Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[C:2]1[S:6][N:5]=[C:4]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)[N:3]=1.[C:13]([O:17][C:18]([N:20]1[CH2:25][CH2:24][NH:23][CH2:22][CH2:21]1)=[O:19])([CH3:16])([CH3:15])[CH3:14].C(N(CC)CC)C.O>CN(C)C=O>[C:7]1([C:4]2[N:3]=[C:2]([N:23]3[CH2:22][CH2:21][N:20]([C:18]([O:17][C:13]([CH3:16])([CH3:15])[CH3:14])=[O:19])[CH2:25][CH2:24]3)[S:6][N:5]=2)[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1
Reactant: Clc1nc(-c2ccccc2)ns1
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Solvent: CN(C)C=O
Solvent: O
Solvent: CCN(CC)CC
Product: CC(C)(C)OC(=O)N1CCN(c2nc(-c3ccccc3)ns2)CC1
Temperature: 25 °C
Reaction time: 3 h
Yield: 52.2 %

Procedure:
To a solution of 5-chloro-3-phenyl-1,2,4-thiadiazole (196 mg, 1.00 mmol) and 1-(tert-butoxycarbonyl)-piperazine (186 mg, 1.00 mmol) in dimethylformamide (2 ml) was added triethylamine (0.558 ml, 4.00 mmol) at room temperature, and the mixture was stirred at room temperature for 3 hours. The reaction mixture was poured to water and extracted with ethyl acetate. The extract was washed with water, and the solvent was distilled off under reduced pressure. The residue was recrystallized from a mixed solvent of ethyl acetate and hexane to yield 181 mg (52.3%) of the desired product.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:19])[C:5](=[CH2:18])[CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH:11]1[CH2:17][CH2:16][CH2:15][CH2:14][CH2:13][CH2:12]1)[CH3:2].ClC1C=CC=C(C(OO)=[O:28])C=1>C(Cl)Cl>[CH2:1]([O:3][C:4]([C:5]1([CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH:11]2[CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17]2)[CH2:18][O:28]1)=[O:19])[CH3:2]
Reactant: C=C(CCCCCC1CCCCCC1)C(=O)OCC
Reactant: O=C(OO)c1cccc(Cl)c1
Solvent: ClCCl
Product: CCOC(=O)C1(CCCCCC2CCCCCC2)CO1

Procedure:
7.5 g of the title compound, in the form of a colourless oil, which is purified by chromatography on silica gel (migrating agent: 90:10 petroleum ether/ethyl acetate; thin layer chromatography on silica gel with petroleum ether/ethyl acetate 8:2: Rf =0.55), are obtained by the procedure described in Example (1a) from 13.1 g of 7-cycloheptyl-2-methyleneheptanoic acid ethyl ester and 12.0 g of m-chloroperbenzoic acid in 200 ml of methylene chloride.
Reaction SMILES: [OH-].[Na+].C(#N)C.[NH2:6][C:7]1[NH:8][C:9]2[CH:15]=[CH:14][CH:13]=[CH:12][C:10]=2[N:11]=1.[CH3:16][N:17]([CH3:22])[S:18](Cl)(=[O:20])=[O:19]>O>[CH3:16][N:17]([CH3:22])[S:18]([N:8]1[C:9]2[CH:15]=[CH:14][CH:13]=[CH:12][C:10]=2[N:11]=[C:7]1[NH2:6])(=[O:20])=[O:19]
Reactant: CN(C)S(=O)(=O)Cl
Reactant: Nc1nc2ccccc2[nH]1
Agent: [Na+]
Agent: [OH-]
Solvent: CC#N
Solvent: O
Product: CN(C)S(=O)(=O)n1c(N)nc2ccccc21
Temperature: 25 °C
Yield: 92.5 %

Procedure:
To a solution of sodium hydroxide (1.8 g) in water (9 mL) add acetonitrile (44 mL). To this solution, add 2-aminobenzimidazole (3.0 g, 22.5 mmol) and dimethylsulfamoyl chloride (2.4 mL, 22.5 mmol). Stir the reaction mixture at room temperature, overnight. Then, cool the mixture at 0° C. and the product crystallized from solution. Filter the product and dry it in vacuum to provide 5.0 g (90% yield) of the title compound as a white solid. MS(ES+): m/z=241.1 (M+H)+
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:9]2[N:14]=[C:13]([OH:15])[CH:12]=[C:11]([CH:16]([CH3:18])[CH3:17])[N:10]=2)[CH:5]=[C:6]([Cl:8])[CH:7]=1.[F:19][C:20]([F:30])([F:29])[C:21]1[CH:28]=[CH:27][C:24]([CH2:25]Br)=[CH:23][CH:22]=1>>[Cl:8][C:6]1[CH:5]=[C:4]([C:9]2[N:10]=[C:11]([CH:16]([CH3:18])[CH3:17])[CH:12]=[C:13]([O:15][CH2:25][C:24]3[CH:23]=[CH:22][C:21]([C:20]([F:19])([F:29])[F:30])=[CH:28][CH:27]=3)[N:14]=2)[CH:3]=[C:2]([Cl:1])[CH:7]=1
Reactant: FC(F)(F)c1ccc(CBr)cc1
Reactant: CC(C)c1cc(O)nc(-c2cc(Cl)cc(Cl)c2)n1
Product: CC(C)c1cc(OCc2ccc(C(F)(F)F)cc2)nc(-c2cc(Cl)cc(Cl)c2)n1

Procedure:
The title compound was prepared from 2-(3,5-dichloro-phenyl)-6-isopropyl-pyrimidin-4-ol (which was obtained in Intermediate 6) and 4-(trifluoromethyl)benzyl bromide according to Method A; LC retention time 4.57 min; MS: m/z (ESI) 441 (M+H).
Reaction SMILES: [Si](O[CH2:9][C@H:10]([CH2:26][CH2:27][O:28]S(C)(=O)=O)[CH2:11][C@H:12]1[CH2:16][O:15][C:14]([CH3:18])([CH3:17])[N:13]1[C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])(C(C)(C)C)(C)C.CCN(CC)CC.C(O)=O>C1COCC1.CC(=O)OCC>[CH3:18][C:14]1([CH3:17])[N:13]([C:19]([O:21][C:22]([CH3:23])([CH3:24])[CH3:25])=[O:20])[C@@H:12]([CH2:11][C@H:10]2[CH2:26][CH2:27][O:28][CH2:9]2)[CH2:16][O:15]1
Reactant: CC(C)(C)OC(=O)N1[C@@H](C[C@@H](CCOS(C)(=O)=O)CO[Si](C)(C)C(C)(C)C)COC1(C)C
Solvent: C1CCOC1
Solvent: O=CO
Solvent: CCN(CC)CC
Product: CC(C)(C)OC(=O)N1[C@@H](C[C@H]2CCOC2)COC1(C)C
Reaction time: 12 h
Yield: 67.2 %

Procedure:
To a solution of (S)-tert-butyl 4-((S)-2-((tert-butyldimethylsilyloxy)methyl)-4-(methylsulfonyloxy)butyl)-2,2-dimethyloxazolidine-3-carboxylate (6.2 g) in 200 mL of THF was added TEAF. The reaction mixture was stirred for 12 h under reflux. The mixture was diluted with EA, washed with water back extracted EA. The combined organic layer was washed with brine, filtered, and concentrated. The crude product was purified by flash column to give the pure product (S)-tert-butyl 2,2-dimethyl-4-(((S)-tetrahydrofuran-3-yl)methyl)oxazolidine-3-carboxylate (2.4 g, 67%).
Reaction SMILES: [NH2:1][CH:2]([C:4]1[N:9]=[N:8][C:7]([NH:10][C:11]2[CH:16]=[C:15]([O:17][CH3:18])[C:14]([O:19][CH3:20])=[C:13]([O:21][CH3:22])[CH:12]=2)=[N:6][CH:5]=1)[CH3:3].[CH3:23][C:24]([CH3:38])([CH3:37])[C:25]([NH:27][C:28]1[CH:36]=[CH:35][CH:34]=[CH:33][C:29]=1[C:30](O)=[O:31])=[O:26].C(N(CC)CC)C>CN(C)C=O>[CH3:23][C:24]([CH3:38])([CH3:37])[C:25]([NH:27][C:28]1[CH:36]=[CH:35][CH:34]=[CH:33][C:29]=1[C:30]([NH:1][CH:2]([C:4]1[N:9]=[N:8][C:7]([NH:10][C:11]2[CH:12]=[C:13]([O:21][CH3:22])[C:14]([O:19][CH3:20])=[C:15]([O:17][CH3:18])[CH:16]=2)=[N:6][CH:5]=1)[CH3:3])=[O:31])=[O:26]
Reactant: CC(C)(C)C(=O)Nc1ccccc1C(=O)O
Reactant: COc1cc(Nc2ncc(C(C)N)nn2)cc(OC)c1OC
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: COc1cc(Nc2ncc(C(C)NC(=O)c3ccccc3NC(=O)C(C)(C)C)nn2)cc(OC)c1OC

Procedure:
In a similar manner as described for Intermediate 18 (below), 6-(1-aminoethyl)-N-(3,4,5-trimethoxyphenyl)-1,2,4-triazin-3-amine (Intermediate 9) (0.050 g, 0.16 mmol) 2-[(2,2-dimethylpropanoyl)amino]benzoic acid (0.040 g, 0.18 mmol), O-(7-azabenzotriazol-1-yl-N,N,N′N′-tetramethyluronium hexafluorophospahte (0.068 g, 0.18 mmol) and triethylamine (0.048 mL, 0.34 mmol) in N,N-dimethylformamide (1.0 mL) gave 2-[(2,2-dimethylpropanoyl)amino]-N-(1-{3-[(3,4,5-trimethoxyphenyl)amino]-1,2,4-triazin-6-yl}ethyl)benzamide (0.040 g) as a white solid. MS m/z 509 (M+1).
Reaction SMILES: [NH2:1][CH2:2][CH2:3][CH2:4][CH2:5][C:6]1[CH:11]=[CH:10][C:9]([C:12]2[CH:13]=[CH:14][C:15](=[O:18])[NH:16][N:17]=2)=[CH:8][CH:7]=1.[CH3:19][C:20]1[CH:24]=[C:23]([C:25](O)=[O:26])[O:22][N:21]=1>>[CH3:19][C:20]1[CH:24]=[C:23]([C:25]([NH:1][CH2:2][CH2:3][CH2:4][CH2:5][C:6]2[CH:7]=[CH:8][C:9]([C:12]3[CH:13]=[CH:14][C:15](=[O:18])[NH:16][N:17]=3)=[CH:10][CH:11]=2)=[O:26])[O:22][N:21]=1
Reactant: NCCCCc1ccc(-c2ccc(=O)[nH]n2)cc1
Reactant: Cc1cc(C(=O)O)on1
Product: Cc1cc(C(=O)NCCCCc2ccc(-c3ccc(=O)[nH]n3)cc2)on1

Procedure:
By treating 6-[4-(4-aminobutyl)phenyl]pyridazin-3(2H)-one and 3-methyl-5-carboxyisoxazole in the same manner as in Example 87, 6-{4-[4-(3-methylisoxazole-5-ylcarbonylamino)butyl]phenyl}pyridazin-3(2H)-one was obtained.
Reaction SMILES: [CH3:1][CH:2]([C:4]1[CH:9]=[CH:8][C:7]([C:10]2[C:11]([NH2:16])=[N:12][CH:13]=[CH:14][CH:15]=2)=[CH:6][CH:5]=1)[CH3:3].[H-].[Na+].Cl[CH2:20][CH2:21][S:22](Cl)(=[O:24])=[O:23].C(=O)([O-])O.[Na+]>C1COCC1.C(OCC)(=O)C>[CH3:3][CH:2]([C:4]1[CH:5]=[CH:6][C:7]([C:10]2[C:11]3=[N:16][S:22](=[O:24])(=[O:23])[CH2:21][CH2:20][N:12]3[CH:13]=[CH:14][CH:15]=2)=[CH:8][CH:9]=1)[CH3:1]
Reactant: O=S(=O)(Cl)CCCl
Reactant: CC(C)c1ccc(-c2cccnc2N)cc1
Agent: O=C([O-])O
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: CC(C)c1ccc(C2=CC=CN3CCS(=O)(=O)N=C23)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 74 %

Procedure:
A mixture of 3-[4-(1-methylethyl)phenyl]pyridin-2-amine (700 mg) in dehydrated THF (15 mL) was added to a mixture of sodium hydride (60%, 659 mg) and 2-chloroethanesulfonyl chloride (1613 mg) in dehydrated THF (15 mL) under ice-cooling. The reaction mixture was stirred at room temperature overnight, and saturated aqueous sodium hydrogen carbonate solution and ethyl acetate were added. The resulting precipitate was collected by filtration, and washed with water and ethyl acetate to give the title compound (738 mg) as a white solid. The obtained solid was crystallized from acetonitrile and diisopropyl ether to give a white solid.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:24]=[CH:23][C:6]([CH2:7][N:8]([C@@H:19]([CH3:22])[CH:20]=[O:21])[C:9](=[O:18])[O:10][CH2:11][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)=[CH:5][CH:4]=1.Br[CH2:26][C:27]([CH3:29])=[CH2:28]>>[OH:21][CH:20]([CH2:28][C:27]([CH3:29])=[CH2:26])[CH:19]([N:8]([CH2:7][C:6]1[CH:5]=[CH:4][C:3]([O:2][CH3:1])=[CH:24][CH:23]=1)[C:9](=[O:18])[O:10][CH2:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)[CH3:22]
Reactant: C=C(C)CBr
Reactant: COc1ccc(CN(C(=O)OCc2ccccc2)[C@@H](C)C=O)cc1
Product: C=C(C)CC(O)C(C)N(Cc1ccc(OC)cc1)C(=O)OCc1ccccc1

Procedure:
The title compound was prepared in analogy to the procedure described for step 23.7 from (S)-benzyl 4-methoxybenzyl(1-oxopropan-2-yl)carbamate and 3-bromo-2-methylprop-1-ene to afford the title compound as a 3:1 mixture of (2S,3R)- and (2S,3S)-diastereomer: tR=1.322 min (major isomer) and 1.329 min (minor isomer) (UPLC 1); tR=1.23 min (major isomer) and 1.24 min (minor isomer) (LC-MS 3); ESI-MS: 384 [M+H]+ (LC-MS 3).
Reaction SMILES: C([Sn](CCCC)(CCCC)[C:6]1[N:7]=[CH:8][N:9]([C:11]2[CH:16]=[C:15]([C:17]([F:20])([F:19])[F:18])[CH:14]=[C:13]([C:21]3[CH:26]=[CH:25][C:24]([C:27]([F:30])([F:29])[F:28])=[CH:23][CH:22]=3)[N:12]=2)[CH:10]=1)CCC.[C:39]([NH:43][S:44]([C:47]1[S:51][C:50](Cl)=[N:49][C:48]=1[CH3:53])(=[O:46])=[O:45])([CH3:42])([CH3:41])[CH3:40].CCCCCCC>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>[C:39]([NH:43][S:44]([C:47]1[S:51][C:50]([C:6]2[N:7]=[CH:8][N:9]([C:11]3[CH:16]=[C:15]([C:17]([F:20])([F:19])[F:18])[CH:14]=[C:13]([C:21]4[CH:22]=[CH:23][C:24]([C:27]([F:29])([F:30])[F:28])=[CH:25][CH:26]=4)[N:12]=3)[CH:10]=2)=[N:49][C:48]=1[CH3:53])(=[O:46])=[O:45])([CH3:42])([CH3:41])[CH3:40]
Reactant: Cc1nc(Cl)sc1S(=O)(=O)NC(C)(C)C
Reactant: CCCC[Sn](CCCC)(CCCC)c1cn(-c2cc(C(F)(F)F)cc(-c3ccc(C(F)(F)F)cc3)n2)cn1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: CCCCCCC
Solvent: Cc1ccccc1
Product: Cc1nc(-c2cn(-c3cc(C(F)(F)F)cc(-c4ccc(C(F)(F)F)cc4)n3)cn2)sc1S(=O)(=O)NC(C)(C)C
Temperature: 25 °C
Yield: 65.1 %

Procedure:
A stirred mixture of 2-(4-tributylstannanyl-imidazol-1-yl)-4-trifluoromethyl-6-(4-trifluoromethyl-phenyl)-pyridine (Example G.11) (0.718 g, 1.0 mmol), 2-chloro-4-methyl-thiazole-5-sulfonic acid tert-butylamide (Example H.5) (0.295 g, 1.1 mmol), tetrakis(triphenylphosphine)palladium (0.058 g, 0.044 mmol) in toluene (5 mL) was heated under reflux conditions for 18 h. Cooled to rt, some precipitate occurred, diluted with toluene (˜5 mL), added heptane, filtered the precipitate off, washed with toluene/heptane, dried in HV to give the title compound as a white solid (384 mg, 59%). MS (ISP) 590.4 [(M+H)+]; mp>250° C.
Reaction SMILES: [NH2:1][C@@H:2]1[C:8](=[O:9])[N:7]([CH3:10])[C:6]2[CH:11]=[CH:12][CH:13]=[C:14]([Cl:15])[C:5]=2[O:4][CH2:3]1.[CH3:16][CH:17]([C:21]([NH:23][CH2:24][C:25]([F:31])([F:30])[C:26]([F:29])([F:28])[F:27])=[O:22])[C:18](O)=[O:19]>>[Cl:15][C:14]1[C:5]2[O:4][CH2:3][C@H:2]([NH:1][C:18](=[O:19])[CH:17]([CH3:16])[C:21]([NH:23][CH2:24][C:25]([F:30])([F:31])[C:26]([F:27])([F:28])[F:29])=[O:22])[C:8](=[O:9])[N:7]([CH3:10])[C:6]=2[CH:11]=[CH:12][CH:13]=1
Reactant: CN1C(=O)[C@@H](N)COc2c(Cl)cccc21
Reactant: CC(C(=O)O)C(=O)NCC(F)(F)C(F)(F)F
Product: CC(C(=O)NCC(F)(F)C(F)(F)F)C(=O)N[C@H]1COc2c(Cl)cccc2N(C)C1=O

Procedure:
The title compounds were obtained according to the procedure described in example 2b) by condensation of (S)-7-amino-4-chloro-9-methyl-6,7-dihydro-9H-5-oxa-9-aza-benzocyclohepten-8-one with 2-methyl-N-(2,2,3,3,3-pentafluoro-propyl)-malonamic acid (ex 1c).
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][N:21]2[C:29]3[C:24](=[CH:25][C:26]([C:30](O)=[O:31])=[CH:27][CH:28]=3)[C:23]([CH3:33])=[C:22]2[CH3:34])=[CH:16][CH:15]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].CCN(C(C)C)C(C)C.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[Br:68][C:69]1[CH:74]=[CH:73][C:72]([C@@H:75]([NH2:77])[CH3:76])=[CH:71][CH:70]=1>CN(C=O)C>[Br:68][C:69]1[CH:74]=[CH:73][C:72]([C@@H:75]([NH:77][C:30]([C:26]2[CH:25]=[C:24]3[C:29](=[CH:28][CH:27]=2)[N:21]([CH2:20][C:17]2[CH:16]=[CH:15][C:14]([C:9]4[C:8]([C:6]([O:5][C:1]([CH3:2])([CH3:3])[CH3:4])=[O:7])=[CH:13][CH:12]=[CH:11][CH:10]=4)=[CH:19][CH:18]=2)[C:22]([CH3:34])=[C:23]3[CH3:33])=[O:31])[CH3:76])=[CH:71][CH:70]=1
Reactant: Cc1c(C)n(Cc2ccc(-c3ccccc3C(=O)OC(C)(C)C)cc2)c2ccc(C(=O)O)cc12
Reactant: C[C@H](N)c1ccc(Br)cc1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: Cc1c(C)n(Cc2ccc(-c3ccccc3C(=O)OC(C)(C)C)cc2)c2ccc(C(=O)N[C@@H](C)c3ccc(Br)cc3)cc12
Reaction time: 0.08 h

Procedure:
To a mixture of 1-((2′-(tert-butoxycarbonyl)biphenyl-4-yl)methyl)-2,3-dimethyl-1H-indole-5-carboxylic acid (46 mg, 0.1 mmol) in DMF (1 mL) was added DIEA (26 mg, 0.2 mmol) and HATU (46 mg, 0.12 mmol). The mixture was stirred for 5 min, and then (S)-1-(4-bromophenyl)ethanamine (20 mg, 0.13 mmol) was added. The reaction mixture was stirred at rt for 30 min. The completion of the reaction was monitored by anal. HPLC. The solvent was removed in vacuo to obtain the crude which was purified by flash chromatography (AcOEt/Hex 10→100%) to obtain the title compound. ESI-MS (m/z): 637/639 [M+H]+.
Reaction SMILES: [ClH:1].[OH:2][CH:3]([CH2:18][O:19][C:20]1[CH:25]=[CH:24][C:23](OC)=[CH:22][CH:21]=1)[CH2:4][NH:5][C:6]([CH3:17])([CH3:16])[CH2:7][C:8]1[CH:13]=[CH:12][C:11]([O:14][CH3:15])=[CH:10][CH:9]=1.Cl.O[CH:30]([CH2:45]OC1C=CC=CC=1C)[CH2:31]NC(C)(C)CC1C=CC(OC)=CC=1>>[ClH:1].[OH:2][CH:3]([CH2:18][O:19][C:20]1[CH:25]=[CH:24][C:23]([CH:30]([CH3:45])[CH3:31])=[CH:22][CH:21]=1)[CH2:4][NH:5][C:6]([CH3:16])([CH3:17])[CH2:7][C:8]1[CH:9]=[CH:10][C:11]([O:14][CH3:15])=[CH:12][CH:13]=1
Reactant: COc1ccc(CC(C)(C)NCC(O)COc2ccccc2C)cc1
Reactant: COc1ccc(CC(C)(C)NCC(O)COc2ccc(OC)cc2)cc1
Agent: Cl
Product: COc1ccc(CC(C)(C)NCC(O)COc2ccc(C(C)C)cc2)cc1

Procedure:
GC/EI-MS, m/z (rel. int.) 356 (M−15,0.1), 251 (18), 250 (100), 163 (7), 121 (23), 117 (7), 114 (8).
Reaction SMILES: [Br:1][C:2]1[C:7]([O:8][CH:9]([CH3:11])[CH3:10])=[CH:6][C:5]([N:12]2[C:17](=[O:18])[CH:16]=[C:15]([C:19]([F:22])([F:21])[F:20])[NH:14][C:13]2=[O:23])=[C:4]([F:24])[CH:3]=1.[C:25](=O)([O-])[O-].[K+].[K+].CI>C(#N)C>[Br:1][C:2]1[C:7]([O:8][CH:9]([CH3:11])[CH3:10])=[CH:6][C:5]([N:12]2[C:17](=[O:18])[CH:16]=[C:15]([C:19]([F:22])([F:21])[F:20])[N:14]([CH3:25])[C:13]2=[O:23])=[C:4]([F:24])[CH:3]=1
Reactant: O=C([O-])[O-]
Reactant: CC(C)Oc1cc(-n2c(=O)cc(C(F)(F)F)[nH]c2=O)c(F)cc1Br
Agent: [K+]
Solvent: CC#N
Solvent: CI
Product: CC(C)Oc1cc(-n2c(=O)cc(C(F)(F)F)n(C)c2=O)c(F)cc1Br

Procedure:
using 3-(4-bromo-2-fluoro-5-isopropoxyphenyl)-6-trifluoromethyl-2,4(1H,3H)-pyrimidinedione with potassium carbonate and methyl iodide in acetonitrile there is obtained 3-(4-bromo-2-fluoro-5-isopropoxyphenyl)-1-methyl-6-trifluoromethyl-2,4(1H,3H)-pyrimidinedione, m.p. 79° C.;
Reaction SMILES: [CH2:1]([N:8]1[C:14](=[O:15])[C:13]2[CH:16]=[CH:17][C:18](F)=[N:19][C:12]=2[O:11][CH2:10][CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Cl:21][C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=1[OH:28].C(=O)([O-])[O-].[K+].[K+].CN(C=O)C>O>[CH2:1]([N:8]1[C:14](=[O:15])[C:13]2[CH:16]=[CH:17][C:18]([O:28][C:23]3[CH:24]=[CH:25][CH:26]=[CH:27][C:22]=3[Cl:21])=[N:19][C:12]=2[O:11][CH2:10][CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C1c2ccc(F)nc2OCCN1Cc1ccccc1
Reactant: Oc1ccccc1Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: O=C1c2ccc(Oc3ccccc3Cl)nc2OCCN1Cc1ccccc1
Temperature: 100 °C
Reaction time: 16 h
Yield: 84 %

Procedure:
A mixture of the compound obtained in Example 28, step 1 (0.50 g), 2-chlorophenol (0.23 mL), potassium carbonate (0.76 g) and DMF (10 mL) was stirred at 100° C. for 16 hr. The reaction solution was poured into water, and the resulting product was extracted with ethyl acetate. The organic layer was washed with water and saturated brine and dried, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (solvent gradient; 0→40% ethyl acetate/hexane) to give 4-benzyl-8-(2-chlorophenoxy)-3,4-dihydropyrido[3,2-f][1,4]oxazepin-5(2H)-one (0.59 g, 84%) as a colorless oil.
Reaction SMILES: [OH:1][CH2:2][C@H:3]1[NH:7][C:6](=[O:8])[CH2:5][CH2:4]1.[C:9]([Si:13](Cl)([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)([CH3:12])([CH3:11])[CH3:10].CCN(CC)CC.N1CCCC1=O>C(Cl)Cl.CN(C1C=CN=CC=1)C>[Si:13]([O:1][CH2:2][C@H:3]1[NH:7][C:6](=[O:8])[CH2:5][CH2:4]1)([C:9]([CH3:12])([CH3:11])[CH3:10])([C:20]1[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=1)[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1
Reactant: CC(C)(C)[Si](Cl)(c1ccccc1)c1ccccc1
Reactant: O=C1CC[C@@H](CO)N1
Agent: CN(C)c1ccncc1
Agent: O=C1CCCN1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(C)(C)[Si](OC[C@@H]1CCC(=O)N1)(c1ccccc1)c1ccccc1
Yield: 73.8 %

Procedure:
To a solution of (S)-5-(hydroxymethyl)pyrrolidin-2-one (10 g, 87 mmol) in CH2Cl2 (50 mL) was added tert-butylchlorodiphenylsilane (25.6 g, 93 mmol), Et3N (12.1 mL, 87 mmol) and DMAP (1.06 g, 8.7 mmol). The mixture was stirred at room temperature until the starting pyrrolidinone was completely consumed and then diluted with CH2Cl2 (50 mL) and washed with water (50 mL). The organic layer was dried (Na2SO4), filtered, evaporated in vacuo and the crude material was submitted to flash chromatography (silica gel; 30 to 100% of EtOAc/hexanes) to afford (S)-5-((tert-butyldiphenylsilyloxy)methyl)pyrrolidin-2-one (22.7 g, 74% yield) as a colorless oil. LC/MS (M+H)+=354.58. 1H NMR (400 MHz, DMSO-d6) δ ppm 7.69 (br s, 1H), 7.64-7.61 (m, 4H), 7.50-7.42 (m, 6H), 3.67-3.62 (m, 1H), 3.58-3.51 (m, 2H), 2.24-2.04 (m, 3H), 1.87-1.81 (m, 1H), 1.00 (s, 9H).
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([C:8]2[S:12][C:11]([C:13]([CH3:16])([CH3:15])[CH3:14])=[N:10][C:9]=2[C:17]2[C:18]([F:35])=[C:19]([NH:23][S:24]([C:27]3[C:32]([F:33])=[CH:31][CH:30]=[CH:29][C:28]=3[F:34])(=[O:26])=[O:25])[CH:20]=[CH:21][CH:22]=2)[CH:5]=[CH:4][N:3]=1.[CH2:36](N(CC)CC)[CH3:37]>C(O)CC.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2]>[CH3:14][C:13]([C:11]1[S:12][C:8]([C:6]2[CH:5]=[CH:4][N:3]=[C:2]([CH:36]=[CH2:37])[N:7]=2)=[C:9]([C:17]2[C:18]([F:35])=[C:19]([NH:23][S:24]([C:27]3[C:32]([F:33])=[CH:31][CH:30]=[CH:29][C:28]=3[F:34])(=[O:26])=[O:25])[CH:20]=[CH:21][CH:22]=2)[N:10]=1)([CH3:16])[CH3:15]
Reactant: CCN(CC)CC
Reactant: CC(C)(C)c1nc(-c2cccc(NS(=O)(=O)c3c(F)cccc3F)c2F)c(-c2ccnc(Cl)n2)s1
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: c1ccc(P(c2ccccc2)[c-]2cccc2)cc1
Solvent: CCCO
Product: C=Cc1nccc(-c2sc(C(C)(C)C)nc2-c2cccc(NS(=O)(=O)c3c(F)cccc3F)c2F)n1
Yield: 84.5 %

Procedure:
N-{3-[5-(2-chloro-4-pyrimidinyl)-2-(1,1-dimethylethyl)-1,3-thiazol-4-yl]-2-fluorophenyl}-2,6-difluorobenzenesulfonamide (0.421 g, 0.781 mmol), potassium vinyl trifluoroborate (0.262 g, 1.953 mmol), PdCl2(dppf)2 (0.057 g, 0.078 mmol), and triethylamine (1.089 ml, 7.81 mmol) in n-propanol (7.81 ml) were heated at 100° C. in a screw-top vial overnight. The reaction mixture was filtered through celite and the celite rinsed with EtOAc. The combined organic portions were washed with water, dried over MgSO4, filtered and concentrated to dryness. The crude mixture was placed on silica gel and chromatography (0 to 80% DCM/EtOAc, gradient) to obtain the title compound (350 mg, 84%). 1H NMR (400 MHz, DMSO-d6) δ ppm 10.88 (s, 1H), 8.56 (d, J=5.31 Hz, 1H), 7.67 (ddd, J=14.28, 8.15, 6.13 Hz, 1H), 7.43 (t, J=7.60 Hz, 2H), 7.31 (t, J=7.69 Hz, 1H), 7.22 (t, J=9.25 Hz, 2H), 6.74 (m, 2H), 6.44 (dd, J=17.58, 1.65 Hz, 1H), 5.75 (dd, J=10.62, 2.01 Hz, 1H), 1.43 (m, 9H); MS (ESI): 531 [M+H]+.
Reaction SMILES: [O:1]1[C:5]2[CH:6]=[CH:7][C:8]([C:10]3[CH:11]=[C:12]([C:17]([O:19]C)=[O:18])[C:13](=[O:16])[NH:14][N:15]=3)=[CH:9][C:4]=2[CH:3]=[CH:2]1.O1C2C=CC(C3C=C(C(OC)=O)C(=O)NN=3)=CC=2CC1.CS(O[CH2:46][CH2:47][CH2:48][C:49]1[CH:54]=[CH:53][CH:52]=[CH:51][C:50]=1[Cl:55])(=O)=O>>[C:17]([C:12]1[C:13](=[O:16])[N:14]([CH2:46][CH2:47][CH2:48][C:49]2[CH:54]=[CH:53][CH:52]=[CH:51][C:50]=2[Cl:55])[N:15]=[C:10]([C:8]2[CH:7]=[CH:6][C:5]3[O:1][CH2:2][CH2:3][C:4]=3[CH:9]=2)[CH:11]=1)([OH:19])=[O:18]
Reactant: COC(=O)c1cc(-c2ccc3occc3c2)n[nH]c1=O
Reactant: CS(=O)(=O)OCCCc1ccccc1Cl
Agent: COC(=O)c1cc(-c2ccc3c(c2)CCO3)n[nH]c1=O
Product: O=C(O)c1cc(-c2ccc3c(c2)CCO3)nn(CCCc2ccccc2Cl)c1=O
Yield: 76.8 %

Procedure:
The general procedure of Example 1 (3) was carried out by use of 6-(2,3-dihydro-1-benzofuran-5-yl)-4-methoxycarbonyl-2H-pyridazin-3-one and 3-(2-chlorophenyl)-1-propanol methanesulfonate, to thereby yield the title compound as a yellow powder (yield: 76.8%).
Reaction SMILES: C(N(CC)CC)C.[CH:8]1[C:13](N=C=S)=[CH:12][C:11]2[C:17]([O:19][C:20]3([C:30]4[CH:31]=[CH:32][C:33]([OH:35])=[CH:34][C:29]=4[O:28][C:22]4[CH:23]=[C:24]([OH:27])[CH:25]=[CH:26][C:21]3=4)[C:10]=2[CH:9]=1)=[O:18]>CN(C=O)C>[CH:8]1[CH:13]=[CH:12][C:11]([C:17]([OH:19])=[O:18])=[C:10]([C:20]2[C:21]3[CH:26]=[CH:25][C:24]([OH:27])=[CH:23][C:22]=3[O:28][C:29]3[C:30]=2[CH:31]=[CH:32][C:33]([CH:34]=3)=[O:35])[CH:9]=1
Reactant: O=C1OC2(c3ccc(O)cc3Oc3cc(O)ccc32)c2ccc(N=C=S)cc21
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: O=C(O)c1ccccc1-c1c2ccc(=O)cc-2oc2cc(O)ccc12
Reaction time: 17 h
Yield: 81.5 %

Procedure:
Under argon atmosphere, to a solution of the crude 21 obtain as above in DMF (3 mL) were successively added triethylamine (29.0 μL, 208 μmol) and fluorescein isothiocyanate isomer I (FITC, 17, commercial product) (90%, HPLC) (45.0 mg, 104 μmol) at room temperature. After stirring for 17 hours at the same temperature, the reaction solution was concentrated under reduced pressure. The residue was purified by flash column chromatography (silica-gel 8 g, dichloromethane/methanol=12/1) to give 1-[2-{(11,12-didehydro-5,6-dihydrodibenzo[a,e]cycloocten-5-yl)oxycarbonylamino}ethyl]-3-(5-fluoresceinyl)thiourea (22) (59.0 mg, 84.8 μmol, 80.7% based on 17) as a yellow solid.
Reaction SMILES: [Cl:1][C:2]1[N:3]=[C:4]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[N:5]2[C:10]=1[CH:9]=[N:8][NH:7][C:6]2=O.P12(SP3(SP(SP(S3)(S1)=S)(=S)S2)=S)=[S:19]>N1C=CC=CC=1>[Cl:1][C:2]1[N:3]=[C:4]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[N:5]2[C:10]=1[CH:9]=[N:8][NH:7][C:6]2=[S:19]
Reactant: O=c1[nH]ncc2c(Cl)nc(-c3ccccc3)n12
Reactant: S=P12SP3(=S)SP(=S)(S1)SP(=S)(S2)S3
Solvent: c1ccncc1
Product: S=c1[nH]ncc2c(Cl)nc(-c3ccccc3)n12
Temperature: 100 °C

Procedure:
To a solution of 8-chloro-6-phenyl-imidazo[1,5-d]-as-triazine-4(3H)-one (5.84) gm.) in pyridine (100 ml.) is added phosphorus pentasulfide (5 gm.) The mixture is heated at 100° C for 6 hours, filtered hot, and poured into dilute hydrochloric acid. The title product is isolated as a solid.