Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C([O:3][C:4]([C:6]1[N:16]=[CH:15][CH:14]=[CH:13][C:7]=1[C:8]([O:10][CH2:11][CH3:12])=[O:9])=[CH2:5])C.Cl>CC(C)=O>[C:4]([C:6]1[N:16]=[CH:15][CH:14]=[CH:13][C:7]=1[C:8]([O:10][CH2:11][CH3:12])=[O:9])(=[O:3])[CH3:5]
Reactant: C=C(OCC)c1ncccc1C(=O)OCC
Agent: Cl
Solvent: CC(C)=O
Product: CCOC(=O)c1cccnc1C(C)=O
Temperature: 25 °C
Reaction time: 8 h
Yield: 63.6 %

Procedure:
To a mixture of ethyl 2-(1-ethoxyvinyl)nicotinate (27 g) and acetone (300 mL) was added 2M hydrochloric acid (370 mL), and the mixture was stirred overnight at room temperature. The solvent was evaporated under reduced pressure, to the residue were added ethyl acetate and saturated aqueous sodium hydrogen carbonate solution, and the mixture was extracted with ethyl acetate. The extract was washed with saturated brine, and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate/hexane) to give the title compound (15 g).
Reaction SMILES: [CH2:1]([CH:8]1[CH2:13][CH2:12][NH:11][CH2:10][CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:14](Cl)([Cl:16])=[O:15]>>[CH2:1]([CH:8]1[CH2:13][CH2:12][N:11]([C:14]([Cl:16])=[O:15])[CH2:10][CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C(Cl)Cl
Reactant: c1ccc(CC2CCNCC2)cc1
Product: O=C(Cl)N1CCC(Cc2ccccc2)CC1
Temperature: 0 °C
Reaction time: 1 h
Yield: 69.1 %

Procedure:
4-Benzylpiperidine (0.5 g, 2.86 mmol) was added to a mixture of phosgene (3.8 ml of 20% phosgene in toluene solution, 7.13 mmol). The mixture was stirred at 0° C. for 1 hour. The reaction mixture was partitioned between water (25 ml) and ethyl acetate (2×25 ml). The organic phase was washed with 1N HCl (1×40 ml), saturated sodium chloride (1×50 ml), dried over sodium sulfate and concentrated to give a yellow oil. Purification by flash column chromatography (silica gel, 0-10% ethyl acetate/hexane) gave 0.47 g of title product. IR (film) 1733.1 cm−1.
Reaction SMILES: Br[C:2]1[C:7]([O:8][CH3:9])=[CH:6][CH:5]=[CH:4][N:3]=1.[NH2:10][C:11]1[C:16]([Cl:17])=[CH:15][C:14]([CH:18]([CH2:20][N:21]([CH2:32][C:33]2[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=2)[CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][O:28][CH2:29][C:30]#[CH:31])[OH:19])=[CH:13][C:12]=1[Cl:39]>C(NCC)C.C1COCC1.[Cu]I>[NH2:10][C:11]1[C:12]([Cl:39])=[CH:13][C:14]([CH:18]([CH2:20][N:21]([CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][O:28][CH2:29][C:30]#[C:31][C:2]2[C:7]([O:8][CH3:9])=[CH:6][CH:5]=[CH:4][N:3]=2)[CH2:32][C:33]2[CH:34]=[CH:35][CH:36]=[CH:37][CH:38]=2)[OH:19])=[CH:15][C:16]=1[Cl:17]
Reactant: COc1cccnc1Br
Reactant: C#CCOCCCCCCN(Cc1ccccc1)CC(O)c1cc(Cl)c(N)c(Cl)c1
Agent: [Cu]I
Solvent: C1CCOC1
Solvent: CCNCC
Product: COc1cccnc1C#CCOCCCCCCN(Cc1ccccc1)CC(O)c1cc(Cl)c(N)c(Cl)c1
Yield: 77.7 %

Procedure:
A solution of 2-bromo-3-methoxypyridine (2 g), 4-amino-3,5-dichloro-α-[[(phenylmethyl)[6-[(2-propynyl)oxy]hexyl]amino]methyl]benzenemethanol (5.74 g), BTPC (150 mg), copper (I) iodide (15 mg) in diethylamine (20 ml) and THF (10 ml) was stirred under nitrogen overnight. The solution was concentrated in vacuo to give a brown oil which was purified by FCC eluting with System C (95:5:1) to give the title compound as a brown oil (4.6 g), t.l.c. (System A 80:20:1) Rf 0.6.
Reaction SMILES: C[Al](C)C.C1(C)C=CC=CC=1.[NH:12]1[CH2:17][CH2:16][O:15][CH2:14][CH2:13]1.C([O:20][C:21](=O)[CH2:22][C:23]1[N:24]=[C:25]2[CH:30]=[CH:29][C:28]([Br:31])=[CH:27][N:26]2[CH:32]=1)C>ClCCl.[Cl-].[NH4+]>[Br:31][C:28]1[CH:29]=[CH:30][C:25]2[N:26]([CH:32]=[C:23]([CH2:22][C:21]([N:12]3[CH2:17][CH2:16][O:15][CH2:14][CH2:13]3)=[O:20])[N:24]=2)[CH:27]=1
Reactant: C1COCCN1
Reactant: CCOC(=O)Cc1cn2cc(Br)ccc2n1
Agent: C[Al](C)C
Agent: [Cl-]
Agent: [NH4+]
Solvent: Cc1ccccc1
Solvent: ClCCl
Product: O=C(Cc1cn2cc(Br)ccc2n1)N1CCOCC1
Temperature: 40 °C
Reaction time: 0.17 h
Yield: 43.7 %

Procedure:
Add 2M trimethylaluminum in toluene (1.94 mL, 3.88 mmol) to a solution of morpholine (0.34 g, 3.88 mmol) in dichloromethane (10 mL). Stir for 10 min and add a solution of (6-bromo-imidazo[1,2-a]pyridin-2-yl)-acetic acid ethyl ester (1.1 g, 3.88 mmol) in dichloromethane (12 mL). Heat at 40° C. for 1 h, carefully dilute with saturated aqueous ammonium chloride and extract into dichloromethane. Concentration followed by filtration gives the titled compound (0.55 g, 43%) as a white solid. TOF MS ES+ exact mass calculated for C13H14BrN3O2 (p+1): m/z=324.0348; Found: 324.0330. 1H NMR (400 MHz, DMSO-d6) δ 8.84 (m, 1H), 7.77 (s, 1H), 7.45 (d, J=10 Hz, 1H), 7.29 (dd, J=10, 2.0 Hz, 1H), 3.81 (s, 2H), 3.55-3.4 (m, 8H).
Reaction SMILES: [CH2:1]([NH2:7])[C:2]1[O:6][CH:5]=[CH:4][CH:3]=1.[OH-].[Na+].C(Cl)Cl.[O-]Cl.[Na+].[C:16](=S)=[S:17]>O>[CH2:1]([N:7]=[C:16]=[S:17])[C:2]1[O:6][CH:5]=[CH:4][CH:3]=1
Reactant: S=C=S
Reactant: NCc1ccco1
Agent: [Na+]
Agent: [O-]Cl
Agent: [OH-]
Solvent: ClCCl
Solvent: O
Product: S=C=NCc1ccco1
Temperature: 20 °C
Reaction time: 16 h

Procedure:
Furfurylamine (9.71 g) is added over 30 minutes to a stirred, cooled mixture of 8.84 g of NaOH, 20 ml of CH2Cl2, 15 ml of H2O and 7.5 ml of CS2. The mixture is stirred 55 minutes in the ice bath and 600 ml of 5.25% aqueous NaOCl solution is added over 1 hour and 45 minutes (temperature is maintained at 8° C. or less). After stirring 16 hours at 20° C., the reaction mixture is extracted three times with CH2Cl2 (total volume of combined CH2Cl2 extracts is 600 ml). The CH2Cl2 extract is washed with 2×100 ml of H2O, dried with Na2SO4 and evaporated to give 12.4 g of crude furfurylisothiocyanate.
Reaction SMILES: Br[CH2:2][C:3]1[CH:8]=[CH:7][C:6]([CH2:9][C:10]([OH:12])=[O:11])=[CH:5][CH:4]=1.[N-:13]=[N+:14]=[N-:15].[Na+]>CC(C)=O.O>[N:13]([CH2:2][C:3]1[CH:8]=[CH:7][C:6]([CH2:9][C:10]([OH:12])=[O:11])=[CH:5][CH:4]=1)=[N+:14]=[N-:15]
Reactant: O=C(O)Cc1ccc(CBr)cc1
Reactant: [N-]=[N+]=[N-]
Agent: [Na+]
Solvent: O
Solvent: CC(C)=O
Product: [N-]=[N+]=NCc1ccc(CC(=O)O)cc1
Temperature: 25 °C
Reaction time: 20 h
Yield: 71.7 %

Procedure:
A solution of p-bromomethylphenylacetic acid (3.64 g, 15.9 mmol) in acetone (100 ml) was treated with a solution of sodium azide (1.04 g, 16.0 mmol) in H2O (15 ml). The mixture was stirred at room temperature overnight (ca. 20 h). After evaporation of the acetone, the residual solution was cooled in an ice-bath. The white gelatinous precipitate that formed was collected, washed with cold water and dried yielding 2.175 g (11.4 mmol, 71.5%) of p-azidomethylphenylacetic acid as a white solid: 1Hmr (DMSO-d6) δ: 3.59 (2H, s,--CH2CO2), 4.42 (2H, s,--CH2N3) and 7.32 ppm (4H, s, aromatic Hs); ir (nujol) νmax : 2500-3400 (b, --CO2H), 2070 (s, --N3) and 1690 cm-1 (s, C=O).
Reaction SMILES: Cl[CH2:2][CH2:3][C:4]([C:6]1[S:10][C:9]2[CH2:11][C:12]([CH3:15])([CH3:14])[CH2:13][C:8]=2[CH:7]=1)=[O:5].S(=O)(=O)(O)O.P([O-])([O-])(O)=O.[K+].[K+].C(OCC)(=O)C>O>[CH3:14][C:12]1([CH3:15])[CH2:13][C:8]2[C:7]3[CH2:2][CH2:3][C:4](=[O:5])[C:6]=3[S:10][C:9]=2[CH2:11]1
Reactant: CC1(C)Cc2cc(C(=O)CCCl)sc2C1
Agent: O=P([O-])([O-])O
Agent: O=S(=O)(O)O
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: O
Product: CC1(C)Cc2sc3c(c2C1)CCC3=O
Temperature: 90 °C
Yield: 37 %

Procedure:
A 100-mL single-neck round-bottomed flask equipped with a magnetic stirrer was charged with crude 105e (2.86 g, 10.0 mmol presuming quantitative yield) and 98% sulfuric acid. The reaction mixture was heated in a 90° C. oil bath overnight. The reaction mixture was placed into an ice/acetone bath, and a cold (5° C.) solution of dipotassium hydrogen phosphate (105 g, 0.603 mol) in water (300 mL) was added in one portion. The resulting mixture was shaken with ethyl acetate (300 mL) and filtered. The filter cake was washed with ethyl acetate (100 mL). The ethyl acetate layer of the filtrate was separated, dried over sodium sulfate and evaporated under reduced pressure on a rotary evaporator. the resulting residue was purified by flash column chromatography (silica, 80:20 hexanes/ethyl acetate) to afford 105f in 37% yield over two steps (683 mg) as an amorphous brown solid: mp 60-62° C.; 1H NMR (500 MHz, CDCl3) d 2.92-2.87 (m, 4H), 2.79 (s, 2H), 2.53 (s, 2H), 1.26 (s, 6H); MS (ESI+) m/z 207.0 (M+H)
Reaction SMILES: [F:1][C:2]([F:15])([F:14])[C:3]1[CH:4]=[C:5]([OH:13])[CH:6]=[C:7]([C:9]([F:12])([F:11])[F:10])[CH:8]=1.Cl[S:17]([N:20]=C=O)(=[O:19])=[O:18]>C1(C)C=CC=CC=1>[F:1][C:2]([F:14])([F:15])[C:3]1[CH:4]=[C:5]([O:13][S:17](=[O:19])(=[O:18])[NH2:20])[CH:6]=[C:7]([C:9]([F:11])([F:10])[F:12])[CH:8]=1
Reactant: O=C=NS(=O)(=O)Cl
Reactant: Oc1cc(C(F)(F)F)cc(C(F)(F)F)c1
Solvent: Cc1ccccc1
Product: NS(=O)(=O)Oc1cc(C(F)(F)F)cc(C(F)(F)F)c1
Yield: 48.1 %

Procedure:
This compound was prepared using the procedure of Example 56 from a mixture of 9.8 g (0.043 mole) of 3,5-bis(trifluoromethyl)phenol and 3.9 ml (0.095 mole) of chlorosulfonyl isocyanate in 50 ml of toluene. The solid product was recrystallized from benzene to yield 6.4 g (48%) of a pale yellow solid, mp 118°-120° C.
Reaction SMILES: [C:1]([O:14][C@H:15]([CH2:41][O:42][C:43](=[O:55])[CH2:44][CH2:45][CH2:46][CH2:47][CH2:48][CH2:49][CH2:50][CH2:51][CH2:52][CH2:53][CH3:54])[CH2:16][S:17][CH2:18][C@@H:19]([C:38](O)=[O:39])[NH:20][C:21](=[O:37])[O:22][CH2:23][CH:24]1[C:36]2[CH:35]=[CH:34][CH:33]=[CH:32][C:31]=2[C:30]2[C:25]1=[CH:26][CH:27]=[CH:28][CH:29]=2)(=[O:13])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH3:12].Cl.[NH2:57][CH2:58][CH2:59][CH2:60][C:61]([P:64](=[O:71])([O:68][CH2:69][CH3:70])[O:65][CH2:66][CH3:67])([F:63])[F:62].CCN(C(C)C)C(C)C.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>C(Cl)Cl>[CH:35]1[C:36]2[CH:24]([CH2:23][O:22][C:21]([NH:20][C@@H:19]([CH2:18][S:17][CH2:16][C@H:15]([O:14][C:1](=[O:13])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH3:12])[CH2:41][O:42][C:43](=[O:55])[CH2:44][CH2:45][CH2:46][CH2:47][CH2:48][CH2:49][CH2:50][CH2:51][CH2:52][CH2:53][CH3:54])[C:38]([NH:57][CH2:58][CH2:59][CH2:60][C:61]([P:64](=[O:71])([O:68][CH2:69][CH3:70])[O:65][CH2:66][CH3:67])([F:62])[F:63])=[O:39])=[O:37])[C:25]3[C:30](=[CH:29][CH:28]=[CH:27][CH:26]=3)[C:31]=2[CH:32]=[CH:33][CH:34]=1
Reactant: CCCCCCCCCCCC(=O)OC[C@H](CSC[C@H](NC(=O)OCC1c2ccccc2-c2ccccc21)C(=O)O)OC(=O)CCCCCCCCCCC
Reactant: CCOP(=O)(OCC)C(F)(F)CCCN
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CCCCCCCCCCCC(=O)OC[C@H](CSC[C@H](NC(=O)OCC1c2ccccc2-c2ccccc21)C(=O)NCCCC(F)(F)P(=O)(OCC)OCC)OC(=O)CCCCCCCCCCC
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of (5R,9R)-9-(dodecanoyloxy)-1-(9H-fluoren-9-yl)-3,12-dioxo-2,11-dioxa-7-thia-4-azatricosane-5-carboxylic acid (6, 1 eq) in DCM (0.1 M) was added diethyl 4-amino-1,1-difluorobutylphosphonate hydrochloride (1.1 eq), DIEA (3.5 eq) and HBTU (1.1 eq). The reaction mixture was then stirred at room temperature for 2 hours. The mixture was purified by flash chromatography on a COMBIFLASH® system (ISCO) using 30-70% EtOAc/Hex to give the product.
Reaction SMILES: C(O)(C(F)(F)F)=O.[Br:8][C:9]1[CH:42]=[CH:41][C:12]([NH:13][C:14]2[C:23]3[C:18](=[CH:19][C:20]([O:26][CH2:27][CH:28]4[CH2:33][CH2:32][N:31](C(OC(C)(C)C)=O)[CH2:30][CH2:29]4)=[C:21]([O:24][CH3:25])[CH:22]=3)[N:17]=[CH:16][N:15]=2)=[C:11]([F:43])[CH:10]=1>C(Cl)Cl>[Br:8][C:9]1[CH:42]=[CH:41][C:12]([NH:13][C:14]2[C:23]3[C:18](=[CH:19][C:20]([O:26][CH2:27][CH:28]4[CH2:29][CH2:30][NH:31][CH2:32][CH2:33]4)=[C:21]([O:24][CH3:25])[CH:22]=3)[N:17]=[CH:16][N:15]=2)=[C:11]([F:43])[CH:10]=1
Reactant: COc1cc2c(Nc3ccc(Br)cc3F)ncnc2cc1OCC1CCN(C(=O)OC(C)(C)C)CC1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: COc1cc2c(Nc3ccc(Br)cc3F)ncnc2cc1OCC1CCNCC1
Temperature: 25 °C
Reaction time: 1 h
Yield: 70.4 %

Procedure:
TFA (3 ml) was added to a suspension of 4-(4-bromo-2-fluoroanilino)-7-(1-(tert-butoxycarbonyl)piperidin-4-ylmethoxy)-6-methoxyquinazoline (673 mg, 1.2 mmol) in methylene chloride (10 ml). After stirring for 1 hour at ambient temperature, the volatiles were removed under vacuum. The residue was triturated with a mixture of water/ether. The organic layer was separated. The aqueous layer was washed again with ether. The aqueous layer was adjusted to pH 10 with 2N aqueous sodium hydroxide. The aqueous layer was extracted with methylene chloride. The organic layer was dried (MgSO4) and the solvent was removed under vacuum. The solid was triturated with a mixture ether/petroleum ether (1/1), filtered, washed with ether and dried under vacuum to give 4-(4-bromo-2-fluoroanilino)-6-methoxy-7-(piperidin-4-ylmethoxy)quinazoline (390 mg, 70.5%).
Reaction SMILES: [Cl:1][C:2]1[CH:21]=[CH:20][C:5]([NH:6][C:7]2[C:16]3[C:11](=[CH:12][C:13]([OH:19])=[C:14]([O:17][CH3:18])[CH:15]=3)[N:10]=[CH:9][N:8]=2)=[C:4]([F:22])[CH:3]=1.Cl.Cl[CH2:25][CH2:26][O:27][C:28]1[CH:29]=[N:30][CH:31]=[CH:32][CH:33]=1.C(=O)([O-])[O-].[K+].[K+]>CN1C(=O)CCC1.O>[Cl:1][C:2]1[CH:21]=[CH:20][C:5]([NH:6][C:7]2[C:16]3[C:11](=[CH:12][C:13]([O:19][CH2:25][CH2:26][O:27][C:28]4[CH:29]=[N:30][CH:31]=[CH:32][CH:33]=4)=[C:14]([O:17][CH3:18])[CH:15]=3)[N:10]=[CH:9][N:8]=2)=[C:4]([F:22])[CH:3]=1
Reactant: ClCCOc1cccnc1
Reactant: COc1cc2c(Nc3ccc(Cl)cc3F)ncnc2cc1O
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN1CCCC1=O
Product: COc1cc2c(Nc3ccc(Cl)cc3F)ncnc2cc1OCCOc1cccnc1
Temperature: 90 °C
Yield: 21.5 %

Procedure:
A mixture of 4-(4-chloro-2-fluoroanilino)-7-hydroxy-6-methoxyquinazoline (350 mg, 1.0 mmol), (prepared as described for the starting material in Example 24), 3-(2-chloroethoxy)pyridine hydrochloride (234 mg, 1.2 mmol) and potassium carbonate (456 mg, 3.3 mmol) in NMP (20 ml) was heated at 90° C. for 2 hours. The mixture was allowed to cool, diluted with water and extracted with ethyl acetate. The combined extracts were washed with water, dried (MgSO4) and the solvent removed by evaporation. The residue was purified by column chromatography eluting with methylene chloride/methanol mixtures (100/0 increasing to 95/5) to give 4-(4-chloro-2-fluoroanilino)-6-methoxy-7-(2-(3-pyridyloxy)ethoxy)quinazoline (95 mg, 20%).
Reaction SMILES: [CH3:1][N:2]1[C:3]2[C:8]([S:9]/[C:10]/1=[N:11]\[NH2:12])=[CH:7][CH:6]=[CH:5][CH:4]=2.C=O.Cl.CN1[C:21]2C=CC=[CH:25][C:20]=2SC1=NN>O>[CH3:21][C:20]([CH3:25])=[N:12]/[N:11]=[C:10]1/[N:2]([CH3:1])[C:3]2[C:8]([S:9]/1)=[CH:7][CH:6]=[CH:5][CH:4]=2
Reactant: Cn1/c(=N/N)sc2ccccc21
Reactant: Cn1c(=NN)sc2ccccc21
Agent: C=O
Agent: Cl
Solvent: O
Product: CC(C)=N/N=c1\sc2ccccc2n1C
Temperature: 25 °C

Procedure:
All reagents were the purest commercially available grade and deionized water was used throughout the preparation. The synthesis was a modification of the Hunig and Fritsch method for the preparation of MBTH-formaldehyde condensation product (Liebigs, Ann. Chem., 1957, 609, 172). 3-Methyl-2-benzothiazolinone hydrazone hydrochloride (Aldrich), 4.0 g, was dissolved in 200 mL of water with stirring and the free base precipitated by the addition of 10 mL of concentrated ammonium hydroxide solution. The crystalline product was filtered with suction and washed until the wash water no longer tested alkaline with pH indicator paper. The solid product was then vacuum dried at room temperature, and dissovled with vigorous shaking in 100 mL of absolute ethanol in a 250 mL round-bottom flask. To this solution, 20 mL of acetone and 10 mL of glacial acetic acid were added, and the solution refluxed over a boiling water bath for 0.5 h. After cooling to room temperature; the slow addition of 300 mL of water produced a white product which, upon filtering and drying at room temperature, was obtained in nearly theoretical yield as 3-methyl-2-benzothiazolinone acetone azine. The product was sufficiently pure for use but it may be further purified by recrystallization for cyclohexanol.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([F:11])([F:10])[F:9])=[CH:4][C:3]=1[OH:12].[C:13](O)(=[O:20])[C:14]1[CH:19]=[CH:18][N:17]=[CH:16][CH:15]=1.CCN=C=NCCCN(C)C.N1C=CC=CC=1>O>[OH:12][C:3]1[CH:4]=[C:5]([C:8]([F:9])([F:10])[F:11])[CH:6]=[CH:7][C:2]=1[NH:1][C:13](=[O:20])[C:14]1[CH:19]=[CH:18][N:17]=[CH:16][CH:15]=1
Reactant: Nc1ccc(C(F)(F)F)cc1O
Reactant: O=C(O)c1ccncc1
Agent: CCN=C=NCCCN(C)C
Solvent: O
Solvent: c1ccncc1
Product: O=C(Nc1ccc(C(F)(F)F)cc1O)c1ccncc1
Temperature: 80 °C
Yield: 72.7 %

Procedure:
A mixture of 1.30 g of 2-amino-5-trifluoromethylphenol, 0.9 g of isonicotinic acid, 1.83 g of WSC and 15 ml of pyridine was stirred while heating at 80° C. for three hours. The mixture was cooled to room temperature, and then water was poured. Precipitated solid was filtered and washed with water, and then dried under reduced pressure to give 1.5 g of N-(2-hydroxy-4-trifluoromethylphenyl)isonicotinamide.
Reaction SMILES: C(NC(C)C)(C)C.C([Li])CCC.[CH3:13][C:14]1[N:22]=[CH:21][CH:20]=[CH:19][C:15]=1[C:16]([OH:18])=[O:17].[F:23][C:24]1[CH:25]=[C:26]([CH:29]=[CH:30][CH:31]=1)[CH2:27]Br>O1CCCC1>[F:23][C:24]1[CH:25]=[C:26]([CH2:27][CH2:13][C:14]2[N:22]=[CH:21][CH:20]=[CH:19][C:15]=2[C:16]([OH:18])=[O:17])[CH:29]=[CH:30][CH:31]=1
Reactant: Cc1ncccc1C(=O)O
Reactant: Fc1cccc(CBr)c1
Agent: [Li]CCCC
Solvent: CC(C)NC(C)C
Solvent: C1CCOC1
Product: O=C(O)c1cccnc1CCc1cccc(F)c1
Temperature: -78 °C
Reaction time: 1 h

Procedure:
Dissolve diisopropylamine (3.8 mL, 27.3 mmol) in dry tetrahydrofuran (75 mL). Chill the resulting mixture to −78° C. and add butyl lithium (1.6M solution in hexanes, 17.1 mL, 27.3 mmol). Warm the reaction mixture to 0° C. and add a fine slurry of 2-methyl-nicotinic acid (1.5 g, 10.9 mmol) in THF (25 mL) portionwise during 10 min. Stir the resulting slurry for 1 h, then add 3-fluorobenzyl bromide (2.0 mL, 16.4 mmol) and stir 5 min. Quench the reaction with water (100 mL). Extract the reaction mixture with diethyl ether (100 mL). Adjust the pH of the aqueous layer to 3.1 with concentrated aqueous hydrochloric acid solution. Treat the resulting slurry with ethyl acetate and stir to dissolve all solids. Separate the layers and extract the aqueous layer with ethyl acetate. Concentrate the combined extracts to dryness. LCMS (APCI-pos): 244.1 (M+H).
Reaction SMILES: [ClH:1].C([N:9]1[CH2:14][CH2:13][N:12]([C:15](=[O:28])[C:16]2[CH:21]=[C:20]([O:22][CH3:23])[C:19]([O:24][CH3:25])=[C:18]([O:26][CH3:27])[CH:17]=2)[CH2:11][CH:10]1[CH2:29][O:30][CH2:31][CH3:32])C1C=CC=CC=1>CO.[H][H].[C].[Pd]>[ClH:1].[CH2:31]([O:30][CH2:29][CH:10]1[NH:9][CH2:14][CH2:13][N:12]([C:15](=[O:28])[C:16]2[CH:21]=[C:20]([O:22][CH3:23])[C:19]([O:24][CH3:25])=[C:18]([O:26][CH3:27])[CH:17]=2)[CH2:11]1)[CH3:32]
Reactant: CCOCC1CN(C(=O)c2cc(OC)c(OC)c(OC)c2)CCN1Cc1ccccc1
Reactant: [H][H]
Agent: [Pd]
Agent: Cl
Solvent: CO
Product: CCOCC1CN(C(=O)c2cc(OC)c(OC)c(OC)c2)CCN1
Yield: 99.2 %

Procedure:
In methanol (15 ml) is dissolved 1-benzyl-2-ethoxymethyl-4-(3,4,5-trimethoxybenzoyl)piperazine hydrochloride (1.0 g) obtained in Reference Example 12. To the solution is added 10% palladium-carbon (0.3 g), and the mixture is stirred for 3 hours in hydrogen streams. The reaction mixture is subjected to filtration, and the filtrate is subjected to distillation under reduced pressure to leave crystals, followed by recrystallization from ethanol-ether to afford 3-ethoxymethyl-1-(3,4,5-trimethoxybenzoyl)piperazine hydrochloride (0.8 g) as colorless crystals, m.p 203-204° C.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([C:8]2[O:12][N:11]=[C:10]([CH3:13])[C:9]=2[NH:14][CH:15]([CH3:26])[CH2:16][CH2:17][C:18]2[C:23]([F:24])=[CH:22][CH:21]=[CH:20][C:19]=2[Cl:25])=[CH:4][CH:3]=1.[CH2:27]([O:29][C:30]([C:32]1([C:35]2[CH:40]=[CH:39][C:38](B3OC(C)(C)C(C)(C)O3)=[CH:37][CH:36]=2)[CH2:34][CH2:33]1)=[O:31])[CH3:28]>>[CH2:27]([O:29][C:30]([C:32]1([C:35]2[CH:40]=[CH:39][C:38]([C:2]3[CH:7]=[CH:6][C:5]([C:8]4[O:12][N:11]=[C:10]([CH3:13])[C:9]=4[NH:14][CH:15]([CH3:26])[CH2:16][CH2:17][C:18]4[C:23]([F:24])=[CH:22][CH:21]=[CH:20][C:19]=4[Cl:25])=[CH:4][CH:3]=3)=[CH:37][CH:36]=2)[CH2:33][CH2:34]1)=[O:31])[CH3:28]
Reactant: CCOC(=O)C1(c2ccc(B3OC(C)(C)C(C)(C)O3)cc2)CC1
Reactant: Cc1noc(-c2ccc(Br)cc2)c1NC(C)CCc1c(F)cccc1Cl
Product: CCOC(=O)C1(c2ccc(-c3ccc(-c4onc(C)c4NC(C)CCc4c(F)cccc4Cl)cc3)cc2)CC1

Procedure:
Prepared according to the procedure described in Example 108, Step 2, using [5-(4-bromo-phenyl)-3-methyl-isoxazol-4-yl]-[3-(2-chloro-6-fluoro-phenyl)-1-methyl-propyl]-amine and 1-[4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-phenyl]-cyclopropanecarboxylic acid ethyl ester.
Reaction SMILES: [H-].[Na+].[C:3]([O:9][CH2:10][CH3:11])(=[O:8])[CH2:4][C:5](C)=O.CS(C1[N:17]=[N:18][C:19]([C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)=[C:20]([C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)[N:21]=1)(=O)=O>C1COCC1>[C:22]1([C:20]2[N:21]=[C:5]([CH2:4][C:3]([O:9][CH2:10][CH3:11])=[O:8])[N:17]=[N:18][C:19]=2[C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=1
Reactant: CCOC(=O)CC(C)=O
Reactant: CS(=O)(=O)c1nnc(-c2ccccc2)c(-c2ccccc2)n1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CCOC(=O)Cc1nnc(-c2ccccc2)c(-c2ccccc2)n1
Temperature: 60 °C
Reaction time: 0.25 h

Procedure:
To a suspension of NaH (41 mg, 1.61 mmol) in THF (2 ml) at 0° C. was added ethyl acetoacetate (105 mg. 0.80 mmol) dropwise. After the mixture was stirred for 15 min, a solution of 3-(methylsulfonyl)-5,6-diphenyl-1,2,4-triazine (Compound 87) (250 mg, 0.80 mmol) in THF (3 ml) was cannulated into the solution, and the resulting solution was heated to 60° C. for 2 hours. The reaction was then quenched with water. The product was extracted with ethyl acetate. The organic layer was washed with water, and brine, and dried over Na2SO4. The filtered solvent was concentrated in vacuo, and the residue was purified by silica gel chromatography (20% ethyl acetate in hexane) to give title compound as a solid.
Reaction SMILES: [H-].[Na+].[CH3:3][CH2:4][O:5][C:6](/[CH:8]=[CH:9]/[CH2:10]P(OCC)(OCC)=O)=[O:7].[CH:19]([C:21]1[N:26]2[CH:27]=[N:28][CH:29]=[C:25]2[CH:24]=[CH:23][CH:22]=1)=O>C1(C)C=CC=CC=1>[CH2:4]([O:5][C:6]([CH:8]=[CH:9][CH:10]=[CH:19][C:21]1[N:26]2[CH:27]=[N:28][CH:29]=[C:25]2[CH:24]=[CH:23][CH:22]=1)=[O:7])[CH3:3]
Reactant: CCOC(=O)/C=C/CP(=O)(OCC)OCC
Reactant: O=Cc1cccc2cncn12
Agent: [H-]
Agent: [Na+]
Solvent: Cc1ccccc1
Product: CCOC(=O)C=CC=Cc1cccc2cncn12
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a stirred suspension of 150 mg of sodium hydride in 25 ml of toluene is added 550 mg of triethyl 4-phosphonocrotonate in a dropwise manner over a 10-minute period. The reaction mixture is maintained at 5° by cooling in an ice-water bath. On completion of the addition, 300 mg of 5-formylimidazol[1,5-a]pyridine is added to the reaction mixture which is then allowed to stir at room temperature for 1 hour. The reaction mixture is poured into 100 ml of ice water and extracted with 2×100 ml of ethyl acetate. The ethyl acetate extracts are combined and dried over magnesium sulfate, filtered and evaporated to dryness to yield an oily residue. This is purified by column chromatography on silica gel using a mixture of diethyl ether and ethyl acetate as eluent. Evaporation of the solvent under reduced pressure yields 5-(4-ethoxycarbonylbuta-1,3-dienyl)-imidazo[1,5-a]pyridine melting at 101°-103°.