Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]([C:14]2[CH:19]=[C:18]([C:20]3[CH:25]=[CH:24][C:23]([F:26])=[CH:22][CH:21]=3)[N:17]=[C:16](Cl)[N:15]=2)[C@H:10]([CH3:28])[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].Br.[CH3:30][C@@H:31]1[CH2:35][CH2:34][CH2:33][NH:32]1.C([O-])([O-])=O.[K+].[K+]>CC(N(C)C)=O.O>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]([C:14]2[CH:19]=[C:18]([C:20]3[CH:25]=[CH:24][C:23]([F:26])=[CH:22][CH:21]=3)[N:17]=[C:16]([N:32]3[CH2:33][CH2:34][CH2:35][C@H:31]3[CH3:30])[N:15]=2)[C@H:10]([CH3:28])[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: C[C@@H]1CN(C(=O)OC(C)(C)C)CCN1c1cc(-c2ccc(F)cc2)nc(Cl)n1
Reactant: C[C@@H]1CCCN1
Agent: Br
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CC(=O)N(C)C
Product: C[C@@H]1CN(C(=O)OC(C)(C)C)CCN1c1cc(-c2ccc(F)cc2)nc(N2CCC[C@H]2C)n1

Procedure:
Heat a mixture of 4-[2-chloro-6-(4-fluoro-phenyl)-pyrimidin-4-yl]-3-(R)-methyl-piperazine-1-carboxylic acid tert-butyl ester (5.0 g, 12.3 mmol), 2-(R)-methyl-pyrrolidine hydrobromide (Nijhuis et. al. (1989) J. Org. Chem. 54:216-220) (3.0 g, 16.0 mmol), and K2CO3 (5.2 g, 37.8 mmol) in DMA at 120° C. for 16 h. Dilute with water, extract with EtOAc, and wash with brine. Dry the organic layer (Na2SO4) and concentrate under reduced pressure. Purify the residue by flash column eluting with EtOAc-Hexanes (1:4) to afford the title compound as a white solid.
Reaction SMILES: [F:1][C:2]1[C:3]2[N:4]([CH:12]=[CH:13][N:14]=2)[CH:5]=[CH:6][C:7]=1[C:8]([F:11])([F:10])[F:9].Br[C:16]1[CH:17]=[CH:18][C:19]([F:30])=[C:20]([C:22]2[C:27]([F:28])=[CH:26][C:25]([F:29])=[CH:24][N:23]=2)[CH:21]=1>>[F:28][C:27]1[C:22]([C:20]2[CH:21]=[C:16]([C:12]3[N:4]4[CH:5]=[CH:6][C:7]([C:8]([F:9])([F:10])[F:11])=[C:2]([F:1])[C:3]4=[N:14][CH:13]=3)[CH:17]=[CH:18][C:19]=2[F:30])=[N:23][CH:24]=[C:25]([F:29])[CH:26]=1
Reactant: Fc1cnc(-c2cc(Br)ccc2F)c(F)c1
Reactant: Fc1c(C(F)(F)F)ccn2ccnc12
Product: Fc1cnc(-c2cc(-c3cnc4c(F)c(C(F)(F)F)ccn34)ccc2F)c(F)c1
Yield: 31.6 %

Procedure:
8-Fluoro-7-trifluoromethylimidazo[1,2-α]pyridine (102 mg, 0.5 mmol) and 2-(5-bromo-2-fluorophenyl)-3,5-difluoropyridine (216 mg, 0.75 mmol) were coupled following the procedure given in Example 6 to afford 3-[3-(3,5-difluoropyridin-2-yl)-4-fluorophenyl]-8-fluoro-7-trifluoromethylimidazo[1,2-α]pyridine (65 mg, 32%) as an off-white solid: δH (360 MHz, CDCl3) 6.97 (1H, dd, J 7 and 6), 7.35-7.42 (2H, m), 7.61-7.65 (1H, m), 7.78 (1H, dd, J 7 and 2), 7.87 (1H, s), 8.16 (1H, d, J 7), 8.49 (1H, d, J 2); m/z (ES+) 412 (100%, [MH]+).
Reaction SMILES: [H-].[Na+].[CH2:3]([OH:7])[C:4]#[C:5][CH3:6].Cl[C:9]1[N:14]=[CH:13][N:12]=[C:11]([N:15]2[CH2:21][C@H:20]([CH3:22])[CH2:19][CH2:18][CH2:17][C@@H:16]2[CH3:23])[CH:10]=1.[Cl-].[NH4+]>O1CCCC1>[CH2:3]([O:7][C:9]1[N:14]=[CH:13][N:12]=[C:11]([N:15]2[CH2:21][C@H:20]([CH3:22])[CH2:19][CH2:18][CH2:17][C@@H:16]2[CH3:23])[CH:10]=1)[C:4]#[C:5][CH3:6]
Reactant: CC#CCO
Reactant: C[C@@H]1CCC[C@H](C)N(c2cc(Cl)ncn2)C1
Agent: [Cl-]
Agent: [H-]
Agent: [NH4+]
Solvent: C1CCOC1
Product: CC#CCOc1cc(N2C[C@H](C)CCC[C@@H]2C)ncn1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 73.1 %

Procedure:
0.07 g of sodium hydride (60% oil suspension) was suspended in 3 ml of tetrahydrofuran. 0.5 ml of tetrahydrofuran solution of 0.11 g of 2-butyn-1-ol was added dropwise at room temperature therein, and the mixture was stirred for 10 minutes. Into the mixture was added dropwise 0.5 ml of tetrahydrofuran solution of 0.30 g of 1-(6-chloropyrimidin-4-yl)-cis-2,6-dimethyl-hexahydro-1H-azepine at room temperature, and stirred for 8 hours at 60° C. After the reaction mixture was cooled to near room temperature, the reaction mixture was poured into a saturated ammonium chloride aqueous solution, and the mixture was extracted with tert-butyl methyl ether three times. The organic layers were washed with a saturated sodium chloride aqueous solution, dried over anhydrous magnesium sulfate and concentrated. The residue was subjected to silica gel column chromatography to obtain 0.25 g of 1-(6-(2-butynyloxy)pyrimidin-4-yl)-cis-2,6-dimethyl-hexahydro-1H-azepine (hereinafter, referred to as Compound (40)).
Reaction SMILES: [NH2:1][C:2]1[N:3]([N:15]=CC2C=CC=CC=2)[CH:4]=[C:5]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=2[O:13][CH3:14])[N:6]=1.O.NN.O>C(O)COCCO>[NH2:15][N:3]1[CH:4]=[C:5]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=2[O:13][CH3:14])[N:6]=[C:2]1[NH2:1]
Reactant: COc1ccccc1-c1cn(N=Cc2ccccc2)c(N)n1
Agent: NN
Solvent: O
Solvent: OCCOCCO
Product: COc1ccccc1-c1cn(N)c(N)n1

Procedure:
A solution of 23.2 g of 2-amino-1-benzylideneamino-4-(2-methoxyphenyl)-imidazole and 15.8 ml of hydrazine hydrate in 80 ml of diethylene glycol is stirred at 170° C. for 7 hours. After cooling, 400 ml of water are added to the reaction mixture. The product that has separated out is filtered off with suction, washed with water and recrystallized from 200 ml of ethanol. In that manner there is obtained the title compound, m.p. 195°-196° C., 1H-NMR (DMSO): δ=7.9 (d, 1H); 7.06 (m, 2H); 6.91 (m, 2H); 5.52 (s, 2H); 5.3 (s, 2H); 3.88 (s, 3H).
Reaction SMILES: [C:1]1([CH3:11])[C:2]([S:7](Cl)(=[O:9])=[O:8])=[CH:3][CH:4]=[CH:5][CH:6]=1.[OH:12][CH2:13][CH2:14][CH2:15][CH2:16][C:17]1[CH:24]=[CH:23][C:20]([C:21]#[N:22])=[CH:19][CH:18]=1>>[C:1]1([CH3:11])[C:2]([S:7]([O:12][CH2:13][CH2:14][CH2:15][CH2:16][C:17]2[CH:18]=[CH:19][C:20]([C:21]#[N:22])=[CH:23][CH:24]=2)(=[O:9])=[O:8])=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: N#Cc1ccc(CCCCO)cc1
Reactant: Cc1ccccc1S(=O)(=O)Cl
Product: Cc1ccccc1S(=O)(=O)OCCCCc1ccc(C#N)cc1

Procedure:
The sub-title compound was prepared by addition of toluenesulphonyl chloride to 4-(4-hydroxybutyl)benzonitrile (see step (ii) above).
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([CH3:8])[C:5]([N+:9]([O-:11])=[O:10])=[CH:4][CH:3]=1.C([O-])([O-])=O.[K+].[K+].Cl.[F:19][C:20]1([F:25])[CH2:24][CH2:23][NH:22][CH2:21]1>CN(C=O)C.C(OCC)(=O)C>[F:19][C:20]1([F:25])[CH2:24][CH2:23][N:22]([C:2]2[N:7]=[C:6]([CH3:8])[C:5]([N+:9]([O-:11])=[O:10])=[CH:4][CH:3]=2)[CH2:21]1
Reactant: Cc1nc(Cl)ccc1[N+](=O)[O-]
Reactant: FC1(F)CCNC1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: Cc1nc(N2CCC(F)(F)C2)ccc1[N+](=O)[O-]
Temperature: 80 °C
Yield: 47.3 %

Procedure:
To a solution of 6-chloro-2-methyl-3-nitropyridine (0.3 g, 1.74 mmol) in DMF (2 mL) was added K2CO3 (0.72 g, 5.23 mmol) followed by 3,3-difluoropyrrolidine hydrochloride (0.74 g, 5.23 mmol) and the reaction mixture was heated for 4 h at 80° C. The reaction mixture was then diluted with ethyl acetate and the organic layer was washed with saturated aqueous sodium bicarbonate solution. The organic layer was then dried over sodium sulphate and concentrated. The crude material obtained was purified by column chromatography (silica: 100-200 mesh, MeOH:DCM 2-3%) to afford the title compound (0.2 g, 47%). LCMS (ES+) 244.05 (M+H)+, RT 3.028 minutes (method 1).
Reaction SMILES: [CH2:1]([S:3]([C:6]1[CH:14]=[CH:13][C:9]([C:10](Cl)=O)=[C:8]([O:15][CH2:16][CH3:17])[CH:7]=1)(=[O:5])=[O:4])[CH3:2].[Cl:18][C:19]1[CH:24]=[CH:23][C:22]([C:25]2([CH3:51])[C:29]([C:31]3[CH:36]=[CH:35][C:34]([Cl:37])=[CH:33][CH:32]=3)([CH3:30])[NH:28]C(C3C=CC(C(C)(C)C)=CC=3OCC)=[N:26]2)=[CH:21][CH:20]=1>>[Cl:18][C:19]1[CH:24]=[CH:23][C:22]([C:25]2([CH3:51])[C:29]([C:31]3[CH:32]=[CH:33][C:34]([Cl:37])=[CH:35][CH:36]=3)([CH3:30])[NH:28][C:10]([C:9]3[CH:13]=[CH:14][C:6]([S:3]([CH2:1][CH3:2])(=[O:5])=[O:4])=[CH:7][C:8]=3[O:15][CH2:16][CH3:17])=[N:26]2)=[CH:21][CH:20]=1
Reactant: CCOc1cc(C(C)(C)C)ccc1C1=NC(C)(c2ccc(Cl)cc2)C(C)(c2ccc(Cl)cc2)N1
Reactant: CCOc1cc(S(=O)(=O)CC)ccc1C(=O)Cl
Product: CCOc1cc(S(=O)(=O)CC)ccc1C1=NC(C)(c2ccc(Cl)cc2)C(C)(c2ccc(Cl)cc2)N1

Procedure:
rac-(4S*,5R*)-4,5-bis-(4-chloro-phenyl)-2-(4-ethanesulfonyl-2-ethoxy-phenyl)-4,5-dimethyl-4,5-dihydro-1H-imidazole was prepared from 4-ethanesulfonyl-2-ethoxy-benzoyl chloride (prepared from ethyl 2-ethoxy-4-fluoro-benzoate and sodium ethanethiolate) and meso-2,3-bis-(4-chlorophenyl)-2,3-butanediamine (example 1) in an analogous manner as described in example 2 (method 1).
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([NH:8][C:9]2[CH:10]=[CH:11][C:12]([NH:15]C(=O)C)=[N:13][CH:14]=2)[CH:5]=[C:4]([CH3:19])[N:3]=1.Cl.O>O1CCOCC1.CO>[NH2:15][C:12]1[N:13]=[CH:14][C:9]([NH:8][C:6]2[CH:5]=[C:4]([CH3:19])[N:3]=[C:2]([NH2:1])[N:7]=2)=[CH:10][CH:11]=1
Reactant: CC(=O)Nc1ccc(Nc2cc(C)nc(N)n2)cn1
Agent: Cl
Solvent: O
Solvent: C1COCCO1
Solvent: CO
Product: Cc1cc(Nc2ccc(N)nc2)nc(N)n1
Yield: 98.9 %

Procedure:
A suspension of 4 (1.53 g, 5.19 mmol), in 1,4-dioxane/MeOH (1:1, 100 mL) and 2 N HCl [10 mL, H2O mL+c.HCl 2 mL)] was refluxed 24 h. The solvents were evaporated to dryness and the residue was basified with aq NH3. The resulting solution was extracted with EtOAc (110×50 mL), dried (Na2SO4) and evaporation of the solvent gave 5 (1.11 g, 99%). A small sample was recrystallized from DCM/Pet.ether; mp (DCM/Pet.ether) 183-186° C.; 1H NMR [(CD3)2SO] δ 8.41 (s, 1 H, NH), 8.01 (d, J=2.5 Hz, 1 H, H-2′), 7.56 (dd, J=8.7, ′), 6.42 (d, 2.6 Hz, 1 H, H-4 J=8.8 Hz, 1 H, H-5′), 5.90 (s, 2 H, NH2), 5.67 (s, 1 H, H-5), 5.59 (s, 2 H, NH2H, CH), 2.03 (s, 33) HRMS (EI+) calc. for C10H12N6 (M+) m/z 216.1123, found 216.1124; Anal. Calc. for C10H12N6.0.25H2O: C, 54.4; H, 5.7; N, 38.1; found, C, 54.4; H, 5.7; N, 37.9%.
Reaction SMILES: Br.[C:2]([N:5]1[CH2:9][C:8]([CH3:11])([CH3:10])[NH:7][C:6]1=[O:12])(=[NH:4])[NH2:3].C[O-].[Na+].[CH3:16][N:17]([C:27]1[CH:32]=[CH:31][CH:30]=[C:29]([C:33]([F:36])([F:35])[F:34])[CH:28]=1)[C:18](=[O:26])[C:19]([C:24]#[N:25])=[CH:20]OCC>C(O)CC.CO>[C:24]([C:19]([C:18](=[O:26])[N:17]([CH3:16])[C:27]1[CH:32]=[CH:31][CH:30]=[C:29]([C:33]([F:36])([F:35])[F:34])[CH:28]=1)=[CH:20][NH:4][C:2](=[NH:3])[N:5]1[CH2:9][C:8]([CH3:10])([CH3:11])[NH:7][C:6]1=[O:12])#[N:25]
Reactant: CCOC=C(C#N)C(=O)N(C)c1cccc(C(F)(F)F)c1
Reactant: CC1(C)CN(C(=N)N)C(=O)N1
Agent: Br
Agent: C[O-]
Agent: [Na+]
Solvent: CO
Solvent: CCCO
Product: CN(C(=O)C(C#N)=CNC(=N)N1CC(C)(C)NC1=O)c1cccc(C(F)(F)F)c1
Temperature: 45 °C
Reaction time: 0.5 h
Yield: 76.3 %

Procedure:
4.74 g (20 mmol) of 1-amidino-4,4-dimethyl-2-oxoimidazolidine hydrobromide were dissolved in 47 ml of boiling 1-propanol and, at 88°-90° C., 3.60 g (=3.67 ml, 20 mmol) of a 30% strength solution of sodium methylate in methanol were added. The resulting suspension was cooled to 45° C., stirred at 45° C. for 30 min and then cooled to 20° C., and 5.97 g (20 mmol) of 2-cyano-3-ethoxyacrylic acid N-methyl-N-(3-trifluoromethylphenyl)amide were added at 20° C., and the mixture was stirred at room temperature for 1.8 hours. The solid which had separated out was, after dilution of the pasty mass with 50 ml of ether, filtered off with suction and washed with ether. This product (initial crystals) and the residue from the original filtrate (mother liquor) were worked up further as described in Example 1 and dried. 6.23 g (=76.3% yield) of, according to TLC, virtually pure compound IV were obtained.
Reaction SMILES: [CH2:1]([O:3][C:4]1[CH:9]=[CH:8][C:7]([CH2:10][CH2:11][O:12][C:13]2[CH:30]=[CH:29][C:16]([CH2:17][C@@H:18]([C:25]([O:27]C)=[O:26])[NH:19][C:20](=[O:24])[CH:21]([CH3:23])[CH3:22])=[CH:15][CH:14]=2)=[CH:6][CH:5]=1)[CH3:2].O.[OH-].[Li+].Cl>O1CCOCC1.O>[CH2:1]([O:3][C:4]1[CH:5]=[CH:6][C:7]([CH2:10][CH2:11][O:12][C:13]2[CH:14]=[CH:15][C:16]([CH2:17][C@@H:18]([C:25]([OH:27])=[O:26])[NH:19][C:20](=[O:24])[CH:21]([CH3:23])[CH3:22])=[CH:29][CH:30]=2)=[CH:8][CH:9]=1)[CH3:2]
Reactant: CCOc1ccc(CCOc2ccc(C[C@H](NC(=O)C(C)C)C(=O)OC)cc2)cc1
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1COCCO1
Product: CCOc1ccc(CCOc2ccc(C[C@H](NC(=O)C(C)C)C(=O)O)cc2)cc1
Reaction time: 8 h
Yield: 102.6 %

Procedure:
Methyl O-[2-(4-ethoxyphenyl)ethyl]-N-isobutyryltyrosinate (0.25 g, 0.61 mmol) was dissolved in dioxane (4 ml). Lithium hydroxide monohydrate (0.1 g, 2.38 mmol) in water (4 ml) was added. The mixture was stirred overnight and then acidified with 1M hydrochloric acid, pH ˜3-4. Dioxane was removed by evaporation in vacuum. The residue was diluted with water and then extracted with dichloromethane. The organic phase was washed with brine and dried with sodium sulfate. The solvent was then evaporated. 0.25 g desired product was obtained, yield 100%.
Reaction SMILES: [CH2:1]([O:8][C:9]([N:11]1[CH2:15][CH2:14][CH2:13][C@H:12]1[CH2:16]OS(C1C=CC(C)=CC=1)(=O)=O)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:28][O:29][C:30]1[CH:37]=[CH:36][CH:35]=[CH:34][C:31]=1[CH2:32][NH2:33].C(N(CC)C(C)C)(C)C>CN1CCN(C)C1=O>[CH2:1]([O:8][C:9]([N:11]1[CH2:15][CH2:14][CH2:13][C@H:12]1[CH2:16][NH:33][CH2:32][C:31]1[CH:34]=[CH:35][CH:36]=[CH:37][C:30]=1[O:29][CH3:28])=[O:10])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: Cc1ccc(S(=O)(=O)OC[C@@H]2CCCN2C(=O)OCc2ccccc2)cc1
Reactant: COc1ccccc1CN
Solvent: CCN(C(C)C)C(C)C
Solvent: CN1CCN(C)C1=O
Product: COc1ccccc1CNC[C@@H]1CCCN1C(=O)OCc1ccccc1
Temperature: 93 °C
Reaction time: 7 h

Procedure:
A mixture of (2S)-2-(4-methylphenylsulfonyloxymethyl)pyrrolidine-1-carboxylic acid benzyl ester (26.2 g), 2-methoxybenzylamine (44 ml) and N,N-diisopropylethylamine (17.6 ml) in 1,3-dimethyl-2-imidazolidinone (393 ml) was stirred at 93° C. for 7 hours. The mixture was poured into ice-water and extracted with ethyl acetate. The extract was washed with brine, dried over magnesium sulfate and evaporated under reduced pressure. The residue was purified by column chromatography on silica gel using a mixed solvent of dichloromethane and methanol (20:1). The fractions containing the objective compound were collected and evaporated under reduced pressure to give a syrup of (2S)-2-[(2-methoxybenzylamino)methyl]pyrrolidine-1-carboxylic acid benzyl ester (15.7 g).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:31])[C:4]1[CH:9]=[C:8](Br)[CH:7]=[C:6]([CH3:11])[C:5]=1[N:12]([S:20]([C:23]1[CH:28]=[CH:27][C:26]([O:29][CH3:30])=[CH:25][CH:24]=1)(=[O:22])=[O:21])[CH2:13][C:14]1[CH:15]=[N:16][CH:17]=[CH:18][CH:19]=1.[CH2:32]([N:35]([CH2:40][CH:41]=[CH2:42])[C:36](=[O:39])[CH:37]=[CH2:38])[CH:33]=[CH2:34]>>[CH3:1][O:2][C:3](=[O:31])[C:4]1[CH:9]=[C:8]([CH:38]=[CH:37][C:36](=[O:39])[N:35]([CH2:32][CH:33]=[CH2:34])[CH2:40][CH:41]=[CH2:42])[CH:7]=[C:6]([CH3:11])[C:5]=1[N:12]([S:20]([C:23]1[CH:28]=[CH:27][C:26]([O:29][CH3:30])=[CH:25][CH:24]=1)(=[O:22])=[O:21])[CH2:13][C:14]1[CH:15]=[N:16][CH:17]=[CH:18][CH:19]=1
Reactant: COC(=O)c1cc(Br)cc(C)c1N(Cc1cccnc1)S(=O)(=O)c1ccc(OC)cc1
Reactant: C=CCN(CC=C)C(=O)C=C
Product: C=CCN(CC=C)C(=O)C=Cc1cc(C)c(N(Cc2cccnc2)S(=O)(=O)c2ccc(OC)cc2)c(C(=O)OC)c1
Yield: 53.7 %

Procedure:
In the same manner as described in Example 203, 550.4 mg (1.0 mmol) of the product of Example 89 and 453.6 mg (3.0 mmol) of N,N-diallylacrylamide provided 309 mg (53%) of the desired product as a yellow gum. Electrospray Mass Spec 576(M+H).
Reaction SMILES: [C:1]1([CH3:20])[CH:6]=[CH:5][CH:4]=[C:3]([C:7]2[C:8]([C:14]3[CH:19]=[CH:18][N:17]=[CH:16][CH:15]=3)=[CH:9][C:10](=O)[NH:11][CH:12]=2)[CH:2]=1.O=P(Cl)(Cl)[Cl:23]>>[Cl:23][C:10]1[CH:9]=[C:8]([C:14]2[CH:19]=[CH:18][N:17]=[CH:16][CH:15]=2)[C:7]([C:3]2[CH:4]=[CH:5][CH:6]=[C:1]([CH3:20])[CH:2]=2)=[CH:12][N:11]=1
Reactant: Cc1cccc(-c2c[nH]c(=O)cc2-c2ccncc2)c1
Reactant: O=P(Cl)(Cl)Cl
Product: Cc1cccc(-c2cnc(Cl)cc2-c2ccncc2)c1

Procedure:
5-m-tolyl-1H-[4,4′]bipyridinyl-2-one (262 mg, 1.0 mmole) in POCl3 (5 mL) was heated to 105° C. for 12 hr. POCl3 was removed under reduced pressure. The residue was diluted with methylene chloride and was carefully quenched with aqueous sodium carbonate. Standard work up, followed by purification (silica gel, hexane/ethyl acetate) gave the title compound. MS (m/z): Calcd. C17H13N2Cl (M+): 280.5, found (M+H)+: 281.0 and 283.1.
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[C:9]([F:11])[C:8]([Cl:12])=[CH:7][C:3]=1[C:4](O)=[O:5]>C1COCC1>[Cl:1][C:2]1[CH:10]=[C:9]([F:11])[C:8]([Cl:12])=[CH:7][C:3]=1[CH2:4][OH:5]
Reactant: O=C(O)c1cc(Cl)c(F)cc1Cl
Solvent: C1CCOC1
Product: OCc1cc(Cl)c(F)cc1Cl
Temperature: 25 °C
Reaction time: 14 h

Procedure:
A solution of 2,5-dichloro-4-fluorobenzoic acid (4.1 g, 19.6 mmol; prepared as described in the literature: Feit, P. W. et al, J. Med. Chem. 1972, Vol. 15, 79-83) in 100 mL THF was treated with 24.5 mL borane methylsulfide complex in THF (2M, 24.5 mL, 49 mmol) at 0-5° C. The mixture was allowed to come to RT, stirred for 14 h at RT and quenched by adding saturated NaHCO3 and 10 mL MeOH. The mixture was extracted with ethyl acetate, the organic layer was washed sequentially with 10% HCl and saturated NaHCO3 solutions, dried over magnesium sulfate and concentrated to give 3.65 g of the title compound as a white solid. ##STR265##
Reaction SMILES: [NH2:1][C:2]1[CH:11]=[CH:10][C:9]([F:12])=[CH:8][C:3]=1[C:4]([O:6][CH3:7])=[O:5].[I:13]N1C(=O)CCC1=O>C(O)(=O)C>[NH2:1][C:2]1[C:11]([I:13])=[CH:10][C:9]([F:12])=[CH:8][C:3]=1[C:4]([O:6][CH3:7])=[O:5]
Reactant: O=C1CCC(=O)N1I
Reactant: COC(=O)c1cc(F)ccc1N
Solvent: CC(=O)O
Product: COC(=O)c1cc(F)cc(I)c1N

Procedure:
Methyl 2-amino-5-fluorobenzoate (1.0 eq, 8.47 g, 0.051 mol) was reacted with N-Iodo succinimide (1.03 eq, 11.6 g, 0.0515 mol) in acetic acid (100 ml) at room temperature for 20 minutes. The solvent was removed in vacuo. A K2CO3 aqueous solution was added and the compound extracted with ethylacetate. The organic layer was washed with 1M sodium thiosulfate, water and then brine. After drying over Na2SO4, and evaporation of the solvent, methyl 2-amino-5-fluoro-3-iodobenzoate was isolated as a purple solid (14.21 g, 96% yield). 1H NMR (CDCl3, 400 MHz) δ 3.8 (s, 3H), 6.3 (br s, 2H), 7.6 (m, 2H) ppm.
Reaction SMILES: [CH2:1]([O:8][C@@H:9]1[C@@H:14]([O:15][CH2:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[C@H:13]([O:23][CH2:24][C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)[C@@H:12]([CH2:31][O:32][CH2:33][C:34]2[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=2)[O:11][C@:10]21[C:43]1[CH:44]=[C:45]([CH2:49][C:50]3[CH:55]=[CH:54][C:53]([CH2:56][CH3:57])=[CH:52][CH:51]=3)[C:46]([Cl:48])=[CH:47][C:42]=1[O:41][C@H:40]2[OH:58])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[BH4-].[Na+]>C1COCC1>[Cl:48][C:46]1[C:45]([CH2:49][C:50]2[CH:55]=[CH:54][C:53]([CH2:56][CH3:57])=[CH:52][CH:51]=2)=[CH:44][C:43]([C@@:10]2([CH2:40][OH:58])[C@H:9]([O:8][CH2:1][C:2]3[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=3)[C@@H:14]([O:15][CH2:16][C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)[C@H:13]([O:23][CH2:24][C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=3)[C@@H:12]([CH2:31][O:32][CH2:33][C:34]3[CH:35]=[CH:36][CH:37]=[CH:38][CH:39]=3)[O:11]2)=[C:42]([OH:41])[CH:47]=1
Reactant: CCc1ccc(Cc2cc3c(cc2Cl)O[C@@H](O)[C@]32O[C@H](COCc3ccccc3)[C@@H](OCc3ccccc3)[C@H](OCc3ccccc3)[C@H]2OCc2ccccc2)cc1
Agent: [BH4-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CCc1ccc(Cc2cc([C@]3(CO)O[C@H](COCc4ccccc4)[C@@H](OCc4ccccc4)[C@H](OCc4ccccc4)[C@H]3OCc3ccccc3)c(O)cc2Cl)cc1
Reaction time: 2 h
Yield: 92.1 %

Procedure:
To a solution of 27 (100 mg, 0.125 mmol) in anhydrous THF (2 mL) under an argon blanket was added sodium borohydride (23.7 mg, 0.627 mmol). The resulting mixture was stirred for 2 hours, after which it was quenched with MeOH (1 mL) and AcOH (0.5 mL), followed by partitioning between water and EtOAc. The organic phase was dried over Na2SO4, filtered, and evaporated. The residue was loaded onto a preparatory TLC plate and eluted with 15% EtOAc in petroleum ether to give 28 (92 mg, 92% yield). 1H NMR (300 MHz, CDCl3) δ 8.64 (s, 1H), 7.15-7.35 (m, 16H), 7.07-7.14 (m, 3H), 6.91-6.99 (m, 7H), 4.78-4.82 (m, 3H), 4.62 (d, J=12.0 Hz, 1H), 4.31-4.48 (m, 4H), 4.15 (dd, J=4.2, 13.2 Hz, 1H), 3.81-4.03 (m, 7H), 3.74 (d, J=10.2 Hz, 1H), 3.63 (dd, J=2.3, 10.2 Hz, 1H), 2.53 (q, J=7.5 Hz), 1.66 (t, broad, J=5.4 Hz, 1H, OH?), 1.16 (t, J=7.5 Hz, 3H). LC/MS m/z 822 (M+Na).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:29])/[CH:4]=[CH:5]/[C:6]1[CH:7]=[CH:8][C:9]2[O:26][C:13]3([CH2:18][CH2:17][N:16]([C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])[CH2:15][CH2:14]3)[NH:12][C:11](=[O:27])[C:10]=2[CH:28]=1.[H-].[Na+].[CH3:32]I>CN(C=O)C>[CH3:1][O:2][C:3](=[O:29])/[CH:4]=[CH:5]/[C:6]1[CH:7]=[CH:8][C:9]2[O:26][C:13]3([CH2:18][CH2:17][N:16]([C:19]([O:21][C:22]([CH3:24])([CH3:25])[CH3:23])=[O:20])[CH2:15][CH2:14]3)[N:12]([CH3:32])[C:11](=[O:27])[C:10]=2[CH:28]=1
Reactant: COC(=O)/C=C/c1ccc2c(c1)C(=O)NC1(CCN(C(=O)OC(C)(C)C)CC1)O2
Reactant: CI
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COC(=O)/C=C/c1ccc2c(c1)C(=O)N(C)C1(CCN(C(=O)OC(C)(C)C)CC1)O2
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 87.9 %

Procedure:
(E)-3-{1′-Tert-butoxycarbonyl-3,4-dihydro-4-oxo-spiro[2H-(1,3)-benzoxazine-2,4′-piperidin]-6-yl}-acrylic acid methyl ester (4.02 g, 10.0 mmol) was dissolved in DMF (35 ml) and added to a stirred suspension of NaH (60% oil dispersion, 480 mg, 12 mmol) in DMF (35 ml) at 4° C. After 10 min CH3I (2.13 g, 15.0 mmol) was added, the resulting mixture was stirred at RT for 30 min and then partitioned between saturated aqueous solution of NH4Cl and AcOEt. The organic phase was rinsed with water, dried over Na2SO4 and evaporated. The crude mixture was purified by trituration in AcOEt and petroleum ether to give (E)-3-{1′-tert-butoxycarbonyl-3,4-dihydro-3-methyl-4-oxo-spiro[2H-(1,3)-benzoxazine-2,4′-piperidin]-6-yl}-acrylic acid methyl ester (3.66 g).
Reaction SMILES: Cl[CH2:2][C:3](=O)[C:4](=[N:10][O:11][CH2:12][C:13]#[CH:14])[C:5]([O:7][CH2:8][CH3:9])=[O:6].[NH2:16][C:17]([NH2:19])=[S:18].O>C(O)C>[NH2:19][C:17]1[S:18][CH:2]=[C:3]([C:4](=[N:10][O:11][CH2:12][C:13]#[CH:14])[C:5]([O:7][CH2:8][CH3:9])=[O:6])[N:16]=1
Reactant: NC(N)=S
Reactant: C#CCON=C(C(=O)CCl)C(=O)OCC
Solvent: CCO
Solvent: O
Product: C#CCON=C(C(=O)OCC)c1csc(N)n1
Yield: 53.5 %

Procedure:
Ethyl 4-chloro-3-oxo-2-propargyloxyiminobutyrate (syn isomer, 61 g.), thiourea (20 g.), sodium acetate 3-hydrate (35.8 g.), water (150 ml.) and ethanol (180 ml.) were treated in a similar manner to that of Example F-(3) to give ethyl 2-(2-aminothiazol-4-yl)-2-propargyloxyiminoacetate (syn isomer, 35.6 g.).
Reaction SMILES: Br[C:2]1[CH:10]=[CH:9][C:8]2[C:4](=[CH:5][N:6]([CH3:11])[N:7]=2)[C:3]=1[C:12]([O:14][CH3:15])=[O:13].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C(=O)([O-])[O-].[K+].[K+].[C:41]([O:45][CH3:46])(=[O:44])[CH:42]=[CH2:43]>CN(C)C=O.O.C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[CH3:46][O:45][C:41](=[O:44])/[CH:42]=[CH:43]/[C:2]1[CH:10]=[CH:9][C:8]2[C:4](=[CH:5][N:6]([CH3:11])[N:7]=2)[C:3]=1[C:12]([O:14][CH3:15])=[O:13]
Reactant: C=CC(=O)OC
Reactant: COC(=O)c1c(Br)ccc2nn(C)cc12
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: O=C([O-])[O-]
Solvent: CN(C)C=O
Solvent: O
Product: COC(=O)/C=C/c1ccc2nn(C)cc2c1C(=O)OC
Temperature: 100 °C
Yield: 78.5 %

Procedure:
A suspension of methyl 5-bromo-2-methyl-2H-indazole-4-carboxylate (1.65 g, 6.18 mmol), palladium acetate (139 mg, 0.62 mmol), triphenylphosphine (325 mg, 1.24 mmol), potassium carbonate (1.28 g, 9.27 mmol) and methyl acrylate (834 μL, 9.27 mmol) in N,N-dimethylformamide (60 mL) was stirred with heating at 100° C. for 50 min. The reaction solution was diluted with water, extracted with ethyl acetate, washed with water and saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure, and the residue was purified by silica gel column chromatography (ethyl acetate/hexane=30/70→70/30) to give the title compound (1.33 g, yield 78%).
Reaction SMILES: [Br:1][C:2]1[CH:8]=[C:7]([CH3:9])[CH:6]=[CH:5][C:3]=1[NH2:4].[S:10]1[C:14]2[CH:15]=[C:16]([S:19](Cl)(=[O:21])=[O:20])[CH:17]=[CH:18][C:13]=2[N:12]=[CH:11]1>>[Br:1][C:2]1[CH:8]=[C:7]([CH3:9])[CH:6]=[CH:5][C:3]=1[NH:4][S:19]([C:16]1[CH:17]=[CH:18][C:13]2[N:12]=[CH:11][S:10][C:14]=2[CH:15]=1)(=[O:20])=[O:21]
Reactant: Cc1ccc(N)c(Br)c1
Reactant: O=S(=O)(Cl)c1ccc2ncsc2c1
Product: Cc1ccc(NS(=O)(=O)c2ccc3ncsc3c2)c(Br)c1

Procedure:
By following a procedure analogous to Example 3 starting from 2-bromo-4-methylaniline and 6-benzothiazolesulfonyl chloride, the expected product is obtained in the form of an orange solid (yield=76%).