Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:8]3=[C:9]([S:11][CH2:12][CH2:13][N:7]3[C@H:6]3[CH2:14][CH2:15][N:16]([C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])[CH2:17][C@@H:5]23)[CH:10]=1.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.[Cl:44][C:45]1[CH:50]=[CH:49][CH:48]=[C:47]([Cl:51])[C:46]=1[Sn](C)(C)C>CN(C=O)C.C(OC(=O)C)C.O.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[Cl:44][C:45]1[CH:46]=[C:47]([Cl:51])[CH:48]=[CH:49][C:50]=1[C:2]1[CH:3]=[C:4]2[C:8]3=[C:9]([S:11][CH2:12][CH2:13][N:7]3[C@H:6]3[CH2:14][CH2:15][N:16]([C:18]([O:20][C:21]([CH3:24])([CH3:22])[CH3:23])=[O:19])[CH2:17][C@@H:5]23)[CH:10]=1
Reactant: CC(C)(C)OC(=O)N1CC[C@H]2[C@@H](C1)c1cc(Br)cc3c1N2CCS3
Reactant: C[Sn](C)(C)c1c(Cl)cccc1Cl
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CN(C)C=O
Solvent: O
Solvent: CCOC(C)=O
Product: CC(C)(C)OC(=O)N1CC[C@H]2[C@@H](C1)c1cc(-c3ccc(Cl)cc3Cl)cc3c1N2CCS3
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 50.5 %

Procedure:
General procedure for stannane coupling with aryl bromide: Degassed DMF (25 mL) was added to a mixture of tert-butyl(6bR,10aS)-5-bromo-1,2,6b,9,10,10a-hexahydropyrido[4,3-b][1,4]thiazino[2,3,4-hi]indole-8(7H)-carboxylate (316 mg, 0.768 mmol), PPh3 (40.4 mg, 0.154 mmol), CuBr (22 mg, 0.20 mmol) and Pd(PPh3)2Cl2 (55 mg, 0.0768 mmol) via cannula, at room temperature under N2 blanket. The reaction mixture was stirred at room temperature for 5 min and then 2,6-dichlorophenyl trimethylstannane (357 mg, 1.15 mmol) was added as a solution in degassed DMF (2.5 mL) and the reaction mixture was heated at 140° C. After 10 min, the solution began to turn black, and a second portion (178 mg, 0.575 mmol) was added after 1 hour, followed by a final portion (178 mg, 0.575 mmol) an hour later. Heating resumed for another 30 min, then the reaction mixture was cooled to room temperature and diluted with ethylacetate/water (20 mL/20 mL). Organic layer was separated, dried over sodium sulfate an concentrated to dryness under reduced pressure to a dark oil. This residue was purified by flash chromatography eluting with 10% EtOAc/Hexanes to give tert-butyl(6bR,10aS)-5-(2,4-dichlorophenyl)-1,2,6b,9,10,10a-hexahydropyrido[4,3-b][1,4]thiazino[2,3,4-hi]indole-8(7H)-carboxylate (185 mg, 50%). 1H NMR (CDCl3, 300 MHz) δ1.46 (s, 9H), 1.82-2.00 (m, 2H), 2.93-3.33 (m, 5H), 3.40-3.51 (m, 4H), 3.52-3.75 (m, 1H), 6.71 (s, 1H), 6.75 (s, 1H), 7.12 (t, 1H, J=7.9 Hz), 7.33 (d, 2H, J=7.9 Hz) ppm.
Reaction SMILES: [I-:1].[K+].CS(O[CH:8]1[CH2:11][N:10]([C:12]([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13])[CH2:9]1)(=O)=O>CS(C)=O.C(OCC)C.O>[I:1][CH:8]1[CH2:11][N:10]([C:12]([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13])[CH2:9]1
Reactant: [I-]
Reactant: CC(C)(C)OC(=O)N1CC(OS(C)(=O)=O)C1
Agent: [K+]
Solvent: O
Solvent: CCOCC
Solvent: CS(C)=O
Product: CC(C)(C)OC(=O)N1CC(I)C1
Temperature: 140 °C
Reaction time: 2 h
Yield: 68 %

Procedure:
Potassium iodide (51.0 g, 307 mind) was added to a solution of tert-butyl 3-((methylsulfonyl)oxy)azetidine-1-carboxylate described in Production Example 26-2 (7.72 g, 30.7 mmol) in dimethylsulfoxide (80 mL) under nitrogen atmosphere at room temperature, and the mixture was stirred at 140° C. for 2 hours. The reaction liquid was diluted with diethyl ether and water. The aqueous layer was extracted with diethyl ether. The combined organic layer was washed serially with an aqueous sodium pyrosulfite solution and a saturated saline solution and then dried over anhydrous sodium sulfate. The drying agent was separated by filtration and then the resultant was concentrated under vacuum. The residue was purified with silica gel column chromatography (n-heptane:ethyl acetate 9:1-1:1) to obtain the title compound (5.91 g, 68%).
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[NH:7][C:8]([CH3:17])=[C:9]([C:12]([O:14][CH2:15][CH3:16])=[O:13])[C:10]=1[CH3:11])=[O:5])[CH3:2].C(OC(C1[N:24](N)C(C(OCC)=O)=CC=1)=O)C>>[CH2:1]([O:3][C:4]([C:6]1[N:7]([NH2:24])[C:8]([CH3:17])=[C:9]([C:12]([O:14][CH2:15][CH3:16])=[O:13])[C:10]=1[CH3:11])=[O:5])[CH3:2]
Reactant: CCOC(=O)c1[nH]c(C)c(C(=O)OCC)c1C
Reactant: CCOC(=O)c1ccc(C(=O)OCC)n1N
Product: CCOC(=O)c1c(C)c(C(=O)OCC)n(N)c1C

Procedure:
Compound 409A was prepared from 3,5-dimethyl-1H-pyrrole-2,4-dicarboxylic acid diethyl ester by a route analogous to that used for the preparation of compound 406C.
Reaction SMILES: [OH:1][CH2:2][CH:3]1[N:8]([CH:9]2[CH2:12][O:11][CH2:10]2)[CH2:7][CH2:6][N:5]([C:13]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14])[CH2:4]1.N1C=CN=C1.[Si:25](Cl)([C:28]([CH3:31])([CH3:30])[CH3:29])([CH3:27])[CH3:26]>CN(C=O)C.CCOC(C)=O>[Si:25]([O:1][CH2:2][CH:3]1[N:8]([CH:9]2[CH2:12][O:11][CH2:10]2)[CH2:7][CH2:6][N:5]([C:13]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14])[CH2:4]1)([C:28]([CH3:31])([CH3:30])[CH3:29])([CH3:27])[CH3:26]
Reactant: CC(C)(C)OC(=O)N1CCN(C2COC2)C(CO)C1
Reactant: CC(C)(C)[Si](C)(C)Cl
Agent: c1c[nH]cn1
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CC(C)(C)OC(=O)N1CCN(C2COC2)C(CO[Si](C)(C)C(C)(C)C)C1
Temperature: 25 °C
Reaction time: 24 h
Yield: 46.9 %

Procedure:
(+/−) Tert-butyl 3-(hydroxymethyl)-4-(oxetan-3-yl)piperazine-1-carboxylate (1 g, 3.67 mmol) was taken up in DMF (2 mL) and imidazole (0.500 g, 7.34 mmol) and TBS-Cl (0.609 g, 4.04 mmol) were added. The reaction was stirred at rt over the weekend. An additional 0.2 eq. of TBS-Cl and 0.5 eq. of imidazole was added, and the reaction mixture was heated at 40° C. overnight, then at 45° C. for 24 h. The reaction mixture was diluted with EtOAc and washed with water 4×. The organic layer was dried over Na2SO4, filtered, and concentrated. The material was purified by flash column chromatography (0-60% EtOAc/Hex). (+/−) Tert-butyl 3-(((tert-butyldimethylsilyl)oxy)methyl)-4-(oxetan-3-yl)piperazine-1-carboxylate (665 mg) was obtained as a colorless oil.
Reaction SMILES: [CH2:1]([C:3]1[N:8]([C:9]2[CH:14]=[CH:13][C:12]([O:15][CH:16]3[CH2:21][CH2:20][CH2:19][CH:18]([OH:22])[CH2:17]3)=[CH:11][CH:10]=2)[C:7](=[O:23])[C:6]([CH2:24][C:25]2[CH:30]=[CH:29][C:28]([C:31]3[CH:36]=[CH:35][CH:34]=[CH:33][C:32]=3[C:37]3[NH:41][C:40](=[O:42])[O:39][N:38]=3)=[CH:27][CH:26]=2)=[C:5]([CH2:43][CH2:44][CH3:45])[N:4]=1)[CH3:2].CC(OI1(OC(C)=O)(OC(C)=O)OC(=O)C2C1=CC=CC=2)=O>ClCCl.C(OCC)(=O)C>[CH2:1]([C:3]1[N:8]([C:9]2[CH:10]=[CH:11][C:12]([O:15][CH:16]3[CH2:21][CH2:20][CH2:19][C:18](=[O:22])[CH2:17]3)=[CH:13][CH:14]=2)[C:7](=[O:23])[C:6]([CH2:24][C:25]2[CH:30]=[CH:29][C:28]([C:31]3[CH:36]=[CH:35][CH:34]=[CH:33][C:32]=3[C:37]3[NH:41][C:40](=[O:42])[O:39][N:38]=3)=[CH:27][CH:26]=2)=[C:5]([CH2:43][CH2:44][CH3:45])[N:4]=1)[CH3:2]
Reactant: CCCc1nc(CC)n(-c2ccc(OC3CCCC(O)C3)cc2)c(=O)c1Cc1ccc(-c2ccccc2-c2noc(=O)[nH]2)cc1
Agent: CC(=O)OI1(OC(C)=O)(OC(C)=O)OC(=O)c2ccccc21
Solvent: CCOC(C)=O
Solvent: ClCCl
Product: CCCc1nc(CC)n(-c2ccc(OC3CCCC(=O)C3)cc2)c(=O)c1Cc1ccc(-c2ccccc2-c2noc(=O)[nH]2)cc1
Reaction time: 1 h
Yield: 76.3 %

Procedure:
2-Ethyl-3-{4-[(3-hydroxycyclohexyl)oxy]phenyl}-5-{[2′-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)biphenyl-4-yl]methyl}-6-propylpyrimidin-4(3H)-one (0.5 g) and 1,1,1-tris(acetyloxy)-1,1-dihydro-1,2-benziodoxol-3(1H)-one (0.52 g) were dissolved in dichloromethane (5 mL) and the mixture was stirred for 1 hr. The reaction mixture was diluted with ethyl acetate, washed with saturated aqueous sodium hydrogen carbonate solution and then with saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure and the residue was purified by silica gel column chromatography to give the title compound (0.38 g, 76%) as a colorless amorphous solid.
Reaction SMILES: [CH2:1]([C:8]1[C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[C:11]([N:18]2[CH2:23][CH2:22][N:21]([C:24]3[N:29]=[CH:28][C:27]([CH:30]=O)=[CH:26][CH:25]=3)[CH2:20][CH2:19]2)=[N:10][N:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+].[NH:46]1[CH2:51][CH2:50][O:49][CH2:48][CH2:47]1.C([O-])(O)=O.[Na+]>C(Cl)Cl.C(O)(=O)C>[CH2:1]([C:8]1[C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[C:11]([N:18]2[CH2:23][CH2:22][N:21]([C:24]3[CH:25]=[CH:26][C:27]([CH2:30][N:46]4[CH2:51][CH2:50][O:49][CH2:48][CH2:47]4)=[CH:28][N:29]=3)[CH2:20][CH2:19]2)=[N:10][N:9]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: C1COCCN1
Reactant: O=Cc1ccc(N2CCN(c3nnc(Cc4ccccc4)c4ccccc34)CC2)nc1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: CC(=O)O
Product: c1ccc(Cc2nnc(N3CCN(c4ccc(CN5CCOCC5)cn4)CC3)c3ccccc23)cc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 78.7 %

Procedure:
To a solution of 6-[4-(4-benzyl-phthalazin-1-yl)-piperazin-1-yl]-pyridine-3-carbaldehyde (40 mg, 0.1 mmol) in 5 mL DCM is added a drop of acetic acid, NaBH(OAc)3 (41.4 mg, 0.2 mmol) and morpholine (7.5 mL, 0.12 mmol). The reaction mixture is stirred for 30 min at rt. Aqueous NaHCO3 solution is added and the reaction mixture is stirred for an additional 30 min. The layers are separated and the aqueous layer is extracted with DCM. The combined organic layers are washed with water, brine, dried over Na2SO4, filtered and concentrated. The crude product is purified by flash chromatography on silica gel (EtOAc/heptane 10%-70%) to yield the title compound (37.8 mg, 80%).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:26])[CH2:5][C:6]1[C:11]([C:12]#[N:13])=[C:10]([C:14]2[CH:22]=[CH:21][C:17]3[O:18][CH2:19][O:20][C:16]=3[CH:15]=2)[C:9]([C:23]#[N:24])=[C:8]([NH2:25])[N:7]=1)[CH3:2].[H-].[Na+].[CH3:29]I.O>CN(C=O)C>[NH2:25][C:8]1[N:7]=[C:6]([CH:5]([CH3:29])[C:4]([O:3][CH2:1][CH3:2])=[O:26])[C:11]([C:12]#[N:13])=[C:10]([C:14]2[CH:22]=[CH:21][C:17]3[O:18][CH2:19][O:20][C:16]=3[CH:15]=2)[C:9]=1[C:23]#[N:24]
Reactant: CI
Reactant: CCOC(=O)Cc1nc(N)c(C#N)c(-c2ccc3c(c2)OCO3)c1C#N
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CCOC(=O)C(C)c1nc(N)c(C#N)c(-c2ccc3c(c2)OCO3)c1C#N
Reaction time: 0.75 h

Procedure:
Ethyl[6-amino-4-(1,3-benzodioxol-5-yl)-3,5-dicyano-2-pyridinyl]acetate (step 1) (2.00 g, 5.71 mmol) is initially charged in 40 ml of DMF. Sodium hydride (0.37 g, 9.19 mmol) is added and the mixture is stirred for 45 minutes. Methyl iodide (0.40 ml, 6.39 mmol) is then added, the color of the yellow reaction solution turning to orange. After five hours, a further 0.2 ml of methyl iodide is added and the mixture is stirred at room temperature overnight. The mixture is poured into water (50 ml), and an emulsion is formed. The emulsion is extracted three times with ether. The combined organic phases are dried over magnesium sulfate, filtered and concentrated using a rotary evaporator. The mixture is chromatographed by RP-HPLC using an acetonitrile/water gradient. The product is obtained as a colorless solid.
Reaction SMILES: [C:1]([O:4][C@H:5]1[C:10](=[CH:11][O:12]CC)[CH2:9][C@H:8]2[C@H:15]3[C@H:24]([CH2:25][CH2:26][C@:6]12[CH3:7])[C:23]1[CH:22]=[CH:21][C:20]([O:27][CH2:28][C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)=[CH:19][C:18]=1[CH2:17][CH2:16]3)(=[O:3])[CH3:2].C([O-])(O)=O.[Na+]>C1COCC1.Cl.O>[C:1]([O:4][C@H:5]1[C@H:10]([CH:11]=[O:12])[CH2:9][C@H:8]2[C@H:15]3[C@H:24]([CH2:25][CH2:26][C@:6]12[CH3:7])[C:23]1[CH:22]=[CH:21][C:20]([O:27][CH2:28][C:29]2[CH:30]=[CH:31][CH:32]=[CH:33][CH:34]=2)=[CH:19][C:18]=1[CH2:17][CH2:16]3)(=[O:3])[CH3:2]
Reactant: CCOC=C1C[C@H]2[C@@H]3CCc4cc(OCc5ccccc5)ccc4[C@H]3CC[C@]2(C)[C@H]1OC(C)=O
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: CC(=O)O[C@H]1[C@H](C=O)C[C@H]2[C@@H]3CCc4cc(OCc5ccccc5)ccc4[C@H]3CC[C@@]21C
Yield: 56.4 %

Procedure:
A solution of 183 mg (0.397 mmol) of 4 in THF (1.5 mL) with 4 drops of 10% aqueous HCl and 2 drops of H2O was stirred at rt for 6 h. Reaction was poured into saturated aqueous NaHCO3 (100 mL) and extracted with CH2Cl2 (3×, 75 mL). Combined organic extracts were dried over Na2SO4 and concentrated in vacuo. Purification of the residue by repeated (3×) flash chromatography on a 2×15 cm column of silica gel using hexanes/acetone (6:1) as eluent gave 96.9 mg (56%) of 5 as a white solid. Data for 5: TLC, T-3, Rf0.22. 1H NMR (500 MHz, CDCl3) δ 0.91 (s, 3H, H-18), 2.10 (s, 3H, OAc), 4.86 (d, 1H, J=8.1 Hz, H-17), 5.04 (s, 2H, benzylic), 6.73 (d, 1H, J=2.7 Hz, H-4), 6.79 (dd, 1H, J=8.5, 2.7 Hz, H-2), 7.19 (d, 1H, J=8.5 Hz, H-1), 7.31-7.44 (m, 5H, Ar—H), 9.83 (d, 1H, J=3.1 Hz, O═CH); HRMS (ES) calcd for C28H32O4Na (M+Na+) m/e 455.2198, found m/e 455.2205.
Reaction SMILES: [Cl:1][C:2]1[CH:9]=[N:8][CH:7]=[C:6](Cl)[C:3]=1[C:4]#[N:5].[CH3:11][S-:12].[Na+]>CN(C)C=O>[Cl:1][C:2]1[CH:9]=[N:8][CH:7]=[C:6]([S:12][CH3:11])[C:3]=1[C:4]#[N:5]
Reactant: C[S-]
Reactant: N#Cc1c(Cl)cncc1Cl
Agent: [Na+]
Solvent: CN(C)C=O
Product: CSc1cncc(Cl)c1C#N
Temperature: 25 °C
Reaction time: 4 h
Yield: 24.9 %

Procedure:
To a solution of 3,5-dichloroisonicotinonitrile (346 mg, 2 mmol) in N,N-dimethylformamide (2 mL) was added sodium thiomethoxide (141 mg, 2 mmol) at 0° C. The mixture was stirred at room temperature for 4 hours. After completion of the reaction, the solution was concentrated under reduced pressure. To the resulting residue was added saturated aqueous sodium hydrogen carbonate and the mixture was extracted with ethyl acetate. The combined organic layer was separated, dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (hexane/ethyl acetate=1/1) to give the desired product (92 mg, 25% yield).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][N:10]=1)[C:5]([OH:7])=O.[F:11][C:12]([F:21])([F:20])[C:13]1[CH:14]=[C:15]([CH:17]=[CH:18][CH:19]=1)[NH2:16]>>[Br:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][N:10]=1)[C:5]([NH:16][C:15]1[CH:17]=[CH:18][CH:19]=[C:13]([C:12]([F:11])([F:20])[F:21])[CH:14]=1)=[O:7]
Reactant: Nc1cccc(C(F)(F)F)c1
Reactant: O=C(O)c1ccnc(Br)c1
Product: O=C(Nc1cccc(C(F)(F)F)c1)c1ccnc(Br)c1

Procedure:
In a manner similar to that described in Preparation 17, 2-bromoisonicotinic acid and 3-trifluoromethylaniline were converted to the title compound
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]2[C:10](=[CH:11][CH:12]=1)[NH:9][N:8]=[C:7]2[OH:13])([O-:3])=[O:2].[CH3:14][N:15]1C(=O)O[C:18](=[O:19])[C:17]2=[CH:23][CH:24]=[CH:25][CH:26]=[C:16]12>>[CH3:14][NH:15][C:16]1[CH:26]=[CH:25][CH:24]=[CH:23][C:17]=1[C:18]([N:9]1[C:10]2[C:6](=[CH:5][C:4]([N+:1]([O-:3])=[O:2])=[CH:12][CH:11]=2)[C:7]([OH:13])=[N:8]1)=[O:19]
Reactant: Cn1c(=O)oc(=O)c2ccccc21
Reactant: O=[N+]([O-])c1ccc2[nH]nc(O)c2c1
Product: CNc1ccccc1C(=O)n1nc(O)c2cc([N+](=O)[O-])ccc21
Yield: 47 %

Procedure:
5-Nitro-1H-indazol-3-ol was reacted with N-methylisatoic anhydride according to the general procedure A above and afforded the desired amine as an orange solid in 47.0% yield; m.p. >270° C.
Reaction SMILES: C[O:2][C:3](=[O:32])[C@H:4]([CH2:6][S:7][C@H:8](/[CH:18]=[CH:19]/[CH:20]=[CH:21]/[CH:22]=[CH:23]\[CH2:24]/[CH:25]=[CH:26]\[CH2:27][CH2:28][CH2:29][CH2:30][CH3:31])[C@@H:9]([OH:17])[CH2:10][CH2:11][CH2:12][C:13]([O:15]C)=[O:14])[NH2:5].[OH-].[K+]>CO.O>[NH4+:5].[OH:17][C@H:9]([C@H:8]([S:7][CH2:6][C@@H:4]([C:3]([O-:32])=[O:2])[NH2:5])/[CH:18]=[CH:19]/[CH:20]=[CH:21]/[CH:22]=[CH:23]\[CH2:24]/[CH:25]=[CH:26]\[CH2:27][CH2:28][CH2:29][CH2:30][CH3:31])[CH2:10][CH2:11][CH2:12][C:13]([OH:15])=[O:14]
Reactant: CCCCC/C=C\C/C=C\C=C\C=C\[C@@H](SC[C@H](N)C(=O)OC)[C@@H](O)CCCC(=O)OC
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: CCCCC/C=C\C/C=C\C=C\C=C\[C@@H](SC[C@H](N)C(=O)[O-])[C@@H](O)CCCC(=O)O
Product: [NH4+]
Reaction time: 1.5 h
Yield: 88.8 %

Procedure:
The 5S,6R dimethylester, i.e. (5S,6R)(E,E,Z,Z)-S-(5-hydroxy-1-methoxy-1-oxoeicosa-7,9,11,14-tetraen-6-yl)-L-cysteine methyl ester (0.3 g) was dissolved in methanol (15 mL) and treated with potassium hydroxide (150 mg) in water (1.5 mL) and left at room temperature for 90 min. Water (20 mL) was then added and the bulk of the solvents were removed in vacuo. The aqueous solution resulting from the above treatment was mixed with Dowex 50W ×4 resin (25 mL) [sulfonated polystyrene ion exchange resin in the acid form] and then poured onto a column of the same material (25 mL). The column was then washed with water until neutral and then eluted with aqueous ammonia solution (10%). As soon as the ammonia front was eluting, 150 mL was collected, treated with n-butanol (10 mL) and concentrated at 45° and 20 nm until all the n-butanol and ammonia were removed. The residual aqueous solution was then freeze-dried to yield the (5S,6R) (E,E,Z,Z)-S-(5-hydroxy-1-hydroxy-1-oxoeicosa-7,9,11,14-tetraen-6-yl)-L-cysteine mono ammonium salt as a powder (130 mg).
Reaction SMILES: C([O:8][C:9]1[CH:33]=[CH:32][C:31]([O:34][CH2:35][CH2:36][N:37]2[CH2:42][CH2:41][N:40]([CH2:43][CH2:44][CH3:45])[CH2:39][CH2:38]2)=[CH:30][C:10]=1[C:11]([NH:13][C:14]1[CH:23]=[C:22]([C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)[CH:21]=[CH:20][C:15]=1[C:16]([O:18][CH3:19])=[O:17])=[O:12])C1C=CC=CC=1.C(Cl)(Cl)Cl>CO.C(OCC)(=O)C.[C].[Pd]>[OH:8][C:9]1[CH:33]=[CH:32][C:31]([O:34][CH2:35][CH2:36][N:37]2[CH2:38][CH2:39][N:40]([CH2:43][CH2:44][CH3:45])[CH2:41][CH2:42]2)=[CH:30][C:10]=1[C:11]([NH:13][C:14]1[CH:23]=[C:22]([C:24]2[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=2)[CH:21]=[CH:20][C:15]=1[C:16]([O:18][CH3:19])=[O:17])=[O:12]
Reactant: CCCN1CCN(CCOc2ccc(OCc3ccccc3)c(C(=O)Nc3cc(-c4ccccc4)ccc3C(=O)OC)c2)CC1
Agent: [Pd]
Solvent: ClC(Cl)Cl
Solvent: CCOC(C)=O
Solvent: CO
Product: CCCN1CCN(CCOc2ccc(O)c(C(=O)Nc3cc(-c4ccccc4)ccc3C(=O)OC)c2)CC1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 62.3 %

Procedure:
To a solution mixture of methyl 2-(2-(benzyloxy)-5-(2-(4-propylpiperazin-1-yl)ethoxy)benzamido)-4-phenylbenzoate (0.081 g) in methanol (1.5 mL) and ethyl acetate (1.5 mL), 10% palladium-carbon (0.081 g) was added, followed by stirring under a hydrogen atmosphere at room temperature for 2 hours and 30 minutes. Chloroform was added to the reaction mixture. The insoluble substance was removed by filtration, and the solvent was evaporated under reduced pressure. Diisopropyl ether was added to the obtained residue, and the solid substance was collected by filtration to obtain 0.043 g of methyl 2-(2-hydroxy-5-(2-(4-propylpiperazin-1-yl)ethoxy)benzamido)-4-phenylbenzoate as an orange solid.
Reaction SMILES: [S:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[NH:3][CH2:2]1.NC1C=CC=CC=1S.C=O.[C:20]([C:22]1[CH:23]=[C:24]([CH:28]=[C:29]([C:33]#[CH:34])[C:30]=1[O:31][CH3:32])[C:25](Cl)=[O:26])#[N:21]>ClCCl.C(N(CC)CC)C>[C:20]([C:22]1[CH:23]=[C:24]([CH:28]=[C:29]([C:33]#[CH:34])[C:30]=1[O:31][CH3:32])[C:25]([N:3]1[C:4]2[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=2[S:1][CH2:2]1)=[O:26])#[N:21]
Reactant: C#Cc1cc(C(=O)Cl)cc(C#N)c1OC
Reactant: c1ccc2c(c1)NCS2
Agent: C=O
Agent: Nc1ccccc1S
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: C#Cc1cc(C(=O)N2CSc3ccccc32)cc(C#N)c1OC
Reaction time: 2.5 h

Procedure:
2,3-dihydro-1,3-benzothiazole synthesized from 2-aminobenzenethiol (570 mg) and 37% formalin (0.38 mL) in the same manner as in Example 1 was dissolved in dichloromethane (10 mL), and triethylamine (1.2 mL) and 3-cyano-5-ethynyl-4-methoxybenzoyl chloride were added to the solution, and then the mixture was stirred at mom temperature for 2.5 hours. The solvent was distilled off under reduced pressure and water was added, and then the mixture was extracted with ethyl acetate. The organic layer was washed with 1N hydrochloric acid, 1N sodium hydroxide and saturated brine, and then dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure and the obtained residue was purified by silica gel column chromatography (n-hexane:ethyl acetate=5:1) to obtain the title compound (283 mg) as a yellow oily substance.
Reaction SMILES: Cl[C:2]1[C:3]2[CH:14]=[C:13]([C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=3)[CH:12]=[CH:11][C:4]=2[N:5]([CH3:10])[C:6](=[O:9])[CH2:7][N:8]=1.C1(B(O)O)C=CC=CC=1.[Cl:30][C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][C:32]=1B(O)O>>[Cl:30][C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][C:32]=1[C:2]1[C:3]2[CH:14]=[C:13]([C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=3)[CH:12]=[CH:11][C:4]=2[N:5]([CH3:10])[C:6](=[O:9])[CH2:7][N:8]=1
Reactant: CN1C(=O)CN=C(Cl)c2cc(-c3ccccc3)ccc21
Reactant: OB(O)c1ccccc1Cl
Agent: OB(O)c1ccccc1
Product: CN1C(=O)CN=C(c2ccccc2Cl)c2cc(-c3ccccc3)ccc21
Yield: 61 %

Procedure:
Prepared from 5-chloro-1-methyl-7-phenyl-1,3-dihydro-benzo[e][1,4]diazepin-2-one using the same method described for Example 9 and instead of using benzene boronic acid, we used 2-chlorophenyl boronic acid. The title compound (115 mg) was obtained as a beige solid, (yield=61%).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([OH:29])[CH2:9][CH2:10][N:11]2[CH2:16][CH2:15][CH:14]([C:17]3[CH:18]=[C:19]([NH:23][C:24](=[O:28])[CH:25]([CH3:27])[CH3:26])[CH:20]=[CH:21][CH:22]=3)[CH2:13][CH2:12]2)=[CH:4][CH:3]=1.[CH3:30][O:31][C:32]1[CH:37]=[CH:36][C:35](O)=[CH:34][CH:33]=1>>[F:1][C:2]1[CH:3]=[CH:4][C:5]([CH:8]([O:29][C:35]2[CH:36]=[CH:37][C:32]([O:31][CH3:30])=[CH:33][CH:34]=2)[CH2:9][CH2:10][N:11]2[CH2:16][CH2:15][CH:14]([C:17]3[CH:18]=[C:19]([NH:23][C:24](=[O:28])[CH:25]([CH3:26])[CH3:27])[CH:20]=[CH:21][CH:22]=3)[CH2:13][CH2:12]2)=[CH:6][CH:7]=1
Reactant: COc1ccc(O)cc1
Reactant: CC(C)C(=O)Nc1cccc(C2CCN(CCC(O)c3ccc(F)cc3)CC2)c1
Product: COc1ccc(OC(CCN2CCC(c3cccc(NC(=O)C(C)C)c3)CC2)c2ccc(F)cc2)cc1

Procedure:
Prepared by Procedure A and Scheme AN using N-(3-{1-[3-(4-fluorophenyl)-3-hydroxypropyl]-4-piperidinyl}phenyl)-2-methylpropanamide and 4-methoxyphenol: ESMS m/e: 505.2 (M+H)+.
Reaction SMILES: [OH:1][C:2]1[N:7]=[CH:6][C:5]([NH:8][C:9](=[O:15])[CH2:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[CH:4][CH:3]=1.[CH3:16][N:17]([C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)[C:18](Cl)=[O:19].N12CCN(CC1)CC2.O>O1CCCC1.CCCCCCC>[CH3:13][C:11]([CH3:12])([CH3:14])[CH2:10][C:9]([NH:8][C:5]1[CH:4]=[CH:3][C:2]([O:1][C:18](=[O:19])[N:17]([CH3:16])[C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)=[N:7][CH:6]=1)=[O:15]
Reactant: CC(C)(C)CC(=O)Nc1ccc(O)nc1
Reactant: CN(C(=O)Cl)c1ccccc1
Agent: C1CN2CCN1CC2
Solvent: O
Solvent: C1CCOC1
Solvent: CCCCCCC
Product: CN(C(=O)Oc1ccc(NC(=O)CC(C)(C)C)cn1)c1ccccc1
Yield: 79.1 %

Procedure:
A solution of N-(6-hydroxy-pyridin-3-yl)-3,3-dimethyl-butyramide (0.42 g, 2.00 mmol), N-methyl-N-phenylcarbamoyl chloride (0.37 g, 2.20 mmol) and 1,4-diazabicyclo[2,2,2]octane (0.25 g, 2.20 mmol) in tetrahydrofuran (20 mL) was stirred at room temperature for 2.5 hours. Water was added and the solution was extracted three times with dichloromethane. The combined organic layers were dried over sodium sulphate, filtered and evaporated in vacuo. The residue was redissolved in ethyl acetate and the solution was filtered over a short pad of silicagel. Evaporation of the solvent and crystallisation of the solid from ethyl acetate:heptane yielded the title compound (0.54 g, 79% yield) as a white solid.
Reaction SMILES: [CH3:1][O:2][C:3]1[N:8]=[C:7]([O:9][CH3:10])[C:6]([B:11]([OH:13])[OH:12])=[CH:5][N:4]=1.O[C:15]([C:18](O)([CH3:20])[CH3:19])([CH3:17])[CH3:16]>O1CCCC1>[CH3:1][O:2][C:3]1[N:8]=[C:7]([O:9][CH3:10])[C:6]([B:11]2[O:12][C:18]([CH3:20])([CH3:19])[C:15]([CH3:17])([CH3:16])[O:13]2)=[CH:5][N:4]=1
Reactant: CC(C)(O)C(C)(C)O
Reactant: COc1ncc(B(O)O)c(OC)n1
Solvent: C1CCOC1
Product: COc1ncc(B2OC(C)(C)C(C)(C)O2)c(OC)n1
Temperature: 25 °C
Reaction time: 1.5 h

Procedure:
To a 100 mL round-bottomed flask charged with 4 Å molecular sieves (approximately 1 g) was added the 2,4-dimethoxypyrimidine-5-boronic acid (5.34 g, 29.0 mmol) and anhydrous tetrahydrofuran (25 mL). The pinocol (2.98 g, 25.3 mmol) was added and the reaction stirred at room temperature for 1.5 hours. Additional 2,4-dimethoxypyrimidine-5-boronic acid (662.2 mg, 3.6 mmol) was added and the reaction stirred overnight. Molecular sieves and 2,4-dimethoxypyrimidine-5-boronic acid (1.53 g, 8.3 mmol) were added and the reaction stirred for 0.5 hours. Pinacol (0.613 g, 5.2 mmol) was then added. After 2 hours, the molecular sieves were removed by filtration and the filtrate was concentrated. After drying under high vacuum, the title compound was obtained as a fine yellow solid (8.61 g, 79%). 1H NMR (300.132 MHz, CDCl3) δ 8.56 (s, 1H), 4.01 (d, J=1.5 Hz, 6H), 1.34 (s, 12H).