Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [ClH:1].[N:2]12[CH2:11][CH:6]3[CH2:7][CH:8]([CH2:10][CH:4]([C@H:5]3[NH2:12])[CH2:3]1)[CH2:9]2.[N:13]1[S:14][N:15]=[C:16]2[CH:21]=[C:20]([C:22](O)=[O:23])[CH:19]=[CH:18][C:17]=12.N>>[ClH:1].[N:2]12[CH2:11][CH:6]3[CH2:7][CH:8]([CH2:10][CH:4]([C@H:5]3[NH:12][C:22]([C:20]3[CH:19]=[CH:18][C:17]4=[N:13][S:14][N:15]=[C:16]4[CH:21]=3)=[O:23])[CH2:3]1)[CH2:9]2
Reactant: O=C(O)c1ccc2nsnc2c1
Reactant: NC1C2CC3CC1CN(C3)C2
Agent: Cl
Agent: N
Product: O=C(NC1C2CC3CC1CN(C3)C2)c1ccc2nsnc2c1

Procedure:
Prepared from (4r)-1-azatricyclo[3.3.1.13,7]dec-4-ylamine hydrochloride and benzo[c][1,2,5]thiadiazole-5-carboxylic acid according to methods A and C. 1H NMR (300 MHz, methanol-d4) δ ppm 2.08-2.34 (m, 5H), 2.51 (s, 2H), 3.42-3.64 (m, 4H), 3.88 (d, J=12.5 Hz, 2H), 4.33 (s, 1H), 7.90-8.51 (m, 1H), 8.98 (s, 1H), 9.57 (s, 1H). MS (DCI/NH3) m/z 315. Anal. Calculated for C16H18N4OS.HCl: C, 54.77; H, 5.46; N, 15.97. Found: C, 53.82; H, 5.31; N, 16.17.
Reaction SMILES: [NH4+].[OH-].S[C:4]1[N:5]=[C:6]([OH:14])[C:7]2[C@H:12]([CH3:13])[CH2:11][CH2:10][C:8]=2[N:9]=1>[Ni].O>[CH3:13][C@H:12]1[C:7]2[C:6]([OH:14])=[N:5][CH:4]=[N:9][C:8]=2[CH2:10][CH2:11]1
Reactant: C[C@@H]1CCc2nc(S)nc(O)c21
Agent: [Ni]
Agent: [NH4+]
Agent: [OH-]
Solvent: O
Product: C[C@@H]1CCc2ncnc(O)c21
Yield: 100.1 %

Procedure:
Raney Nickel (15 g) and NH4OH (20 mL) were added to a suspension of (R)-2-mercapto-5-methyl-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-ol (12 g, 65.8 mmol) in distilled water (100 mL). The mixture was refluxed for 3 hours and then filtered. The filtrate was concentrated to afford (R)-5-methyl-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-ol (9.89 g, 99%). MS (APC+) [M+H]+151.
Reaction SMILES: [N:1]([CH2:4][C:5]1[S:6][C:7]([C:10]2([CH3:15])[O:14][CH2:13][CH2:12][O:11]2)=[CH:8][N:9]=1)=[N+]=[N-].C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.O>C1COCC1>[CH3:15][C:10]1([C:7]2[S:6][C:5]([CH2:4][NH2:1])=[N:9][CH:8]=2)[O:14][CH2:13][CH2:12][O:11]1
Reactant: CC1(c2cnc(CN=[N+]=[N-])s2)OCCO1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: O
Solvent: C1CCOC1
Product: CC1(c2cnc(CN)s2)OCCO1
Temperature: 60 °C

Procedure:
To a solution of the crude azide (565 mg, 2.50 mmol) in THF (12 mL) were added polymer-supported Ph3P (2.0 eq.) and water (4 mL). The reaction mixture was stirred at 60° C. until completion of the reaction, cooled down to rt, filtered and partitioned between EA and sat. aq. NaHCO3. The layers were separated and the aq. layer extracted with EA. The combined org. extracts were dried over MgSO4, filtered and concentrated under reduced pressure to give the title compound as a brown oil after purification by FC (CH2Cl2-MeOH 1:0 to 9:1). LC-MS-conditions 01: tR=0.38 min; [M+H]+=200.96.
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6]([N:9]2[CH2:14][CH2:13][CH2:12][C@H:11]([NH:15][C@@H:16]3[CH2:21][CH2:20][CH2:19][CH2:18][C@H:17]3[NH:22][C:23]3[CH:28]=[C:27](/[CH:29]=[CH:30]\[C:31](O)=[O:32])[CH:26]=[CH:25][N:24]=3)[CH2:10]2)=[CH:5][CH:4]=1)#[N:2].CC[N:36](CC)CC.ClC(OCC(C)C)=O.N>CO.C1COCC1>[C:1]([C:3]1[CH:4]=[CH:5][C:6]([N:9]2[CH2:14][CH2:13][CH2:12][C@H:11]([NH:15][C@@H:16]3[CH2:21][CH2:20][CH2:19][CH2:18][C@H:17]3[NH:22][C:23]3[CH:28]=[C:27](/[CH:29]=[CH:30]\[C:31]([NH2:36])=[O:32])[CH:26]=[CH:25][N:24]=3)[CH2:10]2)=[CH:7][CH:8]=1)#[N:2]
Reactant: CCN(CC)CC
Reactant: N#Cc1ccc(N2CCC[C@H](N[C@@H]3CCCC[C@H]3Nc3cc(/C=C\C(=O)O)ccn3)C2)cc1
Agent: CC(C)COC(=O)Cl
Agent: N
Solvent: CO
Solvent: C1CCOC1
Product: N#Cc1ccc(N2CCC[C@H](N[C@@H]3CCCC[C@H]3Nc3cc(/C=C\C(N)=O)ccn3)C2)cc1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 22.2 %

Procedure:
To a round bottom flask was added (Z)-3-(2-(((1R,2R)-2-(((S)-1-(4-cyanophenyl)piperidin-3-yl)amino)cyclohexyl)amino)pyridin-4-yl)acrylic acid (35 mg, 0.063 mmol), THF (0.8 mL) and Et3N (0.026 mL, 0.188 mmol). The reaction was cooled to 0° C. Then isobutyl chloroformate (9.04 μl, 0.069 mmol) was added to the reaction and the reaction was stirred at 0° C. for 15 mins before ammonia (0.045 mL, 0.313 mmol) in methanol was added to the reaction. The reaction was stirred at 0° C. for 30 mins. The reaction was concentrated and purified using RP prep-HPLC. The desired fraction was concentrated to give (Z)-3-(2-(((1R,2R)-2-(((S)-1-(4-cyanophenyl)piperidin-3-yl)amino)cyclohexyl)amino)pyridin-4-yl)acrylamide (8 mg, 0.014 mmol, 21.98% yield) as a light brown film. Anal. Calcd. for C26H32N6O m/z 444.3, found: 445.5 (M+H)+; 1H NMR (400 MHz, METHANOL-D4) δ ppm 7.87 (d, J=6.6 Hz, 1H), 7.47 (d, J=8.8 Hz, 2H), 7.00-6.89 (m, 3H), 6.84 (br. s., 1H), 6.67 (d, J=12.6 Hz, 1H), 6.35 (d, J=12.6 Hz, 1H), 3.88-3.67 (m, 2H), 3.63-3.52 (m, 1H), 3.50-3.42 (m, 1H), 3.40-3.33 (m, 2H), 3.18-3.08 (m, 1H), 2.34 (d, J=12.6 Hz, 1H), 2.14 (dd, J=9.6, 3.0 Hz, 2H), 1.91-1.72 (m, 4H), 1.66-1.53 (m, 1H), 1.52-1.40 (m, 3H), 1.33-1.26 (m, 1H)
Reaction SMILES: [Br:1][C:2]1[CH:11]=[CH:10][CH:9]=[C:8]2[C:3]=1[CH2:4][CH2:5][C:6]([NH2:15])([C:12]([OH:14])=[O:13])[CH2:7]2.C(N(CC)CC)C.[C:23](=O)([O:39]N1C(=O)CCC1=O)[O:24][CH2:25][CH:26]1[C:38]2[CH:37]=[CH:36][CH:35]=[CH:34][C:33]=2[C:32]2[C:27]1=[CH:28][CH:29]=[CH:30][CH:31]=2>C(#N)C.O>[C:23]([CH:7]1[C:8]2[C:3](=[C:2]([Br:1])[CH:11]=[CH:10][CH:9]=2)[CH2:4][CH2:5][C:6]1([NH2:15])[C:12]([OH:14])=[O:13])([O:24][CH2:25][CH:26]1[C:27]2[C:32](=[CH:31][CH:30]=[CH:29][CH:28]=2)[C:33]2[C:38]1=[CH:37][CH:36]=[CH:35][CH:34]=2)=[O:39]
Reactant: NC1(C(=O)O)CCc2c(Br)cccc2C1
Reactant: O=C(OCC1c2ccccc2-c2ccccc21)ON1C(=O)CCC1=O
Solvent: O
Solvent: CC#N
Solvent: CCN(CC)CC
Product: NC1(C(=O)O)CCc2c(Br)cccc2C1C(=O)OCC1c2ccccc2-c2ccccc21
Temperature: 25 °C
Reaction time: 8 h
Yield: 67.7 %

Procedure:
A mixture of racemic 5-bromo-2 aminotetraline-2-carboxylic acid (882 mg, 3.27 mmole), triethylamine (0.60 ml, 4.30 mmole), 9-fluorenylmethyl succinimidyl carbonate (Fmoc-OSu, 1.32 g, 3.91 mmole) in acetonitrile (30 ml) and water (30 ml) was stirred at room temperature overnight. TLC analysis of the reaction the next day indicated the presence of starting material amino acid. 9-fluorenylmethyl succinimidyl carbonate (0.25 g), triethylamine (0.6 ml) and acetonitrile (5 ml) was added and the mixture was stirred at room temperature for another day. The reaction mixture was concentrated in vacuo to remove most of the acetonitrile, acidified to pH ˜3 with 10% aqueous citric acid solution, and the white emulsion extracted twice with methylene chloride. The combined organic layers were washed with water, brine, dried over magnesium sulfate. Filtration and concentration gave a crude oil which was purified by column chromatography (eluted with 2→5→10% methanol/methylene chloride) to give racemic Fmoc-5-bromo-2 aminotetraline-2-carboxylic acid (1.09 g, 68% yield) as a white solid. HRMS (FAB): C26H22BrNNaO4 (M+Na) calc. 514.0630; observed: 514.0643.
Reaction SMILES: I[C:2]1[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[CH:4][C:3]=1[O:10][CH2:11][O:12][CH3:13].[O:14]1[CH:18]=[CH:17][C:16](B(O)O)=[CH:15]1.C([O-])([O-])=O.[Cs+].[Cs+]>CN(C)C=O.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:14]1[CH:18]=[CH:17][C:16]([C:2]2[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[CH:4][C:3]=2[O:10][CH2:11][O:12][CH3:13])=[CH:15]1
Reactant: COCOc1cc(C#N)ccc1I
Reactant: OB(O)c1ccoc1
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: CN(C)C=O
Product: COCOc1cc(C#N)ccc1-c1ccoc1
Temperature: 100 °C
Yield: 83.9 %

Procedure:
4-Iodo-3-methoxymethoxy-benzonitrile (150 mg, 0.52 mmol) and 3-furanboronic acid (96 mg, 0.86 mmol) and Pd(PPh3)4 (60 mg, 0.052 mmol) and Cs2CO3 (500 mg, 1.53 mmol) is mixed in N,N-dimethylformamide (10 mL) and degassed and then heated at 100° C. for 4 hours. After which, the mixture is allowed to cool to room temperature and an aqueous work up is performed and the residue purified to afford the desired product (100 mg, 84%).
Reaction SMILES: [C:1]([C:4]1[CH:9]=[CH:8][C:7]([C:10]2[C:19]3[C:14](=[C:15]([C:20]4[CH:21]=[C:22]([CH2:26][CH2:27][NH:28]C(=O)OC(C)(C)C)[CH:23]=[N:24][CH:25]=4)[CH:16]=[CH:17][CH:18]=3)[CH:13]=[CH:12][N:11]=2)=[CH:6][C:5]=1[NH:36][CH:37]1[CH2:42][CH2:41][CH:40]([OH:43])[CH2:39][CH2:38]1)(=[O:3])[NH2:2]>C(O)(C(F)(F)F)=O>[NH2:28][CH2:27][CH2:26][C:22]1[CH:21]=[C:20]([C:15]2[CH:16]=[CH:17][CH:18]=[C:19]3[C:14]=2[CH:13]=[CH:12][N:11]=[C:10]3[C:7]2[CH:8]=[CH:9][C:4]([C:1]([NH2:2])=[O:3])=[C:5]([NH:36][CH:37]3[CH2:38][CH2:39][CH:40]([OH:43])[CH2:41][CH2:42]3)[CH:6]=2)[CH:25]=[N:24][CH:23]=1
Reactant: CC(C)(C)OC(=O)NCCc1cncc(-c2cccc3c(-c4ccc(C(N)=O)c(NC5CCC(O)CC5)c4)nccc23)c1
Solvent: O=C(O)C(F)(F)F
Product: NCCc1cncc(-c2cccc3c(-c4ccc(C(N)=O)c(NC5CCC(O)CC5)c4)nccc23)c1
Yield: 56.5 %

Procedure:
A solution of compound (19) (0.047 g) in TFA was stirred at room temperature for 3 hours. The solvent was distilled off, and chloroform was added to the residue. The reaction solution was neutralized with an aqueous sodium bicarbonate solution and partitioned into organic and aqueous layers. The organic layer was washed with brine and then dried over anhydrous sodium sulfate. The solvent was distilled off, and diethyl ether was added to the residue. The deposit was filtrated to obtain compound (20) (0.022 g, yield: 60%) as a white solid.
Reaction SMILES: [C:1]([C:3]1([NH:6][C:7]([C@@H:9]2[CH2:13][C@@H:12]([S:14]([C:17]3[CH:22]=[CH:21][C:20](F)=[CH:19][C:18]=3[Cl:24])(=[O:16])=[O:15])[CH2:11][C@H:10]2[C:25]([N:27]2[CH2:30][C:29]([F:32])([F:31])[CH2:28]2)=[O:26])=[O:8])[CH2:5][CH2:4]1)#[N:2].[CH:33]1([N:36]2[CH2:41][CH2:40][NH:39][CH2:38][CH2:37]2)[CH2:35][CH2:34]1>>[C:1]([C:3]1([NH:6][C:7]([C@@H:9]2[CH2:13][C@@H:12]([S:14]([C:17]3[CH:22]=[CH:21][C:20]([N:39]4[CH2:40][CH2:41][N:36]([CH:33]5[CH2:35][CH2:34]5)[CH2:37][CH2:38]4)=[CH:19][C:18]=3[Cl:24])(=[O:15])=[O:16])[CH2:11][C@H:10]2[C:25]([N:27]2[CH2:28][C:29]([F:32])([F:31])[CH2:30]2)=[O:26])=[O:8])[CH2:5][CH2:4]1)#[N:2]
Reactant: C1CN(C2CC2)CCN1
Reactant: N#CC1(NC(=O)[C@@H]2C[C@@H](S(=O)(=O)c3ccc(F)cc3Cl)C[C@H]2C(=O)N2CC(F)(F)C2)CC1
Product: N#CC1(NC(=O)[C@@H]2C[C@@H](S(=O)(=O)c3ccc(N4CCN(C5CC5)CC4)cc3Cl)C[C@H]2C(=O)N2CC(F)(F)C2)CC1

Procedure:
The title compound was prepared in analogy to example 127 using (1R,2R,4R)-4-(2-chloro-4-fluoro-benzenesulfonyl)-2-(3,3-difluoro-azetidine-1-carbonyl)-cyclopentanecarboxylic acid-(1-cyano-cyclopropyl)-amide (example 119 step 4) and N-cyclopropylpiperazine bis hydrobromic salt (CAS # 159974-58-0). White solid (64%). MS (EI): 596.2 (M+H)+.
Reaction SMILES: [CH3:1][S:2][CH2:3][CH2:4][NH:5][C:6]1[C:15]2[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=2)[N:9]=[CH:8][C:7]=1[NH2:16].[C:17](OC)(OC)(OC)[CH2:18][CH2:19][CH3:20].Cl.N1C=CC=CC=1>C1(C)C=CC=CC=1>[CH3:1][S:2][CH2:3][CH2:4][N:5]1[C:6]2[C:15]3[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=3[N:9]=[CH:8][C:7]=2[N:16]=[C:17]1[CH2:18][CH2:19][CH3:20]
Reactant: CSCCNc1c(N)cnc2ccccc12
Reactant: CCCC(OC)(OC)OC
Agent: Cl
Solvent: c1ccncc1
Solvent: Cc1ccccc1
Product: CCCc1nc2cnc3ccccc3c2n1CCSC
Temperature: 140 °C
Yield: 89.4 %

Procedure:
N4-[2-(Methylthio)ethyl]quinoline-3,4-diamine (4.2 g, 19.2 mmol), trimethyl orthobutyrate (2.86 g, 19.2 mmol), pyridine hydrochloride (catalytic amount) and toluene were combined in a pressure vessel and heated at 140° C. for 1 hour. The reaction mixture was allowed to cool and then it was concentrated under reduced pressure to provide 4.9 g of 1-[2-(methylthio)ethyl]-2-propyl-1H-imidazo[4,5-c]quinoline.
Reaction SMILES: [F:1][C:2]([F:17])([F:16])[C:3]1[N:8]=[CH:7][C:6]([C@@H:9]2[CH2:11][C@H:10]2[C:12]([O:14]C)=[O:13])=[CH:5][CH:4]=1.Cl>C1COCC1.O>[F:16][C:2]([F:1])([F:17])[C:3]1[N:8]=[CH:7][C:6]([C@@H:9]2[CH2:11][C@H:10]2[C:12]([OH:14])=[O:13])=[CH:5][CH:4]=1
Reactant: COC(=O)[C@@H]1C[C@H]1c1ccc(C(F)(F)F)nc1
Agent: Cl
Solvent: O
Solvent: C1CCOC1
Product: O=C(O)[C@@H]1C[C@H]1c1ccc(C(F)(F)F)nc1
Reaction time: 14 h
Yield: 76.9 %

Procedure:
To a stirring solution of 26B (22 mg, 0.09 mmol) in THF (1 mL) at ambient temperature was added LiOH monohydrate (11 mg, 0.26 mmol) as a slurry in H2O (0.500 mL). The reaction was left to stir for 14 h, acidified to pH 4 via 1N HCl(aq), and then extracted with EtOAc (3×10 mL). The organic layers were combined, dried over MgSO4, filtered, and concentrated under reduced pressure to give 16 mg 26C (79% yield). m/z (ES+) M+1=232.0; HPLC tR=1.86 min. 1H NMR (500 MHz, MeOH-d4) δ 8.56 (d, J=2.1 Hz, 1H), 7.78-7.65 (m, 2H), 2.62-2.47 (m, 1H), 1.97 (ddd, J=9.0, 4.7, 4.6 Hz, 1H), 1.63 (ddd, J=9.4, 5.0, 4.8 Hz, 1H), 1.49-1.39 (m, 1H).
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][C:5]([O:45][CH3:46])=[C:6]([C:8]([CH3:44])([CH3:43])[CH2:9][C:10]([OH:42])([C:38]([F:41])([F:40])[F:39])[CH2:11][NH:12][C:13]2[CH:21]=[C:20]([CH3:22])[CH:19]=[C:18]3[C:14]=2[CH:15]=[N:16][N:17]3[C:23]2[CH:24]=[C:25]([C:29]([N:31]([CH3:37])[C@H:32]([C:34]([OH:36])=[O:35])[CH3:33])=[O:30])[CH:26]=[CH:27][CH:28]=2)[CH:7]=1.FC1C=CC(OC)=C(C(C)(C)CC(O)(C(F)(F)F)CNC2C=C(C)C=C3C=2C=NN3C2C=C(C=CC=2)C(O)=O)C=1.CN[C@@H](C(O)=O)C>>[F:1][C:2]1[CH:3]=[CH:4][C:5]([O:45][CH3:46])=[C:6]([C:8]([CH3:43])([CH3:44])[CH2:9][C:10]([OH:42])([C:38]([F:39])([F:40])[F:41])[CH2:11][NH:12][C:13]2[CH:21]=[C:20]([CH3:22])[CH:19]=[C:18]3[C:14]=2[CH:15]=[N:16][N:17]3[C:23]2[CH:24]=[C:25]([C:29]([N:31]([CH3:37])[C@@H:32]([C:34]([OH:36])=[O:35])[CH3:33])=[O:30])[CH:26]=[CH:27][CH:28]=2)[CH:7]=1
Reactant: COc1ccc(F)cc1C(C)(C)CC(O)(CNc1cc(C)cc2c1cnn2-c1cccc(C(=O)N(C)[C@@H](C)C(=O)O)c1)C(F)(F)F
Agent: CN[C@H](C)C(=O)O
Agent: COc1ccc(F)cc1C(C)(C)CC(O)(CNc1cc(C)cc2c1cnn2-c1cccc(C(=O)O)c1)C(F)(F)F
Product: COc1ccc(F)cc1C(C)(C)CC(O)(CNc1cc(C)cc2c1cnn2-c1cccc(C(=O)N(C)[C@H](C)C(=O)O)c1)C(F)(F)F

Procedure:
Prepared similarly to Intermediate 4 from 3-(4-{[4-[5-fluoro-2-(methyloxy)phenyl]-2-hydroxy-4-methyl-2-(trifluoromethyl)pentyl]amino}-6-methyl-1H-indazol-1-yl)benzoic acid and N-methyl-D-alanine.
Reaction SMILES: [CH:1]([N:4]1[C:13]2[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=2)[C:7]([CH3:15])([CH3:14])[CH2:6][C:5]1=[O:16])([CH3:3])[CH3:2].OS(O)(=O)=O.[N+:22]([O-])([OH:24])=[O:23]>>[CH:1]([N:4]1[C:13]2[C:8](=[CH:9][C:10]([N+:22]([O-:24])=[O:23])=[CH:11][CH:12]=2)[C:7]([CH3:14])([CH3:15])[CH2:6][C:5]1=[O:16])([CH3:3])[CH3:2]
Reactant: O=[N+]([O-])O
Reactant: CC(C)N1C(=O)CC(C)(C)c2ccccc21
Agent: O=S(=O)(O)O
Product: CC(C)N1C(=O)CC(C)(C)c2cc([N+](=O)[O-])ccc21
Temperature: -5 °C
Reaction time: 0.17 h

Procedure:
N-Isopropyl 4,4,-dimethyl-2-oxo-quinoline (Compound 39, 472 mg, 2.18 mmol) was added dropwise to H2SO4 (con. 0.3 mL) cooled to -5° C. with a salt-ice bath. To this brown oil was added a mixture of HNO3 (0.16 mL) and H2SO4 (0.65 mL) at a rate so slow that the internal temperature did not exceed 0° C. The resulting dark oil was stirred vigorously for 10 minutes, followed by addition of ice-water. The yellow reaction mixture was extracted with ethyl acetate (2×5 mL). The combined organic layers were washed with NaHCO3 (10%), dried over MgSO4 and concentrated to give yellow solids. 1H NMR d 1.34 (s, 6H), 1.53(d, J=6.8 Hz, 6H), 2.48 (s, 2H), 4.70-4.79 (m, 1H), 7.25 (d, J=6.3 Hz, 1H), 8.10-8.15 (m, 2H).
Reaction SMILES: [CH2:1]([C@@H:8]1[CH2:13][C@@H:12]([N:14]([CH2:21][C:22]2[C:31]3[C:26](=[CH:27][CH:28]=[CH:29][CH:30]=3)[N:25]=[CH:24][CH:23]=2)C(=O)C(F)(F)F)[CH2:11][CH2:10][N:9]1[CH2:32][CH2:33][O:34][C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][C:36]=1[N:41]1[C:45]([Cl:46])=[N:44][CH:43]=[N:42]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[BH4-].[Na+]>>[CH2:1]([C@H:8]1[CH2:13][C@H:12]([NH:14][CH2:21][C:22]2[C:31]3[C:26](=[CH:27][CH:28]=[CH:29][CH:30]=3)[N:25]=[CH:24][CH:23]=2)[CH2:11][CH2:10][N:9]1[CH2:32][CH2:33][O:34][C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][C:36]=1[N:41]1[C:45]([Cl:46])=[N:44][CH:43]=[N:42]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C(N(Cc1ccnc2ccccc12)[C@H]1CCN(CCOc2ccccc2-n2ncnc2Cl)[C@H](Cc2ccccc2)C1)C(F)(F)F
Agent: [BH4-]
Agent: [Na+]
Product: Clc1ncnn1-c1ccccc1OCCN1CC[C@@H](NCc2ccnc3ccccc23)C[C@@H]1Cc1ccccc1

Procedure:
100 mg (0.54 mmol) of (2R*,4S*)-2-benzyl-1-[2-(5-chlor-1H-1,2,4-triazol-1-yl)phenoxyethyl]-N-(4-quinolylmethyl)-N-trifluoroacetyl-4-piperidinamine are reacted with 23 mg (0.62 mmol) of sodium borohydride in analogy to Example 2. The title compound ##STR52## is obtained as white foam. TLC: methylene chloride/methanol/conc. ammonia (1000:50:1) Rf =0.23, FD-MS: M+ =553.
Reaction SMILES: [CH2:1]([O:8][C:9](=[O:23])[C@H:10]([CH2:19][C:20]([OH:22])=[O:21])[NH:11][C:12]([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[NH:24]1[CH2:29][CH2:28][CH2:27][CH2:26][CH2:25]1.CN1CCOCC1.C[N:38]([C:40]([O:44]N1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F>C(#N)C>[CH2:1]([O:8][C:9](=[O:23])[C@H:10]([CH2:19][C:20]([OH:22])=[O:21])[NH:11][C:12]([O:14][C:15]([CH3:17])([CH3:18])[CH3:16])=[O:13])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[NH:24]1[CH2:29][CH2:28][CH:27]([C:40]([NH2:38])=[O:44])[CH2:26][CH2:25]1
Reactant: C1CCNCC1
Reactant: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: CC(C)(C)OC(=O)N[C@@H](CC(=O)O)C(=O)OCc1ccccc1
Agent: F[B-](F)(F)F
Solvent: CN1CCOCC1
Solvent: CC#N
Product: NC(=O)C1CCNCC1

Procedure:
A solution of N-(tert-butoxycarbonyl)-L-aspartic acid 1-benzyl ester (1 g) and piperidine (0.32 mL) in acetonitrile (15 mL) was allowed to react with N-methylmorpholine (0.42 mL) and TBTU (1.2 g) for 6 hr at room temperature. The solvent was removed and the residue, dissolved in EtOAc, was sequentially washed with 2% aqueous hydrochloric acid, saturated aq. NaHCO3 and brine. After drying (Na2SO4) and rotoevaporation, the resulting yellowish oil was purified by flash chromatography over silica to obtain N-(tert-butoxycarbonyl)-L-aspartic acid 1-benzyl ester-4-piperidinamide (900 mg) as a colorless oil.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[CH:4][C:5]([S:8](Cl)(=[O:10])=[O:9])=[N:6][CH:7]=1.[N:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1>C(Cl)Cl>[N:12]1[C:17]2[C:16](=[CH:2][CH:3]=[CH:4][C:5]=2[NH:6][S:8]([C:5]2[CH:4]=[CH:3][C:2]([CH3:1])=[CH:7][N:6]=2)(=[O:10])=[O:9])[CH:15]=[CH:14][CH:13]=1
Reactant: Cc1ccc(S(=O)(=O)Cl)nc1
Reactant: c1ccncc1
Solvent: ClCCl
Product: Cc1ccc(S(=O)(=O)Nc2cccc3cccnc23)nc1
Yield: 25 %

Procedure:
In a similar fashion using route 14 general procedure 27, 8-aminoqunoline (40 mg, 0.27 mmol), 5-methyl-pyridine-2-sulfonyl chloride 440 (79 mg, 0.41 mmol), pyridine (1.5 ml) DMAP (cat.) and DCM (2 ml) gave the title compound (21 mg, 25%) after purification by column chromatography with n-hexane/EtOAc (93:7) as the eluent.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[C:10]3[NH:17][CH:16]=[C:15]([C:18](O)=[O:19])[C:11]=3[N:12]=[CH:13][N:14]=2)=[C:5]([O:21][CH2:22][CH2:23][O:24][CH3:25])[CH:4]=1.[C:26]([O:30][C:31]([N:33]1[CH2:38][CH2:37][CH:36]([NH2:39])[CH2:35][CH2:34]1)=[O:32])([CH3:29])([CH3:28])[CH3:27]>>[C:26]([O:30][C:31]([N:33]1[CH2:38][CH2:37][CH:36]([NH:39][C:18]([C:15]2[C:11]3[N:12]=[CH:13][N:14]=[C:9]([C:6]4[CH:7]=[CH:8][C:3]([O:2][CH3:1])=[CH:4][C:5]=4[O:21][CH2:22][CH2:23][O:24][CH3:25])[C:10]=3[NH:17][CH:16]=2)=[O:19])[CH2:35][CH2:34]1)=[O:32])([CH3:29])([CH3:27])[CH3:28]
Reactant: COCCOc1cc(OC)ccc1-c1ncnc2c(C(=O)O)c[nH]c12
Reactant: CC(C)(C)OC(=O)N1CCC(N)CC1
Product: COCCOc1cc(OC)ccc1-c1ncnc2c(C(=O)NC3CCN(C(=O)OC(C)(C)C)CC3)c[nH]c12

Procedure:
Starting from 4-[4-methoxy-2-(2-methoxy-ethoxy)-phenyl]-5H-pyrrolo[3,2-d]pyrimidine-7-carboxylic acid (example A74) and commercially available 4-amino-piperidine-1-carboxylic acid tert-butyl ester the title compound was obtained as colorless solid.
Reaction SMILES: [H-].[Na+].[F:3][C:4]([F:8])([F:7])[CH2:5][OH:6].[C:9]([CH:11]1[CH2:14][N:13]([C:15](=[O:50])[C@H:16]([NH:20][C:21]([C:23]2[C:31]3[C:26](=[N:27][CH:28]=[C:29]([C:32]4[S:40][C:39]5[C:34](=[N:35][CH:36]=[CH:37][C:38]=5Cl)[CH:33]=4)[N:30]=3)[N:25]([CH2:42][O:43][CH2:44][CH2:45][Si:46]([CH3:49])([CH3:48])[CH3:47])[CH:24]=2)=[O:22])[CH:17]2[CH2:19][CH2:18]2)[CH2:12]1)#[N:10].CCOC(C)=O>CN(C=O)C>[C:9]([CH:11]1[CH2:12][N:13]([C:15](=[O:50])[C@H:16]([NH:20][C:21]([C:23]2[C:31]3[C:26](=[N:27][CH:28]=[C:29]([C:32]4[S:40][C:39]5[C:34](=[N:35][CH:36]=[CH:37][C:38]=5[O:6][CH2:5][C:4]([F:8])([F:7])[F:3])[CH:33]=4)[N:30]=3)[N:25]([CH2:42][O:43][CH2:44][CH2:45][Si:46]([CH3:48])([CH3:47])[CH3:49])[CH:24]=2)=[O:22])[CH:17]2[CH2:19][CH2:18]2)[CH2:14]1)#[N:10]
Reactant: OCC(F)(F)F
Reactant: C[Si](C)(C)CCOCn1cc(C(=O)N[C@@H](C(=O)N2CC(C#N)C2)C2CC2)c2nc(-c3cc4nccc(Cl)c4s3)cnc21
Agent: [H-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: C[Si](C)(C)CCOCn1cc(C(=O)N[C@@H](C(=O)N2CC(C#N)C2)C2CC2)c2nc(-c3cc4nccc(OCC(F)(F)F)c4s3)cnc21
Temperature: 100 °C
Reaction time: 1 h
Yield: 85.7 %

Procedure:
To a suspension of sodium hydride (60% dispersion, 9.6 mg, 0.24 mmol) in DMF (3 mL) was added 2,2,2-trifluoroethanol (59 μL, 0.80 mmol) and then 2-(7-chloro-thieno[3,2-b]pyridin-2-yl)-5-(2-trimethylsilanyl-ethoxymethyl)-5H-pyrrolo[2,3-b]pyrazine-7-carboxylic acid [(R)-2-(3-cyano-azetidin-1-yl)-1-cyclopropyl-2-oxo-ethyl]-amide (50 mg, 0.08 mmol). The reaction mixture was stirred at 100° C. for 1 h under microwave assisted conditions then poured into EtOAc (20 mL) and washed with water (5×20 mL). The organic phase was evaporated under vacuum and the crude residue was purified by preparative TLC (CH2Cl2:MeOH:NH4OH, 94:5.7:0.3) to give 47 mg (85%) of 2-[7-(2,2,2-trifluoroethoxy)-thieno[3,2-b]pyridin-2-yl]-5-(2-trimethylsilanyl-ethoxymethyl)-5H-pyrrolo[2,3-b]pyrazine-7-carboxylic acid [(R)-2-(3-cyano-azetidin-1-yl)-1-cyclopropyl-2-oxo-ethyl]-amide.
Reaction SMILES: Cl.[NH2:2][OH:3].C([O-])(O)=O.[Na+].[CH3:9][O:10][CH:11]([O:15][CH3:16])[CH2:12][C:13]#[N:14]>CO>[OH:3][NH:2][C:13](=[NH:14])[CH2:12][CH:11]([O:15][CH3:16])[O:10][CH3:9]
Reactant: NO
Reactant: COC(CC#N)OC
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CO
Product: COC(CC(=N)NO)OC
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 70 %

Procedure:
To a solution of hydroxylamine monohydrochloride (3.2 g, 45.6 mmol) in MeOH (70 mL), NaHCO3 (3.8 g, 45.6 mmol) was added and stirred for 30 minutes at room temperature, and then a solution of 3,3-dimethoxypropanenitrile (5.0 g, 43.4 mmol) in MeOH (30 mL) was added dropwise thereto. The reaction mixture was stirred for 15 hours at 80° C. The mixture was allowed to cool to room temperature to filter off the salt produced, and the solvent was distilled off under reduced pressure. The obtained residue was purified by column chromatography (HP-Sil 100 g, CHCl3/MeOH=99/1 to 90/10) to obtain the title compound (4.5 g) (pale yellow oil).
Reaction SMILES: [NH2:1][CH2:2][C:3]1[CH:4]=[CH:5][C:6](F)=[C:7]([S:9]([NH:12][C:13]([CH3:16])([CH3:15])[CH3:14])(=[O:11])=[O:10])[CH:8]=1.BrC1C=C(S(Cl)(=O)=O)C=C([C:25]([F:28])([F:27])[F:26])C=1>>[NH2:1][CH2:2][C:3]1[CH:8]=[C:7]([S:9]([NH:12][C:13]([CH3:16])([CH3:15])[CH3:14])(=[O:11])=[O:10])[CH:6]=[C:5]([C:25]([F:28])([F:27])[F:26])[CH:4]=1
Reactant: O=S(=O)(Cl)c1cc(Br)cc(C(F)(F)F)c1
Reactant: CC(C)(C)NS(=O)(=O)c1cc(CN)ccc1F
Product: CC(C)(C)NS(=O)(=O)c1cc(CN)cc(C(F)(F)F)c1

Procedure:
3-Aminomethyl-N-tert-butyl-5-trifluoromethyl-benzenesulfonamide was synthesized in a manner analogous to 5-aminomethyl-N-tert-butyl-2-fluoro-benzenesulfonamide in Example 3, using 3-bromo-5-(trifluoromethyl)benzene-1-sulfonyl chloride in place of 5-chloro-2-fluorobenzene-1-sulfonyl chloride.