Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1][C:2]1[CH:23]=[C:22]([O:24][CH3:25])[C:5]2[N:6]([CH2:18][CH2:19][O:20][CH3:21])[C:7]([C:9]3[CH:14]=[CH:13][C:12]([CH:15]([CH3:17])[CH3:16])=[CH:11][CH:10]=3)=[N:8][C:4]=2[CH:3]=1.[I:26]N1C(=O)CCC1=O>C(#N)C>[I:26][C:3]1[C:4]2[N:8]=[C:7]([C:9]3[CH:14]=[CH:13][C:12]([CH:15]([CH3:17])[CH3:16])=[CH:11][CH:10]=3)[N:6]([CH2:18][CH2:19][O:20][CH3:21])[C:5]=2[C:22]([O:24][CH3:25])=[CH:23][C:2]=1[Br:1]
Reactant: COCCn1c(-c2ccc(C(C)C)cc2)nc2cc(Br)cc(OC)c21
Reactant: O=C1CCC(=O)N1I
Solvent: CC#N
Product: COCCn1c(-c2ccc(C(C)C)cc2)nc2c(I)c(Br)cc(OC)c21
Temperature: 25 °C
Yield: 62.5 %

Procedure:
A solution of 100 mg (0.248 mmol) 5-bromo-2-(4-isopropyl-phenyl)-7-methoxy-1-(2-methoxy-ethyl)-1H-benzoimidazole and 61 mg (0.273 mmol) N-iodosuccinimide in 3 ml acetonitrile is refluxed for 12 h. The reaction mixture is cooled to room temperature and concentrated in vacuo. The residue is purified by flash-chromatography on silica gel (hexane:EtOAc=4:1) and recrystallisation from hexane/diethyl ether afforded 82 mg of the title compound as colorless crystals.
Reaction SMILES: Cl.[NH2:2][C@H:3]1[CH2:7][CH2:6][CH2:5][C@@H:4]1[NH:8][C:9](=[O:22])[C:10]1[CH:15]=[C:14]([CH3:16])[CH:13]=[CH:12][C:11]=1[N:17]1[N:21]=[CH:20][CH:19]=[N:18]1.CCN(C(C)C)C(C)C.[Cl:32][C:33]1[CH:38]=[N:37][C:36](Cl)=[CH:35][N:34]=1.O>CN1C(=O)CCC1>[Cl:32][C:33]1[N:34]=[CH:35][C:36]([NH:2][C@H:3]2[CH2:7][CH2:6][CH2:5][C@@H:4]2[NH:8][C:9](=[O:22])[C:10]2[CH:15]=[C:14]([CH3:16])[CH:13]=[CH:12][C:11]=2[N:17]2[N:18]=[CH:19][CH:20]=[N:21]2)=[N:37][CH:38]=1
Reactant: Cc1ccc(-n2nccn2)c(C(=O)N[C@H]2CCC[C@@H]2N)c1
Reactant: Clc1cnc(Cl)cn1
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: O
Solvent: CN1CCCC1=O
Product: Cc1ccc(-n2nccn2)c(C(=O)N[C@H]2CCC[C@@H]2Nc2cnc(Cl)cn2)c1
Temperature: 180 °C

Procedure:
To a solution of N-[(1S,2S)-2-aminocyclopentyl]-5-methyl-2-(2H-1,2,3-triazol-2-yl)benzamide hydrochloride (Intermediate 7; 100 mg, 0.31 mmol) in NMP (1.0 ml) was added DIPEA (160 mg, 1.24 mmol) and 2,5-dichloropyrazine (CAS number 19745-07-4; 92 mg, 0.62 mmol). The resulting reaction mixture was stirred and heated under microwave irradiation at 180° C. for 15 minutes. Upon completion, the reaction mixture was poured into water (3 ml) and extracted with ethyl acetate (3×10 ml). The combined organics were dried over sodium sulfate and concentrated in vacuo. The crude product was purified by reverse phase preparative HPLC (eluted with acetonitrile/water containing 0.1% ammonia) to afford the title compound.
Reaction SMILES: [F:1][C:2]([F:16])([C:12]([F:15])([F:14])[F:13])[CH2:3][CH2:4][CH2:5][N:6]1[CH2:11][CH2:10][NH:9][CH2:8][CH2:7]1.CN(C)C=O.Cl[CH2:23][CH2:24][O:25][C:26]1[CH:31]=[CH:30][C:29]([CH:32]2[C:41]3[C:36](=[CH:37][C:38]([O:42][CH2:43][O:44][CH3:45])=[CH:39][CH:40]=3)[S:35][CH2:34][C:33]2([C:47]2[CH:52]=[CH:51][C:50]([O:53][CH2:54][O:55][CH3:56])=[CH:49][CH:48]=2)[CH3:46])=[CH:28][CH:27]=1>O>[CH3:45][O:44][CH2:43][O:42][C:38]1[CH:37]=[C:36]2[C:41]([CH:32]([C:29]3[CH:28]=[CH:27][C:26]([O:25][CH2:24][CH2:23][N:9]4[CH2:8][CH2:7][N:6]([CH2:5][CH2:4][CH2:3][C:2]([F:1])([F:16])[C:12]([F:13])([F:14])[F:15])[CH2:11][CH2:10]4)=[CH:31][CH:30]=3)[C:33]([C:47]3[CH:52]=[CH:51][C:50]([O:53][CH2:54][O:55][CH3:56])=[CH:49][CH:48]=3)([CH3:46])[CH2:34][S:35]2)=[CH:40][CH:39]=1
Reactant: COCOc1ccc(C2(C)CSc3cc(OCOC)ccc3C2c2ccc(OCCCl)cc2)cc1
Reactant: FC(F)(F)C(F)(F)CCCN1CCNCC1
Solvent: CN(C)C=O
Solvent: O
Product: COCOc1ccc(C2(C)CSc3cc(OCOC)ccc3C2c2ccc(OCCN3CCN(CCCC(F)(F)C(F)(F)F)CC3)cc2)cc1
Temperature: 80 °C
Reaction time: 8 h
Yield: 71.1 %

Procedure:
Under argon atmosphere 4-(4,4,5,5,5-pentafluoropentyl)piperazine (70 mg, 0.4 mmol) was added to dimethylformamide solution (0.5 ml) of (3RS,4RS)-4-[4-(2-chloroethyloxy)phenyl]-7-methoxymethyloxy-3-[4-(methoxymethyloxy)phenyl]-3-methyl-thiochroman (69 mg, 0.13 mmol) and then stirred for 8 hours at 80° C. After adding water, the reaction solution was extracted with ethyl acetate. The extract was distilled under reduced pressure to remove the solvent and the crude product thus obtained was then purified using amino silica gel plate (ethyl acetate:hexane=1:2) to obtain 67 mg (yield: 77%) of the title compound.
Reaction SMILES: [O:1]1[CH2:6][CH2:5][CH:4]([C:7]([C:9]2[S:13][C:12]([NH2:14])=[N:11][C:10]=2[C:15]2[O:16][CH:17]=[CH:18][CH:19]=2)=[O:8])[CH2:3][CH2:2]1.[F:20][C:21]([F:33])([F:32])[O:22][C:23]1[CH:31]=[CH:30][CH:29]=[CH:28][C:24]=1[C:25](Cl)=[O:26].O>CN(C1C=CN=CC=1)C.N1C=CC=CC=1>[O:16]1[CH:17]=[CH:18][CH:19]=[C:15]1[C:10]1[N:11]=[C:12]([NH:14][C:25](=[O:26])[C:24]2[CH:28]=[CH:29][CH:30]=[CH:31][C:23]=2[O:22][C:21]([F:20])([F:32])[F:33])[S:13][C:9]=1[C:7]([CH:4]1[CH2:5][CH2:6][O:1][CH2:2][CH2:3]1)=[O:8]
Reactant: Nc1nc(-c2ccco2)c(C(=O)C2CCOCC2)s1
Reactant: O=C(Cl)c1ccccc1OC(F)(F)F
Agent: CN(C)c1ccncc1
Solvent: O
Solvent: c1ccncc1
Product: O=C(Nc1nc(-c2ccco2)c(C(=O)C2CCOCC2)s1)c1ccccc1OC(F)(F)F
Temperature: 80 °C
Reaction time: 6 h

Procedure:
Compound 454 (125 mg, 0.450 mmol) and DMAP (0.022 mmol) were suspended in pyridine (2 mL), and 2-(trifluoromethoxy)benzoyl chloride (202 mg, 0.900 mmol) was added thereto, followed by stirring at 80° C. for 6 hours. The reaction mixture was poured into water, followed by extraction with ethyl acetate. The organic layer was washed with a saturated aqueous solution of sodium chloride and dried over anhydrous magnesium sulfate, and then the solvent was distilled away under reduced pressure. The resulting residue was recrystallized from ethanol to afford the entitled Compound 475 (111 mg, 53 as a pale yellow solid.
Reaction SMILES: [OH:1][CH2:2][CH2:3][O:4][C:5]1[CH:10]=[CH:9][C:8]([CH:11]2[CH2:16][CH2:15][N:14]([C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])[CH2:13][CH:12]2[O:24][CH2:25][C:26]2[CH:35]=[CH:34][C:33]3[C:28](=[CH:29][CH:30]=[CH:31][CH:32]=3)[CH:27]=2)=[CH:7][CH:6]=1.Cl[CH2:37][C:38]1[CH:43]=[CH:42][N:41]=[CH:40][CH:39]=1>>[CH:27]1[C:28]2[C:33](=[CH:32][CH:31]=[CH:30][CH:29]=2)[CH:34]=[CH:35][C:26]=1[CH2:25][O:24][CH:12]1[CH:11]([C:8]2[CH:9]=[CH:10][C:5]([O:4][CH2:3][CH2:2][O:1][CH2:37][C:38]3[CH:43]=[CH:42][N:41]=[CH:40][CH:39]=3)=[CH:6][CH:7]=2)[CH2:16][CH2:15][N:14]([C:17]([O:19][C:20]([CH3:23])([CH3:21])[CH3:22])=[O:18])[CH2:13]1
Reactant: ClCc1ccncc1
Reactant: CC(C)(C)OC(=O)N1CCC(c2ccc(OCCO)cc2)C(OCc2ccc3ccccc3c2)C1
Product: CC(C)(C)OC(=O)N1CCC(c2ccc(OCCOCc3ccncc3)cc2)C(OCc2ccc3ccccc3c2)C1

Procedure:
In an analogous manner to that described in Example 1 (g), by alkylating tert-butyl (3RS,4RS)-4-[4-(2-hydroxy-ethoxy)-phenyl]-3-(naphthalen-2-ylmethoxy)-piperidine-1-carboxylate [Example 53 (c)] with 4-chloromethyl-pyridine there was obtained tert-butyl (3RS,4RS)-3-(naphthalen-2-ylmethoxy)-4-{4-[2-(pyridin-4-ylmethoxy)-ethoxy)-phenyl}-piperidine-1-carboxylate as a colourless oil.
Reaction SMILES: [H-].[Na+].C[C:4]1([CH3:11])O[C@H:7]([CH2:9]O)[CH2:6][O:5]1.C(Br)C[CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH3:29].O>C1COCC1>[CH2:6]([O:5][CH2:4][CH2:11][CH2:29][CH2:28][CH2:27][CH2:26][CH2:25][CH2:24][CH2:23][CH2:22][CH2:21][CH2:20][CH2:19][CH2:18][CH2:17][CH2:16][CH2:15][CH3:14])[CH2:7][CH2:9][CH2:28][CH2:27][CH2:26][CH2:25][CH2:24][CH2:23][CH2:22][CH2:21][CH2:20][CH2:19][CH2:18][CH2:17][CH2:16][CH2:15][CH3:14]
Reactant: CCCCCCCCCCCCCCCCCCBr
Reactant: CC1(C)OC[C@@H](CO)O1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: CCCCCCCCCCCCCCCCCCOCCCCCCCCCCCCCCCCCC
Temperature: 80 °C
Reaction time: 8 h
Yield: 60.7 %

Procedure:
To a stirred suspension of NaH (80%; 0.55 g, 17.4 mmol, 2 equiv) in THF (20 ml) was added dropwise a solution of (R)-glycerol acetonide 1 (1.15 g; 1 equiv) in THF (20 ml). After that octadecyl bromide (5.8 g, 17.4 mmol, 2 equiv) dissolved in THF (25 ml) was added dropwise and the mixture obtained was stirred overnight at 80° C. The reaction mixture was cooled to 0° C. and water was added. The resulting mixture was concentrated and the residue was extracted with water and diethyl ether and the combined extracts were dried (MgSO4). The crude product obtained was further purified by flash column chromatography (10% ethyl acetate-n-hexane) to yield the title compound 1b (2.03 g, 5.28 mmol, 61%).
Reaction SMILES: Br[C:2]1[CH:3]=[N+:4]([O-:11])[CH:5]=[CH:6][C:7]=1[N+:8]([O-:10])=[O:9].[NH:12]1[CH2:17][CH2:16][CH2:15][CH2:14][CH2:13]1>C(O)C>[N+:8]([C:7]1[CH:6]=[CH:5][N+:4]([O-:11])=[CH:3][C:2]=1[N:12]1[CH2:17][CH2:16][CH2:15][CH2:14][CH2:13]1)([O-:10])=[O:9]
Reactant: C1CCNCC1
Reactant: O=[N+]([O-])c1cc[n+]([O-])cc1Br
Solvent: CCO
Product: O=[N+]([O-])c1cc[n+]([O-])cc1N1CCCCC1
Yield: 92 %

Procedure:
3-bromo-4-nitropyridine-N-oxide (1.0 equiv.) and piperidine (2.0 equiv.) in ethanol, at a concentration of 0.2 M, was heated at reflux for 16 hours. Upon cooling the ethanol was removed in vacuo. The residue was partitioned between EtOAc and Na2CO3(sat), and washed further with H2O, NaCl(sat.), was dried over MgSO4, was filtered and the volatiles were removed in vacuo yielding 4-nitro-3-(piperidin-1-yl)pyridine 1-oxide (92%). LCMS (m/z): 224.0 (MH+); LC Rt=2.48 min.
Reaction SMILES: [CH:1]1([C:6]2[CH:7]=[C:8]([NH2:11])[NH:9][N:10]=2)[CH2:5][CH2:4][CH2:3][CH2:2]1.[CH2:12]([O:14][C:15](=[O:26])[C:16](=[CH:22]OCC)[C:17](OCC)=[O:18])[CH3:13]>C(O)(=O)C>[CH2:12]([O:14][C:15]([C:16]1[C:17](=[O:18])[N:9]2[N:10]=[C:6]([CH:1]3[CH2:2][CH2:3][CH2:4][CH2:5]3)[CH:7]=[C:8]2[NH:11][CH:22]=1)=[O:26])[CH3:13]
Reactant: Nc1cc(C2CCCC2)n[nH]1
Reactant: CCOC=C(C(=O)OCC)C(=O)OCC
Solvent: CC(=O)O
Product: CCOC(=O)c1c[nH]c2cc(C3CCCC3)nn2c1=O
Temperature: 120 °C
Yield: 70.2 %

Procedure:
To a solution of 5-cyclopentyl-2H-pyrazol-3-ylamine (510 mg, 3.4 mmol, 1 eq) in acetic acid (4.8 mL) was added 2-ethoxymethylene-malonic acid diethyl ester (750 μL, 3.7 mmol, 1.1 eq). The mixture was heated at 120° C. for 3 h in a sealed tube. After cooling, the precipitate was filtered and washed with ethanol and diethyl ether and recrystallised from methanol to afford the expected compound as white powder (657 mg, 71% yield).
Reaction SMILES: [NH:1]1[C:5]2[CH:6]=[C:7]([N:10]3[CH:14]([C:15]4[CH:20]=[CH:19][CH:18]=[C:17]([F:21])[C:16]=4[F:22])[C:13]([CH3:23])=[C:12]([O:24][CH3:25])[C:11]3=[O:26])[CH:8]=[CH:9][C:4]=2[N:3]=[CH:2]1.C([O-])(=O)C.[NH4+]>CO>[NH:1]1[C:5]2[CH:6]=[C:7]([N:10]3[C@@H:14]([C:15]4[CH:20]=[CH:19][CH:18]=[C:17]([F:21])[C:16]=4[F:22])[C:13]([CH3:23])=[C:12]([O:24][CH3:25])[C:11]3=[O:26])[CH:8]=[CH:9][C:4]=2[N:3]=[CH:2]1
Reactant: COC1=C(C)C(c2cccc(F)c2F)N(c2ccc3nc[nH]c3c2)C1=O
Agent: CC(=O)[O-]
Agent: [NH4+]
Solvent: CO
Product: COC1=C(C)[C@H](c2cccc(F)c2F)N(c2ccc3nc[nH]c3c2)C1=O

Procedure:
20 mg/5 ml of 1-(1H-benzo[d]imidazol-6-yl)-5-(2,3-difluorophenyl)-3-methoxy-4-methyl-1H-pyrrol-2(5H)-one (which may be prepared in accordance with Example 8) were subjected to semi-prep chiral chromatography on a 250/21 Chirobiotic Tag (Supplier: Supelco), 5p, detection: UV @ 214 nm, Mobile phase: 40% Ammonium acetate buffer (pH 4.0, 40 mM)/60% MeOH, isocratic, 10 ml/min, r.t., yield 8 mg as second eluting enantiomer, optical rotation c=0.5g/100 ml (MeOH) αD20=214.1°
Reaction SMILES: O[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][C:7]1[CH:11]=[C:10]([CH3:12])[O:9][N:8]=1.[Br:13]Br.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>>[Br:13][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][C:7]1[CH:11]=[C:10]([CH3:12])[O:9][N:8]=1
Reactant: BrBr
Reactant: Cc1cc(CCCCCO)no1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Product: Cc1cc(CCCCCBr)no1
Yield: 77 %

Procedure:
3-(5-Bromopentyl)-5-methylisoxazole was prepared by reacting 3-(5-hydroxypentyl)-5-methylisoxazole with bromine and triphenylphosphine according to the procedure of part (f) above, and was obtained in 77% yield as an oil, b.p. 140°-150° C.(0.05 mm).
Reaction SMILES: [C:1]([C:5]1[N:6]=[C:7]([N:16]2[CH2:20][CH2:19][C:18]([F:22])([F:21])[CH2:17]2)[C:8]2[N:13]=[N:12][N:11]([CH2:14][CH3:15])[C:9]=2[N:10]=1)([CH3:4])([CH3:3])[CH3:2].C(C1N=C(N2CCC(F)(F)C2)C2N=NNC=2N=1)(C)(C)C.BrCC[C:46]1[CH:51]=[CH:50][CH:49]=[CH:48][CH:47]=1>>[C:1]([C:5]1[N:6]=[C:7]([N:16]2[CH2:20][CH2:19][C:18]([F:21])([F:22])[CH2:17]2)[C:8]2[N:13]=[N:12][N:11]([CH2:14][CH2:15][C:46]3[CH:51]=[CH:50][CH:49]=[CH:48][CH:47]=3)[C:9]=2[N:10]=1)([CH3:2])([CH3:3])[CH3:4]
Reactant: CCn1nnc2c(N3CCC(F)(F)C3)nc(C(C)(C)C)nc21
Reactant: BrCCc1ccccc1
Agent: CC(C)(C)c1nc(N2CCC(F)(F)C2)c2nn[nH]c2n1
Product: CC(C)(C)c1nc(N2CCC(F)(F)C2)c2nnn(CCc3ccccc3)c2n1

Procedure:
In analogy to the procedure described for the synthesis of 5-tert-butyl-7-(3,3-difluoro-pyrrolidin-1-yl)-3-ethyl-3H-[1,2,3]triazolo[4,5-d]pyrimidine (example 61), the title compound was prepared from 5-tert-butyl-7-(3,3-difluoropyrrolidin-1-yl)-3H-[1,2,3]triazolo[4,5-d]pyrimidine and (2-bromoethyl)benzene and isolated as light-yellow gum (4.8 mg, 30%). MS (m/e): 387.4 (MH+).
Reaction SMILES: I[CH2:2][CH2:3][CH2:4][C:5]([O:7]C)=[O:6].[NH:9]1[CH2:13][CH2:12][CH2:11][CH2:10]1.[ClH:14]>C1C=CC=CC=1>[ClH:14].[N:9]1([CH2:2][CH2:3][CH2:4][C:5]([OH:7])=[O:6])[CH2:13][CH2:12][CH2:11][CH2:10]1
Reactant: COC(=O)CCCI
Reactant: C1CCNC1
Agent: Cl
Solvent: c1ccccc1
Product: O=C(O)CCCN1CCCC1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
30.0 g. (0.13 mole) of Methyl γ-iodobutyrate (F.F. Blicke, W.B. Wright and M.F. Zienty, J. Amer. Chem. Soc. 63, 2488 (1941) was combined with 36 g. of pyrrolidine (Aldrich) in 300 ml. of benzene, heated at 60° for 0.5 hour and stirred at room temperature for 16 hours. A dark orange layer formed. The benzene solution was decanted, concentrated and distilled (b.p. 100° at 15 mm Hg) to give 10 g. of colorless liquid. The infrared and nmr spectra indicated that product to be methyl Γ-pyrrolidinobutyrate. This material was dissolved in 100 ml. of 18% hydrochloric acid and heated at reflux for 28 hours. The solution was concentrated under reduced pressure to give a semi-solid which was triturated with acetone and filtered. Recrystallization from acetic acid/acetone gave 8.3 g. (33%) of the desired acid hydrochloride as colorless crystals, m.p. 126°-127°. The infrared and nmr spectra are consistent with the proposed structure.
Reaction SMILES: [N+:1]([C:4]1[CH:12]=[CH:11][CH:10]=[CH:9][C:5]=1[CH2:6][CH2:7][OH:8])([O-])=O.O1CC[CH2:15][CH2:14]1>>[NH:1]1[C:4]2[C:12](=[CH:11][CH:10]=[CH:9][C:5]=2[CH2:6][CH2:7][OH:8])[CH:15]=[CH:14]1
Reactant: O=[N+]([O-])c1ccccc1CCO
Reactant: C1CCOC1
Product: OCCc1cccc2cc[nH]c12
Temperature: 15 °C
Reaction time: 2 h

Procedure:
Dissolve the brown oil in tetrahydrofuran (500 mL), add distilled water (100 mL), and cool the mixture to 15° C. Add 1M aqueous hydrochloric acid (100 mL), then stir at 15° C. for 2 hours. Add solid sodium hydrogen carbonate until the reaction mixture is basic, and saturate by adding solid sodium chloride. Separate, filter, and concentrate under reduced pressure to obtain 9.3 of a brown oil, which is a mixture of the title compound and 2-nitrophenethyl alcohol.
Reaction SMILES: Cl.[S:2]1[C:6]2[CH:7]=[CH:8][CH:9]=[CH:10][C:5]=2[N:4]=[C:3]1[C:11]1[CH2:12][CH2:13][NH:14][CH2:15][CH:16]=1.[Cl:17][C:18]1[CH:25]=[CH:24][C:21]([CH2:22]Br)=[CH:20][CH:19]=1>>[S:2]1[C:6]2[CH:7]=[CH:8][CH:9]=[CH:10][C:5]=2[N:4]=[C:3]1[C:11]1[CH2:12][CH2:13][N:14]([CH2:22][C:21]2[CH:24]=[CH:25][C:18]([Cl:17])=[CH:19][CH:20]=2)[CH2:15][CH:16]=1
Reactant: C1=C(c2nc3ccccc3s2)CCNC1
Reactant: Clc1ccc(CBr)cc1
Agent: Cl
Product: Clc1ccc(CN2CC=C(c3nc4ccccc4s3)CC2)cc1
Yield: 60.1 %

Procedure:
4-(Benzothiazol-2-yl)-1,2,3,6-tetrahydropyridine hydrochloride (520 mg, 2 mmol) was reacted with 4-chlorobenzyl bromide (507 mg, 2.4 mmol) as exemplified in Example 1. The crude product was recrystallised from dichloromethane and methanol to afford the title compound as a yellow solid (410 mg, 60%); (Found: C, 66.70; H, 4.87; N, 8.16. C19H17ClN2S requires C, 66.95; H, 5.03; N, 8.22%). δH (CDCl3), 2.74 (2H, m, NCH2CH2), 2.83 (2H, m, NCH2 CH2), 3.22 (2H, m, NCH2CH2), 3.63 (2H, s, NCH2Ar), 6.67 (1H, m, NCH2CH), 7.31 (4H, s, ArH), 7.34 (1H, d of t, J 8.1Hz, J 1.2Hz, ArH), 7.44 (1H, d of t, J 7.4Hz, J 1.2Hz, ArH), 7.82 (1H, d, J 7.8Hz, ArH), 7.97 (1H, d, J 8.1Hz, ArH). m/z (ES+) 341 (M+1)+.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1B(O)O.Br[C:13]1[CH:14]=[CH:15][C:16]([F:22])=[C:17]([N+:19]([O-:21])=[O:20])[CH:18]=1.C(=O)([O-])[O-].[Na+].[Na+]>C1(C)C=CC=CC=1.C(O)C.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[F:22][C:16]1[CH:15]=[CH:14][C:13]([C:4]2[CH:5]=[CH:6][CH:7]=[CH:8][C:3]=2[O:2][CH3:1])=[CH:18][C:17]=1[N+:19]([O-:21])=[O:20]
Reactant: COc1ccccc1B(O)O
Reactant: O=[N+]([O-])c1cc(Br)ccc1F
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: Cc1ccccc1
Solvent: CCO
Product: COc1ccccc1-c1ccc(F)c([N+](=O)[O-])c1

Procedure:
Tetrakis(triphenylphosphine)palladium (1 g) was added to a mixture of 5 g of 2-methoxyphenylboronic acid, 6.6 g of 5-bromo-2-fluoronitrobenzene and 30 mL of 2 M sodium carbonate solution in 50 mL of toluene and 50 mL of ethanol. The mixture was refluxed for 2 hours, concentrated, and the residue extracted twice with ethyl acetate. The ethyl acetate layer was washed with water and brine, dried, and concentrated to give a dark green oil which solidified on standing to give crude 4-fluoro-2′-methoxy-3-nitrobiphenyl.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([C:7]([O:9][CH2:10][CH3:11])=[O:8])[NH:5][CH:6]=1.ClS([N:16]=[C:17]=O)(=O)=O>C(#N)C>[Br:1][C:2]1[CH:3]=[C:4]([C:7]([O:9][CH2:10][CH3:11])=[O:8])[NH:5][C:6]=1[C:17]#[N:16]
Reactant: O=C=NS(=O)(=O)Cl
Reactant: CCOC(=O)c1cc(Br)c[nH]1
Solvent: CC#N
Product: CCOC(=O)c1cc(Br)c(C#N)[nH]1
Temperature: 25 °C
Reaction time: 17 h
Yield: 74.4 %

Procedure:
To a cooled (0° C.) solution of ethyl 4-bromo-1H-pyrrole-2-carboxylate (Belanger, P. Tetrahedron Lett. 1979, 20, 2505) (9.50 g, 43.6 mmol) in acetonitrile (200 mL) was added chlorosulfonyl isocyanate (3.87 mL, 43.6 mmol), drop wise. The reaction was allowed to warm to rt and stir for 17 h. The reaction was quenched with the addition of DMF (17 mL) and the reaction was heated (50° C.) for 2 h then cooled to rt and stirred an additional 2 h. The mixture was poured over ice water (500 mL) and was extracted with ethyl acetate (3×250 mL). The combined organics were washed with brine, dried (Na2SO4) and concentrated. The crude material was purified via flash chromatography on silica gel eluting with 10% to 25% ethyl acetate in hexanes to afford 7.88 g (74%) of the desired product. 1H NMR (300 MHz, DMSO-d6) δ 13.77 (br s, 1 H), 7.01 (s, 1 H), 4.28 (q, 2 H), 1.29 (t, 3 H).
Reaction SMILES: C1C=C[NH+]=CC=1.Br[Br-]Br.[CH3:10][C:11]1[NH:12][C:13](C)=[C:14]([C:27]([O:29][CH3:30])=[O:28])[CH:15]([C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[C:16]=1[C:17]([O:19][CH3:20])=[O:18].N1C=CC=CC=1>C(O)C.C(Cl)(Cl)Cl>[CH3:10][C:11]1[NH:12][C:13]2[CH2:30][O:29][C:27](=[O:28])[C:14]=2[CH:15]([C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[C:16]=1[C:17]([O:19][CH3:20])=[O:18]
Reactant: COC(=O)C1=C(C)NC(C)=C(C(=O)OC)C1c1ccccc1
Agent: c1cc[nH+]cc1
Solvent: c1ccncc1
Solvent: CCO
Solvent: ClC(Cl)Cl
Product: COC(=O)C1=C(C)NC2=C(C(=O)OC2)C1c1ccccc1
Temperature: 0 °C
Reaction time: 0.75 h
Yield: 62.8 %

Procedure:
1.58 grams of 80 percent pyridinium bromide perbromide (3.95 millimoles) was added in one portion to a cooled to 0° C. solution of 1.00 gram (3.32 millimoles) of dimethyl 2,6-dimethyl-4-phenyl-1,4-dihydropyridine-3,5-dicarboxylate and 0.4 milliliter of pyridine in 20 milliliters of dry ethanol-free chloroform. The resulting mixture was stirred for 45 minutes at 0° C. and then heated at reflux temperature for 1.3 hous. Thereafter, the mixture was cooled to room temperature, diluted with chloroform and the resulting solution washed successively with 2N hydrochloric acid and brine, dried over magnesium sulfate, and dried solution filtered to remove the drying agent, and then subjected to reduce pressure to vaporize the solvent and to recover as residue 1.41 grams of product as a yellow oil. The oil was chromatographed on silica gel using 70 percent ethyl acetate--30 percent hexane as eluant to obtain 595 milligrams (63 percent yield) of purified methyl 2-methyl-4-phenyl-5-oxo-1,4,5,7-tetrahydrofuro[3,4-b]-pyridine-3-carboxylate product which after recrystallization from ethyl acetate-hexane and drying at 60° C. at 0.005 millimeters mercury pressure for 17 hours had a melting point of 193°-196° C. Elemental analyses for the product were as follows:
Reaction SMILES: [Cl:1][C:2]1[C:3]2[C:10]([C:11]3[CH:12]=[C:13]([CH:16]=[CH:17][CH:18]=3)[C:14]#[N:15])=[CH:9][N:8](CO)[C:4]=2[N:5]=[CH:6][N:7]=1.C(=O)([O-])[O-].[K+].[K+]>CO>[Cl:1][C:2]1[C:3]2[C:10]([C:11]3[CH:12]=[C:13]([CH:16]=[CH:17][CH:18]=3)[C:14]#[N:15])=[CH:9][NH:8][C:4]=2[N:5]=[CH:6][N:7]=1
Reactant: N#Cc1cccc(-c2cn(CO)c3ncnc(Cl)c23)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CO
Product: N#Cc1cccc(-c2c[nH]c3ncnc(Cl)c23)c1

Procedure:
A solution of 3-[4-chloro-7-(hydroxymethyl)-7H-pyrrolo[2,3-d]pyrimidin-5-yl]benzonitrile (C13) (4 g from the previous step, ≦9.9 mmol) in methanol (100 mL) was adjusted to pH>12 by addition of solid potassium carbonate. Solvent was removed in vacuo and the residue was mixed with water (100 mL). The resulting solid was isolated via filtration and washed with water, providing the product as a white solid. Yield: 1.3 g, 5.1 mmol, 52% over two steps. LCMS m/z 255.0 [M+H+].
Reaction SMILES: C([O:3][C:4]([CH2:6][C:7]1([NH:17][C:18]([CH2:20][C:21]2[CH:26]=[CH:25][C:24]([CH3:27])=[CH:23][CH:22]=2)=[O:19])[C:15]2[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=2)[NH:9][C:8]1=[O:16])=[O:5])C.[OH-].[K+]>C(O)C>[OH:5][C:4]([CH2:6][C:7]1([NH:17][C:18]([CH2:20][C:21]2[CH:22]=[CH:23][C:24]([CH3:27])=[CH:25][CH:26]=2)=[O:19])[C:15]2[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=2)[NH:9][C:8]1=[O:16])=[O:3]
Reactant: CCOC(=O)CC1(NC(=O)Cc2ccc(C)cc2)C(=O)Nc2ccccc21
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Product: Cc1ccc(CC(=O)NC2(CC(=O)O)C(=O)Nc3ccccc32)cc1
Reaction time: 4 h

Procedure:
To a solution of 0.29 g of (RS)-3-(ethoxycarbonylmethyl)-3-((4-methylbenzyl)carbonylamino)indolin-2-one in 10 ml of ethanol was added 2 ml of an aqueous solution of 0.16 g of potassium hydroxide (85%) at room temperature, and the mixture was stirred for 4 hours, followed by concentration. The concentrate was diluted with water, and washed with chloroform. The aqueous layer was adjusted to pH 2 by addition of 2N hydrochloric acid and extracted with ethyl acetate. The organic layer was dried over sodium sulfate and concentrated to obtain (RS)-3-(hydroxycarbonylmethyl)-3-((4-methylbenzyl)carbonylamino)indolin-2-one.