Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1([F:13])[CH2:6][CH2:5][CH:4]([C:7](N(OC)C)=[O:8])[CH2:3]1.[CH3:14][Mg]Br.C(OCC)C>C1COCC1>[F:1][C:2]1([F:13])[CH2:6][CH2:5][CH:4]([C:7](=[O:8])[CH3:14])[CH2:3]1
Reactant: C[Mg]Br
Reactant: CON(C)C(=O)C1CCC(F)(F)C1
Solvent: CCOCC
Solvent: C1CCOC1
Product: CC(=O)C1CCC(F)(F)C1
Reaction time: 1.5 h

Procedure:
To a solution of (rac)-3,3-difluoro-N-methoxy-N-methylcyclopentane-carboxamide (1.90 g, 9.83 mmol) in 20 mL THF at 0° C. was added methylmagnesium bromide 3.0 m in diethyl ether (6.56 mL, 19.67 mmol) slowly dropwise. The reaction mixture became white and cloudy. After 1.5 h, the reaction mixture was quenched carefully with ice and 1N HCl, and diluted with Et2O. The organic layer was washed with brine, dried over magnesium sulfate, filtered, and concentrated in vacuo to give (rac)-1-(3,3-difluorocyclopentyl)ethanone as a light yellow oil. 1H NMR (400 MHz, CDCl3-d) δ ppm 3.03-3.19 (m, 1 H), 2.22-2.48 (m, 2 H), 2.20 (s, 3 H), 2.03-2.16 (m, 3 H), 1.90-1.99 (m, 1 H).
Reaction SMILES: [CH:1]([O:4][C:5]1[CH:10]=[CH:9][C:8]([N+:11]([O-])=O)=[C:7]([CH3:14])[CH:6]=1)([CH3:3])[CH3:2].[C:15](OC(N(C)C)N(C)C)(C)(C)C>>[CH:1]([O:4][C:5]1[CH:6]=[C:7]2[C:8](=[CH:9][CH:10]=1)[NH:11][CH:15]=[CH:14]2)([CH3:3])[CH3:2]
Reactant: CN(C)C(OC(C)(C)C)N(C)C
Reactant: Cc1cc(OC(C)C)ccc1[N+](=O)[O-]
Product: CC(C)Oc1ccc2[nH]ccc2c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 96 %

Procedure:
A mixture of 4-isopropoxy-2-methyl-1-nitrobenzene (3.55 g,0.018 mol) and tert-butoxybis(dimethylamino)methane (9 mL) was refluxed for 4 hours and the volatile was removed. The dark brown residue was dissolved in THF (150 mL) and hydrogenated with catalytic amount of 10% Pd on Carbon with H2 in a balloon. After stirring at room temperature overnight, the catalyst was filtered off and the filtrate was concentrated to afford 3.07 g 5-isopropoxyindole (96%). MS(EI): (M+1) 176.
Reaction SMILES: [NH2:1][CH2:2][C:3]#[C:4][C:5]1[CH:6]=[C:7]2[C:12](=[CH:13][CH:14]=1)[N:11]=[CH:10][N:9]=[C:8]2[NH:15][C:16]1[CH:17]=[C:18]2[C:22](=[CH:23][CH:24]=1)[N:21]([CH2:25][C:26]1[CH:31]=[CH:30][CH:29]=[C:28]([F:32])[CH:27]=1)[N:20]=[CH:19]2.[CH:33]1[CH:38]=[CH:37][C:36]([O:39][C:40](OC2C=CC=CC=2)=[N:41][C:42]#[N:43])=[CH:35][CH:34]=1>CC(O)C.C1COCC1>[F:32][C:28]1[CH:27]=[C:26]([CH:31]=[CH:30][CH:29]=1)[CH2:25][N:21]1[C:22]2[C:18](=[CH:17][C:16]([NH:15][C:8]3[C:7]4[C:12](=[CH:13][CH:14]=[C:5]([C:4]#[C:3][CH2:2][NH:1][C:40](=[N:41][C:42]#[N:43])[O:39][C:36]5[CH:37]=[CH:38][CH:33]=[CH:34][CH:35]=5)[CH:6]=4)[N:11]=[CH:10][N:9]=3)=[CH:24][CH:23]=2)[CH:19]=[N:20]1
Reactant: N#CN=C(Oc1ccccc1)Oc1ccccc1
Reactant: NCC#Cc1ccc2ncnc(Nc3ccc4c(cnn4Cc4cccc(F)c4)c3)c2c1
Solvent: CC(C)O
Solvent: C1CCOC1
Product: N#CN=C(NCC#Cc1ccc2ncnc(Nc3ccc4c(cnn4Cc4cccc(F)c4)c3)c2c1)Oc1ccccc1
Reaction time: 8 h
Yield: 49.6 %

Procedure:
[6-(3-Amino-prop-1-ynyl)-quinazolin-4-yl]-[1-(3-fluoro-benzyl)-1H-indazol-5-yl]-amine (280 mg, 0.663 mmol) is treated with diphenyl cyanocarbonimidate (163 mg, 1.031 equiv.) in a mixture of i-PrOH (12 ml) and THF (4 ml). Stir mixture overnight, then concentrate to dryness and chromatograph on silica (EtOAc/hexanes) to obtain 186.3 mg (49.6%) of pure desired product.
Reaction SMILES: C([O:3][C:4]([C:6]1[C:15](=[O:16])[C:14]2[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=2)[N:8]([CH2:17][C:18]2[CH:23]=[CH:22][CH:21]=[C:20]([Br:24])[N:19]=2)[CH:7]=1)=[O:5])C.[OH-].[Li+].CO.Cl>CO.O>[Br:24][C:20]1[N:19]=[C:18]([CH2:17][N:8]2[C:9]3[C:14](=[CH:13][CH:12]=[CH:11][CH:10]=3)[C:15](=[O:16])[C:6]([C:4]([OH:5])=[O:3])=[CH:7]2)[CH:23]=[CH:22][CH:21]=1
Reactant: CCOC(=O)c1cn(Cc2cccc(Br)n2)c2ccccc2c1=O
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: O=C(O)c1cn(Cc2cccc(Br)n2)c2ccccc2c1=O
Temperature: 65 °C
Reaction time: 8 h
Yield: 68.7 %

Procedure:
14.9 g (38.5 mmol) of 1-(6-bromo-pyridin-2-ylmethyl)-4-oxo-1,4-dihydro-quinoline-3-carboxylic acid ethyl ester was dissolved/suspended in 300 mL of a 1:1 methanol-water mixture. 1.11 g (46.2 mmol) of lithium hydroxide was added and the mixture was heated up to 65° C. and stirred overnight. The mixture was cooled down to r.t., 300 mL of methanol and 4 mL of concentrated aqueous HCl were added and the solids were filtered off. The solids were then dissolved/suspended in 300 mL ethanol, brought to reflux, cooled down to rt, filtered, washed with 50 mL diethyl ether and dried to yield 9.5 g of the product as a white solid.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[CH:9]([CH3:33])[C:10]([C:16]1[CH:17]=[C:18]2[C:22](=[CH:23][CH:24]=1)[N:21]([C:25]1[CH:30]=[CH:29][C:28]([O:31]C)=[CH:27][CH:26]=1)[N:20]=[CH:19]2)([OH:15])[C:11]([F:14])([F:13])[F:12].B(Br)(Br)Br>>[Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[CH:9]([CH3:33])[C:10]([C:16]1[CH:17]=[C:18]2[C:22](=[CH:23][CH:24]=1)[N:21]([C:25]1[CH:26]=[CH:27][C:28]([OH:31])=[CH:29][CH:30]=1)[N:20]=[CH:19]2)([OH:15])[C:11]([F:14])([F:13])[F:12]
Reactant: COc1ccc(-n2ncc3cc(C(O)(C(C)c4ccc(Cl)cc4Cl)C(F)(F)F)ccc32)cc1
Agent: BrB(Br)Br
Product: CC(c1ccc(Cl)cc1Cl)C(O)(c1ccc2c(cnn2-c2ccc(O)cc2)c1)C(F)(F)F

Procedure:
In analogy to Example 183, 3-(2,4-dichloro-phenyl)-1,1,1-trifluoro-2-[1-(4-methoxy-phenyl)-1H-indazol-5-yl]-butan-2-ol (Example 191) was reacted with BBr3 to give the title compound as a colorless foam. MS (m/e)=481.0 [M+H+].
Reaction SMILES: [F:1][C:2]1[N:7]=[CH:6][C:5]([C:8]([C:10]2[CH:15]=[CH:14][C:13]([S:16][CH3:17])=[CH:12][CH:11]=2)=[O:9])=[CH:4][CH:3]=1.[CH3:18][Mg]Br.[Cl-].[NH4+]>C1COCC1>[F:1][C:2]1[N:7]=[CH:6][C:5]([C:8]([C:10]2[CH:15]=[CH:14][C:13]([S:16][CH3:17])=[CH:12][CH:11]=2)([OH:9])[CH3:18])=[CH:4][CH:3]=1
Reactant: CSc1ccc(C(=O)c2ccc(F)nc2)cc1
Reactant: C[Mg]Br
Agent: [Cl-]
Agent: [NH4+]
Solvent: C1CCOC1
Product: CSc1ccc(C(C)(O)c2ccc(F)nc2)cc1
Temperature: 0 °C
Reaction time: 0.33 h
Yield: 102.8 %

Procedure:
(6-Fluoropyridin-3-yl)(4-(methylthio)phenyl)methanone (1.256 g, 5.079 mmol) was dissolved in THF (19 mL) and the flask was cooled in an ice water bath. Then, methylmagnesium bromide (3.0 M in diethyl ether, 3.40 mL, 10.2 mmol) was added via syringe over 5 min. The reaction was stirred at 0° C. under nitrogen for 20 min, and then was treated with saturated ammonium chloride (2.5 mL, added dropwise at first as gas evolution is observed). The reaction was quenched at 0° C. Then, the reaction was diluted with water (15 mL) and the layers were separated. The aqueous phase was extracted with DCM, and the organic phases were combined, dried over sodium sulfate, filtered, concentrated, and dried under high vacuum at room temperature overnight to give 1-(6-fluoropyridin-3-yl)-1-(4-(methylthio)phenyl)ethanol (1.375 g). 1H NMR (CDCl3, 400 MHz) δ 8.26 (d, J=2.35 Hz, 1H), 7.82-7.76 (m, 1H), 7.35-7.30 (m, 2H), 7.25-7.20 (m, 2H), 6.86 (dd, J=8.61 Hz, 2.93 Hz, 1H), 2.48 (s, 3H), 2.30 (s, 1H), 1.96 (s, 3H). m/z (ESI, +ve ion) 264 (M+H)+.
Reaction SMILES: ClC1C=CC2N=C(NC3CCNC3)OC=2C=1.Cl.Cl[C:19]1[N:28]=[CH:27][C:26]2[C:21](=[CH:22][C:23]([Cl:29])=[CH:24][CH:25]=2)[N:20]=1.C(OC([N:37]1[CH2:42][CH2:41][CH2:40][CH:39]([NH2:43])[CH2:38]1)=O)(C)(C)C>>[Cl:29][C:23]1[CH:22]=[C:21]2[C:26]([CH:27]=[N:28][C:19]([NH:43][CH:39]3[CH2:40][CH2:41][CH2:42][NH:37][CH2:38]3)=[N:20]2)=[CH:25][CH:24]=1
Reactant: Clc1ccc2cnc(Cl)nc2c1
Reactant: CC(C)(C)OC(=O)N1CCCC(N)C1
Agent: Cl
Agent: Clc1ccc2nc(NC3CCNC3)oc2c1
Product: Clc1ccc2cnc(NC3CCCNC3)nc2c1

Procedure:
In analogy to the procedure described for the synthesis of (6-Chloro-benzooxazol-2-yl)-pyrrolidin-3-yl-amine; hydrochloride (example 1, step 1) the title compound was prepared from 2,7-dichloro-quinazoline (Synthesis 1978, 5, 379-82) and 3-Amino-piperidine-1-carboxylic acid tert-butyl ester (commercially available) and subsequent cleavage of the tert-butyl oxy carbonyl protecting group under acidic conditions. (MH+) 263.1.
Reaction SMILES: Cl.[Cl:2][CH2:3][C:4](=N)OCC.[NH2:9][C:10]1[CH:11]=[N:12][C:13]2[C:18]([C:19]=1[NH:20][CH:21]([CH3:28])[CH2:22][C:23]([O:25][CH2:26][CH3:27])=[O:24])=[CH:17][CH:16]=[CH:15][CH:14]=2>C(Cl)(Cl)Cl>[Cl:2][CH2:3][C:4]1[N:20]([CH:21]([CH3:28])[CH2:22][C:23]([O:25][CH2:26][CH3:27])=[O:24])[C:19]2[C:18]3[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=3[N:12]=[CH:11][C:10]=2[N:9]=1
Reactant: CCOC(=N)CCl
Reactant: CCOC(=O)CC(C)Nc1c(N)cnc2ccccc12
Agent: Cl
Solvent: ClC(Cl)Cl
Product: CCOC(=O)CC(C)n1c(CCl)nc2cnc3ccccc3c21
Temperature: 25 °C
Reaction time: 72 h
Yield: 97.7 %

Procedure:
Ethyl 2-chloroethanimidoate hydrochloride (10.8 g, 68.4 mmol) was added to a solution of ethyl 3-[(3-aminoquinolin-4-yl)amino]butanoate (9.41 g, 34.4 mmol) in chloroform (130 mL), and the reaction was stirred at room temperature for three days and then heated at reflux for two hours. An analysis by liquid chromatography/mass spectrometry (LC/MS) indicated the presence of starting material, and additional ethyl 2-chloroethanimidoate hydrochloride (2.7 g) was added. The reaction was heated at reflux for an additional 1.5 hours, allowed to cool to room temperature, diluted with chloroform (100 mL), washed sequentially with brine (2×150 mL) and deionized water (100 mL), dried over magnesium sulfate, filtered through a layer of CELITE filter agent, concentrated under reduced pressure, and further dried overnight under high vacuum to provide 11.15 g of ethyl 3-[2-(chloromethyl)-1H-imidazo[4,5-c]quinolin-1-yl]butanoate as a dark yellow solid.
Reaction SMILES: [CH2:1]([N:8]([CH2:46][CH:47]1[CH2:49][CH:48]1[CH3:50])[C:9]1[CH:14]=[C:13]([C:15]2[N:20]=[CH:19][NH:18][CH:17]([C@@:21]([NH:30][C:31](=[O:37])[O:32][C:33]([CH3:36])([CH3:35])[CH3:34])([CH3:29])[CH2:22][C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=3)[CH:16]=2)[CH:12]=[C:11]([N:38]([S:40]([CH:43]([CH3:45])[CH3:44])(=[O:42])=[O:41])[CH3:39])[N:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1>C1(C)C=CC=CC=1>[CH2:1]([N:8]([CH2:46][CH:47]1[CH2:49][CH:48]1[CH3:50])[C:9]1[CH:14]=[C:13]([C:15]2[N:20]=[CH:19][N:18]=[C:17]([C@@:21]([NH:30][C:31](=[O:37])[O:32][C:33]([CH3:34])([CH3:35])[CH3:36])([CH3:29])[CH2:22][C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=3)[CH:16]=2)[CH:12]=[C:11]([N:38]([S:40]([CH:43]([CH3:44])[CH3:45])(=[O:42])=[O:41])[CH3:39])[N:10]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CC1CC1CN(Cc1ccccc1)c1cc(C2=CC([C@@](C)(Cc3ccccc3)NC(=O)OC(C)(C)C)NC=N2)cc(N(C)S(=O)(=O)C(C)C)n1
Solvent: Cc1ccccc1
Product: CC1CC1CN(Cc1ccccc1)c1cc(-c2cc([C@@](C)(Cc3ccccc3)NC(=O)OC(C)(C)C)ncn2)cc(N(C)S(=O)(=O)C(C)C)n1

Procedure:
To a solution of tert-butyl (1R)-1-(6-{2-{benzyl[(2-methylcyclopropyl)methyl]amino}-6-[(isopropylsulfonyl)(methyl)amino]pyridin-4-yl}-3,4-dihydropyrimidin-4-yl)-1-methyl-2-phenylethylcarbamate from Step A above (49 mg, 0.07 mmol) in 2 mL toluene was added dichlorodicyanoquinone (24 mg, 0.11 mmol). The resulting solution was heated at 120 degrees for 30 min., then cooled to it and concentrated to dryness. Purification by reverse phase chromatography yielded tert-butyl (1R)-1-(6-{2-{benzyl[(2-methylcyclopropyl)methyl]amino}-6-[(isopropylsulfonyl)(methyl)amino]pyridin-4-yl}pyrimidin-4-yl)-1-methyl-2-phenylethylcarbamate, which was taken up in 1 mL 20% TFA in dichloromethane. The mixture was allowed to sit for 1 hour, and was concentrated to afford the title compound N-(4-{6-[(1R)-1-amino-1-methyl-2-phenylethyl]pyrimidin-4-yl}-6-{benzyl[(2-methylcyclopropyl)methyl]amino}pyridin-2-yl)-N-methylpropane-2-sulfonamide. 1H NMR (400 MHz, d4-MeOH) δ 9.29 (s, 1H), 7.66-7.65 (m, 1H), 7.31-7.21 (m, 8H), 7.02-7.01 (m, 2H), 6.96-6.93 (m, 2H), 4.98-4.60 (m, 2H), 3.83-3.66 (m, 2H), 3.38 (s, 3H), 3.35-3.25 (m, 4H), 1.81 (s, 3H), 1.16 (d, J=6.8 Hz), 0.96 (dd, J=6 Hz, J=1.8 Hz, 3H) 0.90-0.82 (m, 1H), 0.70-0.62 (m, 1H), 0.45-0.40 (m, 1H), 0.28-0.24 (m, 1H); LCMS [M+H]=599.1.
Reaction SMILES: [H][H].O.O[N:5]1[C:9]2C=[CH:11][CH:12]=[CH:13][C:8]=2N=N1.C(N=C=NC(C)C)(C)C.C(N(C(C)C)C(C)C)C.[Cl:32][CH2:33][Cl:34]>>[Cl:32][CH2:33][Cl:34].[NH:5]1[CH2:11][CH2:12][CH2:13][CH2:8][CH2:9]1
Reactant: [H][H]
Reactant: On1nnc2ccccc21
Agent: CC(C)N=C=NC(C)C
Solvent: CCN(C(C)C)C(C)C
Solvent: O
Solvent: ClCCl
Product: C1CCNCC1
Reaction time: 0.5 h

Procedure:
If R1 and R2 are both hydrogen preferably the first stage is carried out as follows: the aminooxy-2-chlortrityl polystyrene resin is mixed in a suitable solvent, such like dichloromethane, with a compound of formula VI, in which R1 and R2 are both hydrogen, in the presence of 1-hydroxybenzotriazole hydrate and 1,3-diisopropylcarbodiimide and the resulting mixture then treated with N-ethyl-diisopropylamine at room temperature. The obtained resin is isolated and shaken twice for a period of 15 to 45 minutes, e.g. 20 minutes, with a freshly prepared dichloromethane/piperidine solution to provide a compound of formula VII, in which the black circular plane indicates that the compound is bound to a polymer resin and in which R1 and R2 are both hydrogen.
Reaction SMILES: [CH3:1][C:2]1([CH3:12])[CH:7]2[CH2:8][CH:3]1[CH2:4][CH:5]=[C:6]2[CH2:9][CH2:10][OH:11].[H-].[Na+].Cl[CH2:16][C:17]([OH:19])=[O:18].[OH-].[Na+]>C(COC)OC.O>[CH3:1][C:2]1([CH3:12])[C@H:7]2[CH2:8][C@@H:3]1[CH2:4][CH:5]=[C:6]2[CH2:9][CH2:10][O:11][CH2:16][C:17]([OH:19])=[O:18]
Reactant: CC1(C)C2CC=C(CCO)C1C2
Reactant: O=C(O)CCl
Agent: [H-]
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: COCCOC
Product: CC1(C)[C@H]2CC=C(CCOCC(=O)O)[C@@H]1C2
Temperature: 45 °C
Yield: 52609 %

Procedure:
To a solution of (−)-nopol (Aldrich) (100 g, 0.60 mmol) in dimethoxy ethane (350 mL) was added NaH (60% oil dispersion, 31.1 g, 0.81 mmol). The mixture was refluxed for 2.5 hours, cooled to 45° C., and 2-chloroacetic acid (23.5 g 0.25 mmol) in dimethoxy ethane (180 mL) was added drop wise over a period of 1.5 hours. The reaction mixture was refluxed for 1 hour. After cooling at room temperature, water (75 mL) was added slowly, followed by 10% aqueous NaOH. The mixture was extracted with ether (1 L) (discarded), the aqueous phase was acidified and extracted with ether. The organic layer was dried over magnesium sulfate, filtered, and concentrated. The residue was distilled under reduced pressure to yield the title compound (29.5 g, 135-137° C. at 1.0 mm of Hg). n25D 1.4914, mp 78-80° C.
Reaction SMILES: [C:1]12[CH2:7][CH:4]([CH2:5][CH2:6]1)[CH:3]([C:8]([O-:10])=[O:9])[C:2]=2[C:11]([O-:13])=[O:12].[Na+:14].[Na+]>O.[Pd]>[CH:1]12[CH2:7][CH:4]([CH2:5][CH2:6]1)[CH:3]([C:8]([O-:10])=[O:9])[CH:2]2[C:11]([O-:13])=[O:12].[Na+:14].[Na+:14]
Reactant: O=C([O-])C1=C2CCC(C2)C1C(=O)[O-]
Agent: [Pd]
Agent: [Na+]
Solvent: O
Product: O=C([O-])C1C2CCC(C2)C1C(=O)[O-]
Reaction time: 8 h

Procedure:
To a solution of disodium bicyclo[2.2.1]heptene-2,3-dicarboxylate (10.0 g) in water (100 g) was added 0.5 g palladium on activated carbon (5 wt %). The mixture was transferred into a Parr reactor and was subjected to hydrogenation (50 psi, room temperature) for 8 hours. The activated carbon was filtered out. Water is removed in vacuo at 75° C. The resulting product was dried and milled (m.p>300° C.).
Reaction SMILES: [C:1]([N:5]1[C:9]([CH2:10][CH2:11][CH:12]=O)=[CH:8][C:7]([CH2:14][CH2:15][CH3:16])=[N:6]1)([CH3:4])([CH3:3])[CH3:2].[CH3:17][C:18]1[CH:19]=[C:20]([N:25]2[CH2:30][CH2:29][NH:28][CH2:27][CH2:26]2)[CH:21]=[CH:22][C:23]=1[CH3:24].CCN(C(C)C)C(C)C.[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+]>>[C:1]([N:5]1[C:9]([CH2:10][CH2:11][CH2:12][N:28]2[CH2:29][CH2:30][N:25]([C:20]3[CH:21]=[CH:22][C:23]([CH3:24])=[C:18]([CH3:17])[CH:19]=3)[CH2:26][CH2:27]2)=[CH:8][C:7]([CH2:14][CH2:15][CH3:16])=[N:6]1)([CH3:4])([CH3:3])[CH3:2]
Reactant: CCCc1cc(CCC=O)n(C(C)(C)C)n1
Reactant: Cc1ccc(N2CCNCC2)cc1C
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CCN(C(C)C)C(C)C
Product: CCCc1cc(CCCN2CCN(c3ccc(C)c(C)c3)CC2)n(C(C)(C)C)n1

Procedure:
135 mg (69%) of target compound was obtained by using a method same as in Example 1 by using 3-(1-tert-butyl-3-propyl-1H-pyrazol-5-yl)propanal (100 mg, 0.450 mmol), 1-(3,4-dimethylphenyl)piperazine (86 mg, 0.450 mmol), DIPEA (0.118 mL, 0.675 mmol) and NaBH(OAc)3 (286 mg, 1.350 mmol).
Reaction SMILES: [CH3:1][CH2:2][CH2:3][CH2:4][CH2:5][C@H:6]([OH:25])/[CH:7]=[CH:8]/[C@@H:9]1[C@@H:14]([CH2:15]/[CH:16]=[CH:17]\[CH2:18][CH2:19][CH2:20][C:21]([OH:23])=[O:22])[C:12](=[O:13])[CH2:11][C@H:10]1[OH:24].C([O-])(=O)C.[K+]>C(O)C>[CH3:1][CH2:2][CH2:3][CH2:4][CH2:5][C@H:6]([OH:25])/[CH:7]=[CH:8]/[C@@H:9]1[C@H:14]([CH2:15]/[CH:16]=[CH:17]\[CH2:18][CH2:19][CH2:20][C:21]([OH:23])=[O:22])[C:12](=[O:13])[CH2:11][C@H:10]1[OH:24]
Reactant: CCCCC[C@H](O)/C=C/[C@H]1[C@H](O)CC(=O)[C@@H]1C/C=C\CCCC(=O)O
Agent: CC(=O)[O-]
Agent: [K+]
Solvent: CCO
Product: CCCCC[C@H](O)/C=C/[C@H]1[C@H](O)CC(=O)[C@H]1C/C=C\CCCC(=O)O
Reaction time: 144 h

Procedure:
A solution of 1.00 g. of racemic PGE2 and 5 g. of potassium acetate in 100 ml. of 95% ethanol is allowed to stand at room temperature under nitrogen for 6 days; then is concentrated by evaporation under reduced pressure to about one third volume. The concentrated mixture is diluted with 75 ml. of cold water and dilute hydrochloric acid is added until the mixture reaches pH 3. The acidified mixture is extracted twice with ethyl acetate, then is saturated with sodium chloride and extracted once more with ethyl acetate. The ethyl acetate extracts are combined, washed with saturated aqueous sodium chloride, dried over sodium sulfate, and evaporated under reduced pressure, then dried under a stream of nitrogen to remove acetic acid from the residue. Thin layer chromatographic analysis shows that the residue comprises a mixture of racemic PGE2 and racemic 8-iso PGE2. The residue is chromatographed on 200 g. of Silicar CC4, eluting with 500 ml. 40%, 500 ml. 50%, 250 ml. 60%, and 250 ml. 100% ethyl acetate in cyclohexane, collecting 50-ml. fractions. Fractions 23-25 are combined and evaporated to give racemic 8-iso-PGE2. Fractions 27-30 are combined to give racemic PGE2.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([OH:10])[C:5](I)=[N:6][C:7]=1[Cl:8].C(N(CC)CC)C.[C:18]([O:22][C:23]([N:25]1[CH2:29][CH2:28][CH2:27][C@@H:26]1[C:30]#[CH:31])=[O:24])([CH3:21])([CH3:20])[CH3:19].CCOCC>CN(C=O)C.[Cu]I.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[Cl:8][C:7]1[N:6]=[C:5]2[CH:31]=[C:30]([C@H:26]3[CH2:27][CH2:28][CH2:29][N:25]3[C:23]([O:22][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:24])[O:10][C:4]2=[CH:3][C:2]=1[Cl:1]
Reactant: C#C[C@H]1CCCN1C(=O)OC(C)(C)C
Reactant: Oc1cc(Cl)c(Cl)nc1I
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Solvent: CCOCC
Product: CC(C)(C)OC(=O)N1CCC[C@@H]1c1cc2nc(Cl)c(Cl)cc2o1
Temperature: 60 °C
Reaction time: 1 h
Yield: 46.4 %

Procedure:
5,6-Dichloro-2-iodo-3-pyridinol (632 mg, 2.2 mmol), copper(I) iodide (75 mg, 0.40 mmol), bis(triphenylphosphine)palladium(II) chloride (77 mg, 0.11 mmol) and triethylamine (370 mL, 2.6 mmol) were combined in DMF (2.7 mL) and allowed to stir for 1 hour. 1-t-Butyloxycarbonyl-2-(R)-ethynylpyrrolidine (510 mg, 2.6 mmol) in DMF (1 mL) was added and the mixture was heated to 60° C. for 16 hours. After cooling to ambient temperature, the mixture was poured over Et2O/saturated K2CO3 solution and the phases were separated. The organic phase was washed with brine:water (1:1) (4×), dried (MgSO4) and concentrated. The residue was chromatographed (silica gel; EtOAc/hexane, 1:6) to afford an amber oil (365 mg, 46%): 1H NMR (CDCl3, 300 MHz) δ 1.32 and 1.45 (two br s, 9H), 1.95-2.40 (m, 4H), 3.45-3.74 (m, 2H), 4.92-5.13 (m, 1H), 6.62 (s, 1H), 7.81 (s, 1H); MS (CI/NH3) m/z: 357 (M+H)+.
Reaction SMILES: [C:1]([NH:4][C:5]1[C:14]([O:15][CH:16]2[CH2:20][CH2:19][CH2:18][CH2:17]2)=[C:13]([O:21][CH3:22])[CH:12]=[CH:11][C:6]=1[C:7]([O:9][CH3:10])=[O:8])(=[O:3])[CH3:2].Br[CH2:24][CH2:25][O:26][CH:27]1[CH2:32][CH2:31][CH2:30][CH2:29][O:28]1>CN(C)C=O>[CH:16]1([O:15][C:14]2[C:5]([N:4]([CH2:24][CH2:25][O:26][CH:27]3[CH2:32][CH2:31][CH2:30][CH2:29][O:28]3)[C:1](=[O:3])[CH3:2])=[C:6]([CH:11]=[CH:12][C:13]=2[O:21][CH3:22])[C:7]([O:9][CH3:10])=[O:8])[CH2:17][CH2:18][CH2:19][CH2:20]1
Reactant: COC(=O)c1ccc(OC)c(OC2CCCC2)c1NC(C)=O
Reactant: BrCCOC1CCCCO1
Solvent: CN(C)C=O
Product: COC(=O)c1ccc(OC)c(OC2CCCC2)c1N(CCOC1CCCCO1)C(C)=O
Reaction time: 8 h

Procedure:
Methyl 3-(cyclopentyloxy)-4-methoxy-2-(N-(2-(tetrahydro-2H-pyran-2-yloxy)ethyl)acetamido)benzoate was prepared from methyl 2-acetamido-3-(cyclopentyloxy)-4-methoxybenzoate (Example 1, Step 4) and 2-(2-bromoethoxy)-tetrahydro-2H-pyran following the procedure outlined in Example 4 (with the following exceptions: the solvent used was dimethylformamide, the reaction temperature was 33° C., and the reaction was conducted overnight). MS (ESI): 458.2 (M+Na).
Reaction SMILES: [Cl:1]N1C(=O)CCC1=O.[F:9][C:10]1[CH:23]=[CH:22][C:13]2[N:14]([CH2:18][C:19]([NH2:21])=[O:20])[C:15](=[O:17])[O:16][C:12]=2[C:11]=1[F:24]>S(=O)(=O)(O)O>[Cl:1][C:22]1[C:13]2[N:14]([CH2:18][C:19]([NH2:21])=[O:20])[C:15](=[O:17])[O:16][C:12]=2[C:11]([F:24])=[C:10]([F:9])[CH:23]=1
Reactant: NC(=O)Cn1c(=O)oc2c(F)c(F)ccc21
Reactant: O=C1CCC(=O)N1Cl
Agent: O=S(=O)(O)O
Product: NC(=O)Cn1c(=O)oc2c(F)c(F)cc(Cl)c21
Temperature: 25 °C
Reaction time: 48 h
Yield: 73 %

Procedure:
In a three neck flask, fitted with a magnetic stirrer, under inert atmosphere, N-chlorosuccinimide (0.29 g; 2.19 mmol) is added to a suspension of 2-(6,7-difluoro-2-oxo-1,3-benzoxazol-3(2H)-yl)acetamide 18 (0.5 g, 2.19 mmol) and sulfuric acid (90% w/w, 20 ml) at 0° C. The reaction mixture is stirred at room temperature for two days and another portion of N-chlorosuccinimide (0.29 g, 2.19 mmol) is added. After 14 days at room temperature, the reaction mixture is poured carefully into ice. The precipitate is collected by filtration, washed with water and recrystallized EtOH/water (20/80 (v/v)) to afford 0.42 g of a powder which is further purified by column chromatography on reverse phase to give 2-(4-chloro-6,7-difluoro-2-oxo-benzooxazol-3-yl)-acetamide 24 after recrystallization in ethanol.
Reaction SMILES: Br[C:2]1[N:7]=[C:6]([C:8]2[CH:13]=[CH:12][CH:11]=[C:10]([C:14]3[CH:19]=[CH:18][C:17]([CH3:20])=[CH:16][C:15]=3[OH:21])[N:9]=2)[CH:5]=[CH:4][CH:3]=1.[CH3:22][C:23]1[CH:24]=[CH:25][C:26]([OH:32])=[C:27](B(O)O)[CH:28]=1>>[OH:21][C:15]1[CH:16]=[C:17]([CH3:20])[CH:18]=[CH:19][C:14]=1[C:10]1[N:9]=[C:8]([C:6]2[CH:5]=[CH:4][CH:3]=[C:2]([C:25]3[CH:24]=[C:23]([CH3:22])[CH:28]=[CH:27][C:26]=3[OH:32])[N:7]=2)[CH:13]=[CH:12][CH:11]=1
Reactant: Cc1ccc(O)c(B(O)O)c1
Reactant: Cc1ccc(-c2cccc(-c3cccc(Br)n3)n2)c(O)c1
Product: Cc1ccc(-c2cccc(-c3cccc(-c4cc(C)ccc4O)n3)n2)c(O)c1
Yield: 44 %

Procedure:
6-(2-Hydroxy-4-methylphenyl)-6′-(2-hydroxy-5-methylphenyl)-2,2′-bipyridine was prepared from 6-bromo-6′-(2-hydroxy-4-methylphenyl)-2,2′-bipyridine and 5-methyl-2-hydroxyphenylboronic acid in 44% yield using method F; δH [2H6]-DMSO 13.60,(1H, b), 13.10,(1H, b), 8.32,(2H, t), 8.23,(2H, m), 8.13,(2H, d), 8.03,(1H, d), 7.95,(1H, s), 7.18,(1H, d), 6.92,(1H, d), 6.83,(2H, m), 2.33,(3H, s), 2.34,(3H, s), MS 369 (MH)+; HPLC retention time (system 1) 4.46 minutes.