Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([CH:3]1[CH:29]=[C:28]([CH3:30])[CH2:27][CH:26]([CH3:31])[CH2:25][CH:24]([O:32][CH3:33])[CH:23]2[O:34][C:19]([OH:38])([CH:20]([CH3:37])[CH2:21][CH:22]2[O:35][CH3:36])[C:18](=[O:39])[C:17](=[O:40])[N:16]2[CH:11]([CH2:12][CH2:13][CH2:14][CH2:15]2)[C:10](=[O:41])[O:9][CH:8]([C:42]([CH3:53])=[CH:43][CH:44]2[CH2:49][CH2:48][CH:47]([OH:50])[CH:46]([O:51][CH3:52])[CH2:45]2)[CH:7]([CH3:54])[CH:6]([O:55][Si:56]([C:59]([CH3:62])([CH3:61])[CH3:60])([CH3:58])[CH3:57])[CH2:5][C:4]1=[O:63])[CH3:2].ClC(Cl)(Cl)C(=N)O[CH2:68][C:69]1[CH:74]=[CH:73][CH:72]=[C:71]([CH2:75][O:76][Si:77]([C:80]([CH3:83])([CH3:82])[CH3:81])([CH3:79])[CH3:78])[CH:70]=1.FC(F)(F)S(O)(=O)=O>>[CH2:1]([CH:3]1[CH:29]=[C:28]([CH3:30])[CH2:27][CH:26]([CH3:31])[CH2:25][CH:24]([O:32][CH3:33])[CH:23]2[O:34][C:19]([OH:38])([CH:20]([CH3:37])[CH2:21][CH:22]2[O:35][CH3:36])[C:18](=[O:39])[C:17](=[O:40])[N:16]2[CH:11]([CH2:12][CH2:13][CH2:14][CH2:15]2)[C:10](=[O:41])[O:9][CH:8]([C:42]([CH3:53])=[CH:43][CH:44]2[CH2:49][CH2:48][CH:47]([O:50][CH2:68][C:69]3[CH:74]=[CH:73][CH:72]=[C:71]([CH2:75][O:76][Si:77]([C:80]([CH3:83])([CH3:82])[CH3:81])([CH3:79])[CH3:78])[CH:70]=3)[CH:46]([O:51][CH3:52])[CH2:45]2)[CH:7]([CH3:54])[CH:6]([O:55][Si:56]([C:59]([CH3:60])([CH3:61])[CH3:62])([CH3:58])[CH3:57])[CH2:5][C:4]1=[O:63])[CH3:2]
Reactant: CCC1C=C(C)CC(C)CC(OC)C2OC(O)(C(=O)C(=O)N3CCCCC3C(=O)OC(C(C)=CC3CCC(O)C(OC)C3)C(C)C(O[Si](C)(C)C(C)(C)C)CC1=O)C(C)CC2OC
Reactant: CC(C)(C)[Si](C)(C)OCc1cccc(COC(=N)C(Cl)(Cl)Cl)c1
Agent: O=S(=O)(O)C(F)(F)F
Product: CCC1C=C(C)CC(C)CC(OC)C2OC(O)(C(=O)C(=O)N3CCCCC3C(=O)OC(C(C)=CC3CCC(OCc4cccc(CO[Si](C)(C)C(C)(C)C)c4)C(OC)C3)C(C)C(O[Si](C)(C)C(C)(C)C)CC1=O)C(C)CC2OC
Temperature: 25 °C

Procedure:
To a solution of 17-ethyl-1-hydroxy-14-(tert-butyldimethylsiloxy)-12-[2'-(4"-hydroxy-3"-methoxycyclohexyl)-1'-methylvinyl]-23,25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-azatricyclo[22.3.1.04,9 ]octacos-18-ene-2,3,10,16-tetraone (230 mg in 3 ml 33% methylene chloride in cyclohexane) was added m-(tert-butyldimethylsiloxymethyl)-benzyl trichloroacetimidate (198 μl neat) and the reagents allowed to mix for 5 minutes. Trifluoromethanesulfonic acid (4.5 μl neat) was added slowly via syringe and the mixture stirred at room temperature. After 1 hour the reaction was quenched by the addition of saturated sodium bicarbonate and extracted with ethyl acetate (3×8 ml). The combined organics were washed with brine and dried over magnesium sulfate. Purification of the concentrate by preparative TLC on silica gel (ethyl acetate:hexane (1:2)+1% methanol) gave the title compound (165 mg)
Reaction SMILES: [C:1]([O:4][C@H:5]1[CH2:10][CH2:9][C@H:8]2[C@H:11]3[C@:21](Br)([C@@H:22]([F:24])[CH2:23][C@:6]12[CH3:7])[C@:19]1([CH3:20])[C:14](=[CH:15][C:16](=[O:26])[CH:17]=[CH:18]1)[CH:13]=[CH:12]3)(=[O:3])[CH3:2].C1([SnH](C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>O1CCCC1>[C:1]([O:4][C@H:5]1[CH2:10][CH2:9][C@H:8]2[C@H:11]3[C@H:21]([C@@H:22]([F:24])[CH2:23][C@:6]12[CH3:7])[C@:19]1([CH3:20])[C:14](=[CH:15][C:16](=[O:26])[CH:17]=[CH:18]1)[CH:13]=[CH:12]3)(=[O:3])[CH3:2]
Reactant: CC(=O)O[C@H]1CC[C@H]2[C@@H]3C=CC4=CC(=O)C=C[C@]4(C)[C@@]3(Br)[C@@H](F)C[C@]12C
Agent: c1ccc([SnH](c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: CC(=O)O[C@H]1CC[C@H]2[C@@H]3C=CC4=CC(=O)C=C[C@]4(C)[C@H]3[C@@H](F)C[C@]12C

Procedure:
230 mg. of 17β-acetoxy-9-bromo-11β-fluoro-1,4,6-androstatrien-3-one is stirred at room temperature for 5 hours in 7 ml. of tetrahydrofuran with 1 ml. of triphenyltin hydride while adding 1 mg. of α,α'-azoisobutyrodinitrile. The solution is worked up as disclosed in Example 1. After purification by preparative layer chromatography, 70 mg. of 17β-acetoxy-11β-fluoro-1,4,6-androstatrien-3-one is isolated. UV: ε298 = 11,800 (methanol).
Reaction SMILES: [CH3:1][C:2]1[C:6]([N+:7]([O-:9])=[O:8])=[C:5]([C:10](Cl)=[O:11])[N:4]([CH2:13][CH2:14][CH3:15])[N:3]=1.[OH-].[NH4+:17]>CC(C)=O>[CH3:1][C:2]1[C:6]([N+:7]([O-:9])=[O:8])=[C:5]([C:10]([NH2:17])=[O:11])[N:4]([CH2:13][CH2:14][CH3:15])[N:3]=1
Reactant: CCCn1nc(C)c([N+](=O)[O-])c1C(=O)Cl
Reactant: [NH4+]
Agent: [OH-]
Solvent: CC(C)=O
Product: CCCn1nc(C)c([N+](=O)[O-])c1C(N)=O
Yield: 79 %

Procedure:
A solution of 46 g (0.2 mol) of 3-methyl-4-nitro-1-n-propyl-pyrazole-5-carbonyl chloride [J. Med. Chem., 16 1346 (1973)] in 50 ml of acetone is added slowly to 250 ml of cold (5° C.) concentrated ammonium hydroxide. The mixture is filtered to give 33 g (79%) of 3-methyl-4-nitro-1-n-propylpyrazole-5-carboxamide, mp 136°-138° C. The amide (33 g, 0.15 mol) is stirred under reflux in 100 ml of phosphorus oxychloride for 2.5 hours and evaporated in vacuo. The residue is stirred in 250 ml of ice water to give, after filtering, 25.5 g (86%) of 5-cyano-3-methyl-4-nitro-1-n-propylpyrazole. This nitropyrazole (25 g, 0.013 mol) is dissolved in 350 ml of glacial acetic acid and treated at 95° C. portionwise with 12 g iron filings and 20 ml of water. After stirring under reflux three hours the mixture is filtered and the filtrate is concentrated in vacuo. The concentrate is extracted with methylene dichloride and the organic extract is treated with 20 ml of acetic anhydride and refluxed for two hours. The cooled mixure is stirred with saturated aqueous NaHCO3 solution, the organic layer is dried (MgSO4), and evaporated in vacuo to give 16.5 g of N-(5-cyano-3-methyl-1-n-propylpyrazol-4-yl)acetamide, mp 129°-131° C.
Reaction SMILES: C(=O)([O-])[O-].[Cs+].[Cs+].[CH2:7]([C:11]1[N:12]([CH2:20][C:21]2[CH:26]=[CH:25][C:24]([C:27]3[CH:32]=[CH:31][CH:30]=[CH:29][C:28]=3[C:33]3[N:37](C(C4C=CC=CC=4)(C4C=CC=CC=4)C4C=CC=CC=4)[N:36]=[N:35][N:34]=3)=[CH:23][CH:22]=2)[C:13]([C:17]([OH:19])=[O:18])=[C:14]([Cl:16])[N:15]=1)[CH2:8][CH2:9][CH3:10].[C:57](=[O:75])([O:62][C@H:63]1[CH2:67][O:66][C@@H:65]2[C@H:68]([O:71][N+:72]([O-:74])=[O:73])[CH2:69][O:70][C@H:64]12)[O:58][C@@H:59](Cl)[CH3:60].O>CN(C)C=O.CO>[CH2:7]([C:11]1[N:12]([CH2:20][C:21]2[CH:26]=[CH:25][C:24]([C:27]3[CH:32]=[CH:31][CH:30]=[CH:29][C:28]=3[C:33]3[NH:37][N:36]=[N:35][N:34]=3)=[CH:23][CH:22]=2)[C:13]([C:17]([O:19][C@@H:59]([O:58][C:57]([O:62][C@H:63]2[CH2:67][O:66][C@@H:65]3[C@H:68]([O:71][N+:72]([O-:74])=[O:73])[CH2:69][O:70][C@H:64]23)=[O:75])[CH3:60])=[O:18])=[C:14]([Cl:16])[N:15]=1)[CH2:8][CH2:9][CH3:10]
Reactant: CCCCc1nc(Cl)c(C(=O)O)n1Cc1ccc(-c2ccccc2-c2nnnn2C(c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Reactant: C[C@H](Cl)OC(=O)O[C@H]1CO[C@H]2[C@@H]1OC[C@H]2O[N+](=O)[O-]
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CO
Solvent: O
Solvent: CN(C)C=O
Product: CCCCc1nc(Cl)c(C(=O)O[C@H](C)OC(=O)O[C@H]2CO[C@H]3[C@@H]2OC[C@H]3O[N+](=O)[O-])n1Cc1ccc(-c2ccccc2-c2nnn[nH]2)cc1
Temperature: 70 °C
Reaction time: 2 h

Procedure:
Cesium carbonate (5.34 g, 16.4 mmol) was added to a solution of 2-butyl-4-chloro-1-{[2′-(1-trityl-1H-tetrazol-5-yl)biphenyl-4-yl]methyl}-1H-imidazole-5-carboxylic acid (Intermediate 4, 8.56 g, 12.6 mmol) and (1S)-1-chloroethyl (3S,3aR,6R,6aS)-6-(nitrooxy)hexahydrofuro[3,2-b]furan-3-yl carbonate (Intermediate 2, 3.75 g, 12.6 mmol) in N,N-dimethylformamide (126 mL). The mixture was heated to 70° C. for 2 hours. Water was added and the solution was extracted with ethyl acetate (2×). The combined organic layers were dried (magnesium sulfate), filtered, and concentrated in vacuo. The residue was purified by flash chromatography, eluting with 0-100% ethyl acetate in hexanes to give a yellow foam that was subsequently dissolved in methanol (106 mL). The solution was stirred at 70° C. for 2 hours and then concentrated in vacuo. The residue was purified by HPLC reverse phase (C-18), eluting with acetonitrile/water+0.1% trifluoroacetic acid to give the title compound. 1H NMR (500 MHz, CDCl3) δ 8.00 (d, J=7.5 Hz, 1H), 7.61 (t, J=7.5 Hz, 1H), 7.54 (t, J=7.5 Hz, 1H), 7.43 (d, J=8.0 Hz, 1H), 7.15 (d, J=8.0 Hz, 2H), 6.95 (d, J=8.0 Hz, 2H), 6.85 (q, J=5.5 Hz, 1H), 5.55 (d, J=16.5 Hz, 1H), 5.45 (d, J=16.5 Hz, 1H), 5.27 (td, J=5.5, 3.0 Hz, 1H), 5.03 (d, J=3.0 Hz, 1H), 4.84 (t, J=5.5 Hz, 1H), 4.39 (d, J=5.5 Hz, 1H), 4.00 (d, J=11.0 Hz, 1H), 3.95-3.88 (m, 2H), 3.78 (dd, J=11.0, 5.5 Hz, 1H), 2.66 (t, J=8.0 Hz, 2H), 1.68 (quintet, J=8.0 Hz, 2H), 1.60 (d, J=5.5 Hz, 3H), 1.36 (sextet, J=8.0 Hz, 2H), 0.89 (t, J=8.0 Hz, 3H); LC-MS: m/z 698.2 (M+H).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[CH:5]=[CH:6][C:7]=1[CH3:8].[Br:15]N1C(=O)CCC1=O>N(C(C)(C)C#N)=NC(C)(C)C#N.C(Cl)(Cl)(Cl)Cl>[Br:15][CH2:8][C:7]1[CH:6]=[CH:5][C:4]([C:9]2[CH:10]=[CH:11][CH:12]=[CH:13][CH:14]=2)=[CH:3][C:2]=1[F:1]
Reactant: Cc1ccc(-c2ccccc2)cc1F
Reactant: O=C1CCC(=O)N1Br
Agent: CC(C)(C#N)N=NC(C)(C)C#N
Solvent: ClC(Cl)(Cl)Cl
Product: Fc1cc(-c2ccccc2)ccc1CBr
Yield: 97.2 %

Procedure:
A mixture of 3-fluoro-4-methylbiphenyl (6.00 g), N-bromosuccinimide (5.73 g), 2,2′-azobisisobutyronitrile (0.075 g) and carbon tetrachloride (120 ml) is refluxed by heating for five hours. The reaction solution is washed with water. The residue, which is obtained by concentrating the organic layer, is purified using silica gel column chromatography (eluate: hexane/ethyl acetate=9/1) and thus, oily 4-bromomethyl-3-fluorobiphenyl (8.30 g) is obtained. 1H-NMR (CDCl3, δ): 4.57 (2H, s), 7.30 (1H, d, J=11.0 Hz), 7.34-7.40 (2H, m), 7.45 (3H, m), 7.56 (2H, d).
Reaction SMILES: [F:1][C:2]1([F:17])[CH2:6][CH2:5][C@@H:4]([C:7]([O:9]CC2C=CC=CC=2)=[O:8])[CH2:3]1.[Li+].[OH-].O>CO>[F:1][C:2]1([F:17])[CH2:6][CH2:5][C@@H:4]([C:7]([OH:9])=[O:8])[CH2:3]1
Reactant: O=C(OCc1ccccc1)[C@@H]1CCC(F)(F)C1
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: O=C(O)[C@@H]1CCC(F)(F)C1
Yield: 81 %

Procedure:
(R)-benzyl 3,3-difluorocyclopentanecarboxylate (13 g, 54.1 mmol) was dissolved in MeOH (200 mL) at room temperature with stirring then 0.5 M LiOH (216 mL, 108 mmol) was added. After stirring for 2 h, water was added to the reaction mixture and concentrated to remove volatile solvents. The aqueous layer was rinsed with Et2O (2×) then acidified to pH 3 with 1N HCl. The aqueous layer was extracted with methylene chloride (2×) and the organic layers were combined, dried (Na2SO4), and concentrated to give (R)-3,3-difluorocyclopentanecarboxylic acid (6.58 g, 43.8 mmol, 81% yield) as an oil. 1H NMR (MeOD3, 400 MHz) δ 3.03 (m, 1H), 2.33 (m, 2H), 1.95-2.20 (m, 4H); m/z=149.2 (M−H).
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][C:7]=1[NH2:8].Cl[CH2:10][C:11](Cl)=[O:12].[CH2:14]([N:16]=[C:17]=[S:18])[CH3:15]>>[CH2:14](/[N:16]=[C:17]1\[S:18][CH2:10][C:11](=[O:12])[N:8]\1[C:7]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[CH3:1])[CH3:15]
Reactant: O=C(Cl)CCl
Reactant: CCN=C=S
Reactant: Cc1ccccc1N
Product: CC/N=C1\SCC(=O)N1c1ccccc1C

Procedure:
2-[(Z)-Ethylimino]-3-(2-methylphenyl)-thiazolidin-4-one is prepared following Method B and starting from o-tolylamine, chloroacetyl chloride and ethylisothiocyanate. LC-MS: tR=0.59 min, [M+1]+=235, 1H NMR (CDCl3): δ 7.36-7.28 (m 3H), 7.15-7.10 (m, 1H), 4.01 (s, 2H), 3.41-3.30 (m, 2H), 2.19 (s, 3H), 1.20-1.13 (m, 3H).
Reaction SMILES: Cl.[Br:2][C:3]1[N:8]=[CH:7][C:6]([C@H:9]([NH2:11])[CH3:10])=[CH:5][CH:4]=1.[C:12]([C:14]1[CH:48]=[CH:47][C:17]([CH2:18][C@@:19]2([CH3:46])[N:23]3[C:24]([C:27]([NH:29][C:30]4([C:33](O)=[O:34])[CH2:32][CH2:31]4)=[O:28])=[CH:25][N:26]=[C:22]3[N:21]([C:36]3[CH:41]=[C:40]([Cl:42])[C:39]([F:43])=[C:38]([Cl:44])[CH:37]=3)[C:20]2=[O:45])=[CH:16][CH:15]=1)#[N:13].C(N(C(C)C)CC)(C)C.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>CN(C=O)C.C(OCC)(=O)C>[Br:2][C:3]1[N:8]=[CH:7][C:6]([C@H:9]([NH:11][C:33]([C:30]2([NH:29][C:27]([C:24]3[N:23]4[C@@:19]([CH2:18][C:17]5[CH:16]=[CH:15][C:14]([C:12]#[N:13])=[CH:48][CH:47]=5)([CH3:46])[C:20](=[O:45])[N:21]([C:36]5[CH:41]=[C:40]([Cl:42])[C:39]([F:43])=[C:38]([Cl:44])[CH:37]=5)[C:22]4=[N:26][CH:25]=3)=[O:28])[CH2:32][CH2:31]2)=[O:34])[CH3:10])=[CH:5][CH:4]=1
Reactant: C[C@@]1(Cc2ccc(C#N)cc2)C(=O)N(c2cc(Cl)c(F)c(Cl)c2)c2ncc(C(=O)NC3(C(=O)O)CC3)n21
Reactant: C[C@@H](N)c1ccc(Br)nc1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: C[C@@H](NC(=O)C1(NC(=O)c2cnc3n2[C@](C)(Cc2ccc(C#N)cc2)C(=O)N3c2cc(Cl)c(F)c(Cl)c2)CC1)c1ccc(Br)nc1
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 108 %

Procedure:
To a solution of the above (R)-1-(6-bromo-pyridin-3-yl)-ethylamine HCl salt (500 mg, 1.82 mmol) in DMF (10 mL) was added 1-{[(R)-5-(4-Cyano-benzyl)-7-(3,5-dichloro-4-fluoro-phenyl)-5-methyl-6-oxo-6,7-dihydro-5H-imidazo[1,2-α]imidazole-3-carbonyl]-amino}-cyclopropanecarboxylic acid (900 mg, 1.66 mmol) and diisopropylethylamine (1.45 mL, 8.30 mmol). The mixture was stirred at room temperature for 5 min. HATU (694 mg, 1.83 mmol) was added to the mixture and the clear yellow mixture was stirred for 17 h. The mixture was diluted with ethyl acetate (35 mL) and washed with water (8 mL). The organic phase was washed with 5% aqueous NaCl solution (2×10 mL) and brine (20 mL), dried over Na2SO4, filtered, and concentrated to pale yellow oil. The crude oil was purified via flash chromatography on silica gel, eluting with 1-6% MeOH/CH2Cl2, to afford 1.3 g of the title compound as a yellow foam.
Reaction SMILES: O=C1CCC(=O)N1O[C:9](=[O:27])[C:10]1[CH:15]=[CH:14][C:13]([O:16][C:17](=[O:26])[N:18]([CH3:25])[C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)=[CH:12][CH:11]=1.[F:28][C:29]([F:39])([F:38])[C:30]1[CH:37]=[CH:36][C:33]([CH2:34][NH2:35])=[CH:32][CH:31]=1>>[F:28][C:29]([F:38])([F:39])[C:30]1[CH:37]=[CH:36][C:33]([CH2:34][NH:35][C:9]([C:10]2[CH:11]=[CH:12][C:13]([O:16][C:17](=[O:26])[N:18]([CH3:25])[C:19]3[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=3)=[CH:14][CH:15]=2)=[O:27])=[CH:32][CH:31]=1
Reactant: CN(C(=O)Oc1ccc(C(=O)ON2C(=O)CCC2=O)cc1)c1ccccc1
Reactant: NCc1ccc(C(F)(F)F)cc1
Product: CN(C(=O)Oc1ccc(C(=O)NCc2ccc(C(F)(F)F)cc2)cc1)c1ccccc1

Procedure:
The title product was prepared from 4-(methyl-phenyl-carbamoyloxy)-benzoic acid 2,5-dioxo-pyrrolidin-1-yl ester and 4-trifluoromethyl-benzylamine (94%, white crystals). HPLC-MS: m/z=429.2 (M+1); Rt: 4.35 min.
Reaction SMILES: [NH:1]1[C:5](=[O:6])[CH2:4][CH2:3][C:2]1=[O:7].C([O-])([O-])=O.[K+].[K+].[CH2:14](Br)[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1.O>CN(C=O)C>[C:15]1([CH2:14][N:1]2[C:5](=[O:6])[CH2:4][CH2:3][C:2]2=[O:7])[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1
Reactant: O=C1CCC(=O)N1
Reactant: BrCc1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: O=C1CCC(=O)N1Cc1ccccc1
Temperature: 55 °C
Reaction time: 8 h
Yield: 56.6 %

Procedure:
To 2,5-pyrrolidinedione (2.5 g, 25.2 mmol) in DMF (50 mL) was added K2CO3 (4.18 g, 30.3 mmol) followed by benzyl bromide (3.00 mL, 25.2 mmol), and the reaction mixture was stirred overnight at 55° C. Water was added to the reaction mixture (˜200 mL) and a precipitate was immediately observed. The precipitate was filtered, and the white solid was washed with water and dried to afford the title compound (2.7 g, 57%). 1H NMR (400 MHz, CDCl3): δ 2.73 (s, 4H), 4.68 (s, 2H), 7.28-7.37 (m, 3H), 7.39-7.44 (m, 2H).
Reaction SMILES: [Cl:1][C:2]1[C:7]([O:8][CH:9]([CH3:11])[CH3:10])=[CH:6][C:5]([NH:12][NH2:13])=[C:4]([F:14])[CH:3]=1.[C:15]([CH:18]1[CH2:23][CH2:22][CH2:21][CH2:20][C:19]1=O)(=O)[CH3:16].C(O)(=O)C>C1(C)C(C)=CC=CC=1>[CH3:16][C:15]1[N:12]([C:5]2[CH:6]=[C:7]([O:8][CH:9]([CH3:10])[CH3:11])[C:2]([Cl:1])=[CH:3][C:4]=2[F:14])[N:13]=[C:19]2[C:18]=1[CH2:23][CH2:22][CH2:21][CH2:20]2
Reactant: CC(=O)C1CCCCC1=O
Reactant: CC(C)Oc1cc(NN)c(F)cc1Cl
Solvent: CC(=O)O
Solvent: Cc1ccccc1C
Product: Cc1c2c(nn1-c1cc(OC(C)C)c(Cl)cc1F)CCCC2
Yield: 39.1 %

Procedure:
4-Chloro-2-fluoro-5-isopropoxyphenylhydrazine (1.8 g), 2-acetylcyclohexanone (1.0 g) and a catalytic amount of acetic acid were dissolved in xylene (5 ml). The resultant mixture was heated under reflux for 8 hours while removing water. After cooling, the reaction mixture was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography to give 0.9 g of 3-methyl-2-(4-chloro-2-fluoro-5-isopropoxyphenyl)-4,5,6,7-tetrahydro-2H-indazole (Compound No. 5). nD14.5 1.5607.
Reaction SMILES: [CH2:1]([C:3]1[S:35][C:6]2[N:7]([CH2:13][C:14]3[CH:19]=[CH:18][C:17]([C:20]4[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=4[C:26]4[N:30]=[C:29](C(Cl)(Cl)Cl)[O:28][N:27]=4)=[CH:16][CH:15]=3)[C:8](=[O:12])[NH:9][C:10](=[O:11])[C:5]=2[CH:4]=1)[CH3:2].Br[CH2:37][C:38]1[C:42]2[CH:43]=[CH:44][C:45]([F:47])=[CH:46][C:41]=2[O:40][N:39]=1.C(=O)([O-])[O-:49].[K+].[K+]>C(#N)C>[CH2:1]([C:3]1[S:35][C:6]2[N:7]([CH2:13][C:14]3[CH:15]=[CH:16][C:17]([C:20]4[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=4[C:26]4[NH:30][C:29](=[O:49])[O:28][N:27]=4)=[CH:18][CH:19]=3)[C:8](=[O:12])[N:9]([CH2:37][C:38]3[C:42]4[CH:43]=[CH:44][C:45]([F:47])=[CH:46][C:41]=4[O:40][N:39]=3)[C:10](=[O:11])[C:5]=2[CH:4]=1)[CH3:2]
Reactant: CCc1cc2c(=O)[nH]c(=O)n(Cc3ccc(-c4ccccc4-c4noc(C(Cl)(Cl)Cl)n4)cc3)c2s1
Reactant: Fc1ccc2c(CBr)noc2c1
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: CCc1cc2c(=O)n(Cc3noc4cc(F)ccc34)c(=O)n(Cc3ccc(-c4ccccc4-c4noc(=O)[nH]4)cc3)c2s1
Temperature: 50 °C
Reaction time: 2 h
Yield: 19.3 %

Procedure:
A mixture of 6-ethyl-1-({2′-[5-(trichloromethyl)-1,2,4-oxadiazol-3-yl]biphenyl-4-yl}methyl)thieno[2,3-d]pyrimidine-2,4(1H,3H)-dione (0.48 g), 3-(bromomethyl)-6-fluoro-1,2-benzoisoxazole (0.2 g), potassium carbonate (0.24 g) and acetonitrile (40 mL) was stirred at 50° C. for 2 hr. Insoluble material was filtered off, and the solvent was evaporated under reduced pressure. The obtained residue was purified by silica gel column chromatography and dissolved in tetrahydrofuran (10 mL) and acetone (10 mL). 1N Aqueous sodium hydroxide solution (4 mL) was added, and the mixture was stirred at room temperature for 1 hr. The reaction mixture was adjusted to pH 5 with water and 1N hydrochloric acid, and extracted with chloroform. The obtained chloroform layer was washed with saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography to give the title compound as a colorless amorphous solid (0.1 g, 19%).
Reaction SMILES: [CH2:1]([N:3]1[C:16]2[CH:15]=[CH:14][C:13]([CH:17]=O)=[CH:12][C:11]=2[S:10][C:9]2[C:4]1=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH3:2].[C:19]1([NH:25][NH2:26])[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1>CO>[C:19]1([NH:25][N:26]=[CH:17][C:13]2[CH:14]=[CH:15][C:16]3[N:3]([CH2:1][CH3:2])[C:4]4[C:9]([S:10][C:11]=3[CH:12]=2)=[CH:8][CH:7]=[CH:6][CH:5]=4)[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1
Reactant: NNc1ccccc1
Reactant: CCN1c2ccccc2Sc2cc(C=O)ccc21
Solvent: CO
Product: CCN1c2ccccc2Sc2cc(C=NNc3ccccc3)ccc21

Procedure:
10-Ethylphenothiazine-3-carbaldehyde (3 g, 0.012 mol) was dissolved in 30 ml of methanol under mild heating. A solution of 1.9 g (0.018 mol) of N-phenylhydrazine (obtained from Aldrich) in methanol was added to the cooled reaction mixture. Next, the reaction mixture was refluxed for 0.5 hour. The precipitated product was filtered, washed with a large amount of methanol, and dried. The yield of yellowish crystals of 10-ethylphenothiazine-3-carbaldehyde N-phenylhydrazone was 3 g (75%).
Reaction SMILES: FC(F)(F)C(O)=O.[F:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]2[N:16]=[C:17]([O:20][CH2:21][C:22]([OH:24])=O)[S:18][CH:19]=2)=[CH:11][CH:10]=1.[NH2:25][C:26]1[S:27][CH:28]=[CH:29][N:30]=1>>[F:8][C:9]1[CH:10]=[CH:11][C:12]([C:15]2[N:16]=[C:17]([O:20][CH2:21][C:22]([NH:25][C:26]3[S:27][CH:28]=[CH:29][N:30]=3)=[O:24])[S:18][CH:19]=2)=[CH:13][CH:14]=1
Reactant: O=C(O)COc1nc(-c2ccc(F)cc2)cs1
Reactant: Nc1nccs1
Solvent: O=C(O)C(F)(F)F
Product: O=C(COc1nc(-c2ccc(F)cc2)cs1)Nc1nccs1

Procedure:
The title compound was prepared analogously as described in Example 30(d) from 90 mg (0.24 mmol) of [4-(4-fluoro-phenyl)-thiazol-2-yloxy]-acetic acid trifluoroacetic acid salt and 47 mg (0.47 mmol) of 2-amino-thiazole. Yield: 5 mg.
Reaction SMILES: [C:1](=[NH:21])([O:3][CH2:4][CH2:5][C:6]1[CH:11]=[CH:10][C:9]([O:12][C:13]2[CH:18]=[CH:17][C:16]([Cl:19])=[C:15]([CH3:20])[CH:14]=2)=[CH:8][CH:7]=1)[NH2:2].[CH:22]([CH:24]([CH2:29][C:30]1[CH:31]=[N:32][N:33]([CH3:35])[CH:34]=1)[C:25](OC)=O)=[O:23].C([O-])([O-])=O.[K+].[K+]>CN1C(=O)CCC1>[Cl:19][C:16]1[CH:17]=[CH:18][C:13]([O:12][C:9]2[CH:8]=[CH:7][C:6]([CH2:5][CH2:4][O:3][C:1]3[NH:2][CH:25]=[C:24]([CH2:29][C:30]4[CH:31]=[N:32][N:33]([CH3:35])[CH:34]=4)[C:22](=[O:23])[N:21]=3)=[CH:11][CH:10]=2)=[CH:14][C:15]=1[CH3:20]
Reactant: COC(=O)C(C=O)Cc1cnn(C)c1
Reactant: Cc1cc(Oc2ccc(CCOC(=N)N)cc2)ccc1Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN1CCCC1=O
Product: Cc1cc(Oc2ccc(CCOc3nc(=O)c(Cc4cnn(C)c4)c[nH]3)cc2)ccc1Cl
Temperature: 130 °C
Yield: 5.5 %

Procedure:
To the solution of 2-{4-[(4-chloro-3-methylphenyl)oxy]phenyl}ethyl imidocarbamate (50 mg, 0.120 mmol) and methyl 2-formyl-3-(1-methyl-1H-pyrazol-4-yl)propanoate (30 mg, 0.153 mmol) in NMP (2 mL), was added K2CO3 (50 mg, 0.362 mmol). The mixture was heated with a microwave reactor at 130° C. for 1 h. Purification via MDAP then afforded the title compound (3 mg, 5.56% yield). LCMS: rt=3.39 min, [M+H]=451
Reaction SMILES: [CH:1]([C@@H:3]1[N:7]([CH3:8])[C:6](=[O:9])[CH2:5][C@@H:4]1[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)=[O:2].C1COCC1.[C:21]1([CH3:29])[CH:26]=[CH:25][CH:24]=[C:23]([Mg]Cl)[CH:22]=1.[NH4+].[Cl-]>O>[OH:2][C@H:1]([C:23]1[CH:24]=[CH:25][CH:26]=[C:21]([CH3:29])[CH:22]=1)[C@@H:3]1[N:7]([CH3:8])[C:6](=[O:9])[CH2:5][C@@H:4]1[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1
Reactant: Cc1cccc([Mg]Cl)c1
Reactant: CN1C(=O)C[C@H](c2ccccc2)[C@@H]1C=O
Agent: [Cl-]
Agent: [NH4+]
Solvent: C1CCOC1
Solvent: O
Product: Cc1cccc([C@@H](O)[C@H]2[C@@H](c3ccccc3)CC(=O)N2C)c1
Reaction time: 1 h
Yield: 69.4 %

Procedure:
To a 0° C. solution of (±)-(4R*,5R*)-5-formyl-1-methyl-4-phenylpyrrolidin-2-one (Intermediate Z, 74 mg, 0.4 mmol) in anhyd. THF (5 mL) was added a solution of m-tolyl magnesium chloride (1M in THF, 0.5 mL, 0.5 mmol, 1.25 equiv). The reaction mixture was stirred for 1 h, then treated with a saturated NH4Cl solution and water. The resulting mixture was extracted with EtOAc, dried (Na2SO4) and concentrated under reduced pressure. The residue was triturated (Et2O/hex) to give (±)-(4R*,5R*)-5-[(1R*)hydroxy(3-methylphenyl)methyl]-1-methyl-4-phenylpyrrolidin-2-one (82 mg, 77%): mp 163-165° C.; TLC (EtOAc) Rf 0.45.
Reaction SMILES: [CH2:1]([NH:8][C@H:9]([CH3:16])[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH2:17]([Li])CCC.[C:22]1([C:27]([O:29][CH3:30])=[O:28])[CH2:26][CH2:25][CH2:24][CH:23]=1.IC>>[CH2:1]([N:8]([C@@H:9]([C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)[CH3:16])[C@@H:23]1[CH2:24][CH2:25][CH2:26][C@:22]1([CH3:17])[C:27]([O:29][CH3:30])=[O:28])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: COC(=O)C1=CCCC1
Reactant: [Li]CCCC
Reactant: C[C@@H](NCc1ccccc1)c1ccccc1
Solvent: CI
Product: COC(=O)[C@@]1(C)CCC[C@H]1N(Cc1ccccc1)[C@H](C)c1ccccc1
Yield: 78 %

Procedure:
According to the procedure of Example 53, Step 1, using (R)-N-benzyl-N-α-methylbenzylamine (4.2 mL, 4.24 g, 20 mmol), n-butyllithium (2.4 M, 7.4 mL), methyl 1-cyclopentene-1-carboxylate (1.3 mL, 1.29 g, 10.2 mmol), and iodomethane (1.3 mL). methyl (1S,2R)-2-{benzyl[(l R)-1-phenylethyl]amino}-1-methylcyclopentanecarboxylate (2.804 g, 7.97 mmol, 78%) was obtained as a brown oil after column chromatography on silica gel eluting with 5% ethyl acetate/hexanes. 1H NMR (400 MHz, CHLOROFORM-D) δ ppm 0.63 (s, 3H) 1.18-1.29 (m, 5H) 1.52-1.64 (m, 1H) 1.74-1.83 (m, J=12.44, 7.67, 7.67, 2.53 Hz, 1H) 1.85-1.92 (m, 1H) 2.03-2.12 (m, 3H) 2.88 (dd, J=10.86, 7.33 Hz, 1H) 3.50-3.54 (m, 3H) 3.57-3.64 (m, 1H) 3.72-3.77 (m, 1H) 3.83 (q, J=6.82 Hz, 1H) 7.17-7.21 (m, 1H) 7.24-7.35 (m, 6H) 7.50 (d, J=7.33 Hz, 2H).