Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([N:8]1[C:17]([C:18]([OH:20])=O)=[C:16]([C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[C:15]2[C:10](=[CH:11][CH:12]=[C:13]([Br:27])[CH:14]=2)[C:9]1=[O:28])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:29][NH:30][CH3:31].C1COCC1>>[CH3:29][N:30]([CH3:31])[C:18]([C:17]1[N:8]([CH2:1][C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=2)[C:9](=[O:28])[C:10]2[C:15]([C:16]=1[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)=[CH:14][C:13]([Br:27])=[CH:12][CH:11]=2)=[O:20]
Reactant: CNC
Reactant: O=C(O)c1c(-c2ccccc2)c2cc(Br)ccc2c(=O)n1Cc1ccccc1
Solvent: C1CCOC1
Product: CN(C)C(=O)c1c(-c2ccccc2)c2cc(Br)ccc2c(=O)n1Cc1ccccc1

Procedure:
The present compound was synthesized by a method similar to that in Example 249 and using 2-benzyl-6-bromo-1-oxo-4-phenyl-1,2-dihydroisoquinoline-3-carboxylic acid (250 mg) and dimethylamine THF solution. Colorless crystals (180 mg).
Reaction SMILES: [OH-].[K+].[Br:3][C:4]1[CH:22]=[CH:21][C:7]([C:8]([NH:10][C:11]2[CH:20]=[CH:19][C:14]([C:15]([O:17]C)=[O:16])=[CH:13][N:12]=2)=[O:9])=[CH:6][N:5]=1>CO.O>[Br:3][C:4]1[CH:22]=[CH:21][C:7]([C:8]([NH:10][C:11]2[CH:20]=[CH:19][C:14]([C:15]([OH:17])=[O:16])=[CH:13][N:12]=2)=[O:9])=[CH:6][N:5]=1
Reactant: COC(=O)c1ccc(NC(=O)c2ccc(Br)nc2)nc1
Agent: [K+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: O=C(O)c1ccc(NC(=O)c2ccc(Br)nc2)nc1
Reaction time: 4 h
Yield: 37.8 %

Procedure:
KOH pellets (5 g) were added to a suspension of methyl 6-(6-bromonicotinamido) nicotinate 3 (5 g, 14.8 mmol) in methanol and water (150/50 ml). The reaction mixture was stirred for 4 hours. Then the solvent was evaporated and the pH was adjusted to below 2. The white solid was filtered off and washed with cold water and dried under vacuum to give 6-(6-bromonicotinamido)nicotinic acid 4 (1.8 g, 37%). Mp. 270-272° C.
Reaction SMILES: [CH3:1][C:2]([CH3:23])([CH:4]([OH:22])[CH:5]([N:17]1[CH:21]=[N:20][CH:19]=[N:18]1)[CH2:6][CH2:7][CH2:8][CH2:9][O:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)[CH3:3].[H-].[Na+].[CH3:26]I.O>CN(C=O)C>[CH3:3][C:2]([CH3:23])([CH:4]([O:22][CH3:26])[CH:5]([N:17]1[CH:21]=[N:20][CH:19]=[N:18]1)[CH2:6][CH2:7][CH2:8][CH2:9][O:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)[CH3:1]
Reactant: CC(C)(C)C(O)C(CCCCOc1ccccc1)n1cncn1
Reactant: CI
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: COC(C(CCCCOc1ccccc1)n1cncn1)C(C)(C)C
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A solution of 15.4 g of 2,2-dimethyl-4-(1,2,4-triazol-1-yl)-8-phenoxy-octan-3-ol in 50 ml of DMF is added dropwise to a suspension of 1.6 g of sodium hydride in 50 ml of DMF. The mixture is then stirred for 2 hours under reflux. When it has cooled to room temperature, 3.7 ml of methyl iodide are added. This mixture is stirred for five hours under reflux, 200 ml of water are then added, the reaction mixture is extracted three times with 100 ml of diethyl ether at a time and the combined extracts are washed three times with 50 ml of water at a time, dried over magnesium sulfate and concentrated under reduced pressure. The residue consists of 2.2 g of a yellowish resin. Infrared spectrum (film): 2,930, 2,862, 1,588, 1,576, 1,486, 1,460 1,264, 1,233, 1,126, 1,080, 1,005, 745, 682 and 670 cm-1.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([S:9]([NH2:12])(=[O:11])=[O:10])[CH:5]=[CH:6][C:7]=1[OH:8].[C:13](Cl)(Cl)=[S:14]>C1COCC1>[SH:14][C:13]1[O:8][C:7]2[CH:6]=[CH:5][C:4]([S:9]([NH2:12])(=[O:10])=[O:11])=[CH:3][C:2]=2[N:1]=1
Reactant: Nc1cc(S(N)(=O)=O)ccc1O
Reactant: S=C(Cl)Cl
Solvent: C1CCOC1
Product: NS(=O)(=O)c1ccc2oc(S)nc2c1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
To a solution of 3-amino-4-hydroxy-benzenesulfonamide (5.00 g, 26.6 mmol, 1.0 equiv) in anhydrous THF (250 mL) was added slowly thiophosgene (3.67 g, 2.43 mL, 31.9 mmol, 1.2 equiv) via syringe pump over a time period of 1 h. After stirring for 4 h at rt, excess thiophosgene was quenched by addition of a conc. solution of ammonium chloride (100 mL) and the majority of solvent removed by evaporation under reduced pressure. The residue was extracted with ethyl acetate (3×100 mL) and the combined organic phases dried over MgSO4 yielding 6.1 g (92%) of crude product, which was used in the subsequent reaction step without further purification. 1H NMR (300 MHz, DMSO): δ 7.51 (br s, 2H), 7.68 (s, 1H), 7.70 (d, J=7.7 Hz, 1H), 7.78 (d, J=7.7 Hz, 1H), 14.21 (br s, 1H). 13C NMR (75 MHz, DMSO): δ 106.29, 108.47, 120.06, 129.91, 139.54, 148.16, 179.38. MS (ISP): 230.9 [M+H]+.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][C:9]=1[OH:10])[CH:5]=[O:6].[C:11]([O-])([O-])=O.[K+].[K+].CI>CN(C=O)C>[Cl:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][C:9]=1[O:10][CH3:11])[CH:5]=[O:6]
Reactant: O=C([O-])[O-]
Reactant: O=Cc1ccc(O)c(Cl)c1
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CI
Product: COc1ccc(C=O)cc1Cl
Reaction time: 1 h
Yield: 88.5 %

Procedure:
To a stirred solution of 3-chloro-4-hydroxybenzaldehyde (2.9 g, 18.412 mmol) in DMF (30 mL) was added K2CO3 (7.6 g, 55.238 mmol). CH3I (7.80 g, 55.238 mmol) was then added slowly at RT under an inert atmosphere. After addition was completed, the reaction mixture was brought to 80° C. and stirred for 1 h. The reaction mixture was quenched with water (20 mL) and extracted with EtOAc (2×50 mL). The combined organic layers were washed with water and brine, dried over anhydrous Na2SO4, filtered and concentrated in vacuo to obtain crude product. The crude material was purified via silica gel column chromatography to afford 3-chloro-4-methoxybenzaldehyde (2.78 g, 93%) as a yellow solid.
Reaction SMILES: Br[C:2]1[CH:7]=[C:6]([S:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH3:14])[C:5]([Br:15])=[CH:4][C:3]=1[S:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH3:22].C([Li])CCC.CN(C)[CH:30]=[O:31]>>[Br:15][C:5]1[C:6]([S:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH3:14])=[CH:7][C:2]([CH:30]=[O:31])=[C:3]([S:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH3:22])[CH:4]=1
Reactant: CCCCCCSc1cc(Br)c(SCCCCCC)cc1Br
Reactant: CN(C)C=O
Agent: [Li]CCCC
Product: CCCCCCSc1cc(C=O)c(SCCCCCC)cc1Br
Yield: 50 %

Procedure:
BrS6 was converted to BrS6A by the same methods as Br6A and BrC6A, using butyllithium and dimethylformamide. Products were purified by column chromatography with ethylacetate:hexane (1:30) eluent followed by recrystallization from methanol. Yellow powder is collected at a yield of 50%. For BrS6A, 1H NMR (500 MHz, CDCl3): δ 10.39 (s 1H), 7.64 (s 1H), 7.61 (s 1H), 3.00 (t 2H), 2.91 (t 2H), 1.73-1.65 (m 4H), 1.46 (m, 4H), 1.34-1.28 (m 8H), 0.89 (m 6H).
Reaction SMILES: [CH:1]([O:4][C:5](=[O:18])[C@@H:6]([CH2:16][OH:17])[NH:7][C:8](=[O:15])[C@H:9]([CH2:11][C:12](=[O:14])[OH:13])[NH2:10])([CH3:3])[CH3:2].CO[C:21](=[O:47])[C@H:22]([CH2:40][C:41]1C=CC=CC=1)[NH:23][C:24](=O)[C@](C(N1CCCCC1)=O)(CC(=O)O)N>>[CH:1]([O:4][C:5](=[O:18])[C@@H:6]([CH2:16][OH:17])[NH:7][C:8](=[O:15])[C@H:9]([CH2:11][C:12](=[O:13])[OH:14])[NH:10][C:21](=[O:47])[C@H:22]1[CH2:40][CH2:41][CH2:24][NH:23]1)([CH3:3])[CH3:2]
Reactant: COC(=O)[C@H](Cc1ccccc1)NC(=O)[C@@](N)(CC(=O)O)C(=O)N1CCCCC1
Reactant: CC(C)OC(=O)[C@@H](CO)NC(=O)[C@@H](N)CC(=O)O
Product: CC(C)OC(=O)[C@@H](CO)NC(=O)[C@H](CC(=O)O)NC(=O)[C@H]1CCCN1

Procedure:
This compound was prepared from 1.7 g α-L-aspartyl-D-serine isopropyl ester and 2.4 g N-benzyloxycarbonyl-D-proline N-hydroxysuccinimide ester in a manner similar to Example 11 (C) and (D). Yield: 1.7 g, m.p.: 230°-233° C.
Reaction SMILES: [C:1]([CH:4]1[CH2:12][C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:5]1=[O:13])(=[O:3])[CH3:2].C(=O)([O-])[O-].[K+].[K+].Br[CH2:21][CH2:22][C:23]([O:25][CH2:26][CH3:27])=[O:24].Cl>O.CN(C)C=O>[CH2:26]([O:25][C:23](=[O:24])[CH2:22][CH2:21][C:4]1([C:1](=[O:3])[CH3:2])[CH2:12][C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:5]1=[O:13])[CH3:27]
Reactant: CC(=O)C1Cc2ccccc2C1=O
Reactant: CCOC(=O)CCBr
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: CCOC(=O)CCC1(C(C)=O)Cc2ccccc2C1=O
Temperature: 52.5 °C
Reaction time: 0.33 h

Procedure:
2-Acetyl-1-indanone (15 g, cf. Liebigs Ann. Chem. 347 (1906) 112) was added into a mixture of potassium carbonate (8.5 g) and dry N,N-dimethylformamide (45 ml). The mixture was stirred at 50-55° C. for 20 minutes and ethyl 3-bromopropionate (19 g) was then added and the stirring was continued at 50-55° C. for 6 hours. Water (60 ml) was added to the reaction mixture and the pH of the solution was adjusted to 2-3 with hydrochloric acid. The mixture was stirred at 50-55° C. for one hour. The cooled solution was extracted with toluene, washed with water, dried with sodium sulfate, and the solvent removed under reduced pressure. The yield was 23.5 g.
Reaction SMILES: [F:1][C:2]([F:21])([F:20])[C:3]1[C:12]([C:13](Cl)=[O:14])=[C:11]([OH:16])[C:10]2[C:5](=[CH:6][CH:7]=[C:8]([CH:17]([CH3:19])[CH3:18])[CH:9]=2)[N:4]=1.[NH2:22][C:23]1[S:24][CH:25]=[CH:26][N:27]=1>>[F:1][C:2]([F:21])([F:20])[C:3]1[C:12]([C:13]([NH:22][C:23]2[S:24][CH:25]=[CH:26][N:27]=2)=[O:14])=[C:11]([OH:16])[C:10]2[C:5](=[CH:6][CH:7]=[C:8]([CH:17]([CH3:19])[CH3:18])[CH:9]=2)[N:4]=1
Reactant: Nc1nccs1
Reactant: CC(C)c1ccc2nc(C(F)(F)F)c(C(=O)Cl)c(O)c2c1
Product: CC(C)c1ccc2nc(C(F)(F)F)c(C(=O)Nc3nccs3)c(O)c2c1

Procedure:
Using the procedure of Step F of Example 1, the product of Step F and 10 g of 2-amino-thiazole were reacted to obtain after crystallization from isopropanol 9.64 g of 2-trifluoromethyl-6-isopropyl-4-hydroxy-N-(2-thiazolyl)-3-quinolinecarboxamide melting at 262° C.
Reaction SMILES: [CH3:1][S:2]([C:5]1[CH:6]=[CH:7][C:8]([O:14][CH:15]([CH3:20])[C:16]([F:19])([F:18])[F:17])=[C:9]([CH:13]=1)[C:10]([OH:12])=O)(=[O:4])=[O:3].Cl.[F:22][C:23]([F:36])([F:35])[C:24]1[S:28][C:27]([N:29]2[CH2:34][CH2:33][NH:32][CH2:31][CH2:30]2)=[N:26][CH:25]=1>>[CH3:1][S:2]([C:5]1[CH:6]=[CH:7][C:8]([O:14][CH:15]([CH3:20])[C:16]([F:19])([F:18])[F:17])=[C:9]([C:10]([N:32]2[CH2:33][CH2:34][N:29]([C:27]3[S:28][C:24]([C:23]([F:36])([F:22])[F:35])=[CH:25][N:26]=3)[CH2:30][CH2:31]2)=[O:12])[CH:13]=1)(=[O:3])=[O:4]
Reactant: CC(Oc1ccc(S(C)(=O)=O)cc1C(=O)O)C(F)(F)F
Reactant: FC(F)(F)c1cnc(N2CCNCC2)s1
Agent: Cl
Product: CC(Oc1ccc(S(C)(=O)=O)cc1C(=O)N1CCN(c2ncc(C(F)(F)F)s2)CC1)C(F)(F)F
Yield: 64 %

Procedure:
Prepared in analogy to example 1 (b) from 5-methanesulfonyl-2-(2,2,2-trifluoro-1-methyl-ethoxy)-benzoic acid (Example A2) and 1-(5-trifluoromethyl-thiazol-2-yl)-piperazine hydrochloride (Example 58(c)). The crude material was purified by chromatography (SiO2, ethyl acetate/heptane) followed by trituration in pentane to yield the title compound as an off-white crystalline solid (yield 64%). MS (m/e): 532.0 (M+H+, 100%).
Reaction SMILES: [H-].[Na+].[C:3]([O:7][C:8](=[O:16])/[CH:9]=[CH:10]/[C:11]1[CH:15]=[CH:14][NH:13][CH:12]=1)([CH3:6])([CH3:5])[CH3:4].[C:17]1([C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)[CH:22]=[CH:21][C:20]([S:23](Cl)(=[O:25])=[O:24])=[CH:19][CH:18]=1>>[C:3]([O:7][C:8](=[O:16])/[CH:9]=[CH:10]/[C:11]1[CH:15]=[CH:14][N:13]([S:23]([C:20]2[CH:19]=[CH:18][C:17]([C:27]3[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=3)=[CH:22][CH:21]=2)(=[O:25])=[O:24])[CH:12]=1)([CH3:6])([CH3:4])[CH3:5]
Reactant: O=S(=O)(Cl)c1ccc(-c2ccccc2)cc1
Reactant: CC(C)(C)OC(=O)/C=C/c1cc[nH]c1
Agent: [H-]
Agent: [Na+]
Product: CC(C)(C)OC(=O)/C=C/c1ccn(S(=O)(=O)c2ccc(-c3ccccc3)cc2)c1

Procedure:
Starting materials: sodium hydride 60% (0.207 g), (E)-3-(1H-pyrrol-3-yl)-acrylic acid tert-butyl ester (compound D1) (0.531 g), 4-biphenylsulphonylchloride (0.834 g). Reaction conditions: −30° C., 10 min; 30° C., 30 min.
Reaction SMILES: [CH3:1][CH:2]1[CH2:8][O:7][C:6](=[O:9])[N:5]([CH2:10][C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=2[NH:17][S:18]([C:21]([F:24])([F:23])[F:22])(=[O:20])=[O:19])[CH2:4][CH2:3]1.C(=O)([O-])O.[Na+].Cl[C:31]([O:33][CH2:34][CH:35]([CH3:37])[CH3:36])=[O:32].O>C(#N)C>[CH2:34]([O:33][C:31]([N:17]([C:12]1[CH:13]=[CH:14][CH:15]=[CH:16][C:11]=1[CH2:10][N:5]1[CH2:4][CH2:3][CH:2]([CH3:1])[CH2:8][O:7][C:6]1=[O:9])[S:18]([C:21]([F:24])([F:22])[F:23])(=[O:20])=[O:19])=[O:32])[CH:35]([CH3:37])[CH3:36]
Reactant: CC1CCN(Cc2ccccc2NS(=O)(=O)C(F)(F)F)C(=O)OC1
Reactant: CC(C)COC(=O)Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: CC#N
Product: CC(C)COC(=O)N(c1ccccc1CN1CCC(C)COC1=O)S(=O)(=O)C(F)(F)F
Temperature: 25 °C
Yield: 52.3 %

Procedure:
6-Methyl-3-[2-(trifluoromethanesulfonylamino)benzyl]-[1,3]-oxazepan-2-one (0.15 g, 0.41 mmol) and sodium hydrogen carbonate (0.06 g, 0.71 mmol) were suspended in acetonitrile (10 ml), added with isobutyl chloroformate (00.10 g, 0.73 mmol) and heated to reflux for three hours. After cooling to room temperature, the reaction mixture was added with water and extracted with ethyl acetate. The ethyl acetate layer was washed with a saturated brine and then dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (hexane:ethyl acetate=3:1) to obtain 3-(2-[N-(isobutoxycarbonyl)-N-(trifluoromethanesulfonyl)amino]benzyl)-6-methyl-[1,3]-oxazepan-2-one (0.10 g).
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([O:8][CH2:9][CH2:10][C@@H:11]2[CH2:13][C@@H:12]2[CH:14]2[CH2:19][CH2:18][N:17]([C:20]3[N:25]=[CH:24][C:23]([CH2:26][O:27][CH3:28])=[CH:22][N:21]=3)[CH2:16][CH2:15]2)[CH:5]=[CH:4][C:3]=1[CH2:29][C:30]([OH:32])=O.[NH:33]1[CH2:36][CH2:35][CH2:34]1.C(N(CC)C(C)C)(C)C.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>CN(C=O)C>[N:33]1([C:30](=[O:32])[CH2:29][C:3]2[CH:4]=[CH:5][C:6]([O:8][CH2:9][CH2:10][C@@H:11]3[CH2:13][C@@H:12]3[CH:14]3[CH2:19][CH2:18][N:17]([C:20]4[N:21]=[CH:22][C:23]([CH2:26][O:27][CH3:28])=[CH:24][N:25]=4)[CH2:16][CH2:15]3)=[CH:7][C:2]=2[F:1])[CH2:36][CH2:35][CH2:34]1
Reactant: C1CNC1
Reactant: COCc1cnc(N2CCC([C@H]3C[C@H]3CCOc3ccc(CC(=O)O)c(F)c3)CC2)nc1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: COCc1cnc(N2CCC([C@H]3C[C@H]3CCOc3ccc(CC(=O)N4CCC4)c(F)c3)CC2)nc1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
To a solution of {2-fluoro-4-[2-((1S,2R)-2-{1-[5-(methoxymethyl)pyrimidin-2-yl]piperidin-4-yl}cyclopropyl)ethoxy]phenyl}acetic acid (500 mg, 1.13 mmol) in 8 ml of anhydrous DMF at RT was added azetidine (129 mg, 2.26 mmol) and N,N-diisopropylethylamine (0.591 ml, 3.38 mmol). o-(7-Azabenzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium hexafluorophosphate (643 mg, 1.69 mmol) was added to the solution and stirred at RT for 4 hrs. The mixture was purified by column chromatography by loading directly to a preparative biotage reverse phase column (C-18) (50 g column) and eluting with Acetonitrile/Water+0.1% formic acid (35% to 90%). The material was further purified by column chromatography on silica gel Biotage 40S, eluting with EtOAc/hexanes (30% to 90%) to give the title compound. 1H NMR (500 MHz, CDCl3) δ 8.29 (s, 2H), 7.27 (t, J=8.4 Hz, 1H), 6.64 (d, J=2.1 Hz, 1H), 6.20 (d, J=2.3 Hz, 1H), 4.74 (t, J=13.2 Hz, 2H), 4.27 (s, 2H), 4.17 (t, J=7.7 Hz, 2H), 4.04 (m, 4H), 3.40 (s, 2H), 3.35 (s, 3H), 2.85 (m, 2H), 2.14-2.29 (m, 3H), 1.85 (m, 2H), 1.41 (m, 1H), 1.36 (m, 2H), 1.11 (m, 1H), 0.93 (m, 1H), 0.60-0.71 (m, 2H), −0.08 (m, 1H). LC/MS (m/z): 482.4 (M+H)+. GPR119 Human EC50: 0.77 nM
Reaction SMILES: [CH2:1]([N:8]1[CH:12]=[CH:11][N:10]=[CH:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH2:13]=[O:14].[OH-].[Na+]>>[CH2:1]([N:8]1[CH:12]=[CH:11][N:10]=[C:9]1[CH2:13][OH:14])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: C=O
Reactant: c1ccc(Cn2ccnc2)cc1
Agent: [Na+]
Agent: [OH-]
Product: OCc1nccn1Cc1ccccc1

Procedure:
A mixture of 1-benzyl-imidazole (5 g, 32 mmol), formaldehyde 37% (10 ml, 134 mmol) and sodium hydroxide (100 mg) is refluxed for 7 days and is extracted with ethylacetate. Concentration in vacuo yields 1-benzyl-2-hydroxymethyl-imidazole.
Reaction SMILES: [C:1]1([CH:7]([CH2:11][CH3:12])[C:8](Cl)=[O:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[Al+3].[Cl-].[Cl-].[Cl-].O.[C:18]1([O:24][CH3:25])[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1>>[CH3:25][O:24][C:18]1[CH:23]=[CH:22][C:21]([C:8](=[O:9])[CH:7]([C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=2)[CH2:11][CH3:12])=[CH:20][CH:19]=1
Reactant: CCC(C(=O)Cl)c1ccccc1
Reactant: COc1ccccc1
Agent: [Al+3]
Agent: [Cl-]
Solvent: O
Product: CCC(C(=O)c1ccc(OC)cc1)c1ccccc1
Temperature: 0 °C
Reaction time: 2 h
Yield: 100 %

Procedure:
2-Phenylbutyryl chloride (50.0 mL, 299 mmol) was dissolved in anisole (75 mL) and cooled to 0° C. AlCl3 (40.377 g, 303 mmol) was added portionwise and the resulting mixture allowed to warm to RT then stirred for 2 h. Ice was added portionwise followed by H2O (100 mL). The mixture was extracted with CH2Cl2 (3×100 mL) and the combined organics dried (MgSO4) and concentrated. The residue was distilled to remove the remaining anisole (1 mm Hg, 40-55° C.) to provide 2 (77.27 g, 100%) as a tan oil. 1H NMR (400 MHz, CDCl3): δ 0.90 (t, J=7.5 Hz, 3H), 1.85 (dq, 1H), 2.18 (dq, 1H), 3.81 (s, 3H), 4.40 (t, J=7.2 Hz, 1H), 6.85 (d, J=5.0 Hz, 2H), 7.19 (m, 1H), 7.28 (m, 4H), 7.95 (d, J=5.0 Hz, 2H).
Reaction SMILES: CC(C)=[O:3].OS(O)(=O)=O.O=[Cr](=O)=O.[CH3:14][O:15][N:16]=[C:17]([C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=1[Cl:26])[CH2:18][OH:19].C(O)(C)C.O>CC(C)=O>[CH3:14][O:15][N:16]=[C:17]([C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=1[Cl:26])[C:18]([OH:3])=[O:19]
Reactant: CC(C)=O
Reactant: CON=C(CO)c1ccccc1Cl
Agent: O=[Cr](=O)=O
Agent: O=S(=O)(O)O
Solvent: CC(C)O
Solvent: O
Product: CON=C(C(=O)O)c1ccccc1Cl
Temperature: 25 °C
Yield: 75 %

Procedure:
10 ml of Jones reagent (chromic anhydride in dilute sulfuric acid) were added to a solution in acetone of 0.40 g of 2'-chloro-2-hydroxyacetophenone O-methyloxime (the less polar isomer prepared above). The resulting mixture was stirred at room temperature for an hour and then 10 ml of isopropanol were added to it with ice-cooling. The reaction mixture was poured into 100 ml of water and extracted three times with 10 ml portions of ethyl acetate. The combined extracts were washed with a saturated aqueous solution of sodium chloride and dried over magnesium sulfate. The solvent was distilled off to give 320 mg (75%) of the title compound as a crude product.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:8][OH:9])=[N:6][CH:7]=1.[H-].[Na+].I[CH3:13]>C1COCC1>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:8][O:9][CH3:13])=[N:6][CH:7]=1
Reactant: CI
Reactant: OCc1ccc(Br)cn1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: COCc1ccc(Br)cn1
Temperature: 60 °C
Yield: 65 %

Procedure:
To a stirred solution of 5-bromo-2-(hydroxymethyl)pyridine (150 mg, 0.798 mmol) in THF (8 mL) under nitrogen at r.t. was added sodium hydride (60% dispersion in oil, 64 mg, 1.60 mmol). After 30 minutes iodomethane was added and the reaction mixture was heated to 60° C. for 3 h, then cooled to r.t. and concentrated in vacuo. The residue was partitioned between DCM (50 mL) and water (50 mL); the organic fraction was washed with brine (50 mL), dried (MgSO4), and concentrated in vacuo to give the title compound (70 mg, 65%) as 70% pure material. LCMS (ES+) 202.0 (M+H)+, RT 2.40 minutes (Method 1).
Reaction SMILES: C[Si](C)(C)Cl.[I-].[Na+].C(#N)C.[Cl:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=1[C:18]1([F:34])[CH2:23][CH2:22][N:21](C(OCC2C=CC=CC=2)=O)[CH2:20][CH2:19]1>C(OCC)(=O)C>[Cl:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=1[C:18]1([F:34])[CH2:19][CH2:20][NH:21][CH2:22][CH2:23]1
Reactant: O=C(OCc1ccccc1)N1CCC(F)(c2ccccc2Cl)CC1
Agent: C[Si](C)(C)Cl
Agent: [I-]
Agent: [Na+]
Solvent: CC#N
Solvent: CCOC(C)=O
Product: FC1(c2ccccc2Cl)CCNCC1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 76.5 %

Procedure:
1.53 mL of trimethylchlorosilane and 1.82 g of sodium iodide were added to acetonitrile (50 mL) solution of 2.11 g of benzyl 4-(2-chlorophenyl)-4-fluoropiperidine-1-carboxylate, and stirred at room temperature for 30 minutes. 0.77 mL of trimethylchlorosilane and 0.91 g of sodium iodide were further added thereto, and stirred for 10 minutes. Then, the reaction liquid was diluted with ethyl acetate, and back-extracted with 1 M hydrochloric acid. Sodium hydroxide was added to the aqueous layer so that the system was made basic, and then extracted with chloroform, and dried with anhydrous sodium sulfate. The solvent was evaporated off under reduced pressure, and the residue was separated and purified through silica gel column chromatography (chloroform/methanol=10/1) to obtain 992 mg of the entitled compound as a colorless oily substance.
Reaction SMILES: I([O-])(=O)(=O)=[O:2].[Na+].[F:7][C:8]1[CH:9]=[C:10]2[C:15](=[CH:16][CH:17]=1)[N:14]=[C:13]([CH:18]=CN(C)C)[N:12]([C:23]1[C:24]([CH3:29])=[N:25][CH:26]=[CH:27][CH:28]=1)[C:11]2=[O:30]>O1CCCC1>[F:7][C:8]1[CH:9]=[C:10]2[C:15](=[CH:16][CH:17]=1)[N:14]=[C:13]([CH:18]=[O:2])[N:12]([C:23]1[C:24]([CH3:29])=[N:25][CH:26]=[CH:27][CH:28]=1)[C:11]2=[O:30]
Reactant: Cc1ncccc1-n1c(C=CN(C)C)nc2ccc(F)cc2c1=O
Reactant: [O-][I+3]([O-])([O-])[O-]
Agent: [Na+]
Solvent: C1CCOC1
Product: Cc1ncccc1-n1c(C=O)nc2ccc(F)cc2c1=O
Yield: 83.3 %

Procedure:
To a well stirred mixture of sodium periodate (1.76 g, 8.26 mmol) in pH 7 buffer (10 mL) and tetrahydrofuran (15 mL) was added 6-fluoro-2-(2-dimethylamino-vinyl)-3,4-dihydro-3-(2-methyl-pyridin-3-yl)-quinazolin-4-one (0.69 g, 2.12 mmol) all at once. The mixture warmed slightly to the touch and was stirred for 1 hour at ambient temperature. The reaction was concentrated at reduced pressure and the residue treated with a 1:2 mixture of water and chloroform. The tan solid was collected, washed well with water and chloroform and dried under a stream of nitrogen to afford 0.50 g (80%) of 6-fluoro-3,4-dihydro-3-(2-methyl-pyridin-3-yl)-quinazolin-4-one-2-carboxaldehyde as a 1:1 mixture of free aldehyde and hydrate which had: mp 175-177° C.; 1H NMR δ 9.46 (s, 0.5 H) [CHO], 8.53 (br s, 1 H), 8.10-8.07 (s, 0.5 H), 7.94-7.70 (m, 3.5 H), 7.39-7.32 (m, 1 H), 6.59 (br s, 0.5 H) [hydrate OH], 6.47 (br s, 0.5 H) [hydrate OH], 5.17 (s, 0.5 H) [hydrate methine CH], 2.20 (s, 3 H); APCI MS m/z=284.1 (P+1).
Reaction SMILES: [C:1]([O:7][CH2:8][O:9][C:10]([C@@H:12]([CH2:25][C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1)[CH2:13][C@H:14]([CH2:18][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)[C:15](Cl)=[O:16])=[O:11])(=[O:6])[C:2]([CH3:5])([CH3:4])[CH3:3].[CH2:32]([O:39][C:40](=[O:47])[C@H:41]([CH2:43][CH:44]([CH3:46])[CH3:45])[NH2:42])[C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1.C(N(CC)CC)C>C(Cl)Cl>[CH2:32]([O:39][C:40](=[O:47])[C@H:41]([CH2:43][CH:44]([CH3:45])[CH3:46])[NH:42][C:15](=[O:16])[C@@H:14]([CH2:18][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)[CH2:13][C@@H:12]([C:10]([O:9][CH2:8][O:7][C:1](=[O:6])[C:2]([CH3:5])([CH3:4])[CH3:3])=[O:11])[CH2:25][C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1)[C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1
Reactant: CC(C)(C)C(=O)OCOC(=O)[C@@H](Cc1ccccc1)C[C@H](Cc1ccccc1)C(=O)Cl
Reactant: CC(C)C[C@H](N)C(=O)OCc1ccccc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(C)C[C@H](NC(=O)[C@@H](Cc1ccccc1)C[C@H](Cc1ccccc1)C(=O)OCOC(=O)C(C)(C)C)C(=O)OCc1ccccc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
4-(Pivaloyloxymethoxycarbonyl)-2,4-(R*,R*)-dibenzylbutyryl chloride (1.2 g) in 10 ml of methylene chloride is added slowly to a solution of 0.60 g of (L)-leucine benzyl ester and 0.30 ml of triethylamine in 20 ml of methylene chloride. The reaction is stirred overnight at room temperature. The solution is washed with 2 N hydrochloric acid, then with saturated sodium bicarbonate, dried over magnesium sulfate, filtered and concentrted to give N-[4-pivaloyloxymethoxycarbonyl-(R*,R*)-2,4-dibenzylbutyryl]-L-leucine benzyl ester.