Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [O:1]=[C:2]1[CH2:8][CH2:7][CH2:6][CH2:5][CH2:4][N:3]1[C:9]1[CH:10]=[C:11]2[C:15](=[CH:16][CH:17]=1)[N:14](C(OC(C)(C)C)=O)[CH2:13][CH2:12]2.BrCCCCCC(Cl)=O.Cl>O1CCOCC1>[NH:14]1[C:15]2[C:11](=[CH:10][C:9]([N:3]3[CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][C:2]3=[O:1])=[CH:17][CH:16]=2)[CH2:12][CH2:13]1
Reactant: CC(C)(C)OC(=O)N1CCc2cc(N3CCCCCC3=O)ccc21
Agent: Cl
Agent: O=C(Cl)CCCCCBr
Solvent: C1COCCO1
Product: O=C1CCCCCN1c1ccc2c(c1)CCN2
Temperature: 25 °C
Yield: 99.2 %

Procedure:
Part A. To tert-butyl 5-(2-oxohexahydro-1H-azepin-1-yl)-1-indolinecarboxylate (140 mg, 0.42 mmol) that had been prepared as in Part C of Example 15 using 6-bromohexanoyl chloride instead of 5-bromovaleryl chloride was added 10 mL of 4.0 M HCl in dioxane. The resulting solution was maintained at rt under N2 for 2 h and was then concentrated. The resulting residue was dissolved in 25 mL of EtOAc, and the organic layer was washed with saturated aqueous NaHCO3. The aqueous layer was washed with EtOAc (2×50 mL) and the combined organic layers were washed with brine, dried over Na2SO4, filtered, and concentrated to afford 1-(2,3-dihydro-1H-indol-5-yl)hexahydro-2H-azepin-2-one (96 mg, 100%) as a brown oil. LC/MS (ESI+): 231.2 (M+H)+. 1H NMR (CDCl3) δ 6.9 (s, 1H), 6.79 (d, 1H), 6.76 (d, 1H), 3.98 (br s, 1H), 3.66 (br m, 2H), 3.52 (t, 2H), 3.01 (t, 2H), 2.65 (br s, 2H), 1.78 (br s, 6H).
Reaction SMILES: [F:1][C:2]([F:12])([F:11])[C:3]1[CH:8]=[CH:7][C:6]([NH2:9])=[C:5]([NH2:10])[CH:4]=1.[C:13]1(=O)[O:18][CH2:17][CH2:16][CH2:15][CH2:14]1>Cl>[F:1][C:2]([F:11])([F:12])[C:3]1[CH:8]=[CH:7][C:6]2[NH:9][C:13]([CH2:14][CH2:15][CH2:16][CH2:17][OH:18])=[N:10][C:5]=2[CH:4]=1
Reactant: O=C1CCCCO1
Reactant: Nc1ccc(C(F)(F)F)cc1N
Agent: Cl
Product: OCCCCc1nc2cc(C(F)(F)F)ccc2[nH]1
Yield: 77.3 %

Procedure:
4-Trifluoromethyl-1,2-phenylenediamine (3 g, 17.03 mmol) and delta-valerolactone (1.78 ml, 18.74 mmol) in 4M HCl (15 ml) were heated to 110° C. for 18 h. The reaction mixture was quenched by addition to sat. NaHCO3(aq) (100 ml), and the mixture was extracted with EtOAc (3×100 ml). The combined organics were dried (MgSO4) and concentrated to afford a brown oil which was triturated with Et2O to afford 3.4 g (77.3%) of 4-(5-Trifluoromethyl-1H-benzoimidazol-2-yl)-butan-1-ol as a tan powder. MS (ESI+) for C12H13F3N2O m/z 258.95 [M+H]+; HPLC ret. time, 1.22 min. 1H NMR (500 MHz, MeOD) δ ppm 7.82 (1H, br. s.), 7.66 (1H, br. s.), 7.44-7.55 (1H, m), 3.62 (2H, t, J=6.46 Hz), 2.99 (2H, t, J=7.65 Hz), 1.89-2.00 (2H, m), 1.58-1.68 (2H, m).
Reaction SMILES: [CH2:1]([O:3][C:4]([CH:6]1[CH2:11][CH2:10][N:9]([C:12]2[CH:17]=[CH:16][C:15]([NH2:18])=[C:14]([C:19](=[O:23])[N:20]([CH3:22])[CH3:21])[CH:13]=2)[CH2:8][CH2:7]1)=[O:5])[CH3:2].C(N(CC)CC)C.[F:31][C:32]([F:49])([F:48])[C:33]1[CH:38]=[CH:37][C:36]([C:39]2[C:40]([C:45](Cl)=[O:46])=[CH:41][CH:42]=[CH:43][CH:44]=2)=[CH:35][CH:34]=1>C1(C)C=CC=CC=1>[CH2:1]([O:3][C:4]([CH:6]1[CH2:11][CH2:10][N:9]([C:12]2[CH:17]=[CH:16][C:15]([NH:18][C:45]([C:40]3[C:39]([C:36]4[CH:37]=[CH:38][C:33]([C:32]([F:31])([F:48])[F:49])=[CH:34][CH:35]=4)=[CH:44][CH:43]=[CH:42][CH:41]=3)=[O:46])=[C:14]([C:19](=[O:23])[N:20]([CH3:22])[CH3:21])[CH:13]=2)[CH2:8][CH2:7]1)=[O:5])[CH3:2]
Reactant: CCOC(=O)C1CCN(c2ccc(N)c(C(=O)N(C)C)c2)CC1
Reactant: O=C(Cl)c1ccccc1-c1ccc(C(F)(F)F)cc1
Solvent: Cc1ccccc1
Solvent: CCN(CC)CC
Product: CCOC(=O)C1CCN(c2ccc(NC(=O)c3ccccc3-c3ccc(C(F)(F)F)cc3)c(C(=O)N(C)C)c2)CC1
Temperature: 0 °C
Reaction time: 8 h

Procedure:
1-(4-Amino-3-dimethylcarbamoylphenyl)-piperidine-4-carboxylic acid ethyl ester was dissolved in toluene (5 mL), and triethylamine (1.87 mL) was added thereto. The solution was cooled down to 0° C., and 4′-trifluoromethylbiphenyl-2-carbonyl chloride (synthesized from the corresponding carboxylic acid 1.44 g) was added thereto. The mixture was stirred at room temperature overnight. The insoluble matter was filtered off. After removal of the insoluble material by filtration, the filtrate was concentrated and purified by column chromatography on silica gel (acetone:hexane=5:1, v/v) to give the title compound (1.287 g).
Reaction SMILES: [CH3:1][CH:2]([CH3:19])[CH2:3][C@H:4]([NH:8][S:9]([C:12]1[C:13]([CH3:18])=[CH:14][CH:15]=[CH:16][CH:17]=1)(=[O:11])=[O:10])[C:5](=[O:7])[CH3:6].[C:20]([O:24][CH2:25][Li])([CH3:23])([CH3:22])[CH3:21].O>C1COCC1>[C:20]([O:24][CH2:25][C:5]([CH3:6])([OH:7])[CH:4]([NH:8][S:9]([C:12]1[C:13]([CH3:18])=[CH:14][CH:15]=[CH:16][CH:17]=1)(=[O:11])=[O:10])[CH2:3][CH:2]([CH3:19])[CH3:1])([CH3:23])([CH3:22])[CH3:21]
Reactant: CC(=O)[C@H](CC(C)C)NS(=O)(=O)c1ccccc1C
Reactant: [Li]COC(C)(C)C
Solvent: O
Solvent: C1CCOC1
Product: Cc1ccccc1S(=O)(=O)NC(CC(C)C)C(C)(O)COC(C)(C)C
Temperature: 25 °C

Procedure:
To a -78° C. solution of the resultant compound of Example 57 (1.0 g, 3.5 mmol) in dry THF (7 ml) was added 3 equivalent, of t-butoxymethyl lithium [E. J. Corey and T. M. Eckridge, Tetrahedron Letters, 3165 (1983)]. The mixture was warmed to room temperature for 4 hours and then poured into water. Acidification with 0.1 M H3PO4, extraction into ether, washing with brine, drying, and evaporating gave 1.1 (85%) of the desired compound. Mass spectrum: M+ =371.
Reaction SMILES: C([NH:3][C:4]1[S:5][CH:6]=[C:7]([C:9](=[N:27][O:28][CH3:29])[C:10]([NH:12][CH:13]2[C:25](=[O:26])[N:15]3[C:16]([C:22]([OH:24])=[O:23])=[C:17]([CH:20]=[CH2:21])[CH2:18][S:19][C@H:14]23)=[O:11])[N:8]=1)=O.[ClH:30]>CO.O1CCCC1>[ClH:30].[NH2:3][C:4]1[S:5][CH:6]=[C:7]([C:9](=[N:27][O:28][CH3:29])[C:10]([NH:12][CH:13]2[C:25](=[O:26])[N:15]3[C:16]([C:22]([OH:24])=[O:23])=[C:17]([CH:20]=[CH2:21])[CH2:18][S:19][C@H:14]23)=[O:11])[N:8]=1
Reactant: C=CC1=C(C(=O)O)N2C(=O)C(NC(=O)C(=NOC)c3csc(NC=O)n3)[C@H]2SC1
Agent: Cl
Solvent: CO
Solvent: C1CCOC1
Product: C=CC1=C(C(=O)O)N2C(=O)C(NC(=O)C(=NOC)c3csc(N)n3)[C@H]2SC1
Temperature: 25 °C
Reaction time: 2.7 h

Procedure:
To a solution of 7-[2-(2-formamidothiazol-4-yl)-2-methoxyiminoacetamido]-3-vinyl-3-cephem-4-carboxylic acid (syn isomer) (1.4 g) in methanol (30 ml) and tetrahydrofuran (20 ml) was added conc. hydrochloric acid (1.0 ml), and the mixture was stirred at ambient temperature for 2.7 hours. After evaporation of the reaction mixture, the residue was washed with tetrahydrofuran to give 7-[2-(2-aminothiazol-4-yl)-2-methoxyiminoacetamido]-3-vinyl-3-cephem-4-carboxylic acid hydrochloride (syn isomer) (1.2 g).
Reaction SMILES: [C:1]([OH:6])(=[O:5])[C:2]([CH3:4])=[CH2:3].[CH2:7]1[O:10][CH:8]1[CH3:9].CN(CCO)C.C1(C=CC(O)=CC=1)O>[N+](C)([O-])=O>[C:1]([O:6][CH2:7][CH:8]([OH:10])[CH3:9])(=[O:5])[C:2]([CH3:4])=[CH2:3]
Reactant: C=C(C)C(=O)O
Reactant: CC1CO1
Agent: CN(C)CCO
Agent: Oc1ccc(O)cc1
Solvent: C[N+](=O)[O-]
Product: C=C(C)C(=O)OCC(C)O

Procedure:
2-hydroxypropyl methacrylate was prepared in the same apparatus and in the same manner as described in Example 1 by reaction of a mixture of 1000 g/hr methacrylic acid, 887 g/hr propylene oxide, 37 g/hr N,N-dimethylaminoethanol, 5 g/hr nitromethane and 1 g/hr hydroquinone at a temperature of 100° C.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:16]([O:17][CH3:18])=[CH:15][CH:14]=[C:13]([C:19]2[CH:20]=[C:21]3[C:25](=[CH:26][CH:27]=2)[C:24](=[O:28])[O:23][CH2:22]3)[C:4]=1[O:5][CH2:6][C:7]([CH3:12])([CH3:11])[C:8](O)=[O:9].Cl.[CH3:30][N:31](C)[CH2:32]CCN=C=NCC.C(N(CC)CC)C.O.ON1C2C=CC=CC=2N=N1.CNC>ClCCl.O>[CH3:1][O:2][C:3]1[C:16]([O:17][CH3:18])=[CH:15][CH:14]=[C:13]([C:19]2[CH:20]=[C:21]3[C:25](=[CH:26][CH:27]=2)[C:24](=[O:28])[O:23][CH2:22]3)[C:4]=1[O:5][CH2:6][C:7]([CH3:12])([CH3:11])[C:8]([N:31]([CH3:32])[CH3:30])=[O:9]
Reactant: COc1ccc(-c2ccc3c(c2)COC3=O)c(OCC(C)(C)C(=O)O)c1OC
Reactant: CCN=C=NCCCN(C)C
Agent: CNC
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: ClCCl
Solvent: CCN(CC)CC
Solvent: O
Product: COc1ccc(-c2ccc3c(c2)COC3=O)c(OCC(C)(C)C(=O)N(C)C)c1OC
Reaction time: 0.17 h
Yield: 28 %

Procedure:
To a stirring solution of 3-(2,3-dimethoxy-6-(1-oxo-1,3-dihydroisobenzofuran-5-yl)phenoxy)-2,2-dimethylpropanoic acid (100 mg, 0.259 mmol) in dichloromethane (10 mL) was added 1-(3-Dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (EDC.HCl) (74.1 mg, 0.388 mmol), triethylamine (1 mL, 0.77 mmol) and 1-hydroxybenzotriazole hydrate (HOBt) (79.2 mg, 0.518 mmol) and stirred for 10 min. To this dimethylamine (23 mg, 0.518 mmol) was added and the resultant reaction mixture was stirred at RT for 16 h. The reaction mixture was diluted with water and extracted with dichloromethane (3×). The combined dichloromethane layers were washed with brine, dried over anhydrous sodium sulphate and concentrated under reduced pressure. Purification of the residue by column chromatography (silica gel, 0-45% ethyl acetate in pet ether) afforded the title compound as a solid (30 mg, 30%).
Reaction SMILES: [O:1]=[C:2]([C:7]1[CH:8]=[C:9]2[C:14](=[CH:15][CH:16]=1)[NH:13][C:12](=[O:17])[CH2:11][CH2:10]2)[CH2:3][CH2:4][CH2:5]Cl.[I-].[Na+].[Cl:20][C:21]1[CH:22]=[C:23]([N:27]2[CH2:32][CH2:31][NH:30][CH2:29][CH2:28]2)[CH:24]=[CH:25][CH:26]=1.C(=O)([O-])O.[Na+]>CN(C)C=O.C(N(CC)CC)C>[O:1]=[C:2]([C:7]1[CH:8]=[C:9]2[C:14](=[CH:15][CH:16]=1)[NH:13][C:12](=[O:17])[CH2:11][CH2:10]2)[CH2:3][CH2:4][CH2:5][N:30]1[CH2:29][CH2:28][N:27]([C:23]2[CH:24]=[CH:25][CH:26]=[C:21]([Cl:20])[CH:22]=2)[CH2:32][CH2:31]1
Reactant: O=C1CCc2cc(C(=O)CCCCl)ccc2N1
Reactant: Clc1cccc(N2CCNCC2)c1
Agent: O=C([O-])O
Agent: [I-]
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: O=C1CCc2cc(C(=O)CCCN3CCN(c4cccc(Cl)c4)CC3)ccc2N1
Reaction time: 2 h

Procedure:
5.0 Grams of 6-(1-oxo-4-chlorobutyl)-3,4-dihydrocarbostyril and 7.5 g of sodium iodide were dispersed in 120 ml of anhydrous dimethylformamide and the mixture was stirred at 50°-60° C. for 2 hours. To this reaction mixture were added 10 g of 4-(3-chlorophenyl)piperazine and 5 ml of triethylamine and was stirred at 50°-60° C. for 6 hours, then stirred at a room temperature for 24 hours. The reaction mixture was concentrated under a reduced pressure to obtain a residue. To the residue thus obtained was added 80 ml of 5%-sodium hydrogencarbonate solution and the organic layer was extracted with chloroform. The chloroform layer was washed with water, dried and chloroform was removed by distillation. The residue thus obtained was crystallized with ehter to obtain crude crystals and the crude crystals were recrystallized from ethanol to obtain 6.5 g of 6-{1-oxo-4-[4-(3-chlorophenyl)-1-piperazinyl]butyl}-3,4-dihydrocarbostyril in colorless needle-like crystals.
Reaction SMILES: [Br:1][C:2]1[S:6][C:5]([C:7]([O:9]CC)=[O:8])=[C:4]([C:12]2[CH:17]=[CH:16][C:15]([Cl:18])=[CH:14][C:13]=2[Cl:19])[C:3]=1[C:20]#[N:21].O.[OH-].[Na+]>O1CCCC1>[Br:1][C:2]1[S:6][C:5]([C:7]([OH:9])=[O:8])=[C:4]([C:12]2[CH:17]=[CH:16][C:15]([Cl:18])=[CH:14][C:13]=2[Cl:19])[C:3]=1[C:20]#[N:21]
Reactant: CCOC(=O)c1sc(Br)c(C#N)c1-c1ccc(Cl)cc1Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: N#Cc1c(Br)sc(C(=O)O)c1-c1ccc(Cl)cc1Cl
Temperature: 25 °C
Reaction time: 8 h

Procedure:
Ethyl 5-bromo-4-cyano-3-(2,4-dichlorophenyl)thiophene-2-carboxylate (4.60 g, 0.0114 mol) was dissolved in Tetrahydrofuran (100 mL) and Water (20 mL) and 1.00 M of Sodium hydroxide in Water (34.1 mL, 0.0341 mol) was added The mixture was stirred at room temperature overnight. Reaction was quenched by addition of 1N HCl (36 mL), extracted with EA (3×), dried MgSO4, filtered and evaporated to give the product that was used without further purification (4.28 g, 100%). LCMS: (FA) ES−, 374, 376, 378. 1H NMR (400 MHz, d1-chloroform) δ: 7.52 (d, J=1.99 Hz, 1H), 7.35 (dd, J=8.28, 2.02 Hz, 1H), 7.21 (d, J=8.27 Hz, 1H).
Reaction SMILES: [CH2:1]([Li])[CH2:2][CH2:3][CH3:4].[Cl-].C([Zn+])CCC.[Cl:12][C:13]1[N:14]=[C:15]2[CH:20]=[CH:19][C:18](Cl)=[N:17][N:16]2[CH:22]=1.Cl>O1CCCC1.[Cl-].[Zn+2].[Cl-].Cl[Ni]1(Cl)[P](C2C=CC=CC=2)(C2C=CC=CC=2)CCC[P]1(C1C=CC=CC=1)C1C=CC=CC=1>[CH2:1]([C:18]1[CH:19]=[CH:20][C:15]2[N:16]([CH:22]=[C:13]([Cl:12])[N:14]=2)[N:17]=1)[CH2:2][CH2:3][CH3:4]
Reactant: [Li]CCCC
Reactant: Clc1cn2nc(Cl)ccc2n1
Agent: Cl[Ni]1(Cl)[P](c2ccccc2)(c2ccccc2)CCC[P]1(c1ccccc1)c1ccccc1
Agent: CCCC[Zn+]
Agent: Cl
Solvent: C1CCOC1
Product: CCCCc1ccc2nc(Cl)cn2n1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
Zinc chloride (2.04 g, 15.0 mmol) was dried at 180° C. for 2 hours under vacuum and then cooled to room temperature, and anhydrous tetrahydrofuran (20.0 mL) was added thereto. n-Butyl lithium (1.6 M, 9.0 mL, 14.4 mmol) was added dropwise thereto over about 30 minutes under ice-cooling and stirred for 30 minutes under ice-cooling, to prepare a solution of n-butylzinc chloride in tetrahydrofuran. Separately, a suspension of 2,6-dichloroimidazo[1,2-b]pyridazine (1.88 g, 10.0 mmol) and [1,3-bis(diphenylphosphino)propane]nickel (II) dichloride (0.16 g, 0.30 mmol) in anhydrous tetrahydrofuran (20.0 mL) was prepared under a nitrogen atmosphere, and the previously prepared solution of n-butylzinc chloride in tetrahydrofuran while being maintained at 3 to 6° C. was added dropwise thereto over 30 minutes. The mixture was stirred for 15 minutes under ice-cooling and for 3 hours at room temperature, then poured into a saturated saline solution and adjusted to pH 2 with dilute hydrochloric acid. The reaction solution was extracted twice with ethyl acetate, and the extracts were combined, dehydrated over anhydrous magnesium sulfate and concentrated under reduced pressure. The residues were purified by silica gel column chromatography (ethyl acetate:hexane=1:4), to give the title compound as pale yellow crystals. The yield was 2.03 g (96.8%).
Reaction SMILES: [CH3:1][O:2][C:3]1[C:4]([CH3:31])=[C:5]([C:22]([O:29][CH3:30])=[C:23]([O:27][CH3:28])[C:24]=1[O:25][CH3:26])[CH2:6][C:7]1[CH:8]=[CH:9][C:10]([OH:21])=[C:11]([CH:20]=1)[C:12]([N:14]1[CH2:19][CH2:18][O:17][CH2:16][CH2:15]1)=[O:13].C(=O)([O-])[O-].[Na+].[Na+].Br[CH2:39][C:40]([O:42][CH3:43])=[O:41]>CC(C)=O>[CH3:1][O:2][C:3]1[C:4]([CH3:31])=[C:5]([C:22]([O:29][CH3:30])=[C:23]([O:27][CH3:28])[C:24]=1[O:25][CH3:26])[CH2:6][C:7]1[CH:8]=[CH:9][C:10]([O:21][CH2:39][C:40]([O:42][CH3:43])=[O:41])=[C:11]([CH:20]=1)[C:12]([N:14]1[CH2:15][CH2:16][O:17][CH2:18][CH2:19]1)=[O:13]
Reactant: COC(=O)CBr
Reactant: COc1c(C)c(Cc2ccc(O)c(C(=O)N3CCOCC3)c2)c(OC)c(OC)c1OC
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CC(C)=O
Product: COC(=O)COc1ccc(Cc2c(C)c(OC)c(OC)c(OC)c2OC)cc1C(=O)N1CCOCC1
Yield: 85.6 %

Procedure:
N-[5-(3,4,5,6-Tetramethoxy-2-methylbenzyl)-2-hydroxybenzoyl]morpholine (0.200 g, 0.465 mmol) was dissolved in acetone (30 ml) and after adding thereto anhydrous sodium carbonate (0.077 g, 0.558 mmol) and methyl bromoacetate (0.078 g, 0.512 mmol), the solution was refluxed under heating for 3 hours. The reaction solution was filtered, the filtrate was concentrated and the obtained residue was purified by silica gel column chromatography (hexand:ethyl acetate=1:1) to obtain the titled compound (0.230 g, 0.398 mmol, 86%).
Reaction SMILES: [Cl:1][C:2]1[CH:32]=[CH:31][C:5]([O:6][C:7]2[C:12]([F:13])=[CH:11][C:10]([S:14]([N:17]([C:25]3[N:26]=[CH:27][S:28][CH:29]=3)[C:18](=[O:24])[O:19][C:20]([CH3:23])([CH3:22])[CH3:21])(=[O:16])=[O:15])=[C:9]([F:30])[CH:8]=2)=[C:4]([C:33]2[CH:38]=[CH:37][N:36]=[C:35]([CH:39]=O)[CH:34]=2)[CH:3]=1.Cl.[NH:42]1[CH2:45][CH2:44][CH2:43]1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].C(=O)(O)[O-].[Na+]>ClCCl>[N:42]1([CH2:39][C:35]2[CH:34]=[C:33]([C:4]3[CH:3]=[C:2]([Cl:1])[CH:32]=[CH:31][C:5]=3[O:6][C:7]3[C:12]([F:13])=[CH:11][C:10]([S:14]([N:17]([C:25]4[N:26]=[CH:27][S:28][CH:29]=4)[C:18](=[O:24])[O:19][C:20]([CH3:23])([CH3:21])[CH3:22])(=[O:16])=[O:15])=[C:9]([F:30])[CH:8]=3)[CH:38]=[CH:37][N:36]=2)[CH2:45][CH2:44][CH2:43]1
Reactant: CC(C)(C)OC(=O)N(c1cscn1)S(=O)(=O)c1cc(F)c(Oc2ccc(Cl)cc2-c2ccnc(C=O)c2)cc1F
Reactant: C1CNC1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: Cl
Agent: O=C([O-])O
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N(c1cscn1)S(=O)(=O)c1cc(F)c(Oc2ccc(Cl)cc2-c2ccnc(CN3CCC3)c2)cc1F
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
tert-Butyl ({4-[4-chloro-2-(2-formylpyridin-4-yl)phenoxy]-2,5-difluorophenyl}sulfonyl)1,3-thiazol-4-ylcarbamate, (Preparation 879, 0.36 g, 0.00059 mol) was dissolved in dichloromethane (3 mL) then azetidine hydrochloride (0.083 g, 0.00089 mol) was added and reaction allowed to stir at room temperature for 30 minutes. Sodium triacetoxyborohydride (0.144 g, 0.00068 mol) was added and the reaction stirred at room temperature for 18 hours. Saturated aqueous sodium bicarbonate solution (5 mL) was added and the reaction stirred for 30 minutes. The reaction was then passed through a phase separation cartridge and the isolated dichloromethane layer concentrated in vacuo to give the desired product as an orange foam (0.325 g).
Reaction SMILES: [CH3:1][CH:2]1[NH:6][C@H:5]([C:7]([OH:9])=[O:8])[CH2:4][S:3]1.C[Si](N([Si](C)(C)C)C(=O)C(F)(F)F)(C)C.[CH2:25]1[C@H:32]([N:33]2C(=O)C3C(=CC=CC=3)C2=O)[C:30](=[O:31])[O:29][C:27](=[O:28])[CH2:26]1.C(NN)(=O)C1C(=CC=CC=1)C(NN)=O>CC#N.CCN(CC)CC.O>[NH2:33][C@H:32]([C:30]([OH:31])=[O:29])[CH2:25][CH2:26][C:27]([N:6]1[C@H:5]([C:7]([OH:9])=[O:8])[CH2:4][S:3][CH:2]1[CH3:1])=[O:28]
Reactant: O=C1CC[C@H](N2C(=O)c3ccccc3C2=O)C(=O)O1
Reactant: CC1N[C@H](C(=O)O)CS1
Agent: C[Si](C)(C)N(C(=O)C(F)(F)F)[Si](C)(C)C
Agent: NNC(=O)c1ccccc1C(=O)NN
Solvent: CC#N
Solvent: CCN(CC)CC
Solvent: O
Product: CC1SC[C@@H](C(=O)O)N1C(=O)CC[C@H](N)C(=O)O
Temperature: 25 °C

Procedure:
To a stirred suspension of 2(R,S)-methylthiazolidine-4(R)-carboxylic acid (8.51 g, 57.9 mmol) prepared according to Nagasawa et al., J. Med. Chem., 27, 591 (1984), which is incorporated herein by reference, in dry CH3CN (100 mL) under a N2 atmosphere was added bis-(trimethylsilyl)trifluoroacetamide (17.0 mL, 17.7 g, 68.7 mmol, obtained from Sigma Chemical Co., "BSTFA") and the mixture was heated under reflux for 1.25 hours. The solids dissolved within 10 minutes of heating. After cooling to room temperature, N-phthaloyl-L-glutamic anhydride (15.0 g, 58.0 mmol) prepared according to Elbefling et al., Org. Prep. Proceed. Int., 11, 67 (1979), which is incorporated herein by reference, was added, followed by dry CH3CN (25 mL). After 5 days at room temperature the solvent was evaporated in vacuo. To the resultant pale yellow thick oil (41.1 g) were added with stirring under a N2 atmosphere, 1.0M Et3N in CH3OH (220 mL) and 2.0M NH2NH2.H2O in 50% aqueous CH3OH (73 mL). After 2 days of stirring the solvent was evaporated in vacuo. The resultant thick, white, semisolid (51.8 g) was suspended in H2O (150 mL) and the solvent evaporated again to give 49.7 g of a thick, white oil. This was poured into warm H2O (350 mL) with swirling. The resultant precipitate of phthalhydrazide was removed by filtration and the filter cake was rinsed with H2O (approximately 100 mL). The combined filtrate was acidified to pH 3.5 with 1.0N HCl, whereupon more phthalhydrazide precipitated. This was removed by filtration, and the filtrate was evaporated in vacuo, keeping the temperature under 40° C., to give 35.8 g of a thick, pale yellow oil whose NMR spectrum showed the presence of much Et3N and some phthalhydrazide in addition to the desired product. The oil was, therefore, resuspended in H2O (75 mL), the mixture was stirred, and the additional solids that precipitated were removed by filtration. The filtrate was evaporated to incipient dryness in vacuo to give a thick oil (24.6 g).
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([N:10]2[C:14]([C:15]3[CH:20]=[CH:19][C:18]([S:21]([CH3:24])(=[O:23])=[O:22])=[CH:17][CH:16]=3)=[N:13][C:12]([C:25]([F:28])([F:27])[F:26])=[N:11]2)=[CH:6][CH:5]=1)([O-])=O.[Cl-].[NH4+].C(O)C>[Fe].O>[NH2:1][C:4]1[CH:5]=[CH:6][C:7]([N:10]2[C:14]([C:15]3[CH:16]=[CH:17][C:18]([S:21]([CH3:24])(=[O:22])=[O:23])=[CH:19][CH:20]=3)=[N:13][C:12]([C:25]([F:26])([F:27])[F:28])=[N:11]2)=[CH:8][CH:9]=1
Reactant: CS(=O)(=O)c1ccc(-c2nc(C(F)(F)F)nn2-c2ccc([N+](=O)[O-])cc2)cc1
Agent: [Fe]
Agent: [Cl-]
Agent: [NH4+]
Solvent: CCO
Solvent: O
Product: CS(=O)(=O)c1ccc(-c2nc(C(F)(F)F)nn2-c2ccc(N)cc2)cc1
Yield: 89.9 %

Procedure:
A mixture of 1-(4-nitro-phenyl)-5-(4-methylsulfonyl-phenyl)-3-trifluoromethyl-1H-1,2,4-triazole (1.2 g, 2.91 mmol), iron powder (0.8 g, 14.27 mmol), ammonium chloride (0.80 g, 1.45 mmol), ethanol (25 ml) and water (13 ml) was heated to reflux for 1 hour, then cooled and filtered. The filtrate was poured onto water, extracted with ethyl acetate and a dichloromethane/methanol solution. The organic extracts were washed with saturated brine, dried over Na2SO4 and evaporated to give a yellow powder (1 g, 91%), which was used for the next step without further purification.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[C:17]3[C:16]([O:18][CH2:19][C:20]([CH3:24])([CH3:23])[CH2:21][OH:22])=[N:15][CH:14]=[N:13][C:12]=3[O:11][C:10]=2[C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)=[CH:5][CH:4]=1.[C:31]([O:35][C:36](=[O:39])[CH2:37]Br)([CH3:34])([CH3:33])[CH3:32].[OH-].[Na+].C(O)(=O)CC(CC(O)=O)(C(O)=O)O>S([O-])(O)(=O)=O.C([N+](CCCC)(CCCC)CCCC)CCC.ClCCl>[C:31]([O:35][C:36](=[O:39])[CH2:37][O:22][CH2:21][C:20]([CH3:24])([CH3:23])[CH2:19][O:18][C:16]1[C:17]2[C:9]([C:6]3[CH:5]=[CH:4][C:3]([O:2][CH3:1])=[CH:8][CH:7]=3)=[C:10]([C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=3)[O:11][C:12]=2[N:13]=[CH:14][N:15]=1)([CH3:34])([CH3:33])[CH3:32]
Reactant: CC(C)(C)OC(=O)CBr
Reactant: COc1ccc(-c2c(-c3ccccc3)oc3ncnc(OCC(C)(C)CO)c23)cc1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: O=C(O)CC(O)(CC(=O)O)C(=O)O
Agent: O=S(=O)([O-])O
Solvent: ClCCl
Product: COc1ccc(-c2c(-c3ccccc3)oc3ncnc(OCC(C)(C)COCC(=O)OC(C)(C)C)c23)cc1
Temperature: 0 °C

Procedure:
Put 300 mg (0.742 mmol) 3-{[5-(4-methoxyphenyl)-6-phenylfuro[2,3-d]pyrimidin-4-yl]oxy}-2,2-dimethylpropan-1-ol with 723 mg (3.71 mmol) bromoacetic acid tert.-butyl ester and 50 mg (0.148 mmol) tetra-n-butylammonium hydrogensulphate in 6 ml dichloromethane. Cool to 0° C. Then add 750 μl 50% sodium hydroxide solution and stir vigorously for a few minutes at 0° C. Stirring vigorously, allow to return to RT, and continue stirring vigorously overnight. Then dilute with dichloromethane and lightly acidify with 10% citric acid solution. Separate the phases and extract the aqueous phase once with dichloromethane. Combine the organic phases and wash once with satd. sodium chloride solution, dry over magnesium sulphate and concentrate by evaporation. Purify the residue by chromatography on silica gel (solvent: cyclohexane/ethyl acetate 9:1). 295 mg (76.7% of theor.) of the target compound is obtained.
Reaction SMILES: [Mg].Br[C:3]([CH2:5][CH3:6])=[CH2:4].[Br:7][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=1[N+:14]([O-])=O.[Na+].[Cl-]>C1COCC1>[Br:7][C:8]1[CH:13]=[CH:12][CH:11]=[C:10]2[C:9]=1[NH:14][C:3]([CH2:5][CH3:6])=[CH:4]2
Reactant: C=C(Br)CC
Reactant: O=[N+]([O-])c1ccccc1Br
Agent: [Cl-]
Agent: [Mg]
Agent: [Na+]
Solvent: C1CCOC1
Product: CCc1cc2cccc(Br)c2[nH]1
Temperature: 60 °C
Yield: 207.8 %

Procedure:
2.4 g of magnesium are placed in a round-bottomed flask and the magnesium is covered with 10 ml of THF. 1 g of 2-bromo-1-butene, then 10 ml of THF and then again 12.5 g of 2-bromo-1-butene in 30 ml of THF are added. The reaction medium is observed to warm up and then it is heated at 60° C. for 30 minutes after the end of the addition reaction. The mixture is subsequently cooled to −20° C., 20 ml of THF are added and then 6.7 g of 2-bromonitrobenzene are added at −20° C. The mixture is allowed to return to AT. The reaction medium is poured onto 200 ml of a saturated NaCl solution. Extraction is carried out with ether, the extracts are then evaporated and the residue is taken up in DCM. The organic phase is washed with water and then with a saturated NaCl solution. It is dried and evaporated and then the residue is chromatographed on silica while eluting with a cyclohexane/AcOEt (9.5/0.5, v/v) mixture. 3.45 g of the expected compound are obtained.