Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([F:8])[C:3]=1[C:9]1[N:14]=[C:13]([C:15]([O:17]C)=[O:16])[CH:12]=[CH:11][C:10]=1[F:19].O.[OH-].[Li+].C1COCC1.Cl>O>[F:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([F:8])[C:3]=1[C:9]1[N:14]=[C:13]([C:15]([OH:17])=[O:16])[CH:12]=[CH:11][C:10]=1[F:19]
Reactant: COC(=O)c1ccc(F)c(-c2c(F)cccc2F)n1
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: O=C(O)c1ccc(F)c(-c2c(F)cccc2F)n1
Temperature: 50 °C
Yield: 81.4 %

Procedure:
To a mixture of methyl 6-(2,6-difluorophenyl)-5-fluoropyridine-2-carboxylate (210.2 mg, 0.7867 mmol) and lithium hydroxide, monohydrate (162 mg, 3.86 mmol), THF (3.0 mL) was added followed by water (1.0 mL). The mixture was heated at 50° C. for 3 h. The reaction mixture was then cooled to 0° C., and 1 M HCl was added slowly until the pH reached 2. The reaction mixture was then diluted with water (20 mL), extracted with EtOAc (3×20 mL) and the combined organic layers were washed with brine (30 mL), dried over Na2SO4, and concentrated under reduced pressure to yield the sub-title compound as a white solid (162.1 mg, 81%). LCMS calc. for C12H7F3NO2 (M+H)+: m/z=254.0. found 254.0.
Reaction SMILES: [S:1]1[CH2:6][CH2:5][CH2:4][S:3][CH:2]1[C:7]1[N:11]([CH3:12])[CH:10]=[N:9][CH:8]=1.[Li]CCCC.[C:18]1(=[O:23])[O:22][CH2:21][CH:20]=[CH:19]1.O>O1CCCC1.CCCCCC.C(O)(=O)C>[CH3:12][N:11]1[C:7]([C:2]2([CH:20]3[CH2:21][O:22][C:18](=[O:23])[CH2:19]3)[S:3][CH2:4][CH2:5][CH2:6][S:1]2)=[CH:8][N:9]=[CH:10]1
Reactant: Cn1cncc1C1SCCCS1
Reactant: O=C1C=CCO1
Agent: [Li]CCCC
Solvent: O
Solvent: CCCCCC
Solvent: CC(=O)O
Product: Cn1cncc1C1(C2COC(=O)C2)SCCCS1
Temperature: -78 °C
Reaction time: 1.5 h
Yield: 27.3 %

Procedure:
6.9 g (40 mmol) of 5-(1,3-dithian-2-yl)-1-methylimidazole are dissolved in 190 ml of tetrahydrofuran and cooled to -78° C. 40 mmol of n-BuLi in 24 ml of hexane are added dropwise to this and, after 30 minutes, at -78° C., 3.8 ml (54 mmol) of γ-crotonolactone are added. After a further 1.5 hours at -78° C., 190 ml of water are added dropwise, and the mixture is warmed to room temperature. It is subsequently acidified with glacial acetic acid, the organic layer is separated off, and the aqueous phase is washed several times with ethyl acetate. The combined organic extracts are dried over magnesium sulfate and subsequently concentrated in vacuo. The residue is chromatographed on silica gel with dichloromethane/methanol (9:1). 3.1 g (10.9 mmol, 27%) of 3-(2-(1-methylimidazol-5-yl)-1,3-dithian-2-yl)butyrolactone are obtained as a yellow oil in this way.
Reaction SMILES: Cl[C:2]1[C:7]([S:8]([C:11]2[CH:16]=[CH:15][C:14]([O:17][CH3:18])=[CH:13][CH:12]=2)(=[O:10])=[O:9])=[CH:6][N:5]=[C:4]([CH3:19])[N:3]=1.CC([O-])=O.[Na+].C(O)C>[Pd].C1(C)C=CC=CC=1>[CH3:18][O:17][C:14]1[CH:13]=[CH:12][C:11]([S:8]([C:7]2[CH:6]=[N:5][C:4]([CH3:19])=[N:3][CH:2]=2)(=[O:9])=[O:10])=[CH:16][CH:15]=1
Reactant: COc1ccc(S(=O)(=O)c2cnc(C)nc2Cl)cc1
Agent: [Pd]
Agent: CC(=O)[O-]
Agent: [Na+]
Solvent: CCO
Solvent: Cc1ccccc1
Product: COc1ccc(S(=O)(=O)c2cnc(C)nc2)cc1
Yield: 83.4 %

Procedure:
A mixture of 4-chloro-5-(4-methoxy-benzenesulfonyl)-2-methylpyrimidine (468 mg, 1.57 mmol), prepared by the method described in example 1 part E, 10% Pd/C (50 mg), NaOAc (128 mg, 1.57 mmol), ethanol (5 mL) and toluene (15 mL) was hydrogenated at 40 psi (Parr Shaker Apparatus) overnight. The mixture was filtered through a pad of silica gel, and washed with EtOAc. The filtrate was concentrated in vacuo and the residue was purified by chromatography on silica gel (67:33 hexanes/EtOAc) to provide 5-(4-methoxy-benzenesulfonyl)-2-methylpyrimidine (346 mg, 84%) as a white solid: 1H NMR (500 MHz, CDCl3) δ 9.06 (s, 2H), 7.90 (d, J=9.9 Hz, 2H), 7.01 (d, J=9.9 Hz, 2H), 3.88 (s, 3H), 2.80 (s, 3H); ESI MS m/z 265 [(M+H)+, calcd for C12H13N2O3S, 265.1].
Reaction SMILES: [CH3:1][C:2]([CH3:8])([CH2:6][OH:7])[C:3](=[O:5])[CH3:4].Cl[C:10]1[C:15]([Cl:16])=[CH:14][C:13]([C:17]([F:20])([F:19])[F:18])=[CH:12][N:11]=1.C(=O)([O-])[O-].[K+].[K+]>CS(C)=O>[CH3:1][C:2]([CH3:8])([CH2:6][O:7][C:10]1[C:15]([Cl:16])=[CH:14][C:13]([C:17]([F:20])([F:18])[F:19])=[CH:12][N:11]=1)[C:3](=[O:5])[CH3:4]
Reactant: CC(=O)C(C)(C)CO
Reactant: FC(F)(F)c1cnc(Cl)c(Cl)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CS(C)=O
Product: CC(=O)C(C)(C)COc1ncc(C(F)(F)F)cc1Cl
Temperature: 115 °C
Reaction time: 0.33 h
Yield: 93.7 %

Procedure:
3,3-Dimethyl-4-hydroxybutan-2-one (11.2 g) was dissolved in 50 ml of dimethyl sulfoxide, and nitrogen gas was passed therethrough for 20 minutes. Then, 21.6 g of 2,3-dichloro-5-trifluoromethylpyridine and 15 g of anhydrous potassium carbonate were added thereto, and the system was gradually heated to 115° C. and stirred for 4 hours at that temperature. After completion of the reaction, the product was put into ice water, extracted with methylene chloride, washed with water and dried over Glauber's salt. The solvent was distilled off to give 26.7 g of oily 3,3-dimethyl-4-(3-chloro-5trifluoromethylpyridine-2-yloxy)butan-2-one.
Reaction SMILES: [OH-].[K+].[CH2:3]([O:10][C:11]1[CH:21]=[CH:20][C:14]([C:15]([O:17]CC)=[O:16])=[CH:13][CH:12]=1)[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1>CO>[CH2:3]([O:10][C:11]1[CH:12]=[CH:13][C:14]([C:15]([OH:17])=[O:16])=[CH:20][CH:21]=1)[C:4]1[CH:5]=[CH:6][CH:7]=[CH:8][CH:9]=1
Reactant: CCOC(=O)c1ccc(OCc2ccccc2)cc1
Agent: [K+]
Agent: [OH-]
Solvent: CO
Product: O=C(O)c1ccc(OCc2ccccc2)cc1

Procedure:
To the solution of 0.5 g KOH in 40 ml MeOH, was added 6.5 mmol of ethyl 4-benzyloxybenzoate. After the resulting mixture was refluxed for 4 hrs, the excess methanol was removed. The residue was mixed with 30 ml water and extracted with ether twice. The water solution was acidified with conc. HCl and extracted with ethyl acetate. The ethyl acetate solution was washed with brine and dried. After evaporation of solvent, pure product was obtained in quantitative yield.
Reaction SMILES: [NH:1]([C:3]1[CH2:9][N:8]=[C:7]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[C:6]2[CH:16]=[CH:17][CH:18]=[CH:19][C:5]=2[N:4]=1)[NH2:2].[CH:20]([O-])([O-])OCC.S(=O)(=O)(O)O.C(=O)(O)[O-].[Na+]>C(O)C>[C:10]1([C:7]2[C:6]3[CH:16]=[CH:17][CH:18]=[CH:19][C:5]=3[N:4]3[CH:20]=[N:2][N:1]=[C:3]3[CH2:9][N:8]=2)[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1
Reactant: NNC1=Nc2ccccc2C(c2ccccc2)=NC1
Reactant: CCOC([O-])[O-]
Agent: O=C([O-])O
Agent: O=S(=O)(O)O
Agent: [Na+]
Solvent: CCO
Product: c1ccc(C2=NCc3nncn3-c3ccccc32)cc1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a mixture of 1 part of 2-hydrazino-5-phenyl-3H-1,4-benzodiazepine, prepared in Example 3, 2 parts by volume of ethyl orthoformate and 20 parts by volume of ethanol, 0.44 part by volume of concentrated sulfuric acid is added dropwise with ice-cooling. The mixture is stirred at room temperature for 30 minutes and neutralized with saturated aqueous sodium bicarbonate. The resulting oily substance is extracted with methylene chloride. The methylene chloride layer is washed with water, dried over sodium sulfate and the solvent is evaporated, whereby 6-phenyl-4H-s-triazolo [4,3-a] [1,4] benzodiazepine is yielded as crystals. Recrystallization from a mixture of acetone and n-hexane yields colorless needles melting at 195° C to 196° C.
Reaction SMILES: [NH2:1][CH:2]1[N:8]=[C:7]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[C:6]2[CH:15]=[CH:16][CH:17]=[CH:18][C:5]=2[N:4]([CH2:19][C:20](=[O:27])[C:21]2[CH:26]=[CH:25][CH:24]=[N:23][CH:22]=2)[C:3]1=[O:28].[C:29]1([CH3:38])[CH:34]=[CH:33][CH:32]=[C:31]([N:35]=[C:36]=[O:37])[CH:30]=1>>[C:20]([CH2:19][N:4]1[C:5]2[CH:18]=[CH:17][CH:16]=[CH:15][C:6]=2[C:7]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)=[N:8][CH:2]([NH:1][C:36]([NH:35][C:31]2[CH:30]=[C:29]([CH3:38])[CH:34]=[CH:33][CH:32]=2)=[O:37])[C:3]1=[O:28])(=[O:27])[C:21]1[CH:26]=[CH:25][CH:24]=[N:23][CH:22]=1
Reactant: NC1N=C(c2ccccc2)c2ccccc2N(CC(=O)c2cccnc2)C1=O
Reactant: Cc1cccc(N=C=O)c1
Product: Cc1cccc(NC(=O)NC2N=C(c3ccccc3)c3ccccc3N(CC(=O)c3cccnc3)C2=O)c1

Procedure:
3-Amino-1,3-dihydro-1-nicotinoylmethyl-5-phenyl-2H-1,4-benzodiazepin-2-one, and 3-tolyl isocyanate
Reaction SMILES: [F:1][CH:2]([F:9])[C:3]1[CH:8]=[CH:7][N:6]=[CH:5][CH:4]=1.ClC1C=CC=C(C(OO)=[O:18])C=1>C(Cl)Cl>[F:1][CH:2]([F:9])[C:3]1[CH:8]=[CH:7][N+:6]([O-:18])=[CH:5][CH:4]=1
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: FC(F)c1ccncc1
Solvent: ClCCl
Product: [O-][n+]1ccc(C(F)F)cc1
Reaction time: 20.5 h
Yield: 100.1 %

Procedure:
To a stirring solution of 4-difluoromethylpyridine (5.00 g, 38.7 mmol) in CH2Cl2 (77 mL, 0.5 M) at 0° C. was added 77% meta-chloroperbenzoic acid (10.7 g, 46.5 mmol) and the ice bath was removed and stirring continued for 20.5 hr. The reaction mixture was concentrated to dryness and reaction residue purified by flash column chromatography (100:0-95:5 CH2Cl2/MeOH) to afford 4-difluoromethyl-pyridine-N-oxide as a colorless solid (5.62 g, >99%); 1H NMR (400 MHz, CDCl3) δ 8.26 (d, J=6.4 Hz, 2H), 7.40 (d, J=6.4 Hz, 2H), 6.63 (t, J=55.7 Hz, 1H).
Reaction SMILES: Cl[C:2]1[CH:3]=[C:4]2[N:11]([CH3:12])[CH2:10][CH2:9][N:5]2[C:6](=[O:8])[N:7]=1.[H-].[Na+].[F:15][C:16]1[CH:17]=[C:18]([CH2:35][OH:36])[CH:19]=[C:20]([F:34])[C:21]=1[O:22][C:23]1[CH:28]=[CH:27][C:26]([F:29])=[C:25]([C:30]([F:33])([F:32])[F:31])[CH:24]=1>CN(C=O)C>[F:15][C:16]1[CH:17]=[C:18]([CH:19]=[C:20]([F:34])[C:21]=1[O:22][C:23]1[CH:28]=[CH:27][C:26]([F:29])=[C:25]([C:30]([F:33])([F:31])[F:32])[CH:24]=1)[CH2:35][O:36][C:2]1[CH:3]=[C:4]2[N:11]([CH3:12])[CH2:10][CH2:9][N:5]2[C:6](=[O:8])[N:7]=1
Reactant: CN1CCn2c1cc(Cl)nc2=O
Reactant: OCc1cc(F)c(Oc2ccc(F)c(C(F)(F)F)c2)c(F)c1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CN1CCn2c1cc(OCc1cc(F)c(Oc3ccc(F)c(C(F)(F)F)c3)c(F)c1)nc2=O

Procedure:
Prepared in a manner similar to that described for E1 using 7-chloro-1-methyl-2,3-dihydroimidazo[1,2-c]pyrimidin-5(1H)-one (30 mg, 0.162 mmol), sodium hydride (12.93 mg, 0.323 mmol) and (3,5-difluoro-4-(4-fluoro-3-(trifluoromethyl)pheno-xy)phenyl)m-ethanol (52.1 mg, 0.162 mmol) in DMF (1.5 ml).
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([O:12][CH3:13])[CH:10]=2)[N:5]=[C:4]([C:14]([O:16][CH2:17][CH3:18])=[O:15])[N:3]=1.[C:19]([O:23][C:24]([NH:26][C@H:27]1[CH2:32][CH2:31][CH2:30][CH2:29][C@H:28]1[NH2:33])=[O:25])([CH3:22])([CH3:21])[CH3:20].C(N(CC)CC)C>C1(C)C=CC=CC=1>[C:19]([O:23][C:24]([NH:26][C@@H:27]1[CH2:32][CH2:31][CH2:30][CH2:29][C@@H:28]1[NH:33][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([O:12][CH3:13])[CH:10]=2)[N:5]=[C:4]([C:14]([O:16][CH2:17][CH3:18])=[O:15])[N:3]=1)=[O:25])([CH3:22])([CH3:20])[CH3:21]
Reactant: CCOC(=O)c1nc(Cl)c2cc(OC)ccc2n1
Reactant: CC(C)(C)OC(=O)N[C@H]1CCCC[C@H]1N
Solvent: Cc1ccccc1
Solvent: CCN(CC)CC
Product: CCOC(=O)c1nc(N[C@H]2CCCC[C@H]2NC(=O)OC(C)(C)C)c2cc(OC)ccc2n1
Yield: 82.6 %

Procedure:
A solution of 1.96 g of 4-chloro-2-ethoxycarbonyl-6-methoxyquinazoline in 70 mL of toluene was combined with 1.58 g of cis-2-tert-butoxycarbonylaminocyclohexylamine and 0.74 g of triethylamine, and heated under reflux for 15 hours. After concentrating, the mixture was combined with water, extracted with chloroform, and dried. After the solvent was distilled off, the residue was purified by column chromatography on silica gel (chloroform) to obtain 2.70 g of the desirable compound.
Reaction SMILES: [CH2:1]1[C:14]2[C:5](=[N:6][C:7]3[C:12]([C:13]=2[NH2:15])=[CH:11][CH:10]=[CH:9][CH:8]=3)[CH2:4][CH2:3][CH2:2]1.N1CCOCC1.[F:22][C:23]([F:33])([F:32])[C:24]1[CH:31]=[CH:30][C:27]([CH:28]=O)=[CH:26][CH:25]=1>C1(C)C=CC=CC=1>[F:22][C:23]([F:32])([F:33])[C:24]1[CH:25]=[CH:26][C:27]([CH:28]=[N:15][C:13]2[C:12]3[C:7]([N:6]=[C:5]4[C:14]=2[CH2:1][CH2:2][CH2:3][CH2:4]4)=[CH:8][CH:9]=[CH:10][CH:11]=3)=[CH:30][CH:31]=1
Reactant: Nc1c2c(nc3ccccc13)CCCC2
Reactant: O=Cc1ccc(C(F)(F)F)cc1
Solvent: Cc1ccccc1
Solvent: C1COCCN1
Product: FC(F)(F)c1ccc(C=Nc2c3c(nc4ccccc24)CCCC3)cc1

Procedure:
1,2,3,4-Tetrahydro-9-acridinamine (4.00 g) was refluxed for twenty-four (24) hours in 400 ml of toluene that contained morpholine (3.50 g) and 4-trifluoromethylbenzaldehyde (4.35 g). At this time, an additional 2.0 g of aldehyde was added and reflux was continued for another sixteen (16) hours. At the end of this time the reaction mixture was concentrated and the residue was purified by flash chromatography (CH2Cl2, then 20% EtOAc/CH2Cl2). Fractions containing the product were concentrated and recrystallized from benzene/pentane to give 3.46 g of analytically pure product, m.p. 203°-205° C.
Reaction SMILES: [OH-].[Na+].[CH:3]1([C:6]2[C:11]([C:12]3[CH:17]=[CH:16][C:15]([F:18])=[CH:14][C:13]=3[F:19])=[C:10]([F:20])[C:9]([O:21][CH2:22][CH3:23])=[C:8]([CH2:24][N:25]3[CH2:30][CH2:29][CH:28]([N:31]4[CH:36]=[CH:35][C:34]([C:37]([O:39]C)=[O:38])=[C:33]([CH2:41][CH3:42])[C:32]4=[O:43])[CH2:27][CH2:26]3)[CH:7]=2)[CH2:5][CH2:4]1>C(O)C>[CH:3]1([C:6]2[C:11]([C:12]3[CH:17]=[CH:16][C:15]([F:18])=[CH:14][C:13]=3[F:19])=[C:10]([F:20])[C:9]([O:21][CH2:22][CH3:23])=[C:8]([CH2:24][N:25]3[CH2:26][CH2:27][CH:28]([N:31]4[CH:36]=[CH:35][C:34]([C:37]([OH:39])=[O:38])=[C:33]([CH2:41][CH3:42])[C:32]4=[O:43])[CH2:29][CH2:30]3)[CH:7]=2)[CH2:5][CH2:4]1
Reactant: CCOc1c(CN2CCC(n3ccc(C(=O)OC)c(CC)c3=O)CC2)cc(C2CC2)c(-c2ccc(F)cc2F)c1F
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: CCOc1c(CN2CCC(n3ccc(C(=O)O)c(CC)c3=O)CC2)cc(C2CC2)c(-c2ccc(F)cc2F)c1F
Reaction time: 3 h
Yield: 67.2 %

Procedure:
A 2 M aqueous sodium hydroxide solution (1.5 mL) was added to an ethanol (6 mL) solution of methyl 1-(1-((6-cyclopropyl-3-ethoxy-2,2′,4′-trifluorobiphenyl-4-yl)methyl)piperidin-4-yl)-3-ethyl-2-oxo-1,2-dihydropyridine-4-carboxylate (264 mg), and the mixture was stirred at 80 C for 3 hours in a nitrogen atmosphere. Then, the solvent was distilled off under reduced pressure. Water was added to the residue, and the mixture was neutralized with 2 M hydrochloric acid, followed by extraction with a mixed solution of ethyl acetate and THF. The organic layer was separated, then washed with water and saturated saline in this order, and dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. The obtained residue was crystallized (hexane/ethyl acetate) and further recrystallized (hexane/ethanol) to obtain the title compound (173 mg).
Reaction SMILES: C([O:3][C:4]([C:6]1[CH:7]=[CH:8][C:9]2[N:10]([C:12]([S:15][C:16]3[CH:17]=[C:18]4[C:23](=[CH:24][CH:25]=3)[N:22]=[CH:21][C:20]([N:26]3[CH2:31][CH2:30][O:29][CH2:28][CH2:27]3)=[CH:19]4)=[N:13][N:14]=2)[CH:11]=1)=[CH2:5])C.Cl.C([O-])(O)=O.[Na+]>C1COCC1>[O:29]1[CH2:28][CH2:27][N:26]([C:20]2[CH:21]=[N:22][C:23]3[C:18]([CH:19]=2)=[CH:17][C:16]([S:15][C:12]2[N:10]4[CH:11]=[C:6]([C:4](=[O:3])[CH3:5])[CH:7]=[CH:8][C:9]4=[N:14][N:13]=2)=[CH:25][CH:24]=3)[CH2:31][CH2:30]1
Reactant: C=C(OCC)c1ccc2nnc(Sc3ccc4ncc(N5CCOCC5)cc4c3)n2c1
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1CCOC1
Product: CC(=O)c1ccc2nnc(Sc3ccc4ncc(N5CCOCC5)cc4c3)n2c1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 39.8 %

Procedure:
The crude (77.2) was dissolved in THF (20 ml) and 1 ml of HCl (2N) was added. The mixture was stirred at rt for 10 min. The mixture was neutralized by saturated aqueous NaHCO3 and evaporated to dryness. The residue was purified by column chromatography (CombiFlash-ISCO, eluent DCM/MeOH from 20/1 to 8/1 for 40 min gradiently) to afford the title compound (40 mg, yield 39.8% over 2 steps). LCMS (method A): [M+H]+=405.6, tR=2.08 min. 1H NMR (400 MHz, CDCl3) δ ppm 2.57 (s., 3H) 3.17-3.34 (t, 4H) 3.82-4.00 (t, 4H) 7.15 (d, 1H) 7.46 (d, 1H) 7.64 (s, 1H) 7.88 (s, 2H) 7.93 (d, 1H) 8.76 (d, 1H) 8.78 (s, 1H)
Reaction SMILES: [BH4-].[Na+].[C:3]([C:11]1[CH:12]=[CH:13][C:14]2[N:15]([CH:17]=[C:18]([C:20]([NH:22][C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=3)=[O:21])[N:19]=2)[CH:16]=1)(=[O:10])[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1>CO>[OH:10][CH:3]([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1)[C:11]1[CH:12]=[CH:13][C:14]2[N:15]([CH:17]=[C:18]([C:20]([NH:22][C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=3)=[O:21])[N:19]=2)[CH:16]=1
Reactant: O=C(c1ccccc1)c1ccc2nc(C(=O)Nc3ccccc3)cn2c1
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Product: O=C(Nc1ccccc1)c1cn2cc(C(O)c3ccccc3)ccc2n1
Reaction time: 16 h
Yield: 77.3 %

Procedure:
17.4 mg of sodium borohydride are added to a suspension, cooled to 0° C., of 157 mg of 6-benzoyl-N-phenylimidazo[1,2-a]pyridine-2-carboxamide in 10 ml of methanol. The reaction mixture is stirred for 16 hours, while allowing the temperature to rise to 20° C. 20 mg of sodium borohydride are added and the mixture is stirred at 20° C. for a further 1.5 hours. After evaporating to dryness, the residue is taken up in 50 ml of water and 200 ml of ethyl acetate. The organic phase is separated by settling, dried and concentrated to dryness under reduced pressure to give 122 mg of 6-[hydroxy(phenyl)methyl]-N-phenylimidazo[1,2-a]pyridine-2-carboxamide in the form of a white solid.
Reaction SMILES: [CH3:1][N:2]1[CH:6]=[C:5](/[CH:7]=[CH:8]/[C:9]([OH:11])=[O:10])[CH:4]=[N:3]1.OS(O)(=O)=O.[OH-].[Na+].[CH3:19]O>>[CH3:1][N:2]1[CH:6]=[C:5](/[CH:7]=[CH:8]/[C:9]([O:11][CH3:19])=[O:10])[CH:4]=[N:3]1
Reactant: CO
Reactant: Cn1cc(/C=C/C(=O)O)cn1
Agent: O=S(=O)(O)O
Agent: [Na+]
Agent: [OH-]
Product: COC(=O)/C=C/c1cnn(C)c1
Temperature: 25 °C
Yield: 71.8 %

Procedure:
(2E)-3-(1-Methyl-1H-pyrazol-4-yl)-2-propenoic acid (7.5 g, 49.3 mmol) was added to a solution of H2SO4 (1.760 ml, 33.0 mmol) in methanol (40 ml), and the resultant mixture was refluxed for 4 h. It was cooled to room temperature, then poured into ice. The acid was neutralized with aqueous sodium hydroxide and extracted with DCM (80 ml×2). The organic phases were collected and combined, dried over MgSO4, and concentrated. The residue was washed with petroleum ether and concentrated to give the title compound (7 g, 71.8% yield). LCMS: rt=1.13 min, [M+H+]=167
Reaction SMILES: [NH2:1][CH2:2][CH2:3][C:4]([OH:6])=[O:5].C(#N)C.[C:10](OC(=O)C)(=[O:12])[CH3:11]>C([O-])(O)=O.[Na+]>[C:10]([NH:1][CH2:2][CH2:3][C:4]([OH:6])=[O:5])(=[O:12])[CH3:11]
Reactant: NCCC(=O)O
Reactant: CC(=O)OC(C)=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC#N
Product: CC(=O)NCCC(=O)O
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To a solution of β-alanine (2.25 g, 25 mmol) in aq. NaHCO3 (15 mL) was added acetonitrile (15 mL) and acetic anhydride (2.55 g, 25 mmol). The reaction mixture was stirred at room temperature for 3 h. Acetic anhydride (2.55 g. 25 mmol) was added and after 2 h and pH was adjusted to 4-5 by addition of NaH2PO4.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][CH2:9][C:10]1[CH:15]=[CH:14][C:13]([CH2:16][C:17]([OH:19])=O)=[CH:12][CH:11]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].C(N(CC)CC)C.C(Cl)CCl.C1C=CC2N(O)N=NC=2C=1.Cl.[CH3:42][C@@H:43]([NH2:48])[C:44]([F:47])([F:46])[F:45]>C(Cl)Cl.CN(C1C=CN=CC=1)C>[C:1]([O:5][C:6]([NH:8][CH2:9][C:10]1[CH:11]=[CH:12][C:13]([CH2:16][C:17](=[O:19])[NH:48][C@H:43]([CH3:42])[C:44]([F:47])([F:46])[F:45])=[CH:14][CH:15]=1)=[O:7])([CH3:2])([CH3:3])[CH3:4]
Reactant: CC(C)(C)OC(=O)NCc1ccc(CC(=O)O)cc1
Reactant: C[C@@H](N)C(F)(F)F
Agent: CN(C)c1ccncc1
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CCN(CC)CC
Solvent: ClCCl
Solvent: ClCCCl
Product: C[C@@H](NC(=O)Cc1ccc(CNC(=O)OC(C)(C)C)cc1)C(F)(F)F
Yield: 68.3 %

Procedure:
Dissolve [4-(tert-butoxycarbonylamino-methyl)-phenyl]-acetic acid (190 mg, 0.63 mmol) in DCM (12.4 mL) and add triethylamine (354 μL, 2.5 mmol), DMAP (8 mg, 0.063 mmol), EDC (145 mg, 0.756 mmol), HOBt (102 mg, 0.756 mmol) and (R)-1-methyl-2,2,2-trifluoro-ethylamine hydrochloride (71 mg, 0.63 mmol) under nitrogen atmosphere. Stir the reaction overnight at room temperature. Concentrate in vacuo and purify by chromatography on silica gel eluting with hexane/EtOAc (1:1 and 0:1) to obtain the desired intermediate (155 mg, 68%).
Reaction SMILES: [N+](C1C=CC(C([O:10][C@H:11]2[CH2:15][CH2:14][N:13]([CH2:16][CH2:17][C:18]3[CH:23]=[CH:22][C:21]([O:24][CH3:25])=[CH:20][CH:19]=3)[CH2:12]2)=O)=CC=1)([O-])=O.O1CCCC1.O.[Li+].[OH-]>CO>[OH:10][C@H:11]1[CH2:15][CH2:14][N:13]([CH2:16][CH2:17][C:18]2[CH:19]=[CH:20][C:21]([O:24][CH3:25])=[CH:22][CH:23]=2)[CH2:12]1
Reactant: COc1ccc(CCN2CC[C@H](OC(=O)c3ccc([N+](=O)[O-])cc3)C2)cc1
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: CO
Solvent: C1CCOC1
Product: COc1ccc(CCN2CC[C@H](O)C2)cc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
(S)-3-(4-Nitrobenzoyloxy)-1-(4-methoxyphenethyl)pyrrolidine (1.00 g, 2.70 mmol) was dissolved in methanol (20 ml), tetrahydrofuran (20 ml) and water (10 ml). 4 M-LiOH (3 ml) was added dropwise in the obtained solution, and they were stirred at room temperature for 1 hour. The solvent was evaporated under reduced pressure, and then the residue was distributed in water and ether. The organic layer was dried, and the solvent was evaporated under reduced pressure to obtain (S)-3-hydroxy-1-(4-methoxyphenethyl)pyrrolidine in the form of a light yellow oil (541 mg, 91%).
Reaction SMILES: CS([O:5][CH2:6][C:7]1[C:8]([C:16]2[CH:21]=[CH:20][C:19]([Cl:22])=[CH:18][CH:17]=2)=[N:9][S:10][C:11]=1[C:12]([F:15])([F:14])[F:13])(=O)=O.O[C:24]1[CH:29]=[CH:28][C:27]([CH2:30][CH:31]([CH3:37])[C:32]([O:34]CC)=[O:33])=[CH:26][CH:25]=1>>[Cl:22][C:19]1[CH:20]=[CH:21][C:16]([C:8]2[C:7]([CH2:6][O:5][C:24]3[CH:29]=[CH:28][C:27]([CH2:30][CH:31]([CH3:37])[C:32]([OH:34])=[O:33])=[CH:26][CH:25]=3)=[C:11]([C:12]([F:15])([F:14])[F:13])[S:10][N:9]=2)=[CH:17][CH:18]=1
Reactant: CCOC(=O)C(C)Cc1ccc(O)cc1
Reactant: CS(=O)(=O)OCc1c(-c2ccc(Cl)cc2)nsc1C(F)(F)F
Product: CC(Cc1ccc(OCc2c(-c3ccc(Cl)cc3)nsc2C(F)(F)F)cc1)C(=O)O

Procedure:
The title compound was prepared according to the procedure described in Example 1 following Steps 5 and 6 by coupling (3-(4-chlorophenyl)-5-(trifluoromethyl)isothiazol-4-yl)methyl methanesulfonate and ethyl 3-(4-hydroxyphenyl)-2-methyl-propanoate followed by hydrolysis to afford the desired product as an off-white solid. 1H NMR (300 MHz, CD3OD) δ: 7.71 (d, J=8.8 Hz, 2H), 7.48 (d, J=8.4 Hz, 2H), 7.16 (d, J=8.4 Hz, 1H), 6.87 (d, J=8.4 Hz, 1H), 5.09 (s, 2H), 2.93-2.98 (m, 1H), 2.63-2.74 (m, 2H), 1.15 (d, J=6.8 Hz, 3H). Mass spectrum (ESI, m/z): Calcd. for C21H17ClF3NO3S, 454.0 (M−H). found 454.0.
Reaction SMILES: C([Li])CCC.[Cl:6][C:7]1[CH:8]=[C:9]2[C:13](=[CH:14][C:15]=1[F:16])[NH:12][CH:11]=[CH:10]2.CC([O-])(C)C.[K+].[C:23](=[O:25])=[O:24]>CCCCCC.C1COCC1.O>[Cl:6][C:7]1[CH:8]=[C:9]2[C:13](=[C:14]([C:23]([OH:25])=[O:24])[C:15]=1[F:16])[NH:12][CH:11]=[CH:10]2
Reactant: Fc1cc2[nH]ccc2cc1Cl
Reactant: O=C=O
Agent: CC(C)(C)[O-]
Agent: [K+]
Agent: [Li]CCCC
Solvent: O
Solvent: C1CCOC1
Solvent: CCCCCC
Product: O=C(O)c1c(F)c(Cl)cc2cc[nH]c12
Temperature: 10 °C
Reaction time: 2 h

Procedure:
35 ml of THF were cooled to −75° C. and 19.05 ml (30.5 mmol) of a 1.6M solution of n-butyllithium in hexane were added under argon. Then a solution of 2.35 g (13.7 mmol) of 5-chloro-6-fluoro-1H-indole in THF (9 ml) was added dropwise (temperature kept between −70 and −75° C.) over 15 min. After 5 additional min of stirring at this temperature a solution of 3.7 g of potassium tert-butylate in THF (15 ml) was added over period of 10 min (temperature kept between −70 and −75° C.). The resulting brown solution was then stirred for 2 hours at the same temperature and treated with a large excess of solid CO2. The temperature was then raised to 10° C. over a period of 75 min and water (30 ml) was added to the reaction mixture. After separation of the organic layer, the aqueous layer was extracted with ether and treated with concentrated HCl to adjust the pH to 1. The resulting suspension was then filtered and the solid was washed with water and dried in high vacuo. The remaining residue was suspended in 10 ml of hexane/ether 9:1 and stirred for 15 min, filtered off, washed with 5 ml of the same solvent mixture and was dried in high vacuo, leading to 2.2 g of 5-chloro-6-fluoro-1H-indole-7-carboxylic acid as a light brown solid (75%). MS: 212.2 (M−H)−