Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([N:22]([CH2:29][CH2:30][O:31][CH3:32])[CH:23]2[CH2:28][CH2:27][O:26][CH2:25][CH2:24]2)[C:5]([CH3:21])=[C:6]([CH:20]=1)[C:7]([NH:9][CH2:10][C:11]1[C:12](=[O:19])[NH:13][C:14]([CH3:18])=[CH:15][C:16]=1[CH3:17])=[O:8].[O:33]1[CH2:38][CH2:37][N:36]([CH2:39][C:40]2[CH:45]=[CH:44][C:43](B(O)O)=[CH:42][CH:41]=2)[CH2:35][CH2:34]1.C(=O)([O-])[O-].[Na+].[Na+]>O1CCOCC1.O>[CH3:17][C:16]1[CH:15]=[C:14]([CH3:18])[NH:13][C:12](=[O:19])[C:11]=1[CH2:10][NH:9][C:7]([C:6]1[CH:20]=[C:2]([C:43]2[CH:42]=[CH:41][C:40]([CH2:39][N:36]3[CH2:37][CH2:38][O:33][CH2:34][CH2:35]3)=[CH:45][CH:44]=2)[CH:3]=[C:4]([N:22]([CH2:29][CH2:30][O:31][CH3:32])[CH:23]2[CH2:28][CH2:27][O:26][CH2:25][CH2:24]2)[C:5]=1[CH3:21])=[O:8]
Reactant: OB(O)c1ccc(CN2CCOCC2)cc1
Reactant: COCCN(c1cc(Br)cc(C(=O)NCc2c(C)cc(C)[nH]c2=O)c1C)C1CCOCC1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: C1COCCO1
Product: COCCN(c1cc(-c2ccc(CN3CCOCC3)cc2)cc(C(=O)NCc2c(C)cc(C)[nH]c2=O)c1C)C1CCOCC1
Temperature: 100 °C
Yield: 39.5 %

Procedure:
A solution of 5-bromo-N-((4,6-dimethyl-2-oxo-1,2-dihydropyridin-3-yl)methyl)-3-((2-methoxyethyl)(tetrahydro-2H-pyran-4-yl)amino)-2-methylbenzamide (110 mg, 0.21 mmol), (4-(morpholinomethyl)phenyl)boronic acid (99 mg, 0.33 mmol), sodium carbonate (83 mg, 0.78 mmol) in 4 ml of dioxane was degassed with argon for 20 min, Pd(PPh3) (25 mg, 0.02 mmol) was added to the mixture and heated to 100° C. for overnight. The reaction was cooled to room temperature and diluted with water, compound was extracted in 10% MeOH in DCM, dried over Na2SO4, concentrated and crude product purified by silica gel (100-200) chromatography to obtain the title compound (50 mg 38%).
Reaction SMILES: [C:1]1([C@H:7]([NH:9][CH2:10]C(O)=O)[CH3:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH2:14]([O:16][C:17](=[O:25])[N:18]([CH2:22][CH:23]=[CH2:24])[CH2:19][CH:20]=O)[CH3:15]>C1(C)C=CC=CC=1.CO>[C:1]1([C@H:7]([N:9]2[CH:20]3[CH2:19][N:18]([C:17]([O:16][CH2:14][CH3:15])=[O:25])[CH2:22][CH:23]3[CH2:24][CH2:10]2)[CH3:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: C=CCN(CC=O)C(=O)OCC
Reactant: C[C@@H](NCC(=O)O)c1ccccc1
Solvent: CO
Solvent: Cc1ccccc1
Product: CCOC(=O)N1CC2CCN([C@H](C)c3ccccc3)C2C1
Temperature: 90 °C
Reaction time: 14 h
Yield: 100 %

Procedure:
A solution of (1-(R)-phenyl-ethylamino)-acetic acid (25.6 g) in 384 mL of toluene was heated to 90° C. To this 170 g (1.1 equivalents) of a 15.84 wt. % solution of allyl-(2-oxo-ethyl)-carbamic acid ethyl ester (U.S. Pat. No. 5,071,999) in toluene, was added over 20 minutes and the mixture was stirred at 90° C. for 14 hours then at 95° C. for 12 hours. After cooling, the product was extracted with 2×115 g of 20% citric acid solution. The citric acid solution was diluted with 205 mL of isopropyl acetate, and the mixture was neutralized with a solution of 51.2 g K2CO3 in 120 g water, and thoroughly shaken. The layers were separated, and the aqueous layer was extracted again with 102 mL of isopropyl acetate. The organic extracts were combined and distilled under reduced pressure to provide an oil which was then diluted with 125 mL of MeOH to provide 140 g (100% yield) of the title compound as a 30% by weight solution in MeOH.
Reaction SMILES: [CH:1]1([CH2:4][N:5]2[C:10](=[O:11])[C:9]([CH2:12]O)=[CH:8][C:7]([C:14]3[CH:19]=[CH:18][C:17]([O:20][CH3:21])=[C:16]([F:22])[CH:15]=3)=[N:6]2)[CH2:3][CH2:2]1.C(Br)(Br)(Br)[Br:24].N1C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>O1CCCC1>[Br:24][CH2:12][C:9]1[C:10](=[O:11])[N:5]([CH2:4][CH:1]2[CH2:3][CH2:2]2)[N:6]=[C:7]([C:14]2[CH:19]=[CH:18][C:17]([O:20][CH3:21])=[C:16]([F:22])[CH:15]=2)[CH:8]=1
Reactant: BrC(Br)(Br)Br
Reactant: COc1ccc(-c2cc(CO)c(=O)n(CC3CC3)n2)cc1F
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: c1ccncc1
Solvent: C1CCOC1
Product: COc1ccc(-c2cc(CBr)c(=O)n(CC3CC3)n2)cc1F
Reaction time: 1 h
Yield: 69.2 %

Procedure:
2-Cyclopropylmethyl-6-(3-fluoro-4-methoxyphenyl)-4-hydroxymethyl-2H-pyridazin-3-one (185 mg, 0.61 mmol), carbon tetrabromide (404 mg, 1.2 mmol) and pyridine (48 mg, 0.61 mmol) were dissolved in tetrahydrofuran (3 mL), and under ice-cold stirring, a solution of triphenylphosphine (319 mg, 1.2 mmol) in tetrahydrofuran (3 mL) was added. Under ice cooling, the mixture was stirred for 1 hour, and further stirred at room temperature. Insoluble materials were filtered off, the solvent was distilled off under reduced pressure, and the residue was isolated and purified by column chromatography on silica gel (hexane/ethyl acetate=2/1) to yield the title compound as a yellow powder (yield: 155 mg, 69.5%).
Reaction SMILES: [CH2:1]([O:7][CH2:8][CH:9]1[CH2:14][CH2:13][CH2:12][CH2:11][CH2:10]1)[CH2:2][CH2:3][CH2:4][CH:5]=[CH2:6].Br[C:16]1[CH:21]=[CH:20][C:19]([N+:22]([O-:24])=[O:23])=[CH:18][CH:17]=1>>[CH:9]1([CH2:8][O:7][CH2:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][C:16]2[CH:21]=[CH:20][C:19]([N+:22]([O-:24])=[O:23])=[CH:18][CH:17]=2)[CH2:10][CH2:11][CH2:12][CH2:13][CH2:14]1
Reactant: C=CCCCCOCC1CCCCC1
Reactant: O=[N+]([O-])c1ccc(Br)cc1
Product: O=[N+]([O-])c1ccc(CCCCCCOCC2CCCCC2)cc1
Yield: 25.9 %

Procedure:
General procedure M was used to convert 5.21 mmol of 11b and 5.73 mmol of 1-bromo-4-nitrobenzene to 1.35 mmol (26%) of the title compound.
Reaction SMILES: Cl[C:2]1[C:11]2[CH2:10][CH2:9][CH2:8][CH2:7][C:6]=2[N:5]=[C:4]([NH2:12])[N:3]=1.[CH3:13][N:14]1[CH2:19][CH2:18][NH:17][CH2:16][CH2:15]1.CCN(CC)CC>CCO>[CH3:13][N:14]1[CH2:19][CH2:18][N:17]([C:2]2[C:11]3[CH2:10][CH2:9][CH2:8][CH2:7][C:6]=3[N:5]=[C:4]([NH2:12])[N:3]=2)[CH2:16][CH2:15]1
Reactant: CN1CCNCC1
Reactant: Nc1nc(Cl)c2c(n1)CCCC2
Solvent: CCO
Solvent: CCN(CC)CC
Product: CN1CCN(c2nc(N)nc3c2CCCC3)CC1
Temperature: 25 °C
Yield: 22.8 %

Procedure:
A solution of 4-chloro-5,6,7,8-tetrahydro-quinazolin-2-ylamine (100 mg, 0.55 mmol), N-methyl piperazine (91 uL, 1.5 mmol) and Et3N (140 uL, 1.1 mmol) in EtOH (2 ml) was heated at 70° C. for 16 h. The mixture was cooled to rt and concentrated, and the crude residue was purified (2 M NH3 in MeOH/CH2Cl2) to yield a white solid (31 mg, 23%). MS (ESI): mass calcd. for C13H21N5, 247.3; m/z found, 248.2 [M+H]+. 1H NMR (MeOD): 3.30-3.23 (m, 4H), 3.21 (dt, J=3.3, 1.6, 1H), 2.49 (t, J=6.7, 2H), 2.47-2.41 (m, 4H), 2.36 (t, J=5.9, 2H), 2.23 (s, 3H), 1.77-1.67 (m, 2H), 1.62-1.52 (m, 2H).
Reaction SMILES: [N:1]1([CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][C:11]2[S:15][C:14]([C:16](=O)[CH2:17][CH2:18][C:19]([OH:21])=O)=[CH:13][CH:12]=2)[CH:5]=[CH:4][N:3]=[CH:2]1.O.[NH2:24][NH2:25]>O>[N:1]1([CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][C:11]2[S:15][C:14]([C:16]3[CH2:17][CH2:18][C:19](=[O:21])[NH:24][N:25]=3)=[CH:13][CH:12]=2)[CH:5]=[CH:4][N:3]=[CH:2]1
Reactant: NN
Reactant: O=C(O)CCC(=O)c1ccc(CCCCCn2ccnc2)s1
Solvent: O
Product: O=C1CCC(c2ccc(CCCCCn3ccnc3)s2)=NN1
Temperature: 90 °C
Reaction time: 2 h

Procedure:
3.2 g of 4-{5-[5-(1-imidazolyl)-pentyl]-thien-2-yl}-4-oxo-butyric acid are suspended in 10 ml of water, 0.52 g of hydrazine hydrate are added and the mixture is stirred at 90° C. for 2 hours. After the mixture has been cooled, the precipitate formed is filtered off with suction, washed with water and dried.
Reaction SMILES: [Cl:1][C:2]1[CH:23]=[CH:22][C:5]2[C:6](=[CH:14][C:15]3[CH:16]=[C:17]([NH2:21])[CH:18]=[CH:19][CH:20]=3)[C:7]3[CH:8]=[CH:9][S:10][C:11]=3[CH2:12][CH2:13][C:4]=2[CH:3]=1.[Li]CCCC.[Cl:29]C(Cl)(Cl)C(Cl)(Cl)Cl>C1COCC1>[Cl:29][C:9]1[S:10][C:11]2[CH2:12][CH2:13][C:4]3[CH:3]=[C:2]([Cl:1])[CH:23]=[CH:22][C:5]=3[C:6](=[CH:14][C:15]3[CH:16]=[C:17]([NH2:21])[CH:18]=[CH:19][CH:20]=3)[C:7]=2[CH:8]=1
Reactant: Nc1cccc(C=C2c3ccc(Cl)cc3CCc3sccc32)c1
Reactant: ClC(Cl)(Cl)C(Cl)(Cl)Cl
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: Nc1cccc(C=C2c3ccc(Cl)cc3CCc3sc(Cl)cc32)c1
Yield: 21 %

Procedure:
As in Example 553 (above), using 3-(7-chloro-9,10-dihydro-1-thia-benzo[f]azulen-4-ylidenemethyl)-phenylamine, n-BuLi in hexanes, THF, and hexachloroethane. Purify the crude residue by column chromatography (5% to 20% to 30% EtOAc:hexanes) to give title compound as an oil (21%) along with recovered starting material: 1H NMR (CDCl3, 400 MHz) δ 2.06-3.02 (m, 4 H), 3.53 (br s, 2 H), 6.32 (s, 1 H), 6.38 (d, J=7.2 Hz, 1 H), 6.48 (dd, J=7.2 Hz, 1.6 Hz, 1 H), 6.79 (s, 1 H), 6.93-6.96 (m, 3 H), 7.02 (dd, J=8.2 Hz, 2.2 Hz, 1 H), 7.27 (d, J=8.2 Hz, 1 H). TLC Rf=0.55 (30% EtOAc:hexanes).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH3:11])[CH:6]=[C:7]([O:9][CH3:10])[CH:8]=1.[CH3:12][O:13][C:14]1[CH:22]=[CH:21][C:17]([C:18](Cl)=[O:19])=[CH:16][CH:15]=1>O1CCCC1>[CH3:12][O:13][C:14]1[CH:22]=[CH:21][C:17]([C:18]([C:8]2[C:7]([O:9][CH3:10])=[CH:6][C:5]([CH3:11])=[CH:4][C:3]=2[O:2][CH3:1])=[O:19])=[CH:16][CH:15]=1
Reactant: COc1cc(C)cc(OC)c1
Reactant: COc1ccc(C(=O)Cl)cc1
Solvent: C1CCOC1
Product: COc1ccc(C(=O)c2c(OC)cc(C)cc2OC)cc1
Reaction time: 3 h
Yield: 20.4 %

Procedure:
3,5-Dimethoxy toluene (1.00 g) obtained in Example 44 was dissolved in anhydrous tetrahydrofuran (10 ml), commercially available 2.5 M n-butyllithium-hexane solution (2.90 ml) was added at -45° C. under nitrogen, and the admixture was stirred for 3 hours. Commercially available 4-methoxybenzoyl chloride (1.23 g) was dissolved in tetrahydrofuran (10 ml), and the resulting solution was added slowly to the admixture at -45° C. The reaction mixture was stirred at room temperature for 1 hour and then partitioned between water and chloroform. The chloroform layer was dried with anhydrous magnesium sulfate, the solvent was removed by reduced-pressure distillation, and the resulting residue was purified by column chromatography on silica gel eluting with hexane/ethyl acetate (5/1) to obtain 384 mg of the title compound (yield: 20%).
Reaction SMILES: [C:1]1([CH2:7][CH2:8][CH2:9][CH:10]2[NH:17][C:16](=[O:18])[CH2:15][CH2:14][CH2:13][CH2:12][CH2:11]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.F[B-](F)(F)F.[CH3:24][O+](C)C>C(Cl)Cl>[CH3:24][O:18][C:16]1[CH2:15][CH2:14][CH2:13][CH2:12][CH2:11][CH:10]([CH2:9][CH2:8][CH2:7][C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)[N:17]=1
Reactant: O=C1CCCCCC(CCCc2ccccc2)N1
Reactant: C[O+](C)C
Agent: F[B-](F)(F)F
Solvent: ClCCl
Product: COC1=NC(CCCc2ccccc2)CCCCC1

Procedure:
The product of Example 71 is reacted with trimethyloxonium tetrafluoroborate in CH2Cl2 by the method of Example 3 to produce the title material.
Reaction SMILES: N1C=CN=C1.[Si:6](Cl)([C:9]([CH3:12])([CH3:11])[CH3:10])([CH3:8])[CH3:7].[C:14]([O:18][C:19]([NH:21][C:22]1[CH:27]=[C:26]([CH2:28][OH:29])[CH:25]=[CH:24][N:23]=1)=[O:20])([CH3:17])([CH3:16])[CH3:15].C(OCC)(=O)C>CN(C)C=O>[C:14]([O:18][C:19]([NH:21][C:22]1[CH:27]=[C:26]([CH2:28][O:29][Si:6]([C:9]([CH3:12])([CH3:11])[CH3:10])([CH3:8])[CH3:7])[CH:25]=[CH:24][N:23]=1)=[O:20])([CH3:17])([CH3:15])[CH3:16]
Reactant: CC(C)(C)[Si](C)(C)Cl
Reactant: CC(C)(C)OC(=O)Nc1cc(CO)ccn1
Agent: c1c[nH]cn1
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)Nc1cc(CO[Si](C)(C)C(C)(C)C)ccn1
Yield: 96 %

Procedure:
Imidazole (2.1 g, 31 mmol) and tert-butyldimethylsilyl chloride (4.4 g, 29 mmol) were added to a solution of (2-tert-butoxycarbonylaminopyridin-4-yl)methanol (Reference compound No. 4-1, 6.2 g, 28 mmol) in N,N-dimethylformamide (120 mL) at room temperature, and the mixture was stirred for 2 hours. Ethyl acetate (300 mL) was added to the reaction mixture, then the mixture was washed with water (750 mL) and brine (200 mL), and then the mixture was dried over anhydrous magnesium sulfate. The organic layer was evaporated under reduced pressure to give 9.0 g of the title reference compound as a colorless solid. (Yield 96%)
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([CH:9]=[CH:10][C:11]=1[O:12][CH3:13])[C:5]([O:7][CH3:8])=[O:6].Cl[C:15]1[CH:20]=[CH:19][C:18]([N+:21]([O-:23])=[O:22])=[CH:17][N:16]=1.C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O.O>[CH3:13][O:12][C:11]1[CH:10]=[CH:9][C:4]([C:5]([O:7][CH3:8])=[O:6])=[CH:3][C:2]=1[O:1][C:15]1[CH:20]=[CH:19][C:18]([N+:21]([O-:23])=[O:22])=[CH:17][N:16]=1
Reactant: O=[N+]([O-])c1ccc(Cl)nc1
Reactant: COC(=O)c1ccc(OC)c(O)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: COC(=O)c1ccc(OC)c(Oc2ccc([N+](=O)[O-])cn2)c1
Temperature: 60 °C
Reaction time: 14 h
Yield: 119.8 %

Procedure:
To a solution of methyl 3-hydroxy-4-methoxybenzoate (4.87 g, 26.7 mmol) and 2-chloro-5-nitropyridine (4.24 g, 26.7 mmol) in N,N-dimethylformamide (100 mL) was added potassium carbonate (8.13 g, 58.8 mmol), and the mixture was stirred at 60° C. for 14 hr. The reaction solution was cooled to room temperature, diluted with water, and extracted with a mixed solvent (1:1, 100 mL) of ethyl acetate and hexane. The combined organic layer was washed with saturated brine, and dried over anhydrous magnesium sulfate. The insoluble material was filtered off, and the filtrate was concentrated under reduced pressure to give the title compound (9.73 g) as an orange syrup substance.
Reaction SMILES: [Br:1][C:2]1[N:7]2[CH:8]=[C:9]([NH:11]C(=O)OCC)[N:10]=[C:6]2[C:5]([N:17]2[CH2:22][CH2:21][O:20][CH2:19][CH2:18]2)=[N:4][CH:3]=1>[OH-].[Na+].O>[Br:1][C:2]1[N:7]2[CH:8]=[C:9]([NH2:11])[N:10]=[C:6]2[C:5]([N:17]2[CH2:18][CH2:19][O:20][CH2:21][CH2:22]2)=[N:4][CH:3]=1
Reactant: CCOC(=O)Nc1cn2c(Br)cnc(N3CCOCC3)c2n1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: Nc1cn2c(Br)cnc(N3CCOCC3)c2n1
Temperature: 25 °C

Procedure:
A suspension of ethyl (5-bromo-8-morpholinoimidazo[1,2-a]pyrazin-2-yl)carbamate (1.2 g, as prepared above) in 5 N aqueous NaOH was heated at reflux for 18 h. The reaction mixture was allowed to cool to rt, diluted with water (50 mL) and extracted with DCM (3×50 mL). The combined DCM layers were dried over Na2SO4 and concentrated under reduced pressure to give compound 21b, which was dried under reduced pressure overnight and used in next step without further purification. Mass Spectrum (LCMS, ESI pos.) Calcd. For C10H12BrN5O: 298.0 (M+H). Found 298.1.
Reaction SMILES: [OH-].[K+].[CH3:3][NH:4][CH:5]1[CH2:9][N:8]([CH3:10])[CH2:7][CH2:6]1.F[C:12]1[CH:17]=[CH:16][C:15]([N+:18]([O-:20])=[O:19])=[CH:14][CH:13]=1>CS(C)=O>[CH3:3][N:4]([CH:5]1[CH2:6][CH2:7][N:8]([CH3:10])[CH2:9]1)[C:12]1[CH:17]=[CH:16][C:15]([N+:18]([O-:20])=[O:19])=[CH:14][CH:13]=1
Reactant: CNC1CCN(C)C1
Reactant: O=[N+]([O-])c1ccc(F)cc1
Agent: [K+]
Agent: [OH-]
Solvent: CS(C)=O
Product: CN1CCC(N(C)c2ccc([N+](=O)[O-])cc2)C1
Temperature: 62.5 °C

Procedure:
To a suspension of potassium hydroxide (1.4 g, 25 mmol) and N,N′-dimethyl-3-aminopyrrolidine (1.4 g, 12 mmol) in dimethylsulfoxide (13 mL) is added dropwise 4-fluoronitrobenzene (1.1 mL, 10 mmol). The mixture is heated in a 60-65° C. oil bath for 4 hours. After cooling to room temperature, ice is added to the reaction mixture. The resulting precipitate is collected, washed with water, and dried under vacuum to give methyl-(1-methyl-pyrrolidin-3-yl)-(4-nitro-phenyl)-amine.
Reaction SMILES: [C:1]([OH:32])(=O)[CH2:2][CH2:3][C@H:4]([NH:8]C(C1C=CC(NCC2N=C3C(N=C(NC3=O)N)=NC=2)=CC=1)=O)[C:5]([OH:7])=[O:6].CSCC[C@H]([NH:41]C([C@@H](NC(CNC(CNC([C@@H](N)CC1C=CC(O)=CC=1)=O)=O)=O)CC1C=CC=CC=1)=O)C(O)=O>>[NH2:8][C@H:4]([C:5]([OH:7])=[O:6])[CH2:3][CH2:2][C:1](=[O:32])[NH2:41]
Reactant: Nc1nc2ncc(CNc3ccc(C(=O)N[C@@H](CCC(=O)O)C(=O)O)cc3)nc2c(=O)[nH]1
Reactant: CSCC[C@H](NC(=O)[C@H](Cc1ccccc1)NC(=O)CNC(=O)CNC(=O)[C@@H](N)Cc1ccc(O)cc1)C(=O)O
Product: NC(=O)CC[C@H](N)C(=O)O

Procedure:
from about 0.05 mg to about 0.15 mg of folic acid for coenzymatically converting said neurotransmitter substrate into met-enkephalin.
Reaction SMILES: CC1(C)C(C)(C)OB([C:9]2[CH:16]=[CH:15][C:14]([C:17]([F:20])([F:19])[F:18])=[CH:13][C:10]=2[CH:11]=[O:12])O1.[CH3:22][O:23][C:24](=[O:33])[CH2:25][C:26]1[CH:27]=[N:28][CH:29]=[C:30](Br)[CH:31]=1>>[CH3:22][O:23][C:24](=[O:33])[CH2:25][C:26]1[CH:27]=[N:28][CH:29]=[C:30]([C:9]2[CH:16]=[CH:15][C:14]([C:17]([F:18])([F:19])[F:20])=[CH:13][C:10]=2[CH:11]=[O:12])[CH:31]=1
Reactant: COC(=O)Cc1cncc(Br)c1
Reactant: CC1(C)OB(c2ccc(C(F)(F)F)cc2C=O)OC1(C)C
Product: COC(=O)Cc1cncc(-c2ccc(C(F)(F)F)cc2C=O)c1

Procedure:
2-(4,4,5,5-Tetramethyl-[1,3,2]dioxaborolan-2-yl)-5-trifluoromethyl-benzaldehyde and (5-bromo-pyridin-3-yl)-acetic acid methyl ester were reacted as described in Example 8, Step 4 to provide [5-(2-formyl-4-trifluoromethyl-phenyl)-pyridin-3-yl]-acetic acid methyl ester.
Reaction SMILES: [C:1]([O:4][C@H:5]1[O:27][C@@H:26]([CH2:28][O:29][C:30](=[O:37])[C:31]2[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=2)[C@H:16]([O:17][C:18](=[O:25])[C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[C@@H:6]1[O:7]C(=O)C1C=CC=CC=1)(=[O:3])C.Br.O>C(Cl)Cl>[C:1]([O:4][C@@H:5]1[O:27][C@@H:26]([CH2:28][O:29][C:30](=[O:37])[C:31]2[CH:32]=[CH:33][CH:34]=[CH:35][CH:36]=2)[C@H:16]([O:17][C:18](=[O:25])[C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[C@@H:6]1[OH:7])(=[O:3])[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1
Reactant: CC(=O)O[C@H]1O[C@@H](COC(=O)c2ccccc2)[C@H](OC(=O)c2ccccc2)[C@@H]1OC(=O)c1ccccc1
Agent: Br
Solvent: O
Solvent: ClCCl
Product: O=C(OC[C@@H]1O[C@@H](OC(=O)c2ccccc2)[C@@H](O)[C@H]1OC(=O)c1ccccc1)c1ccccc1
Temperature: 0 °C
Reaction time: 3.5 h
Yield: 150.3 %

Procedure:
Compound 10 (9 g, 17.84 mmol) was stirred in 100 mL of CH2Cl2 at 0° C. while 70 mL of CH2Cl2 containing HBr (3.2 g, 30.5 mmol) was added in one portion. The mixture was stirred at 0° C. for 3.5 hrs, water (55 ml) was added and the mixture stirred at room temperature for 18 hours. The organic layer was separated, washed with saturated NaHCO3, dried (MgSO4). After evaporation of the solvent, a foam was obtained, which upon recrystallization from CH2Cl2 and n-hexane, gave 11 as a white solid (6.2 g, 75.5%).
Reaction SMILES: C([N:8]1[CH2:12][CH2:11][C:10]([C:15]2[CH:20]=[CH:19][CH:18]=[C:17]([Cl:21])[C:16]=2[F:22])([O:13][CH3:14])[CH2:9]1)C1C=CC=CC=1.ClCCCl.ClC(OC(Cl)C)=O>CO>[Cl:21][C:17]1[C:16]([F:22])=[C:15]([C:10]2([O:13][CH3:14])[CH2:11][CH2:12][NH:8][CH2:9]2)[CH:20]=[CH:19][CH:18]=1
Reactant: COC1(c2cccc(Cl)c2F)CCN(Cc2ccccc2)C1
Agent: CC(Cl)OC(=O)Cl
Solvent: ClCCCl
Solvent: CO
Product: COC1(c2cccc(Cl)c2F)CCNC1
Yield: 64.6 %

Procedure:
Preparation according to Example 1. (−)-1-benzyl-3-(3-chloro-2-fluorophenyl)-3-methoxypyrrolidine (0.82 g, 2.56 mmol), 1,2-dichloroethane (10 ml), 1-chloroethyl chloroformate (1.12 ml, 10.25 mmol) refluxed for 2 h, and methanol (20 ml) reflux 1 h. Purification by HPLC on waters OBD C18, 5 μm (MeOH/33 mM NH3, 20:80 to 50:50) gave the title compound (0.38 g, 65%). [a]D=−7.1° (methanol). The amine was converted to the oxalic acid salt and recrystallized from methanol/diethyl ether: M.p. 183-185° C. MS m/z (rel. intensity, 70 eV) 229 (M+, 1), 199 (87), 187 (bp), 157 (55), 133 (51).
Reaction SMILES: C([N:4]1[CH2:8][CH2:7][N:6]=[C:5]1[NH:9][C:10]1[N:14]([CH3:15])[N:13]=[CH:12][CH:11]=1)(=O)C.[ClH:16]>CO>[ClH:16].[CH3:15][N:14]1[C:10]([NH:9][C:5]2[NH:6][CH2:7][CH2:8][N:4]=2)=[CH:11][CH:12]=[N:13]1
Reactant: CC(=O)N1CCN=C1Nc1ccnn1C
Agent: Cl
Solvent: CO
Product: Cn1nccc1NC1=NCCN1

Procedure:
1-Acetyl-2(1-methyl-5-pyrazolyl)amino-2-imidazoline (37.4 g.) was treated with HCl in methanol as described in Example II to give 25.9 g. product mp 204-208 which was converted to the hydrochloride salt mp 187°-189°.
Reaction SMILES: [C:1]([C:3]1[CH:15]=[CH:14][CH:13]=[CH:12][C:4]=1[O:5][CH:6]([CH2:10][CH3:11])[C:7]([OH:9])=[O:8])#[N:2].[Si:16]([O:23][C@H:24]1[CH2:33][C@H:32](O)[C@H:31]2[C:26]([CH:27]=[CH:28][C@H:29]([CH3:52])[C@@H:30]2[CH2:35][CH2:36][C@H:37]2[O:42][C:41](=[O:43])[CH2:40][C@H:39]([O:44][Si:45]([C:48]([CH3:51])([CH3:50])[CH3:49])([CH3:47])[CH3:46])[CH2:38]2)=[CH:25]1)([C:19]([CH3:22])([CH3:21])[CH3:20])([CH3:18])[CH3:17]>>[Si:16]([O:23][C@H:24]1[CH2:33][C@H:32]([O:8][C:7](=[O:9])[CH:6]([O:5][C:4]2[CH:12]=[CH:13][CH:14]=[CH:15][C:3]=2[C:1]#[N:2])[CH2:10][CH3:11])[C@H:31]2[C:26]([CH:27]=[CH:28][C@H:29]([CH3:52])[C@@H:30]2[CH2:35][CH2:36][C@H:37]2[O:42][C:41](=[O:43])[CH2:40][C@H:39]([O:44][Si:45]([C:48]([CH3:51])([CH3:50])[CH3:49])([CH3:46])[CH3:47])[CH2:38]2)=[CH:25]1)([C:19]([CH3:20])([CH3:21])[CH3:22])([CH3:18])[CH3:17]
Reactant: CCC(Oc1ccccc1C#N)C(=O)O
Reactant: C[C@H]1C=CC2=C[C@@H](O[Si](C)(C)C(C)(C)C)C[C@H](O)[C@@H]2[C@H]1CC[C@@H]1C[C@@H](O[Si](C)(C)C(C)(C)C)CC(=O)O1
Product: CCC(Oc1ccccc1C#N)C(=O)O[C@H]1C[C@H](O[Si](C)(C)C(C)(C)C)C=C2C=C[C@H](C)[C@H](CC[C@@H]3C[C@@H](O[Si](C)(C)C(C)(C)C)CC(=O)O3)[C@H]21
Yield: 80.6 %

Procedure:
A procedure similar to that described in Example 1, above, was followed, but using 739 mg of (2RS)-2-(2-cyanophenoxy)butyric acid and 1.0 g of (4R,6R)-6-{(1S,2S,6S,8S,8aR)-2-[1,2,6,7,8,8a-hexahydro-6-t-butyldimethylsilyloxy-8-hydroxy-2-methyl-1-naphthyl]ethyl}tetrahydro-4-t-butyldimethylsilyloxy-2H-pyran-2-one [prepared as described in Example B, above], to give 1.08 g of the title compound as a colorless foam.
Reaction SMILES: [Cl-].[Br:2][C:3]1[CH:4]=[CH:5][C:6]2[N:12]([CH2:13][CH:14]=[CH2:15])[CH2:11][CH2:10][C:9]([C:16]([O:18][CH3:19])=[O:17])=[CH:8][C:7]=2[CH:20]=1.CN(C=[O:25])C.O>[Cl-].[Na+].O.[Pd](Cl)Cl>[Br:2][C:3]1[CH:4]=[CH:5][C:6]2[N:12]([CH2:13][C:14](=[O:25])[CH3:15])[CH2:11][CH2:10][C:9]([C:16]([O:18][CH3:19])=[O:17])=[CH:8][C:7]=2[CH:20]=1
Reactant: CN(C)C=O
Reactant: C=CCN1CCC(C(=O)OC)=Cc2cc(Br)ccc21
Agent: Cl[Pd]Cl
Agent: [Cl-]
Agent: [Na+]
Solvent: O
Product: COC(=O)C1=Cc2cc(Br)ccc2N(CC(C)=O)CC1
Temperature: 60 °C
Reaction time: 18 h

Procedure:
A mixture of palladium chloride (96 mg) and curious chloride (218 mg) in DMF-water (7-1 ml) was stirred at 60° C. for 18 hours under oxygen atmosphere. To the reaction system was added a solution of methyl 7-bromo-1-(2-propenyl)-2,3-dihydro-1H-1-benzazepine-4-carboxylate (500 mg) in DMF-water (7-1 ml) was added, and the mixture was stirred at 60° C. for 7 hours. To the reaction system was added saturated brine, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine and dried with magnesium sulfate. After concentration under reduced pressure, the residue was separated and purified with column chromatography (ethyl acetate:hexane=1:4→1:2) to give methyl 7-bromo-1-(2-oxopropyl)-2,3-dihydro-1H-1-benzazepine-4-carboxylate (311 mg) as yellow crystals.
Reaction SMILES: [H-].[Na+].[CH2:3]([O:5][C:6]1[N:11]=[CH:10][C:9]([C@@H:12]([NH:15][C:16]([C@H:18]2[CH2:20][C@@H:19]2[C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)=[O:17])[CH2:13][OH:14])=[CH:8][CH:7]=1)[CH3:4].[CH3:27]I>CN(C=O)C.[Cl-].[Na+].O>[CH2:3]([O:5][C:6]1[N:11]=[CH:10][C:9]([C@@H:12]([NH:15][C:16]([C@H:18]2[CH2:20][C@@H:19]2[C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)=[O:17])[CH2:13][O:14][CH3:27])=[CH:8][CH:7]=1)[CH3:4]
Reactant: CI
Reactant: CCOc1ccc([C@H](CO)NC(=O)[C@H]2C[C@@H]2c2ccccc2)cn1
Agent: [Cl-]
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CCOc1ccc([C@H](COC)NC(=O)[C@H]2C[C@@H]2c2ccccc2)cn1
Reaction time: 0.5 h

Procedure:
NaH (60% suspension in mineral oil) (2.06 g, 51.5 mmol) was suspended in DMF and the reaction vessel was cooled in an ice bath. (1S,2S)-2-Phenyl-cyclopropanecarboxylic acid [(R)-1-(6-ethoxy-pyridin-3-yl)-2-hydroxy-ethyl]-amide (Compound 33) (15 g, 48 mmol) was dissolved in DMF (50 ml) and added drop wise to the sodium hydride suspension at 5-8 C over 20 minutes. The solution was stirred 30 minutes. Methyl iodide (3.30 ml, 53.0 mmol) dissolved in DMF (25 ml) was added drop wise at 5-12 C over 10 minutes and the mixture was stirred at 7-8 C for 30 minutes. The mixture was added to a brine solution and extracted with EtOAc. The organic layer was washed with more brine, dried (MgSO4) filtered and the solvent was evaporated off. The crude product was purified by silica gel chromatography (eluent EtOAc in heptanes 4:1). The fractions that contained the product was collected and the solvent was removed in vac. The residue was redissolved in THF (50 ml) EtOAc (100 ml) and heptanes (25 ml). The mixture was concentrated until 40 ml remained and cooled in ice. A white solid precipitated and was collected by filtration. Yield: 6.75 g (43%) of Compound 46. LC-MS (m/z) 341.2 (MH+). tR=0.64 min (method B).