Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [K].[Br:2][C:3]1[C:13]([Br:14])=[C:12]([Br:15])[C:11]([Br:16])=[C:5]2[C:6]([NH:8][C:9](=[O:10])[C:4]=12)=[O:7].[Br:17][C:18]1[C:23]([C:24](Cl)=[O:25])=[C:22]([Br:27])[C:21]([Br:28])=[C:20]([Br:29])[C:19]=1[Br:30]>O1CCOCC1>[Br:17][C:18]1[C:23]([C:24]([N:8]2[C:9](=[O:10])[C:4]3=[C:3]([Br:2])[C:13]([Br:14])=[C:12]([Br:15])[C:11]([Br:16])=[C:5]3[C:6]2=[O:7])=[O:25])=[C:22]([Br:27])[C:21]([Br:28])=[C:20]([Br:29])[C:19]=1[Br:30]
Reactant: O=C1NC(=O)c2c(Br)c(Br)c(Br)c(Br)c21
Reactant: O=C(Cl)c1c(Br)c(Br)c(Br)c(Br)c1Br
Agent: [K]
Solvent: C1COCCO1
Product: O=C(c1c(Br)c(Br)c(Br)c(Br)c1Br)N1C(=O)c2c(Br)c(Br)c(Br)c(Br)c2C1=O
Temperature: 25 °C

Procedure:
The potassium salt of 3,4,5,6-tetrabromophthalimide (0.10 mole) and dioxane (1200 ml) are charged into a glass reaction vessel equipped with a mechanical stirrer, thermometer and reflux condenser. Pentabromobenzoyl chloride (0.10 mole) is then added dropwise, with stirring, to the reaction mixture at room temperature. After the addition is completed the reaction mixture is heated at reflux for a period of about 1 hour. After this time the reaction mixture is filtered and the filtrate is stripped of solvent to yield the desired product N-(pentabromobenzoyl)-3,4,5,6-tetrabromophthalimide.
Reaction SMILES: [OH:1][CH:2]([CH:10]([S:19]([C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)(=[O:21])=[O:20])[CH2:11][CH2:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)[CH2:3][CH2:4][CH2:5][C:6]([O:8]C)=[O:7].C(=O)([O-])[O-].[Na+].[Na+]>>[OH:1][CH:2]([CH:10]([S:19]([C:22]1[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=1)(=[O:21])=[O:20])[CH2:11][CH2:12][C:13]1[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=1)[CH2:3][CH2:4][CH2:5][C:6]([OH:8])=[O:7]
Reactant: COC(=O)CCCC(O)C(CCc1ccccc1)S(=O)(=O)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Product: O=C(O)CCCC(O)C(CCc1ccccc1)S(=O)(=O)c1ccccc1

Procedure:
Methyl 5-hydroxy-8-phenyl-6-phenylsulphonyl-octanoate was hydrolysed with aqueous sodium carbonate as in the hydrolysis step of Example 16 to afford the title compound as a viscous oil.
Reaction SMILES: [C:1]1([CH3:11])[CH:6]=[CH:5][C:4]([S:7](Cl)(=[O:9])=[O:8])=[CH:3][CH:2]=1.[C:12]([O:16][C:17]([N:19]1[CH2:23][CH2:22][CH:21]([CH2:24][OH:25])[CH2:20]1)=[O:18])([CH3:15])([CH3:14])[CH3:13].O>N1C=CC=CC=1>[C:12]([O:16][C:17]([N:19]1[CH2:23][CH2:22][CH:21]([CH2:24][O:25][S:7]([C:4]2[CH:5]=[CH:6][C:1]([CH3:11])=[CH:2][CH:3]=2)(=[O:9])=[O:8])[CH2:20]1)=[O:18])([CH3:15])([CH3:14])[CH3:13]
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Reactant: CC(C)(C)OC(=O)N1CCC(CO)C1
Solvent: O
Solvent: c1ccncc1
Product: Cc1ccc(S(=O)(=O)OCC2CCN(C(=O)OC(C)(C)C)C2)cc1
Reaction time: 5 h
Yield: 72 %

Procedure:
30.0 g (0.157 mole) of p-toluenesulfonyl chloride were added to a solution of 29.5 g (0.143 mole) of 1-t-butoxycarbonyl-3-hydroxymethylpyrrolidine [prepared as described in Step (2) above] dissolved in 500 ml of pyridine. The mixture was then stirred for 5 hours whilst ice-cooling, after which it was stirred at room temperature overnight. The reaction mixture was poured into 1 liter of water and then extracted with ethyl acetate. The extract was washed with water, dried and concentrated under by evaporation reduced pressure. The residue was subjected to column chromatography through silica gel eluted with a 1:4 by volume mixture of ethyl acetate and toluene, to give 36.6 g of 1-t-butoxycarbonyl-3-(p-toluenesulfonyloxymethyl)pyrrolidine as a pale brown oil, which gradually crystallized.
Reaction SMILES: [C:1]1([C:7]2[N:11]=[C:10]([CH2:12][CH2:13][C:14](O)=[O:15])[O:9][N:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.CO>O1CCCC1>[C:1]1([C:7]2[N:11]=[C:10]([CH2:12][CH2:13][CH2:14][OH:15])[O:9][N:8]=2)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: O=C(O)CCc1nc(-c2ccccc2)no1
Solvent: C1CCOC1
Solvent: CO
Product: OCCCc1nc(-c2ccccc2)no1
Yield: 56.3 %

Procedure:
A solution of 2.5 ml of borane-methyl sulfide complex in 2M solution in tetrahydrofuran, 920 mg of 3-(3-phenyl-1,2,4-oxadiazol 5-yl)-propanoic acid (prepared by SRIRASTAVA et al., J. Heterocycl. Chem., Vol. 21, p. 1193 (1984) and 20 ml of tetrahydrofuran was stirred for one hour at ambient temperature. 10 ml of methanol were added over 5 minutes and evaporation to dryness under reduced pressure was carried out. The residue was chromatographed on silica (eluant: ethyl acetate - hexane (6-4)) to obtain 485 mg of the expected product.
Reaction SMILES: [Cl:1][C:2]1[CH:11]=[N:10][C:5]2[S:6][CH2:7][CH2:8][NH:9][C:4]=2[CH:3]=1.[H-].[Na+].Cl[C:15]1[C:24]2[C:19](=[CH:20][CH:21]=[CH:22][C:23]=2[F:25])[N:18]=[C:17]([C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][N:27]=2)[C:16]=1[CH3:32]>CN(C=O)C>[Cl:1][C:2]1[CH:11]=[N:10][C:5]2[S:6][CH2:7][CH2:8][N:9]([C:15]3[C:24]4[C:19](=[CH:20][CH:21]=[CH:22][C:23]=4[F:25])[N:18]=[C:17]([C:26]4[CH:31]=[CH:30][CH:29]=[CH:28][N:27]=4)[C:16]=3[CH3:32])[C:4]=2[CH:3]=1
Reactant: Clc1cnc2c(c1)NCCS2
Reactant: Cc1c(-c2ccccn2)nc2cccc(F)c2c1Cl
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: Cc1c(-c2ccccn2)nc2cccc(F)c2c1N1CCSc2ncc(Cl)cc21
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
To a stirred solution of 7-chloro-2,3-dihydro-1H-pyrido[2,3-b][1,4]thiazine (100 mg, 0.536 mmol) in DMF (2.0 mL) was added sodium hydride (28.0 mg, 0.643 mmol, 55% dispersion in oil) under a N2 atmosphere. The reaction was stirred at rt for 15 min. After this time 4-chloro-5-fluoro-3-methyl-2-(pyridin-2-yl)quinoline (146 mg, 0.536 mmol) in DMF (3.0 mL) was added and the reaction was heated at 60° C. for 1 h and at 100° C. overnight. After this time more NaH (28.0 mg, 0.643 mmol, 55% dispersion in oil) was added and the reaction was heated at 120° C. for 3 h. The reaction was then cooled to rt and partitioned between EtOAc and water. The separated organic layer was washed with LiCl (1.0M aqueous solution) and then it was dried over MgSO4, filtered and evaporated in vacuo. Column chromatography (Hexanes:EtOAc, 1:0 to 1:1) gave 7-chloro-1-(5-fluoro-3-methyl-2-(pyridin-2-yl)quinolin-4-yl)-2,3-dihydro-1H-pyrido[2,3-b][1,4]thiazine as a yellow film. Mass Spectrum (ESI) m/e=423.0 (M+1).
Reaction SMILES: [OH:1][CH2:2][CH2:3][C:4]1[N:5]([CH2:9][CH2:10][CH2:11][CH2:12][C:13]2[CH:18]=[CH:17][C:16]([OH:19])=[CH:15][CH:14]=2)[CH:6]=[CH:7][N:8]=1.[H-].[Na+].Cl[CH2:23][C:24]1[N:25]=[C:26](/[CH:29]=[CH:30]/[C:31]2[CH:36]=[CH:35][C:34]([F:37])=[CH:33][CH:32]=2)[O:27][CH:28]=1>>[F:37][C:34]1[CH:35]=[CH:36][C:31](/[CH:30]=[CH:29]/[C:26]2[O:27][CH:28]=[C:24]([CH2:23][O:19][C:16]3[CH:15]=[CH:14][C:13]([CH2:12][CH2:11][CH2:10][CH2:9][N:5]4[CH:6]=[CH:7][N:8]=[C:4]4[CH2:3][CH2:2][OH:1])=[CH:18][CH:17]=3)[N:25]=2)=[CH:32][CH:33]=1
Reactant: OCCc1nccn1CCCCc1ccc(O)cc1
Reactant: Fc1ccc(/C=C/c2nc(CCl)co2)cc1
Agent: [H-]
Agent: [Na+]
Product: OCCc1nccn1CCCCc1ccc(OCc2coc(/C=C/c3ccc(F)cc3)n2)cc1
Yield: 84.1 %

Procedure:
Using 4-[4-[2-(2-hydroxyethyl)-1H-imidazol-1-yl]butyl]phenol (391 mg), 65% oily sodium hydride (60 mg) and 4-(chloromethyl)-2-((E)-2-(4-fluorophenyl)ethenyl]-1,3-oxazole (375 mg), the same reaction as Example 2 was carried out to yield the titled compound (583 mg).
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[CH:6][C:7]([N:10]2[CH2:15][CH2:14][N:13]([C:16]3[N:21]=[CH:20][CH:19]=[CH:18][N:17]=3)[CH2:12][CH2:11]2)=[N:8][CH:9]=1)([O-])=O.Cl[Sn]Cl>Cl>[N:17]1[CH:18]=[CH:19][CH:20]=[N:21][C:16]=1[N:13]1[CH2:12][CH2:11][N:10]([C:7]2[N:8]=[CH:9][C:4]([NH2:1])=[CH:5][CH:6]=2)[CH2:15][CH2:14]1
Reactant: O=[N+]([O-])c1ccc(N2CCN(c3ncccn3)CC2)nc1
Agent: Cl
Agent: Cl[Sn]Cl
Product: Nc1ccc(N2CCN(c3ncccn3)CC2)nc1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of 2-[4-(5-nitro-pyridin-2-yl)-piperazin-1-yl]-pyrimidine (600 mg, 2.1 mmol) from above in 2N hydrochloric acid (7.50 mL) was added SnCl2 (1.60 g, 8.4 mmol). The mixture was stirred at room temperature for 2 hr. The mixture was evaporated to dryness and basified with 1N NaOH. The crude solid was triturated in methanol to afford 6-(4-pyrimidin-2-yl-piperazin-1-yl)-pyridin-3-ylamine as a yellow solid. The NMR spectrum obtained on the sample is compatible with its structure. LCMS calcd for C13H16N6 (m/e) 256, obsd 257 (M+H).
Reaction SMILES: [C:1]([NH:5][CH3:6])([CH3:4])([CH3:3])[CH3:2].Cl[S:8]([CH2:11][C:12]([O:14][CH3:15])=[O:13])(=[O:10])=[O:9]>>[CH3:15][O:14][C:12](=[O:13])[CH2:11][S:8](=[O:10])(=[O:9])[N:5]([C:1]([CH3:4])([CH3:3])[CH3:2])[CH3:6]
Reactant: COC(=O)CS(=O)(=O)Cl
Reactant: CNC(C)(C)C
Product: COC(=O)CS(=O)(=O)N(C)C(C)(C)C
Yield: 60296.7 %

Procedure:
The subtitle compound (14.81 g, 59%) was prepared as a yellow oil from tert-butylmethylamine (24.48 g, 0.28 mol) and methyl chlorosulfonylacetate (19.37 g, 0.11 mmol), using the method of Example 1(a).
Reaction SMILES: [CH3:1][C:2]1[CH:11]=[CH:10][C:5]([C:6]([O:8][CH3:9])=[O:7])=[CH:4][C:3]=1[N:12]1[CH:21]=[CH:20][C:19]2[C:14](=[CH:15][C:16](OS(C(F)(F)F)(=O)=O)=[CH:17][CH:18]=2)[C:13]1=[O:30].C(N(CC)CC)C.[N:38]1([CH2:44][C:45]#[CH:46])[CH2:43]COC[CH2:39]1>C(#N)C.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.[Cu]I>[CH3:39][N:38]([CH3:43])[CH2:44][CH2:45][CH2:46][C:16]1[CH:15]=[C:14]2[C:19]([CH:20]=[CH:21][N:12]([C:3]3[CH:4]=[C:5]([CH:10]=[CH:11][C:2]=3[CH3:1])[C:6]([O:8][CH3:9])=[O:7])[C:13]2=[O:30])=[CH:18][CH:17]=1
Reactant: C#CCN1CCOCC1
Reactant: COC(=O)c1ccc(C)c(-n2ccc3ccc(OS(=O)(=O)C(F)(F)F)cc3c2=O)c1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Solvent: CC#N
Solvent: CCN(CC)CC
Product: COC(=O)c1ccc(C)c(-n2ccc3ccc(CCCN(C)C)cc3c2=O)c1
Temperature: 80 °C
Yield: 86.9 %

Procedure:
A mixture of the methyl 4-methyl-3-[1-oxo-7-{[(trifluoromethyl)sulfonyl]oxy} isoquinolin-2(1H)-yl]benzoate (400 mg), PdCl2(PPh3)2 (16 mg), CuI (9 mg) and triethylamine (632 μl) were stirred in acetonitrile (10 ml) for 10 minutes. 3-(4-morpholinyl)-1-propyne (114 mg) in acetonitrile (4 ml) was then added dropwise and the reaction was heated at 80° C. for 18 hours and then concentrated. The residue was dissolved in ethyl acetate, washed with water (×3), brine, dried (magnesium sulfate) and concentrated to a brown oil. The oil was purified by column chromatography on an ion exchange column (isolute SCX column from International Sorbent Technology Limited, Henoed, Mid-Glamorgan, UK) using initially methanol and then a 99:1 mixture of methanol and aqueous ammonia solution to yield methyl 3-[7-[3-(dimethylamino)propyl]-1-oxoisoquinolin-2(1H)-yl]-4-methylbenzoate as a brown oil (298 mg); NMR Spectrum: (DMSOd6) 2.15 (s, 3H), 2.55 (m, 4H), 3.57 (s, 2H), 3.63 (m, 4H), 3.87 (s, 3H), 6.78 (d, 1H), 7.42 (d, 1H), 7.60 (d, 1H), 7.79 (m, 2H), 7.86 (s, 1H), 7.99 (d, 1H), 8.24 (s, 1H); Mass Spectrum: M+H+ 417.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[C:14]2[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=2)[CH:8]=[CH:7][C:6]=1[OH:15])=[O:4].[H][H]>C(O)(=O)C.[Pt]=O>[CH3:1][O:2][C:3]([C:5]1[C:14]2[CH2:13][CH2:12][CH2:11][CH2:10][C:9]=2[CH:8]=[CH:7][C:6]=1[OH:15])=[O:4]
Reactant: COC(=O)c1c(O)ccc2ccccc12
Reactant: [H][H]
Agent: O=[Pt]
Solvent: CC(=O)O
Product: COC(=O)c1c(O)ccc2c1CCCC2
Reaction time: 8 h
Yield: 114.7 %

Procedure:
Under an atmosphere of nitrogen, platinum oxide (5 g) was added to a solution of 2-hydroxy-naphthalene-1-carboxylic acid methyl ester (10 g) in acetic acid (200 mL). The nitrogen atmosphere was replaced by hydrogen, the pressure was increased to 4 bar and the mixture was stirred overnight. The resulting suspension was filtered and the filtrate was concentrated under vacuum to give an oil. The residue was purified by chromatography on silica, eluting with DCM. The fractions containing the desired product were combined and evaporated under vacuum to give the title compound as a colorless oil (11.7 g).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH2:9][N:10]2[C:14]([CH3:15])=[CH:13][CH:12]=[C:11]2[C:16]2[CH:21]=[CH:20][C:19]([OH:22])=[CH:18][CH:17]=2)=[CH:4][CH:3]=1.O[C@@H:24]([CH2:30][C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1)[C:25]([O:27][CH2:28][CH3:29])=[O:26].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OCC)=O)=NC(OCC)=O>C1(C)C=CC=CC=1>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:8][CH2:9][N:10]2[C:14]([CH3:15])=[CH:13][CH:12]=[C:11]2[C:16]2[CH:17]=[CH:18][C:19]([O:22][C@H:24]([CH2:30][C:31]3[CH:32]=[CH:33][CH:34]=[CH:35][CH:36]=3)[C:25]([O:27][CH2:28][CH3:29])=[O:26])=[CH:20][CH:21]=2)=[CH:6][CH:7]=1
Reactant: CCOC(=O)[C@@H](O)Cc1ccccc1
Reactant: Cc1ccc(-c2ccc(O)cc2)n1CCc1ccc(Br)cc1
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: Cc1ccccc1
Product: CCOC(=O)[C@@H](Cc1ccccc1)Oc1ccc(-c2ccc(C)n2CCc2ccc(Br)cc2)cc1
Yield: 54 %

Procedure:
To a solution of 4-[1-[2-(4-bromophenyl)ethan-1-yl]-5-methyl-1H-pyrrol-2-yl]phenol (3.00 g, 8.42 mmol), ethyl (S)-2-hydroxy-3-phenylpropanoate (1.96 g, 10.1 mmol) and triphenylphosphine (2.65 g, 10.1 mmol) in toluene (30 ml) was added diethyl azodicarboxylate (1.76 g, 10.1 mmol) and refluxed for 20 hours under heating. The insoluble matter was filtered out and the filtrate was diluted with ethyl acetate. The obtained solution was washed with water and dried over magnesium sulfate anhydride, and the solvent was removed under reduced pressure. The residue was purified by silica gel column chromatography (hexane:ethyl acetate=8:1) to give the object compound as an oily substance. 2.40 g (yield: 54.0%)
Reaction SMILES: [OH:1][CH:2]([CH3:9])[CH2:3][C:4]([O:6][CH2:7][CH3:8])=[O:5].P([O-])([O-])([O-])=O.[K+].[K+].[K+]>>[OH:1][C@@H:2]([CH3:9])[CH2:3][C:4]([O:6][CH2:7][CH3:8])=[O:5]
Reactant: CCOC(=O)CC(C)O
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Product: CCOC(=O)C[C@H](C)O
Reaction time: 2 h
Yield: 97 %

Procedure:
Racemic ethyl 3-hydroxybutyrate (1%, v/v) was added to the vial containing 5 ml potassium phosphate buffer (pH 8.0, 0.1 M) and Novozyme 435 (4%, w/v). The reaction was carried out at 30° C. for 2 hours. The reaction mixture was extracted with ethyl acetate and analyzed by above-mentioned method. Ethyl (S)-3-hydroxybutyrate (97% e.e) was obtained from organic solvent at 55% conversion. The aqueous solution was acidified with hydrochloric acid and extracted with organic solvent. After esterification, ethyl (R)-3-hydroxybutyrate with optical purity of 80.4% e.e was obtained.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6](Cl)[N:5]=[C:4]([S:9][CH2:10][C:11]2[CH:16]=[CH:15][CH:14]=[C:13]([Cl:17])[C:12]=2[F:18])[N:3]=1.[H-].[Na+].[CH3:21][OH:22]>>[Cl:1][C:2]1[CH:7]=[C:6]([O:22][CH3:21])[N:5]=[C:4]([S:9][CH2:10][C:11]2[CH:16]=[CH:15][CH:14]=[C:13]([Cl:17])[C:12]=2[F:18])[N:3]=1
Reactant: Fc1c(Cl)cccc1CSc1nc(Cl)cc(Cl)n1
Reactant: CO
Agent: [H-]
Agent: [Na+]
Product: COc1cc(Cl)nc(SCc2cccc(Cl)c2F)n1

Procedure:
The subtitle compound was prepared according to the procedure outlined in example 35 Step (i) using 4,6-dichloro-2-[(3-chloro-2-fluorobenzyl)thio]pyrimidine (prepared according to patent WO 2004/011443) (0.65 g), methanol (8 mL) and 60% sodium hydride (88 mg). Yield: 0.57 g.
Reaction SMILES: [CH3:1][C:2]1([CH3:29])[CH:11](O)[CH:10]([C:13]2[C:14](=[O:26])[N:15]([CH2:19][C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)[CH:16]=[CH:17][CH:18]=2)[C:9]2[C:4](=[CH:5][CH:6]=[C:7]([C:27]#[N:28])[CH:8]=2)[O:3]1.[OH-:30].[K+]>C(O)(C)(C)C>[CH3:1][C:2]1([CH3:29])[CH:11]=[C:10]([C:13]2[C:14](=[O:26])[N:15]([CH2:19][C:20]3[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=3)[CH:16]=[CH:17][CH:18]=2)[C:9]2[C:4](=[CH:5][CH:6]=[C:7]([C:27](=[O:30])[NH2:28])[CH:8]=2)[O:3]1
Reactant: CC1(C)Oc2ccc(C#N)cc2C(c2cccn(Cc3ccccc3)c2=O)C1O
Reactant: [OH-]
Agent: [K+]
Solvent: CC(C)(C)O
Product: CC1(C)C=C(c2cccn(Cc3ccccc3)c2=O)c2cc(C(N)=O)ccc2O1
Reaction time: 0.83 h

Procedure:
A mixture of 5.8 g of 2,2-dimethyl-4-(1-benzyl-1,2-dihydro-2-oxo-3-pyridyl)-6-cyano-3-chromanol, 11.6 g of KOH and 90 ml of tert.-butanol is boiled for 50 min., cooled and poured onto ice. Customary working up gives 2,2-dimethyl-4-(1-benzyl-1,2-dihydro-2-oxo-3-pyridyl)-6carbamoyl-3-chromene, m.p. 199°-202°.
Reaction SMILES: [F:1][C:2]([CH3:12])([CH3:11])[CH2:3][C:4]1([OH:10])[CH2:9][CH2:8][NH:7][CH2:6][CH2:5]1.[S:13]1[C:17]2=[CH:18][CH:19]=[CH:20][C:21]([S:22]([NH:25][C:26]3[CH:34]=[CH:33][C:29]([C:30](O)=[O:31])=[CH:28][CH:27]=3)(=[O:24])=[O:23])=[C:16]2[N:15]=[CH:14]1.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>C(Cl)Cl>[F:1][C:2]([CH3:12])([CH3:11])[CH2:3][C:4]1([OH:10])[CH2:5][CH2:6][N:7]([C:30]([C:29]2[CH:28]=[CH:27][C:26]([NH:25][S:22]([C:21]3[CH:20]=[CH:19][CH:18]=[C:17]4[S:13][CH:14]=[N:15][C:16]=34)(=[O:24])=[O:23])=[CH:34][CH:33]=2)=[O:31])[CH2:8][CH2:9]1
Reactant: O=C(O)c1ccc(NS(=O)(=O)c2cccc3scnc23)cc1
Reactant: CC(C)(F)CC1(O)CCNCC1
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: ClCCl
Product: CC(C)(F)CC1(O)CCN(C(=O)c2ccc(NS(=O)(=O)c3cccc4scnc34)cc2)CC1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
To a round-bottom flask was added with 4-(2-fluoro-2-methylpropyl)piperidin-4-ol (25 mg 0.143 mmol), 4-(benzo[d]thiazole-4-sulfonamido)benzoic acid (47 mg, 0.143 mmol), DIPEA (110 mg, 0.85 mmol), HATU (54 mg, 0.143 mmol), and DCM (5 mL). The mixture was stirred at r.t. for 16 hours. After washing with satd. NaHCO3, brine, the combined organic layer was dried over anhy. Na2SO4 and concentrated in vacuo. Purification by a standard method gave the desired compound. 1H NMR (CHLOROFORM-d) δ: 9.31 (s, 1H), 8.19 (dd, J=8.1, 0.8 Hz, 1H), 8.10 (dd, J=7.5, 1.1 Hz, 1H), 7.93 (s, 1H), 7.54 (t, J=7.9 Hz, 1H), 7.16-7.23 (m, J=8.3 Hz, 2H), 7.05-7.15 (m, J=8.3 Hz, 2H), 4.19-4.47 (m, 1H), 3.46 (d, J=15.6 Hz, 1H), 3.35 (d, J=15.3 Hz, 2H), 1.89 (s, 3H), 1.84 (s, 3H), 1.49-1.55 (m, 3H), 1.46 (s, 3H). LC-MS: m/z 492.65 (M+H)+
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:14](=[CH:15][CH:16]=1)[CH:13](O)[CH:12]([C:18]1[CH:23]=[CH:22][C:21]([O:24][CH3:25])=[CH:20][CH:19]=1)[CH:11]1[CH:6]2[CH2:7][CH2:8][CH2:9][CH2:10]1.C1(C)C=CC(S(O)(=O)=O)=CC=1.C1C=CC=CC=1>C(OCC)(=O)C>[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:14](=[CH:15][CH:16]=1)[CH:13]=[C:12]([C:18]1[CH:23]=[CH:22][C:21]([O:24][CH3:25])=[CH:20][CH:19]=1)[CH:11]1[CH:6]2[CH2:7][CH2:8][CH2:9][CH2:10]1
Reactant: COc1ccc(C2C(O)c3ccc(OC)cc3C3CCCCC32)cc1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: CCOC(C)=O
Solvent: c1ccccc1
Product: COc1ccc(C2=Cc3ccc(OC)cc3C3CCCCC23)cc1
Reaction time: 1.5 h
Yield: 85.3 %

Procedure:
Combine 6-methoxy-10-(4-methoxy-phenyl)-1,2,3,4,4a,9,10,10a-octahydro-phenanthren-9-ol (184.3 mg, 0.54 mmol), p-toluene sulfonic acid (20.0 mg, 0.11 mmol), benzene (5 mL), stir, and reflux under nitrogen atmosphere. After 1.5 hours, cool reaction to ambient temperature, add ethyl acetate, wash sat sodium bicarbonate solution (aq), and then with brine, dry over sodium sulfate, and concentrate in vacuum. Flash chromatograph using 0% to 20% ethyl acetate/hexanes to yield the titled compound (147.6 mg, 85%) as a clear oil. TLC Rf=0.51 in 6:1 hexanes:ethyl acetate. 1H NMR (CDCl3): 7.53 (d, 2H, J=8.8 Hz), 7.10 (d, 1H, J=7.9 Hz), 6.93 (m, 3H), 6.72 (m, 2H), 3.85 (m, 6H), 3.21 (m, 1H), 2.79 (m, 1H), 2.49 (m, 1H), 1.80 (m, 1H), 1.58 (m, 4H), 1.30 (m, 2H).
Reaction SMILES: [F:1][C:2]([F:29])([F:28])[CH2:3][NH:4][C:5](=S)[NH:6][C:7]1[CH:12]=[CH:11][N:10]=[C:9]([S:13][CH2:14][CH2:15][N:16]2[C:20](=[O:21])[C:19]3=[CH:22][CH:23]=[CH:24][CH:25]=[C:18]3[C:17]2=[O:26])[N:8]=1.[NH3:30]>CN(C)C=O>[F:1][C:2]([F:29])([F:28])[CH2:3][N:4]=[C:5]([NH2:30])[NH:6][C:7]1[CH:12]=[CH:11][N:10]=[C:9]([S:13][CH2:14][CH2:15][N:16]2[C:20](=[O:21])[C:19]3=[CH:22][CH:23]=[CH:24][CH:25]=[C:18]3[C:17]2=[O:26])[N:8]=1
Reactant: N
Reactant: O=C1c2ccccc2C(=O)N1CCSc1nccc(NC(=S)NCC(F)(F)F)n1
Solvent: CN(C)C=O
Product: NC(=NCC(F)(F)F)Nc1ccnc(SCCN2C(=O)c3ccccc3C2=O)n1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
A mixture of 4-[3-(2,2,2-trifluoroethyl)thioureido]-2-(2-phthalimidoethylthio)pyrimidine (0.65 g.), dimethylformamide (10 ml.), ethanolic ammonia solution (5 ml.) and yellow mercuric oxide was stirred at room temperature for 4 hours. The mixture was filtered and the filtrate evaporated to dryness to give 4-[2-(2,2,2-trifluoroethyl)guanidino]-2-(2-phthalimidoethylthio)pyrimidine (0.62 g.), m.p. 192°-195°.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][C:4]1[CH:9]=[CH:8][C:7]([C:10]2[CH:15]=[CH:14][C:13]([CH:16]([CH3:25])[CH2:17][NH:18][S:19]([CH:22]([CH3:24])[CH3:23])(=[O:21])=[O:20])=[CH:12][CH:11]=2)=[CH:6][CH:5]=1.[CH3:26][O:27][C:28]1[CH:36]=[CH:35][CH:34]=[CH:33][C:29]=1[C:30](Cl)=[O:31]>>[CH3:26][O:27][C:28]1[CH:36]=[CH:35][CH:34]=[CH:33][C:29]=1[C:30]([NH:1][CH2:2][CH2:3][C:4]1[CH:5]=[CH:6][C:7]([C:10]2[CH:15]=[CH:14][C:13]([CH:16]([CH3:25])[CH2:17][NH:18][S:19]([CH:22]([CH3:24])[CH3:23])(=[O:21])=[O:20])=[CH:12][CH:11]=2)=[CH:8][CH:9]=1)=[O:31]
Reactant: CC(CNS(=O)(=O)C(C)C)c1ccc(-c2ccc(CCN)cc2)cc1
Reactant: COc1ccccc1C(=O)Cl
Product: COc1ccccc1C(=O)NCCc1ccc(-c2ccc(C(C)CNS(=O)(=O)C(C)C)cc2)cc1

Procedure:
The title compound was prepared following the method of Example 147 and using 1 mL of a stock solution of 0.6 g (1.8 mmol) of material from Example 50 and 16 mL (0.11 mmol) 2-methoxybenzoyl chloride. NMR was consistent with the proposed compound.
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([NH:8][C:9]2[CH:19]=[CH:18][C:12]([C:13]([O:15][CH2:16][CH3:17])=[O:14])=[CH:11][CH:10]=2)[C:5]([C:20](=[O:28])[NH:21][C:22]2[CH:23]=[N:24][CH:25]=[CH:26][CH:27]=2)=[CH:4][N:3]=1.[CH2:29]([NH:31][C:32]([NH2:34])=[O:33])[CH3:30].CC(C)([O-])C.[Na+].CC(C1C=C(C(C)C)C(C2C=CC=CC=2P(C2CCCCC2)C2CCCCC2)=C(C(C)C)C=1)C>O1CCOCC1>[CH2:29]([NH:31][C:32](=[O:33])[NH:34][C:2]1[CH:7]=[C:6]([NH:8][C:9]2[CH:19]=[CH:18][C:12]([C:13]([O:15][CH2:16][CH3:17])=[O:14])=[CH:11][CH:10]=2)[C:5]([C:20](=[O:28])[NH:21][C:22]2[CH:23]=[N:24][CH:25]=[CH:26][CH:27]=2)=[CH:4][N:3]=1)[CH3:30]
Reactant: CCNC(N)=O
Reactant: CCOC(=O)c1ccc(Nc2cc(Cl)ncc2C(=O)Nc2cccnc2)cc1
Agent: CC(C)(C)[O-]
Agent: CC(C)c1cc(C(C)C)c(-c2ccccc2P(C2CCCCC2)C2CCCCC2)c(C(C)C)c1
Agent: [Na+]
Solvent: C1COCCO1
Product: CCNC(=O)Nc1cc(Nc2ccc(C(=O)OCC)cc2)c(C(=O)Nc2cccnc2)cn1
Temperature: 120 °C

Procedure:
Compound ii (210 mg, 0.53 mmol) and N-ethylurea (93 mg, 1.1 mmol) were dissolved in degassed dioxane (2 mL) under an atmosphere of nitrogen. Sodium tert-butoxide (102 mg, 1.1 mmol), X-phos (2-(Dicyclohexylphosphino)-2′,4′,6′-tri-1-propyl-1,1′-biphenyl, 50 mg, 0.1 mmol) and palladium(0)bis(dibenzylideneacetone) (50 mg, 0.05 mmol) were added sequentially. The mixture was heated at 120° C. in a microwave reactor for 60 min. The mixture was cooled to RT, filtered then evaporated to dryness. The residue was purified by flash chromatography (40 g GraceResolv silica cartridge, 0-15% MeOH in DCM) to yield Compound 15 as an off white solid (160 mg, 68%). 1H NMR (400 MHz, DMSO-d6): δ 10.53 (s, 1H), 10.06 (s, 1H), 9.24 (s, 1H), 8.86 (s, 1H), 8.64 (s, 1H), 8.32 (d, J=4.8 Hz, 1H), 8.12 (d, J=7.6 Hz, 1H), 7.95 (d, J=8.4 Hz, 2H), 7.80 (m, 1H), 7.55 (s, 1H), 7.40 (d, J=8.8 Hz, 311), 4.32-4.27 (m, 2H), 3.17-3.14 (m, 2H), 1.34 (t, J=7.2 Hz, 3H), 1.12-1.09 (m, 3H). [M+H]+ m/z=449.16.
Reaction SMILES: Cl.[O:2]([NH2:4])[CH3:3].[CH3:5][N:6]1[C:15]2[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=2)[C:9](=O)[CH2:8][CH2:7]1>N1C=CC=CC=1>[CH3:3][O:2][N:4]=[C:9]1[C:10]2[C:15](=[CH:14][CH:13]=[CH:12][CH:11]=2)[N:6]([CH3:5])[CH2:7][CH2:8]1
Reactant: CN1CCC(=O)c2ccccc21
Reactant: CON
Agent: Cl
Solvent: c1ccncc1
Product: CON=C1CCN(C)c2ccccc21
Temperature: 25 °C
Reaction time: 8 h

Procedure:
Methoxylamine hydrochloride (0.88 g, 10.6 mmol) was added to a solution of Example 17A (1.55 g, 9.6 mmol) in pyridine (20 mL) and the mixture stirred overnight at ambient temperature. The mixture was concentrated under reduced pressure and ethyl acetate (200 mL) was added. The organic layer was washed twice with water (200 mL) and brine, dried over sodium sulfate, filtered, and concentrate under reduced pressure. The residue was chromatographed on silica gel eluting with 0-20% ethyl acetate in hexane to afford the title compound. 1H NMR (300 MHz, DMSO-d6) δ ppm 2.76 (t, J=6.61 Hz, 2H), 2.83 (s, 3H), 3.11 (t, J=6.61 Hz, 2H), 3.87 (s, 3H), 6.69 (t, J=7.46 Hz, 1H), 6.75 (d, J=8.48 Hz, 1H), 7.22 (td, J=7.80, 1.70 Hz, 1H), 7.73 (dd, J=7.80, 1.70 Hz, 1H). MS (DCI) m/z 191.07 (M+H)1.