Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([N:28]2[CH:32]=[N:31][N:30]=[N:29]2)=[C:6]([CH2:8][NH:9][C:10]([C@@H:12]2[CH2:16][CH:15]=[N:14][N:13]2[C:17](=[O:27])[C@@H:18]([C:20]2[CH:25]=[CH:24][C:23]([F:26])=[CH:22][CH:21]=2)[OH:19])=[O:11])[CH:7]=1.N1C=CC=CC=1.[C:39](Cl)(=[O:46])[C:40]1[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=1>CN(C1C=CN=CC=1)C.C(Cl)Cl>[C:39]([O:19][C@H:18]([C:20]1[CH:25]=[CH:24][C:23]([F:26])=[CH:22][CH:21]=1)[C:17]([N:13]1[C@H:12]([C:10](=[O:11])[NH:9][CH2:8][C:6]2[CH:7]=[C:2]([Cl:1])[CH:3]=[CH:4][C:5]=2[N:28]2[CH:32]=[N:31][N:30]=[N:29]2)[CH2:16][CH:15]=[N:14]1)=[O:27])(=[O:46])[C:40]1[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=1
Reactant: O=C(NCc1cc(Cl)ccc1-n1cnnn1)[C@@H]1CC=NN1C(=O)[C@H](O)c1ccc(F)cc1
Reactant: O=C(Cl)c1ccccc1
Agent: CN(C)c1ccncc1
Solvent: c1ccncc1
Solvent: ClCCl
Product: O=C(O[C@@H](C(=O)N1N=CC[C@H]1C(=O)NCc1cc(Cl)ccc1-n1cnnn1)c1ccc(F)cc1)c1ccccc1
Temperature: 70 °C
Reaction time: 5 h
Yield: 13 %

Procedure:
To a mixture of (3S)—N—[[5-chloro-2-(tetrazol-1-yl)phenyl]methyl]-2-[(2R)-2-(4-fluorophenyl)-2-hydroxy-acetyl]-3,4-dihydropyrazole-3-carboxamide (0.48 g, 1.05 mmol), pyridine (6 mL, 74 mmol), and DMAP (0.023 g, 0.188 mmol) in CH2Cl2 (8 mL) at −10° C. was added benzoyl chloride (135 μL, 1.15 mmol). The reaction mixture was allowed to attain rt and was stirred for 5 h. Another portion of benzoyl chloride (400 μL, 3.4 mmol) was added. The mixture was stirred for 60 h. LCMS analysis indicated only a trace amount of product. The solvents were removed by evaporation and pyridine (5 mL, 62 mmol) was added followed by another portion of benzoyl chloride (400 μL, 3.4 mmol). The reaction mixture was heated to 70° C. overnight. LCMS analysis indicated approximately 20% conversion of starting material. The solvent was evaporated of and the residue was purified by HPLC (MeCN gradient 0 to 100% in 0.1 M NH4OAc buffer containing 5% MeCN). The relevant fractions were combined and lyophilized to give the title compound (77 mg, 13%) together with 289 mg of unreacted starting material.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:8]2=[CH:9][CH:10]=[C:11]3[C:20]([N:19]=[C:18]4[C:13]([CH:14]=[CH:15][CH:16]=[C:17]4[C:21](O)=[O:22])=[N:12]3)=[C:7]2[N:6]=[CH:5][CH:4]=1.[CH3:24][N:25]([CH3:29])[CH2:26][CH2:27][NH2:28]>>[CH3:24][N:25]([CH3:29])[CH2:26][CH2:27][NH:28][C:21]([C:17]1[C:18]2[C:13](=[N:12][C:11]3[C:20]([N:19]=2)=[C:7]2[N:6]=[CH:5][CH:4]=[C:3]([O:2][CH3:1])[C:8]2=[CH:9][CH:10]=3)[CH:14]=[CH:15][CH:16]=1)=[O:22]
Reactant: CN(C)CCN
Reactant: COc1ccnc2c1ccc1nc3cccc(C(=O)O)c3nc12
Product: COc1ccnc2c1ccc1nc3cccc(C(=O)NCCN(C)C)c3nc12

Procedure:
4-Methoxypyrido [2,3-α]phenazine-11-carboxylic acid (2-dimethylamino-ethyl)-amide was prepared from 4-Methoxypyrido[2,3-α]phenazine-11-carboxylic acid (II.1) and N,N-dimethylethylenediamine
Reaction SMILES: [CH3:1][C:2]([C:12]1[CH:20]=[CH:19][CH:18]=[CH:17][C:13]=1[C:14]([NH2:16])=[O:15])([CH3:11])[CH2:3][C@:4]1([C:7]([F:10])([F:9])[F:8])[CH2:6][O:5]1.C([Mg]CCCC)CCC.[Li+].[CH3:31][Si:32]([C:35]#[C-:36])([CH3:34])[CH3:33]>COCCOC>[OH:5][C@@:4]([C:7]([F:8])([F:9])[F:10])([CH2:6][C:36]#[C:35][Si:32]([CH3:34])([CH3:33])[CH3:31])[CH2:3][C:2]([C:12]1[CH:20]=[CH:19][CH:18]=[CH:17][C:13]=1[C:14]([NH2:16])=[O:15])([CH3:11])[CH3:1]
Reactant: CC(C)(C[C@]1(C(F)(F)F)CO1)c1ccccc1C(N)=O
Reactant: [C-]#C[Si](C)(C)C
Agent: CCCC[Mg]CCCC
Agent: [Li+]
Solvent: COCCOC
Product: CC(C)(C[C@@](O)(CC#C[Si](C)(C)C)C(F)(F)F)c1ccccc1C(N)=O
Reaction time: 0.75 h

Procedure:
To a stirred, ice-cooled, solution of (trimethylsilyl)acetylene (72.6 mL, 514 mmol) in 500 mL of ethylene glycol dimethyl ether was added n-butyllithium (185 mL of 2.5 M solution in hexanes, 462 mmol). The reaction mixture, which turned from a colorless to a yellowish solution, was stirred for 50 minutes to give a solution of 462 mmol of lithium (trimethylsilyl)acetylide. A stirred solution of 2-[1,1-dimethyl-2-((R)-2-trifluoromethyloxiranyl)ethyl]benzamide (26.5 g, 92.3 mmol) in ethylene glycol dimethyl ether (250 mL) was cooled to −30° C. Dibutylmagnesium (50.8 mL of 1 M solution in heptane, 50.8 mmol) was added and the mixture stirred for 45 minutes. The above solution of lithium (trimethylsilyl)acetylide was added and the stirring continued at −20° C. After 5 minutes, cooling bath was removed and the reaction mixture was stirred for 3 hours and 15 minutes. The reaction was quenched with 600 mL of saturated ammonium chloride solution and extracted with four 250 mL portions of ethyl acetate. The combined organic extracts were washed with two 250 mL portions of brine, dried over anhydrous sodium sulfate, and the solvent removed in vacuo to give 2-((R)-3-hydroxy-1,1-dimethyl-3-trifluoromethyl-6-trimethylsilanylhex-5-ynyl)benzamide as brownish oil (27 g).
Reaction SMILES: Cl[C:2]1[C:7]([Cl:8])=[CH:6][C:5]([Cl:9])=[CH:4][N:3]=1.[CH3:10][C:11]1[CH:12]=[C:13]([CH:18]=[CH:19][C:20]=1[S:21](=[O:35])(=[O:34])[NH:22][CH2:23][C:24]1[CH:25]=[C:26]2[C:30](=[CH:31][CH:32]=1)[N:29]([CH3:33])[N:28]=[CH:27]2)[C:14]([O:16][CH3:17])=[O:15]>>[Cl:8][C:7]1[C:2]([N:22]([CH2:23][C:24]2[CH:25]=[C:26]3[C:30](=[CH:31][CH:32]=2)[N:29]([CH3:33])[N:28]=[CH:27]3)[S:21]([C:20]2[CH:19]=[CH:18][C:13]([C:14]([O:16][CH3:17])=[O:15])=[CH:12][C:11]=2[CH3:10])(=[O:35])=[O:34])=[N:3][CH:4]=[C:5]([Cl:9])[CH:6]=1
Reactant: Clc1cnc(Cl)c(Cl)c1
Reactant: COC(=O)c1ccc(S(=O)(=O)NCc2ccc3c(cnn3C)c2)c(C)c1
Product: COC(=O)c1ccc(S(=O)(=O)N(Cc2ccc3c(cnn3C)c2)c2ncc(Cl)cc2Cl)c(C)c1

Procedure:
The titled compound was prepared according to the procedure described in step-2 of Example 1 from 2,3,5-trichloropyridine and methyl 3-methyl-4-(N-((1-methyl-1H-indazol-5-yl)methyl)sulfamoyl)benzoate (step-2 of Example 26).
Reaction SMILES: Cl.[Cl:2][C:3]1[S:7][CH:6]=[N:5][C:4]=1[C:8]([NH2:10])=[NH:9].[Cl:11][C:12]1[CH:19]=[C:18]([F:20])[CH:17]=[CH:16][C:13]=1[CH:14]=O.[C:21]([O:27][CH2:28][CH3:29])(=[O:26])[CH2:22][C:23]([CH3:25])=O.C([O-])(=O)C.[Na+]>C(O)C>[Cl:2][C:3]1[S:7][CH:6]=[N:5][C:4]=1[C:8]1[NH:10][C:23]([CH3:25])=[C:22]([C:21]([O:27][CH2:28][CH3:29])=[O:26])[CH:14]([C:13]2[CH:16]=[CH:17][C:18]([F:20])=[CH:19][C:12]=2[Cl:11])[N:9]=1
Reactant: CCOC(=O)CC(C)=O
Reactant: N=C(N)c1ncsc1Cl
Reactant: O=Cc1ccc(F)cc1Cl
Agent: CC(=O)[O-]
Agent: Cl
Agent: [Na+]
Solvent: CCO
Product: CCOC(=O)C1=C(C)NC(c2ncsc2Cl)=NC1c1ccc(F)cc1Cl
Yield: 35 %

Procedure:
2 mmol 5-chloro-4-thiazolformamidine hydrochloride, 2 mmol 2-chloro-4-fluorobenzaldehyde, 2 mmol ethyl acetoacetate and 2.2 mmol sodium acetate were reacted under reflux in 10 ml anhydrous ethanol for 20 hr, concentrated, and then ethyl acetate and water were added to separate the layers. The ethyl acetate layer was dried over anhydrous sodium sulfate, and separated by a column chromatography to obtain 0.29 g of a yellowish solid with mp 149-152° C.; 1H-NMR (400 MHz, DMSO-d6) δ 1.02-1.06 (3H, m); 2.42 (3H, s); 3.92-3.97 (2H, m); 6.01 (1H, br); 7.16-7.41 (3H, m); 9.08 (1H, s); 9.58 (1H, s); MS (EI) 413.1 (M+).
Reaction SMILES: C(OC([NH:11][C@@H:12]([CH2:21][N:22]1[CH2:27][CH2:26][O:25][CH2:24][CH2:23]1)[C@H:13]([C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)[OH:14])=O)C1C=CC=CC=1.C([O-])=O.[NH4+].C(Cl)(Cl)Cl>CO.[C].[Pd]>[NH2:11][C@@H:12]([CH2:21][N:22]1[CH2:23][CH2:24][O:25][CH2:26][CH2:27]1)[C@H:13]([C:15]1[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=1)[OH:14]
Reactant: O=C(N[C@@H](CN1CCOCC1)[C@@H](O)c1ccccc1)OCc1ccccc1
Agent: [Pd]
Agent: O=C[O-]
Agent: [NH4+]
Solvent: CO
Solvent: ClC(Cl)Cl
Product: N[C@@H](CN1CCOCC1)[C@@H](O)c1ccccc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 96.1 %

Procedure:
(1S,2S)-2-Benzyloxycarbonylamino-3-morpholino-1-phenyl-1-propanol (3.82 g, 10.3 mmol) was dissolved in methanol (10 ml), ammonium formate (2.6 g, 41.3 mmol) and 10% palladium-carbon (888.5 mg, 8.09 mol %) were added thereto, and the mixture thus obtained was stirred overnight at room temperature. After confirming completion of the reaction with TLC (chloroform:methanol=9:1 and 7:3), palladium-carbon was removed by filtration and the resulting filtrate was concentrated to obtain the objective compound as a colorless oily material (2.34 g, yield: 99.0%).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([N+:9]([O-])=O)=[CH:5][C:4]=1[C:12]1[CH:13]=[C:14]([CH2:17][N:18]2[CH2:23][CH2:22][N:21]([CH3:24])[CH2:20][CH2:19]2)[O:15][CH:16]=1.[H][H]>CO.[Pd]>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([NH2:9])=[CH:5][C:4]=1[C:12]1[CH:13]=[C:14]([CH2:17][N:18]2[CH2:19][CH2:20][N:21]([CH3:24])[CH2:22][CH2:23]2)[O:15][CH:16]=1
Reactant: COc1ccc([N+](=O)[O-])cc1-c1coc(CN2CCN(C)CC2)c1
Reactant: [H][H]
Agent: [Pd]
Solvent: CO
Product: COc1ccc(N)cc1-c1coc(CN2CCN(C)CC2)c1
Yield: 99.8 %

Procedure:
To a solution of 1-{[4-(2-methoxy-5-nitrophenyl)-2-furyl]methyl}-4-methylpiperazine (396 mg, 1.19 mmol) in 20 mL of methanol was added 10% palladium on carbon (40 mg). The resulting mixture was shaken with hydrogen in a Parr shaker until hydrogen uptake ceased. The reaction mixture was filtered through Celite and the filtrate concentrated in vacuo to give 358 mg (100%) of (4-methoxy-3-[5-[(4-methylpiperazin-1-yl)methyl]-3-furyl}phenyl)amine as a brown oil, 1H NMR (DMSO-d6) δ 2.14 (s, 3H), 2.29 (broad s, 4H), 2.40 (broad s, 4H), 3.49 (s, 2H), 3.72 (s, 3H), 4.61 (s, 2H), 6.47 (d, J=8 Hz, 1H), 6.58 (s, 1H), 6.78 (d, J=9 Hz, 1H), 6.80 (s, 1H), 7.91 (s, 1H); MS 302.1 (M+H)+.
Reaction SMILES: [F:1][C:2]([F:14])([F:13])[C:3]1[CH:4]=[C:5]([CH:10]=[CH:11][CH:12]=1)[C:6](=[N:8][OH:9])[NH2:7].[OH-].[K+].[CH2:17]([CH:19]1[O:21][CH2:20]1)Cl>CS(C)=O.O>[F:1][C:2]([F:13])([F:14])[C:3]1[CH:4]=[C:5]([CH:10]=[CH:11][CH:12]=1)[C:6]([NH:8][O:9][CH2:17][CH:19]1[O:21][CH2:20]1)=[NH:7]
Reactant: NC(=NO)c1cccc(C(F)(F)F)c1
Reactant: ClCC1CO1
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: CS(C)=O
Product: N=C(NOCC1CO1)c1cccc(C(F)(F)F)c1
Temperature: 0 °C
Reaction time: 5 h

Procedure:
50 g (0.245 mol) of m-trifluoromethyl-benzamidoxime and 33.7 g (0.6 mol) of potassium hydroxide was dissolved in a mixture of dimethyl sulphoxide and 170 ml of water, and the mixture was cooled to 0° C. 48 ml (0.6 mol) of epichlorohydrine was added, and the reaction mixture was stirred at 0° C. for 5 hours, then kept in a refrigerator overnight. Next day 250 ml of water was added, and the mixture was extracted with ethyl acetate (4×250 ml). The combined organic phases were washed with water, dried, treated with charcoal and evaporated to dryness, to yield m-trifluoromethyl-N-(2,3-epoxypropoxy)-benzamidine, as a colorless oil.
Reaction SMILES: [N:1]1([CH2:7][C:8]2[CH:13]=[CH:12][N:11]=[C:10]([O:14][CH2:15][CH2:16][CH2:17][CH2:18][NH:19][C:20](=[O:26])[CH2:21][S:22][CH2:23][CH2:24][OH:25])[CH:9]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[C:27](OC(=O)C)(=[O:29])[CH3:28]>>[N:1]1([CH2:7][C:8]2[CH:13]=[CH:12][N:11]=[C:10]([O:14][CH2:15][CH2:16][CH2:17][CH2:18][NH:19][C:20](=[O:26])[CH2:21][S:22][CH2:23][CH2:24][O:25][C:27](=[O:29])[CH3:28])[CH:9]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: CC(=O)OC(C)=O
Reactant: O=C(CSCCO)NCCCCOc1cc(CN2CCCCC2)ccn1
Product: CC(=O)OCCSCC(=O)NCCCCOc1cc(CN2CCCCC2)ccn1
Yield: 84 %

Procedure:
Following a procedure similar to that described in Example 67(c), but using N-[4-(4-piperidinomethyl-2-pyridyloxy)butyl]-2-(2-hydroxyethylthio)acetamide [prepared as described in step (b) above] and acetic anhydride as starting materials, in relative proportions similar to those used in that Example, the title compound was obtained as an oil in an 84% yield.
Reaction SMILES: [C:1]1([C:7]([C:14]2[CH:19]=[CH:18][N:17]=[CH:16][CH:15]=2)([C:9]2[S:10][CH:11]=[CH:12][CH:13]=2)O)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[O-]S([O-])(=S)=O.[Na+].[Na+]>CC#N>[C:1]1([CH:7]([C:14]2[CH:15]=[CH:16][N:17]=[CH:18][CH:19]=2)[C:9]2[S:10][CH:11]=[CH:12][CH:13]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: OC(c1ccccc1)(c1ccncc1)c1cccs1
Agent: O=S([O-])([O-])=S
Agent: [Na+]
Solvent: CC#N
Product: c1ccc(C(c2ccncc2)c2cccs2)cc1
Temperature: 25 °C

Procedure:
NAI (2.27 g, 16.0 mmol) and Me3Sicl (2.02, 16.0 mmol) were stirred in CH3CN (70 mL) at 0° C. (Phenyl)-pyrid-4-yl-(thien-2-yl)methanol (0.534 g, 2.00 mmol (Example 93)) was added at 0° C. and the resulting solution was stirred over night at room temperature. Na2S2O3 (sat., 20 mL) was added and the two phase system was stirred 5 minutes. The phases were separated and the organic layer was dried (MgSO4), filtered and evaporated. The resulting crystals were dissolved in CH2Cl2 (30 mL), the solution was washed with NaHCO3 (30 mL, sat.) and H2O (30 mL), dried (MgSO4) and evaporated yielding 0.41 g which was recrystallized in diisopropyl ether giving 0.22 g (43.8%) of the pure title compound.
Reaction SMILES: [CH3:1][N:2]1[C:11](=[O:12])[C:10]2[N:9](COC(=O)C(C)(C)C)[CH:8]=[N:7][C:6]=2[N:5]([CH2:21][CH2:22][CH2:23][C:24]([O:26]CC)=[O:25])[C:3]1=[O:4].Cl>[OH-].[Na+]>[CH3:1][N:2]1[C:11](=[O:12])[C:10]2[NH:9][CH:8]=[N:7][C:6]=2[N:5]([CH2:21][CH2:22][CH2:23][C:24]([OH:26])=[O:25])[C:3]1=[O:4]
Reactant: CCOC(=O)CCCn1c(=O)n(C)c(=O)c2c1ncn2COC(=O)C(C)(C)C
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Product: Cn1c(=O)c2[nH]cnc2n(CCCC(=O)O)c1=O

Procedure:
An oily suspension of 1-methyl-3(carboethoxypropyl)-7-(pivaloyloxymethyl)xanthine (508 mg) in 2N NaOH (36.2 ml) was heated under nitrogen at 95°-100° for 2 hrs. The oil dissolved and the reaction was shown to be complete by TLC. After cooling the reaction mixure, it was acidified to pH 2-3 with 15 ml 12% hydrochloric acid and the solution extracted with 3×5 ml chloroform to remove the pivalic acid. After washing the chloroform extracts with 5 ml 0.5N HCl, aqueous solutions were combined and stripped to dryness and the residue dried in vacuo at room temperature. The crude product was dissolved in about 22 ml hot water, decolorized and concentrated to 15 ml, at which time 159 mg of a crystalline product was obtained upon cooling. m.p. 220°-221°.
Reaction SMILES: C([O:3][C:4](=[O:31])[CH2:5][C:6]([NH:8][C:9]1[CH:14]=[C:13]([Br:15])[C:12]([O:16][C:17]2[CH:22]=[C:21]([CH:23]([CH3:25])[CH3:24])[C:20]([OH:26])=[C:19]([CH2:27][CH3:28])[CH:18]=2)=[C:11]([Br:29])[C:10]=1[CH3:30])=[O:7])C.[Li+].[OH-].Cl>C1COCC1>[Br:29][C:11]1[C:10]([CH3:30])=[C:9]([NH:8][C:6](=[O:7])[CH2:5][C:4]([OH:31])=[O:3])[CH:14]=[C:13]([Br:15])[C:12]=1[O:16][C:17]1[CH:22]=[C:21]([CH:23]([CH3:25])[CH3:24])[C:20]([OH:26])=[C:19]([CH2:27][CH3:28])[CH:18]=1
Reactant: CCOC(=O)CC(=O)Nc1cc(Br)c(Oc2cc(CC)c(O)c(C(C)C)c2)c(Br)c1C
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Product: CCc1cc(Oc2c(Br)cc(NC(=O)CC(=O)O)c(C)c2Br)cc(C(C)C)c1O
Yield: 41 %

Procedure:
N-[3,5-dibromo-4-[3-ethyl-4-hydroxy-5-isopropylphenoxy]-2-methylphenyl]malonamic acid ethyl ester of Part 9D (130 mg, 0.23 mmol) was dissolved in THF (2 mL) and treated with LiOH (2 mL, 1N) for 1 hour at room temperature. The reaction was acidified with 1N HCl and concentrated in vacuo. The remaining water phase was extracted with EtOAc (3×5 mL) and the combined organic phases were dried over Na2SO4 before concentration in vacuo. The residue was purified on column (MPLC, silica gel, gradient elution: CHCl3/MeOH/AcOH from 1:0:0 to 98:2:0.3) to give 50 mg (41%) of N-[3,5-dibromo-4-[3-ethyl-4-hydroxy-5-isopropylphenoxy]-2-methylphenyl]-malonamic acid as a white solid.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[CH:7]=[N:8][N:9]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][N:16]=2)[C:10]=1[S:11]([NH2:14])(=[O:13])=[O:12])=[O:5])[CH3:2].C(=O)([O-])[O-].[K+].[K+].[CH2:27]([N:31]=[C:32]=[O:33])[CH2:28][CH2:29][CH3:30]>CC(C)=O>[CH2:27]([NH:31][C:32]([NH:14][S:11]([C:10]1[N:9]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][N:16]=2)[N:8]=[CH:7][C:6]=1[C:4]([O:3][CH2:1][CH3:2])=[O:5])(=[O:13])=[O:12])=[O:33])[CH2:28][CH2:29][CH3:30]
Reactant: CCCCN=C=O
Reactant: CCOC(=O)c1cnn(-c2ccccn2)c1S(N)(=O)=O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: CCCCNC(=O)NS(=O)(=O)c1c(C(=O)OCC)cnn1-c1ccccn1
Yield: 95.2 %

Procedure:
To a 70 ml acetone mixture of 8.5 g of 4-ethoxycarbonyl-1-(2-pyridyl)pyrazole-5-sulfonamide and 6.0 g of anhydrous potassium carbonate, added was 3.3 g of n-butylisocyanate at room temperature, followed by heating under reflux for 3 hours. After the reaction was completed, acetone was evaporated under reduced pressure, and then the residue was emptied into ice water to filter insolbles off, and then the filtrate was precipitated with hydrochloric acid. Crystals precipitated was filtered, washed with water and dried to obtain 10.8 g of N-(n-butylcarbamoyl)-4-ethoxycarbonyl-1-(2-pyridyl)pyrazole-5-sulfonamide. m.p.: 180° to 181° C.
Reaction SMILES: [C:1]([O:6][CH2:7][CH2:8][N:9]([CH3:11])[CH3:10])(=[O:5])[C:2]([CH3:4])=[CH2:3].[Cl:12][CH2:13][C:14]1[CH:27]=[CH:26][C:17]([C:18]([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)=[O:19])=[CH:16][CH:15]=1>CC(C)=O>[Cl-:12].[C:18]([C:17]1[CH:26]=[CH:27][C:14]([CH2:13][N+:9]([CH3:11])([CH3:10])[CH2:8][CH2:7][O:6][C:1](=[O:5])[C:2]([CH3:4])=[CH2:3])=[CH:15][CH:16]=1)(=[O:19])[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1
Reactant: O=C(c1ccccc1)c1ccc(CCl)cc1
Reactant: C=C(C)C(=O)OCCN(C)C
Solvent: CC(C)=O
Product: C=C(C)C(=O)OCC[N+](C)(C)Cc1ccc(C(=O)c2ccccc2)cc1
Product: [Cl-]

Procedure:
Dimethylaminoethyl methacrylate (10.13 mls) was added to a stirred solution of 4-chloromethylbenzophenone (11.52g) in acetone (50 mls) at 48° C. and the mixture was stirred for fifteen hours at 48°±2° C. The stirred mixture was cooled in an ice bath for two hours prior to filtration, washing with acetone (X2) and drying under vacuo at room temperature. The crude title compound was obtained as a white crystalline solid (16.82g; m.p. 163°-166° C.) which was recrystallised from a mixture of acetone (30 mls) and isopropanol (30 mls).
Reaction SMILES: [CH2:1]([O:3][C:4]([N:6]1[CH2:11][CH2:10][N:9]([C:12](=[O:39])[C@@H:13]([NH:24][C:25]([C:27]2[CH:36]=[C:35]([OH:37])[C:34]3[C:29](=[CH:30][C:31]([CH3:38])=[CH:32][CH:33]=3)[N:28]=2)=[O:26])[CH2:14][CH2:15][O:16][CH2:17][C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[CH2:8][CH2:7]1)=[O:5])[CH3:2].C(=O)([O-])[O-].[Cs+].[Cs+].[C:46]([O:50][C:51](=[O:54])[CH2:52]Br)([CH3:49])([CH3:48])[CH3:47]>CN(C=O)C.O>[CH2:1]([O:3][C:4]([N:6]1[CH2:11][CH2:10][N:9]([C:12](=[O:39])[C@@H:13]([NH:24][C:25]([C:27]2[CH:36]=[C:35]([O:37][CH2:52][C:51]([O:50][C:46]([CH3:49])([CH3:48])[CH3:47])=[O:54])[C:34]3[C:29](=[CH:30][C:31]([CH3:38])=[CH:32][CH:33]=3)[N:28]=2)=[O:26])[CH2:14][CH2:15][O:16][CH2:17][C:18]2[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=2)[CH2:8][CH2:7]1)=[O:5])[CH3:2]
Reactant: CCOC(=O)N1CCN(C(=O)[C@H](CCOCc2ccccc2)NC(=O)c2cc(O)c3ccc(C)cc3n2)CC1
Reactant: CC(C)(C)OC(=O)CBr
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Solvent: O
Product: CCOC(=O)N1CCN(C(=O)[C@H](CCOCc2ccccc2)NC(=O)c2cc(OCC(=O)OC(C)(C)C)c3ccc(C)cc3n2)CC1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of 1.8 g of 4-{(S)-4-Benzyloxy-2-[(4-hydroxy-7-methyl-quinoline-2-carbonyl)-amino]-butyryl}-piperazine-1-carboxylic acid ethyl ester in 20 ml of DMF, 1.2 g of cesium carbonate and 723 mg of Bromo-acetic acid tert-butyl ester was added and the reaction mixture was stirred for 2 h at RT. Then, the reaction mixture was diluted with water and extracted with ethyl acetate. The organic phase was dried over MgSO4 and the solvents were removed under reduced pressure. The crude product was purified by chromatography on silica gel eluting with a gradient of n-heptane/ethyl acetate. The fractions containing the product were combined and the solvent evaporated under reduced pressure. Yield: 1.3 g.
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][CH2:4][CH:3]([CH2:7][NH:8][C:9]([C:11]2[C:15]3[N:16]=[CH:17][N:18]=[C:19]([C:20]4[C:28]5[O:27][CH2:26][O:25][C:24]=5[CH:23]=[CH:22][C:21]=4[O:29][CH2:30][CH:31]4[CH2:33][CH2:32]4)[C:14]=3[NH:13][CH:12]=2)=[O:10])[CH2:2]1.[CH3:34][O:35][CH2:36][C:37](Cl)=[O:38]>>[CH3:34][O:35][CH2:36][C:37]([N:1]1[CH2:6][CH2:5][CH2:4][CH:3]([CH2:7][NH:8][C:9]([C:11]2[C:15]3[N:16]=[CH:17][N:18]=[C:19]([C:20]4[C:28]5[O:27][CH2:26][O:25][C:24]=5[CH:23]=[CH:22][C:21]=4[O:29][CH2:30][CH:31]4[CH2:33][CH2:32]4)[C:14]=3[NH:13][CH:12]=2)=[O:10])[CH2:2]1)=[O:38]
Reactant: COCC(=O)Cl
Reactant: O=C(NCC1CCCNC1)c1c[nH]c2c(-c3c(OCC4CC4)ccc4c3OCO4)ncnc12
Product: COCC(=O)N1CCCC(CNC(=O)c2c[nH]c3c(-c4c(OCC5CC5)ccc5c4OCO5)ncnc23)C1

Procedure:
Starting from 4-(5-Cyclopropylmethoxy-benzo[1,3]dioxol-4-yl)-5H-pyrrolo[3,2-d]pyrimidine-7-carboxylic acid (piperidin-3-ylmethyl)-amide (example A145) and methoxy-acetyl chloride the title compound is obtained as colorless solid.
Reaction SMILES: O[C:2]1[CH2:7][CH2:6][CH2:5][C:4](=[O:8])[C:3]=1[C:9]([C:11]1[C:12]([CH3:21])=[N:13][C:14]([C:17]([F:20])([F:19])[F:18])=[CH:15][CH:16]=1)=[O:10].C(N(CC)CC)C.CN(C1C=CC=CN=1)C.[C:38]1([SH:44])[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=1>C(Cl)(=O)C(Cl)=O.CN(C)C=O>[CH3:21][C:12]1[C:11]([C:9]([C:3]2[C:4](=[O:8])[CH2:5][CH2:6][CH2:7][C:2]=2[S:44][C:38]2[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=2)=[O:10])=[CH:16][CH:15]=[C:14]([C:17]([F:20])([F:19])[F:18])[N:13]=1
Reactant: Sc1ccccc1
Reactant: Cc1nc(C(F)(F)F)ccc1C(=O)C1=C(O)CCCC1=O
Agent: CN(C)c1ccccn1
Agent: O=C(Cl)C(=O)Cl
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: Cc1nc(C(F)(F)F)ccc1C(=O)C1=C(Sc2ccccc2)CCCC1=O
Reaction time: 1.5 h

Procedure:
4.0 g (0.0134 mol) of 3-hydroxy-2-(2-methyl-6-trifluoromethylpyridine-3-carbonyl)cyclohex-2-enone (compound A2-B1) are suspended in 25 ml of oxalyl chloride, and 0.1 ml of dimethylformamide is subsequently added dropwise. After the vigorous evolution of gas has ceased, the mixture is held for 1.5 hours at a bath temperature of 45° C. and subsequently concentrated, and the residue (3-chloro-2-(2-methyl-6-trifluoromethylpyridine-3-carbonyl)-cyclohex-2-enone) is dissolved in 60 ml of methylene chloride. Triethylamine (3.7 ml, 0.0268 mol), dimethylaminopyridine (160 mg, 1.34 mmol) and 1.5 ml (0.0147 mol) of thiophenol are added at a temperature of 0-5° C. After 20 hours at a temperature of 22° C., the reaction mixture is concentrated and purified on silica gel (hexane/ethyl acetate 5:1). Trituration in hexane gives pure 2-(2-methyl-6-trifluoromethylpyridine-3-carbonyl)-3-phenylsulfanylcyclohex-2-enone in the form of white crystals of melting point 124-125° C. 1H-NMR (CDCl3): 1.99, m, 2H; 2.41, m 4H; 2.80, s, 3H; 2.60: 7.40-7.60, m, 6H; 7.80 ppm, d(J, 8.2 Hz), 1H.
Reaction SMILES: [CH2:1]=[C:2]1[CH2:7][N:6](S(C2C=CC(C)=CC=2)(=O)=O)[CH2:5][C:4]2[CH:18]=[CH:19][S:20][C:3]1=2.CC([O-])(C)C.[K+]>OC(C)(C)C>[CH3:1][C:2]1[C:3]2[S:20][CH:19]=[CH:18][C:4]=2[CH:5]=[N:6][CH:7]=1
Reactant: C=C1CN(S(=O)(=O)c2ccc(C)cc2)Cc2ccsc21
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: CC(C)(C)O
Product: Cc1cncc2ccsc12
Yield: 84.6 %

Procedure:
To a solution of 4,5,6,7-tetrahydro-7-methylene-5-tosylthieno[3,2-c]pyridine (150 mg, 0.491 mmol, 1.0 equiv) in HOt-Bu (5 mL) was added KOt-Bu (110 mg, 0.982 mmol, 2.0 equiv) and heated to reflux for 3 h. Purification by column chromatography using ethyl acetate elution gave 62 mg of the yellow solid, 85%.