Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1][CH2:2][CH2:3][CH2:4][OH:5].[CH3:6][O:7][C:8](=[O:20])[CH:9]([O:18][CH3:19])[CH2:10][C:11]1[CH:16]=[CH:15][CH:14]=[C:13](O)[CH:12]=1.C(OC(=O)[C@@H](OC)CC1C=CC(OCCCBr)=CC=1)C>>[CH3:6][O:7][C:8](=[O:20])[CH:9]([O:18][CH3:19])[CH2:10][C:11]1[CH:16]=[CH:15][CH:14]=[C:13]([O:5][CH2:4][CH2:3][CH2:2][Br:1])[CH:12]=1
Reactant: COC(=O)C(Cc1cccc(O)c1)OC
Reactant: OCCCBr
Agent: CCOC(=O)[C@H](Cc1ccc(OCCCBr)cc1)OC
Product: COC(=O)C(Cc1cccc(OCCCBr)c1)OC

Procedure:
The title compound was prepared from 3-bromo-propan-1-ol (Example 284, Step 1) and 3-(3-hydroxy-phenyl)-2-methoxy-propionic acid methyl ester (Example 291, Step 4) via the same procedure used for the preparation of (2S)-3-[4-(3-bromo-propoxy)-phenyl]-2-methoxy-propionic acid ethyl ester (Example 284, Step 2). 1H-NMR (CDCl3, 200.15 MHz): 7.26–7.16 (m, 1H), 6.80 (t, 3H, J=7.3), 4.09 (t, 2H, J=5.9), 3.97 (dd, 1H, J=7.3, 5.4), 3.73 (s, 3H), 3.60 (t, 2H, J=6.4), 3.36 (s, 3H), 3.00 (s, 1H), 2.97 (d, 1H, J=3.2), 2.31 (qn, 2H, J=6.2).
Reaction SMILES: [CH3:1][C:2]1[C:7]([CH2:8][C:9]([O:11][CH3:12])=[O:10])=[C:6]([N:13]2[CH2:17][CH2:16][CH2:15][CH2:14]2)[N:5]=[C:4]([CH2:18][C:19]2[CH:24]=[CH:23][C:22]([N+:25]([O-])=O)=[CH:21][CH:20]=2)[N:3]=1>C1COCC1.[Pd]>[NH2:25][C:22]1[CH:21]=[CH:20][C:19]([CH2:18][C:4]2[N:3]=[C:2]([CH3:1])[C:7]([CH2:8][C:9]([O:11][CH3:12])=[O:10])=[C:6]([N:13]3[CH2:14][CH2:15][CH2:16][CH2:17]3)[N:5]=2)=[CH:24][CH:23]=1
Reactant: COC(=O)Cc1c(C)nc(Cc2ccc([N+](=O)[O-])cc2)nc1N1CCCC1
Agent: [Pd]
Solvent: C1CCOC1
Product: COC(=O)Cc1c(C)nc(Cc2ccc(N)cc2)nc1N1CCCC1
Reaction time: 1 h

Procedure:
To a solution of methyl [4-methyl-2-(4-nitrobenzyl)-6-pyrrolidin-1-ylpyrimidin-5-yl]acetate (0.074 g, 0.20 mmol) in anhydrous THF (2 mL) was added Pd/C (10% Pd, 0.050 g) and the resulting black suspension was stirred under an atmosphere of hydrogen. After 1 hour; the reaction mixture was filtered through Celite and the filtrate was concentrated in vacuo to give methyl [2-(4-aminobenzyl)-4-methyl-6-pyrrolidin-1-ylpyrimidin-5-yl]acetate.
Reaction SMILES: [CH3:1][C:2]([O:5][C:6](=[O:24])[CH2:7][O:8][C:9]1[CH:22]=[C:21]2[C:12]([CH:13]=[CH:14][C:15]3[O:16][C:17](=[O:23])[CH2:18][CH2:19][C:20]=32)=[CH:11][CH:10]=1)(C)C.S(=O)(=O)(O)O.[CH2:30]([OH:32])[CH3:31]>>[CH2:30]([O:32][C:17](=[O:23])[CH2:18][CH2:19][C:20]1[C:21]2[C:12](=[CH:11][CH:10]=[C:9]([O:8][CH2:7][C:6]([O:5][CH2:2][CH3:1])=[O:24])[CH:22]=2)[CH:13]=[CH:14][C:15]=1[OH:16])[CH3:31]
Reactant: CC(C)(C)OC(=O)COc1ccc2ccc3c(c2c1)CCC(=O)O3
Reactant: CCO
Agent: O=S(=O)(O)O
Product: CCOC(=O)CCc1c(O)ccc2ccc(OCC(=O)OCC)cc12
Temperature: 25 °C
Reaction time: 312 h
Yield: 86 %

Procedure:
To a solution of 2.97 g (9.0 mmol) of [(2,3-dihydro-3-oxo-1H-naphtho[2,1-b]pyran-9-yl)oxy]acetic acid 1,1-dimethylethyl ester from the preceding example, in 120 mL of ethanol, was added 2 mL of concentrated sulfuric acid and the resulting solution was allowed to stir at room temperature for 13 days. Most of ethanol was removed under reduced pressure and the residue was dissolved in ether. The solution was washed with saturated aqueous sodium bicarbonate solution and work-up was completed in the usual manner. The crude product was purified by flash chromatography on 150 g silica gel, eluting with hexane-ethyl acetate (4:1). There was obtained 2.69 g (86.0%) of the title compound as a white solid, mp 112°-113° C.
Reaction SMILES: [CH3:1][S:2]([C:5]1[CH:6]=[CH:7][C:8](B2OC(C)(C)C(C)(C)O2)=[C:9]([NH:11]C(=O)OC(C)(C)C)[CH:10]=1)(=[O:4])=[O:3].Br[C:29]1[C:30]([C:35]#[N:36])=[N:31][CH:32]=[CH:33][CH:34]=1.C(=O)([O-])[O-].[K+].[K+]>C1(C)C=CC=CC=1.CO.ClCCl.O>[CH3:1][S:2]([C:5]1[CH:6]=[CH:7][C:8]2=[C:29]3[C:30](=[C:35]([NH2:36])[N:11]=[C:9]2[CH:10]=1)[N:31]=[CH:32][CH:33]=[CH:34]3)(=[O:3])=[O:4]
Reactant: N#Cc1ncccc1Br
Reactant: CC(C)(C)OC(=O)Nc1cc(S(C)(=O)=O)ccc1B1OC(C)(C)C(C)(C)O1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: Cc1ccccc1
Solvent: ClCCl
Product: CS(=O)(=O)c1ccc2c(c1)nc(N)c1ncccc12
Temperature: 100 °C
Reaction time: 8 h

Procedure:
A solution of tert-butyl 5-(methylsulfonyl)-2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenylcarbamate (from step 3) (1.0 eq.) and 3-bromopicolino-nitrile (1.0 eq.) in toluene (0.24 M) was mixed with tetrakis(triphenyl-phosphine)palladium (5 mol %) and 2N aqueous potassium carbonate solution (4.0 eq.). The reaction was heated to 100° C. and stirred overnight. After cooling to ambient temperature, the reaction content was diluted with 2% methanol in dichloromethane and water. The two phases were separated, and the aqueous layer was extracted twice with 2% methanol in dichloromethane. The combined organic layers were washed with brine, dried over anhydrous MgSO4, and concentrated en vacuo. The crude material was purified by flash chromatography on a COMBIFLASH® system (ISCO) using 0-5% methanol in dichloromethane to give a solid which was then triturated in 1:1 hexane/ethyl acetate to give 8-(methylsulfonyl)benzo[f][1,7]naphthyridin-5-amine 1H NMR (acetone d-6): δ 9.16 (d, 1H), 9.03 (d, 1H), 8.71 (d, 1H), 8.11 (s, 1H), 7.93-7.96 (dd, 1H), 7.81 (d, 1H), 7.0 (br, 2H), 3.19 (s, 3H). LRMS [M+H]=274.1
Reaction SMILES: [C:1]([O:5][CH:6]([C:11]1[N:15]([CH3:16])[N:14]=[C:13]([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][N:18]=2)[C:12]=1[C:23]1[CH:24]=[CH:25][C:26]2[O:31][CH2:30][CH2:29][CH2:28][C:27]=2[CH:32]=1)[C:7]([O:9]C)=[O:8])([CH3:4])([CH3:3])[CH3:2].[OH-].[K+]>C(O)C.O>[C:1]([O:5][CH:6]([C:11]1[N:15]([CH3:16])[N:14]=[C:13]([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][N:18]=2)[C:12]=1[C:23]1[CH:24]=[CH:25][C:26]2[O:31][CH2:30][CH2:29][CH2:28][C:27]=2[CH:32]=1)[C:7]([OH:9])=[O:8])([CH3:4])([CH3:2])[CH3:3]
Reactant: COC(=O)C(OC(C)(C)C)c1c(-c2ccc3c(c2)CCCO3)c(-c2ccccn2)nn1C
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: Cn1nc(-c2ccccn2)c(-c2ccc3c(c2)CCCO3)c1C(OC(C)(C)C)C(=O)O
Yield: 58.5 %

Procedure:
A mixture of methyl 2-(tert-butoxy)-2-[4-(3,4-dihydro-2H-1-benzopyran-6-yl)-1-methyl-3-(pyridin-2-yl)-1H-pyrazol-5-yl]acetate (9h) (58 mg, 0.13 mmol) and potassium hydroxide (65 mg, 0.53 mmol) in a mixture of ethanol (1.0 mL) and water (1.0 mL) was refluxed overnight. The mixture was concentrated in vacuo. Water (2 mL) was added to the residue and the aqueous layer was washed with diethyl ether (2 mL), acidified with 1M hydrochloric acid until pH 3 and extracted with ethyl acetate (2×3 mL). The organic layer was dried over sodium sulfate and concentrated in vacuo to provide 2-(tert-butoxy)-2-[4-(3,4-dihydro-2H-1-benzopyran-6-yl)-1-methyl-3-(pyridin-2-yl)-1H-pyrazol-5-yl]acetic acid (example 9) (32 mg, 0.076 mmol, 57%).
Reaction SMILES: [CH3:1][O:2][C:3]1[C:7](OC)=[N:6][S:5](=[O:10])[N:4]=1.[NH2:11][C:12]1[C:13]([CH2:19][CH2:20][CH2:21][CH2:22][NH2:23])=[N:14][CH:15]=[C:16]([Br:18])[CH:17]=1>CO>[NH2:11][C:12]1[C:13]([CH2:19][CH2:20][CH2:21][CH2:22][NH:23][C:7]2[C:3]([O:2][CH3:1])=[N:4][S:5](=[O:10])[N:6]=2)=[N:14][CH:15]=[C:16]([Br:18])[CH:17]=1
Reactant: COC1=NS(=O)N=C1OC
Reactant: NCCCCc1ncc(Br)cc1N
Solvent: CO
Product: COC1=NS(=O)N=C1NCCCCc1ncc(Br)cc1N
Yield: 74 %

Procedure:
A solution of 3,4-dimethoxy-1,2,5-thiadiazole-1-oxide (0.995 g) in methanol (25 ml) was reacted with a solution of 3-amino-5-bromo-(4-aminobutyl)pyridine (1.5 g) in methanol (25 ml) at room temperature for 3 hours. The solvent was removed in vacuo and the residue was chromatographed on silica in ethanol to give an oil which was triturated with ether and recrystallised from ethanol/ether to give 3-[4-(3-amino-5-bromopyrid-2-yl)butylamino]-4-methoxy-1,2,5-thiadiazole-1-oxide (1.7 g) m.p. 118°-120° C.
Reaction SMILES: [F:1][C:2]1[C:10]([F:11])=[CH:9][C:5]([C:6]([OH:8])=O)=[C:4]([NH:12][C:13]2[CH:18]=[CH:17][C:16]([I:19])=[CH:15][C:14]=2[F:20])[CH:3]=1.C1CN([P+](ON2N=NC3C=CC=CC2=3)(N2CCCC2)N2CCCC2)CC1.F[P-](F)(F)(F)(F)F.CN1CCOCC1.[NH:61]1[CH2:64][CH:63]([NH:65][C:66](=[O:72])[O:67][C:68]([CH3:71])([CH3:70])[CH3:69])[CH2:62]1>CN(C=O)C>[F:1][C:2]1[C:10]([F:11])=[CH:9][C:5]([C:6]([N:61]2[CH2:64][CH:63]([NH:65][C:66](=[O:72])[O:67][C:68]([CH3:70])([CH3:69])[CH3:71])[CH2:62]2)=[O:8])=[C:4]([NH:12][C:13]2[CH:18]=[CH:17][C:16]([I:19])=[CH:15][C:14]=2[F:20])[CH:3]=1
Reactant: O=C(O)c1cc(F)c(F)cc1Nc1ccc(I)cc1F
Reactant: CC(C)(C)OC(=O)NC1CNC1
Agent: F[P-](F)(F)(F)(F)F
Agent: c1ccc2c(c1)nnn2O[P+](N1CCCC1)(N1CCCC1)N1CCCC1
Solvent: CN1CCOCC1
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)NC1CN(C(=O)c2cc(F)c(F)cc2Nc2ccc(I)cc2F)C1
Reaction time: 0.25 h
Yield: 95.7 %

Procedure:
4,5-difluoro-2-[(2-fluoro-4-iodophenyl)amino]benzoic acid (100 mg, 0.25 mmol) was taken into DMF (1 mL) followed by addition of PyBOP (137 mg, 0.26 mmol) and the mixture was stirred for 15 minutes then NMM (60 μL, 0.5 mmol) and commercially available 1,1-dimethylethyl azetidin-3-ylcarbamate (43 mg, 0.25 mmol) were subsequently added. The mixture was allowed to stir for 12 hours at room temperature then partitioned with ethyl acetate and water. The organic phase was washed three times with additional water then brine and dried over anhydrous sodium sulfate. Filtration and concentration followed by silica gel flash chromatography of the residue using hexanes:ethyl acetate 3:1 as eluent afforded 1,1-dimethylethyl [1-({4,5-difluoro-2-[(2-fluoro-4-iodophenyl)amino]phenyl}carbonyl)azetidin-3-yl]carbamate (131 mg) as a colorless oil. The oil was taken into trifluoroacetic acid (1 mL) and allowed to stand at room temperature for 5 minutes then concentrated in vacuo. The residue was portioned with ethyl acetate and saturated aqueous sodium bicarbonate and the organic phase washed with brine then dried over anhydrous sodium sulfate. The organic solution was filtered and concentrated then the residue taken into methanol (1 mL) followed by addition of 4 N HCl in dioxane until the solution was acidic. The solution was concentrated and the residue triturated with ethyl ether to give a thick precipitate. The solid was collected by filtration and dried in vacuo to give 1-({4,5-difluoro-2-[(2-fluoro-4-iodophenyl)amino]phenyl}carbonyl)azetidin-3-amine hydrochloride (67 mg, 55% overall yield). 1H-NMR (400 MHz, D6-DMSO): 9.02 (s, 1H), 8.54 (br s, 3H), 7.68 (dd, 1H), 7.53-7.47 (m, 2H), 7.22 (tr, 1H), 7.16 (dd, 1H), 4.60 (br s, 1H), 4.23 (br s, 2H), 4.03 (br m, 2H). MS (EI) for C16H13F3IN3O: 448 (MH+).
Reaction SMILES: Cl.[C:2]([C:6]1[N:11]=[CH:10][C:9]([C:12]2[N:13]([C:33]([N:35]3[CH2:40][CH2:39][N:38]([CH2:41][C:42]([OH:44])=O)[CH2:37][CH2:36]3)=[O:34])[C@@:14]([C:26]3[CH:31]=[CH:30][C:29]([Cl:32])=[CH:28][CH:27]=3)([CH3:25])[C@@:15]([C:18]3[CH:23]=[CH:22][C:21]([Cl:24])=[CH:20][CH:19]=3)([CH3:17])[N:16]=2)=[C:8]([O:45][CH2:46][CH3:47])[CH:7]=1)([CH3:5])([CH3:4])[CH3:3].[N:48]1[CH:53]=[CH:52][C:51]([NH2:54])=[CH:50][CH:49]=1>>[C:2]([C:6]1[N:11]=[CH:10][C:9]([C:12]2[N:13]([C:33]([N:35]3[CH2:36][CH2:37][N:38]([CH2:41][C:42]([NH:54][C:51]4[CH:52]=[CH:53][N:48]=[CH:49][CH:50]=4)=[O:44])[CH2:39][CH2:40]3)=[O:34])[C@@:14]([C:26]3[CH:27]=[CH:28][C:29]([Cl:32])=[CH:30][CH:31]=3)([CH3:25])[C@@:15]([C:18]3[CH:23]=[CH:22][C:21]([Cl:24])=[CH:20][CH:19]=3)([CH3:17])[N:16]=2)=[C:8]([O:45][CH2:46][CH3:47])[CH:7]=1)([CH3:4])([CH3:5])[CH3:3]
Reactant: CCOc1cc(C(C)(C)C)ncc1C1=N[C@@](C)(c2ccc(Cl)cc2)[C@@](C)(c2ccc(Cl)cc2)N1C(=O)N1CCN(CC(=O)O)CC1
Reactant: Nc1ccncc1
Agent: Cl
Product: CCOc1cc(C(C)(C)C)ncc1C1=N[C@@](C)(c2ccc(Cl)cc2)[C@@](C)(c2ccc(Cl)cc2)N1C(=O)N1CCN(CC(=O)Nc2ccncc2)CC1

Procedure:
In a manner analogous to the method described in examples 99, {4-[(4S,5R)-2-(6-tert-butyl-4-ethoxy-pyridin-3-yl )-4,5-bis-(4-chloro-phenyl)-4,5-dimethyl-4,5-dihydro-imidazole-1-carbonyl]-piperazin-1-yl}-acetic acid hydrochloride (example 94) was coupled with pyridin-4-ylamine (Aldrich) to give the title compound. HR-MS (ES, m/z) calculated for C40H46Cl2N7O3 [(M+H)+] 742.3034, observed 742.3036.
Reaction SMILES: C(=O)([O-])[O-].[Cs+].[Cs+].[N:7]1[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=1[CH2:13][CH2:14][NH2:15].I[C:17]1[CH:18]=[C:19]([CH3:24])[C:20]([CH3:23])=[CH:21][CH:22]=1.C(C1CCCCC1=O)(=O)C>CN(C=O)C.O.[Cu]I>[CH3:24][C:19]1[CH:18]=[C:17]([NH:15][CH2:14][CH2:13][C:8]2[CH:9]=[CH:10][CH:11]=[CH:12][N:7]=2)[CH:22]=[CH:21][C:20]=1[CH3:23]
Reactant: Cc1ccc(I)cc1C
Reactant: NCCc1ccccn1
Agent: [Cu]I
Agent: CC(=O)C1CCCCC1=O
Agent: O=C([O-])[O-]
Solvent: O
Solvent: CN(C)C=O
Product: Cc1ccc(NCCc2ccccn2)cc1C
Temperature: 25 °C
Reaction time: 17 h
Yield: 31.6 %

Procedure:
A dried flask was charged with 21 mg (0.11 mmol) CuI and 1.4 g (4.3 mmol) cesium carbonate under argon. 0.31 g (2.6 mmol) 2-pyridin-2-yl-ethylamine (CAS: 2706-56-1), 0.5 g (2.1 mmol) 4-iodo-0-xylene in solution in 1 mL dried DMF and finally 0.058 mL (0.43 mmol) 2-acetylcyclohexanone were successively added. The mixture was stirred at room temperature for 17 hours and then in a 65° C. oil-bath for 7 hours. The mixture was diluted with water. The aqueous layer was extracted twice with ethyl acetate. The combined extracts were dried over Na2SO4, filtered and concentrated in vacuo. The crude oil was purified with flash column chromatography on silica eluting with a gradient formed from heptane and ethylacetate to provide 0.15 g (31%) of the title compound as a yellow oil. MS (m/e): 227.2 [M+H]+.
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([N:10]2[C:19]3[N:20]4[CH:26]=[C:25]([O:27][CH2:28][CH2:29][O:30]C(=O)C)[CH:24]=[CH:23][C:21]4=[N:22][C:18]=3[C:17]3[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=3)[C:11]2=[O:34])=[CH:6][CH:5]=1)([O-:3])=[O:2]>Cl>[OH:30][CH2:29][CH2:28][O:27][C:25]1[CH:24]=[CH:23][C:21]2[N:20]([CH:26]=1)[C:19]1[N:10]([C:7]3[CH:8]=[CH:9][C:4]([N+:1]([O-:3])=[O:2])=[CH:5][CH:6]=3)[C:11](=[O:34])[C:12]3[C:17]([C:18]=1[N:22]=2)=[CH:16][CH:15]=[CH:14][CH:13]=3
Reactant: CC(=O)OCCOc1ccc2nc3c4ccccc4c(=O)n(-c4ccc([N+](=O)[O-])cc4)c3n2c1
Agent: Cl
Product: O=c1c2ccccc2c2nc3ccc(OCCO)cn3c2n1-c1ccc([N+](=O)[O-])cc1
Yield: 108.7 %

Procedure:
A solution of compound 73 (0.327 mmol, 0.150 g) in concentrated aqueous HCl was stirred at room temperature overnight. The solvent was evaporated under vacuum and the crude reaction product was brought on a filter and washed with isopropanol and isopropylether successively to give the hydrochloride salt of 9-[2-hydroxy-ethoxy]-6-(4-nitrophenyl)-pyrido[2′,1′:2,3]imidazo[4,5-c]isoquinolin-5(6H)-one (74) (0.148 g, yield=100%, purity (LC)=95%).
Reaction SMILES: [H-].[Na+].[C:3](OCC)(=[O:10])[CH2:4][C:5]([O:7]CC)=[O:6].[CH2-]C(C)=O.Br[CH2:19][CH2:20][C@H:21]([OH:24])[CH2:22][OH:23].C(O)(=O)C>CCCCC.O1CCCC1.CCOCC>[C:5]([C@@H:4]1[CH2:19][CH2:20][C@@H:21]([CH2:22][OH:23])[O:24][C:3]1=[O:10])([OH:7])=[O:6]
Reactant: OC[C@@H](O)CCBr
Reactant: CCOC(=O)CC(=O)OCC
Agent: [CH2-]C(C)=O
Agent: [H-]
Agent: [Na+]
Solvent: CC(=O)O
Solvent: C1CCOC1
Solvent: CCOCC
Product: O=C(O)[C@@H]1CC[C@@H](CO)OC1=O
Yield: 31.6 %

Procedure:
To 40 g (1 mole) of 60% sodium hydride washed with dry pentane was added 300 ml of dry tetrahydrofuran, and a solution of 176 g (1.1 moles) of diethyl malonate in 350 ml of tetrahydrofuran was slowly added into the obtained suspension with stirring. After the dropwise addition, 20.7 g (0.1 mole) of (S)-4-bromo-1,2-butanediol acetonide was added into the mixture over a period of 2 hours. The mixture was stirred for 20 hours to effect reaction. Then acetic acid dissolved in ether was added to the mixture to neutralize the excessive alkali, ether was added to the mixture, and the mixture was washed with a saturated saline solution and dried over magnesium sulfate. The solvent was removed under a reduced pressure, and optical resolution was carried out by the silica gel column chromatography to obtain 5.5 g of (2S,5S)-2-carboxy-5-hydroxymethyl-δ-valerolactone.
Reaction SMILES: [F:1][C:2]([F:16])([F:15])[C:3]([C:5]1[C:6]([NH2:14])=[C:7]([CH:11]=[CH:12][CH:13]=1)[C:8](O)=[O:9])=[O:4].O=S(Cl)[Cl:19]>>[F:1][C:2]([F:16])([F:15])[C:3]([C:5]1[C:6]([NH2:14])=[C:7]([CH:11]=[CH:12][CH:13]=1)[C:8]([Cl:19])=[O:9])=[O:4]
Reactant: O=S(Cl)Cl
Reactant: Nc1c(C(=O)O)cccc1C(=O)C(F)(F)F
Product: Nc1c(C(=O)Cl)cccc1C(=O)C(F)(F)F

Procedure:
4.66 g (0.02 mole) of Compound 2, 50 ml EtAc and 15 ml SOCl2 were refluxed until the reaction mixture became a clear, yellow solution (1 h). After removing the solvent and excess reagent, the residue was crystalized from n-hexane. Yield: 4.5 g (85%), m.p. 95-98° C. For the 4-position isomer, yield 4.2 g (81%), m.p. 112-114° C.
Reaction SMILES: [Br:1]Br.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[C:22]1([C:28]2[S:29][CH:30]=[C:31]([CH2:33]O)[N:32]=2)[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1>C(Cl)Cl>[Br:1][CH2:33][C:31]1[N:32]=[C:28]([C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)[S:29][CH:30]=1
Reactant: OCc1csc(-c2ccccc2)n1
Reactant: BrBr
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Product: BrCc1csc(-c2ccccc2)n1
Temperature: -6 °C
Yield: 93.8 %

Procedure:
Bromine (177 mg, 1.1 mmol) was added directly into a solution of triphenylphosphine (288 mg, 1.1 mmol) in DCM (2 mL) to give a kind of white precipitate. The temperature was cooled to −6° C. A solution of commercially available (2-phenylthiazol-4-yl)methanol (200 mg, 1.04 mmol) in DCM (1 mL) was added dropwise. The resulting mixture was maintained at −6° C. for 15 min and then warmed to room temperature for 1 h. A white precipitate was formed. The solution was filtered and the white precipitate was washed with DCM. The white precipitate was collected and dissolved in NaHCO3 0.5M After 30 min of stirring, the aqueous layer was extracted with DCM and the organic phase was washed with water, dried over MgSO4, filtered and evaporated to afford 248 mg of 4-(bromomethyl)-2-phenylthiazole (Yield 71%) as a yellow oil.
Reaction SMILES: [F:1][CH2:2][CH2:3][O:4][CH2:5][CH2:6][O:7][CH2:8][CH2:9][O:10][C:11]1[CH:16]=[CH:15][C:14](/[CH:17]=[CH:18]/[C:19]2[CH:24]=[CH:23][C:22]([N+:25]([O-])=O)=[CH:21][CH:20]=2)=[CH:13][N:12]=1.Cl.[OH-].[Na+].ClCCl>C(O)C>[F:1][CH2:2][CH2:3][O:4][CH2:5][CH2:6][O:7][CH2:8][CH2:9][O:10][C:11]1[CH:16]=[CH:15][C:14](/[CH:17]=[CH:18]/[C:19]2[CH:24]=[CH:23][C:22]([NH2:25])=[CH:21][CH:20]=2)=[CH:13][N:12]=1
Reactant: O=[N+]([O-])c1ccc(/C=C/c2ccc(OCCOCCOCCF)nc2)cc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: ClCCl
Solvent: CCO
Product: Nc1ccc(/C=C/c2ccc(OCCOCCOCCF)nc2)cc1
Yield: 57.7 %

Procedure:
Compound 4 (34 mg, 0.09 mmol) was dissolved in ethanol (5 ml) followed by the addition of stannous chloride (51.4 mg, 0.27 mmol) and concentrated HCl (0.25 ml). The reaction mixture was refluxed for 2 hours and cooled down. 2N NaOH was used to adjust pH to 10. Dichloromethane was added and the organic layer was separated, washed with brine, dried over anhydrous sodium sulfate and evaporated. The residue was purified by PTLC (3% MeOH in DCM as developing solvent) to give product 5 (18 mg, Yield: 58%): 1H NMR (200 MHz, CDCl3): δ.8.14 (1H, d, J=2.2 Hz), 7.76 (1H, d, d, J=8.6 Hz, J2=2.4 Hz), 7.32 (2H, d, J=8.4 Hz), 6.80 (5H, m), 4.53 (2H, d, t, J1=47.6 Hz, J2=4.2 Hz), 4.49 (2H, t, J=4.8 Hz), 3.85 (3H, m), 3.70 (5H, m), 1.8-3.0 (2H, br); HRMS (EI) m/z calcd. for [C19H23FN2O3]+ 376.1693.
Reaction SMILES: [NH2:1][C@H:2]1[CH2:7][CH2:6][C@H:5]([NH:8][C:9]([C:11]2[C:15]3[N:16]=[CH:17][N:18]=[C:19]([C:20]4[CH:25]=[CH:24][C:23]([O:26][CH3:27])=[CH:22][C:21]=4[O:28][CH2:29][CH:30]4[CH2:32][CH2:31]4)[C:14]=3[NH:13][CH:12]=2)=[O:10])[CH2:4][CH2:3]1.[CH:33]1([C:36](Cl)=[O:37])[CH2:35][CH2:34]1>>[CH:33]1([C:36]([NH:1][C@H:2]2[CH2:7][CH2:6][C@H:5]([NH:8][C:9]([C:11]3[C:15]4[N:16]=[CH:17][N:18]=[C:19]([C:20]5[CH:25]=[CH:24][C:23]([O:26][CH3:27])=[CH:22][C:21]=5[O:28][CH2:29][CH:30]5[CH2:31][CH2:32]5)[C:14]=4[NH:13][CH:12]=3)=[O:10])[CH2:4][CH2:3]2)=[O:37])[CH2:35][CH2:34]1
Reactant: COc1ccc(-c2ncnc3c(C(=O)N[C@H]4CC[C@H](N)CC4)c[nH]c23)c(OCC2CC2)c1
Reactant: O=C(Cl)C1CC1
Product: COc1ccc(-c2ncnc3c(C(=O)N[C@H]4CC[C@H](NC(=O)C5CC5)CC4)c[nH]c23)c(OCC2CC2)c1

Procedure:
Starting from trans-4-(2-cyclopropylmethoxy-4-methoxy-phenyl)-5H-pyrrolo[3,2-d]pyrimidine-7-carboxylic acid (4-amino-cyclohexyl)-amide (example A150) and cyclopropanecarbonyl chloride the title compound is obtained as colorless solid.
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3]2([C:13]3=[CH:14][C:15]4[O:19][CH2:18][O:17][C:16]=4[CH:20]=[C:12]3[O:11][CH2:10]2)[C:2]1=[O:21].CC1(C)COC2=CC3OC[C:32]4([C:42]=3[CH:43]=C12)[C:40]1[C:35](=CC=CC=1)NC4=O.BrCC1CC1C.BrCC1OC(C(F)(F)F)=CC=1>>[CH3:35][CH:40]1[CH2:32][CH:42]1[CH2:43][N:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3]2([C:13]3=[CH:14][C:15]4[O:19][CH2:18][O:17][C:16]=4[CH:20]=[C:12]3[O:11][CH2:10]2)[C:2]1=[O:21]
Reactant: CC1(C)COc2cc3c(cc21)C1(CO3)C(=O)Nc2ccccc21
Reactant: O=C1Nc2ccccc2C12COc1cc3c(cc12)OCO3
Agent: CC1CC1CBr
Agent: FC(F)(F)c1ccc(CBr)o1
Product: CC1CC1CN1C(=O)C2(COc3cc4c(cc32)OCO4)c2ccccc21

Procedure:
Following the procedure described in EXAMPLE 10.21, and making non-critical variations using spiro[furo[2,3-f][1,3]benzodioxole-7,3′-indol]-2′(1′H)-one to replace 5,5-dimethyl-5,6-dihydrospiro[benzo[1,2-b:5,4-b′]difuran-3,3′-indol]-2′(1′H)-one, and 1-(bromomethyl)-2-methylcyclopropane to replace 2-(bromomethyl)-5-(trifluoromethyl)furan, the title compound was obtained (37%) as a white solid: MS (ES+) m/z 350.3 (M+1).
Reaction SMILES: O.[OH-].[Li+].[CH3:4][C:5]1[O:9][C:8]([C:10]2[S:11][CH:12]=[CH:13][CH:14]=2)=[N:7][C:6]=1[CH2:15][O:16][C:17]1[CH:38]=[CH:37][C:20]([CH2:21][O:22]/[N:23]=[C:24](/[C:31]2[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=2)\[CH2:25][CH2:26][C:27]([O:29]C)=[O:28])=[CH:19][CH:18]=1.O.Cl>O1CCCC1.CO>[CH3:4][C:5]1[O:9][C:8]([C:10]2[S:11][CH:12]=[CH:13][CH:14]=2)=[N:7][C:6]=1[CH2:15][O:16][C:17]1[CH:38]=[CH:37][C:20]([CH2:21][O:22]/[N:23]=[C:24](/[C:31]2[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=2)\[CH2:25][CH2:26][C:27]([OH:29])=[O:28])=[CH:19][CH:18]=1
Reactant: COC(=O)CC/C(=N\OCc1ccc(OCc2nc(-c3cccs3)oc2C)cc1)c1ccccc1
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Solvent: CO
Product: Cc1oc(-c2cccs2)nc1COc1ccc(CO/N=C(\CCC(=O)O)c2ccccc2)cc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 87.6 %

Procedure:
Lithium hydroxide monohydrate (73.6 mg) was added to a solution of methyl E-4-[4-[5-methyl-2-(2-thienyl)-4-oxazolylmethoxy]benzyloxyimino]-4-phenylbutyrate (430 mg) in tetrahydrofuran (6 ml)-water (4 ml)-methanol (4 ml) and stirred at room temperature for 2 hours. 1N hydrochloric acid (1.8 ml) was added to the reaction mixture and extracted with ethyl acetate. The ethyl acetate layer was washed with an aqueous saturated solution of sodium chloride, dried (MgSO4) and concentrated. The residue was recrystallized from ethyl acetate-hexane to obtain E-4-[4-[5-methyl-2-(2-thienyl)-4-oxazolylmethoxy]benzyloxyimino]-4-phenylbutyric acid (366 mg, yield 88%) as colorless crystals. m.p. 142-143° C.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[C:7](=[O:11])[N:6]([CH3:12])[CH:5]2[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.[CH3:19][Si]([N-][Si](C)(C)C)(C)C.[K+].IC>O1CCCC1.CO>[Br:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[C:7](=[O:11])[N:6]([CH3:12])[C:5]2([CH3:19])[C:13]1[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=1
Reactant: CN1C(=O)c2ccc(Br)cc2C1c1ccccc1
Reactant: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [K+]
Solvent: CI
Solvent: CO
Solvent: C1CCOC1
Product: CN1C(=O)c2ccc(Br)cc2C1(C)c1ccccc1
Temperature: -30 °C
Reaction time: 16 h

Procedure:
To a solution of 5-Bromo-2-methyl-3-phenyl-2,3-dihydro-isoindol-1-one (250 mg; 0.83 mmol) in 2.5 ml of anhydrous tetrahydrofuran at −30° C. is added an 0.5 mol/l potassium bis(trimethylsilyl)amide (2.5 ml; 1.24 mmol) solution. After 30 minutes iodomethane (77 μl; 1.24 mmol) is added and stirred for 16 hours at −30° C. The reaction mixture is diluted with methanol and purified via reversed phase chromatography under basic conditions.