Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[CH:7]=[C:6]([CH2:8][CH2:9][O:10][CH2:11][O:12][CH3:13])[CH:5]=[CH:4][C:3]=1[O:14][CH2:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1.[Cu][C:23]#[N:24].O>CN(C)C=O>[CH2:15]([O:14][C:3]1[CH:4]=[CH:5][C:6]([CH2:8][CH2:9][O:10][CH2:11][O:12][CH3:13])=[CH:7][C:2]=1[C:23]#[N:24])[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1
Reactant: N#C[Cu]
Reactant: COCOCCc1ccc(OCc2ccccc2)c(Br)c1
Solvent: O
Solvent: CN(C)C=O
Product: COCOCCc1ccc(OCc2ccccc2)c(C#N)c1
Temperature: 120 °C
Reaction time: 48 h
Yield: 104.5 %

Procedure:
To a stirred solution of the obtained 4′-benzyloxy-3′-bromophenethyl alcohol (782 mg) in dichloromethane (8 ml) were added N,N-diisopropylethylamine (665 μl) and chloromethyl methyl ether (232 μl) under ice-cooling, and the mixture was stirred for 6 hours at room temperature. The reaction mixture was poured into water and extracted with ethyl acetate. After the extract was washed with brine, removal of the solvent under reduced pressure gave benzyl 2-bromo-4-(2-methoxymethoxyethyl)phenyl ether (804 mg). To a solution of benzyl 2-bromo-4-(2-methoxymethoxyethyl)phenyl ether (804 mg) in N,N-dimethylformamide (5 ml) was added copper(I) cyanide (458 mg) and the mixture was stirred for 2 days at 120° C. The reaction mixture was poured into water and extracted with ethyl acetate. The extract was washed with brine, and removal of the solvent under reduced pressure gave 2-benzyloxy-5-(2-methoxymethoxyethyl)benzonitrile (711 mg).
Reaction SMILES: [Br:1][C:2]1[CH:23]=[CH:22][C:5]([O:6][C:7]2[N:16]=[C:15]([F:17])[C:14]([Si:18]([CH3:21])([CH3:20])[CH3:19])=[CH:13][C:8]=2[C:9]([O:11]C)=O)=[C:4](I)[CH:3]=1.C([Mg]Cl)(C)C>C1COCC1.C(OCC)C>[Br:1][C:2]1[CH:3]=[C:4]2[C:5](=[CH:22][CH:23]=1)[O:6][C:7]1=[N:16][C:15]([F:17])=[C:14]([Si:18]([CH3:19])([CH3:21])[CH3:20])[CH:13]=[C:8]1[C:9]2=[O:11]
Reactant: COC(=O)c1cc([Si](C)(C)C)c(F)nc1Oc1ccc(Br)cc1I
Agent: CC(C)[Mg]Cl
Solvent: CCOCC
Solvent: C1CCOC1
Product: C[Si](C)(C)c1cc2c(=O)c3cc(Br)ccc3oc2nc1F
Temperature: -78 °C
Reaction time: 0.25 h

Procedure:
Methyl 2-(4-bromo-2-iodophenoxy)-6-fluoro-5-(trimethylsilyl)nicotinate (2.04 g, 3.89 mmol) was dissolved in dry THF (80 mL) and cooled in a dry ice bath to −78° C. Isopropylmagnesium chloride (2.0 M solution in diethyl ether, 3.89 mL (7.78 mmol) was added and the solution stirred for 15 minutes. The mixture was removed from the cold bath and allowed to slowly warm to RT. Water (100 mL), saturated ammonium chloride (10 mL), and EtOAc (200 mL) were added and the phases mixed and separated. The organics were dried with magnesium sulfate and evaporated to dryness under reduced pressure. The crude was purified using silica chromatography (hexane to ethyl acetate gradient) to give 7-bromo-2-fluoro-3-(trimethylsilyl)-5H-chromeno[2,3-b]pyridin-5-one.
Reaction SMILES: [Cl:1][C:2]1[N:10]=[C:9]([CH3:11])[CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=[O:5].[CH2:12](O)[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.C(N=C=NCCCN(C)C)C>CN(C)C1C=CN=CC=1.CN(C=O)C.C(OCC)(=O)C>[CH2:12]([O:5][C:4](=[O:6])[C:3]1[CH:7]=[CH:8][C:9]([CH3:11])=[N:10][C:2]=1[Cl:1])[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1
Reactant: Cc1ccc(C(=O)O)c(Cl)n1
Reactant: OCc1ccccc1
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: Cc1ccc(C(=O)OCc2ccccc2)c(Cl)n1
Temperature: 25 °C
Reaction time: 8 h
Yield: 78.7 %

Procedure:
To a solution of 2-chloro-6-methylnicotinic acid (3.0 g), benzyl alcohol (2.27 g), 4-dimethylaminopyridine (2.56 g) in DMF (10 mL) was added 1-ethyl-3-(3′-dimethylaminopropyl) carbodiimide (WSC) hydrochloride (4.02 g). The mixture was stirred at room temperature overnight. The reaction mixture was diluted with ethyl acetate, washed successively with water, saturated aqueous sodium bicarbonate, water, and saturated brine, dried over anhydrous sodium sulfate, and concentrated. The residue was purified by column chromatography on silica gel (hexane:ethyl acetate=4:1, v/v) to give the title compound (3.6 g).
Reaction SMILES: [C:1]([O:5][C:6](=[O:21])[NH:7][C:8]1[CH:13]=[C:12]([CH2:14][CH3:15])[C:11]([C:16]([F:19])([F:18])[F:17])=[CH:10][C:9]=1[NH2:20])([CH3:4])([CH3:3])[CH3:2].C([O:26][C:27](=O)[CH2:28][C:29]([C:31]1[CH:36]=[CH:35][CH:34]=[C:33]([C:37]2[CH:38]=[N:39][C:40]([CH:43]3[CH2:45][CH2:44]3)=[CH:41][CH:42]=2)[CH:32]=1)=[O:30])(C)(C)C>>[C:1]([O:5][C:6](=[O:21])[NH:7][C:8]1[CH:13]=[C:12]([CH2:14][CH3:15])[C:11]([C:16]([F:19])([F:18])[F:17])=[CH:10][C:9]=1[NH:20][C:27](=[O:26])[CH2:28][C:29]([C:31]1[CH:36]=[CH:35][CH:34]=[C:33]([C:37]2[CH:38]=[N:39][C:40]([CH:43]3[CH2:44][CH2:45]3)=[CH:41][CH:42]=2)[CH:32]=1)=[O:30])([CH3:2])([CH3:3])[CH3:4]
Reactant: CCc1cc(NC(=O)OC(C)(C)C)c(N)cc1C(F)(F)F
Reactant: CC(C)(C)OC(=O)CC(=O)c1cccc(-c2ccc(C3CC3)nc2)c1
Product: CCc1cc(NC(=O)OC(C)(C)C)c(NC(=O)CC(=O)c2cccc(-c3ccc(C4CC4)nc3)c2)cc1C(F)(F)F

Procedure:
The title compound was prepared from (2-amino-5-ethyl-4-trifluoromethyl-phenyl)-carbamic acid tert-butyl ester (Example J33) (152 mg, 0.5 mmol) and 3-[3-(6-cyclopropyl-pyridin-3-yl)-phenyl]-3-oxo-propionic acid tert-butyl ester (Example K21) (169 mg, 0.5 mmol) according to the general procedure M. Obtained as a light yellow foam (211 mg, 74%).
Reaction SMILES: [NH2:1][C:2]1[S:3][C:4]([C:8]2[N:9]=[C:10]([CH2:13][C:14]#[N:15])[S:11][CH:12]=2)=[C:5]([CH3:7])[N:6]=1.C(N(CC)C(C)C)(C)C.[N:25]([CH2:28][CH2:29][C:30]([O:32][CH2:33][CH3:34])=[O:31])=[C:26]=[O:27]>C(Cl)Cl>[C:14]([CH2:13][C:10]1[S:11][CH:12]=[C:8]([C:4]2[S:3][C:2]([NH:1][C:26]([NH:25][CH2:28][CH2:29][C:30]([O:32][CH2:33][CH3:34])=[O:31])=[O:27])=[N:6][C:5]=2[CH3:7])[N:9]=1)#[N:15]
Reactant: CCOC(=O)CCN=C=O
Reactant: Cc1nc(N)sc1-c1csc(CC#N)n1
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CCOC(=O)CCNC(=O)Nc1nc(C)c(-c2csc(CC#N)n2)s1
Temperature: 50 °C
Reaction time: 36 h

Procedure:
(2′-Amino-4′-methyl-4,5′-bi-1,3-thiazol-2-yl)acetonitrile, prepared in Step I, described above (236.3 mg; 1 mmol; 1 eq.), is suspended in DCM (5 ml). N,N-Diisopropylethylamine (377 μl; 2.20 mmol; 2.20 eq.) is added, followed by a solution of ethyl 3-isocyanatopropionate (143.1 mg; 1 mmol; 1 eq.) in DCM (3 ml). The reaction mixture is heated at 50° C. overnight. As the reaction is not complete, a second batch of ethyl 3-isocyanatopropionate (Aldrich) (143.1 mg; 1 mmol; 1 eq.) is added. After 36 hours the reaction is complete. The solvents are evaporated. EtOAc is added and the mixture is washed with brine, dried over MgSO4 and evaporated. The resulting crude product is purified by preparative HPLC, affording Compound (50) as white-off solid (76.6 mg; 20%). 1H NMR (DMSO-d6, 300 MHz) δ 1.21 (t, J=7.5 Hz, 3H), 2.44 (s, 3H), 2.58 (m, 2H), 3.39 (q, J=6 Hz, 2H), 4.10 (q, J=7.5 Hz, 2H), 4.62 (s, 2H), 6.72 (t, J=6 Hz, 1H), 7.64 (s, 1H), 10.49 (br s, 1H). M− (ESI): 378.17; M+ (ESI): 380.10. HPLC (method A), Rt: 2.60 min (purity: 100%).
Reaction SMILES: [F:1][C:2]1[CH:3]=[N:4][CH:5]=[CH:6][C:7]=1[C:8]1[C:9]([C:16]2[CH:17]=[N:18][CH:19]=[CH:20][CH:21]=2)=[N:10][C:11]([NH2:15])=[C:12]([NH2:14])[CH:13]=1.C1C[O:25][CH2:24]C1.C(N1C=CN=C1)(N1C=CN=C1)=O>>[F:1][C:2]1[CH:3]=[N:4][CH:5]=[CH:6][C:7]=1[C:8]1[CH:13]=[C:12]2[NH:14][C:24](=[O:25])[NH:15][C:11]2=[N:10][C:9]=1[C:16]1[CH:17]=[N:18][CH:19]=[CH:20][CH:21]=1
Reactant: C1CCOC1
Reactant: Nc1cc(-c2ccncc2F)c(-c2cccnc2)nc1N
Agent: O=C(n1ccnc1)n1ccnc1
Product: O=c1[nH]c2cc(-c3ccncc3F)c(-c3cccnc3)nc2[nH]1
Yield: 16.9 %

Procedure:
To a solution of 3″-fluoro-3,2′:3′,4″-terpyridine-5′,6′-diamine (Intermediate 1, 158 mg, 0.56 mmol) in THF (5 mL) Et3N (156 μL, 1.12 mmol) and carbonyldiimidazole (182 mg, 1.12 mmol) were added sequentially. The reaction mixture was heated to reflux for 4 h and then the solvent was removed under reduced pressure. Flash chromatography of the resulting crude oil (CH2Cl2/EtOH/aq NH3 60:8:1 to 40:8:1) followed by reverse phase chromatography (0% CH3CN in H2O to 25% CH3CN in H2O) gave the title compound as a white solid (29 mg, 17%).
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6]([CH:11]=[O:12])=[CH:7][NH:8]2)=[CH:4][C:3]=1[C:13]1[CH:14]=[N:15][C:16]([N:19]([CH3:21])[CH3:20])=[N:17][CH:18]=1.CC(=CC)C.Cl([O-])=[O:28].[Na+].O.O.OP([O-])(O)=O.[Na+]>C(#N)C.O.C(O)(C)(C)C>[Cl:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6]([C:11]([OH:28])=[O:12])=[CH:7][NH:8]2)=[CH:4][C:3]=1[C:13]1[CH:14]=[N:15][C:16]([N:19]([CH3:21])[CH3:20])=[N:17][CH:18]=1
Reactant: [O-][Cl+][O-]
Reactant: CN(C)c1ncc(-c2cc3c(C=O)c[nH]c3cc2Cl)cn1
Agent: CC=C(C)C
Agent: O=P([O-])(O)O
Agent: [Na+]
Solvent: CC(C)(C)O
Solvent: O
Solvent: CC#N
Product: CN(C)c1ncc(-c2cc3c(C(=O)O)c[nH]c3cc2Cl)cn1
Temperature: 0 °C
Reaction time: 20 h
Yield: 40.8 %

Procedure:
6-chloro-5-[2-(dimethylamino)pyrimidin-5-yl]-1H-indole-3-carbaldehyde (100 mg, 0.333 mmol) was dissolved in acetonitrile (6 mL) and warm tert-butanol (6 mL) and treated with 2-methyl-2-butene (4 mL). The reaction mixture was cooled to 0° C. and treated with a solution of sodium chlorite (450 mg, 6.65 mmol) and sodium phosphate monobasic dihydrate (1.04 g, 6.65 mmol) in water (3 mL) dropwise via addition funnel. The reaction mixture was warmed to room temperature and stirred for 20 hours. The reaction mixture was concentrated to remove the organics and extracted with EtOAc (3×20 mL). The combined organic layers were washed with brine (20 mL), dried and concentrated in vacuo. The crude product was purified by prep-HPLC (Column: Agella venusil ASB C18 150×21.2 mm×5 μm; Mobile phase: from 20% MeCN in water (0.1% HCl) to 45% MeCN in water (0.1% HCl) Wavelength: 220 nm) to give 6-chloro-5-[2-(dimethylamino)pyrimidin-5-yl]-1H-indole-3-carboxylic acid (43 mg, 41% yield) as a yellow solid. MS (ES+) 316.9 (M+H)+. 1H NMR (400 MHz, DMSO-d6) δ 11.98 (s, 1 H), 8.42 (s, 2 H), 8.08 (d, 1 H), 7.93 (s, 1 H), 7.65 (s, 1 H), 3.17 (s, 6 H).
Reaction SMILES: [Br:1][C:2]1[N:7]=[C:6]([NH2:8])[CH:5]=[CH:4][CH:3]=1.[Cl:9]N1C(=O)CCC1=O>C(#N)C.C(OCC)(=O)C>[Br:1][C:2]1[N:7]=[C:6]([NH2:8])[CH:5]=[CH:4][C:3]=1[Cl:9]
Reactant: Nc1cccc(Br)n1
Reactant: O=C1CCC(=O)N1Cl
Solvent: CC#N
Solvent: CCOC(C)=O
Product: Nc1ccc(Cl)c(Br)n1
Temperature: 80 °C

Procedure:
To a solution of 6-bromopyridin-2-amine (10 g, 58 mmol) in acetonitrile (150 mL) was added 1-chloropyrrolidine-2,5-dione (8.1 g, 60 mmol) and the mixture was heated at 80° C. for 10 hours. The mixture was diluted with ethyl acetate (200 mL) and washed with water. The organic phase was concentrated and purified by column chromatography (silica gel, 30% ethyl acetate in hexane) to afford the title compound. LCMS: 208 (M+H)+.
Reaction SMILES: [CH:1]([C:3]([CH3:5])=[O:4])=[CH2:2].[CH:6]([CH:8]1[CH2:13][CH2:12][N:11]([C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])[CH2:10][CH2:9]1)=O.[OH-].[K+].C1CCCCC1>O1CCCC1.C(O)C>[O:4]=[C:3]1[CH2:5][CH2:6][C:8]2([CH2:13][CH2:12][N:11]([C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])[CH2:10][CH2:9]2)[CH:2]=[CH:1]1
Reactant: CC(C)(C)OC(=O)N1CCC(C=O)CC1
Reactant: C=CC(C)=O
Agent: [K+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: C1CCCCC1
Solvent: CCO
Product: CC(C)(C)OC(=O)N1CCC2(C=CC(=O)CC2)CC1
Temperature: -5 °C
Reaction time: 16 h

Procedure:
Methyl vinyl ketone (146 mL, 1.78 mol) was added to a solution of tert-butyl 4-formylpiperidine-1-carboxylate (375 g, 1.76 mol) in tetrahydrofuran (18 L). The reaction mixture was cooled to −5° C. and a solution of potassium hydroxide in ethanol (3N, 0.243 L) was added dropwise over 10 minutes. The reaction mixture was allowed to warm to room temperature and stirred for 16 hours. Cyclohexane (10 L) was added and the solution was washed with saturated sodium chloride (3×10 L). The organic layer was concentrated to an oil. This oil was dissolved in 2 L of 80:20 cyclohexane/ethyl acetate and filtered through Celite® to remove the insoluble material. The filtrate was purified via flash column chromatography (30% ethyl acetate/hexanes) to afford the product as an oil. The oil was triturated in hexanes to afford the title compound as a colorless solid (131 g, 28%).
Reaction SMILES: [CH2:1]1[C@@H:3]2[C@H:4]([OH:29])[CH2:5][C:6]3[C@:19]([CH2:20][O:21]C4CCCCO4)([C@H:2]12)[C@@H:18]1[C@H:9]([C@H:10]2[C@@:14]([CH2:16][CH2:17]1)([CH3:15])[C@@H:13]([OH:28])[CH2:12][CH2:11]2)[CH2:8][CH:7]=3.CC(C)=O.OS(O)(=O)=O.O=[Cr](=O)=O>CC(C)=O>[OH:21][CH2:20][C@@:19]12[C@@H:18]3[C@H:9]([C@H:10]4[C@@:14]([CH2:16][CH2:17]3)([CH3:15])[C:13](=[O:28])[CH2:12][CH2:11]4)[CH2:8][CH2:7][C:6]1=[CH:5][C:4](=[O:29])[C@H:3]1[CH2:1][C@@H:2]21
Reactant: C[C@]12CC[C@H]3[C@@H](CC=C4C[C@@H](O)[C@H]5C[C@H]5[C@@]43COC3CCCCO3)[C@@H]1CC[C@@H]2O
Agent: O=[Cr](=O)=O
Agent: O=S(=O)(O)O
Solvent: CC(C)=O
Product: C[C@]12CC[C@H]3[C@@H](CCC4=CC(=O)[C@H]5C[C@H]5[C@@]43CO)[C@@H]1CCC2=O
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
The 1β,2β-methylene-19-tetrahydropyranyloxy-5-androstene-3β,17β-diol is dissolved in acetone and Jones Reagent added until a persistent yellow-orange color appears. After stirring at room temperature for 10 minutes the mixture is poured onto ice water and the precipitate which forms is collected by filtration. This precipitate is dissolved in a solution of hydrochloric acid in aqueous methanol and stirred for 30 minutes at room temperature. The methanol is removed by evaporation and the residue is triturated with water. The solid which results is filtered and crystallized from an acetone solution to yield 19-hydroxy-1β,2β-methylene-4-androstene-3,17-dione.
Reaction SMILES: [CH:1]1([NH:7][C:8]([NH:10][C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)=S)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C(Cl)(Cl)(Cl)Cl.C(N(CC)CC)C>C(Cl)Cl>[CH:11]1([N:10]=[C:8]=[N:7][C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=2)[CH2:12][CH2:13][CH2:14][CH2:15][CH2:16]1
Reactant: S=C(Nc1ccccc1)NC1CCCCC1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CCN(CC)CC
Solvent: ClC(Cl)(Cl)Cl
Solvent: ClCCl
Product: C(=Nc1ccccc1)=NC1CCCCC1
Yield: 99.3 %

Procedure:
A solution containing 2.0 g (8.55 mmol) of N-cyclohexyl-N'-phenylthiourea, 2.9 g (11.1 mmol) of triphenyl phosphine and 1.16 cm3 (12 mmol) of carbon tetrachloride in 12 cm3 of methylene chloride, is treated with 1.19 cm3 (8.55 mmol) of triethylamine. The solution is heated for 2 hours, the precipitate which forms is eliminated by filtration and the filtrate is concentrated to dryness. The residue obtained is extracted with hexane and then filtered. The filtrates are then concentrated to dryness and 1.7 g (yield 100%) of the desired carbodiimide is obtained in the form of an oil.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[S:8]([NH2:11])(=[O:10])=[O:9].C(N(CC)CC)C.[C:19](Cl)([CH3:21])=[O:20]>C1COCC1>[C:19]([NH:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[S:8]([NH2:11])(=[O:9])=[O:10])(=[O:20])[CH3:21]
Reactant: Nc1ccccc1S(N)(=O)=O
Reactant: CC(=O)Cl
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CC(=O)Nc1ccccc1S(N)(=O)=O
Temperature: 25 °C
Yield: 79.3 %

Procedure:
A stirred solution of 2-aminobenzenesulfonamide (1.72 g; 10 mmol) and triethylamine (1.53 ml; 11 mmol) in THF (25 ml) at 0° C. was added AcCl (0.85 ml; 12 mmol) and left with stirring at rt. over night. The reaction mixture was filtered and adsorbed onto silica. Column chromatography gave 1.7 g (79%) product. M.p. 153.5–155.5° C.
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[C:9]([CH:11](O)[CH3:12])[C:5]2[O:6][CH2:7][O:8][C:4]=2[CH:3]=1.C1C=C[NH+:17]=CC=1.[O-][Cr](Cl)(=O)=O>ClCCl>[Cl:1][C:2]1[CH:10]=[C:9]([CH:11]([NH2:17])[CH3:12])[C:5]2[O:6][CH2:7][O:8][C:4]=2[CH:3]=1
Reactant: CC(O)c1cc(Cl)cc2c1OCO2
Reactant: c1cc[nH+]cc1
Agent: O=[Cr](=O)([O-])Cl
Solvent: ClCCl
Product: CC(N)c1cc(Cl)cc2c1OCO2
Reaction time: 16 h
Yield: 58.5 %

Procedure:
1-(5-Chlorobenzo[d][1,3]dioxol-7-yl)ethanol (155 mg, 0.77 mmol) was dissolved in 6 mL of dichloromethane. PCC (416 mg, 1.93 mmol) was added portionwise and the mixture was stirred for 16 h (reaction is likely to be completed earlier). The mixture was filtered through a plug of celite. The solvent was removed by rotary evaporation to collect the desired product (90 mg, 59% yield). 1H NMR (400 MHz, CDCl3): δ 7.36 (d, 1H), 6.96 (d, 1H), 6.14 (s, 2H), 2.59 (s, 3H).
Reaction SMILES: O1CCOCC1.[OH-].[Na+].C([O:12][C:13]1[CH:42]=[CH:41][C:40]([N:43]2[CH2:48][CH2:47][CH2:46][CH2:45][CH2:44]2)=[CH:39][C:14]=1[C:15]([NH:17][C:18]1[CH:30]=[C:29]([C:31]2[CH:36]=[CH:35][CH:34]=[CH:33][C:32]=2[O:37][CH3:38])[CH:28]=[CH:27][C:19]=1[C:20]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21])=[O:16])(=O)C.C(O)(=O)CC(CC(O)=O)(C(O)=O)O>C(OCC)(=O)C>[OH:12][C:13]1[CH:42]=[CH:41][C:40]([N:43]2[CH2:48][CH2:47][CH2:46][CH2:45][CH2:44]2)=[CH:39][C:14]=1[C:15]([NH:17][C:18]1[CH:30]=[C:29]([C:31]2[CH:36]=[CH:35][CH:34]=[CH:33][C:32]=2[O:37][CH3:38])[CH:28]=[CH:27][C:19]=1[C:20]([O:22][C:23]([CH3:25])([CH3:24])[CH3:26])=[O:21])=[O:16]
Reactant: COc1ccccc1-c1ccc(C(=O)OC(C)(C)C)c(NC(=O)c2cc(N3CCCCC3)ccc2OC(C)=O)c1
Agent: O=C(O)CC(O)(CC(=O)O)C(=O)O
Agent: [Na+]
Agent: [OH-]
Solvent: C1COCCO1
Solvent: CCOC(C)=O
Product: COc1ccccc1-c1ccc(C(=O)OC(C)(C)C)c(NC(=O)c2cc(N3CCCCC3)ccc2O)c1
Temperature: 52.5 °C
Reaction time: 2 h
Yield: 24.6 %

Procedure:
Dioxane (4.0 mL) and a 4 mol/L aqueous solution of sodium hydroxide (0.25 mL) were added to the obtained tert-butyl 2-(2-acetoxy-5-(piperidin-1-yl)benzamido)-4-(2-methoxyphenyl)benzoate (0.11 g), followed by stirring at 50 to 55° C. for 2 hours. The reaction mixture was cooled to room temperature, and a 10% aqueous solution of citric acid and ethyl acetate were added thereto. The organic layer was separated, washed with a saturated aqueous solution of sodium chloride, and dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The obtained residue was purified by silica gel column chromatography [eluent: 95-60% hexane/ethyl acetate] to obtain 0.025 g of tert-butyl 2-(2-hydroxy-5-(piperidin-1-yl)benzamido)-4-(2-methoxyphenyl)benzoate as a yellow solid.
Reaction SMILES: [C:1]1([Si:7]([CH3:21])([CH3:20])[CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][C:14]2(Br)[CH2:16][C:15]2(Br)Br)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C[Li]>CCOCC>[C:1]1([Si:7]([CH3:21])([CH3:20])[CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][C:14]2[CH2:16][CH:15]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: C[Si](C)(CCCCCCC1(Br)CC1(Br)Br)c1ccccc1
Agent: [Li]C
Solvent: CCOCC
Product: C[Si](C)(CCCCCCC1=CC1)c1ccccc1
Reaction time: 0.5 h
Yield: 40.7 %

Procedure:
A solution of 0.95 g (1.9 mmol) of 2-(6-(phenyldimethylsilyl)-hexyl)-1,1,2-tribromocyclopropane in ether was cooled to −78° C. Excess methyllithium (1.4M, 4.1 ml, 5.7 mmol) was added, and the reaction mixture was placed in an ice bath for 30 min, then quenched with water. The phases were separated. The ether phase was washed with water, washed with brine, dried over magnesium sulfate and stripped to give 200 mg of 1-(6-(phenyldimethylsilyl)-hexyl)-cyclopropene as a colorless liquid.
Reaction SMILES: [Br:1][C:2]1[C:7]([O:8][CH3:9])=[CH:6][CH:5]=[C:4](I)[N:3]=1.C([Li])CCC.[CH3:16][C:17]([CH3:19])=[O:18].O>C1(C)C=CC=CC=1.CCCCCC.C(OCC)(=O)C>[Br:1][C:2]1[N:3]=[C:4]([C:17]([OH:18])([CH3:19])[CH3:16])[CH:5]=[CH:6][C:7]=1[O:8][CH3:9]
Reactant: CC(C)=O
Reactant: COc1ccc(I)nc1Br
Agent: [Li]CCCC
Solvent: O
Solvent: Cc1ccccc1
Solvent: CCCCCC
Product: COc1ccc(C(C)(C)O)nc1Br
Reaction time: 1 h

Procedure:
2-Bromo-6-iodo-3-methoxy-pyridine (500 mg) is dissolved in dry toluene (5 ml) and thereto is added dropwise 1.6M n-butyllithium in hexane (1 ml) at −78° C. under nitrogen atmosphere, and the mixture is stirred for 1 hour and thereto is added acetone (0.23 ml), and the mixture is stirred overnight. To the reaction solution are added water and ethyl acetate, and the mixture is separated, and the organic layer is washed with a saturated brine, dried over magnesium sulfate, and concentrated under reduced pressure. The resulting residue is purified by silica gel column chromatography (hexane:ethyl acetate=4:1→3:2) to give 2-(6-bromo-5-methoxy-pyridin-2-yl)-propan-2-ol (197 mg). MS (m/z): 246/248 [M+H]+
Reaction SMILES: [F:1][C:2]1[CH:38]=[C:37]([F:39])[CH:36]=[CH:35][C:3]=1[O:4][C:5]1[C:13]([C:14]2[C:15]3[CH:24]=[CH:23][N:22](S(C4C=CC(C)=CC=4)(=O)=O)[C:16]=3[C:17](=[O:21])[N:18]([CH3:20])[CH:19]=2)=[CH:12][C:8]2[NH:9][N:10]=[N:11][C:7]=2[CH:6]=1.[OH-].[Na+].O>C(O)C>[F:1][C:2]1[CH:38]=[C:37]([F:39])[CH:36]=[CH:35][C:3]=1[O:4][C:5]1[C:13]([C:14]2[C:15]3[CH:24]=[CH:23][NH:22][C:16]=3[C:17](=[O:21])[N:18]([CH3:20])[CH:19]=2)=[CH:12][C:8]2[NH:9][N:10]=[N:11][C:7]=2[CH:6]=1
Reactant: Cc1ccc(S(=O)(=O)n2ccc3c(-c4cc5[nH]nnc5cc4Oc4ccc(F)cc4F)cn(C)c(=O)c32)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: Cn1cc(-c2cc3[nH]nnc3cc2Oc2ccc(F)cc2F)c2cc[nH]c2c1=O
Temperature: 20 °C
Reaction time: 8 h
Yield: 44.5 %

Procedure:
A solution of 4-[5-(2,4-difluorophenoxy)-1H-1,2,3-benzotriazol-6-yl]-6-methyl-1-[(4-methylphenyl)sulfonyl]-1,6-dihydro-7H-pyrrolo[2,3-c]pyridin-7-one (67 mg, 0.12 mmol) in ethanol (7.1 mL) was treated with 3.0 M sodium hydroxide in water (408 μL, 1.22 mmol) and stirred at 20° C. overnight. Purification via preparative LCMS (XBridge C18 column, eluting with a gradient of acetonitrile/water containing 0.1% trifluoroacetic acid, at flow rate of 60 mL/min) gave the desired product (21 mg, 34%). 1H NMR (400 MHz, DMSO-d6) δ 12.06 (s, 1H), 8.01 (br s, 1H), 7.53-7.41 (m, 1H), 7.36 (s, 1H), 7.33-7.21 (m, 2H), 7.16-6.98 (m, 2H), 6.24 (d, J=2.0 Hz, 1H), 3.56 (s, 3H); LCMS calculated for C20H14F2N5O2 (M+H)+: m/z=394.1. found: 394.1.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([N:10]([CH2:18][C:19]2[CH:24]=[CH:23][CH:22]=[C:21]([O:25][C:26]([F:31])([F:30])[CH:27]([F:29])[F:28])[CH:20]=2)[CH2:11][CH:12]([OH:17])[C:13]([F:16])([F:15])[F:14])[CH:7]=[CH:8][CH:9]=1)([O-])=O>C(O)(=O)C.[Zn]>[NH2:1][C:4]1[CH:5]=[C:6]([N:10]([CH2:18][C:19]2[CH:24]=[CH:23][CH:22]=[C:21]([O:25][C:26]([F:30])([F:31])[CH:27]([F:28])[F:29])[CH:20]=2)[CH2:11][CH:12]([OH:17])[C:13]([F:16])([F:15])[F:14])[CH:7]=[CH:8][CH:9]=1
Reactant: O=[N+]([O-])c1cccc(N(Cc2cccc(OC(F)(F)C(F)F)c2)CC(O)C(F)(F)F)c1
Agent: [Zn]
Solvent: CC(=O)O
Product: Nc1cccc(N(Cc2cccc(OC(F)(F)C(F)F)c2)CC(O)C(F)(F)F)c1
Temperature: 25 °C
Reaction time: 18 h
Yield: 78.2 %

Procedure:
The 3-[(3-nitrophenyl)[[3-(1,1,2,2-tetrafluoroethoxy)phenyl]methyl]amino]-1,1,1-trifluoro-2-propanol (1.93 g, 4.2 mmol) from EX-528B) was dissolved in 60 mL of acetic acid. Zinc dust (2.1 g, 31.5 mmol) was added, and the solution was stirred at room temperature for 18 hours, at which time HPLC analysis indicated that no nitro starting material remained. The reaction mixture was filtered through celite and concentrated in vacuo. The residue was dissolved in ethyl acetate and washed with aqueous saturated sodium bicarbonate. The organic layer was washed with brine, then dried over MgSO4, and concentrated in vacuo to give 1.4 g (78%) of the desired 3-[(3-aminophenyl)[[3-(1,1,2,2-tetrafluoroethoxy)phenyl]methyl]amino]-1,1,1-trifluoro-2-propanol product as a red oil. The crude product was used without further purification. HRMS calcd. for C18H18F7N2O2: 427.1256 [M+H]+, found: 427.1251. 1H NMR (CDCl3) δ 3.4-3.7 (m, 4H), 3.8 (dd, 1H), 4.3 (m, 1H), 4.8 (m, 2H), 5.9 (tt, 1H), 6.1 (s, 1H), 6.2 (m, 2H), 7.0-7.2 (m, 4H), 7.3 (t, 1H).