Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[C:2]1[S:3][CH:4]=[CH:5][CH:6]=1.OC1[C:12](C)=[C:11]([O:14]C)[S:10]C=1C(OC)=O.S(=O)(=O)(O)O.C(O)(=S)C>C(O)(=O)C>[C:11]([S:10][C:2]1[S:3][CH:4]=[CH:5][CH:6]=1)(=[O:14])[CH3:12]
Reactant: Clc1cccs1
Reactant: COC(=O)c1sc(OC)c(C)c1O
Agent: CC(O)=S
Agent: O=S(=O)(O)O
Solvent: CC(=O)O
Product: CC(=O)Sc1cccs1
Reaction time: 8 h
Yield: 75 %

Procedure:
The chlorothiophene of (e) above (0.016 mol) in 10 ml of acetic acid was added to a solution of 0.9 ml of concentrated sulphuric acid in 10 ml of acetic acid. Whilst stirring, thioacetic acid (0.016 mol) was added and the mixture stood at room temperature for eight hours. Filtration of the precipitate afforded 75% of acetylthiothiophene which was recrystallised from hexane, m.p. 112°-114° C.
Reaction SMILES: [N:1]1[CH:2]=[C:3]2[N:12]3[C:7](=[CH:8][CH:9]=[CH:10][C:11]=13)[S:6][C:5]([CH2:13][OH:14])=[CH:4]2>C(Cl)(Cl)Cl.[O-2].[O-2].[Mn+4]>[N:1]1[CH:2]=[C:3]2[N:12]3[C:7](=[CH:8][CH:9]=[CH:10][C:11]=13)[S:6][C:5]([CH:13]=[O:14])=[CH:4]2
Reactant: OCC1=Cc2cnc3cccc(n23)S1
Agent: [Mn+4]
Agent: [O-2]
Solvent: ClC(Cl)Cl
Product: O=CC1=Cc2cnc3cccc(n23)S1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
To a solution of 1.073 g (5.253 mM) of 5-thia-1,8b-diazaacenaphthylene-4-methanol in 30 ml of chloroform was added 3 g of activated manganese dioxide (Aldrich) and the mixture was stirred at room temperature for 4 hours. This reaction mixture was filtered and the filter cake was washed with chloroform. The filtrate and washes were pooled and the solvent was distilled off under reduced pressure. The crude 5-thia-1,8b-diazaacenaphthylene-4-carbaldehyde thus obtained was not purified but used as it was in the next reaction.
Reaction SMILES: Br[CH2:2][C:3]([O:5][CH3:6])=[O:4].[NH2:7][C:8]1[N:13]=[C:12]([CH3:14])[C:11]([CH2:15][C:16]2[CH:21]=[CH:20][C:19]([OH:22])=[CH:18][C:17]=2[O:23][CH3:24])=[C:10]([NH:25][CH2:26][CH2:27][CH2:28][CH2:29][CH3:30])[N:9]=1>CN(C=O)C>[NH2:7][C:8]1[N:13]=[C:12]([CH3:14])[C:11]([CH2:15][C:16]2[CH:21]=[CH:20][C:19]([O:22][CH2:2][C:3]([O:5][CH3:6])=[O:4])=[CH:18][C:17]=2[O:23][CH3:24])=[C:10]([NH:25][CH2:26][CH2:27][CH2:28][CH2:29][CH3:30])[N:9]=1
Reactant: COC(=O)CBr
Reactant: CCCCCNc1nc(N)nc(C)c1Cc1ccc(O)cc1OC
Solvent: CN(C)C=O
Product: CCCCCNc1nc(N)nc(C)c1Cc1ccc(OCC(=O)OC)cc1OC
Temperature: 25 °C
Reaction time: 24 h

Procedure:
Methyl bromoacetate (57 ul) was added to a mixture of the product from step (v) (0.2 g) and K2 CO3 (0.251 g) in DMF (10 ml) and the mixture stirred at rt for 24 h. The mixture was partitioned between EtOAc/water, the organics separated, dried and evaporated under reduced pressure. The residue was purified by RPHPLC to afford the title compound, 0.057 g
Reaction SMILES: [N:1]([CH2:4][C@H:5]1[O:9][CH2:8][C@@H:7]([S:10]C(=O)C)[CH2:6]1)=[N+:2]=[N-:3]>O1CCCC1.C[O-].[Na+].CO>[N:1]([CH2:4][C@H:5]1[O:9][CH2:8][C@@H:7]([SH:10])[CH2:6]1)=[N+:2]=[N-:3]
Reactant: CC(=O)S[C@@H]1CO[C@H](CN=[N+]=[N-])C1
Agent: C[O-]
Agent: [Na+]
Solvent: CO
Solvent: C1CCOC1
Product: [N-]=[N+]=NC[C@@H]1C[C@H](S)CO1

Procedure:
The title compound is prepared by the procedure of Example 16 using 0.310 gof product from Example 61 in 4.5 ml of tetrahydrofuran and 0.30 ml of 25% sodium methoxide/methyl alcohol to give 0.159 g of the desired product.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][C:9]=1[O:10][CH3:11])[C:5]#[N:6].C(=O)([O-])[O-].[K+].[K+].CN(C)C=O.Cl[CH2:24][CH2:25][CH2:26][N:27]1[CH2:32][CH2:31][O:30][CH2:29][CH2:28]1>C1(C)C=CC=CC=1>[CH3:11][O:10][C:9]1[CH:8]=[CH:7][C:4]([C:5]#[N:6])=[CH:3][C:2]=1[O:1][CH2:24][CH2:25][CH2:26][N:27]1[CH2:32][CH2:31][O:30][CH2:29][CH2:28]1
Reactant: COc1ccc(C#N)cc1O
Reactant: ClCCCN1CCOCC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: Cc1ccccc1
Solvent: CN(C)C=O
Product: COc1ccc(C#N)cc1OCCCN1CCOCC1
Temperature: 85 °C
Yield: 98.3 %

Procedure:
A mixture of 3-hydroxy-4-methoxybenzonitrile (34.3 kg), potassium carbonate (54.5 kg) and N,N-dimethylformamide (226 kg) was stirred and heated to approximately 85° C. A toluene solution (91.4 kg) containing N-(3-chloropropyl)morpholine (41.1 kg) was added to the heated mixture and the resultant mixture was heated to about 85° C. for an additional 10 hours. The bulk of the N,N-dimethylformamide was removed by vacuum distillation and the residue was diluted with water (286 liters). The aqueous mixture was extracted with three portions of a 1:1 mixture of heptane and ethyl acetate (239 liters, 139 liters and 139 liters respectively). The combined organic layers were washed with water, concentrated to approximately 150 liters by vacuum distillation and diluted with glacial acetic acid (133 kg). Additional solvent was removed by vacuum distillation. Addition of glacial acetic acid (84 kg) provided a solution of 4-methoxy-3-(3-morpholinopropoxy)benzonitrile (62.5 kg) in acetic acid (122 kg) which was used without further purification.
Reaction SMILES: [NH2:1][C:2]1[CH:28]=[C:27]([N:29]2[CH2:34][CH2:33][N:32]([CH3:35])[CH2:31][CH2:30]2)[CH:26]=[CH:25][C:3]=1[C:4]([NH:6][C:7]1[C:15]2[C:10](=[CH:11][CH:12]=[C:13]([CH2:16][C:17]3[CH:22]=[C:21]([F:23])[CH:20]=[C:19]([F:24])[CH:18]=3)[CH:14]=2)[NH:9][N:8]=1)=[O:5].[O:36]1[CH2:41][CH2:40][C:39](=O)[CH2:38][CH2:37]1.FC(F)(F)C(O)=O.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.C[N+](C)(C)C>ClCCl>[F:24][C:19]1[CH:18]=[C:17]([CH:22]=[C:21]([F:23])[CH:20]=1)[CH2:16][C:13]1[CH:14]=[C:15]2[C:10](=[CH:11][CH:12]=1)[NH:9][N:8]=[C:7]2[NH:6][C:4](=[O:5])[C:3]1[CH:25]=[CH:26][C:27]([N:29]2[CH2:30][CH2:31][N:32]([CH3:35])[CH2:33][CH2:34]2)=[CH:28][C:2]=1[NH:1][CH:39]1[CH2:40][CH2:41][O:36][CH2:37][CH2:38]1
Reactant: CN1CCN(c2ccc(C(=O)Nc3n[nH]c4ccc(Cc5cc(F)cc(F)c5)cc34)c(N)c2)CC1
Reactant: O=C1CCOCC1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: C[N+](C)(C)C
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CN1CCN(c2ccc(C(=O)Nc3n[nH]c4ccc(Cc5cc(F)cc(F)c5)cc34)c(NC3CCOCC3)c2)CC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 72.2 %

Procedure:
To a solution of 2-amino-N-[5-(3,5-difluoro-benzyl)-1H-indazol-3-yl]-4-(4-methyl-piperazin-1-yl)-benzamide (1.9 g, 3.98 mmol) in dichloromethane (80 mL) were added tetrahydro-pyran-4-one (0.55 mL, 5.98 mmol), trifluoroacetic acid (4 mL) and tetramethylammonium triacetoxyborohydride (1.57 g, 5.98 mmol). The mixture was stirred at room temperature overnight, and then more tetramethylammonium triacetoxyborohydride (1.57 g) was added. After stirring for additional 3 hours at room temperature the mixture was diluted with dichloromethane, washed with 2N sodium hydroxide and brine, dried over sodium sulfate and evaporated to dryness. The crude was purified by flash chromatography on silica gel using dichloromethane/methanol/NH3 5N in MeOH 96:4:0.5 as the eluant, affording 1.61 g of the title compound (72% yield).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([N:8]2[C:12]3=[N:13][CH:14]=[N:15][C:16]([NH2:17])=[C:11]3[CH:10]=[N:9]2)[CH:5]=[CH:6][CH:7]=1.[Cl:18][C:19]1[CH:24]=[CH:23][C:22]([S:25](Cl)(=[O:27])=[O:26])=[CH:21][CH:20]=1.C(N(C(C)C)CC)(C)C.CN(C=O)C>CO>[NH2:17][C:16]1[N:15]=[CH:14][N:13]=[C:12]2[N:8]([C:4]3[CH:3]=[C:2]([NH:1][S:25]([C:22]4[CH:23]=[CH:24][C:19]([Cl:18])=[CH:20][CH:21]=4)(=[O:27])=[O:26])[CH:7]=[CH:6][CH:5]=3)[N:9]=[CH:10][C:11]=12
Reactant: Nc1cccc(-n2ncc3c(N)ncnc32)c1
Reactant: O=S(=O)(Cl)c1ccc(Cl)cc1
Solvent: CCN(C(C)C)C(C)C
Solvent: CO
Solvent: CN(C)C=O
Product: Nc1ncnc2c1cnn2-c1cccc(NS(=O)(=O)c2ccc(Cl)cc2)c1
Temperature: 25 °C
Reaction time: 18 h
Yield: 68.8 %

Procedure:
Title compound 11B, 1-(3-amino-phenyl)-1H-pyrazolo[3,4-d]pyrimidin-4-ylamine (40 mg, 1.1 eq, 0.18 mmol), 4-chlorobenzenesulphonylchloride (34 mg, 1.0 eq, 0.16 mmol) and diisopropylethylamine (28 μl, 1.0 eq, 0.16 mmol) were added to DMF (1 ml) and the mixture was stirred for 18 hours at room temperature under an inert atmosphere. Methanol was then added (1 ml) and the solvents were removed in vacuo. The resultant oil was purified by semi-preparative HPLC to yield the title compound as a white solid (45 mg, 0.11 mmol, 70%). LCMS: [M+H]+=401, Rt=1.80 min, 100% purity.
Reaction SMILES: [N:1]1([C:9]([O:11][CH2:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)=[O:10])[CH2:8][CH2:7][CH2:6][C@H:2]1[C:3]([OH:5])=O.C(N(CC)CC)C.ClC(OCC(C)C)=O.[CH2:34]([NH2:44])[CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][CH2:40][CH2:41][CH2:42][CH3:43]>CN(C=O)C>[N:1]1([C:9]([O:11][CH2:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)=[O:10])[CH2:8][CH2:7][CH2:6][C@H:2]1[C:3]([NH:44][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][CH2:40][CH2:41][CH2:42][CH3:43])=[O:5]
Reactant: CCCCCCCCCCN
Reactant: O=C(O)[C@@H]1CCCN1C(=O)OCc1ccccc1
Agent: CC(C)COC(=O)Cl
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: CCCCCCCCCCNC(=O)[C@@H]1CCCN1C(=O)OCc1ccccc1
Temperature: -10 °C
Reaction time: 0.5 h
Yield: 69.9 %

Procedure:
5.0 g (20 mmoles) of Z-Pro-OH are dissolved in 50 ml of DMFA, 2.8 ml (20 mmoles) of triethylamine are added to the solution, and the mixture is cooled to -10° C. The mixture is stirred at the same temperature, 2.8 ml (21.5 mmoles) of isobutyl chloroformate are added dropwise, and after 10 minutes 4.4 ml (22 mmoles) of n-decylamine are introduced dropwise. After the addition the reaction mixture is stirred at 0° C. for 30 minutes and then at room temperature for 2 hours. The resulting suspension is filtered, the filtrate is evaporated, and the residue is dissolved in 100 ml of ethyl acetate. The solution is shaken four times with 50 ml of n hydrochloric acid, each, twice with 50 ml of n sodium hydrocarbonate solution, each, and then with 50 ml of water, dried over anhydrous sodium sulfate and evaporated. The oily residue is crystallized from n-hexane to obtain 5.43 g (70%) of Z-Pro-NH-C10H21 ; m.p.: 78°-80° C., Rf2 =0.75.
Reaction SMILES: Cl[C:2]1[N:11]=[CH:10][C:9]2[N:8]([CH3:12])[C:7](=[O:13])[C@@H:6]([CH2:14][CH3:15])[N:5]([CH:16]([CH3:18])[CH3:17])[C:4]=2[N:3]=1.[Cl:19][C:20]1[CH:21]=[C:22]([C:27]2[NH:28][CH:29]=[CH:30][N:31]=2)[CH:23]=[C:24]([Cl:26])[CH:25]=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.C([O-])([O-])=O.[Cs+].[Cs+]>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].O1CCOCC1>[Cl:26][C:24]1[CH:23]=[C:22]([C:27]2[N:31]([C:2]3[N:11]=[CH:10][C:9]4[N:8]([CH3:12])[C:7](=[O:13])[C@@H:6]([CH2:14][CH3:15])[N:5]([CH:16]([CH3:18])[CH3:17])[C:4]=4[N:3]=3)[CH:30]=[CH:29][N:28]=2)[CH:21]=[C:20]([Cl:19])[CH:25]=1
Reactant: Clc1cc(Cl)cc(-c2ncc[nH]2)c1
Reactant: CC[C@@H]1C(=O)N(C)c2cnc(Cl)nc2N1C(C)C
Agent: [Pd]
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Agent: O=C([O-])[O-]
Solvent: C1COCCO1
Solvent: CCOC(C)=O
Product: CC[C@@H]1C(=O)N(C)c2cnc(-n3ccnc3-c3cc(Cl)cc(Cl)c3)nc2N1C(C)C
Temperature: 150 °C
Reaction time: 0.5 h
Yield: 22.5 %

Procedure:
A 5 mL microwave vial was charged with Intermediate C (50 mg, 0.19 mmol), 2-(3,5-dichlorophenyl)-1H-imidazole (80 mg, 0.37 mmol), Pd2(dba)3 (35 mg, 0.04 mmol), BINAP (50 mg, 0.08 mmol), Cs2CO3 (120 mg, 0.37 mmol), and 2 mL of dioxane. The vial was sealed and heated in a microwave to 150° C. for 0.5 h. An additional 20 mg of Pd2(dba)3 was added, and the reaction mix was brought to 150° C. in the microwave again for 0.5 h to drive the reaction to completion. Upon cooling to 23° C., the reaction mix was diluted with EtOAc, and rinsed sequentially with saturated aqueous solutions of ammonium chloride, sodium bicarbonate, and brine. The resulting organic liquid was dried over sodium sulfate and decanted into a 250 mL round bottom flask. After concentration of the product under reduced pressure, the resulting residue was purified by HPLC (30-50% MeCN, 20 mL/min, 210 nM, 0.1% TFA. Stationary Phase: Phenomenex Luna C18, 2×25 cm) to give the title compound (19 mg). LCMS: 445.1 m/z (M+H)+; ret. Time: 4.20 min (Analytical Method C).
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([C:8]2[S:9][CH:10]=[CH:11][CH:12]=2)[CH:5]=[CH:4][N:3]=1.[Cl:13][C:14]1[CH:27]=[CH:26][C:17]([CH2:18][N:19]2[CH2:24][CH2:23][CH:22]([NH2:25])[CH2:21][CH2:20]2)=[CH:16][C:15]=1[O:28][CH2:29][CH3:30]>CC(N(C)C)=O>[Cl:13][C:14]1[CH:27]=[CH:26][C:17]([CH2:18][N:19]2[CH2:24][CH2:23][CH:22]([NH:25][C:2]3[N:7]=[C:6]([C:8]4[S:9][CH:10]=[CH:11][CH:12]=4)[CH:5]=[CH:4][N:3]=3)[CH2:21][CH2:20]2)=[CH:16][C:15]=1[O:28][CH2:29][CH3:30]
Reactant: Clc1nccc(-c2cccs2)n1
Reactant: CCOc1cc(CN2CCC(N)CC2)ccc1Cl
Solvent: CC(=O)N(C)C
Product: CCOc1cc(CN2CCC(Nc3nccc(-c4cccs4)n3)CC2)ccc1Cl
Yield: 13.3 %

Procedure:
A solution of 2-chloro-4-thiophen-2-yl-pyrimidine (49.2 mg, 0.25 mmol, 1.0 equiv; example 4/step 1) and 1-(4-chloro-3-ethoxy-benzyl)-piperidin-4-ylamine (80.6 mg, 0.30 mmol, 1.2 equiv; intermediate A2) in DMAc (2 mL) was heated by microwave irradiation to 220° C. for 1 h. Removal of the solvent under reduced pressure and purification by preparative HPLC on reversed phase eluting with a gradient of acetonitrile/water provided 14.3 mg (13%) of the title compound. MS (ISP): 429.5 [M+H]+.
Reaction SMILES: [Na].[CH2:2]([O:6][C:7](=[O:20])[CH2:8][N:9]1[C:17](=[O:18])[C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[C:10]1=[O:19])[CH2:3][CH2:4][CH3:5].Cl>C(O)CCC>[CH2:2]([O:6][C:7]([C:8]1[N:9]=[C:10]([OH:19])[C:11]2[C:16]([C:17]=1[OH:18])=[CH:15][CH:14]=[CH:13][CH:12]=2)=[O:20])[CH2:3][CH2:4][CH3:5]
Reactant: CCCCOC(=O)CN1C(=O)c2ccccc2C1=O
Agent: Cl
Agent: [Na]
Solvent: CCCCO
Product: CCCCOC(=O)c1nc(O)c2ccccc2c1O
Temperature: 25 °C
Reaction time: 18 h
Yield: 73.9 %

Procedure:
4.41 g of sodium (190 mmol) were dissolved in 250 ml of n-butanol with stirring. After the sodium was completely dissolved the solution was allowed to cool to ambient temperature and a solution of 24.0 g (91.9 mmol) of (1,3-dioxo-1,3-dihydro-isoindol-2-yl)-acetic acid butyl ester in 150 ml of butanol was added with stirring. The solution was heated to 100° C. within 30 min and stirred at this temperature for 1 h. Then the mixture was allowed to cool to ambient temperature and was stored at ambient temperature for 18 h. Then the pH of the mixture was adjusted to 2 to 3 by the addition of aqueous 2N hydrochloric acid with stirring. Stirring was continued for 30 min before the solid component was filtered by suction. The filter cake was washed thoroughly with water, and dried in vacuo at 50° C. to give a white solid. 17.75 g of the title compound were obtained; MS-(+)-ion: M+1=262.1 amu.
Reaction SMILES: [Cl:1][C:2]1[C:7]([Cl:8])=[CH:6][CH:5]=[CH:4][C:3]=1[S:9][CH2:10][CH2:11][C:12]([OH:14])=O.FC(F)(F)C(OC(=O)C(F)(F)F)=O.C(OCC)(=O)C.CCCCCC>FC(F)(F)C(O)=O>[Cl:8][C:7]1[C:2]([Cl:1])=[C:3]2[C:4]([C:12](=[O:14])[CH2:11][CH2:10][S:9]2)=[CH:5][CH:6]=1
Reactant: O=C(O)CCSc1cccc(Cl)c1Cl
Solvent: O=C(O)C(F)(F)F
Solvent: CCOC(C)=O
Solvent: CCCCCC
Product: O=C1CCSc2c1ccc(Cl)c2Cl
Temperature: 25 °C
Reaction time: 68.2 h
Yield: 13.2 %

Procedure:
The 3-(2,3-dichlorophenylthio)propanoic acid from Step 1 (3.88 g, 15 mmol) was dissolved in trifluoroacetic acid (10 mL), treated with trifluoroacetic anhydride (5 mL) and stirred at room temperature for 68.2 hours. The reaction mixture was poured into 10% Na2Cl3 (100 mL), extracted with ethyl acetate, washed with brine, dried over MgSO4, and concentrated in vacuo to give a yellow oil. The crude material was passed through a column of silica gel eluting with 40% ethyl acetate/hexane to give 7,8-dichlorothiochroman-4-one as a white solid (0.46 g, 13%): mp 93°-102° C.; 1H NMR (CDCl3) 300 MHz 7.99 (d, J=8.7 Hz, 1H) 7.27 (d, J=8.7 Hz, 1H) 3.25 (m, 2H) 2.97 (m, 2H). Mass spectrum: M+=233.
Reaction SMILES: [C:1]([O:10]C)(=O)[C:2]1[C:3](=[CH:5][CH:6]=[CH:7][CH:8]=1)[SH:4].[CH2:12]([NH:19][C:20]([C:22]1[CH:27]=[CH:26][CH:25]=[C:24]([C:28]#[N:29])[N:23]=1)=[O:21])[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.C(N(CC)CC)C>C1(C)C=CC=CC=1>[CH2:12]([NH:19][C:20]([C:22]1[CH:27]=[CH:26][CH:25]=[C:24]([C:28]2[S:4][C:3]3[CH:5]=[CH:6][CH:7]=[CH:8][C:2]=3[C:1](=[O:10])[N:29]=2)[N:23]=1)=[O:21])[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1
Reactant: COC(=O)c1ccccc1S
Reactant: N#Cc1cccc(C(=O)NCc2ccccc2)n1
Solvent: CCN(CC)CC
Solvent: Cc1ccccc1
Product: O=C(NCc1ccccc1)c1cccc(-c2nc(=O)c3ccccc3s2)n1
Yield: 70.2 %

Procedure:
A mixture of methyl thiosalicylate (1.3 g, 7.6 mmol), N-benzyl-6-cyano-2-pyridinecarboxamide (0.88 g, 3.7 mmol), triethylamine (2.0 ml, 14 mmol) and toluene (4 ml) was refluxed for 10 hrs as described in Example 1. After cooling, the precipitated crystals were collected by filtration and recrystallized from hexane-tetrahydrofuran to give the titled compound (0.97 g, 97%) as crystals.
Reaction SMILES: [CH2:1]([O:5][C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=1[CH2:12][C:13]([O:15][CH3:16])=[O:14])[CH2:2][CH2:3][CH3:4].[CH3:17][O-:18].[Na+]>C(OC)=O>[CH:17]([CH:12]([C:7]1[CH:8]=[CH:9][CH:10]=[CH:11][C:6]=1[O:5][CH2:1][CH2:2][CH2:3][CH3:4])[C:13]([O:15][CH3:16])=[O:14])=[O:18]
Reactant: CCCCOc1ccccc1CC(=O)OC
Reactant: C[O-]
Agent: [Na+]
Solvent: COC=O
Product: CCCCOc1ccccc1C(C=O)C(=O)OC
Temperature: 25 °C
Yield: 82 %

Procedure:
11.1 g of the product obtained by Method D are dissolved in 50 ml of methyl formate, and the solution is slowly added at 0° C. to 3.5 g of sodium methylate. The mixture is warmed to room temperature, and the bulk of the methyl formate is removed under reduced pressure. The remainder is poured onto cold 2N NaOH, and the mixture is extracted with 30 ml of methyl t-butyl ether. The aqueous phase is acidified, and the methyl α-formyl(2-butoxyphenyl)acetate is extracted with dichloromethane. Drying the organic phase over Na2SO4 gives 10.2 g (82%) of pure product.
Reaction SMILES: Cl.[CH3:2][N:3]1[CH:7]=[C:6]([NH2:8])[N:5]=[C:4]1[CH3:9].Br[C:11]1[C:12](=[O:19])[N:13]([CH3:18])[CH:14]=[C:15]([Br:17])[CH:16]=1.CC1(C)C2C(=C(P(C3C=CC=CC=3)C3C=CC=CC=3)C=CC=2)OC2C(P(C3C=CC=CC=3)C3C=CC=CC=3)=CC=CC1=2.C([O-])([O-])=O.[Cs+].[Cs+]>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].O1CCOCC1>[Br:17][C:15]1[CH:16]=[C:11]([NH:8][C:6]2[N:5]=[C:4]([CH3:9])[N:3]([CH3:2])[CH:7]=2)[C:12](=[O:19])[N:13]([CH3:18])[CH:14]=1
Reactant: Cn1cc(Br)cc(Br)c1=O
Reactant: Cc1nc(N)cn1C
Agent: [Pd]
Agent: CC1(C)c2cccc(P(c3ccccc3)c3ccccc3)c2Oc2c(P(c3ccccc3)c3ccccc3)cccc21
Agent: Cl
Solvent: C1COCCO1
Product: Cc1nc(Nc2cc(Br)cn(C)c2=O)cn1C
Temperature: 90 °C
Yield: 32.7 %

Procedure:
A 100-mL single-neck round-bottomed flask equipped with a magnetic stirrer and a reflux condenser was charged with 337c (400 mg, 3.60 mmol), 3,5-dibromo-1-methylpyridin-2(1H)-one (960 mg, 3.60 mmol), XantPhos (240 mg, 0.40 mmol), tris(dibenzylideneacetone)dipalladium(0) (360 mg, 0.40 mmol), Cs2CO3 (4.69 g, 14.4 mmol), and 1,4-dioxane (20 mL). After three cycles of vacuum/nitrogen flush, the mixture was heated at 90° C. for 2.5 h. It was then cooled to room temperature and filtered. The filtrate was concentrated under reduced pressure and the resulting residue was purified by silica-gel column chromatography eluting with dichloromethane/methanol (30:1 to 20:1) to afford 337d as a pale yellow solid (350 mg, 33%). MS-ESI: [M+H]+ 297.1.
Reaction SMILES: [C:1]1([CH3:19])[CH:6]=[C:5]([CH3:7])[CH:4]=[C:3]([CH3:8])[C:2]=1[S:9]([O:12]/[N:13]=C(\OCC)/C)(=[O:11])=[O:10].Cl(O)(=O)(=O)=O>C1COCC1>[C:1]1([CH3:19])[CH:6]=[C:5]([CH3:7])[CH:4]=[C:3]([CH3:8])[C:2]=1[S:9]([O:12][NH2:13])(=[O:11])=[O:10]
Reactant: CCO/C(C)=N\OS(=O)(=O)c1c(C)cc(C)cc1C
Agent: [O-][Cl+3]([O-])([O-])O
Solvent: C1CCOC1
Product: Cc1cc(C)c(S(=O)(=O)ON)c(C)c1
Temperature: 0 °C
Reaction time: 0.17 h
Yield: 81.2 %

Procedure:
Under argon atmosphere, (Z)-ethyl N-mesitylsulfonyloxyacetimidate (15 g, 52.6 mmol) was dissolved in THF (13 mL) at 0° C. Perchloric acid (70% aqueous solution, 22.6 g, 13.6 mL, 158 mmol) was then added dropwise at 0-5° C. over a period of 50 min. After 10 min, precipitation started and THF (3 mL) was added. After stirring at 0° C. for 30 min, the mixture was poured into ice water (200 mL) under vigorous stirring giving a white suspension. After additional stirring for 15 min, the suspension was filtered and the precipitate was washed with ice water. The white solid was dissolved in diethyl ether (150 mL), dried over MgSO4 and evaporated at RT without heating while the flask was cooled (very important, because the compound can decompose at 25° C.!) to give O-(mesitylsulfonyl)hydroxylamine as white solid (9.2 g, 42.7 mmol, 81.3%). The crude product was used further without purification since O-(mesitylsulfonyl)hydroxylamine is unstable at 25° C.!
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([NH:15][C:16]([NH2:18])=[S:17])[CH:6]=[CH:7][C:8]=1[N:9]1[CH:13]=[C:12]([CH3:14])[N:11]=[CH:10]1.Br[CH:20]1[C:25](=O)[CH:24]([C:27]2[CH:32]=[C:31]([CH3:33])[CH:30]=[CH:29][C:28]=2[CH3:34])[CH2:23][CH2:22][CH2:21]1>C(O)C>[CH3:34][C:28]1[CH:29]=[CH:30][C:31]([CH3:33])=[CH:32][C:27]=1[CH:24]1[C:23]2[N:18]=[C:16]([NH:15][C:5]3[CH:6]=[CH:7][C:8]([N:9]4[CH:13]=[C:12]([CH3:14])[N:11]=[CH:10]4)=[C:3]([O:2][CH3:1])[CH:4]=3)[S:17][C:22]=2[CH2:21][CH2:20][CH2:25]1
Reactant: Cc1ccc(C)c(C2CCCC(Br)C2=O)c1
Reactant: COc1cc(NC(N)=S)ccc1-n1cnc(C)c1
Solvent: CCO
Product: COc1cc(Nc2nc3c(s2)CCCC3c2cc(C)ccc2C)ccc1-n1cnc(C)c1
Temperature: 25 °C
Yield: 9.2 %

Procedure:
A suspension of [3-methoxy-4-(4-methyl-imidazol-1-yl)-phenyl]-thiourea (72 mg, 0.27 mmol) and of crude 6-bromo-2-(2,5-dimethyl-phenyl)-cyclohexanone (81 mg, 0.29 mmol) in ethanol (2 mL) was heated to reflux under an atmosphere of nitrogen for 2 days. After cooling to room temperature the solvent was evaporated under reduced pressure and the residue was purified by reversed preparative HPLC using acetonitril/water (0.1% formic acid) to yield the title compound (11 mg, 9%) as an off-white solid. MS ISP (m/e): 445.3 (100) [(M+H)+]. 1H NMR (CDCl3, 300 MHz): δ (ppm)=7.60 (s, 1H), 7.35 (s, 1H), 7.09 (d, 1H), 7.03 (d, 1H), 2.34 (s, (d, 1H), 6.82 (s, 1H), 6.69 (s, 1H), 6.62 (d, 1H), 4.21 (m, 1H), 3.53 (s, 3H), 2.78 (m, 2H), 2.34 (s, 3H), 2.28 (s, 3H), 2.23 (s, 3H), 2.15 (m, 1H), 1.75-2.05 (m, 3H).
Reaction SMILES: CC(C)C(=O)CC(OCC)=O.Cl.C1(NN)CC1.[CH:18]1([C:21]2[N:25]([CH:26]([CH3:28])[CH3:27])[N:24]=[CH:23][C:22]=2[CH:29]=[O:30])[CH2:20][CH2:19]1>>[CH:26]1([N:25]2[C:21]([CH:18]([CH3:19])[CH3:20])=[C:22]([CH:29]=[O:30])[CH:23]=[N:24]2)[CH2:27][CH2:28]1
Reactant: CC(C)n1ncc(C=O)c1C1CC1
Agent: CCOC(=O)CC(=O)C(C)C
Agent: Cl
Agent: NNC1CC1
Product: CC(C)c1c(C=O)cnn1C1CC1

Procedure:
1-Cyclopropyl-5-isopropyl-1H-pyrazole-4-carbaldehyde was prepared from ethyl 4-methyl-3-oxopentanoate and cyclopropyl hydrazine hydrochloride in the same manner as 5-cyclopropyl-1-isopropyl-1H-pyrazole-4-carbaldehyde (Example 49).
Reaction SMILES: [Cl:1][C:2]1[C:10]([CH2:11][O:12][N:13]=[C:14]([CH3:16])[CH3:15])=[C:9]([S:17]([CH3:20])(=[O:19])=[O:18])[CH:8]=[CH:7][C:3]=1[C:4](O)=[O:5].[CH3:21][N:22]1[C:26]([NH2:27])=[N:25][CH:24]=[N:23]1.S(Cl)(Cl)=O.OS([O-])(=O)=O.[K+]>N1C=CC=CC=1.CN(C)C1C=CN=CC=1.O.CN(C=O)C>[Cl:1][C:2]1[C:10]([CH2:11][O:12][N:13]=[C:14]([CH3:16])[CH3:15])=[C:9]([S:17]([CH3:20])(=[O:19])=[O:18])[CH:8]=[CH:7][C:3]=1[C:4]([NH:27][C:26]1[N:22]([CH3:21])[N:23]=[CH:24][N:25]=1)=[O:5]
Reactant: Cn1ncnc1N
Reactant: CC(C)=NOCc1c(S(C)(=O)=O)ccc(C(=O)O)c1Cl
Agent: CN(C)c1ccncc1
Agent: O=S(=O)([O-])O
Agent: [K+]
Solvent: c1ccncc1
Solvent: O=S(Cl)Cl
Solvent: O
Product: CC(C)=NOCc1c(S(C)(=O)=O)ccc(C(=O)Nc2ncnn2C)c1Cl
Temperature: 70 °C
Reaction time: 5 h

Procedure:
500 mg (1.56 mmol) of 2-chloro-4-(methylsulfonyl)-3-{[(propan-2-ylideneamino)oxy]methyl}benzoic acid and 395 mg (1.34 mmol) of 1-methyl-1H-1,2,4-triazole-5-amine were dissolved in 2.5 ml of pyridine, and 10 mg of 4-dimethylaminopyridine and a drop of DMF were added. At RT, 313 mg (2.58 mmol) of thionyl chloride were then added dropwise, and the mixture was stirred at 70° C. for 5 h. 0.5 ml of water was then added to the reaction, which had once more been cooled, and the mixture was stirred for about 30 min, acidified with a saturated KHSO4 solution and extracted three times with in each case 100 ml of ethyl acetate. The combined organic phases were washed once with 20 ml of a saturated NaHCO3 solution, dried over MgSO4, filtered off and concentrated. The residue was purified chromatographically on a silica gel column. Yield: 153 mg (24%) as a colorless oil.