Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[CH2:13][CH2:12][N:11]([C:14](=[O:26])[CH2:15][N:16]3[C:20]4=[N:21][CH:22]=[CH:23][CH:24]=[C:19]4[C:18](I)=[N:17]3)[CH2:10][CH2:9]2)=[CH:4][C:3]=1[O:27][CH3:28].[C:29]([Cu])#[N:30]>CN1C=CC=CC1=O>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[CH2:13][CH2:12][N:11]([C:14](=[O:26])[CH2:15][N:16]3[C:20]4=[N:21][CH:22]=[CH:23][CH:24]=[C:19]4[C:18]([C:29]#[N:30])=[N:17]3)[CH2:10][CH2:9]2)=[CH:4][C:3]=1[O:27][CH3:28]
Reactant: N#C[Cu]
Reactant: COc1cc(N2CCN(C(=O)Cn3nc(I)c4cccnc43)CC2)ccc1Cl
Agent: Cn1ccccc1=O
Product: COc1cc(N2CCN(C(=O)Cn3nc(C#N)c4cccnc43)CC2)ccc1Cl
Temperature: 165 °C

Procedure:
1-[4-(4-Chloro-3-methoxy-phenyl)-piperazin-1-yl]-2-(3-iodo-pyrazolo[3,4-b]pyridin-1-yl)-ethanone (128 mg) and CuCN (112 mg) were combined in N-methylpyridone (NMP) (1 mL) and heated at 165° C. for 16 hr, then cooled to room temperature. The reaction mixture was purified on preparative HPLC to afford 1-{2-[4-(4-Chloro-3-methoxy-phenyl)-piperazin-1-yl]-2-oxo-ethyl}-1H-pyrazolo[3,4-b]pyridine-3-carbonitrile as a white powder: LCMS (ES) M+H 411.5, Rf 2.33 min (Agilent Zorbax SB-C18, 2.1×50 mm, 5μ, 35° C., 1 ml/min flow rate, a 2.5 min gradient of 20% to 100% B with a 1.1 min wash at 100% B; A=0.1% formic acid/5% acetonitrile/94.9% water, B=0.1% formic acid/5% water/94.9% acetonitrile).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][NH2:9])=[CH:4][CH:3]=1.[C:10]([OH:15])(=[O:14])[C:11]([CH3:13])=O>O>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][N:9]=[C:11]([CH3:13])[C:10]([OH:15])=[O:14])=[CH:4][CH:3]=1
Reactant: CC(=O)C(=O)O
Reactant: NNc1ccc(Cl)cc1
Solvent: O
Product: CC(=NNc1ccc(Cl)cc1)C(=O)O
Temperature: 70 °C
Reaction time: 0.5 h

Procedure:
75.7 g of hydrochloric salt of parachlorophenylhydrazine was dissolved into 350 ml of water. 37.2 g of pyruvic acid was added into the solution. After stirring for 30 minutes at 70° C. while heating, and then cooling, precipitated crystals were filtered out, washed, and dried. These crystals were recrystallized from isopropyl acohol to obtain 57 g of 2-(p-chlorophenylhydrazono)propionic acid having a melting point of 196° to 197° C. (decomposed).
Reaction SMILES: [NH2:1][CH2:2][CH2:3][CH2:4][CH2:5][N:6]1[C:18]2[C:17]3[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=3[N:11]=[C:10]([NH2:19])[C:9]=2[N:8]=[C:7]1[CH3:20].[C:21](Cl)(=[O:25])[CH:22]([CH3:24])[CH3:23]>>[NH2:19][C:10]1[C:9]2[N:8]=[C:7]([CH3:20])[N:6]([CH2:5][CH2:4][CH2:3][CH2:2][NH:1][C:21](=[O:25])[CH:22]([CH3:24])[CH3:23])[C:18]=2[C:17]2[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=2[N:11]=1
Reactant: CC(C)C(=O)Cl
Reactant: Cc1nc2c(N)nc3ccccc3c2n1CCCCN
Product: Cc1nc2c(N)nc3ccccc3c2n1CCCCNC(=O)C(C)C
Yield: 44.6 %

Procedure:
Using the general method of Example 197, 1-(4-aminobutyl)-2-methyl-1H-imidazo[4,5-c]quinolin-4-amine (1.00 g, 3.7 mmol) was reacted with isobutyryl chloride (0.43 mL, 4.1 mmol) to provide 0.56 g of N-[4-(4-amino-2-methyl-1H-imidazo[4,5-c]quinolin-1-yl)butyl]-2-methylpropanamide as an off white solid, m.p. 159.7-160.7° C.
Reaction SMILES: [CH2:1]([O:8][C:9]([N:11]1[CH2:34][CH2:33][CH2:32][C@H:12]1[C:13]([N:15]1[CH2:19][CH2:18][CH2:17][C@H:16]1[CH:20]([OH:31])[CH2:21][S:22]([C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1)(=[O:24])=[O:23])=[O:14])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.CS(C)=O.C1CCC(N=C=NC2CCCCC2)CC1>>[CH2:1]([O:8][C:9]([N:11]1[CH2:34][CH2:33][CH2:32][C@H:12]1[C:13]([N:15]1[CH2:19][CH2:18][CH2:17][C@H:16]1[C:20](=[O:31])[CH2:21][S:22]([C:25]1[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=1)(=[O:24])=[O:23])=[O:14])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C(OCc1ccccc1)N1CCC[C@H]1C(=O)N1CCC[C@H]1C(O)CS(=O)(=O)c1ccccc1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Solvent: CS(C)=O
Product: O=C(CS(=O)(=O)c1ccccc1)[C@@H]1CCCN1C(=O)[C@@H]1CCCN1C(=O)OCc1ccccc1
Yield: 82.7 %

Procedure:
(2S)-1-(N-Benzyloxycarbonyl-L-prolyl)-2-[1-hydroxy-2-(phenylsulfonyl)ethyl]pyrrolidine (500 mg) was subjected to DMSO-DCC oxidation as in Example 1-D) to give 412 mg of (2S)-1-(N-benzyloxycarbonyl-L-prolyl)-2-[(phenylsulfonyl)acetyl]-pyrrolidine (See Table 1).
Reaction SMILES: [CH3:1][O:2][C:3]([NH:5][C@H:6]([C:20]([NH:22][CH2:23][C:24]([F:52])([F:51])[CH2:25][CH2:26][C@@H:27]([C:48](O)=[O:49])[N:28]([S:36]([C:39]1[CH:47]=[CH:46][C:42]2[N:43]=[CH:44][S:45][C:41]=2[CH:40]=1)(=[O:38])=[O:37])[CH2:29][CH:30]1[CH2:33][C:32]([F:35])([F:34])[CH2:31]1)=[O:21])[CH:7]([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)=[O:4].O[N:54]1C2C=CC=CC=2N=N1.[Cl-].[NH4+].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C(N(CC)C(C)C)(C)C>CN(C=O)C.O>[CH3:1][O:2][C:3]([NH:5][C@H:6]([C:20]([NH:22][CH2:23][C:24]([F:51])([F:52])[CH2:25][CH2:26][C@@H:27]([C:48]([NH2:54])=[O:49])[N:28]([S:36]([C:39]1[CH:47]=[CH:46][C:42]2[N:43]=[CH:44][S:45][C:41]=2[CH:40]=1)(=[O:37])=[O:38])[CH2:29][CH:30]1[CH2:31][C:32]([F:35])([F:34])[CH2:33]1)=[O:21])[CH:7]([C:8]1[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=1)[C:14]1[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=1)=[O:4]
Reactant: On1nnc2ccccc21
Reactant: COC(=O)N[C@H](C(=O)NCC(F)(F)CC[C@@H](C(=O)O)N(CC1CC(F)(F)C1)S(=O)(=O)c1ccc2ncsc2c1)C(c1ccccc1)c1ccccc1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Agent: [Cl-]
Solvent: CCN(C(C)C)C(C)C
Solvent: O
Solvent: CN(C)C=O
Product: COC(=O)N[C@H](C(=O)NCC(F)(F)CC[C@@H](C(N)=O)N(CC1CC(F)(F)C1)S(=O)(=O)c1ccc2ncsc2c1)C(c1ccccc1)c1ccccc1
Temperature: 0 °C
Reaction time: 0.08 h

Procedure:
To a solution of the material from Example 4, Step 8 (98 mg, 0.128 mmol) in 1.2 mL of DMF at 0° C. were added 1-hydroxybenzotriazole (26 mg, 0.192 mmol), ammonium chloride (14 mg, 0.256 mmol), HATU (73 mg, 0.192 mmol) and N,N-diisopropylethylamine (67 μL, 0.358 mmol). The reaction mixture was stirred at 0° C. over the week-end. It was poured into water and extracted with EtOAc (2×). The combined organics were washed with brine, dried over MgSO4, filtered and concentrated in vacuo. The residue was purified by reverse phase column using Zorbax Eclise Plus C18 RRHT 3×50 mm, 1.8 u column. Gradient: MeCN/H2O+0.1% HCO2H from 10:90 to 95:5 over 5 minutes. Flow: 1.0 mL/min. Positive ion mode. The title compound was obtained as a colorless foam. LCMS (M+1)=764. 1H NMR (Acetone-d6): δ 9.56 (s, 1H), 8.83 (d, J=12.07 Hz, 1H), 8.41-8.25 (m, 1H), 8.08 (d, J=8.22 Hz, 1H), 7.59 (s, 1H), 7.48-7.38 (m, 4H), 7.35-7.25 (m, 4H), 7.24-7.13 (m, 2H), 6.81 (s, 1H), 6.76-6.60 (m, 1H), 6.46 (d, J=8.74 Hz, 1H), 5.16-5.02 (m, 1H), 4.49-4.41 (m, 1H), 4.38-4.31 (m, 1H), 3.69-3.57 (m, 1H), 3.34 (s, 3H), 3.47-3.20 (m, 3H), 3.14-2.89 (m, 1H), 2.71-2.26 (m, 4H), 2.04-1.84 (m, 2H), 1.52-1.10 (m, 2H).
Reaction SMILES: [C:1]([C:3]([C:6]1[CH:12]=[CH:11][C:9]([NH2:10])=[CH:8][CH:7]=1)([CH3:5])[CH3:4])#[N:2].[CH3:13][O:14][C:15]1[CH:23]=[CH:22][C:18]([C:19](Cl)=[O:20])=[CH:17][CH:16]=1>>[C:1]([C:3]([C:6]1[CH:7]=[CH:8][C:9]([NH:10][C:19](=[O:20])[C:18]2[CH:22]=[CH:23][C:15]([O:14][CH3:13])=[CH:16][CH:17]=2)=[CH:11][CH:12]=1)([CH3:5])[CH3:4])#[N:2]
Reactant: CC(C)(C#N)c1ccc(N)cc1
Reactant: COc1ccc(C(=O)Cl)cc1
Product: COc1ccc(C(=O)Nc2ccc(C(C)(C)C#N)cc2)cc1
Yield: 85 %

Procedure:
Analogously to Example 25, 4-(1-cyano-1-methylethyl)-aniline is reacted with 4-methoxybenzoic acid chloride to give a yield of 85% of theory of the title compound in the form of beige crystals; m.p. 169°-171° C. A sample thereof is recrystallised from ethanol and then has a melting point of 172°-174° C.
Reaction SMILES: Cl[CH2:2][C:3]([CH:5]1[CH2:10][CH2:9][N:8]([C:11]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12])[CH2:7][CH2:6]1)=[O:4].[Cl:18][C:19]1[CH:20]=[CH:21][C:22]([OH:29])=[C:23]([NH:25][C:26]([NH2:28])=[O:27])[CH:24]=1.C([O-])([O-])=O.[K+].[K+]>CS(C)=O>[Cl:18][C:19]1[CH:20]=[CH:21][C:22]([O:29][CH2:2][C:3]([CH:5]2[CH2:10][CH2:9][N:8]([C:11]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12])[CH2:7][CH2:6]2)=[O:4])=[C:23]([NH:25][C:26]([NH2:28])=[O:27])[CH:24]=1
Reactant: NC(=O)Nc1cc(Cl)ccc1O
Reactant: CC(C)(C)OC(=O)N1CCC(C(=O)CCl)CC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CS(C)=O
Product: CC(C)(C)OC(=O)N1CCC(C(=O)COc2ccc(Cl)cc2NC(N)=O)CC1
Reaction time: 14 h
Yield: 25 %

Procedure:
A solution of the crude tert-butyl 4-(2-chloroacetyl)piperidine-1-carboxylate (one third the material from step 1, approximately 5 mmol) in DMSO (20 mL) was charged with 1-(5-chloro-2-hydroxyphenyl)urea (see N. Hossain et al., WO PCT 2004/005295; 980 mg, 5.25 mmol) and K2CO3 (1.38 g, 10 mmol). The reaction was stirred for ˜14 h and then quenched with water (40 mL). The mixture was extracted twice with EtOAc. The organic phases were combined, washed with brine, dried (Na2SO4), filtered, and concentrated in vacuo. The resultant residue was purified by flash chromatography to afford tert-butyl 4-(2-(4-chloro-2-ureidophenoxy)acetyl)piperidine-1-carboxylate (550 mg, ˜25% yield) as a solid. LC/MS [M-Boc]+=312.3, [M+Na]+=434.3.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([NH:8][C:9]2[CH:14]=[CH:13][CH:12]=[C:11]([OH:15])[CH:10]=2)[C:5]([F:16])=[CH:4][N:3]=1.[CH3:17][O:18][C:19]([C:21]1[CH:22]=[C:23]([CH:25]=[C:26]([C:28]([F:31])([F:30])[F:29])[CH:27]=1)[NH2:24])=[O:20]>>[F:16][C:5]1[C:6]([NH:8][C:9]2[CH:14]=[CH:13][CH:12]=[C:11]([OH:15])[CH:10]=2)=[N:7][C:2]([NH:24][C:23]2[CH:25]=[C:26]([C:28]([F:29])([F:30])[F:31])[CH:27]=[C:21]([C:19]([O:18][CH3:17])=[O:20])[CH:22]=2)=[N:3][CH:4]=1
Reactant: Oc1cccc(Nc2nc(Cl)ncc2F)c1
Reactant: COC(=O)c1cc(N)cc(C(F)(F)F)c1
Product: COC(=O)c1cc(Nc2ncc(F)c(Nc3cccc(O)c3)n2)cc(C(F)(F)F)c1

Procedure:
In like manner to the preparation of N4-(3-chloro-4-trifluoromethoxyphenyl)-5-fluoro-N2-(3-hydroxyphenyl)-2,4-pyrimidineamine, the reaction of 2-chloro-5-fluoro-N4-(3-hydroxyphenyl)-4-pyrimidineamine with 3-methoxycarbonyl-5-trifluoromethylaniline gave 5-fluoro-N4-(3-hydroxyphenyl)-N2-(3-methoxycarbonyl-5-trifluoromethylphenyl)-2,4-pyrimidinediamine. 1H NMR (DMSO-d6): δ 9.98 (s, 1H), 9.52 (s, 1H), 8.53 (s, 1H), 8.38 (s, 1H), 8.20 (d, 1H, J=4.2 Hz), 7.69 (s, 1H), 7.27 (d, 1H, J=8.1 Hz), 7.14 (s, 1H), 7.05 (t, 1H, 7.8 Hz), 6.49 (dd, 1H, J=1.8 and 8.4 Hz), 3.80 (s, 3H); LCMS: purity: 82%; MS (m/e): 423 (MH+).
Reaction SMILES: [F:1][C:2]1[C:3]([N+:21]([O-])=O)=[C:4]2[C:9](=[C:10]([O:13][CH3:14])[C:11]=1[F:12])[NH:8][CH:7]=[C:6]([C:15]([O:17][CH2:18][CH3:19])=[O:16])[C:5]2=[O:20]>CN(C=O)C.[Pd]>[NH2:21][C:3]1[C:2]([F:1])=[C:11]([F:12])[C:10]([O:13][CH3:14])=[C:9]2[C:4]=1[C:5](=[O:20])[C:6]([C:15]([O:17][CH2:18][CH3:19])=[O:16])=[CH:7][NH:8]2
Reactant: CCOC(=O)c1c[nH]c2c(OC)c(F)c(F)c([N+](=O)[O-])c2c1=O
Agent: [Pd]
Solvent: CN(C)C=O
Product: CCOC(=O)c1c[nH]c2c(OC)c(F)c(F)c(N)c2c1=O
Yield: 53.9 %

Procedure:
A solution of ethyl 6,7-difluoro-1,4-dihydro-8-methoxy-5-nitro-4-oxoquinoline-3-carboxylate (1.50 g, 4.57 mmol) and 10% Pd/C (40.5 mg) in DMF (20 mL) was stirred under hydrogen atmosphere at room temprature for 14 h. The catalyst was removed by filtration over Celite and the filtrate was concentrated in vacuo. The resulting solid was recrystallized by EtOH, and dried to yield ethyl 5-amino-6,7-difluoro-1,4-dihydro-8-methoxy-4-oxoquinoline-3-carboxylate (735 mg, 54%) as a pale brown solid.
Reaction SMILES: C([O:5][C:6]([C:8]1[O:9][C:10]2[CH:17]=[CH:16][CH:15]=[C:14]([O:18][CH2:19][C:20]3[CH:21]=[N:22][CH:23]=[CH:24][CH:25]=3)[C:11]=2[C:12]=1[CH3:13])=[O:7])(C)(C)C.C(O)(C(F)(F)F)=O.C(Cl)Cl>>[CH3:13][C:12]1[C:11]2[C:14]([O:18][CH2:19][C:20]3[CH:21]=[N:22][CH:23]=[CH:24][CH:25]=3)=[CH:15][CH:16]=[CH:17][C:10]=2[O:9][C:8]=1[C:6]([OH:7])=[O:5]
Reactant: Cc1c(C(=O)OC(C)(C)C)oc2cccc(OCc3cccnc3)c12
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: Cc1c(C(=O)O)oc2cccc(OCc3cccnc3)c12
Temperature: 25 °C
Reaction time: 4 h

Procedure:
The 3-methyl-4-(pyridin-3-ylmethoxy)-benzofuran-2-carboxylic acid t-butyl ester was dissolved into a 40% TFA/methylene chloride solution, and stirred at room temperature for 4 hours. Evaporation of the solvent gave 3-methyl-4-(pyridin-3-ylmethoxy)-benzofuran-2-carboxylic acid in quantitative yield.
Reaction SMILES: [CH2:1]([O:3][C:4]1[CH:5]=[C:6]([NH:13][C:14](=[O:19])[O:15][CH:16]([CH3:18])[CH3:17])[CH:7]=[CH:8][C:9]=1[O:10][CH2:11][CH3:12])[CH3:2].[H-].[Na+].[C:22](Cl)(=[O:29])[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1>CN(C)C=O>[C:22]([N:13]([C:6]1[CH:7]=[CH:8][C:9]([O:10][CH2:11][CH3:12])=[C:4]([O:3][CH2:1][CH3:2])[CH:5]=1)[C:14](=[O:19])[O:15][CH:16]([CH3:17])[CH3:18])(=[O:29])[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1
Reactant: CCOc1ccc(NC(=O)OC(C)C)cc1OCC
Reactant: O=C(Cl)c1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCOc1ccc(N(C(=O)OC(C)C)C(=O)c2ccccc2)cc1OCC
Temperature: 60 °C
Yield: 80 %

Procedure:
Isopropyl N-(3,4-diethoxyphenyl)carbamate (2.7 g) was dissolved in dimethylformamide (50 ml), and sodium hydride dispersion (50%, 0.5 g) was added thereto. The mixture was heated at 60° C. for 15 minutes, treated with benzoyl chloride (1.4 g) and heated for 30 minutes. The reaction mixture was poured into ice-water and extracted with ether. The extract was washed with sodium bicarbonate solution and saturated brine, dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue was purified by silica gel chromatography using hexane-acetone as the eluent to give isopropyl N-benzoyl-N-(3,4-diethoxyphenyl)carbamate (Compound No. 99) (3.1 g) in a yield of 80%. M.P., 120°-121° C.
Reaction SMILES: [CH2:1]([OH:7])[CH2:2]/[CH:3]=[CH:4]/[CH2:5][CH3:6].[H-].[Na+].Cl[C:11]1[C:12]([C:16]2[CH:17]=[N:18][CH:19]=[CH:20][CH:21]=2)=[N:13][S:14][N:15]=1.O>O1CCCC1>[CH2:1]([O:7][C:11]1[C:12]([C:16]2[CH:17]=[N:18][CH:19]=[CH:20][CH:21]=2)=[N:13][S:14][N:15]=1)[CH2:2]/[CH:3]=[CH:4]/[CH2:5][CH3:6]
Reactant: Clc1nsnc1-c1cccnc1
Reactant: CC/C=C/CCO
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: CC/C=C/CCOc1nsnc1-c1cccnc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of trans-3-hexen-1-ol (900 mg, 9 mmol) and sodium hydride (310 mg, 9 mmol) in dry tetrahydrofuran was added a solution of 3-(4-chloro-1,2,5-thiadiazol-3-yl) pyridine (590 mg, 3 mmol) in dry tetrahydrofuran. The reaction mixture was stirred at room temperature for 1 h. Water was added and the mixture was extracted with ether. The ether phase was dried and evaporated to give the title compound.
Reaction SMILES: FC(F)(F)C(O)=O.N1(C2N=CC(C3SC4C=C(C(OCC)=O)C=CC=4N=3)=CC=2)CCNCC1.[CH3:34][O:35][C:36]1[CH:63]=[CH:62][C:39]2[N:40]=[C:41]([C:43]3[CH:44]=[CH:45][C:46]([N:49]4[CH2:54][CH2:53][N:52](C(OC(C)(C)C)=O)[CH2:51][CH2:50]4)=[N:47][CH:48]=3)[S:42][C:38]=2[CH:37]=1.[OH-].[Na+].C(=O)([O-])O.[Na+]>C(Cl)Cl>[CH3:34][O:35][C:36]1[CH:63]=[CH:62][C:39]2[N:40]=[C:41]([C:43]3[CH:48]=[N:47][C:46]([N:49]4[CH2:54][CH2:53][NH:52][CH2:51][CH2:50]4)=[CH:45][CH:44]=3)[S:42][C:38]=2[CH:37]=1
Reactant: COc1ccc2nc(-c3ccc(N4CCN(C(=O)OC(C)(C)C)CC4)nc3)sc2c1
Agent: CCOC(=O)c1ccc2nc(-c3ccc(N4CCNCC4)nc3)sc2c1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: COc1ccc2nc(-c3ccc(N4CCNCC4)nc3)sc2c1

Procedure:
6-Methoxy-2-(6-piperazin-1-ylpyridin-3-yl)-1,3-benzothiazole was prepared according to the method used for the preparation of ethyl 2-(6-piperazin-1-ylpyridin-3-yl)-1,3-benzothiazole-6-carboxylate trifluoroacetate, from tert-butyl 4-[5-(6-methoxy-1,3-benzothiazol-2-yl)pyridin-2-yl]piperazine-1-carboxylate (0.22 g), with the exception that sodium hydroxide was used instead of sat. sodium hydrogencarbonate after completion of the reaction, and that the product was taken up in DCM thereafter. The title compound was obtained as a solid (0.15 g) after drying and concentration. 1H NMR δ 8.71 (d, 1 H) 8.07 (dd, 1 H) 7.85 (d, 1 H) 7.66 (d, 1 H) 7.09 (dd, 1 H) 6.93 (d, 1 H) 3.84 (s, 3 H) 3.47-3.64 (m, 4 H) 2.65-2.89 (m, 4 H); MS m/z (M+H) 327.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([C:8]([F:11])([F:10])[F:9])[CH:5]=[C:4]([Cl:12])[C:3]=1[NH:13][N:14]=[C:15]([C:24]#[N:25])[CH:16]([C:22]#[N:23])[S:17][C:18]([F:21])([F:20])[F:19]>[Cu](Cl)Cl.ClC1C=CC=CC=1>[NH2:23][C:22]1[N:13]([C:3]2[C:4]([Cl:12])=[CH:5][C:6]([C:8]([F:9])([F:11])[F:10])=[CH:7][C:2]=2[Cl:1])[N:14]=[C:15]([C:24]#[N:25])[C:16]=1[S:17][C:18]([F:19])([F:20])[F:21]
Reactant: N#CC(=NNc1c(Cl)cc(C(F)(F)F)cc1Cl)C(C#N)SC(F)(F)F
Agent: Cl[Cu]Cl
Solvent: Clc1ccccc1
Product: N#Cc1nn(-c2c(Cl)cc(C(F)(F)F)cc2Cl)c(N)c1SC(F)(F)F
Temperature: 100 °C
Reaction time: 4 h
Yield: 73 %

Procedure:
A mixture of 1-(2,6-dichloro-4-trifluoromethylphenylhydrazono) 1,2-dicyano-2-trifluoromethylthio ethane (144 mg; 0.34 mmol), prepared according to Example 3, copper (II) chloride (97 mg; 0.71 mmol), and 4 ml of chlorobezene was stirred for 4 hours at 100° C. The solvent was then evaporated under vacuum. The residue was dissolved in CH2CL2 and the solution was washed by an aqueous solution of 1% ammonia in water. The product was dried over sodium sulphate, and solvent was evaporated under reduced pressure. Purification by flash chromatography on silica gel and crystallization from dichloromethane/hexane gave a white solid (105 mg; 73% yield). The product was then recrystallized in a hexane/toluene mixture to provide a light brown powder (93 mg; 65% yield), melting point 163° C. A second recrystallization provided a white powder of the title product with a melting point 165° C.
Reaction SMILES: B#B.[CH:3]12[CH2:13][CH:8]3[CH2:9][CH:10]([CH2:12][CH:6]([CH2:7]3)[C:5](=O)[NH:4]1)[CH2:11]2>O1CCCC1.Cl>[CH:3]12[CH2:13][CH:8]3[CH2:9][CH:10]([CH2:12][CH:6]([CH2:7]3)[CH2:5][NH:4]1)[CH2:11]2
Reactant: O=C1NC2CC3CC(C2)CC1C3
Agent: B#B
Agent: Cl
Solvent: C1CCOC1
Product: C1NC2CC3CC1CC(C3)C2
Yield: 51.9 %

Procedure:
To a solution of diborane in tetrahydrofuran (1M, 20 ml) was added dropwise a solution of 2-azatricyclo[4.3.1.14,8 ]-undecan-3-one (1.01 g) in dry tetrahydrofuran (20 ml) under stirring at cooling in an ice-bath. The mixture was stirred under the same condition for 2 hours and then at room temperature overnight. To the reaction mixture was added dropwise IN hydrochloric acid aqueous solution (20 ml). After removal of the solvent under reduced pressure, the residue was washed with ethyl acetate. The aqueous layer was alkalined with IN sodium hydroxide aqueous solution, extracted with ethyl acetate three times and dried over sodium sulfate. Removal of the solvent gave 2-azatricyclo[4.3.1.14,8 ]undecane (0.48 g), which was used in a following reaction step without further purification.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[C:8](=[O:12])[NH:7][N:6]=[C:5]2[Cl:13].[N:14]1([C:19]2[CH:26]=[CH:25][CH:24]=[CH:23][C:20]=2[CH2:21][NH2:22])[CH:18]=[CH:17][N:16]=[CH:15]1.C1C=CC(P(C2C(C3C(P(C4C=CC=CC=4)C4C=CC=CC=4)=CC=C4C=3C=CC=C4)=C3C(C=CC=C3)=CC=2)C2C=CC=CC=2)=CC=1.CC([O-])(C)C.[Na+]>CC(N(C)C)=O.CCOC(C)=O.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[Cl:13][C:5]1[C:4]2[C:9](=[CH:10][CH:11]=[C:2]([NH:22][CH2:21][C:20]3[CH:23]=[CH:24][CH:25]=[CH:26][C:19]=3[N:14]3[CH:18]=[CH:17][N:16]=[CH:15]3)[CH:3]=2)[C:8](=[O:12])[NH:7][N:6]=1
Reactant: NCc1ccccc1-n1ccnc1
Reactant: O=c1[nH]nc(Cl)c2cc(Br)ccc12
Agent: [Pd]
Agent: CC(C)(C)[O-]
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: CC(=O)N(C)C
Solvent: CCOC(C)=O
Product: O=c1[nH]nc(Cl)c2cc(NCc3ccccc3-n3ccnc3)ccc12
Yield: 8.5 %

Procedure:
A mixture 6-bromo-4-chloro-2H-phthalazin-1-one (148 mg, 0.570 mmol), 2-imidazol-1-yl-benzylamine (110 mg, 0.635 mmol), Pd2(dba)3 (53 mg, 0.0578 mmol), rac-BINAP (117 mg, 0.188 mmol) and NaOtBu (227 mg, 2.362 mmol) in DMA (5 mL) was heated at 85° C. for 45 minutes. The mixture was allowed to cool, diluted with EtOAc and washed with water. The organic layer was washed with sat.aq. NaHCO3, brine and dried (Na2SO4). Chromatography on silica (EtOAc/hexanes) afforded 4-chloro-6-(2-imidazol-1-yl-benzylamino)-2H-phthalazin-1-one (17 mg) as a yellow solid, 1H (400 MHz, d6-DMSO) δ: 4.24 (d, 2H), 6.64 (s, 1H), 7.06 (dd, 1H), 7.11 (s, 1H), 7.41 (m, 1H), 7.46 (m, 2H), 7.52 (m, 2H), 7.59 (t, 1H), 7.92 (m, 2H), 12.36 (1H) ppm; m/z (M+1) 351.99.
Reaction SMILES: [CH3:1][S:2](Cl)(=[O:4])=[O:3].[NH2:6][C:7]1[CH:31]=[CH:30][C:10]2[CH2:11][CH2:12][N:13]([CH2:16][CH2:17][NH:18][C:19](=[O:29])[C:20]3[CH:25]=[CH:24][C:23]([NH2:26])=[CH:22][C:21]=3[O:27][CH3:28])[CH2:14][CH2:15][C:9]=2[CH:8]=1>N1C=CC=CC=1>[CH3:1][S:2]([NH:6][C:7]1[CH:31]=[CH:30][C:10]2[CH2:11][CH2:12][N:13]([CH2:16][CH2:17][NH:18][C:19](=[O:29])[C:20]3[CH:25]=[CH:24][C:23]([NH:26][S:2]([CH3:1])(=[O:4])=[O:3])=[CH:22][C:21]=3[O:27][CH3:28])[CH2:14][CH2:15][C:9]=2[CH:8]=1)(=[O:4])=[O:3]
Reactant: COc1cc(N)ccc1C(=O)NCCN1CCc2ccc(N)cc2CC1
Reactant: CS(=O)(=O)Cl
Solvent: c1ccncc1
Product: COc1cc(NS(C)(=O)=O)ccc1C(=O)NCCN1CCc2ccc(NS(C)(=O)=O)cc2CC1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
Methanesulphonyl chloride (0.155 ml) was added dropwise to a solution of 7-amino-3-[2-(4-amino-2-methoxybenzamido)ethyl]-1,2,4,5-tetrahydro-3H-3-benzazepine in pyridine cooled to 0°, and the reaction mixture was stirred for a further 18 hours at room temperature. The solvent was evaporated in vacuo and the residue taken up in methylene chloride, washed three times with aqueous sodium bicarbonate and three times with brine. The organic layer was dried (Na2SO4), filtered and evaporated to give an oil, in which thin layer chromatography detected the presence of some unreacted starting material. The oil was therefore taken up in pyridine and treated with methanesulphonyl chloride (0.05 ml), and the reaction mixture was stirred at room temperature for 72 hours. The solvent was then evaporated in vacuo and the residue taken up in methylene chloride, washed three times with aqueous sodium bicarbonate and three times with brine. The organic layer was dried (Na2SO4), filtered and evaporated to give an oil. The resulting oil was then purified by column chromatography on silica eluting with methylene chloride containing methanol (0% up to 5%) and the product-containing fractions were combined and evaporated in vacuo to give the title compound as a colourless foam, yield 0.32 g.
Reaction SMILES: Cl.[O:2]1[CH2:6][CH2:5][C@H:4]([NH2:7])[CH2:3]1.C[Al](C)C.[CH3:12][C:13]1[N:14]=[C:15]([CH2:21][CH2:22][C:23]2[C:24]([C:29]3[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=3)=[N:25][O:26][C:27]=2[CH3:28])[S:16][C:17]=1[C:18](O)=[O:19]>C1(C)C=CC=CC=1>[O:2]1[CH2:6][CH2:5][C@H:4]([NH:7][C:18]([C:17]2[S:16][C:15]([CH2:21][CH2:22][C:23]3[C:24]([C:29]4[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=4)=[N:25][O:26][C:27]=3[CH3:28])=[N:14][C:13]=2[CH3:12])=[O:19])[CH2:3]1
Reactant: Cc1nc(CCc2c(-c3ccccc3)noc2C)sc1C(=O)O
Reactant: N[C@H]1CCOC1
Agent: C[Al](C)C
Agent: Cl
Solvent: Cc1ccccc1
Product: Cc1nc(CCc2c(-c3ccccc3)noc2C)sc1C(=O)N[C@H]1CCOC1
Temperature: 90 °C
Reaction time: 2 h
Yield: 45.8 %

Procedure:
To a stirred suspension of (S)-tetrahydrofuran-3-amine HCl (127 mg, 1.0 mmol) in toluene (2 mL) under argon at room temperature was added trimethylaluminium (1 mL of a 2M solution in toluene, 2.0 mmol). After 2 h, a solution of 4-methyl-2-[2-(5-methyl-3-phenyl-isoxazol-4-yl)-ethyl]-thiazole-5-carboxylic acid (130 mg, 0.39 mmol) in toluene (4 mL) was added and the reaction mixture warmed to 90° C. After 2 h, the reaction mixture was cooled, quenched with ice water and extracted with dichloromethane. The combined extracts were washed with Seignette's salt solution then dried, filtered, and concentrated. Purification by chromatography (silica, 0 to 10% methanol in dichloromethane) gave the title compound (71 mg, 45%) as a colourless oil. MS: m/e=398.1 [M+H]+.