Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [O:1]=[CH:2][CH2:3][CH2:4][C@H:5]1[CH2:10][CH2:9][C@H:8]([C:11]2[CH:16]=[CH:15][C:14]([C:17]3[CH:22]=[CH:21][C:20]([C:23]#[N:24])=[CH:19][CH:18]=3)=[CH:13][CH:12]=2)[CH2:7][CH2:6]1.[BH4-].[Na+]>CO.CCOCC>[OH:1][CH2:2][CH2:3][CH2:4][C@H:5]1[CH2:6][CH2:7][C@H:8]([C:11]2[CH:16]=[CH:15][C:14]([C:17]3[CH:18]=[CH:19][C:20]([C:23]#[N:24])=[CH:21][CH:22]=3)=[CH:13][CH:12]=2)[CH2:9][CH2:10]1
Reactant: N#Cc1ccc(-c2ccc([C@H]3CC[C@H](CCC=O)CC3)cc2)cc1
Agent: [BH4-]
Agent: [Na+]
Solvent: CCOCC
Solvent: CO
Product: N#Cc1ccc(-c2ccc([C@H]3CC[C@H](CCCO)CC3)cc2)cc1

Procedure:
A solution of 12 g of trans-4′-[4-(3-oxo-propyl)-cyclohexyl]-biphenyl-4-carbonitrile (preparation: Mol. Cryst. Liq. Cryst. 1985, Vol. 131, 327) in 100 ml methanol/ether (9:1) was added dropwise at 0° C. within 5 minutes to a suspension of 1.39 g of sodium borohydride in 30 ml of methanol/ether (9:1). After 45 minutes a further 1 g of sodium borohydride was added. After a further hour the reaction was interrupted and the mixture was partitioned between methylene chloride and 1N hydrochloric acid. Thereupon, the organic phase was washed several times with water, dried over magnesium sulphate, filtered and evaporated. Crystallization from ethyl acetate/methylene chloride gave 11.5 g of trans-4′-[4-(3-hydroxy-propyl)-cyclohexyl]-biphenyl-4-carbonitrile as yellowish crystals.
Reaction SMILES: [CH3:1][N:2]1[C:14]2[C:13](=[O:15])[C:12]3[CH:11]=[C:10]([N+:16]([O-])=O)[CH:9]=[CH:8][C:7]=3[NH:6][C:5]=2[CH:4]=[N:3]1.P(Cl)(Cl)(Cl)=O>>[NH:16]([C:10]1[CH:9]=[CH:8][C:7]2[NH:6][C:5]3[CH:4]=[N:3][N:2]([CH3:1])[C:14]=3[C:13](=[O:15])[C:12]=2[CH:11]=1)[C:7]1[CH:8]=[CH:9][CH:10]=[CH:11][CH:12]=1
Reactant: Cn1ncc2[nH]c3ccc([N+](=O)[O-])cc3c(=O)c21
Solvent: O=P(Cl)(Cl)Cl
Product: Cn1ncc2[nH]c3ccc(Nc4ccccc4)cc3c(=O)c21
Yield: 135.2 %

Procedure:
A mixture of 1-methyl-7-nitro-1,4-dihydro-9H-pyrazolo[4,3-b]-quinolin-9-one ((Stepanov et. al., Chem. Heterocycl. Compd. (Engl. Transl.), 1985, 21, 905), 0.13 g, 0.53 mmol) and phosphorus oxychloride (3 ml) was refluxed for 3 h. After evaporation, the obtained residue was dissolved in ethyl acetate (100 ml), washed with saturated sodium bicarbonate (50 ml) and dried over sodium sulfate. Removal of solvent gave a residue which was chromatographed on a column of silica gel eluting with ethyl acetate/dichloromethane/hexane (1:4:4) to give 104 mg (78%) of the title compound as a solid.
Reaction SMILES: [C:1]([C:3]1[CH:19]=[CH:18][C:17]([O:20][CH2:21][C:22]2[CH:26]=[CH:25][S:24][CH:23]=2)=[CH:16][C:4]=1[O:5][CH:6]([C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)[C:7]([OH:9])=O)#[N:2].C(=O)=O.[CH:30]([C:33]1[CH:38]=[CH:37][C:36]([S:39]([NH2:42])(=[O:41])=[O:40])=[CH:35][CH:34]=1)([CH3:32])[CH3:31].[H-].[Na+]>ClCCl.CN(C)C=O>[C:1]([C:3]1[CH:19]=[CH:18][C:17]([O:20][CH2:21][C:22]2[CH:26]=[CH:25][S:24][CH:23]=2)=[CH:16][C:4]=1[O:5][CH:6]([C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)[C:7]([NH:42][S:39]([C:36]1[CH:37]=[CH:38][C:33]([CH:30]([CH3:32])[CH3:31])=[CH:34][CH:35]=1)(=[O:40])=[O:41])=[O:9])#[N:2]
Reactant: N#Cc1ccc(OCc2ccsc2)cc1OC(C(=O)O)c1ccccc1
Reactant: CC(C)c1ccc(S(N)(=O)=O)cc1
Agent: O=C=O
Agent: [H-]
Agent: [Na+]
Solvent: ClCCl
Solvent: CN(C)C=O
Product: CC(C)c1ccc(S(=O)(=O)NC(=O)C(Oc2cc(OCc3ccsc3)ccc2C#N)c2ccccc2)cc1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A solution of Example 2 (0.73 g) in dry dichloromethane (50 ml) was treated with N,N' carbonyidilmidazole (0.36 g) and stirred at 25° C. for 2 hours, when evolution of carbon dioxide was complete. A solution of 4-isopropylbenzenesulphonamide (0.60 g) in dry dimethylformamide (20 ml) was treated with sodium hydride (0.13 g, 60% dispersion in mineral oil) and stirred at 25° C. for 2 hours. This solution was then treated dropwise with the solution of acylimidazole prepared above and stirring was continued at 25° C. for 8 hours. The reaction mixture was evaporated, the residue diluted with water (50 ml) and extracted twice with ethyl acetate. The extracts were washed with water, dried and evaporated to give an orange oil which was purified by flash chromatography on silica eluting with ether. Fractions homogenous in the required product were combined and evaporated. The residual pale yellow solid (0.35 g) was recrystallized from a mixture of ethyl acetate and pentane affording the title compound (0.20 g) as colourless crystals, m.p. 187-189° C. [Elemental analysis:- C,63.7; H,4.79; N,5.12%. Calculated:- C,63.7; H,5.17; N,5.17%].
Reaction SMILES: N12CCCN=C1CCCCC2.Cl.[NH2:13][CH2:14][C:15]1[CH:23]=[CH:22][CH:21]=[C:20]2[C:16]=1[CH2:17][N:18]([CH:25]1[CH2:30][CH2:29][C:28](=[O:31])[NH:27][C:26]1=[O:32])[C:19]2=[O:24].[C:33]([NH:40][CH2:41][CH2:42][CH2:43][C:44](O)=[O:45])([O:35][C:36]([CH3:39])([CH3:38])[CH3:37])=[O:34].Cl.CN(C)CCCN=C=NCC>CN(C=O)C>[C:36]([O:35][C:33](=[O:34])[NH:40][CH2:41][CH2:42][CH2:43][C:44](=[O:45])[NH:13][CH2:14][C:15]1[CH:23]=[CH:22][CH:21]=[C:20]2[C:16]=1[CH2:17][N:18]([CH:25]1[CH2:30][CH2:29][C:28](=[O:31])[NH:27][C:26]1=[O:32])[C:19]2=[O:24])([CH3:39])([CH3:37])[CH3:38]
Reactant: CC(C)(C)OC(=O)NCCCC(=O)O
Reactant: NCc1cccc2c1CN(C1CCC(=O)NC1=O)C2=O
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: C1CCC2=NCCCN2CC1
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)NCCCC(=O)NCc1cccc2c1CN(C1CCC(=O)NC1=O)C2=O
Reaction time: 0.17 h
Yield: 77.5 %

Procedure:
1,8-Diazabicyclo[5,4,0]-undec-7-ene (1.8 g, 11.8 mmol) was added to a stirred suspension of 3-(4-aminomethyl-1-oxo-1,3-dihydro-isoindol-2-yl)-piperidine-2,6-dione hydrochloride (1.4 g, 4.5 mmol) in DMF (50 mL). After stirring for 10 minutes, 1-hydroxbenzotriazole (0.7 g, 5.4 mmol) and N—BOC-γ-aminobutyric acid (1.1 g, 5.4 mmol) were added. The reaction was initiated by addition of 1-[3-(dimethylamino)propyl]-3-ethylcarbodiimide hydrochloride (1.3 g, 6.8 mmol). The mixture was stirred at room temperature overnight. The mixture was concentrated, and the residue was stirred with EtOAc (50 mL) and H2O (40 mL) for 30 minutes. The mixture was filtered, and dried to give (3-{[2-(2,6-dioxo-piperidin-3-yl)-1-oxo-2,3-dihydro-1H-isoindol-4-ylmethyl]-carbamoyl}-propyl-carbamic acid t-butyl ester (1.6 g, 77%) as a white solid: mp 199-201° C.; 1H NMR (DMSO-d6) δ 1.37 (s, 9H, 3CH3), 1.58-1.66 (m, 2H, CH2), 1.99-2.16 (m, 3H), 2.36-2.49 (m, 1H), 2.58-2.64 (m, 1H), 2.86-2.94 (m, 3H), 4.31 (d, J=5.6 Hz, 2H, CH2), 4.38 (d, J=17.3 Hz, 1H), 4.46 (d, J=17.3 Hz, 1H), 5.10-5.18 (dd, J=5.0 and 13.1 Hz, 1H, CH), 6.81 (t, J=5.4 Hz, 1H, NH), 7.48-7.64 (m, 3H, Ar), 8.37 (t, J=5.7 Hz, 1H, NH), 11.02 (s, 1H, NH); 13C NMR (DMSO-d6) δ 22.56, 25.72, 28.23, 31.18, 32.63, 38.95, 46.15, 51.56, 77.04, 121.60, 128.27, 130.55, 131.61, 134.70, 140.06, 155.55, 168.04, 170.97, 171.90, 172.82; Anal. calcd. for C23H30N4O6: C, 60.25; H, 6.59; N, 12.22. Found: C, 60.12; H, 6.55; N, 12.15.
Reaction SMILES: C([O:3][C:4](=O)[CH2:5][N:6]([CH2:17][C:18]1[C:19]([NH2:25])=[N:20][CH:21]=[C:22]([Br:24])[CH:23]=1)[CH2:7][CH2:8][CH2:9][N:10]1[CH2:15][CH2:14][N:13]([CH3:16])[CH2:12][CH2:11]1)C.[H-].[Na+]>CS(C)=O.O>[Br:24][C:22]1[CH:21]=[N:20][C:19]2[NH:25][C:4](=[O:3])[CH2:5][N:6]([CH2:7][CH2:8][CH2:9][N:10]3[CH2:15][CH2:14][N:13]([CH3:16])[CH2:12][CH2:11]3)[CH2:17][C:18]=2[CH:23]=1
Reactant: CCOC(=O)CN(CCCN1CCN(C)CC1)Cc1cc(Br)cnc1N
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CS(C)=O
Product: CN1CCN(CCCN2CC(=O)Nc3ncc(Br)cc3C2)CC1
Temperature: 25 °C
Reaction time: 72 h
Yield: 51.4 %

Procedure:
A solution of {(2-amino-5-bromo-pyridin-3-ylmethyl)-[3-(4-methyl-piperazin-1-yl)propyl]amino}acetic acid ethyl ester (0.50 g, 1.17 mmol) in DMSO (10 mL) was treated with NaH (60% dispersion in mineral oil, 47 mg, 1.17 mmol). After stirring at room temperature for 3 d, the mixture was diluted with H2O (30 mL) and then extracted with EtOAc (4×50 mL). The combined organic layers were dried over Na2SO4, filtered and the solvent was removed in vacuo. Purification by flash column chromatography (silica gel, CH2Cl2, MeOH, 92:8 to 87:13) gave the title compound (0.23 g, 51%) as a white solid: MS (ESI) m/e 382 (M+H)+.
Reaction SMILES: [CH3:1][O:2][C:3]1[N:8]=[C:7]([CH3:9])[N:6]=[C:5]([N:10](C2C=CC=CC=2)[C:11](=[O:13])[O-])[N:4]=1.[F:20][C:21]([F:35])([F:34])[CH:22]=[CH:23][C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=1[S:30]([NH2:33])(=[O:32])=[O:31].Cl>O1CCOCC1.O>[F:35][C:21]([F:20])([F:34])[CH:22]=[CH:23][C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=1[S:30]([NH:33][C:11]([NH:10][C:5]1[N:4]=[C:3]([O:2][CH3:1])[N:8]=[C:7]([CH3:9])[N:6]=1)=[O:13])(=[O:32])=[O:31]
Reactant: NS(=O)(=O)c1ccccc1C=CC(F)(F)F
Reactant: COc1nc(C)nc(N(C(=O)[O-])c2ccccc2)n1
Agent: Cl
Solvent: C1COCCO1
Solvent: O
Product: COc1nc(C)nc(NC(=O)NS(=O)(=O)c2ccccc2C=CC(F)(F)F)n1
Reaction time: 3 h
Yield: 86.7 %

Procedure:
5.2 g of N-(4-methoxy-6-methyl-1,3,5-triazin-2-yl)-phenylcarbamate are added to a solution of 5 g of 2-(3,3,3-trifluoro-1-propen-1-yl)-phenylsulfonamide and 3.3 g of 1,5-diazabicyclo[5,4,0]undec-5-one in 80 ml of dioxan, and the mixture is stirred for 3 hours at 20°-25° C. The clear reaction solution is then taken up in 300 ml of water and the aqueous solution is acidified with 2N hydrochloric acid to pH 4-5. The resinous precipitate is extracted from the aqueous phase with ethyl acetate and the organic extract is dried and concentrated. The oily residue is crystallised from a 1:10 mixture of acetone/ether, affording 7.2 g of the title compound with a melting point of 159°-160° C.
Reaction SMILES: CC([O:4][CH2:5][C:6]1[CH2:23][S:22][C@@H:9]2[C@H:10]([NH:13][C:14]([CH2:16][C:17]3[S:21][CH:20]=[CH:19][CH:18]=3)=[O:15])[C:11](=[O:12])[N:8]2[C:7]=1[C:24]([OH:26])=[O:25])=O.C([O-])([O-])=O.[K+].[K+].C(OCC)(=O)C.Cl>O>[OH:4][CH2:5][C:6]1[CH2:23][S:22][C@@H:9]2[CH:10]([NH:13][C:14](=[O:15])[CH2:16][C:17]3[S:21][CH:20]=[CH:19][CH:18]=3)[C:11](=[O:12])[N:8]2[C:7]=1[C:24]([OH:26])=[O:25]
Reactant: CC(=O)OCC1=C(C(=O)O)N2C(=O)[C@@H](NC(=O)Cc3cccs3)[C@H]2SC1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: O
Product: O=C(Cc1cccs1)NC1C(=O)N2C(C(=O)O)=C(CO)CS[C@H]12
Reaction time: 4.25 h

Procedure:
This substance was prepared according to German Offenlegungsschrift No. 2,103,014 as follows. A suspension of 8.0 g of cephalothin (1), available semi-synthetically, in 120 ml. of H2O treated with 8.6 g of K2CO3 and the resulting solution was stirred at 36° for 4.25 hours, then at 30° for 18 hours. The resulting mixture was layered with 500 ml of ethyl acetate and a solution of 10.0 ml of conc. HCl in 50 ml of H2O was added. The ethyl acetate was dried (MgSO4) and removed in vacuo in yield 3.84 g (54%) of 3-hydroxymethyl-7-(2-thienylacetamido)-3-cephem-4-carboxylic acid, mp 138°-145° d. Crystallization from ethyl acetate yielded material, mp 149°-151° d (lit. mp 151.5°-152° d); ir (nujol mull): 3600-2400 (carboxyl -OH), 3450 (amide N-H), 1790 (β-lactam C=O), 1745 (acid C=O), 1650 (amide C=O), and 1510 ("amide II" band) cm-1.
Reaction SMILES: [OH:1][CH2:2][CH:3]1[CH:7]=[CH:6][CH2:5][N:4]1[C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9].[Br:15][C:16]1[CH:21]=[CH:20][C:19]([O:22][CH3:23])=[CH:18][C:17]=1O.CCOC(/N=N/C(OCC)=O)=O>C1COCC1.C1(C)C=CC=CC=1>[Br:15][C:16]1[CH:21]=[CH:20][C:19]([O:22][CH3:23])=[CH:18][C:17]=1[O:1][CH2:2][CH:3]1[CH:7]=[CH:6][CH2:5][N:4]1[C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9]
Reactant: CC(C)(C)OC(=O)N1CC=CC1CO
Reactant: COc1ccc(Br)c(O)c1
Agent: CCOC(=O)/N=N/C(=O)OCC
Solvent: C1CCOC1
Solvent: Cc1ccccc1
Product: COc1ccc(Br)c(OCC2C=CCN2C(=O)OC(C)(C)C)c1
Temperature: 25 °C
Reaction time: 21 h
Yield: 9.5 %

Procedure:
To a solution of tert-butyl 2-(hydroxymethyl)-2,5-dihydro-1H-pyrrole-1-carboxylate (8.96 g, 0.45 mol, from Specialty Chemicals, Inc.) and 2-bromo-5-methoxyphenol (9.32 g, 0.46 mol) in THF (180 mL) was added DEAD (20.5 mL) in toluene (40 wt %) dropwise at 0° C. The reaction was stirred for 21 h at RT and the solvent was evaporated. The residue was suspended in methyl tert-butylether (50 mL) and the solution was filtered and concentrated. The resulting residue was dissolved in DCM, washed with 0.6N NaOH (2×25 mL) and the layers were separated. The organic layer was dried with Na2SO4 and the solvent was evaporated. The crude product was purified using an ISCO instrument (330 g RediSep® column), eluting with a gradient of ethyl acetate in heptane (from 0%-20% ethyl acetate over 6 minutes, then 29% ethyl acetate for 20 min) to afford 16.4 g of the title product.
Reaction SMILES: [CH2:1]([NH2:4])[CH2:2][NH2:3].[CH:5]([C:7]1[CH:8]=[N:9][CH:10]=[N:11][CH:12]=1)=O>C1C=CC=CC=1>[N:9]1[CH:8]=[C:7]([CH2:5][NH:3][CH2:2][CH2:1][NH2:4])[CH:12]=[N:11][CH:10]=1
Reactant: O=Cc1cncnc1
Reactant: NCCN
Solvent: c1ccccc1
Product: NCCNCc1cncnc1
Temperature: 25 °C
Reaction time: 5 h
Yield: 84.8 %

Procedure:
Ethylenediamine (60 g) was dissolved in benzene (200 ml), and 5-formylpyrimidine (21.6 g) was added at room temperature. Subsequently, the mixture was heated, and refluxed for 3 hours while removing water as an azeotrope. After the reaction, benzene and the excess of ethylenediamine were distilled off under reduced pressure. The residue was dissolved in ethanol (200 ml). Sodium borohydride (8.4 g) was added portionwise to this solution at room temperature, and subsequently the mixture was stirred at room temperature for 5 hours. Ethanol was distilled off under reduced pressure. Dichloromethane (100 ml) was added to the residue, and a dichloromethane-soluble portion was separated. Dichloromethane was distilled off from the dichloromethane layer under reduced pressure to give N-(5-pyrimidinylmethyl)ethylenediamine (25.8 g) as a colorless oil. nD25 =1.5532.
Reaction SMILES: [Br:1][C:2]1[C:3]([F:12])=[C:4]2[C:10]([NH2:11])=[CH:9][NH:8][C:5]2=[N:6][CH:7]=1.[CH3:13][O:14][C:15]1[CH:29]=[CH:28][C:18]([CH2:19][N:20]2[CH:24]=[C:23]([C:25](O)=[O:26])[CH:22]=[N:21]2)=[CH:17][CH:16]=1.C1N(P(Cl)(N2C(=O)OCC2)=O)C(=O)OC1.C(N(CC)CC)C>C(Cl)Cl>[Br:1][C:2]1[C:3]([F:12])=[C:4]2[C:10]([NH:11][C:25]([C:23]3[CH:22]=[N:21][N:20]([CH2:19][C:18]4[CH:28]=[CH:29][C:15]([O:14][CH3:13])=[CH:16][CH:17]=4)[CH:24]=3)=[O:26])=[CH:9][NH:8][C:5]2=[N:6][CH:7]=1
Reactant: Nc1c[nH]c2ncc(Br)c(F)c12
Reactant: COc1ccc(Cn2cc(C(=O)O)cn2)cc1
Agent: O=C1OCCN1P(=O)(Cl)N1CCOC1=O
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COc1ccc(Cn2cc(C(=O)Nc3c[nH]c4ncc(Br)c(F)c34)cn2)cc1
Yield: 39.8 %

Procedure:
A mixture of 5-bromo-4-fluoro-1H-pyrrolo[2,3-b]pyridin-3-amine (300 mg, 1.30 mmol, Example 1, Step H), 1-(4-methoxybenzyl)-1H-pyrazole-4-carboxylic acid (636 mg, 2.74 mmol), BOP-Cl (697 mg, 2.74 mmol), and triethylamine (0.909 mL, 6.52 mmol) in DCM (5 mL) was processed as described in Example 62, Step A, to provide N-(5-bromo-4-fluoro-1H-pyrrolo[2,3-b]pyridin-3-yl)-1-(4-methoxybenzyl)-1H-pyrazole-4-carboxamide (230 mg, 39% yield).
Reaction SMILES: [CH3:1][O:2][CH2:3][CH2:4][O:5][CH2:6][O:7][CH2:8][CH2:9][N:10]1[CH2:15][CH2:14][O:13][CH2:12][CH2:11]1.ClC1C=CC=C(C(OO)=[O:24])C=1>ClCCl>[CH3:1][O:2][CH2:3][CH2:4][O:5][CH2:6][O:7][CH2:8][CH2:9][N+:10]1([O-:24])[CH2:15][CH2:14][O:13][CH2:12][CH2:11]1
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: COCCOCOCCN1CCOCC1
Solvent: ClCCl
Product: COCCOCOCC[N+]1([O-])CCOCC1
Reaction time: 1 h

Procedure:
16.1 g of N-2-((2-methoxyethoxy)methoxy)ethylmorpholine was dissolved in 85 g of dichloromethane, which was ice cooled. To the solution, 24.9 g of 65% pure m-chloroperbenzoic acid in 250 g of dichloromethane was added dropwise at such a rate that the mixture might not exceed 5° C. The mixture was allowed to mature for one hour at room temperature. The reaction solution was concentrated below 30° C., and the residue was purified by column chromatography (basic alumina, elute: dichloromethane/methanol). The eluate was concentrated whereupon the desired compound solidified. The amount was 15.5 g.
Reaction SMILES: [NH:1]=[C:2]1[CH2:6][CH2:5][CH2:4][N:3]1[CH3:7].[C:8]1([N:14]=[C:15]=[O:16])[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1>C1C=CC=CC=1>[CH3:7][N:3]1[CH2:4][CH2:5][CH2:6][C:2]1=[N:1][C:15]([NH:14][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)=[O:16]
Reactant: CN1CCCC1=N
Reactant: O=C=Nc1ccccc1
Solvent: c1ccccc1
Product: CN1CCCC1=NC(=O)Nc1ccccc1

Procedure:
After dissolving 4.9 g. (0.05 mole) of 2-imino-1-methylpyrrolidine in anhydrous benzene, 5.96 g. (0.05 mole) of phenylisocyanate is added dropwise with stirring (heat evolves). The reaction mixture is stirred for one-half hour. The solid product which is formed, 1-(1-methyl-2-pyrrolidylidene)-3-phenylurea, is collected (m.p. = 140°-144° C); recrystallized from methanol to give the pure product, m.p. = 146°-147.5° C.
Reaction SMILES: [S:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[C:3]([C:10](N)=[O:11])=[N:2]1.[OH-:13].[Na+].Cl>>[S:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[C:3]([C:10]([OH:11])=[O:13])=[N:2]1
Reactant: [OH-]
Reactant: NC(=O)c1nsc2ccccc12
Agent: Cl
Agent: [Na+]
Product: O=C(O)c1nsc2ccccc12
Temperature: 25 °C
Yield: 96 %

Procedure:
A mixture of 1,2-benzisothiazole-3-carboxamide (5.0 g, 0.028 mole) and 1N aqueous sodium hydroxide (55 ml) is heated on a steam bath until solution is achieved (approximately 30 minutes), cooled to room temperature, and acidified with 2N hydrochloric acid. The resulting precipitate is filtered and dried in vacuo to afford the title compound (1.85 g, 96%) as a white solid, which is identified by NMR and IR spectral analysis.
Reaction SMILES: [Li+].[Br-:2].C1(C)C=CC(S(O[CH2:13][CH:14]([F:21])[CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH3:20])(=O)=O)=CC=1>C(#N)C>[F:21][CH:14]([CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH3:20])[CH2:13][Br:2]
Reactant: [Br-]
Reactant: CCCCCCC(F)COS(=O)(=O)c1ccc(C)cc1
Agent: [Li+]
Solvent: CC#N
Product: CCCCCCC(F)CBr
Reaction time: 5 h
Yield: 91 %

Procedure:
1.51 g (17.4 raM) of LiBr was charged in a 30 ml-round bottomed flask with two ports with grinding fitting, and the interior atmosphere was sufficiently replaced with nitrogen. Dry acetonitrile in an amount of 40 ml was added thereto, and a solution of 3.50 g (11.60 mM) of 2-fluorooctyl p-toluenesulfonate in 4 ml of dry acetonitrile was further added. Thereafter, the system was subjected to about 5 hours of heat refluxing. At this time, as the temperature was raised, the solution became uniform to immediately precipitate a TSO Li salt. After the reaction, the acetonitrile was distilled off, and 10 ml of water and 10 ml of ether were added for extraction. Further, the mixture was subjected to two times of extraction each with 10 ml of ether, and the ether layer was dried with anhydrous sodium sulfate. After the distilling-off of the solvent, 2-fluorooctyl bromide was obtained through distillation in an amount of 2.24 g (yield: 91%, 87°-88° C./28 mm Hg). [α]D26.4 =-24° (C1, CH2Cl2).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH2:20][C:21]([OH:23])=O)[CH:6]=[CH:7][C:8]=1[NH:9][C:10]([NH:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=1[CH3:19])=[O:11].[CH3:24][O:25][C:26]([C:28]1[CH:29]=[CH:30][C:31]([O:34][CH2:35][C@@H:36]2[CH2:40][C@H:39]([O:41][C:42]3[CH:51]=[CH:50][C:49]4[C:44](=[CH:45][CH:46]=[CH:47][CH:48]=4)[CH:43]=3)[CH2:38][NH:37]2)=[N:32][CH:33]=1)=[O:27].CCN=C=NCCCN(C)C.Cl>CN(C1C=CN=CC=1)C.CN(C=O)C>[CH3:24][O:25][C:26]([C:28]1[CH:29]=[CH:30][C:31]([O:34][CH2:35][C@@H:36]2[CH2:40][C@H:39]([O:41][C:42]3[CH:51]=[CH:50][C:49]4[C:44](=[CH:45][CH:46]=[CH:47][CH:48]=4)[CH:43]=3)[CH2:38][N:37]2[C:21](=[O:23])[CH2:20][C:5]2[CH:6]=[CH:7][C:8]([NH:9][C:10]([NH:12][C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=3[CH3:19])=[O:11])=[C:3]([O:2][CH3:1])[CH:4]=2)=[N:32][CH:33]=1)=[O:27]
Reactant: COc1cc(CC(=O)O)ccc1NC(=O)Nc1ccccc1C
Reactant: COC(=O)c1ccc(OC[C@@H]2C[C@H](Oc3ccc4ccccc4c3)CN2)nc1
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: CN(C)C=O
Product: COC(=O)c1ccc(OC[C@@H]2C[C@H](Oc3ccc4ccccc4c3)CN2C(=O)Cc2ccc(NC(=O)Nc3ccccc3C)c(OC)c2)nc1
Temperature: 25 °C
Reaction time: 18 h
Yield: 101.1 %

Procedure:
A mixture of 3-methoxy-4-[N′-(2-methylphenyl)ureido]phenylacetic acid (89 mg, 0.283 mmol), methyl-2-[(2S,4S)-4-(2-naphthyloxy)-2-pyrrolidinyl]methoxypyridine-5-carboxylate (107 mg, 0.78 mmol), EDC.HCl (81 mg, 0.425 mmol) and DMAP (52 mg, 0.425 mmol) in DMF (3 ml) was stirred at room temperature for 18 h. The mixture was poured into ice water and extracted with EtOAc. The combined extracts were washed with ice water and brine. After dried over Na2SO4, the extracts were concentrated in vacuo. The residue was purified on TLC [CHCl3/MeOH (10/1)], to give 2-[(2S,4S)-1-[3-methoxy-4-[N′-(2-methylphenyl)ureido]phenylacetyl]-4-(2-naphthyloxy)-2-pyrrolidinyl]methoxy-5-pyridinecarboxylic acid methyl ester (193 mg, 100%) as a colorless amorphous. 1H-NMR (CDCl3) δ2.27 (d, J=3.2 Hz, 3H), 2.30 (m, 1H), 2.49 (dd, J=14.2, 2.0 Hz, 1H), 3.60 (d, J=3.9 Hz, 1H), 3.67 (d, J=5.9 Hz, 3H), 3.81 (s, 1H), 3.85 (s, 1H), 3.88 and 3.91 (s, 3H, amide isomers), 3.95 (m, 1H), 4.02-5.09 (m, 4H), 6.67 (d, J=8.8 Hz, 1H), 6.73-7.13 (m, 3H), 7.20-7.45 (m, 7H), 7.53 (t, J=7.8 Hz, 1H), 7.67-7.77 (m, 3H), 8.02-8.84 (m, 3H).
Reaction SMILES: C([O:3][C:4](=[O:27])[C@@H:5]([NH:14][C:15]([C:17]1[NH:26][C:20]2=[N:21][C:22]([Cl:25])=[CH:23][CH:24]=[C:19]2[CH:18]=1)=[O:16])[CH2:6][C:7]1[CH:12]=[CH:11][C:10]([F:13])=[CH:9][CH:8]=1)C.[OH-].[Na+]>CO>[Cl:25][C:22]1[N:21]=[C:20]2[NH:26][C:17]([C:15]([NH:14][C@@H:5]([CH2:6][C:7]3[CH:8]=[CH:9][C:10]([F:13])=[CH:11][CH:12]=3)[C:4]([OH:27])=[O:3])=[O:16])=[CH:18][C:19]2=[CH:24][CH:23]=1
Reactant: CCOC(=O)[C@H](Cc1ccc(F)cc1)NC(=O)c1cc2ccc(Cl)nc2[nH]1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: O=C(N[C@@H](Cc1ccc(F)cc1)C(=O)O)c1cc2ccc(Cl)nc2[nH]1
Reaction time: 16 h

Procedure:
To a solution of 2-[(6-chloro-1H-pyrrolo[2,3-b]pyridine-2-carbonyl)amino]-3-(4-fluorophenyl)propionic acid ethyl ester (EXAMPLE 271, 780 mg, 2.0 mmol) in methanol (15 mL) was added 2M NaOH (2 mL, 4.0 mmol) and the reaction was stirred for 16 hr. Solvent was removed in vacuo and crude residue dissolved in water (20 mL). The aqueous phase was washed with ethyl acetate (2×20 mL), then acidified to Ph 3 with 2M HCl. The organics were extracted into ethyl acetate (2×30 mL), and then dried (MgSO4) before concentrating the solvent in vacuo to provide the title compound. m/z (ES+)=361.88 [M+H]+.
Reaction SMILES: N([O-])=O.[Na+].[Br:5][C:6]1[CH:7]=[CH:8][C:9](N)=[N:10][C:11]=1[F:12].S(=O)(=O)(O)[OH:15]>O>[Br:5][C:6]1[CH:7]=[CH:8][C:9]([OH:15])=[N:10][C:11]=1[F:12]
Reactant: Nc1ccc(Br)c(F)n1
Reactant: O=S(=O)(O)O
Agent: O=N[O-]
Agent: [Na+]
Solvent: O
Product: Oc1ccc(Br)c(F)n1
Temperature: 25 °C
Reaction time: 48 h
Yield: 925.6 %

Procedure:
A solution of sodium nitrite (21.67 g, 314.13 mmol) in water (150 mL) was added dropwise to a stirred mixture of 5-bromo-6-fluoropyridin-2-amine (50 g, 261.78 mmol) and sulphuric acid (1.2 mL, 22.51 mmol) in water (750 mL) at 0-5° C. The resulting suspension was stirred for 48 h at ambient temperature then the precipitate collected by filtration, washed with water (200 mL) and dried under vacuum to afford the desired material (40.0 g, 80%) as a pale yellow solid, which was used without further purification. NMR Spectrum: 1H NMR (300 MHz, DMSO-d6) δ 6.55 (1H, d), 8.00 (1H, t), 11.71 (1H, bs). Mass Spectrum: m/z (ES+)[M+H]+=192.