Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C([O:3][C:4]([C:6]1[N:7]([CH3:35])[C:8]2[C:13]([C:14]=1[Cl:15])=[CH:12][C:11]([NH:16][C:17]([C:19]1[C:20]([C:25]3[CH:30]=[CH:29][C:28]([C:31]([F:34])([F:33])[F:32])=[CH:27][CH:26]=3)=[CH:21][CH:22]=[CH:23][CH:24]=1)=[O:18])=[CH:10][CH:9]=2)=[O:5])C.[Li+].[OH-].Cl>C1COCC1.CO.O>[Cl:15][C:14]1[C:13]2[C:8](=[CH:9][CH:10]=[C:11]([NH:16][C:17]([C:19]3[C:20]([C:25]4[CH:30]=[CH:29][C:28]([C:31]([F:32])([F:33])[F:34])=[CH:27][CH:26]=4)=[CH:21][CH:22]=[CH:23][CH:24]=3)=[O:18])[CH:12]=2)[N:7]([CH3:35])[C:6]=1[C:4]([OH:5])=[O:3]
Reactant: CCOC(=O)c1c(Cl)c2cc(NC(=O)c3ccccc3-c3ccc(C(F)(F)F)cc3)ccc2n1C
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Solvent: O
Solvent: C1CCOC1
Product: Cn1c(C(=O)O)c(Cl)c2cc(NC(=O)c3ccccc3-c3ccc(C(F)(F)F)cc3)ccc21
Temperature: 25 °C
Reaction time: 8 h

Procedure:
The product of step (d) may be hydrolyzed as follows: the compound (5.51 g) was dissolved in THF (120 mL) and methanol (40 mL). Under stirring conditions was added LiOH (1.32 g) in water (40 mL). The reaction mixture was stirred at room temperature overnight. To the reaction mixture was then added 1 N HCl solution (60 mL), and the aqueous layer was extracted with EtOAc (250 mL). The organic layer was washed with brine (200 mL), and dried (MgSO4). The solvent was evaporated in vacuo to give the crude product which was purified by recrystallization from 1:1 EtOAc/ether to afford 4.4 g of the title compound.
Reaction SMILES: CC1(C)[O:7][CH2:6][C:5]([NH:27]C(=O)OC(C)(C)C)([CH2:8][N:9]2[C:18]3[C:13](=[CH:14][C:15]([CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH3:26])=[CH:16][CH:17]=3)[CH2:12][CH2:11][CH2:10]2)[CH2:4][O:3]1.CC1(C)OCC(NC(=O)OC(C)(C)C)(CN2CC3C(=CC=C(CCCCCCCC)C=3)C2)CO1>>[NH2:27][C:5]([CH2:8][N:9]1[C:18]2[C:13](=[CH:14][C:15]([CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH3:26])=[CH:16][CH:17]=2)[CH2:12][CH2:11][CH2:10]1)([CH2:6][OH:7])[CH2:4][OH:3]
Reactant: CCCCCCCCc1ccc2c(c1)CCCN2CC1(NC(=O)OC(C)(C)C)COC(C)(C)OC1
Agent: CCCCCCCCc1ccc2c(c1)CN(CC1(NC(=O)OC(C)(C)C)COC(C)(C)OC1)C2
Product: CCCCCCCCc1ccc2c(c1)CCCN2CC(N)(CO)CO
Yield: 36 %

Procedure:
When the product of Step D is substituted for tert-butyl 2,2-dimethyl-5-((5-octylisoindolin-2-yl)methyl)-1,3-dioxan-5-ylcarbamate in Example 2, Step G, the identical process afforded the title compound in 36% yield., as a colourless solid. 1H-NMR (CDCl3) 0.86 (tr, 3H, J=7 Hz); 1.26 (m, 10H); 1.53 (m, 2H); 1.92 (m, 2H); 2.22 (broad s, 4H+H2O); 2.43 (tr, 2H, J=8 Hz); 2.76 (tr, 2H, J=6.4 Hz); 3.23 (s, 2H); 3.26 (tr, 2H, J=3.7 Hz); 3.51-3.61 (m, 4H); 6.7-6.87 (m, 3H).
Reaction SMILES: [I:1][C:2]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][C:9]=2[N+:11]([O-:13])=[O:12])[NH:4][N:3]=1.Br.BrC[C:17]1[CH:22]=[CH:21][N:20]=[CH:19][CH:18]=1.[C:23](N=C(N(C)C)N(C)C)(C)(C)C>CC#N.O>[I:1][C:2]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][C:9]=2[N+:11]([O-:13])=[O:12])[N:4]([CH2:23][C:22]2[CH:21]=[N:20][CH:19]=[CH:18][CH:17]=2)[N:3]=1
Reactant: BrCc1ccncc1
Reactant: CN(C)C(=NC(C)(C)C)N(C)C
Reactant: O=[N+]([O-])c1cccc2[nH]nc(I)c12
Agent: Br
Solvent: O
Solvent: CC#N
Product: O=[N+]([O-])c1cccc2c1c(I)nn2Cc1cccnc1
Reaction time: 8 h
Yield: 76.9 %

Procedure:
To a flask was added 3-iodo-4-nitro-1H-indazole (0.300 g, 1.04 mmol) and 4-(bromomethyl)pyridine hydrobromide (0.315 g, 1.25 mmol) which were slurried in CH3CN (5.0 mL). 2-tert-Butyl-1,1,3,3-tetramethylguanidine (0.460 mL, 2.28 mmol) was added and the mixture was stirred overnight. The mixture was diluted with water (20 mL) and stirred for 15 minutes and filtered. The collected solids were washed with water followed by Et2O and hexanes, and dried under vacuum to provide the title compound as a brown powder (0.304 g, 71%), which was used directly in the subsequent step.
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[C:12]([CH2:13][CH2:14][C:15]3[S:16][C:17]([C:20]([OH:22])=O)=[CH:18][N:19]=3)=[C:11]([CH3:23])[O:10][N:9]=2)=[N:6][CH:7]=1.[CH:24]1([NH2:27])[CH2:26][CH2:25]1>>[CH:24]1([NH:27][C:20]([C:17]2[S:16][C:15]([CH2:14][CH2:13][C:12]3[C:8]([C:5]4[CH:4]=[CH:3][C:2]([F:1])=[CH:7][N:6]=4)=[N:9][O:10][C:11]=3[CH3:23])=[N:19][CH:18]=2)=[O:22])[CH2:26][CH2:25]1
Reactant: Cc1onc(-c2ccc(F)cn2)c1CCc1ncc(C(=O)O)s1
Reactant: NC1CC1
Product: Cc1onc(-c2ccc(F)cn2)c1CCc1ncc(C(=O)NC2CC2)s1
Yield: 55 %

Procedure:
As described for example 40c, 2-{2-[3-(5-fluoro-pyridin-2-yl)-5-methyl-isoxazol-4-yl]-ethyl}-thiazole-5-carboxylic acid (67 mg, 0.20 mmol) was converted, using cyclopropylamine instead of 4-aminotetrahydropyran, to the title compound (42 mg, 55%) which was obtained as a white solid. MS: m/e=373.1 [M+H]+.
Reaction SMILES: C([O:3][C:4](=[O:23])[CH2:5][CH2:6][CH2:7][O:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]2[CH:20]=[CH:19][C:18]([C:21]#[N:22])=[CH:17][CH:16]=2)=[CH:11][CH:10]=1)C.[OH-].[Na+].CO>C1COCC1.O>[C:21]([C:18]1[CH:17]=[CH:16][C:15]([C:12]2[CH:13]=[CH:14][C:9]([O:8][CH2:7][CH2:6][CH2:5][C:4]([OH:23])=[O:3])=[CH:10][CH:11]=2)=[CH:20][CH:19]=1)#[N:22]
Reactant: CCOC(=O)CCCOc1ccc(-c2ccc(C#N)cc2)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: O
Solvent: C1CCOC1
Product: N#Cc1ccc(-c2ccc(OCCCC(=O)O)cc2)cc1
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 75.6 %

Procedure:
To a solution of 4-(4′-cyanobiphenyl-4-yloxy)butyric acid ethyl ester (3.78 g, 12.7 mmol) in THF (50 ml) was added a solution of NaOH (1.0 g, 25 mmol) in water (1.5 ml). The mixture was stirred at room temperature for 1.5 h and then at 67° C. for 3 h. More NaOH (1 g) in water (1 ml) was added, and stirring at room temperature was continued for 15 h. MeOH (10 ml) was added, and after stirring at room temperature for 1.5 h the mixture was diluted with water (150 ml) and acidified with concentrated, aqueous HCl (6.6 ml). The product was isolated by filtration and washed with water (approx 20 ml). The solid was suspended in MeCN (50 ml), heated to reflux (no dissolution) and allowed to cool to room temperature. Filtration and drying under reduced pressure yielded 2.70 g (76%) of 4-(4′-cyanobiphenyl-4-yloxy)butyric acid as a colorless solid.
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][CH:4]([NH:7][C:8]2[S:12][C:11]([C:13]#[N:14])=[N:10][N:9]=2)[CH2:3][CH2:2]1.[F:15][C:16]([F:26])([F:25])[C:17]1[CH:18]=[C:19]([CH:22]=[CH:23][CH:24]=1)[CH:20]=O.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>CN(C)C=O.C(OCC)(=O)C>[F:15][C:16]([F:25])([F:26])[C:17]1[CH:18]=[C:19]([CH:22]=[CH:23][CH:24]=1)[CH2:20][N:1]1[CH2:2][CH2:3][CH:4]([NH:7][C:8]2[S:12][C:11]([C:13]#[N:14])=[N:10][N:9]=2)[CH2:5][CH2:6]1
Reactant: N#Cc1nnc(NC2CCNCC2)s1
Reactant: O=Cc1cccc(C(F)(F)F)c1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: N#Cc1nnc(NC2CCN(Cc3cccc(C(F)(F)F)c3)CC2)s1
Temperature: 25 °C
Reaction time: 16 h
Yield: 9 %

Procedure:
A mixture of 5-(piperidin-4-ylamino)-[1,3,4]thiadiazole-2-carbonitrile (D6) (0.16 g, 0.76 mmol), 3-(trifluoromethyl)benzaldehyde (0.152 ml, 1.14 mmol) and sodium triacetoxyborohydride (0.24 g, 0.95 mmol) in N,N-dimethylformamide (3 ml) was stirred at room temperature for 16 h. After this period, the reaction mixture was diluted with ethyl acetate and extracted with a saturated solution of sodium carbonate (25 ml). The organic layer was separated, dried (Na2SO4) and the solvent evaporated in vacuo. The crude product was purified by flash column chromatography (silica gel; 1-4% ammonia in methanol (7M)/dichloromethane) to yield E17 (0.025 g, 9%) as a white solid. C16H16F3N5S requires 367. Found 368 (MH+).
Reaction SMILES: [OH:1][CH:2]([C:23]1[CH:28]=[CH:27][C:26]([O:29][CH3:30])=[CH:25][CH:24]=1)[CH2:3][CH2:4][N:5]1[CH2:10][CH2:9][CH:8]([C:11]2[CH:12]=[C:13]([NH:17][C:18](=[O:22])[CH:19]([CH3:21])[CH3:20])[CH:14]=[CH:15][CH:16]=2)[CH2:7][CH2:6]1.[Br:31][C:32]1[CH:37]=[CH:36][C:35](O)=[CH:34][CH:33]=1>>[Br:31][C:32]1[CH:37]=[CH:36][C:35]([O:1][CH:2]([C:23]2[CH:24]=[CH:25][C:26]([O:29][CH3:30])=[CH:27][CH:28]=2)[CH2:3][CH2:4][N:5]2[CH2:10][CH2:9][CH:8]([C:11]3[CH:12]=[C:13]([NH:17][C:18](=[O:22])[CH:19]([CH3:21])[CH3:20])[CH:14]=[CH:15][CH:16]=3)[CH2:7][CH2:6]2)=[CH:34][CH:33]=1
Reactant: Oc1ccc(Br)cc1
Reactant: COc1ccc(C(O)CCN2CCC(c3cccc(NC(=O)C(C)C)c3)CC2)cc1
Product: COc1ccc(C(CCN2CCC(c3cccc(NC(=O)C(C)C)c3)CC2)Oc2ccc(Br)cc2)cc1

Procedure:
Prepared by Procedure A and Scheme AN using N-(3-{1-[3-hydroxy-3-(4-methoxyphenyl)propyl]-4-piperidinyl}phenyl)-2-methylpropanamide and 4-bromophenol: ESMS m/e: 564.9 (M+H)+.
Reaction SMILES: [C:1]1([C:7]2[C:8](=O)[O:9][C:10](=[O:12])[CH:11]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.S(O)(O)(=O)=O.[NH2:19][NH2:20]>O>[C:1]1([C:7]2[C:8](=[O:9])[NH:19][NH:20][C:10](=[O:12])[CH:11]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: O=C1C=C(c2ccccc2)C(=O)O1
Reactant: NN
Agent: O=S(=O)(O)O
Solvent: O
Product: O=c1cc(-c2ccccc2)c(=O)[nH][nH]1
Temperature: 115 °C
Reaction time: 5 h
Yield: 95.8 %

Procedure:
46 g (264.1 mmol) 3-Phenyl-furan-2,5-dione were suspended in 1.56 L water. After addition of 34.4 g (264.1 mmol) hydrazine sulfate the reaction mixture was heated to reflux (bath temperature: 115° C.) and kept there for five hours. During the night the reaction mixture was kept at a bath temperature of 98° C. After cooling the precipitate was sucked off, washed with water (100 mL) and dried at 40° C. yielding 47.6 g (95.8%) of the title compound.
Reaction SMILES: [OH-].[Na+].[CH3:3][O:4][C:5]1[CH:10]=[C:9]([O:11][CH3:12])[CH:8]=[CH:7][C:6]=1[C:13]([CH2:24][CH2:25][CH2:26][CH2:27][CH3:28])(C(OCC)=O)[C:14]([O:16]CC)=[O:15].C(OCC)(=O)C.CCCCCC>C(O)C>[CH3:3][O:4][C:5]1[CH:10]=[C:9]([O:11][CH3:12])[CH:8]=[CH:7][C:6]=1[CH:13]([CH2:24][CH2:25][CH2:26][CH2:27][CH3:28])[C:14]([OH:16])=[O:15]
Reactant: CCCCCC(C(=O)OCC)(C(=O)OCC)c1ccc(OC)cc1OC
Agent: [Na+]
Agent: [OH-]
Solvent: CCCCCC
Solvent: CCO
Solvent: CCOC(C)=O
Product: CCCCCC(C(=O)O)c1ccc(OC)cc1OC
Temperature: 25 °C
Yield: 85.1 %

Procedure:
10.0 ml (20.0 mmol) of a 2 N aqueous aqueous solution of sodium hydroxide were added to a solution of 1.30 g (3.55 mmol) of diethyl 2-(2,4-dimethoxyphenyl)-2-pentylmalonate [prepared as described in step (i) above] in 20 ml of ethanol, and the resulting mixture was heated under reflux for 3 hours. At the end of this time, the reaction mixture was freed from ethanol by distillation under reduced pressure, and the resulting residue was acidified with 1 N aqueous hydrochloric acid and then extracted with ethyl acetate. The extract was washed with a saturated aqueous solution of sodium chloride and dried over anhydrous magnesium sulfate, after which the solvent was removed by distillation under reduced pressure. The resulting residue was disssolved in 20 ml of xylene, and the solution was heated under reflux for 80 minutes. At the end of this time, the reaction mixture was cooled to room temperature, after which it was purified by column chromatography through 50 g of silica gel using a gradient elution method, with mixtures of ethyl acetate and hexane ranging from 1:3 to 1:1 by volume as the eluent, to give 805 mg (yield 85%) of the title carboxylic acid derivative as an oily substance.
Reaction SMILES: [Cl:1][C:2]1[C:7]([F:8])=[C:6]([CH3:9])[C:5](I)=[CH:4][N:3]=1.[C:11]([Si:13]([CH3:16])([CH3:15])[CH3:14])#[CH:12].C(N(CC)C(C)C)(C)C>O1CCOCC1.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[Cl:1][C:2]1[C:7]([F:8])=[C:6]([CH3:9])[C:5]([C:12]#[C:11][Si:13]([CH3:16])([CH3:15])[CH3:14])=[CH:4][N:3]=1
Reactant: C#C[Si](C)(C)C
Reactant: Cc1c(I)cnc(Cl)c1F
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Solvent: C1COCCO1
Solvent: CCN(C(C)C)C(C)C
Product: Cc1c(C#C[Si](C)(C)C)cnc(Cl)c1F
Temperature: 60 °C
Yield: 0.1 %

Procedure:
A mixture of 2-chloro-3-fluoro-5-iodo-4-methyl-pyridine (2960 mg, 10.9 mmol), ethynyltrimethylsilane (1.89 mL, 13.1 mmol), N,N-diisopropylethylamine (3.80 mL, 21.8 mmol), dichlorobis(triphenylphosphine)palladium(II) (390 mg, 0.545 mmol), and cuprous iodide (104 mg, 0.55 mmol) in dioxane (40 mL) was heated at 60° C. for 2 hours. The reaction mixture was filtered through a short plug of silica, rinsed with 50 mL of ethyl acetate/heptane (1:1), and the filtrate was evaporated in vacuo to provide an orange oil that was purified by flash chromatography (12 g, Silica, 0-20% ethyl acetate in heptane). Desired fractions were combined and evaporated in vacuo to afford the title compound as a pale yellow oil, (2.35 mg, 89%). 1H NMR (400 MHz, CDCl3) δ 8.21 (s, 1H), 2.40 (d, J=1.9 Hz, 3H), 0.28 (s, 11H).
Reaction SMILES: [CH2:1]([N:3]1[CH2:11][C:10]2[C:5](=[CH:6][CH:7]=[C:8]([N+:12]([O-])=O)[CH:9]=2)[CH2:4]1)[CH3:2].CCN(CC)CC.[CH3:22][C:23](OC(C)=O)=[O:24]>CO.[Pd]>[CH2:1]([N:3]1[CH2:11][C:10]2[C:5](=[CH:6][CH:7]=[C:8]([NH:12][C:23](=[O:24])[CH3:22])[CH:9]=2)[CH2:4]1)[CH3:2]
Reactant: CC(=O)OC(C)=O
Reactant: CCN1Cc2ccc([N+](=O)[O-])cc2C1
Agent: [Pd]
Solvent: CO
Solvent: CCN(CC)CC
Product: CCN1Cc2ccc(NC(C)=O)cc2C1
Temperature: 20 °C
Reaction time: 15 h
Yield: 87.9 %

Procedure:
A solution of isoindole 245 (3.20 g, 16.7 mmol) in MeOH (100 mL) was stirred with Pd/C (5%, 300 mg) under H2 (60 psi) for 16 h. The solution was filtered through Celite, washed with MeOH (3×20 mL) and the solvent evaporated. The residue was dissolved in DCM (130 mL) and Et3N (13 mL, 93 mmol), Ac2O (13 mL, 138 mmol) was added dropwise and the solution stirred at 20° C. for 15 h. The mixture was partitioned between DCM and aqueous Na2CO3 solution. The organic solution was washed with water, dried and the solvent was evaporated to give acetamide 246 (3.00 g, 88%) as a dark oil: 1H NMR δ 7.45 (br s, 1H, H-4), 7.30 (br s, 1H, NH), 7.18 (br d, J=8.0 Hz, 1H, H-6), 7.12 (d, J=8.0 Hz, 1H, H-7), 3.90 (s, 2H, H-1), 3.87 (s, 2H, H-3), 2.76 (q, J=7.2 Hz, 2H, CH2), 2.15 (s, 3H, COCH3) 1.19 (t, J=7.2 Hz, 3H, CH3); HRMS (FAB+) calcd for C12H17N2O (MH+) m/z 203.1184, found 203.1188.
Reaction SMILES: Cl.Cl[C:3]([C:5]1[CH:6]=[CH:7][N:8]2[C:12]=1[CH2:11][S:10][CH:9]2[C:13]1[CH:14]=[N:15][CH:16]=[CH:17][CH:18]=1)=[O:4].[NH2:19][C:20]1[CH:25]=[CH:24][CH:23]=[C:22]([Cl:26])[N:21]=1.C(N(CC)CC)C.C>O1CCOCC1.C(O)CCC>[Cl:26][C:22]1[N:21]=[C:20]([NH:19][C:3]([C:5]2[CH:6]=[CH:7][N:8]3[C:12]=2[CH2:11][S:10][CH:9]3[C:13]2[CH:14]=[N:15][CH:16]=[CH:17][CH:18]=2)=[O:4])[CH:25]=[CH:24][CH:23]=1
Reactant: O=C(Cl)c1ccn2c1CSC2c1cccnc1
Reactant: Nc1cccc(Cl)n1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: C1COCCO1
Solvent: CCCCO
Product: O=C(Nc1cccc(Cl)n1)c1ccn2c1CSC2c1cccnc1
Temperature: 60 °C
Reaction time: 0.75 h
Yield: 52.5 %

Procedure:
7-Chloroformyl-3-(3-pyridyl)-1H,3H-pyrrolo[1,2-c]thiazole hydrochloride (9 g) is added, at a temperature between 60° and 68° C., to a solution of 2-amino-6-chloropyridine (3.9 g) and triethylamine (6.1 g) in dioxane (200 cc) which is heated to a temperature in the vicinity of 60° C., in the course of 5 minutes. The suspension obtained is heated, with stirring, at a temperature in the vicinity of 100° C. for 5 hours and 45 minutes and then stirred at a temperature in the vicinity of 20° C. for 16 hours. The solvent is evaporated off under reduced pressure (20 mm Hg; 2.7 kPa) at a temperature in the vicinity of 60° C. The residue is dissolved in methylene chloride (500 cc). The solution obtained is washed twice with distilled water (300 cc in total), twice with an aqueous 2N sodium hydroxide solution (300 cc in total) and twice with distilled water (300 cc in total) and then dried over anhydrous magnesium sulphate, treated with decolorizing charcoal (0.5 g), filtered and concentrated to dryness under reduced pressure (20 mm Hg; 2.7 kPa) at a temperature in the vicinity of 50° C. A crude product (9.5 g) is thereby obtained, which is dissolved in boiling butan-1-ol (140 cc). Decolorizing charcoal (0.5 g) is added to the solution obtained and the suspension is filtered in the heated state. The filtrate is cooled at a temperature in the vicinity of 4° C. for 16 hours. The crystals formed are separated by filtration, washed 3 times with butan-1-ol (30 cc in total) and 3 times with diethyl ether (150 cc in total) and then dried under reduced pressure (20 mm Hg; 2.7 kPa) at a temperature in the vicinity of 20° C. in the presence of potassium hydroxide pellets. N-(6-chloro-2-pyridyl)-3-(3-pyridyl)-1H, 3H-pyrrolo[1,2-c]thiazole-7-carboxamide (5,6 g) in the form of cream-coloured crystals, m.p. 186° C., is thereby obtained.
Reaction SMILES: [CH2:1]([N:3]([CH2:26][CH3:27])[C:4]1[N:9]=[C:8]([C:10]2[O:14][N:13]=[C:12]([C:15]3[CH:20]=[C:19]([CH3:21])[C:18]([OH:22])=[C:17]([CH2:23][CH3:24])[CH:16]=3)[N:11]=2)[CH:7]=[C:6]([CH3:25])[N:5]=1)[CH3:2].[OH-].[Na+].Br[CH:31]([OH:33])[CH3:32]>C(O)(C)C.CCOC(C)=O>[CH2:26]([N:3]([CH2:1][CH3:2])[C:4]1[N:9]=[C:8]([C:10]2[O:14][N:13]=[C:12]([C:15]3[CH:20]=[C:19]([CH3:21])[C:18]([O:22][CH2:32][CH2:31][OH:33])=[C:17]([CH2:23][CH3:24])[CH:16]=3)[N:11]=2)[CH:7]=[C:6]([CH3:25])[N:5]=1)[CH3:27]
Reactant: CCc1cc(-c2noc(-c3cc(C)nc(N(CC)CC)n3)n2)cc(C)c1O
Reactant: CC(O)Br
Agent: [Na+]
Agent: [OH-]
Solvent: CC(C)O
Solvent: CCOC(C)=O
Product: CCc1cc(-c2noc(-c3cc(C)nc(N(CC)CC)n3)n2)cc(C)c1OCCO
Temperature: 25 °C
Reaction time: 15 h
Yield: 105.4 %

Procedure:
To a solution of Intermediate 11 (1.5 g, 4.08 mmol) in isopropanol (20 mL) is added 3M aq. NaOH (5 mL) followed by bromoethanol (2.90 mL, 40.8 mmol). The reaction mixture is stirred at rt for 15 h, and is then diluted with EtOAc. The org. solution is washed with 1M aq. NaOH followed by brine, dried over Na2SO4, filtered and concentrated. The crude compound is purified by CC (eluting with Heptane/EA 4:1) to give the title compound as a yellow oil (1.77 g); LC-MS: tR=1.16 min; [M+H]+=412.09. 1H NMR (CDCl3) δ1.26 (t, J=7.0 Hz, 6H), 1.33 (t, J=7.5 Hz, 3H), 2.41 (s, 3H), 2.47 (s, 3H), 2.78 (q, J=7.5 Hz, 2H), 2.16 (t, J=5.5 Hz, 1H), 3.76 (q, J=7.0 Hz, 4H), 4.01 (m, 4H), 7.23 (s, 1H), 7.90 (d, J=5.8 Hz, 2H).
Reaction SMILES: [O:1]1[CH2:6][CH2:5][CH2:4][O:3][CH:2]1[CH2:7][NH:8][C:9]1[C:14]([CH3:15])=[CH:13][CH:12]=[CH:11][C:10]=1[CH3:16].C(=O)([O-])[O-].[Na+].[Na+].C1C=CC=CC=1.[Cl:29][CH2:30][C:31](Cl)=[O:32]>CCOCC.O>[Cl:29][CH2:30][C:31]([N:8]([CH2:7][CH:2]1[O:3][CH2:4][CH2:5][CH2:6][O:1]1)[C:9]1[C:14]([CH3:15])=[CH:13][CH:12]=[CH:11][C:10]=1[CH3:16])=[O:32]
Reactant: Cc1cccc(C)c1NCC1OCCCO1
Reactant: O=C(Cl)CCl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: c1ccccc1
Solvent: CCOCC
Solvent: O
Product: Cc1cccc(C)c1N(CC1OCCCO1)C(=O)CCl
Reaction time: 1 h

Procedure:
N-(1,3-Dioxan-2-ylmethyl)-2,6-dimethylaniline prepared in Example 2 (5 grams), sodium carbonate (3 grams), benzene (30 ml) and water (30 ml) were charged into a glass reaction vessel equipped with a mechanical stirrer and thermometer. The mixture was cooled to a temperature of from about 0° to about 5° C. and chloroacetyl chloride (2.8 grams) was slowly added over a period of about 15 minutes. After the addition was completed stirring was continued at room temperature for a period of about one hour. Ether (100 ml) was then added to the reaction mixture and the resulting solution was washed with water. The washed solution was dried over anhydrous magnesium sulfate and stripped of solvents leaving a solid residue. The residue was recrystallized from heptane to yield the desired product N-α-chloroacetyl-N-(1,3-dioxan-2-ylmethyl)-2,6-dimethylaniline having a melting point of 100° to 120° C.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:17]=[CH:16][C:15]([C:18](=[O:21])[CH2:19]Br)=[CH:14][C:10]=1[C:11]([NH2:13])=[O:12])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[BH4-].[Na+]>O1CCCC1.C(O)C>[CH2:1]([O:8][C:9]1[CH:17]=[CH:16][C:15]([CH:18]2[CH2:19][O:21]2)=[CH:14][C:10]=1[C:11]([NH2:13])=[O:12])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: NC(=O)c1cc(C(=O)CBr)ccc1OCc1ccccc1
Agent: [BH4-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CCO
Product: NC(=O)c1cc(C2CO2)ccc1OCc1ccccc1
Yield: 96.2 %

Procedure:
2-(Benzyloxy)-5-(2-bromoacetyl)benzamide (11.3 g, 32.30 mmol) was dissolved in anhydrous tetrahydrofuran (250 mL) and cooled in an ice bath. The solution was diluted with ethanol (250 mL). Sodium borohydride (1.2 g, 32.3 mmol) was added in three portions. Following addition the solvent was removed in vacuo and the residue partitioned between water and ethyl acetate. The organic layer was washed with water, brine, and dried over anhydrous magnesium sulfate. The solution was filtered and the solvent evaporated to dryness in vacuo to yield crude title compound (10.88 g, 31.06 mmol).
Reaction SMILES: [OH:1][CH2:2][CH2:3][CH2:4][CH2:5][NH:6][C:7](=[O:16])[O:8][CH2:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1.C(N(CC)CC)C.[CH3:24][S:25](Cl)(=[O:27])=[O:26]>C1COCC1>[CH3:24][S:25]([O:1][CH2:2][CH2:3][CH2:4][CH2:5][NH:6][C:7]([O:8][CH2:9][C:10]1[CH:11]=[CH:12][CH:13]=[CH:14][CH:15]=1)=[O:16])(=[O:27])=[O:26]
Reactant: CS(=O)(=O)Cl
Reactant: O=C(NCCCCO)OCc1ccccc1
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CS(=O)(=O)OCCCCNC(=O)OCc1ccccc1
Temperature: 22.5 °C
Reaction time: 6 h
Yield: 81.3 %

Procedure:
To a solution of benzyl 4-hydroxybutylcarbamate (1.1 g, 4.9 mmol) and triethylamine (1.7 mL, 9.8 mmol) in THF was added methanesulfonyl chloride (0.67 g, 5.9 mmol) at 0° C. The reaction was stirred at 20-25° C. for 6 hours and concentrated. The residue was partitioned between ethyl acetate and water. The phases were separated, and the organic layer was washed with hydrochloride solution (1 N), saturated sodium bicarbonate solution, and saline. The separated organic layer was dried and concentrated to give 4-(benzyloxycarbonylamino)butyl methanesulfonate (1.2 g).
Reaction SMILES: [F:1][S:2]([F:13])([F:12])([F:11])([F:10])[C:3]1[CH:8]=[CH:7][C:6]([OH:9])=[CH:5][CH:4]=1.[CH2:14]1CCN2C(=NCCC2)CC1>C(=O)(OC)OC.CC(=O)OCC>[CH3:14][O:9][C:6]1[CH:7]=[CH:8][C:3]([S:2]([F:10])([F:11])([F:12])([F:13])[F:1])=[CH:4][CH:5]=1
Reactant: Oc1ccc(S(F)(F)(F)(F)F)cc1
Reactant: C1CCC2=NCCCN2CC1
Solvent: CCOC(C)=O
Solvent: COC(=O)OC
Product: COc1ccc(S(F)(F)(F)(F)F)cc1
Yield: 41.4 %

Procedure:
5.00 g of 4-pentafluorosulfanylphenol were dissolved in 50.00 g of dimethyl carbonate and 3.46 g of DBU were added. The mixture was boiled under reflux for 10 hours, then allowed to cool and diluted with 200 ml of EA. Subsequently, the mixture was washed twice with 100 ml each time of a 5% aqueous HCl solution, then with 100 ml of a 5% aqueous NaOH solution. Drying was effected over MgSO4 and the solvent was removed under reduced pressure. Chromatography on silica gel using 1:1 DIP/HEP afforded 2.2 g of a colorless oil.
Reaction SMILES: [CH3:1][C:2]([N:5]1[N:9]=[N:8][C:7]([CH2:10][C:11]2[CH:16]=[CH:15][C:14]([CH2:17][CH2:18][C:19]([O:21]C(C)(C)C)=[O:20])=[CH:13][CH:12]=2)=[N:6]1)([CH3:4])[CH3:3]>FC(F)(F)C(O)=O>[CH3:4][C:2]([N:5]1[N:9]=[N:8][C:7]([CH2:10][C:11]2[CH:12]=[CH:13][C:14]([CH2:17][CH2:18][C:19]([OH:21])=[O:20])=[CH:15][CH:16]=2)=[N:6]1)([CH3:1])[CH3:3]
Reactant: CC(C)(C)OC(=O)CCc1ccc(Cc2nnn(C(C)(C)C)n2)cc1
Solvent: O=C(O)C(F)(F)F
Product: CC(C)(C)n1nnc(Cc2ccc(CCC(=O)O)cc2)n1
Temperature: 25 °C
Reaction time: 12 h
Yield: 65.5 %

Procedure:
1,1-dimethylethyl 4-[[2-(1,1-dimethylethyl)-2H-tetrazol-5-yl]methyl]benzenepropanoate (3.0 g, 8.7 mmol) was dissolved in trifluoroacetic acid (33 mL) and stirred at room temperature under argon for 12 hours. The mixture was concentrated and then dissolved in water (50 ml). After adding enough sat. NaHCO3 to raise the pH to 8, the solution was washed with diethyl ether (2×25 mL). The aqueous layer was acidified to pH 3 with 1N HCl and the product collected by suction filtration. Recrystallization from hexanes gave 4-[[2-(1,1-dimethylethyl)-2H-tetrazol-5-yl]methyl]benzene-propanoic acid (1.5 g, 5.7 mmol) in 66% yield, mp. 139°-141° C.