Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[CH:10]=[C:9]([F:11])[CH:8]=[C:7]([F:12])[C:3]=1[C:4]([NH2:6])=[O:5].[OH:13][CH2:14][CH2:15][O:16][C:17]1[C:24]([CH3:25])=[CH:23][C:20]([CH:21]=O)=[CH:19][C:18]=1[CH3:26].OS([O-])=O.[Na+].O.C1(C)C=CC(S(O)(=O)=O)=CC=1>CN(C)C(=O)C>[F:12][C:7]1[CH:8]=[C:9]([F:11])[CH:10]=[C:2]2[C:3]=1[C:4](=[O:5])[NH:6][C:21]([C:20]1[CH:23]=[C:24]([CH3:25])[C:17]([O:16][CH2:15][CH2:14][OH:13])=[C:18]([CH3:26])[CH:19]=1)=[N:1]2
Reactant: Cc1cc(C=O)cc(C)c1OCCO
Reactant: NC(=O)c1c(N)cc(F)cc1F
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: O=S([O-])O
Agent: [Na+]
Solvent: O
Solvent: CC(=O)N(C)C
Product: Cc1cc(-c2nc3cc(F)cc(F)c3c(=O)[nH]2)cc(C)c1OCCO
Temperature: 120 °C
Reaction time: 16 h

Procedure:
A mixture of 2-amino-4,6-difluoro-benzamide (0.96 g, 5.60 mmol), 4-(2-hydroxy-ethoxy)-3,5-dimethyl-benzaldehyde (1.09 g, 5.60 mmol), NaHSO3 (58.5 wt %, 1.00 g, 5.60 mmol) and p-toluenesulfonic acid monohydrate (1.44 g, 7.06 mmol) in N,N-dimethylacetamide (25 mL) was stirred at 120° C. for 16 hours, then cooled to room temperature. Solvent was removed under reduced pressure. The residue was diluted with water (100 mL). The solid separated was filtered and washed with water and dried under vacuum to give 5,7-difluoro-2-[4-(2-hydroxy-ethoxy)-3,5-dimethyl-phenyl]-3H-quinazolin-4-one as a white solid. Yield: 1.55 g (79%).
Reaction SMILES: Cl[CH2:2][O:3][C:4]([O:6][CH:7]([CH2:24][O:25][C:26](=[O:39])[C@H:27]([CH:36]([CH3:38])[CH3:37])[NH:28][C:29]([O:31][C:32]([CH3:35])([CH3:34])[CH3:33])=[O:30])[CH2:8][O:9][C:10](=[O:23])[C@H:11]([CH:20]([CH3:22])[CH3:21])[NH:12][C:13]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14])=[O:5].[Na+].[I-:41]>>[I:41][CH2:2][O:3][C:4]([O:6][CH:7]([CH2:24][O:25][C:26](=[O:39])[C@H:27]([CH:36]([CH3:38])[CH3:37])[NH:28][C:29]([O:31][C:32]([CH3:35])([CH3:34])[CH3:33])=[O:30])[CH2:8][O:9][C:10](=[O:23])[C@H:11]([CH:20]([CH3:22])[CH3:21])[NH:12][C:13]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14])=[O:5]
Reactant: [I-]
Reactant: CC(C)[C@H](NC(=O)OC(C)(C)C)C(=O)OCC(COC(=O)[C@@H](NC(=O)OC(C)(C)C)C(C)C)OC(=O)OCCl
Agent: [Na+]
Product: CC(C)[C@H](NC(=O)OC(C)(C)C)C(=O)OCC(COC(=O)[C@@H](NC(=O)OC(C)(C)C)C(C)C)OC(=O)OCI
Temperature: 80 °C
Yield: 92 %

Procedure:
A solution of 2-O-chloromethoxycarbonyl-1,3-di-O-(N-tert-butoxycarbonyl-L-valyl)propane-1,2,3-triol (7.86 g, 13.5 mmol) and NaI (8.09 g, 54.0 mmol) in 135 mL dry acetonitirile was refluxed at 80° C. for 4 h under N2. The reaction mixture was concentrated under vacuum, and then partitioned between 150 mL diethyl ether and 50 mL H2O. The aqueous layer was reextracted with 2×25 mL ether. The combined organic phases were washed successively with 25 mL aqueous Na2S2O3 and 50 mL brine, dried over Na2SO4, and concentrated. Flash column chromatography (silica gel, 2/1 hexane-ethyl acetate gave 8.38 g (92%) title product (alternative name: 2-iodomethoxycarbonyloxy-1,3-bis-(N-tert-butoxycarbonyl-L-valyloxy)propane or 1,3-bis(N-tert-butoxycarbonyl-L-valyloxy)-2-propyl iodomethyl carbonate) as a white solid.
Reaction SMILES: [NH2:1][C:2]([CH3:27])([CH3:26])[CH2:3][C@@:4]1([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[O:9][C:8](=[O:10])[N:7]([C@H:11]([C:13]2[CH:18]=[CH:17][C:16]([Br:19])=[CH:15][CH:14]=2)[CH3:12])[CH2:6][CH2:5]1.[C:28](O)(=[O:33])[C:29]([CH3:32])([CH3:31])[CH3:30]>>[Br:19][C:16]1[CH:17]=[CH:18][C:13]([C@@H:11]([N:7]2[CH2:6][CH2:5][C@:4]([CH2:3][C:2]([NH:1][C:28](=[O:33])[C:29]([CH3:32])([CH3:31])[CH3:30])([CH3:26])[CH3:27])([C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)[O:9][C:8]2=[O:10])[CH3:12])=[CH:14][CH:15]=1
Reactant: C[C@@H](c1ccc(Br)cc1)N1CC[C@](CC(C)(C)N)(c2ccccc2)OC1=O
Reactant: CC(C)(C)C(=O)O
Product: C[C@@H](c1ccc(Br)cc1)N1CC[C@](CC(C)(C)NC(=O)C(C)(C)C)(c2ccccc2)OC1=O

Procedure:
The title compound was prepared (S)-6-(2-amino-2-methylpropyl)-3-((S)-1-(4-bromophenyl)ethyl)-6-phenyl-1,3-oxazinan-2-one following a procedure analogous to that described in Example 688 using pivalic acid. LC-MS Method 1 tR=2.05 min, m/z=515; 1H NMR (CDCl3) 7.36-7.27 (5H, m), 7.22 (2H, d, J=8.5 Hz), 6.79 (2H, d, J=8.2 Hz), 6.20 (1H, s), 5.58 (1H, q, J=7.0 Hz), 2.79 (1H, m), 2.44 (1H, d, J=15.5 Hz), 2.37 (1H, d, J=15.2 Hz), 2.24-2.06 (3H, m), 1.47 (3H, d, J=7.03 Hz), 1.37 (3H, s) 1.10 (9H, s), 1.05 (3H, s).
Reaction SMILES: [NH2:1][C:2]1[CH:11]=[C:10]2[C:5]([CH2:6][CH2:7][CH:8]([N:12]([CH2:24][CH2:25][CH2:26][N:27]3[CH2:32][CH2:31][N:30]([CH3:33])[CH2:29][CH2:28]3)[C:13]([NH:15][C:16]3[CH:21]=[CH:20][C:19]([F:22])=[C:18]([Cl:23])[CH:17]=3)=[O:14])[CH2:9]2)=[CH:4][CH:3]=1.[CH3:34][S:35](Cl)(=[O:37])=[O:36].CCN(C(C)C)C(C)C>C(Cl)Cl>[Cl:23][C:18]1[CH:17]=[C:16]([NH:15][C:13](=[O:14])[N:12]([CH:8]2[CH2:9][C:10]3[CH:11]=[C:2]([NH:1][S:35]([CH3:34])(=[O:37])=[O:36])[CH:3]=[CH:4][C:5]=3[CH2:6][CH2:7]2)[CH2:24][CH2:25][CH2:26][N:27]2[CH2:28][CH2:29][N:30]([CH3:33])[CH2:31][CH2:32]2)[CH:21]=[CH:20][C:19]=1[F:22]
Reactant: CS(=O)(=O)Cl
Reactant: CN1CCN(CCCN(C(=O)Nc2ccc(F)c(Cl)c2)C2CCc3ccc(N)cc3C2)CC1
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CN1CCN(CCCN(C(=O)Nc2ccc(F)c(Cl)c2)C2CCc3ccc(NS(C)(=O)=O)cc3C2)CC1
Reaction time: 3 h
Yield: 85.7 %

Procedure:
To a solution of 1-(7-amino-1,2,3,4-tetrahydro-naphthalen-2-yl)-3-(3-chloro-4-fluoro-phenyl)-1-[3-(4-methyl-piperazin-1-yl)-propyl]-urea (from Preparative Example 27, 0.035 g, 0.074 mmol) in CH2Cl2 (0.2 mL) at 0° C. were added methanesulfonyl chloride (0.0058 mL, 0.074 mmol) and DIEA (0.039 mL, 0.22 mmol). The mixture was stirred from 0° C. to room temperature for 3 hours, then concentrated in vacuo, and the residue was purified by preparative HPLC to give 0.035 g (88%) of N-(7-{3-(3-chloro-4-fluoro-phenyl)-1-[3-(4-methyl-piperazin-1-yl)-propyl]-ureido}-5,6,7,8-tetrahydro-naphthalen-2-yl)-methanesulfonamide as a light yellow gum. 1H NMR (300 MHz, CD3OD): δ 7.59 (dd, 1H, J=6.6, 2.7 Hz), 7.30 (ddd, 1H, J=9.0, 4.2, 2.7 Hz), 7.14 (t, 1H, J=9.0 Hz), 7.08 (d, 1H, J=8.4 Hz), 7.04-6.98 (m, 2H), 4.30 (m, 1H), 3.66 (m, 8H), 3.46 (m, 2H), 2.99 (m, 6H), 2.90 (s, 3H), 2.11 (m, 4H). MS-ESI: 552.0 (M+H+).
Reaction SMILES: [Cl:1][C:2]1[CH:29]=[CH:28][C:5]([CH2:6][N:7]2[CH:12]=[N:11][C:10]([N:13]3[CH2:18][CH:17]([OH:19])[C:16]([C:20]4[CH:25]=[CH:24][C:23]([F:26])=[CH:22][CH:21]=4)=[CH:15][CH2:14]3)=[N:9][C:8]2=[O:27])=[CH:4][CH:3]=1.CO.[H][H]>[Pd].ClCCl>[Cl:1][C:2]1[CH:29]=[CH:28][C:5]([CH2:6][N:7]2[CH:12]=[N:11][C:10]([N:13]3[CH2:14][CH2:15][CH:16]([C:20]4[CH:25]=[CH:24][C:23]([F:26])=[CH:22][CH:21]=4)[CH:17]([OH:19])[CH2:18]3)=[N:9][C:8]2=[O:27])=[CH:4][CH:3]=1
Reactant: [H][H]
Reactant: O=c1nc(N2CC=C(c3ccc(F)cc3)C(O)C2)ncn1Cc1ccc(Cl)cc1
Agent: [Pd]
Solvent: CO
Solvent: ClCCl
Product: O=c1nc(N2CCC(c3ccc(F)cc3)C(O)C2)ncn1Cc1ccc(Cl)cc1
Yield: 71.5 %

Procedure:
A solution of 1-(4-chlorobenzyl)-4-[4-(4-fluorophenyl)-5-hydroxy-5,6-dihydropyridin-1(2H)-yl]-1,3,5-triazin-2(1H)-one (10 mg, 0.03 mmol) synthesized in Reference Synthesis Example 90 and palladium-activated carbon (3 mg) in a solvent mixture of methanol (5 mL) and dichloromethane (5 mL) was stirred in a hydrogen atmosphere for 3 days. After the completion of the reaction, the reaction solution was filtered through Celite and the filtrate was concentrated under reduced pressure to obtain the title compound (8.9 mg, yield: 90%).
Reaction SMILES: FC(F)(F)C(O)=O.[CH3:8][O:9][C:10]1[CH:15]=[C:14]([CH3:16])[C:13]([S:17]([N:20]2[CH2:25][CH2:24][CH2:23][CH2:22][CH:21]2[CH2:26][O:27][CH2:28][C:29]([N:31]2[CH2:36][CH2:35][N:34](C(OC(C)(C)C)=O)[CH2:33][CH2:32]2)=[O:30])(=[O:19])=[O:18])=[C:12]([CH3:44])[CH:11]=1>ClCCl>[CH3:8][O:9][C:10]1[CH:15]=[C:14]([CH3:16])[C:13]([S:17]([N:20]2[CH2:25][CH2:24][CH2:23][CH2:22][CH:21]2[CH2:26][O:27][CH2:28][C:29]([N:31]2[CH2:32][CH2:33][NH:34][CH2:35][CH2:36]2)=[O:30])(=[O:18])=[O:19])=[C:12]([CH3:44])[CH:11]=1
Reactant: COc1cc(C)c(S(=O)(=O)N2CCCCC2COCC(=O)N2CCN(C(=O)OC(C)(C)C)CC2)c(C)c1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: COc1cc(C)c(S(=O)(=O)N2CCCCC2COCC(=O)N2CCNCC2)c(C)c1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
Trifluoroacetic acid (13 eq.) was added at 0° C. to a solution of tert-butyl 4-(2-((1-(4-methoxy-2,6-dimethylphenylsulfonyl)piperidin-2-yl)methoxy)acetyl)piperazine-1-carboxylate (Example 101) (1 eq.) in dichloromethane (10 ml/mmol). The reaction mixture was stirred for 2 h at room temperature and then concentrated in vacuo. The crude product was used in the next synthesis step without being purified further.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][C:5]([Cl:44])=[C:6]([N:8]2[C:12](=[O:13])[N:11]([CH2:14][C:15]3[CH:20]=[CH:19][C:18]([C:21]4[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=4[S:27](=[O:39])(=[O:38])[NH:28][C:29](=[O:37])[C:30]4[CH:35]=[CH:34][CH:33]=[CH:32][C:31]=4[Cl:36])=[CH:17][CH:16]=3)[C:10]([CH2:40][CH2:41][CH2:42][CH3:43])=[N:9]2)[CH:7]=1.[H-].[Na+].[C:47](Cl)(=[O:52])[CH2:48][CH2:49][CH2:50][CH3:51]>>[CH2:40]([C:10]1[N:11]([CH2:14][C:15]2[CH:16]=[CH:17][C:18]([C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=3[S:27](=[O:38])(=[O:39])[NH:28][C:29](=[O:37])[C:30]3[CH:35]=[CH:34][CH:33]=[CH:32][C:31]=3[Cl:36])=[CH:19][CH:20]=2)[C:12](=[O:13])[N:8]([C:6]2[CH:7]=[C:2]([NH:1][C:47](=[O:52])[CH2:48][CH2:49][CH2:50][CH3:51])[CH:3]=[CH:4][C:5]=2[Cl:44])[N:9]=1)[CH2:41][CH2:42][CH3:43]
Reactant: CCCCC(=O)Cl
Reactant: CCCCc1nn(-c2cc(N)ccc2Cl)c(=O)n1Cc1ccc(-c2ccccc2S(=O)(=O)NC(=O)c2ccccc2Cl)cc1
Agent: [H-]
Agent: [Na+]
Product: CCCCC(=O)Nc1ccc(Cl)c(-n2nc(CCCC)n(Cc3ccc(-c4ccccc4S(=O)(=O)NC(=O)c4ccccc4Cl)cc3)c2=O)c1

Procedure:
The title compound was prepared from 2-(5-amino-2-chlorophenyl)-5-n-butyl-4-[[2'-[N-(2-chlorobenzoyl)sulfamoyl]biphenyl-4-yl]methyl]-2,4-dihydro-3H-1,2,4-triazol-3-one (from Example 60), sodium hydride, and valeryl chloride according the procedure of Example 57. The crude product was flash chromatographed over silica gel (gradient elution with 0.5-2.0% MeOH/CH2Cl2) to give the desired compound as a cream-colored solid in 48% yield, mp >110° C. (gradual), homogeneous by TLC (9:1 MeOH/CH2Cl2), mass spectrum (FAB) m/e 734 (M+1)+.
Reaction SMILES: [CH3:1][CH:2]([CH3:20])[C:3]([C:5]1[C:6]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)=[N:7][N:8]2[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=12)=O.Cl.[NH2:22][OH:23].[OH-].[Na+].Cl>CCO.O>[CH3:1][CH:2]([CH3:20])[C:3]([C:5]1[C:6]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)=[N:7][N:8]2[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=12)=[N:22][OH:23]
Reactant: CC(C)C(=O)c1c(-c2ccccc2)nn2ccccc12
Reactant: NO
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: CC(C)C(=NO)c1c(-c2ccccc2)nn2ccccc12
Temperature: 0 °C
Yield: 28.3 %

Procedure:
To a solution of 5.32 g (20 mmol) of 2-methyl-1-(2-phenylpyrazolo[1,5-a]pyridin-3-yl)propan-1-one in 32 ml of anhydrous EtOH was added 3 g of hydroxylamine hydrochloride, followed by dropwise addition of a solution of 4.0 g NaOH in 12 ml water. The mixture was stirred and refluxed over night. After cooling, the solution was poured into a solution of 11 ml of 6N HCl and 200 ml ice water with stirring for 30 minutes. The mixture was extracted with ethyl acetate three times. The organic phase was washed with brine and dried over MgSO4. The solvent was removed under reduced pressure to obtain 4.6 g of crude compound, which was purified on an aluminum oxide column with hexane-dichloromethane-ethyl acetate as eluant to furnish 1.58 g (30.1%) of 2-methyl-1-(2-phenylpyrazolo[1,5-a]pyridin-3-yl)propan-1-one oxime. Compound 1016.
Reaction SMILES: [OH:1][C:2]1[C:3]([C:12]([O:14]C)=O)=[N:4][CH:5]=[C:6]2[C:11]=1[N:10]=[CH:9][CH:8]=[CH:7]2.[N:16]1[CH:21]=[CH:20][C:19]([CH2:22][NH2:23])=[CH:18][CH:17]=1>C1(C)C=CC=CC=1>[OH:1][C:2]1[C:3]([C:12]([NH:23][CH2:22][C:19]2[CH:20]=[CH:21][N:16]=[CH:17][CH:18]=2)=[O:14])=[N:4][CH:5]=[C:6]2[C:11]=1[N:10]=[CH:9][CH:8]=[CH:7]2
Reactant: NCc1ccncc1
Reactant: COC(=O)c1ncc2cccnc2c1O
Solvent: Cc1ccccc1
Product: O=C(NCc1ccncc1)c1ncc2cccnc2c1O

Procedure:
To a solution of methyl 8-hydroxy-1,6-naphthyridine-7-carboxylate from Example 1, Step 2 (0.05 g, 0.245 mmol) in dry toluene (3 mL) was added 1-pyridin-4-ylmethanamine (0.029 g, 0.270 mmol) and the mixture was heated to reflux for 16 hours. The solution was reduced to a smaller volume and refluxed for 4 additional hours. The solvent was removed under reduced pressure and the residue redissolved in DMF and filtered and the solution solution was purified by preparative HPLC (Gilson semipreparative HPLC system and a YMC Combiprep Column (50×20 mm I.D., C18, S-5 uM, 120 A) eluting with 5-95% acetonitrile/water (0.1% TFA) at 15 ml/min) to afford the title compound after lyophilization.
Reaction SMILES: [C:1](OC(=O)C)(=[O:3])[CH3:2].[NH2:8][C:9]1[CH:14]=[C:13]([C:15]([OH:17])=[O:16])[CH:12]=[CH:11][C:10]=1[N:18]([C:20](=[O:22])[CH3:21])[NH2:19]>ClCCl>[C:1]([NH:8][C:9]1[CH:14]=[C:13]([C:15]([OH:17])=[O:16])[CH:12]=[CH:11][C:10]=1[N:18]([C:20](=[O:22])[CH3:21])[NH2:19])(=[O:3])[CH3:2]
Reactant: CC(=O)OC(C)=O
Reactant: CC(=O)N(N)c1ccc(C(=O)O)cc1N
Solvent: ClCCl
Product: CC(=O)Nc1cc(C(=O)O)ccc1N(N)C(C)=O
Yield: 86.5 %

Procedure:
235 ml of acetic anhydride were added to a suspension of 97.5 g of 2-amino-4-carboxy-N-acetylphenylhydrazine in 450 ml of dichloromethane while stirring. The mixture was stirred at room temperature for 3 hours, then the crystals were filtered by suction, washed with dichloromethane and dried at 60° C. Thus, 101.2 g (86.5%) of 2-acetylamino-4-carboxy-N-acetylphenylhydrazine were obtained, m.p.: 238° C. (with decomposition).
Reaction SMILES: [N+:1]([CH2:4][CH:5]1[CH2:13][C:8]2([O:12][CH2:11][CH2:10][O:9]2)[CH:7]([CH2:14][CH:15]=[CH:16][CH2:17][CH2:18][CH2:19][C:20]([OH:22])=[O:21])[CH:6]1[CH:23]=[CH:24][C:25](=[O:31])[CH2:26][CH2:27][CH2:28][CH2:29][CH3:30])([O-:3])=[O:2].[C:32]1([Mg]Br)[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1.[Cl-].[NH4+].C(O)(=O)C>O1CCCC1>[N+:1]([CH2:4][CH:5]1[CH2:13][C:8]2([O:9][CH2:10][CH2:11][O:12]2)[CH:7]([CH2:14][CH:15]=[CH:16][CH2:17][CH2:18][CH2:19][C:20]([OH:22])=[O:21])[CH:6]1[CH:23]=[CH:24][C:25]([OH:31])([C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1)[CH2:26][CH2:27][CH2:28][CH2:29][CH3:30])([O-:3])=[O:2]
Reactant: CCCCCC(=O)C=CC1C(C[N+](=O)[O-])CC2(OCCO2)C1CC=CCCCC(=O)O
Reactant: Br[Mg]c1ccccc1
Agent: [Cl-]
Agent: [NH4+]
Solvent: C1CCOC1
Solvent: CC(=O)O
Product: CCCCCC(O)(C=CC1C(C[N+](=O)[O-])CC2(OCCO2)C1CC=CCCCC(=O)O)c1ccccc1

Procedure:
A solution of 1.88 g. of 7-[8-nitromethyl-7-(3-oxo-1-octenyl)-1,4-dioxaspiro[4.4]non-6-yl]-5-heptenoic acid in 80 ml. of tetrahydrofuran was treated at -10° C. with 6.6 ml. of 3 M phenyl magnesium bromide in tetrahydrofuran and was stirred at 0° C. for one hour. The reaction mixture was added to aqueous ammonium chloride solution, acidified with acetic acid and extracted with ether. After washing with water and drying with magnesium sulfate, the extract was evaporated and the residue chromatographed on silica. Elution with 30% ethyl acetate in hexane gave 0.90 g. of the title product as an oil, λmaxfilm 3.00 (shoulder), 3.50, 5.88, 6.28, 6.47, 6.95, 7.25, 13.30, 14.35 μ. NMR: δ 3.93 (S, 4, ketal), 4.35 (M, 2, --CH2NO2), 5.15-6.05 (M, 4, olefinic --H), 5.88 (S, 2, -OH), 7.45 (M, 5, aromatic-HO ppm. Mass spectrum: M+ at m/e 515 (theory 515), M+--H2O at m/e 497.2776 (theory 497.2776.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:9]=[CH:10][N:11](C(OCC)C)[C:12]=2[C:13]2[CH:18]=[CH:17][C:16]([F:19])=[CH:15][CH:14]=2)=[CH:4][CH:3]=1.[F:25][C:26]([F:31])([F:30])[C:27]([CH3:29])=[O:28]>>[F:19][C:16]1[CH:17]=[CH:18][C:13]([C:12]2[N:11]=[C:10]([C:27]([CH3:29])([C:26]([F:31])([F:30])[F:25])[OH:28])[NH:9][C:8]=2[C:5]2[CH:4]=[CH:3][C:2]([F:1])=[CH:7][CH:6]=2)=[CH:14][CH:15]=1
Reactant: CC(=O)C(F)(F)F
Reactant: CCOC(C)n1cnc(-c2ccc(F)cc2)c1-c1ccc(F)cc1
Product: CC(O)(c1nc(-c2ccc(F)cc2)c(-c2ccc(F)cc2)[nH]1)C(F)(F)F

Procedure:
By the procedure described in the second paragraph of Example 1, 4,5-bis(4-fluorophenyl)-1-(α-ethoxyethyl)imidazole was reacted with 1,1,1-trifluoroacetone to give 4,5-bis(4-fluorophenyl)-α-methyl-α-trifluoromethyl-1H-imidazole-2-methanol, m.p. 191°-192°. The infrared and NMR spectra were consistent with the assigned structure.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([O:8][C:9]2[C:18]3[C:13](=[CH:14][C:15]([OH:21])=[C:16]([O:19][CH3:20])[CH:17]=3)[N:12]=[CH:11][N:10]=2)[CH:5]=[CH:4][C:3]=1[NH:22][C:23](=[O:27])[N:24]([CH3:26])[CH3:25].C(=O)([O-])[O-].[K+].[K+].[Br:34][CH2:35][CH2:36][CH2:37][CH2:38]Br.O>CN(C)C=O>[Br:34][CH2:35][CH2:36][CH2:37][CH2:38][O:21][C:15]1[CH:14]=[C:13]2[C:18]([C:9]([O:8][C:6]3[CH:5]=[CH:4][C:3]([NH:22][C:23](=[O:27])[N:24]([CH3:26])[CH3:25])=[C:2]([Cl:1])[CH:7]=3)=[N:10][CH:11]=[N:12]2)=[CH:17][C:16]=1[O:19][CH3:20]
Reactant: BrCCCCBr
Reactant: COc1cc2c(Oc3ccc(NC(=O)N(C)C)c(Cl)c3)ncnc2cc1O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: COc1cc2c(Oc3ccc(NC(=O)N(C)C)c(Cl)c3)ncnc2cc1OCCCCBr
Temperature: 25 °C
Reaction time: 18 h

Procedure:
A starting compound (N′-{2-chloro-4-[(7-hydroxy-6-methoxy-4-quinazolinyl) oxy]phenyl}-N,N-dimethylurea, 80 mg), potassium carbonate (138 mg), and 1,4-dibromobutane (0.12 ml) were dissolved in N,N-dimethylformamide (1 ml), and the solution was stirred at room temperature for 18 hr. Water was added to the reaction mixture, and the mixture was extracted with chloroform-propanol (3/1). The organic layer was dried over anhydrous sodium sulfate, and the solvent was removed by distillation under the reduced pressure. The residue was washed with ether to give an intermediate (N′-(4-{[7-(4-bromobutoxy)-6-methoxy-4-quinazolinyl]oxy}-2-chloro-phenyl)-N,N-dimethylurea). The intermediate, potassium carbonate (138 mg), and morpholine (0.043 ml) were dissolved in N,N-dimethylformamide (1 ml), and the solution was stirred at room temperature overnight. Water was added to the reaction mixture, and the mixture was extracted with chloroform-propanol (3/1). The organic layer was dried over anhydrous sodium sulfate, and the solvent was removed by distillation under the reduced pressure. The residue was purified by HPLC by development with chloroform/methanol to give 47 mg (yield 44%) of the title compound.
Reaction SMILES: [CH3:1][N:2]1[C:6]2=[CH:7][N:8]=[CH:9][C:10]([C:11]#[C:12][C:13]3[CH:14]=[C:15]([NH2:19])[CH:16]=[CH:17][CH:18]=3)=[C:5]2[CH:4]=[N:3]1.[C:20](=O)(OC1C=CC=CC=1)N>>[CH3:20][C:18]1[CH:17]=[CH:16][C:15]([NH2:19])=[CH:14][C:13]=1[C:12]#[C:11][C:10]1[CH:9]=[N:8][CH:7]=[C:6]2[N:2]([CH3:1])[N:3]=[CH:4][C:5]=12
Reactant: Cn1ncc2c(C#Cc3cccc(N)c3)cncc21
Reactant: NC(=O)Oc1ccccc1
Product: Cc1ccc(N)cc1C#Cc1cncc2c1cnn2C

Procedure:
The following example compound 3.2 was synthesized in analogy to GP 7 and example compound 3.1 by reaction of Intermediate 3.1 with the respective phenyl carbamate.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:35])[C:4]([N:8]1[C@H:11]([S:12]SC2SC3C=CC=CC=3N=2)[C@@H:10]([O:23][C:24](=[O:33])[CH2:25][O:26][C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)[C:9]1=[O:34])=[C:5]([CH3:7])[CH3:6].[BH4-].[Na+].[C:38](Br)(=[O:40])[CH3:39].C1C=CC=CC=1>CN(C)C=O>[CH3:1][O:2][C:3](=[O:35])[C:4]([N:8]1[C@H:11]([S:12][C:38](=[O:40])[CH3:39])[C@@H:10]([O:23][C:24](=[O:33])[CH2:25][O:26][C:27]2[CH:28]=[CH:29][CH:30]=[CH:31][CH:32]=2)[C:9]1=[O:34])=[C:5]([CH3:6])[CH3:7]
Reactant: COC(=O)C(=C(C)C)N1C(=O)[C@H](OC(=O)COc2ccccc2)[C@H]1SSc1nc2ccccc2s1
Reactant: CC(=O)Br
Agent: [BH4-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: c1ccccc1
Product: COC(=O)C(=C(C)C)N1C(=O)[C@H](OC(=O)COc2ccccc2)[C@H]1SC(C)=O
Reaction time: 0.17 h

Procedure:
A solution of 687 mg (1.29 mmole) of 2-[(3S,4R)-4-(benzthiazol-2-yldithio)-3-phenoxyacetoxy-2-oxoazetidin-1-yl]-3-methylcrotonic acid methyl ester in 14 ml of dimethylformamide is added to a solution, cooled to -20°, of 76 mg (2 mmole) of sodium borohydride in 10 ml of dimethylformamide and the mixture is stirred at the same temperature for 10 minutes. 7 ml of freshly distilled acetyl bromide are added to the reaction mixture, which is further stirred at 0° for 40 minutes. After adding 400 ml of benzene, the reaction mixture is washed in succession with aqueous sodium bicarbonate solution, water and sodium chloride solution, dried over sodium sulphate and concentrated by evaporation in vacuo. After chromatography over silica gel with toluene/ethyl acetate (19:1) the residue yields the title compound in the form of an oil, which is further purified on silica gel plates with toluene/ethyl acetate (4:1). The title compound is obtained in oily form.
Reaction SMILES: [C:1]1([Mg]Br)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH:9]([C:11]1[CH:20]=[CH:19][C:14]([C:15]([O:17][CH3:18])=[O:16])=[CH:13][CH:12]=1)=[O:10]>>[OH:10][CH:9]([C:11]1[CH:12]=[CH:13][C:14]([C:15]([O:17][CH3:18])=[O:16])=[CH:19][CH:20]=1)[C:1]1[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: Br[Mg]c1ccccc1
Reactant: COC(=O)c1ccc(C=O)cc1
Product: COC(=O)c1ccc(C(O)c2ccccc2)cc1
Reaction time: 0.17 h

Procedure:
Under a nitrogen atmosphere phenyl magnesium bromide (39 mL of 3M in ether) was added via a syringe over a period of 30 minutes to a solution of methyl 4-formylbenzoate (19.2 g, 117 mmol). The mixture was allowed to stir for an additional 10 minutes and then it was quenched by the addition of 1M hydrochloric acid (125 mL). The reaction mixture was extracted with diethyl ether (2×200 mL). The combined extracts were washed with brine, dried over magnesium sulfate, filtered and then concentrated under vacuum to provide a yellow oil. This material was purified by flash chromatography (silica gel eluting with 6:1 hexanes:ethyl acetate) to provide 6.9 g of methyl 4-(α-hydroxybenzyl)benzoate as a clear oil.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([NH2:14])[C:5]([NH2:13])=[C:6]2[C:11]=1[CH2:10][N:9]([CH3:12])[CH2:8][CH2:7]2.[C:15](O)(=[O:19])[C:16](O)=[O:17]>Cl>[Br:1][C:2]1[C:11]2[CH2:10][N:9]([CH3:12])[CH2:8][CH2:7][C:6]=2[C:5]2[NH:13][C:15](=[O:19])[C:16](=[O:17])[NH:14][C:4]=2[CH:3]=1
Reactant: CN1CCc2c(N)c(N)cc(Br)c2C1
Reactant: O=C(O)C(=O)O
Agent: Cl
Product: CN1CCc2c(c(Br)cc3[nH]c(=O)c(=O)[nH]c23)C1
Temperature: 25 °C
Yield: 24.1 %

Procedure:
A solution of the product from Example 13 (0.62 g, 2.56 mmol) and oxalic acid (0.23 g, 2.56 mmol) in 25 mL of 3N aqueous HCl solution were heated at reflux for 18 hours. The reaction mixture was cooled to room temperature and the solid which formed was collected by filtration and washed with cold water. The solid was recrystallized from hot water and dried under vacuum (100° C., P2O5) to give the title compound as a tan solid (0.191 g, 20%), mp=315-320° C. (dec.).
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([F:10])=[CH:6][C:5]=1[OH:11])([O-:3])=[O:2].Br[CH:13]([CH3:19])[C:14]([O:16][CH2:17][CH3:18])=[O:15].C(=O)([O-])[O-].[K+].[K+]>CC(C)=O.C(OCC)(=O)C>[N+:1]([C:4]1[CH:9]=[CH:8][C:7]([F:10])=[CH:6][C:5]=1[O:11][CH:13]([CH3:19])[C:14]([O:16][CH2:17][CH3:18])=[O:15])([O-:3])=[O:2]
Reactant: O=[N+]([O-])c1ccc(F)cc1O
Reactant: CCOC(=O)C(C)Br
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CC(C)=O
Product: CCOC(=O)C(C)Oc1cc(F)ccc1[N+](=O)[O-]

Procedure:
To a solution of 2-nitro-5-fluorophenol (1.0 g, 1 eq, 6.36 mmol) and ethyl 2-bromopropionate (0.91 ml, 1.1 eq, 6.99 mmol) in dry acetone (32 ml) was added anhydrous potassium carbonate (2.63 g, 3 eq, 19.08 mmol) and the reaction mixture was refluxed for 16 h. The reaction mixture was filtered through celite and then condensed on rotavapour. The residue was diluted with ethyl acetate and washed with water and brine to yield ethyl 2-(2-nitro-5-fluorophenoxy)propanoate as crude compound (1.6 g, yield 98%), which was used in step (ii).