Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N:1]1[C:10]2[C:5](=[CH:6][CH:7]=[C:8]([NH:11][C:12](=[O:14])[CH3:13])[CH:9]=2)[CH:4]=[CH:3][CH:2]=1.[OH-].[Na+]>>[N:1]1[C:10]2[CH2:9][CH:8]([NH:11][C:12](=[O:14])[CH3:13])[CH2:7][CH2:6][C:5]=2[CH:4]=[CH:3][CH:2]=1
Reactant: CC(=O)Nc1ccc2cccnc2c1
Agent: [Na+]
Agent: [OH-]
Product: CC(=O)NC1CCc2cccnc2C1
Yield: 24.6 %

Procedure:
Reaction of N-(quinol-7-yl)acetamide (33 mg, 0.177 mmol) using the general procedure for small scale hydrogenations (workup with NaOH in place of saturated NaHCO3) provided N-(5,6,7,8-tetrahydroquinolin-7-yl)acetamide (8.3 mg, 25%): 1H NMR □ 1.72-1.83 (m, 1H), 1.99 (s, 3H), 2.04-2.20 (m, 2H), 2.72-2.95 (m, 3H), 3.25 (dd, 1H, J=5, 17 Hz), 4.29-4.40 (m, 1H), 5.72 (br s, 1H), 7.05 (dd, 1H, J=4, 8 Hz), 7.38 (d, 1H, J=8 Hz), 8.35 (d, 1H, J=4 Hz); 13C NMR □ 23.9, 26.5, 28.7, 39.0, 45.6, 121.9, 131.4, 137.0, 147.7, 154.8, 170.1; MS m/z: 213 (M+Na+). N-(1,2,3,4-tetrahydroquinolin-7-yl)acetamide also was isolated (6.5 mg, 20%): 1H NMR □ 1.24-1.28 (s, 1H), 1.87-1.95 (m, 2H), 2.70 (dd, 2H, J=6, 6 Hz), 3.28 (dd, 2H, J=5, 5 Hz), 6.46 (d, 1H, J=8 Hz), 6.84 (d, 1H, J=8 Hz), 6.93 (s, 1H), 7.03 (br s, 1H); 13C NMR□ 22.1, 24.7, 26.6, 37.9, 105.6, 108.3, 117.6, 129.6, 136.5, 145.1, 168.1; MS m/z: 213 (M+Na+).
Reaction SMILES: [Br:1][C:2]1[CH:10]=[CH:9][C:5]([C:6](Cl)=[O:7])=[CH:4][CH:3]=1.[NH2:11][C:12]1[CH:26]=[CH:25][CH:24]=[CH:23][C:13]=1[CH2:14][CH2:15][CH:16]1[CH2:21][CH2:20][CH2:19][CH2:18][N:17]1[CH3:22]>>[Br:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([NH:11][C:12]2[CH:26]=[CH:25][CH:24]=[CH:23][C:13]=2[CH2:14][CH2:15][CH:16]2[CH2:21][CH2:20][CH2:19][CH2:18][N:17]2[CH3:22])=[O:7])=[CH:4][CH:3]=1
Reactant: CN1CCCCC1CCc1ccccc1N
Reactant: O=C(Cl)c1ccc(Br)cc1
Product: CN1CCCCC1CCc1ccccc1NC(=O)c1ccc(Br)cc1

Procedure:
Reaction of 4-bromobenzoyl chloride with 2-(o-aminophenethyl)-1-methylpiperidine according to the procedure of Example 114 affords 4-bromo-2'-[2-(1-methyl-2-piperidyl)ethyl]benzanilide, m.p. 137.5°-138.5° C. (corr.), from ethyl acetate.
Reaction SMILES: [CH:1]1([N:6]2[CH2:11][CH2:10][N:9]([C:12]([C:14]3[CH:15]=[C:16]4[C:20](=[CH:21][CH:22]=3)[NH:19][C:18]([C:23]([N:25]3[CH2:30][CH2:29][C:28]([F:32])([F:31])[CH2:27][CH2:26]3)=[O:24])=[CH:17]4)=[O:13])[CH2:8][CH2:7]2)[CH2:5][CH2:4][CH2:3][CH2:2]1.[H-].[Na+].[CH3:35][S:36](Cl)(=[O:38])=[O:37]>CN(C)C=O>[CH:1]1([N:6]2[CH2:7][CH2:8][N:9]([C:12]([C:14]3[CH:15]=[C:16]4[C:20](=[CH:21][CH:22]=3)[N:19]([S:36]([CH3:35])(=[O:38])=[O:37])[C:18]([C:23]([N:25]3[CH2:26][CH2:27][C:28]([F:31])([F:32])[CH2:29][CH2:30]3)=[O:24])=[CH:17]4)=[O:13])[CH2:10][CH2:11]2)[CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: CS(=O)(=O)Cl
Reactant: O=C(c1ccc2[nH]c(C(=O)N3CCC(F)(F)CC3)cc2c1)N1CCN(C2CCCC2)CC1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CS(=O)(=O)n1c(C(=O)N2CCC(F)(F)CC2)cc2cc(C(=O)N3CCN(C4CCCC4)CC3)ccc21
Yield: 35 %

Procedure:
The title compound was synthesized in analogy to example 51, from [5-(4-cyclopentyl-piperazine-1-carbonyl)-1H-indol-2-yl]-(4,4-difluoro-piperidin-1-yl)-methanone (example 8), sodium hydride and methanesulfonyl chloride in N,N-dimethylformamide, to give the desired product as a colorless foam (35%).
Reaction SMILES: [NH2:1][C:2]1[N:6]([CH2:7][C:8]2[CH:13]=[CH:12][C:11]([O:14][CH3:15])=[CH:10][CH:9]=2)[N:5]=[N:4][C:3]=1[C:16]([NH2:18])=[O:17].[C:19](=O)(OCC)[O:20]CC.CC(C)([O-])C.[K+].O>C1COCC1>[CH3:15][O:14][C:11]1[CH:10]=[CH:9][C:8]([CH2:7][N:6]2[C:2]3[N:1]=[C:19]([OH:20])[N:18]=[C:16]([OH:17])[C:3]=3[N:4]=[N:5]2)=[CH:13][CH:12]=1
Reactant: COc1ccc(Cn2nnc(C(N)=O)c2N)cc1
Reactant: CCOC(=O)OCC
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: O
Solvent: C1CCOC1
Product: COc1ccc(Cn2nnc3c(O)nc(O)nc32)cc1
Temperature: 25 °C

Procedure:
To a solution of 5-amino-1-(4-methoxybenzyl)-1H-1,2,3-triazole-4-carboxamide (0.9 g) and diethyl carbonate (1.2 mL) in THF (30 mL) was added potassium tert-butoxide (1.2 g). The mixture was refluxed under nitrogen for 6 h. It was then cooled down to room temperature. Water (20 mL) was added and the reaction mixture was concentrated to about 20 mL. It was neutralized with 1N HCl to pH 6 and filtered. Solid was collected and washed with water, and air dried to give desired product. 1H NMR (400 MHz, MeOD-d4) δ 7.24 (d, 2H), 7.21 (m, 1H), 6.92 (d, 2H), 6.88 (m, 1H), 5.52 (s, 2H), 3.78 (s, 3H) ppm; ESMS calculated for C12H11N5O3 (m/z): 273.0, found (M+H+): 274.0.
Reaction SMILES: O[N:2]=[C:3]([C:11](=O)[C:12]1[CH:17]=[CH:16][N:15]=[CH:14][CH:13]=1)[C:4]([O:6][C:7]([CH3:10])([CH3:9])[CH3:8])=[O:5].[CH2:19]([NH2:26])[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1>C(#N)C>[C:20]1([C:19]2[NH:26][C:11]([C:12]3[CH:17]=[CH:16][N:15]=[CH:14][CH:13]=3)=[C:3]([C:4]([O:6][C:7]([CH3:10])([CH3:9])[CH3:8])=[O:5])[N:2]=2)[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1
Reactant: CC(C)(C)OC(=O)C(=NO)C(=O)c1ccncc1
Reactant: NCc1ccccc1
Solvent: CC#N
Product: CC(C)(C)OC(=O)c1nc(-c2ccccc2)[nH]c1-c1ccncc1
Yield: 38.9 %

Procedure:
tert-Butyl 2-hydroxyimino-3-oxo-3-(4-pyridyl)propionate (2.8 g) and benzylamine (2.4 g) were dissolved in acetonitrile (80 ml), and the mixture was reacted and treated in the same manner as in Starting Material Synthetic Example 5 to give tert-butyl 2-phenyl-5-(4-pyridyl)imidazole-4-carboxylate (1.4 g), melting point 205-206° C.
Reaction SMILES: P(Cl)(Cl)([Cl:3])=O.[Cl:6][C:7]1[C:12]([Cl:13])=[CH:11][CH:10]=[CH:9][C:8]=1[N:14]1[C:18]2=[N:19][CH:20]=[N:21][C:22](O)=[C:17]2[CH:16]=[N:15]1>>[Cl:3][C:22]1[N:21]=[CH:20][N:19]=[C:18]2[N:14]([C:8]3[CH:9]=[CH:10][CH:11]=[C:12]([Cl:13])[C:7]=3[Cl:6])[N:15]=[CH:16][C:17]=12
Reactant: O=P(Cl)(Cl)Cl
Reactant: Oc1ncnc2c1cnn2-c1cccc(Cl)c1Cl
Product: Clc1cccc(-n2ncc3c(Cl)ncnc32)c1Cl
Temperature: 100 °C
Reaction time: 4 h
Yield: 57.5 %

Procedure:
Phosphorus oxychloride (26.5 ml, 284.60 mmol) was added to 1-(2,3-dichlorophenyl)-1H-pyrazolo[3,4-d]pyrimidin-4-ol (Intermediate AR3) (4 g, 14.23 mmol), at ambient temperature. The resulting mixture was stirred at 100° C. for 4 hours. Allowed to cool to Ambient temperature. The reaction mixture was evaporated to near dryness, dissolved in toluene, evaporated, re-dissolved in toluene and evaporated to dryness again. The solid was triturated with EtOH. A solid was filtered off and dried under vacuum to give the product (2.450 g, 57.5%). 1H NMR (400 MHz, DMSO) δ 7.65 (1H, m), 7.73-7.75 (1H, dd), 7.94-7.97 (1H, dd), 8.83 (1H, s), 8.91 (1H, s); m/z (ES+) (M+H)+=518; HPLC tR=1.89 min.
Reaction SMILES: CS([C:5]1[N:10]=[C:9]([N:11]2[C:15]3[CH:16]=[CH:17][CH:18]=[CH:19][C:14]=3[N:13]=[CH:12]2)[CH:8]=[CH:7][N:6]=1)(=O)=O.[CH:20]1([C@@H:26]([NH2:28])[CH3:27])[CH2:25][CH2:24][CH2:23][CH2:22][CH2:21]1>>[CH:20]1([C@@H:26]([NH:28][C:5]2[N:10]=[C:9]([N:11]3[C:15]4[CH:16]=[CH:17][CH:18]=[CH:19][C:14]=4[N:13]=[CH:12]3)[CH:8]=[CH:7][N:6]=2)[CH3:27])[CH2:25][CH2:24][CH2:23][CH2:22][CH2:21]1
Reactant: CS(=O)(=O)c1nccc(-n2cnc3ccccc32)n1
Reactant: C[C@H](N)C1CCCCC1
Product: C[C@H](Nc1nccc(-n2cnc3ccccc32)n1)C1CCCCC1

Procedure:
2-Methanesulfonyl-4-[benzimidazol-1-yl]pyrimidine (EXAMPLE 1) was reacted with (S)-1-cyclohexylethylamine according to the procedure described in EXAMPLE 11, Step C to afford the title compound. Mass Spectrum (ESI): 322.3 (M+1). 1H NMR (500 MHz, CDCl3): δ partial 8.63 (s, 1H); 8.30 (br s, 1H); 8.23 (br, s, 1H); 7.88 (d, J=7.3 Hz, 1H); 7.43 (m, 2H); 6.80 (d, J=5.2 Hz, 1H); 4.10 (m, 1H); 1.69-1.91 (m, 4H); 1.10-1.35 (m, 10H).
Reaction SMILES: [OH:1][C:2]1[CH:11]=[CH:10][C:5]([C:6]([O:8][CH3:9])=[O:7])=[CH:4][C:3]=1[CH2:12][CH:13]=[CH2:14].C(N(CC)CC)C.[C:22]([Si:26]([CH3:29])([CH3:28])Cl)([CH3:25])([CH3:24])[CH3:23]>ClCCl.CN(C)C1C=CN=CC=1>[Si:26]([O:1][C:2]1[CH:11]=[CH:10][C:5]([C:6]([O:8][CH3:9])=[O:7])=[CH:4][C:3]=1[CH2:12][CH:13]=[CH2:14])([C:22]([CH3:25])([CH3:24])[CH3:23])([CH3:29])[CH3:28]
Reactant: CC(C)(C)[Si](C)(C)Cl
Reactant: C=CCc1cc(C(=O)OC)ccc1O
Agent: CN(C)c1ccncc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: C=CCc1cc(C(=O)OC)ccc1O[Si](C)(C)C(C)(C)C
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of 5.168 g (26.9 mmol) of the product of Step B in 50 mL of dichloromethane was added 4.40 mL (2.95 mmol) of triethylamine, 4.46 g (2.95 mmol) of tert-butyldimethylchlorosilane, 0.100 g of 4-dimethylaminopyridine, and the reaction mixture was stirred at room temperature for 2 hours. The mixture was then diluted with 50 mL dichloromethane, washed with 100 mL 1N hydrochloric acid, dried (MgSO4), filtered and evaporated. The residual oil (7.993 g, 97%) was used in the next step without further purification.
Reaction SMILES: [NH2:1][N:2]1[C:11](=[O:12])[C:10]2[C:5](=[CH:6][C:7](F)=[C:8]([F:13])[CH:9]=2)[N:4]([CH:15]2[CH2:17][CH2:16]2)[C:3]1=[O:18].C(N(CC)CC)C.[C:26]([O:30][C:31](=[O:38])[NH:32][C@H:33]1[CH2:37][CH2:36][NH:35][CH2:34]1)([CH3:29])([CH3:28])[CH3:27]>C(#N)C>[NH2:1][N:2]1[C:11](=[O:12])[C:10]2[C:5](=[CH:6][C:7]([N:35]3[CH2:36][CH2:37][C@H:33]([NH:32][C:31]([O:30][C:26]([CH3:29])([CH3:28])[CH3:27])=[O:38])[CH2:34]3)=[C:8]([F:13])[CH:9]=2)[N:4]([CH:15]2[CH2:17][CH2:16]2)[C:3]1=[O:18]
Reactant: CC(C)(C)OC(=O)N[C@H]1CCNC1
Reactant: Nn1c(=O)c2cc(F)c(F)cc2n(C2CC2)c1=O
Solvent: CC#N
Solvent: CCN(CC)CC
Product: CC(C)(C)OC(=O)N[C@H]1CCN(c2cc3c(cc2F)c(=O)n(N)c(=O)n3C2CC2)C1
Yield: 88.2 %

Procedure:
To a solution of 3-amino-1-cyclopropyl-6,7-difluoro-1H-quinazoline-2,4-dione (Example 24a) (50.0 mg, 0.20 mmol) and triethylamine (74 mg, 0.74 mmol) in acetonitrile (3 mL) is added (S)-pyrrolidin-3-yl carbamic acid tert-butyl ester (74 mg, 0.40 mmol). The solution is refluxed for 18 hours, the solvent is removed under reduced pressure, and the residue triturated with water. The solid is collected by filtration and air dried to afford 74 mg of the title compound. MS CI: m/z 420 (MH+).
Reaction SMILES: Br[C:2]1[N:7]=[C:6]2[N:8]([CH2:11][C:12]3[CH:13]=[C:14]4[C:19](=[CH:20][CH:21]=3)[N:18]=[CH:17][CH:16]=[CH:15]4)[N:9]=[N:10][C:5]2=[N:4][CH:3]=1.C([SnH2][C:27]([O:29][CH2:30][CH3:31])=[CH2:28])CCC>C(#N)C.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.[Cu]I>[CH2:30]([O:29][C:27]([C:2]1[N:7]=[C:6]2[N:8]([CH2:11][C:12]3[CH:13]=[C:14]4[C:19](=[CH:20][CH:21]=3)[N:18]=[CH:17][CH:16]=[CH:15]4)[N:9]=[N:10][C:5]2=[N:4][CH:3]=1)=[CH2:28])[CH3:31]
Reactant: C=C(OCC)[SnH2]CCCC
Reactant: Brc1cnc2nnn(Cc3ccc4ncccc4c3)c2n1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Solvent: CC#N
Product: C=C(OCC)c1cnc2nnn(Cc3ccc4ncccc4c3)c2n1
Yield: 55 %

Procedure:
To a solution of 6-(6-bromo-[1,2,3]triazolo[4,5-b]pyrazin-1-ylmethyl)-quinoline (2 g, 5.86 mmol) in ACN (47 mL) (degassed 3 times with nitrogen) was added Pd(PPh3)2Cl2 (205 mg, 0.293 mmol), CuI (167 mg, 0.879 mmol), and butyl-(1-ethoxy-vinyl)-stannane (5.9 mL, 17.59 mmol). The reaction was refluxed for 4 hours until the LC-MS showed complete product. The reaction was filtered over a celite pad and washed with ether (100 mL). The solution was washed with water (1×50 mL), dried over Na2SO4, and concentrated. The crude product was purified by silica gel column chromatography with EtOAc:Hexanes to give 1.05 g of the product 6-[6-(1-ethoxy-vinyl)-[1,2,3]triazolo[4,5-b]pyrazin-1-ylmethyl]-quinoline (55% yield).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:31])[C:4]1[CH:9]=[C:8](Br)[CH:7]=[C:6]([CH3:11])[C:5]=1[N:12]([S:20]([C:23]1[CH:28]=[CH:27][C:26]([O:29][CH3:30])=[CH:25][CH:24]=1)(=[O:22])=[O:21])[CH2:13][C:14]1[CH:15]=[N:16][CH:17]=[CH:18][CH:19]=1.[CH:32]([C:34]1[CH:38]=[CH:37][S:36][C:35]=1B(O)O)=[O:33]>>[CH3:1][O:2][C:3](=[O:31])[C:4]1[CH:9]=[C:8]([C:35]2[S:36][CH:37]=[CH:38][C:34]=2[CH:32]=[O:33])[CH:7]=[C:6]([CH3:11])[C:5]=1[N:12]([S:20]([C:23]1[CH:28]=[CH:27][C:26]([O:29][CH3:30])=[CH:25][CH:24]=1)(=[O:22])=[O:21])[CH2:13][C:14]1[CH:15]=[N:16][CH:17]=[CH:18][CH:19]=1
Reactant: O=Cc1ccsc1B(O)O
Reactant: COC(=O)c1cc(Br)cc(C)c1N(Cc1cccnc1)S(=O)(=O)c1ccc(OC)cc1
Product: COC(=O)c1cc(-c2sccc2C=O)cc(C)c1N(Cc1cccnc1)S(=O)(=O)c1ccc(OC)cc1
Yield: 70.6 %

Procedure:
In the same manner as described in Example 241, 505.4 mg (1.0 mmol) of the product of Example 89 and 343.2 mg (2.2 mmol) of 3-formylthiophene-2-boronic acid provided 379 mg (71%) of the desired product as a pale yellow solid. Electrospray Mass Spec 537 (M+H).
Reaction SMILES: C[O:2][C:3]1(OC)[C:9]([NH:10][C:11](=[O:19])[C:12]2[CH:17]=[CH:16][CH:15]=[N:14][C:13]=2[OH:18])=[CH:8][C:7](=[O:20])[CH:6]2[CH:4]1[O:5]2.FC(F)(F)C(O)=O>ClCCl.C(=O)(O)[O-].[Na+]>[O:2]=[C:3]1[C:9]([NH:10][C:11](=[O:19])[C:12]2[CH:17]=[CH:16][CH:15]=[N:14][C:13]=2[OH:18])=[CH:8][C:7](=[O:20])[CH:6]2[CH:4]1[O:5]2
Reactant: COC1(OC)C(NC(=O)c2cccnc2O)=CC(=O)C2OC21
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: O=C(NC1=CC(=O)C2OC2C1=O)c1cccnc1O
Reaction time: 8 h
Yield: 72.1 %

Procedure:
To a solution of 6a (50 mg, 0.16 mmol) in anhydrous dichloromethane (2 was slowly added trifluoroacetic acid (0.5 mL) at room temperature. After overnight stirring, LC-MS indicated 27% starting material remained. Additional trifluoroacetic acid (0.5 mL) was added and the reaction mixture was stirred an additional 24 hours, at which time it was judged complete. The solution was cooled in an ice bath and diluted with additional dichloromethane (10 mL) before the slow addition of saturated sodium bicarbonate solution until the stirring mixture was alkaline. The mixture was then partitioned and the organic solvents were removed and rinsed with brine. The aqueous layer was extracted twice with ethyl acetate and the organic layer was washed with brine. All organics were pooled and dried over anhydrous magnesium sulfate before filtration and solvent evaporation, giving 7a as a light-yellow solid (30 mg, 71%). LC-MS indicated 80% purity, and the material was used in the next step without further purification.
Reaction SMILES: [CH2:1]([NH:8][CH3:9])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Cl:10][C:11]1[N:12]=[C:13]([N:22]2[CH2:27][CH2:26][S:25](=[O:28])[CH2:24][CH2:23]2)[C:14]2[N:20]=[CH:19][N:18]=[C:17](Cl)[C:15]=2[N:16]=1>O1CCOCC1.O>[CH2:1]([N:8]([CH3:9])[C:17]1[C:15]2[N:16]=[C:11]([Cl:10])[N:12]=[C:13]([N:22]3[CH2:27][CH2:26][S:25](=[O:28])[CH2:24][CH2:23]3)[C:14]=2[N:20]=[CH:19][N:18]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CNCc1ccccc1
Reactant: O=S1CCN(c2nc(Cl)nc3c(Cl)ncnc23)CC1
Solvent: O
Solvent: C1COCCO1
Product: CN(Cc1ccccc1)c1ncnc2c(N3CCS(=O)CC3)nc(Cl)nc12

Procedure:
A solution of 12.2 gm (0.1 mol) of N-benzyl-methylamine in 50 ml of dioxane was slowly poured, while stirring, to a suspension of 15.9 gm (0.05 mol) of 2,8-dichloro-4-(1-oxido-thiomorpholino)-pyrimido-[5,4-d]-pyrimidine in about 250 ml of dioxane, and the resulting mixture was heated at 30°-40° C. for about 30 minutes. After taking up the reaction mixture in about 1 liter of water, the reaction product was obtained as a pale yellow precipitate which, after some standing, was suction filtered off, washed with water and dried at about 60° C.
Reaction SMILES: C(=O)(O)[O-].[Na+].[NH2:6][C:7]([CH3:13])([CH:10]([CH3:12])[CH3:11])[C:8]#[N:9].[Cl:14][C:15]1[CH:26]=[C:25]([Cl:27])[CH:24]=[CH:23][C:16]=1[O:17][C@H:18]([CH3:22])[C:19](Cl)=[O:20].[OH-].[Na+]>O.C1(C)C=CC=CC=1>[C:8]([C:7]([NH:6][C:19](=[O:20])[CH:18]([O:17][C:16]1[CH:23]=[CH:24][C:25]([Cl:27])=[CH:26][C:15]=1[Cl:14])[CH3:22])([CH3:13])[CH:10]([CH3:12])[CH3:11])#[N:9]
Reactant: CC(C)C(C)(N)C#N
Reactant: C[C@@H](Oc1ccc(Cl)cc1Cl)C(=O)Cl
Agent: O=C([O-])O
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: Cc1ccccc1
Product: CC(Oc1ccc(Cl)cc1Cl)C(=O)NC(C)(C#N)C(C)C
Temperature: 55 °C
Reaction time: 0.5 h
Yield: 94.8 %

Procedure:
A stirred mixture of sodium bicarbonate (1.446 kg; 17.2 mol) in water at -3° to 3° C. is treated with a toluene solution of 2-amino-2,3-dimethylbutyronitrile (1.51 kg, 13.46 mol) over a 15 minute period, then treated sequentially with a toluene solution of (R)-2-(2,4-dichlorophenoxy)propionyl chloride (3.346 kg, 13.2 mol) over a 1.5 hour period at ice bath temperatures, stirred for 0.5 hours, treated with 50% NaOH (0.396 kg), heated to 55° C. and stirred for 0.5 hours. The resultant mixture is separated. The organic phase is washed with 5% NaOH and distilled at temperatures up to 80° C. at 10 mm Hg to remove the toluene. The pot residue is crystallized in isopropanol/water to afford the title product as a white solid, 4.131 kg (94.8% yield), characterized by HPLC analysis. The product is 99.7% pure. The isomer ratio is: 94.8% RR, RS and 5.2% SS, SR.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([C:8]2[CH:20]=[CH:19][C:11]3[N:12]=[C:13]([NH:15]C(=O)C)[S:14][C:10]=3[CH:9]=2)[CH:5]=[N:4][CH:3]=1.[CH:21]12[CH2:29][CH2:28][CH:25]([CH2:26][CH2:27]1)[CH2:24][NH:23][CH2:22]2>>[CH:21]12[CH2:29][CH2:28][CH:25]([CH2:26][CH2:27]1)[CH2:24][N:23]([C:2]1[N:7]=[C:6]([C:8]3[CH:20]=[CH:19][C:11]4[N:12]=[C:13]([NH2:15])[S:14][C:10]=4[CH:9]=3)[CH:5]=[N:4][CH:3]=1)[CH2:22]2
Reactant: C1CC2CCC1CNC2
Reactant: CC(=O)Nc1nc2ccc(-c3cncc(Cl)n3)cc2s1
Product: Nc1nc2ccc(-c3cncc(N4CC5CCC(CC5)C4)n3)cc2s1
Temperature: 140 °C
Reaction time: 3 h
Yield: 24.6 %

Procedure:
A 10 mL, CEM microwave vial was charged with N-(6-(6-chloropyrazin-2-yl)benzo[d]thiazol-2-yl)acetamide (0.0657 g, 0.22 mmol), 3-aza-bicyclo[3.2.2]nonane (0.032 g, 0.26 mmol), 1 mL dry TFE and a stirbar. The vessel was flushed with Ar, sealed and heated using a 110° C. heat block for 12 h. The reaction was cooled and 4 mL EtOH was added. The vial was sealed and the slurry was heated to 140° C. using a heat transfer block for 5 minutes and cooled. The slurry was filtered using a course glass filter fitted with a 0.22 μm teflon filter. The solid was dried at 60° C. and <1 mm Hg for 3 h and then dissolved in warm DMF. The turbid solution was filtered through a 0.22 μm teflon filter, and the solvent was removed in vacuo to afford 6-(6-(3-aza-bicyclo[3.2.2]nonan-3-yl)pyrazin-2-yl)benzo[d]thiazol-2-amine (19 mg). 1H NMR (400 MHz, Pyr) δ ppm 1.48-1.68 (m, 8H) 2.01 (s, 2H) 3.83 (d, J=4.11 Hz, 4H) 7.92 (dd, J=8.41, 0.39 Hz, 1H) 8.28 (dd, J=8.41, 1.86 Hz, 1H) 8.34 (s, 1H) 8.71 (s, 1H) 8.75 (dd, J=1.37, 0.49 Hz, 1H) 8.89 (s, 2H). 13C NMR (101 MHz, Pyr) δ ppm 25.05 (s, 4 C) 30.68 (s, 2 C) 53.39 (s, 2 C) 118.92 (s, 1 C) 119.97 (s, 1 C) 125.11 (s, 1 C) 128.54 (s, 1 C) 128.71 (s, 1 C) 131.27 (s, 1 C) 133.33 (s, 1 C) 149.01 (s, 1 C) 155.03 (s, 1 C) 155.42 (s, 1 C) 169.00 (s, 1 C).
Reaction SMILES: [C@H:1]12[CH2:8][CH2:7][CH2:6][C@H:5]1[CH2:4][NH:3][C@@H:2]2[CH2:9][NH:10][C:11]([C:13]1[N:20]2[C:16]([S:17][CH:18]=[CH:19]2)=[N:15][C:14]=1[CH3:21])=[O:12].[CH3:22][C:23]1[CH:24]=[C:25]([C:29]2[C:30]([C:35](O)=[O:36])=[CH:31][CH:32]=[CH:33][CH:34]=2)[CH:26]=[CH:27][CH:28]=1>>[CH3:22][C:23]1[CH:24]=[C:25]([C:29]2[C:30]([C:35]([N:3]3[CH2:4][C@H:5]4[C@H:1]([CH2:8][CH2:7][CH2:6]4)[C@H:2]3[CH2:9][NH:10][C:11]([C:13]3[N:20]4[C:16]([S:17][CH:18]=[CH:19]4)=[N:15][C:14]=3[CH3:21])=[O:12])=[O:36])=[CH:31][CH:32]=[CH:33][CH:34]=2)[CH:26]=[CH:27][CH:28]=1
Reactant: Cc1cccc(-c2ccccc2C(=O)O)c1
Reactant: Cc1nc2sccn2c1C(=O)NC[C@H]1NC[C@@H]2CCC[C@@H]21
Product: Cc1cccc(-c2ccccc2C(=O)N2C[C@@H]3CCC[C@@H]3[C@H]2CNC(=O)c2c(C)nc3sccn23)c1

Procedure:
prepared by reaction of 6-methyl-imidazo[2,1-b]thiazole-5-carboxylic acid-[(1S,2S,5R)-3-aza-bicyclo[3.3.0]oct-2-ylmethyl]-amide with commercially available 3′-methyl-biphenyl-2-carboxylic acid.
Reaction SMILES: [Br:1][C:2]1[N:3]=[C:4]2[C:10]([C:11]([OH:13])=O)=[CH:9][N:8]([CH2:14][O:15][CH2:16][CH2:17][Si:18]([CH3:21])([CH3:20])[CH3:19])[C:5]2=[N:6][CH:7]=1.Cl.Cl.[O:24]1[CH:28]=[CH:27][N:26]=[C:25]1[CH:29]([NH2:31])[CH3:30].C(N(CC)C(C)C)(C)C.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>CN(C=O)C>[O:24]1[CH:28]=[CH:27][N:26]=[C:25]1[CH:29]([NH:31][C:11]([C:10]1[C:4]2[C:5](=[N:6][CH:7]=[C:2]([Br:1])[N:3]=2)[N:8]([CH2:14][O:15][CH2:16][CH2:17][Si:18]([CH3:21])([CH3:20])[CH3:19])[CH:9]=1)=[O:13])[CH3:30]
Reactant: CC(N)c1ncco1
Reactant: C[Si](C)(C)CCOCn1cc(C(=O)O)c2nc(Br)cnc21
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CC(NC(=O)c1cn(COCC[Si](C)(C)C)c2ncc(Br)nc12)c1ncco1
Temperature: 25 °C
Reaction time: 8 h
Yield: 70.9 %

Procedure:
A round-bottomed flask was charged with 2-bromo-5-((2-(trimethylsilyl)ethoxy)methyl)-5H-pyrrolo[2,3-b]pyrazine-7-carboxylic acid (300 mg, 0.81 mmol) and 1-oxazol-2-yl-ethylamine dihydrochloride (244 mg, 1.0 mmol). DMF (4 ml) was added followed by N,N-diisopropylethylamine (0.9 ml, 5.15 mmol) and HATU (337 mg, 0.89 mmol). The reaction mixture was stirred at room temperature overnight then quenched with water and diluted with petroleum ether. The resulting suspension was filtered. The filter cake was washed with water and petroleum ether then dried under high vacuum to afford 268 mg (71%) of 2-bromo-5-(2-trimethylsilanyl-ethoxymethyl)-5H-pyrrolo[2,3-b]pyrazine-7-carboxylic acid (1-oxazol-2-yl-ethyl)-amide as an off-white powder.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]2[CH2:13][CH2:12][NH:11][CH2:10][CH2:9]2)=[CH:4][CH:3]=1.C(N(CC)C(C)C)(C)C.[O:23]1[CH2:26][C:25](=O)[CH2:24]1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>C1COCC1>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]2[CH2:9][CH2:10][N:11]([CH:25]3[CH2:26][O:23][CH2:24]3)[CH2:12][CH2:13]2)=[CH:4][CH:3]=1
Reactant: O=C1COC1
Reactant: Brc1ccc(C2CCNCC2)cc1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CCN(C(C)C)C(C)C
Solvent: C1CCOC1
Product: Brc1ccc(C2CCN(C3COC3)CC2)cc1
Temperature: 25 °C
Reaction time: 16 h
Yield: 56.8 %

Procedure:
In a round-bottomed, single-necked, 100-mL flask were placed 4-(4-bromophenyl)piperidine (500.0 mg, 2.08 mmol), N,N-diisopropylethylamine (0.36 mL, 2.08 mmol), 3-oxetanone (0.27 mL, 4.16 mmol), and sodium triacetoxyborohydride (1544.5 mg, 7.3 mmol) in THF (15 mL). The mixture was stirred at room temperature for 16 h. Then, it was quenched with water and the organic layers extracted with EtOAc (3×5 mL). The combined organic layers were washed with water (2×5 mL) and brine (1×5 mL), dried (Na2SO4), concentrated, and purified by flash chromatography (100% Hexane to 100% EtOAc) to give 350.0 mg (57%) of 4-(4-bromophenyl)-1-(oxetan-3-yl)piperidine.
Reaction SMILES: [CH3:1][N:2]1[C:6](=O)[C@H:5](OS(C)(=O)=O)[CH2:4][C@H:3]1[CH2:13][O:14][C:15]1[CH:16]=[N:17][CH:18]=[CH:19][CH:20]=1.[C-:21]#[N:22].[Na+]>CN(C=O)C.O>[C:21]([C@@H:5]1[CH2:6][N:2]([CH3:1])[C@H:3]([CH2:13][O:14][C:15]2[CH:16]=[N:17][CH:18]=[CH:19][CH:20]=2)[CH2:4]1)#[N:22]
Reactant: CN1C(=O)[C@H](OS(C)(=O)=O)C[C@H]1COc1cccnc1
Reactant: [C-]#N
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CN1C[C@@H](C#N)C[C@H]1COc1cccnc1
Temperature: 100 °C
Yield: 35.1 %

Procedure:
To a solution of 300 mg (1.05 mmol) of 3-((trans-1-methyl-4-methanesulfonyloxy-5-oxo-2(S)-pyrrolidinyl)-methoxy)pyridine, prepared as in Exanmple 88a above, dissolved in 7 mL of 6:1 DMF:H2O was added 0.51 g (10.5 mmol) of NaCN, and the reaction mixture was heated at 100° C. for 5 hours. The reaction mixture was cooled, diluted with water, and extracted with chloroform. The extract was dried over MgSO4 and concentrated. The residue was purified on a silica gel column, eluting with 100:2 chloroform:methanol, to give 80 mg of the title compound.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([CH:21]=[CH:22][CH:23]=1)[O:5][C:6]1[CH:7]=[CH:8][C:9]2[N:10]([CH:12]=[C:13]([NH:15][C:16](=[O:20])[CH2:17][O:18][CH3:19])[N:14]=2)[N:11]=1.[CH3:24][N:25]1[C:29]([C:30](Cl)=[O:31])=[CH:28][C:27]([CH3:33])=[N:26]1>CN(C)C(=O)C>[CH3:19][O:18][CH2:17][C:16]([NH:15][C:13]1[N:14]=[C:9]2[CH:8]=[CH:7][C:6]([O:5][C:4]3[CH:3]=[C:2]([NH:1][C:30]([C:29]4[N:25]([CH3:24])[N:26]=[C:27]([CH3:33])[CH:28]=4)=[O:31])[CH:23]=[CH:22][CH:21]=3)=[N:11][N:10]2[CH:12]=1)=[O:20]
Reactant: COCC(=O)Nc1cn2nc(Oc3cccc(N)c3)ccc2n1
Reactant: Cc1cc(C(=O)Cl)n(C)n1
Solvent: CC(=O)N(C)C
Product: COCC(=O)Nc1cn2nc(Oc3cccc(NC(=O)c4cc(C)nn4C)c3)ccc2n1
Yield: 63.2 %

Procedure:
Using N-[6-(3-aminophenoxy)imidazo[1,2-b]pyridazin-2-yl]-2-methoxyacetamide (200 mg, 0.64 mmol), 1,3-dimethyl-1H-pyrazole-5-carbonyl chloride (162 mg, 1.02 mmol) and N,N-dimethylacetamide (4.0 mL) as starting materials and in the same manner as in Example 120, the title compound (176 mg, 64%) was obtained as a white powder.