Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[CH:7][C:6]([C:12]([CH:14]1[CH2:16][CH2:15]1)=[O:13])=[C:5]2[NH:17][C@H:18]1[CH2:23][CH2:22][C@H:21]([CH2:24][N:25]2[CH2:29][CH2:28][C@@H:27]([F:30])[CH2:26]2)[CH2:20][CH2:19]1.[Cl:31][C:32]1[CH:37]=[C:36](B2OC(C)(C)C(C)(C)O2)[CH:35]=[C:34]([F:47])[C:33]=1[OH:48]>>[Cl:31][C:32]1[CH:37]=[C:36]([C:2]2[CH:3]=[C:4]3[C:9](=[CH:10][CH:11]=2)[N:8]=[CH:7][C:6]([C:12]([CH:14]2[CH2:15][CH2:16]2)=[O:13])=[C:5]3[NH:17][C@H:18]2[CH2:23][CH2:22][C@H:21]([CH2:24][N:25]3[CH2:29][CH2:28][C@@H:27]([F:30])[CH2:26]3)[CH2:20][CH2:19]2)[CH:35]=[C:34]([F:47])[C:33]=1[OH:48]
Reactant: CC1(C)OB(c2cc(F)c(O)c(Cl)c2)OC1(C)C
Reactant: O=C(c1cnc2ccc(Br)cc2c1N[C@H]1CC[C@H](CN2CC[C@@H](F)C2)CC1)C1CC1
Product: O=C(c1cnc2ccc(-c3cc(F)c(O)c(Cl)c3)cc2c1N[C@H]1CC[C@H](CN2CC[C@@H](F)C2)CC1)C1CC1

Procedure:
Following general procedure D, (6-bromo-4-((trans-4-(((R)-3-fluoropyrrolidin-1-yl)methyl)cyclohexyl)amino)quinolin-3-yl)(cyclopropyl)methanone (47 mg, 0.10 mmol) was reacted with 2-chloro-6-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenol (43 mg, 0.16 mmol) to afford the desired product (33.9 mg, 63%) as a yellow solid. 1H NMR (500 MHz, CDCl3) 1H NMR (500 MHz, CDCl3) δ 10.78 (br s, 1H), 9.24 (s, 1H), 8.24 (d, J=2.1 Hz, 1H), 8.03 (d, J=8.7 Hz, 1H), 7.84 (dd, J=8.7, 2.1 Hz, 1H), 7.44-7.39 (d, J=2.0 Hz, 1H), 7.29 (dd, J=11.1, 2.0 Hz, 1H), 5.25-5.10 (m, 1H), 4.10-4.04 (m, 1H), 2.91-2.65 (m, 4H), 2.51-2.27 (m, 5H), 2.24-2.01 (m, 5H), 1.65-1.50 (m, 3H), 1.31-1.21 (m, 1H), 1.13-1.04 (m, 4H). ESI MS m/z 540 [C30H32ClF2N3O2+H]+; HPLC>99% (AUC), tR=10.95 min.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[C:6]([O:8]C)[CH:5]=[CH:4][C:3]=1[C:10](=[O:22])[CH2:11][C:12]1[CH:17]=[C:16]([O:18]C)[CH:15]=[CH:14][C:13]=1OC.N1C(=O)CC[C@H]1C(O)=O.Cl>>[Br:1][C:2]1[CH:7]=[C:6]([OH:8])[CH:5]=[CH:4][C:3]=1[C:10]1[O:22][C:13]2[CH:14]=[CH:15][C:16]([OH:18])=[CH:17][C:12]=2[CH:11]=1
Reactant: COc1ccc(C(=O)Cc2cc(OC)ccc2OC)c(Br)c1
Agent: Cl
Agent: O=C1CC[C@@H](C(=O)O)N1
Product: Oc1ccc(-c2cc3cc(O)ccc3o2)c(Br)c1
Temperature: 25 °C

Procedure:
Compound 101 (1.25 g, 3.4 mmol) was heated at 200° C. with a large excess of Pyr-HCl and followed by TLC for reaction completion (approx 30 min to 1 h). The reaction mixture was allowed to cool to rt and then partitioned between 2 N HCl aq and EtOAc. The organic layer was washed with saturated NaHCO3 aq, brine, and then dried over MgSO4. After filtering, the reaction mixture was concentrated and chromatographed on silica gel (1:1 EtOAc/hexanes) to yield 0.96 g of the desired pdt: Mp=195° C.; 1H NMR (DMSO-d6) δ 10.33 (br s, 1 H), 9.23 (br s, 1 H), 7.70 (d, 1 H, J=8.6 Hz), 7.37 (d, 1 H, J=8.8 Hz), 7.21 (s, 1 H), 7.16 (d, 1 H, J=2.4 Hz), 6.97 (d, 1 H, J=2.4 Hz), 6.92 (dd, 1H, J=8.7 Hz, 2.4 Hz), 6.75 (dd, 1 H, J=8.8 Hz, 2.4 Hz); MS 303 (M−H)−.
Reaction SMILES: O.[OH-].[Li+].[F:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=1[N:11]1[C:15]([C:16]2[N:17]=[CH:18][N:19]([C:21]3[CH:30]=[CH:29][C:24]([C:25]([O:27]C)=[O:26])=[CH:23][N:22]=3)[CH:20]=2)=[C:14]([CH3:31])[N:13]=[N:12]1>O.C1COCC1.CO>[F:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=1[N:11]1[C:15]([C:16]2[N:17]=[CH:18][N:19]([C:21]3[CH:30]=[CH:29][C:24]([C:25]([OH:27])=[O:26])=[CH:23][N:22]=3)[CH:20]=2)=[C:14]([CH3:31])[N:13]=[N:12]1
Reactant: COC(=O)c1ccc(-n2cnc(-c3c(C)nnn3-c3ccccc3F)c2)nc1
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Solvent: O
Product: Cc1nnn(-c2ccccc2F)c1-c1cn(-c2ccc(C(=O)O)cn2)cn1
Temperature: 25 °C
Reaction time: 1 h
Yield: 88.2 %

Procedure:
A solution of lithium hydroxide monohydrate (29 mg, 0.671 mmol) in water (1.3 mL) was added dropwise to a suspension of methyl 6-(4-(1-(2-fluorophenyl)-4-methyl-1H-1,2,3-triazol-5-yl)-1H-imidazol-1-yl)nicotinate (127 mg, 0.336 mmol) in THF (5 mL) and methanol (1 mL). The reaction mixture was then stirred at room temperature for 1 h and was then evaporated and the residue dissolved in water, acidified with HCl (1 N), and the resulting precipitate filtered off to afford the title product (108 mg, 88%) as a white solid. MS: m/e=363.3 [M−H]−.
Reaction SMILES: [C:1]([C:5]1[N:6]=[C:7]([N:22]2[CH2:26][CH2:25][C@H:24]([OH:27])[CH2:23]2)[C:8]2[N:13]=[N:12][N:11]([CH2:14][C:15]3[C:16](Cl)=[N:17][CH:18]=[CH:19][CH:20]=3)[C:9]=2[N:10]=1)([CH3:4])([CH3:3])[CH3:2].[N+:28]([C:31]1[C:36]2=[N:37][O:38][N:39]=[C:35]2[C:34]([NH2:40])=[CH:33][CH:32]=1)([O-:30])=[O:29].CC1(C)C2C(=C(P(C3C=CC=CC=3)C3C=CC=CC=3)C=CC=2)OC2C(P(C3C=CC=CC=3)C3C=CC=CC=3)=CC=CC1=2.C([O-])([O-])=O.[Cs+].[Cs+]>O1CCOCC1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[C:1]([C:5]1[N:6]=[C:7]([N:22]2[CH2:26][CH2:25][C@H:24]([OH:27])[CH2:23]2)[C:8]2[N:13]=[N:12][N:11]([CH2:14][C:15]3[C:16]([NH:40][C:34]4[C:35]5=[N:39][O:38][N:37]=[C:36]5[C:31]([N+:28]([O-:30])=[O:29])=[CH:32][CH:33]=4)=[N:17][CH:18]=[CH:19][CH:20]=3)[C:9]=2[N:10]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: Nc1ccc([N+](=O)[O-])c2nonc12
Reactant: CC(C)(C)c1nc(N2CC[C@H](O)C2)c2nnn(Cc3cccnc3Cl)c2n1
Agent: [Pd]
Agent: CC1(C)c2cccc(P(c3ccccc3)c3ccccc3)c2Oc2c(P(c3ccccc3)c3ccccc3)cccc21
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: C1COCCO1
Product: CC(C)(C)c1nc(N2CC[C@H](O)C2)c2nnn(Cc3cccnc3Nc3ccc([N+](=O)[O-])c4nonc34)c2n1
Temperature: 120 °C
Reaction time: 0.33 h
Yield: 16.5 %

Procedure:
A mixture of (S)-1-[5-tert-Butyl-3-(2-chloro-pyridin-3-ylmethyl)-3H-[1,2,3]triazolo[4,5-d]pyrimidin-7-yl]-pyrrolidin-3-ol (example 140) (5.30 mg, 13.7 μmol), 7-nitrobenzo[c][1,2,5]oxadiazol-4-amine (2.95 mg, 16.4 μmol), Pd2(dba)3 (1.25 mg, 1.37 μmol), xantphos (2.15 mg, 3.71 μmol) and Cs2CO3 (8.06 mg, 24.8 μmol) in dioxane (500 μl) was heated to 120° C. and stirred for 20 min. The crude material was filtered (celite), concentrated and purified by preparative HPLC eluting with a gradient formed from acetonitrile, water and NEt3. The product containing fractions were evaporated to yield 1.2 mg (16%) of the title compound as red solid. MS(m/e): 532.4 (MH+).
Reaction SMILES: [C:1]([NH:9][C:10]1[CH:11]=[C:12]([C:16]2[C:25]3[C:20](=[CH:21][C:22]([O:28][CH3:29])=[C:23]([O:26][CH3:27])[CH:24]=3)[N:19]=[C:18]([NH:30][CH3:31])[N:17]=2)[CH:13]=[CH:14][CH:15]=1)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH:32]([N-]C(C)C)(C)C.[Li+].CI.C(OCC)(=O)C>O1CCCC1.CCCCCC>[C:1]([N:9]([C:10]1[CH:11]=[C:12]([C:16]2[C:25]3[C:20](=[CH:21][C:22]([O:28][CH3:29])=[C:23]([O:26][CH3:27])[CH:24]=3)[N:19]=[C:18]([NH:30][CH3:31])[N:17]=2)[CH:13]=[CH:14][CH:15]=1)[CH3:32])(=[O:8])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CC(C)[N-]C(C)C
Reactant: CNc1nc(-c2cccc(NC(=O)c3ccccc3)c2)c2cc(OC)c(OC)cc2n1
Agent: [Li+]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Solvent: CCCCCC
Product: CNc1nc(-c2cccc(N(C)C(=O)c3ccccc3)c2)c2cc(OC)c(OC)cc2n1
Temperature: -70 °C
Reaction time: 0.5 h

Procedure:
207 mg of 4-(3-benzoylaminophenyl)-6,7-dimethoxy-2-methylaminoquinazoline obtained in Example 1 was dissolved in 5 ml tetrahydrofuran, and 0.667 ml of 1.5 M lithium diisopropylamide in hexane was added dropwise thereto at −70° C. After the dropwise addition, the mixture was stirred at −70° C. for 30 minutes, and then 284 mg of methyl iodide was added thereto. The mixture was returned to room temperature and further stirred for 1 hour. After ethyl acetate was added thereto, the mixture was washed with water twice and with brine, and then dried over anhydrous magnesium sulfate. The solvent was evaporated, and the crude product was purified and separated by silica gel column chromatography (hexane:ethyl acetate=1:3). The product was recrystallized from hexane-ethyl acetate to give 75 mg of the title compound as pale yellow crystals.
Reaction SMILES: [C:1]([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1)(=[O:3])[CH3:2]>C1(C)C=CC=CC=1>[C:4]1([CH:1]([OH:3])[CH3:2])[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1
Reactant: CC(=O)c1ccccc1
Solvent: Cc1ccccc1
Product: CC(O)c1ccccc1
Reaction time: 12 h

Procedure:
Specifically with respect to acetophenone, a resealable NMR tube containing a solution of the catalyst (11.8 mg, 30 μmol) and acetophenone (3.5 μL, 30 μmol) in preferred non-reactive solvent toluene (500 μL) was monitored by 1H NMR spectroscopy over days. After 12 h, about 28% of the catalyst had been converted. Extended reaction times resulted in unidentified decomposition products and free 1-phenylethanol. A similar reaction with acetone generated the mixture of the catalyst and the expected alcohol.
Reaction SMILES: [CH3:1][CH2:2][O:3][C:4]([CH:6]([NH2:13])[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1)=[O:5].C(O)(=O)C(C(C(O)=O)O)O.C(=O)C1C=CC=CC=1>CO>[CH3:1][CH2:2][O:3][C:4]([C@H:6]([NH2:13])[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1)=[O:5]
Reactant: CCOC(=O)C(N)c1ccccc1
Agent: O=C(O)C(O)C(O)C(=O)O
Solvent: O=Cc1ccccc1
Solvent: CO
Product: CCOC(=O)[C@H](N)c1ccccc1
Reaction time: 25 h

Procedure:
A solution of ethyl DL-phenylglycinate (6.26 g., 35 mmole) and (+)-tartaric acid (5.56 g., 1.05 equiv.) in dry methanol containing benzaldehyde (7% v/v benzaldehyde, 1 equiv; total volume 46 ml.) at 50° was cooled from 50° to 22° and stirred for 25 hours. The solid was filtered off and washed with methanol containing 7% benzaldehyde (15 ml.) then methanol (10 ml.) and dried at 22°/2 mm. for 3 hours to give ethyl D-phenylglycinate (+)-hemitartrate as a mono-methanol solvate (5.50 g., 43%), m.p. 131°-135° [α]D24 - 48° (c 2.68, H2O).
Reaction SMILES: [CH:1]1([CH:7]([C:9]2[C:10]([O:25][CH:26]([CH3:28])[CH3:27])=[N:11][N:12]([C:14]3[CH:19]=[CH:18][C:17]([O:20][C:21]([F:24])([F:23])[F:22])=[CH:16][CH:15]=3)[CH:13]=2)O)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[NH2:29][C:30]1[CH:35]=[CH:34][C:33]([C:36]([NH:38][CH2:39][CH2:40][C:41]([O:43]CC)=[O:42])=[O:37])=[CH:32][CH:31]=1>>[CH:1]1([CH:7]([NH:29][C:30]2[CH:31]=[CH:32][C:33]([C:36]([NH:38][CH2:39][CH2:40][C:41]([OH:43])=[O:42])=[O:37])=[CH:34][CH:35]=2)[C:9]2[C:10]([O:25][CH:26]([CH3:27])[CH3:28])=[N:11][N:12]([C:14]3[CH:19]=[CH:18][C:17]([O:20][C:21]([F:22])([F:23])[F:24])=[CH:16][CH:15]=3)[CH:13]=2)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]1
Reactant: CCOC(=O)CCNC(=O)c1ccc(N)cc1
Reactant: CC(C)Oc1nn(-c2ccc(OC(F)(F)F)cc2)cc1C(O)C1CCCCC1
Product: CC(C)Oc1nn(-c2ccc(OC(F)(F)F)cc2)cc1C(Nc1ccc(C(=O)NCCC(=O)O)cc1)C1CCCCC1
Yield: 37.2 %

Procedure:
Using cyclohexyl{3-(1-methylethoxy)-1-[4-(trifluoromethoxy)phenyl]-1H-pyrazol-4-yl}methanol (0.20 g) synthesized above and ethyl 3-{[(4-aminophenyl)carbonyl]amino}propanoate (0.12 g) synthesized in Example 1(2) and in the same manner as in Example 1(7), the title object compound (0.11 g, 36%) was obtained as a white solid.
Reaction SMILES: [CH3:1][C:2]1[C:3]([N+:16]([O-:18])=[O:17])=[C:4]([C:10]([N+:13]([O-:15])=[O:14])=[CH:11][CH:12]=1)[C:5]([O:7][CH2:8][CH3:9])=[O:6].C[C:20]([N:22]([CH3:24])[CH3:23])=O>CN(C=O)C>[CH3:20][N:22]([CH3:24])/[CH:23]=[CH:1]/[C:2]1[C:3]([N+:16]([O-:18])=[O:17])=[C:4]([C:10]([N+:13]([O-:15])=[O:14])=[CH:11][CH:12]=1)[C:5]([O:7][CH2:8][CH3:9])=[O:6]
Reactant: CC(=O)N(C)C
Reactant: CCOC(=O)c1c([N+](=O)[O-])ccc(C)c1[N+](=O)[O-]
Solvent: CN(C)C=O
Product: CCOC(=O)c1c([N+](=O)[O-])ccc(/C=C/N(C)C)c1[N+](=O)[O-]
Temperature: 100 °C
Yield: 57.7 %

Procedure:
A mixture of ethyl 3-methyl-2,6-dinitrobenzoate (35 g, 0.14 mol) and DMA (32 g, 0.27 mol) in DMF (200 mL) was heated at 100° C. for 5 h. The mixture was poured into ice water. The precipitated solid was filtered and washed with water to give (E)-ethyl 3-(2-(dimethylamino)vinyl)-2,6-dinitrobenzoate (25 g, 58%).
Reaction SMILES: [C:1]([CH:9]1[CH2:13][CH2:12][N:11]([C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])[CH2:10]1)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[BH4-].[Na+]>CO>[OH:8][CH:1]([C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1)[CH:9]1[CH2:13][CH2:12][N:11]([C:14]([O:16][C:17]([CH3:19])([CH3:20])[CH3:18])=[O:15])[CH2:10]1
Reactant: CC(C)(C)OC(=O)N1CCC(C(=O)c2ccccc2)C1
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Product: CC(C)(C)OC(=O)N1CCC(C(O)c2ccccc2)C1
Temperature: 25 °C
Reaction time: 72 h

Procedure:
To a stirred solution of tert-butyl 3-benzoylpyrrolidine-1-carboxylate (0.77 g, 2.8 mmol) in methanol (40 mL) was added granular NaBH4 (0.21 g, 5.6 mmol). The mixture was stirred at rt for 3 d and solvent was removed under reduced pressure. The residue was taken up in 5% aq HCl (50 mL) and extracted with ether (2×100 mL). The combined ether extracts were washed with satd aq NaHCO3 (25 mL) and dried over MgSO4. Removal of the solvent left tert-butyl 3-(hydroxy(phenyl)methyl)pyrrolidine-1-carboxylate (0.93 g, quant) as an oil.
Reaction SMILES: [F-].C([N+](CCCC)(CCCC)CCCC)CCC.[Si]([O:26][CH2:27][CH2:28][CH2:29][CH:30]([C:32]1[O:33][C:34]2[C:40]([O:41][CH3:42])=[CH:39][CH:38]=[CH:37][C:35]=2[CH:36]=1)[OH:31])(C(C)(C)C)(C)C>>[CH3:42][O:41][C:40]1[C:34]2[O:33][C:32]([CH:30]([OH:31])[CH2:29][CH2:28][CH2:27][OH:26])=[CH:36][C:35]=2[CH:37]=[CH:38][CH:39]=1
Reactant: COc1cccc2cc(C(O)CCCO[Si](C)(C)C(C)(C)C)oc12
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Product: COc1cccc2cc(C(O)CCCO)oc12
Temperature: 25 °C
Yield: 86.8 %

Procedure:
Tetrabutylammonium fluoride (12 ml,1M in tetrahydrofuran) was added to a stirred solution of 4-(tert-butyldimethylsilanyloxy)-1-(7-methoxybenzofuran-2-yl)-butan-1-ol (4 g) in tetrahdrofuran (50 ml) at 0° C. After stirring cooled for 2 hours the reaction was warmed to room temperature and allowed to stir for a further 1 hour. The solvent was removed in vacuo and the residue partitioned between ethyl acetate (100 ml) and water (50 ml). The organic extract was dried over magnesium sulphate, filtered and preadsorbed onto silica. Purification by column chromatography on silica eluting with ethyl acetate yielded the title compound as a tan oil (2.34 g).
Reaction SMILES: [CH3:1][C:2]1([CH3:24])[CH2:11][CH2:10][C:9]2[C:4](=[CH:5][CH:6]=[C:7]([S:12]([NH:15][CH2:16][C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])(=[O:14])=[O:13])[CH:8]=2)[O:3]1.CCN(P1(N(C)CCCN1C)=NC(C)(C)C)CC.[Br:43][C:44]1[CH:49]=[CH:48][C:47]([O:50][CH3:51])=[C:46]([CH2:52]Br)[CH:45]=1>CC#N>[Br:43][C:44]1[CH:49]=[CH:48][C:47]([O:50][CH3:51])=[C:46]([CH:45]=1)[CH2:52][N:15]([CH2:16][C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])[S:12]([C:7]1[CH:8]=[C:9]2[C:4](=[CH:5][CH:6]=1)[O:3][C:2]([CH3:24])([CH3:1])[CH2:11][CH2:10]2)(=[O:14])=[O:13]
Reactant: CC(C)(C)OC(=O)CNS(=O)(=O)c1ccc2c(c1)CCC(C)(C)O2
Reactant: COc1ccc(Br)cc1CBr
Agent: CCN(CC)P1(=NC(C)(C)C)N(C)CCCN1C
Solvent: CC#N
Product: COc1ccc(Br)cc1CN(CC(=O)OC(C)(C)C)S(=O)(=O)c1ccc2c(c1)CCC(C)(C)O2
Temperature: 90 °C
Yield: 89.7 %

Procedure:
To the solution of tert-butyl 2-(2,2-dimethylchroman-6-sulfonamido)acetate (500 mg, 1.407 mmol) in MeCN (15 mL) was added resin-supported BEMP (786 mg, 1.547 mmol) and 4-bromo-2-(bromomethyl)-1-methoxybenzene (500 mg, 1.786 mmol). The mixture was heated in a microwave synthesizer at 90° C. for 3 hours. The reaction mixture was filtered, rinsed alternatively by dichloromethane and methanol. The filtrate was concentrated to give a reddish orange residue, which was purified by silica chromatography to obtain a white powder (700 mg, 85% yield). 1H NMR (500 MHz, CDCl3) δ 7.56-7.50 (m, 2H), 7.34-7.29 (m, 2H), 6.81 (d, J=8.1 Hz, 1H), 6.66 (d, J=8.5 Hz, 1H), 4.47 (s, 2H), 3.88 (s, 2H), 3.71 (s, 3H), 2.78 (t, J=6.7 Hz, 2H), 1.82 (t, J=6.7 Hz, 2H), 1.38 (s, 9H), 1.34 (s, 6H). LRMS [ESI, MH−] m/z calcd for C25H33BrNO6S 554.12, found 554.1.
Reaction SMILES: [O:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[CH:6]1[NH:10][N:9]([CH3:11])[C:8](=[S:12])[S:7]1.S(OC)(O[CH3:17])(=O)=O.[K]>C(O)C>[CH:6](=[N:10][N:9]([CH3:11])[C:8]([S:7][CH3:17])=[S:12])[C:2]1[O:1][CH:5]=[CH:4][CH:3]=1
Reactant: COS(=O)(=O)OC
Reactant: CN1NC(c2ccco2)SC1=S
Agent: [K]
Solvent: CCO
Product: CSC(=S)N(C)N=Cc1ccco1
Reaction time: 2.5 h

Procedure:
1 g of 2-(2-furyl)-4-methyl-1,3,4-thidiazolidine-5-thione was dissolved in 50 ml of warm ethanol, and after cooling to room temperature 1.26 g of dimethyl sulphate was added. After stirring for 2.5 hours at 50°, 0.69 g potassium was added, the mixture was heated for 1.5 hours at 50°, then allowed to stand overnight. The reaction mixture was filtered and the filtrate was evaporated to dryness. The residue was recrystallised from ethanol and pure S-methyl 3-furfurylidene- 2-methyl-dithiocarbazate (mp = 103°) was obtained.
Reaction SMILES: [O:1]1[CH2:6][CH2:5][N:4]([CH2:7][CH2:8][NH:9][C:10]2[CH:15]=[CH:14][C:13]([NH:16]/[C:17](=[C:24]3\[C:25](=[O:36])[NH:26][C:27]4[C:32]\3=[CH:31][C:30]([N+:33]([O-:35])=[O:34])=[CH:29][CH:28]=4)/[C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)=[CH:12][CH:11]=2)[CH2:3][CH2:2]1.[C:37](Cl)(=[O:39])[CH3:38]>ClCCl>[O:1]1[CH2:6][CH2:5][N:4]([CH2:7][CH2:8][N:9]([C:10]2[CH:11]=[CH:12][C:13]([NH:16]/[C:17](=[C:24]3\[C:25](=[O:36])[NH:26][C:27]4[C:32]\3=[CH:31][C:30]([N+:33]([O-:35])=[O:34])=[CH:29][CH:28]=4)/[C:18]3[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=3)=[CH:14][CH:15]=2)[C:37](=[O:39])[CH3:38])[CH2:3][CH2:2]1
Reactant: CC(=O)Cl
Reactant: O=C1Nc2ccc([N+](=O)[O-])cc2/C1=C(/Nc1ccc(NCCN2CCOCC2)cc1)c1ccccc1
Solvent: ClCCl
Product: CC(=O)N(CCN1CCOCC1)c1ccc(N/C(=C2\C(=O)Nc3ccc([N+](=O)[O-])cc32)c2ccccc2)cc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
486 mg (1.0 mmol) of (Z)-3-{1-[4-(2-morpholinoethylamino)-phenylamino]-1-phenyl-methylidene}-5-nitro-2-indolinone (Example 332) are dissolved in 30 ml of dichloromethane and combined with 1.2 ml (16 mmol) of acetylchloride. The mixture is stirred for 1 hour at ambient temperature. The precipitate is removed by suction filtering and the reaction solution is washed with water. Then the solvent is eliminated in vacuo, the residue is dissolved in 20 ml of methanol and combined with 4 ml of 1 N sodium hydroxide solution. The mixture is stirred for 30 minutes at ambient temperature and then the solvent is eliminated in vacuo. The residue is suspended in water and a little ether. Then the product is suction filtered and dried.
Reaction SMILES: [OH:1][C:2]1[CH:9]=[CH:8][C:5]([CH2:6][OH:7])=[CH:4][CH:3]=1.C([O-])([O-])=O.[K+].[K+].Br[CH2:17][C:18]([C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)=[O:19]>C(#N)C>[OH:7][CH2:6][C:5]1[CH:8]=[CH:9][C:2]([O:1][CH2:17][C:18]([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)=[O:19])=[CH:3][CH:4]=1
Reactant: O=C(CBr)c1ccccc1
Reactant: OCc1ccc(O)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: O=C(COc1ccc(CO)cc1)c1ccccc1
Temperature: 80 °C
Reaction time: 0.08 h
Yield: 82.2 %

Procedure:
To a 100 mL RB flask fitted with magnetic stirrer was charged 20 mL of acetonitrile. To the stirred solvent was added 4-Hydroxy-benzylalcohol (6.74 g, 25.1 mmol) and K2CO3 (10.4 g, 75.3 mmol). Then it was stirred for 5 min. 2-bromo-1-phenylethanone (5 g, 25.1 mmol) was added. Then RM heated 80° C. for 2 h. After completion of the reaction (reaction monitored by TLC), the RM was concentrated in vacuum to remove the acetonitrile. To the residue was then added 10 mL of water and extracted with ethyl acetate (15 mL×2). The organic layer was washed with saturated brine solution (15 mL), dried over anhydrous Na2SO4 and evaporated to dryness gave the titled compound (5 g, yield: 82.2%); 1H NMR (300 MHz, CDCl3): δ 7.92-7.94 (d, 2H), 7.53-7.58 (t, 1H), 7.41-7.46 (t, 2H), 7.21-7.24 (d, 2H), 6.85-6.86 (d, 2H), 5.22 (s, 2H), 4.55 (s, 2H).
Reaction SMILES: [CH3:1][S:2]([C:5]1[S:6][C:7]([NH:10][CH3:11])=[N:8][N:9]=1)(=[O:4])=[O:3].[C:12]([Cl:15])(Cl)=[O:13]>C1C=CC=CC=1>[CH3:1][S:2]([C:5]1[S:6][C:7]([N:10]([CH3:11])[C:12]([Cl:15])=[O:13])=[N:8][N:9]=1)(=[O:4])=[O:3]
Reactant: O=C(Cl)Cl
Reactant: CNc1nnc(S(C)(=O)=O)s1
Solvent: c1ccccc1
Product: CN(C(=O)Cl)c1nnc(S(C)(=O)=O)s1

Procedure:
2-methylsulfonyl-5-methylamino-1,3,4-thiadiazole (0.1 mole) and a solution of phosgene (0.11 mole) in benzene (200 ml) are charged into a glass reaction vessel equipped with a mechanical stirrer and reflux condenser. The reaction mixture is heated at reflux for a period of about 4 hours. After this time the mixture is stripped of benzene and unreacted phosgene to yield the desired product N-(2-methylsulfonyl-1,3,4-thiadiazol-5-yl)-N-methylcarbamoyl chloride.
Reaction SMILES: Cl.Cl.[O:3]1[C:8]2=[CH:9][CH:10]=[CH:11][C:7]2=[CH:6][C:5]([CH:12]2[CH2:17][CH2:16][CH2:15][CH2:14][N:13]2[CH2:18][CH2:19][C@H:20]2[CH2:25][CH2:24][C@H:23]([NH2:26])[CH2:22][CH2:21]2)=[CH:4]1.[CH3:27][C:28]1[CH:32]=[C:31]([C:33](O)=[O:34])[O:30][N:29]=1>>[O:3]1[C:8]2=[CH:9][CH:10]=[CH:11][C:7]2=[CH:6][C:5]([CH:12]2[CH2:17][CH2:16][CH2:15][CH2:14][N:13]2[CH2:18][CH2:19][C@H:20]2[CH2:21][CH2:22][C@H:23]([NH:26][C:33]([C:31]3[O:30][N:29]=[C:28]([CH3:27])[CH:32]=3)=[O:34])[CH2:24][CH2:25]2)=[CH:4]1
Reactant: Cc1cc(C(=O)O)on1
Reactant: N[C@H]1CC[C@H](CCN2CCCCC2c2coc3cccc-3c2)CC1
Agent: Cl
Product: Cc1cc(C(=O)N[C@H]2CC[C@H](CCN3CCCCC3c3coc4cccc-4c3)CC2)on1

Procedure:
The title compound, off-white solid (89 mg, 82%), MS (ISP) m/z=436.3 [(M+H)+], mp 178° C., was prepared in accordance with the general method of example 1 from trans-4-[2-(4-benzofuran-3-yl-piperidin-1-yl)-ethyl]-cyclohexylamine dihydrochloride (intermediate A) (100 mg, 0.25 mmol) and 3-methyl-isoxazole-5-carboxylic acid.
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]([CH:34]([CH3:36])[CH3:35])[C:6]2[O:10][C:9]([C:11]3[CH:32]=[CH:31][C:14]([C:15]([NH:17][CH2:18][CH:19]4[CH2:23][CH2:22][N:21](C(OC(C)(C)C)=O)[CH2:20]4)=[O:16])=[CH:13][CH:12]=3)=[N:8][C:7]=2[CH:33]=1)#[N:2].FC(F)(F)C(O)=O>ClCCl>[C:1]([C:3]1[CH:4]=[C:5]([CH:34]([CH3:36])[CH3:35])[C:6]2[O:10][C:9]([C:11]3[CH:12]=[CH:13][C:14]([C:15]([NH:17][CH2:18][CH:19]4[CH2:23][CH2:22][NH:21][CH2:20]4)=[O:16])=[CH:31][CH:32]=3)=[N:8][C:7]=2[CH:33]=1)#[N:2]
Reactant: CC(C)c1cc(C#N)cc2nc(-c3ccc(C(=O)NCC4CCN(C(=O)OC(C)(C)C)C4)cc3)oc12
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CC(C)c1cc(C#N)cc2nc(-c3ccc(C(=O)NCC4CCNC4)cc3)oc12
Temperature: 25 °C
Reaction time: 2 h
Yield: 90.5 %

Procedure:
To a solution of tert-butyl 3-({[4-(5-cyano-7-isopropyl-1,3-benzoxazol-2-yl)benzoyl]amino}methyl)pyrrolidine-1-carboxylate (910 mg) in dichloromethane (75 ml) was added 20 ml of trifluoroacetic acid. The mixture was stirred at room temperature for 2 h, and then concentrated in vacuo. The residue was basified by the addition of 75 ml of saturated aqueous sodium bicarbonate and diluted with 75 ml of ethyl acetate. The solids were filtered from both layers and dried in vacuo to provide the title compound (655 mg, 90%). Mass spectrum (ESI) 389.9 (M+1).
Reaction SMILES: [I:1][C:2]1[CH:7]=[CH:6][C:5]([O:8]C)=[CH:4][C:3]=1[C:10]1[CH:15]=[C:14]([O:16]C)[CH:13]=[CH:12][C:11]=1[I:18].[Br-].Br.B(Br)(Br)Br>ClCCl>[I:1][C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[CH:4][C:3]=1[C:10]1[CH:15]=[C:14]([OH:16])[CH:13]=[CH:12][C:11]=1[I:18]
Reactant: COc1ccc(I)c(-c2cc(OC)ccc2I)c1
Agent: Br
Agent: BrB(Br)Br
Agent: [Br-]
Solvent: ClCCl
Product: Oc1ccc(I)c(-c2cc(O)ccc2I)c1

Procedure:
The second 2,2'-dihalo-5,5'-dimethoxybiphenyl , and preferably 2,2'-diiodo-5,5'-dimethoxybiphenyl, is then demethylated under temperatures of about -78° C. to about -20° C., and preferably from about -78° C. to about -50° C., and ambient pressure, with a bromide-containing compound such as hydrogen bromide, boron tribromide, or mixtures thereof in a chlorinated solvent such as a chlorohydrocarbon including but not limited to dichloromethane to yield 2,2'-dihalo-5,5'-dihydroxybiphenyl, and preferably 2,2'-diiodo-5,5'-dihydroxybiphenyl. Boron tribromide is the preferred reactant. The concentration of the bromide-containing compound in the chlorinated solvent may range from 0.05M to about 1M, and preferably from about 0.1M to about 0.5M. The period of the demethylation reaction may depend upon the chemical structure, but will generally be from about 5 minutes to about 2 hours, and preferably from about 15 minutes to about 1 hour. The molar ratio of 2,2'-diiodo-5,5'dimethoxybiphenyl to the bromide-containing compound is about 1:3 to 1:10, and preferably about 1:2.5 to 1:5.