Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([C:25](=[O:37])[NH:26][CH2:27][C:28]2[C:29](=[O:36])[NH:30][C:31]([CH3:35])=[CH:32][C:33]=2[CH3:34])[C:5]([CH3:24])=[C:6]([N:8]([CH3:23])[C@@H:9]2[CH2:14][CH2:13][C@H:12]([NH:15]C(=O)OC(C)(C)C)[CH2:11][CH2:10]2)[CH:7]=1.C(O)(C(F)(F)F)=O>C(Cl)Cl>[NH2:15][C@@H:12]1[CH2:11][CH2:10][C@H:9]([N:8]([CH3:23])[C:6]2[C:5]([CH3:24])=[C:4]([CH:3]=[C:2]([Br:1])[CH:7]=2)[C:25]([NH:26][CH2:27][C:28]2[C:29](=[O:36])[NH:30][C:31]([CH3:35])=[CH:32][C:33]=2[CH3:34])=[O:37])[CH2:14][CH2:13]1
Reactant: Cc1cc(C)c(CNC(=O)c2cc(Br)cc(N(C)[C@H]3CC[C@@H](NC(=O)OC(C)(C)C)CC3)c2C)c(=O)[nH]1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: Cc1cc(C)c(CNC(=O)c2cc(Br)cc(N(C)[C@H]3CC[C@@H](N)CC3)c2C)c(=O)[nH]1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
A stirred solution of cis-tert-butyl (4-((5-bromo-3-(((4,6-dimethyl-2-oxo-1,2-dihydropyridin-3-yl)methyl)carbamoyl)-2-methylphenyl)(methyl)amino)cyclohexyl)carbamate (0.8 g, 1.39 mmol) in DCM (25 mL) was cooled to 0° C. and TFA (5 mL) was added to it. The reaction mixture was stirred at room temperature for 1 h. Upon completion, reaction was concentrated to dryness. Residue was basified with aqueous sodium bicarbonate till pH 8 and aqueous layer extracted with 20% MeOH/DCM. The combined organic layers were dried over sodium sulfate, filtered and concentrated to afford the desired compound (600 mg, 91% yield). LCMS: 475.15 (M+1)+; HPLC % 95.88 (@ 254 nm) (Rt; 4.832; Method: Column: YMC ODS-A 150 mm×4.6 mm×5μ; Mobile Phase: A; 0.05% TFA in water/B; 0.05% TFA in acetonitrile; Inj. Vol: 10 μL, Col. Temp.: 30° C.; Flow rate: 1.4 mL/min.; Gradient: 5% B to 95% B in 8 min, Hold for 1.5 min, 9.51-12 min 5% B); 1H NMR (DMSO-d6, 400 MHz) δ 8.22 (t, 1H), 7.20 (s, 1H), 7.01 (s, 1H), 5.85 (s, 1H), 4.23 (d, 2H, J=3.6 Hz), 2.82-2.86 (m, 2H), 2.53 (s, 3H), 2.18 (s, 3H), 2.13 (s, 3H), 2.10 (s, 3H), 1.82-1.84 (m, 2H), 1.34-1.44 (m, 6H).
Reaction SMILES: C([N:4]1[CH:9]([CH3:10])[CH2:8][N:7]([C:11]2[CH:16]=[CH:15][C:14]([C:17]3[NH:26][C:25](=[O:27])[C:24]4[C:19](=[CH:20][C:21]([O:30][CH3:31])=[CH:22][C:23]=4[O:28][CH3:29])[N:18]=3)=[CH:13][CH:12]=2)[CH2:6][CH:5]1[CH3:32])(=O)C.[OH-].[Na+]>Cl>[CH3:10][C@H:9]1[NH:4][C@@H:5]([CH3:32])[CH2:6][N:7]([C:11]2[CH:16]=[CH:15][C:14]([C:17]3[NH:26][C:25](=[O:27])[C:24]4[C:19](=[CH:20][C:21]([O:30][CH3:31])=[CH:22][C:23]=4[O:28][CH3:29])[N:18]=3)=[CH:13][CH:12]=2)[CH2:8]1
Reactant: COc1cc(OC)c2c(=O)[nH]c(-c3ccc(N4CC(C)N(C(C)=O)C(C)C4)cc3)nc2c1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Product: COc1cc(OC)c2c(=O)[nH]c(-c3ccc(N4C[C@@H](C)N[C@@H](C)C4)cc3)nc2c1
Temperature: 25 °C
Yield: 29.8 %

Procedure:
A solution of 2-(4-(4-acetyl-3,5-dimethylpiperazin-1-yl)phenyl)-5,7-dimethoxyquinazolin-4(3H)-one (0.150 g, 0.34 mmol) in 2N HCl was heated at reflux temperature for 3 days. The reaction was cooled to room temperature, basified with 1N NaOH, and extracted with CH2Cl2. Purification by flash chromatography on silica gel, eluting with 0% to 15% MeOH/CH2Cl2, followed by further purification, eluting with 30% to 100% of 92:7:1 CHCl3/MeOH/concentrated NH4OH, afforded the title compound (0.040 g, 30%) as a white solid. 1H NMR (300 MHz, DMSO-d6): δ 11.98 (br s, 1H), 8.08 (d, J=9.0 Hz, 2H), 7.00 (d, J=9.0 Hz, 2H), 6.68 (d, J=2.3 Hz, 1H), 6.46 (d, J=2.3 Hz, 1H), 3.88 (s, 3H), 3.83 (s, 3H), 3.73-3.76 (m, 2H), 2.78-2.81 (m, 2H), 2.19-2.26 (m, 2H), 1.03 (d, J=6.2 Hz, 6H). ESI MS m/z 395 [M+H]+.
Reaction SMILES: [CH:1]1([N:4]2[C:13]3[C:8](=[CH:9][C:10]([F:16])=[C:11](F)[C:12]=3[F:14])[C:7](=[O:17])[C:6]([C:18]([OH:20])=[O:19])=[CH:5]2)[CH2:3][CH2:2]1.Cl.[C:22]1([C:28]2[N:29]=[N:30][N:31]([CH:33]3[CH2:37][CH2:36][NH:35][CH2:34]3)[CH:32]=2)[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1.[N+](=C1CCCCCCCCCC1C1CCCCCCCCCC1)=[N-]>N1C=CC=CC=1>[CH:1]1([N:4]2[C:13]3[C:8](=[CH:9][C:10]([F:16])=[C:11]([N:35]4[CH2:36][CH2:37][CH:33]([N:31]5[CH:32]=[C:28]([C:22]6[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=6)[N:29]=[N:30]5)[CH2:34]4)[C:12]=3[F:14])[C:7](=[O:17])[C:6]([C:18]([OH:20])=[O:19])=[CH:5]2)[CH2:3][CH2:2]1
Reactant: O=C(O)c1cn(C2CC2)c2c(F)c(F)c(F)cc2c1=O
Reactant: c1ccc(-c2cn(C3CCNC3)nn2)cc1
Agent: Cl
Agent: [N-]=[N+]=C1CCCCCCCCCC1C1CCCCCCCCCC1
Solvent: c1ccncc1
Product: O=C(O)c1cn(C2CC2)c2c(F)c(N3CCC(n4cc(-c5ccccc5)nn4)C3)c(F)cc2c1=O
Temperature: 110 °C

Procedure:
A mixture of 1-cyclopropyl-6,7,8-trifluoro-1,4-dihydro-4-oxoquinoline-3-carboxylic acid (150 mg, 0.53 mmol), 3-(4-phenyl-1,2,3-triazol-1-yl)pyrrolidine hydrochloride (252 mg, 1.05 mmol) and diazobicycloundecane (160 mg, 1.05 mmol) in pyridine (5 ml) was heated at 110° C. for 20 hrs, concentrated and diluted with water. The separated solid was filtered, washed with water and crystallized from methanol. Yield: 55 mg (22.3%), m.p. 241.4° C. 1H NMR (TFA) δ: 1.34-1.73 (m, 4H), 2.82-3.09 (m, 2H), 4.20-4.95 (m, 5H), 5.73-5.92 (m, 1H), 7.5-7.92 (m, 4H), 8.15 (d, 1H), 8.80 (s, 1H), 9.30 (s, 1H).
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([O:8][CH2:9][C@@H:10]2[CH2:14][CH2:13][CH2:12][N:11]2[CH3:15])[CH:5]=[N:6][CH:7]=1.[CH3:16][Mg]Br>C1COCC1>[CH3:16][C:2]1[CH:3]=[C:4]([O:8][CH2:9][C@@H:10]2[CH2:14][CH2:13][CH2:12][N:11]2[CH3:15])[CH:5]=[N:6][CH:7]=1
Reactant: CN1CCC[C@H]1COc1cncc(Br)c1
Reactant: C[Mg]Br
Solvent: C1CCOC1
Product: Cc1cncc(OC[C@@H]2CCCN2C)c1
Temperature: 0 °C

Procedure:
A 270 mg (1 mmol) sample of 5-bromo-3-(1-methyl-2-(S)-pyrrolidinylmethoxy)-pyridine, from Example 28 above, was dissolved in 10 mL of THF, 3.25 mg of Ni(dppp)Cl was added, and the mixture was cooled to 0° C. To this solution was added 0.47 mL of methylmagnesium bromide, then the mixture was stirred at reflux for 20 hours. Another 0.2 mL of methylmagnesium bromide was added, and the reaction mixture was stirred for 2 hours. The reaction was quenched by addition of NH4Cl solution, and the mixture was evaporated to dryness. The residue was partitioned between H2O and CHCl3, and the organic extract was dried and concentrated. The residue was purified by chromatography on silica gel, eluting with 5:1 chloroform:methanol, to give 120 mg of the title compound. MS (DCI/NH3) m/e: 207 (M+H)+. 1H NMR (CDCl3, 300 MHz) δ: 8.13 (d, J=2.7 Hz, 1H), 8.05 (s, 1H), 7.03 (m, `H), 4.04-3.89 (m, 2H), 2.66 (m, 1H), 2.48 (s, 3H), 2.32 (s, 3H), 2.35-2.26 (m, 1H), 2.09-1.98 (m, 1H), 1.92-1.68 (m, 3H).
Reaction SMILES: Cl.[C:2]1([C:8]2([C:26]3[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=3)[C@@H:16]3[C@@H:12]([CH2:13][NH:14][CH2:15]3)[C@@:11]([C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=3[O:24][CH3:25])([OH:17])[CH2:10][CH2:9]2)[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:32][O:33][C:34]1[CH:39]=[CH:38][C:37]([CH2:40][C:41](O)=[O:42])=[CH:36][CH:35]=1>>[C:26]1([C:8]2([C:2]3[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=3)[C@@H:16]3[C@@H:12]([CH2:13][N:14]([C:41](=[O:42])[CH2:40][C:37]4[CH:38]=[CH:39][C:34]([O:33][CH3:32])=[CH:35][CH:36]=4)[CH2:15]3)[C@@:11]([C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=3[O:24][CH3:25])([OH:17])[CH2:10][CH2:9]2)[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1
Reactant: COc1ccc(CC(=O)O)cc1
Reactant: COc1ccccc1[C@]1(O)CCC(c2ccccc2)(c2ccccc2)[C@H]2CNC[C@H]21
Agent: Cl
Product: COc1ccc(CC(=O)N2C[C@@H]3[C@H](C2)C(c2ccccc2)(c2ccccc2)CC[C@@]3(O)c2ccccc2OC)cc1
Yield: 66.1 %

Procedure:
By working in accordance with Example 4, starting from 0.75 g of (3aS,4S,7aS)-7,7-diphenyl-4-(2-methoxyphenyl)perhydroisoindol-4-ol hydrochloride and 0.28 g of (4-methoxyphenyl)acetic acid, 0.61 g of (3aS,4S,7aS)-7,7-diphenyl-4-(2-methoxyphenyl)-2-[(4-methoxyphenyl)acetyl]perhydroisoindol-4-ol is obtained in the form of white crystals which melt at 211° C.
Reaction SMILES: [C:1]1(=[O:11])[NH:5][C:4](=[O:6])[C:3]2=[CH:7][CH:8]=[CH:9][CH:10]=[C:2]12.[O:12](C1C=C(C=CC=1)N)C1C=CC(N)=CC=1.NC1C=C(C=CC=1)OC1C=CC=C(OC2C=CC=C(N)C=2)C=1.C1C(C(C2C=CC3C(OC(=O)C=3C=2)=O)=O)=CC2C(OC(=O)C=2C=1)=O.C1(=O)OC(=O)C2=CC=CC=C12>CN1CCCC1=O>[CH:8]1[CH:7]=[C:3]([C:4]([NH2:5])=[O:6])[C:2]([C:1]([OH:11])=[O:12])=[CH:10][CH:9]=1
Reactant: Nc1ccc(Oc2cccc(N)c2)cc1
Reactant: O=C1NC(=O)c2ccccc21
Agent: Nc1cccc(Oc2cccc(Oc3cccc(N)c3)c2)c1
Agent: O=C(c1ccc2c(c1)C(=O)OC2=O)c1ccc2c(c1)C(=O)OC2=O
Agent: O=C1OC(=O)c2ccccc21
Solvent: CN1CCCC1=O
Product: NC(=O)c1ccccc1C(=O)O
Temperature: 25 °C
Reaction time: 6 h

Procedure:
The following example illustrates the synthesis of a phthalimide-terminated imide oligomer with theoretical number average molecular weight of 12,000 g/mole. 3,4'-Oxydianiline (3,4'-ODA) (20.00 mmole, 4.0049 g) and 1,3-bis(3-aminophenoxy)benzene (APB) (20.00 mmole, 5.8467 g) were dissolved in N-methylpyrrolidinone (NMP) (~35 mL) in a flask equipped with a mechanical stirrer, condenser and nitrogen inlet. 3,3',4,4'-Benzophenone tetracarboxylic dianhydride (BTDA) (38.264 mmole, 12.3300 g) and phthalic anhydride (PA) (3.472 mmole, 0.5143 g) were added to the solution with enough NMP to total 90.8 g (20% solids). The reaction was stirred at 25° C. for 6 h to form the phthalamide acid-terminated polyamide acid. The inherent viscosity (ηinh) of the phthalamide acid-terminated polyamide acid was 0.38 dL/g in NMP at 25° C. To imidize, toluene (40 mL) was added and the reaction was heated at 160° C. for 24 h. After cooling, a powder precipitated which was washed twice in water and dried ~230° C. in a vacuum to afford a yellow solid in high yield. The resulting phthalimide-terminated polyimide was insoluble in NMP and had a glass transition temperature 212° C. A film cast from the polyamide acid solution and dried 1 hour each at 100, 225, and 371° C. had a Tg of 222° C. and was tough and creasible.
Reaction SMILES: [CH2:1]([Sn:5]([CH2:27][CH2:28][CH2:29][CH3:30])([CH2:23][CH2:24][CH2:25][CH3:26])[C:6]1[S:7][C:8]([C:11]2C=C[C:14]([CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH3:22])=[CH:13][CH:12]=2)=[CH:9][CH:10]=1)[CH2:2][CH2:3][CH3:4].BrC1[S:33]C(Br)=CC=1>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.C1(C)C=CC=CC=1>[CH2:17]([C:14]1[S:33][C:11]([C:8]2[S:7][C:6]([Sn:5]([CH2:27][CH2:28][CH2:29][CH3:30])([CH2:23][CH2:24][CH2:25][CH3:26])[CH2:1][CH2:2][CH2:3][CH3:4])=[CH:10][CH:9]=2)=[CH:12][CH:13]=1)[CH2:18][CH2:19][CH2:20][CH2:21][CH3:22]
Reactant: Brc1ccc(Br)s1
Reactant: CCCCCCc1ccc(-c2ccc([Sn](CCCC)(CCCC)CCCC)s2)cc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: Cc1ccccc1
Product: CCCCCCc1ccc(-c2ccc([Sn](CCCC)(CCCC)CCCC)s2)s1

Procedure:
5′,2″:5″,2′″:5′″,2″″-pentathiophene (6TTTTT6) is now discussed. The compound 5′-hexyl-5-tributylstannylbithiophene is prepared from 2′-hexylbithiophene using the procedure described for 2-(tri-n-butylstannyl)-5-(4-n-hexylphenyl)thiophene. A measured 6.25 mmol of this compound, 2.5 mmol of 2,5-dibromothiophene, 145 mg of tetrakis(triphenylphosphine)palladium, and 35 mL of toluene are heated just below reflux for three days under nitrogen. The precipitate is successively washed with dilute hydrochloric acid, water, and acetone, and recrystallized from mesitylene with hot filtration.
Reaction SMILES: O.O.O.C([O-])(=O)C.[Na+].Br[CH:10](Br)[C:11](=O)[C:12]([F:15])([CH3:14])[CH3:13].C(=O)(O)O.[NH2:22][NH:23][C:24]([NH2:26])=[NH:25].[OH-].[Na+]>O>[NH2:26][C:24]1[N:23]=[N:22][CH:10]=[C:11]([C:12]([F:15])([CH3:14])[CH3:13])[N:25]=1
Reactant: N=C(N)NN
Reactant: CC(C)(F)C(=O)C(Br)Br
Agent: CC(=O)[O-]
Agent: O=C(O)O
Agent: [Na+]
Solvent: O
Product: CC(C)(F)c1cnnc(N)n1
Temperature: 25 °C
Reaction time: 5 h
Yield: 50.8 %

Procedure:
A stirred solution of sodium acetate trihydrate (23.07 g, 80.7 mmol) and 1,1-dibromo-3-fluoro-3-methylbutan-2-one (21.14 g, 80.7 mmol) in water (80 ml) was heated at reflux under nitrogen for 40 min, then allowed to cool to room temperature before adding solid aminoguanidine bicarbonate (10.99 g, 80.7 mmol). The mixture was stirred at room temperature for 5 h, then 4 N aqueous NaOH solution (40.4 ml, 162 mmol) was added and the mixture was stirred under nitrogen for a further 3 days. The mixture was filtered and the solid was washed with water twice, then dried under vacuum at 60° C. to give 6.40 g (51%) of the title compound as a yellow-brown solid: 1H NMR (360 MHz, DMSO-d6) δ 1.63 (6H, d, J 22.2), 7.32 (2H, br s), 8.73 (1H, d, J 1.0); MS (ES+) m/z 157 [M+H]+.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][CH:9]2[CH2:14][CH2:13][N:12]([C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])[CH2:11][CH2:10]2)=[CH:4][CH:3]=1.Cl[CH2:23][C:24]1[CH:29]=[CH:28][N:27]=[C:26]([C:30]2[CH:35]=[C:34]([O:36][CH3:37])[C:33]([O:38][CH3:39])=[C:32]([O:40][CH3:41])[CH:31]=2)[CH:25]=1>>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]([CH:9]2[CH2:10][CH2:11][N:12]([C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])[CH2:13][CH2:14]2)[CH2:23][C:24]2[CH:29]=[CH:28][N:27]=[C:26]([C:30]3[CH:35]=[C:34]([O:36][CH3:37])[C:33]([O:38][CH3:39])=[C:32]([O:40][CH3:41])[CH:31]=3)[CH:25]=2)=[CH:4][CH:3]=1
Reactant: COc1cc(-c2cc(CCl)ccn2)cc(OC)c1OC
Reactant: CC(C)(C)OC(=O)N1CCC(Nc2ccc(Br)cc2)CC1
Product: COc1cc(-c2cc(CN(c3ccc(Br)cc3)C3CCN(C(=O)OC(C)(C)C)CC3)ccn2)cc(OC)c1OC

Procedure:
4-(4-Bromophenyl)amino-1-(tert-butoxycarbonyl)piperidine (711 mg) and 4-chloromethyl-2-(3,4,5-trimethoxyphenyl)pyridine (588 mg) was treated in the same manner as described in Example 9 to give light yellow amorphous of the title compound.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9](=O)[CH2:10][C:11]([O:13][CH2:14][CH:15]=[CH2:16])=[O:12])=[CH:4][CH:3]=1.C([O-])(=O)C.[NH4+:22].O>C1C=CC=CC=1>[NH2:22]/[C:9](/[CH2:8][C:5]1[CH:6]=[CH:7][C:2]([F:1])=[CH:3][CH:4]=1)=[CH:10]\[C:11]([O:13][CH2:14][CH:15]=[CH2:16])=[O:12]
Reactant: [NH4+]
Reactant: C=CCOC(=O)CC(=O)Cc1ccc(F)cc1
Agent: CC(=O)[O-]
Solvent: c1ccccc1
Solvent: O
Product: C=CCOC(=O)/C=C(\N)Cc1ccc(F)cc1
Yield: 100.4 %

Procedure:
Allyl 4-(4-fluorophenyl)-3-oxobutanoate (47 g, 198.95 mmol) and ammonium acetate (46.00 g, 596.85 mmol) were refluxed in benzene (250 mL) for 2 h with azeotropic removal of H2O and then cooled and concentrated. The residue was redissolved in Et2O and the organics washed with 1N HCl (2×), H2O, brine, and then dried (Na2SO4), filtered and concentrated to give 47 g (100% yield) of the title compound as a yellow oil. 1H NMR (CDCl3, 400 MHz) δ 7.17 (dd, J=8.4, 5.2 Hz, 2H), 6.99 (t, J=8.6 Hz, 2H), 5.28 (dd, J=17.2, 1.6 Hz, 1H), 5.18 (dd, J=10.3, 1.0 Hz, 1H), 4.61 (s, 1H), 4.55 (d, J=5.6 Hz, 2H), 3.41 (s, 2H).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:13]=[CH:14][CH:15]=1)[CH2:5][NH:6][C:7](=[O:12])[C:8]([F:11])([F:10])[F:9].[H-].[Na+].I[CH3:19].O>C1COCC1>[F:1][C:2]1[CH:3]=[C:4]([CH:13]=[CH:14][CH:15]=1)[CH2:5][N:6]([CH3:19])[C:7](=[O:12])[C:8]([F:10])([F:11])[F:9]
Reactant: O=C(NCc1cccc(F)c1)C(F)(F)F
Reactant: CI
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: CN(Cc1cccc(F)c1)C(=O)C(F)(F)F
Temperature: 25 °C
Reaction time: 8 h
Yield: 92 %

Procedure:
A solution of 3-fluoro-N-(trifluoroacetyl)benzylamine (Intermediate 105, 0.508 g) in THF (5 mL) was added to a stirred suspension of sodium hydride (60% oil dispersion, 0.096 g) in THF (5 mL). The resultant mixture was stirred at room temperature for 30 minutes. Iodomethane (0.653 g) was added and the mixture was stirred at room temperature overnight. The mixture was poured into water and extracted with ethyl acetate, washed with water, dried (MgSO4) and filtered. The filtrate was evaporated to dryness to give 3-fluoro-N-methyl-N-(trifluoroacetyl)benzylamine (0.497 g) as a white solid.
Reaction SMILES: CO[CH:3](OC)[N:4]([CH3:6])[CH3:5].[OH:9][C:10]1[CH:22]=[CH:21][C:13]2[N:14]=[C:15]([S:17]([NH2:20])(=[O:19])=[O:18])[S:16][C:12]=2[CH:11]=1>C(#N)C>[CH3:6][N:4]([CH3:5])[CH:3]=[N:20][S:17]([C:15]1[S:16][C:12]2[CH:11]=[C:10]([OH:9])[CH:22]=[CH:21][C:13]=2[N:14]=1)(=[O:18])=[O:19]
Reactant: NS(=O)(=O)c1nc2ccc(O)cc2s1
Reactant: COC(OC)N(C)C
Solvent: CC#N
Product: CN(C)C=NS(=O)(=O)c1nc2ccc(O)cc2s1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
N,N-Dimethylformamide dimethyl acetal (1.5 mL, 11.3 mmol) was added to a partial suspension of 6-hydroxybenzothiazole-2-sulfonamide (2.3 gm, 10 mmol) in acetonitrile (20 mL) to give an immediate solution. After stirring at room temperature for 1 hour, the reaction mixture was cooled and the crystalline product which formed (1.95 gm) was collected m.p. 195°-198° C. Evaporation of the reaction solvent and dissolution of the residue in ethyl acetate/acetonitrile which was washed with water, dried (Na2SO4) and evaporated yielded an additional 0.6 gm from methylene chloride.
Reaction SMILES: C([Li])(C)(C)C.[CH:6]1[CH:11]=[CH:10][C:9]([O:12][C:13]2[CH:18]=[CH:17][C:16](Br)=[CH:15][CH:14]=2)=[CH:8][CH:7]=1.[CH:20]([CH:22]=[CH2:23])=[O:21]>C1COCC1>[CH:22]([CH:20]([C:16]1[CH:17]=[CH:18][C:13]([O:12][C:9]2[CH:10]=[CH:11][CH:6]=[CH:7][CH:8]=2)=[CH:14][CH:15]=1)[OH:21])=[CH2:23]
Reactant: C=CC=O
Reactant: Brc1ccc(Oc2ccccc2)cc1
Agent: [Li]C(C)(C)C
Solvent: C1CCOC1
Product: C=CC(O)c1ccc(Oc2ccccc2)cc1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 72.8 %

Procedure:
tert-Butyllithium (24.5 mL, 1.7M in pentane, 42.2 mmol) was added dropwise over 30 min to a solution of 4-bromodiphenyl ether (5.00 g, 20.1 mmol) in THF (50 mL) at -78° C. under argon. The cooling bath was removed and the bright yellow reaction mixture was warmed to 0° C. over 20 min. The reaction was stirred at 0° C. for 30 min, at which time a tan-colored solution developed. Freshly distilled acrolein (1.6 mL, 24 mmol) was added dropwise over 5 min. The colorless reaction mixture was stirred at 0° C. for 15 min, then quenched by addition of saturated NH4Cl (10 mL). The mixture was diluted with diethyl ether (200 mL) and the organic layer was washed with water (20 mL) and brine (50 mL), then dried over MgSO4. Evaporation gave a crude oil which was purified by flash chromatography on silica gel (400 g) eluted with a step gradient of 10:90 EtOAc/hexane to 15:85 EtOAc/hexane to 20:80 EtOAc/hexane to provide title compound (3.31 g, 73%) as a colorless oil.
Reaction SMILES: [Cl:1]N1C(=O)CCC1=O.[CH:9]([Si:12]([CH:25]([CH3:27])[CH3:26])([CH:22]([CH3:24])[CH3:23])[O:13][C:14]([C:16]1[N:21]=[CH:20][CH:19]=[CH:18][N:17]=1)=[CH2:15])([CH3:11])[CH3:10].CCOCC.[O-]S([O-])(=O)=O.[Mg+2]>C1COCC1.CCCCCC>[Cl:1][CH:15]=[C:14]([C:16]1[N:17]=[CH:18][CH:19]=[CH:20][N:21]=1)[O:13][Si:12]([CH:9]([CH3:10])[CH3:11])([CH:22]([CH3:24])[CH3:23])[CH:25]([CH3:27])[CH3:26]
Reactant: C=C(O[Si](C(C)C)(C(C)C)C(C)C)c1ncccn1
Reactant: O=C1CCC(=O)N1Cl
Agent: O=S(=O)([O-])[O-]
Agent: [Mg+2]
Solvent: CCCCCC
Solvent: CCOCC
Solvent: C1CCOC1
Product: CC(C)[Si](OC(=CCl)c1ncccn1)(C(C)C)C(C)C

Procedure:
N-chlorosuccinimide (9.97 g, 74.7 mmol) was added to a solution of 2-{1-[(Triisopropylsilyl)oxy]vinyl}pyrimidine (17.3 g, 62.2 mmol) in dry THF (120 ml) under N2 then heated at 65° for 5 hr. After cooling, ether (275 ml) was added and then washed with sat sodium bicarbonate solution (2×100 ml). The organic layer was dried over sodium sulfate, filtered and evaporated to leave an amber oil. This oil was dissolved in hexane (250 ml), treated with MgSO4 and filtered. Evaporation afforded the product as a yellow oil in quantitative yield.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([CH:17]=[C:18]([CH:20]=[O:21])[CH:19]=1)[CH2:5][N:6]([CH:14]1[CH2:16][CH2:15]1)[C:7](=[O:13])[O:8][C:9]([CH3:12])([CH3:11])[CH3:10].CC1(C)C(C)(C)OB(/[CH:30]=[CH:31]/[CH2:32][O:33][CH3:34])O1.C([O-])([O-])=O.[Na+].[Na+]>CN(C=O)C.O>[CH:14]1([N:6]([CH2:5][C:4]2[CH:3]=[C:2](/[CH:30]=[CH:31]/[CH2:32][O:33][CH3:34])[CH:19]=[C:18]([CH:20]=[O:21])[CH:17]=2)[C:7](=[O:13])[O:8][C:9]([CH3:12])([CH3:11])[CH3:10])[CH2:16][CH2:15]1
Reactant: COC/C=C/B1OC(C)(C)C(C)(C)O1
Reactant: CC(C)(C)OC(=O)N(Cc1cc(Br)cc(C=O)c1)C1CC1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: COC/C=C/c1cc(C=O)cc(CN(C(=O)OC(C)(C)C)C2CC2)c1
Temperature: 90 °C

Procedure:
To a solution of tert-butyl (3-bromo-5-formylbenzyl)cyclopropylcarbamate (1 eq.) from the previous step and 4,4,5,5-tetramethyl-2-[(1E)-3-(methyloxy)-1-propen-1-yl]-1,3,2-dioxaborolane (1 eq.) in DMF (0.2 M) was added trans-bis(triphenylphosphine) palladium(II) bromide (0.05 eq.). The vessel was repeatedly evacuated and back-filled with nitrogen. Finally, 2 M aq. Na2CO3 (3 eq.) was added and the resulting mixture was heated at 90° C. for 6 h. The now black suspension was cooled to RT, diluted with water and extracted with ether. The combined organic extracts were washed further with 10% aq. HCl, 1 N aq. NaOH, water and brine, dried over Na2SO4, filtered and the filtrate concentrated in vacuo. Purification of the crude product by way of flash chromatography (SiO2, Hex→3:7 (v/v) Hex:EtOAc) afforded the title compound as a pale yellow oil.
Reaction SMILES: Cl[C:2](Cl)=[CH:3][C:4]1[CH:9]=[C:8]([F:10])[CH:7]=[CH:6][C:5]=1[F:11].C([Li])CCC>C1COCC1>[C:3]([C:4]1[CH:9]=[C:8]([F:10])[CH:7]=[CH:6][C:5]=1[F:11])#[CH:2]
Reactant: Fc1ccc(F)c(C=C(Cl)Cl)c1
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: C#Cc1cc(F)ccc1F
Temperature: -55 °C
Yield: 51 %

Procedure:
The title compound of Example 37.1 (10.2 g, 48.7 mmol) was dissolved in dry THF (63 mL), cooled on a dry ice/isopropanol bath to −55° C. and butyl lithium (2.5 M, 42 mL, 105 mmol) was added within 30 min at a rate that kept the temperature below −40° C. LC/MS showed good conversion 20 min after the addition of BuLi and stirring. The mixture was warmed up to 0° C. with the aid of a water bath. At 0° C. the mixture was quenched with potassium hydrogen sulfate (2 M solution) until a neutral aqueous phase was achieved. Diethyl ether was added and the water phase was extracted twice with a small amount of diethyl ether. The organic phases were combined and dried (MgSO4), filtered and carefully evaporated using only heat. The solvent was removed by distillation under normal air pressure with the oil bath temperature at 80° C. The remaining residue was distilled in vacuo, and the fraction at 30° C./0 mmHg was collected. Yield 51%, 3.8 g.
Reaction SMILES: [Br:1][C:2]1[N:3]=[C:4]2[CH:10]=[CH:9][NH:8][C:5]2=[N:6][CH:7]=1.C1C(=O)N([Cl:18])C(=O)C1>C(Cl)Cl.CN(C=O)C>[Br:1][C:2]1[N:3]=[C:4]2[C:10]([Cl:18])=[CH:9][NH:8][C:5]2=[N:6][CH:7]=1
Reactant: O=C1CCC(=O)N1Cl
Reactant: Brc1cnc2[nH]ccc2n1
Solvent: CN(C)C=O
Solvent: ClCCl
Product: Clc1c[nH]c2ncc(Br)nc12
Temperature: 25 °C
Reaction time: 8 h
Yield: 141 %

Procedure:
To a solution of 2-bromo-5H-pyrrolo[2,3-b]pyrazine (1.8 g, 9.09 mmol) in 18 mL of DCM and 18 mL of DMF was added NCS (1.46 g, 10.9 mmol) at RT. The reaction mixture was stirred at RT overnight, then partitioned between EtOAc and brine. The organic layer was dried (MgSO4) concentrated to give 2.98 g of impure 2-bromo-7-chloro-5H-pyrrolo[2,3-b]pyrazine as a yellow oil which was used for the next step without any purification.
Reaction SMILES: [CH2:1]([C@H:4]1[CH2:9][CH2:8][C@H:7]([CH2:10][CH2:11][C:12]2[CH:17]=[CH:16][C:15]([C:18]#[CH:19])=[CH:14][CH:13]=2)[CH2:6][CH2:5]1)[CH2:2][CH3:3].[C:20]([C:23]1[CH:28]=[CH:27][C:26](I)=[CH:25][CH:24]=1)#[C:21][CH3:22]>C(NCC)C.[Cu](I)I>[CH2:20]([C@H:23]1[CH2:28][CH2:27][C@H:26]([CH2:19][CH2:18][C:15]2[CH:16]=[CH:17][C:12]([C:11]#[C:10][C:7]3[CH:6]=[CH:5][C:4]([C:1]#[C:2][CH3:3])=[CH:9][CH:8]=3)=[CH:13][CH:14]=2)[CH2:25][CH2:24]1)[CH2:21][CH3:22]
Reactant: C#Cc1ccc(CC[C@H]2CC[C@H](CCC)CC2)cc1
Reactant: CC#Cc1ccc(I)cc1
Agent: I[Cu]I
Solvent: CCNCC
Product: CC#Cc1ccc(C#Cc2ccc(CC[C@H]3CC[C@H](CCC)CC3)cc2)cc1

Procedure:
4-[2-(Trans-4-propylcyclohexyl)ethyl]phenylacetylene (2.54 g, 0.01 mol) and 4-(1-propynyl)iodobenzene (2.4 g, 0.01 mol) were dissolved in diethylamine (20 ml), and then copper iodide (0.11 g, 0.15 mmol) and dichlorobistriphenylphosphinepalladium dichloride (0.21 g, 0.3 mmol) were added. The resulting mixture was subjected to reaction and purification operations in the same manner as in Example 1, to obtain the objective 4-[2-(trans-4-propylcyclohexyl)ethyl]-4'-(1-propynyl)tolan (compound