Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[C:9]([Cl:10])=[CH:8][CH:7]=[CH:6][C:3]=1[CH:4]=O.[C:11]([O:17][CH2:18][CH2:19][N:20]1[CH2:25][CH2:24][CH:23]([CH:26]([C:33]2[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=2)[C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)[CH2:22][CH2:21]1)(=[O:16])[CH2:12][C:13]([CH3:15])=O.[NH2:39]/[C:40](/[CH3:47])=[CH:41]\[C:42]([O:44][CH2:45][CH3:46])=[O:43]>CC(O)C>[Cl:1][C:2]1[C:9]([Cl:10])=[CH:8][CH:7]=[CH:6][C:3]=1[CH:4]1[C:41]([C:42]([O:44][CH2:45][CH3:46])=[O:43])=[C:40]([CH3:47])[NH:39][C:13]([CH3:15])=[C:12]1[C:11]([O:17][CH2:18][CH2:19][N:20]1[CH2:21][CH2:22][CH:23]([CH:26]([C:33]2[CH:34]=[CH:35][CH:36]=[CH:37][CH:38]=2)[C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)[CH2:24][CH2:25]1)=[O:16]
Reactant: CCOC(=O)/C=C(/C)N
Reactant: CC(=O)CC(=O)OCCN1CCC(C(c2ccccc2)c2ccccc2)CC1
Reactant: O=Cc1cccc(Cl)c1Cl
Solvent: CC(C)O
Product: CCOC(=O)C1=C(C)NC(C)=C(C(=O)OCCN2CCC(C(c3ccccc3)c3ccccc3)CC2)C1c1cccc(Cl)c1Cl

Procedure:
A mixture of 2,3-dichlorobenzaldehyde (0.615 g), 2-(4-diphenylmethylpiperidino)ethyl acetoacetate (1.30 g), ethyl 3-aminocrotonate (0.450 g) and 2-propanol (10 ml) was treated in the same manner as Example 13 to give 2-(4-diphenylmethylpiperidino)ethyl ethyl 4-(2,3-dichlorophenyl)-1,4-dihydro-2,6-dimethyl-3,5-pyridinedicarboxylate as a light-yellow powder. Yield 0.272 g (11.9%). m.p. 81°-85° C. (sintering).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:12]=[C:11]([CH3:13])[O:10][N:9]=2)=[CH:4][CH:3]=1.C([O:17][B:18](OC(C)C)[O:19]C(C)C)(C)C.C([Li])(C)(C)C.[OH-].[Na+]>C1COCC1.O>[CH3:13][C:11]1[O:10][N:9]=[C:8]([C:5]2[CH:6]=[CH:7][C:2]([B:18]([OH:19])[OH:17])=[CH:3][CH:4]=2)[N:12]=1
Reactant: Cc1nc(-c2ccc(Br)cc2)no1
Reactant: CC(C)OB(OC(C)C)OC(C)C
Agent: [Li]C(C)(C)C
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: Cc1nc(-c2ccc(B(O)O)cc2)no1
Temperature: -100 °C
Reaction time: 0.33 h
Yield: 58.6 %

Procedure:
A solution of 3-(4-bromophenyl)-5-methyl-1,2,4-oxadiazole (1.0 g) in dry THF (8 ml) containing triisopropylborate (3.5 ml, 2.82 g) was cooled to -100° C. under nitrogen, and treated cautiously with tert-butyllithium (8.82 ml, 1.7M solution). The temperature was maintained between -90° C. and -105° C. during addition. The mixture was stirred at -100° C. for 20 mins after complete addition, and then allowed to warm to -30° C. The mixture was treated slowly with water (5 ml) and allowed to warm to room temperature, 2N sodium hydroxide (50 ml) was added and the basic aqueous layer washed with dichloromethane (2×50 ml). The aqueous layer was acidified with 2N hydrochloric acid (60 ml) and extracted with dichloromethane (4×50 ml, containing 20% methanol). The combined, dried extracts were concentrated in vacuo to give the title compound as a pale yellow solid (500 mg). m.p . 266°-268° C.
Reaction SMILES: C(N(CC)CC)C.C(=O)([O-])[O-].[K+].[K+].Cl[C:15]1[C:24]2[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=2)[N:18]=[CH:17][C:16]=1[N+:25]([O-:27])=[O:26].Cl.[NH2:29][CH2:30][CH2:31][CH2:32][C:33]([O:35][CH2:36][CH3:37])=[O:34]>O1CCCC1.C(Cl)(Cl)Cl>[N+:25]([C:16]1[CH:17]=[N:18][C:19]2[C:24]([C:15]=1[NH:29][CH2:30][CH2:31][CH2:32][C:33]([O:35][CH2:36][CH3:37])=[O:34])=[CH:23][CH:22]=[CH:21][CH:20]=2)([O-:27])=[O:26]
Reactant: O=[N+]([O-])c1cnc2ccccc2c1Cl
Reactant: CCOC(=O)CCCN
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Solvent: ClC(Cl)Cl
Product: CCOC(=O)CCCNc1c([N+](=O)[O-])cnc2ccccc12
Temperature: 25 °C
Yield: 88.4 %

Procedure:
Triethylamine (50.0 mL, 358 mmol) and potassium carbonate (40 g, 290 mmol) were added to a solution of 4-chloro-3-nitroquinoline (49.6 g, 238 mmol) in tetrahydrofuran (THF) (100 mL) and chloroform (250 mL). Ethyl 4-aminobutyrate hydrochloride (43.8 g, 262 mmol) was added in portions over a period of five minutes during which time an ice bath was used to cool the reaction. The reaction was stirred with cooling for 30 minutes, allowed to warm to ambient temperature, and stirred overnight. An analysis by thin layer chromatography (TLC) indicated the presence of 4-chloro-3-nitroquinoline. Additional ethyl 4-aminobutyrate hydrochloride (8.0 g, 48 mmol) was added, and the reaction was stirred at ambient temperature for one hour and then heated at reflux for two hours. Additional triethylamine (20 mL) was added, and the reaction was heated at reflux for one hour, cooled to ambient temperature, washed with water (3×100 mL), dried over potassium carbonate, filtered, and concentrated under reduced pressure to provide 63.8 g of ethyl 4-(3-nitroquinolin-4-ylamino)butyrate as a yellow solid.
Reaction SMILES: [CH2:1]([NH:11][C:12](=[O:30])[CH:13]=[CH:14][C:15]1[CH:20]=[CH:19][CH:18]=[C:17]([N:21]2[CH2:25][CH:24]([C:26]([OH:28])=[O:27])[CH2:23][C:22]2=[O:29])[CH:16]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH3:10].C(N1C=CN=C1)(N1C=CN=C1)=O.[CH2:43]([N:45]([CH2:48][CH2:49]O)[CH2:46][CH3:47])[CH3:44]>O1CCCC1>[CH2:1]([NH:11][C:12](=[O:30])[CH:13]=[CH:14][C:15]1[CH:20]=[CH:19][CH:18]=[C:17]([N:21]2[CH2:25][CH:24]([C:26]([O:28][CH2:44][CH2:43][N:45]([CH2:48][CH3:49])[CH2:46][CH3:47])=[O:27])[CH2:23][C:22]2=[O:29])[CH:16]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH3:10]
Reactant: CCCCCCCCCCNC(=O)C=Cc1cccc(N2CC(C(=O)O)CC2=O)c1
Reactant: CCN(CC)CCO
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: C1CCOC1
Product: CCCCCCCCCCNC(=O)C=Cc1cccc(N2CC(C(=O)OCCN(CC)CC)CC2=O)c1
Temperature: 25 °C

Procedure:
To a stirred solution of 829 mg. of N-decyl-3-(3-[4-carboxy-2-oxo-pyrrolidino]phenyl)propenamide in 25 ml. of tetrahydrofuran was added 357 mg. of carbonyldiimidazole. The mixture was heated under reflux for 10 minutes, and then 258 mg. of 2-(N,N-diethylamino)ethanol was added. The mixture was again heated under reflux for 10 minutes, and then an additional 258 mg. of 2-(N,N-diethylamino)ethanol was added. The mixture was heated under reflux for 15 minutes and then it was cooled to room temperature. The solvent was removed by evaporation in vacuo, and the residue was dissolved in 75 ml. of ethyl acetate. The ethyl acetate solution was washed successively with water, 1 N sodium hydroxide, water and saturated sodium chloride solution. The ethyl acetate solution was then dried using sodium sulfate, and the ethyl acetate was removed by evaporation in vacuo. The residue (960 mg.) was recrystallized from isopropyl ether giving 570 mg. of the title compound, m.p. 78°-80° C.
Reaction SMILES: [F:1][CH:2]([F:37])[O:3][C:4]1[CH:9]=[CH:8][C:7]([C:10]2[CH:11]=[N:12][C:13]([NH:16][C:17]3[CH:18]=[CH:19][C:20]([CH3:36])=[C:21]([NH:23][C:24]([N:26]4[CH2:31][CH2:30][NH:29][CH:28]([C:32]([F:35])([F:34])[F:33])[CH2:27]4)=[O:25])[CH:22]=3)=[N:14][CH:15]=2)=[CH:6][CH:5]=1.[CH2:38]=[O:39].[O-:40]S([O-])(=O)=O.[Na+].[Na+]>C(Cl)Cl>[F:37][CH:2]([F:1])[O:3][C:4]1[CH:5]=[CH:6][C:7]([C:10]2[CH:11]=[N:12][C:13]([NH:16][C:17]3[CH:18]=[CH:19][C:20]([CH3:36])=[C:21]([NH:23][C:24]([N:26]4[CH2:31][CH2:30][N:29]([CH3:38])[CH:28]([C:32]([F:35])([F:34])[F:33])[CH2:27]4)=[O:25])[CH:22]=3)=[N:14][CH:15]=2)=[CH:8][CH:9]=1.[C:38]([OH:40])([C:32]([F:35])([F:34])[F:33])=[O:39]
Reactant: Cc1ccc(Nc2ncc(-c3ccc(OC(F)F)cc3)cn2)cc1NC(=O)N1CCNC(C(F)(F)F)C1
Reactant: O=S(=O)([O-])[O-]
Reactant: C=O
Agent: [Na+]
Solvent: ClCCl
Product: Cc1ccc(Nc2ncc(-c3ccc(OC(F)F)cc3)cn2)cc1NC(=O)N1CCN(C)C(C(F)(F)F)C1
Product: O=C(O)C(F)(F)F
Reaction time: 12 h

Procedure:
A solution of N-(5-(5-(4-(difluoromethoxy)phenyl)pyrimidin-2-ylamino)-2-methylphenyl)-3-(trifluoromethyl)piperazine-1-carboxamide D11 (0.05 mmol), HCHO (0.15 mmol, 30% aqueous) and anhydrous Na2SO4 (1.5 mmol) in DCM (2 mL) is stirred at rt for 30 min. Then NaHB(OAc)3 (0.3 mmol) is added and the resulting mixture is stirred for 12 h. Purification by prep-HPLC (ACN gradient 10-70%) affords N-(5-(5-(4-(Difluoromethoxy)phenyl)pyrimidin-2-ylamino)-2-methylphenyl)-3-(trifluoromethyl)-4-methylpiperazine-1-carboxamide D12 as a TFA salt. 1H NMR (400 MHz, d6-DMSO) δ 9.69 (s, 1H), 8.80 (s, 2H), 8.15 (s, 1H), 7.76 (d, J=8.8 Hz, 2H), 7.61 (s, 1H), 7.50 (d, J=8.0 Hz, 1H), 7.28 (t, J=74.0 Hz, 1H), 7.27 (d, J=8.8 Hz, 2H), 7.09 (d, J=8.4 Hz, 1H), 3.68 (m, 1H), 3.54 (m, 1H), 2.88 (m, 1H), 2.51 (m, 4H), 2.47 (s, 1H), 2.09 (s, 3H). MS (m/z) (M+1)+: 537.2.
Reaction SMILES: Cl.Cl.[N:3]1[C:12]2[NH:11][CH2:10][CH2:9][CH2:8][C:7]=2[CH:6]=[CH:5][C:4]=1[CH2:13][CH2:14][CH2:15][NH2:16].CO[C:19](=[O:36])[CH:20]([CH2:33][CH:34]=O)[CH:21]([C:26]1[CH:31]=[CH:30][CH:29]=[C:28]([F:32])[CH:27]=1)[CH2:22][C:23]([OH:25])=[O:24].Cl.[CH2:38](OCC)[CH3:39].C(N(CC)CC)C.[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+]>ClCCCl>[CH2:38]([O:25][C:23](=[O:24])[CH2:22][CH:21]([C:26]1[CH:31]=[CH:30][CH:29]=[C:28]([F:32])[CH:27]=1)[CH:20]1[CH2:33][CH2:34][N:16]([CH2:15][CH2:14][CH2:13][C:4]2[CH:5]=[CH:6][C:7]3[CH2:8][CH2:9][CH2:10][NH:11][C:12]=3[N:3]=2)[C:19]1=[O:36])[CH3:39]
Reactant: COC(=O)C(CC=O)C(CC(=O)O)c1cccc(F)c1
Reactant: NCCCc1ccc2c(n1)NCCC2
Reactant: CCOCC
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: Cl
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: ClCCCl
Product: CCOC(=O)CC(c1cccc(F)c1)C1CCN(CCCc2ccc3c(n2)NCCC3)C1=O
Reaction time: 0.17 h

Procedure:
To a mixture of 3-(5,6,7,8-tetrahydro-[1,8]naphthyridin-2-yl)-propylamine (1-8) (67 mg, 0.36 mmol) and 3-(3-fluoro-phenyl)-2-(2-oxoethyl)-pentanedioic acid 1-methyl ester 2-6A (110 mg, 0.36 mmol) in 5 mL 1,2-dichloroethane was added anhydrous hydrogen chloride in ethyl ether (1.0 M, 0.70 ml, 0.7 mmol). After 10 min, triethylamine (0.14 mL, 1.1 mmol) and 4 Å molecular sieves were added. The mixture was stirred for 3 hr. It was treated with NaBH(OAc)3 (111 mg, 0.53 mmol) and stirred for 12 hr. The reaction was quenched with 10% NaHCO3 and extracted with EtOAc (×3). The combined organic layers were washed with brine and dried (Na2SO4). After solvent removal the residue was purified by flash silica chromatography (CHCl3 /MeOH, 10:1) to provide the enantiomeric pair 2-7A as an oil.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([O:15][CH3:16])=[C:6]([CH:8]2[O:12][C:11](=[O:13])[NH:10][C:9]2=[O:14])[CH:7]=1.[CH:17]1([N:23]=[C:24]=[O:25])[CH2:22][CH2:21][CH2:20][CH2:19][CH2:18]1>C(N(CC)CC)C.ClCCCl>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([O:15][CH3:16])=[C:6]([CH:8]2[O:12][C:11](=[O:13])[N:10]([C:24](=[O:25])[NH:23][CH:17]3[CH2:22][CH2:21][CH2:20][CH2:19][CH2:18]3)[C:9]2=[O:14])[CH:7]=1
Reactant: COc1ccc(Cl)cc1C1OC(=O)NC1=O
Reactant: O=C=NC1CCCCC1
Solvent: CCN(CC)CC
Solvent: ClCCCl
Product: COc1ccc(Cl)cc1C1OC(=O)N(C(=O)NC2CCCCC2)C1=O
Temperature: 25 °C
Reaction time: 19 h

Procedure:
5-(5-Chloro-2-methoxyphenyl)oxazolidine-2,4-dione (1.21 g., 5 mmoles) was suspended in 50 ml. of 1,2-dichloroethane. Triethylamine (1 drop) and then cyclohexylisocyanate (626 mg., 5 mmoles) were added. The reaction mixture was stirred for 19 hours at room temperature, washed in sequence with two portions of 1N sodium hydroxide, two portions of 1N hydrochloric acid and once with brine, dried over anhydrous magnesium sulfate, filtered and concentrated to solids. Recrystallization from toluene gave purified 5-(5-chloro-2-methoxyphenyl)-3-cyclohexylcarbamoyloxazolidine-2,4-dione [435 mg., m.p. 150°-153° C., ir (KBr) 1818, 1761, 1527, 1493, 1364 cm-1 ].
Reaction SMILES: Cl[CH2:2][C@@H:3]1[CH2:7][O:6]C(C)(C)[O:4]1.[Br:10][C:11]1[CH:16]=[CH:15][C:14]([NH:17][C:18]2[C:27]3[C:26](=[O:28])[NH:25][CH:24]=[N:23][C:22]=3[N:21]([CH3:29])[C:20](=[O:30])[C:19]=2[CH3:31])=[C:13]([F:32])[CH:12]=1.Cl>>[Br:10][C:11]1[CH:16]=[CH:15][C:14]([NH:17][C:18]2[C:27]3[C:26](=[O:28])[N:25]([CH2:2][C@@H:3]([OH:4])[CH2:7][OH:6])[CH:24]=[N:23][C:22]=3[N:21]([CH3:29])[C:20](=[O:30])[C:19]=2[CH3:31])=[C:13]([F:32])[CH:12]=1
Reactant: Cc1c(Nc2ccc(Br)cc2F)c2c(=O)[nH]cnc2n(C)c1=O
Reactant: CC1(C)OC[C@@H](CCl)O1
Agent: Cl
Product: Cc1c(Nc2ccc(Br)cc2F)c2c(=O)n(C[C@@H](O)CO)cnc2n(C)c1=O

Procedure:
The title compound was prepared according to the procedure used for Example 9 synthesis by reaction of (S)-4-(chloromethyl)-2,2-dimethyl-1,3-dioxolane with compound 9F, followed by hydrolysis with 1N HCl. 1H NMR (400 MHz, MeOD) δ ppm 1.71 (s, 3H) 3.44-3.51 (m, 1H) 3.59 (d, J=5.31 Hz, 2H) 3.74 (s, 3H) 3.76-3.82 (m, 1H) 3.91-4.01 (m, 1H) 4.41 (dd, J=13.64, 3.28 Hz, 1H) 6.77 (t, J=8.59 Hz, 1H) 7.26 (d, J=9.09 Hz, 1H) 7.39 (d, J=2.02 Hz, 1H) 8.38 (s, 1H)) [M+H] calc'd for C18H18BrFN4O4, 454; found, 454.
Reaction SMILES: [CH:1]1[CH:6]=[CH:5][C:4]([CH2:7][O:8][CH2:9][CH:10]([OH:13])[CH2:11][OH:12])=[CH:3][CH:2]=1.[CH3:14][CH2:15][C:16](=O)[CH2:17][CH3:18].O.C1(C)C=CC(S(O)(=O)=O)=CC=1.C(=O)([O-])O.[Na+]>O1CCCC1>[CH2:7]([O:8][CH2:9][CH:10]1[CH2:11][O:12][C:16]([CH2:17][CH3:18])([CH2:15][CH3:14])[O:13]1)[C:4]1[CH:3]=[CH:2][CH:1]=[CH:6][CH:5]=1
Reactant: CCC(=O)CC
Reactant: OCC(O)COCc1ccccc1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: CCC1(CC)OCC(COCc2ccccc2)O1
Reaction time: 22 h
Yield: 67.1 %

Procedure:
To a tetrahydrofuran (30 ml) solution of DL-α-O-benzyl glycerol (3 g, 16.5 mmol), 3-pentanone (17.5 ml, 165 mmol) and p-toluenesulfonic acid monohydrate (300 mg, 1.58 mmol) were added at room temperature and the mixture was stirred at the same temperature for 22 hours. To the reaction mixture, a saturated aqueous sodium hydrogen carbonate solution (5 ml) was added to adjust pH to about 8. The generated precipitate was removed by filtration and the filtrate was concentrated. The obtained residue was purified by silica gel column chromatography (NH silica gel, elution solvent: heptane/ethyl acetate=1/0 to 3/1 gradient). A desired fraction was concentrated to obtain the title compound (2.77 g, 67.1% yield) as a colorless oil.
Reaction SMILES: C(OC([C@H:8]([C:17]([NH:19][C@H:20]([C:22]1[C:31]2[C:26](=[CH:27][CH:28]=[CH:29][CH:30]=2)[CH:25]=[CH:24][CH:23]=1)[CH3:21])=[O:18])[CH2:9][CH2:10][CH2:11][N:12](N)C(=O)[O-])=O)(C)(C)C.[CH:32]([O-:34])=[O:33].[NH4+:35]>C(O)C.[Pd]>[NH2:12][CH2:11][CH2:10][CH2:9][C@H:8]([NH:35][C:32](=[O:34])[O:33][C:22]([CH3:31])([CH3:23])[CH3:20])[C:17]([NH:19][C@H:20]([C:22]1[C:31]2[C:26](=[CH:27][CH:28]=[CH:29][CH:30]=2)[CH:25]=[CH:24][CH:23]=1)[CH3:21])=[O:18]
Reactant: C[C@H](NC(=O)[C@H](CCCN(N)C(=O)[O-])C(=O)OC(C)(C)C)c1cccc2ccccc12
Reactant: [NH4+]
Reactant: O=C[O-]
Agent: [Pd]
Solvent: CCO
Product: C[C@H](NC(=O)[C@H](CCCN)NC(=O)OC(C)(C)C)c1cccc2ccccc12
Temperature: 55 °C
Reaction time: 18 h

Procedure:
A solution of (S)-4-(tert-butoxycarbonyl)-amino-5-((S)-1-(naphthalen-1-yl)ethylamino)-5-oxopentylcarbamate, 23, (28.0 g, 54.0 mmol) in ethanol (600 mL) was added ammonium formate (10.2 g, 160.0 mmol) and palladium (10 wt % on carbon, 1.0 g). The reaction mixture was warmed to 55° C. and stirred for 18 h at 55° C. The mixture was filtered through Celite and washed with ethanol. The resulting filtrate was concentrated in vacuo. The residue was dissolved in ethyl acetate and the organic phase was washed with aqueous saturated NaCl solution. The organic phase was dried (MgSO4), filtered and concentrated in vacuo. The crude residue was used without further purification: 1H NMR (d6-DMSO) δ 8.55 (d, J=7.6 Hz, 1H), 8.04 (d, J=8.4 Hz, 1H), 7.89 (d, J=8.0 Hz, 1H), 7.78 (d, J=8.0 Hz, 1H), 7.53-7.42 (m, 4H), 6.81 (d, J=8.0 Hz, 1H), 5.65-5.62 (m, 1H), 3.96-3.89 (m, 1H), 2.60-2.53 (m, 2H), 1.46-1.40 (m, 7H), 1.33 (s, 9H); ESI+ MS: m/z (rel intensity) 386.2 (100, [M+H]+).
Reaction SMILES: [F:1][CH2:2][CH:3]([NH:8]C(OC(C)(C)C)=O)[CH2:4][C:5]([OH:7])=[O:6].[ClH:16]>CCOCC>[ClH:16].[F:1][CH2:2][CH:3]([NH2:8])[CH2:4][C:5]([OH:7])=[O:6]
Reactant: CC(C)(C)OC(=O)NC(CF)CC(=O)O
Agent: Cl
Solvent: CCOCC
Product: NC(CF)CC(=O)O
Yield: 68 %

Procedure:
4-Fluoro-3-tert-butoxycarbonylamino-1-butanoic acid (545 mg, 2.46 mmoles) is dissolved in dry ether (20 ml) saturated with hydrogen chloride gas. After a few minutes, the solution becomes turbid and white crystals start to precipitate. Recrystallization from ethanol by addition of diethylether affords 4-fluoro-3-amino-1-butanoic acid hydrochloride (265 mg, 68%), m.p. 152°-153° C. (dec).
Reaction SMILES: [CH3:1][C:2]1([CH3:11])[CH2:7][CH2:6][C:5](B(O)O)=[CH:4][CH2:3]1.Cl[C:13]1[C:18]([N+:19]([O-:21])=[O:20])=[CH:17][CH:16]=[CH:15][N:14]=1.C([O-])([O-])=O.[Na+].[Na+]>C1(C)C=CC=CC=1.CCO.CCOC(C)=O.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[CH3:1][C:2]1([CH3:11])[CH2:7][CH2:6][C:5]([C:13]2[C:18]([N+:19]([O-:21])=[O:20])=[CH:17][CH:16]=[CH:15][N:14]=2)=[CH:4][CH2:3]1
Reactant: CC1(C)CC=C(B(O)O)CC1
Reactant: O=[N+]([O-])c1cccnc1Cl
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: Cc1ccccc1
Solvent: CCO
Product: CC1(C)CC=C(c2ncccc2[N+](=O)[O-])CC1
Temperature: 80 °C
Yield: 61 %

Procedure:
A solution of 894 mg (3.78 mmol) of 4,4-dimethyl-cyclohex-1-enylboronic acid and 0.500 g (3.15 mmol) of 2-chloro-3-nitro-pyridine in toluene (20 mL) and EtOH (10 mL) was treated with 12.6 mL (25.2 mmol) of 2.0 M aqueous Na2CO3. The mixture was degassed via sonication, placed under Ar, treated with 364 mg (0.315 mmol) of Pd(PPh3)4, and heated to 80° C. for 2 h. The mixture was cooled to RT, diluted with EtOAc (50 mL), and washed with saturated aqueous NaHCO3 (1×40 mL) and water (1×40 mL). The aqueous layer was extracted with EtOAc (40 mL), and the combined organic layers were dried (MgSO4) and concentrated in vacuo. Silica gel chromatography of the residue with CH2Cl2 afforded 446 mg (61%) of the title compound as a yellow solid: 1H-NMR (CDCl3; 400 MHz): δ 8.73 (dd, 1H, J=4.8, 1.6 Hz), 8.02 (dd, 1H, J=8.4, 1.6 Hz), 7.32 (m, 1H), 5.83 (sept, 1H, J=2.0 Hz), 2.50-2.44 (m, 2H), 1.98-1.93 (m, 2H), 1.56 (t, 2H, J=6.0 Hz), 1.00 (s, 6H).
Reaction SMILES: Br[C:2]1[CH:3]=[N:4][CH:5]=[CH:6][CH:7]=1.[F:8][C:9]([F:19])([F:18])[C:10]1[CH:17]=[CH:16][C:13]([CH:14]=[O:15])=[CH:12][CH:11]=1.N1C=CC=CC=1C=O>>[N:4]1[CH:5]=[CH:6][CH:7]=[C:2]([CH:14]([C:13]2[CH:12]=[CH:11][C:10]([C:9]([F:8])([F:18])[F:19])=[CH:17][CH:16]=2)[OH:15])[CH:3]=1
Reactant: O=Cc1ccc(C(F)(F)F)cc1
Reactant: Brc1cccnc1
Agent: O=Cc1ccccn1
Product: OC(c1ccc(C(F)(F)F)cc1)c1cccnc1

Procedure:
The title compound was prepared analogously to the method in Intermediate 25: step a using 3-bromopyridine and 4-(trifluoromethyl)benzaldehyde in place of 5-bromo-1-methyl-1H-imidazole and picolinaldehyde, respectively.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:22]2[CH:27]=[CH:26][C:25]([C:28]([OH:30])=O)=[CH:24][CH:23]=2)[CH:5]=[C:6]([Cl:21])[C:7]=1[CH2:8][C@@H:9]1[CH2:13][CH2:12][N:11]([N:14]2[CH2:19][CH2:18][CH2:17][CH2:16][CH2:15]2)[C:10]1=[O:20].C(N1C=CN=C1)(N1C=CN=C1)=O.Cl.[F:44][C:45]([F:53])([F:52])[CH:46]1[CH2:51][CH2:50][NH:49][CH2:48][CH2:47]1.C(N(C(C)C)CC)(C)C>C(Cl)Cl>[Cl:1][C:2]1[CH:3]=[C:4]([C:22]2[CH:23]=[CH:24][C:25]([C:28]([N:49]3[CH2:50][CH2:51][CH:46]([C:45]([F:53])([F:52])[F:44])[CH2:47][CH2:48]3)=[O:30])=[CH:26][CH:27]=2)[CH:5]=[C:6]([Cl:21])[C:7]=1[CH2:8][C@@H:9]1[CH2:13][CH2:12][N:11]([N:14]2[CH2:15][CH2:16][CH2:17][CH2:18][CH2:19]2)[C:10]1=[O:20]
Reactant: FC(F)(F)C1CCNCC1
Reactant: O=C(O)c1ccc(-c2cc(Cl)c(C[C@@H]3CCN(N4CCCCC4)C3=O)c(Cl)c2)cc1
Agent: Cl
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: O=C(c1ccc(-c2cc(Cl)c(C[C@@H]3CCN(N4CCCCC4)C3=O)c(Cl)c2)cc1)N1CCC(C(F)(F)F)CC1
Temperature: 25 °C
Reaction time: 1 h
Yield: 55.8 %

Procedure:
Treat a solution of (R)-3′,5′-dichloro-4′-(2-oxo-1-piperidin-1-yl-pyrrolidin-3-ylmethyl)-biphenyl-4-carboxylic acid (0.090 g, 0.2 mmol) in CH2Cl2 (10 mL) with 1,1′-carbonyldiimidazole (0.065 g, 0.4 mmol) and stir for 1 hour at room temperature. Treat the reaction with 4-trifluoromethylpiperidine hydrochloride (0.057 g, 0.3 mmol) and diisopropylethylamine (0.039 g, 0.3 mmol) and stir for 12 hours at room temperature. Purify on silica gel column with 25% to 75% ethyl acetate in hexanes to afford 0.065 g (55%) of the title compound. MS (m/z): 582 (M+).
Reaction SMILES: [ClH:1].C(O[C:5](=[NH:16])[C:6]1[CH:11]=[CH:10][C:9]([NH2:12])=[C:8]([N+:13]([O-:15])=[O:14])[CH:7]=1)C.[NH3:17]>C(O)C>[ClH:1].[NH2:12][C:9]1[CH:10]=[CH:11][C:6]([C:5]([NH2:16])=[NH:17])=[CH:7][C:8]=1[N+:13]([O-:15])=[O:14]
Reactant: CCOC(=N)c1ccc(N)c([N+](=O)[O-])c1
Reactant: N
Agent: Cl
Solvent: CCO
Product: N=C(N)c1ccc(N)c([N+](=O)[O-])c1
Temperature: 0 °C

Procedure:
4-Amino-3-nitro-benzimidic acid ethyl ester hydrochloride (84.5 g, 344 mmol) was suspended in absolute ethanol (750 mL) and then cooled to 0° C. Ammonia was then passed through the solution for a period of 2 h. The flask was tightly sealed and allowed to warm up to room temperature over an 18 h period with stirring. The product was crystallized with diethyl ether and the resulting solid was filtered, washed and dried to give 4-amino-3-nitrobenzamidine monohydrochloride (70.7 g) as an off-white powder.
Reaction SMILES: [O:1]1[CH2:5][C@@H:4]([OH:6])[C@@H:3]2[O:7][CH2:8][C@@H:9]([OH:10])[C@@H:2]12.[C:11]1(C)[C:12]([S:17](Cl)(=[O:19])=[O:18])=[CH:13][CH:14]=[CH:15][CH:16]=1.N1C=CC=C[CH:23]=1>>[OH:6][C@H:4]1[C@H:3]2[O:7][CH2:8][C@@H:9]([O:10][S:17]([C:12]3[CH:11]=[CH:16][C:15]([CH3:23])=[CH:14][CH:13]=3)(=[O:18])=[O:19])[C@H:2]2[O:1][CH2:5]1
Reactant: O[C@@H]1CO[C@H]2[C@H]1OC[C@H]2O
Reactant: c1ccncc1
Reactant: Cc1ccccc1S(=O)(=O)Cl
Product: Cc1ccc(S(=O)(=O)O[C@@H]2CO[C@H]3[C@@H]2OC[C@H]3O)cc1

Procedure:
A solution of 5 g of (3R,3aS,6R,6aR)-hexahydro-furo[3,2-b]furan-3,6-diol in 50 ml of pyridine is stirred for 16 h with 7.8 g of toluenesulfonylchloride. From the mixture obtained solvent is distilled off and the distillation residue obtained is dissolved in EtAc and extracted with 1N HCl, saturated aqueous NaHCO3-solution and H2O. The organic layer obtained is dried, solvent is evaporated and the evaporation residue is subjected to chromatography. Toluene-4-sulfonic acid (3R, 3aS,6R,6aR)-6-hydroxy-hexahydro-furo[3,2-b]furan-3-yl ester is obtained.
Reaction SMILES: CN(C=O)C.[OH:6][C:7]1[CH:8]=[C:9]([CH:12]=[C:13]([O:15][CH3:16])[CH:14]=1)[CH:10]=[O:11].N1C=CN=C1.Cl[Si:23]([CH:30]([CH3:32])[CH3:31])([CH:27]([CH3:29])[CH3:28])[CH:24]([CH3:26])[CH3:25]>C(OCC)(=O)C.O>[CH3:16][O:15][C:13]1[CH:12]=[C:9]([CH:8]=[C:7]([O:6][Si:23]([CH:30]([CH3:32])[CH3:31])([CH:27]([CH3:29])[CH3:28])[CH:24]([CH3:26])[CH3:25])[CH:14]=1)[CH:10]=[O:11]
Reactant: CC(C)[Si](Cl)(C(C)C)C(C)C
Reactant: COc1cc(O)cc(C=O)c1
Agent: c1c[nH]cn1
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Solvent: O
Product: COc1cc(C=O)cc(O[Si](C(C)C)(C(C)C)C(C)C)c1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a 50 ml DMF solution containing 2.8 g of 3-hydroxy-5-methoxybenzaldehyde [CAS No. 57179-35-8] there were added 2.5 g of imidazole and 5.9 ml of chlorotriisopropylsilane. The mixture was stirred at room temperature for 14 hours and 30 minutes. Water was added to the reaction mixture and extraction was performed with ethyl acetate. The organic layer was washed with ice-cooled 1N hydrochloric acid, water and saturated brine and then dried over anhydrous magnesium sulfate. The desiccating agent was filtered off and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate-heptane) to give the title compound (5.7 g) as a light yellow oil.