Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][N:2]([CH3:7])[C:3](OC)=[CH2:4].[C:8]([O:12][C:13]([NH:15][CH:16]1[C:23](=[O:24])[N:22]2[CH:17]1[S:18][CH2:19][C:20]([CH3:37])=[C:21]2[C:25]([O:27][CH2:28][C:29]1[CH:34]=[CH:33][C:32]([O:35][CH3:36])=[CH:31][CH:30]=1)=[O:26])=[O:14])([CH3:11])([CH3:10])[CH3:9]>CN(C)C=O>[C:8]([O:12][C:13]([NH:15][CH:16]1[C:23](=[O:24])[N:22]2[CH:17]1[S:18][CH2:19][C:20]([CH:37]=[C:3]([N:2]([CH3:7])[CH3:1])[CH3:4])=[C:21]2[C:25]([O:27][CH2:28][C:29]1[CH:34]=[CH:33][C:32]([O:35][CH3:36])=[CH:31][CH:30]=1)=[O:26])=[O:14])([CH3:11])([CH3:10])[CH3:9]
Reactant: C=C(OC)N(C)C
Reactant: COc1ccc(COC(=O)C2=C(C)CSC3C(NC(=O)OC(C)(C)C)C(=O)N23)cc1
Solvent: CN(C)C=O
Product: COc1ccc(COC(=O)C2=C(C=C(C)N(C)C)CSC3C(NC(=O)OC(C)(C)C)C(=O)N23)cc1
Temperature: 80 °C

Procedure:
1-Dimethylamino-1-methoxyethylene (4 cc) is added, in the course of 55 minutes, to a solution of 7-t-butoxycarbonylamino-2-(4-methoxybenzyloxycarbonyl)-3-methyl-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene (3.75 g) in dimethylformamide (25 cc), heated to 80° C., the temperature being kept at 80° C. This yields a solution of 7-t-butoxycarbonylamino-3-(2-dimethylaminoprop-1-en-1-yl)-2-(4-methoxybenzyloxycarbonyl)-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene, which is poured into a mixture of iced water (20 cc) and ethyl acetate (150 cc). The organic phase is washed with water (2×200 cc), dried over sodium sulphate and filtered in the presence of decolorising charcoal and the filtrate is evaporated to dryness under reduced pressure (20 mm Hg; 2.7 kPa). The residue is chromatographed on a column of Merck silica gel (0.06-0.2) (45 g) (diameter of the column: 3 cm, height: 15 cm). Elution is carried out with a 20/80 (by volume) ethyl acetate/cyclohexane mixture (500 cc) and 40 cc fractions are collected. Fractions 7 to 10 are concentrated to dryness under reduced pressure (20 mm Hg; 2.7 kPa) and this yields a mixture (70/30) of 3-acetonyl-7-t-butoxycarbonylamino-2-(4-methoxybenzyloxycarbonyl)-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene and -oct-3-ene (0.25 g) in the form of an ochre solid.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:9]=[C:8]([S:10]([CH3:13])(=[O:12])=[O:11])[CH:7]=[CH:6][C:4]=1[NH2:5].Cl[C:15]1[N:20]=[C:19]([NH:21][CH3:22])[C:18]([C:23]([F:26])([F:25])[F:24])=[CH:17][N:16]=1>C(O)CCC.C(O)(C(F)(F)F)=O>[CH3:1][O:2][C:3]1[CH:9]=[C:8]([S:10]([CH3:13])(=[O:12])=[O:11])[CH:7]=[CH:6][C:4]=1[NH:5][C:15]1[N:20]=[C:19]([NH:21][CH3:22])[C:18]([C:23]([F:26])([F:24])[F:25])=[CH:17][N:16]=1
Reactant: COc1cc(S(C)(=O)=O)ccc1N
Reactant: CNc1nc(Cl)ncc1C(F)(F)F
Solvent: O=C(O)C(F)(F)F
Solvent: CCCCO
Product: CNc1nc(Nc2ccc(S(C)(=O)=O)cc2OC)ncc1C(F)(F)F
Temperature: 100 °C
Reaction time: 1.5 h
Yield: 101.8 %

Procedure:
To a mixture of 2-methoxy-4-(methylsulfonyl)aniline (0.095 g, 0.47 mmol) and 2-chloro-N-methyl-5-(trifluoromethyl)pyrimidin-4-amine (0.10 g, 0.47 mmol) in 1-butanol (1.5 mL) was added TFA (0.036 mL, 0.047 mmol). The reaction was stirred in a sealed tube at 100° C. for 1.5 h. The reaction was concentrated and the product was isolated by reverse-phase HPLC to give N2-(2-methoxy-4-(methylsulfonyl)phenyl)-N4-methyl-5-(trifluoromethyl)pyrimidine-2,4-diamine (0.18 g, 20%). 1H NMR (400 MHz, DMSO) δ 8.58 (d, J=12.9, 1H), 8.24 (d, J=5.0, 2H), 7.53 (d, J=10.1, 1H), 7.48 (s, 1H), 7.38-7.29 (m, 1H), 3.99 (s, 3H), 3.20 (s, 3H), 2.94 (d, J=4.3, 3H); LRRK2 Ki=0.002.
Reaction SMILES: [N+:1]([C:4]1[C:5]([CH3:12])=[N:6][C:7]([CH3:11])=[CH:8][C:9]=1[CH3:10])([O-])=O>CO.[Pd]>[NH2:1][C:4]1[C:5]([CH3:12])=[N:6][C:7]([CH3:11])=[CH:8][C:9]=1[CH3:10]
Reactant: Cc1cc(C)c([N+](=O)[O-])c(C)n1
Agent: [Pd]
Solvent: CO
Product: Cc1cc(C)c(N)c(C)n1
Reaction time: 2 h

Procedure:
3-Nitro-2,4,6-trimethylpyridine (14.89 g, 89.70 mmol) in methanol (250 ml) containing 10% palladium/carbon (1.5 g) was hydrogenated at 55 psi for 2 hours. The reaction mixture was filtered through wet celite, and the celite filter rinsed with methanol (5×30 ml). The filtrate was concentrated in vacuo to dryness and the residue purified by chromatography (silica gel; methylene chloride/methanol, 95/5) to 3-amino-2,4,6-trimethylpyridine (12.42 g, 100%) as a viscous oil.
Reaction SMILES: [Cl:1][C:2]1[C:3]2[CH:12]=[C:11]3[O:13][CH2:14][O:15][C:10]3=[CH:9][C:4]=2[S:5][C:6]=1[CH2:7][OH:8]>O1CCOCC1.C(OCC)(=O)C.O=[Mn]=O>[Cl:1][C:2]1[C:3]2[CH:12]=[C:11]3[O:13][CH2:14][O:15][C:10]3=[CH:9][C:4]=2[S:5][C:6]=1[CH:7]=[O:8]
Reactant: OCc1sc2cc3c(cc2c1Cl)OCO3
Agent: O=[Mn]=O
Solvent: CCOC(C)=O
Solvent: C1COCCO1
Product: O=Cc1sc2cc3c(cc2c1Cl)OCO3

Procedure:
3.5 equivalents of MnO2 are added at ambient temperature under an inert atmosphere to a suspension of 0.12 mol of the compound obtained in Step C in 925 ml of anhydrous dioxane. After 3.5 hours' reaction at reflux, the reaction mixture is filtered while hot over Celite and rinsed with dioxane; the filtrate is then concentrated under reduced pressure. The residue obtained is taken up in 100 ml of ethyl acetate and the solution obtained is refluxed and then returned to ambient temperature. A precipitate forms, which is filtered off, rinsed with ethyl acetate and then with water and pentane, and finally dried in vacuo, allowing the expecting product to be isolated.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:17]3[C:12](=[CH:13][C:14]([S:18]([O:21]C4C(F)=C(F)C(F)=C(F)C=4F)(=O)=[O:19])=[CH:15][CH:16]=3)[CH:11]=[CH:10][N:9]=2)=[C:4]([CH3:33])[CH:3]=1.[N:34]1[CH:39]=[CH:38][C:37]([NH2:40])=[N:36][CH:35]=1.C[Si]([N-][Si](C)(C)C)(C)C.[Li+]>C1COCC1>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:17]3[C:16](=[CH:15][C:14]([S:18]([NH:40][C:37]4[CH:38]=[CH:39][N:34]=[CH:35][N:36]=4)(=[O:19])=[O:21])=[CH:13][CH:12]=3)[CH:11]=[CH:10][N:9]=2)=[C:4]([CH3:33])[CH:3]=1
Reactant: Cc1cc(Cl)ccc1-c1nccc2cc(S(=O)(=O)Oc3c(F)c(F)c(F)c(F)c3F)ccc12
Reactant: Nc1ccncn1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: C1CCOC1
Product: Cc1cc(Cl)ccc1-c1nccc2cc(S(=O)(=O)Nc3ccncn3)ccc12
Reaction time: 0.25 h
Yield: 45.2 %

Procedure:
A round-bottom flask was charged with perfluorophenyl 1-(4-chloro-2-methylphenyl)isoquinoline-6-sulfonate (INTERMEDIATE DDDDD, 189 mg, 0.378 mmol), pyrimidin-4-amine (39.6 mg, 0.416 mmol), and THF (1891 μl) to give a clear, lightly-colored solution. The flask was cooled in an ice-bath for 5 min, then lithium bis(trimethylsilyl)amide (1M in THF) (794 μl, 0.794 mmol) was added drop wise over 30 s to give a yellow suspension. After 15 min, the mixture was quenched by the addition of TFA (0.3 mL), and then concentrated. The residue was concentrated from DCM then from MeOH. The residue was then purified by chromatography on silica gel (12-g Redi-Sep Gold column, 5-10% MeOH/DCM). Fractions containing product were combined and concentrated. The residue was taken up in DCM and filtered. The collected solid was washed with DCM (3×), then dried under a stream of N2 (g) for 20 min to give 1-(4-chloro-2-methylphenyl)-N-(pyrimidin-4-yl)isoquinoline-6-sulfonamide (70.2 mg, 0.171 mmol, 45.2% yield) as a white solid. 1H NMR (400 MHz, DMSO-d6) δ=8.72 (d, J=5.7 Hz, 2H), 8.58 (br. s., 1H), 8.26 (br. s., 1H), 8.16 (d, J=5.4 Hz, 1H), 8.00-7.94 (m, 1H), 7.69 (d, J=8.3 Hz, 1H), 7.53 (d, J=2.0 Hz, 1H), 7.46-7.40 (m, 1H), 7.36-7.30 (m, 1H), 7.05 (s, 1H), 1.98 (s, 3H). m/z (ESI) 411.2 (M+H)+.
Reaction SMILES: [C:1]([C:3]1[CH:4]=[N:5][CH:6]=[CH:7][CH:8]=1)#[CH:2].I[C:10]1[CH:11]=[C:12]([CH:32]=[CH:33][C:34]=1[CH3:35])[C:13]([NH:15][C:16]1[CH:21]=[C:20]([C:22]([F:25])([F:24])[F:23])[CH:19]=[C:18]([N:26]2[CH:30]=[C:29]([CH3:31])[N:28]=[CH:27]2)[CH:17]=1)=[O:14]>>[CH3:35][C:34]1[CH:10]=[CH:11][C:12]([C:13]([NH:15][C:16]2[CH:21]=[C:20]([C:22]([F:25])([F:24])[F:23])[CH:19]=[C:18]([N:26]3[CH:30]=[C:29]([CH3:31])[N:28]=[CH:27]3)[CH:17]=2)=[O:14])=[CH:32][C:33]=1[C:2]#[C:1][C:3]1[CH:4]=[N:5][CH:6]=[CH:7][CH:8]=1
Reactant: C#Cc1cccnc1
Reactant: Cc1cn(-c2cc(NC(=O)c3ccc(C)c(I)c3)cc(C(F)(F)F)c2)cn1
Product: Cc1cn(-c2cc(NC(=O)c3ccc(C)c(C#Cc4cccnc4)c3)cc(C(F)(F)F)c2)cn1

Procedure:
The title compound can be synthesized from 3-ethynylpyridine and 3-Iodo-4-methyl-N-(3-(4-methyl-1H-imidazol-1-yl)-5-(trifluoromethyl)phenyl)benzamide in a manner similar to that described for Example 1. 3-ethynylpridine was prepared from 3-bromopyridine and ethynyltrimethylsilane according to the 2 steps procedure described in Example 1.
Reaction SMILES: [C:1]1([C:7]2[NH:8][CH:9]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[C:10]([CH2:18][C:19](=O)[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)(=[O:17])[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1.CC(C)=O>C/C(/[O-])=C/C(C)=O.C/C(/[O-])=C/C(C)=O.[Ni+2].O>[C:20]1([C:19]2[NH:8][CH:9]=[C:7]([C:1]3[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=3)[C:18]=2[C:10](=[O:17])[C:11]2[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=2)[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1
Reactant: O=C(CC(=O)c1ccccc1)c1ccccc1
Reactant: C1=C(c2ccccc2)N1
Agent: [Ni+2]
Agent: CC(=O)/C=C(/C)[O-]
Solvent: CC(C)=O
Solvent: O
Product: O=C(c1ccccc1)c1c(-c2ccccc2)c[nH]c1-c1ccccc1
Temperature: 20 °C

Procedure:
With stirring, 3.0 g of 2-phenylazirine are added dropwise to a solution of 5.6 g of dibenzoylmethane, 10 ml of acetone and 0.1 g of nickel acetylacetonate at 50° C. The mixture is then heated at reflux for 30 minutes, cooled to 20° C., and 25 ml of water are added. The precipitated crystals are filtered with suction, washed with water, and dried to constant weight.
Reaction SMILES: [Cl-].[Al+3].[Cl-].[Cl-].[C:5]1([CH3:11])[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1.[F:12][C:13]([F:21])([F:20])[CH2:14][CH:15]([CH3:19])[C:16](Cl)=[O:17].Cl>ClCCCl>[F:12][C:13]([F:21])([F:20])[CH2:14][CH:15]([CH3:19])[C:16]([C:8]1[CH:9]=[CH:10][C:5]([CH3:11])=[CH:6][CH:7]=1)=[O:17]
Reactant: Cc1ccccc1
Reactant: CC(CC(F)(F)F)C(=O)Cl
Agent: Cl
Agent: [Al+3]
Agent: [Cl-]
Solvent: ClCCCl
Product: Cc1ccc(C(=O)C(C)CC(F)(F)F)cc1
Temperature: 0 °C
Reaction time: 1 h

Procedure:
At 0° C., 16.44 g (123.3 mmol) of aluminum chloride were added a little at a time to 12.6 ml (118.6 mmol) of toluene and 20.9 g (119.7 mmol) of 4,4,4-trifluoro-2-methylbutanoyl chloride in 300 ml of 1,2-dichloroethane, and the mixture was stirred at 0° C. for one hour. The reaction mixture was then slowly warmed to room temperature and stirred at this temperature for three hours. The reaction mixture was then slowly added to 300 ml of ice-cooled 18.5% strength hydrochloric acid, and the organic phase was then removed. The aqueous phase was extracted three more times with dichloromethane. The combined organic phases were dried over sodium sulfate and filtered, and the solvent was removed under reduced pressure. The crude product was purified chromatographically on silica gel (mobile phase cyclohexane/ethyl acetate 4:1). This gave 19.96 g (18.7 mmol, 73% of theory) of the title compound.
Reaction SMILES: [C:1]([NH2:10])(=[O:9])[C:2]1[C:3](=[CH:5][CH:6]=[CH:7][CH:8]=1)[NH2:4].[C:11](O)(=O)[CH3:12]>>[CH3:11][C:12]1[NH:10][C:1](=[O:9])[C:2]2[C:3](=[CH:5][CH:6]=[CH:7][CH:8]=2)[N:4]=1
Reactant: CC(=O)O
Reactant: NC(=O)c1ccccc1N
Product: Cc1nc2ccccc2c(=O)[nH]1

Procedure:
A solution of anthranilamide (13.6 g; 100 mmol) in acetic acid (100 ml) was refluxed for 60 h. The reaction mixture was evaporated to dryness, suspended in H2O, filtered and washed thoroughly with NaHCO3 until the filtrate had a pH of 8-8.5.
Reaction SMILES: [BrH:1].[CH2:2]([N:4]1[CH2:9][CH2:8][CH2:7][CH:6]([CH2:10]O)[CH2:5]1)[CH3:3].O.C(=O)([O-])[O-].[K+].[K+]>ClCCl>[Br:1][CH2:10][CH:6]1[CH2:7][CH2:8][CH2:9][N:4]([CH2:2][CH3:3])[CH2:5]1
Reactant: Br
Reactant: CCN1CCCC(CO)C1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: ClCCl
Solvent: O
Product: CCN1CCCC(CBr)C1

Procedure:
48% Aqueous hydrogen bromide (16 ml) was added to N-ethyl-3-piperidinemethanol (1.53 g) and the stirring mixture refluxed for 6 hours. After cooling, the solvent was stripped, the residue treated with water and made basic by addition of 1M aq. potassium carbonate. The mixture was shaken with dichloromethane, filtered to remove unwanted solid, and the filtrate separated. The aqueous layer was further extracted with dichloromethane and the combined extracts washed with dilute brine, dried by passing through a phase separation cartridge and stripped to give the title compound as a pale oil (1.4 g).
Reaction SMILES: Br[C:2]1[C:7]([Cl:8])=[CH:6][C:5]([C:9](=[O:11])[CH3:10])=[C:4]([OH:12])[CH:3]=1.CC1(C)C2C=CC=C(P(C3C=CC=CC=3)C3C=CC=CC=3)C=2OC2C1=CC=CC=2P(C1C=CC=CC=1)C1C=CC=CC=1.[CH3:55][N:56](C)C=O>[C-]#N.[Zn+2].[C-]#N.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[C:9]([C:5]1[C:4]([OH:12])=[CH:3][C:2]([C:55]#[N:56])=[C:7]([Cl:8])[CH:6]=1)(=[O:11])[CH3:10]
Reactant: CN(C)C=O
Reactant: CC(=O)c1cc(Cl)c(Br)cc1O
Agent: [Pd]
Agent: CC1(C)c2cccc(P(c3ccccc3)c3ccccc3)c2Oc2c(P(c3ccccc3)c3ccccc3)cccc21
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Product: CC(=O)c1cc(Cl)c(C#N)cc1O
Temperature: 120 °C
Yield: 72 %

Procedure:
1-(4-bromo-5-chloro-2-hydroxyphenyl)ethanone (6.2 g, 25 mmol) was combined with zinc cyanide (4.4 g, 37 mmol) in N,N-dimethylformamide (40 mL) degassed with nitrogen and tris(dibenzylideneacetone)dipalladium(0) (0.38 g, 0.42 mmol) and (9,9-dimethyl-9H-xanthene-4,5-diyl)bis(diphenylphosphine) (0.57 g, 0.99 mmol) were added. The reaction was degassed with nitrogen and heated to 120° C. and monitored by LC/MS. After heating for 2 hrs, the reaction was allowed to cool to room temperature, diluted with ethyl acetate, and filtered to remove the solids. The organic layer was washed with water, brine, dried over magnesium sulfate and concentrated in vacuo to give the crude product. The product was purified by FCC on silica gel eluting hexane:ethyl acetate gradient to give 4-acetyl-2-chloro-5-hydroxybenzonitrile as a yellow crystalline solid (3.5 g, 72%).
Reaction SMILES: [CH2:1]([O:4][C:5]([N:7]1[C@H:11]([CH2:12][C:13]2[S:17][C:16]3=[CH:18][N:19]=[C:20]([Cl:21])[N:15]3[CH:14]=2)[CH2:10][C@@H:9](O)[CH2:8]1)=[O:6])[CH:2]=[CH2:3].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OCC)=O)=NC(OCC)=O.[C:54]([OH:62])(=[S:61])[C:55]1[CH:60]=[CH:59][CH:58]=[CH:57][CH:56]=1>C1COCC1>[CH2:1]([O:4][C:5]([N:7]1[C@H:11]([CH2:12][C:13]2[S:17][C:16]3=[CH:18][N:19]=[C:20]([Cl:21])[N:15]3[CH:14]=2)[CH2:10][C@H:9]([S:61][C:54](=[O:62])[C:55]2[CH:60]=[CH:59][CH:58]=[CH:57][CH:56]=2)[CH2:8]1)=[O:6])[CH:2]=[CH2:3]
Reactant: C=CCOC(=O)N1C[C@H](O)C[C@H]1Cc1cn2c(Cl)ncc2s1
Reactant: OC(=S)c1ccccc1
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: C=CCOC(=O)N1C[C@@H](SC(=O)c2ccccc2)C[C@H]1Cc1cn2c(Cl)ncc2s1
Reaction time: 0.38 h

Procedure:
A solution of 438 mg of (3R,5S)-1-allyloxycarbonyl-5-(5-chloroimidazo[5,1-b]thiazol-2-yl)methyl-3-hydroxypyrrolidine and 672 mg of triphenylphosphine in 6.5 ml of anhydrous THF is cooled to −10° C. in an argon atmosphere. Diethyl azodicarboxylate (0.40 ml) is added dropwise to the mixture over a period of 7 min while maintaining the solution at −5° C. or below, and the mixture is stirred in this state for 23 min. Thiobenzoic acid (90%) (0.34 ml) is added dropwise to the mixed solution at −10° C. over a period of 5 min, and the mixture is stirred in this state for additional 25 min. The solvent is removed by evaporation under reduced pressure to give an oil which is then purified by column chromatography on silica gel (hexane:ethyl acetate=1:1) to give 505 mg of the title compound as a bright yellow viscous material.
Reaction SMILES: I[C:2]1[C:12]2[O:11][CH2:10][CH2:9][C:8]([C:13]([O:15][CH2:16][CH3:17])=[O:14])=[CH:7][C:6]=2[CH:5]=[CH:4][CH:3]=1.[C:18]([O:22][CH2:23][CH3:24])(=[O:21])[CH:19]=[CH2:20].C1(C)C=CC=CC=1P(C1C=CC=CC=1C)C1C=CC=CC=1C.C(N(CC)CC)C>C(#N)C.C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[CH2:23]([O:22][C:18](/[CH:19]=[CH:20]/[C:2]1[C:12]2[O:11][CH2:10][CH2:9][C:8]([C:13]([O:15][CH2:16][CH3:17])=[O:14])=[CH:7][C:6]=2[CH:5]=[CH:4][CH:3]=1)=[O:21])[CH3:24]
Reactant: C=CC(=O)OCC
Reactant: CCOC(=O)C1=Cc2cccc(I)c2OCC1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: Cc1ccccc1P(c1ccccc1C)c1ccccc1C
Solvent: CCN(CC)CC
Solvent: CC#N
Product: CCOC(=O)/C=C/c1cccc2c1OCCC(C(=O)OCC)=C2
Temperature: 100 °C
Reaction time: 5 h

Procedure:
A mixture of ethyl 2,3-dihydro-9-iodo-1-benzoxepin-4-carboxylate (0.34 g), ethyl acrylate (0.13 ml), palladium(II) acetate (2.2 mg), tri-o-tolylphosphine (6.0 mg), and triethylamine (0.15 ml) in acetonitrile (1 ml) was stirred at 100° C. under nitrogen atmosphere for 5 hours and partitioned between ethyl acetate and water. The organic layer was washed successively with water and brine, dried over anhydrous magnesium sulfate, and evaporated in vacuo. The residue was triturated in n-hexane to give a solid of ethyl 2,3-dihydro-9-[(E)-(2-ethoxycarbonylvinyl)]-1-benzoxepin-4-carboxylate (0.14 g).
Reaction SMILES: [Cl:1][C:2]1[CH:25]=[CH:24][C:5]2[N:6]=[C:7]([CH2:9][N:10]([C:17]3[CH:22]=[CH:21][C:20]([Cl:23])=[CH:19][CH:18]=3)[CH2:11][C:12]([O:14]CC)=[O:13])[NH:8][C:4]=2[CH:3]=1>CO.O>[Cl:1][C:2]1[CH:25]=[CH:24][C:5]2[N:6]=[C:7]([CH2:9][N:10]([C:17]3[CH:22]=[CH:21][C:20]([Cl:23])=[CH:19][CH:18]=3)[CH2:11][C:12]([OH:14])=[O:13])[NH:8][C:4]=2[CH:3]=1
Reactant: CCOC(=O)CN(Cc1nc2ccc(Cl)cc2[nH]1)c1ccc(Cl)cc1
Solvent: O
Solvent: CO
Product: O=C(O)CN(Cc1nc2ccc(Cl)cc2[nH]1)c1ccc(Cl)cc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 31 %

Procedure:
Ethyl N-[(5-chloro-2-benzimidazolyl)methyl]-N-(4-chlorophenyl)glycinate (0.15 g) was dissolved in methanol (3 ml). A solution of LiOH monohydrate (92 mg) in water (0.5 ml) was added and the cloudy mixture was stirred at rt for 2 h. Water (25 ml) was added and the aqueous layer was washed with EtOAc (20 ml) and diethyl ether (20 ml). By addition of 1M HCl a pH of 5 was adjusted. The white precipitate was extracted with EtOAc (4×50 ml). The combined organic layers were dried (sodium sulfate) and concentrated to give a yellowish solid which was further purified by trituration with acetone to provide N-[(5-chloro-2-benzimidazolyl)methyl]-N-(4-chlorophenyl)glycine (43 mg) as colourless crystals.
Reaction SMILES: [NH2:1][C:2]1[N:7]([CH2:8][CH2:9][CH3:10])[C:6](=[O:11])[N:5]([CH2:12][CH2:13][CH3:14])[C:4](=[O:15])[C:3]=1[NH:16][C:17](=O)[CH:18]([CH3:35])[CH2:19][C:20]1[CH:25]=[CH:24][C:23]([O:26][CH2:27][C:28]([O:30]C(C)(C)C)=[O:29])=[CH:22][CH:21]=1>C(O)C.[OH-].[K+].O>[CH2:12]([N:5]1[C:4](=[O:15])[C:3]2[N:16]=[C:17]([CH:18]([CH3:35])[CH2:19][C:20]3[CH:25]=[CH:24][C:23]([O:26][CH2:27][C:28]([OH:30])=[O:29])=[CH:22][CH:21]=3)[NH:1][C:2]=2[N:7]([CH2:8][CH2:9][CH3:10])[C:6]1=[O:11])[CH2:13][CH3:14]
Reactant: CCCn1c(N)c(NC(=O)C(C)Cc2ccc(OCC(=O)OC(C)(C)C)cc2)c(=O)n(CCC)c1=O
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: CCCn1c(=O)c2nc(C(C)Cc3ccc(OCC(=O)O)cc3)[nH]c2n(CCC)c1=O
Temperature: 55 °C
Reaction time: 5 h
Yield: 40.1 %

Procedure:
Dissolve 2-[[4-[3-[(6-amino-1-propyl-1,2,3,4-tetrahydro-3-propyl-2,4-dioxo-5-pyrimidinyl)amino]-2-methyl-3-oxopropyl]phenyl]oxy]-acetic acid, 1,1-dimethylethyl ester (1.6 g, 3.18 mmol) in a mixture of ethanol (30 mL) and 15% potassium hydroxide (30 mL). Heat at 55° C. and stir for 5 hours. Cool, acidify and dilute with water (200 mL). Filter to give 0.69 g crude product. Recrystallize (5% isopropanol/hexane) to give the title compound (0.546 g); mp 168-70° C.
Reaction SMILES: [O-:1][CH2:2][CH3:3].[Na+].[Na].[Cl:6][C:7]1[CH:8]=[N:9][N:10]([CH:12]([CH3:15])[C:13]#[N:14])[CH:11]=1>C(O)C>[Cl:6][C:7]1[CH:8]=[N:9][N:10]([CH:12]([CH3:15])[C:13](=[NH:14])[O:1][CH2:2][CH3:3])[CH:11]=1
Reactant: CC[O-]
Reactant: CC(C#N)n1cc(Cl)cn1
Agent: [Na+]
Agent: [Na]
Solvent: CCO
Product: CCOC(=N)C(C)n1cc(Cl)cn1
Temperature: 70 °C
Reaction time: 3 h

Procedure:
A solution of sodium ethoxide, prepared by adding solid sodium (420 mg, 18.2 mmol) into ethanol (20 mL), was added to a solution of 2-(4-chloro-1H-pyrazol-1-yl)propanenitrile (2530 mg, 13.0 mmol) in ethanol (4 mL). The reaction mixture was stirred at 70° C. for 3 h. 1H NMR analysis of the reaction mixture showed desired product. The mixture was used without further purification. 1H NMR (500 MHz, CDCl3) δ 1.30 (t, 3H), 1.75 (m, 3H), 4.19 (m, 2H), 4.86 (m, 1H), 7.47 (s, 1H), 7.52 (s, 1H).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][N:5]=[C:4]([O:8][CH3:9])[CH:3]=1.[Br-].[CH2:11]([O:13][C:14](=[O:17])[CH2:15][Zn+])[CH3:12]>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.C1COCC1>[CH3:9][O:8][C:4]1[CH:3]=[C:2]([CH2:15][C:14]([O:13][CH2:11][CH3:12])=[O:17])[CH:7]=[CH:6][N:5]=1
Reactant: CCOC(=O)C[Zn+]
Reactant: COc1cc(Br)ccn1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [Br-]
Solvent: C1CCOC1
Product: CCOC(=O)Cc1ccnc(OC)c1
Yield: 38.5 %

Procedure:
Combined 4-bromo-2-methoxypyridine (654 μl, 5.32 mmol), (2-ethoxy-2-oxoethyl)zinc(II) bromide (5850 μl, 5.85 mmol), and Pd(PPh3)4 catalyst (615 mg, 0.532 mmol) in THF (15.2 mL) and heated to 120° C. in a microwave for 5 minutes. The reaction was filtered through a course glass frit, concentrated to an oil and purified via flash chromatography (100 g silica gel using a 5% to 50% EtOAc in heptane gradient). The appropriate fractions were combined and concentrated to acquire ethyl 2-(2-methoxypyridin-4-yl)acetate (400 mg, 38.5% yield) as a colorless oil. MS m/z [M+H]+ 196.1.
Reaction SMILES: [F:1][C:2]([F:10])([F:9])[C:3]1[CH:7]=[C:6]([NH2:8])[O:5][N:4]=1.C([O-])(=O)C.[Na+].[Br:16]Br>C(O)(=O)C>[F:1][C:2]([F:10])([F:9])[C:3]1[C:7]([Br:16])=[C:6]([NH2:8])[O:5][N:4]=1
Reactant: BrBr
Reactant: Nc1cc(C(F)(F)F)no1
Agent: CC(=O)[O-]
Agent: [Na+]
Solvent: CC(=O)O
Product: Nc1onc(C(F)(F)F)c1Br
Yield: 76.7 %

Procedure:
The reaction was carried out according to the same procedure as described in Example 66 except that 3-trifluoromethyl-5-aminoisoxazole (1.06 g, 7.00 mmole), acetic acid (7 ml), anhydrous sodium acetate (0.57 g, 7.00 mmole) and bromine (1.34 g, 8.40 mmole) were used. The product was then purified by column chromatography on silica gel to give a yellow liquid (1.24 g). This product was distilled under reduced pressure to give the title compound as a colorless liquid. Yield: 1.07 g (66.2%), b.p. 85.5°-86.5° C./4.0 mmHg. The structure of this product was confirmed by IR and NMR.
Reaction SMILES: [O:1]=[C:2]1[C@@H:6]2[CH2:7][N:8]([C:10]([O:12][CH2:13][C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=3)=[O:11])[CH2:9][C@@H:5]2[CH2:4][CH2:3]1.[BH4-].[Li+]>C1COCC1>[OH:1][CH:2]1[C@@H:6]2[CH2:7][N:8]([C:10]([O:12][CH2:13][C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=3)=[O:11])[CH2:9][C@@H:5]2[CH2:4][CH2:3]1
Reactant: O=C1CC[C@H]2CN(C(=O)OCc3ccccc3)C[C@@H]12
Agent: [BH4-]
Agent: [Li+]
Solvent: C1CCOC1
Product: O=C(OCc1ccccc1)N1C[C@@H]2CCC(O)[C@@H]2C1
Temperature: 25 °C
Reaction time: 8 h
Yield: 98.6 %

Procedure:
A solution of benzyl (3aR,6aS)-6-oxo-1,3,3a,4,5,6a-hexahydrocyclopenta[c]pyrrole-2-carboxylate (850 mg, 3.3 mmol) in THF (10 mL) was added dropwise to a suspension of lithium borohydride (86 mg, 4 mmol) in THF (5 mL) at −78° C. The reaction mixture was allowed to warm to room temperature and was stirred overnight. The reaction mixture was then cooled to 0° C. and quenched with H2O2 (30% in H2O) and then poured onto H2O. The aqueous layer was extracted with EtOAc (2×) and the combined organic layer was washed with brine, dried over Na2SO4, filtered and concentrated under reduced pressure to obtain benzyl (3aR,6aS)-6-hydroxy-3,3a,4,5,6,6a-hexahydro-1H-cyclopenta[c]pyrrole-2-carboxylate (850 mg, 99%) as a colorless oil. LC/MS m/z 262.1 [M+H]+.