Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl.[NH2:2][OH:3].[OH-].[Na+].C(O[C:9](=[C:11]([C:14]#[N:15])[C:12]#[N:13])[CH3:10])C>O>[NH2:13][C:12]1[O:3][N:2]=[C:9]([CH3:10])[C:11]=1[C:14]#[N:15]
Reactant: CCOC(C)=C(C#N)C#N
Reactant: NO
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: Cc1noc(N)c1C#N
Temperature: 25 °C
Reaction time: 18 h
Yield: 72.7 %

Procedure:
A mixture of hydroxylamine hydrochloride (27.8 g, 0.4 mol) and sodium hydroxide (16.0 g, 0.4 mol) in water (1000 mL) was treated with 2-(1-ethoxy-ethylidene)-malononitrile (54.42 g, 0.4 mol) over 1 h. After the addition, the reaction mixture was stirred at room temperature for 18 h. The resulting suspension was collected, washed with cold EtOAc (1000 mL) and air dried to afford the desired product as a white solid (35.8 g, 72%); 1H NMR (DMSO-d6) δ 8.32 (s, 2 H), 2.1 (s, 3H).
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][N:5]=[C:4]([NH:8][C:9](=[O:14])[C:10]([CH3:13])([CH3:12])[CH3:11])[CH:3]=1.[Li]C(C)(C)C.CN([CH:23]=[O:24])C.Cl.C([O-])([O-])=O.[K+].[K+]>C(OCC)C>[CH:23]([C:3]1[C:4]([NH:8][C:9](=[O:14])[C:10]([CH3:11])([CH3:13])[CH3:12])=[N:5][CH:6]=[CH:7][C:2]=1[CH3:1])=[O:24]
Reactant: CN(C)C=O
Reactant: Cc1ccnc(NC(=O)C(C)(C)C)c1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOCC
Product: Cc1ccnc(NC(=O)C(C)(C)C)c1C=O
Temperature: -78 °C
Reaction time: 3.5 h
Yield: 58.8 %

Procedure:
To a precooled (−78° C.) solution of 4-methyl-2-(pivaloylamino)pyridine (6.87 g, 36.0 mmol) in diethyl ether (100 mL, dried over molecular seives) was slowly added tert-BuLi (50.0 mL, 75.0 mmol). The resulting solution was stirred at −78° C. for 3.5 h prior to the addition of DMF (5.19 g, 71.0 mmol) and was stirred for additionally 30 min at −78° C. and then allowed to warm to rt, and poored into 2 M HCl (aqueous, 100 mL). After stirring this mixture for 15 min. the pH was adjusted to 7.0 by addition of K2CO3. The aqueous phase washed with diethyl ether (3×75 mL, dried over molecular seives), and the combined organic fractions was washed with brine (100 mL), dried (MgSO4) and evaporated in vacuo. The crude product was recrystallised from ethyl acetate/hexane to give the desired product (4.66 g, 59%) as a slightly tan crystals (mp 117-20° C.). 1H NMR(DMSO-d6): δ 11.19 (s br, 1H), 10.41 (s, 1H), 8.49 (d, 5.0 Hz, 1H), 6.92 (d, 5.0 Hz), 2.69 (s, 3H), 1.37 (s, 9H). 13C NMR (DMSO-d6): δ 192.02, 176.97, 154.15, 152.82, 152.69, 121.70, 116.09, 40.69, 27.46, 18.77. FAB+ MS (m/z): 221.1300 (M+H+, calc. for C12H16N2O2+H+ 221.1290).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[CH:12][C:11]([Br:14])=[CH:10][C:9]=2[CH2:15]O)=[C:4]([CH2:17][OH:18])[CH:3]=1.Br>C1COCC1>[Br:14][C:11]1[CH:12]=[CH:13][C:8]2[C:5]3[CH:6]=[CH:7][C:2]([Br:1])=[CH:3][C:4]=3[CH2:17][O:18][CH2:15][C:9]=2[CH:10]=1
Reactant: OCc1cc(Br)ccc1-c1ccc(Br)cc1CO
Agent: Br
Solvent: C1CCOC1
Product: Brc1ccc2c(c1)COCc1cc(Br)ccc1-2
Yield: 48 %

Procedure:
4,4′-Dibromo-2,2′-bis-hydroxymethyl-biphenyl 23, the structure of which is shown in Scheme 4 above, (5 g, 0.013 moles, prepared according to the procedure described by D. M. Hall, F. Minhaj, J. Chem. Soc., 1957, 4584) was dissolved in THF (50 ml). HBr (48% wt/wt aqueous solution, 40 ml) was added and the solution refluxed overnight. After this period the THF was removed under reduced pressure and the yellow oil extracted between DCM/H2O (DCM is dichloromethane). The combined organic layers were dried (MgSO4), reduced and recrystallised from acetone (100 ml) to yield 3,9-dibromo-5,7-dihydro-dibenz[c,e]oxepin (12) as fine white crystals (1 g). Repeated recrystallisations of the mother liquor gave further product. Total yield after 3 recrystallisations (2.2 g, 0.0062 moles, 48% yield) as fine white crystals.
Reaction SMILES: [OH-].[K+].[N+](=[CH2:5])=[N-].CC1C=CC(S(N(N=O)C)(=O)=O)=CC=1.[C:20]([C:22]([CH2:25][CH2:26][CH2:27][CH2:28][C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1)=[CH:23][OH:24])#[N:21]>O.C(OCC)C.C(O)C>[CH3:5][O:24][CH:23]=[C:22]([C:20]#[N:21])[CH2:25][CH2:26][CH2:27][CH2:28][C:29]1[CH:30]=[CH:31][CH:32]=[CH:33][CH:34]=1
Reactant: C=[N+]=[N-]
Reactant: N#CC(=CO)CCCCc1ccccc1
Agent: Cc1ccc(S(=O)(=O)N(C)N=O)cc1
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Solvent: CCOCC
Product: COC=C(C#N)CCCCc1ccccc1
Temperature: 25 °C

Procedure:
A solution of 3.0 grams of potassium hydroxide in 6 mL of water was placed in a commercially available diazomethane generator. Ethanol, 8 mL, was added to the generator, and the contents of the generator were slowly warmed to 60° C. to 70° C. To this was added dropwise a solution of 4.6 grams (0.021 mole) of Diazald® in a minimum amount of diethyl ether. The diazomethane generated was condensed on a cold finger and, in turn, was allowed to drip into a stirred, cooled solution of 2.5 grams (0.012 mole) of 2-cyano-6-phenyl-1-hexen-1-ol in a minimum of diethyl ether. The complete generation of diazomethane required about 30 to 45 minutes. Upon completion of the diazomethane generation, the reaction mixture was allowed to warm to ambient temperature. After this time the reaction mixture was concentrated under reduced pressure, yielding 2.4 grams of 1-methoxy-2-cyano-6-phenyl-1-hexene. The NMR spectrum was consistent with the proposed structure.
Reaction SMILES: [C:1]([N:8]([CH3:14])[C@H:9]([C:11]([OH:13])=O)[CH3:10])([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C.[CH3:48][O:49][C:50]([CH:52]1[CH2:56][N:55]([C:57]([O:59][CH2:60][C:61]2[CH:66]=[CH:65][CH:64]=[CH:63][CH:62]=2)=[O:58])[CH:54]2[CH2:67][CH2:68][N:69]([C:70](=[O:79])[CH:71]([NH2:78])[CH:72]3[CH2:77][CH2:76][CH2:75][CH2:74][CH2:73]3)[CH:53]12)=[O:51]>CN1C(=O)CCC1.CCOC(C)=O>[CH3:48][O:49][C:50]([CH:52]1[CH2:56][N:55]([C:57]([O:59][CH2:60][C:61]2[CH:62]=[CH:63][CH:64]=[CH:65][CH:66]=2)=[O:58])[CH:54]2[CH2:67][CH2:68][N:69]([C:70](=[O:79])[CH:71]([NH:78][C:11](=[O:13])[CH:9]([N:8]([C:1]([O:3][C:4]([CH3:5])([CH3:6])[CH3:7])=[O:2])[CH3:14])[CH3:10])[CH:72]3[CH2:77][CH2:76][CH2:75][CH2:74][CH2:73]3)[CH:53]12)=[O:51]
Reactant: C[C@@H](C(=O)O)N(C)C(=O)OC(C)(C)C
Reactant: COC(=O)C1CN(C(=O)OCc2ccccc2)C2CCN(C(=O)C(N)C3CCCCC3)C12
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCOC(C)=O
Solvent: CCN(C(C)C)C(C)C
Solvent: CN1CCCC1=O
Product: COC(=O)C1CN(C(=O)OCc2ccccc2)C2CCN(C(=O)C(NC(=O)C(C)N(C)C(=O)OC(C)(C)C)C3CCCCC3)C12
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 115.7 %

Procedure:
A solution of Boc-N(Me)Ala-OH (113 mg, 0.56 mmol) in NMP (4 mL) was cooled to 0° C. and treated with HATU (207 mg, 0.54 mmol) followed by DIPEA (0.15 mL, 0.87 mmol). After 10 min, 17 (245 mg, 0.55 mmol) in NMP (5 mL) was added. The reaction mixture was allowed to warm to ambient temperature overnight. The solution was diluted with EtOAc, washed successively with 1M HCl, saturated NaHCO3, dried over anhydrous Na2SO4, filtered and concentrated to afford 18 as an orange-colored oil (400 mg) which was used without further purification.
Reaction SMILES: [CH:1]([N:4]1[CH2:9][CH2:8][N:7]([C:10]([C@H:12]2[CH2:17][CH2:16][C@H:15]([NH:18][S:19]([C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=3[CH3:28])(=[O:21])=[O:20])[CH2:14][CH2:13]2)=[O:11])[CH2:6][CH2:5]1)([CH3:3])[CH3:2].[C:29](C=P(CCCC)(CCCC)CCCC)#N.CO>C1(C)C=CC=CC=1>[CH:1]([N:4]1[CH2:5][CH2:6][N:7]([C:10]([C@H:12]2[CH2:17][CH2:16][C@H:15]([N:18]([CH3:29])[S:19]([C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=3[CH3:28])(=[O:21])=[O:20])[CH2:14][CH2:13]2)=[O:11])[CH2:8][CH2:9]1)([CH3:3])[CH3:2]
Reactant: CCCCP(=CC#N)(CCCC)CCCC
Reactant: Cc1ccccc1S(=O)(=O)N[C@H]1CC[C@H](C(=O)N2CCN(C(C)C)CC2)CC1
Solvent: Cc1ccccc1
Solvent: CO
Product: Cc1ccccc1S(=O)(=O)N(C)[C@H]1CC[C@H](C(=O)N2CCN(C(C)C)CC2)CC1

Procedure:
A mixture of 41 mg (0.1 mmol) N-{trans-4-[(4-isopropylpiperazin-1-yl)carbonyl]cyclohexyl}-2-methylbenzenesulfonamide (example 4), 72 mg (0.3 mmol) cyanomethylene tri-n-butylphosphorane and 32 mg (1 mmol) methanol in 2 mL toluene was heated for 16 h to 110° C. After evaporation methanol and DMF were added and the mixture was subjected to preparative HPLC purification on reversed phase eluting with a gradient of acetonitrile/water (0.1% NEt3). The combined product fractions were evaporated to dryness to yield 12.4 mg (29%) of the title compound. MS (m/e): 422.2 (MH+).
Reaction SMILES: CN1C=C([C:7]2[CH:8]=[CH:9][C:10]3[N:11]([C:13]([S:16][C:17]4[CH:18]=[CH:19][C:20]5[N:21]([CH:23]=[C:24]([NH:26][C:27]([CH:29]6[CH2:31][CH2:30]6)=[O:28])[N:25]=5)[N:22]=4)=[N:14][N:15]=3)[CH:12]=2)C=N1.[C:32]([C:34]1[CH:35]=[C:36](B(O)O)[CH:37]=[N:38][C:39]=1[O:40][CH2:41][O:42][CH2:43][CH2:44][Si:45]([CH3:48])([CH3:47])[CH3:46])#[N:33]>>[C:32]([C:34]1[CH:35]=[C:36]([C:7]2[CH:8]=[CH:9][C:10]3[N:11]([C:13]([S:16][C:17]4[CH:18]=[CH:19][C:20]5[N:21]([CH:23]=[C:24]([NH:26][C:27]([CH:29]6[CH2:30][CH2:31]6)=[O:28])[N:25]=5)[N:22]=4)=[N:14][N:15]=3)[CH:12]=2)[CH:37]=[N:38][C:39]=1[O:40][CH2:41][O:42][CH2:43][CH2:44][Si:45]([CH3:48])([CH3:47])[CH3:46])#[N:33]
Reactant: Cn1cc(-c2ccc3nnc(Sc4ccc5nc(NC(=O)C6CC6)cn5n4)n3c2)cn1
Reactant: C[Si](C)(C)CCOCOc1ncc(B(O)O)cc1C#N
Product: C[Si](C)(C)CCOCOc1ncc(-c2ccc3nnc(Sc4ccc5nc(NC(=O)C6CC6)cn5n4)n3c2)cc1C#N

Procedure:
The title compound was synthesized using an analogous procedure to that described in the preparation of Compound 5 using 5-cyano-6-((2-(trimethylsilyl)ethoxy)methoxy)pyridin-3-ylboronic acid. The crude reaction was used for the next step without further purification.
Reaction SMILES: ClCCl.[Cr](Cl)([O-])(=O)=O.[NH+]1C=CC=CC=1.[CH3:15][C@@H:16]([C@@H:23]1[C@@:27]2([CH3:43])[CH2:28][CH2:29][C@@H:30]3[C@@:35]4([CH3:41])[CH2:36][CH2:37][C@H:38]([OH:40])[CH2:39][C:34]54[O:42][CH:33]5[CH2:32][C@H:31]3[C@@H:26]2[CH2:25][CH2:24]1)[CH2:17][CH2:18][CH2:19][CH:20]([CH3:22])[CH3:21]>CCOCC>[OH:42][CH:33]1[C:34]2[C@:35]([CH3:41])([CH2:36][CH2:37][C:38](=[O:40])[CH:39]=2)[C@@H:30]2[C@H:31]([C@H:26]3[C@:27]([CH3:43])([CH2:28][CH2:29]2)[C@@H:23]([C@H:16]([CH3:15])[CH2:17][CH2:18][CH2:19][CH:20]([CH3:22])[CH3:21])[CH2:24][CH2:25]3)[CH2:32]1
Reactant: CC(C)CCC[C@@H](C)[C@H]1CC[C@H]2[C@@H]3CC4OC45C[C@@H](O)CC[C@]5(C)[C@H]3CC[C@]12C
Agent: O=[Cr](=O)([O-])Cl
Agent: c1cc[nH+]cc1
Solvent: ClCCl
Solvent: CCOCC
Product: CC(C)CCC[C@@H](C)[C@H]1CC[C@H]2[C@@H]3CC(O)C4=CC(=O)CC[C@]4(C)[C@H]3CC[C@]12C
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 51.7 %

Procedure:
Dichloromethane (50 ml) was added to pyridinium chlorochromate (2.78 g, 12.9 mmol) and molecular shieves (3 A) (4.37 g) and the mixture was stirred under a nitrogen atmosphere at room temperature for 15 minutes. To the resulting mixture was added a dichloromethane solution (30 ml) of 5,6-epoxycholesterol (α:β=5:1) (3.323 g, 8.6 mmol) prepared by the method of Fieser and Fieser (L. F. Fieser and H. Fieser, Reagents for Organic Synthesis, Vol. 1: 136, 1967) and the mixture was stirred for 3 hours. Ether (300 ml) was added to the reaction solution and the resulting solution was filtered through silica gel-magnesium sulfate. The organic layer was washed twice with 50 ml of a saturated saline solution and dried. The solvents were distilled off and the residue was purified by column chromatography. 6-Hydroxy-4-cholesten-3-one (α:β=5:1) was obtained as a colorless crystal from the hexane-ethyl acetate (5:1) eluate (yield: 51.7%).
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][CH:4]([C:7]([OH:9])=[O:8])[CH2:3][CH2:2]1.[OH-].[Na+].[C:12](Cl)([O:14][CH2:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)=[O:13]>O>[CH2:15]([O:14][C:12]([N:1]1[CH2:6][CH2:5][CH:4]([C:7]([OH:9])=[O:8])[CH2:3][CH2:2]1)=[O:13])[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1
Reactant: O=C(Cl)OCc1ccccc1
Reactant: O=C(O)C1CCNCC1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: O=C(O)C1CCN(C(=O)OCc2ccccc2)CC1
Temperature: 0 °C
Reaction time: 4 h
Yield: 91.2 %

Procedure:
Piperidine-4-carboxylic acid (64.8 g, 0.5 mol) in H2O (50 mL) was treated with NaOH (44.0 g, 1.1 mol). The reaction mixture was cooled to 0° C. and treated with CbzCl (93.8 g, 0.55 mol). The reaction mixture was stirred at ambient temperature for 4 hours and the mixture was extracted with Et2O (3 150 mL) The aqueous phase was acidified with 6 N HCl (140 mL) and extracted with EtOAc (3 200 mL). The solution was dried over MgSO4, filtered, and concentrated to afford crude piperidine-1,4-dicarboxylic acid monobenzyl ester (120 g), which was used without further purification: MS (ESI) m/z 262 [M−H]+.
Reaction SMILES: [C:1]1([N:7]=[C:8]=[O:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[NH2:10][N:11]1[CH2:16][CH2:15][N:14]([CH2:17][CH2:18][C:19]2[C:27]3[C:22](=[CH:23][C:24]([O:30][CH3:31])=[C:25]([O:28][CH3:29])[CH:26]=3)[NH:21][C:20]=2[CH3:32])[CH2:13][CH2:12]1.C(Cl)Cl>CCOCC>[CH3:29][O:28][C:25]1[CH:26]=[C:27]2[C:22](=[CH:23][C:24]=1[O:30][CH3:31])[NH:21][C:20]([CH3:32])=[C:19]2[CH2:18][CH2:17][N:14]1[CH2:13][CH2:12][N:11]([NH:10][C:8]([NH:7][C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=2)=[O:9])[CH2:16][CH2:15]1
Reactant: O=C=Nc1ccccc1
Reactant: COc1cc2[nH]c(C)c(CCN3CCN(N)CC3)c2cc1OC
Solvent: CCOCC
Solvent: ClCCl
Product: COc1cc2[nH]c(C)c(CCN3CCN(NC(=O)Nc4ccccc4)CC3)c2cc1OC
Reaction time: 2 h

Procedure:
3.5 G of phenylisocyanate are added dropwise to a stirred solution of 7.78 g of 3-[2-(4-aminopiperazin-1-yl) ethyl]-5,6-dimethoxy-2-methylindole in 100 ml. of dry methylene chloride while maintaining the reaction temperature below 35° C. After 2 hours, 50 ml. of ether are added, the product is filtered and washed with ether. The product is recrystallized from ethyl acetate to give a white solid, m.p. 170°-173°C. of 1-[1-(5,6 -dimethoxy-2-methylindol-3-ylethyl)piperazin-4-yl]-3-phenylurea.
Reaction SMILES: [CH3:1][C:2]1[NH:6][C:5]([C:7]2[CH:8]=[N:9][CH:10]=[CH:11][CH:12]=2)=[N:4][C:3]=1[C:13](=[O:15])[CH3:14].[Br:16]Br>Br>[BrH:16].[BrH:16].[Br:16][CH2:14][C:13]([C:3]1[N:4]=[C:5]([C:7]2[CH:8]=[N:9][CH:10]=[CH:11][CH:12]=2)[NH:6][C:2]=1[CH3:1])=[O:15]
Reactant: CC(=O)c1nc(-c2cccnc2)[nH]c1C
Reactant: BrBr
Agent: Br
Product: Cc1[nH]c(-c2cccnc2)nc1C(=O)CBr
Temperature: 80 °C
Reaction time: 0.17 h

Procedure:
To a stirred solution of 10 g of 1-[5-methyl-2-(3-pyridinyl)-1H-imidazol-4-yl]ethanone in 60 ml of 48% hydrobromic acid at 80° C. was added, dropwise during 5-10 minutes, 2.8 ml of bromine. After addition was complete, the mixture was stirred at 80° C. for 10 minutes, then allowed to cool to room temperature. The resulting solid was collected, washed with three 25 ml portions of acetone and dried, giving 13.4 g of 2-bromo-1-[5-methyl-2-(3-pyridinyl)-1H-imidazol-4-yl]ethanone, dihydrobromide.
Reaction SMILES: [NH2:1][C:2]1[CH:25]=[CH:24][C:5]([O:6][C:7]2[C:16]3[C:11](=[CH:12][C:13]([O:19][CH2:20][CH2:21][O:22][CH3:23])=[C:14]([C:17]#[N:18])[CH:15]=3)[N:10]=[CH:9][CH:8]=2)=[CH:4][C:3]=1[F:26].[F:27][C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][C:29]=1[N:34]=[C:35]=[O:36]>C1(C)C=CC=CC=1>[C:17]([C:14]1[CH:15]=[C:16]2[C:11](=[CH:12][C:13]=1[O:19][CH2:20][CH2:21][O:22][CH3:23])[N:10]=[CH:9][CH:8]=[C:7]2[O:6][C:5]1[CH:24]=[CH:25][C:2]([NH:1][C:35]([NH:34][C:29]2[CH:30]=[CH:31][CH:32]=[CH:33][C:28]=2[F:27])=[O:36])=[C:3]([F:26])[CH:4]=1)#[N:18]
Reactant: O=C=Nc1ccccc1F
Reactant: COCCOc1cc2nccc(Oc3ccc(N)c(F)c3)c2cc1C#N
Solvent: Cc1ccccc1
Product: COCCOc1cc2nccc(Oc3ccc(NC(=O)Nc4ccccc4F)c(F)c3)c2cc1C#N
Yield: 72 %

Procedure:
4-(4-Amino-3-fluorophenoxy)-6-cyano-7-(2-methoxyethoxy)quinoline (100 mg) was added to 4.5 ml of toluene, and the mixture was heated to reflux. After then adding 2-fluorophenyl isocyanate (0.05 ml), the mixture was further heated to reflux for 1 hour. After cooling, the precipitated solid was filtered out and washed with ethyl acetate/toluene=1/1 to obtain 100 mg of the title compound as light brown crystals (72% yield).
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[C:7]1[S:11][C:10]([CH:12]=O)=[CH:9][CH:8]=1.N1(C2C=C[C:22]([CH:23]=[O:24])=CC=2)C=CC=N1>>[N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[C:7]1[S:11][C:10]([CH:12]=[CH:22][CH:23]=[O:24])=[CH:9][CH:8]=1
Reactant: O=Cc1ccc(-c2ccccn2)s1
Reactant: O=Cc1ccc(-n2cccn2)cc1
Product: O=CC=Cc1ccc(-c2ccccn2)s1

Procedure:
The title compound was prepared by a procedure analogous to Reference Example 30 by substituting 5-(2-pyridinyl)-2-thiophenecarboxaldehyde (prepared as described in J. Chem Soc., Perkin Trans. 2 1998, 437) for the 4-(1H-pyrazol-1-yl)-benzaldehyde of Reference Example 30. MS 216 (M+H)+.
Reaction SMILES: OS(O)(=O)=O.C[O-].[Na+].[SH:9][CH:10]([C:14](=[O:19])[CH2:15][CH:16]([CH3:18])[CH3:17])[CH:11]([CH3:13])[CH3:12].[CH3:20][O:21][C:22](=[O:25])[CH2:23]Cl>CO.O>[CH3:20][O:21][C:22]([CH2:23][S:9][CH:10]([C:14](=[O:19])[CH2:15][CH:16]([CH3:18])[CH3:17])[CH:11]([CH3:13])[CH3:12])=[O:25]
Reactant: COC(=O)CCl
Reactant: CC(C)CC(=O)C(S)C(C)C
Agent: C[O-]
Agent: O=S(=O)(O)O
Agent: [Na+]
Solvent: CO
Solvent: O
Product: COC(=O)CSC(C(=O)CC(C)C)C(C)C
Temperature: 24 °C
Reaction time: 0.02 h

Procedure:
Into a 50 ml, round-bottom, three-necked flask equipped with magnetic stirrer, pot thermometer, "Y" tube, nitrogen inlet tube, reflux condenser with cotton plug, H2SO4 bubbler for nitrogen, and cold water bath is added a solution of 0.65 grams of sodium methoxide dissolved in 10 ml anhydrous methanol. At a reaction mass temperature of 25°-28° C. and over a period of 1 minute, with stirring, is added a solution of 2.1 grams of 3-mercapto-2,6-dimethyl-4-heptanone dissolved in 2 ml anhydrous methanol. After stirring 8 minutes, 1.30 grams of methylchloroacetate (0.012 moles) is added over a period of 2 minutes, to the reaction mass; the temperature of the reaction mass rising to 38° C. The reaction mass is allowed to cool to 24° C. and is stirred for a period of 2 hours.
Reaction SMILES: [Na].[NH2:2][C@H:3]([C:9]([O-:11])=[O:10])[CH2:4][CH2:5][C:6]([O-:8])=[O:7].[NH2:12][C@H:13]([C:15]([OH:17])=[O:16])[CH3:14].Cl.C(N=C=NCCCN(C)C)C.Cl>O>[NH2:2][C@H:3]([C:9]([OH:11])=[O:10])[CH2:4][CH2:5][C:6]([OH:8])=[O:7].[NH2:12][C@H:13]([C:15]([OH:17])=[O:16])[CH3:14]
Reactant: N[C@@H](CCC(=O)[O-])C(=O)[O-]
Agent: CCN=C=NCCCN(C)C
Agent: C[C@H](N)C(=O)O
Agent: Cl
Solvent: O
Product: N[C@@H](CCC(=O)O)C(=O)O
Temperature: 25 °C
Reaction time: 8 h

Procedure:
450 mg of the polymer mainly comprising sodium of L-glutamate/L-alanine copolymer obtained in Example 3 was dissolved in 10 ml of water, to which an aqueous solution prepared by dissolving 66.3 mg of 1-ethyl-3-(3-dimethylaminopropyl) carbodiimide hydrochloride (EDC, condensing agent) in 5 ml of water was added. An aqueous solution prepared by dissolving 88.5 mg of P-[bis(2-chloroethyl)amino]L-phenylalanine (melphalan), which is a publicly known anti-cancer drug, in 20 ml of water was added dropwise to the mixed solution in 10 minutes. This reaction solution was stirred overnight at room temperature. When hydrochloric acid was added to the reaction solution to adjust the pH to 4.0, a white precipitate appeared. The precipitate was isolated by centrifugation and was washed with dilute hydrochloric acid. Thus obtained white solid was dissolved in 20 ml of 0.1 N caustic soda solution and dialyzed against pure water at 4° C. for 3 days on a permeable cellophane tube. The dialyzate was lyophilized to give 484 mg of L-glutamic acid/L-alanine copolymer sodium salt-melphalan conjugate as a curdy solid.
Reaction SMILES: Cl.[CH3:2][S:3][C:4]1[CH:9]=[CH:8][C:7]([N:10]2[C:14]([C:15]3[CH:24]=[CH:23][C:18]([O:19][CH2:20][CH2:21][NH2:22])=[CH:17][CH:16]=3)=[CH:13][C:12]([C:25]([F:28])([F:27])[F:26])=[N:11]2)=[CH:6][CH:5]=1.[O:29]([C:31]#[N:32])[Na]>O.CCO>[CH3:2][S:3][C:4]1[CH:9]=[CH:8][C:7]([N:10]2[C:14]([C:15]3[CH:24]=[CH:23][C:18]([O:19][CH2:20][CH2:21][NH:22][C:31]([NH2:32])=[O:29])=[CH:17][CH:16]=3)=[CH:13][C:12]([C:25]([F:28])([F:26])[F:27])=[N:11]2)=[CH:6][CH:5]=1
Reactant: CSc1ccc(-n2nc(C(F)(F)F)cc2-c2ccc(OCCN)cc2)cc1
Reactant: N#CO[Na]
Agent: Cl
Solvent: O
Solvent: CCO
Product: CSc1ccc(-n2nc(C(F)(F)F)cc2-c2ccc(OCCNC(N)=O)cc2)cc1
Reaction time: 5 h
Yield: 53.8 %

Procedure:
To a suspension of (2-{4-[1-[4-(methylthio)phenyl]-3-(trifluoromethyl)-1H-pyrazol-5-yl]phenoxy}ethyl)amine hydrochloride (7.5 g) in H2O (150 ml) and EtOH (75 ml) was added NaOCN (2.27 g) at room temperature. pH was adjusted to 6.3 with 1NHCl . The mixture was stirred for 5 hours under the condition of pH 6.0–7.0. The reaction mixture was extracted with EtOAc and washed with dil. NaCl (twice), dried over MgSO4, filtered and evaporated. The residue was column chromatographed on silica gel (CH2Cl2/MeOH) and evaporated. The residue was crytalized from IPE/EtOH. Recrystalized from EtOH/H2O (50 ml–50 ml Final) and dried to give 4.10 g (54%) of N-(2-{4-[1-[4-(methylthio)phenyl]-3-(trifluoromethyl)-1H-pyrazol-5-yl]phenoxy}ethyl)urea.
Reaction SMILES: [Si]([O:18][CH2:19][C:20]1[S:24][C:23]([C:25]2[CH:26]=[CH:27][C:28]([N+:42]([O-:44])=[O:43])=[C:29]([NH:31][C:32](=[O:41])[C:33]3[CH:38]=[CH:37][C:36]([O:39][CH3:40])=[CH:35][CH:34]=3)[CH:30]=2)=[CH:22][CH:21]=1)(C(C)(C)C)(C1C=CC=CC=1)C1C=CC=CC=1.[F-].C([N+](CCCC)(CCCC)CCCC)CCC.C1COCC1>CCOC(C)=O>[OH:18][CH2:19][C:20]1[S:24][C:23]([C:25]2[CH:26]=[CH:27][C:28]([N+:42]([O-:44])=[O:43])=[C:29]([NH:31][C:32](=[O:41])[C:33]3[CH:38]=[CH:37][C:36]([O:39][CH3:40])=[CH:35][CH:34]=3)[CH:30]=2)=[CH:22][CH:21]=1
Reactant: COc1ccc(C(=O)Nc2cc(-c3ccc(CO[Si](c4ccccc4)(c4ccccc4)C(C)(C)C)s3)ccc2[N+](=O)[O-])cc1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: COc1ccc(C(=O)Nc2cc(-c3ccc(CO)s3)ccc2[N+](=O)[O-])cc1
Yield: 193.9 %

Procedure:
A solution of compound 189 (0.673 g, 1.08 mmol) in a 1M solution of tetrabutylammonium fluoride in THF (1.5 mL, 1.5 mmol) was stirred for 90 min at room temperature. The reaction mixture was diluted with AcOEt, washed with 5% KHSO4, water, dried over MgSO4, filtered and concentrated to give a solid material which was triturated with DCM, to afford title compound 190 (0.805 g, 75% yield). The supernatant was collected, evaporated and the residue was purified by flash column chromatography (eluent: 50% AcOEt in DCM) to afford additional amount of 190 (0.161 g, 15% yield).
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([I:8])[CH:5]=[CH:4][C:3]=1[N:9]1[C:21]2[C:12](=[CH:13][C:14]3[C:15]([CH3:23])=[N:16][CH:17]=[N:18][C:19]=3[C:20]=2[F:22])[N:11]([S:24]([CH:27]2[CH2:29][CH2:28]2)(=[O:26])=[O:25])C1=O.C[Si](C)(C)[O-].[K+]>C1COCC1>[F:1][C:2]1[CH:7]=[C:6]([I:8])[CH:5]=[CH:4][C:3]=1[NH:9][C:21]1[C:20]([F:22])=[C:19]2[C:14]([C:15]([CH3:23])=[N:16][CH:17]=[N:18]2)=[CH:13][C:12]=1[NH:11][S:24]([CH:27]1[CH2:28][CH2:29]1)(=[O:25])=[O:26]
Reactant: Cc1ncnc2c(F)c3c(cc12)n(S(=O)(=O)C1CC1)c(=O)n3-c1ccc(I)cc1F
Agent: C[Si](C)(C)[O-]
Agent: [K+]
Solvent: C1CCOC1
Product: Cc1ncnc2c(F)c(Nc3ccc(I)cc3F)c(NS(=O)(=O)C3CC3)cc12
Temperature: 25 °C
Reaction time: 16 h
Yield: 83.9 %

Procedure:
To a solution of 3-(2-fluoro-4-iodophenyl)-1-(cyclopropylsulfonyl)-4-fluoro-8-methyl-1H-imidazo[4,5-g]quinazolin-2(3H)-one (46 mg, 0.09 mmol) in THF (5 ml) was added potassium trimethylsilanolate (35 mg, 0.27 mmol). The reaction was stirred at room temperature for 16 h, quenched with saturated aqueous NH4Cl solution (5 ml), and extracted with EtOAc (2×10 ml). The combined organic solution was washed with brine (15 ml), dried over MgSO4, and concentrated. Silica gel chromatography (EtOAc:Hexanes=50:50) yielded 39 mg (90%) of the title compound as a light yellow solid. m/z=515 [M−1]−. 1H NMR (DMSO-d6, 400 MHz): δ 0.85 (m, 4H), 2.75 (m, 1H), 2.87 (s, 3H), 6.61 (m, 1H), 7.36 (d, J=8 Hz, 1H), 7.67 (d, J=11 Hz, 1H), 8.02 (s, 2H), 9.07 (s, 1H), 9.78 (s, 1H).
Reaction SMILES: [NH2:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6]([C:21]([NH:23][CH2:24][C:25]3[CH:30]=[CH:29][C:28]([F:31])=[C:27]([F:32])[CH:26]=3)=[O:22])=[C:7]([CH:18]([CH3:20])[CH3:19])[N:8]2[CH2:11][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)=[CH:4][CH:3]=1.[C:33]1(=O)[CH2:37][CH2:36][CH2:35][CH2:34]1>>[CH2:11]([N:8]1[C:9]2[C:5](=[CH:4][CH:3]=[C:2]([NH:1][CH:33]3[CH2:37][CH2:36][CH2:35][CH2:34]3)[CH:10]=2)[C:6]([C:21]([NH:23][CH2:24][C:25]2[CH:30]=[CH:29][C:28]([F:31])=[C:27]([F:32])[CH:26]=2)=[O:22])=[C:7]1[CH:18]([CH3:19])[CH3:20])[C:12]1[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=1
Reactant: O=C1CCCC1
Reactant: CC(C)c1c(C(=O)NCc2ccc(F)c(F)c2)c2ccc(N)cc2n1Cc1ccccc1
Product: CC(C)c1c(C(=O)NCc2ccc(F)c(F)c2)c2ccc(NC3CCCC3)cc2n1Cc1ccccc1

Procedure:
The title compound was prepared from 6-amino-1-benzyl-N-(3,4-difluorobenzyl)-2-isopropyl-1H-indole-3-carboxamide (Compound 125) and cyclopentanone by General Procedure T.