Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([C:16]2[CH:21]=[CH:20][C:19]([F:22])=[CH:18][CH:17]=2)([CH:10]2[CH2:15][CH2:14][NH:13][CH2:12][CH2:11]2)[OH:9])=[CH:4][CH:3]=1.Cl[CH2:24][CH2:25][CH2:26][CH2:27][C:28]([N:30]([CH3:32])[CH3:31])=[O:29].C(=O)([O-])[O-].[Na+].[Na+].[I-].[K+].[C:41]([OH:46])(=[O:45])[C:42]([OH:44])=[O:43]>CN(C)C=O.O>[C:41]([OH:46])(=[O:45])[C:42]([OH:44])=[O:43].[F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([C:16]2[CH:17]=[CH:18][C:19]([F:22])=[CH:20][CH:21]=2)([OH:9])[CH:10]2[CH2:11][CH2:12][N:13]([CH2:24][CH2:25][CH2:26][CH2:27][C:28]([N:30]([CH3:32])[CH3:31])=[O:29])[CH2:14][CH2:15]2)=[CH:4][CH:3]=1
Reactant: OC(c1ccc(F)cc1)(c1ccc(F)cc1)C1CCNCC1
Reactant: CN(C)C(=O)CCCCCl
Agent: O=C(O)C(=O)O
Agent: O=C([O-])[O-]
Agent: [I-]
Solvent: O
Solvent: CN(C)C=O
Product: CN(C)C(=O)CCCCN1CCC(C(O)(c2ccc(F)cc2)c2ccc(F)cc2)CC1
Yield: 52 %

Procedure:
A mixture of 7.0 g (0.023 mole) of α,α-bis(4-fluorophenyl)-4-piperidinemethanol, 4.8 g (0.028 mole) of 5-chloro-N,N-dimethylpentanamide, 9.8 g (0.092 mole) of anhydrous sodium carbonate and 0.3 g (0.008 mole) of potassium iodide in 100 ml of N,N-dimethylformamide was heated on a steam bath for 16 h. The mixture was poured into 1.5 L of water and extracted twice with 200 ml portions of ethyl acetate. The ethyl acetate fractions were combined, washed with water and brine, dried (MgSO4) and concentrated under reduced pressure to give a viscous oil. The oil was purified by column chromatography using 250 g of silica gel on a 69 cm×4 cm column, eluted with 10% methanol in methylene chloride. The fractions containing the desired product were combined and concentrated under reduced pressure to give a viscous oil. The oil was converted to the oxalic acid salt and the solid was recrystallized from 2-propanol to yield 6.2 g (52%) of white solid, mp 193°-195° C.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([CH2:10][NH:11][C:12](=[O:18])[O:13][C:14]([CH3:17])([CH3:16])[CH3:15])[CH:5]=[C:6]([O:8][CH3:9])[CH:7]=1.C1(P(C2CCCCC2)C2C=CC3C(=CC=CC=3)C=2C2C3C(=CC=CC=3)C=CC=2OC)CCCCC1.[O-]P([O-])([O-])=O.[K+].[K+].[K+].[CH3:62][C:63]([Si:66]([CH3:79])([CH3:78])[O:67][CH2:68][C:69]1[CH:70]=[C:71](B(O)O)[CH:72]=[CH:73][CH:74]=1)([CH3:65])[CH3:64]>O1CCOCC1.CC([O-])=O.CC([O-])=O.[Pd+2]>[CH3:65][C:63]([Si:66]([CH3:79])([CH3:78])[O:67][CH2:68][C:69]1[CH:70]=[C:71]([C:2]2[CH:7]=[C:6]([O:8][CH3:9])[CH:5]=[C:4]([CH2:10][NH:11][C:12](=[O:18])[O:13][C:14]([CH3:17])([CH3:16])[CH3:15])[CH:3]=2)[CH:72]=[CH:73][CH:74]=1)([CH3:62])[CH3:64]
Reactant: COc1cc(Br)cc(CNC(=O)OC(C)(C)C)c1
Reactant: CC(C)(C)[Si](C)(C)OCc1cccc(B(O)O)c1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: COc1ccc2ccccc2c1-c1c(P(C2CCCCC2)C2CCCCC2)ccc2ccccc12
Solvent: C1COCCO1
Product: COc1cc(CNC(=O)OC(C)(C)C)cc(-c2cccc(CO[Si](C)(C)C(C)(C)C)c2)c1
Temperature: 80 °C
Yield: 74 %

Procedure:
1,1-dimethylethyl {[3-bromo-5-(methyloxy)phenyl]methyl}carbamate (1.4 g, 4.43 mmol), Pd(OAc)2 (70.0 mg, 0.14 mmol), dicyclohexyl[2′-(methyloxy)-1,1′-binaphthalen-2-yl]phosphane (84.0 mg, 0.175 mmol) and K3PO4 (1.2 g, 5.31 mmol) were dissolved in dioxane (30 mL). The mixture was heated at 80° C. for 30 min, and then [3-({[(1,1-dimethylethyl)(dimethyl)silyl]oxy}methyl)phenyl]boronic acid (1.5 g, 5.76 mmol) was added. The mixture reaction was stirred at reflux for two days. The solvent was removed under reduced pressure, then the residue diluted with CH2Cl2 (100 mL). The organic layer was washed with water (20 mL), brine (20 mL), and dried over Na2SO4. The product 1,1-dimethylethyl[3′-({[(1,1-dimethylethyl)(dimethyl)silyl]oxy}methyl)-5-(methyloxy)-3-biphenylyl]methyl}carbamate (1.5 g) was purified by flash column chomatography (PE:EA=15:1) (yield: 74%).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([Cl:8])=[CH:4][C:3]=1[OH:9].[OH-].[K+:11].O>C1(C)C(C)=CC=CC=1>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([Cl:8])=[CH:4][C:3]=1[O-:9].[K+:11]
Reactant: Oc1cc(Cl)ccc1Cl
Agent: [K+]
Agent: [OH-]
Solvent: Cc1ccccc1C
Solvent: O
Product: [O-]c1cc(Cl)ccc1Cl

Procedure:
A solution of 81.5 gm (0.50 mol) of 2,5-dichloro-phenol in 400 ml of xylene was boiled with 31.8 gm of 88% caustic potash (corresponding to 0.50 mol KOH) in a vessel equipped with an efficient water trap comprising a water-cooled phase separation tube until no more water separated out of the distillate. An anhydrous solution of potassium 2,5-dichlorophenolate in xylene was thus obtained. This solution was filtered and then charged into a shaker autoclave having a capacity of 2 liters, which had been warmed to 40° C. 104 gm (0.75 mol) of finely powdered, anhydrous potassium carbonate were then added to the contents, and the autoclave was flushed with carbon dioxide and then closed. The contents of the autoclave were now shaken for 25 minutes at 40° C. while introducing carbon dioxide at a pressure of 40 bars. Thereafter, the introduction of carbon dioxide was discontinued, and the contents of the autoclave were shaken at 140° C. for 15 hours, whereby the internal pressure rose to 70-80 bars. The contents of the autoclave were now allowed to cool to below 60° C., the pressure was released, and the autoclave was subsequently emptied by first rinsing it with xylene and then with a total of 700 ml of water. The xylene phases, including the solid matter contained therein, were combined. The solid matter was separated from the xylene mother liquor by suction filtration and then dissolved in the aqueous phase. The aqueous solution thus obtained was made strongly acid with concentrated hydrochloric acid, whereupon 3,6-dichloro-salicylic acid precipitated out. The precipitate was collected by suction filtration and, together with three liters of water, subjected to steam distillation. Any dichlorophenol and xylene still present passed over with the steam, whereas the desired product remained in the distillation vessel. When the distillate passing over was clear, the distillation was stopped. The contents of the distillation vessel were now filtered while still hot, and the filtrate was cooled, whereupon the product crystallized out. It was collected by suction filtration and dried (1st product fraction).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[C:11](=[O:12])[CH2:10][CH2:9][C:8](=[O:13])[N:7]([CH2:14][CH2:15][CH2:16][N:17]3[C:25](=[O:26])[C:24]4[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=4)[C:18]3=[O:27])[C:6]=2[CH:28]=1.[CH3:29][N:30]([CH:32](OC)OC)[CH3:31]>>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[C:11](=[O:12])[C:10](=[CH:29][N:30]([CH3:32])[CH3:31])[CH2:9][C:8](=[O:13])[N:7]([CH2:14][CH2:15][CH2:16][N:17]3[C:18](=[O:27])[C:19]4[C:24](=[CH:23][CH:22]=[CH:21][CH:20]=4)[C:25]3=[O:26])[C:6]=2[CH:28]=1
Reactant: O=C1CCC(=O)N(CCCN2C(=O)c3ccccc3C2=O)c2cc(Cl)ccc21
Reactant: COC(OC)N(C)C
Product: CN(C)C=C1CC(=O)N(CCCN2C(=O)c3ccccc3C2=O)c2cc(Cl)ccc2C1=O

Procedure:
In a manner similar to that described for method G, 8-chloro-1-(3-(1,3-dioxoisoindolin-2-yl)propyl)-3,4-dihydro-1H-benzo[b]azepine-2,5-dione (I-40-a) and DMF-DMA were converted to I-40-b and carried on crude: MS m/z═452 (M+H).
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][CH:11]([C:14]([OH:16])=O)[CH2:10][CH2:9]1)=O)(C)(C)C.[NH:17]1[CH2:22][CH2:21][O:20][CH2:19][CH2:18]1.C(N=C=NCCCN(C)C)C.ON1C2C=CC=CC=2N=N1.[ClH:44]>CN(C)C=O>[O:20]1[CH2:21][CH2:22][N:17]([C:14]([CH:11]2[CH2:10][CH2:9][NH:8][CH2:13][CH2:12]2)=[O:16])[CH2:18][CH2:19]1.[ClH:44]
Reactant: C1COCCN1
Reactant: CC(C)(C)OC(=O)N1CCC(C(=O)O)CC1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Product: O=C(C1CCNCC1)N1CCOCC1

Procedure:
A mixture comprising N-(tert-butoxycarbonyl)piperidine-4-carboxylic acid (700 mg), morpholine (319 μL), 1-ethyl-3-(3-dimethylaminopropyl)-carbodiimide (702 mg), 1-hydroxybenzotriazole (495 mg) and N,N-dimethylformamide (9 ml) was stirred at room temperature for 16 hours to undergo reaction, and the resulting compound was acid-treated with hydrochloric acid to obtain 4-(morpholinocarbonyl)piperidine•hydrochloride.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]2[C:20](=[O:21])[NH:19][N:18]=[CH:17][C:6]3=[C:7]([C:11]4[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=4)[NH:8][C:9]([CH:10]=1)=[C:5]23.[F:22][C:23]([F:30])([F:29])[CH2:24][CH2:25][C:26](O)=[O:27].C(N(CC)CC)C.F[P-](F)(F)(F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2N=CC=CC=2N=N1>CN(C=O)C.C(OCC)C.CCCCCC.C(OCC)(=O)C>[F:22][C:23]([F:30])([F:29])[CH2:24][CH2:25][C:26]([NH:1][C:2]1[CH:3]=[C:4]2[C:20](=[O:21])[NH:19][N:18]=[CH:17][C:6]3=[C:7]([C:11]4[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=4)[NH:8][C:9]([CH:10]=1)=[C:5]23)=[O:27]
Reactant: O=C(O)CCC(F)(F)F
Reactant: Nc1cc2c3c(c(-c4ccccc4)[nH]c3c1)C=NNC2=O
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCOC(C)=O
Solvent: CCOCC
Solvent: CCN(CC)CC
Product: O=C(CCC(F)(F)F)Nc1cc2c3c(c(-c4ccccc4)[nH]c3c1)C=NNC2=O
Yield: 31.5 %

Procedure:
Preparation of example 15 from the title compound of Example 7 (15 mg, 0.054 mmol), 4,4,4-trifluorobutyric acid (9 mg, 0.062 mmol), triethylamine (0.030 mL, 0.22 mmol), and O-(7-azabenzotriazol-1yl)-N,N,N′,N′-tetramethyluronium hexafluorophosphate (25 mg, 0.065 mmol) in N,N,-dimethylformamide (1.0 mL) was carried out analogously to Example 11. Silica gel chromatography (1:1 ethyl acetate:hexane), also in an analogous manner, followed by diethyl ether trituration afforded the title compound (7 mg, 0.017 mmol) as a yellow powder in 32% yield.
Reaction SMILES: [C:1]([O:5][C:6](=[O:39])[CH2:7][C@@:8]1([C:23]([NH:25][CH:26]2[CH2:31][CH2:30][N:29]([C:32]([O:34][C:35]([CH3:38])([CH3:37])[CH3:36])=[O:33])[CH2:28][CH2:27]2)=[O:24])[C@H:12]([CH3:13])[CH2:11][N:10](CC2C(Cl)=CC=CC=2Cl)[CH2:9]1)([CH3:4])([CH3:3])[CH3:2].Br[CH2:41][C:42]1[C:47]([C:48]([F:51])([F:50])[F:49])=[CH:46][CH:45]=[CH:44][C:43]=1[Cl:52].C(=O)([O-])[O-].[K+].[K+].C(OCC)(=O)C>CO.CN(C)C=O.[OH-].[Pd+2].[OH-]>[C:1]([O:5][C:6](=[O:39])[CH2:7][C@@:8]1([C:23]([NH:25][CH:26]2[CH2:31][CH2:30][N:29]([C:32]([O:34][C:35]([CH3:38])([CH3:37])[CH3:36])=[O:33])[CH2:28][CH2:27]2)=[O:24])[C@H:12]([CH3:13])[CH2:11][N:10]([CH2:41][C:42]2[C:47]([C:48]([F:51])([F:50])[F:49])=[CH:46][CH:45]=[CH:44][C:43]=2[Cl:52])[CH2:9]1)([CH3:4])([CH3:2])[CH3:3]
Reactant: FC(F)(F)c1cccc(Cl)c1CBr
Reactant: C[C@@H]1CN(Cc2c(Cl)cccc2Cl)C[C@]1(CC(=O)OC(C)(C)C)C(=O)NC1CCN(C(=O)OC(C)(C)C)CC1
Agent: [Pd+2]
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Solvent: CO
Product: C[C@@H]1CN(Cc2c(Cl)cccc2C(F)(F)F)C[C@]1(CC(=O)OC(C)(C)C)C(=O)NC1CCN(C(=O)OC(C)(C)C)CC1
Temperature: 40 °C
Reaction time: 3 h
Yield: 32.4 %

Procedure:
20% palladium hydroxide (75.8 mg) was added to a solution of tert-butyl 4-[(3R*,4S*)-3-[2-(tert-butoxy)-2-oxoethyl]-1-[(2,6-dichlorophenyl)methyl]-4-methylpyrrolidin-3-amido]piperidine-1-carboxylate obtained in Example 5b (a chiral form corresponding to the peak with a shorter retention time) (758 mg, 1.29 mmol) in methanol (20 ml), followed by stirring at 40° C. for three hours under a hydrogen atmosphere. The reaction liquid was filtered, and the filtrate was concentrated to give a crude product (501 mg). 2-(Bromomethyl)-1-chloro-3-(trifluoromethyl)benzene (145 mg, 0.532 mmol) and potassium carbonate (53.2 mg) were added to a solution of this crude product (174 mg) in N,N-dimethylformamide (dehydrated) (6 mL), followed by stirring overnight. 2-(Bromomethyl)-1-chloro-3-(trifluoromethyl)benzene (145 mg, 0.532 mmol) and potassium carbonate (106 mg) were further added, followed by stirring for four hours. Ethyl acetate was added to the reaction liquid, which was washed with a 1N aqueous sodium hydroxide solution and brine. This was dried over anhydrous magnesium sulfate and concentrated. The residue was purified by silica gel column chromatography (elution solvent: heptane/ethyl acetate) to give the title compound (82 mg, yield: 32.4%).
Reaction SMILES: [Cl:1][C:2]1[N:10]=[CH:9][C:8]([S:11](Cl)(=[O:13])=[O:12])=[CH:7][C:3]=1[C:4]([OH:6])=[O:5].[OH-].[NH4+:16]>>[NH2:16][S:11]([C:8]1[CH:9]=[N:10][C:2]([Cl:1])=[C:3]([CH:7]=1)[C:4]([OH:6])=[O:5])(=[O:13])=[O:12]
Reactant: [NH4+]
Reactant: O=C(O)c1cc(S(=O)(=O)Cl)cnc1Cl
Agent: [OH-]
Product: NS(=O)(=O)c1cnc(Cl)c(C(=O)O)c1
Temperature: 0 °C

Procedure:
2-Chloro-5-(chlorosulfonyl)nicotinic acid (400 mg, 1.56 mmol) was stirred in a slurry of ice and excess ammonium hydroxide was added at 0° C. and stirred until all of the ice had melted. The resulting solution was evaporated to afford a white solid 5-(aminosulfonyl)-2-chloronicotinic acid. MS ES+ 237 (M+H). 1H NMR (400 MHz, DMSO-D6) δ ppm 8.1 (dd, J=2.6, 0.9 Hz, 1H), 8.6 (m, 1H).
Reaction SMILES: [CH3:1][N:2]1[C:10]2[C:5](=[CH:6][C:7]([C:11]([O:13]CC3C=CC=CC=3)=[O:12])=[CH:8][CH:9]=2)[CH2:4][C:3]1=[O:21]>C(OCC)(=O)C.CO.[Pd]>[CH3:1][N:2]1[C:10]2[C:5](=[CH:6][C:7]([C:11]([OH:13])=[O:12])=[CH:8][CH:9]=2)[CH2:4][C:3]1=[O:21]
Reactant: CN1C(=O)Cc2cc(C(=O)OCc3ccccc3)ccc21
Agent: [Pd]
Solvent: CCOC(C)=O
Solvent: CO
Product: CN1C(=O)Cc2cc(C(=O)O)ccc21
Reaction time: 18 h
Yield: 56.3 %

Procedure:
A solution of Example 59A (1.2 g, 4.27 mmol) in ethyl acetate (30 mL) and methanol (20 mL) was treated with 10% Pd/C (200 mg), stirred under hydrogen (balloon) for 18 hours, filtered through diatomaceous earth (Celite®) with 9:1 dichloromethane/methanol solution rinses, and concentrated to provide 460 mg of the desired product.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:19])[CH:4](CC1C=CC(O)=CC=1C)[CH2:5][CH2:6][CH2:7][CH2:8][CH3:9].C1(C(C2SC(C3C=CC(C(F)(F)F)=CC=3)=NC=2C)O)CC1.C(P(CCCC)CCCC)CCC.CN(C)C(N=NC(N(C)C)=O)=O>>[CH3:1][O:2][C:3](=[O:19])[CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH3:9]
Reactant: CCCCCC(Cc1ccc(O)cc1C)C(=O)OC
Agent: CCCCP(CCCC)CCCC
Agent: CN(C)C(=O)N=NC(=O)N(C)C
Agent: Cc1nc(-c2ccc(C(F)(F)F)cc2)sc1C(O)C1CC1
Product: CCCCCCC(=O)OC

Procedure:
In analogy to the procedure described in example 10 c], [rac]-2-(4-hydroxy-2-methyl-benzyl)-heptanoic acid methyl ester (example 126 c]) was reacted with [rac]-cyclopropyl-[4-methyl-2-(4-trifluoromethyl-phenyl)-thiazol-5-yl]-methanol (example 121 a]) in the presence of tributylphosphine and N,N,N′,N′-tetramethyl azodicarboxamide to yield 2-(4-cyclopropyl-[4-methyl-2-(4-trifluoromethyl-phenyl)-thiazol-5-yl]-methoxy}-2-methyl-benzyl)-heptanoic acid methyl ester as a mixture of two diastereomeric racemates as yellow oil.
Reaction SMILES: C[O:2][C:3]1[N:8]=[CH:7][C:6]([CH2:9][C:10]2[C:11](=[O:17])[NH:12][C:13](=[S:16])[NH:14][CH:15]=2)=[CH:5][CH:4]=1.Cl>C(O)(=O)C>[O:2]=[C:3]1[NH:8][CH:7]=[C:6]([CH2:9][C:10]2[C:11](=[O:17])[NH:12][C:13](=[S:16])[NH:14][CH:15]=2)[CH:5]=[CH:4]1
Reactant: COc1ccc(Cc2c[nH]c(=S)[nH]c2=O)cn1
Agent: Cl
Solvent: CC(=O)O
Product: O=c1ccc(Cc2c[nH]c(=S)[nH]c2=O)c[nH]1
Temperature: 150 °C
Yield: 76.7 %

Procedure:
5-(6-methoxy-pyridin-3-ylmethyl)-2-thioxo-2,3-dihydro-1H-pyrimidin-4-one (395 mg, 1.58 mmol, 1 eq) was refluxed in an acetic acid, glacial (5 ml)/HCl conc. (5 ml) mixture for 16 hours. (150° C. on display of heating device). Solvent from the mixture was evaporated as much as possible. In the mixture was added 10 ml of water. pH of the mixture was adjusted to 4-5. The resulting precipitate was collected and was dried. It was obtained 5-(6-oxo-1,6-dihydro-pyridin-3-ylmethyl)-2-thioxo-2,3-dihydro-1H-pyrimidin-4-one (285 mg, yield=61.3%, purity=90%) in form of grey powder. MS: [M+H]+=236.20 1H NMR (300 MHz; DMSO-d6) δ/ppm 3.24 (s, 2H), 6.25 (d, J=9.36 Hz, 1H), 7.28-7-36 (m, 2H), 11.39 (br.s, 1H), 12.23 (br.s, 1H), 12.46 (br.s, 1H)
Reaction SMILES: [CH3:1][O:2][C:3]1[C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[NH:11][C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=1.[O-:18][C:19]#[N:20].[Na+].C(O)(=O)C(C1C=CC=CC=1)O>ClCCl>[CH3:1][O:2][C:3]1[C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[N:11]([C:19]([NH2:20])=[O:18])[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=1
Reactant: N#C[O-]
Reactant: COC1=Cc2ccccc2Nc2ccccc21
Agent: O=C(O)C(O)c1ccccc1
Agent: [Na+]
Solvent: ClCCl
Product: COC1=Cc2ccccc2N(C(N)=O)c2ccccc21
Temperature: 25 °C

Procedure:
A suspension of 10 g of 10-methoxyiminostilbene in 250 ml dichloromethane was treated with 17.5 g of sodium cyanate and 24 g of mandelic acid and was heated to reflux for about 6-8 hrs. The reaction mixture was cooled to room temperature and the reaction mixture was washed with distilled water and aqueous sodium bicarbonate and further the organic layer was distilled off completely. The resulting residue was treated with isopropanol; separated solid was filtered and dried to give 10-methoxy carbamazepine.
Reaction SMILES: C[O:2][C:3](=[O:25])[CH:4]([N:11]1[C:16](=[O:17])[CH:15]=[CH:14][C:13]([O:18][C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)=[N:12]1)[CH2:5][CH:6]1[CH2:10][CH2:9][CH2:8][CH2:7]1.[OH-].[Na+]>CO>[CH:6]1([CH2:5][CH:4]([N:11]2[C:16](=[O:17])[CH:15]=[CH:14][C:13]([O:18][C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)=[N:12]2)[C:3]([OH:25])=[O:2])[CH2:10][CH2:9][CH2:8][CH2:7]1
Reactant: COC(=O)C(CC1CCCC1)n1nc(Oc2ccccc2)ccc1=O
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: O=C(O)C(CC1CCCC1)n1nc(Oc2ccccc2)ccc1=O
Temperature: 25 °C
Reaction time: 8 h
Yield: 81.4 %

Procedure:
A solution of 3-cyclopentyl-2-(6-oxo-3-phenoxy-6H-pyridazin-1-yl)-propionic acid methyl ester (1.03 g, 3.03 mmol) in methanol (8.5 mL, 0.36M) was treated with a 4N aqueous sodium hydroxide solution (0.83 mL, 3.34 mmol) and stirred at 25° C. overnight. After this time, the reaction was concentrated in vacuo. The residue was diluted with water (100 mL) and acidified to pH=1 with a 3N aqueous hydrochloric acid solution. The resulting solids were collected by filtration, rinsed with water, air dried and then further dried in vacuo to afford 3-cyclopentyl-2-(6-oxo-3-phenoxy-6H-pyridazin-1-yl)-propionic acid (0.81 g, 81%) as a white solid. 1H-NMR (300 MHz, DMSO-d6) δ ppm 0.94 (br s, 2H), 1.29-1.70 (m, 7H), 1.79 (br s, 1H), 1.85-2.05 (m, 1H), 5.08 (dd, J=10.6, 3.0 Hz, 1H), 7.06 (d, J=9.7 Hz, 1H), 7.10-7.25 (m, 3H), 7.34-7.45 (m, 3H).
Reaction SMILES: [CH3:1][C@@H:2]1[CH2:7][CH2:6][CH2:5][CH2:4][C@H:3]1[N:8]1[C:12]2[CH:13]=[CH:14][C:15]([C:17]([OH:19])=[O:18])=[CH:16][C:11]=2[N:10]=[C:9]1[CH2:20][C:21]1[S:22][CH:23]=[CH:24][CH:25]=1.COC(=O)C1C=CC(N[C@H]2CCCC[C@@H]2C)=C(N)C=1.Cl.C[C@H]1CCCC[C@@H]1N>>[CH3:1][C@H:2]1[CH2:7][CH2:6][CH2:5][CH2:4][C@@H:3]1[N:8]1[C:12]2[CH:13]=[CH:14][C:15]([C:17]([OH:19])=[O:18])=[CH:16][C:11]=2[N:10]=[C:9]1[CH2:20][C:21]1[S:22][CH:23]=[CH:24][CH:25]=1
Reactant: C[C@@H]1CCCC[C@H]1n1c(Cc2cccs2)nc2cc(C(=O)O)ccc21
Agent: COC(=O)c1ccc(N[C@H]2CCCC[C@@H]2C)c(N)c1
Agent: C[C@H]1CCCC[C@@H]1N
Agent: Cl
Product: C[C@H]1CCCC[C@@H]1n1c(Cc2cccs2)nc2cc(C(=O)O)ccc21

Procedure:
1-((1S,2S)-2-Methyl-cyclohexyl)-2-thiophen-2-ylmethyl-1H-benzoimidazole-5-carboxylic acid was prepared in analogy to the synthesis of 1-((1R,2R)-2-Methyl-cyclohexyl)-2-thiophen-2-ylmethyl-1H-benzoimidazole-5-carboxylic acid via 3-Amino-4-((1S,2S)-2-methyl-cyclohexylamino)-benzoic acid methyl ester and starting from (1S,2S)-2-Methyl-cyclohexylamine-hydrochloride.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][N:4]([CH3:12])[C:5](=[O:11])[O:6][C:7]([CH3:10])([CH3:9])[CH3:8].Cl[C:14]([C@:16]12[CH2:51][CH2:50][C@@H:49]([C:52]([CH3:54])=[CH2:53])[C@@H:17]1[C@@H:18]1[C@@:31]([CH3:34])([CH2:32][CH2:33]2)[C@@:30]2([CH3:35])[C@@H:21]([C@:22]3([CH3:48])[C@@H:27]([CH2:28][CH2:29]2)[C:26]([CH3:37])([CH3:36])[C:25]([C:38]2[CH:47]=[CH:46][C:41]([C:42]([O:44][CH3:45])=[O:43])=[CH:40][CH:39]=2)=[CH:24][CH2:23]3)[CH2:20][CH2:19]1)=[O:15]>CN(C1C=CN=CC=1)C.C(Cl)Cl>[C:7]([O:6][C:5]([N:4]([CH3:12])[CH2:3][CH2:2][NH:1][C:14]([C@:16]12[CH2:51][CH2:50][C@@H:49]([C:52]([CH3:54])=[CH2:53])[C@@H:17]1[C@@H:18]1[C@@:31]([CH3:34])([CH2:32][CH2:33]2)[C@@:30]2([CH3:35])[C@@H:21]([C@:22]3([CH3:48])[C@@H:27]([CH2:28][CH2:29]2)[C:26]([CH3:37])([CH3:36])[C:25]([C:38]2[CH:39]=[CH:40][C:41]([C:42]([O:44][CH3:45])=[O:43])=[CH:46][CH:47]=2)=[CH:24][CH2:23]3)[CH2:20][CH2:19]1)=[O:15])=[O:11])([CH3:8])([CH3:9])[CH3:10]
Reactant: C=C(C)[C@@H]1CC[C@]2(C(=O)Cl)CC[C@]3(C)[C@H](CC[C@@H]4[C@@]5(C)CC=C(c6ccc(C(=O)OC)cc6)C(C)(C)[C@@H]5CC[C@]43C)[C@@H]12
Reactant: CN(CCN)C(=O)OC(C)(C)C
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Product: C=C(C)[C@@H]1CC[C@]2(C(=O)NCCN(C)C(=O)OC(C)(C)C)CC[C@]3(C)[C@H](CC[C@@H]4[C@@]5(C)CC=C(c6ccc(C(=O)OC)cc6)C(C)(C)[C@@H]5CC[C@]43C)[C@@H]12
Reaction time: 1 h

Procedure:
To a mixture of tert-butyl 2-aminoethyl(methyl)carbamate (17.68 mg, 0.101 mmol), Hunig'sBase (0.053 mL, 0.304 mmol) and DMAP (1.240 mg, 10.15 μmol) in DCM (1 mL) was added methyl 4-((1R,3aS,5aR,5bR,7aR,11aS,11bR,13aR,13bR)-3a-(chlorocarbonyl)-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 (60 mg, 0.101 mmol) in DCM (1 mL). The reaction mixture was stirred for 1 hour. LCMS indicated the formation of desired product. The reaction mixture was quenched with distilled water, extracted with DCM (3×3 mL). All the extracts were combined, dried over sodium sulfate, filtered and concentrated under reduced pressure to provide the desired product as white solid (65 mg, 88%). LCMS: m/e 729.61 (M+H)+, 2.72 min (method 1).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9]([OH:11])=O)=[CH:4][CH:3]=1.Cl.[O:13]1[C:17]2[CH:18]=[CH:19][C:20]([CH2:22][CH2:23][NH2:24])=[CH:21][C:16]=2[O:15][CH2:14]1.C(N(CC)CC)C.C(P(=O)(OCC)OCC)#N>CN(C=O)C>[O:13]1[C:17]2[CH:18]=[CH:19][C:20]([CH2:22][CH2:23][NH:24][C:9](=[O:11])[CH2:8][C:5]3[CH:4]=[CH:3][C:2]([Br:1])=[CH:7][CH:6]=3)=[CH:21][C:16]=2[O:15][CH2:14]1
Reactant: O=C(O)Cc1ccc(Br)cc1
Reactant: NCCc1ccc2c(c1)OCO2
Agent: CCOP(=O)(C#N)OCC
Agent: Cl
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: O=C(Cc1ccc(Br)cc1)NCCc1ccc2c(c1)OCO2
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a stirred solution of 4-bromophenyl acetic acid 34 (2.000 g, 9.300 mmol) and 2-benzo[1,3]dioxol-5-yl-ethylamine hydrochloride salt 33 (2.063 g, 10.230 mmol) in anhydrous DMF (25 mL) was added triethyl amine (2.823 g, 27.900 mmol) followed by diethyl cyanophosphonate (1.669 g, 10.230 mmol) at 00 C and the reaction mixture was stirred at room temperature overnight, poured into ice-water. The precipitated was filtered, washed with water and air-dried. The crude product was recrystallized using CHCl3-Hexane to get compound 35 as a white sold (3.133 g, 93%). 1H NMR (300 MHz, DMSO-d6) δ 8.06 (t, J=5.1 Hz, 1H, —NH), 7.47 (d, J=8.4 Hz, 2H, ArH), 7.16 (d, J=8.1 Hz, 2H, ArH), 6.79 (d, J=7.8 Hz, 1H, ArH), 6.74 (s, 1H, ArH), 6.60 (d, J=7.8 Hz, 1H, ArH), 5.96 (s, 2H, —CH2), 3.35 (s, 2H, —CH2), 3.32 (q, J=6.9 Hz, 2H, —CH2), 2.60 (t, J=7.2 Hz, 2H, —CH2). MS (ES+) m/z 384 (M+Na)+.
Reaction SMILES: Br[CH2:2][C:3]1[NH:8][C:7]([C:9]2[CH:10]=[N:11][CH:12]=[CH:13][CH:14]=2)=[N:6][CH:5]([C:15]2[CH:20]=[CH:19][C:18]([F:21])=[CH:17][C:16]=2[Cl:22])[C:4]=1[C:23]([O:25][CH2:26][CH3:27])=[O:24].[NH:28]1[CH2:33][CH2:32][O:31][CH2:30][CH:29]1[C:34]([OH:36])=[O:35]>>[Cl:22][C:16]1[CH:17]=[C:18]([F:21])[CH:19]=[CH:20][C:15]=1[CH:5]1[N:6]=[C:7]([C:9]2[CH:10]=[N:11][CH:12]=[CH:13][CH:14]=2)[NH:8][C:3]([CH2:2][N:28]2[CH2:33][CH2:32][O:31][CH2:30][CH:29]2[C:34]([OH:36])=[O:35])=[C:4]1[C:23]([O:25][CH2:26][CH3:27])=[O:24]
Reactant: CCOC(=O)C1=C(CBr)NC(c2cccnc2)=NC1c1ccc(F)cc1Cl
Reactant: O=C(O)C1COCCN1
Product: CCOC(=O)C1=C(CN2CCOCC2C(=O)O)NC(c2cccnc2)=NC1c1ccc(F)cc1Cl
Yield: 35.2 %

Procedure:
Ethyl 6-(bromomethyl)-4-(2-chloro-4-fluorophenyl)-2-(pyridin-3-yl)-1,4-dihydropyrimidine-5-carboxylate (1 g, 2.2 mmol) was reacted with morpholine-3-carboxylic acid (0.29 g, 2.2 mmol) according to the procedure as described in Example 1, Step C to give the title compound as a yellow solid (0.39 g, 35%). The compound was characterized by the following spectroscopic data: