Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([O:9][CH2:10][C:11]2[C:23]([F:24])=[CH:22][C:14]([C:15]([NH:17][S:18]([CH3:21])(=[O:20])=[O:19])=[O:16])=[C:13]([F:25])[CH:12]=2)[CH:5]=[N:6][C:7]=1F.[F:26][C:27]([F:33])([F:32])[C:28]([CH3:31])([OH:30])[CH3:29].C(=O)([O-])[O-].[Cs+].[Cs+]>CS(C)=O.CCOC(C)=O>[Cl:1][C:2]1[CH:3]=[C:4]([O:9][CH2:10][C:11]2[C:23]([F:24])=[CH:22][C:14]([C:15]([NH:17][S:18]([CH3:21])(=[O:20])=[O:19])=[O:16])=[C:13]([F:25])[CH:12]=2)[CH:5]=[N:6][C:7]=1[O:30][C:28]([CH3:31])([CH3:29])[C:27]([F:33])([F:32])[F:26]
Reactant: CS(=O)(=O)NC(=O)c1cc(F)c(COc2cnc(F)c(Cl)c2)cc1F
Reactant: CC(C)(O)C(F)(F)F
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CS(C)=O
Solvent: CCOC(C)=O
Product: CC(C)(Oc1ncc(OCc2cc(F)c(C(=O)NS(C)(=O)=O)cc2F)cc1Cl)C(F)(F)F
Temperature: 100 °C
Reaction time: 16 h
Yield: 19.6 %

Procedure:
To a solution of 4-{[(5-chloro-6-fluoropyridin-3-yl)oxy]methyl}-2,5-difluoro-N-(methylsulfonyl)benzamide (Example 23, 0.092 g, 0.233 mmol) in DMSO (1.0 mL) were added 1,1,1-trifluoro-2-methylpropan-2-ol (0.120 g, 0.937 mmol) and caesium carbonate (0.305 g, 0.936 mmol). The mixture was stirred at 100° C. in a pressure vial for 16 hours. Then 1,1,1-trifluoro-2-methylpropan-2-ol (0.120 g, 0.937 mmol) was added to the mixture and heated at 125° C. for another 24 hours. The reaction mixture was diluted with EtOAc (15.0 mL), washed with water (10.0 mL), aqueous citric solution (10%, 10.0 mL) and water (2×10.0 mL). The organic layer was dried over sodium sulfate, filtered and concentrated in vacuo. The resulting residue was suspended in a mixture of heptane and acetone (8:2, 5.0 mL) and sonicated for 2 minutes. The mixture was filtered to yield the title compound as an off-white solid (0.023 g, 20%).
Reaction SMILES: [CH2:1]([NH:6][C:7]1[CH:16]=[CH:15][C:14]2[C:13]([CH3:18])([CH3:17])[CH2:12][CH2:11][C:10]([CH3:20])([CH3:19])[C:9]=2[CH:8]=1)[CH2:2][CH2:3][CH2:4][CH3:5].[Cl:21][C:22](Cl)([O:24]C(=O)OC(Cl)(Cl)Cl)Cl>O1CCCC1>[CH2:1]([N:6]([C:7]1[CH:16]=[CH:15][C:14]2[C:13]([CH3:18])([CH3:17])[CH2:12][CH2:11][C:10]([CH3:19])([CH3:20])[C:9]=2[CH:8]=1)[C:22]([Cl:21])=[O:24])[CH2:2][CH2:3][CH2:4][CH3:5]
Reactant: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Reactant: CCCCCNc1ccc2c(c1)C(C)(C)CCC2(C)C
Solvent: C1CCOC1
Product: CCCCCN(C(=O)Cl)c1ccc2c(c1)C(C)(C)CCC2(C)C
Yield: 279 %

Procedure:
The crude oil was dissolved in 140 ml of ethanol, treated with a solution of 10 g of potassium hydroxide in 20 ml of water and stirred at room temperature for 2 hours. The reaction mixture was poured on ice water, extracted with ether, dried (Na2SO4) and the solvent evaporated. The oily residue was filtered through silica gel (eluent hexane/10% ethyl acetate) to give 9.8 g of pentyl-(5,5,8,8-tetramethyl-5,6,7,8-tetrahydro-naphthalen-2-yl)-amine as a slightly yellow oil. A solution of 1 g of this amine in 20 ml of tetrahydrofuran was treated with 380 mg of triphosgene, heated to reflux for 3 hours, then poured on ice water and extracted with ethyl acetate. The organic phase was washed with water, dried (MgSO4) and the solvent evaporated. The oily residue was crystallized in pentane to give 1.2 g of pentyl-(5,5,8,8-tetramethyl-5,6,7,8-tetrahydro-naphthalen-2-yl)-carbamoyl chloride in white crystals, m.p. 79-81° C.
Reaction SMILES: [Br:1]N1C(=O)CCC1=O.[CH3:9][N:10]1[CH:14]=[CH:13][CH:12]=[C:11]1[C:15]#[N:16]>CN(C)C=O>[Br:1][C:13]1[CH:12]=[C:11]([C:15]#[N:16])[N:10]([CH3:9])[CH:14]=1
Reactant: O=C1CCC(=O)N1Br
Reactant: Cn1cccc1C#N
Solvent: CN(C)C=O
Product: Cn1cc(Br)cc1C#N
Temperature: 25 °C
Reaction time: 15 h

Procedure:
N-Bromosuccinimide (6.2 g, 34.9 mmol) is added to a solution of 1-methyl-1H-pyrrole-2-carbonitrile (3.7 g, 34.9 mmol) in N,N-dimethylformamide (150 mL). The solution is stirred for 15 hours at ambient temperature. Another amount of N-bromosuccinimide (2.0 g, 11 mmol) is added and the mixture is stirred for 3 hours. The product is purified by chromatography over silica gel (ethyl acetate/heptane gradient) to obtain the expected product in the form of a solid.
Reaction SMILES: [OH:1][N:2]1[C:6](=[O:7])[C:5]2=[CH:8][CH:9]=[CH:10][CH:11]=[C:4]2[C:3]1=[O:12].C(N(CC)CC)C.[Br:20][C:21]1[CH:22]=[CH:23][C:24]2[N:30]3[C:31]([CH2:34]Cl)=[N:32][N:33]=[C:29]3[CH2:28][N:27]=[C:26]([C:36]3[CH:41]=[CH:40][CH:39]=[CH:38][N:37]=3)[C:25]=2[CH:42]=1>CC(N(C)C)=O>[Br:20][C:21]1[CH:22]=[CH:23][C:24]2[N:30]3[C:31]([CH2:34][O:1][N:2]4[C:3](=[O:12])[C:4]5=[CH:11][CH:10]=[CH:9][CH:8]=[C:5]5[C:6]4=[O:7])=[N:32][N:33]=[C:29]3[CH2:28][N:27]=[C:26]([C:36]3[CH:41]=[CH:40][CH:39]=[CH:38][N:37]=3)[C:25]=2[CH:42]=1
Reactant: O=C1c2ccccc2C(=O)N1O
Reactant: ClCc1nnc2n1-c1ccc(Br)cc1C(c1ccccn1)=NC2
Solvent: CC(=O)N(C)C
Solvent: CCN(CC)CC
Product: O=C1c2ccccc2C(=O)N1OCc1nnc2n1-c1ccc(Br)cc1C(c1ccccn1)=NC2

Procedure:
In the manner given in Example 1, N-hydroxyphthalimide and triethylamine in dimethylacetamide is treated with 8-bromo-6-(2-pyridyl)-1-(chloromethyl)-4H-s-triazolo[4,3-a][1,4]benzodiazepine to give 8-bromo-6-(2-pyridyl)-1-[(phthalimidooxy)methyl]-4H-s-triazolo[4,3-a][1,4]benzodiazepine.
Reaction SMILES: Br[C:2]1[S:6][CH:5]=[N:4][C:3]=1[NH:7][C:8](=[O:10])[CH3:9].C(=O)([O-])[O-].[K+].[K+].[CH3:17][C:18]1[N:19]=[C:20]([CH2:23][CH2:24][CH3:25])[NH:21][CH:22]=1>O1CCOCC1>[CH3:17][C:18]1[N:19]=[C:20]([CH2:23][CH2:24][CH3:25])[N:21]([C:2]2[S:6][CH:5]=[N:4][C:3]=2[NH:7][C:8](=[O:10])[CH3:9])[CH:22]=1
Reactant: CCCc1nc(C)c[nH]1
Reactant: CC(=O)Nc1ncsc1Br
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1COCCO1
Product: CCCc1nc(C)cn1-c1scnc1NC(C)=O
Temperature: 100 °C
Yield: 0.8 %

Procedure:
N-(5-bromothiazol-4-yl)acetamide from example 2.4 (0.27 g, 1.22 mmol), potassium carbonate (0.17 g, 1.221 mmol) and 4-methyl-2-propyl-1H-imidazole from example 1.6 (0.15 g, 1.22 mmol) were added sequentially to dioxane (30 mL). The mixture was heated to 100° C. for 18 h. It was purified by pre-HPLC to give the title compound (3 mg, 0.01 mmol, 10%) as a white solid.
Reaction SMILES: [H-].[Na+].[C:3](OC)(=[O:5])[CH3:4].[CH3:8][C:9]1([CH3:16])[C@@H:14]2[C@H:10]1[CH2:11][C:12](=[O:15])[CH2:13]2.C(O)(=O)CC(CC(O)=O)(C(O)=O)O>O1CCOCC1>[C:3]([CH:13]1[C:12](=[O:15])[CH2:11][CH:10]2[CH:14]1[C:9]2([CH3:16])[CH3:8])(=[O:5])[CH3:4]
Reactant: CC1(C)[C@@H]2CC(=O)C[C@@H]21
Reactant: COC(C)=O
Agent: O=C(O)CC(O)(CC(=O)O)C(=O)O
Agent: [H-]
Agent: [Na+]
Solvent: C1COCCO1
Product: CC(=O)C1C(=O)CC2C1C2(C)C
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 147.4 %

Procedure:
To a suspension of NaH (873 mg 55% dispersion in mineral oil, 20 mmol, washed with dioxane prior to use) in dioxane (15 mL) is added methyl acetate (2.22 g, 30 mmol). The suspension is stirred for 5 min at rt and a solution of (1S,5R)-6,6-dimethyl-bicyclo[3.1.0]hexan-3-one (1.24 g, 10 mmol) in dioxane (5 mL) is added. The reaction mixture is stirred at 65° C. overnight. The mixture is poured onto cold 10% aq. citric acid solution (75 mL) and extracted with DCM (3×75 mL). The organic extracts are washed with water, dried over MgSO4 and evaporated to give crude racemic (1R, 2R, 5R)-2-acetyl-6,6-dimethyl-bicyclo[3.1.0]hexan-3-one (2.45 g, contains dioxane) as a dark yellow liquid. 1H NMR (CDCl3): δ 2.61 (dd, J=7.3, 19.6 Hz, 1H), 2.34-2.20 (m, 1H), 2.01 (s, 3H), 1.72 (d, J=8.2 HZ, 1H), 1.40-1.20 (m, 2H), 1.09 (s, 3H), 0.81 (s, 3H).
Reaction SMILES: Br[CH2:2][C@@H:3]1[C@H:7]([F:8])[CH2:6][N:5]([C:9]([O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:10])[CH2:4]1.[CH:16]1([NH2:19])[CH2:18][CH2:17]1>>[C:12]([O:11][C:9]([N:5]1[CH2:6][C@@H:7]([F:8])[C@@H:3]([CH2:2][NH:19][CH:16]2[CH2:18][CH2:17]2)[CH2:4]1)=[O:10])([CH3:15])([CH3:14])[CH3:13]
Reactant: NC1CC1
Reactant: CC(C)(C)OC(=O)N1C[C@H](CBr)[C@H](F)C1
Product: CC(C)(C)OC(=O)N1C[C@H](CNC2CC2)[C@H](F)C1
Temperature: 80 °C
Reaction time: 23 h

Procedure:
(3S,4S)-3-Bromomethyl-1-tert-butoxycarbonyl-4-fluoropyrrolidine (1.91 g) was mixed with cyclopropylamine (23.6 mL). The mixture was stirred at 80° C. for 23 hours and was concentrated under reduced pressure. The residue was dissolved in ethyl acetate (100 mL), washed with saturated brine (2×20 mL), dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (eluant: hexane:ethyl acetate=2:1) to give (3S,4S)-1-tert-butoxycarbonyl-3-cyclopropylaminomethyl-4-fluoropyrrolidine as a pale brown oil (1.67 g).
Reaction SMILES: [CH:1]1([NH:4][C:5]2[N:6]=[N:7][C:8]([C:11]#[CH:12])=[CH:9][CH:10]=2)[CH2:3][CH2:2]1.[Cl:13][C:14]1[CH:40]=[CH:39][C:17]([C:18]([NH:20][C:21]2[CH:26]=[CH:25][C:24]([CH2:27][N:28]3[CH2:33][CH2:32][N:31]([CH3:34])[CH2:30][CH2:29]3)=[C:23]([C:35]([F:38])([F:37])[F:36])[CH:22]=2)=[O:19])=[CH:16][C:15]=1I>>[Cl:13][C:14]1[CH:15]=[CH:16][C:17]([C:18]([NH:20][C:21]2[CH:26]=[CH:25][C:24]([CH2:27][N:28]3[CH2:33][CH2:32][N:31]([CH3:34])[CH2:30][CH2:29]3)=[C:23]([C:35]([F:37])([F:36])[F:38])[CH:22]=2)=[O:19])=[CH:39][C:40]=1[C:12]#[C:11][C:8]1[N:7]=[N:6][C:5]([NH:4][CH:1]2[CH2:3][CH2:2]2)=[CH:10][CH:9]=1
Reactant: C#Cc1ccc(NC2CC2)nn1
Reactant: CN1CCN(Cc2ccc(NC(=O)c3ccc(Cl)c(I)c3)cc2C(F)(F)F)CC1
Product: CN1CCN(Cc2ccc(NC(=O)c3ccc(Cl)c(C#Cc4ccc(NC5CC5)nn4)c3)cc2C(F)(F)F)CC1

Procedure:
The title compound was synthesized from N-cyclopropyl-6-ethynylpyridazin-3-amine and 4-chloro-3-iodo-N-(4-((4-methylpiperazin-1-yl)methyl)-3-(trifluoromethyl)phenyl)benzamide in a manner similar to that described for in Example 1. The intermediate compound 4-chloro-3-iodo-N-(4-((4-methylpiperazin-1-yl)methyl)-3-(trifluoromethyl)phenyl)benzamide was made as for Example 12 (Step 1 to 4) with the spectra below: 1H NMR (300 MHz, DMSO-d6) δ: 10.66 (1H, s), 8.53 (1H, s), 8.19 (1H, s), 8.02-8.05 (1H, d, J=6.0 Hz), 7.98-8.01 (1H, d, J=6.0 Hz), 7.77 (1H, s), 7.70-7.73 (1H, d, J=6.0 Hz), 3.62 (2H, s), 3.33 (2H, m), 2.82 (2H, m), 2.54 (4H, m), 2.50 (3H, s).
Reaction SMILES: [CH:1]1([C:6]2[CH:15]=[C:14]3[C:9]([C@@H:10]([OH:18])[CH2:11][C:12]([CH3:17])([CH3:16])[O:13]3)=[C:8]([C:19]3[CH:24]=[CH:23][C:22]([F:25])=[CH:21][CH:20]=3)[C:7]=2[C:26]([C:28]2[CH:33]=[CH:32][C:31]([C:34]([F:37])([F:36])[F:35])=[CH:30][CH:29]=2)=[O:27])[CH2:5][CH2:4][CH2:3][CH2:2]1.CC1C=CC=C(C)N=1.FC(F)(F)S(O[Si:52]([C:55]([CH3:58])([CH3:57])[CH3:56])([CH3:54])[CH3:53])(=O)=O.Cl>C1(C)C=CC=CC=1>[Si:52]([O:18][C@@H:10]1[C:9]2[C:14](=[CH:15][C:6]([CH:1]3[CH2:2][CH2:3][CH2:4][CH2:5]3)=[C:7]([C:26]([C:28]3[CH:33]=[CH:32][C:31]([C:34]([F:36])([F:37])[F:35])=[CH:30][CH:29]=3)=[O:27])[C:8]=2[C:19]2[CH:24]=[CH:23][C:22]([F:25])=[CH:21][CH:20]=2)[O:13][C:12]([CH3:16])([CH3:17])[CH2:11]1)([C:55]([CH3:58])([CH3:57])[CH3:56])([CH3:54])[CH3:53]
Reactant: CC(C)(C)[Si](C)(C)OS(=O)(=O)C(F)(F)F
Reactant: CC1(C)C[C@H](O)c2c(cc(C3CCCC3)c(C(=O)c3ccc(C(F)(F)F)cc3)c2-c2ccc(F)cc2)O1
Agent: Cl
Solvent: Cc1cccc(C)n1
Solvent: Cc1ccccc1
Product: CC1(C)C[C@H](O[Si](C)(C)C(C)(C)C)c2c(cc(C3CCCC3)c(C(=O)c3ccc(C(F)(F)F)cc3)c2-c2ccc(F)cc2)O1
Temperature: -20 °C
Reaction time: 0.25 h

Procedure:
Under argon, 200 mg (0.39 mmol) of [(4S)-7-cyclopentyl-5-(4-fluorophenyl)-4-hydroxy-2,2-dimethyl-3,4-dihydro-2H-chromen-6-yl][4-(trifluoromethyl)phenyl]methanone (Example 12A) and 180 μl (1.56 mmol) of 2,6-dimethylpyridine are dissolved in 1.25 ml of toluene and cooled to −20° C. A solution of 0.18 ml (0.78 mmol) of tert-butyldimethylsilyl trifluoromethanesulfonate in 1.25 ml of toluene is added dropwise, and the mixture is stirred at −20° C. for 15 min, then warmed to 0° C. and stirred for 1 hour. Another 18 μl (0.078 mmol) of tert-butyldimethylsilyl trifluoromethanesulfonate are added, and stirring is continued for another 1.5 h. 5 ml of 0.1 N hydrochloric acid are added, and the mixture is extracted repeatedly with ethyl acetate. The organic phases are washed with a 1:1 mixture of saturated sodium bicarbonate solution and saturated sodium chloride solution and with saturated sodium chloride solution, dried over sodium sulfate, filtered and concentrated. The residue is purified by column chromatography on silica gel (mobile phase: cyclohexane/ethyl acetate 15:1). This gives 227 mg (93% of theory) of the title compound.
Reaction SMILES: [C:1]([O:4][CH2:5][CH2:6][O:7][C:8]1[CH:9]=[CH:10][CH:11]=[C:12]2[C:17]=1[N:16]=[C:15]([CH3:18])[CH:14]=[CH:13]2)(=[O:3])[CH3:2].[Se](=O)=[O:20]>O1CCOCC1.O>[C:1]([O:4][CH2:5][CH2:6][O:7][C:8]1[CH:9]=[CH:10][CH:11]=[C:12]2[C:17]=1[N:16]=[C:15]([CH:18]=[O:20])[CH:14]=[CH:13]2)(=[O:3])[CH3:2]
Reactant: CC(=O)OCCOc1cccc2ccc(C)nc12
Reactant: O=[Se]=O
Solvent: O
Solvent: C1COCCO1
Product: CC(=O)OCCOc1cccc2ccc(C=O)nc12
Yield: 96.4 %

Procedure:
To a solution of 2-(2-methylquinolin-8-yloxy)ethyl acetate (0.29 g, 1.2 mmol) in dioxane (20 mL) and water (0.20 mL) was added selenium dioxide (0.16 g, 1.4 mmol) and the resultant mixture heated at reflux for 2 hours. The cooled reaction mixture was filtered through a plug of Celite® to remove solids, rinsing with dichloromethane. The filtrate was concentrated under reduced pressure and purified by normal phase chromatography on silica gel (10-20% ethyl acetate/hexanes) to afford the title compound (0.30 g, 99%).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:22])/[C:4](/[NH:11]C(OCC1C=CC=CC=1)=O)=[CH:5]/[C@H:6]1[CH2:9][C@H:8]([CH3:10])[CH2:7]1.[H][H]>[Pd].CO>[CH3:1][O:2][C:3](=[O:22])[CH:4]([NH2:11])[CH2:5][C@H:6]1[CH2:7][C@H:8]([CH3:10])[CH2:9]1
Reactant: [H][H]
Reactant: COC(=O)/C(=C/[C@H]1C[C@H](C)C1)NC(=O)OCc1ccccc1
Agent: [Pd]
Solvent: CO
Product: COC(=O)C(N)C[C@H]1C[C@H](C)C1
Reaction time: 1.5 h
Yield: 87.3 %

Procedure:
In a Parr shaker bottle was placed (Z)-2-benzyloxycarbonylamino-3-(trans-3-methyl-cyclobutyl)-acrylic acid methyl ester (300 mg, 0.99 mmol), methanol (10 mL) and 10% palladium on activated carbon (60 mg). The mixture was placed on the Parr hydrogenator and charged with 40 psi hydrogen pressure and shaken for 1.5 h. After such time, the catalyst was filtered off through a plug of celite and the filterate concentrated in vacuo to afford 2-amino-3-(trans-3-methyl-cyclobutyl)-propionic acid methyl ester (148 mg, 87%) as a pale yellow oil.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[C:6]([O:8][C:9]2[C:10]([CH3:21])=[N:11][CH:12]=[C:13]([C:19]=2[CH3:20])[C:14]([O:16][CH2:17][CH3:18])=[O:15])[CH:5]=[CH:4][N:3]=1.[Br:22]Br>CC(O)=O>[NH2:1][C:2]1[CH:7]=[C:6]([O:8][C:9]2[C:10]([CH3:21])=[N:11][CH:12]=[C:13]([C:19]=2[CH3:20])[C:14]([O:16][CH2:17][CH3:18])=[O:15])[C:5]([Br:22])=[CH:4][N:3]=1
Reactant: CCOC(=O)c1cnc(C)c(Oc2ccnc(N)c2)c1C
Reactant: BrBr
Solvent: CC(=O)O
Product: CCOC(=O)c1cnc(C)c(Oc2cc(N)ncc2Br)c1C
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 59 %

Procedure:
Ethyl 5-(2-aminopyridin-4-yloxy)-4,6-dimethylnicotinate (2.5 g, 8.7 mmol) in AcOH (30 mL) was charged with dropwise addition of bromine (1M in AcOH, 8.7 ml, 8.7 mmol). The solution was stirred at ambient temperature for 30 minutes. The solution was then concentrated and neutralized with saturated NaHCO3 solution. The material was then extracted with EtOAc and the organic layer was dried, and concentrated. Flash chromatography gave the title compound (1.88 g, 59%) as a yellow solid.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([NH:11][C:12]2[C:13]([C:19]3[N:20]([CH:29]([CH3:31])[CH3:30])[C:21]([C:24](OCC)=[O:25])=[N:22][N:23]=3)=[N:14][CH:15]=[C:16]([Cl:18])[CH:17]=2)(=[O:10])=[O:9])=[CH:4][C:3]=1[C:32]([F:35])([F:34])[F:33].[NH:36]([CH3:38])[CH3:37].CCOC(C)=O>C1COCC1>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([NH:11][C:12]2[C:13]([C:19]3[N:20]([CH:29]([CH3:31])[CH3:30])[C:21]([C:24]([N:36]([CH3:38])[CH3:37])=[O:25])=[N:22][N:23]=3)=[N:14][CH:15]=[C:16]([Cl:18])[CH:17]=2)(=[O:10])=[O:9])=[CH:4][C:3]=1[C:32]([F:34])([F:33])[F:35]
Reactant: CCOC(=O)c1nnc(-c2ncc(Cl)cc2NS(=O)(=O)c2ccc(Cl)c(C(F)(F)F)c2)n1C(C)C
Reactant: CNC
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: CC(C)n1c(C(=O)N(C)C)nnc1-c1ncc(Cl)cc1NS(=O)(=O)c1ccc(Cl)c(C(F)(F)F)c1
Temperature: 25 °C
Reaction time: 16 h
Yield: 7 %

Procedure:
To a vial containing ethyl 5-(3-(4-chloro-3-(trifluoromethyl) benzenesulfonamido)-5-chloropyridin-2-yl)-4-isopropyl-4H-1,2,4-triazole-3-carboxylate (57 mg, 0.1 mmol) was added Me2NH in THF (1.0 mL of a 2.0M solution). The solution was stirred at room temperature for 16 h. EtOAc (30 mL) was added. The organic phase washed with water (2×10 mL) and dried over Na2SO4. The volatiles were removed in vacuo. The resulting residue was purified by preparative HPLC (20→95% gradient of MeCN—H2O with 0.1% TFA) and the pure fractions lyophilized to afford the title compound (3.7 mg, 7% yield). HPLC retention time=2.91 minutes. 1H NMR (400 MHz, CDCl3) δ 8.36 (d, J=2.0, 1H), 8.17 (d, J=2.4, 1H), 8.10 (d, J=2.4, 1H), 7.93 (dd, J=2.4, 8.4, 1H), 7.57 (d, J=8.4, 1H), 5.65 (sept, J=7.2, 1H), 3.20 (s, 3H), 3.12 (s, 3H), 1.52 (d, J=7.2, 6H). MS (ES) [M+H]+ expected 551.1. found 551.0.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:26]=[CH:27][C:28]=1[O:29][CH3:30])[CH2:5][NH:6][C:7]1[C:12]([C:13]([O:15][CH3:16])=[O:14])=[C:11]([N:17]2[CH2:22][CH2:21][CH:20]([OH:23])[CH2:19][CH2:18]2)[N:10]=[C:9]([S:24][CH3:25])[N:8]=1.ClC1C=CC=C(C(OO)=[O:39])C=1>C(Cl)(Cl)Cl.C(=O)([O-])O.[Na+]>[Cl:1][C:2]1[CH:3]=[C:4]([CH:26]=[CH:27][C:28]=1[O:29][CH3:30])[CH2:5][NH:6][C:7]1[C:12]([C:13]([O:15][CH3:16])=[O:14])=[C:11]([N:17]2[CH2:18][CH2:19][CH:20]([OH:23])[CH2:21][CH2:22]2)[N:10]=[C:9]([S:24]([CH3:25])=[O:39])[N:8]=1
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: COC(=O)c1c(NCc2ccc(OC)c(Cl)c2)nc(SC)nc1N1CCC(O)CC1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClC(Cl)Cl
Product: COC(=O)c1c(NCc2ccc(OC)c(Cl)c2)nc(S(C)=O)nc1N1CCC(O)CC1
Reaction time: 1 h

Procedure:
A mixture of 4-(3-chloro-4-methoxybenzylamino)-5-methoxycarbonyl-6-(4-hydroxypiperidin-1-yl)-2-methylthiopyrimidine (prepared in the above (4)) 121 mg in chloroform 3 ml is dropped a solution of m-chloroperbenzoic acid 54 mg in chloroform 4 ml on an ice bath over a period of 15 minutes, and the mixture is stirred for 1 hour. The reaction mixture is diluted with an aqueous sodium hydrogen carbonate solution and extracted with ethyl acetate. The organic layer is washed, dried and concentrated in vacuo to give 4-(3-chloro-4-methoxybenzylamino)-5-methoxycarbonyl-6-(4-hydroxypiperidin-1yl)-2-methylsulfinylpyrimidine as a colorless caramel.
Reaction SMILES: [CH:1]([C:4]1[CH:21]=[C:20]([B:22]2[O:26][C:25]([CH3:28])([CH3:27])[C:24]([CH3:30])([CH3:29])[O:23]2)[CH:19]=[CH:18][C:5]=1[O:6][CH2:7][C:8]([O:10]CC1C=CC=CC=1)=[O:9])([CH3:3])[CH3:2]>C(O)C.[C].[Pd]>[CH:1]([C:4]1[CH:21]=[C:20]([B:22]2[O:26][C:25]([CH3:28])([CH3:27])[C:24]([CH3:30])([CH3:29])[O:23]2)[CH:19]=[CH:18][C:5]=1[O:6][CH2:7][C:8]([OH:10])=[O:9])([CH3:3])[CH3:2]
Reactant: CC(C)c1cc(B2OC(C)(C)C(C)(C)O2)ccc1OCC(=O)OCc1ccccc1
Agent: [Pd]
Solvent: CCO
Product: CC(C)c1cc(B2OC(C)(C)C(C)(C)O2)ccc1OCC(=O)O
Temperature: 25 °C
Reaction time: 2 h
Yield: 83.3 %

Procedure:
A mixture of benzyl [2-isopropyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenoxy]acetate (0.24 g) and 10% palladium-carbon (0.05 g) in ethanol (10 mL) was stirred at room temperature for 2 hrs under an atmosphere of hydrogen. The catalyst was removed by filtration, and the solvent was evaporated under reduced pressure to afford the title compound (0.156 g).
Reaction SMILES: [Cl:1][C:2]1[C:7]([C:8]2[N:9]=[C:10]([CH:20]3[CH2:23][CH2:22][CH2:21]3)[S:11][C:12]=2[C:13]2[CH:18]=[CH:17][N:16]=[C:15](Cl)[N:14]=2)=[CH:6][CH:5]=[CH:4][C:3]=1[NH:24][S:25]([C:28]1[C:33]([F:34])=[CH:32][CH:31]=[CH:30][C:29]=1[F:35])(=[O:27])=[O:26].[NH3:36].CO>>[NH2:36][C:15]1[N:14]=[C:13]([C:12]2[S:11][C:10]([CH:20]3[CH2:21][CH2:22][CH2:23]3)=[N:9][C:8]=2[C:7]2[C:2]([Cl:1])=[C:3]([NH:24][S:25]([C:28]3[C:33]([F:34])=[CH:32][CH:31]=[CH:30][C:29]=3[F:35])(=[O:27])=[O:26])[CH:4]=[CH:5][CH:6]=2)[CH:18]=[CH:17][N:16]=1
Reactant: O=S(=O)(Nc1cccc(-c2nc(C3CCC3)sc2-c2ccnc(Cl)n2)c1Cl)c1c(F)cccc1F
Reactant: N
Solvent: CO
Product: Nc1nccc(-c2sc(C3CCC3)nc2-c2cccc(NS(=O)(=O)c3c(F)cccc3F)c2Cl)n1

Procedure:
Following a procedure analogous to the procedure described in Example 51, Step B using N-{2-chloro-3-[5-(2-chloro-4-pyrimidinyl)-2-cyclobutyl-1,3-thiazol-4-yl]phenyl}-2,6-difluorobenzenesulfonamide (0.20 g, 0.36 mmol) and 7N ammonia in MeOH (10 ml, 70 mmol) the title compound was obtained (0.030 g, 0.056 mmol, 15%). 1H NMR (400 MHz, DMSO-d6) δ ppm 10.80 (s, 1H), 7.95 (d, J=5.1 Hz, 1H), 7.64 (dd, J=14.3, 2.0 Hz, 1H), 7.55-7.38 (m, 2H), 7.34 (d, J=7.0 Hz, 1H), 7.18 (t, J=9.1 Hz, 2H), 6.72 (br, 2H), 5.61 (d, J=5.1 Hz, 1H), 3.83 (quin, J=8.4 Hz, 1H), 3.45-3.19 (m, 1H), 2.38 (q, J=8.5 Hz, 1H), 2.24 (quin, J=9.1 Hz, 1H), 2.10-1.92 (m, 1H), 1.86 (q, J=9.4 Hz, 1H), 1.06 (t, J=7.0 Hz, 1H). MS (ESI): 534 [M+H]+.
Reaction SMILES: C1C2C(COC([NH:18][C@@H:19]([CH2:23][S:24][CH2:25][C@H:26]([NH:41][C:42](=[O:54])[CH2:43][CH2:44][CH2:45][CH2:46][CH2:47][CH2:48][CH2:49][CH2:50][CH2:51][CH2:52][CH3:53])[CH2:27][O:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][CH3:40])[C:20]([OH:22])=O)=O)C3C(=CC=CC=3)C=2C=CC=1.[NH2:55][CH2:56][CH2:57][O:58][CH2:59][CH2:60][O:61][CH2:62][CH2:63][O:64][CH2:65][CH2:66][C:67]([O:69]C(C)(C)C)=[O:68]>>[NH2:18][C@@H:19]([CH2:23][S:24][CH2:25][C@H:26]([NH:41][C:42](=[O:54])[CH2:43][CH2:44][CH2:45][CH2:46][CH2:47][CH2:48][CH2:49][CH2:50][CH2:51][CH2:52][CH3:53])[CH2:27][O:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][CH3:40])[C:20](=[O:22])[NH:55][CH2:56][CH2:57][O:58][CH2:59][CH2:60][O:61][CH2:62][CH2:63][O:64][CH2:65][CH2:66][C:67]([OH:69])=[O:68]
Reactant: CCCCCCCCCCCCOC[C@H](CSC[C@H](NC(=O)OCC1c2ccccc2-c2ccccc21)C(=O)O)NC(=O)CCCCCCCCCCC
Reactant: CC(C)(C)OC(=O)CCOCCOCCOCCN
Product: CCCCCCCCCCCCOC[C@H](CSC[C@H](N)C(=O)NCCOCCOCCOCCC(=O)O)NC(=O)CCCCCCCCCCC

Procedure:
The title product was prepared from (R)-2-((((9H-fluoren-9-yl)methoxy)carbonyl)amino)-3-(((R)-2-dodecanamido-3-(dodecyloxy)propyl)thio)propanoic acid (1 eq, from example 26, step 8) and tert-butyl 3-(2-(2-(2-aminoethoxy)ethoxy)ethoxy)propanoate (1.2 eq) by following the procedure described for example 32, step 1-3. 1H NMR (DMSO-d6): δ 8.06 (t, 1H), 7.78 (d, 1H), 5.05 (br s, 2H), 3.90-3.98 (m, 1H), 3.58 (t, 2H), 3.19-3.50 (m, 15H), 2.77 (dd, 2H), 2.62 (dd, 2H), 2.39 (t, 2H), 2.05 (t, 2H), 1.42-1.48 (m, 4H), 1.21-1.29 (m, 36H), 0.85 (t, 6H). LRMS [M+H]=748.5.
Reaction SMILES: CCOC(/N=N/C(OCC)=O)=O.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[Cl:32][C:33]1[CH:34]=[C:35]([OH:40])[CH:36]=[CH:37][C:38]=1[F:39].C(OC([N:48]1[CH2:53][CH2:52][CH:51](O)[CH2:50][CH2:49]1)=O)(C)(C)C.Cl>O1CCOCC1>[Cl:32][C:33]1[CH:34]=[C:35]([CH:36]=[CH:37][C:38]=1[F:39])[O:40][CH:51]1[CH2:52][CH2:53][NH:48][CH2:49][CH2:50]1
Reactant: Oc1ccc(F)c(Cl)c1
Reactant: CC(C)(C)OC(=O)N1CCC(O)CC1
Agent: CCOC(=O)/N=N/C(=O)OCC
Agent: Cl
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1COCCO1
Product: Fc1ccc(OC2CCNCC2)cc1Cl
Reaction time: 8 h
Yield: 105.2 %

Procedure:
DEAD (0.43 ml) was added to a solution of triphenylphosphine (0.72 g), 3-chloro4-fluorophenol (0.403 g) and 4-hydroxy-piperidine-1-carboxylic acid tert-butyl ester (0.5 g) in THP at room temperature (RT). The resulting mixture was stirred overnight, HCl in dioxan (2 ml of 4M) was added and the mixture stirred at RT overnight. The mrixture was then evaporated to dryness and triethylamine (5 ml) was added. The mixture was evaporated and the residue was dissolved in methanol (10 ml), placed onto a SCX cartridge (Varian, 10 g, SCX cartridge available from International Sorbent Technology Isolute® Flash SCX-2) and eluted: first with methanol then with 10% NH3 in methanol. The basic fractions were combined and evaporated to give the product as an oil (0.6 g).
Reaction SMILES: [Br:1][C:2]1[C:3]([C:9]2[S:10][CH:11]=[CH:12][CH:13]=2)=[N:4][C:5](Cl)=[N:6][CH:7]=1.C1COCC1.[CH2:19]([N:21](CC)CC)C.Cl.CN>O>[Br:1][C:2]1[C:3]([C:9]2[S:10][CH:11]=[CH:12][CH:13]=2)=[N:4][C:5]([NH:21][CH3:19])=[N:6][CH:7]=1
Reactant: Clc1ncc(Br)c(-c2cccs2)n1
Reactant: CCN(CC)CC
Agent: CN
Agent: Cl
Solvent: C1CCOC1
Solvent: O
Product: CNc1ncc(Br)c(-c2cccs2)n1
Temperature: 85 °C
Reaction time: 20 h

Procedure:
A 16 by 100 mm vial was charged with 5-bromo-2-chloro-4-(thiophen-2-yl)pyrimidine (1.00 g, 3.6 mmol), THF (4 mL), triethylamine (1.5 ml, 11 mmol), and methylamine hydrochloride (0.49 g, 7.3 mmol), and water (0.4 mL). The vial was capped and heated to 85° C. with stirring for 20 hours. The reaction was cooled to room temperature and concentrated. The residue was purified via column chromatography on silica gel (gradient elution with 0 to 4% methanol in dichloromethane) to afford 5-bromo-N-methyl-4-(thiophen-2-yl)pyrimidin-2-amine. MS m/z=271 [M+H]+. Calc'd for C9H8BrN3S: 270.