Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [O:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]([O:11][C:12]2[C:20]3[N:19]=[C:18]([CH3:21])[N:17]([CH3:22])[C:16]=3[CH:15]=[C:14]([C:23]([OH:25])=O)[CH:13]=2)[CH2:3][CH2:2]1.[NH:26]1[CH2:30][CH2:29][C@@H:28]([OH:31])[CH2:27]1>>[O:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]([O:11][C:12]2[C:20]3[N:19]=[C:18]([CH3:21])[N:17]([CH3:22])[C:16]=3[CH:15]=[C:14]([C:23]([N:26]3[CH2:30][CH2:29][C@@H:28]([OH:31])[CH2:27]3)=[O:25])[CH:13]=2)[CH2:3][CH2:2]1
Reactant: O[C@@H]1CCNC1
Reactant: Cc1nc2c(OC3CCOc4ccccc43)cc(C(=O)O)cc2n1C
Product: Cc1nc2c(OC3CCOc4ccccc43)cc(C(=O)N3CC[C@@H](O)C3)cc2n1C
Yield: 23 %

Procedure:
The title compound was prepared as a white solid in 23% yield (19 mg) from 4-(3,4-dihydro-2H-chromen-4-yloxy)-1,2-dimethyl-1H-benzimidazole-6-carboxylic acid (70 mg, 0.21 mmol, STEP 2 of Example 11) and (R)-(−)-3-pyrrolidinol (77 mg, 0.63 mmol) by the same manner in STEP 3 of Example 11:
Reaction SMILES: C(Cl)(=O)C(Cl)=O.[C:7]([C:10]1[CH:11]=[CH:12][C:13]([O:19][CH2:20][CH2:21][CH3:22])=[C:14]([CH:18]=1)[C:15]([OH:17])=O)(=[O:9])[CH3:8].[NH2:23][C:24]1[C:25]([C:39]([NH2:41])=[O:40])=[N:26][N:27]([CH2:32][C:33]2[CH:38]=[CH:37][CH:36]=[CH:35][N:34]=2)[C:28]=1[CH2:29][CH2:30][CH3:31]>CN(C)C=O.ClCCl>[C:7]([C:10]1[CH:11]=[CH:12][C:13]([O:19][CH2:20][CH2:21][CH3:22])=[C:14]([CH:18]=1)[C:15]([NH:23][C:24]1[C:25]([C:39]([NH2:41])=[O:40])=[N:26][N:27]([CH2:32][C:33]2[CH:38]=[CH:37][CH:36]=[CH:35][N:34]=2)[C:28]=1[CH2:29][CH2:30][CH3:31])=[O:17])(=[O:9])[CH3:8]
Reactant: CCCc1c(N)c(C(N)=O)nn1Cc1ccccn1
Reactant: CCCOc1ccc(C(C)=O)cc1C(=O)O
Agent: O=C(Cl)C(=O)Cl
Solvent: ClCCl
Solvent: CN(C)C=O
Product: CCCOc1ccc(C(C)=O)cc1C(=O)Nc1c(C(N)=O)nn(Cc2ccccn2)c1CCC
Temperature: 25 °C
Reaction time: 18 h

Procedure:
Oxalyl chloride (1.6 ml, 18 mmol) was added to an ice-cooled solution of 5-acetyl-2-n-propoxybenzoic acid (WO 9312095) (2 g, 9 mmol) in N,N-dimethylformamide (0.2 ml) and dichloromethane (200 ml) under nitrogen. Once addition was complete the solution was allowed to warm to room temperature for 3 hours and the solvent was removed under reduced pressure. The intermediate acid chloride was dissolved in pyridine (50 ml) and 4-amino-5-propyl-1-(pyridin-2-ylmethyl)-1H-pyrazole -3-carboxamide (WO 9954333) (1.5 g, 5.8 mmol) and the reaction was stirred at reflux for 3 hours, then at room temperature for 18 hours. The mixture was partitioned between dilute sodium carbonate solution and dichloromethane, and the organic layer was dried over Na2SO4 and concentrated under reduced pressure. The residue was purified by column chromatography on silica gel using dichloromethane:methanol (100:0 changing to 98:2 then 92:8) to afford the title compound as a beige solid, 1.5 g.
Reaction SMILES: [C:1]1([CH:7]=[CH:8][C:9]([NH:11][CH:12]([C:14]2[CH:15]=[C:16]3[C:21](=[CH:22][CH:23]=2)[NH:20][CH2:19][CH2:18][CH2:17]3)[CH3:13])=[O:10])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[BH4-].[Na+].[CH:26](O)=O>>[CH3:26][N:20]1[C:21]2[C:16](=[CH:15][C:14]([CH:12]([NH:11][C:9](=[O:10])[CH:8]=[CH:7][C:1]3[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=3)[CH3:13])=[CH:23][CH:22]=2)[CH2:17][CH2:18][CH2:19]1
Reactant: O=CO
Reactant: CC(NC(=O)C=Cc1ccccc1)c1ccc2c(c1)CCCN2
Agent: [BH4-]
Agent: [Na+]
Product: CC(NC(=O)C=Cc1ccccc1)c1ccc2c(c1)CCCN2C

Procedure:
Example 256 was prepared from 3-phenyl-N-[1-(1,2,3,4-tetrahydro-quinolin-6-yl)-ethyl]-acrylamide by treatment with formic acid and sodium borohydride following the general procedures described by Gribble et. al. (J. Amer. Chem. Soc., 1974, 7812).
Reaction SMILES: [CH3:1][N:2]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[C:4]([CH:11]=O)=[CH:3]1.[CH3:13][NH2:14]>CO>[CH3:1][N:2]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[C:4]([CH2:11][NH:14][CH3:13])=[CH:3]1
Reactant: CN
Reactant: Cn1cc(C=O)c2ccccc21
Solvent: CO
Product: CNCc1cn(C)c2ccccc12
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of 1-methylindole-3-carboxaldehyde (10.0 g, 62.8 mmole) in MeOH (100 mL) was added a solution of 2.0 M CH3NH2 in MeOH (126 mL, 252.0 mmole). The reaction was stirred at RT for 2 hrs, then was concentrated to a light yellow oil. This oil was dissolved in EtOH (300 mL), and NaB3H4 (2.38 g, 62.8 mmole) was added. After 2 hrs the reaction was concentrated to a slurry and dissolved in 1.0 N NaOH (75 mL). The aqueous solution was extracted with Et2O (2×200 mL) and the combined organic fractions were dried over Na2SO4 and concentrated. Flash chromatography on silica gel (9:1 CHCl3/MeOH containing 5% NH4OH) and drying in high vacuum left the title compound (10.1 g, 92%) as a faintly yellow oil: MS (ES) m/e 175 (M+H)+.
Reaction SMILES: [S:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[CH2:6][OH:7].[Cl:8][C:9]1[CH:14]=[CH:13][CH:12]=[C:11](Cl)[N:10]=1>O1CCOCC1.CCCCCC.C(OCC)(=O)C>[Cl:8][C:9]1[CH:14]=[CH:13][CH:12]=[C:11]([O:7][CH2:6][C:2]2[S:1][CH:5]=[CH:4][CH:3]=2)[N:10]=1
Reactant: OCc1cccs1
Reactant: Clc1cccc(Cl)n1
Solvent: CCCCCC
Solvent: CCOC(C)=O
Solvent: C1COCCO1
Product: Clc1cccc(OCc2cccs2)n1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
K-t-BuO (1.70 g, 15.1 mmol) was added portionwise to a stirred mixture of 2-thiophenemethanol (2.14 g, 18.7 mmol) and 2,6-dichloropyridine (2.13 g, 14.4 mmol) in dioxane (3 mL) at room temperature. An exotermic reaction started and more dioxane (3 mL) was added. After 3 h of stirring at room temperature, the reaction mixture was passed through a column of silica using n-hexane/ethyl acetate (85:15) as eluent. A second purification on silica (16×4 cm) using n-hexane/ethyl acetate (9:1) firnished 3.0 g (93%) of the title compound as a light beige oil. HRMS m/z calcd for C10H8ClNOS (M)+ 225.0015, found 225.0022. Anal. (C10H8CINOS) C, H, N. *Previously described in EP 693490.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][S:4][CH:5]1[C:11]2[CH:12]=[CH:13][CH:14]=[CH:15][C:10]=2[CH2:9][O:8][C:7]2[CH:16]=[CH:17][C:18]([C:20]([O:22][CH3:23])=[O:21])=[CH:19][C:6]1=2.[C:24]1([S:30](Cl)(=[O:32])=[O:31])[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1>N1C=CC=CC=1>[C:24]1([S:30]([NH:1][CH2:2][CH2:3][S:4][CH:5]2[C:11]3[CH:12]=[CH:13][CH:14]=[CH:15][C:10]=3[CH2:9][O:8][C:7]3[CH:16]=[CH:17][C:18]([C:20]([O:22][CH3:23])=[O:21])=[CH:19][C:6]2=3)(=[O:32])=[O:31])[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1
Reactant: COC(=O)c1ccc2c(c1)C(SCCN)c1ccccc1CO2
Reactant: O=S(=O)(Cl)c1ccccc1
Solvent: c1ccncc1
Product: COC(=O)c1ccc2c(c1)C(SCCNS(=O)(=O)c1ccccc1)c1ccccc1CO2
Temperature: 25 °C
Reaction time: 8 h

Procedure:
In 100 ml of pyridine was dissolved 9.00 g of methyl 11-(2-aminoethyl)thio-6,11-dihydrodibenz-[b,e]oxepin-2-carboxylate (Compound f) obtained in Reference Example 6. Under ice cooling, 4.2 ml of benzenesulfonyl chloride was dropwise added to the solution and the mixture was stirred at room temperature overnight. Pieces of ice were added to the mixture. After stirring for further an hour, the solvent was distilled off under reduced pressure. The residue was extracted with 500 ml of ethyl acetate and the extract was washed in sequence with saturated sodium bicarbonate aqueous solution and then with saturated sodium chloride aqueous solution. After drying over anhydrous sodium sulfate, the solvent was distilled off under reduced pressure. The resulting residue was subjected to silica gel column chromatography (eluting solvent; hexane:ethyl acetate=7:3) to give 9.90 g of the desired compound.
Reaction SMILES: [NH2:1][C:2]1[N:12]=[CH:11][CH:10]=[CH:9][C:3]=1[C:4]([O:6][CH2:7][CH3:8])=[O:5].[ClH:13].OO.C([O-])(O)=O.[Na+]>O>[NH2:1][C:2]1[N:12]=[CH:11][C:10]([Cl:13])=[CH:9][C:3]=1[C:4]([O:6][CH2:7][CH3:8])=[O:5]
Reactant: Cl
Reactant: CCOC(=O)c1cccnc1N
Agent: O=C([O-])O
Agent: OO
Agent: [Na+]
Solvent: O
Product: CCOC(=O)c1cc(Cl)cnc1N
Temperature: 25 °C

Procedure:
Ethyl 2-aminonicotinate (121, Example 4) (0.1626 g, 0.9906 mmol) was placed in a 10 mL round-bottom flask. Conc. HCl (35%, 1 mL) was added and the mixture stirred. When all of the ester had dissolved, H2O2 (30%, 0.10 mL, d=1.110, 0.98 mmol) was added. The resulting solution was heated at 55°-60° C. for 2 h. The solution was cooled to room temperature, diluted with water (10 mL), and basified to pH 8 (pH paper) with solid NaHCO3. The mixture was filtered, washed with water (2×10 mL) and dried at 45° C. for 2 h to leave the title compound as a white solid, 0.186 g (93.7%), mp 119.5°-121.5° C.; 1H NMR (CDCl3): δ1.39 (t, J=7.05, 3, CH3 CH2), 4.35 (q, J=7.05, 2, CH3CH2O), 6.44 (bm, 2, NH2), 8.11 (d, J=2.40, 1, py), 8.16 (d, J=2.4, 1, py); IR (KBr): 3448, 3441, 3284, 3161, 1709, 1641, 1402, 1307, 1232, 1150, 1109, 796; HPLC: 100%; LRMS (m/z) 202 (30), 200 (M+, 100), 172 (15), 156 (20), 155 (30), 154 (60) 130 (15), 129 (20), 128 (50), 127 (45), 126 (15), 100 (15), 92 (10), 73 (20) 65 (15), 64 (15); HRMS Calcd: 200.0352. Found: 200.0355.
Reaction SMILES: Br[C:2]1[C:7]([C:8]#[N:9])=[CH:6][N:5]([CH:10]([CH3:27])[C:11]([NH:13][C:14]2[CH:26]=[CH:25][C:17]([C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])=[CH:16][CH:15]=2)=[O:12])[C:4](=[O:28])[CH:3]=1.[Cl:29][C:30]1[CH:31]=[CH:32][C:33]([C:39]([F:42])([F:41])[F:40])=[C:34](B(O)O)[CH:35]=1>>[Cl:29][C:30]1[CH:31]=[CH:32][C:33]([C:39]([F:40])([F:41])[F:42])=[C:34]([C:2]2[C:7]([C:8]#[N:9])=[CH:6][N:5]([CH:10]([CH3:27])[C:11]([NH:13][C:14]3[CH:26]=[CH:25][C:17]([C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])=[CH:16][CH:15]=3)=[O:12])[C:4](=[O:28])[CH:3]=2)[CH:35]=1
Reactant: CC(C(=O)Nc1ccc(C(=O)OC(C)(C)C)cc1)n1cc(C#N)c(Br)cc1=O
Reactant: OB(O)c1cc(Cl)ccc1C(F)(F)F
Product: CC(C(=O)Nc1ccc(C(=O)OC(C)(C)C)cc1)n1cc(C#N)c(-c2cc(Cl)ccc2C(F)(F)F)cc1=O

Procedure:
127 mg (purity 70%, 0.2 mmol) of tert-butyl 4-{[2-(4-bromo-5-cyano-2-oxopyridin-1(2H)-yl)propanoyl]amino}benzoate (racemate) and 54 mg (0.24 mmol) of 5-chloro-2-trifluoromethylphenylboronic acid in the presence of [1,1-bis(diphenylphosphino)ferrocene]palladium(II) chloride/dichloromethane monoadduct were reacted according to General Method 2A. After aqueous work-up, the crude product was triturated with water and the solid was filtered off, dried and purified further by flash chromatography (silica gel 60, mobile phase: cyclohexane/ethyl acetate mixtures). Yield: 124 mg (quant.)
Reaction SMILES: [C:1]([O:4][CH:5]([C:18]([O-:20])=[O:19])[C@@H:6]([C:15]([O-:17])=[O:16])[NH:7]C(OC(C)(C)C)=O)(=[O:3])[CH3:2].FC(F)(F)C(O)=O>C(Cl)(Cl)Cl>[C:1]([O:4][CH:5]([C:18]([OH:20])=[O:19])[C@@H:6]([C:15]([OH:17])=[O:16])[NH2:7])(=[O:3])[CH3:2]
Reactant: CC(=O)OC(C(=O)[O-])[C@H](NC(=O)OC(C)(C)C)C(=O)[O-]
Solvent: ClC(Cl)Cl
Solvent: O=C(O)C(F)(F)F
Product: CC(=O)OC(C(=O)O)[C@H](N)C(=O)O
Temperature: 25 °C
Reaction time: 20 h
Yield: 45 %

Procedure:
To a solution of 202 mg (0.50 mmol) of the compound (4) obtained in Step 2 in chloroform (2 ml) was added 2 ml of trifluoroacetic acid, and the mixture was stirred at room temperature for 20 hours. The solvent was distilled off and the residue was purified by C18 silica gel column chromatography (RP-C18, distilled water) to give 43 mg of the title compound (9) (yield 45%).
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][C:9]=1[N+:10]([O-])=O)[CH2:5][OH:6]>C(O)C.[Pd]>[OH:6][CH2:5][C:4]1[CH:7]=[CH:8][C:9]([NH2:10])=[C:2]([CH3:1])[CH:3]=1
Reactant: Cc1cc(CO)ccc1[N+](=O)[O-]
Agent: [Pd]
Solvent: CCO
Product: Cc1cc(CO)ccc1N
Yield: 98.8 %

Procedure:
A solution of 3-methyl-4-nitrobenzyl alcohol (compound 12-1, 8.5 g, 50.9 mmol) in ethanol (100 mL) was stirred at room temperature, while 10% Pd/C (1.0 g) was added in one portion. The resulting suspension was hydrogenated (10 psi) in a Parr apparatus at room temperature for 1.5 hours. The catalyst was removed by filtration, and solvent was evaporated under vacuum to give the title compound (12-2, 6.9 g, 99%). MS (electrospray) 138 (M+1); 1H N MR (CDCl3) δ2.16 (s, 3H), 2.72 (br s, 3H), 4.52 (s, 2H), 6.64 (d, 1H, J=8.0 Hz), 7.02 (d, 1H, J=8.0 Hz), 7.05 (s, 1H).
Reaction SMILES: [NH2:1][CH2:2][C@H:3]1[CH2:8][CH2:7][C@H:6]([C:9]([OH:11])=[O:10])[CH2:5][CH2:4]1.[CH3:12]O>Cl>[NH2:1][CH2:2][C@H:3]1[CH2:4][CH2:5][C@H:6]([C:9]([O:11][CH3:12])=[O:10])[CH2:7][CH2:8]1
Reactant: CO
Reactant: NC[C@H]1CC[C@H](C(=O)O)CC1
Agent: Cl
Product: COC(=O)[C@H]1CC[C@H](CN)CC1

Procedure:
A solution of 15.7 g of trans-4-(aminomethyl)-cyclohexanecarboxylic acid in 150 ml of ethereal hydrochloric acid and 1000 ml of absolute methanol is stirred at room temperature for 20 hours. The solvent is evaporated off under reduced pressure and the residue is triturated with ether and filtered off with suction.
Reaction SMILES: [N:1]([CH2:4][C:5]1[CH:15]=[CH:14][C:8]([C:9]([NH:11][O:12][CH3:13])=[NH:10])=[CH:7][CH:6]=1)=[N+]=[N-]>C(O)C.O=[Pt]=O>[NH2:1][CH2:4][C:5]1[CH:15]=[CH:14][C:8]([C:9]([NH:11][O:12][CH3:13])=[NH:10])=[CH:7][CH:6]=1
Reactant: CONC(=N)c1ccc(CN=[N+]=[N-])cc1
Agent: O=[Pt]=O
Solvent: CCO
Product: CONC(=N)c1ccc(CN)cc1

Procedure:
To a solution of 4-azidomethyl-N-methoxy-benzamidine (11.3 g, 0.055 mol; see step (i) above) in 200 mL of ethanol was added 200 mg of PtO2. The mixture was hydrogenated with constant bubbling of hydrogen for 4 h and subsequently filtered through Celite® and evaporated. Yield: 7.34 g (74%).
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([CH:8]([S:10]([CH2:12][C:13]([OH:15])=[O:14])=[O:11])[CH3:9])[CH:5]=[CH:4][C:3]=1[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1.CO.[CH:24]1(N=C=NC2CCCCC2)CCCCC1>C1C=CC=CC=1>[CH3:24][O:14][C:13](=[O:15])[CH2:12][S:10]([CH:8]([C:6]1[CH:5]=[CH:4][C:3]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)=[C:2]([F:1])[CH:7]=1)[CH3:9])=[O:11]
Reactant: CC(c1ccc(-c2ccccc2)c(F)c1)S(=O)CC(=O)O
Reactant: C(=NC1CCCCC1)=NC1CCCCC1
Solvent: CO
Solvent: c1ccccc1
Product: COC(=O)CS(=O)C(C)c1ccc(-c2ccccc2)c(F)c1
Reaction time: 1 h

Procedure:
A solution of 1.53 gm (5 millimols) of [1-(2-fluoro-4-biphenylyl)-ethylsulfinyl]-acetic acid, m.p. 161°-163° C, in 15 ml of benzene was admixed with 0.24 gm (7.5 millimols) of methanol, and then a solution of 1.25 gm (6 millimols) of dicyclohexyl-carbodiimide in 5 ml of benzene was added. After stirring for one hour, the precipitated dicyclohexylurea was suction-filtered off, the filtrate was evaporated, and the residue was purified by chromatography on 300 gm of silicagel with cyclohexane/ethyl acetate = 1/4. Yield: 1.4 gm (87.6% of theory); oil, Rf -value: 0.5 on carrier 1 with cyclohexane/ethyl acetate = 1/4.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]2[O:8][CH2:9][C:10]([CH2:12][O:13][C:4]=2[CH:3]=1)=[O:11].[CH3:14][N:15]([CH3:28])[C:16]1[C:25]2[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=2)[C:19]([CH:26]=O)=[CH:18][CH:17]=1>>[CH3:14][N:15]([CH3:28])[C:16]1[C:25]2[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=2)[C:19](/[CH:26]=[C:9]2/[C:10](=[O:11])/[C:12](=[CH:26]/[C:19]3[C:20]4[C:25](=[CH:24][CH:23]=[CH:22][CH:21]=4)[C:16]([N:15]([CH3:14])[CH3:28])=[CH:17][CH:18]=3)/[O:13][C:4]3[CH:3]=[C:2]([CH3:1])[CH:7]=[CH:6][C:5]=3[O:8]/2)=[CH:18][CH:17]=1
Reactant: Cc1ccc2c(c1)OCC(=O)CO2
Reactant: CN(C)c1ccc(C=O)c2ccccc12
Product: Cc1ccc2c(c1)O/C(=C\c1ccc(N(C)C)c3ccccc13)C(=O)/C(=C/c1ccc(N(C)C)c3ccccc13)O2

Procedure:
Calone is reacted with 4-dimethylaminonaphthalene-1-carbaldehyde analogously to the reaction conditions of Example 1, giving 2,4-bis[1-(4-dimethylaminonaphthalen-1-yl)meth-(Z)-ylidene]-7-methylbenzo[b]-1,4-dioxepin-3-one.
Reaction SMILES: Cl.[F:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[N:13]=[C:12]([CH:14]3[O:19][CH2:18][CH2:17][NH:16][CH2:15]3)[O:11][N:10]=2)=[CH:5][CH:4]=1.C(N(CC)CC)C.[F:27][C:28]1[CH:36]=[CH:35][C:31]([C:32](Cl)=[O:33])=[CH:30][CH:29]=1.Cl>ClCCl>[F:27][C:28]1[CH:36]=[CH:35][C:31]([C:32]([N:16]2[CH2:17][CH2:18][O:19][CH:14]([C:12]3[O:11][N:10]=[C:9]([C:6]4[CH:7]=[CH:8][C:3]([F:2])=[CH:4][CH:5]=4)[N:13]=3)[CH2:15]2)=[O:33])=[CH:30][CH:29]=1
Reactant: Fc1ccc(-c2noc(C3CNCCO3)n2)cc1
Reactant: O=C(Cl)c1ccc(F)cc1
Agent: Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: O=C(c1ccc(F)cc1)N1CCOC(c2nc(-c3ccc(F)cc3)no2)C1
Temperature: 25 °C
Reaction time: 8 h
Yield: 61 %

Procedure:
To a suspension of 2-[3-(4-fluoro-phenyl)-[1,2,4]oxadiazol-5-yl]-morpholine hydrochloride (0.15 g, 0.53 mmol) in anhydrous dichloromethane (6 mL), under nitrogen atmosphere, triethylamine (155 mL, 1.1 mmol) and 4-fluorobenzoyl chloride (62 mL, 0.53 mmol) were subsequently added at 0° C. The reaction mixture was allowed to warm at room temperature and stirred overnight. HCl 1N (6 mL) was added and the phases were separated. The organic layer was washed sequentially with HCl 1N (6 mL), NaOH 1N (6 mL×2 times) and with water, then was dried over sodium sulphate and evaporated under reduced pressure. The crude was purified by flash chromatography (silica gel, eluent: hexane/ethyl acetate 7/3) to afford 120 mg of (4-fluoro-phenyl)-{2-[3-(4-fluoro-phenyl)-[1,2,4]oxadiazol-5-yl]-morpholin-4-yl}-methanone as a white solid.
Reaction SMILES: [NH:1]1[CH2:4][CH:3]([O:5][C:6]2[CH:11]=[CH:10][C:9]([N:12]3[CH2:17][CH2:16][C:15]4[N:18]=[C:19]([C:21]5[CH:26]=[CH:25][C:24]([Cl:27])=[CH:23][CH:22]=5)[S:20][C:14]=4[C:13]3=[O:28])=[CH:8][C:7]=2[O:29][CH3:30])[CH2:2]1.[F:31][C:32]([F:38])([F:37])[CH2:33][C:34](Cl)=[O:35]>N1C=CC=CC=1>[Cl:27][C:24]1[CH:23]=[CH:22][C:21]([C:19]2[S:20][C:14]3[C:13](=[O:28])[N:12]([C:9]4[CH:10]=[CH:11][C:6]([O:5][CH:3]5[CH2:4][N:1]([C:34](=[O:35])[CH2:33][C:32]([F:38])([F:37])[F:31])[CH2:2]5)=[C:7]([O:29][CH3:30])[CH:8]=4)[CH2:17][CH2:16][C:15]=3[N:18]=2)=[CH:26][CH:25]=1
Reactant: O=C(Cl)CC(F)(F)F
Reactant: COc1cc(N2CCc3nc(-c4ccc(Cl)cc4)sc3C2=O)ccc1OC1CNC1
Solvent: c1ccncc1
Product: COc1cc(N2CCc3nc(-c4ccc(Cl)cc4)sc3C2=O)ccc1OC1CN(C(=O)CC(F)(F)F)C1
Yield: 70.5 %

Procedure:
Dissolve 5-[4-(azetidin-3-yloxy)-3-methoxy-phenyl]-2-(4-chloro-phenyl)-6,7-dihydro-5H-thiazolo[5,4-c]pyridin-4-one (100 mg, 0.226 mmol), and 3,3,3-trifluoropropionyl chloride (137 mg, 0.905 mmol) in dry pyridine (754.3 μL). Add 4-N,N-dimethylpyridine (2.9 mg, 0.0226 mmol) and stir the solution overnight. Add NaHSO4 solution and extract with EtOAc (2×20 mL). Combine the organic portions and wash with water (10 mL). Dry the organic solution with Na2SO4, filter, and concentrate in vacuo. Purify the crude material on silica gel chromatography, using an isocratic gradient of 80% EtOAc in hexanes, to give 88 mg (70%) of the title compound as a yellow solid. ES/MS m/z (35Cl) 552.8 [M+1]−.
Reaction SMILES: [Br:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=O)=[C:4]([F:11])[CH:3]=1.[CH:12]1([NH2:15])[CH2:14][CH2:13]1>>[Br:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([NH:15][CH:12]2[CH2:14][CH2:13]2)=[O:8])=[C:4]([F:11])[CH:3]=1
Reactant: O=C(O)c1ccc(Br)cc1F
Reactant: NC1CC1
Product: O=C(NC1CC1)c1ccc(Br)cc1F

Procedure:
The sub-title compound was prepared by the method of example 18 step a) using) 4-bromo-2-fluorobenzoic acid, and cyclopropylamine.
Reaction SMILES: C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OCC)=O)=NC(OCC)=O.[F:32][C:33]1[CH:57]=[CH:56][CH:55]=[CH:54][C:34]=1[O:35][C:36]1[N:37]=[CH:38][C:39]2[N:44]=[C:43]([C:45]3[CH:50]=[C:49]([CH3:51])[C:48]([OH:52])=[C:47]([CH3:53])[CH:46]=3)[O:42][C:40]=2[N:41]=1.O[CH:59]1[CH2:62][CH:61]([C:63]([O:65][CH2:66][C:67]2[CH:72]=[CH:71][CH:70]=[CH:69][CH:68]=2)=[O:64])[CH2:60]1>O1CCCC1.C(N(CC)CC)C>[F:32][C:33]1[CH:57]=[CH:56][CH:55]=[CH:54][C:34]=1[O:35][C:36]1[N:37]=[CH:38][C:39]2[N:44]=[C:43]([C:45]3[CH:46]=[C:47]([CH3:53])[C:48]([O:52][CH:59]4[CH2:62][CH:61]([C:63]([O:65][CH2:66][C:67]5[CH:68]=[CH:69][CH:70]=[CH:71][CH:72]=5)=[O:64])[CH2:60]4)=[C:49]([CH3:51])[CH:50]=3)[O:42][C:40]=2[N:41]=1
Reactant: O=C(OCc1ccccc1)C1CC(O)C1
Reactant: Cc1cc(-c2nc3cnc(Oc4ccccc4F)nc3o2)cc(C)c1O
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: Cc1cc(-c2nc3cnc(Oc4ccccc4F)nc3o2)cc(C)c1OC1CC(C(=O)OCc2ccccc2)C1
Reaction time: 0.25 h

Procedure:
At 0° C., 179 mg of triphenylphosphine and 107 μl of diethyl azodicarboxylate were initially charged in 4.5 ml of tetrahydrofuran, and the mixture was stirred for 15 min. 200 mg of 4-[5-(2-fluorophenoxy)oxazolo[5,4-d]pyrimidin-2-yl]-2,6-dimethylphenol, 95 μl of triethylamine and 141 mg of benzyl 3-hydroxycyclobutanecarboxylate were then added to the reaction, and the reaction was stirred under argon, initially at room temperature for 3 h. Another 179 mg of triphenylphosphine and 107 μl of diethyl azodicarboxylate were then added, and the reaction was stirred for 12 h. For work-up, the reaction was concentrated and the resulting residue was purified by flash chromatography (silica gel, heptane/ethyl acetate). This gave 216 mg (70%) of the title compound.
Reaction SMILES: [C:1](O)(=[O:3])C.C(O)=O.C1COCC1.[CH3:13][O:14][C:15](=[O:25])[C:16]1[CH:21]=[CH:20][C:19]([NH2:22])=[C:18]([O:23][CH3:24])[CH:17]=1>O>[CH3:13][O:14][C:15](=[O:25])[C:16]1[CH:21]=[CH:20][C:19]([NH:22][CH:1]=[O:3])=[C:18]([O:23][CH3:24])[CH:17]=1
Reactant: CC(=O)O
Reactant: COC(=O)c1ccc(N)c(OC)c1
Solvent: C1CCOC1
Solvent: O=CO
Solvent: O
Product: COC(=O)c1ccc(NC=O)c(OC)c1
Temperature: 25 °C
Reaction time: 0.67 h

Procedure:
Anhydrous acetic acid (268 mL) was added dropwise to formic acid (401 mL) at room temperature, and the reaction solution was agitated for 40 minutes at room temperature. To this reaction solution, a THF (600 mL) solution of 4-amino-3-methoxybenzoic acid methyl ester (134 g) was added dropwise at room temperature, and the reaction solution was agitated for 1 hour. 3.8 L of iced water was added to the reaction solution, and the deposited solids were separated by filtering, and further washed with water (2 L). 111 g of the title compound was obtained by drying the obtained solid at 50° C. overnight. The physical properties was in agreement with the reported values (CAS#700834-18-0).
Reaction SMILES: Br[C:2]1[C:11]([NH:12][C:13](=[O:18])[C:14]([F:17])([F:16])[F:15])=[CH:10][C:9]([F:19])=[CH:8][C:3]=1[C:4]([O:6][CH3:7])=[O:5].[C:20]([C@@:22]1([CH3:37])[CH2:26][CH2:25][CH2:24][N:23]1[C:27]([O:29][CH2:30][C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1)=[O:28])#[CH:21].CN(C)C(=N)N(C)C>CN(C=O)C.CC(=O)OCC.O.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.[Cu]I>[F:19][C:9]1[CH:10]=[C:11]([NH:12][C:13](=[O:18])[C:14]([F:17])([F:16])[F:15])[C:2]([C:21]#[C:20][C@@:22]2([CH3:37])[CH2:26][CH2:25][CH2:24][N:23]2[C:27]([O:29][CH2:30][C:31]2[CH:32]=[CH:33][CH:34]=[CH:35][CH:36]=2)=[O:28])=[C:3]([C:4]([O:6][CH3:7])=[O:5])[CH:8]=1
Reactant: COC(=O)c1cc(F)cc(NC(=O)C(F)(F)F)c1Br
Reactant: C#C[C@@]1(C)CCCN1C(=O)OCc1ccccc1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Agent: CN(C)C(=N)N(C)C
Solvent: CCOC(C)=O
Solvent: O
Solvent: CN(C)C=O
Product: COC(=O)c1cc(F)cc(NC(=O)C(F)(F)F)c1C#C[C@@]1(C)CCCN1C(=O)OCc1ccccc1
Temperature: 80 °C
Yield: 51.8 %

Procedure:
A mixture of methyl 2-bromo-5-fluoro-3-(2,2,2-trifluoroacetamido)benzoate (27.52 g, 80 mmol), (PPh3)2PdCl2 (2.8 g, 4 mmol), (R)-benzyl 2-ethynyl-2-methylpyrrolidine-1-carboxylate (19.44 g, 80 mmol), copper(I) iodide (764 mg, 4 mmol) and tetramethylguanidine (27.6 g, 240 mmol) in DMF (200 mL) was heated at 80° C. with nitrogen protection system for 16 hours. The cooled reaction mixture was diluted with EA (3×200 mL) and water (800 mL). The organic layer was separated, washed with water (2×200 mL), dried (Na2SO4), and concentrated. The remaining residue was chromatographed on silica gel, eluted with gradient 0-30% EtOAc in hexane to give the product (R)-benzyl 2-((4-fluoro-2-(methoxycarbonyl)-6-(2,2,2trifluoroacetamido)phenyl)ethynyl)-2-methylpyrrolidine-1-carboxylate (21 g, 53%) as white solid. 1H NMR (DMSO-d1) δ 11.01 (s, 1H), 7.64-7.77 (m, 1H), 7.36 (m, 5H), 7.19-7.31 (m, 1H), 5.04-5.12 (m, 2H), 3.85 (s, 3H), 3.44-3.47 (m, 2H), 2.0-2.29 (m, 2H), 1.90-1.97 (m, 2H), and 1.69 (s, 3H). MS (ESI) m/e [M+1]+ 507.0.