Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([CH:7]2[NH:11][CH:10]([C:12]([OH:14])=O)[CH2:9][S:8]2)[CH:2]=1.[N:15]1[CH:20]=[CH:19][CH:18]=[C:17]([CH2:21][CH2:22][CH2:23][N:24]2[CH2:29][CH2:28][NH:27][CH2:26][CH2:25]2)[CH:16]=1.ON1C2C=CC=CC=2N=N1.C1(N=C=NC2CCCCC2)CCCCC1>C(OCC)(=O)C.CN(C)C=O>[N:15]1[CH:20]=[CH:19][CH:18]=[C:17]([CH2:21][CH2:22][CH2:23][N:24]2[CH2:29][CH2:28][N:27]([C:12]([CH:10]3[CH2:9][S:8][CH:7]([C:3]4[CH:2]=[N:1][CH:6]=[CH:5][CH:4]=4)[NH:11]3)=[O:14])[CH2:26][CH2:25]2)[CH:16]=1
Reactant: c1cncc(CCCN2CCNCC2)c1
Reactant: O=C(O)C1CSC(c2cccnc2)N1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: On1nnc2ccccc21
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: O=C(C1CSC(c2cccnc2)N1)N1CCN(CCCc2cccnc2)CC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 28.5 %

Procedure:
To a mixture solution of 2-(3-pyridyl)thiazolidine-4-carboxylic acid 1.7 g, 1-[3-(3-pyridyl)propyl]piperazine 1.56 g, 1-hydroxy-benzotriazole 1.3 g and N,N-dimethylformamide 20 ml was added dicyclohexylcarbodiimide 1.67 g under ice-cooling, and the mixture stirred overnight at room temperature. Ethyl acetate 50 ml was added, the precipitated dicyclohexylurea filtered off, water 30 ml added to the filtrate, the resultant solution basified with sodium hydrogen, carbonate and transferred into a separating funnel. The aqueous layer was washed with ethyl acetate, the washings combined with the ethyl acetate layer, and the resultant ethyl acetate solution washed with water and saturated aqueous solution of sodium chloride, dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue was subjected to silica gel column chromatography and eluted with a mixture solution of ethyl acetate methanol (4:1) to give 860 mg of oily 1-[3-(3-pyridyl)propyl]-4-[2-(3-pyridyl)thiazolidine-4-ylcarbonyl]piperazine. This product was dissolved in ethanol 8 ml and after addition of fumaric acid 250 mg, the mixture allowed to stand to yield crystals. The crystals were filtered off and dried to give 580 mg of 1-]3-(3-pyridyl)propyl-4-[2-(3-pyridyl)thiazolidine-4-ylcarbonyl]piperazine. fumarate.
Reaction SMILES: C([Sn]1(CCCC)[O:10][CH2:9][C:8]2([CH2:15][CH2:14][CH:13]=[CH:12][CH2:11]2)[CH2:7][O:6]1)CCC.[CH2:20]([C:22]1([CH2:29][CH3:30])[CH2:27][O:26][C:25](=S)[O:24][CH2:23]1)[CH3:21]>>[CH2:20]([C:22]1([CH2:29][CH3:30])[CH2:27][O:26][C:25]2([O:6][CH2:7][C:8]3([CH2:15][CH2:14][CH:13]=[CH:12][CH2:11]3)[CH2:9][O:10]2)[O:24][CH2:23]1)[CH3:21]
Reactant: CCCC[Sn]1(CCCC)OCC2(CC=CCC2)CO1
Reactant: CCC1(CC)COC(=S)OC1
Product: CCC1(CC)COC2(OC1)OCC1(CC=CCC1)CO2
Temperature: 25 °C
Reaction time: 24 h
Yield: 94 %

Procedure:
To the above solution of 3,3-dibutyl-2,4-dioxa-3-stannaspiro[5.5]undec-8-ene 2 was added 5,5-diethyl-1,3-dioxane-2-thione 1 (10.39 g, 59.6 mmol) in several small portions at room temperature over a period of 20 min. The resulting mixture was allowed to stir at room temperature for 24 hours. The reaction was monitored by TLC (silica gel, 25% ether/hexanes). The reaction mixture was then concentrated under reduced pressure and the residue taken up with ethyl ether (white suspension formed upon standing). The ether solution was filtered and concentrated under reduced pressure to give light yellowish oil. The crude material was purified by column chromatography (silica gel, 10-15% ethyl ether/hexanes). The desired 3,3-diethyl-1,5,7,16-tetraoxadispiro[5.2.5.2]hexadec-11-ene (DECH 3) was obtained as colorless oil in 94% yield. 1H-NMR (CDCl3, 300 MHz) δ 5.68-5.58 (m, 2H), 3.74-3.68 (4s, 8H), 2.08-1.94 (m, 4H), 1.63-1.56 (t, 2H, J=6.6 Hz), 1.46-1.37 (q, 4H, J=7.5 Hz), 0.84-0.76 (t, 6H, J=7.5 Hz); 13C-NMR (CDCl3, 75 MHz) δ 126.03, 124.16, 114.68, 70.03, 69.32, 34.27, 30.50, 26.44, 23.14, 21.30, 13.92, 7.01; IR (neat) (cm−1) 3020, 2960, 2880, 1640, 1450, 1360, 1250, 1220, 1200, 1185, 1160, 1105, 1020, 995, 920, 730, 655; Anal. Calcd for C16H26O4: C, 68.06%; H, 9.28%; Found: C, 68.20%; H, 9.59%.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([C:8]2[N:9]=[C:10]([NH:17][C:18]3[CH:26]=[CH:25][C:21]4[N:22]=[CH:23][S:24][C:20]=4[CH:19]=3)[C:11]3[N:12]([CH:14]=[CH:15][N:16]=3)[CH:13]=2)[CH:5]=[CH:6][CH:7]=1.C(N(CC)CC)C.[C:34]([C:38]1[CH:46]=[CH:45][C:41]([C:42](Cl)=[O:43])=[CH:40][CH:39]=1)([CH3:37])([CH3:36])[CH3:35]>C1COCC1>[S:24]1[C:20]2[CH:19]=[C:18]([NH:17][C:10]3[C:11]4[N:12]([CH:14]=[CH:15][N:16]=4)[CH:13]=[C:8]([C:4]4[CH:3]=[C:2]([NH:1][C:42](=[O:43])[C:41]5[CH:45]=[CH:46][C:38]([C:34]([CH3:36])([CH3:35])[CH3:37])=[CH:39][CH:40]=5)[CH:7]=[CH:6][CH:5]=4)[N:9]=3)[CH:26]=[CH:25][C:21]=2[N:22]=[CH:23]1
Reactant: CC(C)(C)c1ccc(C(=O)Cl)cc1
Reactant: Nc1cccc(-c2cn3ccnc3c(Nc3ccc4ncsc4c3)n2)c1
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CC(C)(C)c1ccc(C(=O)Nc2cccc(-c3cn4ccnc4c(Nc4ccc5ncsc5c4)n3)c2)cc1
Temperature: 0 °C

Procedure:
After dissolving 0.36 g (1 mmole) [6-(3-amino-phenyl)-imidazo[1,2-a]pyrazin-8-yl]-benzothiazol-6-yl-amine in 20 mL anhydrous THF, 3 equivalents of triethylamine are added and the reaction solution is cooled to 0° C. A solution of 0.2 g of 4-tert-butyl-benzoyl chloride (1 mmole) in 5 mL THF is added dropwise to the 0° C. reaction solution under N2. The ice bath is removed and the reaction is allowed to warm slowly to rt for 1 hr. Diethyl ether is then added slowly to the reaction solution and the resulting solid filtered and washed with diethyl ether to provide pure N-{3-[8-(benzothiazol-6-ylamino)-imidazo[1,2-a]pyrazin-6-yl]-phenyl}-4-tert-butyl-benzamide.
Reaction SMILES: [F:1][C:2]1[CH:10]=[C:9]([NH:11][CH3:12])[C:8]([N+:13]([O-:15])=[O:14])=[CH:7][C:3]=1[C:4]([OH:6])=O.ClC(N(C)C)=C(C)C.[Br:24][C:25]1[CH:31]=[CH:30][C:28]([NH2:29])=[CH:27][CH:26]=1.CCN(C(C)C)C(C)C>C(Cl)Cl>[Br:24][C:25]1[CH:31]=[CH:30][C:28]([NH:29][C:4](=[O:6])[C:3]2[CH:7]=[C:8]([N+:13]([O-:15])=[O:14])[C:9]([NH:11][CH3:12])=[CH:10][C:2]=2[F:1])=[CH:27][CH:26]=1
Reactant: CNc1cc(F)c(C(=O)O)cc1[N+](=O)[O-]
Reactant: Nc1ccc(Br)cc1
Agent: CC(C)=C(Cl)N(C)C
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CNc1cc(F)c(C(=O)Nc2ccc(Br)cc2)cc1[N+](=O)[O-]
Reaction time: 0.5 h

Procedure:
A mixture of 2-fluoro-4-methylamino-5-nitro-benzoic acid (0.500 g, 2.34 mmol), (1-chloro-2-methyl-propenyl)-dimethylamine (0.371 mL, 2.80 mmol) and DCM (50 mL) is stirred for 30 min, then 4-bromoaniline (0.402 mg, 2.34 mmol) and DIPEA (0.549 mL, 3.15 mmol) are added and it is stirred for 2 h. The mixture is concentrated, water is added and the precipitate is filtered, washed with water and dried to give the subtitle compound.
Reaction SMILES: [NH2:1][C:2]1[CH:11]=[CH:10][CH:9]=[CH:8][C:3]=1[C:4]([NH:6][OH:7])=[O:5].[CH3:12][O:13][C:14](OC)(OC)OC>CO>[CH3:12][O:13][C:14]1[N:6]([OH:7])[C:4](=[O:5])[C:3]2[C:2](=[CH:11][CH:10]=[CH:9][CH:8]=2)[N:1]=1
Reactant: COC(OC)(OC)OC
Reactant: Nc1ccccc1C(=O)NO
Solvent: CO
Product: COc1nc2ccccc2c(=O)n1O
Temperature: 5 °C
Yield: 59 %

Procedure:
A mixture of 22.8 g (0.15 mol) of o-aminobenzohydroxamic acid, 50 ml of methanol and 27.2 g (0.2 mol) of orthocarbonic acid tetramethyl ester was boiled under reflux for 2 hours and was then cooled to 5° C. The product which had crystallized out was filtered off with suction. 17 g (60% of theory) of 2-methoxy-3-hydroxy-3,4-dihyro-4-oxo-quinazoline were obtained in the form of colorless crystals having a melting point of 220° C.
Reaction SMILES: [C:1]([N:4]1[C:8]([CH3:9])=[C:7]([CH2:10][C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[C:6](=[O:17])[NH:5]1)(=[O:3])[CH3:2].C(=O)([O-])[O-].[K+].[K+].Br[C:25]1(Br)[O:51][C@H:50]([CH2:52][O:53][C:54](=[O:59])[C:55]([CH3:58])([CH3:57])[CH3:56])[C@@H:42]([O:43][C:44](=[O:49])[C:45]([CH3:48])([CH3:47])[CH3:46])[C@H:34]([O:35][C:36](=[O:41])[C:37]([CH3:40])([CH3:39])[CH3:38])[C@H:26]1[O:27][C:28](=[O:33])[C:29]([CH3:32])([CH3:31])[CH3:30]>C(#N)C.O1CCCC1>[C:1]([N:4]1[C:8]([CH3:9])=[C:7]([CH2:10][C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[C:6]([O:17][C@@H:25]2[O:51][C@H:50]([CH2:52][O:53][C:54](=[O:59])[C:55]([CH3:58])([CH3:57])[CH3:56])[C@@H:42]([O:43][C:44](=[O:49])[C:45]([CH3:46])([CH3:47])[CH3:48])[C@H:34]([O:35][C:36](=[O:41])[C:37]([CH3:38])([CH3:39])[CH3:40])[C@H:26]2[O:27][C:28](=[O:33])[C:29]([CH3:32])([CH3:30])[CH3:31])=[N:5]1)(=[O:3])[CH3:2]
Reactant: CC(C)(C)C(=O)OC[C@H]1OC(Br)(Br)[C@H](OC(=O)C(C)(C)C)[C@@H](OC(=O)C(C)(C)C)[C@@H]1OC(=O)C(C)(C)C
Reactant: CC(=O)n1[nH]c(=O)c(Cc2ccccc2)c1C
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1CCOC1
Solvent: CC#N
Product: CC(=O)n1nc(O[C@@H]2O[C@H](COC(=O)C(C)(C)C)[C@@H](OC(=O)C(C)(C)C)[C@H](OC(=O)C(C)(C)C)[C@H]2OC(=O)C(C)(C)C)c(Cc2ccccc2)c1C
Temperature: 25 °C
Yield: 79.2 %

Procedure:
To a suspension of 1-acetyl-4-benzyl-1,2-dihydro-5-methyl-3H-pyrazol-3-one (0.75 g) in acetonitrile (5 mL) and tetrahydrofuran (3 mL) was added potassium carbonate (0.675 g) under stirring at room temperature. After the mixture was stirred at 50° C. for 1 hour, 1-bromo-2,3,4,6-tetra-O-pivaloyl-α-D-glucopyranosyl bromide (2.27 g) was added to the mixture. The mixture was stirred at 50° C. for 6 hours. After the reaction completed, the insoluble materials were removed by filtration, and the filtrate was concentrated under reduced pressure. The residue was purified by column chromatography on silica gel (eluent: ethyl acetate/n-hexane=1/10 to 1/5) to give 1-acetyl-4-benzyl-5-methyl-3-(2,3,4,6-tetra-O-pivaloyl-β-D-glucopyranosyloxy)-1H-pyrazole (1.88 g).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([C:10]2[CH:15]=[CH:14][C:13]([Cl:16])=[CH:12][CH:11]=2)=O)=[CH:4][CH:3]=1.O.[NH2:18][NH2:19]>C(O)C>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8](=[N:18][NH2:19])[C:10]2[CH:15]=[CH:14][C:13]([Cl:16])=[CH:12][CH:11]=2)=[CH:4][CH:3]=1
Reactant: O=C(c1ccc(Cl)cc1)c1ccc(Cl)cc1
Reactant: NN
Solvent: O
Solvent: CCO
Product: NN=C(c1ccc(Cl)cc1)c1ccc(Cl)cc1
Temperature: 21 °C

Procedure:
A solution of bis-(4-chloro-phenyl)-methanone (5.0 g, 19.9 mmol) and hydrazine monohydrate (5 mL, 103 mmol) in ethanol (25 mL) was heated to reflux 18 h, cooled to 21° C., and filtered to afforded the [bis-(4-chloro-phenyl)-methylene]-hydrazine compound as a yellow solid.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][C:10]=1[C:11](=[O:26])[NH:12][C:13]1[CH:18]=[CH:17][C:16]([Cl:19])=[C:15]([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][N:21]=2)[CH:14]=1)[C:5](O)=[O:6].[C:27]1([NH:33][CH2:34][CH2:35][NH2:36])[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1>>[Cl:1][C:2]1[CH:3]=[C:4]([C:5]([NH:36][CH2:35][CH2:34][NH:33][C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)=[O:6])[CH:8]=[CH:9][C:10]=1[C:11]([NH:12][C:13]1[CH:18]=[CH:17][C:16]([Cl:19])=[C:15]([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][N:21]=2)[CH:14]=1)=[O:26]
Reactant: NCCNc1ccccc1
Reactant: O=C(O)c1ccc(C(=O)Nc2ccc(Cl)c(-c3ccccn3)c2)c(Cl)c1
Product: O=C(NCCNc1ccccc1)c1ccc(C(=O)Nc2ccc(Cl)c(-c3ccccn3)c2)c(Cl)c1

Procedure:
62 mg of 3-chloro-4-(4-chloro-3-(pyridin-2-yl)phenylcarbamoyl)benzoic acid was coupled to N1-phenylethane-1,2-diamine via Procedure G. The crude product was purified on reverse phase HPLC to yield 2-chloro-N1-(4-chloro-3-(pyridin-2-yl)phenyl)-N4-(2-(phenylamino)ethyl)terephthalamide. MS (Q1) 505.1 (M)+.
Reaction SMILES: C(N(CC)CC)C.[OH:8][C@:9]1([C:21]2[S:22][C:23]([C:26]3[CH:31]=[C:30]([NH:32][C:33]4[N:38]=[C:37]([C:39]([F:42])([F:41])[F:40])[CH:36]=[CH:35][N:34]=4)[CH:29]=[C:28]([CH2:43][OH:44])[CH:27]=3)=[CH:24][N:25]=2)[CH2:14][CH2:13][C@H:12]([C:15]([O:17][CH3:18])=[O:16])[C:11]([CH3:20])([CH3:19])[CH2:10]1.[CH3:45][S:46](Cl)(=[O:48])=[O:47]>ClCCl>[OH:8][C@:9]1([C:21]2[S:22][C:23]([C:26]3[CH:31]=[C:30]([NH:32][C:33]4[N:38]=[C:37]([C:39]([F:41])([F:42])[F:40])[CH:36]=[CH:35][N:34]=4)[CH:29]=[C:28]([CH2:43][O:44][S:46]([CH3:45])(=[O:48])=[O:47])[CH:27]=3)=[CH:24][N:25]=2)[CH2:14][CH2:13][C@H:12]([C:15]([O:17][CH3:18])=[O:16])[C:11]([CH3:20])([CH3:19])[CH2:10]1
Reactant: COC(=O)[C@H]1CC[C@](O)(c2ncc(-c3cc(CO)cc(Nc4nccc(C(F)(F)F)n4)c3)s2)CC1(C)C
Reactant: CS(=O)(=O)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COC(=O)[C@H]1CC[C@](O)(c2ncc(-c3cc(COS(C)(=O)=O)cc(Nc4nccc(C(F)(F)F)n4)c3)s2)CC1(C)C
Temperature: 23 °C
Reaction time: 120 h
Yield: 88.5 %

Procedure:
Triethylamine (0.200 ml, 1.434 mmol, 1.5 equiv) was added to a stirring solution of methyl (1S,4R)-4-hydroxy-4-{5-[3-(hydroxymethyl)-5-{[4-(trifluoromethyl)pyrimidin-2-yl]amino}phenyl]-1,3-thiazol-2-yl}-2,2-dimethylcyclohexanecarboxylate (513 mg, 0.956 mmol) in anhydrous dichloromethane (15 mL). The orange solution was cooled to 0° C. (water/ice) then charged with methanesulfonyl chloride (0.089 ml, 1.147 mmol, 1.2 equiv). The reaction mixture was allowed to slowly warm to 23° C. and stir for 5 d. The mixture was partitioned between methylene chloride (2×90 ml) and water (95 ml). The combined organic layers were dried over Na2SO4, filtered and concentrated to afford methyl (1S,4R)-4-hydroxy-2,2-dimethyl-4-[5-(3-{[(methylsulfonyl)oxy]methyl}-5-{[4-(trifluoromethyl)pyrimidin-2-yl]amino}phenyl)-1,3-thiazol-2-yl]cyclohexanecarboxylate (520 mg, 71%), as an orange-yellow oil. 1H NMR (500 MHz, CDCl3) δ 8.79 (bs, 1H), 8.66 (d, J=4.9 Hz, 1H), 7.95 (s, 1H), 7.85 (s, 1H), 7.61 (s, 1H), 7.23 (s, 1H), 7.06 (d, J=4.9 Hz, 1H), 4.59 (s, 1H), 3.90 (s, 2H), 3.69 (s, 3H), 3.01 (s, 2H), 2.38-2.25 (m, 2H), 2.01 (m, 3H), 1.95-1.77 (m, 4H), 1.35-1.20 (m, 6H).
Reaction SMILES: [CH3:1][C:2]12[C:8]([CH3:10])([CH3:9])[C:5]([C:11]([NH:13][C:14]3[CH:19]=[CH:18][C:17]([CH2:20][C:21]#[N:22])=[CH:16][CH:15]=3)=[O:12])([CH2:6][CH2:7]1)[O:4][C:3]2=[O:23].[N-:24]=[N+:25]=[N-:26].[Na+].[Cl-].[NH4+].CN(C)C=O>[Cl-].[Na+].O.O>[CH3:1][C:2]12[C:8]([CH3:9])([CH3:10])[C:5]([C:11]([NH:13][C:14]3[CH:19]=[CH:18][C:17]([CH2:20][C:21]4[NH:26][N:25]=[N:24][N:22]=4)=[CH:16][CH:15]=3)=[O:12])([CH2:6][CH2:7]1)[O:4][C:3]2=[O:23]
Reactant: [N-]=[N+]=[N-]
Reactant: CC12CCC(C(=O)Nc3ccc(CC#N)cc3)(OC1=O)C2(C)C
Agent: [Cl-]
Agent: [NH4+]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CC12CCC(C(=O)Nc3ccc(Cc4nnn[nH]4)cc3)(OC1=O)C2(C)C
Temperature: 135 °C
Yield: 60 %

Procedure:
4,7,7-Trimethyl-3-oxo-N-[4-(cyanomethyl)phenyl]-2-oxabicyclo[2.2.1]-heptane-1-carboxamide (6 g, prepared in the preceding paragraph), sodium azide (6.24 g), ammonium chloride (5.1 g) and dimethylformamide (100 mL) were heated in a 135° C. oil bath for 20 hours under a nitrogen atmosphere. Water was added to the hot mixture until homogeneity was achieved. The mixture was then cooled to room temperature, poured onto saturated brine solution in a separatory funnel, and extracted with ethyl acetate. The extracts were washed with saturated brine solution, dried over MgSO4 and concentrated in a rotary evaporator. The crude product was dissolved in hot acetone, then cooled in a 0° C. freezer to yield 4.1 g. (60% yield) of the title compound as a dark yellow solid; m.p. 224°-225° C. (dec.).
Reaction SMILES: [S:1]1[CH2:6][CH2:5][N:4]([C:7]([C:9]2[N:10]=[C:11]([N:14]3[CH2:17][CH:16]([OH:18])[CH2:15]3)[S:12][CH:13]=2)=[O:8])[CH2:3][CH2:2]1.[CH3:19][S:20](Cl)(=[O:22])=[O:21].C(N(CC)CC)C>C(Cl)Cl>[S:1]1[CH2:6][CH2:5][N:4]([C:7]([C:9]2[N:10]=[C:11]([N:14]3[CH2:17][CH:16]([O:18][S:20]([CH3:19])(=[O:22])=[O:21])[CH2:15]3)[S:12][CH:13]=2)=[O:8])[CH2:3][CH2:2]1
Reactant: O=C(c1csc(N2CC(O)C2)n1)N1CCSCC1
Reactant: CS(=O)(=O)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CS(=O)(=O)OC1CN(c2nc(C(=O)N3CCSCC3)cs2)C1
Temperature: 25 °C
Reaction time: 0.67 h
Yield: 78 %

Procedure:
To a solution of 1-(4-thiomorpholinocarbonyl-1,3-thiazol-2-yl)-3-hydroxyazetidine (599 g, 2.50 mmol) (obtained as described in Reference Example 25(2)) in methylene chloride (30 ml) were added methanesulfonyl chloride (0.49 ml, 6.30 mmol) and triethylamine (0.88 ml, 6.30 mmol) in an ice bath. After stirring the mixture in the ice bath for 10 minutes, the mixture was stirred at room temperature for 40 minutes. After checking the completion of the reaction, the reaction mixture was partitioned between ethyl acetate and saturated aqueous sodium hydrogencarbonate solution. The organic layer was washed with saturated aqueous sodium chloride solution, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified by chromatography on a silica gel column using 5% methanol in ethyl acetate as the eluant to afford 1-(4-thiomorpholinocarbonyl-1,3-thiazol-2-yl)-3-methanesulfonyloxyazetidine (709 mg, yield 93%) as a pale yellow solid.
Reaction SMILES: [O:1]1[CH2:6][CH2:5][CH2:4][CH2:3][CH:2]1[O:7][C@H:8]1[CH2:12][C@@H:11]([O:13][C:14]2[C:23]3[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=3)[N:17]=[C:16]([N:24]3[CH2:29][CH2:28][NH:27][CH2:26][CH2:25]3)[N:15]=2)[CH:10]=[CH:9]1.C(N(CC)CC)C.[C:37](Cl)(=[O:46])[O:38][CH2:39][C:40]1[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=1>C(Cl)Cl>[CH2:39]([O:38][C:37]([N:27]1[CH2:26][CH2:25][N:24]([C:16]2[N:15]=[C:14]([O:13][C@@H:11]3[CH2:12][C@H:8]([O:7][CH:2]4[CH2:3][CH2:4][CH2:5][CH2:6][O:1]4)[CH:9]=[CH:10]3)[C:23]3[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=3)[N:17]=2)[CH2:29][CH2:28]1)=[O:46])[C:40]1[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=1
Reactant: O=C(Cl)OCc1ccccc1
Reactant: C1=C[C@H](Oc2nc(N3CCNCC3)nc3ccccc23)C[C@@H]1OC1CCCCO1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: O=C(OCc1ccccc1)N1CCN(c2nc(O[C@H]3C=C[C@@H](OC4CCCCO4)C3)c3ccccc3n2)CC1

Procedure:
To a solution of 4-[(1R,4S)-[4-[(RS)-(tetrahydropyran-2-yl)oxy]cyclopent-2-en-1-yl]oxy]-2-(1-piperazinyl)quinazoline (11.07 g) in dry methylene chloride (110 ml) is added triethylamine (7.75 ml) with stirring under ice-cooling, and thereto is further added dropwise a solution of benzyl chlorocarbonate (4.40 ml) in dry methylene chloride (20 ml). The mixture is stirred under ice-cooling for one hour. The reaction mixture is washed with water, and dried over anhydrous magnesium sulfate. The solution is evaporated to dryness under reduced pressure, and the residue is purified by medium pressure liquid column chromatography (eluent, chloroform) to give 2-[4-(benzyloxycarbonyl)piperazin-1-yl]-4-[(1R,4S)-[4-[(RS)-(tetrahydropyran-2-yl)oxy]cyclopent-2-en-1-yl]oxy]quinazoline (12.57 g) as oil.
Reaction SMILES: [CH2:1]([O:8][C:9]1[N:10]=[N:11][C:12]([CH:23]=[CH2:24])=[CH:13][C:14]=1[O:15][CH2:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.CC1C=CC=CC=1P(C1C=CC=CC=1C)C1C=CC=CC=1C.[F:47][C:48]1[CH:53]=[C:52](I)[CH:51]=[CH:50][C:49]=1[C:55]([F:58])([F:57])[F:56].C(N(CC)CC)C>C([O-])(=O)C.[Pd+2].C([O-])(=O)C.C(#N)C>[CH2:1]([O:8][C:9]1[N:10]=[N:11][C:12](/[CH:23]=[CH:24]/[C:52]2[CH:51]=[CH:50][C:49]([C:55]([F:57])([F:58])[F:56])=[C:48]([F:47])[CH:53]=2)=[CH:13][C:14]=1[O:15][CH2:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: Fc1cc(I)ccc1C(F)(F)F
Reactant: C=Cc1cc(OCc2ccccc2)c(OCc2ccccc2)nn1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: Cc1ccccc1P(c1ccccc1C)c1ccccc1C
Solvent: CC#N
Solvent: CCN(CC)CC
Product: Fc1cc(/C=C/c2cc(OCc3ccccc3)c(OCc3ccccc3)nn2)ccc1C(F)(F)F
Temperature: 80 °C
Yield: 67 %

Procedure:
A vessel containing 3,4-bis(benzyloxy)-6-ethenylpyridazine (Intermediate 78, 1.09 g, 3.42 mmol), tris-(2-methylphenyl)phosphane (0.208 g, 0.685 mmol), 2-fluoro-4-iodo-1-(trifluoromethyl)benzene (1.191 g, 4.11 mmol) and palladium(II) acetate (0.038 g, 0.171 mmol) was evacuated and acetonitrile (10 ml) and triethylamine (9.07 ml, 65.1 mmol) were added in vacuo and then the mixture was flushed with nitrogen. The reaction was then heated in the microwave at 80° C. for 4 hours and, upon cooling, was diluted with dichloromethane and washed with saturated aqueous ammonium chloride solution. The organics were dried (MgSO4), filtered and solvent removed in vacuo to give a brown oil which was purified by column chromatography (silica, eluting with 30-100% dichloromethane in petrol) to yield 3,4-bis(benzyloxy)-6-[(E)-2-[3-fluoro-4-(trifluoromethyl)phenyl]ethenyl]pyridazine (1.1 g, 2.29 mmol, 67% yield).
Reaction SMILES: [CH2:1]([C:3]1[NH:4][C:5]2[C:10]([C:11](=[O:14])[C:12]=1[CH3:13])=[CH:9][C:8]([O:15][C:16]1[CH:21]=[CH:20][C:19]([O:22][C:23]([F:26])([F:25])[F:24])=[CH:18][CH:17]=1)=[C:7]([CH3:27])[CH:6]=2)[CH3:2].[H-].[Na+].Cl[C:31]([O:33][CH3:34])=[O:32]>CC(N(C)C)=O>[C:31](=[O:32])([O:33][CH3:34])[O:14][C:11]1[C:10]2[C:5](=[CH:6][C:7]([CH3:27])=[C:8]([O:15][C:16]3[CH:21]=[CH:20][C:19]([O:22][C:23]([F:24])([F:25])[F:26])=[CH:18][CH:17]=3)[CH:9]=2)[N:4]=[C:3]([CH2:1][CH3:2])[C:12]=1[CH3:13]
Reactant: COC(=O)Cl
Reactant: CCc1[nH]c2cc(C)c(Oc3ccc(OC(F)(F)F)cc3)cc2c(=O)c1C
Agent: [H-]
Agent: [Na+]
Solvent: CC(=O)N(C)C
Product: CCc1nc2cc(C)c(Oc3ccc(OC(F)(F)F)cc3)cc2c(OC(=O)OC)c1C
Temperature: 15 °C
Reaction time: 1 h
Yield: 91.4 %

Procedure:
Dimethyl acetamide (980 ml) and 98 g of 2-ethyl-3,7-dimethyl-6-(4-(trifluoromethoxy)phenoxy)quinolin-4(1H)-one were charged into a glass flask equipped with a stirring device, a thermometer, a reflux condenser, and a calcium chloride tube and having a volume of 2000 ml under a nitrogen atmosphere, and the mixture was cooled to 15° C. 55% sodium hydride (18.2 g) was added thereto, and the mixture was stirred at 15 to 20° C. for one hr. Methyl chloroformate (32.1 g) was added dropwise, and a reaction was allowed to proceed at room temperature for one hr. The reaction mixture was poured into 5 L of ice water contained in a 10-L plastic container, and the mixture was stirred at room temperature for 2 hr. The precipitated solid was collected by a suction filter and was washed with n-hexane and water. The solid was dried in vacuo to give 2-ethyl-3,7-dimethyl-6-(4-(trifluoromethoxy)phenoxy)quinolin-4-yl methyl carbonate (103.3 g, yield 91.4%).
Reaction SMILES: [CH2:1]1[CH2:12][C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:4](=[O:5])[CH2:3][CH2:2]1.[Br:13]N1C(=O)CCC1=O.N(C(C)(C)C#N)=NC(C)(C)C#N.C(Cl)(Cl)Cl>C(Cl)(Cl)(Cl)Cl>[Br:13][CH:12]1[C:11]2[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=2[C:4](=[O:5])[CH2:3][CH2:2][CH2:1]1
Reactant: O=C1CCC(=O)N1Br
Reactant: O=C1CCCCc2ccccc21
Agent: CC(C)(C#N)N=NC(C)(C)C#N
Solvent: ClC(Cl)Cl
Solvent: ClC(Cl)(Cl)Cl
Product: O=C1CCCC(Br)c2ccccc21
Yield: 53.3 %

Procedure:
1-Benzosuberone (960 mg, 6.0 mmol), N-bromosuccinic acid imide (1.1 g, 6.3 mmol) and azobisisobutyronitrile (99 mg, 0.60 mmol) were stirred overnight at 80° C. in carbon tetrachloride (8 ml). The reaction solution was mixed with chloroform (60 ml), washed with saturated sodium bicarbonate aqueous solution and saturated brine and dried with anhydrous sodium sulfate, the solvent was removed by evaporation under a reduced pressure, and the thus obtained material was separated and purified by a silica gel column chromatography to obtain 770 mg (3.2 mmol, 54%) of the title compound.
Reaction SMILES: [CH3:1][CH2:2][C:3](=O)[CH2:4][C:5](=O)[CH2:6][CH3:7].[NH2:10][C:11]1[N:15]=[C:14]([S:16][CH3:17])[NH:13][N:12]=1>C(O)(=O)C>[CH2:2]([C:3]1[CH:4]=[C:5]([CH2:6][CH3:7])[N:12]2[N:13]=[C:14]([S:16][CH3:17])[N:15]=[C:11]2[N:10]=1)[CH3:1]
Reactant: CCC(=O)CC(=O)CC
Reactant: CSc1nc(N)n[nH]1
Solvent: CC(=O)O
Product: CCc1cc(CC)n2nc(SC)nc2n1
Temperature: 135 °C
Yield: 87.9 %

Procedure:
A mixture of 3,5-heptanedione (9.85 g, 76.8 mmol), 3-amino-5-methylthio-1H-1,2,4-triazole (10.0 g, 76.8 mmol), and glacial acetic acid (60 mL) was added to a 200 mL RBF with a magnetic stirring bar. The flask was fitted with a condenser, and warmed in an oil bath to a gentle reflux at 135° C. The mixture was heated for 24 hours. Progress of the reaction was monitored by analytical HPLC with UV detection at 215 and 254 nm. The starting material 3-amino-5-methylthio-1H-1,2,4-triazole eluted rapidly with retention time of 0.7 min, and the product eluted with retention time of 4.7 min. The mixture was cooled to room temperature, then slowly poured into stirring ice/water (800 mL) to precipitate product and stirred ˜20 minutes. Solids were isolated by filtration, rinsed with water (200 mL), and then dried under reduced pressure to afford the title compound as a powder (15.0 g, 88% yield).