Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C([S:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH:10]([CH2:14][CH2:15][CH3:16])[C:11]([OH:13])=[O:12])(=O)C.C1(=O)N(C2C=C(C=CC=2)C(ON2C(=O)CCC2=O)=O)C(=O)C=C1>P([O-])([O-])([O-])=O.O1CCOCC1>[SH:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH:10]([CH2:14][CH2:15][CH3:16])[C:11]([OH:13])=[O:12]
Reactant: CCCC(CCCCCSC(C)=O)C(=O)O
Agent: O=C(ON1C(=O)CCC1=O)c1cccc(N2C(=O)C=CC2=O)c1
Agent: O=P([O-])([O-])[O-]
Solvent: C1COCCO1
Product: CCCC(CCCCCS)C(=O)O
Temperature: 25 °C
Reaction time: 3 h

Procedure:
A solution of 7-mercapto-2-propylheptanoic acid(prepared in Example 2, 150 mg) in 0.1 M phosphate buffer (pH 7.0,10 ml) was added to a solution of BSA(350 mg) in 0.1 M phosphate buffer (pH 7.0,30 ml) in an argon atmosphere. To the solution was added slowly a solution of N-(m-maleimidobenzoyloxy)succinimide (hereinafter referred to as m-MBS, 150 mg) in dioxane (10 ml). The mixture was stirred for 3 hours at ambient temperature, and dialyzed overnight against running water. The dialized solution was adjusted to pH 8.5 with 1 N sodium hydroxide solution and concentrated to about 10 ml by ultrafiltration using PM30 membrane (Amicon Corp.). The concentrate was adjusted to pH 4.5 with diluted hydrochloric acid and left in a cold place for 20 hours. The resulting precipitates were collected by centrifuge (10000 r.p.m., 15 minutes), suspended in a small amount of water, dissolved by adjusting to pH 8.5 with diluted alkali solution and dialyzed for 48 hours against 0.9% sodium chloride solution (2 liters), while the outer solution was renewed four times. The dialyzed solution was lyophilized to give the conjugate (330 mg).
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([CH2:10][CH2:11]O)=[CH:6][CH:5]=1)([O-:3])=[O:2].C(N(S(F)(F)[F:19])CC)C.C(=O)([O-])O.[Na+]>C(Cl)Cl>[F:19][CH2:11][CH2:10][C:7]1[CH:8]=[CH:9][C:4]([N+:1]([O-:3])=[O:2])=[CH:5][CH:6]=1
Reactant: O=[N+]([O-])c1ccc(CCO)cc1
Reactant: CCN(CC)S(F)(F)F
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Product: O=[N+]([O-])c1ccc(CCF)cc1
Reaction time: 0.5 h

Procedure:
A solution of 2-(4-nitrophenyl)ethanol (835 mg) in methylene chloride (30 mL) was stirred at −78° C. under a nitrogen atomosphere. To this solution, diethylaminosulfur trifluoride (1.98 mL) in methylene chloride (20 mL) was added dropwise over 10 minutes. With stirring, the temperature of the reaction mixture was allowed to rise back to room temperature. After 30 minutes, the reaction was stopped by the addition of saturated aqueous sodium hydrogen carbonate solution (50 mL) in an ice bath. The methylene chloride solution was washed with saturated aqueous sodium hydrogen carbonate solution (50 mL). After drying over anhydrous magnesium sulfate, the solvent was evaporated under reduced pressure. The residue was purified by chromatography on a silica gel (25 g) column using hexane:ethyl acetate (7:2) as the eluant to give 1-fluoro-2-(4-nitrophenyl)ethane (359 mg).
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([C:8]#[C:9][CH:10]=[C:11]2[CH2:16][CH2:15][NH:14][CH2:13][CH2:12]2)[N:3]=1.F[C:18]1[CH:19]=[C:20]([CH3:27])[CH:21]=[CH:22][C:23]=1[N+:24]([O-:26])=[O:25]>>[CH3:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([C:8]#[C:9][CH:10]=[C:11]2[CH2:12][CH2:13][N:14]([C:18]3[CH:19]=[C:20]([CH3:27])[CH:21]=[CH:22][C:23]=3[N+:24]([O-:26])=[O:25])[CH2:15][CH2:16]2)[N:3]=1
Reactant: Cc1cccc(C#CC=C2CCNCC2)n1
Reactant: Cc1ccc([N+](=O)[O-])c(F)c1
Product: Cc1ccc([N+](=O)[O-])c(N2CCC(=CC#Cc3cccc(C)n3)CC2)c1
Yield: 39.9 %

Procedure:
A well homogenised mixture of the Compound of Example 3 (19 mg, 0.89 mmol) and 3-fluoro-4-nitrotoluene (20.2 mg, 0.13 mmol) was stirred at 120° C. for 0.5 h. The reaction crude was purified by flash chromatography (EtOAc—Petroleum Ether gradient from 2:8 to 3:7) affording the title product (18 mg).
Reaction SMILES: ClC1C=CC=C(C(OO)=[O:9])C=1.[CH3:12][S:13][C:14]1[CH:19]=[CH:18][C:17]([C:20]2[N:21]=[C:22]([CH3:37])[N:23]([C:25]3[CH:26]=[C:27]4[C:32](=[C:33]([CH3:35])[CH:34]=3)[NH:31][C:30](=[O:36])[CH:29]=[CH:28]4)[CH:24]=2)=[CH:16][CH:15]=1.C(=O)([O-])[O-].[Na+].[Na+]>ClCCl>[CH3:12][S:13]([C:14]1[CH:19]=[CH:18][C:17]([C:20]2[N:21]=[C:22]([CH3:37])[N:23]([C:25]3[CH:26]=[C:27]4[C:32](=[C:33]([CH3:35])[CH:34]=3)[NH:31][C:30](=[O:36])[CH:29]=[CH:28]4)[CH:24]=2)=[CH:16][CH:15]=1)=[O:9]
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: CSc1ccc(-c2cn(-c3cc(C)c4[nH]c(=O)ccc4c3)c(C)n2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: ClCCl
Product: Cc1cc(-n2cc(-c3ccc(S(C)=O)cc3)nc2C)cc2ccc(=O)[nH]c12
Reaction time: 0.5 h

Procedure:
meta-Chloroperbenzoic acid (0.11 g) was added in portions over a period of 5 minutes to a stirred suspension of 6-(4-[4-methylthiophenyl]-2-methylimidazol-1-yl)-8-methyl-2-(1H)-quinolone (0.2 g) in dichloromethane (10 cm3) at 0°. The mixture was stirred at 0° for 30 minutes, then poured into saturated aqueous sodium carbonate solution (30 cm3) and extracted with dichloromethane (3×25 cm3). The combined and dried (MgSO4) extracts were evaporated in vacuo to give a solid which was recrystallised from dichloromethane to give the title compound, m.p. 313°-5°, (0.08 g).
Reaction SMILES: Cl.Cl.[Cl:3][C:4]1[CH:5]=[C:6]([CH:18]=[CH:19][C:20]=1[Cl:21])[O:7][CH:8]1[CH2:13][CH2:12][N:11]([CH2:14][CH2:15][CH2:16][NH2:17])[CH2:10][CH2:9]1.Cl[C:23]1[N:28]=[CH:27][N:26]=[C:25]2[N:29]([CH3:32])[N:30]=[CH:31][C:24]=12.C(N(C(C)C)CC)(C)C>CN1CCCC1=O.C(OCC)(=O)C>[Cl:3][C:4]1[CH:5]=[C:6]([CH:18]=[CH:19][C:20]=1[Cl:21])[O:7][CH:8]1[CH2:9][CH2:10][N:11]([CH2:14][CH2:15][CH2:16][NH:17][C:23]2[N:28]=[CH:27][N:26]=[C:25]3[N:29]([CH3:32])[N:30]=[CH:31][C:24]=23)[CH2:12][CH2:13]1
Reactant: Cn1ncc2c(Cl)ncnc21
Reactant: NCCCN1CCC(Oc2ccc(Cl)c(Cl)c2)CC1
Agent: Cl
Solvent: CN1CCCC1=O
Solvent: CCOC(C)=O
Solvent: CCN(C(C)C)C(C)C
Product: Cn1ncc2c(NCCCN3CCC(Oc4ccc(Cl)c(Cl)c4)CC3)ncnc21

Procedure:
The product from step (ii) (0.08 g), 4-chloro-1-methyl-1H-pyrazolo[3,4-d]pyrimidine (0.054 g) and diisopropylethylamine (0.082 g) in 1-methyl-2-pyrrolidinone (2 ml) was heated at 50° C. for 3 h. The reaction mixture was diluted with ethyl acetate and washed with water. The organic layer was dried and the solvent removed under reduced pressure. Purification was by chromatography eluting with 9% methanol/dichloromethane. Yield 0.052 g
Reaction SMILES: [C:1]([C:5]1[N:6]=[C:7]([C:10]2[O:11][C:12]3[CH:18]=[CH:17][C:16]([CH2:19][N:20]4[C:28]5[C:23](=[CH:24][CH:25]=[CH:26][CH:27]=5)[CH:22]=[C:21]4[C:29]([O:31]C)=[O:30])=[CH:15][C:13]=3[CH:14]=2)[S:8][CH:9]=1)([CH3:4])([CH3:3])[CH3:2].[OH-].[Na+]>O.C(O)C>[C:1]([C:5]1[N:6]=[C:7]([C:10]2[O:11][C:12]3[CH:18]=[CH:17][C:16]([CH2:19][N:20]4[C:28]5[C:23](=[CH:24][CH:25]=[CH:26][CH:27]=5)[CH:22]=[C:21]4[C:29]([OH:31])=[O:30])=[CH:15][C:13]=3[CH:14]=2)[S:8][CH:9]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: COC(=O)c1cc2ccccc2n1Cc1ccc2oc(-c3nc(C(C)(C)C)cs3)cc2c1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: CC(C)(C)c1csc(-c2cc3cc(Cn4c(C(=O)O)cc5ccccc54)ccc3o2)n1
Yield: 96.1 %

Procedure:
A solution of methyl 1-{[2-(4-tert-butylthiazol-2-yl)benzofuran-5-yl]methyl}indole-2-carboxylate (0.86 g) and sodium hydroxide (0.77 g) in a mixture of water (10 ml) and ethanol (20 ml) was stirred under reflux for 2 hours. After removal of solvents, the residue was dissolved into water and the solution was acidified with diluted hydrochloric acid to pH 3. The resulting precipitates were collected by filtration and dried in vacuo to give 1-{[2-(4-tert-butylthiazol-2-yl)benzofuran-5-yl]methyl}indole-2-carboxylic acid (0.80 g).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:16](=[O:17])[C:15]3[N:14]=[CH:13][N:12]([CH3:18])[C:11]=3[N:10]=[C:9]2Cl)=[CH:4][CH:3]=1.[F:20][C:21]1[C:26]([F:27])=[C:25]([F:28])[CH:24]=[CH:23][C:22]=1[OH:29].CO>C(Cl)Cl>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:16](=[O:17])[C:15]3[N:14]=[CH:13][N:12]([CH3:18])[C:11]=3[N:10]=[C:9]2[O:29][C:22]2[CH:23]=[CH:24][C:25]([F:28])=[C:26]([F:27])[C:21]=2[F:20])=[CH:4][CH:3]=1
Reactant: Oc1ccc(F)c(F)c1F
Reactant: Cn1cnc2c(=O)n(-c3ccc(Br)cc3)c(Cl)nc21
Solvent: CO
Solvent: ClCCl
Product: Cn1cnc2c(=O)n(-c3ccc(Br)cc3)c(Oc3ccc(F)c(F)c3F)nc21
Temperature: 140 °C
Reaction time: 23 h

Procedure:
1-(4-Bromophenyl)-2-chloro-9-methyl-1,9-dihydro-6H-purin-6-one (150 mg, 0.4417 mmol) and 2,3,4-trifluorophenol (130.8 mg, 0.8834 mmol) are added to a vial, and the sealed mixture is heated with stirring at 140° C. for 23 h. Silica gel column chromatography (MeOH:CH2Cl2=0.5:99.5) gives the title compound as a white solid. 1H NMR (400 MHz, CDCl3) 7.66 (3H, m), 7.24 (2H, m), 7.00 (2H, m), 3.58 (3H, s). MS (M+1): 451.08; RT=1.31 min. The IC50 determined as described in Example 6 is 100 nanomolar or less.
Reaction SMILES: Br[C:2]1[CH:15]=[C:14]([CH3:16])[C:5]([O:6][Si:7]([C:10]([CH3:13])([CH3:12])[CH3:11])([CH3:9])[CH3:8])=[C:4]([CH3:17])[CH:3]=1.C([Li])CCC.CCCCCC.[NH:29]1[C:39]2[C:34](=[CH:35][CH:36]=[CH:37][CH:38]=2)[C:32](=[O:33])[C:30]1=[O:31].[NH4+].[Cl-]>C1COCC1>[C:10]([Si:7]([CH3:9])([CH3:8])[O:6][C:5]1[C:14]([CH3:16])=[CH:15][C:2]([C:32]2([OH:33])[C:34]3[C:39](=[CH:38][CH:37]=[CH:36][CH:35]=3)[NH:29][C:30]2=[O:31])=[CH:3][C:4]=1[CH3:17])([CH3:13])([CH3:12])[CH3:11]
Reactant: Cc1cc(Br)cc(C)c1O[Si](C)(C)C(C)(C)C
Reactant: O=C1Nc2ccccc2C1=O
Agent: [Cl-]
Agent: [Li]CCCC
Agent: [NH4+]
Solvent: C1CCOC1
Solvent: CCCCCC
Product: Cc1cc(C2(O)C(=O)Nc3ccccc32)cc(C)c1O[Si](C)(C)C(C)(C)C
Temperature: -75 °C
Reaction time: 0.5 h
Yield: 154.3 %

Procedure:
Dissolve (4-bromo-2,6-dimethyl-phenoxy)-tert-butyl-dimethyl-silane (15.77 g, 50 mmol) in anhydrous THF (250 mL) under nitrogen and cool in a dry ice/acetone bath. Add slowly at −75 to −70° C. 1.6M n-butyl lithium in hexane (31.3 mL, 55 mmol). Stir the resulting white precipitate at −75° C. for 30 min. Add isatin (3.68 g, 25 mmol) as a solid while maintaing positive nitrogen pressure. Remove some dry ice and allow the reaction to warm up slowly to −30 to −40° C. over 3 h and then to 15° C. over 1 h. Pour the reaction into NH4Cl solution and wash with EtOAc (2×500 mL, 250 mL). Wash combined organic portions with water (500 mL) and brine (500 mL). Dry (MgSO4), filter and concentrate in vacuo to give 14.8 g of a yellow solid. Triturate in hexane/ether/CH2Cl2, filter and air dry to give 6.0 g (63%) of the title compound as a pale yellow solid. MS (ES): m/z=383 (M−1); 1H NMR(DMSO-d6): δ10.14 (s, 1H), 7.07 (dt, J=1.1 Hz, J=7.6 Hz, 1H), 6.95 (d, J=7.0, 1H), 6.80 (t, J=7.3 Hz, 1H), 6.72 (m, 3H), 6.27 (s, 1H), 1.95 (s, 6H), 0.83 (s, 9H), 0.00 (s, 6H).
Reaction SMILES: B#B.[Cl:3][C:4]1[CH:5]=[C:6]([CH:21]=[CH:22][C:23]=1[Cl:24])[CH2:7][N:8]1[CH2:13][CH2:12][N:11]([C:14]([C@@H:16]([NH2:20])[CH:17]([CH3:19])[CH3:18])=O)[CH2:10][CH2:9]1>O1CCCC1>[Cl:3][C:4]1[CH:5]=[C:6]([CH:21]=[CH:22][C:23]=1[Cl:24])[CH2:7][N:8]1[CH2:13][CH2:12][N:11]([CH2:14][C@@H:16]([NH2:20])[CH:17]([CH3:19])[CH3:18])[CH2:10][CH2:9]1
Reactant: CC(C)[C@H](N)C(=O)N1CCN(Cc2ccc(Cl)c(Cl)c2)CC1
Agent: B#B
Solvent: C1CCOC1
Product: CC(C)[C@H](N)CN1CCN(Cc2ccc(Cl)c(Cl)c2)CC1
Yield: 114.9 %

Procedure:
A 1.0 M diborane solution in tetrahydrofuran (65.2 ml, 65.2 mmol) was added to a solution of 1-(S)-[4-(3,4-dichlorobenzyl)piperazin-1-ylcarbonyl]-2-methylpropylamine (3.2 g, 9.3 mmol) in tetrahydrofuran (15 ml). The mixture was heated at reflux under nitrogen atmosphere for 2 h and then concentrated in vacuo. The residue was dissolved in methanol, acidified with 6 N hydrogen chloride solution (50 ml) and then reheated to 70° C. After heating for 1 h, the reaction mixture was cooled and basified with a sodium hydroxide solution and the product was extracted into ethyl acetate. The ethyl acetate layer was washed with sodium bicarbonate solution, dried over magnesium sulfate, filtered and concentrated to provide 1-(S)-[4-(3,4-dichlorobenzyl)piperazin-1-ylmethyl]-2-methylpropylamine (3.53 g) as an oil.
Reaction SMILES: Cl.[N:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[N:8]([CH2:32][CH2:33][C:34]([O:36][CH3:37])=[O:35])[C:9]([C:11]1[CH:31]=[CH:30][C:14]2[N:15]([CH3:29])[C:16]([CH2:18][NH:19][C:20]3[CH:25]=[CH:24][C:23]([C:26](=[NH:28])[NH2:27])=[CH:22][CH:21]=3)=[N:17][C:13]=2[CH:12]=1)=[O:10].Cl[C:39]([O:41][CH2:42][CH2:43][CH2:44][CH2:45][CH3:46])=[O:40]>ClCCl.CO>[N:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[N:8]([CH2:32][CH2:33][C:34]([O:36][CH3:37])=[O:35])[C:9]([C:11]1[CH:31]=[CH:30][C:14]2[N:15]([CH3:29])[C:16]([CH2:18][NH:19][C:20]3[CH:25]=[CH:24][C:23]([C:26](=[NH:27])[NH:28][C:39]([O:41][CH2:42][CH2:43][CH2:44][CH2:45][CH3:46])=[O:40])=[CH:22][CH:21]=3)=[N:17][C:13]=2[CH:12]=1)=[O:10]
Reactant: CCCCCOC(=O)Cl
Reactant: COC(=O)CCN(C(=O)c1ccc2c(c1)nc(CNc1ccc(C(=N)N)cc1)n2C)c1ccccn1
Agent: Cl
Solvent: ClCCl
Solvent: CO
Product: CCCCCOC(=O)NC(=N)c1ccc(NCc2nc3cc(C(=O)N(CCC(=O)OC)c4ccccn4)ccc3n2C)cc1
Yield: 66 %

Procedure:
Prepared analogously to Example 90 from 1-methyl-2-[N-(4-amidinophenyl)aminomethyl]benzimidazol-5-yl-carboxylic acid-N-(2-pyridyl)-N-(2-methoxycarbonylethyl)amide hydrochloride and n-pentyl chloroformate. Yield: 66% of theory, C32H37N7O5 (599.7); Rf value: 0.58 (silica gel; dichloromethane/methanol=9:1); EKA mass spectrum: (M+H)+=600; (M+H+Na)++=311.7; (M+Na)+=622.
Reaction SMILES: [N:1]1([CH2:6][CH2:7][CH2:8][C:9]2[CH:14]=[CH:13][C:12]([C:15]([C:17]3[CH:22]=[CH:21][C:20]([O:23]C4CCCCO4)=[CH:19][CH:18]=3)=O)=[CH:11][CH:10]=2)[CH2:5][CH2:4][CH2:3][CH2:2]1.[C:30]([C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1)(=O)[CH2:31][CH3:32]>>[C:34]1([C:30]([CH2:31][CH3:32])=[C:15]([C:17]2[CH:18]=[CH:19][C:20]([OH:23])=[CH:21][CH:22]=2)[C:12]2[CH:13]=[CH:14][C:9]([CH2:8][CH2:7][CH2:6][N:1]3[CH2:5][CH2:4][CH2:3][CH2:2]3)=[CH:10][CH:11]=2)[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1
Reactant: CCC(=O)c1ccccc1
Reactant: O=C(c1ccc(CCCN2CCCC2)cc1)c1ccc(OC2CCCCO2)cc1
Product: CCC(=C(c1ccc(O)cc1)c1ccc(CCCN2CCCC2)cc1)c1ccccc1
Yield: 25.3 %

Procedure:
Following general procedure of McMurry reaction as described in example 1, step B, (4-(3-(pyrrolidin-1-yl)propyl)phenyl)(4-(tetrahydro-2H-pyran-2-yloxy)phenyl)methanone (798 mg, 2 mmol) was reacted with propiophenone (800 mg, 6 mmol) to give 208 mg desired product (25%, Z/E=1/1). m/z=412[M+1]+.
Reaction SMILES: [C:1]([N:9]([CH2:11][C:12]1[CH:13]=[C:14]([C:18]2[CH:23]=[CH:22][C:21]([CH:24]=[C:25]([CH2:30][C:31]([O:33][CH2:34][CH3:35])=[O:32])[C:26]([O:28][CH3:29])=[O:27])=[CH:20][CH:19]=2)[CH:15]=[CH:16][CH:17]=1)[CH3:10])(=[O:8])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH3:7]>C(OCC)(=O)C.[Pd]>[C:1]([N:9]([CH2:11][C:12]1[CH:13]=[C:14]([C:18]2[CH:23]=[CH:22][C:21]([CH2:24][CH:25]([CH2:30][C:31]([O:33][CH2:34][CH3:35])=[O:32])[C:26]([O:28][CH3:29])=[O:27])=[CH:20][CH:19]=2)[CH:15]=[CH:16][CH:17]=1)[CH3:10])(=[O:8])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH3:7]
Reactant: CCCCCCC(=O)N(C)Cc1cccc(-c2ccc(C=C(CC(=O)OCC)C(=O)OC)cc2)c1
Agent: [Pd]
Solvent: CCOC(C)=O
Product: CCCCCCC(=O)N(C)Cc1cccc(-c2ccc(CC(CC(=O)OCC)C(=O)OC)cc2)c1
Yield: 77.1 %

Procedure:
In a manner similar to that of Example 1(g), starting with 1.70 g (3.5 mmol) of methyl ethyl 2-{3′-[(heptanoylmethylamino)methyl]biphenyl-4-ylmethylene}succinate and 170 mg (10% by mass) of 10% palladium-on-charcoal in 20 ml of ethyl acetate, 1.30 g (77%) of the expected product are obtained.
Reaction SMILES: [C:1]([C:3]1[C:4]([N:21]2[CH2:29][C@@H:28]3[C@@H:23]([CH2:24][CH2:25][CH2:26][NH:27]3)[CH2:22]2)=[C:5]([F:20])[CH:6]=[C:7]2[C:12]=1[N:11]([CH:13]1[CH2:15][CH2:14]1)[CH:10]=[C:9]([C:16]([OH:18])=[O:17])[C:8]2=[O:19])#[N:2].C1(C)C([S:36]([OH:39])(=[O:38])=[O:37])=CC=CC=1.C(O)C>O>[S:36]([C:6]1[CH:5]=[CH:4][C:3]([CH3:1])=[CH:12][CH:7]=1)([OH:39])(=[O:38])=[O:37].[C:1]([C:3]1[C:4]([N:21]2[CH2:29][C@@H:28]3[C@@H:23]([CH2:24][CH2:25][CH2:26][NH:27]3)[CH2:22]2)=[C:5]([F:20])[CH:6]=[C:7]2[C:12]=1[N:11]([CH:13]1[CH2:14][CH2:15]1)[CH:10]=[C:9]([C:16]([OH:18])=[O:17])[C:8]2=[O:19])#[N:2]
Reactant: Cc1ccccc1S(=O)(=O)O
Agent: N#Cc1c(N2C[C@@H]3CCCN[C@@H]3C2)c(F)cc2c(=O)c(C(=O)O)cn(C3CC3)c12
Solvent: CCO
Solvent: O
Product: Cc1ccc(S(=O)(=O)O)cc1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
250 mg (0.63 mmol) of 8-cyano-1-cyclopropyl-7-((1S,6S)-2,8-diazabicyclo[4.3.0]nonan-8-yl)-6-fluoro-1,4-dihydro-4-oxo-3-quinolinecarboxylic acid are dissolved in 2 ml of water, and one equivalent of toluenesulfonic acid is added. The solution is stirred at room temperature for 30 minutes and then poured onto 20 ml of ethanol. The resulting precipitate is filtered off with suction and then dried.
Reaction SMILES: [O:1]1[CH:5]=[CH:4][C:3]([O:6][CH2:7][C@@H:8]2[O:12][C:11](=[O:13])[N:10]([C:14]3[CH:19]=[CH:18][C:17]([C:20]4[CH2:25][CH2:24][N:23]([CH2:26][CH2:27][OH:28])[CH2:22][CH:21]=4)=[C:16]([F:29])[CH:15]=3)[CH2:9]2)=[N:2]1.C(N(CC)CC)C.[C:37](Cl)(=[O:39])[CH3:38].O>ClCCl>[O:1]1[CH:5]=[CH:4][C:3]([O:6][CH2:7][C@@H:8]2[O:12][C:11](=[O:13])[N:10]([C:14]3[CH:19]=[CH:18][C:17]([C:20]4[CH2:25][CH2:24][N:23]([CH2:26][CH2:27][O:28][C:37](=[O:39])[CH3:38])[CH2:22][CH:21]=4)=[C:16]([F:29])[CH:15]=3)[CH2:9]2)=[N:2]1
Reactant: CC(=O)Cl
Reactant: O=C1O[C@@H](COc2ccon2)CN1c1ccc(C2=CCN(CCO)CC2)c(F)c1
Solvent: O
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(=O)OCCN1CC=C(c2ccc(N3C[C@H](COc4ccon4)OC3=O)cc2F)CC1
Temperature: 25 °C
Reaction time: 1 h
Yield: 95 %

Procedure:
To a stirred solution of Example 57(103 mg, 0.26 mmol) and triethylamine (77.4 mg, 0.77 mmol) in dichloromethane (10 ml) at 0° C. and under an atmosphere of nitrogen, was added dropwise acetyl chloride (60.2 mg, 0.77 mmol). The reaction was then allowed to warm to ambient temperature and stir for 1 hour. Water was added and the organic phase separated, washed with sat NaCl and then dried over MgSO4 and evaporated under reduced pressure. This yielded the title compound as a clear orange glass (110 mg, 97%). MS: ESP+ (M+H)+=446.
Reaction SMILES: Br[C:2]1[CH:10]=[C:9]2[C:5]([CH2:6][C:7](=[O:11])[NH:8]2)=[CH:4][CH:3]=1.[Na+].[I-:13].CN[C@@H]1CCCC[C@H]1NC.[NH4+].[OH-]>[Cu]I.O1CCOCC1>[I:13][C:2]1[CH:10]=[C:9]2[C:5]([CH2:6][C:7](=[O:11])[NH:8]2)=[CH:4][CH:3]=1
Reactant: O=C1Cc2ccc(Br)cc2N1
Reactant: [I-]
Agent: [Cu]I
Agent: CN[C@@H]1CCCC[C@H]1NC
Agent: [NH4+]
Solvent: C1COCCO1
Product: O=C1Cc2ccc(I)cc2N1
Temperature: 25 °C
Yield: 84 %

Procedure:
A schlenk tube and stir bar were dried in an oven overnight and then were evacuated, filled with Ar(g) and cooled. The schlenk tube was charged with CuI (45 mg, 0.236 mmol, 5 mol %), 6-bromoxindole (1.0 g, 4.72 mmol), and NaI (1.42 g, 9.44 mmol). The schlenk tube was evacuated and backfilled with Ar(g) (3 times). Racemic trans-N,N′-dimethyl-1,2-cyclohexanediamine (74 μL, 0.472 mmol, 10 mol %) and anhydrous dioxane (4.72 mL) were added via syringe under Ar(g). The schlenk tube was sealed with a teflon valve and the suspension was stirred at 110° C. for 24 h. The reaction was then cooled to room temperature and 15% NH4OH(aq) (˜50 mL) was added to the reaction mixture while stirring. The suspension was allowed to stir for about 30 min after which the tan solid was vacuum filtered and dried affording 6-Iodooxindole in 84% yield (1.027 g, 3.96 mmol).
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[N:9]=[C:10]=[O:11].[NH2:12][C:13]1[CH:18]=[CH:17][C:16]([C:19]2[CH:23]=[C:22]([C:24]([NH:26][CH:27]([CH2:32][C:33]3[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=3)[C:28]([O:30][CH3:31])=[O:29])=[O:25])[O:21][N:20]=2)=[CH:15][CH:14]=1>>[F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[NH:9][C:10](=[O:11])[NH:12][C:13]1[CH:18]=[CH:17][C:16]([C:19]2[CH:23]=[C:22]([C:24]([NH:26][CH:27]([CH2:32][C:33]3[CH:34]=[CH:35][CH:36]=[CH:37][CH:38]=3)[C:28]([O:30][CH3:31])=[O:29])=[O:25])[O:21][N:20]=2)=[CH:15][CH:14]=1
Reactant: O=C=Nc1ccc(F)cc1F
Reactant: COC(=O)C(Cc1ccccc1)NC(=O)c1cc(-c2ccc(N)cc2)no1
Product: COC(=O)C(Cc1ccccc1)NC(=O)c1cc(-c2ccc(NC(=O)Nc3ccc(F)cc3F)cc2)no1
Yield: 62 %

Procedure:
The title compound was prepared according to the procedure as set forth in example 151, except that 2,4-difluoro-1-isocyanatobenzene was used in place of 1-fluoro-3-isocyanatobenzene and methyl 2-(3-(4-aminophenyl)isoxazole-5-carboxamido)-3-phenylpropanoate was used in place of methyl 2-(3-(4-aminophenyl)isoxazole-5-carboxamido)-3-methylbutanoate to yield 62% of title compound. MS (ESI): m/z 521.2 (M+H)+; 1HNMR (DMSO-d6, 300 MHz) δ: 9.43(d, 1H), 9.28 (s, 1H), 8.58(s, 1H), 8.10 (m, 1H), 7.84 (d, 2H), 7.60 (d, 2H), 7.55 (s, 1H), 7.34 (m, 5H), 7.20 (m, 1H), 7.07 (m, 1H), 4.74 (m. 1H), 3.64 (s, 3H), 3.23 (m, 2H).
Reaction SMILES: N12CCCN=C1CCCCC2.[Br:12][C:13]1[N:18]=[CH:17][C:16]([CH:19]=O)=[CH:15][CH:14]=1.[C:21]([O:25][C:26]([NH:28][CH:29](P(OC)(OC)=O)[C:30]([O:32][CH3:33])=[O:31])=[O:27])([CH3:24])([CH3:23])[CH3:22]>C(Cl)Cl>[Br:12][C:13]1[N:18]=[CH:17][C:16]([CH:19]=[C:29]([NH:28][C:26]([O:25][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:27])[C:30]([O:32][CH3:33])=[O:31])=[CH:15][CH:14]=1
Reactant: O=Cc1ccc(Br)nc1
Reactant: COC(=O)C(NC(=O)OC(C)(C)C)P(=O)(OC)OC
Solvent: C1CCC2=NCCCN2CC1
Solvent: ClCCl
Product: COC(=O)C(=Cc1ccc(Br)nc1)NC(=O)OC(C)(C)C
Reaction time: 2 h
Yield: 84 %

Procedure:
1,8-Diazabicyclo[5.4.0]undec-7-ene (480 uL, 3.2 mmol) was added to a mixture of 6-bromo-pyridine-3-carbaldehyde (Aldrich, Cat. #596280) (500 mg, 3 mmol) and methyl [(tert-butoxycarbonyl)amino](dimethoxyphosphoryl)acetate (Fluka, Cat. #09659) (960 mg, 3.2 mmol) in methylene chloride (5 mL) at r.t. under N2. The reaction was stirred for 2 h. The reaction was partitioned between EtOAc and 1 N HCl. The organic layer was washed with brine, dried over MgSO4, filtered and concentrated under reduced pressure to give crude methyl 3-(6-bromopyridin-3-yl)-2-[(tert-butoxycarbonyl)amino]acrylate (0.9 g, 93%) as an off white solid. Analytical LCMS (M+H)+: m/z=356.8, 358.9.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([NH2:8])[CH:5]=[C:4]([Cl:9])[N:3]=1.C[O:11][CH:12]=[C:13]1C(=O)OC(C)(C)O[C:14]1=O>CC(O)C>[Cl:9][C:4]1[N:3]=[C:2]([Cl:1])[CH:7]=[C:6]2[C:5]=1[C:12]([OH:11])=[CH:13][CH:14]=[N:8]2
Reactant: Nc1cc(Cl)nc(Cl)c1
Reactant: COC=C1C(=O)OC(C)(C)OC1=O
Solvent: CC(C)O
Product: Oc1ccnc2cc(Cl)nc(Cl)c12
Temperature: 100 °C
Yield: 61.8 %

Procedure:
To a flask equipped with a reflux condenser, 2,6-dichloropyridin-4-amine (2.00 g, 12.27 mmol) and 5-(methoxymethylene)-2,2-dimethyl-1,3-dioxane-4,6-dione (2.398 g, 12.88 mmol) were dissolved in IPA (12.00 mL) and heated to 100° C. for 1 hour. The reaction was cooled to room temperature and the solids were filtered. The solids were added to a microwave vial followed by dichlorobenzene (12.00 mL). The vial was capped and heated to 250° C. for 15 minutes. The reaction was purified via silica gel MPLC chromatography (40 g), eluting with 0 to 100% ethyl acetate in heptanes. The fractions were collected and the solvent was removed under reduced pressure to provide 1.63 g of 5,7-dichloro-1,6-naphthyridin-4-ol as an off white solid. m/z (ESI) 215.1 (M+H)+.
Reaction SMILES: [CH3:1][C:2]1([CH3:11])[S:7][CH2:6][CH2:5][NH:4][CH:3]1[C:8]([OH:10])=[O:9].[CH2:12]=O.Cl>C(O)=O>[CH3:1][C:2]1([CH3:11])[S:7][CH2:6][CH2:5][N:4]([CH3:12])[CH:3]1[C:8]([OH:10])=[O:9]
Reactant: C=O
Reactant: CC1(C)SCCNC1C(=O)O
Agent: Cl
Solvent: O=CO
Product: CN1CCSC(C)(C)C1C(=O)O

Procedure:
A mixture of 2,2-Dimethyl-thiomorpholine-3-carboxylic acid (3.51 g, 20 mmol, BE 893025), formic acid (5.12 g of 90%) and formalin (4.5 mL of 37%) is heated at reflux for 8 hours. The reaction mixture is then cooled and treated with hydrochloric acid (10 mL of 4N) and evaporated to dryness. A portion of this residue is purified by HPLC to give 2,2,4-trimethyl-thiomorpholine-3-carboxylic acid, which is used as is. 2,2,4-Trimethyl-thiomorpholine-3-carboxylic acid (388 mg, 2.05 mmol) is stirred with dichloromethane (4 mL) and dimethylformamide (4 mL). To this is added (benzotriazol-1-yloxy)tripyrrolidinophosphonium hexafluorophosphate (PyBOP, 1.07 g, 2.05 mmol). After 15 min, ethyl (2E,4S)-2,5-dimethyl-4-[methyl(3-methyl-L-valyl)amino]hex-2-enoate (0.640 g, 2.05 mmol, WO 99/32509) is added in dichlormethane (5 mL) followed by diisopropylethylamine (0.8 mL, 4.4 mmol). This is stirred at room temperature overnight. The reaction mixture is evaporated in vacuo and the residue treated with ethyl acetate and water. The ethyl acetate layer is dried over sodium sulfate, filtered and concentrated. The resulting material (314 mg, 0.65 mmol) is treated with aqueous 1M lithium hydroxide solution (3.3 mL, 3.3 mmol), water (1.6 mL) and methanol (6.5 mL), to provide the trifluoroacetic acid salt of the title compound as a white solid after preparative HPLC, MS (ES): m/z 456.29 (M+H).