Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([O:8][C:9]2[CH:10]=[CH:11][C:12]([NH:16][C:17]([N:19]3[CH2:23][CH2:22][N:21]([CH:24]4[CH2:29][CH2:28][O:27][CH2:26][CH2:25]4)[C:20]3=[O:30])=[O:18])=[N:13][C:14]=2[CH3:15])[CH:5]=[CH:4][N:3]=1.[C:31]([NH2:34])(=[O:33])[CH3:32].C([O-])([O-])=O.[Cs+].[Cs+].CC(C1C=C(C(C)C)C(C2C=CC=CC=2P(C2CCCCC2)C2CCCCC2)=C(C(C)C)C=1)C>O1CCOCC1.CCOC(C)=O.CC#N.O.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]>[C:31]([NH:34][C:2]1[CH:7]=[C:6]([O:8][C:9]2[CH:10]=[CH:11][C:12]([NH:16][C:17]([N:19]3[CH2:23][CH2:22][N:21]([CH:24]4[CH2:25][CH2:26][O:27][CH2:28][CH2:29]4)[C:20]3=[O:30])=[O:18])=[N:13][C:14]=2[CH3:15])[CH:5]=[CH:4][N:3]=1)(=[O:33])[CH3:32]
Reactant: Cc1nc(NC(=O)N2CCN(C3CCOCC3)C2=O)ccc1Oc1ccnc(Cl)c1
Reactant: CC(N)=O
Agent: [Pd]
Agent: CC(C)c1cc(C(C)C)c(-c2ccccc2P(C2CCCCC2)C2CCCCC2)c(C(C)C)c1
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: O
Solvent: CCOC(C)=O
Solvent: CC#N
Product: CC(=O)Nc1cc(Oc2ccc(NC(=O)N3CCN(C4CCOCC4)C3=O)nc2C)ccn1
Temperature: 80 °C
Reaction time: 16 h
Yield: 65.7 %

Procedure:
To a degassed solution of Example C3 (0.12 g, 0.278 mmol) in dioxane (3 mL) was added acetamide (0.066 g, 1.111 mmol), Cs2CO3 (0.091 g, 0.278 mmol), X-Phos (0.013 g, 0.028 mmol), Pd2(dba)3 (0.025 g, 0.028 mmol) and the mixture was stirred at 80° C. for 16 h. The mixture was diluted with EtOAc (5 mL) and filtered through a pad of diatomaceous earth. The filter pad was washed with EtOAc (3×8 mL). The combined filtrates were washed with water and brine, dried (Na2SO4) and concentrated in vacuo. The residue was purified by chromatography (0-5% MeOH/DCM) to afford a colorless foam. The foam was dissolved in MeCN-water and the solution was frozen and lyophilized to provide N-(5-((2-acetamidopyridin-4-yl)oxy)-6-methylpyridin-2-yl)-2-oxo-3-(tetrahydro-2H-pyran-4-yl)imidazolidine-1-carboxamide (83 mg, 66%) as a white solid. 1H NMR (400 MHz, DMSO-d6): δ 10.89 (s, 1 H), 10.54 (s, 1 H), 8.16 (d, J=5.7 Hz, 1 H), 7.88 (d, J=8.8 Hz, 1 H), 7.60 (d, J=8.8 Hz, 1 H), 7.57 (d, J=2.4 Hz, 1 H), 6.61 (dd, J=5.7, 2.4 Hz, 1 H), 3.93-3.78 (m, 5H), 3.48-3.33 (m, 4 H), 2.20 (s, 3 H), 2.02 (s, 3 H), 1.78-1.67 (m, 2 H), 1.64-1.58 (m, 2H); MS (ESI) m/z: 455.1 (M+H+).
Reaction SMILES: BrC1C=CC(C#N)=CC=1C.BrC1C=CC(C#N)=CC=1.[Br:20][C:21]1[CH:26]=[CH:25][C:24]([C:27]2[N:28]([C:37]3[CH:42]=[CH:41][C:40]([S:43]([CH3:46])(=[O:45])=[O:44])=[C:39]([F:47])[CH:38]=3)CC(O)(C(F)(F)F)[N:31]=2)=[CH:23][C:22]=1[CH3:48]>>[F:47][C:39]1[CH:38]=[C:37]([NH:28][C:27]([C:24]2[CH:25]=[CH:26][C:21]([Br:20])=[C:22]([CH3:48])[CH:23]=2)=[NH:31])[CH:42]=[CH:41][C:40]=1[S:43]([CH3:46])(=[O:45])=[O:44]
Reactant: Cc1cc(C2=NC(O)(C(F)(F)F)CN2c2ccc(S(C)(=O)=O)c(F)c2)ccc1Br
Agent: Cc1cc(C#N)ccc1Br
Agent: N#Cc1ccc(Br)cc1
Product: Cc1cc(C(=N)Nc2ccc(S(C)(=O)=O)c(F)c2)ccc1Br

Procedure:
The subtitle compound was prepared according to the procedure of Example 153 (step 1) using 4-bromo-3-methylbenzonitrile, instead of 4-bromobenzonitrile. 2-(4-Bromo-3-methylphenyl)-1-[3-fluoro-4-(methylsulfonyl)phenyl]-4-hydroxy-4-trifluoromethyl-4,5-dihydro-1H-imidazole. (step 2)
Reaction SMILES: [F:1][C:2]([F:26])([F:25])[C:3]1[N:8]2[N:9]=[CH:10][C:11]([C:12](O)=O)=[C:7]2[N:6]=[C:5]([C:15]2[CH:20]=[CH:19][C:18]([C:21]([F:24])([F:23])[F:22])=[CH:17][CH:16]=2)[CH:4]=1.[OH:27][NH:28][C:29](=[NH:40])[C:30]1[CH:35]=[CH:34][CH:33]=[C:32]([S:36](=[O:39])(=[O:38])[NH2:37])[CH:31]=1>>[F:26][C:2]([F:1])([F:25])[C:3]1[N:8]2[N:9]=[CH:10][C:11]([C:12]3[O:27][N:28]=[C:29]([C:30]4[CH:31]=[C:32]([S:36]([NH2:37])(=[O:38])=[O:39])[CH:33]=[CH:34][CH:35]=4)[N:40]=3)=[C:7]2[N:6]=[C:5]([C:15]2[CH:16]=[CH:17][C:18]([C:21]([F:24])([F:23])[F:22])=[CH:19][CH:20]=2)[CH:4]=1
Reactant: O=C(O)c1cnn2c(C(F)(F)F)cc(-c3ccc(C(F)(F)F)cc3)nc12
Reactant: N=C(NO)c1cccc(S(N)(=O)=O)c1
Product: NS(=O)(=O)c1cccc(-c2noc(-c3cnn4c(C(F)(F)F)cc(-c5ccc(C(F)(F)F)cc5)nc34)n2)c1

Procedure:
The title compound was prepared from 7-trifluoromethyl-5-(4-trifluoromethyl-phenyl)-pyrazolo[1,5-a]pyrimidine-3-carboxylic acid (example C.2) (188 mg, 0.5 mmol) and N-hydroxy-3-sulfamoyl-benzamidine [CAS-No. 9000-88-7] (161 mg, 0.75 mmol) according to general procedure II. Obtained after purification by column chromatography (dichloromethane/MeOH/NH4OH) and crystallization (ethyl acetate/MeOH/hexane) as a yellow solid (175 mg, 63%). MS (ISN) 552.8 [(M−H)−]; mp 262° C.
Reaction SMILES: [CH3:1][O-:2].[Na+].Cl[C:5]1[N:10]2[N:11]=[CH:12][N:13]=[C:9]2[N:8]=[C:7]([CH3:14])[CH:6]=1>CO>[CH3:1][O:2][C:5]1[N:10]2[N:11]=[CH:12][N:13]=[C:9]2[N:8]=[C:7]([CH3:14])[CH:6]=1
Reactant: Cc1cc(Cl)n2ncnc2n1
Reactant: C[O-]
Agent: [Na+]
Solvent: CO
Product: COc1cc(C)nc2ncnn12
Reaction time: 0.5 h

Procedure:
A 28% methanol solution of sodium methoxide, 2.52 g, is diluted with 50 ml of dry methanol To this, 2.00 g of 7-chloro-5-methyl-[1,2,4]triazolo[1,5-a]pyrimidine is added at room temperature and stirred for 30 minutes. The solvent is evaporated under reduced pressure and the residue is treated with water and extracted twice with dichloromethane. The combined extract is washed with saline and dried over anhydrous potassium carbonate. Evaporation of the solvent under reduced pressure gives 1.69 g of the desired compound as colorless crystals.
Reaction SMILES: C([BH-](C(CC)C)C(CC)C)(CC)C.[Li+].[CH2:15]([C:17]([C:35]1[CH:48]=[CH:47][C:38]([O:39][CH2:40][C:41](=[O:46])[C:42]([CH3:45])([CH3:44])[CH3:43])=[C:37]([CH3:49])[CH:36]=1)([C:20]1[CH:25]=[CH:24][C:23]([B:26]2[O:30][C:29]([CH3:32])([CH3:31])[C:28]([CH3:34])([CH3:33])[O:27]2)=[CH:22][CH:21]=1)[CH2:18][CH3:19])[CH3:16].C(=O)(O)[O-].[Na+]>O1CCCC1>[CH2:15]([C:17]([C:35]1[CH:48]=[CH:47][C:38]([O:39][CH2:40][CH:41]([OH:46])[C:42]([CH3:45])([CH3:44])[CH3:43])=[C:37]([CH3:49])[CH:36]=1)([C:20]1[CH:25]=[CH:24][C:23]([B:26]2[O:27][C:28]([CH3:33])([CH3:34])[C:29]([CH3:31])([CH3:32])[O:30]2)=[CH:22][CH:21]=1)[CH2:18][CH3:19])[CH3:16]
Reactant: CCC(CC)(c1ccc(B2OC(C)(C)C(C)(C)O2)cc1)c1ccc(OCC(=O)C(C)(C)C)c(C)c1
Agent: CCC(C)[BH-](C(C)CC)C(C)CC
Agent: O=C([O-])O
Agent: [Li+]
Solvent: C1CCOC1
Product: CCC(CC)(c1ccc(B2OC(C)(C)C(C)(C)O2)cc1)c1ccc(OCC(O)C(C)(C)C)c(C)c1
Reaction time: 0.5 h
Yield: 61.8 %

Procedure:
A solution of lithium tri-sec-butylborohydride in tetrahydrofuran (1.06 M, 0.178 mL, 0.189 mmol) was added to a solution of 1-(4-{1-ethyl-1-[4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-phenyl]-propyl}-2-methyl-phenoxy)-3,3-dimethyl-butan-2-one (Example 143-(4); 75.2 mg, 0.157 mmol) in tetrahydrofuran (3 mL) at −78° C., and the mixture was stirred for 30 minutes. The reaction mixture was then poured into a saturated aqueous sodium bicarbonate solution, followed by extraction with dichloromethane. The organic layer was dried over anhydrous magnesium sulfate, filtered and concentrated under reduced pressure. The resulting residue was purified by silica gel chromatography (hexane:ethyl acetate=2:1) to give the target compound as a colorless oil (46.6 mg, 62%).
Reaction SMILES: Br[C:2]1[C:3]([O:18][CH:19]2[CH2:22][CH2:21][CH2:20]2)=[C:4]2[C:9](=[C:10]([F:13])[C:11]=1[F:12])[N:8]([C:14](=[O:16])[CH3:15])[C@@H:7]([CH3:17])[CH2:6][CH2:5]2.C[C@H]1CCC2C(=CC=C([C:38]3[CH:39]=[N:40][N:41]([CH:43]4[CH2:48][CH2:47][NH:46][CH2:45][CH2:44]4)[CH:42]=3)C=2OCCC)N1C(=O)C>>[CH:19]1([O:18][C:3]2[C:2]([C:38]3[CH:39]=[N:40][N:41]([CH:43]4[CH2:48][CH2:47][NH:46][CH2:45][CH2:44]4)[CH:42]=3)=[C:11]([F:12])[C:10]([F:13])=[C:9]3[C:4]=2[CH2:5][CH2:6][C@H:7]([CH3:17])[N:8]3[C:14](=[O:16])[CH3:15])[CH2:22][CH2:21][CH2:20]1
Reactant: CCCOc1c(-c2cnn(C3CCNCC3)c2)ccc2c1CC[C@H](C)N2C(C)=O
Reactant: CC(=O)N1c2c(F)c(F)c(Br)c(OC3CCC3)c2CC[C@@H]1C
Product: CC(=O)N1c2c(F)c(F)c(-c3cnn(C4CCNCC4)c3)c(OC3CCC3)c2CC[C@@H]1C

Procedure:
(S)-1-(5-cyclobutoxy-7,8-difluoro-2-methyl-6-(1-(piperidin-4-yl)-1H-pyrazol-4-yl)-3,4-dihydroquinolin-1(2H)-yl)ethanone was synthesized from (S)-1-(6-bromo-5-cyclobutoxy-7,8-difluoro-2-methyl-3,4-dihydroquinolin-1(2H)-yl)ethanone according to the procedures described above in Steps 2 and 3 of the synthesis of (S)-1-(2-methyl-6-(1-(piperidin-4-yl)-1H-pyrazol-4-yl)-5-propoxy-3,4-dihydroquinolin-1(2H)-yl)ethanone (Example 4-1). 1H NMR (300 MHz, CD3OD) δ ppm 1.12-1.28 (m, 4H), 1.30-1.41 (m, 1H), 1.56-1.68 (m, 1H), 1.98-2.20 (m, 11H), 2.32-2.49 (m, 2H), 2.75-2.88 (m, 2H), 2.99-3.10 (m, 1H), 3.21-3.25 (m, 2H), 4.17-4.20 (m, 1H), 4.35-4.45 (m, 1H), 4.75-4.82 (m, 1H), 7.91 (s, 1H), 8.12 (s, 1H). MS (ESI, pos. ion) m/z 445 [M+H]+.
Reaction SMILES: [CH2:1]([NH:4][C:5](=[O:13])[C:6]1[CH:11]=[CH:10][CH:9]=[C:8](Br)[CH:7]=1)[CH2:2][CH3:3].[F:14][C:15]1[CH:20]=[CH:19][C:18](B(O)O)=[CH:17][CH:16]=1>>[CH2:1]([NH:4][C:5](=[O:13])[C:6]1[CH:11]=[CH:10][CH:9]=[C:8]([C:18]2[CH:19]=[CH:20][C:15]([F:14])=[CH:16][CH:17]=2)[CH:7]=1)[CH2:2][CH3:3]
Reactant: CCCNC(=O)c1cccc(Br)c1
Reactant: OB(O)c1ccc(F)cc1
Product: CCCNC(=O)c1cccc(-c2ccc(F)cc2)c1
Yield: 70 %

Procedure:
Using Preparation Method 2, N-n-propyl-3-bromobenzamide from Example 1A as reacted with 4-fluorophenylboronic acid. The resulting reaction mixture was purified using SiO2 with CH2Cl2/Petroleum Ether 80:20 to CH2Cl2/Ethyl Acetate 80:20 to give a white solid (70%). NMR 1H (ppm, CDCl3): 7.94 (t, J4=2.1 Hz, 1H), 7.66 (tt, J3=7.8 Hz, J4=0.9 Hz, 2H), 7.58-7.53 (m, 2H), 7.47 (t, J3=7.8 Hz, 1H), 7.13 (t, J3=9 Hz, 2H), 6.12 (br. s., 1H), 3.47-3.40 (m, 2H), 1.65 (sext., J3=7.5 Hz, 2H), 0.99 (t, J3=7.44 Hz, 3H).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:8](=[O:12])([O:10][CH3:11])N>[Cl-].[Zn+2].[Cl-].CO>[CH3:11][O:10][C:8](=[O:12])[NH:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: Nc1ccccc1
Reactant: COC(N)=O
Agent: [Cl-]
Agent: [Zn+2]
Solvent: CO
Product: COC(=O)Nc1ccccc1
Temperature: 190 °C
Yield: 82.3 %

Procedure:
838 g aniline, 676 g methyl carbamate, 1442 g methanol and 30.0 g anhydrous pulverized zinc chloride were introduced into the pressure vessel. The pressure vessel and the column were then purged with nitrogen. The mixture was subsequently heated (with stirring) to 190° C., and the top valve of the column was adjusted so that the pressure in the apparatus was just sufficient for the reactants to reach the reaction temperature. Ammonia which evolved was separated from the evaporating alcohol in the column and then removed from the top of the column. The reaction mixture was stirred for 6.5 hours at 190° C., while the ammonia which evolved was removed. The mixture was then cooled and removed from the pressure vessel after the pressure in the apparatus had been reduced. The mixture was filtered and then distilled at atmospheric pressure to remove the excess methanol. The product was then fractionally distilled at 0.2 m bar. 1120 g N-phenyl-carbamic acid methyl ester (82.3% of the theoretical yield) were collected and crystallized. The product had a melting point of 45° to 46° C.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([C:8]([C:13]2[N:14]=[CH:15][N:16]([C:18]([C:31]3[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=3)([C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=3)[C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)[CH:17]=2)([OH:12])[CH:9]([CH3:11])[CH3:10])[CH:5]=[CH:6][CH:7]=1.[F:37][C:38]1[CH:39]=[C:40](B(O)O)[CH:41]=[CH:42][CH:43]=1.C(=O)([O-])[O-].[Na+].[Na+]>C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[F:37][C:38]1[CH:43]=[C:42]([C:2]2[CH:7]=[CH:6][CH:5]=[C:4]([C:8]([C:13]3[N:14]=[CH:15][N:16]([C:18]([C:25]4[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=4)([C:19]4[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=4)[C:31]4[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=4)[CH:17]=3)([OH:12])[CH:9]([CH3:11])[CH3:10])[CH:3]=2)[CH:41]=[CH:40][CH:39]=1
Reactant: OB(O)c1cccc(F)c1
Reactant: CC(C)C(O)(c1cccc(Br)c1)c1cn(C(c2ccccc2)(c2ccccc2)c2ccccc2)cn1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Product: CC(C)C(O)(c1cccc(-c2cccc(F)c2)c1)c1cn(C(c2ccccc2)(c2ccccc2)c2ccccc2)cn1
Yield: 94.7 %

Procedure:
By the reaction in the same manner as in Example 4-(ii) using 1-(3-bromophenyl)-(1-trityl-1H-imidazol-4-yl)-2-methyl-1-propanol (2.62 g), 3-fluorophenylboronic acid (1.09 g), 2M aqueous sodium carbonate solution (19.5 ml) and tetrakis(triphenylphosphine)palladium(0) (281 mg), the yellow amorphous title compound (2.55 g) was obtained.
Reaction SMILES: C(OC([N:8]1[CH2:20][C@@H:19]([CH3:21])[N:18]2[C@H:10]([CH2:11][C:12]3[C:17]2=[N:16][CH:15]=[C:14]([F:22])[CH:13]=3)[CH2:9]1)=O)(C)(C)C.C([Li])(C)(C)C.[Cl:28]C(Cl)(Cl)C(Cl)(Cl)Cl>C1(C)C=CC=CC=1.CCCCC>[Cl:28][C:15]1[N:16]=[C:17]2[C:12](=[CH:13][C:14]=1[F:22])[CH2:11][C@H:10]1[N:18]2[C@H:19]([CH3:21])[CH2:20][NH:8][CH2:9]1
Reactant: C[C@@H]1CN(C(=O)OC(C)(C)C)C[C@H]2Cc3cc(F)cnc3N21
Reactant: ClC(Cl)(Cl)C(Cl)(Cl)Cl
Agent: [Li]C(C)(C)C
Solvent: Cc1ccccc1
Solvent: CCCCC
Product: C[C@@H]1CNC[C@H]2Cc3cc(F)c(Cl)nc3N21
Temperature: -78 °C
Reaction time: 0.5 h
Yield: 8.8 %

Procedure:
To a solution of 0.23 g (4R,9aR)-7-fluoro-4-methyl-3,4,9,9a-tetrahydro-1H-2,4a,5-triaza-fluorene-2-carboxylic acid tert-butyl ester (intermediate h of examples 54–61) in 5 mL toluene was added dropwise at −78° C. 1.4 mL of a ca 1.3 M solution of t-butyllithium in pentane. The mixture was stirred at −78° C. for 30 min. To the resulting mixture was added 0.3 g hexachloroethane and the mixture was stirred at −78° C. for 30 min and then allowed to thaw to 0° C. over ca 30 min. The reaction was quenched with 10% citric acid and the organic phase was separated and evaporated and the residue purified by chromatography on silica gel with heptane:ethyl acetate (4:1). The product fractions containing the two isomers and some starting material were evaporated and the residue was taken up in 1 mL trifluoroacetic acid and kept at room temperature for 30 min. The solvent was evaporated and the residue was purified by chromatography on silica gel with dichloromethane:methanol:ammonia (9:1:0.1). The product fractions containing the more polar isomer were collected evaporated and dried under high vacuum to yield 0.016 g (4R,9aR)-6-chloro-7-fluoro-4-methyl-1,2,3,4,9,9a-hexahydro-2,4a,5-triaza-fluorene as light brown gum.
Reaction SMILES: [OH:1][CH2:2][CH2:3][NH:4][CH2:5][CH2:6][NH:7][C:8]1[C:21]2[C:20](=[O:22])[C:19]3[C:14](=[C:15]([OH:24])[CH:16]=[CH:17][C:18]=3[OH:23])[C:13](=[O:25])[C:12]=2[C:11]([NH:26][CH2:27][CH2:28][NH:29][CH2:30][CH2:31][OH:32])=[CH:10][CH:9]=1.[F:33][C:34]([F:41])([F:40])[C:35]([O:37]CC)=O>CO>[OH:1][CH2:2][CH2:3][N:4]([CH2:5][CH2:6][NH:7][C:8]1[C:21]2[C:20](=[O:22])[C:19]3[C:14](=[C:15]([OH:24])[CH:16]=[CH:17][C:18]=3[OH:23])[C:13](=[O:25])[C:12]=2[C:11]([NH:26][CH2:27][CH2:28][N:29]([CH2:30][CH2:31][OH:32])[C:35](=[O:37])[C:34]([F:33])([F:40])[F:41])=[CH:10][CH:9]=1)[C:35](=[O:37])[C:34]([F:41])([F:40])[F:33]
Reactant: CCOC(=O)C(F)(F)F
Reactant: O=C1c2c(O)ccc(O)c2C(=O)c2c(NCCNCCO)ccc(NCCNCCO)c21
Solvent: CO
Product: O=C1c2c(O)ccc(O)c2C(=O)c2c(NCCN(CCO)C(=O)C(F)(F)F)ccc(NCCN(CCO)C(=O)C(F)(F)F)c21

Procedure:
A suspension of 1.50 g. of 1,4-bis[2-(2-hydroxyethylamino)ethylamino]-5,8-dihydroxyanthraquinone in 75 ml. of ethyl trifluoroacetate and 75 ml. of methanol is stirred for 10 minutes. Evaporation of the resulting solution in vacuo at 30° C. leaves a residue which is washed and macerated with methylene chloride, giving 2.11 g. of blue-black solid, m.p. 162° C.
Reaction SMILES: [CH2:1]([C:5]1[O:6][C:7]2[CH:15]=[CH:14][CH:13]=[CH:12][C:8]=2[C:9]=1[CH:10]=O)[CH2:2][CH2:3][CH3:4].Cl.[NH2:17][C:18]1[CH:23]=[CH:22][C:21]([OH:24])=[CH:20][CH:19]=1.C([BH3-])#N.[Na+]>CO>[CH2:1]([C:5]1[O:6][C:7]2[CH:15]=[CH:14][CH:13]=[CH:12][C:8]=2[C:9]=1[CH2:10][NH:17][C:18]1[CH:23]=[CH:22][C:21]([OH:24])=[CH:20][CH:19]=1)[CH2:2][CH2:3][CH3:4]
Reactant: CCCCc1oc2ccccc2c1C=O
Reactant: Nc1ccc(O)cc1
Agent: Cl
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CO
Product: CCCCc1oc2ccccc2c1CNc1ccc(O)cc1
Reaction time: 24 h

Procedure:
At ambient temperature, to a stirred solution containing 2-n-butylbenzofuran-3-carboxaldehyde (0.888 g, 4.77 mmol) and 4-aminophenol hydrochloride in MeOH (7 mL) was added sodium cyanoborohydride (0.330 g, 5.25 mmol). After 24 h, the reaction was carefully quenched with 3N HCl, diluted with H2O and extracted with CH2Cl2. The organic extracts were washed with sat. aq. NaHCO3, dried and concentrated. Purification on silica gel eluting with a 20 & 40% EtOAc/pet. ether step gradient gave the title compound as a pale yellow solid. 1H NMR (CDCl3) δ0.93 (t, 3H), 1.38 (sextet, 2H), 1.70 (quintet, 2H), 2.79 (t, 2H), 4.27 (s, 1H), 4.35 (br. s, 1H), 6.62 (d, 2H), 6.75 (d, 2H), 7.18-7.26 (m, 3H), 7.41 (d, 1H), 7.54 (d, 1H).
Reaction SMILES: [C:1]1([C:7]2[CH:12]=[CH:11][C:10]([C:13]([OH:15])=O)=[CH:9][N:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.Cl.CN(C)CCCN=C=NCC.ON1C2C=CC=CC=2N=N1.[F:38][C:39]([F:49])([F:48])[CH2:40][N:41]1[CH2:46][CH2:45][CH:44]([NH2:47])[CH2:43][CH2:42]1.CN1CCOCC1>CN(C)C(=O)C.O>[C:1]1([C:7]2[CH:12]=[CH:11][C:10]([C:13]([NH:47][CH:44]3[CH2:45][CH2:46][N:41]([CH2:40][C:39]([F:49])([F:38])[F:48])[CH2:42][CH2:43]3)=[O:15])=[CH:9][N:8]=2)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: NC1CCN(CC(F)(F)F)CC1
Reactant: O=C(O)c1ccc(-c2ccccc2)nc1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: O
Solvent: CN1CCOCC1
Solvent: CC(=O)N(C)C
Product: O=C(NC1CCN(CC(F)(F)F)CC1)c1ccc(-c2ccccc2)nc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 84.6 %

Procedure:
To a 250 mL 3-necked flask containing 2-phenyl-5-pyridinecarboxylic acid (2.75 g, 13.8 mmol) in N,N-dimethylacetamide (DMA, 35 mL) was added N-(3-dimethylaminopropyl)-N′-ethylcarbodiimide hydrochloride (EDAC/EDC*HCl, 2.95 g, 15.2 mmol), 1-hydroxybenzotriazole (HOBt. 1.89 g, 13.8 mmol), 1-(2,2,2-trifluoroethyl)piperidin-4-amine (3.36 g, 15.2 mmol) and 4-methylmorpholine (NMM, 3.8 mL, 34.5 mmol). After stirring at room temperature for 1 hour, the reaction was diluted with water (˜200 mL) and the resulting solid collected by filtration. The solid was washed with H2O (3×100 mL), collected and dried in a vacuum oven (45° C.) overnight to give the desired product (4.24 g). LCMS (ES+) 4.30 min (TIC, 75%; 1H NMR purity >95%); 1H NMR (400 MHz, DMSO-d6) □ ppm 1.46-1.65 (m, 2H) 1.77 (d, J=10.80 Hz, 2 H) 2.31-2.54 (m, 4H) 2.90 (d, J=11.53 Hz, 2H) 3.65-3.86 (m, 1H) 7.36-7.56 (m, 3H) 8.01 (d, J=8.24 Hz, 1H) 8.09 (d, J=6.95 Hz, 2H) 8.22 (d, J=8.42 Hz, 1H) 8.38 (d, J=7.32 Hz, 1H) 9.02 (s, 1 H); MS(ES+) 364 (M+1); HRMS (TOF, ES+) calculated for C19H20F3N3O+H+: 364.1637; observed 364.1611.
Reaction SMILES: [CH3:1][C:2]1[CH:11]=[C:10](Cl)[C:9]2[C:4](=[C:5]([CH3:13])[CH:6]=[CH:7][CH:8]=2)[N:3]=1.[NH:14]1[CH:18]=[N:17][CH:16]=[N:15]1.C(=O)(O)[O-].[Na+]>C(O)C.O>[N:14]1([C:10]2[C:9]3[C:4](=[C:5]([CH3:13])[CH:6]=[CH:7][CH:8]=3)[N:3]=[C:2]([CH3:1])[CH:11]=2)[CH:18]=[N:17][CH:16]=[N:15]1
Reactant: c1nc[nH]n1
Reactant: Cc1cc(Cl)c2cccc(C)c2n1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: CCO
Product: Cc1cc(-n2cncn2)c2cccc(C)c2n1
Reaction time: 2 h
Yield: 88.1 %

Procedure:
A mixture of 1.91 g of 2,8-dimethyl-4-chloro-quinoline and 1.38 g of 1,2,4-triazole is melt at 120° C. and stirred for 2 hours. The solidified melt is dissolved in a mixture of ethanol and water. The solution is poured into a solution of 0.84 g of sodium bicarbonate and 20 ml of water. The precipitated product is filtered. Thus 1.97 g of the desired compound are obtained, yield 88%, m.p.: 99°-100° C.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[S:6][C:7]([C:10]([OH:12])=O)=[CH:8][CH:9]=1)=[O:4].Cl.CN(C)CCCN=C=NCC.O.ON1C2C=CC=CC=2N=N1.C(N(CC)CC)C.[F:43][C:44]([F:64])([F:63])[O:45][C:46]1[CH:62]=[CH:61][C:49]([CH2:50][O:51][C:52]2[CH:57]=[CH:56][C:55]([CH:58]([NH2:60])[CH3:59])=[CH:54][CH:53]=2)=[CH:48][CH:47]=1>ClCCl>[CH3:1][O:2][C:3]([C:5]1[S:6][C:7]([C:10](=[O:12])[NH:60][CH:58]([C:55]2[CH:56]=[CH:57][C:52]([O:51][CH2:50][C:49]3[CH:61]=[CH:62][C:46]([O:45][C:44]([F:43])([F:63])[F:64])=[CH:47][CH:48]=3)=[CH:53][CH:54]=2)[CH3:59])=[CH:8][CH:9]=1)=[O:4]
Reactant: COC(=O)c1ccc(C(=O)O)s1
Reactant: CC(N)c1ccc(OCc2ccc(OC(F)(F)F)cc2)cc1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: O
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COC(=O)c1ccc(C(=O)NC(C)c2ccc(OCc3ccc(OC(F)(F)F)cc3)cc2)s1
Reaction time: 6.5 h
Yield: 60.4 %

Procedure:
To a solution of 160.0 mg (0.859 mmol) thiophene-2,5-dicarboxylic acid monomethyl ester in 25 ml dichloromethane were added 253.0 mg (1.293 mmol) N′-(3-dimethylaminopropyl)-N-ethylcarbodiimide hydrochloride, 175 mg (1.295 mmol) 1-hydroxybenzotriazole hydrate and 130.7 g (1.291 mmol) triethylamine. After 30 min at room temperature 268.0 mg (0.861 mmol) 1-[4-(4-trifluoromethoxy-benzyloxy)-phenyl]-ethylamine were added. The reaction mixture was stirred for 6.5 h. The solvent was evaporated, to the residue was added ethyl acetate and the organic phase was extracted with saturated aqueous NaHCO3 solution and with water. The organic phase was dried over MgSO4 and the solvent was evaporated. The residue was triturated with diisopropyl to provide 249 mg (0.519 mmol) 5-{1-[4-(4-trifluoromethoxy-benzyloxy)-phenyl]-ethylcarbamoyl}-thiophene-2-carboxylic acid methyl ester.
Reaction SMILES: [C:1]([C:4]1[S:5]C(Br)=C[CH:8]=1)(=O)[CH3:2].[Br:10][C:11]1[S:15][C:14]([C:16]([CH2:18][C:19]#[N:20])=[O:17])=[CH:13][CH:12]=1.N1CCOCC1.[S]>CC(=O)CC>[NH2:20][C:19]1[S:5][C:4]([CH3:8])=[C:1]([CH3:2])[C:18]=1[C:16]([C:14]1[S:15][C:11]([Br:10])=[CH:12][CH:13]=1)=[O:17]
Reactant: CC(=O)c1ccc(Br)s1
Reactant: N#CCC(=O)c1ccc(Br)s1
Agent: [S]
Solvent: CCC(C)=O
Solvent: C1COCCN1
Product: Cc1sc(N)c(C(=O)c2ccc(Br)s2)c1C
Yield: 51 %

Procedure:
The procedure of Example 1 was followed except that 2-acetyl-5-bromothiophene (Aldrich) was used in place of acetophenone to prepare the corresponding 2-(5-bromothiophene-2-carbonyl)acetonitrile (Steps A and B). 2-Butanone (Aldrich), 2-(5-bromothiophene-2-carbonyl)acetonitrile, morpholine, and sulfur were reacted according to the procedure of Step C, Example 1, to afford the desired compound. Yield: 51%; IR (KBr) cm−1: 3348, 1559, 1448, 1413, 1388, 1318, 1263, 974, 769; 1H NMR (CDCl3):δ2.16 (s, 6H), 5.90 (bs, 2H), 7.02 (d, J=4 Hz, 1H), 7.11 (d, 1H, J=4 Hz); orange solid, mp: 128-130° C. (petroleum ether).
Reaction SMILES: [Br:1][C:2]1[CH:11]=[C:10]([N+:12]([O-])=O)[C:9]([NH2:15])=[C:8]2[C:3]=1[CH2:4][CH2:5][N:6]([CH2:16][CH2:17][CH2:18][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)[CH2:7]2>C1COCC1.[Ni]>[Br:1][C:2]1[CH:11]=[C:10]([NH2:12])[C:9]([NH2:15])=[C:8]2[C:3]=1[CH2:4][CH2:5][N:6]([CH2:16][CH2:17][CH2:18][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)[CH2:7]2
Reactant: Nc1c([N+](=O)[O-])cc(Br)c2c1CN(CCCc1ccccc1)CC2
Agent: [Ni]
Solvent: C1CCOC1
Product: Nc1cc(Br)c2c(c1N)CN(CCCc1ccccc1)CC2
Yield: 96.5 %

Procedure:
A solution of the product from Example 12 (1.1 g, 2.82 mmol) in THF (80 mL) was stirred over RaNi under a hydrogen balloon for 19 hours. The catalyst was filtered off and concentrated under vacuum to give the title compound (0.98 g, 96% yield) as a dark brown oil.
Reaction SMILES: [F:1][C:2]1[CH:16]=[CH:15][C:5]2[C:6]([CH:9]3[CH2:14][CH2:13][NH:12][CH2:11][CH2:10]3)=[N:7][O:8][C:4]=2[CH:3]=1.Cl.Cl[CH2:19][CH2:20][N:21]1[CH2:26][CH2:25][O:24][CH2:23][CH2:22]1.C([O-])([O-])=O.[K+].[K+]>C(#N)C.C(Cl)Cl>[F:1][C:2]1[CH:16]=[CH:15][C:5]2[C:6]([CH:9]3[CH2:10][CH2:11][N:12]([CH2:19][CH2:20][N:21]4[CH2:26][CH2:25][O:24][CH2:23][CH2:22]4)[CH2:13][CH2:14]3)=[N:7][O:8][C:4]=2[CH:3]=1
Reactant: Fc1ccc2c(C3CCNCC3)noc2c1
Reactant: ClCCN1CCOCC1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: ClCCl
Solvent: CC#N
Product: Fc1ccc2c(C3CCN(CCN4CCOCC4)CC3)noc2c1

Procedure:
A mixture of 6-fluoro-3-(4-piperidinyl)-1,2-benzisoxazole (3.0 gm, 13.6 mmol), 2-chloroethyl morpholine hydrochloride (4.46 gm, 29.7 mmol) and K2CO3 (7.3 gm, 2.2 eq) in acetonitrile (60 ml) was heated at reflux for 24 hr. The crude mixture was diluted with DCM and filtered. The solvent was concentrated to an oil (~ 7.1 gm). Purification on a silica gel column (55 gm, SiO2, eluted with MeOH:DCM) yielded a solid product weighing 4 gm. Recrystallization from hot ethanol yielded 2.1 gm (48%), m.p. 131°-132° C.