Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C[Si](C)(C)[Br:3].C([O:8][P:9]([CH2:18][C@@H:19]([OH:32])[CH2:20][NH:21][CH:22]([C:24]1[CH:29]=[CH:28][CH:27]=[C:26]([C:30]#[N:31])[CH:25]=1)[CH3:23])([CH2:11][CH:12]1[CH2:17][CH2:16][CH2:15][CH2:14][CH2:13]1)=[O:10])C>ClCCl>[BrH:3].[C:30]([C:26]1[CH:25]=[C:24]([CH:22]([NH:21][CH2:20][C@H:19]([OH:32])[CH2:18][P:9]([CH2:11][CH:12]2[CH2:17][CH2:16][CH2:15][CH2:14][CH2:13]2)(=[O:8])[OH:10])[CH3:23])[CH:29]=[CH:28][CH:27]=1)#[N:31]
Reactant: C[Si](C)(C)Br
Reactant: CCOP(=O)(CC1CCCCC1)C[C@@H](O)CNC(C)c1cccc(C#N)c1
Solvent: ClCCl
Product: Br
Product: CC(NC[C@H](O)CP(=O)(O)CC1CCCCC1)c1cccc(C#N)c1
Temperature: 25 °C
Reaction time: 24 h

Procedure:
0.97 g of trimethylbromosilane is added to a solution of 0.62 g of 3-{N-[1-(3-cyanophenyl)ethyl]amino}-2(S)-hydroxy-propyl(cyclohexylmethyl)phosphinic acid ethyl ester in 10 ml of absolute dichloromethane. The resulting solution is stirred for 24 hours at room temperature, the volatile portions are removed under reduced pressure and the residue is dissolved in 99.9% methanol. The solution is stirred for 1 hour at room temperature, the solvent is removed and the residue is crystallised from ethanol to give 3-{N-[1-(3-cyanophenyl)ethyl]amino}-2(S)-hydroxy-propyl(cyclohexylmethyl)phosphinic acid hydrobromide having a melting point of 209°-210°.
Reaction SMILES: Br[C:2]1[C:3]([Cl:15])=[C:4]([CH:10]=[CH:11][C:12]=1[C:13]#[N:14])[C:5]([O:7]CC)=[O:6].BrC1C(C#N)=CC(Cl)=C(C=1)C(OCC)=[O:23].[CH:31]1([CH:34]([NH2:36])[CH3:35])[CH2:33][CH2:32]1>>[NH2:14][C:13]([C:12]1[CH:11]=[CH:10][C:4]([C:5]([OH:7])=[O:6])=[C:3]([Cl:15])[C:2]=1[NH:36][CH:34]([CH:31]1[CH2:33][CH2:32]1)[CH3:35])=[O:23]
Reactant: CCOC(=O)c1ccc(C#N)c(Br)c1Cl
Reactant: CCOC(=O)c1cc(Br)c(C#N)cc1Cl
Reactant: CC(N)C1CC1
Product: CC(Nc1c(C(N)=O)ccc(C(=O)O)c1Cl)C1CC1

Procedure:
Synthesized according to the method of reagent preparation 46 by first conducting step 2 to give a mixture of ethyl 3-bromo-2-chloro-4-cyanobenzoate and ethyl 5-bromo-2-chloro-4-cyanobenzoate then proceeding with step 1 using 1-cyclopropylethylamine followed by steps 3 and 4. 1HNMR (400 MHz, CD3OD): 7.49 (d, 1H), 7.22 (d, 1H), 2.84 (q, 2H), 1.17 (d, 3H), 0.9-0.76 (m, 1H), 0.3-0.26 (m, 2H), 0.04-0.00 (m, 2H). MS (EI) for C13H15ClN2O3: 284 (MH+).
Reaction SMILES: F[C:2]1[CH:10]=[CH:9][C:8]([S:11]([CH3:14])(=[O:13])=[O:12])=[CH:7][C:3]=1[C:4]([OH:6])=[O:5].[F:15][C:16]([F:22])([F:21])[C:17]([CH3:20])([OH:19])[CH3:18].C(=O)([O-])[O-].[Cs+].[Cs+].C(O)=O>CN(C)C(=O)C>[CH3:14][S:11]([C:8]1[CH:9]=[CH:10][C:2]([O:19][C:17]([CH3:20])([CH3:18])[C:16]([F:22])([F:21])[F:15])=[C:3]([CH:7]=1)[C:4]([OH:6])=[O:5])(=[O:13])=[O:12]
Reactant: CS(=O)(=O)c1ccc(F)c(C(=O)O)c1
Reactant: CC(C)(O)C(F)(F)F
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CC(=O)N(C)C
Solvent: O=CO
Product: CC(C)(Oc1ccc(S(C)(=O)=O)cc1C(=O)O)C(F)(F)F
Temperature: 170 °C
Reaction time: 72 h
Yield: 99 %

Procedure:
To a solution of 2.75 mmol 2-fluoro-5-methanesulfonyl-benzoic acid in 10 ml N,N-dimethylacetamide were added 14.7 mmol 1,1,1-trifluoro-2-methyl-propan-2-ol and 8.29 mmol cesium carbonate and the mixture was stirred at 170° C. for 72 hours. The reaction mixture was then cooled to room temperature, acidified by addition of formic acid, and then concentrated in vacuo. The residue was purified by preparative HPLC to afford the title compound as a light brown solid (yield 99%). MS (m/e): 325.3. ([M−H]−, 100%)
Reaction SMILES: [F:1][C:2]([F:14])([F:13])[C:3]1[CH:12]=[C:11]2[C:6]([CH2:7][CH2:8][CH2:9][NH:10]2)=[CH:5][CH:4]=1.CCN(C(C)C)C(C)C.[Cl:24][C:25]1[N:30]=[C:29](Cl)[N:28]=[CH:27][N:26]=1>CN(C=O)C>[Cl:24][C:25]1[N:30]=[CH:29][N:28]=[C:27]([N:10]2[C:11]3[C:6](=[CH:5][CH:4]=[C:3]([C:2]([F:1])([F:13])[F:14])[CH:12]=3)[CH2:7][CH2:8][CH2:9]2)[N:26]=1
Reactant: Clc1ncnc(Cl)n1
Reactant: FC(F)(F)c1ccc2c(c1)NCCC2
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: FC(F)(F)c1ccc2c(c1)N(c1ncnc(Cl)n1)CCC2
Temperature: 0 °C

Procedure:
7-(Trifluoromethyl)-1,2,3,4-tetrahydroquinoline (440 mg, 2.2 mmol) was dissolved in DMF (10 mL) under N2 at RT. DIEA (284 mg, 2.2 mmol) was added, and the reaction solution was cooled to 0° C. 2,4-Dichloro-1,3,5-triazine was added, and reaction was stirred with gradual warming to RT. The reaction was quenched after 3 h with water, which caused a fine precipitate to form, which is not filterable. This mixture was extracted 3 times with EtOAc. The EtOAc extracts were washed brine, combined, dried over Na2SO4, filtered, concentrated, and dried under high vacuum giving 1-(4-chloro-[1,3,5]triazin-2-yl)-7-trifluoromethyl-1,2,3,4-tetrahydro-quinoline as a yellow oil that was used without further purification.
Reaction SMILES: [N:1]1([C:6]2[CH:26]=[CH:25][C:9]([CH2:10][C:11]3[C:12]([O:23][CH3:24])=[N:13][C:14]4[C:19]([C:20]=3[Cl:21])=[CH:18][C:17](Br)=[CH:16][CH:15]=4)=[CH:8][CH:7]=2)[CH:5]=[CH:4][CH:3]=[N:2]1.[Li][CH2:28]CCC.[CH3:32][N:33]1[C:37]([C:38]([CH:40]2[CH2:45][CH2:44][N:43]([C:46]([O:48]C(C)(C)C)=O)[CH2:42][CH2:41]2)=[O:39])=[CH:36][N:35]=[CH:34]1>C1COCC1>[N:1]1([C:6]2[CH:26]=[CH:25][C:9]([CH2:10][C:11]3[C:12]([O:23][CH3:24])=[N:13][C:14]4[C:19]([C:20]=3[Cl:21])=[CH:18][C:17]([C:38]([OH:39])([C:37]3[N:33]([CH3:32])[CH:34]=[N:35][CH:36]=3)[CH:40]3[CH2:45][CH2:44][N:43]([C:46](=[O:48])[CH3:28])[CH2:42][CH2:41]3)=[CH:16][CH:15]=4)=[CH:8][CH:7]=2)[CH:5]=[CH:4][CH:3]=[N:2]1
Reactant: [Li]CCCC
Reactant: Cn1cncc1C(=O)C1CCN(C(=O)OC(C)(C)C)CC1
Reactant: COc1nc2ccc(Br)cc2c(Cl)c1Cc1ccc(-n2cccn2)cc1
Solvent: C1CCOC1
Product: COc1nc2ccc(C(O)(c3cncn3C)C3CCN(C(C)=O)CC3)cc2c(Cl)c1Cc1ccc(-n2cccn2)cc1
Reaction time: 0.04 h

Procedure:
A solution of 3-(4-(1H-pyrazol-1-yl)benzyl)-6-bromo-4-chloro-2-methoxyquinoline (0.558 g, 1.30 mmol; Intermediate 16) in THF (13 mL) was stirred under argon at ˜−70° C. while n-BuLi (2.56 M in hexanes, 0.484 mL, 1.24 mmol) was added dropwise over 1.5 minutes. After another 2.5 minutes, a solution of 1-(4-(1-methyl-1H-imidazole-5-carbonyl)piperidin-1-yl)ethanone (0.322 g, 1.37 mmol, Intermediate 42: step c) in THF (4.5 mL) was added dropwise over 2.5 minutes, and the dark mixture was stirred in the cold bath for another 5 minutes. The dry ice/acetone bath was then removed and the reaction stirred for 5 minutes under ambient conditions before transferring to an ice bath. After stirring for 2.5 hours at ˜0° C., the reaction was quenched with 5 M aqueous NH4Cl (2 mL) and the organic layer was dried (Na2SO4), filtered, and concentrated. The residue was flash chromatographed with a DCM to 10% MeOH/DCM gradient to provide the title compound as a light yellow foam. 1H NMR (400 MHz, CDCl3) (two conformers) δ ppm 8.17 (br. s, ˜0.5H), 8.12 (br. s, ˜0.5H), 7.85 (d, J=2.53 Hz, 1H), 7.76 (dd, J=2.78, 8.84 Hz, 1H), 7.67 (s, 1H), 7.57 (d, J=8.59 Hz, 2H), 7.44-7.36 (m, 3H), 7.21 (d, J=5.05 Hz, 1H), 7.10 (s, 1H), 6.43 (d, J=2.02 Hz, 1H), 4.71 (d, J=13.14 Hz, ˜0.5H), 4.47-4.61 (m, ˜0.5H), 4.32 (s, 2H), 4.08 (s, 3H), 3.89 (d, J=13.41 Hz, ˜0.5H), 3.69 (d, J=13.14 Hz, ˜0.5H), 3.25 (s, ˜1.5H), 3.21 (s, ˜1.5H), 3.10-3.18 (m, ˜0.5H), 2.87-3.00 (m, ˜0.5H), 2.60 (t, J=12.13 Hz, ˜0.5H), 2.35-2.51 (m, ˜1.5H), 2.29 (d, J=13.40 Hz, ˜0.5H), 2.21 (d, J=13.14 Hz, ˜0.5H), 2.00 (s, ˜1.5H), 1.95 (s, ˜1.5H), 1.10-1.46 (m, 3H). MS m/e 585.3 [M+H]+.
Reaction SMILES: [CH:1]1[CH2:7][CH2:6][CH2:5][CH2:4][CH2:3][CH:2]=1.C(O[K])(C)(C)C.[CH:14](Br)([Br:16])[Br:15].CCCCCC>CCCCC>[Br:15][C:14]1([Br:16])[CH:7]2[CH:1]1[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]2
Reactant: C1=CCCCCC1
Reactant: BrC(Br)Br
Agent: CC(C)(C)O[K]
Solvent: CCCCCC
Solvent: CCCCC
Product: BrC1(Br)C2CCCCCC21
Temperature: 0 °C
Reaction time: 8 h

Procedure:
To a magnetically stirred solution of cycloheptene (500 mg, 5.20 mmol, 1 eq) in dry Pentane (52 ml) under Ar atmosphere, tBuOK (671 mg, 5.98 mmol, 1.15 eq) was added. Suspension was cooled to 0° C. and CHBr3 (466 μl, 5.20 mmol, 1 eq) was added in a time period of six hours. Then the solution was warmed to Room Temperature (RT) and the resulting dark-brown solution was stirred overnight at RT. Reaction was controlled by TLC (Hexane as eluent) and was quenched with water (10 ml) and concentrated HCl until neutralization. Layers were separated and the aqueous layer was extracted with pentane (3×50 ml). Combined organic phases were dried over Na2SO4, filtered and concentrated under vacuum to obtain product 8,8-dibromobicyclo[5.1.0]octane as a brown oil that was used for the next step without further purification.
Reaction SMILES: Cl[C:2]1[CH:7]=[N:6][CH:5]=[C:4]([C:8]2[CH:13]=[CH:12][C:11]([C:14]([F:17])([F:16])[F:15])=[CH:10][CH:9]=2)[N:3]=1.[CH2:18]([NH:22][CH2:23][C:24]1[CH:36]=[CH:35][C:27]([O:28][CH2:29][C:30]([O:32][CH2:33][CH3:34])=[O:31])=[C:26]([CH2:37][CH3:38])[CH:25]=1)[CH2:19][CH2:20][CH3:21].C(N(CC)C(C)C)(C)C>C(Cl)Cl>[CH2:18]([N:22]([CH2:23][C:24]1[CH:36]=[CH:35][C:27]([O:28][CH2:29][C:30]([O:32][CH2:33][CH3:34])=[O:31])=[C:26]([CH2:37][CH3:38])[CH:25]=1)[C:2]1[CH:7]=[N:6][CH:5]=[C:4]([C:8]2[CH:13]=[CH:12][C:11]([C:14]([F:17])([F:16])[F:15])=[CH:10][CH:9]=2)[N:3]=1)[CH2:19][CH2:20][CH3:21]
Reactant: FC(F)(F)c1ccc(-c2cncc(Cl)n2)cc1
Reactant: CCCCNCc1ccc(OCC(=O)OCC)c(CC)c1
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CCCCN(Cc1ccc(OCC(=O)OCC)c(CC)c1)c1cncc(-c2ccc(C(F)(F)F)cc2)n1
Temperature: 100 °C
Yield: 17.3 %

Procedure:
A mixture of 2-chloro-6-[4-(trifluoromethyl)phenyl]pyrazine (0.172 g, 0.56 mmol), ethyl {4-[(butylamino)methyl]-2-ethylphenoxy}acetate (0.25 g, 0.85 mmol) and N,N-diisopropylethylamine (0.099 mL, 0.56 mmol) were heated together in a reactivial at 100° C. for 18 h. The vial was then allowed to cool to room temperature and the residue dissolved in CH2Cl2 (50 mL) and the organic solution washed with water (15 mL) and brine (10 mL). The solution was then passed through a hydrophobic frit and evaporated. Purification by Biotage™ chromatography (Silica, 40 g) eluting 9:1cyclohexane:EtOAc, afforded the title compound as a pale yellow oil (50 mg).
Reaction SMILES: N1CCC[C@H]1C1C=C(C=O)C=NC=1.[C:14]([O:18][C:19]([N:21](C)[C@@H:22](C)C(N[C@@H](C1CCCCC1)C(O)=O)=O)=[O:20])([CH3:17])([CH3:16])[CH3:15].O.[Cl-].COC1N=C(OC)N=C([N+]2(C)CCOCC2)N=1>C1COCC1.CCOC(C)=O>[C:14]([O:18][C:19](=[O:20])[NH:21][CH3:22])([CH3:17])([CH3:16])[CH3:15]
Reactant: C[C@@H](C(=O)N[C@H](C(=O)O)C1CCCCC1)N(C)C(=O)OC(C)(C)C
Agent: COc1nc(OC)nc([N+]2(C)CCOCC2)n1
Agent: O=Cc1cncc([C@@H]2CCCN2)c1
Agent: [Cl-]
Solvent: C1CCOC1
Solvent: O
Solvent: CCOC(C)=O
Product: CNC(=O)OC(C)(C)C
Temperature: 20 °C
Reaction time: 2 h
Yield: 363 %

Procedure:
To a solution of 4-fluoro-phenyl)-((S)-5-pyrrolidin-2-yl-pyridin-3-yl)-methanone (2.57 g, 9.5 mmole) and (S)-[(S)-2-(tert-butoxycarbonyl-methyl-amino)-propionylamino]-cyclohexyl-acetic acid (5) (3.58 g, 10.5 mmole) in 75 mL of THF at 0° C., is added 4-(4,6-dimethoxy-[1,3,5]triazin-2-yl)-4-methyl-morpholinium chloride hydrate (2.97 g, 10.7 mmole) in one portion. After stirring at 20° C. for 2 hours, the reaction mixture is diluted with 100 mL of EtOAc, and washed with 3×20 mL of water. After concentration, the crude product is purified by flash column chromatography (CH2Cl2 95%, MeOH 5%) to give (S)-1-((S)-1-cyclohexyl-2-{(S)-2-[5-(4-fluoro-benzoyl)-pyridin-3-yl]pyrrolidin-1-yl}-2-oxo-ethylcarbamoyl)-ethyl]-methyl-carbamic acid tert-butyl ester (6) (5.0 g, yield 88%) as pale yellow solid.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:14])[CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][C:11](O)=[O:12].B.CSC.C([O-])([O-])=O.[K+].[K+]>C1COCC1>[CH3:1][O:2][C:3](=[O:14])[CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][OH:12]
Reactant: COC(=O)CCCCCCCC(=O)O
Agent: B
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CSC
Solvent: C1CCOC1
Product: COC(=O)CCCCCCCCO
Reaction time: 0.17 h
Yield: 53.1 %

Procedure:
To a solution of nonanedioic acid monomethyl ester (4.80 g, 20 mmol) in THF (20 mL) at −20° C. was added a solution of borane-dimethylsulfide in THF (2.0 M, 10 mL) over 10 min. The resulting mixture was stirred for an additional 10 min, and then allowed to stir at room temperature overnight. Aqueous K2CO3 solution was added, and the product was extracted with ethyl ether (3×). The crude product was purified by flash column chromatography (hexane/EtOAc:2/1) to yield 9-hydroxy-nonanoic acid methyl ester 4-B (2.0 g, 55%).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][C:9]=1[Cl:10])[CH2:5][NH2:6].[CH3:11][O:12][C:13](=[O:33])[C:14]1[CH:19]=[CH:18][C:17]([C:20]2[N:21]=[C:22](Cl)[C:23]3[CH:28]=[C:27]([N+:29]([O-:31])=[O:30])[S:26][C:24]=3[N:25]=2)=[CH:16][CH:15]=1>>[CH3:11][O:12][C:13](=[O:33])[C:14]1[CH:19]=[CH:18][C:17]([C:20]2[N:21]=[C:22]([NH:6][CH2:5][C:4]3[CH:7]=[CH:8][C:9]([Cl:10])=[C:2]([Cl:1])[CH:3]=3)[C:23]3[CH:28]=[C:27]([N+:29]([O-:31])=[O:30])[S:26][C:24]=3[N:25]=2)=[CH:16][CH:15]=1
Reactant: COC(=O)c1ccc(-c2nc(Cl)c3cc([N+](=O)[O-])sc3n2)cc1
Reactant: NCc1ccc(Cl)c(Cl)c1
Product: COC(=O)c1ccc(-c2nc(NCc3ccc(Cl)c(Cl)c3)c3cc([N+](=O)[O-])sc3n2)cc1

Procedure:
The reaction procedure as above wherein 3,4-dichlorobenzylamine is reacted with 4-(4-chloro-6-nitro-thieno-[2,3-d]-pyrimidin-2-yl)-benzoic acid methylester yields 4-[4-(3,4-dichlorobenzylamino)-6-nitro-thieno-[2,3-d]-pyrimidin-2-yl]-benzoic acid methylester.
Reaction SMILES: [CH2:1]([N:8]1[CH2:13][CH2:12][NH:11][CH2:10][CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Cl:14]([O-:18])(=[O:17])(=[O:16])=[O:15].CS[C:21]1[S:25][CH:24]=[CH:23][S+:22]=1>>[Cl:14]([O-:18])(=[O:17])(=[O:16])=[O:15].[S:22]1[CH:23]=[CH:24][S:25][C:21]1=[N+:11]1[CH2:12][CH2:13][N:8]([CH2:1][C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=2)[CH2:9][CH2:10]1
Reactant: c1ccc(CN2CCNCC2)cc1
Reactant: CSc1scc[s+]1
Agent: [O-][Cl+3]([O-])([O-])[O-]
Product: c1ccc(CN2CC[N+](=c3sccs3)CC2)cc1
Yield: 68.6 %

Procedure:
2.2 g of N-benzylpiperazine and 2.5 g of 2-methylthio-1,3-dithiolium perchlorate were treated in the same manner as in Example 26, and the product was recrystallized from water-ethanol, whereby 2.6 g (yield: 68.9%) of 1-(1,3-dithiol-2-ylidene)-4-benzylpiperazinium perchlorate (Compound No. 33) was obtained as crystals having a melting point of from 224° to 226° C.
Reaction SMILES: C(C1C=CC(C#C)=CC=1)(C)(C)C.C[Si]([C:17]#[C:18][C:19]1[CH:24]=[CH:23][C:22]([CH2:25][CH2:26][CH2:27][CH:28]([CH3:30])[CH3:29])=[CH:21][CH:20]=1)(C)C>>[CH3:29][CH:28]([CH3:30])[CH2:27][CH2:26][CH2:25][C:22]1[CH:21]=[CH:20][C:19]([C:18]#[CH:17])=[CH:24][CH:23]=1
Reactant: CC(C)CCCc1ccc(C#C[Si](C)(C)C)cc1
Agent: C#Cc1ccc(C(C)(C)C)cc1
Product: C#Cc1ccc(CCCC(C)C)cc1

Procedure:
Using the same general procedure as described for Compound 19), but using instead trimethylsilyl [4-(4-methylpentyl)] phenylethyne (Compound 31), the title compound was synthesized as a colorless oil. PMR (CDCl3): & 0.94 (6H, d, J~6.6 Hz), 1.20-1.32 (2H, m), 1.56-1.62 (3H, m), 2.64 (2H, t, J~7.8 Hz), 3.08 (1H, s), 7.18 (2H, d, J~8.1 Hz), 7.47 (2H, d, J~8.1 Hz).
Reaction SMILES: [Cl:1][C:2]1[C:3]([C:9](=O)[C@@H:10]([NH:12][C:13](=[O:19])[O:14][C:15]([CH3:18])([CH3:17])[CH3:16])[CH3:11])=[N:4][CH:5]=[C:6]([Cl:8])[CH:7]=1.Cl.[NH2:22][OH:23].N1C=CC=CC=1>C(O)C>[Cl:1][C:2]1[C:3]([C:9](=[N:22][OH:23])[C@@H:10]([NH:12][C:13](=[O:19])[O:14][C:15]([CH3:18])([CH3:17])[CH3:16])[CH3:11])=[N:4][CH:5]=[C:6]([Cl:8])[CH:7]=1
Reactant: NO
Reactant: C[C@H](NC(=O)OC(C)(C)C)C(=O)c1ncc(Cl)cc1Cl
Agent: Cl
Solvent: CCO
Solvent: c1ccncc1
Product: C[C@H](NC(=O)OC(C)(C)C)C(=NO)c1ncc(Cl)cc1Cl
Temperature: 25 °C
Reaction time: 18 h
Yield: 70.7 %

Procedure:
To a solution of 1.0 g of tert-butyl (S)—N-[2-(3,5-dichloropyridin-2-yl)-1-methyl-2-oxoethyl]carbamate and 239 mg of hydroxylamine hydrochloride in 5 ml of ethanol, 272 mg of pyridine was added, and the mixture was stirred at room temperature for 18 hours. After completion of the reaction, the solvent was evaporated under reduced pressure, the resulting residue was mixed with 10 ml of water and extracted with ethyl acetate (10 ml×2), the resulting organic layers were combined, dried over saturated aqueous sodium chloride and then anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure. The resulting residue was purified by silica gel column chromatography using ethyl acetate-hexane (with a gradient of from 5:95 to 40:60) as the eluent to obtain 740 mg of the desired product as pale yellow crystals.
Reaction SMILES: C1[O:6][C:5]([CH2:11][C:12]([OH:14])=[O:13])([CH2:7][C:8]([OH:10])=[O:9])[C:3](=[O:4])[O:2]1.C(N(CC)CC)C.[CH2:22](O)[CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH3:33]>C(O)C>[CH2:33]([CH:7]([C:5]([CH2:11][C:12]([OH:14])=[O:13])([C:3]([OH:2])=[O:4])[OH:6])[C:8]([OH:10])=[O:9])[CH2:32][CH2:31][CH2:30][CH2:29][CH2:28][CH2:27][CH2:26][CH2:25][CH2:24][CH2:23][CH3:22]
Reactant: O=C(O)CC1(CC(=O)O)OCOC1=O
Reactant: CCCCCCCCCCCCO
Solvent: CCN(CC)CC
Solvent: CCO
Product: CCCCCCCCCCCCC(C(=O)O)C(O)(CC(=O)O)C(=O)O

Procedure:
A mixture of 2 (10 g), triethylamine (15 ml) and dodecanol (22 ml) in ethanol-free chloroform (100 ml) was refluxed for 22 hours. Workup in the usual fashion gave the crude product (15.3 g, 86%) as a semi-solid. GC analysis indicated the mixture contained an 89:6 mixture of the major and minor isomers together with about 4% of unreacted 2. Crystallization of this material gave 11.8 g of 3c with mp 74.8°-75.6° C. Recrystallization gave 3c with mp 74.7°-75.3° C., which migrated as a single spot on TLC and as a broad peak, Rt 10.88-10.93, by GC, after derivatization.
Reaction SMILES: [Cl:1][C:2]1[C:3]([NH:29][C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][C:31]=2[S:36]([CH:39]([CH3:41])[CH3:40])(=[O:38])=[O:37])=[N:4][C:5]([NH:8][C:9]2[CH:17]=[C:16]3[C:12]([CH2:13][N:14]([CH:19]4[CH2:24][CH2:23][NH:22][CH2:21][CH2:20]4)[C:15]3=[O:18])=[CH:11][C:10]=2[O:25][CH:26]([CH3:28])[CH3:27])=[N:6][CH:7]=1.C(N(CC)CC)C.Br[CH2:50][C:51]([NH2:53])=[O:52]>CN(C=O)C>[Cl:1][C:2]1[C:3]([NH:29][C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][C:31]=2[S:36]([CH:39]([CH3:41])[CH3:40])(=[O:38])=[O:37])=[N:4][C:5]([NH:8][C:9]2[CH:17]=[C:16]3[C:12]([CH2:13][N:14]([CH:19]4[CH2:20][CH2:21][N:22]([CH2:50][C:51]([NH2:53])=[O:52])[CH2:23][CH2:24]4)[C:15]3=[O:18])=[CH:11][C:10]=2[O:25][CH:26]([CH3:28])[CH3:27])=[N:6][CH:7]=1
Reactant: NC(=O)CBr
Reactant: CC(C)Oc1cc2c(cc1Nc1ncc(Cl)c(Nc3ccccc3S(=O)(=O)C(C)C)n1)C(=O)N(C1CCNCC1)C2
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: CC(C)Oc1cc2c(cc1Nc1ncc(Cl)c(Nc3ccccc3S(=O)(=O)C(C)C)n1)C(=O)N(C1CCN(CC(N)=O)CC1)C2
Temperature: 60 °C
Reaction time: 4 h

Procedure:
To a mixture of 6-{5-Chloro-4-[2-(propane-2-sulfonyl)-phenylamino]-pyrimidin-2-ylamino}-5-isopropoxy-2-piperidin-4-yl-2,3-dihydro-isoindol-1-one (Example 1, 20 mg, 0.033 mmol) and triethylamine (23 uL, 0.165 mmol) in DMF (1.5 mL), is added 2-bromo-acetamide (10 mg, 0.066 mmol). The mixture is stirred at 60° C. for 4 hours. The reaction is filtered and the filtrate is purified by mass-trigger preparative RP LC-MS to afford the title compound 2-[4-(6-{5-Chloro-4-[2-(propane-2-sulfonyl)-phenylamino]-pyrimidin-2-ylamino}-5-isopropoxy-1-oxo-1,3-dihydro-isoindol-2-yl)-piperidin-1-yl]-acetamide (136) as a white solid: 1H NMR (400 MHz, MeOD-d4) δ 8.41 (d, 1H), 8.27 (s, 1H), 8.21 (br, 1H), 7.93 (dd, 1H), 7.73 (m, 1H), 7.40 (dd, 1H), 7.30 (s, 1H), 4.52 (s, 2H), 4.45-4.37 (m, 1H), 4.19-4.15 (br, 2H), 3.87-3.78 (br, 2H), 2.37-2.19 (m, 2H), 2.20-2.15 (m, 1H), 1.40 (d, 6H), 1.25 (d, 6H); ESMS m/z 656.2 (M+H+).
Reaction SMILES: C([O:3][C:4](=[O:32])[CH2:5][S:6][C:7]1[S:11][C:10]([NH:12][C:13]([N:15]([C:24]2[CH:29]=[CH:28][C:27]([F:30])=[C:26]([F:31])[CH:25]=2)[CH2:16][CH:17]2[CH2:22][CH2:21][CH:20]([CH3:23])[CH2:19][CH2:18]2)=[O:14])=[N:9][CH:8]=1)C.C1(CN(C2C=CC(S(C)(=O)=O)=CC=2)C(=O)NC2SC=C(CC(O)=O)N=2)CCCC1.CC1CCC(CNC2C=CC(F)=C(F)C=2)CC1.C(OC(=O)CSC1SC(N)=NC=1)C>>[F:31][C:26]1[CH:25]=[C:24]([N:15]([CH2:16][CH:17]2[CH2:18][CH2:19][CH:20]([CH3:23])[CH2:21][CH2:22]2)[C:13](=[O:14])[NH:12][C:10]2[S:11][C:7]([S:6][CH2:5][C:4]([OH:32])=[O:3])=[CH:8][N:9]=2)[CH:29]=[CH:28][C:27]=1[F:30]
Reactant: CCOC(=O)CSc1cnc(NC(=O)N(CC2CCC(C)CC2)c2ccc(F)c(F)c2)s1
Agent: CC1CCC(CNc2ccc(F)c(F)c2)CC1
Agent: CCOC(=O)CSc1cnc(N)s1
Agent: CS(=O)(=O)c1ccc(N(CC2CCCC2)C(=O)Nc2nc(CC(=O)O)cs2)cc1
Product: CC1CCC(CN(C(=O)Nc2ncc(SCC(=O)O)s2)c2ccc(F)c(F)c2)CC1

Procedure:
The title compound was prepared via {2-[3-(3,4-difluoro-phenyl)-3-(4-methyl-cyclohexylmethyl)-ureido]-thiazol-5-ylsulfanyl}-acetic acid ethyl ester in a similar manner as described for the synthesis of {2-[3-cyclopentylmethyl-3-(4-methanesulfonyl-phenyl)-ureido]-thiazol-4-yl}-acetic acid, using 4-methyl-cyclohexylmethyl-(3,4-difluorophenyl)-amine and (2-amino-thiazol-5-ylsulfanyl)acetic acid ethyl ester.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:36])[CH:5]([O:31][CH2:32][CH2:33][CH:34]=[CH2:35])[CH:6]([C:8]1[CH:13]=[C:12]([CH3:14])[C:11]([O:15][CH2:16][CH2:17][C:18]2[N:19]=[C:20]([C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=3)[O:21][C:22]=2[CH3:23])=[C:10]([CH3:30])[CH:9]=1)[OH:7])[CH3:2].C(N(CC)CC)C.[CH3:44][S:45](Cl)(=[O:47])=[O:46]>ClCCl>[CH2:1]([O:3][C:4](=[O:36])[CH:5]([O:31][CH2:32][CH2:33][CH:34]=[CH2:35])[CH:6]([C:8]1[CH:13]=[C:12]([CH3:14])[C:11]([O:15][CH2:16][CH2:17][C:18]2[N:19]=[C:20]([C:24]3[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=3)[O:21][C:22]=2[CH3:23])=[C:10]([CH3:30])[CH:9]=1)[O:7][S:45]([CH3:44])(=[O:47])=[O:46])[CH3:2]
Reactant: CS(=O)(=O)Cl
Reactant: C=CCCOC(C(=O)OCC)C(O)c1cc(C)c(OCCc2nc(-c3ccccc3)oc2C)c(C)c1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: C=CCCOC(C(=O)OCC)C(OS(C)(=O)=O)c1cc(C)c(OCCc2nc(-c3ccccc3)oc2C)c(C)c1
Temperature: 25 °C

Procedure:
To a solution of 2-but-3-enyloxy-3-{3,5-dimethyl-4-[2-(5-methyl-2-phenyl-oxazol-4-yl)-ethoxy]-phenyl}-3-hydroxy-propionic acid ethyl ester (150 mg, 0.3 mmol) in dichloromethane (2 ml) at 0° C. was added successively triethylamine (55 μl, 0.4 mmol) and methanesulfonic acid chloride (42 μl, 0.36 mmol). The reaction was allowed to warm to ambient temperature over night and then quenched by the addition of sat. NaHCO3. The layers were separated and the aqueous phase was extracted two times with dichloromethane. The combined organic layers were dried over sodium sulfate and concentrated in vacuo to afford crude 2-but-3-enyloxy-3-{3,5-dimethyl-4-[2-(5-methyl-2-phenyl-oxazol-4-yl)-ethoxy]-phenyl}-3-methanesulfonyloxy-propionic acid ethyl ester which was dissolved in THF (2 ml). DBU (139 μl, 0.9 mmol) was added at ambient temperature and the mixture was stirred for 8 h at 50° C. The reaction was quenched by the addition of water, the layers were separated, and the aqueous phase was extracted two times with dichloromethane. The combined organic layers were dried over sodium sulfate, and the solvent was removed under reduced pressure to afford a brown oil which was purified by column chromatography (silica gel, hexane/AcOEt=9/1) to give 79 mg (0.166 mmol, 55%) of the title compound as bright yellow oil and 29 mg (61 μmol, 20%) 2E-but-3-enyloxy-3-{3,5-dimethyl-4-[2-(5-methyl-2-phenyl-oxazol-4-yl)-ethoxy]-phenyl}-acrylic acid ethyl ester as bright yellow oil.
Reaction SMILES: I[C:2]#[C:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][OH:9].[CH3:10][Si:11]([C:14]#[CH:15])([CH3:13])[CH3:12].C(NC(C)C)(C)C>C1COCC1.CCOCC.[Cu](I)I>[CH3:10][Si:11]([CH3:13])([CH3:12])[C:14]#[C:15][C:2]#[C:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][OH:9]
Reactant: OCCCCCC#CI
Reactant: C#C[Si](C)(C)C
Agent: I[Cu]I
Solvent: CCOCC
Solvent: CC(C)NC(C)C
Solvent: C1CCOC1
Product: C[Si](C)(C)C#CC#CCCCCCO
Temperature: 25 °C
Reaction time: 1 h
Yield: 57.1 %

Procedure:
To a solution of 7-iodo-6-heptynol (100 mg, 0.42 mmol), trimethylsilylacetylene (0.072 ml, 0.5 mmol), diphenyldichloropaladium (10 mg) and copper iodide (3 mg) in 5 ml of THF was added diisopropylamine (0.150 ml) at rt in argon atmosphere. After stirring 1 hr at rt, the mixture was diluted with ether, washed with NH4Cl solution, water and brine, dried over MgSO4 and concentrated. Purification by silica gel chromatography (hexanes:ethyl acetate=4:1) gave 50 mg of product (50% yield).