Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1][C:2]1[NH:15][C:5]2[C:6](=[O:14])[NH:7][CH2:8][C@@H:9]([Br:13])[C@H:10](OC)[C:4]=2[C:3]=1[Br:16]>CS(O)(=O)=O.CCOCC>[Br:1][C:2]1[NH:15][C:5]2[C:6](=[O:14])[NH:7][CH2:8][C:9]([Br:13])=[CH:10][C:4]=2[C:3]=1[Br:16]
Reactant: CO[C@@H]1c2c([nH]c(Br)c2Br)C(=O)NC[C@H]1Br
Agent: CS(=O)(=O)O
Solvent: CCOCC
Product: O=C1NCC(Br)=Cc2c1[nH]c(Br)c2Br
Yield: 9.5 %

Procedure:
A solution of 16 (1.0 g, 2.4 mmol) in 5 mL of methanesulfonic acid was stirred at room temperature for 1 d. The reaction mixture was diluted with ether (200 mL), washed with sat. NaHCO3 (100 mL×3), sat. NaCl (100 mL) and dried (MgSO4). Evaporation followed by flash chromatography (CH2Cl2/MeOH sat. with NH3 19:1) afforded 17 (88 mg, 96%) as a colorless solid: 1H NMR (DMSO-d6) d 3.88 (d, 2H, J=4.4), 6.85 (s, 1H), 8.07 (t, 1H, J=4.4), 13.24 (s, 1H); (CD3OD) d 3.87 (s, 2H), 6.88 (S, 1H); 13C NMR (DMSO-d6) d 48.1 (e), 98.2 (e), 107.9 (e), 117.9 (e), 123.7 (e), 126.3 (o), 126.6 (e), 161.6 (e); IR (nujol) 3153, 1660, 1536, 1414, 1257 cm−1; UV (CH3OH) lmax 288, 234 nm; MS m/z (relative intensity) 388 (M++6, 33), 386 (M++4, 100), 384 (M++2, 100), 382 (M+, 33); HRMS, calcd for C8H5N2OBr3 (M+) 381.7952, found 381.7941. Anal. Calcd for C8H5N2OBr3: C, 24.97; H, 1.31; N, 7.28. Found: C, 25.29; H, 1.47; N, 7.25.
Reaction SMILES: [CH3:1][N:2]([CH2:10][CH2:11][N:12]1[C:17](=[O:18])[CH:16]=[CH:15][C:14]([C:19]2[S:20][CH:21]=[C:22]([CH3:24])[CH:23]=2)=[N:13]1)C(=O)OC(C)(C)C>C(Cl)Cl.C(O)(C(F)(F)F)=O>[CH3:1][NH:2][CH2:10][CH2:11][N:12]1[C:17](=[O:18])[CH:16]=[CH:15][C:14]([C:19]2[S:20][CH:21]=[C:22]([CH3:24])[CH:23]=2)=[N:13]1
Reactant: Cc1csc(-c2ccc(=O)n(CCN(C)C(=O)OC(C)(C)C)n2)c1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CNCCn1nc(-c2cc(C)cs2)ccc1=O

Procedure:
A solution of tert-butyl methyl(2-(3-(4-methylthiophen-2-yl)-6-oxopyridazin-1(6H)-yl)ethyl)carbamate (340 mg, 973 μmol) in CH2Cl2 (5 mL) and TFA (5 mL) was stirred for 30 min at 23° C. The solvents were removed under reduced pressure and the residue partitioned between CH2Cl2 (20 mL) and 1M NaOH (10 mL). The organic layer was dried over MgSO4, concentrated and purified on silica (12 g) eluting with 0-6% (2M NH3 in MeOH/CH2Cl2) to give the product as an amber oil. MS (ESI pos. ion) m/z (MH+): 250. Calc'd exact mass for C12H15N3OS: 249. 1H NMR (400 MHz, Chloroform-d) δ ppm 1.60 (br. s., 2 H) 2.28 (d, J=0.78 Hz, 3 H) 2.49 (s, 3 H) 3.07 (t, J=6.06 Hz, 2 H) 4.32 (t, J=6.06 Hz, 2 H) 6.88-7.01 (m, 2 H) 7.18 (d, J=1.17 Hz, 1 H) 7.54 (d, J=9.59 Hz, 1 H).
Reaction SMILES: [Cl:1][CH:2]1[C:4](Cl)([Cl:5])[C:3]1([Cl:8])[Cl:7].[OH-].[K+].[CH2:11]([O:13][CH2:14][C:15]1[O:16][CH:17]=[CH:18][CH:19]=1)[CH3:12]>O1CCOCC1>[Cl:5][C:4]1[C@:15]2([CH2:14][O:13][CH2:11][CH3:12])[O:16][C@H:17]([C:3]([Cl:8])([Cl:7])[C:2]=1[Cl:1])[CH:18]=[CH:19]2
Reactant: CCOCc1ccco1
Reactant: ClC1C(Cl)(Cl)C1(Cl)Cl
Agent: [K+]
Agent: [OH-]
Solvent: C1COCCO1
Product: CCOC[C@]12C=C[C@H](O1)C(Cl)(Cl)C(Cl)=C2Cl
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 65.2 %

Procedure:
Pentachlorocyclopropane (25 g, 0.116 mol) is added to a suspension of potassium hydroxide (7.8 g, 0.139 mol) in 1,4-dioxane (900 ml) and the mixture is stirred at room temperature for 30 minutes and then heated to 65° C. for a further 30 minutes. 2-Ethoxymethylfuran (17.5 g, 0.139 mol) is added to the reaction mixture, the temperature is raised to 85-90° C. and the mixture is stirred for 16 hours. The reaction mixture is cooled to room temperature, filtered through a plug of diatomaceous earth and the filtrate is evaporated under reduced pressure to give (1S*,5S*)-2,3,4,4-tetrachloro-1-ethoxymethyl-8-oxabicyclo[3.2.1]octa-2,6-diene (23 g), used without further purification in the next step.
Reaction SMILES: [NH2:1][C:2]1[N:6]([C@H:7]2[O:13][C@@H:12]([CH2:14][OH:15])[C@H:10]([OH:11])[C@@H:8]2[OH:9])[N:5]=[CH:4][C:3]=1[C:16]#[N:17].OO.C([OH:22])C>[OH-].[NH4+]>[NH2:1][C:2]1[N:6]([C@H:7]2[O:13][C@@H:12]([CH2:14][OH:15])[C@H:10]([OH:11])[C@@H:8]2[OH:9])[N:5]=[CH:4][C:3]=1[C:16]([NH2:17])=[O:22]
Reactant: N#Cc1cnn([C@H]2O[C@@H](CO)[C@H](O)[C@@H]2O)c1N
Reactant: CCO
Agent: OO
Agent: [NH4+]
Agent: [OH-]
Product: NC(=O)c1cnn([C@H]2O[C@@H](CO)[C@H](O)[C@@H]2O)c1N
Temperature: 25 °C
Reaction time: 18 h
Yield: 71 %

Procedure:
To a solution of (25) (4.60 g) in ammonium hydroxide (35 mL) was added 30% hydrogen peroxide (2 mL). The mixture was stirred in a pressure bottle at room temperature for 18 h, the pressure bottle was cooled, opened carefully and the volatile products were evaporated to dryness. The residue thus obtained was co-evaporated with ethanol (3×20 mL). The crude product on crystallization with ethanol/water gave pure compound 3.5 g (71%): 1H NMR (DMSO-d6) δ 3.57 (m, 2H, C5'CH2), 3.86 (q, 1H, C4'H), 4.11 (q, 1H, C3'H), 4.43 (q, 1H, C2'OH), 5.63 (d, 1H, J=3.99 Hz, C1',H), 6.51 (br s, 2H, NH2), 6.71 and 7.26 (2br s, 2H, CONH2) and 7.69 (s, 1H, C3H). Anal. Calc. for C9H14N4O5 (258.23): C, 41.86; H, 5.46; N, 21.69. Found: C, 41.57; H, 5.40; N, 21.61.
Reaction SMILES: [C:1]12([C:11]3[CH:12]=[C:13](Br)[CH:14]=[CH:15][C:16]=3[O:17][CH2:18][O:19][CH2:20][CH2:21][O:22][CH3:23])[CH2:10][CH:5]3[CH2:6][CH:7]([CH2:9][CH:3]([CH2:4]3)[CH2:2]1)[CH2:8]2.[Mg].II.[C:28](=[O:30])=[O:29].[Cl-].[NH4+]>C1COCC1>[C:1]12([C:11]3[CH:12]=[C:13]([CH:14]=[CH:15][C:16]=3[O:17][CH2:18][O:19][CH2:20][CH2:21][O:22][CH3:23])[C:28]([OH:30])=[O:29])[CH2:10][CH:5]3[CH2:6][CH:7]([CH2:9][CH:3]([CH2:4]3)[CH2:2]1)[CH2:8]2
Reactant: COCCOCOc1ccc(Br)cc1C12CC3CC(CC(C3)C1)C2
Reactant: O=C=O
Agent: II
Agent: [Cl-]
Agent: [Mg]
Solvent: C1CCOC1
Product: COCCOCOc1ccc(C(=O)O)cc1C12CC3CC(CC(C3)C1)C2
Temperature: -78 °C
Reaction time: 1 h

Procedure:
The above compound (a) (28.5 g, 72 mmol) was dissolved in 200 ml of THF. The solution obtained was added dropwise to magnesium (2.4 g, 100 mmol) and a crystal of iodine. After introduction, the mixture was heated at reflux for two hours, cooled to -78° C. and a stream of CO2 was passed therethrough for one hour. The reaction medium was permitted to warm to room temperature and was then poured into saturated aqueous ammonium chloride solution and extracted with ethyl ether. The organic phase was separated out after settling had taken place, dried over magnesium sulfate and evaporated. The residue obtained was triturated from hexane, filtered and dried. 15.5 g (60%) of the expected acid, having a melting point of 115°-6° C., were recovered.
Reaction SMILES: [CH:1]1C=C(Cl)C=C(C(OO)=O)C=1.[Cl:12][C:13]1[C:33]2[O:32][C@:19]3([C@H:28]([CH3:29])[CH2:27][C:26]4[N:25]=[C:24]([CH3:30])[CH:23]=[CH:22][C:21]=4[C:20]3=[O:31])[C:18](=[O:34])[C:17]=2[C:16]([O:35][CH3:36])=[CH:15][C:14]=1[O:37][CH3:38]>ClCCl>[Cl:12][C:13]1[C:33]2[O:32][C@:19]3([C@H:28]([CH3:29])[CH2:27][C:26]4[N:25]=[C:24]([CH2:30][CH3:1])[CH:23]=[CH:22][C:21]=4[C:20]3=[O:31])[C:18](=[O:34])[C:17]=2[C:16]([O:35][CH3:36])=[CH:15][C:14]=1[O:37][CH3:38]
Reactant: COc1cc(OC)c2c(c1Cl)O[C@@]1(C(=O)c3ccc(C)nc3C[C@H]1C)C2=O
Reactant: O=C(OO)c1cccc(Cl)c1
Solvent: ClCCl
Product: CCc1ccc2c(n1)C[C@@H](C)[C@]1(Oc3c(Cl)c(OC)cc(OC)c3C1=O)C2=O
Reaction time: 16 h
Yield: 102.1 %

Procedure:
In a 250 mL round-bottomed flask 1.3 g (7.7 mmol, 2 eq.) of mCPBA was added to a solution of (2S,7′R)-7-chloro-4,6-dimethoxy-2′,7′-dimethyl-7′,8′-dihydro-3H,5′H-spiro[benzofuran-2,6′-quinoline]-3,5′-dione (1.5 g, 3.9 mmol, 1.0 eq) in 45 mL of dichloromethane. The mixture was left under agitation at ambient temperature for 16 h, then concentrated under reduced pressure. The residue was dissolved in AcOEt. The organic phase was washed with 10% Na2S2O3 solution, then a saturated NaHCO3 solution, then brine solution and dried over Na2SO4, filtered and concentrated under reduced pressure. A yellow solid (1.6 g) was obtained with a yield of 100%.
Reaction SMILES: [C:1]1([C:39]2[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=2)[CH:6]=[CH:5][C:4]([C:7]2[C:37]([Cl:38])=[CH:36][C:10]3[N:11](COCC[Si](C)(C)C)[C:12]([O:14][C:15]4[CH:16]=[C:17]([S:21]([NH:24][C:25](=[O:27])[CH3:26])(=[O:23])=[O:22])[CH:18]=[CH:19][CH:20]=4)=[N:13][C:9]=3[CH:8]=2)=[CH:3][CH:2]=1.[F-].C([N+](CCCC)(CCCC)CCCC)CCC>C1COCC1>[C:25]([NH:24][S:21]([C:17]1[CH:18]=[CH:19][CH:20]=[C:15]([O:14][C:12]2[NH:11][C:10]3[CH:36]=[C:37]([Cl:38])[C:7]([C:4]4[CH:5]=[CH:6][C:1]([C:39]5[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=5)=[CH:2][CH:3]=4)=[CH:8][C:9]=3[N:13]=2)[CH:16]=1)(=[O:23])=[O:22])(=[O:27])[CH3:26]
Reactant: CC(=O)NS(=O)(=O)c1cccc(Oc2nc3cc(-c4ccc(-c5ccccc5)cc4)c(Cl)cc3n2COCC[Si](C)(C)C)c1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: C1CCOC1
Product: CC(=O)NS(=O)(=O)c1cccc(Oc2nc3cc(-c4ccc(-c5ccccc5)cc4)c(Cl)cc3[nH]2)c1

Procedure:
A solution of N-({3-[(5-biphenyl-4-yl-6-chloro-1-{[2-(trimethylsilyl)ethoxy]methyl}-1 H-benzimidazol-2-yl)oxy]phenyl}sulfonyl)acetamide (38 mg, 0.059 mmol) and tetrabutylammonium fluoride (1 M in THF) (0.234 mL) in THF (3 mL) was heated at 80° C. for 2 h. Volatiles were removed and the residue was purified by reverse HPLC eluting with MeCN/water to give the title compound. LC-MS: calculated for C27H20ClN3O4S 517.09, observed m/e 518 (M+H)+ (Rt 3.77 min).
Reaction SMILES: [C:1](OC(=O)C)(=[O:3])[CH3:2].[Cl:8][C:9]1[CH:14]=[C:13]([Cl:15])[CH:12]=[CH:11][C:10]=1[CH:16]([OH:28])[C:17]([C:22]1[CH:23]=[N:24][CH:25]=[CH:26][CH:27]=1)([OH:21])[CH:18]([CH3:20])[CH3:19].C(N(CC)CC)C.C(=O)(O)[O-].[Na+]>C(Cl)Cl>[C:1]([O:28][CH:16]([C:10]1[CH:11]=[CH:12][C:13]([Cl:15])=[CH:14][C:9]=1[Cl:8])[C:17]([C:22]1[CH:23]=[N:24][CH:25]=[CH:26][CH:27]=1)([OH:21])[CH:18]([CH3:19])[CH3:20])(=[O:3])[CH3:2]
Reactant: CC(C)C(O)(c1cccnc1)C(O)c1ccc(Cl)cc1Cl
Reactant: CC(=O)OC(C)=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(=O)OC(c1ccc(Cl)cc1Cl)C(O)(c1cccnc1)C(C)C
Temperature: 35 °C
Reaction time: 0.5 h
Yield: 56 %

Procedure:
38.2 ml (0.4 mol) of acetic anhydride were added dropwise to a solution of 76 g (0.23 mol) of 1-(2,4-dichlorophenyl)-2-(3-pyridyl)-3-methylbutane-1,2-diol, 197.7 ml (1.318 mol) of triethylamine and about 0.5 g (4 mmol) of 4-N,N-dimethylaminopyridine in 1 1 of methylene chloride while heating at 35° C. After cooling to room temperature, the mixture was stirred for a further 30 minutes and then poured into 500 ml of a saturated sodium bicarbonate solution. The organic phase was separated off and was worked up in a conventional manner to obtain the product. The oily crude product was crystallized by stirring with ethyl acetate. Yield: 56%.
Reaction SMILES: O.C1(C2N=C(C=CC3C=C([NH:19][C:20](=[O:31])[CH2:21][C:22]4[CH:30]=[CH:29][CH:28]=[CH:27][C:23]=4C(O)=O)C=CC=3)SC=2)CCC1.Cl.C(N=C=NCCCN(C)C)C.C(N)C=C>C(Cl)Cl>[C:22]1([CH2:21][C:20]([NH2:19])=[O:31])[CH:30]=[CH:29][CH:28]=[CH:27][CH:23]=1
Reactant: O=C(Cc1ccccc1C(=O)O)Nc1cccc(C=Cc2nc(C3CCC3)cs2)c1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: C=CCN
Solvent: O
Solvent: ClCCl
Product: NC(=O)Cc1ccccc1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
A mixture of 0.1 g (0.13 mmol) of (E)-5-t2-[4-(2-chlorophenyl)-9-methyl-6H-thieno-[3,2-f][1,2,4]triazolo[4,3-a][1,4]diazepin-2-yl]ethyl]-2-[2-[3-[2-(4-cyclobutyl-2-thiazolyl)ethenyl]phenylamino]-2-oxoethyl]-benzoic acid monohydrate, 0.03 g (0.16 mmol) of N-ethyl-N'-(3-dimethylaminopropyl)-carbodiimide hydrochloride, 0.02 mL (4 mmol) of allylamine and 15 mL of dry CH2Cl2 was stirred at room temperature under nitrogen for 18 hours and concentrated to dryness. The residue was purified by thick layer chromatography using ethyl acetate/CH3OH (5:1) as the eluent. The product was isolated and partitioned between CH2Cl2 and dilute NH4OH. The organic phases were concentrated and the residue triturated with hot ethyl acetate and filtered. The filtrates were concentrated and the solid triturated with diethyl ether and filtered to give 60 mg (57%) of (E)-4-[2 -[4-(2-Chlorophenyl)-9-methyl-6H-thieno-[3,2-f][1,2,4]triazolo[4,3-a][1,4 ]-diazepin-2-yl]ethyl]-N-[3-[2-(4-cyclobutyl-2-thiazolyl)ethenyl]-phenyl]-2-[2-propenylamino)carbonyl]benzeneacetamide as a tan powder: mp 127-132° C.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH:8]([C:20]1[CH:33]=[CH:32][C:23]([C:24]([NH:26][CH2:27][C:28]([F:31])([F:30])[F:29])=[O:25])=[C:22]([F:34])[CH:21]=1)[CH2:9][C:10]([C:12]1[CH:17]=[CH:16][C:15](=[O:18])[N:14]([CH3:19])[CH:13]=1)=O.Cl.[NH2:36][OH:37].C([O-])(O)=O.[Na+]>>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH:8]([C:20]1[CH:33]=[CH:32][C:23]([C:24]([NH:26][CH2:27][C:28]([F:30])([F:29])[F:31])=[O:25])=[C:22]([F:34])[CH:21]=1)[CH2:9]/[C:10](=[N:36]\[OH:37])/[C:12]1[CH:17]=[CH:16][C:15](=[O:18])[N:14]([CH3:19])[CH:13]=1
Reactant: NO
Reactant: Cn1cc(C(=O)CC(c2ccc(C(=O)NCC(F)(F)F)c(F)c2)c2ccccc2Cl)ccc1=O
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Product: Cn1cc(/C(CC(c2ccc(C(=O)NCC(F)(F)F)c(F)c2)c2ccccc2Cl)=N/O)ccc1=O

Procedure:
In analogy to example 151, step 3, 4-(1-(2-chlorophenyl)-3-(1-methyl-6-oxo-1,6-dihydropyridin-3-yl)-3-oxopropyl)-2-fluoro-N-(2,2,2-trifluoroethyl)benzamide was reacted with hydroxylamine hydrochloride in the presence of NaHCO3 to give the title compound containing 8% of the corresponding Z isomer as a colorless waxy solid, MS (ESI+): m/z=510.2 [M+H]+.
Reaction SMILES: Br[C:2]1[S:6][C:5]2=[N:7][CH:8]=[C:9]([I:10])[N:4]2[N:3]=1.[N:11]1([S:17]([C:20]2[CH:25]=[CH:24][C:23](B(O)O)=[CH:22][CH:21]=2)(=[O:19])=[O:18])[CH2:16][CH2:15][O:14][CH2:13][CH2:12]1.C([O-])([O-])=O.[Na+].[Na+]>O1CCOCC1.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>[I:10][C:9]1[N:4]2[C:5]([S:6][C:2]([C:23]3[CH:24]=[CH:25][C:20]([S:17]([N:11]4[CH2:12][CH2:13][O:14][CH2:15][CH2:16]4)(=[O:18])=[O:19])=[CH:21][CH:22]=3)=[N:3]2)=[N:7][CH:8]=1
Reactant: O=S(=O)(c1ccc(B(O)O)cc1)N1CCOCC1
Reactant: Brc1nn2c(I)cnc2s1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: C1COCCO1
Product: O=S(=O)(c1ccc(-c2nn3c(I)cnc3s2)cc1)N1CCOCC1
Temperature: 90 °C
Yield: 42.5 %

Procedure:
A mixture of 2-bromo-5-iodoimidazo[2,1-b][1,3,4]thiadiazole (200 mg, 0.44 mmol), 4-(4-morpholinylsulfonyl)phenylboronic acid (144 mg, 0.52 mmol), PdCl2(PPh3)2 (60 mg, 0.088 mmol) and 2M aq Na2CO3 (1.2 mL) in dioxane (8 mL) was heated at 90° C. for 18 h. The solvent was removed in vacuo and the residue was triturated from EtOAc and filtered. The filtrate was evaporated and the residue was recrystallyzed from MeOH to give the desired product (89 mg, 31%) as a brown solid.
Reaction SMILES: [CH2:1]([CH:3]1[NH:7][C:6](=[O:8])[NH:5][C:4]1=[O:9])[CH3:2].[CH3:10]I>>[CH2:1]([CH:3]1[NH:7][C:6](=[O:8])[N:5]([CH3:10])[C:4]1=[O:9])[CH3:2]
Reactant: CCC1NC(=O)NC1=O
Reactant: CI
Product: CCC1NC(=O)N(C)C1=O

Procedure:
Using 5-ethylimidazolidine-2,4-dione (1.00 g) and methyl iodide (0.51 mL) and by the reaction and treatment in the same manner as in Preparation Example 214, the title compound (0.52 g) was obtained.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]([C:38](=[O:41])[CH2:39][CH3:40])[C@H:9]2[C:18]3[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=3)[N:12]([C:19]([C:21]3[CH:36]=[CH:35][C:24]([O:25][CH2:26][CH2:27][C:28]([CH3:34])([CH3:33])[C:29]([O:31]C)=[O:30])=[CH:23][CH:22]=3)=[O:20])[C@@H:11]([CH3:37])[CH2:10]2)=[CH:4][CH:3]=1.[OH-].[Na+]>CO.O1CCCC1.O>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([N:8]([C:38](=[O:41])[CH2:39][CH3:40])[C@H:9]2[C:18]3[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=3)[N:12]([C:19]([C:21]3[CH:22]=[CH:23][C:24]([O:25][CH2:26][CH2:27][C:28]([CH3:34])([CH3:33])[C:29]([OH:31])=[O:30])=[CH:35][CH:36]=3)=[O:20])[C@@H:11]([CH3:37])[CH2:10]2)=[CH:6][CH:7]=1
Reactant: CCC(=O)N(c1ccc(Cl)cc1)[C@@H]1C[C@H](C)N(C(=O)c2ccc(OCCC(C)(C)C(=O)OC)cc2)c2ccccc21
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: O
Solvent: C1CCOC1
Product: CCC(=O)N(c1ccc(Cl)cc1)[C@@H]1C[C@H](C)N(C(=O)c2ccc(OCCC(C)(C)C(=O)O)cc2)c2ccccc21
Temperature: 40 °C
Reaction time: 8 h

Procedure:
Methyl 4-(4-{[(2S,4R)-4-[(4-chlorophenyl)(propionyl)amino]-2-methyl-3,4-dihydroquinolin-1(2H)-yl]carbonyl}phenoxy)-2,2-dimethylbutanoate was dissolved in methanol/tetrahydrofuran/water (2/1/1) then sodium hydroxide (3 equivalents) was added and reaction mixture stirred at 40° C. overnight. The mixture was concentrated, the residue acidified with a 1N HCl aqueous solution and extracted with ethyl acetate. The organic layer was washed with brine, dried over magnesium sulfate, filtered and concentrated to give 4-(4-{[(2S,4R)-4-[(4-chlorophenyl)(propionyl)amino]-2-methyl-3,4-dihydroquinolin-1(2H)-yl]carbonyl}phenoxy)-2,2-dimethylbutanoic acid.
Reaction SMILES: [CH3:1][C:2]1[CH:31]=[CH:30][CH:29]=[C:28]([CH3:32])[C:3]=1[CH2:4][NH:5][C:6]1[CH:7]=[C:8]2[C:13](=[CH:14][C:15]=1[F:16])[N:12]=[C:11]([N:17]1[CH:21]=[C:20]([C:22]([O:24]CC)=[O:23])[CH:19]=[N:18]1)[NH:10][C:9]2=O.[NH:33]1[CH2:38][CH2:37][O:36][CH2:35][CH2:34]1>>[CH3:1][C:2]1[CH:31]=[CH:30][CH:29]=[C:28]([CH3:32])[C:3]=1[CH2:4][NH:5][C:6]1[CH:7]=[C:8]2[C:13](=[CH:14][C:15]=1[F:16])[N:12]=[C:11]([N:17]1[CH:21]=[C:20]([C:22]([OH:24])=[O:23])[CH:19]=[N:18]1)[N:10]=[C:9]2[N:33]1[CH2:38][CH2:37][O:36][CH2:35][CH2:34]1
Reactant: C1COCCN1
Reactant: CCOC(=O)c1cnn(-c2nc3cc(F)c(NCc4c(C)cccc4C)cc3c(=O)[nH]2)c1
Product: Cc1cccc(C)c1CNc1cc2c(N3CCOCC3)nc(-n3cc(C(=O)O)cn3)nc2cc1F

Procedure:
The above compound may be made analogous to Example 1 using ethyl 1-(6-((2,6-dimethylbenzyl)amino)-7-fluoro-4-oxo-3,4-dihydroquinazolin-2-yl)-1H-pyrazole-4-carboxylate in step D and morpholine in step E. MS (ESI): predicted mass calcd. for C25H25FN6O3, 476.2
Reaction SMILES: C([O:9][CH2:10][C@:11]12[CH2:49][CH2:48][C@@H:47]([C:50]([CH3:52])=[CH2:51])[C@@H:12]1[C@@H:13]1[C@@:26]([CH3:29])([CH2:27][CH2:28]2)[C@@:25]2([CH3:30])[C@@H:16]([C@:17]3([CH3:46])[C@@H:22]([CH2:23][CH2:24]2)[C:21]([CH3:32])([CH3:31])[C:20]([C:33]2[CH:45]=[CH:44][C:36]([C:37]([O:39]C(C)(C)C)=[O:38])=[CH:35][CH:34]=2)=[CH:19][CH2:18]3)[CH2:15][CH2:14]1)(=O)C1C=CC=CC=1.[OH-].[Li+]>O1CCOCC1.O>[OH:9][CH2:10][C@:11]12[CH2:49][CH2:48][C@@H:47]([C:50]([CH3:52])=[CH2:51])[C@@H:12]1[C@@H:13]1[C@@:26]([CH3:29])([CH2:27][CH2:28]2)[C@@:25]2([CH3:30])[C@@H:16]([C@:17]3([CH3:46])[C@@H:22]([CH2:23][CH2:24]2)[C:21]([CH3:32])([CH3:31])[C:20]([C:33]2[CH:45]=[CH:44][C:36]([C:37]([OH:39])=[O:38])=[CH:35][CH:34]=2)=[CH:19][CH2:18]3)[CH2:15][CH2:14]1
Reactant: C=C(C)[C@@H]1CC[C@]2(COC(=O)c3ccccc3)CC[C@]3(C)[C@H](CC[C@@H]4[C@@]5(C)CC=C(c6ccc(C(=O)OC(C)(C)C)cc6)C(C)(C)[C@@H]5CC[C@]43C)[C@@H]12
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1COCCO1
Product: C=C(C)[C@@H]1CC[C@]2(CO)CC[C@]3(C)[C@H](CC[C@@H]4[C@@]5(C)CC=C(c6ccc(C(=O)O)cc6)C(C)(C)[C@@H]5CC[C@]43C)[C@@H]12
Temperature: 75 °C
Reaction time: 24 h
Yield: 39.6 %

Procedure:
To a solution of tert-butyl 4-((1R,3aS,5aR,5bR,7aR,11aS,11bR,13aR,13bR)-3a-(benzoyloxymethyl)-5a,5b,8,8,11a-pentamethyl-1-(prop-1-en-2-yl)-2,3,3a,4,5,5a,5b,6,7,7a,8,11,11a,11b,12,13,13a,13b-octadecahydro-1H-cyclopenta[a]chrysen-9-yl)benzoate (7.2 g, 10.21 mmol) in 1,4-dioxane (75 ml) and water (25 ml) was added lithium hydroxide (1.285 g, 30.6 mmol) and the mixture was stirred at 75° C. Dioxane (50 ml) was added to dissolve all solids and the stirring was continued for 24 h. The solvent was removed and the residue was redissolved into CH2Cl2, the insoluble white solid was collected to afford 4-((1R,3aS,5aR,5bR,7aR,11aS,11bR,13aR,13bR)-3a-(hydroxymethyl)-5a,5b,8,8,11a-pentamethyl-1-(prop-1-en-2-yl)-2,3,3a,4,5,5a,5b,6,7,7a,8,11,11a,11b,12,13,13a,13b-octadecahydro-1H-cyclopenta[a]chrysen-9-yl)benzoic acid (2.2 g, 39.5%) LCMS: m/e 545.4 (MH+), 2.68 min (method 2).
Reaction SMILES: [CH2:1]([C:5]1[C:6]([CH3:14])=[CH:7][C:8]([C:11]([OH:13])=O)=[N:9][CH:10]=1)[CH:2]([CH3:4])[CH3:3].[CH2:15]([C:17]1[CH:18]=[C:19]([CH:24]=[C:25]([CH3:28])[C:26]=1[OH:27])[C:20]([NH:22]O)=[NH:21])[CH3:16]>>[CH2:15]([C:17]1[CH:18]=[C:19]([C:20]2[N:22]=[C:11]([C:8]3[CH:7]=[C:6]([CH3:14])[C:5]([CH2:1][CH:2]([CH3:3])[CH3:4])=[CH:10][N:9]=3)[O:13][N:21]=2)[CH:24]=[C:25]([CH3:28])[C:26]=1[OH:27])[CH3:16]
Reactant: Cc1cc(C(=O)O)ncc1CC(C)C
Reactant: CCc1cc(C(=N)NO)cc(C)c1O
Product: CCc1cc(-c2noc(-c3cc(C)c(CC(C)C)cn3)n2)cc(C)c1O

Procedure:
The title compound is prepared in analogy to Example 2 starting from 5-isobutyl-4-methyl-pyridine-2-carboxylic acid and 3-ethyl-4,N-dihydroxy-5-methyl-benzamidine; LC-MS: tR=1.12 min, [M+H]+=352.12.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([N+:8]([O-])=O)[C:5]([F:11])=[CH:4][C:3]=1[CH2:12][C:13]([O:15]CC)=[O:14].Cl[Sn]Cl.[CH3:21][CH2:22]O>>[CH2:21]([CH:12]([C:3]1[CH:4]=[C:5]([F:11])[C:6]([NH2:8])=[CH:7][C:2]=1[F:1])[C:13]([OH:15])=[O:14])[CH3:22]
Reactant: CCO
Reactant: CCOC(=O)Cc1cc(F)c([N+](=O)[O-])cc1F
Agent: Cl[Sn]Cl
Product: CCC(C(=O)O)c1cc(F)c(N)cc1F
Reaction time: 18 h
Yield: 52 %

Procedure:
To a stirred solution of ethyl 2,5-difluoro-4-nitrophenylacetate (5.88 g, 25.4 mol) in EtOH (100 mL), was added SnCl2 (17.2 g, 76.3 mmol) at rt. The stirring was continued for 18 hours at reflux. After removal of the solvent, the residue was dissolved in CHCl3 (100 mL) and poured into ice water-4M NaOH (40 mL of 4M NaOH in 300 mL of ice-water), extracted with CHCl3 (100 mL×2), dried over anhydrous MgSO4, and concentrated under a reduced pressure. The residue was chromatographed on silica gel (middle pressure chromatography system YAMAZEN YFLC-5404, linear gradient of hexane-EtOAc from 9:1 to 7:3, φ50 mm×500 mm, 15 mm) to give ethyl 4-amino-2,5-difluorophenylacetic acid (2.85 g, 52%) as a colorless oil. 1H-NMR (CDCl3) δ1.28 (t, J=7.3 Hz; 3H), 3.51 (s, 2H), 3.78 (brs, 2H), 4.15 (dd, J=7.2 Hz, 14.2 Hz, 2H), 6.47 (dd, J=7.5, 10.4 Hz, 1H), 6.88 (dd, J=6.7, 11.0 Hz, 1H); MS (FAB) m/z 216 (M++1).
Reaction SMILES: C([O:3][C:4](=[O:21])[CH2:5][C:6]([NH:8][C:9]1[C:14]([CH:15]([CH3:17])[CH3:16])=[CH:13][CH:12]=[CH:11][C:10]=1[CH:18]([CH3:20])[CH3:19])=[O:7])C.CO.[OH-].[Na+].Cl>C(OCC)(=O)C.O.CCCCCCC>[CH:15]([C:14]1[CH:13]=[CH:12][CH:11]=[C:10]([CH:18]([CH3:20])[CH3:19])[C:9]=1[NH:8][C:6](=[O:7])[CH2:5][C:4]([OH:21])=[O:3])([CH3:16])[CH3:17]
Reactant: CCOC(=O)CC(=O)Nc1c(C(C)C)cccc1C(C)C
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCOC(C)=O
Solvent: CCCCCCC
Solvent: CO
Product: CC(C)c1cccc(C(C)C)c1NC(=O)CC(=O)O
Yield: 93.3 %

Procedure:
A 5 L 4-necked flask was fitted with a mechanical stirrer and charged with 240.24 g (824 mmol) of the N-(2,6-Diisopropyl-phenyl)-malonamic acid ethyl ester produced immediately above and 1200 mL of methanol. To the clear, orange solution was added 483 mL (966 mmol) of 2.0 N sodium hydroxide. The solution was stirred until HPLC analysis indicated complete reaction (ca. 2.5 h) and then acidified to pH 3 with 3N hydrochloric acid. The suspension was diluted with 2.0 L of ethyl acetate and 0.5 L of water. The aqueous layer was removed and then the organic layer was washed with 0.5 L of water and 0.5 L of brine. The aqueous layers were back-extracted with 0.5 L of ethyl acetate and the combined organic layers were then dried over magnesium sulfate. Evaporation of the solvent at the Rotavap yielded 216 g (99%) of the crude acid as yellowish solids. The crude material was slurried with 2.2 L of heptane and then isolated by filtration. The solids were washed with heptane and petroleum ether and then air-dried giving 202.53 g of the N-(2,6-Diisopropyl-phenyl)-malonamic acid as yellowish solids. HPLC analysis indicated >99% (a/a) purity. The materials 1H-NMR spectrum was consistent with structure.