Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:9]=[CH:8][CH:7]=[C:6]([CH3:10])[C:3]=1[C:4]#[N:5].[Br:11]N1C(=O)CCC1=O.N(C(C)(C)C#N)=NC(C)(C)C#N>C(Cl)(Cl)(Cl)Cl.ClCCl>[Br:11][CH2:10][C:6]1[CH:7]=[CH:8][CH:9]=[C:2]([Cl:1])[C:3]=1[C:4]#[N:5]
Reactant: Cc1cccc(Cl)c1C#N
Reactant: O=C1CCC(=O)N1Br
Agent: CC(C)(C#N)N=NC(C)(C)C#N
Solvent: ClC(Cl)(Cl)Cl
Solvent: ClCCl
Product: N#Cc1c(Cl)cccc1CBr
Yield: 46.7 %

Procedure:
To a solution of 2-chloro-6-methylbenzonitrile (2.0 g, 13 mmol) and N-bromosuccinimide (2.6 g, 15 mmol) in carbon tetrachloride (20 mL) was added azobisisobutyronitrile (0.20 g, 1.2 mmol). The mixture was refluxed for 3 h and then cooled, diluted with dichloromethane and washed with water and brine. The organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated in vacuo. The resultant oil was purified via flash column chromatography (ethyl acetate:hexane, 0:100 to 30:70) to yield white solid product (1.4 g, 46%). 1H NMR (400 MHz, CDCl3) δ 7.43-7.59 (m, 3H), 4.64 (s, 2H).
Reaction SMILES: [N+]([C:4]1[CH:5]=[C:6]2[C:11](=[O:12])[O:10][C:8](=[O:9])[C:7]2=[CH:13][CH:14]=1)([O-])=O.[F-:15].[K+].Cl>CS(C)=O>[F:15][C:4]1[CH:5]=[C:6]2[C:11](=[O:12])[O:10][C:8](=[O:9])[C:7]2=[CH:13][CH:14]=1
Reactant: [F-]
Reactant: O=C1OC(=O)c2cc([N+](=O)[O-])ccc21
Agent: Cl
Agent: [K+]
Solvent: CS(C)=O
Product: O=C1OC(=O)c2cc(F)ccc21
Temperature: 25 °C
Reaction time: 0.58 h
Yield: 34.8 %

Procedure:
To a reaction vessel fitted with a reflux condenser magnetic stirrer and nitrogen inlet were placed 3.35 grams (0.0174 mol) 4-nitrophthalic anhydride, 2.83 grams (0.036 mol) anhydrous potassium fluoride, and 8 ml. dry dimethyl sulfoxide. The reaction vessel was placed in an oil bath at 142°C. and kept at this temperature for about 35 minutes while stirring the reaction mixture. VPC analysis of a portion of the reaction mixture showed that the reaction was complete after about 20 minutes. The reaction mixture was cooled to room temperature and then poured into dilute aqueous hydrochloric acid and extracted with ethyl acetate to give a product which upon distillation gave 1.007 grams (about 35% yield) of 4-fluorophthalic anhydride.
Reaction SMILES: CC(OI1(OC(C)=O)(OC(C)=O)OC(=O)C2C=CC=CC1=2)=O.[CH3:23][O:24][CH2:25][CH2:26][O:27][C:28](=[O:53])[NH:29][C@H:30]([C:35]([NH:37][C@@H:38]([CH2:46][C:47]1[CH:52]=[CH:51][CH:50]=[CH:49][CH:48]=1)[CH:39]([OH:45])[C:40]([NH:42][CH2:43][CH3:44])=[O:41])=[O:36])[CH2:31][CH:32]([CH3:34])[CH3:33].S([O-])([O-])(=O)=S.[Na+].[Na+].C(=O)([O-])O.[Na+]>ClCCl>[CH3:23][O:24][CH2:25][CH2:26][O:27][C:28](=[O:53])[NH:29][C@H:30]([C:35]([NH:37][C@@H:38]([CH2:46][C:47]1[CH:52]=[CH:51][CH:50]=[CH:49][CH:48]=1)[C:39](=[O:45])[C:40](=[O:41])[NH:42][CH2:43][CH3:44])=[O:36])[CH2:31][CH:32]([CH3:34])[CH3:33]
Reactant: CCNC(=O)C(O)[C@H](Cc1ccccc1)NC(=O)[C@H](CC(C)C)NC(=O)OCCOC
Agent: CC(=O)OI1(OC(C)=O)(OC(C)=O)OC(=O)c2ccccc21
Agent: O=C([O-])O
Agent: O=S([O-])([O-])=S
Solvent: ClCCl
Product: CCNC(=O)C(=O)[C@H](Cc1ccccc1)NC(=O)[C@H](CC(C)C)NC(=O)OCCOC
Temperature: 25 °C
Reaction time: 18 h
Yield: 89 %

Procedure:
Triethylamine (1.1 g, 11 mmol) was added to a solution of the compound of Reference Example 1 (1.2 g, 3.6 mmol) and the compound of Reference Example 8 (1.0 g, 4.0 mmol) in DMF. This solution was stirred at room temperature for 18 hours and concentrated in vacuo. The residue was dissolved in ethyl acetate, and the solution was washed with 1M hydrochloric acid, saturated aqueous sodium hydrogen carbonate solution, and saturated saline solution, dehydrated with anhydrous magnesium sulfate, and concentrated in vacuo. The resulting solid was washed with a liquid mixture of ethyl acetate/hexane (1:9) to yield ((1S)-1-((((1S)-1-benzyl-3-ethylamino-2-hydroxy-3-oxopropyl)amino)carbonyl)-3-methylbutyl)carbamic acid 2-methoxyethyl ester (0.75 g, 47%) as a white solid. A Dess-Martin reagent (1.0 g, 2.4 mmol) was added to a solution of ((1S)-1-((((1S)-1-benzyl-3-ethylamino-2-hydroxy-3-oxopropyl)amino)carbonyl)-3-methylbutyl)carbamic acid 2-methoxyethyl ester (0.7 g, 1.6 mmol) in dichloromethane (70 mL), and the resulting solution was stirred at room temperature for 18 hours. Thereafter, a 10% aqueous sodium thiosulfate solution (35 mL) and a saturated aqueous sodium hydrogen carbonate solution (35 mL) were added thereto, and the mixture was stirred at room temperature for 30 minutes. The organic layer was separated, washed with 1M hydrochloric acid, saturated aqueous sodium hydrogen carbonate solution, and saturated saline solution, dehydrated with anhydrous magnesium sulfate, and concentrated in vacuo. The residue was crystallized from a liquid mixture of ethyl acetate/hexane to yield the title compound (0.62 g, 88%) as a colorless crystal.
Reaction SMILES: [C:1]12([C:11]3[CH:16]=[C:15](I)[CH:14]=[CH:13][C:12]=3[O:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH3:26])[CH2:10][CH:5]3[CH2:6][CH:7]([CH2:9][CH:3]([CH2:4]3)[CH2:2]1)[CH2:8]2.IC1C=C2C(C=CN2)=CC=1.[C:37]([C:39]1([NH:47][C:48](=[O:54])[O:49][C:50]([CH3:53])([CH3:52])[CH3:51])[CH2:44][O:43][C:42]([CH3:46])([CH3:45])[O:41][CH2:40]1)#[CH:38].C(C1C=CC(C2C=CC=CC=2C(F)(F)F)=CC=1)#C>>[C:1]12([C:11]3[CH:16]=[C:15]([C:38]#[C:37][C:39]4([NH:47][C:48](=[O:54])[O:49][C:50]([CH3:53])([CH3:52])[CH3:51])[CH2:44][O:43][C:42]([CH3:46])([CH3:45])[O:41][CH2:40]4)[CH:14]=[CH:13][C:12]=3[O:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH3:26])[CH2:10][CH:5]3[CH2:6][CH:7]([CH2:9][CH:3]([CH2:4]3)[CH2:2]1)[CH2:8]2
Reactant: C#CC1(NC(=O)OC(C)(C)C)COC(C)(C)OC1
Reactant: CCCCCCCCOc1ccc(I)cc1C12CC3CC(CC(C3)C1)C2
Agent: C#Cc1ccc(-c2ccccc2C(F)(F)F)cc1
Agent: Ic1ccc2cc[nH]c2c1
Product: CCCCCCCCOc1ccc(C#CC2(NC(=O)OC(C)(C)C)COC(C)(C)OC2)cc1C12CC3CC(CC(C3)C1)C2

Procedure:
When the product of Step A was substituted for 6-iodoindole and tert-butyl 5-ethynyl-2,2-dimethyl-1,3-dioxan-5-ylcarbamate was substituted for 4′-ethynyl-2-(trifluoromethyl) biphenyl in Example 59, Step B the identical process afforded the title compound in 48%, as creamy paste. 1H-NMR (CDCl3) 0.85 (tr, 3H, J=8.99 Hz); 1.27-1.47 (m, 23H); 1.73 (s, 6H); 1.8-1.87 (m, 2H); 2.06 (s, 9H); 3.94 (tr, 2H, J=6.34 Hz); 3.99 (d, 2H, J=11.44 Hz); 4.08 (d, 2H, J=11.52 Hz); 5.17 (s, 1H); 6.73 (d, 1H, J=8.41 Hz); 7.19-7.21 (m, 2H).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([NH:11][C@@H:12]([CH2:16]O)[CH2:13][CH2:14][OH:15])(=[O:10])=[O:9])=[CH:4][CH:3]=1.C(P(CCCC)CCCC)CCC>C1COCC1>[F:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([N:11]2[CH2:16][C@H:12]2[CH2:13][CH2:14][OH:15])(=[O:10])=[O:9])=[CH:4][CH:3]=1
Reactant: O=S(=O)(N[C@@H](CO)CCO)c1ccc(F)cc1
Agent: CCCCP(CCCC)CCCC
Solvent: C1CCOC1
Product: O=S(=O)(c1ccc(F)cc1)N1C[C@H]1CCO
Reaction time: 2 h
Yield: 95 %

Procedure:
To 4-fluoro-N-[(1R)-3-hydroxy-1-(hydroxymethyl)propyl]benzenesulfonamide (35.0 g, 133 mmol) in THF (700 mL) was added 1,1′-(azodicarbonyl)dipepiridine (35.0 g, 139 mmol, 1.04 equiv.) followed by tributylphosphine (28.7 g, 142 mmol, 1.07 equiv.) over 10 min. After a period of 2 h, the reaction mixture was filtered and the solid washed with methyl tert-butyl ether (100 mL). Water (200 mL) was added to the filtrate and the organic phase was separated which in turn was washed with 100 mL of 3% hydrogen peroxide. The organic phase was then washed with water and half-saturated sodium chloride. The organic phase was collected, dried over magnesium sulfate, filtered and evaporated under reduced pressure. The residue was treated with methyl tert-butyl ether and the mixture filtered. The filtrate was evaporated and purified by flash chromatography with 50% ethyl acetate to 70% ethyl acetate in hexane to provide 31 g of the title compound.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:24]=[CH:25][C:26]=1[C:27]([F:30])([F:29])[F:28])/[CH:5]=[C:6]1/[C:7](=[O:23])[C:8]2[C:13]([CH2:14]/1)=[CH:12][C:11]([N:15]1[CH2:20][CH2:19][O:18][CH2:17][CH2:16]1)=[C:10]([O:21][CH3:22])[CH:9]=2>C(OCC)(=O)C.[Pd]>[Cl:1][C:2]1[CH:3]=[C:4]([CH:24]=[CH:25][C:26]=1[C:27]([F:28])([F:29])[F:30])[CH2:5][CH:6]1[CH2:14][C:13]2[C:8](=[CH:9][C:10]([O:21][CH3:22])=[C:11]([N:15]3[CH2:16][CH2:17][O:18][CH2:19][CH2:20]3)[CH:12]=2)[C:7]1=[O:23]
Reactant: COc1cc2c(cc1N1CCOCC1)C/C(=C\c1ccc(C(F)(F)F)c(Cl)c1)C2=O
Agent: [Pd]
Solvent: CCOC(C)=O
Product: COc1cc2c(cc1N1CCOCC1)CC(Cc1ccc(C(F)(F)F)c(Cl)c1)C2=O
Reaction time: 6 h

Procedure:
The 91 (220 mg, 0.502 mmol) was dissolved in ethyl acetate 150 mL, Pd/C 100 mg added, and the reaction stirred under hydrogen balloon for 6 h, then filtered through celite bed and washed with excess methanol. The organic layer was concentrated to get the crude 92 which was purified by flash chromatography using 100-200 mesh silica gel. The compound was eluted at 28% ethyl acetate in hexane as half white coloured solid compound 2-(3-chloro-4-(trifluoromethyl)benzyl)-6-methoxy-5-morpholino-2,3-dihydro-1H-inden-1-one 92. 1HNMR (400 MHz, CDCl3) δ ppm 7.59 (d, 1H), 7.49 (d, 1H), 7.31 (m, 1H), 7.19 (s, 1H), 6.83 (s, 1H), 3.89 (m, 3H), 3.87 (m, 4H), 3.53 (m, 1H), 3.17 (m, 4H), 3.07 (m, 2H), 2.91 (m, 1H), 2.73 (m, 1H); MS (ESI) m/z 440.0 (M+H).
Reaction SMILES: [C:1]([C:5]1[N:6]=[C:7]([CH2:10][CH2:11][C:12]2[CH:13]=[C:14]([CH:41]=[CH:42][CH:43]=2)[C:15]([NH:17][C:18]2[CH:23]=[C:22]([CH2:24][CH2:25][CH2:26][S:27]([C:30]3[CH:35]=[CH:34][C:33]([Cl:36])=[CH:32][CH:31]=3)(=[O:29])=[O:28])[CH:21]=[CH:20][C:19]=2[O:37][CH2:38][C:39]#[N:40])=[O:16])[S:8][CH:9]=1)([CH3:4])([CH3:3])[CH3:2].[Cl-].[NH4+].[N-:46]=[N+:47]=[N-:48].[Na+].C(O)(=O)CC(CC(O)=O)(C(O)=O)O>CN(C)C=O>[C:1]([C:5]1[N:6]=[C:7]([CH2:10][CH2:11][C:12]2[CH:13]=[C:14]([CH:41]=[CH:42][CH:43]=2)[C:15]([NH:17][C:18]2[CH:23]=[C:22]([CH2:24][CH2:25][CH2:26][S:27]([C:30]3[CH:31]=[CH:32][C:33]([Cl:36])=[CH:34][CH:35]=3)(=[O:29])=[O:28])[CH:21]=[CH:20][C:19]=2[O:37][CH2:38][C:39]2[NH:48][N:47]=[N:46][N:40]=2)=[O:16])[S:8][CH:9]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)c1csc(CCc2cccc(C(=O)Nc3cc(CCCS(=O)(=O)c4ccc(Cl)cc4)ccc3OCC#N)c2)n1
Reactant: [N-]=[N+]=[N-]
Agent: O=C(O)CC(O)(CC(=O)O)C(=O)O
Agent: [Cl-]
Agent: [NH4+]
Solvent: CN(C)C=O
Product: CC(C)(C)c1csc(CCc2cccc(C(=O)Nc3cc(CCCS(=O)(=O)c4ccc(Cl)cc4)ccc3OCc3nnn[nH]3)c2)n1
Temperature: 70 °C
Reaction time: 12 h
Yield: 55.6 %

Procedure:
Dimethylformamide (5.0 ml) was added to a mixture of 3-[2-(4-tert-butyl-2-thiazolyl)ethyl]-5'-[3-(4-chlorophenylsulfonyl)propyl]-2'-cyanomethoxybenzanilide (0.57 g, 0.90 mmol), ammonium chloride (96 mg, 1.8 mmol) and sodium azide (0.12 g, 1.9 mmol), and the resulting mixture was stirred at 70° C. for 12 hours. Ice and 10% citric acid aqueous solution were added to the reaction solution, and the product formed was extracted with ethyl acetate. The resulting organic layer was washed with water and brine in that order, dried over anhydrous magnesium sulfate, and then concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (eluent=methanol:chloroform=3:100) and then crystallized from acetonitrile to give 3-[2-(4-tert-butyl-2-thiazolyl)ethyl]-5'-[3-(4-chlorophenylsulfonyl)propyl]-2'-(1H-tetrazol-5-ylmethoxy)benzanilide (0.34 g, 0.50 mmol, 56%) as colorless crystals. Its structure is shown in Table 30.
Reaction SMILES: [F:1][C:2]([F:21])([F:20])[C:3]([C:9]1[CH:14]=[CH:13][C:12]([CH2:15][CH2:16][C:17]([OH:19])=[O:18])=[CH:11][CH:10]=1)([OH:8])[C:4]([F:7])([F:6])[F:5].[N+:22]([O-])([OH:24])=[O:23].O>S(=O)(=O)(O)O>[N+:22]([C:11]1[CH:10]=[C:9]([C:3]([OH:8])([C:4]([F:6])([F:5])[F:7])[C:2]([F:20])([F:21])[F:1])[CH:14]=[CH:13][C:12]=1[CH2:15][CH2:16][C:17]([OH:19])=[O:18])([O-:24])=[O:23]
Reactant: O=C(O)CCc1ccc(C(O)(C(F)(F)F)C(F)(F)F)cc1
Reactant: O=[N+]([O-])O
Agent: O=S(=O)(O)O
Solvent: O
Product: O=C(O)CCc1ccc(C(O)(C(F)(F)F)C(F)(F)F)cc1[N+](=O)[O-]
Reaction time: 18 h

Procedure:
To a solution of 63.2 g (0.20 mole) of 4-[2,2,2-trifluoro-1-hydroxy-1-(trifluoromethyl)ethyl]benzenepropanoic acid in 160 ml of concentrated sulfuric acid is added 40 ml of fuming nitric acid (90%) dropwise with stirring at 0°-5°. Following the nitric acid addition the solution is allowed to warm to 20° with stirring over a 1-hour period. The solutionis then added to a mixture of ice and water and allowed to stand for 18 hours. A precipitate results and is filtered, washed with water and dissolved in ether to obtain a solution which is washed with water, dried with anhydrous magnesium sulfate, filtered, and evaporated to give a residual solid. The residual solid is recrystallized from chlorobutane to give 40 g of 2-nitro-4-[2,2,2-trifluoro-1-hydroxy-1-(trifluoromethyl)ethyl]benzenepropanoic acid having a melting point of 115°-116°.
Reaction SMILES: [C:1]([C:5]1[CH:6]=[C:7]([NH2:14])[C:8]([O:12][CH3:13])=[C:9]([NH2:11])[CH:10]=1)([CH3:4])([CH3:3])[CH3:2].C(N(CC)CC)C.[CH3:22][S:23](Cl)(=[O:25])=[O:24].C(=O)(O)[O-].[Na+]>C(Cl)Cl>[NH2:14][C:7]1[C:8]([O:12][CH3:13])=[C:9]([NH:11][S:23]([CH3:22])(=[O:25])=[O:24])[CH:10]=[C:5]([C:1]([CH3:4])([CH3:2])[CH3:3])[CH:6]=1
Reactant: COc1c(N)cc(C(C)(C)C)cc1N
Reactant: CS(=O)(=O)Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COc1c(N)cc(C(C)(C)C)cc1NS(C)(=O)=O
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
To an oven dried 250 mL round bottom flask containing 5.0 g (25.73 mmol) 5-tert-butyl-2-methoxy-benzene-1,3-diamine, 150 mL DCM was added. The reaction mixture was cooled to 0° C. after which triethylamine (5.0 mL, 36.0 mmol) was added followed by the drop wise addition of methylsulfonyl chloride (1.99 mL, 25.7 mmol). The reaction was allowed to stir at 0° C. for 30 min. then warmed to room temperature stirring for an additional 2 h. The reaction mixture was poured over saturated solution of sodium bicarbonate (100 mL) and the layers separated. The aqueous layer was washed twice more with 50 mL dichloromethane and the combined organic layers were dried over magnesium sulfate and concentrated under vacuum to afford a crude oil that was purified by flash chromatography (silica gel, 1:1 EtOAc:Hex) yo yield 6.1 g of the desired product (87%). Calculated mass=272. Observed mass=273
Reaction SMILES: [N:1]1([C:7]2[CH:8]=[C:9]([C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=3)[CH:10]=[CH:11][CH:12]=2)[CH2:6][CH2:5][NH:4][CH2:3][CH2:2]1.C(=O)([O-])[O-].[K+].[K+].[Cl:25][CH2:26][C:27]1[CH:32]=[CH:31][C:30]([CH3:33])=[CH:29][CH:28]=1.[ClH:34]>C(#N)C.CC(C)=O>[ClH:25].[ClH:34].[CH3:26][C:27]1[CH:32]=[CH:31][C:30]([CH2:33][N:4]2[CH2:5][CH2:6][N:1]([C:7]3[CH:8]=[C:9]([C:13]4[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=4)[CH:10]=[CH:11][CH:12]=3)[CH2:2][CH2:3]2)=[CH:29][CH:28]=1
Reactant: c1ccc(-c2cccc(N3CCNCC3)c2)cc1
Reactant: Cc1ccc(CCl)cc1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Solvent: CC(C)=O
Product: Cc1ccc(CN2CCN(c3cccc(-c4ccccc4)c3)CC2)cc1
Reaction time: 16 h

Procedure:
To a solution of 3-[1-piperazinyl]biphenyl (11.9 g) in aceonitrile (200 cc), there is added potassium carbonate (6.9 g) and then, in the course of 20 minutes, a solution of α-chloro-p-xylene (8 g) in acetonitrile (50 cc), at a temperature in the region of 20° C., and stirring is continued for 16 hours. The insoluble material which has formed is separated by filtration. The solution obtained is concentrated under reduced pressure (20 mm Hg; 2.7 kPa) at 40° C. The residue is dissolved in methylene chloride (30 cc) and the solution poured onto silica (1 kg) contained in a column 8 cm in diameter. Elution is performed with a mixture (3 liters) of methylene chloride and methanol (97.5:2.5 by volume) and the corresponding eluate is concentrated to dryness under reduced pressure (20 mm Hg; 2.7 kPa) at 50° C. The residue obtained is dissolved in acetone (600 cc). The solution is cooled to a temperature in the region of 5° C., 2.5N ethereal hydrogen chloride (40 cc) is added and stirring is maintained for approximately 1 hour. The precipitate formed is separated by filtration and washed with acetone (2×40 cc). 3-[4-(4-Methylbenzyl)-1-piperzinyl]biphenyl dihydrochloride (17.3 g), m.p. 241° C., is thereby obtained.
Reaction SMILES: [CH2:1]=[C:2]([CH2:6][C:7]([OH:9])=[O:8])[C:3]([OH:5])=[O:4].[CH3:10]C1C=CC(S(N)(=O)=O)=CC=1>CO>[CH3:10][O:8][C:7](=[O:9])[CH2:6][C:2](=[CH2:1])[C:3]([OH:5])=[O:4]
Reactant: Cc1ccc(S(N)(=O)=O)cc1
Reactant: C=C(CC(=O)O)C(=O)O
Solvent: CO
Product: C=C(CC(=O)OC)C(=O)O
Temperature: 40 °C
Reaction time: 48 h
Yield: 6533.8 %

Procedure:
To a solution of 2-methylenesuccinic acid (5.0 g, 38.4 mmol) in MeOH (200 mL) was added p-toluenesulfonamide (100 mg). The mixture was stirred at 40° C. for 2 days. The mixture was concentrated to dryness. To the residue was added DCM (200 mL). The precipitate was removed by filtration and the filtrate was concentrated to dryness to give the product as a white solid (5.5 g, 99% yield). ESI MS: m/z 145.1 [M+H]+. 1H NMR (400 MHz, CDCl3): δ 11.17 (bs, 1H), 6.48 (s, 1H), 5.85 (s, 1H), 3.71 (s, 3H), 3.36 (s, 2H).
Reaction SMILES: [Cl:1][C:2]1[C:3](=[O:15])[NH:4][S:5](=[O:14])(=[O:13])[C:6]=1[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1.CI.[C:18](=O)([O-])[O-].[K+].[K+].O>CN(C=O)C>[Cl:1][C:2]1[C:3](=[O:15])[N:4]([CH3:18])[S:5](=[O:13])(=[O:14])[C:6]=1[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1
Reactant: O=C1NS(=O)(=O)C(c2ccccc2)=C1Cl
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Solvent: CI
Product: CN1C(=O)C(Cl)=C(c2ccccc2)S1(=O)=O
Temperature: 25 °C
Reaction time: 21 h
Yield: 104 %

Procedure:
A solution of 4-chloro-5-phenylisothiazol-3(2H)-one 1,1-dioxide (2.0 g, 8.21 mmol) and MeI (3.5 g, 24.6 mmol) in DMF (30 ml) was cooled with an ice bath, and anhydrous potassium carbonate (1.13 g, 8.21 mmol) was added. The mixture was then allowed to warm to rt and stirred for 21 h. Water (60 ml) was added and the white precipitate formed, was filtered off and washed with water. Toluene was added to the precipitate and the mixture was evaporated and the residue was dried for three days under vacuum to give the title compound (2.2 g, 102%) containing traces of water and toluene. 1H NMR (400 MHz, CDCl3): δ 3.23 (s, 3H), 7.52-7.56 (m, 3H), 7.86-7.88 (m, 2H); 13C-NMR (100 MHz, CD3CN): δ 24.5, 123.8, 1291, 129.5, 130.7, 133.0, 143.1, 157.6.
Reaction SMILES: [NH2:1][C:2]1[CH2:3][C:4](=[O:17])[N:5]([C:7]2[CH:12]=[CH:11][C:10]([C:13]([F:16])([F:15])[F:14])=[CH:9][CH:8]=2)[N:6]=1.CN(C)[CH:20]=[CH:21][C:22]([C:24]1[C:29]([CH3:30])=[CH:28][CH:27]=[CH:26][N:25]=1)=O>N1C=CC=CC=1>[CH3:30][C:29]1[C:24]([C:22]2[N:1]=[C:2]3[NH:6][N:5]([C:7]4[CH:8]=[CH:9][C:10]([C:13]([F:16])([F:14])[F:15])=[CH:11][CH:12]=4)[C:4](=[O:17])[C:3]3=[CH:20][CH:21]=2)=[N:25][CH:26]=[CH:27][CH:28]=1
Reactant: Cc1cccnc1C(=O)C=CN(C)C
Reactant: NC1=NN(c2ccc(C(F)(F)F)cc2)C(=O)C1
Solvent: c1ccncc1
Product: Cc1cccnc1-c1ccc2c(=O)n(-c3ccc(C(F)(F)F)cc3)[nH]c2n1
Yield: 23.4 %

Procedure:
A mixture of the product of Step 1 (1.68 g, 0.0074 mol) and 3-(dimethylamino)-1-(3-methyl-2-pyridinyl)-2-propen-1-one (EP-A-0233461) (1.4 g, 0.0074 mol) in pyridine (20 mL) was heated at reflux for 3 h. The mixture was concentrated and then triturated to give a solid which was recrystallised from iPrOH to give 0.64 g (23% yield) of product as a yellow powder. 1H NMR (360 MHz, DMSO): 2.6 (3H, s), 7.45-7.55 (1H, m), 7.55-7.65 (1H, m), 7.85-7.95 (3H, m), 8.20 (2H, d, J 8.5 Hz), 8.39 (1H, d, J 8.0 Hz), 8.61 (1H, d, J 4.6 Hz).
Reaction SMILES: O[CH:2]([C:28]1[C:37]2[C:32](=[CH:33][C:34]([O:38][CH3:39])=[CH:35][CH:36]=2)[N:31]=[CH:30][CH:29]=1)[C:3]1[CH:8]=[CH:7][C:6]([NH:9][C:10]([C:12]2[C:13](=[O:27])[N:14]([C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=3)[N:15]([CH2:18][CH2:19][CH3:20])[C:16]=2[CH3:17])=[O:11])=[CH:5][CH:4]=1>C(O)=O.C(OCC)(=O)C.[Zn]>[CH3:39][O:38][C:34]1[CH:33]=[C:32]2[C:37]([C:28]([CH2:2][C:3]3[CH:4]=[CH:5][C:6]([NH:9][C:10]([C:12]4[C:13](=[O:27])[N:14]([C:21]5[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=5)[N:15]([CH2:18][CH2:19][CH3:20])[C:16]=4[CH3:17])=[O:11])=[CH:7][CH:8]=3)=[CH:29][CH:30]=[N:31]2)=[CH:36][CH:35]=1
Reactant: CCCn1c(C)c(C(=O)Nc2ccc(C(O)c3ccnc4cc(OC)ccc34)cc2)c(=O)n1-c1ccccc1
Agent: [Zn]
Solvent: O=CO
Solvent: CCOC(C)=O
Product: CCCn1c(C)c(C(=O)Nc2ccc(Cc3ccnc4cc(OC)ccc34)cc2)c(=O)n1-c1ccccc1
Temperature: 60 °C
Yield: 24.8 %

Procedure:
In a 25 mL round bottom flask was dissolved N-(4-(hydroxy(7-methoxyquinolin-4-yl)methyl)phenyl)-5-methyl-3-oxo-2-phenyl-1-propyl-2,3-dihydro-1H-pyrazole-4-carboxamide (104 mg, 199 μmol) in 4 mL of formic acid and the resultant was then treated with zinc dust (325 mg, 4975 μmol) and heated at 60° C. After 6 h the reaction mixture was diluted with ethyl acetate, filtered over Celite and neutralized with aqueous NaHCO3 (sat). The aqueous phase was extracted with ethyl acetate, and then the organic layer was dried over Na2SO4, filtered and concentrated under reduced pressure. The crude mixture was purified by MPLC (ISCO, dichloromethane: 1% NH4OH in MeOH, 100:0 to 90:10) to afford N-(4-((7-methoxyquinolin-4-yl)methyl)phenyl)-5-methyl-3-oxo-2-phenyl-1-propyl-2,3-dihydro-1H-pyrazole-4-carboxamide (25 mg, 25% yield) as an off-white solid. MS (ESI pos. ion) m/z: 507 (MH+). Calc'd exact mass for C31H30N4O3: 506. 1H NMR (400 MHz, DMSO-d6) 10.65 (s, 1H), 8.74 (d, J=4.42 Hz, 1H), 8.10 (d, J=9.22 Hz, 1H), 7.57 (t, J=7.52 Hz, 2H), 7.46-7.52 (m, 3H), 7.35-7.44 (m, 3H), 7.14-7.28 (m, 4H), 4.38 (s, 2H), 3.90 (s, 3H), 3.79 (t, J=7.14 Hz, 2H), 2.72 (s, 3H), 1.32-1.41 (m, 2H), 0.66 (t, J=7.39 Hz, 3H).
Reaction SMILES: C(O[C@@H:5]1[O:27][C@H:26]([CH2:28][O:29]C(=O)C2C=CC=CC=2)[C@@H:16]([O:17]C(=O)C2C=CC=CC=2)[C@H:6]1[O:7]C(=O)C1C=CC=CC=1)(=O)C.[OH:38][C:39]1[CH:48]=[CH:47][CH:46]=[C:45]2[C:40]=1[CH2:41][CH2:42][CH2:43][C:44]2=[O:49].B(F)(F)F>ClCCl>[O:38]([C:39]1[CH:48]=[CH:47][CH:46]=[C:45]2[C:40]=1[CH2:41][CH2:42][CH2:43][C:44]2=[O:49])[C@@H:5]1[O:27][C@H:26]([CH2:28][OH:29])[C@@H:16]([OH:17])[C@H:6]1[OH:7]
Reactant: O=C1CCCc2c(O)cccc21
Reactant: CC(=O)O[C@@H]1O[C@H](COC(=O)c2ccccc2)[C@@H](OC(=O)c2ccccc2)[C@H]1OC(=O)c1ccccc1
Agent: FB(F)F
Solvent: ClCCl
Product: O=C1CCCc2c(O[C@@H]3O[C@H](CO)[C@@H](O)[C@H]3O)cccc21
Yield: 139.5 %

Procedure:
A solution of 1-O-acetyl-2,3,5-tri-O-benzoyl-β-D-ribofuranose (426 mg, 0.84 mmol), 5-hydroxy-1-tetralone (122 mg, 0.75 mmol) and boron trifluoride diethyletherate (120 mg, 0.84 mmol, 106 μl) in dichloromethane (4 ml) was stirred at room temperature, under argon for 19 hours. Work-up as for Stage 1 in Example 1 then flash chromatography on silica gel (eluting with 2% acetone in toluene) gave the title compound as a colourless oil (308 mg of approx. 51% purity).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:17]3[C:12](=[N:13][CH:14]=[C:15]([CH2:18][C:19]4[CH:24]=[CH:23][C:22]([F:25])=[CH:21][CH:20]=4)[CH:16]=3)[C:11]([OH:26])=[C:10]([C:27]([NH:29][CH2:30][CH2:31][OH:32])=[O:28])[C:9]2=[O:33])=[CH:4][CH:3]=1.[OH-].[Na+:35]>C(O)C.C(OCC)C>[F:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:17]3[C:12](=[N:13][CH:14]=[C:15]([CH2:18][C:19]4[CH:24]=[CH:23][C:22]([F:25])=[CH:21][CH:20]=4)[CH:16]=3)[C:11]([O-:26])=[C:10]([C:27]([NH:29][CH2:30][CH2:31][OH:32])=[O:28])[C:9]2=[O:33])=[CH:4][CH:3]=1.[Na+:35]
Reactant: O=C(NCCO)c1c(O)c2ncc(Cc3ccc(F)cc3)cc2n(-c2ccc(F)cc2)c1=O
Agent: [Na+]
Agent: [OH-]
Solvent: CCOCC
Solvent: CCO
Product: O=C(NCCO)c1c([O-])c2ncc(Cc3ccc(F)cc3)cc2n(-c2ccc(F)cc2)c1=O
Reaction time: 1 h
Yield: 92 %

Procedure:
1-(4-fluorophenyl)-7-[(4-fluorophenyl)methyl]-4-hydroxy-N-(2-hydroxyethyl)-2-oxo-1,2-dihydro-1,5-naphthyridine-3-carboxamide (311 mg, 0.690 mmol) described in example 200 was suspended in ethanol (10 mL) and 1 N sodium hydroxide was added (0.68 mL) and the resulting white suspension was stirred for 1 hour. The mixture was diluted with diethyl ether (50 mL) and the solid was collected by vacuum filtration to afford sodium 1-(4-fluorophenyl)-7-[(4-fluorophenyl)methyl]-3-{[(2-hydroxyethyl)amino]carbonyl}-2-oxo-1,2-dihydro-1,5-naphthyridine-4-olate (300 mg, 92% yield) as a white solid. 1H NMR (DMSO-d6) δ 10.53 (br s, 1 H), 8.15 (s, 1 H), 7.31 (m, 2 H), 7.19 (m, 2 H), 7.11 (m, 2 H), 7.03 (m, 2 H), 6.48 (s, 1 H), 4.71 (br s, 1 H), 3.85 (s, 2 H), 3.41 (m, 2 H), 3.26 (m, 2 H); MS m/z 452 (M+1).