Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:11][CH:10]([C:12](=[O:17])NCOC)[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH:18]([Mg]Cl)([CH3:20])[CH3:19]>O1CCCC1>[C:1]([O:5][C:6]([N:8]1[CH2:9][CH:10]([C:12](=[O:17])[CH:18]([CH3:20])[CH3:19])[CH2:11]1)=[O:7])([CH3:2])([CH3:3])[CH3:4]
Reactant: CC(C)[Mg]Cl
Reactant: COCNC(=O)C1CN(C(=O)OC(C)(C)C)C1
Solvent: C1CCOC1
Product: CC(C)C(=O)C1CN(C(=O)OC(C)(C)C)C1
Temperature: 4 °C
Reaction time: 0.08 h
Yield: 96.3 %

Procedure:
A solution of 3-(methoxymethylcarbamoyl)azetidine-1-carboxylic acid tert-butyl ester (1.06 g, 4.34 mmol) in anhydrous tetrahydrofuran (15 mL) was cooled to 4° C. under argon gas. 2M solution of isopropyl magnesium chloride (4.35 mL, 8.68 mmol) was added dropwise and the resulting reaction mixture was stirred at 4° C. for 5 min. The temperature was allowed to rise to RT and stirred for 1 h then the mixture was stirred at 40° C. for 1 h. The reaction mixture was quenched by addition of a saturated solution of ammonium chloride (5 mL) and water (10 mL). The aqueous phase was extracted with ethyl acetate (3×20 mL). The organic layer was dried over sodium sulfate, filtered and the solvents reduced in vacuo to afford the title compound as a pale yellow oil (950 mg, 96%) 1H NMR (400 MHz, CDCl3): δ 4.03-4.01 (4 H, m), 3.59-3.59 (1 H, m), 2.61-2.61 (1 H, m), 1.43 (9 H, s), 1.11 (6 H, d, J=6.94 Hz).
Reaction SMILES: [Cl:1][CH2:2][CH2:3][CH2:4][N:5]1[C:9](=[O:10])[C:8]2([CH2:15][CH2:14][N:13]([CH2:16][C:17]3[C:26]4[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=4)[CH:20]=[CH:19][CH:18]=3)[CH2:12][CH2:11]2)[N:7]([C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)[CH2:6]1.[CH3:33][NH:34][CH3:35].[I-].[Na+]>C(O)C>[ClH:1].[ClH:1].[CH3:33][N:34]([CH3:35])[CH2:2][CH2:3][CH2:4][N:5]1[C:9](=[O:10])[C:8]2([CH2:15][CH2:14][N:13]([CH2:16][C:17]3[C:26]4[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=4)[CH:20]=[CH:19][CH:18]=3)[CH2:12][CH2:11]2)[N:7]([C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)[CH2:6]1
Reactant: CNC
Reactant: O=C1N(CCCCl)CN(c2ccccc2)C12CCN(Cc1cccc3ccccc13)CC2
Agent: [I-]
Agent: [Na+]
Solvent: CCO
Product: CN(C)CCCN1CN(c2ccccc2)C2(CCN(Cc3cccc4ccccc34)CC2)C1=O
Product: Cl
Temperature: 25 °C
Reaction time: 24 h
Yield: 93 %

Procedure:
3-(3-chloropropyl)-8-naphthalen-1-ylmethyl-1-phenyl-1,3,8-triaza-spiro[4.5]decan-4-one (0.145 g, 0.30 mmol), prepared using the procedure described in Example 13, was added to a 33% solution of dimethylamine in ethanol. Sodium iodide (0.045 g, 0.3 mmol) was added and the mixture was stirred at room temperature for 24 h. Salts were separated by filtration and the filtrate was evaporated in vacuo. The residue was purified by flash chromatography on silica gel using dichloromethane/ethyl acetate 1:1 containing 2.5% triethylamine as the eluent. The pooled pure fractions were evaporated and the residue dissolved in tetrahydrofuran (5 ml) and the hydrochloride was precipitated by the dropwise addition of a solution of hydrogen chloride in ether in excess. The precipitate was collected by filtration and dried, affording the title compound (148 mg, 93% yield) as a powder.
Reaction SMILES: [CH3:1][C:2]1[C:3](=[O:10])[NH:4][C:5](=[O:9])[NH:6][C:7]=1[CH3:8].[CH3:11][Si](C)(C)N[Si](C)(C)C>CN(C=O)C>[CH3:11][N:6]1[C:7]([CH3:8])=[C:2]([CH3:1])[C:3](=[O:10])[NH:4][C:5]1=[O:9]
Reactant: Cc1[nH]c(=O)[nH]c(=O)c1C
Reactant: C[Si](C)(C)N[Si](C)(C)C
Solvent: CN(C)C=O
Product: Cc1c(C)n(C)c(=O)[nH]c1=O
Temperature: 150 °C

Procedure:
6.00 g (42.9 mmol) 5,6-dimethyluracil was dissolved in 26 mL of hexamethyldisilazane and 2.1 mL DMF. The mixture was heated for 11 hours at 150° C. and the excess of hexamethyldisilazane was removed under reduced pressure. Toluene was added to the mixture and evaporated off under reduced pressure to remove any residual hexamethyldisilazane. The residue was dissolved in 25 mL of iodomethane, refluxed for 2 hours, the excess iodomethane then evaporated off under reduced pressure and the residue recrystallized from deionised water yielding after drying 5.76 g (87%) of 1,5,6-trimethyluracil (m.p. 254–257° C., lit. 256–258° C.).
Reaction SMILES: [CH2:1]([C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=1[OH:11])[CH2:2][CH2:3][CH3:4].[CH3:12][NH:13][C:14](=O)[O:15]CC.P(Cl)(Cl)(Cl)=O>C1(C)C=CC=CC=1>[CH3:12][NH:13][C:14](=[O:15])[O:11][C:6]1[CH:7]=[CH:8][CH:9]=[CH:10][C:5]=1[CH2:1][CH2:2][CH2:3][CH3:4]
Reactant: CCOC(=O)NC
Reactant: CCCCc1ccccc1O
Solvent: O=P(Cl)(Cl)Cl
Solvent: Cc1ccccc1
Product: CCCCc1ccccc1OC(=O)NC

Procedure:
To a solution of 2-sec butylphenol (1.5 g, 0.01 mole) and ethyl N-methylcarbamate (1.03 g, 0.01 mole) in toluene (10 ml) at 60° C., phosphoryl chloride (0.77 g, 0.05 mole) was added dropwise during 0.5 hours and the contents refluxed for 5 hours. It was worked up as described earlier to furnish 2-sec butylphenyl N-methylcarbamate of the formula (III).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:15])[C:4]1[CH:13]=[CH:12][C:7]([C:8]([O:10][CH3:11])=[O:9])=[CH:6][C:5]=1[CH3:14].[Br:16]N1C(=O)CCC1=O>C(Cl)(Cl)(Cl)Cl>[CH3:1][O:2][C:3](=[O:15])[C:4]1[CH:13]=[CH:12][C:7]([C:8]([O:10][CH3:11])=[O:9])=[CH:6][C:5]=1[CH2:14][Br:16]
Reactant: O=C1CCC(=O)N1Br
Reactant: COC(=O)c1ccc(C(=O)OC)c(C)c1
Solvent: ClC(Cl)(Cl)Cl
Product: COC(=O)c1ccc(C(=O)OC)c(CBr)c1

Procedure:
88 G. of dimethyl-2-methylterephthalate in 1000 ml. of carbon tetrachloride containing 89 g. (1 eq.) of N-bromosuccinimide is refluxed for 3 hours using a heat lamp. The solution is cooled, filtered and evaporated to dryness to give dimethyl-2-bromomethylterephthalate.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:9]=[N:10][CH:11]=[C:12]([C:15]=2[NH:16][C:17]2[CH:25]=[CH:24][CH:23]=[C:22]3[C:18]=2[CH:19]=[CH:20][NH:21]3)[C:13]#[N:14])=[CH:4][CH:3]=1.[CH2:26]([C@H:33]([NH:36]C(=O)OC(C)(C)C)[CH2:34]O)[C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.N(C(OCC)=O)=NC(OCC)=O.Cl>C1COCC1>[NH2:36][C@@H:33]([CH2:26][C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1)[CH2:34][O:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[CH:9]=[N:10][CH:11]=[C:12]([C:15]=2[NH:16][C:17]2[CH:25]=[CH:24][CH:23]=[C:22]3[C:18]=2[CH:19]=[CH:20][NH:21]3)[C:13]#[N:14])=[CH:6][CH:7]=1
Reactant: CC(C)(C)OC(=O)N[C@H](CO)Cc1ccccc1
Reactant: N#Cc1cncc(-c2ccc(O)cc2)c1Nc1cccc2[nH]ccc12
Agent: CCOC(=O)N=NC(=O)OCC
Agent: Cl
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: N#Cc1cncc(-c2ccc(OC[C@@H](N)Cc3ccccc3)cc2)c1Nc1cccc2[nH]ccc12
Temperature: 25 °C
Reaction time: 21 h
Yield: 29.5 %

Procedure:
To a suspension of 5-(4-hydroxyphenyl)-4-(1H-indol-4-ylamino)nicotinonitrile 225 (100 mg, 0.31 mmol), tert-butyl (1S)-1-benzyl-2-hydroxyethylcarbamate (77 mg, 0.31 mmol), and Ph3P (97 mg, 0.37 mmol) in THF (2.0 mL) was added diethyl azodicarboxylate (64 mg, 0.37 mmol) via a syringe over 6 min. The resulting mixture was stirred at r.t. for 21 h and treated with concentrated HCl (˜200 mg). After heating at 60° C. for one h, the reaction mixture was partitioned between saturated NaHCO3 and CH2Cl2. The combined organics were dried over Na2SO4, concentrated and purified by silica gel flash column chromatography (eluting with 4% MeOH/CH2Cl2) to give 42 mg (30%) of 5-(4-{[(2S)-2-amino-3-phenylpropyl]oxy}phenyl)-4-(1H-indol-4-ylamino)nicotinonitrile 226 as a white solid. MS: 460.4 (M+H); melting range: 83-85° C.
Reaction SMILES: [Br:1][C:2]1[CH:15]=[CH:14][C:13]2[O:12][C:11]3[C:6](=[CH:7][C:8]([O:16][CH3:17])=[CH:9][CH:10]=3)[C:5](=O)[C:4]=2[CH:3]=1.[CH3:19][Si](C[Li])(C)C.C(Cl)(=O)C>C1COCC1.CCCCC.C(=O)(O)[O-].[Na+]>[Br:1][C:2]1[CH:15]=[CH:14][C:13]2[O:12][C:11]3[C:6](=[CH:7][C:8]([O:16][CH3:17])=[CH:9][CH:10]=3)[C:5](=[CH2:19])[C:4]=2[CH:3]=1
Reactant: COc1ccc2oc3ccc(Br)cc3c(=O)c2c1
Reactant: [Li]C[Si](C)(C)C
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC(=O)Cl
Solvent: C1CCOC1
Solvent: CCCCC
Product: C=C1c2cc(Br)ccc2Oc2ccc(OC)cc21
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
A solution of 2-bromo-7-methoxy-9H-xanthen-9-one (2.035 g, 6.7 mmol) in THF (67 ml) contained in a 250-mL RBF was cooled in a dry ice/acetone bath for 10 min to give a milky-white mixture. Trimethylsilyl methyllithium (10 ml of a 1.0 M solution in pentane, 10 mmol) was added dropwise over 5 min to give a clear orange solution. The mixture was stirred for 15 min, then acetyl chloride (0.76 ml, 11 mmol) was added dropwise, resulting in the formation of a clear, bright-yellow solution. The mixture was warmed to RT for 3 h, then an additional portion of acetyl chloride (0.25 mL) was added. The mixture was stirred for an additional 30 min before being diluted with saturated aqueous sodium bicarbonate solution (100 mL). The biphasic mixture was extracted with EtOAc (2×50 mL), and the combined organic extracts were dried over sodium sulfate, filtered, and evaporated to give a yellow solid that was used without further purification. MS m/z=303.0 [M+H]+. Calc'd for C15H12BrO2: 303.0.
Reaction SMILES: [CH3:1][N:2]1[CH2:6][CH2:5][CH2:4][C:3]1=O.P(Cl)(Cl)(Cl)=O.[NH:13]1[C:21]2[C:16](=[CH:17][CH:18]=[C:19]([C:22]([O:24][CH3:25])=[O:23])[CH:20]=2)[CH:15]=[CH:14]1.C([O-])([O-])=O.[Na+].[Na+]>ClCCCl.O>[CH3:25][O:24][C:22]([C:19]1[CH:20]=[C:21]2[C:16](/[C:15](=[C:3]3/[N:2]([CH3:1])[CH2:6][CH2:5][CH2:4]/3)/[CH:14]=[N:13]2)=[CH:17][CH:18]=1)=[O:23]
Reactant: COC(=O)c1ccc2cc[nH]c2c1
Reactant: CN1CCCC1=O
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: ClCCCl
Solvent: O
Solvent: O=P(Cl)(Cl)Cl
Product: COC(=O)c1ccc2c(c1)N=C/C2=C1/CCCN1C
Reaction time: 0.25 h
Yield: 56.6 %

Procedure:
A mixture of 1.6 mL (16 mmol) 1-methyl-2-pyrrolidone and 10 mL phosphoryl chloride (POCl3) in 10 mL 1,2-dichloroethane was stirred for 15 min and 1.75 g (10 mmol) methyl indole-6-carboxylate and 1.6 mL (16 mmol) 1-methyl-2-pyrrolidone in 10 mL 1,2-dichloroethane was added. The mixture was heated to reflux for 2 h. Water and Na2CO3 aq. was added to adjust to pH=9. Subsequently the mixture was extracted with DCM and the combined organic layers were washed with water, dried with Na2SO4 and evaporated to dryness. Trituration with acetone provided 1.45 g (57%) of the title compound as light brown solid. MS (m/e): 257.2 (MH+).
Reaction SMILES: [F:1][C:2]([F:13])([F:12])[C:3]1[CH:4]=[C:5]([NH:9][C:10]#[N:11])[CH:6]=[CH:7][CH:8]=1.C(=O)([O-])[O-].[K+].[K+].[I-].[K+].[Cl:22][C:23]([CH2:25]Cl)=[CH2:24]>CN(C)C=O>[F:1][C:2]([F:12])([F:13])[C:3]1[CH:4]=[C:5]([N:9]([CH2:25][C:23]([Cl:22])=[CH2:24])[C:10]#[N:11])[CH:6]=[CH:7][CH:8]=1
Reactant: C=C(Cl)CCl
Reactant: N#CNc1cccc(C(F)(F)F)c1
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: CN(C)C=O
Product: C=C(Cl)CN(C#N)c1cccc(C(F)(F)F)c1
Temperature: 50 °C
Yield: 99.1 %

Procedure:
N-(3-(trifluoromethyl)phenyl)cyanamide (18.6 g) was dissolved in N,N-dimethylformamide (DMF) (93.0 g), to which powdered potassium carbonate (20.7 g) and potassium iodide (1.7 g) were added at room temperature with stirring. Further, 2,3-dichloro-1-propene (13.3 g) was added dropwise at room temperature with stirring. The mixture was heated to 50° C. and stirred at the same temperature for 1 hour. After cooling to room temperature, waster was added to the reaction mixture, which was then extracted with ethyl acetate. The organic layer was washed with water. The solvent was removed by distillation under reduced pressure, which afforded 25.8 g of N-(3-(trifluoromethyl)phenyl)-N-(2-chloro-2-propenyl)cyanamide as an oil (99% yield in appearance). The percentage areas of gas chromatography and liquid chromatography were 98% and 99%, respectively.
Reaction SMILES: CN(C)CCN(C)C.[Li]CCCC.[CH3:14][C:15]1[CH:20]=[CH:19][C:18]([SH:21])=[CH:17][CH:16]=1.CN([CH:25]=[O:26])C.Cl>C1CCCCC1>[CH3:14][C:15]1[CH:16]=[CH:17][C:18]([SH:21])=[C:19]([CH:20]=1)[CH:25]=[O:26]
Reactant: Cc1ccc(S)cc1
Reactant: CN(C)C=O
Agent: CN(C)CCN(C)C
Agent: Cl
Agent: [Li]CCCC
Solvent: C1CCCCC1
Product: Cc1ccc(S)c(C=O)c1
Temperature: 0 °C
Reaction time: 0.08 h
Yield: 80.5 %

Procedure:
Tetramethylethylenediamine (TMEDA) (12.6 mL, 83.5 mmol) was added via syringe to n-BuLi (33 mL of 1.6 M in hexanes, 82.5 mmol) and the solution was chilled to 0° C. A solution of p-thiocresol (4.53 g, 36.5 mmol) in cyclohexane (40 mL) was added with stirring over 5 minutes. The resulting tan slurry was stirred overnight at room temperature, chilled to 0° C., and DMF (4.0 mL, 3.77 g, 51.6 mmol) was added via syringe over 2 minutes. The resulting gummy slurry was stirred at room temperature for 1.3 hours. The reaction mixture was added to 3 N HCl (150 mL). This mixture was extracted with ethyl acetate. The combined organic layers were washed with brine, dried over MgSO4, filtered and concentrated in vacuo yielding a brown oil. This oil was purified by flash chromatography over silica gel, eluting with 10% ethyl acetate-hexanes to afford 5-methyl-2-mercaptobenzaldehyde (4.47 g, 69%) as an intensely yellow solid suitable for use without further purification.
Reaction SMILES: [OH:1][C:2]1[C:11]2[N:10]=[CH:9][CH:8]=[CH:7][C:6]=2[C:5]([C:12]([O:14][CH3:15])=[O:13])=[N:4][C:3]=1[C:16]([O:18]C)=O.[F:20][C:21]1[CH:26]=[CH:25][C:24]([CH2:27][NH2:28])=[C:23]([S:29][CH3:30])[CH:22]=1.CN(C=O)C>C1(C)C=CC=CC=1>[F:20][C:21]1[CH:26]=[CH:25][C:24]([CH2:27][NH:28][C:16]([C:3]2[N:4]=[C:5]([C:12]([O:14][CH3:15])=[O:13])[C:6]3[CH:7]=[CH:8][CH:9]=[N:10][C:11]=3[C:2]=2[OH:1])=[O:18])=[C:23]([S:29][CH3:30])[CH:22]=1
Reactant: COC(=O)c1nc(C(=O)OC)c2cccnc2c1O
Reactant: CSc1cc(F)ccc1CN
Solvent: CN(C)C=O
Solvent: Cc1ccccc1
Product: COC(=O)c1nc(C(=O)NCc2ccc(F)cc2SC)c(O)c2ncccc12
Temperature: 110 °C
Reaction time: 18 h

Procedure:
A slurry of dimethyl 8-hydroxy-1,6-naphthyridine-5,7-dicarboxylate (0.25 g, 0.953 mmol), 1-[4-fluoro-2-(methylthio)phenyl]methanamine (0.326 g, 1.91 mmol) and N,N,N-diisopropylethylamine (170 uL, 0.953 mmol) in toluene (4.0 mL) were heated in a pressure tube at 110 degrees C. for 18 hrs. The reaction was incomplete by LCMS analysis and solids remained undissolved. DMF (1 mL) was added to solubilize the reagents and the reaction was again heated in a pressure tube at 110 degrees C. for 18 hrs. Upon cooling to room temperature, the resulting solution was transferred to a round bottom flask and reduced to a small volume. The residue was partitioned between methylene chloride and water. The organic layer was dried with Na2SO4, filtered and reduced in vacuo. The material was crystallized with a small amount of chloroform. The solid was filtered and dried in vacuo to afford the desired compound as a white solid.
Reaction SMILES: I[CH:2]([CH3:4])[CH3:3].C([O-])([O-])=O.[K+].[K+].[F:11][C:12]1[CH:13]=[C:14]2[C:18](=[CH:19][CH:20]=1)[NH:17][C:16]([CH3:21])=[C:15]2[C:22]1[C:27]2[CH:28]=[CH:29][CH:30]=[CH:31][C:26]=2[S:25](=[O:33])(=[O:32])[NH:24][N:23]=1.Br[CH2:35][C:36]([O:38][C:39]([CH3:42])([CH3:41])[CH3:40])=[O:37]>CC#N.O.C(Cl)Cl>[C:39]([O:38][C:36](=[O:37])[CH2:35][N:17]1[C:18]2[C:14](=[CH:13][C:12]([F:11])=[CH:20][CH:19]=2)[C:15]([C:22]2[C:27]3[CH:28]=[CH:29][CH:30]=[CH:31][C:26]=3[S:25](=[O:32])(=[O:33])[N:24]([CH:2]([CH3:4])[CH3:3])[N:23]=2)=[C:16]1[CH3:21])([CH3:42])([CH3:41])[CH3:40]
Reactant: CC(C)I
Reactant: Cc1[nH]c2ccc(F)cc2c1C1=NNS(=O)(=O)c2ccccc21
Reactant: CC(C)(C)OC(=O)CBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Solvent: O
Solvent: ClCCl
Product: Cc1c(C2=NN(C(C)C)S(=O)(=O)c3ccccc32)c2cc(F)ccc2n1CC(=O)OC(C)(C)C
Temperature: 80 °C
Reaction time: 8 h

Procedure:
2-Iodopropane (7 μL, 67 μmol) and K2CO3 (10 mg, 72 mmol) were added to a solution of 4-(5-fluoro-2-methyl-1H-indol-3-yl)-2H-benzo[e][1,2,3]thiadiazine 1,1-dioxide (20 mg, 61 Amok) in CH3CN (1 mL), and stirred overnight at 80° C. An additional amount of K2CO3 (10 mg, 72 μmol) and tert-butyl bromoacetate (14 mL, 92 μmol) was added, and the reaction mixture stirred an additional 2 h at 80° C. The reaction mixture was diluted with H2O and CH2Cl2, and filtered through an Extrelut column. The Extrelut column was washed with CH2Cl2, and the filtrate was concentrated to afford the sub-title compound, which was carried onto the next step without further purification or characterization.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([CH:19]=[CH:20][CH:21]=1)[CH2:5][O:6][C:7]1[CH:12]=[CH:11][C:10]([CH2:13][CH2:14][C:15]([O:17]C)=[O:16])=[CH:9][CH:8]=1.[CH2:22]([NH:29][CH2:30][CH3:31])[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1.C(=O)([O-])[O-].[Cs+].[Cs+].C1(P(C2C=CC=CC=2)C2C=CC3C(=CC=CC=3)C=2C2C3C(=CC=CC=3)C=CC=2P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>C1(C)C=CC=CC=1>[CH2:22]([N:29]([CH2:30][CH3:31])[C:2]1[CH:3]=[C:4]([CH:19]=[CH:20][CH:21]=1)[CH2:5][O:6][C:7]1[CH:12]=[CH:11][C:10]([CH2:13][CH2:14][C:15]([OH:17])=[O:16])=[CH:9][CH:8]=1)[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1
Reactant: COC(=O)CCc1ccc(OCc2cccc(Br)c2)cc1
Reactant: CCNCc1ccccc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Agent: c1ccc(P(c2ccccc2)c2ccc3ccccc3c2-c2c(P(c3ccccc3)c3ccccc3)ccc3ccccc23)cc1
Solvent: Cc1ccccc1
Product: CCN(Cc1ccccc1)c1cccc(COc2ccc(CCC(=O)O)cc2)c1
Temperature: 80 °C
Reaction time: 16 h
Yield: 12.5 %

Procedure:
A mixture of methyl 3-[4-[(3-bromobenzyl)oxy]phenyl]propanoate (0.30 g, 0.86 mmol), benzyl(ethyl)amine (0.20 mL, 1.29 mmol), cesium carbonate (0.39 g, 1.20 mmol), tris(dibenzylidenacetone)dipalladium (0) (0.031 g, 0.034 mmol), rac-2,2′-bis(diphenylphosphino)-1,1′-binaphthyl (0.032 g, 0.052 mmol) and toluene (6 mL) was stirred under a nitrogen atmosphere at 80° C. for 16 hrs. The reaction mixture was cooled, washed with water and saturated brine, dried over magnesium sulfate, and concentrated under reduced pressure. Then the residue was dissolved in a mixed solution of methanol (4 mL) and tetrahydrofuran (6 mL), 1N aqueous sodium hydroxide solution (1.8 mL) was added, and the mixture was stirred at room temperature for 2 hrs. The reaction mixture was adjusted to pH 7 with 1N hydrochloric acid, and separated and extracted with ethyl acetate. The organic layer was washed with water and saturated brine, dried over magnesium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (hexane/ethyl acetate=2/1-1/2) to give the title compound (42 mg, yield 13%) as yellow crystals. MS (APCI−): 388 (M−H).
Reaction SMILES: C[C:2]([CH3:5])([O-:4])C.[K+].[Cl:7][C:8]1[CH:13]=[CH:12][C:11]([C:14]([CH3:18])([CH3:17])[CH:15]=O)=[CH:10][CH:9]=1.C1C[O:22][CH2:21][CH2:20]1>>[Cl:7][C:8]1[CH:13]=[CH:12][C:11]([C:14]([CH3:18])([CH3:17])[CH:15]=[CH:20][C:21]([O:4][CH2:2][CH3:5])=[O:22])=[CH:10][CH:9]=1
Reactant: C1CCOC1
Reactant: CC(C)(C)[O-]
Reactant: CC(C)(C=O)c1ccc(Cl)cc1
Agent: [K+]
Product: CCOC(=O)C=CC(C)(C)c1ccc(Cl)cc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 44.5 %

Procedure:
To a stirring suspension of the triethyl phosphonoacetate (1.695 mL, 8.54 mmol) in 10 mL THF at 0° C. was added 1 M potassium tert-butoxide in THF (8.54 mL, 8.54 mmol). The resulting reddish orange solution was stirred for 30 min and then treated with a solution of the 2-(4-chlorophenyl)-2-methylpropanal (Intermediate I-9A, 0.78 g, 4.27 mmol) in 2.5 mL of THF and slowly warmed to room temperature. The reaction mixture was stirred at room temperature for 3 hrs and quenched with saturated. aq. ammonium chloride. The reaction mixture was partitioned between ethyl acetate and water. The organic layer was then washed with brine, dried over anhyd. magnesium sulfate, concentrated and chromatographed using silica gel flash chromatography to yield ethyl 4-(4-chlorophenyl)-4-methylpent-2-enoate (0.48 g, 1.899 mmol, 44.5% yield) as a clear oil. 1H NMR (400 MHz, CDCl3) δ ppm 7.28 (2H, d, J=8.79 Hz), 7.22 (2H, d, J=8.79 Hz), 7.08 (1H, d, J=16.26 Hz), 5.79 (1H, d, J=15.82 Hz), 4.20 (2H, q, J=7.03 Hz), 1.29 (3H, t, J=7.25 Hz).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[N:9]1[CH:13]=[CH:12][N:11]=[C:10]1[CH2:14][CH2:15][C:16]([O:18][CH2:19][CH3:20])=[O:17].[C:21](N1C=CN=C1)(N1C=CN=C1)=[O:22]>ClC1C=CC=CC=1Cl>[F:8][C:6]1[CH:7]=[C:2]2[C:3](=[CH:4][CH:5]=1)[N:9]1[C:10]([CH2:14][CH2:15][C:16]([O:18][CH2:19][CH3:20])=[O:17])=[N:11][CH:12]=[C:13]1[C:21](=[O:22])[NH:1]2
Reactant: O=C(n1ccnc1)n1ccnc1
Reactant: CCOC(=O)CCc1nccn1-c1ccc(F)cc1N
Solvent: Clc1ccccc1Cl
Product: CCOC(=O)CCc1ncc2c(=O)[nH]c3cc(F)ccc3n12
Reaction time: 3 h

Procedure:
Ethyl 3-[1-(2-amino-4-fluorophenyl)-1H-imidazol-2-yl]-propanoate as synthesized in Production Example 92, 94 mg, 1,1′-carbonyldiimidazole 83 mg and 1,2-dichlorobenzene 1 mL were mixed and heated under reflux for 0.5 hour. Further 1 mL of 1,2-dichlorobenzene was added and the heating under reflux was continued for further 3 hours. Allowing the reaction liquid to cool off, the precipitate was recovered by filtration, and washed with diethyl ether and ethyl acetate, by the order stated. The resulting crystals were dissolved in a liquid mixture of tetrahydrofuran and methanol, and the insoluble matter was separated by filtration. Distilling the solvent off under reduced pressure, 70 mg of the title compound was obtained.
Reaction SMILES: [Br:1][C:2]1[N:3]=[C:4]2[C:11](I)=[C:10]([C:13]3[CH:18]=[CH:17][C:16]([C:19]4([CH3:24])[O:23][CH2:22][CH2:21][O:20]4)=[CH:15][CH:14]=3)[N:9]([CH2:25][O:26][CH2:27][CH2:28][Si:29]([CH3:32])([CH3:31])[CH3:30])[C:5]2=[N:6][C:7]=1[CH3:8].[Li][CH2:34][CH2:35]CC.CI>C1COCC1>[Br:1][C:2]1[N:3]=[C:4]2[C:11]([CH2:34][CH3:35])=[C:10]([C:13]3[CH:18]=[CH:17][C:16]([C:19]4([CH3:24])[O:23][CH2:22][CH2:21][O:20]4)=[CH:15][CH:14]=3)[N:9]([CH2:25][O:26][CH2:27][CH2:28][Si:29]([CH3:32])([CH3:31])[CH3:30])[C:5]2=[N:6][C:7]=1[CH3:8]
Reactant: Cc1nc2c(nc1Br)c(I)c(-c1ccc(C3(C)OCCO3)cc1)n2COCC[Si](C)(C)C
Reactant: [Li]CCCC
Solvent: C1CCOC1
Solvent: CI
Product: CCc1c(-c2ccc(C3(C)OCCO3)cc2)n(COCC[Si](C)(C)C)c2nc(C)c(Br)nc12
Temperature: 20 °C
Reaction time: 0.33 h
Yield: 63.5 %

Procedure:
2-Bromo-7-iodo-3-methyl-6-(4-(2-methyl-1,3-dioxolan-2-yl)phenyl)-5-((2-(trimethylsilyl)ethoxy)methyl)-5H-pyrrolo[2,3-b]pyrazine (12.7 g, 20.2 mmol) in THF (200 mL) was cooled to about −75° C. then n-BuLi (1.5 M, 14.8 mL, 22.2 mmol) was added while maintaining the internal temperature of the mixture between −70 and −75° C. The mixture was stirred for about 20 min then the mixture was treated with MeI (6.51 mL, 81 mmol). The cooling bath was removed and replaced with a warm water bath. The temperature of the mixture was raised to about 20° C. over about 10 min. The mixture was stirred at about 20° C. for about 30 min then saturated aqueous NH4Cl (10 mL) was added. The mixture was stirred for about 15 min then concentrated under reduced pressure. The material was partitioned between Et2O (200 mL) and water (100 mL). The organic layer was isolated and the aqueous layer was extracted with Et2O (50 mL). The combined organics were washed with water (50 mL) then brine (50 mL), dried over anhydrous MgSO4, filtered and concentrated under reduced pressure. The material was purified with an 80 g silica column and eluted with 85:15 heptane/Et2O to give 2-bromo-7-ethyl-3-methyl-6-(4-(2-methyl-1,3-dioxolan-2-yl)phenyl)-5-((2-(trimethylsilyl)ethoxy)methyl)-5H-pyrrolo[2,3-b]pyrazine (6.83 g, 64%): LC/MS (Table 2, Method g) Rt=2.17 min; MS m/z 532 (M+H)+.
Reaction SMILES: [C:1]([O:5][C:6](=[O:22])[NH:7][C:8]1[CH:13]=[C:12]([N:14]([CH2:16][CH:17]([CH3:19])[CH3:18])[CH3:15])[C:11]([Cl:20])=[CH:10][C:9]=1[NH2:21])([CH3:4])([CH3:3])[CH3:2].C([O:27][C:28](=O)[CH2:29][C:30](=[O:50])[C:31]1[CH:36]=[CH:35][CH:34]=[C:33]([N:37]2[C:41]([CH2:42][O:43][CH:44]3[CH2:49][CH2:48][CH2:47][CH2:46][O:45]3)=[CH:40][N:39]=[N:38]2)[CH:32]=1)(C)(C)C>>[C:1]([O:5][C:6](=[O:22])[NH:7][C:8]1[CH:13]=[C:12]([N:14]([CH2:16][CH:17]([CH3:18])[CH3:19])[CH3:15])[C:11]([Cl:20])=[CH:10][C:9]=1[NH:21][C:28](=[O:27])[CH2:29][C:30](=[O:50])[C:31]1[CH:36]=[CH:35][CH:34]=[C:33]([N:37]2[C:41]([CH2:42][O:43][CH:44]3[CH2:49][CH2:48][CH2:47][CH2:46][O:45]3)=[CH:40][N:39]=[N:38]2)[CH:32]=1)([CH3:3])([CH3:2])[CH3:4]
Reactant: CC(C)CN(C)c1cc(NC(=O)OC(C)(C)C)c(N)cc1Cl
Reactant: CC(C)(C)OC(=O)CC(=O)c1cccc(-n2nncc2COC2CCCCO2)c1
Product: CC(C)CN(C)c1cc(NC(=O)OC(C)(C)C)c(NC(=O)CC(=O)c2cccc(-n3nncc3COC3CCCCO3)c2)cc1Cl

Procedure:
The title compound was prepared from [2-amino-4-chloro-5-(isobutyl-methyl-amino)-phenyl]-carbamic acid tert-butyl ester (Example J27) (328 mg, 1.0 mmol) and (RS)-3-oxo-3-{3-[5-(tetrahydro-pyran-2-yloxymethyl)-[1,2,3]triazol-1-yl]-phenyl}-propionic acid tert-butyl ester (Example K5) (401 mg, 1.0 mmol) according to the general procedure M. Obtained as a light brown foam (330 mg, 50%).