Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [ClH:1].C(OC([N:9]1[CH2:13][CH2:12][C:11](=[N:14][O:15][CH3:16])[CH2:10]1)=O)(C)(C)C.CCOCC>C(OCC)(=O)C>[ClH:1].[CH3:16][O:15][N:14]=[C:11]1[CH2:12][CH2:13][NH:9][CH2:10]1
Reactant: CON=C1CCN(C(=O)OC(C)(C)C)C1
Agent: Cl
Solvent: CCOCC
Solvent: CCOC(C)=O
Product: CON=C1CCNC1
Temperature: 40 °C
Reaction time: 1 h

Procedure:
7 ml of a 3M hydrogen chloride solution in ethyl acetate was added to 2.3 g of ice-cooled 1-(t-butoxycarbonyl)-3-methoxyiminopyrrolidine, and the mixture was stirred at about 40° C. for one hour. After completion of the reaction, the solvent was stripped off from the reaction mixture and ether was added to the residue. The crystals which formed were collected by filtration and washed with ether, giving 1.5 g of the title compound.
Reaction SMILES: C(OC(=O)[N:10]([CH2:25][CH3:26])[C:11]1[C:16]([O:17][CH3:18])=[CH:15][C:14]([C:19]([O:21][CH3:22])=[O:20])=[CH:13][C:12]=1[O:23][CH3:24])C1C=CC=CC=1.[H][H]>CO.[Pd]>[CH3:22][O:21][C:19](=[O:20])[C:14]1[CH:15]=[C:16]([O:17][CH3:18])[C:11]([NH:10][CH2:25][CH3:26])=[C:12]([O:23][CH3:24])[CH:13]=1
Reactant: [H][H]
Reactant: CCN(C(=O)OCc1ccccc1)c1c(OC)cc(C(=O)OC)cc1OC
Agent: [Pd]
Solvent: CO
Product: CCNc1c(OC)cc(C(=O)OC)cc1OC

Procedure:
A suspension of 77.5 g. of N-ethyl-2,6-dimethoxy-4-(methoxy-carbonyl)-carbanilic acid benzyl ester in 1 liter of methanol was hydrogenated in the presence of 2 g. of palladium on carbon (5%) until hydrogen uptake ceased. The suspension was heated to boiling and filtered. The filtrate was evaporated under vacuum. After recrystallization of the residue from cyclohexane, there was obtained 4-(ethylamino)-3,5-dimethoxy-benzoic acid methyl ester having a melting point of 50°-51° C.
Reaction SMILES: CO.C(O[C:6]([C:8]1[C:9]([NH:16][C:17]2[CH:25]=[C:24]3[C:20]([CH:21]=[N:22][NH:23]3)=[CH:19][CH:18]=2)=[N:10][C:11]([S:14][CH3:15])=[N:12][CH:13]=1)=[O:7])C.[CH:26]1([NH2:29])[CH2:28][CH2:27]1>O>[CH:26]1([NH:29][C:6]([C:8]2[C:9]([NH:16][C:17]3[CH:25]=[C:24]4[C:20]([CH:21]=[N:22][NH:23]4)=[CH:19][CH:18]=3)=[N:10][C:11]([S:14][CH3:15])=[N:12][CH:13]=2)=[O:7])[CH2:28][CH2:27]1
Reactant: NC1CC1
Reactant: CCOC(=O)c1cnc(SC)nc1Nc1ccc2cn[nH]c2c1
Solvent: O
Solvent: CO
Product: CSc1ncc(C(=O)NC2CC2)c(Nc2ccc3cn[nH]c3c2)n1
Yield: 65 %

Procedure:
To the solution of methanol (20 ml) was added 4-(1H-6-indazolylamino)-2-methylthio-5-pyrimidinecarboxylic acid ethyl ester (1g) prepared from preparation example 2, added cyclopropylamine (7 ml) at room temperature, and reacted at 50° C. for 6 hr. The reaction mixture was cooled, and stirred at 25° C. for 0.5 hr with slowly adding H2O (20 ml). The reaction mixture was filtered, washed with 30% aqueous methanol solution (10 ml), obtained the desired compound (0.67 g, 65%)
Reaction SMILES: COC[C@@H]1[C@H](/C=C/C(/C)=C/C(O)=O)[C@@]1(C)C1C=CC2C(C)(C)CCC(C)(C)C=2C=1.[CH2:30]([O:32][CH2:33][C@@H:34]1[C@@H:36](/[CH:37]=[CH:38]/[C:39](/[CH3:46])=[CH:40]/[C:41]([O:43]CC)=[O:42])[C@:35]1([CH3:61])[C:47]1[CH:56]=[CH:55][C:54]2[C:53]([CH3:58])([CH3:57])[CH2:52][CH2:51][C:50]([CH3:60])([CH3:59])[C:49]=2[CH:48]=1)[CH3:31]>>[CH2:30]([O:32][CH2:33][C@@H:34]1[C@@H:36](/[CH:37]=[CH:38]/[C:39](/[CH3:46])=[CH:40]/[C:41]([OH:43])=[O:42])[C@:35]1([CH3:61])[C:47]1[CH:56]=[CH:55][C:54]2[C:53]([CH3:58])([CH3:57])[CH2:52][CH2:51][C:50]([CH3:60])([CH3:59])[C:49]=2[CH:48]=1)[CH3:31]
Reactant: CCOC[C@@H]1[C@@H](/C=C/C(C)=C/C(=O)OCC)[C@]1(C)c1ccc2c(c1)C(C)(C)CCC2(C)C
Agent: COC[C@@H]1[C@H](/C=C/C(C)=C/C(=O)O)[C@@]1(C)c1ccc2c(c1)C(C)(C)CCC2(C)C
Product: CCOC[C@@H]1[C@@H](/C=C/C(C)=C/C(=O)O)[C@]1(C)c1ccc2c(c1)C(C)(C)CCC2(C)C
Yield: 80 %

Procedure:
Following a procedure similar to that for the preparation of Compound 20a but using Compound 19b as the starting material afforded the title compound (26 mg, 80% yield) as a white solid:
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[C:10]2[N:11]=[CH:12][N:13]=[C:14](Cl)[C:9]=2[NH:8][CH:7]=1)=[O:5])[CH3:2].[CH:16]1([CH2:19][O:20][C:21]2[CH:26]=[C:25]([O:27][CH3:28])[CH:24]=[CH:23][C:22]=2B2OC(C)(C)C(C)(C)O2)[CH2:18][CH2:17]1>>[CH2:1]([O:3][C:4]([C:6]1[C:10]2[N:11]=[CH:12][N:13]=[C:14]([C:22]3[CH:23]=[CH:24][C:25]([O:27][CH3:28])=[CH:26][C:21]=3[O:20][CH2:19][CH:16]3[CH2:18][CH2:17]3)[C:9]=2[NH:8][CH:7]=1)=[O:5])[CH3:2]
Reactant: COc1ccc(B2OC(C)(C)C(C)(C)O2)c(OCC2CC2)c1
Reactant: CCOC(=O)c1c[nH]c2c(Cl)ncnc12
Product: CCOC(=O)c1c[nH]c2c(-c3ccc(OC)cc3OCC3CC3)ncnc12

Procedure:
Starting from 4-chloro-5H-pyrrolo[3,2-d]pyrimidine-7-carboxylic acid ethyl ester and 2-(2-cyclopropylmethoxy-4-methoxy-phenyl)-4,4,5,5-tetramethyl-[1,3,2]dioxaborolane (example A36) the title compound is obtained as colorless solid.
Reaction SMILES: I[C:2]1[N:6]=[C:5]([C:7]2[CH:12]=[CH:11][C:10]([O:13][C:14]([F:17])([F:16])[F:15])=[CH:9][CH:8]=2)[N:4]([CH3:18])[C:3]=1[C:19]([N:21]1[CH2:26][CH2:25][CH:24]([N:27]2[CH2:31][CH2:30][CH2:29][CH2:28]2)[CH2:23][CH2:22]1)=[O:20].[N:32]1[CH:37]=[CH:36][C:35](B(O)O)=[CH:34][CH:33]=1>>[CH3:18][N:4]1[C:3]([C:19]([N:21]2[CH2:26][CH2:25][CH:24]([N:27]3[CH2:31][CH2:30][CH2:29][CH2:28]3)[CH2:23][CH2:22]2)=[O:20])=[C:2]([C:35]2[CH:36]=[CH:37][N:32]=[CH:33][CH:34]=2)[N:6]=[C:5]1[C:7]1[CH:12]=[CH:11][C:10]([O:13][C:14]([F:17])([F:16])[F:15])=[CH:9][CH:8]=1
Reactant: Cn1c(-c2ccc(OC(F)(F)F)cc2)nc(I)c1C(=O)N1CCC(N2CCCC2)CC1
Reactant: OB(O)c1ccncc1
Product: Cn1c(-c2ccc(OC(F)(F)F)cc2)nc(-c2ccncc2)c1C(=O)N1CCC(N2CCCC2)CC1

Procedure:
In analogy to the procedure described for example 7, [5-iodo-3-methyl-2-(4-trifluoromethoxy-phenyl)-3H-imidazol-4-yl]-(4-pyrrolidin-1-yl-piperidin-1-yl)-methanone (example 66) was reacted with pyridine-4-yl-boronic acid to give the title compound as light brown solid. MS: 500.2 (MH+).
Reaction SMILES: Br[C:2]1[O:6][C:5]([CH3:7])=[C:4]([CH:8]=[O:9])[CH:3]=1.[CH3:10][O:11][C:12]([C:14]1[CH:15]=[C:16](B(O)O)[CH:17]=[CH:18][CH:19]=1)=[O:13].C(=O)([O-])[O-].[Na+].[Na+].COCCOC>C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.O>[CH:8]([C:4]1[CH:3]=[C:2]([C:18]2[CH:19]=[C:14]([CH:15]=[CH:16][CH:17]=2)[C:12]([O:11][CH3:10])=[O:13])[O:6][C:5]=1[CH3:7])=[O:9]
Reactant: Cc1oc(Br)cc1C=O
Reactant: COC(=O)c1cccc(B(O)O)c1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: COCCOC
Solvent: O
Product: COC(=O)c1cccc(-c2cc(C=O)c(C)o2)c1
Reaction time: 8 h
Yield: 85.5 %

Procedure:
A mixture of 5-bromo-2-methylfuran-3-carbaldehyde (1.9 g), 3-methoxycarbonylphenylboronic acid (2.2 g), tetrakis(triphenylphosphine)palladium(0) (0.6 g), 2N aqueous sodium carbonate solution (12 mL) and 1,2-dimethoxyethane (20 mL) was stirred overnight with refluxing under an argon atmosphere. The reaction mixture was poured into water, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, and dried over magnesium sulfate. The solvent was evaporated under reduced pressure. The residue was purified by silica gel chromatography (0% ethyl acetate/hexane to 25% ethyl acetate/hexane), and crystallized from ethyl acetate/hexane to give the title compound (2.1 g, 87%) as a yellow crystal.
Reaction SMILES: C([N:8]([CH2:21][CH:22]([OH:32])[CH2:23][O:24][C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=1[CH3:31])[CH2:9][CH2:10][O:11][C:12]1[C:17]([C:18](=[O:20])[NH2:19])=[CH:16][CH:15]=[CH:14][N:13]=1)C1C=CC=CC=1.[H][H]>C(O)C.[Pd]>[C:18]([C:17]1[C:12]([O:11][CH2:10][CH2:9][NH:8][CH2:21][CH:22]([OH:32])[CH2:23][O:24][C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=2[CH3:31])=[N:13][CH:14]=[CH:15][CH:16]=1)(=[O:20])[NH2:19]
Reactant: Cc1ccccc1OCC(O)CN(CCOc1ncccc1C(N)=O)Cc1ccccc1
Reactant: [H][H]
Agent: [Pd]
Solvent: CCO
Product: Cc1ccccc1OCC(O)CNCCOc1ncccc1C(N)=O

Procedure:
A solution of 11.7 g of 1-{N-benzyl-N-[2-(3-carbamoyl-2-pyridyloxy)-ethyl]-amino}-3-(2-methyl-phenyloxy)-2-propanol in 120 ml of ethanol is hydrogenated in the presence of 1.2 g of a 5% strength palladium-on-charcoal catalyst at 20°-30° C. and under atmospheric pressure until the uptake of hydrogen ceases. The reaction product is worked up analogously to the process described in Example 1, giving crude 1-[2-(3-carbamoyl-2-pyridyloxy)-ethylamino]-3-(2-methyl-phenyloxy)-2-propanol. A solution of 1.5 g of fumaric acid in isopropanol is added thereto and the neutral fumaric acid salt of 1-[2-(3-carbamoyl-2-pyridyloxy)-ethyl-amino]-3-(2-methyl-phenyloxy)-2-propanol thus obtainable, is recrystallised from a mixture of isopropanol and water; melting point 156° C.
Reaction SMILES: [CH:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][C:2]=1[NH:11][C:12]1[CH:13]=[CH:14][CH:15]=[C:16]2[C:21]=1[N:20]=[CH:19][CH:18]=[CH:17]2.C(OCC)(=O)C>C(O)(=O)C.[Pt](=O)=O>[CH:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][C:2]=1[NH:11][C:12]1[CH:13]=[CH:14][CH:15]=[C:16]2[C:21]=1[NH:20][CH2:19][CH2:18][CH2:17]2
Reactant: c1ccc2cc(Nc3cccc4cccnc34)ccc2c1
Agent: O=[Pt]=O
Solvent: CC(=O)O
Solvent: CCOC(C)=O
Product: c1cc2c(c(Nc3ccc4ccccc4c3)c1)NCCC2
Reaction time: 4 h
Yield: 101.4 %

Procedure:
A solution of 4.08 grams of N-2-naphthylquinolin-8-amine from above in acetic acid (10 mL) and ethyl acetate (150 mL) containing 0.24 grams of platinum(IV) oxide was hydrogenated at 45 psi for four hours on a Parr low-pressure hydrogenator. The solution was filtered through diatomaceous earth; concentrated in vacuo; and neutralized with 3N aqueous sodium hydroxide. The aqueous phase was diluted with water and extracted three times with ethyl acetate. The combined ethyl acetate layers were washed with brine; dried over anhydrous magnesium sulfate, filtered and concentrated in vacuo to yield 4.2 grams of the desired product as a purple oil. 1H NMR (CDCl3/D2O) δ 7.7 (m, 2H), 7.6 (d,1H), 7.35 (t, 1H), 7.25 (m, 1H), 7.05 (m, 2H), 6.9 (m, 2H), 6.6 (t, 1H), 3.3 (t, 2H), 2.85 (t, 2H), 1.95 (p, 2H).
Reaction SMILES: [F:1][C:2]1[CH:25]=[CH:24][CH:23]=[C:22]([C:26]([F:29])([F:28])[F:27])[C:3]=1[C:4]([NH:6][C:7]1[S:18][C:10]2[C:11]([CH3:17])([CH3:16])[O:12][C:13]([CH3:15])([CH3:14])[C:9]=2[C:8]=1[C:19](O)=[O:20])=[O:5].[OH:30][CH2:31][CH2:32][CH2:33][NH2:34]>>[F:1][C:2]1[CH:25]=[CH:24][CH:23]=[C:22]([C:26]([F:28])([F:29])[F:27])[C:3]=1[C:4]([NH:6][C:7]1[S:18][C:10]2[C:11]([CH3:17])([CH3:16])[O:12][C:13]([CH3:15])([CH3:14])[C:9]=2[C:8]=1[C:19]([NH:34][CH2:33][CH2:32][CH2:31][OH:30])=[O:20])=[O:5]
Reactant: CC1(C)OC(C)(C)c2c1sc(NC(=O)c1c(F)cccc1C(F)(F)F)c2C(=O)O
Reactant: NCCCO
Product: CC1(C)OC(C)(C)c2c1sc(NC(=O)c1c(F)cccc1C(F)(F)F)c2C(=O)NCCCO

Procedure:
The title compound was prepared from the product of Example 45A and commercially available 3-hydroxypropylamine using the procedure described for Example 2B. 1H NMR (DMSO-d6, 300 MHz) δ 1.44 (s, 6H), 1.47 (s, 6H), 1.56-1.65 (m, 2H), 3.18-3.25 (m, 2H), 3.37-3.44 (m, 2H), 4.43 (t, J=4.8 Hz, 1H), 7.67-7.80 (m, 3H), 8.01 (t, J=5.3 Hz, 1H), 11.57 (br s, 1H). MS (ESI+) m/z 489 (M+H)+. Anal. calcd. for C22H24F4N2O4S: C, 54.09; H, 4.95; N, 5.73. Found: C, 53.87; H, 4.86; N, 5.64.
Reaction SMILES: [CH2:1]([O:8][CH2:9][CH2:10][CH2:11][C:12]([OH:14])=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.S(Cl)(Cl)=O.C([O:21][C:22](=[O:30])[C:23]1[CH:28]=[CH:27][CH:26]=[N:25][C:24]=1[NH2:29])C.C(=O)([O-])O.[Na+]>C(Cl)(Cl)Cl.C(N(CC)CC)C>[CH2:1]([O:8][CH2:9][CH2:10][CH2:11][C:12]([NH:29][C:24]1[N:25]=[CH:26][CH:27]=[CH:28][C:23]=1[C:22]([OH:30])=[O:21])=[O:14])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=C(O)CCCOCc1ccccc1
Reactant: CCOC(=O)c1cccnc1N
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClC(Cl)Cl
Solvent: CCN(CC)CC
Solvent: O=S(Cl)Cl
Product: O=C(CCCOCc1ccccc1)Nc1ncccc1C(=O)O
Temperature: 25 °C
Yield: 80 %

Procedure:
4-(benzyloxy)butyric acid (154 mg, 0.79 mmol) was dissolved in chloroform, thionyl chloride (158 mg) was added, and the mixture stirred at room temperature for 1 Hour. The solvent and excess thionyl chloride were distilled off under reduced pressure, the residue was dissolved in chloroform, triethylamine (0.46 mL) and 2-aminonicotinic acid ethyl ester (110 mg, 0.66 mmol) were added, and the mixture stirred at room temperature for 2 hours. Saturated sodium hydrogen carbonate aqueous solution was added to the reaction liquid, the mixture extracted with chloroform, and dried with anhydrous sodium sulfate. The obtained residue was dissolved in methanol, 2N sodium hydroxide aqueous solution (0.66 mL) was added, and the mixture stirred at room temperature for 2 hours. After adding hydrochloric acid aqueous solution to the reaction liquid to render it weakly acid, the solvent was distilled off under reduced pressure. Ethyl acetate and a small amount of ethanol were added to the residue, the solid precipitate was filtered off, and the target compound (166 mg, 80%) was thus obtained as a colorless solid.
Reaction SMILES: [H-].[Na+].[I-].[CH3:4][S+](C)(C)=O.[CH3:9][C:10]1[S:11][C:12]2[C:18](/[CH:19]=[CH:20]/[C:21]([O:23][CH2:24][CH3:25])=[O:22])=[CH:17][CH:16]=[CH:15][C:13]=2[N:14]=1.O>CS(C)=O>[CH3:9][C:10]1[S:11][C:12]2[C:18]([CH:19]3[CH2:4][CH:20]3[C:21]([O:23][CH2:24][CH3:25])=[O:22])=[CH:17][CH:16]=[CH:15][C:13]=2[N:14]=1
Reactant: C[S+](C)(C)=O
Reactant: CCOC(=O)/C=C/c1cccc2nc(C)sc12
Agent: [H-]
Agent: [I-]
Agent: [Na+]
Solvent: O
Solvent: CS(C)=O
Product: CCOC(=O)C1CC1c1cccc2nc(C)sc12
Temperature: 25 °C
Reaction time: 1 h
Yield: 214.1 %

Procedure:
To a suspension of 60% sodium hydride (0.600 g, 15.6 mmol) in dimethyl sulfoxide (10 mL) was added a solution of trimethylsulfoxonium iodide (3.44 g, 15.6 mmol) in dimethyl sulfoxide (35 mL) at 0° C., and the mixture was stirred at room temperature for 1 hr. To the reaction mixture was added a solution of ethyl (2E)-3-(2-methyl-1,3-benzothiazol-7-yl)acrylate (1.60 g, 6.47 mmol) in dimethyl sulfoxide (30 mL) at 0° C., and the mixture was stirred at room temperature for 6 hr. Water was added and the mixture was extracted with ethyl acetate. The extract was washed with saturated brine, and dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate/hexane=1/2) to give the title compound (3.62 g, yield 69%).
Reaction SMILES: [C:1]([NH:4][CH2:5][CH2:6][O:7][C@@H:8]([C:22]1[CH:27]=[CH:26][CH:25]=[C:24]([Cl:28])[C:23]=1[F:29])[C@@H:9]1[CH2:14][CH2:13][CH2:12][N:11](C(OC(C)(C)C)=O)[CH2:10]1)(=[O:3])[CH3:2]>C(O)(C(F)(F)F)=O.C(Cl)Cl>[Cl:28][C:24]1[C:23]([F:29])=[C:22]([C@@H:8]([C@@H:9]2[CH2:14][CH2:13][CH2:12][NH:11][CH2:10]2)[O:7][CH2:6][CH2:5][NH:4][C:1](=[O:3])[CH3:2])[CH:27]=[CH:26][CH:25]=1
Reactant: CC(=O)NCCO[C@@H](c1cccc(Cl)c1F)[C@@H]1CCCN(C(=O)OC(C)(C)C)C1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CC(=O)NCCO[C@@H](c1cccc(Cl)c1F)[C@@H]1CCCNC1
Temperature: 25 °C
Yield: 10.2 %

Procedure:
(R)-tert-butyl 3-((R)-(2-acetamidoethoxy)(3-chloro-2-fluorophenyl)methyl)piperidine-1-carboxylate (95 mg, 1.88 mmol) was dissolved in 20% v/v TFA/CH2Cl2 (8 mL) at 0° C., the mixture was allowed to warm to rt for 1 h and then concentrated in vacuo to give N-(2-((R)-(3-chloro-2-fluorophenyl)((R)-piperidin-3-yl)methoxy)ethyl)acetamide (63 mg, 87%), which was used without further purification. MS (E/Z): 329 (M+)
Reaction SMILES: [CH2:1]([NH:8][C:9]([C:11]1[S:12][C:13]([C:17]2[N:21]=[CH:20][NH:19][N:18]=2)=[CH:14][C:15]=1[CH3:16])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(=O)([O-])[O-].[K+].[K+].[F:28][C:29]1[CH:36]=[CH:35][C:32]([CH2:33]Br)=[CH:31][CH:30]=1>CN(C)C=O>[CH2:1]([NH:8][C:9]([C:11]1[S:12][C:13]([C:17]2[N:21]=[CH:20][N:19]([CH2:33][C:32]3[CH:35]=[CH:36][C:29]([F:28])=[CH:30][CH:31]=3)[N:18]=2)=[CH:14][C:15]=1[CH3:16])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: Cc1cc(-c2nc[nH]n2)sc1C(=O)NCc1ccccc1
Reactant: Fc1ccc(CBr)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: Cc1cc(-c2ncn(Cc3ccc(F)cc3)n2)sc1C(=O)NCc1ccccc1
Temperature: 80 °C
Reaction time: 2 h
Yield: 60.4 %

Procedure:
A mixture of N-benzyl-3-methyl-5-(1H-1,2,4-triazol-3-yl)thiophene-2-carboxamide (0.07 g, 0.22 mmol), potassium carbonate (0.03 g, 0.22 mmol) and 4-fluorobenzyl bromide (0.04 mL, 0.33 mmol) in N,N-dimethylformamide (2 mL) was stirred at 80° C. for 2 h. The reaction mixture was allowed to cool to ambient temperature, and then was partitioned between ethyl acetate (75 mL) and water (50 mL). The organic layer was dried over sodium sulfate, filtered and concentrated in vacuo. The residue was purified by column chromatography eluted with 40% ethyl acetate in hexanes to afford the title compound as a yellowish solid (0.054 g, 61%): mp 128-130° C.; 1H NMR (300 MHz, CDCl3) δ 7.99 (s, 1H), 7.45 (s, 1H), 7.37-7.25 (m, 7H), 7.12-7.03 (m, 2H), 6.11 (t, J=5.8 Hz, 1H), 5.30 (s, 2H), 4.61 (d, J=5.8 Hz, 2H), 2.54 (s, 3H); MS (ES+) m/z 407.2 (M+1).
Reaction SMILES: [NH2:1][C:2]1[S:3][CH:4]=[C:5]([CH2:7][C:8]([N:10]2[CH2:15][CH2:14][N:13]([CH2:16][C:17](=[O:23])[N:18]3[CH2:22][CH2:21][CH2:20][CH2:19]3)[CH2:12][CH2:11]2)=[O:9])[N:6]=1.[C:24](O)(=[O:34])[C:25]1[CH:33]=[CH:32][C:31]2[O:30][CH2:29][O:28][C:27]=2[CH:26]=1>>[O:9]=[C:8]([N:10]1[CH2:15][CH2:14][N:13]([CH2:16][C:17](=[O:23])[N:18]2[CH2:19][CH2:20][CH2:21][CH2:22]2)[CH2:12][CH2:11]1)[CH2:7][C:5]1[N:6]=[C:2]([NH:1][C:24]([C:25]2[CH:33]=[CH:32][C:31]3[O:30][CH2:29][O:28][C:27]=3[CH:26]=2)=[O:34])[S:3][CH:4]=1
Reactant: Nc1nc(CC(=O)N2CCN(CC(=O)N3CCCC3)CC2)cs1
Reactant: O=C(O)c1ccc2c(c1)OCO2
Product: O=C(Nc1nc(CC(=O)N2CCN(CC(=O)N3CCCC3)CC2)cs1)c1ccc2c(c1)OCO2

Procedure:
In analogy to example 37.5, 2-(2-amino-thiazol-4-yl)-1-[4-(2-oxo-2-pyrrolidin-1-yl-ethyl)-piperazin-1-yl]-ethanone (example 37.4) was coupled with piperonylic acid, using general method D, to give benzo[1,3]dioxole-5-carboxylic acid (4-{2-oxo-2-[4-(2-oxo-2-pyrrolidin-1-yl-ethyl)-piperazin-1-yl]-ethyl}-thiazol-2-yl)-amide. Off-white solid. MS 486.4 ([M+H]+)
Reaction SMILES: [Cl-].[CH2:2]([P+:6]([CH2:15][CH2:16][CH2:17][CH3:18])([CH2:11][CH2:12][CH2:13][CH3:14])[CH2:7][CH2:8][CH2:9][OH:10])[CH2:3][CH2:4][CH3:5].COC1C=CC(O)=CC=1.[C:28]([Cl:33])(=[O:32])[C:29]([CH3:31])=[CH2:30]>C(#N)C>[Cl-:33].[CH2:11]([P+:6]([CH2:2][CH2:3][CH2:4][CH3:5])([CH2:15][CH2:16][CH2:17][CH3:18])[CH2:7][CH2:8][CH2:9][O:10][C:28](=[O:32])[C:29]([CH3:31])=[CH2:30])[CH2:12][CH2:13][CH3:14]
Reactant: C=C(C)C(=O)Cl
Reactant: CCCC[P+](CCCC)(CCCC)CCCO
Agent: COc1ccc(O)cc1
Agent: [Cl-]
Solvent: CC#N
Product: C=C(C)C(=O)OCCC[P+](CCCC)(CCCC)CCCC
Reaction time: 2 h

Procedure:
Into a 1 L-four-necked flask equipped with a stirrer, a thermometer and a distillation line, was added the obtained tri-n-butyl(3-hydroxypropyl)phosphonium chloride dissolved in 500 ml of acetonitrile. The solution was heated under a normal pressure while stirring and about 200 ml of acetonitrile was distilled. A condenser having a calcium chloride tube was installed, 1.5 g of hydroquinone monomethyl ether was added as a polymerization inhibitor, and 75.8 g (0.725 mol) of methacryloyl chloride was added thereto dropwise at 50° C. over 2 hours through a dropping funnel, then the solution was maturated for 3 hours at the same temperature as above. The absence of an unreacted substance was confirmed using FT-IR, and the reaction solution was concentrated and dried with a vacuum pump to give 290.3 g of a slightly yellow liquid. The titration purity was 94.6% and the yield was 100.0%.
Reaction SMILES: [CH2:1]([O:8][C:9]([NH:11][C@@H:12]1[CH2:17][N:16]([C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])[CH2:15][C@H:14]([C:25]([O:27]C)=[O:26])[CH2:13]1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[OH-].[Na+]>CO>[CH2:1]([O:8][C:9]([NH:11][C@@H:12]1[CH2:17][N:16]([C:18]([O:20][C:21]([CH3:23])([CH3:24])[CH3:22])=[O:19])[CH2:15][C@H:14]([C:25]([OH:27])=[O:26])[CH2:13]1)=[O:10])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: COC(=O)[C@@H]1C[C@H](NC(=O)OCc2ccccc2)CN(C(=O)OC(C)(C)C)C1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: CC(C)(C)OC(=O)N1C[C@@H](NC(=O)OCc2ccccc2)C[C@@H](C(=O)O)C1
Temperature: 25 °C
Reaction time: 12 h
Yield: 88.8 %

Procedure:
To a solution (700 ml) of 1-tert-butyl 3-methyl (3R,5S)-5-{[(benzyloxy)carbonyl]amino}piperidine-1,3-dicarboxylate (115 g) in methanol was added 1M aqueous sodium hydroxide solution (350 ml) under ice-cooling, and the mixture was stirred at room temperature for 12 hr. The reaction mixture was concentrated under reduced pressure to about 1/3 volume, and the residual aqueous solution was washed with ethyl acetate-hexane (1:1, 600 ml). The aqueous layer was neutralized with 1M hydrochloric acid and the mixture was extracted with ethyl acetate. The extract was washed with saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure to give the object product (98.5 g).
Reaction SMILES: [CH2:1]([O:3][CH:4]([N:6]1[C:10]2[S:11][C:12]([C:14]([O:16]CC)=[O:15])=[CH:13][C:9]=2[C:8]([C:19]2[NH:20][C:21]3[C:26]([CH:27]=2)=[CH:25][CH:24]=[CH:23][CH:22]=3)=[N:7]1)[CH3:5])[CH3:2].[OH-].[Na+]>C(O)C>[CH2:1]([O:3][CH:4]([N:6]1[C:10]2[S:11][C:12]([C:14]([OH:16])=[O:15])=[CH:13][C:9]=2[C:8]([C:19]2[NH:20][C:21]3[C:26]([CH:27]=2)=[CH:25][CH:24]=[CH:23][CH:22]=3)=[N:7]1)[CH3:5])[CH3:2]
Reactant: CCOC(=O)c1cc2c(-c3cc4ccccc4[nH]3)nn(C(C)OCC)c2s1
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: CCOC(C)n1nc(-c2cc3ccccc3[nH]2)c2cc(C(=O)O)sc21
Yield: 93.8 %

Procedure:
0.53 g (1.38 mmol) of ethyl 1-(1-ethoxyethyl)-3-(1H-indol-2-yl)-1H-thieno[2,3-c]pyrazole-5-carboxylate is dissolved with stirring in 40 cm3 of ethanol at a temperature in the region of 20° C. 2.8 cm3 (2.8 mmol) of 1N sodium hydroxide solution are then run in, and the resulting solution is then refluxed for 2 hours. The reaction medium is then concentrated to dryness under reduced pressure (2.7 kPa) and the residue is taken up in 30 cm3 of water to which is added 0.17 g of citric acid. The mixture is extracted with twice 50 cm3 of dichloromethane, and acidification of the aqueous phase is continued by addition of citric acid down to pH 2, and the extraction is then continued with twice 50 cm3 of dichloromethane. The various organic phases are combined, dried and then evaporated to dryness under reduced pressure (2.7 kPa). 0.46 g of 1-(1-ethoxyethyl)-3-(1H-indol-2-yl)-1H-thieno[2,3-c]pyrazole-5-carboxylic acid is thus obtained in the form of a yellow solid melting at 204° C.