Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]1([C:7]2[N:8]=[C:9]([CH:12]3[CH2:17][CH2:16][N:15](C(OC(C)(C)C)=O)[CH2:14][CH2:13]3)[S:10][CH:11]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[ClH:25].O1CCOCC1>C(Cl)Cl>[ClH:25].[C:1]1([C:7]2[N:8]=[C:9]([CH:12]3[CH2:17][CH2:16][NH:15][CH2:14][CH2:13]3)[S:10][CH:11]=2)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: CC(C)(C)OC(=O)N1CCC(c2nc(-c3ccccc3)cs2)CC1
Agent: Cl
Solvent: ClCCl
Solvent: C1COCCO1
Product: c1ccc(-c2csc(C3CCNCC3)n2)cc1
Reaction time: 3 h

Procedure:
Under ice-cooling, to a mixture of tert-butyl 4-(4-phenyl-1,3-thiazol-2-yl)piperidine-1-carboxylate (5.79 g) and DCM (30 mL) was added 4 M hydrogen chloride/dioxane (30 mL), followed by stirring for 3 hours. The resulting solid was collected by filtration, washed with diisopropyl ether, and then dried under reduced pressure to obtain 4-(4-phenyl-1,3-thiazol-2-yl)piperidine hydrochloride (4.51 g).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[C:6]([Br:8])[CH:5]=[C:4](I)[C:3]=1[OH:10].[CH3:11][O:12][C:13]1[CH:18]=[CH:17][C:16]([C:19]#[CH:20])=[CH:15][CH:14]=1.O>CN(C=O)C.C(NCC)C>[Br:8][C:6]1[CH:7]=[C:2]([Br:1])[C:3]2[O:10][C:19]([C:16]3[CH:17]=[CH:18][C:13]([O:12][CH3:11])=[CH:14][CH:15]=3)=[CH:20][C:4]=2[CH:5]=1
Reactant: Oc1c(Br)cc(Br)cc1I
Reactant: C#Cc1ccc(OC)cc1
Solvent: O
Solvent: CN(C)C=O
Solvent: CCNCC
Product: COc1ccc(-c2cc3cc(Br)cc(Br)c3o2)cc1
Reaction time: 1 h

Procedure:
A solution of 2,4-Dibromo-6-iodo-phenol [53872-06-3] (0.7 g, 1.8 mmol), 4-Methoxyphenylacetylene (0.53 g, 4.0 mmol), PdCl2P(PH3)2 (70 mg), and Cul (50 mg) in DMF/Diethylamine (10 ml) was heated to 60° C. After 1 hr, the reaction was cooled and poured into water which was extracted with EtOAc. The organic bayer was dried over MgSO4, filtered and concentrated to give a solid which was triturated with MeOH and filtered to give 87 as a solid.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([NH:8][C@H:9]([CH2:13][CH:14]([CH3:16])[CH3:15])[C:10]([NH2:12])=[O:11])[CH:5]=[N:4][C:3]=1[C:17]#[N:18].[NH2:19][C:20]1[CH:21]=[C:22]2[C:27](=[CH:28][CH:29]=1)[N:26]=[CH:25][CH:24]=[CH:23]2.C([O-])([O-])=O.[K+].[K+].C1C=CC(P(C2C(C3C(P(C4C=CC=CC=4)C4C=CC=CC=4)=CC=C4C=3C=CC=C4)=C3C(C=CC=C3)=CC=2)C2C=CC=CC=2)=CC=1>O1CCOCC1.CC([O-])=O.CC([O-])=O.[Pd+2]>[C:17]([C:3]1[N:4]=[CH:5][C:6]([NH:8][C@H:9]([CH2:13][CH:14]([CH3:16])[CH3:15])[C:10]([NH2:12])=[O:11])=[N:7][C:2]=1[NH:19][C:20]1[CH:21]=[C:22]2[C:27](=[CH:28][CH:29]=1)[N:26]=[CH:25][CH:24]=[CH:23]2)#[N:18]
Reactant: CC(C)C[C@@H](Nc1cnc(C#N)c(Cl)n1)C(N)=O
Reactant: Nc1ccc2ncccc2c1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: O=C([O-])[O-]
Solvent: C1COCCO1
Product: CC(C)C[C@@H](Nc1cnc(C#N)c(Nc2ccc3ncccc3c2)n1)C(N)=O
Reaction time: 20 h

Procedure:
A mixture of (R)-2-(6-chloro-5-cyanopyrazin-2-ylamino)-4-methylpentanamide (80 mg, 0.299 mmol), 6-aminoquinoline (60 mg, 0.416 mmol), K2CO3 (65 mg, 0.471 mmol), BINAP (25 mg, 0.040 mmol) and Pd(OAc)2 (10 mg, 0.044 mmol) in dioxane (2 mL) was degassed with Ar, then was stirred at 100 C for 20 h. Water and EtOAc were added. Organic phase was separated, dried over Na2SO4, concentrated in vacuo to give (R)-2-(5-cyano-6-(quinolin-6-ylamino)pyrazin-2-ylamino)-4-methylpentanamide as a crude residue (151 mg).
Reaction SMILES: [CH3:1][C:2]1[N:6]([CH2:7][C:8]([OH:10])=O)[N:5]=[C:4]([C:11]([F:14])([F:13])[F:12])[CH:3]=1.C(N(CC)CC)C.Cl.[NH:23]1[CH2:28][CH2:27][CH:26]([C:29]2[CH:30]=[C:31]([NH2:35])[CH:32]=[CH:33][CH:34]=2)[CH2:25][CH2:24]1>CN(C=O)C>[NH2:35][C:31]1[CH:30]=[C:29]([CH:26]2[CH2:27][CH2:28][N:23]([C:8](=[O:10])[CH2:7][N:6]3[C:2]([CH3:1])=[CH:3][C:4]([C:11]([F:14])([F:13])[F:12])=[N:5]3)[CH2:24][CH2:25]2)[CH:34]=[CH:33][CH:32]=1
Reactant: Cc1cc(C(F)(F)F)nn1CC(=O)O
Reactant: Nc1cccc(C2CCNCC2)c1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: Cc1cc(C(F)(F)F)nn1CC(=O)N1CCC(c2cccc(N)c2)CC1
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
To a solution of (5-methyl-3-trifluoromethyl-pyrazol-1-yl)-acetic acid (0.49 g, 2.35 mmol) in DMF (10 mL) is added triethylamine (0.65 mL, 4.7 mmol), followed by 1-hydroxy-7-benzotriazole (0.32 g, 2.35 mmol) and 1-Ethyl-3-(3-dimethyllaminopropyl)carbodiimide hydrochloride (0.45 g, 2.35 mmol). After stirring 15 min at RT, 3-Piperidin-4-yl-phenylamine hydrochloride (0.50 g, 2.35 mmol) is added to the reaction mixture. After stirring overnight at RT, solvent is evaporated and the resulting yellow oil is dissolved in ethylacetate (20 mL), washed with saturated aqueous sodium bicarbonate solution (20 mL), and brine (20 mL). The organic layer is dried over sodium sulfate, filtered, and evaporated under reduced pressure to give 1-[4-(3-amino-phenyl)-piperidin-1-yl]-2-(5-methyl-3-trifluoromethyl-pyrazol-1-yl)-ethanone as a crude mixture of good enough purity for the next step (0.86 g, quantitative). 1H-NMR (400 MHz, MeOD): δ=1.52-1.63 (m, 1H), 1.64-1.73 (m, 1H), 1.80-1.93 (m, 2H), 2.33 (s, 3H), 2.68-2.81 (m, 2H), 2.99 (s, 2H), 3.21-3.27 (m, 1H), 4.02-4.09 (m, 1H), 4.55-4.62 (m, 1H), 5.12-5.28 (q, 2H), 6.41 (s, 1H), 6.55-6.60 (m, 1H), 6.61-6.62 (m, 1H), 7.00-7.07 (t, 1H), 7.99 (s, 1H). MS: m/z=367 (M+1).
Reaction SMILES: [F:1][C:2]1[CH:14]=[C:13](F)[C:12]([F:16])=[CH:11][C:3]=1[C:4]([NH:6][S:7]([CH3:10])(=[O:9])=[O:8])=[O:5].[CH3:17][C:18]([CH3:21])([O-:20])[CH3:19].[K+]>CS(C)=O.CCOC(C)=O.C(O)(=O)CC(CC(O)=O)(C(O)=O)O>[C:18]([O:20][C:13]1[C:12]([F:16])=[CH:11][C:3]([C:4]([NH:6][S:7]([CH3:10])(=[O:9])=[O:8])=[O:5])=[C:2]([F:1])[CH:14]=1)([CH3:21])([CH3:19])[CH3:17]
Reactant: CS(=O)(=O)NC(=O)c1cc(F)c(F)cc1F
Reactant: CC(C)(C)[O-]
Agent: O=C(O)CC(O)(CC(=O)O)C(=O)O
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CS(C)=O
Product: CC(C)(C)Oc1cc(F)c(C(=O)NS(C)(=O)=O)cc1F
Yield: 96.7 %

Procedure:
To a solution of 2,4,5-trifluoro-N-(methylsulfonyl)benzamide (Preparation 16, 1.50 g, 5.92 mmol) in DMSO (10 mL) at room temperature was added potassium t-butoxide (1.46 g, 13.0 mmol). After 18 hours the reaction mixture was diluted with EtOAc (30 mL) and 10% aqueous citric acid solution (15 mL). The pH of the aqueous layer was checked to ensure it was acidic. The organic layer was separated and washed with 10% aqueous citric acid solution (15 mL) and brine (15 mL), dried over magnesium sulphate, filtered and evaporated to yield the title compound as a cream solid (1.76 g, 97%).
Reaction SMILES: [CH2:1](I)[CH:2]=[CH2:3].[NH2:5][C:6]1[N:10]([C:11]2[C:16]([Cl:17])=[CH:15][C:14]([C:18]([F:21])([F:20])[F:19])=[CH:13][C:12]=2[Br:22])[N:9]=[C:8]([C:23](=[S:25])[NH2:24])[C:7]=1[S:26]([CH3:28])=[O:27]>>[CH2:1]([S:25][C:23]([C:8]1[C:7]([S:26]([CH3:28])=[O:27])=[C:6]([NH2:5])[N:10]([C:11]2[C:16]([Cl:17])=[CH:15][C:14]([C:18]([F:21])([F:20])[F:19])=[CH:13][C:12]=2[Br:22])[N:9]=1)=[NH:24])[CH:2]=[CH2:3]
Reactant: CS(=O)c1c(C(N)=S)nn(-c2c(Cl)cc(C(F)(F)F)cc2Br)c1N
Reactant: C=CCI
Product: C=CCSC(=N)c1nn(-c2c(Cl)cc(C(F)(F)F)cc2Br)c(N)c1S(C)=O

Procedure:
In a manner similar to that described in EXAMPLE 2, allyl iodide was reacted with 5-amino-1-[2-bromo-6-chloro-4-(trifluoromethyl)phenyl]-4-methylsulfinyl-1H-pyrazole-3-carbothioamide (Compound 6, prepared as described in applicants' concurrently filed, copending application referenced in EXAMPLE 2 above) to give 5-amino-1-[2-bromo-6-chloro-4-(trifluoromethyl)phenyl]-4-methylsulfinyl-1H-pyrazole-3-carboximidothioic acid 2-propenyl ester having a melting point of about 91° C. This compound is referred to hereinafter as Compound 3.
Reaction SMILES: [Cl:1][C:2]1[N:3]=[CH:4][N:5](COCC[Si](C)(C)C)[C:6]=1[C:7]([NH:9][CH2:10][C:11]1[CH:16]=[CH:15][C:14]([Cl:17])=[C:13]([O:18][C:19]2[CH:24]=[CH:23][C:22]([F:25])=[C:21]([C:26]#[N:27])[CH:20]=2)[C:12]=1[F:28])=[O:8].C(O)(C(F)(F)F)=O>C(Cl)Cl>[Cl:1][C:2]1[N:3]=[CH:4][NH:5][C:6]=1[C:7]([NH:9][CH2:10][C:11]1[CH:16]=[CH:15][C:14]([Cl:17])=[C:13]([O:18][C:19]2[CH:24]=[CH:23][C:22]([F:25])=[C:21]([C:26]#[N:27])[CH:20]=2)[C:12]=1[F:28])=[O:8]
Reactant: C[Si](C)(C)CCOCn1cnc(Cl)c1C(=O)NCc1ccc(Cl)c(Oc2ccc(F)c(C#N)c2)c1F
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: N#Cc1cc(Oc2c(Cl)ccc(CNC(=O)c3[nH]cnc3Cl)c2F)ccc1F
Temperature: 25 °C
Reaction time: 2 h
Yield: 55.6 %

Procedure:
To a solution of 4-chloro-N-({4-chloro-3-[(3-cyano-4-fluorophenyl)oxy]-2-fluorophenyl}methyl)-1-({[2-(trimethylsilyl)ethyl]oxy}methyl)-1H-imidazole-5-carboxamide (45 mg, 0.081 mmol) in DCM (4 ml) was added TFA (2.0 mL) and the reaction mixture was stirred at RT for 2 hours. The solvent was removed and the crude material was purified via reverse phase HPLC to give 4-chloro-N-({4-chloro-3-[(3-cyano-4-fluorophenyl)oxy]-2-fluorophenyl}methyl)-1H-imidazole-5-carboxamide (19 mg, 0.045 mmol, 55% yield). 1H NMR (400 MHz, METHANOL-d4) δ ppm 7.74 (s, 1H) 7.29-7.40 (m, 3H) 7.13-7.29 (m, 2H) 4.61 (s, 2H). LC-MS (ES+) m/z 423.12, [M+H].
Reaction SMILES: [N+:1]([C:4]1[N:5]=[N:6][NH:7][CH:8]=1)([O-:3])=[O:2].[H-].[Na+].Cl[CH2:12][O:13][CH2:14][CH2:15][Si:16]([CH3:19])([CH3:18])[CH3:17]>C1COCC1>[N+:1]([C:4]1[CH:8]=[N:7][N:6]([CH2:12][O:13][CH2:14][CH2:15][Si:16]([CH3:19])([CH3:18])[CH3:17])[N:5]=1)([O-:3])=[O:2]
Reactant: C[Si](C)(C)CCOCCl
Reactant: O=[N+]([O-])c1c[nH]nn1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: C[Si](C)(C)CCOCn1ncc([N+](=O)[O-])n1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 57.7 %

Procedure:
To a solution of 4-nitro-1H-triazole (5.00 g, 43.84 mmol) in THF (230 mL), cooled to 0° C., was added sodium hydride (2.28 g, 56.99 mmol) portionwise over 30 min. The mixture was stirred for a further 30 min and then 2-(chloromethoxy)ethyl-trimethyl-silane (7.67 g, 8.15 mL, 46.03 mmol) was added dropwise. The reaction was allowed to warm to room temperature and stirred for 2 h, then re-cooled to 0° C. and quenched with water. The mixture was extracted with EtOAc and the organics washed with brine, dried (MgSO4) and concentrated. The residue was purified by column chromatography eluting with 5% EtOAc in hexanes to afford 4-nitro-2-((2-(trimethylsilyl)ethoxy)methyl)-2H-1,2,3-triazole (6.18 g, 56%) and 4-nitro-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-1,2,3-triazole as an off white solid (3.52 g, 33%).
Reaction SMILES: I[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH:10]1[CH2:18][C:17]2[C:12](=[C:13]([O:25][CH3:26])[C:14]([O:23][CH3:24])=[C:15]([O:21][CH3:22])[C:16]=2[O:19][CH3:20])[CH2:11]1.[C:27]1([CH:33]([C:40]2[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=2)[N:34]2[CH2:39][CH2:38][NH:37][CH2:36][CH2:35]2)[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1.C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C.O>[CH3:26][O:25][C:13]1[C:14]([O:23][CH3:24])=[C:15]([O:21][CH3:22])[C:16]([O:19][CH3:20])=[C:17]2[C:12]=1[CH2:11][CH:10]([CH2:9][CH2:8][CH2:7][CH2:6][CH2:5][CH2:4][CH2:3][CH2:2][N:37]1[CH2:38][CH2:39][N:34]([CH:33]([C:27]3[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=3)[C:40]3[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=3)[CH2:35][CH2:36]1)[CH2:18]2
Reactant: c1ccc(C(c2ccccc2)N2CCNCC2)cc1
Reactant: COc1c2c(c(OC)c(OC)c1OC)CC(CCCCCCCCI)C2
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: COc1c2c(c(OC)c(OC)c1OC)CC(CCCCCCCCN1CCN(C(c3ccccc3)c3ccccc3)CC1)C2
Temperature: 25 °C
Reaction time: 12 h
Yield: 80.6 %

Procedure:
The mixture of 2-(8-iodooctyl)-4,5,6,7-tetramethoxyindan (1.17 g), 1-diphenylmethylpiperazine (1.24 g) and potassium carbonate (1.70 g) in DMF (10 ml) was stirred at room temperature for 12 hr. The reaction mixture was diluted with water and extracted with ethyl acetate. The organic layer was washed with water and saturated aqueous sodium chloride and dried. The solvent was removed in vacuo. The residue was purified by alumina column chromatography (hexane to hexane:ethyl acetate=10:1) to yield the entitled compound (1.19 g) as an oil.
Reaction SMILES: [Si]([O:8][C@@H:9]1[C@@:42]2([CH3:43])[C:13](=[CH:14][CH:15]=[C:16]3[C@@H:41]2[CH2:40][CH2:39][C@@:38]2([CH3:44])[C@H:17]3[CH2:18][CH:19]=[C:20]2[C@@H:21]([O:23][CH2:24]/[CH:25]=[CH:26]\[C:27]([CH3:37])([O:29][Si](CC)(CC)CC)[CH3:28])[CH3:22])[CH2:12][C@@H:11]([O:45][Si](C(C)(C)C)(C)C)[CH2:10]1)(C(C)(C)C)(C)C.[F-].C([N+](CCCC)(CCCC)CCCC)CCC>O1CCCC1>[OH:8][C@@H:9]1[C@@:42]2([CH3:43])[C:13](=[CH:14][CH:15]=[C:16]3[C@@H:41]2[CH2:40][CH2:39][C@@:38]2([CH3:44])[C@H:17]3[CH2:18][CH:19]=[C:20]2[C@@H:21]([O:23][CH2:24]/[CH:25]=[CH:26]\[C:27]([OH:29])([CH3:28])[CH3:37])[CH3:22])[CH2:12][C@@H:11]([OH:45])[CH2:10]1
Reactant: CC[Si](CC)(CC)OC(C)(C)/C=C\CO[C@@H](C)C1=CC[C@H]2C3=CC=C4C[C@@H](O[Si](C)(C)C(C)(C)C)C[C@H](O[Si](C)(C)C(C)(C)C)[C@]4(C)[C@H]3CC[C@]12C
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: C1CCOC1
Product: C[C@H](OC/C=C\C(C)(C)O)C1=CC[C@H]2C3=CC=C4C[C@@H](O)C[C@H](O)[C@]4(C)[C@H]3CC[C@]12C
Yield: 73.9 %

Procedure:
By the same procedure as in Example 9, 1α,3β-bis(tert-butyldimethylsilyloxy)-20(S)-{(Z)-(4-methyl-4-triethylsilyloxy-2-pentenyloxy)}pregna-5,7,16-triene (78.0 mg, 0.101 mmol), tetrahydrofuran (3 ml) and 1M tetra-n-butylammonium fluoride solution in tetrahydrofuran (2 ml) were reacted (heating under reflux for 5.5 hours) and worked up, and then the residue was purified by preparative thin layer chromatography (0.5 mm×1, dichloromethane:ethyl acetate:ethanol=20:80:1, developed once) to give the title compound as a colorless oil (32.0 mg, 74%).
Reaction SMILES: [NH2:1][C:2]1[CH:21]=[CH:20][C:19]([F:22])=[CH:18][C:3]=1[O:4][CH:5]1[CH2:10][CH2:9][N:8]([C:11]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12])[CH2:7][CH2:6]1.Cl[C:24]1[C:25]2[C:32]([CH3:33])=[C:31]([C:34]([O:36][CH3:37])=[O:35])[S:30][C:26]=2[N:27]=[CH:28][N:29]=1.O.[OH-].[NH4+]>O1CCOCC1.O.C1(C)C=CC(S(O)(=O)=O)=CC=1>[C:14]([O:13][C:11]([N:8]1[CH2:9][CH2:10][CH:5]([O:4][C:3]2[CH:18]=[C:19]([F:22])[CH:20]=[CH:21][C:2]=2[NH:1][C:24]2[C:25]3[C:32]([CH3:33])=[C:31]([C:34]([O:36][CH3:37])=[O:35])[S:30][C:26]=3[N:27]=[CH:28][N:29]=2)[CH2:6][CH2:7]1)=[O:12])([CH3:16])([CH3:17])[CH3:15]
Reactant: COC(=O)c1sc2ncnc(Cl)c2c1C
Reactant: CC(C)(C)OC(=O)N1CCC(Oc2cc(F)ccc2N)CC1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: [NH4+]
Agent: [OH-]
Solvent: C1COCCO1
Solvent: O
Product: COC(=O)c1sc2ncnc(Nc3ccc(F)cc3OC3CCN(C(=O)OC(C)(C)C)CC3)c2c1C
Temperature: 25 °C
Yield: 65.7 %

Procedure:
tert-Butyl 4-(2-amino-5-fluorophenoxy)piperidine-1-carboxylate (0.865 g, 2.8 mmol), methyl 4-chloro-5-methylthieno[2,3-d]pyrimidine-6-carboxylate (0.675 g, 2.8 mmol) and para-toluene sulfonic acid (0.026 g, 0.14 mmol) were heated at 90° C. in anhydrous 1,4-dioxane (8 mL) for 1.5 hours. The solution was cooled to ambient temperature, diluted with water (2 mL) and adjusted to pH 10 (4:1 water/ammonium hydroxide solution). The precipitate was collected, washed with water and diethyl ether to yield the title compound as yellow solid (0.95 g, 65%).
Reaction SMILES: [C:1]([O:9][CH2:10]Cl)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[I-:12].[Na+]>C(#N)C.O>[C:1]([O:9][CH2:10][I:12])(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: [I-]
Reactant: O=C(OCCl)c1ccccc1
Agent: [Na+]
Solvent: CC#N
Solvent: O
Product: O=C(OCI)c1ccccc1
Temperature: 25 °C
Reaction time: 18 h
Yield: 71.5 %

Procedure:
Chloromethyl benzoate (2.87 g, 16.82 mmol) was dissolved in acetonitrile (20 mL) and treated portionwise with sodium iodide (5.04 g, 33.6 mmol). The resulting mixture was stirred at room temperature for 18 hours. The reaction mixture was diluted with water and extracted with ethyl acetate (×2). The ethyl acetate layers were combined, dried under magnesium sulfate and evaporated under reduced pressure. The residue was purified by column chromatography (Biotage SP4) eluting with a gradient of 0-20% ethyl acetate and iso-hexane. Product containing fractions were combined and evaporated under reduced pressure to give the title compound as a yellow oil (3.15 g);
Reaction SMILES: [F:1][C:2]1[CH:11]=[C:10]2[C:5]([CH:6]=[CH:7][C:8](=[O:15])[N:9]2[CH2:12][CH:13]=O)=[CH:4][CH:3]=1.[NH:16]1[CH2:21][CH2:20][CH:19]([NH:22][C:23](=[O:29])[O:24][C:25]([CH3:28])([CH3:27])[CH3:26])[CH2:18][CH2:17]1.C(Cl)(Cl)Cl.[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+]>CO>[F:1][C:2]1[CH:11]=[C:10]2[C:5]([CH:6]=[CH:7][C:8](=[O:15])[N:9]2[CH2:12][CH2:13][N:16]2[CH2:17][CH2:18][CH:19]([NH:22][C:23](=[O:29])[O:24][C:25]([CH3:27])([CH3:26])[CH3:28])[CH2:20][CH2:21]2)=[CH:4][CH:3]=1
Reactant: CC(C)(C)OC(=O)NC1CCNCC1
Reactant: O=CCn1c(=O)ccc2ccc(F)cc21
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClC(Cl)Cl
Solvent: CO
Product: CC(C)(C)OC(=O)NC1CCN(CCn2c(=O)ccc3ccc(F)cc32)CC1
Temperature: 25 °C
Reaction time: 1 h
Yield: 117.3 %

Procedure:
A mixture of (7-fluoro-2-oxo-1(2H)-quinolinyl)acetaldehyde (594 mg; 2.89 mmol) and 1,1-dimethylethyl 4-piperidinylcarbamate (578 mg; 2.89 mmol) in a 1:1 mixture of chloroform and methanol (20 ml:20 ml) was stirred at rt under argon for 1 h. The mixture was then treated with NaBH(OAc)3 (1.83 g; 8.67 mmol) and stirred at rt for a 1 h. More 1,1-dimethylethyl 4-piperidinylcarbamate (297 mg; 1.45 mmol) was added and the reaction was stirred under the same conditions for a further 0.5 h. This was then again treated with NaBH(OAc)3 (915 mg; 4.34 mmol) and stirred at rt for a further 0.75 h. More 1,1-dimethylethyl 4-piperidinylcarbamate (118 mg; 0.578 mmol) was then added, the reaction was stirred at rt for a further 10 mins, followed by addition of NaBH(OAc)3 (366 mg; 1.73 mmol), the reaction was stirred for a further 25 mins. The solvents were removed and the crude residue purified by chromatography on silica gel using a 010% MeOH/DCM gradient to provide the impure desired compound (1.32 g, 117%)
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][CH:4]([C:7]2[C:11]3[CH:12]=[CH:13][C:14]([F:16])=[CH:15][C:10]=3[O:9][N:8]=2)[CH2:3][CH2:2]1.Cl[CH2:18][CH2:19][CH2:20][O:21][C:22]1[CH:27]=[CH:26][C:25]([C:28](=[O:31])[CH2:29][OH:30])=[CH:24][C:23]=1[O:32][CH3:33].C([O-])(O)=O.[Na+].CN1CCCC1=O>O>[F:16][C:14]1[CH:13]=[CH:12][C:11]2[C:7]([CH:4]3[CH2:3][CH2:2][N:1]([CH2:18][CH2:19][CH2:20][O:21][C:22]4[CH:27]=[CH:26][C:25]([C:28](=[O:31])[CH2:29][OH:30])=[CH:24][C:23]=4[O:32][CH3:33])[CH2:6][CH2:5]3)=[N:8][O:9][C:10]=2[CH:15]=1
Reactant: COc1cc(C(=O)CO)ccc1OCCCCl
Reactant: Fc1ccc2c(C3CCNCC3)noc2c1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: CN1CCCC1=O
Product: COc1cc(C(=O)CO)ccc1OCCCN1CCC(c2noc3cc(F)ccc23)CC1
Temperature: 100 °C
Reaction time: 6 h

Procedure:
A mixture of 3-(4-piperidinyl)-6-fluoro-1,2-benzisoxazole (1.3 g, 5.8 mmol), 1-[4-(3-chloropropoxy)-3-methoxyphenyl]-2-hydroxyethanone (1.5 g, 5.8 mmol), NaHCO3 (1.5 g) and 1-methyl-2-pyrrolidinone (50 ml) was stirred under N2 at 100° C. for 6 hours. The reaction was poured into H2O, and the aqueous suspension was extracted with EtOAc. The extract was washed (H2O ), dried (MgSO4) and concentrated to afford the product.
Reaction SMILES: [CH3:1][C:2]1[NH:6][N:5]=[CH:4][C:3]=1[N+:7]([O-:9])=[O:8].[CH3:10][C@H:11]1[CH2:13][O:12]1.C(=O)([O-])[O-].[Cs+].[Cs+]>C(#N)C>[CH3:1][C:2]1[N:6]([CH2:10][C@@H:11]([OH:12])[CH3:13])[N:5]=[CH:4][C:3]=1[N+:7]([O-:9])=[O:8]
Reactant: Cc1[nH]ncc1[N+](=O)[O-]
Reactant: C[C@H]1CO1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CC#N
Product: Cc1c([N+](=O)[O-])cnn1C[C@H](C)O
Temperature: 30 °C
Reaction time: 168 h
Yield: 9 %

Procedure:
To a solution of 5-methyl-4-nitro-1H-pyrazole (2.5 g, 19.7 mmol) in acetonitrile (100 mL) was added (S)-2-methyloxirane (1.37 g, 23.6 mmol) and cesium carbonate (19.3 g, 59.1 mmol). The mixture was stirred at 30° C. for 7 days, then cooled to room temperature and filtered. The filtrate was concentrated under reduced pressure, and the residue was purified by Prep-HPLC and then chiral-HPLC to give (S)-1-(5-methyl-4-nitro-1H-pyrazol-1-yl)propan-2-ol (0.33 g) as a yellowish solid. MS (ES+) C7H11N3O3 requires: 185, found: 186 [M+H]+.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH:28]=[CH:29][CH:30]=1)[CH2:5][C:6]1[O:7][C:8]([CH3:27])=[C:9]([CH3:26])[C:10]=1[C:11]([C:13]1[CH:18]=[C:17]([CH:19]([CH3:21])[CH3:20])[C:16]([OH:22])=[C:15]([CH:23]([CH3:25])[CH3:24])[CH:14]=1)=[O:12].Cl[S:32]([C:35]1[CH:43]=[CH:42][C:38]([C:39]([OH:41])=[O:40])=[C:37]([OH:44])[CH:36]=1)(=[O:34])=[O:33]>>[Br:1][C:2]1[CH:3]=[C:4]([CH:28]=[CH:29][CH:30]=1)[CH2:5][C:6]1[O:7][C:8]([CH3:27])=[C:9]([CH3:26])[C:10]=1[C:11]([C:13]1[CH:14]=[C:15]([CH:23]([CH3:24])[CH3:25])[C:16]([O:22][S:32]([C:35]2[CH:43]=[CH:42][C:38]([C:39]([OH:41])=[O:40])=[C:37]([OH:44])[CH:36]=2)(=[O:34])=[O:33])=[C:17]([CH:19]([CH3:21])[CH3:20])[CH:18]=1)=[O:12]
Reactant: O=C(O)c1ccc(S(=O)(=O)Cl)cc1O
Reactant: Cc1oc(Cc2cccc(Br)c2)c(C(=O)c2cc(C(C)C)c(O)c(C(C)C)c2)c1C
Product: Cc1oc(Cc2cccc(Br)c2)c(C(=O)c2cc(C(C)C)c(OS(=O)(=O)c3ccc(C(=O)O)c(O)c3)c(C(C)C)c2)c1C
Yield: 53.8 %

Procedure:
The tide compound was prepared according to the procedure in Example 4 using [2-(3-bromo-benzyl)-4,5-dimethyl-furan-3-yl]-(3,5-diisopropyl-4-hydroxy-phenyl)-methanone (0.300 g, 0.639 mmol) and 4-chlorosulphonyl-2-hydroxybenzoic acid (0.197 g, 0.831 mmol). Purification on Dynamax C18 (95% CH3CN/H20) gave 0.23 g (54%) of the title compound as an off white solid, mp 148° C. 1H NMR (DMSO-d6) δ1.06 (d, 12 H), 1.80 (s, 3 H), 2.21 (s, 3 H), 3.08 (septet, 2 H), 3.87 (s, 2 H), 1 H), 7.21 (t, 1 H), 7.25 (s, 1 H), 7.38 (d, 1 H), 7.44 (s, 1 H), 7.48 (dd, 1 H), 7.51 (s, 2 H), 8.06 (d, 1 H). IR (KBr) 3400, 2950, 1680, 1650 and 1180 cm−1. mass spectrum (−ESI) m/z 667 (M−H). Anal. Calcd. for C33H33BrO8 S: C, 59.19; H, 4.97; N, 0.00. Found: C, 58.86; H, 4.93; N, 0.07.
Reaction SMILES: [C:1]([O:4][CH2:5][C:6]([NH:8][C:9]1[C:10]([I:41])=[C:11]([CH2:36][O:37][C:38](=[O:40])[CH3:39])[C:12]([I:35])=[C:13]([C:33]=1[I:34])[C:14]([NH:16][CH:17]([CH:23]([O:29][C:30](=[O:32])[CH3:31])[CH2:24][O:25][C:26](=[O:28])[CH3:27])[CH2:18][O:19][C:20](=[O:22])[CH3:21])=[O:15])=[O:7])(=[O:3])[CH3:2].[C:42]([O:45][CH2:46][CH2:47]Br)(=[O:44])[CH3:43]>>[C:42]([O:45][CH2:46][CH2:47][N:8]([C:9]1[C:10]([I:41])=[C:11]([CH2:36][O:37][C:38](=[O:40])[CH3:39])[C:12]([I:35])=[C:13]([C:33]=1[I:34])[C:14]([NH:16][CH:17]([CH:23]([O:29][C:30](=[O:32])[CH3:31])[CH2:24][O:25][C:26](=[O:28])[CH3:27])[CH2:18][O:19][C:20](=[O:22])[CH3:21])=[O:15])[C:6](=[O:7])[CH2:5][O:4][C:1](=[O:3])[CH3:2])(=[O:44])[CH3:43]
Reactant: CC(=O)OCC(=O)Nc1c(I)c(COC(C)=O)c(I)c(C(=O)NC(COC(C)=O)C(COC(C)=O)OC(C)=O)c1I
Reactant: CC(=O)OCCBr
Product: CC(=O)OCCN(C(=O)COC(C)=O)c1c(I)c(COC(C)=O)c(I)c(C(=O)NC(COC(C)=O)C(COC(C)=O)OC(C)=O)c1I

Procedure:
5-(Acetoxyacetamido)-3-acetoxymethyl-N-(1,3,4-triacetoxybut-2-yl)-2,4,6-triiodobenzamide was alkylated with 2-bromoethyl acetate according to the procedure in Example 25a. Yield of crude product=97%.
Reaction SMILES: [H-].[Na+].[C:3](OC(C)C)(=[O:7])[C:4]([CH3:6])=O.[S:12]([CH:21](O)[C:22]([O:24][CH:25]([CH3:27])[CH3:26])=[O:23])[CH:13](O)[C:14]([O:16][CH:17]([CH3:19])[CH3:18])=[O:15].Cl>C(O)(C)C>[CH3:6][C:4]1[C:3]([OH:7])=[C:21]([C:22]([O:24][CH:25]([CH3:27])[CH3:26])=[O:23])[S:12][C:13]=1[C:14]([O:16][CH:17]([CH3:19])[CH3:18])=[O:15]
Reactant: CC(C)OC(=O)C(O)SC(O)C(=O)OC(C)C
Reactant: CC(=O)C(=O)OC(C)C
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: CC(C)O
Product: Cc1c(C(=O)OC(C)C)sc(C(=O)OC(C)C)c1O
Temperature: 0 °C
Reaction time: 2 h
Yield: 34.2 %

Procedure:
Sodium hydride (132 g, 5.52 mol) was added gradually into isopropyl alcohol (2-3 l) with cooling. To the resulting solution was then added a mixture of isopropyl pyruvate (360 g, 2.76 mol) and di-isopropyl 2,2'-thiodiglycolate (648 g, 2.76 mol) over 20-30 minutes with ice-cooling so that the solution was kept at 60°-80° C. The solution was stirred further for 2 hours at a temperature of 60°-40° C. The solution was poured into an ice-cooled dilute hydrochloric acid solution to form a white crystalline mass, which was recovered by filtration and then washed with water. It was recrystallized from methanol (3 l) to give pure di-isopropyl 3-methyl-4-hydroxy-2,5-thiophene-dicarboxylate (270 g, 34%), m.p. 87°-89° C.