Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Si:1]([O:8][C@H:9]1[CH2:18][C:17]([CH3:20])([CH3:19])[CH2:16][C:15]2[N:14]=[C:13]([CH:21]3[CH2:25][CH2:24][CH2:23][CH2:22]3)[C:12]([CH:26]=[O:27])=[C:11]([I:28])[C:10]1=2)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].[C:29]([C:33]1[CH:34]=[C:35]([Mg]Br)[CH:36]=[CH:37][CH:38]=1)([CH3:32])([CH3:31])[CH3:30]>>[Si:1]([O:8][C@H:9]1[CH2:18][C:17]([CH3:20])([CH3:19])[CH2:16][C:15]2[N:14]=[C:13]([CH:21]3[CH2:22][CH2:23][CH2:24][CH2:25]3)[C:12]([CH:26]([C:37]3[CH:36]=[CH:35][CH:34]=[C:33]([C:29]([CH3:32])([CH3:31])[CH3:30])[CH:38]=3)[OH:27])=[C:11]([I:28])[C:10]1=2)([C:4]([CH3:5])([CH3:6])[CH3:7])([CH3:3])[CH3:2]
Reactant: CC(C)(C)c1cccc([Mg]Br)c1
Reactant: CC1(C)Cc2nc(C3CCCC3)c(C=O)c(I)c2[C@@H](O[Si](C)(C)C(C)(C)C)C1
Product: CC1(C)Cc2nc(C3CCCC3)c(C(O)c3cccc(C(C)(C)C)c3)c(I)c2[C@@H](O[Si](C)(C)C(C)(C)C)C1

Procedure:
Obtained by starting from (S)-5-(tert-butyldimethylsilyloxy)-2-cyclopentyl-4-iodo-7,7-dimethyl-5,6,7,8-tetrahydroquinoline-3-carbaldehyde and 3-tert.-butylphenylmagnesium bromide. The product is obtained as a diastereomic mixture, which is used directly in the next step.
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([C:10]2([C:14]([O:16][CH2:17][CH3:18])=[O:15])[CH2:13][CH2:12][CH2:11]2)=[CH:6][CH:5]=1)([O-])=O>O1CCCC1.[Pd]>[NH2:1][C:4]1[CH:5]=[CH:6][C:7]([C:10]2([C:14]([O:16][CH2:17][CH3:18])=[O:15])[CH2:11][CH2:12][CH2:13]2)=[CH:8][CH:9]=1
Reactant: CCOC(=O)C1(c2ccc([N+](=O)[O-])cc2)CCC1
Agent: [Pd]
Solvent: C1CCOC1
Product: CCOC(=O)C1(c2ccc(N)cc2)CCC1
Temperature: 23 °C
Reaction time: 1 h

Procedure:
5.5 g of ethyl 1-(4-nitrophenyl)cyclobutanecarboxylate are dissolved in 55 ml of tetrahydrofuran, 2 g of 5% Pd/C (52.3% of water) are added, and the mixture is stirred at 23° C. under a hydrogen atmosphere for 1 h. After aeration, insoluble material is filtered off, and the filtrate is evaporated to dryness in vacuo. Yield: 4.3 g (89%) of ethyl 1-(4-aminophenyl)cyclobutanecarboxylate; LC-MS retention time: 2.05 min (“nonpolar” gradient).
Reaction SMILES: C(OC([NH:8][C@@H:9]([CH3:12])[CH2:10][OH:11])=O)(C)(C)C.O[C:14]1[CH:19]=[CH:18][C:17]([CH2:20][C:21]([O:23][CH3:24])=[O:22])=[CH:16][CH:15]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OCC)=O)=NC(OCC)=O.Cl>O1CCOCC1.CO.C1C=CC=CC=1>[NH2:8][C@@H:9]([CH3:12])[CH2:10][O:11][C:14]1[CH:19]=[CH:18][C:17]([CH2:20][C:21]([O:23][CH3:24])=[O:22])=[CH:16][CH:15]=1
Reactant: COC(=O)Cc1ccc(O)cc1
Reactant: C[C@@H](CO)NC(=O)OC(C)(C)C
Agent: CCOC(=O)N=NC(=O)OCC
Agent: Cl
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: c1ccccc1
Solvent: CO
Solvent: C1COCCO1
Product: COC(=O)Cc1ccc(OC[C@H](C)N)cc1

Procedure:
Following a procedure similar to that described in Preparation 27, but using 15.8 g of (S)-2-t-butoxycarbonylamino-1-propanol, 10.0 g of methyl 4-hydroxyphenylacetate, 24 g of triphenylphosphine, 70 ml of dry benzene, 15.7 g of diethyl azodicarboxylate, 50 ml of methanol and 70 ml of a 4N solution of hydrogen chloride in dioxane, the title compound was obtained. [α]D23 +12.1° (c=1.054, chloroform).
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]2[C:11](=[CH:12][CH:13]=1)[NH:10][C:9](=O)[NH:8][C:7]2=O)([O-:3])=[O:2].[CH2:16]([NH2:19])[CH:17]=[CH2:18]>O>[CH2:16]([NH:19][C:9]1[N:8]=[C:7]([NH:1][CH:4]([CH3:5])[CH:13]=[CH2:12])[C:6]2[C:11](=[CH:12][CH:13]=[C:4]([N+:1]([O-:3])=[O:2])[CH:5]=2)[N:10]=1)[CH:17]=[CH2:18]
Reactant: C=CCN
Reactant: O=c1[nH]c(=O)c2cc([N+](=O)[O-])ccc2[nH]1
Solvent: O
Product: C=CCNc1nc(NC(C)C=C)c2cc([N+](=O)[O-])ccc2n1
Temperature: 25 °C
Reaction time: 3 h
Yield: 34.6 %

Procedure:
2-chloro-4-(1-methyl-2-propenylamino)-6-nitroquinazoline was obtained in accordance with the process described in Example 62, starting from 278 mg (1.45 mmol) of 6-nitroquinazoline-2,4(1H,3H)-dione. After 1.00 ml (13.33 mmol) of allylamine was added to the compound and the reaction mixture was stirred at room temperature for 3 hours, water was added to the reaction solution, followed by extraction with ethyl acetate, washing with brine and drying over anhydrous sodium sulfate. After the solvent was distilled off, the residue was purified by a silica gel column to give 75 mg (18.7%) of the title compound.
Reaction SMILES: [Cl:1][C:2]1[CH:25]=[C:24]([Cl:26])[CH:23]=[CH:22][C:3]=1[NH:4][C:5]1[C:14]2[C:9](=[CH:10][C:11]3[CH:18]=[CH:17][C:16]([OH:19])=[CH:15][C:12]=3[CH:13]=2)[N:8]=[CH:7][C:6]=1[C:20]#[N:21].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[CH3:46][N:47]([CH3:51])[CH2:48][CH2:49]O.N(C(OCC)=O)=NC(OCC)=O>C(Cl)Cl>[Cl:1][C:2]1[CH:25]=[C:24]([Cl:26])[CH:23]=[CH:22][C:3]=1[NH:4][C:5]1[C:14]2[C:9](=[CH:10][C:11]3[CH:18]=[CH:17][C:16]([O:19][CH2:49][CH2:48][N:47]([CH3:51])[CH3:46])=[CH:15][C:12]=3[CH:13]=2)[N:8]=[CH:7][C:6]=1[C:20]#[N:21]
Reactant: CN(C)CCO
Reactant: N#Cc1cnc2cc3ccc(O)cc3cc2c1Nc1ccc(Cl)cc1Cl
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Product: CN(C)CCOc1ccc2cc3ncc(C#N)c(Nc4ccc(Cl)cc4Cl)c3cc2c1
Temperature: 25 °C
Reaction time: 48 h
Yield: 20.5 %

Procedure:
To a suspension of 189.1 mg (0.50 mmol) of 4-(2,4-dichloroanilino)-7-hydroxybenzo[g]quinoline-3-carbonitrile, 207.2 mg (0.79mmol) of triphenylphosphine and 66.9 mg (0.75 mmol) of 2-(dimethylamino)-ethanol in 3.0 mL of anhydrous methylene chloride at 0° C. is added dropwise diethyl azodicarboxylate. The resulting reaction mixture is stirred at room temperature under nitrogen for 2 days. The solvent is concentrated in vacuo and the residue is purified on preparative thin layer chromatography (developing solvent: 9:1 methylene chloride/methanol) to provide 46.3 mg (20.5%) of 4-(2,4-dichloroanilino)-7-[2-(dimethylamino)ethoxy]benzo[g]quinoline-3-carbonitrile as a yellow solid, mp 115-117° C.
Reaction SMILES: ClC1C=CC(N[N:9]=[C:10]2[CH2:15][CH2:14][CH2:13][CH2:12][C:11]2=[O:16])=CC=1.[ClH:17]>C(O)(=O)C>[Cl:17][C:10]1[CH:11]=[C:12]2[C:13](=[CH:14][CH:15]=1)[NH:9][C:10]1[C:11](=[O:16])[CH2:12][CH2:13][CH2:14][C:15]2=1
Reactant: O=C1CCCCC1=NNc1ccc(Cl)cc1
Reactant: Cl
Solvent: CC(=O)O
Product: O=C1CCCc2c1[nH]c1ccc(Cl)cc21
Temperature: 0 °C
Yield: 88 %

Procedure:
A solution of cyclohexane-1,2-dione (4-chlorophenyl)hydrazone (2.3 g, 9.7 mmol) in hydrochloric acid (2 mL) and acetic acid (8 mL) was heated at 120° C. for 20 minutes. The mixture was cooled slightly and treated with ice water. The resulting precipitate was collected by filtration to give 6-chloro-2,3,4,9-tetrahydro-1H-carbazol-1-one (1.9 g, 88% yield) as brown solid. 1H-NMR (DMSO-d6): δ 11.78 (s, 1H), 7.75 (m, 1H), 7.38 (d, 1H), 7.28 (dd, 1H), 2.92 (t, 2H), 2.55 (t, 2H), 2.13 (q, 2H); MS m/z 220 (M+1).
Reaction SMILES: [ClH:1].[CH3:2][N:3]([CH2:5][CH:6]1[CH2:15][CH2:14][C:13]2[C:8](=[CH:9][CH:10]=[C:11](NS(C3C=CC4C(=CC=CC=4)C=3)(=O)=O)[CH:12]=2)[CH2:7]1)[CH3:4].[CH2:30]([C:32]1[CH:37]=[CH:36][C:35]([C:38]2[CH:43]=[CH:42][C:41]([CH2:44][OH:45])=[CH:40][CH:39]=2)=[CH:34][CH:33]=1)[CH3:31].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OCC)=O)=NC(OCC)=O>C1COCC1>[ClH:1].[CH3:4][N:3]([CH2:5][CH:6]1[CH2:15][CH2:14][C:13]2[C:8](=[CH:9][CH:10]=[C:11]([O:45][CH2:44][C:41]3[CH:40]=[CH:39][C:38]([C:35]4[CH:36]=[CH:37][C:32]([CH2:30][CH3:31])=[CH:33][CH:34]=4)=[CH:43][CH:42]=3)[CH:12]=2)[CH2:7]1)[CH3:2]
Reactant: CN(C)CC1CCc2cc(NS(=O)(=O)c3ccc4ccccc4c3)ccc2C1
Reactant: CCc1ccc(-c2ccc(CO)cc2)cc1
Agent: CCOC(=O)N=NC(=O)OCC
Agent: Cl
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: CCc1ccc(-c2ccc(COc3ccc4c(c3)CCC(CN(C)C)C4)cc2)cc1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
2-(N,N-Dimethylamino)methyl-6-hydroxytetralin (300 mg; obtained in Reference Example 16), (4′-ethylbiphenyl-4-yl)methanol (372 mg) and triphenylphosphine (460 mg) were dissolved in THF (5 ml), to which was dropwise added diethyl azodicarboxylate (305 mg) with cooling with ice. The reaction mixture was stirred at room temperature for 4 hours, and then the solvent was evaporated out. Water was added to the residue, which was then extracted with ethyl acetate. The organic layer was washed with a saturated aqueous sodium bicarbonate solution and a saturated aqueous sodium chloride solution, then dried, and concentrated. The residue was purified by alumina column chromatography (eluent:ethyl acetate/hexane=1/10), and then processed with a solution of 4 N hydrochloric acid-ethyl acetate to form a hydrochloride. The thus-formed salt was recrystallized from ethanol-diisopropyl ether to obtain the entitled compound (310 mg).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[C:4]([CH3:9])[CH:3]=1.[Na].[C:11]([O:15][CH2:16][CH3:17])(=[O:14])[CH:12]=[CH2:13]>C(O)C>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][CH2:13][CH2:12][C:11]([O:15][CH2:16][CH3:17])=[O:14])=[C:4]([CH3:9])[CH:3]=1
Reactant: C=CC(=O)OCC
Reactant: Cc1cc(Cl)ccc1O
Agent: [Na]
Solvent: CCO
Product: CCOC(=O)CCOc1ccc(Cl)cc1C

Procedure:
The sub-title compound was prepared according to the method described in Example 27(i) above from 4-chloro-2-methylphenol (4.99 g; 35.0 mmol), sodium (0.055 g; 2.4 mmol), ethanol (1.5 mL) and ethyl acrylate (4.1 g; 41 mmol). The crude product (1.98 g; 23%) was used for the next step without further purification.
Reaction SMILES: Cl[C:2]1[CH:11]=[C:10]2[C:5]([CH:6]=[C:7]([C:14]3[CH:15]=[C:16]([NH:21][C:22](=[O:29])[C:23]4[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=4)[CH:17]=[CH:18][C:19]=3[CH3:20])[C:8](=[O:13])[N:9]2[CH3:12])=[CH:4][N:3]=1.[CH3:30][NH:31][CH3:32]>CN1C(=O)CCC1.CO>[CH3:30][N:31]([CH3:32])[C:2]1[CH:11]=[C:10]2[C:5]([CH:6]=[C:7]([C:14]3[CH:15]=[C:16]([NH:21][C:22](=[O:29])[C:23]4[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=4)[CH:17]=[CH:18][C:19]=3[CH3:20])[C:8](=[O:13])[N:9]2[CH3:12])=[CH:4][N:3]=1
Reactant: Cc1ccc(NC(=O)c2ccccc2)cc1-c1cc2cnc(Cl)cc2n(C)c1=O
Reactant: CNC
Solvent: CN1CCCC1=O
Solvent: CO
Product: Cc1ccc(NC(=O)c2ccccc2)cc1-c1cc2cnc(N(C)C)cc2n(C)c1=O
Temperature: 100 °C

Procedure:
N-(3-(7-chloro-1,2-dihydro-1-methyl-2-oxo-1,6-naphthyridin-3-yl)-4-methylphenyl)benzamide A6 (45 mg, 0.11 mmol) is dissolved in NMP (1 mL) and treated with dimethyl amine (0.56 mL of a 2.0 M solution in methanol). The reaction mixture is heated to 100° C. for 12 h. Upon cooling to rt, the reaction is purified by preparative LCMS. 1H NMR 400 MHz (DMSO-d6) δ 10.23 (s, 1H), 8.51 (s, 1H), 7.97-7.94 (m, 2H), 7.78 (s, 1H), 7.68-7.66 (m, 2H), 7.61-7.51 (m, 3H), 7.23 (d, J=9 Hz, 1H), 6.37 (s, 1H), 3.61 (s, 3H), 3.20 (s, 6H), 2.12 (s, 3H); MS m/z 413.2 (M+1).
Reaction SMILES: NC1C=CC(P(=O)(OC(C)C)OC(C)C)=CC=1.[CH3:18][C:19]1([CH3:35])[CH2:24][O:23][P:22](=[O:34])([C:25]2[CH:30]=[CH:29][C:28]([N+:31]([O-])=O)=[CH:27][CH:26]=2)[O:21][CH2:20]1>>[CH3:18][C:19]1([CH3:35])[CH2:20][O:21][P:22]([C:25]2[CH:30]=[CH:29][C:28]([NH2:31])=[CH:27][CH:26]=2)(=[O:34])[O:23][CH2:24]1
Reactant: CC1(C)COP(=O)(c2ccc([N+](=O)[O-])cc2)OC1
Agent: CC(C)OP(=O)(OC(C)C)c1ccc(N)cc1
Product: CC1(C)COP(=O)(c2ccc(N)cc2)OC1
Yield: 41 %

Procedure:
Prepared according to the procedure described for dipropan-2-yl (4-aminophenyl)phosphonate using 5,5-dimethyl-2-(4-nitrophenyl)-1,3,2-dioxaphosphinane 2-oxide. Yield: 41%. 1H-NMR (DMSO-d6, 400 MHz): δ=0.97 (s, 3 H), 1.02 (s, 3 H), 3.78 (m, 2 H), 4.08 (m, 2 H), 5.91 (s, br, 2 H), 6.61 (dd, J=3.6, 8.4 Hz, 2 H), 7.34 (m, 2 H). MS: m/z 242.10 [MH+].
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([NH:10][C:11]([NH2:13])=[S:12])=[CH:6][CH:5]=1)([O-:3])=[O:2].CO[CH:16](OC)[N:17]([CH3:19])[CH3:18]>>[CH3:16][N:17]([CH:19]=[N:13][C:11]([NH:10][C:7]1[CH:8]=[CH:9][C:4]([N+:1]([O-:3])=[O:2])=[CH:5][CH:6]=1)=[S:12])[CH3:18]
Reactant: COC(OC)N(C)C
Reactant: NC(=S)Nc1ccc([N+](=O)[O-])cc1
Product: CN(C)C=NC(=S)Nc1ccc([N+](=O)[O-])cc1
Temperature: 100 °C
Yield: 74.3 %

Procedure:
A mixture of 5 g (25.3 mmol) (4-nitro-phenyl)-thiourea and 33.8 ml (253 mmol) N,N-Dimethylformamide dimethyl acetal was heated to 100° C. for 1 h. The precipitate was filtered off, washed with diethyl ether and dried to yield 4.74 g (74%) the title compound as orange solid.
Reaction SMILES: [H-].[Na+].[CH3:3][CH2:4][O:5][C:6]([CH:8](P(OCC)(OCC)=O)[F:9])=[O:7].[C:18]([C:21]1[O:25][C:24]2[C:26]([C:30]3[CH:35]=[C:34]([CH:36]([CH3:38])[CH3:37])[CH:33]=[C:32]([CH:39]([CH3:41])[CH3:40])[C:31]=3[O:42][CH2:43][CH:44]([F:46])[F:45])=[CH:27][CH:28]=[CH:29][C:23]=2[CH:22]=1)(=O)[CH3:19].O>CN(C=O)C>[CH2:4]([O:5][C:6](=[O:7])[C:8]([F:9])=[C:18]([C:21]1[O:25][C:24]2[C:26]([C:30]3[CH:35]=[C:34]([CH:36]([CH3:37])[CH3:38])[CH:33]=[C:32]([CH:39]([CH3:41])[CH3:40])[C:31]=3[O:42][CH2:43][CH:44]([F:46])[F:45])=[CH:27][CH:28]=[CH:29][C:23]=2[CH:22]=1)[CH3:19])[CH3:3]
Reactant: CCOC(=O)C(F)P(=O)(OCC)OCC
Reactant: CC(=O)c1cc2cccc(-c3cc(C(C)C)cc(C(C)C)c3OCC(F)F)c2o1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CCOC(=O)C(F)=C(C)c1cc2cccc(-c3cc(C(C)C)cc(C(C)C)c3OCC(F)F)c2o1
Temperature: 40 °C

Procedure:
To a slurry of 74 mg (1.54 mmol) of NaH (50% in mineral oil) in 3 mL of dry DMF was added 285.6 mg (1.27 mmol, 2.5 equivalents) of triethyl 2-fluoro-2-phosphonoacetate (diluted in 1 mL of dry DMF) at 0° C. After the gas evolution has ceased, 0.51 mmol of 2-acetyl-7-[3,5-diisopropyl-2-(2,2-difluoroethoxy)phenyl]-benzo[b]furan (see Example 9, step A) diluted in 3 mL of dry DMF was added dropwise. The red mixture was slowly heated to 40° C. until complexion. After cooling, water was added and the solution was extracted 2 times with ethyl acetate. The organic layers were combined, washed with water and brine and dried over MgSO4. After evaporation of the solvents, the crude oil is purified over a short plug of silica gel (eluent: 95/5 hexane/ethyl acetate) to afford 2-fluoro-3-{7-[2-(2,2-difluoroethoxy)-3,5-diisopropylphenyl]-benzo[b]furan-2-yl}-but-2-enoic acid ethyl ester as a pale yellow oil.
Reaction SMILES: [CH3:1][C:2]1[C:7]2=[CH:8][O:9][N:10]=[C:6]2[CH:5]=[CH:4][CH:3]=1.[Br:11]N1C(=O)CCC1=O>C(Cl)(Cl)(Cl)Cl.C(OOC(=O)C1C=CC=CC=1)(=O)C1C=CC=CC=1>[Br:11][CH2:1][C:2]1[C:7]2=[CH:8][O:9][N:10]=[C:6]2[CH:5]=[CH:4][CH:3]=1
Reactant: Cc1cccc2nocc12
Reactant: O=C1CCC(=O)N1Br
Agent: O=C(OOC(=O)c1ccccc1)c1ccccc1
Solvent: ClC(Cl)(Cl)Cl
Product: BrCc1cccc2nocc12
Yield: 103.8 %

Procedure:
To a solution of 5.99 g (45.0 mmoles) (1) in 135 ml carbon tetrachloride was added 8.81 g (49.5 mmoles) N-bromosuccinimide and 100 mg benzoyl peroxide. The mixture was refluxed while illuminated by a 250 watt sunlamp for 18 hours. The mixture was cooled and filtered, and the filtrate concentrated to give 9.9 g of a dark red oil. The oil was extracted with 500 ml hot hexane. The hexane solution was evaporated to 150 ml and cooled to give 6.60 g (69%) of crystalline (2), m.p. 51.0°-52.5°; nmr (deuteriochloroform): 4.6 (s, 2H), 7.2 (m, 3H), 9.3 (s, 1H).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH2:9][C:10](=[O:18])[CH2:11][CH2:12][N:13]2[CH:17]=[CH:16][N:15]=[CH:14]2)=[CH:4][CH:3]=1.[CH3:19][Mg]Cl.[Cl-].[NH4+]>O1CCCC1>[OH:18][C:10]([CH3:19])([CH2:9][CH2:8][C:5]1[CH:6]=[CH:7][C:2]([Cl:1])=[CH:3][CH:4]=1)[CH2:11][CH2:12][N:13]1[CH:17]=[CH:16][N:15]=[CH:14]1
Reactant: O=C(CCc1ccc(Cl)cc1)CCn1ccnc1
Reactant: C[Mg]Cl
Agent: [Cl-]
Agent: [NH4+]
Solvent: C1CCOC1
Product: CC(O)(CCc1ccc(Cl)cc1)CCn1ccnc1
Reaction time: 1 h

Procedure:
A stirred solution of 5 g. of the above ketone in 150 ml. of dry tetrahydrofuran is treated under nitrogen at -50° C. with excess methyl magnesium chloride (12.5 ml. 33M solution in ether). Stirring is continued for 1 hour. The mixture is then allowed to come to room temperature and stirred for an additional hour. A saturated ammonium chloride solution is added and the mixture is extracted with ether. Any product, which separates out at this point is collected by filtration and washed with water and then with ether. The combined ethereal solutions are then washed with water, dried (MgSO4) and evaporated to yield 1-[3-hydroxy-3-methyl-5-(4-chlorophenyl)n-pentyl]imidazole which may be purified by recrystallization from ethyl acetate or by chromatography on silica gel eluting with 10% methanol in dichloromethane.
Reaction SMILES: [CH3:1][O:2][CH:3]([P:13](=[O:20])([O:17][CH2:18][CH3:19])[O:14][CH2:15][CH3:16])[C:4]1[CH:9]=[CH:8][C:7]([N+:10]([O-])=O)=[CH:6][CH:5]=1>[C].[Pd].CO>[NH2:10][C:7]1[CH:8]=[CH:9][C:4]([CH:3]([P:13](=[O:20])([O:14][CH2:15][CH3:16])[O:17][CH2:18][CH3:19])[O:2][CH3:1])=[CH:5][CH:6]=1
Reactant: CCOP(=O)(OCC)C(OC)c1ccc([N+](=O)[O-])cc1
Agent: [Pd]
Solvent: CO
Product: CCOP(=O)(OCC)C(OC)c1ccc(N)cc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a mixed solution of diethyl α-methoxy-4-nitrobenzylphosphonate (3.7 g) and methanol (50 mL) was added 10% palladium-carbon (0.5 g) and the mixture was stirred overnight at room temperature under an atmospheric hydrogen pressure. Palladium-carbon was removed by filtration and the filtrate was concentrated to give diethyl 4-amino-α-methoxybenzylphosphonate as crystals. Recrystallization from ethyl acetate-isopropyl ether gave yellow prism crystals (2.0 g, yield 60%). melting point: 100–101° C.
Reaction SMILES: [C:1](=[N:9][OH:10])([NH2:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:11][O:12][C:13](=[O:23])[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=1[C:20](Cl)=O.B(F)(F)F.CCOCC>O1CCOCC1>[CH3:11][O:12][C:13](=[O:23])[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=1[C:20]1[O:10][N:9]=[C:1]([C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)[N:8]=1
Reactant: NC(=NO)c1ccccc1
Reactant: COC(=O)c1ccccc1C(=O)Cl
Agent: FB(F)F
Solvent: CCOCC
Solvent: C1COCCO1
Product: COC(=O)c1ccccc1-c1nc(-c2ccccc2)no1

Procedure:
A solution of 13.6 g. (0.1 mole) benzamide oxime in 625 milliliters dioxane is treated dropwise with 19.8 g. (0.1 mole) 2-chloroformyl benzoic acid methyl ester in 200 milliliters dioxane. This mixture is then refluxed for one hour, cooled slightly and treated with 3.3 milliliters of boron trifluoride etherate. The reaction mixture is refluxed for 18 hours. The resulting residue is cooled and filtered to remove a small amount of solid. The filtrate is evaporated in vacuo and the resulting oil is dissolved in ether, washed with water, 10 percent sodium carbonate, water and then brine. The ether solution is dried over anhydrous magnesium sulfate decolorized with charcoal filtered to remove the charcoal and the filtrate evaporated in vacuo to give o-(3-phenyl-1,2,4-oxadiazol-5-yl)-benzoic acid methyl ester.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:42]=[C:43]([F:45])[CH:44]=1)[CH2:5][N:6]1[CH:10]=[C:9]([C:11]2[C:19]3[C:14](=[N:15][CH:16]=[C:17]([C:20]4[CH:21]=[N:22][C:23]([N:26]5[CH2:31][CH2:30][NH:29][CH2:28][CH2:27]5)=[CH:24][CH:25]=4)[CH:18]=3)[N:13]([S:32]([C:35]3[CH:41]=[CH:40][C:38]([CH3:39])=[CH:37][CH:36]=3)(=[O:34])=[O:33])[CH:12]=2)[CH:8]=[N:7]1.FC1C=C(C=C(F)C=1)CN1C=C(C2C3C(=NC=C(C4C=NC(N5CCN(C)CC5)=CC=4)C=3)NC=2)C=N1.Cl[CH2:83][C:84]([NH2:86])=[O:85].C(=O)(O)[O-].[Na+]>C(O)C.CC(C)=O>[F:1][C:2]1[CH:3]=[C:4]([CH:42]=[C:43]([F:45])[CH:44]=1)[CH2:5][N:6]1[CH:10]=[C:9]([C:11]2[C:19]3[C:14](=[N:15][CH:16]=[C:17]([C:20]4[CH:25]=[CH:24][C:23]([N:26]5[CH2:27][CH2:28][N:29]([CH2:83][C:84]([NH2:86])=[O:85])[CH2:30][CH2:31]5)=[N:22][CH:21]=4)[CH:18]=3)[N:13]([S:32]([C:35]3[CH:36]=[CH:37][C:38]([CH3:39])=[CH:40][CH:41]=3)(=[O:33])=[O:34])[CH:12]=2)[CH:8]=[N:7]1
Reactant: NC(=O)CCl
Reactant: Cc1ccc(S(=O)(=O)n2cc(-c3cnn(Cc4cc(F)cc(F)c4)c3)c3cc(-c4ccc(N5CCNCC5)nc4)cnc32)cc1
Agent: CN1CCN(c2ccc(-c3cnc4[nH]cc(-c5cnn(Cc6cc(F)cc(F)c6)c5)c4c3)cn2)CC1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC(C)=O
Solvent: CCO
Product: Cc1ccc(S(=O)(=O)n2cc(-c3cnn(Cc4cc(F)cc(F)c4)c3)c3cc(-c4ccc(N5CCN(CC(N)=O)CC5)nc4)cnc32)cc1
Yield: 91.5 %

Procedure:
Using similar reaction conditions as described in step-i of example-82A, 3-(1-(3,5-difluorobenzyl)-1H-pyrazol-4-yl)-5-(6-(piperazin-1-yl)pyridin-3-yl)-1-tosyl-1H-pyrrolo[2,3-b]pyridine (step 2 compound of example 133) (100 mg, 0.16 mmol) was alkylated using 2-chloroacetamide (30 mg, 0.32 mmol), sodium bicarbonate (40 mg, 0.48 mmol) and ethanol/acetone (3/3 mL) to get 100 mg (91.7%) of the titled compound after purification by column (Silica gel 60/120) using 5% methanol in dichloromethane as eluent. MS: m/z=683.3 (M+1).
Reaction SMILES: [OH:1][CH2:2][C:3]1[CH:8]=[C:7]([N:9]2[CH2:14][CH2:13][O:12][CH2:11][C@@H:10]2[CH3:15])[N:6]=[C:5]([C:16]2[CH:21]=[CH:20][C:19]([NH:22][C:23]([NH:25][CH3:26])=[O:24])=[CH:18][CH:17]=2)[N:4]=1.C(N(CC)CC)C.[CH3:34][S:35](Cl)(=[O:37])=[O:36]>C(Cl)Cl>[CH3:26][NH:25][C:23](=[O:24])[NH:22][C:19]1[CH:20]=[CH:21][C:16]([C:5]2[N:6]=[C:7]([N:9]3[CH2:14][CH2:13][O:12][CH2:11][C@@H:10]3[CH3:15])[CH:8]=[C:3]([CH2:2][O:1][S:35]([CH3:34])(=[O:37])=[O:36])[N:4]=2)=[CH:17][CH:18]=1
Reactant: CS(=O)(=O)Cl
Reactant: CNC(=O)Nc1ccc(-c2nc(CO)cc(N3CCOC[C@@H]3C)n2)cc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CNC(=O)Nc1ccc(-c2nc(COS(C)(=O)=O)cc(N3CCOC[C@@H]3C)n2)cc1
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
1-[4-[4-(Hydroxymethyl)-6-[(3S)-3-methylmorpholin-4-yl]pyrimidin-2-yl]phenyl]-3-methyl-urea (1.24 g) was partially dissolved in DCM (30 mL) and triethylamine (0.724 mL) and the solution was cooled to 0° C. Methane sulfonyl chloride was added (0.405 mL) and the reaction was stirred for 15 minutes at RT then concentrated in vacuo to give the desired material.
Reaction SMILES: [F:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:5]([C:12]2[CH:17]=[C:16]([CH:18]([CH3:20])[CH3:19])[N:15]=[C:14](S(C)(=O)=O)[N:13]=2)=[CH:4][CH:3]=1.[NH2:25][C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1>>[F:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:5]([C:12]2[CH:17]=[C:16]([CH:18]([CH3:20])[CH3:19])[N:15]=[C:14]([NH:25][C:26]3[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=3)[N:13]=2)=[CH:4][CH:3]=1
Reactant: CC(C)c1cc(-c2ccc(F)c3ccccc23)nc(S(C)(=O)=O)n1
Reactant: Nc1ccccc1
Product: CC(C)c1cc(-c2ccc(F)c3ccccc23)nc(Nc2ccccc2)n1

Procedure:
Compounds of Formula I are alternatively prepared by the treatment of 4-(4-fluoronaphth-1-yl)-6-isopropyl-2-methanesulfonylpyrimidine with aniline in the absence of solvent at a higher temperatures of 120° C. to afford 4-(4-fluoronaphth-1-yl)-6-isopropyl-2-phenylaminopyrimidine, m.p. 85.7°-86.3° C.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:8]([NH:9][C:10](=[O:18])OC2C=CC=CC=2)=[CH:7][C:6]([CH2:19][CH2:20][CH3:21])=[C:5]([CH3:22])[N:4]=1.[CH3:23][O:24][C:25]1[CH:26]=[C:27]([N:33]2[CH2:38][CH2:37][NH:36][CH2:35][CH2:34]2)[CH:28]=[C:29]([O:31][CH3:32])[CH:30]=1>>[CH3:1][O:2][C:3]1[C:8]([NH:9][C:10]([N:36]2[CH2:35][CH2:34][N:33]([C:27]3[CH:26]=[C:25]([O:24][CH3:23])[CH:30]=[C:29]([O:31][CH3:32])[CH:28]=3)[CH2:38][CH2:37]2)=[O:18])=[CH:7][C:6]([CH2:19][CH2:20][CH3:21])=[C:5]([CH3:22])[N:4]=1
Reactant: CCCc1cc(NC(=O)Oc2ccccc2)c(OC)nc1C
Reactant: COc1cc(OC)cc(N2CCNCC2)c1
Product: CCCc1cc(NC(=O)N2CCN(c3cc(OC)cc(OC)c3)CC2)c(OC)nc1C
Yield: 67 %

Procedure:
Phenyl N-(2-methoxy-6-methyl-5-propylpyridin-3-yl)carbamate and 1-(3,5-dimethoxyphenyl)piperazine were reacted by the same way with the example 1 to obtain the titled compound.
Reaction SMILES: [F:1][C:2]([F:8])([F:7])[S:3]([O-:6])(=[O:5])=[O:4].[F:9][C:10]1[CH:11]=[C:12]([N+:20]([CH3:23])([CH3:22])[CH3:21])[CH:13]=[CH:14][C:15]=1[C:16]([O:18]C)=[O:17].FC(F)(F)C(O)=O>O>[F:1][C:2]([F:8])([F:7])[S:3]([O-:6])(=[O:5])=[O:4].[C:16]([C:15]1[CH:14]=[CH:13][C:12]([N+:20]([CH3:22])([CH3:21])[CH3:23])=[CH:11][C:10]=1[F:9])([OH:18])=[O:17]
Reactant: COC(=O)c1ccc([N+](C)(C)C)cc1F
Agent: O=S(=O)([O-])C(F)(F)F
Solvent: O=C(O)C(F)(F)F
Solvent: O
Product: C[N+](C)(C)c1ccc(C(=O)O)c(F)c1

Procedure:
A solution of 2.50 g (6.92 mmol) 4b, 60 ml dest. water and 60 ml trifluoroacetic acid was refluxed for 2 days. The reaction mixture was evaporated, dried by use of oil pump vacuum over night and treated with diethyl ether. The resulting solid was filtered, washed extensively with diethyl ether and dried by oil pump vacuum. The solid crude product 4c was obtained in 100% yield (2.40 g; 6.92 mmol) and crude compound 4c was used for the next step without purification.