Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1](=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.N1C=CC=C(C=O)C=1.[NH2:17][CH2:18][CH2:19][CH2:20][CH2:21][N:22]1[C:34]2[C:33]3[CH:32]=[CH:31][CH:30]=[CH:29][C:28]=3[N:27]=[C:26]([NH2:35])[C:25]=2[N:24]=[C:23]1[CH2:36][O:37][CH2:38][CH3:39].NCCCCN1C2C3C=CC=CC=3N=C(N)C=2N=C1COC.FC(F)(F)C([O-])=O>>[CH2:1]([NH:17][CH2:18][CH2:19][CH2:20][CH2:21][N:22]1[C:34]2[C:33]3[CH:32]=[CH:31][CH:30]=[CH:29][C:28]=3[N:27]=[C:26]([NH2:35])[C:25]=2[N:24]=[C:23]1[CH2:36][O:37][CH2:38][CH3:39])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=Cc1ccccc1
Reactant: CCOCc1nc2c(N)nc3ccccc3c2n1CCCCN
Agent: COCc1nc2c(N)nc3ccccc3c2n1CCCCN
Agent: O=C([O-])C(F)(F)F
Agent: O=Cc1cccnc1
Product: CCOCc1nc2c(N)nc3ccccc3c2n1CCCCNCc1ccccc1

Procedure:
The compounds in the table below were prepared and purified according to the methods of Parts B and C of Examples 467-478 using 1-(4-benzylaminobutyl)-2-ethoxymethyl-1H-imidazo[4,5-c]quinolin-4-amine in lieu of 2-methoxymethyl-1-{4-[(pyridin-3-ylmethyl)amino]butyl}-1H-imidazo[4,5-c]quinolin-4-amine. 1-(4-Benzylaminobutyl)-2-ethoxymethyl-1H-imidazo[4,5-c]quinolin-4-amine was prepared according to the general method of Part A of Examples 467-478 using benzaldehyde in lieu of pyridine 3-carboxaldehyde and 1-(4-aminobutyl)-2-ethoxymethyl-1H-imidazo[4,5-c]quinolin-4-amine in lieu of 1-(4-aminobutyl)-2-methoxymethyl-1H-imidazo[4,5-c]quinolin-4-amine. The table below shows the reagent used for each example, the structure of the resulting compound, and the observed accurate mass for the isolated trifluoroacetate salt.
Reaction SMILES: [CH2:1]([O:3][C:4]1[CH:9]=[CH:8][C:7]([O:10][CH2:11][CH3:12])=[CH:6][CH:5]=1)[CH3:2].[CH3:13][O:14]C(Cl)Cl.CCOCC>C(Cl)Cl>[CH2:11]([O:10][C:7]1[CH:8]=[CH:9][C:4]([O:3][CH2:1][CH3:2])=[CH:5][C:6]=1[CH:13]=[O:14])[CH3:12]
Reactant: CCOc1ccc(OCC)cc1
Reactant: COC(Cl)Cl
Solvent: ClCCl
Solvent: CCOCC
Product: CCOc1ccc(OCC)c(C=O)c1
Reaction time: 0.08 h
Yield: 92 %

Procedure:
A mixture of 1,4-diethoxybenzene (24.9 g 0.150 mole) and 1,1-dichloromethyl methyl ether (18 g., 0.157 mole) in methylene chloride (80 ml.) was added with stirring during 20 minutes to a solution of stannic chloride (39 g., 0.150 mole) in methylene chloride (150 ml.) at approximately 0° C. The solution was then stirred at this temperature for 5 minutes and quenched by addition of aqueous hydrochloric acid (6 N., 100 ml.) which was added rapidly. The organic phase was separated washed with saturated aqueous sodium bicarbonate, dried over anhydrous magnesium sulfate, filtered, and the solvent removed from the filtrate by evaporation under reduced pressure to yield a crystalline solid (29 g.) m.p. 57°-59° C. Recrystallation (from ether) gave 2,5-Diethoxybenzaldehyde (27.1 g., 0.138 mole, 93%) m.p. 60°-61° I.R.: 1738 cm-1 (aldehyde CO).
Reaction SMILES: [Cl:1][C:2]([Cl:16])([Cl:15])[CH2:3][O:4][C:5](=[O:14])[NH:6][C@H:7]1[C@@H:11]([O:12][NH2:13])[CH2:10][CH:9]=[CH:8]1.[C:17]([O:21][C:22](ON=C(C1C=CC=CC=1)C#N)=[O:23])([CH3:20])([CH3:19])[CH3:18]>O1CCCC1>[Cl:1][C:2]([Cl:15])([Cl:16])[CH2:3][O:4][C:5](=[O:14])[NH:6][C@H:7]1[C@@H:11]([O:12][NH:13][C:22]([O:21][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:23])[CH2:10][CH:9]=[CH:8]1
Reactant: CC(C)(C)OC(=O)ON=C(C#N)c1ccccc1
Reactant: NO[C@H]1CC=C[C@H]1NC(=O)OCC(Cl)(Cl)Cl
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)NO[C@H]1CC=C[C@H]1NC(=O)OCC(Cl)(Cl)Cl

Procedure:
An 7.8 g. quantity of crude (1R,5S)-2,2,2-trichloroethyl-5-(aminooxy)-2-cyclopentene-1-carbamate is dissolved in 25 ml. of tetrahydrofuran and 6.15 g (25 mm) of 2-(tert-butoxycarbonyloxyimino)-2-phenylacetonitrile and the mixture stirred for 22 hours at room temperature, 20 hours at 50° C., 72 hours at room temperature and then evaporated in vacuo. The residue is chromatographed over 900 g. of silica gel eluted with (15-85) ethylacetate-toluene. Three hundred ml. fractions are collected. The product is found in fractions 10-12. Evaporation and recrystallization of the residue from Skellysolve B yields (1R,5S)-2,2,2-trichloroethyl-5-[[[(t-butyloxy)carbonyl]amino]oxy]-2-cyclopentene-1-carbamate m.p. 83°-84° C. as a white solid.
Reaction SMILES: [Cl:1][C:2]1[C:11]([CH:12]=O)=[CH:10][C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[N:3]=1.[CH2:14]([NH2:16])[CH3:15].C(O)(=O)C.C([BH3-])#N.[Na+].C([O-])(O)=O.[Na+]>CO>[Cl:1][C:2]1[C:11]([CH2:12][NH:16][CH2:14][CH3:15])=[CH:10][C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[N:3]=1
Reactant: O=Cc1cc2ccccc2nc1Cl
Reactant: CCN
Agent: O=C([O-])O
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CO
Product: CCNCc1cc2ccccc2nc1Cl
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
2-Chloro-3-quinolinecarboxaldehyde (2.0 g, 10.4 mmol), ethylamine (2M in MeOH, 5.2 mL, 10.4 mmol), and acetic acid (0.65 mL, 11.4 mmol) were combined in MeOH (15 mL) and stirred at room temperature for 30 minutes until all materials were completely dissolved. Sodium cyanoborohydride (1.31 g, 20.9 mmol) was added portionwise over 5 minutes, and the reaction was stirred for 1 hour. The mixture was worked-up with saturated aqueous NaHCO3 and extracted with CH2Cl2, and the residue was purified by silica gel chromatography (0-5% MeOH in CH2Cl2) to give the title compound.
Reaction SMILES: [CH:1]([C:3]1[C:11]2[O:10][C:9]([CH3:13])([CH3:12])[CH2:8][C:7]=2[C:6]([CH3:14])=[C:5]([NH:15][C:16](=[O:22])[CH2:17][C:18]([CH3:21])([CH3:20])[CH3:19])[C:4]=1[CH3:23])=[O:2].[C:24]1([Mg]Br)[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1>>[OH:2][CH:1]([C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1)[C:3]1[C:11]2[O:10][C:9]([CH3:12])([CH3:13])[CH2:8][C:7]=2[C:6]([CH3:14])=[C:5]([NH:15][C:16](=[O:22])[CH2:17][C:18]([CH3:21])([CH3:20])[CH3:19])[C:4]=1[CH3:23]
Reactant: Br[Mg]c1ccccc1
Reactant: Cc1c(C=O)c2c(c(C)c1NC(=O)CC(C)(C)C)CC(C)(C)O2
Product: Cc1c2c(c(C(O)c3ccccc3)c(C)c1NC(=O)CC(C)(C)C)OC(C)(C)C2

Procedure:
Using N-(7-formyl-2,2,4,6-tetramethyl-2,3-dihydro-1-benzofuran-5-yl)-3,3-dimethyl-butanamide obtained in Example 340 and phenylmagnesium bromide, the title compound was synthesized in the same manner as in Example 239. The yield was quantitative. Amorphous substance.
Reaction SMILES: [CH:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][C:2]=1[C:11]1[C:19]2[C:14](=[N:15][CH:16]=[N:17][C:18]=2[NH2:20])[NH:13][N:12]=1.C([O-])([O-])=O.[K+].[K+].Br[CH2:28]/[CH:29]=[CH:30]/[C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1.O>CN(C=O)C>[CH:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][C:2]=1[C:11]1[C:19]2[C:14](=[N:15][CH:16]=[N:17][C:18]=2[NH2:20])[N:13](/[CH:28]=[CH:29]/[CH2:30][C:31]2[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=2)[N:12]=1
Reactant: BrC/C=C/c1ccccc1
Reactant: Nc1ncnc2[nH]nc(-c3ccc4ccccc4c3)c12
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: Nc1ncnc2c1c(-c1ccc3ccccc3c1)nn2/C=C/Cc1ccccc1
Temperature: 60 °C

Procedure:
3-(naphthalen-2-yl)-1H-pyrazolo[3,4-d]pyrimidin-4-amine (50 mg, 0.21 mmol) was dissolved in DMF (1.5 mL) and K2CO3 (110 mg, 0.8 mmol) and 1-((E)-3-bromoprop-1-enyl)benzene were added. The reaction was heated to 60° C. overnight, then cooled to RT and poured into water (30 mL). The precipitate was collected by filtration. ESI-MS (M+H)+ m/z calcd 378.2, found 378.2.
Reaction SMILES: [N+]([NH:4][C:5]([NH2:7])=[O:6])([O-])=O.[F:8][C:9]([F:22])([F:21])[C:10]1[CH:11]=[C:12]([CH:18]=[CH:19][CH:20]=1)[O:13][CH:14]1[CH2:17]N[CH2:15]1.C(Cl)Cl>C(O)C>[F:8][C:9]([F:21])([F:22])[C:10]1[CH:11]=[C:12]([CH:18]=[CH:19][CH:20]=1)[O:13][CH:14]1[CH2:17][N:4]([C:5]([NH2:7])=[O:6])[CH2:15]1
Reactant: FC(F)(F)c1cccc(OC2CNC2)c1
Reactant: NC(=O)N[N+](=O)[O-]
Solvent: ClCCl
Solvent: CCO
Product: NC(=O)N1CC(Oc2cccc(C(F)(F)F)c2)C1
Temperature: 25 °C
Reaction time: 48 h

Procedure:
A solution of 6 fold molar excess nitrourea and 3-[3-(trifluoromethyl)phenoxy]azetidine in a 50-50 vol. % mixture of methylene chloride and absolute ethyl alcohol is stirred at room temperature for 48 hr. The mixture is filtered. The filtrate is evaporated to dryness and the residue is partitioned between equal volumes of methylene chloride and water. The water layer is extracted 3 times with methylene chloride. The methylene chloride extracts are combined and evaporated to dryness. The residue is washed with a mixture of 1 vol. of methylene chloride to 20 volumes of toluene and filtered. The precipitate is recrystallized from ethanol/water to give pale yellow crystals. The crystals are triturated with a mixture of 2 volumes methylene chloride to 20 volumes of toluene for 2 hr. White crystals of title compound are obtained, m.p. 151°-152° C.
Reaction SMILES: [O:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[CH:3]=[C:2]1[C:10]1[C:11]([NH:17]C(=O)OC(C)(C)C)=[N:12][CH:13]=[C:14](Br)[N:15]=1.[CH2:25]([S:27]([N:30]1[CH2:35][CH2:34][NH:33][CH2:32][CH2:31]1)(=[O:29])=[O:28])[CH3:26].Cl.O1CCOCC1>COCCO>[O:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[CH:3]=[C:2]1[C:10]1[C:11]([NH2:17])=[N:12][CH:13]=[C:14]([N:33]2[CH2:32][CH2:31][N:30]([S:27]([CH2:25][CH3:26])(=[O:28])=[O:29])[CH2:35][CH2:34]2)[N:15]=1
Reactant: CCS(=O)(=O)N1CCNCC1
Reactant: CC(C)(C)OC(=O)Nc1ncc(Br)nc1-c1cc2ccccc2o1
Agent: Cl
Solvent: C1COCCO1
Solvent: COCCO
Product: CCS(=O)(=O)N1CCN(c2cnc(N)c(-c3cc4ccccc4o3)n2)CC1
Temperature: 25 °C
Reaction time: 3 h
Yield: 12 %

Procedure:
A solution of tert-butyl N-[3-(benzofuran-2-yl)-5-bromo-pyrazin-2-yl]carbamate, 1-ethylsulfonylpiperazine (164.5 mg, 0.9228 mmol) and 2-methoxyethanol (3 mL) were heated at 100° C. for 3 hours. The reaction mixture was allowed to cool to RT, treated with HCl in dioxane (384.5 μL of 4 M, 1.538 mmol) and allowed to stir at RT for 3 hours. The mixture was concentrated in vacuo and the resultant residue was purified by reverse phase preparative HPLC [Waters Sunfire C18, 10 uM, 100A column, gradient 10%-95% B (solvent A: 0.05% TFA in water, solvent B: CH3CN) over 16 minutes at 25 mL/min]. The fractions were collected and freeze-dried to give the title compound as an orange solid (15.5 mg, 12% Yield). 1H NMR (DMSO) d 1.24 (3H, t), 3.11 (2H, q), 3.45 masked signal, 3.51 (4H, m), 6.12 (2H, br s), 7.30 (1H, m), 7.34 (1H, m), 7.47 (1H, s), 7.71 (2H, m), 7.98 (1H, s) ppm; MS (ES+) 388.01
Reaction SMILES: O[C:2]1([CH2:16][CH2:17][NH:18][C:19](=[O:23])[O:20][CH2:21][CH3:22])[CH2:11][CH2:10][C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3]21C[CH2:14][CH2:13][CH2:12]2.S(=O)(=O)(O)O.O.[C:30](O)(=O)C>>[N:18]1([C:19]([O:20][CH2:21][CH3:22])=[O:23])[C:17]23[CH2:30][CH2:6][CH2:7][CH2:8][C:9]2([CH2:10][CH2:11][C:2]2[CH:3]=[CH:12][CH:13]=[CH:14][C:16]=23)[CH2:4][CH2:5]1
Reactant: CCOC(=O)NCCC1(O)CCc2ccccc2C12CCCC2
Reactant: CC(=O)O
Agent: O=S(=O)(O)O
Solvent: O
Product: CCOC(=O)N1CCC23CCCCC12c1ccccc1CC3
Yield: 59 %

Procedure:
A solution of the product from Example 13 (1.68 g, 5.29 mmol) in 15 mL of 3:1 acetic acid/concentrated sulfuric acid (v/v) was stirred at room temperature for 18 hours. The reaction mixture was poured into water (50 mL) and the resulting mixture was extracted with CH2Cl2 (4×30 mL). The combined organic extracts were dried (MgSO4), filtered and concentrated. The residue was dissolved in CH2Cl2 (100 mL and washed with saturated aq. bicarbonate solution (30 mL). The organic phase was dried (MgSO4), filtered and concentrated. The residue was purified by chromatography (silica gel, 9:1 heptane/ethyl acetate) to give the title compound (0.94 g, 59%) as a white solid mp 67°-69° C.
Reaction SMILES: [CH3:1][C:2]([CH3:9])=[CH:3][C:4]([O:6][CH2:7][CH3:8])=[O:5].[Br:10]N1C(=O)CCC1=O>C(Cl)(Cl)(Cl)Cl.N(C(C)(C)C#N)=NC(C)(C)C#N>[Br:10][CH2:1][C:2]([CH3:9])=[CH:3][C:4]([O:6][CH2:7][CH3:8])=[O:5]
Reactant: O=C1CCC(=O)N1Br
Reactant: CCOC(=O)C=C(C)C
Agent: CC(C)(C#N)N=NC(C)(C)C#N
Solvent: ClC(Cl)(Cl)Cl
Product: CCOC(=O)C=C(C)CBr
Yield: 106.5 %

Procedure:
The olefins 66 can also be prepared by reacting the corresponding substitued phenols with ethyl 4-bromo-3-methyl-2-butenate in the presence of potassium carbonate and small amount of 18-crown-ether in methylene chloride. The starting material ethyl 4-bromo-3-methylbutenate has been obtained from the reaction of ethyl 3,3-dimethylacrylate with N-bromosuccinimide (NBS) as follows: to 20 g of ethyl 3,3-dimethylacrylate in 250 ml of carbon tetrachloride, 30 g of N-bromosuccinimide (NBS) and 0.01 g of azobisisobutyronitrile were added. The mixture was refluxed for 3 hours. Succinimide was removed by filtration and the filtrate was washed with chloroform. The combined organic layers were washed sequentially with saturated sodium sulfite, saturated sodium chloride and then dried over anhydrous magnesium sulfate. Evaporation of the solvent afforded 34.4 g ethyl 4-bromo-3-methyl-2-butenate (Safaryn, J. E.; Chiarello, J.; Chen, K. M.; Joullie, M. M.; Tetrahedron, 1986, 42, 2635). The product can be further purified by silica gel flash column chromatography using ether/hexane (e.g. 1:50) as eluent, and hydrolyzed to the corresponding carboxylic acid with aqueous methanolic NaOH.
Reaction SMILES: C([Li])CCC.[CH3:6][P:7](=[O:12])([O:10][CH3:11])[O:8][CH3:9].[N:13]1[CH:18]=[CH:17][CH:16]=[C:15]([O:19][CH2:20][C:21](OCC)=[O:22])[CH:14]=1.Cl>CCCCCC.O1CCCC1>[O:22]=[C:21]([CH2:20][O:19][C:15]1[CH:14]=[N:13][CH:18]=[CH:17][CH:16]=1)[CH2:6][P:7](=[O:12])([O:10][CH3:11])[O:8][CH3:9]
Reactant: COP(C)(=O)OC
Reactant: CCOC(=O)COc1cccnc1
Agent: Cl
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CCCCCC
Product: COP(=O)(CC(=O)COc1cccnc1)OC
Temperature: -78 °C
Reaction time: 0.17 h

Procedure:
n-Butyl-lithium (4.76ml. of a 2.1M solution in hexane) was added to a solution of dimethyl methylphosphonate (1.24g.) in dry tetrahydrofuran at -78°C. in an atmosphere of nitrogen. After 10 minutes, a solution of ethyl 3-pyridyloxyacetate (0.90g.) in dry tetrahydrofuran (5ml.) was added dropwise, and the mixture was stirred for 1 hour at -78°C. The reaction mixture was taken to pH 1-2 with 2N hydrochloric acid and the solvents were removed under reduced pressure. The residue was shaken with water (10ml.) and extracted with ether (3 × 10ml.). The extracts were discarded, and the aqueous solution was adjusted to pH 7-8 with sodium bicarbonate solution and extracted with chloroform (6 × 10ml.). The combined extracts were evaporated, to give dimethyl [2-oxo-3-(pyrid-3-yloxy)propyl]phosphonate as an oil, RF = 0.2 (10% methanol in ethyl acetate).
Reaction SMILES: [C:1]([C:4]1[CH:5]=[C:6]2[C:11](=[CH:12][CH:13]=1)[NH:10][CH:9]([C:14]1[CH:19]=[C:18]([O:20][CH3:21])[C:17]([OH:22])=[CH:16][C:15]=1[C:23]1[CH:28]=[CH:27][C:26]([C:29]([OH:31])=O)=[CH:25][C:24]=1[O:32][CH3:33])[CH:8]1[CH2:34][C:35]3[C:40]([CH:7]21)=[CH:39][CH:38]=[CH:37][CH:36]=3)(=[NH:3])[NH2:2].F[P-](F)(F)(F)(F)F.N1(O[P+](N(C)C)(N(C)C)N(C)C)C2C=CC=CC=2N=N1.[CH2:68]([NH2:72])[CH:69]([CH3:71])[CH3:70]>CN(C=O)C>[CH2:68]([NH:72][C:29]([C:26]1[CH:27]=[CH:28][C:23]([C:15]2[CH:16]=[C:17]([OH:22])[C:18]([O:20][CH3:21])=[CH:19][C:14]=2[CH:9]2[CH:8]3[CH2:34][C:35]4[C:40]([CH:7]3[C:6]3[C:11](=[CH:12][CH:13]=[C:4]([C:1](=[NH:3])[NH2:2])[CH:5]=3)[NH:10]2)=[CH:39][CH:38]=[CH:37][CH:36]=4)=[C:24]([O:32][CH3:33])[CH:25]=1)=[O:31])[CH:69]([CH3:71])[CH3:70]
Reactant: COc1cc(C2Nc3ccc(C(=N)N)cc3C3c4ccccc4CC23)c(-c2ccc(C(=O)O)cc2OC)cc1O
Reactant: CC(C)CN
Agent: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Product: COc1cc(C2Nc3ccc(C(=N)N)cc3C3c4ccccc4CC23)c(-c2ccc(C(=O)NCC(C)C)cc2OC)cc1O

Procedure:
A mixture of 2′-(2-Carbamimidoyl-5,6a,7,11b-tetrahydro-6H-indeno[2,1-c]quinolin-6-yl)-5′-hydroxy-2,4′-dimethoxy-biphenyl-4-carboxylic acid (10.7 mg, 0.02 mmol), BOP, (0.04 mmol), diidopropylethylamine (10.3 mg, 0.08 mmol) and isobutylamine (4.4 mg, 0.06 mmol) in DMF was allowed to react at room temperature. Example 235 was purified by HPLC. Mass Spectrum: 591 (M+1).
Reaction SMILES: [CH:1]1([C:4]2[C:5]([N:24]([CH2:29][CH2:30][CH:31]([CH3:33])[CH3:32])[S:25]([CH3:28])(=[O:27])=[O:26])=[CH:6][C:7]3[O:11][C:10]([C:12]4[CH:17]=[CH:16][C:15]([F:18])=[CH:14][CH:13]=4)=[C:9]([C:19](=[NH:22])[NH:20][OH:21])[C:8]=3[CH:23]=2)[CH2:3][CH2:2]1.[C:34](N1C=CN=C1)(N1C=CN=C1)=[O:35].N12CCCN=C1CCCCC2>O1CCOCC1>[CH:1]1([C:4]2[C:5]([N:24]([CH2:29][CH2:30][CH:31]([CH3:33])[CH3:32])[S:25]([CH3:28])(=[O:27])=[O:26])=[CH:6][C:7]3[O:11][C:10]([C:12]4[CH:13]=[CH:14][C:15]([F:18])=[CH:16][CH:17]=4)=[C:9]([C:19]4[NH:22][C:34](=[O:35])[O:21][N:20]=4)[C:8]=3[CH:23]=2)[CH2:2][CH2:3]1
Reactant: CC(C)CCN(c1cc2oc(-c3ccc(F)cc3)c(C(=N)NO)c2cc1C1CC1)S(C)(=O)=O
Reactant: O=C(n1ccnc1)n1ccnc1
Solvent: C1CCC2=NCCCN2CC1
Solvent: C1COCCO1
Product: CC(C)CCN(c1cc2oc(-c3ccc(F)cc3)c(-c3noc(=O)[nH]3)c2cc1C1CC1)S(C)(=O)=O
Yield: 60.1 %

Procedure:
A mixture of Example 10F (355 mg, 0.75 mmol), carbonyldiimidazole (146 mg, 0.900 mmol), and 1,8-diazabicyclo[5.4.0]undec-7-ene (0.124 mL, 0.825 mmol) in dioxane (6 mL) was refluxed for 1 hour, cooled and partitioned between ethyl acetate and 1 M aqueous HCl. The organic layer was washed with brine, dried with sodium sulfate, filtered and concentrated. The residue was chromatographed on silica gel eluting with 10-40% ethyl acetate in hexane to give the title compound as a solid (225 mg, 60%). MS (ESI−) m/z 498 (M−H)−.
Reaction SMILES: [OH:1][CH2:2][C:3]([CH2:14][OH:15])([C:9]([O:11][CH2:12][CH3:13])=[O:10])[C:4]([O:6][CH2:7][CH3:8])=[O:5].C(N(CC)CC)C.[CH3:23][S:24](Cl)(=[O:26])=[O:25]>C(Cl)Cl>[CH2:12]([O:11][C:9](=[O:10])[C:3]([CH2:2][O:1][S:24]([CH3:23])(=[O:26])=[O:25])([CH2:14][O:15][S:24]([CH3:23])(=[O:26])=[O:25])[C:4]([O:6][CH2:7][CH3:8])=[O:5])[CH3:13]
Reactant: CCOC(=O)C(CO)(CO)C(=O)OCC
Reactant: CS(=O)(=O)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCOC(=O)C(COS(C)(=O)=O)(COS(C)(=O)=O)C(=O)OCC
Temperature: -30 °C
Reaction time: 18 h

Procedure:
A solution of diethyl bis(hydroxymethyl)malonate (46.95 g, 0.21 moles) (prepared by the method of P. Block, Jr., Organic Synthesis, Collective Volume V, 381 (1973)) in methylene chloride (500 mL) was treated with triethyl amine (63 mL) and cooled to −30° C. A mixture of methylsulfonyl chloride (35 mL) in methylene chloride (40 mL) was added to the reaction mixture dropwise over 20 minutes and the reaction mixture was allowed to stir at room temperature for 18 hours. The reaction mixture was then poured into ice water and the product was extracted with methylene chloride. The organic extracts were washed with saturated aqueous sodium chloride and then dried over magnesium sulfate. The solvent was removed by rotary evaporation at reduced pressure and the residue was recrystallized from t-butylmethyl ether and hexane to give 2,2-bis-methylsulfonyloxymethyl-malonic acid diethyl ester (55.04 g).
Reaction SMILES: O1CCCC1.[CH3:6][C:7]1[CH:15]=[CH:14][CH:13]=[CH:12][C:8]=1[C:9](Cl)=[O:10].[F:16][C:17]([F:30])([F:29])[O:18][C:19]1[CH:28]=[CH:27][C:22]([O:23][CH2:24][CH2:25][NH2:26])=[CH:21][CH:20]=1>C(N(CC)CC)C>[F:16][C:17]([F:29])([F:30])[O:18][C:19]1[CH:28]=[CH:27][C:22]([O:23][CH2:24][CH2:25][NH:26][C:9](=[O:10])[C:8]2[CH:12]=[CH:13][CH:14]=[CH:15][C:7]=2[CH3:6])=[CH:21][CH:20]=1
Reactant: Cc1ccccc1C(=O)Cl
Reactant: NCCOc1ccc(OC(F)(F)F)cc1
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: Cc1ccccc1C(=O)NCCOc1ccc(OC(F)(F)F)cc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
A tetrahydrofuran (5 ml) solution of 2-methylbenzoyl chloride (0.77 g) was added dropwise under ice-cooling and stirring to a tetrahydrofuran (20 ml) solution of 2-(4-trifluoromethoxyphenoxy)ethylamine (1.10 g) and triethylamine (0.51 g) and the mixture was further stirred at room temperature for one hour.
Reaction SMILES: [CH:1]1([C:4]2([F:25])[CH2:7][N:6]([C:8]3[N:13]=[C:12]([S:14]([CH3:17])(=O)=O)[N:11]=[C:10]([NH:18][C:19]4[NH:23][N:22]=[C:21]([CH3:24])[CH:20]=4)[CH:9]=3)[CH2:5]2)[CH2:3][CH2:2]1.[F:26][C:27]([F:40])([F:39])[CH2:28][C:29]([NH:31][C:32]1[CH:37]=[CH:36]C(S)=[CH:34][CH:33]=1)=[O:30]>CC#N>[CH3:24][C:21]1[CH:20]=[C:19]([NH:18][C:10]2[CH:9]=[C:8]([N:6]3[CH2:7][C:4]([CH:1]4[CH2:3][CH2:2]4)([F:25])[CH2:5]3)[N:13]=[C:12]([S:14][C:17]3[CH:34]=[CH:33][C:32]([NH:31][C:29](=[O:30])[CH2:28][C:27]([F:40])([F:26])[F:39])=[CH:37][CH:36]=3)[N:11]=2)[NH:23][N:22]=1
Reactant: O=C(CC(F)(F)F)Nc1ccc(S)cc1
Reactant: Cc1cc(Nc2cc(N3CC(F)(C4CC4)C3)nc(S(C)(=O)=O)n2)[nH]n1
Solvent: CC#N
Product: Cc1cc(Nc2cc(N3CC(F)(C4CC4)C3)nc(Sc3ccc(NC(=O)CC(F)(F)F)cc3)n2)[nH]n1
Temperature: 0 °C
Reaction time: 0.25 h
Yield: 63.4 %

Procedure:
An slurry of 6-(3-cyclopropyl-3-fluoroazetidin-1-yl)-N-(3-methyl-1H-pyrazol-5-yl)-2-(methylsulfonyl)pyrimidin-4-amine (61 g, 170 mmol) and 3,3,3-trifluoro-N-(4-mercaptophenyl)propanamide (41 g, 175 mmol) in CH3CN (1300 mL) was heated to reflux for 1.5 hours. During this time, the slurry transforms from thin and yellowish to thick and brilliant white. The mixture was then cooled to 0° C. and stirred at this temperature for 15 min. Filtered and washed with cold CH3CN (650 mL). The resulting solid was dried for 20 hours at 38° C. under house vacuum. The white solid was charged to a suitable reactor with EtOAc (1300 mL) and NaHCO3 (sat) (1300 mL). The mixture was stirred until no more solid remained. Then, the layers were separated and washed the aqueous with EtOAc (390 mL). The combined organic layers were dried over MgSO4, filtered, washed with EtOAc (130 mL) and concentrated to minimal volume on rotavap. The resulting mixture was re-crystallized out of EtOAc and hexane to give the desired product as a white solid (56.2 g, 72%) 1H NMR (MeOD, 400 MHz): 0.40-0.45 (2H, m), 0.60-0.65 (2H, m), 1.3-1.4 (1H, m), 2.05 (2H, s), 3.25-3.40 (2H, m), 3.85-3.40 (4H, m), 5.40-5.50 (2H, m), 7.50-7.55 (2H, d), 7.65-7.70 (2H, d). ES+ 522.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[CH:11]=[CH:10][C:9]([O:12][CH2:13][C:14]2[C:15]([C:27]3[CH:32]=[CH:31][C:30]([F:33])=[CH:29][CH:28]=3)=[N:16][O:17][C:18]=2/[CH:19]=C/C2C=CC=CC=2)=[CH:8][N:7]=1)=[O:5])[CH3:2].[BH4-].[Na+].C[OH:37]>>[CH2:1]([O:3][C:4]([C:6]1[CH:11]=[CH:10][C:9]([O:12][CH2:13][C:14]2[C:15]([C:27]3[CH:28]=[CH:29][C:30]([F:33])=[CH:31][CH:32]=3)=[N:16][O:17][C:18]=2[CH2:19][OH:37])=[CH:8][N:7]=1)=[O:5])[CH3:2]
Reactant: CO
Reactant: CCOC(=O)c1ccc(OCc2c(-c3ccc(F)cc3)noc2/C=C/c2ccccc2)cn1
Agent: [BH4-]
Agent: [Na+]
Product: CCOC(=O)c1ccc(OCc2c(-c3ccc(F)cc3)noc2CO)cn1
Reaction time: 1 h
Yield: 59 %

Procedure:
A solution of 5-[3-(4-fluoro-phenyl)-5-((E)-styryl)-isoxazol-4-ylmethoxy]-pyridine-2-carboxylic acid ethyl ester (1.2 g, 3.24 mmol) in methanol (60 mL) was treated at room temperature with sodium borohydride (255.4 mg, 6.48 mmol) and stirred for 1 h. After quenching with aqueous citric acid (100 mL of a 10% solution) and extraction with ethyl acetate the organic phase was dried over sodium sulfate, filtered and concentrated. Purification by chromatography (silica, heptane:ethyl acetete=1:1 to 0:1) afforded the title compound as a white solid (710 mg, 59%). MS: m/e=373.2 [M+H]+.
Reaction SMILES: Cl.[NH2:2][OH:3].C([O-])(=O)C.[Na+].O.[Cl:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=1[N:17]1[C:25]2[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=2)[C:19]([CH2:26][C:27](=O)[CH3:28])=[CH:18]1>C(O)C>[Cl:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=1[N:17]1[C:25]2[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=2)[C:19]([CH2:26][C:27](=[N:2][OH:3])[CH3:28])=[CH:18]1
Reactant: CC(=O)Cc1cn(-c2ccccc2Cl)c2ccccc12
Reactant: NO
Agent: CC(=O)[O-]
Agent: Cl
Agent: [Na+]
Solvent: O
Solvent: CCO
Product: CC(Cc1cn(-c2ccccc2Cl)c2ccccc12)=NO
Reaction time: 8 h

Procedure:
2.1g (0.03 mole) of hydroxylamine hydrochloride and 2.1g of sodium acetate dissolved in 10 ml. of water are added to 5.8g (0.02 mole) of 1-(2-chlorophenyl)-3-(2-oxopropyl)indole dissolved in 50 ml of ethyl alcohol. Stirring is carried out overnight at room temperature, the oxime which has precipitated is filtered (without heat), washed with water and dried. It is recrystallised from 30 ml of di-isopropyl ether.