Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[C:9]([CH3:10])=[C:8](F)[CH:7]=[CH:6][C:3]=1[C:4]#[N:5].[NH:12]1[CH2:19][CH2:18][CH2:17][C@H:13]1[C:14]([OH:16])=[O:15]>CN1CCOCC1>[Cl:1][C:2]1[C:9]([CH3:10])=[C:8]([N:12]2[CH2:19][CH2:18][CH2:17][C@H:13]2[C:14]([OH:16])=[O:15])[CH:7]=[CH:6][C:3]=1[C:4]#[N:5]
Reactant: O=C(O)[C@@H]1CCCN1
Reactant: Cc1c(F)ccc(C#N)c1Cl
Solvent: CN1CCOCC1
Product: Cc1c(N2CCC[C@H]2C(=O)O)ccc(C#N)c1Cl

Procedure:
Heat a slurry of 2-chloro-4-fluoro-3-methyl-benzonitrile (0.4 g, 2.36 mmol) and L-proline (2.11 g, 18.8 mmol) in N-methylmorpholine (1.6 mL) at 200° C. in a microwave for 30 min. Partition the reaction between 2N aqueous hydrochloric acid and ethyl acetate. Separate and extract the organic portion with 2N aqueous sodium hydroxide. Acidify the aqueous extract to pH 1 by adding concentrated hydrochloric acid and back extract into ethyl acetate. Extract the combined organic portions with brine, dry over magnesium sulphate, filter, and concentrate under reduced pressure to give the title compound. (0.395 g, 63%) mass spectrum (m/e): 263 (M−1); 1H NMR (300 MHz, CDCl3): δ 8.66 (bs, 1H0, 7.31 (d, 1H), 6.75 (d, 1H), 4.38 (t, 1H), 3.67 (m, 1H), 3.10 (m, 1H), 2.43 (m, 1H), 2.29 (s, 3H), 2.20-1.90 (m. 3H).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:23]=[CH:22][C:6]([C:7]([N:9]([C:14]2[CH:19]=[CH:18][C:17]([O:20][CH3:21])=[CH:16][CH:15]=2)[NH:10][C:11](=[S:13])[NH2:12])=O)=[CH:5][CH:4]=1.C(O)C>[OH-].[K+]>[CH3:21][O:20][C:17]1[CH:18]=[CH:19][C:14]([N:9]2[C:7]([C:6]3[CH:22]=[CH:23][C:3]([O:2][CH3:1])=[CH:4][CH:5]=3)=[N:12][C:11]([SH:13])=[N:10]2)=[CH:15][CH:16]=1
Reactant: COc1ccc(C(=O)N(NC(N)=S)c2ccc(OC)cc2)cc1
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Product: COc1ccc(-c2nc(S)nn2-c2ccc(OC)cc2)cc1
Yield: 27.5 %

Procedure:
A mixture of 2-(4-methoxybenzoyl)-2-(4-methoxyphenyl)hydrazinecarbothioamide (200 mg, 0.604 mmol) in 10% potassium hydroxide solution (2 mL)-ethanol (1 mL) was refluxed for 4 hours. After cooling, the mixture was adjusted pH to ca. 2 and a generated precipitate was isolated by filtration, washed with water, and dried in vacuo to give 1,5-bis(4-methoxyphenyl)-1H-1,2,4-triazole-3-thiol (52 mg, 27.5% yield).
Reaction SMILES: FC(F)(F)S(OS(C(F)(F)F)(=O)=O)(=O)=O.[Cl:16][C:17]1[N:18]=[C:19]([CH:22](O)[CH2:23][CH2:24][CH2:25][N:26]2[C:34]([C:35]3[CH:36]=[C:37]([CH:40]=[CH:41][CH:42]=3)[C:38]#[N:39])=[C:33]3[C:28]([N:29]([CH3:46])[C:30](=[O:45])[N:31]([CH3:44])[C:32]3=[O:43])=[CH:27]2)[S:20][CH:21]=1.C(N(CC)CC)C>C(Cl)Cl>[Cl:16][C:17]1[N:18]=[C:19]([CH:22]2[C:27]3[N:26]([C:34]([C:35]4[CH:36]=[C:37]([CH:40]=[CH:41][CH:42]=4)[C:38]#[N:39])=[C:33]4[C:32](=[O:43])[N:31]([CH3:44])[C:30](=[O:45])[N:29]([CH3:46])[C:28]4=3)[CH2:25][CH2:24][CH2:23]2)[S:20][CH:21]=1
Reactant: Cn1c(=O)c2c(-c3cccc(C#N)c3)n(CCCC(O)c3nc(Cl)cs3)cc2n(C)c1=O
Agent: O=S(=O)(OS(=O)(=O)C(F)(F)F)C(F)(F)F
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: Cn1c(=O)c2c(-c3cccc(C#N)c3)n3c(c2n(C)c1=O)C(c1nc(Cl)cs1)CCC3
Temperature: -78 °C
Reaction time: 0.02 h

Procedure:
Trifluoromethanesulfonic anhydride (3.95 ml, 23.41 mmol) was added dropwise to a solution of 3-(6-(4-(4-chlorothiazol-2-yl)-4-hydroxybutyl)-1,3-dimethyl-2,4-dioxo-2,3,4,6-tetrahydro-1H-pyrrolo[3,4-d]pyrimidin-5-yl)benzonitrile (5 g, 10.64 mmol) and triethylamine (3.56 ml, 25.5 mmol) in DCM (213 mL) at −78° C. The mixture was stirred for 1 min at −78° C. The reaction was quenched with saturated aqueous NaHCO3(aq) (100 mL) and extracted with DCM (3×100 mL). The combined organic extracts were dried over magnesium sulfate and evaporated under reduced pressure to afford crude racemic 3-(10-(4-chlorothiazol-2-yl)-1,3-dimethyl-2,4-dioxo-1,2,3,4,7,8,9,10-octahydropyrimido[4,5-a]indolizin-5-yl)benzonitrile.
Reaction SMILES: [Si]([O:8][CH2:9][CH2:10][N:11]1[CH2:17][CH2:16][CH2:15][CH2:14][C@H:13]([NH:18]C(=O)OC(C)(C)C)[C:12]1=[O:26])(C(C)(C)C)(C)C.[ClH:27].O1CCOCC1>ClCCl>[ClH:27].[NH2:18][C@H:13]1[CH2:14][CH2:15][CH2:16][CH2:17][N:11]([CH2:10][CH2:9][OH:8])[C:12]1=[O:26]
Reactant: CC(C)(C)OC(=O)N[C@H]1CCCCN(CCO[Si](C)(C)C(C)(C)C)C1=O
Agent: Cl
Solvent: ClCCl
Solvent: C1COCCO1
Product: N[C@H]1CCCCN(CCO)C1=O
Temperature: 25 °C
Reaction time: 16 h
Yield: 100 %

Procedure:
To a solution of (S)-tert-butyl 1-(2-(tert-butyldimethylsilyloxy)ethyl)-2-oxoazepan-3-ylcarbamate (prepared according to Example 15; 243 mg, 0.629 mmol) in dichloromethane (2 mL) was added 4M hydrogen chloride in dioxane (2 mL, 8 mmol), and the reaction mixture was allowed to stir at ambient temperature for 16 hours. The reaction mixture was concentrated to yield (S)-3-amino-1-(2-hydroxyethyl)azepan-2-one hydrochloride (131 mg, 100%), which was taken on to the next reaction without further purification.
Reaction SMILES: [H-].[Na+].[CH2:3]([N:10]1[C:18]2[C:17]([O:19][C:20]3[C:25]([CH3:26])=[CH:24][C:23]([CH3:27])=[CH:22][C:21]=3[CH3:28])=[N:16][C:15](F)=[N:14][C:13]=2[CH:12]=[CH:11]1)[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.C[N:31]1[C:35](=O)[CH2:34][CH2:33][CH2:32]1>O>[CH2:3]([N:10]1[C:18]2[C:17]([O:19][C:20]3[C:25]([CH3:26])=[CH:24][C:23]([CH3:27])=[CH:22][C:21]=3[CH3:28])=[N:16][C:15]([NH:10][C:3]3[CH:32]=[CH:33][C:34]([C:35]#[N:31])=[CH:5][CH:4]=3)=[N:14][C:13]=2[CH:12]=[CH:11]1)[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1
Reactant: CN1CCCC1=O
Reactant: Cc1cc(C)c(Oc2nc(F)nc3ccn(Cc4ccccc4)c23)c(C)c1
Agent: [H-]
Agent: [Na+]
Solvent: O
Product: Cc1cc(C)c(Oc2nc(Nc3ccc(C#N)cc3)nc3ccn(Cc4ccccc4)c23)c(C)c1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 80 %

Procedure:
A stirred suspension of NaH (63.8 mg, 2.66 mmol) in dry NMP (1.5 mL) was added 4-aminobenzylnitrile (188 mg, 2.66 mmol) and stirred at room temperature for 30 min under argon. The reaction mixture was added to a solution of 5-benzyl-2-fluoro-4-(mesityloxy)-5H-pyrrolo[3,2-d]pyrimidine (115 mg, 0.32 mmol) in dry NMP (1.7 mL) and stirred at room temperature for 2 h. After completion of the reaction, the resulting mixture was diluted with water and washed with EtOAc 3 times. The combined organic layers were washed with water, NH4Cl, water×2, and brine, dried over Na2SO4, filtered, and concentrated in vacuo. The crude product was purified by column chromatography, eluting with 1% MeOH:CH2Cl2, which afforded the product as a tan solid (120 mg, 80%).
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([O:15][C:16]2[CH:17]=[N:18][C:19]([S:22]([CH3:25])(=[O:24])=[O:23])=[CH:20][CH:21]=2)[CH:5]=[C:6]2[C:10]=1[NH:9][C:8]([C:11]([O:13][CH3:14])=[O:12])=[CH:7]2.C(P(CCCC)CCCC)CCC.N(C(N1CCCCC1)=O)=NC(N1CCCCC1)=O.[CH3:57][O:58][CH2:59][CH:60](O)[CH2:61][O:62][CH3:63]>O1CCCC1>[CH3:57][O:58][CH2:59][CH:60]([CH2:61][O:62][CH3:63])[O:1][C:2]1[CH:3]=[C:4]([O:15][C:16]2[CH:17]=[N:18][C:19]([S:22]([CH3:25])(=[O:24])=[O:23])=[CH:20][CH:21]=2)[CH:5]=[C:6]2[C:10]=1[NH:9][C:8]([C:11]([O:13][CH3:14])=[O:12])=[CH:7]2
Reactant: COC(=O)c1cc2cc(Oc3ccc(S(C)(=O)=O)nc3)cc(O)c2[nH]1
Reactant: COCC(O)COC
Agent: CCCCP(CCCC)CCCC
Agent: O=C(N=NC(=O)N1CCCCC1)N1CCCCC1
Solvent: C1CCOC1
Product: COCC(COC)Oc1cc(Oc2ccc(S(C)(=O)=O)nc2)cc2cc(C(=O)OC)[nH]c12
Temperature: 50 °C
Reaction time: 13 h
Yield: 116.4 %

Procedure:
A mixture of methyl 7-hydroxy-5-{[6-(methylsulfonyl)pyridin-3-yl]oxy}-1H-indole-2-carboxylate (1.2 g), tributylphosphine (1.6 mL), 1,1′-(azodicarbonyl)dipiperidine (1.7 g), 1,3-dimethoxypropan-2-ol (0.8 g) and tetrahydrofuran (20 mL) was stirred at 50° C. for 13 h. Tributylphosphine (0.82 mL), 1,1′-(azodicarbonyl)dipiperidine (0.83 g) and 1,3-dimethoxypropan-2-ol (0.4 g) were added to the mixture again and the mixture was stirred at 70° C. for 5 h. Furthermore, tributylphosphine (1.64 mL), 1,1′-(azodicarbonyl)dipiperidine (1.66 g) and 1,3-dimethoxypropan-2-ol (0.8 g) were added to the mixture. After stirring at 70° C. for 3 h, the mixture was cooled to 0° C., and insoluble materials were removed by filtration. The filtrate was concentrated and the residue was purified basic silica gel column chromatography (ethyl acetate/hexane=20/80 to 85/15, volume ratio) to give the title compound (1.79 g, 84%) as an orange oil, MS 463 (MH−).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([F:8])=[CH:4][C:3]=1[OH:9].[Br:10][CH2:11][CH2:12][CH2:13]Br.C(=O)([O-])[O-].[K+].[K+]>C(#N)C>[Br:10][CH2:11][CH2:12][CH2:13][O:9][C:3]1[CH:4]=[C:5]([F:8])[CH:6]=[CH:7][C:2]=1[F:1]
Reactant: Oc1cc(F)ccc1F
Reactant: BrCCCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: Fc1ccc(F)c(OCCCBr)c1
Temperature: 80 °C
Yield: 96 %

Procedure:
A mixture of 2,5-difluorophenol (2.60 g, 20.0 mmol), 1,3-dibromopropane (20.3 mL, 200 mmol), and potassium carbonate (2.76 g, 20.0 mmol) in acetonitril (30 mL) was heated at 80° C. overnight. The reaction mixture was filtered and the filtrate was concentrated in vacuo to give 4.82 g of the title compound as a light yellow oil with a purity of ca. 80%. The product was used in the subsequent reaction step without further purification.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[CH:13]=[C:12]2[C:8]([C:9]([CH:16]=[O:17])=[CH:10][N:11]2[CH2:14][CH3:15])=[CH:7][CH:6]=1)=[O:4].CC1C=CC(S([CH2:28][N+:29]#[C-:30])(=O)=O)=CC=1.C([O-])([O-])=O.[K+].[K+]>CO>[CH2:14]([N:11]1[C:12]2[C:8](=[CH:7][CH:6]=[C:5]([C:3]([O:2][CH3:1])=[O:4])[CH:13]=2)[C:9]([C:16]2[O:17][CH:30]=[N:29][CH:28]=2)=[CH:10]1)[CH3:15]
Reactant: CCn1cc(C=O)c2ccc(C(=O)OC)cc21
Reactant: [C-]#[N+]CS(=O)(=O)c1ccc(C)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CO
Product: CCn1cc(-c2cnco2)c2ccc(C(=O)OC)cc21
Yield: 22.9 %

Procedure:
1-Ethyl-3-formyl-1H-indole-6-carboxylic acid methyl ester (100 mg, 0.42 mmol), TOSMIC (100 mg, 0.52 mmol), K2CO3 (178 mg, 1.29 mmol), and MeOH (800 μL) are heated at 80° C. overnight. The reaction mixture is then partitioned between H2O and ether. After drying and concentrating the organic phase, the product is purified by silica gel chromatography (EtOAc/CH2Cl2, 10/90) to give methyl 1-ethyl-3-oxazol-5-yl-1H-indole-6-carboxylate (26 mg, 23%) as an off-white solid.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[N:6][CH:7]=[CH:8][C:9]=1Cl)([O-:3])=[O:2].C([O-])(=O)C.[NH4+:15].N>>[N+:1]([C:4]1[CH:5]=[N:6][CH:7]=[CH:8][C:9]=1[NH2:15])([O-:3])=[O:2]
Reactant: O=[N+]([O-])c1cnccc1Cl
Reactant: [NH4+]
Agent: CC(=O)[O-]
Agent: N
Product: Nc1ccncc1[N+](=O)[O-]
Temperature: 135 °C
Yield: 59 %

Procedure:
Five grams (31.5 mmol) of 3-nitro-4-chloropyridine was mixed with 26 g of ammonium acetate, and the mixture was heated at 130-140° C. for 3 hours. The mixture was allowed to cool, and then adjusted to pH 10 with concentrated aqueous ammonia. The precipitated powder was collected by filtration to obtain 2.6 g of the intended yield: 59%).
Reaction SMILES: [Cl:1][C:2]1([Cl:10])[C:4]([CH3:6])([CH3:5])[CH:3]1[C:7](Cl)=[O:8].[O:11]([C:18]1[CH:19]=[C:20]([CH:25]=[CH:26][CH:27]=1)[CH:21]([OH:24])[C:22]#[N:23])[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1.C(N(CC)CC)C>C1(C)C=CC=CC=1>[Cl:1][C:2]1([Cl:10])[C:4]([CH3:6])([CH3:5])[CH:3]1[C:7]([O:24][CH:21]([C:22]#[N:23])[C:20]1[CH:25]=[CH:26][CH:27]=[C:18]([O:11][C:12]2[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=2)[CH:19]=1)=[O:8]
Reactant: CC1(C)C(C(=O)Cl)C1(Cl)Cl
Reactant: N#CC(O)c1cccc(Oc2ccccc2)c1
Solvent: Cc1ccccc1
Solvent: CCN(CC)CC
Product: CC1(C)C(C(=O)OC(C#N)c2cccc(Oc3ccccc3)c2)C1(Cl)Cl
Temperature: 10 °C
Reaction time: 16 h

Procedure:
2,2-Dichloro-3,3-dimethylcyclopropanoyl chloride (2.69g) was dissolved in dry toluene (50ml) and this solution was added dropwise to a stirred solution of 3-phenoxymandelonitrile (3.0g) and triethylamine (2.69g) in dry toluene (50ml) maintained at 10°C. The mixture was then stirred at room temperature for 16 hours. The mixture was filtered and the filtrate was washed in turn with 5 % sulphuric acid, saturated sodium bicarbonate and water, and then dried (Na2SO4). The solvent was removed under reduced pressure and the residue purified by chromatography on silica gel eluting in turn with toluene, 1 : 1 toluene/hexane and toluene. The required product was obtained as an oil nD20 1.5630.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]([CH:10]1[CH2:14][CH2:13][N:12]([S:15]([C:18]2[C:19]3[C:20]([Cl:29])=[CH:21][N:22]=[C:23](Cl)[C:24]=3[CH:25]=[CH:26][CH:27]=2)(=[O:17])=[O:16])[CH2:11]1)[CH3:9])=[O:7])([CH3:4])([CH3:3])[CH3:2].[O-:30][CH2:31][CH3:32].[Na+]>C(O)C.[Cl-].[Na+].O>[C:1]([O:5][C:6]([N:8]([C@H:10]1[CH2:14][CH2:13][N:12]([S:15]([C:18]2[C:19]3[C:20]([Cl:29])=[CH:21][N:22]=[C:23]([O:30][CH2:31][CH3:32])[C:24]=3[CH:25]=[CH:26][CH:27]=2)(=[O:16])=[O:17])[CH2:11]1)[CH3:9])=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC[O-]
Reactant: CN(C(=O)OC(C)(C)C)C1CCN(S(=O)(=O)c2cccc3c(Cl)ncc(Cl)c23)C1
Agent: [Cl-]
Agent: [Na+]
Solvent: CCO
Solvent: O
Product: CCOc1ncc(Cl)c2c(S(=O)(=O)N3CC[C@H](N(C)C(=O)OC(C)(C)C)C3)cccc12
Temperature: 50 °C
Reaction time: 12 h
Yield: 95 %

Procedure:
A solution of Intermediate 25 (230 mg) obtained in Example 36-1 in ethanol (10 ml) was added with sodium ethoxide (204 mg, Aldrich), and the mixture was stirred at 50° C. for 12 hours. The reaction mixture was added with saturated brine (10 ml), and extracted three times with ethyl acetate (10 ml for each time), and the combined organic layer was washed with saturated brine (20 ml), and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure, and the residue was purified by silica gel chromatography (n-hexane:ethyl acetate=3:1) to obtain the title compound (223 mg).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH2:9][N:10]([CH3:28])[S:11]([C:14]2[C:15]3[CH2:22][CH2:21][CH:20]([O:23][C:24](=[O:26])[CH3:25])[C:19](=O)[C:16]=3[S:17][CH:18]=2)(=[O:13])=[O:12])=[CH:4][CH:3]=1.Cl.[NH2:30][OH:31]>N1C=CC=CC=1.C(OCC)(=O)C>[F:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH2:9][N:10]([CH3:28])[S:11]([C:14]2[C:15]3[CH2:22][CH2:21][CH:20]([O:23][C:24](=[O:26])[CH3:25])/[C:19](=[N:30]/[OH:31])/[C:16]=3[S:17][CH:18]=2)(=[O:13])=[O:12])=[CH:4][CH:3]=1
Reactant: CC(=O)OC1CCc2c(S(=O)(=O)N(C)CCc3ccc(F)cc3)csc2C1=O
Reactant: NO
Agent: Cl
Solvent: CCOC(C)=O
Solvent: c1ccncc1
Product: CC(=O)OC1CCc2c(S(=O)(=O)N(C)CCc3ccc(F)cc3)csc2/C1=N\O
Temperature: 25 °C
Reaction time: 2.5 h

Procedure:
To a solution of 6-acetoxy-7-oxo-4,5,6,7-tetrahydrobenzo[b]thiophene-3-sulfonic acid [2-(4-fluorophenyl)ethyl]-methyl-amide (the compound of Preparation Example 65) (200 mg) in pyridine (2 mL) was added hydroxylamine.hydrochloride (61 mg). After stirring at room temperature for 2.5 hours, two products were observed by TLC. After the solution was diluted with ethyl acetate, the solution was washed with water and saturated sodium chloride water. The crude products obtained after drying with anhydrous sodium sulfate, removing the solvent by evaporation were purified by silica gel column chromatography (ethyl acetate/hexane), the fraction that was eluted by a solvent with a higher polarity (the fractions that demonstrated low Rf values) were collected, and (7Z)-6-acetoxy-7-hydroxyimino-4,5,6,7-tetrahydrobenzo[b]thiophene-3-sulfonic acid[2-(4-fluorophenyl)ethyl]-methyl-amide was obtained. Thereafter, to methanol (1 mL) was added excess potassium carbonate. The solution was stirred at room temperature for 1 hour. Water was added, the solution was extracted with ethyl acetate, and the organic layer was dried with anhydrous magnesium sulfate. The residue resulting from the removal of the solvent by evaporation was purified by LC-MS, and the title compound (0.9 mg) was obtained as a colorless solid.
Reaction SMILES: [BrH:1].[CH3:2][N:3]1[CH2:8][CH2:7][C:6](=O)[CH2:5][CH2:4]1.BrBr.[CH3:12][O:13][C:14]1[CH:19]=[C:18]([O:20][CH3:21])[CH:17]=[C:16]([O:22][CH3:23])[CH:15]=1>C(O)(=O)C.C(OC)(C)(C)C>[BrH:1].[Br:1][CH:5]1[C:6]([C:15]2[C:16]([O:22][CH3:23])=[CH:17][C:18]([O:20][CH3:21])=[CH:19][C:14]=2[O:13][CH3:12])=[CH:7][CH2:8][N:3]([CH3:2])[CH2:4]1
Reactant: COc1cc(OC)cc(OC)c1
Reactant: CN1CCC(=O)CC1
Agent: Br
Agent: BrBr
Solvent: COC(C)(C)C
Solvent: CC(=O)O
Product: COc1cc(OC)c(C2=CCN(C)CC2Br)c(OC)c1
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
75.7 ml (0.44 mol) of 33% strength HBr in glacial acetic acid were added to 200 ml of glacial acetic acid, and 50 g (0.44 mol) of 1-methylpiperidin-4-one (III) were then rapidly added dropwise at 20-25° C. with ice-cooling. 70.4 g (0.44 mol) of bromine were added dropwise at 20-25° C. in the course of 30 min to the suspension of the hydrobromide obtained in this way, a clear, yellowish solution being obtained. This was stirred at 25° C. for a further 15 min and 67.2 g (0.40 mol) of 1,3,5-trimethoxybenzene (V) were then added to the reaction solution. It was then stirred at 25° C. for 1 h. After this, 300 ml of methyl tert-butyl ether were allowed to run in, the product being deposited in oily form. The supernatant was decanted off, the residue was stirred again with 300 ml of methyl tert-butyl ether and the supernatant was decanted off. The residue was then stirred with 150 ml of dichloromethane, the product crystallizing out. The 3(R,S)-bromo-1-methyl-4-(2,4,6-trimethoxyphenyl)-1,2,3,6-tetrahydropyridine hydrobromide (VI) obtained was filtered off with suction, washed with 50 ml of dichloromethane and dried in vacuo.
Reaction SMILES: C1C2C(COC([NH:18][C@@H:19]([C:25]([O:27][C:28]([CH3:31])([CH3:30])[CH3:29])=[O:26])[CH2:20][C:21](=[O:24])[NH:22][CH3:23])=O)C3C(=CC=CC=3)C=2C=CC=1.N1CCCCC1>C(Cl)Cl>[CH3:23][NH:22][C:21](=[O:24])[CH2:20][C@H:19]([C:25]([O:27][C:28]([CH3:30])([CH3:29])[CH3:31])=[O:26])[NH2:18]
Reactant: CNC(=O)C[C@@H](NC(=O)OCC1c2ccccc2-c2ccccc21)C(=O)OC(C)(C)C
Solvent: ClCCl
Solvent: C1CCNCC1
Product: CNC(=O)C[C@@H](N)C(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 1 h
Yield: 226.2 %

Procedure:
To tert-butyl N2-(((9H-fluoren-9-yl)methoxy)carbonyl)-N4-methyl-D-asparaginate (200 mg, 0.47 mmol) in DCM (0.93 mL) was added piperidine (233 μL, 2.35 mmol). The reaction mixture was stirred at room temperature for 1 h. All solvent was removed to give 215 mg of tert-butyl N4-methyl-D-asparaginate as a mixture with 1-((9H-fluoren-9-yl)methyl)piperidine. The mixture was used without purification in the next reaction. LCMS-ESI (m/z) calculated for C9H18N2O3: 202.1. found 203.1 [M+H]+, tR=0.534 min (Method 16).
Reaction SMILES: [CH3:1][O:2][CH2:3][CH2:4][N:5]1[CH2:11][CH2:10][C:9]2[CH:12]=[C:13]([NH2:16])[CH:14]=[CH:15][C:8]=2[CH2:7][CH2:6]1.Cl[C:18]1[N:23]=[C:22]([NH:24][C@@H:25]2[CH2:30][CH2:29][CH2:28][C@@H:27]([NH:31][S:32]([CH3:35])(=[O:34])=[O:33])[CH2:26]2)[C:21]([Cl:36])=[CH:20][N:19]=1>>[Cl:36][C:21]1[C:22]([NH:24][C@@H:25]2[CH2:30][CH2:29][CH2:28][C@@H:27]([NH:31][S:32]([CH3:35])(=[O:34])=[O:33])[CH2:26]2)=[N:23][C:18]([NH:16][C:13]2[CH:14]=[CH:15][C:8]3[CH2:7][CH2:6][N:5]([CH2:4][CH2:3][O:2][CH3:1])[CH2:11][CH2:10][C:9]=3[CH:12]=2)=[N:19][CH:20]=1
Reactant: CS(=O)(=O)N[C@@H]1CCC[C@@H](Nc2nc(Cl)ncc2Cl)C1
Reactant: COCCN1CCc2ccc(N)cc2CC1
Product: COCCN1CCc2ccc(Nc3ncc(Cl)c(N[C@@H]4CCC[C@@H](NS(C)(=O)=O)C4)n3)cc2CC1

Procedure:
rel-N-((1R,3R)-3-{5-Chloro-2-[3-(2-methoxy-ethyl)-2,3,4,5-tetrahydro-1H-benzo[d]azepin-7-ylamino]-pyrimidin-4-ylamino}-cyclohexyl)-methanesulfonamide was prepared from 3-(2-methoxy-ethyl)-2,3,4,5-tetrahydro-1H-benzo[d]azepin-7-ylamine and rel-N-[(1R,3R)-3-(2,5-dichloro-pyrimidin-4-ylamino)-cyclohexyl]-methanesulfonamide in an analogous manner to Example 308c. Product isolated as a white foam (113 mg, 63%). LCMS (m/e) 523 (M+H); 1H-NMR (CDCl3, 400 MHz) δ 7.92 (s, 1H), 7.37 (d, 1H, J=8.1 Hz), 7.23 (s, 1H), 7.07 (d, 1H, J=8.1 Hz), 6.85 (s, 1H), 5.11 (d, 1H, J=7.4 Hz), 4.37 (d, 1H, J=6.7 Hz), 4.36-4.26 (m, 1H), 3.84-3.75 (m, 1H), 3.56 (t, 2H, J=5.7 Hz), 3.39 (s, 3H), 2.98-2.87 (m, 4H), 2.93 (s, 3H), 2.81-2.68 (m, 6H), 2.04-1.91 (m, 2H), 1.91-1.79 (m, 2H), 1.79-1.65 (m, 3H), 1.58-1.47 (m, 1H).
Reaction SMILES: C([O-])([O-])=O.[Cs+].[Cs+].[CH3:7][C:8]1[N:9]=[CH:10][NH:11][CH:12]=1.Br[C:14]1[CH:15]=[CH:16][C:17]([NH2:20])=[N:18][CH:19]=1>[Cu]I.CN(C=O)C>[CH3:7][C:8]1[N:9]=[CH:10][N:11]([C:14]2[CH:15]=[CH:16][C:17]([NH2:20])=[N:18][CH:19]=2)[CH:12]=1
Reactant: Cc1c[nH]cn1
Reactant: Nc1ccc(Br)cn1
Agent: [Cu]I
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: Cc1cn(-c2ccc(N)nc2)cn1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a microwave tube with a magnetic stirring bar was charged CuI (382 mg, 2.0 mmol), Cs2CO3 (6.5 g, 20.0 mmol), 4-methyl-1H-imidazole (1.15 g, 14.0 mmol), 5-bromopyridin-2-amine (1.75 g, 10.0 mmol), and DMF (10 mL) under N2. The system was sealed and then evacuated twice and back filled with N2. The reaction mixture was stirred for 30 min at room temperature, and then heated at 120° C. for 48 h. The reaction mixture was then cooled to ambient temperature, diluted with 30 mL of ethyl acetate, washed with water. The combined organic layers were concentrated, and the resulting residue was purified by column chromatography on silica gel to provide 5-(4-methyl-1H-imidazol-1-yl)pyridin-2-amine (134). 1H NMR (400 MHz, d6-DMSO) δ 8.09 (m, 1H), 7.85 (d, J=1.6 Hz, 1H), 7.56 (dd, J=2.8, 8.8 Hz, 1H), 7.22 (t, J=1.2 Hz, 1H), 6.51 (dd, J=0.8, 8.8 Hz, 1H), 6.15 (s, 2H), 2.14 (d, J=1.2 Hz, 3H). MS m/z 175.1 (M+1)+.
Reaction SMILES: [CH:1]1([C@H:6]([N:11]2[CH:15]=[C:14]([C:16]3[C:17]4[CH:24]=[CH:23][N:22]([CH2:25][O:26][CH2:27][CH2:28][Si:29]([CH3:32])([CH3:31])[CH3:30])[C:18]=4[N:19]=[CH:20][N:21]=3)[CH:13]=[N:12]2)[CH2:7][C:8]([OH:10])=O)[CH2:5][CH2:4][CH2:3][CH2:2]1.C1N=C[N:35](C(N2C=NC=C2)=O)C=1>CN(C=O)C>[CH:1]1([C@H:6]([N:11]2[CH:15]=[C:14]([C:16]3[C:17]4[CH:24]=[CH:23][N:22]([CH2:25][O:26][CH2:27][CH2:28][Si:29]([CH3:30])([CH3:32])[CH3:31])[C:18]=4[N:19]=[CH:20][N:21]=3)[CH:13]=[N:12]2)[CH2:7][C:8]([NH2:35])=[O:10])[CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: C[Si](C)(C)CCOCn1ccc2c(-c3cnn([C@H](CC(=O)O)C4CCCC4)c3)ncnc21
Reactant: O=C(n1ccnc1)n1ccnc1
Solvent: CN(C)C=O
Product: C[Si](C)(C)CCOCn1ccc2c(-c3cnn([C@H](CC(N)=O)C4CCCC4)c3)ncnc21
Temperature: 25 °C

Procedure:
To a stirred solution of (3R)-3-cyclopentyl-3-(4-(7-((2-(trimethylsilyl)ethoxy)methyl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl)propanoic acid ((R)-23, 20 mg, 0.044 mmol) in DMF (1 mL) at room temperature was added N,N-carbonyldiimidazole (CDI, 21 mg, 0.13 mmol, 3.0 equiv). The reaction mixture was then stirred at room temperature and TLC was used to follow the reaction for formation of acyl imidazole (consumption of acid to a higher Rf spot with 30% EtOAc/hexane). When TLC showed that the acyl imidazole transformation was complete, ammonia gas was then bubbled through the stirred solution for 30 min to afford the amide (followed by LCMS). The excess amount of ammonia gas was evaporated by bubbling nitrogen vigorously through the solution. The crude product, (3R)-3-cyclopentyl-3-(4-(7-((2-(trimethylsilyl)ethoxy)methyl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl)propanamide ((R)-24), in DMF was used directly to the following reaction to convert amide ((R)-24) into the corresponding nitrile ((R)-20).
Reaction SMILES: [C:1]([O:5][C:6]([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=1[C:14]1[CH:19]=[CH:18][C:17]([CH2:20][N:21]2[C:25]([CH:26]=[O:27])=[C:24]([CH3:28])[N:23]=[C:22]2[CH2:29][CH2:30][CH3:31])=[CH:16][CH:15]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[BH4-].[Na+].[OH-].[Na+]>CO.O1CCCC1>[C:1]([O:5][C:6]([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=1[C:14]1[CH:19]=[CH:18][C:17]([CH2:20][N:21]2[C:25]([CH2:26][OH:27])=[C:24]([CH3:28])[N:23]=[C:22]2[CH2:29][CH2:30][CH3:31])=[CH:16][CH:15]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CCCc1nc(C)c(C=O)n1Cc1ccc(-c2ccccc2C(=O)OC(C)(C)C)cc1
Agent: [BH4-]
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Product: CCCc1nc(C)c(CO)n1Cc1ccc(-c2ccccc2C(=O)OC(C)(C)C)cc1
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 96.3 %

Procedure:
To a solution of 3.43 g of 1-[(2'-tert-butoxycarbonylbiphenyl-4-yl)methyl]-4-methyl-2-propylimidazole-5-carboxaldehyde (from Example 320, Part D) in 22 mL of methanol and 22 mL of tetrahydrofuran at 25° C. was added in several portions, 3.09 g of sodium borohydride. The reaction mixture was stirred at 25° C. for 1.5 hours and then was poured into dilute aqueous sodium hydroxide solution. After stirring for 0.2 hour at 25° C. this solution was extracted with chloroform. The combined organic phases were washed with water and brine, dried over anhydrous sodium sulfate, filtered, and concentrated. Column chromatography (elution: ethyl acetate/benzene) furnished 3.32 g of 1-[(2'-tert-butoxycarbonylbiphenyl-4-yl)methyl]-5-hydroxymethyl-4-methyl-2-propylimidazole.