Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[CH:10]=[C:9]([Br:11])[C:8](=[O:12])[N:7]([CH2:13][CH:14]2[CH2:19][CH2:18][CH2:17][CH2:16][CH2:15]2)[C:6]=1[CH2:20]Br)=[O:4].[CH3:22][O:23][C:24](=[O:37])[CH2:25][NH:26][S:27]([C:30]1[CH:35]=[CH:34][C:33]([CH3:36])=[CH:32][CH:31]=1)(=[O:29])=[O:28].[I-].[Na+].C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C.[Cl-].[Na+].O>[CH3:1][O:2][C:3]([C:5]1[CH:10]=[C:9]([Br:11])[C:8](=[O:12])[N:7]([CH2:13][CH:14]2[CH2:19][CH2:18][CH2:17][CH2:16][CH2:15]2)[C:6]=1[CH2:20][N:26]([CH2:25][C:24]([O:23][CH3:22])=[O:37])[S:27]([C:30]1[CH:31]=[CH:32][C:33]([CH3:36])=[CH:34][CH:35]=1)(=[O:29])=[O:28])=[O:4]
Reactant: COC(=O)CNS(=O)(=O)c1ccc(C)cc1
Reactant: COC(=O)c1cc(Br)c(=O)n(CC2CCCCC2)c1CBr
Agent: O=C([O-])[O-]
Agent: [Cl-]
Agent: [I-]
Solvent: O
Solvent: CN(C)C=O
Product: COC(=O)CN(Cc1c(C(=O)OC)cc(Br)c(=O)n1CC1CCCCC1)S(=O)(=O)c1ccc(C)cc1
Temperature: 25 °C
Reaction time: 16 h
Yield: 79.2 %

Procedure:
A mixture of 5-bromo-2-bromomethyl-1-cyclohexylmethyl-6-oxo-1,6-dihydro-pyridine-3-carboxylic acid methyl ester (4.49 g, 10.7 mmol), (toluene-4-sulfonylamino)-acetic acid methyl ester (2.46 g, 10.1 mmol), sodium iodide (3.19 g, 21.3 mmol) and potassium carbonate (2.95 g, 21.3 mmol) in DMF (70 mL) was stirred at r.t. for 16 h. Brine (120 mL) was added, and the resulting suspension was extracted with EtOAc. The organic layer was washed with water and dried over MgSO4. After the solvent was evaporated in vacuo, the crude product was chromatographed (60% EtOAc/hexanes) to give 4.67 g of the title compound as a yellow viscous oil. MS: (+) m/z 583.19, 585.14 (M+1, 79/81Br).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([CH:16]=[CH:17][CH:18]=1)[O:5][C:6]1[CH:11]=[CH:10][N:9]=[C:8]2[NH:12][C:13](=[O:15])[NH:14][C:7]=12.[CH3:19][O:20][C:21]1[CH:22]=[C:23]([CH:27]=[CH:28][CH:29]=1)[C:24](Cl)=[O:25]>>[CH3:19][O:20][C:21]1[CH:22]=[C:23]([CH:27]=[CH:28][CH:29]=1)[C:24]([NH:1][C:2]1[CH:18]=[CH:17][CH:16]=[C:4]([O:5][C:6]2[CH:11]=[CH:10][N:9]=[C:8]3[NH:12][C:13](=[O:15])[NH:14][C:7]=23)[CH:3]=1)=[O:25]
Reactant: COc1cccc(C(=O)Cl)c1
Reactant: Nc1cccc(Oc2ccnc3[nH]c(=O)[nH]c23)c1
Product: COc1cccc(C(=O)Nc2cccc(Oc3ccnc4[nH]c(=O)[nH]c34)c2)c1
Yield: 40 %

Procedure:
Method H was used with 7-(3-aminophenoxy)-1H-imidazo[4,5-b]pyridin-2(3H)-one and 3-methoxy-benzoyl chloride to afford the title compound as a brown solid (21 mg, 40%). 1H-NMR (δ, ppm, DMSO-d6): 3.83 (s, 3H, OMe), 6.49 (d, 1H, HPy,5, J=5.8 Hz), 6.90 (d, 1H, Harom, J=7.48 Hz), 7.16 (d, 1H, Harom, J=6.52 Hz), 7.39-7.49 (m, 3H, Harom), 7.52 (d, 1H, Harom, J=7.61 Hz), 7.62-7.68 (m, 2H, Harom), 7.81 (d, 1H, HPy,6, J=5.44 Hz), 10.31 (s, 1H, NHamide), 11.19 (s, 1H, NHPy3), 11.39 (s, 1H, NHPy2).
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9]([O:11][CH3:12])=[O:10])=[CH:4][C:3]=1[O:13][CH3:14].[Cl:15][C:16]1[CH:33]=[CH:32][C:19]([CH2:20][CH2:21][NH:22][C:23](=[O:31])[C:24]2[CH:29]=[CH:28][C:27](I)=[CH:26][CH:25]=2)=[CH:18][CH:17]=1.CC(C)(C(=O)CC(=O)C(C)(C)C)C.C([O-])([O-])=O.[Cs+].[Cs+]>CN1C(=O)CCC1>[Cl:15][C:16]1[CH:17]=[CH:18][C:19]([CH2:20][CH2:21][NH:22][C:23]([C:24]2[CH:25]=[CH:26][C:27]([O:1][C:2]3[CH:7]=[CH:6][C:5]([CH2:8][C:9]([O:11][CH3:12])=[O:10])=[CH:4][C:3]=3[O:13][CH3:14])=[CH:28][CH:29]=2)=[O:31])=[CH:32][CH:33]=1
Reactant: O=C(NCCc1ccc(Cl)cc1)c1ccc(I)cc1
Reactant: COC(=O)Cc1ccc(O)c(OC)c1
Agent: CC(C)(C)C(=O)CC(=O)C(C)(C)C
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN1CCCC1=O
Product: COC(=O)Cc1ccc(Oc2ccc(C(=O)NCCc3ccc(Cl)cc3)cc2)c(OC)c1
Yield: 44.6 %

Procedure:
Methyl 2-(4-hydroxy-3-methoxyphenyl)acetate (0.204 g, 1.04 mmol), N-(4-chlorophenethyl)-4-iodobenzamide (0.200 g, 0.519 mmol), 2,2,6,6-tetramethyl-3,5-heptanedione (0.00956 g, 0.0519 mmol), Cu(I)Cl (0.0257 g, 0.259 mmol) and Cs2CO3 (0.338 g, 1.04 mmol) were stirred together in NMP (2 ml) for 1 hour. The reaction was loaded onto silica gel and the product eluted using a gradient of 5% ethyl acetate/hexanes to 100% ethyl acetate/hexanes. Isolated methyl 2-(4-(4-((4-chlorophenethyl)carbamoyl)phenoxy)-3-methoxyphenyl)acetate (0.105 g, 44.6% yield) as a yellow solid.
Reaction SMILES: [F:1][C:2]1[CH:10]=[C:9]([F:11])[CH:8]=[C:7]([NH:12][C:13]2[C:14]3[CH:39]=[CH:38][N:37](S(C4C=CC(C)=CC=4)(=O)=O)[C:15]=3[N:16]=[C:17]([NH:19][C:20]3[CH:25]=[CH:24][C:23]([CH:26]4[CH2:31][CH2:30][N:29]([CH2:32][CH2:33][CH3:34])[CH2:28][CH2:27]4)=[CH:22][C:21]=3[O:35][CH3:36])[N:18]=2)[C:3]=1[C:4]([NH2:6])=[O:5].[OH-].[K+]>O1CCCC1.O1CCOCC1.O>[F:1][C:2]1[CH:10]=[C:9]([F:11])[CH:8]=[C:7]([NH:12][C:13]2[N:18]=[C:17]([NH:19][C:20]3[CH:25]=[CH:24][C:23]([CH:26]4[CH2:31][CH2:30][N:29]([CH2:32][CH2:33][CH3:34])[CH2:28][CH2:27]4)=[CH:22][C:21]=3[O:35][CH3:36])[NH:16][C:15]3=[N:37][CH:38]=[CH:39][C:14]=23)[C:3]=1[C:4]([NH2:6])=[O:5]
Reactant: CCCN1CCC(c2ccc(Nc3nc(Nc4cc(F)cc(F)c4C(N)=O)c4ccn(S(=O)(=O)c5ccc(C)cc5)c4n3)c(OC)c2)CC1
Agent: [K+]
Agent: [OH-]
Solvent: C1COCCO1
Solvent: O
Solvent: C1CCOC1
Product: CCCN1CCC(c2ccc(Nc3nc(Nc4cc(F)cc(F)c4C(N)=O)c4ccnc-4[nH]3)c(OC)c2)CC1

Procedure:
2,4-difluoro-6-({2-{[2-(methyloxy)-4-(1-propyl-4-piperidinyl)phenyl]amino}-7-[(4-methylphenyl)sulfonyl]-7H-pyrrolo[2,3-d]pyrimidin-4-yl}amino)benzamide (9.5 g, 13.7 mmol) was dissolved in tetrahydrofuran (100 mL) and dioxane (400 mL). A solution of KOH (35 g) in water (100 mL) was added to the reaction mixture. The mixture was heated to reflux overnight, and cooled. The organic layer was separated, dried over sodium sulfate, filtered, and adsorbed over silica. Purification by flash silica gel chromatography with a gradient from 10 to 100% of a 20:20:2:58 mixture of THF/MeOH/NH4OH/DCM in DCM provided the required product which was contaminated with ˜15% p-toluene sulfonic acid. The residue was dissolved in THF (˜400 mL) and refluxed to dissolve most of the solid. The mixture was cooled and then washed with 2 N aqueous NaOH. The separated clear organic layer was dried over sodium sulfate, filtered and concentrated. The solid obtained was recrystallized with 20% MeOH in DCM to obtain 2,4-difluoro-6-[(2-{[2-(methyloxy)-4-(1-propyl-4-piperidinyl)phenyl]amino}-1H-pyrrolo[2,3-d]pyrimidin-4-yl)amino]benzamide (5.8 g, 79%). 1H NMR (400 MHz, DMSO-d6) δ ppm 0.85 (t, J=7.4 Hz, 3H), 1.40-1.50 (m, 2H), 1.60-1.78 (m, 4H), 1.89-1.98 (m, 2H), 2.20-2.27 (m, 2H), 2.37-2.46 (m, 1H), 2.91-2.98 (m, 2H), 3.83 (s, 3H), 6.22 (dd, J=3.4, 1.9 Hz, 1H), 6.77 (dd, J=8.3, 1.6 Hz, 1H), 6.89 (d, J=1.6 Hz, 1H), 6.93 (ddd, J=11.4, 9.0, 2.6 Hz, 1H), 7.00 (dd, J=3.5, 2.2 Hz, 1H), 7.65 (s, 1H), 7.98 (d, J=8.1 Hz, 1H), 8.03 (br. s., 1H), 8.17 (s, 1H), 8.53 (d, J=11.4 Hz, 1H), 11.08 (s, 1H), 11.42 (s, 1H); ESIMS (M+H)+=536.
Reaction SMILES: [C:1]([NH2:5])(=[O:4])[CH:2]=[CH2:3].[CH2:6]([N:9](CC=C)[CH:10]=[CH:11][CH:12]=[C:13]([C:16]#[N:17])[C:14]#[N:15])[CH:7]=[CH2:8].C(O)C>O>[C:1]([NH2:5])(=[O:4])[CH:2]=[CH2:3].[CH2:6]([NH:9][CH:10]=[CH:11][CH:12]=[C:13]([C:14]#[N:15])[C:16]#[N:17])[CH:7]=[CH2:8]
Reactant: C=CCN(C=CC=C(C#N)C#N)CC=C
Agent: C=CC(N)=O
Solvent: O
Solvent: CCO
Product: C=CCNC=CC=C(C#N)C#N

Procedure:
A solution of 120 g. of acrylamide and 114 g. of 3-diallylaminoallylidenemalononitrile (A) in 500 cc. of ethanol was refluxed. 3.2 g. of AZBN were added and the solution was refluxed for one hour under stirring. A solution of 104 g. of acrylamide, 800 cc. of ethanol and 3.2 g. of AZBN was added and the solution was refluxed for one hour under stirring. A solution of 88 g. of acrylamide, 400 cc. of ethanol and 2.4 g. of AZBN was added and refluxed for one hour. A solution of 72 g. of acrylamide, 400 cc. of ethanol and 1.6 g. of AZBN was added and the solution was refluxed for one hour. In conclusion a solution of 56 g. of acrylamide, 400 cc. of ethanol and 1.6 g. of AZBN was added and refluxed for 2 hours. The mixture was cooled, filtered, washed with ethanol and then with ethyl ether and vacuum dried at 50° C. 478 g. of a product containing about 9% aminoallylidenemalononitrile units in weight were obtained, the product solution at 6% in water diluted 1:2000 with water had an optical density of 0.76 at 382 nm.
Reaction SMILES: C(O)=O.[NH2:4][CH2:5][CH2:6][C:7]1[CH:30]=[CH:29][C:10]([NH:11][CH:12]2[CH2:17][CH2:16][N:15]([C:18]([NH:20][CH2:21][C:22]3[CH:27]=[CH:26][CH:25]=[C:24]([F:28])[CH:23]=3)=[O:19])[CH2:14][CH2:13]2)=[CH:9][CH:8]=1.C([Si]([O:48][C:49]1[CH:54]=[CH:53][C:52]([O:55][CH2:56][CH:57]2[CH2:59][O:58]2)=[CH:51][CH:50]=1)(C1C=CC=CC=1)C1C=CC=CC=1)(C)(C)C>C(Cl)(Cl)Cl.CO>[F:28][C:24]1[CH:23]=[C:22]([CH:27]=[CH:26][CH:25]=1)[CH2:21][NH:20][C:18]([N:15]1[CH2:14][CH2:13][CH:12]([NH:11][C:10]2[CH:9]=[CH:8][C:7]([CH2:6][CH2:5][NH:4][CH2:59][C@H:57]([OH:58])[CH2:56][O:55][C:52]3[CH:53]=[CH:54][C:49]([OH:48])=[CH:50][CH:51]=3)=[CH:30][CH:29]=2)[CH2:17][CH2:16]1)=[O:19]
Reactant: NCCc1ccc(NC2CCN(C(=O)NCc3cccc(F)c3)CC2)cc1
Reactant: CC(C)(C)[Si](Oc1ccc(OCC2CO2)cc1)(c1ccccc1)c1ccccc1
Solvent: ClC(Cl)Cl
Solvent: CO
Solvent: O=CO
Product: O=C(NCc1cccc(F)c1)N1CCC(Nc2ccc(CCNC[C@H](O)COc3ccc(O)cc3)cc2)CC1
Yield: 20.8 %

Procedure:
4-[4-(2-Aminoethyl)anilino]-N-(3-fluorobenzyl)-1-piperidinecarboxamide formate (0.50 g, 1.20 mmol) was reacted with tert-butyl-(4-oxiranylmethoxy-phenoxy)-diphenyl-silane (0.436 g, 1.08 mmol) according to Procedure G (eluant: 20:1 chloroform-methanol) to give the title compound (0.174 g, 0.225 mmol).
Reaction SMILES: [CH2:1]([CH:4]1[CH2:9][CH2:8][C:7]([C:10]2[CH:15]=[CH:14][C:13]([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)=[C:12]([F:22])[CH:11]=2)=[CH:6][CH2:5]1)[CH2:2][CH3:3].ClC1C(=O)C(C#N)=C(C#N)C(=O)C=1Cl>C1(C)C=CC=CC=1>[F:22][C:12]1[CH:11]=[C:10]([C:7]2[CH:6]=[CH:5][C:4]([CH2:1][CH2:2][CH3:3])=[CH:9][CH:8]=2)[CH:15]=[CH:14][C:13]=1[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1
Reactant: CCCC1CC=C(c2ccc(-c3ccccc3)c(F)c2)CC1
Agent: N#CC1=C(C#N)C(=O)C(Cl)=C(Cl)C1=O
Solvent: Cc1ccccc1
Product: CCCc1ccc(-c2ccc(-c3ccccc3)c(F)c2)cc1
Temperature: 114 °C
Yield: 101.9 %

Procedure:
A solution of 4-(4-n-propylcyclohexenyl)-2-fluorobiphenyl (20 gram) in toluene (120 ml) was added over a 25 minute period with stirring to a suspension of 2,3-dichloro-5,6-dicyano-1,4-benzoquinone (DDQ) (34 gram) in toluene (200 ml). The temperature rose from 19° C. to 24° C. over the addition, after which time the reaction mixture was heated under reflux (114° C.) for 3 hours. The reaction mixture was cooled, filtered, the filtrate and toluene washings (100 ml) were combined and then washed with saturated sodium metabisulphite solution (250 ml). The organic extract was further washed with water (2×250 ml), dried and evaporated to dryness to give a brown residue (20.1 gram). The residue was dissolved in dichloromethane (120 mls) and adsorbed onto a column of basic alumina (60 gram) over silica gel (60 gram). Elution with dichloromethane (450 ml) gave on evaporation of the solvent an off white solid (14 gram) which was recrystallised from ethanol (80 mls) to yield a white crystalline product (12.8 gram) m.p. 75°-77° C.
Reaction SMILES: [CH3:1][N:2]([CH:4]([CH:7]1[CH2:16][CH2:15][C:10]2([O:14][CH2:13][CH2:12][O:11]2)[CH2:9][CH2:8]1)[C:5]#N)[CH3:3].[C:17]1([Mg]Cl)[CH:22]=[CH:21]C=[CH:19][CH:18]=1.[Cl-].[NH4+].O>C1COCC1>[O:14]1[C:10]2([CH2:15][CH2:16][CH:7]([CH:4]([N:2]([CH3:3])[CH3:1])[C:5]3[CH:21]=[CH:22][CH:17]=[CH:18][CH:19]=3)[CH2:8][CH2:9]2)[O:11][CH2:12][CH2:13]1
Reactant: CN(C)C(C#N)C1CCC2(CC1)OCCO2
Reactant: Cl[Mg]c1ccccc1
Agent: [Cl-]
Agent: [NH4+]
Solvent: O
Solvent: C1CCOC1
Product: CN(C)C(c1ccccc1)C1CCC2(CC1)OCCO2
Temperature: 25 °C
Reaction time: 20 h

Procedure:
A solution of the aminonitrile 4 (23.56 g, 105 mmol) in absol. THF (100 ml) was added dropwise to a 25 percent strength solution of phenylmagnesium chloride (144 ml, 262.5 mmol) in THF under argon and while cooling with ice, and the mixture was stirred at RT for 20 hours. The reaction mixture was worked up by adding saturated ammonium chloride solution (100 ml) and water (100 ml) while cooling with ice, and extracting the mixture with diethyl ether (3×100 ml). The organic phase was washed with water and saturated sodium chloride solution, dried (Na2SO4) and concentrated.
Reaction SMILES: [Cl-].[CH3:2][O:3]C[P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.C([Li])CCC.[S:29]1[C:35]2[CH:36]=[CH:37][CH:38]=[CH:39][C:34]=2[C:33](=O)[CH2:32][CH2:31][CH2:30]1.Cl(O)(=O)(=O)=O>O1CCCC1.CCCCCC>[S:29]1[C:35]2[CH:36]=[CH:37][CH:38]=[CH:39][C:34]=2[CH:33]([CH:2]=[O:3])[CH2:32][CH2:31][CH2:30]1
Reactant: COC[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: O=C1CCCSc2ccccc21
Agent: [Cl-]
Agent: [Li]CCCC
Agent: [O-][Cl+3]([O-])([O-])O
Solvent: C1CCOC1
Solvent: CCCCCC
Product: O=CC1CCCSc2ccccc21
Reaction time: 0.08 h
Yield: 58.3 %

Procedure:
A solution of 20.0 g of methoxymethyltriphenylphosphonium chloride in 60 ml of absolute tetrahydrofuran was treated dropwise at 0° C. under argon with 43 ml of 1.4N n-butyllithium in hexane. The mixture was stirred for 1/4 hour. Thereafter, the mixture was treated with 8.02 g of 3,4-dihydro-1-benzothiepin-5(2H)-one in a small amount of tetrahydrofuran. After 5 minutes, the cooling bath was removed and the reaction mixture was stirred at room temperature for an additional 11/2 hours. Thereafter, the reaction mixture was partitioned between petroleum ether and ethanol/water (8:2). The lighter phase was washed with water, dried over sodium sulfate and evaporated. There were obtained 11.8 g of crude product which were dissolved in 80 ml of tetrahydrofuran and treated under argon with 100 ml of 35% perchloric acid. The reaction mixture was stirred overnight, poured on to ice, extracted with ether, washed with 5% sodium carbonate solution, dried and evaporated. Chromatography on silica gel (petroleum ether/ethyl acetate 92:8) yielded 5.04 g of 2,3,4,5-tetrahydro-1-benzothiepine-5-carboxaldehyde as a colorless oil.
Reaction SMILES: [CH2:1]([CH:3]1[CH:29]=[C:28]([CH3:30])[CH2:27][CH:26]([CH3:31])[CH2:25][CH:24]([O:32][CH3:33])[CH:23]2[O:34][C:19]([OH:38])([CH:20]([CH3:37])[CH2:21][CH:22]2[O:35][CH3:36])[C:18](=[O:39])[C:17](=[O:40])[N:16]2[CH:11]([CH2:12][CH2:13][CH2:14][CH2:15]2)[C:10](=[O:41])[O:9][CH:8]([C:42]([CH3:55])=[CH:43][CH:44]2[CH2:49][CH2:48][CH:47]([NH2:50])[CH:46]([O:51][CH2:52][CH:53]=[CH2:54])[CH2:45]2)[CH:7]([CH3:56])[CH:6]([OH:57])[CH2:5][C:4]1=[O:58])[CH3:2].[C:59]([O:62][CH2:63][C:64](Cl)=[O:65])(=[O:61])[CH3:60]>C(Cl)Cl>[CH2:1]([CH:3]1[CH:29]=[C:28]([CH3:30])[CH2:27][CH:26]([CH3:31])[CH2:25][CH:24]([O:32][CH3:33])[CH:23]2[O:34][C:19]([OH:38])([CH:20]([CH3:37])[CH2:21][CH:22]2[O:35][CH3:36])[C:18](=[O:39])[C:17](=[O:40])[N:16]2[CH:11]([CH2:12][CH2:13][CH2:14][CH2:15]2)[C:10](=[O:41])[O:9][CH:8]([C:42]([CH3:55])=[CH:43][CH:44]2[CH2:49][CH2:48][CH:47]([NH:50][C:64](=[O:65])[CH2:63][O:62][C:59](=[O:61])[CH3:60])[CH:46]([O:51][CH2:52][CH:53]=[CH2:54])[CH2:45]2)[CH:7]([CH3:56])[CH:6]([OH:57])[CH2:5][C:4]1=[O:58])[CH3:2]
Reactant: C=CCOC1CC(C=C(C)C2OC(=O)C3CCCCN3C(=O)C(=O)C3(O)OC(C(OC)CC(C)CC(C)=CC(CC)C(=O)CC(O)C2C)C(OC)CC3C)CCC1N
Reactant: CC(=O)OCC(=O)Cl
Solvent: ClCCl
Product: C=CCOC1CC(C=C(C)C2OC(=O)C3CCCCN3C(=O)C(=O)C3(O)OC(C(OC)CC(C)CC(C)=CC(CC)C(=O)CC(O)C2C)C(OC)CC3C)CCC1NC(=O)COC(C)=O
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
A solution of 17-ethyl-1,14-dihydroxy-12-[2'-(4"-amino-3"-allyloxycyclohexyl)-1'-methylvinyl]-23,25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-azatricyclo[22.3.1.04,9 ]octacos-18-ene-2,3,10,16-tetraone (40 mg) in dry methylene chloride (0.4 ml) is cooled to 0° C. To this solution is added a solution of acetoxyacetyl chloride (9 mg) in methylene chloride (0.5 ml). The reaction mixture is stirred at 0° C. for 30 minutes, and quenched with a drop of methanol. Purification by preparative tlc on silica gel gives the title compound.
Reaction SMILES: [CH3:1][N:2]([CH3:14])[C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[C:9](=[O:13])[NH:8][CH:7]=[CH:6]2.C(=O)([O-])[O-].[K+].[K+].[Br:21][C:22]1[CH:27]=[CH:26][CH:25]=[C:24](Br)[C:23]=1[CH3:29]>CS(C)=O>[Br:21][C:22]1[C:23]([CH3:29])=[C:24]([N:8]2[CH:7]=[CH:6][C:5]3[C:10](=[CH:11][CH:12]=[C:3]([N:2]([CH3:14])[CH3:1])[CH:4]=3)[C:9]2=[O:13])[CH:25]=[CH:26][CH:27]=1
Reactant: Cc1c(Br)cccc1Br
Reactant: CN(C)c1ccc2c(=O)[nH]ccc2c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CS(C)=O
Product: Cc1c(Br)cccc1-n1ccc2cc(N(C)C)ccc2c1=O
Temperature: 150 °C
Yield: 44.4 %

Procedure:
6-Dimethylamino-2H-isoquinolin-1-one (50 mg, 0.27 mmol), cuprous iodide (10 mg, 0.053 mmol), and potassium carbonate (37 mg, 0.27 mmol) were deposited in sealed vessel. 3 mL DMSO and 2,6-dibromotoluene (133 mg, 0.532 mmol) were added. Argon was bubbled through the mixture for 2 minutes and the lid was tightly closed. This was heated at 150° C. for 5 hours. The resulting mixture was partitioned between ethyl acetate and water. The organic layer was washed with brine, dried over anhydrous magnesium sulfate, concentrated in vacuo, and purified by flash chromatography (30% ethyl acetate/hexanes) to yield 2-(3-Bromo-2-methyl-phenyl)-6-dimethylamino-2H-isoquinolin-1-one (43 mg, 0.12 mmol). MS (ESI) 357 (M+H)+.
Reaction SMILES: [OH:1][C:2]1[CH:15]=[CH:14][C:5]2[C@H:6]([CH2:9][C:10]([O:12][CH3:13])=[O:11])[CH2:7][O:8][C:4]=2[CH:3]=1.[C:16]([O:19][CH2:20][C:21]1[CH:26]=[C:25]([O:27][CH2:28][CH2:29][CH2:30][S:31]([CH3:34])(=[O:33])=[O:32])[CH:24]=[C:23]([CH3:35])[C:22]=1[C:36]1[CH:41]=[CH:40][CH:39]=[C:38]([CH2:42]O)[CH:37]=1)(=[O:18])[CH3:17].C(P(CCCC)CCCC)CCC.N(C(N1CCCCC1)=O)=NC(N1CCCCC1)=O>C1(C)C=CC=CC=1.CCCCCC>[C:16]([O:19][CH2:20][C:21]1[CH:26]=[C:25]([O:27][CH2:28][CH2:29][CH2:30][S:31]([CH3:34])(=[O:33])=[O:32])[CH:24]=[C:23]([CH3:35])[C:22]=1[C:36]1[CH:41]=[CH:40][CH:39]=[C:38]([CH2:42][O:1][C:2]2[CH:15]=[CH:14][C:5]3[C@H:6]([CH2:9][C:10]([O:12][CH3:13])=[O:11])[CH2:7][O:8][C:4]=3[CH:3]=2)[CH:37]=1)(=[O:18])[CH3:17]
Reactant: CC(=O)OCc1cc(OCCCS(C)(=O)=O)cc(C)c1-c1cccc(CO)c1
Reactant: COC(=O)C[C@@H]1COc2cc(O)ccc21
Agent: CCCCP(CCCC)CCCC
Agent: O=C(N=NC(=O)N1CCCCC1)N1CCCCC1
Solvent: Cc1ccccc1
Solvent: CCCCCC
Product: COC(=O)C[C@@H]1COc2cc(OCc3cccc(-c4c(C)cc(OCCCS(C)(=O)=O)cc4COC(C)=O)c3)ccc21
Temperature: 25 °C
Reaction time: 3 h
Yield: 72.4 %

Procedure:
A solution of methyl [(3S)-6-hydroxy-2,3-dihydro-1-benzofuran-3-yl]acetate (0.208 g, 1.00 mmol), {3′-(hydroxymethyl)-6-methyl-4-[3-(methylsulfonyl)propoxy]biphenyl-2-yl}methyl acetate (0.360 g, 1.00 mmol) and tributylphosphine (0.324 g, 1.60 mmol) in toluene (15 mL) was stirred, 1,1′-(azodicarbonyl)dipiperidine (0.404 g, 1.60 mmol) was added, and the mixture was stirred at room temperature for 3 hr under nitrogen atmosphere. Hexane (8 mL) was added to the reaction mixture, the precipitated insoluble substance was filtered off, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate:hexane=30:70-70:30) to give the title compound (0.432 g, yield 79%) as a colorless oil.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[C:12]([CH:14]3[CH2:16][CH2:15]3)[N:11]3[N:17]=[CH:18][C:19]([C:20]#[CH:21])=[C:10]3[N:9]=2)=[CH:4][CH:3]=1.Br[C:23]1[CH:28]=[CH:27][C:26]([S:29]([NH2:32])(=[O:31])=[O:30])=[CH:25][CH:24]=1>>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[C:12]([CH:14]3[CH2:16][CH2:15]3)[N:11]3[N:17]=[CH:18][C:19]([C:20]#[C:21][C:23]4[CH:28]=[CH:27][C:26]([S:29]([NH2:32])(=[O:31])=[O:30])=[CH:25][CH:24]=4)=[C:10]3[N:9]=2)=[CH:4][CH:3]=1
Reactant: NS(=O)(=O)c1ccc(Br)cc1
Reactant: C#Cc1cnn2c(C3CC3)cc(-c3ccc(Cl)cc3)nc12
Product: NS(=O)(=O)c1ccc(C#Cc2cnn3c(C4CC4)cc(-c4ccc(Cl)cc4)nc23)cc1

Procedure:
The title compound was prepared from 5-(4-chloro-phenyl)-7-cyclopropyl-3-ethynyl-pyrazolo[1,5-a]pyrimidine (example C.5) (73 mg, 0.25 mmol) and 4-bromo-benzenesulfonamide (59 mg, 0.25 mmol) according to general procedure II. Obtained as a yellow solid (79 mg, 71%). MS (ISP) 449.3 [(M+H)+]; mp 225-228° C.
Reaction SMILES: CS(O[CH2:6][C:7]1[CH:12]=[CH:11][C:10]([C:13]#[N:14])=[C:9]([C:15]2[N:20]=[C:19]3[N:21]([CH3:30])[C:22](=[O:29])[N:23]([CH2:24][C:25]([CH3:28])([CH3:27])[CH3:26])[C:18]3=[CH:17][CH:16]=2)[CH:8]=1)(=O)=O.[NH:31]1[CH2:35][CH2:34][CH2:33][CH2:32]1.C(N(C(C)C)CC)(C)C>CN1C(=O)CCC1.CO>[CH3:26][C:25]([CH3:27])([CH3:28])[CH2:24][N:23]1[C:18]2[C:19](=[N:20][C:15]([C:9]3[CH:8]=[C:7]([CH2:6][N:31]4[CH2:35][CH2:34][CH2:33][CH2:32]4)[CH:12]=[CH:11][C:10]=3[C:13]#[N:14])=[CH:16][CH:17]=2)[N:21]([CH3:30])[C:22]1=[O:29]
Reactant: Cn1c(=O)n(CC(C)(C)C)c2ccc(-c3cc(COS(C)(=O)=O)ccc3C#N)nc21
Reactant: C1CCNC1
Solvent: CN1CCCC1=O
Solvent: CCN(C(C)C)C(C)C
Solvent: CO
Product: Cn1c(=O)n(CC(C)(C)C)c2ccc(-c3cc(CN4CCCC4)ccc3C#N)nc21
Temperature: 65 °C
Reaction time: 4 h

Procedure:
To a microwave vial, 4-cyano-3-[1-(2,2-dimethylpropyl)-3-methyl-2-oxo-2,3-dihydro-1H-imidazo[4,5-b]pyridin-5-yl]benzyl methanesulfonate (21-1) (20 mg, 0.05 mmol) and pyrrolidine (5 mg, 0.07 mmol) were added and dissolved in NMP (0.25 ml). Diisopropyl ethyl amine (18 mg, 0.14 mmol) was then added and the reaction was heated at 65° C. allowed to stir for 4 hours. The mixture was diluted with methanol and purified using reverse phase chromatography (10-100%, 0.1% TFA in H2O/Acetonitrile); the desired fractions were collected and concentrated to produce 2-[1-(2,2-dimethylpropyl)-3-methyl-2-oxo-2,3-dihydro-1H-imidazo[4,5-b]pyridin-5-yl]-4-(pyrrolidin-1-ylmethyl)benzonitrile (13-2). HRMS (M+H)+: observed=404.2456, calculated=404.2445. 1H NMR (400 MHz, CD3 OD): δ 7.91 (s, 1H); 7.83 (d, J=7.9 Hz, 1H); 7.60 (q, J=8.3 Hz, 2H); 7.54 (d, J=8.0 Hz, 1H); 3.82 (s, 2H); 3.77 (s, 2H); 3.55 (s, 3H); 2.64 (m, 4H); 1.85 (m, 4H); 1.06 (s, 9H).
Reaction SMILES: [C:1]1([Mg]Cl)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[Cl-].C1([Zn+])C=CC=CC=1.[CH3:17][O:18][C:19]1[CH:26]=[CH:25][C:22](C#N)=[CH:21][CH:20]=1.CCCCCCCCCCCCC>C1COCC1.[Cl-].[Zn+2].[Cl-]>[C:1]1([C:22]2[CH:25]=[CH:26][C:19]([O:18][CH3:17])=[CH:20][CH:21]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: Cl[Mg]c1ccccc1
Reactant: COc1ccc(C#N)cc1
Agent: CCCCCCCCCCCCC
Agent: [Cl-]
Agent: [Zn+2]
Solvent: C1CCOC1
Product: COc1ccc(-c2ccccc2)cc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 45 %

Procedure:
A solution of zinc chloride (0.48 g; 3.5 mmol) in THF (5 mL) was treated at 0° C. with phenylmagnesium chloride (2.1 mL of a 1.40M solution in THF; 3.0 mmol) and then stirred at room temperature for 30 min. The mixture of phenylzinc chloride thus obtained was then treated with a solution of 4-methoxybenzonitrile (0.27 g; 2.0 mmol), dichlorobis(trimethylphosphine)nickel (0.028 g; 5 mol %), and tridecane (0.18 g; 1.0 mmol; internal GC standard) in THF (2 mL) and heated at 60° C. for 8 h. A sample was withdrawn and quenched in a mixture of 1M sodium citrate (aq) and ether. GC analysis of the organic phase of the hydrolyzed reaction sample showed the presence of 0.90 mmol (45% yield) of 4-phenylanisole, no 4-methoxybenzophenone imine, 0.38 mmol of anisole, 0.82 mmol of biphenyl, 0.23 mmol of 4,4′-dimethoxybiphenyl, and 0.09 mmol of 4-methoxybenzonitrile remaining in the reaction mixture.
Reaction SMILES: [C:1]1([C@@H:7](NC[C@H](CCC)CC(O)=O)[CH3:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C([O:22][CH2:23][CH3:24])(=O)C.Cl>CO>[CH:1]1[CH:6]=[C:5]2[CH:4]=[CH:24][C:23]([OH:22])=[C:7]([C:1]3[C:2]4[C:3](=[CH:8][CH:7]=[CH:23][CH:24]=4)[CH:4]=[CH:5][C:6]=3[OH:22])[C:8]2=[CH:3][CH:2]=1
Reactant: CCOC(C)=O
Reactant: CCC[C@@H](CN[C@@H](C)c1ccccc1)CC(=O)O
Agent: Cl
Solvent: CO
Product: Oc1ccc2ccccc2c1-c1c(O)ccc2ccccc12
Temperature: 50 °C
Reaction time: 1 h

Procedure:
(R,S)-3-[(1-phenyl ethylamino)-methyl]-hexanoic acid (5.0 g) is dissolved in methanol (20 mL) and (RS)-1,1′-bi-2-naphthol (5.75 g) is added to it at room temperature. The mixture is stirred at 50° C. for 1 hour, during which time solid precipitate comes out from the reaction mixture. Reaction mixture is allowed to cool to room temperature and filtered under reduced pressure to obtain 3.7 g of solid complex. Complex is suspended in the biphasic mixture of ethyl acetate (20 mL) and 1 N hydrochloric acid (20 mL) and stirred for 30 to 45 min to decompose the complex. Aqueous phase is washed with 10 mL ethyl acetate. Organic phases are mixed together and washed with brine, followed by drying over sodium sulfate. Solvent is evaporated under vacuum to obtain optically pure (5)-1,1′-bi-2-naphthol (1.56 g) having 95% ee.