Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]12[CH2:10][CH:5]3[CH2:6][CH:7]([CH2:9][CH:3]([CH2:4]3)[CH:2]1[NH:11][C:12]([NH:14][C:15]1[CH:20]=[CH:19][C:18]([O:21]C)=[CH:17][C:16]=1[CH3:23])=[O:13])[CH2:8]2.B(Br)(Br)Br.O>C(Cl)Cl>[CH:1]12[CH2:10][CH:5]3[CH2:6][CH:7]([CH2:9][CH:3]([CH2:4]3)[CH:2]1[NH:11][C:12]([NH:14][C:15]1[CH:20]=[CH:19][C:18]([OH:21])=[CH:17][C:16]=1[CH3:23])=[O:13])[CH2:8]2
Reactant: COc1ccc(NC(=O)NC2C3CC4CC(C3)CC2C4)c(C)c1
Agent: BrB(Br)Br
Solvent: ClCCl
Solvent: O
Product: Cc1cc(O)ccc1NC(=O)NC1C2CC3CC(C2)CC1C3
Temperature: -78 °C
Reaction time: 1 h
Yield: 92.8 %

Procedure:
To a suspension of 1-adamantan-2-yl-3-(4-methoxy-2-methyl-phenyl)-urea 1.56 g (4.88 mmol) in DCM 20 ml was added at −78° C. under argon a solution of boron tribromide 1M in DCM 14.67 ml (14.67 mmol). The reaction mixture was stirred at −78° C. for 1 h then allowed to reach room temperature. Water 60 ml was added, the precipitate was filtered, washed with water and dried under vacuum to give 1.36 g (92%) a white solid.
Reaction SMILES: [O:1]1[CH2:6][CH2:5][CH2:4][CH2:3][CH:2]1[O:7][NH:8][C:9]([C:11]1[CH:12]=[C:13]2[C:18](=[CH:19][CH:20]=1)[CH2:17][N:16](C(OCC1C=CC=CC=1)=O)[CH2:15][CH2:14]2)=[O:10].C(O)C.[H][H]>[Pd].C(N(CC)CC)C>[O:1]1[CH2:6][CH2:5][CH2:4][CH2:3][CH:2]1[O:7][NH:8][C:9]([C:11]1[CH:12]=[C:13]2[C:18](=[CH:19][CH:20]=1)[CH2:17][NH:16][CH2:15][CH2:14]2)=[O:10]
Reactant: O=C(NOC1CCCCO1)c1ccc2c(c1)CCN(C(=O)OCc1ccccc1)C2
Reactant: [H][H]
Agent: [Pd]
Solvent: CCO
Solvent: CCN(CC)CC
Product: O=C(NOC1CCCCO1)c1ccc2c(c1)CCNC2
Yield: 90.6 %

Procedure:
A mixture of 5 g benzyl 6-[(tetrahydro-2H-pyran-2-yloxy)carbamoyl]-3,4-dihydroisoquinoline-2(1H)-carboxylate, 250 mg Pd/C (5%), 250 ml ethanol and 5 ml triethylamine is hydrogenated at ambient hydrogen pressure. The reaction mixture is filtered, evaporated and 3.05 g of yellowish foam are obtained.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9]([OH:11])=[O:10])=[C:4]([OH:12])[CH:3]=1.F[C:14]1[CH:19]=[CH:18][C:17]([S:20]([CH3:23])(=[O:22])=[O:21])=[CH:16][C:15]=1[C:24]([F:27])([F:26])[F:25].C(=O)([O-])[O-].[Cs+].[Cs+]>CN1C(=O)CCC1>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9]([OH:11])=[O:10])=[C:4]([O:12][C:14]2[CH:19]=[CH:18][C:17]([S:20]([CH3:23])(=[O:21])=[O:22])=[CH:16][C:15]=2[C:24]([F:25])([F:27])[F:26])[CH:3]=1
Reactant: CS(=O)(=O)c1ccc(F)c(C(F)(F)F)c1
Reactant: O=C(O)Cc1ccc(Cl)cc1O
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN1CCCC1=O
Product: CS(=O)(=O)c1ccc(Oc2cc(Cl)ccc2CC(=O)O)c(C(F)(F)F)c1

Procedure:
A solution of the product from step (ii) (0.125 g), the product of example 44 step (i) (0.150 g) and cesium carbonate (0.437 g) in NMP (10 ml) was stirred at 80° C. for 10 h. The mixture was partitioned between 2M sodium hydroxide and diethyl ether. The aqueous layer was acidified with 2M hydrochloric acid, extracted with ethyl acetate and the organic layer dried and evaporated under reduced pressure. The residue was purified using RP prep HPLC. Yield 0.025 g.
Reaction SMILES: [C:1]([C:4]1[C:5]([CH3:16])=[C:6](Br)[NH:7][C:8]=1[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)(=[O:3])[CH3:2].[N:17]1[CH:22]=[CH:21][C:20](B(O)O)=[CH:19][CH:18]=1>COCCOC.C([O-])(O)=O.[Na+].C(OCC)(=O)C.O.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[C:1]([C:4]1[C:5]([CH3:16])=[C:6]([C:20]2[CH:21]=[CH:22][N:17]=[CH:18][CH:19]=2)[NH:7][C:8]=1[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)(=[O:3])[CH3:2]
Reactant: OB(O)c1ccncc1
Reactant: CC(=O)c1c(-c2ccccc2)[nH]c(Br)c1C
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: COCCOC
Solvent: O
Product: CC(=O)c1c(-c2ccccc2)[nH]c(-c2ccncc2)c1C
Yield: 30.4 %

Procedure:
To a stirred suspension of 4-acetyl-2-bromo-3-methyl-5-phenyl-1H-pyrrole (139 mg, 0.50 mmol), 4-pyridylboronic acid (307 mg, 2.5 mmol) in DME (1.5 mL) and saturated aqueous NaHCO3 (0.50 mL) was added Pd(PPh3)2Cl2 (70 mg, 0.10 mmol) under nitrogen. The mixture was heated under reflux for 12 hours. After cooling, the mixture was diluted with ethyl acetate (5 mL) and water (10 mL). The organic layer was separated, and then the aqueous layer was extracted with ethyl acetate (5 mL×2). The combined organic layers were extracted with 1M aqueous HCl (3 mL×2). The combined aqueous layes were neutralized by the addition of 10% aqueous KOH until being pH=8. The whole was extracted with CH2Cl2 (10 mL×3), the combined organic layers were dried over MgSO4, and concentrated in vacuo. The residue was purified by flash chromatography eluting with hexane-ethyl acetate (1:2→EtOAc only) to provide the title product (42 mg, 30% yield) as a colorless solid.
Reaction SMILES: [ClH:1].[NH:2]=[C:3]1[N:7]([CH2:8][CH:9](OC(=O)C)[C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[CH2:6][CH2:5][S:4]1.P(Cl)(Cl)(Cl)(Cl)[Cl:21]>C(Cl)(Cl)Cl>[ClH:21].[NH:2]=[C:3]1[N:7]([CH2:8][CH:9]([Cl:1])[C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[CH2:6][CH2:5][S:4]1
Reactant: CC(=O)OC(CN1CCSC1=N)c1ccccc1
Reactant: ClP(Cl)(Cl)(Cl)Cl
Agent: Cl
Solvent: ClC(Cl)Cl
Product: N=C1SCCN1CC(Cl)c1ccccc1

Procedure:
The 2-imino-3-(2'-acetoxy-2'-phenylethyl)thiazolidine hydrochloride (0.01 mole) was heated under reflux with phosphorus pentachloride for one hour in chloroform (5 ml). The solvent was evaporated to leave a colourless solid which was crystallised from ethanol, yield 1.9 g. This compound was used in the synthesis of the compound of Example 75 as described for the corresponding 2-imino derivative in Example 75 Method A.
Reaction SMILES: NC1C=CC(OC2C=C3C(=CC=2)OC(C2C=CC=CC=2)CC3)=NC=1.[F:25][C:26]1[CH:27]=[C:28]([CH:32]2[CH2:41][CH2:40][C:39]3[C:34](=[CH:35][CH:36]=[C:37]([O:42][C:43]4[CH:48]=[CH:47][C:46]([N+:49]([O-])=O)=[CH:45][N:44]=4)[CH:38]=3)[O:33]2)[CH:29]=[CH:30][CH:31]=1>>[F:25][C:26]1[CH:27]=[C:28]([CH:32]2[CH2:41][CH2:40][C:39]3[C:34](=[CH:35][CH:36]=[C:37]([O:42][C:43]4[N:44]=[CH:45][C:46]([NH2:49])=[CH:47][CH:48]=4)[CH:38]=3)[O:33]2)[CH:29]=[CH:30][CH:31]=1
Reactant: O=[N+]([O-])c1ccc(Oc2ccc3c(c2)CCC(c2cccc(F)c2)O3)nc1
Agent: Nc1ccc(Oc2ccc3c(c2)CCC(c2ccccc2)O3)nc1
Product: Nc1ccc(Oc2ccc3c(c2)CCC(c2cccc(F)c2)O3)nc1

Procedure:
6-[2-(3-fluorophenyl)chroman-6-yloxy]-pyridin-3-ylamine was prepared as described for 5-amino-2-(2-phenylchroman-6-yloxy)pyridine in Example 26 starting from 2.34 g of 2-[2-(3-fluorophenyl)chroman-6-yloxy]-5-nitropyridine (Example 9(d)). 1H NMR (400 MHz, d6-DMSO) δ: 7.51 (d, 1H, J 3.0 Hz), 7.44 (m, 1H), 7.30-7.25 (m, 2H), 7.16 (m, 1H), 7.05 (dd, 1H, J 8.6, 3.0 Hz), 6.83-6.73 (m, 3H), 6.69 (d, 1H, J 8.6 Hz), 5.13 (dd, 1H, J 10.0, 3.0 Hz), 5.00 (s, 2H), 2.93 (ddd, 1H, −16.8, 10.5, 5.3 Hz), 2.68 (ddd, 1H, J −16.8, 8.0, 4.4 Hz), 2.18 (m, 1H), 1.96 (m, 1H).
Reaction SMILES: [C:1]([N:8]([C:10]1[CH:15]=[C:14]([N+:16]([O-:18])=[O:17])[CH:13]=[CH:12][C:11]=1[C@:19]1([O:37][C@H:36]([C:38]([O:40][CH3:41])=[O:39])[C@@H:31]([O:32][C:33](=[O:35])[CH3:34])[C@H:26]([O:27][C:28](=[O:30])[CH3:29])[C@H:21]1[O:22][C:23](=[O:25])[CH3:24])[OH:20])C)(OC(C)(C)C)=O.C(=O)(O)[O-].[Na+]>Cl.C(OCC)(=O)C>[CH3:1][NH:8][C:10]1[CH:15]=[C:14]([N+:16]([O-:18])=[O:17])[CH:13]=[CH:12][C:11]=1[C@:19]1([O:37][C@H:36]([C:38]([O:40][CH3:41])=[O:39])[C@@H:31]([O:32][C:33](=[O:35])[CH3:34])[C@H:26]([O:27][C:28](=[O:30])[CH3:29])[C@H:21]1[O:22][C:23](=[O:25])[CH3:24])[OH:20]
Reactant: COC(=O)[C@H]1O[C@](O)(c2ccc([N+](=O)[O-])cc2N(C)C(=O)OC(C)(C)C)[C@H](OC(C)=O)[C@@H](OC(C)=O)[C@@H]1OC(C)=O
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCOC(C)=O
Product: CNc1cc([N+](=O)[O-])ccc1[C@@]1(O)O[C@H](C(=O)OC)[C@@H](OC(C)=O)[C@H](OC(C)=O)[C@H]1OC(C)=O

Procedure:
A solution of methyl 2-(N-BOC,N-methylamino)-4-nitrophenyl-2,3,4-tri-O-acetyl-β-D-glucuronate (5) (3 g, 5.13 mmol) in 2.12 M hydrochloric acid in ethyl acetate (60 ml) was stirred at room temperature for 1 hour. The solution was added to excess, aqueous, saturated sodium bicarbonate solution and the mixture was extracted with ethyl acetate. The organic phase was dried with sodium sulfate and concentrated. The product was chromatographed on silica gel (eluent dichloromethane/methanol 97.5/2.5). Yield 2.14 g (86%), yellow solid.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([CH2:8][CH2:9][C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=2[C:16]2([C:19]([NH2:21])=[O:20])[CH2:18][CH2:17]2)[C:5]([Cl:22])=[CH:4][N:3]=1.[NH2:23][C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1.C1(C)C=CC(S(O)(=O)=O)=CC=1>O1CCOCC1>[Cl:22][C:5]1[C:6]([CH2:8][CH2:9][C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=2[C:16]2([C:19]([NH2:21])=[O:20])[CH2:18][CH2:17]2)=[N:7][C:2]([NH:23][C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)=[N:3][CH:4]=1
Reactant: NC(=O)C1(c2ccccc2CCc2nc(Cl)ncc2Cl)CC1
Reactant: Nc1ccccc1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: C1COCCO1
Product: NC(=O)C1(c2ccccc2CCc2nc(Nc3ccccc3)ncc2Cl)CC1
Temperature: 120 °C
Yield: 46 %

Procedure:
A solution of 1-(2-(2-(2,5-dichloropyrimidin-4-yl)ethyl)phenyl)cyclopropanecarboxamide A14 (0.080 g, 0.24 mmol) in 1,4-dioxane (1.0 mL) containing aniline (0.043 mL, 0.48 mmol) and p-toluenesulfonic acid (4.5 mg, 0.024 mmol) was heated under microwave irradiation at 120° C. for 4 hours. The reaction mixture was adsorbed onto silica gel and purified by silica column chromatography (Combiflash Rf, 12 g SiO2 Cartridge, 20-50% EtOAc in cyclohexane) to give the title product 23 as a light yellow foam (0.044 g, 46%). LCMS-B: rt 7.718 min; m/z 393 [M+H]+.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH2:11][CH2:12][OH:13])[CH:6]=[CH:7][C:8]=1[O:9][CH3:10].C1O[C:17]([CH2:19][CH2:20][CH2:21][Cl:22])([CH3:18])OC1.B(F)(F)F.O>[N+](C)([O-])=O>[Cl:22][CH2:21][CH2:20][CH2:19][C:17]1([CH3:18])[C:6]2[C:5](=[CH:4][C:3]([O:2][CH3:1])=[C:8]([O:9][CH3:10])[CH:7]=2)[CH2:11][CH2:12][O:13]1
Reactant: COc1ccc(CCO)cc1OC
Reactant: CC1(CCCCl)OCCO1
Agent: FB(F)F
Solvent: C[N+](=O)[O-]
Solvent: O
Product: COc1cc2c(cc1OC)C(C)(CCCCl)OCC2
Temperature: 25 °C
Reaction time: 4 h
Yield: 1404.6 %

Procedure:
A mixture of 3,4-dimethoxyphenylethyl alcohol (1.72 g, 0.01 mole), 5-chloro-2-pentanone ethylene ketal (1.64 g, 0.01 mole) and 0.5 ml of BF3 etherate in 20 ml of nitromethane is stirred at room temperature under N2 for 4 hours. The reaction mixture is then poured into cold water and extracted with CH2Cl2. The CH2Cl2 solution is washed with water, dried (Na2SO4) and concentrated to an oil. The oil is chromatographed on silica gel with 10% ethylacetate/Skellysolve B as eluate to give 40 g (54% yield) of 1-(3-chloropropyl)-6,7-dimethoxy-1-methyl-isochroman as a white crystalline product, m.p. 77°-79° C. The nmr of the product is consistent with the structure.
Reaction SMILES: [C:1]1([CH:7]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[CH2:8][CH2:9]O)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH3:17][CH:18]([CH3:34])[C:19]([NH:21][C:22]1[CH:27]=[CH:26][CH:25]=[C:24]([CH:28]2[CH2:33][CH2:32][NH:31][CH2:30][CH2:29]2)[CH:23]=1)=[O:20]>>[C:1]1([CH:7]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[CH2:8][CH2:9][N:31]2[CH2:32][CH2:33][CH:28]([C:24]3[CH:23]=[C:22]([NH:21][C:19](=[O:20])[CH:18]([CH3:17])[CH3:34])[CH:27]=[CH:26][CH:25]=3)[CH2:29][CH2:30]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: OCCC(c1ccccc1)c1ccccc1
Reactant: CC(C)C(=O)Nc1cccc(C2CCNCC2)c1
Product: CC(C)C(=O)Nc1cccc(C2CCN(CCC(c3ccccc3)c3ccccc3)CC2)c1

Procedure:
Prepared by Procedure O and Scheme W using 3,3-diphenyl-1-propanol and 2-methyl-N-[3-(4-piperidinyl)phenyl]propanamide: ESMS m/e: 441.2 (M+H)+.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[N:7]([S:12]([CH3:15])(=[O:14])=[O:13])[CH:8]=[C:9]([NH2:11])[CH:10]=1)=[O:5])[CH3:2].[F:16][C:17]1[C:24]([F:25])=[CH:23][CH:22]=[CH:21][C:18]=1[CH:19]=O.CC1C=CC(S(O)(=O)=O)=CC=1>C1C=CC=CC=1>[CH2:1]([O:3][C:4]([C:6]1[N:7]([S:12]([CH3:15])(=[O:14])=[O:13])[CH:8]=[C:9]([N:11]=[CH:19][C:18]2[CH:21]=[CH:22][CH:23]=[C:24]([F:25])[C:17]=2[F:16])[CH:10]=1)=[O:5])[CH3:2]
Reactant: CCOC(=O)c1cc(N)cn1S(C)(=O)=O
Reactant: O=Cc1cccc(F)c1F
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: c1ccccc1
Product: CCOC(=O)c1cc(N=Cc2cccc(F)c2F)cn1S(C)(=O)=O

Procedure:
To a solution of 4-amino-1-methanesulfonyl-1H-pyrrole-2-carboxylic acid ethyl ester (2.1 g, 9.04 mmol) in anhydrous benzene (100 mL) was added 2,3-difluoro-benzaldehyde (1.29 g, 9.08 mmol) and catalytic amount of TsOH. The reaction mixture was heated under reflux in the presence of Dean-Stark trap for 24 hours. The solvent was then removed by evaporation and the residue was dried on the high vacuum pump for 16 hours for the next step use (2.9 g crude product). 1H NMR (500 MHz, DMSO-d6) δ8.99 (s, 1H), 7.85 (t, 1H), 7.75 (s, 1H), 7.58 (m, 2H), 7.32 (m, 1H), 4.32 (q, 2H), 3.90 (s, 3H), 2.51 (DMSO), 1.35 (t, 3H) ppm.
Reaction SMILES: Cl.Cl.Cl.[O:4]1[C:8]2=[C:9]([N:13]3[CH2:18][CH2:17][N:16]([CH2:19][CH2:20][C@H:21]4[CH2:26][CH2:25][C@H:24]([NH2:27])[CH2:23][CH2:22]4)[CH2:15][CH2:14]3)[N:10]=[CH:11][CH:12]=[C:7]2[CH2:6][CH2:5]1.[OH:28][CH2:29][CH2:30][C:31](O)=[O:32]>>[O:4]1[C:8]2=[C:9]([N:13]3[CH2:18][CH2:17][N:16]([CH2:19][CH2:20][C@H:21]4[CH2:26][CH2:25][C@H:24]([NH:27][C:29](=[O:28])[CH2:30][CH2:31][OH:32])[CH2:23][CH2:22]4)[CH2:15][CH2:14]3)[N:10]=[CH:11][CH:12]=[C:7]2[CH2:6][CH2:5]1
Reactant: N[C@H]1CC[C@H](CCN2CCN(c3nccc4c3OCC4)CC2)CC1
Reactant: O=C(O)CCO
Agent: Cl
Product: O=C(CCO)N[C@H]1CC[C@H](CCN2CCN(c3nccc4c3OCC4)CC2)CC1

Procedure:
The title compound, white solid (99 mg, 98%), MS (ISP) m/z=403.5 [(M+H)+], mp 257° C., was prepared in accordance with the general method of example 6 from trans-4-{2-[4-(2,3-dihydro-furo[2,3-c]pyridin-7-yl)-piperazin-1-yl]-ethyl}-cyclohexylamine trihydrochloride (intermediate B) (110 mg, 0.25 mmol) and 3-hydroxy-propionic acid.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([OH:16])[CH:5]=[C:6]([F:15])[C:7]=1[C:8]([CH3:14])([CH3:13])[C:9]([F:12])([F:11])[F:10].Br[CH2:18][C:19]([O:21][CH2:22][CH3:23])=[O:20].C(=O)([O-])[O-].[K+].[K+]>CC(C)=O>[CH2:22]([O:21][C:19](=[O:20])[CH2:18][O:16][C:4]1[CH:3]=[C:2]([F:1])[C:7]([C:8]([CH3:13])([CH3:14])[C:9]([F:11])([F:12])[F:10])=[C:6]([F:15])[CH:5]=1)[CH3:23]
Reactant: CCOC(=O)CBr
Reactant: CC(C)(c1c(F)cc(O)cc1F)C(F)(F)F
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: CCOC(=O)COc1cc(F)c(C(C)(C)C(F)(F)F)c(F)c1
Yield: 86.1 %

Procedure:
An acetone (5 ml) suspension of 3,5-difluoro-4-(2,2,2-trifluoro-1,1-dimethylethyl)phenol (227 mg, 0.95 mmol), ethyl bromoacetate (174 mg, 1.0 mmol) and potassium carbonate (261 mg, 1.9 mmol) was stirred at reflux for 1 hour. Then, the reaction was quenched with water and the product was extracted with ethyl acetate. The organic layer was dried over sodium sulfate, filtrated and evaporated to furnish 267 mg (87% yield) of the title compound as colorless oil.
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][C:8]([O:14][CH3:15])=[C:9]([O:12][CH3:13])[CH:10]=2)[N:5]=[CH:4][C:3]=1[C:16]#[N:17].[Cl:18][C:19]1[CH:25]=[CH:24][C:22]([NH2:23])=[C:21]([CH3:26])[CH:20]=1.Cl.N1C=CC=CC=1.C(OCCO)C>>[Cl:18][C:19]1[CH:25]=[CH:24][C:22]([NH:23][C:2]2[C:11]3[C:6](=[CH:7][C:8]([O:14][CH3:15])=[C:9]([O:12][CH3:13])[CH:10]=3)[N:5]=[CH:4][C:3]=2[C:16]#[N:17])=[C:21]([CH3:26])[CH:20]=1
Reactant: COc1cc2ncc(C#N)c(Cl)c2cc1OC
Reactant: Cc1cc(Cl)ccc1N
Agent: Cl
Solvent: c1ccncc1
Solvent: CCOCCO
Product: COc1cc2ncc(C#N)c(Nc3ccc(Cl)cc3C)c2cc1OC
Temperature: 139 °C
Reaction time: 24 h
Yield: 70.7 %

Procedure:
A mixture of 0.248 g (1 mmol) of 4-chloro-6,7-dimethoxy-quinoline-3-carbonitrile, 0.156 g (1.1 mmol) of 4-chloro-2-methylaniline, 0.116 g (1 mmol) pyridine hydrochloride and 12 ml of 2-ethoxyethanol was heated in a 138-140° C. oil bath for 24 hours; progress of the reaction was monitored by TLC. After 24 hours an additional 0.156 g of of 4-chloro-2-methylaniline was added and the heating continued for 24 hours. When TLC indicated the disappearance of starting material, the reaction was cooled and concentrated in vacuo to a thick oil. To this oil was added 50 ml of water followed by 5 ml of 1M NaHCO3, approximately pH 8. The gummy solid was dissolved in chloroform and passed through a pad of hydrous magnesium silicate. The liquid was concentrated in vacuo and the residue triturated 5 times with hexane. The resulting precipitate was collected, washed with hexane, and dried in vacuo at 65° C. to give 0.250 g (71%) of the desired product as brown crystals. MP 227-229° C.;: mass spectrum (electrospray, m/e,): 353.8(M+H)+.
Reaction SMILES: [C:1](N1C=CN=C1)(N1C=CN=C1)=[O:2].[N+:13]([C:16]1[CH:17]=[C:18]([CH:23]=[CH:24][CH:25]=1)[C:19]([NH:21][NH2:22])=[O:20])([O-:15])=[O:14].C(N(CC)CC)C>CN(C=O)C.C(Cl)Cl>[N+:13]([C:16]1[CH:17]=[C:18]([C:19]2[O:20][C:1]([OH:2])=[N:22][N:21]=2)[CH:23]=[CH:24][CH:25]=1)([O-:15])=[O:14]
Reactant: NNC(=O)c1cccc([N+](=O)[O-])c1
Reactant: O=C(n1ccnc1)n1ccnc1
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: O=[N+]([O-])c1cccc(-c2nnc(O)o2)c1
Reaction time: 4 h

Procedure:
1,1′-Carbonyldiimidazole (641.18 mg; 3.95 mmol; 1.00 eq.) is added to a 0° C. solution of 3-nitrobenzohydrazide (715.90 mg; 3.95 mmol; 1.00 eq.) and triethylamine (822.18 μl; 5.93 mmol; 1.50 eq.) in DMF (30.00 ml). The reaction mixture is stirred between 0° C. and RT for 4 hours. Solvents are removed under vacuo affording an orange oil which is solubilized in DCM and washed with HCl 0.1 M. The organic phase is concentrated. The resulting precipitate is recovered by filtration, affording 5-(3-nitrophenyl)-1,3,4-oxadiazol-2-ol as a white solid (469.90 mg; 58%).
Reaction SMILES: [CH2:1]([N:5]1[C:10](=[O:11])[C:9]([CH2:12]OS(C)(=O)=O)=[CH:8][C:7]([C:18]2[CH:23]=[CH:22][C:21]([CH3:24])=[CH:20][CH:19]=2)=[N:6]1)[CH:2]([CH3:4])[CH3:3].[CH3:25][NH2:26]>>[CH2:1]([N:5]1[C:10](=[O:11])[C:9]([CH2:12][NH:26][CH3:25])=[CH:8][C:7]([C:18]2[CH:23]=[CH:22][C:21]([CH3:24])=[CH:20][CH:19]=2)=[N:6]1)[CH:2]([CH3:4])[CH3:3]
Reactant: Cc1ccc(-c2cc(COS(C)(=O)=O)c(=O)n(CC(C)C)n2)cc1
Reactant: CN
Product: CNCc1cc(-c2ccc(C)cc2)nn(CC(C)C)c1=O

Procedure:
Following the procedure of Example 9 (4), 2-isobutyl-4-methanesulfonyloxymethyl-6-(4-methylphenyl)-2H-pyridazin-3-one and methylamine were reacted to yield the title compound as a slightly yellow oil (yield: 94.5%).
Reaction SMILES: [CH2:1]([O:5][CH2:6][CH2:7][O:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]2[CH:16]=[CH:17][C:18]3[N:24]([C:25](=[O:30])[C:26]([F:29])([F:28])[F:27])[CH2:23][CH2:22][C:21]([C:31]([OH:33])=O)=[CH:20][C:19]=3[CH:34]=2)=[CH:11][CH:10]=1)[CH2:2][CH2:3][CH3:4].[NH2:35][C:36]1[CH:41]=[CH:40][C:39]([CH:42]([C:44]2[CH:49]=[C:48]([CH3:50])[CH:47]=[CH:46][N:45]=2)[OH:43])=[CH:38][CH:37]=1.ON1C2C=CC=CC=2N=N1.Cl.C(N=C=NCCCN(C)C)C>CN(C)C1C=CN=CC=1.O.C(N(CC)CC)C.CN(C)C=O>[CH2:1]([O:5][CH2:6][CH2:7][O:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]2[CH:16]=[CH:17][C:18]3[N:24]([C:25](=[O:30])[C:26]([F:27])([F:28])[F:29])[CH2:23][CH2:22][C:21]([C:31]([NH:35][C:36]4[CH:37]=[CH:38][C:39]([CH:42]([OH:43])[C:44]5[CH:49]=[C:48]([CH3:50])[CH:47]=[CH:46][N:45]=5)=[CH:40][CH:41]=4)=[O:33])=[CH:20][C:19]=3[CH:34]=2)=[CH:11][CH:10]=1)[CH2:2][CH2:3][CH3:4]
Reactant: Cc1ccnc(C(O)c2ccc(N)cc2)c1
Reactant: CCCCOCCOc1ccc(-c2ccc3c(c2)C=C(C(=O)O)CCN3C(=O)C(F)(F)F)cc1
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Solvent: O
Product: CCCCOCCOc1ccc(-c2ccc3c(c2)C=C(C(=O)Nc2ccc(C(O)c4cc(C)ccn4)cc2)CCN3C(=O)C(F)(F)F)cc1
Reaction time: 8 h
Yield: 95 %

Procedure:
7-[4-(2-butoxyethoxy)phenyl]-1-trifluoroacetyl-2,3-dihydro-1H-1-benzazepine-4-carboxylic acid (0.5 g), (4-aminophenyl) (4-methylpyridin-2-yl)methanol (0.24 g) and 1-hydroxybenzotriazole (0.16 g) were dissolved in. N,N-dimethylformamide (5 ml), and to the solution were added 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (0.4 g), triethylamine (0.44 ml) and 4-dimethylaminopyridine (catalytic amout) at room temperature under ice-cooling, and the mixture was stirred overnight. The mixture was poured into water, and the mixture was extracted with ethyl acetate. The organic layer was washed with water and saturated brine, and dried over anhydrous magnesium sulfate, and then, the solvent was distilled off. The residue was washed with diethyl ether-hexane, to give 7-[4-(2-butoxyethoxy)phenyl]-N-[4-[hydroxy (4-methylpyridin-2-yl)methyl]phenyl]-1-trifluoroacetyl-2,3-dihydro-1H-1-benzazepine-4-carboxamide (0.67 g) as colorless crystals.
Reaction SMILES: C[Mg]Br.Br[C:5]1[CH:6]=[C:7]2[C:11](=[N:12][CH:13]=1)[NH:10][CH:9]=[CH:8]2.C(Cl)Cl.[CH3:17][O:18][C:19]1[CH:20]=[C:21]([CH:24]=[C:25]([O:27][CH3:28])[CH:26]=1)[CH2:22]Br>[Cl-].[Cl-].[Zn+2]>[CH3:28][O:27][C:25]1[CH:24]=[C:21]([CH:20]=[C:19]([O:18][CH3:17])[CH:26]=1)[CH2:22][C:9]1[NH:10][C:11]2=[N:12][CH:13]=[CH:5][CH:6]=[C:7]2[CH:8]=1
Reactant: COc1cc(CBr)cc(OC)c1
Reactant: Brc1cnc2[nH]ccc2c1
Agent: C[Mg]Br
Agent: [Cl-]
Agent: [Zn+2]
Solvent: ClCCl
Product: COc1cc(Cc2cc3cccnc3[nH]2)cc(OC)c1
Yield: 4.4 %

Procedure:
Into a round bottom flask, under an atmosphere of nitrogen, methylmagnesium bromide (0.16 mL, 1.4 mmol) was added to a solution of 7-azaindole (1) (0.150 g, 1.27 mmol) in anhydrous methylene chloride (12 mL, 0.19 mol), at room temperature. The resulting mixture was stirred at room temperature for one hour before zinc dichloride (0.21 g, 1.5 mmol) was added. After stirring for an additional hour, 3,5-dimethoxybenzyl bromide (4) (0.35 g, 1.5 mmol) was added into the reaction mixture. The reaction was stirred overnight at room temperature before it was quenched with methanol. The mixture was evaporated to dryness, dissolved into ethyl acetate and washed with water. The aqueous portion was neutralized with sodium bicarbonate (s.s.) and extracted with ethyl acetate (3×). Organic portions were combined and washed with 0.1N HCl, dried over anhydrous sodium sulfate and evaporated under reduced pressure. Purification by preparative TLC with 50% ethyl acetate/hexane gave Compound 29 as a yellow powder (15 mg; M+H=269.2, M−H=267.2).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:19]=[CH:18][C:6]([CH2:7][N:8]2[C:12]3=[N:13][CH:14]=[CH:15][C:16](Cl)=[C:11]3[CH:10]=[N:9]2)=[CH:5][CH:4]=1.[O:20]1[CH2:25][CH2:24][N:23]([CH2:26][CH2:27][NH2:28])[CH2:22][CH2:21]1>CN1C(=O)CCC1.CCOC(C)=O>[CH3:1][O:2][C:3]1[CH:19]=[CH:18][C:6]([CH2:7][N:8]2[C:12]3[N:13]=[CH:14][CH:15]=[C:16]([NH:28][CH2:27][CH2:26][N:23]4[CH2:24][CH2:25][O:20][CH2:21][CH2:22]4)[C:11]=3[CH:10]=[N:9]2)=[CH:5][CH:4]=1
Reactant: COc1ccc(Cn2ncc3c(Cl)ccnc32)cc1
Reactant: NCCN1CCOCC1
Solvent: CN1CCCC1=O
Solvent: CCOC(C)=O
Product: COc1ccc(Cn2ncc3c(NCCN4CCOCC4)ccnc32)cc1
Temperature: 150 °C
Yield: 56.2 %

Procedure:
1-(4-methoxybenzyl)-4-chloro-1H-pyrazolo[3,4-b]pyridine (0.200 g, 0.731 mmol) was charged to a pressure tube in 5 mL of NMP. 2-morpholinoethanamine (0.144 ml, 1.10 mmol) was added and the reaction was heated to 150° C. for 72 hours. After cooling, the reaction mixture was diluted with 25 mL of EtOAc and washed with water (2×15 mL) and then dried with brine and Na2SO4. Purification via flash Si 10 g eluting with 1-5% MeOH/DCM with NH4OH to afford 151 mg (55%) of product as a yellow oil. 1H NMR (400 MHz, CDCl3) δ 8.20 (d, 1H), 7.92 (s, 1H), 7.30 (t, 2H), 6.83 (m, 2H), 6.14 (d, 1H), 5.56 (s, 2H), 5.41 (s, 1H), 3.75 (m, 7H), 3.44 (m, 2H), 2.73 (t, 2H), 2.51 (bs, 4H).