Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2](=[O:23])[C@@H:3]1[C@:20]2([CH3:21])[C@H:6]([C@H:7]3[C@H:17]([CH2:18][CH2:19]2)[C@:15]2([CH3:16])[C@H:10]([CH2:11][C:12](=[O:22])[CH2:13][CH2:14]2)[CH2:9][CH2:8]3)[CH2:5][CH2:4]1.[CH3:24][Mg]Cl>O1CCOCC1>[CH3:1][C:2]([C@@H:3]1[C@@:20]2([CH3:21])[CH2:19][CH2:18][C@@H:17]3[C@@:15]4([CH3:16])[CH2:14][CH2:13][C@:12]([OH:22])([CH3:24])[CH2:11][C@@H:10]4[CH2:9][CH2:8][C@H:7]3[C@@H:6]2[CH2:5][CH2:4]1)=[O:23]
Reactant: CC(=O)[C@H]1CC[C@H]2[C@@H]3CC[C@H]4CC(=O)CC[C@]4(C)[C@H]3CC[C@]12C
Reactant: C[Mg]Cl
Solvent: C1COCCO1
Product: CC(=O)[C@H]1CC[C@H]2[C@@H]3CC[C@H]4C[C@](C)(O)CC[C@]4(C)[C@H]3CC[C@]12C
Reaction time: 6 h

Procedure:
5α-Pregnane 3,20-dione (10 g) is reacted with a reagent obtained by reacting FeCl3 (5.2 g) and MeMgCl (4 equiv, based on FeCl3) in dioxane (anhydrous, 200 mL) at −25° C. for 5 h. The reaction is quenched with acetic acid (32 ml). The reaction mixture is concentrated in vacuo and the residue is stirred with 3N HCl for 6 h. The solid is collected by filtration, washed with water and dried at 50° C. under vacuum to obtain crude ganaxolone. The crude product is dissolved in THF (33 mL) at reflux and filtered hot. The filtrate is added with water (45 mL) to obtain a suspension, which is collected by filtration, washed with water and dried. The dried product is further slurried in ethyl acetate (50 mL) at 70° C. for 19 h. The suspension is cooled to 0° C. and filtered, washed with cold ethyl acetate. The ethyl acetate slurry step is repeated one more time to obtain purified ganaxolone.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([O:11][CH3:12])=[C:6]([CH:10]=1)[C:7](Cl)=[O:8].Cl.[NH2:14][CH2:15][C:16]1[CH:21]=[CH:20][C:19]([CH2:22][C:23]([OH:25])=[O:24])=[CH:18][CH:17]=1>CC(C)=O.[OH-].[Na+].O>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([O:11][CH3:12])=[C:6]([CH:10]=1)[C:7]([NH:14][CH2:15][C:16]1[CH:21]=[CH:20][C:19]([CH2:22][C:23]([OH:25])=[O:24])=[CH:18][CH:17]=1)=[O:8]
Reactant: COc1ccc(Cl)cc1C(=O)Cl
Reactant: NCc1ccc(CC(=O)O)cc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CC(C)=O
Solvent: O
Product: COc1ccc(Cl)cc1C(=O)NCc1ccc(CC(=O)O)cc1
Temperature: 25 °C
Reaction time: 3 h
Yield: 22.1 %

Procedure:
A solution of 5.0 g 5-chloro-2-methoxybenzoyl chloride in 10 ml acetone is added, with ice cooling, to a solution of 5.0 g 4-aminomethyl-phenylacetic acid hydrochloride in 25 ml 2 N aqueous sodium hydroxide solution and 25 ml acetone. The reaction mixture is then stirred for 3 hours at ambient temperature, diluted with water, filtered with charcoal and the filtrate acidified with 2 N hydrochloric acid. The precipitate obtained is filtered off with suction and dried and then recrystallized from ethyl acetate/petroleum ether. There is obtained 1.8 g (21% of theory) 4-(5-chloro-2-methoxybenzamidomethyl)-phenylacetic acid; m.p. 140°-141° C.
Reaction SMILES: [C:1]1([C:7]2[C:8](=O)[NH:9][C:10]([C:19]([F:22])([F:21])[F:20])=[N:11][C:12]=2[C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C(=O)(O)[O-].[Na+].P(Cl)(Cl)([Cl:31])=O>>[Cl:31][C:8]1[C:7]([C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=2)=[C:12]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[N:11]=[C:10]([C:19]([F:22])([F:21])[F:20])[N:9]=1
Reactant: O=P(Cl)(Cl)Cl
Reactant: O=c1[nH]c(C(F)(F)F)nc(-c2ccccc2)c1-c1ccccc1
Agent: O=C([O-])O
Agent: [Na+]
Product: FC(F)(F)c1nc(Cl)c(-c2ccccc2)c(-c2ccccc2)n1
Temperature: 25 °C
Yield: 76.6 %

Procedure:
5,6-Diphenyl-2-(trifluoromethyl)pyrimidin-4(3H)-one (8.0 g, 25 mmol) (synthesized according to the procedure described in our PCT application No. IB03/01289) was refluxed in phosphorus oxychloride (15 ml) for 5 hours and allowed to cool to room temperature. The reaction mixture was poured onto ice-water mixture and neutralised with saturated sodium bicarbonate solution. The solid thus separated was extracted with dichloromethane. The organic extract was washed with water, dried over anhydrous sodium sulphate and concentrated under reduced pressure to give crude product, which was purified by column chromatography to afford the title compound (6.5 g, 76.6%, HPLC purity 99.8%), mp: 105-107° C.
Reaction SMILES: [CH2:1]([C:8]1[N:9]=[N:10][C:11]2[C:16]([C:17]=1[C:18]1[CH:19]=[C:20]([NH2:24])[CH:21]=[CH:22][CH:23]=1)=[CH:15][CH:14]=[CH:13][C:12]=2[Cl:25])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:26][C:27]1[C:34]([CH3:35])=[CH:33][CH:32]=[CH:31][C:28]=1[CH:29]=O>>[CH2:1]([C:8]1[N:9]=[N:10][C:11]2[C:16]([C:17]=1[C:18]1[CH:19]=[C:20]([NH:24][CH2:29][C:28]3[CH:31]=[CH:32][CH:33]=[C:34]([CH3:35])[C:27]=3[CH3:26])[CH:21]=[CH:22][CH:23]=1)=[CH:15][CH:14]=[CH:13][C:12]=2[Cl:25])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: Nc1cccc(-c2c(Cc3ccccc3)nnc3c(Cl)cccc23)c1
Reactant: Cc1cccc(C=O)c1C
Product: Cc1cccc(CNc2cccc(-c3c(Cc4ccccc4)nnc4c(Cl)cccc34)c2)c1C

Procedure:
The title compound was prepared from [3-(3-benzyl-8-chlorocinnolin-4-yl)phenyl]amine and 2,3-dimethylbenzaldehyde according to the procedure of Step 5 Example 6. MS (ESI) m/z 464.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]2[S:9][C:8]([NH2:10])=[N:7][C:6]=2[CH:11]=1.[CH2:12]([N:14]=[C:15]=[O:16])[CH3:13]>O1CCOCC1>[Br:1][C:2]1[CH:3]=[CH:4][C:5]2[S:9][C:8]([NH:10][C:15]([NH:14][CH2:12][CH3:13])=[O:16])=[N:7][C:6]=2[CH:11]=1
Reactant: CCN=C=O
Reactant: Nc1nc2cc(Br)ccc2s1
Solvent: C1COCCO1
Product: CCNC(=O)Nc1nc2cc(Br)ccc2s1
Temperature: 79 °C
Yield: 50 %

Procedure:
To a suspension of 5-bromo-benzothiazol-2-ylamine IV (0.23 g, 1.0 mmol) in 1,4-dioxane (10 mL) was added ethylisocyanate (0.36 g, 0.38 mL, 5.02 mmol). The reaction mixture was heated up to 78-80° C. overnight. After completion of reaction (TLC monitoring), 1,4-dioxane was distilled off and co evaporated with hexane. The resulting solid was treated with water to 60-70° C. for 3-5 h. The resulting solid was filtered off and again washed with hot water, dried under high vacuum to obtain the desired product as off-white solid (0.15 g, 50%). 1H NMR (DMSO-d6, 400 MHz): δ 1.08 (t, J=7.20 Hz, 3H), 3.18 (m, 2H), 6.70 (br s, 1H), 7.36 (dd, J=1.60 and 8.0 Hz, 1H), 7.79 (d, J=1.60 Hz, 1H), 7.84 (d, J=8.40 Hz, 1H) and 10.85 (br s, 1H). MS: 300.07 (M+H+).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:30]=[CH:29][C:6]2[C:7]([C:15]([C:17]3[CH:22]=[C:21]([O:23][CH3:24])[C:20]([O:25][CH3:26])=[C:19]([O:27][CH3:28])[CH:18]=3)=[O:16])=[C:8]([C:10]3[CH:11]=[N:12][NH:13][CH:14]=3)[O:9][C:5]=2[CH:4]=1.[H-].[Na+].Cl.Cl[CH2:35][CH2:36][N:37]([CH3:39])[CH3:38]>CS(C)=O>[CH3:38][N:37]([CH3:39])[CH2:36][CH2:35][N:13]1[CH:14]=[C:10]([C:8]2[O:9][C:5]3[CH:4]=[C:3]([O:2][CH3:1])[CH:30]=[CH:29][C:6]=3[C:7]=2[C:15]([C:17]2[CH:18]=[C:19]([O:27][CH3:28])[C:20]([O:25][CH3:26])=[C:21]([O:23][CH3:24])[CH:22]=2)=[O:16])[CH:11]=[N:12]1
Reactant: CN(C)CCCl
Reactant: COc1ccc2c(C(=O)c3cc(OC)c(OC)c(OC)c3)c(-c3cn[nH]c3)oc2c1
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: CS(C)=O
Product: COc1ccc2c(C(=O)c3cc(OC)c(OC)c(OC)c3)c(-c3cnn(CCN(C)C)c3)oc2c1
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 43.6 %

Procedure:
To a stirred solution of [6-Methoxy-2-(1H-pyrazol-4-yl)-benzofuran-3-yl]-(3,4,5-trimethoxyphenyl)-methanone (45 mg, 0.11 mmol) in dry DMSO (1.5 mL) was added sodium hydride (60% dispersion in mineral oil, 13 mg, 0.33 mmol) and the reaction was stirred at room temperature for 20 minutes. After this time the resulting yellow suspension was treated with 2-chloroethyl-dimethylamine hydrogen chloride (24 mg, 0.17 mmol) and heated to 35-40° C. for 5 h. The reaction was quenched with water (15 mL) and ethyl acetate (20 mL) and the aqueous layer was washed with further portions of ethyl acetate (2×10 mL). The combined organic layers were dried over magnesium sulphate and the solvent was removed under vacuum. The crude residue was purified by flash chromatography (alumina activated with 1.2% water, sequential elution—1:1 DCM:hexane, 9:1 DCM:ethyl acetate) to afford the product as a yellow resinous gum (23 mg, 44% yield). 1H-NMR (CDCl3) δ 8.17 (s, 1H), 8.00 (s, 1H), 7.12 (s, 2H), 7.11 (d, J=8.7 Hz, 1H), 7.03 (d, J=2.2 Hz, 1H), 6.79 (dd, J=8.7, 2.2 Hz, 1H), 4.23 (t, J=6.7 Hz, 2H), 3.92 (s, 3H), 3.85 (s, 3H), 3.77 (s, 6H), 2.78 (t, J=6.7 Hz, 2H), 2.27 (s, 6H). 13C-NMR (CDCl3) δ 190.3, 158.1, 153.6, 152.9, 142.2, 139.0, 133.7, 130.4, 121.7, 120.9, 113.7, 112.5, 112.2, 111.5, 106.9, 95.5, 61.0, 58.7, 56.1, 55.7, 50.4, 45.4.
Reaction SMILES: I[C:2]1[C:3]([O:10][C:11]2[CH:16]=[CH:15][C:14]([NH:17][C:18]3[CH:23]=[CH:22][C:21]([CH3:24])=[CH:20][N:19]=3)=[CH:13][CH:12]=2)=[N:4][C:5]([O:8][CH3:9])=[N:6][CH:7]=1.[F:25][C:26]1[CH:31]=[C:30](B(O)O)[CH:29]=[CH:28][N:27]=1.C(=O)([O-])[O-].[Na+].[Na+]>O1CCOCC1.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>[F:25][C:26]1[CH:31]=[C:30]([C:2]2[C:3]([O:10][C:11]3[CH:16]=[CH:15][C:14]([NH:17][C:18]4[CH:23]=[CH:22][C:21]([CH3:24])=[CH:20][N:19]=4)=[CH:13][CH:12]=3)=[N:4][C:5]([O:8][CH3:9])=[N:6][CH:7]=2)[CH:29]=[CH:28][N:27]=1
Reactant: OB(O)c1ccnc(F)c1
Reactant: COc1ncc(I)c(Oc2ccc(Nc3ccc(C)cn3)cc2)n1
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: O
Solvent: C1COCCO1
Product: COc1ncc(-c2ccnc(F)c2)c(Oc2ccc(Nc3ccc(C)cn3)cc2)n1
Temperature: 80 °C
Reaction time: 20 h

Procedure:
N-(4-(5-Iodo-2-methoxypyrimidin-4-yloxy)phenyl)-5-methylpyridin-2-amine (0.061 g, 0.14 mmol), 2-fluoropyridine-4-boronic acid (0.030 g, 0.21 mmol), and tetrakis(triphenylphosphine)palladium (0.016 g, 0.014 mmol) were mixed in dioxane (0.5 mL) under an argon atmosphere. Sodium carbonate (0.21 mL, 0.42 mmol, 2.0 M in water) was added via syringe, and the reaction mixture was stirred at 80° C. for 20 h. The reaction mixture was cooled to room temperature, diluted with water, and extracted with EtOAc. The organic layer was separated, washed with sat. sodium chloride, dried over magnesium sulfate, filtered, and concentrated. The resulting crude product was purified by silica gel chromatography to give N-(4-(5-(2-fluoropyridin-4-yl)-2-methoxypyrimidin-4-yloxy)phenyl)-5-methylpyridin-2-amine. MS (ESI, pos. ion) m/z: 404.2 (M+1). IC50 (uM) 0.016.
Reaction SMILES: CC1(C)CCCC(C)(C)N1.C([Li])CCC.C([N:18]([CH2:27][CH3:28])[C:19]([C:21]1[CH:25]=[CH:24][O:23][C:22]=1[CH3:26])=[O:20])C.[CH3:29][N:30]([CH3:35])[CH2:31]CC#N.Cl>O1CCCC1.CC(C)=O>[CH3:29][N:30]([CH3:35])[CH2:31][CH2:28][C:27]1[NH:18][C:19](=[O:20])[C:21]2[CH:25]=[CH:24][O:23][C:22]=2[CH:26]=1
Reactant: CN(C)CCC#N
Reactant: CCN(CC)C(=O)c1ccoc1C
Agent: CC1(C)CCCC(C)(C)N1
Agent: Cl
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CC(C)=O
Product: CN(C)CCc1cc2occc2c(=O)[nH]1
Temperature: 0 °C
Reaction time: 1 h
Yield: 81.7 %

Procedure:
To a solution of 2,2,6,6-tetramethylpiperidine (5.1 ml, 30.4 mmole) in dry tetrahydrofuran (60 ml), cooled at -78° C. (dryice/acetone) under an argon atmosphere, was added dropwise n-butyllithium (17.3 ml, 27.6 mmole). After the addition the reaction was warmed to -10° C. (ice/acetone). To this solution was added N,N-diethyl-2-methylfuran-3-carboxamide (5.0 g, 27.6 mmole) in tetrahydrofuran (15 ml). After stirring this mixture for 1.0 hour, 3-(dimethylamino)propionitrile (3.27 ml, 29.0 mmole) was added dropwise. The reaction was allowed to warm overnight. The reaction was poured into ice/water and acidified to a pH 3.25 with hydrochloric acid. The mixture was then extracted with diethyl ether (3×150 ml). The pH of the aqueous layer was adjusted to 13.0 using sodium hydroxide solution (40%) and this solution was extracted exhaustively using methylene chloride (10×150 ml). The combined extracts were washed with water (2×50 ml), brine (2×100 ml) and dried (MgSO4). After solvent evaporation 8.25 g of an oil was obtained. This was purified by flash chromatography using 15% methanol/chloroform as the eluting solvent to give analytically pure product (4.65 g, 82% yield), mp: 97.5°-98.0° C. Some starting amide (1.05 g) was recovered from the initial diethyl ether extracts.
Reaction SMILES: Cl.[CH3:2][N:3]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[CH:5]=[C:4]1[CH2:12][NH:13][CH2:14][C:15]([OH:17])=O.[CH2:18]([C@H:25]1[CH2:29][NH:28][C@H:27]([C:30]([NH:32][C:33]2[CH:38]=[CH:37][C:36]([O:39][C:40]3[CH:45]=[CH:44][C:43]([F:46])=[CH:42][CH:41]=3)=[CH:35][CH:34]=2)=[O:31])[CH2:26]1)[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1>>[CH2:18]([C@H:25]1[CH2:29][N:28]([C:15](=[O:17])[CH2:14][NH:13][CH2:12][C:4]2[N:3]([CH3:2])[C:11]3[C:6]([CH:5]=2)=[CH:7][CH:8]=[CH:9][CH:10]=3)[C@H:27]([C:30]([NH:32][C:33]2[CH:38]=[CH:37][C:36]([O:39][C:40]3[CH:41]=[CH:42][C:43]([F:46])=[CH:44][CH:45]=3)=[CH:35][CH:34]=2)=[O:31])[CH2:26]1)[C:19]1[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=1
Reactant: Cn1c(CNCC(=O)O)cc2ccccc21
Reactant: O=C(Nc1ccc(Oc2ccc(F)cc2)cc1)[C@@H]1C[C@@H](Cc2ccccc2)CN1
Agent: Cl
Product: Cn1c(CNCC(=O)N2C[C@H](Cc3ccccc3)C[C@H]2C(=O)Nc2ccc(Oc3ccc(F)cc3)cc2)cc2ccccc21
Yield: 30.4 %

Procedure:
Proceeding as in Example 1, but substituting 2-((1-methyl-1H-indol-2-yl)methylamino)acetic acid hydrochloride and (2S,4R)-4-benzyl-N-(4-(4-fluorophenoxy)phenyl)pyrrolidine-2-carboxamide, gave Compound 30, (2S,4R)-4-benzyl-N-(4-(4-fluorophenoxy)phenyl)-1-(2-((1-methyl-1H-indol-2-yl)methylamino)acetyl)pyrrolidine-2-carboxamide (12.6 mg, 30.4%). 1H-NMR (400 MHz, DMSO-D6): σ 9.95 (s, 1H), 7.93 (m, 2H), 7.26 (m, 4H), 7.17 (m, 8H), 6.96 (m, 3H), 4.15 (m, 1H), 3.64 (m, 1H), 3.49 (m, 2H), 3.14 (m, 2H), 2.87 (s, 3H), 2.64 (m, 2H), 2.20 (m, 1H), 1.89 (m, 2H). MS (EI) for C35H34FN5O3: 592.7 (MH+).
Reaction SMILES: CN(C=O)C.[S:6]([Cl:10])(Cl)(=[O:8])=[O:7].[Cl:11][C:12]1[CH:27]=[CH:26][C:15]([CH2:16][C:17]2[S:21][C:20]3[CH:22]=[CH:23][CH:24]=[CH:25][C:19]=3[CH:18]=2)=[CH:14][CH:13]=1>>[Cl:11][C:12]1[CH:27]=[CH:26][C:15]([CH2:16][C:17]2[S:21][C:20]3[CH:22]=[CH:23][CH:24]=[CH:25][C:19]=3[C:18]=2[S:6]([Cl:10])(=[O:8])=[O:7])=[CH:14][CH:13]=1
Reactant: Clc1ccc(Cc2cc3ccccc3s2)cc1
Reactant: O=S(=O)(Cl)Cl
Solvent: CN(C)C=O
Product: O=S(=O)(Cl)c1c(Cc2ccc(Cl)cc2)sc2ccccc12

Procedure:
2-(4-chlorobenzyl)benzo[b]thiophene-3-sulfonylchloride was prepared by the method of Example 40B with DMF (70 mmoles, 5.4 ml), sulfurylchloride (2.3 mmoles, 1.9 ml) and 2-(4-chlorobenzyl)-benzo[b]thiophene (4.6 mmoles, 1.2 g). Flash chromatography (2% ethyl acetate/hexanes) provided 0.51 g (31%) of an orange-yellow oil.
Reaction SMILES: [CH2:1](N(CC)CC)C.B.Cl.[CH3:10][O:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=1[N:18]1[CH2:23][CH2:22][N:21]([CH2:24][CH2:25][NH2:26])[CH2:20][CH2:19]1>O1CCCC1.C(OCC)(=O)C>[CH3:10][O:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=1[N:18]1[CH2:19][CH2:20][N:21]([CH2:24][C@H:25]([NH2:26])[CH3:1])[CH2:22][CH2:23]1
Reactant: COc1ccccc1N1CCN(CCN)CC1
Reactant: CCN(CC)CC
Agent: B
Agent: Cl
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: COc1ccccc1N1CCN(C[C@@H](C)N)CC1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
The above mentioned (R)-{1-methyl-2-[4-(2-methoxyphenyl)-piperazin-1-yl]-2-amino-propan-2-1-one hydrochloride (5.90 g, 19.7 mmol) was dissolved in anhydrous tetrahydrofuran (60 mL) at room temperature. Triethylamine (6.3 mL, 45 mmol) was added, followed by dropwise addition of a 1M solution of borane in tetrahydrofuran (77.5 mL, 45 mmol). The resulting mixture was refluxed for 18 hours. After cooling the reaction mixture to room temperature, ethyl acetate (60 mL) and 2N aqueous HCl were added and the resulting mixture was stirred at room temperature for one hour. The layers were separated and the aqueous layer was made basic by careful addition of 50% aqueous NaOH. The resulting basic mixture was extracted with three 50 mL portions of ethyl acetate. The combined organic layers were washed with brine (50 mL) and dried over anhydrous sodium sulfate. Filtration and concentration on a rotary evaporator yielded 4.62 g (94%) of the desired of 2-[4-(2-methoxyphenyl)-piperazin-1-yl]-ethylamine as a colorless oil which was used without further purification.
Reaction SMILES: [NH2:1][C:2]1[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[CH:4][CH:3]=1.C(N(CC)CC)C.[F:17][C:18]([F:29])([C:22]([F:28])([F:27])[C:23]([F:26])([F:25])[F:24])[C:19](Cl)=[O:20]>ClCCl.Cl>[F:17][C:18]([F:29])([C:22]([F:27])([F:28])[C:23]([F:24])([F:25])[F:26])[C:19]([NH:1][C:2]1[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[CH:4][CH:3]=1)=[O:20]
Reactant: O=C(Cl)C(F)(F)C(F)(F)C(F)(F)F
Reactant: N#Cc1ccc(N)cc1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: N#Cc1ccc(NC(=O)C(F)(F)C(F)(F)C(F)(F)F)cc1
Temperature: 25 °C
Reaction time: 3 h
Yield: 36.9 %

Procedure:
A mixture of 4-aminobenzonitrile (1.58 g), triethylamine (1.36 g), and dichloromethane (20 mL) was cooled in ice under a nitrogen atmosphere. To this mixture was added perfluorobutyryl chloride (3.11 g) in dichloromethane (10 mL) and the resulting mixture was allowed to warm to room temperature and was then stirred for three hours. The reaction mixture was diluted with HCl solution (1N, 50 mL) and the layers were partitioned in a separatory funnel. The organic phase was washed with a saturated brine solution, dried over MgSO4, filtered and concentrated with a rotary evaporator. The residue was dissolved in dichloromethane. Upon dilution with hexane the product precipitated to give 1.55 g of 2,2,3,3,4,4,4-heptafluoro-N-[4-(cyano)phenyl]butanamide, m.p. 116°-118° C.
Reaction SMILES: Cl.[CH3:2][O:3][C:4](=[O:9])[C@@H:5]([CH2:7][OH:8])[NH2:6].CCN(CC)CC.Cl[C:18]([C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1)([C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1)[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1>C(Cl)Cl>[OH:8][CH2:7][C@@H:5]([NH:6][C:18]([C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)([C:31]1[CH:32]=[CH:33][CH:34]=[CH:35][CH:36]=1)[C:25]1[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=1)[C:4]([O:3][CH3:2])=[O:9]
Reactant: COC(=O)[C@H](N)CO
Reactant: ClC(c1ccccc1)(c1ccccc1)c1ccccc1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COC(=O)[C@@H](CO)NC(c1ccccc1)(c1ccccc1)c1ccccc1
Temperature: 0 °C
Reaction time: 24 h
Yield: 96.2 %

Procedure:
(S. Bhatia and J. Hajdu, Tetrahedron Lett. 1998, 29, 31-34). To a solution of D-serine methyl ester hydrochloride (20.00 g, 0.13 mol) and Et3N (35.82 mL, 0.26 mol) in CH2Cl2 (80 mL) at 0° C., was added in one portion a solution of TrCl (36.53 g, 0.13 mol) in CH2Cl2 (80 mL). The mixture was allowed to stir at 0° C. (24 h) under Ar and then successively washed with 10% aqueous citric acid (120 mL) and saturated aqueous brine (120 mL). The organic layer was dried (Na2SO4) and evaporated in vacuo to yield 45.20 g (97%) of crude desired product as a pale yellow crystalline solid. The product was used for next step without further purification: Rf=0.50 (1/1 EtOAc/hexanes); 1H NMR (CDCl3) δ 2.29 (br s, 1H), 2.98 (br s, 1H), 3.29 (s, OCH3), 3.51-3.60 (m, CHH′OH, CH), 3.64-3.74 (m, CHH′OH), 7.16-7.30 (m, 9 PhH), 7.47-7.50 (m, 6 PhH).
Reaction SMILES: [F:1][CH:2]([F:35])[O:3][C:4]1[CH:5]=[C:6]([CH:14]([N:19]2[CH2:27][C:26]3[C:21](=[C:22]([NH:28][C:29]([CH:31]4[CH2:33][CH2:32]4)=[O:30])[CH:23]=[CH:24][CH:25]=3)[C:20]2=[O:34])[CH2:15][C:16](O)=[O:17])[CH:7]=[CH:8][C:9]=1[O:10][CH:11]([F:13])[F:12].[C:36](N1C=CN=C1)([N:38]1C=CN=[CH:39]1)=O.CNC.O>O1CCCC1>[F:1][CH:2]([F:35])[O:3][C:4]1[CH:5]=[C:6]([CH:14]([N:19]2[C:20](=[O:34])[C:21]3[C:26](=[CH:25][CH:24]=[CH:23][C:22]=3[NH:28][C:29]([CH:31]3[CH2:32][CH2:33]3)=[O:30])[CH2:27]2)[CH2:15][C:16](=[O:17])[N:38]([CH3:39])[CH3:36])[CH:7]=[CH:8][C:9]=1[O:10][CH:11]([F:12])[F:13]
Reactant: O=C(n1ccnc1)n1ccnc1
Reactant: O=C(O)CC(c1ccc(OC(F)F)c(OC(F)F)c1)N1Cc2cccc(NC(=O)C3CC3)c2C1=O
Agent: CNC
Solvent: C1CCOC1
Solvent: O
Product: CN(C)C(=O)CC(c1ccc(OC(F)F)c(OC(F)F)c1)N1Cc2cccc(NC(=O)C3CC3)c2C1=O
Temperature: 25 °C
Reaction time: 2 h
Yield: 47.2 %

Procedure:
To a solution of 3-(3,4-bis-difluoromethoxy-phenyl)-3-[7-(cyclopropanecarbonyl-amino)-1-oxo-1,3-dihydro-isoindol-2-yl]-propionic acid (400 mg, 0.81 mmol) in tetrahydrofurane (10 ml) was added carbonyldiimidazole (200 mg, 1.21 mmol) at room temperature. The solution was stirred at room temperature for 2 hours. To the mixture was added dimethylamine in THF (0.8 ml, 1.6 mmol). The resulted mixture was stirred at room temperature for 3 hours. Water (20 ml) was added to the reaction mixture. The solvent was removed in vacuo. The resulted mixture was taken up in ethyl acetate (30 ml) and washed with water (20 ml). The organic layer was washed with saturated sodium bicarbonate solution (3×20 ml), water (20 ml), brine (20 ml) and dried over magnesium sulfate. The solvent was removed in vacuo. The resulted oil was stirred with ether overnight. The suspension was filtered to give a yellowish solid. The solid was purified by HPLC (CH3CN:Water=45:55) to give cyclopropanecarboxylic acid {2-[1-(3,4-bis-difluoromethoxy-phenyl)-2-dimethylcarbamoyl-ethyl]-3-oxo-2,3-dihydro-1H-isoindol-4-yl}-amide as a white solid (200 mg, 50%): mp, 158–160° C.; 1H NMR (CDCl3): δ 0.86–0.92 (m, 2H, cyclopropyl ring CH2), 1.08–1.12 (m, 2H, cyclopropyl ring CH2), 1.66–1.70 (m, 1H, cyclopropyl ring CH), 2.93 (s, 3H, NCH3), 3.04 (dd, J=5, 15 Hz, 1H, CHHCO), 3.10 (s, 3H, NCH3), 3.64 (dd, J=8, 15 Hz, 1H, CHHCO), 4.13 (t, J=15 Hz, 2H, CHHN), 5.56–5.62 (m, 1H, CHN), 6.51 (t, JH-F=75 Hz, 1H, OCF2H), 6.54 (t, JH-F=75 Hz, 1H, OCF2H), 7.01 (d, J=8 Hz, 1H, Ar), 7.23–7.36 (m, 3H, Ar), 7.44 (t, J=8 Hz, 1H, Ar), 8.43 (d, J=8 Hz, 1H, Ar), 10.52 (s, 1H, NHCO); 13C NMR (CDCl3):8.22, 16.16, 35.58, 35.92, 37.27, 49.59, 53.83, 58.94, 111.0, 115.65, 117.64, 117.67, 119.90, 119.80, 121.66, 122.58, 125.64, 133.27, 138.05, 138.69, 141.49, 169.11, 169.81, 172.65; Anal. Calcd. for C25H25F4N3O5: C, 57.36; H, 4.81; N, 8.03. Found: C, 57.22; H, 4.76; N, 8.11.
Reaction SMILES: [NH:1]1[C:5]([CH2:6][CH2:7][C:8]2[N:9]([C:21]3[CH:29]=[CH:28][C:24]([C:25](O)=[O:26])=[CH:23][C:22]=3[CH3:30])[C:10]([C:13]3[CH:18]=[CH:17][C:16]([O:19][CH3:20])=[CH:15][CH:14]=3)=[CH:11][CH:12]=2)=[N:4][N:3]=[N:2]1.C1N=C[N:33](C(N2C=NC=C2)=O)C=1.O.[NH4+]>C1COCC1>[NH:4]1[C:5]([CH2:6][CH2:7][C:8]2[N:9]([C:21]3[CH:29]=[CH:28][C:24]([C:25]([NH2:33])=[O:26])=[CH:23][C:22]=3[CH3:30])[C:10]([C:13]3[CH:14]=[CH:15][C:16]([O:19][CH3:20])=[CH:17][CH:18]=3)=[CH:11][CH:12]=2)=[N:1][N:2]=[N:3]1
Reactant: COc1ccc(-c2ccc(CCc3nnn[nH]3)n2-c2ccc(C(=O)O)cc2C)cc1
Reactant: O=C(n1ccnc1)n1ccnc1
Agent: [NH4+]
Solvent: O
Solvent: C1CCOC1
Product: COc1ccc(-c2ccc(CCc3nnn[nH]3)n2-c2ccc(C(N)=O)cc2C)cc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
4-(2-(2-(1H-tetrazol-5-yl)ethyl)-5-(4-methoxyphenyl)-1H-pyrrol-1-yl)-3-methylbenzoic acid (130 mg, 0.332 mmol) was dissolved in anhydrous THF (3 mL). CDI (68 mg, 0.419 mmol) was added in three portions at room temperature and stirred at this temperature for 1 h. The resultant yellow solution was added dropwise to 25% ammonium hydrate (3 mL) at 0° C. After the addition was complete, the mixture was allowed to warm to room temperature and stirred for 2 h. The mixture was evaporated in vacuo and the residue was purified by prep-HPLC to afford 2H, R2=4-methoxyphenyl as a yellow solid (7 mg, 5.4%).
Reaction SMILES: [Cl:1][C:2]1[C:7]([Cl:8])=[CH:6][C:5]([C:9](=[O:11])[CH3:10])=[C:4]([OH:12])[C:3]=1[I:13].[C:14]1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.CO.N(C(OC(C)C)=O)=NC(OC(C)C)=O>O1CCCC1>[Cl:1][C:2]1[C:7]([Cl:8])=[CH:6][C:5]([C:9](=[O:11])[CH3:10])=[C:4]([O:12][CH3:14])[C:3]=1[I:13]
Reactant: CC(=O)c1cc(Cl)c(Cl)c(I)c1O
Reactant: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Agent: CC(C)OC(=O)N=NC(=O)OC(C)C
Solvent: CO
Solvent: C1CCOC1
Product: COc1c(C(C)=O)cc(Cl)c(Cl)c1I
Temperature: 20 °C
Reaction time: 16 h
Yield: 79.2 %

Procedure:
A solution of 1-(4,5-dichloro-2-hydroxy-3-iodophenyl)ethanone (4.9 g, 15 mmol), triphenylphosphine (5.5 g, 21 mmol), and methanol (0.91 mL, 22 mmol) in tetrahydrofuran (44 mL) at 0° C. was treated with diisopropyl azodicarboxylate (4.1 mL, 21 mmol) dropwise and stirred at 20° C. for 16 h. The reaction mixture was concentrated, diluted with ethyl acetate, and poured into water. The organic layer was separated, washed with brine, dried with magnesium sulfate, filtered, and concentrated to a crude residue. Purification by flash column chromatography using ethyl acetate in hexanes (5%-30%) gave the desired product (4.1 g, 79%). LCMS for C9H8Cl2IO2 (M+H)+: m/z=344.9, 346.9. Found: 344.9, 346.7.