Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([NH:4][CH:5]1[CH2:34][C:9]2=[CH:10][N:11]([S:16]([C:19]3[C:24]([CH:25]([CH3:27])[CH3:26])=[CH:23][C:22]([CH:28]([CH3:30])[CH3:29])=[CH:21][C:20]=3[CH:31]([CH3:33])[CH3:32])(=[O:18])=[O:17])[C:12]3[CH:13]=[CH:14][CH:15]=[C:7]([C:8]=32)[C:6]1=[O:35])(=[O:3])[CH3:2].[CH3:36][Mg]Br.[NH4+].[Cl-]>C1COCC1>[C:1]([NH:4][CH:5]1[CH2:34][C:9]2=[CH:10][N:11]([S:16]([C:19]3[C:20]([CH:31]([CH3:33])[CH3:32])=[CH:21][C:22]([CH:28]([CH3:29])[CH3:30])=[CH:23][C:24]=3[CH:25]([CH3:26])[CH3:27])(=[O:18])=[O:17])[C:12]3[CH:13]=[CH:14][CH:15]=[C:7]([C:8]=32)[C:6]1([OH:35])[CH3:36])(=[O:3])[CH3:2]
Reactant: CC(=O)NC1Cc2cn(S(=O)(=O)c3c(C(C)C)cc(C(C)C)cc3C(C)C)c3cccc(c23)C1=O
Reactant: C[Mg]Br
Agent: [Cl-]
Agent: [NH4+]
Solvent: C1CCOC1
Product: CC(=O)NC1Cc2cn(S(=O)(=O)c3c(C(C)C)cc(C(C)C)cc3C(C)C)c3cccc(c23)C1(C)O
Temperature: 25 °C
Reaction time: 4 h
Yield: 36 %

Procedure:
To a solution of 4-acetylamino-3,4-dihydro-1-(2,4,6-triisopropylphenylsulfonyl)-benz[cd]indol-5-one (3.57 g, 7.0 mmol) in THF (70 ml) was added, at 40° C. in argon streams, a solution of 1M methyl magnesium bromide in THF (8 equivalents relative to ketone compound). The mixture was warmed to room temperature, and stirred for 4 hours. The reaction mixture was added to an ice-cooled saturated aqueous solution of NH4Cl and the mixture was subjected to extraction with ethyl acetate. The extract was washed with an aqueous saline solution and, then, dried (anhydrous Na2SO4). The solvent was distilled off under reduced pressure. The residue was subjected to a silica gel column chromatography, eluting with n-hexane-ethyl acetate (1:2) to afford 1.27 g (36%) of the title compound as an amorphous crystalline product. 1H-NMR(CDCl3, 200MHz) δ: 1.09(d,J=7 Hz,12H), 1.25(d,J=7 Hz,6H), 1.95(s,3H), 2.7-3.0(m,2H), 3.24(dd,J=16, 5 Hz,1H), 4.14(hept,J=7 Hz,2H), 4.54(m,1H), 5.3-5.5(br,1H), 7.1-7.4(m,6H) ppm. IR(KBr):3390, 2965, 1660 cm-1. Anal: Calcd for C29H38N2O4S.H2O: C 65.88%, H 7.63%, N 5.30% Found; C 66.13%, H 7.28%, N 5.69%.
Reaction SMILES: C(N1C=CN=C1)(N1C=CN=C1)=O.[CH3:13][S:14]([CH2:17][CH2:18][C:19]([OH:21])=O)(=[O:16])=[O:15].S(C1C=CC(C)=CC=1)(O)(=O)=O.S(C1C=CC(C)=CC=1)(O)(=O)=O.[CH2:44]([N:51]1[CH2:55][C@@H:54]([F:56])[C@H:53]([NH2:57])[CH2:52]1)[C:45]1[CH:50]=[CH:49][CH:48]=[CH:47][CH:46]=1>C(#N)C>[CH2:44]([N:51]1[CH2:55][C@@H:54]([F:56])[C@H:53]([NH:57][C:19](=[O:21])[CH2:18][CH2:17][S:14]([CH3:13])(=[O:16])=[O:15])[CH2:52]1)[C:45]1[CH:46]=[CH:47][CH:48]=[CH:49][CH:50]=1
Reactant: CS(=O)(=O)CCC(=O)O
Reactant: N[C@@H]1CN(Cc2ccccc2)C[C@H]1F
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: CC#N
Product: CS(=O)(=O)CCC(=O)N[C@@H]1CN(Cc2ccccc2)C[C@H]1F
Temperature: 20 °C
Reaction time: 12 h

Procedure:
A suspension of 1,1′-carbonyldiimidazole (73.0 g, 441 mmol, 1.1 eq) in acetonitrile (3.3 L) was stirred at 20° C. until a clear solution was obtained. 3-(methylsulfonyl)propanoic acid (67.0 g, 440 mmol, 1.1 eq) was then added and the mixture was stirred at 25° C. for 3 hr. (3R,4R)-1-benzyl-4-fluoropyrrolidin-3-amine bis-tosylate (220 g, 400 mmol, 1.0 eq) was added and the mixture was stirred at 25° C. for 16 hr resulting in a fine white slurry. The solids were filtered off and the byproduct cake washed with acetonitrile (600 mL). The acetonitrile solution was then concentrated to a low stir volume and then taken up in EtOAc (2.0 L) and washed with 1 N aqueous sodium bicarbonate (1.3 L). The aqueous layer was back extracted with EtOAc (500 mL) and the combined EtOAc layers were washed with water (1.0 L). The resulting EtOAc solution was distilled to remove about 2.0 L of distillate and then displaced with 2-propanol under atmospheric conditions until the internal temperature rose to 78° C. while maintaining a total volume of 2 L. The batch was then cooled to 20° C. and granulated at 20° C. for 12 hr resulting in product crystallization. The desired product was isolated by filtration and the cake washed with 2-propanol (600 mL), then dried in an oven at 40° C. under reduced pressure for 12 hr. The title compound (108 g, 308 mmol) was isolated in 77% yield. 1H NMR (400 MHz, DMSO-d6) δ ppm 8.36 (br. d., J=7.0 Hz, 1 H) 7.37-7.29 (m, 4 H) 7.29-7.23 (m, 1 H) 4.90 (ddt, J=53.4, 5.3, 2×1.7 Hz, 1 H) 4.25 (dddd, J=26.4, 13.9, 7.0, 1.4 Hz, 1 H) 3.61 (d, J=13.2 Hz, 1 H) 3.57 (d, J=13.2 Hz, 1 H) 3.36-3.28 (m, 2 H) 3.03 (dd, J=9.3, 7.5 Hz, 1 H) 2.97 (s, 3 H) 2.80 (dd, J=24.0, 11.6 Hz, 1 H) 2.66 (ddd, J=30.6, 11.6, 5.3 Hz, 1 H) 2.57 (td, 2×7.7, 1.4 Hz, 2 H) 2.18 (dd, J=9.4, 6.7 Hz, 1 H). m/z (EI+) for C15H21FN2O3S 329.7 (M+H)+.
Reaction SMILES: [C:1]([C:3]1[CH:25]=[CH:24][C:6]([CH2:7][NH:8][C:9](=[O:23])[CH:10]([C:14]2[C:19]([F:20])=[CH:18][C:17]([OH:21])=[CH:16][C:15]=2[F:22])[O:11][CH2:12][CH3:13])=[CH:5][CH:4]=1)#[N:2].[C:26]1(B(O)O)[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1>>[C:1]([C:3]1[CH:4]=[CH:5][C:6]([CH2:7][NH:8][C:9](=[O:23])[CH:10]([C:14]2[C:15]([F:22])=[CH:16][C:17]([O:21][C:26]3[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=3)=[CH:18][C:19]=2[F:20])[O:11][CH2:12][CH3:13])=[CH:24][CH:25]=1)#[N:2]
Reactant: CCOC(C(=O)NCc1ccc(C#N)cc1)c1c(F)cc(O)cc1F
Reactant: OB(O)c1ccccc1
Product: CCOC(C(=O)NCc1ccc(C#N)cc1)c1c(F)cc(Oc2ccccc2)cc1F

Procedure:
In analogy to example 278.4 (RS)-N-(4-cyano-benzyl)-2-(2,6-difluoro-4-hydroxy-phenyl)-2-ethoxy-acetamide (example 293.2) was reacted with phenyl boronic acid to give (RS)-N-(4-cyano-benzyl)-2-(2,6-difluoro-4-phenoxy-phenyl)-2-ethoxy-acetamide. Light yellow solid. MS 423.1 ([M+H]+)
Reaction SMILES: CN([CH2:4][CH2:5]N(C)C)C.C([Li])(CC)C.[C:14]([Si:18]([O:21][CH2:22][C:23]1[CH:28]=[CH:27]C=[C:25]([F:29])[C:24]=1[F:30])([CH3:20])[CH3:19])([CH3:17])([CH3:16])[CH3:15].CI>C1COCC1>[C:14]([Si:18]([O:21][CH2:22][C:23]1[CH:28]=[CH:27][C:4]([CH3:5])=[C:25]([F:29])[C:24]=1[F:30])([CH3:20])[CH3:19])([CH3:17])([CH3:15])[CH3:16]
Reactant: CC(C)(C)[Si](C)(C)OCc1cccc(F)c1F
Reactant: CN(C)CCN(C)C
Agent: [Li]C(C)CC
Solvent: C1CCOC1
Solvent: CI
Product: Cc1ccc(CO[Si](C)(C)C(C)(C)C)c(F)c1F
Reaction time: 0.33 h
Yield: 105.3 %

Procedure:
To a solution of TMEDA (3.9 mL, 3.0 g, 26 mmol) in THF (33 mL) at −78° C. was added sec butyllithium (20 mL, 1.3 M in hexane, 26 mmol). After stirring for 20 minutes, a solution of tert-butyl-(2,3-difluoro-benzyloxy)-dimethyl-silane (6.0 g, 23 mmol) in 17 mL of THF was added dropwise. After stirring for 1 hour, the solution was added dropwise to a solution of methyl iodide (8 mL) in THF (40 mL) at −20° C. After stirring for 18 hours, the mixture was quenched with saturated aqueous NH4Cl, extracted 3× into ether, and the combined organic layers were dried over MgSO4, filtered and concentrated in vacuo, giving 6.6 g of tert-butyl-(2,3-difluoro-4-methyl-benzyloxy)-dimethyl-silane as a light yellow oil. 1H NMR (400 MHz, CDCl3) δ 7.07 (app. t, 1H, J=7.2 Hz), 6.89 (app. t, 1H, d=7.3 Hz), 4.74 (s, 2H), 2.26 (d, 3H, J=1.9 Hz), 0.87 (s, 9H), 0.07 (s, 6H) ppm.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:8]2[O:12][C:11]([C:13]([OH:15])=O)=[CH:10][CH:9]=2)[CH:5]=[CH:6][CH:7]=1.[CH2:16]([O:18][C:19](=[O:29])[CH2:20][O:21][C:22]1[CH:27]=[CH:26][CH:25]=[C:24]([NH2:28])[CH:23]=1)[CH3:17]>>[CH2:16]([O:18][C:19](=[O:29])[CH2:20][O:21][C:22]1[CH:27]=[CH:26][CH:25]=[C:24]([NH:28][C:13]([C:11]2[O:12][C:8]([C:4]3[CH:5]=[CH:6][CH:7]=[C:2]([Cl:1])[CH:3]=3)=[CH:9][CH:10]=2)=[O:15])[CH:23]=1)[CH3:17]
Reactant: O=C(O)c1ccc(-c2cccc(Cl)c2)o1
Reactant: CCOC(=O)COc1cccc(N)c1
Product: CCOC(=O)COc1cccc(NC(=O)c2ccc(-c3cccc(Cl)c3)o2)c1

Procedure:
Carboxylic acid (65) (67 mg, 0.3 mmol) was coupled to ethyl ester (64) (58 mg, 0.25 mmol) using Method C. The crude residue was purified by column chromatography eluting with a stepped gradient of 10-20% EtOAc in heptane to give the title compound.
Reaction SMILES: Cl[C:2]1[C:7]([N+:8]([O-:10])=[O:9])=[C:6]([NH:11][CH:12]([CH2:15][CH3:16])[CH2:13][CH3:14])[CH:5]=[C:4]([CH3:17])[N:3]=1.[CH3:18][C:19]1[CH:25]=[C:24]([CH3:26])[CH:23]=[C:22]([CH3:27])[C:20]=1[NH2:21]>CS(C)=O>[CH2:13]([CH:12]([NH:11][C:6]1[CH:5]=[C:4]([CH3:17])[N:3]=[C:2]([NH:21][C:20]2[C:22]([CH3:27])=[CH:23][C:24]([CH3:26])=[CH:25][C:19]=2[CH3:18])[C:7]=1[N+:8]([O-:10])=[O:9])[CH2:15][CH3:16])[CH3:14]
Reactant: Cc1cc(C)c(N)c(C)c1
Reactant: CCC(CC)Nc1cc(C)nc(Cl)c1[N+](=O)[O-]
Solvent: CS(C)=O
Product: CCC(CC)Nc1cc(C)nc(Nc2c(C)cc(C)cc2C)c1[N+](=O)[O-]
Temperature: 130 °C
Yield: 43.4 %

Procedure:
A mixture of (2-chloro-6-methyl-3-nitro-pyridin-4-yl)-(1-ethyl-propyl)-amine (250 mg, 0.97 mmol) and 2,4,6-trimethylaniline (262 mg, 1.94 mmol) in 4 ml of dry DMSO was heated at 130° C. overnight. The mixture was quenched with water and extracted with ethyl acetate. The organic layer was dried and concentrated to give a yellow oil. The oil was purified through silica gel column chromatography to give 150 mg (43%) of the title compound as yellow solid, mp 104–107° C. 1H NMR (CDCl3) δ 10.36 (s, 1H), 9.24 (d, 1H), 6.93 (s, 2H), 5.86 (s, 1H), 3.45 (m, 1H), 2.32 (s, 3H), 2.18 (s, 6H), 2.13 (s, 3H), 1.55–1.80 (m, 4H), 0.99 (t, 6H) ppm.
Reaction SMILES: [C:1]([C:3](=[CH:9][C:10]1[CH:15]=[CH:14][C:13]([CH2:16][CH2:17][CH3:18])=[CH:12][CH:11]=1)[C:4]([O:6][CH2:7]C)=[O:5])#[N:2].[Mg].Cl>CO>[C:1]([CH:3]([CH2:9][C:10]1[CH:15]=[CH:14][C:13]([CH2:16][CH2:17][CH3:18])=[CH:12][CH:11]=1)[C:4]([O:6][CH3:7])=[O:5])#[N:2]
Reactant: CCCc1ccc(C=C(C#N)C(=O)OCC)cc1
Agent: Cl
Agent: [Mg]
Solvent: CO
Product: CCCc1ccc(CC(C#N)C(=O)OC)cc1
Temperature: 30 °C
Reaction time: 6 h
Yield: 59 %

Procedure:
A mixture of 20.50 g (84.3 mmole) of the product of Part (i), 8.75 g magnesium turnings and 200 ml methanol was stirred under a nitrogen atmosphere for six hours with periodic cooling to maintain a temperature of about 30° C. The mixture was acidified with hydrochloric acid, extracted with ethyl ether, the extracts washed with sodium bicarbonate solution, water, brine and dried over MgSO4. Evaporation of solvent gave 23.8 g of crude product which was purified by column chromatography on silica gel, eluting with methylene chloride to provide 11.55 g (59%) of purified methyl 2-cyano-3-(4-n-propylphenyl)propionate. This was combined with 4.17 g sodium chloride, 175 ml dimethylsulfoxide and 5 ml water under nitrogen and the mixture heated at 150° C. for five hours. The reaction mixture was cooled, poured into 700 ml water and extracted with 2×500 ml ethyl acetate. The combined extracts were washed with brine (300 ml) dried over anhydrous sodium sulfate and concentrated in vacuo to give 12.5 g of the desired nitrile which was purified by distillation, b.p. 124°-128° C. (1.0 mm). 1H-NMR(CDCl3)ppm(delta): 0.75-1.15 (t, 3H), 1.30-2.00 (m, 2H), 2.40-3.10 (m, 6H), 7.15 (s, 4H).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([OH:10])[CH:6]=[C:7]([OH:9])[CH:8]=1.Br[CH2:12][C:13]([O:15][CH2:16][CH3:17])=[O:14].[H-].[Na+]>CN1CCCC1=O.C(OCC)(=O)C>[CH3:1][O:2][C:3]1[CH:8]=[C:7]([O:9][CH2:12][C:13]([O:15][CH2:16][CH3:17])=[O:14])[CH:6]=[C:5]([O:10][CH2:12][C:13]([O:15][CH2:16][CH3:17])=[O:14])[CH:4]=1
Reactant: COc1cc(O)cc(O)c1
Reactant: CCOC(=O)CBr
Agent: [H-]
Agent: [Na+]
Solvent: CN1CCCC1=O
Solvent: CCOC(C)=O
Product: CCOC(=O)COc1cc(OC)cc(OCC(=O)OCC)c1
Temperature: 25 °C
Reaction time: 3 h
Yield: 52.9 %

Procedure:
5.0 g (35.7 mmol) of 5-methoxybenzene-1,3-diol and then, after 10 minutes, 8.7 ml (78.5 mmol) of ethyl 2-bromoacetate are added to the suspension of 3.1 g (71.4 mmol) of sodium hydride (60% dispersion in oil) in 180 ml of 1-methyl-2-pyrrolidinone under argon. The mixture is stirred at ambient temperature for 3 hours. The reaction medium is diluted with ethyl acetate and washed with a saturated aqueous solution of potassium hydrogen sulphate and a saturated solution of sodium chloride and dried over sodium sulphate then concentrated to dryness. The crude product is purified by chromatography on silica gel (dichloromethane/ethyl acetate=95/5). 5.9 g (53%) of a colourless gum are obtained.
Reaction SMILES: [H-].[Na+].[Si:3]([O:10][CH2:11][CH2:12][CH2:13][NH:14][C:15]1[C:22]([F:23])=[CH:21][C:18]([C:19]#[N:20])=[C:17]([Cl:24])[N:16]=1)([C:6]([CH3:9])([CH3:8])[CH3:7])([CH3:5])[CH3:4].[CH3:25]I>CN(C=O)C>[Si:3]([O:10][CH2:11][CH2:12][CH2:13][N:14]([CH3:25])[C:15]1[C:22]([F:23])=[CH:21][C:18]([C:19]#[N:20])=[C:17]([Cl:24])[N:16]=1)([C:6]([CH3:8])([CH3:9])[CH3:7])([CH3:5])[CH3:4]
Reactant: CI
Reactant: CC(C)(C)[Si](C)(C)OCCCNc1nc(Cl)c(C#N)cc1F
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CN(CCCO[Si](C)(C)C(C)(C)C)c1nc(Cl)c(C#N)cc1F
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 105.5 %

Procedure:
Sodium hydride (0.11 g, 4.65 mmol) was added to a solution of 6-[(3-{[tert-butyl(dimethyl)-I4-silyl]oxy}propyl)amino]-2-chloro-5-fluoronicotinonitrile (Example 309, 0.80 g, 2.33 mmol) in DMF (23.26 mL). The mixture was stirred at rt for 30 min, and then MeI (0.58 mL, 9.30 mmol) added. The reaction mixture was stirred at rt for 18 h, quenched with water, and the aqueous phase was extracted with ether. The combined ether extracts were washed with water, brine, and then dried (MgSO4), filtered, and concentrated under reduced pressure. The product (0.88 g, 99%) was isolated after silica gel flash chromatography (2:1 hexanes/EtOAc). 1H NMR (400 MHz, CD3OD) δ 7.53 (d, 1H), 3.70-3.60 (m, 4H), 3.17 (d, 3H), 1.84-1.76 (m, 2H), 0.84 (s, 9H), 0.00 (s, 6H).
Reaction SMILES: [CH3:1][C:2]1([CH3:15])[C@@H:4]2[CH2:5][C:6]3[C:10]([C@H:3]12)=[C:9]([CH3:11])[S:8][C:7]=3[C:12]([OH:14])=O.[Li][CH3:17]>CCOCC>[CH3:15][C:2]1([CH3:1])[C@@H:4]2[CH2:5][C:6]3[C:10]([C@H:3]12)=[C:9]([CH3:11])[S:8][C:7]=3[C:12](=[O:14])[CH3:17]
Reactant: [Li]C
Reactant: Cc1sc(C(=O)O)c2c1[C@H]1[C@@H](C2)C1(C)C
Solvent: CCOCC
Product: CC(=O)c1sc(C)c2c1C[C@@H]1[C@H]2C1(C)C
Reaction time: 0.5 h
Yield: 74.9 %

Procedure:
To a solution of (1aS,5aR)-1,1,2-trimethyl-1,1a,5,5a-tetrahydro-3-thia-cyclopropa[a]pentalene-4-carboxylic acid (220 mg, 1.00 mmol) in Et2O (10 mL) is added a solution of MeLi (1.6 M, 1.4 mL, 2.10 mmol) in Et2O at such a pace that the reaction mixture is refluxing gently. Upon completion of the addition, stirring is continued at rt for 30 min. The reaction is quenched by adding sat. aq. NH4Cl (3 mL). The organic layer is separated, dried over Na2SO4 and the solvent is evaporated to give (1aS,5aR)-1-(1,1,2-trimethyl-1,1a,5,5a-tetrahydro-3-thia-cyclopropa[a]pentalen-4-yl)-ethanone (165 mg) as a pale yellow oil; LC-MS: tR=1.03 min, [M+1]+=221.20; 1H NMR (CDCl3): δ 3.00 (ddd, J=1.8, 4.7, 18.8 Hz, 1H), 2.80 (d, J=18.8 Hz, 1H), 2.38 (s, 6H), 1.93-1.90 (m, 2H), 1.14 (s, 3H), 0.74 (s, 3H).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([F:30])[C:5]([F:29])=[C:6]([C@:8]23[CH2:16][O:15][C@H:14]([C:17]([F:20])([F:19])[F:18])[C@H:13]2[CH2:12][S:11][C:10]([NH:21]C(=O)OC(C)(C)C)=[N:9]3)[CH:7]=1.[F:31][CH:32]([F:42])[C:33]1[N:34]=[CH:35][C:36]([C:39](O)=[O:40])=[N:37][CH:38]=1>>[NH2:21][C:10]1[S:11][CH2:12][C@@H:13]2[C@@H:14]([C:17]([F:20])([F:19])[F:18])[O:15][CH2:16][C@:8]2([C:6]2[CH:7]=[C:2]([NH:1][C:39]([C:36]3[CH:35]=[N:34][C:33]([CH:32]([F:42])[F:31])=[CH:38][N:37]=3)=[O:40])[CH:3]=[C:4]([F:30])[C:5]=2[F:29])[N:9]=1
Reactant: CC(C)(C)OC(=O)NC1=N[C@@]2(c3cc(N)cc(F)c3F)CO[C@H](C(F)(F)F)[C@H]2CS1
Reactant: O=C(O)c1cnc(C(F)F)cn1
Product: NC1=N[C@@]2(c3cc(NC(=O)c4cnc(C(F)F)cn4)cc(F)c3F)CO[C@H](C(F)(F)F)[C@H]2CS1

Procedure:
Synthesized from tert-butyl [(4aS,5S,7aS)-7a-(5-amino-2,3-difluorophenyl)-5-trifluoromethyl-4a,5,7,7a-tetrahydro-4H-furo[3,4-d][1,3]thiazin-2-yl]carbamate and 5-difluoromethyl-pyrazine-2-carboxylic acid according to the general procedure. 1H NMR (400 MHz, CDCl3) δ ppm 2.90 (dd, J=13.8, 3.7 Hz, 1H), 3.19 (dd, J=13.8, 2.7 Hz, 1H), 3.31-3.49 (m, 1H), 3.95 (d, J=7.6 Hz, 1H), 4.44-5.15 (m, 4H), 6.81 (t, J=55.8 Hz, 4H), 7.22-7.35 (m, 1H), 8.08 (ddd, J=11.2, 6.8, 2.7 Hz, 1H), 8.94 (s, 1H), 9.53 (s, 1H), 9.67 (s, 1H)
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[C:6]([C:8]([F:11])([F:10])[F:9])[CH:5]=[CH:4][C:3]=1[C:12]1[N:17]=[CH:16][N:15]=[C:14]([O:18][C:19]2[C:24]3[N:25]=[C:26]([NH:28][C:29](=[O:31])[CH3:30])[S:27][C:23]=3[CH:22]=[CH:21][CH:20]=2)[CH:13]=1.[C:32](OC(=O)C)(=[O:34])[CH3:33]>C1(C)C=CC=CC=1>[C:29]([NH:28][C:26]1[S:27][C:23]2[CH:22]=[CH:21][CH:20]=[C:19]([O:18][C:14]3[N:15]=[CH:16][N:17]=[C:12]([C:3]4[CH:4]=[CH:5][C:6]([C:8]([F:11])([F:9])[F:10])=[CH:7][C:2]=4[NH:1][C:32](=[O:34])[CH3:33])[CH:13]=3)[C:24]=2[N:25]=1)(=[O:31])[CH3:30]
Reactant: CC(=O)Nc1nc2c(Oc3cc(-c4ccc(C(F)(F)F)cc4N)ncn3)cccc2s1
Reactant: CC(=O)OC(C)=O
Solvent: Cc1ccccc1
Product: CC(=O)Nc1nc2c(Oc3cc(-c4ccc(C(F)(F)F)cc4NC(C)=O)ncn3)cccc2s1
Temperature: 25 °C

Procedure:
To a suspension of N-{4-[6-(2-amino-4-trifluoromethyl-phenyl)-pyrimidin-4-yloxy]-benzothiazol-2-yl}-acetamide, (Example 151), (0.20 g, 0.50 mmol) in toluene (10 mL) was added acetic anhydride (0.090 g, 0.80 mmol, Aldrich). The reaction mixture was heated at reflux for 3 h, allowed to cool to room temperature and concentrated in vacuum. The residue was dissolved in EtOAc (20 mL) and washed with satd NaHCO3 (2×20 mL), dried over Na2SO4, filtered and concentrated in vacuum. Purification by silica gel chromatography (1:1:0.5 CH2Cl2/hexanes/EtOAc) provided the title compound as an off-white solid. Mp: 259–261° C. MS (ESI, pos. ion) m/z: 488 (M+1).
Reaction SMILES: Cl[C:2]1[N:7]2[N:8]=[C:9]([C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=3[Cl:24])[C:10]([C:11]3[CH:16]=[CH:15][C:14]([Cl:17])=[CH:13][CH:12]=3)=[C:6]2[N:5]=[C:4]([CH3:25])[N:3]=1.C([Sn](CCCC)(CCCC)[C:31]([O:33][CH2:34][CH3:35])=[CH2:32])CCC>CN(C=O)C.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[Cl:24][C:19]1[CH:20]=[CH:21][CH:22]=[CH:23][C:18]=1[C:9]1[C:10]([C:11]2[CH:16]=[CH:15][C:14]([Cl:17])=[CH:13][CH:12]=2)=[C:6]2[N:5]=[C:4]([CH3:25])[N:3]=[C:2]([C:31]([O:33][CH2:34][CH3:35])=[CH2:32])[N:7]2[N:8]=1
Reactant: Cc1nc(Cl)n2nc(-c3ccccc3Cl)c(-c3ccc(Cl)cc3)c2n1
Reactant: C=C(OCC)[Sn](CCCC)(CCCC)CCCC
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: CN(C)C=O
Product: C=C(OCC)c1nc(C)nc2c(-c3ccc(Cl)cc3)c(-c3ccccc3Cl)nn12
Temperature: 100 °C
Yield: 48.5 %

Procedure:
To a mixture of 4-chloro-7-(2-chlorophenyl)-8-(4-chlorophenyl)-2-methylpyrazolo[1,5-a][1,3,5]triazine (I-2A-1b; 100 mg, 0.257 mmol) and tetrakis(triphenylphosphine)palladium(0) (15 mg, 0.013 mmol) in DMF (0.8 ml) was added tributyl(1-ethoxyvinyl)tin (130 mg, 0.36 mmol) in DMF (1.5 ml). The reaction was degassed (3×) by pulling a vacuum and refilling with nitrogen. After heating at 100° C. for 1 hour under nitrogen, the reaction was cooled and then extracted from water with ethyl acetate. The organic layer was washed with ½ saturated brine and then brine. After drying (MgSO4), the mixture was concentrated, in vacuo, and purified on a Biotage™ Flash 12M column using 10% ethyl acetate in hexanes to afford product 14A-1 as a solid (53 mg, 49%): +APcI MS (M+1) 425.1; 1H NMR (400 MHz, CD3OD) δ 7.50-7.38 (m, 6H), 7.27 (d, J=8.7 Hz, 2H), 6.20 (d, J=3.3 Hz, 1H), 5.19 (d, J=3.3 Hz, 1H), 4.05 (q, J=7.1 Hz, 2H), 2.75 (s, 3H), 1.45 (t, J=7.1 Hz, 3H).
Reaction SMILES: Br[C:2]1[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[C:4]([O:10][CH:11]2[CH2:13][CH2:12]2)[CH:3]=1.[Li+].[Cl-].[CH2:16]([Sn](CCCC)(CCCC)CCCC)[CH:17]=[CH2:18]>C1(C)C=CC=CC=1.CCOC(C)=O.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[CH2:18]([C:2]1[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[C:4]([O:10][CH:11]2[CH2:13][CH2:12]2)[CH:3]=1)[CH:17]=[CH2:16]
Reactant: N#Cc1ccc(Br)cc1OC1CC1
Reactant: C=CC[Sn](CCCC)(CCCC)CCCC
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [Cl-]
Agent: [Li+]
Solvent: Cc1ccccc1
Solvent: CCOC(C)=O
Product: C=CCc1ccc(C#N)c(OC2CC2)c1

Procedure:
To a solution of 4-bromo-2-(cyclopropyloxy)benzonitrile (108 mg, 0.45 mmol) in 20 ml of toluene was added LiCl (38 mg, 0.9 mmol), Pd(PPh3)4 (15 mg), allyl tributyltin (180 g, 0.55 mmol), then the mixture was heated to reflux overnight. After the reaction was completed, the reaction solution was diluted with EtOAc and filtered, the filtrate was concentrated and purified with silica gel column chromatograph to give crude 4-allyl-2-(cyclopropyloxy)benzonitrile.
Reaction SMILES: [CH2:1]([O:8][C:9]1[C:18](=[O:19])[N:17]2[C:12]([C:13]([CH3:21])([CH3:20])[O:14][CH2:15][CH2:16]2)=[N:11][C:10]=1[C:22]([NH:24][CH:25]([C:34]#[N:35])[CH2:26][C:27]1[CH:32]=[CH:31][C:30]([F:33])=[CH:29][CH:28]=1)=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(Cl)(Cl)(Cl)[Cl:37].C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>C(#N)C.CCOCC>[CH2:1]([O:8][C:9]1[C:18](=[O:19])[N:17]2[C:12]([C:13]([CH3:20])([CH3:21])[O:14][CH2:15][CH2:16]2)=[N:11][C:10]=1[C:22]1[NH:24][C:25]([CH2:26][C:27]2[CH:28]=[CH:29][C:30]([F:33])=[CH:31][CH:32]=2)=[C:34]([Cl:37])[N:35]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: ClC(Cl)(Cl)Cl
Reactant: CC1(C)OCCn2c1nc(C(=O)NC(C#N)Cc1ccc(F)cc1)c(OCc1ccccc1)c2=O
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CC#N
Solvent: CCOCC
Product: CC1(C)OCCn2c1nc(-c1nc(Cl)c(Cc3ccc(F)cc3)[nH]1)c(OCc1ccccc1)c2=O
Temperature: 45 °C
Reaction time: 18 h
Yield: 64 %

Procedure:
(procedure adapted from Org. Lett. 2004, 6, 629-631). To a solution of 3-(benzyloxy)-N-(1-cyano-2-(4-fluorophenyl)ethyl)-9,9-dimethyl-4-oxo-4,6,7,9-tetrahydropyrimido[2,1-c][1,4]oxazine-2-carboxamide (0.48 g, 1.01 mmol, 1.0 equiv) and CCl4 (0.24 mL, 2.52 mmol, 2.5 equiv) in acetonitrile (10 mL) under a nitrogen atmosphere, was added PPh3 (0.39 g, 2.52 mmol, 2.5 equiv). The reaction was heated to 45° C. (oil bath). After stirring 18 h, the reaction was cooled to ambient temperature and concentrated in vacuo. The residue was treated with CH2Cl2 (10 mL) and 0.5 M NaOH (20 mL) and stirred vigorously. After stirring 4 h, the mixture was poured into water and extracted with CH2Cl2 (×3). The combined CH2Cl2 extracts were dried (Na2SO4) and concentrated in vacuo. The crude product was purified by silica gel chromatography (20-80% ethyl acetate/hexane) to provide a viscous yellow oil. This oil was taken up in ether and seeded with a crystal of previously isolated material. After crystallization, the solid was filtered to provide the title compound (0.32 g, 64% yield) as an off-white solid. 1H NMR (400 MHz, CDCl3) δ ppm 10.17 (s, 1H), 7.28-7.41 (m, 5H), 6.91-6.96 (m, 4H), 5.27 (s, 2H), 3.95-4.11 (m, 4H), 3.77 (s, 2H), 1.67 (s, 6H); LCMS (ES+, (M+H)+) m/z 495.14.
Reaction SMILES: [F:1][C:2]([F:14])([F:13])[C:3]1[CH:4]=[C:5]([NH:9][C:10]([NH2:12])=[S:11])[CH:6]=[CH:7][CH:8]=1.Br[CH:16](Br)[CH3:17].C(=O)([O-])[O-].[K+].[K+]>CC(C)=O>[NH:12]=[C:10]1[N:9]([C:5]2[CH:6]=[CH:7][CH:8]=[C:3]([C:2]([F:1])([F:13])[F:14])[CH:4]=2)[CH2:17][CH2:16][S:11]1
Reactant: CC(Br)Br
Reactant: NC(=S)Nc1cccc(C(F)(F)F)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: N=C1SCCN1c1cccc(C(F)(F)F)c1
Yield: 110 %

Procedure:
A solution of N-(3-trifluoromethylphenyl)thiourea (6.1 g), dibromoethane (5.7 g) and anhydrous potassium carbonate (11.5 g) in acetone (60 ml) was refluxed for 1 day. The solvent was removed by distillation therefrom, and the residue was extracted with ethyl ether, washed with water, dried over anhydrous magnesium sulfate and subjected to column chromatography to give 7.5 g of 2-imino-3-(3-trifluoromethylphenyl)thiazolidine. The thus obtained 2-imino-3- (3-trifluoromethylphenyl) thiazolidine (1.0 g), n-butyl chlorocarbonate (0.61 g) and triethylamine (1.2 g) were dissolved in tetrahydrofuran, and the resultant solution was stirred at room teperature for 5 hours. The solvent was removed, and the residue was extracted with ethyl acetate, washed with water and dried over anhydrous magnesium sulfate. After removal of the solvent, the residue was subjected to column chromatography to give 0.57 g of 2-butoxycarbonylimino-3-(3-trifluoromethylphenyl)thiazolidine.