Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(N(CC)CC)C.Cl[C:9]1[CH:16]=[CH:15][C:12]([C:13]#[N:14])=[CH:11][N:10]=1.[CH3:17][C@@H:18]1[CH2:23][NH:22][CH2:21][CH2:20][NH:19]1.Cl.C(N(CC)CC)C>CN(C=O)C.CCOC(C)=O.O>[CH3:17][C@H:18]1[NH:19][CH2:20][CH2:21][N:22]([C:9]2[CH:16]=[CH:15][C:12]([C:13]#[N:14])=[CH:11][N:10]=2)[CH2:23]1
Reactant: C[C@@H]1CNCCN1
Reactant: N#Cc1ccc(Cl)nc1
Agent: Cl
Solvent: O
Solvent: CCOC(C)=O
Solvent: CCN(CC)CC
Product: C[C@@H]1CN(c2ccc(C#N)cn2)CCN1
Temperature: 25 °C
Reaction time: 36 h
Yield: 56.9 %

Procedure:
Triethylamine (5.51 g, 4 mL, 54.6 mmol, 2.7 eq) is added to a solution of 6-chloro-nicotinonitrile (2.76 g, 20 mmol, 1 eq), (R)-2-methyl-piperazine (2.00 g, 20 mmol, 1 eq) in DMF (15 mL), and the resulting solution is stirred at rt for 36 h. A white precipitate of triethylamine hydrochloride forms in the course of the reaction. Water (15 mL) and EtOAc (100 mL) are added, the organic layer is separated, dried over sodium sulfate and concentrated under reduced pressure to a white residue. The solid is further dried under high vacuum to yield the desired product as a white solid (2.3 g, 59%).
Reaction SMILES: [O:1]=[CH:2][C@@H:3]([C@H:5]([C@@H:7]([C@@H:9]([CH2:11][OH:12])[OH:10])[OH:8])[OH:6])[OH:4].OCC([C@H]([C@@H]([C@@H](CO)O)O)O)=O>>[CH2:11]([OH:12])[C@H:9]([C@H:7]([C@@H:5]([C@@H:3]([CH2:2][OH:1])[OH:4])[OH:6])[OH:8])[OH:10]
Reactant: O=C[C@H](O)[C@@H](O)[C@H](O)[C@H](O)CO
Agent: O=C(CO)[C@@H](O)[C@H](O)[C@H](O)CO
Product: OC[C@@H](O)[C@@H](O)[C@H](O)[C@H](O)CO

Procedure:
Also, the present Invention is to provide an isolating method for novel strain, Candida magnoliae (KCCM-10252), comprising steps of i) sorting a single colony growing fast at 27˜33° C. by using a plate containing 10˜20 g/L of glucose, 18˜22 g/L of fructose, 15˜25 g/L of peptone, 7˜15 g/L of yeast extract and 12˜17 g/L of agar after diluting a natural sludge sample; ii) sorting the strain producing mannitol most after fermenting such sorted strains in the medium containing 30˜70 g/L of glucose, 50˜100 g/L of fructose, 5˜20 g/L of yeast extract, 1˜5 g/L of ammonium sulfate and 1˜5 g/L of dibasic potassium phosphate for 68˜76 hours, and iii) isolating the novel strain, Candida magnoliae (KCCM-10252) producing the mannitol.
Reaction SMILES: Cl.FC1C=C(C=CC=1)CN1C=C(C2C3C(=NC=C(C4C=CC(C5CCNCC5)=CC=4)C=3)N(S(C3C=CC(C)=CC=3)(=O)=O)C=2)C=N1.[F:46][C:47]1[CH:48]=[C:49]([CH:92]=[CH:93][CH:94]=1)[CH2:50][N:51]1[C:55]([CH3:56])=[C:54]([C:57]2[C:65]3[C:60](=[N:61][CH:62]=[C:63]([C:66]4[CH:71]=[CH:70][C:69]([N:72]5[CH2:77][CH2:76][N:75]([CH2:78][C@@H:79]([OH:81])[CH3:80])[CH2:74][CH2:73]5)=[CH:68][CH:67]=4)[CH:64]=3)[N:59](S(C3C=CC(C)=CC=3)(=O)=O)[CH:58]=2)[CH:53]=[N:52]1.[OH-].[Li+]>C1COCC1.CO.O>[F:46][C:47]1[CH:48]=[C:49]([CH:92]=[CH:93][CH:94]=1)[CH2:50][N:51]1[C:55]([CH3:56])=[C:54]([C:57]2[C:65]3[C:60](=[N:61][CH:62]=[C:63]([C:66]4[CH:67]=[CH:68][C:69]([N:72]5[CH2:77][CH2:76][N:75]([CH2:78][C@@H:79]([OH:81])[CH3:80])[CH2:74][CH2:73]5)=[CH:70][CH:71]=4)[CH:64]=3)[NH:59][CH:58]=2)[CH:53]=[N:52]1
Reactant: Cc1ccc(S(=O)(=O)n2cc(-c3cnn(Cc4cccc(F)c4)c3C)c3cc(-c4ccc(N5CCN(C[C@H](C)O)CC5)cc4)cnc32)cc1
Agent: Cc1ccc(S(=O)(=O)n2cc(-c3cnn(Cc4cccc(F)c4)c3)c3cc(-c4ccc(C5CCNCC5)cc4)cnc32)cc1
Agent: Cl
Agent: [Li+]
Solvent: CO
Solvent: O
Solvent: C1CCOC1
Product: Cc1c(-c2c[nH]c3ncc(-c4ccc(N5CCN(C[C@H](C)O)CC5)cc4)cc23)cnn1Cc1cccc(F)c1
Yield: 6.4 %

Procedure:
Using similar reaction conditions as described in step-iii of example-1, (S)-1-(4-(4-(3-(1-(3-fluorobenzyl)-5-methyl-1H-pyrazol-4-yl)-1-tosyl-1H-pyrrolo[2,3-b]pyridin-5-yl)phenyl)piperazin-1-yl)propan-2-ol (200 mg, 0.29 mmol) was hydrolyzed with lithium hydroxide (37 mg, 0.88 mmol) in THF/methanol/water (6/4/2 mL) to yield 10 mg (6.4% yield) after purification by preparative HPLC along with one more isomer example 130. 1H NMR (CDCl3, 300 MHz): δ 9.12 (s, 1H), 8.548-8.542 (d, 1H), 8.02-8.01 (d, 1H), 7.59 (s, 1H), 7.54-7.51 (d, 2H), 7.36-7.29 (m, 2H), 7.26-6.91 (m, 5H), 5.32 (s, 2H), 3.95-3.90 (m, 1H), 3.30-3.23 (m, 4H), 2.90-2.86 (m, 2H), 2.62-2.60 (m, 2H), 2.43-2.31 (m, 5H), 1.19-1.17 (d, 3H). MS: m/z=524.9 (M+1), HPLC: 95.68% in method A.
Reaction SMILES: [NH2:1][C:2]1[N:6]=[CH:5][NH:4][N:3]=1.C([O:9][CH:10]=[C:11]([C:17](OCC)=O)[C:12]([O:14][CH2:15][CH3:16])=[O:13])C>C(O)(=O)C>[OH:9][C:10]1[N:3]2[N:4]=[CH:5][N:6]=[C:2]2[N:1]=[CH:17][C:11]=1[C:12]([O:14][CH2:15][CH3:16])=[O:13]
Reactant: CCOC=C(C(=O)OCC)C(=O)OCC
Reactant: Nc1nc[nH]n1
Solvent: CC(=O)O
Product: CCOC(=O)c1cnc2ncnn2c1O

Procedure:
A mixture of 3-amino-1,2,4-triazole (8.4g, 100mM) and diethyl ethoxymethylenemalonate (24.0g, 110mM) in glacial acetic acid (150ml) was heated under reflux for six hours. The resulting precipitated product was filtered and dried in vacuo. Yield 8.20g (36.6%). δ (DMSO-d6), 12.85 (1H,s, --OH), 8.87 (1H,s, H2), 8.56 (1H,s, H5), 4.38 (2H,q,--CH2CH3), 1.34 (3H,t, --CH2CH3); νmax (KBr disc) 1730 (ester C=O)cm-1 ; (Found: C, 45.99; H, 3.94; N, 27.29%. C8H8N4O3 requires C, 46.16; H, 3.87; N, 26.91%).
Reaction SMILES: [CH2:1]1[CH:14]2[CH:5]([C:6](=[O:16])[C:7]3[C:12]([C:13]2=[O:15])=[CH:11][CH:10]=[CH:9][CH:8]=3)[CH2:4][CH:3]=[CH:2]1.[H][H]>[Pd].C(O)(=O)C>[CH2:4]1[C:5]2[C:14](=[C:13]([OH:15])[C:12]3[C:7]([C:6]=2[OH:16])=[CH:8][CH:9]=[CH:10][CH:11]=3)[CH2:1][CH2:2][CH2:3]1
Reactant: [H][H]
Reactant: O=C1c2ccccc2C(=O)C2CC=CCC12
Agent: [Pd]
Solvent: CC(=O)O
Product: Oc1c2c(c(O)c3ccccc13)CCCC2
Temperature: 100 °C
Reaction time: 4 h
Yield: 86.7 %

Procedure:
300 ml of acetic acid, 64 g of 1,4,4a,9a-tetrahydro-anthraquinone and 0.6 g of a catalyst containing 5% of palladium deposited on charcoal are introduced into an autoclave. The charge is heated to 100° C. and hydrogen is introduced under a pressure of 30 bars. The reaction is continued for 4 hours while maintaining the pressure at between 20 and 30 bars. After cooling, the precipitate obtained is separated by filtration, washed with water and dried. 56 Grams of 1,2,3,4-tetrahydro-9,10-anthracene-diol (melting point 210°-212° C.) are obtained. The yield is 86.7% without taking into account the fraction of product remaining in solution in the acetic acid.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][CH:9]=1)[CH2:5]O.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OCC)=O)=NC(OCC)=O.[C:41]1([C:47]2[CH:48]=[C:49]3[CH:55]=[C:54]([C:56]([O:58][CH2:59][CH3:60])=[O:57])[NH:53][C:50]3=[CH:51][N:52]=2)[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=1>O1CCCC1>[C:41]1([C:47]2[CH:48]=[C:49]3[CH:55]=[C:54]([C:56]([O:58][CH2:59][CH3:60])=[O:57])[N:53]([CH2:5][C:4]4[CH:7]=[CH:8][CH:9]=[C:2]([F:1])[CH:3]=4)[C:50]3=[CH:51][N:52]=2)[CH:42]=[CH:43][CH:44]=[CH:45][CH:46]=1
Reactant: OCc1cccc(F)c1
Reactant: CCOC(=O)c1cc2cc(-c3ccccc3)ncc2[nH]1
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: CCOC(=O)c1cc2cc(-c3ccccc3)ncc2n1Cc1cccc(F)c1
Temperature: 20 °C
Reaction time: 20 h
Yield: 78.1 %

Procedure:
0.72 g (5.63 mmol) of 3-fluorobenzyl alcohol, 1.47 g (5.63 mmol) of triphenylphosphine and then 1.01 g (5.63 mmol) of diethyl azodicarboxylate are successively added to a solution, stirred at 0° C. under argon, of 1 g (3.76 mmol) of ethyl 5-phenyl-1H-pyrrolo[2,3-c]pyridine-2-carboxylate, obtained in step 18.3, in 30 ml of dry tetrahydrofuran. The mixture is then stirred for 20 hours at 20° C., concentrated under reduced pressure and then purified by chromatography on a column of silica (eluents: heptane/ethyl acetate). 1.1 g of the expected product are thus isolated in the form of a white powder.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([N:10]2[CH2:14][CH2:13][CH2:12][C@H:11]2[CH2:15][N:16]2[CH2:20][CH2:19][CH2:18][CH2:17]2)=[O:9])=[CH:4][CH:3]=1.Cl[CH2:22][C:23]1[CH:33]=[CH:32][C:26]([C:27]([N:29]([CH3:31])[CH3:30])=[O:28])=[CH:25][CH:24]=1>>[CH3:31][N:29]([CH3:30])[C:27](=[O:28])[C:26]1[CH:32]=[CH:33][C:23]([CH2:22][O:1][C:2]2[CH:7]=[CH:6][C:5]([C:8]([N:10]3[CH2:14][CH2:13][CH2:12][C@H:11]3[CH2:15][N:16]3[CH2:17][CH2:18][CH2:19][CH2:20]3)=[O:9])=[CH:4][CH:3]=2)=[CH:24][CH:25]=1
Reactant: CN(C)C(=O)c1ccc(CCl)cc1
Reactant: O=C(c1ccc(O)cc1)N1CCC[C@H]1CN1CCCC1
Product: CN(C)C(=O)c1ccc(COc2ccc(C(=O)N3CCC[C@H]3CN3CCCC3)cc2)cc1

Procedure:
The title compound is prepared in a manner substantially analogous to Procedure C using (4-Hydroxy-phenyl)-(2-(S)-pyrrolidin-1-ylmethyl-pyrrolidin-1-yl)-methanone and 4-chloromethyl-N,N-dimethyl-benzamide [CAS 121083-51-0]. MS (ES+) 436.3
Reaction SMILES: [O:1]1[C:5]2([CH2:10][CH2:9][N:8]([C:11]3[CH:16]=[CH:15][C:14]([N:17]4[CH2:21][C@H:20]([CH2:22][OH:23])[O:19][C:18]4=[O:24])=[CH:13][C:12]=3[F:25])[CH2:7][CH2:6]2)[O:4][CH2:3][CH2:2]1.C(N(CC)CC)C.[CH3:33][S:34](Cl)(=[O:36])=[O:35]>ClCCl>[O:1]1[C:5]2([CH2:6][CH2:7][N:8]([C:11]3[CH:16]=[CH:15][C:14]([N:17]4[CH2:21][C@H:20]([CH2:22][O:23][S:34]([CH3:33])(=[O:36])=[O:35])[O:19][C:18]4=[O:24])=[CH:13][C:12]=3[F:25])[CH2:9][CH2:10]2)[O:4][CH2:3][CH2:2]1
Reactant: CS(=O)(=O)Cl
Reactant: O=C1O[C@@H](CO)CN1c1ccc(N2CCC3(CC2)OCCO3)c(F)c1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CS(=O)(=O)OC[C@H]1CN(c2ccc(N3CCC4(CC3)OCCO4)c(F)c2)C(=O)O1
Reaction time: 18 h
Yield: 62.9 %

Procedure:
(5R)-3-(4-(1,4-Dioxa-8-azaspiro[4,5]dec-8-yl)-3-fluorophenyl)-5-hydroxymethyloxazolidin-2-one (4.024 g, 11.43 mM) was dissolved in dichloromethane (200 ml), and treated with triethylamine (1.45 g, 14.4 mM), then cooled under nitrogen to 0°. Methanesulfonyl chloride (1.32 g, 11.5 mM) was added dropwise, and the mixture stirred 18 hours allowing the temperature to rise to ambient. The mixture was washed with water (3×75 ml), concentrated, and purified by chromatography on a 90 g silica Biotage column, eluting with 1% methanol in dichloromethane. Relevant fractions were combined and evaporated to give the desired product (3.09 g).
Reaction SMILES: [N:1]1[C:8](Cl)=[N:7][C:5](Cl)=[N:4][C:2]=1[Cl:3].[CH2:10]([NH:14][CH:15]1[CH2:20][C:19]([CH3:22])([CH3:21])[NH:18][C:17]([CH3:24])([CH3:23])[CH2:16]1)[CH2:11][CH2:12][CH3:13]>O1CCOCC1>[Cl:3][C:2]1[N:1]=[C:8]([N:14]([CH2:10][CH2:11][CH2:12][CH3:13])[CH:15]2[CH2:16][C:17]([CH3:23])([CH3:24])[NH:18][C:19]([CH3:22])([CH3:21])[CH2:20]2)[N:7]=[C:5]([N:14]([CH:15]2[CH2:16][C:17]([CH3:24])([CH3:23])[NH:18][C:19]([CH3:21])([CH3:22])[CH2:20]2)[CH2:10][CH2:11][CH2:12][CH3:13])[N:4]=1
Reactant: Clc1nc(Cl)nc(Cl)n1
Reactant: CCCCNC1CC(C)(C)NC(C)(C)C1
Solvent: C1COCCO1
Product: CCCCN(c1nc(Cl)nc(N(CCCC)C2CC(C)(C)NC(C)(C)C2)n1)C1CC(C)(C)NC(C)(C)C1

Procedure:
To a solution of 18.4 g of cyanuric chloride in 200 ml of dioxane was added dropwise, with stirring, a solution of 43.6 g of 4-butylamino-2,2,6,6-tetramethylpiperidine in 100 ml of dioxane at 20°-25° C. The mixture was stirred at the same temperature for 2 hours, after which it was stirred at 60°-70° C. for 2 hours. At the end of this time, the dioxane was distilled off and the residue was poured into a 10% aqueous solution of potassium carbonate and extracted with ethyl acetate. The extract was dried over anhydrous potassium carbonate, and then the ethyl acetate was distilled off. The resulting oil was purified by column chromatography through silica gel, eluted with a 20:1:1 by volume mixture of ethyl acetate, ethanol and triethylamine, to give the title compound in the form of crystals melting at 40°-42° C.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:8]2[C:9](=[N:12]O)[CH2:10][O:11][C:7]=2[CH:6]=[CH:5][CH:4]=1>CCO.[Pd]>[CH3:1][O:2][C:3]1[C:8]2[CH:9]([NH2:12])[CH2:10][O:11][C:7]=2[CH:6]=[CH:5][CH:4]=1
Reactant: COc1cccc2c1C(=NO)CO2
Agent: [Pd]
Solvent: CCO
Product: COc1cccc2c1C(N)CO2
Reaction time: 18 h
Yield: 64.4 %

Procedure:
A mixture of the above described 4-methoxy-benzofuran-3-one oxime (6.15 g, 34.3 mmol) in EtOH (500 ml) with 10% Pd/C (6.15 g) was hydrogenated at 23° C. and atmospheric pressure for 18 h. Filtered the catalyst off, washed with EtOH, evaporated the filtrate totally and dried in high vacuum to give (RS)-4-methoxy-2,3-dihydro-benzofuran-3-ylamine as a light yellow oil (3.65 g, 64%); MS: m/e=166.2 (M+H|).
Reaction SMILES: [F:1][C:2]1[C:7]([F:8])=[CH:6][CH:5]=[C:4]([F:9])[C:3]=1[CH2:10][C:11](=[O:13])[CH3:12].[C:14](O)(=O)C.N1CCCCC1.C=O>CC#N>[F:1][C:2]1[C:7]([F:8])=[CH:6][CH:5]=[C:4]([F:9])[C:3]=1[C:10](=[CH2:14])[C:11](=[O:13])[CH3:12]
Reactant: CC(=O)O
Reactant: CC(=O)Cc1c(F)ccc(F)c1F
Agent: C=O
Solvent: CC#N
Solvent: C1CCNCC1
Product: C=C(C(C)=O)c1c(F)ccc(F)c1F
Temperature: 70 °C
Yield: 205 %

Procedure:
A solution of 18 (3.5 g, 18.6 mmol), acetic acid (0.34 ml, 5.58 mmol), piperidine (0.37 ml, 3.72 mmol), formaldehyde (6.0 g, 37% aqueous solution) in MeCN (20 mL) was heated over weekend. The conversion was about 60%. Reaction was heated to 70° C. overnight. The mixture was concentrated and extracted with MTBE and HCl (0.5N). The organic layer was washed with aqueous K2CO3 (0.5N) and water, in turns. The organic layer was concentrated. The product was isolated by chromatography column (hexane and EtOAc), yielding 31 (2.29 g, 61.5%).
Reaction SMILES: Cl[CH2:2][CH2:3][CH2:4][CH2:5][C:6]1[C:14]2[C:9](=[CH:10][CH:11]=[C:12]([C:15]#[N:16])[CH:13]=2)[NH:8][CH:7]=1.[N:17]1([C:23]2[CH:24]=[CH:25][C:26]3[O:30][C:29]([C:31]([NH2:33])=[O:32])=[CH:28][C:27]=3[CH:34]=2)[CH2:22][CH2:21][NH:20][CH2:19][CH2:18]1.C(N(C(C)C)CC)(C)C.CN1CCCC1=O>O.C(#N)C>[CH:11]1[C:12]([C:15]#[N:16])=[CH:13][C:14]2[C:6]([CH2:5][CH2:4][CH2:3][CH2:2][N:20]3[CH2:21][CH2:22][N:17]([C:23]4[CH:24]=[CH:25][C:26]5[O:30][C:29]([C:31]([NH2:33])=[O:32])=[CH:28][C:27]=5[CH:34]=4)[CH2:18][CH2:19]3)=[CH:7][NH:8][C:9]=2[CH:10]=1
Reactant: NC(=O)c1cc2cc(N3CCNCC3)ccc2o1
Reactant: N#Cc1ccc2[nH]cc(CCCCCl)c2c1
Solvent: CCN(C(C)C)C(C)C
Solvent: CC#N
Solvent: O
Product: N#Cc1ccc2[nH]cc(CCCCN3CCN(c4ccc5oc(C(N)=O)cc5c4)CC3)c2c1

Procedure:
3-(4-chlorobutyl)-1H-indole-5-carbonitrile (1.01 g, 1.0 equiv.), 5-(piperazin-1-yl)benzofuran-2-carboxamide (1.10 g, 1.03 equiv.), diisopropylethyl amine (DIPEA, 0.64 g, 1.16 equiv.), and N-Methyl-2-pyrrolidone (NMP, about 40 mL) are charged to a suitable vessel. It is to be noted that 5-(piperazin-1-yl)benzofuran-2-carboxamide may be produced using methods known in the art (see, e.g., U.S. Pat. No. 5,977,112). The mixture is heated and stirred until the reaction is complete. Acetonitrile (about 40 mL) and water (about 40 mL) are charged while maintaining elevated temperature. The mixture is cooled slowly to precipitate vilazodone, filtered, and the wet cake is washed with acetonitrile/water and then with acetonitrile. The wet product is dried to provide crude vilazodone. Purification is carried out via conventional means known in the art, e.g., filtration and precipitation.
Reaction SMILES: [CH2:1]([N:3]1[C:7]2=[N:8][C:9]([CH:26]([CH3:28])[CH3:27])=[C:10](/[CH:19]=[CH:20]/[C:21]([O:23][CH2:24][CH3:25])=[O:22])[C:11]([C:12]3[CH:13]=[N:14][CH:15]=[C:16]([CH3:18])[CH:17]=3)=[C:6]2[CH:5]=[N:4]1)[CH3:2]>CO.CC(O)=O.[OH-].[Pd+2].[OH-]>[CH2:1]([N:3]1[C:7]2=[N:8][C:9]([CH:26]([CH3:28])[CH3:27])=[C:10]([CH2:19][CH2:20][C:21]([O:23][CH2:24][CH3:25])=[O:22])[C:11]([C:12]3[CH:13]=[N:14][CH:15]=[C:16]([CH3:18])[CH:17]=3)=[C:6]2[CH:5]=[N:4]1)[CH3:2]
Reactant: CCOC(=O)/C=C/c1c(C(C)C)nc2c(cnn2CC)c1-c1cncc(C)c1
Agent: [Pd+2]
Agent: [OH-]
Solvent: CO
Solvent: CC(=O)O
Product: CCOC(=O)CCc1c(C(C)C)nc2c(cnn2CC)c1-c1cncc(C)c1
Yield: 45.7 %

Procedure:
A solution of ethyl (2E)-3-[1-ethyl-6-isopropyl-4-(5-methyl-3-pyridyl)-1H-pyrazolo[3,4-b]pyridin-5-yl]acrylate (268 mg) in MeOH-AcOH (90:10, 10 ml) was hydrogenated (3 atm) over palladium hydroxide (38 mg) at room temperature for 8 hours. The reaction mixture was filtered through celite pad and the filtrate was concentrated in vacuo. The residue was dissolved in EtOAc and washed with saturated aqueous NaHCO3, water, brine, dried over anhydrous MgSO4 and concentrated in vacuo. The residue was purified by flash column chromatography on silica gel eluting with a mixture of EtOAc and n-hexane (1:2) to give ethyl 3-[1-ethyl-6-isopropyl-4-(5-methyl-3-pyridyl)-1H-pyrazolo[3,4-b]pyridin-5-yl]propanoate (123 mg) as a colorless oil.
Reaction SMILES: [CH2:1]([NH2:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl[C:10]1[C:19]2[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=2)[N:13]=[CH:12][C:11]=1[N+:20]([O-:22])=[O:21]>>[CH2:1]([NH:8][C:10]1[C:19]2[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=2)[N:13]=[CH:12][C:11]=1[N+:20]([O-:22])=[O:21])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=[N+]([O-])c1cnc2ccccc2c1Cl
Reactant: NCc1ccccc1
Product: O=[N+]([O-])c1cnc2ccccc2c1NCc1ccccc1

Procedure:
Using the method of Example 1, benzylamine and 4-chloro-3-nitroquinoline were reacted to provide 4-benzylamino-3-nitroquinoline. The structural assignment for the crude product (m.p. 178°-196° C.) was supported by infrared spectral analysis.
Reaction SMILES: [O:1]1[CH:5]=[CH:4][C:3]([C:6]2[S:7][C:8]3[CH2:9][C:10]4[C:16]([C:17]5[CH:22]=[CH:21][C:20]([O:23][CH3:24])=[CH:19][CH:18]=5)=[N:15][N:14](COCC[Si](C)(C)C)[C:11]=4[C:12]=3[CH:13]=2)=[CH:2]1.Cl>CO>[O:1]1[CH:5]=[CH:4][C:3]([C:6]2[S:7][C:8]3[CH2:9][C:10]4[C:16]([C:17]5[CH:22]=[CH:21][C:20]([O:23][CH3:24])=[CH:19][CH:18]=5)=[N:15][NH:14][C:11]=4[C:12]=3[CH:13]=2)=[CH:2]1
Reactant: COc1ccc(-c2nn(COCC[Si](C)(C)C)c3c2Cc2sc(-c4ccoc4)cc2-3)cc1
Agent: Cl
Solvent: CO
Product: COc1ccc(-c2n[nH]c3c2Cc2sc(-c4ccoc4)cc2-3)cc1
Temperature: 100 °C
Yield: 70.2 %

Procedure:
2-Furan-3-yl-6-(4-methoxy-phenyl)-4-(2-trimethylsilanyl-ethoxymethyl)-4,7-dihydro-1-thia-4,5-diaza-cyclopenta[a]pentalene (0.3 g, 0.57 mmol) was dissolved in MeOH and treated with concentrated HCl (0.17 mL, 5.7 mmol). The reaction mixture was heated at 100° C. for 4 hr. The solution was cooled to room temperature and the resultant precipitate was filtered, washed with MeOH and concentrated under reduced pressure to provide the corresponding 2-Furan-3-yl-6-(4-methoxy-phenyl)-4,7-dihydro-1-thia-4,5-diaza-cyclopenta[a]pentalene (0.15 g, 0.4 mmol) as brown solid in 78% yield.
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[N:5]=[C:4]([CH2:12][Cl:13])[N:3]=1.O.[NH2:15][NH2:16]>O1CCCC1>[Cl:13][CH2:12][C:4]1[N:3]=[C:2]([NH:15][NH2:16])[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[N:5]=1
Reactant: ClCc1nc(Cl)c2ccccc2n1
Reactant: NN
Solvent: O
Solvent: C1CCOC1
Product: NNc1nc(CCl)nc2ccccc12
Temperature: 0 °C
Reaction time: 4 h

Procedure:
2.1. 46.0g of 4-chloro-2-(chloromethyl)quinazoline are suspended in 600 ml of absolute tetrahydrofuran. The solution is cooled to 0° C. 23.0 ml of hydrazine hydrate are added dropwise within 5 min., whereby a solution results and the temperature rises to 15° to 20° C. The reaction mixture is stirred at room temperature for 4 h. and then evaporated in a vacuum. The residue is triturated with 0.5 l of dichloromethane and 1 l of a saturated aqueous sodium hydrogen carbonate solution and then filtered. The crystals are washed neutral with water and dried in a vacuum. 38 g of 2-(chloromethyl)-4-hydrazinoquinazoline are obtained. The dichloromethane phase of the filtrate is separated and the aqueous phase is extracted with dichloromethane. By evaporation of the organic phases, there are obtained a further 5.8 g of 2-(chloro-methyl)-4-hydrazinoquinazoline. In total there are obtained 43.8 g of 2-(chloromethyl)-4-hydrazino- quinazoline. M.p. 192° C. (dec.).
Reaction SMILES: [CH:1]([C:3]1[C:8]([N+:9]([O-:11])=[O:10])=[CH:7][CH:6]=[CH:5][C:4]=1[NH:12][CH:13]=O)=[O:2].[CH2:15]([NH2:20])[CH2:16][CH2:17][CH2:18][CH3:19]>CCO>[OH:2][CH:1]1[C:3]2[C:4](=[CH:5][CH:6]=[CH:7][C:8]=2[N+:9]([O-:11])=[O:10])[N:12]=[CH:13][N:20]1[CH2:15][CH2:16][CH2:17][CH2:18][CH3:19]
Reactant: CCCCCN
Reactant: O=CNc1cccc([N+](=O)[O-])c1C=O
Solvent: CCO
Product: CCCCCN1C=Nc2cccc([N+](=O)[O-])c2C1O
Temperature: 25 °C
Reaction time: 3 h
Yield: 72.3 %

Procedure:
N-(2-Formyl-3-nitrophenyl)formamide (5a, 20.0 g, 103 mmol) and n-pentylamine (23.9 ml, 206 mmol) were dissolved in EtOH (240 ml) and the mixture stirred at room temperature for 3 h. After the mixture was concentrated under reduced pressure, EtOAc (100 ml) was added to the residue, and the generating yellow crystal was collected by filtration. The crystal was washed with EtOAc and dried under vacuum to obtain 4-hydroxy-5-nitro-3-pentyl-3,4-dihydroquinazoline (6a, 19.6 g, 72%); 1H NMR (270 MHz) δ (CDCl3) 0.91 (t, J=6.7 Hz, 3H), 1.26-1.38 (m, 4H), 1.67-1.78 (m, 2H), 3.21 (dt, J=13.9 and 7.9 Hz, 1H), 3.77 (ddd, J=6.3, 7.6 and 13.9 Hz, 1H), 6.57 (s, 1H), 6.90 (s, 1H), 7.30-7.41 (m, 2H), 7.80 (dd, J=1.7 and 7.6 hz, 1H); MS (ES) m/z 264 (M++1).
Reaction SMILES: COC[CH2:4][CH2:5][NH2:6].[CH3:7][N:8]1[C:12]([C:13]2[CH:18]=[CH:17][N:16]=[C:15]([NH:19][C:20]3[CH:25]=[CH:24][C:23]([S:26](F)(=[O:28])=[O:27])=[CH:22][CH:21]=3)[N:14]=2)=[CH:11][N:10]=[C:9]1[CH3:30]>CN(C)C1C=CN=CC=1.CN1C(=O)CCC1>[CH3:7][N:8]1[C:12]([C:13]2[CH:18]=[CH:17][N:16]=[C:15]([NH:19][C:20]3[CH:25]=[CH:24][C:23]([S:26](=[O:28])(=[O:27])[NH:6][CH2:5][CH2:4][S:26]([CH3:23])(=[O:28])=[O:27])=[CH:22][CH:21]=3)[N:14]=2)=[CH:11][N:10]=[C:9]1[CH3:30]
Reactant: Cc1ncc(-c2ccnc(Nc3ccc(S(=O)(=O)F)cc3)n2)n1C
Reactant: COCCCN
Agent: CN(C)c1ccncc1
Solvent: CN1CCCC1=O
Product: Cc1ncc(-c2ccnc(Nc3ccc(S(=O)(=O)NCCS(C)(=O)=O)cc3)n2)n1C
Temperature: 100 °C
Yield: 161.6 %

Procedure:
4-Dimethylaminopyridine (3 mg, 0.025 mmol) and 3-methyoxypropylamine (200 μl, 2 mmol) were added to a solution of 4-(1,2-dimethylimidazol-5-yl)-2-(4-(fluorosulphonyl)anilino)pyrimidine (Method 59; 87 mg, 0.25 mmol) in NMP (1 mL) and the mixture heated at 100° C. for 18 hours. The mixture was allowed to cool to ambient temperature and the solvent removed by evaporation. The residue was purified by preparative LCMS (constant flow of 5% v/v (35% NH3 in MeOH) with a gradient of H2O:CH3CN (5:95 increasing in polarity to 95:5) over 7.5 min) to give the title compound (91 mg, 81%) as a solid. NMR 2.38 (s, 3H), 2.97 (s, 3H), 3.11 (m, 2H), 3.21 (m, 2H), 3.95 (s, 3H), 7.20 (d, 1H), 7.61 (s, 1H), 7.75 (m, 3H), 7.95 (d, 2H), 8.43 (d, 1H), 9.95 (s, 1H); m/z 451.
Reaction SMILES: C[O:2][C:3](=[O:23])[C@H:4]([CH2:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)[NH:5]C(C1C(C)=CC=CC=1Cl)=O.Cl[C:25]1C=CC=C(Cl)C=1C(Cl)=O>>[CH3:25][C:21]1[CH:22]=[C:17]([CH:18]=[CH:19][CH:20]=1)[CH2:16][C@@H:4]([C:3]([OH:2])=[O:23])[NH2:5]
Reactant: COC(=O)[C@H](Cc1ccccc1)NC(=O)c1c(C)cccc1Cl
Reactant: O=C(Cl)c1c(Cl)cccc1Cl
Product: Cc1cccc(C[C@H](N)C(=O)O)c1

Procedure:
N-[1-(2-chloro-6-methylphenyl)carbonyl]-4-[[2,6-dichlorophenyl)carbonyl]amino]-3-methyl-L-phenylalanine was prepared from 4-amino-3-methyl-N-[[(2-chloro-6-methylphenyl)carbonyl]-L-phenylalanine methyl ester (87.4 mg, 0.22 mmol) and 2,6-dichlorobenzoyl chloride using the procedures described in examples 1 and 120 to give 56 mg of a white powder. HR MS (C25H21N2O4Cl3): Obs. Mass 519.0656. Calcd. Mass 519.0645 (M+H).
Reaction SMILES: Cl[C:2]([CH:4]([CH2:16][CH2:17][CH2:18][CH:19]([O:25][C:26](=[O:28])[CH3:27])[CH2:20][CH2:21][CH2:22][CH2:23][CH3:24])[CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][C:11]([O:13][CH2:14][CH3:15])=[O:12])=[O:3].[NH3:29]>O.CCOCC>[C:2]([CH:4]([CH2:16][CH2:17][CH2:18][CH:19]([O:25][C:26](=[O:28])[CH3:27])[CH2:20][CH2:21][CH2:22][CH2:23][CH3:24])[CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][C:11]([O:13][CH2:14][CH3:15])=[O:12])(=[O:3])[NH2:29]
Reactant: CCCCCC(CCCC(CCCCCCC(=O)OCC)C(=O)Cl)OC(C)=O
Reactant: N
Solvent: CCOCC
Solvent: O
Product: CCCCCC(CCCC(CCCCCCC(=O)OCC)C(N)=O)OC(C)=O

Procedure:
Ethyl 8-chlorocarbonyl-12-acetoxyheptadecanoate (8.38 g.; 0.02 mole) is added with stirring to a 28% solution of ammonia in water (concentrated ammonium hydroxide) (75 ml.). The amide forms at once and separates as a semi-solid. It is dissolved in ether, washed with water and dried over sodium sulfate. The ether is removed under vacuum to give the title compound as a semi-solid, yield 6.8 g. The product is purified by column chromatography on silica gel with 2% methanol in chloroform as eluant; pmr (CDCl3)δ 0.88 (3H,t), 2.02 (3H,s CH3COO), 4.12 (2H,q), 4.85 (1H,m HCO), 5.98 (2H,s NH2).