Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [O:1]1[CH:5]=[CH:4][C:3]([C:6]2[CH:30]=[CH:29][C:9]([O:10][C:11]3[CH:16]=[CH:15][C:14]([S:17]([CH:20]4[CH:25]([C:26]([OH:28])=O)[NH:24][CH2:23][CH2:22][S:21]4)(=[O:19])=[O:18])=[CH:13][CH:12]=3)=[CH:8][CH:7]=2)=[CH:2]1.[Si](O[NH2:49])(C(C)(C)C)(C1C=CC=CC=1)C1C=CC=CC=1.C(Cl)CCl>ClCCl>[O:1]1[CH:5]=[CH:4][C:3]([C:6]2[CH:30]=[CH:29][C:9]([O:10][C:11]3[CH:12]=[CH:13][C:14]([S:17]([CH:20]4[CH:25]([C:26]([NH2:49])=[O:28])[NH:24][CH2:23][CH2:22][S:21]4)(=[O:18])=[O:19])=[CH:15][CH:16]=3)=[CH:8][CH:7]=2)=[CH:2]1
Reactant: CC(C)(C)[Si](ON)(c1ccccc1)c1ccccc1
Reactant: O=C(O)C1NCCSC1S(=O)(=O)c1ccc(Oc2ccc(-c3ccoc3)cc2)cc1
Solvent: ClCCCl
Solvent: ClCCl
Product: NC(=O)C1NCCSC1S(=O)(=O)c1ccc(Oc2ccc(-c3ccoc3)cc2)cc1
Reaction time: 18 h
Yield: 14.5 %

Procedure:
To a solution of 3(S)-4-(4-(4-(furan-3-yl)phenoxy)benzenesulfonyl-tetrahydro-2H-1,4-thiazine-3-carboxylic acid (293 mg, 0.62 mmol) and O-(tert-butyldiphenylsilyl)hydroxylamine (0.22 g, 0.8 mmol) in 5 mL of dichloromethane was added EDC (132 mg, 0.69 mmol). After 18 hours at 25° C., the mixture was partitioned between 1 N aq. sodium bisulfate and dichloromethane. The aqueous layer was extracted twice with dichloromethane, and the combined organic layers were washed with brine, dried over sodium sulfate, and concentrated. The residue was purified by chromatography on silica gel, eluting with a gradient from dichloromethane to 5% methanol in dichloromethane, to provide 3(S)-N-(tert-butyldiphenylsilyl)oxy-4-(4-(4-(furan-3-yl)phenoxy)benzenesulfonyl-tetrahydro-2H-1,4-thiazine-3-carboxamide (40 mg, 8%). FAB+MS Calcd for M+Cs+=859.1308 Obs 859.1274; 1HNMR (d6-DMSO): δ 10.81 (s, 1H), 8.17 (s, 1H), 7.74 (s, 1H), 7.67-7.61 (m, 8H), 7.45-7.30 (m, 6H), 7.10 (d, 2H, J=8.83 Hz), 7.00 (d, 2H, J=8.46 Hz), 6.94 (s, 1H), 4.06 (s, 1H), 3.95-3.89 (bm, 1H), 3.77-3.73 (bm, 1H), 2.87-2.78 (bm, 1H), 1.28 (s, 3H), 0.99 (s, 9H), 0.61 (s, 3H)
Reaction SMILES: C1CCN2C(=NCCC2)CC1.[CH3:12][S:13]([C:16]1[CH:21]=[CH:20][C:19]([NH:22][C:23]2[C:27]([C:28]([NH2:30])=[O:29])=[CH:26][NH:25][N:24]=2)=[CH:18][CH:17]=1)(=[O:15])=[O:14].[C:31]([CH:33]=[C:34]1[CH2:39][CH2:38][N:37]([C:40]([O:42][C:43]([CH3:46])([CH3:45])[CH3:44])=[O:41])[CH2:36][CH2:35]1)#[N:32].O>CN(C=O)C>[C:28]([C:27]1[C:23]([NH:22][C:19]2[CH:18]=[CH:17][C:16]([S:13]([CH3:12])(=[O:14])=[O:15])=[CH:21][CH:20]=2)=[N:24][N:25]([C:34]2([CH2:33][C:31]#[N:32])[CH2:35][CH2:36][N:37]([C:40]([O:42][C:43]([CH3:44])([CH3:45])[CH3:46])=[O:41])[CH2:38][CH2:39]2)[CH:26]=1)(=[O:29])[NH2:30]
Reactant: CC(C)(C)OC(=O)N1CCC(=CC#N)CC1
Reactant: CS(=O)(=O)c1ccc(Nc2n[nH]cc2C(N)=O)cc1
Solvent: C1CCC2=NCCCN2CC1
Solvent: CN(C)C=O
Solvent: O
Product: CC(C)(C)OC(=O)N1CCC(CC#N)(n2cc(C(N)=O)c(Nc3ccc(S(C)(=O)=O)cc3)n2)CC1
Temperature: 50 °C

Procedure:
DBU (0.118 mL, 0.785 mmol) was added 3-((4-(methylsulfonyl)phenyl)amino)-1H-pyrazole-4-carboxamide (Intermediate 34-2) (200 mg, 0.714 mmol) and tert-butyl 4-(cyanomethylidene)piperidine-1-carboxylate (Intermediate 19-1) (317 mg, 1.43 mmol) stirred in DMF (3 mL) and the mixture was heated to 50° C. for 5 h. The reaction mixture was cooled to 23° C., water was added to the reaction mixture and the mixture was extracted with ethyl acetate. The combined organic fractions were dried (Na2SO4), filtered and the solvent was evaporated under reduced pressure. The residue was purified by column chromatography on silica gel eluting with EtOAc/hexanes to afford the title compound.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2([CH3:37])[C:12]([C:14]3[CH:19]=[CH:18][C:17]([Cl:20])=[CH:16][CH:15]=3)([CH3:13])[N:11]([C:21](Cl)=[O:22])[C:10]([C:24]3[CH:29]=[CH:28][C:27]([C:30]([OH:33])([CH3:32])[CH3:31])=[CH:26][C:25]=3[O:34][CH2:35][CH3:36])=[N:9]2)=[CH:4][CH:3]=1.Cl.Cl.[N:40]1([CH2:46][CH2:47][NH:48][S:49]([CH3:52])(=[O:51])=[O:50])[CH2:45][CH2:44][NH:43][CH2:42][CH2:41]1>>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C@@:8]2([CH3:37])[C@:12]([C:14]3[CH:15]=[CH:16][C:17]([Cl:20])=[CH:18][CH:19]=3)([CH3:13])[N:11]([C:21]([N:43]3[CH2:44][CH2:45][N:40]([CH2:46][CH2:47][NH:48][S:49]([CH3:52])(=[O:51])=[O:50])[CH2:41][CH2:42]3)=[O:22])[C:10]([C:24]3[CH:29]=[CH:28][C:27]([C:30]([OH:33])([CH3:31])[CH3:32])=[CH:26][C:25]=3[O:34][CH2:35][CH3:36])=[N:9]2)=[CH:4][CH:3]=1
Reactant: CS(=O)(=O)NCCN1CCNCC1
Reactant: CCOc1cc(C(C)(C)O)ccc1C1=NC(C)(c2ccc(Cl)cc2)C(C)(c2ccc(Cl)cc2)N1C(=O)Cl
Agent: Cl
Product: CCOc1cc(C(C)(C)O)ccc1C1=N[C@@](C)(c2ccc(Cl)cc2)[C@@](C)(c2ccc(Cl)cc2)N1C(=O)N1CCN(CCNS(C)(=O)=O)CC1

Procedure:
In a manner analogous to the method described in example 5, rac-(4S*,5R*)-4,5-bis-(4-chloro-phenyl)-2-[2-ethoxy-4-(1-hydroxy-1-methyl-ethyl)-phenyl]-4,5-dimethyl-4,5-dihydro-imidazole-1-carbonyl chloride was reacted with N-(2-piperazin-1-yl-ethyl)-methanesulfonamide dihydrochloride (prepared as described in Fotouhi, N. et al. WO 2005110996) to give the title compound as a racemic mixture. The enantiomers were then separated by supercritical fluid chromatography (Berger Instrument Multi-Gram II, Daicel ChiralPak OD-H 3×25 cm, 35° C. at 100 bar, eluting with 30% methanol in carbon dioxide). HR-MS (ES, m/z) calculated for C36H45N5O5SCl2 [(M+H)+] 730.2591, observed 730.2585.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([NH:14][C:15]([S-])=[NH:16])[CH:5]=[CH:6][C:7]=1[N:8]1[C:12]([CH3:13])=[N:11][CH:10]=[N:9]1.I.[Cl:19][CH2:20][CH2:21][CH2:22][CH2:23][CH:24]([C:28]1[CH:33]=[CH:32][C:31]([O:34][C:35]([F:38])([F:37])[F:36])=[C:30]([F:39])[CH:29]=1)[C:25](O)=O.CN1CCOCC1.C(N(CC)C(C)C)(C)C.[NH2:56][NH2:57]>>[Cl:19][CH2:20][CH2:21][CH2:22][CH2:23][CH:24]([C:25]1[NH:57][N:56]=[C:15]([NH:14][C:4]2[CH:5]=[CH:6][C:7]([N:8]3[C:12]([CH3:13])=[N:11][CH:10]=[N:9]3)=[C:2]([F:1])[CH:3]=2)[N:16]=1)[C:28]1[CH:33]=[CH:32][C:31]([O:34][C:35]([F:36])([F:37])[F:38])=[C:30]([F:39])[CH:29]=1
Reactant: NN
Reactant: O=C(O)C(CCCCCl)c1ccc(OC(F)(F)F)c(F)c1
Reactant: Cc1ncnn1-c1ccc(NC(=N)[S-])cc1F
Agent: I
Solvent: CN1CCOCC1
Solvent: CCN(C(C)C)C(C)C
Product: Cc1ncnn1-c1ccc(Nc2n[nH]c(C(CCCCCl)c3ccc(OC(F)(F)F)c(F)c3)n2)cc1F

Procedure:
3-Fluoro-4-(5-methyl-1H-1,2,4-triazol-1-yl)phenylcarbamimidothioate, hydroiodide (0.330 g, 0.839 mmol, from preparation C) and 6-chloro-2-(3-fluoro-4-(trifluoromethoxy)phenyl)hexanoic acid (0.345 g, 1.05 mmol, from preparation AY) were coupled [N-methylmorpholine (0.461 mL, 4.20 mmol) was substituted for N,N-diisopropylethylamine] and then reacted with hydrazine (0.132 mL, 4.20 mmol) using a procedure analogous to Step A of Example 13. After an aqueous workup, the crude product, 5-(5-chloro-1-(3-fluoro-4-(trifluoromethoxy)phenyl)pentyl)-N-(3-fluoro-4-(5-methyl-1H-1,2,4-triazol-1-yl)phenyl)-1H-1,2,4-triazol-3-amine was obtained as a brown solid. LC-MS (M+H)+ 542.1. The crude product was used in the next step without purification.
Reaction SMILES: [CH:1]1([N:7]2[C:12](=[O:13])[C:11]([C:14]([NH:16][CH2:17][C:18]([OH:20])=[O:19])=[O:15])=[C:10]([OH:21])[N:9]([CH:22]3[CH2:27][CH2:26][CH2:25][NH:24][CH2:23]3)[C:8]2=[O:28])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[C:29](O)(=[O:31])[CH3:30]>C(OC(=O)C)(=O)C.C(OCC)(=O)C>[C:29]([N:24]1[CH2:25][CH2:26][CH2:27][CH:22]([N:9]2[C:10]([OH:21])=[C:11]([C:14]([NH:16][CH2:17][C:18]([OH:20])=[O:19])=[O:15])[C:12](=[O:13])[N:7]([CH:1]3[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]3)[C:8]2=[O:28])[CH2:23]1)(=[O:31])[CH3:30]
Reactant: CC(=O)O
Reactant: O=C(O)CNC(=O)c1c(O)n(C2CCCNC2)c(=O)n(C2CCCCC2)c1=O
Solvent: CC(=O)OC(C)=O
Solvent: CCOC(C)=O
Product: CC(=O)N1CCCC(n2c(O)c(C(=O)NCC(=O)O)c(=O)n(C3CCCCC3)c2=O)C1
Yield: 31 %

Procedure:
A solution of N-{[3-cyclohexyl-6-hydroxy-2,4-dioxo-1-(3-piperidinyl)-1,2,3,4-tetrahydro-5-pyrimidinyl]carbonyl}glycine (500 mg, 1.26 mmoles) in acetic acid (5.0 mL) and acetic anhydride (5.0 mL) was heated at 130° C. for 2 hours. The mixture was cooled, diluted with ethyl acetate and washed with 1 molar hydrochloric acid (×3), dried and evaporated. Flash chromatography (dichloromethane to 4% methanol-0.1% acetic acid in dichloromethane) and recrystallization from ethanol-water gave the title compound (170 mg, 31%). 1H NMR (400 MHz, DMSO-d6) δ ppm 13.10 (br. s., 1 H), 10.17 (s, 1 H), 4.46-4.73 (m, 2 H), 4.25-4.46 (m, 1H), 4.13 (d, J=5.56 Hz, 2 H), 3.67-3.92 (m, J=4.55 Hz, 1 H), 3.24-3.43 (m, 1 H), 2.94 (t, J=12.63 Hz, 1 H), 2.34-2.48 (m, 1 H), 2.25 (m, 2 H), 1.97, 2.02 (2×s, 3 H), 1.69-1.87 (m, 4 H), 1.62 (m, 3 H), 1.41-1.57 (m, 1 H), 1.19-1.37 (m, 2 H), 0.97-1.18 (m, 1 H)
Reaction SMILES: Cl[C:2]1C=CC=C(C(OO)=O)[CH:3]=1.[CH2:12]([N:14]([C:26]1[CH:31]=[CH:30][C:29]([C:32]([F:35])([F:34])[F:33])=[CH:28][N:27]=1)[C:15](=[O:25])[C:16]1[C:21](SCC)=[CH:20][CH:19]=[CH:18][N:17]=1)[CH3:13].C(=O)(O)[O-].[Na+].[S:41]([O-:45])([O-])(=[O:43])=S.[Na+].[Na+]>C(Cl)(Cl)Cl>[CH2:12]([N:14]([C:26]1[CH:31]=[CH:30][C:29]([C:32]([F:33])([F:35])[F:34])=[CH:28][N:27]=1)[C:15](=[O:25])[C:16]1[C:21]([S:41]([CH2:2][CH3:3])(=[O:45])=[O:43])=[CH:20][CH:19]=[CH:18][N:17]=1)[CH3:13]
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: CCSc1cccnc1C(=O)N(CC)c1ccc(C(F)(F)F)cn1
Reactant: O=S([O-])([O-])=S
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClC(Cl)Cl
Product: CCN(C(=O)c1ncccc1S(=O)(=O)CC)c1ccc(C(F)(F)F)cn1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
0.21 g of m-chloroperbenzoic acid (purity of 68%) was added to a mixture of 0.13 g of N-ethyl-3-ethylsulfanyl-N-(5-trifluoromethylpyridin-2-yl)picolinamide (Compound of Present Invention 26) and 4 mL of chloroform under ice cooling, and the mixture was stirred at room temperature for 3 hours. A saturated aqueous sodium bicarbonate solution and a saturated aqueous sodium thiosulfate solution were poured to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was dried over anhydrous sodium sulfate and then concentrated under reduced pressure, and the resulting residue was applied to a silica gel column chromatography to obtain 0.13 g of N-ethyl-3-ethylsulfonyl-N-(5-trifluoromethylpyridin-2-yl)picolinamide (hereinafter, referred to as Compound of Present Invention 27).
Reaction SMILES: [H-].[Na+].[O:3]=[C:4]1[CH2:9][CH2:8][N:7]([C:10]2[CH:23]=[CH:22][C:13]([CH2:14][CH:15]3[S:19][C:18](=[O:20])[NH:17][C:16]3=[O:21])=[CH:12][CH:11]=2)[CH2:6][CH2:5]1.CN(C=O)C.Br[CH2:30][C:31]([O:33][CH2:34][CH3:35])=[O:32]>O>[O:20]=[C:18]1[N:17]([CH2:30][C:31]([O:33][CH2:34][CH3:35])=[O:32])[C:16](=[O:21])[CH:15]([CH2:14][C:13]2[CH:12]=[CH:11][C:10]([N:7]3[CH2:8][CH2:9][C:4](=[O:3])[CH2:5][CH2:6]3)=[CH:23][CH:22]=2)[S:19]1
Reactant: O=C1CCN(c2ccc(CC3SC(=O)NC3=O)cc2)CC1
Reactant: CCOC(=O)CBr
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CCOC(=O)CN1C(=O)SC(Cc2ccc(N3CCC(=O)CC3)cc2)C1=O
Temperature: 25 °C
Reaction time: 1 h
Yield: 45.8 %

Procedure:
Sodium hydride (60% in mineral oil, 66 mg, 1.65 mmol) was added into a mixture of 5-[4-(4-oxo-1-piperidineyl)benzyl]-1,3-thiazolidine-2,4-dione (500 mg, 1.65 mmol) (which was obtained in Example 38) and DMF. The mixture was stirred for one hour at room temperature, and then ethyl bromoacetate (0.27 mL, 2.47 mmol) was added. The new mixture was stirred for 30 minutes, poured into water, and extracted with ethyl acetate. The organic extracts were dried over MgSO4. Evaporation and purification by flash chromatography (hexanes/ethyl acetate 2/1) gave a viscous oil (295 mg, 46% yield); 1H NMR (300 MHz, DMSO-d6) δ 1.20 (t, J=7.16 Hz, 3H), 2.40 (m, 4H), 2.95-3.00 (m, 1H), 3.4 (m, 1H), 3.60 (m, 2H), 4.10 (q, J=7.16 Hz, 2H), 4.30 (s, 2H), 6.97 (m, 2H), 7.16 (m, 2H); MS (ES) m/z: 391 (MH+);
Reaction SMILES: CO[C:3]1[CH:8]=[CH:7]C=[CH:5][C:4]=1O.C=O.[CH3:12][O:13][C:14]1[CH:22]=[CH:21][C:17]([CH2:18][CH2:19][NH2:20])=[CH:16][CH:15]=1.[O:23]1[CH2:28][CH2:27][O:26][CH2:25][CH2:24]1>>[CH3:27][O:26][C:25]1[C:24]2[O:23][CH2:28][N:20]([CH2:19][CH2:18][C:17]3[CH:21]=[CH:22][C:14]([O:13][CH3:12])=[CH:15][CH:16]=3)[CH2:7][C:8]=2[CH:3]=[CH:4][CH:5]=1
Reactant: COc1ccc(CCN)cc1
Reactant: COc1ccccc1O
Reactant: C1COCCO1
Agent: C=O
Product: COc1ccc(CCN2COc3c(cccc3OC)C2)cc1

Procedure:
To 20 ml. of dioxane are added 5 g. of ortho-methoxyphenol, 9 ml. of 37 % formalin and 6.7 g. of para-methoxyphenethylamine. The mixture is heated on reflux for 4 hours and concentrated to dryness under reduced pressure. The residue is purified by column chromatography on silica gel with a mixture of acetone and benzene (1:4). The resultant oily substance is left standing at cool place for one month to be solidified. Recrystallization from petroleum ether yields 8-methoxy-3-(4-methoxyphenethyl)-3,4-dihydro-2H-1,3-benzoxazine as melting at 69°-70° C.
Reaction SMILES: [O:1]=[C:2]([C:51]1[CH:56]=[CH:55][CH:54]=[CH:53][CH:52]=1)[C:3]([NH:5][C:6]1[CH:11]=[CH:10][CH:9]=[C:8]([C:12]2[C:20]3[C:15](=[CH:16][CH:17]=[C:18]([C:21]4[N:25]=[CH:24][N:23](C(C5C=CC=CC=5)(C5C=CC=CC=5)C5C=CC=CC=5)[N:22]=4)[CH:19]=3)[N:14](C3CCCCO3)[N:13]=2)[CH:7]=1)=[O:4]>Cl.O1CCOCC1>[NH:23]1[CH:24]=[N:25][C:21]([C:18]2[CH:19]=[C:20]3[C:15](=[CH:16][CH:17]=2)[NH:14][N:13]=[C:12]3[C:8]2[CH:7]=[C:6]([NH:5][C:3](=[O:4])[C:2](=[O:1])[C:51]3[CH:52]=[CH:53][CH:54]=[CH:55][CH:56]=3)[CH:11]=[CH:10][CH:9]=2)=[N:22]1
Reactant: O=C(Nc1cccc(-c2nn(C3CCCCO3)c3ccc(-c4ncn(C(c5ccccc5)(c5ccccc5)c5ccccc5)n4)cc23)c1)C(=O)c1ccccc1
Agent: Cl
Solvent: C1COCCO1
Product: O=C(Nc1cccc(-c2n[nH]c3ccc(-c4nc[nH]n4)cc23)c1)C(=O)c1ccccc1
Temperature: 25 °C
Reaction time: 4 h
Yield: 14 %

Procedure:
2-Oxo-N-(3-{1-perhydro-2H-pyran-2-yl-5[1-(triphenylmethyl)(1,2,4-triazol-3-yl)](1H-indazol-3-yl)}phenyl)-2-phenylacetamide was dissolved in 4 mL of 4.0 N HCl in 1,4-dioxane and the reaction was stirred at room temperature for 4 h. After neutralization with aqueous NaHCO3, the crude product was extracted in ethyl acetate and purified by preparative HPLC (0.014 g, 14% yield over 2 steps): 1H NMR (CD3OD) δ 8.80 (s, 1H), 8.39 (t, 1H), 8.21 (m, 2H), 8.13 (d, 1H), 7.94 (dt, 1H), 7.89 (dt, 1H), 7.82-7.69 (m, 3H), 7.64-7.57 (m, 3H); ES-MS (m/z) 409 [M+H]+.
Reaction SMILES: [C:1]([C:4]1[C:21]([OH:22])=[CH:20][C:7]([O:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][C:14]([CH3:19])([CH3:18])[C:15]([OH:17])=[O:16])=[C:6]([CH2:23][CH3:24])[CH:5]=1)(=O)[CH3:2].Cl.[NH2:26][OH:27].C([O-])(=O)C.[Na+]>CO>[OH:27][N:26]=[CH:2][CH2:1][C:4]1[C:21]([OH:22])=[CH:20][C:7]([O:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][C:14]([CH3:19])([CH3:18])[C:15]([OH:17])=[O:16])=[C:6]([CH2:23][CH3:24])[CH:5]=1
Reactant: CCc1cc(C(C)=O)c(O)cc1OCCCCCC(C)(C)C(=O)O
Reactant: NO
Agent: CC(=O)[O-]
Agent: Cl
Agent: [Na+]
Solvent: CO
Product: CCc1cc(CC=NO)c(O)cc1OCCCCCC(C)(C)C(=O)O
Temperature: 25 °C
Yield: 42.5 %

Procedure:
A mixture of 7.1 g of 7-(4-acetyl-2-ethyl-5-hydroxyphenoxy)-2,2-dimethylheptanoic acid, 0.149 g of hydroxylamine hydrochloride, 0.176 g of sodium acetate, and 50 ml of methanol were heated at reflux for 48 hours. The reaction mixture was allowed to cool to room temperature and the resulting solid collected by filtration. The solid was crystallized from methylene chloride/hexane to provide 0.32 g of the desired titled product.
Reaction SMILES: [F:1][C:2]1[S:6][C:5]([C:7]23[CH2:15][N:14]([C:16]4[N:21]=[CH:20][CH:19]=[CH:18][N:17]=4)[CH2:13][CH:12]2[CH2:11][S:10][C:9]([NH:22]C(=O)C2C=CC=CC=2)=[N:8]3)=[CH:4][CH:3]=1.N1C=CC=CC=1.Cl.CON>C(O)C.C(OCC)(=O)C>[F:1][C:2]1[S:6][C:5]([C:7]23[CH2:15][N:14]([C:16]4[N:17]=[CH:18][CH:19]=[CH:20][N:21]=4)[CH2:13][CH:12]2[CH2:11][S:10][C:9]([NH2:22])=[N:8]3)=[CH:4][CH:3]=1
Reactant: O=C(NC1=NC2(c3ccc(F)s3)CN(c3ncccn3)CC2CS1)c1ccccc1
Agent: CON
Agent: Cl
Solvent: CCO
Solvent: CCOC(C)=O
Solvent: c1ccncc1
Product: NC1=NC2(c3ccc(F)s3)CN(c3ncccn3)CC2CS1
Temperature: 58 °C
Yield: 85.1 %

Procedure:
To a stirred solution of the N-[7a-(5-fluoro-2-thienyl)-6-pyrimidin-2-yl-4,4a,5,7-tetrahydropyrrolo[3,4-d][1,3]thiazin-2-yl]benzamide (100 mg, 0.228 mmol) in ethanol (4.6 mL) is added pyridine (0.184 mL, 2.28 mmol) and O-methylhydroxylamine hydrochloride (190 mg, 2.28 mmol). The resulting mixture is heated at 58° C. for 15 hours. The solution is allowed to cool to room temperature, diluted with ethyl acetate (25 mL), and washed with dilute sodium bicarbonate ((20 mL) prepared from water (10 mL) and saturated sodium bicarbonate (10 mL)). The aqueous phase is extracted with ethyl acetate (25 mL). The combined organic extracts are dried over sodium sulfate, filtered, and concentrated. The residue is purified by silica gel flash chromatography eluting with dichloromethane/7 M ammonia in methanol, gradient from 99:1 to 95:5, to give the title compound (65 mg, 0.194 mmol, 85%) as a white solid. ES/MS (m/e): 336 (M+H).
Reaction SMILES: [C:1]([Li])([CH3:4])([CH3:3])[CH3:2].CC[O:8][CH2:9][CH3:10].[CH3:11][CH2:12]OCC.[CH3:16][CH2:17][CH2:18]CC>>[CH2:3]1[C:1]2([CH2:4][CH2:18][CH2:17][CH2:16][CH2:10][C:9]2=[O:8])[CH2:2][CH2:12][CH2:11]1
Reactant: CCOCC
Reactant: [Li]C(C)(C)C
Reactant: CCCCC
Product: O=C1CCCCCC12CCCC2
Temperature: -100 °C

Procedure:
t-Butyl lithium (1.7M in pentane, 20.0 ml., 34 mmol.) was slowly added to ether (38 ml.) at -20° C. as the reaction was further cooled to -100° C. in a methanol/dry ice/liquid nitrogen bath. To this -100° C. solution was added the product from part (c) (5.0 g., 16.1 mmol.) in 2:1 ether/pentane (3 ml.) over 35 minutes, maintaining the temperature below -97° C. The reaction was warmed to -50° C. over two hours then quenched with a saturated solution of ammonium chloride, extracted with ethyl acetate (4×100 ml.), washed with brine, dried (magnesium sulfate), filtered and concentrated to give a clear oil (mixture of desired product and the iodo starting material).
Reaction SMILES: [CH2:1]([C:5]1[CH:6]=[C:7]([CH:20]=O)[C:8]([OH:19])=[C:9]([C:11]2[CH:16]=[CH:15][C:14]([Cl:17])=[C:13]([Cl:18])[CH:12]=2)[CH:10]=1)[CH2:2][CH2:3][CH3:4].[C:22]([NH2:26])([CH3:25])([CH3:24])[CH3:23]>>[ClH:17].[CH2:1]([C:5]1[CH:10]=[C:9]([C:11]2[CH:16]=[CH:15][C:14]([Cl:17])=[C:13]([Cl:18])[CH:12]=2)[C:8]([OH:19])=[C:7]([CH2:20][NH:26][C:22]([CH3:25])([CH3:24])[CH3:23])[CH:6]=1)[CH2:2][CH2:3][CH3:4]
Reactant: CC(C)(C)N
Reactant: CCCCc1cc(C=O)c(O)c(-c2ccc(Cl)c(Cl)c2)c1
Product: CCCCc1cc(CNC(C)(C)C)c(O)c(-c2ccc(Cl)c(Cl)c2)c1
Product: Cl

Procedure:
5-Butyl-3-((tert-butylamino)methyl)-3′,4′-dichloro-[1,1′-biphenyl]-2-ol hydrochloride was prepared as a white solid using the procedure described in Example 9 from 5-butyl-3′,4′-dichloro-2-hydroxy-[1,1′-biphenyl]-3-carbaldehyde and tert-butylamine.
Reaction SMILES: [OH:1][C@H:2]1[CH2:19][CH2:18][C@@:17]2([CH3:20])[C@@H:4]([CH2:5][CH2:6][C@:7]3([CH3:36])[C@@H:16]2[CH2:15][CH2:14][C@H:13]2[C@@:8]3([CH3:35])[CH2:9][CH2:10][C@@:11]3([NH:27][C:28](=[O:34])[O:29][C:30]([CH3:33])([CH3:32])[CH3:31])[CH2:23][CH2:22][C@@H:21]([C:24]([CH3:26])=[CH2:25])[C@@H:12]32)[C:3]1([CH3:38])[CH3:37].[Cr](Cl)([O-])(=O)=O.[NH+]1C=CC=CC=1>ClCCl>[CH3:35][C@:8]12[C@@:7]3([CH3:36])[C@@H:16]([C@:17]4([CH3:20])[C@@H:4]([CH2:5][CH2:6]3)[C:3]([CH3:37])([CH3:38])[C:2](=[O:1])[CH2:19][CH2:18]4)[CH2:15][CH2:14][C@@H:13]1[C@H:12]1[C@H:21]([C:24]([CH3:26])=[CH2:25])[CH2:22][CH2:23][C@:11]1([NH:27][C:28](=[O:34])[O:29][C:30]([CH3:33])([CH3:32])[CH3:31])[CH2:10][CH2:9]2
Reactant: C=C(C)[C@@H]1CC[C@]2(NC(=O)OC(C)(C)C)CC[C@]3(C)[C@H](CC[C@@H]4[C@@]5(C)CC[C@H](O)C(C)(C)[C@@H]5CC[C@]43C)[C@@H]12
Agent: O=[Cr](=O)([O-])Cl
Agent: c1cc[nH+]cc1
Solvent: ClCCl
Product: C=C(C)[C@@H]1CC[C@]2(NC(=O)OC(C)(C)C)CC[C@]3(C)[C@H](CC[C@@H]4[C@@]5(C)CCC(=O)C(C)(C)[C@@H]5CC[C@]43C)[C@@H]12
Temperature: 25 °C
Reaction time: 5 h

Procedure:
To a solution of the resulting tert-butyl ((1R,3aS,5aR,5bR,7aR,9S,11aR,11bR,13aR,13bR)-9-hydroxy-5a,5b,8,8,11a-pentamethyl-1-(prop-1-en-2-yl)icosahydro-1H-cyclopenta[a]chrysen-3a-yl)carbamate in dichloromethane (100 mL) was added pyridinium chlorochromate (4.69 g, 21.74 mmol). The mixture was stirred at rt for 5 h then an additional 1.0 g of PCC was added and the mixture was stirred at rt for 1 h. The mixture was filtered through a plug of silica gel and celite which was washed with a solution of 25% ethyl acetate in hexanes. The filtrate was concentrated under reduced pressure to give tert-butyl ((1R,3 aS,5aR,5bR,7aR,11aR,11bR,13aR,13bR)-5a,5b,8,8,11a-pentamethyl-9-oxo-1-(prop-1-en-2-yl)icosahydro-1H-cyclopenta[a]chrysen-3a-yl)carbamate as a light-yellow foam. 1H NMR (500 MHz, chloroform-d) δ=4.74 (d, J=1.7 Hz, 1H), 4.63 (t, J=1.7 Hz, 1H), 4.34 (br. s., 1H), 2.65-2.34 (m, 5H), 2.05-1.88 (m, 2H), 1.71 (s, 3H), 1.47 (s, 9H), 1.10 (s, 3H), 1.08 (s, 3H), 1.05 (s, 3H), 0.99 (s, 3H), 0.96 (s, 3H), 1.76-0.93 (m, 18H).
Reaction SMILES: [C:1]([C:5]1[C:6](=[O:29])[CH2:7][CH:8]([C:12]2[CH:17]=[CH:16][CH:15]=[C:14]([O:18][C:19]3[CH:24]=[CH:23][CH:22]=[C:21]([S:25]([CH3:28])(=[O:27])=[O:26])[CH:20]=3)[CH:13]=2)[CH2:9][C:10]=1[OH:11])(=O)[CH2:2][CH3:3].Cl.[CH2:31]([O:33][NH2:34])[CH3:32].C([O-])(=O)C.[Na+].O>C(Cl)Cl.C(O)C>[CH2:31]([O:33][N:34]=[C:1]([C:5]1[C:6](=[O:29])[CH2:7][CH:8]([C:12]2[CH:17]=[CH:16][CH:15]=[C:14]([O:18][C:19]3[CH:24]=[CH:23][CH:22]=[C:21]([S:25]([CH3:28])(=[O:27])=[O:26])[CH:20]=3)[CH:13]=2)[CH2:9][C:10]=1[OH:11])[CH2:2][CH3:3])[CH3:32]
Reactant: CCON
Reactant: CCC(=O)C1=C(O)CC(c2cccc(Oc3cccc(S(C)(=O)=O)c3)c2)CC1=O
Agent: CC(=O)[O-]
Agent: Cl
Agent: [Na+]
Solvent: O
Solvent: ClCCl
Solvent: CCO
Product: CCON=C(CC)C1=C(O)CC(c2cccc(Oc3cccc(S(C)(=O)=O)c3)c2)CC1=O
Reaction time: 24 h

Procedure:
A solution of 3.5 g (8.5 mmol) of 2-propionyl-3-hydroxy-5-(3-(3-(methylsulfonyl)phenoxy)phenyl)-cyclohex-2-en-1-one in 10 mL of methylene chloride and 20 mL of absolute ethanol was treated with 1.0 g (1.0 mmol) of ethoxyamine hydrochloride and 0.9 g (1.0 mmol) of anhydrous sodium acetate. After stirring for 24 hours, the mixture was poured into 100 mL of water and extracted thrice with 20 mL portions of methylene chloride. The combined extracts were dried over MgSO4, filtered and passed through a short column of silica gel, eluting with about 200 mL of methylene chloride. Evaporation of the eluent afforded the above named product as a light yellow oil. The product was recovered in a yield of 3.0 g (77 percent of theoretical). 1H NMR (CDCl3) δ1.08-1.49 (m, 6H, both --CH2CH3 's), 2.60-3.65 (m includes s at 3.05 for CH3SO2 --, 10H), 4.12 (q, J=7Hz, 2H, --OCH2), 6.85-7.85 (m, 8H, aromatics), 14.9 (broad s, 1H, enol H) (Compound 1).
Reaction SMILES: Cl.[C:2]([NH:5][C@H:6]([C:8]1[CH:13]=[C:12]([Cl:14])[CH:11]=[CH:10][C:9]=1[CH:15]1[CH2:20][CH2:19][N:18](C(OC(C)(C)C)=O)[CH2:17][CH2:16]1)[CH3:7])(=[O:4])[CH3:3]>C(OCC)(=O)C.C(Cl)Cl>[ClH:14].[Cl:14][C:12]1[CH:11]=[CH:10][C:9]([CH:15]2[CH2:16][CH2:17][NH:18][CH2:19][CH2:20]2)=[C:8]([C@@H:6]([NH:5][C:2](=[O:4])[CH3:3])[CH3:7])[CH:13]=1
Reactant: CC(=O)N[C@@H](C)c1cc(Cl)ccc1C1CCN(C(=O)OC(C)(C)C)CC1
Agent: Cl
Solvent: ClCCl
Solvent: CCOC(C)=O
Product: CC(=O)N[C@@H](C)c1cc(Cl)ccc1C1CCNCC1
Reaction time: 3 h

Procedure:
A saturated solution of hydrogen chloride in ethyl acetate (15 mL) was added to a stirred solution of tert-butyl 4-{2-[(1S)-1-(acetylamino)ethyl]-4-chlorophenyl}piperidine-1-carboxylate (3.66 g, 9.61 mmol) in methylene chloride (15 mL) at 0° C. After 3 h, the volatiles were evaporated in vacuo, and the crude residue triturated twice with dry diethyl ether to give the title compound as a colorless solid.