Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([O:9][C:10]([F:13])([F:12])[F:11])=[CH:5][C:4]=1B(O)O.Br[C:18]1[N:19]=[CH:20][C:21]([NH:25][CH2:26][C:27]2[CH:32]=[CH:31][C:30]([O:33][CH3:34])=[CH:29][CH:28]=2)=[N:22][C:23]=1[Cl:24]>C(OCC)(=O)C.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>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([O:9][C:10]([F:13])([F:12])[F:11])=[CH:5][C:4]=1[C:20]1[C:21]([NH:25][CH2:26][C:27]2[CH:32]=[CH:31][C:30]([O:33][CH3:34])=[CH:29][CH:28]=2)=[N:22][C:23]([Cl:24])=[CH:18][N:19]=1
Reactant: COc1ccc(OC(F)(F)F)cc1B(O)O
Reactant: COc1ccc(CNc2cnc(Br)c(Cl)n2)cc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: CCOC(C)=O
Product: COc1ccc(CNc2nc(Cl)cnc2-c2cc(OC(F)(F)F)ccc2OC)cc1
Temperature: 80 °C

Procedure:
In a pressure tube, a mixture of the product from step A (1 equivalent), 2-methoxy-5-trifluoromethoxyphenylboronic acid (1.6 equivalents) and Pd(PPh3)4 (0.04 equivalents) in toluene (4 ml/mmol of product from step A), ethanol (0.2 ml/mmol of product from step A) and aqueous K2CO3 (2M, 2 ml/mmol of product from step A) is heated to 80° C. for 16 hours. The mixture is diluted with ethyl acetate, and the organic fraction washed with NaOH (2M, 20 mL/mmol of product from step A) and brine (3×20 ml/mmol of product from step A), then dried (MgSO4), filtered and the solvent removed under reduced pressure. Chromatography of the residue provides (3-(2-methoxy-5-trifluoromethoxyphenyl)-6-chloropyrazin-2-yl)[(4-methoxyphenyl)methyl]amine.
Reaction SMILES: Cl[CH2:2][CH2:3][CH2:4][CH2:5][N:6]1[C:14](=[O:15])[N:9]2[CH:10]=[CH:11][CH:12]=[CH:13][C:8]2=[N:7]1.[NH:16]1[CH2:21][CH:20]=[C:19]([C:22]2[C:30]3[C:25](=[CH:26][CH:27]=[CH:28][CH:29]=3)[NH:24][CH:23]=2)[CH2:18][CH2:17]1>>[NH:24]1[C:25]2[C:30](=[CH:29][CH:28]=[CH:27][CH:26]=2)[C:22]([C:19]2[CH2:20][CH2:21][N:16]([CH2:2][CH2:3][CH2:4][CH2:5][N:6]3[C:14](=[O:15])[N:9]4[CH:10]=[CH:11][CH:12]=[CH:13][C:8]4=[N:7]3)[CH2:17][CH:18]=2)=[CH:23]1
Reactant: C1=C(c2c[nH]c3ccccc23)CCNC1
Reactant: O=c1n(CCCCCl)nc2ccccn12
Product: O=c1n(CCCCN2CC=C(c3c[nH]c4ccccc34)CC2)nc2ccccn12

Procedure:
2-{4-[4-(1H-Indol-3-yl)-3,6-dihydro-2H-pyridin-1-yl]-butyl}-2H-[1,2,4]triazolo[4,3-a]pyridin-3-one was prepared by reacting 2-(4-Chloro-butyl)-2H-[1,2,4]triazolo[4,3-a]pyridin-3-one (225 mg, 1 mmol) and 3-(1,2,3,6-Tetrahydro-pyridin-4-yl)-1H-indole (198 mg, 1 mmol) by adopting the procedure as outlined in Experimental 24. Yield: 87 mg (22%) compound was isolated as pale yellow solid.
Reaction SMILES: Br[C:2]1[CH:11]=[CH:10][CH:9]=[C:8]2[C:3]=1[CH:4]=[CH:5][N:6]=[CH:7]2.C(P(C(C)(C)C)C1C=CC=CC=1C1C=CC=CC=1)(C)(C)C.[C:33]([O:37][C:38]([NH:40][C@H:41]1[CH2:46][CH2:45][C@H:44]([NH2:47])[CH2:43][CH2:42]1)=[O:39])([CH3:36])([CH3:35])[CH3:34].CC(C)([O-])C.[Na+]>C1(C)C=CC=CC=1>[C:33]([O:37][C:38]([NH:40][C@H:41]1[CH2:42][CH2:43][C@H:44]([NH:47][C:2]2[CH:11]=[CH:10][CH:9]=[C:8]3[C:3]=2[CH:4]=[CH:5][N:6]=[CH:7]3)[CH2:45][CH2:46]1)=[O:39])([CH3:36])([CH3:34])[CH3:35]
Reactant: CC(C)(C)OC(=O)N[C@H]1CC[C@H](N)CC1
Reactant: Brc1cccc2cnccc12
Agent: CC(C)(C)P(c1ccccc1-c1ccccc1)C(C)(C)C
Agent: CC(C)(C)[O-]
Agent: [Na+]
Solvent: Cc1ccccc1
Product: CC(C)(C)OC(=O)N[C@H]1CC[C@H](Nc2cccc3cnccc23)CC1
Temperature: 70 °C

Procedure:
Under nitrogen atmosphere, a suspension of 5-bromoisoquinoline (100 mg), tris(dibenzylideneacetone)palladium(0) (23 mg), 2-(di-tert-butylphosphino)biphenyl (29 mg), Intermediate 40 (122 mg) and sodium tert-butoxide (66 mg) in toluene was stirred with heating at 70° C. for 3.5 hours. The reaction mixture was cooled to room temperature and purified by silica gel column chromatography (n-hexane:ethyl acetate=1:1) to obtain the title compound (69 mg).
Reaction SMILES: [NH2:1][C:2]1[C:7]([OH:8])=[CH:6][C:5]([F:9])=[CH:4][N:3]=1.Cl[CH:11]([C:17]([CH3:19])=O)[C:12]([O:14][CH2:15][CH3:16])=[O:13]>C(O)C>[F:9][C:5]1[CH:6]=[C:7]([OH:8])[C:2]2[N:3]([C:11]([C:12]([O:14][CH2:15][CH3:16])=[O:13])=[C:17]([CH3:19])[N:1]=2)[CH:4]=1
Reactant: CCOC(=O)C(Cl)C(C)=O
Reactant: Nc1ncc(F)cc1O
Solvent: CCO
Product: CCOC(=O)c1c(C)nc2c(O)cc(F)cn12

Procedure:
3.2 g of 2-amino-5-fluoropyridin-3-ol (Example 8A; 25 mmol, 1 equivalent) were initially charged in 155 ml of ethanol, 1.5 g of powdered molecular sieve 3 Å and 20.6 g of ethyl 2-chloroacetoacetate (125 mmol, 5 equivalents) were added and the mixture was boiled at reflux overnight. The reaction solution was concentrated and chromatographed (Biotage Isolera Four; SNAP Cartridge KP-Sil 50 g; cyclohexane/ethyl acetate gradient; then dichloromethane/methanol gradient). The crude product was partly dissolved in a little methanol, and tert-butyl methyl ether was added. The solid was filtered off and washed with tert-butyl methyl ether. This gave 570 mg (10% of theory) of the title compound.
Reaction SMILES: [CH2:1]([N:3]1[C:7](=[O:8])[C:6]2=[CH:9][CH:10]=[CH:11][CH:12]=[C:5]2[C:4]1=[O:13])[CH3:2]>CO.[BH4-].[K+]>[OH:8][CH:7]1[C:6]2[C:5](=[CH:12][CH:11]=[CH:10][CH:9]=2)[C:4](=[O:13])[N:3]1[CH2:1][CH3:2]
Reactant: CCN1C(=O)c2ccccc2C1=O
Agent: [BH4-]
Agent: [K+]
Solvent: CO
Product: CCN1C(=O)c2ccccc2C1O
Temperature: 20 °C
Reaction time: 20 h
Yield: 47 %

Procedure:
3-Hydroxy-2-ethyl-2,3-dihydroisoindol-1-one is prepared as described in Example 1, starting with 4.0 g of N-ethylphthalimide in 20 cm3 of methanol and 1.2 g of potassium borohydride. The reaction mixture is stirred at a temperature in the region of 20° C. for 20 hours and is then cooled to a temperature in the region of 0° C. and distilled water is added dropwise. The precipitate obtained is filtered off and then washed with cold water. The methanol is then partially evaporated from the filtrate under reduced pressure (2 kPa) at a temperature in the region of 35° C., and the residue is cooled to 0° C. The second precipitate thus obtained is filtered off and then washed with cold water. The two fractions of solid are dried under reduced pressure (2 kPa) at a temperature in the region of 35° C. 1.9 g of 3-hydroxy-2-ethyl-2,3-dihydroisoindol-1-one are thus obtained in the form of a flaky white powder. (Rf=0.5, thin layer chromatography on silica gel, eluent: cyclohexane/ethyl acetate (30/70 by volume)).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[CH:4][CH:3]=1.[CH:9](O)([OH:14])[C:10]([F:13])([F:12])[F:11]>>[F:11][C:10]([F:13])([F:12])[CH:9]([C:6]1[CH:7]=[C:2]([Cl:1])[CH:3]=[CH:4][C:5]=1[OH:8])[OH:14]
Reactant: OC(O)C(F)(F)F
Reactant: Oc1ccc(Cl)cc1
Product: Oc1ccc(Cl)cc1C(O)C(F)(F)F
Temperature: 100 °C
Yield: 45 %

Procedure:
12.5 g (100 mmol) of p-chlorophenol and 3.9 g (25 mmol) of 75% fluoral hydrate are introduced into a 100 ml reactor. 6 g of hydrotalcite Mg6AlGa(O4)16.4H2O are added and the mixture is heated at 100° C. for 7 hours. After treating the reaction medium according to the protocol described in Example 1, a yield of 45% of the expected product is obtained.
Reaction SMILES: [C:1]([C:4]1([O:17][CH3:18])[CH2:9][CH2:8][N:7]([C:10]([O:12][C:13]([CH3:16])([CH3:15])[CH3:14])=[O:11])[CH2:6][CH2:5]1)(=[O:3])[CH3:2].C(NC(C)C)(C)C.[Li].[CH:27](=[O:30])[CH2:28][CH3:29].[Cl-].[NH4+]>O1CCCC1>[OH:30][CH:27]([CH2:28][CH3:29])[CH2:2][C:1]([C:4]1([O:17][CH3:18])[CH2:9][CH2:8][N:7]([C:10]([O:12][C:13]([CH3:14])([CH3:16])[CH3:15])=[O:11])[CH2:6][CH2:5]1)=[O:3]
Reactant: COC1(C(C)=O)CCN(C(=O)OC(C)(C)C)CC1
Reactant: CCC=O
Agent: [Cl-]
Agent: [Li]
Agent: [NH4+]
Solvent: CC(C)NC(C)C
Solvent: C1CCOC1
Product: CCC(O)CC(=O)C1(OC)CCN(C(=O)OC(C)(C)C)CC1
Reaction time: 0.08 h
Yield: 55.9 %

Procedure:
To a solution of tert-butyl 4-acetyl-4-methoxypiperidine-1-carboxylate (0.589 g, 2.29 mmol) from Step A in tetrahydrofuran (20 mL) at −78° C. was added lithium diisopropylamine (0.650 mL, 0.974 mmol) followed by propionaldehyde (0.266 g, 0.330 mL, 4.58 mmol). After 5 min, the reaction mixture was poured into saturated ammonium chloride, and extracted three times with diethyl ether. The organic layers were combined, washed with saturated sodium chloride solution, dried over sodium sulfite, filtered, and concentrated. The residue was purified by flash chromatography eluting with 40% ethyl acetate/hexanes to afford the title compound (0.404 g). MS/EI (acetonitrile/water): m/z 216.1 (M+1−BOC) retention time=2.69 min.
Reaction SMILES: Br[C:2]1[CH:7]=[C:6]([S:8]([CH3:11])(=[O:10])=[O:9])[CH:5]=[CH:4][C:3]=1[F:12].BrC1C=C(S(CC)(=O)=O)C=CC=1OCCC.FC1C=CC(S(C)(=O)=O)=CC=1B1OC(C)(C)C(C)(C)O1.Br[C:50]1[C:55]2[N:56]=[CH:57][N:58]=[CH:59][C:54]=2[C:53](=[O:60])[N:52]([CH3:61])[CH:51]=1>>[F:12][C:3]1[CH:4]=[CH:5][C:6]([S:8]([CH3:11])(=[O:10])=[O:9])=[CH:7][C:2]=1[C:50]1[C:55]2[N:56]=[CH:57][N:58]=[CH:59][C:54]=2[C:53](=[O:60])[N:52]([CH3:61])[CH:51]=1
Reactant: Cn1cc(Br)c2ncncc2c1=O
Reactant: CS(=O)(=O)c1ccc(F)c(Br)c1
Agent: CC1(C)OB(c2cc(S(C)(=O)=O)ccc2F)OC1(C)C
Agent: CCCOc1ccc(S(=O)(=O)CC)cc1Br
Product: Cn1cc(-c2cc(S(C)(=O)=O)ccc2F)c2ncncc2c1=O

Procedure:
2-bromo-1-fluoro-4-methylsulfonylbenzene was substituted for the title compound of Example 225, step 1 and was converted to 2-(2-fluoro-5-methylsulfonylphenyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane in a manner similar to Example 225, step 2 and then reacted with the title compound of Example 231, step 3 in a manner similar to Example 231, step 4. LCMS: 333.9 (M+H)+.
Reaction SMILES: O[CH:2]1[NH:8][C:7](=[O:9])[C:6]2[S:10][CH:11]=[CH:12][C:5]=2[N:4]2[CH:13]=[CH:14][CH:15]=[C:3]12.[CH3:16][C:17]([CH3:19])=[O:18]>[OH-].[Na+]>[CH2:16]([CH:2]1[NH:8][C:7](=[O:9])[C:6]2[S:10][CH:11]=[CH:12][C:5]=2[N:4]2[CH:13]=[CH:14][CH:15]=[C:3]12)[C:17]([CH3:19])=[O:18]
Reactant: O=C1NC(O)c2cccn2-c2ccsc21
Reactant: CC(C)=O
Agent: [Na+]
Agent: [OH-]
Product: CC(=O)CC1NC(=O)c2sccc2-n2cccc21
Temperature: 25 °C
Reaction time: 3 h
Yield: 60 %

Procedure:
1 g (0.0045 mol) of 6-hydroxy-5,6-dihydro-4-oxo -4H-pyrrol-o[1,2-a]thieno[2,3-f][1,4]diazepine is added in a single portion to an emulsion of 20 ml of acetone in 10 ml of 10N sodium hydroxide, and the reaction mixture is stirred vigorously at room temperature for 3 hours. The acetone is then removed under vacuum and 100 ml of water are poured onto the liquid residue. The yellow precipitate obtained is drained, washed with water and recrystallized. 0.7 g of 6-acetonyl-5,6-dihydro-4-oxo-4H -pyrrolo[1,2-a]thieno[2,3-f][1,4]diazepine is obtained in the form of white crystals, melting point 268° C. (isopropanol).
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1.Cl[C:8]1[N:13]=[C:12]([NH:14][C:15]2[NH:19][N:18]=[C:17]([CH:20]3[CH2:22][CH2:21]3)[CH:16]=2)[N:11]=[C:10]([CH:23]2[CH2:27][C@@H:26]([O:28][CH2:29][CH:30]([F:32])[F:31])[CH2:25][C@H:24]2[C:33]([O:35][CH3:36])=[O:34])[N:9]=1>>[CH:20]1([C:17]2[CH:16]=[C:15]([NH:14][C:12]3[N:13]=[C:8]([N:1]4[CH2:6][CH2:5][O:4][CH2:3][CH2:2]4)[N:9]=[C:10]([CH:23]4[CH2:27][C@@H:26]([O:28][CH2:29][CH:30]([F:31])[F:32])[CH2:25][C@H:24]4[C:33]([O:35][CH3:36])=[O:34])[N:11]=3)[NH:19][N:18]=2)[CH2:22][CH2:21]1
Reactant: C1COCCN1
Reactant: COC(=O)[C@@H]1C[C@H](OCC(F)F)CC1c1nc(Cl)nc(Nc2cc(C3CC3)n[nH]2)n1
Product: COC(=O)[C@@H]1C[C@H](OCC(F)F)CC1c1nc(Nc2cc(C3CC3)n[nH]2)nc(N2CCOCC2)n1

Procedure:
124E was prepared from morpholine and 124D using the procedure described in 1. LC/MS [M+H]+: 495; Ret time (Method F): 2.61 min.
Reaction SMILES: [H-].[Na+].[NH:3]1[CH:7]=[CH:6][C:5]([C:8]2[CH:15]=[CH:14][C:11]([C:12]#[N:13])=[CH:10][CH:9]=2)=[N:4]1.Br[CH2:17][CH:18]1[CH2:20][CH2:19]1>CN(C=O)C>[CH:18]1([CH2:17][N:3]2[CH:7]=[CH:6][C:5]([C:8]3[CH:15]=[CH:14][C:11]([C:12]#[N:13])=[CH:10][CH:9]=3)=[N:4]2)[CH2:20][CH2:19]1
Reactant: N#Cc1ccc(-c2cc[nH]n2)cc1
Reactant: BrCC1CC1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: N#Cc1ccc(-c2ccn(CC3CC3)n2)cc1
Temperature: 0 °C
Reaction time: 0.25 h
Yield: 64.8 %

Procedure:
Add sodium hydride (64 mg, 2.65 mmol) to a solution of 4-(1H-pyrazol-3-yl)-benzonitrile (300 mg, 1.77 mmol) in DMF (5 mL) under nitrogen atmosphere. Stir the mixture for 15 min at 0° C. and add (bromomethyl)cyclopropane (206 □l, 2.12 mmol). Stir the mixture for 5 min at 0° C. and then at room temperature overnight. Quenck the reaction mixture with water and extract twice with EtOAc. Dry the combined organics extracts over Na2SO4, filter and concentrate in vacuo. Purify the crude mixture by chromatography on silica gel eluting with hexane/EtOAc (75:25) to obtain the desired intermediate (256 mg, 65%).
Reaction SMILES: [CH2:1]([O:3][C:4]([CH:6]=[C:7]([CH2:18][CH:19]([CH3:21])[CH3:20])[C:8]([O:10]CC1C=CC=CC=1)=[O:9])=[O:5])[CH3:2]>C(O)C.[Pd]>[CH2:1]([O:3][C:4]([CH2:6][CH:7]([CH2:18][CH:19]([CH3:20])[CH3:21])[C:8]([OH:10])=[O:9])=[O:5])[CH3:2]
Reactant: CCOC(=O)C=C(CC(C)C)C(=O)OCc1ccccc1
Agent: [Pd]
Solvent: CCO
Product: CCOC(=O)CC(CC(C)C)C(=O)O

Procedure:
E and Z benzyl 3-(ethoxycarbonyl)-2-(2-methylpropyl)propenoate (25.0 g., 0.09 mol.) was dissolved in ethanol and hydrogenated at 50° C. under 37.5 psi in the presence of 5% palladium on charcoal (2.5 g.). The resultant mixture was filtered through Celite and the solvent removed by evaporation in vacuo to yield 3-(ethoxycarbonyl)-2-(2-methylpropyl)propanoic acid as a mixture of isomers in the form of a thick oil.
Reaction SMILES: C[O:2][CH:3](OC)[CH2:4][CH2:5][N:6]1[CH:11]=[C:10]([C:12]2[CH:17]=[N:16][CH:15]=[CH:14][N:13]=2)[C:9](=[O:18])[NH:8][C:7]1=[O:19]>C1COCC1>[O:19]=[C:7]1[NH:8][C:9](=[O:18])[C:10]([C:12]2[CH:17]=[N:16][CH:15]=[CH:14][N:13]=2)=[CH:11][N:6]1[CH2:5][CH2:4][CH:3]=[O:2]
Reactant: COC(CCn1cc(-c2cnccn2)c(=O)[nH]c1=O)OC
Solvent: C1CCOC1
Product: O=CCCn1cc(-c2cnccn2)c(=O)[nH]c1=O
Temperature: 40 °C
Reaction time: 4 h

Procedure:
1-(3,3-Dimethoxy-propyl)-5-pyrazin-2-yl-1H-pyrimidine-2,4-dione (Prep126, 111 mg, 0.38 mmol) was dissolved in THF (4 ml) and then 1N HClaq (0.38 ml) was added. The solution was stirred at 40° C. for 4 hours. TEA (55 μl, 0.39 mmol) was added and the solvent was removed in vacuum at room temperature. Residue was freeze dried to give a white powder that was used in the next step without further purification (quantitative yield).
Reaction SMILES: [H-].[Al+3].[Li+].[H-].[H-].[H-].[CH2:7]1[CH2:28][O:27][CH:26]2[CH:9]([CH2:10][C:11]34[O:37][C@H:12]3[C:13](=[CH2:36])[C@@H:14]3[C@@H:23]([C@@:24]4([CH3:30])[C@@H:25]2[CH3:29])[CH2:22][CH2:21][C@@:19]2([CH3:20])[C@H:15]3[CH2:16][C@:17]3([F:35])[O:34][CH2:33][CH2:32][O:31][CH:18]32)[O:8]1.C(C(C(C([O-])=O)O)O)([O-])=O.[Na+].[K+]>C(OCC)C.O1CCCC1>[CH2:7]1[CH2:28][O:27][CH:26]2[CH:9]([CH2:10][C:11]3([OH:37])[C@:24]([CH3:30])([C@@H:25]2[CH3:29])[C@@H:23]2[C@H:14]([C@H:15]4[C@@:19]([CH2:21][CH2:22]2)([CH3:20])[CH:18]2[O:31][CH2:32][CH2:33][O:34][C:17]2([F:35])[CH2:16]4)[C:13](=[CH2:36])[CH2:12]3)[O:8]1
Reactant: C=C1[C@@H]2[C@H](CC[C@]3(C)C4OCCO[C@@]4(F)C[C@@H]23)[C@@]2(C)[C@H](C)C3OCCOC3CC23O[C@@H]13
Agent: O=C([O-])C(O)C(O)C(=O)[O-]
Agent: [Al+3]
Agent: [H-]
Solvent: CCOCC
Solvent: C1CCOC1
Product: C=C1CC2(O)CC3OCCOC3[C@@H](C)[C@]2(C)[C@H]2CC[C@]3(C)C4OCCOC4(F)C[C@H]3[C@H]12

Procedure:
To a solution of lithium aluminium hydride (38 mg) in diethylether (10 ml) is added gradually a solution of 3,17-bis(ethylenedioxy)-5,6α-epoxy-16α-fluoro-1β-methyl-7-methylenandrostane (431 mg) in tetrahydrofuran (10 ml). The resulting mixture is stirred at 20°-25° C. for a period of about 18 hrs after which an aqueous solution of potassium sodium tartrate is added. The mixture is filtered and concentrated to a small volume under reduced pressure. The concentrate is taken up in diethyl ether and washed well with water. The ether solution is dried over magnesium sulfate, filtered and the ether removed under vacuum to yield crude 3,17-bis(ethylenedioxy)-16-fluoro-5-hydroxy-1β-methyl-7-methylenandrostane. This intermediate is dissolved in a 2:1 mixture of acetic acid and water (5 ml) and the solution heated for 6 hrs at 40°-50° C. Then water is added and the product extracted with ethyl acetate.
Reaction SMILES: [F:1][C:2]1[CH:22]=[CH:21][CH:20]=[C:19]([F:23])[C:3]=1[CH2:4][O:5][C:6]1[C:7]2[N:8]([C:12]([C:16]([OH:18])=O)=[C:13]([CH3:15])[N:14]=2)[CH:9]=[CH:10][CH:11]=1.FC(F)(F)C(O)=O.[NH2:31][C:32]([C:36]1[O:37][C:38]([CH2:41][CH3:42])=[N:39][N:40]=1)([CH3:35])[CH2:33][OH:34].ON1C2C=CC=CC=2N=N1.C(N(C(C)C)CC)(C)C.Cl.CN(C)CCCN=C=NCC.C(OC(C)C)(C)C>C(OCC)(=O)C.O.CN(C=O)C>[F:1][C:2]1[CH:22]=[CH:21][CH:20]=[C:19]([F:23])[C:3]=1[CH2:4][O:5][C:6]1[C:7]2[N:8]([C:12]([C:16]([NH:31][C:32]([C:36]3[O:37][C:38]([CH2:41][CH3:42])=[N:39][N:40]=3)([CH3:35])[CH2:33][OH:34])=[O:18])=[C:13]([CH3:15])[N:14]=2)[CH:9]=[CH:10][CH:11]=1
Reactant: Cc1nc2c(OCc3c(F)cccc3F)cccn2c1C(=O)O
Reactant: CCc1nnc(C(C)(N)CO)o1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: O
Solvent: CCOC(C)=O
Solvent: CCN(C(C)C)C(C)C
Product: CCc1nnc(C(C)(CO)NC(=O)c2c(C)nc3c(OCc4c(F)cccc4F)cccn23)o1
Temperature: 25 °C
Reaction time: 8 h
Yield: 24.1 %

Procedure:
To a mixture of 165 mg of 8-[(2,6-difluorobenzyl)oxy]-2-methylimidazo[1,2-a]pyridine-3-carboxylic acid, 160 mg of 2-amino-2-(5-ethyl-1,3,4-oxadiazol-2-yl)propan-1-ol trifluoroacetate, 90 mg of 1-hydroxybenzotriazole, 0.35 ml of diisopropylethylamine, and 4 ml of DMF was added 130 mg of N-[3-(dimethylamino)propyl]-N′-ethylcarbodiimide hydrochloride, followed by stirring at room temperature overnight. To the reaction mixture was added water, followed by extraction with ethyl acetate. The organic layer was washed with water and a saturated aqueous sodium chloride solution, and the organic layer was dried over anhydrous magnesium sulfate. The solvent was then evaporated under reduced pressure. The obtained residue was purified by silica gel column chromatography. To the obtained crude product were added ethyl acetate and diisopropyl ether, and the insoluble materials were collected by filtration, and dried under reduced pressure to obtain 59 mg of 8-[(2,6-difluorobenzyl)oxy]-N-[2-(5-ethyl-1,3,4-oxadiazol-2-yl)-1-hydroxypropan-2-yl]-2-methylimidazo[1,2-a]pyridine-3-carboxamide.
Reaction SMILES: C[O:2][C:3]([C@@H:5]1[CH2:14][C:13]2[CH:12]=[C:11]3[O:15][CH2:16][C@H:17]([C:19]4[CH:24]=[CH:23][C:22]([O:25][CH2:26][C:27]5[CH:32]=[CH:31][C:30]([Cl:33])=[C:29]([Cl:34])[CH:28]=5)=[CH:21][CH:20]=4)[O:18][C:10]3=[CH:9][C:8]=2[CH2:7][N:6]1[C@H:35]([C:38]1[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=1)[CH2:36][CH3:37])=[O:4].CO.[Li+].[OH-]>C1COCC1>[Cl:34][C:29]1[CH:28]=[C:27]([CH:32]=[CH:31][C:30]=1[Cl:33])[CH2:26][O:25][C:22]1[CH:21]=[CH:20][C:19]([C@H:17]2[CH2:16][O:15][C:11]3=[CH:12][C:13]4[CH2:14][C@@H:5]([C:3]([OH:4])=[O:2])[N:6]([C@H:35]([C:38]5[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=5)[CH2:36][CH3:37])[CH2:7][C:8]=4[CH:9]=[C:10]3[O:18]2)=[CH:24][CH:23]=1
Reactant: CC[C@@H](c1ccccc1)N1Cc2cc3c(cc2C[C@H]1C(=O)OC)OC[C@H](c1ccc(OCc2ccc(Cl)c(Cl)c2)cc1)O3
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Product: CC[C@@H](c1ccccc1)N1Cc2cc3c(cc2C[C@H]1C(=O)O)OC[C@H](c1ccc(OCc2ccc(Cl)c(Cl)c2)cc1)O3
Temperature: 0 °C
Reaction time: 2 h
Yield: 96.2 %

Procedure:
(3S,8S)-3-[4-(3,4-Dichloro-benzyloxy)-phenyl]-7-((S)-1-phenyl-propyl)-2,3,6,7,8,9-hexahydro-[1,4]dioxino[2,3-g]isoquinoline-8-carboxylic acid methyl ester (872 mg) was dissolved in 24 mL THF and 20 mL MeOH and 591 mg LiOH was added. The flask was flushed with nitrogen and placed under a nitrogen balloon and stirred at 0° C. 12 mL water was then added in portions while stirring, then the reaction stirred at rt 15 h. 119 mg LiOH and 6 mL water were added to the reaction and stirring continued for 2 h. 4 mL water was added and stirring continued for 30 min, then 2 mL water was added. After 1.5 h the pH was adjusted to 7 with 2% w/v aqueous citric acid and the reaction extracted with EtOAc. The organic solution was washed with brine and dried over Na2SO4 and evaporated, to give 820 mg desired compound after drying. LCMS: m/z 605 (M+1).
Reaction SMILES: [C:1]1([CH:7]([OH:19])[CH2:8][C:9](=[O:18])[CH2:10][C:11](=[O:17])[S:12][C:13]([CH3:16])([CH3:15])[CH3:14])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C([BH3-])#N.[Na+]>CC(C)[O-].CC(C)[O-].CC(C)[O-].[Cl-].[Ti+4]>[C:1]1([CH:7]([OH:19])[CH2:8][CH:9]([OH:18])[CH2:10][C:11](=[O:17])[S:12][C:13]([CH3:16])([CH3:14])[CH3:15])[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: CC(C)(C)SC(=O)CC(=O)CC(O)c1ccccc1
Agent: [Ti+4]
Agent: CC(C)[O-]
Agent: [BH3-]C#N
Product: CC(C)(C)SC(=O)CC(O)CC(O)c1ccccc1
Yield: 79.6 %

Procedure:
By carrying out the reaction as in Example 9 but starting from 500 mg of S-t-butyl 5-Phenyl-5-hydroxy-3-oxopentanethioate (1.78 mmol), 0.49 cm3 of titanium chloride triisopropoxide (1.96 mmol) and from 131.9 mg of sodium cyanoborohydride, there is obtained, after 3 hours 40 minutes, with a yield of 79.5%, 400 mg of S-t-butyl 5-phenyl-3,5-dihydroxypentanethioate for which the syn/anti ratio is equal to 90/10.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:12][C@@H:11]([C:13]#[N:14])[CH2:10][C@H:9]1[C:15]([OH:17])=O)=[O:7])([CH3:4])([CH3:3])[CH3:2].[Cl:18][C:19]1[C:20]([F:27])=[C:21]([CH:24]=[CH:25][CH:26]=1)[CH2:22][NH2:23].CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C>CN(C=O)C.O>[C:1]([O:5][C:6]([N:8]1[CH2:12][C@@H:11]([C:13]#[N:14])[CH2:10][C@H:9]1[C:15](=[O:17])[NH:23][CH2:22][C:21]1[CH:24]=[CH:25][CH:26]=[C:19]([Cl:18])[C:20]=1[F:27])=[O:7])([CH3:2])([CH3:3])[CH3:4]
Reactant: NCc1cccc(Cl)c1F
Reactant: CC(C)(C)OC(=O)N1C[C@@H](C#N)C[C@H]1C(=O)O
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: O
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N1C[C@@H](C#N)C[C@H]1C(=O)NCc1cccc(Cl)c1F
Temperature: 25 °C
Reaction time: 48 h

Procedure:
To a mixture of (2S,4S)-4-cyano-pyrrolidine-1,2-dicarboxylic acid 1-tert-butyl ester (700 mg, 2.91 mmol), 3-chloro-2-fluorobenzylamine (558 mg, 3.50 mmol), HBTU (1.66 g, 4.37 mmol) in DMF (15 mL) was added DIPEA (1.5 mL, 8.74 mmol) and the resolution mixture was stirred at RT under nitrogen for 48 h. The mixture was poured in water and extracted with EtOAc (2×). The combined organic extracts were washed with water (1×), dried (Na2SO4), filtered and concentrated. The crude material was purified by flash column chromatography (c-hexane to c-hexane/EtOAc 1:1) to give the desired compound. TLC, Rf (c-hexane/EtOAc 1:1)=0.40; MS: 404.0 [M+Na]+, 380.0 [M−H]−, tR (HPLC conditions a): 3.45 min.
Reaction SMILES: [OH:1][B:2]1[C:6]2[CH:7]=[C:8]([OH:12])[CH:9]=[C:10]([CH3:11])[C:5]=2[CH:4]([CH2:13][C:14]([O:16][CH2:17][CH3:18])=[O:15])[O:3]1.Cl[C:20]1[CH:21]=[C:22]([CH:25]=[CH:26][N:27]=1)[C:23]#[N:24].C(=O)([O-])[O-].[Cs+].[Cs+]>CN(C=O)C>[C:23]([C:22]1[CH:25]=[CH:26][N:27]=[C:20]([O:12][C:8]2[CH:9]=[C:10]([CH3:11])[C:5]3[CH:4]([CH2:13][C:14]([O:16][CH2:17][CH3:18])=[O:15])[O:3][B:2]([OH:1])[C:6]=3[CH:7]=2)[CH:21]=1)#[N:24]
Reactant: CCOC(=O)CC1OB(O)c2cc(O)cc(C)c21
Reactant: N#Cc1ccnc(Cl)c1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: CCOC(=O)CC1OB(O)c2cc(Oc3cc(C#N)ccn3)cc(C)c21
Temperature: 25 °C
Reaction time: 8 h
Yield: 55.7 %

Procedure:
To a mixture of ethyl 2-(1,6-dihydroxy-4-methyl-1,3-dihydrobenzo[c][1,2]oxaborol-3-yl)acetate (2 g, 8 mmol, 1 eq.) and 2-chloroisonicotinonitrile (2.78 g, 20 mmol, 2.5 eq.) in 50 ml DMF was added cesium carbonate (7.82 g, 24 mmol, 3 eq.). The reaction was stirred at room temperature overnight, The reaction was then quenched by water, extracted with EtOAc, washed with brine, dried over Na2SO4, and concentrated under reduced pressure. The crude was purified by column chromatography on silica gel (DCM/methanol=39:1 to 19:1) to give desired product as yellow oil (1.57 g, yield 56%). MS (ESI) m/z=353 [M+H]+.