Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(NC1C=CC(C2C=C3C(CN([C@@H](C(C)C)C(OC)=O)C3=O)=CC=2)=CC=1)(=O)C1C=CC=CC=1.[NH2:34][C:35]1[CH:40]=[CH:39][C:38]([C:41]2[CH:49]=[C:48]3[C:44]([CH2:45][N:46]([C:51]4([C:56]([O:58][CH3:59])=[O:57])[CH2:55][CH2:54][CH2:53][CH2:52]4)[C:47]3=[O:50])=[CH:43][CH:42]=2)=[CH:37][CH:36]=1.[CH2:60]([C:65]1[CH:73]=[CH:72][C:68]([C:69](Cl)=[O:70])=[CH:67][CH:66]=1)[CH2:61][CH2:62][CH2:63][CH3:64]>>[O:50]=[C:47]1[C:48]2[C:44](=[CH:43][CH:42]=[C:41]([C:38]3[CH:37]=[CH:36][C:35]([NH:34][C:69](=[O:70])[C:68]4[CH:72]=[CH:73][C:65]([CH2:60][CH2:61][CH2:62][CH2:63][CH3:64])=[CH:66][CH:67]=4)=[CH:40][CH:39]=3)[CH:49]=2)[CH2:45][N:46]1[C:51]1([C:56]([O:58][CH3:59])=[O:57])[CH2:55][CH2:54][CH2:53][CH2:52]1
Reactant: CCCCCc1ccc(C(=O)Cl)cc1
Reactant: COC(=O)C1(N2Cc3ccc(-c4ccc(N)cc4)cc3C2=O)CCCC1
Agent: COC(=O)[C@H](C(C)C)N1Cc2ccc(-c3ccc(NC(=O)c4ccccc4)cc3)cc2C1=O
Product: CCCCCc1ccc(C(=O)Nc2ccc(-c3ccc4c(c3)C(=O)N(C3(C(=O)OC)CCCC3)C4)cc2)cc1
Yield: 85 %

Procedure:
The compound of example 536 was prepared analogous to compound of example 97 by reaction of compound of example 527 with 4-(n-pentyl)benzoyl chloride.
Reaction SMILES: Cl.[CH3:2][N:3]1[C:12]2[C:7](=[CH:8][C:9]([C:13]3[CH:14]=[N:15][CH:16]=[C:17]([O:19][C@H:20]4[CH2:24][CH2:23][NH:22][CH2:21]4)[CH:18]=3)=[CH:10][CH:11]=2)[CH2:6][CH2:5][C:4]1=[O:25].[C:26](Cl)(=[O:28])[CH3:27]>>[C:26]([N:22]1[CH2:23][CH2:24][C@H:20]([O:19][C:17]2[CH:18]=[C:13]([C:9]3[CH:8]=[C:7]4[C:12](=[CH:11][CH:10]=3)[N:3]([CH3:2])[C:4](=[O:25])[CH2:5][CH2:6]4)[CH:14]=[N:15][CH:16]=2)[CH2:21]1)(=[O:28])[CH3:27]
Reactant: CC(=O)Cl
Reactant: CN1C(=O)CCc2cc(-c3cncc(O[C@H]4CCNC4)c3)ccc21
Agent: Cl
Product: CC(=O)N1CC[C@H](Oc2cncc(-c3ccc4c(c3)CCC(=O)N4C)c2)C1

Procedure:
In analogy to the procedure described in example 76, 1-methyl-6-[5-((S)-pyrrolidin-3-yloxy)-pyridin-3-yl]-3,4-dihydro-1H-quinolin-2-one hydrochloride (example 60) has been reacted with acetyl chloride to give the title compound as a colorless solid. MS: 366.4 (M+H+).
Reaction SMILES: C(N(CC)CC)C.[C:8]([NH2:17])([C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)([CH3:10])[CH3:9].[CH3:18][S:19][C:20]1[S:21][CH:22]=[C:23]([C:25](Cl)=[O:26])[N:24]=1>C1COCC1>[CH3:9][C:8]([NH:17][C:25]([C:23]1[N:24]=[C:20]([S:19][CH3:18])[S:21][CH:22]=1)=[O:26])([C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)[CH3:10]
Reactant: CC(C)(N)c1ccccc1
Reactant: CSc1nc(C(=O)Cl)cs1
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CSc1nc(C(=O)NC(C)(C)c2ccccc2)cs1
Reaction time: 0.25 h

Procedure:
Triethylamine (2.24 ml) was added to a solution of cumylamine (3.2 ml) in anhydrous THF (30 ml). After stirring for 15 min, a solution of 2-(methylthio)-4 -thiazolecarbonyl chloride (Intermediate 12; 3.1 g) in anhydrous THF was added and the reaction mixture was concentrated in vacuo after 15 min. The residue was partitioned with EtOAc and water, dried with MgSO4, and concentrated to an orange oil. Flash purification on silica gel with isocratic elution of DCM yielded the product as a yellow oil (3.7 g). MS (ES) MH+: 293 for C14H16N2OS2; NMR: 1.68 (s, 6H), 2.76 (s, 3H), 7.20 (d, J=7.16 Hz, 1H), 7.29 (t, J=7.54 Hz, 2H), 7.36-7.41 (m, 2H), 8.04 (s, 1H), 8.08 (s, 1H).
Reaction SMILES: [CH3:1][O:2][C:3]1[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[N:6]=[C:5](OS(C(F)(F)F)(=O)=O)[CH:4]=1.[CH3:21][O:22][C:23](=[O:28])[CH:24]([CH3:27])[CH2:25][NH2:26]>C(#N)C>[CH3:21][O:22][C:23](=[O:28])[CH:24]([CH3:27])[CH2:25][NH:26][C:5]1[CH:4]=[C:3]([O:2][CH3:1])[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[N:6]=1
Reactant: COc1cc(OS(=O)(=O)C(F)(F)F)nc2ccccc12
Reactant: COC(=O)C(C)CN
Solvent: CC#N
Product: COC(=O)C(C)CNc1cc(OC)c2ccccc2n1
Temperature: 25 °C
Yield: 41.4 %

Procedure:
A solution of 1,1,1-trifluoromethanesulfonic acid 4-methoxyquinolin-2-yl ester [from Example 1b] (2.03 g, 6.61 mmol) and 3-amino-2-methyl-propionic acid methyl ester (1.5 eq, 1.52 g, 9.91 mmol) in acetonitrile (25 mL) was heated at reflux for five days. It was cooled to room temperature and evaporated to an oil. The crude product was purified via column chromatography on silica (1:1 ethyl acetate/hexane) to give the product (0.75 g, 42%) as an orange oil. [M+H]+ 275.
Reaction SMILES: [CH2:1]([O:9][C:10]1[N:15]=[C:14]([C:16]([O:18]C)=O)[CH:13]=[CH:12][CH:11]=1)[CH2:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.[CH3:20][C:21]#[N:22]>>[O:18]=[C:16]([C:14]1[CH:13]=[CH:12][CH:11]=[C:10]([O:9][CH2:1][CH2:2][C:3]2[CH:4]=[CH:5][CH:6]=[CH:7][CH:8]=2)[N:15]=1)[CH2:20][C:21]#[N:22]
Reactant: COC(=O)c1cccc(OCCc2ccccc2)n1
Reactant: CC#N
Product: N#CCC(=O)c1cccc(OCCc2ccccc2)n1

Procedure:
CH3CN addition to methyl 6-phenethoxypicolinate following the method described in Example 6 gave 3-oxo-3-(6-phenethoxypyridin-2-yl)propanenitrile as a yellow oil which was used in the next step without further purification. Yield (1.33 g, quant.).
Reaction SMILES: [OH:1][C:2]1[C:6]([C:7]([O:9]CC)=[O:8])=[CH:5][NH:4][N:3]=1>[OH-].[Na+].CCO>[OH:1][C:2]1[C:6]([C:7]([OH:9])=[O:8])=[CH:5][NH:4][N:3]=1
Reactant: CCOC(=O)c1c[nH]nc1O
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: O=C(O)c1c[nH]nc1O
Yield: 89.8 %

Procedure:
A solution of ethyl 3-hydroxy-1H-pyrazole-4-carboxylate (625 mg, 4.00 mmol) in 10% NaOH (aq) (20 mL) and EtOH (10 mL) was heated under reflux for 20 h. EtOH was removed under reduced pressure. The residue was diluted with 10 mL of H2O and acidified with 4 N HCl. The precipitates were filtered to afford the titled compound as a white solid (460 mg), which was used without further purification.
Reaction SMILES: N(C(N1CCCCC1)=O)=NC(N1CCCCC1)=O.C(P(CCCC)CCCC)CCC.[C:32]([O:36][C:37]([N:39]1[CH2:42][CH2:41][C@@H:40]1[CH2:43][OH:44])=[O:38])([CH3:35])([CH3:34])[CH3:33].[O:45]([CH2:52][C@H:53]1[CH2:55][C@@H:54]1[C:56]1[CH:57]=[C:58](O)[CH:59]=[N:60][CH:61]=1)[C:46]1[CH:51]=[CH:50][CH:49]=[CH:48][CH:47]=1>C1(C)C=CC=CC=1>[C:32]([O:36][C:37]([N:39]1[CH2:42][CH2:41][C@H:40]1[CH2:43][O:44][C:58]1[CH:59]=[N:60][CH:61]=[C:56]([C@H:54]2[CH2:55][C@@H:53]2[CH2:52][O:45][C:46]2[CH:51]=[CH:50][CH:49]=[CH:48][CH:47]=2)[CH:57]=1)=[O:38])([CH3:35])([CH3:34])[CH3:33]
Reactant: Oc1cncc([C@H]2C[C@@H]2COc2ccccc2)c1
Reactant: CC(C)(C)OC(=O)N1CC[C@@H]1CO
Agent: CCCCP(CCCC)CCCC
Agent: O=C(N=NC(=O)N1CCCCC1)N1CCCCC1
Solvent: Cc1ccccc1
Product: CC(C)(C)OC(=O)N1CC[C@H]1COc1cncc([C@H]2C[C@@H]2COc2ccccc2)c1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 89.9 %

Procedure:
1,1′-(Azodicarbonyl)dipiperidine (253 mg, 1.00 mmol, 1.6 equiv.) was dissolved in 2 mL of toluene (dried with molecular sieve 3 Å) in a 10 mL round-bottom flask with a side neck. The flask was equipped with rubber septa and a magnetic stirrer. The atmosphere was exchanged with Ar (3 times), and the flask was cooled with an ice bath. Tributylphosphine (248 μL, 1.00 mmol, 1.6 equiv.) was added dropwise. The mixture was warmed to room temperature and was stirred for 10 min. The colorless solution formed was then transferred dropwise (via syringe) with ice cooling into a solution of 1-(tert-butoxycarbonyl)-2(R)-azetidinylmethanol (188 mg, 1.00 mmol, 1.6 equiv.) and 5-[(1S,2S)-2-(phenoxymethyl)cyclopropyl]-3-pyridinol (151 mg, 626 μmol) in a 25 mL round-bottom flask equipped with a magnetic stirrer and an Ar balloon. The resulting mixture was warmed to room temperature and stirred overnight. The reaction was quenched by addition of saturated NaHCO3 solution (10 mL). The product was extracted into EtOAc (3×20 mL). The combined organic phases were dried over Na2SO4 and concentrated. The residue was purified by CC on SiO2 (25×2.5 cm, EtOAc/hexanes 2:1) to give the crude product, which was further purified by preparative HPLC in two portions (Supelco Discovery C18, 250×21.2 mm, 5 μm particle size, UV detection at 270 nm, flow rate 12.5 mL/min, gradient from 20% to 100% CH3CN in water within 40 min, then 100% CH3CN for 20 min; tR 29.1-31.1 min) to give the title compound as a yellowish oil (231 mg, 90%). MS (EI) m/z 410 (M+, 0.1%).
Reaction SMILES: [NH2:1][C@H:2]1[CH2:7][CH2:6][CH2:5][N:4]([C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9])[CH2:3]1.F[C:16]1[C:17]([CH3:36])=[N:18][C:19]2[C:24]([N:25]=1)=[C:23]([C:26]1[NH:34][C:33]3[CH2:32][CH2:31][NH:30][C:29](=[O:35])[C:28]=3[CH:27]=1)[CH:22]=[CH:21][CH:20]=2>CS(C)=O>[CH3:36][C:17]1[C:16]([NH:1][C@H:2]2[CH2:7][CH2:6][CH2:5][N:4]([C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9])[CH2:3]2)=[N:25][C:24]2[C:19]([N:18]=1)=[CH:20][CH:21]=[CH:22][C:23]=2[C:26]1[NH:34][C:33]2[CH2:32][CH2:31][NH:30][C:29](=[O:35])[C:28]=2[CH:27]=1
Reactant: Cc1nc2cccc(-c3cc4c([nH]3)CCNC4=O)c2nc1F
Reactant: CC(C)(C)OC(=O)N1CCC[C@H](N)C1
Solvent: CS(C)=O
Product: Cc1nc2cccc(-c3cc4c([nH]3)CCNC4=O)c2nc1N[C@H]1CCCN(C(=O)OC(C)(C)C)C1
Temperature: 100 °C
Yield: 4.3 %

Procedure:
Prepared according to Example 131, (S)-3-amino-1-Boc-piperidine (180 μL, 0.759 mmol, CNH Technologies, Inc., Woburn, Mass.), 2-(3-fluoro-2-methylquinoxalin-5-yl)-6,7-dihydro-1H-pyrrolo[3,2-c]pyridin-4(5H)-one (Example 126; 75 mg, 0.253 mmol), and DMSO (2.5 mL) stirring at 100° C. for 2. Purification by sequential column chromatography (silica gel: 0.5 to 10% MeOH/DCM) and reverse phase chromatography (Phenomenex Gemini column, 10 micron, C18, 100 Å, 150×30 mm, 0.1% TFA in ACN/H2O, gradient 5% to 95%) provided tert-butyl (3S)-3-((3-methyl-8-(4-oxo-4,5,6,7-tetrahydro-1H-pyrrolo[3,2-c]pyridin-2-yl)-2-quinoxalinyl)amino)-1-piperidinecarboxylate (5.2 mg, 4.3%) as the free base after washing with saturated aq. NaHCO3, extracting with 10% MeOH/DCM, drying over Na2SO4, and concentrating under reduced pressure. 1H NMR (CDCl3) δ: 7.92-7.97 (m, 1H), 7.65-7.71 (m, 1H), 7.37-7.45 (m, 1H), 7.13 (s, 2H), 5.42 (br. s., 1H), 4.12 (s, 1H), 3.62-3.70 (m, 3H), 2.91-2.99 (m, 2H), 2.57 (s, 3H), 1.94-2.07 (m, 1H), 1.89-1.90 (m, 1H), 1.80-1.91 (m, 1H), 1.68 (s, 9H), 1.33-1.55 (m, 5H). m/z (ESI, +ve) 477.2 (M+H)+.
Reaction SMILES: [CH2:1]([NH2:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Br:9][C:10]1[CH:11]=[CH:12][C:13]2[N:14]([CH:16]=[C:17]([C:19](OCC)=[O:20])[N:18]=2)[CH:15]=1>>[CH2:1]([NH:8][C:19]([C:17]1[N:18]=[C:13]2[CH:12]=[CH:11][C:10]([Br:9])=[CH:15][N:14]2[CH:16]=1)=[O:20])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: NCc1ccccc1
Reactant: CCOC(=O)c1cn2cc(Br)ccc2n1
Product: O=C(NCc1ccccc1)c1cn2cc(Br)ccc2n1

Procedure:
The title compound was prepared by essentially following the same procedures described for Intermediate I, using benzylamine and ethyl 6-bromoimidazo[1,2-a]pyridine-2-carboxylate as starting materials.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9](=[O:15])[O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[CH:4][CH:3]=1.[N:16]1[CH:21]=[CH:20][C:19](B(O)O)=[CH:18][CH:17]=1.C([O-])([O-])=O.[K+].[K+].C(Cl)Cl>O1CCOCC1.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.CO>[N:16]1[CH:21]=[CH:20][C:19]([C:2]2[CH:7]=[CH:6][C:5]([NH:8][C:9](=[O:15])[O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[CH:4][CH:3]=2)=[CH:18][CH:17]=1
Reactant: CC(C)(C)OC(=O)Nc1ccc(Br)cc1
Reactant: OB(O)c1ccncc1
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: [K+]
Solvent: O
Solvent: ClCCl
Solvent: CO
Product: CC(C)(C)OC(=O)Nc1ccc(-c2ccncc2)cc1
Yield: 90.2 %

Procedure:
4-(Pyridin-4-yl)aniline (20) was prepared in three steps: To a mixture of 4-bromoaniline (950 mg, 5.6 mmol), triethylamine (678 mg, 6.7 mmol) and DMAP (73 mg, 0.56 mmol) in DCM (30 mL) was added Boc2O (1.22g, 5.6 mmol) at 0° C. The reaction mixture was allowed to warm to room temperature and stirred for 2 hr. After the reaction was quenched with 5% NaHCO3, the mixture was extracted with DCM (3×20 mL). The organic layer was combined and dried over anhydrous MgSO4. tert-Butyl 4-bromophenylcarbamate (1.36 g, 90%) was obtained after flash column chromatography (hexane:ethyl acetate, 4:1). Suzuki coupling reaction of tert-butyl 4-bromophenylcarbamate (800 mg, 2.95 mmol) with 4-pyridineboronic acid (300 mg, 2.46 mmol) in the presence of Pd(PPh3)4 (57 mg, 0.05 mmol) and K2CO3 (678 mg, 4.9 mmol) in dioxane- H2O (4:1, 10 mL) at 90° C. for 14 hr. tert-Butyl 4-(pyridin-4-yl)phenylcarbamate (600 mg, 75%) was obtained after flash column chromatography (DCM:MeOH, 20:1). Compound 20 (380 mg, 99%) was obtained after treatment of tert-butyl 4-(pyridin-4-yl)phenylcarbamate (600 mg, 2.2 mmol) with DCM:TFA (1:1, 1 mL) for 2 hr at room temperature followed by solvent removal. To a mixture of 4-(pyridin-4-yl)aniline 20 (380 mg, 2.24 mmol) and pyridine (3 mL) in DCM (3 mL) was added phenyl chloroformate (366 mg, 2.35 mmol) at 0° C. The mixture was allowed to warm to room temperature and stirred for 3 hr. After DCM and pyridine were removed under reduced pressure, the residue was purified by flash column chromatography (DCM:MeOH, 20:1). Compound 21 (400 mg) was obtained in 65% yield.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:16])[C:4]1[CH:9]=[C:8]([N:10]([CH3:12])[CH3:11])[CH:7]=[CH:6][C:5]=1[N+:13]([O-])=O.[CH3:17]O>[Ni]>[CH3:1][O:2][C:3](=[O:16])[C:4]1[CH:9]=[C:8]([N:10]([CH3:12])[CH3:11])[CH:7]=[C:6]([CH3:17])[C:5]=1[NH2:13]
Reactant: CO
Reactant: COC(=O)c1cc(N(C)C)ccc1[N+](=O)[O-]
Agent: [Ni]
Product: COC(=O)c1cc(N(C)C)cc(C)c1N
Yield: 98 %

Procedure:
Raney Nickel (80 mg) was added to a suspension of 5-dimethylamino-2-nitro-benzoic acid methyl ester (400 mg, 1.78 mmol) in methanol (20 mL) and hydrogenated under atmospheric pressure at room temperature for 2 hr. The reaction mixture was filtered over celite and the filtrate was concentrated in vacuum to afford methyl 2-amino-5-dimethylamino-benzoic acid methyl ester (340 mg, 98%) as greenish brown liquid.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([N:8]([CH:18]2[CH2:20][CH2:19]2)[CH2:9][C:10]2[CH:15]=[CH:14][C:13]([O:16][CH3:17])=[CH:12][CH:11]=2)[C:5]2=[N:21][CH:22]=[C:23]([C:24]#[N:25])[N:4]2[N:3]=1.[NH2:26][C:27]1[C:28]([Cl:39])=[CH:29][C:30]([CH2:35][CH2:36][CH:37]=[O:38])=[C:31]([CH:34]=1)[C:32]#[N:33].CC1(C)C2C(=C(P(C3C=CC=CC=3)C3C=CC=CC=3)C=CC=2)OC2C(P(C3C=CC=CC=3)C3C=CC=CC=3)=CC=CC1=2.C(=O)([O-])[O-].[Cs+].[Cs+]>C([O-])(=O)C.[Pd+2].C([O-])(=O)C.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.[Fe+2].O1CCOCC1>[Cl:39][C:28]1[CH:29]=[C:30]([CH2:35][CH2:36][CH:37]=[O:38])[C:31]([C:32]#[N:33])=[CH:34][C:27]=1[NH:26][C:2]1[N:7]=[C:6]([N:8]([CH:18]2[CH2:20][CH2:19]2)[CH2:9][C:10]2[CH:15]=[CH:14][C:13]([O:16][CH3:17])=[CH:12][CH:11]=2)[C:5]2=[N:21][CH:22]=[C:23]([C:24]#[N:25])[N:4]2[N:3]=1
Reactant: COc1ccc(CN(c2nc(Cl)nn3c(C#N)cnc23)C2CC2)cc1
Reactant: N#Cc1cc(N)c(Cl)cc1CCC=O
Agent: [Fe+2]
Agent: [Pd+2]
Agent: CC(=O)[O-]
Solvent: C1COCCO1
Product: COc1ccc(CN(c2nc(Nc3cc(C#N)c(CCC=O)cc3Cl)nn3c(C#N)cnc23)C2CC2)cc1
Temperature: 100 °C
Yield: 19.4 %

Procedure:
2-chloro-4-(cyclopropyl(4-methoxybenzyl)amino)imidazo[2,1-f][1,2,4]triazine-7-carbonitrile (170 mg, 0.479 mmol), 5-amino-4-chloro-2-(3-oxopropyl)benzonitrile (100 mg, 0.479 mmol, Example 566A), palladium(II) acetate (32.3 mg, 0.144 mmol), DPPF (26.6 mg, 0.048 mmol), Xantphos (27.7 mg, 0.048 mmol), and cesium carbonate (312 mg, 0.958 mmol) were combined in a 50 ml round bottom flask and dioxane (4 mL) was added. The flask was evacuated and backfilled with N2 3×, then heated at 100° C. for 2 h. The reaction was cooled to room temperature and filtered through celite, rinsing with EtOAc. The solvent was removed in vacuo and the material was purified by flash column chromatography (0-80% EtOAc/Hex; 40 g column). 2-((2-chloro-5-cyano-4-(3-oxopropyl)phenyl)amino)-4-(cyclopropyl(4-methoxybenzyl)amino)imidazo[2,1-f][1,2,4]triazine-7-carbonitrile (49 mg) was obtained.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[O:12][N:11]=[CH:10][C:9]=2[C:13]([OH:15])=O)=[CH:4][CH:3]=1.C(O)(=O)C(O)=O.[F:22][C:23]([F:36])([F:35])[C:24]1[CH:29]=[CH:28][C:27]([CH:30]2[CH2:34][CH2:33][NH:32][CH2:31]2)=[CH:26][CH:25]=1>>[CH3:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[O:12][N:11]=[CH:10][C:9]=2[C:13]([N:32]2[CH2:33][CH2:34][CH:30]([C:27]3[CH:28]=[CH:29][C:24]([C:23]([F:22])([F:35])[F:36])=[CH:25][CH:26]=3)[CH2:31]2)=[O:15])=[CH:6][CH:7]=1
Reactant: FC(F)(F)c1ccc(C2CCNC2)cc1
Reactant: Cc1ccc(-c2oncc2C(=O)O)cc1
Agent: O=C(O)C(=O)O
Product: Cc1ccc(-c2oncc2C(=O)N2CCC(c3ccc(C(F)(F)F)cc3)C2)cc1

Procedure:
The title compound was prepared from 5-(4-methylphenyl)isoxazole-4-carboxylic acid (10.2 mg, 0.050 mmol) and 3-[4-(trifluoromethyl)phenyl]pyrrolidine oxalate (15.1 mg, 0.050 mmol) as described in synthetic method B and thereafter purified by preparative HPLC method B to give a solid (5.3 mg). Calcd for C22H19F3N2O2: 400.1399, found 400.1403.
Reaction SMILES: C(OC(=O)[NH:7][C@H:8]1[CH2:12][CH2:11][N:10]([C:13]([N:15]2[C@@:19]([C:21]3[CH:26]=[CH:25][C:24]([Cl:27])=[CH:23][CH:22]=3)([CH3:20])[C@@:18]([C:29]3[CH:34]=[CH:33][C:32]([Cl:35])=[CH:31][CH:30]=3)([CH3:28])[N:17]=[C:16]2[C:36]2[CH:37]=[N:38][C:39]([C:45]([CH3:48])([CH3:47])[CH3:46])=[CH:40][C:41]=2[O:42][CH2:43][CH3:44])=[O:14])[CH2:9]1)(C)(C)C.S(Cl)(Cl)=O>CO.FC(F)(F)C(O)=O>[NH2:7][CH:8]1[CH2:12][CH2:11][N:10]([C:13]([N:15]2[C@@:19]([C:21]3[CH:22]=[CH:23][C:24]([Cl:27])=[CH:25][CH:26]=3)([CH3:20])[C@@:18]([C:29]3[CH:30]=[CH:31][C:32]([Cl:35])=[CH:33][CH:34]=3)([CH3:28])[N:17]=[C:16]2[C:36]2[CH:37]=[N:38][C:39]([C:45]([CH3:46])([CH3:48])[CH3:47])=[CH:40][C:41]=2[O:42][CH2:43][CH3:44])=[O:14])[CH2:9]1
Reactant: CCOc1cc(C(C)(C)C)ncc1C1=N[C@@](C)(c2ccc(Cl)cc2)[C@@](C)(c2ccc(Cl)cc2)N1C(=O)N1CC[C@H](NC(=O)OC(C)(C)C)C1
Solvent: CO
Solvent: O=C(O)C(F)(F)F
Solvent: O=S(Cl)Cl
Product: CCOc1cc(C(C)(C)C)ncc1C1=N[C@@](C)(c2ccc(Cl)cc2)[C@@](C)(c2ccc(Cl)cc2)N1C(=O)N1CCC(N)C1
Temperature: 77.5 °C
Reaction time: 1 h

Procedure:
{(S)-1-[(4S,5R)-2-(6-tert-Butyl-4-ethoxy-pyridin-3-yl)-4,5-bis-(4-chloro-phenyl)-4,5-dimethyl-4,5-dihydro-imidazole-1-carbonyl]-pyrrolidin-3-yl}-carbamic acid tert-butyl ester (12.6 mg, example 125) was diluted with methanol (1.5 mL) and trifluoroacetic acid (0.1 mL). The mixture was stirred at 75-80° C. for 1 h. Thionyl chloride (0.3 mL) was added dropwise and the mixture was stirred at 80° C. for 1 h. The mixture was then concentrated and diluted with methanol (2 mL) and neutralized with 15% solution of sodium hydroxide. Purification of the crude product on a preparative HPLC (reversed phase, eluting with acetonitrile and water) gave the title product as a mixture of diastereomers (5.4 mg). HR-MS (ES, m/z) calculated for C33H40Cl2N5O2 [(M+H)+] 608.2554, observed 608.2554.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[CH:8]=[C:7]([S:12]([N:15]([CH2:27][C:28]([O:30][CH3:31])=[O:29])[C@H:16]1[CH2:20][CH2:19][N:18]([C@@H:21]([CH3:25])[C:22]([OH:24])=O)[C:17]1=[O:26])(=[O:14])=[O:13])[CH:6]=[CH:5]2.Cl.CN(C)CCCN=C=NCC.[CH:44]1[CH:45]=[CH:46]C2N(O)N=[N:50][C:48]=2[CH:49]=1.N1CCCCC1>C(Cl)Cl.C(N(CC)CC)C>[Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[CH:8]=[C:7]([S:12]([N:15]([C@H:16]1[CH2:20][CH2:19][N:18]([C@@H:21]([CH3:25])[C:22](=[O:24])[N:50]3[CH2:46][CH2:45][CH2:44][CH2:49][CH2:48]3)[C:17]1=[O:26])[CH2:27][C:28]([O:30][CH3:31])=[O:29])(=[O:14])=[O:13])[CH:6]=[CH:5]2
Reactant: COC(=O)CN([C@H]1CCN([C@@H](C)C(=O)O)C1=O)S(=O)(=O)c1ccc2cc(Cl)ccc2c1
Reactant: On1nnc2ccccc21
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Solvent: C1CCNCC1
Product: COC(=O)CN([C@H]1CCN([C@@H](C)C(=O)N2CCCCC2)C1=O)S(=O)(=O)c1ccc2cc(Cl)ccc2c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 46.5 %

Procedure:
To a solution of (2S)-2-{(3S)-3-[[(6-chloro-2-naphthyl)sulfonyl](2-methoxy-2-oxoethyl)amino]-2-oxopyrrolidin-1-yl}propanoic acid (0.032 g) in DCM (5 ml) were added 1-[3-(dimethylamino)propyl]-3-ethylcarbodiimide hydrochloride (0.02 g), HOBT (0.014 g) and triethylamine (0.034 ml) and the mixture was stirred at room temperature for 1 h. Piperidine (0.01 ml) was added and the resultant mixture stirred at room temperature for 72 h. The mixture was concentrated under reduced pressure and the residue purified using mass directed preparative h.p.l.c. to give the title compound (0.017 g) as a white solid.
Reaction SMILES: [CH2:1]1[C:4]2([CH2:9][CH2:8][CH:7]([CH2:10][OH:11])[CH2:6][CH2:5]2)[CH2:3][CH2:2]1.CC(C)([O-])C.[K+].[N:18]1([S:22]([NH:25][C:26](=[O:36])[C:27]2[CH:32]=[C:31]([Cl:33])[C:30](F)=[CH:29][C:28]=2[F:35])(=[O:24])=[O:23])[CH2:21][CH2:20][CH2:19]1>CS(C)=O>[N:18]1([S:22]([NH:25][C:26](=[O:36])[C:27]2[CH:32]=[C:31]([Cl:33])[C:30]([O:11][CH2:10][CH:7]3[CH2:6][CH2:5][C:4]4([CH2:1][CH2:2][CH2:3]4)[CH2:9][CH2:8]3)=[CH:29][C:28]=2[F:35])(=[O:24])=[O:23])[CH2:21][CH2:20][CH2:19]1
Reactant: OCC1CCC2(CCC2)CC1
Reactant: O=C(NS(=O)(=O)N1CCC1)c1cc(Cl)c(F)cc1F
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: CS(C)=O
Product: O=C(NS(=O)(=O)N1CCC1)c1cc(Cl)c(OCC2CCC3(CCC3)CC2)cc1F
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 35.9 %

Procedure:
To a solution of spiro[3.5]nonan-7-ylmethanol (0.58 g, 3.76 mmol) in anhydrous dimethyl sulfoxide (20 mL) was added potassium t-butoxide (1.05 g, 9.35 mmol) at ambient temperature. After stirring at ambient temperature for 30 minutes, N-(azetidin-1-ylsulfonyl)-5-chloro-2,4-difluorobenzamide (1.17 g, 3.76 mmol) was added to the reaction mixture; stirring was continued at ambient temperature for 2 hours. The mixture was cooled to 0° C. and quenched with 5% aqueous hydrochloride acid (10 mL) followed by extraction with ethyl acetate (100 mL). The organic layer was washed with water (2×40 mL) and brine, dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated in vacuo, the crude product was purified by silica gel column chromatography using 10-40% ethyl acetate (containing 0.2% acetic acid) in hexanes to afford the title compound as a colorless solid (0.60 g, 36%): 1H NMR (300 MHz, CDCl3) δ 8.60 (d, J=15.6 Hz, 1H), 8.10 (d, J=8.4 Hz, 1H), 6.66 (d, J=13.8 Hz, 1H), 4.23 (t, J=7.8 Hz, 4H), 3.82 (d, J=6.3 Hz, 2H), 2.32-2.20 (m, 2H), 1.88-1.66 (m, 11H), 1.35-1.24 (m, 2H), 1.18-1.05 (m, 2H); MS (ES+) m/z 445.1, 447.1 (M+1), MS (ES−) m/z 443.2, 445.2 (M−1).
Reaction SMILES: [OH:1][CH2:2][CH2:3][CH2:4][CH2:5][NH:6][C:7]([N:9]1[CH2:17][C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[CH2:10]1)=[O:8].O=CCCCNC(=O)C1C=CC=CC=1>>[O:1]=[CH:2][CH2:3][CH2:4][CH2:5][NH:6][C:7]([N:9]1[CH2:10][C:11]2[C:16](=[CH:15][CH:14]=[CH:13][CH:12]=2)[CH2:17]1)=[O:8]
Reactant: O=C(NCCCCO)N1Cc2ccccc2C1
Agent: O=CCCCNC(=O)c1ccccc1
Product: O=CCCCNC(=O)N1Cc2ccccc2C1

Procedure:
1,3-Dihydro-isoindole-2-carboxylic acid (4-oxo-butyl)-amide (27C) is prepared from 27B as described for 1E. The crude product is obtained in almost quantitative yield.
Reaction SMILES: [CH2:1]([N:8]1[CH2:17][C:16](C)([CH3:18])[NH:15][CH2:14][C:9]21[CH2:13][CH2:12][CH2:11][CH2:10]2)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.NCC(N)C.OC1(C#N)CCCC1>>[CH2:1]([N:8]1[CH2:17][CH:16]([CH3:18])[NH:15][CH2:14][C:9]21[CH2:10][CH2:11][CH2:12][CH2:13]2)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CC1(C)CN(Cc2ccccc2)C2(CCCC2)CN1
Agent: CC(N)CN
Agent: N#CC1(O)CCCC1
Product: CC1CN(Cc2ccccc2)C2(CCCC2)CN1

Procedure:
6-Benzyl-8-methyl-6,9-diaza-spiro[4.5]decane was synthesized in analogy to 6-benzyl-8,8-dimethyl-6,9-diaza-spiro[4.5]decane starting from 1,2-diamino-propane and 1-hydroxycyclopentane-1-carbonitrile.
Reaction SMILES: [CH3:1][NH:2][CH2:3][CH2:4][C:5]#[C:6][C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][N:8]=1.[F:13][C:14]1[CH:22]=[CH:21][CH:20]=[CH:19][C:15]=1[C:16](Cl)=[O:17]>>[F:13][C:14]1[CH:22]=[CH:21][CH:20]=[CH:19][C:15]=1[C:16]([N:2]([CH3:1])[CH2:3][CH2:4][C:5]#[C:6][C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][N:8]=1)=[O:17]
Reactant: O=C(Cl)c1ccccc1F
Reactant: CNCCC#Cc1ccccn1
Product: CN(CCC#Cc1ccccn1)C(=O)c1ccccc1F
Yield: 32 %

Procedure:
The title compound was prepared in accordance with the general method of Example 199(D), from N-methyl-4-(pyridin-2-yl)but-3-yn-1-amine (50 mg, 0.31 mmol) and 2-fluorobenzoyl chloride (59 mg, 0.37 mmol). The crude residue was purified over silicagel chromatography (prepacked 10 g silicagel column, DCM/MeOH: from 100/0 to 98/2 as eluent) to afford 28 mg of 2-fluoro-N-methyl-N-(4-(pyridin-2-yl)but-3-ynyl)benzamide as a brown oil (Yield: 32%).