CH:20]=[C:21](/[CH:23]=[CH:24]/[C:25]([O:27]CC)=[O:26])[N:22]=2)[CH:7]=[N:6]1)([CH3:4])([CH3:3])[CH3:2].[OH-].[Na+].Cl>C1COCC1.CO>[C:1]([N:5]1[C:9]([C:10]2[CH:11]=[CH:12][C:13]([O:16][CH3:17])=[CH:14][CH:15]=2)=[C:8]([C:18]2[S:19][CH:20]=[C:21](/[CH:23]=[CH:24]/[C:25]([OH:27])=[O:26])[N:22]=2)[CH:7]=[N:6]1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CCOC(=O)/C=C/c1csc(-c2cnn(C(C)(C)C)c2-c2ccc(OC)cc2)n1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Product: COc1ccc(-c2c(-c3nc(/C=C/C(=O)O)cs3)cnn2C(C)(C)C)cc1
Temperature: 60 °C
Reaction time: 3 h
Yield: 96.1 %

Procedure:
To a mixed solution of the compound (200 mg, 0.49 mmol) obtained in step 4 in THF (2 mL) and methanol (2 mL) was added 1N aqueous sodium hydroxide solution (0.972 ml, 0.97 mmol) at room temperature, and the mixture was stirred at 60° C. for 3 hr. The reaction mixture was cooled to room temperature, and 1N hydrochloric acid was added until the mixture became pH 2-3. The mixture was extracted with ethyl acetate, the organic layer was dried, and the solvent was evaporated under reduced pressure to give (E)-3-(2-(1-(tert-butyl)-5-(4-methoxyphenyl)-1H-pyrazol-4-yl)thiazol-4-yl)acrylic acid (180.7 mg, 0.471 mmol, 97%) as a white powder.
Reaction SMILES: [CH2:1]([C:3]1[O:7][C:6]([C:8]2[O:12][C:11]3[CH:13]=[CH:14][CH:15]=[C:16]([OH:17])[C:10]=3[CH:9]=2)=[N:5][CH:4]=1)[CH3:2].S(C1C=CC([N+]([O-])=O)=CC=1)(O[CH2:22][C@H:23]1[O:25][CH2:24]1)(=O)=O.C(=O)([O-])[O-].[K+].[K+]>>[CH2:1]([C:3]1[O:7][C:6]([C:8]2[O:12][C:11]3[CH:13]=[CH:14][CH:15]=[C:16]([O:17][CH2:22][C@H:23]4[O:25][CH2:24]4)[C:10]=3[CH:9]=2)=[N:5][CH:4]=1)[CH3:2]
Reactant: O=[N+]([O-])c1ccc(S(=O)(=O)OC[C@@H]2CO2)cc1
Reactant: CCc1cnc(-c2cc3c(O)cccc3o2)o1
Agent: O=C([O-])[O-]
Agent: [K+]
Product: CCc1cnc(-c2cc3c(OC[C@@H]4CO4)cccc3o2)o1
Yield: 99.7 %

Procedure:
By the reactions in the same manner as in Starting Material Synthesis Example 1 using 2-(5-ethyloxazol-2-yl)-4-hydroxybenzo(b)furan (1.10 g), (S)-glycidyl nosylate (1.24 g) and potassium carbonate (1.99 g), a crude product of the title compound (1.36 g) was obtained as pale-yellow crystals.
Reaction SMILES: [I:1]Cl.[Cl:3][C:4]1[CH:9]=[C:8]([C:10]([F:13])([F:12])[F:11])[CH:7]=[CH:6][C:5]=1[NH2:14].[OH-].[Na+]>Cl.O>[Cl:3][C:4]1[CH:9]=[C:8]([C:10]([F:12])([F:13])[F:11])[CH:7]=[C:6]([I:1])[C:5]=1[NH2:14]
Reactant: Nc1ccc(C(F)(F)F)cc1Cl
Reactant: ClI
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: Nc1c(Cl)cc(C(F)(F)F)cc1I
Temperature: 50 °C
Yield: 97.1 %

Procedure:
Iodine monochloride (17.2 g, 108 mmol) in hydrochloric acid (36%, 21.4 g) and water (35 mL) was added dropwise to 2-chloro-4-(trifluoromethyl)benzenamine (20.0 g, 102 mmol) in hydrochloric acid (36%, 20.7 g) and water (140 mL). The mixture was warmed to 50° C. for a total of 8 h. Sodium hydroxide (50%, 33.5 g, 419 mmol) was added to the mixture at room temperature. The mixture was extracted with dichloromethane (2×250 mL), and the extracts were dried and evaporated to give the product as an oil (31.83 g, 97% yield).
Reaction SMILES: [N:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[N:4]=[CH:3][C:2]=1[O:11][C:12]1[CH:24]=[CH:23][C:15]([O:16][CH:17]([CH3:22])[C:18]([O:20]C)=[O:19])=[CH:14][CH:13]=1.[OH-].[K+]>O.CO>[N:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[N:4]=[CH:3][C:2]=1[O:11][C:12]1[CH:13]=[CH:14][C:15]([O:16][CH:17]([CH3:22])[C:18]([OH:20])=[O:19])=[CH:23][CH:24]=1
Reactant: COC(=O)C(C)Oc1ccc(Oc2cnc3ccccc3n2)cc1
Agent: [K+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: CC(Oc1ccc(Oc2cnc3ccccc3n2)cc1)C(=O)O
Temperature: 25 °C
Reaction time: 8 h

Procedure:
3.2 g (0.01 mole) Methyl 2-[4-(2-quinoxalinyloxy)phenoxy]propanoate was added to a solution of 0.7 g (0.01 mole) potassium hydroxide in 5 cc water and 60 cc methanol. The mixture was stirred at room temperature overnight and then filtered to remove a small amount of insoluble material. The methanol was removed under vacuum. Ice and hydrochloric acid were added to the mixture until it was acidic (pH~2). The precipitated acid was filtered and purified by redissolution into saturated sodium bicarbonate solution, reprecipitation by acidification with dilute hydrochloric acid and crystallization from methanol. Yield 0.7 g, m.p. 137°-141°.
Reaction SMILES: [C:1]([CH2:5][CH2:6][C:7]([NH:9][C:10]1[C:11](=[CH:15][CH:16]=[C:17]([Cl:19])[CH:18]=1)[C:12]([O-:14])=O)=[O:8])([O:3][CH3:4])=[O:2].[Na]>C1(C)C=CC=CC=1>[CH3:4][O:3][C:1]([CH:5]1[C:12](=[O:14])[C:11]2[CH:15]=[CH:16][C:17]([Cl:19])=[CH:18][C:10]=2[NH:9][C:7](=[O:8])[CH2:6]1)=[O:2]
Reactant: COC(=O)CCC(=O)Nc1cc(Cl)ccc1C(=O)[O-]
Agent: [Na]
Solvent: Cc1ccccc1
Product: COC(=O)C1CC(=O)Nc2cc(Cl)ccc2C1=O

Procedure:
The solution of 264 g of N-(3-carbomethoxypropionyl)-4-chloroanthranilate in 1.8 lt of warm toluene is added dropwise to the hot suspension of 42.6 g of sodium in 900 ml of toluene while stirring and the mixture is refluxed for 5 hours. It is cooled, filtered, the residue taken up in 6 lt of water, the pH of the solution adjusted to 3 with 3N hydrochloric acid, the precipitate formed filtered off, washed with water and recrystallized from acetic acid, to yield the 8-chloro-2,3,4,5-tetrahydro-1-benzazepine-2,5-dione-4-carboxylic acid methyl ester melting at 270°-272°.
Reaction SMILES: [CH3:1][N:2]1[C:11](=[O:12])[C:10]2[NH:9][CH:8]=[N:7][C:6]=2[N:5]([CH3:13])[C:3]1=[O:4].C(=O)([O-])[O-].[K+].[K+].[CH3:20][C:21]1[CH:36]=[CH:35][C:24]([C:25]([C:27]2[CH:34]=[CH:33][C:30]([CH2:31]Br)=[CH:29][CH:28]=2)=[O:26])=[CH:23][CH:22]=1>CN(C=O)C.O>[CH3:20][C:21]1[CH:36]=[CH:35][C:24]([C:25]([C:27]2[CH:28]=[CH:29][C:30]([CH2:31][N:9]3[C:10]4[C:11](=[O:12])[N:2]([CH3:1])[C:3](=[O:4])[N:5]([CH3:13])[C:6]=4[N:7]=[CH:8]3)=[CH:33][CH:34]=2)=[O:26])=[CH:23][CH:22]=1
Reactant: Cn1c(=O)c2[nH]cnc2n(C)c1=O
Reactant: Cc1ccc(C(=O)c2ccc(CBr)cc2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: Cc1ccc(C(=O)c2ccc(Cn3cnc4c3c(=O)n(C)c(=O)n4C)cc2)cc1
Yield: 45.9 %

Procedure:
A solution of 1,3-dimethylxanthine (99 mg), potassium carbonate (135 mg), 4-(4-methylbenzoyl)benzyl bromide (201 mg) in DMF (10 ml) was stirred at 60° C. for 5 hours. This reaction mixture was poured in water and extracted with ethyl acetate. The extract was washed with water, dried, and concentrated. The residue was purified by silica gel column chromatography (hexane: ethyl acetate =1:5) and recrystallized from ethyl acetate-isopropyl ether to provide the title compound as colorless solid (98 mg).
Reaction SMILES: [CH2:1]1[O:9][C:8]2[CH:7]=[CH:6][C:5]([CH2:10][C:11]([O:13][CH3:14])=[O:12])=[CH:4][C:3]=2[O:2]1.Cl[Sn](Cl)(Cl)Cl.[O:20]1[CH:24]=[CH:23][CH:22]=[C:21]1[C:25](Cl)=[O:26]>C(Cl)Cl>[O:20]1[CH:24]=[CH:23][CH:22]=[C:21]1[C:25]([C:6]1[CH:7]=[C:8]2[O:9][CH2:1][O:2][C:3]2=[CH:4][C:5]=1[CH2:10][C:11]([O:13][CH3:14])=[O:12])=[O:26]
Reactant: O=C(Cl)c1ccco1
Reactant: COC(=O)Cc1ccc2c(c1)OCO2
Agent: Cl[Sn](Cl)(Cl)Cl
Solvent: ClCCl
Product: COC(=O)Cc1cc2c(cc1C(=O)c1ccco1)OCO2
Yield: 52 %

Procedure:
The title compound was prepared from methyl 3,4-methylenedioxyphenylacetate (336 mg, 1.73 mmol) in CH2Cl2 (10 mL), SnCl4 (1.0M solution in CH2Cl2 ; 2.8 mL, 2.8 mmol) and 2-furoyl chloride (200 μL, 1.92 mmol) as a solid (120 mg, 52% yield at 46% conversion). 1H NMR (CDCl3) 7.68 (brs, 1H), 7.17 (s, 1H), 7.11 (d, 1H, J=3.5), 6.83 (s, 1H), 6.57 (m, 1H), 6.06 (s, 2H), 3.78 (s, 2H), 3.64 (s, 3H).
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]([F:27])=[C:6]([CH2:8][CH2:9][N:10]2[CH2:15][CH2:14][N:13]([C:16]3[CH:25]=[CH:24][CH:23]=[C:22]4[C:17]=3[CH:18]=[CH:19][C:20]([CH3:26])=[N:21]4)[CH2:12][CH2:11]2)[CH:7]=1.[CH3:28][C:29]([CH3:34])([CH3:33])[C:30]([NH2:32])=[O:31]>>[F:27][C:5]1[CH:4]=[CH:3][C:2]([NH:32][C:30](=[O:31])[C:29]([CH3:34])([CH3:33])[CH3:28])=[CH:7][C:6]=1[CH2:8][CH2:9][N:10]1[CH2:15][CH2:14][N:13]([C:16]2[CH:25]=[CH:24][CH:23]=[C:22]3[C:17]=2[CH:18]=[CH:19][C:20]([CH3:26])=[N:21]3)[CH2:12][CH2:11]1
Reactant: CC(C)(C)C(N)=O
Reactant: Cc1ccc2c(N3CCN(CCc4cc(Br)ccc4F)CC3)cccc2n1
Product: Cc1ccc2c(N3CCN(CCc4cc(NC(=O)C(C)(C)C)ccc4F)CC3)cccc2n1
Yield: 52 %

Procedure:
The title compound was prepared in 52% yield according to the general procedure for the preparation of amides, ureas and carbamates (Method A) starting from 5-{4-[2-(5-bromo-2-fluorophenyl)ethyl]-1-piperazinyl}-2-methylquinoline and 2,2-dimethylpropanamide.
Reaction SMILES: [C:1](O)(=[O:11])[C:2]1[CH:10]=[CH:9][C:5]([C:6]([NH2:8])=[O:7])=[CH:4][CH:3]=1.[CH2:13]1[C@H:22]2[C@H:17]([CH2:18][CH2:19][C:20]3[CH:26]=[CH:25][CH:24]=[CH:23][C:21]=32)[NH:16][CH2:15][CH2:14]1>>[CH2:13]1[C@H:22]2[C@H:17]([CH2:18][CH2:19][C:20]3[CH:26]=[CH:25][CH:24]=[CH:23][C:21]=32)[N:16]([C:1]([C:2]2[CH:10]=[CH:9][C:5]([C:6]([NH2:8])=[O:7])=[CH:4][CH:3]=2)=[O:11])[CH2:15][CH2:14]1
Reactant: c1ccc2c(c1)CC[C@@H]1NCCC[C@H]21
Reactant: NC(=O)c1ccc(C(=O)O)cc1
Product: NC(=O)c1ccc(C(=O)N2CCC[C@@H]3c4ccccc4CC[C@@H]32)cc1
Yield: 58 %

Procedure:
The title compound is prepared from terephthalamic acid and cis-1,2,3,4,4a,5,6,10b-octahydro-benzo[f]quinoline following a procedure analogous to that described in Example 1. Yield: 58% of theory; LC (method 1): tR=3.16 min; Mass spectrum (ESI+): m/z=335 [M+H]+.
Reaction SMILES: [CH2:1]([O:8][CH2:9][C:10]([F:19])([F:18])[CH2:11][CH2:12]OS(C)(=O)=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:20]1(=[O:30])[NH:24][C:23](=[O:25])[C:22]2=[CH:26][CH:27]=[CH:28][CH:29]=[C:21]12.[K]>CN(C=O)C>[CH2:1]([O:8][CH2:9][C:10]([F:19])([F:18])[CH2:11][CH2:12][N:24]1[C:23](=[O:25])[C:22]2=[CH:26][CH:27]=[CH:28][CH:29]=[C:21]2[C:20]1=[O:30])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CS(=O)(=O)OCCC(F)(F)COCc1ccccc1
Reactant: O=C1NC(=O)c2ccccc21
Agent: [K]
Solvent: CN(C)C=O
Product: O=C1c2ccccc2C(=O)N1CCC(F)(F)COCc1ccccc1
Temperature: 100 °C

Procedure:
A mixture of 1-benzyloxy-2,2-difluoro-4-methanesulfonyloxybutane (63.44 g, 0.216 moles), potassium phthalimide (44 g, 0.238 moles) and dry DMF (500 mL), distilled from CaH2) is stirred and heated at 100° C. After a short time the mixture solidifies, and an additional dry DMF (500 mL) is added. Upon heating at 90°-100° C. for another 20 hours, salts are removed by filtration, and the DMF is distilled under vacuum (oil pump). The residue is dissolved in CH2Cl2 (800 mL) and washed with 1N KOH (twice) and 1N HCl (twice). Drying (Na2SO4) and evaporation yields N-(4-benzyloxy-3,3-difluorobutyl)-phthalimide as a yellow oil: 68.5 g (92%).
Reaction SMILES: [CH2:1]([NH:5][CH2:6][CH2:7][CH2:8][CH3:9])[CH2:2][CH2:3][CH3:4].[Cl:10][C:11]1[C:19]([S:20](Cl)(=[O:22])=[O:21])=[CH:18][C:14]([C:15]([OH:17])=[O:16])=[CH:13][CH:12]=1>C(Cl)Cl>[Cl:10][C:11]1[C:19]([S:20](=[O:22])(=[O:21])[N:5]([CH2:6][CH2:7][CH2:8][CH3:9])[CH2:1][CH2:2][CH2:3][CH3:4])=[CH:18][C:14]([C:15]([OH:17])=[O:16])=[CH:13][CH:12]=1
Reactant: CCCCNCCCC
Reactant: O=C(O)c1ccc(Cl)c(S(=O)(=O)Cl)c1
Solvent: ClCCl
Product: CCCCN(CCCC)S(=O)(=O)c1cc(C(=O)O)ccc1Cl
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To a solution of 3.9 g. (0.03 mole) of di-n-butylamine in 15 ml. of methylene chloride is added 2.5 g. (0.01 mole) of 4-chloro-5-chlorosulfonylbenzoic acid (J. Pharm. Pharmacol., 683 (1962), and the resulting reaction mixture allowed to stir at room temperature for 3 hrs. The solvent is removed under reduced pressure and the residue partitioned between 1N sodium hydroxide and diethyl ether. The aqueous phase is separated, acidified with 12N hydrochloric acid and the precipitated solid filtered and dried, 3.0 g., m.p. 93°-96° C. Recrystallization from ether-hexane provides the pure product, 2.5 g., m.p. 94.5°-96.5° C.
Reaction SMILES: [C:1]1([C:7](=O)[CH2:8][C:9]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=2[CH3:17])=O)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[NH2:19][NH2:20]>C(O)C>[C:1]1([C:7]2[CH:8]=[C:9]([C:11]3[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=3[CH3:17])[NH:20][N:19]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: NN
Reactant: Cc1ccccc1C(=O)CC(=O)c1ccccc1
Solvent: CCO
Product: Cc1ccccc1-c1cc(-c2ccccc2)n[nH]1

Procedure:
1-Phenyl-3-(o-tolyl)-1,3-propanedione (b.p. 170° C./0.01 mm Hg) is condensed with hydrazine in ethanol to give 3-phenyl-5-(o-tolyl)pyrazole, m.p. 112.5°-113.5° C.
Reaction SMILES: [C:1]1([CH2:7][C:8]([OH:10])=[O:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH:11](=O)[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1.C(OC(=O)C)(=O)C>>[C:1]1([C:7](=[CH:11][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[C:8]([OH:10])=[O:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: O=Cc1ccccc1
Reactant: O=C(O)Cc1ccccc1
Solvent: CC(=O)OC(C)=O
Product: O=C(O)C(=Cc1ccccc1)c1ccccc1

Procedure:
Phenyl acetic acid (1.94 g, 14.24 mmol) and benzaldehyde (1.491 g, 14.05 mmol), TEA (5 ml) and acetic anhydride (5 ml) were reacted to give 2,3-diphenyl-acrylic acid as similar procedure.
Reaction SMILES: [NH2:1][C:2]1[C:7]([C:8]#[N:9])=[C:6]([O:10][CH2:11][CH3:12])[N:5]=[C:4]([C:13]([OH:15])=O)[CH:3]=1.F[B-](F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2C=CC=CC=2N=N1.Cl.[NH2:39][CH2:40][CH2:41][S:42]([CH2:45]CN)(=[O:44])=[O:43].C(N(C(C)C)CC)(C)C>CN(C)C(=O)C>[NH2:1][C:2]1[C:7]([C:8]#[N:9])=[C:6]([O:10][CH2:11][CH3:12])[N:5]=[C:4]([C:13]([NH:39][CH2:40][CH2:41][S:42]([CH3:45])(=[O:44])=[O:43])=[O:15])[CH:3]=1
Reactant: CCOc1nc(C(=O)O)cc(N)c1C#N
Reactant: NCCS(=O)(=O)CCN
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: Cl
Agent: F[B-](F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CC(=O)N(C)C
Product: CCOc1nc(C(=O)NCCS(C)(=O)=O)cc(N)c1C#N
Temperature: 25 °C
Reaction time: 8 h

Procedure:
In a 20 mL vial a solution of Example 104A (32.5 mg, 0.16 mmol) dissolved in N,N-dimethylacetamide (0.8 mL) was added, followed by the addition of O-benzotriazol-1-yl-N,N,N′,N′-tetramethyluronium tetrafluoroborate (50.4 mg, 0.16 mmol) dissolved in N,N-dimethylacetamide (0.8 mL). Then, 2-aminoethylsulfone hydrocloride (30.3 mg, 0.19 mmol) dissolved in N,N-dimethylacetamide (0.6 mL) was added followed by the addition of diisopropyl ethyl amine (57.9 uL, 0.31 mmol) dissolved in N,N-dimethylacetamide (0.8 mL). The mixture was shaken at room temperature overnight. The reaction was checked by LC/MS and concentrated to dryness. The residue was dissolved in 1:1 dimethyl sulfoxide/methanol and purified by reverse phase (0-70% CH3CN in 10 mM aq. ammonium acetate) to give the titled compound. 1H NMR (500 MHz, DMSO-d6) δ ppm 1.26-1.38 (m, 3H) 2.93-3.08 (m, 3H) 3.29-3.47 (m, 2H) 3.72-3.80 (m, 2H) 4.30-4.61 (m, 2H) 7.05-7.09 (m, 1H); MS (ESI) positive ion 313 (M+H).
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]([CH:7]=[CH:8][CH:9]=1)[NH2:6])#[N:2]>CO.[Pd]>[NH2:6][C:5]1[CH:4]=[C:3]([CH:9]=[CH:8][CH:7]=1)[CH2:1][NH2:2]
Reactant: N#Cc1cccc(N)c1
Agent: [Pd]
Solvent: CO
Product: NCc1cccc(N)c1
Yield: 99.9 %

Procedure:
3-Cyanoaniline (0.50 g, 4.23 mmol) in 100 mL of MeOH was stirred overnight at room temperature under a H2 environment in the presence of 10% Pd/C (100 mg). The Pd/C was removed by filtration through a pad of Celilte, and the resulting filtrate was concentrated under reduced pressure to give 0.516 g (˜100%) of 44A as a thick oil. The product was used without any further purification.