Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([C:8]([OH:10])=[S:9])[S:5][C:6]=1[CH3:7].S(Cl)(Cl)=O.[CH3:15]O>>[Br:1][C:2]1[CH:3]=[C:4]([C:8]([O:10][CH3:15])=[S:9])[S:5][C:6]=1[CH3:7]
Reactant: Cc1sc(C(O)=S)cc1Br
Reactant: CO
Solvent: O=S(Cl)Cl
Product: COC(=S)c1cc(Br)c(C)s1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 19 %

Procedure:
To a stirred solution of 4-bromo-5-methylthiothiophene-2-carboxylic acid (87 mmol), prepared according to the procedure of Kleemann, et al., EP 0676395A2, in dry methanol (750 mL) was added thionyl chloride (7 mL, 96 mmol) dropwise. After stirring for 10 min at room temperature, the solution was heated to reflux and stirred 7.5 h. The solution was cooled and the solvents were removed in vacuo. The resulting solid was dissolved in dichloromethane (1500 mL) and washed with saturated sodium bicarbonate (2×300 mL), water (300 mL), saturated brine (300 mL), and dried over anhydrous sodium sulfate. The solvents were removed in vacuo. The resulting solid was recrystallized twice from hexane/ethyl acetate to give methyl 4-bromo-5-methylthiothiophene-2-carboxylate (4.4 g, 19%). 1H-NMR (CDCl3, 400 MHz) δ7.66 (s, 1H), 3.90 (s, 3H), 2.60 (s, 3H).
Reaction SMILES: [NH2:1][C:2]1[CH:11]=[C:10]([O:12][CH2:13][CH2:14][O:15][CH3:16])[C:9]([O:17][CH3:18])=[CH:8][C:3]=1[C:4](OC)=[O:5].Cl.[CH:20](N)=[NH:21]>C(N)=O>[CH3:18][O:17][C:9]1[CH:8]=[C:3]2[C:2](=[CH:11][C:10]=1[O:12][CH2:13][CH2:14][O:15][CH3:16])[N:1]=[CH:20][NH:21][C:4]2=[O:5]
Reactant: N=CN
Reactant: COCCOc1cc(N)c(C(=O)OC)cc1OC
Agent: Cl
Solvent: NC=O
Product: COCCOc1cc2nc[nH]c(=O)c2cc1OC
Temperature: 140 °C
Yield: 73.6 %

Procedure:
According to the procedure described in Example 6A Step 4, a mixture of methyl 2-amino-5-methoxy-4-(2-methoxyethoxy)benzoate (2.69 g, 10.5 mmol) and formamidine hydrochloride (1.208 g, 15 mmol) in formamide (10 mL) was heated at 140° C. for 8 hours, to afford 6-methoxy-7-(2-methoxyethoxy)quinazolin-4(3H)-one as a white solid (1.935 g, 74%). 1H NMR (300 MHz, DMSO-d6) δ 12.1 (br, 1H), 7.98 (s, 1H), 7.44 (s, 1H), 7.14 (s, 1H), 4.23 (t, 2H), 3.87 (s, 3H), 3.72 (t, 2H), 3.32 (s, 3H); LC-MS (ESI) m/z 251 (M+H)+.
Reaction SMILES: [C:1]([CH:9]([CH2:14][CH2:15][C:16]([OH:18])=[O:17])[CH2:10][C:11](O)=[O:12])([CH2:4][C:5]([CH3:8])([CH3:7])[CH3:6])([CH3:3])[CH3:2].CS(O)(=O)=[O:21].[OH:24][OH:25]>>[C:1]([CH:9]([CH2:14][CH2:15][C:16]([O:18][OH:21])=[O:17])[CH2:10][C:11]([O:24][OH:25])=[O:12])([CH2:4][C:5]([CH3:8])([CH3:7])[CH3:6])([CH3:3])[CH3:2]
Reactant: CC(C)(C)CC(C)(C)C(CCC(=O)O)CC(=O)O
Reactant: OO
Reactant: CS(=O)(=O)O
Product: CC(C)(C)CC(C)(C)C(CCC(=O)OO)CC(=O)OO

Procedure:
β-t-octyladipic acid (86.1 g, 0.33 mol) was powdered using a mortar and pestle and added to a beaker containing 98% methanesulfonic acid. The resultant suspension was cooled to 20° C. and 70% hydrogen peroxide was added slowly with constant stirring to maintain the temperature just below 40° C. After the addition was complete (about one-half hour) the suspension was stirred at room temperature for 1 hour after which the resultant clear solution was poured into 500 ml of cold distilled water, and extracted with dichloromethane (3×100 ml). The dichloromethane solution was washed with distilled water (2×50 ml), dried over anhydrous magnesium sulfate after which the solvent was removed on a rotary evaporator to provide a clear oil. Storage of the oil in a stoppered flask overnight at 0.5° C. resulted in crystallization of β-t-octyldiperoxyadipic acid as a white brittle solid (83.4 g,; mp 60°-62° C.; % AvO=9.3, theory 11.0; HPLC, C18ODS column, 70% methanol solent, retention time: 6.3 min., diperoxy-acid, relative peak area 76%; 7.4 min, monoperoxyacid, relative peak area 24%.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[C:6]([Br:8])[CH:5]=[C:4]([CH2:9]Br)[C:3]=1[O:11][CH3:12].[C-:13]#[N:14].[Na+]>C(O)C.O>[Br:1][C:2]1[CH:7]=[C:6]([Br:8])[CH:5]=[C:4]([CH2:9][C:13]#[N:14])[C:3]=1[O:11][CH3:12]
Reactant: [C-]#N
Reactant: COc1c(Br)cc(Br)cc1CBr
Agent: [Na+]
Solvent: CCO
Solvent: O
Product: COc1c(Br)cc(Br)cc1CC#N
Temperature: 0 °C
Reaction time: 0.08 h

Procedure:
A solution of the product of stage (c) (183 g) in ethanol (150 ml) was heated to reflux. A solution of sodium cyanide (25 g) in hot water (50 ml) was added which maintained gentle refluxing. The mixture was then stirred for 5 minutes, poured into ice water, and the product was filtered off, taken up in dichloromethane, washed with water, dried over magnesium sulphate and filtered. The solvent was removed to give a brown oil which slowly crystallised. Recrystallisation from petroleum ether gave the title product as colourless needles, mp 87°-88° C.
Reaction SMILES: [NH2:1][C:2]1[N:6]([C:7]2[C:12]([Cl:13])=[CH:11][CH:10]=[CH:9][C:8]=2[Cl:14])[N:5]=[C:4]([CH:15]([CH3:17])[CH3:16])[C:3]=1[C:18]([NH2:20])=[O:19].[OH:21][C:22]1[CH:27]=[CH:26][C:25]([CH2:28][C:29](OCC)=O)=[CH:24][CH:23]=1.CC[O-].[Na+].CC(O)=O>CCO>[Cl:14][C:8]1[CH:9]=[CH:10][CH:11]=[C:12]([Cl:13])[C:7]=1[N:6]1[C:2]2[N:1]=[C:29]([CH2:28][C:25]3[CH:26]=[CH:27][C:22]([OH:21])=[CH:23][CH:24]=3)[NH:20][C:18](=[O:19])[C:3]=2[C:4]([CH:15]([CH3:16])[CH3:17])=[N:5]1
Reactant: CCOC(=O)Cc1ccc(O)cc1
Reactant: CC(C)c1nn(-c2c(Cl)cccc2Cl)c(N)c1C(N)=O
Agent: CC[O-]
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CCO
Product: CC(C)c1nn(-c2c(Cl)cccc2Cl)c2nc(Cc3ccc(O)cc3)[nH]c(=O)c12
Temperature: 25 °C
Yield: 75.7 %

Procedure:
To a suspension of 5-amino-1-(2,6-dichlorophenyl)-3-isopropyl-1H-pyrazole-4-carboxylic acid amide (5.0 g, 16 mmol) in EtOH (20 mL) was added ethyl 4-hydroxyphenylacetate (8.6 g, 48 mmol) followed by NaOEt (2.66M in EtOH, 36 mL, 96 mmol). The reaction was then heated to reflux for 3 h. The reaction was then cooled to room temp and poured onto 10% aq. HOAc (100 mL). The resulting suspension was then cooled to 0° C. and filtered. The precipitate was then washed with 1:1 MeOH/H2O (100 mL) and 1:1 Et2O/hexane (75 mL). The solid was then dried under vacuum to yield the desired product (5.2 g, 76%).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[C:9]([N:11]1[CH2:16][CH2:15][N:14]2[CH:17]=[CH:18][N:19]=[C:13]2[CH2:12]1)=[O:10].C1C(=O)N([Br:27])C(=O)C1>CN(C)C=O>[Br:27][C:17]1[N:14]2[CH2:15][CH2:16][N:11]([C:9]([C:3]3[CH:4]=[CH:5][C:6]([F:8])=[CH:7][C:2]=3[Cl:1])=[O:10])[CH2:12][C:13]2=[N:19][CH:18]=1
Reactant: O=C(c1ccc(F)cc1Cl)N1CCn2ccnc2C1
Reactant: O=C1CCC(=O)N1Br
Solvent: CN(C)C=O
Product: O=C(c1ccc(F)cc1Cl)N1CCn2c(Br)cnc2C1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
7-[(2-Chloro-4-fluorophenyl)carbonyl]-5,6,7,8-tetrahydroimidazo[1,2-a]pyrazine (I21) (300 mg, 1.073 mmol) was dissolved in N,N-dimethylformamide (DMF) (2 mL) and treated with NBS (200 mg, 1.126 mmol). The solution was stirred at 25° C. for 16 h. The solvents were removed in vacuo and the residue purified by MDAP (High pH method) to afford desired product in 210 mg.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[C:9]1[CH:10]=[C:11]2[C@@H:22]3[CH2:23][N:24]([C:27]([O:29][C:30]([CH3:33])([CH3:32])[CH3:31])=[O:28])[CH2:25][CH2:26][C@@H:21]3[N:13]3[CH2:14][C:15](=O)[N:16]([CH3:19])[C:17]([CH:18]=1)=[C:12]23.B.C1COCC1.CC1C=CC=CC=1C.C=CCCCCCC>C1COCC1>[Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[C:9]1[CH:10]=[C:11]2[C@@H:22]3[CH2:23][N:24]([C:27]([O:29][C:30]([CH3:33])([CH3:32])[CH3:31])=[O:28])[CH2:25][CH2:26][C@@H:21]3[N:13]3[CH2:14][CH2:15][N:16]([CH3:19])[C:17]([CH:18]=1)=[C:12]23
Reactant: CN1C(=O)CN2c3c(cc(-c4ccc(Cl)cc4Cl)cc31)[C@@H]1CN(C(=O)OC(C)(C)C)CC[C@@H]12
Agent: B
Solvent: Cc1ccccc1C
Solvent: C1CCOC1
Solvent: C=CCCCCCC
Product: CN1CCN2c3c(cc(-c4ccc(Cl)cc4Cl)cc31)[C@@H]1CN(C(=O)OC(C)(C)C)CC[C@@H]12
Temperature: 25 °C
Yield: 50.2 %

Procedure:
To a solution of tert-butyl (6bR,10aS)-5-(2,4-dichlorophenyl)-3-methyl-2-oxo-2,3,6b,9,10,10a-hexahydro-1H-pyrido[3′,4′:4,5]pyrrolo[1,2,3-de]quinoxaline-8(7H)-carboxylate (100 mg, 0.21 mmol) in THF (5.0 mL), BH3-THF (1M in THF) (0.82 mL, 0.82 mmol) was added dropwise. After addition was completed, the resulting reaction mixture was refluxed for 4 h, cooled to room temperature, and quenched cautiously with water (1.0 mL). The mixture was evaporated to dryness under reduced pressure and the residue obtained was treated with o-xylene (10 mL) and 1-octene (5 mL) and heated at reflux for 4 h. The reaction mixture was cooled to room temperature and concentrated to dryness under reduced pressure to give tert-butyl (6bR,10aS)-5-(2,4-dichlorophenyl)-3-methyl-2,3,6b,9,10,10a-hexahydro-1H-pyrido[3′,4′:4,5]pyrrolo[1,2,3-de]quinoxaline-8(7H)-carboxylate as a white solid (50 mg, 58%).
Reaction SMILES: [CH:1]([NH:4]C(C)C)(C)[CH3:2].C([Li])CCC.C(#N)C.[Br:16][C:17]1[CH:24]=[CH:23][C:20]([C:21]#[N:22])=[CH:19][CH:18]=1>O1CCCC1.O>[NH2:22][C:21]([C:20]1[CH:23]=[CH:24][C:17]([Br:16])=[CH:18][CH:19]=1)=[CH:2][C:1]#[N:4]
Reactant: CC(C)NC(C)C
Reactant: N#Cc1ccc(Br)cc1
Agent: [Li]CCCC
Solvent: O
Solvent: C1CCOC1
Solvent: CC#N
Product: N#CC=C(N)c1ccc(Br)cc1
Temperature: 0 °C
Reaction time: 0.33 h
Yield: 92.7 %

Procedure:
An oven dried flask was charged with 300 mL of tetrahydrofuran and diisopropylamine (31.4 mL, 223 mmol) and cooled to 0° C. under nitrogen. To the reaction mixture was then added butyl lithium (2.5 M in hexanes) (79.1 mL, 198 mmol) slowly by syringe over 10 minutes. The reaction mixture was then allowed to stir at 0° C. for 20 minutes. The reaction mixture was then cooled to −78° C. and acetonitrile (10.8 mL, 206 mmol) was added slowly over 5 minutes. The reaction mixture was allowed to stir for 10 minutes before 4-bromobenzonitrile (30.0 g, 165 mmol) was added as a solution in 100 mL of tetrahydrofuran over 10 minutes. The reaction mixture was allowed to proceed at −78° C. for an additional 10 minutes before being allowed to slowly warm to ambient temperature and proceed overnight. The reaction mixture was cooled to 0° C. and 200 mL of water was slowly added. The reaction mixture was stirred for 10 minutes and the solids were collected by means of vacuum filtration and dried under high vacuum. The solids were suspended in dichloromethane and the resulting solids were collected by means of vacuum filtration to obtain 3-amino-3-(4-bromophenyl)acrylonitrile (34.2 g, 153 mmol, 93.0% yield). MS (apci) m/z=222.0 (M−H).
Reaction SMILES: [Cl:1][C:2]1[N:3]=[C:4]([C:9]([OH:11])=O)[NH:5][C:6]=1[CH2:7][CH3:8].S(Cl)(Cl)=O.[NH2:16][C:17]1[CH:37]=[CH:36][C:20]2[N:21]([CH2:25][C:26]3[CH:35]=[CH:34][C:29]([C:30]([O:32][CH3:33])=[O:31])=[CH:28][CH:27]=3)[CH2:22][CH2:23][O:24][C:19]=2[CH:18]=1>N1C=CC=CC=1>[Cl:1][C:2]1[N:3]=[C:4]([C:9]([NH:16][C:17]2[CH:37]=[CH:36][C:20]3[N:21]([CH2:25][C:26]4[CH:35]=[CH:34][C:29]([C:30]([O:32][CH3:33])=[O:31])=[CH:28][CH:27]=4)[CH2:22][CH2:23][O:24][C:19]=3[CH:18]=2)=[O:11])[NH:5][C:6]=1[CH2:7][CH3:8]
Reactant: COC(=O)c1ccc(CN2CCOc3cc(N)ccc32)cc1
Reactant: CCc1[nH]c(C(=O)O)nc1Cl
Solvent: O=S(Cl)Cl
Solvent: c1ccncc1
Product: CCc1[nH]c(C(=O)Nc2ccc3c(c2)OCCN3Cc2ccc(C(=O)OC)cc2)nc1Cl
Yield: 70.3 %

Procedure:
The same operation as in Example (91c) was performed using 4-chloro-5-ethyl-1H-imidazole-2-carboxylic acid (0.21 g, 1.2 mmol), thionyl chloride (2 mL), methyl 4-[(7-amino-2,3-dihydro-4H-1,4-benzoxazin-4-yl)methyl]benzoate obtained in Example (101b) (0.28 g, 0.97 mmol) and pyridine (5 mL). The resulting solid was washed with dichloromethane/hexane=1/1 to obtain 0.31 g of the title compound as a light yellow solid (70%).
Reaction SMILES: Cl[C:2]1[CH:11]=[C:10]2[C:5]([CH:6]=[C:7]([C:14]3[CH:15]=[C:16]([NH:21][C:22](=[O:33])[C:23]4[CH:28]=[CH:27][CH:26]=[C:25]([C:29]([F:32])([F:31])[F:30])[CH:24]=4)[CH:17]=[CH:18][C:19]=3[CH3:20])[C:8](=[O:13])[N:9]2[CH3:12])=[CH:4][N:3]=1.[CH3:34][N:35]1[CH2:40][CH2:39][N:38]([C:41]2[CH:42]=[C:43]([NH2:47])[CH:44]=[CH:45][CH:46]=2)[CH2:37][CH2:36]1.[Cl-].C(C1C=CC=C(CCC)C=1[N+]1C=CN(C2C(CCC)=CC=CC=2CCC)C=1)CC>O1CCOCC1>[CH3:20][C:19]1[CH:18]=[CH:17][C:16]([NH:21][C:22](=[O:33])[C:23]2[CH:28]=[CH:27][CH:26]=[C:25]([C:29]([F:30])([F:31])[F:32])[CH:24]=2)=[CH:15][C:14]=1[C:7]1[C:8](=[O:13])[N:9]([CH3:12])[C:10]2[C:5]([CH:6]=1)=[CH:4][N:3]=[C:2]([NH:47][C:43]1[CH:44]=[CH:45][CH:46]=[C:41]([N:38]3[CH2:37][CH2:36][N:35]([CH3:34])[CH2:40][CH2:39]3)[CH:42]=1)[CH:11]=2
Reactant: CN1CCN(c2cccc(N)c2)CC1
Reactant: Cc1ccc(NC(=O)c2cccc(C(F)(F)F)c2)cc1-c1cc2cnc(Cl)cc2n(C)c1=O
Agent: CCCc1cccc(CCC)c1-n1cc[n+](-c2c(CCC)cccc2CCC)c1
Agent: [Cl-]
Solvent: C1COCCO1
Product: Cc1ccc(NC(=O)c2cccc(C(F)(F)F)c2)cc1-c1cc2cnc(Nc3cccc(N4CCN(C)CC4)c3)cc2n(C)c1=O
Reaction time: 14 h

Procedure:
N-[3-(7-Chloro-1-methyl-2-oxo-1,2-dihydro-[1,6]naphthyridin-3-yl)-4-methyl-phenyl]-3-trifluoromethyl-benzamide (50 mg, 0.106 mmol) is mixed with 3-(4-Methyl-piperazin-1-yl)-phenylamine (31 mg, 0.16 mmol), Pd2(dba)2 (2.4 mg, 2.5%), 1,3-Bis(2,6-di-1-propylphenyl)imidazolium chloride (2.3 mg, 5%) and potassium tert-butanoxide (17.8 mg, 0.159 mmol) under an argon environment. 6 mL of anhydrous 1,4-dioxane is added and the reaction is continued at 100° C. for 14 hours. After cooling and removal of solvent under vacuum, the crude product is dissolved in DMSO and purified by reverse phase preparative HPLC to give the final product as a pale solid: 1H NMR 400 MHz (DMSO-d6) δ 10.47 (s, 1H), 9.43 (s, 1H), 8.58 (s, 1H), 8.30 (s, 1H), 8.26 (d, 1H, J=8.1 Hz), 7.21 (d, 1H, J=7.9 Hz), 7.83 (s, 1H), 7.79 (t, 1H, J=7.8 Hz), 7.69 (m, 2H), 7.37 (s, 1H), 7.21 (m, 3H), 6.74 (s, 1H), 6.65 (d, 1H, J=6.5 Hz), 3.80 (d, 2H, J=13.9 Hz), 3.56 (s, 3H), 3.54 (d, 2H, J=13.9 Hz), 3.18 (m, 2H), 2.98 (m, 2H), 2.88 (d, 3H, J=3.8 Hz), 2.14 (s, 3H); MS m/z 627.3 (M+1).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([O:8][CH2:9][CH3:10])=[CH:4][CH:3]=1.[Mg].Cl[CH:13]([SiH3:15])Cl.[CH3:16][Mg]Cl>O1CCCC1.O>[CH2:9]([O:8][C:5]1[CH:6]=[CH:7][C:2]([SiH:15]([CH3:13])[CH3:16])=[CH:3][CH:4]=1)[CH3:10]
Reactant: C[Mg]Cl
Reactant: [SiH3]C(Cl)Cl
Reactant: CCOc1ccc(Br)cc1
Agent: [Mg]
Solvent: C1CCOC1
Solvent: O
Product: CCOc1ccc([SiH](C)C)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 91.1 %

Procedure:
A Grignard solution prepared from 481.4 g of 4-bromophenetole, 61.0 g of magnesium and 1820 ml of tetrahydrofuran is added dropwise at -40 ° C. to a solution of 316 g of dichloromethylsilane in 1450 ml cf anhydrous tetrahydrofuran. Stirring is subsequently continued for 1 hour at -40 ° C., and the mixture is allowed to slowly warm to room temperature. After 1175 ml of a 3M methylmagnesium chloride solution in tetrahydrofuran have been added, the mixture is refluxed for 1 hour and cooled to 30 ° C., and the excess Grignard reagent is decomposed by the dropwise addition of 1100 ml of water. The phases are separated, and the aqueous phase is extracted using 500 ml of tetrahydrofuran. The combined organic phases are freed from solvent in vacuo, and the crude product is distilled in a thin-layer evaporator. 417 g of crude product of a purity of 94.3% (GC) are obtained, which corresponds to a yield of 91.1% of theory. The boiling point at 0.012 bar is 78° to 82 ° C.
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6]([C:9]2[CH:10]=[N:11][N:12]([C:15]3[CH:23]=[CH:22][C:18]([C:19]([OH:21])=O)=[CH:17][N:16]=3)[C:13]=2[OH:14])=[C:5]([F:24])[CH:4]=1)#[N:2].[CH3:25][O:26][CH2:27][CH2:28][C:29]1([NH2:32])[CH2:31][CH2:30]1>>[C:1]([C:3]1[CH:8]=[CH:7][C:6]([C:9]2[CH:10]=[N:11][N:12]([C:15]3[CH:23]=[CH:22][C:18]([C:19]([NH:32][C:29]4([CH2:28][CH2:27][O:26][CH3:25])[CH2:31][CH2:30]4)=[O:21])=[CH:17][N:16]=3)[C:13]=2[OH:14])=[C:5]([F:24])[CH:4]=1)#[N:2]
Reactant: N#Cc1ccc(-c2cnn(-c3ccc(C(=O)O)cn3)c2O)c(F)c1
Reactant: COCCC1(N)CC1
Product: COCCC1(NC(=O)c2ccc(-n3ncc(-c4ccc(C#N)cc4F)c3O)nc2)CC1

Procedure:
The title compound was prepared in a manner similar to Example 198 using 6-(4-(4-cyano-2-fluorophenyl)-5-hydroxy-1H-pyrazol-1-yl)nicotinic acid and 1-(2-methoxyethyl)cyclopropanamine 1H NMR (400 MHz, DMSO-d6) δ ppm 0.58-0.66 (m, 2 H) 0.66-0.73 (m, 2 H) 1.80 (t, J=6.9 Hz, 2 H) 3.14 (s, 3 H) 3.39 (t, J=7.1 Hz, 2 H) 7.61 (dd, J=8.2, 1.6 Hz, 1 H) 7.75 (dd, J=11.9, 1.5 Hz, 1 H) 8.14 (d, J=3.0 Hz, 1 H) 8.30 (dd, J=8.7, 2.1 Hz, 1 H) 8.40 (d, J=8.6 Hz, 1 H) 8.56 (t, J=8.0 Hz, 1 H) 8.76 (s, 1 H) 8.80 (d, J=1.5 Hz, 1H) 13.69 (br. s., 1 H). MS m/z 422 [M+H]+.
Reaction SMILES: [CH3:1][O:2][C:3]([CH2:5]P(OC)(OC)=O)=[O:4].C[Si]([N-][Si](C)(C)C)(C)C.[Na+].[CH:22]([C:24]1[CH:29]=[CH:28][C:27](/[C:30](/[C:40]2[CH:45]=[CH:44][C:43]([F:46])=[CH:42][CH:41]=2)=[C:31](\[C:34]2[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=2)/[CH2:32][CH3:33])=[CH:26][CH:25]=1)=O>C1COCC1.[Cl-].[Na+].O>[F:46][C:43]1[CH:42]=[CH:41][C:40]([C:30]([C:27]2[CH:26]=[CH:25][C:24]([CH:22]=[CH:5][C:3]([O:2][CH3:1])=[O:4])=[CH:29][CH:28]=2)=[C:31]([C:34]2[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=2)[CH2:32][CH3:33])=[CH:45][CH:44]=1
Reactant: CC/C(=C(\c1ccc(F)cc1)c1ccc(C=O)cc1)c1ccccc1
Reactant: COC(=O)CP(=O)(OC)OC
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Cl-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: CCC(=C(c1ccc(F)cc1)c1ccc(C=CC(=O)OC)cc1)c1ccccc1
Temperature: -78 °C
Reaction time: 0.25 h
Yield: 90.1 %

Procedure:
To a solution of trimethyl phosphonoacetate (412 mg, 2.26 mmol) in THF (15 mL) at 0° C. was added 1M sodium bis(trimethylsilyl)amide in THF (2.26 mL, 2.26 mmol) dropwise. After stirring 15 min the mixture was cooled to −78° C. and a solution of aldehyde (4) (625 mg, 1.89 mmol) in THF (8 mL) was added dropwise. The solution was allowed to warm to rt. After stirring 4 h, brine was added and the mixture was extracted with EtOAc. The combined organic layers were washed with water, brine, and dried (MgSO4). The solvent was removed under reduced pressure and the residue was chromatographed (silica gel, 7.5 to 15% EtOAc/hexanes) to give the ester (5) as a white solid (658 mg, 90%): 1 H NMR (CDCl3) δ 7.52 (d, J=16.1 Hz, 1 H), 7.15 (m, 11 H), 6.86 (d, J=8.1 Hz, 2 H), 6.28 (d, J=16.1 Hz, 1 H), 3.76 (s, 3 H), 2.47 (q, J=7.7 Hz, 2 H), 0.93 (t, J=7.7 Hz, 3 H); APcI m/z: 428 (M+H+CH3CN+, 100%).
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6](S(C)(=O)=O)[N:5]=[C:4]([N:12]2[C@H:17]([C:18]([F:21])([F:20])[F:19])[CH2:16][CH2:15][C@H:14]([C:22]([NH:24][CH:25]3[CH2:30][CH2:29][CH2:28][CH2:27][CH2:26]3)=[O:23])[CH2:13]2)[CH:3]=1.CCN(C(C)C)C(C)C.[CH3:40][O:41][C:42]1[CH:47]=[C:46]([O:48][CH3:49])[CH:45]=[CH:44][C:43]=1[CH2:50][NH2:51].CCOC(C)=O>O1CCOCC1>[CH3:40][O:41][C:42]1[CH:47]=[C:46]([O:48][CH3:49])[CH:45]=[CH:44][C:43]=1[CH2:50][NH:51][C:6]1[N:5]=[C:4]([N:12]2[C@H:17]([C:18]([F:21])([F:20])[F:19])[CH2:16][CH2:15][C@H:14]([C:22]([NH:24][CH:25]3[CH2:30][CH2:29][CH2:28][CH2:27][CH2:26]3)=[O:23])[CH2:13]2)[CH:3]=[C:2]([Cl:1])[N:7]=1
Reactant: CS(=O)(=O)c1nc(Cl)cc(N2C[C@@H](C(=O)NC3CCCCC3)CC[C@H]2C(F)(F)F)n1
Reactant: COc1ccc(CN)c(OC)c1
Solvent: CCOC(C)=O
Solvent: CCN(C(C)C)C(C)C
Solvent: C1COCCO1
Product: COc1ccc(CNc2nc(Cl)cc(N3C[C@@H](C(=O)NC4CCCCC4)CC[C@H]3C(F)(F)F)n2)c(OC)c1
Temperature: 60 °C
Reaction time: 8 h
Yield: 90.5 %

Procedure:
To cis-1-[6-chloro-2-(methylsulfonyl)-4-pyrimidinyl]-N-cyclohexyl-6-(trifluoromethyl)-3-piperidinecarboxamide (300 mg, 0.640 mmol) in 1,4-dioxane (8 mL) was added Hunig's base (0.22 mL, 1.28 mmol) followed by {[2,4-bis(methyloxy)phenyl]methyl}amine (0.19 mL, 1.28 mmol), and the reaction mixture was stirred overnight at 60° C. into a sealed tube. This reaction mixture was combined with another similar reaction mixture (˜⅓ the scale) before work up. The combined reaction mixtures were poured onto water and EtOAc. The layers were separated, and the aqueous layer was further extracted with EtOAc. The combined organic layers were washed with brine, dried (MgSO4), filtered and concentrated. Flash chromatography on SiO2 (gradient: 100% Hexanes to 50% EtOAc in Hexanes) afforded the title compound (322 mg) as a white foam. LC-MS (ES) m/z=556 [M+H]+.
Reaction SMILES: [F:1][C:2]([F:18])([F:17])[C:3]1[CH:8]=[CH:7][C:6]([C:9]2[CH:14]=[CH:13][N:12]=[C:11]([CH2:15][NH2:16])[N:10]=2)=[CH:5][CH:4]=1.[F:19][C:20]1[CH:25]=[CH:24][C:23]([S:26]([N:29]2[CH2:33][CH2:32][CH2:31][C@H:30]2[C:34](O)=[O:35])(=[O:28])=[O:27])=[CH:22][CH:21]=1.ON1C2C=CC=CC=2N=N1.CCN(CC)CC>CO.CN(C=O)C>[F:18][C:2]([F:1])([F:17])[C:3]1[CH:4]=[CH:5][C:6]([C:9]2[CH:14]=[CH:13][N:12]=[C:11]([CH2:15][NH:16][C:34]([C@@H:30]3[CH2:31][CH2:32][CH2:33][N:29]3[S:26]([C:23]3[CH:24]=[CH:25][C:20]([F:19])=[CH:21][CH:22]=3)(=[O:28])=[O:27])=[O:35])[N:10]=2)=[CH:7][CH:8]=1
Reactant: O=C(O)[C@@H]1CCCN1S(=O)(=O)c1ccc(F)cc1
Reactant: NCc1nccc(-c2ccc(C(F)(F)F)cc2)n1
Agent: On1nnc2ccccc21
Solvent: CCN(CC)CC
Solvent: CO
Solvent: CN(C)C=O
Product: O=C(NCc1nccc(-c2ccc(C(F)(F)F)cc2)n1)[C@@H]1CCCN1S(=O)(=O)c1ccc(F)cc1
Temperature: 25 °C
Reaction time: 12 h
Yield: 17.2 %

Procedure:
A mixture of C-[4-(4-trifluoromethyl-phenyl)-pyrimidin-2-yl]-methylamine (92 mg, 0.4 mmol), (S)-1-(4-fluoro-benzenesulfonyl)-pyrrolidine-2-carboxylic acid (99 mg, 0.4 mmol), N-(3-dimethylamniopropyl)-N′-ethylcarbodiimide hydrochloride (139 mg, 0.72 mmol), 1-hydroxybenzotriazole (98 mg, 0.73 mmol), Et3N (0.15 mL, 1.10 mmol), and DMF (2 mL) was stirred at rt for 12 hours. After 12 h, MeOH (0.5 mL) was added to the reaction mixture and resulting solution was purified by preparative reverse-phase HPLC to afford (35 mg, 19%) of a white solid. MS (ESI): mass calcd. for C23H20F4N4O3S, 508.1; m/z found, 509.5 [M+H]+. 1H NMR (500 MHz, CDCl3) δ 8.86 (d, J=5.3, 1H), 8.38 (d, J=8.1, 2H), 8.37-8.33 (m, 1H), 7.99-7.92 (m, 2H), 7.82 (d, J=8.2, 2H), 7.70 (d, J=5.3, 1H), 7.30-7.25 (m, 1H), 4.93-4.76 (m, 2H), 4.31-4.22 (m, 1H), 3.69 (td, J=7.3, 3.7, 1H), 3.25 (td, J=9.8, 6.7, 1H), 2.36-2.29 (m, 1H), 1.97-1.59 (m, 3H).
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][CH:9]=1)[CH:5]=[O:6].Cl.Cl[CH2:12][CH2:13][N:14]1[CH2:19][CH2:18][CH2:17][CH2:16][CH2:15]1>C(#N)C>[N:14]1([CH2:13][CH2:12][O:1][C:2]2[CH:3]=[C:4]([CH:7]=[CH:8][CH:9]=2)[CH:5]=[O:6])[CH2:19][CH2:18][CH2:17][CH2:16][CH2:15]1
Reactant: ClCCN1CCCCC1
Reactant: O=Cc1cccc(O)c1
Agent: Cl
Solvent: CC#N
Product: O=Cc1cccc(OCCN2CCCCC2)c1
Temperature: 25 °C
Yield: 60.7 %

Procedure:
To a mixture of 3-hydroxybenzaldehyde (5.42 g, 44.38 mmol), K2 CO3 (13.5 g) and acetonitrile was added N-(2-chloroethyl)piperidine hydrochloride (9.8 g). The reaction mixture was refluxed overnight, cooled to room temperature and filtered. The filtrate was stripped to give an oil which was partitioned between CHCl3 (350 ml) and 1M NaOH (200 ml). The organic layer was separated, washed with 1M NaOH (2×200 ml), treated with DARCO®, then MgSO4, filtered, and stripped to afford, as a dark oily liquid, 6.28 g of 3-[2-(1-piperdinyl)ethoxy]benzaldehyde.
Reaction SMILES: CCN(C(C)C)C(C)C.[CH2:10]([O:17][C:18]1[CH:19]=[C:20]([CH:24]=[C:25]([O:27][C@@H:28]([CH3:41])[CH2:29][O:30][Si:31]([CH:38]([CH3:40])[CH3:39])([CH:35]([CH3:37])[CH3:36])[CH:32]([CH3:34])[CH3:33])[CH:26]=1)[C:21](O)=[O:22])[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[NH2:66][C:67]1[CH:71]=[CH:70][N:69]([C:72]([O:74][C:75]([CH3:78])([CH3:77])[CH3:76])=[O:73])[N:68]=1>CN(C=O)C.O>[CH2:10]([O:17][C:18]1[CH:19]=[C:20]([CH:24]=[C:25]([O:27][C@@H:28]([CH3:41])[CH2:29][O:30][Si:31]([CH:38]([CH3:40])[CH3:39])([CH:32]([CH3:34])[CH3:33])[CH:35]([CH3:37])[CH3:36])[CH:26]=1)[C:21]([NH:66][C:67]1[CH:71]=[CH:70][N:69]([C:72]([O:74][C:75]([CH3:78])([CH3:77])[CH3:76])=[O:73])[N:68]=1)=[O:22])[C:11]1[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=1
Reactant: CC(C)(C)OC(=O)n1ccc(N)n1
Reactant: CC(C)[Si](OC[C@H](C)Oc1cc(OCc2ccccc2)cc(C(=O)O)c1)(C(C)C)C(C)C
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Solvent: O
Product: CC(C)[Si](OC[C@H](C)Oc1cc(OCc2ccccc2)cc(C(=O)Nc2ccn(C(=O)OC(C)(C)C)n2)c1)(C(C)C)C(C)C
Temperature: 25 °C
Reaction time: 8 h
Yield: 30.1 %

Procedure:
DIPEA (0.21 mL, 1.2 mmol) was added to a solution of 3-(benzyloxy)-5-{(1S)-1-methyl-2-[(triisopropylsilyl)oxy]ethoxy}benzoic acid (220 mg, 0.48 mmol), HATU (228 mg, 0.6 mmol), and tert-butyl 3-amino-1H-pyrazole-1-carboxylate (110 mg, 0.66 mmol) in DMF (2 mL) and the reaction mixture stirred at ambient temperature overnight. Water was added to the reaction mixture and extracted with ethyl acetate (3×25 mL). The combined organic extracts were separated and washed with 1M hydrochloric acid, saturated sodium hydrogen carbonate solution, saturated brine solution, dried (MgSO4), filtered and evaporated. The residue was purified by column chromatography on silica, eluting with 0% to 50% ethyl acetate in hexanes, to give a clear oil (90 mg)