Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: FC(F)(F)S(O[C:7]1[CH:12]=[CH:11][CH:10]=[C:9]([CH2:13][CH:14]2[CH2:18][CH2:17][CH:16]=[C:15]2[C:19]2[O:20][C:21]([C:30]3[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=3)=[C:22]([C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=3)[N:23]=2)[CH:8]=1)(=O)=O.[CH3:38][O:39][C:40]([C:42]1[CH:43]=[C:44](B(O)O)[CH:45]=[CH:46][CH:47]=1)=[O:41].C(N(CC)CC)C>CN(C=O)C.CCOC(C)=O.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>[C:24]1([C:22]2[N:23]=[C:19]([C:15]3[CH:14]([CH2:13][C:9]4[CH:10]=[C:11]([C:44]5[CH:45]=[CH:46][CH:47]=[C:42]([C:40]([O:39][CH3:38])=[O:41])[CH:43]=5)[CH:12]=[CH:7][CH:8]=4)[CH2:18][CH2:17][CH:16]=3)[O:20][C:21]=2[C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=2)[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1
Reactant: COC(=O)c1cccc(B(O)O)c1
Reactant: O=S(=O)(Oc1cccc(CC2CCC=C2c2nc(-c3ccccc3)c(-c3ccccc3)o2)c1)C(F)(F)F
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: COC(=O)c1cccc(-c2cccc(CC3CCC=C3c3nc(-c4ccccc4)c(-c4ccccc4)o3)c2)c1
Temperature: 100 °C
Reaction time: 3.5 h
Yield: 68 %

Procedure:
A mixture of 3-{[2-(4,5-diphenyloxazol-2-yl)-2-cyclopenten-1-yl]methyl}phenyl trifluoromethanesulfonate (400 mg), 3-methoxycarbonylphenylboronic acid (177 mg), triethylamine (0.318 ml), and tetrakis(triphenylphosphine)palladium(0) (64 mg) in DMF (8 ml) was stirred at 100° C. for 3.5 hours. After cooling to room temperature, the reaction mixture was diluted with EtOAc, washed with water, 1N HCl, water, saturated sodium hydrogen carbonate, water, and brine, dried over magnesium sulfate, evaporated in vacuo. The residue was purified by silica gel column chromatography (hexane-EtOAc 10:1) to give methyl 3′-{[2-(4,5-diphenyloxazol-2-yl)-2-cyclopenten-1-yl]-methyl}biphenyl-3-carboxylate (264.6 mg) as an oil.
Reaction SMILES: [C:1]([C:4]([CH:17]1[CH2:21][CH2:20][NH:19][CH2:18]1)([C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)[C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1)(=[O:3])[NH2:2].[F:22][C:23]1[CH:31]=[CH:30][C:26]([CH2:27][CH2:28]Br)=[CH:25][CH:24]=1.C(=O)([O-])[O-].[K+].[K+].C(#N)C>O>[C:1]([C:4]([CH:17]1[CH2:21][CH2:20][N:19]([CH2:28][CH2:27][C:26]2[CH:30]=[CH:31][C:23]([F:22])=[CH:24][CH:25]=2)[CH2:18]1)([C:11]1[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=1)[C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1)(=[O:3])[NH2:2]
Reactant: Fc1ccc(CCBr)cc1
Reactant: NC(=O)C(c1ccccc1)(c1ccccc1)C1CCNC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Solvent: O
Product: NC(=O)C(c1ccccc1)(c1ccccc1)C1CCN(CCc2ccc(F)cc2)C1
Temperature: 25 °C

Procedure:
A mixture containing 3-(R,S)-(1-carbamoyl-1,1-diphenylmethyl)pyrrolidine (0.5 g--see Preparation 8), 4-fluorophenethyl bromide (0.36 g--see J.A.C.S., 63, 602 (1941)), anhydrous potassium carbonate (0.5 g) and acetonitrile (15 ml) was heated under reflux for 2 hours. On cooling to room temperature, water (70 ml) was added and the mixture was extracted with dichloromethane (3×50 ml). The combined dichloromethane extracts were dried (MgSO4) and concentrated in vacuo to give a glass which was purified by column chromatography on silica eluting with dichloromethane containing methanol (2% up to 4%). The product-containing fractions were combined and concentrated in vacuo to give the title compound as a colourless glass, yield, 0.056 g.
Reaction SMILES: [C:1]([NH:4][C:5]1[S:6][C:7]([C:11]2[S:15][C:14]([S:16](Cl)(=[O:18])=[O:17])=[CH:13][CH:12]=2)=[C:8]([CH3:10])[N:9]=1)(=[O:3])[CH3:2].[CH3:20][N:21]([CH3:26])[CH2:22][CH2:23][CH2:24][NH2:25].CCN(C(C)C)C(C)C.O>C(Cl)Cl>[CH3:20][N:21]([CH3:26])[CH2:22][CH2:23][CH2:24][NH:25][S:16]([C:14]1[S:15][C:11]([C:7]2[S:6][C:5]([NH:4][C:1](=[O:3])[CH3:2])=[N:9][C:8]=2[CH3:10])=[CH:12][CH:13]=1)(=[O:18])=[O:17]
Reactant: CN(C)CCCN
Reactant: CC(=O)Nc1nc(C)c(-c2ccc(S(=O)(=O)Cl)s2)s1
Solvent: ClCCl
Solvent: O
Solvent: CCN(C(C)C)C(C)C
Product: CC(=O)Nc1nc(C)c(-c2ccc(S(=O)(=O)NCCCN(C)C)s2)s1

Procedure:
5-[2-(acetylamino)-4-methyl-1,3-thiazol-5-yl]thiophene-2-sulfonyl chloride, prepared as in Step II of Example 1 (280 mg; 0.84 mmol; 1 eq), is dissolved in DCM (10 ml). N,N-dimethylpropane-1,3-diamine (0.89 ml; 8.4 mmol; 10 eq) and DIEA (0.17 ml; 0.98 mmol; 3 eq) are added. After one night reaction, water (1 ml) is added and the solvents are evaporated to dryness. The crude product is re-dissolved in DCM and washed with NH4Cl saturated solution, water and dried over MgSO4. After evaporation of the solvents, crude material is precipitated in a mixture of DCM and diethyl ether, affording after filtration, Compound (10) as a white solid (105 mg; 28%).
Reaction SMILES: [CH3:1][N:2]([CH3:22])[C:3](=[O:21])[O:4][C:5]1[CH:10]=[CH:9][CH:8]=[C:7]([NH:11][C:12]([C:14]2([CH3:20])[CH2:19][CH2:18][NH:17][CH2:16][CH2:15]2)=[O:13])[CH:6]=1.Cl[C:24]1[C:25]2[C:32]([CH3:33])=[CH:31][NH:30][C:26]=2[N:27]=[CH:28][N:29]=1.C(N(CC)C(C)C)(C)C>C(O)(C)C>[CH3:22][N:2]([CH3:1])[C:3](=[O:21])[O:4][C:5]1[CH:10]=[CH:9][CH:8]=[C:7]([NH:11][C:12]([C:14]2([CH3:20])[CH2:15][CH2:16][N:17]([C:24]3[C:25]4[C:32]([CH3:33])=[CH:31][NH:30][C:26]=4[N:27]=[CH:28][N:29]=3)[CH2:18][CH2:19]2)=[O:13])[CH:6]=1
Reactant: CN(C)C(=O)Oc1cccc(NC(=O)C2(C)CCNCC2)c1
Reactant: Cc1c[nH]c2ncnc(Cl)c12
Solvent: CCN(C(C)C)C(C)C
Solvent: CC(C)O
Product: Cc1c[nH]c2ncnc(N3CCC(C)(C(=O)Nc4cccc(OC(=O)N(C)C)c4)CC3)c12
Temperature: 100 °C
Yield: 53 %

Procedure:
3-(4-methylpiperidine-4-carboxamido)phenyl dimethylcarbamate from step B (47 mg, 0. 14 mmol) 4-chloro-5-methyl-7H-pyrrolo[2,3-d]pyrimidine (23 mg, 0.138 mmol), N,N-diisopropylethylamine (54 mg, 0.41 mmol), and isopropanol (1.0 mL) were combined in a pressure rated sealed tube and heated at 100° C. for 18 hours. The mixture was concentrated, and the residue was purified by preparative HPLC to give the title compound in 53% yield.
Reaction SMILES: Cl[C:2]1[N:7]=[CH:6][N:5]=[C:4]([NH:8][C:9]2[CH:10]=[C:11]([CH2:15][S:16]([NH2:19])(=[O:18])=[O:17])[CH:12]=[CH:13][CH:14]=2)[N:3]=1.Cl.[N:21]1[C:26]2[CH2:27][CH2:28][NH:29][CH2:30][C:25]=2[CH:24]=[N:23][CH:22]=1>>[N:21]1[C:26]2[CH2:27][CH2:28][N:29]([C:2]3[N:7]=[CH:6][N:5]=[C:4]([NH:8][C:9]4[CH:10]=[C:11]([CH2:15][S:16]([NH2:19])(=[O:18])=[O:17])[CH:12]=[CH:13][CH:14]=4)[N:3]=3)[CH2:30][C:25]=2[CH:24]=[N:23][CH:22]=1
Reactant: NS(=O)(=O)Cc1cccc(Nc2ncnc(Cl)n2)c1
Reactant: c1ncc2c(n1)CCNC2
Agent: Cl
Product: NS(=O)(=O)Cc1cccc(Nc2ncnc(N3CCc4ncncc4C3)n2)c1

Procedure:
B39 was prepared following the general procedure reported for B10 using A1 and 5,6,7,8-tetrahydropyrido[4,3-d]pyrimidine hydrochloride; yield: 29.7 mg (7%), pale yellow solid. MS (ES) C17H18N8O2S requires: 398. found: 399 (M+H)+.
Reaction SMILES: C(C1N=C(N2CCOCC2)C2N=NN(CC3C=CC=CC=3Cl)C=2N=1)(C)(C)C.[C:28]([C:32]1[N:33]=[C:34](Cl)[C:35]2[N:40]=[N:39][N:38]([CH2:41][C:42]3[CH:47]=[CH:46][CH:45]=[CH:44][C:43]=3[Cl:48])[C:36]=2[N:37]=1)([CH3:31])([CH3:30])[CH3:29].[F:50][C@@H:51]1[CH2:55][NH:54][C@H:53]([C:56]#[N:57])[CH2:52]1>>[C:28]([C:32]1[N:33]=[C:34]([N:54]2[CH2:55][C@@H:51]([F:50])[CH2:52][C@H:53]2[C:56]#[N:57])[C:35]2[N:40]=[N:39][N:38]([CH2:41][C:42]3[CH:47]=[CH:46][CH:45]=[CH:44][C:43]=3[Cl:48])[C:36]=2[N:37]=1)([CH3:31])([CH3:30])[CH3:29]
Reactant: CC(C)(C)c1nc(Cl)c2nnn(Cc3ccccc3Cl)c2n1
Reactant: N#C[C@@H]1C[C@H](F)CN1
Agent: CC(C)(C)c1nc(N2CCOCC2)c2nnn(Cc3ccccc3Cl)c2n1
Product: CC(C)(C)c1nc(N2C[C@@H](F)C[C@H]2C#N)c2nnn(Cc3ccccc3Cl)c2n1

Procedure:
In analogy to the procedure described for the synthesis of 5-tert-butyl-3-(2-chloro-benzyl)-7-morpholin-4-yl-3H-[1,2,3]triazolo[4,5-d]pyrimidine (example 1, step c), the title compound was prepared from 5-tert-butyl-7-chloro-3-(2-chlorobenzyl)-3H-[1,2,3]triazolo[4,5-d]pyrimidine and (2S,4S)-4-fluoropyrrolidine-2-carbonitrile and isolated as light-yellow gum (10.6 mg, 54%). MS(m/e): 414.4 (MH+).
Reaction SMILES: [C:1]1([CH:7]([O:14][C:15]([C:17]2[N:18]3[C@H:21]([S:22][CH2:23][C:24]=2[CH2:25][S:26][C:27]2[N:32]4[N:33]=[C:34]([C:36]([O:38][CH:39]([C:46]5[CH:51]=[CH:50][CH:49]=[CH:48][CH:47]=5)[C:40]5[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=5)=[O:37])[N:35]=[C:31]4[N:30]=[C:29]([CH3:52])[CH:28]=2)[C@H:20]([NH:53][C:54](=[O:83])/[C:55](/[C:58]2[N:59]=[C:60]([NH:63][C:64]([C:77]4[CH:82]=[CH:81][CH:80]=[CH:79][CH:78]=4)([C:71]4[CH:76]=[CH:75][CH:74]=[CH:73][CH:72]=4)[C:65]4[CH:70]=[CH:69][CH:68]=[CH:67][CH:66]=4)[S:61][CH:62]=2)=[N:56]\[OH:57])[C:19]3=[O:84])=[O:16])[C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C(=O)([O-])[O-].[K+].[K+].[Cl:91][CH2:92][C:93]([O:95][C:96]1[CH:97]=[C:98]([CH:102]=[C:103]([O:110][C:111](=[O:114])[CH2:112][Cl:113])[C:104]=1[O:105][C:106](=[O:109])[CH2:107][Cl:108])[C:99](Cl)=[O:100])=[O:94]>ClCCl>[C:1]1([CH:7]([O:14][C:15]([C:17]2[N:18]3[C@H:21]([S:22][CH2:23][C:24]=2[CH2:25][S:26][C:27]2[N:32]4[N:33]=[C:34]([C:36]([O:38][CH:39]([C:40]5[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=5)[C:46]5[CH:51]=[CH:50][CH:49]=[CH:48][CH:47]=5)=[O:37])[N:35]=[C:31]4[N:30]=[C:29]([CH3:52])[CH:28]=2)[C@H:20]([NH:53][C:54](=[O:83])/[C:55](/[C:58]2[N:59]=[C:60]([NH:63][C:64]([C:71]4[CH:76]=[CH:75][CH:74]=[CH:73][CH:72]=4)([C:77]4[CH:78]=[CH:79][CH:80]=[CH:81][CH:82]=4)[C:65]4[CH:66]=[CH:67][CH:68]=[CH:69][CH:70]=4)[S:61][CH:62]=2)=[N:56]\[O:57][C:99](=[O:100])[C:98]2[CH:97]=[C:96]([O:95][C:93](=[O:94])[CH2:92][Cl:91])[C:104]([O:105][C:106](=[O:109])[CH2:107][Cl:108])=[C:103]([O:110][C:111](=[O:114])[CH2:112][Cl:113])[CH:102]=2)[C:19]3=[O:84])=[O:16])[C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: Cc1cc(SCC2=C(C(=O)OC(c3ccccc3)c3ccccc3)N3C(=O)[C@@H](NC(=O)/C(=N\O)c4csc(NC(c5ccccc5)(c5ccccc5)c5ccccc5)n4)[C@H]3SC2)n2nc(C(=O)OC(c3ccccc3)c3ccccc3)nc2n1
Reactant: O=C(CCl)Oc1cc(C(=O)Cl)cc(OC(=O)CCl)c1OC(=O)CCl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: ClCCl
Product: Cc1cc(SCC2=C(C(=O)OC(c3ccccc3)c3ccccc3)N3C(=O)[C@@H](NC(=O)/C(=N\OC(=O)c4cc(OC(=O)CCl)c(OC(=O)CCl)c(OC(=O)CCl)c4)c4csc(NC(c5ccccc5)(c5ccccc5)c5ccccc5)n4)[C@H]3SC2)n2nc(C(=O)OC(c3ccccc3)c3ccccc3)nc2n1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 99 %

Procedure:
To an ice-cooled solution of (6R,7R)-7-[2-(2-triphenylmethylamino-4-thiazolyl)-2-(Z-hydroxyimino)acetamido]-3-[(2-diphenylmethyloxycarbonyl-5-methyl-s-triazolo[1,5-a]pyrimidin-7-yl)thiomethyl]-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylic acid diphenylmethyl ester (0.7 g) in dry dichloromethane (17 ml) was added potassium carbonate (0.1 g) all at once, followed by dropwise addition of a solution of 3,4,5-tris(chloroacetoxy)benzoyl chloride (0.376 g) in dry dichloromethane (10 ml) over a period of five minutes, and the yellow mixture was stirred at 0° C. for 30 minutes. After filtering off the insoluble matters, the filtrate was concentrated under reduced pressure, and the yellow residue was crystallized with ether (50 ml), giving 0.92 g of the objective compound as pale yellow crystals.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][N:5]=[C:4]([CH3:8])[CH:3]=1.[C:9]([O:13][CH2:14][CH3:15])(=[O:12])[CH:10]=[CH2:11].C1(C)C=CC=CC=1P(C1C=CC=CC=1C)C1C=CC=CC=1C.C(N(CC)CC)C>CN(C=O)C.C([O-])(=O)C.[Pd+2].C([O-])(=O)C.O>[CH3:8][C:4]1[CH:3]=[C:2](/[CH:11]=[CH:10]/[C:9]([O:13][CH2:14][CH3:15])=[O:12])[CH:7]=[CH:6][N:5]=1
Reactant: C=CC(=O)OCC
Reactant: Cc1cc(Br)ccn1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: Cc1ccccc1P(c1ccccc1C)c1ccccc1C
Solvent: CCN(CC)CC
Solvent: O
Solvent: CN(C)C=O
Product: CCOC(=O)/C=C/c1ccnc(C)c1
Temperature: 100 °C
Reaction time: 1 h

Procedure:
Under an argon atmosphere, to a solution of 4-bromo-2-methylpyridine (1.78 mL) in DMF (35 mL) were added ethyl acrylate (8.13 mL), palladium (II) acetate (168 mg), tri-o-tolylphosphine (685 mg) and triethylamine (6.27 mL), and the mixture was stirred at 100° C. for 1 hr. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The extract was washed with water and saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure to give a crude product of the title compound as a yellow oil. This compound was used for the next step without further purification.
Reaction SMILES: [CH2:1]([NH:3][CH2:4][CH2:5][CH2:6][CH:7]([C:9]1[CH:14]=[CH:13][C:12]([NH:15][S:16]([CH3:19])(=[O:18])=[O:17])=[CH:11][CH:10]=1)[OH:8])[CH3:2].C(=O)(O)[O-].[Na+].[CH:25]1([CH2:28][CH2:29][CH2:30][CH2:31][CH2:32]I)[CH2:27][CH2:26]1>C(#N)C>[CH2:1]([N:3]([CH2:32][CH2:31][CH2:30][CH2:29][CH2:28][CH:25]1[CH2:27][CH2:26]1)[CH2:4][CH2:5][CH2:6][CH:7]([C:9]1[CH:10]=[CH:11][C:12]([NH:15][S:16]([CH3:19])(=[O:17])=[O:18])=[CH:13][CH:14]=1)[OH:8])[CH3:2]
Reactant: ICCCCCC1CC1
Reactant: CCNCCCC(O)c1ccc(NS(C)(=O)=O)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC#N
Product: CCN(CCCCCC1CC1)CCCC(O)c1ccc(NS(C)(=O)=O)cc1

Procedure:
According to Procedure B (Example 17, Step IV), a stirred mixture of N-[4-[4-(ethylamino)-1-hydroxybutyl]phenyl]methanesulfonamide (Example 7, Step II) and sodium bicarbonate in acetonitrile was allowed to react with 1-cyclopropyl-5-iodopentane (Step II) to give N-[4-[4-[ethyl(5-cyclopropylpentyl)amino]-1-hydroxybutyl]phenyl]methanesulfonamide, a compound of Formula I'. A mixture of this compound and 0.5 equivalents of fumaric acid was crystallized from acetone to give the titled product, mp 127°-128° C. Anal. calc'd for C23H38N2O5S: C, 60.76; H, 8.42; N, 6.16; S, 7.05. Found: C, 60.66; H, 8.30; N, 6.17; S, 7.04.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-])=O)=[CH:4][C:3]=1[NH:11][C:12]1[O:13][C:14]([C:17]2[CH:18]=[N:19][CH:20]=[CH:21][CH:22]=2)=[CH:15][N:16]=1.O.O.[Sn](Cl)Cl>C(O)C>[CH3:1][C:2]1[CH:7]=[CH:6][C:5]([NH2:8])=[CH:4][C:3]=1[NH:11][C:12]1[O:13][C:14]([C:17]2[CH:18]=[N:19][CH:20]=[CH:21][CH:22]=2)=[CH:15][N:16]=1
Reactant: Cc1ccc([N+](=O)[O-])cc1Nc1ncc(-c2cccnc2)o1
Agent: Cl[Sn]Cl
Solvent: CCO
Solvent: O
Product: Cc1ccc(N)cc1Nc1ncc(-c2cccnc2)o1
Yield: 65.1 %

Procedure:
To a solution of (2-methyl-5-nitro-phenyl)-(5-pyridin-3-yl-oxazol-2-yl)-amine (600 mg, 2.02 mmol) in ethanol (20 mL) was added tin(II) chloride dihydrate (2.50 g, 10 mmol). The reaction mixture was heated under reflux for 6 h. The mixture was then concentrated, saturated aqueous NaHCO3 was added and the resultant suspension was extracted with ethyl acetate (3×20 mL). The combined organic layers were washed with brine (20 mL), dried over anhydrous MgSO4 and concentrated. The residue was silica gel column chromatographed (dichloromethane/ethanol:97/3). 350 mg (65%) of (2-methyl-5-amino-phenyl)-(5-pyridin-3-yl-oxazol-2-yl)-amine was obtained as pale yellow powder.
Reaction SMILES: [OH:1][C:2]1[CH:11]=[CH:10][C:5]([C:6]([O:8][CH3:9])=[O:7])=[CH:4][C:3]=1[CH2:12][CH2:13][CH3:14].C(=O)([O-])[O-].[Cs+].[Cs+].Br[CH:22]([C:28]1[CH:33]=[CH:32][C:31]2OC[O:36][C:30]=2[CH:29]=1)[C:23]([O:25][CH2:26][CH3:27])=[O:24].CN([CH:40]=[O:41])C>>[C:6]([C:5]1[CH:10]=[CH:11][C:2]([O:1][CH:22]([C:28]2[CH:29]=[C:30]([OH:36])[C:31]3[CH2:33][C:32]=3[C:40]=2[OH:41])[C:23]([O:25][CH2:26][CH3:27])=[O:24])=[C:3]([CH2:12][CH2:13][CH3:14])[CH:4]=1)([O:8][CH3:9])=[O:7]
Reactant: CCOC(=O)C(Br)c1ccc2c(c1)OCO2
Reactant: CN(C)C=O
Reactant: CCCc1cc(C(=O)OC)ccc1O
Agent: O=C([O-])[O-]
Agent: [Cs+]
Product: CCCc1cc(C(=O)OC)ccc1OC(C(=O)OCC)c1cc(O)c2c(c1O)C2
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a 2 L three necked 24/40 round bottom flask equipped with a mechanical stirrer, a nitrogen inlet and a dropping funnel was first added a solution of 36.0 g (0.185 mol) of methyl 4-hydroxy-3-n-propylbenzoate dissolved in 700 mL of anhydrous DMF followed by 66.4 g (0.204 mol) of cesium carbonate. The flask was purged with nitrogen and the reaction mixture was stirred at room temperature for 2 hours. A solution of 58.5 g (0.204 mol) of ethyl α-bromo-3,4-methylenedioxyphenylacetate dissolved in 100 mL of DMF was then added via an addition funnel over a 15 minute period. The reaction mixture was stirred an additional 1 hour at room temperature then quenched by addition to 5 L of a 5% aqueous citric acid solution. The organic product was extracted into diethylether (2×4 L), the organic layers were separated, washed with saturated aqueous NaCl, dried (MgSO4), filtered, and evaporated. The residue was applied to a silica gel (2 kg; 70-230 mesh) column equilibrated in 10% CH2 Cl2 -hexane. The column was then eluted successively with 12 L of 10% CH2Cl2 -hexane, 12 L of 5% EtOAc-hexane, 4 L of 7.5% EtOAc-hexane, 12 L of 10% EtOAc-hexane, and finally 8 L of 20% EtOAc-hexane. Combination of the purified fractions and evaporation in vacuo afforded 76.3 g (74.2 theoretical) of the title compound as a pale yellow oil which was used without further purification in the next step.
Reaction SMILES: [NH2:1][C:2]1[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[CH:4][CH:3]=1.[CH3:10][O:11][C:12](=[O:24])[C:13]1[CH:18]=[CH:17][CH:16]=[C:15]([O:19][CH2:20][C:21](O)=[O:22])[CH:14]=1.P(Cl)(Cl)(Cl)=O>N1C=CC=CC=1.O>[CH3:10][O:11][C:12](=[O:24])[C:13]1[CH:18]=[CH:17][CH:16]=[C:15]([O:19][CH2:20][C:21](=[O:22])[NH:1][C:2]2[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[CH:4][CH:3]=2)[CH:14]=1
Reactant: N#Cc1ccc(N)cc1
Reactant: COC(=O)c1cccc(OCC(=O)O)c1
Solvent: c1ccncc1
Solvent: O=P(Cl)(Cl)Cl
Solvent: O
Product: COC(=O)c1cccc(OCC(=O)Nc2ccc(C#N)cc2)c1
Temperature: 0 °C
Reaction time: 2 h
Yield: 86.6 %

Procedure:
Cool a solution of 4-aminobenzonitrile (0.48 g, 4.02 mmol) in pyridine (30 mL), to 0° C., and add 3-carboxymethoxy-benzoic acid methyl ester (0.79 g, 3.76 mmol) followed by phosphorous oxychloride (0.38 mL, 4.02 mmol). Stir the mixture at 0° C. for 2 h then dilute with water causing a solid to precipitate from solution. Collect the solid by filtration, wash with water, and dry on the filter pad to provide 1.01 g (81.0%) of 3-[(4-cyano-phenylcarbamoyl)-methoxy]-benzoic acid methyl ester.
Reaction SMILES: CO[CH:3](OC)[C:4](=[N:7][OH:8])[C:5]#[N:6].[OH:11][CH2:12][CH2:13][NH:14][NH2:15].[ClH:16]>C(O)C>[ClH:16].[NH2:6][C:5]1[N:14]([CH2:13][CH2:12][OH:11])[N:15]=[CH:3][C:4]=1[N:7]=[O:8]
Reactant: NNCCO
Reactant: COC(OC)C(C#N)=NO
Agent: Cl
Solvent: CCO
Product: Nc1c(N=O)cnn1CCO
Temperature: 76.5 °C
Yield: 91.5 %

Procedure:
To a flask having an inner volume of 200 ml and equipped with a stirring device, a thermometer and a reflux condenser were charged 16.86 g (110 mmol) of 3,3-dimethoxy-2-hydroxyiminopropionitrile with a purity of 94.0% by weight synthesized in the same manner as in Example. 1, 8.02 g (100 mmol) of 2-hydroxyethylhydrazine with a purity of 95% by weight, 100 ml of ethanol and 10 ml (120 mmol) of conc. hydrochloric acid, and the mixture was reacted under reflux (76 to 77° C.) for one hour. After completion of the reaction, when the reaction mixture was analyzed by high performance liquid chromatography (absolute calibration curve method), it was found that 17.62 g of 5-amino-1-(2-hydroxyethyl)-4-nitrosopyrazole hydrochloride (Reaction yield: 91.5%) had been formed.
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[CH:9][C:8]2[NH:7][C:6]3[CH2:11][CH2:12][N:13]([CH3:15])[CH2:14][C:5]=3[C:4]=2[CH:3]=1.[CH:16]([C:18]1[CH:19]=[CH:20][C:21](=[O:24])[NH:22][CH:23]=1)=[CH2:17].[OH-].[K+]>CN1C(=O)CCC1>[Cl:1][C:2]1[CH:10]=[CH:9][C:8]2[N:7]([CH2:17][CH2:16][C:18]3[CH:19]=[CH:20][C:21](=[O:24])[NH:22][CH:23]=3)[C:6]3[CH2:11][CH2:12][N:13]([CH3:15])[CH2:14][C:5]=3[C:4]=2[CH:3]=1
Reactant: CN1CCc2[nH]c3ccc(Cl)cc3c2C1
Reactant: C=Cc1ccc(=O)[nH]c1
Agent: [K+]
Agent: [OH-]
Solvent: CN1CCCC1=O
Product: CN1CCc2c(c3cc(Cl)ccc3n2CCc2ccc(=O)[nH]c2)C1

Procedure:
The title compound is prepared from a mixture of 8-chloro-2,3,4,5-tetrahydro-2-methyl-1H-pyrido[4,3-b]indole, 5-vinylpyridin-2(1H)-one and KOH (5-7 equiv) in NMP at a temperature ranging between 25 deg C. to 100 deg C. The product obtained is isolated by preparative HPLC.
Reaction SMILES: [CH3:1][C:2]1[C:3]([C:11]2[S:12][CH:13]=[CH:14][CH:15]=2)=[N:4][NH:5][C:6]=1[C:7]([F:10])([F:9])[F:8].C([Li])CCC.CCCCCC.Cl[C:28]([O:30]CC)=[O:29]>>[CH3:1][C:2]1[C:3]([C:11]2[S:12][C:13]([C:28]([OH:30])=[O:29])=[CH:14][CH:15]=2)=[N:4][NH:5][C:6]=1[C:7]([F:8])([F:10])[F:9]
Reactant: CCOC(=O)Cl
Reactant: Cc1c(-c2cccs2)n[nH]c1C(F)(F)F
Agent: [Li]CCCC
Solvent: CCCCCC
Product: Cc1c(-c2ccc(C(=O)O)s2)n[nH]c1C(F)(F)F
Reaction time: 0.5 h

Procedure:
4-Methyl-3-(2-thienyl)-5-trifluoromethyl-1H-pyrazole was allowed to react with an n-butyl lithium -n-hexane solution (1.6 M). Further, ethyl chloroformate was added at −50° C. or below. After stirring at −50° C. or below for 30 minutes, it was subjected to purification in the usual way to give a yellow oil. By hydrolyzing this in the usual way, 5-(4-methyl-5-trifluoromethyl-1H-pyrazol-3-yl)thiophene-2-carboxylic acid was obtained as colorless powder crystals.
Reaction SMILES: CO.[OH-].[Na+].[O:5]1[CH2:10][CH2:9][CH:8]([CH2:11][C:12]([O:14]CC)=[O:13])[CH2:7][CH2:6]1>O>[O:5]1[CH2:10][CH2:9][CH:8]([CH2:11][C:12]([OH:14])=[O:13])[CH2:7][CH2:6]1
Reactant: CCOC(=O)CC1CCOCC1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: O=C(O)CC1CCOCC1
Temperature: 80 °C
Reaction time: 1 h

Procedure:
20 ml of methanol, 10 ml of water and 1 g of sodium hydroxide were added to 0.9 g of ethyl 4-tetrahydropyranylacetate and agitated at 80° C. for 1 hour. The solvent was removed by distillation, to which water was added. After washing with ethyl acetate, a hydrochloric acid aqueous solution was added to the resultant aqueous phase to an extent of pH of 3, followed by extraction with chloroform under salting-out conditions and drying with anhydrous magnesium sulfate. This was removed by filtration and the solvent was distilled off, thereby obtaining 0.87 g of a crude intended compound.
Reaction SMILES: [C:1]([O:5][C:6](=[O:31])[CH2:7][C:8]1[CH:24]=[CH:23][C:11]([O:12][C:13]2[CH:22]=[CH:21][C:16]([C:17]([O:19][CH3:20])=[O:18])=[CH:15][CH:14]=2)=[C:10]([CH2:25][NH:26][S:27]([CH3:30])(=[O:29])=[O:28])[CH:9]=1)([CH3:4])([CH3:3])[CH3:2].CI.[C:34]([O-])([O-])=O.[K+].[K+]>CN(C=O)C.C(OCC)(=O)C.Cl>[C:1]([O:5][C:6](=[O:31])[CH2:7][C:8]1[CH:24]=[CH:23][C:11]([O:12][C:13]2[CH:14]=[CH:15][C:16]([C:17]([O:19][CH3:20])=[O:18])=[CH:21][CH:22]=2)=[C:10]([CH2:25][N:26]([CH3:34])[S:27]([CH3:30])(=[O:29])=[O:28])[CH:9]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: O=C([O-])[O-]
Reactant: COC(=O)c1ccc(Oc2ccc(CC(=O)OC(C)(C)C)cc2CNS(C)(=O)=O)cc1
Agent: Cl
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Solvent: CI
Product: COC(=O)c1ccc(Oc2ccc(CC(=O)OC(C)(C)C)cc2CN(C)S(C)(=O)=O)cc1
Temperature: 25 °C
Reaction time: 3 h
Yield: 48.1 %

Procedure:
To a stirred solution of the methyl 4-(4-(2-tert-butoxy-2-oxoethyl)-2-(methylsulfonamidomethyl)phenoxy)benzoate (745 mg, 1.65 mmol) in DMF (10 ml) was added MeI (155 μL, 2.48 mmol) followed by K2CO3 (343 mg, 2.48 mmol). The reaction was stirred at ambient temperature for 3 hours, then diluted with ethyl acetate and 2M HCl. The aqueous phase was extracted with ethyl acetate, and the combined organic layers were washed with brine and dried over MgSO4. The crude mixture was purified by silica gel chromatography to give methyl 4-(4-(2-tert-butoxy-2-oxoethyl)-2-((N-methylmethylsulfonamido)methyl)phenoxy)benzoate (0.368 g).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([C:11]2[NH:15][N:14]=[C:13]([CH3:16])[C:12]=2[NH2:17])[CH:6]=[CH:7][C:8]=1[O:9][CH3:10].[C:18](Cl)(=[O:25])[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1>>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([C:11]2[NH:15][N:14]=[C:13]([CH3:16])[C:12]=2[NH:17][C:18](=[O:25])[C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[CH:6]=[CH:7][C:8]=1[O:9][CH3:10]
Reactant: O=C(Cl)c1ccccc1
Reactant: COc1ccc(-c2[nH]nc(C)c2N)cc1OC
Product: COc1ccc(-c2[nH]nc(C)c2NC(=O)c2ccccc2)cc1OC

Procedure:
The preparation took place in analogy with Example 15a), starting with 500 mg of 5-(3,4-dimethoxyphenyl)-3-methyl-1H-pyrazol-4-ylamine (44) and 280 μl of benzoyl chloride. The following was obtained: 45