Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:35]=[CH:34][C:5]([C:6](=[O:33])[CH2:7][CH2:8][NH:9][C:10]2[C:18]3[C:13](=[CH:14][C:15]([Cl:20])=[CH:16][C:17]=3[Cl:19])[N:12](C(OC(C)(C)C)=O)[C:11]=2[C:28]([O:30][CH2:31][CH3:32])=[O:29])=[CH:4][CH:3]=1.FC(F)(F)C(O)=O>C(Cl)Cl>[F:1][C:2]1[CH:3]=[CH:4][C:5]([C:6](=[O:33])[CH2:7][CH2:8][NH:9][C:10]2[C:18]3[C:13](=[CH:14][C:15]([Cl:20])=[CH:16][C:17]=3[Cl:19])[NH:12][C:11]=2[C:28]([O:30][CH2:31][CH3:32])=[O:29])=[CH:34][CH:35]=1
Reactant: CCOC(=O)c1c(NCCC(=O)c2ccc(F)cc2)c2c(Cl)cc(Cl)cc2n1C(=O)OC(C)(C)C
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CCOC(=O)c1[nH]c2cc(Cl)cc(Cl)c2c1NCCC(=O)c1ccc(F)cc1
Yield: 72.4 %

Procedure:
Dissolve 3-[(p-fluorophenacyl)methylamino]-2-carbethoxy-4,6-dichloro-1-(tert-butyloxycarbonyl)-indole (1.2 g, 2.35 mmol) in methylene chloride. Add trifluoracetic acid and stir for 2 hours. Concentrate the reaction in vacuo and recrystallize the residue from hot ethyl acetate/hexane to yield the title compound (720 mg, 74%).
Reaction SMILES: [O:1]=[C:2]1[N:6]([C:7]2[CH:15]=[CH:14][C:10]([C:11](O)=[O:12])=[CH:9][CH:8]=2)[N:5]=[C:4]2[C:16]3[CH:17]=[CH:18][CH:19]=[CH:20][C:21]=3[S:22][CH:23]=[C:3]12.C(N(C(C)C)CC)(C)C.[CH3:33][N:34]([CH3:39])[CH2:35][CH2:36][CH2:37][NH2:38].F[P-](F)(F)(F)(F)F.N1(OC(=[N+](C)C)N(C)C)C2C=CC=CC=2N=N1>CC(N(C)C)=O>[CH3:33][N:34]([CH3:39])[CH2:35][CH2:36][CH2:37][NH:38][C:11](=[O:12])[C:10]1[CH:9]=[CH:8][C:7]([N:6]2[C:2](=[O:1])[C:3]3=[CH:23][S:22][C:21]4[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=4[C:4]3=[N:5]2)=[CH:15][CH:14]=1
Reactant: CN(C)CCCN
Reactant: O=C(O)c1ccc(-n2nc3c4ccccc4scc-3c2=O)cc1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CC(=O)N(C)C
Solvent: CCN(C(C)C)C(C)C
Product: CN(C)CCCNC(=O)c1ccc(-n2nc3c4ccccc4scc-3c2=O)cc1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
4-(3-oxothiochromeno[4,3-c]pyrazol-2(3H)-yl)benzoic acid (55 mg, 0.17 mmol) was suspended in anhydrous dimethyl acetamide (1 ml). Diisopropyl-ethyl amine (46.5 mg, 0.36 mmol, 62 μl) was added followed by 3-dimethylaminopropylamine (17.5 mg, 0.17 mmol) and [(benzotriazol-1-yloxy)-dimethylamino-methylene]-dimethyl-ammonium hexafluoro phosphate (65 mg, 0.17 mmol). The mixture was stirred at room temperature for 4 h and was purified by preparative HPLC. The title compound was isolated as a brown solid. LCMS: m/z 407 [M+H]+ Activity **
Reaction SMILES: N[C@@H:2]([CH2:6][C:7]#[N:8])[C:3]([OH:5])=O.[CH:9]1([NH:16][C:17]([NH2:19])=[S:18])[CH2:15][CH2:14][CH2:13][CH2:12][CH2:11][CH2:10]1>>[CH:9]1([NH:16][C:17]2[S:18][CH:2]([CH2:6][C:7]#[N:8])[C:3](=[O:5])[N:19]=2)[CH2:15][CH2:14][CH2:13][CH2:12][CH2:11][CH2:10]1
Reactant: NC(=S)NC1CCCCCC1
Reactant: N#CC[C@H](N)C(=O)O
Product: N#CCC1SC(NC2CCCCCC2)=NC1=O

Procedure:
Synthesis was performed from (2S)-2-amino-3-cyanopropanoic acid and N-cycloheptylthiourea according to Method E and C.
Reaction SMILES: FC1C=CC2N(C(CC3N(C)C=CN=3)=C(C3C=CC(F)=CC=3)N=2)C=1.[Cl:25][C:26]1[CH:31]=[CH:30][C:29]([C:32]2[N:33]=[C:34]3[CH:39]=[CH:38][C:37]([CH3:40])=[CH:36][N:35]3[C:41]=2[CH:42]=O)=[CH:28][CH:27]=1.[CH3:44][C:45]1[O:46][CH:47]=[N:48][N:49]=1>>[Cl:25][C:26]1[CH:27]=[CH:28][C:29]([C:32]2[N:33]=[C:34]3[CH:39]=[CH:38][C:37]([CH3:40])=[CH:36][N:35]3[C:41]=2[CH2:42][C:47]2[O:46][C:45]([CH3:44])=[N:49][N:48]=2)=[CH:30][CH:31]=1
Reactant: Cc1ccc2nc(-c3ccc(Cl)cc3)c(C=O)n2c1
Reactant: Cc1nnco1
Agent: Cn1ccnc1Cc1c(-c2ccc(F)cc2)nc2ccc(F)cn12
Product: Cc1ccc2nc(-c3ccc(Cl)cc3)c(Cc3nnc(C)o3)n2c1

Procedure:
The title compound was prepared according to Method C and the experimentals described for compound 199 from 2-(4-chlorophenyl)-6-methylimidazo[1,2-a]pyridine-3-carbaldehyde and 2-methyl-1,3,4-oxadiazole. M/e+ 339 for C18H16ClN4O (M+H)+; 1H-NMR (400 MHz, CDCl3) δ 7.95 (s, 1H), 7.76 (d, J=8.4 Hz, 2H), 7.56 (d, J=9.1 Hz, 1H), 7.45 (d, J=8.4 Hz, 2H), 7.10 (dd, J=9.1, 1.4 Hz, 1H), 4.54 (s, 2H), 2.49 (s, 3H), 2.35 (s, 3H) ppm.
Reaction SMILES: [CH3:1][N:2]1[CH2:26][CH2:25][C@:4]2([N:8]=[C:7]([C:9]3[CH:14]=[C:13]([C:15]4[CH:20]=[CH:19][C:18]([C:21]([F:24])([F:23])[F:22])=[CH:17][CH:16]=4)[CH:12]=[CH:11][N:10]=3)[CH2:6][CH2:5]2)[C:3]1=[O:27].[B-](F)(F)(F)[F:29].[B-](F)(F)(F)F.C1[N+]2(CCl)CC[N+](F)(CC2)C1.FC(F)(F)C(O)=O.[OH-].[Na+]>CC#N>[F:29][CH:6]1[CH2:5][C@@:4]2([CH2:25][CH2:26][N:2]([CH3:1])[C:3]2=[O:27])[N:8]=[C:7]1[C:9]1[CH:14]=[C:13]([C:15]2[CH:16]=[CH:17][C:18]([C:21]([F:24])([F:23])[F:22])=[CH:19][CH:20]=2)[CH:12]=[CH:11][N:10]=1
Reactant: F[B-](F)(F)F
Reactant: CN1CC[C@@]2(CCC(c3cc(-c4ccc(C(F)(F)F)cc4)ccn3)=N2)C1=O
Agent: F[N+]12CC[N+](CCl)(CC1)CC2
Agent: [Na+]
Agent: [OH-]
Solvent: CC#N
Solvent: O=C(O)C(F)(F)F
Product: CN1CC[C@@]2(CC(F)C(c3cc(-c4ccc(C(F)(F)F)cc4)ccn3)=N2)C1=O
Temperature: 90 °C
Reaction time: 0.17 h

Procedure:
Anhydrous MeCN (5 mL) was added to a dry vial charged with (5S)-7-methyl-2-[4-[4-(trifluoromethyl)phenyl]-2-pyridyl]-1,7-diazaspiro[4.4]non-1-en-6-one (which may be prepared as described in Description 118) (339.99 mg, 0.9100 mmol). Selectfluor (1500 mg, 4.23 mmol) was added to the solution followed by trifluoroacetic acid (0.04 mL, 0.5300 mmol). The vial was sealed under nitrogen and was heated to 90° C. for 24 h. The reaction mixture was allowed to cool to room temperature whence it was poured onto 0.5M sodium hydroxide. The mixture was left to stir for 10 min and extracted with ether. The combined organic layer was dried (sodium sulfate), filtered and the filtrate was evaporated to give an amber oil. The crude residue was purified by silica gel chromatography (10 g SiO2) eluting with ethyl acetate in iso-hexane (10-100%). Evaporation of desired fractions gave (5R)-3-fluoro-7-methyl-2-[4-[4-(trifluoromethyl)phenyl]-2-pyridyl]-1,7-diazaspiro[4.4]non-1-en-6-one, as an amber oil, a 2:1 mixture of epimers. The isomers were separated by chiral semi-prep hplc using a ChiralPak AD-H column eluting with ethanol/n-heptane (20%:80%) to obtain a faster running epimer (D119a) (28 mg);
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([NH:8][C:9]2[CH2:13][C:12](=[O:14])[N:11]([C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=3)[N:10]=2)[CH:5]=[CH:6][CH:7]=1.[C:21](OCC)(=[O:26])[CH2:22][C:23]([CH3:25])=O>C(O)(=O)C>[Cl:1][C:2]1[CH:3]=[C:4]([N:8]2[C:21](=[O:26])[CH:22]=[C:23]([CH3:25])[C:13]3[C:12](=[O:14])[N:11]([C:15]4[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=4)[NH:10][C:9]2=3)[CH:5]=[CH:6][CH:7]=1
Reactant: CCOC(=O)CC(C)=O
Reactant: O=C1CC(Nc2cccc(Cl)c2)=NN1c1ccccc1
Solvent: CC(=O)O
Product: Cc1cc(=O)n(-c2cccc(Cl)c2)c2[nH]n(-c3ccccc3)c(=O)c12
Yield: 28.5 %

Procedure:
To 5.7 g of 3-(3-chlorophenylamino)-1-phenyl-2-pyrazolin-5-one were added 2.8 g of ethyl acetoacetate and 40 ml of acetic acid and the mixture was heated while refluxing for 6 hours. The precipitated crystals were filtered and washed with isopropyl alcohol to obtain 2 g of 7-(3-chlorophenyl)-4-methyl-2-phenylpyrazolo[3, 4-b]pyridine-3,6-dione (melting point: 278° to 282° C.). A solution was prepared by adding 24 ml of methanol and 1.12 ml of triethylamine to 1.4 g of the crystals obtained above, 1.13 g of 1,7-diphenyl-1,7-diaza-1,3,5-heptatriene hydrochloride were added to this solution, and then 0.75 ml of anhydrous acetic acid was added with stirring at room temperature for one hour. The precipitate thus formed was filtered and washed with methanol, followed by drying to obtain 5-[5-(N-acetylanilino)-2, 3-pentadienylidene]-7-(3-chlorophenyl)-4-methyl-2-phenylpyrazolo[3, 4-b]pyridine-3,6-dione. 30 ml of N,N-dimethylformamide and 0.32 g of 8-(3-chlorophenyl)-4-methyl-2-phenylpyrazolo[3, 4-b]pyridine-3,6-dione were added to 0.5 g of this product, and the solution was stirred at 50° C. for 2 hours. After filtering the reaction solution, ethyl acetate in an amount of ten times by volume was added while stirring to precipitate crystals. The obtained crystals were dissolved again in a small amount of N,N-dimethylformamide, and then ethyl acetate in an amount of ten times by volume was added to precipitate crystals, followed by filtering, washing with ethyl acetate and drying to obtain 0.4 g of Compound 4. Melting point: 300° C. or higher.
Reaction SMILES: [NH2:1][C:2]1[S:3][CH:4]=[CH:5][C:6]=1[C:7]#[N:8].[CH2:9]([N:11]([CH2:19][CH3:20])[C:12]1[S:16][C:15]([CH:17]=O)=[CH:14][CH:13]=1)[CH3:10].C(O)(C(F)(F)F)=O>C(O)(C)C>[CH2:19]([N:11]([CH2:9][CH3:10])[C:12]1[S:16][C:15]([CH:17]=[N:1][C:2]2[S:3][CH:4]=[CH:5][C:6]=2[C:7]#[N:8])=[CH:14][CH:13]=1)[CH3:20]
Reactant: CCN(CC)c1ccc(C=O)s1
Reactant: N#Cc1ccsc1N
Solvent: O=C(O)C(F)(F)F
Solvent: CC(C)O
Product: CCN(CC)c1ccc(C=Nc2sccc2C#N)s1

Procedure:
In a round bottom flask (50 mL), 30 mg of 2-amino-thiophene-3-carbonitrile was added to 20 mL isopropanol to which was further added 5-diethylamino-thiophene-2-carbaldehyde (48 mg) and a catalytic amount of TFA. The mixture was refluxed for 3 hours. Complete removal of the solvent leads to an orange oil which was purified by flash chromatography (SiO2). The title compound was isolated as an orange solid (63%). 1H-NMR (300 MHz, [D] acetone): δ=8.44 (s, 1H), 7.54 (d, 1H, 3J=4.5 Hz), 7.09 (s, 2H), 6.13 (d, 1H, 3J=4.5 Hz), 3.54 (q, 4H, 3J=7.1 Hz), 1.27 (t, 6H, 3J=7.1 Hz). 13C-NMR (300 MHz, [D] acetone): δ=166.1, 153.2, 141.2, 131.9, 127.9, 123.3, 118.8, 116.0, 104.5, 101.5, 48.2, 12.4.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][N:5]2[C:10]=1[C:9](=O)[NH:8][CH:7]=[N:6]2.C(N(C(C)C)CC)(C)C.O(Cl)[Cl:22].[P+3].C(=O)(O)[O-].[Na+]>C1(C)C=CC=CC=1>[Cl:22][C:9]1[C:10]2=[C:2]([Cl:1])[CH:3]=[CH:4][N:5]2[N:6]=[CH:7][N:8]=1
Reactant: O=c1[nH]cnn2ccc(Cl)c12
Reactant: ClOCl
Agent: O=C([O-])O
Agent: [Na+]
Agent: [P+3]
Solvent: Cc1ccccc1
Solvent: CCN(C(C)C)C(C)C
Product: Clc1ccn2ncnc(Cl)c12
Temperature: 100 °C
Reaction time: 0.5 h
Yield: 67.3 %

Procedure:
To a solution of 5-chloropyrrolo[2,1-f][1,2,4]triazin-4(3H)-one (5.00 g, 29.5 mmol) in toluene (100 mL) at rt under nitrogen was added diisopropylethylamine (5.14 mL, 29.5 mmol) followed by phosphorus(III) oxychloride (8.25 mL, 88.5 mmol). The mixture was heated at 100° C. for 20 h and was then cooled to rt. The reaction was slowly added to saturated aqueous sodium bicarbonate solution (500 mL) at 0° C. After the addition was complete, the mixture was stirred at rt for 30 min. The aqueous phase was extracted with ethyl acetate (3×500 mL), dried over anhydrous MgSO4, and concentrated in vacuo to give the crude product (3.73 g, 67%) as a yellow solid which was used without further purification. 1H NMR (CDCl3) δ 8.03 (s, 1H), 7.70 (d, 1H, J=2.8 Hz), 6.84 (d, 1H, J=2.8 Hz); MS(ESI+) m/z 188.1 (M+H)+.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[N:6][C:7]([NH2:10])=[N:8][CH:9]=1)([O-:3])=[O:2].[Cl:11][C:12]1[CH:13]=[C:14]([CH:18]=[CH:19][C:20]=1[F:21])[C:15](O)=[O:16].O>N1C=CC=CC=1>[Cl:11][C:12]1[CH:13]=[C:14]([CH:18]=[CH:19][C:20]=1[F:21])[C:15]([NH:10][C:7]1[N:8]=[CH:9][C:4]([N+:1]([O-:3])=[O:2])=[CH:5][N:6]=1)=[O:16]
Reactant: O=C(O)c1ccc(F)c(Cl)c1
Reactant: Nc1ncc([N+](=O)[O-])cn1
Solvent: O
Solvent: c1ccncc1
Product: O=C(Nc1ncc([N+](=O)[O-])cn1)c1ccc(F)c(Cl)c1
Temperature: 100 °C
Yield: 55.1 %

Procedure:
To 5-nitropyrimidin-2-amine (1.0 g, 7.1 mmol) in pyridine (10 mL) was added 3-chloro-4-fluorobenzoic acid (1.7 g, 9.7 mmol). The reaction mixture was heated at 100° C. for 4 hrs and allowed to cool to rt. 15 mL H2O was added. A precipitate was collected by filtration and purified by silica gel chromatography, eluting with CH2Cl2 followed by 10% EtOAc/CH2Cl2 to give 1.16 g (55% yield) 1C. RP HPLC ret. t.: 2.22 min. and (M+H)+: 297.
Reaction SMILES: [F:1][C:2]([F:39])([F:38])[C:3]1[CH:4]=[C:5]([CH:31]=[C:32]([C:34]([F:37])([F:36])[F:35])[CH:33]=1)[C:6]([N:8]1[CH2:13][CH2:12][N:11]([CH2:14][CH2:15]OS(C)(=O)=O)[CH2:10][C@H:9]1[CH2:21][C:22]1[C:30]2[C:25](=[CH:26][CH:27]=[CH:28][CH:29]=2)[NH:24][CH:23]=1)=[O:7].[NH2:40][N:41]1[CH2:46][CH2:45][O:44][CH2:43][CH2:42]1.C(N(CC)CC)C>CO>[F:38][C:2]([F:1])([F:39])[C:3]1[CH:4]=[C:5]([CH:31]=[C:32]([C:34]([F:35])([F:36])[F:37])[CH:33]=1)[C:6]([N:8]1[CH2:13][CH2:12][N:11]([CH2:14][CH2:15][NH:40][N:41]2[CH2:46][CH2:45][O:44][CH2:43][CH2:42]2)[CH2:10][C@H:9]1[CH2:21][C:22]1[C:30]2[C:25](=[CH:26][CH:27]=[CH:28][CH:29]=2)[NH:24][CH:23]=1)=[O:7]
Reactant: NN1CCOCC1
Reactant: CS(=O)(=O)OCCN1CCN(C(=O)c2cc(C(F)(F)F)cc(C(F)(F)F)c2)[C@H](Cc2c[nH]c3ccccc23)C1
Solvent: CCN(CC)CC
Solvent: CO
Product: O=C(c1cc(C(F)(F)F)cc(C(F)(F)F)c1)N1CCN(CCNN2CCOCC2)C[C@H]1Cc1c[nH]c2ccccc12
Yield: 27.2 %

Procedure:
A mixture of (2R)-1-[3,5-bis(trifluoromethyl)benzoyl]-2-(1H-indol-3-ylmethyl)-4-(2-methylsulfonyloxyethyl)piperazine (200 mg), 4-aminomorpholine (36 mg) and triethylamine (52 mg) in dry methanol (5 ml) was refluxed for 2 hours. The reaction mixture was concentrated under reduced pressure and the resulting residue was partitioned between ethyl acetate and aqueous sodium hydrogen carbonate solution. The organic layer was washed with brine and dried over magnesium sulfate. After evaporation of the solvent, the residue was purified by column chromatography on silica gel using a mixture of ethyl acetate and methanol (10:1) as an eluent to afford (2R)-1-[3,5-bis(trifluoromethyl)benzoyl]-2-(1H-indol-3-ylmethyl)-4-[2-(morpholinoamino)ethyl]piperazine (55 mg).
Reaction SMILES: Cl[C:2]1[N:3]=[N+:4]([O-:15])[C:5]2[CH:11]=[C:10]3[CH2:12][CH2:13][O:14][C:9]3=[CH:8][C:6]=2[N:7]=1.[N:16]1([CH2:22][CH2:23][CH2:24][NH2:25])[CH2:21][CH2:20][O:19][CH2:18][CH2:17]1>COCCOC>[N:16]1([CH2:22][CH2:23][CH2:24][NH:25][C:2]2[N:3]=[N+:4]([O-:15])[C:5]3[CH:11]=[C:10]4[CH2:12][CH2:13][O:14][C:9]4=[CH:8][C:6]=3[N:7]=2)[CH2:21][CH2:20][O:19][CH2:18][CH2:17]1
Reactant: NCCCN1CCOCC1
Reactant: [O-][n+]1nc(Cl)nc2cc3c(cc21)CCO3
Solvent: COCCOC
Product: [O-][n+]1nc(NCCCN2CCOCC2)nc2cc3c(cc21)CCO3
Yield: 93.3 %

Procedure:
A solution of chloride 206 (250 mg, 1.1 mmol) and 3-(4-morpholinyl)propylamine (0.65 mL, 4.5 mmol) in DME (25 mL) was stirred at reflux temperature for 2 h, the solvent evaporated and the residue purified by chromatography, eluting with a gradient (2-5%) of MeOH/DCM, to give 1-oxide 211 (340 mg, 92%) as a yellow solid: mp 152-154° C.; 1H NMR δ 8.10 (t, J=1.6 Hz, 1H, H-9), 6.79 (s, 1H, H-5), 6.09 (br s, 1H, NH), 4.42 (t, J=8.3 Hz, 2H, H-7), 3.75 (t, J=4.7 Hz, 4H, 2×CH2O), 3.55-3.60 (m, 2H, CH2), 3.30 (dt, J=8.3, 1.6 Hz, 2H, H-7), 2.46-2.52 (m, 6H, 2×CH2N, CH2), 1.82 (p, J=6.5 Hz, 2H, CH2); 13C NMR δ 166.5, 159.4, 151.8, 129.2, 126.4, 116.6, 102.1, 72.9, 67.0 (2), 57.3, 53.8 (2), 40.8, 28.6, 25.3. Anal. calcd for C16H21N5O3: C, 58.0; H, 6.4; N, 21.1. Found: C, 57.8; H, 6.2; N, 21.1%.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Li]CCCC.[C:13]([C:16]1[CH:17]=[C:18]([C:26](=[O:28])[CH3:27])[CH:19]=[C:20]([C:22]([CH3:25])([CH3:24])[CH3:23])[CH:21]=1)(=[O:15])[CH3:14]>C1COCC1>[C:22]([C:20]1[CH:21]=[C:16]([C:13](=[O:15])[CH3:14])[CH:17]=[C:18]([C:26]([OH:28])([C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)[CH3:27])[CH:19]=1)([CH3:23])([CH3:25])[CH3:24]
Reactant: CC(=O)c1cc(C(C)=O)cc(C(C)(C)C)c1
Reactant: Brc1ccccc1
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: CC(=O)c1cc(C(C)(C)C)cc(C(C)(O)c2ccccc2)c1
Reaction time: 0.17 h
Yield: 77.4 %

Procedure:
To 288.0 mg (1.83 mmol) of bromobenzene in 8 ml of dry THF at -78° C. was added 734 ml (1.83 mmol) of n-BuLi (2.5 M in hexanes). The reaction was stirred for 10 min followed by addition of 400 mg (1.83 mmol) of diketone 14 in 2 ml of dry THF. After stirring for 30 min, the mixture was quenched with saturated aqueous NH4Cl and the products were extracted with EtOAc. The EtOAc extracts were washed with water, brine, dried, filtered, and concentrated to give 420 mg of crude compound 15 which was used in the next step without further purification. TLC (20% EtOAC-80% hexanes) Rf 0.7.
Reaction SMILES: [O:1]1[CH2:6][CH2:5][CH:4]([NH2:7])[CH2:3][CH2:2]1.[CH:8]1[C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[CH:11]=[CH:10][C:9]=1[CH:18]=O.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].[OH-].[Na+]>C(Cl)(Cl)Cl>[CH:8]1[C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[CH:11]=[CH:10][C:9]=1[CH2:18][NH:7][CH:4]1[CH2:5][CH2:6][O:1][CH2:2][CH2:3]1
Reactant: O=Cc1ccc2ccccc2c1
Reactant: NC1CCOCC1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Agent: [OH-]
Solvent: ClC(Cl)Cl
Product: c1ccc2cc(CNC3CCOCC3)ccc2c1
Reaction time: 0.5 h
Yield: 68.8 %

Procedure:
To a solution of tetrahydro-2H-pyran-4-amine (500 mg) in chloroform (5 mL), 2-naphthoaldehyde (772 mg) was added and the resulting mixture was stirred for 30 minutes. Sodium (triacetoxy)borohydride (1.57 g) was added and the resulting mixture was stirred for 4 hours at room temperature. To the reaction mixture, an aqueous solution of 1 M sodium hydroxide was added and after stirring the resulting mixture, the chloroform layer was separated and dried over anhydrous sodium sulfate. After filtering off the desiccant, the solvent was distilled off under reduced pressure and the resulting residue was purified by column chromatography (silica gel cartridge; chloroform/methanol=100:0 to 97:3) to give the titled compound (821 mg).
Reaction SMILES: Br[CH2:2][CH2:3][CH2:4][CH:5]=[CH2:6].[Mg].[CH:8]12[O:13][CH:9]1[CH2:10][CH2:11][CH2:12]2>CCOCC.C1COCC1.[Cu]I>[CH2:2]([C@@H:8]1[CH2:12][CH2:11][CH2:10][C@H:9]1[OH:13])[CH2:3][CH2:4][CH:5]=[CH2:6]
Reactant: C1CC2OC2C1
Reactant: C=CCCCBr
Agent: [Cu]I
Agent: [Mg]
Solvent: CCOCC
Solvent: C1CCOC1
Product: C=CCCC[C@@H]1CCC[C@H]1O
Temperature: 20 °C
Reaction time: 0.5 h
Yield: 61.9 %

Procedure:
A solution of 5-bromopent-1-ene (11.81 mL, 100 mmol) in Et2O (100 mL) was added to magnesium (2.43 g, 100 mmol) over 20 minutes. The resulting suspension was heated under reflux for 40 minutes, then cooled to 20° C., taken up in a syringe, and added dropwise at −5° C. to a stirred suspension of CuI (3.17 g, 16.6 mmol) in THF (160 mL). The resulting solution was stirred for 30 minutes at −5° C., then cooled to −20° C. Cyclopentene oxide (7.21 mL, 83 mmol) was added dropwise, and the resulting mixture was warmed to 20° C. over 2 hours, then stirred for 48 hours. The reaction was quenched by addition of NH4Cl(aq.); then the layers were separated, and the aqueous layer was extracted with Et2O. The combined organic phases were washed with H2O and brine, then dried over Na2SO4. Filtration and removal of the volatiles gave a residue that was purified by column chromatography on SiO2 (gradient elution, 1-100% EtOAc/petroleum ether) to afford the title compound (7.92 g, 62%) as a liquid. 1H NMR (400 MHz, CDCl3) δ 5.88-5.76 (m, 1H), 5.01 (d, J=17.2 Hz, 1H), 4.95 (d, J=10.6 Hz, 1H), 3.83 (br s, 1H), 2.12-2.00 (m, 2H), 1.99-1.84 (m, 2H), 1.76-1.30 (m, 7H), 1.24-1.11 (m, 2H).
Reaction SMILES: O1C2C=CC=CC=2N=C1[S:10][CH2:11][CH2:12][CH2:13][CH2:14]CN1C(=O)C2=CC=CC=C2C1=O.O1C2C=CC=CC=2N=[C:28]1[S:36][CH2:37][CH2:38][CH2:39][N:40]1C(=O)C2=CC=CC=C2C1=O>>[S:10]1[CH:11]=[CH:12][CH:13]=[C:14]1[CH2:28][S:36][CH2:37][CH2:38][CH2:39][NH2:40]
Reactant: O=C1c2ccccc2C(=O)N1CCCSc1nc2ccccc2o1
Reactant: O=C1c2ccccc2C(=O)N1CCCCCSc1nc2ccccc2o1
Product: NCCCSCc1cccs1
Yield: 78 %

Procedure:
The same reaction as in Reference Example 4 was repeated except that the N-[5-(2-benzoxazolylthio)pentyl]phthalimide was replaced by N-[3-(2-benzoxazolylthio)propyl]phthalimide, to obtain the title compound at a yield of 78%.
Reaction SMILES: [CH:1]([N:4]1[CH2:9][CH2:8][CH:7]([NH2:10])[CH2:6][CH2:5]1)([CH3:3])[CH3:2].CCN(C(C)C)C(C)C.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[C:44]1([C:50]2[NH:54][C:53]([C:55](O)=[O:56])=[CH:52][CH:51]=2)[CH:49]=[CH:48][CH:47]=[CH:46][CH:45]=1>C(Cl)Cl>[CH:1]([N:4]1[CH2:9][CH2:8][CH:7]([NH:10][C:55]([C:53]2[NH:54][C:50]([C:44]3[CH:45]=[CH:46][CH:47]=[CH:48][CH:49]=3)=[CH:51][CH:52]=2)=[O:56])[CH2:6][CH2:5]1)([CH3:3])[CH3:2]
Reactant: CC(C)N1CCC(N)CC1
Reactant: O=C(O)c1ccc(-c2ccccc2)[nH]1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CC(C)N1CCC(NC(=O)c2ccc(-c3ccccc3)[nH]2)CC1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To 1-isopropyl-piperidin-4-ylamine (350 mg) in DCM (15 mL) was added DIEA (1.67 mL), followed by HATU (935 mg) and 5-phenyl-1H-pyrrole-2-carboxylic acid (461 mg). The mixture was stirred for 1 h at RT whereupon it was washed two times with saturated aqueous NaHCO3 solution, dried over MgSO4 and concentrated to give crude 5-phenyl-1H-pyrrole-2-carboxylic acid (1-isopropyl-piperidin-4-yl)-amide which was used directly in the following step.
Reaction SMILES: C[CH2:2][CH:3]([S:14]([O-:18])=[N:15]C#N)[C:4]1[CH:5]=[N:6][C:7]([C:10]([F:13])([F:12])[F:11])=[CH:8][CH:9]=1.F[C:20](F)(F)C(OC(=O)C(F)(F)F)=O.C(=O)([O-])[O-].[K+].[K+]>C(Cl)Cl>[CH3:20][S:14]([CH:3]([C:4]1[CH:9]=[CH:8][C:7]([C:10]([F:13])([F:12])[F:11])=[N:6][CH:5]=1)[CH3:2])(=[NH:15])=[O:18]
Reactant: O=C(OC(=O)C(F)(F)F)C(F)(F)F
Reactant: CCC(c1ccc(C(F)(F)F)nc1)S([O-])=NC#N
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: ClCCl
Product: CC(c1ccc(C(F)(F)F)nc1)S(C)(=N)=O
Temperature: 25 °C
Yield: 77.1 %

Procedure:
To a stirred solution of methyl(oxido){1-[6-(trifluoromethyl)pyridin-3-yl]ethyl}-λ4-sulfanylidenecyanamide (5 g, 18 mmol) in CH2Cl2 (300 mL) at 0° C. was added trifluoroacetic anhydride (7.5 mL, 54 mmol). The mixture was allowed to react at 25° C. until the starting material was fully consumed. The reaction mixture was concentrated in vacuo, dissolved in methanol (125 mL) and treated with potassium carbonate (12.5 g, 90 mmol). The mixture was allowed to stir at 25° C. until the starting material was consumed. The crude reaction mixture was filtered, concentrated and purified by chromatography (acetone-hexanes) to furnish 5-[1-(methylsulfonimidoyl)ethyl]-2-(trifluoromethyl)pyridine as a white solid (3.5 g, 77%): ESIMS m/z 253 ([M+H]+).
Reaction SMILES: [N+]([C:4]1[CH:11]=[CH:10][CH:9]=[C:8]([N+:12]([O-:14])=[O:13])[C:5]=1[C:6]#[N:7])([O-])=O.[CH3:15][O:16][C:17]1[CH:18]=[C:19]([CH:22]=[CH:23][CH:24]=1)[CH2:20][OH:21]>>[CH3:15][O:16][C:17]1[CH:18]=[C:19]([CH:22]=[CH:23][CH:24]=1)[CH2:20][O:21][C:4]1[CH:11]=[CH:10][CH:9]=[C:8]([N+:12]([O-:14])=[O:13])[C:5]=1[C:6]#[N:7]
Reactant: N#Cc1c([N+](=O)[O-])cccc1[N+](=O)[O-]
Reactant: COc1cccc(CO)c1
Product: COc1cccc(COc2cccc([N+](=O)[O-])c2C#N)c1
Yield: 83 %

Procedure:
Prepared as in Example 158c from 2,6-dinitrobenzonitrile and 3-methoxybenzylalcohol in 83% yield. 1H NMR (400 MHz, d-DMSO) δ 3.75 (s, 3H), 5.38 (s, 2H), 6.91 (d, J=8.0 Hz, 1H), 7.04 (d, J=7.6 Hz, 1H), 7.07 (s, 1H), 7.33 (t, J=8.0 Hz, 1H), 7.78 (d, J=8.8 Hz, 4H), 7.93-7.87 (m, 2H).
Reaction SMILES: [CH2:1]1[C:6]2[C:7]3[N:8]([CH:19]=[N:20][N:21]=3)[C:9]3[CH:17]=[CH:16][C:15](=[O:18])[CH2:14][C:10]=3[N:11]3[CH:12]=[CH:13][C:4]([C:5]=23)=[CH:3][CH2:2]1.C(=O)([O-])[O-].[K+].[K+].Cl[CH2:29][CH:30]1[CH2:32][CH2:31]1>CN(C)C=O>[CH:30]1([CH2:29][CH:14]2[C:10]3[N:11]4[CH:12]=[CH:13][C:4]5[C:5]4=[C:6]([CH2:1][CH2:2][CH:3]=5)[C:7]4[N:8]([CH:19]=[N:20][N:21]=4)[C:9]=3[CH:17]=[CH:16][C:15]2=[O:18])[CH2:32][CH2:31]1
Reactant: ClCC1CC1
Reactant: O=C1C=CC2=C(C1)n1ccc3c1=C(CCC=3)c1nncn12
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: O=C1C=CC2=C(C1CC1CC1)n1ccc3c1=C(CCC=3)c1nncn12
Temperature: 95 °C
Reaction time: 8 h
Yield: 54.8 %

Procedure:
1,2-Dihydrobenzo[b]pyrrolo[3,2,1-jk][1,2,4]triazolo[4,3-d][1,4]benzodiazepin-8(7H)-one (5.2 g) was dissolved in dimethylformamide (150 ml). Potassium carbonate (0.5 g) was added, followed by (chloromethyl)cyclopropane (2.1 ml). The mixture was stirred at 95° C. overnight, filtered, and evaporated under reduced pressure. The residue was purified by high performance liquid chromatography (1% methanol/dichloromethane) to yield 3.4 g (54.8%) of product. Recrystallization from pentane/ether gave the analytical sample, mp 99° C.