Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[C:7]([O:9][CH2:10][O:11][CH3:12])[C:6]([O:13][CH3:14])=[CH:5][C:4]=1[O:15][CH2:16][O:17][CH3:18].CN(C)CCN(C)C.[CH2:27]([Li])[CH2:28][CH2:29][CH3:30].ICCCC>C1(C)C=CC=CC=1.CN(C)P(=O)(N(C)C)N(C)C>[CH2:27]([C:8]1[C:7]([O:9][CH2:10][O:11][CH3:12])=[C:6]([O:13][CH3:14])[CH:5]=[C:4]([O:15][CH2:16][O:17][CH3:18])[C:3]=1[O:2][CH3:1])[CH2:28][CH2:29][CH3:30]
Reactant: COCOc1cc(OC)c(OCOC)cc1OC
Reactant: [Li]CCCC
Agent: CN(C)CCN(C)C
Solvent: Cc1ccccc1
Solvent: CCCCI
Solvent: CN(C)P(=O)(N(C)C)N(C)C
Product: CCCCc1c(OC)c(OCOC)cc(OC)c1OCOC
Reaction time: 0.5 h

Procedure:
10 Grams of 1,4-dimethoxy-2,5-bis(methoxymethoxy)benzene was dissolved in 200 ml of anhydrous toluene under argon gas stream conditions, to this solution were added 50 ml of hexamethylphosphoric triamide and 8.75 ml of N,N,N',N'-tetramethylethylenediamine (TMEDA), and the mixture was cooled in a dry ice-acetone mixture bath. To this cooled mixture was added dropwise 39 ml of n-butyllithium (1.5 M, n-hexane solution), then stirred the mixture for 30 minutes. Next, 8.9 ml of 1-iodobutane was added to the reaction mixture, and the temperature was back to room temperature by taking for 12 hours. By procedures similar to those described in Reference Example 1, the above-mentioned reaction mixture was purified to obtain 8.5 g of 3-butyl-1,4-dimethoxy-2,5-bis(methoxymethoxy)benzene. Colorless oily substance.
Reaction SMILES: [N:1]1([C:7]2[C:8]3[C:15]([C:16]4[CH:17]=[C:18]([CH:21]=[CH:22][CH:23]=4)[C:19]#[N:20])=[CH:14][NH:13][C:9]=3[N:10]=[CH:11][N:12]=2)[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1.ClC1C2C(I)=CN([CH2:35][O:36][CH2:37][CH2:38][Si:39]([CH3:42])([CH3:41])[CH3:40])C=2N=CN=1>>[N:1]1([C:7]2[C:8]3[C:15]([C:16]4[CH:17]=[C:18]([CH:21]=[CH:22][CH:23]=4)[C:19]#[N:20])=[CH:14][N:13]([CH2:35][O:36][CH2:37][CH2:38][Si:39]([CH3:42])([CH3:41])[CH3:40])[C:9]=3[N:10]=[CH:11][N:12]=2)[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1
Reactant: N#Cc1cccc(-c2c[nH]c3ncnc(N4CCOCC4)c23)c1
Reactant: C[Si](C)(C)CCOCn1cc(I)c2c(Cl)ncnc21
Product: C[Si](C)(C)CCOCn1cc(-c2cccc(C#N)c2)c2c(N3CCOCC3)ncnc21

Procedure:
3-[4-(Morpholin-4-yl)-7H-pyrrolo[2,3-d]pyrimidin-5-yl]benzonitrile (4) was converted to the product using the method described for synthesis of 4-chloro-5-iodo-7-{[2-(trimethylsilyl)ethoxy]methyl}-7H-pyrrolo[2,3-d]pyrimidine (C1) in Preparation P1. The product was obtained as a yellow solid. Yield: 0.90 g, 2.1 mmol, 70%. 1H NMR (400 MHz, CDCl3) δ 8.55 (s, 1H), 7.86 (br s, 1H), 7.79 (br d, J=7.6 Hz, 1H), 7.63 (br d, J=7.6 Hz, 1H), 7.57 (dd, J=7.6, 7.6 Hz, 1H), 7.29 (s, 1H), 5.67 (s, 2H), 3.58-3.64 (m, 2H), 3.52-3.58 (m, 4H), 3.27-3.32 (m, 4H), 0.92-0.98 (m, 2H), −0.03 (s, 9H).
Reaction SMILES: [C:1]1([C:7]2[S:8][C:9]3[CH:14]=[CH:13][NH:12][C:11](=[O:15])[C:10]=3[N:16]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[Br:17]Br.O>C(O)(=O)C>[Br:17][C:14]1[C:9]2[S:8][C:7]([C:1]3[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=3)=[N:16][C:10]=2[C:11](=[O:15])[NH:12][CH:13]=1
Reactant: O=c1[nH]ccc2sc(-c3ccccc3)nc12
Reactant: BrBr
Solvent: CC(=O)O
Solvent: O
Product: O=c1[nH]cc(Br)c2sc(-c3ccccc3)nc12
Temperature: 25 °C
Yield: 98 %

Procedure:
A solution of 2-phenyl-5H-thiazolo[4,5-c]pyridin-4-one 44 (400 mg, 1.75 mmol) in acetic acid (5 mL) at rt was treated with bromine (320 mg, 1.93 mmol) and the resulting mixture was heated at reflux for 30 min. After cooling to rt, water (20 mL) was added to the mixture. The yellow solid which formed was filtered, washed with water and dried in the air to afford 45 (527 mg). 1H NMR (400 MHz, d6-DMSO) δ: 7.57 (m, 3H), 7.70 (s, 1H), 8.05 (m, 2H). MS (EI) m/z (M+H+) 308.
Reaction SMILES: [OH:1][N:2]1C(=O)C2=CC=CC=C2C1=O.[CH3:13][C:14]1[CH:21]=[CH:20][C:17]([CH2:18]Br)=[CH:16][C:15]=1[C:22]([F:25])([F:24])[F:23]>>[CH3:13][C:14]1[CH:21]=[CH:20][C:17]([CH2:18][O:1][NH2:2])=[CH:16][C:15]=1[C:22]([F:25])([F:24])[F:23]
Reactant: Cc1ccc(CBr)cc1C(F)(F)F
Reactant: O=C1c2ccccc2C(=O)N1O
Product: Cc1ccc(CON)cc1C(F)(F)F

Procedure:
Prepared by a similar procedure as described for preparation 15, starting from N-hydroxyphthalimide and 4-methyl-3-(trifluoromethyl)benzyl bromide (JRD fluorochemicals). 13C-NMR (CDCl3) δ 136.4, 135.5, 132.1, 131.5, 129.0, 125.8, 124.5, 77.0, 19.1.
Reaction SMILES: CO[C:3]1[C:4](=O)[C:5](=[O:9])[C:6]=1[O:7]C.[CH2:11]([N:15]1[CH2:20][CH2:19][NH:18][CH2:17][CH2:16]1)[CH2:12][CH2:13][CH3:14]>C(O)C>[CH2:11]([N:15]1[CH2:20][CH2:19][N:18]([C:3]2[C:6](=[O:7])[C:5](=[O:9])[C:4]=2[N:18]2[CH2:19][CH2:20][N:15]([CH2:11][CH2:12][CH2:13][CH3:14])[CH2:16][CH2:17]2)[CH2:17][CH2:16]1)[CH2:12][CH2:13][CH3:14]
Reactant: COc1c(OC)c(=O)c1=O
Reactant: CCCCN1CCNCC1
Solvent: CCO
Product: CCCCN1CCN(c2c(N3CCN(CCCC)CC3)c(=O)c2=O)CC1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of 0.9 grams of 3,4-dimethoxy-3-cyclobutene-1,2-dione dissolved in 10 ml. of absolute ethanol is added 1.8 grams of 1-butylpiperazine in 5 ml. of absolute ethanol. The reaction mixture is stirred overnight at room temperature under a nitrogen atmosphere. Then, the solvent is removed with a nitrogen stream, 5 ml. of anhydrous ethyl ether is added, and the resultant solid is filtered, washed with ethyl ether, and dried in air. The resulting product, 3,4-bis(4-butyl-1-piperazinyl)-3-cyclobutene-1,2-dione is obtained as white crystals melting at approximately 137.5°-139° C.
Reaction SMILES: [C:1]1([CH:7]([N:12]2[CH2:17][CH2:16][CH:15]([C:18]3[CH:23]=[CH:22][C:21]([NH:24][C:25]([C:27]4[CH:32]=[CH:31][CH:30]=[CH:29][C:28]=4[C:33]4[CH:38]=[CH:37][C:36]([C:39]([F:42])([F:41])[F:40])=[CH:35][CH:34]=4)=[O:26])=[CH:20][CH:19]=3)[CH2:14][CH2:13]2)[C:8]([O:10]C)=[O:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[ClH:43]>>[ClH:43].[C:1]1([CH:7]([N:12]2[CH2:13][CH2:14][CH:15]([C:18]3[CH:23]=[CH:22][C:21]([NH:24][C:25]([C:27]4[CH:32]=[CH:31][CH:30]=[CH:29][C:28]=4[C:33]4[CH:38]=[CH:37][C:36]([C:39]([F:42])([F:40])[F:41])=[CH:35][CH:34]=4)=[O:26])=[CH:20][CH:19]=3)[CH2:16][CH2:17]2)[C:8]([OH:10])=[O:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: COC(=O)C(c1ccccc1)N1CCC(c2ccc(NC(=O)c3ccccc3-c3ccc(C(F)(F)F)cc3)cc2)CC1
Agent: Cl
Product: O=C(Nc1ccc(C2CCN(C(C(=O)O)c3ccccc3)CC2)cc1)c1ccccc1-c1ccc(C(F)(F)F)cc1

Procedure:
A mixture of intermediate (11) (0.012 mol) in HCl (36%, 100 ml) was stirred and refluxed for 6 hours, then stirred overnight at room temperature. The precipitate was filtered off and triturated under 2-propanol. The precipitate was filtered off and dried, yielding 6.2 g of α-phenyl-4-[4-[[[4′-(trifluoromethyl)[1,1′-biphenyl]-2-yl]carbonyl]-amino]phenyl]-1-piperidineacetic acid monohydrochloride (intermediate 12).
Reaction SMILES: [NH2:1][C:2]1[C:7]([C:8]#[N:9])=[C:6](Cl)[N:5]=[CH:4][N:3]=1.CCN(C(C)C)C(C)C.[F:20][C:21]1[CH:22]=[CH:23][C:24]2[N:28]=[C:27]([CH:29]([NH2:31])[CH3:30])[N:26]([C:32]3[CH:33]=[N:34][CH:35]=[C:36]([F:38])[CH:37]=3)[C:25]=2[CH:39]=1>C(O)CCC>[NH2:1][C:2]1[C:7]([C:8]#[N:9])=[C:6]([NH:31][CH:29]([C:27]2[N:26]([C:32]3[CH:33]=[N:34][CH:35]=[C:36]([F:38])[CH:37]=3)[C:25]3[CH:39]=[C:21]([F:20])[CH:22]=[CH:23][C:24]=3[N:28]=2)[CH3:30])[N:5]=[CH:4][N:3]=1
Reactant: CC(N)c1nc2ccc(F)cc2n1-c1cncc(F)c1
Reactant: N#Cc1c(N)ncnc1Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: CCCCO
Product: CC(Nc1ncnc(N)c1C#N)c1nc2ccc(F)cc2n1-c1cncc(F)c1
Temperature: 120 °C
Reaction time: 4 h

Procedure:
To a microwave vessel was added 4-amino-6-chloropyrimidine-5-carbonitrile (0.075 g, 0.486 mmol), DIEA (0.162 mL, 0.926 mmol), and 1-(6-fluoro-1-(5-fluoropyridin-3-yl)-1H-benzo[d]imidazol-2-yl)ethanamine (0.127 g, 0.463 mmol) in n-butanol (2.315 mL). The solution was stirred at 120° C. for 4 h under microwave irradiation and then purified by column chromatography on a silica gel column using 0 to 10% gradient of MeOH in DCM as eluent to give 4-amino-6-((1-(6-fluoro-1-(5-fluoro-3-pyridinyl)-1H-benzimidazol-2-yl)ethyl)amino)-5-pyrimidinecarbonitrile: 1H NMR (400 MHz, DMSO-d6) δ ppm 1.59 (d, J=6.85 Hz, 3H) 5.60 (qd, J=7.04, 6.85 Hz, 1H) 7.08 (dd, J=9.00, 2.35 Hz, 1H) 7.15 (td, J=9.78, 8.90, 2.45 Hz, 1H) 7.25 (br. s., 2H) 7.69-7.81 (m, 2H) 7.84 (s, 1H) 8.08 (d, J=9.00 Hz, 1H) 8.63 (s, 1H) 8.67 (d, J=2.54 Hz, 1H); LC-MS (ESI) m/z 393.0 [M+H]+.
Reaction SMILES: [CH3:1][N:2]1[C:7]([NH2:8])=[N:6][C:4](=[O:5])[CH2:3]1.[CH3:9][C:10]1[CH:14]=[CH:13][S:12][C:11]=1[N:15]=[C:16]=[O:17].O>CN(C=O)C.C1(C)C=CC=CC=1>[CH3:9][C:10]1[CH:14]=[CH:13][S:12][C:11]=1[NH:15][C:16]([N:8]=[C:7]1[NH:6][C:4](=[O:5])[CH2:3][N:2]1[CH3:1])=[O:17]
Reactant: Cc1ccsc1N=C=O
Reactant: CN1CC(=O)N=C1N
Solvent: CN(C)C=O
Solvent: O
Solvent: Cc1ccccc1
Product: Cc1ccsc1NC(=O)N=C1NC(=O)CN1C
Temperature: 90 °C
Reaction time: 6 h
Yield: 17.9 %

Procedure:
To a stirred suspension of 3.0 g (26.0 mM) of creatinine in 50 ml of anhydrous DMF was added dropwise a solution of 3.7 g (26 mM) of 3-methyl-2-thienyl isocyanate in 35 ml of toluene. After stirring at 90° C. for 6 hrs., the reaction mixture was cooled and poured into 100 ml of water. The separated solid was collected, washed with water and recrystallized from ethyl acetate to give 1.2 g of the above urea as a grey-white solid, m.p. 201°-202° C.
Reaction SMILES: Br[CH2:2][CH2:3][O:4][C:5]1[CH:10]=[CH:9][C:8]([C:11]2[C:15]3[CH:16]=[CH:17][C:18]([F:20])=[CH:19][C:14]=3[O:13][N:12]=2)=[CH:7][CH:6]=1.[NH:21]1[CH2:25][CH2:24][CH2:23][CH2:22]1.C(=O)([O-])[O-].[K+].[K+].[I-].[K+]>C(#N)C>[F:20][C:18]1[CH:17]=[CH:16][C:15]2[C:11]([C:8]3[CH:9]=[CH:10][C:5]([O:4][CH2:3][CH2:2][N:21]4[CH2:25][CH2:24][CH2:23][CH2:22]4)=[CH:6][CH:7]=3)=[N:12][O:13][C:14]=2[CH:19]=1
Reactant: C1CCNC1
Reactant: Fc1ccc2c(-c3ccc(OCCBr)cc3)noc2c1
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: CC#N
Product: Fc1ccc2c(-c3ccc(OCCN4CCCC4)cc3)noc2c1

Procedure:
The title compound is prepared from a mixture of 3[4-(2-bromo-ethoxy)-phenyl]-6-fluoro-benzo[d]isoxazole, pyrrolidine, potassium carbonate, potassium iodide and 5% aqueous acetonitrile at 75° C. essentially as described above in Example 13, except that the column is eluted with 10% methanol in ethyl acetate. Purity by LC/MS=99%, [M+H]+=327.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[C:6]([O:8][C:9]2[C:10]([C:14]([OH:16])=[O:15])=[CH:11][S:12][CH:13]=2)[CH:5]=[CH:4][C:3]=1[CH3:17].[C:18](OC(=O)C)(=[O:20])[CH3:19]>>[C:18]([NH:1][C:2]1[CH:7]=[C:6]([O:8][C:9]2[C:10]([C:14]([OH:16])=[O:15])=[CH:11][S:12][CH:13]=2)[CH:5]=[CH:4][C:3]=1[CH3:17])(=[O:20])[CH3:19]
Reactant: Cc1ccc(Oc2cscc2C(=O)O)cc1N
Reactant: CC(=O)OC(C)=O
Product: CC(=O)Nc1cc(Oc2cscc2C(=O)O)ccc1C

Procedure:
When 7-methyl-thieno[3,4-b][1,5]benzoxazepin-10-(9H)-one is refluxed for 16 hours in 5 N sodium hydroxide, diluted with water, adjusted to pH 4-5 with dilute hydrochloric acid and extracted with methylene chloride, 4-(2-amino-p-tolyloxy)-3-thiophenecarboxylic acid (IX) is obtained. Compound IX is treated with acetic anhydride and extracted with ether to give 4-(2-acetamido-p-tolyloxy)-3-thiophenecarboxylic acid (X). When a stirred mixture of X and lithium aluminum hydride in ether is refluxed for 16 hours and the resulting product is dissolved in ether and treated with alcoholic hydrochloric acid, the compound 4-(2-ethylamino-p-tolyloxy)-3-thiophenemethanol hydrochloride (XI) is obtained.
Reaction SMILES: [C:1]([NH:4][C:5]1[CH:6]=[CH:7][C:8](Br)=[C:9]([CH:13]=1)[C:10]([OH:12])=[O:11])(=[O:3])[CH3:2].CN(C=O)C.[NH2:20][C:21]1[N:25]([CH2:26][CH3:27])[N:24]=[CH:23][CH:22]=1.C([O-])([O-])=O.[K+].[K+]>CC([O-])=O.CC([O-])=O.[Cu+2].C(O)(=O)C.O>[CH2:26]([N:25]1[C:21]([NH:20][C:8]2[C:9](=[CH:13][C:5]([NH:4][C:1](=[O:3])[CH3:2])=[CH:6][CH:7]=2)[C:10]([OH:12])=[O:11])=[CH:22][CH:23]=[N:24]1)[CH3:27]
Reactant: CCn1nccc1N
Reactant: CC(=O)Nc1ccc(Br)c(C(=O)O)c1
Agent: [Cu+2]
Agent: CC(=O)[O-]
Agent: O=C([O-])[O-]
Solvent: O
Solvent: CC(=O)O
Solvent: CN(C)C=O
Product: CCn1nccc1Nc1ccc(NC(C)=O)cc1C(=O)O
Yield: 25.7 %

Procedure:
A mixture of 5-acetamido-2-bromobenzoic acid (7 g, 27 mmol), DMF (25 ml), Cu(OAc)2 (0.2 g), 5-amino-1-ethyl-pyrazole (3 g, 27 mmol) and K2CO3 (3.7 g, 27 mmol) was refluxed for about 2 days. The reaction mixture was poured into water, acidified with acetic acid and cooled. A solid formed which was collected by filtration to afford 2 g of N-(1-ethylpyrazole-5-yl)-5-acetamidoanthranilic acid.
Reaction SMILES: FC(F)(F)S([O:6][C:7]1[CH:20]=[CH:19][C:10]2[C@H:11]([CH2:14][C:15]([O:17]C)=[O:16])[CH2:12][O:13][C:9]=2[CH:8]=1)(=O)=O.[CH3:23][C:24]1[CH:29]=[C:28]([O:30][CH2:31][CH2:32][CH2:33][S:34]([CH3:37])(=[O:36])=[O:35])[CH:27]=[C:26]([CH3:38])[C:25]=1[C:39]1[CH:44]=[CH:43][CH:42]=[C:41]([CH2:45]O)[CH:40]=1.P([O-])([O-])([O-])=O.[K+].[K+].[K+]>C(#N)C>[CH3:38][C:26]1[CH:27]=[C:28]([O:30][CH2:31][CH2:32][CH2:33][S:34]([CH3:37])(=[O:35])=[O:36])[CH:29]=[C:24]([CH3:23])[C:25]=1[C:39]1[CH:44]=[CH:43][CH:42]=[C:41]([CH2:45][O:6][C:7]2[CH:20]=[CH:19][C:10]3[C:11]([CH2:14][C:15]([OH:17])=[O:16])=[CH:12][O:13][C:9]=3[CH:8]=2)[CH:40]=1
Reactant: Cc1cc(OCCCS(C)(=O)=O)cc(C)c1-c1cccc(CO)c1
Reactant: COC(=O)C[C@@H]1COc2cc(OS(=O)(=O)C(F)(F)F)ccc21
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: Cc1cc(OCCCS(C)(=O)=O)cc(C)c1-c1cccc(COc2ccc3c(CC(=O)O)coc3c2)c1
Temperature: 70 °C
Reaction time: 3 h
Yield: 64.3 %

Procedure:
To a solution of methyl(S)-2-(6-(((trifluoromethyl)sulfonyl)oxy)-2,3-dihydrobenzofuran-3-yl)acetate (4.88 g) and (2′,6′-dimethyl-4′-(3-(methylsulfonyl)propoxy)-[1,1′-biphenyl]-3-yl)methanol (5.00 g) in acetonitrile (15 mL) was added tripotassium phosphate (4.57 g), and the mixture was stirred at 70° C. for 3 hr. The mixture was allowed to cool to room temperature and concentrated, toluene (60 mL) and water (60 mL) were added, and an extraction operation was performed. The organic layer was washed with water (60 mL) and 10% brine (60 mL), and concentrated. The obtained oil was dissolved in dimethyl sulfoxide (30 mL), and 2N sodium hydroxide (8 mL) was added at room temperature. The mixture was stirred at 70° C. for 1 hr, and allowed to cool to room temperature. Ethyl acetate (60 mL) and water (60 mL) were added, and the mixture was partitioned. The aqueous layer was acidified with 6N hydrochloric acid to pH 1, ethyl acetate (60 mL) was added, and an extraction operation was performed. The organic layer was washed with water (60 mL), and concentrated. The crude product was recrystallized from acetone (30 mL)-water (60 mL), and the obtained solid was dried at 60° C. under reduced pressure to give the title compound (4.82 g) as white crystals. Yield 64%.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([N:8]([C:16]2[CH:21]=[CH:20][C:19](Br)=[CH:18][CH:17]=2)[C:9]2[CH:14]=[CH:13][C:12](Br)=[CH:11][CH:10]=2)=[CH:4][CH:3]=1.C([Sn](CCCC)(CCCC)[C:28]1[S:29][CH:30]=[CH:31][CH:32]=1)CCC>C1(C)C=CC=CC=1.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>[S:29]1[CH:30]=[CH:31][CH:32]=[C:28]1[C:2]1[CH:7]=[CH:6][C:5]([N:8]([C:16]2[CH:21]=[CH:20][C:19]([C:30]3[S:29][CH:28]=[CH:32][CH:31]=3)=[CH:18][CH:17]=2)[C:9]2[CH:14]=[CH:13][C:12]([C:28]3[S:29][CH:30]=[CH:31][CH:32]=3)=[CH:11][CH:10]=2)=[CH:4][CH:3]=1
Reactant: Brc1ccc(N(c2ccc(Br)cc2)c2ccc(Br)cc2)cc1
Reactant: CCCC[Sn](CCCC)(CCCC)c1cccs1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: Cc1ccccc1
Product: c1csc(-c2ccc(N(c3ccc(-c4cccs4)cc3)c3ccc(-c4cccs4)cc3)cc2)c1
Temperature: 25 °C
Yield: 85 %

Procedure:
First, 1 g (2 mmol) of tris(4-bromophenyl)amine (Aldrich) was dissolved in 100 ml of toluene, and then 2.9 ml (4.5 eq.) of 2-tributylstannylthiophene and 27 mg (1.1%) of Pd(PPh3)4 were added thereto. The mixture was refluxed under a nitrogen atmosphere for 12 hours. The reaction mixture was allowed to cool to room temperature, washed with brine twice, and dried over MgSO4. After the solvent was evaporated, the obtained residue was washed with petroleum ether (PE), and dried, affording 0.87 g (yield: 85%) of tris[4-(2-thienyl)phenyl]amine as a pale yellow solid.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:12]([CH:13]3[CH2:15][CH2:14]3)[C:11](=[O:16])[N:10]([CH2:17][C:18](O)=[O:19])[N:9]=2)=[CH:4][CH:3]=1.[F:21][C:22]([F:34])([F:33])[C:23]1[CH:24]=[C:25]([C:29]([NH2:32])([CH3:31])[CH3:30])[CH:26]=[CH:27][CH:28]=1.C1C=CC2N(O)N=NC=2C=1.CCN=C=NCCCN(C)C.Cl>CN(C)C=O>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[N:12]([CH:13]3[CH2:15][CH2:14]3)[C:11](=[O:16])[N:10]([CH2:17][C:18]([NH:32][C:29]([CH3:31])([C:25]3[CH:26]=[CH:27][CH:28]=[C:23]([C:22]([F:21])([F:33])[F:34])[CH:24]=3)[CH3:30])=[O:19])[N:9]=2)=[CH:6][CH:7]=1
Reactant: O=C(O)Cn1nc(-c2ccc(Cl)cc2)n(C2CC2)c1=O
Reactant: CC(C)(N)c1cccc(C(F)(F)F)c1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Product: CC(C)(NC(=O)Cn1nc(-c2ccc(Cl)cc2)n(C2CC2)c1=O)c1cccc(C(F)(F)F)c1
Reaction time: 0.17 h

Procedure:
70.0 mg (0.238 mmol) of [3-(4-chlorophenyl)-4-cyclopropyl-5-oxo-4,5-dihydro-1H-1,2,4-triazol-1-yl]-acetic acid from Example 88A and 53.3 mg (0.262 mmol) of 1-methyl-1-[(3-trifluoromethyl)-phenyl]ethylamine from Example 1A are placed in 2 ml of dimethylformamide and treated with 38.6 mg (0.286 mmol) of HOBt. After 10 mins' stirring, 59.4 mg (0.310 mmol) of EDC hydrochloride are added and the mixture is stirred overnight at room temperature. For the workup, the reaction mixture is partitioned between dichloromethane and water, and the organic phase is separated, dried over sodium sulphate and concentrated. The residue is purified by flash chromatography on silica gel (eluent: dichloromethane/methanol first 200:1, then 100:1). 97 mg (85% of theory) of the target compound are thus obtained.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][C:6](=[O:11])[C:5]2([F:13])[F:12].[H-].[Na+].[CH3:16][Si:17]([CH2:20][CH2:21][O:22][CH2:23]Cl)([CH3:19])[CH3:18].[NH4+].[Cl-]>CN(C=O)C>[Br:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[N:7]([CH2:23][O:22][CH2:21][CH2:20][Si:17]([CH3:19])([CH3:18])[CH3:16])[C:6](=[O:11])[C:5]2([F:13])[F:12]
Reactant: O=C1Nc2ccc(Br)cc2C1(F)F
Reactant: C[Si](C)(C)CCOCCl
Agent: [Cl-]
Agent: [H-]
Agent: [NH4+]
Solvent: CN(C)C=O
Product: C[Si](C)(C)CCOCN1C(=O)C(F)(F)c2cc(Br)ccc21
Temperature: 25 °C
Reaction time: 0.33 h

Procedure:
To a solution of 5-bromo-3,3-difluoroindolin-2-one (600 mg, 2.42 mmol) in DMF (5 mL), 60% NaH (69.6 mg, 2.90 mmol) was added. The resulting mixture was stirred at rt for 20 min and SEM-Cl (472 μL, 2.66 mmol) was added. The reaction mixture was stirred at rt overnight, poured into saturated NH4Cl (40 mL) and extracted with DCM (3×20 mL). The combined DCM layers were dried over Na2SO4, filtered, and concentrated. The residue obtained was purified by flash column chromatography on silica gel (0-100% EtOAc/hexanes) to obtain 5-bromo-3,3-difluoro-1-((2-(trimethylsilyl)ethoxy)methyl)indolin-2-one, which was subjected to borylation using the methods described in Example 32, Step B to obtain compound 37a. 1H-NMR (CDCl3, 400 MHz) δ (ppm): 8.33 (s, 1H), 8.04 (d, J=9.6 Hz, 1H), 7.57 (d, J=8.6 Hz, 1H), 5.46 (s, 2H), 3.75 (m, 2H), 1.27 (s, 12H), 0.95 (m, 2H).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([CH:21]=[CH:22][CH:23]=1)[CH2:5][N:6]1[CH:14]=[N:13][C:12]2[C:7]1=[N:8][C:9]([NH2:20])=[N:10][C:11]=2[C:15]1[O:16][CH:17]=[CH:18][CH:19]=1.[C:24](Cl)(=[O:26])[CH3:25]>N1C=CC=CC=1>[C:24]([NH:1][C:2]1[CH:3]=[C:4]([CH:21]=[CH:22][CH:23]=1)[CH2:5][N:6]1[CH:14]=[N:13][C:12]2[C:7]1=[N:8][C:9]([NH2:20])=[N:10][C:11]=2[C:15]1[O:16][CH:17]=[CH:18][CH:19]=1)(=[O:26])[CH3:25]
Reactant: CC(=O)Cl
Reactant: Nc1cccc(Cn2cnc3c(-c4ccco4)nc(N)nc32)c1
Solvent: c1ccncc1
Product: CC(=O)Nc1cccc(Cn2cnc3c(-c4ccco4)nc(N)nc32)c1
Temperature: 0 °C
Reaction time: 1 h
Yield: 42.5 %

Procedure:
An ice-cold solution of 9-(3-aminobenzyl)-6-(2-furyl)-9H-purine-2-amine (145 mg, 0.48 mmol) in pyridine (3 mL) was treated with acetyl chloride (38 μL, 0.53 mmol), stirred for 1 h, quenched with water, extracted with EtOAc, dried (MgSO4), concentrated in vacuo and purified by chromatography (SiO2: Hexane:EtOAc (1:3) to EtOAc:MeOH (99:1)) to give the title compound (71 mg, 43%) as a yellow solid.
Reaction SMILES: Cl[CH2:2][CH2:3][CH2:4][O:5][C:6]1[C:7]([O:20][CH3:21])=[CH:8][C:9]2[O:14][C:13](=[O:15])[C:12]3[CH2:16][CH2:17][CH2:18][C:11]=3[C:10]=2[CH:19]=1.[F:22][C:23]1[CH:28]=[CH:27][C:26]([C:29]([C:37]2[CH:42]=[CH:41][C:40]([F:43])=[CH:39][CH:38]=2)([OH:36])[CH:30]2[CH2:35][CH2:34][NH:33][CH2:32][CH2:31]2)=[CH:25][CH:24]=1.CC(C)=O.C([O-])(=O)/C=C/C([O-])=O>O.CC(OC)(C)C>[F:22][C:23]1[CH:28]=[CH:27][C:26]([C:29]([C:37]2[CH:38]=[CH:39][C:40]([F:43])=[CH:41][CH:42]=2)([OH:36])[CH:30]2[CH2:31][CH2:32][N:33]([CH2:2][CH2:3][CH2:4][O:5][C:6]3[C:7]([O:20][CH3:21])=[CH:8][C:9]4[O:14][C:13](=[O:15])[C:12]5[CH2:16][CH2:17][CH2:18][C:11]=5[C:10]=4[CH:19]=3)[CH2:34][CH2:35]2)=[CH:25][CH:24]=1
Reactant: COc1cc2oc(=O)c3c(c2cc1OCCCCl)CCC3
Reactant: OC(c1ccc(F)cc1)(c1ccc(F)cc1)C1CCNCC1
Agent: O=C([O-])/C=C/C(=O)[O-]
Solvent: COC(C)(C)C
Solvent: CC(C)=O
Solvent: O
Product: COc1cc2oc(=O)c3c(c2cc1OCCCN1CCC(C(O)(c2ccc(F)cc2)c2ccc(F)cc2)CC1)CCC3
Yield: 67 %

Procedure:
Method B (38 h at 60° C.); starting materials: 8-(3-chloropropoxy)-2,3-dihydro-7-methoxy-cyclopenta[c][1]benzopyran-4(1H)-one (example 83) and 4-[bis(4-fluorophenyl)hydroxy-methyl]piperidine; yield 67%; fusion point 91° C. (decomposes; from acetone and TBME). Fumarate (×0.5 C4H4O4): method E; yield 70%; fusion point 191° C. (decomposes; from water).
Reaction SMILES: C(N(CC)CC)C.[C:8]([O:12][C:13](=[O:32])[N:14]([CH:16]([CH2:30][OH:31])[CH:17]([C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1)[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)[CH3:15])([CH3:11])([CH3:10])[CH3:9]>CS(C)=O>[C:8]([O:12][C:13](=[O:32])[N:14]([CH:16]([CH:30]=[O:31])[CH:17]([C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1)[C:18]1[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=1)[CH3:15])([CH3:9])([CH3:11])[CH3:10]
Reactant: CN(C(=O)OC(C)(C)C)C(CO)C(c1ccccc1)c1ccccc1
Solvent: CCN(CC)CC
Solvent: CS(C)=O
Product: CN(C(=O)OC(C)(C)C)C(C=O)C(c1ccccc1)c1ccccc1
Temperature: 0 °C

Procedure:
17.8 ml (127 mmol) of triethylamine and a solution of 22.8 g (127 mmol) of sulfur trioxide pyridine complex in 100 ml of dimethyl sulfoxide are added in succession to a solution of 14.5 g (42.5 mmol) of (1-hydroxymethyl-2,2-diphenyl-ethyl)-methyl-carbamic acid tert-butyl ester in 80 ml of dimethyl sulfoxide. After 45 minutes the reaction mixture is poured into ice-water and exhaustively extracted with ether. The combined organic phases are washed twice with 1M potassium hydrogen sulfate, twice with water and once with 1M sodium hydrogen carbonate, dried over sodium sulfate and concentrated by evaporation, yielding the title compound in the form of a yellow oil. TLC: methylene chloride/methanol (95:5) Rf=0.88.