Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[C:3]([C:11]#[N:12])=[CH:4][C:5]2[NH:9][CH:8]=[N:7][C:6]=2[CH:10]=1.[CH2:13]1[CH2:18][O:17][CH:16]=[CH:15][CH2:14]1.CC1C=CC(S(O)(=O)=O)=CC=1>C1COCC1>[F:1][C:2]1[C:3]([C:11]#[N:12])=[CH:4][C:5]2[N:9]([CH:16]3[CH2:15][CH2:14][CH2:13][CH2:18][O:17]3)[CH:8]=[N:7][C:6]=2[CH:10]=1
Reactant: C1=COCCC1
Reactant: N#Cc1cc2[nH]cnc2cc1F
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: C1CCOC1
Product: N#Cc1cc2c(cc1F)ncn2C1CCCCO1
Temperature: 85 °C
Yield: 73.5 %

Procedure:
A mixture of 6-fluoro-3H-benzo[d]imidazole-5-carbonitrile (1.78 g, 11.1 mmol), DHP (1.84 g, 22.2 mmol), and TsOH (212 mg, 1.1 mmol) in THF (20 mL) under nitrogen was heated at 85° C. overnight. The reaction mixture was quenched with water (40 mL) and extracted with EtOAc (50 ml×2). The combined extracts were washed with brine, dried (MgSO4), filtered, and concentrated in vacuo. The residue was purified by SiO2 chromatography eluting petroleum ether:EtOAc (5:1) to afford 5-fluoro-1-(tetrahydro-2H-pyran-2-yl)-1H-benzo[d]imidazole-6-carbonitrile as white solid (2.0 g, 73.8%).
Reaction SMILES: C1C=CC(C[NH:8][CH:9]([C:22]([OH:24])=[O:23])[CH:10]([NH:14]CC2C=CC=CC=2)[C:11]([OH:13])=[O:12])=CC=1.O>C(O)(=O)C.Cl.[Pd]>[CH:9]([NH2:8])([C:22]([OH:24])=[O:23])[CH:10]([NH2:14])[C:11]([OH:13])=[O:12]
Reactant: O=C(O)C(NCc1ccccc1)C(NCc1ccccc1)C(=O)O
Agent: [Pd]
Agent: Cl
Solvent: O
Solvent: CC(=O)O
Product: NC(C(=O)O)C(N)C(=O)O

Procedure:
Meso-2,3-bis(benzylamino)succinic acid (9.5 g, 0.029 mol) was dissolved in a mixture of glacial acetic acid (50 ml) and concentrated hydrochloric acid (50 ml). Hydrogenolysis was effected at ambient temperature with 10% palladium on charcoal (1.0 g) as catalyst. The reaction was run until NMR showed that unreacted starting material was no longer present. Water (100 ml) was added and the catalyst was removed by filtration. The filtrate was concentrated (rotavapor) and the residue was dissolved in dilute aqueous sodium hydroxide. pH was adjusted to approximately 5 upon addition of glacial acetic acid. Crystals were filtered off and washed.
Reaction SMILES: [S:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[C@H:6]1[CH2:8][C@@H:7]1[C:9]([OH:11])=O.C(Cl)(=O)C([Cl:15])=O.CN(C=O)C>ClCCl>[S:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[C@H:6]1[CH2:8][C@@H:7]1[C:9]([Cl:15])=[O:11]
Reactant: O=C(Cl)C(=O)Cl
Reactant: O=C(O)[C@H]1C[C@@H]1c1cccs1
Solvent: ClCCl
Solvent: CN(C)C=O
Product: O=C(Cl)[C@H]1C[C@@H]1c1cccs1
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
To a solution of (1S,2S)-2-Thiophen-2-yl-cyclopropanecarboxylic acid (0.110 g, 0.66 mmol) in dichloromethane (10 ml) in an ice-bath was added oxalyl chloride (0.58 ml, 6.60 mmol), then DMF (0.1 ml) under nitrogen. The reaction mixture was stirred for 30 minutes at 0° C. The excessive solvent was removed on ratovapor and dried under high vacuum for 2 hrs to give (1S,2S)-2-thiophen-2-yl-cyclopropanecarboxylic chloride. In a separated 50 ml round-bottom flask was charged with (R)-2-Amino-2-[4-(2-methyl-pentyloxy)-phenyl]-ethanol HCl (0.47 mmol), dichloromethane (6 ml) and triethylamine (0.31 ml, 2.35 mmol) in an ice cold bath under nitrogen. The (1S,2S)-2-Thiophen-2-yl-cyclopropanecarboxylic chloride, made freshly in dichloromethane (10 ml) was added into the reaction mixture dropwise. The final reaction mixture was stirred for 1.5 hrs at room temperature. The finished reaction was quenched with water. The organic phase was washed with brine (3×10 ml), dried over MgSO4, filtrated, concentrated in vacuum and purified via column chromatography on silica gel with a gradient of 0%-100% of ethyl acetate in hexane to give a white solid (0.088 g, 48% yield): 1H NMR (400 MHz, CHLOROFORM-d) δ ppm 7.14 (m, 2H), 6.99 (dd, J=5.2, 1.1 Hz, 1H), 6.81 (m, 3 H), 6.72 (d, J=3.3 Hz, 1H), 6.14 (d, J=6.3 Hz, 1H), 4.95 (m, 1H), 3.80 (m, 2H), 3.67 (m, 2H), 2.72 (dd, J=7.1, 4.8 Hz, 1H), 2.62 (m, 1H), 1.85 (m, 1H), 1.60 (m, 2H), 1.27 (m, 5H), 0.92 (d, J=6.8 Hz, 3H), 0.83 (m, 3H); LCMS (ESI) m/e 374.2 [(M+H)+, calcd for C22H30NO3S 374.5].
Reaction SMILES: [CH3:1][N:2]([CH3:34])[CH2:3][CH2:4][N:5]([CH3:33])[C:6]1[C:11]([N+:12]([O-])=O)=[CH:10][C:9]([NH:15][C:16]2[N:21]=[C:20]([C:22]3[CH:23]=[N:24][N:25]4[CH2:30][CH2:29][CH2:28][CH2:27][C:26]=34)[CH:19]=[CH:18][N:17]=2)=[C:8]([O:31][CH3:32])[CH:7]=1.[NH4+].[Cl-].O>C(O)C.[Fe]>[CH3:34][N:2]([CH3:1])[CH2:3][CH2:4][N:5]([CH3:33])[C:6]1[C:11]([NH2:12])=[CH:10][C:9]([NH:15][C:16]2[N:21]=[C:20]([C:22]3[CH:23]=[N:24][N:25]4[CH2:30][CH2:29][CH2:28][CH2:27][C:26]=34)[CH:19]=[CH:18][N:17]=2)=[C:8]([O:31][CH3:32])[CH:7]=1
Reactant: COc1cc(N(C)CCN(C)C)c([N+](=O)[O-])cc1Nc1nccc(-c2cnn3c2CCCC3)n1
Agent: [Fe]
Agent: [Cl-]
Agent: [NH4+]
Solvent: CCO
Solvent: O
Product: COc1cc(N(C)CCN(C)C)c(N)cc1Nc1nccc(-c2cnn3c2CCCC3)n1
Yield: 72.2 %

Procedure:
A mixture of N′-(2-dimethylaminoethyl)-2-methoxy-N′-methyl-5-nitro-N-[4-(4,5,6,7-tetrahydropyrazolo[1,5-a]pyridin-3-yl)pyrimidin-2-yl]benzene-1,4-diamine (Intermediate 126, 3.7 g, 7.93 mmol), iron (2.66 g, 47.58 mmol) and NH4Cl (0.318 g, 5.95 mmol) was heated in ethanol (120 mL) and water (40 mL) at reflux for 2.5 h. The mixture was then cooled, filtered and concentrated. The solids were triturated in 5% CH3OH/CH2Cl2 (100 mL) for 15 minutes and then filtered. The filtrate was combined with the concentrated, filtered reaction mixture, washed with brine, dried (Na2SO4) and concentrated in vacuo. Purification by FCC, eluting with 0-2.5% 7N methanolic ammonia in CH2Cl2 gave the title compound (2.50 g, 72%) as a brown gum; 1H NMR (CDCl3): 1.90-1.99 (2H, m), 2.04-2.13 (2H, m), 2.25 (6H, s), 2.37-2.42 (2H, m), 2.67 (3H, s), 2.92-2.98 (2H, m), 3.25 (2H, t), 3.83 (3H, s), 4.00 (2H, s), 4.21 (2H, t), 6.70 (1H, s), 6.79 (1H, d), 7.48 (1H, s), 7.97 (2H, d), 8.30 (1H, d); m/z: ES+ MH+ 437.39.
Reaction SMILES: [N:1]1[CH:2]=[CH:3][N:4]2[CH:9]=[CH:8][C:7]([C:10]3[N:15]=[C:14]([CH2:16][C:17](=O)[CH3:18])[CH:13]=[CH:12][CH:11]=3)=[CH:6][C:5]=12.Cl.[NH:21]1[CH2:26][CH2:25][O:24][CH2:23][CH2:22]1.[BH3-]C#N.[Na+].C1COCC1>CO>[N:21]1([CH:17]([CH3:18])[CH2:16][C:14]2[N:15]=[C:10]([C:7]3[CH:8]=[CH:9][N:4]4[CH:3]=[CH:2][N:1]=[C:5]4[CH:6]=3)[CH:11]=[CH:12][CH:13]=2)[CH2:26][CH2:25][O:24][CH2:23][CH2:22]1
Reactant: C1COCCN1
Reactant: CC(=O)Cc1cccc(-c2ccn3ccnc3c2)n1
Agent: Cl
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CO
Product: CC(Cc1cccc(-c2ccn3ccnc3c2)n1)N1CCOCC1
Reaction time: 24 h
Yield: 71.9 %

Procedure:
In a well mixed round bottomed flask under N2 charge 1-(6-Imidazo[1,2-a]pyridin-7-yl-pyridin-2-yl)-propan-2-one (1.8 g, 7.2 mmol), morpholine mono HCl salt (16 g, 129 mmol), 3 Å molecular sieves (powdered, vacuum oven dried 110° C. for 24 hours., 3.6 g), methanol (200 mL), and 1 M NaCNBH3 solution in THF (12.9 mL, 12.9 mmol). Stir for 24 hours. at room temp. Filter through Celite® strip off solvents under reduced pressure. Take up into DCM and adjust pH to 10 with 5N NaOH and extract with DCM (5×). Concentrate DCM under reduced pressure and chromatograph on (120 g ISCO®) SiO2 eluting with a slow gradient of 0% to 10% 2 M NH3 in MeOH with the balance DCM. Strip off solvents under reduced pressure to give clear oil 1.67 g (72%) MS(ES), m/z 323 (M+1).
Reaction SMILES: [C:1]([O:4][C@@H:5]1[C@@H:10]([O:11][C:12](=[O:14])[CH3:13])[C@@H:9]([O:15][C:16](=[O:18])[CH3:17])[C@@H:8]([CH2:19][O:20][C:21](=[O:23])[CH3:22])[O:7][C@H:6]1[O:24][C:25]1[C:29]([CH2:30][C:31]2[CH:36]=[CH:35][C:34]([CH2:37][CH2:38][CH2:39][C:40](=[O:48])[NH:41][C:42]([C:45](O)=[O:46])([CH3:44])[CH3:43])=[CH:33][CH:32]=2)=[C:28]([CH:49]([CH3:51])[CH3:50])[NH:27][N:26]=1)(=[O:3])[CH3:2].[CH2:52]([O:59][C:60]([N:62]1[CH2:67][CH2:66][NH:65][CH2:64][CH2:63]1)=[O:61])[C:53]1[CH:58]=[CH:57][CH:56]=[CH:55][CH:54]=1.ON1C2C=CC=CC=2N=N1.Cl.C(N=C=NCCCN(C)C)C>CN(C)C=O.O>[C:1]([O:4][C@@H:5]1[C@@H:10]([O:11][C:12](=[O:14])[CH3:13])[C@@H:9]([O:15][C:16](=[O:18])[CH3:17])[C@@H:8]([CH2:19][O:20][C:21](=[O:23])[CH3:22])[O:7][C@H:6]1[O:24][C:25]1[C:29]([CH2:30][C:31]2[CH:36]=[CH:35][C:34]([CH2:37][CH2:38][CH2:39][C:40](=[O:48])[NH:41][C:42]([C:45]([N:65]3[CH2:66][CH2:67][N:62]([C:60]([O:59][CH2:52][C:53]4[CH:58]=[CH:57][CH:56]=[CH:55][CH:54]=4)=[O:61])[CH2:63][CH2:64]3)=[O:46])([CH3:44])[CH3:43])=[CH:33][CH:32]=2)=[C:28]([CH:49]([CH3:51])[CH3:50])[NH:27][N:26]=1)(=[O:3])[CH3:2]
Reactant: CC(=O)OC[C@H]1O[C@@H](Oc2n[nH]c(C(C)C)c2Cc2ccc(CCCC(=O)NC(C)(C)C(=O)O)cc2)[C@H](OC(C)=O)[C@@H](OC(C)=O)[C@H]1OC(C)=O
Reactant: O=C(OCc1ccccc1)N1CCNCC1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: O
Solvent: CN(C)C=O
Product: CC(=O)OC[C@H]1O[C@@H](Oc2n[nH]c(C(C)C)c2Cc2ccc(CCCC(=O)NC(C)(C)C(=O)N3CCN(C(=O)OCc4ccccc4)CC3)cc2)[C@H](OC(C)=O)[C@@H](OC(C)=O)[C@H]1OC(C)=O
Temperature: 25 °C
Reaction time: 8 h
Yield: 85.4 %

Procedure:
3-(2,3,4,6-Tetra-O-acetyl-β-D-galactopyranosyloxy)-4-[(4-{3-[1-carboxy-1-(methyl)-ethylcarbamoyl]propyl}phenyl)methyl]-5-isopropyl-1H-pyrazole (37 g) was dissolved in N,N-dimethylformamide (180 mL). To the solution were added 1-(benzyloxycarbonyl)piperazine (28.4 g), 1-hydroxybenzotriazole (10.5 g) and 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (14.8 g), and the mixture was stirred at room temperature overnight. The reaction mixture was poured into water, and the resulting mixture was extracted with ethyl acetate twice. The extracts were washed with water and brine, and dried over anhydrous sodium sulfate. The solvent was removed under reduced pressure, and the residue was purified by column chromatography on silica gel (eluent: n-hexane/ethyl acetate=1/2-ethyl acetate) to give the title compound (40.5 g).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([C:8]2[O:12][N:11]=[C:10]([CH3:13])[C:9]=2[CH2:14][S:15][CH2:16][CH2:17][C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)=[CH:4][CH:3]=1.[CH2:24]([O:26][C:27](=[O:51])[CH:28]([C:36]1[CH:41]=[CH:40][C:39](B2OC(C)(C)C(C)(C)O2)=[CH:38][CH:37]=1)[CH2:29][C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1)[CH3:25]>>[CH2:24]([O:26][C:27](=[O:51])[CH:28]([C:36]1[CH:41]=[CH:40][C:39]([C:2]2[CH:7]=[CH:6][C:5]([C:8]3[O:12][N:11]=[C:10]([CH3:13])[C:9]=3[CH2:14][S:15][CH2:16][CH2:17][C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)=[CH:4][CH:3]=2)=[CH:38][CH:37]=1)[CH2:29][C:30]1[CH:31]=[CH:32][CH:33]=[CH:34][CH:35]=1)[CH3:25]
Reactant: CCOC(=O)C(Cc1ccccc1)c1ccc(B2OC(C)(C)C(C)(C)O2)cc1
Reactant: Cc1noc(-c2ccc(Br)cc2)c1CSCCc1ccccc1
Product: CCOC(=O)C(Cc1ccccc1)c1ccc(-c2ccc(-c3onc(C)c3CSCCc3ccccc3)cc2)cc1

Procedure:
Prepared according to the procedure described in Example 3, Step 5, using 5-(4-bromo-phenyl)-3-methyl-4-phenethylsulfanylmethyl-isoxazole and 3-phenyl-2-[4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-phenyl]-propionic acid ethyl ester.
Reaction SMILES: [N:1]([CH:4]1[CH2:8][CH2:7][N:6]([C:9]([O:11][CH2:12][CH3:13])=[O:10])[CH2:5]1)=[C:2]=[S:3].[CH3:14][C:15]1[O:19][C:18]([CH2:20][NH:21][C:22]2[C:23]([NH2:28])=[CH:24][CH:25]=[CH:26][CH:27]=2)=[CH:17][CH:16]=1>O1CCCC1>[CH3:14][C:15]1[O:19][C:18]([CH2:20][NH:21][C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=2[NH:28][C:2]([NH:1][CH:4]2[CH2:8][CH2:7][N:6]([C:9]([O:11][CH2:12][CH3:13])=[O:10])[CH2:5]2)=[S:3])=[CH:17][CH:16]=1
Reactant: CCOC(=O)N1CCC(N=C=S)C1
Reactant: Cc1ccc(CNc2ccccc2N)o1
Solvent: C1CCOC1
Product: CCOC(=O)N1CCC(NC(=S)Nc2ccccc2NCc2ccc(C)o2)C1
Temperature: 25 °C
Reaction time: 2 h
Yield: 100 %

Procedure:
A mixture of 80 parts of ethyl 3-isothiocyanato-1-pyrrolidinecarboxylate, 88.8 parts of N1 -[(5-methyl-2-furanyl)methyl]-1,2-benzenediamine and 560 parts of tetrahydrofuran was stirred for 2 hours at reflux temperature. After cooling to room temperature, the reaction mixture was evaporated, yielding 144.9 parts (100%) of ethyl 3-[[[[2-[[(5-methyl-2-furanyl)methyl]amino]phenyl]amino]thioxomethyl]amino]-1-pyrrolidinecarboxylate as a residue (interm. 7).
Reaction SMILES: [Br:1][C:2]1[CH:11]=[C:10]2[C:5]([CH:6]=[CH:7][N:8]=[C:9]2[O:12][C@H:13]2[CH2:17][N:16]([C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])[C@H:15]([C:25]([OH:27])=[O:26])[CH2:14]2)=[CH:4][C:3]=1[O:28][CH3:29].[Si](C=[N+]=[N-])(C)(C)[CH3:31]>CO>[Br:1][C:2]1[CH:11]=[C:10]2[C:5]([CH:6]=[CH:7][N:8]=[C:9]2[O:12][C@H:13]2[CH2:17][N:16]([C:18]([O:20][C:21]([CH3:23])([CH3:24])[CH3:22])=[O:19])[C@H:15]([C:25]([O:27][CH3:31])=[O:26])[CH2:14]2)=[CH:4][C:3]=1[O:28][CH3:29]
Reactant: COc1cc2ccnc(O[C@@H]3C[C@@H](C(=O)O)N(C(=O)OC(C)(C)C)C3)c2cc1Br
Reactant: C[Si](C)(C)C=[N+]=[N-]
Solvent: CO
Product: COC(=O)[C@@H]1C[C@@H](Oc2nccc3cc(OC)c(Br)cc23)CN1C(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 79 %

Procedure:
To a solution of compound 122 in MeOH (0.1 M) was added TMS-diazomethane (4.2 eq.) and the mixture was stirred at RT for 20 min. Volatiles were evaporated and the crude purified by chromatography to obtain 1-tert-butyl 2-methyl (2S,4R)-4-[(7-bromo-6-methoxyisoquinolin-1-yl)oxy]pyrrolidine-1,2-dicarboxylate as a pale orange foam (79%). To the previous compound dissolved in toluene (0.1 M) tetrakis-(triphenylphospin)-palladium(0) (0.1 eq.) and vinyltri-N-butyltin (1 eq) were added and the mixture was heated at 100° C. for 20 h. Volatiles were evaporated and the residue purified by chromatography to obtain 1-tert-butyl 2-methyl (2S,4R)-4-[(6-methoxy-7-vinylisoquinolin-1-yl)oxy]pyrrolidine-1,2-dicarboxylate as a pale yellow foam (45%) that was treated with HCl 4N in dioxane (26 eq) at RT. After 30 min volatiles were evaporated to obtain the title compound 123 in quantitative yield. MS (ES+) m/z 329 (M+H)+.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:29]([O:30][CH3:31])=[CH:28][C:6]2[CH2:7][C:8](=[O:27])[N:9]([CH2:12][CH2:13][CH2:14][N:15]([CH3:26])[CH2:16][CH2:17][CH2:18][S:19][C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)[CH2:10][CH2:11][C:5]=2[CH:4]=1.[Se](=O)=[O:33]>>[CH3:1][O:2][C:3]1[C:29]([O:30][CH3:31])=[CH:28][C:6]2[C:7](=[O:33])[C:8](=[O:27])[N:9]([CH2:12][CH2:13][CH2:14][N:15]([CH3:26])[CH2:16][CH2:17][CH2:18][S:19][C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)[CH2:10][CH2:11][C:5]=2[CH:4]=1
Reactant: COc1cc2c(cc1OC)CC(=O)N(CCCN(C)CCCSc1ccccc1)CC2
Reactant: O=[Se]=O
Product: COc1cc2c(cc1OC)C(=O)C(=O)N(CCCN(C)CCCSc1ccccc1)CC2

Procedure:
The title compound is prepared from N-[3-(7,8-dimethoxy-1,3,4,5-tetrahydro-2H-3-benzazepin-2-on-3-yl)-propyl]-N-[3-(phenylthio)-propyl]-methylamine and selenium dioxide analogously to Example 55.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[CH:4][C:3]=1[F:9].[Cl:10][CH2:11][CH2:12][C:13](Cl)=[O:14]>CC(C)=O>[Cl:10][CH2:11][CH2:12][C:13]([NH:1][C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[CH:4][C:3]=1[F:9])=[O:14]
Reactant: O=C(Cl)CCCl
Reactant: Nc1ccc(O)cc1F
Solvent: CC(C)=O
Product: O=C(CCCl)Nc1ccc(O)cc1F
Yield: 50.7 %

Procedure:
4-Amino-3-fluorophenol (3.4 g) was mixed with 3-chloropropanoyl chloride (3.56 g) in acetone (60 mL) and heated at reflux over 3 hours. After aqueous work-up with EtOAc/water, the isolated organic layers were dried over Na2SO4 and concentrated in vacuo. The crude product was purified with silica gel chromatography to give the product (2.95 g) as a light brown solid.
Reaction SMILES: Br[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][C:8]([O:10][CH2:11][CH3:12])=[O:9].[F:13][C:14]([F:27])([F:26])[C:15]1[CH:16]=[C:17]([OH:25])[CH:18]=[C:19]([C:21]([F:24])([F:23])[F:22])[CH:20]=1.CN(C)C=O.C(=O)([O-])[O-].[K+].[K+]>O>[F:13][C:14]([F:26])([F:27])[C:15]1[CH:16]=[C:17]([CH:18]=[C:19]([C:21]([F:22])([F:23])[F:24])[CH:20]=1)[O:25][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][C:8]([O:10][CH2:11][CH3:12])=[O:9]
Reactant: CCOC(=O)CCCCCCBr
Reactant: Oc1cc(C(F)(F)F)cc(C(F)(F)F)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: CCOC(=O)CCCCCCOc1cc(C(F)(F)F)cc(C(F)(F)F)c1
Temperature: 25 °C

Procedure:
Ethyl 7-bromoheptanoate and 3,5-bis(trifluoromethyl) phenol were added to dimethylformamide (DMF). The solution was added with potassium carbonate and stirred at room temperature. The solution was added with water and extracted twice with ethyl acetate. After the organic layer was washed three times with water and dried over anhydrous magnesium sulfate, the solvent was removed. The residue was purified by silica gel column chromatography to obtain ethyl 7-(3,5-bis (trifluoromethyl)phenoxy)heptanoate.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]2[C:8]([C:11]3[CH2:12][CH2:13][N:14]([CH2:17][CH3:18])[CH2:15][CH:16]=3)=[CH:9][NH:10][C:5]2=[CH:4][CH:3]=1.[F:19][C:20]1[CH:28]=[CH:27][C:23]([C:24](Cl)=[O:25])=[CH:22][CH:21]=1>>[F:19][C:20]1[CH:28]=[CH:27][C:23]([C:24]([NH:1][C:2]2[N:7]=[C:6]3[C:8]([C:11]4[CH2:12][CH2:13][N:14]([CH2:17][CH3:18])[CH2:15][CH:16]=4)=[CH:9][NH:10][C:5]3=[CH:4][CH:3]=2)=[O:25])=[CH:22][CH:21]=1
Reactant: O=C(Cl)c1ccc(F)cc1
Reactant: CCN1CC=C(c2c[nH]c3ccc(N)nc23)CC1
Product: CCN1CC=C(c2c[nH]c3ccc(NC(=O)c4ccc(F)cc4)nc23)CC1

Procedure:
Beginning with 0.015 gm (0.062 mMol) 5-amino-3-(1-ethyl-1,2,3,6-tetrahydropyridin-4-yl)pyrrolo[3,2-b]pyridine and 0.008 mL (0.068 mmol) 4-fluorobenzoyl chloride, the title compound was prepared essentially by the procedure described in Example 7.
Reaction SMILES: Cl.N[OH:3].C[N:5]([CH:7]=[N:8][C:9]1[N:14]=[C:13]([C:15]([F:18])([CH3:17])[CH3:16])[N:12]=[C:11]([NH:19][CH:20]([CH:30]2[CH2:32][CH2:31]2)[CH2:21][CH2:22][CH2:23][C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)[N:10]=1)C>CO>[F:18][C:15]([C:13]1[N:12]=[C:11]([NH:19][CH:20]([CH:30]2[CH2:32][CH2:31]2)[CH2:21][CH2:22][CH2:23][C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)[N:10]=[C:9]([NH:8][CH:7]=[N:5][OH:3])[N:14]=1)([CH3:17])[CH3:16]
Reactant: CN(C)C=Nc1nc(NC(CCCc2ccccc2)C2CC2)nc(C(C)(C)F)n1
Reactant: NO
Agent: Cl
Solvent: CO
Product: CC(C)(F)c1nc(NC=NO)nc(NC(CCCc2ccccc2)C2CC2)n1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
0.69 g (10 mmol) of hydroxylamine hydrochloride are added with stirring at room temperature to a solution of 1.99 g (5 mmol) of 2-dimethylaminomethyleneamino-4-(1-fluoro-1-methylethyl)-6-(1cyclopropyl-4-phenyl-1-butylamino) -1,3,5-triazine in 20 ml of methanol. The reaction mixture is stirred for 2 hours at room temperature. All volatile constituents are carefully distilled off. The crude product is taken up in methylene chloride. The mixture is washed with water, dried over Na2SO4 and evaporated in vacuo. This gives 1.81 g (93.7% of theory) of N-[4-(1-fluoro -1-methylethyl)-6-(1-cyclopropyl-4-phenyl-1-butylamino)-1,3,5-triazin-1-yl]formamide oxime as pale yellow oil.
Reaction SMILES: [CH3:1][C:2]1[N:7]=[C:6]([C:8]2[CH:13]=[CH:12][CH:11]=[C:10]([C:14]3[CH:15]=[C:16]([S:20](Cl)(=[O:22])=[O:21])[CH:17]=[CH:18][CH:19]=3)[N:9]=2)[CH:5]=[C:4]([C:24]2[CH:29]=[CH:28][C:27]([C:30]([F:33])([F:32])[F:31])=[CH:26][CH:25]=2)[CH:3]=1.[CH3:34][O:35][CH2:36][CH2:37][NH2:38]>C1COCC1.CCOC(C)=O>[CH3:34][O:35][CH2:36][CH2:37][NH:38][S:20]([C:16]1[CH:17]=[CH:18][CH:19]=[C:14]([C:10]2[N:9]=[C:8]([C:6]3[CH:5]=[C:4]([C:24]4[CH:29]=[CH:28][C:27]([C:30]([F:31])([F:32])[F:33])=[CH:26][CH:25]=4)[CH:3]=[C:2]([CH3:1])[N:7]=3)[CH:13]=[CH:12][CH:11]=2)[CH:15]=1)(=[O:22])=[O:21]
Reactant: COCCN
Reactant: Cc1cc(-c2ccc(C(F)(F)F)cc2)cc(-c2cccc(-c3cccc(S(=O)(=O)Cl)c3)n2)n1
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: COCCNS(=O)(=O)c1cccc(-c2cccc(-c3cc(-c4ccc(C(F)(F)F)cc4)cc(C)n3)n2)c1
Yield: 61.8 %

Procedure:
The title compound was prepared from 3-[6′-methyl-4′-(4-trifluoromethyl-phenyl)-[2,2′]bipyridinyl-6-yl]-benzenesulfonyl chloride (example I.2) (0.300 g, 0.613 mmol) by treatment with commercially available 2-methoxyethylamine (0.138 mg, 1.84 mmol) in THF (5 mL) at 23° C. for 16 h. Diluted with EtOAc, washed with 5% citric acid, sat. NaHCO3-sol. and brine, dried organic layer over Na2SO4. Removal of the solvent in vacuum left a crude product, which was purified by silica gel column chromatography with EtOAc followed by trituration with diethyl ether/heptane to give the title compound (0.200 g, 62%) as a white solid. MS (ISP) 528.2 [(M+H)+]; mp 126° C.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:12]=[C:11]2[C:6]([CH2:7][CH2:8][CH2:9][C:10]2=[CH:13][C:14]#[N:15])=[CH:5][CH:4]=1.N.C(O)C>C(O)C.[Ni]>[NH2:15][CH2:14][CH:13]=[C:10]1[C:11]2[C:6](=[CH:5][CH:4]=[C:3]([O:2][CH3:1])[CH:12]=2)[CH2:7][CH2:8][CH2:9]1
Reactant: COc1ccc2c(c1)C(=CC#N)CCC2
Agent: [Ni]
Agent: N
Solvent: CCO
Product: COc1ccc2c(c1)C(=CCN)CCC2
Temperature: 50 °C
Reaction time: 8 h
Yield: 80 %

Procedure:
To a solution of (1,2,3,4-tetrahydro-7-methoxy-1-naphthylidene)acetonitrile (15.0 g, 25 mmol) in ethanol (100 ml) were added a saturated ammonia/ethanol solution (30 ml) and Raney nickel (W-2, 3 g). The reaction mixture was stirred for 8 hours at 50° C. under hydrogen atmosphere (3-4 kgf /cm2). The Raney nickel was filtered off, then the solvent was distilled off under reduced pressure to give the above-titled compound (a mixture of isomers (20.4 g, yield 80%, oil). This compound was used in the subsequent reaction without further purification.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([CH:8]([OH:18])[CH2:9][CH2:10][NH:11][C:12](=[O:17])[C:13]([F:16])([F:15])[F:14])[CH:5]=[CH:6][CH:7]=1.[CH3:19][C:20]([OH:26])([CH2:23][CH2:24][CH3:25])[C:21]#[CH:22]>>[F:14][C:13]([F:16])([F:15])[C:12]([NH:11][CH2:10][CH2:9][CH:8]([OH:18])[C:4]1[CH:5]=[CH:6][CH:7]=[C:2]([C:22]#[C:21][C:20]([OH:26])([CH3:19])[CH2:23][CH2:24][CH3:25])[CH:3]=1)=[O:17]
Reactant: C#CC(C)(O)CCC
Reactant: O=C(NCCC(O)c1cccc(Br)c1)C(F)(F)F
Product: CCCC(C)(O)C#Cc1cccc(C(O)CCNC(=O)C(F)(F)F)c1

Procedure:
Sonogashira reaction of 25 with 3-methylhex-1-yn-3-ol yielded 2,2,2-trifluoro-N-(3-hydroxy-3-(3-(3-hydroxy-3-methylhex-1-ynyl)phenyl)propyl)acetamide as dark brown oil. Yield (0.611 g, 55%): 1H NMR (400 MHz, CDCl3) δ 7.41 (s, 1H), 7.24-7.37 (m, 3H), 4.86 (m, 1H), 3.67-3.72 (m, 1H), 3.38-3.44 (m, 1H), 2.32 (bs, 1H), 1.94-2.01 (m, 3H), 1.71-1.76 (m, 2H), 1.59-1.62 (m, 1H), 1.53 (s, 3H), 0.99 (t, J=7.2, 3H).
Reaction SMILES: [C:1]([CH2:4][CH2:5][CH2:6][O:7][C:8]1[CH:9]=[C:10]2[C:15](=[CH:16][CH:17]=1)[NH:14][C:13](=[O:18])[CH:12]=[CH:11]2)([OH:3])=O.[CH3:19][NH:20][CH:21]1[CH2:26][CH2:25][CH2:24][CH2:23][CH2:22]1.O1CCOCC1.C1(N=C=NC2CCCCC2)CCCCC1>C(Cl)Cl>[CH3:19][N:20]([CH:21]1[CH2:26][CH2:25][CH2:24][CH2:23][CH2:22]1)[C:1]([CH2:4][CH2:5][CH2:6][O:7][C:8]1[CH:9]=[C:10]2[C:15](=[CH:16][CH:17]=1)[NH:14][C:13](=[O:18])[CH:12]=[CH:11]2)=[O:3]
Reactant: CNC1CCCCC1
Reactant: O=C(O)CCCOc1ccc2[nH]c(=O)ccc2c1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Solvent: ClCCl
Solvent: C1COCCO1
Product: CN(C(=O)CCCOc1ccc2[nH]c(=O)ccc2c1)C1CCCCC1

Procedure:
2.5 Grams of 6-(3-carboxy)propoxycarbostyril and 1.2 g of N-methylcyclohexylamine are added to a mixed solvent of 20 ml of dioxane and 20 ml of methylene chloride, and to this mixture is added dropwise a solution of 2.1 g of N,N'-dicyclohexylcarbodiimide in 5 ml of methylene chloride maintained at 10°-20° C. under external ice cooling and agitation, followed by additional 3.5-hour agitation at the same temperature. The precipitated crystals are filtered out and the filtrate is concentrated under reduced pressure and evaporated to dryness. The obtained residue is dissolved in 100 ml of methylene chloride and the organic layer is washed with a 5% aqueous solution of hydrochloric acid, a 5% aqueous solution of sodium carbonate and water in that order and then dried with anhydrous sodium sulfate. After distilling off the solvent under reduced pressure, the residue is recrystallized from chloroform-ethanol to obtain 1.9 g of 6-[3-(N-methyl-N-cyclohexylaminocarbonyl)propoxy]-carbostyril in the form of colorless needle-like crystals with melting point of 184.5°- 186° C.