Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]1[C:6]([C:7]2[CH:8]=[C:9]3[C:14](=[C:15]4[CH:19]=[CH:18][O:17][C:16]=24)[NH:13][C:12]([CH3:21])([CH3:20])[C:11](=[O:22])[C:10]3([CH3:24])[CH3:23])=[C:5]([CH3:25])[O:4][N:3]=1.[BrH:26].[NH+]1C=CC=CC=1.[OH-].[Na+]>C1COCC1>[Br:26][C:18]1[O:17][C:16]2=[C:7]([C:6]3[C:2]([CH3:1])=[N:3][O:4][C:5]=3[CH3:25])[CH:8]=[C:9]3[C:14]([NH:13][C:12]([CH3:20])([CH3:21])[C:11](=[O:22])[C:10]3([CH3:24])[CH3:23])=[C:15]2[CH:19]=1
Reactant: Cc1noc(C)c1-c1cc2c(c3ccoc13)NC(C)(C)C(=O)C2(C)C
Reactant: Br
Agent: [Na+]
Agent: [OH-]
Agent: c1cc[nH+]cc1
Solvent: C1CCOC1
Product: Cc1noc(C)c1-c1cc2c(c3cc(Br)oc13)NC(C)(C)C(=O)C2(C)C
Temperature: 25 °C
Reaction time: 1 h
Yield: 44 %

Procedure:
To a solution of 6-(3,5-dimethylisoxazol-4-yl)-2,2,4,4-tetramethyl-1,2,3,4-tetrahydro-furo[2,3-h]quinolin-3-one (31 mg) obtained in Example 93, 3) in THF (1.0 ml) was added pyridinium hydrobromide perbromide (29 mg) under ice-cooling, and the mixture was stirred at room temperature for 1 hr. The reaction solution was neutralized with 1N aqueous sodium hydroxide solution, and extracted with ethyl acetate. The organic layer was washed with water and saturated brine, and dried over sodium sulfate. The solvent was evaporated under reduced pressure. The residue was subjected to normal phase chromatography (elution solvent hexane→hexane-ethyl acetate=3:2) to give the title compound (17 mg, 44%).
Reaction SMILES: CN1CCOCC1.Cl[C:9]([O:11][CH:12]([CH3:14])[CH3:13])=[O:10].Cl.[Cl:16][C:17]1[CH:18]=[CH:19][C:20]([O:23][CH2:24][CH:25]([NH:27][C:28](=[O:34])[C@H:29]([CH:31]([CH3:33])[CH3:32])[NH2:30])[CH3:26])=[N:21][CH:22]=1.O>C(Cl)Cl>[Cl:16][C:17]1[CH:18]=[CH:19][C:20]([O:23][CH2:24][CH:25]([NH:27][C:28](=[O:34])[C@H:29]([CH:31]([CH3:33])[CH3:32])[NH:30][C:9]([O:11][CH:12]([CH3:14])[CH3:13])=[O:10])[CH3:26])=[N:21][CH:22]=1
Reactant: CC(COc1ccc(Cl)cn1)NC(=O)[C@@H](N)C(C)C
Reactant: CC(C)OC(=O)Cl
Agent: Cl
Solvent: O
Solvent: CN1CCOCC1
Solvent: ClCCl
Product: CC(COc1ccc(Cl)cn1)NC(=O)[C@@H](NC(=O)OC(C)C)C(C)C
Temperature: 25 °C
Reaction time: 15 h
Yield: 39.5 %

Procedure:
0.8 g of N-methylmorpholine, and subsequently 0.5 g of isopropyl chloroformate were added to a suspension containing 1.4 g of N1 -[2-(5-chloro-2-pyridyloxy)-1-methylethyl]-L-valinamide hydrochloride suspended in 50 ml of methylene chloride at -15° C. The mixture was allowed to sit and warm naturally to room temperature and stirred for 15 hours at room temperature. Water was subsequently added to the reaction mixture. After the methylene chloride layer was washed with water, the organic layer was dried over anhydrous magnesium sulfate and then the methylene chloride was removed under reduced pressure. The residue was purified by column chromatography on silica gel, thus obtaining 0.6 g of the desired product in the form of colorless grains (yield: 38%).
Reaction SMILES: [CH2:1]([N:8]1[C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[C:10]([CH:17]=[O:18])=[N:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl.O>C1(C)C=CC=CC=1>[CH2:1]([N:8]1[C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[C:10]([CH2:17][OH:18])=[N:9]1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=Cc1nn(Cc2ccccc2)c2ccccc12
Agent: Cl
Solvent: O
Solvent: Cc1ccccc1
Product: OCc1nn(Cc2ccccc2)c2ccccc12

Procedure:
1-benzyl-1H-indazol-3-carbaldehyde (2.36 g, 10 mmol, 1 eq.) and toluene (12 mL) were placed in a thoroughly dried 100 mL flask fitted with a magnetic stirrer and inerted with nitrogen. A 70% solution of sodium dihydro-bis(2-methoxyethoxy)aluminate in toluene (2.8 mL, 10 mmol, 2 eq.) was then slowly added to the solution at room temperature. Once the reaction was complete (after approximately 15 minutes), 2 M HCl (10 mL), H2O (10 mL) and toluene (15 mL) were added. The phases were separated and the aqueous phase was extracted twice with toluene. The pooled organic phases were washed with water and concentrated. The product was then precipitated out by adding n-hexane, filtered and dried. Yield: 1.95 g of white solid (82.0%).
Reaction SMILES: [NH2:1][C:2]1C=[CH:9][C:5](C(O)=O)=[CH:4][C:3]=1O.[O:12]1[C:16]2[CH:17]=[CH:18][C:19]([C:21]([OH:23])=O)=[CH:20][C:15]=2[N:14]=[CH:13]1.C(OC(OCC)OCC)(=O)C.O1C2C=C(C(N3CC=CCC3)=O)C=CC=2N=C1.N1CC=CCC1>>[O:12]1[C:16]2[CH:17]=[CH:18][C:19]([C:21]([N:1]3[CH2:2][CH:3]=[CH:4][CH2:5][CH2:9]3)=[O:23])=[CH:20][C:15]=2[N:14]=[CH:13]1
Reactant: O=C(O)c1ccc2ocnc2c1
Reactant: Nc1ccc(C(=O)O)cc1O
Agent: C1=CCNCC1
Agent: CCOC(OCC)OC(C)=O
Agent: O=C(c1ccc2ncoc2c1)N1CC=CCC1
Product: O=C(c1ccc2ocnc2c1)N1CC=CCC1

Procedure:
4-Amino-3-hydroxybenzoic acid is converted into 1,3-benzoxazol-5-carboxylic acid by treating with diethoxymethyl acetate as described for the preparation of Invention Compound. IX. EMIS m/z=163 (parent), 146 (base), 118, 90, and 63. Coupling of the acid with 1,2,3,6-tetrahydropyridine is performed in the same manner as described for the preparation of isomeric Invention Compound IX. 1H NMR δ 2.1-2.4 (br, 4), 3.4-4.3 (br m, 4), 5.5-5.95 (br m, 2), 7.45 (dd, 1, J=8.17, 1.41 Hz), 7.70 (d, 1, J=0.96 Hz), 7.83 (d, 1, J=8.16 Hz), and 8.18 ppm (s, 1).
Reaction SMILES: [CH2:1]([O:17][CH2:18][CH:19]([CH2:21][OH:22])[OH:20])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8]/[CH:9]=[CH:10]\[CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH3:16].[C:23]1([C:29]([C:37]2[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=2)([C:31]2[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=2)Cl)[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1.C(N(CC)CC)C>C1COCC1.C(#N)C>[CH2:1]([O:17][CH2:18][C@@H:19]([CH2:21][O:22][C:29]([C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)([C:37]1[CH:38]=[CH:39][CH:40]=[CH:41][CH:42]=1)[C:31]1[CH:32]=[CH:33][CH:34]=[CH:35][CH:36]=1)[OH:20])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8]/[CH:9]=[CH:10]\[CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH3:16]
Reactant: ClC(c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: CCCCCC/C=C\CCCCCCCCOCC(O)CO
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Solvent: CC#N
Product: CCCCCC/C=C\CCCCCCCCOC[C@H](O)COC(c1ccccc1)(c1ccccc1)c1ccccc1
Temperature: 25 °C
Yield: 90.7 %

Procedure:
9.07 grams of 1-(cis-9-hexadecenyl)-glycerol was dissolved in a mixture of dry THF (160 ml) and dry acetonitrile (40 ml). 10.52 grams triphenylchloromethane and 10 ml triethylamine were added, and the reaction mixture was refluxed for 15 hours. The reaction mixture was cooled to room temperature, poured on ice (100 grams), transferred to a separatory funnel, and extracted thrice with 100 ml chloroform. The organic phase was washed consecutively with 100 ml water, 100 ml dilute (1.0%) sulfuric acid, 100 ml water, 100 ml saturated aqueous sodium bicarbonate, and again with 100 ml water. The organic phase was dried over anhydrous sodium sulfate and the solvent was removed under reduced pressure. The obtained residue was dissolved in hot hexane (100 ml) and the resulting solution was cooled at 4° C. for 36 hours. Filtration of precipitated by-products and removal of solvent under reduced pressure yielded 14.57 grams of crude product. The crude product was purified by chromatography over silica gel (200 grams). 9.81 grams of pure 1-(cis-9-hexadecenyl)-3-trityl-sn-glycerol was eluted with chloroform. The yield was 61.1%.
Reaction SMILES: Cl.Cl.[CH3:3][C@H:4]1[CH2:9][NH:8][CH2:7][CH2:6][N:5]1[C:10]([C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][N:13]=1)=[O:11].CCN(C(C)C)C(C)C.[C:27]([C:29]1[CH:34]=[CH:33][C:32]([S:35](Cl)(=[O:37])=[O:36])=[CH:31][CH:30]=1)#[N:28].O>C(Cl)Cl>[CH3:3][C@@H:4]1[N:5]([C:10]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][N:13]=2)=[O:11])[CH2:6][CH2:7][N:8]([S:35]([C:32]2[CH:31]=[CH:30][C:29]([C:27]#[N:28])=[CH:34][CH:33]=2)(=[O:37])=[O:36])[CH2:9]1
Reactant: C[C@H]1CNCCN1C(=O)c1ccccn1
Reactant: N#Cc1ccc(S(=O)(=O)Cl)cc1
Agent: Cl
Solvent: ClCCl
Solvent: O
Solvent: CCN(C(C)C)C(C)C
Product: C[C@H]1CN(S(=O)(=O)c2ccc(C#N)cc2)CCN1C(=O)c1ccccn1
Yield: 50.8 %

Procedure:
To a solution of (2S)-2-methyl-1-(2-pyridinylcarbonyl)piperazine dihydrochloride (Description 16) (71 mg, 0.255 mmol) in DCM (3 ml) was added DIPEA (0.183 ml, 1.046 mmol) at room temperature and to it was slowly added 4-cyanobenzenesulfonyl chloride (56.6 mg, 0.281 mmol) and the resultant mixture then stirred for 3 h. 5 ml of water and 5 ml of DCM were added and the organic layer separated with a phase separation cartridge and then evaporated under vacuum. The crude material (120 mg) was purified via Biotage (12M silica column) using a gradient [i-hex/EtOAc] ([90/10] to [40/60]). The desired fractions were then collected and concentrated to dryness giving the title compound (48 mg) as a white solid.
Reaction SMILES: [CH3:1][NH:2][NH2:3].[Cl:4][C:5]1[CH:6]=[C:7]2[C:12](=[CH:13][CH:14]=1)[N:11]([C:15](=[O:18])[CH2:16][CH3:17])[CH2:10][C:9](=[CH:19]O)[C:8]2=O.C(O)(=O)C>CO>[Cl:4][C:5]1[CH:14]=[CH:13][C:12]2[N:11]([C:15](=[O:18])[CH2:16][CH3:17])[CH2:10][C:9]3[CH:19]=[N:3][N:2]([CH3:1])[C:8]=3[C:7]=2[CH:6]=1
Reactant: CNN
Reactant: CCC(=O)N1CC(=CO)C(=O)c2cc(Cl)ccc21
Solvent: CO
Solvent: CC(=O)O
Product: CCC(=O)N1Cc2cnn(C)c2-c2cc(Cl)ccc21
Yield: 39.6 %

Procedure:
Methylhydrazine(30.56 g) was added dropwise to a mixture of 6-chloro-3-hydroxymethylene-4-oxo-1-propionyl-1,2,3,4-tetrahydroquinoline(160.3 g) and acetic acid (75.8 ml) in methanol(1.6 liters) with stirring and cooling over a period of 10 minutes. After being stirred for 1 hour at room temperature, the mixture was filtered by sunction and the filtrate was evaporated in vacuo after addition of acetic acid (160 ml) to it. The residue was neutralized with aqueous sodium hydroxide under ice cooling. The resulting precipitate was collected by filtration, washed with water and recrystallized from aqueous methanol and then ethanol to give 8-chloro-4,5-dihydro-1-methyl-5-propionyl-1H -pyrazolo[4,3-c]-quinoline (65.84 g). The physical data of the compound was identical to that of the object compound of Example 3.
Reaction SMILES: Cl[CH2:2][C:3]1[CH:8]=[CH:7][N:6]2[N:9]=[CH:10][N:11]=[C:5]2[CH:4]=1.[N-:12]=[N+:13]=[N-:14].[Na+]>CN(C=O)C>[N:12]([CH2:2][C:3]1[CH:8]=[CH:7][N:6]2[N:9]=[CH:10][N:11]=[C:5]2[CH:4]=1)=[N+:13]=[N-:14]
Reactant: [N-]=[N+]=[N-]
Reactant: ClCc1ccn2ncnc2c1
Agent: [Na+]
Solvent: CN(C)C=O
Product: [N-]=[N+]=NCc1ccn2ncnc2c1
Temperature: 80 °C
Reaction time: 2 h
Yield: 81.3 %

Procedure:
To a solution of 7-(chloromethyl)-[1,2,4]triazolo[1,5-a]pyridine (4-3) (400 mg, 2.4 mmol) in dried DMF (5 mL) was added NaN3 (250 mg, 3.6 mmol) under N2. The reaction mixture was stirred at 80° C. for 2 h, then quenched with aqueous Na2S2O3. The resulting mixture was extracted with EtOAc, dried on Na2SO4, and concentrated to afford the title compound (340 mg), which was used in next step without further purification. MS (m/z): 175 (M+1)+.
Reaction SMILES: [OH:1][CH:2]([CH2:17][N:18]1[CH2:22][CH2:21][CH2:20][CH2:19]1)[CH2:3][O:4][C:5]1[CH:6]=[C:7]2[C:11](=[CH:12][C:13]=1[O:14][CH3:15])[C:10](=O)[CH2:9][CH2:8]2.[CH3:23][O:24][C:25]1[CH:26]=[C:27]([N:31]=[C:32]=S)[CH:28]=[CH:29][CH:30]=1.C[Si](C)(C)[Si](C)(C)C.[Li].[NH2:43][NH2:44].C(O)(=O)C>O.C1COCC1>[CH3:15][O:14][C:13]1[CH:12]=[C:11]2[C:7]([CH2:8][C:9]3[C:10]2=[N:43][NH:44][C:32]=3[NH:31][C:27]2[CH:28]=[CH:29][CH:30]=[C:25]([O:24][CH3:23])[CH:26]=2)=[CH:6][C:5]=1[O:4][CH2:3][CH:2]([OH:1])[CH2:17][N:18]1[CH2:22][CH2:21][CH2:20][CH2:19]1
Reactant: NN
Reactant: COc1cccc(N=C=S)c1
Reactant: COc1cc2c(cc1OCC(O)CN1CCCC1)CCC2=O
Agent: C[Si](C)(C)[Si](C)(C)C
Agent: [Li]
Solvent: C1CCOC1
Solvent: CC(=O)O
Solvent: O
Product: COc1cccc(Nc2[nH]nc3c2Cc2cc(OCC(O)CN4CCCC4)c(OC)cc2-3)c1

Procedure:
To a mixture of 5-(2-hydroxy-3-pyrrolidin-1-yl-propoxy)-6-methoxy-indan-1-one (Intermediate N) (0.16 g, 0.0005 mole), 3-methoxy-phenyl isothiocyanate (Compound 19a) (0.08 mL, 0.0006 mole) and THF (1.5 mL) was added to lithium hexamethyldisilane (0.7 mL, 0.0007 mole) dropwise at room temperature with stirring. The reaction mixture was stirred for 4 hrs. Hydrazine (0.035 mL, 0.0011 mole) and acetic acid (0.66 mL, 0.0011 mole) were added to the reaction mixture. The reaction mixture was then heated at the reflux temperature for 18 hrs. To the resulting mixture was first added water (10 mL) and then the reaction mixture was extracted with CH2Cl2. The organic layers were combined and washed with aqueous NaHCO3 solution, then washed with water and brine solution, dried (Na2SO4), and solvent was removed in vacuo. The crude material was purified by reverse phase HPLC. Lyophilization yielded the title compound, 1-[7-Methoxy-3-(3-methoxy-phenylamino)-2,4-dihydro-indeno[1,2-c]pyrazol-6-yloxy]-3-pyrrolidin-1-yl-propan-2-ol as a white powder. MS m/z 451 (M+H)+; 1HNMR (DMSO-d6): 1.89(m, 2H), 2.02(m, 2H), 3.12(m, 2H), 3.34(m, 2H), 3.45(s, 2H), 3.62(s, 2H), 3.70(s, 3H), 3.85(s, 3H), 4.00(m, 2H), 4.20(m, 2H), 6.37(d, 1H), 6.71(d, 1H), 6.78(s, 1H), 7.10(t, 1H), 7.25(s, 1H), 7.3(s, 1H), 8.68(br s, 1H), 9.60(br s, 1H).
Reaction SMILES: [CH2:1]([N:13]1[CH2:17][CH2:16][CH2:15][CH2:14]1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH3:12].[Br:18][CH2:19][CH2:20][CH2:21][Cl:22]>CO>[Br-:18].[Cl:22][CH2:21][CH2:20][CH2:19][N+:13]1([CH2:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH3:12])[CH2:14][CH2:15][CH2:16][CH2:17]1
Reactant: ClCCCBr
Reactant: CCCCCCCCCCCCN1CCCC1
Solvent: CO
Product: CCCCCCCCCCCC[N+]1(CCCCl)CCCC1
Product: [Br-]
Temperature: 65 °C
Reaction time: 6 h
Yield: 64.1 %

Procedure:
Pyrrolidine (47 g), 1-bromododecane (149.5 g) and potassium carbonate (83 g) were added to 560 mL of acetone. The reaction mixture was heated to 55° C. for 24 hr. then filtered. Solvent was removed from the filtrate, yielding 92 g of N-dodecylpyrrolidine. N-dodecylpyrrolidine (80 g) and 1-bromo-3-chloropropane (52.6 g) were dissolved in 133 mL of methanol and the reaction mixture was heated to 65° C. for 18 hr. After cooling to room temperature, methanol was removed under reduced pressure. The residue was poured into 2 L of diethylether with stirring and the mixture was allowed to stand for another 6 hr. The white precipitate was filtered and dried at 40° C. under a vacuum for 24 hr yielding 85 g of (3-chloropropyl)dodecylpyrrolidinium bromide as a white solid.
Reaction SMILES: [Cl:1][C:2]1[C:6]([Cl:7])=[C:5]([CH3:8])[NH:4][C:3]=1[C:9]([NH:11][CH:12]1[CH2:17][CH2:16][N:15]([C:18]2[N:23]=[C:22]([O:24][CH2:25][CH2:26]SC)[N:21]=[C:20]([C:29]([NH:31][O:32][CH3:33])=[O:30])[CH:19]=2)[CH2:14][CH2:13]1)=[O:10].[CH:34]1C=C(Cl)C=C(C(OO)=O)C=1.[S:45]([O-:48])([O-])=[O:46].[Na+].[Na+]>C(Cl)Cl>[Cl:1][C:2]1[C:6]([Cl:7])=[C:5]([CH3:8])[NH:4][C:3]=1[C:9]([NH:11][CH:12]1[CH2:13][CH2:14][N:15]([C:18]2[N:23]=[C:22]([O:24][CH2:25][CH2:26][S:45]([CH3:34])(=[O:48])=[O:46])[N:21]=[C:20]([C:29]([NH:31][O:32][CH3:33])=[O:30])[CH:19]=2)[CH2:16][CH2:17]1)=[O:10]
Reactant: O=S([O-])[O-]
Reactant: CONC(=O)c1cc(N2CCC(NC(=O)c3[nH]c(C)c(Cl)c3Cl)CC2)nc(OCCSC)n1
Reactant: O=C(OO)c1cccc(Cl)c1
Agent: [Na+]
Solvent: ClCCl
Product: CONC(=O)c1cc(N2CCC(NC(=O)c3[nH]c(C)c(Cl)c3Cl)CC2)nc(OCCS(C)(=O)=O)n1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
6-(4-{[(3,4-Dichloro-5-methyl-1H-pyrrol-2-yl)carbonyl]amino}piperidin-1-yl)-N-methoxy-2-[2-(methylthio)ethoxy]pyrimidine-4-carboxamide (Example 165, 0.10 g, 0.19 mmol) was suspended in DCM (5 ml) and cooled to 0° C. mCPBA (0.067 g, 0.387 mmol, 70%) was added, then the reaction was warmed to room temperature and stirred for 4 h. A further equivalent of mCPBA was added and the mixture was stirred overnight. A solution of sodium sulfite (5%, 3 ml) was added and the layers separated. The aqueous phase was extracted with EtOAc and the combined organic extract was dried over magnesium sulfate and concentrated to give a white solid which was purified by reverse phase chromatography eluting with (20% to 75% acetonitrile in water, 0.1% TFA) affording the title compound (44 mg).
Reaction SMILES: [F:1][C:2]1[CH:9]=[C:8]([CH2:10][OH:11])[CH:7]=[CH:6][C:3]=1[C:4]#[N:5].C(N(CC)CC)C.[CH3:19][S:20](Cl)(=[O:22])=[O:21]>C(Cl)Cl>[CH3:19][S:20]([O:11][CH2:10][C:8]1[CH:7]=[CH:6][C:3]([C:4]#[N:5])=[C:2]([F:1])[CH:9]=1)(=[O:22])=[O:21]
Reactant: CS(=O)(=O)Cl
Reactant: N#Cc1ccc(CO)cc1F
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CS(=O)(=O)OCc1ccc(C#N)c(F)c1
Reaction time: 1.5 h

Procedure:
2-Fluoro-4-hydroxymethylbenzonitrile (1.3 g, 8.6 mmol; see step (ii) above) was dissolved in 50 mL of CH2Cl2 and cooled on an ice bath. Triethylamine (0.87 g, 8.6 mmol) and methanesulfonyl chloride (0.99 g, 8.7 mmol) were added. After stirring for 1.5 h the reaction mixture was washed with 1M HCl. The organic phase was dried (Na2SO4) and evaporated. The product could be used without purification. Yield of a colourless oil: 1.8 g (92%).
Reaction SMILES: [F:1][C:2]1[CH:24]=[CH:23][CH:22]=[C:21]([C:25]([F:28])([F:27])[F:26])[C:3]=1[C:4]([NH:6][C:7]1[S:8][C:9]2[CH:10]3[O:20][CH:13]([CH2:14][C:15]=2[C:16]=1[C:17]([OH:19])=O)[CH2:12][CH2:11]3)=[O:5].[F:29][C:30]([F:35])([F:34])[CH2:31][CH2:32][NH2:33].N>>[F:1][C:2]1[CH:24]=[CH:23][CH:22]=[C:21]([C:25]([F:26])([F:27])[F:28])[C:3]=1[C:4]([NH:6][C:7]1[S:8][C:9]2[CH:10]3[O:20][CH:13]([CH2:14][C:15]=2[C:16]=1[C:17]([NH:33][CH2:32][CH2:31][C:30]([F:35])([F:34])[F:29])=[O:19])[CH2:12][CH2:11]3)=[O:5]
Reactant: NCCC(F)(F)F
Reactant: O=C(Nc1sc2c(c1C(=O)O)CC1CCC2O1)c1c(F)cccc1C(F)(F)F
Agent: N
Product: O=C(Nc1sc2c(c1C(=O)NCCC(F)(F)F)CC1CCC2O1)c1c(F)cccc1C(F)(F)F

Procedure:
The title compound was prepared from the product of Example 4A and commercially available 3,3,3-trifluoropropylamine according to the procedure described for Example 4B. MS (DCI/NH3) m/z 511 (M+H)+.
Reaction SMILES: [C:1]1([CH2:7][CH2:8][CH2:9][NH2:10])C=CC=CC=1.[CH2:11]1[C:19]2[CH:18]=[CH:17][N:16]=[CH:15][C:14]=2[CH2:13][N:12]1[C:20]([NH:22][C:23]1[CH:31]=[CH:30][C:26]([C:27]([OH:29])=O)=[CH:25][CH:24]=1)=[O:21].C1C2C(=CC=CC=2)CN1[C:41](NC1C=CC(C(O)=O)=CC=1)=[O:42]>>[O:42]1[CH2:1][CH2:7][C@@H:8]([CH2:9][NH:10][C:27]([C:26]2[CH:30]=[CH:31][C:23]([NH:22][C:20]([N:12]3[CH2:11][C:19]4[CH:18]=[CH:17][N:16]=[CH:15][C:14]=4[CH2:13]3)=[O:21])=[CH:24][CH:25]=2)=[O:29])[CH2:41]1
Reactant: O=C(O)c1ccc(NC(=O)N2Cc3ccncc3C2)cc1
Reactant: NCCCc1ccccc1
Reactant: O=C(O)c1ccc(NC(=O)N2Cc3ccccc3C2)cc1
Product: O=C(NC[C@@H]1CCOC1)c1ccc(NC(=O)N2Cc3ccncc3C2)cc1

Procedure:
The title compound was prepared as described in Example 1C, substituting (S)-(tetrahydrofuran-3-yl)methanamine for 3-phenylpropan-1-amine and 4-(2,3-dihydro-1H-pyrrolo[3,4-c]pyridine-2-carboxamido)benzoic acid for 4-(isoindoline-2-carboxamido)benzoic acid. 1H NMR (300 MHz, DMSO-d6) δ 8.64 (s, 2H), 8.61 (s, 1H), 8.50 (d, J=5.0 Hz, 1H), 8.38 (t, J=5.7 Hz, 1H), 7.81-7.74 (m, 2H), 7.69-7.62 (m, 2H), 7.44 (d, J=5.1 Hz, 1H), 4.86-4.79 (m, 4H), 3.80-3.66 (m, 2H), 3.67-3.56 (m, 1H), 3.47 (dd, J=8.5, 5.3 Hz, 1H), 3.21 (dt, J=13.2, 5.8 Hz, 1H), 2.01-1.86 (m, 1H), 1.67-1.53 (m, 1H); MS (ESI(+)) m/e 367 (M+H)+.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[N:11]([CH3:12])[C:10]3=[CH:13][S:14][CH:15]=[C:9]3[C:8](=O)[NH:7][C:6]=2[CH:17]=1.P12(SP3(SP(SP(S3)(S1)=S)(=S)S2)=S)=[S:19]>N1C=CC=CC=1>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[N:11]([CH3:12])[C:10]3=[CH:13][S:14][CH:15]=[C:9]3[C:8](=[S:19])[NH:7][C:6]=2[CH:17]=1
Reactant: S=P12SP3(=S)SP(=S)(S1)SP(=S)(S2)S3
Reactant: CN1c2ccc(Cl)cc2NC(=O)c2cscc21
Solvent: c1ccncc1
Product: CN1c2ccc(Cl)cc2NC(=S)c2cscc21
Reaction time: 18 h

Procedure:
A mixture of 0.5 g. of 7-chloro-4-methyl-4,9-dihydro-10H-thieno[3,4-b][1,5]benzodiazepin-10-one and 0.5 g. of phosphorus pentasulfide in 5 ml. of dry pyridine is stirred and heated under reflux for 4 hours. The mixture is concentrated to dryness and is stirred with 10 ml. of 1N sodium carbonate solution for 18 hours. The precipitate is collected, washed with water and recrystallized from methanol to give a yellow solid, m.p. 238°-240° C.
Reaction SMILES: [Cl:1][C:2]1[C:3]([N:8]2[C:12]([C:13]([O:15][CH3:16])=[O:14])=[CH:11][C:10]([CH:17]=O)=[N:9]2)=[N:4][CH:5]=[CH:6][CH:7]=1.Cl.[NH2:20][OH:21].C([O-])(=O)C.[Na+]>C(O)C.O.C(OC)(C)(C)C>[Cl:1][C:2]1[C:3]([N:8]2[C:12]([C:13]([O:15][CH3:16])=[O:14])=[CH:11][C:10]([CH:17]=[N:20][OH:21])=[N:9]2)=[N:4][CH:5]=[CH:6][CH:7]=1
Reactant: NO
Reactant: COC(=O)c1cc(C=O)nn1-c1ncccc1Cl
Agent: CC(=O)[O-]
Agent: Cl
Agent: [Na+]
Solvent: CCO
Solvent: COC(C)(C)C
Solvent: O
Product: COC(=O)c1cc(C=NO)nn1-c1ncccc1Cl

Procedure:
Methyl 1-(3-chloropyridin-2-yl)-3-formyl-1H-pyrazole-5-carboxylate (0.99 g), hydroxylamine hydrochloride (0.39 g) and sodium acetate (0.61 g) were stirred at RT in a mixture of 5 ml of ethanol and 3 ml of water for 30 min. The mixture was diluted with methyl tert-butyl ether, washed with saturated sodium chloride solution and dried over sodium sulphate. Distillative removal of the solvent gave the desired target product.
Reaction SMILES: [CH:1](NC(C)C)(C)C.[CH2:8]([C@H:10]1[C@@H:14]([OH:15])[CH2:13][C:12](=[O:16])[N:11]1[C:17]1[CH:24]=[CH:23][C:20]([C:21]#[N:22])=[C:19]([O:25][CH3:26])[CH:18]=1)[CH3:9].IC.[Cl-].[NH4+]>O1CCCC1>[CH2:8]([C@H:10]1[C@@H:14]([OH:15])[C@H:13]([CH3:1])[C:12](=[O:16])[N:11]1[C:17]1[CH:24]=[CH:23][C:20]([C:21]#[N:22])=[C:19]([O:25][CH3:26])[CH:18]=1)[CH3:9]
Reactant: CC[C@H]1[C@@H](O)CC(=O)N1c1ccc(C#N)c(OC)c1
Reactant: CC(C)NC(C)C
Agent: [Cl-]
Agent: [NH4+]
Solvent: C1CCOC1
Solvent: CI
Product: CC[C@H]1[C@@H](O)[C@H](C)C(=O)N1c1ccc(C#N)c(OC)c1
Reaction time: 1 h
Yield: 50 %

Procedure:
To a solution of diisopropylamine (0.291 mL) in tetrahydrofuran (8 mL) was added dropwise n-butyllithium-hexane solution (1.24 mL, 1.6 mol/L) at −78° C., the mixture was stirred for 1 hr, and a solution of 4-[(2S,3S)-2-ethyl-3-hydroxy-5-oxopyrrolidin-1-yl]-2-methoxybenzonitrile (206.5 mg) in tetrahydrofuran (6 mL) was added dropwise. The mixture was stirred at −78° C. for 30 min, iodomethane (0.247 mL) was added dropwise at −78° C., and the mixture was stirred at 0° C. for 1 hr. Aqueous ammonium chloride solution was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The extract was dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: hexane/ethyl acetate=30/1→1/4) to give the title compound as a colorless solid (yield: 108.8 mg, 50%).
Reaction SMILES: [CH2:1]([NH:3][CH2:4][CH3:5])[CH3:2].[Cl:6][CH2:7][C:8]([C:10]1[CH:23]=[CH:22][C:21]2[O:20][C:19]3[C:14](=[CH:15][C:16]([C:24](=[O:27])[CH2:25]Cl)=[CH:17][CH:18]=3)[CH2:13][C:12]=2[CH:11]=1)=[O:9].[I-].[K+]>O1CCCC1>[ClH:6].[ClH:6].[CH2:1]([N:3]([CH2:4][CH3:5])[CH2:7][C:8]([C:10]1[CH:23]=[CH:22][C:21]2[O:20][C:19]3[C:14](=[CH:15][C:16]([C:24](=[O:27])[CH2:25][N:3]([CH2:4][CH3:5])[CH2:1][CH3:2])=[CH:17][CH:18]=3)[CH2:13][C:12]=2[CH:11]=1)=[O:9])[CH3:2]
Reactant: O=C(CCl)c1ccc2c(c1)Cc1cc(C(=O)CCl)ccc1O2
Reactant: CCNCC
Agent: [I-]
Agent: [K+]
Solvent: C1CCOC1
Product: CCN(CC)CC(=O)c1ccc2c(c1)Cc1cc(C(=O)CN(CC)CC)ccc1O2
Product: Cl
Reaction time: 168 h

Procedure:
To a solution of 200 ml. of diethylamine in 500 ml. of tetrahydrofuran were added 33.5 g (0.10 mole) of 2,7-bis(2-chloroacetyl)xanthene and 2 g of potassium iodide with warming. The reaction mixture was allowed to stand for 7 days then filtered and the filtrate was concentrated. The residual concentrate was dissolved in tetrahydrofuran, filtered, and the filtrate acidified with ethereal HCl to Congo Red. The resulting precipitate was filtered, recrystallized from diethyl ether, ethanol, and butanone and dried in vacuo to give the desired product. M.P. 164°-167°C. (dec.).
Reaction SMILES: [CH:1]1([NH:4][C:5]([C:7]2[N:8]=[N:9][N:10]([C:24]3[CH:29]=[CH:28][C:27]([C:30]([NH:32][CH2:33][CH3:34])=[O:31])=[CH:26][CH:25]=3)[C:11]=2[CH2:12][N:13]2C(=O)C3C(=CC=CC=3)C2=O)=[O:6])[CH2:3][CH2:2]1.O.NN>C(O)C>[NH2:13][CH2:12][C:11]1[N:10]([C:24]2[CH:25]=[CH:26][C:27]([C:30]([NH:32][CH2:33][CH3:34])=[O:31])=[CH:28][CH:29]=2)[N:9]=[N:8][C:7]=1[C:5]([NH:4][CH:1]1[CH2:3][CH2:2]1)=[O:6]
Reactant: CCNC(=O)c1ccc(-n2nnc(C(=O)NC3CC3)c2CN2C(=O)c3ccccc3C2=O)cc1
Agent: NN
Solvent: O
Solvent: CCO
Product: CCNC(=O)c1ccc(-n2nnc(C(=O)NC3CC3)c2CN)cc1
Yield: 99 %

Procedure:
A solution of N-cyclopropyl-5-[(1,3-dioxo-1,3-dihydro-2H-isoindol-2-yl)methyl]-1-{4-[(ethylamino)carbonyl]phenyl}-1H-1,2,3-triazole-4-carboxamide (0.9 g, 2.0 mmol) obtained in Example 1196 and hydrazine hydrate (200 mg, 4.0 mmol) in ethanol (20 ml) was boiled under reflux for 1 hr, and precipitated insoluble material was filtered off. The filtrate was concentrated to dryness to give the title compound as a white powder (0.65 g, 99%).