Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[C@H:6]([C:18]2[CH:23]=[CH:22][C:21]([F:24])=[CH:20][C:19]=2[Cl:25])[N:7]=[C:8]([C:13]2[S:14][CH:15]=[CH:16][N:17]=2)[NH:9][C:10]=1[CH2:11]Br)=[O:4].[CH2:26]1[CH:35]2[N:30]([C:31](=[O:36])[O:32][CH2:33][CH2:34]2)[CH2:29][CH2:28][NH:27]1.CCN(C(C)C)C(C)C>ClCCCl.CCOC(C)=O>[Cl:25][C:19]1[CH:20]=[C:21]([F:24])[CH:22]=[CH:23][C:18]=1[C@H:6]1[C:5]([C:3]([O:2][CH3:1])=[O:4])=[C:10]([CH2:11][N:27]2[CH2:28][CH2:29][N:30]3[C:31](=[O:36])[O:32][CH2:33][CH2:34][CH:35]3[CH2:26]2)[NH:9][C:8]([C:13]2[S:14][CH:15]=[CH:16][N:17]=2)=[N:7]1
Reactant: O=C1OCCC2CNCCN12
Reactant: COC(=O)C1=C(CBr)NC(c2nccs2)=N[C@H]1c1ccc(F)cc1Cl
Solvent: ClCCCl
Solvent: CCOC(C)=O
Solvent: CCN(C(C)C)C(C)C
Product: COC(=O)C1=C(CN2CCN3C(=O)OCCC3C2)NC(c2nccs2)=N[C@H]1c1ccc(F)cc1Cl
Temperature: 25 °C

Procedure:
To a stirred solution of (R)-6-bromomethyl-4-(2-chloro-4-fluoro-phenyl)-2-thiazol-2-yl-1,4-dihydro-pyrimidine-5-carboxylic acid methyl ester (0.072 g, 0.16 mmol) and hexahydro-pyrazino[1,2-c][1,3]oxazin-6-one trifluoro acetitic acid salt (Compound D, crude, 0.25 mmol) in 1,2-dichloroethane (5 mL) was added dropwise DIPEA (0.078 mL, 0.45 mmol). The reaction mixture was stirred at room temperature until the disappearance of starting material. The mixture was diluted with EtOAc (50 mL) and washed successively with saturated aqueous NH4Cl solution and brine. The organic layer was separated and then dried over Na2SO4. The solvent was concentrated in vacuo and the crude product was purified by prep-HPLC to give methyl (4R)-4-(2-chloro-4-fluoro-phenyl)-6-[(6-oxo-1,3,4,8,9,9a-hexahydropyrazino[1,2-c][1,3]oxazin-2-yl)methyl]-2-thiazol-2-yl-1,4-dihydropyrimidine-5-carboxylate (Example 1) as a light yellow solid (11 mg). 1H NMR (400 MHz, METHANOL-d4) d ppm 7.97 (dd, J=3.01, 1.00 Hz, 1H), 7.81 (d, J=3.01 Hz, 1H), 7.46 (dd, J=8.66, 6.15 Hz, 1H), 7.26 (dd, J=8.78, 2.51 Hz, 1H), 7.00-7.13 (m, 1H), 6.19 (d, J=1.76 Hz, 1H), 4.19-4.48 (m, 4H), 4.11 (d, J=16.06 Hz, 1H), 3.76-3.94 (m, 1H), 3.62 (s, 3H), 3.18-3.31 (m, 2H), 2.37-2.80 (m, 3H), 2.11-2.30 (m, 1H), 1.90 (qdd, J=14.37, 14.37, 14.37, 9.22, 5.40 Hz, 1H). MS: calc'd 520 (MH+), measured 520 (MH+).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:9]([C:18]3[CH:23]=[CH:22][C:21]([C:24]([F:27])([F:26])[F:25])=[CH:20][CH:19]=3)=[N:10][C:11]([CH3:17])=[C:12]([CH:16]=2)[C:13](O)=[O:14])=[CH:4][CH:3]=1.B.CO>C1COCC1>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[CH:16]=[C:12]([CH2:13][OH:14])[C:11]([CH3:17])=[N:10][C:9]=2[C:18]2[CH:19]=[CH:20][C:21]([C:24]([F:25])([F:26])[F:27])=[CH:22][CH:23]=2)=[CH:6][CH:7]=1
Reactant: Cc1nc(-c2ccc(C(F)(F)F)cc2)c(-c2ccc(Cl)cc2)cc1C(=O)O
Agent: B
Solvent: CO
Solvent: C1CCOC1
Product: Cc1nc(-c2ccc(C(F)(F)F)cc2)c(-c2ccc(Cl)cc2)cc1CO
Temperature: 25 °C

Procedure:
To a solution of 1.6 g of 5-(4-Chloro-phenyl)-2-methyl-6-(4-trifluoromethyl-phenyl)-nicotinic acid in 38 ml of THF, were added dropwise 12 ml of a 1M solution of borane in THF at room temperature. Then, the reaction mixture was heated to reflux for 5 h. The reaction mixture was cooled to room temperature and 20 ml of methanol were carefully added. The solvents were removed under reduced pressure and the residue was dissolved in ethyl acetate. The organic layer was washed with 1 M hydrochloric acid, saturated sodium chloride solution and saturated sodium hydrogen carbonate solution. The combined organic layers were dried over MgSO4, filtered and concentrated under reduced pressure. the residue was purified by chromatography on silica gel eluting with a gradient of n-heptane/ethyl acetate. The fractions containing the product were combined and the solvent evaporated under reduced pressure. Yield: 1.2 g.
Reaction SMILES: CN1CCOCC1.[CH:8]1([CH2:13][C@H:14]([CH2:35][N:36]([CH:45]=[O:46])[O:37][CH2:38][C:39]2[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=2)[C:15]([N:17]2[C@H:21]([C:22](O)=[O:23])[CH2:20][CH2:19][N:18]2[C:25]([O:27][CH2:28][C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)=[O:26])=[O:16])[CH2:12][CH2:11][CH2:10][CH2:9]1.COC1N=C(OC)N=C([N+]2(C)CCOCC2)N=1.[CH3:64][C@@H:65]1[CH2:70][N:69]([CH3:71])[CH2:68][CH2:67][N:66]1[C:72]1[N:77]=[CH:76][N:75]=[C:74]([NH2:78])[CH:73]=1>C(#N)C.C(Cl)Cl>[CH:8]1([CH2:13][C@H:14]([CH2:35][N:36]([CH:45]=[O:46])[O:37][CH2:38][C:39]2[CH:40]=[CH:41][CH:42]=[CH:43][CH:44]=2)[C:15]([N:17]2[C@H:21]([C:22]([NH:78][C:74]3[CH:73]=[C:72]([N:66]4[CH2:67][CH2:68][N:69]([CH3:71])[CH2:70][C@H:65]4[CH3:64])[N:77]=[CH:76][N:75]=3)=[O:23])[CH2:20][CH2:19][N:18]2[C:25]([O:27][CH2:28][C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)=[O:26])=[O:16])[CH2:12][CH2:11][CH2:10][CH2:9]1
Reactant: O=CN(C[C@@H](CC1CCCC1)C(=O)N1[C@H](C(=O)O)CCN1C(=O)OCc1ccccc1)OCc1ccccc1
Reactant: C[C@@H]1CN(C)CCN1c1cc(N)ncn1
Agent: COc1nc(OC)nc([N+]2(C)CCOCC2)n1
Solvent: CC#N
Solvent: CN1CCOCC1
Solvent: ClCCl
Product: C[C@@H]1CN(C)CCN1c1cc(NC(=O)[C@@H]2CCN(C(=O)OCc3ccccc3)N2C(=O)[C@H](CC2CCCC2)CN(C=O)OCc2ccccc2)ncn1
Temperature: 0 °C
Reaction time: 0.25 h
Yield: 17.6 %

Procedure:
4-Methylmorpholine (73.6 μl, 0.670 mmol) was added into the solution of (3S)-2-[(2R)-3-cyclopentyl-2-({formyl[(phenylmethyl)oxy]amino}methyl)propanoyl]-1-{[(phenylmethyl)oxy]carbonyl}-3-pyrazolidinecarboxylic acid (300 mg, 0.558 mmol) and 4-[4,6-bis(methyloxy)-1,3,5-triazin-2-yl]-4-methylmorpholin-4-ium (220 mg, 0.670 mmol) in acetonitrile (9.3 ml). The resulting solution was cooled to 0° C., and it was stirred at 0° C. for 15 min. To the reaction mixture was added 6-[(2R)-2,4-dimethyl-1-piperazinyl]-4-pyrimidinamine (139 mg, 0.670 mmol). After stirring for 2 days at ambient temperature, the reaction mixture was concentrated to yield a residue. The residue was dissolved in DCM, and the resulting solution was washed with Na2SO4 (sat.) and brine. The solvent was removed to give a residue again. The residue was purified by RP-HPLC to give an impure product. The impure product was purified by using Silica Gel chromatography (DCM/MeOH/NH4OH=9/1/0.002) to yield phenylmethyl (3S)-2-[(2R)-3-cyclopentyl-2-({formyl[(phenylmethyl)oxy]amino}methyl)propanoyl]-3-[({6-[(2R)-2,4-dimethyl-1-piperazinyl]-4-pyrimidinyl}amino) carbonyl]-1-pyrazolidinecarboxylate (71 mg, 0.098 mmol, 18% yield). MS (ES+) m/z 727.1 (MH+).
Reaction SMILES: [NH2:1][CH2:2][C@H:3]1[N:10]([C:11]([C:13]2[N:14]=[C:15]([CH3:25])[S:16][C:17]=2[C:18]2[CH:19]=[C:20]([CH3:24])[CH:21]=[CH:22][CH:23]=2)=[O:12])[CH2:9][C@H:8]2[C@@H:4]1[CH2:5][CH:6]([CH3:26])[CH2:7]2.[CH3:27][C:28]1[O:29][C:30]2[C:31](=[C:33]([C:37](O)=[O:38])[CH:34]=[CH:35][CH:36]=2)[N:32]=1.[OH-].[Na+]>O.CO>[CH3:26][CH:6]1[CH2:5][C@H:4]2[C@H:8]([CH2:9][N:10]([C:11]([C:13]3[N:14]=[C:15]([CH3:25])[S:16][C:17]=3[C:18]3[CH:19]=[C:20]([CH3:24])[CH:21]=[CH:22][CH:23]=3)=[O:12])[C@@H:3]2[CH2:2][NH:1][C:37]([C:33]2[CH:34]=[CH:35][CH:36]=[C:30]3[O:29][C:28]([CH3:27])=[N:32][C:31]=23)=[O:38])[CH2:7]1
Reactant: Cc1nc2c(C(=O)O)cccc2o1
Reactant: Cc1cccc(-c2sc(C)nc2C(=O)N2C[C@@H]3CC(C)C[C@@H]3[C@H]2CN)c1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: Cc1cccc(-c2sc(C)nc2C(=O)N2C[C@@H]3CC(C)C[C@@H]3[C@H]2CNC(=O)c2cccc3oc(C)nc23)c1

Procedure:
prepared by reaction of [(1S,2S,5R)-2-aminomethyl-7-methyl-3-aza-bicyclo[3.3.0]oct-3-yl]-(2-methyl-5-m-tolyl-thiazol-4-yl)-methanone with 2-methyl-benzoxazole-4-carboxylic acid which was synthesised by saponification of the corresponding methyl ester derivative (Goldstein S et al. J. of Heterocyclic. Chem. 1990, 27, 2, 335-336) with NaOH in a mixture water/MeOH.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[C:14]3[C:9](=[C:10]([CH3:15])[N:11]=[CH:12][CH:13]=3)[C:8](=[O:16])[N:7]([CH3:17])[C:6]=2[CH:18]=1.[Se](=O)=[O:20]>CC(O)=O.ClCCl>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[C:14]3[C:9](=[C:10]([CH:15]=[O:20])[N:11]=[CH:12][CH:13]=3)[C:8](=[O:16])[N:7]([CH3:17])[C:6]=2[CH:18]=1
Reactant: Cc1nccc2c1c(=O)n(C)c1cc(Cl)ccc21
Reactant: O=[Se]=O
Solvent: ClCCl
Solvent: CC(=O)O
Product: Cn1c(=O)c2c(C=O)nccc2c2ccc(Cl)cc21
Temperature: 70 °C
Reaction time: 3 h
Yield: 52.2 %

Procedure:
To a solution of 8-chloro-4,6-dimethylbenzo[c][2,7]naphthyridin-5(6H)-one (100 mg, 0.387 mmol), prepared as described in Example 16, Part G, in AcOH (4 mL) was added selenium dioxide (51.5 mg, 0.464 mmol). The reaction mixture was allowed to stir at 70° C. for 3 h. Volatiles were removed under reduced pressure and the residue so obtained was dissolved in dichloromethane (2 mL). The mixture was filtered through diatomaceous earth (Celite®) and the filtrate was concentrated under reduced pressure to afford the title product (0.1 g, 0.202 mmol, 52% crude yield) as pale yellow solid. The material was carried on without further purification. LC/MS, (ESI) m/z 273.0 [(M+H)+, calcd for C14H10ClN2O2, 273.0]; LC/MS retention time (method H): tR=1.89 min.
Reaction SMILES: [BH4-].[Na+].[Cl:3][C:4]1[CH:30]=[CH:29][C:7]([O:8][CH:9]([N:24]2[CH:28]=[N:27][CH:26]=[N:25]2)[C:10](=[O:23])[C:11]([CH3:22])([CH3:21])[CH2:12][S:13][C:14]2[CH:19]=[CH:18][C:17]([Cl:20])=[CH:16][CH:15]=2)=[CH:6][CH:5]=1>O.CO>[Cl:3][C:4]1[CH:5]=[CH:6][C:7]([O:8][CH:9]([N:24]2[CH:28]=[N:27][CH:26]=[N:25]2)[CH:10]([OH:23])[C:11]([CH3:22])([CH3:21])[CH2:12][S:13][C:14]2[CH:15]=[CH:16][C:17]([Cl:20])=[CH:18][CH:19]=2)=[CH:29][CH:30]=1
Reactant: CC(C)(CSc1ccc(Cl)cc1)C(=O)C(Oc1ccc(Cl)cc1)n1cncn1
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Solvent: O
Product: CC(C)(CSc1ccc(Cl)cc1)C(O)C(Oc1ccc(Cl)cc1)n1cncn1
Temperature: 20 °C
Reaction time: 4 h
Yield: 54.5 %

Procedure:
0.35 g (0.0092 mol) of sodium borohydride in 8 ml of water was added in portions to 10 g (0.023 mol) of 1-(4-chlorophenoxy)-4-(4-chlorophenylmercapto)-3,3-dimethyl-1-(1,2,4-triazol-1-yl)-butan-2-one (Example 4e) in 200 ml of methanol. The reaction mixture was subsequently stirred at 20° C. for 4 hours, poured onto water and extracted with ether. The ether phase was dried over sodium sulphate and concentrated. 5.5 g (54.6% of theory) of 1-(4-chlorophenoxy)-4-(4-chlorophenylmercapto)-3,3-dimethyl-1-(1,2,4-triazol-1-yl)-butan-2-ol of melting point 132° C. were obtained.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]([N:8]2[CH:12]=[C:11]([C:13]([O:15]C)=[O:14])[N:10]=[N:9]2)=[N:6][CH:7]=1.CO.O>O1CCCC1>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([N:8]2[CH:12]=[C:11]([C:13]([OH:15])=[O:14])[N:10]=[N:9]2)=[N:6][CH:7]=1
Reactant: COC(=O)c1cn(-c2ccc(Br)cn2)nn1
Solvent: C1CCOC1
Solvent: CO
Solvent: O
Product: O=C(O)c1cn(-c2ccc(Br)cn2)nn1
Temperature: 70 °C
Yield: 97.5 %

Procedure:
To a solution of methyl 1-(5-bromopyridin-2-yl)-1H-1,2,3-triazole-4-carboxylate (240 mg, 0.85 mmol) in a mixture of tetrahydrofuran (2.4 ml), methanol (2.4 ml) and water (2.4 ml) lithium hydroxide hydrate (107 mg, 2.54 mmol) was added. The solution was heated to 70° C. for 3 h. Most of the organic solvent was removed under reduced pressure. Water was added and the solution was extracted once with ether. Then 4 N hydrochloric acid was added to reach acidic pH. The product precipitated and the mixture was extracted three times with ethyl acetate. The organic layers were combined, dried (MgSO4) and evaporated to yield a light brown solid (223 mg, 98%). MS (ISP): 269.4 ({79Br} [M+H]+), 271.4 ({81Br} [M+H]+).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[N:4][C:5]([O:8][CH3:9])=[CH:6][CH:7]=1.CC[O:12][CH:13]=[C:14]([C:20](OCC)=O)[C:15]([O:17][CH2:18][CH3:19])=[O:16].CCCCC>C1C=CC(C2C=CC=CC=2)=CC=1.C1C=CC(OC2C=CC=CC=2)=CC=1>[CH2:18]([O:17][C:15]([C:14]1[CH:20]=[N:1][C:2]2[C:3]([C:13]=1[OH:12])=[N:4][C:5]([O:8][CH3:9])=[CH:6][CH:7]=2)=[O:16])[CH3:19]
Reactant: CCOC=C(C(=O)OCC)C(=O)OCC
Reactant: COc1ccc(N)cn1
Solvent: CCCCC
Solvent: c1ccc(Oc2ccccc2)cc1
Solvent: c1ccc(-c2ccccc2)cc1
Product: CCOC(=O)c1cnc2ccc(OC)nc2c1O

Procedure:
3-Amino-6-methoxypyridine (12.41 g) and diethyl ethoxymethylene malonate (20.2 ml) in Dowtherm A (400 ml) were heated at reflux, under argon for 1 hour. The cooled reaction mixture was poured into pentane (1 liter). The precipitated solid was collected by filtration, washed with pentane and dried to afforded a solid (24.78 g, crude).
Reaction SMILES: [B:1](OCCCC)([O:7]CCCC)[O:2]CCCC.C([O:19][CH:20](OCC)[C:21]1[CH:26]=[CH:25][C:24]([Mg]Br)=[CH:23][CH:22]=1)C.C(OC)(C)(C)C.S(=O)(=O)(O)O>O1CCCC1>[CH:20]([C:21]1[CH:26]=[CH:25][C:24]([B:1]([OH:7])[OH:2])=[CH:23][CH:22]=1)=[O:19]
Reactant: CCCCOB(OCCCC)OCCCC
Reactant: CCOC(OCC)c1ccc([Mg]Br)cc1
Agent: O=S(=O)(O)O
Solvent: C1CCOC1
Solvent: COC(C)(C)C
Product: O=Cc1ccc(B(O)O)cc1
Temperature: -50 °C
Reaction time: 1 h

Procedure:
Using a method based on that in Liebigs Ann. 1995, 1253-1257, a solution of 120 g of tri-n-butyl borate in 250 g of dry tetrahydrofuran was placed under nitrogen in a dried 2 l flask fitted with a dropping funnel and cooled to -50° C. 535 g of a 26.5% strength solution of 4-diethoxymethylphenylmagnesium bromide in THF are then added dropwise at such a rate that the internal temperature does not exceed −40 to −50° C. The mixture is subsequently stirred at −50° C for another 1 hour. 1 l of methyl t-butyl ether (MTBE) is subsequently added and the mixture is hydrolyzed at 5-10° C. using 650 g of 1M sulfuric acid. The aqueous phase was separated off and extracted three times with 500 ml each time of methyl t-butyl ether. The solvent was distilled off under reduced pressure and the crude boronic acid was once again taken up in 0.5 l of water and 185 ml of 5N aqueous potassium hydroxide (pH 14) at 5° C. The aqueous phase was extracted once with 250 ml of MTBE and subsequently, at 5° C., brought to a pH of 1 using 400 ml of 1M sulfuric acid. The precipitate was filtered off, washed twice with 150 ml of ice water and dried. This gives 66.1 g of 4-formylphenylboronic acid (88% of theory) comprising, according to HPLC, 89% of 4-formylphenylboronic acid, 4% of 4-carboxyphenylboronic acid, 3.8% of 4-hydroxymethylphenylboronic acid.
Reaction SMILES: [F:1][C@@H:2]1[C@@H:6]([CH2:7][OH:8])[O:5][C@@H:4]([N:9]2[CH:16]=[CH:15][C:13](=[O:14])[NH:12][C:10]2=[O:11])[CH2:3]1.[Si:17](Cl)([C:30]([CH3:33])([CH3:32])[CH3:31])([C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1)[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1.N1C=CN=C1>CN(C=O)C>[F:1][C@@H:2]1[C@@H:6]([CH2:7][O:8][Si:17]([C:30]([CH3:33])([CH3:32])[CH3:31])([C:24]2[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=2)[C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[O:5][C@@H:4]([N:9]2[CH:16]=[CH:15][C:13](=[O:14])[NH:12][C:10]2=[O:11])[CH2:3]1
Reactant: O=c1ccn([C@H]2C[C@H](F)[C@@H](CO)O2)c(=O)[nH]1
Reactant: CC(C)(C)[Si](Cl)(c1ccccc1)c1ccccc1
Agent: c1c[nH]cn1
Solvent: CN(C)C=O
Product: CC(C)(C)[Si](OC[C@H]1O[C@@H](n2ccc(=O)[nH]c2=O)C[C@@H]1F)(c1ccccc1)c1ccccc1

Procedure:
The title compound was synthesised following a similar procedure as described for Example 12. 3′-Fluoro-2′,3′-dideoxyuridine (0.176 g, 0.77 mmol) was reacted with tert-butyldiphenylsilyl chloride (0.238 g, 0.87 mmol) and imidazole (0.116 g, 1.70 mmol) in dry DMF (4 mL) for 3 h. Compound WSP948 was obtained as a white solid (0.331 g, 92%).
Reaction SMILES: C(OC([N:8]1[CH2:12][C@H:11]([NH:13][S:14]([C:17]2[CH:22]=[CH:21][C:20]([Cl:23])=[CH:19][CH:18]=2)(=[O:16])=[O:15])[CH2:10][C@H:9]1/[CH:24]=[CH:25]/[C:26]([O:28][CH2:29][CH3:30])=[O:27])=O)(C)(C)C>FC(F)(F)C(O)=O>[Cl:23][C:20]1[CH:19]=[CH:18][C:17]([S:14]([NH:13][C@H:11]2[CH2:12][NH:8][C@H:9](/[CH:24]=[CH:25]/[C:26]([O:28][CH2:29][CH3:30])=[O:27])[CH2:10]2)(=[O:16])=[O:15])=[CH:22][CH:21]=1
Reactant: CCOC(=O)/C=C/[C@@H]1C[C@@H](NS(=O)(=O)c2ccc(Cl)cc2)CN1C(=O)OC(C)(C)C
Solvent: O=C(O)C(F)(F)F
Product: CCOC(=O)/C=C/[C@@H]1C[C@@H](NS(=O)(=O)c2ccc(Cl)cc2)CN1
Yield: 69.3 %

Procedure:
A solution of (2S,4R)-1-t-butoxycarbonyl-4-(4-chlorophenylsulfonylamino)-2-[(E)-2-ethoxycarbonylvinyl]pyrrolidine (1.10 g) in 90% aqueous trifluoroacetic acid (10 ml) was stirred at room temperature for 1 hour and the solvent was evaporated in vacuo. The residue was dissolved in ethyl acetate and the solution was washed successively with saturated aqueous sodium bicarbonate and brine. The organic solution was dried over magnesium sulfate and evaporated in vacuo to give (2S,4R)-4-(4-chlorophenylsulfonylamino)-2-[(E)-2-ethoxycarbonylvinyl]pyrrolidine (596 mg) as an oil.
Reaction SMILES: [C:1]([O:5][CH:6]([C:10]1[C:19]([CH3:20])=[CH:18][C:17]2[C:12](=[CH:13][C:14]([CH:21]=[C:22]([CH3:24])[CH3:23])=[CH:15][CH:16]=2)[C:11]=1[C:25]1[CH:30]=[CH:29][C:28]([Cl:31])=[CH:27][CH:26]=1)[C:7]([OH:9])=[O:8])([CH3:4])([CH3:3])[CH3:2]>CC#N.O>[C:1]([O:5][CH:6]([C:10]1[C:19]([CH3:20])=[CH:18][C:17]2[C:12](=[CH:13][C:14]([CH2:21][CH:22]([CH3:23])[CH3:24])=[CH:15][CH:16]=2)[C:11]=1[C:25]1[CH:26]=[CH:27][C:28]([Cl:31])=[CH:29][CH:30]=1)[C:7]([OH:9])=[O:8])([CH3:3])([CH3:4])[CH3:2]
Reactant: CC(C)=Cc1ccc2cc(C)c(C(OC(C)(C)C)C(=O)O)c(-c3ccc(Cl)cc3)c2c1
Solvent: CC#N
Solvent: O
Product: Cc1cc2ccc(CC(C)C)cc2c(-c2ccc(Cl)cc2)c1C(OC(C)(C)C)C(=O)O

Procedure:
2-tert-Butoxy-2-(1-(4-chlorophenyl)-7-isobutyl-3-methylnaphthalen-2-yl)acetic acid (94) was prepared using the procedure of Example 87 from 2-tert-butoxy-2-(1-(4-chlorophenyl)-3-methyl-7-(2-methylprop-1-enyl)naphthalen-2-yl)acetic acid. 1H-NMR: 400 MHz, (CD3OD) δ: 7.66 (m, 3H), 7.55 (m, 2H), 7.28 (m, 2H), 6.97 (s, 1H), 5.13 (s, 1H), 2.59 (s, 3H), 2.44 (d, J=7 Hz, 2H), 0.96 (s, 9H), 0.83 (m, 6H). HPLC (Kinetex 2.6u, 50×4.6 mm, 2-100% MeCN/H2O+0.05% HOAc, 4.0 min run): tR (min)=3.03.
Reaction SMILES: [CH3:1][C:2]([CH3:30])([CH3:29])[C:3](=[O:28])[CH2:4][O:5][C:6]1[CH:11]=[CH:10][C:9]([C:12]([C:17]2[S:21][C:20]([S:22]([NH2:25])(=[O:24])=[O:23])=[C:19]([CH3:26])[CH:18]=2)([CH2:15][CH3:16])[CH2:13][CH3:14])=[CH:8][C:7]=1[CH3:27].[CH:31]1([C:34](O)=[O:35])[CH2:33][CH2:32]1>>[CH:31]1([C:34]([NH:25][S:22]([C:20]2[S:21][C:17]([C:12]([C:9]3[CH:10]=[CH:11][C:6]([O:5][CH2:4][C:3](=[O:28])[C:2]([CH3:1])([CH3:29])[CH3:30])=[C:7]([CH3:27])[CH:8]=3)([CH2:13][CH3:14])[CH2:15][CH3:16])=[CH:18][C:19]=2[CH3:26])(=[O:24])=[O:23])=[O:35])[CH2:33][CH2:32]1
Reactant: CCC(CC)(c1ccc(OCC(=O)C(C)(C)C)c(C)c1)c1cc(C)c(S(N)(=O)=O)s1
Reactant: O=C(O)C1CC1
Product: CCC(CC)(c1ccc(OCC(=O)C(C)(C)C)c(C)c1)c1cc(C)c(S(=O)(=O)NC(=O)C2CC2)s1
Yield: 60 %

Procedure:
Using a procedure analogous to Example 163, 5-{1-[4-(3,3-dimethyl-2-oxo-butoxy)-3-methyl-phenyl]-1-ethyl-propyl}-3-methyl-thiophene-2-sulfonic acid amide and cyclopropanecarboxylic acid give the title compound (60%).
Reaction SMILES: [CH3:1][S:2]([N:5]1[CH2:15][CH:14]2[CH2:16][CH:7]([C:8]3[C:13]2=[CH:12][C:11]([N+:17]([O-])=O)=[CH:10][CH:9]=3)[CH2:6]1)(=[O:4])=[O:3].[H][H]>CCO.C(Cl)Cl.[Pd]>[CH3:1][S:2]([N:5]1[CH2:15][CH:14]2[CH2:16][CH:7]([C:8]3[C:13]2=[CH:12][C:11]([NH2:17])=[CH:10][CH:9]=3)[CH2:6]1)(=[O:4])=[O:3]
Reactant: [H][H]
Reactant: CS(=O)(=O)N1CC2CC(C1)c1cc([N+](=O)[O-])ccc12
Agent: [Pd]
Solvent: CCO
Solvent: ClCCl
Product: CS(=O)(=O)N1CC2CC(C1)c1cc(N)ccc12
Yield: 103.7 %

Procedure:
10-methanesulfonyl-4-nitro-10-aza-tricyclo[6.3.1.0*2,7*]dodeca-2,4,6-triene (170 mg, 0.60 mmol) in 8 ml EtOH and 2 ml methylene chloride in a Parr bottle was treated with 50 mg 10% Pd/C and subjected to hydrogen (g) at 40 psi for 2 h. The suspension was filtered and the solvent removed under reduced pressure to yield 10-methanesulfonyl-10-aza-tricyclo[6.3.1.0*2,7*]dodeca-2,4,6-trien-4-ylamine (157 mg, 99%). 1H-NMR (CDCl3) δ 7.03, (d, J=7.8 Hz, 1H), 6.64 (s, 1H), 6.52 (dd, J=7.8, 2.3 Hz, 1H), 3.77-3.68 (m, 1H), 3.67-3.54 (m, 3H), 3.36 (dd, J=12.6, 6.8 Hz, 2H), 3.13-3.05 (m, 2H), 2.38-2.28 (m, 1H), 2.03 (s, 3H), 1.78 (d, J=10.9 Hz, 1H), 1.24 (t, J=7.0 Hz, 3H); LC/MS (ESI+): 253 (M+H).
Reaction SMILES: [CH3:1][C:2]1[NH:3][C:4]2[C:9]([CH:10]=1)=[C:8]([C:11]([F:14])([F:13])[F:12])[C:7]([C:15]#[N:16])=[CH:6][CH:5]=2.Cl[CH2:18][C:19]1[N:20]=[C:21]([C:24]2[CH:29]=[CH:28][C:27]([Cl:30])=[CH:26][CH:25]=2)[S:22][CH:23]=1>>[Cl:30][C:27]1[CH:26]=[CH:25][C:24]([C:21]2[S:22][CH:23]=[C:19]([CH2:18][N:3]3[C:4]4[C:9](=[C:8]([C:11]([F:12])([F:14])[F:13])[C:7]([C:15]#[N:16])=[CH:6][CH:5]=4)[CH:10]=[C:2]3[CH3:1])[N:20]=2)=[CH:29][CH:28]=1
Reactant: Cc1cc2c(C(F)(F)F)c(C#N)ccc2[nH]1
Reactant: ClCc1csc(-c2ccc(Cl)cc2)n1
Product: Cc1cc2c(C(F)(F)F)c(C#N)ccc2n1Cc1csc(-c2ccc(Cl)cc2)n1

Procedure:
Synthesized as described in Example 4 using 2-methyl-4-(trifluoromethyl)-1H-indole-5-carbonitrile (Example 120) and 4-(chloromethyl)-2-(4-chlorophenyl)-1,3-thiazole: MS (ES) m/z 432 (M+1) and 434 (M+1, isotope).
Reaction SMILES: [N:1]1[CH:6]=[CH:5][C:4]([N:7]2[CH2:12][CH2:11][CH:10]([CH2:13][N:14]3[CH2:19][CH2:18][NH:17][CH2:16][C:15]3=[O:20])[CH2:9][CH2:8]2)=[CH:3][CH:2]=1.C(N(CC)CC)C.[Br:28][C:29]1[CH:30]=[C:31]([S:35](Cl)(=[O:37])=[O:36])[CH:32]=[CH:33][CH:34]=1>ClCCl>[Br:28][C:29]1[CH:30]=[C:31]([S:35]([N:17]2[CH2:18][CH2:19][N:14]([CH2:13][CH:10]3[CH2:11][CH2:12][N:7]([C:4]4[CH:5]=[CH:6][N:1]=[CH:2][CH:3]=4)[CH2:8][CH2:9]3)[C:15](=[O:20])[CH2:16]2)(=[O:37])=[O:36])[CH:32]=[CH:33][CH:34]=1
Reactant: O=S(=O)(Cl)c1cccc(Br)c1
Reactant: O=C1CNCCN1CC1CCN(c2ccncc2)CC1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: O=C1CN(S(=O)(=O)c2cccc(Br)c2)CCN1CC1CCN(c2ccncc2)CC1
Yield: 26 %

Procedure:
To a solution of 1-[1-(4-pyridyl)-4-piperidylmethyl]-2-piperazinone (2.74 g) and triethylamine (1.67 ml) in dichioromethane (50 ml) was added dropwise at 0° C. 3-bromobenzenesulfonyl chloride (2.56 g), and the mixture was stirred at 0° C. for 1 hour. The reaction solution was diluted with dichioromethane, was washed with water and saturated brine, dried (MgSO4) and concentrated, and the residue was purified with silica gel column chromatography (acetone methanol=9:1=>1:1) and washed with water to give colorless crystals of 4-(3-bromobenzenesulfonyl)-1-[1-(4-pyridyl)-4-piperidylmethyl]-2-piperazinone (1.28 g). A part of the crystals were treated with hydrochloric acid to give colorless crystals of the title compound as hydrochloride.
Reaction SMILES: [OH-].[Na+].[Cl:3][C:4]1[CH:35]=[CH:34][C:7]([CH2:8][O:9][C:10]2[CH:15]=[CH:14][N:13]([C:16]3[CH:17]=[CH:18][C:19]4[N:23]=[C:22]([CH:24]5[CH2:26][CH:25]5[C:27]([O:29]C)=[O:28])[N:21]([CH3:31])[C:20]=4[CH:32]=3)[C:12](=[O:33])[CH:11]=2)=[CH:6][CH:5]=1.CO.Cl>C1COCC1>[Cl:3][C:4]1[CH:35]=[CH:34][C:7]([CH2:8][O:9][C:10]2[CH:15]=[CH:14][N:13]([C:16]3[CH:17]=[CH:18][C:19]4[N:23]=[C:22]([CH:24]5[CH2:26][CH:25]5[C:27]([OH:29])=[O:28])[N:21]([CH3:31])[C:20]=4[CH:32]=3)[C:12](=[O:33])[CH:11]=2)=[CH:6][CH:5]=1
Reactant: COC(=O)C1CC1c1nc2ccc(-n3ccc(OCc4ccc(Cl)cc4)cc3=O)cc2n1C
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Product: Cn1c(C2CC2C(=O)O)nc2ccc(-n3ccc(OCc4ccc(Cl)cc4)cc3=O)cc21
Yield: 81 %

Procedure:
Sodium hydroxide (1.811 ml) was added to a solution of methyl(1RS,2RS)-2-(6-(4-((4-chlorobenzyl)oxy)-2-oxopyridin-1 (2H)-yl)-1-methyl-1H-benzimidazol-2-yl)cyclopropanecarboxylate (280 mg) in THF (3 ml)-MeOH (3 ml) at room temperature. The mixture was neutralized with 1 M HCl at 0° C. and extracted with EtOAc and MeOH. The organic layer was separated, washed with water and brine, dried over MgSO4 and concentrated in vacuo. The resulting solid was washed with IPE and dried to give the title compound (220 mg) as a white solid.
Reaction SMILES: Cl.Cl.[Cl:3][C:4]1[N:9]=[C:8]([NH:10][CH:11]2[CH2:16][CH2:15][NH:14][CH2:13][CH2:12]2)[CH:7]=[CH:6][N:5]=1.C(O)(=O)C.C(N(C(C)C)C(C)C)C.[CH2:30]([O:32][C:33]1[CH:34]=[C:35]([CH:38]=[CH:39][C:40]=1[CH3:41])[CH:36]=O)[CH3:31].C([BH3-])#N.[Na+]>C(O)C>[Cl:3][C:4]1[N:9]=[C:8]([NH:10][CH:11]2[CH2:16][CH2:15][N:14]([CH2:36][C:35]3[CH:38]=[CH:39][C:40]([CH3:41])=[C:33]([O:32][CH2:30][CH3:31])[CH:34]=3)[CH2:13][CH2:12]2)[CH:7]=[CH:6][N:5]=1
Reactant: Clc1nccc(NC2CCNCC2)n1
Reactant: CCOc1cc(C=O)ccc1C
Agent: Cl
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CCO
Solvent: CC(=O)O
Solvent: CCN(C(C)C)C(C)C
Product: CCOc1cc(CN2CCC(Nc3ccnc(Cl)n3)CC2)ccc1C
Temperature: 55 °C
Reaction time: 1 h
Yield: 4.4 %

Procedure:
To a solution of (2-chloro-pyrimidin-4-yl)-piperidin-4-yl-amine dihydrochloride (42.9 mg, 0.15 mmol, 1.0 equiv; intermediate C1) in ethanol (2 mL), acetic acid (72.1 mg, 1.2 mmol, 8.0 equiv) and N-ethyl diisopropylamine (77.6 mg, 0.6 mmol, 4.0 equiv) was added 3-ethoxy-4-methyl-benzaldehyde (29.6 mg, 0.18 mmol, 1.2 equiv; intermediate D10, vide infra) and the mixture stirred at 55° C. After 1 h, sodium cyanoborohydride (47.1 mg, 0.75 mmol, 5.0 equiv), dissolved in ethanol (0.5 mL), was added and the mixture stirred at 55° C. over night. Removal of the solvent under reduced pressure and purification by preparative HPLC on reversed phase eluting with a gradient of acetonitrile/water provided 2.4 mg (4%) of the title compound. MS (ISP): 361.3 [M+H]+.