Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1][C:2]1[C:7](=[O:8])[CH:6]=[CH:5][O:4][C:3]=1[CH3:9].[N+:10]([C:13]1[CH:18]=[CH:17][C:16]([S:19](Cl)(=[O:21])=[O:20])=[CH:15][CH:14]=1)([O-:12])=[O:11]>N1C=CC=CC=1>[N+:10]([C:13]1[CH:14]=[CH:15][C:16]([S:19]([O:1][C:2]2[C:7](=[O:8])[CH:6]=[CH:5][O:4][C:3]=2[CH3:9])(=[O:21])=[O:20])=[CH:17][CH:18]=1)([O-:12])=[O:11]
Reactant: O=[N+]([O-])c1ccc(S(=O)(=O)Cl)cc1
Reactant: Cc1occc(=O)c1O
Solvent: c1ccncc1
Product: Cc1occc(=O)c1OS(=O)(=O)c1ccc([N+](=O)[O-])cc1
Yield: 58 %

Procedure:
3-Hydroxy-2-methyl-4H-pyran-4-one (0.5 g, 4.0 mmol) was reacted with 4-nitrobenzenesulfonyl chloride (0.88 g, 4.0 mmol) in 15 mL of pyridine to afford PZBG-2c in 58% yield (0.71 g, 2.3 mmol). 1H NMR (500 MHz, CDCl3) δ=8.42 (d, J=9.2 Hz, 2H), 8.31 (d, J=9.2 Hz, 2H), 7.69 (d, J=5.7 Hz, 1H), 6.34 (d, J=5.8 Hz, 1H), 2.53 (s, 3H, CH3). 13C NMR (100 MHz, CDCl3) δ=171.8, 163.5, 154.6, 151.2, 142.3, 138.6, 130.4, 124.3, 117.6, 16.3. ESI-MS(+): m/z 312.06 [M+H]+.
Reaction SMILES: [O:1]=[C:2]1[C:11]2[C:6](=[CH:7][C:8]([C:12]([O:14]C)=[O:13])=[CH:9][CH:10]=2)[CH:5]=[CH:4][NH:3]1.O1CCCC1.[OH-].[Li+]>O>[O:1]=[C:2]1[C:11]2[C:6](=[CH:7][C:8]([C:12]([OH:14])=[O:13])=[CH:9][CH:10]=2)[CH:5]=[CH:4][NH:3]1
Reactant: COC(=O)c1ccc2c(=O)[nH]ccc2c1
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: O=C(O)c1ccc2c(=O)[nH]ccc2c1
Reaction time: 4 h
Yield: 44.9 %

Procedure:
To a mixture of methyl 1-oxo-1,2-dihydroisoquinoline-6-carboxylate (25 g, 0.133 mol), tetrahydrofuran (200 mL) and water (200 mL) was added lithium hydroxide (16.8 g, 0.40 mol) at room temperature, and the mixture was stirred for four hours. Thin layer chromatography (petroleum ether/ethyl acetate=1:1) indicated the reaction was complete. The reaction mixture was extracted with ethyl acetate (100 mL×3) to remove impurities. The aqueous layer was acidified with 4 N aqueous HCl to pH 5 and filtered. The solid was dried in vacuum to give 1-oxo-1,2-dihydroisoquinoline-6-carboxylic acid (11.3 g, 48%) as a light yellow solid. 1H NMR (400 MHz, DMSO-d6) δ ppm 11.48 (s, 1H), 8.24 (d, 2H), 7.93 (d, 1H), 7.22 (d, 1H), 6.68 (d, 1H).
Reaction SMILES: [NH2:1][C@@H:2]([C@@H:6]([CH3:9])[CH2:7][CH3:8])[C:3]([OH:5])=[O:4].[OH-].[Na+].Cl[C:13]([O:15][CH3:16])=[O:14]>O1CCOCC1.CCOC(C)=O>[CH3:16][O:15][C:13]([NH:1][C@@H:2]([C@@H:6]([CH3:9])[CH2:7][CH3:8])[C:3]([OH:5])=[O:4])=[O:14]
Reactant: CC[C@H](C)[C@H](N)C(=O)O
Reactant: COC(=O)Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCOC(C)=O
Solvent: C1COCCO1
Product: CC[C@H](C)[C@H](NC(=O)OC)C(=O)O
Temperature: 25 °C
Reaction time: 2 h
Yield: 97.1 %

Procedure:
To a solution of (2S,3S)-2-amino-3-methylpentanoic acid (1.0 g, 7.62 mmol) in dioxane (10 mL) at 0° C. was added NaOH (12.58 g, 25.2 mmol) followed by dropwise addition of methyl chloroformate (1.18 mL, 15.25 mmol). The solution was warmed to room temperature with stirring over 2 h, diluted with EtOAc, washed with 1 N HCl, brine, dried (Na2SO4), filtered and solvent removed in vacuo to give the title compound (1.4 g, 7.4 mmol, 97%). 1H NMR (400 MHz, CDCl3) δ ppm 1.27-1.39 (m, 1H) 1.38-1.53 (m, 2 H) 1.58-1.72 (m, 3H) 1.82-1.94 (m, 2H) 2.04 (d, J=3.8 Hz, 2H) 3.70 (s, 3H) 4.94 (br s, 1H).
Reaction SMILES: [C:1]([O:5][C:6](=[O:40])[NH:7][C@H:8]([C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1)[CH2:9][N:10]1[C:15](=[O:16])[C:14]([N:17]2[CH2:22][CH2:21][NH:20][CH2:19][C:18]2=[O:23])=[CH:13][N:12]([CH2:24][C:25]2[C:30]([F:31])=[CH:29][CH:28]=[CH:27][C:26]=2[F:32])[C:11]1=[O:33])([CH3:4])([CH3:3])[CH3:2].C(=O)([O-])[O-].[K+].[K+].[CH2:47](Br)[C:48]1[CH:53]=[CH:52][CH:51]=[CH:50][CH:49]=1>CN(C=O)C.ClCCl>[C:1]([O:5][C:6](=[O:40])[NH:7][C@H:8]([C:34]1[CH:35]=[CH:36][CH:37]=[CH:38][CH:39]=1)[CH2:9][N:10]1[C:15](=[O:16])[C:14]([N:17]2[CH2:22][CH2:21][N:20]([CH2:47][C:48]3[CH:53]=[CH:52][CH:51]=[CH:50][CH:49]=3)[CH2:19][C:18]2=[O:23])=[CH:13][N:12]([CH2:24][C:25]2[C:26]([F:32])=[CH:27][CH:28]=[CH:29][C:30]=2[F:31])[C:11]1=[O:33])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)N[C@@H](Cn1c(=O)c(N2CCNCC2=O)cn(Cc2c(F)cccc2F)c1=O)c1ccccc1
Reactant: BrCc1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: ClCCl
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N[C@@H](Cn1c(=O)c(N2CCN(Cc3ccccc3)CC2=O)cn(Cc2c(F)cccc2F)c1=O)c1ccccc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 94.6 %

Procedure:
To a solution of {(R)-2-[3-(2,6-difluoro-benzyl)-2,6-dioxo-5-(2-oxo-piperazin-1-yl)-3,6-dihydro-2H-pyrimidin-1-yl]-1-phenyl-ethyl}-carbamic acid tert-butyl ester (7) (20 mg, 0.036 mmol) in DMF (1 mL) were added potassium carbonate (12 mg, 0.09 mmol) and benzyl bromide (7 mg, 0.040 mmol) in that order, followed by stirring at room temperature for 1 hr. The solution was diluted with dichloromethane and washed with distilled water. The organic layer thus formed was separated and concentrated, and the residue was purified using silica gel chromatography (eluent: dichloromethane/methanol, 30/1) and dried in a vacuum to afford 22 mg of the compound as a white solid (yield 96%). 1H NMR (300 MHz, CDCl3) δ 1.32 (9H, s), 2.86 (2H, t), 3.32 (2H, s), 3.58 (2H, m), 3.73 (2H, s), 4.04 (1H, m), 4.46 (1H, t), 5.05 (3H, m), 5.53 (1H, m), 6.98 (2H, t), 7.24-7.38 (6H, m), 7.56 (2H, m), 7.71 (1H, d), 8.20 (1H, dd), 8.26 (1H, s)
Reaction SMILES: ClC[C:3]([N:5]1[CH2:10][CH2:9][N:8]([S:11]([C:14]2[CH:23]=[CH:22][C:21]3[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=3)[CH:15]=2)(=[O:13])=[O:12])[CH2:7][CH2:6]1)=[O:4].[N:24]1[CH:29]=[CH:28][CH:27]=[C:26]([CH2:30][OH:31])[CH:25]=1.ClC(Cl)(OC(=O)OC(Cl)(Cl)Cl)Cl>C(Cl)Cl>[CH:15]1[C:16]2[C:21](=[CH:20][CH:19]=[CH:18][CH:17]=2)[CH:22]=[CH:23][C:14]=1[S:11]([N:8]1[CH2:7][CH2:6][N:5]([C:3]([O:31][CH2:30][C:26]2[CH:25]=[N:24][CH:29]=[CH:28][CH:27]=2)=[O:4])[CH2:10][CH2:9]1)(=[O:13])=[O:12]
Reactant: O=C(CCl)N1CCN(S(=O)(=O)c2ccc3ccccc3c2)CC1
Reactant: OCc1cccnc1
Agent: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Solvent: ClCCl
Product: O=C(OCc1cccnc1)N1CCN(S(=O)(=O)c2ccc3ccccc3c2)CC1
Temperature: 25 °C
Reaction time: 3 h
Yield: 29.3 %

Procedure:
To a stirred solution of 2-chloro-1-(4-(naphthalen-2-ylsulfonyl)piperazin-1-yl)ethanone (compound 4, 0.250 g, 0.905 mmol) and pyridin-3-yl-methanol (98 mg, 0.905 mmol) taken in dry DCM (10 mL), triphosgene (294 mg, 0.99 mmol) was added at 0° C. and allowed to stir at room temperature for 3 h. The mixture was then diluted with DCM washed with water (2×10 mL) & brine (2×10 mL). The organic extract was dried over anhydrous sodium sulphate, filtered and concentrated under reduced pressure. The crude material was purified by column chromatography to yield the title compound (0.109 g, 30.27%) as a solid.
Reaction SMILES: [CH2:1]([C:4]1[O:5][CH2:6][C:7]([CH3:11])([CH2:9][OH:10])[N:8]=1)[CH2:2][CH3:3].[C:12](O)(=[O:15])[CH2:13][CH3:14]>>[CH2:1]([C:4]1[O:5][CH2:6][C:7]([CH3:11])([CH2:9][O:10][C:12](=[O:15])[CH2:13][CH3:14])[N:8]=1)[CH2:2][CH3:3]
Reactant: CCCC1=NC(C)(CO)CO1
Reactant: CCC(=O)O
Product: CCCC1=NC(C)(COC(=O)CC)CO1

Procedure:
The 2-propyl-4-methyl-4-hydroxymethyl-2-oxazoline is reacted with propionic acid in a 1:1 molar ratio following the method of Purcell to form 2-propyl-4-methyl-4-propionyloxymethyl-2-oxazoline.
Reaction SMILES: [NH2:1][C:2]1[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[CH:4][CH:3]=1.[H-].[Na+].[CH2:12]([N:19]1[C:23]2[N:24]=[C:25](F)[N:26]=[C:27]([O:28][C:29]3[C:36]([CH3:37])=[CH:35][C:32]([C:33]#[N:34])=[CH:31][C:30]=3[CH3:38])[C:22]=2[CH:21]=[CH:20]1)[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1>>[CH2:12]([N:19]1[C:23]2[N:24]=[C:25]([NH:1][C:2]3[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[CH:4][CH:3]=3)[N:26]=[C:27]([O:28][C:29]3[C:30]([CH3:38])=[CH:31][C:32]([C:33]#[N:34])=[CH:35][C:36]=3[CH3:37])[C:22]=2[CH:21]=[CH:20]1)[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1
Reactant: Cc1cc(C#N)cc(C)c1Oc1nc(F)nc2c1ccn2Cc1ccccc1
Reactant: N#Cc1ccc(N)cc1
Agent: [H-]
Agent: [Na+]
Product: Cc1cc(C#N)cc(C)c1Oc1nc(Nc2ccc(C#N)cc2)nc2c1ccn2Cc1ccccc1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 65.4 %

Procedure:
To a solution of 4-aminobenzonitrile (54 mg, 0.46 mmol) in 1-methyl-2-pyrridone (1 mL) was added NaH (18 mg, 0.46 mmol). The reaction mixture was stirred at room temperature for 15 min and a solution of 4-(7-benzyl-2-fluoro-7H-pyrrolo[2,3-d]pyrimidin-4-yloxy)-3,5-dimethyl-benzonitrile (34 mg, 0.091 mmol) in 1-methyl-2-pyrridone (1 mL) was added to the mixture. The mixture was stirred at room temperature for 1 h, poured into ice water and extracted with EtOAc (2×20 mL). The combined organic solution was washed with H2O (20 mL) and brine (20 mL), dried with Na2SO4, and concentrated to dryness. Silica gel chromatography (Hexanes:EtOAc=75:25) yielded 28 mg (65%) of 4-[7-benzyl-2-(4-cyano-phenylamino)-7H-pyrrolo[2,3-d]pyrimidin-4-yloxy]-3,5-dimethyl-benzonitrile.
Reaction SMILES: B(Br)(Br)Br.[C:5]1([S:11]([NH:14][CH:15]([C:22]2[CH:27]=[CH:26][CH:25]=[C:24]([O:28]C)[CH:23]=2)[CH2:16][C:17]([O:19][CH2:20]C)=[O:18])(=[O:13])=[O:12])[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1.CO>ClCCl>[C:5]1([S:11]([NH:14][CH:15]([C:22]2[CH:27]=[CH:26][CH:25]=[C:24]([OH:28])[CH:23]=2)[CH2:16][C:17]([O:19][CH3:20])=[O:18])(=[O:12])=[O:13])[CH:6]=[CH:7][CH:8]=[CH:9][CH:10]=1
Reactant: CCOC(=O)CC(NS(=O)(=O)c1ccccc1)c1cccc(OC)c1
Agent: BrB(Br)Br
Solvent: ClCCl
Solvent: CO
Product: COC(=O)CC(NS(=O)(=O)c1ccccc1)c1cccc(O)c1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
A solution of BBr3 in dichloromethane (1M) was added at −78° C. to a solution of 2.0 g of (8c) in 50 ml of dichloromethane. After stirring at room temperature for 3 hours, the solution was cooled to −78° C. and 100 ml of methanol were then added. The mixture was stirred at room temperature overnight and then concentrated.
Reaction SMILES: [C:1]1([C:7]2[O:8][CH:9]=[C:10]([CH2:12][CH2:13][O:14][C:15]3[CH:20]=[CH:19][C:18]([OH:21])=[CH:17][CH:16]=3)[N:11]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C(=O)([O-])[O-].[Cs+].[Cs+].Br[C:29]([CH3:36])([CH3:35])[C:30]([O:32][CH2:33][CH3:34])=[O:31]>CN(C=O)C>[CH3:35][C:29]([O:21][C:18]1[CH:17]=[CH:16][C:15]([O:14][CH2:13][CH2:12][C:10]2[N:11]=[C:7]([C:1]3[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=3)[O:8][CH:9]=2)=[CH:20][CH:19]=1)([CH3:36])[C:30]([O:32][CH2:33][CH3:34])=[O:31]
Reactant: CCOC(=O)C(C)(C)Br
Reactant: Oc1ccc(OCCc2coc(-c3ccccc3)n2)cc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: CCOC(=O)C(C)(C)Oc1ccc(OCCc2coc(-c3ccccc3)n2)cc1
Temperature: 25 °C
Reaction time: 24 h

Procedure:
4-[2-(2-Phenyloxazol-4-yl)ethoxy]phenol (3.7 g, 13.0 mmol) and cesium carbonate (4.71 g, 14.5 mmol) were suspended in anhydrous DMF (100 mL) and treated with dropwise addition of ethyl 2-bromoisobutyrate (2.54 g, 13.0 mmol, 1.93 mL). The reaction mixture was stirred at ambient temperature for 24 h and then partitioned between ether (200 mL) and 1.0 N HCl (200 mL). The organic layer was washed with water (100 mL), dried over MgSO4 and concentrated to a brown oil, which was purified by gradient column chromatography (200 mL SiO2, 100% hexanes to 20% EtOAc/hexanes) to provide 2-methyl-2-{4-[2-(2-phenyloxazol-4-yl)ethoxy]phenoxy}propionic acid, ethyl ester (2.54 g,
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[C:6]([N:8]2[CH2:12][CH2:11][CH:10]([N:13]3[CH2:17][CH2:16][CH2:15][CH:14]3[CH3:18])[CH2:9]2)[CH:5]=[CH:4][C:3]=1[NH2:19].[N:20]1([C:26]2[CH:34]=[CH:33][C:29]([C:30](O)=[O:31])=[CH:28][N:27]=2)[CH2:25][CH2:24][O:23][CH2:22][CH2:21]1>>[CH3:1][C:2]1[CH:7]=[C:6]([N:8]2[CH2:12][CH2:11][CH:10]([N:13]3[CH2:17][CH2:16][CH2:15][CH:14]3[CH3:18])[CH2:9]2)[CH:5]=[CH:4][C:3]=1[NH:19][C:30](=[O:31])[C:29]1[CH:33]=[CH:34][C:26]([N:20]2[CH2:21][CH2:22][O:23][CH2:24][CH2:25]2)=[N:27][CH:28]=1
Reactant: O=C(O)c1ccc(N2CCOCC2)nc1
Reactant: Cc1cc(N2CCC(N3CCCC3C)C2)ccc1N
Product: Cc1cc(N2CCC(N3CCCC3C)C2)ccc1NC(=O)c1ccc(N2CCOCC2)nc1

Procedure:
The title compound was prepared in a manner substantially the same as example 1 by coupling 2-methyl-4-(2-methyl-[1,3′]bipyrrolidinyl-1′-yl)-phenylamine with 6-morpholin-4-yl-nicotinic acid. MS: 450.5 (M+H).
Reaction SMILES: [C:1]([C:4]1[CH:9]=[CH:8][C:7]([S:10]([NH:13][C:14]2[CH:19]=[CH:18][C:17]([Cl:20])=[CH:16][C:15]=2[N:21]2[C:29]3[C:24](=[N:25][CH:26]=[CH:27][CH:28]=3)[N:23]=[N:22]2)(=[O:12])=[O:11])=[CH:6][CH:5]=1)(=[O:3])[CH3:2].[C:30]([Si](C)(C)C)([F:33])([F:32])[F:31].[F-].C([N+](CCCC)(CCCC)CCCC)CCC>CCOC(C)=O>[Cl:20][C:17]1[CH:18]=[CH:19][C:14]([NH:13][S:10]([C:7]2[CH:6]=[CH:5][C:4]([C:1]([OH:3])([CH3:2])[C:30]([F:33])([F:32])[F:31])=[CH:9][CH:8]=2)(=[O:12])=[O:11])=[C:15]([N:21]2[C:29]3[C:24](=[N:25][CH:26]=[CH:27][CH:28]=3)[N:23]=[N:22]2)[CH:16]=1
Reactant: C[Si](C)(C)C(F)(F)F
Reactant: CC(=O)c1ccc(S(=O)(=O)Nc2ccc(Cl)cc2-n2nnc3ncccc32)cc1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: CCOC(C)=O
Product: CC(O)(c1ccc(S(=O)(=O)Nc2ccc(Cl)cc2-n2nnc3ncccc32)cc1)C(F)(F)F
Temperature: 25 °C
Reaction time: 16 h

Procedure:
To 4-acetyl-N-(4-chloro-2-[1,2,3]triazolo[4,5-b]pyridin-1-yl-phenyl)-benzene-sulfonamide (synthesized according to general procedures F and G, 500 mg, 1.17 mmol) was added CF3-TMS (trifluoromethyl-trimethylsilane) (4.7 mL, 0.5 M solution in THF), followed by TBAF (tetra-n-butylammonium fluoride) (2.34 mL, 1.0 M solution in THF) at 0° C., and the solution was stirred at room temperature for 16 hours. Both TLC and LCMS analysis indicated ˜10-15% completion of reaction. The reaction mixture was diluted with EtOAc (50 mL) and the organics were washed with washed with 2 N HCl (2×25 mL), water (25 mL), and brine (25 mL). The organics were subsequently dried (Na2SO4), concentrated in vacuo, and purified by automated flash chromatography followed by preparative HPLC to afford the title compound as a white powder: MS (ES) M+H expected 498.1, found 498.0.
Reaction SMILES: [C:1]([N:6]1[C:10](=[O:11])[C:9]2=[CH:12][CH:13]=[CH:14][CH:15]=[C:8]2[C:7]1=[O:16])(OCC)=O.[NH:17]1[C:25]2[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=2)[C:19]([CH2:26]CN)=[CH:18]1>>[NH:17]1[C:25]2[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=2)[C:19]([CH2:26][CH2:1][N:6]2[C:7](=[O:16])[C:8]3[C:9](=[CH:12][CH:13]=[CH:14][CH:15]=3)[C:10]2=[O:11])=[CH:18]1
Reactant: CCOC(=O)N1C(=O)c2ccccc2C1=O
Reactant: NCCc1c[nH]c2ccccc12
Product: O=C1c2ccccc2C(=O)N1CCc1c[nH]c2ccccc12
Temperature: 25 °C
Yield: 85.5 %

Procedure:
To a stirred suspension of 2-(1H-indol-3-yl)ethylamine (2.0 g in 20 mL of dry tetrahydrofuran) was added N-carbethoxyphthalimide (2.85 g) and the mixture heated to reflux on an oil bath. After 48 hours the reaction was cooled to room temperature, filtered and the filtrate concentrated in vacuo. The resulting solid was suspended in a mixture of hexane/methylene chloride (2.5:1) and filtered. Purification of the collected solids by flash chromatography (methylene chloride:methanol, 97:3) gave the title compound (3.1 g).
Reaction SMILES: [NH2:1][CH2:2][CH2:3][O:4][CH2:5][C:6]([OH:8])=[O:7].CCOCC.C(=O)(O)[O-].[Na+].[N+:19]([C:22]1[CH:32]=[CH:31][C:25]([CH2:26][O:27][C:28](Cl)=[O:29])=[CH:24][CH:23]=1)([O-:21])=[O:20]>O>[N+:19]([C:22]1[CH:23]=[CH:24][C:25]([CH2:26][O:27][C:28]([NH:1][CH2:2][CH2:3][O:4][CH2:5][C:6]([OH:8])=[O:7])=[O:29])=[CH:31][CH:32]=1)([O-:21])=[O:20]
Reactant: O=C(Cl)OCc1ccc([N+](=O)[O-])cc1
Reactant: NCCOCC(=O)O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCOCC
Solvent: O
Product: O=C(O)COCCNC(=O)OCc1ccc([N+](=O)[O-])cc1
Temperature: 25 °C
Reaction time: 17 h
Yield: 99.2 %

Procedure:
With cooling on an ice bath, to 596 mg of 2-(2-aminoethoxy)acetic acid dissolved in 10 ml of water was added an ether solution of 883 mg sodium bicarbonate and 1.29 g p-nitrobenzyloxycarbonyl chloride in dropwise manner. After stirring the reaction solution for 17 hours at room temperature, the resulting aqueous layer was collected, adjusted to acidic with concentrated hydrochloric acid and extracted with ethyl acetate, and the resulting organic layer was washed with water and dried over sodium sulfate, followed by evaporation of the solvent under a reduced pressure to yield 1.48 g of 2-(2-(p-nitrobenzyloxycarbonylamino)ethoxy)acetic acid.
Reaction SMILES: [NH2:1][CH:2]([CH:10]([OH:26])[CH2:11][N:12]1[CH2:17][CH2:16][CH:15]([CH2:18][C:19]2[CH:24]=[CH:23][C:22]([F:25])=[CH:21][CH:20]=2)[CH2:14][CH2:13]1)[CH2:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.[C:27]([C:29]1[CH:30]=[C:31]([N:35]=[C:36]=[O:37])[CH:32]=[CH:33][CH:34]=1)#[N:28]>C1COCC1>[C:27]([C:29]1[CH:30]=[C:31]([NH:35][C:36]([NH:1][CH:2]([CH2:3][C:4]2[CH:5]=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:10]([OH:26])[CH2:11][N:12]2[CH2:13][CH2:14][CH:15]([CH2:18][C:19]3[CH:24]=[CH:23][C:22]([F:25])=[CH:21][CH:20]=3)[CH2:16][CH2:17]2)=[O:37])[CH:32]=[CH:33][CH:34]=1)#[N:28]
Reactant: N#Cc1cccc(N=C=O)c1
Reactant: NC(Cc1ccccc1)C(O)CN1CCC(Cc2ccc(F)cc2)CC1
Solvent: C1CCOC1
Product: N#Cc1cccc(NC(=O)NC(Cc2ccccc2)C(O)CN2CCC(Cc3ccc(F)cc3)CC2)c1
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
To a solution of 2-amino-4-[4-(4-fluorophenyl)methyl-1-piperidinyl]-1-phenyl-butan-3-ol (50 mg, 0.14 mmoles) in 2.5 mL of dry THF was added 3-cyanophenyl isocyanate (20.2 mg, 0.14 mmoles) and the mixture was stirred for 15 minutes at room temperature. Then the solvent was evaporated off to give an oily residue. It was purified by column chromatography on silica gel with elution by EtOAc to give pure titled compound as an amorphous solid. MS (ES+) for C30H33FN4O2: 501.
Reaction SMILES: F[S:2]([C:5]1[N:6]=[N:7][C:8]([O:11][CH3:12])=[CH:9][CH:10]=1)(=[O:4])=[O:3].[NH:13]1[C:22]2[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=2)[CH2:16][CH2:15][CH2:14]1>>[CH3:12][O:11][C:8]1[N:7]=[N:6][C:5]([S:2]([N:13]2[C:22]3[CH:17]([CH2:18][CH:19]=[CH:20][CH:21]=3)[CH2:16][CH2:15][CH2:14]2)(=[O:4])=[O:3])=[CH:10][CH:9]=1
Reactant: COc1ccc(S(=O)(=O)F)nn1
Reactant: c1ccc2c(c1)CCCN2
Product: COc1ccc(S(=O)(=O)N2CCCC3CC=CC=C32)nn1
Temperature: 140 °C
Yield: 73.4 %

Procedure:
A mixture of 3-fluorosulfonyl-6-methoxypyridazine (2 mmol, 384 mg) and tetrahydroquinoline (4 mmol, 532 mg) was heated at 140° C. for two hours. The reaction mixture was cooled, extracted with EtOAc (20 mL), and the EtOAc extract was dried, filtered and evaporated to obtain 3-methoxy-6-(tetrahydroquinoline-1-sulfonyl)-pyridazine (73%, 451 mg).
Reaction SMILES: C1(C([O:9][C:10]2[C:15]([CH3:16])=[CH:14][CH:13]=[CH:12][C:11]=2[C:17](=[O:19])[CH3:18])=O)CCCCC1.[H-].[Na+].O.[C:23]([OH:26])(=O)[CH3:24]>O1CCCC1>[CH:24]1([C:23](=[O:26])[CH2:18][C:17]([C:11]2[CH:12]=[CH:13][CH:14]=[C:15]([CH3:16])[C:10]=2[OH:9])=[O:19])[CH2:14][CH2:15][CH2:10][CH2:11][CH2:12]1
Reactant: CC(=O)O
Reactant: CC(=O)c1cccc(C)c1OC(=O)C1CCCCC1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: Cc1cccc(C(=O)CC(=O)C2CCCCC2)c1O
Temperature: 25 °C

Procedure:
2-Acetyl-6-methylphenyl cyclohexanecarboxylate (5.2 g) was dissolved in anhydrous tetrahydrofuran (50 ml) and to the solution was added 60% sodium hydride (880 mg) by portions with stirring at room temperature. After stirring under reflux for 2 hours, the mixture was poured into cold water, acidified with acetic acid and then extracted with ethyl acetate. The extract was washed with water, dried (MgSO4) and then concentrated under reduced pressure to obtain the title compound (5.2 g) as crystals in a quantitative yield. The crystals were recrystallized from methanol to obtain the prisms, m.p. 42°-43° C.
Reaction SMILES: [CH3:1][N:2]([CH2:16][CH2:17][C:18]1[CH:23]=[CH:22][C:21]([O:24][C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)=[CH:20][CH:19]=1)[CH:3]1[CH2:8][CH2:7][N:6](C(OC(C)(C)C)=O)[CH2:5][CH2:4]1.Cl>ClC(Cl)C.O1CCOCC1>[CH3:1][N:2]([CH2:16][CH2:17][C:18]1[CH:23]=[CH:22][C:21]([O:24][C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)=[CH:20][CH:19]=1)[CH:3]1[CH2:4][CH2:5][NH:6][CH2:7][CH2:8]1
Reactant: CN(CCc1ccc(Oc2ccccc2)cc1)C1CCN(C(=O)OC(C)(C)C)CC1
Agent: Cl
Solvent: CC(Cl)Cl
Solvent: C1COCCO1
Product: CN(CCc1ccc(Oc2ccccc2)cc1)C1CCNCC1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
A solution of 1,1-dimethylethyl 4-(methyl(2-(4-phenoxyphenyl)ethyl)amino)-1-piperidinecarboxylate (290 mg, 0.71 mmol) in dichloroethane was added a solution of hydrogen chloride in dioxane (4N). The reaction was stirred at ambient temperature for 4 hours. The reaction mixture was concentrated to dryness to give N-methyl-N-[2-(4-phenoxyphenyl)ethyl]-4-piperidinamine.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([F:8])[C:3]=1[C:9]1[NH:13][C:12](=[O:14])[N:11]([C:15]2[CH:23]=[CH:22][C:18]([C:19]([OH:21])=O)=[C:17]([O:24][CH3:25])[CH:16]=2)[N:10]=1.C(N(C(C)C)CC)(C)C.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F.[F:57][C:58]([F:70])([F:69])[C:59]1[CH:64]=[CH:63][CH:62]=[CH:61][C:60]=1[C:65]1([NH2:68])[CH2:67][CH2:66]1>C1COCC1>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([F:8])[C:3]=1[C:9]1[NH:13][C:12](=[O:14])[N:11]([C:15]2[CH:23]=[CH:22][C:18]([C:19]([NH:68][C:65]3([C:60]4[CH:61]=[CH:62][CH:63]=[CH:64][C:59]=4[C:58]([F:57])([F:69])[F:70])[CH2:67][CH2:66]3)=[O:21])=[C:17]([O:24][CH3:25])[CH:16]=2)[N:10]=1
Reactant: COc1cc(-n2nc(-c3c(F)cccc3Cl)[nH]c2=O)ccc1C(=O)O
Reactant: NC1(c2ccccc2C(F)(F)F)CC1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: C1CCOC1
Product: COc1cc(-n2nc(-c3c(F)cccc3Cl)[nH]c2=O)ccc1C(=O)NC1(c2ccccc2C(F)(F)F)CC1
Yield: 13.5 %

Procedure:
The title compound was prepared according to the procedure described in Example-17 by using 4-(3-(2-chloro-6-fluorophenyl)-5-oxo-4,5-dihydro-1H-1,2,4-triazol-1-yl)-2-methoxybenzoic acid (Intermediate-15, 0.100 g, 0.270 mmol), THF (5 mL), di-isopropyl ethyl amine (2.0 mL), TBTU (0.177 g, 0.540 mmol) and 1-[2-(trifluoromethyl)phenyl]cyclopropanamine (Intermediate-12, 0.082 g, 0.410 mmol) to afford 0.020 g of desired product. 1H NMR (300 MHz, DMSO d6): δ 1.27-1.31 (m, 4H), 3.90 (s, 3H), 7.47 (t, J=8.1 Hz, 2H), 7.54-7.69 (m, 6H), 7.87 (t, J=8.4 Hz, 1H), 7.99 (d, J=7.8 Hz, 1H), 8.61 (s, 1H); MS (m/z): 547.15 (M+).
Reaction SMILES: [F:1][C:2]1[CH:8]=[CH:7][C:6]([F:9])=[CH:5][C:3]=1[NH2:4].[N-:10]([C:13]#[N:14])[C:11]#[N:12].[Na+]>>[C:11]([N:10]=[C:13]([NH2:14])[NH:4][C:3]1[CH:5]=[C:6]([F:9])[CH:7]=[CH:8][C:2]=1[F:1])#[N:12]
Reactant: Nc1cc(F)ccc1F
Reactant: N#C[N-]C#N
Agent: [Na+]
Product: N#CN=C(N)Nc1cc(F)ccc1F

Procedure:
2,5-Difluoroaniline and sodium dicyanamide were procesed as described in Example 71A to provide the desired compound.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[C:6]([CH3:8])[CH:5]=[C:4]([CH2:9][CH2:10][C:11]2[NH:20][C:14]3=[N:15][CH:16]=[C:17](Br)[CH:18]=[C:13]3[N:12]=2)[N:3]=1.[Cl:21][C:22]1[CH:23]=[C:24](B(O)O)[CH:25]=[C:26]([Cl:28])[CH:27]=1>O1CCOCC1.C([O-])([O-])=O.[Na+].[Na+]>[Cl:21][C:22]1[CH:23]=[C:24]([C:17]2[CH:18]=[C:13]3[N:12]=[C:11]([CH2:10][CH2:9][C:4]4[N:3]=[C:2]([NH2:1])[CH:7]=[C:6]([CH3:8])[CH:5]=4)[NH:20][C:14]3=[N:15][CH:16]=2)[CH:25]=[C:26]([Cl:28])[CH:27]=1
Reactant: OB(O)c1cc(Cl)cc(Cl)c1
Reactant: Cc1cc(N)nc(CCc2nc3cc(Br)cnc3[nH]2)c1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: C1COCCO1
Product: Cc1cc(N)nc(CCc2nc3cc(-c4cc(Cl)cc(Cl)c4)cnc3[nH]2)c1
Yield: 30.9 %

Procedure:
The title compound is synthesized according to General Procedure A. 100 mg of 2-[2-(2-amino-4-methylpyridin-6-yl)ethyl]-6-bromo-3H-imidazo[4,5-b]pyridine in 5.0 ml dioxane, 903 μl Na2CO3 solution, 65 mg of 3,5-dichlorophenylboronic acid, 13 mg of PdCl2(PCy3)2, 120° C. for 64 h. During extraction with 20 ml of CH2Cl2/H2O the title compound starts precipitating in the organic layer. Subsequently, 37 mg of the pure title compound can be obtained as a colorless powder after filtration and lyophilization from 2.0 ml dioxane and 1.0 ml water. M.p. 224° C. ESI-MS: 398.3, 400.2, 402.3 (MH+; 100%, 65%, 13%). TLC: Rf=0.24 (dichloromethane/methanol 10:1).