Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [S:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[C:6]1([CH2:9][NH2:10])[CH2:8][CH2:7]1.[Cl:11][CH2:12][C@H:13]1[O:17][C@@H:16]([N:18]2[C:37]3[N:36]=[CH:35][N:34]=[C:22](NCC4(C5C=CC=CC=5)CC4)[C:21]=3[N:20]=[CH:19]2)[C@H:15]([OH:38])[C@@H:14]1[OH:39].C(N(CC)CC)C>C(O)=O>[Cl:11][CH2:12][C@H:13]1[O:17][C@@H:16]([N:18]2[C:37]3[N:36]=[CH:35][N:34]=[C:22]([NH:10][CH2:9][C:6]4([C:2]5[S:1][CH:5]=[CH:4][CH:3]=5)[CH2:8][CH2:7]4)[C:21]=3[N:20]=[CH:19]2)[C@H:15]([OH:38])[C@@H:14]1[OH:39]
Reactant: O[C@@H]1[C@H](O)[C@@H](CCl)O[C@H]1n1cnc2c(NCC3(c4ccccc4)CC3)ncnc21
Reactant: NCC1(c2cccs2)CC1
Solvent: CCN(CC)CC
Solvent: O=CO
Product: O[C@@H]1[C@H](O)[C@@H](CCl)O[C@H]1n1cnc2c(NCC3(c4cccs4)CC3)ncnc21
Yield: 29 %

Procedure:
(1-Thien-2-ylcyclopropyl)methylamine (0.55 g, 3.6 mmol), see Example 3, 6-chloropurine-5'-deoxy-5'-chlororiboside-2',3'-isopropylidene (1.25 g, 3.6 mmol, as prepared in Example 5) and triethylamine (0.75 g, 7.5 mmol) are reacted together as described in Example 5. Aqueous formic acid hydrolysis gives 5'-chloro-5'-deoxy-N6-((1-thien-2-ylcyclopropyl)methyl)adenosine (0.44 g, 29%) as a light khaki solid foam m.p. 69°-75° C. Found: C, 50.53; H, 4.90; N, 15.90; Cl, 9.13; S, 7.22%. C18H20ClN5O3S calculated requires: C, 51.25; H, 4.74; N, 16.61; Cl, 8.42; S, 7.59%.
Reaction SMILES: N1C=CC(NC[CH:9]2[CH2:14][CH2:13][NH:12][CH2:11][CH2:10]2)=CN=1.O=C1CCC(=O)N1[O:22][C:23](=O)[O:24][CH2:25][C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1>CN(C=O)C>[CH2:25]([O:24][C:23]([N:12]1[CH2:11][CH2:10][CH2:9][CH2:14][CH2:13]1)=[O:22])[C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1
Reactant: O=C(OCc1ccccc1)ON1C(=O)CCC1=O
Reactant: c1cc(NCC2CCNCC2)cnn1
Solvent: CN(C)C=O
Product: O=C(OCc1ccccc1)N1CCCCC1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a stirred solution of 4-[(pyridazin-4-ylamino)-methyl]-piperidine (0.20 g, 1.04 mmol), in DMF (3 mL) was added carbonic acid benzyl ester 2,5-dioxo-pyrrolidin-1-yl ester (0.26 g, 1.04 mmol). The resulting reaction solution was stirred at rt for 0.5 h, then concentrated in vacuo. The residue was purified by silica gel chromatography (1–7 (10% NH4OH in MeOH)/99–93 CH2Cl2) to give 4-(pyridazin-4-ylamino)-methyl]-piperidine-1-carboxylic acid benzyl ester.
Reaction SMILES: C([N:4]1[C:12]2[C:7](=[CH:8][C:9]([S:13]([CH2:16][N+:17]([O-:19])=[O:18])(=[O:15])=[O:14])=[CH:10][CH:11]=2)[CH2:6][CH2:5]1)(=O)C.Cl>C(O)C>[N+:17]([CH2:16][S:13]([C:9]1[CH:8]=[C:7]2[C:12](=[CH:11][CH:10]=1)[NH:4][CH2:5][CH2:6]2)(=[O:14])=[O:15])([O-:19])=[O:18]
Reactant: CC(=O)N1CCc2cc(S(=O)(=O)C[N+](=O)[O-])ccc21
Agent: Cl
Solvent: CCO
Product: O=[N+]([O-])CS(=O)(=O)c1ccc2c(c1)CCN2
Temperature: 0 °C
Reaction time: 0.08 h

Procedure:
1-Acetyl-5-(nitromethylsulphonyl)indoline (5.41 g, 19 mmol) was added in one portion to a boiling mixture of 2 M hydrochloric acid (60 ml) and ethanol (20 ml). The mixture was heated at reflux until a clear solution formed, and then for a further 5 minutes. The hot reaction mixture was poured into ice-cold saturated sodium hydrogen carbonate solution (100 ml) and then extracted with ethyl acetate. The combined extracts were dried (MgSO4) and the solvent was removed by evaporation. The resultant yellow oil was purified by flash chromatography on silica (Merck kieselgel Art. 7736), eluting with dichloromethane, to give 5-(nitromethylsulphonyl)indoline as a pale yellow solid, m.p. 139° C.; microanalysis, found: C,44.5; H,4.1; N,11.4%; C9H10N2O4S requires: C,44.6; H,4.1; N,11.6%.
Reaction SMILES: [C:1](Cl)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[NH2:10][CH2:11][CH2:12][O:13][C:14]1[N:21]=[C:20]([C:22]2[CH:27]=[CH:26][C:25]([Cl:28])=[CH:24][C:23]=2[Cl:29])[C:19]([C:30]2[CH:35]=[CH:34][C:33]([Cl:36])=[CH:32][CH:31]=2)=[CH:18][C:15]=1[C:16]#[N:17]>>[Cl:36][C:33]1[CH:32]=[CH:31][C:30]([C:19]2[CH:18]=[C:15]([C:16]#[N:17])[C:14]([O:13][CH2:12][CH2:11][NH:10][C:1](=[O:8])[C:2]3[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=3)=[N:21][C:20]=2[C:22]2[CH:27]=[CH:26][C:25]([Cl:28])=[CH:24][C:23]=2[Cl:29])=[CH:35][CH:34]=1
Reactant: N#Cc1cc(-c2ccc(Cl)cc2)c(-c2ccc(Cl)cc2Cl)nc1OCCN
Reactant: O=C(Cl)c1ccccc1
Product: N#Cc1cc(-c2ccc(Cl)cc2)c(-c2ccc(Cl)cc2Cl)nc1OCCNC(=O)c1ccccc1

Procedure:
In the following Examples 28-31, the procedure described in Example 27 was repeated but substituting the appropriate acid chloride for benzoyl chloride in the reaction with 2-(2-aminoethoxy)-5-(4-chlorophenyl)-6-(2,4-dichlorophenyl)-nicotinonitrile from Example 26 to afford the following compounds:
Reaction SMILES: C([O:3][C:4](=[O:21])[CH2:5][C:6]1[CH:11]=[CH:10][CH:9]=[C:8]([CH2:12][O:13][C:14]2[CH:19]=[CH:18][C:17](I)=[CH:16][CH:15]=2)[CH:7]=1)C.[CH3:22][O:23][CH2:24][C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=1B(O)O>>[CH3:22][O:23][CH2:24][C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=1[C:17]1[CH:16]=[CH:15][C:14]([O:13][CH2:12][C:8]2[CH:7]=[C:6]([CH2:5][C:4]([OH:3])=[O:21])[CH:11]=[CH:10][CH:9]=2)=[CH:19][CH:18]=1
Reactant: COCc1ccccc1B(O)O
Reactant: CCOC(=O)Cc1cccc(COc2ccc(I)cc2)c1
Product: COCc1ccccc1-c1ccc(OCc2cccc(CC(=O)O)c2)cc1

Procedure:
[3-(2′-Methoxymethyl-biphenyl-4-yloxymethyl)-phenyl]-acetic acid was prepared using general procedure 4 from [3-(4-iodo-phenoxymethyl)-phenyl]-acetic acid ethyl ester (of intermediate 4) and 2-methoxymethylphenylboronic acid (available from Apollo Scientific Ltd., Stockport, UK). Mass spectrum MH+=363.
Reaction SMILES: [CH2:1]([C:8]1[N:9]=[N:10][C:11](Cl)=[C:12]([CH3:15])[C:13]=1[CH3:14])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH2:17]([O:19][C:20]([CH:22]1[CH2:27][CH2:26][NH:25][CH2:24][CH2:23]1)=[O:21])[CH3:18].CCN(C(C)C)C(C)C>CN1C(=O)CCC1>[CH2:17]([O:19][C:20]([CH:22]1[CH2:27][CH2:26][N:25]([C:11]2[N:10]=[N:9][C:8]([CH2:1][C:2]3[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=3)=[C:13]([CH3:14])[C:12]=2[CH3:15])[CH2:24][CH2:23]1)=[O:21])[CH3:18]
Reactant: Cc1c(Cl)nnc(Cc2ccccc2)c1C
Reactant: CCOC(=O)C1CCNCC1
Solvent: CCN(C(C)C)C(C)C
Solvent: CN1CCCC1=O
Product: CCOC(=O)C1CCN(c2nnc(Cc3ccccc3)c(C)c2C)CC1
Temperature: 210 °C
Yield: 61.7 %

Procedure:
To a solution of 3-benzyl-6-chloro-4,5-dimethyl-pyridazine (1.0 g, 4.31 mmol) in NMP (10 mL) is added piperidine-4-carboxylic acid ethyl ester (2.0 g, 12.9 mmol) and DIPEA (3.7 mL, 21.6 mmol). The mixture is heated in microwave at 210° C. for 1.5 h. The mixture is concentrated at 80° C. by rotovaporation. The crude product is purified by HPLC (CH3CN/H2O: 22%˜45% with 0.1% TFA) to give 1-(6-benzyl-4,5-dimethyl-pyridazin-3-yl)-piperidine-4-carboxylic acid ethyl ester (0.94 g, 61%).
Reaction SMILES: [C:1]([C:5]1[CH:6]=[C:7](Br)[CH:8]=[CH:9][C:10]=1[O:11][CH3:12])([CH3:4])([CH3:3])[CH3:2].[Mg].Br[C:16]1[S:20][C:19]([C:21]([O:23][CH3:24])=[O:22])=[CH:18][CH:17]=1>C1COCC1.[Cl-].[Zn+2].[Cl-]>[C:1]([C:5]1[CH:6]=[C:7]([C:16]2[S:20][C:19]([C:21]([O:23][CH3:24])=[O:22])=[CH:18][CH:17]=2)[CH:8]=[CH:9][C:10]=1[O:11][CH3:12])([CH3:4])([CH3:3])[CH3:2]
Reactant: COC(=O)c1ccc(Br)s1
Reactant: COc1ccc(Br)cc1C(C)(C)C
Agent: [Cl-]
Agent: [Mg]
Agent: [Zn+2]
Solvent: C1CCOC1
Product: COC(=O)c1ccc(-c2ccc(OC)c(C(C)(C)C)c2)s1
Temperature: 0 °C
Reaction time: 1 h

Procedure:
A solution of 2 g (8.2 mmol) of 3-tert-butyl-4-methoxybromobenzene is added dropwise to a suspension of 300 mg (12 mmol) of magnesium in 10 ml of THF. Once the addition is complete, the mixture is refluxed for one hour. At room temperature, 1.35 g (9.9 mmol) of anhydrous zinc chloride are added and the mixture is stirred for one hour. 1.2 g (5.5 mmol) of methyl 5-bromo-2-thiophenecarboxylate and 60 mg (0.12 mmol) of the NiCl2 /DPPE complex are then added successively and the mixture is left stirring at room temperature for 12 hours. The reaction medium is poured into ice-water and extracted with ethyl ether and the organic phase is separated out after settling has taken place, dried over magnesium sulphate and evaporated. The residue obtained is chromatographed on a column of silica eluted with a mixture of hexane and dichloromethane (50/50% by volume). After evaporation of the solvents, 1.56 g (93%) of the expected methyl ester are collected, with a melting point of 94-5° C.
Reaction SMILES: Cl.[Br:2][C:3]1[CH:15]=[CH:14][C:6]([CH2:7][CH:8]2[CH2:13][CH2:12][NH:11][CH2:10][CH2:9]2)=[CH:5][C:4]=1[O:16][CH2:17][CH2:18][O:19]C.B(Br)(Br)Br.CO>ClCCl>[Br:2][C:3]1[CH:15]=[CH:14][C:6]([CH2:7][CH:8]2[CH2:13][CH2:12][NH:11][CH2:10][CH2:9]2)=[CH:5][C:4]=1[O:16][CH2:17][CH2:18][OH:19]
Reactant: COCCOc1cc(CC2CCNCC2)ccc1Br
Agent: BrB(Br)Br
Agent: Cl
Solvent: CO
Solvent: ClCCl
Product: OCCOc1cc(CC2CCNCC2)ccc1Br
Reaction time: 0.5 h
Yield: 116.2 %

Procedure:
A solution of 4-[4-bromo-3-(2-methoxyethoxy)benzyl]piperidine hydrochloride (RE1) (3.00 g, 8.3 mmol) in dichloromethane (100 mL) was cooled in a salt-ice bath. A 1 M solution of boron tribromide in dichloromethane (7.8 mL, 7.8 mmol) was added dropwise thereto at 0° C. in 30 minutes, and the reaction mixture was stirred for 1.5 hours under ice cooling. Methanol (20 mL) was added thereto, and the solvent was distilled off under reduced pressure. A 5% aqueous potassium carbonate solution (50 mL) was added to the obtained concentrated residue, followed by extraction with chloroform. The organic layer was dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure to obtain the title compound (RE2) (3.03 g, quantitative).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([NH:11][C@H:12]([CH2:16][CH2:17][C:18]([F:21])([F:20])[F:19])[C:13]([NH2:15])=[O:14])(=[O:10])=[O:9])=[CH:4][CH:3]=1.Br[CH2:23][C:24]1[CH:31]=[CH:30][C:27]([C:28]#[N:29])=[CH:26][C:25]=1[F:32].C([O-])([O-])=O.[Cs+].[Cs+]>CN(C=O)C.CCOC(C)=O>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([N:11]([C@H:12]([CH2:16][CH2:17][C:18]([F:21])([F:19])[F:20])[C:13]([NH2:15])=[O:14])[CH2:23][C:24]2[CH:31]=[CH:30][C:27]([C:28]#[N:29])=[CH:26][C:25]=2[F:32])(=[O:10])=[O:9])=[CH:4][CH:3]=1
Reactant: N#Cc1ccc(CBr)c(F)c1
Reactant: NC(=O)[C@@H](CCC(F)(F)F)NS(=O)(=O)c1ccc(Cl)cc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: N#Cc1ccc(CN([C@H](CCC(F)(F)F)C(N)=O)S(=O)(=O)c2ccc(Cl)cc2)c(F)c1
Temperature: 25 °C
Reaction time: 0.75 h

Procedure:
To a solution of (R)-2-(4-chlorophenylsulfonamido)-5,5,5-trifluoropentanamide (6.88 g, 20.0 mmol) and 4-(bromomethyl)-3-fluorobenzonitrile (6.43 g, 30 mmol) in DMF (35 mL) was added anhydrous Cs2CO3 (19.56 g, 60 mmol). The resulting mixture was stirred at room temperature for 45 min. and then diluted with EtOAc (200 mL), washed with water (100 mL×4) and dried over Na2SO4. The product was purified by Biotage (40+M column, 3% to 80% EtOAc in hexanes, 651 mL). The title compound was obtained as a white solid (6.50 g, 68.1% yield). 1H NMR (DMSO-d6, 400 MHz) δ 7.80-7.88 (m, 3H), 7.70-7.75 (m, 2H), 7.67 (d, 2H, J=8), 7.60 (s, 1H), 7.26 (s, 1H), 4.99 (d, 1H, J=16), 4.68 (d, 1H, J=16), 4.14 (t, 1H, J=8), 1.99-2.17 (m, 2H), 1.80-1.94(m, 1H), 1.40-1.56(m, 1H). LC/MS M+H478.14, 94%.
Reaction SMILES: Br.[C:2]([O:5][C@@H:6]1[C@@H:11]([O:12][C:13](=[O:15])[CH3:14])[C@H:10]([O:16][C:17](=[O:19])[CH3:18])[C@@H:9]([CH2:20][O:21][C:22](=[O:24])[CH3:23])[O:8][C@H:7]1[S:25]C(=N)N)(=[O:4])[CH3:3].C(Cl)(Cl)Cl.[C:33](Cl)([C:46]1[CH:51]=[CH:50][CH:49]=[CH:48][CH:47]=1)([C:40]1[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=1)[C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1>N1C=CC=CC=1>[C:33]([S:25][C@@H:7]1[O:8][C@H:9]([CH2:20][O:21][C:22](=[O:24])[CH3:23])[C@@H:10]([O:16][C:17](=[O:19])[CH3:18])[C@H:11]([O:12][C:13](=[O:15])[CH3:14])[C@H:6]1[O:5][C:2](=[O:4])[CH3:3])([C:46]1[CH:51]=[CH:50][CH:49]=[CH:48][CH:47]=1)([C:40]1[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=1)[C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1
Reactant: ClC(c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: CC(=O)OC[C@H]1O[C@@H](SC(=N)N)[C@H](OC(C)=O)[C@@H](OC(C)=O)[C@@H]1OC(C)=O
Agent: Br
Solvent: c1ccncc1
Solvent: ClC(Cl)Cl
Product: CC(=O)OC[C@H]1O[C@@H](SC(c2ccccc2)(c2ccccc2)c2ccccc2)[C@H](OC(C)=O)[C@@H](OC(C)=O)[C@@H]1OC(C)=O
Temperature: 25 °C
Reaction time: 8 h

Procedure:
2,3,4,6-Tetra-O-acetyl-1-thio-β-D-glucopyranose, obtained from the hydrolysis of 29 g. of S-(2,3,4,6-tetra-O-acetyl-β-D-glucopyranosyl) thiopseudourea hydrobromide as in "Methods in Carbohydrate Chemistry", Vol. II, page 436 (Whistler and Wolfrom editors, Academic Press Inc., 1963), was dissolved in 250 ml. of chloroform and cooled to 0°-5° C. in an ice bath. Anhydrous pyridine (20 ml.) was added, followed by 27.9 g. of trityl chloride. The mixture was stirred overnight at ambient temperature and the organic solution was extracted with dilute hydrochloric acid, washed with 5% aqueous sodium carbonate solution and with brine, dried over magnesium sulfate and evaporated under reduced pressure. The residue was crystallized from ether, then recrystallized from benzene-cyclohexane to give S-trityl-2,3,4,6-tetra-O-acetyl-1-thio-β-D-glucopyranose, m.p. 177.5°-179.5° C.
Reaction SMILES: [NH2:1][C:2]1[N:3]([CH3:22])[C:4](=[O:21])[C:5]([C:14]2[CH:15]=[C:16]([CH:19]=[O:20])[NH:17][CH:18]=2)([C:7]2[CH:12]=[CH:11][CH:10]=[C:9]([Br:13])[CH:8]=2)[N:6]=1.C(=O)([O-])[O-].[Cs+].[Cs+].I[CH2:30][CH3:31]>CN(C=O)C.C(Cl)(Cl)Cl>[NH2:1][C:2]1[N:3]([CH3:22])[C:4](=[O:21])[C:5]([C:14]2[CH:15]=[C:16]([CH:19]=[O:20])[N:17]([CH2:30][CH3:31])[CH:18]=2)([C:7]2[CH:12]=[CH:11][CH:10]=[C:9]([Br:13])[CH:8]=2)[N:6]=1
Reactant: CN1C(=O)C(c2cccc(Br)c2)(c2c[nH]c(C=O)c2)N=C1N
Reactant: CCI
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: ClC(Cl)Cl
Solvent: CN(C)C=O
Product: CCn1cc(C2(c3cccc(Br)c3)N=C(N)N(C)C2=O)cc1C=O
Temperature: 25 °C
Reaction time: 20 h
Yield: 73 %

Procedure:
In DMF, (7 mL) is dissolved 4-[2-amino-4-(3-bromophenyl)-1-methyl-5-oxo-4,5-dihydro-1H-imidazol-4-yl]-1H-pyrrole-2-carbaldehyde (1.50 g; 4.15 mmol). To this solution is added cesium carbonate (1.35 g; 4.15 mmol) and iodoethane (0.43 mL; 5.4 mmol), and the mixture is stirred for 20 hours at room temperature. The mixture is diluted to 50 mL with chloroform, washed twice with water, dried over MgSO4, filtered, and evaporated. The residue was crystallized in ethyl acetate to give the title product as light-brown crystals, 1.18 g (73% yield), mp 194-195° C.; MS (ES) m/z 387.0, [M−H]−.
Reaction SMILES: [Br:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][NH:18][C:19]1[CH:27]=[CH:26][C:22]([C:23]([OH:25])=[O:24])=[CH:21][CH:20]=1.B(F)(F)F.[CH3:32]COCC>CO>[Br:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][NH:18][C:19]1[CH:20]=[CH:21][C:22]([C:23]([O:25][CH3:32])=[O:24])=[CH:26][CH:27]=1
Reactant: CCOCC
Reactant: O=C(O)c1ccc(NCCCCCCCCCCCCCCCCBr)cc1
Agent: FB(F)F
Solvent: CO
Product: COC(=O)c1ccc(NCCCCCCCCCCCCCCCCBr)cc1
Temperature: 0 °C

Procedure:
A solution of 50.5 g. of 4-(16-bromohexadecylamino)benzoic acid and 34.4 ml. of boron trifluoride etherate in 200 ml. of methanol is stirred under reflux for 44 hours, allowed to cool, and is poured into 1.20 liters of ice-cold 5% aqueous sodium carbonate solution. The white solid is collected by filtration and recrystallized from benzene-ethanol to yield methyl 4-(16-bromohexadecylamino)benzoate, m.p. 92°-93° C.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]([C:14]2[CH:19]=[CH:18][C:17]([N:20]3[CH2:24][C@H:23]([CH2:25][OH:26])[O:22][C:21]3=[O:27])=[CH:16][C:15]=2[F:28])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].O[C:30]1[CH:34]=[CH:33][O:32][N:31]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.CC(OC(/N=N/C(OC(C)C)=O)=O)C>O1CCCC1>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]([C:14]2[CH:19]=[CH:18][C:17]([N:20]3[CH2:24][C@H:23]([CH2:25][O:26][C:30]4[CH:34]=[CH:33][O:32][N:31]=4)[O:22][C:21]3=[O:27])=[CH:16][C:15]=2[F:28])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)N1CCN(c2ccc(N3C[C@H](CO)OC3=O)cc2F)CC1
Reactant: Oc1ccon1
Agent: CC(C)OC(=O)/N=N/C(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1CCN(c2ccc(N3C[C@H](COc4ccon4)OC3=O)cc2F)CC1
Reaction time: 2 h
Yield: 87.2 %

Procedure:
3-(4-(4-t-Butoxycarbonyl-piperazin-1-yl)-3-fluorophenyl)-5(R)-hydroxymethyloxazolidin-2-one (WO 93/23384; 10 g, 25.3 mmol), 3-hydroxyisoxazole (2.58 g, 30 mmol), and triphenylphosphine (9.95 g, 37.8 mmol) were dissolved in anhydrous tetrahydrofuran (300 ml), and cooled under nitrogen to 4°. Diisopropylazodicarboxylate (6.04 g, 30 mmol) was added dropwise over 10 minutes, and stirring was continued at the same temperature for 2 hours. The mixture was evaporated to dryness, and the residue purified by flash chromatography on silica, eluting with 50% EtOAc in isohexane. Relevant fractions were combined and evaporated to give the desired product (10.2 g).
Reaction SMILES: [Br:1][C:2]1[C:3]([CH3:9])=[CH:4][C:5](=[O:8])[NH:6][CH:7]=1.C([O-])([O-])=O.[K+].[K+].[C:16]([O:20][CH3:21])(=[O:19])[CH:17]=[CH2:18]>CN(C=O)C>[Br:1][C:2]1[C:3]([CH3:9])=[CH:4][C:5](=[O:8])[N:6]([CH2:18][CH2:17][C:16]([O:20][CH3:21])=[O:19])[CH:7]=1
Reactant: Cc1cc(=O)[nH]cc1Br
Reactant: C=CC(=O)OC
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: COC(=O)CCn1cc(Br)c(C)cc1=O
Temperature: 80 °C
Reaction time: 1 h

Procedure:
To a solution of 5-bromo-4-methylpyridin-2(1H)-one (1.0 g, 5.3 mmol) in DMF (10 mL), K2CO3 (1.5 g, 10.6 mmol) was added, followed by addition of methyl acrylate (0.91 g, 10.6 mmol) at 80° C. The mixture was stirred at 80° C. for 1 h. The mixture was allowed to cool to room temperature and then partitioned between ethyl acetate and water. The organic layer was washed with brine, dried over Na2SO4, filtered and concentrated in vacuo. The residue was used directly in the next step without further purification.
Reaction SMILES: [CH:1]1([CH2:6][CH:7]([C:18]2[NH:19][C:20]([C:23]([CH:25]3[CH2:27][CH2:26]3)=[O:24])=[CH:21][N:22]=2)[C:8]2[CH:13]=[CH:12][C:11]([S:14]([CH3:17])(=[O:16])=[O:15])=[CH:10][CH:9]=2)[CH2:5][CH2:4][CH2:3][CH2:2]1.[Br:28]N1C(=O)CCC1=O>CN(C)C=O.C(OCC)(=O)C>[Br:28][C:21]1[N:22]=[C:18]([CH:7]([C:8]2[CH:9]=[CH:10][C:11]([S:14]([CH3:17])(=[O:16])=[O:15])=[CH:12][CH:13]=2)[CH2:6][CH:1]2[CH2:2][CH2:3][CH2:4][CH2:5]2)[NH:19][C:20]=1[C:23]([CH:25]1[CH2:27][CH2:26]1)=[O:24]
Reactant: O=C1CCC(=O)N1Br
Reactant: CS(=O)(=O)c1ccc(C(CC2CCCC2)c2ncc(C(=O)C3CC3)[nH]2)cc1
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CS(=O)(=O)c1ccc(C(CC2CCCC2)c2nc(Br)c(C(=O)C3CC3)[nH]2)cc1
Temperature: 50 °C
Reaction time: 16 h
Yield: 56.8 %

Procedure:
To a solution (5 mL) of (2-{2-cyclopentyl-1-[4-(methylsulfonyl)phenyl]ethyl}-1H-imidazol-5-yl)(cyclopropyl)methanone (0.038 g) in N,N-dimethylformamide was added N-bromosuccinimide (0.024 g) and the mixture was stirred at 50° C. for 16 hr. The reaction mixture was diluted with ethyl acetate, washed successively with water and saturated brine, dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate:hexane=10:90-50:50, volume ratio) and recrystallized from diisopropyl ether-hexane to give the title compound (0.026 g, yield 56%) as colorless crystals. melting point 160-161° C.
Reaction SMILES: [C:1]1([C:7]2[CH:13]=[C:12]([OH:14])[CH:11]=[CH:10][C:8]=2[OH:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.O.[C:16](O)(=[O:18])[CH3:17]>>[C:16]([C:11]1[CH:10]=[C:8]([OH:9])[C:7]([C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)=[CH:13][C:12]=1[OH:14])(=[O:18])[CH3:17]
Reactant: Oc1ccc(O)c(-c2ccccc2)c1
Reactant: CC(=O)O
Solvent: O
Product: CC(=O)c1cc(O)c(-c2ccccc2)cc1O
Temperature: 80 °C

Procedure:
A suspension of 32.4 g of phenylhydroquinone in 30 ml of acetic acid was made. It was heated to 80° C. and boron trifluoride gas was bubbled through. After a reaction period of 4 h the reaction mixture was poured into water. The precipitation formed was suction-filtered and stirred in water whereto some sodium carbonate was added up to pH 8. The precipitate was suction-filtered again, washed with water, dried and recrystallized from toluene. Yield: 23 g of purified product. Melting point: 169° C.
Reaction SMILES: [CH3:1][C@H:2]([OH:5])[CH2:3][CH3:4].[H-].[Na+].F[C:9]1[CH:16]=[CH:15][C:14]([CH:17]=[O:18])=[CH:13][C:10]=1[C:11]#[N:12]>CN(C=O)C>[CH:17]([C:14]1[CH:15]=[CH:16][C:9]([O:5][C@@H:2]([CH3:1])[CH2:3][CH3:4])=[C:10]([CH:13]=1)[C:11]#[N:12])=[O:18]
Reactant: N#Cc1cc(C=O)ccc1F
Reactant: CC[C@H](C)O
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CC[C@H](C)Oc1ccc(C=O)cc1C#N
Temperature: 0 °C
Reaction time: 0.17 h
Yield: 8.3 %

Procedure:
(2S)-2-Butanol (0.99 g, 0.013 mol) was dissolved in DMF (50 ml) and the solution cooled to 0° C. To this was added sodium hydride, (60% dispersion in mineral oil, 1.54 g, 0.036 mol) in a portion-wise manner, the mixture was stirred at 0° C. for 10 minutes after complete addition. 2-Fluoro-5-formylbenzonitrile (2.0 g, 0.013 mol) was then added and the reaction mixture allowed to warm to room temperature (slowly within the ice bath) and the reaction mixture was stirred overnight at room temperature. The reaction mixture was then cooled to 0° C., quenched with brine and diluted with EtOAc (˜25 ml). The mixture was partitioned and the organic fraction extracted with water (˜30 ml), the combined organics were dried by passing through a phase separating cartridge and then evaporated to dryness under reduced pressure to give the crude product. The crude residue was purified on a 40+M Biotage cartridge, eluting with a 20 to 50% mixture of EtOAc in hexane. This gave the title compound (220 mg) as a white solid. MS (ES): C12H13NO2 requires 203; found 204 (MH+).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[C:7]([O:9][CH3:10])[CH:6]=[CH:5][C:4]=1[C:11]1[C:19]2[C:14](=[C:15]([C:20]([F:23])([F:22])[F:21])[CH:16]=[CH:17][CH:18]=2)[NH:13][N:12]=1.I[CH2:25][CH2:26][CH3:27]>>[CH3:1][O:2][C:3]1[CH:8]=[C:7]([O:9][CH3:10])[CH:6]=[CH:5][C:4]=1[C:11]1[N:12]([CH2:25][CH2:26][CH3:27])[N:13]=[C:14]2[C:19]=1[CH:18]=[CH:17][CH:16]=[C:15]2[C:20]([F:23])([F:22])[F:21]
Reactant: CCCI
Reactant: COc1ccc(-c2n[nH]c3c(C(F)(F)F)cccc23)c(OC)c1
Product: CCCn1nc2c(C(F)(F)F)cccc2c1-c1ccc(OC)cc1OC

Procedure:
Prepared according to Example 101 from 3-(2,4-dimethoxyphenyl)-7-(trifluoromethyl)-1H-indazole and 1-iodopropane.
Reaction SMILES: [OH:1][C:2]([CH3:25])([CH2:20][CH2:21][O:22][CH2:23][CH3:24])[CH:3]=[CH:4][CH:5]1[CH:9]([CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][C:16]([OH:18])=[O:17])[C:8](=[O:19])[CH2:7][CH2:6]1.[OH-].[Na+].[CH3:28]I>CN(P(N(C)C)(N(C)C)=O)C>[OH:1][C:2]([CH3:25])([CH2:20][CH2:21][O:22][CH2:23][CH3:24])[CH:3]=[CH:4][CH:5]1[CH:9]([CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][C:16]([O:18][CH3:28])=[O:17])[C:8](=[O:19])[CH2:7][CH2:6]1
Reactant: CCOCCC(C)(O)C=CC1CCC(=O)C1CCCCCCC(=O)O
Reactant: CI
Agent: [Na+]
Agent: [OH-]
Solvent: CN(C)P(=O)(N(C)C)N(C)C
Product: CCOCCC(C)(O)C=CC1CCC(=O)C1CCCCCCC(=O)OC
Temperature: 25 °C
Reaction time: 2 h

Procedure:
7-[5-(3-Hydroxy-3-methyl-5-ethoxypent-1-enyl)-2-oxocyclopentyl]heptanoic acid (0.24 g.) was diluted with hexamethylphosphotriamide (1.8 ml.) and treated with aqueous sodium hydroxide solution (25% w/v; 0.163 ml.). After stirring for two hours at room temperature, methyl iodide (0.177 ml.) was added and stirring continued for a further 24 hours. The reaction mixture was extracted twice with diethyl ether and the combined ethereal extracts were washed twice with water and dried over anhydrous sodium sulphate. Evaporation gave crude methyl 7-[5-(3-hydroxy-3-methyl-5-ethoxypent-1-enyl)-2-oxocyclopentyl]heptanoate (0.17 g.) as the residue. This was purified by preparative thin-layer chromatography on silica gel, using mixture of toluene, dioxan and acetic acid (65:15:1 by volume) as eluant, to give methyl 7-[5-(3-hydroxy-3-methyl-5-ethoxypent-1-enyl)-2-oxocyclopentyl]-heptanoate (30 mg.). Elemental analysis: found: C, 68.3; H, 10.1%; C21H36O5 requires: C, 68.5; H, 9.9%. N.M.R. (approximately 10% solution in deuterochloroform): triplet at 1.2δ (J=7 cycles/sec.), singlet at 1.3δ, multiplets at 1.0-2.0δ, 2.0-2.5δ, 3.2-3.75δ, singlet at 3.6δ, and multiplet at 5.6-5.8δ.