Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH-].[Na+].[CH:3]([C:5]1[C:14]([CH3:15])=[CH:13][C:12]2[C:11]([CH3:17])([CH3:16])[CH2:10][CH2:9][C:8]([CH3:19])([CH3:18])[C:7]=2[C:6]=1[OH:20])=[O:4].S(OC)(O[CH3:25])(=O)=O>O.CCCCCCCC[N+](CCCCCCCC)(CCCCCCCC)C.[Cl-].C(Cl)Cl>[CH:3]([C:5]1[C:14]([CH3:15])=[CH:13][C:12]2[C:11]([CH3:16])([CH3:17])[CH2:10][CH2:9][C:8]([CH3:19])([CH3:18])[C:7]=2[C:6]=1[O:20][CH3:25])=[O:4]
Reactant: COS(=O)(=O)OC
Reactant: Cc1cc2c(c(O)c1C=O)C(C)(C)CCC2(C)C
Agent: CCCCCCCC[N+](C)(CCCCCCCC)CCCCCCCC
Agent: [Cl-]
Agent: [Na+]
Solvent: ClCCl
Solvent: O
Product: COc1c(C=O)c(C)cc2c1C(C)(C)CCC2(C)C
Reaction time: 4 h
Yield: 78.7 %

Procedure:
Methylation. A solution of sodium hydroxide (0.98 g, 0.0244 mol) in water (24 mL) was added in one portion to a solution of 2-formyl-1-hydroxy-3,5,5,8,8-pentamethyl-5,6,7,8-tetrahydronaphthalene (3 g, 0.0122 mol), dimethyl sulfate (3.07 g, 0.0244 mol) and Adogen 464* (0.56 g) in methylene dichloride (48 mL). The mixture was stirred vigorously at 38°-40° C. for 4 h. After cooling, the organic layer was separated, washed with brine (3×20 mL) and dried (Na2SO4). The solvent was removed by distillation and the residue was distilled to yield 2-formyl-1-methoxy-3,5,5,8,8-pentamethyl-5,6,7,8-tetrahydronaphthalene (3a), (2.5 g), mp 78° C. (from hexane), GLC purity 99.7%, exhibiting the expected spectral data.
Reaction SMILES: [CH3:1][C:2]1[CH:8]=[C:7]([Cl:9])[C:6]([Cl:10])=[CH:5][C:3]=1[NH2:4].C(N(CC)CC)C.Cl[C:19]([C:21]1([C:24]([O:26][CH2:27][CH3:28])=[O:25])[CH2:23][CH2:22]1)=[O:20]>O1CCCC1.CCOCC>[CH3:1][C:2]1[CH:8]=[C:7]([Cl:9])[C:6]([Cl:10])=[CH:5][C:3]=1[NH:4][C:19]([C:21]1([C:24]([O:26][CH2:27][CH3:28])=[O:25])[CH2:23][CH2:22]1)=[O:20]
Reactant: CCOC(=O)C1(C(=O)Cl)CC1
Reactant: Cc1cc(Cl)c(Cl)cc1N
Solvent: CCOCC
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CCOC(=O)C1(C(=O)Nc2cc(Cl)c(Cl)cc2C)CC1
Temperature: 25 °C

Procedure:
Into a nitrogen-purged round bottom flask was charged 5.53 grams (0.03 mole) of 2-methyl-4,5-dichloroaniline, 3.18 grams (0.03 mole) of triethylamine and 190 milliliters of tetrahydrofuran solvent. With vigorous stirring, a 5.55 gram (0.03 mole) portion of ethyl 1-chlorocarbonylcyclopropanecarboxylate prepared in Example XVIII was added in one portion, after which the mixture was stirred at ambient temperature for a six-hour period. A precipitate of triethylamine hydrochloride was then filtered off and the filtrate vacuum stripped to give a light yellow solid. The solid was taken up in ether and the solution water-washed, dried over magnesium sulfate, and solvent evaporated to give a yellow powder. Recrystallization from ethyl acetate-hexane gave 4.51 grams (0.01 mole) of ethyl 1-(2-methyl-4,5-dichlorophenylaminocarbonyl)cyclopropanecarboxylate having a melting point of 105° C.-107° C. Elemental analysis of the product indicated the following:
Reaction SMILES: [C:1]([O:9][C:10]1[CH:15]=[CH:14][CH:13]=[C:12]([N+:16]([O-])=O)[CH:11]=1)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.O.O.[Sn](Cl)Cl.C(=O)([O-])[O-].[Na+].[Na+]>C(O)C>[C:1]([O:9][C:10]1[CH:15]=[CH:14][CH:13]=[C:12]([NH2:16])[CH:11]=1)(=[O:8])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=C(Oc1cccc([N+](=O)[O-])c1)c1ccccc1
Agent: Cl[Sn]Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: CCO
Product: Nc1cccc(OC(=O)c2ccccc2)c1
Temperature: 100 °C
Yield: 100 %

Procedure:
3-Nitrophenyl benzoate (2.7080 g, 11.144 mmol) and tin (II) chloride dihydrate (12.564 g, 55.720 mmol) were dissolved in 60 mL of ethanol and heated at 100° C. for 1 hour. The reaction crude was allowed to cool to room temperature, and an aqueous solution of sodium carbonate was added until pH 8. The crude material was extracted with dichloromethane (3×50 mL), magnesium sulfate was added to the organic phase, filtered and the solvent was removed under reduced pressure, thus affording 2.374 g (11.143 mmol, yield=100%) of 3-aminophenyl benzoate.
Reaction SMILES: P(Cl)(Cl)(Cl)=O.[Cl:6][C:7]1[CH:12]=[CH:11][C:10]([CH2:13][C:14]([OH:16])=O)=[CH:9][CH:8]=1.[OH-].[Na+].C(=O)([O-])[O-].[K+].[K+].[CH3:25][N:26]([CH3:29])[CH:27]=O>>[Cl:6][C:7]1[CH:8]=[CH:9][C:10]([C:13](=[CH:25][N:26]([CH3:29])[CH3:27])[CH:14]=[O:16])=[CH:11][CH:12]=1
Reactant: CN(C)C=O
Reactant: O=C(O)Cc1ccc(Cl)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Agent: [Na+]
Solvent: O=P(Cl)(Cl)Cl
Product: CN(C)C=C(C=O)c1ccc(Cl)cc1
Temperature: 70 °C
Reaction time: 8 h

Procedure:
Phosphorus oxychloride (28 ml) was added dropwise with stirring to dry dimethylformamide (38 ml) with cooling in an ice-bath to keep the temperature below 20° C. p-Chlorophenylacetic acid (17.05 g) was added, and the solution was heated to 70° C. for 6 hours and then left to stand overnight. The red solution was poured onto ice and neutralised with 40% sodium hydroxide whilst cooling in an ice/salt bath. Potassium carbonate (150 g) was added and the mixture was heated to boiling for 0.5 hour. The precipitate which formed was filtered off, washed well with water and recrystallised from carbon tetrachloride to give, as white crystals, 2-(p-chlorophenyl)-3-dimethylaminoprop-2-enal, m.p. 120° C.
Reaction SMILES: [N:1]1([CH2:7][CH2:8][O:9][C:10]2[CH:11]=[C:12]([NH2:16])[CH:13]=[CH:14][CH:15]=2)[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1.[C:17]([NH:21][S:22]([C:25]1[CH:30]=[CH:29][CH:28]=[C:27]([C:31]2[N:39]3[C:34]([CH:35]=[N:36][C:37](S(C)=O)=[N:38]3)=[CH:33][CH:32]=2)[CH:26]=1)(=[O:24])=[O:23])([CH3:20])([CH3:19])[CH3:18].[O-]S(C(F)(F)F)(=O)=O>>[C:17]([NH:21][S:22]([C:25]1[CH:30]=[CH:29][CH:28]=[C:27]([C:31]2[N:39]3[C:34]([CH:35]=[N:36][C:37]([NH:16][C:12]4[CH:13]=[CH:14][CH:15]=[C:10]([O:9][CH2:8][CH2:7][N:1]5[CH2:6][CH2:5][O:4][CH2:3][CH2:2]5)[CH:11]=4)=[N:38]3)=[CH:33][CH:32]=2)[CH:26]=1)(=[O:23])=[O:24])([CH3:20])([CH3:18])[CH3:19]
Reactant: Nc1cccc(OCCN2CCOCC2)c1
Reactant: CS(=O)c1ncc2ccc(-c3cccc(S(=O)(=O)NC(C)(C)C)c3)n2n1
Agent: O=S(=O)([O-])C(F)(F)F
Product: CC(C)(C)NS(=O)(=O)c1cccc(-c2ccc3cnc(Nc4cccc(OCCN5CCOCC5)c4)nn23)c1

Procedure:
Prepared by following a procedure analagous to Example 251c by using 3-(2-Morpholin-4-yl-ethoxy)-phenylamine and N-tert-Butyl-3-(2-methanesulfinyl-pyrrolo[2,1-f][1,2,4]triazin-7-yl)-benzenesulfonamide as a triflate salt. 1H-NMR (DMSO) δ 9.9 (br s, 1H), 9.6 (s, 1H), 9.15 (s, 1H), 8.5 (s, 1H), 8.4 (d, J=8.0 Hz, 1H), 7.9 (d, J=8.0 Hz, 1H), 7.75 (m, 1H), 7.6 (s, 1H), 7.55 (d, J=8.3 Hz, 1H), 7.3 (m, 2H), 7.2 (d, J=4.7 Hz, 1H), 7 (d, J=4.7 Hz, 1H), 6.7 (d, J=10.4 Hz, 1H), 4.3-3.3 (m, 12H), 1.1 (s, 9H); LC/MS (ESI+): 551 (M+H).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[C:9]1[C:29](=[O:30])[N:28]([CH3:31])[C:12]2[N:13]([CH3:27])[C:14]3[C:19]([C:11]=2[CH:10]=1)=[CH:18][C:17]([C:20]1[N:21]=[C:22]([CH2:25][OH:26])[S:23][CH:24]=1)=[CH:16][CH:15]=3.[CH3:32][O:33][CH2:34]Br>>[Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[C:9]1[C:29](=[O:30])[N:28]([CH3:31])[C:12]2[N:13]([CH3:27])[C:14]3[C:19]([C:11]=2[CH:10]=1)=[CH:18][C:17]([C:20]1[N:21]=[C:22]([CH2:25][O:26][CH2:32][O:33][CH3:34])[S:23][CH:24]=1)=[CH:16][CH:15]=3
Reactant: COCBr
Reactant: Cn1c(=O)c(-c2ccc(Cl)cc2Cl)cc2c3cc(-c4csc(CO)n4)ccc3n(C)c21
Product: COCOCc1nc(-c2ccc3c(c2)c2cc(-c4ccc(Cl)cc4Cl)c(=O)n(C)c2n3C)cs1

Procedure:
The process is carried out as indicated in Example 10 above, with the compound from Example 9, 3-(2,4-dichlorophenyl)-6-(2-hydroxymethylthiazol-4-yl)-1,9-dimethyl-1,9-dihydropyrido[2,3-b]indol-2-one, and bromomethyl methyl ether.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[CH2:9][C:8](=[O:15])[CH2:7][CH2:6]2.[N+:16]([C:19]1[CH:26]=[CH:25][CH:24]=[CH:23][C:20]=1[CH:21]=O)([O-:18])=[O:17]>>[N+:16]([C:19]1[CH:26]=[CH:25][CH:24]=[CH:23][C:20]=1[CH:21]=[C:9]1[C:10]2[C:5](=[CH:4][C:3]([O:2][CH3:1])=[C:12]([O:13][CH3:14])[CH:11]=2)[CH2:6][CH2:7][C:8]1=[O:15])([O-:18])=[O:17]
Reactant: O=Cc1ccccc1[N+](=O)[O-]
Reactant: COc1cc2c(cc1OC)CC(=O)CC2
Product: COc1cc2c(cc1OC)C(=Cc1ccccc1[N+](=O)[O-])C(=O)CC2

Procedure:
Prepared from 6,7-dimethoxy-2-tetralone and 2-nitrobenzaldehyde; mp 63-64° C.; IR (Nujol): 1712, 1540; 1H NMR: δ2.69 (2H, t), 3.01 (2H t), 3.25 (3H, s), 3.88 (3H, s), 6.26 (1H, s), 6.72 (1H, s), 7.25-7.26 (1H, m), 7.44-7.50 (2H, m), 7.87 (1H, s), 8.12-8.17 (1H, m); 13C NMR: δ28.0, 37.9, 55.7, 56.3, 108.6, 111.3, 112.5, 124.2, 124.9, 125.4, 129.3, 130.1, 131.8, 133.5, 133.9, 134.7, 147.5, 149.6, 200.7.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([O:8][C:9]([F:25])([F:24])[C:10]2[CH:15]=[CH:14][C:13]([O:16][CH2:17][CH2:18][CH2:19][C:20]([F:23])([F:22])[F:21])=[CH:12][CH:11]=2)=[CH:4][CH:3]=1.C(N(CC)CC)C.[C:33]([O:37][CH3:38])(=[O:36])[CH:34]=[CH2:35]>CN(C=O)C.CC(OC)(C)C.CC([O-])=O.CC([O-])=O.[Pd+2]>[F:24][C:9]([F:25])([C:10]1[CH:15]=[CH:14][C:13]([O:16][CH2:17][CH2:18][CH2:19][C:20]([F:23])([F:22])[F:21])=[CH:12][CH:11]=1)[O:8][C:5]1[CH:6]=[CH:7][C:2](/[CH:35]=[CH:34]/[C:33]([O:37][CH3:38])=[O:36])=[CH:3][CH:4]=1
Reactant: C=CC(=O)OC
Reactant: FC(F)(F)CCCOc1ccc(C(F)(F)Oc2ccc(Br)cc2)cc1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Solvent: COC(C)(C)C
Product: COC(=O)/C=C/c1ccc(OC(F)(F)c2ccc(OCCCC(F)(F)F)cc2)cc1
Temperature: 130 °C
Reaction time: 2 h
Yield: 75.7 %

Procedure:
554 mg (2.469 mmol) of Pd(OAc)2, 2.70 g (7.41 mmol) of dicyclohexyl(2′-methylbuphenyl-2-yl)phosphine, 35 g (82 mmol) of 1-bromo-4-{difluoro[4-(4,4,4-trifluorobutoxy)phenyl]methoxy}-benzene, 17.2 ml (123 mmol) of triethylamine and 14.84 ml (165 mmol) of methyl acrylate are solubilised in 500 ml of DMF and heated to 130° C. After 2 hours, the solution is diluted to room temperature and diluted with 500 ml of TBME. The solution is filtrated over a plug of Hyflo. The organic phase is washed repeatedly with water, dried over sodium sulfate, filtrated and concentrated under reduced pressure. Crystallisation from toluene/heptane mixture yields 26.7 g of methyl (2E)-3-(4-{difluoro[4-(4,4,4-trifluorobutoxy)phenyl]methoxy}phenyl)-prop-2-enoate.
Reaction SMILES: [F:1][C:2]([F:23])([F:22])[C:3]1[C:11]2[CH2:10][CH2:9][CH2:8][CH2:7][C:6]=2[N:5]([C:12]2[CH:17]=[CH:16][C:15]([CH2:18][C:19]([OH:21])=O)=[CH:14][CH:13]=2)[N:4]=1.[CH2:24]([NH:26][CH3:27])[CH3:25]>>[CH2:24]([N:26]([CH3:27])[C:19](=[O:21])[CH2:18][C:15]1[CH:14]=[CH:13][C:12]([N:5]2[C:6]3[CH2:7][CH2:8][CH2:9][CH2:10][C:11]=3[C:3]([C:2]([F:23])([F:22])[F:1])=[N:4]2)=[CH:17][CH:16]=1)[CH3:25]
Reactant: CCNC
Reactant: O=C(O)Cc1ccc(-n2nc(C(F)(F)F)c3c2CCCC3)cc1
Product: CCN(C)C(=O)Cc1ccc(-n2nc(C(F)(F)F)c3c2CCCC3)cc1

Procedure:
The title compound was prepared from {4-[3-(trifluoromethyl)-4,5,6,7-tetrahydro-1H-indazol-1-yl]phenyl}acetic acid and N-ethylmethylamine using a similar procedure to that described for Example 13, but purified by flash column chromatography eluting from 0-100% ethyl acetate in hexane.
Reaction SMILES: [S:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[C:2]1[S:10][CH2:11][C:12]([OH:14])=O.[NH:15]1[CH2:21][CH2:20][CH2:19][C:18](=[O:22])[C:17]2[CH:23]=[CH:24][CH:25]=[CH:26][C:16]1=2>>[S:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[C:2]1[S:10][CH2:11][C:12]([N:15]1[CH2:21][CH2:20][CH2:19][C:18](=[O:22])[C:17]2[CH:23]=[CH:24][CH:25]=[CH:26][C:16]1=2)=[O:14]
Reactant: O=C1CCCNc2ccccc21
Reactant: O=C(O)CSc1nc2ccccc2s1
Product: O=C1CCCN(C(=O)CSc2nc3ccccc3s2)c2ccccc21
Yield: 29 %

Procedure:
The title compound was synthesized according to General Procedure B using 2-(benzo[d]thiazol-2-ylthio)acetic acid and 1,2,3,4-tetrahydrobenzo[b]azepin-5-one (5) to yield 37 (160 mg, 29%): MS (APCI): m/z 369 [M+H]+. Anal. Calcd. for C19H16N2O2S2: C, 61.93; H, 4.38; N, 7.60. Found: C, 61.72; H, 4.31; N, 7.40.
Reaction SMILES: [C:1]([C:5]1[CH:10]=[C:9]([F:11])[C:8]([N+:12]([O-])=O)=[CH:7][C:6]=1[OH:15])([CH3:4])([CH3:3])[CH3:2].C([O-])=O.[NH4+]>CCO.[Pd]>[C:1]([C:5]1[CH:10]=[C:9]([F:11])[C:8]([NH2:12])=[CH:7][C:6]=1[OH:15])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)c1cc(F)c([N+](=O)[O-])cc1O
Agent: [Pd]
Agent: O=C[O-]
Agent: [NH4+]
Solvent: CCO
Product: CC(C)(C)c1cc(F)c(N)cc1O
Yield: 159.7 %

Procedure:
To a refluxing solution of 2-tert-butyl-4-fluoro-5-nitrophenol (400 mg, 1.88 mmol) and ammonium formate (400 mg, 6.1 mmol) in EtOH (20 mL) was added 5% Pd-C (260 mg). The mixture was refluxed for additional 1 h, cooled and filtered through Celite. The solvent was removed by evaporation to give 2-tert-butyl-5-amino-4-fluorophenol (C-7) (550 mg, 83%). 1H NMR (400 MHz, DMSO-d6) δ 8.83 (br s, 1H), 6.66 (d, J=13.7 Hz, 1H), 6.22 (d, J=8.5 Hz, 1H), 4.74 (br s, 2H), 1.26 (s, 9H); HPLC ret. time 2.58 min, 10-99% CH3CN, 5 min run; ESI-MS 184.0 m/z (MH+).
Reaction SMILES: Cl.Cl.[CH3:3][C@@:4]1([CH2:15][N:16]2[CH2:21][CH2:20][NH:19][CH2:18][CH2:17]2)[O:8][C:7]2=[N:9][C:10]([N+:12]([O-:14])=[O:13])=[CH:11][N:6]2[CH2:5]1.CN(C=O)C.C(=O)([O-])[O-].[K+].[K+].[Cl:33][C:34]1[CH:39]=[CH:38][C:37]([CH2:40][CH2:41][S:42](Cl)(=[O:44])=[O:43])=[CH:36][CH:35]=1>O>[Cl:33][C:34]1[CH:35]=[CH:36][C:37]([CH2:40][CH2:41][S:42]([N:19]2[CH2:18][CH2:17][N:16]([CH2:15][C@:4]3([CH3:3])[O:8][C:7]4=[N:9][C:10]([N+:12]([O-:14])=[O:13])=[CH:11][N:6]4[CH2:5]3)[CH2:21][CH2:20]2)(=[O:44])=[O:43])=[CH:38][CH:39]=1
Reactant: O=S(=O)(Cl)CCc1ccc(Cl)cc1
Reactant: C[C@]1(CN2CCNCC2)Cn2cc([N+](=O)[O-])nc2O1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: C[C@]1(CN2CCN(S(=O)(=O)CCc3ccc(Cl)cc3)CC2)Cn2cc([N+](=O)[O-])nc2O1
Temperature: 25 °C
Reaction time: 8 h
Yield: 24.2 %

Procedure:
A mixture of (S)-2-methyl-6-nitro-2-(piperazin-1-ylmethyl)-2,3-dihydroimidazo[2,1-b]oxazole dihydrochloride prepared in Example 408 (236 mg, 0.88 mmol) and DMF (3 ml) was added potassium carbonate (500 mg, 3.62 mmol) and 2-(4-chlorophenyl)ethanesulfonyl chloride (240 mg, 1 mmol) in this order followed by stirring at room temperature overnight. To the reaction mixture, water was added, and the solution was extracted with ethyl acetate. The organic phase was washed with water three times and saturated saline solution, dried over sodium sulfate and then filtered. The filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (methylene chloride/methanol=50/1) to afford (S)-2-{4-[2-(4-chlorophenyl)ethanesulfonyl]piperazin-1-ylmethyl}-2-methyl-6-nitro-2,3-dihydroimidazo[2,1-b]oxazole (100 mg, yield 26%) as a white powder.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][CH:9]([C:11]1[S:12][C:13]([C:16]([OH:18])=[O:17])=[CH:14][N:15]=1)[CH3:10])=[O:7])([CH3:4])([CH3:3])[CH3:2].[OH-].[K+].[CH2:21](Br)[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1>CS(C)=O>[C:1]([O:5][C:6]([NH:8][CH:9]([C:11]1[S:12][C:13]([C:16]([O:18][CH2:21][C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)=[O:17])=[CH:14][N:15]=1)[CH3:10])=[O:7])([CH3:2])([CH3:3])[CH3:4]
Reactant: CC(NC(=O)OC(C)(C)C)c1ncc(C(=O)O)s1
Reactant: BrCc1ccccc1
Agent: [K+]
Agent: [OH-]
Solvent: CS(C)=O
Product: CC(NC(=O)OC(C)(C)C)c1ncc(C(=O)OCc2ccccc2)s1
Temperature: 25 °C
Reaction time: 8 h
Yield: 73.4 %

Procedure:
To a solution of 2-(1-(tert-butoxycarbonylamino)ethyl)thiazole-5-carboxylic acid (0.14 g, 0.5 mmol) in DMSO (1 mL) was added KOH (0.031 g, 0.55 mmol). The mixture was stirred at room temperature until the full dissolution of KOH was observed. Benzyl bromide (0.06 mL, 0.53 mmol) was added and the reaction solution was stirred at room temperature overnight. The solution was partitioned between EtOAc and saturated aqueous NaHCO3. The organic layer was dried over anhydrous MgSO4, concentrated and purified by column chromatography to afford a colorless oil (0.133 g, 73%). LC-MS: (FA) ES+ 363.
Reaction SMILES: C(O[C:4]([C:6]1[N:7]=[C:8]([C:26]#[N:27])[C:9]2[C:14]([C:15]=1[OH:16])=[CH:13][CH:12]=[C:11]([O:17][C:18]1[C:23]([F:24])=[CH:22][CH:21]=[CH:20][C:19]=1[F:25])[CH:10]=2)=[O:5])C.[C:28]([O:32][C:33](=[O:39])[C:34]([CH3:38])([CH3:37])[CH2:35][NH2:36])([CH3:31])([CH3:30])[CH3:29]>CCO>[C:28]([O:32][C:33](=[O:39])[C:34]([CH3:38])([CH3:37])[CH2:35][NH:36][C:4]([C:6]1[N:7]=[C:8]([C:26]#[N:27])[C:9]2[C:14]([C:15]=1[OH:16])=[CH:13][CH:12]=[C:11]([O:17][C:18]1[C:19]([F:25])=[CH:20][CH:21]=[CH:22][C:23]=1[F:24])[CH:10]=2)=[O:5])([CH3:31])([CH3:29])[CH3:30]
Reactant: CCOC(=O)c1nc(C#N)c2cc(Oc3c(F)cccc3F)ccc2c1O
Reactant: CC(C)(C)OC(=O)C(C)(C)CN
Solvent: CCO
Product: CC(C)(C)OC(=O)C(C)(C)CNC(=O)c1nc(C#N)c2cc(Oc3c(F)cccc3F)ccc2c1O
Yield: 103.1 %

Procedure:
A mixture of 1-cyano-7-(2,6-difluoro-phenoxy)-4-hydroxy-isoquinoline-3-carboxylic acid ethyl ester (26 mg) and 3-amino-2,2-dimethyl-propionic acid tert-butyl ester (26 mg) in EtOH (0.5 mL) was microwaved at 140° C. for 1 h. The mixture was cooled, concentrated and the residue was column purified to give the desired product (36 mg). LC MS ESI+: 498 (M+1)+.
Reaction SMILES: [H-].[Na+].Br[C:4]1[CH:12]=[CH:11][CH:10]=[C:9]2[C:5]=1[CH:6]=[CH:7][NH:8]2.C([Li])(C)(C)C.C([O:22][B:23](OCCCC)[O:24]CCCC)CCC.Cl>O1CCCC1>[NH:8]1[C:9]2[CH:10]=[CH:11][CH:12]=[C:4]([B:23]([OH:24])[OH:22])[C:5]=2[CH:6]=[CH:7]1
Reactant: CCCCOB(OCCCC)OCCCC
Reactant: Brc1cccc2[nH]ccc12
Agent: Cl
Agent: [H-]
Agent: [Li]C(C)(C)C
Solvent: C1CCOC1
Product: OB(O)c1cccc2[nH]ccc12
Temperature: 0 °C
Reaction time: 0.25 h
Yield: 46 %

Procedure:
To a suspension of sodium hydride (130 mg, 5.41 mmol) in anhydrous tetrahydrofuran (20 mL) was added 4-bromoindole (973 mg, 4.96 mmol) (see Kosuge et al. supra) at 0° C. After 15 min. of stirring at 0° C., the reaction was cooled to −78° C., and tert-butyllithium (10.2 mmol, 1.7 M in hexane) (Aldrich) was added dropwise (a white precipitate immediately formed). After 10 min. tri-n-butylborate (2.75 mL, 10.2 mmol) (Aldrich) was added dropwise. The reaction was allowed to slowly warm to room temperature, then the suspension was poured into an ice cold solution of 1N HCl. The organic phase was separated, and the aqueous phase was washed with ether. The combined organic extracts were extracted with 1N NaOH (3×25 mL), and the combined alkaline extracts were acidified to pH 1 with 1N HCl. The product was then extracted with ether, and the combined ether layers were dried over magnesium sulfate and concentrated in vacuo to yield a brownish solid. The product was recrystallized from boiling water to yield 367 mg (46%) white crystals.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([N:8]2[CH2:13][CH2:12][N:11]([CH2:14][CH2:15][NH2:16])[CH2:10][CH2:9]2)[CH:5]=[CH:6][CH:7]=1.[C:17]1([N:23]2[C:27]([C:28]3[O:29][CH:30]=[CH:31][CH:32]=3)=[CH:26][C:25]([CH:33]=O)=[N:24]2)[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1>>[Cl:1][C:2]1[CH:3]=[C:4]([N:8]2[CH2:9][CH2:10][N:11]([CH2:14][CH2:15][NH:16][CH2:33][C:25]3[CH:26]=[C:27]([C:28]4[O:29][CH:30]=[CH:31][CH:32]=4)[N:23]([C:17]4[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=4)[N:24]=3)[CH2:12][CH2:13]2)[CH:5]=[CH:6][CH:7]=1
Reactant: O=Cc1cc(-c2ccco2)n(-c2ccccc2)n1
Reactant: NCCN1CCN(c2cccc(Cl)c2)CC1
Product: Clc1cccc(N2CCN(CCNCc3cc(-c4ccco4)n(-c4ccccc4)n3)CC2)c1
Yield: 68.6 %

Procedure:
Compound 80 was prepared using the same method as that of Example 1 except that 4-(3-chlorophenyl)piperazin-1-ylethylamine and 1-phenyl-5-(2-furyl)pyrazole-3-carbaldehyde were used.
Reaction SMILES: [C:1]([O:5][C:6]([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=1[C:14]1[CH:19]=[CH:18][C:17]([CH2:20][NH:21][C:22](=S)[S:23]C)=[CH:16][CH:15]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].O.[NH2:27][NH2:28]>C(O)C>[C:1]([O:5][C:6]([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=1[C:14]1[CH:15]=[CH:16][C:17]([CH2:20][NH:21][C:22](=[S:23])[NH:27][NH2:28])=[CH:18][CH:19]=1)=[O:7])([CH3:3])([CH3:2])[CH3:4]
Reactant: CSC(=S)NCc1ccc(-c2ccccc2C(=O)OC(C)(C)C)cc1
Reactant: NN
Solvent: CCO
Solvent: O
Product: CC(C)(C)OC(=O)c1ccccc1-c1ccc(CNC(=S)NN)cc1

Procedure:
A mixture of 1.53 g (4.1 mmole) of methyl N-[[2'-(t-butoxycarbonyl)biphenyl-4-yl]methyl]dithiocarbamate, 796 μl (820 mg, 16.4 mmole) of hydrazine hydrate, and 10 ml of absolute ethanol was stirred at reflux under N2. After 2 hours the resulting solution was cooled and concentrated. The residual oil was chromatographed on a column of silica gel (elution with 99:1 and the 98:2 CH2Cl2) to give (after concentration and vacuum-drying) 1.15 g (79%) of a stiff, white foam, mp>45° C. (gradual); homogeneous by TLC in 19:1 CH2Cl2 -MeOH; mass spectrum (FAB) m/e 358 (M+1)+.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[CH:6][C:5]([C:8]2[N:15]3[C:11]([S:12][C:13]([C:16]4[CH:21]=[CH:20][C:19]([OH:22])=[C:18]([O:23][CH3:24])[CH:17]=4)=[N:14]3)=[N:10][C:9]=2[CH3:25])=[CH:4][C:3]=1[C:26]([F:29])([F:28])[F:27].Br[CH2:31][CH2:32][NH:33][C:34](=[O:40])[O:35][C:36]([CH3:39])([CH3:38])[CH3:37].C([O-])([O-])=O.[K+].[K+]>CN(C=O)C>[NH2:1][C:2]1[N:7]=[CH:6][C:5]([C:8]2[N:15]3[C:11]([S:12][C:13]([C:16]4[CH:21]=[CH:20][C:19]([O:22][CH2:31][CH2:32][NH:33][C:34](=[O:40])[O:35][C:36]([CH3:39])([CH3:38])[CH3:37])=[C:18]([O:23][CH3:24])[CH:17]=4)=[N:14]3)=[N:10][C:9]=2[CH3:25])=[CH:4][C:3]=1[C:26]([F:28])([F:27])[F:29]
Reactant: COc1cc(-c2nn3c(-c4cnc(N)c(C(F)(F)F)c4)c(C)nc3s2)ccc1O
Reactant: CC(C)(C)OC(=O)NCCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: COc1cc(-c2nn3c(-c4cnc(N)c(C(F)(F)F)c4)c(C)nc3s2)ccc1OCCNC(=O)OC(C)(C)C
Temperature: 105 °C
Reaction time: 2 h
Yield: 15.2 %

Procedure:
To a solution of 4-(5-(6-amino-5-(trifluoromethyl)pyridin-3-yl) -6-methylimidazo[2,1-b][1,3,4]thiadiazol-2-yl)-2-methoxyphenol (0.030 g, 0.07 mmol, 1 eq) in dry DMF (0.8 mL), tert-butyl 2-bromoethylcarbamate (0.020 g, 0.09 mmol, 1.25 eq) and K2CO3 (0.01 g, 0.09 mmol, 1.25 eq) were added. The mixture was stirred at 105° C. for 2 h and cooled to RT. The solvent was evaporated, and the dry residue was taken up in DCM, washed with water (2×1 mL), dried (MgSO4), filtered and concentrated to dryness. Purification by preparative HPLC (RP-C18, ACN/water) gave the desired product (0.006 g, 15%). HPLC-MS: (50-100% B in 8 min, 0.8 mL/min): tR=1.75 min, [M+H]+ m/z 565; 1H NMR (300 MHz, CDCl3) δ/ppm 8.42 (d, J=1.7, 1H), 7.95 (d, J=1.8, 1H), 7.49 (s, 1H), 7.41 (t, J=2.5, 1H), 7.32 (t, J=4.5, 1H), 5.19 (s, 2H), 5.01 (s, 1H), 3.99 (s, 3H), 3.48-3.43 (m, 2H), 2.40-2.32 (m, 3H), 2.19-2.07 (m, 8H), 1.98 (s, 3H).
Reaction SMILES: [NH:1]1[CH:5]=[CH:4][CH:3]=[CH:2]1.Cl[C:7]1[S:8][C:9]([N+:13]([O-:15])=[O:14])=[C:10]([Cl:12])[N:11]=1>CN1CCCC1=O>[Cl:12][C:10]1[N:11]=[C:7]([N:1]2[CH:5]=[CH:4][CH:3]=[CH:2]2)[S:8][C:9]=1[N+:13]([O-:15])=[O:14]
Reactant: c1cc[nH]c1
Reactant: O=[N+]([O-])c1sc(Cl)nc1Cl
Solvent: CN1CCCC1=O
Product: O=[N+]([O-])c1sc(-n2cccc2)nc1Cl
Temperature: 70 °C
Yield: 71.9 %

Procedure:
6.7 g (0.1 mol) of pyrrole are added to a solution of 0.0 g (0.05 mol) of 2,4-dichloro-5-nitrothiazole in 00 ml of N-methyl-2-pyrrolidinone at room temperature. The mixture is then heated at 70° C. for 5 hours and subsequently cooled to room temperature and stirred into 1 l of ice-water. The precipitate formed is filtered off, washed with water and dried. 8.25 g (72.0% of theory) of 4-chloro-5-nitro-2-(1-pyrrolyl)-thiazole of melting point 138° C. to 139° C. (yellow needles from toluene) are obtained.
Reaction SMILES: [CH2:1]([Sn:9]([CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH3:25])(OC(=O)C)[O:10]C(=O)C)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH3:8].[OH-].[K+]>CC(C)CCO>[CH2:1]([Sn:9](=[O:10])[CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH3:25])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH3:8]
Reactant: CCCCCCCC[Sn](CCCCCCCC)(OC(C)=O)OC(C)=O
Agent: [K+]
Agent: [OH-]
Solvent: CC(C)CCO
Product: CCCCCCCC[Sn](=O)CCCCCCCC

Procedure:
Although 1,1,3,3-tetra-n-octyl-1,3-bis(3-methylbutyloxy)distannoxane was obtained by reacting di-n-octyl-diacetoxy tin and aqueous alkaline solution (aqueous potassium hydroxide solution) instead of directly reacting the di-n-octyl-diacetoxy tin obtained in step (I-2) with 3-methyl-1-butanol in step (I-3) to obtain dioctyl tin oxide, followed by reacting the dioctyl tin oxide with 3-methyl-1-butanol, since the dioctyl tin oxide was a solid thereby requiring the procedure of recovering the solid by filtration, the procedure is excessively complex in terms of industrial application.