Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[C:10](/[CH:17]=[CH:18]/[C:19]([OH:21])=O)=[CH:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[Cl:22][C:23]1[CH:24]=[C:25]([CH:33]=[CH:34][CH:35]=1)[C:26]([NH:28][NH:29][CH:30]([CH3:32])[CH3:31])=[O:27].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C(N(CC)C(C)C)(C)C>CN(C=O)C.CCOC(C)=O>[Cl:22][C:23]1[CH:24]=[C:25]([CH:33]=[CH:34][CH:35]=1)[C:26]([NH:28][N:29]([C:19](=[O:21])/[CH:18]=[CH:17]/[C:10]1[C:11]2[C:16](=[CH:15][CH:14]=[CH:13][CH:12]=2)[N:8]([C:6]([O:5][C:1]([CH3:2])([CH3:3])[CH3:4])=[O:7])[CH:9]=1)[CH:30]([CH3:32])[CH3:31])=[O:27]
Reactant: CC(C)(C)OC(=O)n1cc(/C=C/C(=O)O)c2ccccc21
Reactant: CC(C)NNC(=O)c1cccc(Cl)c1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CC(C)N(NC(=O)c1cccc(Cl)c1)C(=O)/C=C/c1cn(C(=O)OC(C)(C)C)c2ccccc12
Temperature: 25 °C
Reaction time: 12 h

Procedure:
To solution containing (E)-3-(1-(tert-butoxycarbonyl)-1H-indol-3-yl)acrylic acid (200.0 mg, 0.70 mmol), 3-chloro-N′-isopropylbenzohydrazide (223.3 mg, 1.05 mmol) and HATU (399.2 mg, 1.05 mmol) dissolved in DMF (5.0 ml), N,N-diisopropylethylamine (DIPEA)(0.18 ml, 1.05 mmol) was slowly drop-wise added and stirred at room temperature for 12 hr. The reaction mixture was diluted with EtOAc, washed with water and brine, dried with anhydrous MgSO4, filtered, and concentrated under reduced pressure. The residue was separated through silica gel chromatography (40% EtOAc) for refinement and dried so that white ((E)-tert-butyl 3-(3-(2-(3-chlorobenzoyl)-1-isopropylhydrazinyl)-3-oxoprop-1-enyl)-1H-indole-1-carboxylate was obtained (166.0 mg, 49.2%).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][CH:6]=[C:5]([O:9][CH3:10])[C:4]=1[O:11][CH3:12].[Cl:13][S:14](O)(=[O:16])=[O:15].P(Cl)(Cl)(Cl)=O>C(Cl)(Cl)Cl>[CH3:1][O:2][C:3]1[C:4]([O:11][CH3:12])=[C:5]([O:9][CH3:10])[CH:6]=[CH:7][C:8]=1[S:14]([Cl:13])(=[O:16])=[O:15]
Reactant: O=S(=O)(O)Cl
Reactant: COc1cccc(OC)c1OC
Solvent: O=P(Cl)(Cl)Cl
Solvent: ClC(Cl)Cl
Product: COc1ccc(S(=O)(=O)Cl)c(OC)c1OC
Temperature: 25 °C
Reaction time: 2 h
Yield: 2.8 %

Procedure:
To a solution of 10.0 g of 1,2,3-trimethoxy benzene in CHCl3 (100 ml) was added dropwise 6.90 g of chlorosulfonic acid over 10 minutes under ice cooling. After stirring at room temperature for two hours, the solution was poured into ice water and the resulting mixture was extracted with CHCl3. The aqueous layer was filtered with celite, the filtrate was neutralized with an aqueous solution of 2 mol/L KOH (pH=9), and the solvent was evaporated under reduced pressure to obtain 1.40 g. Phosphorus oxychloride (7 ml) was added to the obtained residue and the mixture was stirred at external temperature of 100° C. for one hour. The solution was poured into ice water, the resulting mixture was extracted with Et2O, the organic layer was washed with water and with saturated brine and then dried over MgSO4; the drying agent was separated by filtration, and then the solvent was evaporated under reduced pressure. The obtained residue was purified by column chromatography (silicagel 60N; mobile phase: EtOAc/n-hexane=1/10 to 1/4; v/v) to obtain 450 mg of the title compound.
Reaction SMILES: C[O:2][C:3]([C:5]1[O:6][C:7]([C:10]2[CH:11]=[C:12]3[C:17](=[CH:18][CH:19]=2)[N:16]=[CH:15][N:14]=[C:13]3[NH:20][C:21]2[CH:26]=[CH:25][C:24]([O:27][CH2:28][C:29]3[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=3)=[CH:23][CH:22]=2)=[CH:8][CH:9]=1)=[O:4].C(Cl)(Cl)[Cl:36]>CCO.[OH-].[Na+]>[ClH:36].[CH2:28]([O:27][C:24]1[CH:23]=[CH:22][C:21]([NH:20][C:13]2[C:12]3[C:17](=[CH:18][CH:19]=[C:10]([C:7]4[O:6][C:5]([C:3]([OH:4])=[O:2])=[CH:9][CH:8]=4)[CH:11]=3)[N:16]=[CH:15][N:14]=2)=[CH:26][CH:25]=1)[C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1
Reactant: ClC(Cl)Cl
Reactant: COC(=O)c1ccc(-c2ccc3ncnc(Nc4ccc(OCc5ccccc5)cc4)c3c2)o1
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: Cl
Product: O=C(O)c1ccc(-c2ccc3ncnc(Nc4ccc(OCc5ccccc5)cc4)c3c2)o1
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
5-(4-(4-Benzyloxy-phenylamino)-quinazolin-6-yl)-furan-2-carboxylic acid methyl ester (0.150 g, 0.332 mmol) was suspended in a mixture of EtOH (2 ml) and 2N aqueous NaOH (2 ml). The mixture was stirred at room temperature for 15 mins. To facilitate dissolution, CHCl3 (2 ml) was added and stirring was continued for 3 days, by which time tlc showed there to be no remaining starting material. The organic solvents were removed in vacuo and the residue diluted with water and treated with 2N aqueous HCl to give the product as a yellow solid, which was collected by filtration (0.130 g, 0.274 mmol, 83%); m/z (M+1+) 438.
Reaction SMILES: [C:1]([C:4]1[C:24]([CH3:25])=[CH:23][C:7]2[NH:8][C:9]([S:11][CH2:12][C:13]3[C:18]([O:19][CH3:20])=[C:17]([O:21][CH3:22])[CH:16]=[CH:15][N:14]=3)=[N:10][C:6]=2[CH:5]=1)(=[O:3])[CH3:2].C([O-])(O)=[O:27].[Na+].ClC1C=CC=C(C(OO)=O)C=1>C(Cl)Cl.O>[C:1]([C:4]1[C:24]([CH3:25])=[CH:23][C:7]2[NH:8][C:9]([S:11]([CH2:12][C:13]3[C:18]([O:19][CH3:20])=[C:17]([O:21][CH3:22])[CH:16]=[CH:15][N:14]=3)=[O:27])=[N:10][C:6]=2[CH:5]=1)(=[O:3])[CH3:2]
Reactant: O=C([O-])O
Reactant: COc1ccnc(CSc2nc3cc(C(C)=O)c(C)cc3[nH]2)c1OC
Agent: O=C(OO)c1cccc(Cl)c1
Agent: [Na+]
Solvent: ClCCl
Solvent: O
Product: COc1ccnc(CS(=O)c2nc3cc(C(C)=O)c(C)cc3[nH]2)c1OC
Reaction time: 0.17 h

Procedure:
5-Acetyl-6-methyl-2-[[(3,4-dimethoxy-2-pyridinyl)methyl]thio]-1H-benzimidazole (3.75 g, 10 mmol) was dissolved in CH2Cl2 (70 ml). NaHCO3 (1.76 g, 21 mmol) in H2O (25 ml) was added and the mixture was cooled to ≈+3° C. m-Chloroperbenzoic acid 69.5% (2.43 g, 9.8 mmol) dissolved in CH2Cl2 (20 ml) was added dropwise under stirring. Stirring was continued for 10 min. The phases were separated and the organic phase was dried over Na2SO4 and evaporated under reduced pressure. The residue was crystallized from CH3CN giving the title compound (2.25 g, 60%).
Reaction SMILES: CS(C)=O.[Cl:5][C:6]1[C:11]([CH:12]([OH:16])[CH:13]([CH3:15])[CH3:14])=[C:10]([Cl:17])[CH:9]=[CH:8][N:7]=1.C(Cl)(=O)C(Cl)=O.C(N(CC)CC)C>ClCCl>[Cl:5][C:6]1[C:11]([C:12](=[O:16])[CH:13]([CH3:15])[CH3:14])=[C:10]([Cl:17])[CH:9]=[CH:8][N:7]=1
Reactant: CC(C)C(O)c1c(Cl)ccnc1Cl
Agent: O=C(Cl)C(=O)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Solvent: CS(C)=O
Product: CC(C)C(=O)c1c(Cl)ccnc1Cl
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 85.7 %

Procedure:
Normal-butyllithium (a 1.6 M solution in hexane, 8.13 mL) was dropwise added to a solution of N,N-diisopropylamine (1.99 mL) in THF (30 mL) at −78° C. under a nitrogen atmosphere, followed by increasing the temperature to 0° C. Then, the solution was cooled to −78° C., and a solution of 2,4-dichloropyridine (1.0 g) in THF (3 mL) wad dropwise added thereto at −78° C., followed by stirring for 1.5 hr. Then, a solution of isobutylaldehyde (1.85 mL) in THF (3 mL) was dropwise added to the reaction solution at −78° C., followed by stirring at the same temperature for 30 min. Then, the reaction solution was poured into ice water and was extracted with ethyl acetate. The organic layer was washed with saturated saline, and the organic layer after the washing was dried over anhydrous sodium sulfate. Then, the solvent was distilled away, and the residue was purified by neutral silica gel column chromatography (n-hexane/ethyl acetate) to obtain 1-(2,4-dichloropyridin-3-yl)-2-methylpropan-1-ol (1.48 g, 99%) as a colorless oily substance. A solution of DMSO (0.9 mL) in dichloromethane (5 mL) and a solution of 1-(2,4-dichloropyridin-3-yl)-2-methylpropan-1-ol (1.39 g) in dichloromethane (5 mL) were sequentially added to a solution of oxalyl chloride (0.8 mL) in dichloromethane (30 mL) at −78° C., followed by stirring for 30 min. Then, triethylamine (3.52 mL) was added to the reaction solution at 0° C., followed by stirring for 1 hr. The reaction solution was poured into ice water and was extracted with chloroform. The organic layer was washed with saturated saline. The organic layer after the washing was dried over anhydrous sodium sulfate, and then the solvent was distilled away. The residue was purified by neutral silica gel column chromatography (n-hexane/ethyl acetate) to obtain 1-(2,4-dichloropyridin-3-yl)-2-methylpropan-1-one (1.18 g, 86%) as a colorless oily substance. Hydrazine monohydrate (1.3 mL) was added to a solution of 1-(2,4-dichloropyridin-3-yl)-2-methylpropan-1-one (0.93 g) in THF (13 mL), followed by stirring at room temperature for 12 hr and then at 50° C. for 25 hr. The reaction solvent was distilled away under reduced pressure, and the residue was purified by neutral silica gel column chromatography (n-hexane/ethyl acetate) to obtain compound (4a) (0.55 g, 66%) as a colorless oily substance.
Reaction SMILES: [F:1][C:2]1[C:11]([N+:12]([O-])=O)=[CH:10][CH:9]=[CH:8][C:3]=1[C:4]([O:6][CH3:7])=[O:5].O.NN>C1COCC1.CO.[Ni]>[NH2:12][C:11]1[C:2]([F:1])=[C:3]([CH:8]=[CH:9][CH:10]=1)[C:4]([O:6][CH3:7])=[O:5]
Reactant: COC(=O)c1cccc([N+](=O)[O-])c1F
Agent: [Ni]
Agent: NN
Solvent: CO
Solvent: O
Solvent: C1CCOC1
Product: COC(=O)c1cccc(N)c1F
Temperature: 70 °C

Procedure:
To a solution of methyl 2-fluoro-3-nitrobenzoate (78 g) in THF (400 ml) and methanol (100 ml) was added Raney Ni (40 g), the mixture was heated to 70° C., and then 25 ml of hydrazine hydrate (N2H4.H2O, 85%) was added dropwise. The reaction was monitored by TLC, when the starting material was totally consumed the addition of hydrazine was stop. The mixture was cooled to rt and filtered, the filtrate was concentrated under vacuum to leave a brown oil, which was purified by chromatography (SiO2, 300-400 mesh, PE: EtOAc=11:2) to afford the title compound was obtained as a yellow oil (45 g, 68%). 1H NMR (300 MHz, DMSO) δ ppm 6.96 (m, 3H), 5.36 (s, 2H), 3.81 (s, 3H).
Reaction SMILES: Cl[C:2]1[C:7]2=[N:8][N:9]([C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=3[Cl:24])[C:10]([C:11]3[CH:16]=[CH:15][C:14]([Cl:17])=[CH:13][CH:12]=3)=[C:6]2[CH:5]=[CH:4][N:3]=1.[OH-:25].[Na+]>C1COCC1.Cl>[Cl:24][C:19]1[CH:20]=[CH:21][CH:22]=[CH:23][C:18]=1[N:9]1[C:10]([C:11]2[CH:16]=[CH:15][C:14]([Cl:17])=[CH:13][CH:12]=2)=[C:6]2[C:7]([C:2]([OH:25])=[N:3][CH:4]=[CH:5]2)=[N:8]1
Reactant: [OH-]
Reactant: Clc1ccc(-c2c3ccnc(Cl)c3nn2-c2ccccc2Cl)cc1
Agent: Cl
Agent: [Na+]
Solvent: C1CCOC1
Product: Oc1nccc2c(-c3ccc(Cl)cc3)n(-c3ccccc3Cl)nc12
Temperature: 60 °C
Reaction time: 8 h
Yield: 80 %

Procedure:
A mixture of 7-chloro-2-(2-chlorophenyl)-3-(4-chlorophenyl)-2H-pyrazolo[3,4-c]pyridine (I-9A-1a, 420 mg, 1.12 mmol) in THF (12 ml) and 3M aqueous HCl (7.5 ml) was stirred overnight at 60° C. The reaction mixture was cooled, adjusted to pH=7.5 with 5M aqueous NaOH, and extracted into ethyl acetate. The combined organic layers were dried (Na2SO4), concentrated under reduced pressure, and then repulped from 40% ethyl acetate in isopropyl ether to give the desired product (I-9A-1a) as a colorless solid (320 mg, 80%): +ES MS (M+1) 356.3; 1H NMR (400 MHz, CD2Cl2): δ 9.64 (br s, 1H), 7.55–7.41 (m, 4H), 7.36–7.32 (m, 2H), 7.23–7.19 (m, 2H), 6.96 (dd, J=7.5, 5.8 Hz, 1H), 6.50 (d, J=7.5 Hz, 1H).
Reaction SMILES: Cl.[NH2:2][CH2:3][CH2:4][NH:5][S:6]([C:9]1[C:17]2[C:12](=[CH:13][CH:14]=[C:15]([Br:18])[CH:16]=2)[N:11]([S:19]([C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)(=[O:21])=[O:20])[C:10]=1[C:28]([O:30][CH2:31][CH3:32])=[O:29])(=[O:8])=[O:7].C(N(CC)CC)C.Cl[C:41](Cl)([O:43]C(=O)OC(Cl)(Cl)Cl)Cl.[CH3:52][O:53][C:54]1[CH:60]=[CH:59][C:57]([NH2:58])=[CH:56][CH:55]=1>C1COCC1.CCOC(C)=O>[Br:18][C:15]1[CH:16]=[C:17]2[C:12](=[CH:13][CH:14]=1)[N:11]([S:19]([C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)(=[O:21])=[O:20])[C:10]([C:28]([O:30][CH2:31][CH3:32])=[O:29])=[C:9]2[S:6]([NH:5][CH2:4][CH2:3][NH:2][C:41]([NH:58][C:57]1[CH:59]=[CH:60][C:54]([O:53][CH3:52])=[CH:55][CH:56]=1)=[O:43])(=[O:8])=[O:7]
Reactant: COc1ccc(N)cc1
Reactant: CCOC(=O)c1c(S(=O)(=O)NCCN)c2cc(Br)ccc2n1S(=O)(=O)c1ccccc1
Reactant: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Agent: Cl
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CCOC(=O)c1c(S(=O)(=O)NCCNC(=O)Nc2ccc(OC)cc2)c2cc(Br)ccc2n1S(=O)(=O)c1ccccc1
Temperature: 0 °C
Reaction time: 0.08 h

Procedure:
A solution of the material from Step A above (25 mg) was dissolved in 1 mL of THF and cooled to 0° C. Triethylamine (25 μL) was added, followed by 4 mg of triphosgene. The reaction stirred for 5 minutes at 0° C., then 5 minutes at room temperature and then was recooled to 0° C. and stirred for 5 minutes more. A solution of 4-methoxyaniline in 1 mL of THF was added slowly. The reaction was stirred for 40 minutes, diluted with EtOAc and washed with 10% citric acid solution, saturated NaHCO3 and brine. The solution was dried (Na2SO4) and concentrated in vacuo to give the titled product.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([OH:31])[CH2:9][CH2:10][CH:11]2[CH:14]([C:15]3[CH:20]=[CH:19][C:18]([O:21][CH3:22])=[CH:17][CH:16]=3)[N:13]([C:23]3[CH:28]=[CH:27][C:26]([OH:29])=[CH:25][CH:24]=3)[C:12]2=[O:30])=[CH:4][CH:3]=1.[Br:32][CH2:33][C:34]1[CH:39]=[CH:38][C:37]([CH2:40]Br)=[CH:36][CH:35]=1.C(=O)([O-])[O-].[K+].[K+]>>[Br:32][CH2:33][C:34]1[CH:39]=[CH:38][C:37]([CH2:40][O:29][C:26]2[CH:25]=[CH:24][C:23]([N:13]3[CH:14]([C:15]4[CH:20]=[CH:19][C:18]([O:21][CH3:22])=[CH:17][CH:16]=4)[CH:11]([CH2:10][CH2:9][CH:8]([C:5]4[CH:4]=[CH:3][C:2]([F:1])=[CH:7][CH:6]=4)[OH:31])[C:12]3=[O:30])=[CH:28][CH:27]=2)=[CH:36][CH:35]=1
Reactant: COc1ccc(C2C(CCC(O)c3ccc(F)cc3)C(=O)N2c2ccc(O)cc2)cc1
Reactant: BrCc1ccc(CBr)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Product: COc1ccc(C2C(CCC(O)c3ccc(F)cc3)C(=O)N2c2ccc(OCc3ccc(CBr)cc3)cc2)cc1

Procedure:
3-[3-(4-Fluorophenyl)-3-hydroxypropyl]-1-(4-hydroxyphenyl)-4-(4-methoxyphenyl)-azetidin-2-one was reacted with 1,4-bisbromomethylbenzene and potassium carbonate analogously to Example IV, giving a colorless solid (25) of molecular weight 604.52 (C33H31BrFNO4); MS (ESI): 605.2 (MH+).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[CH:7][C:6](C(O)=O)=[C:5]2[NH:15][CH2:16][C@@H:17]([O:19][CH3:20])[CH3:18].C([N:23]([CH2:26]C)CC)C.C1C=CC([O:34]P(OC2C=CC=CC=2)(N=[N+]=[N-])=O)=CC=1>CN(C)C=O.O>[Br:1][C:2]1[CH:11]=[CH:10][C:9]2[N:8]=[CH:7][C:6]3[NH:23][C:26](=[O:34])[N:15]([CH2:16][C@@H:17]([O:19][CH3:20])[CH3:18])[C:5]=3[C:4]=2[CH:3]=1
Reactant: [N-]=[N+]=NP(=O)(Oc1ccccc1)Oc1ccccc1
Reactant: CO[C@@H](C)CNc1c(C(=O)O)cnc2ccc(Br)cc12
Reactant: CCN(CC)CC
Solvent: O
Solvent: CN(C)C=O
Product: CO[C@@H](C)Cn1c(=O)[nH]c2cnc3ccc(Br)cc3c21
Temperature: 70 °C
Reaction time: 1 h
Yield: 88.2 %

Procedure:
Suspend 6-bromo-4-[[(2S)-2-methoxypropyl]amino]quinoline-3-carboxylic acid (510 g, 1.5 mol) in dimethylformamide (7.65 L) and add triethylamine (419 mL, 3 mol, 2 eq.) at 70° C. Add diphenylphosphonic azide (390 mL, 1.8 mol., 1.2 eq.) dropwise over 30 minutes. Heat the mixture to 70° C. (internal temperature) for 1 hour. Cool to 10° C. and dilute with water (5 L). Stir the mixture for 1 hour, filter the precipitate, wash it with water (2×1 L) and methyl tert-butyl ether (2×1 L), and then let it dry to give the titled compound as a white solid (445 g, 88%). MS (ESI) m/z (M+H)+ 335.9, 337.9.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:18])[C:5]([F:17])([F:16])[CH2:6][NH:7][CH2:8][CH2:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)[CH3:2].[Cl:19][C:20]1[N:25]=[C:24](Cl)[C:23]([N+:27]([O-:29])=[O:28])=[CH:22][N:21]=1.C(=O)(O)[O-].[Na+]>C(OCC)(=O)C>[CH2:1]([O:3][C:4](=[O:18])[C:5]([F:17])([F:16])[CH2:6][N:7]([C:22]1[C:23]([N+:27]([O-:29])=[O:28])=[CH:24][N:25]=[C:20]([Cl:19])[N:21]=1)[CH2:8][CH2:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)[CH3:2]
Reactant: CCOC(=O)C(F)(F)CNCCc1ccccc1
Reactant: O=[N+]([O-])c1cnc(Cl)nc1Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCOC(C)=O
Product: CCOC(=O)C(F)(F)CN(CCc1ccccc1)c1nc(Cl)ncc1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 17 h
Yield: 135.9 %

Procedure:
A solution of 0.57 g (0.0022 mole) of 2,2-difluoro-3-phenethylamino-propionic acid ethyl ester in 1 mL of ethyl acetate was added over 5 minutes to a cooled (0 degrees) mixture of 0.43 g (0.0022 mole) of 2,4-dichloro-5-nitro-pyrimidine, 0.75 g (0.0088 mole) of sodium bicarbonate and 6 mL of ethyl acetate. The cooling bath was removed and the mixture stirred for 17 hours at room temperature. Activated charcoal was added and after stirring briefly, the mixture was filtered through a pad of Celite, washing the filter pad with ethyl acetate. The filtrate was concentrated under reduced pressure to give 1.24 g of 3-[(2-chloro-5-nitro-pyrimidin-4-yl)-phenethyl-amino]-2,2-difluoro-propionic acid ethyl ester (IV-275) as a yellow thick oil. This material was used directly in the next step without further purification.
Reaction SMILES: NC1C=CC(F)=CC=1C(NC)=O.[F:13][C:14]1[CH:19]=[CH:18][CH:17]=[C:16]([N+:20]([O-])=O)[C:15]=1[O:23][CH3:24]>>[CH3:24][O:23][C:15]1[C:14]([F:13])=[CH:19][CH:18]=[CH:17][C:16]=1[NH2:20]
Reactant: COc1c(F)cccc1[N+](=O)[O-]
Agent: CNC(=O)c1cc(F)ccc1N
Product: COc1c(N)cccc1F

Procedure:
The title compound was prepared according to the procedure for Compound 102A (2-Amino-5-fluoro-N-methylbenzamide) with 1-fluoro-2-methoxy-3-nitrobenzene (Compound 147J). 1H NMR (CDCl3, 400 MHz): δ=3.92 (d, J=1.52 Hz, 3 H), 6.44-6.53 (m, 2 H), 6.80 (td, J=8.15, 5.68 Hz, 1 H). MS (ES+): m/z 142.07 [MH+] (TOF, polar).
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([S:8]([CH3:11])(=[O:10])=[O:9])[CH:5]=[CH:4][C:3]=1[C:12]1[CH:33]=[CH:32][C:15]2[NH:16][C:17]([CH:19]3[CH2:24][CH2:23][N:22]([C:25]([O:27][C:28]([CH3:31])([CH3:30])[CH3:29])=[O:26])[CH2:21][CH2:20]3)=[N:18][C:14]=2[CH:13]=1.[H-].[Na+].CI.[CH3:38]COC(C)=O.O>C1COCC1>[F:1][C:2]1[CH:7]=[C:6]([S:8]([CH3:11])(=[O:9])=[O:10])[CH:5]=[CH:4][C:3]=1[C:12]1[CH:33]=[CH:32][C:15]2[N:16]([CH3:38])[C:17]([CH:19]3[CH2:24][CH2:23][N:22]([C:25]([O:27][C:28]([CH3:30])([CH3:29])[CH3:31])=[O:26])[CH2:21][CH2:20]3)=[N:18][C:14]=2[CH:13]=1
Reactant: CCOC(C)=O
Reactant: CC(C)(C)OC(=O)N1CCC(c2nc3cc(-c4ccc(S(C)(=O)=O)cc4F)ccc3[nH]2)CC1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Solvent: CI
Product: Cn1c(C2CCN(C(=O)OC(C)(C)C)CC2)nc2cc(-c3ccc(S(C)(=O)=O)cc3F)ccc21
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
Tert-butyl 4-{5-[2-fluoro-4-(methylsulfonyl)phenyl]-1H-benzo[d]imidazol-2-yl}piperidine-1-carboxylate (85 mg, 0.17 mmol) dissolved in THF (15 ml) and cooled to 0° C. Sodium hydride (9 mg, 0.342 mmol) added to the above mixture and stirred at the same temperature for 30 mins. To this mixture methyl iodide (48 mg, 0.342 mmol) added at same temperature and stirred the reaction mixture at rt for 3 h. Reaction mixture diluted with ice and worked up (EtOAc/H2O). Crude was purified by column chromatography on 60-120 mesh silica gel using EtOAc:Petether (3:1) as eluent to afford the title compound (50 mg) as an orange solid. M.P.: 85-88° C. 1H-NMR (δ ppm, CDCl3, 400 MHz): 7.85-7.75 (m, 2H), 7.73-7.64 (m, 2H), 7.56-7.51 (m, 1H), 7.50-7.45 (m, 1H), 4.39-4.21 (m, 2H), 3.82 (s, 3H), 3.11 (s, 3H), 3.10-3.00 (m, 2H), 3.00-2.88 (m, 2H), 2.05-1.93 (m, 3H), 1.48 (s, 9H).
Reaction SMILES: CS([C:5]1[N:10]=[C:9]([C:11]2[CH:16]=[CH:15][C:14]([S:17]([CH3:20])(=[O:19])=[O:18])=[CH:13][CH:12]=2)[CH:8]=[C:7]([C:21]([F:24])([F:23])[F:22])[N:6]=1)(=O)=O.[NH2:25][CH2:26][C:27]1[CH:32]=[CH:31][N:30]=[CH:29][CH:28]=1>CC#N>[CH3:20][S:17]([C:14]1[CH:15]=[CH:16][C:11]([C:9]2[CH:8]=[C:7]([C:21]([F:24])([F:23])[F:22])[N:6]=[C:5]([NH:25][CH2:26][C:27]3[CH:32]=[CH:31][N:30]=[CH:29][CH:28]=3)[N:10]=2)=[CH:12][CH:13]=1)(=[O:19])=[O:18]
Reactant: CS(=O)(=O)c1ccc(-c2cc(C(F)(F)F)nc(S(C)(=O)=O)n2)cc1
Reactant: NCc1ccncc1
Solvent: CC#N
Product: CS(=O)(=O)c1ccc(-c2cc(C(F)(F)F)nc(NCc3ccncc3)n2)cc1
Yield: 57 %

Procedure:
To a stirred solution of 2-(methylsulfonyl)-4-[4-(methylsulfonyl)phenyl]-6-(trifluoromethyl)-pyrimidine (0.10 g, 0.26 mmol) in MeCN (4 ml) was added 4-(aminomethyl)-pyridine (0.14 ml, 5 eq) and the resultant solution heated under reflux for 18 h. The cooled reaction mixture was concentrated in vacuo and purified by SPE chromatography using chloroform, diethyl ether, ethyl acetate, acetone and methanol as the eluotropic series of solvents. Concentration in vacuo of the combined fractions containing pure product gave the title compound as a colourless solid (0.061 g, 57%).
Reaction SMILES: [C:1]([C:5]1[O:9][N:8]=[C:7]([NH:10][C:11]([NH:13][C:14]2[CH:19]=[CH:18][CH:17]=[C:16]([O:20][C:21]3[C:30]4[C:25](=[CH:26][C:27]([O:32][CH3:33])=[C:28]([OH:31])[CH:29]=4)[N:24]=[CH:23][N:22]=3)[CH:15]=2)=[O:12])[CH:6]=1)([CH3:4])([CH3:3])[CH3:2].[CH2:34]([CH:36]1[O:38][CH2:37]1)Cl>>[C:1]([C:5]1[O:9][N:8]=[C:7]([NH:10][C:11]([NH:13][C:14]2[CH:19]=[CH:18][CH:17]=[C:16]([O:20][C:21]3[C:30]4[C:25](=[CH:26][C:27]([O:32][CH3:33])=[C:28]([O:31][CH2:34][C@H:36]5[CH2:37][O:38]5)[CH:29]=4)[N:24]=[CH:23][N:22]=3)[CH:15]=2)=[O:12])[CH:6]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: ClCC1CO1
Reactant: COc1cc2ncnc(Oc3cccc(NC(=O)Nc4cc(C(C)(C)C)on4)c3)c2cc1O
Product: COc1cc2ncnc(Oc3cccc(NC(=O)Nc4cc(C(C)(C)C)on4)c3)c2cc1OC[C@H]1CO1
Yield: 8.9 %

Procedure:
1-(5-tert-butylisoxazol-3-yl)-3-(3-(6-hydroxy-7-methoxyquinazolin-4-yloxy)phenyl)urea (320 mg, 0.712 mol) and (R) (−) epichlorohydrin (288 μL, 3.56 mmol) were reacted using the same procedureas described before from Example 111A to afford (R)-1-(5-tert-butylisoxazol-3-yl)-3-(3-(7-methoxy-6-(oxiran-2-ylmethoxy)quinazolin-4-yloxy)phenyl)urea (160 mg, 44%). LC-MS (ESI) m/z 506 (M+H)+.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[N:9]=[CH:8][CH:7]=[C:6]2[O:15][C:16]1[CH:23]=[CH:22][C:21]([I:24])=[CH:20][C:17]=1[CH:18]=[O:19].[CH2:25]([Mg]Br)[CH3:26].O>O1CCCC1>[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[N:9]=[CH:8][CH:7]=[C:6]2[O:15][C:16]1[CH:23]=[CH:22][C:21]([I:24])=[CH:20][C:17]=1[CH:18]([OH:19])[CH2:25][CH3:26]
Reactant: COc1cc2nccc(Oc3ccc(I)cc3C=O)c2cc1OC
Reactant: CC[Mg]Br
Solvent: O
Solvent: C1CCOC1
Product: CCC(O)c1cc(I)ccc1Oc1ccnc2cc(OC)c(OC)cc12
Temperature: 0 °C
Reaction time: 1 h

Procedure:
2-[(6,7-Dimethoxy-4-quinolyl)oxy]-5-iodobenzaldehyde was dissolved in anhydrous tetrahydrofuran (1 ml) to prepare a solution. A 1 M tetrahydrofuran solution (0.5 ml) of ethylmagnesium bromide was added to the solution at 0° C., and the mixture was stirred at 0° C. for one hr. Water (1 ml) was added dropwise to the reaction solution to stop the reaction. The mixture was extracted with ethyl acetate, and the ethyl acetate layer was then washed with water and saturated brine and was dried over anhydrous sodium sulfate. The solvent was removed by distillation under the reduced pressure to give 1-{2-[(6,7-dimethoxy-4-quinolyl)oxy]-5-iodophenyl}-1-propanol.
Reaction SMILES: [CH3:1][C:2](O)([CH2:5][C:6](C)=[CH2:7])[CH:3]=C.C([O:12][CH2:13][CH3:14])C>O1CCCC1>[CH3:3][C:2](=[CH2:1])[CH2:5][CH2:6][CH2:7][C:13](=[O:12])[CH3:14]
Reactant: C=CC(C)(O)CC(=C)C
Reactant: CCOCC
Solvent: C1CCOC1
Product: C=C(C)CCCC(C)=O

Procedure:
A mixture of 3,5-dimethylhexa-1,5-dien-3-ol (0.126 g; 10-3 mol) and dichloro-bis-(benzonitrile)-palladium(II) (0.0153 g; 0.04.10-3 mol) in tetrahydrofuran (7.5 cc) is kept at a temperature of the order of 20° C. under an inert atmosphere. After a reaction time of 5 hours, diethyl ether (50 cc) is added and the reaction mixture is then washed with water (7×10 cc). After drying of the organic layer over magnesium sulphate and evaporation of the solvent under reduced pressure (20 mm Hg; 2.7 kPa), 6-methylhept-6-en-2-one (0.125 g) is obtained, which has the following characteristics: