Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6]([CH:9]2[N:14]([CH2:15][C:16]([OH:18])=O)[C:13](=[O:19])[N:12]([C:20]3[CH:25]=[CH:24][CH:23]=[C:22]([C:26]([F:29])([F:28])[F:27])[CH:21]=3)[C:11]([CH3:30])=[C:10]2[C:31]([C:33]2[O:34][CH:35]=[CH:36][CH:37]=2)=[O:32])=[CH:5][CH:4]=1)#[N:2].C1(N=C=NC2CCCCC2)CCCCC1.[C:53]([C:55]1[CH:60]=[CH:59][C:58]([S:61]([NH2:64])(=[O:63])=[O:62])=[CH:57][CH:56]=1)#[N:54]>CN(C)C1C=CN=CC=1.ClCCl>[C:1]([C:3]1[CH:8]=[CH:7][C:6]([CH:9]2[N:14]([CH2:15][C:16]([NH:64][S:61]([C:58]3[CH:57]=[CH:56][C:55]([C:53]#[N:54])=[CH:60][CH:59]=3)(=[O:62])=[O:63])=[O:18])[C:13](=[O:19])[N:12]([C:20]3[CH:25]=[CH:24][CH:23]=[C:22]([C:26]([F:27])([F:28])[F:29])[CH:21]=3)[C:11]([CH3:30])=[C:10]2[C:31]([C:33]2[O:34][CH:35]=[CH:36][CH:37]=2)=[O:32])=[CH:5][CH:4]=1)#[N:2]
Reactant: CC1=C(C(=O)c2ccco2)C(c2ccc(C#N)cc2)N(CC(=O)O)C(=O)N1c1cccc(C(F)(F)F)c1
Reactant: N#Cc1ccc(S(N)(=O)=O)cc1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Product: CC1=C(C(=O)c2ccco2)C(c2ccc(C#N)cc2)N(CC(=O)NS(=O)(=O)c2ccc(C#N)cc2)C(=O)N1c1cccc(C(F)(F)F)c1
Reaction time: 48 h

Procedure:
A mixture of [6-(4-cyanophenyl)-5-(2-furoyl)-4-methyl-2-oxo-3-[3-(trifluoromethyl)phenyl]-3,6-dihydropyrimidin-1(2H)-yl]acetic acid (Example 29A) (75 mg, 0.14 mmol), 1,3-dicyclohexylcarbodiimide (33 mg, 0.16 mmol), 4-cyanobenzene-1-sulfonamide (30 mg, 0.16 mmol) and 4-dimethylaminopyridine (20 mg, 0.16 mol) in dichloromethane (4 ml) is stirred for 48 hours. The product is extracted with dichloromethane, washed with 2 N hydrochloric acid and brine, dried over anhydrous magnesium sulfate, filtered and concentrated. The residue is purified by preparative HPLC (RP18 column; eluent: acetonitrile/water 10:90→90:10).
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][NH:4][CH2:3][CH2:2]1.[Li].CO[C:10]1[CH:11]=[C:12]2[C:17](=[CH:18][CH:19]=1)[CH:16]=[C:15]([C:20](=[O:22])[CH3:21])[CH:14]=[CH:13]2>>[N:1]1([C:10]2[CH:11]=[C:12]3[C:17](=[CH:18][CH:19]=2)[CH:16]=[C:15]([C:20](=[O:22])[CH3:21])[CH:14]=[CH:13]3)[CH2:6][CH2:5][NH:4][CH2:3][CH2:2]1
Reactant: C1CNCCN1
Reactant: COc1ccc2cc(C(C)=O)ccc2c1
Agent: [Li]
Product: CC(=O)c1ccc2cc(N3CCNCC3)ccc2c1
Reaction time: 65 h

Procedure:
Anhydrous piperazine (7° g., 81.3 mmol; dried in a vacuum desiccator over KOH-drierite mixture for 3 days) was dissolved in a mixture of dry, freshly distilled toluene and hexamethyl phosphoric amide (HMPA), 25 mL each. To the solution was added 556 mg (80.1 mmol) of lithium rod, cut in small pieces under argon atmosphere, and the mixture was stirred under argon for 24 hours, during which time all lithium has dissolved. Vacuum-dried 1-(6-methoxy-2-naphthyl)-1-ethanone (prepared as described in Arsenijevic et al., Org. Synth. Coll. 1988 6:34-36, the disclosure of which is incorporated herein by reference) (3.5 g, 17.5 mmol) was added. and stirring was continued for additional 65 hours. After quenching with 300 m L of water, extraction with dichloromethane (3×300 mL), drying with anhydrous magnesium sulfate, and evaporation, a mixture of white and yellow solids was obtained. Extraction with 300 mL of hot methanol gave raw product, 1-(6-piperazino-2-naphthyl)-1-ethanone, which was purified by column chromatography (70-230 mesh silica, 25×120 mm, 5% methanol in dichloromethane). The yield was 1.54 g (35%). After recrystallization from ethyl acetate, the sample melted at 170.5-172° C.
Reaction SMILES: Cl[CH2:2][C@H:3]([CH3:13])[CH2:4][O:5][C:6]1[CH:11]=[CH:10][C:9]([Br:12])=[CH:8][CH:7]=1.[CH3:14][CH:15]([CH3:31])[C:16]([NH:18][C:19]1[CH:24]=[CH:23][CH:22]=[C:21]([CH:25]2[CH2:30][CH2:29][NH:28][CH2:27][CH2:26]2)[CH:20]=1)=[O:17]>>[Br:12][C:9]1[CH:10]=[CH:11][C:6]([O:5][CH2:4][C@@H:3]([CH3:13])[CH2:2][N:28]2[CH2:29][CH2:30][CH:25]([C:21]3[CH:20]=[C:19]([NH:18][C:16](=[O:17])[CH:15]([CH3:14])[CH3:31])[CH:24]=[CH:23][CH:22]=3)[CH2:26][CH2:27]2)=[CH:7][CH:8]=1
Reactant: C[C@@H](CCl)COc1ccc(Br)cc1
Reactant: CC(C)C(=O)Nc1cccc(C2CCNCC2)c1
Product: CC(C)C(=O)Nc1cccc(C2CCN(C[C@H](C)COc3ccc(Br)cc3)CC2)c1

Procedure:
Prepared by Procedure G and Scheme B1 using 4-bromophenyl(2R)-3-chloro-2-methylpropyl ether and 2-methyl-N-[3-(4-piperidinyl)phenyl]propanamide: ESMS m/e: 473.0 (M+H)+.
Reaction SMILES: [F:1][C:2]([F:7])([F:6])[C:3]([OH:5])=[O:4].[C:8]1([C:14]2[CH:19]=[C:18]([CH:20]3[CH2:25][CH2:24][NH:23][CH2:22][CH2:21]3)[CH:17]=[CH:16][C:15]=2[NH:26][C:27]([C:29]2[NH:30][CH:31]=[C:32]([C:34]#[N:35])[N:33]=2)=[O:28])[CH2:13][CH2:12][CH2:11][CH2:10][CH:9]=1.[N:36]1[CH:41]=[CH:40][C:39]([CH2:42][C:43](O)=[O:44])=[CH:38][CH:37]=1>>[F:1][C:2]([F:7])([F:6])[C:3]([OH:5])=[O:4].[C:8]1([C:14]2[CH:19]=[C:18]([CH:20]3[CH2:21][CH2:22][N:23]([C:43](=[O:44])[CH2:42][C:39]4[CH:40]=[CH:41][N:36]=[CH:37][CH:38]=4)[CH2:24][CH2:25]3)[CH:17]=[CH:16][C:15]=2[NH:26][C:27]([C:29]2[NH:30][CH:31]=[C:32]([C:34]#[N:35])[N:33]=2)=[O:28])[CH2:13][CH2:12][CH2:11][CH2:10][CH:9]=1
Reactant: O=C(O)Cc1ccncc1
Reactant: N#Cc1c[nH]c(C(=O)Nc2ccc(C3CCNCC3)cc2C2=CCCCC2)n1
Solvent: O=C(O)C(F)(F)F
Product: N#Cc1c[nH]c(C(=O)Nc2ccc(C3CCN(C(=O)Cc4ccncc4)CC3)cc2C2=CCCCC2)n1

Procedure:
The title compound was prepared from 4-cyano-1H-imidazole-2-carboxylic acid (2-cyclohex-1-enyl-4-piperidin-4-yl-phenyl)-amide TFA salt (as prepared in Example 14, step (b)), according to the procedure in Example 29 using pyridin-4-yl-acetic acid. 1H-NMR (400 MHz, CD3OD): δ 8.78 (d, 2H), 8.12 (d, 1H), 8.00 (m, 3H), 7.18 (dd, 1H), 7.08 (d, 1H), 5.80 (m, 1H), 4.66 (m, 1H), 4.22 (s, 2H), 4.18 (m, 1H), 3.34 (m, 1H), 2.84 (m, 2H), 2.24 (m, 4H), 2.00-1.70 (m, 7H), 1.64 (m, 1H). Mass spectrum (ESI, m/z): Calcd. for C29H30N6O2, 495.2 (M+H), found 495.2.
Reaction SMILES: [CH2:1]([N:3]([C:20](=[O:24])[CH:21]([CH3:23])[CH3:22])[C:4]1[CH:5]=[C:6]([C:17](O)=[O:18])[CH:7]=[C:8]([C:10]2[CH:15]=[CH:14][C:13]([CH3:16])=[CH:12][CH:11]=2)[CH:9]=1)[CH3:2].[N:25]1[CH:30]=[CH:29][N:28]=[CH:27][C:26]=1[CH:31]([NH2:33])[CH3:32]>>[N:25]1[CH:30]=[CH:29][N:28]=[CH:27][C:26]=1[CH:31]([NH:33][C:17]([C:6]1[CH:7]=[C:8]([C:10]2[CH:11]=[CH:12][C:13]([CH3:16])=[CH:14][CH:15]=2)[CH:9]=[C:4]([N:3]([CH2:1][CH3:2])[C:20](=[O:24])[CH:21]([CH3:22])[CH3:23])[CH:5]=1)=[O:18])[CH3:32]
Reactant: CC(N)c1cnccn1
Reactant: CCN(C(=O)C(C)C)c1cc(C(=O)O)cc(-c2ccc(C)cc2)c1
Product: CCN(C(=O)C(C)C)c1cc(C(=O)NC(C)c2cnccn2)cc(-c2ccc(C)cc2)c1

Procedure:
5-(Ethyl-isobutyryl-amino)-4′-methyl-biphenyl-3-carboxylic acid was reacted with 1-pyrazin-2-yl-ethylamine following the procedure of step 5 of Example 1 to give 5-(ethyl-isobutyryl-amino)-4′-methyl-biphenyl-3-carboxylic acid (1-pyrazin-2-yl-ethyl)-amide, MS (M+H)=431.
Reaction SMILES: F[C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=[O:7])=[CH:4][N:3]=1.[CH:11]1([NH2:16])[CH2:15][CH2:14][CH2:13][CH2:12]1.C(N(CC)CC)C>C1COCC1>[CH:11]1([NH:16][C:2]2[CH:10]=[CH:9][C:5]([C:6]([OH:8])=[O:7])=[CH:4][N:3]=2)[CH2:15][CH2:14][CH2:13][CH2:12]1
Reactant: O=C(O)c1ccc(F)nc1
Reactant: NC1CCCC1
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: O=C(O)c1ccc(NC2CCCC2)nc1
Temperature: 60 °C
Yield: 14.3 %

Procedure:
6-Fluoronicotinic acid (300 mg, 2.13 mmol) and cyclopentylamine (0.84 mL, 8.50 mmol) were combined in anhydrous THF (5 mL) and triethylamine (0.59 mL, 4.25 mmol). The mixture was heated at 60° C. for 3 days. The mixture was concentrated under reduced pressure, and the residue was suspended in water. The aqueous mixture was brought to pH 3 with phosphoric acid. The resulting precipitate was collected by vacuum filtration, washed with water, and dried in a vacuum oven for 1 h at 50° C. to give the title compound as a solid (63 mg, 14%): HPLC MS RT=1.14 min, MH+=207.2; 1H NMR (DMSO-d6) δ: 12.29 (1H, broad s), 8.50 (1H, d), 7.73 (1H, dd), 7.29 (1H, d), 6.42 (1H, d), 4.16 (1H, broad s), 1.90 (2H, m), 1.67 (2H, m), 1.53 (2H, m), 1.43 (2H, m).
Reaction SMILES: C1CCC(N=C=NC2CCCCC2)CC1.[NH:16]([C:31]([O:33][CH2:34][C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1)=[O:32])[C@H:17]([C:28]([OH:30])=O)[CH2:18][C:19]1[C:27]2[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=2)[NH:21][CH:20]=1.[NH:41]1[CH2:52][CH2:51][CH2:50][C@H:42]1[C:43]([O:45][C:46]([CH3:49])([CH3:48])[CH3:47])=[O:44].C1C=CC2N(O)N=NC=2C=1>CN(C)C=O>[NH:16]([C:31]([O:33][CH2:34][C:35]1[CH:36]=[CH:37][CH:38]=[CH:39][CH:40]=1)=[O:32])[C@H:17]([C:28]([N:41]1[CH2:52][CH2:51][CH2:50][C@H:42]1[C:43]([O:45][C:46]([CH3:48])([CH3:49])[CH3:47])=[O:44])=[O:30])[CH2:18][C:19]1[C:27]2[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=2)[NH:21][CH:20]=1
Reactant: O=C(N[C@@H](Cc1c[nH]c2ccccc12)C(=O)O)OCc1ccccc1
Reactant: CC(C)(C)OC(=O)[C@@H]1CCCN1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)[C@@H]1CCCN1C(=O)[C@H](Cc1c[nH]c2ccccc12)NC(=O)OCc1ccccc1
Temperature: 0 °C
Reaction time: 2 h

Procedure:
10.92 g (53 mmoles) of DCC are added at 0° C. to a solution of 16.9 g (50 mmoles) of Z-Trp-OH, 8.55 g (50 mmoles) of H-Pro-OBut and 6.75 g (50 mmoles) of HOBt in 75 ml of dimethylformamide. The mixture is stirred for 2 hours at 0° C. and left to stand overnight at room temperature. The precipitate is filtered off and the filtrate is concentrated. The residue is worked up analogously to Example 1 a. The residue is triturated with ether. Yield 19.49 g (79%), melting point 173°, [α]D25 =-54.2° (c=1, dimethylformamide).
Reaction SMILES: [NH2:1][C:2]1[S:3][C:4]([S:7][C:8]2[CH:13]=[CH:12][N:11]=[CH:10][CH:9]=2)=[CH:5][N:6]=1.N1C=CC=CC=1.[F:20][C:21]1[CH:29]=[CH:28][C:24]([C:25](Cl)=[O:26])=[CH:23][CH:22]=1>CN(C)C=O>[F:20][C:21]1[CH:29]=[CH:28][C:24]([C:25]([NH:1][C:2]2[S:3][C:4]([S:7][C:8]3[CH:13]=[CH:12][N:11]=[CH:10][CH:9]=3)=[CH:5][N:6]=2)=[O:26])=[CH:23][CH:22]=1
Reactant: O=C(Cl)c1ccc(F)cc1
Reactant: Nc1ncc(Sc2ccncc2)s1
Solvent: c1ccncc1
Solvent: CN(C)C=O
Product: O=C(Nc1ncc(Sc2ccncc2)s1)c1ccc(F)cc1
Yield: 63.2 %

Procedure:
To a mixture of 2-amino-5-(4-pyridylthio)thiazole (2.5 g) and pyridine (3 g) in N,N-dimethylformamide (25 ml) was added dropwise the 4-fluorobenzoyl chloride (2.7 g) at 5° C. under ice cooling with stirring. The mixture was stirred at 5° C. for 4 hours under ice cooling. The reaction mixture was concentrated under reduced pressure and the residue was triturated with water. The precipitates were collected by filtration, washed with water and dried in vacuo to give 2-(4-fluorobenzoylamino)-5-(4-pyridylthio)thiazole (2.5 g, yield: 63.1%). mp: 220°-225° C. (dec.)
Reaction SMILES: [I:1][C:2]1[C:10]2[C:5](=[N:6][CH:7]=[N:8][C:9]=2[NH2:11])[NH:4][N:3]=1.F[C:13]1[CH:18]=[CH:17][C:16]([N+:19]([O-:21])=[O:20])=[CH:15][N:14]=1.C([O-])([O-])=O.[K+].[K+].O>CN(C=O)C>[I:1][C:2]1[C:10]2[C:5](=[N:6][CH:7]=[N:8][C:9]=2[NH2:11])[N:4]([C:13]2[CH:18]=[CH:17][C:16]([N+:19]([O-:21])=[O:20])=[CH:15][N:14]=2)[N:3]=1
Reactant: O=[N+]([O-])c1ccc(F)nc1
Reactant: Nc1ncnc2[nH]nc(I)c12
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: Nc1ncnc2c1c(I)nn2-c1ccc([N+](=O)[O-])cn1
Temperature: 80 °C
Reaction time: 8 h
Yield: 68.1 %

Procedure:
To a solution of 3-iodo-1H-pyrazolo[3,4-d]pyrimidin-4-amine (1) (3 g, 11.5 mmol) and 2-fluoro-5-nitropyridine (1.96 g, 13.8 mmol) in DMF (50 mL) was added K2CO3 (4.77 g, 43.5 mmol). After the mixture was stirred at 80° C. under N2 overnight, it was slowly poured into stirred water (200 mL). The resulting precipitate was collected by filtration, washed with methanol (50 mL×3) and dried in vacuo to afford 3-iodo-1-(5-nitropyridin-2-yl)-1H-pyrazolo[3,4-d]pyrimidin-4-amine (61) (3 g, 68%) as a brown solid. LC-MS (ESI): m/z (M+1) 384.
Reaction SMILES: [C:1]([C@H:6]1[O:10][C@H:9](C(=O)C)[CH2:8][O:7]1)([O:3][CH2:4][CH3:5])=[O:2].ClC1C=CC=[C:17]([C:21]([O:23]O)=[O:22])C=1.C(=O)([O-])[O-].[Na+].[Na+]>ClCCl.O>[C:1]([C@H:6]1[O:10][C@@H:9]([O:23][C:21](=[O:22])[CH3:17])[CH2:8][O:7]1)([O:3][CH2:4][CH3:5])=[O:2]
Reactant: CCOC(=O)[C@@H]1OC[C@@H](C(C)=O)O1
Reactant: O=C(OO)c1cccc(Cl)c1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: ClCCl
Product: CCOC(=O)[C@@H]1OC[C@H](OC(C)=O)O1
Temperature: 25 °C
Reaction time: 16 h
Yield: 11 %

Procedure:
A 2.5:1 mixture of cis and trans-2-carboethoxy-4-acetyl-1,3-dioxolane (406 mg, 2.16 mmol), 85% meta-chloroperbenzoic acid (mCPBA) (68 mg, 3.81 mmol) and sodium carbonate (389 mg, 3.67 mmol) in dry dichloromethane (10 mL) was stirred under argon for 16 hours at room temperature. The resultant suspension was diluted with dichloromethane and water and stirred for 10 minutes. The aqueous phase was removed and the organic phase was washed successively with saturated sodium thiosulfate, water, brine and then was dried over anhydrous magnesium sulfate. The solvent was removed under reduced pressure and the crude product thus obtained was subjected to flash column chromatography (30% EtOAc-Hexanes) to give the title compound (11% yield) which displayed the following spectral characteristics; 1H NMR (CDCl3): δ 1.31 (t, 3H, J=7.2 Hz), 2.07 (s, 1H), 4.15 (d of d, 1H, J=4.5, 9.1 Hz), 4.21-4.29 (m, 3H), 5.42 (s, 1H), 6.39 (d of d, 1H, J=2.4, 4.5 Hz); 13C NMR (CDCl3): δ 14.05, 20.97, 29.69, 71.34, 94.04, 99.80, 167.19, 170.11.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[CH:4][CH:3]=1.[CH2:9](Br)[CH2:10][C@H:11]([CH2:13][CH2:14][CH:15]=[C:16]([CH3:18])[CH3:17])[CH3:12].C(=O)([O-])[O-].[K+].[K+]>CC(=O)CC>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][CH2:9][CH2:10][C@@H:11]([CH3:12])[CH2:13][CH2:14][CH:15]=[C:16]([CH3:18])[CH3:17])=[CH:4][CH:3]=1
Reactant: Oc1ccc(Br)cc1
Reactant: CC(C)=CCC[C@H](C)CCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCC(C)=O
Product: CC(C)=CCC[C@H](C)CCOc1ccc(Br)cc1
Yield: 590.9 %

Procedure:
A mixture of 4-bromophenol (34.6 g, 0.20 mol), (S)-(+)-citronellyl bromide (50 g, 0.023 mol) and potassium carbonate (45 g, 0.33 mol) in butanone (500 cm3) was heated under reflux overnight. The cooled reaction mixture was filtered and the filtrate concentrated under reduced pressure. The crude product was purified by fractional distillation to yield 42.3 g (68.2%) of the desired product.
Reaction SMILES: [S:1]([O:8]S(C(F)(F)F)(=O)=O)([C:4]([F:7])([F:6])[F:5])(=[O:3])=[O:2].[Br:16][C:17]1[CH:18]=[C:19]([CH:22]=[C:23]([Br:26])[C:24]=1O)[CH:20]=[O:21].O>N1C=CC=CC=1>[Br:16][C:17]1[CH:18]=[C:19]([CH:22]=[C:23]([Br:26])[C:24]=1[O:8][S:1]([C:4]([F:7])([F:6])[F:5])(=[O:3])=[O:2])[CH:20]=[O:21]
Reactant: O=S(=O)(OS(=O)(=O)C(F)(F)F)C(F)(F)F
Reactant: O=Cc1cc(Br)c(O)c(Br)c1
Solvent: O
Solvent: c1ccncc1
Product: O=Cc1cc(Br)c(OS(=O)(=O)C(F)(F)F)c(Br)c1
Reaction time: 1 h

Procedure:
14.73 ml of triflic anhydride is added, under inert gas and at 0° C., to 19.0 g of 3,5-dibromo-4-hydroxy-benzaldehyde in 100 ml of pyridine. Agitation is carried out for 1 hour while allowing the temperature to return to ambient, the reraction medium is poured into water and the aqueous phase is extracted with 3 times 150 ml of dichloromethane. The organic phases are dried and evaporated to dryness under reduced pressure. 23.83 g of crude product is obtained which is purified by filtration chromatography using a cyclohexane/ethyl acetate mixture 1/1 as eluant. In this way 23.83 g of expected product is obtained. Rf: 0.71, cyclohexane/ethyl acetate 1/1.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[C:6]3[C:15]([CH2:16][OH:17])=[N:14][N:13]([C:18]4[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=4)[C:12](=[O:24])[C:7]=3[N:8]([CH3:11])[C:9]=2[CH:10]=1>ClCCl.[O-2].[O-2].[Mn+4]>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[C:6]3[C:15]([CH:16]=[O:17])=[N:14][N:13]([C:18]4[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=4)[C:12](=[O:24])[C:7]=3[N:8]([CH3:11])[C:9]=2[CH:10]=1
Reactant: Cn1c2cc(Cl)ccc2c2c(CO)nn(-c3ccccc3)c(=O)c21
Agent: [Mn+4]
Agent: [O-2]
Solvent: ClCCl
Product: Cn1c2cc(Cl)ccc2c2c(C=O)nn(-c3ccccc3)c(=O)c21
Reaction time: 24 h
Yield: 87.9 %

Procedure:
5.7 g (65.6 mmol) of manganese dioxide are added to a solution of 3.3 g (9.7 mmol) of 7-chloro-1-(hydroxymethyl)-5-methyl-3-phenyl-3,5-dihydro-4H-pyridazino[4,5-b]indol-4-one in 300 ml of dichloromethane and the reaction mixture is stirred for 24 hours at reflux. The mixture is cooled and filtered through a Teflon® membrane, the solid is rinsed with dichloromethane and then the filtrate is concentrated under reduced pressure. 2:88 g (8.53 mmol) of compound are isolated in the form of a white solid which is used as is in the following stage.
Reaction SMILES: [OH:1][C:2]1[CH:11]=[C:10]2[C:5]([CH2:6][CH2:7][CH2:8][C:9]2=[O:12])=[CH:4][CH:3]=1.Cl[C:14]1[CH:22]=[CH:21][C:17]([C:18]([NH2:20])=[O:19])=[CH:16][N:15]=1.C([O-])([O-])=O.[K+].[K+].CC(N(C)C)=O>C1(C)C=CC=CC=1>[O:12]=[C:9]1[C:10]2[CH:11]=[C:2]([O:1][C:22]3[CH:14]=[N:15][CH:16]=[C:17]([CH:21]=3)[C:18]([NH2:20])=[O:19])[CH:3]=[CH:4][C:5]=2[CH2:6][CH2:7][CH2:8]1
Reactant: O=C1CCCc2ccc(O)cc21
Reactant: NC(=O)c1ccc(Cl)nc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(=O)N(C)C
Solvent: Cc1ccccc1
Product: NC(=O)c1cncc(Oc2ccc3c(c2)C(=O)CCC3)c1
Temperature: 25 °C

Procedure:
Combine 7-hydroxy-1-tetralone (J. Med. Chem. (1998), 41(7), 1068-1083), (3.37 g, 20.7 mmol), 6-chloronicotinamide (available from Aldrichj Chemical Company, Milwaukee, USA) (2.95 g, 18.8 mmol, K2CO3 (3.91 g, 28.3 mmol), DMA (dimethylacetamide) (45 ml) and toluene (25 ml) in a round bottom flask, equipped with Dean-Stark trap, condenser, and nitrogen inlet. Reflux the suspension for 2-3 hours before cooling to ambient temperature. Remove the solids via filtration, wash solids with EtOAc, and concentrate the filtrate/wash on a rotary evaporator. Dissolve the remaining oil in EtOAc, wash with water (2×) and brine, dry (MgSO4) and concentrate. Triturate the resulting brown solid with boiling EtOAc, cool, and collect solid via filtration to give 4.76 g of the title compound as a yellow solid. Mass spectrum (ion spray): m/z=283 (M+1); 1HNMR (DMSO-d6): 8.56 (s, 1H), 8.25 (d, 1H), 8.02 (s, 1H), 7.52 (s, 1H), 7.48 (s, 1H), 7.42 (d, 1H), 7.35 (d, 1H), 7.12 (d, 1H), 2.95 (t, 2H), 2.60 (t, 2H), 2.05 (m, 2H).
Reaction SMILES: [CH3:1][C:2]1[NH:3][C:4]([CH3:9])=[C:5]([CH2:7][OH:8])[N:6]=1.[N+]([O-])(O)=O.C(=O)([O-])[O-].[Na+].[Na+]>>[CH3:1][C:2]1[NH:3][C:4]([CH3:9])=[C:5]([CH:7]=[O:8])[N:6]=1
Reactant: Cc1nc(CO)c(C)[nH]1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O=[N+]([O-])O
Product: Cc1nc(C=O)c(C)[nH]1

Procedure:
A 42.2 gm. portion of 2,5-dimethyl-4-imidazolemethanol and 44.8 ml. of concentrated nitric acid are mixed. When the initial reaction subsides, the solution is heated on a steam bath for 1 hour. The reaction mixture is neutralized with concentrated aqueous sodium carbonate, then concentrated under vacuum. After leaching the residue with 150 ml. of hot ethanol several times, the combined organic solution are concentrated under vacuum. Chromatographing the residual oil on silica gel gives a solid which is recrystallized from isopropanolethyl acetate to give the desired product, m.p. 164.5°-166° C.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[CH:6][C:5]([OH:8])=[C:4]([I:9])[CH:3]=1.C(=O)([O-])[O-].[K+].[K+].I[CH2:17][CH3:18]>CN(C=O)C>[Cl:1][C:2]1[CH:3]=[C:4]([I:9])[C:5]([O:8][CH2:17][CH3:18])=[CH:6][N:7]=1
Reactant: Oc1cnc(Cl)cc1I
Reactant: CCI
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCOc1cnc(Cl)cc1I
Temperature: 25 °C

Procedure:
6-Chloro-4-iodo-pyridin-3-ol (0.41 g, 1.62 mmol) was dissolved in anhydrous DMF (4 mL) and stirred at room temperature. Potassium carbonate (0.67 g, 4.9 mmol) and iodoethane (0.40 mL, 4.9 mmol) were added sequentially. The mixture was heated to 60° C. and maintained for 2 hours. The mixture was cooled to room temperature and filtered. The filtrate was diluted with diethyl ether (25 mL) and washed with 20% aqueous citric acid (25 mL). The aqueous was extracted with diethyl ether (2×20 mL). The combined organics were washed with brine, dried over Na2SO4, filtered and concentrated. The residue was triturated with hexane resulting in a tan solid (0.42 g, 91%). 1H NMR (400 MHz, CDCl3): δ 7.80 (s, 1H), 7.74 (s, 1H) 4.18 (q, J=7.1 Hz, 2H), 1.51 (t, J=7.1 Hz, 3H).
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][C:8]([CH3:14])=[C:9]([O:12][CH3:13])[CH:10]=2)[N:5]=[CH:4][N:3]=1.C(N(CC)CC)C>CN(C)C=O.[OH-].[Pd+2].[OH-]>[CH3:13][O:12][C:9]1[CH:10]=[C:11]2[C:6](=[CH:7][C:8]=1[CH3:14])[N:5]=[CH:4][N:3]=[CH:2]2
Reactant: COc1cc2c(Cl)ncnc2cc1C
Agent: [Pd+2]
Agent: [OH-]
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: COc1cc2cncnc2cc1C
Temperature: 25 °C
Reaction time: 8 h
Yield: 91.9 %

Procedure:
4-Chloro-6-methoxy-7-methyl-quinazoline (99 mg) was dissolved in N,N-dimethylformamide (6 ml) to prepare a solution. Triethylamine (0.6 ml) and 20% palladium hydroxide (4 mg) were added to the solution, and the mixture was stirred under hydrogen pressure at room temperature overnight. The reaction solution was filtered through Celite and was then washed with chloroform and methanol, and the solvent was removed by distillation under the reduced pressure. Water was added to the residue, and the mixture was extracted with ethyl acetate. The ethyl acetate layer was then washed with saturated brine and was dried over anhydrous sodium sulfate. The solvent was removed by distillation under the reduced pressure, and the residue was purified by thin layer chromatography using chloroform-methanol to give 6-methoxy-7-methyl-quinazoline (76 mg, yield 93%).
Reaction SMILES: [CH:1]1([C:4]2[N:9]3[N:10]=[CH:11][C:12]([C:13]([OH:15])=O)=[C:8]3[N:7]=[C:6]([C:16]3[CH:21]=[CH:20][C:19]([C:22]([F:25])([F:24])[F:23])=[CH:18][CH:17]=3)[CH:5]=2)[CH2:3][CH2:2]1.O[NH:27][C:28](=[NH:39])[C:29]1[CH:34]=[CH:33][C:32]([S:35](=[O:38])(=[O:37])[NH2:36])=[CH:31][CH:30]=1>>[CH:1]1([C:4]2[N:9]3[N:10]=[CH:11][C:12]([C:13]4[O:15][N:39]=[C:28]([C:29]5[CH:30]=[CH:31][C:32]([S:35]([NH2:36])(=[O:37])=[O:38])=[CH:33][CH:34]=5)[N:27]=4)=[C:8]3[N:7]=[C:6]([C:16]3[CH:21]=[CH:20][C:19]([C:22]([F:25])([F:24])[F:23])=[CH:18][CH:17]=3)[CH:5]=2)[CH2:2][CH2:3]1
Reactant: N=C(NO)c1ccc(S(N)(=O)=O)cc1
Reactant: O=C(O)c1cnn2c(C3CC3)cc(-c3ccc(C(F)(F)F)cc3)nc12
Product: NS(=O)(=O)c1ccc(-c2noc(-c3cnn4c(C5CC5)cc(-c5ccc(C(F)(F)F)cc5)nc34)n2)cc1

Procedure:
The title compound was prepared from 7-cyclopropyl-5-(4-trifluoromethyl-phenyl)-pyrazolo[1,5-a]pyrimidine-3-carboxylic acid (example C.29) (174 mg, 0.5 mmol) and N-hydroxy-4-sulfamoyl-benzamidine [CAS-No. 4476-10-2] (161 mg, 0.75 mmol) according to general procedure II. Obtained after purification by column chromatography (dichloromethane/MeOH/NH4OH) and crystallization (dichloromethane/MeOH/hexane) as a light yellow solid (191 mg, 73%). MS (EI) 526.1 [(M)+]; mp 313° C.
Reaction SMILES: C([O:3][C:4](=O)[CH2:5][N:6]([CH2:17][CH2:18][CH2:19][N:20]([CH2:28][C:29]1[CH:37]=[CH:36][C:32]2[O:33][CH2:34][O:35][C:31]=2[CH:30]=1)C(OC(C)(C)C)=O)[C:7]1[S:11][N:10]=[C:9]([N:12]2[CH:16]=[CH:15][N:14]=[CH:13]2)[N:8]=1)C.[NH3:39]>CO.CCOC(C)=O>[O:33]1[C:32]2[CH:36]=[CH:37][C:29]([CH2:28][NH:20][CH2:19][CH2:18][CH2:17][N:6]([C:7]3[S:11][N:10]=[C:9]([N:12]4[CH:16]=[CH:15][N:14]=[CH:13]4)[N:8]=3)[CH2:5][C:4]([NH2:39])=[O:3])=[CH:30][C:31]=2[O:35][CH2:34]1
Reactant: N
Reactant: CCOC(=O)CN(CCCN(Cc1ccc2c(c1)OCO2)C(=O)OC(C)(C)C)c1nc(-n2ccnc2)ns1
Solvent: CCOC(C)=O
Solvent: CO
Product: NC(=O)CN(CCCNCc1ccc2c(c1)OCO2)c1nc(-n2ccnc2)ns1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 60 %

Procedure:
A mixture of [[3-(benzo[1,3]dioxol-5-ylmethyl-tert-butoxycarbonyl-amino)-propyl]-(3-imidazol-1-yl-[1,2,4]thiadiazol-5-yl)-amino]-acetic acid ethyl ester from Step 1 (115 mg, 211 μmol) and a 2.0 M solution NH3 in MeOH (10 mL) was stirred at r.t. for 24 h. The reaction mixture was concentrated to a yellow oil. The crude residue was dissolved in TFA/DCM (1:1, 3 mL) and stirred at room temperature for 30 min. The solvent was evaporated to afford an orange oil. The crude product was diluted with EtOAc (50 mL), washed with 1M NaOH (50 mL), brine (50 mL), dried over Na2SO4, filtered and concentrated to an oil. Purification was achieved using column chromatography (CH2Cl2 to 4:1 CH2Cl2/MeOH) to afford 53 mg (60%) of 2-[{3-[(benzo[1,3]dioxol-5-ylmethyl)-amino]-propyl}-(3-imidazol-1-yl-[1,2,4]thiadiazol-5-yl)-amino]-acetamide as a white solid. [M+H]+ 415.97; 1H NMR (400 MHz, d6-DMSO) δ 8.29 (s, 1H), 7.72 (s, 1H), 7.63 (br s, 1H), 7.28 (br s, 1H), 7.09 (s, 1H), 6.92 (s, 1H), 6.82 (m, 2H), 5.98 (s, 2H), 4.20 (br s, 1H), 3.60 (s, 2H), 3.33 (s, 2H), 2.54 (m, 4H), 1.80 (m, 2H).