Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N+:1]([O-:4])([O-])=[O:2].[K+].Cl.[CH:7]1[N:11]2[C:12]3[CH2:23][C:22]4[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=4[C:13]=3[NH:14][C:15](=[O:16])[C:10]2=[N:9][CH:8]=1>S(=O)(=O)(O)O>[N+:1]([C:20]1[CH:19]=[CH:18][C:17]2[C:13]3[NH:14][C:15](=[O:16])[C:10]4[N:11]([CH:7]=[CH:8][N:9]=4)[C:12]=3[CH2:23][C:22]=2[CH:21]=1)([O-:4])=[O:2]
Reactant: O=c1[nH]c2c(n3ccnc13)Cc1ccccc1-2
Reactant: O=[N+]([O-])[O-]
Agent: Cl
Agent: O=S(=O)(O)O
Agent: [K+]
Product: O=c1[nH]c2c(n3ccnc13)Cc1cc([N+](=O)[O-])ccc1-2
Temperature: 25 °C
Reaction time: 3 h
Yield: 79.2 %

Procedure:
5H,10H-8--Nitroimidazo[1,2-a]indeno[1,2-e]-pyrazin-4-one may be prepared in the following way: 1 g of potassium nitrate is added over 10 minutes, at a temperature in the region of 5° C., to a solution of 2.6 g of 5H,10H-imidazo[1,2-a]indeno[1,2-e]pyrazin-4-one hydrochloride in 20 ml of concentrated sulphuric acid (d=1.83). The mixture is stirred for 30 minutes at the same temperature and for 3 hours at 25° C., then is poured onto 150 ml of ice-water. The crystals formed are isolated by filtration, washed with distilled water and then with acetone and dried under reduced pressure (1 mmHg; 0.13 kPa) at 80° C. 2.1 g of 8-nitro-5H,10H-imidazo[1,2-a]indeno[1,2-e]pyrazin-4-one are thus obtained, decomposing without melting above 300° C. [NMR spectrum: (200 MHz; DMSO-d6 ; δ in ppm): 4.23 (s, 2H: --CH2-- at 10); 7.68 and 8.12 (2 broad s, 1H each: --H of the imidazole); 8.07 (dd, J=8.5 Hz, 1H: --H6); 8.38 (dd, J=8.5 and 1.5 Hz, 1H: --H7; 8.50 (d, J=1.5 Hz, 1H: --H9); 12.64 (mult., 1H: --CONH--)].
Reaction SMILES: NN.CC([CH2:7][N:8]([CH2:12][CH:13]([N:21]1C(=O)C2C(=CC=CC=2)C1=O)[CH2:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)[C:9](=[O:11])[O-:10])(C)C>C1COCC1.CO>[NH2:21][CH:13]([CH2:14][C:15]1[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=1)[CH2:12][N:8]([CH3:7])[C:9](=[O:11])[O:10][C:15]([CH3:20])([CH3:16])[CH3:14]
Reactant: CC(C)(C)CN(CC(Cc1ccccc1)N1C(=O)c2ccccc2C1=O)C(=O)[O-]
Agent: NN
Solvent: C1CCOC1
Solvent: CO
Product: CN(CC(N)Cc1ccccc1)C(=O)OC(C)(C)C
Reaction time: 8 h
Yield: 0.6 %

Procedure:
NH2NH2 (7 mL, 0.2 mol) was added to a THF/MeOH (100 mL/25 mL) solution of 1,1-dimethylethyl[2-(1,3-dioxo-1,3-dihydro-2H-isoindol-2-yl)-3-phenylpropyl]methylcarbamate (2.7 g, 6.8 mmol) and stirred overnight. After 12 hours, the solution was absorbed onto silica and purified by column chromatography using 5% MeOH in CHCl3 containing 0.5% NH4OH to give the title compound (5.8 mg, 88%) as a white solid: LC-MS (ES) m/z=265 (M+H)+.
Reaction SMILES: Br[C:2]1[CH:17]=[CH:16][C:5]([C:6]([O:8][CH2:9][C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)=[O:7])=[C:4]([CH3:18])[CH:3]=1.[F:19][C:20]1[CH:21]=[CH:22][C:23]([OH:29])=[C:24](B(O)O)[CH:25]=1>>[F:19][C:20]1[CH:25]=[CH:24][C:23]([OH:29])=[C:22]([C:2]2[CH:17]=[CH:16][C:5]([C:6]([O:8][CH2:9][C:10]3[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=3)=[O:7])=[C:4]([CH3:18])[CH:3]=2)[CH:21]=1
Reactant: Cc1cc(Br)ccc1C(=O)OCc1ccccc1
Reactant: OB(O)c1cc(F)ccc1O
Product: Cc1cc(-c2cc(F)ccc2O)ccc1C(=O)OCc1ccccc1

Procedure:
In accordance with the method of Example 1-3, the compound of Example 15-1 was used instead of the compound of Example 1-2, and 5-fluoro-2-hydroxyphenylboronic acid was used instead of 2-hydroxyphenylboronic acid to afford benzyl 5′-fluoro-2′-hydroxy-3-methylbiphenyl-4-carboxylate.
Reaction SMILES: [O:1]=[S:2]1(=[O:42])[C:8]2[CH:9]=[C:10]([O:13][CH2:14][C:15]([O:17]CC)=[O:16])[CH:11]=[CH:12][C:7]=2[N:6]([C:20]2[CH:25]=[CH:24][C:23]([NH:26][C:27]([O:29][C:30]([CH3:33])([CH3:32])[CH3:31])=[O:28])=[CH:22][CH:21]=2)[CH2:5][C:4]([CH2:38][CH2:39][CH2:40][CH3:41])([CH2:34][CH2:35][CH2:36][CH3:37])[CH2:3]1.O.[Li+].[OH-].Cl>C1COCC1>[O:42]=[S:2]1(=[O:1])[C:8]2[CH:9]=[C:10]([O:13][CH2:14][C:15]([OH:17])=[O:16])[CH:11]=[CH:12][C:7]=2[N:6]([C:20]2[CH:25]=[CH:24][C:23]([NH:26][C:27]([O:29][C:30]([CH3:32])([CH3:33])[CH3:31])=[O:28])=[CH:22][CH:21]=2)[CH2:5][C:4]([CH2:38][CH2:39][CH2:40][CH3:41])([CH2:34][CH2:35][CH2:36][CH3:37])[CH2:3]1
Reactant: CCCCC1(CCCC)CN(c2ccc(NC(=O)OC(C)(C)C)cc2)c2ccc(OCC(=O)OCC)cc2S(=O)(=O)C1
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: CCCCC1(CCCC)CN(c2ccc(NC(=O)OC(C)(C)C)cc2)c2ccc(OCC(=O)O)cc2S(=O)(=O)C1
Reaction time: 1 h
Yield: 99.4 %

Procedure:
1,1-Dioxo-3,3-dibutyl-5-(4-t-butoxycarbonylaminophenyl)-8-ethoxycarbonylmethoxy-2,3,4,5-tetrahydro-1,5-benzothiazepine (Method 108; 607 mg, 1.0 mmol) was dissolved in THF (6 ml), H2O (6 ml) and LiOH (127 mg, 3.02 mmol, monohydrate) was added. The mixture was stirred for 1 hour. The mixture was poured into water and the solution was acidified using HCl-solution (aq, 1M). The water layer was extracted two times with EtOAc. The combined organic layer was wash once with brine, dried, filtered and evaporated under reduced pressure to give the title compound 0.571 g (99%). M/z 575.4.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([Cl:8])=[CH:4][C:3]=1[C:9]([C:11]1[CH:12]=[N:13][C:14]([CH3:17])=[CH:15][CH:16]=1)=[O:10].[Br:18][C:19]1[CH:24]=[CH:23][C:22]([S:25](Cl)(=[O:27])=[O:26])=[CH:21][C:20]=1[F:29]>N1C=CC=CC=1>[Br:18][C:19]1[CH:24]=[CH:23][C:22]([S:25]([NH:1][C:2]2[CH:7]=[CH:6][C:5]([Cl:8])=[CH:4][C:3]=2[C:9]([C:11]2[CH:12]=[N:13][C:14]([CH3:17])=[CH:15][CH:16]=2)=[O:10])(=[O:27])=[O:26])=[CH:21][C:20]=1[F:29]
Reactant: Cc1ccc(C(=O)c2cc(Cl)ccc2N)cn1
Reactant: O=S(=O)(Cl)c1ccc(Br)c(F)c1
Solvent: c1ccncc1
Product: Cc1ccc(C(=O)c2cc(Cl)ccc2NS(=O)(=O)c2ccc(Br)c(F)c2)cn1

Procedure:
The title compound was prepared according to the general procedures for the synthesis of N-Aryl-benzenesulfonamides previously described using (2-amino-5-chloro-phenyl)-(6-methyl-pyridin-3-yl)-methanone 2.4 g (8.77 mmol) and 4-bromo-3-fluoro-benzenesulfonyl chloride 2.16 g (8.77 mmol) stirred in 14 ml pyridine. Purification on silica gel with flash column chromatography gave a light orange solid.
Reaction SMILES: CC(OI1(OC(C)=O)(OC(C)=O)OC(=O)C2C1=CC=CC=2)=O.[C:23]([C:27]1[O:28][C:29]([CH2:36][OH:37])=[CH:30][C:31]=1[S:32]([NH2:35])(=[O:34])=[O:33])([CH3:26])([CH3:25])[CH3:24].S([O-])([O-])(=O)=S.[Na+].[Na+]>C(Cl)Cl>[C:23]([C:27]1[O:28][C:29]([CH:36]=[O:37])=[CH:30][C:31]=1[S:32]([NH2:35])(=[O:34])=[O:33])([CH3:26])([CH3:24])[CH3:25]
Reactant: CC(C)(C)c1oc(CO)cc1S(N)(=O)=O
Agent: CC(=O)OI1(OC(C)=O)(OC(C)=O)OC(=O)c2ccccc21
Agent: O=S([O-])([O-])=S
Agent: [Na+]
Solvent: ClCCl
Product: CC(C)(C)c1oc(C=O)cc1S(N)(=O)=O
Reaction time: 0.42 h
Yield: 89.8 %

Procedure:
At room temperature, 1,1,1-triacetoxy-1,1-dihydro-1,2-benziodoxol-3(1H)-one (0.60 g) was added to a solution of 2-tert-butyl-5-hydroxymethyl-furan-3-sulfonamide (0.30 g) in methylene chloride (10 ml), followed by stirring for 25 min. The reaction mixture was mixed with a 20% aqueous sodium thiosulfate solution, extracted with methylene chloride. The organic layer was washed with a saturated aqueous sodium bicarbonate solution, dried over magnesium sulfate and evaporated under reduced pressure to remove the solvent; the thus obtained residue was subjected to silica gel column chromatography (developing solvent: n-hexane:ethyl acetate=2:1) to give the titled compound (267 mg, 90%).
Reaction SMILES: FC(F)(F)C(O)=O.C([O:12][C:13](=[O:29])[CH2:14][CH:15]([NH:20][C:21](=[O:28])[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)[C:16](=[O:19])[CH2:17][F:18])(C)(C)C>C(Cl)Cl>[C:21]([NH:20][CH:15]([C:16](=[O:19])[CH2:17][F:18])[CH2:14][C:13]([OH:29])=[O:12])(=[O:28])[C:22]1[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=1
Reactant: CC(C)(C)OC(=O)CC(NC(=O)c1ccccc1)C(=O)CF
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: O=C(O)CC(NC(=O)c1ccccc1)C(=O)CF
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
Trifluoroacetic acid (TFA) (10 ml) was added to a stirred ice cold solution of above prepared 3-benzoylamino-5-fluoro-4-oxo-pentanoic acid tert-butyl ester (600 mg, 1.94 mmol) in dry DCM (10 ml). The mixture was stirred at 0° C. for 0.5 h then at r.t. for 0.5 h. The mixture was concentrated under reduced pressure and the residue redissolved in dry DCM. This process was repeated several times in order to remove excess TFA. The resulting gum was triturated with Et2O. Filtration of the resulting suspension yielded the title compound as finely divided white powder (333 mg, 68%): 1H NMR (DMSO) δ 12.6 (1H, br s), 8.8 (1H, br m), 7.85 (2H, m), 7.50 (3H, m), 4.90 (2H, m), 4.80 (1H, m), 2.80 (2H, m); 13C NMR (DMSO) δ 166.97, 133.72, 132.5, 128.70, 127.83, 52.64, 34.58; 19F NMR (DMSO) δ −226.66(m), −230.34(m), −232.24(m); Acc. Mass; Calc. 254.0828, Found 254.0793.
Reaction SMILES: [Br:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][OH:8].C1COCC1.[C:14](Cl)(=[O:23])[CH:15]=[CH:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1>C(N(CC)CC)C>[C:14]([O:8][CH2:7][CH2:6][CH2:5][CH2:4][CH2:3][CH2:2][Br:1])(=[O:23])[CH:15]=[CH:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1
Reactant: O=C(Cl)C=Cc1ccccc1
Reactant: OCCCCCCBr
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: O=C(C=Cc1ccccc1)OCCCCCCBr
Yield: 53 %

Procedure:
7 g of 6-bromohexanol was dissolved in a mixed solution of 5 ml of triethylamine as base and 50 ml of THF, and then, cinnamoyl chloride was added dropwise thereto at 0° C. The resultant was filtered to remove the solvent and the residue was purified with a SiO2 column chromatography (EA:n-Hexane=1:5) to obtain 8 g of 6-bromohexyl cinnamate (yield: 53%).
Reaction SMILES: [CH2:1]([N:4]([CH2:27][CH2:28][C:29]([O:31][CH2:32][CH3:33])=[O:30])[C:5]([C:7]1[CH:26]=[CH:25][C:10]2[N:11]([CH3:24])[C:12]([CH2:14][NH:15][C:16]3[CH:21]=[CH:20][C:19]([C:22]#[N:23])=[CH:18][CH:17]=3)=[N:13][C:9]=2[CH:8]=1)=[O:6])[C:2]#[CH:3].[ClH:34].C(O)C.C(=O)([O-])[O-].[NH4+:42].[NH4+]>ClCCl.C(O)C>[ClH:34].[CH2:1]([N:4]([CH2:27][CH2:28][C:29]([O:31][CH2:32][CH3:33])=[O:30])[C:5]([C:7]1[CH:26]=[CH:25][C:10]2[N:11]([CH3:24])[C:12]([CH2:14][NH:15][C:16]3[CH:21]=[CH:20][C:19]([C:22](=[NH:42])[NH2:23])=[CH:18][CH:17]=3)=[N:13][C:9]=2[CH:8]=1)=[O:6])[C:2]#[CH:3]
Reactant: C#CCN(CCC(=O)OCC)C(=O)c1ccc2c(c1)nc(CNc1ccc(C#N)cc1)n2C
Reactant: [NH4+]
Agent: Cl
Agent: O=C([O-])[O-]
Solvent: CCO
Solvent: ClCCl
Product: C#CCN(CCC(=O)OCC)C(=O)c1ccc2c(c1)nc(CNc1ccc(C(=N)N)cc1)n2C
Yield: 81 %

Procedure:
Prepared analogously to Example 25d from 1-methyl-2-[N-(4-cyanophenyl)aminomethyl]benzimidazol-5-yl-carboxylic acid-N-propargyl-N-(2-ethoxycarbonylethyl)amide, ethanolic hydrochloric acid, ethanol, and ammonium carbonate. Yield: 81% of theory, C25H28N6O3 (460.6); Rf value: 0.094 (silica gel; dichloromethane/ethanol=4:1); EKA mass spectrum: (M+H)+=461; (M+H+Na)++=242; (M+2H)++=231.
Reaction SMILES: [N:1]1([CH2:6][C:7]2[CH:12]=[CH:11][C:10]([N:13]3[CH2:18][CH2:17][CH:16]([CH:19]=O)[CH2:15][CH2:14]3)=[CH:9][CH:8]=2)[CH2:5][CH2:4][CH2:3][CH2:2]1.[CH3:21][N:22]1[CH2:27][CH2:26][NH:25][CH2:24][CH2:23]1>>[CH3:21][N:22]1[CH2:27][CH2:26][N:25]([CH2:19][CH:16]2[CH2:17][CH2:18][N:13]([C:10]3[CH:11]=[CH:12][C:7]([CH2:6][N:1]4[CH2:5][CH2:4][CH2:3][CH2:2]4)=[CH:8][CH:9]=3)[CH2:14][CH2:15]2)[CH2:24][CH2:23]1
Reactant: O=CC1CCN(c2ccc(CN3CCCC3)cc2)CC1
Reactant: CN1CCNCC1
Product: CN1CCN(CC2CCN(c3ccc(CN4CCCC4)cc3)CC2)CC1

Procedure:
Prepared from the product of Example 16 and N-methylpiperazine.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:8]([O:9][CH2:10][O:11][CH3:12])=[CH:7][C:6]([O:13][CH3:14])=[C:5]([O:15][CH2:16][O:17][CH3:18])[C:4]=1[CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][C:24]1[C:29]([O:30][CH2:31][O:32][CH3:33])=[C:28]([O:34][CH3:35])[CH:27]=[C:26]([O:36][CH2:37][O:38][CH3:39])[C:25]=1[O:40][CH3:41].CN(C)CCN(C)C.C([Li])CCC.[CH3:55][S:56]C>O1CCCC1.CN(C)P(=O)(N(C)C)N(C)C>[CH3:41][O:40][C:25]1[C:26]([O:36][CH2:37][O:38][CH3:39])=[CH:27][C:28]([O:34][CH3:35])=[C:29]([O:30][CH2:31][O:32][CH3:33])[C:24]=1[CH2:23][CH2:22][CH2:21][CH2:20][CH2:19][C:4]1[C:5]([O:15][CH2:16][O:17][CH3:18])=[C:6]([O:13][CH3:14])[C:7]([S:56][CH3:55])=[C:8]([O:9][CH2:10][O:11][CH3:12])[C:3]=1[O:2][CH3:1]
Reactant: COCOc1cc(OC)c(OCOC)c(CCCCCc2c(OC)c(OCOC)cc(OC)c2OCOC)c1OC
Reactant: CSC
Agent: CN(C)CCN(C)C
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CN(C)P(=O)(N(C)C)N(C)C
Product: COCOc1cc(OC)c(OCOC)c(CCCCCc2c(OCOC)c(OC)c(SC)c(OCOC)c2OC)c1OC
Temperature: -78 °C
Reaction time: 0.5 h

Procedure:
1.51 Grams of 2,2'-pentamethylenebis[1,4-dimethoxy- 3,6-bis(methoxymethoxy)benzene] was dissolved in a mixed solvent of 40 ml of tetrahydrofuran with 4 ml of hexamethylphosphoric triamide, to this solution was added 0.55 ml of N,N,N',N'-tetramethylethylenediamine and the whole mixture was cooled to -78° C., on a dry ice-acetone bath. Then, 2.41 ml of n-butyllithium (1.6 M, n-hexane solution) was added dropwise to the reaction mixture and stirred for 30 minutes. Next, 0.25 ml of dimethyl sulfide was added to the reaction mixture and stirred overnight. The solvent was removed by evaporation under reduced pressure, then the residue obtained was extracted twice with 100 ml of ethyl acetate, then the ethyl acetate layer was washed twice with 100 ml of water, and twice with a saturated sodium chloride aqueous solution, then dried over anhydrous magnesium sulfate. The solvent was removed by evaporation under reduced pressure, and the residue obtained was purified by means of a preparative thin layer chromatography (thickness: 2 mm, adsorbent: Merck Art 5717 silica gel, developing solvent: 20% ethyl acetate-n-hexane). There were obtained 572 mg of 1-[2,5-dimethoxy-3,6-bis(methoxymethoxy)phenyl]5-[2,5-dimethoxy-3,6-bis(methoxymethoxy)-4-(methylthio)phenyl]pentane, as well as 522 mg of 2,2'-pentamethylenebis[1,4-dimethoxy-3,6-bis(methoxymethoxy)-5-(methylthio)benzene].
Reaction SMILES: Cl[CH2:2][C:3]1[CH:4]=[CH:5][C:6]([O:23][CH2:24][CH2:25][CH3:26])=[C:7]([C:9]2[NH:10][C:11](=[O:22])[C:12]3[N:17]([CH3:18])[N:16]=[C:15]([CH2:19][CH2:20][CH3:21])[C:13]=3[N:14]=2)[CH:8]=1.[NH:27]1[CH2:32][CH2:31][O:30][CH2:29][CH2:28]1.CCCCCC>CC(=O)CC>[CH3:18][N:17]1[C:12]2[C:11](=[O:22])[NH:10][C:9]([C:7]3[CH:8]=[C:3]([CH2:2][N:27]4[CH2:32][CH2:31][O:30][CH2:29][CH2:28]4)[CH:4]=[CH:5][C:6]=3[O:23][CH2:24][CH2:25][CH3:26])=[N:14][C:13]=2[C:15]([CH2:19][CH2:20][CH3:21])=[N:16]1
Reactant: CCCOc1ccc(CCl)cc1-c1nc2c(CCC)nn(C)c2c(=O)[nH]1
Reactant: C1COCCN1
Solvent: CCC(C)=O
Solvent: CCCCCC
Product: CCCOc1ccc(CN2CCOCC2)cc1-c1nc2c(CCC)nn(C)c2c(=O)[nH]1
Yield: 52.9 %

Procedure:
A solution of 5-(5-chloromethyl-2-n-propoxyphenyl)-1-methyl-3-n-propyl-1,6-dihydro-7H-pyrazolo[4,3-d]pyrimidin-7-one (Preparation 16, 0.60 g, 0.0016 mol) in 2-butanone (10 ml) was added dropwise to a stirred solution of morpholine (0.42 g, 0.0048 mol) in 2-butanone (40 ml) at 0° C. The solution was then heated under reflux for 16 hours, cooled and evaporated under vacuum. The residue was suspended in water (50 ml) and the suspension extracted with ethyl acetate (3×20 ml). The organic extracts were combined, washed with brine (2×30 ml), dried (Na2SO4) and evaporated under vacuum. The residue was chromatographed on silica gel (12 g), using an elution gradient of methanol in dichloromethane (0-2% methanol), to give an oil which solidified on trituration with hexane. Crystallisation from ethyl acetate-hexane gave the title compound as a colourless solid (0.36 g, 53%), m.p. 106°-107° C. Found: C,64.76; H,7.34; N,16.36. C23H31N5O3 requires C,64.92; H,7.34; N,16.46%.
Reaction SMILES: Cl[C:2]1[CH:3]=[C:4]([CH:22]=[CH:23][N:24]=1)[C:5]([NH:7][C:8]1[S:9][CH:10]=[C:11]([C:13]2[C:18]([CH3:19])=[CH:17][C:16]([CH3:20])=[CH:15][C:14]=2[CH3:21])[N:12]=1)=[O:6].[NH:25]1[CH2:30][CH2:29][CH2:28][CH2:27][CH2:26]1.O>CN1CCCC1=O>[C:14]1([CH3:21])[CH:15]=[C:16]([CH3:20])[CH:17]=[C:18]([CH3:19])[C:13]=1[C:11]1[N:12]=[C:8]([NH:7][C:5](=[O:6])[C:4]2[CH:22]=[CH:23][N:24]=[C:2]([N:25]3[CH2:30][CH2:29][CH2:28][CH2:27][CH2:26]3)[CH:3]=2)[S:9][CH:10]=1
Reactant: C1CCNCC1
Reactant: Cc1cc(C)c(-c2csc(NC(=O)c3ccnc(Cl)c3)n2)c(C)c1
Solvent: O
Solvent: CN1CCCC1=O
Product: Cc1cc(C)c(-c2csc(NC(=O)c3ccnc(N4CCCCC4)c3)n2)c(C)c1
Temperature: 150 °C
Reaction time: 16 h
Yield: 33.3 %

Procedure:
A mixture of 2-chloro-N-(4-mesitylthiazol-2-yl)isonicotinamide (200 mg, 0.60 mmol, 1.0 equiv) and piperidine (0.70 mL, 6.7 mmol, 12 equiv) in methylpyrrolidone (6.0 mL) was stirred at 150° C. for 16 h. The mixture was poured into icy H2O (10.0 mL) and the resultant solids were filtered. The solids were purified by column chromatography on silica gel (15% EtOAc in hexanes as eluant) to provide N-(4-mesitylthiazol-2-yl)-2-(piperidin-1-yl)isonicotinamide (87.2 mg, 0.20 mmol) as yellow solids in 38% yield: 1H NMR (CDCl3, 500 MHz) δ 8.29 (d, J=5.1 Hz, 1 H), 7.15 (s, 1 H), 6.83-6.90 (m, 3 H), 6.79 (s, 1 H), 3.61-3.63 (m, 4 H), 2.31 (s, 3 H), 2.08 (s, 6 H), 1.57-1.67 (m, 6 H); ESI-MS: m/z 407.2 (M+H)+.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([S:9]([NH:12][C:13]2[CH:21]=[C:20]3[C:16]([CH:17]=[CH:18][N:19]3[CH3:22])=[CH:15][CH:14]=2)(=[O:11])=[O:10])[CH:5]=[C:6]([Cl:8])[CH:7]=1.[C:23](Cl)(=[O:27])[C:24]([Cl:26])=[O:25]>C(OCC)C>[Cl:1][C:2]1[CH:3]=[C:4]([S:9]([NH:12][C:13]2[CH:21]=[C:20]3[C:16]([C:17]([C:23](=[O:27])[C:24]([Cl:26])=[O:25])=[CH:18][N:19]3[CH3:22])=[CH:15][CH:14]=2)(=[O:11])=[O:10])[CH:5]=[C:6]([Cl:8])[CH:7]=1
Reactant: O=C(Cl)C(=O)Cl
Reactant: Cn1ccc2ccc(NS(=O)(=O)c3cc(Cl)cc(Cl)c3)cc21
Solvent: CCOCC
Product: Cn1cc(C(=O)C(=O)Cl)c2ccc(NS(=O)(=O)c3cc(Cl)cc(Cl)c3)cc21
Temperature: 0 °C
Reaction time: 12 h

Procedure:
1.1 g 3,5-dichloro-N-(1-methyl-1H-indol-6-yl)phenylsulphonamide are dissolved in 15 ml diethyl ether, cooled to 0° C. and combined with 296 μl oxalyl chloride. Then the mixture is stirred for 2 hours at 0° C. and for 12 hours at ambient temp. The solvents are distilled off at 50° C. The crude product thus obtained is further reacted directly (XLVII).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:37])[CH:5]=[CH:6][CH:7]([N:19]([CH3:36])[C:20](=[O:35])[C:21]1[CH:26]=[C:25]([C:27]([F:30])([F:29])[F:28])[CH:24]=[C:23]([C:31]([F:34])([F:33])[F:32])[CH:22]=1)[CH2:8][C:9]1[C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[N:11]([CH3:18])[CH:10]=1)[CH3:2].ClC1C=CC=CC=1Cl>O1CCCC1.[Pd]>[CH2:1]([O:3][C:4](=[O:37])[CH2:5][CH2:6][CH:7]([N:19]([CH3:36])[C:20](=[O:35])[C:21]1[CH:26]=[C:25]([C:27]([F:29])([F:28])[F:30])[CH:24]=[C:23]([C:31]([F:32])([F:33])[F:34])[CH:22]=1)[CH2:8][C:9]1[C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[N:11]([CH3:18])[CH:10]=1)[CH3:2]
Reactant: CCOC(=O)C=CC(Cc1cn(C)c2ccccc12)N(C)C(=O)c1cc(C(F)(F)F)cc(C(F)(F)F)c1
Agent: [Pd]
Solvent: Clc1ccccc1Cl
Solvent: C1CCOC1
Product: CCOC(=O)CCC(Cc1cn(C)c2ccccc12)N(C)C(=O)c1cc(C(F)(F)F)cc(C(F)(F)F)c1

Procedure:
A solution of 16.82 g of 4-[N-methyl-N-(3,5-bistrifluoromethyl-benzoyl)-amino]-5-(1-methyl-indol-3-yl)-pent-2-enoic acid ethyl ester in 170 ml of tetrahydrofuran is hydrogenated for 70 minutes at 20° C. in the presence of 1.7 g of palladium/activated carbon (10%) and 0.2 g of 1,2-dichlorobenzene. The reaction mixture is then filtered and concentrated by evaporation. In this way the title compound is obtained in the form of a brownish-green resin. Rf value=0.265 (ethyl acetate/hexane 2/3).
Reaction SMILES: [H-].[Na+].CN(C=O)C.[C:8]12([C:18]3[CH:19]=[C:20]([CH:25]=[CH:26][C:27]=3[OH:28])[C:21]([O:23][CH3:24])=[O:22])[CH2:17][CH:12]3[CH2:13][CH:14]([CH2:16][CH:10]([CH2:11]3)[CH2:9]1)[CH2:15]2.[CH3:29][N:30]([CH3:34])[C:31](Cl)=[S:32]>O>[C:8]12([C:18]3[CH:19]=[C:20]([CH:25]=[CH:26][C:27]=3[O:28][C:31]([N:30]([CH3:34])[CH3:29])=[S:32])[C:21]([O:23][CH3:24])=[O:22])[CH2:9][CH:10]3[CH2:16][CH:14]([CH2:13][CH:12]([CH2:11]3)[CH2:17]1)[CH2:15]2
Reactant: CN(C)C(=S)Cl
Reactant: COC(=O)c1ccc(O)c(C23CC4CC(CC(C4)C2)C3)c1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: COC(=O)c1ccc(OC(=S)N(C)C)c(C23CC4CC(CC(C4)C2)C3)c1
Yield: 6 %

Procedure:
Into a round bottom flask, there are introduced 2.4 g (0.08 mole) of sodium hydride (80% in oil) and 250 ml of DMF. Under a nitrogen current, there are slowly added 22.9 g (0.08 g mole) of methyl 3-(1-adamantyl)-4-hydroxybenzoate. The mixture is stirred until the cessation of gaseous emission. There are then added, all at once, 12.9 g (0.104 mole) of dimethylthiocarbamoyl chloride and the mixture is stirred for 16 hours at ambient temperature. The reaction medium is poured into water and extracted with ethyl ether. The organic phase is decanted, dried on magnesium sulfate and evaporated. The resulting residue is purified by chromatography on a silica column eluted with a 70:30 mixture of dichloromethane and hexane. After evaporation of the solvents, 1.8 g (63% yield) of the expected product having a melting point of 174°-175° C. are recovered.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([C:10]#[CH:11])[CH:7]=[CH:8][CH:9]=1)([O-])=O.[H][H]>CO>[NH2:1][C:4]1[CH:5]=[C:6]([C:10]#[CH:11])[CH:7]=[CH:8][CH:9]=1
Reactant: [H][H]
Reactant: C#Cc1cccc([N+](=O)[O-])c1
Solvent: CO
Product: C#Cc1cccc(N)c1
Yield: 70 %

Procedure:
Example 3 was repeated using 25 grams of 3-nitrophenylacetylene (10% wt. conc.) in methanol in the presence of 16.0 grams of a cobalt polysulfide catalyst prepared as per Example 1. The weight ratio of NPA to Co was 25:1. Reaction was carried out at 120° C., 1000 psig (6.9 MPa) of hydrogen pressure for 0.5 hours. Analysis showed quantitative conversion of feed and a 70% yield of 3-aminophenylacetylene. All byproducts were polymeric and easily separated. The results are summarized in Table 1 below.
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][CH:4]([CH2:7][CH2:8][O:9][C:10]2[CH:19]=[C:18]3[C:13]([C:14](=[O:28])[N:15]([CH2:20][O:21][C:22](=[O:27])[C:23]([CH3:26])([CH3:25])[CH3:24])[CH:16]=[N:17]3)=[CH:12][C:11]=2[O:29][CH3:30])[CH2:3][CH2:2]1.C=O.[C:33](O)(=O)C.C(O)(=O)C.C(O)(=O)C.C(O)(=O)C.[BH4-].[Na+]>CO.C(Cl)Cl>[CH3:33][N:1]1[CH2:6][CH2:5][CH:4]([CH2:7][CH2:8][O:9][C:10]2[CH:19]=[C:18]3[C:13]([C:14](=[O:28])[N:15]([CH2:20][O:21][C:22](=[O:27])[C:23]([CH3:26])([CH3:24])[CH3:25])[CH:16]=[N:17]3)=[CH:12][C:11]=2[O:29][CH3:30])[CH2:3][CH2:2]1
Reactant: CC(=O)O
Reactant: COc1cc2c(=O)n(COC(=O)C(C)(C)C)cnc2cc1OCCC1CCNCC1
Agent: C=O
Agent: [BH4-]
Agent: [Na+]
Solvent: ClCCl
Solvent: CO
Product: COc1cc2c(=O)n(COC(=O)C(C)(C)C)cnc2cc1OCCC1CCN(C)CC1
Temperature: 25 °C
Reaction time: 1 h
Yield: 67.6 %

Procedure:
To a solution of 7-(2-(piperidin-4-yl)ethoxy)-6-methoxy-3-((pivaloyloxy)methyl)-3,4-dihydroquinazolin-4-one (6 g, 14.4 mmol) in methanol (30 ml) and methylene chloride (60 ml) was added 37% aqueous formaldehyde (2.2 ml; 28.9 mmol) followed by acetic acid (990 μl; 17.3 mmol). Sodium borohydride triacetate (4.6 g, 21.6 mmol) was added in portions. After stirring for 1 hour at ambient temperature, the volatiles were removed under vacuum and the residue was partitioned between water (50 ml) and methylene chloride (50 ml). The pH of the aqueous layer was adjusted to 7, washed with water, brine, dried (MgSO4) and evaporated. The solid was triturated with ether, filtered, washed with ether and dried under vacuum to give 7-(2-(1-methylpiperidin-4-yl)ethoxy)-6-methoxy-3-((pivaloyloxy)methyl)-3,4-dihydroquinazolin-4-one (4.2 g, 68%).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH2:11][CH:10]([OH:14])[CH:9]1[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].Br[CH2:22][C:23]1[CH:28]=[CH:27][CH:26]=[C:25]([C:29]#[N:30])[CH:24]=1>>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH2:11][C@@H:10]([O:14][CH2:22][C:23]2[CH:28]=[CH:27][CH:26]=[C:25]([C:29]#[N:30])[CH:24]=2)[C@H:9]1[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)N1CCCC(O)C1c1ccccc1
Reactant: N#Cc1cccc(CBr)c1
Product: CC(C)(C)OC(=O)N1CCC[C@@H](OCc2cccc(C#N)c2)[C@H]1c1ccccc1

Procedure:
This compound was prepared from 1-t-butyloxycarbonyl-3-hydroxy-2-phenylpiperidine (Description 1c) and α-bromo-m-tolunitrile according to the procedure described in Example 1d. 1H NMR (360 MHz, CDCl3) δ1.49 (9H,s, (CH3)3), 1.6-1.72 (2H, m), 1.87-1.99 (2H, m), 2.72 (1H, dt, J=13, 4 Hz, NCHH), 3.80-3.95 (2H, m, CHO+NCHH), 4.65 (2H, q, J=12 Hz, OCH2), 5.69 (1H, brs, CHPh), 7.1-7.5 (9H, m, ArH).
Reaction SMILES: [S:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[CH:6]=O.[CH3:8][C:9]1[O:10][CH2:11][C:12]([CH3:15])([CH3:14])[N:13]=1>>[CH3:14][C:12]1([CH3:15])[CH2:11][O:10][C:9]([CH:8]=[CH:6][C:2]2[S:1][CH:5]=[CH:4][CH:3]=2)=[N:13]1
Reactant: CC1=NC(C)(C)CO1
Reactant: O=Cc1cccs1
Product: CC1(C)COC(C=Cc2cccs2)=N1

Procedure:
4,4-Dimethyl-2-[2-(2-thienyl)ethenyl]-2-oxazoline (P-1894) was synthesized by reacting 2-thiophenecarboxaldehyde with 2,4,4-trimethyl-2-oxazoline.