Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[C:12]([C:14]([N:16]3[CH2:20][CH2:19][CH2:18][CH2:17]3)=[O:15])[CH:11]=[C:10]([C:21]([OH:23])=O)[CH:9]=2)=[CH:4][CH:3]=1.[Cl:24][C:25]1[CH:30]=[CH:29][C:28]([CH:31]([NH2:33])[CH3:32])=[CH:27][C:26]=1[S:34]([CH3:37])(=[O:36])=[O:35].F[P-](F)(F)(F)(F)F.C[N+](C)=C(N(C)C)ON1C2N=CC=CC=2N=N1.C(N(CC)C(C)C)(C)C>CN(C)C=O>[Cl:24][C:25]1[CH:30]=[CH:29][C:28]([CH:31]([NH:33][C:21]([C:10]2[CH:9]=[C:8]([C:5]3[CH:4]=[CH:3][C:2]([CH3:1])=[CH:7][CH:6]=3)[CH:13]=[C:12]([C:14]([N:16]3[CH2:17][CH2:18][CH2:19][CH2:20]3)=[O:15])[CH:11]=2)=[O:23])[CH3:32])=[CH:27][C:26]=1[S:34]([CH3:37])(=[O:35])=[O:36]
Reactant: Cc1ccc(-c2cc(C(=O)O)cc(C(=O)N3CCCC3)c2)cc1
Reactant: CC(N)c1ccc(Cl)c(S(C)(=O)=O)c1
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: Cc1ccc(-c2cc(C(=O)NC(C)c3ccc(Cl)c(S(C)(=O)=O)c3)cc(C(=O)N3CCCC3)c2)cc1
Temperature: 50 °C
Reaction time: 16 h

Procedure:
To a solution of 4′-methyl-5-(pyrrolidine-1-carbonyl)biphenyl-3-carboxylic acid (17 mg, 0.055 mmol) in N,N-dimethylformamide (0.5 mL) were added 1-(4-chloro-3-(methylsulfonyl)phenyl)ethanamine (50 mg, 0.21 mmol), N,N,N′,N′-tetramethyl-O-(7-azabenzotriazol-1-yl)uronium hexafluorophosphate (80 mg, 0.21 mmol) and N,N-diisopropylethylamine (80 μL, 0.46 mmol). The reaction mixture was stirred for 16 hours at 50° C. LC-MS indicated the reaction was complete. The mixture was purified by preparative HPLC to afford the final product as an off white solid.
Reaction SMILES: [Cl:1][C:2]1[N:3]([C@@H:15]2[O:21][C@H:20]([CH2:22][OH:23])[C@@H:18]([OH:19])[C@H:16]2[OH:17])[C:4]2[C:9]([C:10]=1[CH:11]=O)=[CH:8][C:7]([Cl:13])=[C:6]([Cl:14])[CH:5]=2.Cl.[O:25]([NH2:27])C.C(=O)(O)[O-].[Na+].CO.O>CO.O.S([O-])([O-])(=O)=S.[Na+].[Na+]>[Cl:1][CH:2]1[C:10](=[C:11]=[N:27][OH:25])[C:9]2[C:4](=[CH:5][C:6]([Cl:14])=[C:7]([Cl:13])[CH:8]=2)[N:3]1[C@@H:15]1[O:21][C@H:20]([CH2:22][OH:23])[C@@H:18]([OH:19])[C@H:16]1[OH:17]
Reactant: CON
Reactant: O=Cc1c(Cl)n([C@@H]2O[C@H](CO)[C@@H](O)[C@H]2O)c2cc(Cl)c(Cl)cc12
Agent: Cl
Agent: O=C([O-])O
Agent: O=S([O-])([O-])=S
Solvent: CO
Solvent: O
Product: OC[C@H]1O[C@@H](N2c3cc(Cl)c(Cl)cc3C(=C=NO)C2Cl)[C@H](O)[C@@H]1O
Temperature: 25 °C
Reaction time: 16 h
Yield: 69.7 %

Procedure:
To a solution of 2,5,6-trichloro-3-formyl-1-(β-D-ribofuranosyl)indole (4.3, 170 mg, 0.45 mmol) in MeOH (10 mL) was added a solution of methoxylamine hydrochloride (39 mg, 0.56 mmol) and sodium bicarbonate (49 mg, 0.48 mmol) in water (2.0 mL). The resulting mixture was stirred at room temperature for 16 h, then the solvent was evaporated to provide a pale yellow residue. The residue was suspended in 20 mL of 5% aqueous sodium thiosulfate and extracted with EtOAc (2×50 mL). The combined organic extracts were washed with brine (25 mL), dried over MgSO4, filtered and evaporated to yield a pink residue. The residue was subjected to column chromatography (40×350 mm) on C18 reverse-phase silica gel with 75% MeOH/H2O. The appropriate UV-active fractions were pooled and evaporated to yield 124 mg (70%) of 4.29 as a white powder. A portion was recrystallized from Et2O/hexane to yield a white crystalline solid: mp 208-209 C; Rf0.2 (10% MeOH/CHCl3); 1H NMR (500 MHz, DMSO-d6) δ 11.31 (s, 1H), 8.54 (s, 1H), 8.22 (s, 1H), 8.19 (s, 1H), 5.93 (d, 1H), 5.37 (m, 2H, D2O exch.), 5.25 (m, 1H, D2O exch.), 4.43 (m, 1H), 4.16 (m, 1H), 3.99 (m, 1H), 3.73 (m, 2H). 13C NMR (125 MHz, DMSO-d6) δ 141.30, 133.03, 128.48, 125.85, 124.73, 124.05, 121.76, 115.31, 106.70, 88.81, 86.02, 71.39, 69.65, 61.11. HRMS (EI) m/z calcd. for C14H13Cl3N2O5 393.9890, found 393.9892. Anal calcd for C14H13Cl3N2O5.½Et2O: C, 44.41; H, 4.19; N, 6.47. Found: C, 44.16; H, 4.18; N, 6.48.
Reaction SMILES: [BH4-].[Na+].[C:3]([C:7]1[CH:8]=[C:9]([N+:17]([O-:19])=[O:18])[C:10]([O:15][CH3:16])=[C:11]([CH:14]=1)[CH:12]=[O:13])([CH3:6])([CH3:5])[CH3:4]>ClCCl.CO>[C:3]([C:7]1[CH:8]=[C:9]([N+:17]([O-:19])=[O:18])[C:10]([O:15][CH3:16])=[C:11]([CH2:12][OH:13])[CH:14]=1)([CH3:6])([CH3:4])[CH3:5]
Reactant: COc1c(C=O)cc(C(C)(C)C)cc1[N+](=O)[O-]
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Solvent: ClCCl
Product: COc1c(CO)cc(C(C)(C)C)cc1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 2 h

Procedure:
At approx. 10° C., 0.65 g sodium borohydride are added to a solution of 3.75 g 5-tert-butyl-2-methoxy-3-nitro-benzaldehyde in 15 ml dichloromethane and 15 ml of methanol. The solution is stirred for 2 h at ambient temperature and then evaporated down. The residue is combined with aqueous acetic acid and extracted with ethyl acetate. The combined extracts are washed with water and with saturated aqueous saline solution, dried (MgSO4) and evaporated to dryness.
Reaction SMILES: [CH3:1][CH:2]([NH:4][CH2:5][C:6]1[C:11]([F:12])=[CH:10][CH:9]=[CH:8][C:7]=1[N+:13]([O-])=O)[CH3:3].O.O.[Sn](Cl)(Cl)(Cl)Cl.Cl.[OH-].[Na+]>O>[CH3:3][CH:2]([NH:4][CH2:5][C:6]1[C:11]([F:12])=[CH:10][CH:9]=[CH:8][C:7]=1[NH2:13])[CH3:1]
Reactant: CC(C)NCc1c(F)cccc1[N+](=O)[O-]
Agent: Cl
Agent: Cl[Sn](Cl)(Cl)Cl
Agent: [Na+]
Solvent: O
Product: CC(C)NCc1c(N)cccc1F

Procedure:
A suspension of N-(1-methylethyl)-(2-nitro-6-fluorophenyl)methylamine (0.4 g, 1.89 mmol), tin chloride dihydrate (1.75 g) in water (8 ml) was added HCl 12N (2 ml). The mixture was refluxed for 4 hours. Then, the reaction mixture was allowed to reach room temperature and was neutralized by addition of NaOH 2N and extracted with diethyl ether (1×100 ml), dried over MgSO4 and evaporated under reduced pressure to afford N-(1-methylethyl)-(2-amino-6-fluorophenyl)methylamine.
Reaction SMILES: C(Cl)(=O)C(C)(C)C.[CH:8]1([CH2:14][CH2:15][CH2:16][C:17]([OH:19])=O)[CH2:13][CH2:12][CH2:11][CH2:10][CH2:9]1.C(N(CC)CC)C.O1CCNC1=O.[Li]CCCC.[C:38]1([CH2:44][C@H:45]2[CH2:49][O:48][C:47](=[O:50])[NH:46]2)[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=1>C1COCC1>[CH:8]1([CH2:14][CH2:15][CH2:16][C:17]([N:46]2[C@@H:45]([CH2:44][C:38]3[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=3)[CH2:49][O:48][C:47]2=[O:50])=[O:19])[CH2:9][CH2:10][CH2:11][CH2:12][CH2:13]1
Reactant: O=C(O)CCCC1CCCCC1
Reactant: O=C1N[C@@H](Cc2ccccc2)CO1
Agent: CC(C)(C)C(=O)Cl
Agent: O=C1NCCO1
Agent: [Li]CCCC
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: O=C(CCCC1CCCCC1)N1C(=O)OC[C@@H]1Cc1ccccc1
Temperature: -78 °C
Reaction time: 0.17 h
Yield: 85 %

Procedure:
A solution of pivaloyl chloride (3.57 g, 2.96 mmol) in THF (25 ml) was added to a cold (-78° C.) solution of 4-cyclohexylbutyric acid (5.042 g, 29.62 mmol) and triethyl amine (3.60 g, 35.6 mmol) in THF (100 mL). The resultant white suspension was stirred for 10 min. at -78° C. and then warmed to 0° C. and kept there for 30 min. The reaction mixture was recooled to -78° C. and a cold (-78° C.) metallated oxazolidinone solution in THF (125 ml) [prepared by the addition of n-BuLi (17.65 ml. of 1.65M solution in hexane, 28.2 mmol) to a -78° C. solution of (S)-4-(phenylmethyl)-2-oxazolidinone in THF (125 ml)] was added via a cannula under the positive pressure of argon. The reaction mixture was then warmed to 0° C. and kept there for another 30 min. The reaction was quenched by the addition of saturated NH4Cl (75 ml). The volatiles were removed on rotavapor at reduced pressure and the residue was extracted with CH2Cl2 (3×200 ml). The combined organic phases were washed with 1N NaOH (150 ml) and dried (Na2SO4). The organic layer was concentrated and the residue was purified by flash silica gel chromatography, eluting with hexane:ethyl acetate (3:1) to yield 8.066 g (85%) of (S)-3-(4-cyclohexyl-1-oxobutyl)-4-(phenylmethyl)-2-oxazolidinone: Rf 0.34 (3:1 hexane:ethyl acetate), m.p. 69°-70° C. [α]D25 +47.3° (c 0.97 CHCl3).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH2:8][C:9]([C:11]1[C:12](=[O:32])[N:13]([C:22]2[CH:27]=[CH:26][CH:25]=[C:24]([C:28]([F:31])([F:30])[F:29])[CH:23]=2)[C:14]2[C:19]([C:20]=1O)=[CH:18][CH:17]=[CH:16][N:15]=2)=O.O.[NH2:34][NH2:35].C(=O)([O-])O.[Na+]>CN(C=O)C>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH2:8][C:9]1[C:11]2[C:12](=[O:32])[N:13]([C:22]3[CH:27]=[CH:26][CH:25]=[C:24]([C:28]([F:29])([F:31])[F:30])[CH:23]=3)[C:14]3[N:15]=[CH:16][CH:17]=[CH:18][C:19]=3[C:20]=2[NH:35][N:34]=1
Reactant: NN
Reactant: O=C(Cc1ccccc1Cl)c1c(O)c2cccnc2n(-c2cccc(C(F)(F)F)c2)c1=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: O=c1c2c(Cc3ccccc3Cl)n[nH]c2c2cccnc2n1-c1cccc(C(F)(F)F)c1
Temperature: 115 °C
Reaction time: 2 h

Procedure:
To a suspension of 3-(2-chlorophenylacetyl)-4-hydroxy-1-(3-trifluoromethylphenyl)-1,8-naphthyridin-2(1H)-one (687 mg, 1.5 mmol) produced in Synthesis Example 35 in DMF (6 mL) was added hydrazine monohydrate (purity of 80%, 240 μL), and the mixture was stirred at 110 to 120° C. for 2 hours. To the reaction solution was added a sodium hydrogencarbonate aqueous solution. The resulting precipitate was separated by filtration, washed with water, and dried to give 3-(2-chlorobenzyl)-5-(3-trifluoromethylphenyl)-1H-pyrazolo[4,3-c][1,8]-naphthyridin-4(5H)-one as a form of crystal (632 mg, yield 93%).
Reaction SMILES: FC(F)(F)S(O[C:7]1[C:12]([C:13](=[O:15])[CH3:14])=[CH:11][C:10]([Cl:16])=[C:9]([CH3:17])[C:8]=1[C:18]#[N:19])(=O)=O.[F:22][C:23]1[CH:24]=[C:25](B(O)O)[CH:26]=[CH:27][CH:28]=1.O.N#N>C1(C)C=CC=CC=1.[Na].C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[C:13]([C:12]1[CH:11]=[C:10]([Cl:16])[C:9]([CH3:17])=[C:8]([C:18]#[N:19])[C:7]=1[C:27]1[CH:26]=[CH:25][CH:24]=[C:23]([F:22])[CH:28]=1)(=[O:15])[CH3:14]
Reactant: CC(=O)c1cc(Cl)c(C)c(C#N)c1OS(=O)(=O)C(F)(F)F
Reactant: OB(O)c1cccc(F)c1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: N#N
Agent: [Na]
Solvent: O
Solvent: Cc1ccccc1
Product: CC(=O)c1cc(Cl)c(C)c(C#N)c1-c1cccc(F)c1
Temperature: 80 °C
Yield: 98.5 %

Procedure:
A biphasic solution of 6-acetyl-4-chloro-2-cyano-3-methylphenyl trifluoromethanesulfonate (2.537 g, 7.425 mmol) and (3-fluorophenyl)boronic acid (1.56 g, 11.1 mmol) in toluene (70 mL) and 0.8 M sodium hydrogenecarbonate in water (70 mL, 50 mmol) was bubbled with N2 to degas. Tetrakis(triphenylphosphine)palladium(0) (0.429 g, 0.371 mmol) was added. The mixture was degassed with N2 for an additional 5 minutes and then heated at 80° C. for 2 hours. After cooling to room temperature, the mixture was diluted with ethyl acetate. The layers were separated and the aq. layer was extracted with ethyl acetate. The combined extracts were washed with brine, dried over Na2SO4, filtered, and concentrated to a dark solid. The material was dissolved in CHCl3 and was purified on silica gel column, eluting with 0 to 40% ethyl acetate in hexane, to give the desired product (2.105 g, 99%). LCMS calculated for C16H12ClFNO (M+H)+: m/z=288.1; Found: 288.1.
Reaction SMILES: [OH:1][CH:2]1[CH2:7][CH2:6][NH:5][CH2:4][CH2:3]1.[Na].[Cl:9][C:10]1[CH:11]=[CH:12][C:13]2[S:17][C:16](=[O:18])[N:15]([CH2:19][C:20](OC)=[O:21])[C:14]=2[CH:24]=1>C[O-].[Na+].CO>[OH:1][CH:2]1[CH2:7][CH2:6][N:5]([C:20]([CH2:19][N:15]2[C:14]3[CH:24]=[C:10]([Cl:9])[CH:11]=[CH:12][C:13]=3[S:17][C:16]2=[O:18])=[O:21])[CH2:4][CH2:3]1
Reactant: OC1CCNCC1
Reactant: COC(=O)Cn1c(=O)sc2ccc(Cl)cc21
Agent: C[O-]
Agent: [Na+]
Agent: [Na]
Solvent: CO
Product: O=C(Cn1c(=O)sc2ccc(Cl)cc21)N1CCC(O)CC1
Temperature: 0 °C
Yield: 80.8 %

Procedure:
4-Hydroxypiperidine (47.2 g) was added at room temperature to and dissolved in a methanolic sodium methoxide solution prepared from sodium metal (2.2 g) in dry methanol (100 ml). To the resultant solution was added methyl 5-chloro-2-oxo-3-benzothiazolineacetate (100 g), and the mixture was heated for 3 hours under reflux with stirring. The reaction mixture was left to cool, poured into ice water (500 ml) and stirred for 30 minutes. The precipitates were collected, washed with water and then dried to give 3-(4-hydroxypiperidino)carbonylmethyl-5-chloro-2-benzothiazolinone (102.5 g), which was recrystallized from 90% aqueous methanol to give colorless crystals, m.p. 180.1° C.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[N:6]=[C:7](Br)[C:8]2[C:13]([C:14]=1[OH:15])=[CH:12][CH:11]=[C:10]([O:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)[CH:9]=2)=[O:4].[Sn](C)(C)(C)[CH3:25]>CN1CCCC1=O>[CH3:1][O:2][C:3]([C:5]1[N:6]=[C:7]([CH3:25])[C:8]2[C:13]([C:14]=1[OH:15])=[CH:12][CH:11]=[C:10]([O:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)[CH:9]=2)=[O:4]
Reactant: C[Sn](C)(C)C
Reactant: COC(=O)c1nc(Br)c2cc(Oc3ccccc3)ccc2c1O
Solvent: CN1CCCC1=O
Product: COC(=O)c1nc(C)c2cc(Oc3ccccc3)ccc2c1O
Temperature: 25 °C
Yield: 58.2 %

Procedure:
To a mixture of 1-bromo-4-hydroxy-7-phenoxy-isoquinoline-3-carboxylic acid methyl ester (500 mg, 1.34 mmol) in N-methylpyrrolidone (NMP) (7 mL) was added SnMe4 (358 mg, 2.0 mmol) and resin-bound-Pd(PPh3)2Cl2 (Sigma-Aldrich) (1-2 mmol/g) (40 mg, ca. 0.03 mmol). The resultant mixture was stirred in a 130° C. oil bath for 3 h. Reaction mixture was filtered and rinsed with NMP (1 mL). Filtrate was poured into water (120 mL) and stirred at room temperature until good precipitate formed. Solid was collected and rinsed with water (100 mL) and then hexanes (50 mL). Solid was dried and purified by silica gel chromatography, eluting with 2-50% EtOAc/hexanes, to provide the title compound 240 mg (0.78 mmol) in 58% yield. 1H NMR (200 MHz) CDCl3, δ in ppm: 11.68 (s, 1H), 8.37 (d, J=9.3 Hz, 1H), 7.48-7.08 (m, 7H), 4.07 (s, 3H), 2.75 (s, 3H).
Reaction SMILES: [CH3:1][C@H:2]1[CH2:7][CH2:6][C@H:5]([NH:8][C:9](=[O:23])[CH2:10][C:11]2[CH:16]=[CH:15][C:14]([O:17][CH2:18][CH2:19]Cl)=[C:13]([O:21][CH3:22])[CH:12]=2)[CH2:4][CH2:3]1.[CH3:24][NH:25][CH3:26]>CC(CC(C)C)=O>[CH3:1][C@H:2]1[CH2:7][CH2:6][C@H:5]([NH:8][C:9](=[O:23])[CH2:10][C:11]2[CH:16]=[CH:15][C:14]([O:17][CH2:18][CH2:19][N:25]([CH3:26])[CH3:24])=[C:13]([O:21][CH3:22])[CH:12]=2)[CH2:4][CH2:3]1
Reactant: CNC
Reactant: COc1cc(CC(=O)N[C@H]2CC[C@H](C)CC2)ccc1OCCCl
Solvent: CC(=O)CC(C)C
Product: COc1cc(CC(=O)N[C@H]2CC[C@H](C)CC2)ccc1OCCN(C)C

Procedure:
Using 1.38 g of N-(trans-4-methylcyclohexyl)-2-[4-(2-chloroethoxy)-3-methoxyphenyl]acetamide (Example 128), 50 ml of methylisobutylketone, and 40 ml of 50% aqueous dimethylamine solution, a reaction similar to that conducted in Example 107 was carried out. As a result, 1.08 g of N-(trans-4-methylcyclohexyl)-2-[4-(2-dimethylaminoethoxy)-3-methoxyphenyl]acetamide (a compound of the present invention) was obtained as pale yellowish white crystal, which had the following physiochemical properties:
Reaction SMILES: [CH3:1][C:2](=[CH2:4])[CH3:3].[F:5][C@@H:6]([CH2:11][CH2:12][CH2:13][CH3:14])[C@@H:7]([OH:10])[C:8]#[CH:9].B(F)(F)F.OP(O)(O)=O.C(=O)(O)[O-].[Na+]>C(Cl)Cl>[C:2]([O:10][C@H:7]([C@@H:6]([F:5])[CH2:11][CH2:12][CH2:13][CH3:14])[C:8]#[CH:9])([CH3:3])([CH3:1])[CH3:4]
Reactant: C#C[C@H](O)[C@@H](F)CCCC
Reactant: C=C(C)C
Agent: FB(F)F
Agent: O=C([O-])O
Agent: O=P(O)(O)O
Solvent: ClCCl
Product: C#C[C@H](OC(C)(C)C)[C@@H](F)CCCC
Reaction time: 0.67 h

Procedure:
Isobutylene (7 ml) was condensed from a cylinder below -20° under N2 and diluted with precooled 25 ml CH2Cl2. This solution was cooled to -60° and there was added 2.9 g (21 mmol) of (3S,4S)-4-fluoro-1-octyne-3-ol, in 15 ml of CH2Cl2, 0.70 ml of BF3 etherate and 0.34 ml of anhydrous H3PO4, in the order given. The mixture was allowed to warm to 0°-15° and stirred for 40 min at that temperature. The resulting pale yellow solution was cooled again to -50° and poured into a vigorously stirred solution of saturated sodium bicarbonate (70 ml) kept cool in an ice water bath. The heterogeneous mixture was agitated vigorously until the organic layer became basic towards pH paper. The CH2Cl2 layer was separated, washed with water (40 ml ) and brine (30 ml) and dried over anhydrous Na2SO4. Concentration on a rotary evaporator afforded 9.87 g of a colorless oil which was chromatographed on 70 g of silica gel. Less polar impurities were eluted with hexane. Elution with pentane-ether 9:1 (100 ml) gave the crude t-butyloxy fluorooctyne, which on distillation under vacuum (bp 57° at 3-4 min) gave 3.69 g (91%) of pure material.
Reaction SMILES: C([O:3][C:4](=O)[CH2:5][N:6]1[C:10]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)=[CH:9][CH:8]=[C:7]1[C:17]1[CH:22]=[CH:21][C:20]([C:23](=[O:33])[N:24]([CH2:26][C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)[CH3:25])=[CH:19][CH:18]=1)C.[NH2:35][C:36]([NH2:38])=[NH:37]>CS(C)=O>[NH2:37][C:36]([NH:38][C:4](=[O:3])[CH2:5][N:6]1[C:10]([C:11]2[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=2)=[CH:9][CH:8]=[C:7]1[C:17]1[CH:22]=[CH:21][C:20]([C:23]([N:24]([CH2:26][C:27]2[CH:28]=[CH:29][CH:30]=[CH:31][CH:32]=2)[CH3:25])=[O:33])=[CH:19][CH:18]=1)=[NH:35]
Reactant: N=C(N)N
Reactant: CCOC(=O)Cn1c(-c2ccccc2)ccc1-c1ccc(C(=O)N(C)Cc2ccccc2)cc1
Solvent: CS(C)=O
Product: CN(Cc1ccccc1)C(=O)c1ccc(-c2ccc(-c3ccccc3)n2CC(=O)NC(=N)N)cc1
Reaction time: 16 h

Procedure:
To the ester from step 6 (200 μmol) is disslved in DMSO (1 mL) and a solution of neutralized guanidine in DMSO is added (500 μL, 2 M in DMSO) and allowed to sit at room temperature for 16 h. The reaction is quenched by the addition of glacial AcOH (100 μL) and distilled water (200 μL) and concentrated in vacuo. The residue is dissolved in a mixture of DMSO, MeOH and water (1.5 mL total) and purified by Gilson preparative HPLC system.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([C:8]2([C:21]([O:23]CC)=[O:22])[CH2:13][CH2:12][N:11]([C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])[CH2:10][CH2:9]2)[CH:5]=[CH:4][N:3]=1.[OH-].[Na+]>C(O)C>[C:17]([O:16][C:14]([N:11]1[CH2:12][CH2:13][C:8]([C:6]2[CH:5]=[CH:4][N:3]=[C:2]([Cl:1])[CH:7]=2)([C:21]([OH:23])=[O:22])[CH2:9][CH2:10]1)=[O:15])([CH3:20])([CH3:18])[CH3:19]
Reactant: CCOC(=O)C1(c2ccnc(Cl)c2)CCN(C(=O)OC(C)(C)C)CC1
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: CC(C)(C)OC(=O)N1CCC(C(=O)O)(c2ccnc(Cl)c2)CC1
Yield: 88 %

Procedure:
To a mixture of the compound 1-tert-butyl 4-ethyl 4-(2-chloropyridin-4-yl)piperidine-1,4-dicarboxylate (50 g, 0.14 mols, 1 equiv.) in ethanol (75 mL) was added 500 mL of a 10% solution of NaOH. The mixture was refluxed for 2 h. The reaction was monitored by TLC (ethyl acetate/petroleum ether; 1/5), cooled, concentrated to a half of the primary volume and extracted with methyltertiarybutyl ether (3×150 mL). The aqueous layer was acidified with 3M hydrochloric acid to pH=4 and extracted with dichloromethane (2×350 mL). The combined organic layers were dried over anhydrous sodium sulfate. The organic was concentrated to give crude product 1-(tert-butoxycarbonyl)-4-(2-chloropyridin-4-yl)piperidine-4-carboxylic acid (42 g, 91% crude). The crude was used as is in Step C.
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][C:8]([O:14][CH2:15][CH2:16][O:17][CH3:18])=[C:9]([O:12][CH3:13])[CH:10]=2)[N:5]=[CH:4][N:3]=1.[C:19]1([C:25]2[CH2:29][C:28](=[O:30])[NH:27][N:26]=2)[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1.[H-].[Na+]>CN(C=O)C>[CH3:13][O:12][C:9]1[CH:10]=[C:11]2[C:6](=[CH:7][C:8]=1[O:14][CH2:15][CH2:16][O:17][CH3:18])[N:5]=[CH:4][N:3]=[C:2]2[O:30][C:28]1[CH:29]=[C:25]([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[NH:26][N:27]=1
Reactant: COCCOc1cc2ncnc(Cl)c2cc1OC
Reactant: O=C1CC(c2ccccc2)=NN1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COCCOc1cc2ncnc(Oc3cc(-c4ccccc4)[nH]n3)c2cc1OC

Procedure:
Using an analogous procedure to that described for Example 1, 4-chloro-6-methoxy-7-(2-methoxyethoxy)quinazoline (134 mg, 0.5 mmol) was reacted with 3-phenyl-4,5-dihydro-1H-pyrazol-5-one (160 mg, 1 mmol), (J. Org. Chem., 1967, 32, 3321-3324), in the presence of sodium hydride (40 mg, 1 mmol, prewashed with THF) in DMF (3 ml) to give 6-methoxy-7-(2-methoxyethoxy)-4-(5-phenylpyrazol-3-yloxy)quinazoline as the free base. The free base was dissolved in a mixture of methylene chloride/methanol (1/1) and 3M hydrochloric acid in methanol was added. The volatiles were removed by evaporation to give 6-methoxy-7-(2-methoxyethoxy)-4-(5-phenylpyrazol-3-yloxy)quinazoline hydrochloride (155 mg, 72%).
Reaction SMILES: [C:1]([C:4]1[CH:5]=[C:6]([NH:10][C:11](=[O:14])[CH2:12][CH3:13])[CH:7]=[CH:8][CH:9]=1)(=[O:3])[CH3:2].CO[CH:17](OC)[N:18]([CH3:20])[CH3:19]>>[CH3:17][N:18]([CH3:20])[CH:19]=[CH:2][C:1]([C:4]1[CH:5]=[C:6]([NH:10][C:11](=[O:14])[CH2:12][CH3:13])[CH:7]=[CH:8][CH:9]=1)=[O:3]
Reactant: CCC(=O)Nc1cccc(C(C)=O)c1
Reactant: COC(OC)N(C)C
Product: CCC(=O)Nc1cccc(C(=O)C=CN(C)C)c1

Procedure:
A 20 g portion of N-(3-acetylphenyl)propanamide in 50 ml of dimethylformamide dimethylacetal was refluxed for 8 hours, then evaporated. The residue was taken up in 200 ml of dichloromethane, passed through hydrous magnesium silicate, diluted with hexane and concentrated, giving 21.17 g of the desired compound.
Reaction SMILES: [Si:1]([O:8][CH2:9][CH2:10][O:11][C:12]1[CH:17]=[CH:16][C:15](Br)=[CH:14][CH:13]=1)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].[Li]CCCC.[CH3:24][O:25][C:26]([C:28]1[CH2:29][N:30]([C:42]([O:44][C:45]([CH3:48])([CH3:47])[CH3:46])=[O:43])[CH2:31][CH2:32][C:33]=1OS(C(F)(F)F)(=O)=O)=[O:27].[NH4+].[Cl-]>C1COCC1.[Cl-].[Cl-].[Zn+2].C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.CCOC(C)=O>[CH3:24][O:25][C:26]([C:28]1[CH2:29][N:30]([C:42]([O:44][C:45]([CH3:48])([CH3:47])[CH3:46])=[O:43])[CH2:31][CH2:32][C:33]=1[C:15]1[CH:16]=[CH:17][C:12]([O:11][CH2:10][CH2:9][O:8][Si:1]([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2])=[CH:13][CH:14]=1)=[O:27]
Reactant: CC(C)(C)[Si](C)(C)OCCOc1ccc(Br)cc1
Reactant: COC(=O)C1=C(OS(=O)(=O)C(F)(F)F)CCN(C(=O)OC(C)(C)C)C1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [Cl-]
Agent: [Li]CCCC
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: COC(=O)C1=C(c2ccc(OCCO[Si](C)(C)C(C)(C)C)cc2)CCN(C(=O)OC(C)(C)C)C1
Temperature: -78 °C
Reaction time: 0.5 h
Yield: 82.4 %

Procedure:
To a sol. of 4-[2-(tert-butyldimethylsilanyloxy)ethoxy]bromobenzene (WO 03/093267, 7.95 g, 24 mmol) in THF (200 mL) at −78° C. was added BuLi (1.6M in hexane, 17.12 mL, 27.4 mmol). The sol. was stirred at −78° C. for 30 min, then ZnCl2 (1M in THF, 30 mL, 30 mmol) was added. The resulting sol. was allowed to warm to rt, and 4-trifluoromethanesulfonyloxy-5,6-dihydro-2H-pyridine-1,3-dicarboxylic acid 1-tert-butyl ester 3-methyl ester (WO 2004/002957, 7.79 g, 20 mmol) in THF (20 mL) and Pd(PPh3)4 (0.69 g, 0.60 mmol) were added. The reaction mixture was heated to 50° C. for 1 h, and stirred 16 h at rt. The mixture was cooled to 0° C., and aq. sat. NH4Cl was added. EtOAc was added, and the org. phase was washed with brine, dried over MgSO4, filtered, and the solvents were removed under reduced pressure. Purification of the residue by FC (EtOAc/heptane 2:8→1:0) yielded the title compound (8.1 g, 82%). LC-MS: tR=1.23 min, ES+: 506.47.