Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]1[S:3][C:4]2[CH:10]=[C:9]([C:11]3[O:12][C:13]4[CH:19]=[CH:18][CH:17]=[CH:16][C:14]=4[N:15]=3)[CH:8]=[CH:7][C:5]=2[N:6]=1.[S:20]([C:25]1[CH:31]=[CH:30][C:28]([CH3:29])=[CH:27][CH:26]=1)([O:23][CH3:24])(=[O:22])=[O:21]>>[S:20]([C:25]1[CH:31]=[CH:30][C:28]([CH3:29])=[CH:27][CH:26]=1)([O-:23])(=[O:22])=[O:21].[CH3:1][C:2]1[S:3][C:4]2[CH:10]=[C:9]([C:11]3[O:12][C:13]4[CH:19]=[CH:18][CH:17]=[CH:16][C:14]=4[N:15]=3)[CH:8]=[CH:7][C:5]=2[N+:6]=1[CH3:24]
Reactant: COS(=O)(=O)c1ccc(C)cc1
Reactant: Cc1nc2ccc(-c3nc4ccccc4o3)cc2s1
Product: Cc1ccc(S(=O)(=O)[O-])cc1
Product: Cc1sc2cc(-c3nc4ccccc4o3)ccc2[n+]1C
Temperature: 25 °C

Procedure:
2-methyl-6-(benzoxazol-2-yl)-benzothiazole (50 mg, 0.22 mmol) was stirred for 3 h at 90° C. in m excess of melted methyl tosylate (900 mg, 4.78 mmol). After being allowed to cool to room temperature, the product was precipitated by addition of acetone and collected by filtration. The precipitate was washed with acetone and allowed to dry over night. This gave the product as light brown crystals. Yield: 56 mg, 56%. 1H NMR (DMSO): δ 2.27 (s, 3H, CH3), 3.21 (s, 3H, —CH3), 4.24 (s, 3H, —CH3), 7.09 (d, J=8, 2H, ArH), 7.47 (M, 4H, ArH), 7.88 (t, J=8.8, 2H, ArH), 8.49 (d, J=8.8, 1H, ArH), 8.64 (d, J=8.8, 1H, ArH), 9.32 (a, 1H, ArH). HR-FAB-MS m/z Found: 281.078 C16H13N2OS (M+): requires M, 281.075.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:9]=[CH:10][C:11]3[O:17][CH2:16][CH2:15][N:14]([C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])[CH2:13][C:12]=3[CH:25]=2)=[CH:4][C:3]=1[N+:26]([O-])=O.[CH3:29][O:30][C:31]([NH:33][C:34](=NC(OC)=O)SC)=[O:32]>[Pd].C(O)C>[CH3:29][O:30][C:31]([NH:33][C:34]1[NH:26][C:3]2[CH:4]=[C:5]([C:8]3[CH:9]=[CH:10][C:11]4[O:17][CH2:16][CH2:15][N:14]([C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])[CH2:13][C:12]=4[CH:25]=3)[CH:6]=[CH:7][C:2]=2[N:1]=1)=[O:32]
Reactant: COC(=O)N=C(NC(=O)OC)SC
Reactant: CC(C)(C)OC(=O)N1CCOc2ccc(-c3ccc(N)c([N+](=O)[O-])c3)cc2C1
Agent: [Pd]
Solvent: CCO
Product: COC(=O)Nc1nc2ccc(-c3ccc4c(c3)CN(C(=O)OC(C)(C)C)CCO4)cc2[nH]1
Temperature: 80 °C
Yield: 79.4 %

Procedure:
1,1-Dimethylethyl 7-(4-amino-3-nitrophenyl)-2,3-dihydro-1,4-benzoxazepine-4(5H)-carboxylate (3.3 g, 8.56 mmol) and 10% palladium on carbon (300 mg) were suspended in ethanol (100 mL) and the mixture was hydrogenated at 50 psi using a Parr apparatus for 12 h. The mixture was filtered through a celite pad and the filtrate concentrated. The residue was taken into acetic acid (25 mL) followed by addition of 1,3-bis(methoxycarbonyl)-2-methyl-2-thiopseudourea (2.3 g, 11.15 mmol) and the resulting mixture heated to 80° C. for 30 minutes. The mixture was cooled to room temperature then concentrated and partitioned with ethyl ether (60 mL) and dilute aqueous sodium bicarbonate. The biphasic mixture was allowed to stand for several minutes until a precipitate formed. The solid was collected by filtration, washed with water then ethyl ether and dried to give 1,1-dimethylethyl 7-(2-{[(methyloxy)carbonyl]amino}-1H-benzimidazol-6-yl)-2,3-dihydro-1,4-benzoxazepine-4(5H)-carboxylate (2.98 g, 80% yield) as a white solid. MS (EI) for C23H26N4O5: 439 (MH+).
Reaction SMILES: [NH:1]1[CH2:4][CH:3]([C:5]2[C:6]([O:11][C:12]3[CH:17]=[CH:16][C:15]([C:18]([C:20]4[NH:24][C:23]5[CH:25]=[CH:26][CH:27]=[CH:28][C:22]=5[N:21]=4)=[O:19])=[CH:14][CH:13]=3)=[N:7][CH:8]=[CH:9][CH:10]=2)[CH2:2]1.C(N(CC)CC)C.N1([C:41](=[O:43])[CH3:42])C=CN=C1.C1COCC1>CN(C=O)C>[NH:24]1[C:23]2[CH:25]=[CH:26][CH:27]=[CH:28][C:22]=2[N:21]=[C:20]1[C:18]([C:15]1[CH:16]=[CH:17][C:12]([O:11][C:6]2[C:5]([CH:3]3[CH2:4][N:1]([C:41](=[O:43])[CH3:42])[CH2:2]3)=[CH:10][CH:9]=[CH:8][N:7]=2)=[CH:13][CH:14]=1)=[O:19]
Reactant: CC(=O)n1ccnc1
Reactant: O=C(c1ccc(Oc2ncccc2C2CNC2)cc1)c1nc2ccccc2[nH]1
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Solvent: CN(C)C=O
Product: CC(=O)N1CC(c2cccnc2Oc2ccc(C(=O)c3nc4ccccc4[nH]3)cc2)C1
Temperature: 25 °C
Reaction time: 2 h
Yield: 11.3 %

Procedure:
To a solution of (4-(3-(azetidin-3-yl)pyridin-2-yloxy)phenyl)(1H-benzo[d]imidazol-2-yl)methanone (279 mg, 0.753 mmol) in DMF (1.0 mL) is added triethylamine (0.386 mL, 3.01 mmol) and 1-(1H-imidazol-1-yl)ethanone (100 mg, 0.904 mmol). A solid crashed out, so THF (2 mL) was added to give a homogeneous solution and the reaction was stirred at rt 2 h. The reaction mixture was quenched with saturated NaHCO3 and extracted with CH2Cl2 (3×5 mL). The combined organic layers were dried (MgSO4) and concentrated, then purified by RPHPLC to give 1-(3-(2-(4-(1H-benzo[d]imidazole-2-carbonyl)phenoxy)pyridin-3-yl)azetidin-1-yl)ethanone (35 mg, 0.085 mmol, 11.27% yield over 2 steps) as a white solid. MS (ESI, pos. ion) m/z: 413.0 (M+1). IC50 (uM) +++++.
Reaction SMILES: N1C2C=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=N1.OCCN1CCN(C2C=CC([C:25]3[NH:34][C:33](=O)[C:32]4[C:27](=[CH:28][C:29](OC)=[CH:30][C:31]=4OC)[N:26]=3)=CC=2)CC1.C=O>O>[N:3]1([CH2:33][N:34]2[C:32]3[CH:31]=[CH:30][CH:29]=[CH:28][C:27]=3[N:26]=[CH:25]2)[CH2:4][CH2:9][CH2:8][CH2:7]1
Reactant: COc1cc(OC)c2c(=O)[nH]c(-c3ccc(N4CCN(CCO)CC4)cc3)nc2c1
Reactant: c1ccc2[nH]nnc2c1
Agent: C=O
Solvent: O
Product: c1ccc2c(c1)ncn2CN1CCCC1
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
To a suspension of 1H-benzotriazole (10.0 g, 83.9 mmol) in water (84 mL) was added pyrrolidine 2 (6.3 mL, 226.6 mmol). After 10 minutes of vigorous stirring at room temperature, formaldehyde 37% aqueous solution was added. The reaction mixture was stirred for 1 hour, then the precipitate was filtered off, and washed with water to afford 1-pyrrolidin-1-ylmethyl-1H-benzoimidazole as an off-white solid. Yield: 14.58 g (85.9%).
Reaction SMILES: [CH:1]([N:3]1[CH2:8][CH2:7][CH2:6][CH2:5][CH:4]1OC)=O.Cl.COC=O.C([N:18]1[CH2:23][CH2:22][CH2:21][CH2:20][CH2:19]1)=O.[OH-].[K+]>CO>[CH2:21]1[CH2:20][CH:19]2[CH:7]3[CH:1]([N:3]4[CH2:8][CH2:7][CH2:6][CH2:5][CH:4]4[N:18]2[CH2:23][CH2:22]1)[NH:3][CH2:4][CH2:5][CH2:6]3
Reactant: O=CN1CCCCC1
Reactant: COC1CCCCN1C=O
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: COC=O
Solvent: CO
Product: C1CNC2C(C1)C1CCCCN1C1CCCCN21

Procedure:
28.6 g (0.2 mol) of 1-formyl-2-methoxypiperidine and 0.3 mol of methanolic HCl were refluxed for 4 hours. At atmospheric pressure in a boiling range of from 30° to 50° C. a mixture of formic acid methyl ester and methanol, which could be re-used for the preparation of 1-formyl-piperidine, was distilled off. The distillation residue was added dropwise to a solution of 21.7 g of KOH (85% strength, 0.33 mol) in methanol and the whole was refluxed for 4 hours. Working up as described in Example 4 yielded 13.3 g (80.1% of the theory) of isotripiperidein melting at 87°-91° C.
Reaction SMILES: Cl[C:2]1[C:3]2[CH:10]=[CH:9][NH:8][C:4]=2[N:5]=[CH:6][N:7]=1.[Br-].[CH:12]1([Zn+])[CH2:16][CH2:15][CH2:14][CH2:13]1.O1CCOCC1>Cl[Ni]1(Cl)[P](C2C=CC=CC=2)(C2C=CC=CC=2)CCC[P]1(C1C=CC=CC=1)C1C=CC=CC=1.CO>[CH:12]1([C:2]2[C:3]3[CH:10]=[CH:9][NH:8][C:4]=3[N:5]=[CH:6][N:7]=2)[CH2:16][CH2:15][CH2:14][CH2:13]1
Reactant: Clc1ncnc2[nH]ccc12
Reactant: [Zn+]C1CCCC1
Agent: Cl[Ni]1(Cl)[P](c2ccccc2)(c2ccccc2)CCC[P]1(c1ccccc1)c1ccccc1
Agent: [Br-]
Solvent: C1COCCO1
Solvent: CO
Product: c1nc(C2CCCC2)c2cc[nH]c2n1
Temperature: 110 °C
Yield: 16.4 %

Procedure:
4-chloro-7H-pyrrolo[2,3-d]pyrimidine (1, 0.503 g, 3.28 mmol), cyclopentylzinc bromide (47, 29.5 mL, 0.500 M in tetrahydrofuran, 14.7 mmol), [1,3-bis(diphenylphosphino)propane]nickel(II) chloride (0.178 g, 0.328 mmol) and 9.3 mL of 1,4-dioxane were combined. The reaction mixture was heated at 110° C. overnight. Methanol was added and the reaction was concentrated under vacuum. Ethyl acetate and water were added to the residue, filtered through a bed of celite, and the celite washed with ethyl acetate. The filtrate layers were separated and the aqueous layer was extracted with ethyl acetate. The organic layers were combined, washed with brine, dried over sodium sulfate, filtered and the filtrate concentrated under vacuum. The resulting material was purified by silica gel column chromatography, eluting with ethyl acetate and hexane. Appropriate fractions were combined and the solvents removed under vacuum to provide the desired compound (48, 0.101 g). MS (ESI) [M+H+]+=188.0.
Reaction SMILES: [CH3:1][N:2]1[CH:6]=[CH:5][N:4]=[C:3]1[N:7]1[CH2:16][CH2:15][C:14]2[C:13]([N:17]3[CH2:22][CH2:21][O:20][CH2:19][CH2:18]3)=[N:12][C:11]([C:23]3[CH:28]=[CH:27][C:26]([N+:29]([O-])=O)=[CH:25][CH:24]=3)=[N:10][C:9]=2[CH2:8]1.C([O:34]C(OCC)CN)C.[N:41]1[CH:46]=CC=[CH:43][CH:42]=1>>[CH2:42]([NH:41][C:46]([NH:29][C:26]1[CH:27]=[CH:28][C:23]([C:11]2[N:12]=[C:13]([N:17]3[CH2:18][CH2:19][O:20][CH2:21][CH2:22]3)[C:14]3[CH2:15][CH2:16][N:7]([C:3]4[N:2]([CH3:1])[CH:6]=[CH:5][N:4]=4)[CH2:8][C:9]=3[N:10]=2)=[CH:24][CH:25]=1)=[O:34])[CH3:43]
Reactant: CCOC(CN)OCC
Reactant: c1ccncc1
Reactant: Cn1ccnc1N1CCc2c(nc(-c3ccc([N+](=O)[O-])cc3)nc2N2CCOCC2)C1
Product: CCNC(=O)Nc1ccc(-c2nc3c(c(N4CCOCC4)n2)CCN(c2nccn2C)C3)cc1
Temperature: 115 °C
Yield: 57 %

Procedure:
Step 3—Synthesis of 4-(7-(1-methyl-1H-imidazol-2-yl)-2-(4-nitrophenyl)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)morpholine (mp): To a solution of product mo from step 2 (260 mg, 0.5 mmol) in pyridine (3 mL) was added dropwise 2,2-diethoxyethanamine (82 μL, 0.6 mmol) at rt. The resulting solution was heated at 115° C. for 3.5 hrs. After the reaction mixture cooled, it was concentrated in vacuo. The residue was treated with 2 N aqueous HCl (2.5 mL), and heated to reflux for 1 hr. The reaction solution was then cooled, and diluted with H2O, made basic with sat. aq. NaHCO3, extracted with EtOAc (3×10 mL). The combined organics were dried over Magnesium sulfate, filtered, concentrated onto Celite, and chromatographed (ISCO, 12 g column, 0-5% MeOH/EtOAc) to afford 113 mg (57%) of desired compound mp as a yellow solid. 1H NMR (400 MHz, CDCl3) δ 8.59-8.53 (m, 2H), 8.32-8.26 (m, 2H), 6.83 (d, J=1.4, 1H), 6.74 (d, J=1.4, 1H), 4.38 (s, 2H), 3.91-3.85 (m, 4H), 3.62-3.56 (m, 7H), 3.38 (t, J=5.4, 2H), 2.90-2.84 (m, 2H). LC-MS: m/z=+422 (M+H)+.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([NH2:8])=[CH:4][CH:3]=1.[N+:9]([C:12]1[CH:19]=[CH:18][CH:17]=[CH:16][C:13]=1[CH:14]=O)([O-:11])=[O:10].[CH3:20][C:21]([CH3:23])=[CH2:22]>C(#N)C.FC(F)(F)S([O-])(=O)=O.[Yb+3].FC(F)(F)S([O-])(=O)=O.FC(F)(F)S([O-])(=O)=O>[Cl:1][C:2]1[CH:7]=[C:6]2[C:5](=[CH:4][CH:3]=1)[NH:8][CH:14]([C:13]1[CH:16]=[CH:17][CH:18]=[CH:19][C:12]=1[N+:9]([O-:11])=[O:10])[CH2:20][C:21]2([CH3:23])[CH3:22]
Reactant: C=C(C)C
Reactant: Nc1ccc(Cl)cc1
Reactant: O=Cc1ccccc1[N+](=O)[O-]
Agent: O=S(=O)([O-])C(F)(F)F
Agent: [Yb+3]
Solvent: CC#N
Product: CC1(C)CC(c2ccccc2[N+](=O)[O-])Nc2ccc(Cl)cc21
Temperature: 80 °C
Reaction time: 16 h
Yield: 30.8 %

Procedure:
To a stirred suspension of 4-chloro-phenylamine (10.2 g, 80 mmol), 2-nitrobenzaldehyde (12.1 g, 80 mmol), and 2-methylpropene (25 ml, pre-cooled to −78° C.) in acetonitrile was added ytterbium trifluoromethanesulfonate (1.3 g, 2.1 mmol) at ice-bath. The resulting mixture was stirred at 80° C. for 16 h in sealed tube. The reaction mixture was cooled to 0° C. The mixture was concentrated in vacuum. The residue was diluted with water, extracted with diethyl ether. The extracts were washed with brine and then dried over anhydrous sodium sulfate, concentrated in vacuo. The residue was purified by column chromatography to give 6-chloro-4,4-dimethyl-2-(2-nitrophenyl)-1,2,3,4-tetrahydroquinoline (7.8 g, 30.8%). LC/MS m/e obsd. (ESI+) [(M+H)+] 317.1.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([N:8]2[CH2:13][CH2:12][CH2:11][C@H:10]([C:14]([OH:16])=O)[CH2:9]2)[CH:5]=[C:4]([C:17]2[CH:22]=[CH:21][C:20]([C:23]#[N:24])=[C:19]([F:25])[CH:18]=2)[N:3]=1.C(Cl)CCl.C1C=CC2N(O)N=NC=2C=1.[CH3:40][O:41][C:42]1[CH:47]=[CH:46][CH:45]=[C:44]([NH2:48])[CH:43]=1>CN(C=O)C.CCOC(C)=O>[NH2:1][C:2]1[N:7]=[C:6]([N:8]2[CH2:13][CH2:12][CH2:11][C@H:10]([C:14]([NH:48][C:44]3[CH:45]=[CH:46][CH:47]=[C:42]([O:41][CH3:40])[CH:43]=3)=[O:16])[CH2:9]2)[CH:5]=[C:4]([C:17]2[CH:22]=[CH:21][C:20]([C:23]#[N:24])=[C:19]([F:25])[CH:18]=2)[N:3]=1
Reactant: COc1cccc(N)c1
Reactant: N#Cc1ccc(-c2cc(N3CCC[C@H](C(=O)O)C3)nc(N)n2)cc1F
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: ClCCCl
Solvent: CCOC(C)=O
Product: COc1cccc(NC(=O)[C@H]2CCCN(c3cc(-c4ccc(C#N)c(F)c4)nc(N)n3)C2)c1
Temperature: 25 °C
Reaction time: 4 h
Yield: 99 %

Procedure:
To a solution of (3S)-1-[2-amino-6-(4-cyano-3-fluorophenyl)-4-pyrimidinyl]-3-piperidinecarboxylic acid (150 mg, 0.439 mmol), EDC (118 mg, 0.615 mmol), and HOBT (83 mg, 0.615 mmol) in DMF (3 mL) was added m-anisidine (54 mg, 0.44 mmol), and the mixture was stirred at room temperature for 4 hours. LCMS showed reaction was completed. The reaction was poured onto water, and EtOAc was added to extract the product. The product stayed in the EtOAc layer. The organic solution was concentrated to dryness to give the title compound (194 mg) as a yellow solid. LC-MS (ES) m/z=447 [M+H]+.
Reaction SMILES: Cl[CH2:2][C:3]([C:5]1[CH:10]=[CH:9][C:8]([F:11])=[CH:7][C:6]=1[F:12])=O.COCC[SH:17].C(=O)([O-])[O-].[K+].[K+].[CH3:24][CH2:25][O:26][CH2:27]C>CO>[F:12][C:6]1[CH:7]=[C:8]([F:11])[CH:9]=[CH:10][C:5]=1[C:3](=[S:17])[CH2:2][CH2:24][CH2:25][O:26][CH3:27]
Reactant: O=C(CCl)c1ccc(F)cc1F
Reactant: COCCS
Reactant: CCOCC
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CO
Product: COCCCC(=S)c1ccc(F)cc1F
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 67 %

Procedure:
To a solution of 2-chloro-2',4'-difluoroacetophenone (2.7 g, 0.014 mol) and 2-methoxyethanethiol (J. Med. Chem., 39, 1253(1996)) (1.4 g, 0.015 mol) in methanol (50 ml), potassium carbonate (2.3 g, 0.016 mol) was added under ice cooling, followed by stirring at room temperature for 30 minutes. After the completion of the reaction, the insoluble matter was filtered off and the filtrate was distilled off under reduced pressure. The residue so obtained was diluted with ether, washed with water, dried over magnesium sulfate and distilled off under reduced pressure, whereby 2',4'-difluoro-2-(2-methoxyethyl)thioacetophenone (2.3 g, yield: 67.0%) was obtained as a colorless oil.
Reaction SMILES: [O:1]=[C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:9]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)=[N:10][N:11]3[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=23)=[N:4][NH:3]1.[H-].[Na+].[O:25]1[CH:27]2[CH2:28][CH2:29][CH2:30][CH2:31][CH:26]12>CN(C)C=O>[OH:25][C@H:26]1[CH2:31][CH2:30][CH2:29][CH2:28][C@H:27]1[N:3]1[C:2](=[O:1])[CH:7]=[CH:6][C:5]([C:8]2[C:9]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)=[N:10][N:11]3[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=23)=[N:4]1
Reactant: O=c1ccc(-c2c(-c3ccccc3)nn3ccccc23)n[nH]1
Reactant: C1CCC2OC2C1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: O=c1ccc(-c2c(-c3ccccc3)nn3ccccc23)nn1[C@@H]1CCCC[C@@H]1O
Temperature: 5 °C
Reaction time: 0.25 h
Yield: 3.1 %

Procedure:
To a solution of 3-(3-oxo-2,3-dihydropyridazin-6-yl)-2-phenylpyrazolo[1,5-a]pyridine (1.58 g) in 80 ml of N,N-dimethylformamide was added sodium hydride (60% dispersion in mineral oil, 242 mg) at 5° C. After being stirred for 15 minutes at 5° C., the mixture was treated with epoxycyclohexane (1.62 g) and heated to 127° C. for 4.5 hours. The reaction mixture was poured into ice-water (200 ml), and the mixture was extracted with ethyl acetate (100 ml, 50 ml). The combined extracts were washed with water (50 ml) and brine (50 ml), dried over sodium sulfate, and concentrated in vacuo. The crude materials were purified by column chromatography on silica gel (40 g). The fractions containing minor cis isomer eluted with a mixture of dichloromethane and ethyl acetate (10:1-10:2) were collected, and the solvent was removed in vacuo to give cis-3-[2-(2-hydroxycyclohexyl)-3-oxo-2,3-dihydropyridazin-6-yl]-2-phenylpyrazolo[1,5-a]pyridine (65.1 mg). The physical data for this compound were idendical with those of the authentic sample prepared by the method described in Example 4.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([CH:7]=O)[CH:2]=1.[NH2:9][N:10]1[CH2:15][CH:14]([CH3:16])[NH:13][NH:12][C:11]1=[O:17]>S(=O)(=O)(O)O.C(O)C>[CH3:16][CH:14]1[NH:13][NH:12][C:11](=[O:17])[N:10]([N:9]=[CH:7][C:3]2[CH:2]=[N:1][CH:6]=[CH:5][CH:4]=2)[CH2:15]1
Reactant: CC1CN(N)C(=O)NN1
Reactant: O=Cc1cccnc1
Agent: O=S(=O)(O)O
Solvent: CCO
Product: CC1CN(N=Cc2cccnc2)C(=O)NN1

Procedure:
2.2 g of pyridine-3-carbaldehyde and 2 drops of sulfuric acid are added to a solution of 3 g of 4-amino-6-methyl-3-oxo-1,4,5,6-tetrahydro-1,2,4-triazine in 30 ml of ethanol. The reaction mixture is then maintained under reflux for 90 minutes and then the resulting suspension is cooled to 200°, filtered and dried. 4.1 g of the title compound having a melting point of 235°-237° are obtained.
Reaction SMILES: FC(F)(F)C(O)=O.[N:8]1([CH2:13][C:14]2[CH:33]=[CH:32][C:17]([O:18][C@H:19]3[CH2:22][C@H:21]([CH2:23][NH:24]C(=O)OC(C)(C)C)[CH2:20]3)=[CH:16][CH:15]=2)[CH2:12][CH2:11][CH2:10][CH2:9]1>ClCCl>[N:8]1([CH2:13][C:14]2[CH:33]=[CH:32][C:17]([O:18][C@H:19]3[CH2:22][C@H:21]([CH2:23][NH2:24])[CH2:20]3)=[CH:16][CH:15]=2)[CH2:12][CH2:11][CH2:10][CH2:9]1
Reactant: CC(C)(C)OC(=O)NC[C@H]1C[C@H](Oc2ccc(CN3CCCC3)cc2)C1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: NC[C@H]1C[C@H](Oc2ccc(CN3CCCC3)cc2)C1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
Trifluoro-acetic acid (3.5 mL, 49 mmol) was added to a solution of Example 38, tert-butyl ({trans-3-[4-(pyrrolidin-1-ylmethyl)phenoxy]cyclobutyl}methyl)carbamate (2.16 g, 6 mmol) in dichloro-methane (20 mL). The reaction mass was stirred at room temperature for 2 h and evaporated in vacuo. The residue was diluted with water (50 mL), and the obtained solution was extracted with CH2Cl2. The organic layer was discarded. The aqueous one was alkalized with 10 N NaOH to pH 12 and extracted with CHCl3 (3×50 mL). The combined extracts were dried and evaporated to afford the title compound (1.4 g, 91%) as a yellow oil. LCMS-data: M+H 261.2, 262.2 (calc 260.38). 1H NMR-data (DMSO-d6): 7.17 (d, 2H, Ph, J=8.6 Hz); 6.72 (d, 2H, Ph, J=8.6 Hz); 4.65-4.76 (m, 1H); 3.47 (s, 3H, CH2); 2.63 (d, 2H, CH2, J=6.6 Hz); 2.32-2.42 (m, 4H); 2.18-2.28 (m, 3H); 2.00-2.13 (m, 2H); 1.60-1.72 (m, 4H).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C@H:8]2[C:17]3[C:12](=[CH:13][C:14]([O:22][CH3:23])=[C:15]([O:18][CH:19]([CH3:21])[CH3:20])[CH:16]=3)[CH2:11][C:10](=[O:24])[N:9]2[C:25]2[N:30]=[CH:29][C:28]([N:31]([CH2:33][C@H:34]3[CH2:39][CH2:38][C@H:37]([NH:40][CH2:41][C:42]([NH:44][CH3:45])=[O:43])[CH2:36][CH2:35]3)[CH3:32])=[CH:27][CH:26]=2)=[CH:4][CH:3]=1.[CH2:46]=O>CCO>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C@H:8]2[C:17]3[C:12](=[CH:13][C:14]([O:22][CH3:23])=[C:15]([O:18][CH:19]([CH3:20])[CH3:21])[CH:16]=3)[CH2:11][C:10](=[O:24])[N:9]2[C:25]2[CH:26]=[CH:27][C:28]([N:31]([CH3:32])[CH2:33][C@H:34]3[CH2:35][CH2:36][C@H:37]([N:40]4[CH2:41][C:42](=[O:43])[N:44]([CH3:46])[CH2:45]4)[CH2:38][CH2:39]3)=[CH:29][N:30]=2)=[CH:4][CH:3]=1
Reactant: CNC(=O)CN[C@H]1CC[C@H](CN(C)c2ccc(N3C(=O)Cc4cc(OC)c(OC(C)C)cc4[C@@H]3c3ccc(Cl)cc3)nc2)CC1
Reactant: C=O
Solvent: CCO
Product: COc1cc2c(cc1OC(C)C)[C@H](c1ccc(Cl)cc1)N(c1ccc(N(C)C[C@H]3CC[C@H](N4CC(=O)N(C)C4)CC3)cn1)C(=O)C2

Procedure:
The mixture of Example 122 (38 mg, 0.061 mmol) and formaldehyde (0.046 ml, 37% solution, 10 eq, 0.612 mmol) was heated for 15 h in EtOH (1 mL) at 80° C. The reaction mixture was concentrated to dryness and the residue was purified by Combi-Flash Companion™ (Isco Inc.) column chromatography (SiO2; gradient elution, DCM/[DCM/MeOH 9:1] 1:0→0:1) yielding the title compound as a colorless solid (31 mg, 0.048 mmol, 79%). HPLC: FtRet=1.236; LC-MS: m/z 646.4 [M+H]+.
Reaction SMILES: C([Si]([O:8][C:9]1[CH:14]=[CH:13][C:12]([F:15])=[CH:11][C:10]=1[F:16])(C)C)(C)(C)C.C([Li])CCC.CCCCCC.CN(C)[CH:30]=[O:31].[BH4-].[Na+]>O1CCCC1.CO>[F:16][C:10]1[C:11]([CH2:30][OH:31])=[C:12]([F:15])[CH:13]=[CH:14][C:9]=1[OH:8]
Reactant: CN(C)C=O
Reactant: CC(C)(C)[Si](C)(C)Oc1ccc(F)cc1F
Agent: [BH4-]
Agent: [Li]CCCC
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CO
Solvent: CCCCCC
Product: OCc1c(F)ccc(O)c1F
Temperature: -78 °C
Reaction time: 2 h

Procedure:
To a stirred solution of tert-butyl(2,4-difluorophenoxy)dimethylsilane (J. Med. Chem. 1993, 36, 3947., 1.50 g, 6.14 mmol) in tetrahydrofuran (30 mL) was added a 1.57 M solution of n-butyllithium in hexane (4.69 mL, 7.37 mmol) at −78° C. over 10 minutes, and the mixture was stirred at −78° C. for 2 h. To the mixture, N,N-dimethylformamide (0.950 mL, 2.28 mmol) was added at −78° C. The mixture was stirred at −78° C. for 1 h, allowed to warm to room temperature and stand at room temperature for 16 h. The mixture was diluted with methanol (20 mL), and to the mixture was added sodium borohydride (696 mg, 18.4 mmol) at 0° C. The mixture was stirred at room temperature for 1.5 h. The reaction was quenched by addition of aqueous ammonium chloride at 0° C. to be pH=7. The mixture was extracted with diethyl ether (200 mL) and the organic layer was washed with brine, dried over magnesium sulfate and evapolated. The residue was purified by column chromatography on silica gel (100 g) eluting with hexane/ethyl acetate (2/1) to afford 410 mg (42%) of the title as a colorless oil:
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH2:11][CH2:10][C@@H:9]1[C:14](O)=[O:15])=[O:7])([CH3:4])([CH3:3])[CH3:2].B.O1CCCC1.O>C1COCC1>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH2:11][CH2:10][C@@H:9]1[CH2:14][OH:15])=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)OC(=O)N1CCCC[C@@H]1C(=O)O
Agent: B
Solvent: O
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1CCCC[C@@H]1CO
Temperature: 2.5 °C
Reaction time: 2 h
Yield: 99.1 %

Procedure:
To a solution of (R)-Piperidine-1,2-dicarboxylic acid 1-tert-butyl ester (5 g, 21.8 mmol) in anhydrous THF (32 mL) at 0-5° C. was added borane-tetrahydrofuran complex (1M solution in THF) (3.6 g, 41.84 mmol) over a period of 15 min. The mixture was stirred at 0-5° C. for 2 h and then at rt for 2 h. The mixture was added over a period of 10 min to cold water (75 mL) and extracted with EtOAc (300 mL). The aqueous layer was re-extracted with EtOAc (2×150 mL). The organic layers were combined, dried over anhydrous Na2SO4 and concentrated to obtain the title product as a colorless oil (4.65 g., 99%).
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@H:9]([C:16]([OH:18])=O)[CH2:10][C:11]1[N:12]=[CH:13][S:14][CH:15]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].Cl.[CH2:20]([O:27][C:28](=[O:34])[C@@H:29]1[CH2:33][CH2:32][CH2:31][NH:30]1)[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1.C1C=CC2N(O)N=NC=2C=1.C(N(CC)CC)C.C1CCC(N=C=NC2CCCCC2)CC1>O1CCCC1>[CH2:20]([O:27][C:28](=[O:34])[C@@H:29]1[CH2:33][CH2:32][CH2:31][N:30]1[C:16](=[O:18])[C@H:9]([CH2:10][C:11]1[N:12]=[CH:13][S:14][CH:15]=1)[NH:8][C:6]([O:5][C:1]([CH3:2])([CH3:3])[CH3:4])=[O:7])[C:21]1[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=1
Reactant: CC(C)(C)OC(=O)N[C@@H](Cc1cscn1)C(=O)O
Reactant: O=C(OCc1ccccc1)[C@@H]1CCCN1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N[C@@H](Cc1cscn1)C(=O)N1CCC[C@H]1C(=O)OCc1ccccc1
Temperature: 25 °C
Reaction time: 18 h
Yield: 90.5 %

Procedure:
A solution of N-(tert-butyloxycarbonyl)-3-(4-thiazolyl)-L-alanine (2.72 g, 10 mmol), L-proline benzyl ester hydrochloric acid (2.42 g, 10 mmol), and HOBT (135 mg, 1 mmol) in tetrahydrofuran (60 ml) was added triethylamine (1.4 ml, 10 mmol) and DCC (2.43 g, 11.8 mmol) and the resulting mixture was stirred for 18 h at room temperature. After the precipitation which appeared was filtered off, the filtrate was concentrated in vacuo. The residue (5.5 g) was subjected to silica gel column chromatography with Lobar® column C (Merck inc.) (toluene:acetone=9:1) to give 4.16 g of the compound (30).