Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]([C:4]1[CH:9]=[CH:8][C:7]([O:10][C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)=[CH:6][CH:5]=1)=[O:3].[CH2:17]([O:19][C:20](=[O:23])[CH2:21]Br)[CH3:18].C1C=CC=CC=1>C1(C)C=CC=CC=1>[CH2:17]([O:19][C:20](=[O:23])[CH2:21][C:2]([C:4]1[CH:9]=[CH:8][C:7]([O:10][C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)=[CH:6][CH:5]=1)([OH:3])[CH3:1])[CH3:18]
Reactant: CCOC(=O)CBr
Reactant: CC(=O)c1ccc(Oc2ccccc2)cc1
Solvent: Cc1ccccc1
Solvent: c1ccccc1
Product: CCOC(=O)CC(C)(O)c1ccc(Oc2ccccc2)cc1
Reaction time: 1 h

Procedure:
21.2 g. of 4-phenoxyacetophenone and 11.1 ml. of bromoacetic acid ethyl ester are dissolved in a mixture of 75 ml. of benzene and 75 ml. of toluene. 40 ml. of this solution are added to 7 g. of zinc powder (previously washed successively with 1% hydrochloric acid, water and acetone, and then dried) and the mixture is heated to 70° while stirring and passing in nitrogen. After the reaction has begun, the remainder of the solution is added dropwise, the mixture is boiled for one hour and cooled and 40 ml. of 20% sulfuric acid are added dropwise in order to decompose the resulting alcoholate of the formula C6H5O--p--C6H4 --C(CH3)--(OZnBr)--CH2 --COOC2H5. The organic phase is separated off and standard working up gives 3-p-phenoxyphenyl-3-hydroxy-butyric acid ethyl ester.
Reaction SMILES: [N+](C1C=CC([O:10][C:11](=O)[C@H:12]([CH:21]([C:25]([CH3:28])([CH3:27])[CH3:26])[C:22]([OH:24])=[O:23])[NH:13][C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])=CC=1)([O-])=O.Cl.[CH3:31][O:32][C:33](=[O:43])[C@H:34]([CH2:36][C:37]1[CH2:38][CH:39]=[CH:40][CH2:41][CH:42]=1)[NH2:35].CN(C)C=O.C(N(CC)CC)C>C(OCC)(=O)C>[CH3:31][O:32][C:33](=[O:43])[C@H:34]([CH2:36][C:37]1[CH2:42][CH:41]=[CH:40][CH2:39][CH:38]=1)[NH:35][C:11](=[O:10])[C@H:12]([CH:21]([C:25]([CH3:28])([CH3:27])[CH3:26])[C:22](=[O:23])[OH:24])[NH:13][C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15]
Reactant: CC(C)(C)OC(=O)N[C@H](C(=O)Oc1ccc([N+](=O)[O-])cc1)C(C(=O)O)C(C)(C)C
Reactant: COC(=O)[C@@H](N)CC1=CCC=CC1
Agent: Cl
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: COC(=O)[C@H](CC1=CCC=CC1)NC(=O)[C@@H](NC(=O)OC(C)(C)C)C(C(=O)O)C(C)(C)C

Procedure:
β-tert.-butyl-Nα-tert.-butyloxycarbonyl-L-aspartic acid p-nitrophenyl ester (26.7 g.) is added to a mixture of 2,5-dihydro-L-phenylalanine methyl ester hydrochloride (11.8 g.), dimethylformamide (50 ml.) and triethylamine (7.6 ml.). After two hours at room temperature the reaction mixture is diluted with ethyl acetate and washed with 20% aqueous citric acid, water, saturated sodium bicarbonate and water. After drying over magnesium sulfate the solvent is removed in vacuo. Yield: 13.2 g.
Reaction SMILES: [NH2:1][CH2:2][C:3]1[C:11]2[S:10](=[O:13])(=[O:12])[N:9]=[C:8]([C:14]3[C:15](=[O:32])[C@@:16]([CH2:26][CH2:27][C:28]([CH3:31])([CH3:30])[CH3:29])([CH3:25])[C:17]4[C:22]([C:23]=3[OH:24])=[CH:21][CH:20]=[CH:19][CH:18]=4)[NH:7][C:6]=2[S:5][CH:4]=1.C(N(CC)CC)C.[CH3:40][S:41](Cl)(=[O:43])=[O:42]>CN(C)C=O.O>[CH3:29][C:28]([CH3:31])([CH3:30])[CH2:27][CH2:26][C@:16]1([CH3:25])[C:17]2[C:22](=[CH:21][CH:20]=[CH:19][CH:18]=2)[C:23]([OH:24])=[C:14]([C:8]2[NH:7][C:6]3[S:5][CH:4]=[C:3]([CH2:2][NH:1][S:41]([CH3:40])(=[O:43])=[O:42])[C:11]=3[S:10](=[O:13])(=[O:12])[N:9]=2)[C:15]1=[O:32]
Reactant: CS(=O)(=O)Cl
Reactant: CC(C)(C)CC[C@@]1(C)C(=O)C(C2=NS(=O)(=O)c3c(CN)csc3N2)=C(O)c2ccccc21
Solvent: CN(C)C=O
Solvent: O
Solvent: CCN(CC)CC
Product: CC(C)(C)CC[C@@]1(C)C(=O)C(C2=NS(=O)(=O)c3c(CNS(C)(=O)=O)csc3N2)=C(O)c2ccccc21
Temperature: 25 °C
Reaction time: 2 h
Yield: 75.5 %

Procedure:
A solution of Example 186B (168 mg, 0.36 mmol) in 3 mL of N,N-dimethyl formamide was cooled to 0° C., treated with triethylamine (90 μL, 0.82 mmol) and methanesulfonyl chloride (32 μL, 0.41 mmol), allowed to warm to room temp, stirred for 2 h, diluted with water, and extracted with ethyl acetate. The organic phase was washed with water and concentrated in vacuo to afford a yellow foam. The concentrate was purified on silica gel with a gradient of methanol in dichloromethane (0-2%) to afford the title compound (150 mg, 76% yield). 1H NMR (500 MHz, C6D6) δ ppm 0.40 (m, 1 H) 0.72 (s, 9 H) 0.82 (m, 1 H) 1.55 (s, 3 H) 2.01 (m, 1 H) 2.21 (td, J=12.66, 3.97 Hz, 1 H) 2.97 (s, 3 H) 4.28 (d, J=5.49 Hz, 2 H) 7.30 (s, 1 H) 7.49 (m, 1 H) 7.66 (t, J=6.10 Hz, 1 H) 7.70 (s, 2 H) 8.12 (d, J=7.32 Hz, 1 H) 14.42 (m, 1 H); MS (APCI−) m/z 550 (M−H)−.
Reaction SMILES: [NH2:1][C:2]1[C:9]([O:10][CH3:11])=[CH:8][C:5]([C:6]#[N:7])=[C:4]([F:12])[CH:3]=1.Cl[C:14]1[N:19]=[C:18]([NH:20][CH3:21])[C:17]([C:22]([F:25])([F:24])[F:23])=[CH:16][N:15]=1.C(O)(C(F)(F)F)=O>C(O)CCC>[F:12][C:4]1[CH:3]=[C:2]([NH:1][C:14]2[N:19]=[C:18]([NH:20][CH3:21])[C:17]([C:22]([F:25])([F:23])[F:24])=[CH:16][N:15]=2)[C:9]([O:10][CH3:11])=[CH:8][C:5]=1[C:6]#[N:7]
Reactant: CNc1nc(Cl)ncc1C(F)(F)F
Reactant: COc1cc(C#N)c(F)cc1N
Solvent: O=C(O)C(F)(F)F
Solvent: CCCCO
Product: CNc1nc(Nc2cc(F)c(C#N)cc2OC)ncc1C(F)(F)F
Temperature: 75 °C
Reaction time: 2 h

Procedure:
To a mixture of 4-amino-2-fluoro-5-methoxybenzonitrile (66 mg, 0.40 mmol) and 2-chloro-N-methyl-5-(trifluoromethyl)pyrimidin-4-amine (0.10 g, 0.47 mmol) in 1-butanol (2 mL) was added TFA (0.05 mL, 0.07 mmol). The reaction was stirred in a sealed tube at 75° C. for 2 h. The reaction was concentrated and the product was isolated by reverse-phase HPLC to give 2-fluoro-5-methoxy-4-(4-(methylamino)-5-(trifluoromethyl)pyrimidin-2-ylamino)benzonitrile. 1H NMR (400 MHz, DMSO) δ 8.57 (d, J=13.4, 2H), 8.34 (s, 1H), 8.29 (d, J=6.1, 1H), 7.56-7.42 (m, 3H), 3.93 (s, 3H), 2.95 (s, 3H); LRRK2 Ki=0.022.
Reaction SMILES: FC(F)(F)C(O)=O.[F:8][C@@H:9]1[C@@H:14]([C:15]2[CH:20]=[CH:19][C:18]([OH:21])=[CH:17][CH:16]=2)[CH2:13][CH2:12][NH:11][CH2:10]1.C([O-])([O-])=O.[K+].[K+].Br[CH:29]1[CH2:33][CH2:32][N:31]([C:34]2[CH:39]=[CH:38][C:37]([CH3:40])=[C:36]([F:41])[CH:35]=2)[C:30]1=[O:42].CCOC(C)=O>CN(C=O)C>[F:8][C@@H:9]1[C@@H:14]([C:15]2[CH:20]=[CH:19][C:18]([OH:21])=[CH:17][CH:16]=2)[CH2:13][CH2:12][N:11]([CH:29]2[CH2:33][CH2:32][N:31]([C:34]3[CH:39]=[CH:38][C:37]([CH3:40])=[C:36]([F:41])[CH:35]=3)[C:30]2=[O:42])[CH2:10]1
Reactant: Cc1ccc(N2CCC(Br)C2=O)cc1F
Reactant: Oc1ccc([C@H]2CCNC[C@@H]2F)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Solvent: O=C(O)C(F)(F)F
Product: Cc1ccc(N2CCC(N3CC[C@H](c4ccc(O)cc4)[C@@H](F)C3)C2=O)cc1F
Temperature: 60 °C
Reaction time: 0.5 h

Procedure:
To a solution of 4-((3R,4R)-3-fluoropiperidin-4-yl)phenol trifluoroacetate, from step B (120 mg, 0.39 mmol) in DMF (2.0 mL) was added K2CO3 (134 mg, 0.97 mmol) and racemic 3-bromo-1-(3-fluoro-4-methyl-phenyl)pyrrolidin-2-one (106 mg, 0.39 mmol, from step C). The mixture was heated to 60° C. and stirred for 30 min. It was then allowed to cool to rt and stirred overnight, followed by the addition of 50 mL of EtOAc, which induced precipitation of a solid. The solid was removed by filtration and discarded, and the filtrate was concentrated in vacuo. The residue was purified via silica gel chromatography eluting with a gradient of 0-100% ethyl acetate/hexanes to give 110 mg of (R and S) 3-((3R,4R)-3-fluoro-4-(4-hydroxyphenyl)piperidin-1-yl)-1-(3-fluoro-4-methylphenyl)pyrrolidin-2-one) as a mixture of two diastereomers. A portion (35 mg) of the diastereomer mixture was separated (chiral HPLC method H) into homochiral example 49 P-1 (14 mg) and P-2 (14 mg). Data for P-1 (S)-3-((3R,4R)-3-fluoro-4-(4-hydroxyphenyl)piperidin-1-yl)-1-(3-fluoro-4-methylphenyl)-pyrrolidin-2-one: Chiral HPLC (method H-2) RT 6.97 min, 98% AP; 1H NMR (500 MHz, methanol-d4) δ 7.60-7.52 (m, 1H), 7.32-7.22 (m, 2H), 7.12 (d, J=8.5 Hz, 2H), 6.76 (d, J=8.5 Hz, 2H), 4.72-4.65 (m, 1H), 4.63-4.55 (m, 1H), 3.84 (d, J=9.2 Hz, 4H), 3.51-3.44 (m, 1H), 2.87-2.80 (m, 1H), 2.76-2.68 (m, 1H), 2.64-2.54 (m, 1H), 2.53-2.46 (m, 1H), 2.37-2.30 (m, 1H), 2.26 (d, J=1.4 Hz, 3H), 2.24-2.18 (m, 1H), 1.84 (br s, 3H). Data for P-2 (R)-3-((3R,4R)-3-fluoro-4-(4-hydroxyphenyl)-piperidin-1-yl)-1-(3-fluoro-4-methylphenyl)-pyrrolidin-2-one: Chiral HPLC (method H-2) RT 8.84 min, 99.3% AP; 1H NMR (500 MHz, methanol-d4) δ 7.56 (dd, J=12.0, 1.9 Hz, 1H), 7.32-7.23 (m, 2H), 7.12 (d, J=8.4 Hz, 2H), 6.80-6.73 (m, 2H), 4.70-4.63 (m, 1H), 4.60-4.54 (m, 1H), 3.88-3.77 (m, 5H), 3.23-3.17 (m, 2H), 3.07 (d, J=10.7 Hz, 2H), 2.75-2.68 (m, 2H), 2.64-2.48 (m, 4H), 2.33 (dd, J=6.6, 2.4 Hz, 2H), 2.26 (d, J=1.5 Hz, 5H), 2.21 (dd, J=12.7, 9.6 Hz, 2H), 1.90-1.83 (m, 4H).
Reaction SMILES: [OH:1][C:2]1[CH:9]=[C:8]([OH:10])[CH:7]=[C:6]([CH3:11])[C:3]=1[CH:4]=[O:5].[O:12]1[CH:17]=[CH:16][CH2:15][CH2:14][CH2:13]1>ClCCl>[OH:1][C:2]1[CH:9]=[C:8]([O:10][CH:13]2[CH2:14][CH2:15][CH2:16][CH2:17][O:12]2)[CH:7]=[C:6]([CH3:11])[C:3]=1[CH:4]=[O:5]
Reactant: Cc1cc(O)cc(O)c1C=O
Reactant: C1=COCCC1
Solvent: ClCCl
Product: Cc1cc(OC2CCCCO2)cc(O)c1C=O
Temperature: 25 °C
Reaction time: 18 h
Yield: 98.1 %

Procedure:
To a mixture of 2,4-dihydroxy-6-methyl-benzaldehyde (6.37 g, 37.88 mmol) in dichloromethane (150 mL) was added 3,4-dihydro-2H-pyran (4.78 g, 56.82 mmol) and pyridium p-toluenesulfonic acid (1.90 g, 7.58 mmol) at room temperature. The resulting mixture was stirred at room temperature for 18 hours then quenched by adding saturated NaHCO3 at 0° C. The organic layer was washed with brine, dried over Na2SO4 and concentrated in vacuo. The residue was purified by silica gel flash column chromatography (EtOAc/hexane=1:3) to give pure product (8.78 g, 98.1%). 1H NMR (400 MHz, CDCl3) δ ppm 12.33 (s, 1H), 10.11 (s, 1H), 6.47 (s, 1H), 6.39 (s, 1H), 5.49 (t, J=3.13 Hz, 1H), 3.78-3.90 (m, 1H), 3.52-3.72 (m, 1H), 2.54 (s, 3H), 1.77-2.03 (m, 3H), 1.53-1.70 (m, 3H); MS (ESI) m/z=285 [M+H]+.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:10]=[CH:11][C:12](Br)=[C:13]([CH:32]=1)[O:14][CH2:15][C@H:16]([NH2:31])[C:17]1[CH:22]=[CH:21][C:20]([O:23][CH2:24][C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)=[CH:19][CH:18]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C1(P(C2C=CC=CC=2)C2C=CC3C(=CC=CC=3)C=2C2C3C(=CC=CC=3)C=CC=2P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.CC(C)([O-])C.[K+].O>C1(C)C=CC=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.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd].C(OCC)(=O)C.CCCCCC>[CH2:1]([O:8][C:9]1[CH:10]=[CH:11][C:12]2[NH:31][C@H:16]([C:17]3[CH:22]=[CH:21][C:20]([O:23][CH2:24][C:25]4[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=4)=[CH:19][CH:18]=3)[CH2:15][O:14][C:13]=2[CH:32]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: N[C@@H](COc1cc(OCc2ccccc2)ccc1Br)c1ccc(OCc2ccccc2)cc1
Agent: [Pd]
Agent: CC(C)(C)[O-]
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: CCOC(C)=O
Solvent: O
Solvent: Cc1ccccc1
Product: c1ccc(COc2ccc([C@@H]3COc4cc(OCc5ccccc5)ccc4N3)cc2)cc1
Yield: 55 %

Procedure:
A solution of (R)-2-(5-benzyloxy-2-bromophenoxy)-1-(4-benzyloxyphenyl)ethylamine (120 mg, 0.238 mmol), tris(dibenzylideneacetone)dipalladium (11 mg, 0.012 mmol), 2,2′-bis(diphenylphosphino)-1,1′-binaphthyl (15 mg, 0.024 mmol) and potassium-t-butoxide (37 mg, 0.330 mmol) in toluene (2.5 ml) was stirred for 3 hours at 100° C. under a nitrogen stream. After cooling, water was added to the reaction mixture, which was then extracted with ethyl acetate. The organic layer was washed with saturated aqueous sodium chloride, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (eluent: ethyl acetate/hexane=1/5, v/v) to give (R)-7-benzyloxy-3-(4-benzyloxy-phenyl)-3,4-dihydro-2H-benzo[1,4]oxazine (55.4 mg, Yield 55%).
Reaction SMILES: [CH2:1]([CH:8]1[C:17]2[C:12](=[CH:13][CH:14]=[C:15]([O:18][CH3:19])[CH:16]=2)[CH2:11][CH2:10][C:9]1=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl.[NH2:22][OH:23]>C(O)C>[CH2:1]([CH:8]1[C:17]2[C:12](=[CH:13][CH:14]=[C:15]([O:18][CH3:19])[CH:16]=2)[CH2:11][CH2:10][C:9]1=[N:22][OH:23])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: NO
Reactant: COc1ccc2c(c1)C(Cc1ccccc1)C(=O)CC2
Agent: Cl
Solvent: CCO
Product: COc1ccc2c(c1)C(Cc1ccccc1)C(=NO)CC2
Temperature: 65 °C
Reaction time: 1.5 h
Yield: 102.6 %

Procedure:
To a solution of 4.47 mmol of 1-benzyl-7-methoxy-3,4-dihydronaphthalen-2(1H)-one in 15 ml ethanol were added 5.59 mmol hydroxylamine hydrochloride (dissolved in 3 ml water). The solution was stirred at 65° C. for 1.5 h. The mixture was cooled to RT and concentrated. The residue was dissolved in methyl tert-butylether and washed with water (2×), dried over MgSO4 and filtered. Evaporation of the solvent gave 1.29 g of 1-benzyl-7-methoxy-3,4-dihydronaphthalen-2(1H)-one oxime (mixture of E- and Z-isomer, 100%).
Reaction SMILES: [CH3:1][C:2]1[O:6][N:5]=[C:4]([CH2:7][C:8]([OH:10])=O)[CH:3]=1.[NH2:11][C:12]1[CH:17]=[CH:16][C:15]([Cl:18])=[CH:14][C:13]=1[C:19]([C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)=O>>[Cl:18][C:15]1[CH:14]=[C:13]2[C:12](=[CH:17][CH:16]=1)[NH:11][C:8](=[O:10])[C:7]([C:4]1[CH:3]=[C:2]([CH3:1])[O:6][N:5]=1)=[C:19]2[C:21]1[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=1
Reactant: Nc1ccc(Cl)cc1C(=O)c1ccccc1
Reactant: Cc1cc(CC(=O)O)no1
Product: Cc1cc(-c2c(-c3ccccc3)c3cc(Cl)ccc3[nH]c2=O)no1
Yield: 69 %

Procedure:
Synthesized from (5-methyl-isoxazol-3-yl)-acetic acid (J. Med. Chem., 34(2), 518, 1991) and (2-amino-5-chloro-phenyl)-phenyl-methanone according to general procedure 2. Yield 69%.
Reaction SMILES: [Cl:1][C:2]1[N:12]=[CH:11][C:10]2[O:9][CH2:8][CH2:7][N:6]3[CH:13]=[C:14]([C:16]([N:18]=[CH:19][N:20](C)C)=O)[N:15]=[C:5]3[C:4]=2[CH:3]=1.Cl.[CH:24]([NH:27]N)([CH3:26])[CH3:25]>C(O)(=O)C>[Cl:1][C:2]1[N:12]=[CH:11][C:10]2[O:9][CH2:8][CH2:7][N:6]3[CH:13]=[C:14]([C:16]4[N:27]([CH:24]([CH3:26])[CH3:25])[N:20]=[CH:19][N:18]=4)[N:15]=[C:5]3[C:4]=2[CH:3]=1
Reactant: CN(C)C=NC(=O)c1cn2c(n1)-c1cc(Cl)ncc1OCC2
Reactant: CC(C)NN
Agent: Cl
Solvent: CC(=O)O
Product: CC(C)n1ncnc1-c1cn2c(n1)-c1cc(Cl)ncc1OCC2
Temperature: 85 °C

Procedure:
A mixture of 660 mg (2.06 mmol) of 10-chloro-N-((dimethylamino)methylene)-5,6-dihydroimidazo[1,2-d]pyrido[4,3-f][1,4]oxazepine-2-carboxamide and isopropylhydrazine hydrochloride (0.332 g, 3.00 mmol) in 44 ml of acetic acid was heated at 85° C. for 3 hours. The mixture was cooled, filtered and mixed with 15 ml of water. A precipitate was filtered out, washed with water and dried in high vacuum. The above solid was triturated with 10 ml of ethyl acetate, filtered out, washed with ethyl acetate, ethyl ether and dried on air. Yield 0.710 g. MS: 331.2. 1H NMR (500 MHz, DMSO) δ 8.26 (s, 1H), 8.20 (s, 1H), 8.11 (s, 1H), 7.96 (s, 1H), 5.76 (dt, J=13.1, 6.6, 1H), 4.62 (q, J=5.6, 4H), 1.50 (d, J=6.6, 6H).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C:8]2[CH:13]=[CH:12][C:11]([O:14]COC)=[CH:10][N:9]=2)[CH:5]=[CH:6][CH:7]=1.C([Li])(C)(C)C.[B:23](OC(C)C)([O:28]C(C)C)[O:24]C(C)C>O1CCCC1>[F:1][C:2]1[CH:3]=[C:4]([C:8]2[CH:13]=[C:12]([B:23]([OH:28])[OH:24])[C:11]([OH:14])=[CH:10][N:9]=2)[CH:5]=[CH:6][CH:7]=1
Reactant: CC(C)OB(OC(C)C)OC(C)C
Reactant: COCOc1ccc(-c2cccc(F)c2)nc1
Agent: [Li]C(C)(C)C
Solvent: C1CCOC1
Product: OB(O)c1cc(-c2cccc(F)c2)ncc1O
Temperature: -78 °C
Reaction time: 0.5 h
Yield: 50.1 %

Procedure:
100 mg (1.0 eq) of the obtained 2-(3-fluorophenyl)-5-(methoxymethoxy)pyridine was dissolved in 4.3 mL of tetrahydrofuran. After cooling to −78° C., tert-butyllithium 1.7 M solution (0.5 mL, 2.0 eq) was added slowly. The mixture was stirred at the same temperature for 30 minutes. 121 mg (1.5 eq) of B(O-iPr)3 was dissolved in 2.1 mL of tetrahydrofuran, and added to the above mixture. The mixture was stirred at the same temperature for 1 hour, and stirred for 3 hours as warming to room temperature. After quenching by adding distilled water, tetrahydrofuran solution was added, and washed with brine. The reaction solution was dried with magnesium sulfate to remove water, concentrated under reduced pressure, and crystallized with methylchloride to obtain 50 mg of (2-(3-fluorophenyl)-5-hydroxypyridin-4-yl)boronic acid as white solid.
Reaction SMILES: [OH:1][C@@H:2]1[CH2:5][C@H:4]([CH2:6][NH:7][C:8](=[O:14])[O:9][C:10]([CH3:13])([CH3:12])[CH3:11])[CH2:3]1.C(N(CC)CC)C.[CH3:22][S:23](Cl)(=[O:25])=[O:24].O>C(Cl)Cl>[CH3:22][S:23]([O:1][C@H:2]1[CH2:5][C@@H:4]([CH2:6][NH:7][C:8]([O:9][C:10]([CH3:11])([CH3:13])[CH3:12])=[O:14])[CH2:3]1)(=[O:25])=[O:24]
Reactant: CS(=O)(=O)Cl
Reactant: CC(C)(C)OC(=O)NC[C@H]1C[C@@H](O)C1
Solvent: ClCCl
Solvent: O
Solvent: CCN(CC)CC
Product: CC(C)(C)OC(=O)NC[C@H]1C[C@@H](OS(C)(=O)=O)C1
Reaction time: 1 h
Yield: 68.8 %

Procedure:
Intermediate 29, tert-Butyl [(cis-3-Hydroxycyclobutyl)methyl]carbamate (5.15 g, 26 mmol) and triethylamine (8.9 mL, 61 mmol) were dissolved in CH2Cl2 (50 mL). MsCl (2.4 mL, 31 mmol) was added dropwise at −20° C. under stirring in argon. The temperature was brought to ambient within 1 h. Water (100 mL) was added, and the layers were separated. The organic one was washed with water, brine, dried with Na2SO4, and evaporated, to give the title compound (5 g, 70%) white crystals. This crude product was used for the next stage without additional purification. 1H NMR-data (DMSO-d6): 6.74-7.00 (m, 1H, NH); 4.73-4.86 (m, 1H); 3.10 (s, 3H, MS); 2.97 (t, 2H, CH2, J=5.7 Hz); 2.32-2.42 (m, 2H); 1.80-2.43 (m, 3H); 1.38 (s, 9H, Boc).
Reaction SMILES: [O:1]1[CH2:6][CH2:5][N:4]([C:7]2[CH:8]=[C:9]([CH:13]=[C:14]([N+:16]([O-:18])=[O:17])[CH:15]=2)[C:10]([OH:12])=O)[CH2:3][CH2:2]1.C(Cl)(=O)C(Cl)=O.[CH3:25][NH:26][CH3:27].C1COCC1.C(N(CC)CC)C>C(Cl)Cl.CN(C=O)C.Cl>[CH3:25][N:26]([CH3:27])[C:10](=[O:12])[C:9]1[CH:13]=[C:14]([N+:16]([O-:18])=[O:17])[CH:15]=[C:7]([N:4]2[CH2:3][CH2:2][O:1][CH2:6][CH2:5]2)[CH:8]=1
Reactant: O=C(O)c1cc(N2CCOCC2)cc([N+](=O)[O-])c1
Reactant: CNC
Agent: Cl
Agent: O=C(Cl)C(=O)Cl
Solvent: ClCCl
Solvent: C1CCOC1
Solvent: CN(C)C=O
Product: CN(C)C(=O)c1cc(N2CCOCC2)cc([N+](=O)[O-])c1

Procedure:
To a solution of 3-morpholino-5-nitrobenzoic acid (0.500 g, 1.982 mmol) in DCM (5.0 mL) were added oxalyl chloride (0.23 mL, 2.58 mmol) and 1 drop DMF. The mixture was stirred under nitrogen (vessel vented with a needle) at 23° C. for 45 minutes, then concd under vacuum. The resulting residue was taken up in 4 mL DCM and added dropwise to a stirring solution of 2.0M dimethylamine in THF (1.289 mL, 2.58 mmol) and triethylamine (0.414 mL, 2.97 mmol). The reaction was stirred under nitrogen for 15 minutes, then diluted with 1N HCl. The organic phase was washed with 1M sodium hydroxide and brine, then dried over magnesium sulfate and concd. This afforded N,N-dimethyl-3-morpholino-5-nitrobenzamide as an orange amorphous solid. Mass Spectrum (ESI) m/e=280.2 (M+1).
Reaction SMILES: [CH2:1]([N:3]1[C:8]2[N:9]=[C:10]([NH:13][C:14]3[CH:19]=[CH:18][C:17]([CH:20]4[CH2:25][CH2:24][N:23]([CH2:26][CH2:27][C:28]([F:31])([F:30])[F:29])[CH2:22][CH2:21]4)=[CH:16][C:15]=3[O:32][CH3:33])[N:11]=[CH:12][C:7]=2[C:6](=[O:34])[C:5]([C:35]([NH2:37])=[O:36])=[C:4]1[NH:38][CH3:39])[CH3:2].CC[Cl:42].CCOCC>ClCCl.CO>[ClH:42].[CH2:1]([N:3]1[C:8]2[N:9]=[C:10]([NH:13][C:14]3[CH:19]=[CH:18][C:17]([CH:20]4[CH2:21][CH2:22][N:23]([CH2:26][CH2:27][C:28]([F:31])([F:30])[F:29])[CH2:24][CH2:25]4)=[CH:16][C:15]=3[O:32][CH3:33])[N:11]=[CH:12][C:7]=2[C:6](=[O:34])[C:5]([C:35]([NH2:37])=[O:36])=[C:4]1[NH:38][CH3:39])[CH3:2]
Reactant: CCCl
Agent: CCn1c(NC)c(C(N)=O)c(=O)c2cnc(Nc3ccc(C4CCN(CCC(F)(F)F)CC4)cc3OC)nc21
Solvent: CO
Solvent: ClCCl
Solvent: CCOCC
Product: Cl
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of 0.08 g (0.15 mmol) of the product prepared in step 16.5 in 6 mL of a dichloromethane/methanol mixture (v/v=1/1) is added 0.44 mL (0.44 mmol) of a 1M solution of hydrochloric ether. The mixture is stirred for 1 hour at room temperature, and ether is then added. The solid is drained by suction, rinsed with pentane and dried in an oven under vacuum. 0.09 g of the expected product is finally obtained in the form of a yellow solid. Yield (dihydrochloride)=99%. M+H+=548.
Reaction SMILES: Cl.[NH:2]([C:4]1[CH:12]=[CH:11][CH:10]=[CH:9][C:5]=1[C:6]([OH:8])=[O:7])N.[C:13]1(=O)[CH2:17][CH2:16][CH2:15][CH2:14]1.OS(O)(=O)=O>O1CCOCC1>[CH2:15]1[C:14]2[C:12]3[C:4](=[C:5]([C:6]([OH:8])=[O:7])[CH:9]=[CH:10][CH:11]=3)[NH:2][C:13]=2[CH2:17][CH2:16]1
Reactant: O=C1CCCC1
Reactant: NNc1ccccc1C(=O)O
Agent: Cl
Agent: O=S(=O)(O)O
Solvent: C1COCCO1
Product: O=C(O)c1cccc2c3c([nH]c12)CCC3
Temperature: 25 °C

Procedure:
To a stirred solution of 2-hydrazinobenzoic acid hydrochloride (53 mmol, 10.0 g) and cyclopentanone (58 mmol, 4.9 g) in 1,4-dioxane (100 mL) was added dropwise concentrated H2SO4 (˜18M, 63 mmol, 3.5 mL). The resulting solution was heated to reflux for 2 hours. 1H NMR analysis of a crude aliquot indicated complete reaction. The reaction was allowed to cool to room temperature and then concentrated to dryness to give a red solid which was used without further purification.
Reaction SMILES: O1C=CCCC1.[Na].O.[C:9]1([CH3:19])[CH:14]=[CH:13][C:12](S(O)(=O)=O)=[CH:11]C=1.[C:20](=[O:23])(O)[O-:21].[Na+]>C(Cl)Cl>[O:21]1[C:20](=[O:23])[CH:19]=[C:9]2[CH:11]=[CH:12][CH:13]=[C:14]12
Reactant: O=C([O-])O
Reactant: Cc1ccc(S(=O)(=O)O)cc1
Agent: C1=COCCC1
Agent: [Na+]
Agent: [Na]
Solvent: ClCCl
Solvent: O
Product: O=C1C=C2C=CC=C2O1

Procedure:
571.5 mg (1.82 mmol) of [3S-[3S-[3α,3aα,4α(1E,3R*),5β,6aα]]-hexahydro-3-fluoro-5-hydroxy-4-(3-hydroxy-4,4-dimethyl-1-octenyl)-2H-cyclopenta[b]furan-2-one was dissolved in 20 ml of methylene chloride (freshly filtered through aluminum oxide, activity I) under a positive argon pressure. 2.0 ml (21.9 mmol) of dihydropyran (freshly dist. from sodium) was added under stirring followed by a crystal of p-toluenesulfonic acid monohydrate (9.7 mg; 0.05 mmol). The mixture was stirred at room temperature for 30 min, poured into 50 ml of sat. aqueous sodium bicarbonate and extracted three times with 30 ml of methylene chloride. The extracts were washed twice with 50 ml of brine, combined, dried over MgSO4 and concentrated at reduced pressure. The crude product (1.14 g, oil) was chromatographed on a 100 g silica gel column with ether/petroleum ether (1:1) yielding 797 mg (1.65 mmol)91% of [3S-[3α,3aα,4α(1E,3R*),-5β,6aα]]-hexahydro-3-fluoro-5-[(tetrahydro-2H-pyran-2-yl)oxy]-4-[3-(tetrahydro-2H-pyran-2-yl)oxy]-4,4-dimethyl-1-octenyl]-2H-cyclopenta[b]furan-2-one as a clear oil(mixture of THP-diastereomers). [α]D25 -32.46° in CHCl3, c=0.8780.
Reaction SMILES: [O:1]=[C:2]1[NH:7][C:6]2[CH:8]=[C:9]([C:11]3[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=3)[S:10][C:5]=2[C:4](=[O:17])[N:3]1[CH:18]1[CH2:23][CH2:22][N:21]([C:24]([O:26][C:27]([CH3:30])([CH3:29])[CH3:28])=[O:25])[CH2:20][CH2:19]1.Cl[CH2:32][C:33]1[S:37][N:36]=[C:35]([CH2:38][CH3:39])[N:34]=1.C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C>[CH2:38]([C:35]1[N:34]=[C:33]([CH2:32][N:7]2[C:6]3[CH:8]=[C:9]([C:11]4[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=4)[S:10][C:5]=3[C:4](=[O:17])[N:3]([CH:18]3[CH2:23][CH2:22][N:21]([C:24]([O:26][C:27]([CH3:30])([CH3:29])[CH3:28])=[O:25])[CH2:20][CH2:19]3)[C:2]2=[O:1])[S:37][N:36]=1)[CH3:39]
Reactant: CCc1nsc(CCl)n1
Reactant: CC(C)(C)OC(=O)N1CCC(n2c(=O)[nH]c3cc(-c4ccccc4)sc3c2=O)CC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCc1nsc(Cn2c(=O)n(C3CCN(C(=O)OC(C)(C)C)CC3)c(=O)c3sc(-c4ccccc4)cc32)n1
Temperature: 100 °C
Reaction time: 3 h

Procedure:
According to GP1 tert-butyl 4-(2,4-dioxo-6-phenyl-1,4-dihydrothieno[3,2-d]pyrimidin-3(2H)-yl)piperidine-1-carboxylate (563 mg; compound B50) is reacted with 5-(chloromethyl)-3-ethyl-1,2,4-thiadiazole (226 mg; compound D20) in the presence of potassium carbonate (364 mg) in DMF (10 ml). After 3 h and additionally after 6 h at 100° C. additional 5-(chloromethyl)-3-ethyl-1,2,4-thiadiazole (214 mg and 107 mg; compound D20) in DMF (5 ml each) is added, and the mixture is stirred at 100° C. for another 5 h. Using WU2 the title compound is obtained after flash column chromatography [silica gel, eluent: cyclohexane/EtOAc, 3/1 (v/v)] as a solid.