Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(NCCCCC1C=CC([N+]([O-])=O)=CC=1)CCCCC.C=O.Cl.[CH3:24][N:25]([CH2:32][CH2:33][CH2:34][CH2:35][C:36]1[CH:41]=[CH:40][C:39]([N+:42]([O-:44])=[O:43])=[CH:38][CH:37]=1)[CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH3:31].[C:45]([OH:50])(=[O:49])[C:46]([OH:48])=[O:47]>C(OCC)(=O)C.C(O)=O>[C:45]([O-:50])(=[O:49])[C:46]([O-:48])=[O:47].[CH3:24][NH+:25]([CH2:32][CH2:33][CH2:34][CH2:35][C:36]1[CH:37]=[CH:38][C:39]([N+:42]([O-:44])=[O:43])=[CH:40][CH:41]=1)[CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH3:31].[CH3:24][NH+:25]([CH2:32][CH2:33][CH2:34][CH2:35][C:36]1[CH:37]=[CH:38][C:39]([N+:42]([O-:44])=[O:43])=[CH:40][CH:41]=1)[CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH3:31]
Reactant: CCCCCCN(C)CCCCc1ccc([N+](=O)[O-])cc1
Reactant: O=C(O)C(=O)O
Agent: C=O
Agent: CCCCCCNCCCCc1ccc([N+](=O)[O-])cc1
Agent: Cl
Solvent: CCOC(C)=O
Solvent: O=CO
Product: CCCCCC[NH+](C)CCCCc1ccc([N+](=O)[O-])cc1
Product: O=C([O-])C(=O)[O-]
Temperature: 95 °C

Procedure:
To a cold stirred solution of 2.0 g. of N-n-hexyl-4-(4-nitrophenyl)butylamine in 7 ml. of formic acid were added dropwise 7 ml. of 37% aqueous formaldehyde. The reaction mixture was heated to 95° C. and stirred at this temperature for sixteen hours. The reaction mixture next was cooled and acidified by the addition of 10 ml. of 4 N hydrochloric acid. The aqueous acid mixture was washed twice with diethyl ether, and then made alkaline by the addition of 5 N sodium hydroxide. The product was extracted into diethyl ether. The ethereal extracts were combined, washed with water and dried. Removal of the solvent by evaporation under reduced pressure provided 2.2 g. of N-methyl-N-n-hexyl-4-(4-nitrophenyl)butylamine. The amine was dissolved in ethyl acetate and treated with oxalic acid to give, after crystallization from isopropanol, 2.1 g. of N-methyl-N-n-hexyl-4-(4-nitrophenyl)butylaminium oxalate. M.P. 103°-105° C.
Reaction SMILES: [C:1]([Cl:9])(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[NH2:10][C:11]1[CH:12]=[N:13][C:14]2[C:19]([C:20]=1[NH:21][CH2:22][CH2:23][CH2:24][CH2:25][NH:26][C:27](=[O:33])[O:28][C:29]([CH3:32])([CH3:31])[CH3:30])=[CH:18][CH:17]=[CH:16][CH:15]=2>ClCCl>[ClH:9].[C:1]([NH:10][C:11]1[CH:12]=[N:13][C:14]2[C:19]([C:20]=1[NH:21][CH2:22][CH2:23][CH2:24][CH2:25][NH:26][C:27](=[O:33])[O:28][C:29]([CH3:31])([CH3:30])[CH3:32])=[CH:18][CH:17]=[CH:16][CH:15]=2)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CC(C)(C)OC(=O)NCCCCNc1c(N)cnc2ccccc12
Reactant: O=C(Cl)c1ccccc1
Solvent: ClCCl
Product: CC(C)(C)OC(=O)NCCCCNc1c(NC(=O)c2ccccc2)cnc2ccccc12
Product: Cl
Temperature: 25 °C
Yield: 61.9 %

Procedure:
A solution of benzoyl chloride (5.3 g, 37.7 mmol) in dichloromethane (100 mL) was slowly added to a solution of tert-butyl N-{4-[(3-aminoquinolin-4-yl)amino]butyl}carbamate (12.5 g, 37.7 mmol) in dichloromethane (250 mL) at ambient temperature. The reaction mixture was maintained at ambient temperature overnight. The resulting precipitate was isolated by filtration and dried to provide 11.0 g of tert-butyl N-(4-{[3-(benzoylamino)quinolin-4-yl]amino}butyl)carbamate hydrochloride as a white solid.
Reaction SMILES: N(C(OCC)=O)=NC(OCC)=O.[Si:13]([O:30][C@H:31]1[CH2:36][C@H:35]2[CH2:37][C@@H:32]1[CH2:33][C@H:34]2O)([C:26]([CH3:29])([CH3:28])[CH3:27])([C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1.[C:39]1(=[O:49])[NH:43][C:42](=[O:44])[C:41]2=[CH:45][CH:46]=[CH:47][CH:48]=[C:40]12.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>C1COCC1>[Si:13]([O:30][C@H:31]1[CH2:36][C@H:35]2[CH2:37][C@@H:32]1[CH2:33][C@@H:34]2[N:43]1[C:39](=[O:49])[C:40]2[C:41](=[CH:45][CH:46]=[CH:47][CH:48]=2)[C:42]1=[O:44])([C:26]([CH3:29])([CH3:27])[CH3:28])([C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)[C:14]1[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=1
Reactant: CC(C)(C)[Si](O[C@H]1C[C@H]2C[C@@H]1C[C@H]2O)(c1ccccc1)c1ccccc1
Reactant: O=C1NC(=O)c2ccccc21
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: CC(C)(C)[Si](O[C@H]1C[C@H]2C[C@@H]1C[C@@H]2N1C(=O)c2ccccc2C1=O)(c1ccccc1)c1ccccc1
Reaction time: 32 h

Procedure:
A solution of diethyl azodicarboxylate (2.58 mL, 16.4 mmol) in anhydrous THF (10.0 mL) was added dropwise to a mixture of (1R,2R,4R,5S)-5-(tert-butyldiphenylsilyloxy)bicyclo[2.2.1 ]heptan-2-ol (5.00 g, 13.6 mmol), phthalimide (2.31 g, 15.7 mmol), and triphenyl phosphine (4.11 g, 15.7 mmol) in anhydrous THF (60 mL) at ambient temp. under nitrogen. After stirring for 32 h, the solvents were removed in vacuo. The residue was purified by flash column chromatography (0 to 20% of ethyl acetate in hexanes) to give the title compound as a white solid. MS m/z: 496.3 (M+H)+.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([CH2:11][C:12](O)=O)(=[O:10])=[O:9])=[CH:4][CH:3]=1.[CH3:15][O:16][C:17]1[CH:24]=[CH:23][C:20](C=O)=[CH:19][CH:18]=1>>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([S:8](/[CH:11]=[CH:12]/[C:20]2[CH:23]=[CH:24][C:17]([O:16][CH3:15])=[CH:18][CH:19]=2)(=[O:9])=[O:10])=[CH:6][CH:7]=1
Reactant: COc1ccc(C=O)cc1
Reactant: O=C(O)CS(=O)(=O)c1ccc(Cl)cc1
Product: COc1ccc(/C=C/S(=O)(=O)c2ccc(Cl)cc2)cc1
Yield: 68 %

Procedure:
A solution of 4-chlorophenyl sulfonylacetic acid (0.01 mol) and 4-methoxybenzaldehyde (0.01 mol) was subjected to Procedure 1, Part B. The title compound was obtained in 68-70% yield.
Reaction SMILES: Cl.[NH2:2][C:3]1[C:14]2[C:6](=[N:7][C:8]3[CH2:9][NH:10][CH2:11][C:12]=3[C:13]=2[C:15]2[S:16][CH:17]=[CH:18][CH:19]=2)[S:5][C:4]=1[C:20]([NH2:22])=[O:21].[Cl:23][CH2:24][CH2:25][CH2:26]Br.C(N(CC)CC)C>CN(C=O)C>[NH2:2][C:3]1[C:14]2[C:6](=[N:7][C:8]3[CH2:9][N:10]([CH2:26][CH2:25][CH2:24][Cl:23])[CH2:11][C:12]=3[C:13]=2[C:15]2[S:16][CH:17]=[CH:18][CH:19]=2)[S:5][C:4]=1[C:20]([NH2:22])=[O:21]
Reactant: NC(=O)c1sc2nc3c(c(-c4cccs4)c2c1N)CNC3
Reactant: ClCCCBr
Agent: Cl
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: NC(=O)c1sc2nc3c(c(-c4cccs4)c2c1N)CN(CCCCl)C3
Temperature: 60 °C

Procedure:
A mixture of 3-amino-4-thiophen-2-yl-6,7-dihydro-5H-1-thia-6,8-diaza-s-indacene-2-carboxylic acid amide hydrochloride (0.7 g, 2 mmol), 1-chloro-3-bromopropane (4 mmol), and triethylamine (2 ml) in 10 ml of anhydrous DMF was heated at 60° C. for 24 hours. The solvent was removed in vacuo, and the residue was purified by silica gel column (chloroform/methanol, 40:1) to give pure compound as a yellow solid. 1H-NMR (300 MHz, DMSO-d6): δ 7.88 (d, J=5.1 Hz, 1H), 7.29 (d, J=3.6 Hz, 1H), 7.27 (dd, J=3.6, 5.1 Hz, 1H), 7.22 (brs, 2H), 5.98 (brs, 2H), 4.00 (s, 2H), 3.77 (s, 2H), 3.67 (t, J=6.3 Hz, 2H), 2.78 (t, J=6.3 Hz, 2H), 1.90 (m, 2H). ES MS m/z 393, 395 (M+H)+.
Reaction SMILES: COC1C=CC(C[S:8][C@@H:9]2[CH2:13][N:12]([C:14]([O:16][CH2:17][C:18]3[CH:23]=[CH:22][C:21]([N+:24]([O-:26])=[O:25])=[CH:20][CH:19]=3)=[O:15])[C@H:11]([C:27]([OH:29])=O)[CH2:10]2)=CC=1.[CH3:32][C@H:33]1[CH2:38][NH:37][CH2:36][C@@H:35]([CH3:39])[NH:34]1>>[CH3:32][C@H:33]1[NH:34][C@@H:35]([CH3:39])[CH2:36][N:37]([C:27]([C@@H:11]2[CH2:10][C@H:9]([SH:8])[CH2:13][N:12]2[C:14]([O:16][CH2:17][C:18]2[CH:19]=[CH:20][C:21]([N+:24]([O-:26])=[O:25])=[CH:22][CH:23]=2)=[O:15])=[O:29])[CH2:38]1
Reactant: COc1ccc(CS[C@H]2C[C@@H](C(=O)O)N(C(=O)OCc3ccc([N+](=O)[O-])cc3)C2)cc1
Reactant: C[C@@H]1CNC[C@H](C)N1
Product: C[C@@H]1CN(C(=O)[C@@H]2C[C@H](S)CN2C(=O)OCc2ccc([N+](=O)[O-])cc2)C[C@H](C)N1
Yield: 50 %

Procedure:
Following a procedure similar to that described in Preparation 8, but using 3.3 g of (2S,4S)-4-(4-methoxybenzylthio)-1-(4-nitrobenzyloxycarbonyl)-2-pyrrolidinecarboxylic acid, 1.4 g of N,N'-carbonyldiimidazole and 1.0 g of cis-2,6-dimethylpiperazine, 1.56 g of the title compound was obtained as an amorphous solid.
Reaction SMILES: [CH2:1]([CH:3](CC)/[C:4](/[CH3:13])=[CH:5]/[CH2:6][CH2:7]/[C:8](/[CH3:12])=[CH:9]/CN)C.C(C(CC)C(C)=CCC/C(/C)=C\CN)C.C(O)(=[O:33])C.O>C1COCC1>[CH3:9][C:8](=[CH:7][CH2:6][CH2:5][CH:4]([CH2:3][CH:1]=[O:33])[CH3:13])[CH3:12]
Reactant: CCC(CC)/C(C)=C/CC/C(C)=C/CN
Reactant: CC(=O)O
Agent: CCC(CC)C(C)=CCC/C(C)=C\CN
Solvent: C1CCOC1
Solvent: O
Product: CC(C)=CCCC(C)CC=O
Temperature: 0 °C
Reaction time: 1 h

Procedure:
Precursor complex: [Rh(COD)2 ]+X- (X=anion as defined above) In a glove box, a solution of 0.025 mmole of the respective precursor complex (for example [Rh(COD)2 ]+SO3CF3-) in 2.5 ml of THF (0.01 M) was added to 0.025 mmole of the respective ligand in a one-necked flask equipped with a stopcock. The solution was stirred for 1 h, then a solution of 10 mmole of diethylgeranylamine or diethylnerylamine in 10 ml of the respective solvent was added. The flask was then equipped with a reflux condenser connected to a Schlenk line, the apparatus was purged with argon and the solution brought to reflux. Reaction temperature was held constant during the reaction time indicated in the table. The mixture was then cooled to 0° C. before adding 5 ml of a 1:4 of acetic acid/water. The reaction mixture was raised to room temperature and the solution extracted with diethyl ether. The extract was washed with water (10 ml), 15% NaOH solution (2×10 ml), then neutralized with water and thereafter dried over MgSO4. After concentration of the resulting solution, the residue was distilled in a bulb-to-bulb apparatus to give optically active citronellal and with the conversions and ee's as indicated in the tables below.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([NH:8][C:9]2[CH:10]=[N:11][C:12]([O:15][CH3:16])=[CH:13][CH:14]=2)[C:5]([I:17])=[CH:4][N:3]=1.[CH3:18][NH:19][CH3:20]>C(O)C>[I:17][C:5]1[C:6]([NH:8][C:9]2[CH:10]=[N:11][C:12]([O:15][CH3:16])=[CH:13][CH:14]=2)=[N:7][C:2]([N:19]([CH3:20])[CH3:18])=[N:3][CH:4]=1
Reactant: CNC
Reactant: COc1ccc(Nc2nc(Cl)ncc2I)cn1
Solvent: CCO
Product: COc1ccc(Nc2nc(N(C)C)ncc2I)cn1
Temperature: 140 °C
Yield: 80 %

Procedure:
A glass microwave reaction vessel was charged with 2-chloro-5-iodo-N-(6-methoxypyridin-3-yl)pyrimidin-4-amine (150 mg, 0.414 mmol), dimethylamine (2.0 M solution in tetrahydrofuran) (0.044 mL, 0.827 mmol) and ethanol (2 mL). The reaction mixture was stirred and heated in a Emrys Optimizer microwave reactor (Personal Chemistry, Biotage AB, Inc., Upssala, Sweden) at 140° C. for 20 min. The solvent was removed in vacuo and the residue was purified by silica gel chromatography eluting with 50% EtOAc/hexanes to give 5-iodo-N4-(6-methoxypyridin-3-yl)-N2,N2-dimethylpyrimidine-2,4-diamine (123 mg, 0.331 mmol, 80% yield). 1H NMR (300 MHz, CDCl3) δ 8.30 (s, 1H); 8.18 (s, 1H); 7.84 (dd, J=8.92, 2.48 Hz, 1H); 6.75 (d, J=8.92 Hz, 1H); 6.65 (s, 1H); 3.94 (s, 3H); 3.09 (s, 6H). m/z (ESI, +ve ion) 371.9 (M+H)+.
Reaction SMILES: [OH:1][C:2]1[CH:11]=[CH:10][C:5]2[C:6](=[O:9])[CH2:7][O:8][C:4]=2[C:3]=1[CH2:12][N:13]1[CH2:18][CH2:17][N:16]([C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])[CH2:15][CH2:14]1.[CH3:26][S:27]([N:30]1[C:38]2[C:33](=[CH:34][CH:35]=[CH:36][CH:37]=2)[C:32]([CH:39]=O)=[CH:31]1)(=[O:29])=[O:28].N1CCCCC1>CO>[OH:1][C:2]1[CH:11]=[CH:10][C:5]2[C:6](=[O:9])/[C:7](=[CH:39]/[C:32]3[C:33]4[C:38](=[CH:37][CH:36]=[CH:35][CH:34]=4)[N:30]([S:27]([CH3:26])(=[O:29])=[O:28])[CH:31]=3)/[O:8][C:4]=2[C:3]=1[CH2:12][N:13]1[CH2:14][CH2:15][N:16]([C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])[CH2:17][CH2:18]1
Reactant: CC(C)(C)OC(=O)N1CCN(Cc2c(O)ccc3c2OCC3=O)CC1
Reactant: CS(=O)(=O)n1cc(C=O)c2ccccc21
Solvent: CO
Solvent: C1CCNCC1
Product: CC(C)(C)OC(=O)N1CCN(Cc2c(O)ccc3c2O/C(=C\c2cn(S(C)(=O)=O)c4ccccc24)C3=O)CC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 65.5 %

Procedure:
A solution of tert-butyl 4-[(6-hydroxy-3-oxo-2,3-dihydrobenzofuran-7-yl)methyl]piperazine-1-carboxylate (0.100 g, 0.287 mmol) obtained in Example A16, Step 1 in methanol (2 mL) was added with 1-(methanesulfonyl)-1H-indole-3-carboxaldehyde (0.0641 g, 0.287 mmol) and piperidine (0.00244 g, 0.0287 mmol), and the mixture was stirred overnight at room temperature. The reaction mixture was added with methanol (2 mL), and the solid was suspended in methanol and thereby washed to obtain tert-butyl (Z)-4-[(6-hydroxy-2-{[1-(methylsulfonyl)-1H-indol-3-yl]methylene}-3-oxo-2,3-dihydrobenzofuran-7-yl)methyl]piperazine-1-carboxylate (0.104 g, 66%).
Reaction SMILES: [CH:1]1[C:11]2[C:10]3[CH:12]=[CH:13][CH:14]=[CH:15][C:9]=3[CH2:8][N:7]([C:16](=[NH:20])[O:17][CH2:18][CH3:19])[CH2:6][C:5]=2[CH:4]=[CH:3][CH:2]=1.[Cl:21][C:22]1[CH:27]=[C:26]([C:28](Cl)=[O:29])[CH:25]=[C:24]([Cl:31])[N:23]=1>>[Cl:21][C:22]1[CH:27]=[C:26]([CH:25]=[C:24]([Cl:31])[N:23]=1)[C:28]([N:20]=[C:16]([N:7]1[CH2:6][C:5]2[CH:4]=[CH:3][CH:2]=[CH:1][C:11]=2[C:10]2[CH:12]=[CH:13][CH:14]=[CH:15][C:9]=2[CH2:8]1)[O:17][CH2:18][CH3:19])=[O:29]
Reactant: CCOC(=N)N1Cc2ccccc2-c2ccccc2C1
Reactant: O=C(Cl)c1cc(Cl)nc(Cl)c1
Product: CCOC(=NC(=O)c1cc(Cl)nc(Cl)c1)N1Cc2ccccc2-c2ccccc2C1

Procedure:
starting from ethyl 5,7-dihydro-6H-dibenz[c,e]azepine-6-carboximidate and 2,6-dichloropyridine-4-carboxylic acid chloride, there is obtained ethyl N-(2,6-dichloroisonicotinoyl)-5,7-dihydro-6H-dibenz[c,e]azepine-6-carboximidate, m.p. 151°-152° C.;
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([NH:11][C@@H:12]2[CH2:18][C:17]([F:20])([F:19])[CH2:16][CH2:15][NH:14][C:13]2=[O:21])(=[O:10])=[O:9])=[CH:4][CH:3]=1.[F:22][C:23]1[CH:28]=[C:27]([O:29][CH3:30])[CH:26]=[CH:25][C:24]=1[CH2:31]O>>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([N:11]([C@@H:12]2[CH2:18][C:17]([F:19])([F:20])[CH2:16][CH2:15][NH:14][C:13]2=[O:21])[CH2:31][C:24]2[CH:25]=[CH:26][C:27]([O:29][CH3:30])=[CH:28][C:23]=2[F:22])(=[O:9])=[O:10])=[CH:4][CH:3]=1
Reactant: O=C1NCCC(F)(F)C[C@H]1NS(=O)(=O)c1ccc(Cl)cc1
Reactant: COc1ccc(CO)c(F)c1
Product: COc1ccc(CN([C@@H]2CC(F)(F)CCNC2=O)S(=O)(=O)c2ccc(Cl)cc2)c(F)c1

Procedure:
4-Chloro-N-((R)-5,5-difluoro-2-oxo-azepan-3-yl)-benzenesulfonamide was reacted with (2-fluoro-4-methoxy-phenyl)-methanol analogous to Example 3a to afford 4-chloro-N-((R)-5,5-difluoro-2-oxo-azepan-3-yl)-N-(2-fluoro-4-methoxy-benzyl)-benzenesulfonamide:
Reaction SMILES: [Br:1][CH2:2][CH2:3]Br.[Br:5][C:6]1[C:7]([OH:16])=[C:8]([O:14][CH3:15])[CH:9]=[C:10]([CH:13]=1)[CH:11]=[O:12].C(=O)([O-])[O-].[K+].[K+].O>CN(C=O)C>[Br:1][CH2:2][CH2:3][O:16][C:7]1[C:8]([O:14][CH3:15])=[CH:9][C:10]([CH:11]=[O:12])=[CH:13][C:6]=1[Br:5]
Reactant: BrCCBr
Reactant: COc1cc(C=O)cc(Br)c1O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: COc1cc(C=O)cc(Br)c1OCCBr
Temperature: 25 °C
Reaction time: 16 h
Yield: 94.3 %

Procedure:
1,2-Dibromoethane (37 mL, 0.43 moles) was added to a mixture of 5-bromovanillin (10 g, 43 mmoles) and potassium carbonate (30 g, 216 mmoles) in DMF (150 ml) and the resulting mixture was stirred vigorously at room temperature for 16 hours followed by vigorously stirring at 60° C. for 16 hours. The cooled mixture was poured into water (1 L) and extracted with ethyl acetate (3×250 mL). The combined organic phases were washed with saturated sodium chloride (300 mL), dried over MgSO4 and evaporated in vacuo to afford 13.7 g (94%) of 4-(2-bromoethoxy)-3-bromo-5-methoxybenzaldehyde.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:15]=[CH:16][CH:17]=1)[CH2:5][O:6][C:7]1[CH:12]=[CH:11][C:10]([CH2:13][OH:14])=[CH:9][CH:8]=1.[H-].[Na+].Cl[CH2:21][C:22]([NH2:24])=[O:23].O>O1CCCC1>[F:1][C:2]1[CH:3]=[C:4]([CH:15]=[CH:16][CH:17]=1)[CH2:5][O:6][C:7]1[CH:12]=[CH:11][C:10]([CH2:13][O:14][CH2:21][C:22]([NH2:24])=[O:23])=[CH:9][CH:8]=1
Reactant: NC(=O)CCl
Reactant: OCc1ccc(OCc2cccc(F)c2)cc1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: NC(=O)COCc1ccc(OCc2cccc(F)c2)cc1
Reaction time: 1 h
Yield: 5.1 %

Procedure:
A solution of 500 mg of [4-(3-fluoro-benzyloxy)-phenyl]-methanol [Example 25b)] in 10 ml of tetrahydrofurane was treated at room temperature with 57 mg of sodium hydride (55% dispersion in oil) and stirred for 1 h. Thereafter, 183 mg of chloroacetamide were added and the mixture was heated to reflux for 48 h. For the working-up, the cooled mixture was treated with water and extracted with ethyl acetate. The organic layer was dried over magnesium sulphate and evaporated under reduced pressure. For purification, the crude material obtained was chromatographed on silica gel using a gradient of dichloromethane to a 4:1-mixture-mixture of dichloromethane and methanol as the eluent. After crystallisation from ether, there were obtained 29 mg (5% of theory) of 2-[4-(3-fluoro-benzyloxy)-benzyloxy]-acetamide as a white solid; MS: m/e=307 (M+NH4)+.
Reaction SMILES: [Cl:1][SiH:2]([Cl:4])[Cl:3].[Cl-:5].[Cl-].[CH2:7]([Zr:11]([CH3:33])(=[SiH2:32])([CH:22]1[C:30]2[C:25](=[CH:26][CH:27]=[CH:28][CH:29]=2)[CH:24]=[C:23]1[CH3:31])[CH:12]1[C:20]2[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=2)[CH:14]=[C:13]1[CH3:21])[CH2:8][CH:9]=[CH2:10]>C1(C)C=CC=CC=1>[Cl-:1].[Cl-:5].[Cl:1][Si:2]([Cl:4])([Cl:3])[CH2:10][CH2:9][CH2:8][CH2:7][Zr:11]([CH3:33])(=[SiH2:32])([CH:22]1[C:30]2[C:25](=[CH:26][CH:27]=[CH:28][CH:29]=2)[CH:24]=[C:23]1[CH3:31])[CH:12]1[C:20]2[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=2)[CH:14]=[C:13]1[CH3:21]
Reactant: Cl[SiH](Cl)Cl
Reactant: C=CCC[Zr](C)(=[SiH2])(C1C(C)=Cc2ccccc21)C1C(C)=Cc2ccccc21
Agent: [Cl-]
Solvent: Cc1ccccc1
Product: CC1=Cc2ccccc2C1[Zr](C)(=[SiH2])(CCCC[Si](Cl)(Cl)Cl)C1C(C)=Cc2ccccc21
Temperature: 25 °C
Reaction time: 24 h

Procedure:
0.4 g (3 mmol) of trichlorosilane and 10 mg of H2PtCl6.6H2 O were added to a solution of 0.52 g (1 mmol) of (3-butenyl)(methyl)silanediyl[bis(2-methylindenyl)]zirconium dichloride in 5 ml of toluene. After stirring for 24 hours at room temperature, the excess trichlorosilane and the toluene were removed in an oil pump vacuum. This gives 0.69 g of an oil which no longer shows any resonance signals of the vinyl protons in the 1H-NMR spectrum.
Reaction SMILES: C1(C(C2C=CC=CC=2)=[N:8][NH:9][C:10]2[CH:11]=[C:12]3[C:17](=[CH:18][CH:19]=2)[N:16]=[CH:15][CH:14]=[CH:13]3)C=CC=CC=1.[CH:26]1([C:31](=O)[CH2:32][C:33]#[N:34])[CH2:30][CH2:29][CH2:28][CH2:27]1>>[CH:26]1([C:31]2[CH:32]=[C:33]([NH2:34])[N:9]([C:10]3[CH:11]=[C:12]4[C:17](=[CH:18][CH:19]=3)[N:16]=[CH:15][CH:14]=[CH:13]4)[N:8]=2)[CH2:30][CH2:29][CH2:28][CH2:27]1
Reactant: c1ccc(C(=NNc2ccc3ncccc3c2)c2ccccc2)cc1
Reactant: N#CCC(=O)C1CCCC1
Product: Nc1cc(C2CCCC2)nn1-c1ccc2ncccc2c1
Yield: 53.3 %

Procedure:
Using a procedure analogous to Example B3, 6-(2-(diphenylmethylene)hydrazinyl)quinoline (5.0 g, 15.5 mmol) and 3-cyclopentyl-3-oxopropanenitrile (3.0 g, 1.1 eq) were combined to yield 3-cyclopentyl-1-(quinolin-6-yl)-1H-pyrazol-5-amine (2.3 g, 53% yield). 1H NMR (300 MHz, DMSO-d6) δ 8.87 (m, 1H), 8.38 (dd, J=1.5, 8.4 Hz, 1H), 8.10 (s, 1H), 8.04-8.02 (m, 2H), 7.55 (dd, J=4.2, 8.1 Hz, 1H), 5.41 (br s, 2H), 5.38 (s, 1H), 2.90 (m, 1H), 1.85-1.96 (m, 2H), 1.53-1.70 (m, 6H); MS (ESI) m/z: 279.3 (M+H+).
Reaction SMILES: [CH2:1]([O:3][CH2:4][CH2:5][S:6][C:7]1[S:8][CH:9]=[C:10]([C:12]2[CH:13]=[N:14][CH:15]=[CH:16][CH:17]=2)[N:11]=1)[CH3:2].OO.C(=O)([O-])[OH:21].[Na+]>C(O)(=O)C.O.[O-][W]([O-])(=O)=O.[Na+].[Na+]>[CH2:1]([O:3][CH2:4][CH2:5][S:6]([C:7]1[S:8][CH:9]=[C:10]([C:12]2[CH:13]=[N:14][CH:15]=[CH:16][CH:17]=2)[N:11]=1)=[O:21])[CH3:2]
Reactant: O=C([O-])O
Reactant: CCOCCSc1nc(-c2cccnc2)cs1
Agent: O=[W](=O)([O-])[O-]
Agent: OO
Agent: [Na+]
Solvent: O
Solvent: CC(=O)O
Product: CCOCCS(=O)c1nc(-c2cccnc2)cs1
Temperature: 25 °C
Reaction time: 4 h
Yield: 77 %

Procedure:
Dissolved in 1.7 ml of acetic acid were 0.33 g (1.24 mmol) of the compound obtained in Example 1, and 0.15 ml (1.32 mmol) of a 30% aqueous solution of hydrogen peroxide and a catalytic amount of sodium tungstate were successively added to the solution, which was stirred at room temperature for 4 hours. The reaction solution was poured in 34 ml of water, neutralized with sodium hydrogencarbonate and extracted with 34 ml of chloroform. After separation of the chloroform layer, the organic layer was dried over anhydrous magnesium sulfate and concentrated in vacuo. The residues were purified by silica gel chromatography to obtain 0.27 g of white crystalline powders (77% yield).
Reaction SMILES: Cl.[CH3:2][S:3]([C:6]1[CH:12]=[CH:11][C:9]([NH2:10])=[CH:8][CH:7]=1)(=[O:5])=[O:4].C[Al](C)C.[C:17]([C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][N:20]=1)#[N:18]>C1(C)C=CC=CC=1.C(Cl)(Cl)Cl>[CH3:2][S:3]([C:6]1[CH:12]=[CH:11][C:9]([NH:10][C:17]([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][N:20]=2)=[NH:18])=[CH:8][CH:7]=1)(=[O:4])=[O:5]
Reactant: N#Cc1ccccn1
Reactant: CS(=O)(=O)c1ccc(N)cc1
Agent: C[Al](C)C
Agent: Cl
Solvent: Cc1ccccc1
Solvent: ClC(Cl)Cl
Product: CS(=O)(=O)c1ccc(NC(=N)c2ccccn2)cc1
Temperature: 25 °C
Reaction time: 2.5 h

Procedure:
To a suspension of 4-(methylsulfonyl)aniline hydrochloride (6 g, 28.8 mmol) in toluene (150 ml) at 0° C., trimethylaluminum (2M solution in toluene, 21.6 ml, 43.2 mmol) was added over 15 minutes. The reaction mixture was warmed to room temperature and stirred for 2.5 hours. A solution of 2-cyanopyridine (6 g, 57.6 mmol) in toluene (150 ml) was added over 10 minutes and the reaction mixture was heated to 85°-90° C. After 24 hours, the reaction mixture was cooled to room temperature and poured over a slurry of silica gel in chloroform. After filtration, the residue was washed with a mixture of methylene chloride/methanol and later methanol. The combined filtrates were concentrated and the resulting yellowish solid was stirred with ethyl acetate (1500 ml) and filtered. The pale yellow solid (5.2 g, 66%) was used in the next reaction without further purification.
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:11]=1[N:10]=[C:9]([Cl:12])[N:8]=[C:7]2[N:13]1[CH2:18][CH2:17][O:16][CH2:15][CH2:14]1.[OH:19][C:20]1[CH:21]=[C:22](B(O)O)[CH:23]=[CH:24][CH:25]=1.C(=O)([O-])[O-].[Na+].[Na+].CN(C=O)C>Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.O>[Cl:12][C:9]1[N:8]=[C:7]([N:13]2[CH2:18][CH2:17][O:16][CH2:15][CH2:14]2)[C:6]2[C:11](=[C:2]([C:24]3[CH:25]=[C:20]([OH:19])[CH:21]=[CH:22][CH:23]=3)[CH:3]=[CH:4][CH:5]=2)[N:10]=1
Reactant: OB(O)c1cccc(O)c1
Reactant: Clc1nc(N2CCOCC2)c2cccc(Br)c2n1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: Oc1cccc(-c2cccc3c(N4CCOCC4)nc(Cl)nc23)c1
Temperature: 95 °C
Reaction time: 2 h
Yield: 60.7 %

Procedure:
To a 50 mL round bottom flask, 8-bromo-2-chloro-4-morpholin-4-yl-quinazoline (150 mg, 0.00046 mol), 3-hydroxyphenylboronic acid (57 mg, 0.00041 mol), sodium carbonate (97 mg, 0.00091 mol), DMF (10 mL) and water (5 mL) were added. The reaction mixture was degassed with nitrogen for 5-10 min. To the same flask Pd(PPh3)2Cl2 (16 mg, 0.000022 mol) was added and again degassed with nitrogen for 5-10 min. The reaction mixture was stirred at 95° C. for 2 h. The reaction mixture was cooled and diluted with ethyl acetate. The organic layer was washed with water, brine and dried over sodium sulfate. The solvent was removed under reduced pressure to afford the crude residue. The crude product was purified using column chromatography (60-120 silica gel, 1% MeOH in chloroform) to yield the desired title product (85 mg, 46%). 1H NMR: (300 MHz, CDCl3): δ 7.70-7.78 (m, 2H), 7.40-7.44 (m, 1H), 7.20-7.26 (m, 1H), 7.03-7.05 (m, 2H), 6.78-6.83 (m, 1H), 3.81-3.83 (m, 8H); LC-MS (ESI): Calculated mass: 341.1; Observed mass: 342.1 [M+H]+ (RT: 1.53 min).
Reaction SMILES: N[C:2]1[CH:6]=[C:5]([C:7]([CH3:10])([CH3:9])[CH3:8])[NH:4][C:3]=1[C:11]([O:13][CH3:14])=[O:12].[H-].[Na+].[C:17](Cl)(=[O:26])[O:18][CH2:19][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1>C1COCC1.C(OCC)(=O)C>[CH2:19]([O:18][C:17]([C:2]1[CH:6]=[C:5]([C:7]([CH3:10])([CH3:9])[CH3:8])[NH:4][C:3]=1[C:11]([O:13][CH3:14])=[O:12])=[O:26])[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1
Reactant: O=C(Cl)OCc1ccccc1
Reactant: COC(=O)c1[nH]c(C(C)(C)C)cc1N
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: COC(=O)c1[nH]c(C(C)(C)C)cc1C(=O)OCc1ccccc1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
A mixture of the previously prepared methyl 3-amino-5-tert-butyl-1H-pyrrole-2-carboxylate (0.400 g, 2.0 mmol) and NaH (60% w/w, 0.760 g, 4.5 mmol) in THF (4 mL) was stirred at room temperature for 30 min. To the resulting mixture was added benzyl carbonochloridate drop wise and stirred at room temperature overnight. The reaction mixture was diluted with ethyl acetate and washed with saturated sodium bicarbonate solution. The crude product was recrystallized from dichloromethane:hexane to afford the desired methyl 3-(benzyloxycarbonyl)-5-tert-butyl-1H-pyrrole-2-carboxylate (0.560 g) as a white solid.