Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: O=S(Cl)[Cl:3].O[CH2:6][C:7]1[N:12]=[C:11]([C:13]([O:15][CH3:16])=[O:14])[CH:10]=[CH:9][CH:8]=1.C([O-])([O-])=O.[K+].[K+]>ClCCl>[Cl:3][CH2:6][C:7]1[N:12]=[C:11]([C:13]([O:15][CH3:16])=[O:14])[CH:10]=[CH:9][CH:8]=1
Reactant: COC(=O)c1cccc(CO)n1
Reactant: O=S(Cl)Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: ClCCl
Product: COC(=O)c1cccc(CCl)n1
Temperature: 40 °C
Reaction time: 1 h
Yield: 101.4 %

Procedure:
SOCl2 (57 g, 0.48 mol) was added to a solution of methyl 6-(hydroxymethyl)picolinate 70 (40.0 g, 0.239 mol) (Chem. Eur. J. 2006, 12, 6393-6402) in dichloromethane (500 mL) at room temperature. The mixture was stirred at 40° C. for 1 h and sat. aq K2CO3 was added to adjust the pH to 9. The mixture was extracted with CH2Cl2 and the combined organics were washed with brine, dried (Na2SO4), and concentrated in vacuo to give 71 (45 g).
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6]([CH3:9])=[CH:5][C:4]=1[NH:10][C:11](=O)[C:12]1[C:17]([O:18][CH3:19])=[CH:16][CH:15]=[CH:14][C:13]=1[F:20])#[N:2].[OH-:22].[Na+].OO.Cl>C(O)C>[F:20][C:13]1[CH:14]=[CH:15][CH:16]=[C:17]([O:18][CH3:19])[C:12]=1[C:11]1[NH:2][C:1](=[O:22])[C:3]2[C:4](=[CH:5][C:6]([CH3:9])=[CH:7][CH:8]=2)[N:10]=1
Reactant: COc1cccc(F)c1C(=O)Nc1cc(C)ccc1C#N
Reactant: [OH-]
Agent: Cl
Agent: OO
Agent: [Na+]
Solvent: CCO
Product: COc1cccc(F)c1-c1nc2cc(C)ccc2c(=O)[nH]1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 89 %

Procedure:
To a suspension of N-(2-cyano-5-methylphenyl)-2-fluoro-6-methoxybenzamide (31.5 g, 111 mmol) in ethanol (626 mL) was added 6 M aqueous NaOH solution (205 mL). After 10 minutes, 30% aqueous H2O2 (60 mL) was added, forming a slurry. The reaction was heated to reflux for 18 h and cooled to room temperature. NaOH (22.2 g, 0.56 mol) and 30% aqueous H2O2 (26 mL) were added, and the reaction was heated to reflux for six hours. The reaction cooled to room temperature, 30% aqueous H2O2 (45 mL) was added, and the reaction was heated to reflux for 18 h. The reaction was cooled to room temperature, NaOH (10 g, 0.25 mol) and 30% aqueous H2O2 (70 mL) were added, and the reaction was heated to reflux for six hours. The reaction was cooled to room temperature and poured over ice (800 mL). The pH was adjusted to 3-4 by addition of conc. HCl solution, and the precipitated off-white solid was filtered and washed with water (3×40 mL). The solid was dried under vacuum to provide 2-(2-fluoro-6-methoxy-phenyl)-7-methyl-3H-quinazolin-4-one (28 g, 89%).
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([NH:8][C@H:9]([CH3:12])[CH2:10][OH:11])[C:5]([C:13]2[S:14][CH:15]=[CH:16][CH:17]=2)=[CH:4][N:3]=1.[NH2:18][C:19]1[CH:24]=[CH:23][C:22]([S:25]([CH3:32])(=[N:27][CH2:28][CH2:29][O:30][CH3:31])=[O:26])=[CH:21][CH:20]=1>>[CH3:31][O:30][CH2:29][CH2:28][N:27]=[S:25]([C:22]1[CH:21]=[CH:20][C:19]([NH:18][C:2]2[N:7]=[C:6]([NH:8][C@H:9]([CH3:12])[CH2:10][OH:11])[C:5]([C:13]3[S:14][CH:15]=[CH:16][CH:17]=3)=[CH:4][N:3]=2)=[CH:24][CH:23]=1)([CH3:32])=[O:26]
Reactant: COCCN=S(C)(=O)c1ccc(N)cc1
Reactant: C[C@H](CO)Nc1nc(Cl)ncc1-c1cccs1
Product: COCCN=S(C)(=O)c1ccc(Nc2ncc(-c3cccs3)c(N[C@H](C)CO)n2)cc1
Yield: 3 %

Procedure:
In the reaction of (R)-2-(2-chloro-5-(2-thienyl)pyrimidine-4-ylamino)propan-1-ol (248.2 mg, 0.92 mmol) with (RS)—S-(4-aminophenyl)-N-(2-methoxy-ethyl)-S-methylsulphoximide (191 mg, 0.84 mmol) according to procedure 5c, the desired product is obtained in 3% yield (10 mg) after chromatographic purification (silica gel, dichloromethane/ethanol (0%-20% ethanol) and HPLC).
Reaction SMILES: [O:1]=[C:2]1[CH:7]=[C:6]([C:8](O)=[O:9])[NH:5][C:4]2[C:11](=[O:19])[O:12][C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=3[C:3]1=2.C(N1C=CN=C1)(N1C=CN=C1)=O.O.[NH2:33][C:34]1[NH:38][N:37]=[N:36][N:35]=1>CN(C)C=O>[O:1]=[C:2]1[CH:7]=[C:6]([C:8]([NH:33][C:34]2[NH:38][N:37]=[N:36][N:35]=2)=[O:9])[NH:5][C:4]2[C:11](=[O:19])[O:12][C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=3[C:3]1=2
Reactant: Nc1nnn[nH]1
Reactant: O=C(O)c1cc(=O)c2c([nH]1)c(=O)oc1ccccc12
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: O
Solvent: CN(C)C=O
Product: O=C(Nc1nnn[nH]1)c1cc(=O)c2c([nH]1)c(=O)oc1ccccc12
Yield: 46.6 %

Procedure:
A mixture of 1,5-dihydro-1,5-dioxo-4H-1-benzopyrano[3,4-b]pyridine-3-carboxylic acid (2.57 g, 0.01 mole) and 1,1'-carbonyldiimidazole (3.24 g, 0.02 mole) in dimethylformamide (50 ml) is heated at 100 for 60 minutes under nitrogen. The reaction mixture is cooled. 5-aminotetrazole monohydrate (1.03 g, 0.01 mole) is added and the resulting mixture is heated at 100 for 60 minutes, cooled and filtered. The product is recrystallized from dimethylformamide to give white crystals (1.51 g, 39%) mp 265-270. The product crystallizes as a 1:1 salt or complex with 1H-imidazole.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][CH2:4][N:5]([CH2:10][C:11]1[CH:16]=[CH:15][CH:14]=[C:13]([C:17]2[CH:22]=[CH:21][N:20]=[C:19]([NH:23][CH2:24][CH2:25][C:26]3[CH:31]=[CH:30][C:29]([OH:32])=[CH:28][CH:27]=3)[N:18]=2)[CH:12]=1)[S:6]([CH3:9])(=[O:8])=[O:7].[N:33]1[CH:38]=[CH:37][CH:36]=[CH:35][C:34]=1[C:39](O)=[O:40]>>[OH:32][C:29]1[CH:28]=[CH:27][C:26]([CH2:25][CH2:24][NH:23][C:19]2[N:18]=[C:17]([C:13]3[CH:12]=[C:11]([CH:16]=[CH:15][CH:14]=3)[CH2:10][N:5]([S:6]([CH3:9])(=[O:8])=[O:7])[CH2:4][CH2:3][CH2:2][NH:1][C:39]([C:34]3[CH:35]=[CH:36][CH:37]=[CH:38][N:33]=3)=[O:40])[CH:22]=[CH:21][N:20]=2)=[CH:31][CH:30]=1
Reactant: O=C(O)c1ccccn1
Reactant: CS(=O)(=O)N(CCCN)Cc1cccc(-c2ccnc(NCCc3ccc(O)cc3)n2)c1
Product: CS(=O)(=O)N(CCCNC(=O)c1ccccn1)Cc1cccc(-c2ccnc(NCCc3ccc(O)cc3)n2)c1

Procedure:
Compound 2 was coupled with pyridine-2-carboxylic acid following procedure K. LC-MS showed the product had the expected M+H+ of 561. 1H NMR (Varian 300 MHz, DMSO-D6, shifts relative to the solvent peak at 2.49 ppm) δ 8.7 (d, 1H) 8.6 (t, 1H) 8.3 (d, 1H) 8.0 (s, 1H) 7.9 (t, 1H), 7.5 (m, 3H), 7.2 (t, 1H), 7.0 (m, 3H), 6.6 (d, 2H), 4.4 (s, 2H), δ 3.4 (t, 2H), 3.2 (m, 4H), 3.0 (s, 3H), 2.7 (t, 2H), δ 1.7 (m, 2H).
Reaction SMILES: [Br:1]Br.[C:3]([C:6]1[CH:17]=[C:16]([Cl:18])[C:9]([O:10][CH2:11][C:12]([O:14][CH3:15])=[O:13])=[C:8]([Cl:19])[CH:7]=1)(=[O:5])[CH3:4]>C(Cl)(Cl)Cl>[Br:1][CH2:4][C:3]([C:6]1[CH:7]=[C:8]([Cl:19])[C:9]([O:10][CH2:11][C:12]([O:14][CH3:15])=[O:13])=[C:16]([Cl:18])[CH:17]=1)=[O:5]
Reactant: BrBr
Reactant: COC(=O)COc1c(Cl)cc(C(C)=O)cc1Cl
Solvent: ClC(Cl)Cl
Product: COC(=O)COc1c(Cl)cc(C(=O)CBr)cc1Cl
Temperature: 40 °C
Reaction time: 18 h

Procedure:
A solution of bromine (0.77 ml) in chloroform (10 ml) was added dropwise over 15 minutes to a stirred solution of the product from step (i) (4.16 g) in chloroform (40 ml) at 25° C. The temperature was raised to 40° C. for 1 hour and then stirring continued for a further 18 hours at ambient temperature. The solvent was removed in vacuo and the residual oil purified by flash chromatography on silica, eluting with dichloromethane, to give a crystalline solid. Recrystallisation from methanol gave methyl 4-bromoacetyl-2,6-dichlorophenoxyacetate, 1.88 g, as white crystals: m.p. 89°-90° C.; NMR (d6DMSO) δ8.06 (2H, s), 4.93 (2H, s) 4.82 (2H, s) 3.72 (3H, s); m/e 355/357 (M+H)+, 1 Br pattern; calculated for C11H9BrCl2O4 : C, 37.1; H, 2.3. found: C, 36.8; H, 2.4%.
Reaction SMILES: Cl.[NH2:2][CH2:3][CH:4]1[CH2:8][CH2:7][CH2:6][N:5]1[CH2:9][C@@H:10]([C:12]1[CH:21]=[CH:20][C:15]2[C:16](=[O:19])[O:17][CH2:18][C:14]=2[C:13]=1[CH3:22])[OH:11].[N:23]1([C:28]2[CH:33]=[CH:32][C:31]([S:34](Cl)(=[O:36])=[O:35])=[CH:30][CH:29]=2)[CH:27]=[N:26][N:25]=[N:24]1>>[OH:11][C@H:10]([C:12]1[C:13]([CH3:22])=[C:14]2[C:15](=[CH:20][CH:21]=1)[C:16](=[O:19])[O:17][CH2:18]2)[CH2:9][N:5]1[CH2:6][CH2:7][CH2:8][CH:4]1[CH2:3][NH:2][S:34]([C:31]1[CH:30]=[CH:29][C:28]([N:23]2[CH:27]=[N:26][N:25]=[N:24]2)=[CH:33][CH:32]=1)(=[O:35])=[O:36]
Reactant: O=S(=O)(Cl)c1ccc(-n2cnnn2)cc1
Reactant: Cc1c([C@@H](O)CN2CCCC2CN)ccc2c1COC2=O
Agent: Cl
Product: Cc1c([C@@H](O)CN2CCCC2CNS(=O)(=O)c2ccc(-n3cnnn3)cc2)ccc2c1COC2=O

Procedure:
N-((1-((R)-2-Hydroxy-2-(4-methyl-1-oxo-1,3-dihydroisobenzofuran-5-yl)ethyl)pyrrolidin-2-yl)methyl)-4-(1H-tetrazol-1-yl)benzenesulfonamide was prepared in a similar fashion to that described for the synthesis of EXAMPLE 13 starting from 5-41R)-2-(2-(aminomethyl)pyrrolidin-1-yl)-1-hydroxyethyl)-4-methylisobenzofuran-1(3H)-one hydrochloride [INTERMEDIATE 3] and commercially available 4-(1H-tetrazol-1-yl)benzene-1-sulfonyl chloride.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([CH3:8])[C:3]=1[N:9]1[CH:13]=[CH:12][C:11](/[C:14](/[CH3:19])=[CH:15]\[C:16](O)=[O:17])=[CH:10]1.[CH3:20][NH:21][OH:22]>>[CH3:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([CH3:8])[C:3]=1[N:9]1[CH:13]=[CH:12][C:11](/[C:14](/[CH3:19])=[CH:15]\[C:16]([N:21]([OH:22])[CH3:20])=[O:17])=[CH:10]1
Reactant: CNO
Reactant: C/C(=C/C(=O)O)c1ccn(-c2c(C)cccc2C)c1
Product: C/C(=C/C(=O)N(C)O)c1ccn(-c2c(C)cccc2C)c1

Procedure:
Condensation of (Z)-3-[1-(2,6-dimethylphenyl)-1H-pyrrol-3-yl]-2-butenoic acid is condensed with N-methylhydroxylamine as described in example 1(a) to yield (Z)-3-[1-(2,6-dimethylphenyl)-1H-pyrrol-3-yl]-N-hydroxy-N-methyl-2-butenamide, m.p. 158°-160°.
Reaction SMILES: [H-].[Na+].[Cl:3][C:4]1[CH:5]=[C:6]2[C:10](=[CH:11][CH:12]=1)[NH:9][C:8]([C:13]1[CH:18]=[CH:17][C:16]([Cl:19])=[CH:15][CH:14]=1)=[C:7]2[CH2:20][CH2:21][C:22]([N:24]1[CH2:29][CH2:28][N:27]([C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][C:31]=2[O:36][CH3:37])[CH2:26][CH2:25]1)=[O:23].I[CH3:39].O>CN(C)C=O>[Cl:3][C:4]1[CH:5]=[C:6]2[C:10](=[CH:11][CH:12]=1)[N:9]([CH3:39])[C:8]([C:13]1[CH:14]=[CH:15][C:16]([Cl:19])=[CH:17][CH:18]=1)=[C:7]2[CH2:20][CH2:21][C:22]([N:24]1[CH2:25][CH2:26][N:27]([C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][C:31]=2[O:36][CH3:37])[CH2:28][CH2:29]1)=[O:23]
Reactant: CI
Reactant: COc1ccccc1N1CCN(C(=O)CCc2c(-c3ccc(Cl)cc3)[nH]c3ccc(Cl)cc23)CC1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: COc1ccccc1N1CCN(C(=O)CCc2c(-c3ccc(Cl)cc3)n(C)c3ccc(Cl)cc23)CC1
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
Sodium hydride (60% suspension in mineral oil, 40 mg, 1 mmol) was added to a solution of 1-{3-[5-chloro-2-(4-chlorophenyl)-1H-indol-3-yl]-1-oxopropyl}-4-(2-methoxyphenyl)piperazine (Description 33, 270 mg, 0.53 mmol) in dimethylformamide (10 mL) and the mixture was stirred at room temperature for 10 min. Iodomethane (165 μl, 376 mg, 2.65 mmol) was added and the mixture was stirred at room temperature for 1 h. Water (100 mL) was added and the mixture was extracted with ether (2×40 mL). The combined organic fractions were washed with water (3×40 mL) and brine (40 mL), dried (MgSO4) and the solvent was evaporated under reduced pressure to give the title compound as a beige foam. 1H NMR (360 MHz, CDCl3) δ 7.60 (1H, d, J 1.7 Hz), 7.48 (2H, d, J 8.4 Hz), 7.32 (2H, d, J 8.4 Hz), 7.24 (1H, d, J 8.5 Hz), 7.20 (1H, dd, J 8.5, 1.7 Hz), 7.02 (1H, t, J 7.8 Hz), 6.94-6.82 (3H, m), 3.86 (3H, s), 3.75 (2H, t, J 5.0 Hz), 3.54 (3H, s), 3.40 (2H, t, J 5.0 Hz), 3.02 (2H, t, J 8.1 Hz), 2.95 (2H, t, J 5.0 Hz), 2.80 (2H, t, J 5.0 Hz), and 2.55 (2H, t, J 8.1 Hz). m/z (ES+) 522, 524 (M+1).
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([NH:8][C:9]2[CH:14]=[CH:13][C:12]([O:15][CH3:16])=[CH:11][C:10]=2[N:17]2[CH:21]=[CH:20][CH:19]=[N:18]2)[C:5]([Cl:22])=[CH:4][N:3]=1.[NH2:23][C:24]1[CH:37]=[CH:36][C:27]2[NH:28][C:29](=[O:35])[CH2:30][CH2:31][C:32]([CH3:34])([CH3:33])[C:26]=2[CH:25]=1>>[Cl:22][C:5]1[C:6]([NH:8][C:9]2[CH:14]=[CH:13][C:12]([O:15][CH3:16])=[CH:11][C:10]=2[N:17]2[CH:21]=[CH:20][CH:19]=[N:18]2)=[N:7][C:2]([NH:23][C:24]2[CH:37]=[CH:36][C:27]3[NH:28][C:29](=[O:35])[CH2:30][CH2:31][C:32]([CH3:34])([CH3:33])[C:26]=3[CH:25]=2)=[N:3][CH:4]=1
Reactant: CC1(C)CCC(=O)Nc2ccc(N)cc21
Reactant: COc1ccc(Nc2nc(Cl)ncc2Cl)c(-n2cccn2)c1
Product: COc1ccc(Nc2nc(Nc3ccc4c(c3)C(C)(C)CCC(=O)N4)ncc2Cl)c(-n2cccn2)c1

Procedure:
(2,5-Dichloro-pyrimidin-4-yl)-(4-methoxy-2-pyrazol-1-yl-phenyl)-amine was reacted with 7-amino-5,5-dimethyl-1,3,4,5-tetrahydro-bezo[b]azepin-2-one, in a similar manner as Example 601b, to yield desired product 7-[5-Chloro-4-(4-methoxy-2-pyrazol-1-yl-phenylamino)-pyrimidin-2-ylamino]-5,5-dimethyl-1,3,4,5-tetrahydro-benzo[b]azepin-2-one as a lyophylate (20%); 1H NMR (400 MHz, DMSO-d6) δ 9.91 (s, 1H), 9.37 (s, 2H), 8.26 (s, 1H), 8.12 (s, 1H), 8.03 (d, J=8.90 Hz, 1H), 7.84 (s, 1H), 7.55 (d, J=8.56 Hz, 1H), 7.40 (s, 1H), 7.22 (d, J=1.87 Hz, 1H), 6.98 (d, J=8.64 Hz, 1H), 6.78 (d, J=8.45 Hz, 1H), 6.55 (s, 1H), 3.86 (s, 3H), 2.16 (m, 2H), 1.95 (m, 2H), 1.24 (s, 6H); MS (m/e) 504.45 (M+H).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([C:20]2[CH:25]=[CH:24][C:23]([F:26])=[CH:22][C:21]=2[F:27])[CH2:9][C:10]([C:12]2[CH:13]=[N:14][C:15]([O:18]C)=[CH:16][CH:17]=2)=[O:11])=[CH:4][CH:3]=1.Cl.C(OCC)(=O)C>O1CCOCC1>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([CH:8]([C:20]2[CH:25]=[CH:24][C:23]([F:26])=[CH:22][C:21]=2[F:27])[CH2:9][C:10]([C:12]2[CH:17]=[CH:16][C:15](=[O:18])[NH:14][CH:13]=2)=[O:11])=[CH:6][CH:7]=1
Reactant: COc1ccc(C(=O)CC(c2ccc(Br)cc2)c2ccc(F)cc2F)cn1
Agent: Cl
Solvent: C1COCCO1
Solvent: CCOC(C)=O
Product: O=C(CC(c1ccc(Br)cc1)c1ccc(F)cc1F)c1ccc(=O)[nH]c1
Temperature: 100 °C

Procedure:
To a solution of 3-(4-bromophenyl)-3-(2,4-difluorophenyl)-1-(6-methoxypyridin-3-yl)propan-1-one (0.245 g, 567 μmol) in dioxane (6 mL) was added 37% hydrochloric acid (1.23 g, 1.04 mL, 12.5 mmol) and the resulting mixture was heated at 100° C. for 1½ h. After cooling to room temperature, the reaction mixture was poured on water and ethyl acetate and the layers were separated. The aqueous layer was extracted twice with ethyl acetate. The organic layers were washed with brine, dried over magnesium sulfate, filtered, and evaporated. Off-white solid (0.227 g, 95%). MS (ESI−): m/z=418.0 ([M−H]−).
Reaction SMILES: [CH3:1][C:2]1([CH3:19])[CH2:6][O:5][C:4]2[CH:7]=[C:8]([CH3:18])[C:9]([C:11]3[N:12]=[CH:13][C:14]([NH2:17])=[N:15][CH:16]=3)=[CH:10][C:3]1=2.[Cl:20][C:21]1[CH:29]=[CH:28][CH:27]=[CH:26][C:22]=1[C:23](Cl)=[O:24]>>[Cl:20][C:21]1[CH:29]=[CH:28][CH:27]=[CH:26][C:22]=1[C:23]([NH:17][C:14]1[CH:13]=[N:12][C:11]([C:9]2[C:8]([CH3:18])=[CH:7][C:4]3[O:5][CH2:6][C:2]([CH3:19])([CH3:1])[C:3]=3[CH:10]=2)=[CH:16][N:15]=1)=[O:24]
Reactant: O=C(Cl)c1ccccc1Cl
Reactant: Cc1cc2c(cc1-c1cnc(N)cn1)C(C)(C)CO2
Product: Cc1cc2c(cc1-c1cnc(NC(=O)c3ccccc3Cl)cn1)C(C)(C)CO2
Yield: 50.1 %

Procedure:
Similarly, (2-chlorophenyl)-N-[5-(3,3,6-trimethyl(2,3-dihydrobenzo[b]furan-5-yl))-pyrazin-2-yl]carboxamide (180) (14.8 mg, yield: 50.1%, purity>95%) as white solid was prepared from 5-(3,3,6-trimethyl-2,3-dihydrobenzo[3,4-b]furan-5-yl)pyrazine-2-ylamine (177) (19 mg, 0.075 mmol) and 2-chlorobenzoyl chloride (19 μl).
Reaction SMILES: [CH2:1]([C:5]1[N:6]([CH2:17][C:18]2[CH:23]=[CH:22][C:21]([C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=3[C:30]3[NH:34][N:33]=[N:32][N:31]=3)=[CH:20][CH:19]=2)[C:7]([C:15]#[N:16])=[C:8]([CH:10]([OH:14])[CH:11]([CH3:13])[CH3:12])[N:9]=1)[CH2:2][CH2:3][CH3:4].[OH-:35].[Na+]>>[CH2:1]([C:5]1[N:6]([CH2:17][C:18]2[CH:23]=[CH:22][C:21]([C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=3[C:30]3[NH:34][N:33]=[N:32][N:31]=3)=[CH:20][CH:19]=2)[C:7]([C:15]([NH2:16])=[O:35])=[C:8]([CH:10]([OH:14])[CH:11]([CH3:12])[CH3:13])[N:9]=1)[CH2:2][CH2:3][CH3:4]
Reactant: [OH-]
Reactant: CCCCc1nc(C(O)C(C)C)c(C#N)n1Cc1ccc(-c2ccccc2-c2nnn[nH]2)cc1
Agent: [Na+]
Product: CCCCc1nc(C(O)C(C)C)c(C(N)=O)n1Cc1ccc(-c2ccccc2-c2nnn[nH]2)cc1

Procedure:
Following a procedure similar to that described in Example 74(d), but using 0.34 g of 2-butyl-4-(1-hydroxy-2-methylpropyl)-1-{4-[2-(tetrazol-5-yl)phenyl]-phenyl}methylimidazole-5-carbonitrile [prepared as described in step (c) above] in a 1N aqueous solution of sodium hydroxide, 0.24 g of the title compound was obtained as a powder, melting at 155°-157° C.
Reaction SMILES: [OH:1][C:2]1[CH:33]=[CH:32][C:5]([CH2:6][CH:7]2[C:16]3[C:11](=[CH:12][C:13]([O:19][CH3:20])=[C:14]([O:17][CH3:18])[CH:15]=3)[CH2:10][CH2:9][N:8]2[CH2:21][C:22]([NH:24][CH2:25][C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)=[O:23])=[CH:4][C:3]=1[O:34][CH3:35].[CH2:36](I)[CH3:37]>>[CH2:36]([O:1][C:2]1[CH:33]=[CH:32][C:5]([CH2:6][CH:7]2[C:16]3[C:11](=[CH:12][C:13]([O:19][CH3:20])=[C:14]([O:17][CH3:18])[CH:15]=3)[CH2:10][CH2:9][N:8]2[CH2:21][C:22]([NH:24][CH2:25][C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)=[O:23])=[CH:4][C:3]=1[O:34][CH3:35])[CH3:37]
Reactant: CCI
Reactant: COc1cc(CC2c3cc(OC)c(OC)cc3CCN2CC(=O)NCc2ccccc2)ccc1O
Product: CCOc1ccc(CC2c3cc(OC)c(OC)cc3CCN2CC(=O)NCc2ccccc2)cc1OC

Procedure:
prepared by reaction of 2-[1-(4-hydroxy-3-methoxy-benzyl)-6,7-dimethoxy-3,4-dihydro-1H-isoquinolin-2-yl]-N-benzyl-acetamide with ethyl iodide
Reaction SMILES: ClCl.S1C2C=CC=CC=2N=[C:4]1[S:12][S:13][C:14]1[S:15][C:16]2[CH:22]=[CH:21][CH:20]=[CH:19][C:17]=2[N:18]=1.S[CH2:24][CH:25]([OH:27])C>ClC1C=CC=CC=1>[OH:27][CH:25]([CH3:24])[CH2:4][S:12][S:13][C:14]1[S:15][C:16]2[CH:22]=[CH:21][CH:20]=[CH:19][C:17]=2[N:18]=1
Reactant: c1ccc2sc(SSc3nc4ccccc4s3)nc2c1
Reactant: CC(O)CS
Agent: ClCl
Solvent: Clc1ccccc1
Product: CC(O)CSSc1nc2ccccc2s1
Temperature: 25 °C
Reaction time: 7 h
Yield: 146.1 %

Procedure:
Chlorine gas (17.5 g/0.25 mole) was passed at 0 to 5° C. into a suspension of 2,2'-dithiobisbenzthiazole (83 g/0.25 mole) in chlorobenzene (600 ml). 1-mercapto-2-propanol (46 g/0.5 mole) was then added drop-wise to this solution, followed by stirring for 7 hours at room temperature. The precipitated product was filtered off and mixed with methylene chloride (500 ml) and 5% NaHCO3 solution (500 ml). The organic phase was then washed twice with water and concentrated by evaporation. A yellowish-brown oil (94 g) was obtained.
Reaction SMILES: ClC(Cl)(Cl)[C:3]([C:5]1[NH:6][CH:7]=[C:8]([C:10](=[O:19])[CH2:11][C:12]2[CH:17]=[CH:16][CH:15]=[C:14]([Cl:18])[CH:13]=2)[CH:9]=1)=[O:4].[NH:22]1[CH2:27][CH2:26][O:25][CH2:24][CH2:23]1>CN(C=O)C>[Cl:18][C:14]1[CH:13]=[C:12]([CH2:11][C:10]([C:8]2[CH:9]=[C:5]([C:3]([N:22]3[CH2:27][CH2:26][O:25][CH2:24][CH2:23]3)=[O:4])[NH:6][CH:7]=2)=[O:19])[CH:17]=[CH:16][CH:15]=1
Reactant: C1COCCN1
Reactant: O=C(Cc1cccc(Cl)c1)c1c[nH]c(C(=O)C(Cl)(Cl)Cl)c1
Solvent: CN(C)C=O
Product: O=C(Cc1cccc(Cl)c1)c1c[nH]c(C(=O)N2CCOCC2)c1
Reaction time: 24 h

Procedure:
To a solution of compound 1 (1 equivalent) in DMF, at ambient temperature, was added morpholine (1.2 equivalents). After 24 hours, the solvent was evaporated and the crude product 4 was used without purification. FIA/MS (M+1) 333.3, (M−1) 331.2; 1H NMR was consistent with expected structure.
Reaction SMILES: [C:1]([Br:5])(Br)(Br)Br.[Br:6][C:7]1[N:12]=[C:11](CO)[CH:10]=[CH:9][CH:8]=1.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>ClCCl>[Br:6][C:7]1[CH:8]=[CH:9][CH:10]=[C:11]([CH2:1][Br:5])[N:12]=1
Reactant: BrC(Br)(Br)Br
Reactant: OCc1cccc(Br)n1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Product: BrCc1cccc(Br)n1
Temperature: 0 °C
Reaction time: 2 h

Procedure:
Carbon tetrabromide (12.90 g, 38.88 mmol) was added in four portions to a solution of (6-bromo-pyridin-2-yl)methanol (5.00 g, 29.91 mmol) and PPh3 (8.24 g, 31.40 mmol) in dichloromethane (50 ml) at 0° C. The resulting solution was stirred 2 hours at 0° C. Solvent was removed under reduced pressure. The title compound was obtained by column chromatography. Spectroscopic data: 1H NMR (300 MHz, Acetone-d6) δ 4.66 (s, 2H) 7.57-7.60 (m, 2H) 7.76 (t, J=7.42 Hz, 1H).
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[N:6][NH:7][CH:8]=1)([O-:3])=[O:2].C(=O)([O-])[O-].[K+].[K+].Br[CH2:16][CH2:17][C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1>CN(C)C=O.CCOC(C)=O>[N+:1]([C:4]1[CH:5]=[N:6][N:7]([CH2:16][CH2:17][C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[CH:8]=1)([O-:3])=[O:2]
Reactant: O=[N+]([O-])c1cn[nH]c1
Reactant: BrCCc1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: O=[N+]([O-])c1cnn(CCc2ccccc2)c1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of 4-nitro-1H-pyrazole (226 mg, 2.0 mmol) in N,N-dimethylformamide (3 mL) were added potassium carbonate (0.33 g, 2.4 mmol) and 1-bromo-2-phenylethane (0.44 g, 2.4 mmol). The resulting mixture was stirred at rt overnight. TLC showed the reaction was complete. The mixture was diluted with EtOAc (40 mL), then washed with water (2×20 mL), brine (20 mL), and dried over anhydrous sodium sulfate. The crude material was purified by chromatography on silica gel, eluting with Hex:EtOAc=80:20→70:30 to give the title compound as a white solid. 1H NMR (CDCl3, 400 MHz): δ=3.20 (t, J=7.0 Hz, 2H), 4.37 (t, J=7.0 Hz, 2H), 7.04-7.07 (m, 2H), 7.25-7.32 (m, 3H), 7.81 (s, 1H), 8.09 (s, 1H).
Reaction SMILES: [I:1][C:2]1[CH:7]=[CH:6][C:5]([SH:8])=[CH:4][CH:3]=1.C1(C)C=CC(S(O[CH2:19][CH:20]2[CH2:24][CH2:23][CH2:22][N:21]2[C:25]([O:27][C:28]([CH3:31])([CH3:30])[CH3:29])=[O:26])(=O)=O)=CC=1.[OH-].[K+]>N1C=CC=CC=1.CCOC(C)=O>[I:1][C:2]1[CH:7]=[CH:6][C:5]([S:8][CH2:19][CH:20]2[CH2:24][CH2:23][CH2:22][N:21]2[C:25]([O:27][C:28]([CH3:29])([CH3:31])[CH3:30])=[O:26])=[CH:4][CH:3]=1
Reactant: Sc1ccc(I)cc1
Reactant: Cc1ccc(S(=O)(=O)OCC2CCCN2C(=O)OC(C)(C)C)cc1
Agent: [K+]
Agent: [OH-]
Solvent: c1ccncc1
Solvent: CCOC(C)=O
Product: CC(C)(C)OC(=O)N1CCCC1CSc1ccc(I)cc1
Reaction time: 4 h
Yield: 52.6 %

Procedure:
To a stirred mixture of p-iodothiophenol (1.75 g, 7.43 mmol) and N-(tert-butoxycarbonyl)-2-pyrrolidinylmethyl p-toluenesulfonate (2.39 g, 6.75 mmol) in pyridine (12.7 mL) was added 8 N KOH (1.27 mL) at room temp, and the resulting mixture was stirred for 4 hr at the same temp. The reaction mixture was diluted with EtOAc. The solution was washed with H2O, sat. NH4Cl, brine, and dried over Na2SO4. The organic layer was concentrated under a reduced pressure. The residue was chromatographed on silica-gel with n-hexane-EtOAc (5:1, v/v) as eluent to afford 1.49 g (530%) [N-(tert-butoxycarbonyl)-2-pyrrolidinyl]methyl 4-iodophenyl sulfide as a pale yellowish oil. 1H-NMR (400 MHz, CDCl3) δ (s, 9H), 1.78–2.01 (br m, 4H), 2.71 (dt, 1H), 3.32–3.49 (br m, 3H), 3.90–4.02 (br m, 1H), 7.12 (d, J=7.8 Hz, 1H), 7.18 (d, J=7.8 Hz, 1), 7.57 (dd, J=2.0,8.3 Hz, 2H);MS(FAB)m/z 420(M++1).
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([O:8][CH3:9])[N:5]=[C:4]([NH:10][CH2:11][CH2:12][C:13]2[CH:18]=[CH:17][C:16]([O:19][CH3:20])=[C:15]([F:21])[CH:14]=2)[CH:3]=1.[C:22]([C:24]1[CH:25]=[C:26](B(O)O)[CH:27]=[CH:28][CH:29]=1)#[N:23].C([O-])([O-])=O.[Cs+].[Cs+]>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.O.COCCOC>[F:21][C:15]1[CH:14]=[C:13]([CH2:12][CH2:11][NH:10][C:4]2[N:5]=[C:6]([O:8][CH3:9])[N:7]=[C:2]([C:28]3[CH:29]=[C:24]([CH:25]=[CH:26][CH:27]=3)[C:22]#[N:23])[CH:3]=2)[CH:18]=[CH:17][C:16]=1[O:19][CH3:20]
Reactant: N#Cc1cccc(B(O)O)c1
Reactant: COc1nc(Cl)cc(NCCc2ccc(OC)c(F)c2)n1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: O
Solvent: COCCOC
Product: COc1nc(NCCc2ccc(OC)c(F)c2)cc(-c2cccc(C#N)c2)n1
Yield: 56.6 %

Procedure:
(6-chloro-2-methoxy-pyrimidin-4-yl)-[2-(3-fluoro-4-methoxyphenyl)-ethyl]amine [1.6 g, Intermediate (5)], 3-cyano-phenylboronic acid [1.5 g, Intermediate (6)], Cs2CO3 (8.3 g) and tetrakis(triphenylphosphine)palladium (45 mg) in a solution of water (8 mL) and ethylene glycol dimethyl ether (32 mL) is heated at 90° C. for 16 hours. The solution is poured into water and extracted twice with EtOAc (200 mL). The combined extracts are dried over sodium sulfate, filtered, and evaporated. The residue is subjected to chromatography on silica gel eluting with EtOAc to give 3-{6-[2-(3-fluoro-4-methoxy-phenyl)-ethylamino]-2-methoxy-pyrimidin-4-yl}-benzonitrile [1.1 g, Example 1]. MS: 379 (M+H); 1H NMR (CDCl3): δ 8.3 (1H, s); 8.2 (1H, d (J=5.1 Hz)); 7.9 (1H, d (J=5.1 Hz)); 7.6 (1H, t); 7-7.2 (4H, m); 6.4 (1H, s); 5 (1H, m); 3.95 (3H, s); 3.8 (3H, s); 3.7 (2H, t); 3 (2H, t).